WO2018157730A1

WO2018157730A1 - Urea-substituted aromatic ring-linked dioxane-quinazoline and -linked dioxane-quinoline compounds, preparation method therefor and use thereof

Info

Publication number: WO2018157730A1
Application number: PCT/CN2018/076232
Authority: WO
Inventors: 张强; 张宏波; 杨磊夫; 杨海龙; 周利凯; 郑南桥; 于善楠; 王钟祥; 冯守业; 徐占强
Original assignee: 北京赛特明强医药科技有限公司
Priority date: 2017-03-01
Filing date: 2018-02-11
Publication date: 2018-09-07

Abstract

The present invention relates to a urea-substituted aromatic ring-linked dioxane-quinazoline compound of formula (1) and a urea-substituted aromatic ring-linked dioxane-quinoline, or a pharmaceutically acceptable salt thereof or a hydrate thereof. Also provided are the preparation of the compound as shown in formula (1) and the pharmaceutically acceptable salt thereof and the use thereof as a drug. The drug is used as an inhibitor of tyrosine kinases (e.g., VEGFR-2, C-RAF, B-RAF) for treating tyrosine kinase-related diseases.

Description

Urea-substituted aromatic ring dioxane quinazoline and dioxane quinolinol compound and preparation method and application thereof

Technical field

The invention relates to a urea-substituted aromatic ring dioxane quinazoline and a dioxane quinolin compound, and a preparation method and application thereof, and belongs to the technical field of medicinal chemistry.

Background technique

Angiogenesis and angiogenesis must have the presence of VEGF (vascular endothelial growth factor). During embryogenesis, angiogenesis is divided into two phases: angiogenesis and angiogenesis. Angiogenesis is the differentiation of primitive progenitor cells into endothelial cells. Cells; angiogenesis is the growth of new capillaries from existing blood vessels in the form of budding. Normal adult mammals have only one form of angiogenesis, namely angiogenesis, local basement membrane breakdown around endothelial cells, and endothelial cell invasion into the stroma. This invasion is accompanied by the proliferation of endothelial cells, which form a migrating column of endothelial cells that change shape and form a ring shape, and a new vascular lumen is formed.

VEGF is also essential for angiogenesis of tumor tissues, and vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor receptor 2 (VEGFR-2) signaling pathways play the most important role in affecting the proliferation of tumor tissue endothelial cells. Survival, budding, migration, affecting the permeability of tumor blood vessels. In the absence of VEGF protein-stimulated endothelial cells, autocrine VEGF proteins can also be relied upon to ensure their integrity and survival. Vascular endothelial growth factor C VEGFR-C/vascular endothelial growth factor D VEGF-D mediates lymphangiogenesis in tumor tissues and promotes metastasis of tumor tissues. Therefore, drugs targeting angiogenesis have become a hot spot for drug development.

Bevacizumab is a 93% humanized murine VEGF monoclonal antibody that binds to all subtypes of human VEGF A, blocks the VEGF/VEGFR signaling pathway, and inhibits tumor angiogenesis. In 2004, bevacizumab (trade name Avastin) was marketed in the United States with FDA approval and used in combination with chemotherapeutic drugs as the first line of anti-tumor angiogenesis drugs for the treatment of metastatic colorectal cancer. Bevacizumab can improve the abnormalities of tumor blood vessels, making them normalized and helping chemotherapy drugs reach tumor tissues. Due to the mechanism of apoptosis induced by radiotherapy and chemotherapy, the hypoxic partial pressure in tumor tissues induces the expression of VEGF, and the combination of bevacizumab and chemoradiotherapy drugs effectively prevents such secondary reactions.

To date, targeting VEGFR-2/KDR includes nine drugs: sorafenib, sunitinib, pazopanib, axitinib, vandetanib, regorafenib, lenvatinib, nintedanib and silidini Cloth (AZD2171), which has been approved by the FDA for the treatment of cancer.

Lenvatinib, trade name Lenvima, is a thyroid cancer drug developed by Eisai Corporation of Japan. It has specific inhibitory effects on VEGFR-1, VEGFR-2 and VEGFR-3, and also acts on PDGFRβ and FGFR-1. It is a class of TKIs that selectively target multiple receptors. Similar to the mechanism of action of sorafenib, it inhibits neovascularization by inhibiting VEGFR-1, 2, 3 and PDGFR, and directly inhibits tumor cell proliferation by inhibiting FGFR-1. In 2015, the FDA approved Lenvatinib for the treatment of thyroid cancer.

B-RAF is a kind of tyrosine kinase receptor, and its abnormal activation plays an important role in the occurrence and development of various malignant tumors. In most cases, abnormal activation of B-RAF is caused by genetic mutations. B-RAF belongs to the proto-oncogene, and studies have shown that more than 30 B-RAF gene mutations are associated with cancer, especially the V600E gene mutation. Mutations in the B-RAF gene usually cause two diseases. First, mutations can be inherited and cause birth defects. Second, as oncogenes, mutations inherited by genetics can lead to cancer in later life. B-RAF mutations have been found in many cancer tissues, including melanoma, colon cancer, thyroid cancer, non-small cell lung cancer, and glioma.

Sorafenib, trade name Nexavar, is a drug developed by Onyx Pharmaceuticals of the United States and Bayer AG of Germany, targeting the RAF/MEK/ERK signaling pathway, which mainly inhibits C-RAF and B-RAF, and also inhibits VEGFR-2. The activities of VEGFR-3, PDGFR-β, Flt-3, and c-Kit receptors can effectively inhibit tumor cell proliferation and angiogenesis in preclinical experiments. In a clinical phase III trial of metastatic renal cell carcinoma, sorafenib significantly increased the overall survival of the patient. In July 2005, sorafenib was approved by the FDA as a drug for the treatment of advanced renal cell carcinoma.

Similar to Lenvatinib and Sorafenib, there are many advantages to multi-target inhibitors, and research on this type of inhibitor is also very hot. However, there are still few similar drugs currently on the market, the channels available are limited, and the drugs on the market are subject to drug resistance and side effects. Therefore, this multi-target small molecule inhibitor will have better therapeutic effects and application prospects than the single target inhibitors already on the market.

Summary of the invention

In view of the deficiencies of the prior art, the present invention provides a compound of formula (I), and pharmaceutically acceptable salts, isomers, hydrates, solvates, or prodrugs thereof,

In formula (I),

X is O or NH;

Y is N or CH;

Z is N or CH;

R ¹ is H, C ₁ -C ₉ alkyl, C ₃ -C ₇ cycloalkyl, 4-7 membered heterocyclic, C ₃ -C ₇ cycloalkyl substituted C ₁ -C ₆ alkyl a 4-7 membered heterocyclic substituted C ₁ -C ₆ alkyl group, substituted C ₁ -C ₉ alkyl group, the substituent in the substituted C ₁ -C ₉ alkyl group is a hydroxyl group, C ₁ -C _{One or more of a 6} -alkoxy group, a C ₁ -C ₆ alkylthio group, a mono- or bi-C ₁ -C ₆ alkyl-substituted amino group or an unsubstituted amino group,

The above 4-7 membered heterocyclic group is a 4-7 membered heterocyclic group having 1 to 2 atoms selected from N, O and S, and the 4-7 membered heterocyclic group is not substituted or C ₁ -C ₆ An alkyl group, a C ₁ -C ₃ acyl group substituted or oxidized by one to two oxygen atoms;

R ² is H or halogen;

R ³ is H or halogen;

R ⁴ is H or halogen;

R ⁵ is H, C ₁ -C ₉ alkyl, C ₃ -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkyl substituted C ₁ -C ₆ alkyl, substituted or unsubstituted aryl Or a heteroaryl group, the substituted aryl or heteroaryl substituent being C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, mono or di C ₁ One or more of -C ₃ substituted amino or unsubstituted amino, halogen, trifluoromethyl, aryloxy or methylsulfonyl;

The heteroaryl group is a monocyclic or bicyclic group having 5 to 10 ring atoms, and the ring contains 1-3 atoms selected from N, O, and S.

In a preferred embodiment, R ¹ is H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 5-6 membered heterocyclyl, C ₃ -C ₆ cycloalkyl substituted C ₁ a C ₃ alkyl group, a 5-6 membered heterocyclic group-substituted C ₁ -C ₃ alkyl group, a substituted C ₁ -C ₆ alkyl group, wherein the substituent in the substituted C ₁ -C ₆ alkyl group is a hydroxyl group, One or more of a C ₁ -C ₃ alkoxy group, a C ₁ -C ₃ alkylthio group, a mono- or bi-C ₁ -C ₃ alkyl-substituted amino group or an unsubstituted amino group,

The above 5- to 6-membered heterocyclic group is a 5-6 membered heterocyclic group having 1 to 2 atoms selected from N, O and S, and the 5-6 membered heterocyclic group is not substituted or C ₁ -C ₃ The alkyl group, C ₁ -C ₃ acyl group is substituted or oxidized by one to two oxygen atoms.

In a preferred embodiment, R ^{1 is} selected from the group consisting of: H, methyl, ethyl, propyl, isopropyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, Methoxyhexyl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydropyrrole-1-ethyl, tetrahydropyrrole-1-propyl, morpholin-4-ethyl, Porphyrin-4-propyl, methylpiperazine-4-ethyl, methylpiperazine-4-propyl, N-formylpiperazine-4-ethyl, N-formylpiperazine-4-propyl , N-acetylpiperazine-4-ethyl, N-acetyl piperazine-4-propyl, (1,1-dioxothiomorpholinyl)-4-ethyl, (1,1-di Oxythiomorpholinyl)-4-propyl, methylthioethyl, methylthiopropyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, diethylaminoethyl, two Ethylaminopropyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, aminoethyl, aminopropyl, aminobutyl, 2-methyl-2-hydroxypropyl, 3-methyl 3-hydroxybutyl, (3S)-3-aminobutyl, (3R)-3-aminobutyl, (3S)-3-hydroxybutyl or (3R)-3-hydroxybutyl.

In a preferred embodiment, the halogen of R ² , R ³ , R ⁴ is F, Cl or Br.

In a preferred embodiment, R ⁵ is H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkyl substituted C ₁ -C ₃ alkyl, substituted Or an unsubstituted aryl or heteroaryl group, the substituted aryl or heteroaryl substituent being a C ₁ -C ₃ alkyl group, a C ₁ -C ₃ alkoxy group, a C ₁ -C ₃ group One or more of an alkylthio group, a mono- or bi-C ₁ -C ₃ -substituted amino group or an unsubstituted amino group, a halogen, a trifluoromethyl group, an aryloxy group or a methylsulfone group;

The heteroaryl group is a monocyclic or bicyclic group having 5 to 10 ring atoms, and the ring contains 1-2 atoms selected from N, O, and S.

In a preferred embodiment, R ⁵ is H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkyl substituted C ₁ -C ₃ alkyl, substituted or non. a substituted phenyl, naphthyl or heteroaryl group wherein the substituent of the phenyl, naphthyl or heteroaryl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy Base, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, amino, methylamino, ethylamino, dimethylamino, diethylamino, fluoro, chloro, bromo, trifluoromethyl One or more of a phenoxy group or a methylsulfone group;

The heteroaryl group is selected from the group consisting of pyridine, pyrimidine, quinoline, quinazoline, oxazole, isoxazole, thiazole, thiadiazole, pyrazole, imidazole, pyrrole.

In a preferred technical solution,

The R ^{5 is} selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2-methoxyphenyl , 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-phenoxyphenyl, 3-(methylsulfonyl) Phenyl, 4-(methylsulfonyl)phenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 2,4-dichlorophenyl, 2 , 5-dichlorophenyl, 3,4-dichlorophenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 3-fluoro -4-(Trifluoromethyl)phenyl, 3-fluoro-5-(trifluoromethyl)phenyl, 3-trifluoromethyl-4fluorophenyl, 2-fluoro-4-chlorophenyl, 2 -Fluoro-5-chlorophenyl, 3-fluoro-4-chlorophenyl, 3-fluoro-5-chlorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-4-(trifluoromethyl) Phenyl, 2-chloro-5-(trifluoromethyl)phenyl, 3-chloro-4-(trifluoromethyl)phenyl, 3-chloro-5-(trifluoromethyl)phenyl, 3 -trifluoromethyl-4-chlorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-fluorophenyl, 3-chloro-4-fluorophenyl, pyridin-2-yl, pyridine- 3-yl, pyridin-4-yl, 2-methoxy-pyridin-4-yl, 3-methyl-isoxazol-5-yl, naphthalen-1-yl.

The present invention also provides a salt of the compound of the formula (I), wherein the salt is an acidic/anionic salt or a basic/cationic salt; the pharmaceutically acceptable acidic/anionic salt is usually in the form of a base Nitrogen is protonated by inorganic or organic acids. Representative organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, Succinic acid, maleic acid, tartaric acid, malic acid, citric acid, fumaric acid, gluconic acid benzoic acid, mandelic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, oxalic acid, palmitic acid, 2-naphthalene Acid, p-toluenesulfonic acid, cyclohexylamine sulfonic acid, salicylic acid, hexanoic acid, trifluoroacetic acid. Pharmaceutically acceptable basic/cationic salts include, of course, not limited to aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc.

In one aspect of the invention, there is provided a process for the preparation of a compound of the formula (I), or a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof, comprising II) reacting a compound with H ₂ NR ⁵ to prepare a compound of formula (I), wherein X, Y, Z, R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} as defined above,

In another aspect of the invention, there is provided a process for the preparation of a compound of the formula (I), a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof, which comprises A compound of the formula (II') is reacted with a compound of the formula (III), wherein X, Y, Z, R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} as defined above,

Detailed description of the invention

The term "substituted" as used herein, includes complex substituents (e.g., phenyl, aryl, heteroalkyl, heteroaryl), suitably 1 to 5 substituents, preferably 1 to 3 One, preferably one or two, can be freely selected from the list of substituents.

Unless otherwise specified, alkyl, including saturated straight chain, branched hydrocarbon groups, C ₁ -C ₉ represents a carbon atom of the alkyl group having ₁ to 9 carbon atoms, and the same C ₁ -C ₃ represents an alkyl group, for example. A carbon atom having 1 to 3 carbon atoms, for example, a C ₁ -C ₆ alkyl group includes a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tertiary group. Butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. Alkoxy is an alkyl ether consisting of a straight chain, branched chain as previously described. Similarly, alkenyl and alkynyl groups include straight-chain, branched alkenyl or alkynyl groups.

A cycloalkyl group means a cyclic group formed by a carbon atom. For example, C ₃ -C ₇ represents a carbon atom of an alkyl group having ₃ to 7 carbon atoms, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. , cycloheptyl, similar, likewise includes a cyclic alkenyl group.

The term "aryl" as used herein, unless otherwise specified, refers to an unsubstituted or substituted aryl group, such as phenyl, naphthyl, anthracenyl. The term "aroyl" refers to -C(O)-aryl.

"Oxidation by one or two oxygen atoms" means that a sulfur atom is oxidized by an oxygen atom to form a double bond between sulfur and oxygen, or is oxidized by two oxygen atoms to form sulfur and a double bond between two oxygen atoms.

The term "heterocyclyl" as used herein, unless otherwise specified, represents an unsubstituted or substituted stable 3 to 8 membered monocyclic saturated ring system selected from carbon atoms and from N, O, S. The composition of one to three heteroatoms, wherein the N, S heteroatoms can be arbitrarily oxidized, and the N heteroatoms can also be quaternized at random. The heterocyclic ring can be combined with any hetero atom or carbon atom to form a stable structure. Examples of such heterocyclic rings include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperidine Pyridyl, piperazinyl, piperazinyl, piperidinyl, dioxetane, dioxetyltetrahydroimidazolyl, tetrahydrooxazolyl, thiomorpholine sulfoxide, thio Morpholine sulfone and oxadiazolyl.

The term "heteroaryl" as used herein, unless otherwise specified, represents a stable 5 or 6 membered monocyclic aromatic ring system which is unsubstituted or substituted, and may also represent unsubstituted or substituted 9 or a 10-ring atomic benzene fused heteroaromatic ring system or a bicyclic heteroaromatic ring system consisting of a carbon atom and one or three heteroatoms selected from N, O, S, wherein the N, S heteroatoms can be Oxidation, N heteroatoms can also be quaternized. The heteroaryl group can be bonded to any hetero atom or carbon atom to form a stable structure. Heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, pyranyl, pyridyl, piperazinyl, pyrimidinyl, pyrazine, Pyridazinyl, pyrazolyl, thiadiazolyl, triazolyl, fluorenyl, azaindole, oxazolyl, azacarbazolyl, benzimidazolyl, benzofuranyl, benzothiophene Benzoisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adenyl, quinolinyl or isoquinoline base.

The term "carbonyl" refers to a C(O) group.

Whenever the terms "alkyl" or "aryl" or any of their prefix radicals appear in the name of a substituent (eg, aralkyl, dialkylamine), it will be considered to contain the above "alkane" Those limitations given by "base" and "aryl". The specified number of carbon atoms (eg, C ₁ -C ₆ ) will independently represent a carbon atom in an alkyl moiety or an alkyl moiety in a larger substituent (wherein the alkyl group is the prefix root) Quantity.

In a preferred embodiment of the invention there is provided a compound of formula (I), or an isomer, tautomer, solvate, hydrate thereof, and pharmaceutically acceptable salts thereof,

The invention also provides methods of preparing the corresponding compounds, which can be prepared using a variety of synthetic methods, including the methods described below, the compounds of the invention or pharmaceutically acceptable salts, isomers or hydrates thereof The synthesis is carried out using the methods described below in the art of organic chemical synthesis, or by variations of those methods as understood by those skilled in the art, and the preferred methods include, but are not limited to, the methods described below.

In one embodiment, the compound of the invention or a pharmaceutically acceptable salt, isomer or hydrate thereof is prepared by the following method,

Scheme 1, wherein X is N, Z is N, Y, R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} as described above,

Reaction conditions:

Step 1) A compound of the formula (V) is reacted with NH ₂ -R ^{5 in the} presence of a condensing agent to obtain a compound of the formula (IV).

Preferably, the condensing agent comprises, but is not limited to, triphosgene, carbonyl diimidazole, phenyl chloroformate, phenyl p-nitrochloroformate;

This reaction can also be carried out in the presence of a base. The base includes, but is not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene or N-methyl. One or a combination of two or more of morpholine; the aprotic solvent includes, but is not limited to, one of dichloromethane, tetrahydrofuran, DMF, dioxane, dichloroethane, and a combination of two or more;

Preferably, step 1) is carried out in an aprotic solvent, including but not limited to one of dichloromethane, tetrahydrofuran, DMF, dioxane, dichloroethane, and a combination of two or more thereof. .

Step 2) The compound represented by the formula (IV) is subjected to a nitro reduction reaction to obtain a compound of the formula (II'-A), and the nitro reduction can be carried out by a person skilled in the art;

Preferably, the conditions of the nitro reduction-reduction reaction include, but are not limited to, hydrogen and Raney nickel, hydrogen and palladium carbon, iron powder, zinc powder, stannous chloride;

Step 3) reacting a compound of the formula (II'-A) with a compound of the formula (III) in a base and an organic solvent to obtain a compound of the formula (I-A),

Step 3) Preferably, the reaction temperature is room temperature to reflux; the base is selected from one or a combination of two or more of sodium carbonate, potassium carbonate and cesium carbonate; the organic solvent is selected from the group consisting of tetrahydrofuran, dioxane, isopropanol, ethanol, DMF , DMA, acetonitrile, DMSO or a combination of two or more.

Scheme 2, wherein X is O, Z is N, Y, R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} as described above.

Reaction conditions:

Step 1) A compound of the formula (IV') is reacted with a formula of NH ₂ -R ^{5 in the} presence of a condensing agent to give a compound of the formula (II'-B).

This reaction can also be carried out in the presence of a base. The base includes, but is not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene or N-methyl. One or a combination of two or more of morpholine;

Step 2) reacting a compound of the formula (II'-B) with a compound of the formula (III) in a base and an organic solvent to obtain a compound of the formula (I-B);

Step 2) Preferably, the reaction temperature is room temperature to reflux; the base is selected from one or a combination of two or more of sodium carbonate, potassium carbonate and cesium carbonate; the organic solvent is selected from the group consisting of tetrahydrofuran, dioxane, isopropanol, ethanol, DMF , DMA, acetonitrile, DMSO or a combination of two or more.

The compound of the formula (I), wherein Z is CH, X, Y, R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} as described above.

Reaction conditions:

The nitrification conditions in step 1) are nitric acid and acetic acid.

Step 2) performing a nitro reduction reaction, and the nitro reduction can be carried out by a person skilled in the art;

Preferably, the conditions of the nitro reduction-reduction reaction include, but are not limited to, hydrogen and Raney nickel, hydrogen and palladium carbon, iron powder, zinc powder or stannous chloride;

Step 3) 1-(8-Methoxy-6-amino-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)ethyl-1-one and formic acid Methyl ester or ethyl formate in an organic solvent, catalyzed by a base to give 10-hydroxy-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quina a porphyrin, wherein the organic solvent includes, but is not limited to, one or a combination of two or more of ethylene glycol dimethyl ether, dioxane, tetrahydrofuran, tert-butanol, ethanol, methanol; It is limited to sodium t-butoxide, potassium t-butoxide, sodium methoxide, and sodium ethoxide; the reaction can also be carried out under heating, and the temperature of the heating is from room temperature to reflux.

In step 4), 10-hydroxy-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline is reacted with a chlorinating reagent in an organic solvent to prepare 10 -chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline, wherein the chlorinating reagent is phosphorus oxychloride; The organic solvent includes, but is not limited to, one or a combination of two or more of benzene, toluene, chlorobenzene, and xylene; the reaction can also be carried out in the presence of an organic base, which is triethylamine or two. Isopropyl ethylamine.

In step 4a), 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline is obtained in the organic solvent under the action of a Lewis acid. 5-hydroxy-10-chloro-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline, wherein the Lewis acid is boron tribromide or boron trichloride The organic solvent is dichloromethane.

Preparation of formula III-A in step 4b) with 5-hydroxy-10-chloro-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline and R ¹ X in an organic solvent a compound of the formula wherein R ¹ is as defined in claims 1-3; the organic solvent includes, but is not limited to, one of tetrahydrofuran, dioxane, DMF, DMA, DMSO, acetonitrile or a combination of two or more; R ¹ X X is chlorine, bromine, iodine, mesylate, p-toluenesulfonate or triflate.

Step 5) The compound of the formula III-A is mixed with the formula IV'-A in an organic solvent and heated to 100 ° C to 140 ° C to obtain a compound represented by II-A; the organic solvent is selected from the group consisting of toluene, chlorobenzene, One or a combination of two or more of xylene, DMF, DMA, DMSO.

Step 6) performing a nitro reduction reaction, and the nitro reduction can be carried out by a person skilled in the art;

Step 7) a compound of the formula (II-A) is reacted with a formula of NH ₂ -R ^{5 in the} presence of a condensing agent to give a compound of the formula (IC);

This reaction can also be carried out in the presence of a base. The base includes, but is not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene or N-methyl. One or a combination of two or more of morpholine; the aprotic solvent includes, but is not limited to, one of dichloromethane, tetrahydrofuran, DMF, dioxane, dichloroethane, and a combination of two or more.

Preferably, step 7) is carried out in an aprotic solvent, including but not limited to one of dichloromethane, tetrahydrofuran, DMF, dioxane, dichloroethane, and a combination of two or more thereof. ;

When R ¹ is -CH ₃ , step 4a) and step 4b) may be omitted, and after step 4), the operation of step 5) may be performed.

The invention also provides a process for the preparation of the corresponding compounds, in particular by the methods described below.

The synthesis method of the intermediate (2) is as follows:

The synthesis method of the intermediate (2) is in accordance with the patent CN104530063

It will be apparent that the compounds, isomers, crystalline forms or prodrugs of Formula I, and pharmaceutically acceptable salts thereof, may exist in both solvated and unsolvated forms. For example, the solvated form can be in a water soluble form. The invention includes all such solvated and unsolvated forms.

The compounds of the invention may have asymmetric carbon atoms which, depending on their physicochemical differences, may be separated by known techniques, such as by chromatography or fractional crystallization. Into a single diastereomer. Separation of the enantiomers can be carried out by first reacting the appropriate optically active compound, converting the enantiomeric mixture into a diastereomeric mixture, separating the diastereomers, and then separating the individual The enantiomers are converted (hydrolyzed) to the corresponding pure enantiomers. All such isomers, including mixtures of diastereomers and pure enantiomers, are considered to be part of this invention.

The compound of the present invention as an active ingredient, and a method of preparing the same, are all contents of the present invention. Moreover, the crystalline form of some of the compounds may exist as polycrystals, and such forms may also be included in the current invention. Additionally, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of the invention.

The compounds of the invention may be used in the free form for treatment or, where appropriate, in the form of a pharmaceutically acceptable salt or other derivative for treatment. As used herein, the term "pharmaceutically acceptable salt" refers to organic and inorganic salts of the compounds of the present invention which are suitable for use in humans and lower animals without undue toxicity, irritation, allergic response, etc., and have reasonable Benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art. The salt can be formed by reacting a compound of the invention with a suitable free base or acid. Including, but not limited to, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, These salts are obtained either by methods well known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, hydrogen sulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, citrate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerol phosphate, gluconic acid Salt, hemisulfate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, methane Sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, per-3-phenylpropionate, Phosphate, picrate, propionate, stearate, sulfate, thiocyanate, p-toluenesulfonate, undecanoate, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include suitable non-toxic ammonium, quaternary ammonium, and the use of such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates. An amine cation formed by the acid salt.

Further, the term "prodrug" as used herein means that a compound can be converted into a compound of the formula (I) of the present invention in vivo. This transformation is affected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent compound in the blood or tissue.

The pharmaceutical composition of the present invention comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, a kinase inhibitor (small molecule, polypeptide, antibody, etc.), an immunosuppressant, an anticancer drug, an antiviral agent, an antibiotic An additional agent of an inflammatory, antifungal, antibiotic or anti-vascular hyperproliferative compound; and any pharmaceutically acceptable carrier, adjuvant or excipient.

The compounds of the invention may be used alone or in combination with one or more other compounds of the invention or with one or more other agents. When administered in combination, the therapeutic agents can be formulated for simultaneous administration or sequentially at different times, or the therapeutic agents can be administered as a single composition. By "combination therapy" is meant the use of a compound of the invention in combination with another agent in the form of co-administration of each agent or sequential administration of each agent, in either case, for the purpose Achieve the best results of the drug. Co-administration includes simultaneous delivery of the dosage form, as well as separate dosage forms for each compound. Thus, administration of the compounds of the invention can be used in conjunction with other therapies known in the art, for example, in the treatment of cancer using radiation therapy or cytostatic agents, cytotoxic agents, other anticancer agents, and the like to improve Cancer-like. The invention is not limited to the order of administration; the compounds of the invention may be administered previously, simultaneously, or after other anticancer or cytotoxic agents.

In order to prepare the pharmaceutical ingredient of the present invention, one or more compounds or salts of the formula (I) as an active ingredient thereof can be intimately mixed with a pharmaceutical carrier, which is carried out according to a conventional pharmaceutical ingredient technique. The carrier can be used in a wide variety of forms depending on the form of preparation which is designed for different modes of administration (for example, oral or parenteral administration). Suitable pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and the British Pharmaceutical Society.

The pharmaceutical composition of the present invention may have the following forms, for example, suitable for oral administration, such as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; for parenteral injections such as clear solutions, suspensions, Emulsion; or for topical use such as creams, creams; or as a suppository for rectal administration. The pharmaceutical ingredient may also be presented in unit dosage form for administration in a precise dosage. The pharmaceutical ingredient will include a conventional pharmaceutical carrier or excipient and a compound as an active ingredient prepared according to the present invention, and may also include other medical or pharmaceutical preparations, carriers, adjuvants, and the like.

Therapeutic compounds can also be administered to mammals other than humans. The dosage of the drug to be administered to a mammal will depend on the species of the animal and its disease state or the disordered condition in which it is located. The therapeutic compound can be administered to the animal in the form of a capsule, a bolus, or a pill. The therapeutic compound can also be introduced into the animal by injection or infusion. We prepare these forms of the drug in a traditional manner consistent with veterinary practice standards. As an alternative, the pharmaceutical synthetic drug can be mixed with the animal feed and fed to the animal, so that the concentrated feed additive or premix can be prepared by mixing ordinary animal feed.

It is a further object of the present invention to provide a method for treating cancer in a subject in need thereof which comprises administering to the subject a method of administering a therapeutically effective amount of a composition comprising a compound of the present invention.

The invention also encompasses the use of a compound of the invention, or a pharmaceutically acceptable derivative thereof, for the manufacture of a cancer (including non-solid tumors, solid tumors, primary or metastatic cancer, as indicated elsewhere herein and including cancer) An agent that is resistant or refractory to one or more other treatments, as well as other diseases including, but not limited to, fundus diseases, psoriasis, atheroma, pulmonary fibrosis, liver fibrosis, myelofibrosis, and the like . The cancer includes, but is not limited to, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, intrauterine Membrane cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, esophageal cancer, brain Any of tumor, B cell and T cell lymphoma, lymphoma, multiple myeloma, cholangiocarcinoma, and cholangiocarcinoma.

The invention is better illustrated by the examples provided below, all temperatures being in degrees Celsius unless otherwise stated.

Detailed ways

Preparation of intermediates:

Preparation of intermediate 1) 2-chloro-4-nitroaniline:

14 g (100 mmol) of compound 4-nitroaniline, 200 mL of isopropanol was added to the reaction vessel, stirred, heated to 60 ° C, and 13.4 g (100 mmol) of N-chlorosuccinimide was added, and the temperature was raised to 80 ° C. half an hour. After the reaction was completed, it was cooled, poured into 2 L of ice water, stirred for half an hour, filtered, washed with water and dried to give 16 g of a yellow solid.

Preparation of intermediate 2) 1-(2-chloro-4nitrophenyl)-3-cyclopropylurea:

173 mg (1 mmol) of 2-chloro-4-nitroaniline, 200 mg (0.67 mmol) of triphosgene, 10 mL of dichloromethane were added to the reaction vessel, stirred at 0 ° C for 10 minutes, and 405 mg of triethylamine was added dropwise. 4 mmol), the reaction was continued at 0 ° C for 2 hours, and 114 mg (2 mmol) of cyclopropylamine was added dropwise, and stirred at room temperature for 15 hours. The reaction was completed, concentrated and recrystallized from methanol to yieldd <RTIgt;

Preparation of intermediate 3) 1-(4-aminophenyl)-3cyclopropylurea:

1-(2-Chloro-4-nitrophenyl)-3-cyclopropyl urea 90 mg (0.35 mmol), wet palladium on carbon 10 mg (% 5 purity, containing 55% water), 10 mL methanol was added to the reaction kettle The reaction system was pumped three times with hydrogen, and stirred at room temperature for 5 hours under a hydrogen atmosphere of 1 atm. End of the reaction, filtered and the filtrate was concentrated to give a pale purple solid 60mg, yield 90%, MS: 192 [M + H] +.

Preparation of intermediate 4) 1-(4-amino-2-chlorophenyl)-3-cyclopropylurea:

1-(2-Chloro-4-nitrophenyl)-3-cyclopropyl urea 90 mg (0.35 mmol), zinc powder 230 mg (4 mmol), was added to a reaction kettle containing 15 mL of acetic acid, and stirred at 60 ° C for 2 hours. Filtration and concentrating the filtrate to give abr. EtOAc (EtOAc: EtOAc) ⁺ .

Preparation of intermediate 5) 1-(2-chloro-4-nitrophenyl)-3-(3-methoxyphenyl)urea

Working with intermediate 2), 2-chloro-4-nitroaniline (173 mg, 1 mmol) and 3-methoxyaniline (250 mg, 2 mmol) afforded 1-(2-chloro-4-nitrophenyl)- 3-(3-methoxyphenyl)urea 200 mg, 68% yield

¹ H NMR (CD ₃ OD, 400 MHz) δ ppm: 3.81 (3H, s), 6.66 (1H, d, J = 8.0 Hz), 6.96 (1H, d, J = 8.0 Hz), 7.21. (1H, d, J = 8.0 Hz), 7.25 (1H, s), 8.19 (1H, d, J = 8.0 Hz), 8.35 (1H, s), 8.61 (1H, d, J = 8.0 Hz). MS: 322 [M+H] ⁺ .

Intermediate 6) 1-(4-Aminophenyl)-3-(3-methoxyphenyl)urea

Working with intermediate 3), from 1-(2-chloro-4-nitrophenyl)-3-(3-methoxyphenyl)urea (100 mg, 0.3 mmol). Yield, MS: 258 [M+H] ⁺ .

Preparation of intermediate 7) 1-(4-Amino-2-chlorophenyl)3-(3-methoxyphenyl)urea

Working with intermediate 4), from the reduction of zinc powder using 1-(2-chloro-4-nitrophenyl)-3-(3-methoxyphenyl)urea (100 mg, 0.3 mmol), Yield 77%, MS: 292 [M+H] ⁺ .

Intermediate 8) 1-(4-Amino-2-chlorophenyl)-3(pyridin-2-yl)urea

Working with intermediates 2), 4), 2-aminopyridine (94 mg, 1 mmol) and 2-chloro-4-nitroaniline (142 mg, 1 mmol) afforded the desired product 160 mg, yield 62% in two steps; MS: 263[M+H] ⁺ .

Intermediate 9) 1-(4-Amino-2-chlorophenyl)-3-(3-fluorophenyl)urea

The reaction with the intermediate 2), 4) was carried out from 3-fluoroaniline (111 mg, 1 mmol) and 2-chloro-4-nitroaniline (142 mg, 1 mmol) to give the desired product (200 mg).

¹ H NMR (CD ₃ OD, 400 MHz) δ ppm: 6.66 (1H, d, J = 8.0 Hz), 6.80 (1H, s), 7.04 (2H, d, J = 8.0 Hz), 7.41 (2H, d, J = 8.0 Hz), 7.50 (1H, d, J = 8.0 Hz), MS: 280 [M+H] ⁺ .

Intermediate 10) 1-(4-Amino-2-chlorophenyl)-3-(3-methylisoxazol-5-yl)urea

Working with the intermediates 2), 4), the nitro substituted product obtained by the reaction of 3-methylisoxazole-5-amine (98 mg, 1 mmol) and 2-chloro-4-nitroaniline (142 mg, 1 mmol) Reduction of zinc powder to obtain 220 mg of the target product, the yield is 84%;

¹ H NMR (CD ₃ OD, 400 MHz) δ ppm: 2.39 (3H, s), 6.34 (1H, s), 6.65 (1H, d, J = 8.0 Hz), 6.80 (1H, s), 7.51 (1H, d, J = 8.0 Hz), MS: 267 [M+H] ⁺ .

Intermediate 11) 1-(4-Amino-2-chlorophenyl)-3-isopropylurea

The nitro product obtained by the reaction of isopropylamine (110 mg, 2 mmol) and 2-chloro-4-nitroaniline (142 mg, 1 mmol), 215 mg, 86% yield. MS: 258 [M+H] ⁺ .

Intermediate 12) 1-(2-Chloro-4-aminophenyl)-3-(2-methoxypyridin-4-yl)urea

Working with intermediates 2), 4), the nitro substituted product obtained from the reaction of 2-methoxy-4-aminopyridine (124 mg, 1 mmol) and 2-chloro-4-nitroaniline (142 mg, 1 mmol) from zinc Powder reduction to obtain 206 mg of the target product, the yield is 70%;

¹ H NMR (CD ₃ OD, 400 MHz) δ ppm: 3.80 (3H, s), 6.65 (1H, d, J = 8.0 Hz), 6.79 (1H, s), 6.95 (1H, d, J = 8.0 Hz), 7.07 (1H, s), 7.51 (1H, d, J = 8.0 Hz), 7.93 (1H, s), MS: 293 [M+H] ⁺ .

Intermediate 13) 1-(4-Amino-2-chlorophenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea

With the intermediates 2), 4), the nitro substituted product obtained by the reaction of 4-chloro-3-trifluoromethylaniline (200 mg, 1 mmol) and 2-chloro-4-nitroaniline (142 mg, 1 mmol) Reduction of zinc powder gave the target product 250 mg, yield 73%, MS: 364 [M+H] ⁺ .

Intermediate 14) 1-(4-Amino-2-chlorophenyl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea

With the intermediates 2), 4), the nitro group was obtained by the reaction of 2-fluoro-4-(trifluoromethyl)aniline (180 mg, 1 mmol) and 2-chloro-4-nitroaniline (142 mg, 1 mmol). The product was reduced from zinc powder to give the desired product 208 mg, yield 65%, MS: 348[M+H] ⁺ .

Intermediate 15) 1-(4-Amino-2-chlorophenyl)-3-(4-(phenoxy)phenyl)urea

With the intermediates 2), 4), the nitro substituted product obtained by the reaction of 4-phenoxyaniline (185 mg, 1 mmol) and 2-chloro-4-nitroaniline (142 mg, 1 mmol) was reduced by zinc powder to obtain the target. Product 235 mg, yield 72%, MS: 354[M+H] ⁺ .

Intermediate 16) 1-(4-Amino-2-chlorophenyl)-3-(3-(methylsulfonyl)phenyl)urea

With the intermediates 2), 4), the nitro substituted product obtained by the reaction of 3-(methylsulfonyl)aniline (170 mg, 1 mmol) and 2-chloro-4-nitroaniline (142 mg, 1 mmol) was reduced from zinc powder. The target product was obtained 190 mg, yield 61%, MS: 340 [M+H] ⁺ .

Preparation of intermediate 17) 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea

300 mg of triphosgene, 0.3 ml of triethylamine, and 5 ml of toluene were placed in the reaction vessel, and a solution of 490 mg of 4-chloro-3-(trifluoromethyl)aniline in 490 mg of toluene was added dropwise thereto in an ice water bath. After completion of the dropwise addition, the reaction was carried out in an ice water bath for 1 hour, and then the temperature was raised to 80 ° C for 2 hours. After cooling, the solvent was evaporated to dryness and dissolved in 10 ml of dichloromethane. 270 mg of 4-aminophenol was added, and the reaction was carried out overnight at normal temperature. The reaction mixture was concentrated to give a purple solid. m. m. m. MS: 331 [M+H] ⁺ .

Preparation of intermediate 18) 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-chloro-4-hydroxyphenyl)urea

The title compound was obtained as an off-white compound from 4-chloro-3-(trifluoromethyl)aniline and 3-fluoro-4-aminophenol in the same procedure as Intermediate 17). MS: 349 [M+H] ⁺ .

Preparation of intermediate 19) 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea

The purple target compound was obtained from 2-fluoro-5-(trifluoromethyl)aniline and 4-aminophenol in the same manner as the intermediate 17), yield 82%. MS: 283 [M+H] ⁺ .

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 6.57-6.79 (2H, m), 7.18-7.28 (2H, m), 7.30-7.40 (1H, m), 7.42-7.58 (1H, m), 8.55 -8.71 (1H, m), 8.80 (1H, d, J = 3.0 Hz), 8.91 (1H, s), 9.18 (1H, s).

Preparation of intermediate 20) 1-(2,4-difluorophenyl)-3-(2-fluoro-4-hydroxyphenyl)urea

The pale white target compound was obtained from 2,4-difluoroaniline and 3-fluoro-4-aminophenol in the same manner as the intermediate 17), yield 68%. MS: 283 [M+H] ⁺ .

Preparation of intermediate 21) 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea

0.3 ml of pyridine, 300 mg of 4-amino-3-chlorophenol hydrochloride, and 5 ml of DMF were added to the reaction vessel, and the mixture was reacted for 30 minutes in an ice bath. 0.3 ml of phenyl chloroformate was added dropwise, and the reaction was carried out for 30 min. The reaction mixture was extracted with 1N EtOAc EtOAc. The concentrate was dissolved in 5 ml of DMF, and 0.3 ml of cyclopropylamine was added thereto, and the reaction was carried out overnight at normal temperature. The reaction mixture was extracted with EtOAc EtOAc. A white powder solid 325 mg was obtained in a yield of 85%. MS: 227 [M+H] ⁺ .

Preparation of intermediate 22) 1-(2-chloro-4-aminophenyl)-3-cyclohexylurea

Working with the intermediates 2), 4), from 2-chloro-4-nitroaniline and cyclohexylamine afforded the product as a pale yellow solid, yield 56%, MS: 268 [M+H] ⁺

Preparation of intermediate 23) 1-(4-hydroxy-2-chlorophenyl)-3-(4-fluorophenyl)urea

The title compound was obtained as white crystals (yield: 68%) from 4-fluoroaniline and 3-chloro-4-aminophenol. MS: 281 [M+H] ⁺ .

Preparation of intermediate 24) 1-(3-chloro-4-fluorophenyl)-3-(4-hydroxyphenyl)urea

Reaction with 4-aminophenol and 3-chloro-4-fluoroaniline gave the compound as a white solid, yield 45%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 6.65-6.72 2H, m), 7.18-7.23 (2H, m), 7.29-7.32 (1H, m), 7.35-7.37 (1H, m), 7.67-7.71 (1H, m), 7.79-7.82 (1H, m), 8.57 (1H, s), 8.96 (1H, s), MS: 281 [M+H] ⁺ .

Preparation of intermediate 25) 1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea

The intermediate 17) was obtained by the reaction of 4-aminophenol and 4-fluoro-3-(trifluoromethyl)aniline to give a white solid compound, yield 55%; 1H NMR (DMSO-d6, 400 MHz) δ 6.66- 6.73(2H,m), 7.17-7.26(2H,m), 7.36-7.50(2H,m), 7.56-7.64(1H,m),8.00-8.11(1H,m),8.63(1H,s), 9.14(1H,s);MS:315[M+H] ⁺

Preparation of intermediate 26) 1-(5-chloro-2-fluorophenyl)-3-(4-hydroxyphenyl)urea

Intermediate 17) The same procedure was carried out from 4-aminophenol and 5-chloro-2-fluoroaniline to give a white solid compound, yield 63%; 1H NMR (DMSO-d6, 400 MHz) δ 6.66-6.74 (2H, m ), 6.98-7.05 (1H, m), 7.19-7.25 (2H, m), 7.25-7.32 (1H, m), 8.28-8.31 (1H, m), 8.65 (1H, s), 8.85 (1H, s ), 9.16 (1H, s); MS: 281 [M + H] +

Preparation of intermediate 27) 1-(4-hydroxyphenyl)-3-(naphthalen-1-yl)urea

Working in the same manner as the intermediate 21), 4-hydroxybenzene and naphthalene-1-amine gave a white solid compound in a yield of 65%; MS: 279 [M+H] ⁺

Intermediate 28) Synthesis method of intermediate (2)

Preparation of 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline

For detailed synthesis intermediates, see patent document CN104530063. Compound A1 is reacted with methyl iodide in a solution of potassium carbonate in N'N-dimethylformyl to a temperature of 80 ° C for 2 hours, added to water, filtered to dryness to obtain a white solid A2; A2 is dissolved in acetic acid at 0 ° C. The mixed acid of fuming nitric acid and acetic acid is added dropwise thereto, and after the dropwise addition is completed, the reaction mixture is reacted at 0 ° C for one hour, and the reaction liquid is poured into crushed ice and stirred, and filtered to obtain a pale yellow solid A3; A3 is dissolved in methanol and then hydrogen The reaction was carried out for 1 hour under palladium on carbon, filtered, and the filtrate was concentrated to give a pale purple oil (A4). Compound A4 and dimethylhydrazine acetate were reacted under reflux in ethanol for 10 hours, cooled overnight, and the reaction mixture was filtered and dried to give a pale gray solid A5; The mixture was heated under reflux for 10 hours in phosphorus oxychloride. The reaction was completed, concentrated, and dichloromethane was added thereto, crushed ice, potassium carbonate, and the pH was adjusted to 9, and the organic phase was washed with saturated brine and dried. Concentration gave the title product as a yellow solid, yield 55%. MS: 253 [M+H] ⁺

Intermediate 29: 10-Chloro-5-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydro-[1,4]dioxane[2,3-f Preparation of quinazoline

The same procedure as in Intermediate 28) gave the product as a yellow solid, yield 45%. MS: 323[M+H] ⁺

Intermediate 30: Preparation of 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline

The same procedure as in Intermediate 28) gave the product as a yellow solid, yield 60%. MS: 297[M+H] ⁺

Intermediate 31: Preparation of 10-chloro-5-(2-morpholinoethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline

Synthetic method with intermediate 28) gave the product as a yellow solid, MS: 352 [M+H] ⁺

¹ H NMR (DMSO-d ₆ , 300 MHz) δ ppm: 3.16 (1H, d, J = 5.0 Hz), 3.43 (4H, s), 3.71 (4H, d, J = 5.1 Hz), 3.87 (1H, s) , 4.29–4.55 (6H, m), 6.90 (1H, s), 8.38 (1H, d, J = 2.9 Hz).

Intermediate 32: 10-Chloro-5-((2-tetrahydropyrrol-1-yl)ethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Preparation of quinazoline

Synthetic method with intermediate 28) gave the product as a yellow solid, MS: 336[M+H] ⁺

Intermediate 33: 3-((10-Chloro-2,3-dihydro-[1,4]dioxane[2,3-f]quinazolin-5-yl)oxy)-N,N -Preparation of dimethylpropan-1-amine

Synthetic method with intermediate 28) gave the product as a yellow solid, MS: 324 [M+H] ⁺

Intermediate 34: 10-Chloro-5-(3-(tetrahydropyrrol-1-yl)propoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Preparation of quinazoline

Synthetic method with intermediate 28) gave the product as a yellow solid, MS: 350 [M+H] ⁺

Intermediate 35: Preparation of 10-chloro-5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline

Synthetic method with intermediate 28) gave the product as a yellow solid, MS: 366[M+H] ⁺

Intermediate 36: Preparation of 10-chloro-5-(1-methylthiopropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline

Synthetic method with intermediate 28) gave the product as a yellow solid, MS: 327[M+H] ⁺

Intermediate 37: 10-Chloro-5-(3-(4-methylpiperazin-1-yl)propoxy)-2,3-dihydro-[1,4]dioxane[2,3 -f]Preparation of quinazoline

Synthetic method with intermediate 28) gave the product as a yellow solid, MS: 379 [M+H] ⁺

Intermediate 38: 10-Chloro-5-(3-(piperidin-1-yl)propoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quina Preparation of oxazoline

Synthetic method with intermediate 28) gave the product as a yellow solid, MS: 364[M+H] ⁺

Intermediate 39: 4-(3-((10-chloro-2,3-dihydro-[1,4]dioxane[2,3-f]quinazolin-5-yl)oxy)propane Preparation of thiomorpholine-1,1-dioxide

Synthetic method with intermediate 28) gave the product as a yellow solid, MS: 414 [M+H] ⁺

Intermediate 40: Preparation of 10-chloro-5-(6-methoxyhexyloxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline

Synthetic method with intermediate 28) gave the product as a yellow solid, MS: 353[M+H] ⁺

Intermediate 41: Preparation of 10-chloro-5-(6-(dimethylamino)hexyl)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline

Intermediate 42: Preparation of 10-chloro-5-isopropoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline

Synthetic method with intermediate 28) gave the product as a yellow solid, MS: 281 [M+H] ⁺

Preparation of intermediate 43) 1-(2-chloro-4-hydroxyphenyl)-3-phenylurea

Reaction with 4-amino-3-chlorophenol and aniline gave the compound as a white solid, yield 70%; MS: 263 [M+H] ⁺

Preparation of intermediate 44) 1-(2-chloro-4-hydroxyphenyl)-3-isopropylurea

Reaction with 4-amino-3-chlorophenol and isopropylamine gave the title compound as a white solid, yield 72%; MS: 229 [M+H] ⁺

Preparation of intermediate 45) 1-(2-chloro-4-hydroxyphenyl)-3-(4-fluorophenyl)urea

Working in the same manner as the intermediate 21), 4-amino-3-chlorophenol and p-fluoroaniline gave a white solid compound, yield 60%; MS: 281 [M+H] ⁺

Preparation of intermediate 45) 1-(4-hydroxyphenyl)-3-(2-methoxypyridin-4-yl)urea

Reaction with 4-aminophenol and 2-methoxypyridin-4-amine gave the title compound as a white solid, yield 50%; MS: 260 [M+H] ⁺

Preparation of intermediate 46) 1-(2-chloro-4-hydroxyphenyl)-3-cyclopentylurea

Working in the same manner as the intermediate 21), 4-amino-3-chlorophenol and cyclopentylamine gave a white solid compound (yield 70%; MS: 254 [M+H] ⁺

Preparation of intermediate 47) 1-(2-chloro-4-hydroxyphenyl)-3-cyclobutylurea

Reaction with 4-amino-3-chlorophenol and cyclobutylamine to give a white solid compound in the same manner as Intermediate 21), yield 50%; MS: 240 [M+H] ⁺

Intermediate 48) 1-(4-Amino-2-chlorophenyl)-3-cyclobutylurea

Working with intermediates 2), 4), from 2-chloro-4-nitroaniline and cyclobutylamine to give a white solid compound, yield 50%; MS: 240 [M+H] ⁺

Intermediate 49) 1-(4-Amino-2-chlorophenyl)-3-cyclopentylurea

Working with intermediates 2), 4), from 2-chloro-4-nitroaniline and cyclopentylamine to give a white solid compound, yield 50%; MS: 254 [M+H] ⁺

Intermediate 50) 1-(4-Amino-2-chlorophenyl)-3-isopentylurea

Working with intermediates 2), 4), from 2-chloro-4-nitroaniline and isoamylamine to give a white solid compound, yield 50%; MS: 256 [M+H] ⁺

Preparation of intermediate 51) 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(6-hydroxypyridin-3-yl)urea

Intermediate 17) The same procedure was carried out from 5-aminopyridine-2(1H)-one and 4-chloro-3-(trifluoromethyl)aniline to give a white solid compound, yield 45%; MS: 332 [M+ H] ⁺

Preparation of intermediate 52) 1-(3-chloro-4-hydroxyphenyl)-3-(2-methoxypyridin-4-yl)urea

Reaction with 4-amino-2-chlorophenol and 2-methoxypyridin-4-amine gave the title compound as a white solid, yield 45%, MS: 295 [M+H] ⁺

Example 1. 1-(4-((5-Methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazolin-10-yl)amino) Preparation of phenyl)-3-cyclopropylurea

10-Chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline 51 mg (0.2 mmol), 1-(4-aminobenzene 38.5 mg (0.2 mmol) of 3-cyclopropyl urea, 10 mL of isopropanol was added to the reaction vessel, and reacted at 80 ° C for 5 hours. After completion of the reaction, the mixture was cooled, filtered, washed with isopropyl alcohol three times and dried to give a yellow solid (yield: 50 mg, yield: 50%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 0.41 (2H, br), 0.64 (2H, br ), 2.50 (1H, br), 3.98 (3H, s), 4.44 (2H, br), 4.61 (2H, br), 6.63 (1H, s), 7.00 (1H, s), 7.45 (2H, d, J = 8.0 Hz), 7.50 (2H, d, J = 8.0 Hz), 8.69 (1H, s), 8.76 (1H, s), 10.51 (1H, s); MS: 408 [M+H] ⁺ .

Example 2. 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazolin-10- Preparation of phenyl)amino)phenyl)-3-cyclopropylurea

Working with Example 1, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(4-amino -2-Chlorophenyl)-3-cyclopropylurea gave the desired product as a yellow solid, yield 58%;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 0.43 (2H, br), 0.67 (2H, br), 2.51 (1H, br), 3.98 (3H, s), 4.44 (2H, br), 4.60 (2H) , br), 6.97 (1H, s), 7.30 (1H, s), 7.49 (1H, d, J = 8.0 Hz), 7.79 (1H, s), 8.04 (1H, s), 8.23 (1H, d, J = 8.0 Hz), 8.74 (1H, s), 10.47 (1H, s); MS: 442 [M+H] ⁺ .

Example 3. 1 (4-((5-Methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazolin-10-yl)amino)benzene Preparation of benzyl-3-(3-methoxyphenyl)urea

Working with Example 1, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(4-amino Phenyl)-3-(3-methoxyphenyl)urea gave a yellow solid product in a yield of 58%;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.55 (3H, s), 3.98 (3H, s), 4.44 (2H, br), 4.61 (2H, br), 6.56 (1H, d, J = 4.0 Hz ), 6.94-6.99 (2H, m), 7.18-7.21 (2H, m), 7.50 (2H, d, J = 8.0 Hz), 7.56 (2H, d, J = 8.0 Hz), 8.71 (1H, s) , 9.19 (1H, s), 9.33 (1H, s), 10.55 (1H, s), MS: 474 [M+H] ⁺ .

Example 4. 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3,f]quinazoline-10- Of phenyl)phenyl)-3-(3-methoxyphenyl)urea

Working with Example 1, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(4-amino -2-Chloro-phenyl)-3-(3-methoxyphenyl)urea gave the product as a yellow solid, yield 58%;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.75 (3H, s), 3.93 (3H, s), 4.40 (2H, br), 4.60 (2H, br), 6.58 (1H, d, J = 4.0 Hz ), 6.96 (2H, d, J = 8.0 Hz), 7.22 (2H, t, J = 8.0 Hz), 7.65 (1H, d, J = 8.0 Hz), 8.09 (1H, d, J = 8.0 Hz), 8.18 (1H, s), 8.26 (1H, s), 8.43 (1H, s), 9.34 (1H, s), 9.58 (1H, s), MS: 508 [M+H] ⁺ .

Example 5. 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3,f]quinazoline-10- Of phenyl)phenyl)-3-(pyridin-2-yl)urea

Working with Example 1, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(4-amino 2-Chlorophenyl)-3-(pyridin-2-yl)urea gave a yellow solid in 71% yield: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.97 (3H, s), 4.41-4.44 (2H , m), 4.60-4.63 (2H, m), 6.94 (1H, s), 7.06 (1H, t, J = 8.0 Hz), 7.25 (1H, d, J = 8.0 Hz), 7.61 (1H, d, J = 8.0 Hz), 7.79 (1H, d, J = 8.0 Hz), 7.98 (1H, s), 8.33 (1H, s), 8.39 (1H, d, J = 8.0 Hz), 8.68 (1H, s) , 10.05 (1H, s), 10.29 (1H, s), MS: 479 [M+H] ⁺ .

Example 6. 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3,f]quinazoline-10- Of phenyl)phenyl)-3-phenylurea

Working with Example 1, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(4-amino 2-Chlorophenyl)-3-phenylurea gave a yellow solid in a yield of 62%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.98 (3H, s), 4.44 (2H, s), 4.62 (2H, s), 7.00 (2H, t, J = 8.0 Hz), 7.30 (2H, t, J = 8.0 Hz), 7.52 (2H, d, J = 8.0 Hz), 7.55 (1H, d, J = 8.0 Hz), 7.86 (1H, s), 8.23 (1H, d, J = 8.0 Hz), 8.57 (1H, s), 8.74 (1H, s), 9.77 (1H, br), 10.47 (1H, s) , MS: 478 [M+H] ⁺ .

Example 7. 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3,f]quinazoline-10- Of phenyl)phenyl)-3-(4-fluorophenyl)urea

Working with Example 1, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(4-amino -2-Chlorophenyl)-3-(3-fluorophenyl)urea obtained as a yellow solid, yield 51%;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.92 (3H, s), 4.40 (2H, s), 4.60 (2H, s), 6.90 (1H, t, J = 8.0 Hz), 7.15 (2H, t, J = 12.0 Hz), 7.49 (2H, t, J = 8.0 Hz), 7.66 (1H, d, J = 8.0 Hz), 8.08 (1H, d, J = 8.0 Hz), 8.18 (1H, s) , 8.27 (1H, s), 8.43 (1H, s), 9.37 (1H, s), 9.60 (1H, s), MS: 496 [M+H] ⁺ .

Example 8. 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline-10- Of phenyl)phenyl)-3-(3-methylisoxazole-5-yl)urea

Working with Example 1, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(4-amino 2-Chlorophenyl)-3-(3-methylisoxazol-5-yl)-urea gave a yellow solid in 80% yield;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 2.38 (3H, s), 3.98 (3H, s), 4.44 (2H, s), 4.62 (2H, s), 6.51 (1H, s), 7.03 (1H) , s), 7.58 (1H, d, J = 8.0 Hz), 7.89 (1H, s), 8.19 (1H, d, J = 8.0 Hz), 8.74 (1H, s), 8.90 (1H, s), 10.30 (1H, s), 10.45 (1H, s); MS: 483 [M+H] ⁺ .

Example 9. 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline-10- Of phenyl)phenyl)-3-isopropylurea

Working with Example 1, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(2-chloro -4-Nitrophenyl)-3-isopropylurea gave a yellow solid in 70% yield;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 1.11 (6H, d, J = 8.0 Hz), 3.73-3.79 (1H, m), 3.92 (3H, s), 4.39 (2H, br), 4.58 (2H) , br), 6.87 (1H, d, J = 8.0 Hz), 6.92 (1H, s), 7.56 (1H, d, J = 8.0 Hz), 7.87 (1H, s), 8.11 (2H, d, J = 8.0 Hz), 8.41 (1H, s), 9.56 (1H, s); MS: 444 [M+H] ⁺ .

Example 10. 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline-10- Of phenyl)phenyl)-3-(2-methoxypyridin-4-yl)urea

Working with Example 1, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(2-chloro 4-Nitrophenyl)-3-(2-methoxypyridin-4-yl)urea gave a yellow solid in a yield of 72%;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.17 (3H, s), 3.99 (3H, s), 4.45 (2H, br), 4.61 (2H, br), 7.04 (1H, s), 7.20 (1H) , d, J = 4.0 Hz) 7.39 (1H, s), 7.60 (1H, s), 7.87 (1H, s), 8.14 (2H, d, J = 8.0 Hz), 8.18 (1H, s), 8.79 ( 1H, s), 9.11 (1H, s), 10.60 (1H, s); MS: 509 [M+H] ⁺ .

Example 11. 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline-10- Of phenyl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea

Working with Example 1, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(2-chloro 4-Aminophenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea obtained as a yellow solid, yield 76%;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.93 (3H, s), 4.40 (2H, s), 4.59 (2H, s), 6.90 (1H, s), 7.64 (2H, s), 7.68 (1H) , d, J = 8.0 Hz), 8.04 (1H, d, J = 8.0 Hz), 8.13 (1H, d, J = 8.0 Hz), 8.20 (1H, s), 8.41 (1H, s), 8.44 (1H) , s) 9.62 (1H, s), 9.79 (1H, s); MS: 580 [M+H] ⁺ .

Example 12. 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline-10- Of phenyl)phenyl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea

Working with Example 1, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(2-chloro 4-aminophenyl)-3-(4-fluoro-4-(trifluoromethyl)phenyl)urea obtained as a yellow solid, yield 66%;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.92 (3H, s), 4.40 (2H, s), 4.60 (2H, s), 6.91 (1H, s), 7.42 (1H, s), 7.52 (1H) , t, J = 8.0 Hz), 7.67 (1H, d, J = 8.0 Hz), 8.08 (1H, d, J = 8.0 Hz), 8.21 (1H, s), 8.44 (1H, s), 8.65 (1H) , s) 8.91 (1H, s), 9.62 (2H, s); MS: 564 [M+H] ⁺ .

Example 13. 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline-10- Of phenyl)phenyl)-3-(4-(phenoxy)phenyl)urea

Working with Example 1, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(2-chloro 4-Aminophenyl)-3-(4-(phenoxy)phenyl)urea obtained as a yellow solid, yield 78%;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.93 (3H, s), 4.41 (2H, br), 4.59 (2H, br), 6.90 (1H, s), 6.96-7.02 (4H, m), 7.10 (1H, t, J = 8.0 Hz), 7.37 (2H, t, J = 8.0 Hz), 7.50 (2H, d, J = 8.0 Hz), 7.62 - 7.65 (1H, m), 8.11 - 8.14 (2H , m), 8.29 (1H, s), 8.48 (1H, s), 9.38 (1H, s), 9.74 (1H, s); MS: 570 [M+H] ⁺ .

Example 14. 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline-10- Preparation of oxy)phenyl)-3-phenylurea

Step a) 10-(3-Chloro-4-nitrophenoxy)-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazole Preparation of porphyrin

10-Chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline (25 mg, 0.1 mmol), 3-chloro-4- Nitrophenol, potassium carbonate and K ₂ CO ₃ (20 mg, 0.15 mmol) were reacted in isopropyl alcohol (10 ml) at 80 ° C for 3 h. After cooling, suction filtration with water gave a yellow solid (yield: <RTI ID=0.0>&^gt;

Step b) 2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazolin-10-yl)oxy Preparation of aniline

10-(3-Chloro-4-nitrophenoxy)-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline ( 31 mg, 0.08 mmol) was dissolved in 5 ml of methanol, 50 mg of Raney nickel was added, and the mixture was stirred under a hydrogen atmosphere for 2 hours, filtered and concentrated to give the product 28 mg, yield 99%. MS: 360 [M+H] ⁺ .

Step c) 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazolin-10-yl) Preparation of oxy)phenyl)-3-phenylurea

2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)aniline (28mg, 0.08mmol) was dissolved in 5 ml of dichloromethane, 0.2 ml of triethylamine was added, and triphosgene (29 mg, 0.1 mmol) was stirred for 0.5 hour, then aniline (9 mg, 0.1 mmol) was added and stirring was continued until the reaction was completed. After concentration, column chromatography gave the product 30 mg, yield 80%.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.97 (3H, s), 4.40 (2H, br), 4.45 (2H, br), 7.00 (1H, t, J = 8.0 Hz), 7.07 (1H, s), 7.20-7.23 (1H, m), 7.29-7.33 (2H, m), 7.46-7.50 (3H, m), 8.19 (1H, d, J = 8.0 Hz), 8.40 (1H, s), 8.49 (1H, s), 9.48 (1H, s); MS: 479 [M+H] ⁺ .

Example 15. 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline-10- Of oxy)phenyl)-3-isopropylurea

Referring to the operation of Example 14, the aniline can be replaced by isopropylamine to obtain 35 mg of a yellow solid in a yield of 80%;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 1.12 (6H, d, J = 8.0 Hz), 3.77 (1H, p, J = 8.0 Hz), 3.97 (3H, s), 4.39 (2H, br) , 4.45 (2H, br), 6.93 (1H, t, J = 8.0 Hz), 7.05 (1H, s), 7.13 (1H, d, J = 12.0 Hz), 7.38 (1H, s), 7.94 (1H, s), 8.20 (1H, d, J = 8.0 Hz), 8.45 (1H, s); MS: 445 [M+H] ⁺ .

Example 16. 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3,f]quinazoline-10- Of oxy)phenyl)-3-(4-fluorophenyl)urea

Refer to the operation of Example 14 to replace the aniline with p-fluoroaniline to obtain 25 mg of a yellow solid with a yield of 65%;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.97 (3H, s), 4.39 (2H, br), 4.45 (2H, br), 7.06 (1H, s), 7.15 (2H, t, J = 8.0 Hz), 7.21 (1H, d, J = 8.0 Hz), 7.46-7.51 (3H, m), 8.17 (1H, d, J = 8.0 Hz), 8.33 (1H, s), 8.46 (1H, s), 9.42 (1H, s) MS: 497 [M+H] ⁺ .

Example 17. 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3,f]quinazoline-10- Of phenyl)phenyl)-3-(3-methylsulfonylphenyl)urea

Working with Example 1, consisting of 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1 (4-amino- 2-Chlorophenyl)-3-(3-(methylsulfonyl)phenyl)urea gives a yellow solid;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.21 (3H, s), 3.97 (3H, s), 4.31-4.70 (4H, m), 6.97 (1H, s), 7.49-7.64 (3H, m ), 7.68 (1H, d, J = 5.7 Hz), 7.94 (1H, s), 8.20 (2H, d, J = 8.2 Hz), 8.66 (2H, d, J = 25.9 Hz), 10.19 (1H, s ), 10.31 (1H, s); MS: 556 [M+H] ⁺ .

Example 18. 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-methoxy-2,3-dihydro-[1,4]dioxin) Preparation of alkano[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

From 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea and 10-chloro-5-methoxy-2,3-dihydro-[1 4] Dioxo[2,3-f]quinazoline and K ₂ CO ₃ (20 mg, 0.15 mmol) were reacted in isopropyl alcohol (10 ml) at 80 ° C for 3 h. After cooling, the mixture was extracted with ethyl acetate and brine, and then evaporated. Purified to give 30 mg of a yellow solid, yield 53%;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.97 (3H, s), 4.28-4.58 (4H, m), 7.05 (1H, s), 7.15 (2H, d, J = 8.9 Hz), 7.53 (2H) , d, J = 9.0 Hz), 7.76 - 7.59 (2H, m), 8.13 (1H, d, J = 2.4 Hz), 8.43 (1H, s), 8.93 (1H, s), 9.20 (1H, s) ;MS: 547 [M+H] ⁺ .

Example 19. 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-((5-methoxy-2,3-dihydro-[1, 4] Preparation of dioxo[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

The same procedure as in Example 18, from 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-hydroxyphenyl)urea and 10-chloro-5-methoxy Reaction of benzyl-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline to give the desired product as a gray solid, yield 74%; ¹ HNMR (DMSO-d ₆ , 400 MHz δ ppm: 3.97 (3H, s), 4.27 - 4.54 (4H, m), 7.06 (2H, s), 7.32 (1H, d, J = 11.7), 7.63 (2H, s), 8.10 (2H, d, J = 19.4), 8.46 (1H, s), 8.69 (1H, d, J = 1.8 Hz), 9.51 (1H, s); MS: 565 [M+H] ⁺ .

Example 20. 1-(2-Fluoro-5-(trifluoromethyl)phenyl)-3-(4-((5-methoxy-2,3-dihydro-[1,4]dioxin) Preparation of alkano[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

The same procedure as in Example 18, from 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea and 10-chloro-5-methoxy-2, Reaction of 3-dihydro-[1,4]dioxane[2,3-f]quinazoline to give the title compound as a white solid, yield 55%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.97 (3H, s), 4.42 (4H, d, J = 25.9), 7.05 (1H, s), 7.17 (2H, d, J = 8.9 Hz), 7.53 (4H, d, J = 8.9 Hz), 8.43 (1H, s), 8.64 (1H, dd, J = 7.3, 2.1 Hz), 8.91 (1H, d, J = 2.8 Hz), 9.25 (1H, s); MS: 531 [M+H] ⁺ .

Example 21. 1-(2,4-Difluorophenyl)-3-(2-fluoro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane) Preparation of [2,3-f]quinazolin-10-yl)oxy)phenyl)urea

The same procedure as in Example 18, from 1-(2,4-difluorophenyl)-3-(2-fluoro-4-hydroxyphenyl)urea and 10-chloro-5-methoxy-2,3- Reaction of dihydro-[1,4]dioxane[2,3-f]quinazoline to give the title product as a purple solid, yield 55%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.97 ( 3H, s), 4.42 (4H, d, J = 25.9), 7.05-7.07 (3H, m), 7.29-7.33 (2H, m), 8.13-8.16 (2H, m), 8.44 (1H, s), 8.98 (1H, s), 9.00 (1H, s); MS: 499 [M+H] ⁺ .

Example 22. 1-(2-Chloro-4-((5-methoxy-2,3-2hydro-[1,4]dioxin[2,3-f]quinazolin-10-yl) Preparation of oxy)phenyl)-3-cyclopropylurea

Working with Example 18, from the compound 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(2 -Chloro-4-hydroxyphenyl)-3-cyclopropylamine urea should give a pale purple solid in a yield of 48%;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 0.36-0.47 (2H, m), 0.67 (2H, br), 2.58 (1H, dd, J = 6.8, 3.7 Hz), 3.96 (3H, s), 4.32 -4.49(4H,m),7.05(1H,s),7.09-7.24(2H,m),7.39(1H,dJ=2.7Hz),7.92(1H,s),8.17(1H,d,J=9.0 Hz), 8.45 (1H, s); MS: 443 [M+H] ⁺ .

Example 23. 1-(4-((5-Methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazolin-10-yl)oxy) Preparation of phenyl)-3-(3-methoxyphenyl)urea

Working with Example 18, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(4-hydroxyl Benzyl)-3-(3-methoxyphenyl)urea gave the desired product as a pale yellow solid, yield 52%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.74 (3H, s), 3.97 (3H, s), 4.39 (2H, br), 4.46 (2H, br), 6.55 (1H, d, J = 8.0 Hz), 6.96 (1H, d, J = 8.0 Hz), 7.05 (1H, s ), 7.12 - 7.22 (3H, m), 7.52 (2H, d, J = 8.0 Hz), 7.84 (1H, s), 8.43 (1H, s), 8.88 (1H, s), 8.91 (1H, s) ;MS: 475 [M+H] ⁺ .

Example 24. 1-(3-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline-10- Of oxy)phenyl)-3-(3-methoxyphenyl)urea

Working with Example 18, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(3-chloro Reaction of -4-hydroxyphenyl)-3-(3-methoxyphenyl)urea to give the title compound as a white solid, yield: 58%; ¹ HNMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.74 (3H, s), 3.98 (3H, s), 4.40 (2H, br), 4.47 (2H, br), 6.58 (1H, d, J = 8.0 Hz), 6.96 (1H, d, J = 8.0 Hz), 7.08 ( 1H, s), 7.17-7.21 (2H, m), 7.30-7.38 (2H, m), 7.84 (1H, s), 8.44 (1H, s), 8.89 (1H, s), 9.02 (1H, s) ;MS: 509 [M+H] ⁺ .

Example 25. 1-(4-((5-Methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazolin-10-yl)oxy) Preparation of phenyl)-3-(2-methoxypyridin-4-yl)urea

Working with Example 18, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(4-hydroxyl Phenyl)-3-(2-methoxypyridin-4-yl)urea gave the desired product as a pale yellow solid, yield 56%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.82 (3H, s), 3.97 (3H, s), 4.40 (2H, br), 4.47 (2H, br), 6.97-7.00 (2H, m), 7.05 (1H, s), 7.16 (2H, d, J = 8.0 Hz) ), 7.52 (2H, d, J = 8.0 Hz), 7.97 (1H, d, J = 4.0 Hz), 8.43 (1H, s), 9.21 (1H, s), 9.43 (1H, s); MS: 476 [M+H] ⁺ .

Example 26. 1-(3-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline-10- Of oxy)phenyl)-3-(2-methoxypyridin-4-yl)urea

Working with Example 18, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(3-chloro -4-Hydroxyphenyl)-3-(2-methoxypyridin-4-yl)urea gave the desired product as a pale yellow solid, yield 52%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm : 3.81 (3H, s), 3.97 (3H, s), 4.39 (2H, br), 4.46 (2H, br), 6.98-7.00 (2H, m), 7.08 (1H, s), 7.34 (1H, d , J = 8.0 Hz), 7.40 (1H, d, J = 12.0 Hz), 7.83 (1H, s), 7.99 (1H, d, J = 4.0 Hz), 8.45 (1H, s), 9.12 (1H, s ), 9.29 (1H, s); MS: 510 [M+H] ⁺ .

Example 27. 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline-10- Amino)phenyl)-3-cyclobutylurea

Working with Example 1, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(4-amino -2-Chlorophenyl)-3-cyclobutylurea gives the desired product as a yellow solid, yield 55%,

¹ H NMR (CD ₃ OD + DMSO-d ₆ (1:1), 400 MHz) δ ppm: 1.61-1.64 (2H, m), 1.80-1.86 (2H, m), 2.20-2.22 (2H, m), 3.94 ( 3H, s), 4.10-4.15 (1H, m), 4.38-4.40 (2H, m), 4.55-4.57 (2H, br), 6.84 (1H, s), 7.43 (1H, d, J = 8.0 Hz) , 7.80 (1H, s), 8.10 (1H, d, J = 8.0 Hz), 8.55 (1H, s); MS: 456 [M+H] ⁺ .

Example 28. 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline-10- Amino)phenyl)-3-cyclopentylurea

Working with Example 1, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(4-amino -2-Chlorophenyl)-3-cyclopentylurea gave the desired product as a yellow solid, yield 58%;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 1.38-1.42 (2H, m), 1.54-1.57 (4H, m), 1.82-1.85 (2H, m), 3.76-3.77 (1H, m), 3.98 ( 3H, s), 4.41-4.43 (2H, m), 4.59-4.61 (2H, m), 7.00 (1H, s), 7.20 (1H, d, J = 8.0 Hz), 7.48 (1H, d, J = 8.0 Hz), 7.83 (1H, s), 8.05 (1H, s), 8.23 (1H, d, J = 8.0 Hz), 8.67 (1H, s), 10.30 (1H, s), MS: 470 [M+ H] ⁺ .

Example 29. 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline-10- Amino)phenyl)-3-cyclohexylurea

Working with Example 1, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(4-amino 2-Chlorophenyl)-3-cyclohexylurea gave the desired product as a yellow solid, yield 52%;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 1.7-1.34 (6H, m), 1.66-1.70 (2H, m), 1.81-1.84 (2H, m), 3.76-3.77 (1H, m), 3.97 ( 3H, s), 4.42-4.44 (2H, m), 4.59-4.61 (2H, m), 7.05 (1H, s), 7.16 (1H, d, J = 8.0 Hz), 7.47 (1H, d, J = 8.0 Hz), 7.77 (1H, s), 8.12 (1H, d, J = 8.0 Hz), 8.24 (1H, d, J = 12.0 Hz), 8.74 (1H, s), 10.47 (1H, s) MS: 484[M+H] ⁺ .

Example 30. 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline-10- Amino)phenyl)-3-isoamylurea

Working with Example 1, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(4-amino -2-Chlorophenyl)-3-isopentylurea obtained the desired product as a yellow solid, yield 46%;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 0.91 (6H, d, J = 6.8 Hz), 1.32-1.37 (2H, m), 1.62-1.65 (1H, m), 3.12-3.14 (2H, m) , 3.98 (3H, s), 4.43-4.44 (2H, m), 4.59-4.60 (2H, m), 7.02 (1H, s), 7.12 (1H, s), 7.47 (1H, d, J = 12.0 Hz) ), 7.77 (1H, s), 8.15 (1H, s), 8.23 (1H, d, J = 12.0 Hz), 8.74 (1H, s), 10.47 (1H, s); MS: 472 [M+H] ⁺ .

Example 31. 1-(4-((5-(3-morpholinyloxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline -10-yl)oxy)phenyl)-3-(naphthalen-1-yl)urea

Working with Example 18, from 10-chloro-5-(3-morpholinyloxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline Reaction with 1-(4-hydroxyphenyl)-3-(naphthalen-1-yl)urea to give the title compound as a yellow solid.

¹ H NMR (DMSO-d ₆ , 300 MHz) δ 1.85 - 2.09 (2H, m), 2.23 - 2.47 (6H, m), 3.52 - 3.74 (4H, m), 4.21. (2H, d, J = 6.8 Hz ), 4.43 (4H, d, J = 15.9 Hz), 7.04 (1H, s), 7.16 (2H, d, J = 8.3 Hz), 7.43 - 7.70 (6H, m), 7.95 (1H, d, J = 7.8 Hz), 8.04 (1H, d, J = 7.4 Hz), 8.16 (1H, d, J = 8.2 Hz), 8.43 (1H, d, J = 3.3 Hz), 8.84 (1H, s), 9.20 (1H) , s); MS: 608 [M+H] ⁺ .

Example 32. 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline-10- (oxy)phenyl)-3-cyclopentylurea

Working with Example 18, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(2-chloro -4-hydroxyphenyl)-3-cyclopentyl urea was reacted to give the title compound as a yellow solid, yield 58%;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.34 - 1.46 (2H, m), 1.50 - 1.60 (2H, m), 1.61 - 1.72 (2H, m), 1.78 - 1.91 (2H, m), 1.95 –2.04(1H,m),3.96(3H,s),4.34–4.41(2H,m),4.42-4.46(2H,m),7.02–7.08(2H,m),7.10–7.16(1H,m) , 7.39 (1H, d, J = 2.7 Hz), 7.95 (1H, s), 8.20 (1H, d, J = 9.0 Hz), 8.45 (1H, s); MS: 471 [M+H] ⁺ .

Example 33. 1-(2-Chloro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline-10- Oxy)phenyl)-3-cyclohexylurea

Working with Example 18, from 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(2-chloro Reaction of 4-hydroxyphenyl)-3-cyclohexylurea to give the title compound as a yellow solid, yield 58%;

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.14 - 1.36 (6H, m), 1.61 - 1.74 (2H, m), 1.78 - 1.91 (2H, m), 3.44 - 3.58 (1H, m), 3.96 (3H, s), 4.32 - 4.56 (4H, m), 6.98 (1H, d, J = 7.6 Hz), 7.05 (1H, s), 7.09 - 7.19 (1H, m), 7.38 (1H, d, J = 2.7 Hz), 7.99 (1H, s), 8.19 (1H, d, J = 9.0 Hz), 8.45 (1H, s); MS: 485 [M+H] ⁺ .

Example 34. 1-(2-Chloro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Of quinazolin-10-yl)amino)phenyl)-3-cyclopropylurea

Working with Example 1, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline Reaction with 1-(4-amino-2-chlorophenyl)-3-cyclopropylurea gave the title compound as a yellow solid, yield 53%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 0.42 (2H , br), 0.65 (2H, br), 2.52 (1H, br), 3.33 (3H, s), 3.72 (2H, br), 4.24 (2H, br), 4.41 (2H, br), 4.59 (2H, Br), 6.91 (1H, s), 7.09 (1H, s), 7.40-7.46 (1H, m), 7.59 (1H, d, J = 8.0 Hz), 7.85 (1H, s), 8.06-8.11 (1H , m), 8.40 (1H, s), 9.56 (1H, s); MS: 486 [M+H] ⁺ .

Example 35. 1-(2-Chloro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3,f Of quinazolin-10-yl)amino)phenyl)-3-(3-methoxyphenyl)urea

Working with Example 1, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline Reaction with 1-(4-amino-2-chlorophenyl)-3-(3-methoxyphenyl)urea gave the title compound as a yellow solid, yield 56%; ¹ H NMR (DMSO-d ₆ , 400MHz) δppm: 3.34 (3H, s), 3.75 (3H, s), 3.76 (2H, br), 4.30 (2H, br), 4.45 (2H, br), 4.61 (2H, br), 6.59 (1H, d, J = 12.0 Hz), 6.97-6.99 (2H, m), 7.18-7.21 (2H, m), 7.56 (1H, d, J = 12.0 Hz), 7.87 (1H, s), 8.22 (1H, d , J = 8.0 Hz), 8.51 (1H, s), 8.72 (1H, s), 9.68 (1H, s), 10.48 (1H, s); MS: 552 [M+H] ⁺ .

Example 36. 1-(2-Chloro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3,f Of quinazolin-10-yl)amino)phenyl)-3-(pyridin-2-yl)urea

Working with Example 1, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline Reaction with 1-(4-amino-2-chlorophenyl)-3-(pyridin-2-yl)urea gave the title compound as a yellow solid, yield 52%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.35 (3H, s), 3.76 (2H, br), 4.29 (2H, br), 4.46 (2H, br), 4.62 (2H, br), 7.01 (2H, s), 7.06 (1H, t, J = 8.0 Hz), 7.26 (1H, d, J = 8.0 Hz), 7.59 (1H, d, J = 8.0 Hz), 7.80 (1H, t, J = 8.0 Hz), 7.92 (1H, s), 8.33 (1H, s), 8.41 (1H, d, J = 8.0 Hz), 8.73 (1H, s), 10.07 (1H, s), 10.46 (1H, s); MS: 523 [M+H] ⁺ .

Example 37. 1-(2-Chloro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3,f Preparation of quinazolin-10-yl)amino)phenyl)-3-phenylurea

Working with Example 1, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline Reaction with 1-(4-amino-2-chlorophenyl)-3-phenylurea gave the title compound as a yellow solid, yield 62%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.34 (3H , s), 3.76 (2H, br), 4.29 (2H, br), 4.46 (2H, br), 4.62 (2H, br), 6.98-7.04 (2H, m), 7.29-7.32 (2H, m), 7.49-7.51 (3H, m), 7.85 (1H, s), 8.23 (1H, d, J = 8.0 Hz), 8.58 (1H, s), 8.73 (1H, s), 9.79 (1H, s), 10.47 (1H, s); MS: 522 [M+H] ⁺ .

Example 38. 1-(2-Chloro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3,f Preparation of quinazolin-10-yl)amino)phenyl)-3-(4-fluorophenyl)urea

Working with Example 1, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline Reaction with 1-(4-amino-2-chlorophenyl)-3-(4-fluorophenyl)urea to give the title compound as a yellow solid, yield 55%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm :3.32(3H,s),3.73(2H,br),4.25(2H,br),4.40(2H,br),4.59(2H,br),6.90(1H,s),7.12-7.16(2H,m ), 7.49 (2H, br), 7.64 - 7.68 (1H, m), 8.07-8.09 (1H, m), 8.18 (1H, s), 8.26 (1H, s), 8.42 (1H, s), 9.36 ( 1H, s), 9.59 (1H, s); MS: 540 [M+H] ⁺ .

Example 39. 1-(2-Chloro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Preparation of quinazolin-10-yl)amino)phenyl)-3-(3-methylisoxazol-5-yl)urea

Working with Example 1, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline Reaction with 1-(4-amino-2-chlorophenyl)-3-(3-methylisoxazol-5-yl)urea to give the title compound as a yellow solid, yield 65%; ¹ H NMR (DMSO -d ₆ , 400 MHz) δ ppm: 2.38 (3H, s), 3.34 (3H, s), 3.76 (2H, s), 4.29 (2H, s), 4.46 (2H, s), 4.62 (2H, s), 6.51 (1H, s), 7.03 (1H, s), 7.58 (1H, d, J = 12.0 Hz), 7.88 (1H, s), 8.20 (1H, d, J = 12.0 Hz), 8.74 (1H, s ), 8.90 (1H, s), 10.31 (1H, s), 10.48 (1H, s); MS: 527 [M+H] ⁺ .

Example 40. 1-(2-Chloro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Of quinazolin-10-yl)amino)phenyl)-3-isopropylurea

Working with Example 1, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline Reaction with 1-(4-amino-2-chlorophenyl)-3-isopropylurea gave the title compound as a yellow solid, yield: 58%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 1.12 ( 6H,d,J=6.0Hz), 3.34(3H,s), 3.74(2H,br),3.77(1H,p,J=6.0Hz), 4.27(2H,br),4.43(2H,br), 4.59 (2H, br), 6.90 (1H, s), 6.94 (1H, d, J = 8.0 Hz), 7.51 (1H, d, J = 12 Hz), 7.94 (2H, d, J = 8.0 Hz), 8.19 (1H, d, J = 12 Hz), 8.58 (1H, s), 10.04 (1H, s); MS: 488 [M+H] ⁺ .

Example 41. 1-(2-Chloro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Preparation of quinazolin-10-yl)amino)phenyl)-3-(2-methoxypyridin-4-yl)urea

Working with Example 1, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline Reaction with 1-(4-amino-2-chlorophenyl)-3-(2-methoxypyridin-4-yl)urea gave the title compound as a yellow solid, yield 62%; ¹ H NMR (DMSO- d ₆ , 400 MHz) δ ppm: 3.34 (3H, s), 3.77 (2H, br), 3.84 (3H, s), 4.31 (2H, br), 4.46 (2H, br), 4.62 (2H, br), 6.95 -6.98(2H,m),7.06(1H,t,J=8.0Hz), 7.58(1H,d,J=8.0Hz),7.88(1H,s),8.02(1H,d,J=4.0Hz) , 8.18 (1H, t, J = 12.0 Hz), 8.69 (1H, s), 8.74 (1H, s), 10.08 (1H, s), 10.49 (1H, s); MS: 553 [M+H] ⁺ .

Example 42. 1-(2-Chloro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Preparation of quinazolin-10-yl)amino)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea

Working with Example 1, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1- (4-amino-2-chlorophenyl) -3- (4-chloro-3- (trifluoromethyl) phenyl) urea to afford the desired product as a yellow solid, yield 47%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.34 (3H, s), 3.74 (2H, br), 4.26 (2H, br), 4.43 (2H, br), 4.61 (2H, br), 6.93 (1H, s), 7.62-7.65 (3H, m), 8.07-8.14 (3H, m), 8.55-8.57 (2H, m), 9.96 (1H, s), 10.05 (1H, s); MS: 624 [M+ H] ⁺ .

Example 43. 1-(2-Chloro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Preparation of quinazolin-10-yl)amino)phenyl)-3-(2-fluoro-4-(trifluoromethyl)phenyl)urea

Working with Example 1, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1- (4-amino-2-chlorophenyl) -3- (2-fluoro-4- (trifluoromethyl) phenyl) urea to afford the desired product as a yellow solid, yield 41%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.33 (3H, s), 3.73 (2H, br), 4.26 (2H, br), 4.42 (2H, br), 4.60 (2H, br), 6.92 (1H, s), 7.42 (1H, s), 7.50-7.52 (1H, m), 7.67 (1H, d, J = 8.0 Hz), 8.08 (1H, d, J = 8.0 Hz), 8.21 (1H, s), 8.43 (1H, s), 8.65-8.66 (1H, m), 8.90 (1H, s), 9.62 (2H, s); MS: 608 [M+H] ⁺ .

Example 44. 1-(2-Chloro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Of quinazolin-10-yl)amino)phenyl)-3-(4-(phenoxy)phenyl)urea

Working with Example 1, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline And 1-(2-chloro-4-aminophenyl)-3-(4-(phenoxy)phenyl)urea obtained as a yellow solid (yield: 62%; ¹ HNMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.33(3H, s), 3.73 (2H, br), 4.25 (2H, br), 4.42 (2H, br), 4.60 (2H, br), 6.91 (1H, s), 6.96-7.02 (4H, m) , 7.10-7.12 (1H, m), 7.37 (2H, t, J = 8.0 Hz), 7.49-7.51 (2H, m), 7.63-7.66 (1H, m), 8.10-8.16 (2H, m), 8.28 (1H, s), 8.45 (1H, s), 9.38 (1H, s), 9.67 (1H, s); MS: 614 [M+H] ⁺ .

Example 45. 1-(2-Chloro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxin[2,3-f] Preparation of quinazolin-10-yl)oxy)phenyl)-3-cyclopropylurea

Working with Example 18, the compound 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazole The porphyrin is reacted with 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea to give a white solid. Yield 48%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 0.43 (2H, d, J = 5.1 Hz), 0.67 (2H, d, J = 5.1 Hz), 2.57 (1H, dd, J = 6.9, 3.4 Hz), 3.39 (3H, s), 3.68-3.81 (2H, m), 4.22–4.33 (2H, m), 4.36–4.50 (4H, m), 7.06 (1H, s), 7.12–7.22 (2H, m), 7.39 (1H, d, J = 2.6 Hz), 7.92 (1H, s), 8.17 (1H, d, J = 9.1 Hz), 8.44 (1H, s); MS: 487 [M+ H] ⁺ .

Example 46. 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(2-methoxyethoxy))-2,3-dihydro- Preparation of [1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

Working with Example 18, from 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea and 10-chloro-5-(2-methoxyethyl Reaction of oxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline to give a pale-yellow solid, yield 62%; ¹ H NMR (DMSO-d ₆ , 400MHz) δ3.37(3H,s), 3.71–3.80(2H,m), 4.25– 4.36(2H,m), 4.43(4H,dd,J=18.9,4.5Hz),7.05(1H,s), 7.16 (2H, d, J = 8.9 Hz), 7.53 (2H, d, J = 8.9 Hz), 7.65 (2H, d, J = 15.8 Hz), 8.13 (1H, d, J = 2.2 Hz), 8.42 ( 1H, s), 8.92 (1H, s), 9.19 (1H, s); MS: 591 [M+H] ⁺ .

Example 47. 1-(2-Fluoro-5-(trifluoromethyl)phenyl)-3-(4-((5-(2-methoxyethoxy))-2,3-dihydro- Preparation of [1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

The same procedure as in Example 18, from 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea and 10-chloro-5-(2-methoxy Reaction of ethoxy)phenyl)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline to give the desired product as a white solid, yield 59%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 3.40 (3H, s), 3.71 - 3.77 (2H, m), 4.26 - 4.34 (2H, m), 4.43 (4H, d, J = 7.1 Hz), 7.06 (1H) , s), 7.17 (2H, d, J = 8.9), 7.40 (1H, d, J = 2.5 Hz), 7.53 (3H, dd, J = 9.7, 2.8 Hz), 8.42 (1H, s), 8.63 ( 1H, dd, J = 7.4, 2.1 Hz), 8.91 (1H, d, J = 2.8 Hz), 9.25 (1H, s); MS: 575 [M+H] ⁺ .

Example 48. 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-((5-(2-methoxyethoxy))-2,3 -Preparation of dihydro-[1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

The same procedure as in Example 18, from 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-hydroxyphenyl)urea and 10-chloro-5-(2 -methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline to give the desired product as a gray solid, yield 67%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 3.40 (3H, s), 3.71-3.78 (2H, m), 4.23 - 4.34 (2H, m), 4.43 (4H, d, J = 19.0 Hz), 7.07 ( 2H, s), 7.23 (1H, d, J = 11.7 Hz), 7.63 (2H, s), 8.09 (2H, d, J = 20.2 Hz), 8.45 (1H, s), 8.69 (1H, s), 9.50 (1H, s); MS: 609 [M+H] ⁺ .

Example 49. 1-(2,4-Difluorophenyl)-3-(2-fluoro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1 , 4] Preparation of dioxo[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

The same procedure as in Example 18, from 1-(2,4-difluorophenyl)-3-(2-fluoro-4-hydroxyphenyl)urea and 10-chloro-5-(2-methoxyethoxy Reaction of 2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline to give the title product as a pale purple solid, yield 63%; ¹ H NMR (DMSO-d ₆ , 400MHz) δ3.37(3H,s), 3.69–3.80(2H,m), 4.25–4.36(2H,m), 4.25-4.51(4H,m),7.02-7.08(3H,m),7.26 -7.38 (2H, m), 8.15 (2H, d, J = 16.6 Hz), 8.45 (1H, s), 8.99 (2H, d, J = 9.5 Hz); MS: 543 [M+H] ⁺ .

Example 50. 1-(4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline Preparation of -10-yl)oxy)phenyl)-3-(3-methoxyphenyl)urea

Working with Example 18, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline Reaction with 1-(4-hydroxyphenyl)-3-(3-methoxyphenyl)urea gave the title compound as a pale yellow solid, yield 61%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 3.35 (3H, s), 3.74 (3H, s), 3.75 (2H, s), 4.30 (2H, s), 4.40 (2H, s), 4.45 (2H, s), 6.56 (1H, d, J = 8.0 Hz), 6.95 (1H, d, J = 8.0 Hz), 7.06 (1H, s), 7.13-7.16 (2H, m), 7.18-7.21 (2H, m), 7.51 (2H, d, J = 8.0) Hz), 8.42 (1H, s), 8.73 (1H, s), 8.76 (1H, s); MS: 519 [M+H] ⁺ .

Example 51. 1-(3-Chloro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Of quinazolin-10-yl)oxy)phenyl)-3-(3-methoxyphenyl)urea

Working with Example 18, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline Reaction with 1-(3-chloro-4-hydroxyphenyl)-3-(3-methoxyphenyl)urea to give the title compound as a pale yellow solid, yield 49%; ¹ H NMR (DMSO-d ₆ , 400MHz) δppm: 3.34 (3H, s), 3.74 (3H, s), 3.76 (2H, s), 4.31 (2H, s), 4.42 (2H, s), 4.47 (2H, s), 6.58 (1H, d, J = 8.0 Hz), 6.95 (1H, d, J = 8.0 Hz), 7.09 (1H, s), 7.17 - 7.21 (2H, m), 7.30-7.35 (2H, m), 7.84 (1H, s ), 8.44 (1H, s), 8.86 (1H, s), 8.99 (1H, s); MS: 553 [M+H] ⁺ .

Example 52. 1-(4-((5-(2-methoxyethoxy))-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline Preparation of -10-yl)oxy)phenyl)-3-(2-methoxypyridin-4-yl)urea

Working with Example 18, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline Reaction with 1-(4-hydroxyphenyl)-3-(2-methoxypyridin-4-yl)urea gave the title compound as a pale yellow solid, yield 51%; ¹ H NMR (DMSO-d ₆ , 400MHz) δppm: 3.34 (3H, s), 3.75 (2H, s), 3.82 (3H, s), 4.30 (2H, s), 4.41 (2H, s), 4.46 (2H, s), 6.97 (1H, d, J = 4.0 Hz), 6.98 (1H, s), 7.06 (1H, s), 7.16 (2H, d, J = 8.0 Hz), 7.52 (2H, d, J = 8.0 Hz), 7.97 (1H, d, J = 8.0 Hz), 8.42 (1H, s), 9.11 (1H, s), 9.31 (1H, s); MS: 520 [M+H] ⁺

Example 53. 1-(3-Chloro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Of quinazolin-10-yloxy)phenyl)-3-(2-methoxypyridin-4-yl)urea

Working with Example 18, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline Reaction with 1-(3-chloro-4-hydroxyphenyl)-3-(2-methoxypyridin-4-yl)urea to give the title compound as a pale yellow solid, yield 54%; ¹ H NMR (DMSO -d ₆ , 400 MHz) δ ppm: 3.34 (3H, s), 3.75 (2H, s), 3.82 (3H, s), 4.31 (2H, s), 4.42 (2H, s), 4.47 (2H, s), 6.98(1H,d,J=4.0Hz), 6.99(1H,s),7.08(1H,s),7.33-7.38(2H,m),7.82(1H,s),7.98(1H,d,J= 8.0 Hz), 8.44 (1H, s), 9.21 (1H, s), 9.32 (1H, s); MS: 554 [M+H] ⁺ .

Example 54. 1-(2-Chloro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Of quinazolin-10-yl)oxy)phenyl)-3-cyclobutylurea

Working with Example 18, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline Reaction with 1-(4-hydroxy-2-chlorophenyl)-3-cyclobutylurea to give the title compound as a white solid, yield: 58%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.56 –1.72(2H,m), 1.77–1.91(2H,m), 2.15–2.30(2H,m), 3.38(3H,s),3.74(2H,s),4.05–4.20(1H,m),4.23 –4.33(2H,m), 4.34–4.52(4H,m),7.05(1H,s),7.11–7.18(1H,m), 7.27(1H,d,J=7.8Hz),7.39(1H,d , J = 2.6 Hz), 7.95 (1H, s), 8.15 (1H, d, J = 9.0 Hz), 8.44 (1H, s); MS: 501 [M+H] ⁺ .

Example 55. 1-(2-Chloro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Of quinazolin-10-yl)oxy)phenyl)-3-cyclopentylurea

Working with Example 18, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline Reaction with 1-(4-hydroxy-2-chlorophenyl)-3-cyclopentylurea to give the title compound as a white solid, yield 65%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.33 –1.46(2H,m), 1.50–1.61(2H,m),1.62–1.72(2H,m),1.79–1.91(2H,m),3.34(3H,s),3.69–3.78(2H,m) , 3.88–4.04(1H,m), 4.24–4.33(2H,m), 4.36–4.56(4H,m),7.05(2H,d,J=6.2Hz),7.10–7.22(1H,m),7.39 (1H, d, J = 2.7 Hz), 7.94 (1H, s), 8.20 (1H, d, J = 9.1 Hz), 8.44 (1H, s); MS: 515 [M+H] ⁺ .

Example 56. 1-(2-Chloro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Preparation of quinazolin-10-yl)oxy)phenyl)-3-cyclohexylurea

Working with Example 18, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline Reaction with 1-(4-hydroxy-2-chlorophenyl)-3-cyclohexylurea gave the title compound as a white solid, yield 68%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.13– 1.35 (6H, m), 1.61–1.73 (2H, m), 1.75–1.90 (2H, m), 3.38 (3H, s), 3.50 (1H, d, J = 9.8 Hz), 3.69–3.80 (2H, m), 4.22–4.33 (2H, m), 4.35–4.53 (4H, m), 6.99 (1H, d, J=7.6 Hz), 7.06 (1H, s), 7.10–7.18 (1H, m), 7.39 (1H, d, J = 2.7 Hz), 7.99 (1H, s), 8.19 (1H, d, J = 9.1 Hz), 8.44 (1H, s): MS: 529 [M+H] ⁺ .

Example 57. 1-(2-Fluoro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Of quinazolin-10-yloxy)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

Working with Example 18, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1- (2-fluoro-4-hydroxyphenyl) -3- (2-fluoro-5- (trifluoromethyl) phenyl) urea to afford the desired product as a white solid, yield 42%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 3.34 (3H, s), 3.67–3.79 (2H, m), 4.24–4.35 (2H, m), 4.36–4.52 (4H, m), 7.03–7.11 (2H) , m), 7.31–7.38 (1H, m), 7.39–7.46 (1H, m), 7.48–7.60 (1H, m), 8.15–8.26 (1H, m), 8.46 (1H, s), 8.60–8.72 (1H, m), 9.24 (1H, d, J = 2.3 Hz), 9.42 (1H, d, J = 2.9 Hz); MS: 593 [M+H] ⁺ .

Example 58. 1-(3-Fluoro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Of quinazolin-10-yloxy)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

Working with Example 18, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1- (3-fluoro-4-hydroxyphenyl) -3- (2-fluoro-5- (trifluoromethyl) phenyl) urea to afford the desired product as a white solid, yield 46%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 3.34 (3H, s), 3.69 - 3.80 (2H, m), 4.24 - 4.35 (2H, m), 4.37 - 4.60 (4H, m), 7.09 (1H, s ), 7.18–7.24 (1H, m), 7.30–7.38 (1H, m), 7.40–7.47 (1H, m), 7.49–7.58 (1H, m), 7.63–7.78 (1H, m), 8.46 (1H) , s), 8.57 - 8.74 (1H, m), 9.11 (1H, d, J = 2.8 Hz), 9.72 (1H, s); MS: 593 [M+H] ⁺ .

Example 59. 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((5-(2-methoxyethoxy))-2,3 -Preparation of dihydro-[1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

Working with Example 18, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1- (4-chloro-3- (trifluoromethyl) phenyl) -3- (3-fluoro-4-hydroxyphenyl) urea to afford the desired product as a white solid, yield 46%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 3.34 (3H, s), 3.67–3.82 (2H, m), 4.26–4.36 (2H, m), 4.36–4.58 (4H, m), 7.09 (1H, s ), 7.19–7.26 (1H, m), 7.29–7.40 (1H, m), 7.58–7.82 (3H, m), 8.12 (1H, d, J=2.4Hz), 8.46 (1H, s), 9.44 ( 1H, s), 9.60 (1H, s); MS: 609 [M+H] ⁺ .

Example 60. 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(6-((5-(2-methoxyethoxy))-2,3-dihydro- Preparation of [1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)pyridin-3-yl)urea

Working with Example 18, from 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline Reaction with 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(6-hydroxypyridin-3-yl)urea to give the title compound as a white solid, yield 44%; ¹ H NMR (DMSO-d ₆ , 300MHz) δ 3.38 (3H, s), 3.67–3.81 (2H, m), 4.24–4.36 (2H, m), 4.36–4.57 (4H, m), 7.08 (1H, s) , 7.25 (1H, d, J = 8.9 Hz), 7.66 (2H, d, J = 6.8 Hz), 8.09 (2H, d, J = 20.4 Hz), 8.44 (2H, d, J = 12.6 Hz), 9.35 (1H, s), 9.61 (1H, s); MS: 592 [M+H] ⁺ .

Example 61. 1-(2-Chloro-4-((5-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-[1,4]dioxane[ Preparation of 2,3-f]quinazolin-10-yl)amino)phenyl)-3-cyclopropylurea

Working with Example 1, from 10-chloro-5-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-[1,4]dioxane[2,3- f] quinazoline and 1-(4-amino-2-chlorophenyl)-3-cyclopropylurea are reacted to give the title compound as a yellow solid, yield 48%; ¹ HNMR (DMSO-d ₆ , 400 MHz) δ ppm: 0.43 (2H, d, J = 4.0 Hz), 0.66 (2H, d, J = 4.0 Hz), 1.69 (4H, br), 1.95-2.01 (4H, m), 2.46 (4H, m), 2.56 (1H, m), 4.15-4.18 (2H, m), 4.41 (2H, br), 4.59 (2H, br), 6.86 (1H, s), 7.10 (1H, s), 7.59 (1H, d, J = 8.0 Hz), 7.85 (1H, s), 8.08 (1H, d, J = 8.0 Hz), 8.13 (1H, s), 8.40 (1H, s), 9.54 (1H, s); MS: 539 [M +H] ⁺ .

Example 62. 1-(2-Chloro-4-((5-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-[1,4]dioxane[ Preparation of 2,3-f]quinazolin-10-yl)oxy)phenyl)-3-cyclopropylurea

Step a) 10-(3-Chloro-4-nitrophenoxy)-5-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-[1,4] Preparation of oxane[2,3-f]quinazoline

10-Chloro-5-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline ( 35 mg, 0.1 mmol), 3-chloro-4-nitrophenol, potassium carbonate and K ₂ CO ₃ (20 mg, 0.15 mmol) in isopropyl alcohol (10 ml). After cooling, suction filtration with water gave a yellow solid (yield: 39 mg, yield: 80%; MS: 487 [M+H] ⁺ .

Step b) 2-Chloro-4-((5-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-[1,4]dioxane[2,3- Preparation of f]quinazolin-10-yl)oxy)aniline

10-(3-Chloro-4-nitrophenoxy)-5-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-[1,4]dioxane And [2,3-f]quinazoline (39mg, 0.08mmol) was dissolved in 5ml of methanol, 50mg of Raney nickel was added, stirred under hydrogen for 2 hours, filtered and concentrated to give product 36 mg. 99%. MS: 457 [M+H] ⁺ .

Step c) 1-(2-Chloro-4-((5-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-[1,4]dioxane[2] , 3-f]quinazolin-10-yl)oxy)phenyl)-3-cyclopropylurea

2-Chloro-4-((5-(3-(pyrrolidin-1-yl)propoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] The quinazolin-10-yl)oxy)aniline (36 mg, 0.08 mmol) was dissolved in dichloromethane (5 mL), EtOAc (3 mL, EtOAc (EtOAc) 6 mg, 0.1 mmol) was stirred until the reaction was completed. After concentration of the reaction mixture, column chromatography gave product 34 mg, yield 80%. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 0.43 (2H, d, J = 4.0 Hz), 0.67 (2H, d, J = 4.0 Hz), 1.70 (4H, br), 1.95-1.99 (2H, m ), 2.46 (4H, m), 2.57 (3H, m), 4.20-4.23 (2H, m), 4.42 (4H, d, J = 10.0 Hz), 7.03 (1H, s), 7.13-7.16 (2H, m), 7.39 (1H, s), 7.92 (1H, s), 8.17 (1H, d, J = 8.0 Hz), 8.44 (1H, s), MS: 540 [M+H] ⁺ .

Example 63. 1-(2-Chloro-4-((5-(3-(morpholinepropyloxy)-2,3-dihydro-[1,4]dioxane[2,3- Preparation of f]quinazolin-10-yl)amino)phenyl)-3-cyclopropylurea

Working with Example 1, from 10-chloro-5-(3-(morpholinyloxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline Reaction of the porphyrin with 1-(4-amino-2-chlorophenyl)-3-cyclopropylurea afforded the title compound as a yellow solid, yield 52%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 0.42 (2H, d, J = 8.0 Hz), 0.64 (2H, d, J = 8.0 Hz), 1.95-2.01 (2H, m), 2.39-2.50 (4H, m), 2.55-2.57 (1H, m), 3.05-3.09(4H,m), 3.60(2H,br),3.18(2H,br),4.40(2H,br),4.58(2H,br),6.87(1H,s),7.13(1H,s) , 7.59 (1H, d, J = 8.0 Hz), 7.86 (1H, s), 8.07-8.12 (2H, m), 8.40 (1H, s), 9.55 (1H, s); MS: 555 [M+H ] ⁺ .

Example 64. 1-(2-Chloro-4-((5-(3-(morpholinyloxy)-2,3-dihydro-[1,4]dioxane[2,3- Preparation of f]quinazolin-10-yl)oxy)phenyl)-3-cyclopropylurea

Referring to the synthetic strategy of Example 62, 10-chloro-5-(3-(morpholinyloxy)-2,3-dihydro-[1,4]dioxane[2,3-f The quinazoline was used as a starting material to prepare the target compound 25 mg, yield 46%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm: 0.43 (2H, d, J = 8.0 Hz), 0.67 (2H, d, J=8.0Hz), 1.95-1.98(2H,m), 2.39(4H,br), 2.47(2H,t,J=8.0Hz),2.55-2.57(1H,m),3.59(4H,t,J =4.0 Hz), 4.22 (2H, t, J = 6.0 Hz), 4.42 (4H, d, J = 20.0 Hz), 7.03 (1H, s), 7.13-7.16 (2H, m), 7.39 (1H, s ), 7.92 (1H, s), 8.17 (1H, d, J = 8.0 Hz), 8.44 (1H, s); MS: 556 [M+H] ⁺ .

Example 65. 1-(2-Fluoro-5-(trifluoromethyl)phenyl)-3-(4-((5-(3-morpholinepropoxy)-2,3-dihydro-[ 1,4] Preparation of dioxo[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

Working with Example 18, from 10-chloro-5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and Reaction of 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea to give the title compound as a white solid, yield 45%; ¹ H NMR (DMSO-d ₆ , 400MHz) δ1.91–2.09(2H,m),2.33-2.45(4H,m),3.05–3.10(2H,m),3.55-3.65(4H,m),4.16–4.32(2H,m) , 4.36–4.55 (4H, m), 7.05 (1H, s), 7.13–7.20 (2H, m), 7.35–7.44 (1H, m), 7.48–7.52 (1H, m), 7.52–7.58 (2H, m), 8.43 (1H, s), 8.64 (1H, dd, J = 7.4, 2.4 Hz), 9.05 (1H, d, J = 3.3 Hz), 9.52-9.56 (1H, m); MS: 644 [M +H] ⁺ .

Example 66. 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-morpholinepropoxy)-2,3-dihydro-[ Preparation of 1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

Working with Example 18, from 10-chloro-5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and Reaction of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea to give the title compound as a white solid, yield 41%; ¹ H NMR (DMSO-d ₆ , 400MHz) δ1.95–2.11(2H,m), 2.33-2.50(4H,m), 3.01–3.16(2H,m),3.64(4H,br),4.19–4.29(2H,m),4.36 –4.57(4H,m),7.05(1H,s),7.11–7.21(2H,m), 7.49–7.58(2H,m),7.61–7.69(2H,m),8.13(1H,d,J= 2.3 Hz), 8.43 (1H, s), 9.15 (1H, s), 9.46 (1H, s); MS: 660 [M+H] ⁺ .

Example 67. 1-(3-Fluoro-4-((5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Preparation of quinazolin-10-yl)oxy)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

Working with Example 18, from 10-chloro-5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and Reaction of 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(3-fluoro-4-hydroxyphenyl)urea to give the title compound as a white solid, yield 47%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.86–2.10 (2H, m), 2.35–2.46 (6H, m), 3.51–3.69 (4H, m), 4.16–4.28 (2H, m), 4.34–4.55 ( 4H,m),7.07(1H,s),7.17–7.25(1H,m),7.31–7.37(1H,m),7.39–7.47(1H,m),7.49–7.58(1H,m),7.65– 7.75 (1H, m), 8.46 (1H, s), 8.55 - 8.68 (1H, m), 9.09 (1H, d, J = 3.2 Hz), 9.67 (1H, d, J = 9.7 Hz); MS: 662 [M+H] ⁺ .

Example 68. 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((5-(3-morpholinepropoxy)-2,3- Preparation of dihydro-[1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

Working with Example 18, from 10-chloro-5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and Reaction of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-hydroxyphenyl)urea to give the title compound as a white solid, yield 52%; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 1.92–2.02 (2H, m), 2.22–2.49 (6H, m), 3.51–3.71 (4H, m), 4.15–4.31 (2H, m), 4.31–4.57 ( 4H,m), 6.95–7.14(2H,m), 7.22–7.44(1H,m), 7.64(2H,d,J=1.7Hz),8.03–8.23(2H,m),8.43(1H,d, J = 15.7 Hz), 8.79 (1H, d, J = 2.2 Hz), 9.72 (1H, s); MS: 678 [M+H] ⁺ .

Example 69. 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-((5-(3-morpholinepropoxy)-2,3- Preparation of dihydro-[1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

Working with Example 18, from 10-chloro-5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and Reaction of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-hydroxyphenyl)urea to give the title compound as a white solid, yield 55%; ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 1.85–2.07 (2H, m), 2.22–2.44 (6H, m), 3.50–3.73 (4H, m), 4.11–4.31 (2H, m), 4.31–4.57 ( 4H,m), 6.98–7.15(2H,m), 7.32 (1H,d,J=11.7Hz), 7.55–7.73(2H,m),8.02–8.20(2H,m),8.45(1H,s) , 8.79 (1H, s), 9.71 (1H, s); MS: 678 [M+H] ⁺ .

Example 70. 1-(2-Fluoro-4-((5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Preparation of quinazolin-10-yl)oxy)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

Working with Example 18, from 10-chloro-5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and Reaction of 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(2-fluoro-4-hydroxyphenyl)urea to give the title compound as a white solid, yield 45%, ¹ H NMR (400MHz, DMSO-d ₆ ) δppm 1.93-2.03 (2H, m), 2.39 (4H, s), 2.46 (2H, t, J = 7.1 Hz), 3.59 (4H, t, J = 4.7 Hz), 4.22 (2H, t, J = 6.4 Hz), 4.37-4.48 (4H, m), 7.05 (1H, s), 7.02-7.10 (1H, m), 7.34 (1H, d, J = 11.8 Hz), 7.43 ( 1H, s), 7.48-7.58 (1H, m), 8.19 (1H, t, J = 9.1 Hz), 8.45 (1H, s), 8.66 (1H, d, J = 7.4 Hz), 9.25 (1H, s ), 9.43 (1H, d, J = 2.8 Hz); MS: 662 [M+H] ⁺ .

Example 71. 1-(2-Chloro-4-((5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Preparation of quinazolin-10-yl)oxy)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

Working with Example 18, from 10-chloro-5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1- (2-chloro-4-hydroxyphenyl) -3- (2-fluoro-5- (trifluoromethyl) phenyl) urea to afford the desired product as a white solid, a yield of 45% ,; ¹ H NMR (DMSO-d ₆ , 300 MHz) δ ppm 1.96-1.20 (2H, m), 2.35-2.42 (6H, m), 3.59 (4H, br), 4.19-2.45 (2H, m), 4.43 (4H, d, J = 15.0 Hz), 7.05 (1H, s), 7.23 (1H, d, J = 9.1 Hz), 7.43 - 7.53 (3H, m), 8.18 (1H, d, J = 8.7 Hz), 8.46 (1H, s), 8.64 - 8.66 (1H, m), 9.03 (1H, s), 9.72 (1H, s); MS: 678 [M+H] ⁺ .

Example 72. 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(2-morpholinoethoxy)-2,3-dihydro-[ Preparation of 1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

Working with Example 18, from 10-chloro-5-(2-morpholinoethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and Reaction of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea to give the title compound as a white solid, yield 55%; ¹ H NMR (DMSO-d ₆ , 300MHz) δ 3.43 (4H, br), 3.72 (4H, br), 4.23 - 4.57 (8H, m), 6.96 (3H, br), 7.37 (2H, br), 7.62 (2H, br), 8.11 (1H, s), 8.40 (1H, s), 8.76 (1H, s), 9.18 (1H, s); MS: 646 [M+H] ⁺ .

Example 73. 1-(2-Fluoro-5-(trifluoromethyl)phenyl)-3-(4-((5-(3-morpholinoethoxy)-2,3-dihydro-[ Preparation of 1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

Working with Example 18, from 10-chloro-5-(2-morpholinoethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and Reaction of 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea to give the title compound as a white solid, yield 54%; ¹ H NMR (DMSO-d ₆ , 300MHz) δ 3.43 (4H, s), 3.73 (4H, s), 4.10–4.71 (8H, m), 6.96 (3H, br), 7.21–7.63 (4H, m), 8.40 (1H, s ), 8.62 (1H, d, J = 7.1 Hz), 8.85 (1H, s), 9.05 (1H, s); MS: 630 [M+H] ⁺ .

Example 74. 1-(3-Chloro-4-fluorophenyl)-3-(4-((5-(3-morpholinepropoxy)-2,3-dihydro-[1,4] Preparation of oxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

Working with Example 18, from 10-chloro-5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(3-Chloro-4-fluorophenyl)-3-(4-hydroxyphenyl)urea gave the desired product as a white solid, yield 45%; ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 1 .89–2.05(2H,m),2.31–2.46(6H,m),3.59(4H,s),4.16–4.28(2H,m),4.32–4.55(4H,m),7.03(1H,s) , 7.14 (2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 7.4 Hz), 7.51 (2H, d, J = 8.5 Hz), 7.82 (1H, d, J = 7.1 Hz), 8.41 (1H, d, J = 2.8 Hz), 8.87 - 9.03 (2H, m); MS: 610 [M+H] ⁺ .

Example 75. 1-(4-Fluoro-3-(trifluoromethyl)phenyl)-3-(4-((5-(3-morpholinepropoxy)-2,3-dihydro-[ Preparation of 1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

Working with Example 18, from 10-chloro-5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and Reaction of 1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea to give the title compound as a white solid, yield 41%; ¹ H NMR (DMSO-d ₆ , 300MHz) δ2.01(2H, s), 3.24–3.55(6H,m), 3.63(4H,s), 4.23(2H,s), 4.37–4.51(4H,m),7.04(1H,s ), 7.14 (2H, d, J = 8.3 Hz), 7.45 (1H, s), 7.50 - 7.60 (2H, m), 7.67 (1H, s), 8.03 (1H, s), 8.42 (1H, s) , 9.06 (1H, s), 9.24 (1H, s); MS: 644 [M+H] ⁺ .

Example 76. 1-(2-Fluoro-5-(trifluoromethyl)phenyl)-3-(4-((5-(2-(tetrahydropyrrol-1-yl)ethoxy)-2) Of 3-(3-hydrogen-[1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

Working with Example 18, from 10-chloro-5-(2-(tetrahydropyrrol-1-yl)ethoxy)-2,3-dihydro-[1,4]dioxane [2,3 -f] quinazoline and 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea are reacted to give the title compound as a white solid. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 1.81 (4H, s), 3.59 (4H, s), 4.16 - 4.56 (8H, m), 6.83 (1H, s), 6.97 (2H, d, J = 8.3 Hz), 7.39 (4H, s), 8.19 (2H, s), 8.85 (1H, s), 9.05 (1H, s); MS: 614 [M+H] ⁺ .

Example 77. 1-(4-((5-Ethoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazolin-10-yl)oxy) Preparation of phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

Working with Example 18, from 10-chloro-5-ethoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(2-fluoro -5-(Trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea gave the desired product as a white solid, yield 55%; ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 1. 42(3H,t,J=6.9Hz), 4.18-4.27(2H,m), 4.36-4.42(2H,m),4.42-4.49(2H,m),7.02(1H,s),7.17(2H, d, J=8.4 Hz), 7.40 (1H, s), 7.49-7.58 (3H, m), 8.42 (1H, d, J = 2.9 Hz), 8.59-8.68 (1H, m), 8.98 (1H, s ), 9.35 (1H, s); MS: 545 [M+H] ⁺ .

Example 78. 1-(4-((5-Isopropoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazolin-10-yl)oxyl Of phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

Working with Example 18, from 10-chloro-5-isopropoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and 1-(2- Reaction of fluoro-5-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea to give the title compound as a white solid, yield 55%; ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 1 .37(6H,d,J=5.8Hz), 4.41(4H,d,J=15.9Hz),4.83-4.98(1H,m),7.04(1H,s),7.16(2H,d,J=8.4 Hz), 7.41 (1H, s), 7.49-7.57 (3H, m), 8.41 (1H, s), 8.64 (1H, d, J = 7.1 Hz), 8.93 (1H, s), 9.27 (1H, s );

MS: 559 [M+H] ⁺ .

Example 79. 1-(2-Fluoro-5-(trifluoromethyl)phenyl)-3-(4-((5-((tetrahydro-2H-pyran-4-yl)oxy))- Preparation of 2,3-dihydro-[1,4]dioxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

Working with Example 18, from 10-chloro-5-((tetrahydro-2H-pyran-4-yl)oxy)-2,3-dihydro-[1,4]dioxane [2, Reaction of 3-f]quinazoline with 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea afforded the title compound as a white solid. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 2.22-2.49 (4H, m), 3.77-4.00 (4H, m), 4.42 (4H, d, J = 15.8 Hz), 5.27 (1H, s) , 7.01 (1H, s), 7.17 (2H, d, J = 8.4 Hz), 7.40 (1H, s), 7.48-7.58 (3H, m), 8.42 (1H, d, J = 2.9 Hz), 8.64 ( 1H,d,J=7.2Hz), 8.93(1H,s), 9.27(1H,s);MS:601[M+H] ⁺

Example 80. 1-(2-Fluoro-5-(trifluoromethyl)phenyl)-3-(4-((5-((tetrahydrofuran-3-yl)oxy)-2,3-dihydro) -[1,4] Preparation of Dioxo[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

Working with Example 18, from 10-chloro-5-((tetrahydrofuran-3-yl)oxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazole Reaction of the porphyrin with 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea to give the title compound as a white solid, yield 53%; ¹ H NMR (DMSO -d ₆ , 300MHz) δ1.91-2.03(2H,m), 2.60-2.69(2H,m), 2.73(1H,br),4.16-4.28(2H,m),4.42(4H,d,J= 15.5 Hz), 7.06 (1H, s), 7.17 (2H, d, J = 8.4 Hz), 7.40 (1H, s), 7.47-7.59 (3H, m), 8.42 (1H, s), 8.59-8.68 ( 1H, m), 8.93 (1H, s), 9.27 (1H, s); MS: 587 [M+H] ⁺ .

Example 81. 1-(4-((5-(3-(1,1-thiomorpholine dioxide)propoxy)-2,3-dihydro-[1,4]dioxane Preparation of [2,3-f]quinazolin-10-yl)oxy)phenyl)-3-(2-fluoro-5-(trifluoromethyl)phenyl)urea

Working with Example 18, consisting of 10-chloro-5-(3-(1,1-thiomorpholine dioxide)propoxy)-2,3-dihydro-[1,4]dioxane. [2,3-f]quinazoline and 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea are reacted to give the desired product as a white solid. The rate is 53%; ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 1.58-1.75 (2H, m), 2.00-2.14 (2H, m), 3.33-3.38 (6H, m), 3.55 (2H, t, J = 10.7 Hz), 3.83 - 3.95 (2H, m), 4.43 (4H, d, J = 14.6 Hz), 7.10 - 7.23 (3H, m), 7.41 (1H, s), 7.46 - 7.59 (3H, m ), 8.41 (1H, d, J = 2.9 Hz), 8.64 (1H, d, J = 7.2 Hz), 8.93 (1H, s), 9.27 (1H, s); MS: 692 [M+H] ⁺

Example 82. 1-(2-Chloro-4-((5-(3-(dimethylamino)propoxy)-2,3-dihydro-[1,4]dioxane[2, 3-f]quinazolin-10-yl)amino)phenyl)-3-cyclopropylurea

Working with Example 1, from 10-chloro-5-(3-(dimethylamino)propoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Quinazoline and 1-(4-amino-2-chlorophenyl)-3-cyclopropylurea gave a pale yellow solid in a yield of 51%;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0.45-0.39 (2H, m), 0.61-0.70 (2H, m), 1.97-2.01 (4H, m), 2.34 (6H, s), 2.53-2.56 (1H,m), 4.17(2H,t,J=6.3Hz), 4.37-4.44(2H,m),4.56-4.61(2H,m),6.87(1H,s),7.13(1H,d,J = 2.9 Hz), 7.59 (1H, d, J = 9.0 Hz), 7.88 (1H, s), 8.05-8.15 (2H, m), 8.40 (1H, s), 9.55 (1H, s); MS: 513 [M+H] ⁺ .

Example 83. 1-(2-Chloro-4-((5-(2-(1-methylpiperazin-4-yl)ethoxy)-2,3-dihydro-[1,4] Oxa[2,3-f]quinazolin-10-yl)amino)phenyl)-3-cyclopropylurea

Working with Example 1, consisting of 10-chloro-5-(2-(1-methylpiperazin-4-yl)ethoxy)-2,3-dihydro-[1,4]dioxane [ 2,3-f]quinazoline and 1-(4-amino-2-chlorophenyl)-3-cyclopropylurea gave a pale yellow solid, yield 56%; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0.42 (2H, d, J = 7.1 Hz), 0.65 (2H, d, J = 7.1 Hz), 2.15 (3H, s), 2.25-2.40 (8H, m), 2.53-2.58 (1H, m ), 2.74 (2H, d, J = 5.8 Hz), 4.22 (2H, t, J = 5.8 Hz), 4.36 - 4.43 (2H, m), 4.55 - 4.62 (2H, m), 6.90 (1H, s) , 7.16 (1H, d, J = 2.9 Hz), 7.59 (1H, d, J = 9.1 Hz), 7.89 (1H, s), 8.04 - 8.15 (2H, m), 8.40 (1H, s), 9.55 ( 1H, s); MS: 554 [M+H] ⁺ .

Example 84. 1-(2-Chloro-4-((5-(2-methylthioethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Of quinazolin-10-yl)amino)phenyl)-3-cyclopropylurea

Working with Example 18, from 10-chloro-5-(2-methylthioethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline And 1-(4-Amino-2-chlorophenyl)-3-cyclopropylurea gave a pale yellow solid, yield 71%;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0.38-0.46 (2H, m), 0.63-0.68 (2H, m), 2.20 (3H, s), 2.54-2.57 (1H, m), 2.91 (2H) , t, J = 6.5 Hz), 4.30 (2H, t, J = 6.5 Hz), 4.39 - 4.41 (2H, br), 4.58 - 4.60 (2H, br), 6.90 (1H, s), 7.12 (1H, d, J = 2.9 Hz), 7.59 (1H, d, J = 9.0 Hz), 7.87 (1H, s), 8.08 (1H, d, J = 9.0 Hz), 8.13 (1H, s), 8.41 (1H, s), 9.55 (1H, s); MS: 502 [M+H] ⁺ .

Example 85. 1-(2-Chloro-4-((5-(2-methylthio)ethoxy)-2,3-dihydro-[1,4]dioxane[2,3 Preparation of -f]quinazolin-10-yl)oxy)phenyl)-3-cyclopropylurea

Working with Example 18, from 10-chloro-5-((2-methylthio)ethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quina Oxazoline and 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea gave a pale yellow solid in a yield of 77%;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0.38-0.40 (2H, m), 0.61-0.63 (2H, m), 2.05 (3H, s), 2.52-2.57 (1H, m), 2.69-2.74 (2H, m), 4.30-4.47 (6H, m), 6.78-6.79 (1H, m), 6.85-6.86 (1H, m), 7.22 (1H, s), 7.59 (1H, s), 7.69-7.73 (2H, m), 8.75 (1H, s); MS: 503 [M+H] ⁺ .

Example 86. 1-(2-Chloro-4-((5-(3-methoxy)propoxy)-2,3-dihydro-[1,4]dioxane[2,3 Preparation of -f]quinazolin-10-yl)oxy)phenyl)-3-cyclopropylurea

Working with Example 18, from 10-chloro-5-((3-methoxy)propoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quina Oxazoline and 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea gave a pale yellow solid in a yield of 74%;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0.36-0.49 (2H, m), 0.67 (2H, d, J = 7.0 Hz), 2.01-2.07 (2H, m), 2.53-2.56 (1H, m ), 3.38 (3H, s), 3.51 (2H, t, J = 6.2 Hz), 4.22 (2H, t, J = 6.4 Hz), 4.43 (4H, d, J = 18.0 Hz), 7.03 (1H, s ), 7.13 - 7.16 (2H, m), 7.40 (1H, d, J = 2.7 Hz), 7.94 (1H, d, J = 9.0 Hz), 8.17 (1H, d, J = 9.0 Hz), 8.44 (1H) , s); MS: 501 [M+H] ⁺ .

Example 87. 1-(2-Chloro-4-((5-(2-dimethylamino)ethoxy)-2,3-dihydro-[1,4]dioxane[2,3- Preparation of f]quinazolin-10-yl)amino)phenyl)-3-cyclopropylurea

Working with Example 1, from 10-chloro-5-((2-dimethylamino)ethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f] Quinazoline and 1-(2-chloro-4-aminophenyl)-3-cyclopropylurea gave a pale yellow solid in a yield of 66%;

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.39-0.46 (2H, m), 0.66 (2H, d, J = 6.9 Hz), 2.25 (6H, br), 2.53-2.56 (1H, m), 2.70 (2H, t, J = 5.7 Hz), 4.20 (2H, br), 4.40 (2H, br), 4.60 (2H, br), 6.91 (1H, d, J = 6.4 Hz), 7.11 (1H, d, J=2.9 Hz), 7.49 (1H, d, J=8.8 Hz), 7.60-7.64 (1H, m), 7.88-7.91 (1H, m), 8.03-8.17 (1H, m), 8.42 (1H, d , J = 8.8 Hz), 9.59 (1H, s); MS: 499 [M+H] ⁺ .

Example 88. 1-(2-Chloro-4-((5-(6-methoxy)hexyloxy)-2,3-dihydro-[1,4]dioxane[2,3- Preparation of f]quinazolin-10-yl)oxy)phenyl)-3-cyclopropylurea

Working with Example 18, from 10-chloro-5-((6-methoxyhexyl)oxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quina Oxazoline and 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea give a pale yellow solid in 70% yield;

^{1 H NMR (300MHz, DMSO-} d 6) δ0.43 (2H, s), 0.66 (2H, s), 1.41 (4H, s), 1.52 (2H, s), 1.79 (2H, t, J = 7.2 Hz), 2.57 (1H, d, J = 6.6 Hz), 3.22 (3H, d, J = 2.7 Hz), 3.30 - 3.33 (2H, m), 4.14 (2H, d, J = 6.6 Hz), 4.41 ( 4H, d, J = 13.5 Hz), 7.02 (1H, s), 7.15 (2H, d, J = 9.4 Hz), 7.40 (1H, d, J = 2.9 Hz), 7.94 (1H, s), 8.17 ( 1H, d, J = 9.0 Hz), 8.43 (1H, d, J = 2.7 Hz); MS: 543 [M+H] ⁺ .

Example 89. 1-(2-Fluoro-5-chlorophenyl)-3-(4-((5-(3-morpholinepropoxy)-2,3-dihydro-[1,4] Preparation of oxane[2,3-f]quinazolin-10-yl)oxy)phenyl)urea

Working with Example 18, from 10-chloro-5-(3-morpholinepropoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinazoline and Reaction of 1-(5-chloro-2-fluorophenyl)-3-(4-hydroxyphenyl)urea to give the title compound as a white solid, yield 41%; ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 1 .88–2.03(2H,m), 2.34–2.46(6H,m),3.59(4H,s),4.14–4.27(2H,m),4.34–4.51(4H,m),6.98–7.10(2H, m), 7.16 (2H, d, J = 8.3 Hz), 7.26 - 7.38 (1H, m), 7.52 (2H, d, J = 8.4 Hz), 8.29 (1H, d, J = 4.2 Hz), 8.42 ( 1H, s), 8.79 (1H, s), 9.23 (1H, s); MS: 610 [M+H] ⁺ .

Example 90

1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2] , 3-f]-quinoline-10-yloxy)phenyl)urea

Step 1) Preparation of 1-(8-methoxy-6-nitro-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)ethyl-1-one

1-(8-Methoxy-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)ethyl-1-one (20.8 g, 100 mmol), nitric acid ( 22 mL) and acetic acid (44 mL) were placed in a round bottom flask and stirred until the reaction was completed, poured into crushed ice, and filtered to give 16.5 g of a yellow solid product, yield 66%. ¹ H NMR (400 MHz, Chloroform-d) δ 7.37 (s, 1H), 4.43 (dd, J = 5.4, 2.7 Hz, 2H), 4.35 (dd, J = 5.3, 2.7 Hz, 2H), 3.98 (s , 3H), 2.57 (s, 3H); MS: 254 [M+H] ⁺ .

Step 2) Preparation of 1-(8-methoxy-6-amino-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)ethyl-1-one

1-(8-Methoxy-6-nitro-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)ethyl-1-one (16.5 g, 65 mmol) was placed in a reaction flask, and palladium carbon (2 g) was added thereto under stirring in a hydrogen atmosphere until the reaction was completed, and concentrated by suction filtration to give a white solid product (13.7 g, yield: 95%). H NMR (400MHz, DMSO-d6) δ 6.90 (s, 2H), 5.96 (s, 1H), 4.32 - 4.25 (m, 2H), 4.18 - 4.09 (m, 2H), 3.72 (s, 3H), 2.41 (s, 3H); MS: 224 [M+H] ⁺ .

Step 3) Preparation of 10-hydroxy-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline

1-(6-Amino-8-methoxy-2,3-dihydrobenzo[b][1,4]dioxan-5-yl)ethyl-1-one (13.7 g, 62 mmol Ethyl formate (27.5 g, 372 mmol) was dissolved in dioxane, sodium tert-butoxide (17.8 g, 186 mmol) was added to stir until the starting material disappeared, 10 ml of methanol was added and stirring was continued until the reaction was completed, and the reaction solution was neutralized with hydrochloric acid. After neutralization, it was suction filtered and concentrated to give a white solid product of 14.4 g, yield 99%. ^{1 H NMR (400MHz, DMSO-} d6) δ11.26 (s, 1H), 7.59 (d, J = 7.3Hz, 1H), 6.55 (s, 1H), 5.77 (d, J = 7.2Hz, 1H), 4.34–4.13 (m, 4H), 3.82 (s, 3H); MS: 234 [M+H] ⁺ .

Step 4) Preparation of 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline

10-Hydroxy-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline (14.4 g, 61 mmol) was placed in a reaction flask and toluene was added. After dissolving, triethylamine (42 mL, 305 mmol) and phosphorus oxychloride (17 mL, 183 mmol) were added and stirred until the reaction was completed. The solvent was evaporated, and the obtained solid was washed with aqueous sodium hydrogen carbonate and filtered to give a white solid. The yield was 92%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.51 (d, J = 4.9 Hz, 1H), 7.38 (d, J = 4.8 Hz, 1H), 7.12 (s, 1H), 4.49 - 4.29 (m, 4H), 3.93 (s, 3H); MS: 252 [M+H] ⁺ .

Step 5) Preparation of 5-methoxy-10-(4-nitrophenoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline

10-Chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline (251 mg, 1 mmol) and p-nitrophenol (139 mg, 1 mmol) ), placed in a reaction flask, added with chlorobenzene, and heated to reflux until the reaction is completed. After cooling, it was suction filtered, and the obtained solid was washed with EtOAc EtOAc MS: 355 [M+H] ⁺ .

Step 6) Preparation of 4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl)oxy)aniline

5-methoxy-10-(4-nitrophenoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline (250 mg, 0.7 mmol) The mixture was placed in a reaction flask, and methanol and Raney nickel (250 mg) were added, and the mixture was stirred under a hydrogen atmosphere until the reaction was completed. MS: 325 [M+H] ⁺ .

Step 7) 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-methoxy-2,3-dihydro-[1,4]dioxane) Preparation of [2,3-f]quinolin-10-yl)oxy)phenyl)urea

4-((5-Methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl)oxy)phenylamine (226 mg, 0.7 mmol) And 4-chloro-3-(trifluoromethyl)aniline (195 mg, 1 mmol) dissolved in dichloromethane, triethylamine (0.4 mL, 3 mmol) and triphos (296 mg, 1 mmol) The mixture was extracted with aqueous sodium carbonate and ethyl acetate. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.22 (s, 1H), 8.97 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H), 7.73–7.59 (m, 2H), 7.59–7.49 (m, 2H), 7.15–6.98 (m, 3H), 6.44 (d, J=5.2 Hz, 1H), 4.34 (s, 4H), 3.93 (s, 3H); MS: 546 [M+H] ⁺ .

Example 91

1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((5-methoxy-2,3-dihydro-[1,4]dioxin) Preparation of alkano[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Steps 1 to 4 are the same as steps 1 to 4 of the preparation of Example 90.

Step 5) 10-(2-Fluoro-4-nitrophenoxy)-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline Preparation

Reference Example 90, Synthesis Step 5, which operates exactly the same, substituting the same molar equivalent of 2-fluoro-4-nitrophenol for p-nitrophenol. ^{1 H NMR (400MHz, DMSO-} d 6) δ8.67 (d, J = 5.0Hz, 1H), 8.44-8.27 (m, 1H), 8.13-7.93 (m, 1H), 7.19 (s, 1H), 7.07 (d, J = 4.9 Hz, 1H), 6.98 (t, J = 8.7 Hz, 1H), 4.31 - 4.18 (m, 2H), 4.16 - 4.06 (m, 2H), 3.95 (s, 3H); :373[M+H] ⁺ .

Step 6) 3-Fluoro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl)oxy) Preparation of aniline

Reference Example 90, Synthesis Step 6, which operates identically, in the same molar equivalent of 10-(2-fluoro-4-nitrophenoxy)-5-methoxy-2,3-dihydro-[1, 4] Dioxo[2,3-f]quinoline is substituted for 5-methoxy-10-(4-nitrophenoxy)-2,3-dihydro-[1,4]dioxane and [2,3-f]quinoline can be used. ¹ H NMR (400 Hz, DMSO-d6) δ 8.38 (d, J = 5.2 Hz, 1H), 7.05 (s, 1H), 6.99 (t, J = 9.0 Hz, 1H), 6.61 - 6.49 (m, 1H) ), 6.49–6.38 (m, 1H), 6.33 (d, J=5.3 Hz, 1H), 5.53–5.37 (m, 2H), 4.36–4.38 (m, 4H), 3.92 (s, 3H); MS: 343[M+H] ⁺ .

Step 7) 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((5-methoxy-2,3-dihydro-[1,4] Preparation of Dioxo[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Reference Example 90, Synthesis Step 7, which operates identically, in the same molar equivalent of 3-fluoro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2] , 3-f]quinoline-10-yloxy)aniline instead of 4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f] Quinoline-10-yl)oxy)aniline can be used. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.32 (s, 1H), 9.22 (s, 1H), 8.48 (d, J = 5.3 Hz, 1H), 8.16 (d, J = 2.5 Hz, 1H), 7.82–7.61 (m, 3H), 7.37–7.24 (m, 2H), 7.13 (s, 1H), 6.47 (d, J = 5.3 Hz, 1H), 4.41 (s, 4H), 3.98 (s, 3H) ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 161.1, 152.8, 152.5, 152.4, 149.6, 146.6, 139.5, 138.2, 138.2, 136.0, 132.4, 132.3, 123.8, 123.7, 123.0, 117.4, 115.7, 107.9, 107.7, 103.9 , 101.5, 64.5, 63.9, 56.2, 49.0; MS: 564 [M+H] ⁺ .

Example 92

1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-((5-methoxy-2,3-dihydro-[1,4]dioxin) Preparation of alkano[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Steps 1 to 4 are the same as steps 1 to 4 of the preparation of Example 90.

Step 5) 10-(3-Fluoro-4-nitrophenoxy)-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline Preparation

Reference Example 90, Synthesis Step 5, which operates exactly the same, substituting the same molar equivalent of 3-fluoro-4-nitrophenol for p-nitrophenol. MS: 373 [M+H] ⁺ .

Step 6) 2-Fluoro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl)oxy) Preparation of aniline

Reference Example 90, Synthesis Step 6, which operates identically, in the same molar equivalent of 10-(3-fluoro-4-nitrophenoxy)-5-methoxy-2,3-dihydro-[1, 4] Dioxo[2,3-f]quinoline is substituted for 5-methoxy-10-(4-nitrophenoxy)-2,3-dihydro-[1,4]dioxane and [2,3-f]quinoline can be used. ¹ H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 5.2 Hz, 1H), 7.04 (s, 1H), 6.98 - 6.91 (m, 1H), 6.89 - 6.79 (m, 1H), 6.78 - 6.67 (m, 1H), 6.37 (d, J = 5.2 Hz, 1H), 5.14 (s, 2H), 4.43 - 4.30 (m, 4H), 3.91 (s, 3H); MS: 343 [M+H] ⁺ .

Step 7) 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(2-fluoro-4-((5-methoxy-2,3-dihydro-[1,4] Preparation of Dioxo[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Reference Example 90 Synthesis Step 7, which operates identically, in the same molar equivalent of 2-fluoro-4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2] , 3-f]quinoline-10-yloxy)aniline instead of 4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f] Quinoline-10-yl)oxy)aniline can be used. ^{1 HNMR (400MHz, DMSO-d6} ) δ9.48 (s, 1H), 8.66 (d, J = 2.3Hz, 1H), 8.48 (d, J = 5.2Hz, 1H), 8.20-8.00 (m, 2H) , 7.62 (d, J = 1.5 Hz, 2H), 7.20 - 7.13 (m, 1H), 7.09 (s, 1H), 6.97 - 6.87 (m, 1H), 6.59 (d, J = 5.2 Hz, 1H), 4.52–4.18 (m, 4H), 3.93 (s, 3H); ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 160.4, 152.7, 152.4, 149.7, 146.8, 139.5, 138.0, 132.5, 132.3, 123.4, 123.1, 117.10, 116.1, 108.8, 108.3, 106.7, 101.6, 64.4, 63.9, 56.2, 40.2; MS: 564 [M+H] ⁺ .

Example 93

1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(2-methoxyethoxy))-2,3-dihydro-[1,4 Preparation of Dioxo[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Steps 1 to 4 are the same as steps 1 to 4 of the preparation of Example 90.

Step 4a) Preparation of 5-hydroxy-10-chloro-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline

Dissolve 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline (251 mg, 1 mmol) in dichloromethane and drip One mole of a solution of boron tribromide in dichloromethane (3 mL, 3 mmol) was stirred until the reaction was completed. Concentrated to a pale yellow solid product 236 mg, yield 99%. MS: 238 [M+H] ⁺ .

Step 4b) Preparation of 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]-quinoline

Dissolving 5-hydroxy-10-chloro-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline (236 mg, 1 mmol) in N,N-dimethylformamide 1-Bromo-2-methoxyethane (138 mg, 1 mmol) and potassium carbonate (414 mg, 3 mmol) were added, and the mixture was stirred with heating until completion. After adding water and ethyl acetate, the organic phase was concentrated and purified by column chromatography to yield 236 mg of white solid. ^{1 H NMR (400MHz, DMSO-} d6) δ8.70-8.46 (m, 1H), 7.50-7.33 (m, 1H), 7.25-7.09 (m, 1H), 4.40 (s, 4H), 4.30-4.23 ( m, 2H), 3.77 - 3.71 (m, 2H), 3.33 - 3.32 (m, 3H); MS: 296 [M+H] ⁺ .

Step 5) 5-(2-Methoxyethoxy)-10-(4-nitrophenoxy)-2,3-dihydro-[1,4]dioxane[2,3-f Preparation of quinoline

Reference Example 90 Synthesis Step 5, which operates identically, in the same molar equivalent of 10-chloro-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane. And [2,3-f]quinoline is substituted for 10-chloro-5-methoxy-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline. MS: 399 [M+H] ⁺ .

Step 6) 4-((5-(2-Methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl) Preparation of oxy)aniline

Reference Example 90, Synthesis Step 6, which operates identically, in the same molar equivalent of 5-(2-methoxyethoxy)-10-(4-nitrophenoxy)-2,3-dihydro- [1,4]Dioxo[2,3-f]quinoline in place of 5-methoxy-10-(4-nitrophenoxy)-2,3-dihydro-[1,4] Oxa[2,3-f]quinoline can be used. MS: 369 [M+H] ⁺ .

Step 7) 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-((5-(2-methoxyethoxy)-2,3-dihydro-[ Preparation of 1,4]dioxane[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Reference Example 90 Synthesis Step 7, which operates identically, in the same molar equivalent of 4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane And [2,3-f]quinolin-10-yl)oxy)aniline in place of 4-((5-methoxy-2,3-dihydro-[1,4]dioxane[2,3 -f]quinoline-10-yl)oxy)aniline. ^{1 HNMR (400MHz, DMSO-d6} ) δ9.15 (s, 1H), 8.91 (s, 1H), 8.34 (d, J = 5.2Hz, 1H), 8.05 (d, J = 2.4Hz, 1H), 7.63 –7.53 (m, 2H), 7.50–7.39 (m, 2H), 7.11–6.90 (m, 3H), 6.36 (d, J = 5.2 Hz, 1H), 4.37–4.21 (m, 4H), 4.21–4.13 (m, 2H), 3.70 - 3.63 (m, 2H), 3.28 (s, 3H); MS: 590 [M+H] ⁺ .

Example 94

1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((5-(2-methoxyethoxy)-2,3-dihydro-) Preparation of [1,4]dioxane[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Steps 1 to 4b are the same as Steps 1 to 4b of the preparation of Example 93.

Step 5) 10-(2-Fluoro-4-nitrophenoxy)-5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2 , 3-f] Preparation of quinoline

Reference Example 93, Synthesis Step 5, which operates exactly the same, substituting the same molar equivalent of 2-fluoro-4-nitrophenol for p-nitrophenol. MS: 417 [M+H] ⁺ .

Step 6) 3-Fluoro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4]dioxane[2,3-f]quinoline- Preparation of 10-yl)oxy)aniline

Reference Example 90, Synthesis Step 6, which operates identically, in the same molar equivalent of 10-(2-fluoro-4-nitrophenoxy)-5-(2-methoxyethoxy)-2,3 -Dihydro-[1,4]dioxane[2,3-f]quinoline in place of 5-methoxy-10-(4-nitrophenoxy)-2,3-dihydro-[1 , 4] dioxo[2,3-f]quinoline. MS: 387 [M+H] ⁺ .

Step 7) 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(3-fluoro-4-((5-(2-methoxyethoxy)-2,3- Preparation of dihydro-[1,4]dioxane[2,3-f]quinolin-10-yl)oxy)phenyl)urea

Reference Example 90 Synthesis Step 7, which operates identically, in the same molar equivalent of 3-fluoro-4-((5-(2-methoxyethoxy)-2,3-dihydro-[1,4 Dioxo[2,3-f]quinolin-10-yl)oxy)phenylamine in place of 4-((5-methoxy-2,3-dihydro-[1,4]dioxane [2,3-f]quinolin-10-yl)oxy)aniline may be used. ^{1 HNMR (300MHz, DMSO-d6} ) δ9.33 (s, 1H), 9.22 (s, 1H), 8.42 (d, J = 4.8Hz, 1H), 8.11 (d, J = 2.0Hz, 1H), 7.77 –7.52 (m, 3H), 7.25 (d, J = 2.5 Hz, 2H), 7.12–7.04 (m, 1H), 6.47–6.35 (m, 1H), 4.47–4.32 (m, 4H), 4.30–4.19 (m, 2H), 3.80 - 3.69 (m, 2H), 3.35 (s, 3H); MS: 608 [M+H] ⁺ .

Example 95. 1-(2-Fluoro-5-(trifluoromethyl)phenyl)-3-(4-((5-(3-morpholinepropoxy)-2,3-dihydro-[ Preparation of L-malic acid salt of 1,4]dioxane[2,3-f]quinazolin-10-yloxy)phenyl)urea

The compound obtained in Example 65 (645 mg, 1 mmol) was dissolved in 15 mL of acetone and stirred at room temperature for 15 min, then 2 mL of aqueous solution of L-malic acid (134 mg, 1 mmol) was added, and stirring was continued for 12 hours, and the reaction mixture was filtered to give a white solid (400 mg). The solid was dissolved in 15 mL of ethanol and heated under reflux. After completely dissolved, it was cooled and allowed to stand, and filtered to yield white crystal compound 260 mg, HPLC>99%. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 2.03 - 2.37 (4H, m) , 3.24–3.75(6H,m), 3.61–4.22(5H,m), 4.23–4.35(2H,m), 4.37–4.51(4H,m),7.07(1H,s),7.16(2H,d, J = 8.2 Hz), 7.40 (1H, s), 7.45 - 7.62 (3H, m), 8.44 (1H, s), 8.63 (1H, d, J = 7.1 Hz), 9.08 (1H, s), 9.59 ( 1H, s); MS: 644 [M+H] ⁺ .

Experimental Example 1. Test for inhibition of VEGFR-2 kinase activity by small molecule compounds

The test method is as follows:

1. Compound dilution: a total of 12 concentrations after a 4-fold gradient dilution from the highest concentration of 10000 nM (the maximum final concentration of the drug used in this experiment is 10000 nM, the minimum final concentration is 0.002384 nM).

2. Using a lance, take 2.5 μl of the graded compound and add to the 384-well plate.

3. Add enzyme: 5μl 2X VEGFR-2 kinase was added to the corresponding reaction well of 384-well plate with a lance, mixed and pre-reacted at room temperature for 30 min.

4. Take 2.5 μl of 4X substrate/ATP Mix into the corresponding reaction well of the 384-well plate.

5. Negative control: Add 2.5 μl/well 4X substrate/ATP Mix and 7.5 μl 1X Kinase Assay Buffer to the 384-well plate well.

Positive control: 2.5 μl/well 4X substrate/ATP Mix, 2.5 μl/well 1X Kinase Assay Buffer with 4% DMSO, 5 μl/well 2X VEGFR-2 solution were added to 384-well plates. The final concentration of DMSO in the reaction system is 4%.

6. Mix by centrifugation and avoid reaction at room temperature for 60 min.

7. Stop the enzymatic reaction: add 5 μl of 4X Stop solution to the wells of a 384-well plate with a lance, mix by centrifugation, and react at room temperature for 5 min.

8. Color reaction: 5 μl of 4X Detection Mix was added to the wells of a 384-well plate for color development, and the mixture was centrifuged at room temperature for 60 min.

9. Place the 384-well plate into the Envision plate reader and read the appropriate program detection signal.

10. Analysis and processing of raw data:

The drug concentration and the corresponding inhibition rate were calculated and input into GraphPad Prism5, and the inhibition rate of the compound was calculated as follows: inhibition rate (%) = [1 - (experimental well reading - negative control well reading value) / (positive control well reading value) - Negative control well reading)) x 100%. Using GraphPad Prism5 software deal with the corresponding IC ₅₀ values (concentration of compound inhibition rate of enzyme up 50%).

Table (1) lists the results of the determination of the tyrosine kinase inhibitory activity of some of the compounds of the present invention, and the intervals of IC ₅₀ are represented by A, B, and C, wherein A represents an IC _{50 of} less than or equal to 50 nM, and B represents an IC ₅₀ greater than 50 nM but less than or equal to 500 nM, C indicates an IC ₅₀ greater than 500 nM but less than or equal to 5000 nM, and D indicates an IC ₅₀ greater than 5000 nM.

Table (I), results of determination of VEGFR-2 tyrosine kinase inhibitory activity by some compounds of the present invention

Experimental Example 2. Test of inhibition of C-RAF and B-RAF kinase activity by small molecule compounds, the test methods are as follows:

1. Preparation of test compound: Depending on the molecular weight of the compound, directly add appropriate volume of DMSO to dissolve the test compound (see Table 1). The concentration of DMSO in the storage of the compound is 100%, and the final concentration in the experimental system is 1% ( See Table 2, 3). The compound was serially diluted with DMSO at a concentration of 3 times, with a maximum concentration of 1000 nM and a minimum concentration of 0.46 nM for a total of 8 dilution points.

2. Preparation of the positive control sorafenib: Sorafenib was a selective inhibitor of BRAF and RAF1, and as a positive control for this experiment, the dilution method was the same as that of the above test compound.

3. Test conditions:

Enzyme: B-RAF: 0.1 ng/ul (final concentration in the reaction system); C-RAF: 0.1 ng/ul (final concentration in the reaction system)

Substrate and ATP: inactive MEK1: 2 ng/ul (final concentration in the reaction system); ATP: 35 uM (final concentration in the reaction system)

HPE: no enzyme reaction (1% DMSO)

ZPE: reaction plus enzyme, but no compound (1% DMSO)

4. Test procedure:

a) add 1 ul of 10-fold diluted compound or 10% DMSO to a 384-well assay plate,

b) add 4ul enzyme solution or assay buffer to the well of the assay plate,

c) Centrifuge at 1000 rpm for 1 minute to mix.

d) adding 5 ul of ATP-substrate mixture to the wells of the assay plate,

e) Shake and mix for 2 minutes,

f) Incubate at 30 degrees for 1 hour,

g) Add 10ul of ADP-Glo reagent to the wells of the assay plate and incubate for 27 minutes at 27 degrees.

h) add 20 ul of kinase assay solution to the wells and incubate for 27 minutes at 27 degrees.

i) Read the chemiluminescent signal with Envision.

5. Analysis of results: Calculation of compound inhibition rate:

Inhibition rate (%) = (without compound control measured value - sample measured value) / (without compound control measured value - without enzyme control measured value) 100%

Using Prism software to calculate IC ₅₀ values of test compounds and the positive control compound in accordance with variable slope curve.

Table (2) lists the results of the determination of the inhibitory activities of some of the compounds in this patent on tyrosine kinases, C-RAF and B-RAF, using A, B, C to represent the IC ₅₀ interval, where A indicates an IC _{50 is} less than Or equal to 200 nM, B indicates an IC ₅₀ greater than 200 nM but less than or equal to 500 nM, C indicates an IC ₅₀ greater than 500 nM but less than or equal to 1000 nM, and D indicates an IC ₅₀ greater than 1000 nM.

Table (2), results of determination of C-RAF and B-RAF tyrosine kinase inhibitory activity by some compounds of the present invention

Experimental Example 3. Test of cell survival of small molecule compounds, the specific method is as follows:

1. Add 600 μL of trypsin to a T75 cell culture flask, digest it in a 37 ° C incubator for about 1 min, then add 5 mL of DMEM in complete medium, blow evenly, transfer to a 15 mL centrifuge tube, centrifuge at 1000 rpm for 4 min;

2. Discard the supernatant, add 5 mL of DMEM complete medium, blow evenly, mix 10 μL of cell suspension and 10 μL of 0.4% trypan blue, and count under the cell counter;

3. Cells of 6 different cell lines (MHCC97H, HuH7, HepG2, A549, 8505C) were inoculated in a 96-well plate at a cell density of 6000 cells/80 μL of complete culture solution/well, and the 96-well plate was not covered with 36 wells. Adding cells only with sterile water, only 60 wells inside for cell experiments and controls;

4. Compound dilution: the compound was diluted 3 times with a concentration of 10 mM, a total of 10 concentrations,

5. Add 20 μL of different kinds of compounds in different concentrations to each well, and shake the remaining wells with 20 μL of complete medium, and the concentration of DMSO in each well is 0.25%.

6. After incubation for 72 h, 10 μL of CCK-8 reagent was added to each well, and cultured at 37 ° C for 1-2 h; the OD value was read at 450 nm.

7. Cell viability (%) = [(As-Ab) / (Ac-Ab)] * 100%

As: experimental well (cell-containing medium, CCK-8, compound)

Ac: Control well (cell-containing medium, CCK-8)

Ab: blank well (cell and compound-free medium, CCK-8)

8. The value introduced into Graphpad Prism5 software IC ₅₀ (concentration of compound highest survival rate of 50%) is calculated.

Table (3) lists the results of assays for the activity of representative compounds of the present invention against various cancer cells, wherein MHCC97H, HuH7, and HepG2 are liver cancer cell lines, A549 is a lung cancer cell line, and 8505C is a thyroid cancer cell line.

Table (3), results of measurement of cell activity of representative compounds of the present invention

The biological data provided by the present invention indicate that the compounds of the present invention are useful for treating or preventing diseases caused by abnormalities of tyrosine kinases such as VEGFR-2 and/or C-RAF and/or B-RAF. Some of the compounds of the present invention have potent in vitro inhibitory activities against cancer cells, including liver cancer cells MHCC97, HuH7, HepG2, lung cancer cells A549, and thyroid cancer cells 8505C. Thus, the compounds of the invention are useful in the treatment of cancer, including primary and metastatic cancers, including solid tumors. Such cancers include, but are not limited to, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, intrauterine Membrane cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, esophageal cancer, brain Tumor, B-cell and T-cell lymphoma, lymphoma, multiple myeloma, biliary sarcoma, cholangiocarcinoma. The compounds of the invention also include cancers that are resistant to one or more other therapeutic methods.

The compounds of the present invention are also useful in diseases other than cancer associated with tyrosine kinases including, but not limited to, fundus diseases, psoriasis, rheumatoid arthritis, atheroma, pulmonary fibrosis, liver fibrosis . The compounds of the present invention may be administered as a monotherapy or a combination therapy, in combination with a plurality of compounds of the present invention or in combination with other drugs other than the present invention.

The above is a preferred embodiment of the present invention, and it should be noted that those skilled in the art can make several improvements and modifications to the embodiments of the present invention without departing from the principles of the present invention. These modifications and modifications are also considered to be within the scope of the invention.

Claims

a compound of the formula (I), a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof:

In formula (I),

X is O or NH;

Y is N or CH;

Z is N or CH;

R 1 is H, C 1 -C 9 alkyl, C 3 -C 7 cycloalkyl, 4-7 membered heterocyclic, C 3 -C 7 cycloalkyl substituted C 1 -C 6 alkyl a 4-7 membered heterocyclic substituted C 1 -C 6 alkyl group, substituted C 1 -C 9 alkyl group, the substituent in the substituted C 1 -C 9 alkyl group is a hydroxyl group, C 1 -C One or more of a 6 -alkoxy group, a C 1 -C 6 alkylthio group, a mono- or bi-C 1 -C 6 alkyl-substituted amino group or an unsubstituted amino group,

The above 4-7 membered heterocyclic group is a 4-7 membered heterocyclic group having 1 to 2 atoms selected from N, O and S, and the 4-7 membered heterocyclic group is not substituted or C 1 -C 6 An alkyl group, a C 1 -C 3 acyl group substituted or oxidized by one to two oxygen atoms;

R 2 is H or halogen;

R 3 is H or halogen;

R 4 is H or halogen;

R 5 is H, C 1 -C 9 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl substituted C 1 -C 6 alkyl, substituted or unsubstituted aryl Or a heteroaryl group, the substituted aryl or heteroaryl substituent being C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, mono or di C 1 One or more of -C 3 substituted amino or unsubstituted amino, halogen, trifluoromethyl, aryloxy or methylsulfonyl;

The heteroaryl group is a monocyclic or bicyclic group having 5 to 10 ring atoms, and the ring contains 1-3 atoms selected from N, O, and S.
The compound according to claim 1, a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof, wherein R 1 is H, C 1 -C 6 alkyl, C 3 -C 6 Cycloalkyl, 5-6 membered heterocyclyl, C 3 -C 6 cycloalkyl substituted C 1 -C 3 alkyl, 5-6 membered heterocyclyl substituted C 1 -C 3 alkyl, substituted a C 1 -C 6 alkyl group, wherein the substituent in the substituted C 1 -C 6 alkyl group is a hydroxyl group, a C 1 -C 3 alkoxy group, a C 1 -C 3 alkylthio group, a mono or a double C 1 One or more of an alkyl-substituted amino group or an unsubstituted amino group of -C 3 ,

The above 5- to 6-membered heterocyclic group is a 5-6 membered heterocyclic group having 1 to 2 atoms selected from N, O and S, and the 5-6 membered heterocyclic group is not substituted or C 1 -C 3 The alkyl group, C 1 -C 3 acyl group is substituted or oxidized by one to two oxygen atoms.
A compound according to claim 2, a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof,

R 1 is selected from the group consisting of: H, methyl, ethyl, propyl, isopropyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, tetrahydrofuran 3-yl, tetrahydro-2H-pyran-4-yl, tetrahydropyrrole-1-ethyl, tetrahydropyrrole-1-propyl, morpholin-4-ethyl, morpholin-4-propyl ,methylpiperazine-4-ethyl, methylpiperazine-4-propyl, N-formylpiperazine-4-ethyl, N-formylpiperazine-4-propyl, N-acetylpiper Pyridin-4-ethyl, N-acetyl piperazine-4-propyl, (1,1-dioxothiomorpholinyl)-4-ethyl, (1,1-dioxothiomorpholinyl )-4-propyl, methylthioethyl, methylthiopropyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminobutyl, diethylaminoethyl, diethylaminopropyl, hydroxy Ethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, aminoethyl, aminopropyl, aminobutyl, 2-methyl-2-hydroxypropyl, 3-methyl-3-hydroxybutyl Base, (3S)-3-aminobutyl, (3R)-3-aminobutyl, (3S)-3-hydroxybutyl or (3R)-3-hydroxybutyl.
The compound according to claim 1, a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof, wherein the halogen of R 2 , R 3 or R 4 is F, Cl or Br.
A compound according to claim 1 or a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof, R 5 is H, C 1 -C 6 alkyl, C 3 -C 6 a cycloalkyl, C 3 -C 6 cycloalkyl substituted C 1 -C 3 alkyl group, a substituted or unsubstituted aryl group or a heteroaryl group, the substituted aryl or heteroaryl group having a substituent C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, mono or di C 1 -C 3 substituted amino or unsubstituted amino, halogen, trifluoromethyl One or more of an aryloxy group or a methylsulfone group;

The heteroaryl group is a monocyclic or bicyclic group having 5 to 10 ring atoms, and the ring contains 1-2 atoms selected from N, O, and S.
A compound according to claim 1, a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof, wherein R 5 is H, C 1 -C 6 alkyl, C 3 -C 6 ring Alkyl, C 3 -C 6 cycloalkyl substituted C 1 -C 3 alkyl, substituted or unsubstituted phenyl, naphthyl or heteroaryl, wherein substituents of phenyl, naphthyl or heteroaryl are selected From methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, amino, One or more of methylamino, ethylamino, dimethylamino, diethylamino, fluoro, chloro, bromo, trifluoromethyl, phenoxy or methylsulfonyl;

The heteroaryl group is selected from the group consisting of pyridine, pyrimidine, quinoline, quinazoline, oxazole, isoxazole, thiazole, thiadiazole, pyrazole, imidazole, pyrrole.
A compound according to claim 1, a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof, and R 5 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, and iso Pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl , 3-fluorophenyl, 4-fluorophenyl, 4-phenoxyphenyl, 3-(methylsulfonyl)phenyl, 4-(methylsulfonyl)phenyl, 2,4-difluorophenyl, 2,5-Difluorophenyl, 3,4-difluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2-fluoro-4 -(Trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 3-fluoro-4-(trifluoromethyl)phenyl, 3-fluoro-5-(trifluoromethyl) Phenyl, 3-trifluoromethyl-4fluorophenyl, 2-fluoro-4-chlorophenyl, 2-fluoro-5-chlorophenyl, 3-fluoro-4-chlorophenyl, 3-fluoro -5-chlorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-4-(trifluoromethyl)phenyl, 2-chloro-5-(trifluoromethyl)phenyl, 3-chloro -4-(Trifluoromethyl)phenyl, 3-chloro-5-(trifluoromethyl)phenyl, 3-trifluoromethyl-4-chlorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-fluorophenyl, 3-chloro-4-fluorophenyl, pyridin-2-yl, 3-yl, pyridin-4-yl, 2-methoxy - pyridin-4-yl, 3-methyl - isoxazol-5-yl, naphthalene-1-yl.
A salt of a compound of formula (I) according to claims 1-7, wherein the salt is an acidic/anionic salt or a basic/cationic salt; the pharmaceutically acceptable acidic/anionic salt is usually in the form The basic nitrogen is protonated by an inorganic or organic acid, and representative organic or inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, glycolic acid, Lactic acid, succinic acid, maleic acid, tartaric acid, malic acid, citric acid, fumaric acid, gluconic acid, benzoic acid, mandelic acid, methanesulfonic acid, isethionic acid, benzenesulfonic acid, oxalic acid, palmitic acid, 2 Naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, salicylic acid, hexanoic acid, trifluoroacetic acid. Pharmaceutically acceptable basic/cationic salts include, of course, not limited to aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc.
A process for the preparation of a compound according to claims 1-7, a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof, comprising a compound of formula (II) and H 2 NR 5 reacting to prepare a compound of the formula (I), wherein X, Y, Z, R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claims 1-7,
A process for the preparation of a compound according to claims 1-7, a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof, which comprises a compound of formula (II') and a compound (III) reacting to prepare a compound of the formula (I), wherein X, Y, Z, R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claims 1-7,
A compound of the formula (II), wherein X, Y, Z, R 1 , R 2 , R 3 , and R 4 are as defined in claims 1-7,
A pharmaceutical composition for treating a disease associated with a tyrosine kinase (e.g., VEGFR-2, C-RAF, B-RAF, etc.), the compound of formula (I) according to claims 1-7, a pharmaceutically acceptable thereof The acceptable salt, hydrate thereof or prodrug thereof is comprised of a pharmaceutically acceptable carrier or excipient.
A pharmaceutical composition comprising a compound of formula (I) according to claims 1-7, a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as active ingredient, one or more Other therapeutic agents, as well as one or more pharmaceutically acceptable carriers or excipients.
A compound of formula (I), or a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof, according to any one of claims 1-7, in the treatment of a tyrosine kinase, such as Use of a drug for VEGFR-2, C-RAF, B-RAF-related diseases, including but not limited to: fundus diseases, psoriasis, rheumatoid arthritis, atheroma, pulmonary fibrosis, liver Fibrosis, tumors, etc.
The use according to claim 14, wherein the tumor includes, but is not limited to, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer , colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin's lymph Any of tumor, nasopharyngeal carcinoma, esophageal cancer, brain tumor, B cell and T cell lymphoma, lymphoma, multiple myeloma, biliary sarcoma, and cholangiocarcinoma.