WO2019154132A1 - 脲取代的芳环连二噁烷并喹啉类化合物及其制备方法与应用 - Google Patents
脲取代的芳环连二噁烷并喹啉类化合物及其制备方法与应用 Download PDFInfo
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- WO2019154132A1 WO2019154132A1 PCT/CN2019/073259 CN2019073259W WO2019154132A1 WO 2019154132 A1 WO2019154132 A1 WO 2019154132A1 CN 2019073259 W CN2019073259 W CN 2019073259W WO 2019154132 A1 WO2019154132 A1 WO 2019154132A1
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- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- 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
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
Definitions
- the invention relates to a urea-substituted aromatic ring dioxane quinolinol compound, a preparation method and application thereof, and belongs to the technical field of medicinal chemistry.
- Angiogenesis and angiogenesis must have the presence of VEGF (vascular endothelial growth factor).
- VEGF vascular endothelial growth factor
- Angiogenesis is the differentiation of primitive progenitor cells into endothelial cells.
- Cells; angiogenesis is the growth of new capillaries from existing blood vessels in the form of budding.
- Normal adult mammals have only one form of angiogenesis, namely angiogenesis, local basement membrane breakdown around endothelial cells, and endothelial cell invasion into the stroma. This invasion is accompanied by the proliferation of endothelial cells, which form a migrating column of endothelial cells that change shape and form a ring shape, and a new vascular lumen is formed.
- VEGF is also essential for angiogenesis of tumor tissues, and vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor receptor 2 (VEGFR-2) signaling pathways play the most important role in affecting the proliferation of tumor tissue endothelial cells. Survival, budding, migration, affecting the permeability of tumor blood vessels. In the absence of VEGF protein-stimulated endothelial cells, autocrine VEGF proteins can also be relied upon to ensure their integrity and survival. Vascular endothelial growth factor C VEGFR-C/vascular endothelial growth factor D VEGF-D mediates lymphangiogenesis in tumor tissues and promotes metastasis of tumor tissues. Therefore, drugs targeting angiogenesis have become a hot spot for drug development.
- VEGFR-C vascular endothelial growth factor A
- VEGFR-D vascular endothelial growth factor receptor 2
- Bevacizumab is a 93% humanized murine VEGF monoclonal antibody that binds to all subtypes of human VEGF A, blocks the VEGF/VEGFR signaling pathway, and inhibits tumor angiogenesis.
- bevacizumab (trade name Avastin) was marketed in the United States with FDA approval and used in combination with chemotherapeutic drugs as the first line of anti-tumor angiogenesis drugs for the treatment of metastatic colorectal cancer.
- Bevacizumab can improve the abnormalities of tumor blood vessels, making them normalized and helping chemotherapy drugs reach tumor tissues. Due to the mechanism of apoptosis induced by radiotherapy and chemotherapy, the hypoxic partial pressure in tumor tissues induces the expression of VEGF, and the combination of bevacizumab and chemoradiotherapy drugs effectively prevents such secondary reactions.
- targeting VEGFR-2/KDR includes nine drugs: sorafenib, sunitinib, pazopanib, axitinib, vandetanib, regorafenib, lenvatinib, nintedanib and silidini Cloth (AZD2171), which has been approved by the FDA for the treatment of cancer.
- Lenvatinib trade name Lenvima
- Lenvima is a thyroid cancer drug developed by Eisai Corporation of Japan. It has specific inhibitory effects on VEGFR-1, VEGFR-2 and VEGFR-3, and also acts on PDGFR ⁇ and FGFR-1. It is a class of TKIs that selectively target multiple receptors. Similar to the mechanism of action of sorafenib, it inhibits neovascularization by inhibiting VEGFR-1, 2, 3 and PDGFR, and directly inhibits tumor cell proliferation by inhibiting FGFR-1. In 2015, the FDA approved Lenvatinib for the treatment of thyroid cancer.
- B-RAF is a kind of tyrosine kinase receptor, and its abnormal activation plays an important role in the occurrence and development of various malignant tumors. In most cases, abnormal activation of B-RAF is caused by genetic mutations. B-RAF belongs to the proto-oncogene, and studies have shown that more than 30 B-RAF gene mutations are associated with cancer, especially the V600E gene mutation. Mutations in the B-RAF gene usually cause two diseases. First, mutations can be inherited and cause birth defects. Second, as oncogenes, mutations inherited by genetics can lead to cancer in later life. B-RAF mutations have been found in many cancer tissues, including melanoma, colon cancer, thyroid cancer, non-small cell lung cancer, and glioma.
- Sorafenib trade name Nexavar, is a drug developed by Onyx Pharmaceuticals of the United States and Bayer AG of Germany, targeting the RAF/MEK/ERK signaling pathway, which mainly inhibits C-RAF and B-RAF, and also inhibits VEGFR-2.
- the activities of VEGFR-3, PDGFR- ⁇ , Flt-3, and c-Kit receptors can effectively inhibit tumor cell proliferation and angiogenesis in preclinical experiments.
- sorafenib significantly increased the overall survival of the patient.
- sorafenib was approved by the FDA as a drug for the treatment of advanced renal cell carcinoma.
- RET is also a type of transmembrane receptor tyrosine kinase that is essential for the normal development of tissues such as the brain, nervous system, thyroid and lung. Activating mutations and oncogenic fusion of receptor tyrosine kinases have been found in a variety of tumor types, including thyroid, lung, breast and colon cancers. At present, there is no marketed drug with RET as a specific target, so the development of a small molecule inhibitor against RET has extremely high application value.
- the present invention provides a compound of formula (I), and pharmaceutically acceptable salts, isomers, hydrates, solvates, or prodrugs thereof,
- X is O or NH
- Y is CH
- R 1 is H, C 1 -C 9 alkyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocyclic, C 3 -C 7 cycloalkyl substituted C 1 -C 6 alkyl a 4-7 membered heterocyclic substituted C 1 -C 6 alkyl group, substituted C 1 -C 9 alkyl group, the substituent in the substituted C 1 -C 9 alkyl group is a hydroxyl group, C 1 -C One or more of a 6 -alkoxy group, a C 1 -C 6 alkylthio group, a mono- or bi-C 1 -C 6 alkyl-substituted amino group or an unsubstituted amino group,
- the above 4-7 membered heterocyclic group is a 4-7 membered heterocyclic group having 1 to 2 atoms selected from N, O and S, and the 4-7 membered heterocyclic group is not substituted or C 1 -C 6
- R 2 is H or halogen
- R 3 is H or halogen
- R 4 is H or halogen
- R 5 is H, C 1 -C 9 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl substituted C 1 -C 6 alkyl, substituted or unsubstituted aryl Or a heteroaryl group, the substituted aryl or heteroaryl substituent being C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, mono or di C 1 One or more of -C 3 alkyl substituted amino or unsubstituted amino, halogen, trifluoromethyl, aryloxy or methylsulfonyl;
- the heteroaryl group is a monocyclic or bicyclic group having 5 to 10 ring atoms, and the ring contains 1-3 atoms selected from N, O, and S.
- R 1 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 5-6 membered heterocyclyl, C 3 -C 6 cycloalkyl substituted C 1 a C 3 alkyl group, a 5-6 membered heterocyclic group-substituted C 1 -C 3 alkyl group, a substituted C 1 -C 6 alkyl group, wherein the substituent in the substituted C 1 -C 6 alkyl group is a hydroxyl group, One or more of a C 1 -C 3 alkoxy group, a C 1 -C 3 alkylthio group, a mono- or bi-C 1 -C 3 alkyl-substituted amino group or an unsubstituted amino group,
- the above 5- to 6-membered heterocyclic group is a 5-6 membered heterocyclic group having 1 to 2 atoms selected from N, O and S, and the 5-6 membered heterocyclic group is not substituted or C 1 -C 3
- the alkyl group, C 1 -C 3 acyl group is substituted or oxidized by one to two oxygen atoms.
- R 1 is selected from the group consisting of: H, methyl, ethyl, propyl, isopropyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, Methoxyhexyl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydropyrrole-1-ethyl, tetrahydropyrrole-1-propyl, piperidin-1-ethyl, piperidine Pyridin-1-propyl, piperazine-1-ethyl, piperazine-1-propyl, morpholin-4-ethyl, morpholin-4-propyl, methylpiperazine-4-ethyl, A Piperazine-4-propyl, N-formylpiperazine-4-ethyl, N-formylpiperazine-4-propyl, N-acetylpiperaz
- R 1 is selected from the group consisting of: butyl, isobutyl, pentyl, isopentyl, hexyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, ring Butylethyl, cyclobutylpropyl, 4,4-dimethylpiperidine-1-ethyl, 4,4-dimethylpiperidine-1-propyl, dimethylaminopentyl, dimethylamino Hexyl, oxetane-3-yl.
- the halogen of R 2 , R 3 , R 4 is F, Cl or Br.
- R 5 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl substituted C 1 -C 3 alkyl, substituted Or an unsubstituted aryl or heteroaryl group, the substituted aryl or heteroaryl substituent being a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a C 1 -C 3 group One or more of an alkylthio group, a mono- or di-C 1 -C 3 alkyl-substituted amino group or an unsubstituted amino group, a halogen, a trifluoromethyl group, an aryloxy group or a methylsulfone group;
- the heteroaryl group is a monocyclic or bicyclic group having 5 to 10 ring atoms, and the ring contains 1-2 atoms selected from N, O, and S.
- R 5 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl substituted C 1 -C 3 alkyl, substituted or non.
- a substituted phenyl, naphthyl or heteroaryl group wherein the substituent of the phenyl, naphthyl or heteroaryl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy Base, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, fluoro, chloro, bromo, trifluoromethyl One or more of a phenoxy group or a methylsulfone group;
- the heteroaryl group is selected from the group consisting of pyridine, pyrimidine, quinoline, quinazoline, oxazole, isoxazole, thiazole, thiadiazole, pyrazole, imidazole, pyrrole.
- the R 5 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-phenoxyphenyl, 3-(Methylsulfonyl)phenyl, 4-(methylsulfonyl)phenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 2,4 -dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 2-fluoro
- the R 5 is selected from the group consisting of: butyl, isobutyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methyl-5- ( Trifluoromethyl)phenyl, 2-methyl-4-(trifluoromethyl)phenyl, 3-methyl-4-(trifluoromethyl)phenyl, 3-methyl-5-(trifluoro Methyl)phenyl, 2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl, 3-chloro-4-methylphenyl.
- the present invention relates to a compound of the formula (I), a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof:
- X is O or NH
- Y is CH
- R 1 is a substituent consisting of 1 to 3 selected from a C 1 -C 3 acyl group, a halogen, a trifluoromethyl group, a cyano group, a -CONH 2 , a -NR a R b or a 4-7 membered heteroalicyclic group.
- the 4-7 membered heteroalicyclic group being a 4-7 membered heteroalicyclic group having 1-2 atoms selected from N, O, and S as a ring atom, and
- the 4-7 membered heteroalicyclic group is substituted with 1 to 3 substituents selected from the group consisting of halogen, C 1 -C 3 alkyl, hydroxy, -NH 2 , C 1 -C 3 acyl group,
- R a and R b are each independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy substituted C 1 -C 6 alkyl, C 1 -C a 3 -alkylthio substituted C 1 -C 6 alkyl group, a mono or di C 1 -C 3 alkyl substituted amino substituted C 1 -C 6 alkyl group, or an unsubstituted amino substituted C 1 -C 6 alkyl group;
- R 2 , R 3 , and R 4 are each independently H or halogen
- R 5 is H, C 1 -C 9 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl substituted C 1 -C 6 alkyl, 1-3 substituents -B substituted or unsubstituted aryl or heteroaryl, the substituents -B are each independently hydroxy, cyano, C 1 -C. 3 alkyl, C 1 -C. 3 alkoxy, C 1 -C 3 alkylthio, mono or di-substituted C 1 -C 3 amino or substituted amino, halo, trifluoromethyl, methylsulfonyl, or an aryloxy group;
- the heteroaryl group is a monocyclic or bicyclic group having 5 to 10 ring atoms, and the ring contains 1-3 atoms selected from N, O, and S.
- R 1 is C substituted by 1 to 3 substituents selected from -F, trifluoromethyl, cyano, -CONH 2 , -NR a R b or 4-7 membered heteroalicyclic group a 1- to 6- membered heteroalicyclic group, which is a 4-7 membered heteroalicyclic group having 1-2 atoms selected from N, O, and S as a ring atom, and the 4
- the -7 membered heteroalicyclic group is substituted by 1 to 3 substituents selected from the group consisting of -F, C 1 -C 3 alkyl, hydroxy, -NH 2 , C 1 -C 3 acyl,
- R a and R b are each independently H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy substituted C 1 -C 3 alkyl, C 1 -C 3 alkylthio substituted C 1 -C 3 alkyl, mono or di C 1 -C 3 alkyl substituted amino substituted C 1 -C 3 alkyl, or unsubstituted amino substituted C 1 -C 3 alkyl.
- R 5 is H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyl substituted C 1 -C 3 alkyl, 1-3 substituent-B a substituted or unsubstituted phenyl, naphthyl or heteroaryl group, wherein the substituents -B are each independently methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy , isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, fluoro, chloro, bromo, trifluoromethyl, Phenoxy or methylsulfonyl;
- the heteroaryl group is selected from the group consisting of pyridine, pyrimidine, quinoline, quinazoline, oxazole, isoxazole, thiazole, thiadiazole, pyrazole, imidazole, pyrrole.
- R 1 is selected from the group consisting of cyanomethyl, cyanoethyl, cyanopropyl, -CH 2 CONH 2 , -CH 2 CF 3 , 4-methyl-4-hydroxypiperidine-1-propyl, 4-methyl-4-hydroxypiperidine-1-ethyl, 4-methyl-4-aminopiperidine-1-propyl, 4-methyl- 4-aminopiperidine-1-ethyl, hydroxyethylaminoethyl, hydroxypropylaminoethyl, hydroxyethylaminopropyl, methoxyethylaminoethyl, methoxypropylaminoethyl, A Oxyethylaminopropyl, N-methyl-N-hydroxyethylaminoethyl, N-methyl-N-hydroxypropylaminoethyl, N-methyl-N-hydroxyethylaminopropyl, N-methyl-N-methoxyethylamin
- R 5 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzene Base, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-phenoxybenzene , 3-(methylsulfonyl)phenyl, 4-(methylsulfonyl)phenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 2 , 4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2-fluoro-4-(trifluoromethyl)pheny
- the present invention also provides a salt of the compound of the formula (I), wherein the salt is an acidic/anionic salt or a basic/cationic salt; the pharmaceutically acceptable acidic/anionic salt is usually in the form of a base Nitrogen is protonated by inorganic or organic acids.
- organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, Succinic acid, maleic acid, tartaric acid, malic acid, citric acid, fumaric acid, gluconic acid benzoic acid, mandelic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, oxalic acid, palmitic acid, 2-naphthalene Acid, p-toluenesulfonic acid, cyclohexylamine sulfonic acid, salicylic acid, hexanoic acid, trifluoroacetic acid.
- Pharmaceutically acceptable basic/cationic salts include, of course, not limited to aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium
- a process for the preparation of a compound of the formula (I), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof comprising II) reacting a compound with H 2 NR 5 to prepare a compound of formula (I), wherein X, Y, Z, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above,
- substituted includes complex substituents (e.g., phenyl, aryl, heteroalkyl, heteroaryl), suitably 1 to 5 substituents, preferably 1 to 3
- substituents e.g., phenyl, aryl, heteroalkyl, heteroaryl
- 1 to 5 substituents preferably 1 to 3
- alkyl including saturated straight chain, branched hydrocarbon groups
- C 1 -C 9 represents a carbon atom of the alkyl group having 1 to 9 carbon atoms
- C 1 -C 3 represents an alkyl group, for example.
- a carbon atom having 1 to 3 carbon atoms, for example, a C 1 -C 6 alkyl group includes a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tertiary group.
- alkoxy group is an alkyl-O- group formed by the linear or branched alkyl group described above and -O-.
- alkenyl and alkynyl groups include straight-chain, branched alkenyl or alkynyl groups.
- a cycloalkyl group means a cyclic group formed by a carbon atom.
- a C 3 -C 7 cycloalkyl group may include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like.
- aryl refers to an unsubstituted or substituted aryl group, such as phenyl, naphthyl, anthracenyl.
- Oxidation by one or two oxygen atoms means that a sulfur atom is oxidized by an oxygen atom to form a double bond between sulfur and oxygen, or is oxidized by two oxygen atoms to form sulfur and a double bond between two oxygen atoms.
- heterocyclyl as used herein, unless otherwise specified, represents an unsubstituted or substituted stable 3 to 8 membered monocyclic saturated ring system selected from carbon atoms and from N, O, S.
- heterocyclic rings include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperidine Pyridyl, piperazinyl, piperazinyl, piperidinyl, dioxetane, dioxetyltetrahydroimidazolyl, tetrahydrooxazolyl, thiomorpholine sulfoxide, thio Morpholine sulfone and oxadiazolyl.
- heteroaryl represents a stable 5 or 6 membered monocyclic aromatic ring system which is unsubstituted or substituted, and may also represent unsubstituted or substituted 9 or a 10-ring atomic benzene fused heteroaromatic ring system or a bicyclic heteroaromatic ring system consisting of a carbon atom and one or three heteroatoms selected from N, O, S, wherein the N, S heteroatoms can be Oxidation, N heteroatoms can also be quaternized.
- the heteroaryl group can be bonded to any hetero atom or carbon atom to form a stable structure.
- Heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, pyranyl, pyridyl, piperazinyl, pyrimidinyl, pyrazine, Pyridazinyl, pyrazolyl, thiadiazolyl, triazolyl, fluorenyl, azaindole, oxazolyl, azacarbazolyl, benzimidazolyl, benzofuranyl, benzothiophene Benzoisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adenyl, quinolinyl or isoquinoline base.
- carbonyl refers to a -C(O)- group.
- alkyl or aryl or any of their prefix radicals appear in the name of a substituent (eg, aralkyl, dialkylamine), it will be considered to contain the above “alkane” Those limitations given by “base” and “aryl”.
- base e.g., aralkyl, dialkylamine
- aryl e.g., aralkyl, dialkylamine
- the specified number of carbon atoms eg, C 1 -C 6
- the compounds, isomers, crystalline forms or prodrugs of Formula I, and pharmaceutically acceptable salts thereof may exist in both solvated and unsolvated forms.
- the solvated form can be in a water soluble form.
- the invention includes all such solvated and unsolvated forms.
- the compounds of the invention may have asymmetric carbon atoms which, depending on their physicochemical differences, may be separated by known techniques, such as by chromatography or fractional crystallization. Into a single diastereomer. Separation of the enantiomers can be carried out by first reacting the appropriate optically active compound, converting the enantiomeric mixture into a diastereomeric mixture, separating the diastereomers, and then separating the individual The enantiomers are converted (hydrolyzed) to the corresponding pure enantiomers. All such isomers, including mixtures of diastereomers and pure enantiomers, are considered to be part of this invention.
- the compound of the present invention as an active ingredient, and a method of preparing the same, are all contents of the present invention.
- the crystalline form of some of the compounds may exist as polycrystals, and such forms may also be included in the current invention.
- some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of the invention.
- the compounds of the invention may be used in the free form for treatment or, where appropriate, in the form of a pharmaceutically acceptable salt or other derivative for treatment.
- pharmaceutically acceptable salt refers to organic and inorganic salts of the compounds of the present invention which are suitable for use in humans and lower animals without undue toxicity, irritation, allergic response, etc., and have reasonable Benefit/risk ratio.
- Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art.
- the salt can be formed by reacting a compound of the invention with a suitable free base or acid.
- salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid,
- inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid
- salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, hydrogen sulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, citrate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerol phosphate, gluconic acid Salt, hemisulfate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, methane Sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, per-3-phenylpropionate, Phosphate, picrate, propionate
- Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Other pharmaceutically acceptable salts include suitable non-toxic ammonium, quaternary ammonium, and the use of such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.
- prodrug as used herein means that a compound can be converted into a compound of the formula (I) of the present invention in vivo. This transformation is affected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent compound in the blood or tissue.
- the pharmaceutical composition of the present invention comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, a kinase inhibitor (small molecule, polypeptide, antibody, etc.), an immunosuppressant, an anticancer drug, an antiviral agent, an antibiotic An additional agent of an inflammatory, antifungal, antibiotic or anti-vascular hyperproliferative compound; and any pharmaceutically acceptable carrier, adjuvant or excipient.
- a kinase inhibitor small molecule, polypeptide, antibody, etc.
- an immunosuppressant an anticancer drug
- an antiviral agent an antibiotic
- an additional agent of an inflammatory, antifungal, antibiotic or anti-vascular hyperproliferative compound an additional agent of an inflammatory, antifungal, antibiotic or anti-vascular hyperproliferative compound.
- the compounds of the invention may be used alone or in combination with one or more other compounds of the invention or with one or more other agents.
- the therapeutic agents can be formulated for simultaneous administration or sequentially at different times, or the therapeutic agents can be administered as a single composition.
- “combination therapy” is meant the use of a compound of the invention in combination with another agent in the form of co-administration of each agent or sequential administration of each agent, in either case, for the purpose Achieve the best results of the drug.
- Co-administration includes simultaneous delivery of the dosage form, as well as separate dosage forms for each compound.
- administration of the compounds of the invention can be used in conjunction with other therapies known in the art, for example, in the treatment of cancer using radiation therapy or cytostatic agents, cytotoxic agents, other anticancer agents, and the like to improve Cancer-like.
- the invention is not limited to the order of administration; the compounds of the invention may be administered previously, simultaneously, or after other anticancer or cytotoxic agents.
- one or more compounds or salts of the formula (I) as an active ingredient thereof can be intimately mixed with a pharmaceutical carrier, which is carried out according to a conventional pharmaceutical ingredient technique.
- the carrier can be used in a wide variety of forms depending on the form of preparation which is designed for different modes of administration (for example, oral or parenteral administration).
- Suitable pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and the British Pharmaceutical Society.
- the pharmaceutical composition of the present invention may have the following forms, for example, suitable for oral administration, such as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; for parenteral injections such as clear solutions, suspensions, Emulsion; or for topical use such as creams, creams; or as a suppository for rectal administration.
- the pharmaceutical ingredient may also be presented in unit dosage form for administration in a precise dosage.
- the pharmaceutical ingredient will include a conventional pharmaceutical carrier or excipient and a compound as an active ingredient prepared according to the present invention, and may also include other medical or pharmaceutical preparations, carriers, adjuvants, and the like.
- Therapeutic compounds can also be administered to mammals other than humans.
- the dosage of the drug to be administered to a mammal will depend on the species of the animal and its disease state or the disordered condition in which it is located.
- the therapeutic compound can be administered to the animal in the form of a capsule, a bolus, or a pill.
- the therapeutic compound can also be introduced into the animal by injection or infusion. We prepare these forms of the drug in a traditional manner consistent with veterinary practice standards.
- the pharmaceutical synthetic drug can be mixed with the animal feed and fed to the animal, so that the concentrated feed additive or premix can be prepared by mixing ordinary animal feed.
- the invention also encompasses the use of a compound of the invention, or a pharmaceutically acceptable derivative thereof, for the manufacture of a cancer (including non-solid tumors, solid tumors, primary or metastatic cancer, as indicated elsewhere herein and including cancer)
- a cancer including non-solid tumors, solid tumors, primary or metastatic cancer, as indicated elsewhere herein and including cancer
- An agent that is resistant or refractory to one or more other treatments, as well as other diseases including, but not limited to, fundus diseases, psoriasis, atheroma, pulmonary fibrosis, liver fibrosis, myelofibrosis, and the like .
- the cancer includes, but is not limited to, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, intrauterine Membrane cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, esophageal cancer, brain Any of tumor, B cell and T cell lymphoma, lymphoma, multiple myeloma, cholangiocarcinoma, and cholangiocarcinoma.
- the invention also provides methods of preparing the corresponding compounds, which can be prepared using a variety of synthetic methods, including the methods described below.
- the compound of the present invention or a pharmaceutically acceptable salt, isomer or hydrate thereof can be synthesized by the following methods and synthetic methods known in the art of organic chemical synthesis, or by variations of those methods as understood by those skilled in the art. Preferred methods include, but are not limited to, the methods described below.
- the compound of the present invention or a pharmaceutically acceptable salt, isomer or hydrate thereof is prepared by the method wherein X is N or O, R 1 , R 2 , R 3 , R 4 and R 5 as described above,
- step 1) 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline is obtained in the organic solvent under the action of a Lewis acid.
- the organic solvent is dichloromethane.
- Step 2 Preparation of the formula III-A in step 2) with 5-hydroxy-10-chloro-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline and R 1 X in an organic solvent a compound of the formula wherein R 1 is as defined above; the organic solvent includes, but is not limited to, one of tetrahydrofuran, dioxane, DMF, DMA, DMSO, acetonitrile or a combination of two or more; X in R 1 X is chlorine, Bromine, iodine, mesylate, p-toluenesulfonate or triflate.
- Step 3 The compound of the formula III-A is mixed with the formula IV'-A in an organic solvent and heated to 100 ° C to 140 ° C to obtain a compound represented by III";
- the organic solvent is selected from the group consisting of toluene, chlorobenzene, and One or a combination of two or more of toluene, DMF, DMA, DMSO.
- Step 4) performing a nitro reduction reaction, and the nitro reduction can be carried out by a person skilled in the art;
- the conditions of the nitro reduction-reduction reaction include, but are not limited to, hydrogen and Raney nickel, hydrogen and palladium carbon, iron powder, zinc powder, stannous chloride;
- Step 5 a compound of the formula (II-A) is reacted with a formula of NH 2 -R 5 in the presence of a condensing agent to give a compound of the formula (IC);
- the condensing agent includes, but is not limited to, triphosgene, carbonyl diimidazole, phenyl chloroformate, phenyl p-nitrochloroformate;
- the reaction can also be carried out in the presence of a base including, but not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo ring.
- a base including, but not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo ring.
- a base including, but not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo ring.
- a base including, but not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo ring.
- aprotic solvents including but not limited to one of dichloromethane,
- step 5 is carried out in an aprotic solvent including, but not limited to, one of dichloromethane, tetrahydrofuran, DMF, dioxane, dichloroethane, and a combination of two or more thereof. ;
- step 1) and step 2) may be omitted. Meanwhile, the order of steps 1 and 2 and step 3 may not be fixed. For example, step 3 may be performed first, and steps 1 and 2 may be performed.
- Example 1 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-methoxy-2,3-dihydro-[1,4] dioxole) Preparation of alkano[2,3-f]-quinolin-10-yl)oxy)phenyl)urea
- Step 1) 10-Chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline (251 mg, 1 mmol, synthetic route reference CN201810160412X And p-nitrophenol (139 mg, 1 mmol) was placed in a reaction flask, chlorobenzene was added, and the mixture was heated to reflux until the reaction was completed. After cooling, suction filtration, the obtained solid was washed with aqueous potassium carbonate to give a pale-yellow solid (5-methoxy-10-(4-nitrophenoxy)-2,3-dihydro-[1,4] diox. Alkano[2,3-f]quinoline 250 mg, 71% yield. MS: 355 [M+H] + .
- Step 2) The product prepared in step 1 (250 mg, 0.7 mmol) was placed in a reaction flask, methanol, Raney nickel (250 mg) was added, and the reaction was completed under a hydrogen atmosphere until the reaction was completed. (4-((5-Methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl)oxy)aniline) 226 mg, produced The rate is 99%. MS: 325 [M+H] + .
- Step 3) Dissolve triphosgene (296 mg, 1 mmol) in tetrahydrofuran, add 4-chloro-3-(trifluoromethyl)aniline (195 mg, 1 mmol) and triethylamine (0.4 mL, 3 mmol) and stir for 1 hour. After that, the product obtained in the step 2 (226 mg, 0.7 mmol) and triethylamine (0.4 mL, 3 mmol) in tetrahydrofuran were added and stirred until the reaction was completed. A white solid was obtained 306 mg, yield 80%.
- Step 1) Dissolve 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline (251 mg, 1 mmol) in dichloromethane Into, 1 mol of a solution of boron tribromide in dichloromethane (3 mL, 3 mmol) was added dropwise, and the mixture was stirred until the reaction was completed. The pale yellow solid product (5-hydroxy-10-chloro-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline) 236 mg was obtained. MS: 238 [M+H] + .
- Step 2 The product obtained in Step 1 (236 mg, 1 mmol) was dissolved in N,N-dimethylformamide, 1-bromo-2-methoxyethane (138 mg, 1 mmol) and potassium carbonate (414 mg, 3 mmol) ), heating and stirring until the reaction is completed. After adding water and ethyl acetate, the organic phase was concentrated and purified by column chromatography to give white crystals (10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4] Oxa[2,3-f]-quinoline) 236 mg, yield 80%.
- Steps 3-5) were carried out in a similar manner to Example 1, except that the product prepared in the same molar equivalent of the step 2) in the step 3) (10-chloro-5-(2) -methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline) in place of 10-chloro-5- in step 1) of Example 1. Methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline.
- Example 8 The preparation was carried out in the same manner as in Example 8, except that the 1-bromo-2-methoxyethane in the step 2) of Example 8 was replaced with the same molar equivalent of iodoethane.
- Example 10 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-isopropoxy-2,3-dihydro-[1,4]) Preparation of oxane[2,3-f]quinolin-10-yl)oxy)phenyl)urea
- Example 8 The preparation was carried out in the same manner as in Example 8, except that the 1-bromo-2-methoxyethane in the step 2) of Example 8 was replaced by the same molar equivalent of isopropyl bromide.
- Example 8 The preparation was carried out in a similar manner to Example 8, except that the 1-bromo-2-methoxyethane in the step 2) of Example 8 was replaced by the same molar equivalent of isobutyl bromide.
- Example 12 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(cyclopropylmethoxy)-2,3-dihydro-[1 , 4] Preparation of dioxo[2,3-f]quinolin-10-yl)oxy)phenyl)urea
- Example 8 The preparation was carried out in the same manner as in Example 8, except that the 1-bromo-2-methoxyethane in the step 2) of Example 8 was replaced with the same molar equivalent of bromomethylcyclopropane.
- Example 8 The preparation was carried out in the same manner as in Example 8 except that the 1-bromo-2-methoxyethane in the step 2) of Example 8 was replaced with the same molar equivalent of bromoacetonitrile.
- MS 571 [M+H] + .
- Example 14 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(2-hydroxyethoxy))-2,3-dihydro-[1 , 4] Preparation of dioxo[2,3-f]quinolin-10-yl)oxy)phenyl)urea
- Example 15 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-hydroxypropoxy)-2,3-dihydro-[1 , 4] Preparation of dioxo[2,3-f]quinolin-10-yl)oxy)phenyl)urea
- Example 8 The preparation was carried out in a similar manner to Example 8, except that the 1-bromo-2-methoxyethane in the step 2) of Example 8 was replaced by the same molar equivalent of 3-bromopropan-1-ol.
- Example 8 The preparation was carried out in a similar manner to Example 8, except that 1-bromo-2-methoxyethyl in the step 2) of Example 8 was replaced by the same molar equivalent of 1-bromo-3-methoxypropane. alkyl.
- Example 17 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-(dimethylamino)propoxy)-2,3-di) Preparation of hydrogen-[1,4]dioxane[2,3-f]quinolin-10-yl)oxy)phenyl)urea
- Example 8 The preparation was carried out in the same manner as in Example 8, except that the same molar equivalent of 3-chloro-N,N-dimethylpropyl-1-amine hydrochloride was used in place of the step 2) of Example 8 1-Bromo-2-methoxyethane.
- Example 18 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-(pyrrol-1-yl)propoxy)-2,3 -Preparation of dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl)oxy)phenyl)urea
- Example 8 The preparation was carried out in a similar manner to Example 8, except that 1-bromo-2-methyl in the step 2) of Example 8 was replaced by the same molar equivalent of 1-(3-chloropropyl)pyrrole hydrochloride. Oxyethane.
- Example 8 Prepared in a similar manner to Example 8, except that 1-bromo-2- in step 2) of Example 8 was replaced by the same molar equivalent of 1-(3-chloropropyl)piperidine hydrochloride.
- Example 22 1-(4-((5-(3-(4-Acetylpiperazin-1-yl)propoxy)-2,3-dihydro-[1,4]dioxane[ Preparation of 2,3-f]quinoline-10-yloxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea
- Example 2 Prepared in a similar manner to Example 8, except that the same molar equivalent of 1-(4-(3-chloropropyl)piperazin-1-yl)ethyl-1-one hydrochloride was replaced Example 1 1-Bromo-2-methoxyethane in step 2).
- Example 8 The preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of 4-(3-chloropropyl)thiomorpholine-1,1-dioxide hydrochloride was used instead of the procedure of Example 8. 1-Bromo-2-methoxyethane in 2).
- Example 8 The preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of 1-(3-chloropropyl)-4,4-dimethylpiperidine hydrochloride was substituted for Example 8 Step 2) 1-Bromo-2-methoxyethane.
- Example 26 1-(4-((5-(3-(4-Amino-4-methylpiperidin-1-yl)propoxy)-2,3-dihydro-[1,4] Preparation of oxane[2,3-f]quinolin-10-yl)oxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea
- Step 1-5 (1-(3-((10-(4-(4-(4-(4-(3-(3-(trifluoromethyl)phenyl)))) yloxy)-2,3 -Dihydro-[1,4]dioxane[2,3-f]quinolin-5-yl)oxy)propyl)-4-methylpiperazin-4-yl)carbamic acid tert-butyl ester
- Example 1 The preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of (1-(3-chloropropyl)-4-methylpiperidin-4-yl)carbamic acid tert-butyl ester was used instead.
- Example 1 1-Bromo-2-methoxyethane in step 2). MS: 786 [M+H] + .
- Step 6 The product obtained in the above step 1-5 (79 mg, 1 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise and reacted for 3 hours. The reaction was quenched with aq. methanol (EtOAc) (EtOAc).
- Example 27 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-((2-methoxyethyl))methyl)amino) Preparation of propoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl)oxy)phenyl)urea
- Example 8 The preparation was carried out in the same manner as in Example 8, except that the iodoethane in the step 2) of Example 8 was replaced with the same molar equivalent of 1,3-dibromopropane. MS: 652 [M+H] + .
- Step 6 The product obtained in the step 1-5) (1-(4-((5-(3-bromopropyloxy)-2,3-dihydro-[1,4]dioxane] 2,3-f]quinolin-10-yl)oxy)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenylurea) (65 mg, 1 mmol) dissolved in EtOAc (3 mL) Triethylamine (202 mg, 2 mmol) and 2-methoxy-N-methylethyl-1-amine (135 mg, 1.5 mmol) were added, and the mixture was reacted at 25 ° C for 3 hours. 20 mg.
- Example 28 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-(cyclobutyl))(methyl)amino)propoxy)) Preparation of -2,3-dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl)oxy)phenyl)urea
- Example 8 The preparation was carried out in a similar manner to Example 8, except that the 1-bromo-2-methoxy group in the step 2) of Example 8 was replaced by the same molar equivalent of 1-chloro-6-methoxyhexane.
- Example 30 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-((6-(dimethylamino)hexyl))oxy)-2,3 -Preparation of dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl)oxy)phenyl)urea
- Example 8 Prepared in a similar manner to Example 8, except that the 1-bromo- in step 2) of Example 8 was replaced by the same molar equivalent of 6-chloro-N,N-dimethylhexyl-1-amine. 2-methoxyethane.
- Example 8 The preparation was carried out in a similar manner to Example 8, except that the 1-bromo-2 in the step 2) of Example 8 was replaced by the same molar equivalent of 4-oxobenzenesulfonate. -methoxyethane.
- Example 32 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-((tetrahydrofuran-3-yl)oxy)-2,3-dihydro) -[1,4] Preparation of Dioxo[2,3-f]quinolin-10-yl)oxy)phenyl)urea
- Example 8 Prepared in a similar manner to Example 8, except that the 1-bromo in step 2) of Example 8 was replaced by the same molar equivalent of tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate. -2-methoxyethane can be used.
- Example 8 The preparation was carried out in the same manner as in Example 8, except that the 1-bromo-2-methoxyethane in the step 2) of Example 8 was replaced with the same molar equivalent of iodoethane in the same molar equivalent. 3-Fluoro-4-nitrophenol was substituted for 4-nitrophenol in step 3) of Example 8.
- Example 36 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((5-(2-methoxyethoxy))-2,3 -Preparation of dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl)oxy)phenyl)urea
- Example 8 The preparation was carried out in the same manner as in Example 8, except that the p-nitrophenol in the step 3) of Example 8 was replaced with the same molar equivalent of 2-fluoro-4-nitrophenol.
- Example 37 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-((5-(2-methoxyethoxy))-2,3 -Preparation of dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl)oxy)phenyl)urea
- Example 8 The preparation was carried out in a similar manner to Example 8, except that the p-nitrophenol in the step 3) of Example 8 was replaced by the same molar equivalent of 3-fluoro-4-nitrophenol.
- MS 608 [M+H] + .
- Example 38 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((5-(3-methoxypropoxy))-2,3 -Preparation of dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl)oxy)phenyl)urea
- Example 8 The preparation was carried out in a similar manner to Example 8, except that 1-bromo-2-methoxyethane in the step 2) of Example 8 was replaced by the same molar equivalent of 1-bromo-3-methoxypropane.
- the p-nitrophenol in step 3) of Example 8 was replaced with the same molar equivalent of 2-fluoro-4-nitrophenol.
- Example 39 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-((5-(3-methoxypropoxy))-2,3 -Preparation of dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl)oxy)phenyl)urea
- Example 8 The preparation was carried out in a similar manner to Example 8, except that 1-bromo-2-methoxyethyl in the step 2) of Example 8 was replaced by the same molar equivalent of 1-bromo-3-methoxypropane.
- the alkane was replaced with the same molar equivalent of 3-fluoro-4-nitrophenol as the p-nitrophenol in step 3) of Example 8.
- Example 40 1-(2-Fluoro-5-(trifluoromethyl)phenyl)-3-(4-((5-(3-methoxypropoxy)-2,3-dihydro-) Preparation of [1,4]dioxane[2,3-f]quinolin-10-yl)oxy)phenyl)urea
- Example 8 The preparation was carried out in a similar manner to Example 8, except that 1-bromo-2-methoxyethyl in the step 2) of Example 8 was replaced by the same molar equivalent of 1-bromo-3-methoxypropane.
- the alkane was replaced by the same molar equivalent of 2-fluoro-5-(trifluoromethyl)aniline as the 4-chloro-3-(trifluoromethyl)aniline of Example 8 Step 5).
- Example 8 Prepared in a similar manner to Example 8, except that the same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was substituted for 1-bromo-2- in step 2) of Example 8. Methoxyethane, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 2-fluoro-4-nitrophenol.
- Example 42 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-((5-(3-morpholinepropoxy)-2,3- Preparation of dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl)oxy)phenyl)urea
- Example 8 Prepared in a similar manner to Example 8, except that the same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was substituted for 1-bromo-2- in step 2) of Example 8. Methoxyethane, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-fluoro-4-nitrophenol.
- Example 8 The preparation was carried out in the same manner as in Example 8, except that the 1-bromo-2-methoxyethane in the step 2) of Example 8 was replaced with the same molar equivalent of iodoethane in the same molar equivalent. 3-Chloro-4-nitrophenol instead of p-nitrophenol in step 3) of Example 8, replacing 4-chloro-3-(trifluoromethyl) in step 5) of Example 8 with the same molar equivalent of cyclopropylamine )aniline.
- Example 8 The preparation was carried out in the same manner as in Example 8, except that the 1-bromo-2-methoxyethane in the step 2) of Example 8 was replaced with the same molar equivalent of isopropyl bromide in the same molar equivalent. Substituting 3-chloro-4-nitrophenol for p-nitrophenol in step 3) of Example 8, replacing 4-chloro-3-(trifluoromethyl) in step 5) of Example 8 with the same molar equivalent of cyclopropylamine Aniline. .
- Example 8 Prepared in a similar manner to Example 8, except that the same molar equivalent of isobutyl bromide was used in place of 1-bromo-2-methoxyethane in Step 2) of Example 8, in the same molar Equivalent 3-chloro-4-nitrophenol in place of p-nitrophenol in step 3) of Example 8, replacing 4-chloro-3-(trifluoro) in step 5) of Example 8 with the same molar equivalent of cyclopropylamine Methyl) aniline.
- Example 46 1-(2-Chloro-4-((5-(cyclopropylmethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinaline Preparation of phenyl-10-yl)oxy)phenyl)-3-cyclopropylurea
- Example 8 The preparation was carried out in the same manner as in Example 8, except that the same molar equivalent of bromomethylcyclopropane was substituted for 1-bromo-2-methoxyethane in the step 2) of Example 8, in the same molar amount.
- Example 8 The preparation was carried out in the same manner as in Example 8, except that the 1-bromo-2-methoxyethane in the step 2) of Example 8 was replaced with the same molar equivalent of bromoacetonitrile in the same molar equivalent of 3 -Chloro-4-nitrophenol instead of p-nitrophenol in step 3) of Example 8, replacing 4-chloro-3-(trifluoromethyl) in step 5) of Example 8 with the same molar equivalent of cyclopropylamine aniline.
- Example 48 1-(2-Chloro-4-((5-(2-hydroxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinaline Preparation of phenyl-10-yl)oxy)phenyl)-3-cyclopropylurea
- Example 8 The preparation was carried out in a similar manner to Example 8, except that the 1-bromo-2-methoxyethane in the step 2) of Example 8 was replaced by the same molar equivalent of 2-bromoethyl-1-ol. Substituting the same molar equivalent of 3-chloro-4-nitrophenol for p-nitrophenol in step 3) of Example 8, replacing 4-chloro-3 in step 5) of Example 8 with the same molar equivalent of cyclopropylamine -(Trifluoromethyl)aniline.
- Example 8 The preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of 3-chloro-4-nitrophenol was substituted for the p-nitrophenol in the step 3) of Example 8, in the same molar equivalent of the ring.
- the propylamine was substituted for 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8.
- Example 50 1-(2-Chloro-4-((5-(3-hydroxypropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quina Preparation of phenyl-10-yl)oxy)phenyl)-3-cyclopropylurea
- Example 8 The preparation was carried out in a similar manner to Example 8, except that the 1-bromo-2-methoxyethane in the step 2) of Example 8 was replaced by the same molar equivalent of 3-bromopropan-1-ol. Substituting the same molar equivalent of 3-chloro-4-nitrophenol for p-nitrophenol in step 3) of Example 8, substituting the same molar equivalent of cyclopropylamine for 4-chloro-3- in step 5) of Example 8. (Trifluoromethyl) aniline.
- Example 8 The preparation was carried out in a similar manner to Example 8, except that 1-bromo-2-methoxyethyl in the step 2) of Example 8 was replaced by the same molar equivalent of 1-bromo-3-methoxypropane. Alkane, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-chloro-4-nitrophenol, replacing the 4-chloro in step 5) of Example 8 with the same molar equivalent of cyclopropylamine. 3-(Trifluoromethyl)aniline.
- Example 8 The preparation was carried out in the same manner as in Example 8, except that the same molar equivalent of 3-chloro-N,N-dimethylpropyl-1-amine hydrochloride was used in place of the step 2) of Example 8 1-Bromo-2-methoxyethane, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-chloro-4-nitrophenol, replacing the same molar equivalent of cyclopropylamine 4-Chloro-3-(trifluoromethyl)aniline in 8 step 5).
- Example 8 The preparation was carried out in a similar manner to Example 8, except that 1-bromo-2-methyl in the step 2) of Example 8 was replaced by the same molar equivalent of 1-(3-chloropropyl)pyrrole hydrochloride. Ethyloxyl, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-chloro-4-nitrophenol, replacing the same molar equivalent of cyclopropylamine in step 8) of Example 8 4-chloro-3-(trifluoromethyl)aniline.
- Example 54 1-(2-Chloro-4-((5-(3-(piperidin-1-yl)propoxy)-2,3-dihydro-[1,4]dioxane[ Preparation of 2,3-f]quinoline-10-yl)oxy)phenyl)-3-cyclopropylurea
- Example 8 Prepared in a similar manner to Example 8, except that 1-bromo-2- in step 2) of Example 8 was replaced by the same molar equivalent of 1-(3-chloropropyl)piperidine hydrochloride. Methoxyethane, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-chloro-4-nitrophenol, replacing the same molar equivalent of cyclopropylamine in step 5) of Example 8 4-Chloro-3-(trifluoromethyl)aniline.
- Example 55 1-(2-Chloro-4-((5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Preparation of quinoline-10-yl)oxy)phenyl)-3-cyclopropylurea
- Example 8 Prepared in a similar manner to Example 8, except that the same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was substituted for 1-bromo-2- in step 2) of Example 8. Methoxyethane, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-chloro-4-nitrophenol, replacing the same molar equivalent of cyclopropylamine in step 5) of Example 8 4-Chloro-3-(trifluoromethyl)aniline.
- Example 56 1-(2-Chloro-4-((5-(3-(4-methylpiperazin-1-yl)propoxy)-2,3-dihydro-[1,4] Preparation of oxane[2,3-f]quinolin-10-yl)oxy)phenyl)-3-cyclopropylurea
- Example 8 Prepared in a similar manner to Example 8, except that the same molar equivalent of 1-(3-chloropropyl)-4-methylpiperazine hydrochloride was substituted for 1 in Example 2, Step 2) -Bromo-2-methoxyethane, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-chloro-4-nitrophenol, replacing Example 8 with the same molar equivalent of cyclopropylamine 4-Chloro-3-(trifluoromethyl)aniline in step 5).
- Example 57 1-(4-((5-(3-(4-Acetylpiperazin-1-yl)propoxy)-2,3-dihydro-[1,4]dioxane[ Preparation of 2,3-f]quinoline-10-yl)oxy)-2-chlorophenyl)-3-cyclopropylurea
- Example 8 Prepared in a similar manner to Example 8, except that the same molar equivalent of 1-(4-(3-chloropropyl)piperazin-1-yl)ethyl-1-one hydrochloride was replaced The 1-bromo-2-methoxyethane in the step 2) of Example 8 was replaced by the same molar equivalent of 3-chloro-4-nitrophenol as the p-nitrophenol in the step 3) of Example 8. The molar equivalent of cyclopropylamine replaces 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8.
- Example 58 1-(2-Chloro-4-((5-(3-(1,1-dioxothiomorpholine)propoxy)-2,3-dihydro-[1,4] Preparation of oxane[2,3-f]quinolin-10-yl)oxy)phenyl)-3-cyclopropylurea
- Example 8 The preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of 4-(3-chloropropyl)thiomorpholine-1,1-dioxide hydrochloride was used instead of the procedure of Example 8. 1-Bromo-2-methoxyethane in 2), replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-chloro-4-nitrophenol, in the same molar equivalent of the ring The propylamine was substituted for 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8.
- Example 8 The preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of 1-(3-chloropropyl)-4,4-dimethylpiperidine hydrochloride was substituted for Example 8 Step 2) 1-bromo-2-methoxyethane in the same molar equivalent of 3-chloro-4-nitrophenol instead of p-nitrophenol in step 3) of Example 8, substituting the same molar equivalent of cyclopropylamine Example 8 4-Chloro-3-(trifluoromethyl)aniline in step 5).
- Example 60 1-(2-Chloro-4-((5-(3-(4-hydroxy-4-methylpiperidin-1-yl)propoxy)-2,3-dihydro-[1 , 4] Preparation of dioxo[2,3-f]quinolin-10-yl)oxy)phenyl)-3-cyclopropylurea
- Example 8 Prepared in a similar manner to Example 8, except that the same molar equivalent of 1-(3-chloropropyl)-4-methylpiperidin-4-ol was used in place of Step 2 in Example 8 1-Bromo-2-methoxyethane, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-chloro-4-nitrophenol, replacing the same molar equivalent of cyclopropylamine 4-Chloro-3-(trifluoromethyl)aniline in 8 step 5).
- Step 1-5) (1-(3-((3-cyclopropyl))phenoxy)-2,3-dihydro-[1,4 Preparation of tert-butyl dioxo[2,3-f]quinolin-5-yl)oxy)propyl)-4-methylpiperidin-4-yl)carbamate
- the equivalent of cyclopropylamine replaces 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8.
- Step 6) The final product (68 mg, 1 mmol) obtained in Step 1-5) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added dropwise. The reaction was quenched with aq. methanol (EtOAc) (EtOAc).
- Example 62 1-(2-Chloro-4-((5-(3-((2-methoxyethyl))(methyl)amino)propoxy)-2,3-dihydro-[1 , 4] Preparation of dioxo[2,3-f]quinolin-10-yl)oxy)phenyl)-3-cyclopropylurea
- Example 8 The preparation was carried out in a similar manner to Example 8, except that the 1-bromo-2-methoxyethane in the step 2) of Example 8 was replaced by the same molar equivalent of 1,3-dibromoethane. Substituting the same molar equivalent of 3-chloro-4-nitrophenol for p-nitrophenol in step 3) of Example 8, substituting the same molar equivalent of cyclopropylamine for 4-chloro-3- in step 5) of Example 8. (Trifluoromethyl) aniline. MS: 548 [M+H] + .
- Step 6) The final product (55 mg, 1 mmol) prepared in steps 1-5) was dissolved in acetonitrile (3 mL), triethylamine (202 mg, 2 mmol) and 2-methoxy-N-methylethyl 1-amine (135 mg, 1.5 mmol) was reacted at 25 ° C for 3 hours.
- Example 64 1-(2-Chloro-4-((5-(6-(dimethylamino)hexyl)oxy)-2,3-dihydro-[1,4]dioxane[2] , 3-f]quinoline-10-yl)oxy)phenyl)-3-cyclopropylurea
- Example 8 Prepared in a similar manner to Example 8, except that the 1-bromo- in step 2) of Example 8 was replaced by the same molar equivalent of 6-chloro-N,N-dimethylhexyl-1-amine. 2-methoxyethane, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-chloro-4-nitrophenol, replacing step 8 of Example 8 with the same molar equivalent of cyclopropylamine. 4-Chloro-3-(trifluoromethyl)aniline.
- Example 65 1-(2-Chloro-4-((5-(oxetan-3-yloxy)-2,3-dihydro-[1,4]dioxane[2, Preparation of 3-f]quinoline-10-yl)oxy)phenyl)-3-cyclopropylurea
- Example 8 Prepared in a similar manner to Example 8, except that the 1-bromo- in step 2) of Example 8 was replaced by the same molar equivalent of 4-methylbenzenesulfonate oxetane-3-ester. 2-methoxyethane, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-chloro-4-nitrophenol, replacing step 8 of Example 8 with the same molar equivalent of cyclopropylamine. 4-Chloro-3-(trifluoromethyl)aniline.
- Example 66 1-(2-Chloro-4-((5-((tetrahydrofuran-3-yl)oxy)-2,3-dihydro-[1,4]dioxane[2,3- Preparation of f]quinoline-10-yl)oxy)phenyl)-3-cyclopropylurea
- Example 8 Prepared in a similar manner to Example 8, except that the same molar equivalent of 4-methylbenzenesulfonic acid tetrahydrofuran-3-ester was substituted for 1-bromo-2-methoxy in step 2) of Example 8. Substituting the same molar equivalent of 3-chloro-4-nitrophenol for p-nitrophenol in step 3) of Example 8, replacing 4- in step 5) of Example 8 with the same molar equivalent of cyclopropylamine Chloro-3-(trifluoromethyl)aniline.
- Example 8 Prepared in a similar manner to Example 8, except that the 1-bromo in step 2) of Example 8 was replaced by the same molar equivalent of tetrahydro 2H-pyran-4-yl 4-methylbenzenesulfonate. 2-methoxyethane, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-chloro-4-nitrophenol, replacing step 5 of Example 8 with the same molar equivalent of cyclopropylamine 4-Chloro-3-(trifluoromethyl)aniline in .
- Example 68 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl) Of oxy)phenyl)-3-cyclobutylurea
- Example 2 The preparation was carried out in a similar manner to Example 1, except that the same molar equivalent of 3-chloro-4-nitrophenol was substituted for the p-nitrophenol in the step 1) of Example 1, in the same molar equivalent of the ring. Butylamine replaces 4-chloro-3-(trifluoromethyl)aniline in step 3) of Example 1.
- Example 69 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl) Of oxy)phenyl)-3-cyclopentylurea
- Example 2 The preparation was carried out in a similar manner to Example 1, except that the same molar equivalent of 3-chloro-4-nitrophenol was substituted for the p-nitrophenol in the step 1) of Example 1, in the same molar equivalent of the ring. Pentylamine was substituted for 4-chloro-3-(trifluoromethyl)aniline in step 3) of Example 1.
- Example 70 1-(2-Chloro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Preparation of quinoline-10-yl)oxy)phenyl)-3-cyclobutylurea
- Example 8 The preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of 3-chloro-4-nitrophenol was substituted for the p-nitrophenol in the step 3) of Example 8, in the same molar equivalent of the ring. Butylamine replaces 4-chloro-3-(trifluoromethyl)aniline in Step 5) of Example 8.
- Example 8 The preparation was carried out in a similar manner to Example 8, except that the same molar equivalent of 3-chloro-4-nitrophenol was substituted for the p-nitrophenol in the step 3) of Example 8, in the same molar equivalent of the ring. Pentylamine was substituted for 4-chloro-3-(trifluoromethyl)aniline in step 3) of Example 8.
- Example 72 1-(2-Chloro-4-((5-(3-methoxypropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f Preparation of quinoline-10-yl)oxy)phenyl)-3-cyclobutylurea
- Example 8 The preparation was carried out in a similar manner to Example 8, except that 1-bromo-2-methoxyethyl in the step 2) of Example 8 was replaced by the same molar equivalent of 1-bromo-3-methoxypropane. Alkane, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-chloro-4-nitrophenol, replacing 4-chloro in step 5) of Example 8 with the same molar equivalent of cyclobutylamine -3-(trifluoromethyl)aniline.
- Example 73 1-(2-Chloro-4-((5-(3-methoxypropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f Preparation of quinoline-10-yl)oxy)phenyl)-3-cyclopentylurea
- Example 8 The preparation was carried out in a similar manner to Example 8, except that 1-bromo-2-methoxyethyl in the step 2) of Example 8 was replaced by the same molar equivalent of 1-bromo-3-methoxypropane. Alkane, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-chloro-4-nitrophenol, replacing 4-chloro in step 5) of Example 8 with the same molar equivalent of cyclopentylamine -3-(trifluoromethyl)aniline.
- Example 74 1-(2-Chloro-4-((5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Preparation of quinoline-10-yl)oxy)phenyl)-3-cyclobutylurea
- Example 8 Prepared in a similar manner to Example 8, except that the same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was substituted for 1-bromo-2- in step 2) of Example 8. Methoxyethane, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-chloro-4-nitrophenol, replacing the same molar equivalent of cyclobutylamine in step 8) of Example 8 4-chloro-3-(trifluoromethyl)aniline.
- Example 75 1-(2-Chloro-4-((5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Preparation of quinoline-10-yl)oxy)phenyl)-3-cyclopentylurea
- Example 8 Prepared in a similar manner to Example 8, except that the same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was substituted for 1-bromo-2- in step 2) of Example 8. Methoxyethane, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-chloro-4-nitrophenol, replacing step 8 of Example 8 with the same molar equivalent of cyclopentylamine) 4-Chloro-3-(trifluoromethyl)aniline.
- Example 76 1-(2-Fluoro-5-(trifluoromethyl)phenyl)-3-(4-((5-(3-morpholinepropoxy)-2,3-dihydro-[ Preparation of 1,4]dioxane[2,3-f]quinolin-10-yl)oxy)phenyl)urea
- Example 8 Prepared in a similar manner to Example 8, except that the same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was substituted for 1-bromo-2- in step 2) of Example 8. Methoxyethane, replacing 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 with the same molar equivalent of 2-fluoro-5-(trifluoromethyl)aniline.
- Example 77 1-(4-Fluorophenyl)-3-(4-((5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[ Preparation of 2,3-f]quinoline-10-yloxy)phenyl)urea
- Example 8 Prepared in a similar manner to Example 8, except that the same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was substituted for 1-bromo-2- in step 2) of Example 8. Methoxyethane, replacing 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 with the same molar equivalent of p-fluoroaniline.
- Example 78 1-(2,4-Fluorophenyl)-3-(4-((5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane Preparation of [2,3-f]quinolin-10-yl)oxy)phenyl)urea
- Example 8 Prepared in a similar manner to Example 8, except that the same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was substituted for 1-bromo-2- in step 2) of Example 8. Methoxyethane, replacing 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8 with the same molar equivalent of 2,4-difluoroaniline.
- Example 2 The preparation was carried out in the same manner as in Example 1, except that the same molar equivalent of 3-chloro-4-nitrophenol was substituted for the p-nitrophenol in the step 1) of Example 1, in the same molar equivalent of A.
- the amine was substituted for 4-chloro-3-(trifluoromethyl)aniline in step 3) of Example 1.
- Example 80 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl) Preparation of oxy)phenyl)-3-ethylurea
- Example 1 Prepared in a similar manner to Example 1, except that the same molar equivalent of 3-chloro-4-nitrophenol was substituted for the p-nitrophenol in step 1) of Example 1, in the same molar equivalent of B. The amine was substituted for 4-chloro-3-(trifluoromethyl)aniline in step 3) of Example 1.
- Example 1 Prepared in a similar manner to Example 1, except that the same molar equivalent of 3-chloro-4-nitrophenol was substituted for the p-nitrophenol in step 1) of Example 1, with the same molar equivalent of propylamine. Instead of 4-chloro-3-(trifluoromethyl)aniline in step 3) of Example 1.
- Example 82 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl) Preparation of oxy)phenyl)-3-isopropylurea
- Example 2 The preparation was carried out in the same manner as in Example 1, except that the same molar equivalent of 3-chloro-4-nitrophenol was substituted for the p-nitrophenol in the step 1) of Example 1, in the same molar equivalent.
- the propylamine was substituted for 4-chloro-3-(trifluoromethyl)aniline in step 3) of Example 1.
- Example 83 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl) Preparation of oxy)phenyl)-3-isobutylurea
- Example 2 The preparation was carried out in the same manner as in Example 1, except that the same molar equivalent of 3-chloro-4-nitrophenol was substituted for the p-nitrophenol in the step 1) of Example 1, in the same molar equivalent. Butylamine replaces 4-chloro-3-(trifluoromethyl)aniline in step 3) of Example 1.
- Example 84 1-cyclopropyl-3-(2-fluoro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f] Preparation of quinoline-10-yloxy)phenyl)urea
- Example 1 The preparation was carried out in a similar manner to Example 1, except that the same molar equivalent of 3-fluoro-4-nitrophenol was substituted for the p-nitrophenol in the step 1) of Example 1, in the same molar equivalent of the ring.
- the propylamine was substituted for 4-chloro-3-(trifluoromethyl)aniline in step 1) of Example 1.
- Example 8 Prepared in a similar manner to Example 8, except that the same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was substituted for 1-bromo-2- in step 2) of Example 8. Methoxyethane, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-chloro-4-nitrophenol, replacing the same molar equivalent of methylamine in step 5) of Example 8 4-Chloro-3-(trifluoromethyl)aniline.
- Example 86 1-(2-Chloro-4-((5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Preparation of quinoline-10-yloxy)phenyl)-3-ethylurea
- Example 8 Prepared in a similar manner to Example 8, except that the same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was substituted for 1-bromo-2- in step 2) of Example 8. Methoxyethane, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-chloro-4-nitrophenol, replacing the same molar equivalent of ethylamine in step 5) of Example 8 4-Chloro-3-(trifluoromethyl)aniline.
- Example 87 1-(2-Chloro-4-((5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Preparation of quinoline-10-yloxy)phenyl)-3-propylurea
- Example 8 Prepared in a similar manner to Example 8, except that the same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was substituted for 1-bromo-2- in step 2) of Example 8. Methoxyethane, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-chloro-4-nitrophenol, replacing 4 of Example 5, Step 5) with the same molar equivalent of propylamine -Chloro-3-(trifluoromethyl)aniline.
- Example 88 1-(2-Chloro-4-((5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Preparation of quinoline-10-yl)oxy)phenyl)-3-isopropylurea
- Example 8 Prepared in a similar manner to Example 8, except that the same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was substituted for 1-bromo-2- in step 2) of Example 8. Methoxyethane, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-chloro-4-nitrophenol, replacing the same molar equivalent of isopropylamine in step 5) of Example 8 4-Chloro-3-(trifluoromethyl)aniline.
- Example 8 Prepared in a similar manner to Example 8, except that the same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was substituted for 1-bromo-2- in step 2) of Example 8. Methoxyethane, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-chloro-4-nitrophenol, replacing the same molar equivalent of isobutylamine in step 8) of Example 8 4-chloro-3-(trifluoromethyl)aniline.
- Example 90 1-Cyclopropyl-3-(4-((5-ethoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline-10) Preparation of -yl)oxy)-2-fluorophenyl)urea
- Example 8 Prepared in a similar manner to Example 8, except that the 1-bromo-2-methoxyethane in Step 2) of Example 8 was replaced with the same molar equivalent of ethyl bromide in the same molar equivalents. 3-fluoro-4-nitrophenol instead of p-nitrophenol in step 3) of Example 8, replacing 4-chloro-3-(trifluoromethyl) in step 5) of Example 8 with the same molar equivalent of cyclopropylamine )aniline.
- Example 8 The preparation was carried out in the same manner as in Example 8, except that the same molar equivalent of 3-fluoro-4-nitrophenol was substituted for the p-nitrophenol in the step 3) of Example 8, in the same molar equivalent of the ring.
- the propylamine was substituted for 4-chloro-3-(trifluoromethyl)aniline in step 5) of Example 8.
- Example 92 1-cyclopropyl-3-(2-fluoro-4-((5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[ Preparation of 2,3-f]quinoline-10-yloxy)phenyl)-3-urea
- Example 8 Prepared in a similar manner to Example 8, except that the same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was substituted for 1-bromo-2- in step 2) of Example 8. Methoxyethane, replacing the p-nitrophenol in step 3) of Example 8 with the same molar equivalent of 3-fluoro-4-nitrophenol, replacing the same molar equivalent of cyclopropylamine in step 5) of Example 8 4-Chloro-3-(trifluoromethyl)aniline.
- Example 93 1-(2-Chloro-4-((5-(3-cyanopropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Preparation of quinoline-10-yl)oxy)phenyl)-3-cyclopropylurea
- Example 8 The preparation was carried out in a similar manner to Example 8, except that the 1-bromo-2-methoxyethane in the step 2) of Example 8 was replaced by the same molar equivalent of 4-bromobutyronitrile in the same molar equivalent. Substituting 3-chloro-4-nitrophenol for p-nitrophenol in step 3) of Example 8, replacing 4-chloro-3-(trifluoromethyl) in step 5) of Example 8 with the same molar equivalent of cyclopropylamine Aniline.
- Example 8 The preparation was carried out in the same manner as in Example 8, except that the 1-bromo-2-methoxyethane in the step 2) of Example 8 was replaced by the same molar equivalent of 4-bromobutyronitrile.
- Example 96 1-(2-Methyl-5-(trifluoromethyl)phenyl)-3-(4-((5-(3-morpholinepropoxy)-2,3-dihydro- Preparation of [1,4]dioxane[2,3-f]quinolin-10-yl)oxy)phenyl)urea
- Example 8 Prepared in a similar manner to Example 8, except that the same molar equivalent of 4-(3-chloropropyl)morpholine hydrochloride was substituted for 1-bromo-2-methoxy in step 2) of Example 8. The ethyl ethane was replaced by the same molar equivalent of 2-methyl-5-(trifluoromethyl)aniline as the 4-chloro-3-(trifluoromethyl)aniline of Example 8 Step 5).
- test method is as follows:
- Negative control 2.5 ⁇ L/well 4X substrate/ATP mixture and 7.5 ⁇ L 1X Kinase Assay Buffe were added to the 384-well plate well.
- Positive control 2.5 ⁇ L/well 4X substrate/ATP mixture, 2.5 ⁇ L/well 1X Kinase Assay Buffer containing 16% DMSO, 5 ⁇ L/well 2X RET kinase solution were added to a 384-well plate. The final concentration of DMSO in the reaction system was 4%.
- inhibition rate (%) (positive well reading value - experimental well reading value) / (positive control well reading value - negative control well) Read value) x100%.
- inhibition rate (%) (positive well reading value - experimental well reading value) / (positive control well reading value - negative control well) Read value) x100%.
- IC 50 values concentration of compound inhibition rate of enzyme up 50%).
- Table 1 lists the results of determination of tyrosine kinase RET inhibitory activity by some compounds of the present invention, wherein A represents an IC 50 of less than or equal to 50 nM, B represents an IC 50 of greater than 50 nM but less than or equal to 500 nM, and C represents an IC 50 of greater than 500 nM. But less than or equal to 5000 nM, D means IC 50 is greater than 5000 nM.
- test method is as follows:
- Negative control 2.5 ⁇ L/well 4X substrate/ATP mixture and 7.5 ⁇ L 1X Kinase Assay Buffe were added to the 384-well plate well.
- Color reaction 5 ⁇ L of 4X detection solution was added to the wells of a 384-well plate for color development, and the mixture was centrifuged at room temperature for 60 minutes.
- inhibition rate (%) (positive well reading value - experimental well reading value) / (positive control well reading value - negative control well) Read value) x100%.
- inhibition rate (%) (positive well reading value - experimental well reading value) / (positive control well reading value - negative control well) Read value) x100%.
- IC 50 values concentration of compound inhibition rate of enzyme up 50%).
- Table 2 lists the results of assays for the tyrosine kinase VEGFR-2 inhibitory activity of some of the compounds of the present invention, wherein A represents an IC 50 of less than or equal to 50 nM, and B represents an IC 50 of greater than 50 nM but less than or equal to 500 nM, and C represents an IC 50 . Greater than 500 nM but less than or equal to 5000 nM, D indicates an IC 50 greater than 5000 nM.
- the biological data provided by the present invention indicate that the compounds of the present invention are useful for treating or preventing diseases caused by abnormalities of VEGFR-2 and RET kinase.
- the compounds of the invention are useful in the treatment of cancer, including primary and metastatic cancers, including solid tumors.
- Such cancers include, but are not limited to, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, intrauterine Membrane cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, esophageal cancer, brain Tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary sarcoma, cholangiocarcinoma.
- the compounds of the invention also include cancers that are resistant to one or more other therapeutic methods.
- the compounds of the invention are also useful in diseases other than cancer associated with VEGFR-2 kinase and/or RET kinase, including but not limited to fundus diseases, psoriasis, rheumatoid arthritis, atheroma, pulmonary fibrosis ,Liver Fibrosis.
- the compounds of the present invention may be administered as a monotherapy or a combination therapy, in combination with a plurality of compounds of the present invention or in combination with other drugs other than the present invention.
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Abstract
Description
Claims (16)
- 一种式(I)所示的化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药:式(I)中,X为O或者NH;Y为CH;Z为CH;R 1为H、C 1-C 9的烷基、C 3-C 7的环烷基、4-7元杂环基、C 3-C 7的环烷基取代的C 1-C 6烷基、4-7元杂环基取代的C 1-C 6烷基、取代的C 1-C 9烷基,所述取代的C 1-C 9烷基中的取代基为羟基、C 1-C 6烷氧基、C 1-C 6烷硫基、单或双C 1-C 6的烷基取代的氨基或未取代氨基中的一种或一种以上,上述4-7元杂环基为含有1-2个选自N、O、S中的原子的4-7元杂环基,4-7元杂环基不被取代或被C 1-C 6烷基、C 1-C 3酰基取代或被一至二个氧原子氧化;R 2为H或卤素;R 3为H或卤素;R 4为H或卤素;R 5为H、C 1-C 9的烷基、C 3-C 8的环烷基、C 3-C 8的环烷基取代的C 1-C 6烷基、取代或非取代的芳基或者杂芳基,所述取代的芳基或者杂芳基的取代基为C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷硫基、单或双C 1-C 3烷基取代的氨基或未取代氨基、卤素、三氟甲基、芳氧基或甲砜基中的一种或一种以上;所述杂芳基为含有5至10个环原子的单环或双环基团,环中含有1-3个选自N、O、S中的原子。
- 根据权利要求1所述的化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药,其中,R 1为H、C 1-C 6烷基、C 3-C 6的环烷基、5-6元杂环基、C 3-C 6的环烷基取代的C 1-C 3烷基、5-6元杂环基取代的C 1-C 3烷基、取代的C 1-C 6烷基,所述取代的C 1-C 6烷 基中取代基为羟基、C 1-C 3的烷氧基、C 1-C 3的烷硫基、单或双C 1-C 3的烷基取代的氨基或未取代氨基中的一种或一种以上,上述5-6元杂环基为含有1-2个选自N、O、S中的原子的5-6元杂环基,5-6元杂环基不被取代或被C 1-C 3烷基、C 1-C 3酰基取代或被一至二个氧原子氧化。
- 根据权利要求2所述的化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药,其中,R 1选自:H、甲基、乙基、丙基、异丙基、甲氧基乙基、甲氧基丙基、甲氧基丁基、甲氧基戊基、甲氧基己基、四氢呋喃-3-基、四氢-2H-吡喃-4-基、四氢吡咯-1-乙基、四氢吡咯-1-丙基、哌啶-1-乙基、哌啶-1-丙基、哌嗪-1-乙基、哌嗪-1-丙基、吗啉-4-乙基、吗啉-4-丙基、甲基哌嗪-4-乙基、甲基哌嗪-4-丙基、N-甲酰基哌嗪-4-乙基、N-甲酰基哌嗪-4-丙基、N-乙酰基哌嗪-4-乙基、N-乙酰基哌嗪-4-丙基、(1,1-二氧硫代吗啉基)-4-乙基、(1,1-二氧硫代吗啉基)-4-丙基、甲硫基乙基、甲硫基丙基、二甲氨基乙基、二甲氨基丙基、二甲氨基丁基、二乙氨基乙基、二乙氨基丙基、羟基乙基、羟基丙基、羟基丁基、羟基戊基、羟基己基、氨基乙基、氨基丙基、氨基丁基、2-甲基-2-羟基丙基、3-甲基-3-羟基丁基、(3S)-3-氨基丁基、(3R)-3-氨基丁基、(3S)-3-羟基丁基或(3R)-3-羟基丁基。
- 根据权利要求1所述的化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药,其中,R 1选自:丁基、异丁基、戊基、异戊基、己基、环丙基甲基、环丙基乙基、环丙基丙基、环丁基甲基、环丁基乙基、环丁基丙基、4,4-二甲基哌啶-1-乙基、4,4-二甲基哌啶-1-丙基、二甲氨基戊基、二甲氨基己基、氧杂环丁烷-3-基。
- 根据权利要求1所述的化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药,其中,R 2、R 3、R 4中,所述的卤素为F、Cl或Br。
- 根据权利要求1所述化合物或其药学上可接受的盐、异构体、水合物、溶剂化物、或前药,其中,R 5为H、C 1-C 6的烷基、C 3-C 6的环烷基、C 3-C 6的环烷基取代的C 1-C 3烷基、取代或非取代的芳基或者杂芳基,所述取代的芳基或者杂芳基的取代基为C 1-C 3的烷基、C 1-C 3的烷氧基、C 1-C 3的烷硫基、单或双C 1-C 3烷基取代的氨基或未取代氨基、卤素、三氟甲基、芳氧基或甲砜基中的一种或一种以上;杂芳基为含有5至10个环原子的单环或双环基团,环中含有1-2个选自N、O、S中的原子。
- 根据权利要求1所述化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药,R 5为H、C 1-C 6烷基、C 3-C 6的环烷基、C 3-C 6环烷基取代的C 1-C 3烷基、取代或非取代的苯基、萘基或者杂芳基,其中苯基、萘基或者杂芳基的取代基选自甲基、乙基、 丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、丙硫基、异丙硫基、氨基、甲氨基、乙氨基、二甲氨基、二乙氨基、氟、氯、溴、三氟甲基、苯氧基或甲砜基中的一种或一种以上;所述杂芳基选自吡啶、嘧啶、喹啉、喹唑啉、噁唑、异噁唑、噻唑、噻二唑、吡唑、咪唑、吡咯。
- 根据权利要求1所述化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药,R 5选自H、甲基、乙基、丙基、异丙基、异戊基、环丙基、环丁基、环戊基、环己基、苯基、2-甲氧基苯基、3-甲氧基苯基、4-甲氧基苯基、2-氟苯基、3-氟苯基、4-氟苯基、4-苯氧基苯基、3-(甲砜基)苯基、4-(甲砜基)苯基、2,4-二氟苯基、2,5-二氟苯基、3,4-二氟苯基、2,4-二氯苯基、2,5-二氯苯基、3,4-二氯苯基、2-氟-4-(三氟甲基)苯基、2-氟-5-(三氟甲基)苯基、3-氟-4-(三氟甲基)苯基、3-氟-5-(三氟甲基)苯基、3-三氟甲基-4氟苯基、2-氟-4-氯苯基、2-氟-5-氯苯基、3-氟-4-氯苯基、3-氟-5-氯苯基、3-氯-4-氟苯基、2-氯-4-(三氟甲基)苯基、2-氯-5-(三氟甲基)苯基、3-氯-4-(三氟甲基)苯基、3-氯-5-(三氟甲基)苯基、3-三氟甲基-4-氯苯基、2-氯-4-氟苯基、2-氯-5-氟苯基、3-氯-4-氟苯基、吡啶-2-基、吡啶-3-基、吡啶-4-基、2-甲氧基-吡啶-4-基、3-甲基-异噁唑-5-基、萘-1-基。
- 根据权利要求1所述化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药,R 5选自:丁基、异丁基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-甲基-5-(三氟甲基)苯基、2-甲基-4-(三氟甲基)苯基、3-甲基-4-(三氟甲基)苯基、3-甲基-5-(三氟甲基)苯基、2-氯-4-甲基苯基、2-氯-5-甲基苯基、3-氯-4-甲基苯基。
- 一种式(I)所示的化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药:式(I)中,X为O或者NH;Y为CH;Z为CH;R 1为由1至3个选自C 1-C 3酰基、卤素、三氟甲基、氰基、-CONH 2、-NR aR b或4-7 元杂脂环基中的取代基所取代的C 1-C 6烷基,所述4-7元杂脂环基为含有1-2个选自N、O、S中的原子作为环原子的4-7元杂脂环基,且所述4-7元杂脂环基被1至3个选自卤素、C 1-C 3的烷基、羟基、-NH 2、C 1-C 3酰基中的取代基所取代,R a和R b各自独立地为H、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 3烷氧基取代的C 1-C 6烷基、C 1-C 3烷硫基取代的C 1-C 6烷基、单或双C 1-C 3烷基取代氨基取代的C 1-C 6烷基、或非取代氨基取代的C 1-C 6烷基;R 2、R 3、R 4各自独立地为H或卤素;R 5为H、C 1-C 9的烷基、C 3-C 8的环烷基、C 3-C 8的环烷基取代的C 1-C 6烷基、被1-3个取代基-B取代或非取代的芳基或者杂芳基,所述取代基-B各自独立地为羟基、氰基、C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷硫基、单或双C 1-C 3取代的氨基或未取代氨基、卤素、三氟甲基、芳氧基或甲砜基;所述杂芳基为含有5至10个环原子的单环或双环基团,环中含有1-3个选自N、O、S中的原子。
- 根据权利要求10所述化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药,其中,R 1为由1至3个选自-F、三氟甲基、氰基、-CONH 2、-NR aR b或4-7元杂脂环基中的取代基所取代的C 1-C 6烷基,所述4-7元杂脂环基为含有1-2个选自N、O、S中的原子作为环原子的4-7元杂脂环基,且所述4-7元杂脂环基被1至3个选自-F、C 1-C 3的烷基、羟基、-NH 2、C 1-C 3酰基中的取代基所取代,R a和R b各自独立地为H、C 1-C 3烷基、C 3-C 6环烷基、C 1-C 3烷氧基取代的C 1-C 3烷基、C 1-C 3烷硫基取代的C 1-C 3烷基、单或双C 1-C 3烷基取代氨基取代的C 1-C 3烷基、或非取代氨基取代的C 1-C 3烷基;R 5为H、C 1-C 6烷基、C 3-C 6的环烷基、C 3-C 6环烷基取代的C 1-C 3烷基、被1-3个取代基-B取代或非取代的苯基、萘基或者杂芳基,其中所述取代基-B各自独立地为甲基、乙基、丙基、异丙基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、丙硫基、异丙硫基、氨基、甲氨基、乙氨基、二甲氨基、二乙氨基、氟、氯、溴、三氟甲基、苯氧基或甲砜基;所述杂芳基选自吡啶、嘧啶、喹啉、喹唑啉、噁唑、异噁唑、噻唑、噻二唑、吡唑、咪唑、吡咯。
- 根据权利要求1-11所述化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药,其中,所述化合物的药学上可接受的盐为选自所述化合物的盐酸盐、氢溴酸 盐、氢碘酸盐、高氯酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、乙酸盐、丙酸盐、羟基乙酸盐、乳酸盐、琥珀酸盐、马来酸盐、酒石酸盐、苹果酸盐、柠檬酸盐、富马酸盐、葡萄糖酸盐、安息香酸盐、扁桃酸盐、甲磺酸盐、羟乙基磺酸盐、苯磺酸盐、草酸盐、棕榈酸盐、2-萘磺酸盐、对甲苯磺酸盐、环己氨基磺酸盐、水杨酸盐、己糖酸盐、三氟乙酸盐、铝盐、钙盐、氯普鲁卡因盐、胆碱盐、二乙醇胺盐、乙二胺盐、锂盐、镁盐、钾盐、钠盐和锌盐中的一种或多种。
- 一种治疗与酪氨酸激酶VEGFR-2、C-RAF、B-RAF、RET相关疾病的药用组合物,其由权利要求1-11所述的式(I)的化合物、其药学上可接受的盐、其水合物或其前药与药学上可接受的载体或赋形剂组成。
- 一种药用组合物:其中包含如权利要求1-11所述的式(I)的化合物、其药学上可接受的盐、水合物、溶剂化物、或前药作为活性成分,一个或多个其它的治疗剂,以及一种或多种药学上可接受的载体或赋形剂。
- 根据权利要求1-11中任一项所述的式(I)的化合物或其药学上可接受的盐、异构体、水合物、溶剂化物、或前药在制备治疗与酪氨酸激酶VEGFR-2、C-RAF、B-RAF、RET相关疾病的药物中的应用,其中所述疾病包括:眼底疾病、银屑病、风湿性关节炎、动脉粥样化、肺纤维化、肝纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌。
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