RU2821945C1 - Compound, method for preparation and use thereof for producing anticancer drug - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention relates to a pyrazolo[3,4-d]pyrimidine compound of formula (I), use thereof for preparing an anticancer drug and a pharmaceutical composition. In formula (I): Ar is R is H, CF₃, (CH₃)₂NCH₂ or CH₃ and the linker is and said compound also includes compound 25 and compound 26.

EFFECT: disclosed compounds have an inhibitory effect on FGFR to block the FGF/FGFR signaling pathway and can be used to treat cancer associated with FGFR.

5 cl, 4 dwg, 2 tbl, 44 ex

Description

[0001] The present invention claims priority to Chinese Patent Application No. 202011483614.1, filed with the China National Intellectual Property Administration (CNIPA) on December 16, 2020, entitled "Compound, Method of Preparation Thereof and Use thereof for the Preparation of an Anti-Cancer Drug", the entire contents of which are incorporated in this application by reference.

Field of technology to which the invention relates

[0002] The present invention relates to the field of pharmaceutical technology and, in particular, to a 2H-pyrazolo[3,4-d]pyrimidine derivative, a method for its preparation and its use for the production of an anticancer drug.

State of the art

[0003] Fibroblast growth factor receptors (FGFRs) are members of the receptor tyrosine kinase (RTK) family and are receptor protein tyrosine kinases (RPTKs), including four highly conserved transmembrane tyrosine kinases: FGFR1, FGFR2, FGFR3 and FGFR4. The FGFR signaling pathway involves a ligand binding to the receptor to induce FGFR dimerization, thereby causing cascade activation of downstream signaling pathways such as Ras-MAPK, PI3K-Akt, STAT, and PLCγ. FGFRs play important roles in various cellular functions such as cell proliferation and differentiation, as well as biological processes including development, angiogenesis, homeostasis, and wound healing. According to studies ^(1-3) , 7.1% of cancer patients have FGFR disorders. For example, FGFR1 amplification was most commonly observed in patients with squamous cell non-small cell lung cancer (NSCLC) with a proportion of 20%, and was observed in 10% of patients with breast cancer, 5% of patients with ovarian cancer, and 3% of patients with bladder cancer. Currently, FGFR2 mutations are found in gastric cancer (10%), endometrial cancer (12%), squamous cell NSCLC (5%), and triple negative breast cancer (TNBC) (4%); and FGFR3 mutations are well known in bladder cancer (50% to 60%) and myeloma (15% to 20%). Disruption of FGF19/FGFR4 signaling is closely associated with hepatocellular carcinoma (HCC). Therefore, the development of a novel selective FGFR inhibitor to block the FGF/FGFR signaling pathway represents a promising therapeutic strategy for the treatment of FGFR-associated cancers ^(4–5) .

[0004] Researchers are seeking to develop an FGFR inhibitor as a new anticancer agent for the treatment of FGFR-associated cancers. Several multitargeted tyrosine kinase inhibitors (TKIs) were initially used to treat cancers associated with FGFR abnormalities ⁽⁶⁾ , such as dovitinib (TKI-258), lucitanib (E-3810) ⁽⁷⁾ , nintedanib (BIBF-1120) ^{(8 )} and ponatinib (AP-24534) ⁽⁹⁾ . These previously developed FGFR inhibitors are nonselective ⁽¹⁰⁾ . Subsequently, several FGFR-selective TKIs with different scaffolds were developed. Several TKIs are currently in various stages of clinical development, such as AZD-4547 (Phase III) ⁽¹¹⁾ , BGJ-398 (Phase II) ⁽¹²⁾ , LY-2874455 (Phase II) ⁽¹³⁾ and JNJ-42756493 . (phase II) ⁽¹⁴⁾ and these selective FGFR inhibitors are ATP-competitive inhibitors that bind to the active form of FGFR. In addition, FGFR inhibitors developed by many pharmaceutical chemistry laboratories have been reported ^(15–21) .

The essence of the invention

[0005] The technical problems/objectives solved by the present invention include at least overcoming the disadvantages of the prior art and creating a 2H-pyrazolo[3,4-d]pyrimidine derivative, developing a method for its preparation, and using it to obtain anticancer drug.

[0006] To solve the above problems, the present invention discloses the following technical solutions:

[0007] The present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof:

[0008] formula I,

[0009] where Ar represents any element selected from the group consisting of a substituted aryl and a substituted heterocyclic group;

[0010] R is any structure selected from the group consisting of H, alkyl, aryl, -CF ₃ and alkyl-tert-amine; And

[0011] The linker is any linker selected from the group consisting of alkyl, alkoxy, heteroatom substituent and substituted N-heterocyclic ring.

[0012] Preferably Ar is [0013] Preferably R is H, CF ₃ , (CH ₃ ) ₂ NCH ₂ or CH ₃ .

[0014] Preferably the linker is or

[0015] Preferably, the compound is selected from the group consisting of compound 1 - compound 40:

connection 1, connection 2, connection 3, connection 4, connection 5, connection 6, connection 7, connection 8, connection 9, connection 10, connection 11, connection 12, connection 13, connection 14, connection 15, connection 16, connection 17, connection 18, connection 19, connection 20, connection 21, connection 22, connection 23, connection 24, connection 25, connection 26, connection 27, connection 28, connection 29, connection 30, connection 31, connection 32, connection 33, connection 34, connection 35, connection 36,

connection 37, connection 38, connection 39 and connection 40.

[0016] The present invention also relates to a method for producing a compound or a pharmaceutically acceptable salt thereof in accordance with the above technical solution with the following synthesis method:

[0017]

[0018] Preferably, the production method may include the following steps:

[0019] subjecting the compound with the structure shown in formula a and the compound with the structure shown in formula b to the Mitsunobu reaction at room temperature for 4 hours to obtain a compound with the structure shown in formula c;

[0020] subjecting the compound with the structure shown in formula c and the compound with the structure shown in formula d to a Suzuki coupling reaction at a temperature of 80°C to obtain a compound with the structure shown in formula e;

[0021] subjecting the compound with the structure shown in formula e and trifluoroacetic acid (TFA) to a deprotection reaction at a temperature of 0°C to obtain a compound with the structure shown in formula f; And

[0022] subjecting a compound with the structure shown in formula f to an acylation reaction at room temperature to produce a compound with the structure shown in formula I.

[0023] formula a, formula b, formula c, Ar-B(OH) ₂ formula d, formula e and formula f.

[0024] The present invention also relates to the use of a compound or a pharmaceutically acceptable salt thereof in accordance with the above technical solution for the preparation of a tumor cell proliferation inhibitor, wherein the tumor cell is a tumor cell associated with an FGFR abnormality.

[0025] Preferably, the tumor cell includes NCI-H1581 or SNU-16.

[0026] The present invention also relates to the use of a compound or a pharmaceutically acceptable salt thereof in accordance with the above technical solution for blocking the fibroblast growth factor (FGF)/FGFR signaling pathway in a tumor cell, where the tumor cell is a tumor cell associated with an FGFR abnormality.

[0027] Preferably, the tumor cell includes NCI-H1581 or SNU-16.

[0028] The present invention also relates to a pharmaceutical composition containing a compound or a pharmaceutically acceptable salt thereof in accordance with the above technical solution, wherein the pharmaceutical composition further contains one or more pharmaceutically acceptable excipients; And

[0029] The dosage form of the pharmaceutical composition is any pharmaceutically acceptable dosage form.

[0030] The present invention also relates to the use of a compound or a pharmaceutically acceptable salt thereof according to the above technical solution or a pharmaceutical composition according to the above technical solution for the preparation of a medicament for the treatment and/or prevention of cancer.

[0031] Preferably, the cancer is a cancer associated with an FGFR abnormality.

[0032] The present invention also relates to the use of a pharmaceutical composition in accordance with the above technical solution for obtaining an irreversible pan-FGFR inhibitor.

[0033] The present invention also relates to a method of treating cancer, comprising the following step:

[0034] administering an anticancer drug to a patient via oral administration or intraperitoneal injection,

[0035] wherein the anticancer drug includes a compound or a pharmaceutically acceptable salt thereof according to the above technical solution.

[0036] Preferably, the anticancer drug includes compound 10 or compound 36.

[0037] Preferably, the anticancer drug is administered at a dose of 50 mg/kg or 100 mg/kg; And

[0038] the dose is calculated according to the dosage of compound 10 or compound 36.

[0039] Preferably, when the anti-cancer drug includes compound 10, the anti-cancer drug is administered orally.

[0040] Preferably, when the anti-cancer drug includes compound 36, the anti-cancer drug is administered by intraperitoneal injection.

[0041] In the present invention, the term "pharmaceutically acceptable adjuvant" includes pharmaceutically acceptable carriers, excipients, diluents and the like compatible with the active pharmaceutical ingredients. The preparation of a pharmaceutical composition with a pharmaceutically acceptable adjuvant is well known to those skilled in the art.

[0042] In the present invention, the pharmaceutical composition can be combined with a pharmaceutically acceptable adjuvant (such as a carrier, excipient, diluent, and the like, well known to those skilled in the art) to prepare various formulations, preferably including solid formulations and liquid preparations such such as tablets, pills, capsules, powders, suspensions, granules, syrups, emulsions, suspensions and various sustained release dosage forms, which can preferably be administered orally.

Brief description of drawings

[0043] Figure 1 shows that compound 10 inhibits the activation of FGFR1 and its downstream signaling pathway in NCI-H1581 cells and inhibits the activation of FGFR2 and its downstream signaling pathway in SNU-16 cells in a concentration gradient manner, where A shows inhibition of FGFR1 activation. and its downstream signaling pathway in NCI-H1581 cells, and B shows inhibition of FGFR2 activation and its downstream signaling pathway in SNU-16 cells;

[0044] Figure 2 shows that compound 36 inhibits FGFR1 activation and its downstream signaling in NCI-H1581 cells and inhibits FGFR2 activation and its downstream signaling in SNU-16 cells in a concentration gradient manner, where A shows inhibition of FGFR1 activation. and its downstream signaling pathway in NCI-H1581 cells, and B shows inhibition of FGFR2 activation and its downstream signaling pathway in SNU-16 cells;

[0045] Figure 3 shows tumor volume curves (A), a statistical plot of tumor weight after 26 days of treatment (B), weight change curves during treatment (C), and a photograph of tumors after 26 days of treatment (D) in a tumor model with subcutaneously transplanted NCI-H1581 tumor cells when tumor proliferation was inhibited by compound 10; And

[0046] Figure 4 shows tumor volume curves (A), tumor weight statistical chart after 26 days of treatment (B), body weight curves during treatment (C), photograph of tumors after 26 days of treatment (D), and phosphorylation levels FGFR1 in tissues from different treatments detected by immunohistochemistry (IHC) (E) in a tumor model with subcutaneously transplanted NCI-H1581 tumor cells when tumor proliferation was inhibited by compound 36.

Detailed Description of Embodiments of the Invention

[0047] Unless otherwise indicated, the technical terms used in the following examples have the same meanings as commonly understood by those skilled in the art to which the present invention relates. Unless otherwise indicated, in the following examples, all test reagents used are conventional biochemical reagents and all test methods are conventional methods.

[0048] The present invention will be described in detail below with reference to examples.

[0049] Example 1: Receiving connection 1

connection 1

[0050]

[0051] The specific production method was as follows:

[0052] 1) Receive connection (1-1)

connection (1-1)

[0053]

[0054] 3-Bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 2.34 mmol) was dissolved in dry tetrahydrofuran (THF) (23 ml) and then added to triphenylphosphine (TPP) (2.08 g, 7.94 mmol) and 1-Boc-3-azetidinemethanol; Diisopropyl azodiformate (DIAD) (1.60 g, 7.94 mmol) was added dropwise at 0°C under argon protection, then the temperature was slowly raised to room temperature and allowed to react for another 4 hours; and the reaction solution was dried by centrifugation and purified by column chromatography (petroleum ether:ethyl acetate = 5:1 to 2:1) to obtain compound 1-1 (yellow oily liquid, 685 mg, 69%).

[0055] The results of the nuclear magnetic resonance (NMR) analysis of compound 1-1 were as follows:

[0056] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (s, 1H), 7.96-7.87 (m, 6H), 7.64 - 7.45 (m, 9H), 4 .48 (d, J=7.3 Hz, 2H), 3.97 (t, J=8.5 Hz, 2H), 3.88-3.74 (m, 2H), 3.19-2, 98 (m, 1H), 1.41 (s, 9H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.1, 163.0, 156.2, 155.9, 154.6, 154.5, 133.4, 133.4, 133.3, 133.3 , 132.4, 132.3, 132.2, 128.8, 128.7, 128.7, 128.6, 128.6, 128.5, 128.4, 127.8, 127.4, 120 ,9, 107.1, 79.3, 52.9, 51.5, 49.7, 28.8, 28.4, 21.7, 14.2. MSHR (ESI) calculated for C ₃₂ H ₃₂ BrN ₆ NaO ₂ P ⁺ : 665.1400, found 665.1402.

[0057] 2) Receive connection (1-2)

connection (1-2)

[0058]

[0059] Compound 1-1 (5.01 mg, 6.74 mmol) and 3,5-dimethoxyphenylboronic acid (1.59 g, 8.76 mmol) were dissolved in a mixed solution of 1,4-dioxane and water (9 ml , v:v = 3:1), and then potassium carbonate (1.87 g, 13.5 mmol) and Pd(PPh ₃ ) ₄ (778 mg, 0.674 mmol) were added; the resulting system was replaced with argon three times and then heated to 80°C in an oil bath to react overnight; and after completion of the reaction, the resulting reaction system was washed with saturated sodium chloride solution (270 ml), then extracted with ethyl acetate (90 ml), the resulting organic phase was dried, concentrated and purified by column chromatography (dichloromethane (DCM): methanol = 70:1 to 30: 1) to obtain compound 1-2 (yellow oily liquid, 4.3 g, 60%).

[0060] The results of the NMR analysis of compound 1-2 were as follows:

[0061] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (d, J=3.2 Hz, 1H), 7.89-7.71 (m, 6H), 7.56-7.40 (m, 11H), 6.70-6.41 (m, 1H), 4.58 (dd, J=7.3, 3.2 Hz, 2H), 4.11-3.96 (m, 2H ), 3.92-3.84 (m, 2H), 3.76 (d, J=3.1 Hz, 6H), 3.26 - 3.07 (m, 1H), 1.41 (d, J=3.1 Hz, 9H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 163.9, 163.9, 163.5, 163.4, 160.3, 156.3, 156.3, 155.2, 154.7, 146.1 , 135.6, 134.2, 133.5, 133.4, 133.4, 133.3, 132.3, 132.2, 132.0, 132.0, 132.0, 1292, 128.6 , 128.6, 128.5, 128.5, 128.4, 128.4, 128.2, 128.2, 127.8, 107.9, 100.6, 79.3, 77.4, 55 ,3, 49.5, 28.9, 28.4, 24.5. MSHR (ESI) calculated for C ₄₀ H ₄₁ N ₆ NaO ₄ P ⁺ : 723.2819, found 723.2822.

[0062] 3) Receive connection (1-3)

connection (1-3)

[0063]

[0064] At 0°C, compound 1-2 (450 mg, 0.587 mmol) was dissolved in DCM (5 ml), then TFA (5 ml) was slowly added dropwise, after 30 min the reaction was complete; The alkalinity of the resulting reaction solution was adjusted with saturated NaHCO ₃ and the resulting organic phase was concentrated by drying to give a brownish-yellow oily intermediate. At 0°C, this intermediate was dissolved in 5 ml DCM, then triethylamine (TEA) (98.2 µl, 0.704 mmol) was added and then acryloyl chloride (52.2 µl, 0.646 mmol) was added dropwise; and then the reaction was left for 1 hour at room temperature; and when completion of the reaction was determined by thin layer chromatography (TLC), the resulting reaction system was washed with saturated NaCl solution and then subjected to extraction with ethyl acetate, and the resulting organic phase was dried, concentrated and purified by column chromatography (DCM:methanol = 30:1 to 10:1 ) to obtain compound 1-3 (yellow oily liquid, 78 mg, 72%).

[0065] 4) Preparation of compound 1-3: Compound 1-3 (100 mg, 0.189 mmol) was added to a mixed solution of acetic acid, THF and water (3 ml, 3:1:2) and the reaction was carried out at room temperature for 18 hours; and when the completion of the reaction was determined by TLC, the pH of the resulting reaction solution was adjusted to 7-8 with saturated NaHCO ₃ solution (15 ml), extraction was carried out with ethyl acetate (10 ml x 2) and the resulting organic phase was dried, concentrated and purified by column chromatography (DCM:methanol = 15:1 to 7:1) to give compound 1-3 (yellow solid, 57.8 mg, 70%).

[0066] The results of the NMR analysis of compound 1 were as follows:

[0067] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 6.80 (d, J = 2.3 Hz, 2H), 6.57 (t, J = 2.3 Hz, 1H), 6.33 (dd, J=17.0, 1.9 Hz, 1H), 6.17 (dd, J=17.0, 10.3 Hz, 1H), 5.76-5 .57 (m, 3H), 4.76-4.61 (m, 2H), 4.38-4.14 (m, 3H), 4.02 (dd, J=10.5, 5.5 Hz , 1H), 3.87 (s, 6H), 3.49-3.25 (m, 1H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.7, 161.6, 157.8, 156.2, 154.7, 144.7, 134.8, 127.4, 127.2, 125.7 , 106.3, 101.2, 98.4, 55.6, 53.5, 50.8, 49.4, 32.7, 29.1, 27.9. MSHR (ESI) calculated for C ₂₀ H ₂₂ N ₆ NaO ₃ ⁺ : 417.1646, found 417.1648.

[0068] Example 2: Receiving connection 2

connection 2

[0069]

[0070] The specific production method was the same as the production method of compound 1, except that one of the starting materials was an equimolar amount of 1-Boc-3-hydroxymethylpyrrolidine instead of 1-Boc-3-azetidinemethanol in the production method of compound (1 -1). The results of NMR analysis of compound 2 were as follows:

[0071] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 6.81 (d, J = 2.2 Hz, 2H), 6.62-6.54 (m, 2H ), 6.25 (dd, J=16.9, 2.0 Hz, 1H), 5.76 (s, 2H), 5.66 (dd, J=10.6, 2.0 Hz, 1H) , 4.65 (d, J=13.3 Hz, 1H), 4.49 (t, J=7.2 Hz, 2H), 3.99 (d, J=13.7 Hz, 1H), 3 .86 (s, 6H), 3.00 (t, J=12.6 Hz, 1H), 2.64-2.52 (m, 1H), 1.97-1.94 (m, 1H), 1.91(s,2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 164.5, 161.5, 158.0, 156.0, 154.6, 144.6, 134.9, 128.5, 127.5, 106.4 , 101.3, 98.3, 55.6, 50.0, 49.1, 45.7, 45.2, 39.9, 37.74 29.6, 27.9. MSHR (ESI) calculated for C ₂₁ H ₂₄ N ₆ NaO ₃ ⁺ : 431.1802, found 431.1804.

[0072] Example 3: Receiving Compound 3

connection 3

[0072]

[0074] The specific production method was the same as the method for producing compound 1, except that one of the starting materials was an equimolar amount of N-Boc-4-hydroxypiperidine instead of 1-Boc-3-azetidinemethanol in the method for producing compound (1 -1). The results of NMR analysis of compound 3 were as follows:

[0075] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 6.80 (d, J=2.2 Hz, 2H), 6.67-6.51 (m, 2H ), 6.31 (dd, J=16.8, 1.8 Hz, 1H), 5.84-5.63 (m, 3H), 5.05 (tt, J=11.3, 4.2 Hz, 1H), 4.85 (d, J=13.4 Hz, 1H), 4.20 (d, J=13.9 Hz, 1H), 3.86 (s, 6H), 3.33 ( t, J=12.7 Hz, 1H), 3.02 - 2.85 (m, 1H), 2.34 (t, J=11.8 Hz, 2H), 2.11 (d, J=13 ,0 Hz, 2H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 161.5, 157.8, 155.8, 154.7, 154.3, 144.1, 135.1, 132.1, 131.6, 106.3 , 101.1, 100.0, 98.3, 79.6, 55.7, 55.6, 52.9, 45.5, 29.7, 28.4, 26.8. MSHR (ESI) calculated for C ₂₁ H ₂₄ N ₆ NaO ₃ ⁺ : 431.1802, found 431.1805.

[0076] Example 4: Receiving Compound 4

connection 4

[0077]

[0078] The specific production method was the same as the production method of compound 1, except that one of the starting materials was an equimolar amount of N-Boc-4-piperidinemethanol instead of 1-Boc-3-azetidinemethanol in the production method of compound (1 -1). The results of NMR analysis of compound 4 were as follows:

[0079] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (s, 1H), 6.80 (d, J=2.3 Hz, 2H), 6.57-6.49 (m, 2H ), 6.23 (d, J=16.8 Hz, 1H), 5.89 (s, 2H), 5.64 (d, J=10.6 Hz, 1H), 4.65 (d, J =13.3 Hz, 1H), 4.33 (d, J=7.1 Hz, 2H), 3.97 (d, J=13.8 Hz, 1H), 3.85 (s, 6H), 3.00 (t, J=12.9 Hz, 1H), 2.62 (t, J=12.9 Hz, 1H), 2.33 (d, J=11.0 Hz, 1H), 1, 66 (d, J=16.3 Hz, 3H), 1.33 (td, J=14.3, 7.5 Hz, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.4, 161.5, 161.5, 157.9, 156.0, 154.7, 144.3, 134.9, 127.9, 127.9 , 127.4, 106.4, 101.1, 99.9, 98.2, 55.6, 51.9, 45.6, 41.8, 36.8, 30.5, 29.4. MSHR (ESI) calculated for C ₂₂ H ₂₆ N ₆ NaO ₃ ⁺ : 445.1959, found 445.1961.

[0080] Example 5: Receiving connection 5

connection 5

[0081]

[0082] The specific production method was the same as the production method of compound 1, except that one of the starting materials was an equimolar amount of N-Boc-4-piperidineethanol instead of 1-Boc-3-azetidinemethanol in the production method of compound (1 -1). The results of NMR analysis of compound 5 were as follows:

[0083] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (d, J=1.1 Hz, 1H), 6.81 (d, J=2.3 Hz, 2H), 6.57 ( d, J=2.4 Hz, 1H), 6.44-6.36 (m, 2H), 5.68 (dd, J=9.6, 2.7 Hz, 1H), 4.50 (dd , J=12.8, 6.9 Hz, 2H), 3.87 (s, 7H), 3.80-3.72 (m, 2H), 3.72-3.65 (m, 1H), 3.57-3.47 (m, 2H), 3.01 (d, J=7.3 Hz, 1H), 1.65 (m, 4H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.3, 162.5, 158.7, 156.8, 155.2, 145.2, 136.0, 128.9, 128.4, 107.4 , 102.1, 99.3, 56.6, 47.3, 45.6, 43.2, 36.9, 34.6, 33.5, 32.9, 32.6, 30.7, 30 ,4. MSHR (ESI) calculated for C ₂₃ H ₂₈ N ₆ NaO ₃ ⁺ : 459.2115, found 459.2115.

[0084] Example 6: Receiving connection 6

connection 6

[0085]

[0086] The specific production method was the same as the production method of compound 1, except that one of the starting materials was an equimolar amount of 1-Boc-3-hydroxymethylpiperidine instead of 1-Boc-3-azetidinemethanol in the production method of compound (1 -1). The results of NMR analysis of compound 6 were as follows:

[0087] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39-8.33 (m, 1H), 6.93-6.75 (m, 2H), 6.63-6.46 (m, 2H), 6.21 (dd, J=16.9, 8.7 Hz, 1H), 5.99 (s, 2H), 5.61 (dd, J=32.0, 10.5 Hz, 1H ), 4.53-4.27 (m, 3H), 3.86 (s, 6H), 3.07 (dt, J=23.7, 12.4 Hz, 1H), 2.81 (dt, J = 44.0, 12.0 Hz, 1H), 2.35 (s, 1H), 1.93 (s, 1H), 1.58 - 1.29 (m, 2H), 1.26 (m , 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.5, 161.6, 157.9, 155.9, 154.7, 127.8, 127.4, 106.3, 101.3, 98.2 , 55.6, 49.8, 49.7, 49.5, 46.5, 45.8, 42.7, 37.4, 36.4, 28.7, 25.2, 24.1. MSHR (ESI) calculated for C ₂₂ H ₂₆ N ₆ NaO ₃ ⁺ : 445.1959, found 445.1961.

[0088] Example 7: Obtaining connection 7

connection 7

[0089]

[0090] The specific preparation method was the same as the preparation method of compound 1, except that one of the starting materials was an equimolar amount of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate instead of 1-Boc-3 -azetidinemethanol in the method for preparing compound (1-1). The results of NMR analysis of compound 7 were as follows:

[0091] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36 (s, 1H), 6.80 (d, J=2.3 Hz, 2H), 6.60-6.47 (m, 2H ), 6.26 (dd, J=16.8, 1.9 Hz, 1H), 5.67 (dd, J=10.5, 1.9 Hz, 1H), 4.57 (t, J = 6.7 Hz, 2H), 3.85 (s, 6H), 3.62 (s, 2H), 3.49 (s, 2H), 2.96 (t, J=6.7 Hz, 2H) , 2.56 (t, J=5.0 Hz, 4H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.3, 161.5, 157.4, 155.1, 154.5, 144.6, 134.8, 127.9, 127.4, 106.3 , 101.2, 98.2, 95.6, 56.7, 55.6, 52.6, 50.9, 45.6, 44.4, 41.8, 31.9, 29.1. MSHR (ESI) calculated for C ₂₂ H ₂₇ N ₇ NaO ₃ ⁺ : 460.2068, found 460.2072.

[0092] Example 8: Obtaining connection 8

connection 8

[0093]

[0094] The specific preparation method was the same as the preparation method of compound 1, except that one of the starting materials was an equimolar amount of 1-Boc-4-(3-hydroxypropane)piperazine instead of 1-Boc-3-azetidinomethanol in method of obtaining compound (1-1). The results of NMR analysis of compound 8 were as follows:

[0095] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36 (s, 1H), 6.81 (d, J=2.3 Hz, 2H), 6.58-6.50 (m, 2H ), 5.88 (s, 2H), 5.69 (dd, J=10.5, 1.9 Hz, 1H), 4.52 (t, J=6.9 Hz, 2H), 3.86 (s, 6H), 3.69 (d, J=6.9 Hz, 2H), 3.57 (s, 2H), 2.51 (dt, J=10.8, 6.0 Hz, 6H) , 2.21 (p, J=7.0 Hz, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.3, 160.3, 154.4, 133.4, 133.3, 132.2, 132.1, 132.0, 129.0, 128.6 , 128.6, 128.4, 128.1, 127.3, 127.3, 107.9, 100.5, 55.4, 55.3, 53.1, 52.5, 45.2, 26 ,4. MSHR (ESI) calculated for C ₂₃ H ₂₉ N ₇ NaO ₃ ⁺ : 474.2224, found 474.2226.

[0096] Example 9: Receiving connection 9

connection 9

[0097]

[0098] The specific preparation method was the same as the preparation method of compound 1, except that one of the starting materials was an equimolar amount of 1-Boc-4-(4-hydroxybutane)piperazine instead of 1-Boc-3-azetidinomethanol in method of obtaining compound (1-1). The results of NMR analysis of compound 9 were as follows:

[0099] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.40-8.36 (m, 1H), 6.81 (dd, J=3.2, 2.0 Hz, 2H), 6.54 (ddd, J=17.4, 8.7, 4.1 Hz, 2H), 6.28 (dt, J=16.9, 2.5 Hz, 1H), 5.72 - 5.66 (m , 1H), 5.61 (s, 2H), 4.46 (s, 2H), 3.89 - 3.82 (m, 6H), 3.67 (s, 2H), 3.54 (s, 2H), 2.41 (s, 6H), 2.01 (s, 2H), 1.56 (s, 2H). ¹³ C NMR (100 MHz, MeOD) δ 169.4, 166.0, 152.2, 151.70, 147.6, 145.9, 132.7, 128.5, 126.6, 106.2, 106.1, 101.5, 101.4, 96.5, 56.6, 54.7, 53.5, 51.1, 40.5, 39.1, 38.5, 35.2, 28, 3, 22.7. MSHR (ESI) calculated for C ₂₄ H ₃₁ N ₇ NaO ₃ ⁺ : 488.2381, found 488.2383.

[0100] Example 10: Receiving connection 10

connection 10

[0101]

[0102] The specific preparation method was the same as the preparation method of compound 1, except that one of the starting materials was an equimolar amount of 1-Boc-4-(5-hydroxypentane)piperazine instead of 1-Boc-3-azetidinomethanol in method of obtaining compound (1-1). The results of NMR analysis of compound 10 were as follows:

[0103] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 6.82-6.80 (m, 2H), 6.58-6.55 (m, 1H), 6 .53 (d, J=10.4 Hz, 1H), 6.27 (d, J=16.7 Hz, 1H), 5.68 (d, J=10.6 Hz, 1H), 5.61 (s, 2H), 4.43 (s, 2H), 3.86 (s, 6H), 3.67 (s, 2H), 3.53 (s, 2H), 2.42-2.38 ( m, 4H), 2.34-2.30 (m, 2H), 2.02-1.96 (m, 2H), 1.54 (d, J=7.4 Hz, 2H), 1.39 (d, J=6.9 Hz, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.3, 161.6, 157.7, 155.9, 154.3, 144.0, 135.1, 127.7, 127.5, 106.4 , 101.1, 100.0, 98.3, 58.2, 55.6, 53.4, 52.7, 47.1, 45.7, 41.8, 40.5, 29.6, 29 ,3, 26.2, 24.5. MSHR (ESI) calculated for C ₂₅ H ₃₃ N ₇ NaO ₃ ⁺ : 502.2537, found 502.2539.

[0104] Example 11: Receiving connection 11

connection 11

[0105]

[0106] The specific preparation method was the same as the preparation method of compound 1, except that one of the starting materials was an equimolar amount of 1-Boc-4-(6-hydroxyhexane)piperazine instead of 1-Boc-3-azetidinomethanol in method of obtaining compound (1-1). The results of NMR analysis of compound 11 were as follows:

[0107] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (d, J=1.3 Hz, 1H), 6.81 (dd, J=2.3, 1.3 Hz, 2H), 6.61-6.52 (m, 2H), 6.29 (dt, J=16.9, 1.6 Hz, 1H), 6.00 (s, 2H), 5.69 (dt, J= 10.5, 1.6 Hz, 1H), 4.43 (t, J=7.3 Hz, 2H), 3.86 (d, J=1.3 Hz, 6H), 3.69 (t, J=5.0 Hz, 2H), 3.56 (t, J=4.9 Hz, 2H), 2.42 (t, J=5.0 Hz, 4H), 2.33 (t, J= 7.6 Hz, 2H), 1.97 (t, J=7.2 Hz, 2H), 1.54-1.45 (m, 2H), 1.38 (t, J=4.3 Hz, 4H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.3, 161.5, 157.8, 155.3, 154.1, 144.2, 135.0, 135.0, 127.9, 127.5 , 127.5, 106.4, 106.4, 101.1, 98.2, 58.3, 55.6, 53.4, 52.7, 47.2, 45.7, 41.8, 29 ,7, 27.0, 26.6, 26.5. MSHR (ESI) calculated for C ₂₆ H ₃₅ N ₇ NaO ₃ ⁺ : 516.2694, found 516.2696.

[0108] Example 12: Receiving connection 12

connection 12

[0109]

[0110] The specific preparation method was the same as the preparation method of compound 1, except that one of the starting materials was an equimolar amount of 1-Boc-4-(7-hydroxyheptane)piperazine instead of 1-Boc-3-azetidinomethanol in method of obtaining compound (1-1). The results of NMR analysis of compound 12 were as follows:

[0111] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (d, J=2.8 Hz, 1H), 6.82 (t, J=2.5 Hz, 2H), 6.62- 6.50 (m, 2H), 6.33-6.23 (m, 1H), 5.77-5.56 (m, 3H), 4.42 (s, 2H), 3.86 (d, J=2.8 Hz, 6H), 3.70 (s, 2H), 3.57 (s, 2H), 2.50-2.37 (m, 4H), 2.33 (s, 2H), 1.96 (s, 2H), 1.47 (s, 2H), 1.33 (d, J=27.0 Hz, 6H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 165.6, 161.8, 158.1, 156.1, 154.5, 144.3 135.5, 135.5, 128.1, 127.8, 106.7, 101.4, 101.4, 98.6, 58.7, 55.9, 53.7, 53.1, 47.5, 46.0, 42.2, 30.0, 29, 9, 29.3, 27.6, 26.9, 26.8. MSHR (ESI) calculated for C ₂₇ H ₃₇ N ₇ NaO ₃ ⁺ : 530.2850, found 530.2852.

[0112] Example 13: Receiving connection 13

connection 13

[0113]

[0114] The specific production method was the same as the production method of compound 1, except that one of the starting materials was an equimolar amount of 3,4-methylenephenylboronic acid instead of 3,5-dimethoxyphenylboronic acid in the production method of compound (1-2 ). The results of NMR analysis of compound 13 were as follows:

[0115] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36 (s, 1H), 7.16 (d, J=2.7 Hz, 1H), 6.97 (d, J=7.9 Hz, 1H), 6.62-6.49 (m, 1H), 6.28 (dd, J=16.9, 2.0 Hz, 1H), 6.06 (s, 2H), 5.86 -5.65 (m, 3H), 4.42 (t, J=7.2 Hz, 2H), 3.70 (d, J=7.5 Hz, 2H), 3.55 (t, J= 5.1 Hz, 2H), 2.43 (t, J=4.9 Hz, 4H), 2.35 (t, J=7.6 Hz, 2H), 1.99 (td, J=16, 9, 15.0, 9.4 Hz, 2H), 1.79-1.14 (m, 6H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.2, 157.8, 155.7, 154.2, 148.6, 148.5, 143.8, 127.4, 127.1, 122.1 , 109.0, 108.9, 101.6, 101.5, 98.2, 58.1, 53.3, 52.7, 46.9, 45.6, 41.7, 29.5, 26 ,1, 24.5. MSHR (ESI) calculated for C ₂₄ H ₂₉ N ₇ NaO ₃ ⁺ : 4860.2224, found 4860.2226.

[0116] Example 14: Receiving connection 14

connection 14

[0117]

[0118] The specific production method was the same as the production method of compound 1, except that one of the starting materials was an equimolar amount of benzofuran-2-boronic acid instead of 3,5-dimethoxyphenylboronic acid in the production method of compound (1-2 ). The results of NMR analysis of compound 14 were as follows:

[0119] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 (s, 1H), 7.68 (dd, J=7.3, 1.5 Hz, 1H), 7.59-7.55 (m, 1H), 7.40-7.32 (m, 3H), 6.53 (dd, J=16.8, 10.6 Hz, 1H), 6.28 (dd, J=16.9 , 1.9 Hz, 1H), 5.68 (dd, J=10.6, 2.0 Hz, 1H), 4.46 (t, J=7.2 Hz, 2H), 3.69 (s , 2H), 3.55 (s, 2H), 2.44 (s, 4H), 2.36 (t, J=7.6 Hz, 2H), 2.01 (p, J=7.4 Hz , 2H), 1.57 (q, J=7.6 Hz, 2H), 1.44-1.36 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.3, 163.8, 157.6, 156.0 154.4, 149.5, 134.7, 128.3, 127.8, 127.4, 125.1, 124.0, 121.7, 111.0, 104.3, 97.9, 58.1, 53.3, 52.7, 47.3, 45.6, 41.7, 29, 5, 26.1, 24.4. MSHR (ESI) calculated for C ₂₅ H ₂₉ N ₇ NaO ₂ ⁺ : 482.2269, found 482.2271.

[0120] Example 15: Receiving connection 15

connection 15

[0121]

[0122] The specific production method was the same as the production method of compound 1, except that one of the starting materials was an equimolar amount of p-methoxyboronic acid instead of 3,5-dimethoxyphenylboronic acid in the production method of compound (1-2). The results of NMR analysis of compound 15 were as follows:

[0123] ^1H NMR (400 MHz, MeOD) δ 8.24 (s, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.18-7.06 (m, 2H) , 6.82-6.64 (m, 1H), 6.19 (dd, J=16.7, 2.0 Hz, 1H), 5.74 (dd, J=10.6, 1.9 Hz , 1H), 4.41 (t, J=6.8 Hz, 2H), 3.88 (s, 3H), 3.62 (s, 4H), 2.48 (s, 4H), 2.39 (s, 2H), 1.96 (q, J=7.3 Hz, 2H), 1.60-1.52 (m, 2H), 1.35 (q, J=7.9 Hz, 2H) . ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.3, 157.7, 155.9, 155.9, 154.4, 143.6, 140.4, 133.9, 132.5, 129.6 , 127.8, 126.7, 125.9, 124.7, 64.1, 58.2, 53.4, 52.7, 48.6, 47.1, 29.5, 26.0, 24 ,5, 15.5. MSHR (ESI) calculated for C ₂₄ H ₃₁ N ₇ NaO ₂ ⁺ : 472.2426, found 472.2428.

[0124] Example 16: Receiving connection 16

connection 16

[0125]

[0126] The specific production method was the same as the production method of compound 1, except that one of the starting materials was an equimolar amount of 4-acetylaminophenylboronic acid instead of 3,5-dimethoxyphenylboronic acid in the production method of compound (1-2). The results of NMR analysis of compound 16 were as follows:

[0127] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.24 (d, J=1.3 Hz, 1H), 8.01 (s, 1H), 7.54-7.43 (m, 3H ), 6.72 (dd, J=16.9, 10.7 Hz, 1H), 6.18 (dt, J=16.8, 1.7 Hz, 1H), 5.73 (dt, J= 10.6, 1.7 Hz, 1H), 4.43 (t, J=6.7 Hz, 2H), 3.60 (q, J=6.7, 4.6 Hz, 4H), 2, 46 (d, J=5.2 Hz, 4H), 2.37 (t, J=7.6 Hz, 2H), 2.16 (d, J=1.4 Hz, 3H), 1.97 ( t, J=7.4 Hz, 2H), 1.57 (dd, J=11.0, 4.7 Hz, 2H), 1.34 (p, J=7.6 Hz, 2H). ¹³ C NMR (100 MHz, MeOD) δ 170.6, 165.9, 158.4, 155.4, 153.8, 144.4, 139.14, 133.2, 129.6, 127.3, 127.3, 123.7, 120.4, 120.1, 100.0, 97.6, 57.6, 52.8, 52.3, 45.0, 41.3, 28.9, 25, 3, 23.9, 22.4. MSHR (ESI) calculated for C ₂₅ H ₃₂ N ₈ NaO ₂ ⁺ : 472.2426, found 472.2428.

[0128] Example 17: Receiving connection 17

connection 17

[0129]

[0130] The specific production method was the same as the production method of compound 1, except that an equimolar amount of 4-trifluoromethoxyphenylboronic acid was used instead of 3,5-dimethoxyphenylboronic acid in the production method of compound (1-2). The results of NMR analysis of compound 17 were as follows:

[0131] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 (s, 1H), 7.70 (t, J=7.6 Hz, 1H), 7.63 (d, J=10.6 Hz, 1H), 7.49-7.42 (m, 1H), 7.35 (dd, J=7.8, 5.3 Hz, 1H), 6.73 (dd, J=16.8, 10.7 Hz, 1H), 6.18 (dd, J=16.8, 1.9 Hz, 1H), 5.73 (dd, J=10.7, 2.0 Hz, 1H), 4, 44 (t, J=6.8 Hz, 2H), 3.61 (d, J=5.4 Hz, 4H), 2.50-2.37 (m, 4H), 2.35 (d, J =7.7 Hz, 2H), 1.99 (q, J=7.1 Hz, 2H), 1.59-1.55 (m, 2H), 1.35 (s, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.2, 158.5, 156.8, 155.4, 150.6, 143.3, 136.3, 131.8, 128.6, 128.4 , 127.6, 122.3, 121.9, 120.1, 99.2, 59.1, 54.3, 53.6, 48.1, 46.6, 42.8, 30.4, 27 ,1, 25.4. MSHR (ESI) calculated for C ₂₄ H ₂₈ F ₃ N ₇ NaO ₂ ⁺ : 526.2143, found 526.2145.

[0132] Example 18: Receiving connection 18

connection 18

[0133]

[0134] The specific production method was the same as the production method of compound 1, except that one of the starting materials was an equimolar amount of 2-naphthaleneboronic acid instead of 3,5-dimethoxyphenylboronic acid in the production method of compound (1-2). The results of NMR analysis of compound 18 were as follows:

[0135] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.41 (s, 1H), 8.17 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7, 93 (dd, J=9.3, 3.6 Hz, 2H), 7.82 (d, J=8.4 Hz, 1H), 7.58 (dd, J=6.2, 3.2 Hz , 2H), 6.51 (dd, J=16.8, 10.5 Hz, 1H), 6.27 (d, J=16.8 Hz, 1H), 5.67 (d, J=10, 7 Hz, 1H), 4.49 (t, J=7.2 Hz, 2H), 3.68 (s, 2H), 3.51 (d, J=15.2 Hz, 2H), 2.37 (dd, J=19.5, 12.3 Hz, 6H), 2.04 (dd, J=14.6, 7.4 Hz, 2H), 1.57 (dd, J=14.7, 7 .5 Hz, 2H), 1.42 (dd, J=14.9, 7.9 Hz, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.28, 157.63, 155.97, 154.54, 149.88, 142.42, 135.37, 135.35, 130.91, 127.75 , 127.50, 127.24, 126.68, 121.64, 121.38, 121.00, 118.73, 98.31, 58.16, 53.43, 52.73, 47.17, 45 .72, 41.87, 29.53, 26.24, 24.52. MSHR (ESI) calculated for C ₂₇ H ₃₁ N ₇ NaO ⁺ : 492.2482, found 492.2484.

[0136] Example 19: Receiving connection 19

connection 19

[0137]

[0138] The specific production method was the same as the production method of compound 1, except that one of the starting materials was an equimolar amount of 4-methylnaphthaleneboronic acid instead of 3,5-dimethoxyphenylboronic acid in the production method of compound (1-2). The results of NMR analysis of compound 19 were as follows:

[0139] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.63-7.41 (m, 4H), 6.52 (dd, J=16.8, 10.5 Hz, 1H), 6.26 (dd, J=16.8, 1.7 Hz, 1H), 5.67 (dd, J=10.5, 1.7 Hz, 1H), 4.50 (t, J=7.1 Hz, 2H), 3.66 (s, 2H), 3.49 (d, J=16.9 Hz, 2H), 2.78 (s, 3H), 2.36 (dd, J=19.3, 12.0 Hz, 6H), 2, 13-1.98 (m, 2H), 1.57 (dt, J=14.9, 7.6 Hz, 2H), 1.42 (dt, J=15.0, 7.6 Hz, 2H) . ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.27, 159.72, 157.75, 155.67, 154.23, 144.16, 134.49, 130.52, 127.93, 127.88 , 127.43, 120.40, 120.11, 115.46, 114.30, 98.54, 98.31, 63.68, 58.15, 53.31, 52.69, 47.03, 41 .74, 29.71, 29.54, 26.11, 24.50, 24.04. MSHR (ESI) calculated for C ₂₈ H ₃₃ N ₇ NaO ⁺ : 570.1587, found 570.1590.

[0140] Example 20: Receiving connection 20

connection 20

[0141]

[0142] The specific production method was the same as the production method of compound 1, except that one of the starting materials was an equimolar amount of 4-bromonaphthaleneboronic acid instead of 3,5-dimethoxyphenylboronic acid in the production method of compound (1-2). The results of NMR analysis of compound 20 were as follows:

[0143] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.92 (d, J=8.3 Hz, 1H), 7.64-7.42 (m, 4H), 6.53 (dd, J=16.8, 10.5 Hz, 1H), 6.27 (dd, J=16.8, 1.7 Hz, 1H), 5.68 (dd, J=10.5, 1.7 Hz, 1H), 4.51 (t, J=7.1 Hz, 2H), 3.67 (s, 2H), 3.50 (d, J=17.0 Hz, 2H), 2.37 (dd, J=19.3, 12.0 Hz, 6H), 2.13-1.99 (m, 2H ), 1.58 (dt, J=14.9, 7.6 Hz, 2H), 1.43 (dt, J=15.0, 7.6 Hz, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.16, 157.62, 157.55, 155.88, 154.26, 149.40, 134.60, 128.22, 127.80, 127.72 , 127.32, 125.04, 123.91, 121.64, 121.60, 110.91, 104.17, 99.87, 97.77, 58.01, 53.21, 52.59, 47 ,20, 45.47, 41.63, 29.34, 24.31. MSHR (ESI) calculated for C ₂₇ H ₃₀ BrN ₇ NaO ⁺ : 570.1587, found 570.1590.

[0144] Example 21: Receiving connection 21

connection 21

[0145]

[0146] The specific production method was the same as the production method of compound 1, except that one of the starting materials was an equimolar amount of 2,5-dimethoxyphenylboronic acid instead of 3,5-dimethoxyphenylboronic acid in the production method of compound (1-2 ). The results of NMR analysis of compound 21 were as follows:

[0147] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 (s, 1H), 7.07 (s, 1H), 7.02 (d, J=8.6 Hz, 2H), 6, 56 (dd, J=16.8, 10.6 Hz, 1H), 6.28 (d, J=16.8 Hz, 1H), 5.70 (d, J=7.6 Hz, 1H), 4.44 (t, J=7.1 Hz, 2H), 3.81 (d, J=11.0 Hz, 6H), 3.69 (s, 2H), 3.55 (s, 2H), 2.47-2.32 (m, 6H), 2.03 (dd, J=14.0, 7.0 Hz, 2H), 1.61 - 1.52 (m, 2H), 1.41 ( dd, J=14.7, 7.6 Hz, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.28, 158.41, 155.55, 154.40, 153.90, 150.49, 140.79, 127.83, 127.47, 123.11 , 117.10, 116.10, 113.43, 100.37, 58.17, 56.76, 55.85, 53.35, 52.72, 47.06, 45.66, 41.80, 29 .55, 26.21. MSHR (ESI) calculated for C ₂₅ H ₃₃ N ₇ NaO ₃ ⁺ : 502.2537, found 502.2539.

[0148] Example 22: Receiving connection 22

connection 22

[0149]

[0150] The specific production method was the same as the production method of compound 1, except that one of the starting materials was an equimolar amount of 3,4-dimethoxyphenylboronic acid instead of 3,5-dimethoxyphenylboronic acid in the production method of compound (1-2 ). The results of NMR analysis of compound 22 were as follows:

[0151] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.39 (s, 1H), 7.27 (s, 1H), 6.89 (s, 2H), 6.64-6.50 (m , 1H), 6.29 (d, J=16.6 Hz, 1H), 5.70 (d, J=10.2 Hz, 3H), 4.43 (d, J=6.9 Hz, 2H ), 3.94 (s, 3H), 3.91 (s, 3H), 3.69 (s, 2H), 3.56 (s, 2H), 2.38 (dd, J=22.3, 15.1 Hz, 6H), 2.03-1.98 (m, 2H), 1.57 (d, J=6.9 Hz, 2H), 1.40 (d, J=7.0 Hz, 2H). ¹³ C NMR (100 MHz, CDCl ₃ )δ 165.34, 165.29, 157.82, 155.94, 155.91, 155.87, 154.22, 154.05, 153.99, 144.18 , 138.75, 128.59, 127.92, 127.42, 105.53, 98.33, 61.03, 58.18, 56.33, 53.39, 52.70, 47.06, 29 .61, 26.19, 24.53. MSHR (ESI) calculated for C ₂₅ H ₃₃ N ₇ NaO ₃ ⁺ : 502.2537, found 502.2539.

[0152] Example 23: Receiving connection 23

connection 23

[0153]

The specific production method was the same as the production method of compound 1, except that one of the starting materials was an equimolar amount of 3,4,5-trimethoxyphenylboronic acid instead of 3,5-dimethoxyphenylboronic acid in the production method of compound (1-2) . The results of NMR analysis of compound 23 were as follows:

[0155] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30 (s, 1H), 6.82 (d, J=1.3 Hz, 2H), 6.47 (ddd, J=16.8 , 10.5, 1.3 Hz, 1H), 6.19 (dt, J=16.8, 1.6 Hz, 1H), 5.87 (s, 2H), 5.60 (dt, J= 10.5, 1.6 Hz, 1H), 4.36 (t, J=7.3 Hz, 2H), 3.86 (d, J=1.3 Hz, 6H), 3.83 (d, J=1.3 Hz, 3H), 3.60 (t, J=5.0 Hz, 2H), 3.47 (t, J=5.0 Hz, 2H), 2.33 (t, J= 5.1 Hz, 4H), 2.27 (d, J=7.5 Hz, 2H), 1.93 (q, J=7.6 Hz, 2H), 1.49 (t, J=7, 6 Hz, 2H), 1.33 (d, J=7.6 Hz, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.2, 158.0, 155.8, 154.2, 153.9, 144.1, 138.8, 128.6, 128.6, 128.4 , 127.7, 127.5, 105.6, 98.3, 61.0, 58.2, 56.3, 53.4, 52.7, 47.0, 45.7, 41.9, 29 ,7, 29.6, 26.3, 24.5. MSHR (ESI) calculated for C ₂₆ H ₃₅ N ₇ NaO ₄ ⁺ : 532.2643, found 536.2645.

[0156] Example 24: Receiving connection 24

connection 24

[0157]

[0158] The specific production method was the same as the production method of compound 1, except that one of the starting materials was an equimolar amount of 3-trifluoromethylphenylboronic acid instead of 3,5-dimethoxyphenylboronic acid in the production method of compound (1-2). The results of NMR analysis of compound 24 were as follows:

[0159] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 7.68-7.54 (m, 3H), 7.33 (d, J=6.5 Hz, 1H ), 6.59-6.47 (m, 1H), 6.25 (dd, J=16.8, 4.6 Hz, 1H), 5.95-5.59 (m, 3H), 4, 43 (d, J=6.6 Hz, 2H), 3.64 (d, J=9.2 Hz, 2H), 3.52 (s, 2H), 2.39 (d, J=5.7 Hz, 4H), 2.32 (d, J=7.3 Hz, 2H), 1.98 (q, J=7.1 Hz, 2H), 1.56 (s, 2H), 1.42- 1.32 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.3, 157.7, 155.8, 154.5, 149.8, 142.5, 135.3, 130.9, 127.7, 127.5 , 126.7, 121.4, 121.0, 98.3, 58.1, 53.4, 52.7, 47.2, 45.7, 41.9, 29.7, 29.5, 26 ,2, 24.5. MSHR (ESI) calculated for C ₂₄ H ₂₈ F ₃ N ₇ NaO ⁺ : 510.2205, found 510.2207.

[0160] Example 25: Receiving connection 25

connection 25

[0161]

[0162] The specific production method was the same as the production method of compound 1, except that one of the starting materials was an equimolar amount of 3-isopropoxyphenylboronic acid instead of 3,5-dimethoxyphenylboronic acid in the production method of compound (1-2). The results of NMR analysis of compound 25 were as follows:

[0163] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.15 (d, J=1.2 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.11 ( dd, J=8.2, 5.0 Hz, 2H), 7.00-6.95 (m, 1H), 6.70-6.60 (m, 1H), 6.09 (dt, J= 16.8, 1.6 Hz, 1H), 5.64 (dt, J=10.6, 1.6 Hz, 1H), 4.60 (q, J=6.0 Hz, 1H), 4, 32 (t, J=6.8 Hz, 2H), 3.53 (t, J=6.3 Hz, 4H), 2.38 (s, 4H), 2.30 (t, J=7.6 Hz, 2H), 1.87 (d, J=7.1 Hz, 2H), 1.48 (t, J=7.8 Hz, 2H), 1.25 (dd, J=6.0, 1 .3 Hz, 6H), 1.22 (d, J=7.4 Hz, 2H). ¹³ C NMR (100 MHz, MeOD) δ 166.0, 158.6, 158.5, 155.4, 153.7, 144.7, 134.0, 130.2, 127.3, 127.3, 120.1, 116.4, 115.5, 100.0, 97.6, 69.9, 57.6, 52.8, 52.3, 46.4, 45.0, 41.3, 28, 9, 25.2, 23.9, 21.0. MSHR (ESI) calculated for C ₂₆ H ₃₅ N ₇ NaO ₂ ⁺ : 500.2744, found 500.2747.

[0164] Example 26: Receiving connection 26

connection 26

[0165]

[0166] The specific production method was the same as the production method of compound 1, except that one of the starting materials was an equimolar amount of 3-benzyloxyphenylboronic acid instead of 3,5-dimethoxyphenylboronic acid in the production method of compound (1-2). The results of NMR analysis of compound 26 were as follows:

[0167] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (s, 1H), 7.49-7.27 (m, 8H), 7.11 (d, J=8.5 Hz, 1H ), 6.54 (dd, J=16.8, 10.4 Hz, 1H), 6.28 (d, J=16.8 Hz, 1H), 5.69 (d, J=10.4 Hz , 1H), 5.43 (s, 2H), 5.17 (s, 2H), 4.44 (t, J=7.4 Hz, 2H), 3.62 (d, J=49.9 Hz , 4H), 2.39 (d, J=27.3 Hz, 6H), 2.03-1.93 (m, 2H), 1.38 (s, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.3, 159.4, 157.7, 155.4, 154.2, 144.1, 136.6, 134.5, 133.3, 130.6 , 128.7, 128.1, 127.7, 127.5, 127.4, 120.9, 116.0, 114.5, 98.2, 70.0, 58.1, 53.3, 52 ,7, 47.1, 45.7, 41.8, 29.5, 26.2, 24.5, 21.2. MSHR (ESI) calculated for C ₃₀ H ₃₅ N ₇ NaO ₂ ⁺ : 548.2744, found 548.2747.

[0168] Example 27: Receiving connection 27

connection 27

[0169]

[0170] The specific production method was the same as the method for producing compound 1, except that one of the starting materials was an equimolar amount of 2-chloro-5-methoxyphenylboronic acid instead of 3,5-dimethoxyphenylboronic acid in the method for producing compound (1 -2). The results of NMR analysis of compound 27 were as follows:

[0171] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 (d, J=4.2 Hz, 1H), 7.43 (s, 1H), 6.99 (dq, J=19.8 , 3.2 Hz, 2H), 6.53 (ddd, J=15.6, 10.7, 3.9 Hz, 1H), 6.25 (dd, J=16.9, 3.9 Hz, 1H), 5.80-5.22 (m, 3H), 4.45 (t, J=6.5 Hz, 2H), 3.82 (d, J=4.9 Hz, 3H), 3, 68-3.63 (m, 2H), 3.51 (s, 2H), 2.39 (d, J=5.4 Hz, 4H), 2.31 (q, J=6.2, 5, 4 Hz, 2H), 1.99 (q, J=6.8 Hz, 2H), 1.53 (q, J=7.1 Hz, 2H), 1.42 - 1.28 (m, 2H) . ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.3, 158.6, 157.7, 155.9, 153.8, 141.1, 132.6, 131.1, 127.7, 127.5 , 124.7, 116.9, 99.9, 70.5, 58.2, 55.7, 53.4, 52.7, 47.1, 45.7, 41.9, 29.5, 26 ,2, 24.5. MSHR (ESI) calculated for C ₂₄ H ₃₀ ClN ₇ NaO ₂ ⁺ : 506.2042, found 506.2044.

[0172] Example 28: Receiving connection 28

connection 28

[0173]

[0174] The specific production method was the same as the production method of compound 1, except that one of the starting materials was an equimolar amount of p-fluorophenylboronic acid instead of 3,5-dimethoxyphenylboronic acid in the production method of compound (1-2). The results of NMR analysis of compound 28 were as follows:

[0175] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (s, 1H), 7.25 (s, 2H), 6.54 (dd, J=16.8, 10.5 Hz, 1H ), 6.29 (dd, J=16.8, 1.7 Hz, 1H), 6.24 (s, 2H), 5.70 (d, J=10.5 Hz, 1H), 4.35 (t, J=7.0 Hz, 2H), 3.69 (t, J=29.6 Hz, 4H), 2.44 (d, J=31.0 Hz, 6H), 1.92 (dd , J=14.9, 7.4 Hz, 2H), 1.58 (s, 2H), 1.35-1.30 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.21, 158.54, 157.68, 155.61, 153.68, 141.11, 132.50, 131.04, 127.66, 127.44 , 124.68, 116.84, 99.80, 58.07, 55.65, 53.26, 52.63, 47.07, 45.59, 41.74, 29.40, 26.09, 24 ,40. MSHR (ESI) calculated for C ₂₃ H ₂₈ FN ₇ NaO ⁺ : 460.2232, found 460.2230.

[0176] Example 29: Receiving connection 29

connection 29

[0177]

[0178] The specific production method was the same as the method for producing compound 1, except that one of the starting materials was an equimolar amount of 3-fluoro-4-hydroxyphenylboronic acid instead of 3,5-dimethoxyphenylboronic acid in the method for producing compound (1 -2). The results of NMR analysis of compound 29 were as follows:

[0179] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (s, 1H), 7.72-7.62 (m, 2H), 7.26-7.23 (m, 1H), 6 .55 (dd, J=16.8, 10.5 Hz, 1H), 6.28 (dd, J=16.8, 1.9 Hz, 1H), 5.69 (dd, J=10.5 , 1.9 Hz, 1H), 4.44 (t, J=7.2 Hz, 2H), 3.68 (s, 2H), 3.51 (d, J=21.5 Hz, 2H), 2.47-2.39 (m, 4H), 2.36-2.31 (m, 2H), 1.99 (dt, J=15.0, 7.5 Hz, 2H), 1.55 ( dd, J=15.1, 7.6 Hz, 2H), 1.42-1.33 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.30, 162.94, 161.55, 157.73, 157.26, 156.54, 154.10, 119.85, 117.25, 100.41 , 100.29, 99.99, 61.49, 57.97, 53.20, 52.53, 47.28, 29.69, 29.65, 29.40, 29.26, 24.72, 24 ,24. MSHR (ESI) calculated for C ₂₃ H ₂₈ FN ₇ NaO ₂ ⁺ : 476.2181, found 476.2180.

[0180] Example 30: Receiving connection 30

connection 30

[0181]

[0182] The specific production method was the same as the production method of compound 1, except that one of the starting materials was an equimolar amount of 6-methoxynaphthalene-2-boronic acid instead of 3,5-dimethoxyphenylboronic acid in the production method of compound (1 -2). The results of NMR analysis of compound 30 were as follows:

[0183] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.37 (d, J=5.6 Hz, 1H), 8.08 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.77 (dd, J=8.4, 1.6 Hz, 1H), 7.26-7.19 (m , 2H), 6.51 (dd, J=16.8, 10.5 Hz, 1H), 6.31 - 6.16 (m, 1H), 5.77 (d, J=66.8 Hz, 2H), 5.67 (dd, J=10.5, 1.9 Hz, 1H), 4.47 (t, J=7.2 Hz, 2H), 3.97 (s, 3H), 3, 69 (s, 2H), 3.54 (s, 2H), 2.38 (dd, J=21.6, 14.2 Hz, 6H), 2.02 (dt, J=14.8, 7, 4 Hz, 2H), 1.63 - 1.53 (m, 2H), 1.41 (dt, J=15.1, 7.5 Hz, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.27, 158.50, 157.93, 155.54, 154.31, 144.47, 134.66, 129.73, 128.92, 128.23 , 128.12, 127.81, 127.54, 127.43, 126.28, 119.94, 105.79, 98.49, 58.13, 55.42, 53.27, 52.70, 47 .05, 45.55, 41.71, 29.57, 26.08, 24.51. MSHR (ESI) calculated for C ₂₈ H ₃₃ N ₇ NaO ₂ ⁺ : 522.2588, found 522.2587.

[0184] Example 31: Receiving connection 31

connection 31

[0185]

[0186] The specific production method was the same as the production method of compound 1, except that one of the starting materials was an equimolar amount of p-nitrophenylboronic acid instead of 3,5-dimethoxyphenylboronic acid in the production method of compound (1-2). The results of NMR analysis of compound 31 were as follows:

[0187] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45-8.36 (m, 3H), 7.92 (d, J=8.8 Hz, 2H), 6.54 (dd, J =16.8, 10.5 Hz, 1H), 6.27 (dd, J=16.9, 2.0 Hz, 1H), 5.90-5.63 (m, 3H), 4.48 ( t, J=7.2 Hz, 2H), 3.67 (s, 2H), 3.59-3.50 (m, 2H), 2.42 (t, J=5.1 Hz, 4H), 2.35 (dd, J=8.5, 6.5 Hz, 2H), 2.01 (p, J=7.6 Hz, 2H), 1.63-1.55 (m, 2H), 1 .41 (dt, J=11.4, 6.8 Hz, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.3, 157.6, 155.9, 154.7, 148.0, 141.7, 139.6, 129.2, 127.8, 127.5 , 124.6, 98.4, 77.2, 58.1, 53.4, 52.7, 47.4, 45.7, 41.8, 29.7, 29.5, 26.2, 24 ,5. MSHR (ESI) calculated for C ₂₃ H ₂₈ N ₈ NaO ₃ ⁺ : 487.2177, found 487.2179.

[0188] Example 32: Receiving connection 32

connection 32

[0189]

[0190] The specific production method was the same as the method for producing compound 1, except that one of the starting materials was an equimolar amount of 3-fluoro-5-methoxyphenylboronic acid instead of 3,5-dimethoxyphenylboronic acid in the method for producing compound (1 -2). The results of NMR analysis of compound 31 were as follows:

[0191] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 7.24 (d, J=2.1 Hz, 2H), 6.99-6.87 (m, 1H ), 6.54 (dd, J=1 6.8, 10.6 Hz, 1H), 6.27 (dd, J=1 6.8, 1.9 Hz, 1H), 5.80-5, 63 (m, 3H), 4.44 (t, J=7.2 Hz, 2H), 3.92 (s, 3H), 3.66 (d, J=1 2.5 Hz, 2H), 3 .54 (s, 2H), 2.45-2.33 (m, 6H), 2.02-1.96 (m, 2H), 1.55 (dd, J=1 5.0, 7.5 Hz, 2H), 1.37 (dd, J=1 5.2, 7.2 Hz, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.31, 164.85, 164.72, 162.35, 162.23, 157.51, 155.78, 154.50, 127.78, 127.48 , 111.59, 111.33, 104.53, 104.28, 98.15, 58.13, 53.38, 52.69, 47.23, 45.66, 41.82, 29.49, 26 ,17, 24.51. MSHR (ESI) calculated for C ₂₄ H ₃₀ FN ₇ NaO ₂ ⁺ : 490.2337, found 490.2335.

[0192] Example 33: Receiving connection 33

connection 33

[0193]

[0194] The specific production method was the same as the method for producing Compound 1, except that one of the starting materials was an equimolar amount of 3,5-difluorophenylboronic acid, which was used instead of 3,5-dimethoxyphenylboronic acid in the method for producing Compound ( 1-2). The results of NMR analysis of compound 33 were as follows:

[0195] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.36 (s, 1H), 7.01 (dd, J=8.4, 2.2 Hz, 2H), 6.73 (dt, J =10.5, 2.3 Hz, 1H), 6.55 (dd, J=16.8, 10.6 Hz, 1H), 6.28 (dd, J=16.8, 1.9 Hz, 1H), 5.83 (s, 2H), 5.69 (dd, J=10.5, 1.9 Hz, 1H), 4.44 (t, J=7.2 Hz, 2H), 3, 66 (m, J=16.1 Hz, 2H), 3.55 (m, 2H), 2.37 (dd, J=23.0, 15.7 Hz, 6H), 1.98 (dd, J =14.9, 7.5 Hz, 2H), 1.56 (dd, J=14.8, 7.4 Hz, 2H), 1.45-1.36 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.28, 162.81, 161.77, 161.65, 157.58, 155.96, 154.41, 127.74, 127.49, 110.07 , 110.04, 107.79, 107.57, 102.38, 102.13, 98.25, 58.15, 55.81, 53.35, 52.74, 47.12, 29.51, 24 ,50. MSHR (ESI) calculated for C ₂₃ H ₂₇ F ₂ N ₇ NaO ⁺ : 478.2137, found 478.2139.

[0196] Example 34: Receiving connection 34

connection 34

[0197]

[0198] The specific production method was the same as the production method of Compound 1, except that one of the starting materials was an equimolar amount of 3,5-bis(trifluoromethyl)phenylboronic acid instead of 3,5-dimethoxyphenylboronic acid in the production method (1-2). The results of NMR analysis of compound 34 were as follows:

[0199] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.44 (s, 1H), 8.20 (s, 2H), 7.99 (s, 1H), 6.61-6.51 (m , 1H), 6.28 (d, J=17.0 Hz, 1H), 5.69 (d, J=10.6 Hz, 1H), 4.48 (t, J=7.0 Hz, 2H ), 3.64 (s, 4H), 2.39 (d, J=26.1 Hz, 6H), 2.05-1.99 (m, 2H), 1.78 (s, 2H), 1 .38 (dd, J=23.0, 12.9 Hz, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.3, 157.5, 156.0, 154.8, 140.9, 135.5, 133.2, 132.9, 132.6, 128.5 , 127.8, 127.5, 124.4, 122.5, 121.7, 98.4, 58.1, 53.4, 52.7, 47.35 45.7, 41.8, 29, 5, 26.2, 24.5. MSHR (ESI) calculated for C ₂₅ H ₂₇ F ₆ N ₇ NaO ⁺ : 578.2073, found 578.2075.

[0200] Example 35: Receiving connection 35

connection 35

[0201]

[0202] The specific production method was the same as the method for producing compound 1, except that one of the starting materials was an equimolar amount of 3-fluoro-5-trifluoromethylphenylboronic acid instead of 3,5-dimethoxyphenylboronic acid in the method for producing compound (1 -2). The results of NMR analysis of compound 35 were as follows:

[0203] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.35 (s, 1H), 7.73 (s, 1H), 7.58 (dd, J=8.7, 2.0 Hz, 1H ), 7.40-7.37 (m, 1H), 6.48 (dd, J=16.8, 10.5 Hz, 1H), 6.20 (dd, J=16.8, 1.9 Hz, 1H), 5.61 (dd, J=10.5, 1.9 Hz, 1H), 4.39 (t, J=7.2 Hz, 2H), 3.60 (s, 2H), 3.47 (s, 2H), 2.34 (t, J=5.1 Hz, 4H), 2.30 - 2.24 (m, 2H), 1.96-1.90 (m, 2H) , 1.52-1.47 (m, 2H), 1.32 (t, J=7.6 Hz, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 162.0, 161.5, 157.8, 155.6, 154.1, 144.2, 135.0, 129.5, 127.8, 127.7 , 106.4, 101.0, 98.2, 58.0, 55.6, 53.3, 52.5, 47.0, 46.0, 42.2, 29.7, 29.5, 26 ,2, 24.5. MSHR (ESI) calculated for C ₂₄ H ₂₇ F ₄ N ₇ NaO ⁺ : 528.2105, found 528.2107.

[0204] Example 36: Receiving connection 36

connection 36

[0205]

[0206] The specific production method was the same as the production method of compound 10, except that one of the starting materials was an equimolar amount of 4,4,4-trifluorocrotonic acid instead of acryloyl chloride in the production method of compound (1-3). The results of NMR analysis of compound 36 were as follows:

[0207] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32 (s, 1H), 6.92 (dt, J=15.4, 2.1 Hz, 1H), 6.78 (d, J =2.3 Hz, 2H), 6.73 - 6.64 (m, 1H), 6.52 (t, J=2.3 Hz, 1H), 4.40 (t, J=7.2 Hz , 2H), 3.82 (s, 6H), 3.65 (t, J=5.2 Hz, 2H), 3.50 (t, J=5.0 Hz, 2H), 2.40 (q , J=4.7 Hz, 4H), 2.32 (t, J=7.5 Hz, 2H), 1.96 (p, J=7.4 Hz, 2H), 1.52 (q, J =7.6 Hz, 2H), 1.36 (q, J=8.2 Hz, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 162.3, 161.8, 158.1, 155.8, 154.3, 144.4, 135.3, 129.7, 129.4, 128.0 , 127.9, 121.4, 106.6, 101.3, 98.5, 58.3, 55.8, 53.5, 52.7, 47.3, 46.2, 42.5, 29 ,9, 29.8, 26.4, 24.7. MSHR (ESI) calculated for C ₂₆ H ₃₂ F ₃ N ₇ NaO ₃ ⁺ : 570.2411, found 570.2413.

[0208] Example 37: Receiving connection 37

connection 37

[0209]

[0210] The specific production method was the same as the production method of compound 34, except that one of the starting materials was an equimolar amount of 4,4,4-trifluorobutenoic acid instead of acryloyl chloride in the production method of compound (1-3). The results of NMR analysis of compound 37 were as follows:

[0211] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43 (d, J=2.3 Hz, 1H), 8.20 (s, 2H), 7.99 (s, 1H), 6, 94 (d, J=15.5 Hz, 1H), 6.72 (dt, J=14.9, 6.8 Hz, 1H), 4.48 (t, J=7.0 Hz, 2H), 3.69 (s, 2H), 3.54 (s, 2H), 2.41 (d, J=31.2 Hz, 6H), 2.02 (q, J=7.8 Hz, 2H), 1.59 (s, 2H), 1.44-1.26 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 164.1, 162.1, 161.6, 157.4, 155.9, 154.7, 141.3, 136.6, 127.7, 121.0 , 118.9, 118.7, 113.4, 113.2, 98.2, 58.0, 53.3, 52.5, 47.2, 45.9, 42.2, 29.7, 29 ,5, 26.1, 24.5, 14.1. MSHR (ESI) calculated for C ₂₆ H ₂₆ F ₉ N ₇ NaO ⁺ : 646.1947, found 646.1947.

[0212] Example 38: Receiving connection 38

connection 38

[0213]

[0214] The specific production method was the same as the production method of compound 35, except that one of the starting materials was an equimolar amount of 4,4,4-trifluorobutenoic acid instead of acryloyl chloride in the production method of compound (1-3). The results of NMR analysis of compound 38 were as follows:

[0215] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.43 (d, J=2.3 Hz, 1H), 8.20 (s, 2H), 7.99 (s, 1H), 6.94 (d, J=15.5 Hz, 1H ), 6.71 (dq, J=14.2, 6.7 Hz, 1H), 4.48 (t, J=7.0 Hz, 2H), 3.69 (s, 2H), 3.54 (s, 2H), 2.41 (d, J=31.2 Hz , 6H), 2.01 (t, J=7.6 Hz, 2H), 1.59 (s, 2H), 1.48-1.27 (m, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 162.0, 155.2, 154.6, 142.9, 133.2, 132.1, 132.1, 129.4, 129.0, 128.6, 128.5, 127.9, 121.3, 120.8, 111.6, 105.6, 58.1, 53.3, 52.6, 46.9 , 46.0, 42.3, 29.5, 26.3, 24.5, 22.1. MSHR (ESI) calculated for C ₂₆ H ₂₆ F ₉ N ₇ NaO ⁺ : 646.1947, found 646.1947.

[0216] Example 39: Receiving connection 39

connection 39

[0217]

[0218] The specific production method was the same as the production method of compound 10, except that one of the starting materials was an equimolar amount of trans-4-dimethylaminocrotonic acid instead of acryloyl chloride in the production method of compound (1-3). The results of NMR analysis of compound 39 were as follows:

[0219] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (s, 1H), 6.81 (d, J=2.3 Hz, 2H), 6.56 (t, J=2.3 Hz, 1H), 5.60 (s, 2H), 4.43 (t, J=7.2 Hz, 2H), 3.86 (s, 6H), 3.67 (t, J=5.1 Hz, 2H), 3.59 (t, J=5.1 Hz, 2H), 3.49 (s, 1H), 2.45 (t, J=5.1 Hz, 4H), 2.33 ( t, J=7.4 Hz, 2H), 1.96 (d, J=7.5 Hz, 2H), 1.50-1.35 (m, 4H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 161.5, 161.5, 157.7, 155.9, 144.0, 135.1, 106.4, 101.0, 100.0 98.3, 58.1, 55.6, 53.1, 52.4, 52.3, 49.4, 47.1, 45.8, 43.4, 43.3, 43.2, 37.4, 29, 6, 26.9, 26.5. MSHR (ESI) calculated for C ₂₅ H ₃₁ N ₇ NaO ₃ ⁺ : 500.2831, found 500.2833.

[0220] Example 40: Receiving connection 40

connection 40

[0221]

[0222] The specific production method was the same as the production method of compound 10, except that one of the starting materials was an equimolar amount of crotonic acid instead of acryloyl chloride in the production method of compound (1-3). The results of NMR analysis of compound 40 were as follows:

[0223] ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (s, 1H), 6.88-6.73 (m, 3H), 6.52 (t, J=2.3 Hz, 1H ), 6.20 (dq, J=15.0, 1.7 Hz, 1H), 4.39 (t, J=7.2 Hz, 2H), 3.82 (s, 6H), 3.62 (d, J=8.1 Hz, 2H), 3.56-3.43 (m, 2H), 2.36 (t, J=5.1 Hz, 4H), 2.29 (dd, J= 8.7, 6.4 Hz, 2H), 2.01-1.91 (m, 2H), 1.83 (dd, J=6.9, 1.7 Hz, 3H), 1.52 (t , J=7.6 Hz, 2H), 1.36 (ddd, J=15.3, 9.1, 5.4 Hz, 2H). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.5, 161.5, 158.0, 155.7, 154.1, 144.1, 141.5, 135.1, 121.4, 119.9 , 106.4, 101.1, 98.2, 60.4, 58.2, 55.5, 53.5, 53.4, 52.8, 47.0, 45.5, 41.8, 29 ,6, 26.2, 24.5, 18.2. MSHR (ESI) calculated for C ₂₆ H ₃₅ N ₇ NaO ₃ ⁺ : 516.2694, found 516.2696.

[0224] Example 41 Enzyme activity test.

[0225] In the present invention, homogeneous time-resolved fluorescence (HTRF) technology was used to evaluate the inhibitory effect of a compound on the four subtypes FGFR1, FGFR2, FGFR3 and FGFR4. First, prokaryotic expression vectors FGFR1, FGFR2, FGFR3, and FGFR4 were constructed; and when prokaryotic expression vectors were identified as correct, FGFR proteins were expressed and purified on a large scale in the Escherichia coli ( E. coli ) system and protein concentrations were determined. The resulting proteins were stored in aliquots. Before starting the enzyme activity test, Cisbio's HTRF KinEA Reagent Kit (62TK0PEB) was used to pre-dilute each component required in the enzyme activity measurement system with enzyme activity buffer to the required working concentration. A 384-well plate (66PL384025) was prepared, 5 μL of protein solution, 1 μL of compound and 2 μL of substrate were added to each well, and lastly 2 μL of ATP was added to initiate the reaction. For each concentration, three parallel experiments were performed. In the control group, 1 μl of compound was replaced by 1 μl of dimethyl sulfoxide (DMSO); and in the positive control group, the positive drug AZD4547 was used instead, leaving other conditions unchanged. The 384-well plate was sealed and incubated at room temperature for approximately 1 hour. After completion of incubation, 5 μl of lanthanide-labeled phosphorylated substrate antibody (donor) and 5 μl of streptavidin-labeled XL665 reagent (receptor) were added to each well to stop the reaction, after which the plate was incubated at room temperature for approximately 1 h in the dark. Finally, a TECAN Infinite M1000PRO multifunctional microplate reader was used to detect the fluorescent signal, the inhibition rate was calculated, and the IC50 value was determined using GraphPad Prism 7.0 software.

[0226] The results showed that compounds 1-40 can inhibit the protein activity of FGFR1/2/3/4 to varying degrees.

[0227] Table 1. Structure-activity relationship (SAR) studies based on enzyme activity measurements

No. Connection Ar Linker R Enzyme activity (IC ₅₀ /nM) FGFR1 FGFR2 FGFR3 FGFR4 1 H 315 540 520 1921 2 818 666 525 >5000 3 433 424 371 2730 4 615 641 521 >5000 5 741 1210 580 1780 6 790 1130 769 >5000 7 372 455 335 1610 8 323 351 414 4700 9 36.0 27.4 22.5 4210 10 3.2 1.4 2.7 3270 eleven 12.9 11.2 11.3 3207 12 5.9 2.2 3.4 >5000 13 476 789 875 2709 14 2109 1864 344 >5000 15 >5000 3121 >5000 >5000 16 1353 2511 1321 >5000 17 3523 4111 >5000 >5000 18 >5000 >5000 >5000 >5000 19 >5000 >5000 >5000 >5000 20 >5000 >5000 >5000 >5000 21 866 954 1978 >5000 22 324 231 523 >5000 23 277 223 486 4910 24 1877 >5000 >5000 3903 25 >5000 >5000 >5000 2246 26 1501 2345 >5000 >5000 27 554 763 731 2723 28 185 337 321 2987 29 417 560 318 2580 thirty >5000 >5000 >5000 >5000 31 >5000 >5000 >5000 >5000 32 118 133 132 >5000 33 790 >10 >10 4112 34 133 165 115 3921 35 14.1 29.3 13.2 4102 36 CF ₃ 0.7 0.7 0.9 809 37 9.9 12.1 10.2 >5000 38 101 65 97 2401 39 (CH ₃ ) ₂ NCH ₂ 13.8 37.5 15.5 >5000 40 CH ₃ 16.6 26.3 12.4 >5000 AZD4547 N.D. 1.1 2.2 1.8 660

[0228] Example 42 Cell Proliferation Assay

[0229] In the present invention, compounds 10 and 36 were selected, and the methylthiazolyltetrazole (MTT) colorimetric method was used to evaluate the proliferation inhibitory effect of compounds 10 and 36 on various tumor cells. Tumor cells in the logarithmic growth phase were collected by trypsinization and resuspended in 1 ml of fresh medium, a small amount of the resulting suspension was collected, diluted, and cells were counted using a hemocytometer. Depending on the growth rate, tumor cells were seeded in a 96-well plate at a density of 3000 cells per well to 5000 cells per well and then cultured in an incubator for 24 hours. Tumor cells were treated with compounds 10 and 36 in 8 concentrations, three wells for each concentration, and then incubated for 96 hours. After completion of incubation, 10 μl of MTT solution (5 mg/ml) was added to each well, the plate was tapped to mix thoroughly, and then incubated in the incubator for 3-4 hours. At the end of the incubation, the liquid in the wells was carefully pipetted and removed, and then 100 μl of DMSO solution was added to each well. The microplate reader programs were set to detect absorbance values at wavelengths of 490 nm and 570 nm, respectively, the rate of proliferation inhibition at each concentration was calculated according to the formula, and finally Graphpad Prism 7 software was used to process the data to calculate IC ₅₀ .

[0230] The results shown in Table 1 showed that compounds 10 and 36 significantly inhibited the proliferation of NCI-H1581 human lung squamous cell carcinoma cells (FGFR1 amplification) and SNU-16 human gastric cancer cells (FGFR2 amplification) and inhibited cell proliferation to some extent human hepatoma SK-hep-1 (FGFR4 amplification), but did not have a clear inhibitory effect on tumor cells with normal FGFR expression, indicating the high selectivity of compounds 10 and 36.

[0231] Table 2. Antiproliferative activity of compound 36 against specific cancer cell lines

Compound IC ₅₀ /µM NCI-H1581 FGFR1 amplification SNU-16 FGFR2 amplification SK-hep-1 FGFR4 amplification Huh-7 A549 AZD4547 0.042±0.002 0.006±0.001 2.78±0.069 >10 >10 10 0.051±0.003 0.037±0.005 2.86±0.250 >10 >10 36 0.055±0.008 0.043±0.006 3.05±0.120 >10 >10

[0232] Example 43 Compounds 10 and 36 inhibit FGF/FGFR and their downstream signaling pathways.

[0233] To further elucidate the effect of compounds 10 and 36 on FGF/FGFR signaling, the effect of the compounds on phosphorylation of FGFR and downstream signaling protein was confirmed by Western blotting (WB). NCI-H1581 human squamous cell lung carcinoma cells and SNU-16 human gastric cancer cells were collected at logarithmic growth phase by trypsinization and resuspended in 1 ml of fresh medium, then a small volume of the resulting tumor cell suspension was collected, diluted, and cell counts were performed using a hemocytometer. An appropriate volume of tumor cell suspension was selected, seeded into a 6-well plate at a density of 3×10 ⁵ cells per well, and cultured in an incubator for 24 hours. After complete cell adhesion, the used medium was pipetted and removed, fresh media with compounds 10 and 36 at different concentrations were added, and the plate was incubated in an incubator for 12 hours. After completion of incubation, the culture supernatant was pipetted and discarded, and the plate was washed three times with a pre-cooled 1X PBS solution to completely remove the residual solution by pipetting. 60 μl of RIPA lysis buffer was added to each well and the cells were gently scraped with a cell scraper; the resulting lysis buffer was transferred into a 1.5 ml Eppendorf tube, incubated in an ice bath for 10 minutes and centrifuged at 14,000 rpm for 10 minutes, the resulting supernatant was pipetted into a new 1.5 ml Eppendorf tube, and a small amount of supernatant was pipetted to determine protein content; and an appropriate volume of 5× loading buffer was added to the remaining supernatant, the resulting mixture was vortexed to mix thoroughly and placed in a metal bath at 100°C for 10 minutes. Based on the determined protein content, the corresponding loading amount was calculated at 30 μg of protein per well. Proteins were isolated by 8% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), the isolated proteins were transferred to a polyvinylidene fluoride (PVDF) membrane, stained with Ponceau S, and the PDVF membrane with proteins was cut according to the molecular weight of the target protein, washed with 1X TBST for removal of Ponceau S and blocked with 5% skimmed milk powder for 30 min. The PDVF membrane was washed three times with 1X TBST solution, the PDVF membrane with the target protein band was placed in an incubation box, the appropriate primary antibody incubation solution was added, and the PDVF membrane was incubated at 4°C overnight. After incubation with primary antibodies was completed, the membrane was washed three times with 1X TBST, the appropriate secondary antibody incubation solution was added, and the membrane was incubated at room temperature for 1.5 hours. After completion of incubation, the membrane was washed three times with 1X TBST and color developed using an ultrasensitive horseradish peroxidase (HRP) chemiluminescence kit.

[0234] As shown in Figure 1 and Figure 2, compounds 10 and 36 not only significantly inhibited FGFR1 phosphorylation in NCI-H1581 cells and FGFR2 phosphorylation in SNU-16 cells, but also dose-dependently inhibited the activation of downstream PLCγ, AKT and ERK. That is, compounds 10 and 36 can potently inhibit FGF/FGFR and downstream signaling pathways in vitro .

[0235] Example 44 Significant inhibition of tumor growth in mice by compounds 10 and 36.

[0236] To evaluate the antitumor effects of compounds 10 and 36 in vivo, a mouse subcutaneous xenograft model of NCI-H1581 human squamous cell carcinoma cells with high expression of FGFR1 was generated. Cells in logarithmic growth phase were collected by trypsinization and washed three times with 1X PBS. The resulting cell pellet was diluted to 1×10 ⁸ cells/ml with a resuspension solution (medium 1640: Matrigel = 1:1) and inoculated into the lower parts of the axillae of the forelimbs of 5-6-week-old female BALB/c Nude mice in an amount of 5× 10 ⁶ cells per mouse. As the tumor volume increased from 50 mm ³ to 100 mm ^{3 ,} mice were randomly divided into three groups (control, 50 mg/kg and 100 mg/kg) of 6 mice each. Compound 10 was administered orally every day, and Compound 36 was administered intraperitoneally every day. The tumor volume and body weight of the mouse were measured. Mice were treated 26 days after administration, and tumor tissue was excised and fixed in formalin solution for later use.

[0237] As shown in Figure 3 and Figure 4, compounds 10 and 36 inhibited the proliferation of NCI-H1581 cells in mice in a dose-dependent manner with an inhibition rate of 72% in the high dose group; inhibited the activation of FGFR1 phosphorylation in tumor tissue; and did not result in obvious body weight loss, indicating that compounds 10 and 36 were well tolerated in vivo at all doses.

[0238] In conclusion, the present invention optimizes 2H-pyrazolo[3,4-d]pyrimidine to produce its new derivatives (compounds 10 and 36), and compounds 10 and 36 serve as effective and selective inhibitors of FGFR1, FGFR2 and FGFR3, which exhibit irreversible effect of binding to the target protein. The compounds are lead compounds that can not only inhibit FGF/FGFR and downstream signaling pathways at low concentrations, but also exert significant antiproliferative effects on the NCI-H1581 cancer cell line in vitro and in vivo . In addition, compounds 10 and 36 have low toxicity and excellent pharmacokinetic properties and are currently being identified as potential drug candidates.

[0239] The above description represents only examples of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements consistent with the spirit and principle of the present invention are intended to be included within the claimed scope of the present invention.

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Claims (14)

1. Compound of formula I or a pharmaceutically acceptable salt thereof: formula I, where Ar represents R is H, CF ₃ , (CH ₃ ) ₂ NCH ₂ or CH ₃ and the linker is or and said connection also includes connection 25 and connection 26. 2. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is a compound selected from the group consisting of: connection 7, connection 8, connection 9, connection 10, connection 11, connection 12, connection 13, connection 14, connection 15, connection 16, connection 17, connection 18, connection 19, connection 20, connection 21, connection 22, connection 23, connection 24, connection 27, connection 28, connection 29, connection 30, connection 31, connection 32, connection 33, connection 34, connection 35, connection 36, connection 37, connection 38, connection 39 and connection 40. 3. A pharmaceutical composition for inhibiting the protein activity of FGFR1/2/3/4 to varying degrees, containing a compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, where the pharmaceutical composition also contains one or more pharmaceutically acceptable excipients; And the dosage form of the pharmaceutical composition is any pharmaceutically acceptable dosage form. 4. Use of a compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2 or a pharmaceutical composition according to claim 3 for the preparation of a medicament for the treatment and/or prevention of cancer associated with an FGFR abnormality. 5. Use of a compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2 or a pharmaceutical composition according to claim 3 to obtain an irreversible pan-FGFR inhibitor.