Naphthylamide compounds as VEGFR inhibitors and their applications

Abstract

The present invention belongs to the field of medicinal chemistry and relates to naphthamide compounds as VEGFR inhibitors, their use in treating VEGFR-related diseases, and methods for preparing the same. Specifically, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing the same, and the use of these drugs or pharmaceutical compositions as drugs for treating VEGFR-related diseases.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to naphthamide compounds as VEGFR inhibitors, their use in treating VEGFR-related diseases, and their preparation methods. Background Art

[0002] Angiogenesis, the formation of new blood vessels from existing capillaries or post-capillary veins, plays an important role in tumor growth, proliferation, and metastasis. Vascular endothelial growth factor receptor (VEGFR) is the primary regulatory receptor for the angiogenic signaling pathway and is considered a key signal transducer for both physiological and pathological angiogenesis. It participates in various angiogenic strategies, including vascular permeability, endothelial cell proliferation, and migration. However, new blood vessels are also a prerequisite for malignant tumors to maintain their growth, invasion, and metastasis. The occurrence and development of solid tumors depend on angiogenesis, and VEGFA / VEGFR signaling-induced angiogenesis has been found in many solid tumors. Therefore, VEGFR has become an important anticancer drug target. Binding of antibodies or small molecule drugs to VEGFR can block the VEGF signaling pathway, thereby inhibiting angiogenesis and suppressing tumor growth.

[0003] Currently, inhibitors targeting VEGFR kinases all have strong side effects such as cardiovascular and hepatotoxicity. For example, Ponatinib (AP24534), which has been approved by the FDA for the treatment of patients with resistant or intolerant chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), has excellent effects in inhibiting multiple kinases such as VEGFR2, FGFR1, and ABL. 50The values ​​are 0.037nM, 1.1nM and 1.5nM respectively (J Med Chem, 2010, 53(12):4701-19). However, its long-term use has obvious side effects, including vascular embolism, heart failure, thrombocytopenia, nausea and vomiting, etc. The instructions contain a black box warning, warning of the risk of vascular occlusion, heart failure and liver toxicity, and its clinical use is restricted (Cancer Discov. 2013, 3, 264.). It is speculated that on the one hand, it may be related to its excessive inhibitory effect, which not only inhibits tumor cell angiogenesis but also inhibits the physiological functions of normal cells. On the other hand, it is closely related to the presence of active groups such as alkynyl in its structure, which can bind to multiple active sites in the body, thereby affecting normal tissue metabolism. Another example is Axitinib (AG-013736), developed by Pfizer for the second-line treatment of advanced renal cancer. It acts on multiple targets including VEGFR, Kit, PDGFR, and RET, and has adverse reactions such as hypertension and hypertensive crisis, arterial thromboembolism, heart failure, pain in the hands and feet, and muscle spasms. It is speculated that this is because it has too many targets and is not very selective.

[0004] Therefore, it is necessary to develop a class of VEGFR inhibitors that can effectively inhibit tumor cell angiogenesis while reducing toxic side effects to meet the actual needs of clinical diagnosis and treatment. Summary of the Invention

[0005] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0006]

[0007] in,

[0008] R1 is selected from hydrogen, alkyl, haloalkyl or halogen;

[0009] R2 is selected from hydrogen, alkyl, alkoxy, hydroxy, cycloalkyloxy, arylalkyloxy;

[0010] R3 is selected from hydrogen, alkyl, cycloalkyl or haloalkyl;

[0011] X is selected from a bond or a heteroatom;

[0012] Ar is selected from fused bicyclic heteroaryl or substituted fused bicyclic heteroaryl.

[0013] In some preferred embodiments, the compound of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from C 1-6 Alkyl or halogenated C 1-6 Alkyl; further preferably, R1 is halogenated C 1-6 More preferably, R1 is trifluoromethyl.

[0014] In some preferred embodiments, the compound of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R2 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, C 3-6 Cycloalkyloxy, benzyloxy; further preferably, R2 is selected from C 1-6 Alkoxy; more preferably, R2 is selected from methoxy, ethoxy, propoxy, isopropoxy, cyclopentyloxy, butoxy, benzyloxy.

[0015] In some preferred embodiments, the compound of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R3 is selected from hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl; further preferably, R3 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl; further preferably, R3 is selected from methyl, ethyl, propyl.

[0016] In some preferred embodiments, the compound of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X is selected from a bond, -NH-, -O-, -S-; further preferably, X is selected from a bond or -NH-; further preferably, X is a bond.

[0017] In some preferred embodiments, the compound of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Ar is selected from a fused bicyclic nitrogen heteroaryl, a fused bicyclic sulfur heteroaryl, a fused bicyclic oxygen heteroaryl, a fused bicyclic nitrogen sulfur heteroaryl, a fused bicyclic nitrogen oxygen heteroaryl, and the fused bicyclic nitrogen heteroaryl, the fused bicyclic sulfur heteroaryl, the fused bicyclic oxygen heteroaryl, the fused bicyclic nitrogen sulfur heteroaryl, and the fused bicyclic nitrogen oxygen heteroaryl may be substituted with one or more halogens or alkyls; further preferably, Ar is selected from a benzoxeteryl, a benzoazetyl, and a benzoazetyl heteroaryl, and the benzoxeteryl, the benzoazetyl, and the benzoazetyl heteroaryl may be substituted with one or more halogens or C 1-6 Alkyl substituted; further preferably, Ar is selected from benzothienyl, benzofuranyl, benzothiazolyl, benzopyrazolyl, indolyl, quinolyl, imidazopyridazinyl, indazolyl, and the benzothienyl, benzofuranyl, benzothiazolyl, benzopyrazolyl, indolyl, quinolyl, imidazopyridazinyl, indazolyl may be substituted by one or more fluorine, chlorine, methyl, or ethyl.

[0018] In some embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein formula (I) has the following structure of formula (Ia) or (Ib),

[0019]

[0020] Wherein, R1 is selected from C 1-6 Alkyl or halogenated C 1-6 alkyl;

[0021] R2 is selected from C 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, C 3-6 Cycloalkyloxy, benzyloxy;

[0022] R3 is selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl;

[0023] Ar is selected from benzoxeteryl, benzoazaheteroaryl, benzoazathioheteroaryl, benzoazaxeteryl, and said benzoxeteryl, benzoazaheteroaryl, benzoazathioheteroaryl, and benzoazaxeteryl may be substituted by one or more halogens, C 1-6 Alkyl substitution.

[0024] Further preferably, R1 is trifluoromethyl; R2 is selected from methoxy, ethoxy, propoxy, isopropoxy, cyclopentyloxy, butoxy, benzyloxy; R3 is selected from methyl, ethyl, propyl; Ar is selected from benzothienyl, benzofuranyl, benzothiazolyl, benzopyrazolyl, indolyl, quinolyl, imidazopyridazinyl, indazolyl, and the benzothienyl, benzofuranyl, benzothiazolyl, benzopyrazolyl, indolyl, quinolyl, imidazopyridazinyl, indazolyl may be substituted by one or more fluorine, chlorine, methyl, or ethyl.

[0025] More preferably, R1 is trifluoromethyl; R2 is selected from methoxy, ethoxy, propoxy, isopropoxy; R3 is selected from methyl, ethyl, propyl; Ar is selected from quinolin-3-yl, imidazo[1,2-b]pyridazine-3-yl, 6-chloroimidazo[1,2-b]pyridazine-3-yl, benzo[d]thiazol-2-yl.

[0026] The present invention provides the following specific compounds or pharmaceutically acceptable salts thereof:

[0027]

[0028]

[0029] The inventors have designed various types of junction structures and conducted pharmacological experiments to find that analogs of compounds with acetylenic or olefinic bonds can show certain inhibitory activity against cancer cells (such as human colon cancer cell line (HT-29), human hepatocellular carcinoma cell line (HepG2) and human umbilical vein endothelial cells (HUVEC)), but also have a very obvious inhibitory effect on normal cell lines (liver cell line L02), IC 50The present inventors unexpectedly discovered that when the core is designed as a naphthamide structure substituted with N-piperazinylmethylphenyl and various fused bicyclic heteroaryl groups or fused bicyclic heteroaryl amino groups are introduced on the naphthalene ring, the inhibitory activity against HT-29 and HepG2 is excellent (IC 50 The value is at the micromolar concentration level, which is comparable to the marketed drug Sunitinib). At the same time, the inhibitory activity against normal cell lines is significantly reduced, IC 50 The value exceeds 10μM, which is more than 20 times different from the inhibitory activity of cancer cell lines, and can provide a larger therapeutic safety window; and the introduction of a monocyclic aromatic group or a monocyclic heteroaromatic group on the naphthalene ring reduces its VEGFR enzyme inhibitory activity.

[0030] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof, or comprises a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The compound of the present invention or a pharmaceutically acceptable salt thereof can be mixed with a pharmaceutically acceptable carrier, a diluent or an excipient to prepare a pharmaceutical preparation, suitable for oral or parenteral administration. Examples of orally administered preparations include solid or liquid dosage forms, specifically, tablets, capsules, granules, powders, pills, infusions, etc. The preparation can be prepared by methods known in the art and includes carriers, diluents or excipients conventionally used in the field of pharmaceutical preparations.

[0032] In a third aspect, the present invention provides a compound represented by formula (I), formula (Ia) or formula (Ib) of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same for preparing a drug for treating VEGFR-related diseases, wherein the VEGFR-related diseases include but are not limited to: cancer, proliferative diseases or blood diseases.

[0033] In some preferred embodiments, the VEGFR-related diseases described in the present invention include, but are not limited to, acute myeloid leukemia, chronic lymphocytic leukemia, liver cancer, lung cancer, multiple myeloma, colorectal cancer, uterine cancer, endometrial cancer, breast cancer, kidney cancer, prostate cancer, breast cancer, ovarian cancer, cervical cancer, and gastric cancer.

[0034] In a fourth aspect, the present invention provides a method for preparing a compound of formula (Ia), the method comprising:

[0035] A. The compound of formula (1) is protected by methylation to generate the compound of formula (2);

[0036] B. The compound of formula (2) is subjected to a substitution reaction with a borate ester to obtain a borate ester compound of formula (3); the obtained compound of formula (3) is subjected to a coupling reaction with a halogenated aryl group represented by formula (4) to obtain a compound represented by formula (5); or the compound of formula (2) is directly reacted with an aryl boronic acid represented by formula (6) to obtain a compound represented by formula (5);

[0037] C. Hydrolyzing the compound of formula (5) to remove the protecting group to obtain the compound of formula (7);

[0038] D. The compound of formula (7) is condensed with the compound of formula (8) to obtain the compound of formula (Ia). The reaction scheme is as follows:

[0039]

[0040] wherein M and Y are independently selected from iodine, bromine, or chlorine; and R1, R2, R3 and Ar have the definitions described above for formula (Ia).

[0041] In a fifth aspect, the present invention provides a method for preparing a compound of formula (Ib), the method comprising:

[0042] E. The compound of formula (1) is reacted with the compound of formula (11) to obtain an amide compound of formula (12); F. The compound of formula (12) is reacted with an aromatic amine of formula (13) to obtain a compound of formula (Ib). The reaction scheme is as follows:

[0043]

[0044] wherein M is selected from iodine, bromine, or chlorine; and R1, R2, R3, and Ar have the definitions described above for formula (Ib).

[0045] Explanation of terms

[0046] The "alkyl" in the present invention refers to a straight-chain or branched hydrocarbon group, preferably C 1-6 Alkyl, suitable C 1-6 The alkyl group is methyl, ethyl, isopropyl, isobutyl, cyclopentyl, or benzyl.

[0047] The term "halogen" as used herein refers to fluorine, chlorine, bromine, or iodine. The term "halogenated" as used herein refers to substitution with fluorine, chlorine, bromine, or iodine.

[0048] The "haloalkyl" described in the present invention refers to an alkyl group substituted by at least one halogen.

[0049] The "alkoxy" described in the present invention refers to an -O-alkyl group.

[0050] The "cycloalkyl" mentioned in the present invention refers to a cyclic saturated hydrocarbon group, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0051] The term "fused bicyclic heteroaryl" as used herein refers to a 9- to 12-membered fused bicyclic aromatic system containing 1-4 heteroatoms (each heteroatom independently selected from oxygen, sulfur, and nitrogen). Examples include, but are not limited to, benzothiophenyl, benzofuranyl, benzothiazolyl, benzopyrazolyl, indolyl, quinolinyl, imidazopyridazinyl, and indazolyl. When the fused bicyclic heteroaryl is substituted with a substituent, the substituent may be located at any available attachment point.

[0052] As used herein, a "pharmaceutical composition" refers to a mixture comprising any of the compounds described herein and one or more pharmaceutically acceptable carriers and / or excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism. Such compositions are generally used to treat and / or prevent diseases mediated by VEGFR. DETAILED DESCRIPTION

[0053] The present invention is further described in detail below with reference to the examples. Unless otherwise specified, the materials used in the following examples are commercially available.

[0054] Example 1: Preparation of 7-(imidazo[1,2-b]pyridazin-3-yl)-3-methoxy-N-(4-((4-methylpiperazin-1-yl))methyl)-3-(trifluoromethyl)phenyl)-2-naphthamide (I-10)

[0055] (1) Synthesis of methyl 7-bromo-3-methoxy-2-naphthoate

[0056]

[0057] Under ice bath conditions, weigh 7-bromo-3-hydroxy-2-naphthoic acid (4g, 14.98mmol) into a flask, add DMF and stir to disperse it evenly. Then slowly add sodium hydride (1.8g, 75mmol) to the reaction flask, react for 5min and transfer to room temperature. In a fume hood, slowly add iodomethane (6g, 42mmol) dropwise, let it react at room temperature for 1h, and TLC monitoring shows that the reaction is complete. Slowly add 100ml of ethyl acetate to quench the reaction. The reaction solution is filtered to obtain the mother liquor. Water is added to the filtrate for extraction (100ml×3). The organic layers are combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and concentrated to obtain 3.8g of light yellow solid compound with a yield of 86%.

[0058] (2) Synthesis of methyl 3-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-2-naphthoate

[0059]

[0060] The compounds 7-bromo-3-methoxy-2-naphthoic acid methyl ester (2.7 g, 9.15 mmol), bipyraclostrobin (3.8 g, 14.96 mmol), [1,1-bis(diphenylphosphino)ferrocene] palladium dichloride (0.47 g, 0.64 mmol) and potassium acetate (2.7 g, 27.55 mmol) were weighed in sequence and dissolved in a 250 ml reaction flask. 24 ml of a 1.4-dioxane / H2O (5:1) mixed solvent was added to dissolve the mixture. The system was replaced with nitrogen three times, and then the reaction was carried out at 100 ° C for 3 h under nitrogen protection. The reaction of the raw material was monitored by TLC until complete, and 150 ml of ethyl acetate was added to quench the reaction. The reaction solution was filtered through diatomaceous earth to obtain the mother liquor, and water (150 ml × 3) was added to the filtrate for extraction. The organic layers were combined and washed with saturated brine, then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and concentrated to obtain a solid. The residue was purified by silica gel column chromatography to obtain 1.5 g of a light yellow solid compound in a yield of 47%.

[0061] (3) Synthesis of methyl 7-imidazo[1,2-b]pyridazin-3-yl)-3-methoxy-2-naphthoate

[0062]

[0063] 3-Methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-2-naphthoic acid methyl ester (3 g, 8.77 mmol), 3-bromoimidazo[1,2-b]pyridazine (2.5 g, 12.6 mmol), [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (0.6 g, 0.81 mmol) and potassium carbonate (2.4 g, 17.39 mmol) were weighed in sequence and placed in a 250 ml reaction flask. 20 ml of a 1.4-dioxane / H2O (3:1) mixed solvent was added to dissolve the mixture. The system was replaced with nitrogen three times and then reacted at 80°C under nitrogen protection for 3 h. The reaction of the raw material was monitored by TLC until completion. 150 ml of ethyl acetate was added to quench the reaction. The reaction solution was filtered through diatomaceous earth to obtain the mother liquor. Water (150 ml × 3) was added to the filtrate for extraction. The organic layers were combined and washed with saturated brine. The organic layers were then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and concentrated to obtain a solid. The residue was purified by silica gel column chromatography to obtain 1.4 g of a yellow solid compound in a yield of 25%.

[0064] (4) Synthesis of 7-imidazo[1,2-b]pyridazin-3-yl)-3-methoxy-2-naphthoic acid

[0065]

[0066] To a 250 mL reaction flask were added methyl 7-imidazo[1,2-b]pyridazin-3-yl)-3-methoxy-2-naphthoate (2.2 g, 6.6 mmol), potassium hydroxide (1.8 g, 32 mmol), 15 mL of ethanol, and 3 mL of water. The reaction was allowed to proceed at 60°C for 1 h. The reaction was monitored by TLC until completion. The solvent was removed under reduced pressure, and the pH was adjusted by slowly adding 4 mol / L hydrochloric acid to the residue in an ice bath. After stirring for 5 min, a brown solid precipitated. The target compound was filtered and dried to obtain 1.6 g of a yellow solid compound in a yield of 76.2%.

[0067] (5) Synthesis of 7-(imidazo[1,2-b]pyridazin-3-yl)-3-methoxy-N-(4-((4-methylpiperazin-1-yl))methyl)-3-(trifluoromethyl)phenyl)-2-naphthamide

[0068]

[0069] To a 250 mL reaction flask were added (7-imidazo[1,2-b]pyridazin-3-yl)-3-methoxy-2-naphthoic acid (0.5 g, 1.57 mmol), HATU (1.2 g, 3.15 mmol), and 10 mL of dry DMF. DIEA (0.4 g, 3.1 mmol) was slowly added dropwise and stirred at room temperature for 1 hour. 4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (0.38 g, 1.39 mmol) was added, and the reaction temperature was raised to 60°C for 3 hours. TLC monitored the complete reaction of the starting material. The reaction was quenched by the addition of 50 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated NaCl, dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography to afford 0.2 g of a light yellow solid in a 23% yield. 1 H NMR (600MHz, DMSO-d6) δ10.64(s,1H),8.87(s,1H),8.71(dd,J=4.4,1.7Hz,1H),8.40(s,1H),8.28(dd,J=9.2,1.7Hz,1H),8.26-8.22(m ,3H),8.07-8.03(m,2H),7.72(d,J=8.5Hz,1H),7.58(s,1H),7.34(dd,J=9.2,4.4Hz,1H),4.00(s,3H),3.65(s,2H),3.25-2.52(m,11H). 13C NMR(151MHz,DMSO-d6)δ165.53,158.98,154.90,144.48,140.47,138.99,134.68,133.67,132.09,131.51,130.22,128.06,1 27.85,126.85,126.61,125.50,124.96,123.47,121.61,117.30,107.12,100.17,96.61,57.22,56.44,53.34,51.92,49.74.

[0070] Example 2: Preparation of 7-(Benzofuran-2-yl)-3-methoxy-N-(4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-naphthamide (I-2)

[0071]

[0072] The operation was carried out in the same manner as in Example 1, and 200 mg of a white solid was obtained by column chromatography. 1 H NMR(600MHz,DMSO-d6)δ10.63(s,1H),8.50(s,1H),8.27(s,1H),8.24(d,J= 2.2Hz,1H),8.10(dd,J=8.6,1.8Hz,1H),8.02(d,J=8.7Hz,1H),7.96(d,J=10 .7Hz,1H),7.73-7.65(m,3H),7.58(s,1H),7.53(s,1H),7.37-7.32(m,1H),7 .31-7.27(m,1H),3.99(s,3H),3.58(s,2H),2.45-2.40(m,8H),2.17(s,3H). 13 C NMR(151MHz,DMSO-d6)δ165.43,155.71,155.17,154.81,138.63,135.34,132.51,131.88,130.22,129.42,128.55,128.13,127.95,127.9 1,126.16,125.70,125.14,124.98,124.17,123.78,123.40,122.08, 117.01,111.56,106.62,103.14,61.01,57.91,56.46,55.18,53.10.

[0073] Example 3: Preparation of 3-methoxy-7-(1-methyl-1H-indazol-5-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-naphthamide (I-3)

[0074]

[0075] The operation was carried out in the same manner as in Example 1, and 100 mg of a white solid was obtained by column chromatography. 1 H NMR(600MHz,DMSO-d6)δ10.62(s,1H),8.31(s,1H),8.25-8.23(m,2H),8.1 6(d,J=0.9Hz,1H),8.13(d,J=0.9Hz,1H),8.03-7.96(m,3H),7.88(dd,J=8. 8,1.7Hz,1H),7.77(d,J=9.7Hz,1H),7.71(d,J=8.5Hz,1H),7.56(s,1H),4. 10(s,3H),3.99(s,3H),3.65(s,2H),3.03-2.92(m,5H),2.73-2.63(m,6H). 13 C NMR(151MHz,DMSO-d6)δ165.64,154.46,139.63,139.03,137.57,135.08,133.35,132.87,132.16,131.29,130.22,128.40,127.83,1 27.72,126.17,125.98,125.65,124.73,123.83,122.91,119.06,117.19,111.12,106.85,57.04,56.41,53.97,50.50,44.63,33.53.

[0076] Example 4: Preparation of 3-methoxy-N-(4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-7-(quinolin-3-yl)-2-naphthamide (I-5)

[0077]

[0078] The operation was carried out in the same manner as in Example 1, and 50 mg of a white solid was obtained by column chromatography. 1H NMR (600MHz, DMSO-d6) δ10.63(s,1H),9.42(d,J=2.4Hz,1H),8.80-8.75(m,1H),8.55(d,J=1.9Hz,1H),8.30(s,1H),8.24(d,J=2.2Hz,1H),8.15- 8.06(m,4H),7.98(dd,J=8.4,2.2Hz,1H),7.79(m,1H),7.74-7.66(m,2H) ,7.61(s,1H),4.01(s,3H),3.58(s,2H),2.32-2.45(m,8H),2.20(s,3H). 13 C NMR(151MHz,DMSO-d6)δ165.40,155.00,150.01,147.28,138.62,134.98 ,133.29,133.24,132.91,132.48,131.87,130.47,130.00,129.17,128.8 8,128.30,128.23,128.12,127.95,127.57,127.28,126.94,125.71,123 .89,123.48,117.11,117.07,106.93,57.90,56.46,55.12,53.01,46.03.

[0079] Example 5: Preparation of 7-(Benzothiophene-3-yl)-3-methoxy-N-(4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-naphthamide (I-6)

[0080]

[0081] The operation was carried out in the same manner as in Example 1, and 100 mg of a white solid was obtained by column chromatography. 1 H NMR (600MHz, DMSO-d6) δ10.62(s,1H),8.28(d,J=1.9Hz,1H),8.24(s,2H),7.99-8.01(m,2H),7.91(dd,J=8.6,1.9Hz,1H),7.83-7.78( m,2H),7.71(d,J=8.4Hz,1H),7.56(s,1H),7.52(t,J=7.7Hz,2H),7.40(t,J=7.4Hz,1H),3.99(s,3H),3.65(s,2H),3.02-2.63(m,11H). 13C NMR(151MHz,DMSO-d6)δ165.44,155.05,146.39,143.66,140.43,138.72,134.79,132.48,130.16,130.01,128.46,128.07,128.02,1 26.40,125.66,125.36,125.21,124.22,123.43,122.96,121.61,120.68,117.66,112.11,107.12,64.86,58.58,56.46,54.68,51.98

[0082] Example 6: Preparation of 7-(1H-indol-5-yl)-3-methoxy-N-(4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-naphthamide (I-8)

[0083]

[0084] The operation was carried out in the same manner as in Example 1, and 45 mg of a white solid was obtained by column chromatography. 1 H NMR (600MHz, DMSO-d6) δ11.17(s,1H),10.62(s,1H),8.30-8.20(m,3H),8.02(dd,J=8.4,2.2Hz,1H),7.99-7.90(m,3H),7.72(d ,J=8.5Hz,1H),7.59-7.50(m,3H),7.40(t,J=2.7Hz,1H),6.52(t,J=2.5Hz,1H),3.99(s,3H),3.68(s,2H),3.16-2.77(m,11H). 13 C NMR(151MHz,DMSO-d6)δ194.21,165.72,154.20,139.04,138.32,136.01,134.01,132.14,131.36,130.10,128.83,128.11,127.95,1 27.69,127.52,126.63,125.66,125.46,123.45,120.94,118.77,117.21,112.40,106.82,102.05,57.08,56.38,53.47,50.09,42.86.

[0085] Example 7: Preparation of 7-(Benzo[d]thiazol-2-yl)-3-methoxy-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-naphthamide (I-7)

[0086]

[0087] The same operation as in Example 1 was performed, and 50 mg of a light yellow solid was obtained by column chromatography. 1 H NMR(600MHz,DMSO-d6)δ10.68(s,1H),8.74(d,J=1.8Hz,1H),8.38(s,1H),8.2 9-8.20(m,2H),8.18(d,J=7.5Hz,1H),8.09(dd,J=10.9,8.4Hz,2H),8.02(dd,J =8.4,2.2Hz,1H),7.72(d,J=8.5Hz,1H),7.64(s,1H),7.60-7.54(m,1H),7.52 -7.42(m,1H),4.01(s,3H),3.69(s,2H),3.04-2.69(m,9H),2.39-2.34(m,2H). 13 C NMR (151 MHz, DMSO-d6) δ 167.74, 165.40, 155.89, 154.14, 138.98, 136.80, 134.97, 132.20, 131.38, 130.71, 129.38, 128.88, 128.24, 128.19, 127.74, 127.20, 126.20, 126.02, 123.40, 123.26, 122.86, 120.80, 118.58, 116.53, 107.24, 57.03, 56.57, 53.37, 49.92, 42.69. A method for preparing the above-mentioned VEGFR-targeting compound (II) comprises the following steps:

[0088] Example 8: Preparation of 7-((6-chloroimidazo[1,2-b]pyridazin-3-yl)amino)-3-methoxy-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-naphthamide (I-13)

[0089] Synthesis of 7-bromo-3-methoxy-2-naphthoic acid

[0090]

[0091] To a 250 mL reaction flask were added methyl 7-bromo-3-methoxy-2-naphthoate (2 g, 3.17 mmol), potassium hydroxide (1.8 g, 32 mmol), 15 mL of ethanol, and 3 mL of water. The reaction was carried out at 60°C for 1 h. The reaction was monitored by TLC until completion. The solvent was removed under reduced pressure, and 4 mol / L hydrochloric acid was slowly added to the residue in an ice bath to adjust the pH. After stirring for 5 min, a brown solid precipitated. The target compound was filtered and dried to obtain the target compound. The product was purified by silica gel column chromatography to obtain 1.6 g of a yellow solid in a yield of 76.2%.

[0092] Synthesis of 7-bromo-3-methoxy-N-(4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-naphthamide

[0093]

[0094] To a 250 mL reaction flask, 7-bromo-3-methoxy-2-naphthoic acid (1 g, 3.55 mmol), HATU (2.7 g, 7.10 mmol), and 15 mL of dry DMF were added sequentially. DIEA (0.9 g, 6.97 mmol) was slowly added dropwise and the mixture was stirred at room temperature for 1 hour. 4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (0.77 g, 2.82 mmol) was added and the reaction temperature was raised to 60°C for 3 hours. TLC monitored the reaction until the starting material reacted completely. The reaction was quenched by adding 50 mL of water and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated NaCl, dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography to yield 0.7 g of a light yellow solid in a 45% yield.

[0095] Synthesis of 7-((6-chloroimidazo[1,2-b]pyridazin-3-yl)amino)-3-methoxy-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-naphthamide

[0096]

[0097] To a 100 mL reaction flask were added 7-bromo-3-methoxy-N-(4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-naphthamide (0.6 g, 1.12 mmol), 6-chloroimidazo[1,2-b]pyridazin-3-amine (0.4 g, 2.38 mmol), tris(dibenzylideneindeneacetone)dipalladium (0.085 g, 0.09 mmol), cesium carbonate (1 g, 3.07 mmol), Xantphos (0.2 g, 0.34 mmol), and 20 mL of dry toluene. The system was purged with nitrogen three times, and the reaction was then incubated at 100°C under nitrogen for 5 h. The reaction of the raw material was monitored by TLC until completion. 50 ml of ethyl acetate was added to quench the reaction. The reaction solution was filtered through diatomaceous earth to obtain the mother liquor. Water (50 ml × 3) was added to the filtrate for extraction. The organic layers were combined and washed with saturated brine. The organic layers were then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and concentrated to obtain a solid. The residue was purified by silica gel column chromatography to obtain 50 mg of a yellow solid in a yield of 15%. 1 H NMR (600MHz, DMSO-d6) δ10.52(s,1H),8.70(s,1H),8.23-8.17(m,2H),7.99-7.89(m,3H),7.79(d,J=8.9Hz,1H),7.69 (d,J=8.4Hz,1H),7.41(d,J=9.0Hz,2H),7.30-7.24(m,2H),3.93(s,3H),3.57(s,2H),2.48-2.23(m,8H),2.18(s,3H). 13 C NMR(151MHz,DMSO-d6)δ165.76,152.45,146.83,140.99,138.67,134.36,132.32,131.81,130.03,129.43,129.16,128.44,128.3 4,128.12,127.89,127.55,125.22,123.42,120.40,117.30,116.99,108.63,107.16,102.97,57.88,56.23,55.12,53.01,46.04.

[0098] Example 9: Preparation of 7-(imidazo[1,2-b]pyridazin-3-ylamino)-3-methoxy-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-naphthamide (I-11)

[0099]

[0100] The operation was carried out in the same manner as in Example 11, and 50 mg of a light yellow solid was obtained by column chromatography.1 H NMR(600MHz,DMSO-d6)δ10.50(s,1H),8.58(s,1H),8.51(dd,J=4.4,1.5Hz,1 H),8.20(d,J=2.3Hz,1H),8.11(dd,J=9.2,1.6Hz,1H),7.97-7.91(m,2H),7. 85(s,1H),7.76(d,J=8.9Hz,1H),7.69(d,J=8.4Hz,1H),7.40-7.33(m,2H),7 .19-7.13(m,2H),3.92(s,3H),3.56(s,2H),2.49-2.29(m,8H),2.17(s,3H). 13 C NMR(151MHz,DMSO-d6)δ165.78,152.28,143.83,141.62,138.68,135.77,132.33,131.79,129.80,129.22,128.56,128.31,128.04,1 27.87,127.51,126.26,125.70,124.62,123.88,123.40,120.32,117.02,116.20,108.10,107.16,57.90,56.20,55.17,53.09,46.13.

[0101] Example 10: Preparation of 7-((6-chloroimidazo[1,2-b]pyridazin-3-yl)amino)-3-hydroxy-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-naphthamide (I-12)

[0102]

[0103] The same operation as in Example 11 was performed, and 45 mg of a reddish-brown solid was obtained by column chromatography. 1 H NMR (600MHz, DMSO-d6) δ10.74(s,1H),8.67(s,1H),8.26(s,1H),8.21-8.18(m,2H),7.96(dd,J=8.4,2.2Hz,1H),7.90(s,1H),7.72(d,J=8.5Hz, 1H),7.69(d,J=8.9Hz,1H),7.39(dd,J=8.9,2.4Hz,1H),7.28-7.23(m,2 H),7.19(d,J=2.3Hz,1H),3.59(s,2H),2.48-2.40(m,8H),2.25(s,3H). 13CNMR(151MHz,DMSO-d6)δ166.89,157.78,152.17,146.87,140.55,138.12,134.43,132.71,132.50,131.83,131.32,129.46,1 28.98,128.38,127.47,125.81,125.43,124.20,122.10,121.34,117.82,117.34,111.31,108.59,57.79,54.96,52.75,45.74

[0104] Example 11: Preparation of 3-methoxy-N-(4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-7-(quinolin-3-ylamino)-2-naphthamide (I-17)

[0105]

[0106] The operation was carried out in the same manner as in Example 11, and 30 mg of a white solid was obtained by column chromatography. 1 H NMR (600MHz, DMSO-d6) δ10.57(s,1H),8.94(s,1H),8.78(d,J=2.8Hz,1H),8.23(d,J=2.3Hz,1H),8.11(s,1H),8.02-7.95(m, 2H),7.90-7.81(m,4H),7.71(d,J=8.5Hz,1H),7.53-7.43(m,4H),3.95(s,3H),3.57(s,2H),2.35-2.25(m,8H),2.19(s,3H). 13 CNMR(151MHz,DMSO-d6)δ165.77,152.95,145.57,142.89,139.13,138.65,137.80,132.38,131.82,130.86,129.27,129.04,128.92,128.78,1 28.35,127.70,127.33,127.19,126.22,125.70,123.88,123.42,122.5 6,117.01,114.35,112.09,107.14,57.89,56.27,55.15,53.08,46.13.

[0107] Example 12: Preparation of 3-methoxy-N-(4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-7-(phenylamino)-2-naphthamide (I-18)

[0108]

[0109] The operation was carried out in the same manner as in Example 11, and 50 mg of a white solid was obtained by column chromatography. 1 H NMR (600MHz, DMSO-d6) δ10.55(s,1H),8.36(s,1H),8.22(d,J=2.2Hz,1H),8.00(dd,J= 8.5,2.2Hz,1H),7.96(s,1H),7.79(d,J=8.8Hz,1H),7.70(d,J=8.5Hz,1H),7.55(d,J=2 .3Hz,1H),7.40(s,1H),7.35(dd,J=8.8,2.3Hz,1H),7.29-7.25(m,2H),7.19-7.14(m,2 H),6.87-6.85(m,1H),3.93(s,3H),3.67(s,2H),3.13-2.69(m,9H),2.44-2.27(m,2H). 13 C NMR(151MHz,DMSO-d6)δ165.85,152.53,143.83,140.48,139.06,132.10,131.20,130.29,129.71,129.13,128.34,128.10,1 28.08,127.50,125.65,123.83,123.42,122.53,120.33,117.24,117.18,110.81,107.21,57.05,56.26,53.40,49.99,42.75.

[0110] Example 13: Preparation of 3-methoxy-7-((1-methyl-1H-pyrazol-5-yl)amino)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-naphthamide (I-19)

[0111]

[0112] The operation was carried out in the same manner as in Example 11, and 50 mg of a light green solid was obtained by column chromatography. 1H NMR(600MHz,DMSO-d6)δ10.50(s,1H),8.22-8.16(m,2H),7.97-7.92(m,2H ),7.77(d,J=8.9Hz,1H),7.69(d,J=8.5Hz,1H),7.38(d,J=2.1Hz,2H),7.27 (dd,J=8.8,2.3Hz,1H),7.17(d,J=2.3Hz,1H),6.08(d,J=1.9Hz,1H),3.92( s,3H),3.68(s,3H),3.57(d,J=2.4Hz,2H),2.37-2.20(m,8H),2.16(s,3H). 13 C NMR(151MHz,DMSO-d6)δ165.74,152.40,141.78,141.47,138.66,138.19,132.36,131.80,129.89,129.14,128.25, 128.20,127.64,123.41,120.33,117.09,116.99,108.67,107.18,96.15,57.91,56.23,55.19,53.12,46.17,37.40.

[0113] Example 14: Preparation of 7-((2,3-dimethyl-2H-indazol-5-yl)amino)-3-methoxy-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-naphthamide (I-20)

[0114]

[0115] The operation was carried out in the same manner as in Example 11, and 30 mg of a white solid was obtained by column chromatography. 1 H NMR(600MHz,DMSO-d6)δ10.56(s,1H),8.33(s,1H),8.23(d,J=2.3Hz,1H),8.04 -7.94(m,2H),7.79(d,J=8.8Hz,1H),7.70(d,J=8.5Hz,1H),7.62-7.52(m,2H),7 .42-7.35(m,2H),7.16(d,J=1.8Hz,1H),6.84(dd,J=8.9,1.9Hz,1H),3.96(s,3H ),3.93(s,3H),3.67(s,2H),3.15-2.75(m,9H),2.55(s,3H),2.40-2.25(m,2H). 13C NMR(151MHz,DMSO-d6)δ165.88,152.51,148.31,141.37,140.92,139.09,132.10,131.87,131.16,130.18,129.18,128.27,128.03,127.53, 125.65,123.83,123.42,122.64,121.24,117.18,117.12,116.36,110 .82,107.25,98.74,60.23,57.03,56.26,53.35,49.90,42.66,37.30.

[0116] Example 15: Preparation of 7-((6-chloroimidazo[1,2-b]pyridazin-3-yl)amino)-3-methoxy-N-(4-(piperidin-1-ylmethyl)phenyl)-2-naphthamide (I-21)

[0117]

[0118] The same operation as in Example 11 was performed and 25 mg of a yellow solid was obtained by column chromatography. 1 H NMR (600MHz, DMSO-d6) δ10.21(s,1H),8.70(s,1H),8.19(d,J=9.4Hz,1H),7.96-7.89(m,2H),7.78(d,J=8.8Hz,1H),7.68(d,J= 8.1Hz,2H),7.43-7.33(m,2H),7.33-7.16(m,4H),3.93(s,3H),3.33(s,2H),2.44-2.35(m,4H),1.50-1.48(m,4H),1.38(s,2H). 13 C NMR (151MHz, DMSO-d6) δ165.09,152.53,146.81,140.89,138.35,134.32,129.96,129.63,129.48,129.22,128. 48,128.34,128.07,127.80,125.12,120.31,119.87,117.24,108.66,107.13,62.91,56.22,54.25,26.01,24.51

[0119] Example 16: Preparation of 7-((6-chloroimidazo[1,2-b]pyridazin-3-yl)amino)-3-methoxy-N-(4-(morpholinomethyl)phenyl)-2-naphthamide (I-22)

[0120]

[0121] The operation was carried out in the same manner as in Example 11, and 30 mg of a white solid was obtained by column chromatography. 1 H NMR (600MHz, DMSO-d6) δ10.22(s,1H),8.70(s,1H),8.19(d,J=9.4Hz,1H),7.96-7.91(m,2H),7.78(d,J=8.9Hz,1H),7.73 -7.67(m,2H),7.43-7.36(m,2H),7.31-7.23(m,4H),3.93(s,3H),3.57(t,J=4.5Hz,4H),3.42(s,2H),2.36-2.30(m,4H). 13 C NMR(151MHz,DMSO-d6)δ165.11,152.53,146.81,140.90,138.53,134.32,133.26,129.97,129.78,129.48,129.22,128.4 9,128.33,128.07,127.79,125.13,120.32,119.91,119.53,117.24,115.36,108.67,107.14,66.67,62.52,56.23,53.59.

[0122] Example 17: Preparation of 7-((6-chloroimidazo[1,2-b]pyridazin-3-yl)amino)-3-methoxy-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-2-naphthamide (I-23)

[0123]

[0124] The operation was carried out in the same manner as in Example 11, and 20 mg of a white solid was obtained by column chromatography. 1 H NMR (600MHz, DMSO-d6) δ10.24(s,1H),8.71(s,1H),8.19(d,J=9.4Hz,1H),7.96-7.91(m,2H),7.80-7.68(m,3H ),7.43-7.37(m,2H),7.31-7.23(m,4H),3.93(s,3H),3.52-3.43(m,2H),2.65-2.52(m,4H),2.49-2.25(m,7H). 13C NMR (151MHz, DMSO-d6) δ165.14,152.52,146.81,140.92,138.61,134.33,132.16,129.96,129.80,129.47,129.22,128. 47,128.34,128.08,127.78,125.17,120.33,119.94,117.25,108.65,107.15,75.12,61.70,56.24,54.41,51.79,45.01

[0125] Example 18: Preparation of 7-((6-chloroimidazo[1,2-b]pyridazin-3-yl)amino)-3-methoxy-N-(4-(4-methylpiperazin-1-yl)phenyl)-2-naphthamide (I-24)

[0126]

[0127] The same operation as in Example 11 was performed and 25 mg of a yellow solid was obtained by column chromatography. 1 H NMR (600MHz, DMSO-d6) δ10.02(s,1H),8.69(s,1H),8.19(d,J=9.3Hz,1H),7.97-7.91(m,2H),7.77(d,J=8.9Hz,1H),7.59(d,J=2.2 Hz,2H),7.41-7.37(m,2H),7.31-7.23(m,2H),6.96-6.89(m,2H),3.93(s,3H),3.12-3.05(m,4H),2.49-2.43(m,4H),2.23(s,3H). 13 C NMR(151MHz,DMSO-d6)δ164.45,152.60,147.87,146.80,140.86,134.31,131.64,129.93,129.50,129.25,128.5 8,128.33,128.04,127.73,125.10,121.17,120.26,117.22,116.07,108.70,107.12,56.23,55.09,49.01,46.23.

[0128] Example 19: Preparation of 7-((6-chloroimidazo[1,2-b]pyridazin-3-yl)amino)-3-ethoxy-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-naphthamide (I-25)

[0129]

[0130] The same operation as in Example 11 was performed and 15 mg of dark yellow solid was obtained by column chromatography. 1 H NMR (600MHz, DMSO-d6) δ10.49(s,1H),8.70(s,1H),8.22-8.17(m,2H),8.02(s,1H),7.94-7.90(m,2H),7.77(d,J=8.9Hz,1H),7.70(d,J =8.5Hz,1H),7.42-7.38(m,2H),7.25(s,2H),4.21(q,J=6.9Hz,2H),3.57(s,2H),2.45-2.39(m,8H),2.19(s,3H),1.41(t,J=6.9Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ165.48,151.73,146.81,140.96,138.65,134.35,132.32,131.88,130.21,129.43,129.14,128.99,128.34, 128.09,127.14,125.19,123.87,123.28,120.52,117.26,116.92,110.91,108.67,108.14,64.51,57.90,55.14,53.04,46.07,13.33

[0131] Example 20: 7-((6-chloroimidazo[1,2-b]pyridazin-3-yl)amino)-3-isopropoxy-N-(4-

[0132] Preparation of ((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-naphthamide (I-26)

[0133]

[0134] The same operation as in Example 11 was performed and 25 mg of a yellow solid was obtained by column chromatography. 1 H NMR (600MHz, DMSO-d6) δ10.48(s,1H),8.70(s,1H),8.19(d,J=9.6Hz,2H),8.02(s,1H),7.94-7.86(m,2H),7.77(d,J=8.9Hz,1H),7.70 (d,J=8.6Hz,1H),7.46-7.36(m,2H),7.31-7.22(m,2H),4.78(m,1H),3.57(s,2H),2.49-2.38(m,8H),2.18(s,3H),1.42-1.34(m,6H). 13C NMR(151MHz,DMSO-d6)δ165.56,150.55,146.81,141.00,138.60,134.36,132.34,131.90,130.23,129.42,129.17,129.01,128.35,1 28.12,127.91,125.66,125.21,123.91,123.25,120.51,117.27,116.85,110.05,108.58,71.62,57.89,55.15,53.07,46.09,22.28.

[0135] Example 21: Preparation of 7-((6-chloroimidazo[1,2-b]pyridazin-3-yl)amino)-3-(cyclopentyloxy)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-naphthamide (I-27)

[0136]

[0137] The same operation as in Example 11 was performed and 35 mg of a yellow solid was obtained by column chromatography. 1 H NMR(600MHz,DMSO-d6)δ10.41(s,1H),8.70(s,1H),8.23-8.14(m,2H),8.0 1(s,1H),7.95-7.85(m,2H),7.80-7.68(m,2H),7.42-7.37(m,2H),7.26(d, J=9.4Hz,2H),5.01(m,1H),3.56(s,2H),2.45-2.35(m,8H),2.17(s,3H),2 .02-1.95(m,2H),1.88-1.83(m,2H),1.65-1.72(m,2H),1.62-1.58(m,2H). 13 C NMR(151MHz,DMSO-d6)δ165.55,150.63,146.81,140.91,138.59,134.34 ,132.35,131.90,130.18,129.44,129.07,128.97,128.34,128.11,127. 93,127.83,125.67,125.18,123.86,123.19,120.48,117.26,116.87,11 6.83,109.54,108.64,80.47,57.91,55.18,53.12,46.13,32.71,24.00.

[0138] Example 22: Preparation of 3-(benzyloxy)-7-((6-chloroimidazo[1,2-b]pyridazin-3-yl)amino)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-naphthamide (I-28)

[0139]

[0140] The same operation as in Example 11 was performed and 35 mg of a yellow solid was obtained by column chromatography. 1 H NMR(600MHz,DMSO-d6)δ10.54(s,1H),8.73(s,1H),8.20(d,J=9.4Hz,1H),8.02 (d,J=2.2Hz,2H),7.93-7.85(m,2H),7.78(d,J=8.9Hz,1H),7.66(d,J=8.6Hz,1 H),7.58-7.51(m,3H),7.42(dd,J=8.8,2.4Hz,1H),7.38-7.31(m,3H),7.31-7. 25(m,2H),5.28(s,2H),3.55(d,J=6.0Hz,2H),2.45-2.35(m,8H),2.17(s,3H). 13 C NMR(151MHz,DMSO-d6)δ165.47,151.50,146.83,141.14,138.54,137.23,134.38,132.32,131.83,130.05,129.37,128.96,128.83,128.42,1 28.34,128.21,128.13,127.74,127.35,125.28,123.82,123.12,120.5 8,117.31,116.83,108.68,108.61,70.46,57.89,55.15,53.08,46.12.

[0141] Example 23: Preparation of 3-(sec-butoxy)-7-((6-chloroimidazo[1,2-b]pyridazin-3-yl)amino)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-naphthamide (I-29)

[0142]

[0143] The operation was carried out in the same manner as in Example 11, and 40 mg of a light yellow solid was obtained by column chromatography. 1H NMR (600MHz, DMSO-d6) δ10.45 (s, 1H), 8.63 (s, 1H), 8.17 (d, J = 9.2Hz, 2H), 8. 01(s,1H),7.87(m,2H),7.77(d,J=8.9Hz,1H),7.70(d,J=8.5Hz,1H),7.44-7 .35(m,2H),7.24(d,J=9.3Hz,2H),4.59(m,1H),3.57(s,2H),2.45-2.35(m,8 H),2.17(s,3H),1.79-1.65(m,2H),1.34(d,J=6.1Hz,3H),0.98-0.92(m,3H). 13 C NMR(151MHz,DMSO-d6)δ165.67,150.73,146.81,140.94,138.61,134.34,132.33,131.89,130.18,129.43,129.12,128.76,128.34,128.13 ,125.71,125.18,123.86,123.21,120.45,117.26,116.84,109.78,1 08.54,76.11,57.89,55.15,53.07,46.09,28.98,26.81,19.26,9.83.

[0144] Example 24: Preparation of 7-(imidazo[1,2-b]pyridazin-3-ylamino)-3-methoxy-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)quinoline-2-carboxamide (I-30)

[0145]

[0146] The same operation as in Example 11 was performed, and 30 mg of a light yellow solid was obtained by column chromatography. 1 H NMR (600MHz, DMSO-d6) δ12.72(s,1H),8.87(d,J=18.1Hz,2H),8.52(d,J=4.3Hz,1H),8.28-8.14(m,2H),7.87-7.64 (m,4H),7.52-7.41(m,2H),7.23(dd,J=9.2,4.4Hz,1H),4.04(s,3H),3.55(s,2H),2.48-2.30(m,8H),2.18(s,3H). 13C NMR(151MHz,DMSO-d6)δ175.36,163.82,147.54,144.12,143.97,138.36,136.66,133.63,132.06,131.91,128.53,127.29,1 26.94,126.50,125.67,123.85,123.33,121.98,119.57,117.00,116.85,109.20,106.85,57.86,55.13,53.05,46.06,41.95.

[0147] Example 25: Preparation of 3-(Benzofuran-2-yl)-1-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-1H-indole-5-carboxamide (I-31)

[0148]

[0149] The same operation as in Example 1 was performed, and 25 mg of a white solid was obtained by column chromatography. 1 H NMR(600MHz,DMSO-d6)δ10.62(s,1H),8.69(d,J=1.7Hz,1H),8.31(d,J=2.2Hz ,1H),8.19-8.10(m,2H),7.95(dd,J=8.6,1.7Hz,1H),7.73(dd,J=8.6,6.3Hz,2 H),7.69-7.59(m,2H),7.36-7.23(m,3H),3.95(s,3H),3.69(s,2H),3.35-3.31 (m,2H),3.08-3.04(m,2H),2.95-2.91(m,2H),2.82(s,3H),2.40-2.38(m,2H). 13 C NMR(151MHz,DMSO-d6)δ166.97,153.77,152.52,139.51,139.32,131.93,130.99,130.71,129.84,128.13,127.93,127.21,125.76,1 24.13,124.03,123.92,123.50,122.66,120.74,120.57,117.98,111.07,111.05,107.01,99.91,60.22,57.05,53.34,49.92,42.64.

[0150] Example 26: Preparation of 7-(6-chloroimidazo[1,2-b]pyridazin-3-yl)-3-methoxy-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-2-naphthamide (I-32)

[0151]

[0152] The operation was carried out in the same manner as in Example 1, and 50 mg of a light green solid was obtained by column chromatography. 1 H NMR (600MHz, DMSO-d6) δ10.64(s,1H),8.76(s,1H),8.44(s,1H),8.34(d,J=9.4Hz,1H),8.27-8.23(m,3H),8.05(d,J=8.7Hz,1H),7.97(d,J= 8.2Hz,1H),7.72(d,J=8.4Hz,1H),7.57(d,J=12.5Hz,1H),7.46(d,J=9.4Hz,1H),4.00(s,3H),3.58(s,2H),2.49-2.41(m,8H),2.21(s,3H). 13 C NMR (151MHz, DMSO-d6) δ165.37,155.08,146.93,139.23,138.62,134.87,134.54,132.50,131.84,130.26,129.48,128.65,128. 25,128.18,127.90,127.75,127.59,126.64,125.85,124.18,123.47,119.12,107.08,57.91,56.44,55.19,53.13,46.17,40.52.

[0153] Experimental Example 1 VEGFR kinase inhibitory activity test

[0154] Positive and negative control wells were set up in a 384-well reaction plate. Various concentrations of compound and VEGFR2 kinase were added to the remaining wells. After centrifugation, the plate was incubated at room temperature for 15 minutes. Fluorescent substrate and ATP were added. After the reaction was complete, stop solution was added and the conversion rate was read using a Caliper EZ reader. The percentage inhibition rate was then calculated using the following formula: Enzyme inhibition rate = Mean (maximum) - Sample signal / Mean (maximum) - Blank multiplied by 100%. The experimental results are shown in Table 1.

[0155] Table 1. Inhibition rate of VEGFR2 by compounds at 100 and 10 nM concentrations

[0156]

[0157] The IC values ​​of some compounds with good inhibitory activity were calculated by fitting the corresponding concentration inhibition rate and the concentration logarithm. 50 Among them, the IC values ​​of compounds I-11, I-12, I-13, and I-32 are 50 The IC of Sunitinib was determined by the same method. 50 It is 33.6.

[0158] Experimental Example 2 Cell proliferation inhibition activity test

[0159] Given that the target compound showed good inhibitory effect on VEGFR, the anti-proliferative activity of the target compound was further evaluated. Human colon cancer cell line (HT-29), human hepatocellular carcinoma cell line (HepG2) and human umbilical vein endothelial cell (HUVEC) cell lines were selected for evaluation. At the same time, a normal liver cell line (L02) group was set up to evaluate its side effects on normal cells. The experiment set up a solvent control group and a drug experimental group. Each drug experimental group had 8 concentrations, and 3 parallel wells were set up at each concentration. Each experiment was repeated three times. In a 96-well plate, a cell concentration of 1×10 5 100 μL of cell suspension containing 3×10 cells / mL, i.e., each well contains 3×10 cells 3 When inoculating, pay attention to ensure that the cells are evenly distributed in each well. After the cells adhere, 100 μL of the target compound at different concentrations is added to each well in the drug experimental group. The 96-well plate is placed in a 37°C, 5% CO2 incubator for continued culture, and the culture is terminated after 72 hours. After 72 hours of drug treatment of the cells, the 96-well plate is removed, the cell culture medium is discarded, 100uL of serum-free culture medium is added to each well, and then 20uL of MTT reagent is added to each well in the dark. After continuing to incubate in the cell culture incubator for 4 hours, the 96-well plate is removed, the culture medium containing MTT is aspirated, 150uL of DMSO solution is added to each well, and shaken on a shaker in the dark for 15 minutes. The absorbance value (A) of each well is then measured at 570nm on an automatic microplate reader. The inhibition rate is calculated by the formula. A linear regression analysis of the inhibition rate and the drug concentration is performed, and the IC is calculated using the linear equation. 50 value.

[0160] Table 2. Antiproliferation activity of compounds against different tumor cell lines a

[0161] a The data reported are the mean values ​​from three independent experiments.

[0162]

[0163] As shown in Table 2, the compounds of the present invention exhibited good cell proliferation inhibitory activity against the three cell types, IC 50 The values ​​were in the micromolar range; especially compound I-32 had a relatively strong inhibitory effect on HT-29 cells (IC 50 =0.58μM), which is comparable to Ponatinib and Sunitinib. 50 When the concentration exceeds 10μM, the toxic and side effects are significantly better than those of Ponatinib.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds:

2. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 2 for preparing a drug for treating and / or preventing cancer.

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