WO2020042972A1 - Composé de dioxane et de quinazoline ou de quinoléine lié à un cycle aromatique substitué par urée, composition et utilisation associée - Google Patents

Composé de dioxane et de quinazoline ou de quinoléine lié à un cycle aromatique substitué par urée, composition et utilisation associée 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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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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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

La présente invention concerne un nouveau composé servant de VEGFR-2 et de CSF1R, une composition, et une utilisation associée. Plus particulièrement, la présente invention concerne un composé (tel que représenté par la formule (I)) capable d'inhiber fortement des activités de VEGFR-2 et de CSF1R, ou des isomères, solvates, hydrates, sels pharmaceutiquement acceptables et promédicaments de celui-ci, ainsi qu'une composition pharmaceutique comprenant ledit composé. L'invention concerne également une utilisation du composé ou de la composition pharmaceutique selon la présente invention dans la préparation de médicaments, le médicament étant utilisé pour traiter des maladies telles que des maladies auto-immunes, des tumeurs et la maladie d'Alzheimer. (I)
PCT/CN2019/101623 2018-08-27 2019-08-20 Composé de dioxane et de quinazoline ou de quinoléine lié à un cycle aromatique substitué par urée, composition et utilisation associée WO2020042972A1 (fr)

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