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WO2018157730A1 - Composés de dioxane-quinazoline et de dioxane-quinoléine liés à un cycle aromatique substitués par de l'urée, leur procédé de préparation et leur utilisation - Google Patents

Composés de dioxane-quinazoline et de dioxane-quinoléine liés à un cycle aromatique substitués par de l'urée, leur procédé de préparation et leur utilisation Download PDF

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Publication number
WO2018157730A1
WO2018157730A1 PCT/CN2018/076232 CN2018076232W WO2018157730A1 WO 2018157730 A1 WO2018157730 A1 WO 2018157730A1 CN 2018076232 W CN2018076232 W CN 2018076232W WO 2018157730 A1 WO2018157730 A1 WO 2018157730A1
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Prior art keywords
chloro
phenyl
acid
group
dioxane
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PCT/CN2018/076232
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English (en)
Chinese (zh)
Inventor
张强
张宏波
杨磊夫
杨海龙
周利凯
郑南桥
于善楠
王钟祥
冯守业
徐占强
Original Assignee
北京赛特明强医药科技有限公司
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Priority claimed from CN201710161891.2A external-priority patent/CN108530455B/zh
Application filed by 北京赛特明强医药科技有限公司 filed Critical 北京赛特明强医药科技有限公司
Priority to EP18761220.5A priority Critical patent/EP3590941B1/fr
Priority to AU2018226922A priority patent/AU2018226922B2/en
Priority to US16/489,989 priority patent/US10980809B2/en
Priority to CN201810982631.6A priority patent/CN110156802A/zh
Publication of WO2018157730A1 publication Critical patent/WO2018157730A1/fr
Priority to EP19751364.1A priority patent/EP3750894B1/fr
Priority to US16/968,793 priority patent/US11479559B2/en
Priority to JP2020543109A priority patent/JP7018224B2/ja
Priority to SG11202007521PA priority patent/SG11202007521PA/en
Priority to CA3090829A priority patent/CA3090829C/fr
Priority to AU2019218186A priority patent/AU2019218186B2/en
Priority to KR1020207025247A priority patent/KR102436669B1/ko
Priority to PCT/CN2019/073259 priority patent/WO2019154132A1/fr
Priority to CN201980012394.3A priority patent/CN111757885B/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • 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 quinazoline and a dioxane quinolin compound, and 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.
  • 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 N or CH
  • Z is N or 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 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, morpholin-4-ethyl, Porphyrin-4-propyl, methylpiperazine-4-ethyl, methylpiperazine-4-propyl, N-formylpiperazine-4-ethyl, N-formylpiperazine-4-propyl , N-acetylpiperazine-4-ethyl, N-acetyl piperazine-4-propyl, (1,1-dioxothiomorpholinyl
  • 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 bi-C 1 -C 3 -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-5-(trifluor
  • 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,
  • a process for the preparation of a compound of the formula (I), a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof which comprises A compound of the formula (II') is reacted with a compound of the formula (III), 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 is an alkyl ether consisting of a straight chain, branched chain as previously described.
  • alkenyl and alkynyl groups include straight-chain, branched alkenyl or alkynyl groups.
  • a cycloalkyl group means a cyclic group formed by a carbon atom.
  • C 3 -C 7 represents a carbon atom of an alkyl group having 3 to 7 carbon atoms, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • cycloheptyl similar, likewise includes a cyclic alkenyl group.
  • aryl refers to an unsubstituted or substituted aryl group, such as phenyl, naphthyl, anthracenyl.
  • aroyl refers to -C(O)-aryl.
  • 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 represents an unsubstituted or substituted stable 3 to 8 membered monocyclic saturated ring system selected from carbon atoms and from N, O, S.
  • the heterocyclic ring can be combined with any hetero atom or carbon atom to form a stable structure.
  • 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 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 compounds of the invention or pharmaceutically acceptable salts, isomers or hydrates thereof
  • the synthesis is carried out using the methods described below in the art of organic chemical synthesis, or by variations of those methods as understood by those skilled in the art, and the preferred methods include, but are not limited to, the methods described below.
  • the compound of the invention or a pharmaceutically acceptable salt, isomer or hydrate thereof is prepared by the following method,
  • Step 1) A compound of the formula (V) is reacted with NH 2 -R 5 in the presence of a condensing agent to obtain a compound of the formula (IV).
  • the condensing agent comprises, but is not limited to, triphosgene, carbonyl diimidazole, phenyl chloroformate, phenyl p-nitrochloroformate;
  • This reaction can also be carried out in the presence of a base.
  • the base includes, but is not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene or N-methyl.
  • One or a combination of two or more of morpholine; the aprotic solvent includes, but is not limited to, one of dichloromethane, tetrahydrofuran, DMF, dioxane, dichloroethane, and a combination of two or more;
  • step 1) 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. .
  • an aprotic solvent including but not limited to one of dichloromethane, tetrahydrofuran, DMF, dioxane, dichloroethane, and a combination of two or more thereof.
  • Step 2 The compound represented by the formula (IV) is subjected to a nitro reduction reaction to obtain a compound of the formula (II'-A), 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 3 reacting a compound of the formula (II'-A) with a compound of the formula (III) in a base and an organic solvent to obtain a compound of the formula (I-A),
  • the reaction temperature is room temperature to reflux;
  • the base is selected from one or a combination of two or more of sodium carbonate, potassium carbonate and cesium carbonate;
  • the organic solvent is selected from the group consisting of tetrahydrofuran, dioxane, isopropanol, ethanol, DMF , DMA, acetonitrile, DMSO or a combination of two or more.
  • Step 1) A compound of the formula (IV') is reacted with a formula of NH 2 -R 5 in the presence of a condensing agent to give a compound of the formula (II'-B).
  • the condensing agent comprises, 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.
  • the base includes, but is not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene or N-methyl.
  • step 1) 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. .
  • an aprotic solvent including but not limited to one of dichloromethane, tetrahydrofuran, DMF, dioxane, dichloroethane, and a combination of two or more thereof.
  • Step 2 reacting a compound of the formula (II'-B) with a compound of the formula (III) in a base and an organic solvent to obtain a compound of the formula (I-B);
  • the reaction temperature is room temperature to reflux;
  • the base is selected from one or a combination of two or more of sodium carbonate, potassium carbonate and cesium carbonate;
  • the organic solvent is selected from the group consisting of tetrahydrofuran, dioxane, isopropanol, ethanol, DMF , DMA, acetonitrile, DMSO or a combination of two or more.
  • the nitrification conditions in step 1) are nitric acid and acetic acid.
  • Step 2) 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 or stannous chloride;
  • Step 3) 1-(8-Methoxy-6-amino-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)ethyl-1-one and formic acid Methyl ester or ethyl formate in an organic solvent, catalyzed by a base to give 10-hydroxy-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quina a porphyrin, wherein the organic solvent includes, but is not limited to, one or a combination of two or more of ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, tert-butanol, ethanol, methanol; It is limited to sodium t-butoxide, potassium t-butoxide, sodium methoxide, and sodium ethoxide; the reaction can also be carried out under heating, and the temperature of the heating is from room temperature to reflux.
  • the organic solvent includes, but is
  • step 4 10-hydroxy-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline is reacted with a chlorinating reagent in an organic solvent to prepare 10 -chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline, wherein the chlorinating reagent is phosphorus oxychloride;
  • the organic solvent includes, but is not limited to, one or a combination of two or more of benzene, toluene, chlorobenzene, and xylene; the reaction can also be carried out in the presence of an organic base, which is triethylamine or two. Isopropyl ethylamine.
  • step 4a 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 5 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 II-A;
  • the organic solvent is selected from the group consisting of toluene, chlorobenzene, One or a combination of two or more of xylene, DMF, DMA, DMSO.
  • Step 6) 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 7) 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 comprises, but is not limited to, triphosgene, carbonyl diimidazole, phenyl chloroformate, phenyl p-nitrochloroformate;
  • This reaction can also be carried out in the presence of a base.
  • the base includes, but is not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene or N-methyl.
  • One or a combination of two or more of morpholine; the aprotic solvent includes, but is not limited to, one of dichloromethane, tetrahydrofuran, DMF, dioxane, dichloroethane, and a combination of two or more.
  • step 7) 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 4a) and step 4b) may be omitted, and after step 4), the operation of step 5) may be performed.
  • the invention also provides a process for the preparation of the corresponding compounds, in particular by the methods described below.
  • 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 purple target compound was obtained from 2-fluoro-5-(trifluoromethyl)aniline and 4-aminophenol in the same manner as the intermediate 17), yield 82%. MS: 283 [M+H] + .
  • the pale white target compound was obtained from 2,4-difluoroaniline and 3-fluoro-4-aminophenol in the same manner as the intermediate 17), yield 68%. MS: 283 [M+H] + .
  • the intermediate 17) was obtained by the reaction of 4-aminophenol and 4-fluoro-3-(trifluoromethyl)aniline to give a white solid compound, yield 55%; 1H NMR (DMSO-d6, 400 MHz) ⁇ 6.66- 6.73(2H,m), 7.17-7.26(2H,m), 7.36-7.50(2H,m), 7.56-7.64(1H,m),8.00-8.11(1H,m),8.63(1H,s), 9.14(1H,s);MS:315[M+H] +
  • the mixed acid of fuming nitric acid and acetic acid is added dropwise thereto, and after the dropwise addition is completed, the reaction mixture is reacted at 0 ° C for one hour, and the reaction liquid is poured into crushed ice and stirred, and filtered to obtain a pale yellow solid A3; A3 is dissolved in methanol and then hydrogen The reaction was carried out for 1 hour under palladium on carbon, filtered, and the filtrate was concentrated to give a pale purple oil (A4).
  • the aniline can be replaced by isopropylamine to obtain 35 mg of a yellow solid in a yield of 80%;
  • Example 14 Refer to the operation of Example 14 to replace the aniline with p-fluoroaniline to obtain 25 mg of a yellow solid with a yield of 65%;
  • Example 1 Working with Example 1, consisting of 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1 (4-amino- 2-Chlorophenyl)-3-(3-(methylsulfonyl)phenyl)urea gives a yellow solid;
  • Example 24 1-(3-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline-10- Of oxy)phenyl)-3-(3-methoxyphenyl)urea
  • Example 48 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-((5-(2-methoxyethoxy))-2,3 -Preparation of dihydro-[1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea
  • Example 50 1-(4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline Preparation of -10-yl)oxy)phenyl)-3-(3-methoxyphenyl)urea
  • Example 58 1-(3-Fluoro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Of quinazolin-10-yloxy)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea
  • Example 59 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((5-(2-methoxyethoxy))-2,3 -Preparation of dihydro-[1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea
  • Example 60 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(6-((5-(2-methoxyethoxy))-2,3-dihydro- Preparation of [1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)pyridin-3-yl)urea
  • Example 62 1-(2-Chloro-4-((5-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-[1,4]dioxane[ Preparation of 2,3-f]quinazolin-10-yl)oxy)phenyl)-3-cyclopropylurea
  • Step c) 1-(2-Chloro-4-((5-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-[1,4]dioxane[2] , 3-f]quinazolin-10-yl)oxy)phenyl)-3-cyclopropylurea
  • Example 63 1-(2-Chloro-4-((5-(3-(morpholinepropyloxy)-2,3-dihydro-[1,4]dioxane[2,3- Preparation of f]quinazolin-10-yl)amino)phenyl)-3-cyclopropylurea
  • Example 64 1-(2-Chloro-4-((5-(3-(morpholinyloxy)-2,3-dihydro-[1,4]dioxane[2,3- Preparation of f]quinazolin-10-yl)oxy)phenyl)-3-cyclopropylurea
  • Example 65 1-(2-Fluoro-5-(trifluoromethyl)phenyl)-3-(4-((5-(3-morpholinepropoxy)-2,3-dihydro-[ 1,4] Preparation of dioxo[2,3-f]quinazolin-10-yl)oxy)phenyl)urea
  • Example 66 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-morpholinepropoxy)-2,3-dihydro-[ Preparation of 1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea
  • Example 68 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((5-(3-morpholinepropoxy)-2,3- Preparation of dihydro-[1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea
  • Example 69 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-((5-(3-morpholinepropoxy)-2,3- Preparation of dihydro-[1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea
  • Example 70 1-(2-Fluoro-4-((5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Preparation of quinazolin-10-yl)oxy)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea
  • Example 72 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(2-morpholinoethoxy)-2,3-dihydro-[ Preparation of 1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea
  • Example 74 1-(3-Chloro-4-fluorophenyl)-3-(4-((5-(3-morpholinepropoxy)-2,3-dihydro-[1,4] Preparation of oxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea
  • Example 75 1-(4-Fluoro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-morpholinepropoxy)-2,3-dihydro-[ Preparation of 1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea
  • Example 76 1-(2-Fluoro-5-(trifluoromethyl)phenyl)-3-(4-((5-(2-(tetrahydropyrrol-1-yl)ethoxy)-2) Of 3-(3-hydrogen-[1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea
  • Example 78 1-(4-((5-Isopropoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazolin-10-yl)oxyl Of phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea
  • Example 79 1-(2-Fluoro-5-(trifluoromethyl)phenyl)-3-(4-((5-((tetrahydro-2H-pyran-4-yl)oxy))- Preparation of 2,3-dihydro-[1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea
  • Example 80 1-(2-Fluoro-5-(trifluoromethyl)phenyl)-3-(4-((5-((tetrahydrofuran-3-yl)oxy)-2,3-dihydro) -[1,4] Preparation of Dioxo[2,3-f]quinazolin-10-yl)oxy)phenyl)urea
  • Example 81 1-(4-((5-(3-(1,1-thiomorpholine dioxide)propoxy)-2,3-dihydro-[1,4]dioxane Preparation of [2,3-f]quinazolin-10-yl)oxy)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea
  • Example 18 Working with Example 18, consisting of 10-chloro-5-(3-(1,1-thiomorpholine dioxide)propoxy)-2,3-dihydro-[1,4]dioxane. [2,3-f]quinazoline and 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea are reacted to give the desired product as a white solid.
  • Example 82 1-(2-Chloro-4-((5-(3-(dimethylamino)propoxy)-2,3-dihydro-[1,4]dioxane[2, 3-f]quinazolin-10-yl)amino)phenyl)-3-cyclopropylurea
  • Example 84 1-(2-Chloro-4-((5-(2-methylthioethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Of quinazolin-10-yl)amino)phenyl)-3-cyclopropylurea
  • Example 86 1-(2-Chloro-4-((5-(3-methoxy)propoxy)-2,3-dihydro-[1,4]dioxane[2,3 Preparation of -f]quinazolin-10-yl)oxy)phenyl)-3-cyclopropylurea
  • Example 87 1-(2-Chloro-4-((5-(2-dimethylamino)ethoxy)-2,3-dihydro-[1,4]dioxane[2,3- Preparation of f]quinazolin-10-yl)amino)phenyl)-3-cyclopropylurea
  • Example 88 1-(2-Chloro-4-((5-(6-methoxy)hexyloxy)-2,3-dihydro-[1,4]dioxane[2,3- Preparation of f]quinazolin-10-yl)oxy)phenyl)-3-cyclopropylurea
  • Steps 1 to 4 are the same as steps 1 to 4 of the preparation of Example 90.
  • Steps 1 to 4 are the same as steps 1 to 4 of the preparation of Example 90.
  • Steps 1 to 4 are the same as steps 1 to 4 of the preparation of Example 90.
  • Steps 1 to 4b are the same as Steps 1 to 4b of the preparation of Example 93.
  • Example 95 1-(2-Fluoro-5-(trifluoromethyl)phenyl)-3-(4-((5-(3-morpholinepropoxy)-2,3-dihydro-[ Preparation of L-malic acid salt of 1,4]dioxane[2,3-f]quinazolin-10-yloxy)phenyl)urea
  • Example 65 The compound obtained in Example 65 (645 mg, 1 mmol) was dissolved in 15 mL of acetone and stirred at room temperature for 15 min, then 2 mL of aqueous solution of L-malic acid (134 mg, 1 mmol) was added, and stirring was continued for 12 hours, and the reaction mixture was filtered to give a white solid (400 mg). The solid was dissolved in 15 mL of ethanol and heated under reflux. After completely dissolved, it was cooled and allowed to stand, and filtered to yield white crystal compound 260 mg, HPLC>99%.
  • the test method is as follows:
  • Compound dilution a total of 12 concentrations after a 4-fold gradient dilution from the highest concentration of 10000 nM (the maximum final concentration of the drug used in this experiment is 10000 nM, the minimum final concentration is 0.002384 nM).
  • Negative control Add 2.5 ⁇ l/well 4X substrate/ATP Mix and 7.5 ⁇ l 1X Kinase Assay Buffer to the 384-well plate well.
  • Positive control 2.5 ⁇ l/well 4X substrate/ATP Mix, 2.5 ⁇ l/well 1X Kinase Assay Buffer with 4% DMSO, 5 ⁇ l/well 2X VEGFR-2 solution were added to 384-well plates. The final concentration of DMSO in the reaction system is 4%.
  • Stop the enzymatic reaction add 5 ⁇ l of 4X Stop solution to the wells of a 384-well plate with a lance, mix by centrifugation, and react at room temperature for 5 min.
  • inhibition rate (%) [1 - (experimental well reading - negative control well reading value) / (positive control well reading value) - Negative control well reading)) x 100%.
  • inhibition rate (%) [1 - (experimental well reading - negative control well reading value) / (positive control well reading value) - Negative control well reading)) x 100%.
  • GraphPad Prism5 software deal with the corresponding IC 50 values (concentration of compound inhibition rate of enzyme up 50%).
  • Table (1) lists the results of the determination of the tyrosine kinase inhibitory activity of some of the compounds of the present invention, and the intervals of IC 50 are represented by A, B, and C, wherein A represents an IC 50 of less than or equal to 50 nM, and B represents an IC 50 greater than 50 nM but less than or equal to 500 nM, C indicates an IC 50 greater than 500 nM but less than or equal to 5000 nM, and D indicates an IC 50 greater than 5000 nM.
  • test compound Depending on the molecular weight of the compound, directly add appropriate volume of DMSO to dissolve the test compound (see Table 1). The concentration of DMSO in the storage of the compound is 100%, and the final concentration in the experimental system is 1% ( See Table 2, 3). The compound was serially diluted with DMSO at a concentration of 3 times, with a maximum concentration of 1000 nM and a minimum concentration of 0.46 nM for a total of 8 dilution points.
  • Sorafenib was a selective inhibitor of BRAF and RAF1, and as a positive control for this experiment, the dilution method was the same as that of the above test compound.
  • Enzyme B-RAF: 0.1 ng/ul (final concentration in the reaction system); C-RAF: 0.1 ng/ul (final concentration in the reaction system)
  • Substrate and ATP inactive MEK1: 2 ng/ul (final concentration in the reaction system); ATP: 35 uM (final concentration in the reaction system)
  • Inhibition rate (%) (without compound control measured value - sample measured value) / (without compound control measured value - without enzyme control measured value) 100%
  • Table (2) lists the results of the determination of the inhibitory activities of some of the compounds in this patent on tyrosine kinases, C-RAF and B-RAF, using A, B, C to represent the IC 50 interval, where A indicates an IC 50 is less than Or equal to 200 nM, B indicates an IC 50 greater than 200 nM but less than or equal to 500 nM, C indicates an IC 50 greater than 500 nM but less than or equal to 1000 nM, and D indicates an IC 50 greater than 1000 nM.
  • Table (3) lists the results of assays for the activity of representative compounds of the present invention against various cancer cells, wherein MHCC97H, HuH7, and HepG2 are liver cancer cell lines, A549 is a lung cancer cell line, and 8505C is a thyroid cancer cell line.
  • 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 tyrosine kinases such as VEGFR-2 and/or C-RAF and/or B-RAF.
  • Some of the compounds of the present invention have potent in vitro inhibitory activities against cancer cells, including liver cancer cells MHCC97, HuH7, HepG2, lung cancer cells A549, and thyroid cancer cells 8505C.
  • 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 present invention are also useful in diseases other than cancer associated with tyrosine kinases 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

La présente invention concerne un composé de dioxane-quinazoline lié à un cycle aromatique substitué par de l'urée de formule (1) et un dioxane-quinoléine lié à un cycle aromatique substitué par de l'urée, ou un sel pharmaceutiquement acceptable ou un hydrate de ceux-ci. L'invention concerne également une préparation du composé tel que représenté par la formule (1) et son sel pharmaceutiquement acceptable, ainsi que son utilisation en tant que médicament. Selon l'invention, le médicament est utilisé comme inhibiteur de tyrosines kinases (par exemple, VEGFR-2, C-RAF, B-RAF) pour traiter des maladies associées à la tyrosine kinase.
PCT/CN2018/076232 2017-03-01 2018-02-11 Composés de dioxane-quinazoline et de dioxane-quinoléine liés à un cycle aromatique substitués par de l'urée, leur procédé de préparation et leur utilisation WO2018157730A1 (fr)

Priority Applications (13)

Application Number Priority Date Filing Date Title
EP18761220.5A EP3590941B1 (fr) 2017-03-01 2018-02-11 Composés de dioxane-quinazoline et de dioxane-quinoléine liés à un cycle aromatique substitués par de l'urée, leur procédé de préparation et leur utilisation
AU2018226922A AU2018226922B2 (en) 2017-03-01 2018-02-11 Urea-substituted aromatic ring-linked dioxane-quinazoline and -linked dioxane-quinoline compounds, preparation method therefor and use thereof
US16/489,989 US10980809B2 (en) 2017-03-01 2018-02-11 Urea-substituted aromatic ring-linked dioxane-quinazoline and -linked dioxane-quinoline compounds, preparation method therefor and use thereof
CN201810982631.6A CN110156802A (zh) 2017-03-01 2018-08-27 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
CN201980012394.3A CN111757885B (zh) 2017-03-01 2019-01-25 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
PCT/CN2019/073259 WO2019154132A1 (fr) 2018-02-11 2019-01-25 Composé de dioxazoline lié au cycle aromatique à substitution d'urée, son procédé de préparation et ses applications
US16/968,793 US11479559B2 (en) 2018-02-11 2019-01-25 Urea-substituted aromatic ring-linked dioxinoquinoline compounds, preparation method and uses thereof
EP19751364.1A EP3750894B1 (fr) 2018-02-11 2019-01-25 Composé de dioxazoline lié au cycle aromatique à substitution d'urée, son procédé de préparation et ses applications
JP2020543109A JP7018224B2 (ja) 2018-02-11 2019-01-25 尿素置換芳香族環結合ジオキシノキノリン系化合物、その調製方法および使用
SG11202007521PA SG11202007521PA (en) 2017-03-01 2019-01-25 Urea-substituted aromatic ring-linked dioxazoline compound, preparation method therefor, and uses thereof
CA3090829A CA3090829C (fr) 2018-02-11 2019-01-25 Composes de dioxazoline lies au cycle aromatique d'uree substitue, procede de preparation et utilisations
AU2019218186A AU2019218186B2 (en) 2017-03-01 2019-01-25 Urea-substituted aromatic ring-linked dioxinoquinoline compounds, preparation method and uses thereof
KR1020207025247A KR102436669B1 (ko) 2018-02-11 2019-01-25 우레아-치환된 방향족 고리-연결된 디옥시노퀴놀린 화합물 및 이의 제조방법 및 용도

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