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  • A61K31/5375—1,4-Oxazines, e.g. morpholine
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  • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • C07F7/0832—Other preparations

Definitions

• the present invention relates to the field of medicine, in particular to a compound having Axl and c-Met kinase inhibitory activity and its preparation and application.
• Protein kinase is a protein (enzyme) that regulates various cellular functions by phosphorylation of specific amino acids on the protein. Proteins adjust their activity and their ability to bind to their chemical components through conformational changes.
• the activity of protein kinase refers to the rate at which the kinase binds phosphate groups to the substrate, and this rate can be determined by detecting the amount of substrate converted into a product within a certain period of time. The phosphorylation of the substrate occurs at the activation site of the protein kinase.
• Tyrosine kinase is a protein enzyme that can catalyze the transfer of adenosine triphosphate to protein tyrosine residues. These kinases play an important role in the process of cell proliferation, differentiation and migration triggered by growth factor transduction.
• Axl (also known as Ufo, Ark or Tyro7) is a receptor tyrosine kinase, which, together with Tyro3 and Mer, forms the receptor tyrosine kinase TAM subfamily.
• the protein molecule encoded by growth arrest-specific gene 6 (Gas6) is one of the common ligands of members of the TAM subfamily.
• the activation of Axl occurs through the binding of its homologous protein ligand growth arrest specific protein 6 (Gas6), through homodimerization of its extracellular domain or crosstalk via interleukin IL-15 receptor or HER2.
• Axl plays an important regulatory role in regulating the body's inflammatory immune response, maintaining the steady state of phagocytosis, and regulating the differentiation and maturation of NK cells. Changes in the expression of the Axl gene have been confirmed in various human cancers. The abnormal expression of Axl activates and antagonizes tumor cell apoptosis, promotes tumor cell invasion and metastasis, and promotes tumor angiogenesis, which promotes the occurrence and development of tumors in multiple links. It is particularly noteworthy that recent studies have shown that Axl overexpression and the dimer produced by binding to EGFR is an important reason for the acquired resistance of tumor cells to EGFR inhibitors; preclinical studies of the combination of Axl inhibitors can Effectively overcome EGFR inhibitor resistance.
• Axl abnormal activation of Axl overexpression is also closely related to the resistance of other targeted inhibitors and chemotherapeutic drugs, suggesting that Axl may have a wide range of applications for combination drugs.
• Axl is highly expressed in macrophages and dendritic cells in the tumor microenvironment, and can synergistically promote tumor progression by interacting with tumor cells and other stromal cells. Therefore, in recent years, the research and development of targeted Axl inhibitors has become the frontier and hot spot of anti-tumor drug research. Small molecule inhibitors developed for it have shown effects in tumor treatment.
• c-Met also known as tyrosine protein kinase Met or HGFR
• the c-Met protein can transform non-tumorigenic cells and endow them with invasive and metastatic properties.
• the carcinogenic potential is the result of spontaneous dimerization and constitutive activation of c-Met.
• the abnormal expression of HGF and MET is associated with the occurrence and poor prognosis of a wide range of solid tumors, including breast cancer, prostate cancer, thyroid cancer, lung cancer and the like. In vitro and in vivo studies have shown that increased and dysregulation of c-Met activation causes a wide range of biological responses associated with malignant phenotypes.
• pathological conditions related to protein kinases also include psoriasis, liver cirrhosis, diabetes, angiogenesis, restenosis, ophthalmic diseases, rheumatoid arthritis and other inflammatory diseases, immune diseases, cardiovascular diseases such as arteriosclerosis and various kidney diseases.
• the purpose of the present invention is to provide a compound represented by formula (I) and a preparation method thereof and its use in anti-tumor.
• the first aspect of the present invention provides a compound represented by formula (I) or its stereoisomers, geometric isomers, tautomers, its pharmaceutically acceptable salts, its prodrugs, its Hydrate or solvate,
• T is selected from the following group: substituted or unsubstituted C3-C11 cycloalkyl, substituted or unsubstituted 3-11 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted A substituted 5-10 membered heteroaryl group;
• substituted refers to one or more hydrogen atoms on the group being substituted by a substituent selected from the following group: further substituted or unsubstituted C1-C6 alkyl, further substituted Or unsubstituted C3-C8 cycloalkyl, halogen, hydroxyl, mercapto, cyano, amino, further substituted or unsubstituted C1-C6 alkoxy, further substituted or unsubstituted C1-C6 alkylamino and further substituted Or unsubstituted C1-C6 alkylthio;
• U is selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C11 cycloalkyl , Substituted or unsubstituted 3-11 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl and substituted or unsubstituted 5-10 membered heteroaryl; the “substituted” refers to the group One or more hydrogen atoms of is substituted by a group selected from the following group: hydroxyl, further substituted or unsubstituted C1-C6 alkyl, further substituted or unsubstituted C1-C6 alkoxy, further substituted or unsubstituted C1-C6 alkylamino, further substituted or unsubstituted C1
• Q is selected from N or CR c ;
• V1, V2, V3, and V4 can be the same or different, and are independently selected from N or CR d ;
• Z is selected from the group represented by formula (II), formula (III), formula (IV) or formula (V):
• W1, W2, W3, W4, Y1, Y2, Y3 are independently selected from: N or CR 1a each time they appear;
• M is C-H or N
• Each bond represented by the dashed line is selected from the following group: single bond, double bond;
• X does not exist, or X is CR l , NR l , O, S, N;
• R g , R h , R i , R j , and R k may independently exist or not exist at each occurrence, provided that the number of R g , R h , R i , R j , and R k groups present is such that the number of groups remains The valence of each atom in ring B; or,
• R g and R h together, or R i and R j together, form 0; or,
• R g and R i can form a substituted or unsubstituted 5-10 membered aryl group, substituted or unsubstituted C3-C11 cycloalkyl group, substituted or unsubstituted 3-15 together with the atom to which they are connected Member heterocycloalkyl or substituted or unsubstituted 5-10 membered heteroaryl, and the new ring formed is in a parallel relationship with ring B;
• Each t is independently selected from: 0, 1, 2, 3, or 4;
• R a , R b , R c , R e , R f , R m , R n , R o is independently selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or Unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C11 cycloalkyl, substituted or unsubstituted 3-11 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl and substituted or unsubstituted 5-10 membered heteroaryl;
• R d is selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, halogen, hydroxyl, cyano, amino, substituted or unsubstituted C1-C6 alkane Oxy, substituted or unsubstituted C1-C6 alkylamino and substituted or unsubstituted C1-C6 alkylthio;
• R p and R q are independently selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, Substituted or unsubstituted C3-C11 cycloalkyl, substituted or unsubstituted 3-11 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, and substituted or unsubstituted 5-10 membered heteroaryl Base; or,
• R p and R q can form a substituted or unsubstituted 5-10 membered aryl group, a substituted or unsubstituted C3-C11 cycloalkyl group, a substituted or unsubstituted 3-11 membered hetero Cycloalkyl or substituted or unsubstituted 5-10 membered heteroaryl;
• substitution in f , R m , R n , R o , R p , and R q means that one or more hydrogen atoms on the group are replaced by a group selected from the following group: C1-C6 alkyl, Halogenated C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, hydroxy, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 alkyl sulfide Group, halogenated C1-C6 alkylthio, C1-C6 alkylsilyl, halogenated C1-C6 alkylsily
• the compound is selected from compounds represented by formula (VI) or formula (VII):
• T, U, Q, V1, V2, V3, V4, W1, W2, W3, W4 are defined as described above;
• R 2d and R 2e is independently selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, Substituted or unsubstituted C3-C11 cycloalkyl, substituted or unsubstituted 3-11 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, and substituted or unsubstituted 5-10 membered heteroaryl Base; or
• R 2d and R 2e can form a substituted or unsubstituted 5-10 membered aryl group, a substituted or unsubstituted C3-C11 cycloalkyl group, a substituted or unsubstituted 3-11 membered hetero Cycloalkyl or substituted or unsubstituted 5-10 membered heteroaryl;
• Each d and t is independently selected from 0, 1, 2, 3 or 4;
• R a and R b are as defined above.
• the compound is selected from the compound represented by formula (IX) or formula (X):
• T, U, Q, V1, V2, V3, V4, R e and R f are as described above;
• R 3a , R 3b , R 3c , R 3d , and R 3e is independently selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, Substituted or unsubstituted C2-C6 alkynyl, halogen, substituted or unsubstituted -(CH 2 ) t -(C3-C11 cycloalkyl), substituted or unsubstituted -(CH 2 ) t -(3-11 member Heterocycloalkyl), substituted or unsubstituted -(CH 2 ) t -CN, substituted or unsubstituted -(CH 2 ) t -OR 3f , substituted or unsubstituted -(CH 2 ) t -NR 3f R 3g , substituted or unsubstituted -(CH 2
• R 3f and R 3g is independently selected from the following group: H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, Substituted or unsubstituted C3-C11 cycloalkyl, substituted or unsubstituted 3-11 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl, and substituted or unsubstituted 5-10 membered heteroaryl Base; or
• R 3f and R 3g can form a substituted or unsubstituted 5-10 membered aryl group, a substituted or unsubstituted C3-C11 cycloalkyl group, a substituted or unsubstituted 3-11 membered hetero Cycloalkyl or substituted or unsubstituted 5-10 membered heteroaryl;
• t is independently selected from 0, 1, 2, 3 or 4;
• R a and R b are as defined above.
• the compound is selected from the compound represented by formula (XI) or formula (XII):
• T, U, Q, V1, V2, V3, V4, M, R g , R h , R i , R j , R k , and the dashed line are defined as described above;
• X 1 is N or O
• R 4a is selected from the following group: H, halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3 -C11 cycloalkyl, substituted or unsubstituted 3-11 membered heterocycloalkyl, substituted or unsubstituted 5-10 membered aryl and substituted or unsubstituted 5-10 membered heteroaryl; the "substituted” It means that one or more hydrogen atoms on the group are substituted by a group selected from the group consisting of: further substituted or unsubstituted C1-C6 alkyl, further substituted or unsubstituted C1-C6 alkoxy, further substituted or Unsubstituted C1-C6 alkylamino, further substituted or unsubstitute
• R a and R b are as defined above.
• Q is C-H.
• T is selected from the following group: substituted or unsubstituted C3-C11 cycloalkyl, substituted or unsubstituted 5-10 membered aryl; the "substituted” refers to one or more of the group One hydrogen atom is substituted by a substituent selected from the following group: further substituted or unsubstituted C1-C6 alkyl, further substituted or unsubstituted C3-C8 cycloalkyl, halogen, hydroxyl, mercapto, cyano, amino, further A substituted or unsubstituted C1-C6 alkoxy group, a further substituted or unsubstituted C1-C6 alkylamino group, and a further substituted or unsubstituted C1-C6 alkylthio group; the "further substituted” refers to one of the groups Or multiple hydrogen atoms are substituted by substituents selected from the following group: C1-C11 cyclo
• R a and R b are as defined above.
• U is selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C11 cycloalkyl, substituted or unsubstituted 5-10 membered aryl group.
• the compound is selected from the compounds shown in Table 1.
• a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more therapeutically effective amounts of the compound according to the first aspect of the present invention or its stereoisomers and geometrical differences. Constructs, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates or solvates thereof.
• the dosage form of the pharmaceutical composition is selected from the following group: oral dosage form, lyophilized preparation, and injection.
• the third aspect of the present invention provides a compound according to the first aspect of the present invention or its stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs thereof,
• the use of its hydrate or solvate is used for preparing medicine, and the medicine is used for the purpose selected from the following group:
• the tumor-related disease is selected from the group consisting of chronic myelogenous leukemia, chronic myelodysplastic disease, lung cancer, skin cancer, prostate cancer, esophageal cancer, ovarian cancer, pancreatic cancer, stomach pain, gastric cancer, liver cancer , Thyroid cancer, kidney cancer, glioblastoma, malignant glioma, breast cancer, acute myeloid leukemia, colorectal cancer, colon cancer, rectal cancer, endometrial cancer, uterine cancer, cervical cancer, malignant glial Tumor, pigment melanoma, osteosarcoma, soft tissue sarcoma, glioma, melanoma, head and neck cancer, bladder cancer, bile duct cancer, nasopharyngeal cancer, synovial sarcoma, rhabdomyosarcoma, fibrosarcoma, leiomyosarcoma , Myeloma and lymphoma.
• the melanoma is malignant melanoma.
• the lung cancer is non-small cell lung cancer (NSCLC).
• NSCLC non-small cell lung cancer
• the disease related to protein tyrosine kinase activity is selected from the group consisting of psoriasis, liver cirrhosis, diabetes, angiogenesis, restenosis, ophthalmological diseases, inflammatory diseases, immune diseases, and cardiovascular diseases.
• the inflammatory disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, nephritis, multiple sclerosis, and myocarditis.
• the cardiovascular disease is selected from the group consisting of arteriosclerosis, nephropathy, hypertension, myocardial hypertrophy, and myocardial infarction.
• a tyrosine kinase inhibitor comprising an inhibitory effective amount of one or more of the compounds described in the first aspect of the present invention or their stereoisomers, geometric isomers, and mutual Tautomers, their pharmaceutically acceptable salts, their prodrugs, their hydrates or solvates.
• the inhibitor is an Axl inhibitor.
• the inhibitor is a c-Met inhibitor.
• the fifth aspect of the present invention provides a method for use selected from the following group,
• the method includes the steps of: administering an inhibitory effective amount of the compound or its stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, and Hydrate or solvate.
• the method is non-diagnostic and/or non-therapeutic.
• the sixth aspect of the present invention provides a method for use selected from the following group:
• the method includes the steps of: administering a preventive and/or therapeutically effective amount of the compound or its stereoisomers, geometric isomers, tautomers, or pharmaceutically acceptable salts thereof, to the patient in need, Its prodrug, its hydrate or solvate.
• the diseases related to the abnormal expression of the Gas6/Axl signaling pathway are selected from the group consisting of colon cancer, rectal cancer, skin cancer, gastric cancer, lung cancer, endometrial cancer, malignant melanoma, thyroid cancer, and neuroglial.
• Mass tumors, esophageal cancer, prostate cancer, ovarian cancer, breast pain and other tumors have diseases related to poor prognosis, and their high expression may mediate the acquired drug resistance of EGFR.
• the diseases related to abnormal expression of the HGF/c-Met signaling pathway are selected from the group consisting of breast cancer, prostate cancer, thyroid cancer, and lung cancer.
• the kinase inhibitor prepared with the compound of the present invention can achieve a significant inhibitory effect on the enzyme activity of Axl and/or c-Met at the nM level, and the inhibitor can inhibit the proliferation of Axl or c-Met-dependent cancer cells at the cellular level. It also has a significant inhibitory effect, which is of great significance for the development of new anti-tumor drugs. On this basis, the inventor completed the present invention.
• halogen refers to F, Cl, Br or I.
• C1-C6 alkyl refers to a straight or branched alkyl group containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl Group, tert-butyl group, neopentyl group, p-pentyl group, or similar groups.
• C2-C6 alkenyl refers to a straight or branched chain alkenyl group having 2 to 6 carbon atoms containing a double bond, including but not limited to vinyl, propenyl, butenyl , Isobutenyl, pentenyl and hexenyl etc.
• C2-C6 alkynyl refers to a straight-chain or branched alkynyl group having 2 to 6 carbon atoms and containing a triple bond, and includes, without limitation, ethynyl, propynyl, butyne Group, isobutynyl, pentynyl and hexynyl, etc.
• C3-C11 cycloalkyl refers to a cyclic alkyl group having 3 to 11 carbon atoms in the ring, and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, cycloheptyl, cyclooctyl, etc.
• C3-C8 cycloalkyl and “C3-C6 cycloalkyl” have similar meanings.
• C3-C11 cycloalkyl is all monovalent groups
• C3-C8 cycloalkyl is all monovalent groups
• C3-C6 cycloalkyl is all monovalent groups
• C3-C11 cycloalkylene and “C3-C8 cycloalkyl” "Cycloalkyl” and “C3-C6 cycloalkylene” have similar meanings, but are divalent groups.
• C1-C6 alkoxy refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, including non-limiting methoxy, ethoxy, propoxy, Isopropoxy and butoxy, etc. Preferably, it is a C1-C4 alkoxy group.
• C1-C6 alkylamino group has the following structure: -NH-C1-C6 alkyl or -N-(C1-C6 alkyl) 2 , which may be mono- or di-substituted: representative sexual examples include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamine Group, diisopropylamino, dibutylamino, diisobutyl gum, di-sec-butylamino, di-tert-butylamino, or similar groups.
• C1-C6 alkylthio has the following structure: -S-C1-C6 alkyl, representative examples include but are not limited to methylthio, ethylthio, propylthio, isopropylthio , Butylthio, isobutylthio, sec-butylthio, tert-butylthio, or similar groups.
• C1-C6 alkylsilyl group refers to a silyl group substituted with a linear or branched alkyl group having 1 to 6 carbon atoms, which may be monosubstituted, disubstituted or trisubstituted; on behalf of Examples include, but are not limited to, methylsilyl, ethylsilyl, propylsilyl, isopropylsilyl, butylsilyl, isobutylsilyl, sec-butylsilyl, tert-butylsilyl, dimethylsilyl, diethylsilyl, dipropylsilyl, two Isopropylsilyl, dibutylsilyl, diisobutylsilyl, di-sec-butylsilyl, di-tert-butylsilyl, trimethylsilyl, triethylsilyl, tripropylsilyl, triis
• the term "3-11 membered heterocycloalkyl” refers to a 3-11 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O, S, Se, wherein each cycloalkane
• the ring system of the group can be monocyclic or polycyclic, including (but not limited to) the following groups: tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, tetrahydrothienyl, piperidinyl, aza Cyclobutyl, azepanyl, morpholinyl, or similar groups.
• the term “3-15 membered heterocycloalkyl” has a similar meaning.
• the term "3-11 membered heterocycloalkyl” is a monovalent group, and the term “3-11 membered heterocycloalkylene” has a similar meaning but is a divalent group.
• the terms "5-10 membered aromatic ring” or “5-10 membered aryl group” have the same meaning, and are preferably “C6-C10 aryl group”.
• C6-C10 aryl group refers to an aromatic ring group having 6 to 10 carbon atoms that does not contain heteroatoms in the ring, such as phenyl, naphthyl, and the like.
• the term "5-10 membered aromatic heterocyclic ring” or “5-10 membered heteroaryl group” has the same meaning and refers to a heteroaromatic group containing one to more heteroatoms, and a heteroaryl ring
• the shape system can be monocyclic or polycyclic.
• C3-C10 heteroaryl refers to an aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen and selenium and 3-10 carbon atoms.
• Non-limiting examples include: furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like.
• the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, and the ring connected to the parent structure is a heteroaryl ring.
• Heteroaryl groups can be optionally substituted or unsubstituted.
• halo refers to substitution by halogen.
• substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
• the specific substituents are the substituents correspondingly described in the foregoing, or the substituents appearing in each embodiment.
• a substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituent may be the same or different in each position.
• substituents contemplated by the present invention are those that are stable or chemically achievable.
• the substituents such as (but not limited to): halogen, hydroxyl, carboxy (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-to 12-membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C1-C6 alkoxy group, C1-C10 sulfonyl group, etc.
• the term "plurality” means 2, 3, 4, 5 independently.
• the chiral carbon atom of the compound may optionally be R configuration or S configuration, or a mixture of R configuration and S configuration.
• the structural formula described in the present invention is intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers): for example, containing asymmetric centers
• the R and S configurations, the (Z), (E) isomers and the (Z), (E) conformational isomers of the double bond Therefore, the single stereochemical isomers of the compounds of the present invention or their enantiomers Mixtures of isomers, diastereomers or geometric isomers (or conformational isomers) all fall within the scope of the present invention.
• tautomers means that structural isomers with different energies can exceed the low energy barrier to convert into each other.
• proton tautomers ie, proton transfer
• interconversion through proton transfer such as 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole
• Valence tautomers include interconversion through some bond-forming electron recombination.
• the present invention provides a compound represented by formula (I) or its stereoisomer, geometric isomer, tautomer, its pharmaceutically acceptable salt, its prodrug, its hydrate or solvate Things,
• each group is defined as described above.
• the compound is selected from the compounds listed in Table 1.
• the term "pharmaceutically acceptable salt” refers to a salt formed by a compound of the present invention and an acid or base suitable for use as a medicine.
• Pharmaceutically acceptable salts include inorganic salts and organic salts.
• a preferred class of salts are the salts of the compounds of this invention with acids.
• Acids suitable for salt formation include, but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and other organic acids; and Amino acids such as amino acid, phenylalanine, aspartic acid and glutamic acid.
• a base such as alkali metal salt (such as sodium or potassium salt), alkaline earth metal salt (such as magnesium salt or calcium salt), ammonium salt (such as lower alkanolammonium Salt and other pharmaceutically acceptable amine salts), such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tert-butyl Amine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.
• alkali metal salt such as sodium or potassium salt
• alkaline earth metal salt such as magnesium salt or calcium salt
• ammonium salt such as lower alkanolammonium Salt and other pharmaceutically acceptable amine salts
• methylamine salt such as sodium or potassium salt
• alkaline earth metal salt such as magnesium salt or calcium
• solvate refers to a complex in which the compound of the present invention coordinates with solvent molecules to form a specific ratio.
• “Hydrate” refers to a complex formed by coordination of the compound of the present invention with water.
• prodrug includes biologically active or inactive itself, and when taken by a proper method, it undergoes metabolism or chemical reaction in the human body to convert it into a class of compounds of formula (I), or A salt or solution composed of a compound of formula (I).
• the prodrugs include (but are not limited to) carboxylic acid esters, carbonate esters, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, and azo compounds of the compound , Phosphoramide, glucoside, ether, acetal and other forms.
• reaction is carried out in a solvent suitable for the reagents, and the materials used are suitable for the transformation being performed.
• solvent suitable for the reagents and the materials used are suitable for the transformation being performed.
• all the proposed reaction conditions including the choice of solvent, reaction atmosphere, reaction temperature, experiment duration, and post-treatment procedures, are selected to be used by those skilled in the field of organic synthesis. Easily recognized conditions that are standard for this reaction.
• the preparation process of the compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased through commercial channels unless otherwise specified.
• T, U, Q, V1, V2, V3, V4, and Z are defined as above.
• the compound of the present invention has excellent kinase inhibitory activity, especially Axl and c-Met kinase inhibitory activity, the compound of the present invention and various crystal forms thereof, and pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof
• Drugs and pharmaceutical compositions containing the compounds of the present invention as the main active ingredients can be used to treat, prevent and alleviate diseases related to the activity or expression of kinases, especially Axl and/or c-Met.
• the compounds of the present invention can be used to treat the following diseases: cancer; the cancers include chronic myelogenous leukemia, chronic myelogenous proliferative disease, lung cancer, skin cancer, prostate cancer, esophageal cancer, ovarian cancer, pancreatic cancer, gastric cancer , Liver cancer, thyroid cancer, kidney cancer, glioblastoma, malignant glioma, breast cancer, acute myeloid leukemia, colorectal cancer, uterine cancer, cervical cancer, malignant glioma, eye pigment melanoma, Osteosarcoma, soft tissue sarcoma, glioma, melanoma, head and neck cancer, bladder cancer, cholangiocarcinoma, nasopharyngeal carcinoma, synovial sarcoma, rhabdomyosarcoma, fibrosarcoma, leiomyosarcoma, myeloma, and lymphoma.
• cancer include chronic mye
• the pharmaceutical composition of the present invention contains the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
• the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
• the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per agent, more preferably, 50-200 mg of the compound of the present invention per agent.
• the "one dose" is a capsule or tablet.
• “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
• pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
• Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
• vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
• polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
• emulsifiers such as Tween
• wetting agents such as sodium lauryl sulfate
• coloring agents such as sodium lauryl sulfate
• flavoring agents such as pepperminophen, sorbitol, etc.
• antioxidants
• the pharmaceutical composition is injection, capsule, tablet, pill, powder or granule.
• the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited.
• Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration .
• Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
• the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycty
• Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into a microcapsule form with one or more of the above-mentioned excipients.
• Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
• the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
• composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
• adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
• the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
• suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
• composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
• Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
• the dosage forms of the compound of the present invention for topical administration include ointments, powders, patches, sprays and inhalants.
• the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
• the compound of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-tumor drugs).
• the treatment method of the present invention can be administered alone or in combination with other treatment means or therapeutic drugs.
• a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment.
• the dosage is usually 1 to 2000 mg, preferably 5 to 500 mg.
• the specific dosage should also consider factors such as the route of administration and the patient's health status, which are all within the skill range of a skilled physician.
• the present invention has the following main advantages:
• the compound of the present invention can effectively inhibit the activities of Axl enzyme and c-Met enzyme;
• the compound of the present invention can effectively inhibit the proliferation activity of Axl-dependent cell lines and c-Met-dependent cell lines.
• Step 2 Preparation of ethyl 3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
• Step 3 Preparation of 3-(4-fluorophenyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester
• Step 4 Preparation of 3-(4-fluorophenyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• the reaction solution was poured into water, extracted with ethyl acetate four times, the ethyl acetate layers were combined, washed with saturated sodium chloride water five times, and finally the organic phase was dried over anhydrous sodium sulfate and concentrated.
• the crude product was 1.27g.
• reaction solution was poured into water, extracted with ethyl acetate twice, the ethyl acetate layers were combined, washed with saturated sodium chloride water, and finally the organic phase was dried over anhydrous sodium sulfate. Concentrated and purified by column chromatography to obtain the product, yield: 643 mg, yield: 100%.
• Step 7 Preparation of N-(3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(4- (Fluorophenyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 2 Preparation of 3-(4-fluorophenyl)-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Step 3 Preparation of 1-ethyl-N-(3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)- 3-(4-Fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester
• Step 2 Preparation of 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Step 3 Preparation of N-(3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(4- (Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 3-(4-fluorophenyl)-1-propyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester
• Step 2 Preparation of 3-(4-fluorophenyl)-1-propyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Step 3 Preparation of N-(3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(4- (Fluorophenyl)-1-propyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 1-cyclopropylmethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester
• Step 2 Preparation of 1-cyclopropylmethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Step 3 Preparation of 1-(cyclopropylmethyl)-N-(3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy )Phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 1-(cyclopentylmethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester
• Step 2 Preparation of 1-(cyclopentylmethyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Step 3 Preparation of 1-(cyclopentylmethyl)-N-(3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy )Phenyl)-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 1-allyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester
• Step 2 Preparation of 1-allyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Ethyl 1-allyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (159mg, 0.5mmol) was dissolved in Tetrahydrofuran, 2mL of 0.5mol/L sodium hydroxide aqueous solution was added dropwise with stirring, and then the stirring was continued. After 20 minutes, the stirring was stopped, the reaction mixture was used ethyl acetate-water solution, the aqueous layer was retained and washed three times with ethyl acetate. The pH of the aqueous layer was adjusted to about 2, and then extracted with dichloromethane three times, combined, dried over anhydrous sodium sulfate, concentrated, and then subjected to column chromatography to obtain the product, the yield: 53%.
• Step 3 Preparation of 1-allyl-N-(3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl) -3-(4-Fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 3-(4-fluorophenyl)-1-propargyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester
• Step 2 Preparation of 3-(4-fluorophenyl)-1-propargyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Step 3 Preparation of N-(3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(4- (Fluorophenyl)-2,4-dioxo-1-propargyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of ethyl 3-(4-fluorophenyl)-1-(2-hydroxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
• Step 2 Preparation Preparation of 3-(4-fluorophenyl)-1-(2-hydroxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Step 3 N-(3-Fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(4-fluoro Phenyl)-1-(2-hydroxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 3-(4-fluorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester
• Step 2 Preparation of 3-(4-fluorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Step 3 Preparation of N-(3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(4- Fluorophenyl)-1-(2-methoxyethyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 1-cyclopentyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester
• Step 2 Preparation of 1-cyclopentyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Step 3 1-Cyclopentyl-N-(3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)- 3-(4-Fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 1,3-bis(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester
• Step 2 Preparation of 1,3-bis(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Step 3 Preparation of N-(3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-1,3-di (4-Fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Step 2 N-(3-Fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-1-isopropyl- 2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 3-(4-chlorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Step 2 3-(4-chlorophenyl)-N-(3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy) (Phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 1-isopropyl-2,4-dioxo-3-p-tolyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Step 2 N-(3-Fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-1-isopropyl- 2,4-dioxo-3-p-tolyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 1-isopropyl-3-(4-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Step 2 N-(3-Fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-1-isopropyl- 3-(4-Methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 3-(3-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Step 2 N-(3-Fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(3-fluoro (Phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Step 2 N-(3-Fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-1-isopropyl- 2,4-dioxo-3-(2-fluorophenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 3-(3,4-difluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Step 2 3-(3,4-Difluorophenyl)-N-(3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl) (Oxy)phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 1-isopropyl-2,4-dioxo-3-(pyridin-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Step 2 N-(3-Fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-1-isopropyl- 2,4-dioxo-3-(pyridin-4-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 1-isopropyl-3-(1-methyl-1H-pyrazol-4-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5- Formic acid
• Step 2 N-(3-Fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-1-isopropyl- 3-(1-methyl-1H-pyrazol-4-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 1-isopropyl-3-((1R,4R)-4-methylcyclohexyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Step 2 N-(3-Fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-1-isopropyl- 3-((1R,4R)-4-methylcyclohexyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 2 4-(4-Fluorophenyl)-5-oxo-3-thio-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid ethyl ester
• Step 3 Preparation of 4-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid ethyl ester
• Step 4 Preparation of 4-(4-fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6- Ethyl formate
• Step 5 Preparation of 4-(4-fluorophenyl)-2-isopropyl-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6- Formic acid
• the 4-amino-2-fluorophenol was replaced with p-aminophenol, and the remaining required raw materials, reagents and preparation methods were the same as those shown in step 5 to step 6 in Example 1.
• the product was obtained with a yield rate of 89%.
• Step 7 Preparation of 4-(4-fluorophenyl)-2-isopropyl-N-(4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl) (Oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide
• Step 2 Preparation of N-(2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(4- (Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 2 Preparation of N-(2,3-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3- (4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 2 Preparation of N-(3,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3- (4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 2 Preparation of N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3- (4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 2 Preparation of 3-(4-fluorophenyl)-1-isopropyl-N-(3-methyl-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridine -4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 2 Preparation of N-(4-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)- 1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole- 1-yl)propan-2-ol
• Step 2 Preparation of 1-(4-(4-(4-amino-2-fluorophenoxy)pyridin-2-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol
• Step 3 Preparation of N-(3-fluoro-4-((2-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy )Phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 4 Preparation of N-(4-((2-(1-cyclopropyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4 -Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl -1-ol
• Step 2 Preparation of methanesulfonic acid 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1- Yl) ethyl ester
• Step 3 Preparation of 1-methyl-4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- Pyrazol-1-yl)ethyl)piperazine
• the methanesulfonic acid 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl The ester (250 mg, 0.79 mmol) and N-methylpiperazine (875 ⁇ L, 7.9 mmol) were added to 1.5 mL of N,N-dimethylformamide and reacted at 50°C. After 2.5 hours, the heating was stopped and the temperature was lowered to room temperature. The obtained product is directly thrown into the next step without purification.
• Step 4 Preparation of 3-fluoro-4-((2-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)pyridin-4-yl )Oxy)aniline
• Step 5 Preparation of N-(3-fluoro-4-((2-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)pyridine- 4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-methyl Amide
• Step 2 Preparation of N-(4-((2-(1,3-dimethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-3-fluorophenyl)-3- (4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 3 Preparation of 3-(4-fluorophenyl)-1-isopropyl-N-(4-((3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl) (Oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• reaction solution was separated with ethyl acetate-saturated sodium carbonate aqueous solution.
• the organic layer was dried over anhydrous sodium sulfate and concentrated, and then purified by column chromatography to obtain the product. Yield: 142mg, Yield: 42%.
• Step 3 Preparation of N-(4-(2-amino-5-(3,4-dimethoxyphenyl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl )-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 3-(4-amino-2-fluorophenyl)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-ylamine
• Step 2 Preparation of N-(4-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4- (Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of (R)-2-(4-((1,4-dioxane-2-yl)methoxy)-3-methoxyphenyl)-4,4,5,5- Tetramethyl-1,3,2-dioxaborolane
• Step 2 Preparation of (R)-5-(4-((1,4-dioxan-2-yl)methoxy)-3-methoxyphenyl)-3-(4-amino-2 -Fluorophenyl)pyridin-2-ylamine
• Step 3 Preparation of (R)-N-(4-(5-(4-((1,4-dioxan-2-yl)methoxy)-3-methoxyphenyl)-2- Aminopyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5-formamide
• Step 2 Preparation of N-(4-(2-amino-5-(1H-pyrazol-4-yl)pyridin-3-yl)-3-fluorophenyl)-3-(4-fluorophenyl)- 1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 3 Preparation of N-(4-((1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluorophenyl)-1 -Isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 3 Preparation of N-(4-((3-bromo-1H-pyrazolo[2,3-b]pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4-fluoro (Phenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 4-chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine
• reaction solution was poured into water, extracted with ethyl acetate 3 times, the ethyl acetate layers were combined, washed 5 times with saturated aqueous sodium chloride solution, concentrated, and then purified by column chromatography. Yield: 2.4g, Yield: 81%.
• Step 3 Preparation of 3-fluoro-4-((5-phenyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine -4-yl)oxy)aniline
• reaction solution was separated with ethyl acetate-saturated ammonium chloride aqueous solution, and the organic layer was dried over anhydrous sodium sulfate and concentrated, and then purified by column chromatography to obtain the product, yield: 348 mg, yield: 77%.
• Step 4 Preparation of N-(3-fluoro-4-((5-phenyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3- d)Pyrimidine-4-yl)oxy)phenyl)-3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine -5-formamide
• Step 1 Preparation of 3,3-dibromo-4-(2-fluoro-4-nitrophenoxy)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one
• Step 3 Preparation of N-(3-fluoro-4-((2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)phenyl) -3-(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of tert-butyl (3-fluoro-4-hydroxyphenyl) carbamate
• Step 2 Preparation of tert-butyl (4-((2-amino-3-nitropyridin-4-yl)oxy)-3-fluorophenyl)carbamate
• Step 3 Preparation of tert-butyl (4-((2,3-diaminopyridin-4-yl)oxy)-3-fluorophenyl)carbamate
• Step 4 Preparation of tert-butyl (3-fluoro-4-((3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yl)oxy)phenyl)carbamate ester
• Step 6 Preparation of N-(3-fluoro-4-((3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yl)oxy)phenyl)-3 -(4-Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 3 Preparation of 8-bromo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylic acid tert-butyl ester
• Step 4 Preparation of 8-(4-(((benzyloxy)formyl)amino)phenoxy)-2,3-dihydro-4H-pyrido[3,2-b][1,4] Tert-Butyl oxazine-4-carboxylate
• Step 5 Preparation of 8-(4-aminophenoxy)-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazine-4-carboxylic acid tert-butyl ester
• Step 7 Preparation of 4-(5-(2-fluoro-4-nitrophenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester
• Step 8 Preparation of 4-(5-(4-amino-2-fluorophenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester
• Step 9 Preparation of 4-(5-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetra Hydropyrimidine-5-formylamino)phenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester
• reaction solution was carefully poured into a saturated sodium bicarbonate aqueous solution, extracted twice with ethyl acetate, the ethyl acetate layers were combined, and washed once with a saturated sodium chloride aqueous solution.
• the ethyl acetate layer was concentrated and purified by column chromatography to obtain the product, yield: 10.8 mg, yield: 50%.
• Step 2 Preparation of tert-butyl 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate
• Step 3 Preparation of 4-(4-amino-2-fluorophenoxy)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester
• Step 4 Preparation of 4-(2-fluoro-4-(3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine- 5-carboxamido)phenoxy)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester
• Step 5 Preparation of N-(4-((2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy)-3-fluorophenyl)-3-(4 -Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 3-(4-fluorophenyl)-2,4-dioxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4- Tetrahydropyrimidine-5-ethyl carboxylate
• Step 2 Preparation of 3-(4-fluorophenyl)-2,4-dioxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4- Tetrahydropyrimidine-5-carboxylic acid
• Step 3 Preparation of 3-(4-fluorophenyl)-N-(4-((3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl) -2,4-dioxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 1 Preparation of 3-(4-fluorophenyl)-1-(3-methoxypropyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester ester
• Step 2 Preparation of 3-(4-fluorophenyl)-1-(3-methoxypropyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid
• Step 3 Preparation of N-(3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(4- Fluorophenyl)-1-(3-methoxypropyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 2 Preparation of N-(3-chloro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(4- (Fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Step 2 Preparation of 3-(4-fluorophenyl)-1-isopropyl-N-(3-methoxy-4-((2-(1-methyl-1H-pyrazol-4-yl) (Pyridin-4-yl)oxy)phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxamide
• Example 59 Effect of compound molecular level on kinase activity
• T-PBS potential-free PBS containing 0.1% Tween-20, 200 ⁇ L/well
• 50mM MgCl 2 50mM MgCl 2 , 0.5mM MnCl 2 , 0.2mM Na 3 VO 4 , 1mM DTT
• 50mM MgCl 2 50mM MgCl 2 , 0.5mM MnCl 2 , 0.2mM Na 3 VO 4 , 1mM DTT
• antibody PY99 diluent (antibody is diluted 1:500 with T-PBS containing BSA 5mg/mL), 100 ⁇ L/well, shake at 37°C for 0.5 hour. Discard the liquid in the well and wash the plate three times with T-PBS.
• the IC 50 value was obtained by the four-parameter regression using the software that came with the microplate reader.
• a means IC 50 is less than ( ⁇ )10nM
• IC 50 is less than ( ⁇ ) 100nM and greater than (>) 10nM
• C means IC 50 is greater than (>)100nM
• Example 60 Compound cellular level activity
• the TEL-AXL fusion protein in BaF3-TEL-AXL cells is expressed in the cytoplasm, which is an Axl-dependent sensitive cell line; BaF3 background cells do not have the ability to proliferate and survive, and only with IL-3 can they proliferate and survive.
• the compound's inhibitory effect on the proliferation of BaF3-TEL-AXL cells was tested with CCK-8 Cell Counting Kit (Dojindo).
• the specific steps are as follows: BaF3-TEL-AXL cells in the logarithmic growth phase are seeded into 96-well culture plates at an appropriate density. After overnight culture, different concentrations of compounds are added for 72 hours, and a solvent control group (negative control) is set. . After the compound acts on the cells for 72 hours, the effect of the compound on cell proliferation is tested by using the CCK-8 Cell Counting Kit (Dojindo). Add 10 ⁇ L CCK-8 reagent to each well and place it in a 37°C incubator for 2-4 hours. Use the full-wavelength microplate microplate reader SpectraMax 190 to read, and the measured wavelength is 450nm.
• Inhibition rate (%) (OD control hole-OD dosing hole)/OD control hole ⁇ 100%
• the IC 50 value was obtained by the four-parameter regression using the software that came with the microplate reader.
• MKN45 is a gastric cancer cell line. Amplification of the MET gene leads to continuous Met activation, which is a c-Met-dependent tumor cell line.
• MKN45 cells in the logarithmic growth phase are seeded into 96-well culture plates at an appropriate density, and after overnight culture, different concentrations of compounds are added for 72 hours, with three replicate wells for each concentration, and a solvent control group is set (Negative control).
• Inhibition rate (%) (OD control hole-OD dosing hole)/OD control hole ⁇ 100%
• the IC 50 value was obtained by the four-parameter regression using the software that came with the microplate reader.
• the compound of the present invention has a significant inhibitory effect on the proliferation activity of Axl-dependent cell lines and c-Met-dependent cell lines.

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