WO2014154173A1

WO2014154173A1 - Anti-angiogenic compound

Info

Publication number: WO2014154173A1
Application number: PCT/CN2014/074306
Authority: WO
Inventors: 侯睿; 罗红蓉
Original assignee: 广州康睿生物医药科技有限公司
Priority date: 2013-03-28
Filing date: 2014-03-28
Publication date: 2014-10-02
Also published as: CN104072481B; CN106146473B; CN104072481A; CN106146473A; CN106188001A

Abstract

Provided in the present invention are a new anti-angiogenic compound and a preparation method and use thereof. The compound of the present invention has a good anti-angiogenic effect, and this compound is initially considered to act by inhibiting VEGFR2 (i.e. KDR), thereby generating activity. Such compounds can be used for the treatment of diseases caused by abnormal protein kinase such as neovascularization, VEGFR2, PDGFR-β, and KIT, for example, wet macular degeneration, malignant tumours etc.

Description

Instruction manual

Anti-angiogenic compound

The present invention relates to a novel compound and use.

Background technique

Angiogenesis is the process of sprouting new blood vessels from existing blood vessels. This process is associated with vascular endothelial cell migration and proliferation. Angiogenesis is associated with a variety of major human diseases, such as malignant tumors. It has been found that ocular neovascular diseases, including age-related macular degeneration (AMD), diabetic retinopathy, neovascular glaucoma, etc., are common features of these diseases in the abnormal proliferation of ocular neovascularization (Jin Xiao, et al. , Research progress in the application and mechanism of anti-VEGF drugs in ophthalmic diseases, Chinese and Foreign Medical, 2012).

Among them, macular degeneration is mainly dry and wet. The characteristic of wet macular degeneration (AMD) is that the choroidal neovascularization enters the subretinal and subsequent pathological changes such as hemorrhage, exudation and edema. Wetness quickly loses sight and is more severe than dryness. At present, there has been good progress in the treatment of wet macular degeneration. Early laser burnt hemostasis was replaced by vascular endothelial factor antagonists, but because of the poor effect of the latter, it was quickly replaced by photodynamic therapy. Although photodynamic therapy has improved the therapeutic effect, it is still not ideal. In recent years, a new vascular endothelial factor antagonist, Lucentis (Ranibizumab), is a recombinant of a human VEGF subtype monoclonal antibody fragment that reduces neovascularization. In 2006, the drug was approved by the US FDA for the treatment of wet macular degeneration, and its efficacy was good. At the same time, it is also found that this type of anti-VEGF drug has therapeutic effects on diabetic retinopathy and neovascular glaucoma. However, because Lucentis is an antibody drug, the price is extremely high, and it cannot be popularized all over the world. Therefore, the study of small-molecule angiogenesis inhibitors with good efficacy and low cost is the focus of fierce competition in the international pharmaceutical industry today.

Summary of the invention

It is an object of the present invention to provide a novel compound, its preparation and use.

The present invention provides a compound of formula A and a pharmaceutically acceptable salt or prodrug thereof:

Formula A

Among them, Z. Is 0 or S; X is C, Y is N _{; ;} Z ₂ are independently selected from N or -CR _S;

r _{7 is} selected from hydrogen or dC ₆ fluorenyl; ^ is selected from hydrogen or dC ₆ fluorenyl; _Γι . Selected from H, amino, hydroxy, decyl, dC ₆ fluorenyl or

(CH ₂ ) m Hri, wherein, =l-5, ϋ is H or C1-3 sulfhydryl;

r _{9 is} selected from the group consisting of H, amino, hydroxy, decyl, (Cr _u r ₁₂ ) nNr ₁₃ r ₁₄ , (C_r _u r ₁₂ ) n0r ₁₅ , (Cr _u r ₁₂ ) „C (0) Er ₁₃

(C-rnrJ ^ W mrn; or r _s and ^ together with the atom to which they are attached form a saturated 4-7-membered heterocyclic or substituted heterocyclic ring, Wherein the heterocyclic or substituted heterocyclic ring contains 1 or 2 heteroatoms selected from N, 0 or S, the substituents of which are 0, 1, or 2, each independently selected from an oxo group, C1-C6垸, C1-C6 halogenated fluorenyl, C1-C6 decyloxy, C1-C6 halodecyloxy, C 1-C 6 decanoyl, C1-C6 decylamino, C3-C7 cyclodecyl, halogen, Hydroxy, amino, carbonyl, aminocarbonyl, C1-C6 amidinocarbonyl, C1-C4 acyl, C1-C6 methoxycarbonyl, C1-C6 sulfonyl, aminosulfonyl;

Ar _{2 is} selected from phenyl, naphthyl, monocyclic or bicyclic heteroaryl, bicyclic or tricyclic heterocyclic groups wherein each heteroaryl or heterocyclic group has 1, 2, 3 or 4 selected from N a hetero atom of 0 or S; the phenyl, naphthyl, heteroaryl or heterocyclic group is an unsubstituted or substituted phenyl, naphthyl, heteroaryl or heterocyclic group having a substituent 1, 2, or 3, independently selected from C1-C8 fluorenyl, C1-C8 halogenated fluorenyl, hydroxy C1-C 6 fluorenyl, C1-C8 decyloxy, C1-C8 halogenated decyloxy , halogen, hydroxy, amino, amino C-C6 fluorenyl, C1-C6 decylamino, phenyl, C3-C 7 cyclodecyl, spiro C3-C7 cyclodecyl, sulfamoyl, C1-C6 垸Aminosulfonyl;

m is 0, 1, or 2; n is 0, 1, 2, or 3; E is empty, oxygen or _Nr _ls;

Γπ, r _{12 and} P r _ls are the same or different and are each independently selected from hydrogen or C1-C4 fluorenyl; r ₁₃ , r ₁₄ , r ₁₅ , r ₁₆ and r _{17 are} independently selected from hydrogen, C1-C6 fluorenyl , a C1-C6 acyl group, a phenyl group and a heterocyclic ring, or a substituted C1-C6 fluorenyl group, a C1-C6 acyl group, a phenyl group and a heterocyclic ring having a substituent of 0, 1 or 2, each independently selected from C1- C4 decyloxy, C1-C4 fluorenyl, halogen, hydroxy, amino, C1-C6 amidoxime

Further, the structural formula of the compound is as follows:

Formula I

Where X is C and Y is N;

Ri is selected from H, amino, hydroxy or decyl; R _{2 is} selected from H, amino, hydroxy, decyl or -(CH ₂ ) _n NHR ₈ , wherein n=l-5 is 11 or C1-3 fluorenyl; R _{3 is} selected from H or C 1-6 fluorenyl; R ₄ , R ₅ , R ₆ are each independently selected from H, halogen, C1-6 fluorenyl or halogen-substituted fluorenyl; R _{7 is} selected from H, C1-6 Sulfhydryl or halogen;

Alternatively, R ₂ and R _{3 together} with the carbon atom to which they are bonded form a substituted or unsubstituted five- or six-membered ring having from 1 to 2 heteroatoms, said hetero atom being N, 0 or S, the substituent of which is C1 -6 垸 base.

Further, X and Y are different; selected from H or amino; R _{2 is} selected from H, amino or -(CH ₂ ) _n NHR ₈ , wherein n=l-3, ₁₈ is 11 or C1-2 R _{3 is} selected from H or C 1-2 fluorenyl; R ₅ , Re are each independently selected from halogen, C 1-2 fluorenyl or halogen substituted fluorenyl; R _{7 is} selected from H or halogen;

Alternatively, R ₂ and R _{3 together} with the carbon atom to which they are bonded constitute a substituted or unsubstituted five- or six-membered ring containing one N, and the substituent is a fluorenyl group of C1-3.

Further, R _{2 is} selected from an amino group or -(CH ₂ ) _n HR _{8 ;} or R ₂ , a carbon atom to which it is bonded, constitutes a substituted or unsubstituted five- or six-membered ring containing one N, a substituent It is a thiol group of C1-3.

Further, the structural formula of the compound is as follows:

Formula II III

When the compound is of formula II, W1 and W2 are each independently selected from C or a hetero atom, n=l or 2; R9 is H, C1-C4 fluorenyl or halogen; R10 is halogen; wherein, when n=l, Wl, W2 When not, C1, W2 is a hetero atom at the same time, and the hetero atom is preferably N; when n=2, W1 and W2 are simultaneously C;

When the compound is of the formula III, W3 is selected from C or a hetero atom, the hetero atom is preferably N; and R10 is a halogen.

Further, the halogen is F or Cl.

Preferably, the compound is:

KDR8A KDR8B KDR4

The present invention also provides the use of the above compound and a pharmaceutically acceptable salt or prodrug thereof for the preparation of an angiogenesis inhibitor.

Further, the angiogenesis inhibitor is a vascular endothelial growth factor receptor 2 inhibitor.

Further, the inhibitor is a drug that is resistant to ocular angiogenesis.

Further, the drug is a choroidal neovascularization inhibitor.

Further, the medicament is a medicament for treating or preventing wet macular degeneration, diabetic retinopathy or neovascular glaucoma.

The invention also provides the use of the above compounds, and pharmaceutically acceptable salts or prodrugs thereof, in the manufacture of a VEGFR2, PDGFR-P or/and KIT inhibitor. The present invention also provides a pharmaceutical composition which is an ophthalmic preparation containing the above compound and a pharmaceutically acceptable salt thereof. In addition to the above-mentioned compounds provided by the present invention, other agents known to have similar therapeutic uses may be included in the formulation.

Further, the ophthalmic preparation is an eye drop, an eye ointment or an ophthalmic injection.

Salts of the compounds of the invention can be prepared by methods known in the art. Treatment with an acid, or with a suitable anion exchanger, can form a salt with the above compounds. The pharmaceutically acceptable salt of the compound of the present invention may be an organic or inorganic acid addition salt having a basic nitrogen atom from the above compound.

Preferably, suitable inorganic acids include, but are not limited to, hydrohalic acids such as hydrochloric acid, sulfuric acid, or phosphoric acid.

Preferably, suitable organic acids include, but are not limited to, carboxylic acids, phosphoric acids, sulfonic acids or aminocarboxylic acids such as acetic acid, propionic acid, caprylic acid, capric acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, Succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acid, such as glutamic acid or aspartic acid, maleic acid, hydroxy acid, methyl mala Acid, cyclohexyl carboxylic acid, adamant carboxylic acid, benzoic acid, salicylic acid, 4 aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, formazan or acetophenone sulfonic acid , 2 - hydroxyethanesulfonic acid, acetam-1,2-disulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, 2-methylbenzenesulfonic acid, p-methylbenzene Sulfonic acid, ethylsulfate, acid of dodecyl sulfate, N cyclohexylaminoacetic acid, N-methyl-N-ethyl-N-propyl-sulfamic acid, or other organic acids such as ascorbic acid.

Alternatively, it may be used in isolation or purification as a pharmaceutically unacceptable salt, such as picrate or perchlorate. However, for therapeutic use, it can only be a pharmaceutically acceptable salt or free compound, in the form of a suitable pharmaceutical preparation.

The pharmaceutically acceptable prodrug of the present invention refers to a compound obtained by chemically modifying the compound to release an active ingredient by enzymatic or non-enzymatic conversion in vivo to exert a pharmacological effect. In one embodiment of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is also isotopically labeled, and the isotopically labeled compound means the same as the compound listed herein, but one or more of the atoms are Another atomic substitution, the atomic mass or mass of the atom is different from the atomic mass or mass number that is common in nature. Isotopes which may be introduced into the compound include hydrogen, carbon, nitrogen, oxygen, sulfur, i.e., 2 H, 3 H, 13 C, 14 C, 15 N, 17 0, 18 0, 35 S. Compounds containing the above isotopes and I or other atomic isotopes and stereoisomers thereof, as well as pharmaceutically acceptable salts of the compounds, stereoisomers, are intended to be encompassed within the scope of the invention.

The key intermediates and compounds in the present invention are isolated and purified by the separation and purification methods commonly used in organic chemistry and examples of the methods include filtration, extraction, drying, spin drying, and various types of chromatography. Alternatively, the intermediate can be subjected to the next reaction without purification.

In certain embodiments, one or more compounds of the invention may be used in combination with one another. Alternatively, the compounds of the invention may be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition for modulating cellular function or treating a disease. If a group of compounds is used, these compounds can be administered to the subject simultaneously, separately or sequentially.

The compounds of the present invention have a good anti-angiogenic effect, and it is preliminarily believed that such compounds are active by inhibiting VEGFR2 (i.e., KDR). Such compounds can be used for the treatment of diseases caused by abnormalities of protein kinases such as neovascularization and VEGFR2, such as wet macular degeneration, malignant tumors and the like.

DRAWINGS

Figure 1 Inhibition of zebrafish vascular development by the compounds of the invention

Figure 2: Negative control results, in which zebrafish vascular development is normal

Figure 3 is a graph of the results of the drug group, in which the zebrafish vascular development site is partially inhibited by the compound of the present invention.

Figure 4 is a graph of the results of the drug group, in which the zebrafish vascular development site is completely inhibited by the compound of the present invention. Figure 5 Inhibition of VEGFR2 by the compound of the present invention in vitro

Fig. 6 Inhibition of choroidal neovascularization of the compound of the present invention KDR4, wherein: A: negative control, B: KDR4 Fig. 7 Inhibition of choroidal neovascularization of the compound V01 of the present invention, wherein: A: negative control, B: V01

Figure 8 Nuclear magnetic diagram of compound V01

Figure 9 Mass spectrum of compound V3

Figure 10 Mass spectrum of compound V4

Figure 11 Mass spectrum of compound V5

Figure 12 Nuclear magnetic diagram of compound V5

Figure 13 Mass spectrum of compound V6

Figure 14 Mass spectrum of compound KDR3

Figure 15 KDR4 compound mass spectrum

Figure 16 Spectrum of KDR6

Figure 17 Mass spectrum of KDR6A

Figure 18 Mass spectrum of KDR8

Figure 19 Nuclear magnetic map of KDR8A

Figure 20 Spectrum of KDR8A

Figure 21 Mass spectrum of KDR8B

Figure 22 Dose-effect curve of compound V01

Figure 23 Effect of compound V01 on ocular neovascularization and hemorrhage in mice, A: right eye V01 treatment, B: left eye PBS control

Example 1 Preparation of the intermediate of the present invention

Proceed as follows:

Step 1: Mix Mic acid (75. 3 g, 0.522 mol) and triethyl orthoformate (92 mL, 0.55 mol), heat to 55 ° C for 90 minutes, then cool to 45 ° C. Compound 1 (92 g, 0.5 mol) was dissolved in methanol (200 mL) and added to the reaction mixture for 45 minutes while maintaining the temperature of the reaction mixture below 50 V, then stirred at room temperature overnight, thin layer chromatography (PE) / EA = 3 : 1) Monitoring until the reaction is completed. The reaction mixture was cooled to 0 ° C, and the precipitate was filtered and dried to give white crystals of Compound 2 (155.9 g, yield: 96%).

Step 2: Compound 2 (155. 9 g, 0.441 mol) was heated to 100 ° C in a Dowtherm A heat pipe (1 L) and then slowly added to the flask to which the Dowtherm A heat pipe was attached ( 500mL, preheated to 210 °C) while keeping the temperature above 207 ° C. The reaction was stirred at 210 ° C for one hour and then cooled to room temperature. The collected precipitate was filtered, washed with diethyl ether and acetone, and dried to give brown solid compound 3 (67 g, yield: 61%).

Step 3: Add compound 3 (10 g, 0.0398 mol) to phosphorus oxychloride P °C13 (35 mL) with stirring at room temperature. After the addition, the reaction mixture was stirred under reflux for 3 hours, and thin layer chromatography (dichloromethane DCM / methanol = 10:1) was followed to complete the reaction, and then the reaction mixture was poured into ice water, and sodium carbonate was alkalized to adjust pH = 8, and then The organic phase was extracted with EtOAc. EtOAc (EtOAc) (EtOAc) Compound 4 (6.0 g, yield: 56%).

Step 4: Compound 4 (10.0 g, 37 mmol), zinc powder (0·36 g, 555 ol), Zn (CN) 2 (2.69 g, 22.9 Zn), dppf (8.82 g, 15.9 mmol) Mix with Pd2 (dba) 3 (7.8 g, 8.51 mmol) in DMA (50 mL) and stir at 80 °C overnight. Thin layer chromatography (PE / EA = 5:1) was traced to almost all of the compound 4 was consumed. After the reaction mixture was cooled to room temperature, poured into water, filtered, and then filtered, ethyl acetate was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. 10:1) Obtained a pale yellow solid pure compound 5 (6.0 g, yield: 62.3%).

Step 5: Mix compound 5 (6.0 g, 23.08 mmol), sodium hydroxide (10 g, 250 mmol) in ethylene glycol (70 mL) and water (10 mL). Thin layer chromatography (DCM/methanol = 10:1) was followed until the reaction was completed. The reaction mixture was cooled to room temperature, aqueous citric acid was added and acidified to pH = 4, filtered, and dried to give a pale yellow solid compound 6 (6.0 g, yield: 93. 2%).

Step 6: Compound mixture was stirred for 6 (6.0 g, 21.5mmol) in methanol (lOOmL) in the 0 ° C was added dropwise S0C1 ₂ (4.7mL, 64.5mmol). After the addition, the reaction mixture was stirred at room temperature for 1 hour and then heated to reflux overnight. Thin layer chromatography (DCM / methanol = 10:1) was followed until the reaction was completed. The reaction mixture was evaporated to remove most of the solvent, the residue was poured into ice water, and then filtered and evaporated to ethyl acetate. The organic phase was collected, washed with brine, dried over Na2S04 and concentrated to give a brown solid. 7 (3.9 g, yield: 61.9%).

Step 7: The compound 7 (3.9 g, 13.3 mmol) and 10% Pd / C (1.0 g) were stirred in methanol (150 mL) at room temperature for 2 hr. Thin layer chromatography (PE / EA = 2:1) was followed until the reaction was completed. The reaction mixture was filtered, and the filtrate was concentrated to give brown solid compound 8 (2.6 g, yield: 96.3%).

Step 8: Stir compound 8 (0.5 g, 2.46 mmol) in MeOH (5 mL). EtOAc (2 mL EtOAc. /methanol = 10:1) indicates the completion of the reaction. The reaction mixture was evaporated, the residue was diluted with water, and extracted with ethyl acetate. The ethyl acetate layer was discarded, aqueous citric acid was added and adjusted to pH = 2, filtered, and dried. After that, pure compound 9 (0.4 g, yield: 86%) was obtained.

Step 9: Mixing the compound 9 (0.4 g, 2. llmmol), 3-trifluoromethyl aniline

(375 mg, 2.32 mmol), HATU (960 mg, 2.53 mmol). Thin layer chromatography (DCM/methanol = 10:1) showed the reaction was completed. The reaction mixture was diluted with water and extracted with ethyl acetate. EtOAc was evaporated. EtOAcjjjjjjjjjjjjj ).

Example 2 Preparation of Compound V01 (also referred to as V01 in the present invention)

step 1:

Compound 11 A (20 g, 0.15 mol), DMAP (1.9 g, 15.4 ol) and (BoC) ₂ 0 (75 g, 0.34 mol) were combined in THF (750 mL). Thin layer chromatography (PE / EA = 3:1) showed the reaction was completed. The reaction mixture was concentrated and taken up in EtOAc EtOAc (EtOAc:EtOAc)

Step 2:

Compound 10 (50 mg, 0.15 ol) and P Cs2C03 (150 mg, 0.45 ol) were stirred in DMSO (1 mL) and stirred at room temperature for half an hour, then compound ll (60 mg) was added. The resulting reaction mixture was stirred for half an hour and was detected by thin layer chromatography (DCM / methanol = 10:1). The reaction mixture was diluted with water and extracted with EtOAc. EtOAc was evaporated.

Compound 12 (20 mg, 0.032 mmol) and TFA (0.1 mL) were mixed with N2 at room temperature for half an hour. Thin layer chromatography (DCM / methanol = 10:1) showed the reaction was completed. The reaction mixture was basified with EtOAc (EtOAc) (EtOAc) eluted eluted eluted eluted eluted %), see Figure 8 for structural identification.

Example 3 Preparation of Compound V3 (also referred to as V03 in the present invention)

step 1:

Compound 13 (5.0 g, 45 mmol) and pyridine (200 mL) were stirred, and (Boc) ₂ 0 (14.7 g, 67.5 mmol) was added dropwise to the mixture at 65 °C. After the addition, the reaction was stirred at 85 ° C for 4 hours. Thin layer chromatography (DCM / methanol = 10:1) was followed. After completion of the reaction, the reaction mixture was cooled to 0 ° C, concentrated HCl (100 mL) and H20 (50 mL) were added. After EA extraction, the organic phase was collected and NaHC03 aqueous solution was used. After washing, dried over Na2SO4, EtOAc (EtOAc)

Mixture of compound 14 (2.4 g, 11.4 mmol) and N,N-dimethylaniline (6.6 mL) in DCM (84 mL) In N2, P0C1 ₃ (3.2 mL, 34. 2 mmol) was added dropwise. After the addition, the reaction mixture was stirred at room temperature for 2 hours. Thin layer chromatography (PE / EA = 2: 1) was followed until the reaction was completed, and the reaction mixture was poured into ice water. The organic phase was washed with EtOAc (EtOAc m.)

Mix the compound 15 (100 mg, 0. 47 mmol) and DMAP (12 mg, 0.09 mmol) in THF (1 mL) at room temperature (B0C) ₂ 0 (124 mg, 0. 57 mmol), then Stir at room temperature overnight. Thin layer chromatography (PE / EA = 2: 1) indicated that after the reaction was completed, the reaction mixture was diluted with water, EA was taken, and then the organic phase was collected, washed with brine, dried and concentrated on Na2S04 to give crude product, which was purified by silica gel column chromatography. Pure compound 16 (70 mg, 44.8%) was obtained as white solid.

Compound 10 (50 mg, 0.15 mmol) and Cs ₂ C0 ₃ (150 mg, 0. 45 mmol) were mixed and stirred in N ₂ in DMS0 (1 mL) for half an hour, then compound 16 (60 mg) , 0. 18 mmol), stir for another half an hour. Thin layer chromatography (PE / EA = 2: 1) indicated that after the reaction was completed, the reaction mixture was diluted with water and extracted with EA. The organic phase was collected, washed with brine, dried and concentrated on Na2S04 to give crude product, which was purified by silica gel column chromatography. Obtained the yellow solid pure compound 17 (50 mg 53.3%) Step 2:

Compound 17 (50 mg, 0.08 mmol) and P TFA (0.2 mL) were stirred for a half hour at room temperature in DMS0 (1 mL). Thin layer chromatography (DCM / methanol = 10: 1) indicated that after the reaction was completed, the mixture was basified from Na2CO3 and then extracted with DCM. The organic phase was washed with a salt and dried and concentrated on Na2SO4 to give a crude product which was purified by silica gel column chromatography to obtain a yellow solid solid compound V3 (15 mg, 44%).

Example 3 Preparation of Compound V4 (also referred to as V04 in the present invention)

step 1 :

Mixing compound 18 (50 g 0. 47 mol) in DCM (600 mL), adding TEA (94 g 0. 93 mol) and then adding ethyl bromoacetate (94 g 0. 56 mol) at 0 °C N2. ). The reaction mixture was stirred at room temperature overnight. Thin layer chromatography (PE/EA = 1:1) indicated that after the reaction was completed, the reaction mixture was washed with brine, dried and concentrated on Na2SO4 to give crude yield. Purification by silica gel column chromatography eluting with EtOAc (EtOAc:EtOAc:EtOAc

Compound 19 (38 g, 196.65 mmol) and TEA (29.9 g, 295 mmol) were stirred in a solution of toluene (800 mL) at 95 ° C, and ethyl 4-bromobutyrate (72.9 g, 373.65 mmol) was added dropwise. After the completion, the mixture was heated under reflux overnight. Thin layer chromatography (PE/EA = 5:1) indicated that after the reaction was completed, the reaction mixture was concentrated and purified by silica gel column chromatography eluting with PE/EA = 20:1 to 5: g, yield: 53%).

Compound 20 (32 g, 104.3 mmol) was stirred in toluene (800 mL) and t-BuOK (51.2 g, 456.3 mmol). After the addition, the reaction mixture was reacted at room temperature for 1 hour. Thin layer chromatography (PE/EA=5:1) indicated that after completion of the reaction, 2NHC1 was added to adjust pH = 6, then EA was extracted, and the organic phase was collected, washed with brine, dried and concentrated on Na2SO4 to give crude product 21 (17 g, Yield: 62.5%), as a dark yellow oil, can be used directly in the next step without further purification.

Me0Na ((ll g, 161.65 mmol) was dissolved in methanol (280 mL), and the reaction mixture was cooled to 5 ° C, then acetonitrile (3.0 g, 29.15 mmol) was added. The reaction mixture was stirred for half an hour, and then compound 21 was added. (17 g, 65. Immol). The reaction mixture was stirred at 40 ° C overnight. TLC (DCM /methanol = 10:1), after the reaction was completed, the reaction mixture was cooled to room temperature and evaporated to remove the solvent. The water was treated with water and EtOAc was evaporated. EtOAcjjjjjjjjjj

Compound 22 (2.5 g, 10.4 mmol), 10% Pd/C (0.5 g) and (B ° C) ₂ 0 (2.7 g, 12.4 mmol) in Me OH (40) were stirred overnight at a pressure of 0.5 MPa 3⁄4 In mL). Thin layer chromatography (DCM / MeOH = 10:1) showed that the reaction mixture was filtered and concentrated to give a yellow solid compound 23 (2.6 g, 100%).

Compound 23 (1.6 g, 6.3 mmol), PPh ₃ (3.33 g, 12.6 mmol) and CC1 ₄ (2.93 g, 18.9 mmol) were mixed in 1,2-DCE (64 mL) and heated at 70 ° C for 1 hour. Thin layer chromatography (DCM / MeOH = 10:1) EtOAc (EtOAc: EtOAc)

Mix compound 10 (100 mg, 0.3 mmol) and P Cs ₂ C0 ₃ (300 mg, 0.9 mmol) in DMS0 (2 mL) for half an hour at room temperature in N2, then add compound 24 (97 mg, 0.36 mmol) . The reaction mixture was stirred and mixed for half an hour. Thin layer chromatography (DCM/Me0H = 10:1) indicated that after the reaction was completed, the mixture was diluted with water and then extracted with EA. The organic phase was washed with EtOAc (EtOAc m.)

Compound 25 (21 mg, 0.037 mmol) and TFA (0.2 mL) were mixed and stirred for half an hour at room temperature in N2. Thin layer chromatography (DCM/Me0H = 10:1) indicated that the reaction was completed. The reaction mixture was basified from Na.sub.2CO.sub.sub.sub. The organic phase was washed with brine, dried and evaporated to dryness eluted eluted eluted elution Preparation of Compound V5 of Example 4 (also referred to as V05 in the present invention)

step 1:

(S) 1-Phenylethylamine (10 g, 8.26 mmol) and ethyllevulinic acid (1·9 g, 8.26 mmol) in 1,2-DCE (200 mL), NaBH (0Ac) ) ₃ (35 g, 16.52 mmol). After the addition was completed, the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was basified with aqueous NaHC0 ₃ was added, and extracted with DCM, organic phase was separated and washed with saturated brine, dried on Na2S04, and concentrated to give crude compound 34 (20.5 g, yield: 100%), may Further purification was used directly in the next step.

Mixture compound 34 (20.5 g, 82 mmol) and ethyl glyoxylate (33 mL, 165 mmol, 50% in toluene), NaBH(0Ac) ₃ (35) in 1,2-DCE (200 mL) g, 165 mmol), stirred at room temperature for 4 hours. then the reaction mixture was washed with NaHC0 ₃ aqueous solution was basified, and extracted with DCM. separate the organic phase was washed with saturated brine, dried over Na2S04 dried and concentrated to give crude compound 35 (26 g, 100%) was used in the next step without further purification.

Compound 35 (26 g, 78 mmol) and t-Bu0K (22 g, 156 mmol). The reaction mixture was basified with aqueous NaHC0 ₃ and extracted with DCM. The organic phase was washed with brine, dried over Na 2 EtOAc andEtOAc

The crude compound 36 was purified by silica gel chromatography (EtOAc / EtOAc = 20:1) to afford purified compound 37 (3 g). NaOEt (2.38 g, 0.035 mol) was added to the mixture of the compound 37 (3.0 g, 0.01 mol) and formazan acetate (3.24 g, 0.03 mol) in ethanol (50 mL). The reaction mixture was stirred at 90 ° C overnight and then evaporated to remove most of the solvent. The residue was diluted with H20, acidified to pH 6 with 2N EtOAc, and then extracted with DCM. The organic phase was washed with EtOAc (EtOAc m.

Compound 38 (L0 g, 10.4 mmol), 10% Pd / C (0·1 g) and (B ° C) ₂ 0 (2.7 g, 12.4 mmol) were mixed in MeOH (40 mL) under pressure Stir for 0.5 MPa of hydrogen overnight. TLC (DCM/methanol = 10:1) indicates The reaction is complete. The reaction mixture was filtered, and then evaporated tolulululululululululululululululululululu

Compound 39 (0.7 g, 6.3 mmol) and triphenylphosphine PPh ₃ (3.33 g, 12.6 mmol) were mixed in carbon tetrachloride (10 mL) and stirred at 80 ° C overnight. TLC (DCM / methanol = 15:1) indicated that the reaction was completed. The reaction mixture was concentrated, EtOAcjjjjjjjjj

Compound 10 (150 mg, 0.45 liter 1) and compound Cs ₂ C0 ₃ (440 mg, 1.35 mmol) were combined in DMS0 (2 ml), stirred at room temperature for half an hour, then compound 40 (153 mg, 0.54 mmol). The resulting reaction mixture was stirred for half an hour and TLC (DCM / methanol = 10:1) indicated that the reaction was completed. The reaction mixture was diluted with water and extracted with EA. The organic phase was washed with brine, dried N¾S0 ₄ and concentrated to give the crude product, which was purified by preparative TLC to give pure compound 41 (60mg, 23%), as a yellow solid.

A mixture of compound 41 (60 mg, 0.104 mmol) and TFA (0.3 mL) was stirred at room temperature under nitrogen for half an hour. TLC (DCM / methanol = 10:1) indicated that the reaction was completed. The reaction mixture was basified with aqueous NaHC0 ₃ and extracted with DCM. Washed with brine and the organic phase was dried and concentrated in N¾S0 _4, to give a crude product, which was purified by preparative TLC to give pure Compound V5 (20 mg, 40.3%) , as a yellow solid, which structural identification data 11, 12 .

Example 5 Preparation of Compound V6 (also referred to as V06 in the present invention)

A 3 L flask equipped with a mechanical stirrer and a calcium chloride tube was charged with compound 26 (100 g, 0.716 mol) and ethanol (1.0 L). The mixture was stirred for 20 minutes, then triethylamine (72.5 g, 0.716 mol) was added dropwise. The resulting mixture was stirred for 10 minutes, then ethyl acrylate (61.6 g, 0.716 mol) was added. The reaction mixture was stirred at room temperature for 17 hours. (B0C) ₂ 0 (234.5 g, 1.08 mol) was added dropwise at room temperature. After the end of the dropwise addition, the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to remove most of the EtOH. The residue was dissolved in water (3 L) and extracted with Et 2 0 (1 L X3). The combined organic phases were washed with aq. EtOAc EtOAc (EtOAc (EtOAc) No additional purification is required. Sodium (27.6 g, 0.765 mol) was added to absolute ethanol (1.5 L). When the solid sodium completely disappeared, compound 28 (300 g, 1.04 mol) was added to the hot solution. The reaction mixture was refluxed overnight. Thin layer chromatography (petroleum ether / ethyl acetate = 4:1) indicated that the starting material was completely consumed. The reaction mixture was evaporated, the residue was dissolved in water (1L), The mixture was then extracted with EtOAc (1 L EtOAc). The extracts were combined and washed with brine (1LX3), in N¾S0 ₄ dried and evaporated to give compound 29 (169 g, 63.4%) , as a brown oil. This crude product was used in the next step without further purification.

Sodium methoxide (2.6 g, 48.58 mmol) was dissolved in MeOH (50 mL) and the solution was cooled to 5 °C. Methyl hydrazine acetate (3.0 g, 29.15 mmol) was added and the reaction mixture was stirred for half an hour. Compound 29 (5.0 g, 19.43 mmol) was added and the~~~~~ TLC (DCM / methanol = 10:1) indicated that the reaction was completed. The reaction mixture was cooled to room temperature and evaporated to remove most of solvent. The residue was treated with water and extracted with EA. The organic phase was washed with brine, dried N¾S0 ₄ and concentrated to give the crude product, which was purified by silica gel chromatography, to give pure compound 30 (680 mg, yield: 14.7), as a pale yellow solid.

Phosphorus oxychloride (P°C13, 174 mg, 1.26 mmol) was added to a DCM stirred with compound 30 (100 mg, 0.42 mmol) and N,N-dimethylaniline (0.28 mL) under nitrogen at 0 °C. (4 mL), after the addition was completed, the reaction mixture was poured into ice water, basified by the addition of solid sodium carbonate, and then extracted with DCM. The organic phase was washed with brine, dried N¾S0 ₄ and concentrated to give the crude product, which was purified by preparative TLC to give the pure compound 31 (60 mg, 55.6%) , as a white solid.

Compound 10 (50 mg, 0.15 mmol) and Cs ₂ C0 ₃ (150 mg, 0.45 mmol) were mixed in DMS0 (1 mL) under nitrogen, and the mixture was stirred at room temperature for half an hour, then compound 31 (46 mg, 0.18) was added. Mm). The resulting reaction mixture was stirred for half an hour and TLC (DCM / methanol = 10:1) indicated that the reaction was completed. The reaction mixture was diluted with water and extracted with EA. The organic phase was washed with EtOAc (EtOAc m.

Step 2:

A mixture of compound 32 (13 mg, 0.038 mmol) and TFA (0.1 mL) was stirred at room temperature for half an hour under nitrogen. TLC (DCM / methanol = 10:1) indicated that the reaction was completed. The reaction mixture was basified with aqueous Na 2 CO 3 and extracted with DCM. The organic phase was washed with brine, dried over Na2~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 13.

Example 6 Preparation Method of KDR3

Step 1: Compound 1 (1.4 g, O.Olmmol), 4-(benzyloxymethyl)-6-chloropyrimidine (4.7 g, 0.02) and K 2 CO 3 (4.2 g, 0.03 mol) in DMF (50 mL) was mixed and stirred at 100 ° C for 2 hours. TLC (PE/EA = 4:1) indicated the reaction was complete. The reaction mixture was cooled to room temperature and diluted with water and extracted with EtOAc. The organic phase was collected, washed with brine, dried over NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

Step 2: A mixture of Compound 2 (1. <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; TLC (PE/EA = 2:1) indicated that the reaction was complete. The reaction mixture is filtered and concentrated by filtration to give a crude material which is purified by column chromatography

(0.8 g, Yield: 73%), as a yellow solid.

Step 3: TCDI (0.78 g, 4.4 mmol) and compound 3 (0.9 g, 2.93 mmol) were slowly mixed in dry DCM (10 mL) under nitrogen at 0 °C. After the addition was completed, the reaction mixture was stirred at room temperature for half an hour. TLC (PE/EA = 1:1) indicated completion in the reaction mixture. The reaction mixture was concentrated to give a crystallite.

Step 4: Compound 4 (1.1 g, 3.15 mmol), 4-methyl-5-(trifluoromethyl)benzene 1,2 -diamine (0.6 g, 3.15 mmol) and carbodiimide (1.2) Grams, 6.30 mmol) of THF (50 mL). TLC (DCM / methanol = 10:1) indicated that the reaction mixture was completed. The reaction mixture was diluted with EA and the precipitate was filtered. The filtrate was evaporated to give a crude material, which was purified eluted from EtOAc (EtOAc: EtOAc (EtOAc)

Step 5: The mixture of compound 5 (0.7 g, 1.38 mmol) and TFA (15 ml) was stirred at 60 ° C overnight. The reaction mixture was warmed to 70 ° C and stirred at this temperature for 1 hour. TLC (DCM / methanol = 10:1) indicated that the reaction mixture was completed. The reaction mixture was cooled to room temperature and poured into ice water, basified to pH 10 with 2N NaOH and then extracted with EA. The organic phase was washed with EtOAc EtOAc m.

Step 6: In a stirred solution of Compound 6 (60 mg, 0.1445 mmol per day) in DCM (5 mL), TEA (30) Mg, 0.289 mmol) Wo P MSCL (25 mg, 0.2168 mmol) under nitrogen at 0 °C. After the completion of the dropwise addition, the reaction was completed. The mixture was diluted with EtOAc EtOAc EtOAc m.

Step 7: A mixture of compound 7 (60 mg, 0.12 mmol) and EtOAc (EtOAc (EtOAc) TLC (DCM / methanol = 10:1) indicated that the reaction mixture was completed. The reaction mixture was concentrated and the residue was purified EtOAcjjjjjjjj

Real

First step: Compound 1 (1.0 g, 4.5 mmol) was mixed with 2-chloro-5-nitropyridine 2-chloro-5-nitropyridine (0.8 g, 5 mmol) in ACN (20 mL). Cesium carbonate (3.3 g, 10 mmol) was stirred at room temperature overnight. TLC (PE/EA = 1:1) indicated completion in the reaction mixture. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was washed with EtOAc (EtOAc m.

The second step: To a stirred mixture of compound 2 (0.3 g, 0.83 mmol) in THF (5 mL), EtOAc (0.1 g). A solution of H2N-H2 H20 (1.66 mmol) in THF (5 mL) was added dropwise. The resulting reaction mixture was stirred for 10 minutes. TLC (DCM / methanol = 15:1) indicated that the reaction mixture was completed. The reaction mixture was filtered and concentrated to give crystals crystals crystals

The third step: TCDI (95 mg, 0.531 mmol) was added to DCM (10 mL) in a stirred solution of compound 3 (0.16 g, 0.483 mmol). After the end of the dropwise addition, the reaction mixture was stirred at room temperature. overnight. TLC (DCM / methanol = 10:1) indicated that the reaction mixture was completed. The reaction mixture was concentrated to give a crystal crystal crystal crystal crystal crystal crystal crystal crystal

Step 4: Compound 4 (50 mg, 0.134 mmol), 4-methyl-5-(trifluoromethyl)-benzene-1,2-diamine (25.5 mg, 0.134 mmol) and PEDCI (51 m) The mixture was stirred under nitrogen for 1 hour under anhydrous THF (10 mL). TLC (DCM/MEOH = 15:1) indicated that the reaction mixture was completed. The reaction mixture was diluted with EtOAc and EtOAc (EtOAc)EtOAc.

The fifth step: a mixture of compound 5 (20 mg, 0.038 mmol) and trifluoroacetic acid (0.2 ml) was stirred at room temperature for half an hour. TLC (DCM / methanol = 5:1) indicated that the reaction mixture was completed. Evaporating the reaction mixture to remove TFA, will The residue was dissolved in THF, basified from solid K 2 CO 3 , filtered and concentrated to give purified compound KD (yield: 62 g, yield: 62.5%) as white solid.

Example 10 KDR6 compounding

First step: 7-methoxyquinoline-4-ol (10.0 g, 57.1 mmol) was dissolved in 50 ml of phosphorus oxychloride, and then the reaction mixture was heated at 120 ° C for 3 hours. The mixture was then cooled to room temperature and poured into ice water (50 mL). The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. Purification, the obtained product (8.5 g, yield: 76.9%) as a white solid.

The second step: 4-chloro-7-methoxyquinoline (5.5G, 28.4mmol), zinc (276.9mg, 4.26mmol), Zn(CN) 2 (2.07g, 17.6mmol), DPPF (6.65g, 12.21 mmol), PD2 (DBA) 3 (5.98 g, 6.53 mmol) was dissolved in 100 mL of DMAc, the mixture was covered with argon and heated at 160 ° C overnight, then the mixture was cooled to room temperature and filtered through celite. The filtrate was treated with H20, then EtOAc was evaporated. Purification by flash chromatography (eluent eluting with EtOAc/EtOAc = EtOAc) EtOAc (EtOAc)

The third step: 7-methoxyquinoline-4-carbonitrile (4.38 g, 23.78 mmol) was dissolved in 30 mL of H20, and sodium hydroxide (2.38 g, 59.45 mmol) was added. The mixture was then heated to 100 ° C overnight. The reaction mixture was cooled to room temperature and extracted with EA to remove impurities. The aqueous phase was acidified by the addition of 6N hydrochloric acid to pH 2. The yellow precipitate was collected by filtration and dried to give <RTI ID=0.0>>>

The fourth step: 7-methoxyquinoline-4-carboxylic acid (2.0 g, 9.84 mmol) and DIPEA (3.82 g, 29.52 mmol) were dissolved in DMF. The reaction mixture was then cooled to 0 ° C and HATU (4.49 g, 11.81 mmol) and 3-(trifluoromethyl)aniline (1.74 g, 10.82 mmol). The mixture was covered with argon and then stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc EtOAc. The organic layer was washed with EtOAc EtOAc (EtOAc m. Rate: 79.6%) is a pale yellow solid.

Step 5: 7-Methoxy-N-(3-(trifluoromethyl)phenyl)quinoline-4 -carboxamide (0.6 g, 1.733 mmol) in DCM (50 mL) BBr3 (1.73 mL, 6.93 mmol) was added dropwise under nitrogen. After the addition was completed, the reaction mixture was stirred at room temperature for 100 hrs. TLC (DCM/methanol = 15:1) indicated that the reaction was completed. The reaction mixture was poured into ice-water The organic layer was washed with EtOAc (EtOAc m.) Step 6: 7-Hydroxy-N-(3-(trifluoromethyl)phenyl)quinoline-4-carboxamide (50 mg, 0.151 mmol), tert-butyl (6-chloropyrimidin-4-yl) The methyl (meth)carbamic acid tert-butyl ester (46.6 mg, 0.181 mmol) and K 2 CO 3 (41.7 mg, 0.302 mmol) were mixed in DMSO (2 ml) and stirred at 90 ° C overnight. TLC (PE/EA = 1:2) indicated that the reaction was complete. The reaction mixture was diluted with water and extracted with EA. The organic layer was washed with EtOAc (EtOAc m.). Step 7: tert-Butylmethyl((6-(4-(3-(trifluoromethyl)phenylcarbamoyl)quinolin-7-yloxy)pyrimidin-4-yl)methyl)carbamic acid A mixture of butyl ester (25 mg, 0.045 mmol) and TFA (0.25 mL) was stirred at 0 ° C for half an hour. TLC (DCM / methanol = 5:1) indicated the reaction was completed. The TFA was evaporated and the residue was basified by aqueous.

Na2C03 and extracted with DCM. The organic phase was washed, washed with brine, dried over Na2~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ See Figure 16.

Example 11 Preparation of KDR6A Compound

The second step: 4-chloro-7-methoxyquinoline (5.5G, 28.4mmol), zinc (276.9mg, 4.26mmol), zinc (CN) 2 (2.07g, 17.6mmol), DPPF (6.65g, 12.21mmol), PD2 (DBA) 3 (5.98 g, 6.53 mmol) was dissolved in 100 mL of DMAc, the mixture was covered with argon and heated at 160 ° C overnight, then the mixture was cooled to room temperature and filtered through celite. The filtrate was treated with H.sub.2, then EtOAc was evaporated. Purification by flash chromatography (eluent eluting with EtOAc/EtOAc = EtOAc) EtOAc (EtOAc)

The third step: 7-methoxyquinoline-4-carbonitrile (4.38 g, 23.78 mmol) was dissolved in 30 mL of H 20 and sodium hydroxide (2.38 g, 59.45 mmol) was added. The mixture was then heated to 100 ° C overnight. The reaction mixture was cooled to room temperature and extracted with EA to remove impurities. The aqueous phase was acidified by the addition of 6N hydrochloric acid to pH 2. The yellow precipitate was collected by filtration and dried to give <RTI ID=0.0>>>

Step 4: 7-methoxyquinolin-4-carboxylic acid (406 mg, 2 mmol) and DIPEA (775 mg, 6 mmol) dissolved in In DMF (5mL). The reaction mixture was cooled to 5 <0>C then HATU ( </RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; The mixture was flushed with argon at ambient temperature overnight. TLC (PE/EA = 1:2) indicated that the reaction was complete. The reaction mixture was diluted with water and extracted with EA. The organic layer was washed with EtOAc EtOAc EtOAc m.

Step 5: In a solution of N-(4-fluoro-3-(trifluoromethyl)phenyl)-7-methoxyquinolin-4-carboxamide (0.2 g, 0.549 mmol) in DCM (10 mL) 4NBBr3 (0.68 ml, 2.75 mmol) in DCM was added with stirring at 0 ° C under N.sub.2 atmosphere. After the addition was completed, the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was then stirred at -30 ° C for 4 hours. TLC (DCM/methanol = 10:1) indicated that starting material remained. The reaction mixture was poured into ice-water and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate Trifluoromethyl)phenyl)-indole-hydroxyquinoline-4-carboxamide

(60 mg, 78%), as a white solid.

Step 6: N-(4-Fluoro-3-(trifluoromethyl)phenyl)-7-hydroxyquinoline-4-carboxamide (30 mg, 0.086 mmol), tert-butyl (6-chloropyrimidine) -4-yl) tert-butyl methyl(methyl)carbamate (26.5 mg, 0.103 mmol) and PK 2 CO 3

(23.8 mg, 0.172 mmol) was stirred at 50 ° C for 15 hours in DMF (1 mL). TLC (DCM / methanol = 10:1) indicated the reaction was completed. The reaction mixture was diluted with water. And extract the EA. The organic layer was washed with brine, dried over anhydrous sodium sulfate Methyl tert-butyl) phenylcarbamoyl) quinoline-7-yloxy)

Pyrimidin-4-yl)-tert-butyl methyl (meth)carbamate (20 mg, yield: 41%) as a yellow solid.

Step 7: Mixture of tert-butyl ester (6-(4-(4-fluoro-3-(trifluoromethyl)phenylcarbamoyl)quino-7-yloxy)pyrimidin-4-yl) tert-Butyl methyl (meth)carbamate (20 mg, 0.035 mmol) and trifluoroacetic acid (0.3 mL) were stirred at room temperature for one hour. TLC (DCM/MEOH = 5:1) indicated that the reaction was completed. The TFA was evaporated and the residue was basified from Na.sub.2CO.sub.3 and extracted with DCM. The organic phase was washed, washed with brine, dried over Na2~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ See Figure 17.

Example 12 Preparation of KDR8 Compound

KDR08

Step 1: Heat a mixture of diethyl oxalate (70 ml) to 120 ° C, add compound 1 (50 g, 0.4 mol), and The mixture was heated to 180 ° C for 5 minutes. The mixture was refrigerated overnight, and a white solid was collected by filtration and dried to yield Compound 2 (75.0 g, yield: 59.11%).

Step 2: Compound 2 (25 g, 0.11 mol) was dissolved in boiling xylene (1 L). P2S5 (9.5 g, 0.0385 mol) was slowly added and refluxed until the reaction was completed (about 5 hours). Continue to return. The amide TLC (PE/EA = 5/1) indicated that after the reaction was completed, the reaction mixture was cooled and extracted with 1N NaOH, and the aqueous phase was acidified with hydrochloric acid to collect a yellow precipitate which was then dissolved in EtO Ac and washed with H20. Drying over Na 2 SO 4 and concentration gave Compound 3 (19 g, yield: 70.9%) as a red oil.

Step 3: Compound 3 (30 g, 0.142 mol, dissolved in 1N sodium hydroxide (500 mL), oxidized with potassium ferricyanide (135 g, 0.416 mol, in 340 ml of water) by slowly adding thioamide to ferricyanide The solution was carried out to keep the temperature below 10 ° C. After 1 hour, TLC (DCM / MeOH = 3 / 1) indicated that the reaction was complete. The reaction mixture was diluted with water and acidified (from 2N of HCl to pH 6), and then filtered to give the compound 4 (15 g, yield: 50.48%). Step 4: Compound 4 (1 g, 4.34 mmol) dissolved in DMF (20 mL), 1 -methyl-5 - (trifluoromethyl)- 1 H-pyrazol-3 -amine (0.717 g, 4.35 mmol), followed by addition of HATU (2.47 g, 6.5 mmol) and DIEA (U2 g, 8.6 mmol) at room temperature under nitrogen. TLC (PE I EA = 2/1), which was taken to dryness eluted eluted eluted eluted eluted with EtOAc. Obtain a crude product by silica gel chromatography (PE/EA elution = 20/ Purification by 1-5/1) gave the pure compound 5 (900 mg, yield: 75.5%).

Step 5: Add BBr 3 (10 mL, 4N in DCM) to a solution of compound 5 (0.4 g, 1.12 mmol) in EtOAc (10 mL). 1/1) The reaction was completed. Then, ice was added to the reaction, and the undissolved material was removed by filtration. The filtrate was separated and extracted with DCM. The organic phase was washed with brine, dried over Na 2SO 4 and concentrated to give a crude product. Purification, a pure compound of Compound 6 (100 mg, yield: 26.02%) was obtained from TLC.

Step 6: To a solution of compound 6 (50 mg, 0.146 mmol) in DMF (10 mL) was added K2C03 (70 mg, 0.500 mmol) and tert-butyl (6-chloropyrimidin-4-yl)methyl (methyl) carbamate (41.41 Mg, 0.161 mmol). The reaction mixture was stirred at 50 ° C under nitrogen overnight. TLC (PE/EA = 1/1) indicated completion of the reaction. The reaction mixture was washed with water and extracted with EtOAc. The organic phase was washed 4 times with aq. EtOAc (EtOAc) (EtOAc) Step 7: Compound 7 (40 mg, 0.071 mmol) and TFA (0.4 mL) were stirred at room temperature under nitrogen and stirred for half an hour. TLC (DCM / methanol = 10/1) indicated that the reaction was completed. The reaction mixture was evaporated to remove TFA. The residue was basified with Na ₂ C0 ₃ was basified to pH 9, then extracted with DCM. The organic phase was washed with EtOAc (EtOAc m. See Figure 18 for its structural identification data. Example 13 Preparation of KDR8A Compound

KDR8A

Step 1: Diethyl oxalate (70 ml) was heated to 120 ° C, compound 1 (50 g, 0.4 mol) was added, and the mixture was heated to 180 ° C for 5 minutes. After cooling, the mixture was placed in a refrigerator overnight, 50 ml of water was added, and a white precipitate formed. The solid was collected and dried to give 2 (75.0 g, yield: 59.11%) as a white powder. Step 2: Compound 2 (25 g, 0.11 mol) was dissolved in boiling xylene (1 L). P2S5 (9.5 g, 0.0385 mol) was slowly added and refluxed until the reaction was completed (about 5 hours) and reflux was continued. TLC (PE/EA=5/1) indicates that after completion of the reaction, the reaction mixture was cooled and extracted with 1N NaOH. The aqueous phase was acidified with hydrochloric acid to collect a yellow precipitate, which was then dissolved in EtO Ac and washed with H.sub.2. Drying and concentration gave Compound 3 (19 g, yield: 70.9%) as a red oil.

Step 3: Crude compound 3 (30 g, 0.142 mol) was dissolved in IN sodium hydroxide (500 mL) and oxidized with potassium ferricyanide (135 g, 0.416 mol, in 340 ml water) by slowly adding thioamide to iron The cyanide solution was carried out to keep the temperature below 10 °C. After 1 hour, TLC (DCM I MeOH = 3/1) indicated that the reaction was completed. The reaction mixture was diluted in water, adjusted to pH 6 with 2N HCl, and then filtered to give compound 4 (15 g, yield: 50.48%)

Step 4: Compound 4 (1 g, 4.78 mmol). To a solution of <RTI ID=0.0>>&&&&&&&&&&&&&& Millimol), stirred at room temperature under nitrogen. After stirring at the same temperature overnight, TLC (PE/EA = 2/1) indicated that after the reaction was completed, the reaction mixture was poured into water and extracted with EtO Ac. The organic phase was washed with EtOAc (EtOAc m.) Yield: 99.0%). Step 5: Add 4N BBr3 to a solution of compound 5 (0.1 g, 0.283 mmol) in DCM (10 mL) at -10 °C under nitrogen.

(0.5 mL). After 4 hours, TLC (PE/EA = 1/1) indicated that after completion of the reaction, ice was added and then filtered to remove the undissolved material. The filtrate was extracted with DCM. The organic phase was washed with brine, dried over Na2~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

Step 6: To a solution of compound 6 (64 mg, 0.189 mmol) in DMF (10 ml), K2CO3 (78 mg, 0.567 mmol) and tert-butyl(6-chloropyrimidin-4-yl)methyl (methyl) tert-butyl (6-chloropyrimidin-4-yl)methyl (methyl) carbamate, 53 mg, 0.208 mmol. The reaction mixture was stirred at 50 ° C overnight under nitrogen, and TLC (PE/EA = 1/1) indicated that the reaction was completed. The reaction mixture was washed with water and extracted with EtOAc. The organic phase was washed with EtOAc (3 mL). Step 7: A mixture of compound 7 (20 mg, 0.035 mmol) and TFA (0.2 mL) was stirred at room temperature under nitrogen for half an hour. TLC (DCM / MeOH = 10/1) indicated that the reaction was completed. The reaction mixture was evaporated to remove the TFA. The residue was adjusted to pH 9 with sNa.sub.2CO.sub.3 then extracted with DCM. The organic phase was washed, washed with brine, dried over Na2~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ .

Example 14 Preparation of KDR8B Compound

Step 1: A mixture of diethyl oxalate (70 ml) was heated to 120 ° C, compound 1 (50 g, 0.4 mol) was added, and the mixture was heated to 180 ° C for 5 minutes. The mixture was refrigerated overnight to form a white precipitate. The solid was collected by filtration and dried to give 2 (75.0 g, yield: 59.11%) of compound as a white powder.

Step 2: Compound 2 (25 g, 0.11 mol) was dissolved in boiling xylene (1 L), P2S5 (9.5 g, 0.0385 mol) was slowly added and refluxed until the reaction was completed (about 5 hours). TLC (PE/EA = 5/1) indicates that the reaction is complete. The reaction mixture was cooled and extracted with EtOAc EtOAc (EtOAc)EtOAc. Rate: 70.9%) as a red oil.

Step 3: Compound 3 (30 g, 0.142 mol) was dissolved in IN sodium hydroxide (500 mL) and oxidized with potassium ferricyanide (135 g, 0.416 mol, in 340 ml water) by slowly adding thioamide to iron The cyanide solution was carried out to keep the temperature below 10 °C. After 1 hour, TLC (DCM I MeOH = 3/1) indicated that the reaction was completed. The reaction mixture was diluted with water, acidified (from 2NHC1 to pH 6), and then filtered to afford compound 4 (15 g, yield: 50.48%). Step 4: To a solution of compound 4 (1 g, 4.78 mmol) in DMF <RTI ID=0.0>(20 </RTI> <RTIgt; </RTI> <RTIgt; 3-(triflu.romethyl)aniline Hydrochloride, 1.24 g, 5.74 mmol, followed by HATU (2.73 g, 7.17 mmol) and DIEA (1.85 g, 14.34 mmol). After stirring at the same temperature overnight, TLC (PE/EA = 2/1) indicated that the reaction was completed. The reaction mixture was poured into water and extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4) and concentrated to afford crude crystals

Purification by EA = 20/1 5/1) gave pure compound 5 (1.3 g, yield: 73.4% Step 5: In a solution of compound 5 (0.5 g, 1.35 mmol) in DCM (10 mL), 4NBBr3 (2.5 mL) was added under nitrogen at -10 ° C. After 4 hours of reaction, TLC (PE / EA = 1/1) ) indicates that the reaction is complete. Ice is added to the reaction and then filtered to remove undissolved material. The filtrate was separated and extracted with DCM. The organic phase was washed with brine, dried over Na2~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

Step 6: In a solution of compound 6 (70 mg, 0.196 mmol) in DMF (10 mL), K2CO3 (81.46 mg, 0.589 mmol) and tert-butyl(6-chloropyrimidin-4-yl)methyl (Methyl)-tert-butyl (6-chloropyrimidin-4-yl)methyl (methyl) carbamate, 55.70 mg, 0.216 mmol, and the mixture was stirred at 50 ° C under nitrogen overnight. TLC (PE/EA = 1/1) indicated the reaction was complete. The reaction mixture was washed with water and extracted with EA. The organic phase was washed, washed with EtOAc EtOAc EtOAc (EtOAc)

Step 7: A mixture of compound 7 (38 mg, 0.071 mmol) and TFA (0.4 mL) was stirred at room temperature under nitrogen for half an hour. TLC (DCM/MeOH = 10/1) indicated that the reaction was completed. The reaction mixture was evaporated to remove TFA. The residue was adjusted to pH 9 with Na2CO3 then extracted with DCM. The organic phase was washed, washed with brine, dried over Na2~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The beneficial effects of the present invention will be specifically described below by way of test examples.

Test Example 1 Zebrafish vascular development inhibition test

The zebrafish (Daniorerio) is a teleost fish of the genus Danio (Cyprinidae). The similarity between the gene and the human gene is as high as 85%, and the female can lay 200 to 300 eggs at a time. The fertilization and embryo development process are carried out in vitro, and the formation can be formed within 24 hours, and the embryo is transparent and easy to observe. Changes in organ tissue. Many characteristics make it one of the five fish experimental animals recognized by the International Organization for Standardization. At present, zebrafish have been widely used in human disease research, and there are many studies on cardiovascular systems.

Experimental Methods: This experiment uses an zebrafish that is commonly used as a screening compound for the effects of angiogenesis as an animal model. After the birth, the zebrafish embryos are selected, placed in a culture dish and placed in an incubator for 3-5 days. The compound of the present invention is directly added to the zebrafish at different concentrations (1 μΜ, 10 μΜ, 30 μΜ, ΙΟΟμΜ) after birth. In the culture solution. The development of spinal vascular tubes was examined 24 hours later and photographed with a fluorescence microscope. 130B was Pazopanib, and as a positive control, DMS0 was used as a negative control.

The test results are shown in Figures 1-4, Table la, lb.

Table la: Inhibition of KDR series of small molecules on vascular development of FLK-1 transgenic zebrafish

Table lb Inhibition of KDR series small molecules on vascular development of FLK-1 transgenic zebrafish

AI: vascular inhibition rate

It can be seen from Figures 1-4 that the compounds KDR4 and V01-v6 of the present invention can inhibit the vascular development of zebrafish, especially V01, v3, v6, and the pharmacodynamic activity thereof is remarkable.

As shown in Table lb, the activity of the compound DKR4 is significantly better than that of KDR3, KDR6, KDR8 and KDR8A, and the activities of the compounds V01 and V03 are significantly better than those of KDR4.

Test Example 2 Pharmacodynamic experiment of the compound of the present invention

1. VEGFR2 in vitro inhibition test

The experimental methods for detecting the inhibition of VEG F R2 kinase phosphorylation by the compounds of the present invention are as follows:

1) Transfer the P3-P5 HUVEC cells to a 6-well plate with approximately 2*10 ⁵ cells per well.

2) After the cells are grown to 70-80%, the candidate small molecule inhibitor (10ηΜ, Ι ΟΟηΜ οΠ μΜ) is added and incubated for 30 minutes.

3) Stimulate with VEGF 50ng/ml for 10min

4) Add non-denaturing lysate to stop the reaction, collect cell lysate, and perform protein quantification

5) SDS-PAGE electrophoresis, transfer, and the membrane was cut out and blocked with 5% skim milk in TTBS buffer (Tris-buffered saline/0.01% Tween 20) for 2 hours.

6) Wash the membrane and block overnight with anti-phospho-VEGFR2 antibody (1:1000 dilution) at 4°C

7) After washing the membrane on the second day, the horseradish peroxidase-labeled goat anti-rabbit secondary antibody was incubated with the membrane for 1 hour.

8) After washing the film, use a chemiluminescence kit (Millipore) to develop color and take a picture.

See Figure 5 for the test results.

As can be seen from Fig. 5, the compounds KDR4, V01 and V3 of the present invention can inhibit VEGFR2, and the compounds V01 and V3 are better than KDR4.

Test Example 3 Inhibition of choroidal neovascularization by the compound of the present invention

The mouse was c57/BL and was experimentally performed using a laser-induced choroidal neovascularization (CNV) animal model. This model is currently the most widely used animal model used to study the effects of drugs on CNV. CNV formation induced by laser retinal photocoagulation in C57/W6 mice (4 laser spots per retina) using a 532 laser. Immediately after the laser was administered, one mouse was injected with KDR4 at a concentration of 150 uM in the right eye, and the other mouse was injected with V01 at a concentration of luM in the right eye. Both mice were injected with the same volume of PBS as the control. The animals were sacrificed and eyeballs were taken 5 days after the injection. After removing the anterior segment of the eye, the vitreous and the retina, a choroidal patch was made in parallel with I sol ectin staining. Photographing and CNV area measurements were performed using a Zei ss fluorescence microscope system. The results are shown in Figure 6 and Figure 7.

According to Fig. 6, the compounds KDR4 (150 uM) and V01 (luM) can significantly inhibit choroidal neovascularization and effectively treat or alleviate wet macular degeneration. Test Example 4 Effect of the compound of the present invention on kinase

Protein kinases, also known as protein phosphakinase ₀ , are enzymes that catalyze the phosphorylation of proteins. It can transfer the γ-phosphate on adenosine triphosphate (ATP) to the hydroxyl group of certain serine, threonine or tyrosine residues on the amino acid residue of the protein molecule, thereby changing the conformation and activity of the protein and enzyme. . Phosphorylation of proteins is an important part of many signaling pathways. Most important life processes in cells are inseparable from protein phosphorylation.

Protein kinases are classified into five classes: protein serine/threonine kinase, protein tyrosine kinase, protein histidine kinase, protein tryptophan kinase, and protein aspartyl/glutamyl kinase. Protein kinases play an important role in the regulation and maintenance of cellular processes, and abnormalities in kinase activity have been observed in many disease states, including: malignant tumors, immune diseases, cardiovascular diseases, diabetes, infectious diseases, joints. Inflammation and other immune disorders, nervous systems such as Alzheimer's disease, Alzheimer's disease AD, etc., have been found to be associated with more than 400 human diseases and protein kinases.

Among them, members of the VEGFR (vascular endothelial growth factor receptor) family are receptor tyrosine kinases, such as VEGFR VEGFR2, which are involved in the growth and metastasis of malignant tumors and vascular proliferative diseases (such as macular degeneration, tumors). ) and other diseases have important influences in the development process.

Members of the PDGFR (platelet-derived growth factor receptor) family are receptor tyrosine kinases, such as PDGFR a and PDGFR β, as well as the colony-stimulating factor 1 receptor, the stem cell growth factor receptor KIT, etc., and such kinases and tumors are also currently found. There is a close relationship between the occurrence and development. For example, abnormal expression of PDGFR has been found in melanoma, meningiomas, neuroendocrine tumors, ovarian cancer, prostate cancer, lung cancer and pancreatic cancer. Abnormal activation of KIT is a direct cause of many tumorigenesis and development.

1) Inhibitor effect study

Compound V01 was dissolved in 100% DMS0 and diluted to 3 series concentrations, and DMS0 was maintained at 1% in the final test. The highest concentration tested was 50 uM. Staurosporine, an activity inhibitor of non-selective protein kinase, was used as a reference with a maximum concentration of 1 uM. The results are shown in Table 3 and Figure 22.

Table 2

Table 3 shows the inhibitory activity against KDR

2) Inhibition specificity study

For compound V01, 22 kinase activity inhibition assays were tested at a test concentration of 5 mM, repeated twice, at the ATP Km test. V01 was first dissolved in 100% DMS0 at a concentration of 100 times the final test concentration, and all final tests had a DMS0 of 1%. Staurosporine, an inhibitor of non-selective protein kinase activity, was used as a control with a maximum concentration of 10 mM.

The specific test methods and reagents are shown in the following table: Table 4

The average inhibition rate of V01 for kinase two trials is as follows:

table 5

%

Compound test concentration (n [ATP] mean inhibition staurosporine M) (Km app) test kinase % inhibition rate test difference IC50

V01 5000 130 AKT2 0.69 0.02 0.355 0.67 0.1 1

V01 5000 10 AURORA-B 22.88 21 .55 22.215 1 .33 0.00149

V01 5000 35 BRAF 1 .97 -5.23 -1 .63 7.2 0.0768

V01 5000 50 CDK2 1.72 1 .36 1 .54 0.36 0.00259

V01 5000 50 CHEK1 6.27 5.58 5.925 0.69 0.000385

V01 5000 DMPK 3 1 2 2 0.06

V01 5000 3 EGFR 3.24 1 .47 2.355 1 .77 0.131

V01 5000 75 FGFR2 18.37 13.83 16.1 4.54 0.00357

V01 5000 10 GSK-3- β 1 .39 0.91 1 .15 0.48 0.0197

V01 5000 12 JAK2 3.85 3.46 3.655 0.39 0.000645

V01 5000 80 KDR 100.75 100.39 100.57 0.36 0.00585 V01 5000 400 KIT 68.04 65.36 66.7 2.68 0.00154

V01 5000 50 MAPK3 2.13 -0.27 0.93 2.4 2.1 1

V01 5000 35 MEK1 6.34 1 .39 3.865 4.95 0.00159

V01 5000 45 MET 0.29 5.13 2.71 -4.84 0.181

V01 5000 130 P38- a 25.18 23.06 24.12 2.12 0.0053

V01 5000 30 PDGFR- β 56.2 49.13 52.665 7.07 0.000254

-1 .545959 -3.259553 -2.402756 1 .7135938

V01 5000 50 PI3KA 706 596 651 91 0.006374886

V01 5000 20 PKC- a 4.1 2.57 3.335 1 .53 0.000269

V01 5000 5 ROCK1 4.74 0.38 2.56 4.36 0.00308

V01 5000 25 SRC 3.42 7.03 5.225 -3.61 0.00694

V01 5000 30 SYK 1.74 -2.88 -0.57 4.62 0.000225 From the test results, V01 inhibits protein kinase KDR by up to 100%, and also inhibits other two tumor-associated protein kinases, among them, PDGFR-β The inhibition rate was 52.7%, and the KIT inhibition rate was 68%, but most of the other protein kinase inhibitory activities of V01 were less than 5%. It can be seen that the compounds of the present invention have high specificity and high inhibition of KDR compared with the previously developed small molecule kinase inhibitors, and two proteins closely related to tumors, PDGFR-β and KIT. Kinase also has a certain inhibitory effect, which indicates that compound V01 has potential therapeutic activity against various tumors associated with abnormal activation of KDR, PDGFR-β and KIT, and age-related wet macular degeneration.

3) Study of neovascularization

A total of 5 rats were tested. Chemical burns were induced in the center of the cornea using a 75 % silver nitrate solution and a 25 % potassium nitrate rod. Immediately after the chemical burn, 0.2 ml of compound V01 was injected into the conjunctiva of the right eye, and then 0.2 ml of compound V01 was added twice a day.

After 7 days, the cornea was photographed and compared.

As shown in Figure 23, compound V01 significantly reduced neovascularization and hemorrhage. In summary, the compounds of the present invention have a good anti-angiogenic effect, and it is presumed that such compounds are active by inhibiting VEGFR2 (i.e., KDR). Such compounds can be used for the treatment of diseases caused by abnormalities of protein kinases such as neovascularization, VEGFR2, PDGFR-β, and KIT, such as wet macular degeneration and malignant tumors.

Claims

Claim

1. A compound of formula A and a pharmaceutically acceptable salt or prodrug thereof:

(CH ₂ ) m Hri , wherein, =l-5, ϋ is H or C1-3 sulfhydryl;

(C-rnrJ ^ W mrn; or r _s and ^ together with the atom to which they are attached form a saturated 4-7-membered heterocyclic or substituted heterocyclic ring wherein the heterocyclic or substituted heterocyclic ring contains 1 or 2 selected from N, 0 Or a hetero atom of S having a substituent of 0, 1, or 2, independently selected from the group consisting of an oxo group, a C1-C6 fluorenyl group, a C1-C6 halogenated fluorenyl group, a C1-C6 decyloxy group, C1 -C6 halodecyloxy, C 1-C 6 decanoyl, C1-C6 decylamino, C3-C7 cyclodecyl, halogen, hydroxy, amino, carbonyl, aminocarbonyl, C1-C6 amidinocarbonyl, C1 -C4 acyl group, C1-C6 methoxycarbonyl group, C1-C6 sulfonyl group, aminosulfonyl group;

m is 0, 1, or 2; n is 0, 1, 2, or 3; E is empty, oxygen or _Nr _ls;

Rn, r _{12 and} P r _ls are the same or different, each independently selected from hydrogen or C1-C4 fluorenyl; r ₁₃ , r ₁₄ , r ₁₅ , r ₁₆ and r _{17 are} independently selected from hydrogen, C1-C6 fluorenyl , a C1-C6 acyl group, a phenyl group and a heterocyclic ring, or a substituted C1-C6 fluorenyl group, a C1-C6 acyl group, a phenyl group and a heterocyclic ring having a substituent of 0, 1 or 2, each independently selected from C1- C4 decyloxy, C1-C4 fluorenyl, halogen, hydroxy, amino, C1-C6 amidoxime

The compound according to claim 1 or a pharmaceutically acceptable salt or prodrug thereof, wherein the compound has the following structural formula:

Where X is C and Y is N; Ri is selected from H, amino, hydroxy or decyl; R _{2 is} selected from H, amino, hydroxy, decyl or -(CH ₂ ) _n NHR ₈ , wherein n=l-5, 1 ₈ is 11 or C1-3 R _{3 is} selected from H or C 1-6 fluorenyl; R ₄ , R ₅ , and R ₆ are each independently selected from H, halogen, C1-6 fluorenyl or halogen-substituted fluorenyl; R _{7 is} selected from H, C1- a sulfhydryl group or a halogen;

The compound according to claim 2 or a pharmaceutically acceptable salt or prodrug thereof, wherein: X, Y are not the same; Ri is selected from H or an amino group; and R _{2 is} selected from H, amino or - ( CH ₂ ) _n NHR ₈ , wherein n=l-3, 1 ₈ is 11 or Cl-2 fluorenyl; R _{3 is} selected from H or C1-2 fluorenyl; and R ₅ and Re are each independently selected from halogen, a fluorenyl or halogen-substituted fluorenyl group of C1-2; R _{7 is} selected from H or halogen;

The compound according to claim 3 or a pharmaceutically acceptable salt or prodrug thereof, wherein R _{2 is} selected from amino group or -(CH ₂ ) _n HR _8; or, R ₂ , R ₃ and The linked carbon atoms together constitute a substituted or unsubstituted five- or six-membered ring containing one N, and the substituent is a fluorenyl group of C1-3.

The compound according to any one of claims 1 to 5, and a pharmaceutically acceptable salt or prodrug thereof, wherein the halogen is F or Cl.

The compound according to any one of claims 1 to 6, and a pharmaceutically acceptable salt or prodrug thereof, wherein: the compound is:

2

, J

V4 V5 V6

KDR6A KDR3 KDR8

KDR8A KDR8B KDR4

The use of the compound according to any one of claims 1 to 7 and a pharmaceutically acceptable salt or prodrug thereof for the preparation of an angiogenesis inhibitor.

9. Use according to claim 8, characterized in that the angiogenesis inhibitor is a vascular endothelial growth factor receptor 2 inhibitor.

10. Use according to claim 8 or 9, characterized in that the inhibitor is a drug against ocular neovascularization.

11. Use according to claim 10, characterized in that the medicament is a choroidal neovascularization inhibitor.

The use according to claim 10 or 11, wherein the drug is a drug for treating or preventing wet macular degeneration, diabetic retinopathy or neovascular glaucoma.

13. Use of a compound according to any one of claims 1 to 7 and a pharmaceutically acceptable salt or prodrug thereof for the manufacture of a VEGFR2, PDGFR- or/and KIT inhibitor.

A pharmaceutical composition which is an ophthalmic preparation containing the compound according to any one of claims 1 to 7 and a pharmaceutically acceptable salt or prodrug thereof.

3