WO2020042972A1 - Urea-substituted aromatic ring-linked dioxane and quinazoline or quinoline compound, composition and application thereof - Google Patents

Urea-substituted aromatic ring-linked dioxane and quinazoline or quinoline compound, composition and application thereof Download PDF

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WO2020042972A1
WO2020042972A1 PCT/CN2019/101623 CN2019101623W WO2020042972A1 WO 2020042972 A1 WO2020042972 A1 WO 2020042972A1 CN 2019101623 W CN2019101623 W CN 2019101623W WO 2020042972 A1 WO2020042972 A1 WO 2020042972A1
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substituted
alkyl
cancer
group
compound
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张强
于善楠
孙月明
郑南桥
杨磊夫
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北京赛特明强医药科技有限公司
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Definitions

  • the invention belongs to the field of medicinal chemistry, and particularly relates to a class of urea-substituted aromatic cyclodioxoquinazoline or quinoline compounds, isomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof. , And their pharmaceutical compositions and their use in the treatment of autoimmune diseases, tumors, and Alzheimer's disease associated with vascular endothelial growth factor receptor 2 (VEGFR-2) and / or colony stress factor 1 receptor (CSF1R) Application in pharmaceutical preparation.
  • VAGFR-2 vascular endothelial growth factor receptor 2
  • CSF1R colony stress factor 1 receptor
  • PK Protein kinase
  • RTK tyrosine kinase
  • Vascular endothelial growth factor receptor (vascular endothelial growth factor receptor) is one of the family of receptor tyrosine kinases. It combines with its ligand, vascular endothelial growth factor (VEGF), to produce a series of biochemical and The physiological process eventually promotes the formation of new blood vessels. Tumor angiogenesis and their permeability are mainly regulated by vascular endothelial cell growth factor (VEGF), which functions through at least two different receptors (VEGFR-1, VEGFR-2).
  • VEGF vascular endothelial cell growth factor
  • VEGF is an important stimulator of normal and pathological angiogenesis and vascular permeability (Jakeman et al., 1993, Endocrinology 133: 848-859; Kolch et al., 1995, Breast Cancer Research and Treatment , 36: 139-155; Connolly et al., 1989, J. Biol. Chem. 264: 20017-20024).
  • Vascular endothelial cell growth factor induces the angiogenic budding phenotype by inducing endothelial cell proliferation, protease expression and migration, and subsequent cellular tissue formation of capillaries. Therefore, the antagonism of VEGF produced by the chelation of VEGF by antibodies can lead to the inhibition of tumor growth (Kim et al., 1993, Nature 362: 841-844).
  • VEGFR-2 is mainly distributed in vascular endothelial cells, it can bind to VEGF-A, VEGF-C, VEGF-D, and VEGF-E. And VEGF stimulates the proliferation of endothelial cells, increases the permeability of blood vessels and the formation of new blood vessels is mainly achieved by binding and activating VEGFR-2. If the activity of VEGFR-2 is blocked, tumor growth and metastasis can be inhibited through direct and indirect pathways, and the ideal antitumor effect can be achieved. Therefore, finding small molecule inhibitors with high activity and selectivity for VEGFR-2 has become a very promising tumor treatment strategy.
  • Colony stimulating factor 1 receptor (hereinafter referred to as CSF1R, also known in the art as FMS, FIM2, C-FMS, MCSF receptor, and CD115) has an N-terminal extracellular domain (ECD) and a C-terminal intracellular domain.
  • ECD extracellular domain
  • the domain of a single transmembrane receptor with tyrosine kinase activity is a member of the CSF1 / PDGF receptor tyrosine kinase family.
  • CSF1 or interleukin 34 ligand also known as IL-34
  • IL-34 interleukin 34 ligand
  • CSF1R activation by CSF1 or IL-34 results in the proliferation, survival, movement, and differentiation of cells in monocytes (such as osteoclasts, dendritic cells, and microglia) / macrophages, and thus in general Tissue development and immune defense play important roles.
  • monocytes such as osteoclasts, dendritic cells, and microglia
  • CSF1R may be an effective therapeutic target for these solid tumors.
  • the present application provides a class of urea-substituted aromatic cyclodioxoquinazoline or quinoline compounds that exhibit good CSF1R inhibitory activity and VEGFR-2 inhibitory activity and are expected to be used as CSF1R and / or VEGFR-2 inhibitor
  • the agent is used in the preparation of a medicine for treating an autoimmune disease, a tumor or Alzheimer's disease.
  • the present invention aims to provide a urea-substituted aromatic cyclodioxoquinazoline or quinoline compound, isomer, hydrate, solvate, pharmaceutically acceptable salt or Prodrugs, and pharmaceutical compositions thereof, and their use in the preparation of medicaments for the treatment of autoimmune diseases, tumors, or Alzheimer's disease related to VEGFR-2 and / or CSF1R.
  • One aspect of the present invention provides a urea-substituted aromatic cyclodioxoquinazoline or quinoline compound, isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, the
  • the compound has the structural formula (I):
  • Q is N or CH
  • G is O or NH
  • 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 3 -alkylthio-substituted C 1 -C 6 alkyl or mono- or di-C 1 -C 3 alkyl-substituted or unsubstituted amino-substituted C 1 -C 6 alkyl;
  • R 2 and R 3 are each independently -H, -CF 3 , halogen, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy.
  • R 2 and R 3 are only Represents double substitution, without limiting their substitution position on the benzene ring;
  • R 4 is -H, C 1 -C 3 alkyl
  • R 5 is-(CH 2 ) m R 7 , where m is an integer from 0 to 3, the R 7 is an aryl or heteroaryl group substituted or unsubstituted by one to two substituents -A, the substitution -A are each independently C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, halogen, trifluoromethyl or methylsulfone,
  • the heteroaryl group is a monocyclic or bicyclic heteroaryl group containing 1-3 heteroatoms selected from N, O, and S as ring atoms and containing 5 to 10 ring atoms.
  • G is O.
  • R 1 is -H, or an unsubstituted C 3 -C 8 cycloalkyl group, or 1 to 3 alkoxy groups selected from C 1 -C 6 , C 1- C 6 alkylthio, C 1 -C 3 acyl, hydroxyl, -F, trifluoromethyl, cyano, -CONH 2 , C 3 -C 6 cycloalkyl or -NR a R b substituent Substituted or unsubstituted C 1 -C 8 alkyl,
  • R 6 is a substituted or unsubstituted 4-8 member heteroalicyclic group, and the 4-8 member heteroalicyclic group contains 1-2 members selected from N, O
  • the atom in S is a 4-8 membered heteroalicyclic group as a ring atom, and the substituted 4-8 membered heteroalicyclic group is substituted by 1 to 3 alkyl groups selected from -F, C 1 -C 3 , C 1- C 3 alkoxy, hydroxy, -NR a R b , C 1 -C 3 acyl, substituents in oxo, n is 0 to 8,
  • R a and R b are each independently -H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 3 alkoxy-substituted C 1 -C 6 alkyl.
  • R 1 is -H, an unsubstituted C 3 -C 6 cycloalkyl group, from 1 to 3 selected from C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, C 1 -C 3 acyl, hydroxyl, -F, trifluoromethyl, cyano, -CONH 2 , C 3 -C 5 cycloalkyl, or -NR a R b substituted or unsubstituted C 1 -C 8 alkyl,
  • R 6 is a substituted or unsubstituted 4-6 membered heteroalicyclic group, and the 4-6 membered heteroalicyclic group contains 1-2 members selected from N
  • R a and R b are each independently -H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 3 alkoxy-substituted C 1 -C 3 alkyl.
  • R 1 is -H, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or from 1 to 3 selected from methoxy, ethoxy, methylthio, ethylthio, Formyl, acetyl, hydroxy, -F, trifluoromethyl, cyano, -CONH 2 , cyclopropyl, cyclobutyl, cyclopentyl, -NR a R b substituted or unsubstituted C 1- C 6 alkyl, or-(CH 2 ) nR 6 , wherein R 6 is a substituted or unsubstituted 4-6 membered heteroalicyclic group, and the 4-6 membered heteroalicyclic group contains 1-2 A 4-6 membered heteroalicyclic group having an atom selected from N, O, S as a ring atom, and the substituted 4-6 membered heteroalicyclic group is selected from 1 to 3 selected
  • the 4-6 membered heteroalicyclic group is selected from a 4-6 membered oxetanyl group, or a 4-6 membered azacycloalkyl group, or a 4-6 membered thiacycloalkyl group, or the following groups:
  • R a and R b are each independently -H, methyl, ethyl, methoxymethyl, methoxyethyl, methoxypropyl, cyclopropyl, or cyclobutyl.
  • the oxetanyl group, azacycloalkyl group, and thiocycloalkyl group refer to an alicyclic group in which an alicyclic group ring is respectively doped with an oxygen atom, a nitrogen atom, or a sulfur atom.
  • R 1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetan-3-yl, tetrahydrofuran- 3-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, hydroxyethyl, hydroxypropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxy Propylpropyl, methylthiopropyl, ethylthiopropyl, cyanomethyl, cyanoethyl, cyanopropyl, cyclopropylmethyl, cyclopropylethyl, -CH 2 CONH 2 ,- CH 2 CF 3 , 2-methyl 2-hydroxypropyl, -(CH 2 ) t-NR a R b
  • R 2 and R 3 are each independently -H, -CF 3 , -F, -Cl, methyl, ethyl, methoxy, or ethoxy.
  • R 4 is H, methyl or ethyl.
  • R 5 is-(CH 2 ) m R 7 , where m is an integer of 0-3, and R 7 is substituted by one or two substituents -A or Unsubstituted aryl or heteroaryl
  • the substituents -A are each independently a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a C 1 -C 3 alkylthio group,- F, -Cl, trifluoromethyl or methylsulfone, wherein the aryl group is phenyl, naphthyl, phenanthryl, and the heteroaryl group is pyrrolyl, furyl, pyridyl, thienyl, imidazolyl , Thiazolyl, isothiazolyl, indazolyl, indolyl, indazolyl, isoindolyl, dihydroindolyl, isod
  • aryl is phenyl and the heteroaryl is thiazolyl.
  • R 5 is phenyl or thiazolyl substituted or unsubstituted by one or more of methyl, ethyl, methoxy, ethoxy, F, Cl, trifluoromethyl, or Said methyl, ethyl substituted with one or more of methyl, ethyl, methoxy, ethoxy, F, Cl, trifluoromethyl or substituted or unsubstituted phenyl or thiazolyl.
  • the pharmaceutically acceptable salt of the urea-substituted aromatic cyclodioxoquinazoline or quinoline compound is selected from the hydrochloride, hydrobromide salt of the compound , Hydroiodate, perchlorate, sulfate, nitrate, phosphate, formate, acetate, propionate, glycolate, lactate, succinate, maleate, Tartrate, malate, citrate, fumarate, gluconate, benzoate, mandelate, mesylate, isethionate, benzenesulfonate, oxalate, palm Acid salt, 2-naphthalenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, salicylate, hexose, trifluoroacetate, aluminum, calcium, chloroprocaine One or more of a salt, a choline salt, a diethanolamine
  • Another aspect of the invention relates to the urea-substituted aromatic cyclodioxoquinazoline or quinoline compounds, isomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof
  • the diseases related to VEGFR-2 and / or CSF1R include Alzheimer's disease, fundus disease, dry eye disease, psoriasis , Vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atherosclerosis, pulmonary fibrosis, liver fibrosis, myelofibrosis, non-small cell lung cancer , Small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer
  • compositions which comprises the urea-substituted aromatic cyclodioxoquinazoline or quinoline compounds, isomers, hydrates, and solvents of the present application.
  • Compounds, pharmaceutically acceptable salts or prodrugs, and one or more pharmaceutically acceptable carriers or excipients are also useful as pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical composition may further include one or more other therapeutic agents.
  • the urea-substituted aromatic cyclodioxoquinazoline or quinoline compounds of the present application show strong inhibitory activity against VEGFR-2 and CSF1R.
  • the urea-substituted aromatic cyclodioxoquinazoline Or quinoline compounds, its isomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and their pharmaceutical compositions are expected to be used for the preparation of autoimmune diseases related to VEGFR-2 and / or CSF1R , Tumors and Alzheimer's disease drugs.
  • Example 1 shows a liquid chromatogram of a mixture of compounds prepared in Example 127 and Example 171 of the present application
  • Figure 2 shows a liquid chromatogram of the compound prepared in Example 127 of the present application
  • Example 171 of the present application shows a liquid chromatogram of the compound prepared in Example 171 of the present application
  • FIG. 4 is a diagram showing the inhibition of M-CSFR (cFMS) phosphorylation in RAW264.7 cells by using the protein labeling method of the compound prepared in Example 41 of the present application;
  • FIG. 4 is a diagram showing the inhibition of M-CSFR (cFMS) phosphorylation in RAW264.7 cells by using the protein labeling method of the compound prepared in Example 41 of the present application;
  • FIG. 5 shows the inhibitory rate of the compound prepared in Example 41 of the present application on M-CSFR (cFMS) phosphorylation in RAW264.7 cells at different concentrations;
  • FIG. 6 is a graph showing the detection of the inhibitory effect of M-CSFR (cFMS) phosphorylation on RAW264.7 cells by a protein labeling method using the compound prepared in Example 100 of the present application;
  • FIG. 7 shows the inhibitory rate of the compound prepared in Example 100 of the present application on M-CSFR (cFMS) phosphorylation in RAW264.7 cells at different concentrations.
  • Alkyl refers to an aliphatic hydrocarbon group. Alkyl is saturated or unsaturated. The alkyl moiety, whether saturated or unsaturated, can be branched or linear. "Alkyl” may have 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms. In one aspect, the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
  • Typical alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, allyl, Vinyl, acetylene, but-2-enyl, but-3-enyl and the like.
  • cycloalkyl refers to a monocyclic or polycyclic aliphatic non-aromatic group in which each atom (i.e., a backbone atom) constituting the ring is a carbon atom. Cycloalkyl can be saturated or partially unsaturated. A cycloalkyl group can be fused with an aromatic ring and the point of attachment is on a carbon that is not an aromatic ring carbon atom. Cycloalkyl includes groups having 3 to 10 ring atoms.
  • cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • Cycloalkyl can be substituted or unsubstituted.
  • a cycloalkyl is a C 3 -C 8 cycloalkyl.
  • Alkoxy refers to a (alkyl) -0- group and “alkylthio” refers to a (alkyl) -S- group, where alkyl is as defined herein.
  • the alkoxy group is a C 1 -C 6 alkoxy group, and more preferably a C 1 -C 3 alkoxy group.
  • the alkylthio group is a C 1 -C 6 alkylthio group, and more preferably a C 1 -C 3 alkylthio group.
  • heteroalicyclic refers to a heterocycloalkyl ring containing one or more heteroatoms in the ring, wherein each heteroatom in the ring is selected from O, S, and N, and specifically, may contain 1-2 selected from The atoms in N, O, and S are ring atoms, and each heterocyclic group may contain 4 to 8 atoms, preferably 4 to 6 atoms in its ring system. Moreover, the heteroalicyclic group may be unsubstituted or substituted.
  • heteroalicyclic ring in the heteroalicyclic group containing 1-2 heteroatoms selected from N, O, and S may be any one selected from the following ring structures:
  • isomers in the present application are different compounds having the same molecular formula, and may include various isomeric forms such as stereoisomers and tautomers.
  • “Stereoisomers” are isomers that differ only in the arrangement of their atoms in space. Certain compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomers that can be defined as (R)-or (S)-based on absolute stereochemistry form.
  • the chemical entities, pharmaceutical compositions and methods of the present invention are intended to include all of these possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures.
  • Optically active (R)-and (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the optical activity of a compound can be analyzed by any suitable method, including, but not limited to, chiral chromatography and polarimetry, and the degree of dominance of one stereoisomer over other isomers can be determined.
  • Tautomers are structurally different isomers that can be converted to each other through tautomerization.
  • “Tautomerization” is a form of isomerization and includes proton transfer or proton transfer tautomerization, which can be considered as a subset of acid-base chemistry.
  • “Proton transfer tautomerization” or “proton transfer tautomerization” involves the migration of a proton accompanied by a bond-level transformation, which is often the exchange of a single bond with an adjacent double bond. When tautomerization is possible (eg, in solution), the chemical equilibrium of the tautomers can be reached.
  • An example of tautomerization is keto-enol tautomerization.
  • compounds, isomers, crystals or prodrugs of formula (I) and their pharmaceutically acceptable salts may exist in solvated and unsolvated forms.
  • the solvated form may be a water-soluble form.
  • the invention includes all of these solvated and unsolvated forms.
  • the invention also provides a method for preparing the corresponding compound, which can be specifically prepared through the following route.
  • Three representative synthetic routes are shown below:
  • the reaction solvent was provided by Sinopharm
  • Thin layer chromatography silica gel plate (thickness 0.5mm, 1mm, 200X200mm) provided by Yantai Xinnuo Chemical Co., Ltd.
  • Step 1) A solution of 3-methoxyresorcinol (25.3 g, 180 mmol), potassium carbonate (104.5 g, 756 mmol), and 1,2-dibromoethane (74.4 g, 396 mmol) in DMF (100 mL) The reaction was heated in a nitrogen system at 60 ° C for 6 hours. After quenching with water, extraction was performed with ethyl acetate; the organic phase was washed with a saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated to obtain a dark gray oil: 5-methoxy -2,3-dihydrobenzo [b] [1,4] dioxane (25.4g, 153mmol, yield 85%);
  • Step 2 Slowly add acetyl chloride (5.57 mL, 78 mmol) to nitromethane (200 mL) containing AlCl 3 (12.0 g, 90 mmol) under ice-water bath conditions in a nitrogen atmosphere. Then slowly add 5-methoxy -2,3-dihydrobenzo [b] [1,4] dioxane (10.0g, 60mmol) in a solution of nitromethane (100mL). The reaction was stirred at room temperature for 5 hours, and quenched by the addition of a 1N hydrogen chloride solution. The organic phase was washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated.
  • Step 3 In a solution of 5-acetyl-2,3-dihydro-8-methoxy-1,4-benzodioxane (10.1 g, 49 mmol) in acetic acid (60 mL) under ice-water bath conditions Add concentrated nitric acid (62%, 20mL) dropwise, stir at room temperature for 3 hours, add water to beat, filter and dry to obtain a yellow solid product: 1- (8-methoxy-6-nitro-2,3-dihydrobenzo [b ] [1,4] Dioxane-5-yl) ethyl-1-one 10.5g, 85% yield;
  • Step 4) To 1- (8-methoxy-6-nitro-2,3-dihydrobenzo [b] [1,4] dioxane-5-yl) ethyl-1-one ( A solution of 10.1 g, 40 mmol) in methanol (100 mL) was added to wet palladium on carbon (10%, 0.5 g), and the reaction was stirred for 10 hours after being replaced with hydrogen, filtered, and concentrated to give a purple oil: 1- (6-amino-8-methoxy -2,3-dihydrobenzo [b] [1,4] dioxane-5-yl) ethyl-1-one (8.8 g, yield 95%), MS: 224 [M + H ] +
  • Step 5 To 1- (6-amino-8-methoxy-2,3-dihydrobenzo [b] [1,4] dioxane-5-yl) ethyl-1-one (4.5 g, 20 mmol) of dioxane (80 mL) solution was added sodium tert-butoxide (4.4 g, 46 mmol), stirred at room temperature for half an hour, and a solution of methyl formate (10.8 mL, 132 mmol) in dioxane (10 mL) was added.
  • sodium tert-butoxide 4.4 g, 46 mmol
  • Example 1 1- (1- (4-fluorophenyl) ethyl) -3- (4-((5- (3-morpholinyl) -2,3-dihydro- [1,4] Preparation of dioxane [2,3-f] quinazolin-10-yl) oxy) phenyl) urea
  • Step 1) Under ice water bath conditions, add phenyl chloroformate and pyridine to the DMF solution of 1- (4-fluorophenyl) ethyl-1-amine, and stir at room temperature for 8 hours.
  • the product (1- (4 -Fluorophenyl) ethyl) phenyl carbamate was used directly in the next step, MS: 260 [M + H] +
  • Step 2) Add 4-aminophenol to the reaction solution obtained in step 1), and heat the reaction at 50 ° C for two hours, cool, quench with water, extract with ethyl acetate, wash with saturated brine, dry the organic phase, and concentrate to obtain a gray color.
  • the solid product 1- (1- (4-fluorophenyl) ethyl) -3- (4-hydroxyphenyl) urea was used directly in the next step;
  • Step 3) The product obtained in step 2), 10-chloro-5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f ] Quinazoline (intermediate 2) and potassium carbonate were added to DMF, heated to 80 ° C for 5 hours, cooled, slurried with water, filtered, and dried to obtain a pale yellow solid, which was purified by column chromatography to obtain a white solid product (1- (1 -(4-fluorophenyl) ethyl) -3- (4-((5- (3-morpholinyl) -2,3-dihydro- [1,4] dioxane [2,3 -f] quinazolin-10-yl) oxy) phenyl) urea);
  • Example 2 The same operation as in Example 1 was carried out by replacing 4-aminophenol in step 2) with 4-amino-3-trifluoromethylphenol to obtain a white solid product.
  • Example 2 The same operation as in Example 1 was carried out by replacing 4-aminophenol in step 2) with 4-amino-3-methoxyphenol to obtain a white solid product.
  • Example 2 The same operation as in Example 1 was carried out by replacing 4-aminophenol in step 2) with 4-amino-2-methoxyphenol to obtain a white solid product.
  • Examples 11-25 in the following Table 1 were prepared using similar procedures to Example 1, except that the raw materials with different substituents were used to obtain the corresponding target compounds, as shown in the following table.
  • Examples 26-34 in Table 2 below were prepared using similar procedures to Example 1, except that the raw materials with different substituents were used to obtain the corresponding target compounds, as shown in the following table.
  • Example 35 1- (3-fluoro-4-((5-methoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinazoline-10- ) Oxy) phenyl) -3- (4-fluorobenzyl) urea
  • Step 1) Under ice water bath conditions, add phenyl chloroformate and pyridine to the DMF solution of 4-fluorobenzylamine, and stir at room temperature for 8 hours.
  • the product (1- (4-fluorophenyl) methyl) amino Phenyl formate was used directly in the next step, MS: 246 [M + H] + ;
  • Step 2) Add 2-fluoro-4aminophenol to the reaction solution obtained in step 1), and heat the reaction at 50 ° C for two hours, cool, quench with water, extract with ethyl acetate, wash with saturated brine, and dry the organic phase. Concentrated to give the product 1- (3-fluoro-4-hydroxyphenyl) -3- (4-fluorobenzyl) urea as a gray solid, which was directly used in the next step;
  • Step 3) 5- (benzyloxy) -10-chloro-2,3-dihydro- [1,4] dioxane [2,3-f] quinazoline (330 mg, 1 mmol), step 2)
  • the obtained product (280mg, 1mmol) and potassium carbonate (210mg, 1.5mmol) in DMF (5mL) were heated to 80 ° C for 5 hours, cooled, slurried with water, filtered and dried to give 450 mg of a yellow-black solid ((5- (Benzyloxy) -2,3-dihydro- [1,4] dioxane [2,3-f] quinazolin-10-yl) oxy) -3-fluorobenzene ) -3- (4-fluorobenzyl) urea, yield 79%, MS: 571 [M + H] +;
  • Step 4) Pd / C (10% Pd, 50% wet) was added to a methanol solution of the product obtained in step 3) (285 mg, 0.05 mmol). The system was replaced with hydrogen and reacted for 10 hours under hydrogen conditions, and then filtered. Washed with DMF, and the filtrate was concentrated to obtain 220 mg of 1- (3-fluoro-4-((5-hydroxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinazole) as a gray solid product. Phenolin-10-yl) oxy) phenyl) -3- (4-fluorobenzyl) urea, yield 92%, MS: 481 [M + H] + ;
  • Step 5) The product obtained in step 4) (50mg, 0.1mmol), methyl iodide (0.05mL, 0.8mmol) and potassium carbonate (70mg, 0.5mmol) in DMF (1mL) were heated and reacted at 80 ° C.
  • Examples 36-58 in Table 3 below were prepared using similar procedures to Example 35, except that the raw materials with different substituents were used to obtain the corresponding target compounds, as shown in the following table.
  • Example 60 in Table 4 below was prepared using a method similar to Example 1, and Examples 61-87 were prepared using a method similar to Example 35, with the difference being that raw materials with different substituents were used to obtain the corresponding The target compounds are shown in the table below.
  • Step 1) 10-chloro-5-methoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinoline (5.0 g, 20 mmol), 4- Nitrophenol (2.8 g, 20 mmol) was added to chlorobenzene (50 mL), and the reaction was heated and stirred at 150 ° C for 20 hours. After cooling, concentrating to a paste, water was added for pulping, and the earthy yellow solid was filtered to obtain 4.6 g.
  • Step 2) Add the product (0.36g, 1mmol) obtained in step 1) to a dichloromethane solution of boron tribromide (1M, 5mL), stir at room temperature overnight, quench with water (0.3mL), and concentrate the resulting yellow 0.36 g of solid as the hydrogen bromide of 10- (4-nitrophenoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-5-phenol Salt, used directly in the next step, MS: 341 [M + H] +
  • Step 3) To a solution of the product obtained in step 2) (0.36 g, 0.9 mmol) in DMF (5 mL) were added bromoethane (0.32 g, 3 mmol) and potassium carbonate (0.41 g, 3 mmol), respectively, and heated to 80 ° C. and The reaction was stirred for 5 hours, cooled, slurried with water, filtered and dried to obtain 0.29 g of a yellow solid, which was 5-ethoxy-10- (4-nitrophenyloxy) -2,3-dihydro- [1,4]. Dioxane [2,3-f] quinoline, yield 93%, MS: 369 [M + H] + ;
  • Step 4) Dissolve the product obtained in step 3) (0.29g, 0.8mmol) in methanol (10mL), add palladium on carbon (10% palladium content, wet) to catalyze, and stir the reaction at room temperature under hydrogen for 2 hours. Filter through celite and dry the filtrate to obtain 0.22g of 4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinoline-10- (Yl) oxy) aniline, yield 82%, MS: 339 [M + H] + ;
  • Step 5 (4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) phenyl)
  • phenyl carbamate The product (170 mg, 0.5 mmol) obtained in step 4) was dissolved in dry DMF (3 mL), and then phenyl chloroformate (160 mg, 1 mmol) and pyridine (0.5 mL) were added dropwise to stir the reaction at room temperature. TLC monitoring, do not process after the reaction is completed, proceed directly to the next step;
  • Step 6) Add 4-fluorobenzylamine (190 mg, 1.5 mmol) to the reaction solution of the intermediate obtained in step 5), heat to 60 ° C. and stir for 3 hours, cool, add water and filter to obtain a gray solid. Column chromatography Purified to give 26mg of white solid;
  • Examples 89-118 in Table 5 below were prepared using a method similar to Example 88, except that the raw materials with different substituents were used to obtain the corresponding target compounds, as shown in the following table.
  • Examples 119-162 in Table 6 below were prepared using a method similar to Example 88, except that the raw materials with different substituents were used to obtain the corresponding target compounds, as shown in the following table.
  • Examples 163-206 in Table 7 below were prepared using a method similar to Example 88, except that the raw materials with different substituents were used to obtain the corresponding target compounds, as shown in the following table.
  • Example 207 1- (4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) Phenyl) -3- (3-fluorobenzyl) urea
  • Example 210 1- (3-fluorobenzyl) -3- (4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) phenyl) urea
  • Example 88 The same operation as in Example 88 was carried out by replacing 4-bromoethane in step 3) with 4- (3-chloropropyl) -morpholine to obtain a white solid product, and replacing 4-fluoro in step 6) with 3-fluorobenzylamine. The benzylamine was reacted to give the product as a white solid.
  • Example 88 The same operation as in Example 88 was carried out by replacing 4-bromoethane in step 3) with 4- (3-chloropropyl) -morpholine to obtain a white solid product, and replacing 4-fluoro in step 6) with 2-fluorobenzylamine. amine to give the product as a white solid.
  • Example 212 1- (2-chlorobenzyl) -3- (4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) phenyl) urea
  • Example 88 The same operation as in Example 88 was carried out by replacing 4-bromoethane in step 3) with 4- (3-chloropropyl) -morpholine to obtain a white solid product, and replacing 4-fluoro in step 6) with 2-chlorobenzylamine. The benzylamine was reacted to give the product as a white solid.
  • Example 214 1- (4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) -3-fluorophenyl) -3- (2-fluorobenzyl) urea
  • Example 216 1- (3-fluoro-4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] Quinolin-10-yl) oxy) phenyl) -3- (3-fluorobenzyl) urea
  • Example 217 1- (3-fluoro-4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] Quinolin-10-yl) oxy) phenyl) -3- (2-fluorobenzyl) urea
  • Example 218 1- (3-fluoro-4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] Quinolin-10-yl) oxy) phenyl) -3- (2-chlorobenzyl) urea
  • Example 220 1- (4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) Phenyl) -3- (1- (2-fluorophenyl) ethyl) urea
  • Example 222 1- (1- (3-fluorophenyl) ethyl) -3- (4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4 ] Dioxane [2,3-f] quinolin-10-yl) oxy) phenyl) urea
  • Example 224 1- (1- (2-chlorophenyl) ethyl) -3- (4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4 ] Dioxane [2,3-f] quinolin-10-yl) oxy) phenyl) urea
  • Example 225 1- (4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) -3-fluorophenyl) -3- (1- (3-fluorophenyl) ethyl) urea
  • step 1 4-nitrophenol in step 1) was replaced by 2-fluoro-4nitrophenol, and 4 in step 6) was replaced by 1- (3-fluorophenyl) ethyl-1-amine. -Fluorobenzylamine was reacted to give the product as a white solid.
  • Example 226 1- (4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) -3-fluorophenyl) -3- (1- (2-fluorophenyl) ethyl) urea
  • step 1) 4-nitrophenol in step 1) was replaced by 2-fluoro-4nitrophenol, and 4 in step 6) was replaced by 1- (2-chlorophenyl) ethyl-1-amine. -Fluorobenzylamine was reacted to give the product as a white solid.
  • Example 228 1- (3-Fluoro-4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] Quinolin-10-yl) oxy) phenyl) -3- (1- (3-fluorophenyl) ethyl) urea
  • Example 230 1- (3-fluoro-4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] Quinolin-10-yl) oxy) phenyl) -3- (1- (2-chlorophenyl) ethyl) urea
  • Example 232 1- (3-fluoro-4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] Quinolin-10-yl) oxy) phenyl) -3-phenethylurea
  • Example 233 1- (3-Fluoro-4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] Quinolin-10-yl) oxy) phenyl) -3- (4-fluorophenethyl) urea
  • Example 235 1- (2-fluoro-4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] Quinolin-10-yl) oxy) phenyl) -3- (4-fluorobenzyl) urea
  • Example 88 The same operation as in Example 88 was carried out by replacing 4-nitrophenol in step 1) with 3-fluoro-4nitrophenol and replacing bromoethane in step 3) with 4- (3-bromopropyl) -morpholine.
  • Example 238 1- (4-((5-((1-aminocyclopropyl) methoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] Quinoline-10-yl) oxy) -3-fluorophenyl) -3- (4-fluorobenzyl) urea
  • Example 88 The same operation as in Example 88 was performed, in which 4-nitrophenol in step 1) was replaced with 2-fluoro-4nitrophenol, and 4-toluenesulfonic acid (1-((tert-butyloxycarbonyl) amino) cyclopropyl) The methyl ester was used instead of the bromoethane in step 3) to obtain a white solid product;
  • Example 240 1- (2-chloro-5-fluoro-4-((5-methoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinoline -10-yl) methoxy) phenyl) -3- (4-fluorobenzyl) urea
  • Step 1) Separately 10-chloro-5-methoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinoline (5.0 g, 20 mmol), 2-fluoro 4-Nitrophenol (3.1 g, 20 mmol) was added to chlorobenzene (50 mL) and heated and stirred at 150 ° C for 20 hours. After cooling, concentrating to a paste, a 1N sodium hydroxide aqueous solution was added for beating and filtering to obtain After drying the khaki solid, 4.5 g was obtained. The obtained filtrate was extracted with dichloromethane.
  • Step 2) The product obtained in step 1) (0.37 g, 1 mmol) was dissolved in methanol (10 mL), palladium on carbon (10% palladium content, wet) was added to catalyze, and the reaction was stirred at room temperature under hydrogen for 2 hours. Filtration and drying of the filtrate gave 0.30 g of 3-fluoro-4-((5-methoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinoline) as a pale purple solid product. -10-yl) oxy) aniline, yield 85%, MS: 343 [M + H] + ;
  • Step 3 The product (170 mg, 0.5 mmol) obtained in step 2) was dissolved in dry DMF (3 mL), and then phenyl chloroformate (160 mg, 1 mmol) and pyridine (0.5 mL) were added dropwise to stir the reaction at room temperature. TLC monitoring, reaction Do not process after completion, and proceed directly to the next step;
  • Step 4) Add 4-fluorobenzylamine (190 mg, 1.5 mmol) to the reaction solution of the intermediate obtained in step 3), heat to 60 ° C. and stir for 3 hours, cool, add water and filter to obtain a gray solid, and purify it by column chromatography.
  • Example 241 The same operation as in Example 241 was carried out by replacing the 4-fluorobenzylamine in step 4) with an equimolar equivalent of (R) -1- (4-fluorophenyl) ethyl-1-amine (210 mg, 1.5 mmol).
  • Example 241 The same operation as in Example 241 was carried out by replacing the 4-fluorobenzylamine in step 4) with an equimolar equivalent of (S) -1- (4-fluorophenyl) ethyl-1-amine (210 mg, 1.5 mmol).
  • Example 127 ((R) -1- (1- (4-fluorophenyl) ethyl) -3- (4-((5-oxetanyloxy-2,3-dihydro- [ 1,4] dioxane [2,3-f] quinolin-10-yl) oxy) phenyl) urea) and Example 171 ((S) -1- (1- (4-fluorophenyl ) Ethyl) -3- (4-((5-oxetanyloxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinoline-10- A pair of enantiomers of the group) (oxy) phenyl) urea) were tested for chiral purity. The test was performed using a chromatograph (Shimadzu LC-20A). The test conditions were as follows:
  • FIG. 1 shows a liquid chromatographic separation diagram of a mixture of enantiomers of Examples 127 and 171
  • FIG. 2 and FIG. 3 show a liquid chromatographic separation diagram of the compound of Example 127 and Example 171, respectively. It can be seen from the figure that the retention time of the compound of Example 127 is 9.1 and the retention time of the compound of Example 171 is 10.9, and the compounds of Example 127 and Example 171 are pure R-configuration and S-configuration compounds.
  • test method is as follows:
  • Compound Dilution A total of 11 concentrations after a 3-fold gradient dilution starting from the highest concentration of 2500 nM (the maximum final concentration of the drug used in this experiment is 2500 nM and the lowest final concentration is 0.042 nM).
  • Negative control Add 2.5 ⁇ L / well 4X substrate / ATP mixture and 7.5 ⁇ L 1X Kinase Assay Buffe to the 384-well plate well.
  • Terminate the enzymatic reaction Use a row gun to take 5 ⁇ L of 4X stop solution into the well of a 384-well plate, mix by centrifugation, and react at room temperature for 5 minutes.
  • Chromogenic reaction Use a row gun to take 5 ⁇ L of 4X detection solution into the well of a 384-well plate for color development, mix by centrifugation, and react at room temperature for 60 minutes.
  • inhibition rate (%) (positive well reading-experimental well reading) / (positive control well reading-negative control well) (Read value) x100%.
  • IC 50 values (compound concentration at the highest enzyme inhibition rate of 50%) were obtained by processing with GraphPad Prism5 software.
  • Table 8 shows the results of measuring the tyrosine kinase VEGFR-2 inhibitory activity of some compounds in the present invention, where A means IC 50 is less than or equal to 50 nM, B means IC 50 is greater than 50 nM but less than or equal to 500 nM, and C means IC 50 More than 500 nM but less than or equal to 5000 nM, D means that the IC 50 is greater than 5000 nM.
  • Compound Dilution A total of 9 concentrations after a 3-fold gradient dilution starting from the highest concentration of 5000 nM (the maximum final concentration of the drug used in this experiment is 5000 nM and the lowest final concentration is 0.76 nM).
  • M-NFS-60 cells transfer them to a 15 mL centrifuge tube, and centrifuge at 1000 rpm for 5 minutes.
  • i.As the OD value of experimental wells (medium containing cells, CCK-8, compounds),
  • ii.Ac OD value of control wells (cell-containing medium, CCK-8),
  • iii.Ab OD value of blank wells (medium without cells and compounds, CCK-8),
  • Table 9 lists the results of measuring the inhibitory activity of M-NFS-60 cell proliferation by representative compounds in the present invention, where A represents an IC 50 of less than or equal to 100 nM, B represents an IC 50 of greater than 100 nM but less than or equal to 1000 nM, and C represents The IC 50 is greater than 1000 nM.
  • sample loading buffer after denaturing the sample protein, add 30-50 ⁇ g protein sample or protein marker to each well;
  • Table 10 lists the inhibitory rates of some compounds of the present invention on CSF-1R (cFMS) phosphorylation in RAW264.7 cells as measured by protein labeling.
  • Figures 4-7 show the results of the compounds of Examples 41 and 100 for inhibiting CSF-1R (cFMS) phosphorylation in RAW264.7 cells using a protein labeling method. The results show that all the tested compounds have a strong inhibitory effect on CSF-1R phosphorylation in RAW264.7 cells, and this inhibitory effect is dose-dependent, and the inhibitory effect decreases as the compound concentration decreases.
  • the biological data provided by the present invention show that the compounds of the present invention are beneficial for the treatment or prevention of diseases caused by abnormalities of tyrosine kinase (CSF1R).
  • CSF1R tyrosine kinase
  • the compounds of the present invention have been shown to be able to potently inhibit the activity of VEGFR-2 and CSF1R tyrosine kinases, and the VEGFR-2 and CSF1R kinase families are closely related to the occurrence and metastasis of autoimmune diseases and cancer.
  • the compounds of the present invention are useful for treating autoimmune diseases, including but not limited to: psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, and Crohn's disease.
  • the compounds of the invention are also useful for treating 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 myelogenous leukemia, acute myeloid leukemia, non-Hodgkin lymphoma, nasopharyngeal cancer, esophageal cancer, brain Tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary sarcoma, bile duct cancer.
  • the compounds of the invention also include treating cancers that are resistant to one or more other treatments.
  • the compounds of the present invention can also be used in diseases other than autoimmune diseases and cancer related to VEGFR-2 kinase and / or CSF1R kinase, including but not limited to fundus diseases, pulmonary fibrosis, liver fibrosis, Alzheimer's disease Wait.
  • the compound of the present invention can be used as a monotherapy or a combination therapy, and can be used in combination with a plurality of compounds of the present invention or in combination with other drugs other than the present invention.
  • the pharmaceutical method of the invention includes determining a therapeutically effective amount for a subject in need of a compound of the invention.
  • a "therapeutically effective dose” will vary depending on the stage, progression or severity of the disease.
  • the daily dosage of the compounds and compositions of the present invention will depend on a number of factors in the patient, including the condition being treated, the severity of the condition, the efficacy of the particular compound employed, the particular composition, age, weight, general Health status, gender and diet, route and schedule of administration, metabolism and / or excretion rate of the compound, duration of treatment, and the like.
  • the required dose of the compound of the present invention can be administered to humans and other animals after being formulated with a pharmaceutically acceptable carrier.
  • Modes of administration include oral, rectal, parenteral, intracranial, intravaginal, intraperitoneal, topical (eg, via transdermal patches, powders, ointments, or drops), sublingual, transbuccal, or nasal spray.
  • the effective dose of the compound of the present invention is generally measured in terms of the amount administered per kg of the patient's body weight, preferably 0.1 to 125 mg / kg body weight, and generally 0.01 to 500 mg / kg body weight.
  • Administration can be one or more times, daily, weekly, every other day or every other day, or an intermittent schedule.
  • the compound may be administered daily, weekly (e.g., every Monday), indefinitely, or for several weeks (e.g., 4-10 weeks).
  • the effective dose of the compound of the present invention will vary depending on the compound used, the mode of administration, the severity of the disease, the condition to be treated, and various physical factors of the relevant patient. In most cases, a satisfactory therapeutic effect can be achieved when the daily dosage of the preferred compound of the present invention is about 0.01 to 500 mg / kg. A preferred dose is 0.1 to 125 mg / kg, and a more preferred dose is 1 to 25 mg / kg.
  • the parenteral dose is usually at an oral dose level of about 10% -20%.
  • the components of each composition will be administered during a desired treatment period. Whether as a separate dosage unit or as a single dosage form containing two components, the components in the composition can be administered simultaneously during the treatment period, or at different times during the treatment period, or one can be used as a pretreatment for the other Apply.
  • the compounds of the present invention can be used for treatment in free form or, where appropriate, in the form of a pharmaceutically acceptable salt or other derivative.
  • pharmaceutically acceptable salt refers to the organic and inorganic salts of the compounds of the present invention. This salt is suitable for humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and is 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 the compound isolated and purified in the present invention with a suitable free base or acid.
  • Salts formed from pharmaceutically non-toxic acids including but not limited to, 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, These salts are obtained from amino salts of succinic acid, malonic acid, or by using methods well known in the art, such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, and camphoric acid Salt, camphor sulfonate, citrate, cyclopentane, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glyceryl phosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lactate, lactate, laurate, lauryl sulfate, malate, Maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, paraben, pectate Salt, persulfate
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Other pharmaceutically acceptable salts include appropriate non-toxic ammonium, quaternary ammonium, and use such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate Amino cations formed by acid salts.
  • prodrug as used herein means that a compound can be converted into a compound represented by formula (I) of the present invention in vivo. This transformation is converted to the parent compound by hydrolysis of the prodrug in the blood or by enzyme action in the blood or tissue.
  • composition described herein is composed of any one of the compounds described herein (or a prodrug, or a pharmaceutically acceptable salt thereof, or other pharmaceutically acceptable derivative), and one or more pharmaceutically acceptable Carriers or excipients. These compositions may optionally further comprise one or more additional therapeutic agents.
  • the compounds of the invention can be combined with the administration of one or more other treatment regimens (e.g., Tofacitinib or other kinase inhibitors, interferons, bone marrow transplants, farnesyl transferase inhibitors, bisphosphonates, thalidomide) , Cancer vaccines, hormone therapy, antibodies, radiation, etc.) are co-administered to the desired patient.
  • the pharmaceutical composition of the compound may be another or more anti-inflammatory or anti-cancer agents.
  • the composition of the invention comprises a compound of the invention and a pharmaceutically acceptable carrier and / or excipient, including any and all solvents, diluents or other carriers, dispersion or suspension aids, surfactants , Isotonicity agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., to suit the specific dosage form required.
  • a pharmaceutically acceptable carrier and / or excipient including any and all solvents, diluents or other carriers, dispersion or suspension aids, surfactants , Isotonicity agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., to suit the specific dosage form required.
  • Some pharmaceutically acceptable carrier materials include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose And cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil Ethylene glycol, such as propylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; Ethanol, and phosphate-buffered solutions, and other non-toxic compatible lubricants such as sodium lauryl sulfate
  • the invention also encompasses a class of compositions (collectively referred to herein as "carrier” materials) in which the active compound of the invention is used in combination with one or more pharmaceutically acceptable carriers and / or diluents and / or adjuvants. And, if necessary, other active ingredients.
  • carrier materials
  • the active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition suitable for such route of administration, for the effective dose required for the intended treatment.
  • the compounds and compositions of the present invention may be administered orally, mucosally, topically, rectally, via the lung (such as by inhalation spray), or parenterally, including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly , Intrasternal and infusion techniques.
  • Its administration is in the form of a dosage unit, and contains pharmaceutically acceptable carriers, adjuvants, and excipients.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. Examples of such dosage units are tablets or capsules.
  • they may contain the active ingredient in an amount of 1 to 2000 mg, preferably 1 to 500 mg, and more commonly 5 to 200 mg.
  • the appropriate daily dose for a human or other mammal may vary depending on the patient and other factors, but can be determined again using conventional methods.
  • the amount of compound in the administration and dosage regimen of the compounds and / or compositions according to the present invention depends on a variety of factors, including the subject's age, weight, gender and medical conditions, the type of disease, the Severity of the disease, route and frequency of administration, and the specific compound used. Therefore, the dosage regimen can vary widely, but can be determined using standard methods.
  • a typical daily dose is 0.01 to 500 mg / kg body weight, preferably 0.1 to 125 mg / kg body weight, and more preferably 1 to 25 mg / kg body weight.
  • the active compounds of the present invention usually constitute an administration route with one or more adjuvants, excipients or carriers. If administered orally, the compound can be combined with lactose, sucrose, starch powder, cellulose alkanoates, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, phosphoric acid and sodium sulfate and Calcium salt, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol are mixed and then compressed into tablets or capsules for convenient administration. Such capsules or tablets may contain a controlled release formulation, which may be provided by dispersing the active compound in hydroxypropyl methylcellulose.
  • Formulations suitable for topical administration include liquid or semi-liquid formulations (such as tinctures, lotions, ointments, creams or pastes) suitable for penetration through the skin and drops suitable for administration to the eyes, ears or nose.
  • a suitable topical dose of the compound of the present invention is 0.1 to 150 mg, one to four times a day, preferably one to two times a day.
  • the active ingredient can be used as a base with any paraffin or water-miscible ointment.
  • the active ingredients can be formulated as a water-in-oil emulsion base cream.
  • the aqueous phase of the cream base may include, for example, at least 30% by weight of a polyol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol, and mixtures thereof.
  • Topical formulations may include compounds that enhance absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.
  • the compounds can also be administered via a transdermal device. Preferably, transdermal administration will be accomplished using a patch containing a reservoir and a porous membrane or a solid matrix.
  • the oily phase of the emulsion of the present invention may be composed of known ingredients in a known manner, comprising a mixture of at least one emulsifier with a fat or oil or a mixture of both fats and oils.
  • the hydrophilic emulsifier can be used in combination with a lipophilic emulsifier as a stabilizer, and it is also preferable that it can also be used in combination with oil and fat.
  • Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present invention include Tween 60, Span 80, cetylstearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, single dihydrate Glyceryl stearate or a mixture thereof with an emulsifying wax, or other materials known in the art.
  • the cream should preferably be a non-greasy, non-coloring and washable product and have a suitable consistency to avoid leakage from a tube or other container.
  • Linear or branched, mono- or di-alkyl esters such as diisoadipate, isohexadecyl stearate, propylene glycol diesters of coconut fatty acids, isopropyl myristate, decyl oleate, palm Isopropyl acid, butyl stearate, 2-ethylhexyl palmitate or mixed branched esters can also be used.
  • high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • the weight ratio of the active ingredient in these preparations is preferably 0.5% to 20%, a more favorable ratio is 0.5 to 10%, and the most preferable concentration is about 1.5%.
  • the formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from one or more sterile powders or granules, by using the formulations mentioned herein for oral administration or by using other suitable dispersing or wetting agents and suspending agents, carriers or diluents. While prepared.
  • the compound can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth, and / or various buffers.
  • Other adjuvants and modes of administration are well known in the pharmaceutical art.
  • the active ingredient may also be administered by injection, a composition with a suitable carrier including saline, dextrose or water, or solubilized with cyclodextrin (Captisol), a co-solvent (i.e., propylene glycol) or a micelle (i.e. Wen 80).
  • the formulation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as 1,3-butanediol.
  • the solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, non-volatile oils are commonly used as solvents or suspension media. Any mild fixed oil can be used for this purpose, including synthetic mono- or diglycerides.
  • the pharmaceutical composition may be administered in the form of an aerosol or with an inhaler, including a dry powder aerosol.
  • Suppositories for rectal administration can be prepared by combining the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycol which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum And release the drug.
  • the pharmaceutical composition can be added to conventional pharmaceutical operations such as sterilization and / or tablets and pills that can contain conventional adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc. can also be enteric coated preparation.
  • Such compositions may also contain adjuvants such as wetting agents, sweeteners, flavoring agents, and fragrances.
  • the pharmaceutical composition of the present invention comprises a compound of the formula (I) described herein or a pharmaceutically acceptable salt thereof, a kinase inhibitor (small molecule, polypeptide, antibody, etc.), an immunosuppressive agent, an anticancer drug, an antiviral agent, an antiviral agent Inflammatory agents, antifungals, antibiotics or additional active agents of an anti-hyperplasia compound; and any pharmaceutically acceptable carrier, adjuvant or excipient.
  • Alternative compositions of the invention include a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or excipient as described herein.
  • compositions may optionally include one or more additional therapeutic agents, including, for example, kinase inhibitors (small molecules, polypeptides, antibodies, etc.), immunosuppressants, anticancer agents, antiviral agents, anti-inflammatory agents , Antifungals, antibiotics or anti-hyperplasia compounds.
  • additional therapeutic agents including, for example, kinase inhibitors (small molecules, polypeptides, antibodies, etc.), immunosuppressants, anticancer agents, antiviral agents, anti-inflammatory agents , Antifungals, antibiotics or anti-hyperplasia compounds.
  • pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that can be administered to a patient with a compound of the present invention and does not destroy the pharmaceutical activity, and when the dosage is sufficient to deliver the therapeutic amount administered Is non-toxic.
  • compositions of the present invention can be used in the pharmaceutical compositions of the present invention, including, but not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) Such as d-atocopHerol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, such as Tween or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine , Sorbic acid, potassium sorbate, partial glycerol esters of saturated vegetable fatty acids using surfactants, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, Colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, poly(SEDDS)
  • Cyclodextrins such as ⁇ -, ⁇ -, and ⁇ -cyclodextrin, or chemically modified derivatives such as hydroxyalkyl, including 2 and 3-hydroxypropyl-cyclodextrin, or other dissolved derivatives may also be advantageous Ground is used to enhance the delivery of compounds of the formulae described herein.
  • the pharmaceutical composition can be administered orally in any acceptable dosage form, including but not limited to capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricants such as, for example, magnesium stearate, are also commonly added.
  • useful diluents include lactose and dried corn starch.
  • the active ingredients When administered orally using aqueous suspensions and / or emulsions, the active ingredients may be suspended or dissolved in the oily phase with emulsifying and / or suspending agents. If desired, certain sweetening, flavoring and / or coloring agents may be added.
  • the pharmaceutical composition may include the use of liposomes or microencapsulation techniques, different examples of which can be found in the literature.
  • the pharmaceutical composition can be administered by nasal aerosol or inhalation.
  • compositions are prepared according to techniques known in the art of pharmaceutical formulations and can be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons, and And / or other solubilizers or dispersants, examples of which are also well known in the art.
  • the compounds of the present invention can be used alone or in combination with one or more other compounds of the present invention or with one or more other agents.
  • the therapeutic agents can be formulated to be administered simultaneously or sequentially at different times, or the therapeutic agents can be administered as a single composition.
  • the so-called "combination therapy" refers to the use of the compound of the present invention together with another agent.
  • the method of administration is simultaneous administration of each agent or sequential administration of each agent. In either case, the purpose is to To achieve the best results of the drug.
  • Co-administration includes simultaneous delivery of the dosage forms, as well as separate dosage forms for each compound.
  • the administration of the compounds of the present invention can be used concurrently with other known therapies in the art, for example, the use of radiation therapy or additional therapies such as cytostatic agents, cytotoxic agents, and other anticancer agents in cancer treatment to improve Symptoms of cancer.
  • additional therapies such as cytostatic agents, cytotoxic agents, and other anticancer agents in cancer treatment to improve Symptoms of cancer.
  • the invention is not limited to the order of administration; the compounds of the invention may be administered previously, concomitantly, or after other anticancer or cytotoxic agents.

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Abstract

The present invention relates to a novel compound serving as VEGFR-2 and CSF1R, a composition and an application thereof. Specifically, the present invention provides a compound (as represented by formula (I)) capable of strongly inhibiting VEGFR-2 and CSF1R activities, or isomers, solvates, hydrates, pharmaceutically acceptable salts, and prodrugs thereof, as well as a pharmaceutical composition comprising said compound. Also disclosed is an application of the compound or the pharmaceutical composition of the present invention in the preparation of drugs, wherein the drug are used for treating diseases such as autoimmune diseases, tumors, and Alzheimer's disease. (I)

Description

脲取代的芳环连二噁烷并喹唑啉或喹啉类化合物、组合物及其应用Urea substituted aromatic dioxoquinazoline or quinoline compounds, compositions and applications thereof 技术领域Technical field
本发明属于药物化学领域，具体涉及一类脲取代的芳环连二噁烷并喹唑啉或喹啉类化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，及其药物组合物和它们在治疗与血管内皮生长因子受体2(VEGFR-2)和/或集落剌激因子1受体(CSF1R)相关的自身免疫疾病、肿瘤以及阿尔兹海默病的药物制备中的应用。The invention belongs to the field of medicinal chemistry, and particularly relates to a class of urea-substituted aromatic cyclodioxoquinazoline or quinoline compounds, isomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof. , And their pharmaceutical compositions and their use in the treatment of autoimmune diseases, tumors, and Alzheimer's disease associated with vascular endothelial growth factor receptor 2 (VEGFR-2) and / or colony stress factor 1 receptor (CSF1R) Application in pharmaceutical preparation.
背景技术Background technique
蛋白激酶(PK)是能催化蛋白质磷酸化过程的酶。到目前为止，已发现的蛋白激酶约有400多种。作为蛋白激酶的一个子家族，酪氨酸激酶(RTK)在细胞信号转导中起重要作用，并参与了肿瘤发生过程，包括细胞增殖、存活、血管生成、侵入和转移。Protein kinase (PK) is an enzyme that catalyzes the process of protein phosphorylation. So far, more than 400 protein kinases have been discovered. As a subfamily of protein kinases, tyrosine kinase (RTK) plays an important role in cell signal transduction and is involved in tumorigenic processes including cell proliferation, survival, angiogenesis, invasion and metastasis.
血管内皮生长因子受体(vascular endothelial growth factor receptor，VEGFR)是受体酪氨酸激酶家族中的一种，通过与其配体血管内皮生长因子(vascular endothelial growth factor,VEGF)结合产生一系列生化和生理过程，最终促使新生血管形成。肿瘤血管的生成和它们的通透性主要通过血管内皮细胞生长因子(VEGF)调节，其通过至少两种不同的受体(VEGFR-1、VEGFR-2)发挥作用。根据Jakeman、Kolch、Connolly等的研究显示：VEGF是正常和病理性血管生成和血管渗透性的重要刺激物(Jakeman等，1993，Endocrinology 133：848-859；Kolch等，1995，Breast Cancer Research and Treatment，36：139-155；Connolly等，1989，J.Biol.Chem.264：20017-20024)。血管内皮细胞生长因子通过诱导内皮细胞增殖、蛋白酶表达和迁移及随后形成毛细管的细胞组织来诱发血管芽生表型。因此，通过抗体对VEGF的螯合作用产生的对VEGF的拮抗作用可导致肿瘤生长的抑制(Kim等，1993，Nature 362：841-844)。Vascular endothelial growth factor receptor (vascular endothelial growth factor receptor) is one of the family of receptor tyrosine kinases. It combines with its ligand, vascular endothelial growth factor (VEGF), to produce a series of biochemical and The physiological process eventually promotes the formation of new blood vessels. Tumor angiogenesis and their permeability are mainly regulated by vascular endothelial cell growth factor (VEGF), which functions through at least two different receptors (VEGFR-1, VEGFR-2). According to research by Jakeman, Kolch, Connolly, etc .: VEGF is an important stimulator of normal and pathological angiogenesis and vascular permeability (Jakeman et al., 1993, Endocrinology 133: 848-859; Kolch et al., 1995, Breast Cancer Research and Treatment , 36: 139-155; Connolly et al., 1989, J. Biol. Chem. 264: 20017-20024). Vascular endothelial cell growth factor induces the angiogenic budding phenotype by inducing endothelial cell proliferation, protease expression and migration, and subsequent cellular tissue formation of capillaries. Therefore, the antagonism of VEGF produced by the chelation of VEGF by antibodies can lead to the inhibition of tumor growth (Kim et al., 1993, Nature 362: 841-844).
由于VEGFR-2主要分布在血管内皮细胞内，可以与VEGF-A、VEGF-C、VEGF-D、VEGF-E结合。而VEGF刺激内皮细胞的增殖、增加血管的通透性和新血管的生成作用主要是通过结合和激活VEGFR-2来实现的。如果阻断VEGFR-2的活性，可以通过直接和间接途径抑制肿瘤的生长和转移，进而达到理想的抗肿瘤效果。因此，寻找对VEGFR-2具有高活性、高选择性的小分子抑制剂成为非常有前景的肿瘤治疗策略。Because VEGFR-2 is mainly distributed in vascular endothelial cells, it can bind to VEGF-A, VEGF-C, VEGF-D, and VEGF-E. And VEGF stimulates the proliferation of endothelial cells, increases the permeability of blood vessels and the formation of new blood vessels is mainly achieved by binding and activating VEGFR-2. If the activity of VEGFR-2 is blocked, tumor growth and metastasis can be inhibited through direct and indirect pathways, and the ideal antitumor effect can be achieved. Therefore, finding small molecule inhibitors with high activity and selectivity for VEGFR-2 has become a very promising tumor treatment strategy.
集落剌激因子1受体(下文中以CSF1R表示，在本领域也称为FMS、FIM2、C-FMS、MCSF受体及CD115)是具有N末端胞外结构域(ECD)及C末端胞内结构域的拥有酪氨酸激酶活性的单跨膜受体，是CSF1/PDGF受体酪氨酸激酶家族的一员。CSF1或白细胞介素34配体(也称为IL-34)与CSF1R的配体结合导致了受体的二聚化和自动磷酸化，并激活了 下游信号转导途径包括PI3K/Akt和分裂原活化蛋白激酶MAPK途径。通过CSF1或IL-34引起的CSF1R活化导致单核细胞(如破骨细胞、树突细胞及小神经胶质细胞)/巨噬细胞系的细胞的增殖、存活、运动和分化，并从而在普通组织发育和免疫防御中扮演了重要角色。现有的研究发现，CSF1R参与包括炎性、肿瘤、骨和神经系统相关的疾病，因此，CSF1R抑制剂有望可以用于治疗炎性、肿瘤、骨和神经系统相关的疾病。Colony stimulating factor 1 receptor (hereinafter referred to as CSF1R, also known in the art as FMS, FIM2, C-FMS, MCSF receptor, and CD115) has an N-terminal extracellular domain (ECD) and a C-terminal intracellular domain. The domain of a single transmembrane receptor with tyrosine kinase activity is a member of the CSF1 / PDGF receptor tyrosine kinase family. The binding of CSF1 or interleukin 34 ligand (also known as IL-34) to the ligand of CSF1R leads to dimerization and autophosphorylation of the receptor and activates downstream signal transduction pathways including PI3K / Akt and mitogen Activated protein kinase MAPK pathway. CSF1R activation by CSF1 or IL-34 results in the proliferation, survival, movement, and differentiation of cells in monocytes (such as osteoclasts, dendritic cells, and microglia) / macrophages, and thus in general Tissue development and immune defense play important roles. Existing studies have found that CSF1R is involved in diseases related to inflammatory, tumor, bone and nervous system. Therefore, CSF1R inhibitors are expected to be used to treat diseases related to inflammatory, tumor, bone and nervous system.
目前，已在患有急性骨髓性白血病、前列腺癌、乳腺癌、卵巢癌、子宫内膜癌、结肠直肠癌、胰腺癌以及多种其它癌症的患者中发现了CSF1R和/或其配体更高的表达或激活，并发现升高水平的M-CSF与某些癌症的较差预后有关(参见,Muller-Tidow等人Clin Cancer Res,2004,10:1241-1249,Bauknecht等人Cancer Detect.Prev.,1994,18:231-239；Baiocchi G等人Cancer1991,67:990-996；Kirma等人Cancer Res.2007；Sa pi等人Exp.Biol.Med.,2004,229:1-11；Kluger等人Clin.Canc.Res.200410:173-177；Mroczko等人,Clin.Chem.Lab.Med.200543:146-50和Mroczko等人,Clin.Chim.Acta2007,380:208–212)。该数据提示CSF1R可能是这些实体肿瘤的有效的治疗靶标。Currently, higher CSF1R and / or its ligands have been found in patients with acute myeloid leukemia, prostate cancer, breast cancer, ovarian cancer, endometrial cancer, colorectal cancer, pancreatic cancer, and many other cancers. Expression or activation, and found that elevated levels of M-CSF are associated with poor prognosis in certain cancers (see, Muller-Tidow et al. Clin Cancer Res, 2004, 10: 1241-1249, Bauknecht et al Cancer Detect.Prev ., 1994, 18: 231-239; Baiocchi et al. Cancer 1991, 67: 990-996; Kirma et al. Cancer Res. 2007; Sapi et al. Exp. Biol. Med., 2004, 229: 1-11; Kluger Et al. Clin. Canc. Res. 200410: 173-177; Mroczko et al., Clin. Chem. Lab. Med. 200543: 146-50 and Mroczko et al., Clin. Chim. Acta 2007, 380: 208-212). This data suggests that CSF1R may be an effective therapeutic target for these solid tumors.
同时，Claudia Balducci等人研究发现，活化的小神经胶质细胞在阿尔兹海默病的演化中扮演了重要的角色(Pharmacological Research.2018；130：402-413)；Murphy GM等人研究发现在阿尔兹海默样的老鼠大脑中检测到小神经胶质细胞表达M-CSF1R(American Journal of Pathology,Vol.157,No.3,September 2000)；Dagher等人研究发现在阿尔兹海默样的老鼠大脑中，CSF1R抑制剂会减少小神经胶质细胞的数量并抑制细胞因子的表达(Journal of Neuroinflammation(2015)12:139)。因此，CSF1R抑制剂有望可以应用于阿尔兹海默病的治疗。At the same time, research by Claudia Balducci et al. Found that activated microglia played an important role in the evolution of Alzheimer's disease (Pharmacological Research. 2018; 130: 402-413); Murphy et al. Microglia expressing M-CSF1R was detected in the brain of Alzheimer-like mice (American Journal of Pathology, Vol. 157, No. 3, September 2000); Dagher et al. In the mouse brain, CSF1R inhibitors reduce the number of microglial cells and inhibit the expression of cytokines (Journal of Neuroinflammation (2015) 12: 139). Therefore, CSF1R inhibitors are expected to be applied to the treatment of Alzheimer's disease.
目前，关于CSF1R抑制剂，有一些正在进行的研究，但是未有成功上市的药品。亟需更多基于CSF1R抑制剂的药品的研究和开发。At present, there are some ongoing studies on CSF1R inhibitors, but no drugs have been successfully marketed. There is an urgent need for more research and development of drugs based on CSF1R inhibitors.
本申请提供了一类脲取代的芳环连二噁烷并喹唑啉或喹啉类化合物，表现出良好的CSF1R抑制活性，以及VEGFR-2抑制活性，有望作为CSF1R和/或VEGFR-2抑制剂应用于治疗自身免疫疾病、肿瘤或者阿尔兹海默病的药物的制备中。The present application provides a class of urea-substituted aromatic cyclodioxoquinazoline or quinoline compounds that exhibit good CSF1R inhibitory activity and VEGFR-2 inhibitory activity and are expected to be used as CSF1R and / or VEGFR-2 inhibitor The agent is used in the preparation of a medicine for treating an autoimmune disease, a tumor or Alzheimer's disease.
发明内容Summary of the Invention
鉴于上述讨论的内容，本发明旨在提供一种脲取代的芳环连二噁烷并喹唑啉或喹啉类化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，及其药物组合物，并涉及它们在制备治疗与VEGFR-2和/或CSF1R相关的自身免疫疾病、肿瘤或者阿尔兹海默病等疾病的药物中的应用。In view of the above discussion, the present invention aims to provide a urea-substituted aromatic cyclodioxoquinazoline or quinoline compound, isomer, hydrate, solvate, pharmaceutically acceptable salt or Prodrugs, and pharmaceutical compositions thereof, and their use in the preparation of medicaments for the treatment of autoimmune diseases, tumors, or Alzheimer's disease related to VEGFR-2 and / or CSF1R.
本发明的一个方面提供了一种脲取代的芳环连二噁烷并喹唑啉或喹啉类化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，该化合物具有结构式(I)：One aspect of the present invention provides a urea-substituted aromatic cyclodioxoquinazoline or quinoline compound, isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, the The compound has the structural formula (I):
Figure PCTCN2019101623-appb-000001
Figure PCTCN2019101623-appb-000001
其中，among them,
Q为N或者CH；Q is N or CH;
G为O或者NH；G is O or NH;
R 1为-H，或由1至3个选自C 1-C 6的烷氧基、C 1-C 6的烷硫基、C 1-C 3酰基、羟基、卤素、三氟甲基、氰基、-CONH 2、氧代(＝O)或-NR aR b中的取代基所取代或者非取代的C 3-C 8的环烷基，或由1至3个选自C 1-C 6的烷氧基、C 1-C 6的烷硫基、C 1-C 3酰基、羟基、卤素、三氟甲基、氰基、-CONH 2、C 3-C 7的环烷基或-NR aR b的取代基所取代或者非取代的C 1-C 10烷基，或-(CH 2)n-R 6，所述R 6为取代或者非取代的4-8元杂脂环基，所述4-8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4-8元杂脂环基，且所述取代的4-8元杂脂环基被1至3个选自卤素、C 1-C 3的烷基、C 1-C 3的烷氧基、C 1-C 3的烷硫基、羟基、-NR aR b、C 1-C 3酰基、氧代中的取代基所取代，n为0至10， R 1 is -H, or consists of 1 to 3 alkoxy groups selected from C 1 -C 6 , alkylthio groups of C 1 -C 6 , C 1 -C 3 acyl groups, hydroxy, halogen, trifluoromethyl, C 3 -C 8 cycloalkyl substituted or unsubstituted by substituents in cyano, -CONH 2 , oxo (= O) or -NR a R b , or from 1 to 3 selected from C 1- C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 3 acyl, hydroxyl, halogen, trifluoromethyl, cyano, -CONH 2 , C 3 -C 7 cycloalkyl or substituent or unsubstituted C -NR a R b in 1 -C 10 alkyl, or - (CH 2) nR 6, R 6 is a substituted or unsubstituted 4-8 membered heteroalicyclic group, The 4-8 membered heteroalicyclic group is a 4-8 membered heteroalicyclic group containing 1-2 atoms selected from N, O, S as ring atoms, and the substituted 4-8 membered heteroalicyclic group The cyclic group is 1 to 3 selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, hydroxyl, -NR a R b , C 1 -C 3 acyl, substituted by substituents in oxo, n is 0 to 10,
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烷基或者单或双C 1-C 3烷基取代或非取代氨基取代的C 1-C 6烷基； 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 3 -alkylthio-substituted C 1 -C 6 alkyl or mono- or di-C 1 -C 3 alkyl-substituted or unsubstituted amino-substituted C 1 -C 6 alkyl;
R 2、R 3各自独立地为-H、-CF 3、卤素、C 1-C 3的烷基、C 1-C 3的烷氧基，在式(I)中，R 2、R 3仅表示双取代，不限定它们在苯环上的取代位置； R 2 and R 3 are each independently -H, -CF 3 , halogen, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy. In formula (I), R 2 and R 3 are only Represents double substitution, without limiting their substitution position on the benzene ring;
R 4为-H，C 1-C 3烷基； R 4 is -H, C 1 -C 3 alkyl;
R 5为-(CH 2) mR 7，其中m为0-3整数，所述R 7为由一个至两个取代基-A所取代或者非取代的芳基或杂芳基，所述取代基-A各自独立地为C 1-C 3的烷基、C 1-C 3的烷氧基、C 1-C 3的烷硫基、卤素、三氟甲基或甲砜基， R 5 is-(CH 2 ) m R 7 , where m is an integer from 0 to 3, the R 7 is an aryl or heteroaryl group substituted or unsubstituted by one to two substituents -A, the substitution -A are each independently C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, halogen, trifluoromethyl or methylsulfone,
所述杂芳基为含有1-3个选自N、O、S中的杂原子作为环原子、且含有5至10个环原子的单环或双环杂芳基。The heteroaryl group is a monocyclic or bicyclic heteroaryl group containing 1-3 heteroatoms selected from N, O, and S as ring atoms and containing 5 to 10 ring atoms.
根据本申请的一些优选实施方案，G为O。According to some preferred embodiments of the present application, G is O.
根据本申请的一些优选实施方案，R 1为-H，或非取代的C 3-C 8的环烷基，或由1至3个选自C 1-C 6的烷氧基、C 1-C 6的烷硫基、C 1-C 3酰基、羟基、-F、三氟甲基、氰基、-CONH 2、C 3-C 6的环烷基或-NR aR b的取代基所取代或者非取代的C 1-C 8烷基， According to some preferred embodiments of the present application, R 1 is -H, or an unsubstituted C 3 -C 8 cycloalkyl group, or 1 to 3 alkoxy groups selected from C 1 -C 6 , C 1- C 6 alkylthio, C 1 -C 3 acyl, hydroxyl, -F, trifluoromethyl, cyano, -CONH 2 , C 3 -C 6 cycloalkyl or -NR a R b substituent Substituted or unsubstituted C 1 -C 8 alkyl,
或-(CH 2)n-R 6，所述R 6为取代或者非取代的4-8元杂脂环基，所述4-8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4-8元杂脂环基，且所述取代的4-8元杂 脂环基被1至3个选自-F、C 1-C 3的烷基、C 1-C 3的烷氧基、羟基、-NR aR b、C 1-C 3酰基、氧代中的取代基所取代，n为0至8， Or-(CH 2 ) nR 6 , wherein R 6 is a substituted or unsubstituted 4-8 member heteroalicyclic group, and the 4-8 member heteroalicyclic group contains 1-2 members selected from N, O, The atom in S is a 4-8 membered heteroalicyclic group as a ring atom, and the substituted 4-8 membered heteroalicyclic group is substituted by 1 to 3 alkyl groups selected from -F, C 1 -C 3 , C 1- C 3 alkoxy, hydroxy, -NR a R b , C 1 -C 3 acyl, substituents in oxo, n is 0 to 8,
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、或者C 1-C 3烷氧基取代的C 1-C 6烷基。 R a and R b are each independently -H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 3 alkoxy-substituted C 1 -C 6 alkyl.
更优选地，R 1为-H，非取代的C 3-C 6的环烷基，由1至3个选自C 1-C 3的烷氧基、C 1-C 3的烷硫基、C 1-C 3酰基、羟基、-F、三氟甲基、氰基、-CONH 2、C 3-C 5的环烷基或-NR aR b的取代基所取代或者非取代的C 1-C 8烷基， More preferably, R 1 is -H, an unsubstituted C 3 -C 6 cycloalkyl group, from 1 to 3 selected from C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, C 1 -C 3 acyl, hydroxyl, -F, trifluoromethyl, cyano, -CONH 2 , C 3 -C 5 cycloalkyl, or -NR a R b substituted or unsubstituted C 1 -C 8 alkyl,
或-(CH 2) n-R 6，所述R 6为取代或者非取代的4-6元杂脂环基，所述4-6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4-6元杂脂环基，且所述取代的4-6元杂脂环基被1至3个选自-F、C 1-C 3的烷基、C 1-C 3的烷氧基、羟基、-NR aR b、C 1-C 3酰基、氧代中的取代基所取代，n为0至6， Or-(CH 2 ) n -R 6 , wherein R 6 is a substituted or unsubstituted 4-6 membered heteroalicyclic group, and the 4-6 membered heteroalicyclic group contains 1-2 members selected from N, A 4- to 6-membered heteroalicyclic group of an atom in O, S as a ring atom, and the substituted 4-6-membered heteroalicyclic group is substituted by 1 to 3 alkyl groups selected from -F, C 1 -C 3 , C 1 -C 3 alkoxy, hydroxyl, -NR a R b , C 1 -C 3 acyl, substituents in oxo, n is 0 to 6,
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、或者C 1-C 3烷氧基取代的C 1-C 3烷基。 R a and R b are each independently -H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 3 alkoxy-substituted C 1 -C 3 alkyl.
更更优选地，R 1为-H，环丙基，环丁基，环戊基，环己基，或者由1至3个选自甲氧基、乙氧基、甲硫基、乙硫基、甲酰基、乙酰基、羟基、-F、三氟甲基、氰基、-CONH 2、环丙基、环丁基、环戊基、-NR aR b的取代基所取代或者非取代的C 1-C 6烷基，或-(CH 2)n-R 6，所述R 6为取代或者非取代的4-6元杂脂环基，所述4-6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4-6元杂脂环基，且所述取代的4-6元杂脂环基被1至3个选自-F、甲基、乙基、羟基、氨基、乙酰基、甲酰基、三氟甲基、氰基、氧代中的取代基所取代，n为0至6， More preferably, R 1 is -H, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or from 1 to 3 selected from methoxy, ethoxy, methylthio, ethylthio, Formyl, acetyl, hydroxy, -F, trifluoromethyl, cyano, -CONH 2 , cyclopropyl, cyclobutyl, cyclopentyl, -NR a R b substituted or unsubstituted C 1- C 6 alkyl, or-(CH 2 ) nR 6 , wherein R 6 is a substituted or unsubstituted 4-6 membered heteroalicyclic group, and the 4-6 membered heteroalicyclic group contains 1-2 A 4-6 membered heteroalicyclic group having an atom selected from N, O, S as a ring atom, and the substituted 4-6 membered heteroalicyclic group is selected from 1 to 3 selected from -F, methyl, Substituted with ethyl, hydroxy, amino, acetyl, formyl, trifluoromethyl, cyano, oxo substituents, n is 0 to 6,
所述4-6元杂脂环基选自4-6元氧杂环烷基，或4-6元氮杂环烷基，或4-6元硫杂环烷基，或以下基团：The 4-6 membered heteroalicyclic group is selected from a 4-6 membered oxetanyl group, or a 4-6 membered azacycloalkyl group, or a 4-6 membered thiacycloalkyl group, or the following groups:
Figure PCTCN2019101623-appb-000002
Figure PCTCN2019101623-appb-000002
R a和R b各自独立地为-H、甲基、乙基、甲氧基甲基、甲氧基乙基、甲氧基丙基、环丙基、或者环丁基。尤其，n＝0时，R 6可以为4-6元氧杂环烷基，或4-6元氮杂环烷基，或4-6元硫杂环烷基，n＝1-6时，R 6可以为取代或者非取代的4-6元杂脂环基。 R a and R b are each independently -H, methyl, ethyl, methoxymethyl, methoxyethyl, methoxypropyl, cyclopropyl, or cyclobutyl. In particular, when n = 0, R 6 may be a 4-6 membered oxetanyl group, or a 4-6 membered azacycloalkyl group, or a 4-6 membered thiacycloalkyl group, and when n = 1-6, R 6 may be a substituted or unsubstituted 4-6 membered heteroalicyclic group.
本申请中，所述氧杂环烷基、氮杂环烷基、硫杂环烷基是指脂环基的环上分别掺杂一个氧原子、氮原子或者硫原子的脂环基。In the present application, the oxetanyl group, azacycloalkyl group, and thiocycloalkyl group refer to an alicyclic group in which an alicyclic group ring is respectively doped with an oxygen atom, a nitrogen atom, or a sulfur atom.
最优选地，R 1为甲基、乙基、丙基、异丙基、丁基、异丁基、环丁基、环戊基、环己基、氧杂环丁烷-3-基、四氢呋喃-3-基、四氢吡喃-4-基、四氢吡喃-3-基、羟乙基、羟丙基、甲氧基乙基、甲氧基丙基、乙氧基乙基、乙氧基丙基、甲硫基丙基、乙硫基丙基、氰基甲基、氰基乙基、氰基丙基、环丙基甲基、环丙基乙基、-CH 2CONH 2、-CH 2CF 3、2-甲基2-羟基丙基、
Figure PCTCN2019101623-appb-000003
Figure PCTCN2019101623-appb-000004
-(CH 2)t-NR aR b，R a和R b各自独立地为H、甲基、乙基、甲氧基甲基、甲氧基乙基、环丙基、环丁基，t为1-6。 Most preferably, R 1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetan-3-yl, tetrahydrofuran- 3-yl, tetrahydropyran-4-yl, tetrahydropyran-3-yl, hydroxyethyl, hydroxypropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxy Propylpropyl, methylthiopropyl, ethylthiopropyl, cyanomethyl, cyanoethyl, cyanopropyl, cyclopropylmethyl, cyclopropylethyl, -CH 2 CONH 2 ,- CH 2 CF 3 , 2-methyl 2-hydroxypropyl,
Figure PCTCN2019101623-appb-000003
Figure PCTCN2019101623-appb-000004
-(CH 2 ) t-NR a R b , R a and R b are each independently H, methyl, ethyl, methoxymethyl, methoxyethyl, cyclopropyl, cyclobutyl, t For 1-6.
根据本申请的一些优选实施方案，R 2、R 3各自独立地为-H、-CF 3、-F、-Cl、甲基、乙基、甲氧基或者乙氧基。 According to some preferred embodiments of the present application, R 2 and R 3 are each independently -H, -CF 3 , -F, -Cl, methyl, ethyl, methoxy, or ethoxy.
根据本申请的一些优选实施方案，R 4为H，甲基或者乙基。 According to some preferred embodiments of the application, R 4 is H, methyl or ethyl.
根据本申请的一些优选实施方案，R 5中，R 5为-(CH 2) mR 7，其中m为0-3整数，所述R 7为由一个至两个取代基-A所取代或者非取代的芳基或杂芳基，所述取代基-A各地独立地为C 1-C 3的烷基、C 1-C 3的烷氧基、C 1-C 3的烷硫基、-F、-Cl、三氟甲基或甲砜基，其中，所述芳基为苯基、萘基、菲基，所述杂芳基为吡咯基、呋喃基、吡啶基、噻吩基、咪唑基、噻唑基、异噻唑基、吲唑基、吲哚基、吲唑基、异吲哚基、二氢吲哚基、异二氢吲哚基、异喹啉基、吲嗪基、异噁唑基、1,5-萘啶基、1,6-萘啶酮基、噁二唑基、噁唑基、1-苯基-1H-吡咯基、吩嗪基、吩噻嗪基、吩噁嗪基、酞嗪基、蝶啶基、嘌呤基、吡喃基、吡唑基、吡唑并[3,4-d]嘧啶基、吡啶基、吡啶并[3,2-d]嘧啶基、吡啶并[3,4-d]嘧啶基、吡嗪基、嘧啶基、哒嗪基、喹唑啉基、喹喔啉基、喹啉基、异喹啉基。 According to some preferred embodiments of the present application, in R 5 , R 5 is-(CH 2 ) m R 7 , where m is an integer of 0-3, and R 7 is substituted by one or two substituents -A or Unsubstituted aryl or heteroaryl, the substituents -A are each independently a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a C 1 -C 3 alkylthio group,- F, -Cl, trifluoromethyl or methylsulfone, wherein the aryl group is phenyl, naphthyl, phenanthryl, and the heteroaryl group is pyrrolyl, furyl, pyridyl, thienyl, imidazolyl , Thiazolyl, isothiazolyl, indazolyl, indolyl, indazolyl, isoindolyl, dihydroindolyl, isodihydroindolyl, isoquinolinyl, indazinyl, isoxazole Base, 1,5-naphthyridinyl, 1,6-naphthyridinyl, oxadiazolyl, oxazolyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazine Base, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazolyl, pyrazolo [3,4-d] pyrimidinyl, pyridyl, pyrido [3,2-d] pyrimidinyl, pyridine And [3,4-d] pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl.
更优选地，其中，所述芳基为苯基，所述杂芳基为噻唑基。More preferably, wherein the aryl is phenyl and the heteroaryl is thiazolyl.
最优选地，R 5为被甲基、乙基、甲氧基、乙氧基、F、Cl、三氟甲基中的一种或多种取代或者非取代的苯基或者噻唑基，或者所述被甲基、乙基、甲氧基、乙氧基、F、Cl、三氟甲基中的一种或多种取代或者非取代的苯基或者噻唑基取代的甲基、乙基。 Most preferably, R 5 is phenyl or thiazolyl substituted or unsubstituted by one or more of methyl, ethyl, methoxy, ethoxy, F, Cl, trifluoromethyl, or Said methyl, ethyl substituted with one or more of methyl, ethyl, methoxy, ethoxy, F, Cl, trifluoromethyl or substituted or unsubstituted phenyl or thiazolyl.
根据本申请的一些实施方案，所述脲取代的芳环连二噁烷并喹唑啉或喹啉类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。According to some embodiments of the present application, the pharmaceutically acceptable salt of the urea-substituted aromatic cyclodioxoquinazoline or quinoline compound is selected from the hydrochloride, hydrobromide salt of the compound , Hydroiodate, perchlorate, sulfate, nitrate, phosphate, formate, acetate, propionate, glycolate, lactate, succinate, maleate, Tartrate, malate, citrate, fumarate, gluconate, benzoate, mandelate, mesylate, isethionate, benzenesulfonate, oxalate, palm Acid salt, 2-naphthalenesulfonate, p-toluenesulfonate, cyclohexylsulfamate, salicylate, hexose, trifluoroacetate, aluminum, calcium, chloroprocaine One or more of a salt, a choline salt, a diethanolamine salt, an ethylenediamine salt, a lithium salt, a magnesium salt, a potassium salt, a sodium salt, and a zinc salt.
本发明的另一方面涉及所述的脲取代的芳环连二噁烷并喹唑啉或喹啉类化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药在制备治疗与VEGFR-2和/或CSF1R相关疾病的药物中的应用，其中，所述与VEGFR-2和/或CSF1R相关的疾病包括阿尔兹海默病、眼底疾病、干眼症、银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、系统性红斑狼疮、克罗恩病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、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。Another aspect of the invention relates to the urea-substituted aromatic cyclodioxoquinazoline or quinoline compounds, isomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof Application for preparing a medicine for treating diseases related to VEGFR-2 and / or CSF1R, wherein the diseases related to VEGFR-2 and / or CSF1R include Alzheimer's disease, fundus disease, dry eye disease, psoriasis , Vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atherosclerosis, pulmonary fibrosis, liver fibrosis, myelofibrosis, non-small cell lung cancer , Small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer , Liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myelogenous leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, lymphoma Multiple bone marrow , Biliary tract cancer, sarcoma, cholangiocarcinoma.
本发明的又一方面提供了一种药物组合物，该药物组合物包括本申请的脲取代的芳环连二噁烷并喹唑啉或喹啉类化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，以及一种或多种药学上可接受的载体或赋形剂。Another aspect of the present invention provides a pharmaceutical composition, which comprises the urea-substituted aromatic cyclodioxoquinazoline or quinoline compounds, isomers, hydrates, and solvents of the present application. Compounds, pharmaceutically acceptable salts or prodrugs, and one or more pharmaceutically acceptable carriers or excipients.
根据本申请的一些实施方案，该药物组合物还可以包括一种或多种其他治疗剂。According to some embodiments of the present application, the pharmaceutical composition may further include one or more other therapeutic agents.
有益效果Beneficial effect
本申请的脲取代的芳环连二噁烷并喹唑啉或喹啉类化合物表现出了强力的对VEGFR-2和CSF1R的抑制活性，该脲取代的芳环连二噁烷并喹唑啉或喹啉类化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，及其药物组合物有望用于制备治疗与VEGFR-2和/或CSF1R相关的自身免疫疾病、肿瘤以及阿尔兹海默病等疾病的药物中。The urea-substituted aromatic cyclodioxoquinazoline or quinoline compounds of the present application show strong inhibitory activity against VEGFR-2 and CSF1R. The urea-substituted aromatic cyclodioxoquinazoline Or quinoline compounds, its isomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and their pharmaceutical compositions are expected to be used for the preparation of autoimmune diseases related to VEGFR-2 and / or CSF1R , Tumors and Alzheimer's disease drugs.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
从下面结合附图的详细描述中，将会更加清楚地理解本发明的上述及其他目的、特征和其他优点，其中，The above and other objects, features, and other advantages of the present invention will be more clearly understood from the following detailed description in conjunction with the accompanying drawings. Among them,
图1示出了本申请实施例127和实施例171制备的化合物的混合物的液相色谱图；1 shows a liquid chromatogram of a mixture of compounds prepared in Example 127 and Example 171 of the present application;
图2示出了本申请实施例127制备的化合物的液相色谱图；Figure 2 shows a liquid chromatogram of the compound prepared in Example 127 of the present application;
图3示出了本申请实施例171制备的化合物的液相色谱图；3 shows a liquid chromatogram of the compound prepared in Example 171 of the present application;
图4示出了本申请实施例41制备的化合物利用蛋白标记法检测对RAW264.7细胞中M-CSFR(cFMS)磷酸化的抑制作用的图；FIG. 4 is a diagram showing the inhibition of M-CSFR (cFMS) phosphorylation in RAW264.7 cells by using the protein labeling method of the compound prepared in Example 41 of the present application; FIG.
图5示出了本申请实施例41制备的化合物在不同浓度下对RAW264.7细胞中M-CSFR(cFMS)磷酸化作用的抑制率；FIG. 5 shows the inhibitory rate of the compound prepared in Example 41 of the present application on M-CSFR (cFMS) phosphorylation in RAW264.7 cells at different concentrations;
图6示出了本申请实施例100制备的化合物利用蛋白标记法检测对RAW264.7细胞中M-CSFR(cFMS)磷酸化的抑制作用的图；FIG. 6 is a graph showing the detection of the inhibitory effect of M-CSFR (cFMS) phosphorylation on RAW264.7 cells by a protein labeling method using the compound prepared in Example 100 of the present application;
图7示出了本申请实施例100制备的化合物在不同浓度下对RAW264.7细胞中M-CSFR(cFMS)磷酸化作用的抑制率。FIG. 7 shows the inhibitory rate of the compound prepared in Example 100 of the present application on M-CSFR (cFMS) phosphorylation in RAW264.7 cells at different concentrations.
具体实施方式detailed description
除非另有说明，在本申请(包括说明书和权利要求书)中使用的以下术语具有下面给出的定义。在本申请中，除非另外说明，使用“或”或“和”意味着“和/或”。此外，术语“包括”以及其它形式的使用，例如“包含”、“含有”和“具有”，不是限制性的。本文使用的章节标题仅仅是为了组织的目的，而不应解释为对所述的主题的限制。Unless otherwise stated, the following terms used in this application (including the specification and claims) have the definitions given below. In this application, the use of "or" or "and" means "and / or" unless stated otherwise. Furthermore, the terms "including" and other forms of use, such as "including," "containing," and "having," are not limiting. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.
“烷基”是指脂肪族烃基。烷基是饱和或不饱和的。烷基部分，不管是饱和的还是不饱和的，可以是支链的或直链的。“烷基”可以具有1-10个碳原子，优选具有1-8个碳原子。 在一个方面，烷基选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基。典型的烷基包括但绝不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、新戊基、己基、烯丙基、乙烯基、乙炔、丁-2-烯基、丁-3-烯基等。"Alkyl" refers to an aliphatic hydrocarbon group. Alkyl is saturated or unsaturated. The alkyl moiety, whether saturated or unsaturated, can be branched or linear. "Alkyl" may have 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms. In one aspect, the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Typical alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, allyl, Vinyl, acetylene, but-2-enyl, but-3-enyl and the like.
术语“环烷基”是指单环或多环脂肪族非芳香族基团，其中构成环的每个原子(即骨架原子)是碳原子。环烷基可以是饱和或部分不饱和的。环烷基可以与芳环稠合，并且连接点处于不是芳环碳原子的碳上。环烷基包括具有3-10个环原子的基团。在一些实施方案中，环烷基选自环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基和环辛基。环烷基可以是取代或未取代的。在一个方面，环烷基是C 3-C 8环烷基。 The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic non-aromatic group in which each atom (i.e., a backbone atom) constituting the ring is a carbon atom. Cycloalkyl can be saturated or partially unsaturated. A cycloalkyl group can be fused with an aromatic ring and the point of attachment is on a carbon that is not an aromatic ring carbon atom. Cycloalkyl includes groups having 3 to 10 ring atoms. In some embodiments, cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Cycloalkyl can be substituted or unsubstituted. In one aspect, a cycloalkyl is a C 3 -C 8 cycloalkyl.
“烷氧基”是指(烷基)-O-基团，“烷硫基”是指(烷基)-S-基团，其中烷基如本文所定义。优选地，所述烷氧基为C 1-C 6烷氧基，更优选为C 1-C 3烷氧基。优选地，所述烷硫基为C 1-C 6烷硫基，更优选为C 1-C 3烷硫基。 "Alkoxy" refers to a (alkyl) -0- group and "alkylthio" refers to a (alkyl) -S- group, where alkyl is as defined herein. Preferably, the alkoxy group is a C 1 -C 6 alkoxy group, and more preferably a C 1 -C 3 alkoxy group. Preferably, the alkylthio group is a C 1 -C 6 alkylthio group, and more preferably a C 1 -C 3 alkylthio group.
术语“杂脂环基”是指环中含有一个或多个杂原子的杂环烷基环，其中环中的各个杂原子选自O、S和N，具体地，可以含有1-2个选自N、O、S中的原子作为环原子，各个杂环基团在其环体系中可以含有4-8个原子，优选4-6个原子。而且该杂脂环基可以为未取代或取代的。The term "heteroalicyclic" refers to a heterocycloalkyl ring containing one or more heteroatoms in the ring, wherein each heteroatom in the ring is selected from O, S, and N, and specifically, may contain 1-2 selected from The atoms in N, O, and S are ring atoms, and each heterocyclic group may contain 4 to 8 atoms, preferably 4 to 6 atoms in its ring system. Moreover, the heteroalicyclic group may be unsubstituted or substituted.
更具体地，所述含有1-2个选自N、O、S的杂原子的杂脂环基中的杂脂环可以为选自以下环结构中的任一种：More specifically, the heteroalicyclic ring in the heteroalicyclic group containing 1-2 heteroatoms selected from N, O, and S may be any one selected from the following ring structures:
Figure PCTCN2019101623-appb-000005
Figure PCTCN2019101623-appb-000005
其中在环结构上可以进行取代，取代基可以如前文所描述。Wherein the ring structure may be substituted, and the substituent may be as described above.
本申请中术语“异构体”为具有相同分子式的不同化合物，可以包括立体异构、互变异构等各种异构形式。“立体异构体”是仅原子在空间的排列方式不同的异构体。本文描述的某些化合物含有一个或多个不对称中心，且因此可以产生对映体、非对映体和其他依据绝对立体化学可以被定义为(R)-或(S)-的立体异构形式。本发明的化学实体、药物组合物和方法旨在包括所有这些可能的异构体，包括外消旋混合物、光学纯形式和中间的混合物。旋光(R)-和(S)-异构体可以使用手性合成子或手性试剂来制备，或使用常规技术来拆分。化合物的光学活性可以通过任何合适的方法进行分析，包括但不限于手性色谱法和旋光测定法，且可确定一种立体异构体超越其他异构体的优势程度。The term "isomers" in the present application are different compounds having the same molecular formula, and may include various isomeric forms such as stereoisomers and tautomers. "Stereoisomers" are isomers that differ only in the arrangement of their atoms in space. Certain compounds described herein contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomers that can be defined as (R)-or (S)-based on absolute stereochemistry form. The chemical entities, pharmaceutical compositions and methods of the present invention are intended to include all of these possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)-and (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed by any suitable method, including, but not limited to, chiral chromatography and polarimetry, and the degree of dominance of one stereoisomer over other isomers can be determined.
当本文所述的化合物含有烯烃双键时，除非另有说明，其意指该化合物包括各种顺反异构体。When a compound described herein contains an olefinic double bond, it is meant that the compound includes various cis-trans isomers unless otherwise stated.
“互变异构体”是可通过互变异构化互相转换的结构上不同的异构体。“互变异构化”是异构化的一种形式，且包括质子移变或质子转移互变异构化，可认为它是酸碱化学的子集。 “质子移变互变异构化”或“质子转移互变异构化”涉及伴有键级变换的质子迁移，往往是单键与相邻的双键的互换。当可能发生互变异构化时(例如，在溶液中)，可达到互变异构体的化学平衡。互变异构化的一个实例为酮-烯醇互变异构化。"Tautomers" are structurally different isomers that can be converted to each other through tautomerization. "Tautomerization" is a form of isomerization and includes proton transfer or proton transfer tautomerization, which can be considered as a subset of acid-base chemistry. "Proton transfer tautomerization" or "proton transfer tautomerization" involves the migration of a proton accompanied by a bond-level transformation, which is often the exchange of a single bond with an adjacent double bond. When tautomerization is possible (eg, in solution), the chemical equilibrium of the tautomers can be reached. An example of tautomerization is keto-enol tautomerization.
本申请中，结构式(I)的化合物、异构体、结晶或前药及其可药用盐可以存在溶剂化形式和非溶剂化形式。例如溶剂化形式可以是水溶形式。本发明包括所有这些溶剂化的和未溶剂化的形式。In the present application, compounds, isomers, crystals or prodrugs of formula (I) and their pharmaceutically acceptable salts may exist in solvated and unsolvated forms. For example, the solvated form may be a water-soluble form. The invention includes all of these solvated and unsolvated forms.
本发明还提供了制备相应化合物的方法，具体可通过下述的路线制备。三种代表性的合成路线如下所示：The invention also provides a method for preparing the corresponding compound, which can be specifically prepared through the following route. Three representative synthetic routes are shown below:
合成路线(I)Synthesis route (I)
Figure PCTCN2019101623-appb-000006
Figure PCTCN2019101623-appb-000006
合成路线(II)Synthesis route (II)
Figure PCTCN2019101623-appb-000007
Figure PCTCN2019101623-appb-000007
合成路线(III)Synthesis route (III)
Figure PCTCN2019101623-appb-000008
Figure PCTCN2019101623-appb-000008
以上反应式中，R 1、R 2、R 3、R 4、R 5的定义见前文所述。 In the above reaction formulas, the definitions of R 1 , R 2 , R 3 , R 4 , and R 5 are described above.
以上合成路线只是出于示例的目的提供，本申请化合物的合成方法不限于上述路线，而且，上述路线图中的具体条件也只是出于示例的目的提供，本领域技术人员可以理解，不限于上述具体条件。The above synthetic routes are provided only for the purpose of illustration, and the synthetic methods of the compounds of the present application are not limited to the above routes, and the specific conditions in the above route map are provided for the purpose of illustration only, and those skilled in the art can understand that they are not limited to the above Specific conditions.
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合具体实施例和附图，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅用以解释本发明，并不用于限定本发明。实施例中未注明具体技术或条件的，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。In order to make the objectives, technical solutions, and advantages of the present invention clearer, the present invention is further described in detail below with reference to specific embodiments and drawings. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. If the specific technology or condition is not indicated in the examples, the technology or condition described in the literature in the art or the product description is performed. If the reagents or instruments used are not specified by the manufacturer, they are all conventional products that are commercially available. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.
在下文的描述中，本领域技术人员可以理解，苯甲胺与苄胺以及苯甲基与苄基表示相同的含义，同时，例如4-氨基-2-甲基苯酚与2-甲基-4-氨基苯酚，只是书写的区别，表示相同的化合物。本申请部分化合物命名采用chemdraw命名后翻译为中文。In the following description, those skilled in the art can understand that benzylamine and benzylamine and benzyl and benzyl have the same meaning, and at the same time, for example, 4-amino-2-methylphenol and 2-methyl-4 -Aminophenol, which is only a written difference, means the same compound. The names of some of the compounds in this application are translated into Chinese after being named by chemdraw.
部分化学试剂来源Some chemical reagent sources
反应溶剂由中国国药试剂提供The reaction solvent was provided by Sinopharm
普通反应化学原料由伊诺凯、安耐吉、麦克林、百灵威、药石等公司提供Common reaction chemical raw materials are provided by companies such as Inoke, Energie, Macleans, Braunwell, Medicine Stone, etc.
薄层层析硅胶板(厚度0.5mm,1mm，200X200mm)由烟台新诺化工有限公司提供Thin layer chromatography silica gel plate (thickness 0.5mm, 1mm, 200X200mm) provided by Yantai Xinnuo Chemical Co., Ltd.
硅胶(200-300目)由中国国药试剂公司提供Silica gel (200-300 mesh) provided by China National Pharmaceutical Reagent Company
化学简称Chemical abbreviation
DMF：N’N-二甲基甲酰胺DMF: N’N-dimethylformamide
DIEA：N’N-二异丙基乙基胺DIEA: N’N-diisopropylethylamine
NMP：N-甲基吡咯烷酮NMP: N-methylpyrrolidone
Pd(OAc) 2：醋酸钯 Pd (OAc) 2 : Palladium acetate
Pd 2(dba) 3：三(二亚苄基茚丙酮)二钯 Pd 2 (dba) 3 : Tris (dibenzylideneindeneacetone) dipalladium
Xantphos：4,5-双二苯基膦-9,9-二甲基氧杂蒽Xantphos: 4,5-bisdiphenylphosphine-9,9-dimethylxanthene
Binap：1,1'-联萘-2,2'-双二苯膦Binap: 1,1'-binapthyl-2,2'-bisdiphenylphosphine
(Boc) 2O：二碳酸二叔丁酯 (Boc) 2 O: Di-tert-butyl dicarbonate
中间体的合成Synthesis of intermediates
Figure PCTCN2019101623-appb-000009
Figure PCTCN2019101623-appb-000009
中间体1，中间体2合成方法见专利申请WO 2016112847For the synthesis method of Intermediate 1, Intermediate 2, see patent application WO2016112847
中间体3的制备.Preparation of intermediate 3.
Figure PCTCN2019101623-appb-000010
Figure PCTCN2019101623-appb-000010
步骤1)将3-甲氧基苯二酚(25.3g,180mmol),碳酸钾(104.5g,756mmol),和1,2-二溴乙烷(74.4g,396mmol)的DMF(100mL)的溶液在60℃的氮气体系中反应加热6小时.加水淬灭后用乙酸乙酯萃取；有机相用饱和碳酸氢钠溶液洗涤，硫酸镁干燥，过滤，浓缩得深灰色油状物：5-甲氧基-2,3-二氢苯并[b][1,4]二氧六环(25.4g,153mmol,收率85％)；Step 1) A solution of 3-methoxyresorcinol (25.3 g, 180 mmol), potassium carbonate (104.5 g, 756 mmol), and 1,2-dibromoethane (74.4 g, 396 mmol) in DMF (100 mL) The reaction was heated in a nitrogen system at 60 ° C for 6 hours. After quenching with water, extraction was performed with ethyl acetate; the organic phase was washed with a saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated to obtain a dark gray oil: 5-methoxy -2,3-dihydrobenzo [b] [1,4] dioxane (25.4g, 153mmol, yield 85%);
步骤2)在氮气氛的冰水浴条件下,向含有AlCl 3(12.0g,90mmol)的硝基甲烷(200mL)中缓慢滴加乙酰氯(5.57mL,78mmol).然后缓慢滴加5-甲氧基-2,3-二氢苯并[b][1,4]二氧六环(10.0g,60mmol)的硝基甲烷(100mL)溶液.室温搅拌反应5小时，加入1N的氯化氢溶液淬灭.有机相分别用饱和氯化钠溶液洗涤，硫酸镁干燥，过滤，浓缩.在异丙醇(25mL)中回流加热，冷却静置，过滤得灰色固体产物：5-乙酰基-2,3-二氢-8-甲氧基-1,4-苯并二氧六环(10.1g,49mmol,81％)； Step 2) Slowly add acetyl chloride (5.57 mL, 78 mmol) to nitromethane (200 mL) containing AlCl 3 (12.0 g, 90 mmol) under ice-water bath conditions in a nitrogen atmosphere. Then slowly add 5-methoxy -2,3-dihydrobenzo [b] [1,4] dioxane (10.0g, 60mmol) in a solution of nitromethane (100mL). The reaction was stirred at room temperature for 5 hours, and quenched by the addition of a 1N hydrogen chloride solution. The organic phase was washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The mixture was heated under reflux in isopropanol (25 mL), allowed to stand still, and filtered to obtain a gray solid product: 5-acetyl-2,3- Dihydro-8-methoxy-1,4-benzodioxane (10.1 g, 49 mmol, 81%);
步骤3)在冰水浴条件下向5-乙酰基-2,3-二氢-8-甲氧基-1,4-苯并二氧六环(10.1g,49mmol)的醋酸(60mL)溶液中滴加浓硝酸(62％，20mL)，室温搅拌3小时，加水打浆，过滤干燥得黄色固体产物：1-(8-甲氧基-6-硝基-2,3-二氢苯并[b][1,4]二氧六环-5-基)乙基-1-酮10.5g， 85％收率；Step 3) In a solution of 5-acetyl-2,3-dihydro-8-methoxy-1,4-benzodioxane (10.1 g, 49 mmol) in acetic acid (60 mL) under ice-water bath conditions Add concentrated nitric acid (62%, 20mL) dropwise, stir at room temperature for 3 hours, add water to beat, filter and dry to obtain a yellow solid product: 1- (8-methoxy-6-nitro-2,3-dihydrobenzo [b ] [1,4] Dioxane-5-yl) ethyl-1-one 10.5g, 85% yield;
步骤4)向1-(8-甲氧基-6-硝基-2,3-二氢苯并[b][1,4]二氧六环-5-基)乙基-1-酮(10.1g,40mmol)的甲醇(100mL)溶液加入湿钯碳(10％,0.5g)，氢气置换后搅拌反应10小时，过滤，浓缩得紫色油状物：1-(6-氨基-8-甲氧基-2,3-二氢苯并[b][1,4]二氧六环-5-基)乙基-1-酮(8.8g,收率95％),MS:224[M+H] + Step 4) To 1- (8-methoxy-6-nitro-2,3-dihydrobenzo [b] [1,4] dioxane-5-yl) ethyl-1-one ( A solution of 10.1 g, 40 mmol) in methanol (100 mL) was added to wet palladium on carbon (10%, 0.5 g), and the reaction was stirred for 10 hours after being replaced with hydrogen, filtered, and concentrated to give a purple oil: 1- (6-amino-8-methoxy -2,3-dihydrobenzo [b] [1,4] dioxane-5-yl) ethyl-1-one (8.8 g, yield 95%), MS: 224 [M + H ] +
步骤5)向1-(6-氨基-8-甲氧基-2,3-二氢苯并[b][1,4]二氧六环-5-基)乙基-1-酮(4.5g,20mmol)的二氧六环(80mL)溶液中加入叔丁醇钠(4.4g,46mmol)，室温搅拌半小时，加入甲酸甲酯(10.8mL,132mmol)的二氧六环(10mL)溶液，室温搅拌15小时，加入冰水中并使用2N稀盐酸调节PH为7后打浆，过滤干燥得灰色固体产物：5-甲氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-醇3.8克，收率82％，MS:234[M+H] + Step 5) To 1- (6-amino-8-methoxy-2,3-dihydrobenzo [b] [1,4] dioxane-5-yl) ethyl-1-one (4.5 g, 20 mmol) of dioxane (80 mL) solution was added sodium tert-butoxide (4.4 g, 46 mmol), stirred at room temperature for half an hour, and a solution of methyl formate (10.8 mL, 132 mmol) in dioxane (10 mL) was added. , Stirred at room temperature for 15 hours, added ice water and adjusted the pH to 7 with 2N dilute hydrochloric acid, and then slurried, filtered and dried to obtain a gray solid product: 5-methoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-ol 3.8 g, yield 82%, MS: 234 [M + H] +
步骤6)在冰水浴条件下向5-甲氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-醇(2.4g,10mmol)的三氯氧磷(30mL)溶液中加入三乙胺(3mL)，回流加热反应5小时，冷却，浓缩，加水溶解并用碳酸氢钾调节pH值至9，打浆，过滤干燥得土黄色固体产物2.2g：10-氯-5-甲氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉，88％收率，MS:252[M+H] + Step 6) Under ice-water bath conditions, 5-methoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-ol (2.4g, 10mmol) Triethylamine (3mL) was added to the solution of phosphorus trichloride (30mL), and the reaction was heated under reflux for 5 hours, cooled, concentrated, dissolved by adding water and adjusted to pH 9 with potassium bicarbonate, beaten, filtered and dried to obtain a khaki solid product 2.2 g: 10-chloro-5-methoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinoline, 88% yield, MS: 252 [M + H ] +
实施例Examples
实施例1. 1-(1-(4-氟苯基)乙基)-3-(4-((5-(3-吗啉丙基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹唑啉-10-基)氧基)苯基)脲的制备Example 1. 1- (1- (4-fluorophenyl) ethyl) -3- (4-((5- (3-morpholinyl) -2,3-dihydro- [1,4] Preparation of dioxane [2,3-f] quinazolin-10-yl) oxy) phenyl) urea
Figure PCTCN2019101623-appb-000011
Figure PCTCN2019101623-appb-000011
步骤1)：在冰水浴条件下，向1-(4-氟苯基)乙基-1-胺的DMF溶液中分别加入氯甲酸苯酯和吡啶，室温搅拌8小时，产物(1-(4-氟苯基)乙基)氨基甲酸苯酯直接用于下一步，MS:260[M+H] + Step 1): Under ice water bath conditions, add phenyl chloroformate and pyridine to the DMF solution of 1- (4-fluorophenyl) ethyl-1-amine, and stir at room temperature for 8 hours. The product (1- (4 -Fluorophenyl) ethyl) phenyl carbamate was used directly in the next step, MS: 260 [M + H] +
步骤2)：向步骤1)所得反应液中加入4-氨基苯酚，并在50℃加热反应两小时，冷却，加水淬灭，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩得到灰色固体产物1-(1-(4-氟苯基)乙基)-3-(4-羟基苯基)脲直接用于下一步；Step 2): Add 4-aminophenol to the reaction solution obtained in step 1), and heat the reaction at 50 ° C for two hours, cool, quench with water, extract with ethyl acetate, wash with saturated brine, dry the organic phase, and concentrate to obtain a gray color. The solid product 1- (1- (4-fluorophenyl) ethyl) -3- (4-hydroxyphenyl) urea was used directly in the next step;
步骤3)：分别将步骤2)所得产品,10-氯-5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹唑啉(中间体2)和碳酸钾加入DMF中，加热至80℃反应5小时，冷却，加水打浆，过滤，干燥得浅黄色固体经柱层析纯化得到白色固体产物(1-(1-(4-氟苯基)乙基)-3-(4-((5-(3-吗啉丙基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹唑啉-10-基)氧基)苯基)脲)；Step 3): The product obtained in step 2), 10-chloro-5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f ] Quinazoline (intermediate 2) and potassium carbonate were added to DMF, heated to 80 ° C for 5 hours, cooled, slurried with water, filtered, and dried to obtain a pale yellow solid, which was purified by column chromatography to obtain a white solid product (1- (1 -(4-fluorophenyl) ethyl) -3- (4-((5- (3-morpholinyl) -2,3-dihydro- [1,4] dioxane [2,3 -f] quinazolin-10-yl) oxy) phenyl) urea);
1H NMR(300MHz,DMSO-d 6)δ8.49(s,1H),8.39(s,1H),7.43-7.37(m,4H),7.20-7.14(m,2H),7.07-7.01(m,3H),6.68(d,J＝9.0Hz,1H),4.85-4.80(m,1H),4.43-4.38(m,4H),4.20(br,2H),3.58(br,4H),2.49-2.38(m,6H),1.96(br,2H),1.38(d,J＝6.0Hz,3H).MS:604[M+H] +. 1 H NMR (300MHz, DMSO-d 6 ) δ 8.49 (s, 1H), 8.39 (s, 1H), 7.43-7.37 (m, 4H), 7.20-7.14 (m, 2H), 7.07-7.01 (m , 3H), 6.68 (d, J = 9.0Hz, 1H), 4.85-4.80 (m, 1H), 4.43-4.38 (m, 4H), 4.20 (br, 2H), 3.58 (br, 4H), 2.49- 2.38 (m, 6H), 1.96 (br, 2H), 1.38 (d, J = 6.0Hz, 3H) .MS: 604 [M + H] + .
实施例2. 1-(1-(4-氟苯基)乙基)-3-(2-甲基-4-((5-(3-吗啉丙基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹唑啉-10-基)氧基)苯基)脲Example 2.1- (1- (4-fluorophenyl) ethyl) -3- (2-methyl-4-((5- (3-morpholinyl) -2,3-dihydro- [1,4] Dioxane [2,3-f] quinazolin-10-yl) oxy) phenyl) urea
Figure PCTCN2019101623-appb-000012
Figure PCTCN2019101623-appb-000012
同实施例1操作，由4-氨基-3-甲基苯酚代替步骤2)中的4-氨基苯酚进行反应得到白色固体产物； 1H NMR(300MHz,DMSO-d 6)δ8.40(s,1H),7.84(d,J＝6.0Hz,1H),7.70(s,1H),7.42-7.37(m,2H),7.18(t,J＝9.0Hz,2H),7.07(d,J＝6.0Hz,1H),7.01-6.99(m,2H),6.92(d,J＝9.0Hz,1H),4.85-4.80(m,1H),4.43-4.38(m,4H),4.20(br,2H),3.58(br,4H),2.45-2.38(m,6H),2.19(s,3H),1.96(br,2H),1.39(d,J＝6.0Hz,3H).MS:618[M+H] +. The same operation as in Example 1 was carried out by replacing 4-aminophenol in step 2) with 4-amino-3-methylphenol to obtain a white solid product; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.40 (s, 1H), 7.84 (d, J = 6.0Hz, 1H), 7.70 (s, 1H), 7.42-7.37 (m, 2H), 7.18 (t, J = 9.0Hz, 2H), 7.07 (d, J = 6.0 Hz, 1H), 7.01-6.99 (m, 2H), 6.92 (d, J = 9.0Hz, 1H), 4.85-4.80 (m, 1H), 4.43-4.38 (m, 4H), 4.20 (br, 2H) , 3.58 (br, 4H), 2.45-2.38 (m, 6H), 2.19 (s, 3H), 1.96 (br, 2H), 1.39 (d, J = 6.0Hz, 3H) .MS: 618 [M + H ] + .
实施例3. 1-(1-(4-氟苯基)乙基)-3-(3-甲基-4-((5-(3-吗啉丙基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹唑啉-10-基)氧基)苯基)脲Example 3.1- (1- (4-fluorophenyl) ethyl) -3- (3-methyl-4-((5- (3-morpholinyl) -2,3-dihydro- [1,4] Dioxane [2,3-f] quinazolin-10-yl) oxy) phenyl) urea
Figure PCTCN2019101623-appb-000013
Figure PCTCN2019101623-appb-000013
同实施例1操作，由4-氨基-2-甲基苯酚代替步骤2)中的4-氨基苯酚进行反应得到白色固体产物； 1H NMR(300MHz,DMSO-d 6)δ8.48(s,1H),8.38(s,1H),7.51-7.48(m,1H),7.41-7.33(m,2H),7.25-7.17(m,3H),7.02-6.97(m,2H),6.72(d,J＝9.0Hz,1H),4.82(t,J＝6.0Hz,1H),4.45-4.38(m,4H),4.20(br,2H),3.58(br,4H),2.45-2.38(m,6H),1.98-1.94(m,5H),1.38(d,J＝6.0Hz,3H).MS:618[M+H] +. The same operation as in Example 1 was carried out by replacing 4-aminophenol in step 2) with 4-amino-2-methylphenol to obtain a white solid product; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.48 (s, 1H), 8.38 (s, 1H), 7.51-7.48 (m, 1H), 7.41-7.33 (m, 2H), 7.25-7.17 (m, 3H), 7.02-6.97 (m, 2H), 6.72 (d, J = 9.0Hz, 1H), 4.82 (t, J = 6.0Hz, 1H), 4.45-4.38 (m, 4H), 4.20 (br, 2H), 3.58 (br, 4H), 2.45-2.38 (m, 6H ), 1.98-1.94 (m, 5H), 1.38 (d, J = 6.0Hz, 3H) .MS: 618 [M + H] + .
实施例4. 1-(1-(4-氟苯基)乙基)-3-(2-氯-4-((5-(3-吗啉丙基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹唑啉-10-基)氧基)苯基)脲Example 4.1- (1- (4-fluorophenyl) ethyl) -3- (2-chloro-4-((5- (3-morpholinyl) -2,3-dihydro- [ 1,4] dioxane [2,3-f] quinazolin-10-yl) oxy) phenyl) urea
Figure PCTCN2019101623-appb-000014
Figure PCTCN2019101623-appb-000014
同实施例1操作，由4-氨基-3-氯苯酚代替步骤2)中的4-氨基苯酚进行反应得到白色固体 产物； 1H NMR(300MHz,DMSO-d 6)δ8.42(s,1H),8.17-8.11(m,2H),7.56-7.55(m,1H),7.39(br,3H),7.21-7.10(m,3H),7.03(s,1H),4.83(t,J＝6.0Hz,1H),4.43-4.38(m,4H),4.21(br,2H),3.58(br,4H),2.44-2.38(m,6H),1.96(br,2H),1.39(d,J＝6.0Hz,3H).MS:638[M+H] +. The same operation as in Example 1 was carried out by replacing 4-aminophenol in step 2) with 4-amino-3-chlorophenol to obtain a white solid product; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.42 (s, 1H ), 8.17-8.11 (m, 2H), 7.56-7.55 (m, 1H), 7.39 (br, 3H), 7.21-7.10 (m, 3H), 7.03 (s, 1H), 4.83 (t, J = 6.0 Hz, 1H), 4.43-4.38 (m, 4H), 4.21 (br, 2H), 3.58 (br, 4H), 2.44-2.38 (m, 6H), 1.96 (br, 2H), 1.39 (d, J = 6.0Hz, 3H) .MS: 638 [M + H] + .
实施例5. 1-(1-(4-氟苯基)乙基)-3-(3-氯-4-((5-(3-吗啉丙基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹唑啉-10-基)氧基)苯基)脲Example 5.1- (1- (4-fluorophenyl) ethyl) -3- (3-chloro-4-((5- (3-morpholinyl) -2,3-dihydro- [ 1,4] dioxane [2,3-f] quinazolin-10-yl) oxy) phenyl) urea
Figure PCTCN2019101623-appb-000015
Figure PCTCN2019101623-appb-000015
同实施例1操作，由4-氨基-2-氯苯酚代替步骤2)中的4-氨基苯酚进行反应得到白色固体产物； 1H NMR(300MHz,DMSO-d 6)δ8.68(s,1H),8.41(s,1H),7.77(s,1H),7.39-7.37(m,2H),7.24-7.14(m,4H),7.05(s,1H),6.80(d,J＝9.0Hz,1H),4.85-4.82(m,1H),4.46-4.40(m,4H),4.22(s,2H),3.60-3.57(m,4H),2.46-2.38(m,6H),1.96(s,2H),1.39(d,J＝6.0Hz,3H)；MS:638[M+H] +. The same operation as in Example 1 was carried out by replacing 4-aminophenol in step 2) with 4-amino-2-chlorophenol to obtain a white solid product; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.68 (s, 1H ), 8.41 (s, 1H), 7.77 (s, 1H), 7.39-7.37 (m, 2H), 7.24-7.14 (m, 4H), 7.05 (s, 1H), 6.80 (d, J = 9.0Hz, 1H), 4.85-4.82 (m, 1H), 4.46-4.40 (m, 4H), 4.22 (s, 2H), 3.60-3.57 (m, 4H), 2.46-2.38 (m, 6H), 1.96 (s, 2H), 1.39 (d, J = 6.0Hz, 3H); MS: 638 [M + H] + .
实施例6. 1-(1-(4-氟苯基)乙基)-3-(2-氟-4-((5-(3-吗啉丙基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹唑啉-10-基)氧基)苯基)脲Example 6. 1- (1- (4-fluorophenyl) ethyl) -3- (2-fluoro-4-((5- (3-morpholinyl) -2,3-dihydro- [ 1,4] dioxane [2,3-f] quinazolin-10-yl) oxy) phenyl) urea
Figure PCTCN2019101623-appb-000016
Figure PCTCN2019101623-appb-000016
同实施例1操作，由4-氨基-3-氟苯酚代替步骤2)中的4-氨基苯酚进行反应得到白色固体产物； 1H NMR(300MHz,DMSO-d 6)δ8.42(s,1H),8.34(s,1H),8.13-8.08(m,1H),7.41-7.36(m,2H),7.25-7.15(m,4H),7.03(s,1H),6.95(d,J＝9.0Hz,1H),4.85-4.81(m,1H),4.44-4.39(m,4H),4.21(s,2H),3.58(s,4H),2.49-2.38(m,6H),1.95(s,2H),1.38(d,J＝6.0Hz,3H)；MS:622[M+H] +. The same operation as in Example 1 was carried out by replacing 4-aminophenol in step 2) with 4-amino-3-fluorophenol to obtain a white solid product; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.42 (s, 1H ), 8.34 (s, 1H), 8.13-8.08 (m, 1H), 7.41-7.36 (m, 2H), 7.25-7.15 (m, 4H), 7.03 (s, 1H), 6.95 (d, J = 9.0 Hz, 1H), 4.85-4.81 (m, 1H), 4.44-4.39 (m, 4H), 4.21 (s, 2H), 3.58 (s, 4H), 2.49-2.38 (m, 6H), 1.95 (s, 2H), 1.38 (d, J = 6.0Hz, 3H); MS: 622 [M + H] + .
实施例7. 1-(1-(4-氟苯基)乙基)-3-(3-氟-4-((5-(3-吗啉丙基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹唑啉-10-基)氧基)苯基)脲Example 7.1- (1- (4-fluorophenyl) ethyl) -3- (3-fluoro-4-((5- (3-morpholinyl) -2,3-dihydro- [ 1,4] dioxane [2,3-f] quinazolin-10-yl) oxy) phenyl) urea
Figure PCTCN2019101623-appb-000017
Figure PCTCN2019101623-appb-000017
同实施例1操作，由2-氟-4氨基苯酚代替步骤2)4-氨基苯酚进行反应得到白色固体产物； 1H NMR(300MHz,DMSO-d 6)δ8.84(s,1H),8.42(s,1H),7.58(d,J＝12Hz,1H),7.39-7.36(m,2H),7.28-7.14(m,3H),7.08-7.05(m,2H),6.88(d,J＝9.0Hz,1H),4.83(t,J＝6.0Hz,1H),4.45- 4.40(m,4H),4.22-4.20(m,2H),3.59(br,4H),2.45-2.38(m,6H),2.00-1.90(m,2H),1.39(d,J＝9.0Hz,3H).MS:622[M+H] +. The same operation as in Example 1 was carried out by using 2-fluoro-4aminophenol instead of step 2) 4-aminophenol to obtain a white solid product; 1 H NMR (300MHz, DMSO-d 6 ) δ8.84 (s, 1H), 8.42 (s, 1H), 7.58 (d, J = 12Hz, 1H), 7.39-7.36 (m, 2H), 7.28-7.14 (m, 3H), 7.08-7.05 (m, 2H), 6.88 (d, J = 9.0Hz, 1H), 4.83 (t, J = 6.0Hz, 1H), 4.45- 4.40 (m, 4H), 4.22-4.20 (m, 2H), 3.59 (br, 4H), 2.45-2.38 (m, 6H ), 2.00-1.90 (m, 2H), 1.39 (d, J = 9.0Hz, 3H) .MS: 622 [M + H] + .
实施例8. 1-(1-(4-氟苯基)乙基)-3-(2-三氟甲基-4-((5-(3-吗啉丙基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹唑啉-10-基)氧基)苯基)脲Example 8.1- (1- (4-fluorophenyl) ethyl) -3- (2-trifluoromethyl-4-((5- (3-morpholinyl) -2,3-di Hydrogen- [1,4] dioxane [2,3-f] quinazolin-10-yl) oxy) phenyl) urea
Figure PCTCN2019101623-appb-000018
Figure PCTCN2019101623-appb-000018
同实施例1操作，由4-氨基-3-三氟甲基苯酚代替步骤2)中的4-氨基苯酚进行反应得到白色固体产物 1H NMR(300MHz,DMSO-d 6)δ8.42(s,1H),7.96(d,J＝9.0Hz,1H),7.88(s,1H),7.54-7.40(m,5H),7.18(t,J＝9.0Hz,2H),7.02(s,1H),4.83(t,J＝7.5Hz,1H),4.43-4.39(m,4H),4.20(t,J＝6.0Hz,2H),3.58(br,4H),2.44-2.37(m,6H),1.95(br,2H),1.39(d,J＝6.0Hz,3H).MS:672[M+H] +. The same operation as in Example 1 was carried out by replacing 4-aminophenol in step 2) with 4-amino-3-trifluoromethylphenol to obtain a white solid product. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.42 (s , 1H), 7.96 (d, J = 9.0Hz, 1H), 7.88 (s, 1H), 7.54-7.40 (m, 5H), 7.18 (t, J = 9.0Hz, 2H), 7.02 (s, 1H) , 4.83 (t, J = 7.5 Hz, 1H), 4.43-4.39 (m, 4H), 4.20 (t, J = 6.0 Hz, 2H), 3.58 (br, 4H), 2.44-2.37 (m, 6H), 1.95 (br, 2H), 1.39 (d, J = 6.0Hz, 3H) .MS: 672 [M + H] + .
实施例9. 1-(1-(4-氟苯基)乙基)-3-(2-甲氧基-4-((5-(3-吗啉丙基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹唑啉-10-基)氧基)苯基)脲Example 9.1- (1- (4-fluorophenyl) ethyl) -3- (2-methoxy-4-((5- (3-morpholinyl) -2,3-dihydro -[1,4] dioxane [2,3-f] quinazolin-10-yl) oxy) phenyl) urea
Figure PCTCN2019101623-appb-000019
Figure PCTCN2019101623-appb-000019
同实施例1操作，由4-氨基-3-甲氧基苯酚代替步骤2)中的4-氨基苯酚进行反应得到白色固体产物 1H NMR(300MHz,DMSO-d 6)δ8.41(s,1H),8.08-8.05(m,1H),7.98(s,1H),7.39-7.35(m,3H),7.20-7.17(m,2H),7.02(s,1H),6.88(s,1H),6.67-6.64(m,1H),4.85-4.82(m,1H),4.44-4.39(m,4H),4.20(s,2H),3.82(s,3H),3.58(s,4H),2.45-2.38(m,6H),1.96(br,2H),1.37(d,J＝6.0Hz,3H).MS:634[M+H] +. The same operation as in Example 1 was carried out by replacing 4-aminophenol in step 2) with 4-amino-3-methoxyphenol to obtain a white solid product. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.41 (s, 1H), 8.08-8.05 (m, 1H), 7.98 (s, 1H), 7.39-7.35 (m, 3H), 7.20-7.17 (m, 2H), 7.02 (s, 1H), 6.88 (s, 1H) , 6.67-6.64 (m, 1H), 4.85-4.82 (m, 1H), 4.44-4.39 (m, 4H), 4.20 (s, 2H), 3.82 (s, 3H), 3.58 (s, 4H), 2.45 -2.38 (m, 6H), 1.96 (br, 2H), 1.37 (d, J = 6.0Hz, 3H) .MS: 634 [M + H] + .
实施例10. 1-(1-(4-氟苯基)乙基)-3-(3-甲氧基-4-((5-(3-吗啉丙基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹唑啉-10-基)氧基)苯基)脲Example 10.1- (1- (4-fluorophenyl) ethyl) -3- (3-methoxy-4-((5- (3-morpholinyl) -2,3-dihydro -[1,4] dioxane [2,3-f] quinazolin-10-yl) oxy) phenyl) urea
Figure PCTCN2019101623-appb-000020
Figure PCTCN2019101623-appb-000020
同实施例1操作，由4-氨基-2-甲氧基苯酚代替步骤2)中的4-氨基苯酚进行反应得到白色固体产物 1H NMR(300MHz,DMSO-d 6)δ8.56(s,1H),8.36(s,1H),7.41-7.35(m,3H),7.17(t, J＝9.0Hz,2H),7.00(d,J＝9.0Hz,2H),6.84(d,J＝9.0Hz,1H),6.73(d,J＝9.0Hz,1H),4.83-4.80(m,1H),4.43-4.38(m,4H),4.21(br,2H),3.65-3.55(m,7H),2.49-2.39(m,6H),1.96-1.91(m,2H),1.39(d,J＝9.0Hz,3H).MS:634[M+H] +. The same operation as in Example 1 was carried out by replacing 4-aminophenol in step 2) with 4-amino-2-methoxyphenol to obtain a white solid product. 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.36 (s, 1H), 7.41-7.35 (m, 3H), 7.17 (t, J = 9.0Hz, 2H), 7.00 (d, J = 9.0Hz, 2H), 6.84 (d, J = 9.0 Hz, 1H), 6.73 (d, J = 9.0 Hz, 1H), 4.83-4.80 (m, 1H), 4.43-4.38 (m, 4H), 4.21 (br, 2H), 3.65-3.55 (m, 7H) , 2.49-2.39 (m, 6H), 1.96-1.91 (m, 2H), 1.39 (d, J = 9.0Hz, 3H). MS: 634 [M + H] + .
下表1中的实施例11-25采用与实施例1相似的步骤进行制备，区别在于采用具有不同的取代基的原料，以获得相应的目标化合物，具体见下表。Examples 11-25 in the following Table 1 were prepared using similar procedures to Example 1, except that the raw materials with different substituents were used to obtain the corresponding target compounds, as shown in the following table.
Figure PCTCN2019101623-appb-000021
Figure PCTCN2019101623-appb-000021
Figure PCTCN2019101623-appb-000022
Figure PCTCN2019101623-appb-000022
Figure PCTCN2019101623-appb-000023
Figure PCTCN2019101623-appb-000023
Figure PCTCN2019101623-appb-000024
Figure PCTCN2019101623-appb-000024
表1实施例11-25的合成与表征Table 1 Synthesis and characterization of Examples 11-25
下表2中的实施例26-34采用与实施例1相似的步骤进行制备，区别在于采用具有不同的取代基的原料，以获得相应的目标化合物，具体见下表。Examples 26-34 in Table 2 below were prepared using similar procedures to Example 1, except that the raw materials with different substituents were used to obtain the corresponding target compounds, as shown in the following table.
Figure PCTCN2019101623-appb-000025
Figure PCTCN2019101623-appb-000025
Figure PCTCN2019101623-appb-000026
Figure PCTCN2019101623-appb-000026
Figure PCTCN2019101623-appb-000027
Figure PCTCN2019101623-appb-000027
表2实施例26-34的合成与表征Table 2 Synthesis and characterization of Examples 26-34
实施例35. 1-(3-氟-4-((5-甲氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹唑啉-10-基)氧基)苯基)-3-(4- 氟苯甲基)脲Example 35. 1- (3-fluoro-4-((5-methoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinazoline-10- ) Oxy) phenyl) -3- (4-fluorobenzyl) urea
Figure PCTCN2019101623-appb-000028
Figure PCTCN2019101623-appb-000028
步骤1)：在冰水浴条件下，向4-氟苯甲胺的DMF溶液中分别加入氯甲酸苯酯和吡啶，室温搅拌8小时，产物(1-(4-氟苯基)甲基)氨基甲酸苯酯直接用于下一步，MS:246[M+H] +； Step 1): Under ice water bath conditions, add phenyl chloroformate and pyridine to the DMF solution of 4-fluorobenzylamine, and stir at room temperature for 8 hours. The product (1- (4-fluorophenyl) methyl) amino Phenyl formate was used directly in the next step, MS: 246 [M + H] + ;
步骤2)：向步骤1)所得反应液中加入2-氟-4氨基苯酚，并在50℃加热反应两小时，冷却，加水淬灭，乙酸乙酯萃取，饱和食盐水洗涤，有机相干燥，浓缩得到灰色固体产物1-(3-氟-4-羟基苯基)-3-(4-氟苯甲基)脲直接用于下一步；Step 2): Add 2-fluoro-4aminophenol to the reaction solution obtained in step 1), and heat the reaction at 50 ° C for two hours, cool, quench with water, extract with ethyl acetate, wash with saturated brine, and dry the organic phase. Concentrated to give the product 1- (3-fluoro-4-hydroxyphenyl) -3- (4-fluorobenzyl) urea as a gray solid, which was directly used in the next step;
步骤3)：5-(苯甲氧基)-10-氯-2,3-二氢-[1,4]二氧六环[2,3-f]喹唑啉(330mg,1mmol)，步骤2)所得的产品(280mg,1mmol)和碳酸钾(210mg,1.5mmol)的DMF(5mL)溶液加热到80℃反应5小时，冷却，加水打浆，过滤干燥得黄黑色固体450mg 1-(4-((5-(苯甲氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹唑啉-10-基)氧基)-3-氟苯基)-3-(4-氟苯甲基)脲，收率79％，MS:571[M+H]+；Step 3): 5- (benzyloxy) -10-chloro-2,3-dihydro- [1,4] dioxane [2,3-f] quinazoline (330 mg, 1 mmol), step 2) The obtained product (280mg, 1mmol) and potassium carbonate (210mg, 1.5mmol) in DMF (5mL) were heated to 80 ° C for 5 hours, cooled, slurried with water, filtered and dried to give 450 mg of a yellow-black solid ((5- (Benzyloxy) -2,3-dihydro- [1,4] dioxane [2,3-f] quinazolin-10-yl) oxy) -3-fluorobenzene ) -3- (4-fluorobenzyl) urea, yield 79%, MS: 571 [M + H] +;
步骤4)：将步骤3)所得的产品(285mg,0.05mmol)的甲醇溶液中加入Pd/C(10％Pd,50％湿)，体系由氢气置换后在氢气条件下反应10小时，过滤，DMF洗涤，滤液浓缩得灰色固体产物220mg 1-(3-氟-4-((5-羟基-2,3-二氢-[1,4]二氧六环[2,3-f]喹唑啉-10-基)氧基)苯基)-3-(4-氟苯甲基)脲，收率92％，MS:481[M+H] +； Step 4): Pd / C (10% Pd, 50% wet) was added to a methanol solution of the product obtained in step 3) (285 mg, 0.05 mmol). The system was replaced with hydrogen and reacted for 10 hours under hydrogen conditions, and then filtered. Washed with DMF, and the filtrate was concentrated to obtain 220 mg of 1- (3-fluoro-4-((5-hydroxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinazole) as a gray solid product. Phenolin-10-yl) oxy) phenyl) -3- (4-fluorobenzyl) urea, yield 92%, MS: 481 [M + H] + ;
步骤5)：将步骤4)所得的产品(50mg,0.1mmol)，碘甲烷(0.05mL，0.8mmol)和碳酸钾(70mg,0.5mmol)的DMF(1mL)溶液在80℃条件下加热反应3小时，冷却，加水打浆有浅黄色固体析出，过滤干燥得1-(3-氟-4-((5-甲氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹唑啉-10-基)氧基)苯基)-3-(4-氟苯甲基)脲26mg，收率51％； 1H NMR(300MHz,DMSO-d 6)δ8.91(s,1H),8.44(s,1H),7.63(d,J＝15.0Hz,1H),7.38-7.33(m,2H),7.27-7.10(m,4H),7.06(s,1H),6.80-6.76(m,1H),4.47-4.39(m,4H),4.30(d,J＝6.0Hz,2H),3.97(s,3H)；MS:495[M+H] +. Step 5): The product obtained in step 4) (50mg, 0.1mmol), methyl iodide (0.05mL, 0.8mmol) and potassium carbonate (70mg, 0.5mmol) in DMF (1mL) were heated and reacted at 80 ° C. 3 Hours, cooling, beating with water to precipitate light yellow solid, filtering and drying to obtain 1- (3-fluoro-4-((5-methoxy-2,3-dihydro- [1,4] dioxane [2 , 3-f] quinazolin-10-yl) oxy) phenyl) -3- (4-fluorobenzyl) urea 26mg, yield 51%; 1 H NMR (300MHz, DMSO-d 6 ) δ8 .91 (s, 1H), 8.44 (s, 1H), 7.63 (d, J = 15.0Hz, 1H), 7.38-7.33 (m, 2H), 7.27-7.10 (m, 4H), 7.06 (s, 1H ), 6.80-6.76 (m, 1H), 4.47-4.39 (m, 4H), 4.30 (d, J = 6.0Hz, 2H), 3.97 (s, 3H); MS: 495 [M + H] + .
下表3中的实施例36-58采用与实施例35相似的步骤进行制备，区别在于采用具有不同的取代基的原料，以获得相应的目标化合物，具体见下表。Examples 36-58 in Table 3 below were prepared using similar procedures to Example 35, except that the raw materials with different substituents were used to obtain the corresponding target compounds, as shown in the following table.
Figure PCTCN2019101623-appb-000029
Figure PCTCN2019101623-appb-000029
Figure PCTCN2019101623-appb-000030
Figure PCTCN2019101623-appb-000030
Figure PCTCN2019101623-appb-000031
Figure PCTCN2019101623-appb-000031
Figure PCTCN2019101623-appb-000032
Figure PCTCN2019101623-appb-000032
Figure PCTCN2019101623-appb-000033
Figure PCTCN2019101623-appb-000033
Figure PCTCN2019101623-appb-000034
Figure PCTCN2019101623-appb-000034
表3实施例36-58的合成与表征Table 3 Synthesis and characterization of Examples 36-58
实施例59.(S)-1-(1-(4-氟苯基)乙基)-3-(4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹唑啉-10-基)氧基)苯基)脲Example 59. (S) -1- (1- (4-fluorophenyl) ethyl) -3- (4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] Dioxane [2,3-f] quinazolin-10-yl) oxy) phenyl) urea
Figure PCTCN2019101623-appb-000035
Figure PCTCN2019101623-appb-000035
同实施例1操作，由(S)-1-(1-(4-氟苯基)乙基)-1-胺代替步骤1)1-(4-氟苯基)乙基-1-胺反应得到白色固体产物； 1H NMR(300MHz,DMSO-d 6)δ8.48(s,1H),8.39(s,1H),7.40(t,J＝8.6Hz,4H),7.17(t,J＝8.4Hz,2H),7.11–6.98(m,3H),6.66(d,J＝7.8Hz,1H),4.84(br,1H),4.41 (d,J＝14.2Hz,4H),4.21(s,2H),3.59(t,J＝4.7Hz,4H),2.44(d,J＝6.7Hz,2H),2.38(br,4H),1.96(br,2H),1.39(d,J＝6.9Hz,3H).MS:604[M+H] +； The same operation as in Example 1 was carried out by replacing (S) -1- (1- (4-fluorophenyl) ethyl) -1-amine with step 1) 1- (4-fluorophenyl) ethyl-1-amine White solid product was obtained; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.48 (s, 1H), 8.39 (s, 1H), 7.40 (t, J = 8.6 Hz, 4H), 7.17 (t, J = 8.4Hz, 2H), 7.11–6.98 (m, 3H), 6.66 (d, J = 7.8Hz, 1H), 4.84 (br, 1H), 4.41 (d, J = 14.2Hz, 4H), 4.21 (s, 2H), 3.59 (t, J = 4.7Hz, 4H), 2.44 (d, J = 6.7Hz, 2H), 2.38 (br, 4H), 1.96 (br, 2H), 1.39 (d, J = 6.9Hz, 3H) .MS: 604 [M + H] + ;
下表4中的实施例60采用与实施例1相似的方法进行制备，实施例61-87采用与实施例35相似的方法进行制备，区别在于采用具有不同的取代基的原料，以获得相应的目标化合物，具体见下表。Example 60 in Table 4 below was prepared using a method similar to Example 1, and Examples 61-87 were prepared using a method similar to Example 35, with the difference being that raw materials with different substituents were used to obtain the corresponding The target compounds are shown in the table below.
Figure PCTCN2019101623-appb-000036
Figure PCTCN2019101623-appb-000036
Figure PCTCN2019101623-appb-000037
Figure PCTCN2019101623-appb-000037
Figure PCTCN2019101623-appb-000038
Figure PCTCN2019101623-appb-000038
Figure PCTCN2019101623-appb-000039
Figure PCTCN2019101623-appb-000039
Figure PCTCN2019101623-appb-000040
Figure PCTCN2019101623-appb-000040
Figure PCTCN2019101623-appb-000041
Figure PCTCN2019101623-appb-000041
Figure PCTCN2019101623-appb-000042
Figure PCTCN2019101623-appb-000042
Figure PCTCN2019101623-appb-000043
Figure PCTCN2019101623-appb-000043
表4实施例60-87的合成与表征Table 4 Synthesis and characterization of Examples 60-87
实施例88. 1-(4-氟苄基)-3-(4-((5-乙氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)脲的制备Example 88. 1- (4-fluorobenzyl) -3- (4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] Preparation of quinolin-10-yl) oxy) phenyl) urea
Figure PCTCN2019101623-appb-000044
Figure PCTCN2019101623-appb-000044
步骤1)：分别将10-氯-5-甲氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉(5.0g,20mmol),4-硝基苯酚(2.8g,20mmol)加入氯苯(50mL)中并在150℃条件下加热搅拌反应20小时，冷却，浓 缩至糊状后加水进行打浆，过滤得到土黄色固体经过干燥后得4.6g，所得滤液由二氯甲烷萃取，有机相干燥浓缩再由柱层析纯化得到1.3g 5-甲氧基-10-(4-硝基苯基氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉，总收率83％，MS:355[M+H] +； Step 1): 10-chloro-5-methoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinoline (5.0 g, 20 mmol), 4- Nitrophenol (2.8 g, 20 mmol) was added to chlorobenzene (50 mL), and the reaction was heated and stirred at 150 ° C for 20 hours. After cooling, concentrating to a paste, water was added for pulping, and the earthy yellow solid was filtered to obtain 4.6 g. The obtained filtrate was extracted with dichloromethane, the organic phase was dried and concentrated, and then purified by column chromatography to obtain 1.3 g of 5-methoxy-10- (4-nitrophenyloxy) -2,3-dihydro- [1 , 4] Dioxane [2,3-f] quinoline, total yield 83%, MS: 355 [M + H] + ;
步骤2)：将步骤1)所得产品(0.36g,1mmol)加入到三溴化硼(1M,5mL)的二氯甲烷溶液，室温搅拌过夜，加水(0.3mL)淬灭后，浓缩得到的黄色固体0.36g，为10-(4-硝基苯氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-5-酚的溴化氢盐，直接用于下一步，MS:341[M+H] + Step 2): Add the product (0.36g, 1mmol) obtained in step 1) to a dichloromethane solution of boron tribromide (1M, 5mL), stir at room temperature overnight, quench with water (0.3mL), and concentrate the resulting yellow 0.36 g of solid as the hydrogen bromide of 10- (4-nitrophenoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-5-phenol Salt, used directly in the next step, MS: 341 [M + H] +
步骤3)：将步骤2)所得产品(0.36g，0.9mmol)的DMF(5mL)溶液中分别加入溴乙烷(0.32g,3mmol)和碳酸钾(0.41g,3mmol)，加热至80℃并搅拌反应5小时，冷却，加水打浆，过滤干燥得黄色固体0.29g，为5-乙氧基-10-(4-硝基苯基氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉，收率93％，MS:369[M+H] +； Step 3): To a solution of the product obtained in step 2) (0.36 g, 0.9 mmol) in DMF (5 mL) were added bromoethane (0.32 g, 3 mmol) and potassium carbonate (0.41 g, 3 mmol), respectively, and heated to 80 ° C. and The reaction was stirred for 5 hours, cooled, slurried with water, filtered and dried to obtain 0.29 g of a yellow solid, which was 5-ethoxy-10- (4-nitrophenyloxy) -2,3-dihydro- [1,4]. Dioxane [2,3-f] quinoline, yield 93%, MS: 369 [M + H] + ;
步骤4)：将步骤3)所得产品(0.29g,0.8mmol)溶于甲醇(10mL)中，加入钯碳(10％钯含量，湿)催化，在氢气条件下室温搅拌反应2小时，用硅藻土过滤，滤液干燥得到浅紫色固体产物0.22g4-((5-乙氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯胺，收率82％，MS:339[M+H] +； Step 4): Dissolve the product obtained in step 3) (0.29g, 0.8mmol) in methanol (10mL), add palladium on carbon (10% palladium content, wet) to catalyze, and stir the reaction at room temperature under hydrogen for 2 hours. Filter through celite and dry the filtrate to obtain 0.22g of 4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinoline-10- (Yl) oxy) aniline, yield 82%, MS: 339 [M + H] + ;
步骤5)(4-((5-乙氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)氨基甲酸苯酯的制备：将步骤4)所得产品(170mg，0.5mmol)溶于干燥DMF(3mL)中，随后滴加氯甲酸苯酯(160mg,1mmol)和吡啶(0.5mL)室温搅拌反应，TLC监测，反应完毕后不处理，直接进行下一步；Step 5) (4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) phenyl) Preparation of phenyl carbamate: The product (170 mg, 0.5 mmol) obtained in step 4) was dissolved in dry DMF (3 mL), and then phenyl chloroformate (160 mg, 1 mmol) and pyridine (0.5 mL) were added dropwise to stir the reaction at room temperature. TLC monitoring, do not process after the reaction is completed, proceed directly to the next step;
步骤6)：将步骤5)所得中间体的反应液中加入4-氟苯甲胺(190mg,1.5mmol)，并加热至60℃搅拌3小时，冷却，加水打浆过滤得灰色固体经柱层析纯化得白色固体26mg；Step 6): Add 4-fluorobenzylamine (190 mg, 1.5 mmol) to the reaction solution of the intermediate obtained in step 5), heat to 60 ° C. and stir for 3 hours, cool, add water and filter to obtain a gray solid. Column chromatography Purified to give 26mg of white solid;
1H NMR(400MHz,DMSO-d 6)δ8.86(s,1H),8.38(d,J＝5.2Hz,1H),7.55-7.43(m,2H),7.40-7.31(m,2H),7.22-7.09(m,2H),7.03-7.01(m,3H),6.78(t,J＝6.0Hz,1H),6.37(d,J＝5.3Hz,1H),4.33(s,4H),4.29(d,J＝6.0Hz,2H),4.18(q,J＝6.9Hz,2H),1.41(t,J＝6.9Hz,3H).MS:490[M+H] + 1 H NMR (400MHz, DMSO-d 6 ) δ8.86 (s, 1H), 8.38 (d, J = 5.2Hz, 1H), 7.55-7.43 (m, 2H), 7.40-7.31 (m, 2H), 7.22-7.09 (m, 2H), 7.03-7.01 (m, 3H), 6.78 (t, J = 6.0Hz, 1H), 6.37 (d, J = 5.3Hz, 1H), 4.33 (s, 4H), 4.29 (d, J = 6.0 Hz, 2H), 4.18 (q, J = 6.9 Hz, 2H), 1.41 (t, J = 6.9 Hz, 3H). MS: 490 [M + H] +
下表5中的实施例89-118采用与实施例88相似的方法进行制备，区别在于采用具有不同的取代基的原料，以获得相应的目标化合物，具体见下表。Examples 89-118 in Table 5 below were prepared using a method similar to Example 88, except that the raw materials with different substituents were used to obtain the corresponding target compounds, as shown in the following table.
Figure PCTCN2019101623-appb-000045
Figure PCTCN2019101623-appb-000045
Figure PCTCN2019101623-appb-000046
Figure PCTCN2019101623-appb-000046
Figure PCTCN2019101623-appb-000047
Figure PCTCN2019101623-appb-000047
Figure PCTCN2019101623-appb-000048
Figure PCTCN2019101623-appb-000048
Figure PCTCN2019101623-appb-000049
Figure PCTCN2019101623-appb-000049
Figure PCTCN2019101623-appb-000050
Figure PCTCN2019101623-appb-000050
Figure PCTCN2019101623-appb-000051
Figure PCTCN2019101623-appb-000051
Figure PCTCN2019101623-appb-000052
Figure PCTCN2019101623-appb-000052
Figure PCTCN2019101623-appb-000053
Figure PCTCN2019101623-appb-000053
表5实施例89-118的合成与表征Table 5 Synthesis and characterization of Examples 89-118
下表6中的实施例119-162采用与实施例88相似的方法进行制备，区别在于采用具有不同的取代基的原料，以获得相应的目标化合物，具体见下表。Examples 119-162 in Table 6 below were prepared using a method similar to Example 88, except that the raw materials with different substituents were used to obtain the corresponding target compounds, as shown in the following table.
Figure PCTCN2019101623-appb-000054
Figure PCTCN2019101623-appb-000054
Figure PCTCN2019101623-appb-000055
Figure PCTCN2019101623-appb-000055
Figure PCTCN2019101623-appb-000056
Figure PCTCN2019101623-appb-000056
Figure PCTCN2019101623-appb-000057
Figure PCTCN2019101623-appb-000057
Figure PCTCN2019101623-appb-000058
Figure PCTCN2019101623-appb-000058
Figure PCTCN2019101623-appb-000059
Figure PCTCN2019101623-appb-000059
Figure PCTCN2019101623-appb-000060
Figure PCTCN2019101623-appb-000060
Figure PCTCN2019101623-appb-000061
Figure PCTCN2019101623-appb-000061
Figure PCTCN2019101623-appb-000062
Figure PCTCN2019101623-appb-000062
Figure PCTCN2019101623-appb-000063
Figure PCTCN2019101623-appb-000063
Figure PCTCN2019101623-appb-000064
Figure PCTCN2019101623-appb-000064
表6实施例119-162的合成与表征Table 6 Synthesis and characterization of Examples 119-162
下表7中的实施例163-206采用与实施例88相似的方法进行制备，区别在于采用具有不同的取代基的原料，以获得相应的目标化合物，具体见下表。Examples 163-206 in Table 7 below were prepared using a method similar to Example 88, except that the raw materials with different substituents were used to obtain the corresponding target compounds, as shown in the following table.
Figure PCTCN2019101623-appb-000065
Figure PCTCN2019101623-appb-000065
Figure PCTCN2019101623-appb-000066
Figure PCTCN2019101623-appb-000066
Figure PCTCN2019101623-appb-000067
Figure PCTCN2019101623-appb-000067
Figure PCTCN2019101623-appb-000068
Figure PCTCN2019101623-appb-000068
Figure PCTCN2019101623-appb-000069
Figure PCTCN2019101623-appb-000069
Figure PCTCN2019101623-appb-000070
Figure PCTCN2019101623-appb-000070
Figure PCTCN2019101623-appb-000071
Figure PCTCN2019101623-appb-000071
Figure PCTCN2019101623-appb-000072
Figure PCTCN2019101623-appb-000072
Figure PCTCN2019101623-appb-000073
Figure PCTCN2019101623-appb-000073
Figure PCTCN2019101623-appb-000074
Figure PCTCN2019101623-appb-000074
Figure PCTCN2019101623-appb-000075
Figure PCTCN2019101623-appb-000075
Figure PCTCN2019101623-appb-000076
Figure PCTCN2019101623-appb-000076
表7实施例163-206的合成与表征Table 7 Synthesis and characterization of Examples 163-206
实施例207. 1-(4-((5-乙氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(3-氟苯甲基)脲Example 207. 1- (4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) Phenyl) -3- (3-fluorobenzyl) urea
Figure PCTCN2019101623-appb-000077
Figure PCTCN2019101623-appb-000077
同实施例88操作，由3-氟苄胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ9.10(s,1H),8.37(d,J＝5.3Hz,1H),7.50(s,2H),7.18–7.13(m,3H),7.11–7.05(m,2H),7.02(d,J＝5.1Hz,3H),6.37(d,J＝5.3Hz,1H),4.33(s,6H),4.17(q,J＝6.9Hz,2H),1.41(t,J＝6.9Hz,3H).MS:490[M+H] + The same operation as in Example 88 was performed, and 3-fluorobenzylamine was used instead of 4-fluorobenzylamine in step 6) to obtain a white solid product. 1 H NMR (400MHz, DMSO-d 6 ) δ9.10 (s, 1H), 8.37 (d, J = 5.3Hz, 1H), 7.50 (s, 2H), 7.18–7.13 (m, 3H), 7.11– 7.05 (m, 2H), 7.02 (d, J = 5.1Hz, 3H), 6.37 (d, J = 5.3Hz, 1H), 4.33 (s, 6H), 4.17 (q, J = 6.9Hz, 2H), 1.41 (t, J = 6.9Hz, 3H) .MS: 490 [M + H] +
实施例208. 1-(4-((5-乙氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(2-氟苯甲基)脲Example 208. 1- (4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) Phenyl) -3- (2-fluorobenzyl) urea
Figure PCTCN2019101623-appb-000078
Figure PCTCN2019101623-appb-000078
同实施例88操作，由2-氟苄胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.70(s,1H),8.38(d,J＝5.2Hz,1H),7.48(d,J＝8.5Hz,2H),7.39(t,J＝7.8Hz,1H),7.32(d,J＝5.9Hz,1H),7.20(d,J＝7.9Hz,2H),7.06–6.99(m,3H),6.64(s,1H),6.37(d,J＝5.2Hz,1H),4.34(d,J＝7.1Hz,6H),4.17(q,J＝7.1Hz,2H),1.41(t,J＝7.0Hz,3H).MS:490[M+H] + The reaction was carried out in the same manner as in Example 88, and 2-fluorobenzylamine was used instead of 4-fluorobenzylamine in step 6) to obtain a white solid product. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.70 (s, 1 H), 8.38 (d, J = 5.2 Hz, 1 H), 7.48 (d, J = 8.5 Hz, 2 H), 7.39 (t, J = 7.8Hz, 1H), 7.32 (d, J = 5.9Hz, 1H), 7.20 (d, J = 7.9Hz, 2H), 7.06–6.99 (m, 3H), 6.64 (s, 1H), 6.37 (d, J = 5.2Hz, 1H), 4.34 (d, J = 7.1Hz, 6H), 4.17 (q, J = 7.1Hz, 2H), 1.41 (t, J = 7.0Hz, 3H) .MS: 490 (M + H] +
实施例209. 1-(4-((5-乙氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(2-氯苯甲基)脲Example 209. 1- (4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) Phenyl) -3- (2-chlorobenzyl) urea
Figure PCTCN2019101623-appb-000079
Figure PCTCN2019101623-appb-000079
同实施例88操作，由2-氯苄胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.79(s,1H),8.38(d,J＝5.2Hz,1H),7.55-7.35(m 3H),7.33-7.21(m,2H),7.06–6.99(m,3H),6.78–6.55(m,2H),6.37(d,J＝5.2Hz,1H),4.43–4.24(m,6H),4.18(d,J＝6.9Hz,2H),1.41(t,J＝6.9Hz,3H).MS:506[M+H] + The reaction was carried out in the same manner as in Example 88, and 2-chlorobenzylamine was used instead of 4-fluorobenzylamine in step 6) to obtain a white solid product. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.79 (s, 1H), 8.38 (d, J = 5.2Hz, 1H), 7.55-7.35 (m 3H), 7.33-7.21 (m, 2H), 7.06 --6.99 (m, 3H), 6.78--6.55 (m, 2H), 6.37 (d, J = 5.2Hz, 1H), 4.43--4.24 (m, 6H), 4.18 (d, J = 6.9Hz, 2H), 1.41 (t, J = 6.9Hz, 3H) .MS: 506 [M + H] +
实施例210. 1-(3-氟苯甲基)-3-(4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)脲Example 210. 1- (3-fluorobenzyl) -3- (4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) phenyl) urea
Figure PCTCN2019101623-appb-000080
Figure PCTCN2019101623-appb-000080
同实施例88操作，由4-(3-氯丙基)-吗啉代替步骤3)中的溴乙烷进行反应得到白色固体产物，由3-氟苄胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.86(s,1H),8.40(d,J＝5.2Hz,1H),7.51(d,J＝8.4Hz,2H),7.41-7.36(m,1H),7.19–7.12(m,2H),7.11-7.07(m,2H),7.03(d,J＝8.5Hz,2H),6.80(t,J＝6.2Hz,1H),6.40(d,J＝5.3Hz,1H),4.33(d,J＝11.6Hz,6H),4.22(t,J＝5.9Hz,2H),3.78(s,4H),2.48-2.39(m,6H),2.17(d,J＝9.5Hz,2H).MS:589[M+H] + The same operation as in Example 88 was carried out by replacing 4-bromoethane in step 3) with 4- (3-chloropropyl) -morpholine to obtain a white solid product, and replacing 4-fluoro in step 6) with 3-fluorobenzylamine. The benzylamine was reacted to give the product as a white solid. 1 H NMR (400MHz, DMSO-d 6 ) δ8.86 (s, 1H), 8.40 (d, J = 5.2Hz, 1H), 7.51 (d, J = 8.4Hz, 2H), 7.41-7.36 (m, 1H), 7.19–7.12 (m, 2H), 7.11-7.07 (m, 2H), 7.03 (d, J = 8.5Hz, 2H), 6.80 (t, J = 6.2Hz, 1H), 6.40 (d, J = 5.3Hz, 1H), 4.33 (d, J = 11.1Hz, 6H), 4.22 (t, J = 5.9Hz, 2H), 3.78 (s, 4H), 2.48-2.39 (m, 6H), 2.17 (d , J = 9.5Hz, 2H) .MS: 589 [M + H] +
实施例211. 1-(2-氟苯甲基)-3-(4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)脲Example 211. 1- (2-fluorobenzyl) -3- (4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) phenyl) urea
Figure PCTCN2019101623-appb-000081
Figure PCTCN2019101623-appb-000081
同实施例88操作，由4-(3-氯丙基)-吗啉代替步骤3)中的溴乙烷进行反应得到白色固体产物，由2-氟苄胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物. 1H NMR(400MHz,DMSO-d 6)δ8.71(s,1H),8.38(d,J＝5.2Hz,1H),7.52–7.45(m,2H),7.44–7.29(m,2H),7.21-7.16(m,2H),7.04-7.01(m,3H),6.65(t,J＝6.0Hz,1H),6.37(d,J＝5.2Hz,1H),4.39–4.31(m,6H),4.16(t,J＝6.4Hz,2H),3.59(t,J＝4.5Hz,4H),2.46(d,J＝7.3Hz,2H),2.39(s,4H),2.00–1.92(m,2H).MS:589[M+H] + The same operation as in Example 88 was carried out by replacing 4-bromoethane in step 3) with 4- (3-chloropropyl) -morpholine to obtain a white solid product, and replacing 4-fluoro in step 6) with 2-fluorobenzylamine. amine to give the product as a white solid. 1 H NMR (400MHz, DMSO -d 6) δ8.71 (s, 1H), 8.38 (d, J = 5.2Hz, 1H), 7.52-7.45 (m, 2H), 7.44--7.29 (m, 2H), 7.21-7.16 (m, 2H), 7.04-7.01 (m, 3H), 6.65 (t, J = 6.0Hz, 1H), 6.37 (d, J = 5.2Hz, 1H) , 4.39–4.31 (m, 6H), 4.16 (t, J = 6.4Hz, 2H), 3.59 (t, J = 4.5Hz, 4H), 2.46 (d, J = 7.3Hz, 2H), 2.39 (s, 4H), 2.00-1.92 (m, 2H) .MS: 589 [M + H] +
实施例212. 1-(2-氯苯甲基)-3-(4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)脲Example 212. 1- (2-chlorobenzyl) -3- (4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) phenyl) urea
Figure PCTCN2019101623-appb-000082
Figure PCTCN2019101623-appb-000082
同实施例88操作，由4-(3-氯丙基)-吗啉代替步骤3)中的溴乙烷进行反应得到白色固体产物，由2-氯苄胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.78(s,1H),8.38(d,J＝5.3Hz,1H),7.52–7.38(m,4H),7.40–7.28(m,2H),7.04-7.02(m,3H),6.69(d,J＝6.0Hz,1H),6.37(d,J＝5.1Hz,1H),4.38(d,J＝5.9Hz,2H),4.33(s,4H),4.17(t,J＝6.4Hz,2H),3.59(t,J＝4.5Hz,4H),2.45(d,J＝7.2Hz,2H),2.39(s,4H),2.00–1.92(m,2H).MS:605[M+H] + The same operation as in Example 88 was carried out by replacing 4-bromoethane in step 3) with 4- (3-chloropropyl) -morpholine to obtain a white solid product, and replacing 4-fluoro in step 6) with 2-chlorobenzylamine. The benzylamine was reacted to give the product as a white solid. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.78 (s, 1H), 8.38 (d, J = 5.3Hz, 1H), 7.52–7.38 (m, 4H), 7.40–7.28 (m, 2H), 7.04-7.02 (m, 3H), 6.69 (d, J = 6.0 Hz, 1H), 6.37 (d, J = 5.1 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 4.33 (s, 4H ), 4.17 (t, J = 6.4Hz, 2H), 3.59 (t, J = 4.5Hz, 4H), 2.45 (d, J = 7.2Hz, 2H), 2.39 (s, 4H), 2.00-1.92 (m , 2H) .MS: 605 [M + H] +
实施例213. 1-(4-((5-乙氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)-3-氟苯基)-3-(3-氟苯甲基)脲Example 213 1- (4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) -3-fluorophenyl) -3- (3-fluorobenzyl) urea
Figure PCTCN2019101623-appb-000083
Figure PCTCN2019101623-appb-000083
同实施例88操作，由2-氟-4硝基苯酚代替步骤1)中的4-硝基苯酚，由3-氟苄胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.97(s,1H),8.39(d,J＝5.1Hz,1H),7.68(dd,J＝13.6,2.3Hz,1H),7.39(q,J＝7.2Hz,1H),7.24–7.01(m,6H),6.81(d,J＝6.6Hz,1H),6.36(d,J＝5.2Hz,1H),4.36-4.33(m,6H),4.18(q,J＝6.9Hz,2H),1.42(t,J＝6.9Hz,3H).MS:508[M+H] + The reaction was carried out in the same manner as in Example 88, and 2-fluoro-4nitrophenol was used instead of 4-nitrophenol in step 1), and 3-fluorobenzylamine was used instead of 4-fluorobenzylamine in step 6) to obtain a white solid product. . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.97 (s, 1H), 8.39 (d, J = 5.1 Hz, 1H), 7.68 (dd, J = 13.6, 2.3 Hz, 1H), 7.39 (q, J = 7.2Hz, 1H), 7.24–7.01 (m, 6H), 6.81 (d, J = 6.6Hz, 1H), 6.36 (d, J = 5.2Hz, 1H), 4.36-4.33 (m, 6H), 4.18 (q, J = 6.9Hz, 2H), 1.42 (t, J = 6.9Hz, 3H). MS: 508 [M + H] +
实施例214. 1-(4-((5-乙氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)-3-氟苯基)-3-(2-氟苯甲基)脲Example 214. 1- (4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) -3-fluorophenyl) -3- (2-fluorobenzyl) urea
Figure PCTCN2019101623-appb-000084
Figure PCTCN2019101623-appb-000084
同实施例88操作，由2-氟-4硝基苯酚代替步骤1)中的4-硝基苯酚，由2-氟苄胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.94(s,1H),8.38(d,J＝5.1Hz,1H),7.68(d,J＝13.4Hz,1H),7.41-7.30(m,3H),7.21-7.15(m,3H),7.04(s,1H),6.76(s,1H),6.36(d,J＝5.3Hz,1H),4.37-4.32(m,6H),4.18(q,J＝6.9Hz,2H),1.42(t,J＝6.9Hz,3H).MS:508[M+H] + The reaction was carried out in the same manner as in Example 88, and 2-fluoro-4nitrophenol was used instead of 4-nitrophenol in step 1), and 2-fluorobenzylamine was used instead of 4-fluorobenzylamine in step 6) to obtain a white solid product. . 1 H NMR (400MHz, DMSO-d 6 ) δ 8.94 (s, 1H), 8.38 (d, J = 5.1 Hz, 1H), 7.68 (d, J = 13.4 Hz, 1H), 7.41-7.30 (m, 3H), 7.21-7.15 (m, 3H), 7.04 (s, 1H), 6.76 (s, 1H), 6.36 (d, J = 5.3Hz, 1H), 4.37-4.32 (m, 6H), 4.18 (q , J = 6.9Hz, 2H), 1.42 (t, J = 6.9Hz, 3H). MS: 508 [M + H] +
实施例215. 1-(4-((5-乙氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)-3-氟苯基)-3-(2-氯苯甲基)脲Example 215. 1- (4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) -3-fluorophenyl) -3- (2-chlorobenzyl) urea
Figure PCTCN2019101623-appb-000085
Figure PCTCN2019101623-appb-000085
同实施例88操作，由2-氟-4硝基苯酚代替步骤1)中的4-硝基苯酚，由2-氯苄胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ9.04(s,1H),8.39(d,J＝5.2Hz,1H),7.72–7.64(m,1H),7.50–7.27(m,4H),7.24–7.10(m,2H),7.04(s,1H),6.81(t,J＝6.1Hz,1H),6.36(d,J＝5.2Hz,1H),4.39(d,J＝5.9Hz,2H),4.36(s,4H),4.18(q,J＝6.9Hz,2H),1.42(t,J＝6.9Hz,3H).MS:524[M+H] + The reaction was carried out in the same manner as in Example 88. 2-fluoro-4nitrophenol was used instead of 4-nitrophenol in step 1), and 2-chlorobenzylamine was used instead of 4-fluorobenzylamine in step 6) to obtain a white solid product. . 1 H NMR (400MHz, DMSO-d 6 ) δ9.04 (s, 1H), 8.39 (d, J = 5.2Hz, 1H), 7.72–7.64 (m, 1H), 7.50–7.27 (m, 4H), 7.24--7.10 (m, 2H), 7.04 (s, 1H), 6.81 (t, J = 6.1Hz, 1H), 6.36 (d, J = 5.2Hz, 1H), 4.39 (d, J = 5.9Hz, 2H ), 4.36 (s, 4H), 4.18 (q, J = 6.9Hz, 2H), 1.42 (t, J = 6.9Hz, 3H) .MS: 524 [M + H] +
实施例216. 1-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(3-氟苯甲基)脲Example 216. 1- (3-fluoro-4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] Quinolin-10-yl) oxy) phenyl) -3- (3-fluorobenzyl) urea
Figure PCTCN2019101623-appb-000086
Figure PCTCN2019101623-appb-000086
同实施例88操作，由2-氟-4硝基苯酚代替步骤1)中的4-硝基苯酚，由4-(3-氯丙基)-吗啉代替步骤3)中的溴乙烷，由3-氟苄胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.97(s,1H),8.39(d,J＝5.3Hz,1H),7.69(d,J＝13.4Hz,1H),7.42-7.36(m,1H),7.24–7.03(m,6H),6.82(d,J＝6.4Hz,1H),6.37(d,J＝5.3Hz,1H),4.39–4.30(m,6H),4.17(t,J＝6.4Hz,2H),3.59(t,J＝4.6Hz,4H),2.45(d,J＝7.2Hz,2H),2.39(s,4H),2.00–1.92(m,2H).MS:607[M+H] + Following the same procedure as in Example 88, 2-nitro-4nitrophenol was used to replace 4-nitrophenol in step 1), and 4- (3-chloropropyl) -morpholine was used to replace the bromoethane in step 3). The reaction was replaced with 3-fluorobenzylamine in step 6) to obtain a white solid product. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.97 (s, 1 H), 8.39 (d, J = 5.3 Hz, 1 H), 7.69 (d, J = 13.4 Hz, 1 H), 7.42-7.36 (m, 1H), 7.24–7.03 (m, 6H), 6.82 (d, J = 6.4Hz, 1H), 6.37 (d, J = 5.3Hz, 1H), 4.39–4.30 (m, 6H), 4.17 (t, J = 6.4Hz, 2H), 3.59 (t, J = 4.6Hz, 4H), 2.45 (d, J = 7.2Hz, 2H), 2.39 (s, 4H), 2.00-1.92 (m, 2H) .MS: 607 [M + H] +
实施例217. 1-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(2-氟苯甲基)脲Example 217. 1- (3-fluoro-4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] Quinolin-10-yl) oxy) phenyl) -3- (2-fluorobenzyl) urea
Figure PCTCN2019101623-appb-000087
Figure PCTCN2019101623-appb-000087
同实施例88操作，由2-氟-4硝基苯酚代替步骤1)中的4-硝基苯酚，由4-(3-氯丙基)-吗啉代替步骤3)中的溴乙烷，由2-氟苄胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.94(s,1H),8.39(d,J＝5.2Hz,1H),7.68(d,J＝13.7Hz,1H),7.41-7.30(m,2H),7.21-7.12(m,4H),7.05(s,1H),6.76(t,J＝5.8Hz,1H),6.36(d,J＝5.2Hz,1H),4.37(br,6H),4.17(br,2H),3.59(t,J＝4.6Hz,4H),2.46(t,J＝7.1Hz,2H),2.39(s,4H),2.01–1.92(m,2H).MS:607[M+H] + Following the same procedure as in Example 88, 2-nitro-4nitrophenol was used to replace 4-nitrophenol in step 1), and 4- (3-chloropropyl) -morpholine was used to replace the bromoethane in step 3). The reaction was replaced with 2-fluorobenzylamine in step 6) to obtain a white solid product. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.94 (s, 1H), 8.39 (d, J = 5.2 Hz, 1H), 7.68 (d, J = 13.7 Hz, 1H), 7.41-7.30 (m, 2H), 7.21-7.12 (m, 4H), 7.05 (s, 1H), 6.76 (t, J = 5.8Hz, 1H), 6.36 (d, J = 5.2Hz, 1H), 4.37 (br, 6H), 4.17 (br, 2H), 3.59 (t, J = 4.6Hz, 4H), 2.46 (t, J = 7.1Hz, 2H), 2.39 (s, 4H), 2.01--1.92 (m, 2H) .MS: 607 [M + H] +
实施例218. 1-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(2-氯苯甲基)脲Example 218. 1- (3-fluoro-4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] Quinolin-10-yl) oxy) phenyl) -3- (2-chlorobenzyl) urea
Figure PCTCN2019101623-appb-000088
Figure PCTCN2019101623-appb-000088
同实施例88操作，由2-氟-4硝基苯酚代替步骤1)中的4-硝基苯酚，由4-(3-氯丙基)-吗啉代替步骤3)中的溴乙烷，由2-氯苄胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ9.03(s,1H),8.39(d,J＝5.3Hz,1H),7.73–7.64(m,1H),7.49–7.44(m,1H),7.41(d,J＝7.3Hz,1H),7.40–7.26(m,2H),7.22-7.13(m,2H),7.05(s,1H),6.80(t,J＝5.9Hz,1H),6.37(d,J＝5.3Hz,1H),4.39(d,J＝6.0Hz,2H),4.36(s,4H),4.17(t,J＝6.2Hz,2H),3.59(t,J＝4.5Hz,4H),2.46(t,J＝7.1Hz,2H),2.39(s,4H),2.01–1.92(m,2H).MS:623[M+H] + Following the same procedure as in Example 88, 2-nitro-4nitrophenol was used to replace 4-nitrophenol in step 1), and 4- (3-chloropropyl) -morpholine was used to replace the bromoethane in step 3). The reaction was replaced by 2-chlorobenzylamine in place of 4-fluorobenzylamine in step 6) to obtain a white solid product. 1 H NMR (400MHz, DMSO-d 6 ) δ9.03 (s, 1H), 8.39 (d, J = 5.3Hz, 1H), 7.73–7.64 (m, 1H), 7.49–7.44 (m, 1H), 7.41 (d, J = 7.3Hz, 1H), 7.40-7.26 (m, 2H), 7.22-7.13 (m, 2H), 7.05 (s, 1H), 6.80 (t, J = 5.9Hz, 1H), 6.37 (d, J = 5.3Hz, 1H), 4.39 (d, J = 6.0Hz, 2H), 4.36 (s, 4H), 4.17 (t, J = 6.2Hz, 2H), 3.59 (t, J = 4.5Hz , 4H), 2.46 (t, J = 7.1Hz, 2H), 2.39 (s, 4H), 2.01–1.92 (m, 2H) .MS: 623 [M + H] +
实施例219. 1-(4-((5-乙氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(1-(3-氟苯基)乙基)脲Example 219. 1- (4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) Phenyl) -3- (1- (3-fluorophenyl) ethyl) urea
Figure PCTCN2019101623-appb-000089
Figure PCTCN2019101623-appb-000089
同实施例88操作，由1-(3-氟苯基)乙基-1-胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.51(s,1H),8.37(d,J＝5.2Hz,1H),7.42(dd,J＝25.8,7.9Hz,3H),7.19(t,J＝9.6Hz,2H),7.11–6.98(m,4H),6.69(d,J＝7.8Hz,1H),6.36(d,J＝5.2Hz,1H),4.85(t,J＝7.2Hz,1H),4.33(s,4H),4.17(q,J＝6.9Hz,2H),1.45–1.36(m,6H).MS:504[M+H] + The same operation as in Example 88 was performed, and 1- (3-fluorophenyl) ethyl-1-amine was used instead of 4-fluorobenzylamine in step 6) to obtain a white solid product. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.51 (s, 1 H), 8.37 (d, J = 5.2 Hz, 1 H), 7.42 (dd, J = 25.8, 7.9 Hz, 3 H), 7.19 (t, J = 9.6Hz, 2H), 7.11–6.98 (m, 4H), 6.69 (d, J = 7.8Hz, 1H), 6.36 (d, J = 5.2Hz, 1H), 4.85 (t, J = 7.2Hz, 1H), 4.33 (s, 4H), 4.17 (q, J = 6.9Hz, 2H), 1.45–1.36 (m, 6H) .MS: 504 [M + H] +
实施例220. 1-(4-((5-乙氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(1-(2-氟苯基)乙基)脲Example 220. 1- (4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) Phenyl) -3- (1- (2-fluorophenyl) ethyl) urea
Figure PCTCN2019101623-appb-000090
Figure PCTCN2019101623-appb-000090
同实施例88操作，由1-(2-氟苯基)乙基-1-胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.55(s,1H),8.37(d,J＝5.2Hz,1H),7.44(d,J＝9.1Hz,2H),7.23–7.17(m,2H),7.01(d,J＝9.2Hz,3H),6.72(d,J＝7.9Hz,1H),6.44(d,J＝8.3Hz,2H),6.35(d,J＝5.1Hz,1H),4.96–4.87(m,1H),4.33(s,4H),4.17(d,J＝7.1Hz,2H), 1.41(t,J＝7.1Hz,6H).MS:504[M+H] + The same operation as in Example 88 was performed, and 1- (2-fluorophenyl) ethyl-1-amine was used instead of 4-fluorobenzylamine in step 6) to obtain a white solid product. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.55 (s, 1H), 8.37 (d, J = 5.2Hz, 1H), 7.44 (d, J = 9.1Hz, 2H), 7.23–7.17 (m, 2H), 7.01 (d, J = 9.2Hz, 3H), 6.72 (d, J = 7.9Hz, 1H), 6.44 (d, J = 8.3Hz, 2H), 6.35 (d, J = 5.1Hz, 1H) , 4.96--4.87 (m, 1H), 4.33 (s, 4H), 4.17 (d, J = 7.1Hz, 2H), 1.41 (t, J = 7.1Hz, 6H) .MS: 504 [M + H] +
实施例221. 1-(4-((5-乙氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(1-(2-氯苯基)乙基)脲Example 221. 1- (4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) Phenyl) -3- (1- (2-chlorophenyl) ethyl) urea
Figure PCTCN2019101623-appb-000091
Figure PCTCN2019101623-appb-000091
同实施例88操作，由1-(2-氯苯基)乙基-1-胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.56(s,1H),8.37(d,J＝5.2Hz,1H),7.44(d,J＝8.7Hz,2H),7.32–7.13(m,2H),7.08–6.95(m,3H),6.85(d,J＝7.6Hz,1H),6.55(dd,J＝7.9,3.5Hz,2H),6.36(d,J＝5.2Hz,1H),5.15(t,J＝7.1Hz,1H),4.33(s,4H),4.17(q,J＝6.9Hz,2H),1.28(dd,J＝9.1,6.9Hz,6H).MS:520[M+H] + The same operation as in Example 88 was performed, and 1- (2-chlorophenyl) ethyl-1-amine was used instead of 4-fluorobenzylamine in step 6) to obtain a white solid product. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.56 (s, 1H), 8.37 (d, J = 5.2 Hz, 1H), 7.44 (d, J = 8.7 Hz, 2H), 7.32-7.13 (m, 2H), 7.08-6.95 (m, 3H), 6.85 (d, J = 7.6Hz, 1H), 6.55 (dd, J = 7.9, 3.5Hz, 2H), 6.36 (d, J = 5.2Hz, 1H), 5.15 (t, J = 7.1Hz, 1H), 4.33 (s, 4H), 4.17 (q, J = 6.9Hz, 2H), 1.28 (dd, J = 9.1, 6.9Hz, 6H) .MS: 520 [M + H] +
实施例222. 1-(1-(3-氟苯基)乙基)-3-(4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)脲Example 222. 1- (1- (3-fluorophenyl) ethyl) -3- (4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4 ] Dioxane [2,3-f] quinolin-10-yl) oxy) phenyl) urea
Figure PCTCN2019101623-appb-000092
Figure PCTCN2019101623-appb-000092
同实施例88操作，由4-(3-氯丙基)-吗啉代替步骤3)中的溴乙烷，由1-(3-氟苯基)乙基-1-胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.51(s,1H),8.37(d,J＝5.1Hz,1H),7.45(d,J＝8.5Hz,2H),7.38(t,J＝7.3Hz,1H),7.19(t,J＝9.5Hz,2H),7.10–6.99(m,4H),6.70(d,J＝7.7Hz,1H),6.36(d,J＝5.1Hz,1H),4.85(t,J＝7.2Hz,1H),4.33(s,4H),4.16(t,J＝6.5Hz,2H),3.59(t,J＝4.7Hz,4H),2.45(d,J＝7.0Hz,2H),2.39(s,4H),1.96(t,J＝6.9Hz,2H),1.40(d,J＝6.9Hz,3H).MS:603[M+H] + Following the procedure of Example 88, 4- (3-chloropropyl) -morpholine was used in place of the bromoethane in step 3), and 1- (3-fluorophenyl) ethyl-1-amine was used in step 6). The 4-fluorobenzylamine was reacted to give the product as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.51 (s, 1 H), 8.37 (d, J = 5.1 Hz, 1 H), 7.45 (d, J = 8.5 Hz, 2 H), 7.38 (t, J = 7.3Hz, 1H), 7.19 (t, J = 9.5Hz, 2H), 7.10–6.99 (m, 4H), 6.70 (d, J = 7.7Hz, 1H), 6.36 (d, J = 5.1Hz, 1H) , 4.85 (t, J = 7.2 Hz, 1H), 4.33 (s, 4H), 4.16 (t, J = 6.5 Hz, 2H), 3.59 (t, J = 4.7 Hz, 4H), 2.45 (d, J = 7.0Hz, 2H), 2.39 (s, 4H), 1.96 (t, J = 6.9Hz, 2H), 1.40 (d, J = 6.9Hz, 3H). MS: 603 [M + H] +
实施例223. 1-(1-(2-氟苯基)乙基)-3-(4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)脲Example 223. 1- (1- (2-fluorophenyl) ethyl) -3- (4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4 ] Dioxane [2,3-f] quinolin-10-yl) oxy) phenyl) urea
Figure PCTCN2019101623-appb-000093
Figure PCTCN2019101623-appb-000093
同实施例88操作，由4-(3-氯丙基)-吗啉代替步骤3)中的溴乙烷，由1-(2-氟苯基)乙基-1-胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.55(s,1H),8.37(d,J＝5.3Hz,1H),7.48–7.38(m,3H),7.30(t,J＝7.0Hz,1H),7.25–7.13(m,2H),7.06–6.97(m,3H),6.72(d,J＝7.9Hz,1H),6.36(d,J＝5.2Hz,1H),5.07(t,J＝ 7.3Hz,1H),4.33(s,4H),4.16(t,J＝6.5Hz,2H),3.59(t,J＝4.5Hz,4H),2.46(t,J＝7.1Hz,2H),2.39(s,4H),2.00–1.92(m,2H),1.40(d,J＝6.9Hz,3H).MS:603[M+H] + Following the procedure of Example 88, 4- (3-chloropropyl) -morpholine was used in place of the bromoethane in step 3), and 1- (2-fluorophenyl) ethyl-1-amine was used in step 6). The 4-fluorobenzylamine was reacted to give the product as a white solid. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.55 (s, 1H), 8.37 (d, J = 5.3Hz, 1H), 7.48–7.38 (m, 3H), 7.30 (t, J = 7.0Hz, 1H), 7.25–7.13 (m, 2H), 7.06–6.97 (m, 3H), 6.72 (d, J = 7.9Hz, 1H), 6.36 (d, J = 5.2Hz, 1H), 5.07 (t, J = 7.3Hz, 1H), 4.33 (s, 4H), 4.16 (t, J = 6.5Hz, 2H), 3.59 (t, J = 4.5Hz, 4H), 2.46 (t, J = 7.1Hz, 2H), 2.39 (s, 4H), 2.00-1.92 (m, 2H), 1.40 (d, J = 6.9Hz, 3H) .MS: 603 [M + H] +
实施例224. 1-(1-(2-氯苯基)乙基)-3-(4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)脲Example 224. 1- (1- (2-chlorophenyl) ethyl) -3- (4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4 ] Dioxane [2,3-f] quinolin-10-yl) oxy) phenyl) urea
Figure PCTCN2019101623-appb-000094
Figure PCTCN2019101623-appb-000094
同实施例88操作，由4-(3-氯丙基)-吗啉代替步骤3)中的溴乙烷，由1-(2-氯苯基)乙基-1-胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.57(s,1H),8.37(d,J＝5.1Hz,1H),7.45(dt,J＝15.9,7.5Hz,4H),7.39–7.34(m,1H),7.27(td,J＝7.6,1.8Hz,1H),7.06–6.97(m,3H),6.85(d,J＝7.6Hz,1H),6.35(d,J＝5.2Hz,1H),5.15(p,J＝7.4,6.8Hz,1H),4.33(s,4H),4.16(t,J＝6.4Hz,2H),3.59(t,J＝4.5Hz,4H),2.46(t,J＝7.1Hz,2H),2.39(s,4H),1.96(t,J＝6.9Hz,2H),1.37(d,J＝6.9Hz,3H).MS:619[M+H] + Following the procedure of Example 88, 4- (3-chloropropyl) -morpholine was used in place of the bromoethane in step 3), and 1- (2-chlorophenyl) ethyl-1-amine was used in step 6). The 4-fluorobenzylamine was reacted to give the product as a white solid. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.57 (s, 1H), 8.37 (d, J = 5.1Hz, 1H), 7.45 (dt, J = 15.9, 7.5Hz, 4H), 7.39–7.34 ( m, 1H), 7.27 (td, J = 7.6, 1.8 Hz, 1H), 7.06-6.97 (m, 3H), 6.85 (d, J = 7.6 Hz, 1H), 6.35 (d, J = 5.2 Hz, 1H ), 5.15 (p, J = 7.4, 6.8 Hz, 1H), 4.33 (s, 4H), 4.16 (t, J = 6.4 Hz, 2H), 3.59 (t, J = 4.5 Hz, 4H), 2.46 (t , J = 7.1Hz, 2H), 2.39 (s, 4H), 1.96 (t, J = 6.9Hz, 2H), 1.37 (d, J = 6.9Hz, 3H). MS: 619 [M + H] +
实施例225. 1-(4-((5-乙氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)-3-氟苯基)-3-(1-(3-氟苯基)乙基)脲Example 225. 1- (4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) -3-fluorophenyl) -3- (1- (3-fluorophenyl) ethyl) urea
Figure PCTCN2019101623-appb-000095
Figure PCTCN2019101623-appb-000095
同实施例88操作，由2-氟-4硝基苯酚代替步骤1)中的4-硝基苯酚，由1-(3-氟苯基)乙基-1-胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.74(s,1H),8.38(d,J＝5.2Hz,1H),7.65(dd,J＝13.4,2.4Hz,1H),7.39(q,J＝7.5Hz,1H),7.19(t,J＝9.4Hz,3H),7.13-7.01(m,3H),6.81(d,J＝7.8Hz,1H),6.35(d,J＝5.3Hz,1H),4.91-4.80(m,1H),4.35(s,4H),4.18(q,J＝6.9Hz,2H),1.40(d,J＝7.2Hz,6H).MS:522[M+H] + As in Example 88, 4-nitrophenol in step 1) was replaced by 2-fluoro-4nitrophenol, and 4 in step 6) was replaced by 1- (3-fluorophenyl) ethyl-1-amine. -Fluorobenzylamine was reacted to give the product as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.74 (s, 1 H), 8.38 (d, J = 5.2 Hz, 1 H), 7.65 (dd, J = 13.4, 2.4 Hz, 1 H), 7.39 (q, J = 7.5Hz, 1H), 7.19 (t, J = 9.4Hz, 3H), 7.13-7.01 (m, 3H), 6.81 (d, J = 7.8Hz, 1H), 6.35 (d, J = 5.3Hz, 1H), 4.91-4.80 (m, 1H), 4.35 (s, 4H), 4.18 (q, J = 6.9Hz, 2H), 1.40 (d, J = 7.2Hz, 6H) .MS: 522 (M + H ] +
实施例226. 1-(4-((5-乙氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)-3-氟苯基)-3-(1-(2-氟苯基)乙基)脲Example 226. 1- (4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) -3-fluorophenyl) -3- (1- (2-fluorophenyl) ethyl) urea
Figure PCTCN2019101623-appb-000096
Figure PCTCN2019101623-appb-000096
同实施例88操作，由2-氟-4硝基苯酚代替步骤1)中的4-硝基苯酚，由1-(2-氟苯基)乙基-1-胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO- d 6)δ8.77(s,1H),8.38(d,J＝5.2Hz,1H),7.64(d,J＝13.3Hz,1H),7.42(t,J＝7.7Hz,1H),7.35-7.26(m,1H),7.25-7.13(m,3H),7.10-7.04(m,2H),6.83(d,J＝7.9Hz,1H),6.38-6.31(m,1H),5.07(t,J＝7.1Hz,1H),4.35(s,4H),4.18(q,J＝7.0Hz,2H),1.43-1.40(m,6H).MS:522[M+H] + As in Example 88, 2-nitro-4nitrophenol was used to replace 4-nitrophenol in step 1), and 1- (2-fluorophenyl) ethyl-1-amine was used to replace 4 in step 6). -Fluorobenzylamine was reacted to give the product as a white solid. 1 H NMR (400 MHz, DMSO- d 6 ) δ 8.77 (s, 1 H), 8.38 (d, J = 5.2 Hz, 1 H), 7.64 (d, J = 13.3 Hz, 1 H), 7.42 (t, J = 7.7Hz, 1H), 7.35-7.26 (m, 1H), 7.25-7.13 (m, 3H), 7.10-7.04 (m, 2H), 6.83 (d, J = 7.9Hz, 1H), 6.38-6.31 (m , 1H), 5.07 (t, J = 7.1Hz, 1H), 4.35 (s, 4H), 4.18 (q, J = 7.0Hz, 2H), 1.43-1.40 (m, 6H) .MS: 522 (M + H] +
实施例227. 1-(4-((5-乙氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)-3-氟苯基)-3-(1-(2-氯苯基)乙基)脲Example 227. 1- (4-((5-ethoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl) oxy) -3-fluorophenyl) -3- (1- (2-chlorophenyl) ethyl) urea
Figure PCTCN2019101623-appb-000097
Figure PCTCN2019101623-appb-000097
同实施例88操作，由2-氟-4硝基苯酚代替步骤1)中的4-硝基苯酚，由1-(2-氯苯基)乙基-1-胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.77(s,1H),8.38(d,J＝5.2Hz,1H),7.64(dd,J＝13.5,2.4Hz,1H),7.48(d,J＝7.7Hz,1H),7.43(d,J＝7.9Hz,1H),7.38(d,J＝7.1Hz,1H),7.28(t,J＝7.5Hz,1H),7.22–7.01(m,3H),6.94(d,J＝7.5Hz,1H),6.35(d,J＝5.2Hz,1H),5.15(t,J＝7.1Hz,1H),4.35(s,4H),4.18(q,J＝6.9Hz,2H),1.46–1.35(m,6H).MS:538[M+H] + As in Example 88, 4-nitrophenol in step 1) was replaced by 2-fluoro-4nitrophenol, and 4 in step 6) was replaced by 1- (2-chlorophenyl) ethyl-1-amine. -Fluorobenzylamine was reacted to give the product as a white solid. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.77 (s, 1H), 8.38 (d, J = 5.2Hz, 1H), 7.64 (dd, J = 13.5, 2.4Hz, 1H), 7.48 (d, J = 7.7Hz, 1H), 7.43 (d, J = 7.9Hz, 1H), 7.38 (d, J = 7.1Hz, 1H), 7.28 (t, J = 7.5Hz, 1H), 7.22-7.01 (m, 3H), 6.94 (d, J = 7.5Hz, 1H), 6.35 (d, J = 5.2Hz, 1H), 5.15 (t, J = 7.1Hz, 1H), 4.35 (s, 4H), 4.18 (q, J = 6.9Hz, 2H), 1.46–1.35 (m, 6H) .MS: 538 [M + H] +
实施例228. 1-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(1-(3-氟苯基)乙基)脲Example 228. 1- (3-Fluoro-4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] Quinolin-10-yl) oxy) phenyl) -3- (1- (3-fluorophenyl) ethyl) urea
Figure PCTCN2019101623-appb-000098
Figure PCTCN2019101623-appb-000098
同实施例88操作，由2-氟-4硝基苯酚代替步骤1)中的4-硝基苯酚，由4-(3-氯丙基)-吗啉代替步骤3)中的溴乙烷，由1-(3-氟苯基)乙基-1-胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.78(s,1H),8.38(d,J＝5.2Hz,1H),7.65(d,J＝13.5Hz,1H),7.43–7.34(m,1H),7.22–7.15(m,3H),7.11(s,1H),7.09-7.05(m,2H),6.85(d,J＝7.6Hz,1H),6.35(d,J＝5.2Hz,1H),4.85(t,J＝7.2Hz,1H),4.36(s,4H),4.17(t,J＝6.4Hz,2H),3.59(t,J＝4.6Hz,4H),2.46(t,J＝7.1Hz,2H),2.39(s,4H),1.96(t,J＝7.0Hz,2H),1.40(d,J＝6.9Hz,3H).MS:621[M+H] + Following the same procedure as in Example 88, 2-nitro-4nitrophenol was used to replace 4-nitrophenol in step 1), and 4- (3-chloropropyl) -morpholine was used to replace the bromoethane in step 3). The reaction was replaced by 1- (3-fluorophenyl) ethyl-1-amine in place of 4-fluorobenzylamine in step 6) to give a white solid product. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.78 (s, 1H), 8.38 (d, J = 5.2 Hz, 1H), 7.65 (d, J = 13.5 Hz, 1H), 7.43--7.34 (m, 1H), 7.22-7.15 (m, 3H), 7.11 (s, 1H), 7.09-7.05 (m, 2H), 6.85 (d, J = 7.6Hz, 1H), 6.35 (d, J = 5.2Hz, 1H ), 4.85 (t, J = 7.2 Hz, 1H), 4.36 (s, 4H), 4.17 (t, J = 6.4 Hz, 2H), 3.59 (t, J = 4.6 Hz, 4H), 2.46 (t, J = 7.1Hz, 2H), 2.39 (s, 4H), 1.96 (t, J = 7.0Hz, 2H), 1.40 (d, J = 6.9Hz, 3H). MS: 621 [M + H] +
实施例229. 1-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(1-(2-氟苯基)乙基)脲Example 229. 1- (3-Fluoro-4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] Quinolin-10-yl) oxy) phenyl) -3- (1- (2-fluorophenyl) ethyl) urea
Figure PCTCN2019101623-appb-000099
Figure PCTCN2019101623-appb-000099
同实施例88操作，由2-氟-4硝基苯酚代替步骤1)中的4-硝基苯酚，由4-(3-氯丙基)-吗啉代替步骤3)中的溴乙烷，由1-(2-氟苯基)乙基-1-胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.81(s,1H),8.38(d,J＝5.2Hz,1H),7.64(dd,J＝13.5,2.5Hz,1H),7.43(t,J＝7.6Hz,1H),7.34–7.26(m,1H),7.25–7.13(m,3H),7.13–7.02(m,2H),6.86(d,J＝7.9Hz,1H),6.35(d,J＝5.3Hz,1H),5.07(p,J＝7.8,7.2Hz,1H),4.35(s,4H),4.17(t,J＝6.4Hz,2H),3.59(t,J＝4.5Hz,4H),2.50–2.37(m,2H),2.39(s,4H),2.00–1.92(m,2H),1.41(d,J＝7.0Hz,3H).MS:621[M+H] + Following the same procedure as in Example 88, 2-nitro-4nitrophenol was used to replace 4-nitrophenol in step 1), and 4- (3-chloropropyl) -morpholine was used to replace the bromoethane in step 3). The reaction was replaced by 1- (2-fluorophenyl) ethyl-1-amine in place of 4-fluorobenzylamine in step 6) to give a white solid product. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.81 (s, 1H), 8.38 (d, J = 5.2Hz, 1H), 7.64 (dd, J = 13.5, 2.5Hz, 1H), 7.43 (t, J = 7.6Hz, 1H), 7.34–7.26 (m, 1H), 7.25–7.13 (m, 3H), 7.13–7.02 (m, 2H), 6.86 (d, J = 7.9Hz, 1H), 6.35 (d , J = 5.3Hz, 1H), 5.07 (p, J = 7.8, 7.2Hz, 1H), 4.35 (s, 4H), 4.17 (t, J = 6.4Hz, 2H), 3.59 (t, J = 4.5Hz , 4H), 2.50-2.37 (m, 2H), 2.39 (s, 4H), 2.00-1.92 (m, 2H), 1.41 (d, J = 7.0Hz, 3H) .MS: 621 [M + H] +
实施例230. 1-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(1-(2-氯苯基)乙基)脲Example 230. 1- (3-fluoro-4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] Quinolin-10-yl) oxy) phenyl) -3- (1- (2-chlorophenyl) ethyl) urea
Figure PCTCN2019101623-appb-000100
Figure PCTCN2019101623-appb-000100
同实施例88操作，由2-氟-4硝基苯酚代替步骤1)中的4-硝基苯酚，由4-(3-氯丙基)-吗啉代替步骤3)中的溴乙烷，由1-(2-氯苯基)乙基-1-胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.81(s,1H),8.38(d,J＝5.2Hz,1H),7.64(dd,J＝13.4,2.4Hz,1H),7.52–7.33(m,3H),7.28(td,J＝7.6,1.7Hz,1H),7.22–7.02(m,3H),6.97(d,J＝7.5Hz,1H),6.35(d,J＝5.2Hz,1H),5.15(p,J＝6.8Hz,1H),4.35(s,4H),4.17(t,J＝6.3Hz,2H),3.59(t,J＝4.5Hz,4H),2.46(t,J＝7.1Hz,2H),2.39(s,4H),1.96(t,J＝6.9Hz,2H),1.38(d,J＝6.9Hz,3H).MS:637[M+H] + Following the same procedure as in Example 88, 2-nitro-4nitrophenol was used to replace 4-nitrophenol in step 1), and 4- (3-chloropropyl) -morpholine was used to replace the bromoethane in step 3). The reaction was replaced by 1- (2-chlorophenyl) ethyl-1-amine in place of 4-fluorobenzylamine in step 6) to give a white solid product. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.81 (s, 1H), 8.38 (d, J = 5.2Hz, 1H), 7.64 (dd, J = 13.4, 2.4Hz, 1H), 7.52-7.33 ( m, 3H), 7.28 (td, J = 7.6, 1.7 Hz, 1H), 7.22–7.02 (m, 3H), 6.97 (d, J = 7.5 Hz, 1H), 6.35 (d, J = 5.2 Hz, 1H ), 5.15 (p, J = 6.8 Hz, 1 H), 4.35 (s, 4 H), 4.17 (t, J = 6.3 Hz, 2 H), 3.59 (t, J = 4.5 Hz, 4 H), 2.46 (t, J = 7.1Hz, 2H), 2.39 (s, 4H), 1.96 (t, J = 6.9Hz, 2H), 1.38 (d, J = 6.9Hz, 3H). MS: 637 [M + H] +
实施例231. 1-(1-(4-氟苯基)丙基)-3-(4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)脲Example 231. 1- (1- (4-fluorophenyl) propyl) -3- (4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4 ] Dioxane [2,3-f] quinolin-10-yl) oxy) phenyl) urea
Figure PCTCN2019101623-appb-000101
Figure PCTCN2019101623-appb-000101
同实施例88操作，由4-(3-氯丙基)-吗啉代替步骤3)中的溴乙烷，由1-(4-氟苯基)丙基-1-胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.50(s,1H),8.37(d,J＝5.3Hz,1H),7.48-7.41(m,2H),7.35(dd,J＝8.5,5.6Hz,2H),7.16(t,J＝8.8Hz,2H),7.06-6.97(m,3H),6.67(d,J＝8.2Hz,1H),6.35(d,J＝5.2Hz,1H),4.62(q,J＝7.3Hz,1H),4.33(s,4H),4.16(t,J＝6.4Hz,2H),3.59(t,J＝4.6Hz,4H),2.46(t,J＝7.1Hz,2H),2.39(s,4H),2.00-1.92(m,2H),1.71(t,J＝7.4Hz,2H),0.85(t,J＝7.3Hz,3H).MS:617[M+H] + Following the procedure of Example 88, 4- (3-chloropropyl) -morpholine was used in place of the bromoethane in step 3), and 1- (4-fluorophenyl) propyl-1-amine was used in step 6). The 4-fluorobenzylamine was reacted to give the product as a white solid. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.50 (s, 1H), 8.37 (d, J = 5.3Hz, 1H), 7.48-7.41 (m, 2H), 7.35 (dd, J = 8.5, 5.6 Hz, 2H), 7.16 (t, J = 8.8Hz, 2H), 7.06-6.97 (m, 3H), 6.67 (d, J = 8.2Hz, 1H), 6.35 (d, J = 5.2Hz, 1H), 4.62 (q, J = 7.3 Hz, 1H), 4.33 (s, 4H), 4.16 (t, J = 6.4 Hz, 2H), 3.59 (t, J = 4.6 Hz, 4H), 2.46 (t, J = 7.1 Hz, 2H), 2.39 (s, 4H), 2.00-1.92 (m, 2H), 1.71 (t, J = 7.4Hz, 2H), 0.85 (t, J = 7.3Hz, 3H) .MS: 617 (M + H] +
实施例232. 1-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-苯乙基脲Example 232. 1- (3-fluoro-4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] Quinolin-10-yl) oxy) phenyl) -3-phenethylurea
Figure PCTCN2019101623-appb-000102
Figure PCTCN2019101623-appb-000102
同实施例88操作，由2-氟-4硝基苯酚代替步骤1)中的4-硝基苯酚，由4-(3-氯丙基)-吗啉代替步骤3)中的溴乙烷，由苯乙胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.82(s,1H),8.39(d,J＝5.2Hz,1H),7.68(d,J＝13.7,Hz,1H),7.34-7.15(m,6H),7.11-7.05(m,2H),6.36(d,J＝5.2Hz,1H),6.24(t,J＝5.7Hz,1H),4.36(s,4H),4.17(t,J＝6.4Hz,2H),3.59(t,J＝4.4Hz,4H),3.38(br,2H),2.77(t,J＝7.1Hz,2H),2.46(t,J＝7.1Hz,2H),2.39(s,4H),1.96(t,J＝7.0Hz,2H).MS:603[M+H] + Following the same procedure as in Example 88, 2-nitro-4nitrophenol was used to replace 4-nitrophenol in step 1), and 4- (3-chloropropyl) -morpholine was used to replace the bromoethane in step 3). The reaction was replaced by phenylethylamine in place of 4-fluorobenzylamine in step 6) to obtain a white solid product. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.82 (s, 1 H), 8.39 (d, J = 5.2 Hz, 1 H), 7.68 (d, J = 13.7, Hz, 1 H), 7.34-7.15 (m , 6H), 7.11-7.05 (m, 2H), 6.36 (d, J = 5.2Hz, 1H), 6.24 (t, J = 5.7Hz, 1H), 4.36 (s, 4H), 4.17 (t, J = 6.4Hz, 2H), 3.59 (t, J = 4.4Hz, 4H), 3.38 (br, 2H), 2.77 (t, J = 7.1Hz, 2H), 2.46 (t, J = 7.1Hz, 2H), 2.39 (s, 4H), 1.96 (t, J = 7.0Hz, 2H) .MS: 603 [M + H] +
实施例233. 1-(3-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(4-氟苯乙基)脲Example 233. 1- (3-Fluoro-4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] Quinolin-10-yl) oxy) phenyl) -3- (4-fluorophenethyl) urea
Figure PCTCN2019101623-appb-000103
Figure PCTCN2019101623-appb-000103
同实施例88操作，由2-氟-4硝基苯酚代替步骤1)中的4-硝基苯酚，由4-(3-氯丙基)-吗啉代替步骤3)中的溴乙烷，由4-氟苯乙胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.83(s,1H),8.39(d,J＝5.2Hz,1H),7.67(dd,J＝13.6,2.4Hz,1H),7.32-7.24(m,2H),7.21-7.07(m,4H),7.05(s,1H),6.36(d,J＝5.2Hz,1H),6.26(t,J＝5.8Hz,1H),4.36(s,4H),4.17(t,J＝6.4Hz,2H),3.59(t,J＝4.5Hz,4H),3.37(s,2H),2.76(t,J＝7.1Hz,2H),2.46(t,J＝7.1Hz,2H),2.39(s,4H),1.96(t,J＝7.0Hz,2H).MS:621[M+H] + Following the same procedure as in Example 88, 2-nitro-4nitrophenol was used to replace 4-nitrophenol in step 1), and 4- (3-chloropropyl) -morpholine was used to replace the bromoethane in step 3). The reaction was replaced by 4-fluorophenylethylamine in place of 4-fluorobenzylamine in step 6) to obtain a white solid product. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.83 (s, 1H), 8.39 (d, J = 5.2 Hz, 1H), 7.67 (dd, J = 13.6, 2.4 Hz, 1H), 7.32-7.24 ( m, 2H), 7.21-7.07 (m, 4H), 7.05 (s, 1H), 6.36 (d, J = 5.2Hz, 1H), 6.26 (t, J = 5.8Hz, 1H), 4.36 (s, 4H ), 4.17 (t, J = 6.4 Hz, 2H), 3.59 (t, J = 4.5 Hz, 4H), 3.37 (s, 2H), 2.76 (t, J = 7.1 Hz, 2H), 2.46 (t, J = 7.1Hz, 2H), 2.39 (s, 4H), 1.96 (t, J = 7.0Hz, 2H). MS: 621 [M + H] +
实施例234. 1-(4-((5-((6-(二甲氨基)己基)氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(4-氟苯甲基)脲Example 234. 1- (4-((5-((6- (dimethylamino) hexyl) oxy) -2,3-dihydro- [1,4] dioxane [2,3-f ] Quinolin-10-yl) oxy) phenyl) -3- (4-fluorobenzyl) urea
Figure PCTCN2019101623-appb-000104
Figure PCTCN2019101623-appb-000104
同实施例88操作，由6-氯-N’N-二甲基己基-1-胺代替步骤3)中的溴乙烷进行反应得到白色固体产物。 1H NMR(400MHz,DMSO-d 6)δ8.78(s,1H),8.38(d,J＝5.2Hz,1H),7.53–7.46(m,2H),7.35(dd,J＝8.5,5.7Hz,2H),7.21–7.11(m,2H),7.02(d,J＝9.7Hz,3H),6.71(t,J＝ 6.0Hz,1H),6.36(d,J＝5.2Hz,1H),4.36–4.25(m,6H),4.12(t,J＝6.5Hz,2H),2.73(br,2H),2.52(s,6H),1.85–1.77(m,2H),1.64–1.32(m,6H).MS:589[M+H] + The same operation as in Example 88 was performed, and 6-chloro-N'N-dimethylhexyl-1-amine was used instead of the bromoethane in step 3) to obtain a white solid product. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.78 (s, 1H), 8.38 (d, J = 5.2 Hz, 1H), 7.53-7.46 (m, 2H), 7.35 (dd, J = 8.5, 5.7 Hz, 2H), 7.21–7.11 (m, 2H), 7.02 (d, J = 9.7 Hz, 3H), 6.71 (t, J = 6.0 Hz, 1H), 6.36 (d, J = 5.2 Hz, 1H), 4.36-4.25 (m, 6H), 4.12 (t, J = 6.5Hz, 2H), 2.73 (br, 2H), 2.52 (s, 6H), 1.85-1.77 (m, 2H), 1.64-1.32 (m, 6H) .MS: 589 [M + H] +
实施例235. 1-(2-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(4-氟苯甲基)脲Example 235. 1- (2-fluoro-4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] Quinolin-10-yl) oxy) phenyl) -3- (4-fluorobenzyl) urea
Figure PCTCN2019101623-appb-000105
Figure PCTCN2019101623-appb-000105
同实施例88操作，由3-氟-4硝基苯酚代替步骤1)中的4-硝基苯酚，由4-(3-溴丙基)-吗啉代替步骤3)中的溴乙烷进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ8.46–8.36(m,2H),8.12(t,J＝9.2Hz,1H),7.38–7.31(m,2H),7.19–7.01(m,5H),6.88-6.85(m,1H),6.50(d,J＝5.2Hz,1H),4.35–4.27(m,6H),4.16(t,J＝6.4Hz,2H),3.58(t,J＝4.6Hz,4H),2.45(t,J＝7.1Hz,2H),2.39(d,J＝5.0Hz,4H),2.02-1.93(m,2H).MS:607[M+H] + The same operation as in Example 88 was carried out by replacing 4-nitrophenol in step 1) with 3-fluoro-4nitrophenol and replacing bromoethane in step 3) with 4- (3-bromopropyl) -morpholine. The reaction yielded a white solid product; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.46–8.36 (m, 2H), 8.12 (t, J = 9.2Hz, 1H), 7.38–7.31 (m, 2H), 7.19 --7.01 (m, 5H), 6.88-6.85 (m, 1H), 6.50 (d, J = 5.2Hz, 1H), 4.35--4.27 (m, 6H), 4.16 (t, J = 6.4Hz, 2H), 3.58 (t, J = 4.6Hz, 4H), 2.45 (t, J = 7.1Hz, 2H), 2.39 (d, J = 5.0Hz, 4H), 2.02-1.93 (m, 2H) .MS: 607 [M + H] +
实施例236.(R)-1-(2-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(1-(4-氟苯基)乙基)脲Example 236. (R) -1- (2-Fluoro-4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2, 3-f) quinolin-10-yl) oxy) phenyl) -3- (1- (4-fluorophenyl) ethyl) urea
Figure PCTCN2019101623-appb-000106
Figure PCTCN2019101623-appb-000106
同实施例88操作，由3-氟-4硝基苯酚代替步骤1)中的4-硝基苯酚，由4-(3-溴丙基)-吗啉代替步骤3)中的溴乙烷，由(R)-1-(4-氟苯基)乙基-1-胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ8.36(d,J＝5.2Hz,1H),8.22(d,J＝2.5Hz,1H),8.04(t,J＝9.2Hz,1H),7.39-7.24(m,2H),7.19-6.93(m,5H),6.81-6.74(m,1H),6.42(d,J＝5.2Hz,1H),4.76(t,J＝7.1Hz,1H),4.28-4.20(m,4H),4.11(t,J＝6.1Hz,2H),3.54(s,4H),2.38(s,2H),2.35(s,4H),1.93(d,J＝8.4Hz,2H),1.31(d,J＝6.9Hz,3H).MS:621[M+H] + Following the same procedure as in Example 88, 4-nitrophenol in step 1) was replaced with 3-fluoro-4nitrophenol, and bromoethane in step 3) was replaced with 4- (3-bromopropyl) -morpholine. Reaction of (R) -1- (4-fluorophenyl) ethyl-1-amine in place of 4-fluorobenzylamine in step 6) to obtain a white solid product; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8 .36 (d, J = 5.2 Hz, 1H), 8.22 (d, J = 2.5 Hz, 1H), 8.04 (t, J = 9.2 Hz, 1H), 7.39-7.24 (m, 2H), 7.19-6.93 ( m, 5H), 6.81-6.74 (m, 1H), 6.42 (d, J = 5.2 Hz, 1H), 4.76 (t, J = 7.1 Hz, 1H), 4.28-4.20 (m, 4H), 4.11 (t , J = 6.1Hz, 2H), 3.54 (s, 4H), 2.38 (s, 2H), 2.35 (s, 4H), 1.93 (d, J = 8.4Hz, 2H), 1.31 (d, J = 6.9Hz , 3H) .MS: 621 [M + H] +
实施例237.(S)-1-(2-氟-4-((5-(3-吗啉丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(1-(4-氟苯基)乙基)脲Example 237. (S) -1- (2-fluoro-4-((5- (3-morpholinepropoxy) -2,3-dihydro- [1,4] dioxane [2, 3-f) quinolin-10-yl) oxy) phenyl) -3- (1- (4-fluorophenyl) ethyl) urea
Figure PCTCN2019101623-appb-000107
Figure PCTCN2019101623-appb-000107
同实施例88操作，由3-氟-4硝基苯酚代替步骤1)中的4-硝基苯酚，由4-(3-溴丙基)-吗啉代替步骤3)中的溴乙烷，由(S)-1-(4-氟苯基)乙基-1-胺代替步骤6)中的4-氟苄胺进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ8.36(d,J＝5.2Hz,1H),8.22(d,J＝2.6Hz,1H),8.04(t,J＝9.2Hz,1H),7.35–7.26(m,2H),7.14–7.07(m,2H),7.06–7.00(m,2H),6.99(s,1H),6.81–6.74(m,1H),6.42(d,J＝5.2Hz,1H),4.76(t,J＝7.2Hz,1H),4.28–4.19(m,4H),4.10(t,J＝6.4Hz,2H),3.53(br,4H),2.40(br,2H),2.33(s,4H),1.96–1.85(m,2H),1.31(d,J＝7.0Hz,3H).MS:621[M+H] + Following the same procedure as in Example 88, 4-nitrophenol in step 1) was replaced with 3-fluoro-4nitrophenol, and bromoethane in step 3) was replaced with 4- (3-bromopropyl) -morpholine. Reaction of (S) -1- (4-fluorophenyl) ethyl-1-amine in place of 4-fluorobenzylamine in step 6) to obtain a white solid product; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8 .36 (d, J = 5.2 Hz, 1H), 8.22 (d, J = 2.6 Hz, 1H), 8.04 (t, J = 9.2 Hz, 1H), 7.35–7.26 (m, 2H), 7.14–7.07 ( m, 2H), 7.06--7.00 (m, 2H), 6.99 (s, 1H), 6.81--6.74 (m, 1H), 6.42 (d, J = 5.2Hz, 1H), 4.76 (t, J = 7.2Hz , 1H), 4.28--4.19 (m, 4H), 4.10 (t, J = 6.4Hz, 2H), 3.53 (br, 4H), 2.40 (br, 2H), 2.33 (s, 4H), 1.96--1.85 ( m, 2H), 1.31 (d, J = 7.0Hz, 3H) .MS: 621 [M + H] +
实施例238. 1-(4-((5-((1-氨基环丙基)甲氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-yl)oxy)-3-氟苯基)-3-(4-氟苯甲基)脲Example 238. 1- (4-((5-((1-aminocyclopropyl) methoxy) -2,3-dihydro- [1,4] dioxane [2,3-f] Quinoline-10-yl) oxy) -3-fluorophenyl) -3- (4-fluorobenzyl) urea
Figure PCTCN2019101623-appb-000108
Figure PCTCN2019101623-appb-000108
同实施例88操作，由2-氟-4硝基苯酚代替步骤1)中的4-硝基苯酚，由4-甲苯磺酸(1-((叔丁基氧羰基)氨基)环丙基)甲基酯代替步骤3)中的溴乙烷进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ8.97(s,1H),8.38(d,J＝5.3Hz,1H),7.68(dd,J＝13.6,2.4Hz,1H),7.43–7.30(m,2H),7.25–7.07(m,4H),7.02(s,1H),6.80(t,J＝6.0Hz,1H),6.36(dd,J＝5.2,1.0Hz,1H),4.38(s,4H),4.29(d,J＝5.9Hz,2H),4.03(s,2H),0.64(dt,J＝9.6,2.1Hz,4H).MS:549[M+H] +； The same operation as in Example 88 was performed, in which 4-nitrophenol in step 1) was replaced with 2-fluoro-4nitrophenol, and 4-toluenesulfonic acid (1-((tert-butyloxycarbonyl) amino) cyclopropyl) The methyl ester was used instead of the bromoethane in step 3) to obtain a white solid product; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.97 (s, 1 H), 8.38 (d, J = 5.3 Hz, 1 H) , 7.68 (dd, J = 13.6, 2.4Hz, 1H), 7.43–7.30 (m, 2H), 7.25–7.07 (m, 4H), 7.02 (s, 1H), 6.80 (t, J = 6.0Hz, 1H ), 6.36 (dd, J = 5.2, 1.0 Hz, 1H), 4.38 (s, 4H), 4.29 (d, J = 5.9 Hz, 2H), 4.03 (s, 2H), 0.64 (dt, J = 9.6, 2.1Hz, 4H) .MS: 549 [M + H] + ;
实施例239. 1-(3-氟-4-((5-(2-羟基-2-甲基丙氧基)-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(4-氟苯甲基)脲Example 239. 1- (3-fluoro-4-((5- (2-hydroxy-2-methylpropoxy) -2,3-dihydro- [1,4] dioxane [2, 3-f) quinolin-10-yl) oxy) phenyl) -3- (4-fluorobenzyl) urea
Figure PCTCN2019101623-appb-000109
Figure PCTCN2019101623-appb-000109
同实施例88操作，由2-氟-4硝基苯酚代替步骤1)中的4-硝基苯酚，由1-溴-2-甲基丙基-2-醇代替步骤3)中的溴乙烷进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ8.94(s,1H),8.39(d,J＝5.2Hz,1H),7.68(dd,J＝13.6,2.4Hz,1H),7.39–7.30(m,2H),7.22–7.09(m,4H),7.03(s,1H),6.78(t,J＝6.0Hz,1H),6.36(dd,J＝5.2,1.1Hz,1H),4.68(s,1H),4.37(s,4H),4.29(d,J＝6.0Hz,2H),3.86(s,2H),1.25(s,6H).MS:552[M+H] +； In the same manner as in Example 88, 2-nitro-4nitrophenol was used to replace 4-nitrophenol in step 1), and 1-bromo-2-methylpropyl-2-ol was used to replace bromoethyl in step 3). Alkane reaction to give a white solid product; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.94 (s, 1 H), 8.39 (d, J = 5.2 Hz, 1 H), 7.68 (dd, J = 13.6, 2.4 Hz , 1H), 7.39–7.30 (m, 2H), 7.22–7.09 (m, 4H), 7.03 (s, 1H), 6.78 (t, J = 6.0Hz, 1H), 6.36 (dd, J = 5.2, 1.1 Hz, 1H), 4.68 (s, 1H), 4.37 (s, 4H), 4.29 (d, J = 6.0Hz, 2H), 3.86 (s, 2H), 1.25 (s, 6H) .MS: 552 (M + H] + ;
实施例240. 1-(2-氯-5-氟-4-((5-甲氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)甲氧基)苯基)-3-(4-氟苯甲基)脲Example 240. 1- (2-chloro-5-fluoro-4-((5-methoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinoline -10-yl) methoxy) phenyl) -3- (4-fluorobenzyl) urea
Figure PCTCN2019101623-appb-000110
Figure PCTCN2019101623-appb-000110
同实施例88操作，由5-氯-2-氟-4-硝基苯酚代替步骤1)中的4-硝基苯酚，由碘甲烷代替步骤3)中的溴乙烷进行反应得到白色固体产物； 1H NMR(400MHz,DMSO-d 6)δ8.43(d,J＝5.3Hz,1H),8.36–8.27(m,2H),7.61(t,J＝5.8Hz,1H),7.50(d,J＝8.3Hz,1H),7.41–7.32(m,2H),7.23–7.14(m,2H),7.08(s,1H),6.50(dd,J＝5.2,0.9Hz,1H),4.37–4.29(m,6H),3.92(s,3H).MS:528[M+H] + The reaction was carried out in the same manner as in Example 88. 5-chloro-2-fluoro-4-nitrophenol was used instead of 4-nitrophenol in step 1), and methyl iodide was used instead of bromoethane in step 3) to obtain a white solid product. ; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.43 (d, J = 5.3 Hz, 1 H), 8.36-8.27 (m, 2 H), 7.61 (t, J = 5.8 Hz, 1 H), 7.50 (d , J = 8.3Hz, 1H), 7.41–7.32 (m, 2H), 7.23–7.14 (m, 2H), 7.08 (s, 1H), 6.50 (dd, J = 5.2, 0.9Hz, 1H), 4.37– 4.29 (m, 6H), 3.92 (s, 3H) .MS: 528 [M + H] +
实施例241. 1-(3-氟-4-((5-甲氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(4-氟苄基)脲Example 241.1- (3-Fluoro-4-((5-methoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl ) Oxy) phenyl) -3- (4-fluorobenzyl) urea
Figure PCTCN2019101623-appb-000111
Figure PCTCN2019101623-appb-000111
步骤1)分别将10-氯-5-甲氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉(5.0g,20mmol)，2-氟-4-硝基苯酚(3.1g,20mmol)加入氯苯(50mL)中并在150℃条件下加热搅拌反应20小时，冷却，浓缩至糊状后加1N的氢氧化钠水溶液进行打浆，过滤得到土黄色固体经过干燥后得4.5g，所得滤液由二氯甲烷萃取，有机相干燥浓缩再由柱层析纯化得到1.5g 10-(2-氟-4-硝基苯氧基)-5-甲氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉，总收率71％，Step 1) Separately 10-chloro-5-methoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinoline (5.0 g, 20 mmol), 2-fluoro 4-Nitrophenol (3.1 g, 20 mmol) was added to chlorobenzene (50 mL) and heated and stirred at 150 ° C for 20 hours. After cooling, concentrating to a paste, a 1N sodium hydroxide aqueous solution was added for beating and filtering to obtain After drying the khaki solid, 4.5 g was obtained. The obtained filtrate was extracted with dichloromethane. The organic phase was dried and concentrated and purified by column chromatography to obtain 1.5 g of 10- (2-fluoro-4-nitrophenoxy) -5-formaldehyde. Oxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinoline, with a total yield of 71%,
步骤2)将步骤1)所得产品(0.37g,1mmol)溶于甲醇(10mL)中，加入钯碳(10％钯含量，湿)催化，在氢气条件下室温搅拌反应2小时，用硅藻土过滤，滤液干燥得到浅紫色固体产物0.30g 3-氟-4-((5-甲氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯胺，收率85％，MS:343[M+H] +； Step 2) The product obtained in step 1) (0.37 g, 1 mmol) was dissolved in methanol (10 mL), palladium on carbon (10% palladium content, wet) was added to catalyze, and the reaction was stirred at room temperature under hydrogen for 2 hours. Filtration and drying of the filtrate gave 0.30 g of 3-fluoro-4-((5-methoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinoline) as a pale purple solid product. -10-yl) oxy) aniline, yield 85%, MS: 343 [M + H] + ;
步骤3)将步骤2)所得产品(170mg，0.5mmol)溶于干燥DMF(3mL)中，随后滴加氯甲酸苯酯(160mg,1mmol)和吡啶(0.5mL)室温搅拌反应，TLC监测，反应完毕后不处理，直接进行下一步；Step 3) The product (170 mg, 0.5 mmol) obtained in step 2) was dissolved in dry DMF (3 mL), and then phenyl chloroformate (160 mg, 1 mmol) and pyridine (0.5 mL) were added dropwise to stir the reaction at room temperature. TLC monitoring, reaction Do not process after completion, and proceed directly to the next step;
步骤4)将步骤3)所得中间体的反应液中加入4-氟苯甲胺(190mg,1.5mmol)，并加热至60℃搅拌3小时，冷却，加水打浆过滤得灰色固体经柱层析纯化得白色固体36mg； 1H NMR(400 MHz,DMSO-d 6)δ8.94(s,1H),8.40(d,J＝5.2Hz,1H),7.69(dd,J＝13.6,2.4Hz,1H),7.40–7.31(m,2H),7.25–7.10(m,4H),7.07(s,1H),6.78(t,J＝6.0Hz,1H),6.37(dd,J＝5.2,1.1Hz,1H),4.36(hept,J＝3.4Hz,4H),4.30(d,J＝5.9Hz,2H),3.92(s,3H).MS:494[M+H] + Step 4) Add 4-fluorobenzylamine (190 mg, 1.5 mmol) to the reaction solution of the intermediate obtained in step 3), heat to 60 ° C. and stir for 3 hours, cool, add water and filter to obtain a gray solid, and purify it by column chromatography. 36 mg of white solid was obtained; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.94 (s, 1H), 8.40 (d, J = 5.2 Hz, 1H), 7.69 (dd, J = 13.6, 2.4 Hz, 1H ), 7.40–7.31 (m, 2H), 7.25–7.10 (m, 4H), 7.07 (s, 1H), 6.78 (t, J = 6.0Hz, 1H), 6.37 (dd, J = 5.2, 1.1Hz, 1H), 4.36 (hept, J = 3.4Hz, 4H), 4.30 (d, J = 5.9Hz, 2H), 3.92 (s, 3H) .MS: 494 [M + H] +
实施例242.(R)-1-(3-氟-4-((5-甲氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(1-(4-氟苯基)乙基)脲Example 242. (R) -1- (3-fluoro-4-((5-methoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinoline -10-yl) oxy) phenyl) -3- (1- (4-fluorophenyl) ethyl) urea
Figure PCTCN2019101623-appb-000112
Figure PCTCN2019101623-appb-000112
同实施例241操作，由等摩尔当量的(R)-1-(4-氟苯基)乙-1-胺(210mg,1.5mmol)代替步骤4)中的4-氟苯甲胺进行反应得到白色固体产物30mg； 1H NMR(400MHz,DMSO-d 6)δ8.72(s,1H),8.39(d,J＝5.2Hz,1H),7.65(dd,J＝13.6,2.5Hz,1H),7.43–7.35(m,2H),7.23–7.04(m,5H),6.77(d,J＝7.8Hz,1H),6.35(d,J＝5.3Hz,1H),4.83(t,J＝7.2Hz,1H),4.36(s,4H),3.92(s,3H),1.39(d,J＝6.9Hz,3H).MS:508[M+H] + The same operation as in Example 241 was carried out by replacing the 4-fluorobenzylamine in step 4) with an equimolar equivalent of (R) -1- (4-fluorophenyl) ethyl-1-amine (210 mg, 1.5 mmol). 30 mg of white solid product; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.72 (s, 1 H), 8.39 (d, J = 5.2 Hz, 1 H), 7.65 (dd, J = 13.6, 2.5 Hz, 1 H) , 7.43–7.35 (m, 2H), 7.23–7.04 (m, 5H), 6.77 (d, J = 7.8Hz, 1H), 6.35 (d, J = 5.3Hz, 1H), 4.83 (t, J = 7.2 Hz, 1H), 4.36 (s, 4H), 3.92 (s, 3H), 1.39 (d, J = 6.9Hz, 3H). MS: 508 [M + H] +
实施例243.(S)-1-(3-氟-4-((5-甲氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(1-(4-氟苯基)乙基)脲Example 243. (S) -1- (3-Fluoro-4-((5-methoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinoline -10-yl) oxy) phenyl) -3- (1- (4-fluorophenyl) ethyl) urea
Figure PCTCN2019101623-appb-000113
Figure PCTCN2019101623-appb-000113
同实施例241操作，由等摩尔当量的(S)-1-(4-氟苯基)乙-1-胺(210mg,1.5mmol)代替步骤4)中的4-氟苯甲胺进行反应得到白色固体产物35mg； 1H NMR(400MHz,DMSO-d 6)δ8.72(s,1H),8.39(d,J＝5.2Hz,1H),7.65(dd,J＝13.6,2.5Hz,1H),7.44-7.35(m,2H),7.18(td,J＝8.9,5.2Hz,3H),7.14-7.06(m,1H),7.06(s,1H),6.77(d,J＝7.8Hz,1H),6.35(dd,J＝5.3,1.0Hz,1H),4.88-4.79(m,1H),4.40-4.31(m,4H),3.92(s,3H),1.40(d,J＝6.9Hz,3H).MS:508[M+H] + The same operation as in Example 241 was carried out by replacing the 4-fluorobenzylamine in step 4) with an equimolar equivalent of (S) -1- (4-fluorophenyl) ethyl-1-amine (210 mg, 1.5 mmol). 35 mg of white solid product; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.72 (s, 1 H), 8.39 (d, J = 5.2 Hz, 1 H), 7.65 (dd, J = 13.6, 2.5 Hz, 1 H) , 7.44-7.35 (m, 2H), 7.18 (td, J = 8.9, 5.2Hz, 3H), 7.14-7.06 (m, 1H), 7.06 (s, 1H), 6.77 (d, J = 7.8Hz, 1H ), 6.35 (dd, J = 5.3, 1.0 Hz, 1H), 4.88-4.79 (m, 1H), 4.40-4.31 (m, 4H), 3.92 (s, 3H), 1.40 (d, J = 6.9Hz, 3H) .MS: 508 [M + H] +
实施例244. 1-(2-氯-4-((5-甲氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(4-氟苄基)脲Example 244. 1- (2-chloro-4-((5-methoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinolin-10-yl ) Oxy) phenyl) -3- (4-fluorobenzyl) urea
Figure PCTCN2019101623-appb-000114
Figure PCTCN2019101623-appb-000114
同实施例241操作，由等摩尔当量的3-氯-4-硝基苯酚代替步骤1)中的4-硝基苯酚进行反 应，得到白色固体产物38mg； 1H NMR(400MHz,DMSO-d 6)δ8.45(d,J＝5.2Hz,1H),8.22-8.13(m,2H),7.42(t,J＝5.8Hz,1H),7.41-7.32(m,2H),7.26(d,J＝2.8Hz,1H),7.23-7.14(m,2H),7.10-7.02(m,2H),6.57-6.49(m,1H),4.34-4.27(m,6H),3.92(s,3H).MS:510[M+H] + The same operation as in Example 241 was carried out by replacing the 4-nitrophenol in step 1) with an equimolar equivalent of 3-chloro-4-nitrophenol to obtain 38 mg of a white solid product; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.45 (d, J = 5.2Hz, 1H), 8.22-8.13 (m, 2H), 7.42 (t, J = 5.8Hz, 1H), 7.41-7.32 (m, 2H), 7.26 (d, J = 2.8Hz, 1H), 7.23-7.14 (m, 2H), 7.10-7.02 (m, 2H), 6.57-6.49 (m, 1H), 4.34-4.27 (m, 6H), 3.92 (s, 3H). MS: 510 [M + H] +
实施例245.(R)-1-(2-氯-4-((5-甲氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(1-(4-氟苯基)乙基)脲Example 245. (R) -1- (2-Chloro-4-((5-methoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinoline -10-yl) oxy) phenyl) -3- (1- (4-fluorophenyl) ethyl) urea
Figure PCTCN2019101623-appb-000115
Figure PCTCN2019101623-appb-000115
同实施例241操作，由等摩尔当量的3-氯-4-硝基苯酚代替步骤1)中的4-硝基苯酚，由等摩尔当量的(R)-1-(4-氟苯基)乙-1-胺(210mg,1.5mmol)代替步骤4)中的4-氟苯甲胺进行反应得到白色固体产物38mg； 1H NMR(400MHz,DMSO-d 6)δ8.44(d,J＝5.2Hz,1H),8.18(d,J＝9.1Hz,1H),8.08(s,1H),7.49(d,J＝7.6Hz,1H),7.43–7.34(m,2H),7.29–7.13(m,3H),7.10–6.99(m,2H),6.50(d,J＝5.2Hz,1H),4.83(p,J＝7.0Hz,1H),4.31(p,J＝4.4,3.8Hz,4H),3.92(s,3H),1.39(d,J＝6.9Hz,3H).MS:524[M+H] + The same operation as in Example 241 was performed, and equimolar equivalent of 3-chloro-4-nitrophenol was used instead of 4-nitrophenol in step 1), and equimolar equivalent of (R) -1- (4-fluorophenyl) Ethyl-1-amine (210 mg, 1.5 mmol) was substituted for 4-fluorobenzylamine in step 4) to obtain 38 mg of a white solid product; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.44 (d, J = 5.2Hz, 1H), 8.18 (d, J = 9.1Hz, 1H), 8.08 (s, 1H), 7.49 (d, J = 7.6Hz, 1H), 7.43–7.34 (m, 2H), 7.29–7.13 ( m, 3H), 7.10--6.99 (m, 2H), 6.50 (d, J = 5.2Hz, 1H), 4.83 (p, J = 7.0Hz, 1H), 4.31 (p, J = 4.4, 3.8Hz, 4H ), 3.92 (s, 3H), 1.39 (d, J = 6.9Hz, 3H) .MS: 524 [M + H] +
实施例246.(S)-1-(2-氯-4-((5-甲氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)-3-(1-(4-氟苯基)乙基)脲Example 246. (S) -1- (2-Chloro-4-((5-methoxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinoline -10-yl) oxy) phenyl) -3- (1- (4-fluorophenyl) ethyl) urea
Figure PCTCN2019101623-appb-000116
Figure PCTCN2019101623-appb-000116
同实施例241操作，由等摩尔当量的3-氯-4-硝基苯酚代替步骤1)中的4-硝基苯酚，由等摩尔当量的(S)-1-(4-氟苯基)乙-1-胺(210mg,1.5mmol)代替步骤4)中的4-氟苯甲胺进行反应得到白色固体产物42mg； 1H NMR(400MHz,DMSO-d 6)δ8.44(d,J＝5.2Hz,1H),8.18(d,J＝9.1Hz,1H),8.07(s,1H),7.48(d,J＝7.6Hz,1H),7.43–7.34(m,2H),7.28–7.13(m,3H),7.10–6.99(m,2H),6.50(d,J＝5.2Hz,1H),4.83(t,J＝7.1Hz,1H),4.30(tt,J＝6.1,3.2Hz,4H),3.92(s,3H),1.40(d,J＝7.0Hz,3H).MS:524[M+H] + The same operation as in Example 241 was performed, and equimolar equivalent of 3-chloro-4-nitrophenol was used instead of 4-nitrophenol in step 1), and equimolar equivalent of (S) -1- (4-fluorophenyl) Ethyl-1-amine (210 mg, 1.5 mmol) was substituted for 4-fluorobenzylamine in step 4) to obtain 42 mg of a white solid product; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.44 (d, J = 5.2Hz, 1H), 8.18 (d, J = 9.1Hz, 1H), 8.07 (s, 1H), 7.48 (d, J = 7.6Hz, 1H), 7.43–7.34 (m, 2H), 7.28–7.13 ( m, 3H), 7.10--6.99 (m, 2H), 6.50 (d, J = 5.2Hz, 1H), 4.83 (t, J = 7.1Hz, 1H), 4.30 (tt, J = 6.1, 3.2Hz, 4H ), 3.92 (s, 3H), 1.40 (d, J = 7.0Hz, 3H) .MS: 524 [M + H] +
手性纯度测试Chiral purity test
对实施例127((R)-1-(1-(4-氟苯基)乙基)-3-(4-((5-氧杂环丁基氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)脲)和实施例171((S)-1-(1-(4-氟苯基)乙基)-3-(4-((5-氧杂环丁基氧基-2,3-二氢-[1,4]二氧六环[2,3-f]喹啉-10-基)氧基)苯基)脲)的一对对映异构体进行了手性纯度测试。测试采用色谱仪(岛津LC-20A)进行，测试条件如下：For Example 127 ((R) -1- (1- (4-fluorophenyl) ethyl) -3- (4-((5-oxetanyloxy-2,3-dihydro- [ 1,4] dioxane [2,3-f] quinolin-10-yl) oxy) phenyl) urea) and Example 171 ((S) -1- (1- (4-fluorophenyl ) Ethyl) -3- (4-((5-oxetanyloxy-2,3-dihydro- [1,4] dioxane [2,3-f] quinoline-10- A pair of enantiomers of the group) (oxy) phenyl) urea) were tested for chiral purity. The test was performed using a chromatograph (Shimadzu LC-20A). The test conditions were as follows:
Figure PCTCN2019101623-appb-000117
Figure PCTCN2019101623-appb-000117
测试结果如图1-3所示。图1示出了实施例127和171的对映异构体的混合物的液相色谱分离图，图2和图3分别示出了实施例127和实施例171的化合物的液相色谱分离图，由图可知，实施例127的化合物保留时间在9.1，实施例171的化合物保留时间在10.9，而且，实施例127和实施例171的化合物为纯的R构型和S构型化合物。The test results are shown in Figure 1-3. FIG. 1 shows a liquid chromatographic separation diagram of a mixture of enantiomers of Examples 127 and 171, and FIG. 2 and FIG. 3 show a liquid chromatographic separation diagram of the compound of Example 127 and Example 171, respectively. It can be seen from the figure that the retention time of the compound of Example 127 is 9.1 and the retention time of the compound of Example 171 is 10.9, and the compounds of Example 127 and Example 171 are pure R-configuration and S-configuration compounds.
实验例1.小分子化合物抑制VEGFR-2活性测试Experimental example 1. Small molecule compounds inhibit VEGFR-2 activity test
基于Perkin Elmer公司的LANCE TR-FRET技术，测试方法如下：Based on the LANCE TR-FRET technology from Perkin Elmer, the test method is as follows:
1.化合物稀释：从最高浓度2500nM开始进行3倍梯度稀释后共11个浓度(本实验使用的药物的最大终浓度为2500nM，最低终浓度为0.042nM)。1. Compound Dilution: A total of 11 concentrations after a 3-fold gradient dilution starting from the highest concentration of 2500 nM (the maximum final concentration of the drug used in this experiment is 2500 nM and the lowest final concentration is 0.042 nM).
2.用排枪取2.5μL经梯度稀释的化合物，加入384孔板中。2. Using a row gun, take 2.5 μL of the diluted compound and add it to a 384-well plate.
3.加酶：用排枪取5μL 2X VEGFR-2激酶溶液(浓度为0.5nM)加入到384孔板相应的反应孔中，混匀后室温预反应30分钟。3. Add enzyme: Take 5μL 2XVEGFR-2 kinase solution (concentration 0.5nM) with a row gun and add it to the corresponding reaction well of a 384-well plate. After mixing, pre-react at room temperature for 30 minutes.
4.排枪取2.5μL 4X Ultra ULight TM-JAK-1(Tyr1023)Peptide(浓度为200nM)/ATP(浓度为40μM)混合液加入到384孔板相应的反应孔中。 4. Dispense 2.5 μL of 4X Ultra ULight TM -JAK-1 (Tyr1023) Peptide (200 nM) / ATP (40 μM) mixture into the corresponding reaction wells of a 384-well plate.
5.阴性对照：在384孔板孔加入2.5μL/孔4X底物/ATP混合液和7.5μL 1X Kinase Assay Buffe。5. Negative control: Add 2.5 μL / well 4X substrate / ATP mixture and 7.5 μL 1X Kinase Assay Buffe to the 384-well plate well.
6.阳性对照：在384孔板中加入2.5μL/孔4X底物/ATP混合液，2.5μL/孔含16％DMSO的1X Kinase Assay Buffer，5μL/孔2X VEGFR-2激酶溶液。反应体系中DMSO的终浓度为4％。6. Positive control: 2.5 μL / well 4X substrate / ATP mixed solution, 2.5 μL / well 1X Kinase Assay buffer containing 16% DMSO, 5 μL / well 2X VEGFR-2 kinase solution. The final concentration of DMSO in the reaction system was 4%.
7.离心混匀，避光室温反应60分钟。7. Mix by centrifugation and react at room temperature for 60 minutes in the dark.
8.终止酶促反应：用排枪取5μL 4X终止液加入到384孔板中孔中，离心混匀，室温反应5分钟。8. Terminate the enzymatic reaction: Use a row gun to take 5 μL of 4X stop solution into the well of a 384-well plate, mix by centrifugation, and react at room temperature for 5 minutes.
9.显色反应：用排枪取5μL 4X检测液加入到384孔板中孔中进行显色，离心混匀，室温反应60分钟。9. Chromogenic reaction: Use a row gun to take 5 μL of 4X detection solution into the well of a 384-well plate for color development, mix by centrifugation, and react at room temperature for 60 minutes.
10.将384孔板放入Envision读板仪读板，调取相应的程序检测信号。10. Place the 384-well plate into the Envision plate reader and retrieve the corresponding program detection signal.
11.原始数据的分析和处理：11. Analysis and processing of raw data:
将药物浓度和相应抑制率输入GraphPad Prism5计算处理，化合物的抑制率的计算方法如下：抑制率(％)＝(阳性孔读值-实验孔读值)/(阳性对照孔读值-阴性对照孔读值)x100％。用GraphPad Prism5软件处理得出相应的IC 50值(酶最高抑制率50％时的化合物浓度)。 The drug concentration and the corresponding inhibition rate were input to GraphPad Prism5 for calculation and treatment. The inhibition rate of the compound was calculated as follows: inhibition rate (%) = (positive well reading-experimental well reading) / (positive control well reading-negative control well) (Read value) x100%. Corresponding IC 50 values (compound concentration at the highest enzyme inhibition rate of 50%) were obtained by processing with GraphPad Prism5 software.
表8列出了本发明中部分化合物对酪氨酸激酶VEGFR-2抑制活性的测定结果，其中A表示IC 50小于或等于50nM，B表示IC 50大于50nM但小于或等于500nM，C表示IC 50大于500nM但小于或等于5000nM，D表示IC 50大于5000nM。 Table 8 shows the results of measuring the tyrosine kinase VEGFR-2 inhibitory activity of some compounds in the present invention, where A means IC 50 is less than or equal to 50 nM, B means IC 50 is greater than 50 nM but less than or equal to 500 nM, and C means IC 50 More than 500 nM but less than or equal to 5000 nM, D means that the IC 50 is greater than 5000 nM.
表8、本发明部分化合物对VEGFR-2酪氨酸激酶抑制活性测定结果Table 8. Results of determination of VEGFR-2 tyrosine kinase inhibitory activity of some compounds of the present invention
Figure PCTCN2019101623-appb-000118
Figure PCTCN2019101623-appb-000118
Figure PCTCN2019101623-appb-000119
Figure PCTCN2019101623-appb-000119
Figure PCTCN2019101623-appb-000120
Figure PCTCN2019101623-appb-000120
实验例2.小分子化合物对M-NFS-60细胞增殖抑制活性的测试Experimental example 2. Test of small molecule compounds on M-NFS-60 cell proliferation inhibitory activity
具体实验步骤如下：The specific experimental steps are as follows:
1.化合物稀释：从最高浓度5000nM开始进行3倍梯度稀释后共9个浓度(本实验使用的药物的最大终浓度为5000nM，最低终浓度为0.76nM)。1. Compound Dilution: A total of 9 concentrations after a 3-fold gradient dilution starting from the highest concentration of 5000 nM (the maximum final concentration of the drug used in this experiment is 5000 nM and the lowest final concentration is 0.76 nM).
2.收集M-NFS-60细胞后转移至15mL离心管中，以1000rpm的速度离心5分钟。2. Collect M-NFS-60 cells, transfer them to a 15 mL centrifuge tube, and centrifuge at 1000 rpm for 5 minutes.
3.弃去上清液，加入完全培养液，吹打均匀，取10μL细胞悬浮液和10μL 0.4％台盼蓝混匀，用细胞计数仪进行计数，记录细胞数及存活率；3. Discard the supernatant, add the complete culture solution, and mix by pipetting. Take 10 μL of the cell suspension and 10 μL of 0.4% trypan blue, mix with a cell counter, and record the number of cells and survival rate.
4.每孔接种10000细胞/80μL的细胞悬液到96孔板中；4. Inoculate 10,000 cells / 80 μL of cell suspension into 96-well plates per well;
5.在每孔中加入20μL对应的上述用培养液稀释过的5×化合物溶液，混合摇匀；5. Add 20 μL of the corresponding 5 × compound solution diluted with the culture solution to each well, mix and shake well;
6.培养72小时后每孔加入10μL CCK-8试剂，培养2小时(可以根据颜色深浅来调节反应时间)；6. After 72 hours of incubation, add 10 μL of CCK-8 reagent to each well and incubate for 2 hours (the reaction time can be adjusted according to the color depth);
7.在多功能读板机于450nm处读其OD值。7. Read the OD value at 450nm on a multi-plate reader.
8.数据处理：细胞存活率(％)＝[(As-Ab)/(Ac-Ab)]*100％8. Data processing: cell survival rate (%) = [(As-Ab) / (Ac-Ab)] * 100%
i.As：实验孔(含有细胞的培养基、CCK-8、化合物)的OD值，i.As: the OD value of experimental wells (medium containing cells, CCK-8, compounds),
ii.Ac：对照孔(含有细胞的培养基、CCK-8)的OD值，ii.Ac: OD value of control wells (cell-containing medium, CCK-8),
iii.Ab：空白孔(不含细胞和化合物的培养基、CCK-8)的OD值，iii.Ab: OD value of blank wells (medium without cells and compounds, CCK-8),
iv.然后将数值导入Graphpad Prism5软件进行曲线拟合，计算IC50。iv. Then import the value into Graphpad Prism5 software for curve fitting and calculate IC50.
表9列出了本发明中代表性的化合物对M-NFS-60细胞增殖抑制活性的测定结果，其中A表示IC 50小于或等于100nM，B表示IC 50大于100nM但小于或等于1000nM，C表示IC 50大于1000nM。 Table 9 lists the results of measuring the inhibitory activity of M-NFS-60 cell proliferation by representative compounds in the present invention, where A represents an IC 50 of less than or equal to 100 nM, B represents an IC 50 of greater than 100 nM but less than or equal to 1000 nM, and C represents The IC 50 is greater than 1000 nM.
表9、本发明代表性的化合物对M-NFS-60细胞增殖抑制活性的测定结果Table 9. Measurement results of M-NFS-60 cell proliferation inhibitory activity of representative compounds of the present invention
Figure PCTCN2019101623-appb-000121
Figure PCTCN2019101623-appb-000121
Figure PCTCN2019101623-appb-000122
Figure PCTCN2019101623-appb-000122
Figure PCTCN2019101623-appb-000123
Figure PCTCN2019101623-appb-000123
Figure PCTCN2019101623-appb-000124
Figure PCTCN2019101623-appb-000124
实验例3.本发明化合物对RAW264.7细胞中CSF-1R(cFMS)磷酸化的抑制作用Experimental Example 3. Inhibition of CSF-1R (cFMS) phosphorylation in RAW264.7 cells by the compound of the present invention
具体实验过程如下：The specific experimental process is as follows:
1.细胞收集及蛋白样品提取1. Cell collection and protein sample extraction
a)收集细胞培养瓶中的细胞，用无血清的DMEM培养基离心洗三遍(1000rpm离心5min)，细胞计数；a) Collect the cells in the cell culture flask, centrifuge and wash three times with serum-free DMEM medium (1000 rpm for 5 min), and count the cells;
b)以1×10 6细胞/1mL/孔的细胞密度将细胞种植于12孔板中，在37℃细胞培养箱中孵育过夜，第二天每孔加入稀释好的不同浓度的化合物(终浓度为1000nM、100nM、10nM、0nM)，混匀，培养1h； b) The cells were seeded in a 12-well plate at a cell density of 1 × 10 6 cells / 1 mL / well, and incubated in a 37 ° C cell incubator overnight. The next day, each well was added with a diluted compound of different concentration (final concentration). 1000nM, 100nM, 10nM, 0nM), mix well and culture for 1h;
c)在各孔加入M-CSF，终浓度为100ng/mL，刺激5min.；c) Add M-CSF to each well, the final concentration is 100ng / mL, stimulate for 5min .;
d)用PBS洗2遍后加入裂解液；d) After washing twice with PBS, add lysate;
e)每孔中加入配制好的完全细胞裂解液100μL，混匀，冰上裂解15min(在裂解的过程中吹打每一个孔使裂解液分布均匀)；e) Add 100 μL of the prepared complete cell lysate to each well, mix well, and lyse on ice for 15min (the lysate is distributed uniformly during the lysing process);
f)裂解完全后转移至提前标好1.5mL离心管中，于4℃，14000rpm，离心20min；f) After the lysis is completed, transfer to a 1.5 mL centrifuge tube labeled in advance, and centrifuge at 4 ° C, 14000 rpm for 20 min;
g)离心后取上清，放入做好标记的离心管中(管上标记每个孔的位置)，置于冰上；g) After centrifugation, take the supernatant, put it into a labeled centrifuge tube (the position of each well marked on the tube), and place it on ice;
h)用BCA试剂盒测定蛋白浓度。h) Determine protein concentration using BCA kit.
2.对样品蛋白变性处理后加入上样缓冲液，每孔加入30～50μg的蛋白样品或蛋白marker；2. Add sample loading buffer after denaturing the sample protein, add 30-50 μg protein sample or protein marker to each well;
3.恒压条件下以100V电压电泳30min后将电压增加至120V，电泳时间设置120min或 者适当延长，当凝胶上Marker条带跑出泳道下边缘时，停止电泳。电泳结束后取下凝胶夹，在拆开凝胶夹的过程中需注意不能破坏凝胶；3. Increase the voltage to 120V after electrophoresis at 100V for 30min under constant voltage. Set the electrophoresis time to 120min or extend it appropriately. When the Marker band on the gel runs out of the lower edge of the lane, stop the electrophoresis. Remove the gel clip after the electrophoresis is completed. Be careful not to damage the gel during the process of disassembling the gel clip;
4.电泳结束后，用剥胶铲轻轻撬起短玻璃板，弃去上层浓缩胶，轻轻剥下分离胶后置于转膜液中；4. After the electrophoresis is completed, gently pry the short glass plate with a peeling shovel, discard the upper concentrated gel, gently peel off the separating gel, and place it in the transfer membrane solution;
5.根据凝胶大小剪一块大小适中的NC膜，然后浸入预冷过的转膜液中；同时将海绵与滤纸浸泡在电泳转膜缓冲液中；5. Cut a medium-sized NC membrane according to the size of the gel, and then immerse it in the pre-cooled transfer membrane solution; at the same time, soak the sponge and filter paper in the electrophoresis transfer membrane buffer solution;
6.在转印夹中按照海绵、滤纸、凝胶、PVDF膜、滤纸、海绵的顺序组装，将转印夹装入
Figure PCTCN2019101623-appb-000125
TurboTM快速电转仪，使用标准程序“Standard SD”转膜； 6. Assemble the sponge, filter paper, gel, PVDF film, filter paper, sponge in the order of the transfer clip, and put the transfer clip
Figure PCTCN2019101623-appb-000125
TurboTM fast electrorotator, using standard program "Standard SD" to transfer film;
7.用去离子水稍加漂洗载有蛋白的NC膜，加入封闭液使膜浸没，于室温下在摇床上缓慢摇动封闭1小时；7. Rinse the protein-loaded NC membrane slightly with deionized water, add the blocking solution to immerse the membrane, and slowly shake on a shaker at room temperature for 1 hour to block;
8.封闭完成后用TBST漂洗，放入抗体孵育盒中，将一抗按1：1000比例稀释，加入抗体孵育盒后于室温下摇床上轻摇孵育1小时；8. After the completion of blocking, rinse with TBST, put it into the antibody incubation box, dilute the primary antibody at a ratio of 1: 1000, add the antibody incubation box and incubate for 1 hour on a shaker at room temperature;
9.孵育完成后用TBST洗膜3次，每次10分钟；9. After incubation, wash the membrane 3 times with TBST for 10 minutes each time.
10.根据一抗来源选择二抗，按1:10000～1:15000比例用二抗稀释液稀释二抗，加入抗体孵育盒后将膜浸没于其中，于室温下摇床上轻摇孵育1小时；10. Select the secondary antibody according to the source of the primary antibody. Dilute the secondary antibody with the secondary antibody dilution solution in the ratio of 1: 10000 ~ 1: 15000. Add the antibody incubation box and immerse the membrane in it.
11.孵育完成后用TBST洗膜3次，每次10分钟；11. After the incubation, wash the membrane 3 times with TBST for 10 minutes each time.
12.用纯水漂洗膜一次，用Odyssey CLX红外荧光扫描成像系统扫描膜获取图像，并采用其系统自带的灰度读取功能读取条带的灰度值。12. Rinse the membrane once with pure water, scan the membrane with an Odyssey CLX infrared fluorescence scanning imaging system to obtain an image, and use its own grayscale reading function to read the grayscale value of the strip.
表10列出了利用蛋白标记法测得的本发明中部分化合物对RAW264.7细胞中CSF-1R(cFMS)磷酸化的抑制率。图4-7给出了实施例41和100的化合物利用蛋白标记法测试对RAW264.7细胞中CSF-1R(cFMS)磷酸化的抑制结果。结果显示，所有测试的化合物均对RAW264.7细胞中CSF-1R磷酸化有强效抑制作用，并且这种抑制作用具有剂量依赖性，随化合物浓度的降低，抑制作用减弱。Table 10 lists the inhibitory rates of some compounds of the present invention on CSF-1R (cFMS) phosphorylation in RAW264.7 cells as measured by protein labeling. Figures 4-7 show the results of the compounds of Examples 41 and 100 for inhibiting CSF-1R (cFMS) phosphorylation in RAW264.7 cells using a protein labeling method. The results show that all the tested compounds have a strong inhibitory effect on CSF-1R phosphorylation in RAW264.7 cells, and this inhibitory effect is dose-dependent, and the inhibitory effect decreases as the compound concentration decreases.
表10、本发明中部分化合物对RAW264.7细胞中CSF-1R(cFMS)磷酸化的抑制Table 10. Inhibition of CSF-1R (cFMS) phosphorylation in RAW264.7 cells by some compounds of the present invention
Figure PCTCN2019101623-appb-000126
Figure PCTCN2019101623-appb-000126
Figure PCTCN2019101623-appb-000127
Figure PCTCN2019101623-appb-000127
Figure PCTCN2019101623-appb-000128
Figure PCTCN2019101623-appb-000128
用途，制剂，给药Use, preparation, administration
医药用途、适应症Medical uses, indications
本发明所提供的生物学数据表明，本发明的化合物有利于治疗或预防由于酪氨酸激酶(CSF1R)异常而引起的疾病。本发明的化合物已被证实能够强力抑制VEGFR-2及CSF1R酪氨酸激酶活性，而VEGFR-2及CSF1R激酶家族与自身免疫疾病及癌症的发生及转移有密切关系。因此，本发明的化合物有利于治疗自身免疫疾病，包括但不限于：银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、系统性红斑狼疮、克罗恩病。本发明的化合物还有利于治疗癌症，包括原发性和转移性癌症，包括实体瘤。此类癌症包括但不限于: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。本发明的化合物也包括治疗耐一种或多种其它治疗方法的癌症。本发明的化合物还可用于与VEGFR-2激酶和/或CSF1R激酶有关的除了自身免疫疾病和癌症以外的其他疾病，包括但不限于眼底疾病，肺纤维化、肝纤维化、阿尔茨海默病等。本发明的化合物可以作为单一疗法或联合疗法，可以与多个本发明的化合物联合用药或与本发 明以外的其他药物联合用药。The biological data provided by the present invention show that the compounds of the present invention are beneficial for the treatment or prevention of diseases caused by abnormalities of tyrosine kinase (CSF1R). The compounds of the present invention have been shown to be able to potently inhibit the activity of VEGFR-2 and CSF1R tyrosine kinases, and the VEGFR-2 and CSF1R kinase families are closely related to the occurrence and metastasis of autoimmune diseases and cancer. Therefore, the compounds of the present invention are useful for treating autoimmune diseases, including but not limited to: psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, and Crohn's disease. The compounds of the invention are also useful for treating 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 myelogenous leukemia, acute myeloid leukemia, non-Hodgkin lymphoma, nasopharyngeal cancer, esophageal cancer, brain Tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary sarcoma, bile duct cancer. The compounds of the invention also include treating cancers that are resistant to one or more other treatments. The compounds of the present invention can also be used in diseases other than autoimmune diseases and cancer related to VEGFR-2 kinase and / or CSF1R kinase, including but not limited to fundus diseases, pulmonary fibrosis, liver fibrosis, Alzheimer's disease Wait. The compound of the present invention can be used as a monotherapy or a combination therapy, and can be used in combination with a plurality of compounds of the present invention or in combination with other drugs other than the present invention.
制药方法Pharmaceutical methods
本发明的制药方法包括对需要本发明化合物的受试者确定治疗有效量。“治疗有效剂量”依疾病的阶段、进展或严重程度而不同。本发明的化合物和组合物的每日剂量将取决于患者的多种因素，包括所治疗的病症、该病症的严重程度、所采用的具体化合物的药效、特定组合物、年龄、体重、一般健康状况、性别和饮食、给药的途径和时间表、代谢和/或所述化合物的排泄速率、治疗的持续时间等。此外，本发明的化合物所需剂量与药学上可接受的载体制成药剂后，可施用于人和其他动物。给药模式包括口服、直肠、肠胃外、脑池内、阴道内、腹膜内、局部(如通过透皮贴剂、粉剂、软膏、或滴剂)、舌下、经颊、或鼻喷雾等。本发明的化合物的有效剂量通常以每公斤患者体重所施药量来计量，优选于0.1～125毫克/千克体重，一般为0.01～500毫克/千克体重。给药可以是一次或多次、每天、每周、每隔一日或每隔多日、或一个间歇时间表。例如，所述化合物可以每天给药、每周给药(例如，每周一)、无限期给药或延续数周给药(例如4-10周)。本发明的化合物的有效剂量将根据所使用的化合物，给药模式、疾病的严重性、所治疗条件以及相关的患者的各种物理因素而变化。在多数情况下，当本发明的优选化合物的每日剂量约为0.01～500毫克/公斤时，可以达到令人满意的治疗效果。优选剂量为0.1～125毫克/千克，更优选的剂量为1～25毫克/千克。肠胃外给药剂量通常是在大约10％-20％的口服剂量水平。当本发明的化合物被用作组合治疗方案的一部分时，每一个组合物的组分将在一个所需的治疗期间被施用。无论是作为单独的剂量单元或者作为单一剂型包含两种组分，组合物中的组分可以在治疗期中同时施用，也可以在治疗期中的不同时间施用，或者某个可以作为另一个的预处理施用。The pharmaceutical method of the invention includes determining a therapeutically effective amount for a subject in need of a compound of the invention. A "therapeutically effective dose" will vary depending on the stage, progression or severity of the disease. The daily dosage of the compounds and compositions of the present invention will depend on a number of factors in the patient, including the condition being treated, the severity of the condition, the efficacy of the particular compound employed, the particular composition, age, weight, general Health status, gender and diet, route and schedule of administration, metabolism and / or excretion rate of the compound, duration of treatment, and the like. In addition, the required dose of the compound of the present invention can be administered to humans and other animals after being formulated with a pharmaceutically acceptable carrier. Modes of administration include oral, rectal, parenteral, intracranial, intravaginal, intraperitoneal, topical (eg, via transdermal patches, powders, ointments, or drops), sublingual, transbuccal, or nasal spray. The effective dose of the compound of the present invention is generally measured in terms of the amount administered per kg of the patient's body weight, preferably 0.1 to 125 mg / kg body weight, and generally 0.01 to 500 mg / kg body weight. Administration can be one or more times, daily, weekly, every other day or every other day, or an intermittent schedule. For example, the compound may be administered daily, weekly (e.g., every Monday), indefinitely, or for several weeks (e.g., 4-10 weeks). The effective dose of the compound of the present invention will vary depending on the compound used, the mode of administration, the severity of the disease, the condition to be treated, and various physical factors of the relevant patient. In most cases, a satisfactory therapeutic effect can be achieved when the daily dosage of the preferred compound of the present invention is about 0.01 to 500 mg / kg. A preferred dose is 0.1 to 125 mg / kg, and a more preferred dose is 1 to 25 mg / kg. The parenteral dose is usually at an oral dose level of about 10% -20%. When a compound of the invention is used as part of a combined treatment regimen, the components of each composition will be administered during a desired treatment period. Whether as a separate dosage unit or as a single dosage form containing two components, the components in the composition can be administered simultaneously during the treatment period, or at different times during the treatment period, or one can be used as a pretreatment for the other Apply.
关于化合物About compounds
本发明的化合物可以以游离的形式用于治疗，或者在适当情况下以药学上可接受的盐或其它衍生物的形式用于治疗。如本文所用，术语“药学上可接受的盐”是指本发明的化合物的有机盐及无机盐，此盐适用于人类和低等动物，无过度毒性、刺激性、过敏反应等，具有合理的利益/风险比。胺，羧酸，膦酸盐，和其它类型的化合物的药学上可接受的盐在所属领域中是众所周知的。该盐可以由本发明中分离纯化的化合物与合适的游离碱或酸反应而成。The compounds of the present invention can be used for treatment in free form or, where appropriate, in the form of a pharmaceutically acceptable salt or other derivative. As used herein, the term "pharmaceutically acceptable salt" refers to the organic and inorganic salts of the compounds of the present invention. This salt is suitable for humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and is 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 the compound isolated and purified in the present invention with a suitable free base or acid.
药学上无毒的酸形成的盐，包括但不限于，与无机酸如盐酸、氢溴酸、磷酸、硫酸、高氯酸或与有机酸如乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸、丙二酸形成的氨基盐，或通过使用本领域熟知的方法，例如离子交换法，来得到这些盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷、二葡糖酸盐、十二烷基硫 酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚、己酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲烷磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、过3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、戊酸盐等。代表性的碱或碱土金属盐包括钠、锂、钾、钙、镁、等。其他药学上可接受的盐包括适当的无毒的铵、季铵，和使用诸如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根，低级烷基磺酸盐和芳基磺酸盐形成的氨基阳离子。Salts formed from pharmaceutically non-toxic acids, including but not limited to, 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, These salts are obtained from amino salts of succinic acid, malonic acid, or by using methods well known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, and camphoric acid Salt, camphor sulfonate, citrate, cyclopentane, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glyceryl phosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lactate, lactate, laurate, lauryl sulfate, malate, Maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, paraben, pectate Salt, persulfate, per-3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate , P-toluenesulfonate, undecanoate, valerate, etc. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include appropriate non-toxic ammonium, quaternary ammonium, and use such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate Amino cations formed by acid salts.
另外，本文所用术语“前药”是指一个化合物在体内可以转化为本发明式(I)所示的化合物。此转化是通过前体药物在血液中水解或在血液或组织中经酶作用而转化为母体化合物的。In addition, the term "prodrug" as used herein means that a compound can be converted into a compound represented by formula (I) of the present invention in vivo. This transformation is converted to the parent compound by hydrolysis of the prodrug in the blood or by enzyme action in the blood or tissue.
组合物combination
本申请所述组合物是由本文所述任一个化合物(或前药、或其药学上可接受的盐、或其他药学上可接受的衍生物)，以及一种或多种药学上可接受的载体或赋形剂所组成。这些组合物可任选进一步包含一种或多种另外的治疗剂。本发明的化合物可以与一种或多种其它治疗方案(例如，Tofacitinib或其他激酶抑制剂、干扰素、骨髓移植、法尼基转移酶抑制剂、二膦酸盐、沙利度胺的施用组合、癌症疫苗、激素疗法、抗体、辐射等)共同施用于所需患者。化合物的药物组合物可以是另一种或多种抗炎剂或抗癌剂。The composition described herein is composed of any one of the compounds described herein (or a prodrug, or a pharmaceutically acceptable salt thereof, or other pharmaceutically acceptable derivative), and one or more pharmaceutically acceptable Carriers or excipients. These compositions may optionally further comprise one or more additional therapeutic agents. The compounds of the invention can be combined with the administration of one or more other treatment regimens (e.g., Tofacitinib or other kinase inhibitors, interferons, bone marrow transplants, farnesyl transferase inhibitors, bisphosphonates, thalidomide) , Cancer vaccines, hormone therapy, antibodies, radiation, etc.) are co-administered to the desired patient. The pharmaceutical composition of the compound may be another or more anti-inflammatory or anti-cancer agents.
如本文所述，本发明的组合物包含本发明的化合物与药学上可接受的载体和/或赋形剂，包括任何和所有溶剂、稀释剂或其它载体、分散或悬浮助剂、表面活性剂、等渗剂、增稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂等，以适合于所需的特定剂型。一些药学上可接受的载体材料的实例包括但不限于，糖，如乳糖、葡萄糖和蔗糖；淀粉如玉米淀粉和马铃薯淀粉；纤维素及其衍生物如羧甲基纤维素钠、乙基纤维素和醋酸纤维素；西黄蓍胶粉；麦芽；明胶；滑石粉；赋形剂，例如可可脂和栓剂蜡；油如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油；乙二醇，例如丙二醇；酯类如油酸乙酯和月桂酸乙酯、琼脂；缓冲剂例如氢氧化镁和氢氧化铝；藻酸；无热原水；等渗盐水；林格氏溶液；乙醇，和磷酸盐缓冲溶液，以及其它无毒的相容性润滑剂如月桂基硫酸钠和硬脂酸镁、以及着色剂、释放剂、包衣剂、甜味剂、调味剂和芳香剂、防腐剂和抗氧化剂也可以可存在于组合物中。As described herein, the composition of the invention comprises a compound of the invention and a pharmaceutically acceptable carrier and / or excipient, including any and all solvents, diluents or other carriers, dispersion or suspension aids, surfactants , Isotonicity agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., to suit the specific dosage form required. Examples of some pharmaceutically acceptable carrier materials include, but are not limited to, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose And cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil Ethylene glycol, such as propylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; Ethanol, and phosphate-buffered solutions, and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coatings, sweeteners, flavorants, and fragrances, Preservatives and antioxidants may also be present in the composition.
配方formula
本发明还涵盖本发明中的活性化合物与一种或多种药学上可接受的载体和/或稀释剂和/或佐剂联合使用的一类组合物(在本文中统称为“载体”材料)，并且如果需要的话，也包括其它活性成分。本发明的活性化合物可以通过任何合适的途径给药，优选以适合这种给 药途径的药物组合物的形式用于预期治疗所需的有效剂量。本发明的化合物和组合物的给药形式可以是，口服、粘膜、局部、直肠、经肺(如通过吸入喷雾)、或胃肠外，包括血管内、静脉内、腹膜内、皮下、肌内、胸骨内和输注技术。其给药是以剂量单位为准的制剂形式并含有药学上可接受的载体，佐剂，和赋形剂。对于口服给药，药物组合物可以是下列形式，例如，片剂、胶囊剂、混悬剂或液体。所述剂量单位的实例是片剂或胶囊。例如，它们可以包含活性成分的量为1至2000毫克，优选为1至500毫克，更常见的为5至200毫克。一个人或其它哺乳动物合适的每日剂量可根据患者和其他因素有所不同，但可以使用常规方法来再次确定。如前所述，本发明所涉及的化合物和/或组合物的给药和剂量方案中化合物的量取决于多种因素，包括受试者的年龄，体重，性别和医疗条件，疾病类型，该疾病严重程度，给药途径和频率，以及所使用的特定化合物。因此，剂量方案可以变化很大，但可使用标准方法来确定。典型的日剂量为0.01～500毫克/公斤体重，优选为0.1～125毫克/公斤体重，更优选为1～25毫克/公斤体重。The invention also encompasses a class of compositions (collectively referred to herein as "carrier" materials) in which the active compound of the invention is used in combination with one or more pharmaceutically acceptable carriers and / or diluents and / or adjuvants. And, if necessary, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition suitable for such route of administration, for the effective dose required for the intended treatment. The compounds and compositions of the present invention may be administered orally, mucosally, topically, rectally, via the lung (such as by inhalation spray), or parenterally, including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly , Intrasternal and infusion techniques. Its administration is in the form of a dosage unit, and contains pharmaceutically acceptable carriers, adjuvants, and excipients. For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. Examples of such dosage units are tablets or capsules. For example, they may contain the active ingredient in an amount of 1 to 2000 mg, preferably 1 to 500 mg, and more commonly 5 to 200 mg. The appropriate daily dose for a human or other mammal may vary depending on the patient and other factors, but can be determined again using conventional methods. As mentioned previously, the amount of compound in the administration and dosage regimen of the compounds and / or compositions according to the present invention depends on a variety of factors, including the subject's age, weight, gender and medical conditions, the type of disease, the Severity of the disease, route and frequency of administration, and the specific compound used. Therefore, the dosage regimen can vary widely, but can be determined using standard methods. A typical daily dose is 0.01 to 500 mg / kg body weight, preferably 0.1 to 125 mg / kg body weight, and more preferably 1 to 25 mg / kg body weight.
本发明的活性化合物通常与一种或多种佐剂、赋形剂或载体来组成给药途径。如果口服给药，所述化合物可以与乳糖、蔗糖、淀粉粉末、链烷酸纤维素酯、纤维素烷基酯、滑石、硬脂酸、硬脂酸镁、氧化镁、磷酸和硫酸的钠和钙盐、明胶、金合欢胶、藻酸钠、聚乙烯吡咯烷酮和/或聚乙烯醇相混合，然后压片或制成胶囊以方便给药。这样的胶囊剂或片剂可以包含一种控释制剂，可将活性化合物分散于羟丙基甲基纤维素来提供。适合于局部给药的制剂包括适于渗透穿过皮肤的液体或半液体制剂(如搽剂、洗剂、软膏剂、乳膏剂或糊剂)和适合施用于眼、耳或鼻的滴液。本发明的化合物适宜的局部给药剂量为0.1～150毫克，每日一至四次，优选每日1至2次。对于局部给药，使用软膏剂时，活性成分可与任何石蜡或水混溶性软膏为基质。或者，活性成分可以配制成油包水乳剂基质霜剂。如果需要，乳膏基质的水相可包括例如至少30％重量比的多元醇，如丙二醇、丁烷-1,3-二醇、甘露醇、山梨醇、甘油、聚乙二醇和它们的混合物。局部制剂可以包括能使通过皮肤或其它受影响区域增强活性成分吸收或渗透的化合物。此类真皮渗透增强剂的实例包括二甲基亚砜和相关类似物。化合物还可以通过透皮装置给药。优选透皮给药将使用含有储液器和多孔质膜或者固体基质的贴剂来实现。本发明的乳剂的油相可以由已知成分以已知方式构成，包含至少一种乳化剂与脂肪或油的混合物或与两者的脂肪和油的混合物。优选地，亲水性乳化剂可同时与作为稳定剂的亲脂性乳化剂合用，另外优选的是它也可以与油和脂肪合用。适合于在本发明的制剂中使用的乳化剂和乳液稳定剂包括吐温60、司盘80、鲸蜡硬脂醇、肉豆蔻醇、单硬脂酸甘油酯、月桂基硫酸钠、单一的二硬脂酸甘油酯或与其与乳化蜡的混合物，或本领域中公知的其他材料。乳膏应当优选不油腻、不着色和可洗的产品，并具有合适的稠度以避免从管或其他容器中渗漏。直链或支链、一元或二元烷基酯如二异己二酸酯、异十六烷基硬脂酸酯、椰子脂肪酸的丙二醇二酯、肉豆蔻酸异丙酯、油酸癸酯、棕榈酸异丙酯、硬脂酸丁酯、2-乙基己基棕榈酸酯或混合的支链的酯也可使用。作为选择，高熔点脂质如白色软石蜡和/或液体石蜡或其它矿物油都可以使用。适于局部给药至眼部的 制剂还包括滴眼剂，其中活性成分溶解或悬浮于合适的载体，特别是对于活性成分的水性溶剂。活性成分在这些制剂中重量比优选为0.5％至20％，更有利的比例是0.5～10％，最佳为约1.5％的浓度。制剂用于肠胃外给药可以是以水性或非水性的等渗无菌注射溶液或悬浮液的形式。这些溶液和悬浮液可以从一个或多个无菌粉末或颗粒，通过使用本文提到的用于口服给药的制剂或使用其他合适的分散剂或润湿剂和助悬剂的载体或稀释剂而制备。化合物可以溶解在水、聚乙二醇、丙二醇、乙醇、玉米油、棉籽油、花生油、芝麻油、苄醇、氯化钠、黄蓍胶、和/或各种缓冲液。其它辅助剂和给药方式是在制药领域中众所周知的。The active compounds of the present invention usually constitute an administration route with one or more adjuvants, excipients or carriers. If administered orally, the compound can be combined with lactose, sucrose, starch powder, cellulose alkanoates, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, phosphoric acid and sodium sulfate and Calcium salt, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone and / or polyvinyl alcohol are mixed and then compressed into tablets or capsules for convenient administration. Such capsules or tablets may contain a controlled release formulation, which may be provided by dispersing the active compound in hydroxypropyl methylcellulose. Formulations suitable for topical administration include liquid or semi-liquid formulations (such as tinctures, lotions, ointments, creams or pastes) suitable for penetration through the skin and drops suitable for administration to the eyes, ears or nose. A suitable topical dose of the compound of the present invention is 0.1 to 150 mg, one to four times a day, preferably one to two times a day. For topical administration, when using an ointment, the active ingredient can be used as a base with any paraffin or water-miscible ointment. Alternatively, the active ingredients can be formulated as a water-in-oil emulsion base cream. If desired, the aqueous phase of the cream base may include, for example, at least 30% by weight of a polyol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol, and mixtures thereof. Topical formulations may include compounds that enhance absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs. The compounds can also be administered via a transdermal device. Preferably, transdermal administration will be accomplished using a patch containing a reservoir and a porous membrane or a solid matrix. The oily phase of the emulsion of the present invention may be composed of known ingredients in a known manner, comprising a mixture of at least one emulsifier with a fat or oil or a mixture of both fats and oils. Preferably, the hydrophilic emulsifier can be used in combination with a lipophilic emulsifier as a stabilizer, and it is also preferable that it can also be used in combination with oil and fat. Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present invention include Tween 60, Span 80, cetylstearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, single dihydrate Glyceryl stearate or a mixture thereof with an emulsifying wax, or other materials known in the art. The cream should preferably be a non-greasy, non-coloring and washable product and have a suitable consistency to avoid leakage from a tube or other container. Linear or branched, mono- or di-alkyl esters such as diisoadipate, isohexadecyl stearate, propylene glycol diesters of coconut fatty acids, isopropyl myristate, decyl oleate, palm Isopropyl acid, butyl stearate, 2-ethylhexyl palmitate or mixed branched esters can also be used. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils can be used. Formulations suitable for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The weight ratio of the active ingredient in these preparations is preferably 0.5% to 20%, a more favorable ratio is 0.5 to 10%, and the most preferable concentration is about 1.5%. The formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions can be prepared from one or more sterile powders or granules, by using the formulations mentioned herein for oral administration or by using other suitable dispersing or wetting agents and suspending agents, carriers or diluents. While prepared. The compound can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth, and / or various buffers. Other adjuvants and modes of administration are well known in the pharmaceutical art.
所述活性成分还可以通过注射给药、与合适的载体包括盐水、葡萄糖或水的组合物、或者与环糊精(Captisol)、共溶剂增溶(即丙二醇)或胶束增溶(即吐温80)。制剂还可以是无菌注射溶液或在无毒的肠胃外可接受的稀释剂或溶剂中的悬浮液，例如1,3-丁二醇。可使用的溶剂有水、林格氏溶液和等渗氯化钠溶液。此外，无菌、不挥发性油通常用作溶剂或悬浮介质。用于此目的的任何温和的固定油都可以使用，包括合成的单或二甘油酯。The active ingredient may also be administered by injection, a composition with a suitable carrier including saline, dextrose or water, or solubilized with cyclodextrin (Captisol), a co-solvent (i.e., propylene glycol) or a micelle (i.e. Wen 80). The formulation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as 1,3-butanediol. The solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are commonly used as solvents or suspension media. Any mild fixed oil can be used for this purpose, including synthetic mono- or diglycerides.
对于肺部给药，所述药物组合物可以施用以气雾剂的形式或用吸入器，包括干粉气雾剂。用于直肠给药的栓剂可通过将药物与适宜的无刺激性赋形剂来制备，如可可脂和聚乙二醇在常温下是固体，但在直肠温度为液体，因此将在直肠中融化并释放出药物。该药物组合物可以加入常规的药物操作如灭菌和/或可以含有常规的佐剂，如防腐剂、稳定剂、润湿剂、乳化剂、缓冲剂等的片剂和丸剂还可用肠溶衣制备。这样的组合物还可以包含佐剂，如润湿剂、甜味剂、矫味剂和芳香剂。For pulmonary administration, the pharmaceutical composition may be administered in the form of an aerosol or with an inhaler, including a dry powder aerosol. Suppositories for rectal administration can be prepared by combining the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycol which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum And release the drug. The pharmaceutical composition can be added to conventional pharmaceutical operations such as sterilization and / or tablets and pills that can contain conventional adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc. can also be enteric coated preparation. Such compositions may also contain adjuvants such as wetting agents, sweeteners, flavoring agents, and fragrances.
本发明的药物组合物包含本文所述结构式(I)化合物或其药学上可接受的盐、激酶抑制剂(小分子，多肽，抗体等)、免疫抑制剂、抗癌药、抗病毒剂、抗炎剂、抗真菌剂、抗生素或抗血管过度增生化合物的另外的活性剂；以及任何药学上可接受的载体、佐剂或赋形剂。本发明的可替代的组合物包括具有本文所述式(I)的化合物或其药学上可接受的盐和药学上可接受的载体，佐剂或赋形剂。这样的组合物可任选地包含一种或多种额外治疗剂，包括，例如，激酶抑制剂(小分子，多肽，抗体等)、免疫抑制剂、抗癌剂、抗病毒剂、抗炎剂、抗真菌剂、抗生素或抗血管过度增生化合物。The pharmaceutical composition of the present invention comprises a compound of the formula (I) described herein or a pharmaceutically acceptable salt thereof, a kinase inhibitor (small molecule, polypeptide, antibody, etc.), an immunosuppressive agent, an anticancer drug, an antiviral agent, an antiviral agent Inflammatory agents, antifungals, antibiotics or additional active agents of an anti-hyperplasia compound; and any pharmaceutically acceptable carrier, adjuvant or excipient. Alternative compositions of the invention include a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or excipient as described herein. Such compositions may optionally include one or more additional therapeutic agents, including, for example, kinase inhibitors (small molecules, polypeptides, antibodies, etc.), immunosuppressants, anticancer agents, antiviral agents, anti-inflammatory agents , Antifungals, antibiotics or anti-hyperplasia compounds.
术语“药学上可接受的载体或佐剂”是指一种可与本发明的化合物一起被施用给患者的载体或佐剂，并且其不破坏药物活性，并且在剂量足以递送给药治疗量时是无毒的。药学上可接受的载体、佐剂和赋形剂可用于本发明的药物组合物，包括但不限于、离子交换剂、氧化铝、硬脂酸铝、卵磷脂、自乳化药物传递系统(SEDDS)、如d-atocopHerol聚乙二醇1000琥珀酸盐，药物剂型中使用的表面活性剂，如吐温或其他类似的聚合物递送基质，血清蛋白如人血清白蛋白，缓冲物质如磷酸盐，甘氨酸，山梨酸，山梨酸钾，饱和植物脂肪酸的偏甘油酯混合物中使用表面活性剂，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶体二氧化硅，三硅酸镁，聚乙烯吡咯烷酮，基于纤维素的物质，聚乙二醇，羧甲基纤维素钠，聚丙烯酸酯，蜡，聚乙烯-聚氧丙烯嵌段聚合物，聚乙 二醇和羊毛脂。环糊精如α-，β-，和γ-环糊精，或化学改性衍生物如羟基烷基，包括2和3-羟丙基-环糊精，或者其它溶解的衍生物也可有利地用于提高递送本文所述结构式的化合物。所述药物组合物可以任意使用可接受的剂型口服给药，包括但不限于胶囊，片剂，乳剂和水性悬浮液，分散体和溶液。在用于口服使用的片剂的情况下，通常使用的载体包括乳糖和玉米淀粉。润滑剂，诸如如硬脂酸镁，也通常被加入。对于以胶囊形式的口服给药，有用的稀释剂包括乳糖和干燥的玉米淀粉。当使用水性悬浮液和/或乳状液口服给药时，活性成分可与乳化和/或悬浮剂悬浮或溶解于油相中。如果需要，某些甜味剂，矫味剂和/或着色剂可以被加入。该药物组合物可以包括使用脂质体或微胶囊化技术，其不同的实施例在文献中可以查到。所述药物组合物可通过鼻气雾剂或吸入给药。这样的组合物是根据药物制剂领域中的已知技术制备的，并且可以在盐水中制备成溶液，采用苯甲醇或其它合适的防腐剂，吸收促进剂以提高生物利用度，碳氟化合物，和/或其它增溶剂或分散剂，其例子也是众所周知的现有技术。The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that can be administered to a patient with a compound of the present invention and does not destroy the pharmaceutical activity, and when the dosage is sufficient to deliver the therapeutic amount administered Is non-toxic. Pharmaceutically acceptable carriers, adjuvants, and excipients can be used in the pharmaceutical compositions of the present invention, including, but not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) Such as d-atocopHerol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, such as Tween or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine , Sorbic acid, potassium sorbate, partial glycerol esters of saturated vegetable fatty acids using surfactants, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, Colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polymer Glycol and lanolin. Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkyl, including 2 and 3-hydroxypropyl-cyclodextrin, or other dissolved derivatives may also be advantageous Ground is used to enhance the delivery of compounds of the formulae described herein. The pharmaceutical composition can be administered orally in any acceptable dosage form, including but not limited to capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricants, such as, for example, magnesium stearate, are also commonly added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When administered orally using aqueous suspensions and / or emulsions, the active ingredients may be suspended or dissolved in the oily phase with emulsifying and / or suspending agents. If desired, certain sweetening, flavoring and / or coloring agents may be added. The pharmaceutical composition may include the use of liposomes or microencapsulation techniques, different examples of which can be found in the literature. The pharmaceutical composition can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques known in the art of pharmaceutical formulations and can be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorocarbons, and And / or other solubilizers or dispersants, examples of which are also well known in the art.
联合用药Combination medication
本发明的化合物可以作为单独使用，也可以与一种或多种其它本发明的化合物或与一种或多种其它药剂联合使用。当联合给药时，治疗剂可以配制成同时给药或顺序地在不同的时间给药，或者所述治疗剂可以作为单一组合物给药。所谓“组合疗法”，指的是使用本发明的化合物与另一种药剂一起使用，给药方式为每种药剂同时共同给药或每种药剂顺序给药，无论哪种情况，目的都是要达到药物的最佳效果。共同给药包括同时递送剂型，以及每种化合物分别的单独剂型。因此，本发明的化合物的给药可以与已知的本领域的其他疗法同时使用，例如，在癌症治疗中使用放射治疗或细胞生长抑制剂、细胞毒性剂、其它抗癌剂等附加疗法来改善癌症状。本发明并不限于给药的顺序；本发明的化合物可以先前施用，同时施用，或在其他抗癌剂或细胞毒性剂之后施用。The compounds of the present invention can be used alone or in combination with one or more other compounds of the present invention or with one or more other agents. When administered in combination, the therapeutic agents can be formulated to be administered simultaneously or sequentially at different times, or the therapeutic agents can be administered as a single composition. The so-called "combination therapy" refers to the use of the compound of the present invention together with another agent. The method of administration is simultaneous administration of each agent or sequential administration of each agent. In either case, the purpose is to To achieve the best results of the drug. Co-administration includes simultaneous delivery of the dosage forms, as well as separate dosage forms for each compound. Therefore, the administration of the compounds of the present invention can be used concurrently with other known therapies in the art, for example, the use of radiation therapy or additional therapies such as cytostatic agents, cytotoxic agents, and other anticancer agents in cancer treatment to improve Symptoms of cancer. The invention is not limited to the order of administration; the compounds of the invention may be administered previously, concomitantly, or after other anticancer or cytotoxic agents.
以上所述仅为本发明的较佳实施方式而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。The above are only the preferred embodiments of the present invention, and are not intended to limit the present invention. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention shall be included in the protection of the present invention. Within range.

Claims (11)

  1. 一种结构式(I)的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药：A compound of formula (I), its isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
    Figure PCTCN2019101623-appb-100001
    Figure PCTCN2019101623-appb-100001
    其中，among them,
    Q为N或者CH；Q is N or CH;
    G为O或者NH；G is O or NH;
    R 1为-H，或由1至3个选自C 1-C 6的烷氧基、C 1-C 6的烷硫基、C 1-C 3酰基、羟基、卤素、三氟甲基、氰基、-CONH 2、氧代(＝O)或-NR aR b中的取代基所取代或者非取代的C 3-C 8的环烷基，或由1至3个选自C 1-C 6的烷氧基、C 1-C 6的烷硫基、C 1-C 3酰基、羟基、卤素、三氟甲基、氰基、-CONH 2、C 3-C 7的环烷基或-NR aR b的取代基所取代或者非取代的C 1-C 10烷基，或-(CH 2)n-R 6，所述R 6为取代或者非取代的4-8元杂脂环基，所述4-8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4-8元杂脂环基，且所述取代的4-8元杂脂环基被1至3个选自卤素、C 1-C 3的烷基、C 1-C 3的烷氧基、C 1-C 3的烷硫基、羟基、-NR aR b、C 1-C 3酰基、氧代中的取代基所取代，n为0至10， R 1 is -H, or consists of 1 to 3 alkoxy groups selected from C 1 -C 6 , alkylthio groups of C 1 -C 6 , C 1 -C 3 acyl groups, hydroxy, halogen, trifluoromethyl, C 3 -C 8 cycloalkyl substituted or unsubstituted by substituents in cyano, -CONH 2 , oxo (= O) or -NR a R b , or from 1 to 3 selected from C 1- C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 3 acyl, hydroxyl, halogen, trifluoromethyl, cyano, -CONH 2 , C 3 -C 7 cycloalkyl or substituent or unsubstituted C -NR a R b in 1 -C 10 alkyl, or - (CH 2) nR 6, R 6 is a substituted or unsubstituted 4-8 membered heteroalicyclic group, The 4-8 membered heteroalicyclic group is a 4-8 membered heteroalicyclic group containing 1-2 atoms selected from N, O, S as ring atoms, and the substituted 4-8 membered heteroalicyclic group The cyclic group is 1 to 3 selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, hydroxyl, -NR a R b , C 1 -C 3 acyl, substituted by substituents in oxo, n is 0 to 10,
    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烷基或者单或双C 1-C 3烷基取代或非取代氨基取代的C 1-C 6烷基； 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 3 -alkylthio-substituted C 1 -C 6 alkyl or mono- or di-C 1 -C 3 alkyl-substituted or unsubstituted amino-substituted C 1 -C 6 alkyl;
    R 2、R 3各自独立地为-H、-CF 3、卤素、C 1-C 3的烷基、C 1-C 3的烷氧基； R 2 and R 3 are each independently -H, -CF 3 , halogen, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;
    R 4为-H，C 1-C 3烷基； R 4 is -H, C 1 -C 3 alkyl;
    R 5为-(CH 2) mR 7，其中m为0-3整数，所述R 7为由一个至两个取代基-A所取代或者非取代的芳基或杂芳基，所述取代基-A各自独立地为C 1-C 3的烷基、C 1-C 3的烷氧基、C 1-C 3的烷硫基、卤素、三氟甲基或甲砜基， R 5 is-(CH 2 ) m R 7 , where m is an integer from 0 to 3, the R 7 is an aryl or heteroaryl group substituted or unsubstituted by one to two substituents -A, the substitution -A are each independently C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, halogen, trifluoromethyl or methylsulfone,
    所述杂芳基为含有1-3个选自N、O、S中的杂原子作为环原子、且含有5至10个环原子的单环或双环杂芳基。The heteroaryl group is a monocyclic or bicyclic heteroaryl group containing 1-3 heteroatoms selected from N, O, and S as ring atoms and containing 5 to 10 ring atoms.
  2. 如权利要求1所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中，R 1为-H，或非取代的C 3-C 8的环烷基，或由1至3个选自C 1-C 6的烷氧基、C 1-C 6的烷硫基、C 1-C 3酰基、羟基、-F、三氟甲基、氰基、-CONH 2、C 3-C 6的环烷基或-NR aR b 的取代基所取代或者非取代的C 1-C 8烷基， C compound according to claim 1, their isomers, hydrates, solvates, pharmaceutically acceptable salt or prodrug thereof, wherein, R 1 is -H, or unsubstituted cycloalkyl of 3 -C 8 Or 1 to 3 selected from C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 3 acyl, hydroxyl, -F, trifluoromethyl, cyano, -CONH 2 , C 3 -C 6 cycloalkyl or -NR a R b substituted or unsubstituted C 1 -C 8 alkyl,
    或-(CH 2)n-R 6，所述R 6为取代或者非取代的4-8元杂脂环基，所述4-8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4-8元杂脂环基，且所述取代的4-8元杂脂环基被1至3个选自-F、C 1-C 3的烷基、C 1-C 3的烷氧基、羟基、-NR aR b、C 1-C 3酰基、氧代中的取代基所取代，n为0至8， Or-(CH 2 ) nR 6 , wherein R 6 is a substituted or unsubstituted 4-8 member heteroalicyclic group, and the 4-8 member heteroalicyclic group contains 1-2 members selected from N, O, The atom in S is a 4-8 membered heteroalicyclic group as a ring atom, and the substituted 4-8 membered heteroalicyclic group is substituted by 1 to 3 alkyl groups selected from -F, C 1 -C 3 , C 1- C 3 alkoxy, hydroxy, -NR a R b , C 1 -C 3 acyl, substituents in oxo, n is 0 to 8,
    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、或者C 1-C 3烷氧基取代的C 1-C 6烷基。 R a and R b are each independently -H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 3 alkoxy-substituted C 1 -C 6 alkyl.
  3. 如权利要求2所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中，R 1为-H，非取代的C 3-C 6的环烷基，由1至3个选自C 1-C 3的烷氧基、C 1-C 3的烷硫基、C 1-C 3酰基、羟基、-F、三氟甲基、氰基、-CONH 2、C 3-C 5的环烷基或-NR aR b的取代基所取代或者非取代的C 1-C 8烷基， The compound, isomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof according to claim 2, wherein R 1 is -H, an unsubstituted C 3 -C 6 cycloalkyl group , From 1 to 3 selected from C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, C 1 -C 3 acyl, hydroxyl, -F, trifluoromethyl, cyano, -CONH 2 , C 3 -C 5 cycloalkyl or -NR a R b substituted or unsubstituted C 1 -C 8 alkyl,
    或-(CH 2) n-R 6，所述R 6为取代或者非取代的4-6元杂脂环基，所述4-6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4-6元杂脂环基，且所述取代的4-6元杂脂环基被1至3个选自-F、C 1-C 3的烷基、C 1-C 3的烷氧基、羟基、-NR aR b、C 1-C 3酰基、氧代中的取代基所取代，n为0至6， Or-(CH 2 ) n -R 6 , wherein R 6 is a substituted or unsubstituted 4-6 membered heteroalicyclic group, and the 4-6 membered heteroalicyclic group contains 1-2 members selected from N, A 4- to 6-membered heteroalicyclic group of an atom in O, S as a ring atom, and the substituted 4-6-membered heteroalicyclic group is substituted by 1 to 3 alkyl groups selected from -F, C 1 -C 3 , C 1 -C 3 alkoxy, hydroxyl, -NR a R b , C 1 -C 3 acyl, substituents in oxo, n is 0 to 6,
    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、或者C 1-C 3烷氧基取代的C 1-C 3烷基。 R a and R b are each independently -H, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 3 alkoxy-substituted C 1 -C 3 alkyl.
  4. 如权利要求3所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中，R 1为-H，环丙基，环丁基，环戊基，环己基，或者由1至3个选自甲氧基、乙氧基、甲硫基、乙硫基、甲酰基、乙酰基、羟基、-F、三氟甲基、氰基、-CONH 2、环丙基、环丁基、环戊基、-NR aR b的取代基所取代或者非取代的C 1-C 6烷基，或-(CH 2)n-R 6，所述R 6为取代或者非取代的4-6元杂脂环基，所述4-6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4-6元杂脂环基，且所述取代的4-6元杂脂环基被1至3个选自-F、甲基、乙基、羟基、氨基、乙酰基、甲酰基、三氟甲基、氰基、氧代中的取代基所取代，n为0至6， The compound as claimed in claim 3, acceptable isomers, hydrates, solvate, pharmaceutically acceptable salt or prodrug thereof, wherein, R 1 is -H, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, or from 1 to 3 selected from methoxy, ethoxy, methylthio, ethylthio, formyl, acetyl, hydroxyl, -F, trifluoromethyl, cyano, -CONH 2 , Cyclopropyl, cyclobutyl, cyclopentyl, -NR a R b substituted or unsubstituted C 1 -C 6 alkyl, or-(CH 2 ) nR 6 , where R 6 is substituted or Unsubstituted 4-6 membered heteroalicyclic group, said 4-6 membered heteroalicyclic group is a 4-6 membered heteroalicyclic group containing 1-2 atoms selected from N, O, S as ring atoms And the substituted 4-6 membered heteroalicyclic group is selected from 1 to 3 selected from -F, methyl, ethyl, hydroxyl, amino, acetyl, formyl, trifluoromethyl, cyano, oxo Is substituted with a substituent in, n is 0 to 6,
    所述4-6元杂脂环基选自4-6元氧杂环烷基，或4-6元氮杂环烷基，或4-6元硫杂环烷基，或以下基团：The 4-6 membered heteroalicyclic group is selected from a 4-6 membered oxetanyl group, or a 4-6 membered azacycloalkyl group, or a 4-6 membered thiacycloalkyl group, or the following groups:
    Figure PCTCN2019101623-appb-100002
    Figure PCTCN2019101623-appb-100002
    R a和R b各自独立地为-H、甲基、乙基、甲氧基甲基、甲氧基乙基、甲氧基丙基、环丙基、或者环丁基。 R a and R b are each independently -H, methyl, ethyl, methoxymethyl, methoxyethyl, methoxypropyl, cyclopropyl, or cyclobutyl.
  5. 如权利要求1所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中，R 2、R 3各自独立地为-H、-CF 3、-F、-Cl、甲基、乙基、甲氧基或者乙氧基。 The compound, isomer, hydrate, solvate, pharmaceutically acceptable salt, or prodrug thereof according to claim 1, wherein R 2 and R 3 are each independently -H, -CF 3 , -F , -Cl, methyl, ethyl, methoxy or ethoxy.
  6. 如权利要求1所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中，R 4为H，甲基或者乙基。 The compound, isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein R 4 is H, methyl or ethyl.
  7. 如权利要求1所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中，R 5为-(CH 2) mR 7，其中m为0-3整数，所述R 7为由一个至两个取代基-A所取代或者非取代的芳基或杂芳基，所述取代基-A各自独立地为C 1-C 3的烷基、C 1-C 3的烷氧基、C 1-C 3的烷硫基、-F、-Cl、三氟甲基或甲砜基， The compound, isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to claim 1, wherein R 5 is-(CH 2 ) m R 7 , wherein m is 0-3 An integer, wherein R 7 is an aryl or heteroaryl group substituted or unsubstituted by one to two substituents -A, each of which is independently a C 1 -C 3 alkyl group, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, -F, -Cl, trifluoromethyl or methylsulfone,
    所述芳基为苯基、萘基、菲基，所述杂芳基为吡咯基、呋喃基、吡啶基、噻吩基、咪唑基、噻唑基、异噻唑基、吲唑基、吲哚基、吲唑基、异吲哚基、二氢吲哚基、异二氢吲哚基、异喹啉基、吲嗪基、异噁唑基、1,5-萘啶基、1,6-萘啶酮基、噁二唑基、噁唑基、1-苯基-1H-吡咯基、吩嗪基、吩噻嗪基、吩噁嗪基、酞嗪基、蝶啶基、嘌呤基、吡喃基、吡唑基、吡唑并[3,4-d]嘧啶基、吡啶基、吡啶并[3,2-d]嘧啶基、吡啶并[3,4-d]嘧啶基、吡嗪基、嘧啶基、哒嗪基、喹唑啉基、喹喔啉基、喹啉基、异喹啉基。The aryl group is phenyl, naphthyl, phenanthryl, and the heteroaryl group is pyrrolyl, furyl, pyridyl, thienyl, imidazolyl, thiazolyl, isothiazolyl, indazolyl, indolyl, Indazolyl, isoindolyl, dihydroindolyl, isodihydroindolyl, isoquinolinyl, indazinyl, isoxazolyl, 1,5-naphthyridinyl, 1,6-naphthyridine Keto, oxadiazolyl, oxazolyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl , Pyrazolyl, pyrazolo [3,4-d] pyrimidinyl, pyridyl, pyrido [3,2-d] pyrimidinyl, pyrido [3,4-d] pyrimidinyl, pyrazinyl, pyrimidine , Pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl.
  8. 如权利要求1至7中任一项所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，其中，所述化合物选自：The compound according to any one of claims 1 to 7, its isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein the compound is selected from:
    Figure PCTCN2019101623-appb-100003
    Figure PCTCN2019101623-appb-100003
    Figure PCTCN2019101623-appb-100004
    Figure PCTCN2019101623-appb-100004
    Figure PCTCN2019101623-appb-100005
    Figure PCTCN2019101623-appb-100005
    Figure PCTCN2019101623-appb-100006
    Figure PCTCN2019101623-appb-100006
    Figure PCTCN2019101623-appb-100007
    Figure PCTCN2019101623-appb-100007
    Figure PCTCN2019101623-appb-100008
    Figure PCTCN2019101623-appb-100008
    Figure PCTCN2019101623-appb-100009
    Figure PCTCN2019101623-appb-100009
    Figure PCTCN2019101623-appb-100010
    Figure PCTCN2019101623-appb-100010
    Figure PCTCN2019101623-appb-100011
    Figure PCTCN2019101623-appb-100011
    Figure PCTCN2019101623-appb-100012
    Figure PCTCN2019101623-appb-100012
    Figure PCTCN2019101623-appb-100013
    Figure PCTCN2019101623-appb-100013
  9. 权利要求1至7中任一项所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药在制备治疗与VEGFR-2和/或CSF1R相关疾病的药物中的应用，其中，所述与VEGFR-2和/或CSF1R相关的疾病包括阿尔兹海默病、眼底疾病、干眼症、银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、系统性红斑狼疮、克罗恩病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、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。The compound according to any one of claims 1 to 7, an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof in the manufacture of a medicament for the treatment of diseases related to VEGFR-2 and / or CSF1R Application, wherein the diseases related to VEGFR-2 and / or CSF1R include Alzheimer's disease, fundus disease, dry eye disease, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis , Multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atherosclerosis, pulmonary fibrosis, liver fibrosis, bone marrow fibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma Glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic granulocyte Leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary sarcoma, and bile duct cancer.
  10. 一种药物组合物，包括权利要求1至7中任一项所述的化合物、其异构体、水合物、溶剂化物、药学上可接受的盐或前药，以及一种或多种药学上可接受的载体或赋形剂。A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, its isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, and one or more pharmaceutically acceptable An acceptable carrier or excipient.
  11. 权利要求10所述的药物组合物，还包括一种或多种其他治疗剂。The pharmaceutical composition of claim 10, further comprising one or more other therapeutic agents.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104530063A (en) * 2015-01-13 2015-04-22 北京达立泰制药科技有限公司 Quinazoline and heterocyclic ring compounds, preparing method of compounds, and application of compounds serving as epidermal growth factor receptor inhibitors used for treating cancer
CN105837586A (en) * 2015-12-14 2016-08-10 北京赛特明强医药科技有限公司 Dioxanoquinazoline amine compound and preparation method thereof, and application of dioxanoquinazoline amine compound as epidermal growth factor receptor inhibitor
WO2019154132A1 (en) * 2018-02-11 2019-08-15 北京赛特明强医药科技有限公司 Urea-substituted aromatic ring-linked dioxazoline compound, preparation method therefor, and uses thereof

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL112249A (en) * 1994-01-25 2001-11-25 Warner Lambert Co Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds
EP1535910A4 (en) * 2002-05-01 2007-03-14 Kirin Brewery Quinoline derivatives and quinazoline derivatives inhibiting autophosphorylation of macrophage colony stimulating factor receptor
BR0314353A (en) * 2002-09-17 2005-07-19 Actelion Pharmaceuticals Ltd Compounds, pharmaceutical compositions, use of one or more compounds in combination with other pharmacologically active compounds, and method for treating a patient suffering from a disorder.
EP1566379A4 (en) * 2002-10-29 2005-11-09 Kirin Brewery QUINOLINE DERIVATIVES AND QUINAZOLINE DERIVATIVES INHIBITING AUTOPHOSPHORYLATION OF Flt3 AND MEDICINAL COMPOSITIONS CONTAINING THE SAME
ES2466818T3 (en) * 2003-09-26 2014-06-11 Exelixis, Inc. C-Met modulators and methods of use
DK2268623T3 (en) * 2008-03-17 2015-06-29 Ambit Biosciences Corp QUINAZOLINE DERIVATIVES AS RAF CHINESE MODULATORS AND PROCEDURES FOR USE THEREOF
CN102532042A (en) * 2010-12-30 2012-07-04 上海医药工业研究院 Aryl urea compound as well as intermediate and application thereof
CN103382206B (en) * 2012-05-04 2016-09-28 上海恒瑞医药有限公司 Quinoline or quinazoline derivative, its preparation method and in application pharmaceutically
CN104230826B (en) * 2013-06-08 2017-03-29 复旦大学 2 fluoro quinazoline cyclics and preparation method thereof and pharmaceutical usage
CN108341813B (en) * 2017-01-24 2020-11-17 四川大学 Substituted 1- (isoxazol-3-yl) -3- (3-fluoro-4-phenyl) urea derivative and preparation method and application thereof
CN108530455B (en) * 2017-03-01 2021-01-12 北京赛特明强医药科技有限公司 Urea substituted aromatic ring connecting dioxane and quinazoline compound or medicinal salt or hydrate and application as tyrosine kinase inhibitor

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104530063A (en) * 2015-01-13 2015-04-22 北京达立泰制药科技有限公司 Quinazoline and heterocyclic ring compounds, preparing method of compounds, and application of compounds serving as epidermal growth factor receptor inhibitors used for treating cancer
CN105837586A (en) * 2015-12-14 2016-08-10 北京赛特明强医药科技有限公司 Dioxanoquinazoline amine compound and preparation method thereof, and application of dioxanoquinazoline amine compound as epidermal growth factor receptor inhibitor
WO2019154132A1 (en) * 2018-02-11 2019-08-15 北京赛特明强医药科技有限公司 Urea-substituted aromatic ring-linked dioxazoline compound, preparation method therefor, and uses thereof

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