CN110862397A

CN110862397A - Dioxane quinazoline and dioxane quinoline compounds, and preparation method and application thereof

Info

Publication number: CN110862397A
Application number: CN201810982633.5A
Authority: CN
Inventors: 张强; 刘彦生; 胡晨明
Original assignee: Beijing Scitech MQ Pharmaceuticals Ltd
Current assignee: Beijing Scitech MQ Pharmaceuticals Ltd
Priority date: 2018-08-27
Filing date: 2018-08-27
Publication date: 2020-03-06

Abstract

The present invention relates to dioxanoquinazolines and dioxanoquinolines having formula (I) or pharmaceutically acceptable salts thereof. The invention also provides a process for the preparation of the compounds of formula (I) and their pharmaceutically acceptable salts and their use as medicaments as inhibitors of tyrosine kinases such as VEGFR-2, c-MET and RET for the treatment of tyrosine kinase related diseases.

Description

Dioxane quinazoline and dioxane quinoline compounds, and preparation method and application thereof

Technical Field

The invention relates to dioxane chinazoline and dioxane quinoline compounds, pharmaceutically acceptable salts, isomers, hydrates, solvates or prodrugs thereof, and a preparation method and application thereof.

Background

Receptor Tyrosine Kinases (RTKs) span the cell membrane and affect the transmission of biochemical signals across the cell membrane, and consist of an extracellular domain containing a ligand binding site, a single transmembrane domain, and an intracellular domain containing tyrosine protein kinase activity. Binding of the ligand to the receptor stimulates receptor-associated tyrosine kinase activity, which leads to phosphorylation of tyrosine residues on the receptor and other intracellular molecules, which in turn initiates a cascade of signals leading to a variety of cellular responses. The overexpression of the tyrosine receptor activates a downstream signal transduction pathway, finally leads to the abnormal transformation and proliferation of cells, and promotes the generation and development of tumors.

VEGFR (vascular endothelial growth factor) is one of receptor tyrosine kinase families, and a series of biochemical and physiological processes are generated by combining with VEGF (vascular endothelial growth factor) serving as a ligand of VEGFR, so that new blood vessels are finally formed. The generation of tumor vessels and their permeability is mainly regulated by Vascular Endothelial Growth Factor (VEGF), which acts via at least two different receptors (VEGFR-1, VEGFR-2). Studies according to Jakeman, Kolch, Connolly et al show that: VEGF is an important stimulator of normal and pathological angiogenesis and vascular permeability (Jakeman et al, 1993, Endocrinology 133: 848-859; Kolch et al, 1995, Breast Cancer Research and Treatment, 36: 139-155; Connolly et al, 1989, J.biol.chem.264: 20017-20024). Vascular endothelial cell growth factor induces the angiogenic phenotype by inducing endothelial cell proliferation, protease expression and migration and subsequent formation of capillary cellular tissue. Thus, antagonism of VEGF by chelation of VEGF by antibodies can lead to inhibition of tumor growth (Kim et al, 1993, Nature 362: 841-844).

Since VEGFR-2 is mainly distributed in vascular endothelial cells, it can bind to VEGF-A, VEGF-C, VEGF-D, VEGF-E. The effects of VEGF in stimulating endothelial cell proliferation, increasing vascular permeability and neovascularization are primarily achieved by binding to and activating VEGFR-2. If the activity of VEGFR-2 is blocked, the growth and metastasis of tumor can be inhibited through direct and indirect ways, and further the ideal anti-tumor effect is achieved. Therefore, the search for small molecule inhibitors with high activity and selectivity for VEGFR-2 is a promising strategy for tumor therapy.

The hepatocyte growth factor receptor (c-MET) is one of the tyrosine kinase receptors, and its abnormal activation plays an important role in the development and progression of various malignancies, including lung cancer. Hepatocyte Growth Factor (HGF) is a specific ligand of c-MET, and after being combined with HGF, the c-MET plays a biological role through an HGF/c-MET signal channel. The HGF/c-MET signal channel can induce a series of biological effects of cell proliferation, dispersion, migration, organ morphogenesis, angiogenesis and the like. Aberrant activation of c-MET may manifest as receptor overexpression, gene mutation, amplification, ectopy, rearrangement, and the like. These changes can lead to down-stream signaling pathway disorders such as serine/threonine protein kinase (AKT), extracellular signal kinase (ERK), phosphatidylinositol-3-hydroxykinase, retinoblastoma inhibitory protein (Rb) pathway, and the like, mediating processes such as tumorigenesis, invasion and metastasis, angiogenesis, epithelial-mesenchymal transition, and the like. c-MET plays an important role in cell proliferation, metabolism, tumor production, metastasis, and angiogenesis, and has become an important target for anti-tumor therapy. The targeted therapy targeting c-MET has shown its important implications in the treatment of a variety of malignancies, including lung cancer.

RET is also a transmembrane receptor tyrosine kinase that is essential for normal development of tissues such as the brain, nervous system, thyroid and lung. Activating mutations and oncogenic fusions of receptor tyrosine kinases have been found in a variety of tumor types, including thyroid, lung, breast and colon cancers. At present, no drug which takes RET as a specific target point is on the market, so that the development of a small molecule inhibitor aiming at RET has extremely high application value.

During the treatment process of using the antitumor drug, the interaction of multiple signal pathways can influence the action effect of the antitumor drug, for example, the interaction of the HFG/c-MET signal pathway and other pathways influences the treatment effect of the antitumor drug, and drug resistance is generated. Therefore, the multi-kinase target combined drug becomes a new anti-tumor treatment means, and the successful marketing of Crizotinib and Cabozantinib indicates that the development of the multi-kinase target inhibitor has good potential and application value.

Cabozantinib is a small molecule inhibitor of protein kinase, and has inhibitory effect on various kinases such as c-MET, VEGFR-2, Ret, Kit, AXL, etc. Cabozantinib can inhibit phosphorylation of c-MET and VEGFR-2 in tumor model, and shows effective anti-tumor metastasis and anti-angiogenesis activity in preclinical drug effect model. No increase in tumor burden was observed in the pulmonary tumor metastasis model treated with Cabozantinib compared to inhibitors acting on VEGFR targets alone, suggesting that Cabozantinib is a potent inhibitor of tumor angiogenesis and metastasis in tumor patients with dysregulated c-MET and VEGFR-2 signaling pathways. The FDA approved Cabozantinib for marketing on day 29/11 of 2012 for the treatment of patients with progressive, metastatic Medullary Thyroid Carcinoma (MTC).

Inhibitors that act on multiple targets like Cabozantinib have many advantages, and studies on this type of inhibitor are also very hot. The medicines on the market at present are few, the available channels are limited, and the medicines on the market have the problems of drug resistance, side effects and the like in use. Therefore, compared with the single-target inhibitors which are already on the market, the multi-target small molecule inhibitor has better treatment effect and application prospect.

Disclosure of Invention

The present invention provides compounds represented by formula (I), pharmaceutically acceptable salts, isomers, hydrates, solvates, or prodrugs thereof, which are useful for treating or preventing diseases caused by tyrosine kinases such as VEGFR-2, c-MET and/or RET.

In the formula (I), the compound is shown in the specification,

q is N or CH;

L₁is selected from: c₁-C₃A linear or branched alkylene group, a carbonyl group,

The linking group in (1) is a group,

g is selected from the following groups:

x and Y are each independently H or C₁-C₃Wherein when n is 0, G represents

L₂Is a linking group selected from a direct bond, a carbon-carbon double bond or a carbon-carbon triple bond, wherein said direct bond is R²A group directly attached to the ring, L₂In the case of a carbon-carbon double bond, the compounds of the present application are intended to include all possible cis-trans isomers.

R¹is-H, C₁-C₉Alkyl radical, C₃-C₇Ring ofAlkyl radical, C₃-C₇Cycloalkyl-substituted C₁-C₆Alkyl, aryl substituted C₁-C₆Alkyl, heteroaryl or heteroaryl substituted C₁-C₆An alkyl group;

the aryl and heteroaryl are unsubstituted or substituted by 1-3 substituents selected from hydroxy, amino, cyano, C₁-C₃Alkyl of (C)₁-C₃Alkoxy group of (C)₁-C₃Alkylthio, mono-or di-C of₁-C₃Substituted by one or more substituents selected from the group consisting of amino, halogen, trifluoromethyl and methylsulfonyl;

the heteroaryl group is a monocyclic or bicyclic group containing 1 to 3 heteroatoms selected from N, O, S and containing 5 to 10 ring atoms;

R²is-H, or from 1 to 3 are selected from C₁-C₆Alkoxy group of (C)₁-C₆Alkylthio of, C₁-C₃Acyl, hydroxy, halogen, trifluoromethyl, cyano, -CONH₂Oxo (═ O) or-NR^aR^bC substituted or unsubstituted by the substituent in (1)₃-C₈Or from 1 to 3 cycloalkyl groups selected from C₁-C₆Alkoxy group of (C)₁-C₆Alkylthio of, C₁-C₃Acyl, hydroxy, halogen, trifluoromethyl, cyano, -CONH₂、C₃-C₇Cycloalkyl, 4-8 membered heteroalicyclic or-NR of^aR^bC substituted or unsubstituted by a substituent of (A)₁-C₁₀Alkyl, said 4-8 membered heteroalicyclic is 4-8 membered heteroalicyclic comprising 1-2 atoms selected from N, O, S as ring atoms, and said 4-8 membered heteroalicyclic is optionally substituted with 1 to 3 atoms selected from halogen, C₁-C₃Alkyl of (C)₁-C₃Alkoxy group of (C)₁-C₃Alkylthio, hydroxy, -NR^aR^b、C₁-C₃Acyl, oxo, substituted or unsubstituted,

R^aand R^bEach independently is-H, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₁-C₃Alkoxy-substituted C₁-C₆Alkyl radical, C₁-C₃Alkylthio substituted C₁-C₆Alkyl or mono-or di-C₁-C₃Alkyl-substituted or unsubstituted amino-substituted C₁-C₆An alkyl group;

R³、R⁴each independently is-H or halogen.

According to a preferred embodiment, R¹Is aryl, aryl-substituted C₁-C₃Alkyl, heteroaryl or heteroaryl substituted C₁-C₃Alkyl, said aryl and/or heteroaryl being unsubstituted or substituted by 1 to 3 substituents selected from hydroxy, amino, cyano, C₁-C₃Alkyl of (C)₁-C₃Alkoxy group of (C)₁-C₃Alkylthio, mono-or di-C of₁-C₃Substituted by one or more substituents selected from the group consisting of amino, -F, -Cl, trifluoromethyl and methylsulfonyl;

the aryl group is selected from phenyl, naphthyl, phenanthryl, the heteroaryl group is selected from pyrrolyl, furyl, pyridyl, thienyl, imidazolyl, thiazolyl, isothiazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 1, 5-naphthyridinyl, 1, 6-naphthyridinonyl, oxadiazolyl, oxazolyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazolyl, pyrazolo [3,4-d ] pyrimidinyl, pyridyl, pyrido [3,2-d ] pyrimidinyl, pyrido [3,4-d ] pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalyl, quinolyl, isoquinolyl, more preferably, the aryl group is phenyl and the heteroaryl group may be pyridyl or thiazolyl.

More preferably, R¹Selected from phenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 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) Phenyl, 3-fluoro-4- (trifluoromethyl) phenyl, 3-fluoro-5- (trifluoromethyl) phenyl, 3-trifluoromethyl-4-fluorophenyl, 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, m, 2-chloro-5-fluorophenyl, 3-chloro-4-fluorophenyl, benzyl, phenethyl, 4-fluorobenzyl, naphthalen-1-yl, 3-methyl-isoxazol-5-yl, 4-phenoxyphenyl, 3- (methylsulfonyl) phenyl, 4- (methylsulfonyl) phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 3-methoxybenzyl, 1- (4-fluorophenyl) ethyl, thiazol-2-yl-methyl, 1- (thiazol-2-yl) ethyl or 4-methoxybenzyl.

According to a preferred embodiment, R³、R⁴Each independently is-H, -F, or-Cl.

According to a preferred embodiment, R²Is 1 to 3 selected from C₁-C₃Alkoxy group of (C)₁-C₃Alkylthio of, C₁-C₃Acyl, hydroxy, halogen, trifluoromethyl, cyano, -CONH₂、C₃-C₇Cycloalkyl, 4-8 membered heteroalicyclic or-NR of^aR^bC substituted or unsubstituted by a substituent of (A)₁-C₆Alkyl, said 4-8 membered heteroalicyclic is 4-8 membered heteroalicyclic comprising 1-2 atoms selected from N, O, S as ring atoms, and said 4-8 membered heteroalicyclic is optionally substituted with 1 to 3 atoms selected from halogen, C₁-C₃Alkyl of (C)₁-C₃Alkoxy group of (C)₁-C₃Alkylthio, hydroxy, -NR^aR^b、C₁-C₃Acyl, oxo, substituted or unsubstituted,

R^aand R^bEach independently is-H, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₁-C₃Alkoxy-substituted C₁-C₆Alkyl radical, C₁-C₃Alkylthio substituted C₁-C₆Alkyl orA single or double C₁-C₃Alkyl-substituted or unsubstituted amino-substituted C₁-C₆An alkyl group.

More preferably, R²Is C substituted or unsubstituted by a 4-to 6-membered heteroalicyclic group₁-C₆Alkyl, the 4-6 membered heteroalicyclic is 4-6 membered heteroalicyclic comprising 1-2 atoms selected from N, O, S as ring atoms, and the 4-6 membered heteroalicyclic is optionally substituted with 1 to 3 atoms selected from-F, -Cl, C₁-C₃Alkyl of (C)₁-C₃Alkoxy group of (C)₁-C₃Alkylthio, hydroxy, -NR^aR^b、C₁-C₃Acyl, oxo, substituted or unsubstituted,

R^aand R^bEach independently is-H, C₁-C₃Alkyl radical, C₃-C₆Cycloalkyl radical, C₁-C₃Alkoxy-substituted C₁-C₃Alkyl radical, C₁-C₃Alkylthio substituted C₁-C₃Alkyl or mono-or di-C₁-C₃Alkyl-substituted or unsubstituted amino-substituted C₁-C₃An alkyl group.

Most preferably, R²Selected from the group consisting of tetrahydropyrrole-1-methyl, tetrahydropyrrole-1-ethyl, tetrahydropyrrole-1-propyl, tetrahydropyrrole-1-butyl, piperidine-1-methyl, piperidine-1-ethyl, piperidine-1-propyl, piperidine-1-butyl, piperazine-1-methyl, piperazine-1-ethyl, piperazine-1-propyl, piperazine-1-butyl, morpholine-4-methyl, morpholine-4-ethyl, morpholine-4-propyl, morpholine-4-butyl, methylpiperazin-4-methyl, methylpiperazin-4-ethyl, methylpiperazin-4-propyl, methylpiperazin-4-butyl, and mixtures thereof, N-formylpiperazine-4-ethyl, N-formylpiperazine-4-propyl, N-acetylpiperazine-4-ethyl, N-acetylpiperazine-4-propyl, (1, 1-dioxothiomorpholinyl) -4-methyl, (1, 1-dioxothiomorpholinyl) -4-ethyl, (1, 1-dioxothiomorpholinyl) -4-propyl, (1, 1-dioxothiomorpholinyl) -4-butyl, 4-dimethylpiperidin-1-methyl, 4-dimethylpiperidin-1-ethyl, 4-dimethylpiperidin-1-propyl, 4-dimethylpiperidin-1-butyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, decyl, and, 4-methyl-4-hydroxypiperidine-1-methyl, 4-methyl-4-hydroxypiperidine1-propyl group, 4-methyl-4-hydroxypiperidine-1-ethyl group, 4-methyl-4-hydroxypiperidine-1-butyl group, 4-methyl-4-aminopiperidine-1-methyl group, 4-methyl-4-aminopiperidine-1-propyl group, 4-methyl-4-aminopiperidine-1-ethyl group, and 4-methyl-4-aminopiperidine-1-butyl group.

According to a preferred embodiment, L₁Is carbonyl or

According to some embodiments of the present application, the pharmaceutically acceptable salt of the dioxanoquinazolines or quinolines compound is selected from the hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, nitrate, phosphate, formate, acetate, propionate, glycolate, lactate, succinate, maleate, tartrate, malate, citrate, fumarate, gluconate, benzoate, mandelate salts of said compound, one or more of mesylate, isethionate, benzenesulfonate, oxalate, palmitate, 2-naphthalenesulfonate, p-toluenesulfonate, cyclamate, salicylate, gluconate, trifluoroacetate, aluminum salt, calcium salt, chloroprocaine salt, choline salt, diethanolamine salt, ethylenediamine salt, lithium salt, magnesium salt, potassium salt, sodium salt, and zinc salt.

Another aspect of the invention relates to the use of the dioxanoquinazolines or quinolines, isomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof in the preparation of a medicament for treating diseases associated with VEGFR-2, c-MET and/or RET, wherein the diseases associated with VEGFR-2, c-MET and/or RET comprise ocular fundus diseases, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, Crohn's disease, atheroma, pulmonary fibrosis, hepatic fibrosis, myelofibrosis, non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, Bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myelogenous leukemia, acute myelogenous leukemia, non-hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumor, B-cell and T-cell lymphoma, multiple myeloma, biliary tract carcinosarcoma, cholangiocarcinoma.

In a further aspect of the invention there is provided a pharmaceutical composition comprising a dioxanoquinazoline or quinoline compound of the present application, an isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, and one or more pharmaceutically acceptable carriers or excipients.

According to some embodiments of the present application, the pharmaceutical composition may further comprise one or more additional therapeutic agents.

Detailed Description

Unless otherwise indicated, the following terms used in the present application (including the specification and claims) have the definitions given below. In this application, the use of "or" and "means" and/or "unless stated otherwise. Furthermore, the use of the terms "including" and other forms, such as "including", "comprising", and "having", are not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

Detailed Description

The term "substituted" as used herein includes complex substituents (e.g., phenyl, aryl, heteroalkyl, heteroaryl), suitably 1 to 5 substituents, preferably 1 to 3 substituents, and most preferably 1 to 2 substituents, which are freely selectable from the list of substituents.

Unless otherwise specified, alkyl includes saturated straight-chain, branched-chain hydrocarbon radicals, C₁-C₉C representing a carbon atom number of 1 to 9 of the alkyl group₁-C₃For example, a carbon atom having 1 to 3 carbon atoms, e.g. C, representing an alkyl group₁-C₆Alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentylN-hexyl, 2-methylpentyl and the like. Alkoxy is an alkyl-O-group formed from the previously described linear or branched alkyl groups with-O-. Similarly, alkenyl and alkynyl groups include straight chain, branched chain alkenyl or alkynyl groups.

Cycloalkyl, meaning a cyclic group formed by carbon atoms, e.g. C₃-C₇Cycloalkyl groups of (a) may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and similarly, cyclic alkenyl groups are also included.

The term "aryl" as used herein, unless otherwise specified, refers to an unsubstituted or substituted aromatic radical, such as phenyl, naphthyl, anthracenyl.

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

The term "heterocyclyl", as used herein, unless otherwise specified, represents an unsubstituted or substituted stable 3 to 8 membered monocyclic saturated ring system consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, O, S, wherein the N, S heteroatoms may be optionally oxidized and the N heteroatoms may be optionally quaternized. Examples of such heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl oxide, piperidinyl oxide, dioxolanyl, dioxanyl tetrahydroimidazolyl, tetrahydrooxazolyl, thiomorpholino sulfoxide, thiomorpholino sulfone, and oxadiazolyl.

The term "heteroaryl" as used herein, unless otherwise specified, represents an unsubstituted or substituted stable 5 or 6 membered monocyclic aromatic ring system, and may also represent an unsubstituted or substituted 9 or 10 ring atom fused benzene or bicyclic heteroaromatic ring system consisting of carbon atoms and from 1 to 3 heteroatoms selected from N, O, S, wherein the N, S heteroatom may be oxidized and the N heteroatom may also be quaternized. The heteroaryl group may be attached to any heteroatom 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, indolyl, azaindolyl, indazolyl, azaindazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adenylyl, quinolinyl, or isoquinolinyl.

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

Whenever the term "alkyl" or "aryl" or any of their prefix roots appear in the name of a substituent (e.g., aralkyl, dialkylamino), it is to be considered as encompassing those limitations given above for "alkyl" and "aryl". Specified number of carbon atoms (e.g., C)₁-C₆) Will independently represent the number of carbon atoms in an alkyl moiety or an alkyl moiety in a larger substituent (where alkyl is taken as its prefix root).

It is clear that the compounds of formula I, isomers, crystalline forms or prodrugs, and pharmaceutically acceptable salts thereof, may exist in solvated as well as unsolvated forms. For example, the solvated form may be water soluble. The present invention includes all such solvated and unsolvated forms.

The compounds of the invention may have asymmetric carbon atoms and, depending on their physicochemical differences, such diastereomeric mixtures may be separated into the individual diastereomers by methods well known in the art, for example, chromatography or fractional crystallization. Enantiomers can be separated by first converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitably optically active compound, separating the diastereomers, and then converting (hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers are considered as part of the invention.

The compounds of the present invention as active ingredients, as well as methods for preparing the compounds, are the subject of the present invention. Furthermore, some crystalline forms of the compounds may exist as polymorphs and as such may be included in the present invention. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of this invention.

The compounds of the invention may be used in therapy in free form or, where appropriate, in the form of pharmaceutically acceptable salts or other derivatives. As used herein, the term "pharmaceutically acceptable salts" 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 and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art. The salts may be formed by reacting a compound of the invention with a suitable free base or acid. Including, but not limited to, salts formed 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, or by using methods well known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, caproates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, laurylsulfates, malates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoate, pectinates, persulfates, per3-phenylpropionates, phosphates, picrates, propionates, stearates, sulfates, thiocyanates, 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 the appropriate non-toxic ammonium, quaternary ammonium, and amine-based cations formed using such salts as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

In addition, the term "prodrug" as used herein means a compound which can be converted in vivo to a compound of the formula (I) of the present invention. This conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent compound in the blood or tissue.

The pharmaceutical compositions of the invention comprise a compound of structural formula (I) as described herein or a pharmaceutically acceptable salt thereof, a kinase inhibitor (small molecule, polypeptide, antibody, etc.), an immunosuppressive agent, an anticancer agent, an antiviral agent, an anti-inflammatory agent, an antifungal agent, an antibiotic, or an additional active agent that is an anti-vascular hyperproliferative compound; and any pharmaceutically acceptable carrier, adjuvant or vehicle.

The compounds of the present invention may be used alone or in combination with one or more other compounds of the present invention or with one or more other agents. When administered in combination, the therapeutic agents may be formulated for simultaneous administration or for sequential administration at different times, or the therapeutic agents may be administered as a single composition. By "combination therapy" is meant the use of a compound of the invention in combination with another agent, either by co-administration of each agent simultaneously or by sequential administration of each agent, in either case, for the purpose of achieving optimal effect of the drug. Co-administration includes simultaneous delivery dosage forms, as well as separate dosage forms for each compound. Thus, administration of the compounds of the invention may be used concurrently with other therapies known in the art, for example, radiation therapy or adjunctive therapies such as cytostatic agents, cytotoxic agents, other anti-cancer agents, etc. in the treatment of cancer to ameliorate the symptoms of the cancer. The present invention is not limited to the order of administration; the compounds of the invention may be administered previously, concurrently, or after other anti-cancer or cytotoxic agents.

To prepare the pharmaceutical compositions of this invention, one or more compounds or salts of formula (I) as the active ingredient may be intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending on the form of preparation designed for administration by any convenient route, e.g. oral or parenteral. 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, which is published by the United states society of pharmacy and British pharmaceutical society.

The pharmaceutical compositions of the invention may be in a form, for example, suitable for oral administration, for example, as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; for parenteral injection such as clear solutions, suspensions, emulsions; or for topical application such as creams; or as suppositories for rectal administration. The pharmaceutical compositions may also be in unit dosage form suitable for single use administration of the precise dosage. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and the compound as an active ingredient prepared in accordance with the present invention, and may also include other medicinal or pharmaceutical agents, carriers, adjuvants, and the like.

Therapeutic compounds may also be administered to mammals other than humans. The dosage of the drug administered to a mammal will depend on the species of the animal and its disease state or disorder in which it is suffering. The therapeutic compound may be administered to the animal in the form of a capsule, bolus, tablet or solution. Therapeutic compounds may also be administered into the animal by injection or infusion. We prepared these pharmaceutical forms according to conventional means which meet the criteria of veterinary practice. Alternatively, the pharmaceutical composition may be mixed with animal feed for feeding to the animal, and thus, the concentrated feed supplement or premix may be prepared for mixing with conventional animal feed.

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

The invention also includes the use of a compound of the invention, or a pharmaceutically acceptable derivative thereof, for the manufacture of a medicament for the treatment of cancer (including non-solid tumors, primary or metastatic cancer, as noted elsewhere herein and including one or more other treatments for which the cancer is resistant or refractory) as well as other diseases (including but not limited to ocular fundus disease, psoriasis, atheroma, pulmonary fibrosis, liver fibrosis, bone marrow fibrosis, etc.). Such cancers include, but are not limited to: non-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 tumors, thyroid cancer, chronic myelogenous leukemia, acute myelogenous leukemia, non-hodgkin lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumors, B-cell and T-cell lymphomas, lymphoma, multiple myeloma, biliary sarcoma, bile duct cancer.

The present invention also provides methods for preparing the corresponding compounds, and the compounds described herein can be prepared using a variety of synthetic methods, including those referred to in the examples below, and the compounds of the present invention, or pharmaceutically acceptable salts, isomers, or hydrates thereof, can be synthesized using the methods described below, and synthetic methods known in the art of organic chemical synthesis, or by variations on these methods as understood by those skilled in the art, with preferred methods including, but not limited to, the methods described below.

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. The examples, where specific techniques or conditions are not indicated, are to be construed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items. The examples provided below are intended to better illustrate the invention, all temperatures being in degrees Celsius unless otherwise indicated.

Preparation of a portion of the intermediate

Intermediate 1: preparation of N- (2-fluoro-4-hydroxyphenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide

Step 1): adding 1, 1-cyclopropyl dicarboxylic acid (1.04 g) into anhydrous tetrahydrofuran (20mL), slowly dropwise adding triethylamine (0.84g) into the stirred suspension under the ice-water bath condition, stirring for half an hour, then dropwise adding thionyl chloride (1.1g) at the temperature of 0 ℃, continuing to stir for 1 hour after the addition is finished, then respectively adding triethylamine (0.8g) and a tetrahydrofuran (10mL) solution of tetrafluoroaniline (0.9g), and reacting and stirring for 2 hours; concentrating, dissolving in 1N sodium hydroxide, extracting with ethyl acetate, adjusting pH of the water phase to 2.0 with 1N dilute hydrochloric acid solution, stirring for half an hour, filtering to obtain 1.1g white solid product, yield 62%, MS: 224[ M + H]⁺。

Step 2): 1- ((4-fluorophenyl) carbamoyl) cyclopropane-1-carboxylic acid (650mg, 2.9mmol), 4-amino-3-fluorophenol (446mg, 3.5mmol), EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) (670mg, 3.5mmol) were dissolved in dichloromethane (9ml) and reacted at 25 ℃ for 16 h. The reaction solution was diluted with dichloromethane, extracted with 1M dilute hydrochloric acid and saturated brine respectively, dried over anhydrous sodium sulfate of the organic phase, evaporated to dryness, and rinsed with a mixed solution of dichloromethane and petroleum ether to give an off-white solid 730mg, 75% yield.¹H NMR(DMSO-d₆,300MHz)δ10.21(1H,s),9.98(1H,s),9.83(1H,s),7.62(2H,dd,J＝9.1,5.0Hz),7.46(1H,t,J＝8.9Hz),7.15(2H,t,J＝8.7Hz),6.70-6.47(2H,m),1.54(4H,d,J＝4.8Hz)；LCMS:m/z＝333.1(M+H)⁺。

Intermediate 2: preparation of N- (3-fluoro-4-hydroxyphenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide

Reacting 1- [ (4-fluorophenyl) carbamoyl group]CyclopropanAlkane-1-carboxylic acid (650mg, 2.9mmol), 4-amino-2-fluorophenol (446mg, 3.5mmol), EDCI (670mg, 3.5mmol) were dissolved in dichloromethane (9ml) and reacted at 25 ℃ for 16 h. The reaction solution was diluted with dichloromethane, extracted with 1M dilute hydrochloric acid and saturated brine respectively, dried over anhydrous sodium sulfate of organic phase, evaporated to dryness, and rinsed with mixed solution of dichloromethane and petroleum ether to obtain a off-white solid 775mg, yield 80%. LCMS M/z 333.1(M + H)⁺。

Intermediate 3: preparation of 1- [ 2-fluoro-5- (trifluoromethyl) phenyl ] -3- (4-hydroxyphenyl) urea

To a mixed solution of 2-fluoro-5- (trifluoromethyl) aniline (1g, 5.58mmol) and triethylamine (1.2g, 11.88mmol) in tetrahydrofuran (20mL) under ice-water bath conditions was added triphosgene (1.66g, 5.59 mmol). After 1.5 hours of reaction in an ice-water bath, 4-aminophenol (518mg, 4.74mmol) was added and the reaction was allowed to proceed overnight at room temperature. The reaction solution was concentrated and column chromatography was carried out to give 1.2g of a gray solid in 81% yield.¹H NMR(DMSO-d₆,400MHz)δ6.57-6.79(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＝3.0Hz),8.91(1H,s),9.18(1H,s)；LCMS:m/z＝315.1[M+H]⁺。

Intermediates 4-10 were prepared according to the procedure for intermediate 3, the specific structures and characteristics of which are shown in table 1 below:

table 1: structure and characterization of intermediates 4 to 10

Intermediate 11: preparation of 1-methyl-4- (prop-2-ynyl) piperazine

To a tetrahydrofuran solution (10mL) of propargyl bromide (880mg,7.4mmol) was added 4-methylpiperazine (621mg, 6.2mmol), and the reaction mixture was stirred for 5 minutes, followed by addition of potassium carbonate (1.71g, 12.37mmol) and heating under argon atmosphere for reflux for 24 hours. The reaction solution was cooled and filtered, and concentrated by column chromatography to give 670mg of a yellow oil in 78% yield. LCMS (liquid Crystal Module) with M/z of 139.1[ M + H ]]⁺。

Intermediate 12: preparation of 4- (prop-2-yn-1-yl) morpholine

The procedure was as for the preparation of intermediate 11 except that morpholine was used instead of 4-methylpiperazine and LCMS: M/z 126.1[ M + H ═ M]⁺。

Intermediate 13: preparation of 4- (prop-2-yn-1-yl) pyrrole

The procedure was as for the preparation of intermediate 11 except that pyrrole was used instead of 4-methylpiperazine and LCMS: M/z 110.1[ M + H]⁺。

Intermediate 14: preparation of 4- (prop-2-yn-1-yl) piperidine

The procedure was as for the preparation of intermediate 11 except that piperidine was used instead of 4-methylpiperazine, LCMS: M/z 124.1[ M + H ═ M]⁺。

Preparation of intermediate 154- (prop-2-yn-1-yl) thiomorpholine-1, 1-dioxide

The procedure was as for the preparation of intermediate 11, except that thiomorpholine-1, 1-dioxide was used instead of 4-methylpiperazine, LCMS: M/z 174.1[ M + H ]]⁺。

Preparation of intermediate 164- (but-3-yn-1-yl) morpholine

To an ethanol solution (10mL) of but-3-ynyl p-toluenesulfonate (4.5g, 20.1mmol) and morpholine (4mL) was added an aqueous solution (5mL) of potassium carbonate (2.8g, 20.3mmol), and the mixture was reacted for 2 hours at 80. Cooling, extraction with dichloromethane, drying over sodium sulphate for the organic phase, concentration and column chromatography gave 2.2g of a yellow oil with a yield of 80%. LCMS (liquid Crystal Module) 140.1[ M + H ] M/z]⁺。

Intermediate 17: preparation of 10-chloro-5-hydroxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] quinoline

Step 1): 1- (8-methoxy-2, 3-dihydrobenzo [ b ]][1,4]Placing dioxane-5-yl) ethyl-1-ketone (20.8g,100mmol), nitric acid (22mL) and acetic acid (44mL) in a round-bottom flask, stirring until the reaction is finished, pouring into crushed ice, and filtering to obtain a yellow solid product (1- (8-methoxy-6-amino-2, 3-dihydrobenzo [ b ] b)][1,4]Dioxane-5-yl) ethylYl-1-one) 16.5g, yield 66%.¹HNMR(400MHz,Chloroform-d)δ7.37(s,1H),4.43(dd,J＝5.4,2.7Hz,2H),4.35(dd,J＝5.3,2.7Hz,2H),3.98(s,3H),2.57(s,3H)；MS:254[M+H]⁺。

Step 2): putting the product (16.5g,65mmol) obtained in the step 1 into a reaction bottle, adding palladium carbon (2g) into the reaction bottle, stirring the mixture under the hydrogen environment till the reaction is finished, and performing suction filtration and concentration to obtain a white solid product (1- (6-amino-8-methoxy-2, 3-dihydrobenzo [ b ] b)][1,4]Dioxan-5-yl) ethyl-1-one) 13.7g, yield 95%.¹HNMR(400MHz,DMSO-d6)δ6.90(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): dissolving the product (13.7g,62mmol) obtained in the step 2 and ethyl formate (27.5g,372mmol) in dioxane, adding sodium tert-butoxide (17.8g,186mmol), stirring until the raw material disappears, adding 10ml of methanol, continuing stirring until the reaction is finished, neutralizing the reaction solution with hydrochloric acid to neutrality, filtering, concentrating to obtain a white solid product (10-hydroxy-5-methoxy-2, 3-dihydro- [1,4]]Dioxane [2,3-f ]]Quinoline) 14.4g, yield 99%.¹HNMR(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): placing the product (14.4g,61mmol) obtained in the step 3 in a reaction bottle, adding toluene for dissolving, then adding triethylamine (42mL,305mmol) and phosphorus oxychloride (17mL,183mmol), heating and stirring until the reaction is finished, evaporating the solvent, washing the obtained solid with a sodium bicarbonate aqueous solution, and performing suction filtration to obtain a white-like solid (10-chloro-5-methoxy-2, 3-dihydro- [1, 4-dihydro- [ 1-5-methoxy-2, 3-dihydro- [1 ] 1]Dioxane [2,3-f ]]Quinoline) 14.1 g, yield 92%.¹HNMR(400MHz,DMSO-d₆)δ8.51(d,J＝4.9Hz,1H),7.38(d,J＝4.8Hz,1H),7.12(s,1H),4.49–4.29(m,4H),3.93(s,3H)；MS:252[M+H]⁺。

EXAMPLE 1 preparation of N- { 3-fluoro-4- [ (5- (3- (4-methylpiperazin-1-yl) propyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide

Step 1): reacting 8-hydroxy-2, 3-dihydrobenzo [ b ]][1,4]Dioxane-5-carboxylic acid methyl ester (3.6g, 14.6mmol, synthesis reference CN201510015411.2), potassium carbonate (5g, 36.2mmol), benzyl bromide (4.39g, 17.55mol) and acetonitrile (45mL) were mixed and reacted at 80 ℃ for 2 hours. Cooled to room temperature, appropriately concentrated and poured into water, filtered to give 4g of a yellow solid, 91.3% yield. LCMS (liquid Crystal Module) with M/z of 301.1[ M + H ]]⁺。

Step 2): the product obtained in step 1) (4g, 13.3mmol) was added to glacial acetic acid (20mL) and the temperature was controlled<Concentrated nitric acid (20mL) was added dropwise at 10 ℃ and the reaction was carried out for 2 hours at 25 ℃. Poured into crushed ice, stirred for 1 hour and filtered to obtain 4.22g of yellow solid with the yield of 92 percent. LCMS M/z 346.1[ M + H ]]⁺。

Step 3): dissolving the product (4.22g, 12.2mmol) obtained in the step 2) in glacial acetic acid (40mL), adding zinc powder (3.2g, 48.9mmol) in batches, reacting at 40 ℃ for 1 hour, filtering, pouring the filtrate into crushed ice, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering, concentrating, and directly using for the next reaction. LCMS M/z 316.1[ M + H ]]⁺。

Step 4): the crude product obtained in step 3) was dissolved in ethanol (60mL), formamidine acetate (2.54g, 24.4mmol) was added, and the reaction was carried out at 75 ℃ for 16 hours. After cooling, filtration gave 2.9g of an off-white solid, in 77% yield in steps 3) and 4), LCMS: M/z 311.1[ M + H ]]⁺。

Step 5): the product (2.9g, 9.3mmol) obtained in step 4) was dissolved in acetonitrile (30mL), and phosphorus oxychloride (2.9g, 18.9mmol) was slowly added and reacted at 80 ℃ for 6 hours. After cooling, concentration, dilution with dichloromethane, pouring into ice water, separation of the organic phase, extraction of the aqueous phase with dichloromethane, combination of the organic phases, drying over anhydrous sodium sulfate, filtration and spin-drying, 2.45g of a pale yellow solid, 80% yield, LCMS: M/z. 329.1[ M + H ]]⁺。

Step 6): the product obtained in step 5) (200mg, 0.6mmol), N- (3-fluoro-4-hydroxyphenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (202mg, 0.6mmol) and potassium carbonate (170mg, 1.23mmol) were dissolved in N, N-dimethylformamide (4mL), and 90The reaction was carried out at room temperature for 2 hours. The reaction mixture was poured into water and filtered to give the crude product as a brown solid 330mg, crude yield 88%, LCMS: M/z-625.2 [ M + H ]]⁺。

Step 7): the product (330mg, 0.52mmol) obtained in step 6) was dissolved in a mixed solvent of ethanol (1.5mL) and ethyl acetate (1.5mL), and palladium on carbon (10%, 30mg) was added to react under hydrogen atmosphere for 3 hours. Filtering the reaction solution, evaporating the filtrate to dryness to obtain crude product 160mg, yield 57%, LCMS (liquid Crystal display System): M/z is 535.1[ M + H ]]⁺。

Step 8): the product (150mg, 0.28mmol) from step 7) was dissolved in DCM and pyridine (71mg, 0.90mmol) and trifluoromethanesulfonic anhydride (103mg, 0.36mmol) were added under argon protection at 0 deg.C and reacted for 2 hours at 25 deg.C. Diluting the reaction solution with dichloromethane, washing with saturated sodium bicarbonate water solution and saturated saline solution, respectively, drying with anhydrous sodium sulfate, filtering, evaporating, and performing column chromatography to obtain yellow oily substance 100mg with yield of 53.5%, and LCMS (liquid crystal display system) with M/z ═ 667.5[ M + H ], (M + H)]⁺。

Step 9): the product (100mg, 0.15mmol) obtained in step 8) was dissolved in anhydrous N, N-dimethylformamide (2mL), and 1-methyl-4- (prop-2-ynyl) piperazine (94mg, 0.75mmol, intermediate 11), bis (triphenylphosphine) palladium dichloride (11mg, 0.016mmol), cuprous iodide (6mg, 0.03mmol), triethylamine (600mg, 5.9mmol) and under the protection of argon were added and reacted at 50 ℃ for 3 hours. Concentrating the reaction solution, performing column chromatography to obtain white solid 30mg with yield of 30.5%,¹H NMR(300MHz,DMSO-d₆)δ10.33(s,1H),10.04(s,1H),8.51(s,1H),7.82(d,J＝13.0Hz,1H),7.72–7.61(m,2H),7.57(s,1H),7.52–7.41(m,1H),7.41–7.27(m,1H),7.26–7.04(m,2H),4.60–4.36(m,4H),3.61(s,2H),2.67–2.55(m,4H),2.43–2.24(m,4H),2.17(s,3H),1.57–1.36(m,4H).LCMS:m/z＝655.7[M+H]⁺。

examples 2 to 28

Examples 2-28 were prepared in a similar manner to example 1, except using intermediates having different substituents, and the specific structures and characteristics of the resulting compounds are shown in the following structural formula and table 2.

Table 2 structure and characterization of examples 2-28

The compounds of examples 2-28 are named as follows:

example 2: n- { 3-fluoro-4- [ (5- (3-morpholinopropyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide

Example 3: n- {4- [ (5- (3- (1, 1-dioxothiomorpholine) propyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] -3-fluorophenyl } -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide

Example 4: n- { 3-fluoro-4- [ (5- (3- (piperidin-1-yl) propyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide

Example 5: n- { 3-fluoro-4- [ (5- (3- (pyrrol-1-yl) propyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide

Example 6: 1- [ 2-fluoro-5- (trifluoromethyl) phenyl ] -3- {4- [ (5- (3- (4-methylpiperazin-1-yl) propyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } urea

Example 7: 1- [ 2-fluoro-5- (trifluoromethyl) phenyl ] -3- {4- [ (5- (3-morpholinopropyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } urea

Example 8: 1- {4- [ (5- (3- (1, 1-dioxythiomorpholine) propyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } -3- [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Example 9: 1- [ 2-fluoro-5- (trifluoromethyl) phenyl ] -3- {4- [ (5- (3- (piperidin-1-yl) propyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } urea

Example 10: 1- [ 2-fluoro-5- (trifluoromethyl) phenyl ] -3- {4- [ (5- (3- (pyrrol-1-yl) propyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } urea

Example 11: 1- [ 4-chloro-3- (trifluoromethyl) phenyl ] -3- {4- [ (5- (3-morpholinopropyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } urea

Example 12: 1- [ 4-chloro-3- (trifluoromethyl) phenyl ] -3- { 3-fluoro-4- [ (5- (3-morpholinopropyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } urea

Example 13: 1- [ 4-chloro-3- (trifluoromethyl) phenyl ] -3- { 2-fluoro-4- [ (5- (3-morpholinopropyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } urea

Example 14: 1- { 3-fluoro-4- [ (5- (3-morpholinopropyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } -3- [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Example 15: 1- { 2-fluoro-4- [ (5- (3-morpholinopropyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } -3- [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Example 16: 1- (4-fluorobenzyl) -3- {4- [ (5- (3-morpholinopropyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } urea

Example 17: 1- [1- (4-fluorophenyl) ethyl ] -3- {4- [ (5- (3-morpholinopropyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } urea

Example 18: 1- {4- [ (5- (3-morpholinopropyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } -3- (thiazol-2-ylmethyl) urea

Example 19: 1- {4- [ (5- (3-morpholinopropyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } -3- [1- (thiazol-2-yl) ethyl) urea

Example 20: n- { 2-fluoro-4- [ (5- (3-morpholinopropyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide

Example 21: 1- [ 4-chloro-3- (trifluoromethyl) phenyl ] -3- {4- [ (5- (3- (4-methylpiperazin-1-yl) propyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } urea

Example 22: 1- [ 4-chloro-3- (trifluoromethyl) phenyl ] -3- { 3-fluoro-4- [ (5- (3- (4-methylpiperazin-1-yl) propyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } urea

Example 23: 1- [ 4-chloro-3- (trifluoromethyl) phenyl ] -3- { 2-fluoro-4- [ (5- (3- (4-methylpiperazin-1-yl) propyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } urea

Example 24: 1- { 3-fluoro-4- [ (5- (3- (4-methylpiperazin-1-yl) propyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } -3- [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Example 25: 1- { 2-fluoro-4- [ (5- (3- (4-methylpiperazin-1-yl) propyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } -3- [ 2-fluoro-5- (trifluoromethyl) phenyl ] urea

Example 26: n- (4-fluorophenyl) -N- {4- [ (5- (3- (4-methylpiperazin-1-yl) propyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } cyclopropane-1, 1-dicarboxamide

Example 27: n- { 2-fluoro-4- [ (5- (3- (4-methylpiperazin-1-yl) propyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide

Example 28: n- { 2-fluoro-4- [ (5- (4-morpholinylbutyl-1-yn-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] phenyl } -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide

Example 29: preparation of N- { 2-fluoro-4- [ (5- (4-morpholinbutyl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinazolin-10-yl) oxy ] -phenyl } -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide

Step 1) methyl 8-benzyloxy-2, 3-dihydrobenzo [ b ] [1,4] dioxane-5-carboxylate (2.2g, 7.33mmol) was dissolved in a mixed solution of ethyl acetate (8mL) and ethanol (8mL), and palladium on carbon (220mg, 10%) was added, followed by reaction under hydrogen conditions for 3 hours. The resulting product was filtered through celite and evaporated to dryness to give an off-white solid (1.43 g, 93% yield). LCMS M/z 211.1[ M + H ] +.

Step 2): the product (1.2g, 5.71mmol) from step 1) was dissolved in DCM (20mL) and pyridine (1.45g, 18.3mmol) and trifluoromethanesulfonic anhydride (2.1g, 7.44mmol) were added under argon protection at 0 deg.C and reacted for 2 hours at 25 deg.C. Diluting the reaction solution with dichloromethane, washing with saturated sodium bicarbonate water solution and saturated brine respectively, drying with anhydrous sodium sulfate, filtering, evaporating, and performing column chromatography to obtain yellow oily substance 1.6g, yield 81.9%, and LCMS (liquid Crystal display System): M/z ═ 343.0[ M + H ])]⁺。

Step 3): the product (750mg, 2.19mmol) obtained in step 2) was dissolved in anhydrous N, N-dimethylformamide (10mL), and 4- (butyl-3-yn-1-yl) morpholine (1.5g, 10.71mmol, intermediate 16), bis (triphenylphosphine) palladium dichloride (151mg, 0.22mmol), cuprous iodide (82mg, 0.43mmol), triethylamine (910mg, 9.01mmol), and reacted at 50 ℃ for 2 hours under argon protection. The reaction mixture was concentrated and subjected to column chromatography to give 680mg of brown oil in 93.3% yield, LCMS: M/z 332.1[ M + H ]]⁺。

Step 4): dissolving the product (680mg, 2.05mmol) obtained in step 3) in a mixed solution of ethyl acetate (5mL) and ethanol (5mL),palladium on carbon (80mg) and concentrated hydrochloric acid (0.1mL) were added thereto, and the mixture was reacted under hydrogen conditions for 5 hours. Filtering with diatomaceous earth, evaporating the filtrate to dryness to obtain yellow oil 650mg, yield 94.4%, and LCMS (liquid Crystal display System): M/z is 336.2[ M + H ]]⁺。

Step 5): the product from step 4) (640mg, 1.91mmol) was added to glacial acetic acid (8mL) and the temperature was controlled<Concentrated nitric acid (4mL) was added dropwise at 10 ℃ and the reaction was carried out for 3 hours at 25 ℃. Pouring into crushed ice, adjusting the pH value to 9 with sodium carbonate solid, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering, evaporating, and performing column chromatography to obtain yellow oily matter 280mg with the yield of 38.6%. LCMS M/z 381.2[ M + H ]]⁺。

Step 6): the product (280mg, 0.74mmol) obtained in step 5) was dissolved in glacial acetic acid (4mL), and zinc powder (60mg, 0.92mmol) was added in portions and reacted at 40 ℃ for 30 minutes. Filtered, and the filtrate was concentrated and used directly in the next reaction. LCMS M/z 351.2[ M + H ]]⁺。

Step 7): the crude product obtained in step 6) was dissolved in ethanol (10mL), and formamidine acetate (143mg, 1.37mmol) was added to react at 90 ℃ for 3 hours. Cooling, evaporating to dryness, and performing column chromatography to obtain white solid 80mg with yield of 36.7% and LCMS (liquid Crystal display System) M/z-346.2 [ M + H ]]⁺。

Step 8): mixing the product obtained in step 7) (80mg, 0.23mol), DBU (bicyclo [4.3.0 ]]-1, 5-Dioxo-5-undecene) (71mg, 0.47mmol) and BOP (benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate) (153mg, 0.35mmol) were dissolved in N, N-dimethylformamide (3mL) and reacted at 25 ℃ for 2 hours, N- (2-fluoro-4-hydroxyphenyl) -N- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide (108mg, 0.33mmol) was added and the reaction was continued for 16 hours. The reaction solution is concentrated and thin layer chromatography is carried out to obtain light yellow solid 10mg, the yield is 6.5 percent,¹H NMR(300MHz,DMSO-d₆)δ10.53(s,1H),10.00(s,1H),8.47(s,1H),7.99–7.84(m,1H),7.72–7.56(m,2H),7.37(s,1H),7.35–7.27(m,1H),7.25–7.12(m,2H),7.12–7.04(m,1H),4.60–4.31(m,4H),3.59–3.52(m,4H),2.84–2.73(m,2H),2.35–2.29(m,4H),1.71–1.62(m,2H),1.62–1.54(m,4H),1.54–1.43(m,2H),0.97–0.90(m,2H).LCMS:m/z＝660.3(M+H)⁺.

example 30: n- (3-fluoro-4- ((5- (4-morpholinbutyl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide

Step 1): a solution of 10-chloro-5-methoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] quinoline (2.5g,10mmol), 2-fluoro-4-nitrophenol (1.6g,10mmol) and potassium carbonate (2.1g,15mmol) in DMF (20mL) was heated to 80 ℃ for reaction for 3 hours, cooled, slurried with water, filtered and dried to give an off-white solid product, 3.5g, yield 94%;

10- (2-fluoro-4-nitrophenoxy) -5-methoxy-2, 3-dihydro- [1,4] dioxano [2,3-f ] quinoline (350mg, 1mmol) was added to a solution of hydrogen bromide in acetic acid (33%, 5mL), heated to 90 deg.C for 15 hours, cooled, slurried with ethyl acetate (15mL), filtered and dried to give a light green solid 3.8g, 87% yield, MS:359[ M + H ] +;

step 2): weighing 200mg of the product obtained in the step 1) into a flask containing 10ml of dichloromethane, placing the flask in an ice salt bath, adding 395mg of triethylamine (3.5eq), adding 378mg (1.2eq) of trifluoromethanesulfonic anhydride, reacting for 4 hours at room temperature, adding silica gel, stirring the sample, and directly carrying out column chromatography to obtain a white solid with the yield of 40%.¹H NMR(400MHz,DMSO-d₆)δ8.81(d,J＝5.0Hz,1H),8.41(dd,J＝10.7,2.7Hz,1H),8.08(dd,J＝8.9,2.4Hz,1H),7.80(s,1H),7.25(dd,J＝11.3,6.7Hz,2H),4.45–4.38(m,2H),4.30(t,J＝4.0Hz,2H).

Step 3): weighing 93mg of the product obtained in the step 2), 132mg (5eq) of 4- (but-3-yn-1-yl) morpholine, 96mg (5eq) of triethylamine, 10mg of palladium dichloride of triphenylphosphine and 10mg of cuprous iodide, reacting for three hours at 50 ℃ under the protection of argon, extracting, rotary-steaming, and carrying out column chromatography to obtain a yellow solid with the yield of 91%.¹H NMR(400MHz,DMSO-d₆)δ8.73(d,J＝4.9Hz,1H),8.37(dd,J＝10.7,2.7Hz,1H),8.08–8.00(m,1H),7.67(s,1H),7.17(d,J＝4.9Hz,1H),7.06(t,J＝8.7Hz,1H),4.34–4.28(m,2H),4.11(t,J＝4.0Hz,2H),3.57(dt,J＝14.3,4.6Hz,4H),2.67(d,J＝6.9Hz,2H),2.60(t,J＝7.0Hz,2H),2.49–2.44(m,4H).MS:480[M+H]+；

Step 4): weighing the product (83mg) obtained in the step 3), dissolving the product in 15ml of methanol containing 5mg of Raney nickel, reacting for 5h at 50 ℃ under the condition of hydrogen, and directly carrying out the next step after the target product is not purified.

Step 5): dissolving the crude product obtained in the step 4) in dichloromethane, dripping into a dichloromethane solution containing 80mg of 1- ((4-fluorophenyl) carbamoyl) cyclopropane-1-carboxylic acid, adding 80 microliters of triethylamine, reacting for three hours at room temperature, extracting and spin-drying, and preparing a product by plate chromatography.¹H NMR(400MHz,DMSO-d₆)δ10.33(s,1H),10.00(s,1H),8.45(d,J＝5.1Hz,1H),7.87(dd,J＝13.3,2.4Hz,1H),7.64(dd,J＝8.8,5.0Hz,2H),7.47(d,J＝9.2Hz,1H),7.40(s,1H),7.26-7.13(m,3H),6.47(d,J＝5.1Hz,1H),4.41–4.31(m,4H),3.55(t,J＝4.6Hz,4H),2.74(t,J＝7.5Hz,2H),2.31(q,J＝7.8,6.3Hz,6H),1.71–1.62(m,2H),1.50(d,J＝15.9Hz,6H).MS:659[M+H]+

Example 31: (E) -N- (3-fluoro-4- ((5- (4-morpholinylbutyl-1-en-1-yl) -2, 3-dihydro- [1,4] dioxano [2,3-f ] quinolin-10-yl) oxy) phenyl) -N- (4-fluorophenyl) cyclopropyl-1, 1-dicarboxamide

Step 1): the product (83mg) obtained in step 3) of example 30 was dissolved in 5ml of glacial acetic acid, 200mg of zinc powder was added, the reaction was carried out at 40 ℃ for 3 hours, most of the glacial acetic acid was filtered with celite, and the product was extracted and subjected to column chromatography in a yield of 60%.

Step 2): dissolving the product obtained in the step 1) in dichloromethane, dripping the solution into dichloromethane solution containing 80mg of 1- ((4-fluorophenyl) carbamoyl) cyclopropane-1-carboxylic acid, adding 80 microliters of triethylamine, reacting for three hours at room temperature, extracting and spin-drying, and preparing the product by plate chromatography.¹H NMR(400MHz,DMSO-d₆)δ10.27(s,1H),9.93(s,1H),8.39(d,J＝5.1Hz,1H),7.91–7.74(m,1H),7.67–7.49(m,3H),7.39(d,J＝9.3Hz,1H),7.19(t,J＝9.1Hz,1H),7.08(t,J＝8.9Hz,2H),6.69(d,J＝15.9Hz,1H),6.55–6.44(m,1H),6.41–6.38(m,1H),4.31(dd,J＝14.6,4.5Hz,4H),3.52(t,J＝4.7Hz,4H),2.41–2.30(m,8H),1.40(d,J＝2.4Hz,4H).MS:657[M+H]+

EXPERIMENTAL EXAMPLE 1 test for the inhibition of VEGFR-2 kinase Activity by Small molecule Compounds

Based on the LANCE TR-FRET technique of Perkin Elmer, the test method is as follows:

1. compound dilution: a total of 11 concentrations were obtained starting from the highest 2500nM concentration at a 3-fold gradient (2500 nM maximum final concentration and 0.042nM minimum final concentration of drug used in this experiment).

2. mu.L of the compound diluted in a gradient was taken with a discharge gun and added to a 384-well plate.

3. Adding an enzyme: mu.L of 2X VEGFR-2 kinase solution (concentration: 0.5nM) was added to the corresponding reaction well of 384-well plate using a line gun, mixed well and pre-reacted at room temperature for 30 minutes.

4. Discharging 2.5 μ L4X Ultra height^TMThe JAK-1(Tyr1023) Peptide (200 nM)/ATP (40. mu.M) mixture was added to the corresponding reaction wells of a 384-well plate.

5. Negative control: add 2.5. mu.L/well of 4 Xsubstrate/ATP mix and 7.5. mu.L of 1X KinaseAssay buffer to the 384 well plate.

6. Positive control: to a 384 well plate was added 2.5. mu.L/well of 4X substrate/ATP mix, 2.5. mu.L/well of 1X Kinase Assay Buffer containing 16% DMSO, 5. mu.L/well of 2X VEGFR-2 Kinase solution. The final concentration of DMSO in the reaction system was 4%.

7. And (4) centrifuging, mixing uniformly, and reacting for 60 minutes at room temperature in the dark.

8. Termination of the enzymatic reaction: and 5 mu L of 4X stop solution is taken by a discharging gun and added into a mesopore of a 384-pore plate, and the mixture is centrifuged and mixed evenly and reacted for 5 minutes at room temperature.

9. And (3) color development reaction: and (3) adding 5 mu L of 4X detection solution into a mesopore of a 384-pore plate by using a discharge gun for color development, centrifuging and uniformly mixing, and reacting for 60 minutes at room temperature.

10. And (3) putting the 384-well plate into an Envision plate reading instrument to read the plate, and calling a corresponding program detection signal.

11. Analysis and processing of raw data:

the drug concentration and the corresponding inhibition rate are input into GraphPad Prism5 for calculation, and the inhibition rate of the compound is calculated as follows: inhibition (%) - (positive well read-experimental well read)/(positive control well readValue-negative control well reading) x 100%. The corresponding IC was obtained by software processing of GraphPad Prism5₅₀Value (concentration of compound at which the highest inhibition of the enzyme was 50%).

Table 3 shows the results of the determination of the inhibitory activity of some of the compounds of the invention on the tyrosine kinase VEGFR-2, in which A denotes IC₅₀Less than or equal to 50nM, B represents IC₅₀Greater than 50nM but less than or equal to 500nM, C represents IC₅₀Greater than 500nM but less than or equal to 5000nM, D represents IC₅₀Greater than 5000 nM.

TABLE 3 results of the determination of VEGFR-2 tyrosine kinase inhibitory Activity of some of the Compounds of the invention

EXAMPLE 2 test for the inhibition of RET kinase Activity by Small molecule Compounds

3. Adding an enzyme: mu.L of 2X RET kinase solution (concentration: 0.8nM) was added to the corresponding reaction well of 384-well plate using a line gun, mixed well and pre-reacted at room temperature for 30 minutes.

Positive control: to a 384 well plate was added 2.5. mu.L/well of 4 Xsubstrate/ATP mix, 2.5. mu.L/well of 1X Kinase Assay Buffer containing 16% DMSO, 5. mu.L/well of 2X RET Kinase solution. The final concentration of DMSO in the reaction system was 4%.

6. And (4) centrifuging, mixing uniformly, and reacting for 60 minutes at room temperature in the dark.

7. Termination of the enzymatic reaction: and 5 mu L of 4X stop solution is taken by a discharging gun and added into a mesopore of a 384-pore plate, and the mixture is centrifuged and mixed evenly and reacted for 5 minutes at room temperature.

8. And (3) color development reaction: and (3) adding 5 mu L of 4X detection solution into a mesopore of a 384-pore plate by using a discharge gun for color development, centrifuging and uniformly mixing, and reacting for 60 minutes at room temperature.

9. And (3) putting the 384-well plate into an Envision plate reading instrument to read the plate, and calling a corresponding program detection signal.

10. Analysis and processing of raw data:

the drug concentration and the corresponding inhibition rate are input into GraphPad Prism5 for calculation, and the inhibition rate of the compound is calculated as follows: inhibition (%) - (positive well reading-experimental well reading)/(positive control well reading-negative control well reading) x 100%. The corresponding IC was obtained by software processing of GraphPad Prism5₅₀Value (concentration of compound at which the highest inhibition of the enzyme was 50%).

Table 4 shows the results of measurement of the inhibitory activity of a part of the compounds of the present invention on tyrosine kinase RET, wherein A represents IC₅₀Less than or equal to 50nM, B represents IC₅₀Greater than 50nM but less than or equal to 500nM, C represents IC₅₀Greater than 500nM but less than or equal to 5000nM, D represents IC₅₀Greater than 5000 nM.

TABLE 4 results of the test for RET tyrosine kinase inhibitory Activity of some of the Compounds of the invention

EXAMPLE 3 test of Small molecule Compounds for inhibition of c-MET kinase Activity

11. compound dilution: a total of 11 concentrations were obtained starting from the highest 2500nM concentration at a 3-fold gradient (2500 nM maximum final concentration and 0.042nM minimum final concentration of drug used in this experiment).

12. mu.L of the compound diluted in a gradient was taken with a discharge gun and added to a 384-well plate.

13. Adding an enzyme: mu.L of 2X c-MET kinase solution (concentration: 2nM) was added to the corresponding reaction well of 384-well plate by a line gun, mixed well and pre-reacted at room temperature for 5 minutes.

14. Discharging 2.5 μ L4X Ultra height^TMThe JAK-1(Tyr1023) Peptide (400 nM concentration)/ATP (40. mu.M) mixture was added to the corresponding reaction wells of a 384-well plate.

15. Negative control: add 2.5. mu.L/well of 4 Xsubstrate/ATP mix and 7.5. mu.L of 1X KinaseAssay buffer to the 384 well plate.

16. Positive control: to a 384 well plate was added 2.5. mu.L/well of 4X substrate/ATP mix, 2.5. mu.L/well of 1X Kinase Assay Buffer containing 16% DMSO, 5. mu.L/well of 2X c-MET Kinase solution. The final concentration of DMSO in the reaction system was 4%.

17. And (4) centrifuging, mixing uniformly, and reacting for 60 minutes at room temperature in the dark.

18. Termination of the enzymatic reaction: and 5 mu L of 4X stop solution is taken by a discharging gun and added into a mesopore of a 384-pore plate, and the mixture is centrifuged and mixed evenly and reacted for 5 minutes at room temperature.

19. And (3) color development reaction: and (3) adding 5 mu L of 4X detection solution into a mesopore of a 384-pore plate by using a discharge gun for color development, centrifuging and uniformly mixing, and reacting for 60 minutes at room temperature.

20. And (3) putting the 384-well plate into an Envision plate reading instrument to read the plate, and calling a corresponding program detection signal.

21. Analysis and processing of raw data:

22. the drug concentration and the corresponding inhibition rate are input into GraphPad Prism5 for calculation, and the inhibition rate of the compound is calculated as follows: inhibition (%) - (positive well reading-experimental well reading)/(positive control well reading-negative control well reading) x 100%. Treatment with GraphPad Prism5 software gave the corresponding IC50 value (concentration of compound at which the highest inhibition of the enzyme was 50%).

Table 5 shows the results of measurement of the inhibitory activity of a part of the compounds of the present invention on the tyrosine kinase c-MET, wherein A represents IC₅₀Less than or equal to 50nM, B represents IC₅₀Greater than 50nM but less than or equal to 500nM, C represents IC₅₀Greater than 500nM but less than or equal to 5000nM, D represents IC₅₀Greater than 5000 nM.

TABLE 5 results of determination of c-MET tyrosine kinase inhibitory Activity of partial Compounds of the present invention

The biological data provided herein indicate that the compounds of the invention are useful for treating or preventing diseases caused by abnormal VEGFR-2, RET or c-MET kinases. Accordingly, the compounds of the present 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, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myelogenous leukemia, acute myelogenous leukemia, non-Hodgkin's lymphoma, nasopharyngeal cancer, esophageal cancer, brain tumors, B-cell and T-cell lymphomas, lymphoma, multiple myeloma, biliary sarcoma, biliary tract cancer. The compounds of the invention also include the treatment of cancer resistant to one or more other therapeutic methods. The compounds of the present invention are also useful in diseases other than cancer associated with VEGFR-2, RET and/or c-MET kinases, including but not limited to ocular fundus disease, psoriasis, rheumatoid arthritis, atheroma, pulmonary fibrosis, liver fibrosis. The compounds of the present invention may be administered as monotherapy or in combination therapy, in combination with a plurality of the compounds of the present invention or in combination with other drugs other than those of the present invention.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims

1. A compound represented by the formula (I), a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof,

in the formula (I), the compound is shown in the specification,

q is N or CH;

The linking group in (1) is a group,

g is selected from the following groups:

x and Y are each independently H or C₁-C₃N is 0 to 3;

L₂is a linking group selected from a direct bond, a carbon-carbon double bond, or a carbon-carbon triple bond;

R¹is-H, C₁-C₉Alkyl radical, C₃-C₇Cycloalkyl of, C₃-C₇Cycloalkyl-substituted C₁-C₆Alkyl, aryl substituted C₁-C₆Alkyl, heteroaryl or heteroaryl substituted C₁-C₆An alkyl group;

R²is-H, or from 1 to 3 are selected from C₁-C₆Alkoxy group of,C₁-C₆Alkylthio of, C₁-C₃Acyl, hydroxy, halogen, trifluoromethyl, cyano, -CONH₂Oxo (═ O) or-NR^aR^bC substituted or unsubstituted by the substituent in (1)₃-C₈Or from 1 to 3 cycloalkyl groups selected from C₁-C₆Alkoxy group of (C)₁-C₆Alkylthio of, C₁-C₃Acyl, hydroxy, halogen, trifluoromethyl, cyano, -CONH₂、C₃-C₇Cycloalkyl, 4-8 membered heteroalicyclic or-NR of^aR^bC substituted or unsubstituted by a substituent of (A)₁-C₁₀Alkyl, said 4-8 membered heteroalicyclic is 4-8 membered heteroalicyclic comprising 1-2 atoms selected from N, O, S as ring atoms, and said 4-8 membered heteroalicyclic is optionally substituted with 1 to 3 atoms selected from halogen, C₁-C₃Alkyl of (C)₁-C₃Alkoxy group of (C)₁-C₃Alkylthio, hydroxy, -NR^aR^b、C₁-C₃Acyl, oxo, substituted or unsubstituted,

R³、R⁴each independently is-H or halogen.

2. The compound of claim 1, a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof, wherein R is¹Is aryl, aryl-substituted C₁-C₃Alkyl, heteroaryl or heteroaryl substituted C₁-C₃Alkyl, said aryl and/or heteroaryl being unsubstituted or substituted by 1 to 3 substituents selected from hydroxy, amino, cyano, C₁-C₃Alkyl of (C)₁-C₃Alkoxy group of (C)₁-C₃Alkylthio, mono-or di-C of₁-C₃Substituted by one or more substituents selected from the group consisting of amino, -F, -Cl, trifluoromethyl and methylsulfonyl;

the aryl is selected from phenyl, naphthyl and phenanthryl, the heteroaryl is selected from pyrrolyl, furyl, pyridyl, thienyl, imidazolyl, thiazolyl, isothiazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 1, 5-naphthyridinyl, 1, 6-naphthyridinonyl and oxadiazolyl, oxazolyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazolyl, pyrazolo [3,4-d ] pyrimidinyl, pyridyl, pyrido [3,2-d ] pyrimidinyl, pyrido [3,4-d ] pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl.

3. The compound, a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof according to claim 2, wherein R¹Selected from the group consisting of phenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 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-4 fluorophenyl, 2-fluoro-4-chlorophenyl, 2-fluoro-5-chlorophenyl, 3-fluoro-4-chlorophenyl, 2-fluoro-4-chlorophenyl, 3-chloro-4-chlorophenyl, C-fluoro-4-chlorophenyl, C-O-phenyl, C, 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, benzyl, phenethyl, 4-fluorobenzyl, naphthalen-1-yl, 3-methyl-isoxazol-5-yl, 4-phenoxyphenyl, 3- (methylsulfonyl) phenyl, 4- (methylsulfonyl) phenyl, trifluoromethyl-4- (trifluoromethyl) phenyl, trifluoromethyl-4-chlorophenyl, 3-trifluoromethyl-4-chlorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-fluorophenyl, 4-fluorobenzyl, naphthalene-1-yl, 3, Pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 3-methoxybenzyl, 1- (4-fluorophenyl)) Ethyl, thiazol-2-yl-methyl, 1- (thiazol-2-yl) ethyl or 4-methoxybenzyl.

4. The compound, a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof according to any one of claims 1 to 3, wherein R³、R⁴Each independently is-H, -F, or-Cl.

5. The compound, a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof according to any one of claims 1 to 4, wherein R²Is 1 to 3 selected from C₁-C₃Alkoxy group of (C)₁-C₃Alkylthio of, C₁-C₃Acyl, hydroxy, halogen, trifluoromethyl, cyano, -CONH₂、C₃-C₇Cycloalkyl, 4-8 membered heteroalicyclic or-NR of^aR^bC substituted or unsubstituted by a substituent of (A)₁-C₆Alkyl, said 4-8 membered heteroalicyclic is 4-8 membered heteroalicyclic comprising 1-2 atoms selected from N, O, S as ring atoms, and said 4-8 membered heteroalicyclic is optionally substituted with 1 to 3 atoms selected from halogen, C₁-C₃Alkyl of (C)₁-C₃Alkoxy group of (C)₁-C₃Alkylthio, hydroxy, -NR^aR^b、C₁-C₃Acyl, oxo, substituted or unsubstituted,

R^aand R^bEach independently is-H, C₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radical, C₁-C₃Alkoxy-substituted C₁-C₆Alkyl radical, C₁-C₃Alkylthio substituted C₁-C₆Alkyl or mono-or di-C₁-C₃Alkyl-substituted or unsubstituted amino-substituted C₁-C₆An alkyl group.

6. The compound according to claim 5, pharmaceutically acceptable salts, isomers, hydrates, solvates thereof,Or a prodrug thereof, wherein R²Selected from the group consisting of tetrahydropyrrole-1-methyl, tetrahydropyrrole-1-ethyl, tetrahydropyrrole-1-propyl, tetrahydropyrrole-1-butyl, piperidine-1-methyl, piperidine-1-ethyl, piperidine-1-propyl, piperidine-1-butyl, piperazine-1-methyl, piperazine-1-ethyl, piperazine-1-propyl, piperazine-1-butyl, morpholine-4-methyl, morpholine-4-ethyl, morpholine-4-propyl, morpholine-4-butyl, methylpiperazin-4-methyl, methylpiperazin-4-ethyl, methylpiperazin-4-propyl, methylpiperazin-4-butyl, and mixtures thereof, N-formylpiperazine-4-ethyl, N-formylpiperazine-4-propyl, N-acetylpiperazine-4-ethyl, N-acetylpiperazine-4-propyl, (1, 1-dioxothiomorpholinyl) -4-methyl, (1, 1-dioxothiomorpholinyl) -4-ethyl, (1, 1-dioxothiomorpholinyl) -4-propyl, (1, 1-dioxothiomorpholinyl) -4-butyl, 4-dimethylpiperidin-1-methyl, 4-dimethylpiperidin-1-ethyl, 4-dimethylpiperidin-1-propyl, 4-dimethylpiperidin-1-butyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, decyl, and, 4-methyl-4-hydroxypiperidine-1-methyl group, 4-methyl-4-hydroxypiperidine-1-propyl group, 4-methyl-4-hydroxypiperidine-1-ethyl group, 4-methyl-4-hydroxypiperidine-1-butyl group, 4-methyl-4-aminopiperidine-1-methyl group, 4-methyl-4-aminopiperidine-1-propyl group, 4-methyl-4-aminopiperidine-1-ethyl group, and 4-methyl-4-aminopiperidine-1-butyl group.

7. The compound, a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof according to any one of claims 1 to 6, wherein L₁Is carbonyl or

8. The compound, its isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof according to any of claims 1 to 7, wherein the pharmaceutically acceptable salt of the compound is selected from hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, nitrate, phosphate, formate, acetate, propionate, glycolate, lactate, succinate, maleate, tartrate, malate, citrate, fumarate, gluconate, benzoate, mandelate, methanesulfonate, isethionate, benzenesulfonate, oxalate, palmitate, 2-naphthalenesulfonate, p-toluenesulfonate, cyclamate, salicylate, hexonate, trifluoroacetate, aluminum salt, calcium salt, chloroprocaine salt, choline salt, or prodrug thereof, One or more of diethanolamine salt, ethylenediamine salt, lithium salt, magnesium salt, potassium salt, sodium salt and zinc salt.

9. Use of a compound of any one of claims 1 to 7, or an isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof for the manufacture of a medicament for treating VEGFR-2, c-Met and/or RET related diseases, wherein the VEGFR-2, c-Met and/or RET related diseases include ocular fundus disease, dry eye, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, systemic lupus erythematosus, crohn's disease, atheroma, pulmonary fibrosis, hepatic fibrosis, myelofibrosis, non-small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, renal cancer, bladder cancer, and other diseases, Gastric cancer, liver cancer, gastrointestinal stromal tumors, thyroid cancer, chronic myelogenous leukemia, acute myelogenous leukemia, non-hodgkin's lymphoma, nasopharyngeal carcinoma, esophageal cancer, brain tumors, B-cell and T-cell lymphomas, lymphoma, multiple myeloma, sarcoma of biliary tract cancer, cholangiocarcinoma.

10. A pharmaceutical composition comprising a compound of any one of claims 1 to 7, an isomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug thereof, and one or more pharmaceutically acceptable carriers or excipients.