WO2014029251A1

WO2014029251A1 - Benazepine compound and application thereof

Info

Publication number: WO2014029251A1
Application number: PCT/CN2013/079885
Authority: WO
Inventors: 李建其; 王文雅; 黄道伟; 杜振新; 卢秀莲; 王佳静; 黄美花
Original assignee: 辰欣药业股份有限公司; 上海医药工业研究院
Priority date: 2012-08-24
Filing date: 2013-07-23
Publication date: 2014-02-27
Also published as: CN103626762A; CN103626762B

Abstract

Disclosed are a benazepine compound and an application thereof. The benazepine compound, as a synthon for preparing a novel compound with an anti-tumor activity, results in a compound that has a significantly improved ex vivo enzyme-inhibiting activity, and shows a multi-target inhibitory effect, and thus has a notable scientific advancement and a value of in-depth research and development. The benazepine compound is a compound shown in formula (I) or a pharmaceutically acceptable salt thereof.

Description

Benzopyridine azepine compounds and their applications

Technical field

The present invention relates to benzopyridinium azide compounds and the use of such compounds in the preparation of antitumor compounds. Scene

Hepatocyte growth factor (HGF), also known as Scatter Factor (SF), is a multifunctional cytokine that promotes many types of cells such as hepatocytes, epithelial cells, endothelial cells, and hematopoietic cells. The role of growth, migration and morphogenesis. The c-Met transmembrane protein is a protein product encoded by the c-met proto-oncogene and is a high affinity receptor for HGF. When HGF binds to its receptor c-Met, it leads to autophosphorylation of c-Met tyrosine kinase, which activates c-Met tyrosine kinase activity, further activates many different downstream signaling molecules in cells, induces cell development. A range of biological effects such as cell dispersion, movement, proliferation, invasion, migration, and ultimately metastasis and angiogenesis (Bottaro et al, Science, 1991, 251, 802-804).

Numerous studies have shown that HGF/c-Met signaling plays an important role in the development, progression and secondary metastasis of malignant tumors, and is closely related to the poor prognosis of patients (Sattler et al, Curr Oncol Rep, 2007, 9). , 102-108; Mazzone et al, FASEB J, 2006, 20, 1611-1621; Trusolino et al, Nature Rev, Cancer 2002, 2, 289-300). The continuous activation of c-Met will destroy the adhesion between tumor cells, promote cell movement and tumor angiogenesis, and make tumor cells easy to enter the blood circulation and obtain the ability to invade and metastasize. In many cancers, c-Met and HGF are overexpressed relative to surrounding tissues, such as thyroid cancer, breast cancer, lung cancer, stomach cancer, colon cancer, pancreatic cancer, prostate cancer, kidney cancer, liver cancer, ovarian cancer, and brain glue. Qualitative tumors, etc. (Birchmeier et al, Nat Rev Mol Cell Biol, 2003, 4, 915-925; Otsuka et al, Cancer Res, 1998, 58, 5157-5167; Parr et al, Clin Cancer Res, 2004, 10, 202-211) . Other studies have shown that MET gene amplification is closely associated with acquired resistance to 20% of epidermal growth factor inhibitors (EGFR-TKIs) (Engelman et al, Science, 2007, 316, 1039-1043). Therefore, small molecule kinase inhibitors targeting c-Met have important research significance for the treatment of the aforementioned cancers.

At present, several c-Met small molecule inhibitors have been in preclinical and clinical research. Among them, Crizotinib (XALKORI) developed by Pfizer has been approved by the FDA in August 2011 for the treatment of patients with advanced non-small cell lung cancer (NSCLC) expressing abnormal anaplastic lymphoma kinase (ALK) gene, showing good results. treatment effect. This indicates that c-Met has been confirmed as a novel anti-tumor target, and it indicates that c-Met inhibitor has broad development and therapeutic prospects.

C-Met inhibitors that are clinically studied differ in their binding patterns to the c-Met kinase domain and can be divided into two broad categories: (1) U-type small molecule inhibitors: such as Crizotinib and MK-2461;

(2) Linear small molecule inhibitors such as Cabozantinib (XL184) and Foretinib (XL880). Among them, the first type of U-type small molecule inhibitor acts on the ATP-binding site at the beginning of the c-Met kinase pocket, surrounding the amino acid residue Metl211, mainly as a highly selective inhibitor of c-Met; the second type of linear type Small molecule inhibitors are novel c-Met inhibitors developed in recent years, acting through a stretched conformation on deep Ilel l45 hydrophobic pockets from the ATP-binding site, the kinase junction chain to the C-terminal helix region, mainly Target inhibitor. In view of the complex pathogenesis of tumors, a single inhibition of a certain signal transduction pathway is likely to cause tumors to develop resistance through escape mechanisms. Studies have shown that certain mutations near the c-Met active site lead to resistance to the first class of small molecule inhibitors (Berthcm et al, Oncogene 2004, 23, 5387-5393; Buchanan et al, Mol. Cancer Ther. 2009, 8, 3181—3190). The second type of linear small molecule inhibitor not only acts on the starting end of the c-Met active site, but also helps prevent the formation of drug resistance, and simultaneous inhibition of multiple targets will lead to better antitumor effect, so this class Anti-tumor drugs will achieve better therapeutic results. Among them, two representative drugs are Cabozantinib (Clinical Stage) and Foretinib (Clinical Phase II) jointly developed by Elixis and Bristol-Myers Squibb and GlaxoSmithKline. Therefore, the design and synthesis of novel c-Met inhibitors, especially multi-target inhibitors, can help to find new anti-tumor drugs with strong anti-tumor activity, low toxic side effects and inhibiting tumor cell growth and metastasis, and also c- The structural diversity of Met inhibitors and the binding mode studies with target enzymes provide scientific guidance.

The linear small molecule c-Met inhibitor consists of an aromatic ring, an aromatic ring linking region and a three-membered carbocyclic diamide side chain, which act on the ATP-binding site, the linking region and the C-terminal helix of the c-Met enzyme, respectively. Deep Ilel l45 hydrophobic pocket near the area. Among them, the two carbonyl oxygen atoms in the side chain of the ternary carbocyclic diamide can form two hydrogen bonds with the amino acid residues in the hydrophobic pocket, and are the basic pharmacological groups of such compounds having c-Met inhibitory activity. The aromatic ring acting on the ATP-binding site has the function of regulating the physicochemical properties of the molecule, regulating the affinity and specificity of the inhibitor molecule and the c-Met target enzyme, and finally improving its inhibitory activity. Therefore, it is important to find and discover aromatic structures of different structures as synthons for the synthesis of novel high-activity linear small molecule c-Met inhibitors.

The object of the present invention is to disclose a benzopyridinium azide compound and its use in the preparation of an antitumor compound.

The benzopyridinium azide compound of the present invention is a compound having the formula (I) or a pharmaceutically acceptable salt thereof:

among them-

X is selected from halogen;

Y is selected from NH, NHBn, NCH ₃ , 0 or S;

Ri is selected from H or methyl;

R _{2 is} selected from H, CN, methyl, methoxy or fluoro;

R ₃ and each independently selected from hydrazine, 03⁄4 d- ₅ alkyl, amino, NH, halogen, cyano, nitro, substituted amino, phenyl, heterocyclyl, substituted phenyl or substituted heterocyclic;

Wherein - the Cw alkyl group is preferably a methyl group, an ethyl group or an isopropyl group;

The substituted amino group is preferably d- ₅ alkylamino, morpholine-N-propylamino, piperidin-4-methylamino or piperidin-1-propyl; heterocyclic group is preferably morpholine-1-yl, piperidine-Φ Or a piperidin-1-yl group;

The substituted phenyl or substituted heterocyclic group is a phenyl or heterocyclic group having 1 to 4 substituents, and the substituent is preferably a hydroxyl group, a methoxy group, a methyl group or an amino group;

R _{6 is} selected from hydrogen, d- ₅ straight or branched alkyl, aryl, aralkyl, heterocyclyl, heterocycloalkyl, substituted Cw alkyl, substituted aryl, substituted aralkyl, Substituted heterocyclic or substituted heterocycloalkyl;

Wherein - the Cw branched or branched alkyl group is preferably methyl, ethyl or isopropyl;

The aryl group is preferably a phenyl group;

The aralkyl group is preferably a benzyl group, a 3,4-dimethoxybenzyl group or a 3-(3,4-dimethoxyphenoloxy)propyl group; the heterocyclic group is preferably an imidazolyl group, a thiazolyl group or Pyridyl group;

The heterocycloalkyl group is preferably morphinolylpropyl, piperidine-4-methyl, piperidin-1-propyl, N-methylpiperidin-1-propyl or pyrrolidinyl;

The substituted d- ₅ alkyl group is preferably a methylol group, an aminomethyl group, a 3-(hydroxy)propyl group or a 3-(dimethylamino)propyl group; the substituted aryl group is preferably a 3,4-dimethoxy group. a phenyl group, a 4-methylphenyl group, a 4-aminophenyl group or a 4-fluorophenyl group; the substituted heterocyclic group or substituted heterocycloalkyl group is a heterocyclic group or a heterocycloalkyl group having 1 to 4 a substituent, preferably a hydroxyl group, a methoxy group, a methyl group or an amino group;

R _{5 is} divided into two cases:

When the seven-membered ring is C=N, there is no R _{5 ;}

When the seven-membered ring is CN, R _{5 is} selected from H, Cw alkyl or Cw acyl, wherein: the Cw alkyl group is preferably a methyl group, and the C _1-4 acyl group is preferably an acetyl group;

In order to facilitate the understanding of the present invention, the following specific compounds are preferred from the compounds of the formula (I), but the benzopyridinium compounds of the present invention are not limited to the following compounds: 1-1 4-chloro-11H-benzopyridine [3,2-6][l,4]diazepine,

1-2 4-chloro-benzopyridine [2,3-6][1,4]oxazepine,

1-3 4-chloro-benzopyridine [2,3-6][1,4]thiazepine,

1-4 4-chloro-6,11-dihydro-5H-benzopyridine [3,2-6][1,4]diazepine,

1-5 4-Chloro-5,6-dihydrobenzopyridine [2,3-6][1,4]oxazepine,

1-6 4-Chloro-5,6-dihydrobenzopyridine [2,3-6][1,4]thiazepine,

I -7 4-chloro-2-methyl- 11H-benzopyridine [3,2-6] [ 1 ,4]diazepine,

1-8 4-Chloro-2-methyl-6,11-dihydro-5H-benzopyridine [3,2-6][1,4]diazepine,

1-9 4-Chloro-11H-benzopyridine [3,2-6][1,4]diazepine-3-carbonitrile,

1-10 4-chloro-3-methyl-11?-benzopyridine [3,2-6][1,4]diazepine,

1-11 4-Chloro-3-methoxy-11 benzopyridine [3,2-6][1,4]diazepine,

1-12 4-chloro-3-fluoro-11?-benzopyridine [3,2-6][1,4]diazepine,

1-13 4-Chloro-11-methyl-11 benzopyridine [3,2-6][1,4]diazepine,

1-14 4-Chloro-5-methyl-6,11-dihydro-5^benzopyridine [3,2-6][1,4]diazepine,

1-15 1-(4-Chloro-6,11-dihydro-5H-benzopyridine [3,2-6][1,4]diazepine-5-yl)ethyl ketone,

1-16 4-Chloro-8-methoxy-11?-benzopyridine [3,2-6][1,4]diazepine,

1-17 4-Chloro-8,9-dimethoxy-11 benzopyridine [3,2-6][1,4]diazepine,

ΐ ΐ δ ^ Ρ - - chloro-8-methoxy -11H-benzopyridine [3,2-6][1,4]diazepine-9-yl)oxy]propyl }morpholine,

I - 19 4-chloro-9-methyl- 11H-benzopyridyl [3,2-6] [ 1 ,4]diazepine,

1-20 4-chloro-8-fluoro-11H-benzopyridine [3,2-6][1,4]diazepine,

1-21 4-Chloro-11H-benzopyridine [3,2-6][1,4]diazepine-9-carbonitrile,

1-22 4-Chloro-8-nitro-11H-benzopyridine [3,2-6][1,4]diazepine,

1-23 4-Chloro-11H-benzopyridine [3,2-6][1,4]diazepine-8-amine,

1-24 3-[(4-Chloro-8-methoxy-11H-benzopyridine [3,2-6][1,4]diazepin-9-yl)oxy]-N,N- Dimethyl-1-propylamine,

1-25 4-Chloro-9-(lH-imidazolium-5-yl)-8-methoxy-11H-benzopyridine [3,2-6][1,4]diazepine,

I -26 4-chloro-8-methoxy-9-(;thiophen-2-yloxy) - 11H-benzopyridine [3 ,2-b] [ 1 ,4]diazepine,

1-27 4-Chloro-8,9-dimethoxy-6,11-dihydro-5H-benzopyridine [3,2-6][1,4]diazepine,

1-28 4-{3-[(4-Chloro-8-methoxy-6,11-dihydro-5H-benzopyridine [3,2-6][1,4]diazepine-9- Alkyl propyl morpholine

The compound of the formula (I) or the salt of any one of 1-1 to 1-28, which is a hydrochloride, a hydrobromide, a sulfate, an acetate, a lactate, a tartrate, a citrate, Citrate, trifluoroacetate, malate, maleate, Succinate, p-toluenesulfonic acid or methanesulfonate. The structural formula of the above compounds is shown in Table 1.

91-1

10

51-1

10 people _Γ

Ει-ι

10

10 π-ι

10

01 -ι

10

6-1

10

S886 .0/CT0ZN3/X3d Please ΪΟΖ OAV

Please Ϊ0Ζ OAV

Raw material 1 and raw material 2 were reacted with K ₂ C0 ₃ as a base, and stirred in a DMF solution at room temperature for 12 h to obtain Intermediate 3. The intermediate is catalytically reduced by iron powder and ammonium chloride in a mixed solvent of ethanol and water under reflux to obtain Intermediate 4.

Intermediate 4 is reacted with paraformaldehyde in the presence of trifluoroacetic acid and anhydrous MgS0 ₄ in a dichloromethane solution at 40 ° C overnight to give the title compound II wherein R ₅ is H. Compound II and methyl iodide in the presence of potassium carbonate in DMF The reaction mixture is stirred at room temperature for 4 h to obtain the target compound III wherein R ₅ is a methyl group; Compound II and acetyl chloride are stirred in CH ₂ C _{1 2} in the presence of triethylamine at room temperature for 2 h to obtain an acetyl group. Target compound III.

Intermediate 4 is reacted with a mixed solution of formic acid and acetic anhydride to obtain a formylated product 5. Compound 5 is refluxed in phosphorus oxychloride and polyphosphoric acid to obtain the target compound IV.

The compound of the present invention can be used for preparing a benzopyridinium azalea antitumor compound, for example, when the compound of the present invention 1- 17 is used as a raw material, an antitumor compound V can be prepared (N-{4-[( 8,9-Dimethoxy-11H-benzopyridine [3,2-6][1,4]diazepine-Φ-yloxy]phenyl}-N-(4-fluorophenyl) ring Propane-1,1-diamide), when using 1-18 as a raw material, an antitumor compound VKN-(4-fluorophenyl)-N-{4-[8-methoxy-9-(3) can be prepared. -morpholinepropoxy)-llH-

1-17: R! = R ₂ = H, R ₃ = R ₄ = OCH ₃ ; V: = R ₂ = H, R ₃ = R ₄ = OCH ₃ ;

-O.

1-18: = H, R ₃ = OCH ₃ , R ₄ = NO VI: = H, R ₃ = OCH3, R ₄ = -NO

The compound IV of the present invention and N-(4-fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane-1,1-diamide (compound 6) undergo Ullmann reaction under Cu catalysis, and an anti- Tumor active compound. Among them, the synthesis of the compound 6 can be carried out by a two-step acylation reaction with 4-fluoroaniline and 4-aminophenol, respectively, starting from cyclopropane-1,1-dicarboxylic acid according to the method reported in WO2005030140.

The above preparation method may further comprise reacting a compound of the formula I with a mineral acid or an organic acid in a solvent to cool a salt of the compound of the formula I.

In the above reaction method, R ₂ , R ₃ , R ₄ , R ₅ , Y are as described above;

Compounds 1, 2, etc. can be purchased commercially.

The in vitro inhibition assay showed that the compound V and the compound VI synthesized by the compound of the present invention as an intermediate inhibited the activity of c-Met aC ₅ Q _: V, 15.0 nM _; VI, 18.4 nM) compared with the positive control drug Cabozantinib.

(XL184, clinical drug, 60.9 nM) has a large increase, which is 3-4 times that of XL184. Furthermore, the two compounds also showed good inhibitory activity against VEGFR2 and EGFR. Among them, the inhibitory activity of compound V on VEGFR2 and EGFR (VEGFR2, IC ₅₀ = 31.7 nM; EGFR, IC50 = 1.05 μΜ) is the positive control drug XL184

(VEGFR2, IC ₅₀ = 74.8 nM _; EGFR, IC ₅₀ = 3.74 μΜ) 2 to 3 times. Pharmacological tests have shown that the compound of the present invention has a great significance for improving the inhibitory activity of the compound when used as a synthon for preparing a novel antitumor compound, suggesting that the benzopyridinium compound of the present invention is a novel antibiotic. When the synthon of the tumor active compound is used, it has a multi-target anti-enzyme action and a stronger anti-tumor effect.

In summary, the compound of the present invention is used as a synthon for preparing a novel antitumor active compound, and the obtained compound has an improved inhibitory activity in vitro, and exhibits multi-target inhibition effect, and has significant scientific progress and in-depth research. Development value. difficult

The present invention will be further described in detail below with reference to the embodiments, but the embodiments of the invention are not limited thereto.

Example 1

Synthesis of benzyl-4-chloro-3-nitro-N-phenylpyridine-2-amine (Intermediate 3-1)

2,4-Dichloro-3-nitropyridine ( 1.93 g, 10 mmol) and K ₂ C0 ₃ ( 1.66 g, 12 mmol) were dissolved in DMF 10 mL, and N-benzyl group was slowly added dropwise thereto. 10 mL of aniline (1.83 g, 10 mmol) in DMF was stirred at room temperature for 12 h. After the reaction was completed, the mixture was diluted with EtOAc (30 mL), EtOAc (EtOAc)EtOAc. After filtration and concentration, the obtained solid was recrystallized from ethanol to yield 2.91 g of a yellow solid.

ESI-MS [M+H] ⁺ : m/z 340.3

^{! H NMR 8ppm (400MHz, DMSO} -de): 8.40 (d, 1H, J = 7 Hz, pyridine-6-H), 6.87-7.84 (m, 11H, Ar-H, pyridine-5-H), 4.53 (s, 2H, CH ₂ ).

Example 2

Synthesis of Benzyl-4-chloro-N ² -phenylpyridin-2,3-diamine (Intermediate 4-1)

Intermediate 3-1 (3.40 g, 10 mmol) was dissolved in a mixture of 40 mL of ethanol and 10 mL of water, and iron powder ( 1.68 g, 30 mmol) and NH ₄ C1 (0.32 g, 6 mmol) were added thereto. The temperature was raised to reflux and the reaction was stirred for 5 h. After the reaction was cooled to room temperature, filtered through celite, the filtrate was concentrated, 50 mL diluted with ethyl acetate and saturated NaHC0 ₃ solution, water and saturated brine, the organic layer was dried over anhydrous sodium sulfate, respectively. Filtration, concentrating, and EtOAc EtOAc (EtOAc):

ESI-MS [M+H] ⁺ : m/z 310.4

^{! H NMR (400MHz, DMSO-} de) 8ppm: 8.02 (d, 1H, J = 8 Hz, pyridine-6-H), 6.85-7.79 (m, 11H, Ar-H, pyridine-5-H), 5.25 (s, 2H, NH ₂ ), 4.51 (s, 2H, CH ₂ ).

Example 3

Synthesis of N-{2-[benzyl(phenyl)amino]-4-chloro-pyridin-3-yl]carboxamide (Intermediate 5-1) 8 mL of acetic anhydride was added dropwise to 20 mL of a formic acid solution containing Intermediate 4-1 (3.10 g, 10 mmol) at 0 ° C, and the mixture was stirred at 20 ° C for 2 h. After completion of the reaction, the solvent was evaporated to dryness, and the solvent was evaporated to the residue, and the solvent was evaporated, and the mixture was twice, to give a white solid, 3.30 g, yield 97.7%. The product does not require purification and can be directly subjected to the next reaction.

ESI-MS [M+H] ⁺ : m/z 338.7

^{! H NMR 8ppm (400MHz, DMSOd} 6): 9.17 (s, 1H, CHO), 8.45 (s, 1H, NHCHO), 8.11 (d 1H, J = 8 Hz, pyridine-6-H), 6.91-7.85 ( m, 11H, Ar-H, pyridine-5-H), 4.51 (s, 2H, CH ₂ ).

Example 4

Synthesis of 4-chloro-11H-benzopyridine [3,2-b][l,4]diazepine (target compound 1-1 )

Intermediate 5-1 (34 g, 1 mmol) and BPA (0.51 g, 1.5 mmol) were dissolved in 6 mL of POCl ₃ and refluxed overnight. After the reaction is completed, the solvent is evaporated to dryness, and the residue is diluted with water (20 mL), ethyl acetate (15 mL x 3 ), and the aqueous layer is adjusted to pH 9 to 10 with 1 N NaOH solution and extracted with ethyl acetate (10 mL x 2) The organic layer was combined, washed with saturated aqueous NaHCO? The residue was purified by column chromatography eluting with petroleum ether: ethyl acetate (V/V, 5:1) to give 11-benzyl-4-chloro-11H-benzopyridine [3,2-b][ l,4] Diazepine is a yellow solid 0.17 g, yield 53.1%.

The obtained solid (0.17 g, 0.53 mmol) was dissolved in dichloromethane (2 mL), and ethyl 1-chloroethyl chloroformate (0.38 g, 2.66 mmol) was added thereto, and the mixture was refluxed for 2 h. Then, the solvent was evaporated, and 1 mL of methanol was added thereto, and the mixture was further stirred under reflux for 1 hour. After completion of the reaction, the solvent was evaporated to dryness, 15 mL of methylene chloride was added and 15 mL of saturated NaHC0 ₃ solution, the organic layer was separated, with saturated NaHC0 ₃ solution and saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give debenzylation The base product target compound 1- 1 was a pale yellow solid, 0.08 g, yield 66.7%.

ESI-MS [M+H] ⁺ : m/z 230.5

^{! H NMR (400MHz, DMSO-} d 6) 8ppm: 9.27 (s, 1H, Ar-NH), 8.81 (s, 1H, C (H) = N), 7.95 (d, 1H, J = 8 Hz, pyridine -6-H), 7.23-7.79 (m, 5H, Ar-H, pyridine- 5 -H).

Example 5

Synthesis of 4-chloro-benzopyrazole[2,3-6][l,4]oxazepine (target compound 1-2)

Starting from 2,4-dichloro-3-nitropyridine and phenol, the carboxamide intermediate 5 was prepared according to Example 1, Example 2 and Example 3, and then the ring-closing product was prepared according to Example 4. 1-2, the yield was 58.3%.

ESI-MS [M+H] ⁺ : m/z 231.7

^{! H NMR (400MHz, DMSO-} de) 8ppm: 8.81 (s, 1H, C (H) = N), 7.23-7.64 (m, 6H, Ar-H, pyridine-5,6-2H).

Example 6

Synthesis of 4-chloro-benzopyrazole[2,3-6][l,4]thiazepine (target compound 1-3) Starting from 2,4-dichloro-3-nitropyridine and thiophenol, the formamide intermediate 5 was prepared according to Example 1, Example 2 and Example 3, and then the target was prepared according to Example 4. Compound 1-3, yield 50.2%.

ESI-MS [M+H] ⁺ : m/z 247.5

^{_{! H NMR (400MHz, DMSOd 6}} ) 8ppm: 8.81 (s, IH, C (H) = N), 8.30 (d, IH, J = 8 Hz, pyridine-6-H), 7.33-7.82 (m, 5H , Ar-H, pyridine -5 -H).

Example 7

Synthesis of 4-chloro-6,11-dihydro-5H-benzopyridine [3,2-ό][1,4]diazepine (target compound 1-4)

Starting from 2,4-dichloro-3-nitropyridine and aniline, 4-chloro-phenylpyridin-2,3-diamine (intermediate 4-) was prepared according to Example 1 and Example 2. 4).

Intermediate 4-4 (1.10 g, 5 mmol), paraformaldehyde (0.23 g, 7.5 mmol) and anhydrous magnesium sulfate (1.20 g, 10 mmol) were dissolved in dichloromethane (20 mL). Acetic acid (0.33 mL, 4.5 mmol) was warmed to 40 ° C and stirred overnight. After completion of the reaction, it was cooled to room temperature, filtered, and the filter cake was stirred with 20 mL of dichloromethane. The methylene chloride layer was combined and washed with 20 mL of water and 20 mL of brine. The organic layer was dried, filtered and concentrated. EtOAc EtOAc EtOAc After cooling, filtration gave a pale yellow solid (yield: 0.75 g, yield: 64.7%).

ESI-MS [M+H] ⁺ : m/z 232.4

^{_{! H NMR (400MHz, DMSOd 6}} ) 8ppm: 9.26 (s, IH, Ar-NH), 7.83 (d, IH, J = 8 Hz, pyridine-6-H), 6.65-7.19 (m, 5H, Ar- H, pyridine -5 -H), 5.58 (s, IH, CH ₂ NH), 4.20 (s, 2H, Example 8

Synthesis of 4-chloro-5,6-dihydrobenzopyridine [2,3-6][l,4]oxazepine (target compound 1-5)

Using the 2,4-dichloro-3-nitropyridine and phenol as starting materials, the title compound 1-5 was obtained according to Example 7, yield 67.2%.

ESI-MS [M+H] ⁺ : m/z 233.7

^{! H NMR 8ppm (400MHz, DMSO} -d 6): 6.72-7.15 (m, 6H, Ar-H), 5.72 (s, IH, CH 2 NH), 4.180, 2H, CH 2).

Example 9

Synthesis of 4-chloro-5,6-dihydrobenzopyridine [2,3-6][l,4]thiazepine (target compound 1-6)

Using 2,4-dichloro-3-nitropyridine and thiophenol as raw materials, the target compound can be prepared according to Example 7.

1-6, yield 63.8%.

ESI-MS [M+H] ⁺ : m/z 249.6

^{! H NMR (400MHz, DMSO-} de) 8ppm: 7.87 (d, IH, J = 8 Hz, pyridine-6-H), 6.72-7.15 (m, 5H, Ar-H, pyridine-5-H), 5.70 (s, IH, CH ₂ NH), 4.19 (s, 2H, CH ₂ ).

Example 10

Synthesis of 4-chloro-2-methyl-11H-benzopyridine [3,2-ό][1,4]diazepine (target compound 1-7)

Starting from 2,4-dichloro-6-methyl-3-nitropyridine and N-benzylaniline, the carboxamide intermediate 5 was prepared according to Example 1, Example 2 and Example 3, followed by implementation. Example 7, the target compound 1-7 can be prepared, yield

55.9%.

ESI-MS [M+H] ⁺ : m/z 244.3

¹ H NMR (400MHz, DMSO-de) 8ppm: 9.25 (s, IH, Ar-NH), 8.80 (s, IH, C(H)=N), 7.23-7.62 (m, 4H, Ar-H), 6.89 (s, IH, pyridine-5-H), 2.58 (s, 3H, CH ₃ ).

Example 11

Synthesis of 4-chloro-2-methyl-6,11-dihydro-5H-benzopyridine [3,2-ό][1,4]diazepine (target compound 1-8)

Starting from 2,4-dichloro-6-methyl-3-nitropyridine and aniline, the title compound 1-8 was prepared according to Example 1, Example 2 and Example 4 in a yield of 65.1%. .

ESI-MS [M+H] ⁺ : m/z 246.7

^{! H NMR 8ppm (400MHz, DMSO} -d 6): 9.26 (s, IH, Ar-NH), 6.51-7.19 (m, 5H, Ar-H, pyridine-5H), 5.54 (s, IH, CH ₂ NH), 4.19 (s, 2H, CHzNH), 2.58 (s, 3H, CH ₃ ).

Example 12

Synthesis of 4-chloro-11H-benzopyr[3,2-indene][1,4]diazepine-3-carbonitrile (target compound 1-9)

Starting from 5-amino-4,6-dichloronicotinonitrile and aniline, the carboxamide intermediate 5 was prepared according to Example 1, Example 2 and Example 3, and then the target compound 1 was prepared according to Example 7. -9, yield 48.9%.

ESI-MS [M+H] ⁺ : m/z 244.3

¹ H NMR (400MHz, DMSO-d ₆ ) 8ppm: 9.25 (s, IH, Ar-NH), 8.80 (s, IH, C(H)=N), 7.23-7.62 (m, 4H, Ar-H) , 6.89 (s, IH, pyridine-5-H), 2.58 (s, 3H, CH ₃ ).

Example 13

Synthesis of 4-chloro-3-methyl-11H-benzopyridine [3,2-ό][1,4]diazepine (target compound 1-10)

Using 4,6-dichloro-5-methylpyridin-3-amine and aniline as raw materials, followed by Example 1, Example 2 and Examples

3 Preparation of Formamide Intermediate 5 Next, the title compound 1-10 was obtained according to Example 7, yield 52.6%.

ESI-MS [M+H] ⁺ : m/z 255.7

^{! H NMR (400MHz, DMSO-} d 6) 8ppm: 9.27 (s, IH, Ar-NH), 8.85 (s, IH, C (H) = N), 8.67 (s, IH, pyridine -6-H) , 7.26-7.71 (m, 4H, Ar-H).

Example 14

Synthesis of 4-chloro-3-methoxy-11H-benzopyridine [3,2-ό][1,4]diazepine (target compound 1-11) Starting from 4,6-dichloro-5-methoxypyridin-3-amine and aniline, the carboxamide intermediate 5 was prepared according to Example 1, Example 2 and Example 3, followed by Example 7, ie The target compound 1-11 can be produced in a yield of 54.2%.

ESI-MS [M+H] ⁺ : m/z 260.6

^{! H NMR (400MHz, DMSO-} de) 8ppm: 9.23 (s, 1H, Ar-NH), 8.80 (s, 1H, C (H) = N), 7.81 (s, 1H, pyridine -6-H), 7.16-7.58 (m, 4H, Ar-H), 3.98 (s, 3H, OCH ₃ ).

Example 15

Synthesis of 4-chloro-3-fluoro-11H-benzopyridine [3,2-ό][1,4]diazepine (target compound 1-12)

Starting from 4,6-dichloro-5-fluoropyridin-3-amine and aniline, the carboxamide intermediate 5 was prepared according to Example 1, Example 2 and Example 3, and then prepared according to Example 7. Target compound 1- 12, yield 51.8%.

ESI-MS [M+H] ⁺ : m/z 248.3

¹ H NMR (400MHz, DMSO-d ₆ ) 8ppm: 9.25 (s, 1H, Ar-NH), 8.80 (s, 1H, C(H)=N), 7.24-7.66 (m, 5H, Ar-H, Pyridine-6-H).

Example 16

I

Synthesis of 4-chloro-11-methyl-11H-benzopyridine [3,2-6][l,4]diazepine (target compound 1-13)

Starting from 2,4-dichloro-3-nitropyridine and N-methylaniline, the formamide intermediate 5 was prepared according to Example 1, Example 2 and Example 3, and then according to Example 7, The target compound 1-13 was prepared in a yield of 58.3 %.

ESI-MS [M+H] ⁺ : m/z 244.7

^{! H NMR (400MHz, DMSO-} de) 8ppm: 9.25 (s, 1H, Ar-NH), 8.80 (s, 1H, C (H) = N), 8.35 (d, 1H, J = 8 Hz, pyridine- 6-H), 7.25-7.82 (m, 5H, Ar-H, pyridine-5-H), 3.50 (s, 3H, CH ₃ ).

Example 17

Synthesis of 4-chloro-5-methyl-6,11-dihydro-5H-benzopyridine [3,2-ό][1,4]diazepine (target compound 1- 14)

Starting from 4,6-dichloropyridin-3-amine and N-benzylaniline, according to Example 1, Example 2 and Example 4, 11-benzyl-4-chloro-6,11 can be prepared. -Dihydro 5H-benzopyridine [3,2-6][1,4]diazepine.

Take 11-benzyl-4-chloro-6,11-dihydro 5H-benzopyridine [3,2-6][1,4]diazepine (0.64 g, 2 mmol) and methyl iodide (0.57 g, 4 mmol) was dissolved in DMF 10 mL, and K ₂ C0 ₃ (0. 55 g, 4 mmol) was added thereto, and the mixture was stirred at room temperature for 4 h. After completion of the reaction, the mixture was filtered, and the solvent was evaporated to dryness. After suction filtration, the obtained solid was purified by EtOAcjjjjjjjjj The obtained solid was subjected to the removal of the benzyl group by the method of Example 7 to give the title compound 1-14, yield: 80.5%.

ESI-MS [M+H] ⁺ : m/z 246.8

^{_{! H NMR (400MHz, DMSOd 6}} ) 8ppm: 9.26 (s, 1H, Ar-NH), 7.75 (d, 1H, J = 8 Hz, Pyridine-6-H), 6.59-7. 11 (m, 5H, Ar-H, pyridine -5 -H), 4.20 (s, 2H, CH ₂ NH), 2.21 (s, 3H, CH ₃ ).

Example 18

1-(4-Chloro-6,11-dihydro-5H-benzopyridine [3,2-indolyl][1,4]diazepin-5-yl)ethyl ketone (target compound 1-15) Synthesis

Take 11-benzyl-4-chloro-6,11-dihydro 5H-benzopyridine [3,2-6][1,4]diazepine (0.64 g, 2 mmol) and triethylamine (0.30 g) , 3.0 mmol) was dissolved in THF 10 mL, to which was added dropwise acetyl chloride under ice-cooling (0.19 g, 2.4 mmol) ₀ dropwise, the reaction was stirred at room temperature for 2 h. After completion of the reaction, the solvent was evaporated to dryness, and then filtered and evaporated. The obtained solid was subjected to the removal of the benzyl group according to the procedure of Example 7 to give the title compound 1-15, yield 78.3%.

ESI-MS [M+H] ⁺ : m/z 274.9

^{! H NMR 8ppm (400MHz, DMSOd} 6): 9.26 (s, 1H, Ar-NH), 7.81 (d, 1H, J = 8 Hz, pyridine-6-H), 6.61-7.14 (m, 5H, Ar- H, pyridine -5 -H), 4.25 (s, 2H, CH2NH), 2.03 (s, 3H, CH ₃ ).

Example 19

Synthesis of 4-chloro-8-methoxy-11H-benzopyridine [3,2-ό][1,4]diazepine (target compound 1-16)

Starting from 2,4-dichloro-3-nitropyridine and N-benzyl-4-methoxyaniline, the carboxamide intermediate 5 was prepared according to Example 1, Example 2 and Example 3, followed by In Example 7, the target compound 1-16 was obtained in a yield of 53.1%.

The above 1-16 (0.20 g) was dissolved in hot ethanol (5 mL), and a solution of methanesulfonic acid in ethanol was added thereto, and the mixture was heated under reflux for 30 min, and then concentrated, evaporated, evaporated, evaporated, and evaporated. A solid, i.e., a methanesulfonate compound of 1-16.

ESI-MS [M+H] ⁺ : m/z 260.6

^{! H NMR (400MHz, DMSO-} de) 8ppm: 9.25 (s, 1H, Ar-NH), 8.80 (s, 1H, C (H) = N), 8.25 (d, 1H, J = 8 Hz, pyridine- 6-H), 6.87-7.62 (m, 4H, Ar-H, pyridine-5-H), 4.15 (s, 3H, OCH ₃ ).

Example 20

Synthesis of 4-chloro-8,9-dimethoxy-11H-benzopyridine [3,2-ό][1,4]diazepine (target compound 1-17)

Formamide intermediate 5 was prepared according to Example 1, Example 2 and Example 3 using 2,4-dichloro-3-nitropyridine and N-benzyl-3,4-dimethoxyaniline as starting materials. Then, according to Example 7, the title compound 1-17 was obtained in a yield of 50.2%.

The above 1-17 (0.20 g) was dissolved in 1 mol/L hydrochloric acid/ethanol (5 mL), concentrated, evaporated to dryness, and then recrystallized from ethanol, and the solid was solidified to be 1-17 hydrochloric acid. Salt compound.

ESI-MS [M+H] ⁺ : m/z 290.5 ^{! H NMR (400MHz, DMSO-} d 6) 8ppm: 9.24 (s, 1H, Ar-NH), 8.75 (s, 1H, C (H) = N), 8.23 (d, 1H, J = 8 Hz, pyridine -6-H), 6.42-7.53 (m, 3H, Ar-H, pyridine-5-H), 4.15 (s, 6H, 2xOCH ₃ ).

Example 21

4-{3-[(4-Chloro-8-methoxy-11H-benzopyridine [3,2-indolyl][1,4]diazepin-9-yl)oxy]propyl}morpholine Synthesis of (target compound 1- 18)

Using 2,4-dichloro-3-nitropyridine and N-benzyl-4-methoxy-3-(3-morpholinepropoxy)aniline as raw materials, followed by Example 1, Example 2 and Example 3 Preparation of Formamide Intermediate 5, followed by the preparation of the title compound 1- 18 in a yield of 47.6 %.

Dissolve the above 1-18 (0. 20 g) in hot ethanol (5 mL), slowly add concentrated sulfuric acid (98%) 0.1 mL, concentrate to evaporate the solvent, and recrystallize from ethanol to cool the solid. , that is, a sulfate compound of 1-18.

ESI-MS [M+H] ⁺ : m/z 403.9

^{! H NMR 8ppm (400MHz, DMSO} -d 6): 9.26 (s, 1H, Ar-NH), 8.71 (s, 1H, C (H) = N), 8.18 (d, 1H, J = 8 Hz, pyridine -6-H), 6.40-7.54 (m, 3H, Ar-H, pyridine-5-H), 4.16 (t, 2H, J = 5.6 Hz, CH ₂ 0), 3.98 (s, 3H, OCH ₃ ) , 3.68-3.76 (m, 4H, morpholine- ₃ , 5-2CH ₂ ), 2.56 (t, 2H, J = 6.2 Hz, NCH ₂ ), 2.45-2.51 (m, 4H, morpholine- ₂ , 6-2CH ₂ ), 2.11-2.13 (m, 2H, CH ₂ CH ₂ CH ₂ ).

Example 22

Synthesis of 4-chloro-9-methyl-11H-benzopyridine [3,2-ό][1,4]diazepine (target compound 1-19)

Starting from 2,4-dichloro-3-nitropyridine and N-benzyl-3-methylaniline, the carboxamide intermediate 5 was prepared according to Example 1, Example 2 and Example 3, followed by implementation. Example 7, the target compound 1-19 can be prepared, the yield

61.3%.

ESI-MS [M+H] ⁺ : m/z 244.6

^{! H NMR 8ppm (400MHz, DMSO} -de): 9.25 (s, 1H, Ar-NH), 8.78 (s, 1H, C (H) = N), 8.25 (d, 1H, J = 8 Hz, pyridine- 6-H), 7.21-7.74 (m, 4H, Ar-H, pyridine-5-H), 2.45 (s, 3H, CH ₃ ).

Example 23

Synthesis of 4-chloro-9-methyl-11H-benzopyridine [3,2-ό][1,4]diazepine (target compound 1-20)

Starting from 2,4-dichloro-3-nitropyridine and N-benzyl-4-fluoroaniline, the carboxamide intermediate 5 was prepared according to Example 1, Example 2 and Example 3, followed by the examples. 7, the target compound 1-20 was prepared in a yield of 64.7%.

ESI-MS [M+H] ⁺ : m/z 248.9

¹ H NMR (400MHz, DMSO-d ₆ ) 8ppm: 9.25 (s, 1H, Ar-NH), 8.80 (s, 1H, C(H)=N), 8.25 (d, 1H, J = 8 Hz, pyridine -6-H), 7.25-7.78 (m, 4H, Ar-H, pyridine- 5 -H).

Example 24 Synthesis of 4-chloro-11H-benzopyr[3,2-indolyl][1,4]diazepine-9-carbonitrile (target compound 1-21) as 2,4-dichloro-3-nitro Starting from pyridine and N-benzyl-3-cyanoaniline, the carboxamide intermediate 5 was prepared according to Example 1, Example 2 and Example 3, and then the target compound 1-21 was prepared according to Example 7. Yield

57.9%.

ESI-MS [M+H] ⁺ : m/z 254.8

¹ H NMR (400MHz, DMSO-d ₆ ) 8ppm: 9.25 (s, IH, Ar-NH), 8.84 (s, IH, C(H)=N), 8.25 (d, 1H, J = 8 Hz, pyridine -6-H), 7.26-7.87 (m, 4H, Ar-H, pyridine- 5 -H).

Example 25

Synthesis of 4-chloro-8-nitro-11H-benzopyridine [3,2-ό][1,4]diazepine (target compound 1-22)

Starting from 2,4-dichloro-3-nitropyridine and N-benzyl-4-nitroaniline, the carboxamide intermediate 5 was prepared according to Example 1, Example 2 and Example 3, followed by implementation. Example 7, the target compound 1-22 can be prepared, the yield

43.7%.

ESI-MS [M+H] ⁺ : m/z 275.4

^{! H NMR (400MHz, DMSO-} d 6) 8ppm: 9.25 (s, IH, Ar-NH), 8.80 (s, IH, C (H) = N), 8.36 (s, lH, Ar-H), 7.25 -8.25 (m, 4H, Ar-H, pyridine-5-H).

Example 26

Synthesis of 4-chloro-11H-benzopyridine [3,2-ό][1,4]diazepine-8-amine (target compound 1-23)

4-Chloro-8-nitro-11H-benzopyrazole [3,2-ό][1,4]diazepine (target compound 1-22) was used as the starting material, according to Example 2, by Fe/NH ₄ C1 was reduced to prepare the target compound 1-23 in a yield of 87.4%.

ESI-MS [M+H] ⁺ : m/z 245.7

¹ H NMR (400MHz, DMSO-d ₆ ) 8ppm: 9.25 (s, IH, Ar-NH), 8.80 (s, IH, C(H)=N), 8.25 (d, 1H, J = 8 Hz, pyridine -6-H), 6.87-7.63 (m, 4H, Ar-H, pyridine-5-H), 6.42 (s, 2H, NH ₂ ).

Example 27

3-[(;4-chloro-8-methoxy-11H-benzopyridine [3,2-indolyl][1,4]diazepin-9-yl)oxy]-N,N-dimethyl Synthesis of keto-1-propylamine (target compound 1-24)

Using 2,4-dichloro-3-nitropyridine and N-benzyl-3-[(3-dimethylamino)propoxy]-4-methoxyaniline as raw materials, followed by Example 1, Example 2 and Example 3 were prepared as the carboxamide intermediate 5, followed by the preparation of the title compound 1-24 in a yield of 50.4%.

The above 1-24 (0. 20 g) was dissolved in hot ethanol (5 mL), malic acid (0.1 g) was added thereto, and the mixture was heated under reflux for 30 min, then concentrated and evaporated to dryness. The precipitated solid is cooled to be a malate compound of 1-24.

ESI-MS [M+H] ⁺ : m/z 361.4 ^{! H NMR (400MHz, DMSO-} d 6) 8ppm: 9.24 (s, 1H, Ar-NH), 8.72 (s, 1H, C (H) = N), 8.19 (d, 1H, J = 8 Hz, pyridine -6-H), 6.40-7.58 (m, 3H, Ar-H, pyridine-5-H), 4.17 (t, 2H, J = 5.6 Hz, CH ₂ 0), 3.98 (s, 3H, OCH ₃ ) , 2.45 (t, 2H, J = 6.0 Hz, NCH ₂ ), 2.30 (s, 6H, N(CH ₃ ) ₂ ), 2.10-2.12 (m, 2H, CH2CH2CH2).

Example 28

Synthesis of 4-chloro-9- 1H-imidazole-5-yl)methoxy- 11H-benzopyridine [3,2-ό][1,4]diazepine (target compound 1-25 )

Using 2,4-dichloro-3-nitropyridine and N-benzyl-3-(lH-imidazol-5-yl)-4-methoxyaniline as raw materials, followed by Example 1, Example 2 and Example 3 Preparation of Formamide Intermediate 5, followed by the preparation of the title compound 1-25 in a yield of 47.2%.

ESI-MS [M+H] ⁺ : m/z 326.8

^{! H NMR 8ppm (400MHz, DMSO} -de): 13.02 (s, 1H, imidazole-NH), 9.26 (s, 1H, Ar-NH) 8.81 (s, 1H, C (H) = N), 7.21-8.34 (m, 6H, Ar-H, pyridine-5, 6-2H, imidazole-H), 3.98 (s, 3H, Example 29

4-chloro-8-methoxy-9-(thiophen-2-yloxy) > 11H-benzopyridine [3,2-indolyl][1,4]diazepine (target compound 1-26) Synthesis

Using 2,4-dichloro-3-nitropyridine and N-benzyl-4-methoxy-3-(thiophen-2-yloxy)aniline as raw materials, followed by Example 1, Example 2 and Example 3 Preparation of Formamide Intermediate 5, followed by the preparation of the title compound 1-26 in a yield of 49.5%.

The above 1-26 (0. 20 g) was dissolved in hot ethanol (5 mL), p-toluenesulfonic acid (0.1 g) was added thereto, and the mixture was heated under reflux for 30 min, then concentrated and evaporated to dryness. Recrystallization, cooling of the precipitated solid, which is a p-toluenesulfonate compound of 1-26.

ESI-MS [M+H] ⁺ : m/z 358.9

¹ H NMR (400MHz, DMSO-d ₆ ) 8ppm: 9.26 (s, 1H, Ar-NH), 8.80 (s, 1H, C(H)=N), 6.74-8.25 (m, 7H, Ar-H, Pyridine-5,6-2H, thiophene-H), 3.98 (s, 3H, OCH ₃ ).

Example 30

Synthesis of 4-chloro-8,9-dimethoxy-6,11-dihydro-5H-benzopyridine [3,2-indolyl][1,4]diazepine (target compound 1-27) 2,4-Dichloro-3-nitropyridine and 3,4-dimethoxyaniline were used as starting materials, and the target compound 1-27 was prepared according to Example 1, Example 2 and Example 4, yield. 62.7%.

ESI-MS [M+H] ⁺ : m/z 292.5

^{! H NMR (400MHz, DMSO-} de) 8ppm: 9.26 (s, 1H, Ar-NH), 6.51-7.19 (m, 4H, Ar-H, Pyridine-5,6-2H), 5.54 (s, IH, CH ₂ NH), 4.19 (s, 2H, CH, NH), 3.98 (s, 6H, 2xOCH ₃ ).

Example 31

4-{3-[(4-Chloro-8-methoxy-6,11-dihydro-5H-benzopyridine [3,2-indolyl][1,4]diazepin-9-yl)oxy Synthesis of propyl] morpholine (target compound 1-28)

Using 2,4-dichloro-3-nitropyridine and 4-methoxy-3-(3-morpholinepropoxy)aniline as raw materials, followed by Example 1, Example 2 and Example 4, The title compound 1-28 was obtained in a yield of 58.2%.

ESI-MS [M+H] ⁺ : m/z 406.0

^{! H NMR (400MHz, DMSO-} de) 8ppm: 9.26 (s, IH, Ar-NH), 6.45-7.12 (m, 4H, Ar-H, pyridine-5,6-2H), 5.26 (s, IH, CH ₂ NH), 4.19 (s, 2H, CH2NH), 4.16 (t, 2H, J = 5.6 Hz, CH ₂ 0), 3.98 (s, 3H, OCH3), 3.64-3.72 (m, 4H, morpholine-3 ,5-2CH ₂ ), 2.55 (t, 2H, J = 6.2 Hz, NCH ₂ ) 2.45-2.51 (m, 4H, morpholine- ₂ , 6-2CH ₂ ), 2.11-2.13 (m, 2H, CH ₂ CH2CH ₂ ).

Example 32

N-{4-[(8,9-Dimethoxy-11H-benzopyridine [3,2-indolyl][1,4]diazepin-4-yl)oxy]phenyl}-N- Synthesis of (4-fluorophenyl)cyclopropane-1,1-diamide (Compound V)

The compound of the invention 1- 17 (0.29 g, 1 mmol) and ΛΚ4-fluorophenyl)-indole 4-hydroxyphenyl)cyclopropane-1,1-diamide (intermediate 6) (0.47 g, 1.5 mmol) Cu powder (6.1 mg, 0.1 mmol) and B C3⁄4C0 ₃ (0.98 g, 3 mmol) were added to DMF 3 mL, placed in a microwave reactor, power set at 60 W, and stirred at 100 ° C for 10 Min. After the reaction is completed, the mixture is filtered, and the solvent is evaporated to dryness, and 10 mL of water is slowly added dropwise with stirring, and the solid is precipitated and purified by column chromatography. The solvent is petroleum ether: ethyl acetate (V/V, 1:1), and the target compound V is white. The solid was 0.23 g, and the yield was 40.5%.

ESI-MS [M+H] ⁺ : m/z 538.9

^{! H NMR (400MHz, DMSO-} dg) δρρηι: 10.09 (s, IH, C (O) NH), 10.07 (s, IH, C (O) NH), 9.23 (s, IH, NH), 8.62 (s , IH, C(H)=N), 6.78-7.79 (m, 12H, Ar-H), 4.15 (s, 6H, 2xOCH ₃ ),

Example 33

N-(4-fluorophenyl)-N-{4-[8-methoxy-9-0 morphinphyrinpropoxy)-llH-benzopyridine [3,2-ό][1,4] Synthesis of Nitrozol-4-yloxy]phenyl}cyclopropane-1,1-diamide (Compound VI)

Using the compound 1- 18 and the intermediate 6 of the present invention as a starting material, the title compound VI was obtained according to Example 32, yield 24.6%.

ESI-MS [M+H] ⁺ : m/z 681.3

^{! H NMR (400MHz, DMSO-} dg) δρρηι: 10.09 (s, IH, C (O) NH), 10.07 (s, IH, C (O) NH), 9.26 (s, IH, NH), 8.64 (s , IH, C(H)=N), 7.08-7.76 (m, 12H, Ar-H), 4.16 (t, 2H, J = 5.6 Hz, CH ₂ 0), 3.98 (s, 3H, OCH ₃ ), 3.68-3.76 (m, 4H, morpholine- ₃ , 5-2CH ₂ ), 2.56 (t, 2H, J = 6.2 Hz _: NCH ₂ ), 2.45- 2.51 (m, 4H, morpholine- ₂ , 6-2CH ₂ ), 2.11-2.13 (m, 2H, CH2CH2CH2), 1.46 (s,

Example 34

Inhibitory activity of compounds on c-Met, VEGFR2 and EGFR in vitro:

The EGFR enzyme (Cat: 14-526) kit from Millipore, the VEGFR2 enzyme (Cat: K2643) kit from Sigma and the EGFR (Cat: PV3872) kit from B Invitrogen were used to test the inhibition of the three enzymes. Enzyme IC _5Q test, the experimental operation is carried out according to the kit instructions. The experimental results are shown in Table 1.

Table 1 Results of in vitro inhibitory activities of compounds on c-Met, VEGFR2 and EGFR

ICso

Number c-Met VEGFR2 EGFR

(nM) (nM) ( μΜ)

XL184 60.9 74.8 3.74

V 15.0 31.7 1.05

VI 18.4 45.6 1.21

It can be seen from the above Table 1 that the compound V and the compound VI synthesized by using the compound of the present invention as an intermediate have an inhibitory activity against c-Met (IC ₅ : V, 15.0 nM; VI, 18.4 nM ) than the positive control drug Cabozantinib ( XL184, Phase III clinical drug, 60.9 nM) has a large improvement, which is 3-4 times that of XL184. In addition, the two compounds also showed good inhibitory activity against VEGFR2 and EGFR, showing a multi-target inhibition effect. Among them, the inhibitory activity of compound V on VEGFR2 and EGFR (VEGFR2, ICso = 31.7 nM; EGFR, IC ₅₀ = 1.05 μΜ) were positive control drug XL184 (VEGFR2, IC ₅₀ = 74.8 nM; EGFR, IC ₅₀ = 3.74 μΜ). 2 to 3 times.

Claims

Claim

A benzopyridinium azide compound characterized by having a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof:

among them-

X is selected from halogen;

Y is selected from NH, NHBn, NCH ₃ , 0 or S;

Selected from H or methyl;

R _{2 is} selected from H, CN, methyl, methoxy or fluoro;

The substituted phenyl or substituted heterocyclic group is a phenyl or heterocyclic group having 1 to 4 substituents, and the substituent is a hydroxyl group, a methoxy group, a methyl group or an amino group;

R _{6 is} selected from hydrogen, d- ₅ straight or branched alkyl, aryl, aralkyl, heterocyclic, heterocycloalkyl, substituted d- ₅ alkyl, substituted aryl, substituted aralkyl, Substituted heterocyclic or substituted heterocycloalkyl;

Wherein - the substituted heterocyclic group or substituted heterocycloalkyl group is a heterocyclic group or a heterocycloalkyl group having 1 to 4 substituents, and the substituent is preferably a hydroxyl group, a methoxy group, a methyl group or an amino group;

R _{5 is} divided into two cases:

When the seven-membered ring is C=N, there is no R _{5 ;}

When the seven-membered ring is CN, R _{5 is} selected from H, C ₁₄ alkyl or C ₁₄ acyl.

The benzopyridinium azide compound according to claim 1, wherein the Cw alkyl group represented by R ₃ and R ₄ is a methyl group, an ethyl group or an isopropyl group.

The benzopyridinium azide compound according to claim 1, wherein the substituted amino group represented by the group is d- ₅ alkylamino, morpholine-N-propylamino, piperidine-4-methyl Amino or piperidin-1-propyl.

The benzopyridinium azide compound according to claim 1, wherein the heterocyclic group represented by and is morphinolin-1-yl, piperidinyl-pyridyl or piperidin-1-yl.

The benzopyridinium azide compound according to claim 1, wherein the d- ₅ straight chain or branched alkyl group represented by R ₆ is a methyl group, an ethyl group or an isopropyl group.

The benzopyridinium azide compound according to claim 1, wherein the aryl group represented by R ₆ is a phenyl group.

The benzopyridinium azide compound according to claim 1, wherein the aralkyl group represented by the formula is a benzyl group, a 3,4-dimethoxybenzyl group or a 3-(3,4-di) group. Methoxyphenoloxy)propyl.

The benzopyridinium azide compound according to claim 1, wherein the heterocyclic group represented by R ₆ is an imidazolyl group, a thiazolyl group or a pyridyl group.

The benzopyridinium azide compound according to claim 1, wherein the heterocycloalkyl group is morphinylpropyl, piperidin-4-methyl, piperidin-1-propyl, N-methylpiperidin-1-propyl or pyrrolidinylpropyl.

The benzopyridinium azide compound according to claim 1, wherein the substituted C alkyl group represented by R ₆ is a methylol group, an aminomethyl group, a 3-(hydroxy)propyl group or 3 - (Dimethylamino)propyl.

The benzopyridinium azide compound according to claim 1, wherein the substituted aryl group represented by R ₆ is 3,4-dimethoxyphenyl, 4-methylphenyl, 4 -Aminophenyl or 4-fluorophenyl.

According to claim 1, the pyridine-benzo diazepine compound, wherein, R ₅ represents C _w of alkyl groups are methyl, R ₅ represents Cw of the acyl group is acetyl.

13. A benzopyridinium azide compound, characterized by comprising:

1-1 4-Chloro-11H-benzopyridine [3,2-6][1,4]diazepine,

1-2 4-chloro-benzopyridine [2,3-6][ 1,4]oxazepine,

1-3 4-chloro-benzopyridine [2,3-6][1,4]thiazepine,

1-4 4-chloro-6,11-dihydro-5H-benzopyridine [3,2-6][1,4]diazepine,

1-5 4-Chloro-5,6-dihydrobenzopyridine [2,3-6][1,4]oxazepine,

1-6 4-Chloro-5,6-dihydrobenzopyridine [2,3-6][1,4]thiazepine,

I -7 4-chloro-2-methyl- 11H-benzopyridine [3,2-6] [ 1 ,4]diazepine, 1-8 4-chloro-2-methyl-6,11-dihydro-5H-benzopyridine [3,2-6][l,4]diazepine,

1-9 4-Chloro-11H-benzopyridine [3,2-6][1,4]diazepine-3-carbonitrile,

1-10 4-chloro-3-methyl-11?-benzopyridine [3,2-6][1,4]diazepine,

1-11 4-Chloro-3-methoxy-11 benzopyridine [3,2-6][1,4]diazepine,

1-12 4-chloro-3-fluoro-11?-benzopyridine [3,2-6][1,4]diazepine,

1-13 4-Chloro-11-methyl-11 benzopyridine [3,2-6][1,4]diazepine,

1-14 4-Chloro-5-methyl-6,11-dihydro-5^benzopyridine [3,2-6][1,4]diazepine,

1-16 4-Chloro-8-methoxy-11?-benzopyridine [3,2-6][1,4]diazepine,

1-17 4-Chloro-8,9-dimethoxy-11 benzopyridine [3,2-6][1,4]diazepine,

I - 19 4-chloro-9-methyl- 11H-benzopyridyl [3,2-6] [ 1 ,4]diazepine,

1-20 4-chloro-8-fluoro-11H-benzopyridine [3,2-6][1,4]diazepine,

1-21 4-Chloro-11H-benzopyridine [3,2-6][1,4]diazepine-9-carbonitrile,

1-22 4-Chloro-8-nitro-11H-benzopyridine [3,2-6][1,4]diazepine,

1-23 4-Chloro-11H-benzopyridine [3,2-6][1,4]diazepine-8-amine,

1-27 4-Chloro-8,9-dimethoxy-6,11-dihydro-5H-benzopyridine [3,2-6][1,4]diazepine or

1-28 4-{3-[(4-Chloro-8-methoxy-6,11-dihydro-5H-benzopyridine [3,2-6][1,4]diazepine-9- Alkyloxypropylmorpholine.

The benzopyridinium azide compound according to any one of claims 1 to 13, wherein the salt is a hydrochloride, a hydrobromide, a sulfate, an acetate, or a lactic acid. Salt, tartrate, citrate, citrate, trifluoroacetate, malate, maleate, succinate, p-toluenesulfonic acid or methanesulfonate.

The use of the benzopyridinium azide compound according to any one of claims 1 to 14, which is characterized in that it is used for the preparation of an antitumor active compound.