WO2023082044A1 - 5-formyl heterocyclic amide compound and use thereof - Google Patents

5-formyl heterocyclic amide compound and use thereof Download PDF

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Publication number
WO2023082044A1
WO2023082044A1 PCT/CN2021/129535 CN2021129535W WO2023082044A1 WO 2023082044 A1 WO2023082044 A1 WO 2023082044A1 CN 2021129535 W CN2021129535 W CN 2021129535W WO 2023082044 A1 WO2023082044 A1 WO 2023082044A1
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formyl
amino
cyano
pyridin
pyridine
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PCT/CN2021/129535
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French (fr)
Chinese (zh)
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陆小云
陈永恒
杨芳
陈小娟
丁克
张志民
斯美而·杰弗里·布鲁斯
帕特森·亚当·逢
涂正超
宋晓娟
邓武清
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暨南大学
中南大学湘雅医院
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Priority to PCT/CN2021/129535 priority Critical patent/WO2023082044A1/en
Publication of WO2023082044A1 publication Critical patent/WO2023082044A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/4353—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
    • A61K31/4375—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 six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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 invention belongs to the technical field of chemistry and medicine, and in particular relates to a 5-formyl heterocyclic amide compound and its application.
  • Fibroblast growth factor receptors FGFRs belong to the family of receptor tyrosine kinases (RTKs), which contain four receptor subtypes FGFR1, FGFR2, FGFR3 and FGFR4.
  • RTKs receptor tyrosine kinases
  • the structure of FGFRs mainly consists of three parts: an extracellular region consisting of three immunoglobulin-like domains, a single transmembrane region, and an intracellular region containing a kinase domain.
  • the activation mechanism of FGFR4 is the same as that of other receptor tyrosine kinases.
  • the ligand binds tightly to the complex formed by the receptor and co-receptor, induces receptor dimerization, phosphorylates tyrosine residues in the intracellular region of the receptor, and activates Receptor kinase activity.
  • Activated FGFR4 can phosphorylate downstream target proteins to initiate a signaling cascade.
  • FGFR4 subtypes are mainly distributed in liver, lung, lymph and breast tissue, and FGFR4 and its specific ligand fibroblast factor FGF19 play important physiological functions in liver, lung and breast tissue. Studies have shown that FGF19/FGFR4 is up-regulated in 30-50% of liver cancers, and this up-regulation is closely related to the poor prognosis of liver cancer, and it has become an effective new target for the treatment of liver cancer and other related tumors.
  • FGFR4 has become a hot target in today's anti-tumor research, attracting the attention and R&D boom of many scientific research institutions and pharmaceutical companies.
  • Hagel et al. developed the first selective inhibitor BLU554 based on the difference between the 552 key cysteine and other members of FGFR4 and entered clinical research (NCT02508467), which showed better treatment in patients with liver cancer and cholangiocarcinoma Effect.
  • the FGFR4 selective inhibitor H3B-6527 developed by H3 Biomedicine has also entered the clinical phase I (NCT03424577).
  • the present invention provides a 5-formyl heterocyclic amide compound or its pharmaceutically acceptable salt, stereoisomer and its prodrug molecule, which can inhibit FGFR4 protein kinase with high selectivity active.
  • the 5-formyl heterocyclic amide compound has the structure of formula (I) or its pharmaceutically acceptable salt, stereoisomer and its prodrug molecule:
  • n 0 or 1
  • X is selected from NH, NR 4 , S or O; the R 4 is optionally selected from CN, 6-membered aromatic ring containing CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkanoyl , C 1-6 sulfonic acid group, C 2-4 alkynyl, C 1-6 alkyl containing a 4- to 12-membered heterocyclic group optionally selected from N, O and S heteroatoms;
  • W, Y and Z are independently selected from C or N;
  • R is optionally selected from hydrogen, halogen, cyano, trifluoromethyl, formamido, sulfonamide, C 1-3 thio, C 1-6 alkyl, halogenated C 1-4 alkyl, halo C 1-4 alkoxy, C 1-3 alkylthio, 6-membered aromatic ring thio, C 1- of a 4- to 12-membered heterocyclic group containing heteroatoms optionally selected from N, O and S 6 alkyl, C 1-6 alkanoyl, C 1-6 cycloalkyl, C 1-6 alkyl sulfide group, C 2-4 alkenyl or C 2-4 alkynyl;
  • R 2 is optionally selected from hydrogen, halogen, amino, cyano, hydroxyl, nitro, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, carboxyl substituted C 1- 6 alkyl, carboxyl substituted C 1-6 alkoxy, OR 5 , NHR 5 or NR 5 R 6 , the R 5 and R 6 are optionally selected from C 1-6 alkyl, C 1-6 alkoxy, 4- to 12-membered heterocyclic group, 6-membered aryl group, 5-6 membered heteroaryl group, C 2-4 alkenyl, C 2-4 alkynyl or C 3-10 cycloalkyl;
  • R 3 is optionally selected from hydrogen, halogen, amino, cyano, hydroxyl, nitro, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, carboxyl substituted C 1- 6 alkyl, carboxyl substituted C 1-6 alkoxy, OR 5 , NHR 5 or NR 5 R 6 , the R 5 and R 6 are optionally selected from C 1-6 alkyl, C 1-6 alkoxy, Halogenated 6-membered aryl C 3-6 cycloalkyl, 4- to 12-membered heterocyclic group containing heteroatoms optionally selected from N, O and S, 6-membered aryl, 5-6-membered heteroaryl, Halogenated 5-6 membered heteroaryl, alkoxy 6-membered aryl C 3-6 cycloalkyl, C 3-6 cycloalkyl containing aromatic ring, single ring, spiro ring or parallel ring, C 2-4 Alkenyl, C
  • the compound is a compound having a structure of formula (II) or a pharmaceutically acceptable salt, stereoisomer and prodrug molecule thereof:
  • n 0 or 1;
  • R is optionally selected from hydrogen, halogen, cyano, trifluoromethyl, formamido, sulfonamide, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-4 alkyl or halo Substituting C 1-4 alkoxy, C 1-3 thio, C 1-3 alkylthio, 6-membered aromatic ring thio, 4- to 12-containing heteroatoms optionally selected from N, O and S C 1-6 alkyl of membered heterocyclic group;
  • said R is selected from hydrogen, cyano, cyclopropyl or trifluoromethyl;
  • R is optionally selected from hydrogen, halogen, amino, cyano, hydroxyl, nitro, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, carboxy substituted C 1-6 alkyl, carboxy substituted C 1-6 alkoxy, OR 5 , NHR 5 or NR 5 R 6 , the R 5 and R 6 are optionally selected from C 1-6 alkyl, C 1-6 alkoxy, halogenated 6-membered aryl C 3-6 cycloalkyl, 4- to 12-membered heterocyclic group containing heteroatoms optionally selected from N, O and S, 6-membered aryl , 5-6 membered heteroaryl, halogenated 5-6 membered heteroaryl, alkoxy 6 membered aryl C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 3 -10 cycloalkyl;
  • the R 2 is selected from OR 5 , NHR 5 or NR 5 R 6 , and the R 5 and R 6 are optionally selected from C 1-6 alkyl, C 1-6 alkoxy, containing optionally selected from N , 4- to 12-membered heterocyclic group, 6-membered aryl group, 5-6-membered heteroaryl group, C 2-4 alkenyl, C 2-4 alkynyl or C 3-10 ring of heteroatoms of O and S alkyl;
  • R is optionally selected from hydrogen, halogen, amino, cyano, hydroxyl, nitro, carboxyl, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, hydroxyl substituted C 1-6 alkoxy, amino substituted C 1-6 alkyl, amino substituted C 1-6 alkoxy, carboxyl substituted C 1-6 alkyl, carboxyl substituted C 1 -6 alkoxy, N, O and S substituted 4- to 12-membered aromatic rings, monocyclic, spiro or parallel rings;
  • said R 3 is selected from the following structures:
  • the R3 is selected from the following structures:
  • R is optionally selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl containing 4- to 12-membered heterocyclyls optionally selected from N, O and S heteroatoms;
  • R 4 is selected from C 1-6 alkyl.
  • the 5-formyl heterocyclic amide compounds or their pharmaceutically acceptable salts, stereoisomers and prodrug molecules are used in the preparation of treatment or prevention of transitional proliferative diseases caused by abnormal FGFR4 signaling pathways, such as liver cancer and cholangiocarcinoma , breast cancer, gastric cancer, prostate cancer and other anti-tumor and anti-cancer drugs.
  • the pharmaceutical composition for treating or preventing transitional proliferative diseases includes an active ingredient and a pharmaceutically acceptable carrier, and the active ingredient includes the above-mentioned 5-formyl heterocyclic amide compound or its pharmaceutically acceptable Salts, stereoisomers and their prodrug molecules.
  • the present invention provides a structure and preparation method of a novel 5-formyl heterocyclic amide compound or its pharmaceutically acceptable salt, stereoisomer and prodrug molecule, which can be used for treatment or prevention Transitional proliferative diseases caused by abnormalities in the FGFR4 signaling pathway;
  • the present invention provides a pharmaceutical composition for preventing and/or treating tumors, which consists of active ingredients and pharmaceutically acceptable excipients.
  • the "plurality” mentioned in the present invention means two or more.
  • “And/or” describes the association relationship of associated objects, indicating that there may be three types of relationships, for example, A and/or B may indicate: A exists alone, A and B exist simultaneously, and B exists independently.
  • the character “/” generally indicates that the contextual objects are an "or” relationship.
  • any variable eg, R5, R6, etc.
  • its definition for each occurrence is independent of the definition for each other occurrence.
  • combinations of substituents and variables are permissible only if such combinations render the compounds stable.
  • a line drawn from a substituent into a ring system indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic it means that such bonds are only to any suitable carbon atoms of adjacent rings. It is understood that one of ordinary skill in the art can select substituents and substitution patterns on the compounds of the present invention to provide compounds that are chemically stable and can be readily synthesized from readily available starting materials by skill in the art and by methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stabilized.
  • alkyl as used herein is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C1-C20 in “C1-C20 alkyl” includes groups having 1, 2, 3, 4, 5... or 20 carbon atoms arranged in a linear or branched chain.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • cycloalkyl includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl and the like.
  • alkoxy denotes an alkyl-oxy group wherein alkyl is as defined above.
  • halogen as used herein is meant to include chlorine, fluorine, bromine and iodine.
  • the present invention includes the free form of the compound of formula (I), as well as its pharmaceutically acceptable salt, its stereoisomer and its prodrug molecule.
  • the term "free form” refers to a compound in non-salt form.
  • the inclusion of pharmaceutically acceptable salts includes not only the exemplary salts of the specific compounds described herein, but also all typical pharmaceutically acceptable salts of the free form of the compounds of formula (I).
  • the free form of a particular salt of the compound may be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous base, such as dilute aqueous NaOH, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate.
  • the free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms for the purposes of the invention.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention that contain a basic or acidic moiety by conventional chemical methods.
  • the salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric amount or excess of the desired salt form of an inorganic or organic acid in a suitable solvent or combination of solvents.
  • salts of acidic compounds are formed by reaction with an appropriate inorganic or organic base.
  • pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting a basic compound of the present invention with an inorganic or organic acid.
  • salts refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Step b Preparation of 2-chloro-6-(1,3-dioxolan-2-yl)-3-nitropyridine (compound 1-2)
  • Step c Preparation of diethyl 2-(6-(1,3-dioxolan-2-yl)-3-nitropyridin-2-yl)malonate (compound 1-3)
  • Step d Preparation of ethyl 2-(6-(1,3-dioxolan-2-yl)-3-nitropyridin-2-yl)acetate (compound 1-4)
  • Step e ethyl 2-(6-(1,3-dioxolan-2-yl)-3-nitropyridin-2-yl)-3-(dimethylamino)acrylate (compound 1-5 ) preparation
  • Dissolve compound 1-4 (2.48g, 1.0eq), N,N-dimethylformamide dimethyl acetal (1.57g, 1.5eq) in 20mL DMF, react at 80°C, and monitor the reaction of raw materials by TLC After completion, cool to room temperature, wash the organic phase with water, extract with ethyl acetate, concentrate the organic phase under reduced pressure, and separate the product by column chromatography to obtain 1.8 g, with a yield of 61.45%.
  • Step f Preparation of ethyl 5-(1,3-dioxolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (compound 1-6)
  • Step g Ethyl 5-(1,3-dioxolan-2-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (compound 1-7) preparation of
  • Step a1 Preparation of 2-amino-4-fluoro-5-iodopyridine (compound 1-8)
  • Step b1 Preparation of 2-amino-4-fluoro-5-cyanopyridine (compound 1-9)
  • Step c1 Preparation of 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (compound 1-10)
  • Step h N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolan-2-yl)-1
  • Step h N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolan-2-yl)-1
  • Dissolve compound 1-11 (90.0 mg, 1.0 eq.) in 5 ml of THF, add 1.0 ml of 2N hydrochloric acid, and react at room temperature. After the system is monitored by TLC for complete reaction, add saturated sodium bicarbonate to adjust the pH to 8.0. The ester was extracted, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 48.0 mg of the target compound with a yield of 59.54%.
  • Step c1 Preparation of 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (compound 1-10)
  • Step b and step c N-(5-cyano-4-(isopropoxy)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b] Preparation of pyridine-3-carboxamide (compound 12)
  • Step i N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolan-2-yl)-1
  • Step i N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolan-2-yl)-1
  • Step j N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(1-methyl-1H-pyrazole- Preparation of 4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 18)
  • Step a N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolan-2-yl)-6 Preparation of -((4-methylpiperazin-1-yl)methyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 28-1)
  • Step b N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-((4-methylpiperazine-1- Base) methyl)-1-methyl-1H-pyrrole [3,2-b] pyridine-3-carboxamide (compound 28) preparation
  • Step a ethyl 6-bromo-5-(1,3-dioxolan-2-yl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate ( Compound 29-1) Preparation
  • Step b 6-Bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolane-2- base)-1-isopropyl-1H-pyrrole[3,2-b]pyridine-3-carboxamide (compound 29-2)
  • Step c N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolan-2-yl)-6 -((4-methylpiperazin-1-yl)methyl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 29-3)
  • the synthesis method is the same as compound 26-1.
  • Step d N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-((4-methylpiperazine-1- base)methyl)-1-isopropyl-1H-pyrrole[3,2-b]pyridine-3-carboxamide (compound 29)
  • Step b 6-Bromo-N-(5-cyano-4-((2-morpholinyl)amino)pyridin-2-yl)-5-(1,3-dioxolan-2-yl )-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 33-2)
  • Step a Preparation of N-(2-(((tert-butoxycarbonyl)amino)ethyl)-N-methylglycine ethyl ester (compound 35-1)
  • Step b Preparation of N-(2-aminoethyl)-N-methylglycine ethyl ester (compound 35-2)
  • Dissolve compound 35-1 (1.3g, 1.0eq.), trifluoroacetic acid (1.14g, 2.0eq.) in 10mL DCM, and react at room temperature for 3h.
  • Step c N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolan-2-yl)-6 - Preparation of vinyl-1-isopropyl-1H-pyrrole[3,2-b]pyridine-3-carboxamide (compound 35-3)
  • Step d N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolan-2-yl)-6 - Preparation of aldehyde-1-isopropyl-1H-pyrrole[3,2-b]pyridine-3-carboxamide (compound 35-4)
  • Step e N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolan-2-yl)-6 -((4-methyl-2-oxopiperazin-1-yl)methyl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 35- 5)
  • Step e N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolan-2-yl)-6 -((4-methyl-2-oxopiperazin-1-yl)methyl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 35- 5)
  • Step f N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-((4-methyl-2-oxo Preparation of piperazin-1-yl)methyl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 35)
  • Compound 36-1 (2.0g, 1.0eq) was mixed with 2-methoxyethylamine (510.0mg, 1.05eq), Pd 2 dba 3 (300.0mg, 0.05eq), 4,5-bisdiphenylphosphine- 9,9-Dimethylxanthene (Xantphos, 190.0mg, 0.05eq) and cesium carbonate (6.4g, 3.0eq) were added to 50mL of toluene, the system was replaced with argon and then transferred to 80°C for overnight reaction, the system was directly Concentrate under reduced pressure and separate by column chromatography to obtain 400.0 mg of the target product with a yield of 24.2%.
  • Step b N-(2,4-dimethoxybenzyl)-N-(2-methoxyethyl)-5-(trifluoromethyl)pyridine-2,4-diamine (compound 36- 3) Preparation
  • Compound 36-2 (400.0mg, 1.0eq) was mixed with 2.4-dimethoxyaniline (2.6g, 10.0eq), Pd 2 dba 3 (72.0mg, 0.05eq), Xantphos (45.0mg, 0.05eq) and carbonic acid Cesium (1.54g, 3.0eq) was added to 10mL of toluene, the system was replaced with argon and then transferred to 100°C for overnight reaction, the system was directly concentrated under reduced pressure and separated by column chromatography to obtain 250.0mg of the target product with a yield of 41.2%.
  • Step c Preparation of N-(2-methoxyethyl)-5-(trifluoromethyl)pyridine-2,4-diamine (Compound 36-4)
  • Step d and step e N-(5-trifluoromethyl-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrole
  • Step a Preparation of ethyl 5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (compound 37-1)
  • Step b Preparation of ethyl 5-formylpyrazolo[1,5-a]pyrimidine-3-carboxylate (compound 37-2)
  • Step c Preparation of ethyl 5-(1,3-dioxolan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (compound 37-3)
  • Step d N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolan-2-yl)pyrazole Preparation of [1,5-a]pyrimidine-3-carboxamide (compound 37-4)
  • the synthetic method is as compound 35.
  • Example 39 IC50 test results of compounds against FGFR1-4 kinase
  • FGFR1-4 Kinase Inhibition Assay The inhibitory activity of compounds against FGFR1-4 was determined using the FRET-based Z'-Lyte Assay System according to the manufacturer's instructions (Life Technologies, Carlsbad, CA, USA). Reactions were performed in 5 ⁇ L reaction volumes in 384-well plates in 50 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, and 0.01% Brij-35 with the appropriate amount of kinase.
  • reaction solution was incubated for 1.5 hours at room temperature in the presence of 2 ⁇ M substrate and the corresponding ATP concentration of each kinase (FGFR1: 25 ⁇ M, FGFR2: 5 ⁇ M, FGFR3: 75 ⁇ M, FGFR4: 150 ⁇ M) and in the presence of various concentrations of compounds, and then added 2.5 ⁇ L of developer was incubated for another 1 h at room temperature, after which 2.5 ⁇ L of stop solution was added.
  • the fluorescence signal ratio of 445 nm (coumarin)/520 nm (fluorescein) was detected with EnVision Multilabel Reader (Perkin Elmer, Inc.).
  • IC50 Data were analyzed using Graphpad Prism 5 (Graphpad Software, Inc).
  • Phosphorylation ratio 1– ⁇ (emission ratio ⁇ F100%–C100%)/[C 0%–C 100%+emission ratio ⁇ (F100%–F0%)] ⁇ 100;
  • Inhibition rate 100 x (1 - compound phosphorylation ratio / negative control phosphorylation ratio).
  • IC50 values were calculated using medical graphics software (GraphPad Prism5.0).
  • Example 1 Compound number FGFR4 FGFR1 FGFR2 FGFR3 Example 1 10.0 >10uM >10uM >10uM Example 2 178.0 >10uM >10uM >10uM Example 3 12.0 >10uM >10uM >10uM Example 4 3.8 >10uM >10uM >10uM Example 5 4.7 >10uM >10uM >10uM Example 6 12.6 >10uM >10uM >10uM Example 7 >1000 NT NT NT Example 8 >1000 NT NT NT Example 9 >1000 NT NT NT Example 10 >1000 NT NT NT Example 11 2.96 >10uM >10uM >10uM Example 12 1.63 >10uM >10uM >10uM Example 13 2.43 >10uM >10uM >10uM Example 14 1.92 >10uM >10uM >10uM Example 15 578.2 >10uM >10uM >10uM Example 16 39.84 >10uM >10uM >10
  • Example 21 179.1 >10uM >10uM >10uM
  • Example 22 88.9 >10uM >10uM >10uM
  • Example 23 71.91 >10uM >10uM >10uM
  • Example 24 7.187 >10uM >10uM >10uM
  • Example 25 161.2 >10uM >10uM >10uM
  • Example 26 116.9 >10uM >10uM >10uM
  • Example 27 96.19 >10uM >10uM >10uM
  • Example 28 1.37 >10uM >10uM >10uM
  • Example 29 212.7 >10uM >10uM >10uM
  • Example 30 39.37 >10uM >10uM >10uM
  • Example 31 655.3 >10uM >10uM >10uM
  • Example 32 189.3 >10uM >10uM >10uM
  • Example 33 97.05 >10uM >10uM >10uM
  • Example 34 17.61 >
  • Ba/F3 cells used in this experiment were purchased from ThermoFisher, Ba/F3-TEL-FGFR4 wild type and Ba/F3-TEL-FGFR4(V550L), Ba/F3-TEL-FGFR4(V550M) Stable strains of drug-resistant mutants were all constructed by our laboratory, and were identified through experiments such as positive drug activity, protein expression, and gene sequencing to be completely correct.
  • kinase domain gene of human FGFR4 (NM_002011.5) was fused to the N-terminus of ETV6 (NM_001987.4), and then the fusion gene TEL-FGFR4 was cloned into the pMSCV vector, and positive clones were picked and verified by sequencing.
  • the screened positive stable cell lines were verified by western-blot.
  • Table 2 Test results of activity of some compounds on Ba/F3-FGFR4 cells (IC 50 : nM)
  • Example 8 Compound number Ba/F3-FGFR4 Compound number Ba/F3-FGFR4 Example 8 6.4 Example 25 312.0 Example 9 67.0 Example 26 519.0 Example 10 27.0 Example 27 27.0 Example 18 47.0 Example 28 117.0 Example 19 >3000 Example 29 15.0 Example 20 38.0 Example 30 35.0 Example 21 29.0 Example 31 20.0 Example 22 10.0 Example 38 7.0 Example 23 11.0 FGFR401 4.0 Example 24 12.8 the the

Abstract

A 5-formyl heterocyclic amide compound and a use thereof, said class of compound having a structure represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer or prodrug molecule thereof. Said class of compound has FGFR4 inhibitory activity, and may be used to prevent or treat diseases related to abnormal FGFR4 activity such as fusion or overexpression, such as liver cancer, bile duct cancer, breast cancer, gastric cancer and prostate cancer, and may also be used in combination with other drugs and used in anti-tumor and anticancer drugs.

Description

5-醛基杂环酰胺类化合物及其应用5-formyl heterocyclic amide compound and its application 技术领域technical field
本发明属于化学医药技术领域，具体涉及一种5-醛基杂环酰胺类化合物及其应用。The invention belongs to the technical field of chemistry and medicine, and in particular relates to a 5-formyl heterocyclic amide compound and its application.
技术背景technical background
成纤维细胞生长因子受体FGFRs属于受体酪氨酸激酶家族(RTKs)，含有四种受体亚型FGFR1,FGFR2,FGFR3和FGFR4。FGFRs的结构主要包含三个部分：由三个免疫球蛋白样域组成的胞外区，单次跨膜区以及含激酶域的胞内区。FGFR4的激活机制与其他受体酪氨酸激酶相同，配体与受体和共受体形成的复合物紧密结合，诱导受体二聚，磷酸化受体胞内区酪氨酸残基，激活受体激酶活性。激活的FGFR4能够磷酸化下游靶蛋白引起信号级联反应。其中FGFR4亚型主要分布在肝、肺、淋巴以及乳腺组织中，FGFR4同其特异性配体成纤维细胞因子FGF19在肝脏、肺和乳腺组织中发挥重要的生理学功能。研究显示在30-50％的肝癌中有FGF19/FGFR4上调，并且这种上调同肝癌的不良预后密切相关，成为肝癌等相关肿瘤治疗的有效新靶标。Fibroblast growth factor receptors FGFRs belong to the family of receptor tyrosine kinases (RTKs), which contain four receptor subtypes FGFR1, FGFR2, FGFR3 and FGFR4. The structure of FGFRs mainly consists of three parts: an extracellular region consisting of three immunoglobulin-like domains, a single transmembrane region, and an intracellular region containing a kinase domain. The activation mechanism of FGFR4 is the same as that of other receptor tyrosine kinases. The ligand binds tightly to the complex formed by the receptor and co-receptor, induces receptor dimerization, phosphorylates tyrosine residues in the intracellular region of the receptor, and activates Receptor kinase activity. Activated FGFR4 can phosphorylate downstream target proteins to initiate a signaling cascade. Among them, FGFR4 subtypes are mainly distributed in liver, lung, lymph and breast tissue, and FGFR4 and its specific ligand fibroblast factor FGF19 play important physiological functions in liver, lung and breast tissue. Studies have shown that FGF19/FGFR4 is up-regulated in 30-50% of liver cancers, and this up-regulation is closely related to the poor prognosis of liver cancer, and it has become an effective new target for the treatment of liver cancer and other related tumors.
FGFR4已成为当今抗肿瘤研究的热点靶标，吸引了不少科研机构和医药企业的关注和研发热潮。目前，已有多个选择性FGFR4抑制剂被报道。2015年，Hagel等根据FGFR4的552位关键半胱氨酸与其他成员的差异，开发了首个选择性抑制剂BLU554进入临床研究(NCT02508467)，在肝癌和胆管癌病人中表现出较好的治疗效果。H3 Biomedicine公司研发的FGFR4选择性抑制剂H3B-6527也进入临床I期(NCT03424577)。然而最新研究表明FGFR4蛋白可以快速再合成，合成速率小于2h。针对这一问题，诺华公司研发了一类选择性FGFR4的可逆共价抑制剂，其中代表化合物FGF401已经进入临床I/II期(NCT02325739)，用于治疗FGFR4过表达的肝癌。虽然国内外很多公司也相继研究FGFR4的选择性抑制剂，目前无FGFR4选择性抑制剂获批上市，临床急需更多有效的FGFR4选择性抑制剂。FGFR4 has become a hot target in today's anti-tumor research, attracting the attention and R&D boom of many scientific research institutions and pharmaceutical companies. Currently, several selective FGFR4 inhibitors have been reported. In 2015, Hagel et al. developed the first selective inhibitor BLU554 based on the difference between the 552 key cysteine and other members of FGFR4 and entered clinical research (NCT02508467), which showed better treatment in patients with liver cancer and cholangiocarcinoma Effect. The FGFR4 selective inhibitor H3B-6527 developed by H3 Biomedicine has also entered the clinical phase I (NCT03424577). However, recent studies have shown that FGFR4 protein can be rapidly resynthesized, and the synthesis rate is less than 2h. In response to this problem, Novartis has developed a class of selective reversible covalent inhibitors of FGFR4, of which the representative compound FGF401 has entered clinical phase I/II (NCT02325739) for the treatment of FGFR4 overexpressed liver cancer. Although many companies at home and abroad are also researching selective inhibitors of FGFR4, no FGFR4 selective inhibitors have been approved for marketing at present, and more effective FGFR4 selective inhibitors are urgently needed in clinical practice.
发明内容Contents of the invention
针对现有技术的不足，本发明提供了一种5-醛基杂环酰胺类化合物或者其药学上可接受的盐、立体异构体以及其前药分子，能够高选择性地抑制FGFR4蛋白激酶活性。Aiming at the deficiencies of the prior art, the present invention provides a 5-formyl heterocyclic amide compound or its pharmaceutically acceptable salt, stereoisomer and its prodrug molecule, which can inhibit FGFR4 protein kinase with high selectivity active.
所述5-醛基杂环酰胺类化合物具有式(I)的结构或者其药学上可接受的盐、立体异构体以及其前药分子：The 5-formyl heterocyclic amide compound has the structure of formula (I) or its pharmaceutically acceptable salt, stereoisomer and its prodrug molecule:
Figure PCTCN2021129535-appb-000001
Figure PCTCN2021129535-appb-000001
式(I)中n＝0或1；In formula (I), n=0 or 1;
X选自NH、NR 4、S或O；所述R 4任选自CN、含CN的6元芳环、C 1-6烷基、C 1-6烷氧基、C 1-6烷酰基、C 1-6磺酸基、C 2-4炔基、含有任选自N、O和S的杂原子的4-至12-元杂环基的C 1-6烷基； X is selected from NH, NR 4 , S or O; the R 4 is optionally selected from CN, 6-membered aromatic ring containing CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkanoyl , C 1-6 sulfonic acid group, C 2-4 alkynyl, C 1-6 alkyl containing a 4- to 12-membered heterocyclic group optionally selected from N, O and S heteroatoms;
W,Y和Z分别独立选自C或N；W, Y and Z are independently selected from C or N;
R 1任选自氢、卤素、氰基、三氟甲基、甲酰胺基、磺酰胺基、C 1-3硫基、C 1-6烷基、卤代C 1-4烷基、卤代C 1-4烷氧基、C 1-3烷基硫基、6元芳环硫基、含有任选自N、O和S的杂原子的4-至12-元杂环基的C 1-6烷基、C 1-6烷酰基、C 1-6环烷基、C 1-6烷基硫醚基、C 2-4烯基或C 2-4炔基； R is optionally selected from hydrogen, halogen, cyano, trifluoromethyl, formamido, sulfonamide, C 1-3 thio, C 1-6 alkyl, halogenated C 1-4 alkyl, halo C 1-4 alkoxy, C 1-3 alkylthio, 6-membered aromatic ring thio, C 1- of a 4- to 12-membered heterocyclic group containing heteroatoms optionally selected from N, O and S 6 alkyl, C 1-6 alkanoyl, C 1-6 cycloalkyl, C 1-6 alkyl sulfide group, C 2-4 alkenyl or C 2-4 alkynyl;
R 2任选自氢、卤素、氨基、氰基、羟基、硝基、羧基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、羧基取代C 1-6烷基、羧基取代C 1-6烷氧基、OR 5、NHR 5或NR 5R 6，所述R 5和R 6任选自C 1-6烷基、C 1-6烷氧基、含有任选自N、O和S的杂原子的4-至12-元杂环基、6元芳基、5-6元杂芳基、C 2-4烯基、C 2-4炔基或C 3-10环烷基； R 2 is optionally selected from hydrogen, halogen, amino, cyano, hydroxyl, nitro, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, carboxyl substituted C 1- 6 alkyl, carboxyl substituted C 1-6 alkoxy, OR 5 , NHR 5 or NR 5 R 6 , the R 5 and R 6 are optionally selected from C 1-6 alkyl, C 1-6 alkoxy, 4- to 12-membered heterocyclic group, 6-membered aryl group, 5-6 membered heteroaryl group, C 2-4 alkenyl, C 2-4 alkynyl or C 3-10 cycloalkyl;
R 3任选自氢、卤素、氨基、氰基、羟基、硝基、羧基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、羧基取代C 1-6烷基、羧基取代C 1-6烷氧基、OR 5、NHR 5或NR 5R 6，所述R 5和R 6任选自C 1-6烷基、C 1-6烷氧基、卤代6元芳基C 3-6环烷基、含有任选自N、O和S的杂原子的4-至12-元杂环基、6元芳基、5-6元杂芳基、卤代5-6元杂芳基、烷氧基6元芳基C 3-6环烷基、含有芳环、单环、螺环或并环的C 3-6环烷基、C 2-4烯基、C 2-4烯基C 3-6环烷基、C 2-4炔基或C 3-10环烷基。 R 3 is optionally selected from hydrogen, halogen, amino, cyano, hydroxyl, nitro, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, carboxyl substituted C 1- 6 alkyl, carboxyl substituted C 1-6 alkoxy, OR 5 , NHR 5 or NR 5 R 6 , the R 5 and R 6 are optionally selected from C 1-6 alkyl, C 1-6 alkoxy, Halogenated 6-membered aryl C 3-6 cycloalkyl, 4- to 12-membered heterocyclic group containing heteroatoms optionally selected from N, O and S, 6-membered aryl, 5-6-membered heteroaryl, Halogenated 5-6 membered heteroaryl, alkoxy 6-membered aryl C 3-6 cycloalkyl, C 3-6 cycloalkyl containing aromatic ring, single ring, spiro ring or parallel ring, C 2-4 Alkenyl, C 2-4 alkenyl, C 3-6 cycloalkyl, C 2-4 alkynyl or C 3-10 cycloalkyl.
优选地，所述化合物为具有式(II)结构的化合物或者其药学上可接受的盐、立体异构体以及其前药分子：Preferably, the compound is a compound having a structure of formula (II) or a pharmaceutically acceptable salt, stereoisomer and prodrug molecule thereof:
Figure PCTCN2021129535-appb-000002
Figure PCTCN2021129535-appb-000002
式(II)中n＝0或1；In formula (II), n=0 or 1;
R 1任选自氢、卤素、氰基、三氟甲基、甲酰胺基、磺酰胺基、C 1-6烷基、C 1-6烷氧基、卤代C 1-4烷基或卤代C 1-4烷氧基、C 1-3硫基、C 1-3烷基硫基、6元芳环硫基、含有任选自N、O和S的杂原子的4-至12-元杂环基的C 1-6烷基； R is optionally selected from hydrogen, halogen, cyano, trifluoromethyl, formamido, sulfonamide, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-4 alkyl or halo Substituting C 1-4 alkoxy, C 1-3 thio, C 1-3 alkylthio, 6-membered aromatic ring thio, 4- to 12-containing heteroatoms optionally selected from N, O and S C 1-6 alkyl of membered heterocyclic group;
优选地，所述R 1选自氢、氰基、环丙基或三氟甲基； Preferably, said R is selected from hydrogen, cyano, cyclopropyl or trifluoromethyl;
R 2任选自氢、卤素、氨基、氰基、羟基、硝基、羧基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、卤代C 1-6烷基、羧基取代C 1-6烷基、羧基取代C 1-6烷氧基、OR 5、NHR 5或NR 5R 6，所述R 5和R 6任选自C 1-6烷基、C 1-6烷氧基、、卤代6元芳基C 3-6环烷基、含有任选自N、O和S的杂原子的4-至12-元杂环基、6元芳基、5-6元杂芳基、卤代5-6元杂芳基、烷氧基6元芳基C 3-6环烷基、C 2-4烯基、C 2-4炔基或C 3-10环烷基； R is optionally selected from hydrogen, halogen, amino, cyano, hydroxyl, nitro, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, carboxy substituted C 1-6 alkyl, carboxy substituted C 1-6 alkoxy, OR 5 , NHR 5 or NR 5 R 6 , the R 5 and R 6 are optionally selected from C 1-6 alkyl, C 1-6 alkoxy, halogenated 6-membered aryl C 3-6 cycloalkyl, 4- to 12-membered heterocyclic group containing heteroatoms optionally selected from N, O and S, 6-membered aryl , 5-6 membered heteroaryl, halogenated 5-6 membered heteroaryl, alkoxy 6 membered aryl C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 3 -10 cycloalkyl;
优选的，所述R 2选自OR 5、NHR 5或NR 5R 6，所述R 5和R 6任选自C 1-6烷基、C 1-6烷氧基、含有任选自N、O和S的杂原子的4-至12-元杂环基、6元芳基、5-6元杂芳基、C 2-4烯基、C 2-4炔基或C 3-10环烷基； Preferably, the R 2 is selected from OR 5 , NHR 5 or NR 5 R 6 , and the R 5 and R 6 are optionally selected from C 1-6 alkyl, C 1-6 alkoxy, containing optionally selected from N , 4- to 12-membered heterocyclic group, 6-membered aryl group, 5-6-membered heteroaryl group, C 2-4 alkenyl, C 2-4 alkynyl or C 3-10 ring of heteroatoms of O and S alkyl;
R 3任选自氢、卤素、氨基、氰基、羟基、硝基、羧基、羧基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、羟基取代C 1-6烷基、羟基取代C 1-6烷氧基、氨基取代的C 1-6烷基、氨基取代的C 1-6烷氧基、羧基取代C 1-6烷基、羧基取代C 1-6烷氧基、N、O和S取代的4-至12-元芳环、单环、螺环或并环； R is optionally selected from hydrogen, halogen, amino, cyano, hydroxyl, nitro, carboxyl, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, hydroxyl substituted C 1-6 alkoxy, amino substituted C 1-6 alkyl, amino substituted C 1-6 alkoxy, carboxyl substituted C 1-6 alkyl, carboxyl substituted C 1 -6 alkoxy, N, O and S substituted 4- to 12-membered aromatic rings, monocyclic, spiro or parallel rings;
优选地，当n＝0时，所述R 3选自下述结构： Preferably, when n=0, said R 3 is selected from the following structures:
Br；
Figure PCTCN2021129535-appb-000003
Br;
Figure PCTCN2021129535-appb-000003
Figure PCTCN2021129535-appb-000004
Figure PCTCN2021129535-appb-000004
优选地，n＝1时，所述R 3选自下述结构： Preferably, when n=1, the R3 is selected from the following structures:
Figure PCTCN2021129535-appb-000005
Figure PCTCN2021129535-appb-000005
Figure PCTCN2021129535-appb-000006
Figure PCTCN2021129535-appb-000006
R 4任选自C 1-6烷基、C 1-6烷氧基、含有任选自N、O和S的杂原子的4-至12-元杂环基的C 1-6烷基； R is optionally selected from C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl containing 4- to 12-membered heterocyclyls optionally selected from N, O and S heteroatoms;
优选地，R 4选自C 1-6烷基。 Preferably, R 4 is selected from C 1-6 alkyl.
所述5-醛基杂环酰胺类化合物或者其药学上可接受的盐、立体异构体以及其前药分子在制备治疗或者预防由FGFR4信号通路异常引起的过渡增殖性疾病如肝癌、胆管癌、乳腺癌、胃癌、前列腺癌等抗肿瘤、抗癌药物中的应用。The 5-formyl heterocyclic amide compounds or their pharmaceutically acceptable salts, stereoisomers and prodrug molecules are used in the preparation of treatment or prevention of transitional proliferative diseases caused by abnormal FGFR4 signaling pathways, such as liver cancer and cholangiocarcinoma , breast cancer, gastric cancer, prostate cancer and other anti-tumor and anti-cancer drugs.
所述的一种治疗或者预防过渡增殖性疾病的药物组合物包括活性成分以及药学上可接受的载体，所述活性成分包括上述的5-醛基杂环酰胺类化合物或者其药学上可接受的盐、立体异构体以及其前药分子。The pharmaceutical composition for treating or preventing transitional proliferative diseases includes an active ingredient and a pharmaceutically acceptable carrier, and the active ingredient includes the above-mentioned 5-formyl heterocyclic amide compound or its pharmaceutically acceptable Salts, stereoisomers and their prodrug molecules.
本发明的有益效果如下：The beneficial effects of the present invention are as follows:
(1)本发明提供了一种结构新颖的5-醛基杂环酰胺类化合物或者其药学上可接受的盐、立体异构体以及其前药分子的结构和制备方法，可用于治疗或者预防由FGFR4信号通路异常引起的过渡增殖性疾病；(1) The present invention provides a structure and preparation method of a novel 5-formyl heterocyclic amide compound or its pharmaceutically acceptable salt, stereoisomer and prodrug molecule, which can be used for treatment or prevention Transitional proliferative diseases caused by abnormalities in the FGFR4 signaling pathway;
(2)本发明提供了一种预防和/或治疗肿瘤的药用组合物，组成包括活性成分和药学上可接受的辅料。(2) The present invention provides a pharmaceutical composition for preventing and/or treating tumors, which consists of active ingredients and pharmaceutically acceptable excipients.
具体实施方式Detailed ways
本发明下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商 所建议的条件。实施例中所用到的各种常用化学试剂，均为市售产品。The experimental method that does not indicate specific conditions in the following examples of the present invention, usually according to conventional conditions, or according to the conditions suggested by the manufacturer. Various commonly used chemical reagents used in the examples are all commercially available products.
除非另有定义，本发明所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不用于限制本发明。Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly understood by one of ordinary skill in the technical field of the present invention. Terms used in the description of the present invention are only for the purpose of describing specific embodiments, and are not used to limit the present invention.
本发明的术语“包括”和“具有”以及它们任何变形，意图在于覆盖不排他的包含。例如包含了一系列步骤的过程、方法、装置、产品或设备没有限定于已列出的步骤或模块，而是可选地还包括没有列出的步骤，或可选地还包括对于这些过程、方法、产品或设备固有的其它步骤。The terms "including" and "having" and any variations thereof in the present invention are intended to cover a non-exclusive inclusion. For example, a process, method, device, product or equipment that includes a series of steps is not limited to the listed steps or modules, but optionally also includes steps that are not listed, or optionally also includes for these processes, Other steps inherent in a method, product, or apparatus.
在本发明中提及的“多个”是指两个或两个以上。“和/或”，描述关联对象的关联关系，表示可以存在三种关系，例如，A和/或B，可以表示：单独存在A，同时存在A和B，单独存在B这三种情况。字符“/”一般表示前后关联对象是一种“或”的关系。The "plurality" mentioned in the present invention means two or more. "And/or" describes the association relationship of associated objects, indicating that there may be three types of relationships, for example, A and/or B may indicate: A exists alone, A and B exist simultaneously, and B exists independently. The character "/" generally indicates that the contextual objects are an "or" relationship.
本发明所述化合物中，当任何变量(例如R5、R6等)在任何组分中出现超过一次，则其每次出现的定义独立于其它每次出现的定义。同样，允许取代基及变量的组合，只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环，其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易合成的化合物。如果取代基自身被超过一个基团取代，应理解这些基团可在相同碳原子上或不同碳原子上，只要使结构稳定。In compounds described herein, when any variable (eg, R5, R6, etc.) occurs more than once in any component, its definition for each occurrence is independent of the definition for each other occurrence. Also, combinations of substituents and variables are permissible only if such combinations render the compounds stable. A line drawn from a substituent into a ring system indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic it means that such bonds are only to any suitable carbon atoms of adjacent rings. It is understood that one of ordinary skill in the art can select substituents and substitution patterns on the compounds of the present invention to provide compounds that are chemically stable and can be readily synthesized from readily available starting materials by skill in the art and by methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stabilized.
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如，“C1-C20烷基”中“C1-C20”的定义包括以直链或支链排列的具有1、2、3、4、5….或20个碳原子的基团。术语“环烷基”指具有特定碳原子数目的单环饱和脂肪烃基。例如“环烷基”包括环丙基、甲基-环丙基、2,2-二甲基-环丁基、2-乙基-环戊基、环己基等。The term "alkyl" as used herein is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, the definition of "C1-C20" in "C1-C20 alkyl" includes groups having 1, 2, 3, 4, 5... or 20 carbon atoms arranged in a linear or branched chain. The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example "cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl and the like.
本文所用术语“烷氧基”代表烷基-氧基基团，其中烷基的定义如上所示。The term "alkoxy" as used herein denotes an alkyl-oxy group wherein alkyl is as defined above.
正如本领域技术人员所理解的，本文中所用“卤素”意指包括氯、氟、溴和碘。As understood by those skilled in the art, "halogen" as used herein is meant to include chlorine, fluorine, bromine and iodine.
本发明包括式(I)化合物的游离形式，也包括其药学上可接受的盐、其立体异构体及其前药分子。术语“游离形式”指以非盐形式的化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐，也包括所有式(I)化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如，可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别，但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。The present invention includes the free form of the compound of formula (I), as well as its pharmaceutically acceptable salt, its stereoisomer and its prodrug molecule. The term "free form" refers to a compound in non-salt form. The inclusion of pharmaceutically acceptable salts includes not only the exemplary salts of the specific compounds described herein, but also all typical pharmaceutically acceptable salts of the free form of the compounds of formula (I). The free form of a particular salt of the compound may be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous base, such as dilute aqueous NaOH, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms for the purposes of the invention.
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常，通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的，通过和适当的无机或有机碱反应形成酸性化合物的盐。The pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention that contain a basic or acidic moiety by conventional chemical methods. Generally, the salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric amount or excess of the desired salt form of an inorganic or organic acid in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with an appropriate inorganic or organic base.
因此，本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。Accordingly, pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting a basic compound of the present invention with an inorganic or organic acid.
如果本发明化合物为酸性的，则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐。Where the compound of the present invention is acidic, appropriate "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
为使本发明的目的、技术方案和优点更加清楚明了，下面结合具体实施方式，对本发明进一步详细说明。应该理解，这些描述只是示例性的，而并非要限制本发明的范围。此外，在以下说明中，省略了对公知结构和技术的描述，以避免不必要地混淆本发明的概念。In order to make the object, technical solution and advantages of the present invention clearer, the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that these descriptions are exemplary only, and are not intended to limit the scope of the present invention. Also, in the following description, descriptions of well-known structures and techniques are omitted to avoid unnecessarily obscuring the concept of the present invention.
以下实施例对本发明做进一步的描述，但该实施例并非用于限制本发明的保护范围。The following examples further describe the present invention, but the examples are not intended to limit the protection scope of the present invention.
实施例1Example 1
化合物1：N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺Compound 1: N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2 -b] pyridine-3-carboxamide
Figure PCTCN2021129535-appb-000007
Figure PCTCN2021129535-appb-000007
步骤a：2-氯-3-硝基-6-吡啶甲醛(化合物1-1)的制备Step a: Preparation of 2-chloro-3-nitro-6-pyridinecarbaldehyde (compound 1-1)
将二氧化硒(12.86g,2.0eq)加到2-氯-3-硝基-6-甲基吡啶(10.0g,1.0eq)的二氧六环(50mL)溶液中，120℃反应，体系经TLC监测反应完全后，降至室温后搅拌状态下缓慢加入饱和碳酸氢钠调至pH＝8.0，用乙酸乙酯萃取,有机层经减压浓缩，柱层析分离得产物2.7g，产率25％。Add selenium dioxide (12.86g, 2.0eq) to a solution of 2-chloro-3-nitro-6-methylpyridine (10.0g, 1.0eq) in dioxane (50mL), react at 120°C, and the system After the completion of the reaction was monitored by TLC, after cooling down to room temperature and stirring, slowly added saturated sodium bicarbonate to adjust the pH to 8.0, extracted with ethyl acetate, concentrated the organic layer under reduced pressure, and separated by column chromatography to obtain 2.7 g of the product. The yield was 25%.
1H NMR(400MHz,DMSO-d 6)δ9.94(d,J＝0.8Hz,1H),8.78(dd,J＝8.1,0.8Hz,1H),8.16(d,J＝8.1Hz,1H).LC-MS(ESI)m/z 185.0[M–H] -. 1 H NMR (400MHz, DMSO-d 6 ) δ9.94 (d, J = 0.8Hz, 1H), 8.78 (dd, J = 8.1, 0.8Hz, 1H), 8.16 (d, J = 8.1Hz, 1H) .LC-MS(ESI) m/z 185.0[M–H] - .
步骤b：2-氯-6-(1,3-二氧戊环-2-基)-3-硝基吡啶(化合物1-2)的制备Step b: Preparation of 2-chloro-6-(1,3-dioxolan-2-yl)-3-nitropyridine (compound 1-2)
将化合物1-1(2.7g，1.0eq),乙二醇(2.7g,3.0eq)与对甲苯磺酸一水合物(1.38g,0.5eq)溶于20mL甲苯中，115℃反应1h。反应结束后，加入乙酸乙酯，用水洗涤有机相，取有机相减压浓缩，柱层析分离得产物2.8g,产率83.88％。Compound 1-1 (2.7g, 1.0eq), ethylene glycol (2.7g, 3.0eq) and p-toluenesulfonic acid monohydrate (1.38g, 0.5eq) were dissolved in 20mL of toluene, and reacted at 115°C for 1h. After the reaction, ethyl acetate was added, the organic phase was washed with water, the organic phase was concentrated under reduced pressure, and separated by column chromatography to obtain 2.8 g of the product, with a yield of 83.88%.
1H NMR(400MHz,DMSO-d 6)δ8.63(d,J＝8.2Hz,1H),7.81(d,J＝8.2Hz,1H),5.85(s,1H),4.12–4.08(m,2H),4.04–4.00(m,2H).LC-MS(ESI)m/z 229.0[M–H] -. 1 H NMR (400MHz, DMSO-d 6 )δ8.63(d, J=8.2Hz, 1H), 7.81(d, J=8.2Hz, 1H), 5.85(s, 1H), 4.12–4.08(m, 2H), 4.04–4.00(m,2H). LC-MS (ESI) m/z 229.0[M–H] - .
步骤c：2-(6-(1,3-二氧戊环-2-基)-3-硝基吡啶-2-基)丙二酸二乙酯(化合物1-3)的制备Step c: Preparation of diethyl 2-(6-(1,3-dioxolan-2-yl)-3-nitropyridin-2-yl)malonate (compound 1-3)
将化合物1-2(2.8g,1.0eq)，丙二酸二乙酯(3.9g,2.0eq)溶于20mL重蒸四氢呋喃溶液中，0℃下缓慢加入钠氢(1.0g,2.0eq)，搅拌10min后转至70℃下反应2h，冷却至室温，用水洗涤有机相，乙酸乙酯萃取，减压浓缩有机相，柱层析分离得产物3.5g,产率81.35％。Compound 1-2 (2.8g, 1.0eq), diethyl malonate (3.9g, 2.0eq) was dissolved in 20mL redistilled tetrahydrofuran solution, sodium hydrogen (1.0g, 2.0eq) was slowly added at 0°C, After stirring for 10 min, transfer to 70°C for 2 h, cool to room temperature, wash the organic phase with water, extract with ethyl acetate, concentrate the organic phase under reduced pressure, and separate by column chromatography to obtain 3.5 g of the product with a yield of 81.35%.
1H NMR(400MHz,DMSO-d 6)δ8.68(d,J＝8.5Hz,1H),7.83(d,J＝8.5Hz,1H),5.82(s,1H),5.61(s,1H),4.20(p,J＝7.1Hz,4H),4.14–4.07(m,2H),4.07–4.00(m,2H),1.20(t,J＝7.1Hz,6H).LC-MS(ESI)m/z 353.1[M–H] -. 1 H NMR (400MHz, DMSO-d 6 ) δ8.68(d, J=8.5Hz, 1H), 7.83(d, J=8.5Hz, 1H), 5.82(s, 1H), 5.61(s, 1H) ,4.20(p,J=7.1Hz,4H),4.14–4.07(m,2H),4.07–4.00(m,2H),1.20(t,J=7.1Hz,6H).LC-MS(ESI)m /z 353.1[M–H] - .
步骤d：2-(6-(1,3-二氧戊环-2-基)-3-硝基吡啶-2-基)乙酸乙酯(化合物1-4)的制备Step d: Preparation of ethyl 2-(6-(1,3-dioxolan-2-yl)-3-nitropyridin-2-yl)acetate (compound 1-4)
将化合物1-3(3.5g,1.0eq)，氯化锂(0.63g,1.5eq)溶于20ml DMSO和H 2O(50：1)的混合溶液中，120℃反应8h。冷却至室温，用水洗涤有机相，乙酸乙酯萃取，减压浓缩有机相，柱层析分离得产物2.48g,产率88.95％。 Compound 1-3 (3.5g, 1.0eq), lithium chloride (0.63g, 1.5eq) was dissolved in a mixed solution of 20ml DMSO and H 2 O (50:1), and reacted at 120°C for 8h. Cool to room temperature, wash the organic phase with water, extract with ethyl acetate, concentrate the organic phase under reduced pressure, and separate by column chromatography to obtain 2.48 g of the product, with a yield of 88.95%.
1H NMR(400MHz,DMSO-d 6)δ8.61(d,J＝8.4Hz,1H),7.77(d,J＝8.5Hz,1H),5.83(s,1H),4.25(s,2H),4.15–4.12(m,2H),4.12–4.09(m,2H),4.04–4.01(m,2H),1.17(t,J＝7.1Hz,3H).LC-MS(ESI)m/z 281.1[M–H] -. 1 H NMR (400MHz, DMSO-d 6 )δ8.61(d, J＝8.4Hz, 1H), 7.77(d, J＝8.5Hz, 1H), 5.83(s, 1H), 4.25(s, 2H) ,4.15–4.12(m,2H),4.12–4.09(m,2H),4.04–4.01(m,2H),1.17(t,J=7.1Hz,3H).LC-MS(ESI)m/z 281.1 [M–H] - .
步骤e：2-(6-(1,3-二氧戊环-2-基)-3-硝基吡啶-2-基)-3-(二甲基氨基)丙烯酸乙酯(化合物1-5)的制备Step e: ethyl 2-(6-(1,3-dioxolan-2-yl)-3-nitropyridin-2-yl)-3-(dimethylamino)acrylate (compound 1-5 ) preparation
将化合物1-4(2.48g,1.0eq)，N,N-二甲基甲酰胺二甲基缩醛(1.57g,1.5eq)溶于20mL DMF中，80℃反应，体系经TLC监测原料反应完全后冷却至室温，用水洗涤有机相，乙酸乙酯萃取，减压浓缩有机相，柱层析分离得产物1.8g,产率61.45％。Dissolve compound 1-4 (2.48g, 1.0eq), N,N-dimethylformamide dimethyl acetal (1.57g, 1.5eq) in 20mL DMF, react at 80°C, and monitor the reaction of raw materials by TLC After completion, cool to room temperature, wash the organic phase with water, extract with ethyl acetate, concentrate the organic phase under reduced pressure, and separate the product by column chromatography to obtain 1.8 g, with a yield of 61.45%.
1H NMR(400MHz,DMSO-d 6)δ8.34(d,J＝8.3Hz,1H),7.70(s,1H),7.52(d,J＝8.3Hz,1H),5.81(s,1H),4.09(d,J＝7.2Hz,2H),4.03–4.00(m,2H),3.94(m,2H),2.89(s,3H),2.73(s,3H),1.05(t,J＝6.7Hz,3H).LC-MS(ESI)m/z 338.1[M+H] +. 1 H NMR (400MHz,DMSO-d 6 )δ8.34(d,J=8.3Hz,1H),7.70(s,1H),7.52(d,J=8.3Hz,1H),5.81(s,1H) ,4.09(d,J=7.2Hz,2H),4.03–4.00(m,2H),3.94(m,2H),2.89(s,3H),2.73(s,3H),1.05(t,J=6.7 Hz,3H).LC-MS(ESI)m/z 338.1[M+H] + .
步骤f：5-(1,3-二氧戊环-2-基)-1H-吡咯并[3,2-b]吡啶-3-羧酸乙酯(化合物1-6)的制备Step f: Preparation of ethyl 5-(1,3-dioxolan-2-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (compound 1-6)
将化合物1-5(1.8g,1.0eq),铁粉(1.5g,5.0eq)溶于20mL醋酸中，50℃反应1h。体系冷却至室温后缓慢加入饱和碳酸氢钠调至pH＝8.0，用乙酸乙酯萃取,减压浓缩有机相，柱层析分离得产物0.6g，产率42.87％。Compound 1-5 (1.8g, 1.0eq), iron powder (1.5g, 5.0eq) were dissolved in 20mL of acetic acid, and reacted at 50°C for 1h. After the system was cooled to room temperature, saturated sodium bicarbonate was slowly added to adjust the pH to 8.0, extracted with ethyl acetate, the organic phase was concentrated under reduced pressure, and the product was separated by column chromatography to obtain 0.6 g, with a yield of 42.87%.
1H NMR(400MHz,CDCl 3)δ11.18(s,1H),8.25(s,1H),7.88(d,J＝8.5Hz,1H),7.47(d,J＝8.5Hz,1H),5.94(s,1H),4.35(q,J＝7.0Hz,2H),4.20–4.13(m,2H),4.06–3.99(m,2H),1.35(t,J＝7.1Hz,3H).LC-MS(ESI)m/z 263.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ11.18(s, 1H), 8.25(s, 1H), 7.88(d, J=8.5Hz, 1H), 7.47(d, J=8.5Hz, 1H), 5.94 (s,1H),4.35(q,J=7.0Hz,2H),4.20–4.13(m,2H),4.06–3.99(m,2H),1.35(t,J=7.1Hz,3H).LC- MS(ESI)m/z 263.1[M+H] + .
步骤g：5-(1,3-二氧戊环-2-基)-1-甲基-1H-吡咯并[3,2-b]吡啶-3-羧酸乙酯(化合物1-7)的制备Step g: Ethyl 5-(1,3-dioxolan-2-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate (compound 1-7) preparation of
将化合物1-6(200mg,1.0eq),碳酸钾(210mg,2.0eq),碘甲烷(130mg,1.2eq)溶于10mL无水THF中，室温反应，体系经TLC监测原料反应完毕后，加入乙酸乙酯，用水洗涤有机相，减压浓缩有机相后柱层析分离得产物182mg,产率86.38％。Dissolve compound 1-6 (200mg, 1.0eq), potassium carbonate (210mg, 2.0eq), iodomethane (130mg, 1.2eq) in 10mL of anhydrous THF, and react at room temperature. After the reaction of the raw materials is monitored by TLC, add Ethyl acetate, washed the organic phase with water, concentrated the organic phase under reduced pressure and separated by column chromatography to obtain 182 mg of product with a yield of 86.38%.
1H NMR(400MHz,CDCl 3)δ7.93(s,1H),7.65(d,J＝8.6Hz,1H),7.46(d,J＝8.6Hz,1H),6.05(s,1H),4.40(q,J＝7.1Hz,2H),4.27–4.20(m,2H),4.14–4.07(m,2H),3.82(s,3H),1.42(t,J＝7.1Hz,3H).LC-MS(ESI)m/z 277.1[M+H] +. 1 H NMR (400MHz, CDCl 3 )δ7.93(s,1H),7.65(d,J=8.6Hz,1H),7.46(d,J=8.6Hz,1H),6.05(s,1H),4.40 (q,J=7.1Hz,2H),4.27–4.20(m,2H),4.14–4.07(m,2H),3.82(s,3H),1.42(t,J=7.1Hz,3H).LC- MS(ESI)m/z 277.1[M+H] + .
步骤a1：2-氨基-4-氟-5-碘吡啶(化合物1-8)的制备Step a1: Preparation of 2-amino-4-fluoro-5-iodopyridine (compound 1-8)
将4-氟吡啶-2-胺(10.0g,1.0eq),NIS(22.0g,1.1eq)，TFA(4.0g,0.4eq)溶于30ml MeCN中，室温反应过夜后，加入饱和Na 2SO 3水溶液,再加入乙酸乙酯萃取，无水硫酸钠干燥，减压浓缩有机相得到化合物1-8(17.6g,82.84％)。 Dissolve 4-fluoropyridin-2-amine (10.0g, 1.0eq), NIS (22.0g, 1.1eq), TFA (4.0g, 0.4eq) in 30ml MeCN, react overnight at room temperature, add saturated Na 2 SO 3 aqueous solution, then added ethyl acetate for extraction, dried over anhydrous sodium sulfate, and concentrated the organic phase under reduced pressure to obtain compound 1-8 (17.6 g, 82.84%).
1H NMR(400MHz,DMSO-d 6)δ8.10(d,J＝9.8Hz,1H),6.41(br,2H),6.29(d,J＝10.9Hz,1H).LC-MS(ESI)m/z 239.0[M+H] +. 1 H NMR (400MHz, DMSO-d 6 ) δ8.10(d, J=9.8Hz, 1H), 6.41(br, 2H), 6.29(d, J=10.9Hz, 1H).LC-MS(ESI) m/z 239.0[M+H] + .
步骤b1：2-氨基-4-氟-5-氰基吡啶(化合物1-9)的制备Step b1: Preparation of 2-amino-4-fluoro-5-cyanopyridine (compound 1-9)
将上述化合物1-8(17.6g,1.0eq)，Zn(CN) 2(9.1g,1.05eq),Zn(1.0g,0.2eq),1,1'-双(二苯基膦)二茂铁(8.2g,0.2eq)和Pd2(dba)3(2.7g,0.04eq)溶于50mLDMA中，体系置换氩气后转至110℃反应5h后，冷却至室温，加入饱和NaHCO3溶液，并用乙酸乙酯萃取，减压浓缩有机相，柱层析分离得产物8.1g,产率79.93％。 The above compound 1-8 (17.6g, 1.0eq), Zn(CN) 2 (9.1g, 1.05eq), Zn (1.0g, 0.2eq), 1,1'-bis(diphenylphosphine)dicene Iron (8.2g, 0.2eq) and Pd2(dba)3 (2.7g, 0.04eq) were dissolved in 50mL of DMA, and the system was replaced with argon and then transferred to 110°C for 5 hours of reaction. After cooling to room temperature, saturated NaHCO3 solution was added, and acetic acid Extracted with ethyl ester, concentrated the organic phase under reduced pressure, and separated by column chromatography to obtain 8.1 g of the product with a yield of 79.93%.
1H NMR(400MHz,DMSO-d 6)δ7.95(d,J＝10.2Hz,1H),6.50(s,2H),6.25(d,J＝5.7Hz,1H).LC-MS(ESI)m/z 138.0[M+H] +. 1 H NMR (400MHz,DMSO-d 6 )δ7.95(d,J=10.2Hz,1H),6.50(s,2H),6.25(d,J=5.7Hz,1H).LC-MS(ESI) m/z 138.0[M+H] + .
步骤c1：6-氨基-4-((2-甲氧基乙基)氨基)烟腈(化合物1-10)的制备Step c1: Preparation of 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (compound 1-10)
将化合物1-9(2.0g,1.0eq),和2-甲氧基乙胺(2.2g,2.0eq)溶于20mLTHF中，60℃反应过夜。加入饱和NH 4Cl水溶液，乙酸乙酯萃取，减压浓缩有机相，柱层析分离得产物2.4g,产率85.60％。 Compound 1-9 (2.0g, 1.0eq), and 2-methoxyethylamine (2.2g, 2.0eq) were dissolved in 20mLTHF, and reacted overnight at 60°C. Saturated NH 4 Cl aqueous solution was added, extracted with ethyl acetate, the organic phase was concentrated under reduced pressure, and the product was separated by column chromatography to obtain 2.4 g, with a yield of 85.60%.
1H NMR(400MHz,DMSO-d 6)δ7.90(s,1H),6.39(s,2H),6.14(t,J＝5.7Hz,1H),5.62(s,1H),3.47(t,J＝5.9Hz,2H),3.27(s,3H),3.24(dd,J＝6.0Hz,5.9Hz,2H).LC-MS(ESI)m/z192.1[M+H] +. 1 H NMR (400MHz, DMSO-d 6 )δ7.90(s,1H),6.39(s,2H),6.14(t,J=5.7Hz,1H),5.62(s,1H),3.47(t, J＝5.9Hz, 2H), 3.27(s, 3H), 3.24(dd, J＝6.0Hz, 5.9Hz, 2H).LC-MS (ESI) m/z192.1[M+H] + .
步骤h：N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-(1,3-二氧戊环-2-基)-1-甲基-1H-吡咯并[3,2-b]吡啶-3-羧酰胺(化合物1-11)的制备Step h: N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolan-2-yl)-1 Preparation of -methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 1-11)
将化合物1-7(150.0mg,1.5eq.)与化合物1-10(70.0mg,1.0eq.)溶于5ml甲苯中，氩气保护，0℃下缓慢滴加三甲基铝(0.36mL,2.0eq,2.0M)并搅拌10min，随后缓慢升温至115℃， 反应24h。体系冷却至室温后加入甲醇淬灭，体系直接减压抽滤，柱层析分离得产物90.0mg,产率58.43％。Compound 1-7 (150.0mg, 1.5eq.) and compound 1-10 (70.0mg, 1.0eq.) were dissolved in 5ml of toluene, protected by argon, and trimethylaluminum (0.36mL, 2.0eq, 2.0M) and stirred for 10min, then slowly raised the temperature to 115°C, and reacted for 24h. After the system was cooled to room temperature, methanol was added to quench the system. The system was directly vacuum-filtered and separated by column chromatography to obtain 90.0 mg of the product with a yield of 58.43%.
1H NMR(400MHz,CDCl 3)δ11.09(s,1H),8.09(s,1H),8.04(s,1H),7.87(s,1H),7.77(d,J＝8.0Hz,1H),7.53(d,J＝8.0Hz,1H),6.17(s,1H),5.15(t,J＝4.0Hz,1H),4.38–4.36(s,2H),4.19–4.16(s,2H),3.93(s,3H),3.69(t,J＝4.0Hz,2H),3.52(dd,J＝4.0Hz,8.0Hz,2H),3.44(s,3H).LC-MS(ESI)m/z 423.2[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ11.09(s,1H),8.09(s,1H),8.04(s,1H),7.87(s,1H),7.77(d,J＝8.0Hz,1H) ,7.53(d,J=8.0Hz,1H),6.17(s,1H),5.15(t,J=4.0Hz,1H),4.38–4.36(s,2H),4.19–4.16(s,2H), 3.93(s,3H),3.69(t,J=4.0Hz,2H),3.52(dd,J=4.0Hz,8.0Hz,2H),3.44(s,3H).LC-MS(ESI)m/z 423.2[M+H] + .
步骤iN-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物1)的制备Step iN-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b ] The preparation of pyridine-3-carboxamide (compound 1)
将化合物1-11(90.0mg,1.0eq.)溶于5ml THF中,加入1.0ml 2N盐酸,室温反应，体系经TLC监测反应完全后，加入饱和碳酸氢钠调至pH＝8.0，用乙酸乙酯萃取,用无水硫酸钠干燥，减压浓缩，柱层析分离得目标化合物48.0mg，产率59.54％。Dissolve compound 1-11 (90.0 mg, 1.0 eq.) in 5 ml of THF, add 1.0 ml of 2N hydrochloric acid, and react at room temperature. After the system is monitored by TLC for complete reaction, add saturated sodium bicarbonate to adjust the pH to 8.0. The ester was extracted, dried with anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 48.0 mg of the target compound with a yield of 59.54%.
1H NMR(400MHz,DMSO-d 6)δ11.09(s,1H),10.08(s,1H),8.64(s,1H),8.32(d,J＝9.2Hz,2H),7.95(d,J＝8.5Hz,1H),7.77(s,1H),7.08(t,J＝5.7Hz,1H),3.99(s,3H),3.56(t,J＝5.8Hz,2H),3.42(q,J＝5.7Hz,2H),3.34(s,3H).LC-MS(ESI)m/z 379.1[M+H] +. 1 H NMR (400MHz, DMSO-d 6 ) δ11.09(s, 1H), 10.08(s, 1H), 8.64(s, 1H), 8.32(d, J=9.2Hz, 2H), 7.95(d, J＝8.5Hz, 1H), 7.77(s, 1H), 7.08(t, J＝5.7Hz, 1H), 3.99(s, 3H), 3.56(t, J＝5.8Hz, 2H), 3.42(q, J=5.7Hz, 2H), 3.34(s, 3H). LC-MS (ESI) m/z 379.1[M+H] + .
实施例2 N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物2)Example 2 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1H-pyrrolo[3,2-b]pyridine- 3-Formamide (Compound 2)
Figure PCTCN2021129535-appb-000008
Figure PCTCN2021129535-appb-000008
以化合物1-6和化合物1-10为原料，合成方法同实施例1。 1H NMR(400MHz,DMSO-d 6)δ12.79(s,1H),11.19(s,1H),10.12(s,1H),8.65(d,J＝3.1Hz,1H),8.37(s,1H),8.20(d,J＝8.4Hz,1H),7.93(d,J＝8.4Hz,1H),7.78(s,1H),7.24(d,J＝5.8Hz,1H),3.55(s,2H),3.44(q,J＝5.7Hz,2H),3.31(s,3H).LC-MS(ESI)m/z 365.1[M+H] +. Using compound 1-6 and compound 1-10 as raw materials, the synthesis method is the same as in Example 1. 1 H NMR (400MHz, DMSO-d 6 )δ12.79(s,1H),11.19(s,1H),10.12(s,1H),8.65(d,J=3.1Hz,1H),8.37(s, 1H), 8.20(d, J=8.4Hz, 1H), 7.93(d, J=8.4Hz, 1H), 7.78(s, 1H), 7.24(d, J=5.8Hz, 1H), 3.55(s, 2H), 3.44(q, J=5.7Hz, 2H), 3.31(s, 3H). LC-MS(ESI) m/z 365.1[M+H] + .
实施例3 N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-乙基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物3)Example 3 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-ethyl-1H-pyrrolo[3,2 -b] pyridine-3-carboxamide (compound 3)
Figure PCTCN2021129535-appb-000009
Figure PCTCN2021129535-appb-000009
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),10.08(s,1H),8.72(s,1H),8.40(d,J＝8.5Hz,1H),8.31(s,1H),7.94(d,J＝8.5Hz,1H),7.78(s,1H),7.08(t,J＝5.5Hz,1H),4.42(q,J＝7.2Hz,2H),3.56(t,J＝5.8Hz,2H),3.42(q,J＝5.7Hz,2H),3.34(s,3H),1.44(t,J＝7.2Hz,3H).LC-MS(ESI)m/z 393.2[M+H] +. The synthesis method is as in Example 1. 1H NMR (400MHz, DMSO-d6) δ11.07(s, 1H), 10.08(s, 1H), 8.72(s, 1H), 8.40(d, J=8.5Hz, 1H) ,8.31(s,1H),7.94(d,J=8.5Hz,1H),7.78(s,1H),7.08(t,J=5.5Hz,1H),4.42(q,J=7.2Hz,2H) ,3.56(t,J=5.8Hz,2H),3.42(q,J=5.7Hz,2H),3.34(s,3H),1.44(t,J=7.2Hz,3H).LC-MS(ESI) m/z 393.2[M+H] + .
实施例4 N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-丙基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物4)Example 4 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-propyl-1H-pyrrolo[3,2 -b] pyridine-3-carboxamide (compound 4)
Figure PCTCN2021129535-appb-000010
Figure PCTCN2021129535-appb-000010
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.08(s,1H),10.08(s,1H),8.71(s,1H),8.42(d,J＝8.5Hz,1H),8.31(s,1H),7.94(d,J＝8.6Hz,1H),7.78(s,1H),7.09(t,J＝5.5Hz,1H),4.36(t,J＝7.0Hz,2H),3.56(t,J＝5.8Hz,2H),3.42(q,J＝5.8Hz,2H),3.31(s,3H),1.85(h,J＝7.3Hz,2H),0.84(t,J＝7.4Hz,3H).LC-MS(ESI)m/z 407.2[M+H] +. The synthesis method is as in Example 1. 1H NMR (400MHz, DMSO-d6) δ11.08(s, 1H), 10.08(s, 1H), 8.71(s, 1H), 8.42(d, J=8.5Hz, 1H) ,8.31(s,1H),7.94(d,J=8.6Hz,1H),7.78(s,1H),7.09(t,J=5.5Hz,1H),4.36(t,J=7.0Hz,2H) ,3.56(t,J=5.8Hz,2H),3.42(q,J=5.8Hz,2H),3.31(s,3H),1.85(h,J=7.3Hz,2H),0.84(t,J= 7.4Hz,3H).LC-MS (ESI) m/z 407.2[M+H] + .
实施例5 N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-异丙基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物5)Example 5 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-isopropyl-1H-pyrrolo[3, 2-b] Pyridine-3-carboxamide (Compound 5)
Figure PCTCN2021129535-appb-000011
Figure PCTCN2021129535-appb-000011
合成方法如实施例1。1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.08(s,1H),8.81(s,1H),8.45(d,J＝8.6Hz,1H),8.31(s,1H),7.94(d,J＝8.6Hz,1H),7.80(s,1H),7.10(t,J＝5.7Hz,1H),4.98(hept,J＝6.7Hz,1H),3.55(t,J＝5.8Hz,2H),3.42(q,J＝5.8Hz,2H),3.31(s,3H),1.55(d,J＝6.7Hz,6H).LC-MS(ESI)m/z 407.2[M+H] +. The synthesis method is as in Example 1. 1H NMR (400MHz, DMSO-d6) δ11.09(s, 1H), 10.08(s, 1H), 8.81(s, 1H), 8.45(d, J=8.6Hz, 1H) ,8.31(s,1H),7.94(d,J=8.6Hz,1H),7.80(s,1H),7.10(t,J=5.7Hz,1H),4.98(hept,J=6.7Hz,1H) ,3.55(t,J=5.8Hz,2H),3.42(q,J=5.8Hz,2H),3.31(s,3H),1.55(d,J=6.7Hz,6H).LC-MS(ESI) m/z 407.2[M+H] + .
实施例6 N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-异丁基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物6)Example 6 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-isobutyl-1H-pyrrolo[3, 2-b]pyridine-3-carboxamide (compound 6)
Figure PCTCN2021129535-appb-000012
Figure PCTCN2021129535-appb-000012
合成方法如实施例1。 1H NMR(400MHz,DMSO-d 6)δ11.10(s,1H),10.09(s,1H),8.68(s,1H),8.43(d,J＝8.6Hz,1H),8.32(s,1H),7.95(d,J＝8.6Hz,1H),7.79(s,1H),7.09(t,J＝5.7Hz,1H),4.22(d,J＝7.4Hz,2H),3.55(t,J＝5.8Hz,2H),3.42(q,J＝5.5Hz,2H),3.31(s,3H),2.18(hept,J＝6.9Hz,1H),0.86(d,J＝6.6Hz,6H).LC-MS(ESI)m/z 421.2[M+H] +. The synthesis method is as in Example 1. 1 H NMR (400MHz,DMSO-d 6 )δ11.10(s,1H),10.09(s,1H),8.68(s,1H),8.43(d,J=8.6Hz,1H),8.32(s, 1H), 7.95(d, J=8.6Hz, 1H), 7.79(s, 1H), 7.09(t, J=5.7Hz, 1H), 4.22(d, J=7.4Hz, 2H), 3.55(t, J＝5.8Hz, 2H), 3.42(q, J＝5.5Hz, 2H), 3.31(s, 3H), 2.18(hept, J＝6.9Hz, 1H), 0.86(d, J＝6.6Hz, 6H) .LC-MS(ESI) m/z 421.2[M+H] + .
实施例7 N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-(环丙基甲基)1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物7)Example 7 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-(cyclopropylmethyl)1H-pyrrolo [3,2-b]pyridine-3-carboxamide (Compound 7)
Figure PCTCN2021129535-appb-000013
Figure PCTCN2021129535-appb-000013
合成方法如实施例1。 1H NMR(400MHz,DMSO-d 6)δ11.11(s,1H),10.11(s,1H),8.77(s,1H),8.46(d,J＝8.0Hz,1H),8.32(s,1H),7.97(d,J＝8.0Hz,1H),7.81(s,1H),7.09(t,J＝6.0Hz,1H),4.29(d,J＝8.0Hz,2H),3.57(t,J＝6.0Hz,2H),3.44(q,J＝4.0Hz,8.0Hz,2H),3.32(s,3H),1.38–1.34(m,1H).1.23(s,4H).LC-MS(ESI)m/z 419.2[M+H] +. The synthesis method is as in Example 1. 1 H NMR (400MHz,DMSO-d 6 )δ11.11(s,1H),10.11(s,1H),8.77(s,1H),8.46(d,J=8.0Hz,1H),8.32(s, 1H), 7.97(d, J=8.0Hz, 1H), 7.81(s, 1H), 7.09(t, J=6.0Hz, 1H), 4.29(d, J=8.0Hz, 2H), 3.57(t, J＝6.0Hz, 2H), 3.44(q, J＝4.0Hz, 8.0Hz, 2H), 3.32(s, 3H), 1.38–1.34(m, 1H). 1.23(s, 4H).LC-MS( ESI)m/z 419.2[M+H] + .
实施例8 N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-(2-甲氧基乙基)-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物8)Example 8 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-(2-methoxyethyl)-1H -pyrrolo[3,2-b]pyridine-3-carboxamide (compound 8)
Figure PCTCN2021129535-appb-000014
Figure PCTCN2021129535-appb-000014
合成方法如实施例1。 1H NMR(400MHz,DMSO-d6)δ11.09(s,1H),10.09(s,1H),8.64(s,1H),8.39(d,J＝8.5Hz,1H),8.32(s,1H),7.95(d,J＝8.5Hz,1H),7.79(s,1H),7.10(t,J＝5.7Hz,1H),4.57(t,J＝4.9Hz,2H),3.72(t,J＝4.9Hz,2H),3.55(t,J＝5.8Hz,2H),3.43(m,2H),3.31(s,3H),3.22(s,3H).LC-MS(ESI)m/z 423.2[M+H] +. The synthesis method is as in Example 1. 1 H NMR (400MHz,DMSO-d6)δ11.09(s,1H),10.09(s,1H),8.64(s,1H),8.39(d,J=8.5Hz,1H),8.32(s,1H ),7.95(d,J=8.5Hz,1H),7.79(s,1H),7.10(t,J=5.7Hz,1H),4.57(t,J=4.9Hz,2H),3.72(t,J =4.9Hz, 2H), 3.55(t, J=5.8Hz, 2H), 3.43(m, 2H), 3.31(s, 3H), 3.22(s, 3H).LC-MS(ESI) m/z 423.2 [M+H] + .
实施例9 N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-环戊基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物9)Example 9 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-cyclopentyl-1H-pyrrolo[3, 2-b]pyridine-3-carboxamide (Compound 9)
Figure PCTCN2021129535-appb-000015
Figure PCTCN2021129535-appb-000015
合成方法如实施例1。 1H NMR(400MHz,DMSO-d 6)δ11.05(s,1H),10.06(s,1H),8.67(s,1H),8.40(d,J＝8.5Hz,1H),8.28(s,1H),7.91(d,J＝8.6Hz,1H),7.77(s,1H),7.08(t,J＝5.7Hz,1H),5.06(p,J＝7.4Hz,1H),3.55(t,J＝5.9Hz,2H),3.41(q,J＝5.9Hz,2H),3.31(s,3H),2.23(m,2H),1.96(m,2H),1.88(t,J＝6.3,2.3Hz,2H),1.73(dq,J＝8.3,3.8Hz,2H).LC-MS(ESI)m/z 433.2[M+H] +. The synthesis method is as in Example 1. 1 H NMR (400MHz,DMSO-d 6 )δ11.05(s,1H),10.06(s,1H),8.67(s,1H),8.40(d,J=8.5Hz,1H),8.28(s, 1H), 7.91(d, J=8.6Hz, 1H), 7.77(s, 1H), 7.08(t, J=5.7Hz, 1H), 5.06(p, J=7.4Hz, 1H), 3.55(t, J＝5.9Hz, 2H), 3.41(q, J＝5.9Hz, 2H), 3.31(s, 3H), 2.23(m, 2H), 1.96(m, 2H), 1.88(t, J＝6.3, 2.3 Hz, 2H), 1.73 (dq, J=8.3, 3.8Hz, 2H). LC-MS (ESI) m/z 433.2[M+H] + .
实施例10 N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-(2-吗啉代乙基)-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物10)Example 10 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-(2-morpholinoethyl)-1H -pyrrolo[3,2-b]pyridine-3-carboxamide (compound 10)
Figure PCTCN2021129535-appb-000016
Figure PCTCN2021129535-appb-000016
合成方法如实施例1。 1H NMR(400MHz,CDCl 3)δ11.30(s,1H),10.34(s,1H),8.37(s,1H),8.29(s,1H),8.04(d,J＝8.5Hz,1H),7.92(d,J＝8.4Hz,1H),7.87(s,1H),5.38(t,J＝5.1Hz,1H),4.35(t,J＝6.0Hz,2H),3.69(m,4H),3.68–3.66(m,2H),3.55(q,J＝5.1Hz,2H),3.44(s,3H),2.83(t,J＝6.1Hz,2H),2.51(t,J＝4.7Hz,4H).LC-MS(ESI)m/z 478.2[M+H] +. The synthesis method is as in Example 1. 1 H NMR (400MHz, CDCl 3 ) δ11.30(s,1H),10.34(s,1H),8.37(s,1H),8.29(s,1H),8.04(d,J＝8.5Hz,1H) ,7.92(d,J=8.4Hz,1H),7.87(s,1H),5.38(t,J=5.1Hz,1H),4.35(t,J=6.0Hz,2H),3.69(m,4H) ,3.68–3.66(m,2H),3.55(q,J=5.1Hz,2H),3.44(s,3H),2.83(t,J=6.1Hz,2H),2.51(t,J=4.7Hz, 4H).LC-MS (ESI) m/z 478.2[M+H] + .
实施例11 N-(5-氰基-4-((2-吗啉代乙基)氨基)吡啶-2-基)-5-醛基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物11)Example 11 N-(5-cyano-4-((2-morpholinoethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2 -b] pyridine-3-carboxamide (compound 11)
Figure PCTCN2021129535-appb-000017
Figure PCTCN2021129535-appb-000017
合成方法如实施例1。 1H NMR(400MHz,CDCl 3)δ11.10(s,1H),10.09(s,1H),8.81(s,1H),8.45(d,J＝8.6Hz,1H),8.31(s,1H),7.94(d,J＝8.6Hz,1H),δ8.05(s,1H),5.62(s,1H),4.76(s,2H),3.81–3.68(m,4H),3.20(dd,J＝11.3,5.3Hz,2H),2.72–2.62(m,2H),2.51(d,J＝4.0Hz,4H).LC-MS(ESI)m/z 434.2[M+H] +. The synthesis method is as in Example 1. 1 H NMR (400MHz, CDCl 3 )δ11.10(s,1H),10.09(s,1H),8.81(s,1H),8.45(d,J＝8.6Hz,1H),8.31(s,1H) ,7.94(d,J＝8.6Hz,1H),δ8.05(s,1H),5.62(s,1H),4.76(s,2H),3.81–3.68(m,4H),3.20(dd,J =11.3, 5.3Hz, 2H), 2.72–2.62(m, 2H), 2.51(d, J=4.0Hz, 4H). LC-MS (ESI) m/z 434.2[M+H] + .
实施例12Example 12
Figure PCTCN2021129535-appb-000018
Figure PCTCN2021129535-appb-000018
步骤a：6-氨基-4-异丙氧基烟腈(化合物12-2)的制备Step a: Preparation of 6-amino-4-isopropoxynicotinonitrile (compound 12-2)
Figure PCTCN2021129535-appb-000019
Figure PCTCN2021129535-appb-000019
向重蒸无水DMF中加入化合物12-1(420.0mg,1.0eq)后，转至0℃搅拌下缓慢加入NaH(550.0mg，2.0eq)继续反应30分钟后，加入化合物1-9(950.0mg，1.0eq)，继续搅拌10分钟后转移至室温反应，TLC监测反应完全后，加入饱和氯化铵淬灭，乙酸乙酯萃取，旋干,过柱得到目标产物600.0mg，收率为48.8％。After adding compound 12-1 (420.0mg, 1.0eq) to redistilled anhydrous DMF, NaH (550.0mg, 2.0eq) was slowly added under stirring at 0°C and continued to react for 30 minutes, then compound 1-9 (950.0 mg, 1.0eq), continue to stir for 10 minutes and then transfer to room temperature for reaction. After TLC monitors that the reaction is complete, add saturated ammonium chloride to quench, extract with ethyl acetate, spin dry, pass through the column to obtain 600.0 mg of the target product, and the yield is 48.8 %.
1H NMR(400MHz,DMSO-d 6)δ8.10(s,1H),6.79(s,2H),6.04(s,1H),4.67–4.64(m,1H),1.29(d,J＝7.1Hz,6H).LC-MS(ESI)m/z 178.1[M+H] +. 1 H NMR (400MHz, DMSO-d 6 )δ8.10(s,1H),6.79(s,2H),6.04(s,1H),4.67–4.64(m,1H),1.29(d,J=7.1 Hz,6H).LC-MS(ESI)m/z 178.1[M+H] + .
步骤c1：6-氨基-4-((2-甲氧基乙基)氨基)烟腈(化合物1-10)的制备Step c1: Preparation of 6-amino-4-((2-methoxyethyl)amino)nicotinonitrile (compound 1-10)
步骤b和步骤c:N-(5-氰基-4-(异丙氧基)吡啶-2-基)-5-醛基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物12)的制备Step b and step c: N-(5-cyano-4-(isopropoxy)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b] Preparation of pyridine-3-carboxamide (compound 12)
Figure PCTCN2021129535-appb-000020
Figure PCTCN2021129535-appb-000020
合成方法如实施例1。The synthesis method is as in Example 1.
1H NMR(400MHz,CDCl 3)δ11.44(s,1H),10.33(s,1H),8.43(s,1H),8.24(s,1H),8.22(s,1H),8.05(d,J＝8.5Hz,1H),7.91(d,J＝8.5Hz,1H),4.96–4.85(m,1H),4.01(s,3H),1.49(d,J＝6.1Hz,6H).LC-MS(ESI)m/z 364.1[M+H] +. 1 H NMR (400MHz, CDCl 3 )δ11.44(s,1H),10.33(s,1H),8.43(s,1H),8.24(s,1H),8.22(s,1H),8.05(d, J＝8.5Hz, 1H), 7.91(d, J＝8.5Hz, 1H), 4.96–4.85(m, 1H), 4.01(s, 3H), 1.49(d, J＝6.1Hz, 6H).LC- MS(ESI)m/z 364.1[M+H] + .
实施例13 N-(5-氰基-4-((2-(二甲基氨基)乙基)氨基)吡啶-2-基)-5-醛基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物13)Example 13 N-(5-cyano-4-((2-(dimethylamino)ethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[ 3,2-b]pyridine-3-carboxamide (compound 13)
Figure PCTCN2021129535-appb-000021
Figure PCTCN2021129535-appb-000021
合成方法如实施例1。 1H NMR(400MHz,CDCl3)δ11.10(s,1H),10.09(s,1H),8.81(s,1H),8.45(d,J＝8.6Hz,1H),8.31(s,1H),8.05(s,1H),7.94(d,J＝8.6Hz,1H),5.62(s,1H),3.14(dd,J＝10.9,5.8Hz,2H),2.54(t,J＝6.1Hz,2H),2.24(s,6H).LC-MS(ESI)m/z 392.2[M+H] +. The synthesis method is as in Example 1. 1 H NMR (400MHz, CDCl3) δ11.10(s, 1H), 10.09(s, 1H), 8.81(s, 1H), 8.45(d, J=8.6Hz, 1H), 8.31(s, 1H), 8.05(s,1H),7.94(d,J=8.6Hz,1H),5.62(s,1H),3.14(dd,J=10.9,5.8Hz,2H),2.54(t,J=6.1Hz,2H ), 2.24(s,6H). LC-MS (ESI) m/z 392.2[M+H] + .
实施例14 N-(5-氰基-4-((2-(4-甲基哌嗪-1-基)乙基)氨基)吡啶-2-基)-5-醛基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物14)Example 14 N-(5-cyano-4-((2-(4-methylpiperazin-1-yl)ethyl)amino)pyridin-2-yl)-5-formyl-1-methyl -1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 14)
Figure PCTCN2021129535-appb-000022
Figure PCTCN2021129535-appb-000022
合成方法如实施例1。 1H NMR(400MHz,DMSO-d 6)δ11.09(s,1H),10.11(s,1H),8.64(s,1H),8.35(s,1H),8.34(d,J＝8.0Hz,1H),7.97(d,J＝8.0Hz,1H),7.77(s,1H),6.96(t,J＝4.0Hz,1H),4.01(s,3H),2.99(s,6H),2.67(s,4H),2.62(s,3H).LC-MS(ESI)m/z 447.2[M+H] +. The synthesis method is as in Example 1. 1 H NMR (400MHz,DMSO-d 6 )δ11.09(s,1H),10.11(s,1H),8.64(s,1H),8.35(s,1H),8.34(d,J＝8.0Hz, 1H), 7.97(d, J=8.0Hz, 1H), 7.77(s, 1H), 6.96(t, J=4.0Hz, 1H), 4.01(s, 3H), 2.99(s, 6H), 2.67( s,4H),2.62(s,3H).LC-MS(ESI)m/z 447.2[M+H] + .
实施例15 N-(5-氯-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物15)Example 15 N-(5-chloro-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2- b] pyridine-3-carboxamide (compound 15)
Figure PCTCN2021129535-appb-000023
Figure PCTCN2021129535-appb-000023
以5-氯-4-氟吡啶-2-胺为起始原料，合成方法同化合物1。Using 5-chloro-4-fluoropyridin-2-amine as the starting material, the synthesis method is the same as compound 1.
1H NMR(400MHz,DMSO-d 6)δ11.88(s,1H),10.11(s,1H),8.61(s,1H),8.33(d,J＝8.0Hz,1H),8.01(s,1H),7.97(d,J＝8.0Hz,1H),7.80(s,1H),6.30(t,J＝6.0Hz,1H),4.00(s,1H),3.58(t,J＝6.0Hz,2H),3.41(q,J＝8.0Hz,12.0Hz,2H),3.32(s,3H).LC-MS(ESI)m/z 388.1[M+H] +. 1 H NMR (400MHz,DMSO-d 6 )δ11.88(s,1H),10.11(s,1H),8.61(s,1H),8.33(d,J=8.0Hz,1H),8.01(s, 1H), 7.97(d, J=8.0Hz, 1H), 7.80(s, 1H), 6.30(t, J=6.0Hz, 1H), 4.00(s, 1H), 3.58(t, J=6.0Hz, 2H), 3.41(q, J=8.0Hz, 12.0Hz, 2H), 3.32(s, 3H).LC-MS(ESI) m/z 388.1[M+H] + .
实施例16 N-(4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物16)Example 16 N-(4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine- 3-Formamide (Compound 16)
Figure PCTCN2021129535-appb-000024
Figure PCTCN2021129535-appb-000024
合成方法同实施例15。 1H NMR(400MHz,CDCl 3)δ11.10(s,1H),10.07(s,1H),8.60(s,1H),8.30(s,1H),8.45(d,J＝8.0Hz,1H),7.92(d,J＝8.0Hz,1H),7.75(s,1H),7.02(t,J＝4.0Hz,1H),3.98(s,1H),3.56(t,J＝6.0Hz,2H),3.44–3.40(m,2H),3.32(s,3H).LC-MS(ESI)m/z354.1[M+H] +. The synthesis method is the same as in Example 15. 1 H NMR (400MHz, CDCl 3 ) δ11.10(s,1H),10.07(s,1H),8.60(s,1H),8.30(s,1H),8.45(d,J＝8.0Hz,1H) ,7.92(d,J=8.0Hz,1H),7.75(s,1H),7.02(t,J=4.0Hz,1H),3.98(s,1H),3.56(t,J=6.0Hz,2H) ,3.44–3.40(m,2H),3.32(s,3H).LC-MS(ESI)m/z354.1[M+H] + .
实施例17 N-(5-环丙基吡啶-2-基)-5-醛基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物17)Example 17 N-(5-cyclopropylpyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 17)
Figure PCTCN2021129535-appb-000025
Figure PCTCN2021129535-appb-000025
以5-环丙基吡啶-2-胺为起始原料，合成方法同化合物1。Using 5-cyclopropylpyridin-2-amine as the starting material, the synthesis method is the same as compound 1.
1H NMR(400MHz,DMSO-d 6)δ11.00(s,1H),10.12(s,1H),8.63(s,1H),8.31(d,J＝8.0Hz,1H),8.22–8.20(m,2H),7.96(d,J＝8.0Hz,1H),7.50(dd,J＝4.0Hz,8.0Hz,1H),3.99(s,3H),1.98–1.92(m,1H),1.01–0.96(m,2H),0.75–0.71(m,2H).LC-MS(ESI)m/z 394.2[M+H] +. 1 H NMR (400MHz, DMSO-d 6 ) δ11.00(s, 1H), 10.12(s, 1H), 8.63(s, 1H), 8.31(d, J=8.0Hz, 1H), 8.22–8.20( m,2H),7.96(d,J=8.0Hz,1H),7.50(dd,J=4.0Hz,8.0Hz,1H),3.99(s,3H),1.98–1.92(m,1H),1.01– 0.96(m,2H),0.75–0.71(m,2H).LC-MS(ESI)m/z 394.2[M+H] + .
实施例18Example 18
化合物18的合成路线如下：The synthetic route of compound 18 is as follows:
Figure PCTCN2021129535-appb-000026
Figure PCTCN2021129535-appb-000026
步骤a-h：6-溴-N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-(1,3-二氧戊环-2-基)-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物18-2)的制备Steps a-h: 6-Bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolane-2- base)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 18-2)
以化合物2-氯-3-硝基-5-溴-6-甲基吡啶(化合物18-1)为起始原料，合成方法同实施例1，得到化合物18-2。Using compound 2-chloro-3-nitro-5-bromo-6-methylpyridine (compound 18-1) as the starting material, the synthesis method was the same as that in Example 1 to obtain compound 18-2.
Figure PCTCN2021129535-appb-000027
Figure PCTCN2021129535-appb-000027
1H NMR(400MHz,CDCl 3)δ11.27(s,1H),8.24(s,1H),8.06(s,1H),7.95(s,1H),7.81(s,1H),6.65(s,1H),5.35–5.30(m,1H),4.63(t,J＝6.8Hz,2H),4.21(t,J＝6.8Hz,2H),3.90(s,3H),3.67(t,J＝5.0Hz,2H),3.52(dd,J＝10.1,5.0Hz,2H),3.43(s,3H).LC-MS(ESI)m/z501.1[M+H] +. 1 H NMR (400MHz, CDCl 3 )δ11.27(s,1H),8.24(s,1H),8.06(s,1H),7.95(s,1H),7.81(s,1H),6.65(s, 1H), 5.35–5.30(m, 1H), 4.63(t, J=6.8Hz, 2H), 4.21(t, J=6.8Hz, 2H), 3.90(s, 3H), 3.67(t, J=5.0 Hz, 2H), 3.52(dd, J=10.1, 5.0Hz, 2H), 3.43(s, 3H).LC-MS(ESI) m/z501.1[M+H] + .
步骤i：N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-(1,3-二氧戊环-2-基)-1-甲基-6-(1-甲基-1H)-吡唑-4-基)-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物18-3)的制备Step i: N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolan-2-yl)-1 Preparation of -methyl-6-(1-methyl-1H)-pyrazol-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 18-3)
将化合物18-2(50mg,1.0eq.)、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑(25.0mg,1.2eq)、Pd 2(dba) 3(9.0mg,0.1eq)、XantPhos(6.0mg,0.1eq)与碳酸铯(100.0mg，3.0eq)溶于8ml 1.4-二氧六环中，再加入1ml水，体系置换氩气后于80℃下反应，TLC板监测原料反应完毕后抽滤，取有机层加入硅胶粉旋干，柱层析分离得产物35.0mg，产率69.7％ Compound 18-2 (50mg, 1.0eq.), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (25.0mg, 1.2eq), Pd 2 (dba) 3 (9.0mg, 0.1eq), XantPhos (6.0mg, 0.1eq) and cesium carbonate (100.0mg, 3.0eq) were dissolved in 8ml 1.4- Add 1ml of water to the dioxane, replace the system with argon, and react at 80°C. After the reaction of the raw materials is monitored by TLC, filter with suction, take the organic layer, add silica gel powder and spin dry, and separate by column chromatography to obtain 35.0 mg of the product. Yield 69.7%
Figure PCTCN2021129535-appb-000028
Figure PCTCN2021129535-appb-000028
1H NMR(400MHz,CDCl 3)δ11.60(s,1H),8.25(s,1H),8.10(s,1H),7.85(s,1H),7.75(s,1H),7.67(s,1H),6.34(s,1H),5.34(s,1H),5.33(t,J＝4.0Hz,1H),4.69(t,J＝6.0Hz,2H),4.19(t,J＝8.0Hz,2H),4.03(s,3H),3.93(s,3H),3.68(t,J＝6.0Hz,2H),3.56–3.52(m,2H),3.44(s,3H).LC-MS(ESI)m/z 503.2[M+H] +. 1 H NMR (400MHz, CDCl 3 )δ11.60(s,1H),8.25(s,1H),8.10(s,1H),7.85(s,1H),7.75(s,1H),7.67(s, 1H), 6.34(s, 1H), 5.34(s, 1H), 5.33(t, J=4.0Hz, 1H), 4.69(t, J=6.0Hz, 2H), 4.19(t, J=8.0Hz, 2H), 4.03(s, 3H), 3.93(s, 3H), 3.68(t, J=6.0Hz, 2H), 3.56–3.52(m, 2H), 3.44(s, 3H).LC-MS (ESI )m/z 503.2[M+H] + .
步骤j：N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-(1-甲基-1H-吡唑-4-基)-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物18)的制备Step j: N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(1-methyl-1H-pyrazole- Preparation of 4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 18)
合成方法同化合物1。The synthesis method is the same as compound 1.
Figure PCTCN2021129535-appb-000029
Figure PCTCN2021129535-appb-000029
1H NMR(400MHz,CDCl 3)δ11.25(s,1H),10.39(s,1H),8.28(s,1H),8.20(s,1H),7.83(s,1H),7.82(s,1H),7.75(s,1H),7.72(s,1H),5.37(s,1H),4.03(s,3H),3.97(s,3H),3.68(t,J＝8.0Hz,2H),3.55–3.53(m,2H),3.44(s,3H).LC-MS(ESI)m/z 459.2[M+H] +. 1 H NMR (400MHz, CDCl 3 )δ11.25(s,1H),10.39(s,1H),8.28(s,1H),8.20(s,1H),7.83(s,1H),7.82(s, 1H),7.75(s,1H),7.72(s,1H),5.37(s,1H),4.03(s,3H),3.97(s,3H),3.68(t,J＝8.0Hz,2H), 3.55–3.53(m,2H),3.44(s,3H).LC-MS(ESI) m/z 459.2[M+H] + .
实施例19 N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-(1,3-二甲基-1H-吡唑-4-基)-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物19)Example 19 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(1,3-dimethyl-1H- Pyrazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 19)
Figure PCTCN2021129535-appb-000030
Figure PCTCN2021129535-appb-000030
合成方法同实施例18。The synthesis method is the same as in Example 18.
1H NMR(400MHz,CDCl 3)δ11.37(s,1H),10.34(s,1H),8.32(s,1H),8.25(s,1H),7.86(s,1H),7.67(s,1H),7.46(s,1H),5.41(s,1H),3.98(s,3H),3.97(s,3H),3.68(s,2H),3.58–3.55(m,2H),3.45(s,3H),2.18(s,3H).LC-MS(ESI)m/z 473.2[M+H] +. 1 H NMR (400MHz, CDCl 3 )δ11.37(s,1H),10.34(s,1H),8.32(s,1H),8.25(s,1H),7.86(s,1H),7.67(s, 1H),7.46(s,1H),5.41(s,1H),3.98(s,3H),3.97(s,3H),3.68(s,2H),3.58–3.55(m,2H),3.45(s ,3H),2.18(s,3H).LC-MS(ESI)m/z 473.2[M+H] + .
实施例20 N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-(1-甲基-1H-吡唑-5- 基)-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物20)Example 20 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(1-methyl-1H-pyrazole- 5-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 20)
Figure PCTCN2021129535-appb-000031
Figure PCTCN2021129535-appb-000031
合成方法如实施例18。The synthesis method is as in Example 18.
1H NMR(400MHz,DMSO-d 6)δ11.10(s,1H),10.07(s,1H),8.76(s,1H),8.36(s,1H),8.35(s,1H),7.81(s,1H),7.55(d,J＝1.2Hz,1H),6.40(d,J＝1.2Hz,1H),5.77(s,1H),5.32(t,J＝3.2Hz,1H),4.02(s,2H),3.60(s,2H),3.31(s,3H),3.17(s,3H),3.16(s,3H).LC-MS(ESI)m/z458.2[M+H] +. 1 H NMR (400MHz,DMSO-d 6 )δ11.10(s,1H),10.07(s,1H),8.76(s,1H),8.36(s,1H),8.35(s,1H),7.81( s,1H),7.55(d,J=1.2Hz,1H),6.40(d,J=1.2Hz,1H),5.77(s,1H),5.32(t,J=3.2Hz,1H),4.02( s,2H),3.60(s,2H),3.31(s,3H),3.17(s,3H),3.16(s,3H).LC-MS(ESI)m/z458.2[M+H] + .
实施例21 N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-(吡啶-3-基)-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物21)Example 21 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(pyridin-3-yl)-1-methyl Base-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 21)
Figure PCTCN2021129535-appb-000032
Figure PCTCN2021129535-appb-000032
合成方法同实施例18。The synthesis method is the same as in Example 18.
1H NMR(400MHz,DMSO-d 6)δ11.14(s,1H),10.10(s,1H),8.71–8.71(m,2H),8.65(dd,J 1＝0.8Hz,3.2Hz,1H),8.34(s,1H),8.33(s,1H),7.97–7.95(m,1H),7.80(s,1H),7.53(dd,J＝1.2Hz,5.2Hz,1H),7.14(t,J＝3.2Hz,1H),4.02(s,3H),3.56(t,J＝4.0Hz,2H),3.45–3.43(m,2H),3.32(s,3H).LC-MS(ESI)m/z 456.2[M+H] +. 1 H NMR (400MHz, DMSO-d 6 ) δ11.14(s,1H), 10.10(s,1H), 8.71–8.71(m,2H), 8.65(dd,J 1 =0.8Hz,3.2Hz,1H ),8.34(s,1H),8.33(s,1H),7.97–7.95(m,1H),7.80(s,1H),7.53(dd,J＝1.2Hz,5.2Hz,1H),7.14(t ,J=3.2Hz,1H),4.02(s,3H),3.56(t,J=4.0Hz,2H),3.45–3.43(m,2H),3.32(s,3H).LC-MS(ESI) m/z 456.2[M+H] + .
实施例22 N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-(噻吩-2-基))-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物22)Example 22 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(thiophen-2-yl))-1- Methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 22)
Figure PCTCN2021129535-appb-000033
Figure PCTCN2021129535-appb-000033
合成方法同实施例18。The synthesis method is the same as in Example 18.
1H NMR(400MHz,DMSO-d 6)δ11.03(s,1H),10.14(s,1H),8.66(s,1H),8.33(s,1H),8.32(s,1H),7.79(d,J＝4.0Hz,1H),7.78(s,1H),7.33(d,J＝1.6Hz,1H),7.24(t,J＝3.2Hz,1H),7.10(s,1H),4.00(s,3H),3.56(t,J＝3.6Hz,2H),3.55(dd,J＝4.0Hz,8.0Hz,2H),3.31(s,3H).LC-MS(ESI)m/z 461.1[M+H] +. 1 H NMR (400MHz,DMSO-d 6 )δ11.03(s,1H),10.14(s,1H),8.66(s,1H),8.33(s,1H),8.32(s,1H),7.79( d,J=4.0Hz,1H),7.78(s,1H),7.33(d,J=1.6Hz,1H),7.24(t,J=3.2Hz,1H),7.10(s,1H),4.00( s, 3H), 3.56(t, J=3.6Hz, 2H), 3.55(dd, J=4.0Hz, 8.0Hz, 2H), 3.31(s, 3H).LC-MS (ESI) m/z 461.1[ M+H] + .
实施例23 N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-(呋喃-2-基)-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物23)Example 23 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(furan-2-yl)-1-methyl Base-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 23)
Figure PCTCN2021129535-appb-000034
Figure PCTCN2021129535-appb-000034
合成方法同实施例18。The synthesis method is the same as in Example 18.
1H NMR(400MHz,DMSO-d 6)δ11.04(s,1H),10.14(s,1H),8.66(s,1H),8.32(s,1H),7.92(s,1H),7.76(d,J＝4.0Hz,1H),7.66(s,1H),7.35(d,J＝1.6Hz,1H),7.27(t,J＝3.8Hz,1H),7.14(s,1H),4.06(s,3H),3.55(t,J＝3.6Hz,2H),3.50(dd,J＝4.0Hz,8.0Hz,2H),3.31(s,3H).LC-MS(ESI)m/z 445.1[M+H] +. 1 H NMR (400MHz,DMSO-d 6 )δ11.04(s,1H),10.14(s,1H),8.66(s,1H),8.32(s,1H),7.92(s,1H),7.76( d,J=4.0Hz,1H),7.66(s,1H),7.35(d,J=1.6Hz,1H),7.27(t,J=3.8Hz,1H),7.14(s,1H),4.06( s, 3H), 3.55(t, J=3.6Hz, 2H), 3.50(dd, J=4.0Hz, 8.0Hz, 2H), 3.31(s, 3H).LC-MS (ESI) m/z 445.1[ M+H] + .
实施例24 N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-(2-甲基噻唑-5-基)-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物24)Example 24 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(2-methylthiazol-5-yl) -1-Methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Compound 24)
Figure PCTCN2021129535-appb-000035
Figure PCTCN2021129535-appb-000035
合成方法同实施例18。The synthesis method is the same as in Example 18.
1H NMR(400MHz,DMSO-d 6)δ11.04(s,1H),10.15(s,1H),8.71(s,1H),8.36(s,1H),8.33(s,1H),7.80(s,1H),7.78(s,1H),7.07(t,J＝4.0Hz,1H),3.99(s,3H),3.57(t,J＝6.0Hz,2H),3.44(dd,J＝4.0Hz,8.0Hz,2H),3.32(s,3H),2.75(s,3H).LC-MS(ESI)m/z 476.1[M+H] +. 1 H NMR (400MHz,DMSO-d 6 )δ11.04(s,1H),10.15(s,1H),8.71(s,1H),8.36(s,1H),8.33(s,1H),7.80( s,1H),7.78(s,1H),7.07(t,J=4.0Hz,1H),3.99(s,3H),3.57(t,J=6.0Hz,2H),3.44(dd,J=4.0 Hz,8.0Hz,2H),3.32(s,3H),2.75(s,3H).LC-MS(ESI)m/z 476.1[M+H] + .
实施例25 N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-(2-氟-6-甲氧基苯基)-1-甲基-1H-吡咯并[3，2-b]吡啶-3-甲酰胺(化合物25)Example 25 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(2-fluoro-6-methoxybenzene Base)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 25)
Figure PCTCN2021129535-appb-000036
Figure PCTCN2021129535-appb-000036
合成方法同实施例18。The synthesis method is the same as in Example 18.
1H NMR(400MHz,DMSO-d 6)δ11.10(s,1H),11.03(s,1H),8.68(s,1H),8.33(s,1H),8.26(s,1H),7.81(s,1H),7.58–7.54(m.1H),7.48(d,J＝8.0Hz,1H),7.07(t,J＝4.0Hz,1H),7.01(dd,J＝8.0Hz,16.0Hz,1H),5.32(t,J＝4.0Hz,1H)),3.99(s,3H),3.05(s,3H),3.57(t,J＝6.0Hz,2H),3.45(dd,J＝4.0Hz,8.0Hz,2H),3.32(s,3H),2.75(s,3H).LC-MS(ESI)m/z 503.2[M+H] +. 1 H NMR (400MHz,DMSO-d 6 )δ11.10(s,1H),11.03(s,1H),8.68(s,1H),8.33(s,1H),8.26(s,1H),7.81( s,1H),7.58–7.54(m.1H),7.48(d,J＝8.0Hz,1H),7.07(t,J＝4.0Hz,1H),7.01(dd,J＝8.0Hz,16.0Hz, 1H), 5.32(t, J=4.0Hz, 1H)), 3.99(s, 3H), 3.05(s, 3H), 3.57(t, J=6.0Hz, 2H), 3.45(dd, J=4.0Hz ,8.0Hz,2H),3.32(s,3H),2.75(s,3H).LC-MS(ESI)m/z 503.2[M+H] + .
实施例26 N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-(2-甲氧基苯基)-1-甲基-1H-吡咯并[3，2-b]吡啶-3-甲酰胺(化合物26)Example 26 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(2-methoxyphenyl)-1 -Methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 26)
Figure PCTCN2021129535-appb-000037
Figure PCTCN2021129535-appb-000037
合成方法同实施例18。The synthesis method is the same as in Example 18.
1H NMR(400MHz,DMSO-d 6)δ11.11(s,1H),9.95(s,1H),8.61(s,1H),8.32(s,1H),8.14(s,1H),7.80(s,1H),7.47(t,J＝8.0Hz,1H),7.40(t,J＝8.0Hz,1H),7.13(t,J＝6.0Hz,1H),7.04(t,J＝4.0Hz,1H)),3.99(s,3H),3.68(s,3H),3.57(t,J＝6.0Hz,2H),3.32(s,3H),3.17(d,J＝8.0Hz,2H).LC-MS(ESI)m/z 485.2[M+H] +. 1 H NMR (400MHz,DMSO-d 6 )δ11.11(s,1H),9.95(s,1H),8.61(s,1H),8.32(s,1H),8.14(s,1H),7.80( s,1H),7.47(t,J=8.0Hz,1H),7.40(t,J=8.0Hz,1H),7.13(t,J=6.0Hz,1H),7.04(t,J=4.0Hz, 1H)), 3.99(s, 3H), 3.68(s, 3H), 3.57(t, J=6.0Hz, 2H), 3.32(s, 3H), 3.17(d, J=8.0Hz, 2H).LC -MS(ESI)m/z 485.2[M+H] + .
实施例27Example 27
6-溴-N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物27)6-Bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3, 2-b]pyridine-3-carboxamide (Compound 27)
Figure PCTCN2021129535-appb-000038
Figure PCTCN2021129535-appb-000038
以化合物18-10为原料，合成方法同化合物1.Using compound 18-10 as raw material, the synthesis method is the same as compound 1.
1H NMR(400MHz,DMSO-d 6)δ10.82(s,1H),10.20(s,1H),8.67(s,1H),8.64(s,1H),8.31(s,1H),7.75(s,1H),7.05(s,1H),3.97(s,3H),3.56(t,J＝4.0Hz,2H),3.56(br,2H),3.31(s,3H).LC-MS(ESI)m/z 457.1[M+H] +. 1 H NMR (400MHz,DMSO-d 6 )δ10.82(s,1H),10.20(s,1H),8.67(s,1H),8.64(s,1H),8.31(s,1H),7.75( s,1H),7.05(s,1H),3.97(s,3H),3.56(t,J=4.0Hz,2H),3.56(br,2H),3.31(s,3H).LC-MS(ESI )m/z 457.1[M+H] + .
实施例28Example 28
Figure PCTCN2021129535-appb-000039
Figure PCTCN2021129535-appb-000039
步骤a：N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-(1,3-二氧戊环-2-基)-6-((4-甲基哌嗪-1-基)甲基)-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物28-1)的制备Step a: N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolan-2-yl)-6 Preparation of -((4-methylpiperazin-1-yl)methyl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 28-1)
将化合物18-2(200.0mg,1.0eq),1-甲基-4-(亚甲基三氟硼酸哌嗪)钾盐(166.0mg,2.0eq)，醋酸钯(8.5mg,0.1eq),X-Phos(18.0mg,0.1eq.),碳酸铯(370.0mg,3.0eq.),溶于10mL四氢呋喃中，加入1ml H2O,体系置换氩气后转至80℃反应过夜，直接减压浓缩，柱层析分离得到含有少量杂质的目标产物50.0mg，收率为37.5％。Compound 18-2 (200.0mg, 1.0eq), 1-methyl-4-(piperazine trifluoroborate) potassium salt (166.0mg, 2.0eq), palladium acetate (8.5mg, 0.1eq), X-Phos (18.0mg, 0.1eq.), cesium carbonate (370.0mg, 3.0eq.), dissolved in 10mL tetrahydrofuran, added 1ml H2O, the system was replaced with argon, then transferred to 80°C for overnight reaction, directly concentrated under reduced pressure, Column chromatography separated to obtain 50.0 mg of the target product containing a small amount of impurities, and the yield was 37.5%.
1H NMR(400MHz,CDCl 3)δ11.06(s,1H),10.23(s,1H),8.58(s,1H),8.33(s,1H),8.21(s,1H),7.83(s,1H),7.00(t,J＝4.0Hz,1H),6.20–6.11(m,1H),5.72–5.67(m,2H),5.57–5.48(m,2H),4.09(s,2H),3.96(s,3H),3.59(t,J＝6.0Hz,2H),3.46(q,J＝4.0Hz,12.0Hz,2H),3.28(s,3H),2.72–2.61(m,4H),2.46(br,4H).LC-MS(ESI)m/z 535.3[M+H] +. 1 H NMR (400MHz, CDCl 3 )δ11.06(s,1H),10.23(s,1H),8.58(s,1H),8.33(s,1H),8.21(s,1H),7.83(s, 1H), 7.00(t, J=4.0Hz, 1H), 6.20–6.11(m, 1H), 5.72–5.67(m, 2H), 5.57–5.48(m, 2H), 4.09(s, 2H), 3.96 (s,3H),3.59(t,J=6.0Hz,2H),3.46(q,J=4.0Hz,12.0Hz,2H),3.28(s,3H),2.72–2.61(m,4H),2.46 (br,4H).LC-MS(ESI)m/z 535.3[M+H] + .
步骤b：N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-((4-甲基哌嗪-1-基)甲基)-1-甲基-1H-吡咯[3,2-b]吡啶-3-甲酰胺(化合物28)的制备Step b: N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-((4-methylpiperazine-1- Base) methyl)-1-methyl-1H-pyrrole [3,2-b] pyridine-3-carboxamide (compound 28) preparation
合成方法同化合物1.The synthetic method is the same as compound 1.
Figure PCTCN2021129535-appb-000040
Figure PCTCN2021129535-appb-000040
1H NMR(400MHz,CDCl 3)δ11.06(s,1H),10.24(s,1H),8.61(s,1H),8.32(s,1H),8.26(s,1H),7.8(s,1H),7.05(t,J＝4.0Hz,1H),4.07(s,2H),3.99(s,3H),3.56(t,J＝6.0Hz,2H),3.44(q, J＝4.0Hz,12.0Hz,2H),3.31(s,3H),2.72–2.61(m,4H),2.45(br,4H).LC-MS(ESI)m/z 1 H NMR (400MHz, CDCl 3 )δ11.06(s,1H),10.24(s,1H),8.61(s,1H),8.32(s,1H),8.26(s,1H),7.8(s, 1H), 7.05(t, J=4.0Hz, 1H), 4.07(s, 2H), 3.99(s, 3H), 3.56(t, J=6.0Hz, 2H), 3.44(q, J=4.0Hz, 12.0Hz,2H),3.31(s,3H),2.72–2.61(m,4H),2.45(br,4H).LC-MS(ESI)m/z
491.2[M+H] +. 491.2[M+H] + .
实施例29Example 29
Figure PCTCN2021129535-appb-000041
Figure PCTCN2021129535-appb-000041
步骤a：6-溴-5-(1,3-二氧戊环-2-基)-1-异丙基-1H-吡咯并[3,2-b]吡啶-3-羧酸乙酯(化合物29-1)的制备Step a: ethyl 6-bromo-5-(1,3-dioxolan-2-yl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylate ( Compound 29-1) Preparation
合成方法同化合物1-7。 1H NMR(400MHz,CDCl 3)δ8.12(s,1H),7.89(s,1H),6.53(s,1H),4.59–4.57(m,1H),4.47–4.43(m,2H),4.38(q,J＝7.1Hz,2H),4.15–4.11(m,2H),1.54(s,3H),1.55(s,3H),1.42(t,J＝7.1Hz,3H).LC-MS(ESI)m/z 383.1[M+H] +. The synthesis method is the same as compound 1-7. 1 H NMR (400MHz, CDCl 3 )δ8.12(s,1H),7.89(s,1H),6.53(s,1H),4.59–4.57(m,1H),4.47–4.43(m,2H), 4.38(q, J=7.1Hz, 2H), 4.15–4.11(m, 2H), 1.54(s, 3H), 1.55(s, 3H), 1.42(t, J=7.1Hz, 3H).LC-MS (ESI)m/z 383.1[M+H] + .
步骤b：6-溴-N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-(1,3-二氧戊环-2-基)-1-异丙基-1H-吡咯[3,2-b]吡啶-3-甲酰胺(化合物29-2)的制备Step b: 6-Bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolane-2- base)-1-isopropyl-1H-pyrrole[3,2-b]pyridine-3-carboxamide (compound 29-2)
合成方法同化合物1-11。 1HNMR(400MHz,DMSO-d 6)δ11.10(s,1H),8.66(s,1H),8.64(s,1H),8.29(s,1H),7.77(s,1H),7.09(t,J＝5.7Hz,1H),6.40(s,1H),4.93(p,J＝6.6Hz,1H),4.47–4.41(m,2H),4.11–4.05(m,2H),3.54(t,J＝5.8Hz,2H),3.44(dd,J＝6.0Hz,12.0Hz,2H),3.30(s,3H),1.52(s,3H),1.52(s,3H).LC-MS(ESI)m/z 529.1[M+H] +. The synthesis method is the same as compound 1-11. 1 HNMR (400MHz, DMSO-d 6 )δ11.10(s,1H),8.66(s,1H),8.64(s,1H),8.29(s,1H),7.77(s,1H),7.09(t ,J=5.7Hz,1H),6.40(s,1H),4.93(p,J=6.6Hz,1H),4.47–4.41(m,2H),4.11–4.05(m,2H),3.54(t, J＝5.8Hz, 2H), 3.44(dd, J＝6.0Hz, 12.0Hz, 2H), 3.30(s, 3H), 1.52(s, 3H), 1.52(s, 3H).LC-MS(ESI) m/z 529.1[M+H] + .
步骤c：N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-(1,3-二氧戊环-2-基)-6-((4-甲基哌嗪-1-基)甲基)-1-异丙基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物29-3)Step c: N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolan-2-yl)-6 -((4-methylpiperazin-1-yl)methyl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 29-3)
合成方法同化合物26-1。The synthesis method is the same as compound 26-1.
1H NMR(400MHz,CDCl 3)δ11.08(s,1H),10.22(s,1H),8.56(s,1H),8.32(s,1H),8.20(s,1H),7.85(s,1H),7.00(t,J＝4.0Hz,1H),6.22-6.01(m,1H),6.20–6.11(m,1H),5.72–5.67(m,2H),5.57–5.48(m,2H),4.12(s,2H),3.98(s,3H),3.62(t,J＝6.0Hz,2H),3.45(q,J＝4.0Hz,12.0Hz,2H),3.28(s,3H),2.72–2.61(m,4H),2.46(br,4H),1.62(s,3H),1.62(s,3H).LC-MS(ESI)m/z 563.3[M+H] +. 1 H NMR (400MHz, CDCl 3 )δ11.08(s,1H),10.22(s,1H),8.56(s,1H),8.32(s,1H),8.20(s,1H),7.85(s, 1H),7.00(t,J＝4.0Hz,1H),6.22-6.01(m,1H),6.20–6.11(m,1H),5.72–5.67(m,2H),5.57–5.48(m,2H) ,4.12(s,2H),3.98(s,3H),3.62(t,J=6.0Hz,2H),3.45(q,J=4.0Hz,12.0Hz,2H),3.28(s,3H),2.72 –2.61(m,4H),2.46(br,4H),1.62(s,3H),1.62(s,3H).LC-MS(ESI)m/z 563.3[M+H] + .
步骤d：N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-((4-甲基哌嗪-1-基)甲基)-1-异丙基-1H-吡咯[3,2-b]吡啶-3-甲酰胺(化合物29)的制备Step d: N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-((4-methylpiperazine-1- base)methyl)-1-isopropyl-1H-pyrrole[3,2-b]pyridine-3-carboxamide (compound 29)
合成方法同化合物1。 1H NMR(400MHz,CDCl 3)δ11.22(s,1H),10.38(s,1H),8.37(s,1H),8.23(s,1H),8.08(s,1H),7.83(s,1H),5.35(t,J＝5.2Hz,1H),4.76(hept,J＝6.8Hz,1H),4.17(s,2H),3.64(t,J＝5.1Hz,2H),3.50(q,J＝5.2Hz,2H),3.40(s,3H),2.72–2.70(m,8H),2.42(s,3H),1.63(s,3H),1.62(s,3H).LC-MS(ESI)m/z 519.3[M+H] +. The synthesis method is the same as compound 1. 1 H NMR (400MHz, CDCl 3 )δ11.22(s,1H),10.38(s,1H),8.37(s,1H),8.23(s,1H),8.08(s,1H),7.83(s, 1H), 5.35(t, J=5.2Hz, 1H), 4.76(hept, J=6.8Hz, 1H), 4.17(s, 2H), 3.64(t, J=5.1Hz, 2H), 3.50(q, J＝5.2Hz,2H),3.40(s,3H),2.72–2.70(m,8H),2.42(s,3H),1.63(s,3H),1.62(s,3H).LC-MS(ESI )m/z 519.3[M+H] + .
实施例30 N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-(吗啉甲基)-1-异丙基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物30)Example 30 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(morpholinylmethyl)-1-isopropyl Base-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 30)
Figure PCTCN2021129535-appb-000042
Figure PCTCN2021129535-appb-000042
合成方法同实施例27。 1H NMR(400MHz,CDCl 3)δ11.22(s,1H),10.38(s,1H),8.37(s,1H),8.23(s,1H),8.08(s,1H),7.83(s,1H),5.35(t,J＝5.2Hz,1H),4.76(hept,J＝6.8Hz,1H),4.17(s,2H),3.64(t,J＝5.1Hz,2H),3.50(q,J＝5.2Hz,2H),3.40(s,3H),2.61–2.58(m,8H),1.62(s,3H),1.61(s,3H).LC-MS(ESI)m/z 506.2[M+H] +. The synthesis method is the same as in Example 27. 1 H NMR (400MHz, CDCl 3 )δ11.22(s,1H),10.38(s,1H),8.37(s,1H),8.23(s,1H),8.08(s,1H),7.83(s, 1H), 5.35(t, J=5.2Hz, 1H), 4.76(hept, J=6.8Hz, 1H), 4.17(s, 2H), 3.64(t, J=5.1Hz, 2H), 3.50(q, J＝5.2Hz, 2H), 3.40(s, 3H), 2.61–2.58(m, 8H), 1.62(s, 3H), 1.61(s, 3H).LC-MS (ESI) m/z 506.2[M +H] + .
实施例31 N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-6-((((3S,5R)-3,5-二甲基哌嗪-1-基)甲基)-5-醛基-1-异丙基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物31)Example 31 N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-6-((((3S,5R)-3,5-dimethyl Piperazin-1-yl)methyl)-5-formyl-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 31)
Figure PCTCN2021129535-appb-000043
Figure PCTCN2021129535-appb-000043
合成方法同实施例27。 1H NMR(400MHz,CDCl 3)δ11.29(s,1H),10.41(s,1H),8.37(s,1H),8.26(s,1H),8.14(s,1H),7.85(s,1H),6.98(d,J＝0.7Hz,1H),5.34(t,J＝4.4Hz,1H),4.77(dt,J＝13.4,6.7Hz,1H),4.11(s,2H),3.66(dd,J＝5.6,4.6Hz,2H),3.53(t,J＝5.1Hz,2H),3.42 (s,2H),3.02–2.95(m,2H),2.27(s,2H),1.63(d,J＝6.7Hz,6H),1.37(s,2H),1.06(d,J＝6.5Hz,6H).LC-MS(ESI)m/z 533.3[M+H] +。 The synthesis method is the same as in Example 27. 1 H NMR (400MHz, CDCl 3 )δ11.29(s,1H),10.41(s,1H),8.37(s,1H),8.26(s,1H),8.14(s,1H),7.85(s, 1H), 6.98(d, J=0.7Hz, 1H), 5.34(t, J=4.4Hz, 1H), 4.77(dt, J=13.4, 6.7Hz, 1H), 4.11(s, 2H), 3.66( dd,J=5.6,4.6Hz,2H),3.53(t,J=5.1Hz,2H),3.42(s,2H),3.02–2.95(m,2H),2.27(s,2H),1.63(d , J = 6.7Hz, 6H), 1.37 (s, 2H), 1.06 (d, J = 6.5Hz, 6H). LC-MS (ESI) m/z 533.3 [M+H] + .
实施例32 6-溴-N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-异丙基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物32)Example 32 6-bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-isopropyl-1H-pyrrole A[3,2-b]pyridine-3-carboxamide (compound 32)
Figure PCTCN2021129535-appb-000044
Figure PCTCN2021129535-appb-000044
以化合物29-2为原料，脱保护，合成方法同化合物1。Using compound 29-2 as raw material, deprotection, the synthesis method is the same as compound 1.
1H NMR(400MHz,DMSO-d 6)δ10.87(s,1H),10.21(s,1H),8.83(s,1H),8.78(s,1H),8.31(s,1H),7.78(s,1H),7.09(d,J＝4.0Hz,1H),5.01–4.97(m,1H),3.55(t,J＝4.0Hz,2H),2.31(s,3H),1.54(s,3H),1.53(s,3H).LC-MS(ESI)m/z 485.1[M+H] +. 1 H NMR (400MHz,DMSO-d 6 )δ10.87(s,1H),10.21(s,1H),8.83(s,1H),8.78(s,1H),8.31(s,1H),7.78( s,1H),7.09(d,J=4.0Hz,1H),5.01–4.97(m,1H),3.55(t,J=4.0Hz,2H),2.31(s,3H),1.54(s,3H ), 1.53(s,3H). LC-MS(ESI) m/z 485.1[M+H] + .
实施例33Example 33
化合物33的合成路线如下：The synthetic route of compound 33 is as follows:
Figure PCTCN2021129535-appb-000045
Figure PCTCN2021129535-appb-000045
步骤a：6-氨基-4-((2-吗啉乙基)氨基)烟腈(化合物33-1)的制备Step a: Preparation of 6-amino-4-((2-morpholinoethyl)amino)nicotinonitrile (Compound 33-1)
合成方法同化合物1-10。 1HNMR(400MHz,CDCl 3)δ8.25(s,1H),7.92(s,1H),5.86(t,J＝4.0Hz,1H),3.76–3.74(m,4H),3.40(dd,J＝8.0Hz,12.0Hz,2H),2.71(t,J＝6.0Hz,2H),2.56–2.53(m,4H).LC-MS(ESI)m/z 248.1[M+H] +. The synthesis method is the same as compound 1-10. 1 HNMR (400MHz, CDCl 3 )δ8.25(s,1H),7.92(s,1H),5.86(t,J＝4.0Hz,1H),3.76–3.74(m,4H),3.40(dd,J =8.0Hz, 12.0Hz, 2H), 2.71(t, J=6.0Hz, 2H), 2.56–2.53(m, 4H). LC-MS (ESI) m/z 248.1[M+H] + .
步骤b：6-溴-N-(5-氰基-4-((2-吗啉乙基)氨基)吡啶-2-基)-5-(1,3-二氧戊环-2-基)-1-异丙基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物33-2)的制备Step b: 6-Bromo-N-(5-cyano-4-((2-morpholinyl)amino)pyridin-2-yl)-5-(1,3-dioxolan-2-yl )-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 33-2)
合成方法同化合物1-11。 1H NMR(400MHz,CDCl 3)δ11.31(s,1H),8.26(s,1H),8.25(s,1H),8.01(s,1H),6.65(s,1H),5.86(t,J＝4.0Hz,1H),4.69–4.61(m,3H),4.23–4.20(m,2H),3.79–3.77(m,4H),3.40(dd,J＝8.0Hz,12.0Hz,2H),2.73(t,J＝6.0Hz,2H),2.56–2.54(m,4H),1.63(s,3H),1.62(s,3H).LC-MS(ESI)m/z 584.1[M+H] +. The synthesis method is the same as compound 1-11. 1 H NMR (400MHz, CDCl 3 )δ11.31(s,1H),8.26(s,1H),8.25(s,1H),8.01(s,1H),6.65(s,1H),5.86(t, J＝4.0Hz, 1H), 4.69–4.61(m, 3H), 4.23–4.20(m, 2H), 3.79–3.77(m, 4H), 3.40(dd, J＝8.0Hz, 12.0Hz, 2H), 2.73(t,J=6.0Hz,2H),2.56–2.54(m,4H),1.63(s,3H),1.62(s,3H).LC-MS(ESI)m/z 584.1[M+H] + .
步骤c：6-溴-N-(5-氰基-4-((2-吗啉乙基)氨基)吡啶-2-基)-5-醛基-1-异丙基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物33)的制备Step c: 6-Bromo-N-(5-cyano-4-((2-morpholinoethyl)amino)pyridin-2-yl)-5-formyl-1-isopropyl-1H-pyrrolo Preparation of [3,2-b]pyridine-3-carboxamide (compound 33)
合成方法同化合物1。 1H NMR(400MHz,DMSO-d 6)δ10.88(s,1H),10.26(s,1H),8.82(s,1H),8.77(s,1H),8.30(s,1H),7.74(s,1H),6.96(t,J＝4.0Hz,1H),5.01–4.96(m,1H),3.61–3.59(m,4H),3.38–3.35(m,2H),2.57(t,J＝4.0Hz,2H),2.47(br,2H),1.54(s,3H),1.53(s,3H).LC-MS(ESI)m/z 540.1[M+H] +. The synthesis method is the same as compound 1. 1 H NMR (400MHz,DMSO-d 6 )δ10.88(s,1H),10.26(s,1H),8.82(s,1H),8.77(s,1H),8.30(s,1H),7.74( s,1H),6.96(t,J=4.0Hz,1H),5.01–4.96(m,1H),3.61–3.59(m,4H),3.38–3.35(m,2H),2.57(t,J= 4.0Hz, 2H), 2.47(br, 2H), 1.54(s, 3H), 1.53(s, 3H). LC-MS (ESI) m/z 540.1[M+H] + .
实施例34Example 34
化合物34：6-溴-N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-(2-吗啉乙基)-1H-吡咯并[3,2-b]吡啶-3-甲酰胺Compound 34: 6-bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-(2-morpholine ethyl )-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
Figure PCTCN2021129535-appb-000046
Figure PCTCN2021129535-appb-000046
合成方法同实施例25。 1H NMR(400MHz,DMSO-d 6)δ10.88(s,1H),10.21(s,1H),8.76(s,1H),8.70(s,1H),8.33(s,1H),7.77(s,1H),7.07(t,J＝4.0Hz,1H),4.49(t,J＝4.0Hz,1H),3.56(t,J＝6.0Hz,2H),3.51–3.49(m,4H),3.43(dd,J＝6.0Hz,9.0Hz,2H),3.31(s,3H),2.72(t,J＝6.0Hz,2H),2.46–2.44(m,4H).LC-MS(ESI)m/z 556.1[M+H] +. The synthesis method is the same as in Example 25. 1 H NMR (400MHz,DMSO-d 6 )δ10.88(s,1H),10.21(s,1H),8.76(s,1H),8.70(s,1H),8.33(s,1H),7.77( s,1H),7.07(t,J=4.0Hz,1H),4.49(t,J=4.0Hz,1H),3.56(t,J=6.0Hz,2H),3.51–3.49(m,4H), 3.43(dd, J=6.0Hz, 9.0Hz, 2H), 3.31(s, 3H), 2.72(t, J=6.0Hz, 2H), 2.46–2.44(m, 4H).LC-MS(ESI)m /z 556.1[M+H] + .
实施例35Example 35
化合物35的合成路线如下：The synthetic route of compound 35 is as follows:
Figure PCTCN2021129535-appb-000047
Figure PCTCN2021129535-appb-000047
步骤a：N-(2-(((叔丁氧基羰基)氨基)乙基)-N-甲基甘氨酸乙酯(化合物35-1)的制备Step a: Preparation of N-(2-(((tert-butoxycarbonyl)amino)ethyl)-N-methylglycine ethyl ester (compound 35-1)
将2-(甲基氨基)乙基氨基甲酸叔丁酯(1.0g,1.0eq.),溴乙酸乙酯(958.0mg,1.0eq),三乙胺(608mg,1.05eq)溶于10mLTHF中，室温反应6h。减压浓缩有机相，柱层析分离得产物1.3g,产率87％。Dissolve tert-butyl 2-(methylamino)ethylcarbamate (1.0g, 1.0eq.), ethyl bromoacetate (958.0mg, 1.0eq), triethylamine (608mg, 1.05eq) in 10mLTHF, Reaction at room temperature for 6h. The organic phase was concentrated under reduced pressure and separated by column chromatography to obtain 1.3 g of the product with a yield of 87%.
1H NMR(400MHz,CDCl 3)δ5.59(s,1H),4.11(q,J＝8.0Hz,20.0Hz,2H),3.21(s,1H),3.14(dd,J＝8.0Hz,12.0Hz,2H),2.57(t,J＝6.0Hz,2H),2.32(s,3H),1.39(s,9H),1.22(t,J＝6.0Hz,2H).LC-MS(ESI)m/z 261.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ5.59(s, 1H), 4.11(q, J=8.0Hz, 20.0Hz, 2H), 3.21(s, 1H), 3.14(dd, J=8.0Hz, 12.0 Hz,2H),2.57(t,J=6.0Hz,2H),2.32(s,3H),1.39(s,9H),1.22(t,J=6.0Hz,2H).LC-MS(ESI)m /z 261.1[M+H] + .
步骤b：N-(2-氨基乙基)-N-甲基甘氨酸乙酯(化合物35-2)的制备Step b: Preparation of N-(2-aminoethyl)-N-methylglycine ethyl ester (compound 35-2)
将化合物35-1(1.3g,1.0eq.),三氟乙酸(1.14g,2.0eq.)溶于10mL DCM中，室温反应3h,将体系先选干，再加入饱和碳酸氢钠调至pH＝8.0，用乙酸乙酯萃取,减压浓缩有机相，柱层析分离得产物680mg,产率85％。Dissolve compound 35-1 (1.3g, 1.0eq.), trifluoroacetic acid (1.14g, 2.0eq.) in 10mL DCM, and react at room temperature for 3h. The system was first dried, and then added saturated sodium bicarbonate to adjust the pH =8.0, extracted with ethyl acetate, concentrated the organic phase under reduced pressure, and separated by column chromatography to obtain 680 mg of product with a yield of 85%.
1H NMR(400MHz,CDCl 3)δ4.16(q,J＝7.0Hz,2H),3.29(s,2H),3.20(d,J＝5.2Hz,2H),2.65(t,J＝5.6Hz,2H),2.39(s,3H),1.40(s,2H),1.26(t,J＝7.1Hz,3H).LC-MS(ESI)m/z161.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ4.16(q, J=7.0Hz, 2H), 3.29(s, 2H), 3.20(d, J=5.2Hz, 2H), 2.65(t, J=5.6Hz ,2H),2.39(s,3H),1.40(s,2H),1.26(t,J=7.1Hz,3H).LC-MS(ESI)m/z161.1[M+H] + .
步骤c：N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-(1,3-二氧戊环-2-基)-6-乙烯基-1-异丙基-1H-吡咯[3,2-b]吡啶-3-甲酰胺(化合物35-3)的制备Step c: N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolan-2-yl)-6 - Preparation of vinyl-1-isopropyl-1H-pyrrole[3,2-b]pyridine-3-carboxamide (compound 35-3)
将化合物18-2(100.0mg，1.0eq)，Pd(dppf)Cl 2(15.0mg，0.1eq)，碳酸铯(195.0mg,3.0eq),1.4-二氧六环5ml及水1ml加入Schlenk瓶中，体系置换氩气后再加入乙烯基硼酸频哪 醇酯(310.0mg,10.0eq)，转至110℃下反应2h，体系直接浓缩柱层析，得到目标化合物50.0mg，收率为55.6％。 Add compound 18-2 (100.0mg, 1.0eq), Pd(dppf)Cl 2 (15.0mg, 0.1eq), cesium carbonate (195.0mg, 3.0eq), 5ml of 1.4-dioxane and 1ml of water into a Schlenk bottle In the system, the system was replaced with argon, and then vinyl boric acid pinacol ester (310.0mg, 10.0eq) was added, and then transferred to 110°C for 2h, and the system was directly concentrated and column chromatographed to obtain 50.0mg of the target compound, with a yield of 55.6% .
1H NMR(400MHz,CDCl 3)δ11.49(s,1H),8.27(s,1H),7.87(s,1H),7.36(dd,J＝10.0Hz,20.0Hz.1H),6.39(s,1H),5.73(d,J＝20.0Hz,1H),5.46(d,J＝12.0Hz,1H),5.33(d,J＝6.0Hz,1H),4.77–4.71(m,1H),4.51–4.47(m,2H),4.21–4.17(m,2H),3.67(t,J＝4.0Hz,2H),3.54(t,J＝6.0Hz,2H),3.44(s,3H),1.63(s,3H),1.62(s,3H).LC-MS(ESI)m/z 477.2[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ11.49(s, 1H), 8.27(s, 1H), 7.87(s, 1H), 7.36(dd, J=10.0Hz, 20.0Hz.1H), 6.39(s ,1H),5.73(d,J=20.0Hz,1H),5.46(d,J=12.0Hz,1H),5.33(d,J=6.0Hz,1H),4.77–4.71(m,1H),4.51 –4.47(m,2H),4.21–4.17(m,2H),3.67(t,J=4.0Hz,2H),3.54(t,J=6.0Hz,2H),3.44(s,3H),1.63( s,3H),1.62(s,3H).LC-MS(ESI)m/z 477.2[M+H] + .
步骤d：N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-(1,3-二氧戊环-2-基)-6-醛基-1-异丙基-1H-吡咯[3,2-b]吡啶-3-甲酰胺(化合物35-4)的制备Step d: N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolan-2-yl)-6 - Preparation of aldehyde-1-isopropyl-1H-pyrrole[3,2-b]pyridine-3-carboxamide (compound 35-4)
向单口瓶中分别加入化合物35-3(50.0mg,1.0eq)，锇酸钾二水合物(5.2mg,0.15eq),1.4-二氧六环(10ml)与水(1ml)，搅拌5min后再加入高碘酸钠(82.0mg,4.0eq),继续反应2h，原料经TLC监测反应完毕后直接浓缩柱层析，得到化合物25.0mg，收率为50.0％。Add compound 35-3 (50.0mg, 1.0eq), potassium osmate dihydrate (5.2mg, 0.15eq), 1.4-dioxane (10ml) and water (1ml) into the single-necked bottle respectively, and stir for 5min Sodium periodate (82.0mg, 4.0eq) was added, and the reaction was continued for 2h. After the reaction was monitored by TLC, the raw material was directly concentrated by column chromatography to obtain 25.0mg of the compound with a yield of 50.0%.
1H NMR(400MHz,CDCl 3)δ11.27(s,1H),10.69(s,1H),8.48(s,1H),8.45(s,1H),8.29(s,1H),7.87(s,1H),6.41(s,1H),5.36(t,J＝4.0Hz,1H),4.85–4.79(m,1H),4.44–4.40(m,2H),4.25–4.22(m,2H),3.68(t,J＝6.0Hz,2H),3.54(q,J＝6.0Hz,10.0Hz,2H),3.44(s,3H),1.66(s,6H).LC-MS(ESI)m/z 479.2[M+H] +. 1 H NMR (400MHz, CDCl 3 )δ11.27(s,1H),10.69(s,1H),8.48(s,1H),8.45(s,1H),8.29(s,1H),7.87(s, 1H),6.41(s,1H),5.36(t,J＝4.0Hz,1H),4.85–4.79(m,1H),4.44–4.40(m,2H),4.25–4.22(m,2H),3.68 (t, J = 6.0Hz, 2H), 3.54 (q, J = 6.0Hz, 10.0Hz, 2H), 3.44 (s, 3H), 1.66 (s, 6H). LC-MS (ESI) m/z 479.2 [M+H] + .
步骤e：N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-(1,3-二氧戊环-2-基)-6-((4-甲基-2-氧代哌嗪-1-基)甲基)-1-异丙基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物35-5)的制备Step e: N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolan-2-yl)-6 -((4-methyl-2-oxopiperazin-1-yl)methyl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 35- 5) Preparation
将化合物35-4(25.0mg,1.0eq),化合物35-2(22.0,1.5eq.)和三乙酰基硼氢化钠(30.0mg,5.0eq.)溶于5mL无水二氯甲烷中，室温反应24h。用饱和碳酸氢钠调至pH＝8.0，用二氯甲烷萃取,减压浓缩有机相，柱层析分离得产物14.0mg，产率45.7％。Compound 35-4 (25.0mg, 1.0eq), compound 35-2 (22.0, 1.5eq.) and sodium triacetylborohydride (30.0mg, 5.0eq.) were dissolved in 5mL of anhydrous dichloromethane, room temperature Reaction 24h. Adjust the pH to 8.0 with saturated sodium bicarbonate, extract with dichloromethane, concentrate the organic phase under reduced pressure, and separate by column chromatography to obtain 14.0 mg of the product with a yield of 45.7%.
1H NMR(400MHz,CDCl 3)δ11.41(s,1H),8.27(s,1H),8.26(s,1H),6.28(s,1H),5.35–5.27(m,1H),5.02(s,3H),4.73–4.67(m,1H),4.43–4.41(m,2H),4.24–4.16(m,2H),3.67(t,J＝8.0Hz,2H),3.53(t,J＝6.0Hz,2H),3.44(s,3H),3.32(t,J＝6.0Hz,2H),3.25(s,3H),2.62(t,J＝4.0Hz,2H),2.36(s,3H),1.59(s,3H),1.58(s,3H).LC-MS(ESI)m/z 577.28[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ11.41(s,1H),8.27(s,1H),8.26(s,1H),6.28(s,1H),5.35–5.27(m,1H),5.02( s,3H),4.73–4.67(m,1H),4.43–4.41(m,2H),4.24–4.16(m,2H),3.67(t,J＝8.0Hz,2H),3.53(t,J＝ 6.0Hz, 2H), 3.44(s, 3H), 3.32(t, J=6.0Hz, 2H), 3.25(s, 3H), 2.62(t, J=4.0Hz, 2H), 2.36(s, 3H) ,1.59(s,3H),1.58(s,3H).LC-MS(ESI)m/z 577.28[M+H] + .
步骤f：N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-((4-甲基-2-氧代哌嗪-1-基)甲基)-1-异丙基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物35)的制备Step f: N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-((4-methyl-2-oxo Preparation of piperazin-1-yl)methyl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 35)
合成方法同化合物1。The synthesis method is the same as compound 1.
H NMR(400MHz,DMSO-d 6)δ11.09(s,1H),10.22(s,1H),8.79(s,1H),8.31(s,1H),7.92(s,1H),7.80(s,1H),7.08(t,J＝6.0Hz,1H),5.10(s,2H),5.01–4.94(m,1H),3.56(t,J＝6.0Hz,2H),3.45–3.41(m,2H),3.32(s,3H),3.28(s,2H),3.12(s,2H),2.66(t,J＝6.0Hz,2H),2.27(s,3H),1.56(s,3H),1.54(s,3H).LC-MS(ESI)m/z 533.3[M+H] +. H NMR (400MHz,DMSO-d 6 )δ11.09(s,1H),10.22(s,1H),8.79(s,1H),8.31(s,1H),7.92(s,1H),7.80(s ,1H),7.08(t,J=6.0Hz,1H),5.10(s,2H),5.01–4.94(m,1H),3.56(t,J=6.0Hz,2H),3.45–3.41(m, 2H),3.32(s,3H),3.28(s,2H),3.12(s,2H),2.66(t,J=6.0Hz,2H),2.27(s,3H),1.56(s,3H), 1.54(s,3H).LC-MS(ESI)m/z 533.3[M+H] + .
实施例36Example 36
Figure PCTCN2021129535-appb-000048
Figure PCTCN2021129535-appb-000048
步骤a：2-氯-N-(2-甲氧基乙基)-5-(三氟甲基)吡啶-4-胺(化合物36-2)的制备Step a: Preparation of 2-Chloro-N-(2-methoxyethyl)-5-(trifluoromethyl)pyridin-4-amine (Compound 36-2)
将化合物36-1(2.0g，1.0eq)与2-甲氧基乙胺(510.0mg，1.05eq)，Pd 2dba 3(300.0mg，0.05eq)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(Xantphos，190.0mg，0.05eq)以及碳酸铯(6.4g，3.0eq)加入到50mL甲苯中，体系置换氩气后转至80℃反应过夜后，体系直接减压浓缩，柱层析分离得到目标产物400.0mg，收率为24.2％。 Compound 36-1 (2.0g, 1.0eq) was mixed with 2-methoxyethylamine (510.0mg, 1.05eq), Pd 2 dba 3 (300.0mg, 0.05eq), 4,5-bisdiphenylphosphine- 9,9-Dimethylxanthene (Xantphos, 190.0mg, 0.05eq) and cesium carbonate (6.4g, 3.0eq) were added to 50mL of toluene, the system was replaced with argon and then transferred to 80°C for overnight reaction, the system was directly Concentrate under reduced pressure and separate by column chromatography to obtain 400.0 mg of the target product with a yield of 24.2%.
1H NMR(400MHz,CDCl 3)δ8.24(s,1H),6.62(s,1H),5.32(br,1H),3.65(t,J＝4.0Hz,2H),3.34(s,3H),3.40–3.36(m,2H).LC-MS(ESI)m/z 255.1[M+H] +。 1 H NMR (400MHz, CDCl 3 )δ8.24(s,1H),6.62(s,1H),5.32(br,1H),3.65(t,J=4.0Hz,2H),3.34(s,3H) , 3.40–3.36 (m,2H). LC-MS (ESI) m/z 255.1 [M+H] + .
步骤b：N-(2,4-二甲氧基苄基)-N-(2-甲氧基乙基)-5-(三氟甲基)吡啶-2,4-二胺(化合物36-3)的制备Step b: N-(2,4-dimethoxybenzyl)-N-(2-methoxyethyl)-5-(trifluoromethyl)pyridine-2,4-diamine (compound 36- 3) Preparation
将化合物36-2(400.0mg，1.0eq)与2.4-二甲氧基苯胺(2.6g，10.0eq)，Pd 2dba 3(72.0mg，0.05eq)，Xantphos(45.0mg，0.05eq)以及碳酸铯(1.54g,3.0eq)加入到10mL甲苯中，体系置换氩气后转至100℃反应过夜后，体系直接减压浓缩，柱层析分离得到目标产物250.0mg，收率为41.2％。 Compound 36-2 (400.0mg, 1.0eq) was mixed with 2.4-dimethoxyaniline (2.6g, 10.0eq), Pd 2 dba 3 (72.0mg, 0.05eq), Xantphos (45.0mg, 0.05eq) and carbonic acid Cesium (1.54g, 3.0eq) was added to 10mL of toluene, the system was replaced with argon and then transferred to 100°C for overnight reaction, the system was directly concentrated under reduced pressure and separated by column chromatography to obtain 250.0mg of the target product with a yield of 41.2%.
1H NMR(400MHz,CDCl 3)δ8.62(s,1H),8.20(s,1H),7.24–7.18(m,3H),6.58(s,1H),5.40(s,2H),5.28(br,1H),3.78(s,6H),3.64(t,J＝4.0Hz,2H),3.32(s,3H),3.41–3.35(m,2H).LC-MS(ESI)m/z 386.2[M+H] +。 1 H NMR (400MHz, CDCl 3 )δ8.62(s,1H),8.20(s,1H),7.24–7.18(m,3H),6.58(s,1H),5.40(s,2H),5.28( br, 1H), 3.78(s, 6H), 3.64(t, J=4.0Hz, 2H), 3.32(s, 3H), 3.41–3.35(m, 2H). LC-MS (ESI) m/z 386.2 [M+H] + .
步骤c：N-(2-甲氧基乙基)-5-(三氟甲基)吡啶-2,4-二胺(化合物36-4)的制备Step c: Preparation of N-(2-methoxyethyl)-5-(trifluoromethyl)pyridine-2,4-diamine (Compound 36-4)
将化合物36-3(250.0mg，1.0eq)加入到二氯甲烷10.0ml中，再往体系中缓慢加入三氟乙酸3.0ml，体系经TLC监测原料反应完全后，充分旋干后得到产物160.0mg，收率104.6％(成三氟乙酸盐)，直接投下一步。LC-MS(ESI)m/z 236.1[M+H] +。 Compound 36-3 (250.0mg, 1.0eq) was added to 10.0ml of dichloromethane, and then 3.0ml of trifluoroacetic acid was slowly added to the system. After the system was monitored by TLC, the reaction of the raw materials was complete, and the product was fully spin-dried to obtain 160.0mg of the product , the yield was 104.6% (into trifluoroacetate), and it was directly cast into the next step. LC-MS (ESI) m/z 236.1 [M+H] + .
步骤d与步骤e：N-(5-三氟甲基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物36)的制备Step d and step e: N-(5-trifluoromethyl-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrole Preparation of [3,2-b]pyridine-3-carboxamide (compound 36)
合成方法同实施例1Synthetic method is with embodiment 1
结果分析： 1HNMR(400MHz,DMSO-d 6)δ11.05(s,1H),10.12(s,1H),8.66(s,1H),8.35(d,J＝8.0Hz,1H),7.98(d,J＝8.0Hz,1H),7.87(s,1H),5.32(t,J＝4.0Hz,1H),4.01(s,2H),3.58(t,J＝6.0Hz,2H),3.47–3.44(m,2H).LC-MS(ESI)m/z 422.2[M+H] +. Result analysis: 1 HNMR (400MHz, DMSO-d 6 ) δ11.05(s, 1H), 10.12(s, 1H), 8.66(s, 1H), 8.35(d, J＝8.0Hz, 1H), 7.98( d,J=8.0Hz,1H),7.87(s,1H),5.32(t,J=4.0Hz,1H),4.01(s,2H),3.58(t,J=6.0Hz,2H),3.47– 3.44(m,2H).LC-MS(ESI)m/z 422.2[M+H] + .
实施例37Example 37
化合物37的合成路线如下：The synthetic route of compound 37 is as follows:
Figure PCTCN2021129535-appb-000049
Figure PCTCN2021129535-appb-000049
步骤a：5-甲基吡唑并[1,5-a]嘧啶-3-羧酸乙酯(化合物37-1)的制备Step a: Preparation of ethyl 5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (compound 37-1)
将3-氨基-1H-吡唑-4-羧酸乙酯(10g,1.0eq.)与4,4-二甲氧基-2-丁酮(12.3g,1.3eq)溶于50ml甲苯中，100℃反应5h.减压浓缩有机相，柱层析分离得到产物10g，产率为75.8％。3-Amino-1H-pyrazole-4-carboxylic acid ethyl ester (10g, 1.0eq.) and 4,4-dimethoxy-2-butanone (12.3g, 1.3eq) were dissolved in 50ml of toluene, The reaction was carried out at 100° C. for 5 h. The organic phase was concentrated under reduced pressure and separated by column chromatography to obtain 10 g of the product with a yield of 75.8%.
1H NMR(400MHz,DMSO-d 6)δ9.11(d,J＝7.1Hz,1H),8.52(s,1H),7.17(d,J＝7.1Hz,1H),4.28(q,J＝7.1Hz,2H),2.62(s,3H),1.30(t,J＝7.1Hz,3H).LC-MS(ESI)m/z 206.1[M+H] +. 1 H NMR (400MHz, DMSO-d 6 ) δ9.11(d, J=7.1Hz, 1H), 8.52(s, 1H), 7.17(d, J=7.1Hz, 1H), 4.28(q, J= 7.1Hz, 2H), 2.62(s, 3H), 1.30(t, J=7.1Hz, 3H). LC-MS (ESI) m/z 206.1[M+H] + .
步骤b：5-甲酰基吡唑并[1,5-a]嘧啶-3-羧酸乙酯(化合物37-2)的制备Step b: Preparation of ethyl 5-formylpyrazolo[1,5-a]pyrimidine-3-carboxylate (compound 37-2)
合成方法同化合物1-1。 1H NMR(400MHz,DMSO-d 6)δ9.98(d,J＝0.7Hz,1H),9.47(dd,J＝7.1,0.8Hz,1H),8.82(s,1H),7.60(d,J＝7.1Hz,1H),4.36(q,J＝7.1Hz,2H),1.35(t,J＝7.1Hz,3H).LC-MS(ESI)m/z 220.0[M+H] +. The synthesis method is the same as compound 1-1. 1 H NMR (400MHz, DMSO-d 6 )δ9.98(d, J=0.7Hz, 1H), 9.47(dd, J=7.1, 0.8Hz, 1H), 8.82(s, 1H), 7.60(d, J＝7.1Hz, 1H), 4.36(q, J＝7.1Hz, 2H), 1.35(t, J＝7.1Hz, 3H).LC-MS (ESI) m/z 220.0[M+H] + .
步骤c：5-(1,3-二氧戊环-2-基)吡唑并[1,5-a]嘧啶-3-羧酸乙酯(化合物37-3)的制备Step c: Preparation of ethyl 5-(1,3-dioxolan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (compound 37-3)
合成方法同化合物1-2。 1H NMR(400MHz,DMSO-d 6)δ9.32(d,J＝7.2Hz,1H),8.66(s,1H),7.33(d,J＝7.2Hz,1H),5.80(s,1H),4.30(q,J＝7.1Hz,2H),4.22–4.15(m,2H),4.10–4.03(m,2H),1.31(t,J＝7.1Hz,3H).LC-MS(ESI)m/z 264.1[M+H] +. The synthesis method is the same as compound 1-2. 1 H NMR (400MHz, DMSO-d 6 )δ9.32(d, J=7.2Hz, 1H), 8.66(s, 1H), 7.33(d, J=7.2Hz, 1H), 5.80(s, 1H) ,4.30(q,J=7.1Hz,2H),4.22–4.15(m,2H),4.10–4.03(m,2H),1.31(t,J=7.1Hz,3H).LC-MS(ESI)m /z 264.1[M+H] + .
步骤d：N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-(1,3-二氧戊环-2-基)吡唑并[1,5-a]嘧啶-3-甲酰胺(化合物37-4)的制备Step d: N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-(1,3-dioxolan-2-yl)pyrazole Preparation of [1,5-a]pyrimidine-3-carboxamide (compound 37-4)
合成方法同化合物1-11。 1HNMR(400MHz,DMSO-d 6)δ10.34(s,1H),8.86(d,J＝8.0Hz,1H),8.76(s,1H),8.25(s,1H),7.85(s,1H),7.28(d,J＝8.0Hz,1H),6.02(s,1H),5.38(t,J＝4.0Hz,1H),4.34–4.27(m,2H),4.22–4.18(m,2H),3.68(t,J＝6.0Hz,2H),3.54(q,J＝4.0Hz,12.0Hz,2H),3.44(s,3H).LC-MS(ESI)m/z 410.1[M+H] +. The synthesis method is the same as compound 1-11. 1 HNMR (400MHz, DMSO-d 6 )δ10.34(s,1H),8.86(d,J＝8.0Hz,1H),8.76(s,1H),8.25(s,1H),7.85(s,1H ),7.28(d,J=8.0Hz,1H),6.02(s,1H),5.38(t,J=4.0Hz,1H),4.34–4.27(m,2H),4.22–4.18(m,2H) ,3.68(t,J=6.0Hz,2H),3.54(q,J=4.0Hz,12.0Hz,2H),3.44(s,3H).LC-MS(ESI)m/z 410.1[M+H] + .
步骤e：N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1H-吡唑并[1,5-a]嘧啶-3-甲酰胺(化合物37)的制备Step e: N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1H-pyrazolo[1,5-a]pyrimidine - Preparation of 3-formamide (compound 37)
合成方法同化合物1。 1H NMR(400MHz,DMSO-d 6)δ10.30(s,1H),10.03(s,1H),9.59(d,J＝7.1Hz,1H),8.97(s,1H),7.68(d,J＝7.1Hz,1H),5.64(s,2H),3.68(br,2H),3.56(d,J＝2.5Hz,2H),3.31(s,3H).LC-MS(ESI)m/z 366.1[M+H] +. The synthesis method is the same as compound 1. 1 H NMR (400MHz, DMSO-d 6 )δ10.30(s,1H),10.03(s,1H),9.59(d,J=7.1Hz,1H),8.97(s,1H),7.68(d, J＝7.1Hz, 1H), 5.64(s, 2H), 3.68(br, 2H), 3.56(d, J＝2.5Hz, 2H), 3.31(s, 3H).LC-MS(ESI) m/z 366.1[M+H] + .
实施例38：N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-甲酰基-1-甲基-6-((4-甲基-2-氧代哌嗪-1-基)甲基)-1H-吡咯并[3,2-b]吡啶-3-甲酰胺(化合物38)Example 38: N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-6-((4-methyl Base-2-oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (compound 38)
Figure PCTCN2021129535-appb-000050
Figure PCTCN2021129535-appb-000050
合成方法如化合物35。The synthetic method is as compound 35.
H NMR(400MHz,DMSO-d 6)δ11.06(s,1H),10.23(s,1H),8.65(s,1H),8.32(s,1H),7.82(s,1H),7.78(s,1H),7.07(s,1H),5.10(s,2H),3.99(s,2H),3.57–3.54(m,2H),3.44–3.42(m,2H),3.35(s,3H),3.32(s,3H),3.12(s,2H),2.68–2.66(m,2H),2.27(s,3H).LC-MS(ESI)m/z505.2[M+H] +. H NMR (400MHz,DMSO-d 6 )δ11.06(s,1H),10.23(s,1H),8.65(s,1H),8.32(s,1H),7.82(s,1H),7.78(s ,1H),7.07(s,1H),5.10(s,2H),3.99(s,2H),3.57–3.54(m,2H),3.44–3.42(m,2H),3.35(s,3H), 3.32(s,3H),3.12(s,2H),2.68–2.66(m,2H),2.27(s,3H).LC-MS(ESI)m/z505.2[M+H] + .
实施例39：化合物对FGFR1-4激酶的IC 50测试结果 Example 39: IC50 test results of compounds against FGFR1-4 kinase
FGFR1-4激酶抑制实验：使用基于FRET的Z’-Lyte分析系统，根据制造商的说明(美国加利福尼亚州卡尔斯巴德的生命技术公司)，确定化合物对FGFR1-4的抑制活性。反应在384孔板中以5μL反应体积在50mM HEPES(pH 7.5)，10mM MgCl2、1mM EGTA和0.01％Brij-35中用适量的激酶进行。将反应液在室温下在2μM底物与各激酶对应ATP浓度(FGFR1：25μM，FGFR2：5μM，FGFR3：75μM，FGFR4：150μM)存在下以及在各种浓度的化合物存在下孵育1.5小时，然后添加2.5μL显影剂再在室温下孵育1小时，然后添加2.5μL终止溶液。用EnVision Multilabel Reader(Perkin Elmer，Inc.)检测445nm(香豆素)/520nm(荧光素)的荧光信号比。IC 50使用Graphpad Prism 5(Graphpad Software，Inc)分析数据。 FGFR1-4 Kinase Inhibition Assay: The inhibitory activity of compounds against FGFR1-4 was determined using the FRET-based Z'-Lyte Assay System according to the manufacturer's instructions (Life Technologies, Carlsbad, CA, USA). Reactions were performed in 5 μL reaction volumes in 384-well plates in 50 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, and 0.01% Brij-35 with the appropriate amount of kinase. The reaction solution was incubated for 1.5 hours at room temperature in the presence of 2 μM substrate and the corresponding ATP concentration of each kinase (FGFR1: 25 μM, FGFR2: 5 μM, FGFR3: 75 μM, FGFR4: 150 μM) and in the presence of various concentrations of compounds, and then added 2.5 μL of developer was incubated for another 1 h at room temperature, after which 2.5 μL of stop solution was added. The fluorescence signal ratio of 445 nm (coumarin)/520 nm (fluorescein) was detected with EnVision Multilabel Reader (Perkin Elmer, Inc.). IC50 Data were analyzed using Graphpad Prism 5 (Graphpad Software, Inc).
计算：通过全活性孔和对照信号孔计算出每个孔的抑制率，数据分析方法如下：Calculation: Calculate the inhibition rate of each well through all active wells and control signal wells, and the data analysis method is as follows:
磷酸化比率＝1–{(发射比×F100％–C100％)/[C 0％–C 100％+发射比×(F100％–F0％)]}×100；Phosphorylation ratio=1–{(emission ratio×F100%–C100%)/[C 0%–C 100%+emission ratio×(F100%–F0%)]}×100;
抑制率＝100×(1–化合物磷酸化比率/阴性对照磷酸化比率)。Inhibition rate = 100 x (1 - compound phosphorylation ratio / negative control phosphorylation ratio).
IC 50值采用医学绘图软件(GraphPad Prism5.0)软件计算求得。 IC50 values were calculated using medical graphics software (GraphPad Prism5.0).
表1：部分化合物对FGFR4激酶活性测试结果(IC50:nM)Table 1: Test results of some compounds on FGFR4 kinase activity (IC50:nM)
化合物编号Compound number FGFR4FGFR4 FGFR1FGFR1 FGFR2FGFR2 FGFR3FGFR3
实施例1Example 1 10.010.0 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例2Example 2 178.0178.0 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例3Example 3 12.012.0 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例4Example 4 3.83.8 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例5Example 5 4.74.7 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例6Example 6 12.612.6 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例7Example 7 >1000>1000 NTNT NTNT NTNT
实施例8Example 8 >1000>1000 NTNT NTNT NTNT
实施例9Example 9 >1000>1000 NTNT NTNT NTNT
实施例10Example 10 >1000>1000 NTNT NTNT NTNT
实施例11Example 11 2.962.96 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例12Example 12 1.631.63 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例13Example 13 2.432.43 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例14Example 14 1.921.92 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例15Example 15 578.2578.2 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例16Example 16 39.8439.84 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例17Example 17 20.220.2 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例18Example 18 5.585.58 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例19Example 19 2.012.01 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例20Example 20 117.9117.9 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例21Example 21 179.1179.1 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例22Example 22 88.988.9 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例23Example 23 71.9171.91 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例24Example 24 7.1877.187 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例25Example 25 161.2161.2 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例26Example 26 116.9116.9 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例27Example 27 96.1996.19 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例28Example 28 1.371.37 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例29Example 29 212.7212.7 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例30Example 30 39.3739.37 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例31Example 31 655.3655.3 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例32Example 32 189.3189.3 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例33Example 33 97.0597.05 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例34Example 34 17.6117.61 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例35Example 35 13.7313.73 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例36Example 36 362.2362.2 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例37Example 37 35.2235.22 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
实施例38Example 38 38.1938.19 ＞10uM>10uM ＞10uM>10uM ＞10uM>10uM
FGFR401FGFR401 3.33.3 ＞1uM>1uM ＞1uM>1uM ＞1uM>1uM
NT＝Not TestNT＝Not Test
从表1数据可以看出，本发明的部分5-醛基杂环酰胺类化合物对FGFR4激酶具有强抑制活性；且对FGFR家族另外三种亚型FGFR1-3具有优异的选择性。It can be seen from the data in Table 1 that some of the 5-formyl heterocyclic amide compounds of the present invention have strong inhibitory activity on FGFR4 kinase; and have excellent selectivity to the other three subtypes of FGFR family, FGFR1-3.
实施例40：基于BaF3-FGFR4稳定株的细胞增殖抑制活性结果Example 40: Results of Cell Proliferation Inhibitory Activity Based on BaF3-FGFR4 Stable Strains
本实验使用的Ba/F3细胞(小鼠前B细胞)购自ThermoFisher，Ba/F3-TEL-FGFR4野生型及Ba/F3-TEL-FGFR4(V550L)、Ba/F3-TEL-FGFR4(V550M)耐药突变体稳定株均由本实验室构建，并通过阳性药活性、蛋白表达及基因测序等实验鉴定完全正确。Ba/F3 cells (mouse pre-B cells) used in this experiment were purchased from ThermoFisher, Ba/F3-TEL-FGFR4 wild type and Ba/F3-TEL-FGFR4(V550L), Ba/F3-TEL-FGFR4(V550M) Stable strains of drug-resistant mutants were all constructed by our laboratory, and were identified through experiments such as positive drug activity, protein expression, and gene sequencing to be completely correct.
稳定株构建的简要步骤如下：The brief steps of stable strain construction are as follows:
1、在ETV6(NM_001987.4)的N端融合人的FGFR4(NM_002011.5)的激酶域基因，再将融合基因TEL-FGFR4克隆入pMSCV载体中，挑取阳性克隆并经测序验证。1. The kinase domain gene of human FGFR4 (NM_002011.5) was fused to the N-terminus of ETV6 (NM_001987.4), and then the fusion gene TEL-FGFR4 was cloned into the pMSCV vector, and positive clones were picked and verified by sequencing.
2、以重组质粒TEL-FGFR4-pMSCV为模板，构建FGFR4守门员突变体质粒TEL-FGFR4(V550L)-pMSCV和TEL-FGFR4(V550M)-pMSCV。2. Using the recombinant plasmid TEL-FGFR4-pMSCV as a template, construct FGFR4 gatekeeper mutant plasmids TEL-FGFR4(V550L)-pMSCV and TEL-FGFR4(V550M)-pMSCV.
3、将构建成功的三种质粒及无目的基因的空质粒转染293T细胞，收集并保存含病毒上清培养基。3. Transfect the three successfully constructed plasmids and the empty plasmid without the target gene into 293T cells, collect and save the medium containing the virus supernatant.
4、用此上清培养基感染Ba/F3细胞三天，换成含嘌呤霉素的正常培养基复苏一天，然后在无白介素3及添加嘌呤霉素的条件下筛选阳性细胞株。4. Use the supernatant medium to infect Ba/F3 cells for three days, replace with normal medium containing puromycin for recovery for one day, and then select positive cell lines under the condition of no interleukin-3 and addition of puromycin.
5、筛选得到的阳性稳定细胞株进行western-blot验证。5. The screened positive stable cell lines were verified by western-blot.
细胞增殖抑制活性研究：Cell Proliferation Inhibitory Activity Study:
1、将筛选得到的阳性稳定细胞株以2000个/孔加入96孔细胞培养板中，以转染无目的基因的空质粒的Ba/F3细胞株为对照。1. Add 2000 positive stable cell lines obtained by screening into a 96-well cell culture plate, and use the Ba/F3 cell line transfected with an empty plasmid without the target gene as a control.
2、6-12h后加入等体积的事先稀释好的小分子抑制剂(3倍稀释)。2. Add an equal volume of pre-diluted small molecule inhibitors (3-fold dilution) after 6-12 hours.
3、72h后加入CCK-8试剂检测细胞活力。3. After 72 hours, CCK-8 reagent was added to detect cell viability.
4、利用GraphPadprism软件计算小分子抑制的IC 50。 4. Use GraphPadprism software to calculate the IC 50 of small molecule inhibition.
表2：部分化合物对Ba/F3-FGFR4细胞活性测试结果(IC 50:nM) Table 2: Test results of activity of some compounds on Ba/F3-FGFR4 cells (IC 50 : nM)
化合物编号Compound number Ba/F3-FGFR4Ba/F3-FGFR4 化合物编号Compound number Ba/F3-FGFR4Ba/F3-FGFR4
实施例8Example 8 6.46.4 实施例25Example 25 312.0312.0
实施例9Example 9 67.067.0 实施例26Example 26 519.0519.0
实施例10Example 10 27.027.0 实施例27Example 27 27.027.0
实施例18Example 18 47.047.0 实施例28Example 28 117.0117.0
实施例19Example 19 >3000>3000 实施例29Example 29 15.015.0
实施例20Example 20 38.038.0 实施例30Example 30 35.035.0
实施例21Example 21 29.029.0 实施例31Example 31 20.020.0
实施例22Example 22 10.010.0 实施例38Example 38 7.07.0
实施例23Example 23 11.011.0 FGFR401FGFR401 4.04.0
实施例24Example 24 12.812.8  the  the
从表2数据可以看出，本发明的部分5-醛基杂环酰胺类化合物对Ba/F3-FGFR4稳定株的细胞增殖有较强的抑制活性。It can be seen from the data in Table 2 that some 5-formyl heterocyclic amide compounds of the present invention have strong inhibitory activity on the cell proliferation of the Ba/F3-FGFR4 stable strain.
表3.代表化合物对耐药细胞的活性补充Table 3. Supplementary activity of representative compounds on drug-resistant cells
Figure PCTCN2021129535-appb-000051
Figure PCTCN2021129535-appb-000051
从表3数据可以看出，本发明的部分5-醛基杂环酰胺类化合物对Ba/F3-FGFR4突变为V550L或V550M的稳定株细胞具有较好的抑增值制活性。It can be seen from the data in Table 3 that some of the 5-formyl heterocyclic amides compounds of the present invention have better anti-proliferation activity on stable cell lines with Ba/F3-FGFR4 mutated to V550L or V550M.
需要说明的是，本说明书中描述的具体特征、结构、材料或者特点可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例以及不同实施例的特征进行结合和组合。It should be noted that the specific features, structures, materials or features described in this specification can be combined arbitrarily. For the sake of concise description, all possible combinations of the technical features in the above embodiments are not described. In case of conflict, those skilled in the art can combine and combine different embodiments and features of different embodiments described in this specification.
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。The above-mentioned embodiments only express several implementation modes of the present invention, and the descriptions thereof are relatively specific and detailed, but should not be construed as limiting the patent scope of the invention. It should be noted that, for those skilled in the art, several modifications and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent for the present invention should be based on the appended claims.

Claims (10)

  1. 5-醛基杂环酰胺类化合物，其特征在于，所述化合物为具有式(I)结构的化合物或者其药学上可接受的盐、立体异构体以及其前药分子：The 5-formyl heterocyclic amide compound is characterized in that the compound is a compound with the structure of formula (I) or its pharmaceutically acceptable salt, stereoisomer and its prodrug molecule:
    Figure PCTCN2021129535-appb-100001
    Figure PCTCN2021129535-appb-100001
    式(I)中n＝0或1；In formula (I), n=0 or 1;
    X选自NH、NR 4、S或O；所述R 4任选自CN、含CN的6元芳环、C 1-6烷基、C 1-6烷氧基、C 1-6烷酰基、C 1-6磺酸基、C 2-4炔基、含有任选自N、O和S的杂原子的4-至12-元杂环基的C 1-6烷基； X is selected from NH, NR 4 , S or O; the R 4 is optionally selected from CN, 6-membered aromatic ring containing CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkanoyl , C 1-6 sulfonic acid group, C 2-4 alkynyl, C 1-6 alkyl containing a 4- to 12-membered heterocyclic group optionally selected from N, O and S heteroatoms;
    W,Y和Z分别独立选自C或N；W, Y and Z are independently selected from C or N;
    R 1任选自氢、卤素、氰基、三氟甲基、甲酰胺基、磺酰胺基、C 1-3硫基、C 1-6烷基、卤代C 1-4烷基、卤代C 1-4烷氧基、C 1-3烷基硫基、6元芳环硫基、含有任选自N、O和S的杂原子的4-至12-元杂环基的C 1-6烷基、C 1-6烷酰基、C 1-6环烷基、C 1-6烷基硫醚基、C 2-4烯基或C 2-4炔基； R is optionally selected from hydrogen, halogen, cyano, trifluoromethyl, formamido, sulfonamide, C 1-3 thio, C 1-6 alkyl, halogenated C 1-4 alkyl, halo C 1-4 alkoxy, C 1-3 alkylthio, 6-membered aromatic ring thio, C 1- of a 4- to 12-membered heterocyclic group containing heteroatoms optionally selected from N, O and S 6 alkyl, C 1-6 alkanoyl, C 1-6 cycloalkyl, C 1-6 alkyl sulfide group, C 2-4 alkenyl or C 2-4 alkynyl;
    R 2任选自氢、卤素、氨基、氰基、羟基、硝基、羧基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、羧基取代C 1-6烷基、羧基取代C 1-6烷氧基、OR 5、NHR 5或NR 5R 6，所述R 5和R 6任选自C 1-6烷基、C 1-6烷氧基、卤代6元芳基C 3-6环烷基、含有任选自N、O和S的杂原子的4-至12-元杂环基、6元芳基、5-6元杂芳基、卤代5-6元杂芳基、烷氧基6元芳基C 3-6环烷基、含有芳环、单环、螺环或并环的C 3-6环烷基、C 2-4烯基、C 2-4烯基C 3-6环烷基、C 2-4炔基或C 3-10环烷基； R 2 is optionally selected from hydrogen, halogen, amino, cyano, hydroxyl, nitro, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, carboxyl substituted C 1- 6 alkyl, carboxyl substituted C 1-6 alkoxy, OR 5 , NHR 5 or NR 5 R 6 , the R 5 and R 6 are optionally selected from C 1-6 alkyl, C 1-6 alkoxy, Halogenated 6-membered aryl C 3-6 cycloalkyl, 4- to 12-membered heterocyclic group containing heteroatoms optionally selected from N, O and S, 6-membered aryl, 5-6-membered heteroaryl, Halogenated 5-6 membered heteroaryl, alkoxy 6-membered aryl C 3-6 cycloalkyl, C 3-6 cycloalkyl containing aromatic ring, single ring, spiro ring or parallel ring, C 2-4 Alkenyl, C 2-4 alkenyl C 3-6 cycloalkyl, C 2-4 alkynyl or C 3-10 cycloalkyl;
    R 3任选自氢、卤素、氨基、氰基、羟基、硝基、羧基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、羟基取代C 1-6烷基、羟基取代C 1-6烷氧基、氨基取代的C 1-6烷基、氨基取代的C 1-6烷氧基、羧基取代C 1-6烷基、羧基取代C 1-6烷氧基、取代的N、O和S的杂原子的4-至12-元杂环基，所述杂环基包括芳环、单环、螺环或并环。 R 3 is optionally selected from hydrogen, halogen, amino, cyano, hydroxyl, nitro, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy substituted C 1- 6 alkyl, hydroxyl substituted C 1-6 alkoxy, amino substituted C 1-6 alkyl, amino substituted C 1-6 alkoxy, carboxyl substituted C 1-6 alkyl, carboxyl substituted C 1-6 Alkoxy, 4- to 12-membered heterocyclic groups of heteroatoms substituted with N, O and S, said heterocyclic groups include aromatic rings, monocyclic rings, spiro rings or parallel rings.
  2. 根据权利要求1所述的5-醛基杂环酰胺类化合物，其特征在于，所述化合物为具有式(II)结构的化合物或者其药学上可接受的盐、立体异构体以及其前药分子：The 5-formyl heterocyclic amide compound according to claim 1, wherein the compound is a compound having the structure of formula (II) or its pharmaceutically acceptable salt, stereoisomer and prodrug thereof molecular:
    Figure PCTCN2021129535-appb-100002
    Figure PCTCN2021129535-appb-100002
    式(II)中n＝0或1；In formula (II), n=0 or 1;
    R 1任选自氢、卤素、氰基、三氟甲基、甲酰胺基、磺酰胺基、C 1-6烷基、C 1-6烷氧基、卤代C 1-4烷基或卤代C 1-4烷氧基、C 1-3硫基、C 1-3烷基硫基、6元芳环硫基、含有任选自N、O和S的杂原子的4-至12-元杂环基的C 1-6烷基； R is optionally selected from hydrogen, halogen, cyano, trifluoromethyl, formamido, sulfonamide, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-4 alkyl or halo Substituting C 1-4 alkoxy, C 1-3 thio, C 1-3 alkylthio, 6-membered aromatic ring thio, 4- to 12-containing heteroatoms optionally selected from N, O and S C 1-6 alkyl of membered heterocyclic group;
    R 2任选自氢、卤素、氨基、氰基、羟基、硝基、羧基、C 1-6烷基、C 1-6烷氧基、C 3-6环烷基、卤代C 1-6烷基、羧基取代C 1-6烷基、羧基取代C 1-6烷氧基、OR 5、NHR 5或NR 5R 6，所述R 5和R 6任选自C 1-6烷基、C 1-6烷氧基、、卤代6元芳基C 3-6环烷基、含有任选自N、O和S的杂原子的4-至12-元杂环基、6元芳基、5-6元杂芳基、卤代5-6元杂芳基、烷氧基6元芳基C 3-6环烷基、C 2-4烯基、C 2-4炔基或C 3-10环烷基； R is optionally selected from hydrogen, halogen, amino, cyano, hydroxyl, nitro, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, carboxy substituted C 1-6 alkyl, carboxy substituted C 1-6 alkoxy, OR 5 , NHR 5 or NR 5 R 6 , the R 5 and R 6 are optionally selected from C 1-6 alkyl, C 1-6 alkoxy, halogenated 6-membered aryl C 3-6 cycloalkyl, 4- to 12-membered heterocyclic group containing heteroatoms optionally selected from N, O and S, 6-membered aryl , 5-6 membered heteroaryl, halogenated 5-6 membered heteroaryl, alkoxy 6 membered aryl C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl or C 3 -10 cycloalkyl;
    R 3任选自氢、卤素、氨基、氰基、羟基、硝基、羧基、羧基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、羟基取代C 1-6烷基、羟基取代C 1-6烷氧基、氨基取代的C 1-6烷基、氨基取代的C 1-6烷氧基、羧基取代C 1-6烷基、羧基取代C 1-6烷氧基、N、O和S取代的4-至12-元芳环、单环、螺环或并环； R3 is optionally selected from hydrogen, halogen, amino, cyano, hydroxyl, nitro, carboxyl, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl, hydroxy substituted C 1-6 alkyl, hydroxyl substituted C 1-6 alkoxy, amino substituted C 1-6 alkyl, amino substituted C 1-6 alkoxy, carboxyl substituted C 1-6 alkyl, carboxyl substituted C 1 -6 alkoxy, N, O and S substituted 4- to 12-membered aromatic rings, monocyclic, spiro or parallel rings;
    R 4任选自C 1-6烷基或烷氧基、含有任选自N、O和S的杂原子的4-至12-元杂环基的C 1-6烷基。 R 4 is optionally selected from C 1-6 alkyl or alkoxy, C 1-6 alkyl of 4- to 12-membered heterocyclyl containing heteroatoms optionally selected from N, O and S.
  3. 根据权利要求1-2任一所述的5-醛基杂环酰胺类化合物，其特征在于：所述R 1选自氢、氰基、环丙基或三氟甲基。 The 5-formyl heterocyclic amide compound according to any one of claims 1-2, wherein said R is selected from hydrogen, cyano, cyclopropyl or trifluoromethyl.
  4. 根据权利要求1-2任一所述的5-醛基杂环酰胺类化合物，其特征在于：所述R 2选自OR 5、NHR 5或NR 5R 6，所述R 5和R 6任选自C 1-6烷基、C 1-6烷氧基、含有任选自N、O和S的杂原子的4-至12-元杂环基、6元芳基、5-6元杂芳基、C 2-4烯基、C 2-4炔基或C 3-10环烷基。 According to the 5-formyl heterocyclic amide compound according to any one of claims 1-2, it is characterized in that: said R 2 is selected from OR 5 , NHR 5 or NR 5 R 6 , and said R 5 and R 6 are either selected from C 1-6 alkyl, C 1-6 alkoxy, 4- to 12-membered heterocyclyl containing heteroatoms optionally selected from N, O and S, 6-membered aryl, 5-6-membered hetero Aryl, C 2-4 alkenyl, C 2-4 alkynyl or C 3-10 cycloalkyl.
  5. 根据权利要求1-2任一所述的5-醛基杂环酰胺类化合物，其特征在于：According to the arbitrary described 5-formyl heterocyclic amides compound of claim 1-2, it is characterized in that:
    n＝0时，所述R 3选自下述结构： When n=0, the R3 is selected from the following structures:
    Figure PCTCN2021129535-appb-100003
    Figure PCTCN2021129535-appb-100003
    n＝1时，所述R 3选自下述结构： When n=1, the R3 is selected from the following structures:
    Figure PCTCN2021129535-appb-100004
    Figure PCTCN2021129535-appb-100004
    Figure PCTCN2021129535-appb-100005
    Figure PCTCN2021129535-appb-100005
  6. 根据权利要求2所述的5-醛基杂环酰胺类化合物，其特征在于：所述R 4选自C 1-6烷基。 The 5-formyl heterocyclic amide compound according to claim 2, characterized in that: said R 4 is selected from C 1-6 alkyl.
  7. 根据权利要求2所述的5-醛基杂环酰胺类化合物，其特征在于：所述式(II)化合物选自下列化合物：5-formyl heterocyclic amide compounds according to claim 2, characterized in that: the compound of formula (II) is selected from the following compounds:
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺；N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1H-pyrrolo[3,2-b]pyridine-3-methyl amides;
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b] Pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-乙基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-ethyl-1H-pyrrolo[3,2-b] Pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-丙基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-propyl-1H-pyrrolo[3,2-b] Pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-异丙基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-isopropyl-1H-pyrrolo[3,2-b ]pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-异丁基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-isobutyl-1H-pyrrolo[3,2-b ]pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-(环丙基甲基)1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-(cyclopropylmethyl)1H-pyrrolo[3, 2-b]pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-(2-甲氧基乙基)-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-(2-methoxyethyl)-1H-pyrrolo [3,2-b]pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-环戊基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-cyclopentyl-1H-pyrrolo[3,2-b ]pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-(2-吗啉代乙基)-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-(2-morpholinoethyl)-1H-pyrrolo [3,2-b]pyridine-3-carboxamide
    N-(5-氰基-4-((2-吗啉代乙基)氨基)吡啶-2-基)-5-醛基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-morpholinoethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b] Pyridine-3-carboxamide
    N-(5-氰基-4-(异丙氧基)吡啶-2-基)-5-醛基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-(isopropoxy)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
    N-(5-氰基-4-((2-(二甲基氨基)乙基)氨基)吡啶-2-基)-5-醛基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-(dimethylamino)ethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2 -b] pyridine-3-carboxamide
    N-(5-氰基-4-((2-(4-甲基哌嗪-1-基)乙基)氨基)吡啶-2-基)-5-醛基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-(4-methylpiperazin-1-yl)ethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H- Pyrrolo[3,2-b]pyridine-3-carboxamide
    N-(5-氯-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-chloro-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine -3-Carboxamide
    N-(4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-methyl Amide
    N-(5-环丙基吡啶-2-基)-5-醛基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyclopropylpyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-(1-甲基-1H-吡唑-4-基)-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(1-methyl-1H-pyrazol-4-yl )-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-(1,3-二甲基-1H-吡唑-4-基)-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(1,3-dimethyl-1H-pyrazole- 4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-(1-甲基-1H-吡唑-5-基)-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(1-methyl-1H-pyrazol-5-yl )-1-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-(吡啶-3-基)-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(pyridin-3-yl)-1-methyl-1H -pyrrolo[3,2-b]pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-(噻吩-2-基))-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(thiophen-2-yl))-1-methyl- 1H-pyrrolo[3,2-b]pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-(呋喃-2-基)-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(furan-2-yl)-1-methyl-1H -pyrrolo[3,2-b]pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-(2-甲基噻唑-5-基)-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(2-methylthiazol-5-yl)-1- Methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-(2-氟-6-甲氧基苯基)-1-甲基-1H-吡咯并[3，2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(2-fluoro-6-methoxyphenyl)- 1-Methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-(2-甲氧基苯基)-1-甲基-1H-吡咯并[3，2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(2-methoxyphenyl)-1-methyl -1H-pyrrolo[3,2-b]pyridine-3-carboxamide
    6-溴-N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺6-Bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3, 2-b]pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-((4-甲基哌嗪-1-基)甲基)-1-甲基-1H-吡咯[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-((4-methylpiperazin-1-yl)methyl Base)-1-methyl-1H-pyrrole[3,2-b]pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-((4-甲基哌嗪-1-基)甲基)-1-异丙基-1H-吡咯[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-((4-methylpiperazin-1-yl)methyl Base)-1-isopropyl-1H-pyrrole[3,2-b]pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-(吗啉甲基)-1-异丙基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-(morpholinylmethyl)-1-isopropyl-1H -pyrrolo[3,2-b]pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-6-((((3S,5R)-3,5-二甲基哌嗪-1-基)甲基)-5-醛基-1-异丙基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-6-((((3S,5R)-3,5-dimethylpiperazine- 1-yl)methyl)-5-formyl-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
    6-溴-N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-异丙基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺6-Bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-isopropyl-1H-pyrrolo[3 ,2-b]pyridine-3-carboxamide
    6-溴-N-(5-氰基-4-((2-吗啉乙基)氨基)吡啶-2-基)-5-醛基-1-异丙基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺6-Bromo-N-(5-cyano-4-((2-morpholinoethyl)amino)pyridin-2-yl)-5-formyl-1-isopropyl-1H-pyrrolo[3, 2-b]pyridine-3-carboxamide
    6-溴-N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-(2-吗啉乙基)-1H-吡咯并[3,2-b]吡啶-3-甲酰胺6-Bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-(2-morpholinoethyl)-1H -pyrrolo[3,2-b]pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-6-((4-甲基-2-氧代哌嗪-1-基)甲基)-1-异丙基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-6-((4-methyl-2-oxopiperazine- 1-yl)methyl)-1-isopropyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide
    N-(5-三氟甲基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1-甲基-1H-吡咯并[3,2-b]吡啶-3-甲酰胺N-(5-trifluoromethyl-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-1H-pyrrolo[3,2- b] pyridine-3-carboxamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-醛基-1H-吡唑并[1,5-a]嘧啶-3-甲酰胺N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1H-pyrazolo[1,5-a]pyrimidine-3- Formamide
    N-(5-氰基-4-((2-甲氧基乙基)氨基)吡啶-2-基)-5-甲酰基-1-甲基-6-((4-甲基-2-氧代哌嗪-1-基)甲基)-1H-吡咯并[3,2-b]吡啶-3-甲酰胺。N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-5-formyl-1-methyl-6-((4-methyl-2- Oxopiperazin-1-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide.
  8. 权利要求1-7任一所述5-醛基杂环酰胺类化合物或者其药学上可接受的盐、立体异构体以及其前药分子在制备治疗或者预防由FGFR4信号通路异常引起的过渡增殖性疾病的药物中的应用。The 5-formyl heterocyclic amide compounds or their pharmaceutically acceptable salts, stereoisomers and prodrug molecules according to any one of claims 1-7 are used in the preparation of treatment or prevention of excessive proliferation caused by abnormal FGFR4 signaling pathways application in medicine for diseases.
  9. 根据权利要求8所述的应用，其特征在于，所述过渡增殖性疾病为肿瘤，所述肿瘤为 实体瘤或体液瘤，优选的所述实体瘤包括肝癌、胆管癌、乳腺癌、胃癌、前列腺癌、肺癌、鼻咽癌、口腔癌、肠癌。The application according to claim 8, wherein the transitional proliferative disease is a tumor, and the tumor is a solid tumor or a humoral tumor, and preferably the solid tumor includes liver cancer, bile duct cancer, breast cancer, gastric cancer, prostate cancer cancer, lung cancer, nasopharyngeal cancer, oral cancer, colon cancer.
  10. 一种治疗或者预防过渡增殖性疾病的药物组合物，其特征在于，所述组合物的组成包括活性成分和药学上可接受的载体，所述活成分包括权利要求1-7任一所述的5-醛基杂环酰胺类化合物或者其药学上可接受的盐、立体异构体以及其前药分子。A pharmaceutical composition for treating or preventing transitional proliferative diseases, characterized in that the composition comprises an active ingredient and a pharmaceutically acceptable carrier, and the active ingredient includes any one of claims 1-7. 5-formyl heterocyclic amide compounds or pharmaceutically acceptable salts, stereoisomers and prodrug molecules thereof.
PCT/CN2021/129535 2021-11-09 2021-11-09 5-formyl heterocyclic amide compound and use thereof WO2023082044A1 (en)

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