WO2019080723A1 - Dérivé de pyridone polysubstitué, son procédé de préparation et son utilisation médicale - Google Patents

Dérivé de pyridone polysubstitué, son procédé de préparation et son utilisation médicale

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WO2019080723A1
WO2019080723A1 PCT/CN2018/109969 CN2018109969W WO2019080723A1 WO 2019080723 A1 WO2019080723 A1 WO 2019080723A1 CN 2018109969 W CN2018109969 W CN 2018109969W WO 2019080723 A1 WO2019080723 A1 WO 2019080723A1
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group
cycloalkyl
alkyl
cancer
aryl
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PCT/CN2018/109969
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Chinese (zh)
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段茂圣
刘佳乐
田世鸿
戴权
熊艳林
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北京越之康泰生物医药科技有限公司
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Priority to CN201880024273.6A priority Critical patent/CN110520416B/zh
Publication of WO2019080723A1 publication Critical patent/WO2019080723A1/fr

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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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered

Definitions

  • the present invention relates to a polysubstituted pyridone derivative, a process for the preparation thereof, a pharmaceutical composition containing the same, and its use as an Axl/c-MET inhibitor, particularly in the treatment of cancer.
  • Receptor tyrosine kinases are multidomain transmembrane proteins that function as sensors for extracellular receptor ligands in cells. When the ligand binds to the receptor, the receptor is dimerized on the surface of the cell membrane and activates the kinase domain within the membrane, resulting in phosphorylation of tyrosine and further activation of a cascade of signaling pathways downstream. To date, nearly 60 receptor tyrosine kinases have been found in the human genome, which extensively regulate the cellular metabolic processes, including survival, growth, differentiation, proliferation, adhesion, and death.
  • the TAM family of receptor tyrosine kinases has three members, Axl, Mer, and Tyro-3, which regulate a variety of cytological responses including cell survival, differentiation, migration, and adhesion. Studies have shown that the signaling of receptor TAM also controls vascular smooth muscle homeostasis, platelet function, microthrombus stability and erythrocyte formation. The receptor TAM also plays a key role in immunity and inflammation. It promotes phagocytosis of apoptotic cells and stimulates the differentiation of NK cells.
  • Axl is a member of the TAM family of receptor tyrosine kinases. Among the three members, Axl and Tyro-3 have the most similar gene structure, while Axl and Mer have the most similar tyrosine kinase domain amino acid sequence.
  • Axl is an important regulator of cell survival, proliferation, aggregation, migration and adhesion. Axl is widely expressed in cells and organs such as monocytes, macrophages, platelets, endothelial cells, cerebellum, heart, skeletal muscle, liver and kidney. In the study of many cancer cells, the Axl gene in hematopoietic cells, mesenchymal cells and endothelial cells is overexpressed or ectopically expressed. Overexpression of Axl is particularly prominent in all types of leukemia and most solid tumors. Moreover, Axl is more highly expressed in metastatic or malignant tumors than normal tissues or primary tumors, and its high expression is closely related to poor clinical treatment.
  • Axl is involved in drug resistance caused by different mechanisms in a variety of tumor cells, and overexpression of Axl kinase has become an important marker of cancer drug resistance in cancer patients. Inhibition of Axl receptor tyrosine kinase can reduce the activation of pro-survival signals of tumor cells, block tumor invasion, and increase the sensitivity of targeted drug therapy and chemoradiotherapy. Therefore, Axl is an effective target for cancer treatment.
  • tyrosine kinase inhibitors such as Cabozinidinib, Foretinib, Merestinib, Crizotinib, etc.
  • Cabozinidinib Foretinib
  • Merestinib Merestinib
  • Crizotinib etc.
  • Axl kinase inhibitor activity they are multi-target molecules, Not selective.
  • BGB324 The only clinical candidate for Axl selectivity in the world is BGB324, which is undergoing multiple clinical phase II trials. Therefore, there is currently no new drug for Axl inhibitors for patients.
  • c-MET is a member of the transmembrane tyrosine kinase receptor (RTKs) family with autonomous phosphorylation activity.
  • the c-MET receptor contains a tyrosine residue that regulates the activity of the enzyme in the tyrosine kinase catalytic domain of the cell, forming a docking site for several signaling proteins, which in turn leads to a biological response.
  • c-MET was first isolated from cell lines derived from human osteosarcoma, primarily on epithelial cells. During embryonic development and adulthood, many organ epithelial cells express c-MET receptors on the surface, including liver, pancreas, prostate, kidney, muscle, and bone marrow.
  • HGF is the only ligand for c-MET.
  • c-MET When c-MET binds to it, it triggers receptor dimerization, thereby activating tyrosine kinase in the c-MET cytoplasmic protein kinase domain, causing autophosphorylation of c-MET carboxy terminal tyrosine (Tyrl349, Tyrl356) Chemical.
  • c-MET activates the recruitment of the adaptor proteins Gabl and Grb2, activates Shp2, Ras and ERK/MAPK, and multiple effector proteins in the cytoplasm are recruited to the phosphorylated carboxy terminus and rapidly phosphorylated, resulting in activation of multiple signaling pathways within the cell, such as PI3K/AKT, Ras-Rac/Rho, MAPK and STAT3 pathways promote various biological functions such as cell deformation, proliferation, anti-apoptosis, cell separation, exercise and invasion.
  • the normal HGF/c-MET signaling pathway participates in various physiological processes in different cells and different stages of cell differentiation, such as controlling cell migration during embryonic development and repairing after tissue damage.
  • abnormal c-MET disorders include overexpression, sustained activation of constituent kinases, gene amplification, by HGF paracrine and autocrine activation, c-MET mutations, and subsequent changes.
  • Abnormal HGF/c-MET signaling pathway plays a very important role in tumorigenesis and can induce tumor growth, invasion, drug resistance and survival. Therefore, effective inhibition of HGF/c-MET signaling pathways in tumor cells will have a significant effect on a variety of cancers.
  • the present inventors have developed new AxL/c-MET inhibitors. It can be used alone or in combination with other active drugs, providing a broad prospect for the treatment of cancer.
  • the inventors have deliberately studied and designed a series of polysubstituted pyridone derivatives, and intensive studies have shown that such compounds can be used as effective Axl/c-MET inhibitors. It can be used alone or in combination with other active drugs for the treatment of cancer, in particular solid tumors or hematological tumors with high expression of Axl/c-MET.
  • the present invention relates to a compound of the formula (I) or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or a pharmaceutically acceptable form thereof salt,
  • W and V are each independently selected from CH, CF or N;
  • R a is selected from -OR 1 , -SR 1 or -NR 1 R 2 ;
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;
  • R a is -NR 1 R 2
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano Substituting one or more groups of a group, a hydroxyl group, a thiol group, a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group;
  • R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic
  • the base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;
  • R a is -NR 1 R 2
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring
  • R 3 is bonded to the nitrogen-containing heterocyclic ring to further form a fused heterocyclic ring
  • said nitrogen heterocycle is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, thiol, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, Substituting one or more groups of a heteroaryl group;
  • R 4 is selected from an aryl group, a heteroaryl group or an alkynyl group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, thiol, carboxyl, ester, Substituting one or more groups of oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
  • R 4 when R 4 is aryl or heteroaryl, R a is bonded to R 4 to form a heterocyclic ring fused to R 4 , which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, Substituting one or more groups of a hydroxyl group, a mercapto group, a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
  • R 5 is selected from alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or OR 6 , said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, The aryl and heteroaryl are optionally further substituted with one or more groups selected from the group Q;
  • Q is selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
  • the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl group is optionally further selected from the group consisting of halogen, nitro, cyano, hydroxy, decyl, oxo, alkyl, cycloalkyl, Heterocyclyl, aryl, heteroaryl, -OR b , -O(CH 2 ) m OR b , -OC(O)R b , -C(O)OR b , -C(O)NR b R c , -NHC(O)R b , -S(O)R b , -S(O) 2 R b ,
  • R 6 is selected from the group consisting of alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl; said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl Further selected from the group consisting of halogen, nitro, cyano, hydroxy, decyl, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR b , -O(CH 2 ) m OR b , -OC(O)R b , -C(O)OR b , -C(O)NR b R c , -NHC(O)R b , -S(O)R b , -S(O) 2 R b , -S(O)NR b R c , -NR b R c , -NR b R c , -NR b R
  • R b and R c are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl And the heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;
  • R b and R c together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
  • R 7 is selected from the group consisting of hydrogen, halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl
  • the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, thiol, carboxy, ester, and oxygen. Substituting one or more groups of a substituent, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
  • n is an integer from 1 to 6;
  • n is an integer from 1 to 4.
  • each H atom of the compound of formula (I) may optionally be independently replaced by a D atom.
  • the compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer thereof, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R a is selected from -NR 1 R 2 ;
  • R 1 and R 2 are as defined by the formula (I).
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof in another preferred embodiment of the invention, or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;
  • R a is -NR 1 R 2
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano Substituting one or more groups of a group, a hydroxyl group, a thiol group, a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group;
  • the nitrogen-containing heterocyclic ring is preferably a 4- to 7-membered nitrogen-containing heterocyclic ring, more preferably the following heterocyclic ring:
  • R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic
  • the base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group.
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof in another preferred embodiment of the invention, or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R a is selected from -NR 1 R 2 ;
  • R 1 or R 2 is bonded to R 3 to form a nitrogen-containing heterocyclic ring fused to a pyridone ring, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, Substituting one or more groups of a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;
  • R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic
  • the base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;
  • the nitrogen-containing heterocyclic ring fused to the pyridone ring is preferably a 6- or 12-membered nitrogen-containing heterocyclic ring, more preferably the following nitrogen-containing heterocyclic ring:
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof in another preferred embodiment of the invention, or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R a is selected from -NR 1 R 2 ;
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic ring, and R 3 is bonded to the nitrogen-containing heterocyclic ring to further form a fused heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, Substituting one or more groups of nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;
  • R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic
  • the base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;
  • the fused heterocyclic ring is preferably a 10-12 membered fused heterocyclic ring, more preferably:
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (II) or a mesogen, a racemate, an enantiomer, a diastereomer thereof, or a form of the mixture, or a pharmaceutically acceptable salt thereof,
  • Y is selected from CH or N;
  • q is an integer from 1 to 4.
  • W, V, R a , R 3 , R 4 , R 7 , Q, n are as defined in the general formula (I).
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof in another preferred embodiment of the invention, or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 4 is selected from 5- to 6-membered aryl or heteroaryl, or alkynyl, and the aryl, heteroaryl, alkynyl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, Substituting one or more groups of a carboxyl group, an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
  • the aryl, heteroaryl, alkynyl group is preferably:
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (III) or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a form of the mixture, or a pharmaceutically acceptable salt thereof,
  • Y is selected from CH or N;
  • R 8 is selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • p is an integer from 1 to 4.
  • q is an integer from 1 to 4.
  • W, V, R a , R 3 , R 7 , Q, n are as defined in the general formula (I).
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (IV) or a mesogen, racemate, enantiomer, diastereomer thereof, or a form of the mixture, or a pharmaceutically acceptable salt thereof,
  • Y is selected from CH or N;
  • R 8 is selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • Q is selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl;
  • the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl group is optionally further selected from the group consisting of halogen, nitro, cyano, hydroxy, decyl, oxo, alkyl, cycloalkyl, Heterocyclyl, aryl, heteroaryl, -OR b , -O(CH 2 ) m OR b , -OC(O)R b , -C(O)OR b , -C(O)NR b R c , -NHC(O)R b , -S(O)R b , -S(O) 2 R b ,
  • Q' is selected from -NR b R c ;
  • R b and R c are each independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl And the heteroaryl group is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group;
  • R b and R c together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
  • p is an integer from 1 to 4.
  • W, V, R a , R 3 , R 7 , m, n are as defined in the general formula (I).
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof in another preferred embodiment of the invention, or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • Q is selected from aryl or heteroaryl; the aryl or heteroaryl is optionally further selected from the group consisting of halogen, alkyl, cycloalkyl, heterocyclyl, -OR b , -O(CH 2 ) m OR b Substituted by one or more groups;
  • R b is selected from the group consisting of hydrogen, alkyl and cycloalkyl, wherein the alkyl and cycloalkyl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo. Substituting one or more groups of a cycloalkyl group or a heterocyclic group;
  • n 1 to 6.
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof in another preferred embodiment of the invention, or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R a is selected from -NR 1 R 2 ;
  • R 1 or R 2 is bonded to R 4 to form a heterocyclic ring fused to R 4 , preferably a 6-membered heterocyclic ring, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy Substituting one or more groups of an ester group, an oxo group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl Substituting one or more groups of a heterocyclic group, an aryl group, or a heteroaryl group;
  • R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic
  • the base and heteroaryl are optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituting one or more groups of a heteroaryl group.
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof in another preferred embodiment of the invention, or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 5 is OR 6 or SR 6 ;
  • R 6 is as defined in the general formula (I);
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof in another preferred embodiment of the invention, or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 6 is selected from the group consisting of aryl and heteroaryl; the aryl and heteroaryl are optionally further selected from the group consisting of halogen, hydroxy, thiol, oxo, alkyl, cycloalkyl, heterocyclyl, aryl, hetero Substituting one or more groups of aryl, -OR b , -O(CH 2 ) m OR b , -NR b R c ;
  • R b and R c are each independently selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, wherein the alkyl, cycloalkyl, optionally further selected from the group consisting of halogen, amino, nitro, cyano, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an oxo group, a cycloalkyl group, or a heterocyclic group;
  • R b and R c together with the nitrogen atom to which they are attached form a nitrogen-containing heterocyclic group, which is optionally further selected from the group consisting of halogen, amino, nitro, cyano, oxo, hydroxy, decyl Substituting one or more groups of a carboxyl group, an ester group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group;
  • n 1 to 6.
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof in another preferred embodiment of the invention, or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 7 is selected from the group consisting of hydrogen, halogen, alkyl, and the alkyl group is optionally further substituted with one or more halogens;
  • n 1 or 2.
  • the compound of the formula (I) according to the invention or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof in another preferred embodiment of the invention, or a mesogen, racemate, enantiomer or diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 5 is the following group:
  • Exemplary compounds of the invention include, but are not limited to, the following compounds:
  • Another aspect of the invention provides a compound of the formula (I) or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof, or A method for preparing a medicinal salt, comprising the steps of:
  • NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-arylamide (Ig) is first subjected to ester hydrolysis, and then to R 1 R 2 NH is subjected to amidation reaction to obtain a compound of the formula (I) via a two-step process;
  • R a is selected from -OR 1 when 1 or -SR
  • the NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-arylamide (Ig) is first subjected to ester hydrolysis to obtain the acid (Ig'). Further reacting with an alcohol or a thiol under the action of EDCI to obtain a compound of the formula (I);
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , W, V, n are as defined in the formula (I).
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer thereof, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the pharmaceutical composition may further comprise another therapeutically active ingredient, preferably another therapeutically active ingredient, preferably a rectal cancer, an intestinal cancer, a pancreatic cancer, a breast cancer, a prostate cancer, Esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer and kidney cancer, more preferably blood cancer, lung cancer, breast cancer, Pancreatic cancer and stomach cancer.
  • another therapeutically active ingredient preferably another therapeutically active ingredient, preferably a rectal cancer, an intestinal cancer, a pancreatic cancer, a breast cancer, a prostate cancer, Esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer and kidney cancer, more preferably blood cancer, lung cancer, breast cancer, Pan
  • the present invention also relates to a process for the preparation of the above composition, which comprises the compound of the formula (I) or a racemate, a racemate, an enantiomer thereof, a diastereomer thereof, Or a mixture thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, is admixed with a pharmaceutically acceptable carrier, diluent or excipient.
  • the invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use in the preparation of an Axl/c-MET inhibitor.
  • the invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for use in the manufacture of a medicament for treating cancer.
  • the cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer.
  • cervical cancer, bladder cancer and kidney cancer more preferably blood cancer, lung cancer, breast cancer, pancreatic cancer and gastric cancer.
  • the cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, Ovarian cancer, cervical cancer, bladder cancer, and kidney cancer, and more preferably, blood cancer, lung cancer, breast cancer, pancreatic cancer, and stomach cancer.
  • the invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as an Axl/c-MET inhibitor.
  • the invention further provides a compound of the formula (I) according to the invention or a racemate, a racemate, an enantiomer, a diastereomer thereof, or a mixture thereof Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a medicament for treating cancer;
  • the cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, Lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer, and kidney cancer, and more preferably, blood cancer, lung cancer, breast cancer, pancreatic cancer, and stomach cancer.
  • the cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal Cancer, ovarian cancer, cervical cancer, bladder cancer, and kidney cancer, and more preferably, blood cancer, lung cancer, breast cancer, pancreatic cancer, and stomach cancer.
  • a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) according to the invention or a mesogen, racemate, enantiomer thereof a form, a mixture of diastereomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, preferably a rectal cancer, an intestinal cancer, a pancreatic cancer, a breast cancer, a prostate cancer, an esophageal cancer , gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer, skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer and kidney cancer, more preferably blood cancer, lung cancer, breast cancer, pancreatic cancer And stomach cancer.
  • a rectal cancer an intestinal cancer, a pancreatic cancer, a breast cancer, a prostate cancer, an esophageal cancer , gastric cancer, blood cancer, lung cancer
  • a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) according to the invention or a mesogen, racemate, enantiomer thereof , a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition therewith, and another therapeutically active ingredient, wherein the other therapeutically active ingredient
  • the cancer is preferably rectal cancer, intestinal cancer, pancreatic cancer, breast cancer, prostate cancer, esophageal cancer, gastric cancer, blood cancer, lung cancer, liver cancer, thyroid cancer, sarcoma, brain cancer , skin cancer, head and neck cancer, nasopharyngeal cancer, ovarian cancer, cervical cancer, bladder cancer and kidney cancer, more preferably blood cancer, lung cancer, breast cancer, pancreatic cancer and gastric cancer.
  • the compound of the formula (I) of the present invention can form a pharmaceutically acceptable acid addition salt with an acid according to a conventional method in the art to which the present invention pertains.
  • the acid includes inorganic acids and organic acids, and acceptable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.
  • Acceptable organic acids include methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, Naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.
  • the compound of the formula (I) of the present invention can form a pharmaceutically acceptable base addition salt with a base according to a conventional method in the art to which the present invention pertains.
  • the base includes an inorganic base and an organic base, and acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc., and acceptable inorganic bases include aluminum hydroxide and hydroxide. Calcium, potassium hydroxide, sodium carbonate and sodium hydroxide.
  • the pharmaceutical composition of the present invention includes any one or more of the compounds of the present invention (or a pharmaceutically acceptable salt, solvate, hydrate, prodrug or derivative thereof) and optionally a pharmaceutically acceptable Carrier. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. Alternatively, the compounds of the invention may be administered to a patient in need thereof in combination with one or more other therapeutic agents. It will also be understood that certain compounds of the invention may exist in free form or, where appropriate, in the form of their pharmaceutically acceptable salts for therapeutic use.
  • the pharmaceutical compositions of the present invention also include a pharmaceutically acceptable carrier.
  • the carrier includes any or all solvents, diluents, or other liquid carriers, dispersion or suspending adjuvants, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricating agents Agents, etc., which are adjusted to the particular dosage form desired.
  • Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers for formulating pharmaceutical compositions, as well as known techniques for their preparation.
  • any conventional carrier medium is contemplated to be within the scope of the invention unless it is incompatible with the compounds of the invention, for example, by producing any undesirable biological effects or interacting in a deleterious manner with any other component of the pharmaceutical composition.
  • materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl Cellulose and cellulose acetate; powdered tragacanth; maltose; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and Soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide
  • the compounds of the invention can be administered to a patient by a variety of routes of administration. These routes of administration include, but are not limited to, oral, sublingual, subcutaneous, intravenous, nasal, topical, dermal, intraperitoneal, intramuscular, pulmonary, and the like.
  • compositions containing the active ingredient may be in the form of solids, semi-solids, liquids and aerosols, for example, tablets, granules, capsules, powders, liquids, suspensions, suppositories, and the like. It can also be administered in a sustained release manner, for example, by a long-acting injection, an osmotic pump, a pill, a patch, or the like.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as a) filler or filler, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) viscous Mixtures such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants such as glycerin, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch , alginic acid, certain silicates and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and mono-hard Glycerol, h) absorbents such as kaolin and bentonite,
  • Solid compositions of a similar type may also be employed as fillers in filling soft or hard gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycols.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells (e.g., enteric coatings and other coatings well known in the pharmaceutical formulation art). It may optionally comprise an opacifying agent, and may also be a composition which is released only, or preferably in certain parts of the intestinal tract, optionally releasing the active ingredient in a delayed manner.
  • coatings and shells e.g., enteric coatings and other coatings well known in the pharmaceutical formulation art.
  • It may optionally comprise an opacifying agent, and may also be a composition which is released only, or preferably in certain parts of the intestinal tract, optionally releasing the active ingredient in a delayed manner.
  • useful embedding compositions include polymeric materials and waxes.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid Benzyl ester, propylene glycol, 1,3-butanediol, dimethylformamide, oil (especially cottonseed, groundnut (peanut), corn, germ, olive, ramie and sesame oil), glycerin, tetrahydrofurfuryl alcohol, Polyethylene glycol and sorbitan fatty acid esters, and mixtures thereof.
  • the oral compositions may also include adjuvants such
  • Injectable preparations may be formulated in accordance with the prior art using suitable dispersion or wetting agents and suspensions.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol.
  • Acceptable carriers or solvents include water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspension.
  • any bland fixed oil may be employed, including the prepared mono or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the injectable preparation may be sterile, for example, by filtration through a bacteria-resistance filter, or by adding a bactericidal agent in the form of a sterile solid composition before use, which may be dissolved or dispersed in sterile water or other In bacteria injectable medium.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by admixing a compound of the present invention with a suitable non- irritating excipient or carrier (for example, cocoa butter, polyethylene glycol or suppository wax) in the environment It is a solid at temperature and is a liquid at body temperature, thus melting and releasing the active compound in the rectum or vaginal cavity.
  • a suitable non- irritating excipient or carrier for example, cocoa butter, polyethylene glycol or suppository wax
  • the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the conduct of the patient, the patient Diet, time of administration, mode of administration, rate of excretion, combination of drugs, and the like.
  • the optimal mode of treatment such as the mode of treatment, the daily amount of the compound of the formula, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment regimens.
  • the compounds or pharmaceutical compositions of the invention may be formulated and used in combination therapy, i.e., the compounds and pharmaceutical compositions may be formulated simultaneously, prior or subsequently with one or more other desired therapies or procedures. Apply.
  • the particular combination of treatments (therapies or procedures) employed in the combination regimen will take into account the compatibility of the desired therapy and/or procedure, as well as the desired therapeutic effect to be achieved.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • the alkyl group of the atom is a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl,
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • an alkane Base alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, hetero
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3- Butyl group and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group.
  • alkynyl refers to an alkyl radical as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl and the like.
  • the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
  • spirocycloalkyl refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have complete Conjugate ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • heterocyclyl or “heterocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from the group consisting of nitrogen and oxygen. Or a hetero atom of S(O) m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • ring atoms Preferably comprising from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; most preferably from 3 to 8 ring atoms, wherein from 1 to 3 are heteroatoms; most preferably from 5 to 7 ring atoms, wherein 1 to 2 or 1 to 3 are heteroatoms.
  • monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine.
  • the group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like are preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclyl or “spiroheterocycle” refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen. a hetero atom of oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
  • Non-limiting examples of spiroheterocyclyl groups include:
  • fused heterocyclic refers to 5 to 20 members, each ring of the system sharing an adjacent pair of atomic polycyclic heterocyclic groups with one or more of the other rings in the system, one or more A ring may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) a hetero atom, the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused heterocyclic groups include:
  • bridge heterocyclyl or “bridge heterocycle” refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but None of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bridge heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. More preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 10 members, and has 1 to 3 hetero atoms; more preferably 5 or 6 members, and 1 to 2 hetero atoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridyl An oxazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more selective Pyrazolyl or thiazolyl.
  • the heteroaryl ring may be fused to an aryl, hetero
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • hydroxy refers to an -OH group.
  • halogen means fluoro, chloro, bromo or iodo.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • mercapto refers to -SH.
  • ester group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • acyl refers to a compound containing a -C(O)R group, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • sulfonic acid group refers to -S(O) 2 OH.
  • sulfonate group refers to -S (O) 2 O (alkyl), or -S (O) 2 O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
  • the present invention adopts the following technical solutions.
  • Step 1 Ethyl acetoacetate and N,N-dimethylformamide dimethyl acetal are directly condensed at room temperature to obtain (Z)-2-((dimethylamino)methylene)-3- Ethyl oxobutyrate (Ia);
  • Step 2 (Z)-2-((Dimethylamino)methylene)-3-oxobutanoate ethyl ester (Ia) is reacted with strong sodium hydride in anhydrous tetrahydrofuran to form an enol sodium salt intermediate And then undergoing a cyclization reaction with diethyl oxalate to obtain diethyl 4-oxo-4H-pyran-2,5-dicarboxylate (Ib);
  • Step 3 Diethyl 4-oxo-4H-pyran-2,5-dicarboxylate (Ib) and amine (R 3 NH 2 ) are subjected to an addition-condensation reaction to obtain NR 3 -4-oxo- Diethyl 1,4-dihydropyridine-2,5-dicarboxylate (Ic);
  • Step 4 NR 3 -1-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Ic) is brominated by N-bromosuccinimide (NBS). NR 3 -3-bromo-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Id) was obtained.
  • Step 5 NR 3 -3-bromo-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Id) and the corresponding boric acid by Suzuki coupling reaction (potassium carbonate as a base, Pd(dppf)Cl 2 is a catalyst, dioxane/water is a mixed solvent, and the reaction temperature is 80 ° C), and NR 3 -3-R 4 -4-oxo-1,4-dihydropyridine-2 is obtained.
  • 5-dicarboxylic acid diethyl ester (Ie) 5-dicarboxylic acid diethyl ester (Ie);
  • Step 6 Selective hydrolysis of NR 3 -3-R 4 -4-oxo-1,4-dihydropyridine-2,5-dicarboxylate diethyl ester (Ie) under the action of sodium hydroxide to obtain NR 3-6- (ethoxycarbonyl) -5-R 4 -4- oxo-1,4-dihydropyridine-3-carboxylic acid (the If);
  • Step 7 NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-carboxylic acid (If) with aromatic amine (Ih) via HATU and N , N-diisopropylethylamine (DIPEA) was subjected to amidation to give NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3- Aromatic amide (Ig);
  • Step 8 NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-arylamide (Ig) can be directly amine with R 1 R 2 NH Transesterification to obtain a compound of the formula (I); or a two-step process of amidation with a pre-ester group followed by amidation with R 1 R 2 NH to give a compound of the formula (I).
  • R a is selected from -OR 1 or -SR 1 when, (I) a compound of formula 2 was prepared according to the following scheme:
  • Step 1 Alkaline hydrolysis of ester groups by NaOH with NR 3 -6-(ethoxycarbonyl)-5-R 4 -4-oxo-1,4-dihydropyridine-3-aramidamide (Ig) NR 3 -6-carboxy-5-R 4 -4-oxo-1,4-dihydropyridine-3-aryl amic acid (Ig');
  • Step 2 NR 3 -6-carboxy-5-R 4 -4-oxo-1,4-dihydropyridine-3-aryl amic acid (Ig') is reacted with an alcohol or a thiol under the action of EDCI. a compound of formula (I).
  • Step 1 NR 3 -3-bromo-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Id) and substituted aryl boronic acid in Pd(dppf)Cl 2 and Suzuki coupling under the action of K 2 CO 3 , while the substituent amino group, hydroxyl group or sulfhydryl group on the aryl group is cyclized with the ortho ester group to obtain cyclized NR 3 -4-oxo-1,4-di Hydropyridine-5-carboxylate ethyl ester (Ii);
  • Step 2 Cyclized NR 3 -4-oxo-1,4-dihydropyridine-5-carboxylate ethyl ester (Ii) is hydrolyzed under basic conditions (NaOH) to give cyclized NR 3 -4-oxyl Des-1,4-dihydropyridin-5-carboxylic acid (Ij);
  • Step 3 Cyclization of NR 3 -4-oxo-1,4-dihydropyridine-5-carboxylic acid (Ij) with aromatic amine (Ih) via HATU and N,N-diisopropylethylamine (DIPEA) The amidation reaction is carried out to obtain a compound of the formula (I').
  • Step 1 Diethyl 4-oxo-4H-pyran-2,5-dicarboxylate (Ib) with an amino group (-NH 2 ) at one end and an amine with PG-X by addition-condensation Reaction to give N-substituted-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Ik);
  • Step 2 N-substituted 4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Ik) is deprotected and then cyclized with an ortho ester group to obtain a cyclization reaction.
  • Step 3 Cyclization of ethyl 4-oxo-1,4-dihydropyridine-5-carboxylate (Il) by bromination of NBS to give cyclized 3-bromo-4-oxo-1,4-di Hydropyridine-5-formic acid ethyl ester (Im);
  • Step 4 Cyclization of ethyl 3-bromo-4-oxo-1,4-dihydropyridine-5-carboxylate (Im) with the corresponding boronic acid by Suzuki coupling reaction (potassium carbonate as base, Pd(dppf)Cl 2 is a catalyst, dioxane/water is a mixed solvent, and the reaction temperature is 80 ° C) to obtain a cyclized 3-R 4 -4-oxo-1,4-dihydropyridine-5-carboxylic acid ethyl ester (In );
  • Step 5 The cyclized 3-R 4 -4-oxo-1,4-dihydropyridine-5-carboxylic acid ethyl ester intermediate (In) is hydrolyzed under basic conditions (NaOH) to give a cyclized 3- R 4 -4-oxo-1,4-dihydropyridine-5-carboxylic acid intermediate (Io);
  • Step 6 Cyclized 3-R 4 -4-oxo-1,4-dihydropyridine-5-carboxylic acid intermediate (Io) with aromatic amine (Ih) via HATU and N,N-diisopropyl B
  • the amine (DIPEA) is subjected to an amidation reaction to give a compound of the formula (I").
  • Step 1 Diethyl 4-oxo-4H-pyran-2,5-dicarboxylate (Ib) and aminoacetaldehyde dimethylacetal are obtained by addition-condensation reaction to obtain 1-(2,2-dimethoxy Ethyl ethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Ip);
  • Step 2 1-(2,2-Dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (Ip) with amino alcohol, amino mercaptan Or the diamine is first subjected to a aldehyde condensation reaction of methanol, and then cyclized with an ortho ester group to obtain a fused ring of ethyl 4-oxo-1,4-dihydropyridine-5-carboxylate (Iq);
  • Step 3 The fused ring of ethyl 4-oxo-1,4-dihydropyridine-5-carboxylate (Iq) is brominated by NBS to give the cyclized 3-bromo-4-oxo-1,4-di Hydropyridine-5-formic acid ethyl ester (Ir);
  • Step 4 3-bromo-4-oxo-1,4-dihydropyridine-5-carboxylic acid ethyl ester (Ir) and the corresponding boronic acid by Suzuki coupling reaction (potassium carbonate as base, Pd(dppf)Cl 2 as catalyst , dioxane / water is a mixed solvent, the reaction temperature is 80 ° C), to give 3-R 4 -4-oxo-1,4-dihydropyridine-5-carboxylic acid ethyl ester (Is);
  • Step 5 Ethyl 3-R 4 -4-oxo-1,4-dihydropyridine-5-carboxylate (Is) is hydrolyzed under basic conditions (NaOH) to give cyclized 3-R 4 -4- Oxo-1,4-dihydropyridine-5-carboxylic acid (It);
  • Step 6 Cyclized 3-R 4 -4-oxo-1,4-dihydropyridine-5-carboxylic acid (It) with aromatic amine (Ih) via HATU and N,N-diisopropylethylamine ( DIPEA) is subjected to an amidation reaction to give a compound of the formula (I"').
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , W, V, n are as defined in the formula (I).
  • Figure 1 Growth curve of tumor volume in treated and control mice in the EBC-1 non-small cell lung cancer model.
  • Figure 2 Plot of body weight versus treatment time in treatment and control mice in the EBC-1 non-small cell lung cancer model.
  • the compounds of the present invention are prepared using convenient starting materials and common preparatory procedures.
  • the present invention provides typical or propensating reaction conditions such as reaction temperature, time, solvent, pressure, molar ratio of reactants. However, other reaction conditions can be adopted unless otherwise stated. Optimization conditions may vary with the use of a particular reactant or solvent, but under normal circumstances, the reaction optimization steps and conditions can be determined.
  • protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions.
  • protecting groups suitable for the various functional groups and their protection or deprotection conditions are well known to those skilled in the art. For example, T. W. Greene and G. M. Wuts, "Protective Groups in Organic Preparation” (3rd edition, Wiley, New York, 1999, and references cited in the book) describe in detail the protection or deprotection of a large number of protecting groups.
  • the separation and purification of the compounds and intermediates are carried out according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer chromatography, preparative high performance liquid chromatography or a mixture of the above methods.
  • the specific method of use can be referred to the examples described in the present invention.
  • other similar separation and purification methods can be employed. It can be characterized using conventional methods, including physical constants and spectral data.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR shift is given in units of 10 -6 (ppm).
  • the NMR was determined by using a Brukerdps300 type nuclear magnetic instrument.
  • the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethyl. Silane (TMS).
  • the MS was measured using an ACQUITY H-Class UPLC mass spectrometer (QDa Detector) (manufacturer: Waters).
  • the liquid phase was prepared using a Waters 2545 High Performance Liquid Chromatograph (Waters 2489 UV/visible Detector, 2767 Sample MGR, Unitary C18, 5 ⁇ m 20 mm x 250 mm) (manufacturer: Waters)
  • Thin layer chromatography silica gel plate uses Qingdao Ocean Chemical GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm ⁇ 0.5. Mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Netcom Mall, Beijing Coupling, Sigma, Belling, Yi Shiming, Shanghai Shuya, Shanghai Inoke, An Nike Chemical, Shanghai Bi De and other companies.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the reaction solvent, organic solvent or inert solvent is each expressed as a solvent which does not participate in the reaction under the described reaction conditions, and includes, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform.
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • NMP nitrogen-methylpyrrolidone
  • pyridine pyridine
  • the chemical reactions described in the present invention are generally carried out under normal pressure.
  • the reaction temperature is between -78 ° C and 200 ° C.
  • the reaction time and conditions are, for example, one atmosphere, between -78 ° C and 200 ° C, and completed in about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. There is no particular description in the examples, and the reaction temperature is room temperature and is 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • the column chromatography eluent system and the thin layer chromatography developer system include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: petroleum ether and acetic acid
  • A dichloromethane and methanol systems
  • B n-hexane and ethyl acetate systems
  • C petroleum ether and acetic acid
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid may be added for adjustment.
  • ⁇ M micromolar
  • DIPEA diisopropylethylamine
  • IC 50 concentration that inhibits 50% activity
  • NBS N-bromosuccinimide
  • PE petroleum ether
  • TBDPS tert-butyldiphenyl silicon
  • Step 1 Preparation of ethyl (Z)-2-((dimethylamino)methylene)-3-oxobutanoate (a1)
  • Step 4 Preparation of 3-bromo-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (a4)
  • Step 5 Preparation of diethyl 3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate (a5)
  • Step 6 Preparation of 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (a)
  • 5-(4-fluorophenyl)-4 was obtained in the same manner as in Preparation Example 1, except that (tetrahydro-2H-pyran-4-yl)methanamine (Shanghai Pide) was used instead of the aqueous methylamine solution.
  • -oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-3-carboxylic acid (c) (white solid, four-step yield: 36.8%)
  • Step 2 Preparation of 1-(3-aminopropyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid ethyl ester hydrochloride (d2)
  • Step 4 10-Bromo-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane- Preparation of 8-carboxylic acid ethyl ester (d4)
  • Step 5 10-(4-Fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4] Preparation of azacycloheptane-8-carboxylic acid ethyl ester (d5)
  • 1,3-Diamino-2-hydroxypropane (4 g, 44.4 mmol) and imidazole (6.1 g, 88.8 mmol) were added to a round bottom flask containing DMF (30 mL) at room temperature.
  • the mixture was cooled to 0 ° C, and a solution of TBDPSCl in DMF (30 mL, 88.8 mmol) was slowly added dropwise. After the addition was completed, the temperature was raised to room temperature and stirred overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut 12.4 g, yellow oil, yield 85.1%).
  • Step 2 4-((tert-Butyldiphenylsilyl)oxy)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2- Preparation of a][1,4]diazepane-8-carboxylic acid ethyl ester (f2)
  • Step 3 10-Bromo-4-((tert-butyldiphenylsilyl)oxy)-1,9-dioxo-1,2,3,4,5,9-hexahydropyridyl[ Preparation of 1,2-a][1,4]diazepane-8-carboxylic acid ethyl ester (f3)
  • Step 4 4-((tert-Butyldiphenylsilyl)oxy)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9 -Preparation of ethyl hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylate (f4)
  • Step 5 10-(4-Fluorophenyl)-4-hydroxy-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1 , 4] Preparation of diazepane-8-carboxylic acid (f)
  • Step 1 1 - ((1-(tert-Butoxycarbonyl)piperidin-2-yl)methyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester ( Preparation of g1)
  • Step 3 Preparation of 3-bromo-4-oxo-1-(piperidin-2-ylmethyl)-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester hydrochloride (g3)
  • Step 4 1-Bromo-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyrido[1,2-a:1',2'-d Preparation of pyrazine-3-carboxylic acid ethyl ester (g4)
  • Step 5 1-(4-Fluorophenyl)-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyrido[1,2-a:1 Preparation of ',2'-d]pyrazine-3-carboxylic acid ethyl ester (g5)
  • Step 6 1-(4-Fluorophenyl)-2,12-dioxo-2,6,6a,7,8,9,10,12-octahydrodipyrido[1,2-a:1 Preparation of ',2'-d]pyrazine-3-carboxylic acid (g)
  • Morpholine-3-carboxylic acid (3.0 g, 22.9 mmol) and potassium carbonate (15.8 g, 114.4 mmol) were added to a round bottom flask containing acetone (20 mL) and water (10 mL). Boc 2 O (7.5 g, 34.4 mmol) was slowly added dropwise with stirring, and the mixture was stirred at this temperature overnight. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc EtOAc : 34.1%).
  • Step 2 Preparation of 3-carbamoylmorpholine-4-carboxylic acid tert-butyl ester (j1-2)
  • Step 3 Preparation of 3-(aminomethyl)morpholine-4-carboxylic acid tert-butyl ester (j1)
  • PREPARATIVE EXAMPLE 10 7-(4-Fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4 ,5]Preparation of pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (intermediate k)
  • Step 2 Preparation of 3-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (k2)
  • Step 4 7-(4-Fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5
  • pyrazino[2,1-B][1,3]oxazine-9-carboxylic acid ethyl ester k4
  • Step 5 7-(4-Fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5
  • PREPARATIVE EXAMPLE 12 7-(6-Methylpyridin-3-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1', Preparation of 2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (intermediate m)
  • PREPARATIVE EXAMPLE 13 7-(5-Methylthiophen-2-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1', Preparation of 2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (intermediate n)
  • PREPARATIVE EXAMPLE 16 (3R)-6-(4-Fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[ Preparation of 3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (intermediate q)
  • PREPARATIVE EXAMPLE 17 (3S)-6-(4-Fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[ Preparation of 3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (intermediate r)
  • PREPARATIVE EXAMPLE 18 (4R)-7-(4-Fluorophenyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyridine And [1', 2': 4,5] Preparation of pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (intermediate s)
  • Step 2 Preparation of tert-butyl 4-(4-(6-amino-5-bromopyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (u2)
  • Step 1 Preparation of 4-((4-bromo-2-methoxyphenoxy)methyl)-2,2-dimethyl-1,3-dioxolan (bb1)
  • 3-(4-Bromo-2-methoxyphenoxy)propane-1,2-diol (2.1 g, 7.58 mmol) was added sequentially to a reaction flask containing 1,2-dibromoethane (30 mL). Tetrabutylammonium bromide (488 mg, 1.52 mmol) and 50% (w/w) sodium hydroxide solution (30 mL). After heating the mixture to 55 ° C and stirring for 6 hours, additional 1,2-dibromoethane (30 mL) and 50% (w/w) sodium hydroxide solution (30 mL) were added and stirring was continued at this temperature overnight. .
  • reaction solution was cooled to room temperature, it was diluted with water and extracted with dichloromethane (100 mL x 3), and the organic phase was combined. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography (EtOAc:EtOAc: Dioxane (1.7 g, yellow solid, yield: 73.9%).
  • Step 4 2-(4-((1,4-Dioxa-2-yl)methoxy)-3-methoxyphenyl)-4,4,5,5-tetramethyl-1, Preparation of 3,2-dioxaborane (bb4)
  • Step 6 5-(4-((1,4-Dioxa-2-yl)methoxy)-3-methoxyphenyl)-3-(4-amino-2-fluorophenyl)pyridine
  • Step 2 4-((2-(4-Bromo-2-methoxyphenoxy)ethoxy)methyl)-2,2-dimethyl-1,3-dioxolane (cc) Preparation
  • Step 1 Preparation of 4-(2-(4-bromo-2-methoxyphenoxy)ethyl)morpholine (ee1-1)
  • Step 2 4-(2-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy) Preparation of ethyl)ethyl)morpholine (ee1)
  • Step 1 4-(((2,2-Dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methyl)amino)-2-methoxybenzene Preparation of methyl formate (hh1)
  • Methyl 4-amino-2-methoxybenzoate (5 g, 27.6 mmol) was added to a reaction flask containing isopropyl alcohol (100 mL) at room temperature. The mixture was warmed to 50 ° C and stirred for 10 minutes, then added 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (Shanghai Bi De , 5.13 g, 27.6 mmol). The mixture was further heated to 80 ° C and stirred for 1 hour.
  • Step 3 Preparation of 4-(2-fluoro-4-nitrophenoxy)-6-methoxy-7-(2-methoxyethoxy)quinazoline (oo3)
  • Step 4 Preparation of 3-fluoro-4-((6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl)oxy)phenylamine (oo)
  • PREPARATIVE EXAMPLE 42 4-(2-((4-(4-Amino-2-fluorophenoxy)-6-methoxyquinazolin-7-yl)oxy)ethyl)piperazine-1 -Preparation of tert-butyl formate (intermediate qq)
  • Step 1 5-((4-(2-Amino-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridine-3- Ethyl 3-fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylate (1a)
  • Step 2 5-((4-(2-Amino-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridine-3- Of 3-(fluorophenyl)carbamoyl)-3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (1b)
  • Step 3 4-(4-(6-Amino-5-(4-(6-carbamoyl-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-di) Preparation of tert-butyl ester (1c) of hydropyridine-3-carboxamido)-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate
  • Step 4 N 5 -(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) Preparation of -3-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (1)
  • Example 2 The same procedure as in Example 1 was carried out except that 5-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4- Dihydropyridine-3-carboxylic acid (c) in place of 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3- Carboxylic acid (a) to give N 5 -(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3 -fluorophenyl)-3-(4-fluorophenyl)-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2 , 5-dimethylformamide (7) (white solid, four-step yield: 11.2%).
  • Step 1 4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine-2,5-dicarboxylic acid diethyl ester (9a) preparation
  • Step 4 5-((4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)carbamoyl)-3-bromo-4-oxo
  • Step 5 5-((4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)carbamoyl)-4-oxo-1-( Preparation of ethyl (tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1,4-dihydropyridine-2-carboxylate (9e)
  • Step 6 5-((4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)carbamoyl)-4-oxo-1-( Preparation of (tetrahydro-2H-pyran-4-yl)methyl)-3-(p-tolyl)-1,4-dihydropyridine-2-carboxylic acid (9f)
  • Step 7 N 5 -(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-N 2 -methyl-4-oxo-1
  • Step 7 N 5 -(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-N 2 -methyl-4-oxo-1
  • Example 10 N 5 -(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorobenzene Of 1-(1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (10)
  • Example 10 The same procedure as in Example 10 was employed except that 6-(ethoxycarbonyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-
  • the carboxylic acid (a) is substituted for 5-(4-fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-3-carboxylic acid (b) to obtain N 5 -(4- (2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)-1-methyl-4- Oxo-1,4-dihydropyridine-2,5-dimethylformamide (11) (white solid, three-step yield: 18.8%).
  • Example 11 The same procedure as in Example 11 was employed except that 3-(4-amino-2-fluorophenyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (v) was used. Instead of 3-(4-amino-2-fluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (x), N 5 -(4-(2-amino) was obtained.
  • Example 13 N 5 -(4-(2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4 Of -fluorophenyl)-1-isopropyl-4-oxo-1,4-dihydropyridine-2,5-dimethylformamide (13)
  • Example 14 N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9 hexahydropyrido[1,2- ⁇ ][1,4]diazepine Preparation of heptane-8-carboxamide (14)
  • Step 1 4-(4-(6-Amino-5-(2-fluoro-4-(10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5 ,9-Hexidopyrido[1,2- ⁇ ][1,4]diazepane-8-formylamino)phenyl)pyridin-3-yl)-1H-pyrazol-1-yl
  • piperidine-1-carboxylic acid tert-butyl ester 14a
  • Step 2 N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)- 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2- ⁇ ][1,4]diazepine
  • Example 14 The same procedure as in Example 14 was employed except that 4-(4-(6-amino-5-(4-amino-2,5-difluorophenyl)pyridin-3-yl)-1H-pyrazole-1 was used.
  • Example 16 N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-pyrido[1',2':4,5]pyridyl Preparation of oxazolo[2,1-C][1,4]oxazine-9-carboxamide (16)
  • Example 14 The same procedure as in Example 14 was carried out except that 7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-pyrido[1] was used.
  • Example 14 The same procedure as in Example 14 was carried out except that 7-(4-fluorophenyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1] was used.
  • Example 14 The same procedure as in Example 14 was carried out except that 6,8-dioxy-7-(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2 was used.
  • Example 20 N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -10-(4-fluorophenyl)-4-hydroxy-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2- ⁇ ][1,4 Preparation of diazepane-8-carboxamide (20)
  • Example 14 The same procedure as in Example 14 was carried out except that 10-(4-fluorophenyl)-4-hydroxy-1,9-dioxo-1,2,3,4,5,9-hexahydropyridyl[ 1,2-a][1,4]diazepane-8-carboxylic acid (f) instead of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4 ,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (d), to give N-(4-(2-amino-5-( 1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-10-(4-fluorophenyl)-4-hydroxy-1, 9-dioxo 1,2,3,4,5,9 hexahydropyrido[1,2- ⁇ ][1,4]diazepane
  • Example 14 The same procedure as in Example 14 was employed except that (4R)-7-(4-fluorophenyl)-4-methyl-6,8-dioxo-3,4,6,8,12,12a- Hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (s) in place of 10-(4-fluorobenzene) -1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid ( d), (4R)-N-(4-(2-amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3 -fluorophenyl)-7-(4-fluorophenyl)-4-methyl-6,8-dioxo-3,4,6,8,12
  • Example 23 N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl) -6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2- d] Preparation of pyrazine-8-carboxamide (23)
  • Example 14 The same procedure as in Example 14 was carried out except that 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole [3,2 -a]pyrido[1,2-d]pyrazine-8-carboxylic acid (o) instead of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5 , 9-hexahydropyrido[1,2-a][1,4]diazepan-8-carboxylic acid (d), to obtain N-(4-(2-amino-5-(1-) (piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo- 2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido
  • Example 24 (3R)-N-(4-(2-Amino-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3- Fluorophenyl)-6-(4-fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[3,2- Preparation of a] pyrido[1,2-d]pyrazine-8-carboxamide (24)
  • Example 25 N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl) )-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide Preparation of (25)
  • Example 23 The same procedure as in Example 23 was carried out except that 3-(4-amino-2-fluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (x) was used instead of 4- (4-(6-Amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (u), Preparation of N-(4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl)- 5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (25 (white solid, one step yield: 40.2%).
  • Example 26 N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-10-(4-fluorophenyl) -1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2- ⁇ ][1,4]diazepane-8-carboxamide ( Preparation of 26)
  • Example 27 N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-1,9-dioxo-10-(pair Of -tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2- ⁇ ][1,4]diazepane-8-carboxamide (27)
  • Example 19 The same procedure as in Example 19 was carried out except that 3-(4-amino-2-methylphenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (aa) was used instead of 4-( 4-(6-Amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (u), made N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-1,9-dioxo-10-(p-tolyl) -1,2,3,4,5,9-hexahydropyrido[1,2- ⁇ ][1,4]diazepane-8-carboxamide (27) (white solid, one step Rate: 37.9%).
  • Example 27 The same procedure as in Example 27 was employed except that (3R)-6-(4-fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a- Instead of 1,9-dioxo-10-(p-tolyl)-1, hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (q) 2,3,4,5,9-Hexidopyrido[1,2-a][1,4]diazepane-8-carboxylic acid (e), (3R)-N-(4) -(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-6-(4-fluorophenyl)-3-methyl-5,7-di Oxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8
  • Example 28 The same procedure as in Example 28 was employed except that (3S)-6-(4-fluorophenyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a- Hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (r) in place of 1,9-dioxo-10-(p-tolyl)-1, 2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (e), (3S)-N-(4) -(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-6-(4-fluorophenyl)-3-methyl-5,7-di Oxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8
  • Example 30 N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-2,5-difluorophenyl)-6-(4- Fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8 - Preparation of formamide (30)
  • Step 1 Preparation of 3-(4-amino-2,5-difluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (Intermediate 30a)
  • 3-bromo-5-(3,4-dimethoxyphenyl)pyridine was added to a reaction flask containing (10 mL) a mixture of 1,4-dioxane and water (4:1) at room temperature.
  • 2-Amine prepared according to Example 30 of WO2013115280, page 130) (500 mg, 1.62 mmol), 4-amino-2,5-difluorophenylboronic acid pinacol ester (619 mg, 2.43 mmol), potassium carbonate (671 mg, 4.86 mmol), Pd(dppf)Cl 2 .DCM (130 mg, 0.16 mmol). Sealed, replaced with nitrogen three times, heated to 90 ° C and stirred overnight.
  • Step 2 N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-2,5-difluorophenyl)-6-(4-fluoro Phenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8- Preparation of formamide (30)
  • Example 31 N-(4-(2-Amino-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-6-(4- Fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8 - Preparation of formamide (31)
  • Example 30 The same procedure as in Example 30 was employed except that 3-(4-amino-2-fluorophenyl)-5-(1-ethyl-1H-pyrazol-4-yl)pyridin-2-amine (v) Instead of 3-(4-amino-2,5-difluorophenyl)-5-(3,4-dimethoxyphenyl)pyridin-2-amine (30a), N-(4-(2) was obtained.
  • Example 31 The same procedure as in Example 31 was carried out except that 10-(4-fluorophenyl)-4-hydroxy-1,9-dioxo-1,2,3,4,5,9-hexahydropyridyl[ 1,2-a][1,4]diazepane-8-carboxylic acid (f) in place of 6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7 ,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (o), N-(4-(2-amino-5) -(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-10-(4-fluorophenyl)-4-hydroxy-1-,9-di Oxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepan
  • Example 35 N-(4-(2-Amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)phenyl -1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazacyclocycle Preparation of heptane-8-carboxamide (35)
  • Example 36 N-(4-(2-Amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3 -fluorophenyl)-1,9-dioxo-10-(p-tolyl)-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4] Preparation of diazepane-8-carboxamide (36)
  • Example 37 N-(4-(2-Amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3 -fluorophenyl)-7-(6-methylpyridin-3-yl)-6,8-dioxo 3,4,6,8,12,12a-hexahydro-2H-pyrido[1', Preparation of 2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide (37)
  • Example 36 The same procedure as in Example 36 was employed except that 7-(6-methylpyridin-3-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H- Pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxylic acid (m) instead of 1,9-dioxo-10-(pair Tolyl-1,2,3,4,5,9-hexahydropyrido[1,2-a][1,4]diazepane-8-carboxylic acid (e), to give N- (4-(2-Amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)- 7-(6-Methylpyridin-3-yl)-6,8-dioxo-3,4,6,8,12,12a-hex
  • Example 14 The same procedure as in Example 14 was employed except that 3-(4-amino-2-fluorophenyl)-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridine- 2-amine (ee) instead of 4-(4-(6-amino-5-(4-amino-2-fluorophenyl)pyridin-3-yl)-1H-pyrazol-1-yl)piperidine-1 - tert-butyl formate (u) to give N-(4-(2-amino-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-3-yl) 3-fluorophenyl)-10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9-hexahydropyrido[1,2-a][ 1,4]diazepane-8-carboxamide (38) (white solid, one step yield: 21.3%).
  • Example 39 N-(4-(2-Amino-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-3-yl)-3-fluorophenyl) -7-(5-methylthiophen-2-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4 ,5]Preparation of pyrazino[2,1-b][1,3]oxazine-9-carboxamide (39)
  • Example 38 The same procedure as in Example 38 was employed except for 7-(5-methylthiophen-2-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyridine.
  • Example 40 N-(4-(5-(4-(2-((1,4-dioxo)-2-yl)methoxy)ethoxy)-3-methoxyphenyl)- 2-amino-pyridin-3-yl)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydro Preparation of oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (40)
  • Example 38 The same procedure as in Example 38 was carried out except that 6-(4-methylphenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a ] Pyrido[1,2-d]pyrazine-8-carboxylic acid (p) in place of 10-(4-fluorophenyl)-1,9-dioxo-1,2,3,4,5,9 -Hexidopyrido[1,2-a][1,4]diazepan-8-carboxylic acid (d) to give N-(4-(2-amino-5-(3-methoxy) 4-(2-morpholinoethoxy)phenyl)pyridin-3-yl)-3-fluorophenyl)-5,7-dioxo-6-(p-tolyl)-2,3, 5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazin
  • Example 42 N-(4-(5-(4-(4-1,4-dioxan-2-yl)methoxy)-3-methoxyphenyl)-2-amino-pyridine-3 -yl)-3-fluorophenyl)-6-(4-fluorophenyl)-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazole[3,2 -a]Preparation of pyrido[1,2-d]pyrazine-8-carboxamide (42)
  • Example 41 The same procedure as in Example 41 was carried out except that 6,8-dioxo-7-(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2 ':4,5]pyrazine[2,1-b][1,3]oxazine-9-carboxylic acid (l) instead of 6-(4-methylphenyl)-5,7-dioxo-2, 3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxylic acid (p) to give N-(4-( 2-Amino-5-(3-methoxy-4-(2-morpholinoethoxy)phenyl)pyridin-3-yl)-3-fluorophenyl)-6,8-dioxo-7 -(p-tolyl)-3,4,6,8,12,12a-hexahydro-2H-pyrido
  • Example 44 N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-1,5-dioxo-4-(( Preparation of tetrahydro-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridin-2-carboxamide (44)
  • Step 1 N-(4-(2-Amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)phenyl)-1,5-dioxo-4-((four Preparation of hydrogen-2H-pyran-4-yl)methyl)-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridin-2-carboxamide (44)
  • Step 2 5-((4-(2-Amino-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyridine-3- 3-fluorophenyl)carbamoyl)-3-bromo-4-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,4-dihydropyridine
  • ethyl-2-carboxylate 45b
  • Step 3 4-(4-(6-Amino-5-(2-fluoro-4-(8-fluoro-1,5-dioxo-4-((tetrahydro-2H-pyran-4-yl)) [Methyl)-1,4,5,6-tetrahydrobenzo[f][1,7]naphthyridin-2-carboxamido)phenyl)pyridin-3-yl)-1H-pyrazole- Preparation of tert-butyl ester of 1-yl) piperidine-1-carboxylate (45c)

Abstract

La présente invention concerne un dérivé de pyridone polysubstitué, son procédé de préparation et son utilisation médicale. En particulier, la présente invention concerne un dérivé de pyridone polysubstitué de formule générale (I), un procédé de préparation de celui-ci, une composition pharmaceutique le contenant, et l'utilisation de celui-ci en tant qu'inhibiteur de Axl/c-MET dans le traitement de cancers, les définitions de chaque groupe dans la formule générale (I) étant les mêmes que celles données dans la description.
PCT/CN2018/109969 2017-10-26 2018-10-12 Dérivé de pyridone polysubstitué, son procédé de préparation et son utilisation médicale WO2019080723A1 (fr)

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CN111233779A (zh) * 2020-04-02 2020-06-05 廖文英 一种来氟米特的制备方法
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CN112625027A (zh) * 2019-09-24 2021-04-09 南京药捷安康生物科技有限公司 杂环衍生物及其用途
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