WO2021088911A1 - 3,6-diazabicyclo[3.1.1]heptane derivative as ret kinase inhibitor - Google Patents

3,6-diazabicyclo[3.1.1]heptane derivative as ret kinase inhibitor Download PDF

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WO2021088911A1
WO2021088911A1 PCT/CN2020/126668 CN2020126668W WO2021088911A1 WO 2021088911 A1 WO2021088911 A1 WO 2021088911A1 CN 2020126668 W CN2020126668 W CN 2020126668W WO 2021088911 A1 WO2021088911 A1 WO 2021088911A1
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compound
methyl
pyridine
heptan
pyrazole
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French (fr)
Chinese (zh)
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洪健
吕裕斌
达斯D.
金燕芬
王景炳
孙丽蕊
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杭州邦顺制药有限公司
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the present invention belongs to the field of medicinal chemistry, and relates to 3, 6 diazabicyclo[3.1.1] heptane derivatives as RET kinase inhibitors, and specifically relates to new compounds that exhibit RET kinase inhibition and mutant RET kinase inhibition, including the compound
  • the pharmaceutical composition, the method for preparing the compound and the application of the compound in RET kinase related treatment includes 3, 6 diazabicyclo[3.1.1] heptane derivatives as RET kinase inhibitors, and specifically relates to new compounds that exhibit RET kinase inhibition and mutant RET kinase inhibition, including the compound
  • the pharmaceutical composition, the method for preparing the compound and the application of the compound in RET kinase related treatment includes 3, 6 diazabicyclo[3.1.1] heptane derivatives as RET kinase inhibitors, and specifically relates to new compounds that exhibit RET kinase inhibition and mutant RET kinase inhibition, including
  • RET receptor tyrosine kinase
  • MTC medullary thyroid carcinoma
  • LAD lung adenocarcinoma
  • NSCLC non-small cell lung cancer
  • RET dimerization and autophosphorylation of intracellular tyrosine residues activate adaptor and signaling proteins, thereby stimulating multiple downstream pathways.
  • the adaptor protein that binds to these docking sites activates the RAS-MAPK and PI3K-AKT-mTOR signaling pathways, and the function of these signaling pathways is to down-regulate RET-mediated functions.
  • RET kinase inhibitors such as cabozantinib (Bentzein, F, Thyroid 2013, 23, 1569-1577), vandetanib (Wedge, S et al. Cancer Res. 2002, 62, 4645-4655) ) Can be obtained from the market. These inhibitors are non-selective RET inhibitors. These inhibitors can also act as potent VEGFR2 kinase or KDR inhibitors and cause side effects during treatment. Therefore, a strong and highly selective RET inhibitor is needed clinically, and the inhibitor does not show off-target pharmacological inactivation of KDR.
  • LOXO292 is conducting Phase1/2 clinical trials for patients with advanced solid tumors, RET fusion-positive solid tumors and medullary thyroid carcinoma (https://clinicaltrials.gov/ct2/show/NCT03157128).
  • the purpose of the present invention is to overcome the defects of the prior art and provide a high-efficiency RET inhibitor.
  • the present invention provides a compound of formula I, and/or pharmaceutically acceptable salts, stereoisomers, and deuterated compounds, wherein:
  • A is Or -NHRa
  • the Cyc is a 4-7 membered heterocyclic ring connected by a N atom; the Cyc is a monocyclic ring, a bridged ring or a spiro ring; in addition to the N atom at the connection point, the Cyc also contains 0 or 1 selected from N, O , S heteroatom; the Cyc is substituted by 0, 1 or 2 R1;
  • the Ra is a C1-C4 alkyl group; the Ra is substituted with 0, 1 or 2 R2;
  • the R1 is optionally selected from hydroxyl, halogen or methyl
  • the R2 is optionally selected from hydroxyl, halogen, methyl or methoxy;
  • B is methyl or deuterated methyl.
  • A is selected from the following heterocycles substituted with 0, 1, or 2 R1:
  • A is selected from:
  • A is selected from:
  • A is selected from:
  • A is selected from:
  • B is a deuterated methyl group
  • it is selected from -CD 3 .
  • the present invention also provides a compound of formula II, and/or pharmaceutically acceptable salts, stereoisomers, and deuterated compounds, wherein:
  • A is -ORc
  • the Rc is a C1-C4 alkyl group and is substituted with 0, 1 or 2 groups selected from halogen, hydroxy or methoxy;
  • the C1-C4 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or neobutyl;
  • B is methyl or deuterated methyl.
  • the compound of formula I or formula II includes:
  • the compound includes:
  • the compound of formula I may be a salt, wherein the salt is phosphate or citrate.
  • the compound of formula I includes:
  • the present invention also provides a pharmaceutical composition, which contains any of the above-mentioned compounds and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition described therein can be prepared into various preparations such as solid preparations, liquid preparations, etc., and can be administered orally, parenterally, intravenously or through the skin.
  • the present invention also provides a use of the above-mentioned pharmaceutical composition or compound in the preparation of a medicine for treating diseases related to RET kinase and/or mutant RET kinase.
  • the RET kinase and/or mutant RET kinase related diseases include but are not limited to non-small cell lung cancer (NSCLC), lung adenocarcinoma (LAD), medullary thyroid cancer (MTC), and papillary thyroid cancer.
  • NSCLC non-small cell lung cancer
  • LAD lung adenocarcinoma
  • MTC medullary thyroid cancer
  • papillary thyroid cancer papillary thyroid cancer
  • the present invention also provides compounds of formula X, and/or pharmaceutically acceptable salts, stereoisomers, deuterium substituted derivatives, hydrates, solvates or solvent complexes, wherein:
  • W1, W2, and W3 are selected from C or N atoms, and at least one of them is N atom, and satisfies the valence bond theory;
  • D is a C atom substituted by a N atom or a cyano group
  • a, -(C2-C5) alkyl group containing 0 or 1 unsaturated double bond or triple bond, and optionally substituted by 0 or 1 hydroxyl group;
  • the Cyc1 is a 5-6 membered heterocyclic ring connected through a C atom, containing one or more heteroatoms selected from N, O or S, and containing 0 or 1 unsaturated bond;
  • Ra and Rb are optionally selected from H, -(C1-C4)alkyl, where -(C1-C4)alkyl is substituted by 0 or 1 hydroxy or methoxy;
  • the Cyc2 is a 4- to 7-membered heterocyclic ring connected through an N atom; the Cyc2 contains 0, 1 or 2 heteroatoms optionally selected from N, O, S in addition to the N atom at the connection point; the Cyc is 0, 1 or several hydroxy, halogen, (C1-C3) alkyl substitutions; the Cyc2 is monocyclic or polycyclic; the polycyclic means that Cyc2 contains a bridging group, a bridge bond or a spiro ring;
  • G is a 5-6 membered heteroaromatic ring containing at least one N;
  • M is a chemical bond or methylene group
  • E is a 5-6 membered aryl or heteroaryl group, the 5-6 membered aryl or heteroaryl group is selected from (C1-C3)alkyl, (C1-C3)alkoxy, halogen , Cyano or trifluoromethyl substituents.
  • A is selected from the following structures:
  • the G is selected from the following structures:
  • the E is selected from the following structures:
  • W1 is a N atom
  • W2 and W3 are a C atom
  • D is a C atom substituted by a cyano group
  • a, -(C2-C5) alkyl group containing 0 or 1 unsaturated double bond or triple bond, and optionally substituted by 0 or 1 hydroxyl group;
  • the Cyc1 is a 5-6 membered heterocyclic ring connected through a C atom, containing one or more heteroatoms selected from N, O or S, and containing 0 or 1 unsaturated bond;
  • Ra and Rb are optionally selected from H, -(C1-C4)alkyl, where -(C1-C4)alkyl is substituted by 0 or 1 hydroxy or methoxy;
  • the Cyc2 is a 4- to 7-membered heterocyclic ring connected through an N atom; the Cyc2 contains 0, 1 or 2 heteroatoms optionally selected from N, O, S in addition to the N atom at the connection point; the Cyc is 0, 1 or several hydroxy, halogen, (C1-C3) alkyl substitutions; the Cyc2 is monocyclic or polycyclic; the polycyclic means that Cyc2 contains a bridging group, a bridge bond or a spiro ring;
  • G is a 5-6 membered heteroaromatic ring containing at least one N;
  • M is a chemical bond or methylene group
  • E is a 5-6 membered aryl or heteroaryl group, the 5-6 membered aryl or heteroaryl group is selected from (C1-C3)alkyl, (C1-C3)alkoxy, halogen , Cyano or trifluoromethyl substituents.
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • Ra and Rb are optionally selected from H, -(C1-C4)alkyl, where -(C1-C4)alkyl is substituted by 0 or 1 hydroxy or methoxy;
  • the Cyc2 is a 4- to 7-membered heterocyclic ring connected through an N atom; the Cyc2 contains 0, 1 or 2 heteroatoms optionally selected from N, O, S in addition to the N atom at the connection point; the Cyc is 0, 1 or several hydroxy, halogen, (C1-C3) alkyl substitutions; the Cyc2 is monocyclic or polycyclic; the polycyclic means that Cyc2 contains a bridging group, a bridge bond or a spiro ring;
  • G is pyridine
  • M is a chemical bond or methylene group
  • E is a 5-6 membered aryl or heteroaryl group, the 5-6 membered aryl or heteroaryl group is selected from (C1-C3)alkyl, (C1-C3)alkoxy, halogen , Cyano or trifluoromethyl substituents.
  • A is The Cyc2 is a 4- to 7-membered heterocyclic ring connected through an N atom; the Cyc2 contains 0, 1 or 2 heteroatoms optionally selected from N, O, S in addition to the N atom at the connection point; the Cyc is 0, 1 or 2 hydroxyl, halogen, methyl substitution; the Cyc2 is monocyclic or polycyclic; the polycyclic means that Cyc2 contains a bridging group, a bridge bond or a spiro ring;
  • G is pyridine
  • M is methylene
  • E is pyridyl substituted by methoxy
  • A is Said Cyc2 is a 4-7 membered heterocyclic ring connected by N atom; Said Cyc2 contains 0 or 1 heteroatom optionally selected from N, O, S in addition to the N atom at the connection point; Said Cyc is divided by 0, 1 or 2 hydroxy and methyl substitutions; the Cyc2 is monocyclic or polycyclic; the polycyclic means that Cyc2 contains a bridging group, a bridge bond or a spiro ring.
  • A is selected from
  • W1 is a N atom
  • W2 and W3 are C atoms
  • D is a N atom
  • a, -(C2-C5) alkyl group containing 0 or 1 unsaturated double bond or triple bond, and optionally substituted by 0 or 1 hydroxyl group;
  • the Cyc1 is a 5-6 membered heterocyclic ring connected through a C atom, containing one or more heteroatoms selected from N, O or S, and containing 0 or 1 unsaturated bond;
  • Ra and Rb are optionally selected from H, -(C1-C4)alkyl, where -(C1-C4)alkyl is substituted by 0 or 1 hydroxy or methoxy;
  • the Cyc2 is a 4- to 7-membered heterocyclic ring connected through an N atom; the Cyc2 contains 0, 1 or 2 heteroatoms optionally selected from N, O, S in addition to the N atom at the connection point; the Cyc is 0, 1 or several hydroxy, halogen, (C1-C3) alkyl substitutions; the Cyc2 is monocyclic or polycyclic; the polycyclic means that Cyc2 contains a bridging group, a bridge bond or a spiro ring;
  • G is a 5-6 membered heteroaromatic ring containing at least one N;
  • M is a chemical bond or methylene group
  • E is a 5-6 membered aryl or heteroaryl group, the 5-6 membered aryl or heteroaryl group is selected from (C1-C3)alkyl, (C1-C3)alkoxy, halogen , Cyano or trifluoromethyl substituents.
  • W1 and W3 are N atoms, W2 is a C atom, and D is a carbon atom substituted by a cyano group;
  • a, -(C2-C5) alkyl group containing 0 or 1 unsaturated double bond or triple bond, and optionally substituted by 0 or 1 hydroxyl group;
  • the Cyc1 is a 5-6 membered heterocyclic ring connected through a C atom, containing one or more heteroatoms selected from N, O or S, and containing 0 or 1 unsaturated bond;
  • Ra and Rb are optionally selected from H, -(C1-C4)alkyl, where -(C1-C4)alkyl is substituted by 0 or 1 hydroxy or methoxy;
  • the Cyc2 is a 4- to 7-membered heterocyclic ring connected through an N atom; the Cyc2 contains 0, 1 or 2 heteroatoms optionally selected from N, O, S in addition to the N atom at the connection point; the Cyc is 0, 1 or several hydroxy, halogen, (C1-C3) alkyl substitutions; the Cyc2 is monocyclic or polycyclic; the polycyclic means that Cyc2 contains a bridging group, a bridge bond or a spiro ring;
  • G is a 5-6 membered heteroaromatic ring containing at least one N;
  • M is a chemical bond or methylene group
  • E is a 5-6 membered aryl or heteroaryl group, the 5-6 membered aryl or heteroaryl group is selected from (C1-C3)alkyl, (C1-C3)alkoxy, halogen , Cyano or trifluoromethyl substituents.
  • W2 is a N atom
  • said W1 and W3 are C atoms
  • D is a carbon atom substituted by a cyano group
  • a, -(C2-C5) alkyl group containing 0 or 1 unsaturated double bond or triple bond, and optionally substituted by 0 or 1 hydroxyl group;
  • the Cyc1 is a 5-6 membered heterocyclic ring connected through a C atom, containing one or more heteroatoms selected from N, O or S, and containing 0 or 1 unsaturated bond;
  • Ra and Rb are optionally selected from H, -(C1-C4)alkyl, where -(C1-C4)alkyl is substituted by 0 or 1 hydroxy or methoxy;
  • the Cyc2 is a 4- to 7-membered heterocyclic ring connected through an N atom; the Cyc2 contains 0, 1 or 2 heteroatoms optionally selected from N, O, S in addition to the N atom at the connection point; the Cyc is 0, 1 or several hydroxy, halogen, (C1-C3) alkyl substitutions; the Cyc2 is monocyclic or polycyclic; the polycyclic means that Cyc2 contains a bridging group, a bridge bond or a spiro ring;
  • G is a 5-6 membered heteroaromatic ring containing at least one N;
  • M is a chemical bond or methylene group
  • E is a 5-6 membered aryl or heteroaryl group, and the 5-6 membered aryl or heteroaryl group is selected from (C1-C3)alkyl, (C1-C3)alkoxy, Substituents substituted by halogen, cyano or trifluoromethyl.
  • W2 is a N atom
  • W1 and W3 are C atoms
  • D is a N atom
  • a, -(C2-C5) alkyl group containing 0 or 1 unsaturated double bond or triple bond, and optionally substituted by 0 or 1 hydroxyl group;
  • the Cyc1 is a 5-6 membered heterocyclic ring connected through a C atom, containing one or more heteroatoms selected from N, O or S, and containing 0 or 1 unsaturated bond;
  • Ra and Rb are optionally selected from H, -(C1-C4)alkyl, where -(C1-C4)alkyl is substituted by 0 or 1 hydroxy or methoxy;
  • the Cyc2 is a 4- to 7-membered heterocyclic ring connected through an N atom; the Cyc2 contains 0, 1 or 2 heteroatoms optionally selected from N, O, S in addition to the N atom at the connection point; the Cyc is 0, 1 or several hydroxy, halogen, (C1-C3) alkyl substitutions; the Cyc2 is monocyclic or polycyclic; the polycyclic means that Cyc2 contains a bridging group, a bridge bond or a spiro ring;
  • G is a 5-6 membered heteroaromatic ring containing at least one N;
  • M is a chemical bond or methylene group
  • E is a 5-6 membered aryl or heteroaryl group, the 5-6 membered aryl or heteroaryl group is selected from (C1-C3)alkyl, (C1-C3)alkoxy, halogen , Cyano or trifluoromethyl substituents.
  • the present invention also provides the following compounds, and/or pharmaceutically acceptable salts, stereoisomers, deuterium substituted derivative hydrates, solvates or solvent complexes, including:
  • the compound or the pharmaceutical composition is characterized in that it is used alone or in combination with other therapeutic agents.
  • the compound or pharmaceutical composition is characterized in that it is administered orally, parenterally, intravenously or through the skin.
  • the present invention also provides the use of the compound or the pharmaceutical composition in the preparation of a medicine for treating diseases related to RET kinase and/or mutant RET kinase.
  • the RET kinase and/or mutant RET kinase related diseases include but are not limited to non-small cell lung cancer (NSCLC), lung adenocarcinoma (LAD), medullary thyroid cancer (MTC), and papillary thyroid cancer.
  • NSCLC non-small cell lung cancer
  • LAD lung adenocarcinoma
  • MTC medullary thyroid cancer
  • papillary thyroid cancer papillary thyroid cancer
  • the compound disclosed in the present invention exhibits excellent activity at the kinase and cell levels, and has superior pharmacodynamics; at the same time, it has excellent pharmacokinetic properties, selectivity and less toxic and side effects.
  • the main ring is 3-cyano-pyrazolo[1,5-a]pyridine, and the atom connecting A to the main ring is a C atom.
  • the compound has the structure of formula Ia, and it can also be pharmaceutically acceptable. Acceptable salts and solvates in which the G ring is as described for the compound of formula X.
  • R 3 , R 4 , R 5 independently represent 1-6 carbon chains or hydrogen, R 3 , R 4 or R 5 may contain 0 or 1 alkynyl or alkenyl group, or independently by 0 or 1 hydroxyl group replace;
  • R 3 , R 4 or R 5 can also form a ring between two of the central C atoms connected to form a three-membered, four-membered, five-membered or six-membered carbocyclic ring; the formed carbocyclic ring may contain 0 or 1 A carbon-carbon double bond, the formed carbocyclic ring may also contain 0 or 1 heteroatom selected from N, O, S;
  • the main ring is 3-cyano-pyrazolo[1,5-a]pyridine, and the atom connecting A to the main ring is an N atom.
  • the compound has the structure of formula Ib, and it can also be pharmaceutically acceptable. Acceptable salts and solvates.
  • R 3 and R 4 independently represent 1 to 6 carbon chains or hydrogen, and R 3 or R 4 can be independently substituted with 0 or 1 hydroxyl, methoxy, ethoxy or other alkoxy groups;
  • R 3 and R 4 can also form a saturated 4-7 membered cycloalkyl group with the N atom.
  • the cycloalkyl group can be a monocyclic alkyl group or a polycycloalkane containing a bridging group, a bridge bond or a spiro ring.
  • the cycloalkyl group can also contain 0 or 1 heteroatom selected from N, O, S; the cycloalkyl group can also be selected from the group consisting of 0, 1 or 2 methyl, ethyl Group, propyl, isopropyl, hydroxy, methoxy, ethoxy.
  • the main ring is 3-cyano-pyrazolo[1,5-a]pyridine, and the atom connecting A to the main ring is an N atom.
  • the compound has the structure of formula Ic, and it can also be a pharmacological compound. Acceptable salts and solvates.
  • A is alkoxy (methoxy), alkoxy alcohol.
  • the main ring is [1,2,4]triazolo[1,5-a]pyridine
  • the compound can be the structure of Id or Ie, or its pharmaceutically acceptable salt and solvent ⁇
  • the atom connecting A to the main ring is the N atom.
  • R 3 and R 4 independently represent 1 to 6 carbon chains or hydrogen, and R 3 or R 4 can be independently substituted with 0 or 1 hydroxyl, methoxy, ethoxy or other alkoxy groups;
  • R 3 and R 4 can also form a saturated 4-7 membered cycloalkyl group with the N atom.
  • the cycloalkyl group can be a monocyclic alkyl group or a polycycloalkane containing a bridging group, a bridge bond or a spiro ring.
  • the cycloalkyl group can also contain 0 or 1 heteroatom selected from N, O, S; the cycloalkyl group can also be selected from the group consisting of 0, 1 or 2 methyl, ethyl Group, propyl, isopropyl, hydroxy, methoxy, ethoxy.
  • the main ring is pyrazolo[1,5-a]pyrazine, and the atom connecting A to the main ring is an N atom.
  • the compound has the structure of formula Ig, and may also be pharmaceutically acceptable. Salts and solvates.
  • R 3 and R 4 independently represent 1 to 6 carbon chains or hydrogen, and R 3 or R 4 can be independently substituted with 0 or 1 hydroxyl, methoxy, ethoxy or other alkoxy groups;
  • R 3 and R 4 can also form a saturated 4-7 membered cycloalkyl group with the N atom.
  • the cycloalkyl group can be a monocyclic alkyl group or a polycycloalkane containing a bridging group, a bridge bond or a spiro ring.
  • the cycloalkyl group can also contain 0 or 1 heteroatom selected from N, O, S; the cycloalkyl group can also be selected from the group consisting of 0, 1 or 2 methyl, ethyl Group, propyl, isopropyl, hydroxy, methoxy, ethoxy.
  • the main ring is pyrazolo[1,5-a]pyrazine, and the atom connecting A to the main ring is an N atom.
  • the compound has the structure of formula Ih, and may also be pharmaceutically acceptable. Salts and solvates.
  • R 3 and R 4 independently represent 1 to 6 carbon chains or hydrogen, and R 3 or R 4 can be independently substituted with 0 or 1 hydroxyl, methoxy, ethoxy or other alkoxy groups;
  • R 3 and R 4 can also form a saturated 4-7 membered cycloalkyl group with the N atom.
  • the cycloalkyl group can be a monocyclic alkyl group or a polycycloalkane containing a bridging group, a bridge bond or a spiro ring.
  • the cycloalkyl group can also contain 0 or 1 heteroatom selected from N, O, S; the cycloalkyl group can also be selected from the group consisting of 0, 1 or 2 methyl, ethyl Group, propyl, isopropyl, hydroxy, methoxy, ethoxy.
  • the synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with commercially available 2-((trimethylsilyl)oxy)ethane-1-amine.
  • the synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with commercially available 1-amino-2-methylpropan-2-ol.
  • the product was purified by column chromatography to obtain (24 mg, 28%).
  • the synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with commercially available tetrahydropyrrole.
  • the product was purified by column chromatography to obtain (23 mg, 33%).
  • the synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with a commercially available piperazine.
  • the product was purified by column chromatography to obtain (21 mg, 16%).
  • the synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with the commercially available (2S,6R)-2,6-dimethylmorpholine.
  • the synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with commercially available thiomorpholine.
  • the product was purified by column chromatography to obtain (23mg, 30%).
  • the synthesis refers to the synthesis of I-7 in Example 7 herein, and only the raw material propyl-1-amine is substituted for the commercially available 2-oxa-6-aza-spiro[3,3]heptane.
  • the product was purified by column chromatography to obtain (10 mg, 35%).
  • the synthesis refers to the synthesis of I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with commercially available azetidine-3-ol.
  • the product was purified by column chromatography to obtain (21 mg, 29%).
  • the synthesis refers to the synthesis of I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with commercially available (R)-3-pyrrolidinol.
  • the product was purified by column chromatography to obtain (15 mg, 36%).
  • the synthesis refers to the synthesis of I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with commercially available (S)-3-pyrrolidinol.
  • the product was purified by column chromatography to obtain (17mg, 40%).
  • the synthesis refers to the synthesis of I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with commercially available 4-hydroxypiperidine.
  • the product was purified by column chromatography to obtain (27mg, 34%).
  • the synthesis is the classic Buchwald reaction between compound I-24 in Example 24 and the commercially available compound morpholine, and the reaction conditions can refer to the synthesis conditions of Compound 6 in Example 7.
  • the product was purified by column chromatography to obtain (13 mg, 19%).
  • the synthesis refers to the synthesis of compound I-26 in Example 26 herein, and only the raw material intermediate P-10 is replaced with intermediate P-11.
  • the synthesis refers to the synthesis of compound I-21 in Example 21 herein, and only the raw material is replaced from intermediate P-3 to P-12.
  • the synthesis is prepared by reducing the alkynyl group of compound 1-32 in Example 32.
  • the synthesis is prepared by reducing the alkynyl group of compound 1-33 in Example 33.
  • the synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the starting material compound 6-methoxy-3-pyridinecarboxaldehyde is replaced with commercially available p-fluorotoluene.
  • the synthesis refers to the synthesis of compound I-12 in Example 12 herein, and only the starting material compound 6-methoxy-3-pyridinecarbaldehyde is replaced with commercially available 5-thiazole carbaldehyde.
  • the synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the starting material compound propylamine is replaced with commercially available 3-azabicyclo[3.1.0]hexane.
  • the product was purified by column chromatography to obtain (31 mg, 49%).
  • the synthesis refers to the synthesis of compound I-12 in Example 12 herein, and only the starting material compound 6-methoxy-3-pyridinecarbaldehyde is replaced with commercially available N-methyl-3-pyrrolecarbaldehyde.
  • the synthesis refers to the synthesis of compound I-17 in Example 17 herein, and only the raw material 6-methoxy-3-pyridinecarboxaldehyde is replaced with compound 8.
  • the product was purified by column chromatography to obtain (14 mg, 22%).
  • the synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with commercially available 3-methyl-3-acridol.
  • the product was purified by column chromatography to obtain (16 mg, 27%).
  • the IC50 values of the test compounds in the detection series are RET, KDR, RET V804M, RET V804L and RET M918T kinases.
  • the test compounds were screened on RET, KDR, RET V804M, RET V804L and RET M918T kinases, with an initial concentration of 0.1 ⁇ M, 3 times dilution, 10 concentrations, and multiple well detection.
  • test compound was prepared as a 10 mM stock solution with DMSO (dimethyl sulfoxide) and frozen for later use. Before the test, it was diluted with DMSO to a test solution with an initial concentration of 0.1 ⁇ M, which was successively diluted 3 times to 10 concentrations, and tested in multiple holes.
  • DMSO dimethyl sulfoxide
  • test conditions are as follows (substrate concentration is 3 ⁇ M):
  • a dispenser to transfer 250 nL/well of the test compound test solution to the target plate well, with 10 concentrations of each compound, and add an equal volume of DMSO to the negative control well.
  • the read data was converted into inhibition rate, and the analysis software GraphPad Prism 5 was used to fit the dose-effect curve to obtain the IC50 value of each compound's inhibition of enzyme activity.
  • Test compound pair BaF3-KIF5B-RET, BaF3-KIF5B-RET-V804M, BaF3-KIF5B-RET-V804L, BaF3-tel-RET-M918T, BaF3-CCDC6-RET, BaF3-tel-VEGFR2, MTC-TT
  • the cell's inhibition IC50 value The cell's inhibition IC50 value.
  • the cells were digested with 0.25% Trypsin-EDTA, and the resuspended cells were counted with an automatic cell counter. According to the seeding density, the cell suspension was diluted to the required density, and about 100ul cells were spread in 96 wells and incubated overnight at 37°C.
  • the compound was prepared into a 10mM-20mM stock solution, diluted 200-1000 times with the culture medium, and an appropriate volume of the compound test solution was added to each well, and the wells with the same volume of DMSO were added as a control, and cultured for 72 hours.
  • the detection data was converted to inhibition rate, and the analysis software GraphPad Prism 5 was used to fit the dose-response curve to obtain the IC50 value of each compound's inhibition of cell activity.
  • Test procedure Beagle dogs, 8.09-10.430kg, male, 5 in each group, fasted overnight before administration, and 4 hours after administration with free food and water. Oral gavage 10mg/kg (2mg/mL, 5mL/kg).
  • a 200 ⁇ L blood sample was taken from the jugular vein at 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, and 24 hours after administration, and placed in a micro-K2EDTA tube. Place the blood sample on ice, centrifuge at 6000 rpm for 8 minutes at 4°C, and collect plasma by centrifugation within 30 minutes after collection.
  • the LC-MS/MS method was used to determine the blood drug concentration. 8.2.0 software, calculated pharmacokinetic parameters are as follows:
  • the Ba/F3-CCDC6-RET cell line was cultured with 1640 medium + 10% fetal bovine serum + 1% double antibody (Penicillin Streptomycin solution), cultured at 37°C, 5% CO2, and passaged twice a week. When the cell saturation is 80% to 90%, the cells are collected, counted, and seeded. 0.2ml of cell suspension was inoculated subcutaneously in the right axilla of each mouse. That is, each mouse is inoculated with 1*10 ⁇ 6 Ba/F3-CCDC6-RET cells. After the inoculation, the tumor growth status was observed daily. When the average tumor volume was greater than or equal to 200 mm3, the mice were randomly divided into 5 groups according to the tumor volume. According to the weight of the mouse, 10 ⁇ l/g. If the weight loss exceeds 20%, the dosage regimen will be adjusted accordingly.
  • Routine checks include the animal’s tumor growth, mobility, diet, weight, eyes, hair, and other abnormal behaviors.
  • the tumor volume and weight are measured twice a week (Tuesday and Friday). .
  • the compound's inhibitory effect on tumor growth was evaluated by the relationship between tumor volume and time.
  • Test statistics include the mean (Mean) and standard error (SEM) of the tumor volume at each time point in each group (see the table below for specific data).
  • the treatment group showed the best treatment effect on day D18 after administration, so statistical analysis was performed based on this data to evaluate the difference between the groups.
  • a one-way analysis of variance (one-way ANOVA) test method was used to compare whether the tumor volume of the treatment group was significantly different from the tumor volume of the control group. P ⁇ 0.05 indicates a significant difference.
  • the experimental index is to investigate whether the tumor growth is inhibited, delayed or cured.
  • the compound's anti-tumor efficacy uses the relative tumor proliferation rate T/C (%) as the test evaluation index.
  • the evaluation criteria are: T/C(%)>40% is invalid; T/C(%) ⁇ 40%, and P ⁇ 0.05 is a significant difference.
  • c.p value is calculated based on tumor volume.
  • TRTV treatment group RTV
  • CRTV negative control group RTV
  • RTV the relative tumor volume
  • V0 the tumor volume measured in cages (i.e. d0)
  • Vt the tumor volume at each measurement
  • TGI (%) calculation formula: TGI(TGI(%) [1-(Td -T0)/(Vd-V0)] ⁇ 100).
  • Td tumor volume measured after treatment in the treatment group
  • T0 tumor volume measured when the treatment group was administered in cages (i.e. d0)
  • Vd tumor volume measured after the control group was given the vehicle
  • T0 control group The tumor volume measured at the time of cage administration (i.e. d0)).
  • c.p value is calculated based on tumor weight.

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Abstract

A 3,6-diazabicyclo[3.1.1]heptane derivative as a RET kinase inhibitor. Disclosed are a heterocyclic derivative represented by the following chemical formula, or a pharmaceutically acceptable salt, a stereoisomer, a deuterated compound, a pharmaceutical composition, and use thereof in the preparation of a medicament for treating diseases related to RET kinase and/or mutant RET kinase. The compound exhibits excellent activity at both kinase level and cell level, and has good efficacy; meanwhile, the compound has excellent pharmacokinetic properties, selectivity, and fewer toxic side effects. (I)

Description

作为RET激酶抑制剂的3、6二氮杂双环[3.1.1]庚烷衍生物3, 6 diazabicyclo[3.1.1] heptane derivatives as RET kinase inhibitors
本申请要求申请日为2019年11月8日，申请号为201911092023.9的中国申请的优先权。This application claims the priority of the Chinese application whose filing date is November 8, 2019, and the application number is 201911092023.9.
技术领域Technical field
本发明属于医药化学领域，涉及作为RET激酶抑制剂的3、6二氮杂双环[3.1.1]庚烷衍生物，具体涉及表现出RET激酶抑制和突变RET激酶抑制的新化合物、包含该化合物的药物组合物、制备该化合物的方法以及该化合物在RET激酶相关治疗中的应用。The present invention belongs to the field of medicinal chemistry, and relates to 3, 6 diazabicyclo[3.1.1] heptane derivatives as RET kinase inhibitors, and specifically relates to new compounds that exhibit RET kinase inhibition and mutant RET kinase inhibition, including the compound The pharmaceutical composition, the method for preparing the compound and the application of the compound in RET kinase related treatment.
背景技术Background technique
RET(在转染过程中重新排列)是一种受体酪氨酸激酶(RTK)，它激活细胞增殖和存活的多个下游通路。RET是几种组织和细胞正常发育、成熟和维持所必需的(Mulligan,L.M.,Nature Reviews Cancer,2014,14,173-186).RET融合体涉及多种癌症，包括甲状腺髓样癌(MTC)、甲状腺乳头状癌、肺腺癌(LAD)、非小细胞肺癌(NSCLC)(Kohno,T.et.al Cancer Sci 2013；104:1396–1400.,Roskoski Jr.R.Pharmacological Research 2018,128,1-17)。RET (rearranged during transfection) is a receptor tyrosine kinase (RTK) that activates multiple downstream pathways for cell proliferation and survival. RET is necessary for the normal development, maturation and maintenance of several tissues and cells (Mulligan, LM, Nature Reviews Cancer, 2014, 14, 173-186). RET fusion involves a variety of cancers, including medullary thyroid carcinoma (MTC), thyroid Papillary carcinoma, lung adenocarcinoma (LAD), non-small cell lung cancer (NSCLC) (Kohno,T.et.al Cancer Sci 2013;104:1396–1400.,Roskoski Jr.R.Pharmacological Research 2018,128,1- 17).
与配体-共受体复合物的结合，RET二聚和胞内酪氨酸残基的自磷酸化激活了适配器和信号蛋白，从而刺激多个下游通路。与这些对接位点结合的衔接蛋白会激活RAS-MAPK和PI3K-AKT-mTOR信号通路，这些信号通路的功能是向下调节RET-介导的功能。Binding to the ligand-co-receptor complex, RET dimerization and autophosphorylation of intracellular tyrosine residues activate adaptor and signaling proteins, thereby stimulating multiple downstream pathways. The adaptor protein that binds to these docking sites activates the RAS-MAPK and PI3K-AKT-mTOR signaling pathways, and the function of these signaling pathways is to down-regulate RET-mediated functions.
几种可用的RET激酶抑制剂，如卡博替尼(Bentzein,F,Thyroid 2013,23,1569-1577),凡德他尼(Wedge,S et al.Cancer Res.2002,62,4645-4655)均可以从市场上获得。这些抑制剂是非选择性RET抑制剂。这些抑制剂也可作为强效的VEGFR2激酶或KDR抑制剂，并在治疗期间引起副作用。因此，在临床上就需要一种强有力的且高选择性的RET抑制剂，而且该抑制剂不显示KDR脱靶药理学失活。最近，两种抑制剂BLU667和LOXO292(Cancer Discov 2018,8,904-905)被认为是RET激酶的选择性抑制剂，而不是KDR。目前，LOXO292正在对晚期实体瘤、RET融合体阳性实体瘤和甲状腺髓样癌患者进行Phase1/2临床试验研究(https://clinicaltrials.gov/ct2/show/NCT03157128)。Several available RET kinase inhibitors, such as cabozantinib (Bentzein, F, Thyroid 2013, 23, 1569-1577), vandetanib (Wedge, S et al. Cancer Res. 2002, 62, 4645-4655) ) Can be obtained from the market. These inhibitors are non-selective RET inhibitors. These inhibitors can also act as potent VEGFR2 kinase or KDR inhibitors and cause side effects during treatment. Therefore, a strong and highly selective RET inhibitor is needed clinically, and the inhibitor does not show off-target pharmacological inactivation of KDR. Recently, two inhibitors, BLU667 and LOXO292 (Cancer Discov 2018, 8,904-905), are considered to be selective inhibitors of RET kinase rather than KDR. Currently, LOXO292 is conducting Phase1/2 clinical trials for patients with advanced solid tumors, RET fusion-positive solid tumors and medullary thyroid carcinoma (https://clinicaltrials.gov/ct2/show/NCT03157128).
发明内容Summary of the invention
本发明的目的在于克服现有技术的缺陷，提供一种高效率的RET抑制剂。The purpose of the present invention is to overcome the defects of the prior art and provide a high-efficiency RET inhibitor.
为实现上述目的所采取的具体技术方案为：The specific technical solutions adopted to achieve the above objectives are:
本发明提供了一种具有式I的化合物，和/或药学上可接受的盐、立体异构体、氘代化物，其中：The present invention provides a compound of formula I, and/or pharmaceutically acceptable salts, stereoisomers, and deuterated compounds, wherein:
Figure PCTCN2020126668-appb-000001
Figure PCTCN2020126668-appb-000001
A是
Figure PCTCN2020126668-appb-000002
或-NHRa； A is
Figure PCTCN2020126668-appb-000002
Or -NHRa;
所述Cyc为通过N原子连接的4-7元杂环；所述Cyc为单环、桥环或螺环；所述Cyc除连接处N原子外，还含有0或1个选自N、O、S的杂原子；所述Cyc被0、1或2个R1取代；The Cyc is a 4-7 membered heterocyclic ring connected by a N atom; the Cyc is a monocyclic ring, a bridged ring or a spiro ring; in addition to the N atom at the connection point, the Cyc also contains 0 or 1 selected from N, O , S heteroatom; the Cyc is substituted by 0, 1 or 2 R1;
所述Ra为C1-C4的烷基；所述Ra被0、1或2个R2取代；The Ra is a C1-C4 alkyl group; the Ra is substituted with 0, 1 or 2 R2;
所述R1任选自羟基、卤素或甲基；The R1 is optionally selected from hydroxyl, halogen or methyl;
所述R2任选自羟基、卤素、甲基或甲氧基；The R2 is optionally selected from hydroxyl, halogen, methyl or methoxy;
B为甲基或氘代甲基。B is methyl or deuterated methyl.
作为优选，A选自被0、1或2个R1取代的如下杂环：Preferably, A is selected from the following heterocycles substituted with 0, 1, or 2 R1:
Figure PCTCN2020126668-appb-000003
Figure PCTCN2020126668-appb-000003
或or
选自被0、1或2个R2取代的如下烷基：Selected from the following alkyl groups substituted with 0, 1, or 2 R2:
Figure PCTCN2020126668-appb-000004
Figure PCTCN2020126668-appb-000004
进一步优选，A选自：More preferably, A is selected from:
Figure PCTCN2020126668-appb-000005
Figure PCTCN2020126668-appb-000005
进一步优选，A选自：More preferably, A is selected from:
Figure PCTCN2020126668-appb-000006
Figure PCTCN2020126668-appb-000006
进一步优选，A选自：More preferably, A is selected from:
Figure PCTCN2020126668-appb-000007
Figure PCTCN2020126668-appb-000007
进一步优选，A选自：More preferably, A is selected from:
Figure PCTCN2020126668-appb-000008
Figure PCTCN2020126668-appb-000008
作为优选，当B为氘代甲基，选自-CD 3。 Preferably, when B is a deuterated methyl group, it is selected from -CD 3 .
本发明还提供了了一种式II化合物，和/或药学上可接受的盐、立体异构体、氘代化物，其中：The present invention also provides a compound of formula II, and/or pharmaceutically acceptable salts, stereoisomers, and deuterated compounds, wherein:
Figure PCTCN2020126668-appb-000009
Figure PCTCN2020126668-appb-000009
A是-ORc；A is -ORc;
所述Rc为C1-C4的烷基，并被0、1或2个选自卤素、羟基或甲氧基的基团取代；The Rc is a C1-C4 alkyl group and is substituted with 0, 1 or 2 groups selected from halogen, hydroxy or methoxy;
所述C1-C4的烷基选自甲基、乙基、正丙基、异丙基、正丁基、异丁基或新丁基；The C1-C4 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or neobutyl;
B为甲基或氘代甲基。B is methyl or deuterated methyl.
作为优选，式I或式II化合物包括：Preferably, the compound of formula I or formula II includes:
Figure PCTCN2020126668-appb-000010
Figure PCTCN2020126668-appb-000010
Figure PCTCN2020126668-appb-000011
Figure PCTCN2020126668-appb-000011
Figure PCTCN2020126668-appb-000012
Figure PCTCN2020126668-appb-000012
进一步优选，化合物包括：More preferably, the compound includes:
Figure PCTCN2020126668-appb-000013
Figure PCTCN2020126668-appb-000013
Figure PCTCN2020126668-appb-000014
Figure PCTCN2020126668-appb-000014
式I化合物可以为盐，其中所述的盐为磷酸盐或柠檬酸盐。The compound of formula I may be a salt, wherein the salt is phosphate or citrate.
作为优选，式I化合物包括：Preferably, the compound of formula I includes:
6-[(2-羟基-2-甲基丙基)胺基]-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的磷酸盐；6-[(2-Hydroxy-2-methylpropyl)amino]-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazepine Heterobicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)-6-吗啉基-吡唑[1,5-a]吡啶-3-腈的磷酸盐；4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridine-3- Yl)-6-morpholinyl-pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)-6-硫代吗啉基-吡唑[1,5-a]吡啶-3-腈的磷酸盐；4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridine-3- Yl)-6-thiomorpholinyl-pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)-6-(2-氧杂-6-氮杂[3.3]庚烷-6-基)-吡唑[1,5-a]吡啶-3-腈的磷酸盐；4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridine-3- Yl)-6-(2-oxa-6-aza[3.3]heptane-6-yl)-pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
6-(3-羟基氮杂环丁烷-1-基)-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的磷酸盐；6-(3-Hydroxyazetidin-1-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazepine Cyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
6-[(2-甲氧基乙基)胺基]-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的磷酸盐；6-[(2-Methoxyethyl)amino]-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo [3.1.1]Heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
6-(3-氮杂双环[3.1.0]己烷-3-基)-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮 杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的磷酸盐；6-(3-Azabicyclo[3.1.0]hexane-3-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6- Diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
6-(1,4-双氮杂庚烷-1-基)-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的磷酸盐；6-(1,4-bisazaheptan-1-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazepine Bicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)-6-(1,4-氧氮杂庚烷-4-基)吡唑[1,5-a]吡啶-3-腈的磷酸盐；4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridine-3- Yl)-6-(1,4-oxazepin-4-yl)pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
6-(3-羟基氮杂环丁烷-1-基)-4-(6-{6-[(6-(三氘代甲氧基)吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的磷酸盐；6-(3-Hydroxyazetidin-1-yl)-4-(6-{6-[(6-(Trideuteromethoxy)pyridin-3-yl)methyl]-3,6 -Diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
4-(6-{6-[(6-(三氘代甲氧基)吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)-6-吗啉基-吡唑[1,5-a]吡啶-3-腈的磷酸盐；4-(6-{6-[(6-(Trideuteromethoxy)pyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl }Pyridin-3-yl)-6-morpholinyl-pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
6-(3-羟基-3甲基氮杂环丁烷-1-基)-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的磷酸盐；6-(3-Hydroxy-3methylazetidin-1-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6- Diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
6-(3,6-二氮杂二环[3.1.1]庚烷-3-基)-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的磷酸盐；6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]- Phosphate of 3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile;
或or
6-[(2-羟基-2-甲基丙基)胺基]-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；6-[(2-Hydroxy-2-methylpropyl)amino]-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazepine Heterobicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
6-(3-氮杂双环[3.1.0]己烷-3-基)-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；6-(3-Azabicyclo[3.1.0]hexane-3-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6- Diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
6-(1,4-双氮杂庚烷-1-基)-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；6-(1,4-bisazaheptan-1-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazepine The citrate of bicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile;
4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)-6-(1,4-氧氮杂庚烷-4-基)吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridine-3- Yl)-6-(1,4-oxazepin-4-yl)pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)-6-吗啉基-吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridine-3- Yl)-6-morpholinyl-pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)-6-硫代吗啉基-吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridine-3- Yl)-6-thiomorpholinyl-pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)-6-(2-氧杂-6-氮杂[3.3]庚烷-6-基)-吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridine-3- Yl)-6-(2-oxa-6-aza[3.3]heptane-6-yl)-pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
6-(3-羟基氮杂环丁烷-1-基)-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；6-(3-Hydroxyazetidin-1-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazepine Cyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
6-[(2-甲氧基乙基)胺基]-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；6-[(2-Methoxyethyl)amino]-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo [3.1.1]Heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
6-(3-羟基氮杂环丁烷-1-基)-4-(6-{6-[(6-(三氘代甲氧基)吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；6-(3-Hydroxyazetidin-1-yl)-4-(6-{6-[(6-(Trideuteromethoxy)pyridin-3-yl)methyl]-3,6 -Diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
4-(6-{6-[(6-(三氘代甲氧基)吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)-6-吗啉基-吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；4-(6-{6-[(6-(Trideuteromethoxy)pyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl }Pyridin-3-yl)-6-morpholinyl-pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
6-(3-羟基-3甲基氮杂环丁烷-1-基)-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；6-(3-Hydroxy-3methylazetidin-1-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6- Diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
6-(3,6-二氮杂二环[3.1.1]庚烷-3-基)-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6 -二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的柠檬酸盐。6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]- The citrate of 3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile.
本发明还提供了一种药物组合物，含有如上任一所述化合物及药学上可接受的载体。The present invention also provides a pharmaceutical composition, which contains any of the above-mentioned compounds and a pharmaceutically acceptable carrier.
其中所述的药物组合物可以制为固体制剂、液体制剂等各类制剂，可以以口服、非肠道、静脉注射或经皮肤给药。The pharmaceutical composition described therein can be prepared into various preparations such as solid preparations, liquid preparations, etc., and can be administered orally, parenterally, intravenously or through the skin.
本发明还提供了一种上述药物组合物或化合物在制备治疗与RET激酶和/或突变RET激酶相关的疾病的药物中的用途。The present invention also provides a use of the above-mentioned pharmaceutical composition or compound in the preparation of a medicine for treating diseases related to RET kinase and/or mutant RET kinase.
作为优选，所述RET激酶和/或突变RET激酶相关疾病，包括但不限于非小细胞肺癌(NSCLC)、肺腺癌(LAD)、髓样甲状腺癌(MTC)、乳头状甲状腺癌。Preferably, the RET kinase and/or mutant RET kinase related diseases include but are not limited to non-small cell lung cancer (NSCLC), lung adenocarcinoma (LAD), medullary thyroid cancer (MTC), and papillary thyroid cancer.
在部分实施例中，本发明还提供了具有式X的化合物，和/或药学上可接受的盐、立体异构体、氘取代衍生物、水合物、溶剂化物或溶剂络合物，其中：In some embodiments, the present invention also provides compounds of formula X, and/or pharmaceutically acceptable salts, stereoisomers, deuterium substituted derivatives, hydrates, solvates or solvent complexes, wherein:
Figure PCTCN2020126668-appb-000015
Figure PCTCN2020126668-appb-000015
W1、W2和W3选自C或N原子，且至少一个为N原子，并满足价键理论；W1, W2, and W3 are selected from C or N atoms, and at least one of them is N atom, and satisfies the valence bond theory;
D是N原子或氰基取代的C原子；D is a C atom substituted by a N atom or a cyano group;
A是A is
a、-(C2-C5)烷基，含有0或1个不饱和双键或三键，且任被0或1个羟基取代；a, -(C2-C5) alkyl group, containing 0 or 1 unsaturated double bond or triple bond, and optionally substituted by 0 or 1 hydroxyl group;
b、-(C3-C6)环烷基，所述-(C3-C6)的环烷基含有0或1个不饱和键；b. -(C3-C6) cycloalkyl, said -(C3-C6) cycloalkyl contains 0 or 1 unsaturated bond;
c、-O-(C1-C4)基，且被0或1个羟基、氨基、卤素取代；c, -O-(C1-C4) group, and substituted by 0 or 1 hydroxyl, amino, halogen;
d、
Figure PCTCN2020126668-appb-000016
所述Cyc1为通过C原子连接的5-6元杂环，含有1个以上选自N、O或S的杂原子，且含有0或1个不饱和键； d.
Figure PCTCN2020126668-appb-000016
The Cyc1 is a 5-6 membered heterocyclic ring connected through a C atom, containing one or more heteroatoms selected from N, O or S, and containing 0 or 1 unsaturated bond;
e、-NRaRb；Ra、Rb任选自H、-(C1-C4)烷基，其中-(C1-C4)烷基被0或1个羟基或甲氧基取代；e, -NRaRb; Ra and Rb are optionally selected from H, -(C1-C4)alkyl, where -(C1-C4)alkyl is substituted by 0 or 1 hydroxy or methoxy;
f、
Figure PCTCN2020126668-appb-000017
所述Cyc2为通过N原子连接的4-7元杂环；所述Cyc2除连接处N原子外，还含有0、1或2个任选自N、O、S的杂原子；所述Cyc被0、1或若干个羟基、卤素、(C1-C3)烷基取代；所述Cyc2为单环或者多环；所述多环指Cyc2含有桥基、桥键或螺环； f.
Figure PCTCN2020126668-appb-000017
The Cyc2 is a 4- to 7-membered heterocyclic ring connected through an N atom; the Cyc2 contains 0, 1 or 2 heteroatoms optionally selected from N, O, S in addition to the N atom at the connection point; the Cyc is 0, 1 or several hydroxy, halogen, (C1-C3) alkyl substitutions; the Cyc2 is monocyclic or polycyclic; the polycyclic means that Cyc2 contains a bridging group, a bridge bond or a spiro ring;
g、卤素；g. Halogen;
h、吡唑或甲基吡唑；h. Pyrazole or methylpyrazole;
G是至少含有一个N的5-6元杂芳环；G is a 5-6 membered heteroaromatic ring containing at least one N;
M为化学键或亚甲基；M is a chemical bond or methylene group;
E为5-6元芳基或杂芳基，所述5-6元芳基或杂芳基被0或1个选自(C1-C3)烷基、(C1-C3)烷氧基、卤素、氰基或三氟甲基的取代基取代。E is a 5-6 membered aryl or heteroaryl group, the 5-6 membered aryl or heteroaryl group is selected from (C1-C3)alkyl, (C1-C3)alkoxy, halogen , Cyano or trifluoromethyl substituents.
作为优选，A选自以下结构：Preferably, A is selected from the following structures:
Figure PCTCN2020126668-appb-000018
Figure PCTCN2020126668-appb-000018
在一些实施例中，In some embodiments,
所述G选自以下结构：The G is selected from the following structures:
Figure PCTCN2020126668-appb-000019
Figure PCTCN2020126668-appb-000019
作为优选，所述E选自以下结构：Preferably, the E is selected from the following structures:
Figure PCTCN2020126668-appb-000020
Figure PCTCN2020126668-appb-000020
作为优选，所述W1为N原子，W2和W3为C原子，D为氰基取代的C原子；Preferably, W1 is a N atom, W2 and W3 are a C atom, and D is a C atom substituted by a cyano group;
A是A is
a、-(C2-C5)烷基，含有0或1个不饱和双键或三键，且任被0或1个羟基取代；a, -(C2-C5) alkyl group, containing 0 or 1 unsaturated double bond or triple bond, and optionally substituted by 0 or 1 hydroxyl group;
b、-(C3-C6)环烷基，所述-(C3-C6)的环烷基含有0或1个不饱和键；b. -(C3-C6) cycloalkyl, said -(C3-C6) cycloalkyl contains 0 or 1 unsaturated bond;
c、-O-(C1-C4)基，且被0或1个羟基、氨基、卤素取代；c, -O-(C1-C4) group, and substituted by 0 or 1 hydroxyl, amino, halogen;
d、
Figure PCTCN2020126668-appb-000021
所述Cyc1为通过C原子连接的5-6元杂环，含有1个以上选自N、O或S的杂原子，且含有0或1个不饱和键； d.
Figure PCTCN2020126668-appb-000021
The Cyc1 is a 5-6 membered heterocyclic ring connected through a C atom, containing one or more heteroatoms selected from N, O or S, and containing 0 or 1 unsaturated bond;
e、-NRaRb；Ra、Rb任选自H、-(C1-C4)烷基，其中-(C1-C4)烷基被0或1个羟基或甲氧基取代；e, -NRaRb; Ra and Rb are optionally selected from H, -(C1-C4)alkyl, where -(C1-C4)alkyl is substituted by 0 or 1 hydroxy or methoxy;
f、
Figure PCTCN2020126668-appb-000022
所述Cyc2为通过N原子连接的4-7元杂环；所述Cyc2除连接处N原子外，还含有0、1或2个任选自N、O、S的杂原子；所述Cyc被0、1或若干个羟基、卤素、(C1-C3)烷基取代；所述Cyc2为单环或者多环；所述多环指Cyc2含有桥基、桥键或螺环； f.
Figure PCTCN2020126668-appb-000022
The Cyc2 is a 4- to 7-membered heterocyclic ring connected through an N atom; the Cyc2 contains 0, 1 or 2 heteroatoms optionally selected from N, O, S in addition to the N atom at the connection point; the Cyc is 0, 1 or several hydroxy, halogen, (C1-C3) alkyl substitutions; the Cyc2 is monocyclic or polycyclic; the polycyclic means that Cyc2 contains a bridging group, a bridge bond or a spiro ring;
g、卤素；g. Halogen;
h、吡唑或甲基吡唑；h. Pyrazole or methylpyrazole;
G是至少含有一个N的5-6元杂芳环；G is a 5-6 membered heteroaromatic ring containing at least one N;
M为化学键或亚甲基；M is a chemical bond or methylene group;
E为5-6元芳基或杂芳基，所述5-6元芳基或杂芳基被0或1个选自(C1-C3)烷基、(C1-C3)烷氧基、卤素、氰基或三氟甲基的取代基取代。E is a 5-6 membered aryl or heteroaryl group, the 5-6 membered aryl or heteroaryl group is selected from (C1-C3)alkyl, (C1-C3)alkoxy, halogen , Cyano or trifluoromethyl substituents.
作为优选，A是Preferably, A is
e、-NRaRb；Ra、Rb任选自H、-(C1-C4)烷基，其中-(C1-C4)烷基被0或1个羟基或甲氧基取代；e, -NRaRb; Ra and Rb are optionally selected from H, -(C1-C4)alkyl, where -(C1-C4)alkyl is substituted by 0 or 1 hydroxy or methoxy;
f、
Figure PCTCN2020126668-appb-000023
所述Cyc2为通过N原子连接的4-7元杂环；所述Cyc2除连接处N原子外，还含有0、1或2个任选自N、O、S的杂原子；所述Cyc被0、1或若干个羟基、卤素、(C1-C3)烷基取代；所述Cyc2为单环或者多环；所述多环指Cyc2含有桥基、桥键或螺环； f.
Figure PCTCN2020126668-appb-000023
The Cyc2 is a 4- to 7-membered heterocyclic ring connected through an N atom; the Cyc2 contains 0, 1 or 2 heteroatoms optionally selected from N, O, S in addition to the N atom at the connection point; the Cyc is 0, 1 or several hydroxy, halogen, (C1-C3) alkyl substitutions; the Cyc2 is monocyclic or polycyclic; the polycyclic means that Cyc2 contains a bridging group, a bridge bond or a spiro ring;
G是吡啶；G is pyridine;
M为化学键或亚甲基；M is a chemical bond or methylene group;
E为5-6元芳基或杂芳基，所述5-6元芳基或杂芳基被0或1个选自(C1-C3)烷基、(C1-C3)烷氧基、卤素、氰基或三氟甲基的取代基取代。E is a 5-6 membered aryl or heteroaryl group, the 5-6 membered aryl or heteroaryl group is selected from (C1-C3)alkyl, (C1-C3)alkoxy, halogen , Cyano or trifluoromethyl substituents.
作为优选，A是
Figure PCTCN2020126668-appb-000024
所述Cyc2为通过N原子连接的4-7元杂环；所述Cyc2除连接处N原子外，还含有0、1或2个任选自N、O、S的杂原子；所述Cyc被0、1或2个羟基、卤素、甲基取代；所述Cyc2为单环或者多环；所述多环指Cyc2含有桥基、桥键或螺环； Preferably, A is
Figure PCTCN2020126668-appb-000024
The Cyc2 is a 4- to 7-membered heterocyclic ring connected through an N atom; the Cyc2 contains 0, 1 or 2 heteroatoms optionally selected from N, O, S in addition to the N atom at the connection point; the Cyc is 0, 1 or 2 hydroxyl, halogen, methyl substitution; the Cyc2 is monocyclic or polycyclic; the polycyclic means that Cyc2 contains a bridging group, a bridge bond or a spiro ring;
G是吡啶；G is pyridine;
M为亚甲基；M is methylene;
E为甲氧基取代的吡啶基；E is pyridyl substituted by methoxy;
Figure PCTCN2020126668-appb-000025
Figure PCTCN2020126668-appb-000025
作为优选，A是
Figure PCTCN2020126668-appb-000026
所述Cyc2为通过N原子连接的4-7元杂环；所述Cyc2除连接处N原子外，还含有0或1个任选自N、O、S的杂原子；所述Cyc被0、1或2个羟基、甲基取代；所述Cyc2为单环或者多环；所述多环指Cyc2含有桥基、桥键或螺环。 Preferably, A is
Figure PCTCN2020126668-appb-000026
Said Cyc2 is a 4-7 membered heterocyclic ring connected by N atom; Said Cyc2 contains 0 or 1 heteroatom optionally selected from N, O, S in addition to the N atom at the connection point; Said Cyc is divided by 0, 1 or 2 hydroxy and methyl substitutions; the Cyc2 is monocyclic or polycyclic; the polycyclic means that Cyc2 contains a bridging group, a bridge bond or a spiro ring.
作为优选，A选自Preferably, A is selected from
Figure PCTCN2020126668-appb-000027
Figure PCTCN2020126668-appb-000027
作为优选，所述W1为N原子，W2和W3为C原子，D为N原子；Preferably, W1 is a N atom, W2 and W3 are C atoms, and D is a N atom;
Figure PCTCN2020126668-appb-000028
Figure PCTCN2020126668-appb-000028
A是A is
a、-(C2-C5)烷基，含有0或1个不饱和双键或三键，且任被0或1个羟基取代；a, -(C2-C5) alkyl group, containing 0 or 1 unsaturated double bond or triple bond, and optionally substituted by 0 or 1 hydroxyl group;
b、-(C3-C6)环烷基，所述-(C3-C6)的环烷基含有0或1个不饱和键；b. -(C3-C6) cycloalkyl, said -(C3-C6) cycloalkyl contains 0 or 1 unsaturated bond;
c、-O-(C1-C4)基，且被0或1个羟基、氨基、卤素取代；c, -O-(C1-C4) group, and substituted by 0 or 1 hydroxyl, amino, halogen;
d、
Figure PCTCN2020126668-appb-000029
所述Cyc1为通过C原子连接的5-6元杂环，含有1个以上选自N、O或S的杂原子，且含有0或1个不饱和键； d.
Figure PCTCN2020126668-appb-000029
The Cyc1 is a 5-6 membered heterocyclic ring connected through a C atom, containing one or more heteroatoms selected from N, O or S, and containing 0 or 1 unsaturated bond;
e、-NRaRb；Ra、Rb任选自H、-(C1-C4)烷基，其中-(C1-C4)烷基被0或1个羟基或甲氧基取代；e, -NRaRb; Ra and Rb are optionally selected from H, -(C1-C4)alkyl, where -(C1-C4)alkyl is substituted by 0 or 1 hydroxy or methoxy;
f、
Figure PCTCN2020126668-appb-000030
所述Cyc2为通过N原子连接的4-7元杂环；所述Cyc2除连接处N原子外，还含有0、1或2个任选自N、O、S的杂原子；所述Cyc被0、1或若干个羟基、卤素、(C1-C3)烷基取代；所述Cyc2为单环或者多环；所述多环指Cyc2含有桥基、桥键或螺环； f.
Figure PCTCN2020126668-appb-000030
The Cyc2 is a 4- to 7-membered heterocyclic ring connected through an N atom; the Cyc2 contains 0, 1 or 2 heteroatoms optionally selected from N, O, S in addition to the N atom at the connection point; the Cyc is 0, 1 or several hydroxy, halogen, (C1-C3) alkyl substitutions; the Cyc2 is monocyclic or polycyclic; the polycyclic means that Cyc2 contains a bridging group, a bridge bond or a spiro ring;
g、卤素；g. Halogen;
h、吡唑或甲基吡唑；h. Pyrazole or methylpyrazole;
G是至少含有一个N的5-6元杂芳环；G is a 5-6 membered heteroaromatic ring containing at least one N;
M为化学键或亚甲基；M is a chemical bond or methylene group;
E为5-6元芳基或杂芳基，所述5-6元芳基或杂芳基被0或1个选自(C1-C3)烷基、(C1-C3)烷氧基、卤素、氰基或三氟甲基的取代基取代。E is a 5-6 membered aryl or heteroaryl group, the 5-6 membered aryl or heteroaryl group is selected from (C1-C3)alkyl, (C1-C3)alkoxy, halogen , Cyano or trifluoromethyl substituents.
作为优选，所述W1和W3为N原子，W2为C原子，D为氰基取代的碳原子；Preferably, W1 and W3 are N atoms, W2 is a C atom, and D is a carbon atom substituted by a cyano group;
Figure PCTCN2020126668-appb-000031
Figure PCTCN2020126668-appb-000031
A是A is
a、-(C2-C5)烷基，含有0或1个不饱和双键或三键，且任被0或1个羟基取代；a, -(C2-C5) alkyl group, containing 0 or 1 unsaturated double bond or triple bond, and optionally substituted by 0 or 1 hydroxyl group;
b、-(C3-C6)环烷基，所述-(C3-C6)的环烷基含有0或1个不饱和键；b. -(C3-C6) cycloalkyl, said -(C3-C6) cycloalkyl contains 0 or 1 unsaturated bond;
c、-O-(C1-C4)基，且被0或1个羟基、氨基、卤素取代；c, -O-(C1-C4) group, and substituted by 0 or 1 hydroxyl, amino, halogen;
d、
Figure PCTCN2020126668-appb-000032
所述Cyc1为通过C原子连接的5-6元杂环，含有1个以上选自N、O或S的杂原子，且含有0或1个不饱和键； d.
Figure PCTCN2020126668-appb-000032
The Cyc1 is a 5-6 membered heterocyclic ring connected through a C atom, containing one or more heteroatoms selected from N, O or S, and containing 0 or 1 unsaturated bond;
e、-NRaRb；Ra、Rb任选自H、-(C1-C4)烷基，其中-(C1-C4)烷基被0或1个羟基或甲氧基取代；e, -NRaRb; Ra and Rb are optionally selected from H, -(C1-C4)alkyl, where -(C1-C4)alkyl is substituted by 0 or 1 hydroxy or methoxy;
f、
Figure PCTCN2020126668-appb-000033
所述Cyc2为通过N原子连接的4-7元杂环；所述Cyc2除连接处N原子外，还含有0、1或2个任选自N、O、S的杂原子；所述Cyc被0、1或若干个羟基、卤素、(C1-C3)烷基取代；所述Cyc2为单环或者多环；所述多环指Cyc2含有桥基、桥键或螺环； f.
Figure PCTCN2020126668-appb-000033
The Cyc2 is a 4- to 7-membered heterocyclic ring connected through an N atom; the Cyc2 contains 0, 1 or 2 heteroatoms optionally selected from N, O, S in addition to the N atom at the connection point; the Cyc is 0, 1 or several hydroxy, halogen, (C1-C3) alkyl substitutions; the Cyc2 is monocyclic or polycyclic; the polycyclic means that Cyc2 contains a bridging group, a bridge bond or a spiro ring;
g、卤素；g. Halogen;
h、吡唑或甲基吡唑；h. Pyrazole or methylpyrazole;
G是至少含有一个N的5-6元杂芳环；G is a 5-6 membered heteroaromatic ring containing at least one N;
M为化学键或亚甲基；M is a chemical bond or methylene group;
E为5-6元芳基或杂芳基，所述5-6元芳基或杂芳基被0或1个选自(C1-C3)烷基、(C1-C3)烷氧基、卤素、氰基或三氟甲基的取代基取代。E is a 5-6 membered aryl or heteroaryl group, the 5-6 membered aryl or heteroaryl group is selected from (C1-C3)alkyl, (C1-C3)alkoxy, halogen , Cyano or trifluoromethyl substituents.
作为优选，W2为N原子，所述W1和W3为C原子，D为氰基取代的碳原子；Preferably, W2 is a N atom, said W1 and W3 are C atoms, and D is a carbon atom substituted by a cyano group;
Figure PCTCN2020126668-appb-000034
Figure PCTCN2020126668-appb-000034
A是A is
a、-(C2-C5)烷基，含有0或1个不饱和双键或三键，且任被0或1个羟基取代；a, -(C2-C5) alkyl group, containing 0 or 1 unsaturated double bond or triple bond, and optionally substituted by 0 or 1 hydroxyl group;
b、-(C3-C6)环烷基，所述-(C3-C6)的环烷基含有0或1个不饱和键；b. -(C3-C6) cycloalkyl, said -(C3-C6) cycloalkyl contains 0 or 1 unsaturated bond;
c、-O-(C1-C4)基，且被0或1个羟基、氨基、卤素取代；c, -O-(C1-C4) group, and substituted by 0 or 1 hydroxyl, amino, halogen;
d、
Figure PCTCN2020126668-appb-000035
所述Cyc1为通过C原子连接的5-6元杂环，含有1个以上选自N、O或S的杂原子，且含有0或1个不饱和键； d.
Figure PCTCN2020126668-appb-000035
The Cyc1 is a 5-6 membered heterocyclic ring connected through a C atom, containing one or more heteroatoms selected from N, O or S, and containing 0 or 1 unsaturated bond;
e、-NRaRb；Ra、Rb任选自H、-(C1-C4)烷基，其中-(C1-C4)烷基被0或1个羟基或甲氧基取代；e, -NRaRb; Ra and Rb are optionally selected from H, -(C1-C4)alkyl, where -(C1-C4)alkyl is substituted by 0 or 1 hydroxy or methoxy;
f、
Figure PCTCN2020126668-appb-000036
所述Cyc2为通过N原子连接的4-7元杂环；所述Cyc2除连接处N原子外，还含有0、1或2个任选自N、O、S的杂原子；所述Cyc被0、1或若干个羟基、卤素、(C1-C3)烷基取代；所述Cyc2为单环或者多环；所述多环指Cyc2含有桥基、桥键或螺环； f.
Figure PCTCN2020126668-appb-000036
The Cyc2 is a 4- to 7-membered heterocyclic ring connected through an N atom; the Cyc2 contains 0, 1 or 2 heteroatoms optionally selected from N, O, S in addition to the N atom at the connection point; the Cyc is 0, 1 or several hydroxy, halogen, (C1-C3) alkyl substitutions; the Cyc2 is monocyclic or polycyclic; the polycyclic means that Cyc2 contains a bridging group, a bridge bond or a spiro ring;
g、卤素；g. Halogen;
h、吡唑或甲基吡唑；h. Pyrazole or methylpyrazole;
G是至少含有一个N的5-6元杂芳环；G is a 5-6 membered heteroaromatic ring containing at least one N;
M为化学键或亚甲基；M is a chemical bond or methylene group;
E为5-6元芳基或杂芳基，所述5-6元芳基或杂芳基被0或1个选自(C1-C3)烷基、(C 1-C3)烷氧基、卤素、氰基或三氟甲基的取代基取代。E is a 5-6 membered aryl or heteroaryl group, and the 5-6 membered aryl or heteroaryl group is selected from (C1-C3)alkyl, (C1-C3)alkoxy, Substituents substituted by halogen, cyano or trifluoromethyl.
作为优选，W2为N原子，所述W1和W3为C原子，D为N原子；Preferably, W2 is a N atom, the W1 and W3 are C atoms, and D is a N atom;
Figure PCTCN2020126668-appb-000037
Figure PCTCN2020126668-appb-000037
A是A is
a、-(C2-C5)烷基，含有0或1个不饱和双键或三键，且任被0或1个羟基取代；a, -(C2-C5) alkyl group, containing 0 or 1 unsaturated double bond or triple bond, and optionally substituted by 0 or 1 hydroxyl group;
b、-(C3-C6)环烷基，所述-(C3-C6)的环烷基含有0或1个不饱和键；b. -(C3-C6) cycloalkyl, said -(C3-C6) cycloalkyl contains 0 or 1 unsaturated bond;
c、-O-(C1-C4)基，且被0或1个羟基、氨基、卤素取代；c, -O-(C1-C4) group, and substituted by 0 or 1 hydroxyl, amino, halogen;
d、
Figure PCTCN2020126668-appb-000038
所述Cyc1为通过C原子连接的5-6元杂环，含有1个以上选自N、O或S的杂原子，且含有0或1个不饱和键； d.
Figure PCTCN2020126668-appb-000038
The Cyc1 is a 5-6 membered heterocyclic ring connected through a C atom, containing one or more heteroatoms selected from N, O or S, and containing 0 or 1 unsaturated bond;
e、-NRaRb；Ra、Rb任选自H、-(C1-C4)烷基，其中-(C1-C4)烷基被0或1个羟基或甲氧基取代；e, -NRaRb; Ra and Rb are optionally selected from H, -(C1-C4)alkyl, where -(C1-C4)alkyl is substituted by 0 or 1 hydroxy or methoxy;
f、
Figure PCTCN2020126668-appb-000039
所述Cyc2为通过N原子连接的4-7元杂环；所述Cyc2除连接处N原子外，还含有0、1或2个任选自N、O、S的杂原子；所述Cyc被0、1或若干个羟基、卤素、(C1-C3)烷基取代；所述Cyc2为单环或者多环；所述多环指Cyc2含有桥基、桥键或螺环； f.
Figure PCTCN2020126668-appb-000039
The Cyc2 is a 4- to 7-membered heterocyclic ring connected through an N atom; the Cyc2 contains 0, 1 or 2 heteroatoms optionally selected from N, O, S in addition to the N atom at the connection point; the Cyc is 0, 1 or several hydroxy, halogen, (C1-C3) alkyl substitutions; the Cyc2 is monocyclic or polycyclic; the polycyclic means that Cyc2 contains a bridging group, a bridge bond or a spiro ring;
g、卤素；g. Halogen;
h、吡唑或甲基吡唑；h. Pyrazole or methylpyrazole;
G是至少含有一个N的5-6元杂芳环；G is a 5-6 membered heteroaromatic ring containing at least one N;
M为化学键或亚甲基；M is a chemical bond or methylene group;
E为5-6元芳基或杂芳基，所述5-6元芳基或杂芳基被0或1个选自(C1-C3)烷基、(C1-C3)烷氧基、卤素、氰基或三氟甲基的取代基取代。E is a 5-6 membered aryl or heteroaryl group, the 5-6 membered aryl or heteroaryl group is selected from (C1-C3)alkyl, (C1-C3)alkoxy, halogen , Cyano or trifluoromethyl substituents.
本发明还提供了如下化合物，和/或药学上可接受的盐、立体异构体、氘取代衍生物水合物、溶剂化物或溶剂络合物，包括：The present invention also provides the following compounds, and/or pharmaceutically acceptable salts, stereoisomers, deuterium substituted derivative hydrates, solvates or solvent complexes, including:
Figure PCTCN2020126668-appb-000040
Figure PCTCN2020126668-appb-000040
Figure PCTCN2020126668-appb-000041
Figure PCTCN2020126668-appb-000041
Figure PCTCN2020126668-appb-000042
Figure PCTCN2020126668-appb-000042
Figure PCTCN2020126668-appb-000043
Figure PCTCN2020126668-appb-000043
Figure PCTCN2020126668-appb-000044
Figure PCTCN2020126668-appb-000044
作为优选，所述化合物或所述的药物组合物，其特征在于，单独使用或与其他治疗剂联合使用。Preferably, the compound or the pharmaceutical composition is characterized in that it is used alone or in combination with other therapeutic agents.
作为优选，所述化合物或药物组合物，其特征在于，以口服、非肠道、静脉注射或经皮肤给药。Preferably, the compound or pharmaceutical composition is characterized in that it is administered orally, parenterally, intravenously or through the skin.
本发明还提供了所述化合物或所述药物组合物在制备治疗与RET激酶和/或突变RET激酶相关的疾病的药物中的用途。The present invention also provides the use of the compound or the pharmaceutical composition in the preparation of a medicine for treating diseases related to RET kinase and/or mutant RET kinase.
作为优选，所述RET激酶和/或突变RET激酶相关疾病，包括但不限于非小细胞肺癌(NSCLC)、肺腺癌(LAD)、髓样甲状腺癌(MTC)、乳头状甲状腺癌。Preferably, the RET kinase and/or mutant RET kinase related diseases include but are not limited to non-small cell lung cancer (NSCLC), lung adenocarcinoma (LAD), medullary thyroid cancer (MTC), and papillary thyroid cancer.
本发明所公开的化合物，在激酶、细胞水平上均表现出优良的活性，药效优越；同时具有优异的药代动力学性质、选择性及更小的毒副作用。The compound disclosed in the present invention exhibits excellent activity at the kinase and cell levels, and has superior pharmacodynamics; at the same time, it has excellent pharmacokinetic properties, selectivity and less toxic and side effects.
具体实施方式Detailed ways
以下实施例举例说明本发明。The following examples illustrate the invention.
在一些实施例中，主环为3-氰基-吡唑并[1,5-a]吡啶，A与主环相连的原子为C原子，该化合物具有式Ia的结构，也可是其药学上可接受的盐和溶剂化物，其中G环如的式X的化合物所描述的。In some embodiments, the main ring is 3-cyano-pyrazolo[1,5-a]pyridine, and the atom connecting A to the main ring is a C atom. The compound has the structure of formula Ia, and it can also be pharmaceutically acceptable. Acceptable salts and solvates in which the G ring is as described for the compound of formula X.
Figure PCTCN2020126668-appb-000045
Figure PCTCN2020126668-appb-000045
R 3、R 4、R 5独立地表示1-6个碳链或氢，R 3、R 4或R 5可以含有0或1个炔基或烯基，也可以独立地被0或1个羟基取代； R 3 , R 4 , R 5 independently represent 1-6 carbon chains or hydrogen, R 3 , R 4 or R 5 may contain 0 or 1 alkynyl or alkenyl group, or independently by 0 or 1 hydroxyl group replace;
包括但不限于以下结构：Including but not limited to the following structures:
Figure PCTCN2020126668-appb-000046
Figure PCTCN2020126668-appb-000046
R 3、R 4或R 5也可以通过连接的中心C原子两两之间成环，形成三元，四元，五元或六元的碳环；所形成的碳环中可以含有0或1个碳碳双键，所形成的碳环也可以含有0或1个选自N、O、S的杂原子； R 3 , R 4 or R 5 can also form a ring between two of the central C atoms connected to form a three-membered, four-membered, five-membered or six-membered carbocyclic ring; the formed carbocyclic ring may contain 0 or 1 A carbon-carbon double bond, the formed carbocyclic ring may also contain 0 or 1 heteroatom selected from N, O, S;
包括但不限于以下结构：Including but not limited to the following structures:
Figure PCTCN2020126668-appb-000047
Figure PCTCN2020126668-appb-000047
在一些实施例中，主环为3-氰基-吡唑并[1,5-a]吡啶，A与主环相连的原子为N原子，该化合物具有式Ib的结构，也可是其药学上可接受的盐及溶剂化物。In some embodiments, the main ring is 3-cyano-pyrazolo[1,5-a]pyridine, and the atom connecting A to the main ring is an N atom. The compound has the structure of formula Ib, and it can also be pharmaceutically acceptable. Acceptable salts and solvates.
Figure PCTCN2020126668-appb-000048
Figure PCTCN2020126668-appb-000048
R 3、R 4独立地表示1-6个碳链或氢，R 3或R 4可以独立地被0或1个羟基、甲氧基、乙氧基或其他烷氧基取代； R 3 and R 4 independently represent 1 to 6 carbon chains or hydrogen, and R 3 or R 4 can be independently substituted with 0 or 1 hydroxyl, methoxy, ethoxy or other alkoxy groups;
包括但不限于以下结构：Including but not limited to the following structures:
Figure PCTCN2020126668-appb-000049
Figure PCTCN2020126668-appb-000049
R 3与R 4也可以与N原子形成饱和的4-7元环烷基，所述的环烷基可以是单环烷基，也可以是含有桥基、桥键或螺环的多环烷基；环烷基除连接主环的N原子外，还可以含有0或1个选自N、O、S的杂原子；环烷基也可以被0、1或2个选自甲基、乙基、丙基、异丙基、羟基、甲氧基、乙氧基的基团取代。 R 3 and R 4 can also form a saturated 4-7 membered cycloalkyl group with the N atom. The cycloalkyl group can be a monocyclic alkyl group or a polycycloalkane containing a bridging group, a bridge bond or a spiro ring. In addition to the N atom connecting the main ring, the cycloalkyl group can also contain 0 or 1 heteroatom selected from N, O, S; the cycloalkyl group can also be selected from the group consisting of 0, 1 or 2 methyl, ethyl Group, propyl, isopropyl, hydroxy, methoxy, ethoxy.
包括但不限于以下结构：Including but not limited to the following structures:
Figure PCTCN2020126668-appb-000050
Figure PCTCN2020126668-appb-000050
在一些实施例中，主环为3-氰基-吡唑并[1,5-a]吡啶，A与主环相连的原子为N原子，该化合物具有式Ic的结构，也可以是其药学上可接受的盐及溶剂化物。In some embodiments, the main ring is 3-cyano-pyrazolo[1,5-a]pyridine, and the atom connecting A to the main ring is an N atom. The compound has the structure of formula Ic, and it can also be a pharmacological compound. Acceptable salts and solvates.
Figure PCTCN2020126668-appb-000051
Figure PCTCN2020126668-appb-000051
A为烷氧基(甲氧基)，烷氧基醇。A is alkoxy (methoxy), alkoxy alcohol.
在一些实施例中，主环为[1,2,4]三唑并[1,5-a]吡啶，该化合物可以是Id或Ie的结构，也可以是其药学上可接受的盐及溶剂化物。A与主环相连的原子为N原子。In some embodiments, the main ring is [1,2,4]triazolo[1,5-a]pyridine, the compound can be the structure of Id or Ie, or its pharmaceutically acceptable salt and solvent化物。 The atom connecting A to the main ring is the N atom.
Figure PCTCN2020126668-appb-000052
Figure PCTCN2020126668-appb-000052
R 3、R 4独立地表示1-6个碳链或氢，R 3或R 4可以独立地被0或1个羟基、甲氧基、乙氧基或其他烷氧基取代； R 3 and R 4 independently represent 1 to 6 carbon chains or hydrogen, and R 3 or R 4 can be independently substituted with 0 or 1 hydroxyl, methoxy, ethoxy or other alkoxy groups;
包括但不限于以下结构：Including but not limited to the following structures:
Figure PCTCN2020126668-appb-000053
Figure PCTCN2020126668-appb-000053
R 3与R 4也可以与N原子形成饱和的4-7元环烷基，所述的环烷基可以是单环烷基，也可以是含有桥基、桥键或螺环的多环烷基；环烷基除连接主环的N原子外，还可以含有0或1个选自N、O、S的杂原子；环烷基也可以被0、1或2个选自甲基、乙基、丙基、异丙基、羟基、甲氧基、乙氧基的基团取代。 R 3 and R 4 can also form a saturated 4-7 membered cycloalkyl group with the N atom. The cycloalkyl group can be a monocyclic alkyl group or a polycycloalkane containing a bridging group, a bridge bond or a spiro ring. In addition to the N atom connecting the main ring, the cycloalkyl group can also contain 0 or 1 heteroatom selected from N, O, S; the cycloalkyl group can also be selected from the group consisting of 0, 1 or 2 methyl, ethyl Group, propyl, isopropyl, hydroxy, methoxy, ethoxy.
包括但不限于以下结构：Including but not limited to the following structures:
Figure PCTCN2020126668-appb-000054
Figure PCTCN2020126668-appb-000054
在一些实施例中，主环为吡唑并[1,5-a]吡嗪，A与主环相连的原子为N原子，该化合物具有式Ig的结构，也可以是其药学上可接受的盐及溶剂化物。In some embodiments, the main ring is pyrazolo[1,5-a]pyrazine, and the atom connecting A to the main ring is an N atom. The compound has the structure of formula Ig, and may also be pharmaceutically acceptable. Salts and solvates.
Figure PCTCN2020126668-appb-000055
Figure PCTCN2020126668-appb-000055
R 3、R 4独立地表示1-6个碳链或氢，R 3或R 4可以独立地被0或1个羟基、甲氧基、乙氧基或其他烷氧基取代； R 3 and R 4 independently represent 1 to 6 carbon chains or hydrogen, and R 3 or R 4 can be independently substituted with 0 or 1 hydroxyl, methoxy, ethoxy or other alkoxy groups;
包括但不限于以下结构：Including but not limited to the following structures:
Figure PCTCN2020126668-appb-000056
Figure PCTCN2020126668-appb-000056
R 3和R 4也可以与N原子形成饱和的4-7元环烷基，所述的环烷基可以是单环烷基，也可以是含有桥基、桥键或螺环的多环烷基；环烷基除连接主环的N原子外，还可以含有0或1个选自N、O、S的杂原子；环烷基也可以被0、1或2个选自甲基、乙基、丙基、异丙基、羟基、甲氧基、乙氧基的基团取代。 R 3 and R 4 can also form a saturated 4-7 membered cycloalkyl group with the N atom. The cycloalkyl group can be a monocyclic alkyl group or a polycycloalkane containing a bridging group, a bridge bond or a spiro ring. In addition to the N atom connecting the main ring, the cycloalkyl group can also contain 0 or 1 heteroatom selected from N, O, S; the cycloalkyl group can also be selected from the group consisting of 0, 1 or 2 methyl, ethyl Group, propyl, isopropyl, hydroxy, methoxy, ethoxy.
包括但不限于以下结构：Including but not limited to the following structures:
Figure PCTCN2020126668-appb-000057
Figure PCTCN2020126668-appb-000057
在一些实施例中，主环为吡唑并[1,5-a]吡嗪，A与主环相连的原子为N原子，该化合物具有式Ih的结构，也可以是其药学上可接受的盐及溶剂化物。In some embodiments, the main ring is pyrazolo[1,5-a]pyrazine, and the atom connecting A to the main ring is an N atom. The compound has the structure of formula Ih, and may also be pharmaceutically acceptable. Salts and solvates.
Figure PCTCN2020126668-appb-000058
Figure PCTCN2020126668-appb-000058
R 3、R 4独立地表示1-6个碳链或氢，R 3或R 4可以独立地被0或1个羟基、甲氧基、乙氧基或其他烷氧基取代； R 3 and R 4 independently represent 1 to 6 carbon chains or hydrogen, and R 3 or R 4 can be independently substituted with 0 or 1 hydroxyl, methoxy, ethoxy or other alkoxy groups;
包括但不限于以下结构：Including but not limited to the following structures:
Figure PCTCN2020126668-appb-000059
Figure PCTCN2020126668-appb-000059
R 3与R 4也可以与N原子形成饱和的4-7元环烷基，所述的环烷基可以是单环烷基，也可以是含有桥基、桥键或螺环的多环烷基；环烷基除连接主环的N原子外，还可以含有0或1个选自N、O、S的杂原子；环烷基也可以被0、1或2个选自甲基、乙基、丙基、异丙基、羟基、甲氧基、乙氧基的基团取代。 R 3 and R 4 can also form a saturated 4-7 membered cycloalkyl group with the N atom. The cycloalkyl group can be a monocyclic alkyl group or a polycycloalkane containing a bridging group, a bridge bond or a spiro ring. In addition to the N atom connecting the main ring, the cycloalkyl group can also contain 0 or 1 heteroatom selected from N, O, S; the cycloalkyl group can also be selected from the group consisting of 0, 1 or 2 methyl, ethyl Group, propyl, isopropyl, hydroxy, methoxy, ethoxy.
包括但不限于以下结构：Including but not limited to the following structures:
Figure PCTCN2020126668-appb-000060
Figure PCTCN2020126668-appb-000060
E为以下结构：E is the following structure:
Figure PCTCN2020126668-appb-000061
Figure PCTCN2020126668-appb-000061
合成化学实施例Examples of synthetic chemistry
化合物实施例1-67的制备Preparation of Compound Examples 1-67
实施例中的原料，如无特殊说明，均从市场购得。The raw materials in the examples are all purchased from the market unless otherwise specified.
表1：中间体P1-P12结构及其来源或制备参考文献。Table 1: Intermediate P1-P12 structure and its source or preparation references.
Figure PCTCN2020126668-appb-000062
Figure PCTCN2020126668-appb-000062
Figure PCTCN2020126668-appb-000063
Figure PCTCN2020126668-appb-000063
实施例1：Example 1:
Figure PCTCN2020126668-appb-000064
Figure PCTCN2020126668-appb-000064
化合物I-1的合成：Synthesis of compound I-1:
Figure PCTCN2020126668-appb-000065
Figure PCTCN2020126668-appb-000065
化合物1的合成：Synthesis of compound 1:
化合物1的合成分两步进行。2,5-二溴噻唑与6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷在碱和溶剂得作用下发生芳香取代反应，得到产物再与六正丁基二锡在催化剂四(三苯基膦)钯的作用下发生反应生成化合物1，收率28.6％，MS m/z＝571.3[M+H] +，化合物1未经纯化，直接用于下一步。 The synthesis of compound 1 was carried out in two steps. 2,5-Dibromothiazole and 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane undergo an aromatic substitution reaction under the action of a base and a solvent, and the product is then reacted with hexan The butyl ditin reacts under the action of the tetrakis (triphenylphosphine) palladium catalyst to produce compound 1, the yield is 28.6%, MS m/z=571.3[M+H] + , compound 1 is used directly without purification Next step.
化合物2的合成：Synthesis of compound 2:
氮气保护下，将化合物1(856.5mg，1.50mmol)和中间体P-1(333mg,1.33mmol)加入至甲苯(20mL)中，再向搅拌的溶液中加入Pd(PPh3)4(384mg,0.3mmol),将反应加热至85℃继续搅拌2小时，反应完成后，减压除去溶剂，得到的粗品用柱层析纯化得到化合物2(180mg,30％)。Under the protection of nitrogen, compound 1 (856.5mg, 1.50mmol) and intermediate P-1 (333mg, 1.33mmol) were added to toluene (20mL), and then Pd(PPh3)4 (384mg, 0.3 mmol), the reaction was heated to 85° C. and stirred for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the obtained crude product was purified by column chromatography to obtain compound 2 (180 mg, 30%).
1H-NMR(CDCl 3,400MHz)δ(ppm):8.134(s,1H),8.010(s,1H),7.535(s,1H),7.080(d,1H),4.218(d,2H),4.065(d,2H),3.819(s,3H),2.650(m,1H),1.343(s,9H),1.325(d,2H),1.180(br,2H),MS m/z＝453.5[M+H] +。 1 H-NMR (CDCl 3 , 400MHz) δ (ppm): 8.134 (s, 1H), 8.010 (s, 1H), 7.535 (s, 1H), 7.080 (d, 1H), 4.218 (d, 2H), 4.065(d,2H),3.819(s,3H),2.650(m,1H),1.343(s,9H),1.325(d,2H),1.180(br,2H),MS m/z=453.5[M +H] + .
化合物I-1的合成Synthesis of compound I-1
将化合物2(170mg,0.38mmol)溶于二氯甲烷(1.08mL)中，加入三氟乙酸(1.08mL,0.2162mmol)后，在室温下搅拌3小时，反应完成后，将反应液用二氯甲烷稀释，并用饱和的碳酸钠水溶液洗涤，将有机相用无水硫酸镁干燥，过滤除去固体，向得到的滤液中加入6-甲氧基-3-吡啶甲醛(103mg,0.75mmol)和1滴冰醋酸，反应液在室温下搅拌半个小时后，再向反应混合物中分批加入醋酸硼氢化钠(239mg,1.13mmol).反应混合物在室温下继续搅拌过夜，反应完成后，滤除不溶物，将滤液直接用柱色谱纯化得到化合物I-1(78mg,40％yield)。Compound 2 (170 mg, 0.38 mmol) was dissolved in dichloromethane (1.08 mL), trifluoroacetic acid (1.08 mL, 0.2162 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was replaced with dichloromethane Dilute with methane and wash with saturated aqueous sodium carbonate solution. Dry the organic phase over anhydrous magnesium sulfate. Filter to remove solids. Add 6-methoxy-3-pyridinecarboxaldehyde (103 mg, 0.75 mmol) and 1 drop to the resulting filtrate. Glacial acetic acid. After the reaction solution was stirred at room temperature for half an hour, sodium acetate borohydride (239mg, 1.13mmol) was added to the reaction mixture in batches. The reaction mixture was stirred overnight at room temperature. After the reaction was completed, the insoluble matter was filtered out , The filtrate was directly purified by column chromatography to obtain compound I-1 (78 mg, 40% yield).
1H NMR(CDCl 3,400MHz)δ(ppm):8.148(s,1H),8.055(d,1H),8.025(d,1H),7.575(m,2H),7.105(d,1H),6.645(d,1H),3.850(s,3H),3.827(s,3H),3.801(m,1H),3.772(m,1H),3.693(s,2H),3.535(br,2H),3.478(br,2H),2.660(m,1H),1.625(d,1H),MS m/z＝526.2[M+H] +。 1 H NMR (CDCl 3 , 400MHz) δ (ppm): 8.148 (s, 1H), 8.055 (d, 1H), 8.025 (d, 1H), 7.575 (m, 2H), 7.105 (d, 1H), 6.645 (d, 1H), 3.850 (s, 3H), 3.827 (s, 3H), 3.801 (m, 1H), 3.772 (m, 1H), 3.693 (s, 2H), 3.535 (br, 2H), 3.478 ( br, 2H), 2.660 (m, 1H), 1.625 (d, 1H), MS m/z=526.2 [M+H] + .
实施例2Example 2
Figure PCTCN2020126668-appb-000066
Figure PCTCN2020126668-appb-000066
化合物I-2的合成：Synthesis of compound I-2:
参考本文实施例1中化合物I-1的合成，仅在第一步Still偶联中将反应物中间体P-1替换换成中间体P-4即可。柱色谱纯化得化合物I-2(29mg,34％yield)。With reference to the synthesis of compound I-1 in Example 1 herein, only the reactant intermediate P-1 can be replaced with intermediate P-4 in the first Still coupling. Purified by column chromatography, compound I-2 (29 mg, 34% yield) was obtained.
1H-NMR(CDCl 3,400MHz)δ(ppm):8.156(s,1H),8.060(d,2H),7.585(d,2H),7.168(d,1H),6.655(d,1H),3.855(s,3H),3.815(s,1H),3.789(s,2H),3.710(s,2H),3.549(br,2H),3.520(br,2H),2.690(m,1H),1.975(m,1H),1.625(d,1H)1.357(s,6H)。MS m/z＝532.6[M+H] +. 1 H-NMR (CDCl 3 , 400MHz) δ (ppm): 8.156 (s, 1H), 8.060 (d, 2H), 7.585 (d, 2H), 7.168 (d, 1H), 6.655 (d, 1H), 3.855(s, 3H), 3.815(s, 1H), 3.789(s, 2H), 3.710(s, 2H), 3.549(br, 2H), 3.520(br, 2H), 2.690(m, 1H), 1.975 (m, 1H), 1.625 (d, 1H) 1.357 (s, 6H). MS m/z=532.6[M+H] + .
实施例3Example 3
Figure PCTCN2020126668-appb-000067
Figure PCTCN2020126668-appb-000067
化合物I-3的合成：Synthesis of compound I-3:
参考本文实施例1中化合物I-1的合成，仅在化合物1的合成中将2,5-二溴噻唑替换成商业可得2,4-二溴噻唑。化合物经过制备色谱分离(16mg,21％yield)，MS m/z＝532.4[M+H] +。 With reference to the synthesis of compound 1-1 in Example 1 herein, only 2,5-dibromothiazole was replaced with commercially available 2,4-dibromothiazole in the synthesis of compound 1. The compound was separated by preparative chromatography (16mg, 21% yield), MS m/z=532.4[M+H] + .
实施例4Example 4
Figure PCTCN2020126668-appb-000068
Figure PCTCN2020126668-appb-000068
化合物I-4的合成：Synthesis of compound I-4:
Figure PCTCN2020126668-appb-000069
Figure PCTCN2020126668-appb-000069
化合物3的合成：Synthesis of compound 3:
氮气保护下，将中间体P-3(500mg,1.35mmol),环丙烷硼酸(174mg,2mmol),水合磷酸钾(860mg,4mmol)加入至甲苯和水(5ml/1ml)混合溶液中，再向搅拌的反应液中加入醋酸钯(60mg,0.2mmol)，将反应混合物在50℃搅拌6小时，反应完成后，加入乙酸乙酯和水的混合溶液，将有机相分离并浓缩，得到的粗产品柱层析纯化得到化合物3(251mg,71％)。MS m/z＝263.8[M+H] +. Under the protection of nitrogen, intermediate P-3 (500mg, 1.35mmol), cyclopropaneboronic acid (174mg, 2mmol), potassium phosphate hydrate (860mg, 4mmol) were added to the mixed solution of toluene and water (5ml/1ml), and then added to the mixed solution of toluene and water (5ml/1ml). Palladium acetate (60mg, 0.2mmol) was added to the stirred reaction solution, and the reaction mixture was stirred at 50°C for 6 hours. After the reaction was completed, a mixed solution of ethyl acetate and water was added, the organic phase was separated and concentrated to obtain the crude product Purification by column chromatography gave compound 3 (251 mg, 71%). MS m/z=263.8[M+H] + .
化合物4的合成：Synthesis of compound 4:
氮气搅拌下，将化合物3(240mg,0.91mmol),2-氟-5-吡啶硼酸(208mg,1.48mmol),碳酸钠(313mg,2.95mmol)的水溶液加入至四氢呋喃(4ml)中,向搅拌的上述溶液中加入四(三苯基磷)钯(11.4mg,0.01eq),将反应液加热至85℃搅拌6小时，反应完成后，将反应液冷至室温并加入乙酸乙酯和水的混合液，分离出有机相，干燥浓缩，柱层析纯化得到化合物4(205mg,80％),MS m/z＝279.2[M+H] +。 Under nitrogen stirring, an aqueous solution of compound 3 (240mg, 0.91mmol), 2-fluoro-5-pyridineboronic acid (208mg, 1.48mmol), and sodium carbonate (313mg, 2.95mmol) was added to tetrahydrofuran (4ml), and added to the stirred Add tetrakis(triphenylphosphorus)palladium (11.4mg, 0.01eq) to the above solution, heat the reaction solution to 85°C and stir for 6 hours. After the reaction is complete, cool the reaction solution to room temperature and add ethyl acetate and water to mix The organic phase was separated, dried and concentrated, and purified by column chromatography to obtain compound 4 (205 mg, 80%), MS m/z=279.2 [M+H] + .
化合物5的合成：Synthesis of compound 5:
其合成参考实施例1中的与6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷反应制备化合物1。产物经柱层析纯化得到化合物5(105mg,95％)，Its synthesis refers to the reaction with 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane in Example 1 to prepare compound 1. The product was purified by column chromatography to obtain compound 5 (105 mg, 95%),
1H NMR(CDCl3,400MHz)δ(ppm):8.278(d,1H),8.251(s,1H),8.143(m,1H),7.660(dd,1H),6.987(s,1H),6.580(d,1H),4.248(d,2H),3.487(m,2H),2.610(m,1H),1.476(d,2H),1.350(m,2H),1.318(s,9H),1.000(d,2H),0.808(m,2H).MS m/z＝457.3[M+H] +。 1 H NMR (CDCl3, 400MHz) δ (ppm): 8.278 (d, 1H), 8.251 (s, 1H), 8.143 (m, 1H), 7.660 (dd, 1H), 6.987 (s, 1H), 6.580 ( d, 1H), 4.248 (d, 2H), 3.487 (m, 2H), 2.610 (m, 1H), 1.476 (d, 2H), 1.350 (m, 2H), 1.318 (s, 9H), 1.000 (d , 2H), 0.808 (m, 2H). MS m/z=457.3 [M+H] + .
化合物I-4的合成：Synthesis of compound I-4:
其合成参考本文化合物I-1的合成。产物经柱层析纯化得到(65mg,53％)。For its synthesis, refer to the synthesis of compound I-1 herein. The product was purified by column chromatography to obtain (65mg, 53%).
1H NMR(CDCl 3,400MHz)δ(ppm):8.322(d,1H),8.319(s,1H),8.162(s,1H),8.051(t,1H),7.719(m,1H),7.648(t,1H),6.997(d,1H),6.645(m,2H),3.854(s,3H),3.820(m,4H),3.595(m,4H),2.751(s,1H),1.931(m,1H),1.620(m,2H),1.051(m,3H).MS m/z＝478.3[M+H] +。 1 H NMR (CDCl 3 , 400MHz) δ (ppm): 8.322 (d, 1H), 8.319 (s, 1H), 8.162 (s, 1H), 8.051 (t, 1H), 7.719 (m, 1H), 7.648 (t, 1H), 6.997 (d, 1H), 6.645 (m, 2H), 3.854 (s, 3H), 3.820 (m, 4H), 3.595 (m, 4H), 2.751 (s, 1H), 1.931 ( m, 1H), 1.620 (m, 2H), 1.051 (m, 3H). MS m/z=478.3 [M+H] + .
实施例5Example 5
Figure PCTCN2020126668-appb-000070
Figure PCTCN2020126668-appb-000070
化合物I-5的合成：Synthesis of compound I-5:
其合成参考本文实施例4中化合物I-4的合成，仅在第一步中将起始原料环丙烷硼酸替换成商业可得的环戊烷硼酸即可。产物经柱层析纯化得到(27mg，41％)，MS m/z＝506.3[M+H] +。 For its synthesis, refer to the synthesis of compound 1-4 in Example 4 herein, and only in the first step the starting material cyclopropaneboronic acid is replaced with commercially available cyclopentaneboronic acid. The product was purified by column chromatography to obtain (27 mg, 41%), MS m/z=506.3 [M+H] + .
实施例6Example 6
Figure PCTCN2020126668-appb-000071
Figure PCTCN2020126668-appb-000071
化合物I-6的合成：Synthesis of compound I-6:
其合成参考实施例4中化合物I-4的合成，仅在第一步中将起始原料环丙烷硼酸替换成商业可得的环己烷硼酸。产物经柱层析纯化得到(19mg，26％)，MS m/z＝520.2[M+H] +。 Its synthesis refers to the synthesis of compound 1-4 in Example 4, only in the first step, the starting material cyclopropaneboronic acid is replaced with commercially available cyclohexaneboronic acid. The product was purified by column chromatography to obtain (19 mg, 26%), MS m/z=520.2 [M+H] + .
实施例7Example 7
Figure PCTCN2020126668-appb-000072
Figure PCTCN2020126668-appb-000072
化合物I-7的合成：Synthesis of compound I-7:
Figure PCTCN2020126668-appb-000073
Figure PCTCN2020126668-appb-000073
化合物6的合成：Synthesis of compound 6:
氮气保护下，将中间体P-3(500mg,1.37mmol)，丙基-1-胺(160mg,2.74mmol)和叔丁醇钠(394.73mg,4.11mmol)加入至无水甲苯中(5mL),搅拌下加入1,1'-联萘-2,2'-双二苯膦(15mg,0.015eq)和三(二亚苄基丙酮)二钯(0)(12.5mg,0.01eq),反应混合物在45℃时搅拌1小时，将反应液冷至室温，加入饱和氯化铵的溶液，并用二氯甲烷萃取，有机相用无水硫酸镁干燥，柱层析纯化得到化合物13(210mg,56％)，MS m/z＝279.6[M+H] +。 Under nitrogen protection, intermediate P-3 (500mg, 1.37mmol), propyl-1-amine (160mg, 2.74mmol) and sodium tert-butoxide (394.73mg, 4.11mmol) were added to dry toluene (5mL) , Under stirring, add 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (15mg, 0.015eq) and tris(dibenzylideneacetone)dipalladium(0)(12.5mg, 0.01eq), react The mixture was stirred at 45°C for 1 hour, the reaction solution was cooled to room temperature, saturated ammonium chloride solution was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate and purified by column chromatography to obtain compound 13 (210mg, 56 %), MS m/z=279.6 [M+H] + .
其它步骤的合成参考本文实施例4化合物I-4的合成，仅在第二步Suzuki中将原料化合物3替换成化合物6与2-氟-5-吡啶硼酸反应即可。产物经柱层析纯化得到(11mg，36％)，MS m/z＝495.2[M+H] +。 For the synthesis of other steps, refer to the synthesis of compound I-4 in Example 4 herein, and only in the second step Suzuki, the raw material compound 3 is replaced with compound 6 and 2-fluoro-5-pyridineboronic acid is reacted. The product was purified by column chromatography to obtain (11 mg, 36%), MS m/z=495.2 [M+H] + .
实施例8Example 8
Figure PCTCN2020126668-appb-000074
Figure PCTCN2020126668-appb-000074
化合物I-8的合成：Synthesis of compound I-8:
其合成参考本文实施例7中化合物I-7的合成，仅将原料丙基-1-胺替换成商业可得的2-((三甲基硅基)氧基)乙烷-1-胺。产物经柱层析纯化得到(17mg，20％)，MS m/z＝497.3[M+H] +。 The synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with commercially available 2-((trimethylsilyl)oxy)ethane-1-amine. The product was purified by column chromatography to obtain (17 mg, 20%), MS m/z=497.3 [M+H] + .
实施例9Example 9
Figure PCTCN2020126668-appb-000075
Figure PCTCN2020126668-appb-000075
化合物I-9的合成：Synthesis of compound I-9:
其合成参考本文实施例7中化合物I-7的合成，仅将原料丙基-1-胺替换成商业可得的1-胺基-2-甲基丙烷-2-醇即可。产物经柱层析纯化得到(24mg，28％)。The synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with commercially available 1-amino-2-methylpropan-2-ol. The product was purified by column chromatography to obtain (24 mg, 28%).
1H NMR(400MHz,CDCl3)δ(ppm):8.335(d,1H),8.524(d,1H)，8.128(s,1H),8.052(d,1H),7.976(d,1H),7.734(m,2H),7.110(d,1H),6.603(m,2H),4.38(s,1H),3.855(s,3H),3.815(s,1H),3.789(s,2H),3.710(s,2H),3.549(br,2H),3.520(br,2H),2.690(m,1H),1.975(m,1H),1.625(d,1H)1.357(s,6H)，MS m/z＝525.4[M+H] +。 1 H NMR (400MHz, CDCl3) δ (ppm): 8.335 (d, 1H), 8.524 (d, 1H), 8.128 (s, 1H), 8.052 (d, 1H), 7.976 (d, 1H), 7.734 ( m, 2H), 7.110 (d, 1H), 6.603 (m, 2H), 4.38 (s, 1H), 3.855 (s, 3H), 3.815 (s, 1H), 3.789 (s, 2H), 3.710 (s ,2H),3.549(br,2H),3.520(br,2H),2.690(m,1H),1.975(m,1H),1.625(d,1H)1.357(s,6H), MS m/z= 525.4[M+H] + .
实施例10Example 10
Figure PCTCN2020126668-appb-000076
Figure PCTCN2020126668-appb-000076
化合物I-10的合成：Synthesis of compound I-10:
其合成参考本文实施例7中化合物I-7的合成，仅将原料丙基-1-胺替换成商业可得的四氢吡咯即可。产物经柱层析纯化得到(23mg，33％)。The synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with commercially available tetrahydropyrrole. The product was purified by column chromatography to obtain (23 mg, 33%).
1H NMR(400MHz,CDCl 3)δ(ppm):8.348(d,1H),8.055(s,2H),7.749(m,3H),6.880(d,1H),6.660(m,2H),3.930(d,2H),3.884(s,3H),3.862(s,1H),3.852(s,1H),3.660(m,4H),3.257(m,4H),2.851(m,1H),2.020(m,4H),1.670(d,1H)，MS m/z＝507.2[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.348 (d, 1H), 8.055 (s, 2H), 7.749 (m, 3H), 6.880 (d, 1H), 6.660 (m, 2H), 3.930 (d, 2H), 3.884 (s, 3H), 3.862 (s, 1H), 3.852 (s, 1H), 3.660 (m, 4H), 3.257 (m, 4H), 2.851 (m, 1H), 2.020 ( m, 4H), 1.670 (d, 1H), MS m/z=507.2 [M+H] + .
实施例11Example 11
Figure PCTCN2020126668-appb-000077
Figure PCTCN2020126668-appb-000077
化合物I-11的合成：Synthesis of compound I-11:
其合成参考实施例7中化合物I-7的合成，仅将原料丙基-1-胺替换成商业可获得的哌啶即可。产物经柱层析纯化得到(24mg，37％)，MS m/z＝521.2[M+H] +。 Its synthesis refers to the synthesis of compound I-7 in Example 7, and only the raw material propyl-1-amine is replaced with commercially available piperidine. The product was purified by column chromatography to obtain (24 mg, 37%), MS m/z=521.2 [M+H] + .
实施例12Example 12
Figure PCTCN2020126668-appb-000078
Figure PCTCN2020126668-appb-000078
化合物I-12的合成：Synthesis of compound I-12:
其合成参考实施例7中化合物I-7的合成，仅将原料丙基-1-胺替换成商业可得的吗啉即可。产物经柱层析纯化得到(18mg，19％)。Its synthesis refers to the synthesis of compound I-7 in Example 7, and only the raw material propyl-1-amine is replaced with commercially available morpholine. The product was purified by column chromatography to obtain (18 mg, 19%).
1H NMR(400MHz,CDCl3)δ(ppm):8.335(d,1H),8.128(s,1H),8.052(d,1H),7.976(d,1H),7.734(m,2H),7.110(d,1H),6.603(m,2H),3.960(m,2H),3.898(s,2H),3.890(m,1H),3.854(s,3H),3.831(m,2H),3.687(br,4H),3.659(s,1H),3.105(m,4H),2.730(s,1H),1.680(d,1H),MS m/z＝523.3[M+H] +。 1 H NMR (400MHz, CDCl3) δ (ppm): 8.335 (d, 1H), 8.128 (s, 1H), 8.052 (d, 1H), 7.976 (d, 1H), 7.734 (m, 2H), 7.110 ( d, 1H), 6.603 (m, 2H), 3.960 (m, 2H), 3.898 (s, 2H), 3.890 (m, 1H), 3.854 (s, 3H), 3.831 (m, 2H), 3.687 (br , 4H), 3.659 (s, 1H), 3.105 (m, 4H), 2.730 (s, 1H), 1.680 (d, 1H), MS m/z=523.3 [M+H] + .
实施例13Example 13
Figure PCTCN2020126668-appb-000079
Figure PCTCN2020126668-appb-000079
化合物I-13的合成：Synthesis of compound I-13:
其合成参考本文实施例7中化合物I-7的合成，仅将原料丙基-1-胺替换成商业上可得的哌嗪即可。产物经柱层析纯化得到(21mg,16％)。The synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with a commercially available piperazine. The product was purified by column chromatography to obtain (21 mg, 16%).
1H NMR(400MHz,CDCl 3)δ(ppm):8.337(d,1H),8.126(s,1H),8.057(d,1H),7.972(d,1H),7.734(m,2H),7.119(d,1H),6.613(m,2H),3.961(m,2H),3.893(s,2H),3.889(m,1H),3.854(s,3H),3.831(m,2H),3.658(s,1H),3.141(m,4H),2.505(m,4H),2.728(s,1H),1.679(d,1H)，MS m/z＝522.3[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.337 (d, 1H), 8.126 (s, 1H), 8.057 (d, 1H), 7.972 (d, 1H), 7.734 (m, 2H), 7.119 (d, 1H), 6.613 (m, 2H), 3.961 (m, 2H), 3.893 (s, 2H), 3.889 (m, 1H), 3.854 (s, 3H), 3.831 (m, 2H), 3.658 ( s, 1H), 3.141 (m, 4H), 2.505 (m, 4H), 2.728 (s, 1H), 1.689 (d, 1H), MS m/z=522.3[M+H] + .
实施例14Example 14
Figure PCTCN2020126668-appb-000080
Figure PCTCN2020126668-appb-000080
化合物I-14的合成：Synthesis of compound I-14:
其合成参考本文实施例7中化合物I-7的合成，仅将原料丙基-1-胺替换成商业上可得的(2S,6R)-2,6-二甲基吗啉即可。产物经柱层析纯化得到(11mg,32％)，MS m/z＝551.3[M+H] +。 The synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with the commercially available (2S,6R)-2,6-dimethylmorpholine. The product was purified by column chromatography to obtain (11 mg, 32%), MS m/z=551.3 [M+H] + .
实施例15Example 15
Figure PCTCN2020126668-appb-000081
Figure PCTCN2020126668-appb-000081
化合物I-15的合成：Synthesis of compound I-15:
其合成参考本文实施例7中化合物I-7的合成，仅将原料丙基-1-胺替换成商业上可得的硫代吗啉即可。产物经柱层析纯化得到(23mg,30％)。The synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with commercially available thiomorpholine. The product was purified by column chromatography to obtain (23mg, 30%).
1H NMR(400MHz,CDCl3)δ(ppm):8.332(d,1H),8.125(s,1H),8.064(d,1H),7.969(d,1H),7.729(m,2H),7.110(d,1H),6.603(m,2H),,3.890(m,1H),3.854(s,3H),3.831(m,2H),3.687(br,4H),3.659(s,1H),3.105(m,4H),2.756(m,4H),2.730(s,1H),1.680(d,1H)，MS m/z＝539.6[M+H] +。 1 H NMR (400MHz, CDCl3) δ (ppm): 8.332 (d, 1H), 8.125 (s, 1H), 8.064 (d, 1H), 7.969 (d, 1H), 7.729 (m, 2H), 7.110 ( d, 1H), 6.603(m, 2H),, 3.890(m, 1H), 3.854(s, 3H), 3.831(m, 2H), 3.687(br, 4H), 3.659(s, 1H), 3.105( m, 4H), 2.756 (m, 4H), 2.730 (s, 1H), 1.680 (d, 1H), MS m/z=539.6 [M+H] + .
实施例16Example 16
Figure PCTCN2020126668-appb-000082
Figure PCTCN2020126668-appb-000082
化合物I-16的合成：Synthesis of compound I-16:
其合成参考本文实施例7中I-7的合成，仅将原料丙基-1-胺替换商业上可得的2-氧杂-6-氮杂-螺[3,3]庚烷即可。产物经柱层析纯化得到(10mg,35％)。The synthesis refers to the synthesis of I-7 in Example 7 herein, and only the raw material propyl-1-amine is substituted for the commercially available 2-oxa-6-aza-spiro[3,3]heptane. The product was purified by column chromatography to obtain (10 mg, 35%).
1H NMR(400MHz,CDCl3)δ(ppm):8.335(d,1H),8.128(s,1H),8.052(d,1H),7.976(d,1H),7.734(m,2H),7.110(d,1H),6.603(m,2H),4.582(s,4H),3.890(m, 1H),3.854(s,3H),3.831(m,2H),3.621(s,4H),3.659(s,1H),3.105(m,4H),2.730(s,1H),1.680(d,1H)，MS m/z＝535.6[M+H] +。 1H NMR (400MHz, CDCl3) δ (ppm): 8.335 (d, 1H), 8.128 (s, 1H), 8.052 (d, 1H), 7.976 (d, 1H), 7.734 (m, 2H), 7.110 (d ,1H),6.603(m,2H),4.582(s,4H),3.890(m,1H),3.854(s,3H),3.831(m,2H),3.621(s,4H),3.659(s, 1H), 3.105 (m, 4H), 2.730 (s, 1H), 1.680 (d, 1H), MS m/z=535.6[M+H] + .
实施例17Example 17
Figure PCTCN2020126668-appb-000083
Figure PCTCN2020126668-appb-000083
化合物I-17的合成：Synthesis of compound I-17:
其合成参考本文实施例7中I-7的合成，仅将原料丙基-1-胺替换成商业上可得的氮杂环丁烷-3-醇即可。产物经柱层析纯化得到(21mg,29％)。The synthesis refers to the synthesis of I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with commercially available azetidine-3-ol. The product was purified by column chromatography to obtain (21 mg, 29%).
1H NMR(400MHz,CDCl 3)δ(ppm):8.290(d,1H),8.055(s,1H),8.025(d,1H),7.715(dd,1H),7.618(d,1H),7.596(d,1H),6.650(m,3H),4.764(t,1H),4.136(d,2H),3.839(s,3H),3.796(s,1H),3.760(s,2H),3.744(s,1H),3.680(m,2H),3.568(s,1H),3.538(s,3H),3.205(m,1H),2.670(d,1H),1.610(d,1H)，MS m/z＝509.3[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.290 (d, 1H), 8.055 (s, 1H), 8.025 (d, 1H), 7.715 (dd, 1H), 7.618 (d, 1H), 7.596 (d, 1H), 6.650 (m, 3H), 4.764 (t, 1H), 4.136 (d, 2H), 3.839 (s, 3H), 3.796 (s, 1H), 3.760 (s, 2H), 3.744 ( s,1H), 3.680 (m, 2H), 3.568 (s, 1H), 3.538 (s, 3H), 3.205 (m, 1H), 2.670 (d, 1H), 1.610 (d, 1H), MS m/ z=509.3 [M+H] + .
实施例18Example 18
Figure PCTCN2020126668-appb-000084
Figure PCTCN2020126668-appb-000084
化合物I-18的合成：Synthesis of compound I-18:
其合成参考本文实施例7中I-7的合成，仅将原料丙基-1-胺替换成商业可得的(R)-3-吡咯烷醇即可。产物经柱层析纯化得到(15mg,36％)。The synthesis refers to the synthesis of I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with commercially available (R)-3-pyrrolidinol. The product was purified by column chromatography to obtain (15 mg, 36%).
1H NMR(400MHz,CDCl 3)δ(ppm):8.326(d,1H),8.064(s,1H),8.034(d,1H),7.740(m,2H),7.580(m,1H),6.862(d,1H),6.637(t,2H),4.619(br,1H),3.850(s,3H),3.780(br,2H),3.730(br,2H),3.520(m,1H),3.513(s,2H),3.480(m,2H),3.325(s,1H),3.245(d,1H),2.650(m,1H),2.105(m,1H),1.975(m,1H),1.590(d,1H),1.227(m,2H)，MS m/z＝523.3[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.326 (d, 1H), 8.064 (s, 1H), 8.034 (d, 1H), 7.740 (m, 2H), 7.580 (m, 1H), 6.862 (d, 1H), 6.637 (t, 2H), 4.619 (br, 1H), 3.850 (s, 3H), 3.780 (br, 2H), 3.730 (br, 2H), 3.520 (m, 1H), 3.513 ( s, 2H), 3.480 (m, 2H), 3.325 (s, 1H), 3.245 (d, 1H), 2.650 (m, 1H), 2.105 (m, 1H), 1.975 (m, 1H), 1.590 (d , 1H), 1.227 (m, 2H), MS m/z=523.3 [M+H] + .
实施例19Example 19
Figure PCTCN2020126668-appb-000085
Figure PCTCN2020126668-appb-000085
化合物I-19的合成：Synthesis of compound I-19:
其合成参考本文实施例7中I-7的合成，仅将原料丙基-1-胺替换成商业可得的(S)-3-吡咯烷醇即可。产物经柱层析纯化得到(17mg,40％)。The synthesis refers to the synthesis of I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with commercially available (S)-3-pyrrolidinol. The product was purified by column chromatography to obtain (17mg, 40%).
1H NMR(400MHz,CDCl 3)δ(ppm):8.325(d,1H),8.062(s,1H),8.034(d,1H),7.745(d,1H),7.720(d,1H),7.590(m,1H),6.860(d,1H),6.638(t,2H),4.618(s,1H),3.849(s,3H),3.780(br,2H),3.740(br,2H),3.570(m,1H),3.551(s,2H),3.502(m,2H),3.320(m,1H),3.240(d,1H),2.651(m,1H),2.167(m,1H),2.088(m,1H),1.600(d,1H),1.229(m,2H)，MS m/z＝523.3[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.325 (d, 1H), 8.062 (s, 1H), 8.034 (d, 1H), 7.745 (d, 1H), 7.720 (d, 1H), 7.590 (m, 1H), 6.860(d, 1H), 6.638(t, 2H), 4.618(s, 1H), 3.849(s, 3H), 3.780(br, 2H), 3.740(br, 2H), 3.570( m, 1H), 3.551 (s, 2H), 3.502 (m, 2H), 3.320 (m, 1H), 3.240 (d, 1H), 2.651 (m, 1H), 2.167 (m, 1H), 2.088 (m , 1H), 1.600 (d, 1H), 1.229 (m, 2H), MS m/z=523.3 [M+H] + .
实施例20Example 20
Figure PCTCN2020126668-appb-000086
Figure PCTCN2020126668-appb-000086
化合物I-20的合成：Synthesis of compound I-20:
其合成参考本文实施例7中I-7的合成，仅将原料丙基-1-胺替换成商业可得的4-羟基哌啶即可。产物经柱层析纯化得到(27mg,34％)。The synthesis refers to the synthesis of I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with commercially available 4-hydroxypiperidine. The product was purified by column chromatography to obtain (27mg, 34%).
1H NMR(400MHz,CDCl 3)δ(ppm):8.318(d,1H),8.104(s,1H),8.032(d,1H),7.960(d,1H),7.710(dd,1H),7.615(dd,1H),7.122(d,1H),6.630(m,2H),3.885(m,1H),3.845(s,3H),3.802(s,1H),3.767(s,2H),3.751(s,1H),3.572(s,1H),3.543(s,2H),3.143(m,2H),2.920(m,2H),2.678(m,1H),1.993(m,2H),1.711(m,2H),1.615(d,1H),1.211(m,2H)，MS m/z＝537.2[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.318 (d, 1H), 8.104 (s, 1H), 8.033 (d, 1H), 7.960 (d, 1H), 7.710 (dd, 1H), 7.615 (dd, 1H), 7.122 (d, 1H), 6.630 (m, 2H), 3.885 (m, 1H), 3.845 (s, 3H), 3.802 (s, 1H), 3.767 (s, 2H), 3.751 ( s, 1H), 3.572 (s, 1H), 3.543 (s, 2H), 3.143 (m, 2H), 2.920 (m, 2H), 2.678 (m, 1H), 1.993 (m, 2H), 1.711 (m , 2H), 1.615 (d, 1H), 1.211 (m, 2H), MS m/z=537.2 [M+H] + .
实施例21Example 21
Figure PCTCN2020126668-appb-000087
Figure PCTCN2020126668-appb-000087
化合物I-21的合成：Synthesis of compound I-21:
其合成参考本文实施例7中I-7的合成，仅将原料中间体P-3替换成中间体P-9即可。产物经柱层析纯化得到(19mg,27％)。For its synthesis, refer to the synthesis of I-7 in Example 7 herein, and only the raw material intermediate P-3 is replaced with intermediate P-9. The product was purified by column chromatography to obtain (19mg, 27%).
1H NMR(400MHz,CDCl 3)δ(ppm):9.413(s,1H),8.671(s,1H),7.976(d,1H),7.641(m,2H),7.121(d,1H),6.613(m,2H),3.960(m,2H),3.898(s,2H),3.890(m, 1H),3.854(s,3H),3.831(m,2H),3.687(br,4H),3.659(s,1H),3.105(m,4H),2.730(s,1H),1.680(d,1H)，MS m/z＝524.2[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 9.413 (s, 1H), 8.671 (s, 1H), 7.976 (d, 1H), 7.641 (m, 2H), 7.121 (d, 1H), 6.613 (m, 2H), 3.960 (m, 2H), 3.898 (s, 2H), 3.890 (m, 1H), 3.854 (s, 3H), 3.831 (m, 2H), 3.687 (br, 4H), 3.659 ( s, 1H), 3.105 (m, 4H), 2.730 (s, 1H), 1.680 (d, 1H), MS m/z=524.2 [M+H] + .
实施例22Example 22
Figure PCTCN2020126668-appb-000088
Figure PCTCN2020126668-appb-000088
化合物I-22的合成：Synthesis of compound I-22:
其合成参考实施例21中的化合物I-21的合成，仅将原料吗啉替换成商业可得的氮杂环丁烷-3-醇即可。产物经柱层析纯化得到(25mg,39％)，MS m/z＝510.3[M+H] +。 Its synthesis refers to the synthesis of compound I-21 in Example 21, and only the raw material morpholine is replaced with commercially available azetidine-3-ol. The product was purified by column chromatography to obtain (25mg, 39%), MS m/z=510.3[M+H] + .
实施例23Example 23
Figure PCTCN2020126668-appb-000089
Figure PCTCN2020126668-appb-000089
化合物I-23的合成：Synthesis of compound I-23:
其合成参考实施例21中的化合物I-21的合成，仅将原料吗啉替换成商业可得的四氢吡咯即可。产物经柱层析纯化得到(14mg,19％)，MS m/z＝508.2[M+H] +。 Its synthesis refers to the synthesis of compound I-21 in Example 21, and only the raw material morpholine is replaced with commercially available tetrahydropyrrole. The product was purified by column chromatography to obtain (14 mg, 19%), MS m/z=508.2 [M+H] + .
实施例24Example 24
Figure PCTCN2020126668-appb-000090
Figure PCTCN2020126668-appb-000090
化合物I-24的合成：Synthesis of compound I-24:
其合成参考实施例4中的化合物I-4合成，仅将第二步Suzuki反应中的原料化合物6替换成中间体P-10，再与2-氟-5-吡啶硼酸反应即可。产物经柱层析纯化得到(36mg,59％)。Its synthesis refers to the synthesis of compound 1-4 in Example 4, only the raw material compound 6 in the second step of the Suzuki reaction is replaced with intermediate P-10, and then it is reacted with 2-fluoro-5-pyridineboronic acid. The product was purified by column chromatography to obtain (36 mg, 59%).
1H NMR(400MHz,CDCl 3)δ(ppm):8.750(d,1H),8.554(d,1H),8.290(t,1H),7.737(s,1H),7.631(s 2H),7.476(s,1H),7.350(s,1H),6.615(d,1H),3.867(br,2H),3.854(s,3H),3.830(br,2H),3.601(br,2H),3.586(m,2H),2.751(br,1H),1.620(d,1H)，MS m/z＝492.1[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.750 (d, 1H), 8.554 (d, 1H), 8.290 (t, 1H), 7.737 (s, 1H), 7.631 (s 2H), 7.476 ( s, 1H), 7.350 (s, 1H), 6.615 (d, 1H), 3.867 (br, 2H), 3.854 (s, 3H), 3.830 (br, 2H), 3.601 (br, 2H), 3.586 (m , 2H), 2.751 (br, 1H), 1.620 (d, 1H), MS m/z=492.1 [M+H] + .
实施例25Example 25
Figure PCTCN2020126668-appb-000091
Figure PCTCN2020126668-appb-000091
化合物I-25的合成：Synthesis of compound I-25:
其合成是由实施例24中的化合物I-24和商业可获得的化合物(1-甲基-1H-吡唑-4-基)硼酸发生的经典Suzuki反应，其反应条件可参考实施例4中的化合物3合成条件。产物经柱层析纯化得到(61mg,73％)。The synthesis is the classical Suzuki reaction between the compound I-24 in Example 24 and the commercially available compound (1-methyl-1H-pyrazol-4-yl)boronic acid, and the reaction conditions can be referred to in Example 4. Synthetic conditions of compound 3. The product was purified by column chromatography to obtain (61 mg, 73%).
1H NMR(400MHz,CDCl 3)δ(ppm):8.780(d,1H),8.578(d,1H),8.330(dd,1H),8.301(s,1H),8.030(d,1H),7.750(s,1H),7.697(br,1H),7.646(t,2H),6.670(m, 2H),3.944(s,3H),3.881(s,2H),3.855(s,3H),3.854(s,1H),3.656(br,1H),3.613(br,3H),3.514(br,1H),2.815(m,1H),1.650(d,1H)，MS m/z＝494.3[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.780 (d, 1H), 8.578 (d, 1H), 8.330 (dd, 1H), 8.301 (s, 1H), 8.030 (d, 1H), 7.750 (s, 1H), 7.697 (br, 1H), 7.646 (t, 2H), 6.670 (m, 2H), 3.944 (s, 3H), 3.881 (s, 2H), 3.855 (s, 3H), 3.854 ( s,1H),3.656(br,1H),3.613(br,3H),3.514(br,1H),2.815(m,1H),1.650(d,1H), MS m/z=494.3[M+H ] + .
实施例26Example 26
Figure PCTCN2020126668-appb-000092
Figure PCTCN2020126668-appb-000092
化合物I-26的合成：Synthesis of compound I-26:
其合成是由实施例24中的化合物I-24和商业可获得的化合物吗啉发生的经典Buchwald反应，其反应条件可参考实施例7中的化合物6合成条件。产物经柱层析纯化得到(13mg,19％)。The synthesis is the classic Buchwald reaction between compound I-24 in Example 24 and the commercially available compound morpholine, and the reaction conditions can refer to the synthesis conditions of Compound 6 in Example 7. The product was purified by column chromatography to obtain (13 mg, 19%).
1H NMR(400MHz,CDCl 3)δ(ppm):8.705(d,1H),8.250(dd,1H),8.216(s,1H),8.010(d,1H),7.954(d,1H),7.555(m 1H),7.380(d,1H),6.640(m,2H),3.867(br,2H),3.855(m,2H),3.845(s,3H),3.793(br,1H),3.763(br,1H),3.720(d,2H),3.530(m,4H),3.137(s,1H),3.100(t,3H),2.640(d,1H),1.570(d,1H)，MS m/z＝499.3[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.705 (d, 1H), 8.250 (dd, 1H), 8.216 (s, 1H), 8.010 (d, 1H), 7.954 (d, 1H), 7.555 (m 1H), 7.380(d, 1H), 6.640(m, 2H), 3.867(br, 2H), 3.855(m, 2H), 3.845(s, 3H), 3.793(br, 1H), 3.763(br ,1H),3.720(d,2H),3.530(m,4H),3.137(s,1H),3.100(t,3H),2.640(d,1H),1.570(d,1H), MS m/z = 499.3 [M+H] + .
实施例27Example 27
Figure PCTCN2020126668-appb-000093
Figure PCTCN2020126668-appb-000093
化合物I-27的合成：Synthesis of compound I-27:
其合成参考本文实施例4中的化合物I-4的合成，仅在第二步中将化合物3替换成中间体P-6即可。产物经柱层析纯化得到(25mg,32％)，MS m/z＝468.2[M+H] +。 For its synthesis, refer to the synthesis of compound 1-4 in Example 4 herein, and only replace compound 3 with intermediate P-6 in the second step. The product was purified by column chromatography to obtain (25mg, 32%), MS m/z=468.2[M+H] + .
实施例28Example 28
Figure PCTCN2020126668-appb-000094
Figure PCTCN2020126668-appb-000094
化合物I-7的合成：Synthesis of compound I-7:
其合成参考本文实施例27中化合物I-27的合成，仅将中间体P-6替换成中间体P-7即可，产物经柱层析纯化得到(14mg,27％)，MS m/z＝526.2[M+H] +。 For its synthesis, refer to the synthesis of compound I-27 in Example 27 herein, just replace Intermediate P-6 with Intermediate P-7. The product is purified by column chromatography to obtain (14mg, 27%), MS m/z =526.2[M+H] + .
实施例29Example 29
Figure PCTCN2020126668-appb-000095
Figure PCTCN2020126668-appb-000095
化合物I-29的合成：Synthesis of compound I-29:
其合成参考本文实施例26中化合物I-26的合成，仅将原料中间体P-10替换成中间体P-11即可。产物经柱层析纯化得到(37mg,38％)，MS m/z＝499.2[M+H] +。 The synthesis refers to the synthesis of compound I-26 in Example 26 herein, and only the raw material intermediate P-10 is replaced with intermediate P-11. The product was purified by column chromatography to obtain (37 mg, 38%), MS m/z=499.2 [M+H] + .
实施例30Example 30
Figure PCTCN2020126668-appb-000096
Figure PCTCN2020126668-appb-000096
化合物I-30的合成：Synthesis of compound I-30:
其合成参考本文实施例7中化合物I-7合成，仅将起始原料化合物丙胺替换成商业可得的二乙胺即可。产物经柱层析纯化得到(23mg,41％)，MS m/z＝509.3[M+H] +。 Its synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the starting material compound propylamine is replaced with commercially available diethylamine. The product was purified by column chromatography to obtain (23 mg, 41%), MS m/z=509.3 [M+H] + .
实施例31Example 31
Figure PCTCN2020126668-appb-000097
Figure PCTCN2020126668-appb-000097
化合物I-31的合成：Synthesis of compound I-31:
化合物7的合成：Synthesis of compound 7:
Figure PCTCN2020126668-appb-000098
Figure PCTCN2020126668-appb-000098
氮气保护下，将中间体P-3(3.88g,10.5mmol),双三苯基磷二氯化钯(0.18g,2.5mol％)和碘化亚铜(0.050g,2.5mol％)加入至四氢呋喃中，搅拌下加入三乙胺(17mL)使温度不超过30℃，然后加入三甲基乙炔基硅(1.7mL,11.6mmol)，在室温下搅拌3小时，反应完成后，在反应中加入水和二氯甲烷，分出有机相，干燥，浓缩，得到的粗产物经柱层析纯化得到(492mg,15％)。MS m/z＝318.5[M+H] +。 Under nitrogen protection, intermediate P-3 (3.88g, 10.5mmol), bistriphenylphosphonium dichloride (0.18g, 2.5mol%) and cuprous iodide (0.050g, 2.5mol%) were added to In tetrahydrofuran, add triethylamine (17mL) under stirring so that the temperature does not exceed 30℃, then add trimethylethynyl silicon (1.7mL, 11.6mmol), stir at room temperature for 3 hours, after the reaction is complete, add to the reaction The organic phase was separated with water and dichloromethane, dried and concentrated, and the crude product obtained was purified by column chromatography (492 mg, 15%). MS m/z = 318.5 [M+H] + .
其它步骤的合成参考本文实施例4中化合物I-4的合成，仅在第二步Suzuki反应中将原料化合物3替换成化合物7与2-氟-5-吡啶硼酸即可。产物经柱层析纯化得到(12mg,21％)。For the synthesis of other steps, refer to the synthesis of compound 1-4 in Example 4 herein, and only in the second step of Suzuki reaction, the starting material compound 3 is replaced with compound 7 and 2-fluoro-5-pyridineboronic acid. The product was purified by column chromatography to obtain (12mg, 21%).
1H NMR(400MHz,CDCl 3)δ(ppm):8.314(d,1H),8.151(t,1H),8.025(d,1H),7.768(m 1H),7.717(d,1H),7.641(s,1H),7.398(d,1H),6.645(m,2H),4.131(s,1H),3.862(br,2H),3.854(s,3H),3.830(br,2H),3.611(br,2H),3.584(m,2H),2.748(br,1H),1.623(d,1H)，MS m/z＝462.2[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.314 (d, 1H), 8.151 (t, 1H), 8.025 (d, 1H), 7.768 (m 1H), 7.717 (d, 1H), 7.641 ( s, 1H), 7.398 (d, 1H), 6.645 (m, 2H), 4.131 (s, 1H), 3.862 (br, 2H), 3.854 (s, 3H), 3.830 (br, 2H), 3.611 (br , 2H), 3.584 (m, 2H), 2.748 (br, 1H), 1.623 (d, 1H), MS m/z=462.2 [M+H] + .
实施例32Example 32
Figure PCTCN2020126668-appb-000099
Figure PCTCN2020126668-appb-000099
化合物I-32的合成：Synthesis of compound I-32:
其合成参考本文实施例31中化合物I-31的合成，仅将起始原料三甲基乙炔基硅替换成商业上可得的[(1,1-二甲基-2-丙炔基)氧基]三甲基硅烷即可。产物经柱层析纯化得到(13mg,17％)，MS m/z＝492.2[M+H] +。 Its synthesis refers to the synthesis of compound I-31 in Example 31 herein, and only the starting material trimethylethynyl silicon is replaced with commercially available [(1,1-dimethyl-2-propynyl)oxy Group] trimethylsilane is sufficient. The product was purified by column chromatography to obtain (13 mg, 17%), MS m/z=492.2 [M+H] + .
实施例33Example 33
Figure PCTCN2020126668-appb-000100
Figure PCTCN2020126668-appb-000100
化合物I-33的合成：Synthesis of compound I-33:
其合成参考本文实施例31中化合物I-31的合成，仅将起始原料三甲基乙炔基硅替换成商业上可得的2-甲基-2-((三甲基硅)氧)丙烷-1-胺即可。产物经柱层析纯化得到(22mg,28％)，MS m/z＝520.2[M+H] +。 Its synthesis refers to the synthesis of compound I-31 in Example 31 herein, and only the starting material trimethylethynyl silicon is replaced with commercially available 2-methyl-2-((trimethylsilyl)oxy)propane Just -1-amine. The product was purified by column chromatography to obtain (22 mg, 28%), MS m/z=520.2 [M+H] + .
实施例34Example 34
Figure PCTCN2020126668-appb-000101
Figure PCTCN2020126668-appb-000101
化合物I-34的合成：Synthesis of compound I-34:
其合成参考本文实施例21中的化合物I-21的合成，仅将原料从中间体P-3替换成P-12即可。产物经柱层析纯化得到(17mg,35％)，MS m/z＝498.3[M+H] +。 The synthesis refers to the synthesis of compound I-21 in Example 21 herein, and only the raw material is replaced from intermediate P-3 to P-12. The product was purified by column chromatography to obtain (17mg, 35%), MS m/z=498.3[M+H] + .
实施例35Example 35
Figure PCTCN2020126668-appb-000102
Figure PCTCN2020126668-appb-000102
化合物I-35的合成：Synthesis of compound I-35:
其合成参考本文实施例4中化合物I-4的合成(仅在第二步Suzuki反应中将化合物3替换成中间体P-2)，得到的产物经三氟甲磺酰化(参考P-3的合成)、叠氮化和桑德迈尔反应而制备。产物经柱层析纯化得到(36mg,75％)。For its synthesis, refer to the synthesis of compound 1-4 in Example 4 (only in the second step of Suzuki reaction, compound 3 is replaced with intermediate P-2), and the obtained product is trifluoromethanesulfonated (refer to P-3 Synthesis), azide and Sandmeier reaction. The product was purified by column chromatography to obtain (36mg, 75%).
1H NMR(400MHz,CDCl 3)δ(ppm):8.640(d,1H),8.347(d,1H),8.204(s,1H),8.060(d,1H),7.720(m,2H),7.345(d,1H),6.660(m,2H),3.990(d,2H),3.948(s,1H),3.928(m,1H),3.918(s,3H),3.730(br,4H),2.953(m,1H),1.730(d,1H)，MS m/z＝516.2[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.640 (d, 1H), 8.347 (d, 1H), 8.204 (s, 1H), 8.060 (d, 1H), 7.720 (m, 2H), 7.345 (d, 1H), 6.660 (m, 2H), 3.990 (d, 2H), 3.948 (s, 1H), 3.928 (m, 1H), 3.918 (s, 3H), 3.730 (br, 4H), 2.953 ( m, 1H), 1.730 (d, 1H), MS m/z=516.2 [M+H] + .
实施例36Example 36
Figure PCTCN2020126668-appb-000103
Figure PCTCN2020126668-appb-000103
化合物I-36的合成：Synthesis of compound I-36:
其合成是以实施例32中的化合物I-32经过炔基的还原反应而制备。产物经柱层析纯化得到(9mg,40％)，MS m/z＝496.2[M+H] +。 The synthesis is prepared by reducing the alkynyl group of compound 1-32 in Example 32. The product was purified by column chromatography to obtain (9 mg, 40%), MS m/z=496.2 [M+H] + .
实施例37Example 37
Figure PCTCN2020126668-appb-000104
Figure PCTCN2020126668-appb-000104
化合物I-37的合成：Synthesis of compound I-37:
其合成是以实施例33中的化合物I-33经过炔基的还原反应而制备。产物经柱层析纯化得到(15mg,37％)，MS m/z＝524.3[M+H] +。 The synthesis is prepared by reducing the alkynyl group of compound 1-33 in Example 33. The product was purified by column chromatography to obtain (15mg, 37%), MS m/z=524.3[M+H] + .
实施例38Example 38
Figure PCTCN2020126668-appb-000105
Figure PCTCN2020126668-appb-000105
化合物I-38的合成：Synthesis of compound I-38:
其合成是以实施例35中的化合物I-35与商业上可获得的三丁基乙烯基锡发生经典的Still偶连而制备，可参考文献：Tetrahedron 74(21):2574-2560,2018。产物经柱层析纯化得到(11mg,19％)，MS m/z＝464.2[M+H] +。 The synthesis is prepared by classic Still coupling between compound I-35 in Example 35 and commercially available tributylvinyltin, which can be referred to: Tetrahedron 74(21):2574-2560, 2018. The product was purified by column chromatography to obtain (11 mg, 19%), MS m/z=464.2 [M+H] + .
实施例39Example 39
Figure PCTCN2020126668-appb-000106
Figure PCTCN2020126668-appb-000106
化合物I-39的合成：Synthesis of compound I-39:
其合成参考本文实施例7中化合物I-7合成，仅将起始原料化合物丙胺替换成商业可得的二乙胺即可。产物经柱层析纯化得到(20mg,43％)。Its synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the starting material compound propylamine is replaced with commercially available diethylamine. The product was purified by column chromatography to obtain (20mg, 43%).
1H NMR(400MHz,CDCl 3)δ(ppm):8.642(d,1H),8.420(s,1H),8.346(d,1H),8.212(s,1H),8.058(d,1H),7.720(m,2H),7.345(d,1H),6.660(m,2H),3.990(d,2H),3.948(s,1H),3.928(m,1H),3.925(s,3H),3.918(s,3H),3.845(t,2H),3.730(br,4H),3.361(t,2H),2.953(m,1H),1.730(d,1H)，MS m/z＝511.3[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.642 (d, 1H), 8.420 (s, 1H), 8.346 (d, 1H), 8.212 (s, 1H), 8.058 (d, 1H), 7.720 (m, 2H), 7.345 (d, 1H), 6.660 (m, 2H), 3.990 (d, 2H), 3.948 (s, 1H), 3.928 (m, 1H), 3.925 (s, 3H), 3.918 ( s,3H),3.845(t,2H),3.730(br,4H),3.361(t,2H),2.953(m,1H),1.730(d,1H), MS m/z=511.3[M+H ] + .
实施例40Example 40
Figure PCTCN2020126668-appb-000107
Figure PCTCN2020126668-appb-000107
化合物I-40的合成：Synthesis of compound I-40:
其合成参考本文实施例12中化合物I-12合成，仅将起始原料化合物6-甲氧基-3-吡啶甲醛替换成商业可得的6-氯烟醛即可。产物经柱层析纯化得到(17mg,23％)，MS m/z＝527.3[M+H] +。 Its synthesis refers to the synthesis of compound I-12 in Example 12 herein, and only the starting material compound 6-methoxy-3-pyridinecarbaldehyde is replaced with commercially available 6-chloronicotinaldehyde. The product was purified by column chromatography to obtain (17 mg, 23%), MS m/z=527.3 [M+H] + .
实施例41Example 41
Figure PCTCN2020126668-appb-000108
Figure PCTCN2020126668-appb-000108
化合物I-41的合成：Synthesis of compound I-41:
其合成参考本文实施例12中化合物I-12合成，仅将起始原料化合物6-甲氧基-3-吡啶甲醛替换成商业可得的6-三氟甲基吡啶-3-醛即可。产物经柱层析纯化得到(11mg,12％)，MS m/z＝561.4[M+H] +。 Its synthesis refers to the synthesis of compound I-12 in Example 12 herein, and only the starting material compound 6-methoxy-3-pyridinecarboxaldehyde is replaced with commercially available 6-trifluoromethylpyridine-3-aldehyde. The product was purified by column chromatography to obtain (11 mg, 12%), MS m/z=561.4 [M+H] + .
实施例42Example 42
Figure PCTCN2020126668-appb-000109
Figure PCTCN2020126668-appb-000109
化合物I-42的合成：Synthesis of compound I-42:
其合成参考本文实施例12中化合物I-12合成，仅将起始原料化合物6-甲氧基-3-吡啶甲醛替换成商业可得的3-醛基-6-甲基吡啶即可。产物经柱层析纯化得到(23mg,36％)，MS m/z＝507.3[M+H] +。 Its synthesis refers to the synthesis of compound I-12 in Example 12 herein, and only the starting material compound 6-methoxy-3-pyridinecarboxaldehyde is replaced with commercially available 3-aldehyde-6-methylpyridine. The product was purified by column chromatography to obtain (23 mg, 36%), MS m/z=507.3 [M+H] + .
实施例43Example 43
Figure PCTCN2020126668-appb-000110
Figure PCTCN2020126668-appb-000110
化合物I-43的合成：Synthesis of compound I-43:
其合成参考本文实施例12中化合物I-12合成，仅将起始原料化合物6-甲氧基-3-吡啶甲醛替换成商业可得的5-甲酰基吡啶-2-甲腈即可。产物经柱层析纯化得到(12mg,26％)，MS m/z＝518.2[M+H] +。 Its synthesis refers to the synthesis of compound I-12 in Example 12 herein, and only the starting material compound 6-methoxy-3-pyridinecarboxaldehyde is replaced with commercially available 5-formylpyridine-2-carbonitrile. The product was purified by column chromatography to obtain (12 mg, 26%), MS m/z=518.2 [M+H] + .
实施例44Example 44
Figure PCTCN2020126668-appb-000111
Figure PCTCN2020126668-appb-000111
化合物I-44的合成：Synthesis of compound I-44:
其合成参考本文实施例7中化合物I-7合成，仅将起始原料化合物6-甲氧基-3-吡啶甲醛替换成商业可得的对氟甲苯即可。产物经柱层析纯化得到(20mg,43％)，MS m/z＝492.3[M+H] +。 The synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the starting material compound 6-methoxy-3-pyridinecarboxaldehyde is replaced with commercially available p-fluorotoluene. The product was purified by column chromatography to obtain (20mg, 43%), MS m/z=492.3[M+H] + .
实施例45Example 45
Figure PCTCN2020126668-appb-000112
Figure PCTCN2020126668-appb-000112
化合物I-45的合成：Synthesis of compound I-45:
其合成参考本文实施例12中化合物I-12合成，仅将起始原料化合物6-甲氧基-3-吡啶甲醛替换成商业可得的对甲基苯甲醛即可。产物经柱层析纯化得到(41mg,59％)，MS m/z＝490.4[M+H] +。 Its synthesis refers to the synthesis of compound I-12 in Example 12 herein, and only the starting material compound 6-methoxy-3-pyridinecarboxaldehyde is replaced with commercially available p-methylbenzaldehyde. The product was purified by column chromatography to obtain (41 mg, 59%), MS m/z=490.4 [M+H] + .
实施例46Example 46
Figure PCTCN2020126668-appb-000113
Figure PCTCN2020126668-appb-000113
化合物I-46的合成：Synthesis of compound I-46:
其合成参考本文实施例12中化合物I-12合成，仅将起始原料化合物6-甲氧基-3-吡啶甲醛替换成商业可得的1,3-二甲基-1H-吡唑-5-甲醛即可。产物经柱层析纯化得到(17mg,8％)，MS m/z＝510.3[M+H] +。 Its synthesis refers to the synthesis of compound I-12 in Example 12 herein, and only the starting material compound 6-methoxy-3-pyridinecarboxaldehyde is replaced with commercially available 1,3-dimethyl-1H-pyrazole-5 -Formaldehyde is fine. The product was purified by column chromatography to obtain (17mg, 8%), MS m/z=510.3[M+H] + .
实施例47Example 47
Figure PCTCN2020126668-appb-000114
Figure PCTCN2020126668-appb-000114
化合物I-47的合成：Synthesis of compound I-47:
其合成参考本文实施例12中化合物I-12合成，仅将起始原料化合物6-甲氧基-3-吡啶甲醛替换成商业可得的5-噻唑甲醛即可。产物经柱层析纯化得到(11mg,19％)，MS m/z＝499.3[M+H] +。 The synthesis refers to the synthesis of compound I-12 in Example 12 herein, and only the starting material compound 6-methoxy-3-pyridinecarbaldehyde is replaced with commercially available 5-thiazole carbaldehyde. The product was purified by column chromatography to obtain (11 mg, 19%), MS m/z=499.3 [M+H] + .
实施例48Example 48
Figure PCTCN2020126668-appb-000115
Figure PCTCN2020126668-appb-000115
化合物I-48的合成：Synthesis of compound I-48:
其合成参考本文实施例12中化合物I-12合成，仅将起始原料化合物6-甲氧基-3-吡啶甲醛替换成商业可得的1-甲基-1氢-5-醛基-咪唑即可。产物经柱层析纯化得到(21mg,33％)，MS m/z＝496.3[M+H] +。 Its synthesis refers to the synthesis of compound I-12 in Example 12 herein, and only the starting material compound 6-methoxy-3-pyridinecarboxaldehyde is replaced with commercially available 1-methyl-1-hydro-5-aldehyde-imidazole That's it. The product was purified by column chromatography to obtain (21 mg, 33%), MS m/z=496.3 [M+H] + .
实施例49Example 49
Figure PCTCN2020126668-appb-000116
Figure PCTCN2020126668-appb-000116
化合物I-49的合成：Synthesis of compound I-49:
其合成参考本文实施例12中化合物I-12合成，仅将起始原料化合物6-甲氧基-3-吡啶甲醛替换成商业可得的2-甲氧基-5-醛基嘧啶即可。产物经柱层析纯化得到(33mg,41％)，MS m/z＝524.2[M+H] +。 Its synthesis refers to the synthesis of compound I-12 in Example 12 herein, and only the starting material compound 6-methoxy-3-pyridinecarboxaldehyde is replaced with commercially available 2-methoxy-5-aldehyde pyrimidine. The product was purified by column chromatography to obtain (33 mg, 41%), MS m/z=524.2 [M+H] + .
实施例50Example 50
Figure PCTCN2020126668-appb-000117
Figure PCTCN2020126668-appb-000117
化合物I-50的合成：Synthesis of compound I-50:
其合成参考本文实施例12中化合物I-12合成，仅将起始原料化合物6-甲氧基-3-吡啶甲醛替换成商业可得的2-甲氧基-5-甲酰基吡嗪即可。产物经柱层析纯化得到(29mg,38％)，MS m/z＝524.3[M+H] +。 Its synthesis refers to the synthesis of compound I-12 in Example 12 herein, and only the starting material compound 6-methoxy-3-pyridinecarboxaldehyde is replaced with commercially available 2-methoxy-5-formylpyrazine. . The product was purified by column chromatography to obtain (29 mg, 38%), MS m/z=524.3 [M+H] + .
实施例51Example 51
Figure PCTCN2020126668-appb-000118
Figure PCTCN2020126668-appb-000118
化合物I-51的合成：Synthesis of compound I-51:
其合成参考本文实施例7中化合物I-7合成，仅将起始原料化合物丙胺替换成商业可得的3-氮杂双环[3.1.0]己烷即可。产物经柱层析纯化得到(31mg,49％)。The synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the starting material compound propylamine is replaced with commercially available 3-azabicyclo[3.1.0]hexane. The product was purified by column chromatography to obtain (31 mg, 49%).
1H NMR(400MHz,CDCl 3)δ(ppm):8.352(d,1H),8.049(s,2H),7.751(m,3H),6.879(d,1H),6.658(m,2H),3.931(d,2H),3.881(s,3H),3.857(s,1H),3.852(s,1H),3.660(m,4H),3.257(m,4H),2.851(m,1H),1.820(m,2H),1.670(d,1H)，0.721(m,1H)，0.302(m,1H)，MS m/z＝519.3[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.352 (d, 1H), 8.049 (s, 2H), 7.751 (m, 3H), 6.879 (d, 1H), 6.658 (m, 2H), 3.931 (d, 2H), 3.881 (s, 3H), 3.857 (s, 1H), 3.852 (s, 1H), 3.660 (m, 4H), 3.257 (m, 4H), 2.851 (m, 1H), 1.820 ( m, 2H), 1.670 (d, 1H), 0.721 (m, 1H), 0.302 (m, 1H), MS m/z=519.3 [M+H] + .
实施例52Example 52
Figure PCTCN2020126668-appb-000119
Figure PCTCN2020126668-appb-000119
化合物I-52的合成：Synthesis of compound I-52:
其合成参考本文实施例7中化合物I-7合成，仅将起始原料化合物丙胺替换成商业可得的1,4-二氮杂环庚烷-1-甲酸叔丁酯即可。产物经柱层析纯化得到(12mg,21％)。Its synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the starting material compound propylamine is replaced with commercially available 1,4-diazepan-1-carboxylic acid tert-butyl ester. The product was purified by column chromatography to obtain (12mg, 21%).
1H NMR(400MHz,CDCl 3)δ(ppm):8.337(d,1H),8.126(s,1H),8.057(d,1H),7.972(d,1H),7.734(m,2H),7.119(d,1H),6.613(m,2H),3.961(m,2H),3.893(s,2H),3.889(m, 1H),3.854(s,3H),3.831(m,2H),3.658(s,1H),3.141(m,4H),2.505(m,4H),2.728(s,1H),1.716(m,4H),1.679(d,1H)，MS m/z＝536.2[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.337 (d, 1H), 8.126 (s, 1H), 8.057 (d, 1H), 7.972 (d, 1H), 7.734 (m, 2H), 7.119 (d, 1H), 6.613 (m, 2H), 3.961 (m, 2H), 3.893 (s, 2H), 3.889 (m, 1H), 3.854 (s, 3H), 3.831 (m, 2H), 3.658 ( s,1H),3.141(m,4H),2.505(m,4H),2.728(s,1H),1.716(m,4H),1.679(d,1H), MS m/z=536.2[M+H ] + .
实施例53Example 53
Figure PCTCN2020126668-appb-000120
Figure PCTCN2020126668-appb-000120
化合物I-53的合成：Synthesis of compound I-53:
其合成参考本文实施例7中化合物I-7合成，仅将起始原料化合物丙胺替换成商业可得的1,4-氧杂氮杂环庚烷即可。产物经柱层析纯化得到(16mg,29％)，Its synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the starting material compound propylamine is replaced with commercially available 1,4-oxazepine. The product was purified by column chromatography to obtain (16mg, 29%),
1H NMR(400MHz,CDCl 3)δ(ppm):8.341(d,1H),8.131(s,1H),8.052(d,1H),7.985(d,1H),7.721(m,2H),7.120(d,1H),6.612(m,2H),3.938(m,2H),3.887(s,2H),3.887(m,1H),3.849(s,3H),3.831(m,2H),3.687(br,4H),3.659(s,1H),3.112(m,4H),2.740(s,1H),1.712(m,2H),1.672(d,1H),MS m/z＝537.2[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.341 (d, 1H), 8.131 (s, 1H), 8.052 (d, 1H), 7.985 (d, 1H), 7.721 (m, 2H), 7.120 (d, 1H), 6.612 (m, 2H), 3.938 (m, 2H), 3.887 (s, 2H), 3.887 (m, 1H), 3.849 (s, 3H), 3.831 (m, 2H), 3.687 ( br,4H),3.659(s,1H),3.112(m,4H),2.740(s,1H),1.712(m,2H),1.672(d,1H),MS m/z=537.2[M+H ] + .
实施例54Example 54
Figure PCTCN2020126668-appb-000121
Figure PCTCN2020126668-appb-000121
化合物I-54的合成：Synthesis of compound I-54:
其合成参考本文实施例7中化合物I-7合成，仅将起始原料化合物丙胺替换成商业可得的2-氮杂-双环[2,2,1]庚烷即可。产物经柱层析纯化得到(40mg,59％)，MS m/z＝533.3[M+H] +。 Its synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the starting material compound propylamine is replaced with commercially available 2-aza-bicyclo[2,2,1]heptane. The product was purified by column chromatography to obtain (40 mg, 59%), MS m/z=533.3 [M+H] + .
实施例55Example 55
Figure PCTCN2020126668-appb-000122
Figure PCTCN2020126668-appb-000122
化合物I-55的合成：Synthesis of compound I-55:
其合成参考本文实施例4中化合物I-4的合成，仅在第一步中将起始原料环丙烷硼酸替换成商业可得的环戊烯-1-基硼酸即可。产物经柱层析纯化得到(9mg,11％)，MS m/z＝504.2[M+H] +。 For its synthesis, refer to the synthesis of compound 1-4 in Example 4 herein, and only in the first step the starting material cyclopropaneboronic acid is replaced with commercially available cyclopenten-1-ylboronic acid. The product was purified by column chromatography to obtain (9mg, 11%), MS m/z=504.2[M+H] + .
实施例56Example 56
Figure PCTCN2020126668-appb-000123
Figure PCTCN2020126668-appb-000123
化合物I-56的合成：Synthesis of compound I-56:
其合成参考本文实施例4中化合物I-4的合成，仅在第一步中将起始原料环丙烷硼酸替换成商业可得的环己烯-1-基硼酸即可。产物经柱层析纯化得到(15mg,13％)，MS m/z＝518.3[M+H] +。 For its synthesis, refer to the synthesis of compound 1-4 in Example 4 herein, and only in the first step, the starting material cyclopropaneboronic acid is replaced with commercially available cyclohexen-1-ylboronic acid. The product was purified by column chromatography to obtain (15mg, 13%), MS m/z=518.3[M+H] + .
实施例57Example 57
Figure PCTCN2020126668-appb-000124
Figure PCTCN2020126668-appb-000124
化合物I-57的合成：Synthesis of compound I-57:
其合成参考本文实施例4中化合物I-4的合成，仅在第一步中将起始原料环丙烷硼酸替换成商业可得的3,6-二氢-2H-吡喃-4-硼酸即可。产物经柱层析纯化得到(10mg,14％)，MS m/z＝520.2[M+H] +。 Its synthesis refers to the synthesis of compound 1-4 in Example 4 herein. Only in the first step, the starting material cyclopropaneboronic acid is replaced with commercially available 3,6-dihydro-2H-pyran-4-boronic acid. can. The product was purified by column chromatography to obtain (10 mg, 14%), MS m/z=520.2 [M+H] + .
实施例58Example 58
Figure PCTCN2020126668-appb-000125
Figure PCTCN2020126668-appb-000125
化合物I-58的合成：Synthesis of compound I-58:
其合成参考本文实施例4中化合物I-4的合成，仅在第一步中将起始原料环丙烷硼酸替换成商业可得的1,2,3,6-四氢吡啶-4-硼酸频哪醇酯即可。产物经柱层析纯化得到(11mg,16％)，MS m/z＝519.2[M+H] +。 For its synthesis, refer to the synthesis of compound 1-4 in Example 4 herein. Only in the first step, the starting material cyclopropaneboronic acid was replaced with commercially available 1,2,3,6-tetrahydropyridine-4-boronic acid frequency. Which alcohol ester is sufficient. The product was purified by column chromatography to obtain (11 mg, 16%), MS m/z=519.2 [M+H] + .
实施例59Example 59
Figure PCTCN2020126668-appb-000126
Figure PCTCN2020126668-appb-000126
化合物I-59的合成：Synthesis of compound I-59:
其合成参考本文实施例4中化合物I-4的合成，仅在第一步中将起始原料环丙烷硼酸替换成商业可得的2-(2,5-二氢呋喃-3-基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷即可。产物经柱层析纯化得到(8mg,10％)，MS m/z＝506.3[M+H] +。 Its synthesis refers to the synthesis of compound 1-4 in Example 4 herein. Only in the first step, the starting material cyclopropaneboronic acid is replaced with commercially available 2-(2,5-dihydrofuran-3-yl)- 4,4,5,5-tetramethyl-1,3,2-dioxole is sufficient. The product was purified by column chromatography to obtain (8mg, 10%), MS m/z=506.3[M+H] + .
实施例60Example 60
Figure PCTCN2020126668-appb-000127
Figure PCTCN2020126668-appb-000127
化合物I-60的合成：Synthesis of compound I-60:
其合成参考本文实施例4中化合物I-4的合成，仅在第一步中将起始原料环丙烷硼酸替换成商业可得的1-叔丁氧羰基-2,5-二氢-1H-吡咯-3-硼酸频哪醇酯即可。产物经柱层析纯化得到(14mg,20％)，MS m/z＝505.3[M+H] +。 For its synthesis, refer to the synthesis of compound 1-4 in Example 4 herein. Only in the first step, the starting material cyclopropaneboronic acid was replaced with commercially available 1-tert-butoxycarbonyl-2,5-dihydro-1H- Pyrrole-3-boronic acid pinacol ester is sufficient. The product was purified by column chromatography to obtain (14 mg, 20%), MS m/z=505.3 [M+H] + .
实施例61Example 61
Figure PCTCN2020126668-appb-000128
Figure PCTCN2020126668-appb-000128
化合物I-61的合成：Synthesis of compound I-61:
其合成参考本文实施例12中化合物I-12合成，仅将起始原料化合物6-甲氧基-3-吡啶甲醛替换成商业可得的1-甲基-1H-吡唑-3-甲醛即可。产物经柱层析纯化得到(21mg,28％)，MS m/z＝496.2[M+H] +。 Its synthesis refers to the synthesis of compound I-12 in Example 12 herein, and only the starting material compound 6-methoxy-3-pyridinecarboxaldehyde is replaced with commercially available 1-methyl-1H-pyrazole-3-carbaldehyde. can. The product was purified by column chromatography to obtain (21 mg, 28%), MS m/z=496.2 [M+H] + .
实施例62Example 62
Figure PCTCN2020126668-appb-000129
Figure PCTCN2020126668-appb-000129
化合物I-62的合成：Synthesis of compound I-62:
其合成参考本文实施例12中化合物I-12合成，仅将起始原料化合物6-甲氧基-3-吡啶甲醛替换成商业可得的N-甲基-3-吡咯甲醛即可。产物经柱层析纯化得到(18mg,31％)，MS m/z＝495.3[M+H] +。 The synthesis refers to the synthesis of compound I-12 in Example 12 herein, and only the starting material compound 6-methoxy-3-pyridinecarbaldehyde is replaced with commercially available N-methyl-3-pyrrolecarbaldehyde. The product was purified by column chromatography to obtain (18 mg, 31%), MS m/z=495.3 [M+H] + .
实施例63Example 63
Figure PCTCN2020126668-appb-000130
Figure PCTCN2020126668-appb-000130
化合物I-63的合成：Synthesis of compound I-63:
其合成参考本文实施例12中化合物I-12合成，仅将起始原料化合物6-甲氧基-3-吡啶甲醛替换成商业可得的5-甲基-2-噻吩甲醛即可。产物经柱层析纯化得到(9mg,17％)，MS m/z＝511.2[M+H] +。 Its synthesis refers to the synthesis of compound I-12 in Example 12 herein, and only the starting material compound 6-methoxy-3-pyridinecarbaldehyde is replaced with commercially available 5-methyl-2-thiophene carbaldehyde. The product was purified by column chromatography to obtain (9mg, 17%), MS m/z=511.2[M+H] + .
实施例64Example 64
Figure PCTCN2020126668-appb-000131
Figure PCTCN2020126668-appb-000131
化合物8的合成：Synthesis of compound 8:
Figure PCTCN2020126668-appb-000132
Figure PCTCN2020126668-appb-000132
氮气保护下，将商业可得的原料2-氟吡啶-5-甲醛(0.41g，3.3mmol)、碳酸铯(21.5g，6.6mmol)加入至氘代甲醇(CD 3OD)中，将混合溶液升温至60℃左右搅拌，反应完成后，将反应液加入至冰水混合物中，用稀盐酸调节体系至pH为7左右，乙酸乙酯萃取三次，合并有机相并用无水硫酸钠干燥，浓缩并柱层析纯化得化合物8(0.4g，88％)。 1H NMR(400MHz,DMSO-d 6)δ9.97(s,1H),8.77(d,J＝1.9Hz,1H),8.12(dd,J＝8.6,2.4Hz,1H),6.99(d,J＝8.7Hz,1H)，MS m/z＝140.9[M+H] +。 Under the protection of nitrogen, the commercially available raw materials 2-fluoropyridine-5-carbaldehyde (0.41g, 3.3mmol) and cesium carbonate (21.5g, 6.6mmol) were added to deuterated methanol (CD 3 OD), and the mixed solution Raise the temperature to about 60°C and stir. After the reaction is complete, add the reaction solution to a mixture of ice and water, adjust the system to a pH of about 7 with dilute hydrochloric acid, extract three times with ethyl acetate, combine the organic phases and dry with anhydrous sodium sulfate, concentrate and Purification by column chromatography gave compound 8 (0.4 g, 88%). 1 H NMR(400MHz,DMSO-d 6 )δ9.97(s,1H), 8.77(d,J=1.9Hz,1H), 8.12(dd,J=8.6,2.4Hz,1H), 6.99(d, J=8.7 Hz, 1H), MS m/z=140.9 [M+H] + .
化合物I-64的合成：Synthesis of compound I-64:
其合成参考本文实施例17中化合物I-17的合成，仅将原料6-甲氧基-3-吡啶甲醛替换成化合物8即可。产物经柱层析纯化得到(14mg，22％)。The synthesis refers to the synthesis of compound I-17 in Example 17 herein, and only the raw material 6-methoxy-3-pyridinecarboxaldehyde is replaced with compound 8. The product was purified by column chromatography to obtain (14 mg, 22%).
1H NMR(400MHz,CDCl 3)δ(ppm):8.291(d,1H),8.057(s,1H),8.030(d,1H),7.718(dd,1H),7.619(d,1H),7.597(d,1H),6.652(m,3H),4.765(t,1H),4.138(d,2H),3.798(s,1H),3.762(s,2H),3.739(s,1H),3.682(m,2H),3.570(s,1H),3.540(s,3H),3.208(m,1H),2.671(d,1H),1.611(d,1H)，MS m/z＝512.2[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.291 (d, 1H), 8.057 (s, 1H), 8.030 (d, 1H), 7.718 (dd, 1H), 7.619 (d, 1H), 7.597 (d, 1H), 6.652 (m, 3H), 4.765 (t, 1H), 4.138 (d, 2H), 3.798 (s, 1H), 3.762 (s, 2H), 3.739 (s, 1H), 3.682 ( m,2H),3.570(s,1H),3.540(s,3H),3.208(m,1H),2.671(d,1H),1.611(d,1H), MS m/z＝512.2[M+H ] + .
实施例65Example 65
Figure PCTCN2020126668-appb-000133
Figure PCTCN2020126668-appb-000133
化合物I-65的合成：Synthesis of compound I-65:
其合成参考本文实施例12中化合物I-12的合成，仅将原料6-甲氧基-3-吡啶甲醛替换成化合物8即可。产物经柱层析纯化得到(17mg，31％)。For its synthesis, refer to the synthesis of compound I-12 in Example 12 herein, and just replace the raw material 6-methoxy-3-pyridinecarbaldehyde with compound 8. The product was purified by column chromatography to obtain (17 mg, 31%).
1H NMR(400MHz,CDCl 3)δ(ppm):8.337(d,1H),8.129(s,1H),8.054(d,1H),7.978(d,1H),7.735(m,2H),7.120(d,1H),6.605(m,2H),3.968(m,2H),3.901(s, 2H),3.892(m,1H),3.832(m,2H),3.685(br,4H),3.661(s,1H),3.110(m,4H),2.734(s,1H),1.681(d,1H)，MS m/z＝526.3[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.337 (d, 1H), 8.129 (s, 1H), 8.054 (d, 1H), 7.978 (d, 1H), 7.735 (m, 2H), 7.120 (d, 1H), 6.605 (m, 2H), 3.968 (m, 2H), 3.901 (s, 2H), 3.892 (m, 1H), 3.832 (m, 2H), 3.685 (br, 4H), 3.661 ( s, 1H), 3.110 (m, 4H), 2.734 (s, 1H), 1.681 (d, 1H), MS m/z=526.3 [M+H] + .
实施例66Example 66
Figure PCTCN2020126668-appb-000134
Figure PCTCN2020126668-appb-000134
化合物I-66的合成：Synthesis of compound I-66:
其合成参考本文实施例7中化合物I-7的合成，仅将原料丙基-1-胺替换成商业可得的3-甲基-3-吖啶醇即可。产物经柱层析纯化得到(16mg，27％)。The synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with commercially available 3-methyl-3-acridol. The product was purified by column chromatography to obtain (16 mg, 27%).
1H NMR(400MHz,CDCl 3)δ(ppm):8.295(d,1H),8.065(s,1H),8.032(d,1H),7.721(dd,1H),7.623(d,1H),7.605(d,1H),6.648(m,3H),4.759(t,1H),4.142(s,2H),3.841(s,3H),3.757(s,2H),3.751(s,1H),3.676(m,2H),3.571(s,1H),3.542(s,3H),3.212(m,1H),2.668(d,1H),1.614(d,1H)，1.470(s,3H)，MS m/z＝523.2[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.295 (d, 1H), 8.065 (s, 1H), 8.032 (d, 1H), 7.721 (dd, 1H), 7.623 (d, 1H), 7.605 (d, 1H), 6.648 (m, 3H), 4.759 (t, 1H), 4.142 (s, 2H), 3.841 (s, 3H), 3.757 (s, 2H), 3.751 (s, 1H), 3.676 ( m,2H),3.571(s,1H),3.542(s,3H),3.212(m,1H),2.668(d,1H),1.614(d,1H), 1.470(s,3H), MS m/ z=523.2[M+H] + .
实施例67Example 67
Figure PCTCN2020126668-appb-000135
Figure PCTCN2020126668-appb-000135
化合物I-67的合成：Synthesis of compound I-67:
其合成参考本文实施例7中化合物I-7的合成，仅将原料丙基-1-胺替换成商业可得的6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷即可，得到的偶联产品再经过三氟乙酸脱Boc保护处理。产物经柱层析纯化得到(21mg，33％)。Its synthesis refers to the synthesis of compound I-7 in Example 7 herein, and only the raw material propyl-1-amine is replaced with commercially available 6-(tert-butoxycarbonyl)-3,6-diazabicyclo [3.1. 1] Heptane is sufficient, and the obtained coupling product is treated with trifluoroacetic acid for de-Boc protection. The product was purified by column chromatography to obtain (21 mg, 33%).
1H NMR(400MHz,CDCl 3)δ(ppm):8.335(d,1H),8.128(s,1H),8.052(d,1H),7.976(d,1H),7.734(m,2H),7.110(d,1H),6.603(m,2H),3.890(m,2H),3.854(s,3H),3.831(m,2H),3.687(br,8H),3.659(s,2H),2.730(s,2H),1.680(d,2H)，MS m/z＝534.2[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 8.335 (d, 1H), 8.128 (s, 1H), 8.052 (d, 1H), 7.976 (d, 1H), 7.734 (m, 2H), 7.110 (d, 1H), 6.603 (m, 2H), 3.890 (m, 2H), 3.854 (s, 3H), 3.831 (m, 2H), 3.687 (br, 8H), 3.659 (s, 2H), 2.730 ( s, 2H), 1.680 (d, 2H), MS m/z=534.2 [M+H] + .
生物学实验例Biological experiment example
实验例1 激酶活性测试Experimental example 1 Kinase activity test
试验目的：Test purposes:
检测系列受试化合物在RET，KDR，RET V804M，RET V804L和RET M918T激酶上IC50值。利用Mobility shift assay的方法，在RET，KDR，RET V804M，RET V804L和RET M918T激酶上进行受试化合物的筛选，起始浓度0.1μM，3倍稀释，10个浓度，复孔检测。The IC50 values of the test compounds in the detection series are RET, KDR, RET V804M, RET V804L and RET M918T kinases. Using the method of Mobility shift assay, the test compounds were screened on RET, KDR, RET V804M, RET V804L and RET M918T kinases, with an initial concentration of 0.1 μM, 3 times dilution, 10 concentrations, and multiple well detection.
化合物配制：Compound preparation:
受试化合物用DMSO(二甲亚砜)配制成10mM的储备液冻存备用，测试前用DMSO稀释成起始浓度为0.1μM的测试液，依次3倍稀释10个浓度，复孔检测。The test compound was prepared as a 10 mM stock solution with DMSO (dimethyl sulfoxide) and frozen for later use. Before the test, it was diluted with DMSO to a test solution with an initial concentration of 0.1 μM, which was successively diluted 3 times to 10 concentrations, and tested in multiple holes.
测试条件如下表(底物浓度为3μM)：The test conditions are as follows (substrate concentration is 3μM):
表1、测试条件Table 1. Test conditions
浓度concentration RETRET KDRKDR RET V804MRET V804M RET V804LRET V804L RET M918TRET M918T
激酶(nM)Kinase (nM) 11 0.20.2 0.6250.625 2.52.5 0.50.5
ATP(μM)ATP (μM) 1616 9595 12.212.2 7.57.5 11.111.1
激酶反应过程：Kinase reaction process:
用分液器向目的板孔转移受试化合物测试液250nL/孔，每个化合物10个浓度，阴性对照孔加入等体积的DMSO。用1×Kinase buffer配制激酶溶液，在化合物孔和阳性对照孔分别加入对应浓度的激酶溶液；在阴性对照孔中加10μl的1×Kinase buffer，1000rpm离心30秒，反应板振荡混匀后室温孵育10分钟。用1×Kinase buffer配制对应浓度的ATP和底物混合溶液，加入15μl的ATP和底物混合溶液，将孔板1000rpm离心30秒，振荡混匀后室温孵育相应的时间。Use a dispenser to transfer 250 nL/well of the test compound test solution to the target plate well, with 10 concentrations of each compound, and add an equal volume of DMSO to the negative control well. Prepare kinase solution with 1×Kinase buffer, add kinase solution of corresponding concentration to compound wells and positive control wells respectively; add 10μl of 1×Kinase buffer to negative control wells, centrifuge at 1000rpm for 30 seconds, shake and mix the reaction plate and incubate at room temperature 10 minutes. Prepare a mixed solution of ATP and substrate with corresponding concentration with 1×Kinase buffer, add 15μl of ATP and substrate mixed solution, centrifuge the well plate at 1000 rpm for 30 seconds, shake and mix, and incubate at room temperature for the corresponding time.
反应检测Reaction detection
加入30μl终止检测液停止激酶反应，1000rpm离心30秒，振荡混匀。用Caliper EZ Reader读取转化率。Add 30μl of stop detection solution to stop the kinase reaction, centrifuge at 1000rpm for 30 seconds, shake and mix. Use Caliper EZ Reader to read the conversion rate.
数据分析：data analysis:
将读取的数据转化为抑制率，采用分析软件GraphPad Prism 5拟合量效曲线，得出各化合物对酶活性抑制的IC50值。The read data was converted into inhibition rate, and the analysis software GraphPad Prism 5 was used to fit the dose-effect curve to obtain the IC50 value of each compound's inhibition of enzyme activity.
表2：部分化合物激酶测试的IC50值Table 2: IC50 values of some compounds tested by kinases
Figure PCTCN2020126668-appb-000136
Figure PCTCN2020126668-appb-000136
Figure PCTCN2020126668-appb-000137
Figure PCTCN2020126668-appb-000137
实验例2 细胞活性测试Experimental example 2 Cell activity test
试验目的Test purposes
测试受试化合物对BaF3‐KIF5B‐RET、BaF3‐KIF5B‐RET‐V804M、BaF3‐KIF5B‐RET‐V804L、BaF3‐tel‐RET‐M918T、BaF3‐CCDC6‐RET、BaF3‐tel‐VEGFR2、MTC‐TT细胞的抑制IC50值。Test compound pair BaF3-KIF5B-RET, BaF3-KIF5B-RET-V804M, BaF3-KIF5B-RET-V804L, BaF3-tel-RET-M918T, BaF3-CCDC6-RET, BaF3-tel-VEGFR2, MTC-TT The cell's inhibition IC50 value.
试验过程Experimental procedure
将细胞用0.25％Trypsin‐EDTA消化，重悬细胞用自动细胞计数器计数。根据播种密度,将细胞悬浮液稀释至所需密度，96孔铺约100ul细胞37℃培养过夜。将化合物配成10mM～20mM储备液，用培养基稀释200‐1000倍，每孔加适量体积的化合物测试液，以加入同样体积DMSO的孔作为对照，培养72小时。The cells were digested with 0.25% Trypsin-EDTA, and the resuspended cells were counted with an automatic cell counter. According to the seeding density, the cell suspension was diluted to the required density, and about 100ul cells were spread in 96 wells and incubated overnight at 37°C. The compound was prepared into a 10mM-20mM stock solution, diluted 200-1000 times with the culture medium, and an appropriate volume of the compound test solution was added to each well, and the wells with the same volume of DMSO were added as a control, and cultured for 72 hours.
检测Detect
将96孔细胞板平衡到室温。每孔加
Figure PCTCN2020126668-appb-000138
试剂，振荡2分钟静置60分钟。用Envision检测。 Equilibrate the 96-well cell plate to room temperature. Add per hole
Figure PCTCN2020126668-appb-000138
Reagent, shake for 2 minutes and let stand for 60 minutes. Use Envision to detect.
数据分析data analysis
将检测数据转为抑制率，采用分析软件GraphPad Prism 5拟合量效曲线，得出各化合物对细胞活性抑制的IC50值。The detection data was converted to inhibition rate, and the analysis software GraphPad Prism 5 was used to fit the dose-response curve to obtain the IC50 value of each compound's inhibition of cell activity.
表3：部分化合物细胞测试IC50(单位：nM)Table 3: Cell test IC50 of some compounds (unit: nM)
Figure PCTCN2020126668-appb-000139
Figure PCTCN2020126668-appb-000139
Figure PCTCN2020126668-appb-000140
Figure PCTCN2020126668-appb-000140
实验例3 药代动力学研究Experimental example 3 Pharmacokinetic study
试验过程：比格犬，8.09～10.430kg，雄性，每组5只，给药前禁食过夜，给药后4小时自由饮食与水。经口灌胃10mg/kg(2mg/mL，5mL/kg)。给药后0、5、15、30分钟、1、2、4、6、8、24小时从颈静脉取200μL血液样本，放入微量K2EDTA管中。将血样放在冰上，在4℃下以6000转/分的速度离心8分钟，在采集后30分钟内离心收集血浆。采用LC‐MS/MS法测定血药浓度，用
Figure PCTCN2020126668-appb-000141
8.2.0软件，计算得到药代动力学参数如下： Test procedure: Beagle dogs, 8.09-10.430kg, male, 5 in each group, fasted overnight before administration, and 4 hours after administration with free food and water. Oral gavage 10mg/kg (2mg/mL, 5mL/kg). A 200 μL blood sample was taken from the jugular vein at 0, 5, 15, 30 minutes, 1, 2, 4, 6, 8, and 24 hours after administration, and placed in a micro-K2EDTA tube. Place the blood sample on ice, centrifuge at 6000 rpm for 8 minutes at 4°C, and collect plasma by centrifugation within 30 minutes after collection. The LC-MS/MS method was used to determine the blood drug concentration.
Figure PCTCN2020126668-appb-000141
8.2.0 software, calculated pharmacokinetic parameters are as follows:
表4、药代动力学参数Table 4. Pharmacokinetic parameters
Figure PCTCN2020126668-appb-000142
Figure PCTCN2020126668-appb-000142
Figure PCTCN2020126668-appb-000143
Figure PCTCN2020126668-appb-000143
实验例4 Ba/F3‐CCDC6‐RET细胞皮下同种移植肿瘤BALB/c裸小鼠的药效学实验Experimental example 4 The pharmacodynamics experiment of Ba/F3‐CCDC6‐RET cell subcutaneous allograft tumor BALB/c nude mice
Ba/F3‐CCDC6‐RET细胞株用1640培养基+10％胎牛血清+1％双抗(Penicillin Streptomycin solution)，37℃、5％CO2培养，一周两次传代处理。当细胞饱和度为80％～90％时，收取细胞，计数，接种。每只小鼠右腋皮下接种细胞悬液0.2ml。即每只小鼠接种Ba/F3‐CCDC6‐RET细胞1*10^6个。接种完成后，逐日观察肿瘤生长状态，肿瘤平均体积≥200mm3时，将小鼠按肿瘤体积随机分为5组。按照小鼠体重给药：10μl/g。如果体重下降超过20％，给药方案做出相应调整。The Ba/F3-CCDC6-RET cell line was cultured with 1640 medium + 10% fetal bovine serum + 1% double antibody (Penicillin Streptomycin solution), cultured at 37°C, 5% CO2, and passaged twice a week. When the cell saturation is 80% to 90%, the cells are collected, counted, and seeded. 0.2ml of cell suspension was inoculated subcutaneously in the right axilla of each mouse. That is, each mouse is inoculated with 1*10^6 Ba/F3-CCDC6-RET cells. After the inoculation, the tumor growth status was observed daily. When the average tumor volume was greater than or equal to 200 mm3, the mice were randomly divided into 5 groups according to the tumor volume. According to the weight of the mouse, 10μl/g. If the weight loss exceeds 20%, the dosage regimen will be adjusted accordingly.
每天检测动物的健康状况及死亡情况，例常检查包括动物的肿瘤生长情况，活动能力，饮食，体重，眼睛，毛发和其他异常行为，每周两次(周二和周五)测量肿瘤体积及体重。Check the animal’s health and death every day. Routine checks include the animal’s tumor growth, mobility, diet, weight, eyes, hair, and other abnormal behaviors. The tumor volume and weight are measured twice a week (Tuesday and Friday). .
化合物对肿瘤生长抑制效果通过肿瘤体积与时间的关系进行评估。其中肿瘤体积通过游标卡尺测量，公式为TV＝0.5a×b2，其中a是肿瘤的长径，b是肿瘤的短径。The compound's inhibitory effect on tumor growth was evaluated by the relationship between tumor volume and time. The tumor volume is measured by a vernier caliper, and the formula is TV=0.5a×b2, where a is the long diameter of the tumor and b is the short diameter of the tumor.
试验统计数据，包括每个组的每个时间点的肿瘤体积的平均值(Mean)和标准误(SEM)(具体数据见下表)。治疗组在给药后D18天表现出最好的治疗效果，因此基于此数据进行统计学分析评估组间差异。用单因素方差分析(one way ANOVA)检验方法比较治疗组肿瘤体积与对照组肿瘤体积相比有无显著性差异。P<0.05为具有显著性差异。Test statistics include the mean (Mean) and standard error (SEM) of the tumor volume at each time point in each group (see the table below for specific data). The treatment group showed the best treatment effect on day D18 after administration, so statistical analysis was performed based on this data to evaluate the difference between the groups. A one-way analysis of variance (one-way ANOVA) test method was used to compare whether the tumor volume of the treatment group was significantly different from the tumor volume of the control group. P<0.05 indicates a significant difference.
实验指标是考察肿瘤生长是否被抑制、延缓或治愈。化合物的抑瘤疗效采用相对肿瘤增殖率T/C(％)作为试验评价指标。评价标准为：T/C(％)>40％为无效；T/C(％)≤40％，且P<0.05为具有显著性差异。The experimental index is to investigate whether the tumor growth is inhibited, delayed or cured. The compound's anti-tumor efficacy uses the relative tumor proliferation rate T/C (%) as the test evaluation index. The evaluation criteria are: T/C(%)>40% is invalid; T/C(%)≤40%, and P<0.05 is a significant difference.
表5对Ba/F3-CCDC6-RET细胞同种移植瘤模型的抑瘤药效评价(基于给药后第18天肿瘤体积计算得出)Table 5 Evaluation of anti-tumor efficacy on Ba/F3-CCDC6-RET cell allograft tumor model (calculated based on tumor volume on the 18th day after administration)
Figure PCTCN2020126668-appb-000144
Figure PCTCN2020126668-appb-000144
注1：a.Mean±SEM。Note 1: a.Mean±SEM.
b.肿瘤生长抑制由T/C％＝TRTV/CRTV*100％和TGI(TGI(％)＝[1-(Td-T0)/(Vd-V0)]×100)计算。b. Tumor growth inhibition is calculated by T/C%=TRTV/CRTV*100% and TGI (TGI(%)=[1-(Td-T0)/(Vd-V0)]×100).
c.p值根据肿瘤体积计算。c.p value is calculated based on tumor volume.
注2：相对肿瘤增殖率T/C(％)计算公式：T/C％＝TRTV/CRTV*100％。(TRTV：治疗组RTV；CRTV：阴性对照组RTV)；相对肿瘤体积(RTV)计算公式：RTV＝Vt/V0。其中V0为分笼给药时(即d0)测量所得肿瘤体积，Vt为每一次测量时的肿瘤体积；相对肿瘤抑制率TGI(％)计算公式：TGI(TGI(％)＝[1-(Td-T0)/(Vd-V0)]×100)。(Td：治疗组给药后测量所得的肿瘤体积，T0：治疗组分笼给药时(即d0)测量所得肿瘤体积；Vd：对照组给溶媒后测量所得的肿瘤体积，T0：对照组分笼给药时(即d0)测量所得的肿瘤体积)。Note 2: The relative tumor proliferation rate T/C(%) calculation formula: T/C%=TRTV/CRTV*100%. (TRTV: treatment group RTV; CRTV: negative control group RTV); the relative tumor volume (RTV) calculation formula: RTV=Vt/V0. Where V0 is the tumor volume measured in cages (i.e. d0), and Vt is the tumor volume at each measurement; the relative tumor inhibition rate TGI (%) calculation formula: TGI(TGI(%)=[1-(Td -T0)/(Vd-V0)]×100). (Td: tumor volume measured after treatment in the treatment group, T0: tumor volume measured when the treatment group was administered in cages (i.e. d0); Vd: tumor volume measured after the control group was given the vehicle, T0: control group The tumor volume measured at the time of cage administration (i.e. d0)).
表6各组肿瘤重量Table 6 Tumor weight in each group
Figure PCTCN2020126668-appb-000145
Figure PCTCN2020126668-appb-000145
注：Note:
a.Mean±SEM。a. Mean±SEM.
b.相对肿瘤重量由T/Cweight＝TWtreatment/TWvehicle计算。b. The relative tumor weight is calculated by T/Cweight=TWtreatment/TWvehicle.
c.p值根据瘤重计算。c.p value is calculated based on tumor weight.

Claims (16)

  1. 具有式I的化合物，和/或药学上可接受的盐、立体异构体、氘代化物，其中：Compounds of formula I, and/or pharmaceutically acceptable salts, stereoisomers, and deuterated compounds, wherein:
    Figure PCTCN2020126668-appb-100001
    Figure PCTCN2020126668-appb-100001
    A是
    Figure PCTCN2020126668-appb-100002
    或-NHRa；     A is
    Figure PCTCN2020126668-appb-100002
    Or -NHRa;
    所述Cyc为通过N原子连接的4-7元杂环；所述Cyc为单环、桥环或螺环；所述Cyc除连接处N原子外，还含有0或1个选自N、O、S的杂原子；所述Cyc被0、1或2个R1取代；The Cyc is a 4-7 membered heterocyclic ring connected by a N atom; the Cyc is a monocyclic ring, a bridged ring or a spiro ring; in addition to the N atom at the connection point, the Cyc also contains 0 or 1 selected from N, O , S heteroatom; the Cyc is substituted by 0, 1 or 2 R1;
    所述Ra为C1-C4的烷基；所述Ra被0、1或2个R2取代；The Ra is a C1-C4 alkyl group; the Ra is substituted with 0, 1 or 2 R2;
    所述R1任选自羟基、卤素或甲基；The R1 is optionally selected from hydroxyl, halogen or methyl;
    所述R2任选自羟基、卤素、甲基或甲氧基；The R2 is optionally selected from hydroxyl, halogen, methyl or methoxy;
    B为甲基或氘代甲基。B is methyl or deuterated methyl.
  2. 如权利要求1所述的化合物，其特征在于：The compound of claim 1, wherein:
    A选自被0、1或2个R1取代的如下杂环：A is selected from the following heterocycles substituted with 0, 1, or 2 R1:
    Figure PCTCN2020126668-appb-100003
    Figure PCTCN2020126668-appb-100003
    或or
    选自被0、1或2个R2取代的如下烷基：Selected from the following alkyl groups substituted with 0, 1, or 2 R2:
    Figure PCTCN2020126668-appb-100004
    Figure PCTCN2020126668-appb-100004
  3. 如权利要求2所述的化合物，其特征在于：The compound of claim 2, wherein:
    A选自A is selected from
    Figure PCTCN2020126668-appb-100005
    Figure PCTCN2020126668-appb-100005
  4. 如权利要求3所述的化合物，其特征在于：The compound of claim 3, wherein:
    A选自A is selected from
    Figure PCTCN2020126668-appb-100006
    Figure PCTCN2020126668-appb-100006
  5. 如权利要求4所述的化合物，其特征在于：The compound of claim 4, wherein:
    A选自A is selected from
    Figure PCTCN2020126668-appb-100007
    Figure PCTCN2020126668-appb-100007
  6. 如权利要求5所述的化合物，其特征在于：The compound of claim 5, wherein:
    A选自A is selected from
    Figure PCTCN2020126668-appb-100008
    Figure PCTCN2020126668-appb-100008
  7. 如权利要求1所述的化合物，其特征在于：所述的氘代甲基为-CD 3。 The compound of claim 1, wherein the deuterated methyl group is -CD 3 .
  8. 具有式II的化合物，和/或药学上可接受的盐、立体异构体、氘代化物，其中：Compounds of formula II, and/or pharmaceutically acceptable salts, stereoisomers, and deuterated compounds, wherein:
    Figure PCTCN2020126668-appb-100009
    Figure PCTCN2020126668-appb-100009
    A是-ORc；A is -ORc;
    所述Rc为C1-C4的烷基，并被0、1或2个选自卤素、羟基或甲氧基的基团取代；The Rc is a C1-C4 alkyl group and is substituted with 0, 1 or 2 groups selected from halogen, hydroxy or methoxy;
    所述C1-C4的烷基选自甲基、乙基、正丙基、异丙基、正丁基、异丁基或新丁基；The C1-C4 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or neobutyl;
    B为甲基或氘代甲基。B is methyl or deuterated methyl.
  9. 如权利要求1或8所述化合物，其特征在于，包括：The compound of claim 1 or 8, characterized in that it comprises:
    Figure PCTCN2020126668-appb-100010
    Figure PCTCN2020126668-appb-100010
    Figure PCTCN2020126668-appb-100011
    Figure PCTCN2020126668-appb-100011
    Figure PCTCN2020126668-appb-100012
    Figure PCTCN2020126668-appb-100012
  10. 如权利要求9所述化合物，其特征在于，包括：The compound of claim 9, which comprises:
    Figure PCTCN2020126668-appb-100013
    Figure PCTCN2020126668-appb-100013
    Figure PCTCN2020126668-appb-100014
    Figure PCTCN2020126668-appb-100014
  11. 如权利要求1或8所述的化合物，其特征在于，所述的盐为磷酸盐或柠檬酸盐。The compound of claim 1 or 8, wherein the salt is phosphate or citrate.
  12. 如权利要求1或8所述的化合物，其特征在于，包括：The compound of claim 1 or 8, which comprises:
    6-[(2-羟基-2-甲基丙基)胺基]-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的磷酸盐；6-[(2-Hydroxy-2-methylpropyl)amino]-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazepine Heterobicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
    4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)-6-吗啉基-吡唑[1,5-a]吡啶-3-腈的磷酸盐；4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridine-3- Yl)-6-morpholinyl-pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
    4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)-6-硫代吗啉基-吡唑[1,5-a]吡啶-3-腈的磷酸盐；4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridine-3- Yl)-6-thiomorpholinyl-pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
    4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)-6-(2-氧杂-6-氮杂[3.3]庚烷-6-基)-吡唑[1,5-a]吡啶-3-腈的磷酸盐；4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridine-3- Yl)-6-(2-oxa-6-aza[3.3]heptane-6-yl)-pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
    6-(3-羟基氮杂环丁烷-1-基)-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的磷酸盐；6-(3-Hydroxyazetidin-1-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazepine Cyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
    6-[(2-甲氧基乙基)胺基]-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的磷酸盐；6-[(2-Methoxyethyl)amino]-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo [3.1.1]Heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
    6-(3-氮杂双环[3.1.0]己烷-3-基)-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二 环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的磷酸盐；6-(3-Azabicyclo[3.1.0]hexane-3-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6- Diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
    6-(1,4-双氮杂庚烷-1-基)-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的磷酸盐；6-(1,4-bisazaheptan-1-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazepine Bicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
    4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)-6-(1,4-氧氮杂庚烷-4-基)吡唑[1,5-a]吡啶-3-腈的磷酸盐；4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridine-3- Yl)-6-(1,4-oxazepin-4-yl)pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
    6-(3-羟基氮杂环丁烷-1-基)-4-(6-{6-[(6-(三氘代甲氧基)吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的磷酸盐；6-(3-Hydroxyazetidin-1-yl)-4-(6-{6-[(6-(Trideuteromethoxy)pyridin-3-yl)methyl]-3,6 -Diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
    4-(6-{6-[(6-(三氘代甲氧基)吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)-6-吗啉基-吡唑[1,5-a]吡啶-3-腈的磷酸盐；4-(6-{6-[(6-(Trideuteromethoxy)pyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl }Pyridin-3-yl)-6-morpholinyl-pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
    6-(3-羟基-3甲基氮杂环丁烷-1-基)-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的磷酸盐；6-(3-Hydroxy-3methylazetidin-1-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6- Diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile phosphate;
    6-(3,6-二氮杂二环[3.1.1]庚烷-3-基)-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的磷酸盐；6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]- Phosphate of 3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile;
    或or
    6-[(2-羟基-2-甲基丙基)胺基]-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；6-[(2-Hydroxy-2-methylpropyl)amino]-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazepine Heterobicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
    6-(3-氮杂双环[3.1.0]己烷-3-基)-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；6-(3-Azabicyclo[3.1.0]hexane-3-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6- Diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
    6-(1,4-双氮杂庚烷-1-基)-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；6-(1,4-bisazaheptan-1-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazepine The citrate of bicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile;
    4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)-6-(1,4-氧氮杂庚烷-4-基)吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridine-3- Yl)-6-(1,4-oxazepin-4-yl)pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
    4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)-6-吗啉基-吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridine-3- Yl)-6-morpholinyl-pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
    4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)-6-硫代吗啉基-吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridine-3- Yl)-6-thiomorpholinyl-pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
    4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)-6-(2-氧杂-6-氮杂[3.3]庚烷-6-基)-吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridine-3- Yl)-6-(2-oxa-6-aza[3.3]heptane-6-yl)-pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
    6-(3-羟基氮杂环丁烷-1-基)-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；6-(3-Hydroxyazetidin-1-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazepine Cyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
    6-[(2-甲氧基乙基)胺基]-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；6-[(2-Methoxyethyl)amino]-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6-diazabicyclo [3.1.1]Heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
    6-(3-羟基氮杂环丁烷-1-基)-4-(6-{6-[(6-(三氘代甲氧基)吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；6-(3-Hydroxyazetidin-1-yl)-4-(6-{6-[(6-(Trideuteromethoxy)pyridin-3-yl)methyl]-3,6 -Diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
    4-(6-{6-[(6-(三氘代甲氧基)吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)-6-吗啉基-吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；4-(6-{6-[(6-(Trideuteromethoxy)pyridin-3-yl)methyl]-3,6-diazabicyclo[3.1.1]heptan-3-yl }Pyridin-3-yl)-6-morpholinyl-pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
    6-(3-羟基-3甲基氮杂环丁烷-1-基)-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的柠檬酸盐；6-(3-Hydroxy-3methylazetidin-1-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]-3,6- Diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile citrate;
    6-(3,6-二氮杂二环[3.1.1]庚烷-3-基)-4-(6-{6-[(6-甲氧基吡啶-3-基)甲基]-3,6-二氮 杂二环[3.1.1]庚烷-3-基}吡啶-3-基)吡唑[1,5-a]吡啶-3-腈的柠檬酸盐。6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-4-(6-{6-[(6-methoxypyridin-3-yl)methyl]- The citrate of 3,6-diazabicyclo[3.1.1]heptan-3-yl}pyridin-3-yl)pyrazole[1,5-a]pyridine-3-carbonitrile.
  13. 药物组合物，含有如权利要求1-12任一所述化合物及药学上可接受的载体。A pharmaceutical composition comprising the compound according to any one of claims 1-12 and a pharmaceutically acceptable carrier.
  14. 如权利要求13所述的药物组合物，制成固体制剂、液体制剂。The pharmaceutical composition according to claim 13 is made into a solid preparation or a liquid preparation.
  15. 如权利要求1-12任一所述化合物或权利要求13-14任一所述药物组合物在制备治疗与RET激酶和/或突变RET激酶相关的疾病的药物中的用途。The use of the compound of any one of claims 1-12 or the pharmaceutical composition of any one of claims 13-14 in the preparation of a medicine for treating diseases related to RET kinase and/or mutant RET kinase.
  16. 如权利要求15所述化合物或药物组合物，其特征在于，所述RET激酶和/或突变RET激酶相关疾病为非小细胞肺癌(NSCLC)、肺腺癌(LAD)、髓样甲状腺癌(MTC)、乳头状甲状腺癌。The compound or pharmaceutical composition of claim 15, wherein the RET kinase and/or mutant RET kinase related diseases are non-small cell lung cancer (NSCLC), lung adenocarcinoma (LAD), medullary thyroid cancer (MTC) ), papillary thyroid cancer.
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