Novel n-terphenylpicolinamide derivatives and their use

Abstract

Disclosed are novel N-terphenylpicolinamide derivatives representing small molecule inhibitors of the PD-1 / PD-L1 pathway, which is a key control point of the immune response which may be used in cancer immunotherapy.

Description

[0001] Novel N-terphenylpicolinamide derivatives and their use

[0002] The subject of the invention are novel N-terphenylpicolinamide derivatives representing small molecule inhibitors of the PD-1 / PD-L1 pathway, which is a key control point of the immune response, which may be used in cancer immunotherapy.

[0003] Cancer is still a challenge for medical sciences, despite widely developed treatment methods (Chakraborty 2012). So far, many treatment methods have been developed, such as surgery, radiotherapy, chemotherapy, targeted therapies or hormone therapy, however, the breakthrough was the emergence of cancer immunotherapy (Couzin-Frankel 2013). Immunotherapy presents a modem approach, based on the control of the body's immune mechanisms in order to recognize and fight cancer cells. Cancer therapy based on inhibiting negative regulation of the immune system has become an extremely promising method of cancer treatment (Ledford et al. 2018). Unlike conventional methods that often affect both healthy and malignant cells, cancer immunotherapy offers a more targeted and individualized approach aimed at enhancing the immune system's ability to identify and eliminate cancers with remarkable precision(Schuster et al. 2006).

[0004] In recent years, the field of cancer immunotherapy has been revolutionized by the discovery and understanding of immune regulation pathways. Among these pathways, PD-1 / PD-L1 interaction stands out as a key regulator of the immune response(Alsaab et al. 2017).

[0005] Programmed Death Receptor 1 (PD-1), also known as CD279, is a glycoprotein with a mass of about 55 kDa, consisting of 288 amino acids, belonging to the B7-CD28 protein family. It is composed of three domains: an extracellular IgV-like domain, a transmembrane domain, and a cytoplasmic domain. PD-1 acts as a negative regulator of the immune response. The pdcdl gene, which encodes PD-1, is located on the second chromosome (2q37) and is expressed on the surface of activated T and B lymphocytes.

[0006] PD-1 protein ligand, PD-L1, also called CD270 or B7-H1, is a glycoprotein with a mass of 33 kDa, consisting of 290 amino acids, which gene is located on chromosome 9p24. It is a type I transmembrane protein, has Ig- and IgC domains in the extracellular area. PD-L1 expression occurs primarily on the surface of dendritic cells and macrophages. Overexpression of PD-L1 has been observed in various types of cancer cells, leading to a weakening of the body's immune response(Wu et al. 2015). When T cells encounter tumor cells exposing PD-L1, the PD-1 / PD-L1 interaction sends a signal that inhibits the activity of T cells. This allows the tumor cells to evade the control of the immune system(Hino et al. 2010). Blocking this pathway, for example with specific antibodies, restores cytotoxic functions to T cells, normalizing the body's immune response. This is a key component of cancer immunotherapy.

[0007] So far, monoclonal antibodies have been used in therapies based on blocking the interaction of PD- 1 / PD-L1, while in clinical trials there are four small -molecule inhibitors targeting PD-L1. These PD- 1 / PD-L1 interaction modulators represent a promising strategy in cancer immunotherapy due to the much lower production costs, the possibility of oral administration, as well as the potential absence of side effects associated with the patient's immune response, which is characteristic of antibody-based therapies.

[0008] The aim of the invention is to provide novel compounds that would act as small-molecule inhibitors of the PD-1 / PD-L1 pathway, which is a key control point of the immune response. Such compounds could, in particular, find use in cancer immunotherapy.

[0009] The aforementioned problem has been solved by the present invention.

[0010] The present invention relates to compounds and uses thereof as defined in the appended claims.

[0011] Detailed description of the invention

[0012] An exemplary embodiment of the invention are inhibitors of the PD-1 / PD-L1 interaction of the general formula (Scheme 1),

[0013] Scheme 1. Structure of inhibitors based on N-terphenylpicolinamide core wherein R1is a respectively: -H, -F, -Cl, -Br, -CH3,-O-alkyl, -NH-alkyl, -N-dialkyl, -CN, -NO2;

[0014] R2 are substituents which increase water-solubility, examples of which are shown below:

[0015] or their pharmaceutically acceptable salts that can find use as drugs in the treatment of cancer. In order to confirm the activity of the compounds in the dissociation of the PD-1 / PD-L1 protein complex, methods based on cellular tests were used.

[0016] For a better description of the invention, it is explained in the following examples.

[0017] In the context of the present invention, "-O-alkyl" is to be understood as an alkoxy group preferably comprising from 1 to 4 carbon atoms, particularly preferably one carbon atom.

[0018] In the context of the present invention, "-NH-alkyl" is to be understood as an amino group comprising alkyl fragment, preferably comprising from 1 to 4 carbon atoms, particularly preferably one carbon atom.

[0019] In the context of the present invention, "-N-dialkyl" is to be understood as an amino group comprising two alkyl fragments, preferably comprising from 2 to 6 carbon atoms, particularly preferably two carbon atoms. All reagents and solvents used in the synthesis came from commercial sources, without additional purification, except where required.1H and13C NMR spectra were recorded on 300 MHz and 600 MHz Bruker Avance, as well as 400 MHz Jeol spectrometers. All chemical shifts (5) are given in ppm, and coupling constants (J) in hertz [Hz], Chemical shifts were referenced to an internal TMS standard, or analyzed with reference to solvents such as CDCL, MeOD-d4, DMSO-d6. The compounds were purified by column chromatography using a Grace Reveleris X2 flash chromatograph with Grace Resolv Silica columns. The reaction progress was monitored by visualization of TLC silica gel plates of the TLC Merck 60 254 to 365 nm type. In order to obtain chromatograms and mass spectra, the UPLC-MS system composed of TQD Waters Acquity Premier coupled with the Waters Xevo TQ-S Cronos mass spectrometer was used. (Column: ACQUITY UPLC BEH C18 VanGuard, 1.7 pm, 2.1 x 100 mm, precolumn: ACQUITY UPLC BEH C18, 1.7 pm, 2. 1 x 10 mm, method: column kept at 40°C, gradient: from 95% to 0% of eluent A over 10 minutes, flow rate 0.3 mL / min. Eluent A: water / formic acid (0. 1% v / v; eluent B: acetonitrile / formic acid (0.1%, v / v)). Chromatograms were recorded using Waters c'z. PDA detector. MS Detection Settings: Temperature: 150°C, desolvation 250°C, desolvation gas flow rate 600 L / h, cone gas flow 100 L / h, capillary potential 3.00 kV, cone potential 30 V. Nitrogen was used for both nebulization and drying gas. The data was obtained in scanning mode in the range of 50 to 1000 m / z at intervals of 0.5 s.

[0020] SUMMARY OF PROCEDURES USED DURING THE SYNTHESIS OF INHIBITORS

[0021] PROCEDURE 1. General procedure for borylation of Miyaura.

[0022] Bis(pinacolano)diboron, anhydrous potassium acetate, corresponding aryl bromide, and anhydrous dioxane were placed in a round-bottomed flask under argon atmosphere. The solution was deoxidized by passing argon for half hour and then Pd(dppf)C12'DCM complex was added. The reaction mixture was heated at 80 °C overnight in an oil bath. After this time, water was added and extracted with ethyl acetate. The organic phases were collected, dried over anhydrous MgSCL, and evaporated. The crude product was purified on a chromatography column (SiCf. hexane / dichloromethane, or hexane / ethyl acetate).

[0023] PROCEDURE 2. General Suzuki coupling procedure leading to biphenyl derivatives.

[0024] The respective pinacolic ester of boric acid, l,3-dibromo-2-chlorobenzene, potassium carbonate, and a mixture of dioxane and water (2 / 1, v / v) or acetonitrile were placed in a round bottom flask. The solution was deoxidized by passing argon for half hour and then Pd(dppf)C12'DCM complex was added. The reaction mixture was heated at 80 °C for 4 hours in an oil bath. After this time, the solution was poured into a separator and extracted with ethyl acetate. The organic phases were collected, dried over anhydrous MgSCh, and evaporated. The crude product was purified on a chromatography column fSiCF. hexane / ethyl acetate, or chloroform / ethyl acetate).

[0025] PROCEDURE 3. General procedure for the synthesis of N-biphenylpicolinamide derivatives.

[0026] 5-(Methoxycarbonyl)picolinic acid was placed in a round-bottom flask under reflux and thionyl chloride was added. The mixture was heated under reflux for 2 h. After this time, thionyl chloride was evaporated, the resulting precipitate was dissolved in a small amount of anhydrous toluene and the solvent was evaporated again.

[0027] In a further step, the resulting acid chloride was dissolved in anhydrous THF under argon atmosphere, anhydrous triethylamine was added, and the mixture was cooled to 0°C with an ice bath. A solution of the corresponding l,l'-biphenyl-3-amine in anhydrous THF was then added in portions. The contents of the flask were stirred overnight on a magnetic stirrer and then the solvent was evaporated. The resulting slurry was dissolved in chloroform, then poured into a separator and washed with saturated aqueous NaHCOs. The organic phases were collected, dried over anhydrous MgSCh, and evaporated. The crude product was purified on a chromatography column fSiCF. hexane / ethyl acetate, or chloroform / ethyl acetate).

[0028] PROCEDURE 4. General ester reduction procedure. A suitable N-biphenylpicolinamide derivative was placed in a round-bottom flask. After rinsing the flask with argon, a mixture of anhydrous THF and methanol (2 / 1, v / v) was added. The solution was then cooled with an ice bath and LiBth was added in portions over 30 minutes. The contents of the flask were stirred for one hour followed by a TLC control analysis (Si O2- chloroform / ethyl acetate, 9 / 1, v / v). After complete disappearance of the substrate, IM HC1 solution was added up to pH 2. The resulting mixture was poured into a separator and extracted three times with DCM. The organic phases were collected, dried over anhydrous MgSCh, and evaporated. The crude product was purified on a chromatography column (SiC>2, hexane / ethyl acetate, or chloroform / ethyl acetate).

[0029] PROCEDURE 5. General Suzuki coupling procedure leading to N-terphenylpicolinamide derivatives.

[0030] The respective derivative of N-biphenylpicolinamide, (2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)methanol, caesium carbonate, and a mixture of 1,4-dioxane and water (2 / 1, v / v) were placed in a round bottom flask. The solution was deoxidized by passing argon for half hour and then Pd(dppf)C12-DCM complex was added. The reaction mixture was heated at 80 °C for 4 hours in an oil bath. After this time, the solution was poured into a separator and extracted with chloroform. The organic phases were collected, dried over anhydrous MgSCL, and evaporated. The crude product was purified on a chromatography column (Si O2- hexane / ethyl acetate, or chloroform / ethyl acetate).

[0031] PROCEDURE 6. General procedure for amine alkylation.

[0032] A suitable diol was placed in a spherical flask with anhydrous dichloromethane and a few drops of anhydrous DMF (0.2 mL per 2 mmol of alcohol), after which the solution was cooled in an ice bath. Thionyl chloride was then added dropwise. The contents of the flask were stirred for about 2 hours at room temperature and the progress of the reaction was controlled by TLC (SiCL, chloroform / ethyl acetate, 1 / 1, v / v). After the substrate disappeared, the reaction mixture was poured onto saturated NaHCOs and extracted with dichloromethane. The organic phases were combined, dried over anhydrous MgSCL, and the solvent was evaporated. The crude product was used without further purification.

[0033] Crude alkyl chloride was dissolved in anhydrous DMF and then the respective amine (NHR2) and diisopropylethylamine (DIPEA) or triethylamine were added. The reaction mixture was stirred overnight at 70°C. After completion of the reaction, the solvent was evaporated, then the solid product was dissolved in a 1 / 9 chloroform / methanol mixture, poured into saturated NaHCOs solution and extracted with chloroform (four times). The organic phases were collected, dried over anhydrous MgSC , and the solvent was evaporated. The crude product was purified by column chromatography (SiO , CHCls / methanol / ? M NH3 in methanol, 9 / 1 / 1, v / v / v).

[0034] EXAMPLE 1. N-(2'-chloro-4"-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-3"- methoxy-[ 1 , T : 3', T ’ -terphenyl] -3-yl)-5-((( 1,3-dihy droxy-2-(hydroxymethyl)propan-2- yl)amino)methyl)picolinamide (1)

[0035] Intermediate product la; 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline During the synthesis PROCEDURE 1 was used

[0036] 3 -bromoaniline (1.00 g, 5.81 mmol, 1.0 eq.), bis(pinacolato)diboron (2.21 g, 8.72 mmol, 1.5 eq.), potassium acetate anhydrous (1.71 g, 17.44 mmol, 3.0 eq.), Pd(dppf)C12'DCM (0.24 g, 0.29 mmol, 0.05 eq.), anhydrous 1,4-dioxane (20 mL). Product la was obtained as a brown precipitate with 85% (1.08 g) yield.

[0037] Rf= 0.09 (SiO2, DCM); 'H NMR (600 MHz, CDCL) 5 [ppm]: 'H NMR (600 MHz, CDCL) 5 7.21 (d, J= 7.2 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.14 (d, J= 2.2 Hz, 1H), 6.79 (ddd, J= 7.8, 2.5, 1.2 Hz, 1H),

[0038] 3.65 (s, 2H), 1.34 (s, 12H);13C NMR (151 MHz, CDCL) 5 145.8, 128.8, 125.0, 121.2, 118.1, 83.7, 24.9; IR (ATR) [cm ]: 3464, 3375, 2981, 1627, 1356, 1139, 705;

[0039] Intermediate product lb; 3'-bromo-2’-chloro-[l,l’-biphenyl]-3-amine

[0040] During the synthesis PROCEDURE 2 was used

[0041] 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline la (1.35 g, 6.16 mmol, 1.0 eq.), l,3-dibromo-2- chlorobenzene (2.50 g, 9.24 mmol, 1.5 eq.), potassium carbonate (2.55 g, 18.49 mmol, 3.0 eq.), Pd(dppf)CL DCM (0.25 g, 0.31 mmol, 0.05 eq.), 1,4-dioxane / water (40 mL / 20 mL). Product lb was obtained as a brownish precipitate with 75% (1.30 g) yield.

[0042] Rf= 0.58 (SiO2, chloroform / ethyl acetate, 9: 1); 'H NMR (600 MHz, CDCL) 5 7.56 (dd, J= 8.0, 1.6 Hz, 1H), 7.20 (dd, J= 7.6, 1.6 Hz, 1H), 7. 16 (t, J= 7.8 Hz, 1H), 7.08 (t, J= 7.8 Hz, 1H), 6.74-6.69 (m, 1H),

[0043] 6.65 (ddd, J = 8.0, 2.3, 0.9 Hz, 1H), 6.64-6.61 (m, 1H), 3.68 (s, 2H);13C NMR (151 MHz, CDCL) 5 146.2, 143.1, 140.7, 132.8, 132.7, 130.1, 129.1, 127.5, 123.8, 119.6, 115.9, 114.7; IR (ATR) [cm4]: 3419, 3338, 3016, 1582, 1397, 778, 696.

[0044] Intermediate product 1c; Methyl 6-((3'-bromo-2’-chloro-[l,l’-biphenyl]-3-yl)carbamoyl)nicotinate During the synthesis PROCEDURE 3 was used 5-(methoxycarbonyl)picolinic acid (0.14 g, 0.76 mmol, 1.2 eq.), 3'-bromo-2’-chloro-[l,l'-biphenyl]-3- amine lb (0.18 g, 0.64 mmol, 1.0 eq.), SOC12(5 mL), triethylamine (0.44 mL, 3.2 mmol, 5.0 eq.), anhydrous THF (7 mL). Product 1c was obtained as a colorless precipitate with 92% (0.26 g) yield.

[0045] Rf= 0.59 (SiO2, chloroform / ethyl acetate, 9 / 1); 'H NMR (600 MHz, CDC13) 5 10.09 (s, 1H), 9.20 (d, J = 1.2 Hz, 1H), 8.52 (dd, J= 8.1, 1.7 Hz, 1H), 8.38 (d, J= 8. 1 Hz, 1H), 7.89-7.79 (m, 2H), 7.65 (dd, J= 8.0, 1.5 Hz, 1H), 7.47 (dd, J= 8.6, 7.8 Hz, 1H), 7.32 (dd, J= 7.6, 1.5 Hz, 1H), 7.21 (d, J= 7.8 Hz, 1H), 7.18 (t, J= 7.8 Hz, 1H), 4.01 (s, 3H);13C NMR (151 MHz, CDCh) 5 165.0, 161.0, 158.5, 152.6, 149.2,

[0046] 142.3, 140.6, 139.1, 137.3, 133.0, 130.2, 129.0, 128.4, 127.5, 125.6, 123.9, 122.2, 120.6, 119.3, 52.8; IR (ATR) [cm ]: 3343, 2956, 1727, 1681, 1535, 1433, 783, 701, 671.

[0047] Intermediate product Id; N-(3’-bromo-2’-chloro-[l,l’-biphenyl]-3-yl)-5-

[0048] (hydroxymethyl)picolin amide

[0049] During the synthesis PROCEDURE 4 was used

[0050] Methyl 6-((3'-bromo-2'-chloro-[l,l'-biphenyl]-3-yl)carbamoyl)nicotinate 1c (1.24 g, 2.78 mmol, 1.0 eq.), LiBH4 (0.30 g, 13.91 mmol, 5.0 eq.), anhydrous mixture of THF / methanol (40 mL / 20 mL). Product Id was obtained as a colorless precipitate with 54% (0.63 g) yield.

[0051] Rf= 0.18 (SiO2, chloroform / ethyl acetate, 3 / 1); 'H NMR (600 MHz, CDCI3) 5 10.08 (s, 1H), 8.59 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.87-7.77 (m, 2H), 7.64 (dd, J = 8.0, 1.5 Hz, 1H), 7.45 (dd, J= 10.3, 6.0 Hz, 1H), 7.31 (dd, J= 7.6, 1.5 Hz, 1H), 7.22-7.13 (m, J = 14.8, 7.1 Hz, 2H), 4.84 (s, 2H), 2.17 (s, 1H);13C NMR (151 MHz, CDCI3) 5 162.0, 148.9, 146.6, 142.4, 140.5, 139.4, 137.6, 136.1, 133.0, 130.2, 128.9, 127.5, 125.3, 123.8, 122.30, 120.6, 119.2, 62.4; IR (ATR) [cm4]: 3331, 1683, 1606, 1544, 1419, 1014, 772, 691.

[0052] Intermediate product le; N -(2 ’ -chloro-4 ’ ’ -(hydroxymethyl)-3 ’ ’ -methoxy - [ 1 , 1 ’ : 3 ’ , 1 ” -terphenyl] - 3 -y 1) - 5-(hydroxymethyl)picolin amide

[0053] During the synthesis PROCEDURE 5 was used

[0054] N-(3'-bromo-2'-chloro-[l,r-biphenyl]-3-yl)-5-(hydroxymethyl)picolinamide Id (0.24 g, 0.57 mmol, 1.0 eq.), (2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)methanol (0.30 g, 1.15 mmol, 2.0 eq.), caesium carbonate (0.56 g, 1.72 mmol, 3.0 eq.), Pd(dppf)Cl2DCM complex (0.02 g, 0.03 mmol, 0.05 eq.), 1,4-dioxane / water (4mL / 2 mL). Product le was obtained as a brown precipitate with 71% (0.19 g) yield.

[0055] Rf= 0.24 (SiO2, hexane / ethyl acetate 1:2; 'H NMR (600 MHz, CDCl3 / MeOD-d4, 1 / 2) 5 8.59 (s, 1H), 8.24-8.12 (m, 1H), 7.91 (d, J= 7.6 Hz, 1H), 7.86-7.81 (m, 1H), 7.78 (d, J= 8.1 Hz, 1H), 7.46-7.41 (m, 1H), 7.40-7.36 (m, 1H), 7.36-7.28 (m, 3H), 7.23 (d, J= 7.6 Hz, 1H), 7.00 (d, J= 7.6 Hz, 1H), 6.96 (s, 1H), 4.73 (s, 2H), 4.69 (s, 2H), 3.85 (s, 3H);13C NMR (151 MHz, CDCl3 / MeOD-d4, 1 / 2) 5 166.6, 160.4,

[0056] 152.3, 150.7, 145.4, 145.1, 144.9, 144.5, 141.1, 140.1, 134.7, 134.4, 134.3, 132.6, 132.4, 131.7, 130.3, 129.7, 126.0, 125.5, 125.1, 123.0, 115.6, 65.3, 63.9, 59.2; IR (ATR) [cm4]: 3333, 2937, 1687, 1467, 1404, 1228, 1008, 780.

[0057] Final product 1; N-(2’-chloro-4”-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)- 3 ’ ’-methoxy-[l, 1 ’ :3 ’, 1 ” -terphenyl] -3 -yl)-5 - ((( 1,3 -dihy droxy-2-(hy droxymethyl)propan-2- yl)amino)methyl)picolinamide

[0058] During the synthesis PROCEDURE 6 was used

[0059] Step 1: N-(2'-chloro-4"-(hydroxymethyl)-3"-methoxy-[l,r:3',l"-terphenyl]-3-yl)-5-

[0060] (hydroxymethyl)picolinamide le (0.10 g, 0.21 mmol, 1.0 eq.), SOCL (0.09 ml, 1.26 mmol, 6.0 eq.), anhydrous DMF (5 drops), anhydrous DCM (5 mL).

[0061] Step 2: Tris(hydroxymethyl)aminomethane (0.15 g, 1.26 mmol, 6 eq.). ACA'-diisopropylcthylaminc (0.15 ml, 0.84 mmol, 4 eq.), anhydrous DMF (3 mL). Product 1 was obtained as a colorless precipitate with 58% (0.08 g) yield.

[0062] Rf= 0.33 (SiO2, CHCl3 / MeOH / 7M NH3in MeOH, 10 / 3 / 1 v / v); 'H NMR (600 MHz, MeOD) 5 8.73 (d, J = 1.7 Hz, 1H), 8. 17 (d, J = 8.0 Hz, 1H), 8.06 (dd, J= 8.0, 2.0 Hz, 1H), 7.94 (t, J= 1.8 Hz, 1H), 7.80 (ddd, J= 8. 1, 2.0, 0.9 Hz, 1H), 7.46 (t, J= 8.0 Hz, 1H), 7.43 (d, J= 7.4 Hz, 1H), 7.42-7.39 (m, J= 4.6, 2.3 Hz, 2H), 7.37 (dd, J= 7.3, 2.0 Hz, 1H), 7.24 (d, J= 7.7 Hz, 1H), 7.09 (d, J= 1.3 Hz, 1H), 7.03 (dd, J= 7.6, 1.5 Hz, 1H), 4.06 (s, 2H), 3.98 (s, 2H), 3.92 (s, 3H), 3.73 (s, 6H), 3.66 (s, 6H);13C NMR (151 MHz, MeOD) 5 163.2, 157.4, 148.5, 148.4, 141.5, 141.4, 141.4, 140.8, 140.2, 137.6, 137.5, 130.4, 130.3, 130.2, 129.9, 128.3, 126.4, 125.4, 121.7, 121.6, 121.2, 119.3, 111.9, 62.2, 61.5, 60.4, 54.8, 42.9, 41.2; IR (ATR) [cm4]: 3286, 2930, 1662, 1534, 1418, 1225, 1024, 784, 698. LC-MS (DAD / ESI): tR= 4.44 min, calculated for C35H4IC1N4O8(m / z) [M+FA-H]’ 725.26; found [M+FA-H]’ 725.42; HRMS (ESI): calculated for C35H4IC1N4O8[m / z] [M+H]+681.2685; found [M+H]+681.2686.

[0063] EXAMPLE 2. N-(2'-chloro-4”-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-2,3"- dimethoxy-[l,l':3',l”-terphenyl]-3-yl)-5-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2- yl)amino)methyl)picolinamide (2)

[0064] Intermediate product 2a; 2-methoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline

[0065] During the synthesis PROCEDURE 1 was used

[0066] 3-bromo-2-methoxyaniline (1.00 g, 4.94 mmol, 1.0 eq.), bis(pinacolato)diboron (1.88 g, 7.41 mmol, 1.5 eq.), potassium acetate anhydrous (1.45 g, 14.82 mmol, 3.0 eq.), Pd(dppf)C12'DCM (0.22 g, 0.27 mmol, 0.05 eq.), anhydrous 1,4-dioxane (20 mL). Product 2a was obtained as a brown precipitate with 60% (0.75 g) yield.

[0067] Rf= 0. 10 (SiO2, DCM); 'H NMR (600 MHz, CDCL) 5 7. 14 (dd, J= 7.3, 1.7 Hz, 1H), 6.95 (t, J= 7.5 Hz, 1H), 6.88 (dd, J= 7.8, 1.7 Hz, 1H), 3.83 (s, 3H), 1.38 (s, 12H);13C NMR (151 MHz, CDCL) 5 152.6, 139.5, 126.1, 124.2, 119.1, 83.5, 61.4, 24.8; IR (ATR) [cm ]: 3463, 3351, 2975, 1597, 1355, 1138, 766.

[0068] Intermediate product 2b; 3 ’ -bromo-2 ’ -chloro-2-methoxy- [ 1,1’ -biphenyl] -3 -amine

[0069] During the synthesis PROCEDURE 2 was used

[0070] 2-methoxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline 2a (0.72 g, 2.89 mmol, 1.0 eq.), 1,3- dibromo-2-chlorobenzene (1.17 g, 4.34 mmol, 1.5 eq.), potassium carbonate (1.20 g, 8.67 mmol, 3.0 eq.), Pd(dppf)CL DCM (0.12 g, 0.14 mmol, 0.05 eq.), 1,4-dioxane / water (40 mL / 20 mL). Product 2b was obtained as a brown precipitate with 61% (0.55 g) yield.

[0071] Rf= 0.26 (SiO2, hexane / ethyl acetate 3: 1); 'H NMR (600 MHz, CDC13) 5 7.67 (dd, J= 8.0, 1.6 Hz, 1H), 7.33 (dd, J = 7.6, 1.6 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.00 (t, J = 7.7 Hz, 1H), 6.83 (dd, J = 7.9, 1.5 Hz, 1H), 6.61 (dd, J= 7.6, 1.5 Hz, 1H), 3.89 (s, 2H), 3.45 (s, 3H);13C NMR (151 MHz, CDC13) 5 144.6, 140.0 139.9, 133.8, 133.1, 132.9, 130.5, 127.2, 124.2, 123.3, 120.5, 116.0, 59.9; IR (ATR) [cm4]: 3473, 3369, 2991, 2933, 1606, 1399, 1214, 992, 782, 725, 606.

[0072] Intermediate product 2c; Methyl 6-((3’-bromo-2’-chloro-2-methoxy-[l,l’-biphenyl]-3- yl)carbamoyl)nicotinate

[0073] During the synthesis PROCEDURE 3 was used

[0074] 5-(methoxycarbonyl)picolinic acid (0.46 g, 2.55 mmol, 1.7 eq.), 3'-bromo-2’-chloro-2-methoxy-[l,l'- biphenyl]-3-amine 2b (0.47 g, 1.50 mmol, 1.0 eq.), SOC12(10 mL), triethylamine (2.09 mL, 15.00 mmol, 10.0 eq.), anhydrous THF (10 mL). Product 2c was obtained as a colorless precipitate with 77% (0.55 g) yield.

[0075] Rf= 0. 19 (SiO2, DCM); ' H NMR (600 MHz, CDCL) 5 10.69 (s, 1H), 9. 19 (dd, J = 2.0, 0.7 Hz, 1H), 8.63 (dd, J= 8.2, 1.6 Hz, 1H), 8.48 (dd, J= 8.1, 2.0 Hz, 1H), 8.36 (dd, J= 8.1, 0.7 Hz, 1H), 7.66 (dd, J = 8.0, 1.6 Hz, 1H), 7.32 (dd, J= 7.6, 1.6 Hz, 1H), 7.24-7. 15 (m, J= 19.0, 7.8 Hz, 2H), 6.98 (dd, J= 7.7 , 1.6 Hz, 1H), 3.96 (s, 3H), 3.50 (s, 3H);13C NMR (151 MHz, CDCL) 5 165.0, 161.1, 153.0, 149.5, 147.0, 139.0, 138.8, 133.8, 133.3, 132.4, 131.4, 130.5, 128.2, 127.4, 126.3, 124.3, 123.6, 122.0, 120.3, 61.2, 52.7; IR (ATR) [cm-1]: 3333, 2951, 1719, 1688, 1523, 1399, 1278, 1122, 726, 682.

[0076] Intermediate product 2d; N-(3’-bromo-2’-chloro-2-methoxy-[l,l’-biphenyl]-3-yl)-5- (hydroxymethyl)picolin amide

[0077] During the synthesis PROCEDURE 4 was used Methyl 6-((3’-bromo-2’-chloro-2-methoxy-[l,r-biphenyl]-3-yl)carbamoyl)nicotinate 2c (0.28 g, 0.60 mmol, 1.0 eq.), LiBth (0.07 g, 3.02 mmol, 5.0 eq.), anhydrous mixture of THF / methanol (8 mL / 4 mL). Product 2d was obtained as a white precipitate with 77% (0.20 g) yield.

[0078] Rf= 0.24 (SiO2, chloroform / ethyl acetate, 3 / 1); 'H NMR (600 MHz, CDCL) 5 10.68 (s, 1H), 8.64-8.53 (m, 2H), 8.15 (d, J= 8.0 Hz, 1H), 7.92-7.81 (m, 1H), 7.72-7.61 (m, 1H), 7.32 (dd, J= 7.6, 1.5 Hz, 1H), 7.20 (dt, J = 16.7, 7.9 Hz, 2H), 7.01-6.95 (m, 1H), 4.79 (s, 2H), 3.49 (s, 3H), 3.13 (s, 1H);13C NMR (151 MHz, CDCL) 5 162.3, 148.9, 147.0, 147.0, 139.8, 139.1, 136.0, 133.8, 133.3, 132.5, 131.4, 130.5,

[0079] 127.4, 126.2, 124.3, 123.5, 122.1, 120.2, 62.3, 61.2; IR (ATR) [cm4]: 3444, 3335, 2919, 2850, 1683, 1524, 1415, 997, 717, 684.

[0080] Intermediate product 2e; N-(2'-chloro-4’ ’ -(hydroxymethyl)-2,3 ’ ’ -dimethoxy- [1,1':3’,1” -terphenyl] -3 - yl)-5-(hydroxymethyl)picolinamide

[0081] During the synthesis PROCEDURE 5 was used

[0082] N-(3’-bromo-2’-chloro-2-methoxy-[l,r-biphenyl]-3-yl)-5-(hydroxymethyl)picolinamide 2d (0.20 g, 0.45 mmol, 1.0 eq.), (2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)methanol (0.24 g, 0.90 mmol, 2.0 eq.), caesium carbonate (0.44 g, 1.35 mmol, 3.0 eq.), Pd(dppf)Cl2DCM complex (0.02 g, 0.03 mmol, 0.05 eq.), 1,4-dioxane / water (4mL / 2 mL). Product 2e was obtained as a colorless precipitate with 89% (0.20 g) yield.

[0083] Rf= 0.21 (SiO2, hexane / ethyl acetate 1:3); 'H NMR (600 MHz, CDCL) 5 10.71 (s, 1H), 8.61 (dd, J = 8.2, 1.4 Hz, 1H), 8.57 (d, J= 1.2 Hz, 1H), 8.20 (d, J= 8.0 Hz, 1H), 7.87 (dd, J= 8.0, 1.7 Hz, 1H), 7.37 (s, 3H), 7.34 (d, J= 7.6 Hz, 1H), 7.22 (t, J= 7.9 Hz, 1H), 7.08-7.02 (m, J= 7.5, 4.7, 1.5 Hz, 2H), 7.00 (d, J= 1.3 Hz, 1H), 4.78 (s, 2H), 4.73 (s, 2H), 3.88 (s, 3H), 3.56 (s, 3H);13C NMR (151 MHz, CDCL) 5 162.2, 157.0, 149.3, 147.2, 147.0, 141.3, 140.7, 139.4, 138.1, 136.0, 132.8, 131.8, 131.5, 130.8, 130.7,

[0084] 128.4, 128.4, 126.4, 126.3, 124.2, 122.2, 121.9, 120.0, 111.8, 62.4, 61.9, 61. 1, 55.5; IR (ATR) [cm4]: 3342, 2933, 1671, 1523, 1455, 1224, 998, 726.

[0085] Final product 2; N-(2’-chloro-4”-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)- 2,3 ” -dimethoxy- [1, 1 ’ :3 ’, 1 ”-terphenyl]-3-yl)-5-((( l,3-dihydroxy-2-(hydroxymethyl)propanyl-2- yl)amino)methyl)picolinamide

[0086] During the synthesis PROCEDURE 6 was used

[0087] Step 1: N-(2'-chloro-4”-(hydroxymethyl)-2,3”-dimethoxy-[l,l':3',l"-terphenyl]-3-yl)-5-

[0088] (hydroxymethyl)picolinamide 2e (0.15 g, 0.30 mmol, 1.0 eq.), SOC12(0.22 ml, 3.00 mmol, 10.0 eq.), anhydrous DMF (5 drops), anhydrous DCM (5 mL).

[0089] Step 1: Tris(hydroxymethyl)aminomethane (0.22 g, 1.80 mmol, 6 eq.). ACA'-diisopropylcthylaminc (0.20 ml, 1.20 mmol, 4 eq.), anhydrous DMF (5 mL). Product 2 was obtained as a colorless precipitate with 49% (0.10 g) yield. Rf = 0. 16 (SiO2, CHCl3 / MeOH / 7M NH3in MeOH, 10 / 1 / 1 v / v / v); 'H NMR (600 MHz, MeOD) 5 8.68 (d, J = 1.5 Hz, 1H), 8.47 (dd, J = 8.2, 1.5 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.05 (dd, J = 8.0, 2.0 Hz, 1H), 7.45-7.40 (m, 2H), 7.41-7.36 (m, 2H), 7.19 (t, J= 7.9 Hz, 1H), 7.10 (d, J= 1.3 Hz, 1H), 7.04 (dd, J= 7.7, 1.5 Hz, 1H), 6.99 (dd, J= 7.7 , 1.6 Hz, 1H), 4.26 (s, 2H), 3.99 (s, 2H), 3.92 (s, 3H), 3.76 (s, 6H), 3.63 (s, 6H), 3.50 (s, 3H);13C NMR (151 MHz, MeOD) 5 162.5, 157.6, 148.8, 148.4, 147.4, 142.4, 141.0, 139.5, 138.1, 137.8, 133.0, 131.4, 131.1, 130.9, 130.7, 130.5, 126.4, 123.7, 121.9, 121.6, 121.3, 119.8, 112.0, 64.9, 61.2, 61.1, 60.2, 59.0, 55.0, 42.9, 41.6; IR (ATR) [cm ]: 3319, 2937, 1671, 1525, 1456, 1228, 1026, 790. LC-MS (DAD / ESI): tR= 4.58 min, calculated for C36H43C1N4O9 (m / z) [M+FA- H]’ 755.27; found [M+FA-H]’ 755.48; HRMS (ESI): calculated for C36H43C1N4O9 [m / z] [M+H]+711.2791; found [M+H]+711.2789.

[0090] EXAMPLE 3. N-(2'-chloro-4”-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-3"- methoxy-2-methyl-[l , 1': 3', 1 ’’-terphenyl] -3 -yl)-5-((( l,3-dihydroxy-2-(hydroxymethyl)propan-2- yl)amino)methyl)picolinamide (3)

[0091] Intermediate product 3a; 2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline

[0092] During the synthesis PROCEDURE 1 was used

[0093] 3-bromo-2-methoxyaniline (1.00 g, 5.37 mmol, 1.0 eq.), bis(pinacolato)diboron (2.05 g, 8.06 mmol, 1.5 eq.), potassium acetate anhydrous (1.58 g, 16.11 mmol, 3.0 eq.), Pd(dppf)Cl2DCM (0.21 g, 0.25 mmol, 0.05 eq.), anhydrous 1,4-dioxane (20 mL). Product 3a was obtained as a colorless precipitate with 60% (0.75 g) yield.

[0094] Rf= 0.37 (SiO2, hexane / ethyl acetate 4: 1); 'H NMR (600 MHz, CDC13) 5 7.26 (dd, J= 7.4, 1. 1 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.80 (dd, J= 7.8, 1.1 Hz, 1H), 3.55 (s, 2H), 2.41 (s, 3H), 1.38 (s, 12H);13C NMR (151 MHZ, CDC13) 5 144.5, 128.5, 126.4, 125.9, 117.7, 83.5, 24.9, 15.8; IR (ATR) [cm4]: 3425, 3340, 2977, 1452, 1345, 1141, 856, 726.

[0095] Intermediate product 3b; 3 ’ -bromo-2 ’ -chloro-2-methyl- [1,1’ -biphenyl] -3 -amine

[0096] During the synthesis PROCEDURE 2 was used

[0097] 2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline 3a (0.50 g, 2.14 mmol, 1.0 eq.), 1,3- dibromo-2-chlorobenzene (0.87 g, 3.22 mmol, 1.5 eq.), potassium carbonate (0.89 g, 6.43 mmol, 3.0 eq.), Pd(dppf)Cl2DCM (0.09 g, 0.11 mmol, 0.05 eq.), 1,4-dioxane / water (40 mL / 20 mL). Product 3b was obtained as a brown precipitate with 51% (0.34 g) yield. Rf = 0.26 (SiO2, hexane / ethyl acetate 3: 1); 'H NMR (600 MHz, CDCL) 5 7.69 (dd, J= 7.9, 1.7 Hz, 1H), 7.25 (dd, J = 1.6, 1.7 Hz, 1H), 7.21 (t, J= 7.7 Hz, 1H), 7.15 (t, J= 7.7 Hz, 1H), 6.79 (dd, J = 1.9, 0.8 Hz, 1H), 6.64 (dd, J = 1.5, 0.9 Hz, 1H), 3.74 (s, 2H), 1.97 (s, 3H);13C NMR (151 MHz, CDCL) 5

[0098] 144.8, 143.3, 140.4, 133.9, 132.7, 130.1, 127.5, 126.3, 123.3, 120.5, 119.8, 114.9, 14.1; IR (ATR) [cm’1]: 3442, 3364, 2917, 1616, 1462, 1398, 1043, 783, 719, 604.

[0099] Intermediate product 3c; Methyl 6-((3’-bromo-2’-chloro-2-methyl-[l,l -biphenyl]-3- yl)carbamoyl)nicotinate

[0100] During the synthesis PROCEDURE 3 was used

[0101] 5-(methoxycarbonyl)picolinic acid (0.23 g, 1.24 mmol, 1.3 eq.), 3’-bromo-2’-chloro-2-methyl-[l,l'- biphenyl]-3-amine 3b (0.30 g, 0.92 mmol, 1.0 eq.), SOCL (8 mL), triethylamine (1.30 mL, 9.20 mmol, 1.0 eq.), anhydrous THF (10 mL). Product 3c was obtained as a colorless precipitate with 59% (0.26 g) yield.

[0102] Rf= 0.41 (SiO2, DCM); *H NMR (600 MHz, CDCL) 5 10.15 (s, 1H), 9.23 (dd, J= 2.0, 0.8 Hz, 1H), 8.52 (dd, J= 8.1, 2.0 Hz, 1H), 8.41 (dd, J= 8.1, 0.8 Hz, 1H), 8.36-8.25 (m, 1H), 7.67 (dd, J= 7.2, 2.4 Hz, 1H), 7.35 (t, J= 7.9 Hz, 1H), 7.24-7. 13 (m, 2H), 6.99 (dd, J= 7.6, 1.0 Hz, 1H), 4.00 (s, 3H), 2. 16 (s, 3H);13C NMR (151 MHz, CDC13) 5 165.0, 161.1, 153.0, 149.4, 142.5, 140.4, 139.0, 135.8, 133.9, 133.0, 130.0, 128.4, 127.5, 126.8, 126.4, 126.0, 123.4, 122.1, 121.6, 52.8, 14.5; IR (ATR) [cm’1]: 3304, 2952, 1721, 1686, 1540, 1432, 1281, 1122, 712, 682.

[0103] Intermediate product 3d; N-(3’-bromo-2’-chloro-2-methyl-[l,l ’-biphenyl]-3-yl)-5- (hydroxymethyl)picolin amide

[0104] During the synthesis PROCEDURE 4 was used

[0105] Methyl 6-((3’-bromo-2’-chloro-2-methyl-[l,l'-biphenyl]-3-yl)carbamoyl)nicotinate 3c (0.24 g, 0.52 mmol, 1.0 eq.), LiBH4 (0.06 g, 2.61 mmol, 5.0 eq.), mixture of anhydrous THF / methanol (8 mL / 4 mL). Product 3d was obtained as a white precipitate with 95% (0.22 g) yield.

[0106] Rf= 0.44 (SiO2, DCM / octan etylu, 1 / 1); 'H NMR (600 MHz, CDCL) 5 10.16 (s, 1H), 8.62 (d, J = 1.3 Hz, 1H), 8.29 (d, J= 7.8 Hz, 2H), 7.93 (dd, J= 8.0, 2.0 Hz, 1H), 7.67 (dd, J= 7.5, 2. 1 Hz, 1H), 7.34 (t, J= 7.9 Hz, 1H), 7.24-7. 15 (m, 2H), 6.97 (dd, J= 7.6, 0.9 Hz, 1H), 4.85 (s, 2H), 2. 15 (s, 3H);13C NMR (151 MHz, CDCL) 5 161.9, 149.2, 146.6, 142.6, 140.3, 139.5, 136.2, 136.0, 133.9, 132.9, 130.0, 127.5,

[0107] 126.8, 126.3, 125.8, 123.4, 122.4, 121.7, 62.4, 14.5; IR (ATR) [cm’1]: 3517, 3247, 1703, 1568, 1531, 1454, 1294, 783, 690.

[0108] Intermediate product 3e; N-(2’-chloro-4”-(hydroxymethyl)-3”-methoxy-2-methyl-[l,l’:3’,l”- terphenyl]-3-yl)-5-(hydroxymethyl)picolinamide

[0109] During the synthesis PROCEDURE 5 was used N-(3’-bromo-2’-chloro-2-methyl-[l J'-biphenyl]-3-yl)-5-(hydroxymethyl)picolinamide 3d (0.20 g, 0.47 mmol, 1.0 eq.), (2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)methanol (0.25 g, 0.94 mmol, 2.0 eq.), caesium carbonate (0.46 g, 1.41 mmol, 3.0 eq.), Pd(dppf)Cl2DCM complex (0.02 g, 0.02 mmol, 0.05 eq.), 1,4-dioxane / water (6 mL / 3 mL). Product 3e was obtained as a brown precipitate with 48% (0. 11 g) yield.

[0110] Rf= 0.26 (SiO2, hexane / ethyl acetate 1:3); 'H NMR (600 MHz, CDC13) 5 10.14 (s, 1H), 8.57 (d, J= 1.4 Hz, 1H), 8.28 (d, J= 8. 1 Hz, 1H), 8.24 (d, J= 8.0 Hz, 1H), 7.89 (dd, J= 8.0, 1.9 Hz, 1H), 7.40-7.31 (m, 4H), 7.28-7.23 (m, 1H), 7.09-7.02 (m, 2H), 7.00 (d, J= 1.4 Hz, 1H), 4.79 (s, 2H), 4.74 (s, 2H), 3.89 (s, 3H), 2.20 (s, 3H),13C NMR (151 MHz, CDCL) 5 162.1, 156.9, 149.1, 146.8, 141.4, 141.0, 140.8, 140.7,

[0111] 139.7, 136.0, 135.9, 131.8, 130.4, 130.3, 128.4, 128.4, 127.0, 126.5, 126.2, 126.1, 122.2, 121.9, 121.3, 111.9, 62.3, 61.9, 55.5, 14.6; IR (ATR) [cm4]: 3336, 2920, 1670, 1529, 1434, 1225, 1037, 721.

[0112] Final product 3; N-(2’-chloro-4”-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)- 3 ’ ’-methoxy-2-methyl-[l, 1 ’ :3 ’, 1 ”-terphenyl]-3-yl)-5-((( l,3-dihydroxy-2-(hydroxymethyl)propan-2- yl)amino)methyl)picolinamide

[0113] During the synthesis PROCEDURE 6 was used

[0114] Step 1: N-(2’-chloro-4”-(hydroxymethyl)-3 ’’-methoxy -2-methyl-[l,l': 3', 1 "-terphenyl] -3 -yl)-5- (hydroxymethyl)picolinamide 3e (0.10 g, 0.20 mmol, 1.0 eq.), SOC12(0.15 ml, 2.00 mmol, 10.0 eq.), anhydrous DMF (5 drops), anhydrous DCM (5 mL).

[0115] Step 2: Tris(hydroxymethyl)aminomethane (0.15 g, 1.20 mmol, 6 eq.), ACA'-diisopropylcthylaminc (0. 14 ml, 0.8 mmol, 4 eq.), anhydrous DMF (5 mL). Product 3 was obtained as a colorless precipitate with 40% (0.06 g) yield.

[0116] Rf= 0.20 (SiO2, CHCl3 / MeOH / 7M NH3in MeOH, 10 / 1 / 1 v / v / v); 'H NMR (600 MHz, MeOD) 5 8.72 (s, 1H), 8.19 (d, J= 8.0 Hz, 1H), 8.08 (d, J= 8.0 Hz, 1H), 7.96 (d, J= 8.0 Hz, 1H), 7.50-7.37 (m, 3H), 7.37-7.32 (m, J= 10.7, 4.9 Hz, 1H), 7.32-7.25 (m, 1H), 7.11-7.04 (m, J= 8.0, 3.7 Hz, 2H), 7.02 (d, J = 7.6 Hz, 1H), 3.99 (s, 2H), 3.95 (s, 2H), 3.91 (s, 3H), 3.69 (s, 6H), 3.66 (s, 6H), 2.15 (s, 3H);13C NMR (151 MHz, MeOD) 5 163.3, 157.3, 148.6, 148.3, 141.3, 141.2, 141.0, 140.6, 140.4, 137.5, 135.7, 131.3, 130.3, 130.0, 129.5, 128.9, 126.7, 126.5, 126.4, 125.7, 122.7, 121.7, 121.5, 111.8, 61.6, 61.1, 60.9, 60.3,

[0117] 54.7, 42.9, 41.0, 13.6; IR (ATR) [cm4]: 3320, 2931, 1671, 1529, 1460, 1394, 1227, 1026, 789. LC- MS (DAD / ESI): tR= 4.45 min, calculated for C36H43C1N4O8(m / z) [M+FA-H]’ 739.27; found [M+FA- H]’ 739.52; HRMS (ESI): calculated for C36H43C1N4O8[m / z] [M+H]+695.2842; found [M+H]+695.2841.

[0118] EXAMPLE 4. N-(2'-chloro-4”-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-2- fluoro-3"-methoxy-[l,r:3',r’-terphenyl]-3-yl)-5-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2- yl)amino)methyl)picolinamide (4)

[0119] Intermediate product 4a; 2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline During the synthesis PROCEDURE 1 was used

[0120] 3-bromo-2-fluoroaniline (0.52 g, 2.74 mmol, 1.0 eq.), bis(pinacolato)diboron (1.04 g, 4.10 mmol, 1.5 eq.), potassium acetate anhydrous (0.81 g, 8.21 mmol, 3.0 eq.), Pd(dppf)C12'DCM (0.11 g, 0.14 mmol, 0.05 eq.), anhydrous 1,4-dioxane (10 mL). Product 4a was obtained as a brownish precipitate with 88% (0.57 g) yield.

[0121] Rf= 0. 11 (SiO2, DCM); 'H NMR (600 MHz, CDCL) 8 7.11 - 6.87 (m, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.91-6.87 (m, 1H), 3.72 (s, 2H), 1.37 (s, 12H),;13C NMR (151 MHz, CDCL) 5 155.8 (d, JC-F = 243.6 Hz), 134.3 (d, JC-F = 14.9 Hz), 125.3 (d, JC-F = 7. 1 Hz), 124.0 (d, JC-F = 2.9 Hz), 120.0 (d, JC-F = 3.9 Hz), 83.8, 24.8; IR (ATR) [cm’1]: 3471, 3377, 2985, 1628, 1357, 1300, 1137, 734.

[0122] Intermediate product 4b; 3 ’-bromo-2’-chloro-2-fluoro-[ 1,1 ’-biphenyl] -3 -amine

[0123] During the synthesis PROCEDURE 2 was used

[0124] 2-fluoro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline 4a (0.24 g, 1.01 mmol, 1.0 eq.), 1,3- dibromo-2-chlorobenzene (0.55 g, 2.02 mmol, 2.0 eq.), potassium carbonate (0.42 g, 3.04 mmol, 3.0 eq.), Pd(dppf)C12'DCM (0.04 g, 0.05 mmol, 0.05 eq.), 1,4-dioxane / water (20 mL / 10 mL). Product 4b was obtained as an orange precipitate with 80% (0.24 g) yield.

[0125] Rf= 0.62 (SiO2, chloroform / ethyl acetate, 9: 1); 'H NMR (600 MHz, CDC13) 5 7.68 (dd, J= 8.0, 1.6 Hz, 1H), 7.29 (dd, J= 7.6, 1.5 Hz, 1H), 7. 19 (t, J= 7.8 Hz, 1H), 7.02 (td, J= 7.8, 0.9 Hz, 1H), 6.86 (td, J= 8.2, 1.6 Hz, 1H), 6.65 (ddd, J= 7.8, 6.5, 1.6 Hz, 1H), 3.81 (s, 2H);13C NMR (151 MHz, CDCL) 5 148.4 (d, Jc-F= 240.7 Hz), 137.4, 134.6 (d, J C-F= 13.1 HZ), 133.3, 130.4, 128.4 (d, J C-F= 10.9 Hz), 127.4, 127.2 (d, JC-F= 13.9 Hz), 124.0 (d, JC-F= 4.1 Hz), 123.5, 120.1, 117.0 (d, JC-F = 3.3 Hz); IR (ATR) [cm’1]: 3443, 3365, 3060, 1627, 1476, 1403, 1198, 776, 726, 576.

[0126] Intermediate product 4c; Methyl 6-((3’-bromo-2’-chloro-2-fluoro-[l,l’-biphenyl]-3- yl)carbamoyl)nicotinate

[0127] During the synthesis PROCEDURE 3 was used

[0128] 5-(methoxycarbonyl)picolinic acid (0.22 g, 1.20 mmol, 1.5 eq.), 3’-bromo-2’-chloro-2-fluoro-[l,l'- biphenyl]-3-amine 4b (0.24 g, 0.80 mmol, 1.0 eq.), SOCL (5 mL), triethylamine (0.56 mL, 4.00 mmol, 5.0 eq.), anhydrous THF (5 mL). Product 4c was obtained as a colorless precipitate with 83% (0.31 g) yield. Rf = 0.60 (SiO2, chloroform / ethyl acetate, 9 / 1); 'H NMR (600 MHz, CDC13) 5 10.41 (s, 1H), 9.23 (dd, J= 2.0, 0.7 Hz, 1H), 8.71-8.60 (m, 1H), 8.54 (dd, J= 8.1, 2.0 Hz, 1H), 8.40 (dd, J= 8.1, 0.7 Hz, 1H), 7.72 (dd, J= 8.0, 1.5 Hz, 1H), 7.32 (dd, J= 7.6, 1.5 Hz, 1H), 7.29 (d, J= 7.1 Hz, 1H), 7.23 (t, J= 7.8 Hz, 1H), 7.11-7.02 (m, J = 7.8, 1.6 Hz, 1H), 4.02 (s, 3H);13C NMR (151 MHz, CDC13) 5 164.9,

[0129] 161.3, 152.4, 149.7 (d, JC-F = 246.4 Hz), 149.5, 139.0, 136.5, 134.0, 133.7, 130.4, 128.5, 128.3 (d, JC-F = 9.5 Hz), 127.50, 127.0 (d, JC-F = 14.3 Hz), 126.4 (d, JC-F = 10.4 Hz), 126.0, 124.3 (d, JC-F = 4.0 Hz),

[0130] 123.6, 122.1, 121.3, 52.80; IR (ATR) [cm4]: 3306, 2956, 1725, 1692, 1538, 1434, 1274, 1121, 721, 682.

[0131] Intermediate product 4d; N-(3’-bromo-2’-chloro-2-fluoro-[l,l ’-biphenyl]-3-yl)-5- (hydroxymethyl)picolin amide

[0132] During the synthesis PROCEDURE 4 was used

[0133] Methyl 6-((3’-bromo-2’-chloro-2-fluoro-[l,r-biphenyl]-3-yl)carbamoyl)nicotinate 4c (0.28 g, 0.60 mmol, 1.0 eq.), LiBH4 (0.07 g, 3.02 mmol, 5.0 eq.), mixture of anhydrous THF / methanol (2 / 1, 8 mL / 4 mL)). Product 4d was obtained as a colorless precipitate with 77% (0.20 g) yield.

[0134] Rf= 0.24 (SiO2, chloroform / ethyl acetate, 3 / 1); 'H NMR (600 MHz, CDC13) 5 10.39 (s, 1H), 8.69-8.55 (m, 2H), 8.27 (d, J= 8.0 Hz, 1H), 7.93 (dd, J = 8.0, 2.1 Hz, 1H), 7.69 (dd, J= 8.0, 1.5 Hz, 1H), 7.31- 7.24 (m, 2H), 7.20 (t, J = 7.8 Hz, 1H), 7.06-6.98 (m, 1H), 4.85 (s, 2H), 1.95 (s, 1H);13C NMR (151 MHz, CDC13) 5 162.2, 149.6 (d, JC-F = 279.0 Hz), 146.8, 139.6, 136.6, 136.1, 134.1, 133.6, 130.4, 127.5, 126.9 (d, Jc.F = 14.6 Hz), 126.6 (d, C- = 10.3 Hz), 125.7, 124.3 (d, C-F = 4.1 Hz), 123.6, 122.3, 121.3, 62.4; IR (ATR) [cm’1]: 3343, 1686, 1539, 1399, 1013, 771, 680.

[0135] Intermediate product 4e; N-(2'-chloro-2-fluoro-4”-(hydroxymethyl)-3”-methoxy-[l,l':3',l”- terphenyl]-3-yl)-5-(hydroxymethyl)picolinamide

[0136] During the synthesis PROCEDURE 5 was used

[0137] N-(3’-bromo-2’-chloro-2-fluoro-[l,r-biphenyl]-3-yl)-5-(hydroxymethyl)picolinamide 4d (0.20 g, 0.46 mmol, 1.0 eq.), (2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)methanol (0.24 g, 0.92 mmol, 2.0 eq.), caesium carbonate (0.44 g, 1.38 mmol, 3.0 eq.), Pd(dppf)Cl2DCM complex (0.02 g, 0.02 mmol, 0.05 eq.), 1,4-dioxane / water (20 mL / 10 mL). Product 4e was obtained as a brown precipitate with 59% (0.13 g) yield.

[0138] Rf= 0.31 (SiO2, hexane / ethyl acetate 1:3); 'H NMR (600 MHz, CDCl3 / MeOD-d4, 1 / 2) 5 8.60 (s, 1H), 8.49 (t, J = 7.2 Hz, 1H), 8.20 (d, J= 8.0 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.44-7.35 (m, J = 14.1, 5.6 Hz, 3H), 7.32 (dd, J = 8.4, 3.9 Hz, 1H), 7.25 (t, J = 7.9 Hz, 1H), 7.09 (t, J = 6.8 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.97 (s, 1H), 4.73 (s, 2H), 4.69 (s, 2H), 3.85 (s, 3H);13C NMR (151 MHz, CDC13) 5 166.7,

[0139] 160.4, 154.0 (d, JC-F = 245.5 Hz), 152.0, 150.9 (d, C-F = 15.0 Hz), 145.3, 144.7, 144.1, 139.9, 139.3,

[0140] 135.7, 135.1, 134.4, 132.6, 131.6, 131.5 (d, C-F = 14.8 Hz), 130.4, 130.1 (d, C-F = 10.4 Hz), 128.0, 125.9 (d, JC-F = 15.9 Hz), 125.5, 125.0 (d, JC-F = 19.3 Hz), 115.6, 65.3, 63.7, 59.1; IR (ATR) [cm ]: 3324, 2920, 1694, 1555, 1394, 1228, 1033, 1013, 780.

[0141] Final product 4; N-(2’-chloro-4”-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-2- fluoro-3”-methoxy-[l,l’:3’,l”-terphenyl]-3-yl)-5-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2- yl)amino)methyl)picolinamide

[0142] During the synthesis PROCEDURE 6 was used

[0143] Step 1: N-(2’-chloro-2-fluoro-4”-(hydroxymethyl)-3”-methoxy-[l,r:3',l"-terphenyl]-3-yl)-5- (hydroxymethyl)picolinamide 4e (0.04 g, 0.09 mmol, 1.0 eq.), SOCL (0.04 ml, 0.52 mmol, 6.0 eq.), anhydrous DMF (2 drops), anhydrous DCM (3 mL).

[0144] Step 2: Tris(hydroxymethyl)aminomethane (0.06 g, 0.52 mmol, 6 eq.). ACA'-diisopropylcthylaminc (0.06 ml, 0.35 mmol, 4 eq.), anhydrous DMF (3 mL). Product 4 was obtained as a brown precipitate with 65% (0.04 g) yield.

[0145] Rf= 0.20 (SiO2, CHCl3 / MeOH / 7M NH3in MeOH, 10 / 2 / 1 v / v / v); 'H NMR (600 MHz, MeOD-d6) 5

[0146] 8.80 (d, J = 1.6 Hz, 1H), 8.41-8.32 (m, 1H), 8.24 (d, J = 8.0 Hz, 1H), 8.18 (dd, J = 8.1, 2.1 Hz, 1H), 7.46 (dd, J= 15.0, 7.6 Hz, 2H), 7.42 (dd, J = 7.7, 1.9 Hz, 1H), 7.38 (dd, J= 7.4, 1.9 Hz, 1H), 7.28 (t, J = 7.9 Hz, 1H), 7. 16-7.09 (m, 2H), 7.06 (dd, J= 7.7 , 1.5 Hz, 1H), 4.40 (s, 2H), 4.39 (s, 2H), 3.94 (s, 3H),

[0147] 3.81 (s, 6H), 3.78 (s, 6H);13C NMR (151 MHz, MeOD) 5 162.4, 157.7, 150.6 (d, JC-F = 245.3 Hz), 145.0 (d, JC-F = 5.2 Hz)„ 149.3, 142.9, 140.8, 139.6, 135.5, 133.4, 131.4, 131.2, 130.9, 130.8, 127.6 (d, JC-F = 14.8 Hz), 126.7, 125.9 (d, JC-F = 10.9 Hz), 124.0, 121.9, 119.3, 112.1, 65.8, 61.4, 59.6, 58.7, 55.1, 42.9, 41.8; IR (ATR) [cm4]: 3282, 2939, 1684, 1534, 1441, 1397, 1026, 785. LC-MS (DAD / ESI): tR= 4.48 min, calculated for C35H4OC1FN408 (m / z) [M+FA-H]’ 743.25; found [M+FA-H]’ 743.37; HRMS (ESI): calculated for C35H4OC1FN408 [m / z] [M+H]+699.2591; found [M+H]+699.2590.

[0148] EXAMPLE 5. N-(2'-chloro-4”-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-2- (dimethylamino)-3"-methoxy-[l,r:3',l”-terphenyl]-3-yl)-5-(((l,3-dihydroxy-2-

[0149] (hydroxymethyl)propan-2-yl)amino)methyl)picolinamide (5)

[0150] Intermediate product 5a; 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolan

[0151] During the synthesis PROCEDURE 1 was used l-bromo-2-fluoro-3-nitrobenzene (1.00 g, 4.55 mmol, 1.0 eq.), bis(pinacolato)diboron (1.73 g, 6.82 mmol, 1.5 eq.), potassium acetate anhydrous (1.34 g, 13.64 mmol, 3.0 eq.), Pd(dppf)C12'DCM (0.19 g, 0.23 mmol, 0.05 eq.), anhydrous 1,4-dioxane (20 mL). Product 5a was obtained as a brown precipitate with 71% (0.86 g) yield.

[0152] Rf= 0.25 (SiO2, DCM); 'H NMR (600 MHz, CDCL) 5 8.10-8.05 (m, 1H), 8.01-7.97 (m, 1H), 7.28 (dd, J= 8.7, 6.8 Hz, 1H), 1.36 (s, 12H);13C NMR (151 MHz, CDCL) 5 159.1 (d, JC-F = 268.7 Hz), 142.2 (d, JC-F = 8.9 Hz), 137.7 (d, JC-F = 9.3 Hz), 128.7 (s), 124. 1 (d, JC-F = 4.0 Hz), 84.6, 24.8; IR (ATR) [cm ]: 3076, 2978, 1614, 1533, 1334, 1145, 748.

[0153] Intermediate product 5b; 3-bromo-2-chloro-2'-fluoro-3 ’-nitro- 1,1 ’-biphenyl During the synthesis PROCEDURE 2 was used

[0154] 2-(2-fluoro-3-nitrophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolan 5a (0.28 g, 1.05 mmol, 1.0 eq.), 1,3- dibromo-2-chlorobenzene (0.43 g, 1.57 mmol, 1.5 eq.), potassium carbonate (0.44 g, 3.15 mmol, 3.0 eq.), Pd(dppf)Cl2DCM (0.04 g, 0.05 mmol, 0.05 eq.), acetonitrile (15 mL). Product 5b was obtained as a colorless precipitate with 38% (0.13 g) yield.

[0155] Rf= 0.61 (SiO2, chloroform); 'H NMR (600 MHz, CDCL) 5 8.13 (ddd, J= 8.4, 6.9, 1.8 Hz, 1H), 7.76 (dd, J= 7.9, 1.7 Hz, 1H), 7.60 (ddd, J= 7.7 , 6.0, 1.7 Hz, 1H), 7.43-7.38 (m, 1H), 7.30 (dd, J= 7.6, 1.7 Hz, 1H), 7.26 (t, J= 7.8 Hz, 1H);13C NMR (151 MHz, CDCL) 5 152.6 (d, JCF = 265.7 Hz), 138.0 (d, JC-F = 9.0 Hz), 136.7 (d, JC-F = 3.1 Hz), 134.6, 134.5, 134.0, 130.3, 130.1, 127.8, 126.1, 124. 1 (d, JC-F = 5.0 Hz), 123.9; IR (ATR) [cm4]: 3086, 1530, 1405, 1344, 781, 714, 664.

[0156] Intermediate product 5c; 3'-bromo-2'-chloro-N,N-dimethyl-3-nitro-[l,l'-biphenyl]-2-amine

[0157] In a round-bottomed flask, 3 -bromo-2-chloro-2'-fluoro-3'-nitro- 1,1 '-biphenyl 5b (0. 10 g, 0.30 mmol, 1.0 eq.) was placed and dissolved in anhydrous DMF (3 mL), followed by the addition of N,N- dimethylamine (2M solution in THF, 0.25 mL, 0.45 mmol, 1.5 eq.) and ACA'-diisopropylcthylaminc (0.08 mL, 0.45 mmol, 1.5 eq.). The resulting solution was stirred at room temperature overnight. The solvent was evaporated the next day, the resulting oil was dissolved in dichloromethane (10 mL) and transferred to a water separator (10 mL). The content of the separator was shaken out and the organic fraction was collected after separation of the layers. The aqueous layer was washed twice with dichloromethane, the organic layers were combined and dried over anhydrous MgSCL. The drying agent was filtered and the solvent was evaporated. The product was chromatographically purified (SiO2, hexane / ethyl acetate, 9: 1) to give a 5c product with a 90% (0. 10 g) yield.

[0158] Rf= 0.39 (SiO2, hexane / ethyl acetate 9: 1); 'H NMR (600 MHz, CDCL) 5 7.71 (d, J= 8.1 Hz, 1H), 7.68 (dd, J = 6.5, 2.9 Hz, 1H), 7.31 (d, J= 7.5 Hz, 1H), 7.25-7.21 (m, 2H), 7.13 (t, J= 7.8 Hz, 1H), 2.55 (s, 6H);13C NMR (151 MHZ, CDCI3) 5 146.2, 144.8, 140.6, 138.3, 135.3, 133.7, 133.1, 130.2, 127.7, 125.5, 123.7, 122.0, 42.0, IR (ATR) [cm’1]: 2921, 2873, 1528, 1357, 957, 814, 722, 666.

[0159] Intermediate product 5d; 3'-bromo-2'-chloro-N2,N2-dimethyl-[l,l'-biphenyl]-2,3-diamine In a round-bottomed flask, 3'-bromo-2'-chloro-A'.A''-dimcthyl-3-nitro-| l . l '-biphcnyl |-2-aminc 5c (0.07 g, 0.30 mmol, 1.0 eq.) was placed and dissolved in anhydrous 1,4-dioxane (5 mL), and then SnCl2-2H2O (0.26 g, 1.00 mmol, 5.0 eq.) and two drops of IM HC1 were added. The resulting suspension was stirred at room temperature overnight. The solvent was evaporated the next day, the resulting solid was washed with dichloromethane twice (2x10 mL) and the combined organic fractions were transferred to a water separator (10 mL). The content of the separator was shaken out and the organic fraction was collected after separation of the layers. The aqueous layer was additionally washed twice with dichloromethane (2x10 mL), the organic layers were combined and dried over anhydrous MgSCL. The drying agent was filtered and the solvent was evaporated. The product was chromatographically purified (SiO?. chloroform / ethyl acetate, 9: 1) to give a 5d product with a 66% (0.04 g) yield.

[0160] Rf= 0.60 (SiO2, chloroform / ethyl acetate, 9: 1); 'H NMR (600 MHz, CDCL) 5 7.67 (dd, J = 7.9, 1.6 Hz, 1H), 7.23 (dd, J = 1.6, 1.6 Hz, 1H), 7.18 (t, J= 7.8 Hz, 1H), 6.99 (t, J= 7.7 Hz, 1H), 6.81 (dd, J = 1.9, 1.5 Hz, 1H), 6.48 (dd, J= 7.6, 1.5 Hz, 1H), 4.16 (s, 2H), 2.50 (s, 6H);13C NMR (151 MHz, CDCL) 5

[0161] 144.3, 142.9, 137.4, 136.3, 133.9, 132.7, 130.8, 126.7, 124.6, 123.4, 120.9, 114.8, 43.1(szeroki); IR (ATR) [cm’1]: 3437, 3415, 2919, 2831, 1595, 1440, 1397, 780, 724, 601.

[0162] Intermediate product 5e; Methyl 6-((3’-bromo-2’-chloro-2-(dimethylamino-[l,l’-biphenyl]-3- yl)carbamoyl)nicotinate

[0163] During the synthesis PROCEDURE 3 was used

[0164] 5-(methoxycarbonyl)picolinic acid (0.25 g, 1.38 mmol, 1.5 eq.), 3’-bromo-2’-chloro-N2,N2-dimethyl- [1,1 ’-biphenyl] -2, 3 -diamine 5d (0.30 g, 0.92 mmol, 1.0 eq.), SOCL (5 mL), triethylamine (0.64 mL, 4.61 mmol, 5.0 eq.), anhydrous THF (5 mL). Product 5e was obtained as a yellow precipitate with 49% (0.22 g) yield.

[0165] Rf= 0.62 (SiO2, chloroform / ethyl acetate, 9 / 1); 'H NMR (600 MHz, CDCL) 8 11.16 (s, 1H), 9.24 (dd, J= 2.0, 0.8 Hz, 1H), 8.64 (dd, J= 8.1, 1.5 Hz, 1H), 8.49 (dd, J= 8.1, 2.1 Hz, 1H), 8.39 (dd, J= 8.1, 0.7 Hz, 1H), 7.67 (dd, J= 7.9, 1.7 Hz, 1H), 7.29-7. 12 (m, 3H), 6.83 (dd, J= 7.7, 1.5 Hz, 1H), 3.98 (s, 3H), 2.57 (s, 6H);13C NMR (151 MHz, CDCL) 5 165.1, 161.1, 153.7, 149.7, 141.8, 139.8, 138.7, 137.4,

[0166] 135.3, 134.0, 133.1, 130.7, 128.0, 126.9, 126.8, 125.0, 123.6, 122.0, 119.5, 52.7, 43.6; IR (ATR) [cm’ ']: 3279, 2952, 2837, 1728, 1683, 1511, 1436, 1293, 1123, 729, 680.

[0167] Intermediate product 5f; N-(3’-bromo-2’-chloro-2-(dimethylamino)-[l,l ’-biphenyl]-3-yl)-5- (hydroxymethyl)picolin amide

[0168] During the synthesis PROCEDURE 4 was used

[0169] Methyl 6-((3’-bromo-2’-chloro-2-(dimethylamino-[l,T-biphenyl]-3-yl)carbamoyl)nicotinate 5e (0.39 g, 0.80 mmol, 1.0 eq.), LiBH4 (0.09 g, 3.99 mmol, 5.0 eq.), mixture of anhydrous THF / methanol (2 / 1, 8 mL / 12 mL). Product 5f was obtained as a colorless precipitate with 92% (0.34 g) yield. Rf = 0.24 (SiO2, chloroform / ethyl acetate, 3 / 1); 'H NMR (600 MHz, CDC13) 5 11.10 (s, 1H), 8.69-8.56 (m, 2H), 8.30 (d, J = 8.0 Hz, 1H), 7.91 (dd, J = 8.0, 2.1 Hz, 1H), 7.68 (dd, J= 7.9, 1.7 Hz, 1H), 7.26- 7.15 (m, 3H), 6.83 (dd, J = 7.7, 1.5 Hz, 1H), 4.84 (s, 2H), 2.59 (s, 6H), 1.95 (s, 1H);13C NMR (151 MHz, CDC13) 5 162.2, 149.9, 147.0, 141.9, 139.7, 139.0, 137.2, 135.9, 135.4, 134.0, 133.1, 130.7, 126.9,

[0170] 126.6, 125.1, 123.6, 122.3, 119.8, 62.5, 43.5; IR (ATR) [cm’1]: 3279, 2934, 2797, 1648, 1514, 1397, 1016, 760, 695.

[0171] Intermediate product 5g; N-(2’-chloro-2-(dimethylamino)-4”-(hydroxymethyl)-3”-methoxy- [1,1’:3*, 1” -terphenyl] - 3 -y 1) - 5 -(hydroxymethy l)picolinamide

[0172] During the synthesis PROCEDURE 5 was used

[0173] N-(3 ’ -bromo-2’ -chloro-2-(dimethylamino)- [ 1 , l'-biphenyl] -3 -y 1) - 5 -(hydroxymethy l)picolinamide 5f (0.30 g, 0.65 mmol, 1.0 eq.), (2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)methanol (0.34 g, 1.30 mmol, 2.0 eq.), caesium carbonate (0.64 g, 1.95 mmol, 3.0 eq.), Pd(dppf)Cl2DCM complex (0.03 g, 0.03 mmol, 0.05 eq.). Product 5g was obtained as a colorless precipitate with 41% (0.14 g) yield.

[0174] Rf= 0.32 (SiO2, hexane / ethyl acetate 1:3); 'H NMR (600 MHz, CDCl3 / MeOD-d4, 1 / 2) 5 8.59 (d, J = 1.4 Hz, 1H), 8.47 (dd, J= 8.1, 1.4 Hz, 1H), 8.16 (d, J= 8.0 Hz, 1H), 7.88 (dd, J= 8.0, 2.1 Hz, 1H), 7.37 (d, J= 7.7 Hz, 1H), 7.35-7.28 (m, 2H), 7.21 (dd, J= 6.7, 2.5 Hz, 1H), 7. 15 (t, J= 7.9 Hz, 1H), 6.97 (dd, J= 7.7, 1.5 Hz, 1H), 6.92 (d, J= 1.4 Hz, 1H), 6.85 (dd, J= 7.7 , 1.5 Hz, 1H), 4.69 (s, 2H), 4.65 (s, 2H), 3.81 (s, 3H), 2.55 (s, 6H);13C NMR (151 MHz, CDCl3 / MeOD-d4, 1 / 2) 5 162.6, 156.5, 149.1, 147.2,

[0175] 141.6, 140.5, 140.2, 140.2, 140.1, 138.0, 135.8, 135.0, 131.7, 130.8, 130.6, 128.7, 127.6, 127.1, 125.8,

[0176] 124.6, 121.9, 121.6, 119.0, 111.5, 61.3, 59.5, 55.1, 43.2; IR (ATR) [cm4]: 3355, 2934, 2795, 1664, 1570, 1519, 1379, 1223, 1033, 784.

[0177] Final product 5; N-(2’-chloro-4”-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-2- (dimethylamino)-3”-methoxy-[l,l’:3’,l”-terphenyl]-3-yl)-5-(((l,3-dihydroxy-2- (hydroxymethyl)propan-2-yl)amino)methyl)picolinamide

[0178] During the synthesis PROCEDURE 6 was used

[0179] Step 1 : N-(2’-chloro-2-(dimethylamino)-4”-(hydroxymethyl)-3 ”-methoxy-[l ,1': 3', 1 "-terphenyl] -3 -yl)- 5-(hydroxymethyl)picolinamide 5g (0.29 g, 0.56 mmol, 1.0 eq.), SOC12(0.25 ml, 3.35 mmol, 6.0 eq.), anhydrous DMF (5 drops), anhydrous DCM (5 mL).

[0180] Step 2: Tris(hydroxymethyl)aminomethane (0.41 g, 3.35 mmol, 6 eq.). ACA'-diisopropylcthylaminc (0.39 ml, 2.24 mmol, 4 eq.), anhydrous DMF (5 mL). Product 6 was obtained as a brown precipitate with 61% (0.25 g) yield.

[0181] Rf= 0.20 (SiO2, CHCl3 / MeOH / 7M NH3in MeOH, 10 / 2 / 1 v / v / v); 'H NMR (600 MHz, MeOD) 5 8.66 (d, J = 1.5 Hz, 1H), 8.46 (dd, J = 8.1, 1.5 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 8.02 (dd, J = 8.1, 2.0 Hz, 1H), 7.42-7.34 (m, 2H), 7.26 (dd, J= 6.8, 2.4 Hz, 1H), 7.15 (t, J= 7.9 Hz, 1H), 7.04 (d, J= 1.4 Hz, 1H), 6.99 (dd, J = 7.7, 1.5 Hz, 1H), 6.81 (dd, J = 7.7 , 1.5 Hz, 1H), 4.17 (s, 2H), 3.95 (s, 2H), 3.88 (s, 3H), 3.73 (s, 6H), 3.62 (s, 6H), 2.54 (s, 6H);13C NMR (151 MHz, MeOD) 5 162.5, 157.5, 148.9, 148.8, 141.9, 141.2, 140.7, 140.1, 139.5, 138.0, 137.6, 135.1, 131.4, 131.1, 130.5, 130.4, 126.8, 125.9, 124.5, 122.4, 121.8, 121.6, 118.8, 111.9, 64.1, 61.3, 60.9, 59.4, 54.9, 43.0, 42.6, 41.4; IR (ATR) [cm4]: 3289, 2931, 1662, 1575, 1520, 1458, 1227, 1025, 784. LC-MS (DAD / ESI): tR= 4.67 min, calculated for C37H46CIN5O8 (m / z) [M+FA-H]’ 768.30; found [M+FA-H]’ 768.64; HRMS (ESI): calculated for C37H46CIN5O8 [m / z] [M+H]+724.3108; found [M+H]+724.3110.

[0182] EXAMPLE 6. N-(2,2'-dichloro-4"-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)- 3"-methoxy-[l,r:3',l"-terphenyl]-3-yl)-5-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2- yl)amino)methyl)picolinamide (6)

[0183] Intermediate product 6a; 2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline

[0184] During the synthesis PROCEDURE 1 was used

[0185] 3-bromo-2-chloroaniline (1.00 g, 4.84 mmol, 1.0 eq.), bis(pinacolato)diboron (1.84 g, 7.26 mmol, 1.5 eq.), potassium acetate anhydrous (1.42 g, 14.52 mmol, 3.0 eq.), Pd(dppf)C12'DCM (0.20 g, 0.24 mmol, 0.05 eq.), anhydrous 1,4-dioxane (20 mL). Product 6a was obtained as a colorless precipitate with 73% (0.90 g) yield.

[0186] Rf= 0.23 (SiO2, hexane / ethyl acetate 3: 1); 'H NMR (600 MHz, CDCI3) 5 [ppm]: 7.07-6.99 (m, 2H); 6.79 (dd, J = 7.7; 1.8 Hz, 1H); 4.04 (s, 2H); 1.34 (s, 12H);13C NMR (151 MHz, CDCI3) 5 [ppm]: 143.0, 126.9, 125.6, 123.9, 118.2, 84.0, 24.8; IR (ATR) [cm4]: 3473, 3364, 2978, 1733, 1619, 1567, 848, 791.

[0187] Intermediate product 6b; 3’-bromo-2,2’-dichloro-[l,l’-biphenyl]-3-amine

[0188] During the synthesis PROCEDURE 2 was used

[0189] 2-chloro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline 6a (0.16 g, 0.62 mmol, 1.0 eq.), 1,3- dibromo-2-chlorobenzene (0.25 g, 0.92 mmol, 1.5 eq.), potassium carbonate (0.26 g, 1.85 mmol, 3.0 eq.), Pd(dppf)C12-DCM (0.03 g, 0.03 mmol, 0.05 eq.), 1,4-dioxane / water (20 mL / 10 mL). Product 6b was obtained as a colorless precipitate with 53% (0. 10 g) yield.

[0190] Rf= 0.35 (SiO2, hexane / ethyl acetate 3: 1); 'H NMR (600 MHz, CDCI3) 5 7.69 (dd, J= 7.9, 1.7 Hz, 1H), 7.24 (dd, J = 7.6, 1.7 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 6.85 (dd, J = 8.0, 1.5 Hz, 1H), 6.65 (dd, J= 7.5, 1.5 Hz, 1H), 4.20 (s, 2H);13C NMR (151 MHz, CDCI3) 5 143.3, 141.0, 139.2, 133.8, 133.2, 129.9, 127.4, 127.1, 123.3, 120.1, 118.4, 115.4; IR (ATR) [cm-1]: 3474, 3364, 2977, 1615, 1438, 1361, 1139, 847, 790, 673.

[0191] Intermediate product 6c; Methyl 6-((3’-bromo-2,2’-dichloro-[l,l’-biphenyl]-3- yl)carbamoyl)nicotinate

[0192] During the synthesis PROCEDURE 3 was used

[0193] 5-(methoxycarbonyl)picolinic acid (0.07 g, 0.38 mmol, 1.2 eq.), 3’-bromo-2,2’-dichloro-[l,l'- biphenyl]-3-amine 6b (0.10 g, 0.32 mmol, 1.0 eq.), SOC12(3 mL), triethylamine (0.22 mL, 1.58 mmol, 5.0 eq.), anhydrous THF (5 mL). Product 6c was obtained as a brown precipitate with 87% (0.13 g) yield.

[0194] Rf= 0.30 (SiO2, chloroform); 'H NMR (600 MHz, CDCL) 5 10.84 (s, 1H), 9.28 (dd, J = 2.0, 0.8 Hz, 1H), 8.74 (dd, J = 8.3, 1.5 Hz, 1H), 8.55 (dd, J = 8.1, 2.0 Hz, 1H), 8.41 (dd, J= 8.1, 0.8 Hz, 1H), 7.73 (dd, J = 7.5, 2.1 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.27-7.21 (m, 2H), 7.07 (dd, J = 7.6, 1.5 Hz, 1H), 4.02 (s, 3H);13C NMR (151 MHz, CDCL) 5 165.0, 161.4, 152.6, 149.6, 140.3, 139.1, 139.0, 134.9,

[0195] 133.9, 133.6, 129.9, 128.5, 127.5, 127.3, 126.1, 123.5, 123.0, 122.1, 120.8, 52.8; IR (ATR) [cm’1]: 3363, 2978, 1728, 1681, 1440, 1360, 1279, 1119, 847, 728, 674.

[0196] Intermediate product 6d; N-(3’-bromo-2,2’-dichloro-[l,l’-biphenyl]-3-yl)-5- (hydroxymethyl)picolin amide

[0197] During the synthesis PROCEDURE 4 was used

[0198] Methyl 6-((3’-bromo-2,2’-dichloro-[l,l'-biphenyl]-3-yl)carbamoyl)nicotinate 6c (0.80 g, 1.67 mmol, 1.0 eq.), LiBH4 (0.36 g, 16.70 mmol, 10.0 eq.), anhydrous mixture of THF / methanol (20 mL / 10 mL). Product 6d was obtained as a brown precipitate with 80% (0.60 g) yield.

[0199] Rf= 0.38 (SiO2, hexane / ethyl acetate 1 / 3); 'H NMR (600 MHz, CDCL) 5 10.79 (s, 1H), 8.70 (dd, J = 8.3, 1.5 Hz, 1H), 8.63 (d, J= 1.4 Hz, 1H), 8.26 (d, J= 8.0 Hz, 1H), 7.92 (dd, J= 8.0, 2.1 Hz, 1H), 7.70 (dd, J = 7.6, 2.0 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.24-7.16 (m, 2H), 7.02 (dd, J = 7.6, 1.5 Hz, 1H), 4.84 (s, 2H), 2.16 (s, 1H);13C NMR (151 MHz, CDCL) 5 162.3, 148.9, 147.0, 140.4, 139.6, 139.0, 136.0, 135.1, 133.9, 133.5, 129.9, 127.5, 127.3, 125.8, 123.5, 122.9, 122.3, 120.8, 62.4; IR (ATR) [cm’ ']: 3474, 3361, 2978, 1671, 1535, 1441, 1360, 1140, 728, 674.

[0200] Intermediate product 6e; N-(2,2 ’ -dichloro-4’ ’ -(hydroxymethyl)-3 ’ ’ -methoxy - [ 1 , 1 ’ : 3 ’ , 1 ” -terphenyl] - 3-yl)-5-(hydroxymethyl)picolinamide

[0201] During the synthesis PROCEDURE 5 was used

[0202] N-(3’-bromo-2,2’-dichloro-[l,r-biphenyl]-3-yl)-5-(hydroxymethyl)picolinamide 6d (0.40 g, 0.90 mmol, 1.0 eq.), (2-methoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)methanol (0.28 g, 1.10 mmol, 1.2 eq.), caesium carbonate (0.86 g, 2.70 mmol, 3.0 eq.), Pd(dppf)C DCM complex (0.04 g, 0.05 mmol, 0.05 eq.), 1,4-dioxane / water (20 mL / 10 mL). Product 6e was obtained as a brown precipitate with 51% (0.23 g) yield.

[0203] Rf= 0.27 (SiO2, hexane / ethyl acetate 1:3); 'H NMR (600 MHz, CDC13) 5 10.82 (s, 1H), 8.71 (dd, J = 8.3, 1.5 Hz, 1H), 8.64 (s, 1H), 8.29 (d, J = 7.9 Hz, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.44-7.38 (m, 3H), 7.36 (d, J= 7.6 Hz, 1H), 7.28 (dd, J= 5.9, 3.4 Hz, 1H), 7. 11 (dd, J= 7.6, 1.5 Hz, 1H), 7.07 (dd, J= 7.6, 1.5 Hz, 1H), 7.02 (d, J = 1.4 Hz, 1H), 4.84 (s, 2H), 4.75 (s, 2H), 3.90 (s, 3H);13C NMR (151 MHz, CDCL) 5 162.3, 157.0, 149.0, 147.0, 141.1, 140.5, 139.6, 139.5, 139.4, 136.0, 135.0, 131.8, 131.0, 130.1, 128.4, 128.4, 127.2, 126.4, 126.1, 123.2, 122.4, 121.9, 120.6, 111.9, 62.4, 62.0, 55.5; IR (ATR) [cm ]: 3314, 2922, 1682, 1524, 1475, 1395, 1226, 1033, 724.

[0204] Final product 6; N-(2,2’-dichloro-4”-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2- yl)amino)methyl)-3 ”-methoxy-[ 1 , 1 ’ : 3 ’ , 1 ” -terphenyl]-3-yl)-5-((( 1 ,3-dihydroxy-2-

[0205] (hydroxymethyl)propan-2-yl)amino)methyl)picolinamide

[0206] During the synthesis PROCEDURE 6 was used

[0207] Step 1: N-(2,2’-dichloro-4”-(hydroxymethyl)-3”-methoxy-[l,r:3',l"-terphenyl]-3-yl)-5-

[0208] (hydroxymethyl)picolinamide 6e (0.25 g, 0.16 mmol, 1.0 eq.), SOCh (0.12 ml, 1.57 mmol, 10.0 eq.), anhydrous DMF (10 drops), anhydrous DCM (5 mL).

[0209] Step 2: Tris(hydroxymethyl)aminomethane (0. 11 g, 0.90 mmol, 6 eq.). ACA'-diisopropylcthylaminc (0. 11 ml, 0.63 mmol, 4 eq.), anhydrous DMF (3 mL). Product 6 was obtained as a colorless precipitate with 36% (0.04 g) yield.

[0210] Rf= 0. 18 (SiO2, CHCL / MeOH / 7M NH3in MeOH, 10 / 1 / 1 v / v / v); 'H NMR (600 MHz, MeOD) 5 8.70 (d, J = 1.5 Hz, 1H), 8.59 (dd, J = 8.3, 1.5 Hz, 1H), 8.20 (d, J = 7.9 Hz, 1H), 8.08 (dd, J = 8.0, 2.1 Hz, 1H), 7.48-7.40 (m, 3H), 7.38 (d, J = 7.7 Hz, 1H), 7.30 (dd, J = 6.8, 2.5 Hz, 1H), 7.12 (dd, J = 7.6, 1.5 Hz, 1H), 7.06 (d, J= 1.4 Hz, 1H), 7.01 (dd, J= 7.6, 1.5 Hz, 1H), 3.97 (s, 2H), 3.95 (s, 2H), 3.89 (s, 3H), 3.69 (s, 6H), 3.65 (s, 6H);13C NMR (151 MHz, MeOD) 5 162.6, 157.3, 148.6, 147.8, 141.2, 140.7,

[0211] 140.5, 139.8, 139.2, 137.6, 134.8, 131.3, 130.8, 129.9, 129.6, 126.9, 126.5, 126.2, 123.1, 121.7, 121.6,

[0212] 120.5, 111.7, 61.5, 61.0, 60.4, 54.7, 42.9, 41.0; IR (ATR) [cm-1]: 3310, 2930, 1689, 1598, 1524, 1474, 1396, 1226, 1032, 780, 723. LC-MS (DAD / ESI): tR = 4.68 min, calculated for C^H-wCEN-fOs (m / z) [M+FA-H]’ 759.22; found [M+FA-H]’ 659.47; HRMS (ESI): calculated for C35H4OC12N408 [m / z] [M+H]+715.2296; found [M+H]+715.2294.

[0213] EXAMPLE 7. N-(2,2'-dichloro-4”-(((l,3-dihydroxypropan-2-yl)amino)methyl)-3"-methoxy- [ 1 , 1' : 3 ', 1 "-terphenyl] - 3 -y 1) - 5 -((( 1 ,3 -dihy droxypropan-2-yl)amino)methyl)picolinamide (7)

[0214] During the synthesis PROCEDURE 6 was used

[0215] Step 1: N-(2,2’-dichloro-4”-(hydroxymethyl)-3”-methoxy-[l,r:3',l"-terphenyl]-3-yl)-5-

[0216] (hydroxymethyl)picolinamide 6e (0.13 g, 0.25 mmol, 1.0 eq.), SOC12(0.1 ml, 1.5 mmol, 6.0 eq.), anhydrous DMF (5 drops), anhydrous DCM (5 mL).

[0217] Step 2: Serynol (0.10 g, 1.10 mmol, 6 eq.), A / A'-diisopropylcthylaminc (0.13 ml, 0.73 mmol, 4 eq.), anhydrous DMF (3 mL). Product 7 was obtained as a yellowish precipitate with 42% (0.05 g) yield.

[0218] Rf= 0.21 (SiO2, CHCl3 / MeOH / 7M NH3in MeOH, 5 / 1 / 0, 1 v / v / v); 'H NMR (600 MHz, MeOD-d4) 8.72- 8.67 (d, J= 1.5 Hz, 1H), 8.58 (dd, J= 8.3, 1.4 Hz, 1H), 8.21 (d, J= 8.0 Hz, 1H), 8.06 (dd, J= 8.0, 2.0 Hz, 1H), 7.48-7.41 (m, 3H), 7.36 (d, J= 7.7 Hz, 1H), 7.30 (dd, J= 6.9, 2.3 Hz, 1H), 7.12 (dd, J = 7.6, 1.5 Hz, 1H), 7.09-7.06 (d, J = 1.3 Hz, 1H), 7.02 (dd, J = 7.6, 1.5 Hz, 1H), 4.00 (s, 2H), 3.99 (s, 2H), 3.90 (s, 3H), 3.72-3.63 (m, 4H), 3.63-3.55 (m, 4H), 2.87 (q, J= 5.5 Hz, 1H), 2.74 (q, J= 5.5 Hz, 1H);13C NMR (151 MHz, MeOD-d4) 5 162.6, 157.5, 148.6, 148.0, 141.1, 140.8, 140.0, 139.8, 139.3, 137.6, 134.8, 131.3, 130.8, 129.9, 129.8, 127.0, 126.5, 126.2, 125.1, 123.2, 121.8, 121.5, 120.5, 111.8, 61.2, 60.5, 60.0, 59.9, 54.7, 46.0; IR (ATR) [cm4]: 3301, 2924, 1685, 1522, 1456, 1395, 1227, 1027, 789, 723, 689; LC-MS (DAD / ESI): tR= 4.73 min, calculated for C33H36C12N4O6 (m / z) [M+FA-H]’ 699.19; found [M+FA-H]’ 699.35; HRMS (ESI): calculated for C33H36C12N4O6 [m / z] [M+H]+655.2085; found [M+H]+655.2085.

[0219] EXAMPLE 8. N-(2,2'-dichloro-4"-(((2-hydroxyethyl)amino)methyl)-3"-methoxy-[l,r:3',l"- terphenyl]-3-yl)-5-(((2-hydroxyethyl)amino)methyl)picolinamide (8)

[0220] During the synthesis PROCEDURE 6 was used

[0221] Step 1: N-(2,2’-dichloro-4”-(hydroxymethyl)-3”-methoxy-[l,r:3',l"-terphenyl]-3-yl)-5-

[0222] (hydroxymethyl)picolinamide 6e (0.15 g, 0.38 mmol, 1.0 eq.), SOC12(0.15 ml, 2.3 mmol, 6.0 eq.), anhydrous DMF (5 drops), anhydrous DCM (5 mL).

[0223] Step 2: Ethanolamine (0.10 g, 1.8 mmol, 6 eq.), A'.A'-diisopropylcthylaminc (0.2 ml, 1.2 mmol, 4 eq.), anhydrous DMF (3 mL). Product 8 was obtained as a yellowish precipitate with 42% (0.05 g) yield. Rf = 0.22 (SiO2, CHCl3 / MeOH / 7M NH3in MeOH, 10 / 1 / 0,5 v / v / v); 'H NMR (400 MHz, MeOD-d4) 5 8.69 (bs, 1H), 8.60 (d, J= 7.9 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 8.05 (dd, J = 8.0, 1.6 Hz, 1H), 7.50- 7.43 (m, 3H), 7.39 (dd, J= 7.6, 3.1 Hz, 1H), 7.33 (dd, J= 6.7, 2.4 Hz, 1H), 7.16-7.03 (m, 3H), 4.03 (s, 2H), 3.95 (s, 2H), 3.93 (s, 3H), 3.77-3.73 (m, 2H), 3.69 (t, J = 5.5 Hz, 2H), 2.91 (t, J = 5.3 Hz, 2H), 2.76 (t, J = 5.5 Hz, 2H);13C NMR (101 MHz, MeOD-d4) 5 162.4, 161.7, 157.2, 148.9, 147.7, 141.3, 141.1, 139.7, 139.3, 139.2, 138.2, 135.1, 131.8, 131.1, 130.6, 129.3, 128.1, 127.6, 127.4, 126.9, 123.3, 122.4, 121.7, 121.5, 112.2, 60.8, 60.3, 60.2, 55.9, 51.4, 51.4, 50.3, 47.5; IR (ATR) [cm4]: 3308, 2923, 1684, 1523, 1457, 1396, 1228, 1029, 789; LC-MS (DAD / ESI): tR= 4.85 min, calculated for C3IH32C12N4O4(m / z) [M+FA-H]' 639.18; found [M+FA-H]' 639.37; HRMS (ESI): calculated for C3IH32C12N4O4[m / z] [M+H]+595.1873; found [M+H]+595.1876.

[0224] EXAMPLE 9. N-(2,2'-dichloro-4"-(((l-hydroxy-2-methylpropan-2-yl)amino)methyl)-3"-methoxy- [ 1 , 1' :3', 1' ’ -terphenyl] -3 -yl) -5 - ((( 1 -hydroxy-2-methylpropan-2-yl)amino)methy l)picolinamide (9)

[0225] During the synthesis PROCEDURE 6 was used

[0226] Step 1: N-(2,2’-dichloro-4”-(hydroxymethyl)-3”-methoxy-[l,l':3',l"-terphenyl]-3-yl)-5-

[0227] (hydroxymethyl)picolinamide 6e (0.13 g, 0.25 mmol, 1.0 eq.), SOC12(0.1 ml, 1.5 mmol, 6.0 eq.), anhydrous DMF (5 drops), anhydrous DCM (5 mL).

[0228] Step 2: 2-amino-2-methylpropan-l-ol (0.09 g, 1.0 mmol, 6 eq.), A / A'-diisopropylcthylaminc (0.1 ml, 0.64 mmol, 4 eq.), anhydrous DMF (3 mL). Product 9 was obtained as a colorless precipitate with 28% (0.03 g) yield.

[0229] Rf= 0.38 (SiO2, CHCl3 / MeOH / 7M NH3in MeOH, 5 / 1 / 0, 1 v / v / v); 'H NMR (400 MHz, CDC13) 5 10.82 (s, 1H), 8.72 (dd, J= 8.3, 1.5 Hz, 1H), 8.63 (d, J= 1.5 Hz, 1H), 8.26 (d, J= 8.0 Hz, 1H), 7.91 (dd, J = 8.0, 2.1 Hz, 1H), 7.44-7.38 (m, 3H), 7.35 (d, J= 7.6 Hz, 1H), 7.30-7.27 (m, 1H), 7.10 (dd, J= 7.6, 1.6 Hz, 1H), 7.05 (dd, J= 7.6, 1.5 Hz, 1H), 7.01 (d, J= 1.5 Hz, 1H), 3.89 (s, 3H), 3.81 (s, 2H), 3.73 (s, 2H), 3.42 (s, 2H), 3.40 (s, 2H), 1.17 (s, 6H), 1.16 (s, 6H);13C NMR (101 MHz, CDC13) 5 162.4, 157.0, 148.7, 148.3, 141.2, 140.1, 140.0, 139.6, 139.5, 137.3, 135.2, 131.9, 131.1, 130.1, 129.7, 127.8, 127.2, 126.5, 126.1, 123.2, 122.3, 122.0, 120.6, 112.1, 68.6, 67.8, 55.6, 54.4, 54.3, 43.9, 41.7, 24.3, 24.2; IR (ATR) [cm4]: 3309, 2963, 1685, 1522, 1457, 1395, 1227, 1034, 789, 723, 689; LC-MS (DAD / ESI): tR= 5.14 min, calculated for C35H40Cl2N4O4(m / z) [M+FA-H]' 695.24; found [M+FA-H]' 695.49; HRMS (ESI): calculated for C35H40Cl2N4O4[m / z] [M+H]+651.2499; found [M+H]+651.2496. EXAMPLE 10. N-(2,2’-dichloro-4”-(((2-(dimethylamino)ethyl)amino)methyl)-3"-methoxy- [1,1’:3*, 1” -terphenyl] - 3 -y 1) - 5 -(((2-dimethylamino)ethyl)amino)methyl)picolinamide (10)

[0230] During the synthesis PROCEDURE 6 was used

[0231] Step 1: N-(2,2’-dichloro-4”-(hydroxymethyl)-3”-methoxy-[l,r:3',l"-terphenyl]-3-yl)-5-

[0232] (hydroxymethyl)picolinamide 6e (0.10 g, 0.19 mmol, 1.0 eq.), SOCh (0.08 ml, 1.5 mmol, 6.0 eq.), anhydrous DMF (5 drops), anhydrous DCM (5 mL).

[0233] Step 2: / V, / V-dimethylethylene-l,2-diamine (0.10 g, 1.00 mmol, 6.0 eq.), ACA'Miisopropylcthylaminc (0.09 ml, 0.66 mmol, 4 eq.), anhydrous DMF (3 mL). Product 10 was obtained as a colorless precipitate with 34% (0.04 g) yield.

[0234] Rf= 0.36 (SiO2, CHCl3 / MeOH / 7M NH3in MeOH, 3 / 1 / 0, 1 v / v / v); 'H NMR (400 MHz, CDC13) 5 10.83 (s, 1H), 8.72 (dd, J= 8.3, 1.5 Hz, 1H), 8.61 (d, J= 1.6 Hz, 1H), 8.26 (d, J= 8.0 Hz, 1H), 7.91 (dd, J = 8.0, 2.0 Hz, 1H), 7.44-7.37 (m, 3H), 7.33 (d, J= 7.6 Hz, 1H), 7.29-7.26 (m, 1H), 7.10 (dd, J= 7.6, 1.5 Hz, 1H), 7.03 (dd, J= 7.6, 1.5 Hz, 1H), 6.99 (d, J= 1.4 Hz, 1H), 3.92 (s, 2H), 3.87 (s, 2H), 3.87 (s, 3H), 2.75 (t, J = 6.2 Hz, 2H), 2.69 (t, J = 5.9 Hz, 2H), 2.47-2.41 (m, 4H), 2.21 (s, 6H), 2.19 (s, 6H);13C NMR NMR (101 MHz, CDC13) 5 162.5, 157.2, 148.6, 148.4, 141.3, 139.9, 139.6, 139.5, 137.3, 135.2, 131.9, 131.1, 130.1, 129.6, 127.2, 126.5, 126.1, 123.2, 122.3, 121.7, 120.5, 111.9, 59.0, 58.9, 55.5, 51.3, 49.1, 46.8, 46.6, 45.6, 45.5; IR (ATR) [cm4]: 3310, 2934, 1690, 1522, 1456, 1395, 1225, 1034, 723, 689; LC-MS (DAD / ESI): tR= 3.83 min, calculated for CMH^CLNSCL (m / z) [M+2H]2+325.14; found [M+2H]2+325.37; HRMS (ESI): calculated for C^HtCLNgCh [m / z] [M+H]+649.2819; found [M+H]+649.2820.

[0235] EXAMPLE 11. 4-((6-((4”-((4-carbamoilopiperazin-l-yl)methyl)-2,2'-dichloro-3"-methoxy-[l,r:3',l"- terphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)piperazine-l-carboxamide (11)

[0236] 11

[0237] During the synthesis PROCEDURE 6 was used

[0238] Step 1: N-(2,2’-dichloro-4”-(hydroxymethyl)-3”-methoxy-[l,r:3',l"-terphenyl]-3-yl)-5-

[0239] (hydroxymethyl)picolinamide 6e (0.13 g, 0.25 mmol, 1.0 eq.), SOCL (0.10 ml, 1.50 mmol, 6.0 eq.), anhydrous DMF (5 drops), anhydrous DCM (5 mL). Step 2: Piperazine- 1 -carboxamide (0.05 g, 0.36 mmol, 2.0 eq.), triethylamine (0.05 ml, 0.36 mmol, 2 eq.), anhydrous DMF (3 mL). Product 11 was obtained as a yellow precipitate with 21% (0.03 g) yield. Rf= 0.52 (SiO2, CHCl3 / MeOH / 7M NH3in MeOH, 5 / 1 / 0, 1 v / v / v); 'H NMR (600 MHz, MeOD-d4) 5 8.67 (d, J= 1.5 Hz, 1H), 8.59 (dd, J= 8.3, 1.4 Hz, 1H), 8.23 (d, J= 8.0 Hz, 1H), 8.02 (dd, J= 8.0, 1.9 Hz, 1H), 7.50-7.43 (m, J= 11.3, 4.1 Hz, 3H), 7.40 (d, J = 7.6 Hz, 1H), 7.31 (dd, J= 6.1, 3.1 Hz, 1H), 7.14 (dd, J= 7.6, 1.5 Hz, 1H), 7.06 (d, J= 1.3 Hz, 1H), 7.03 (dd, J= 7.7, 1.5 Hz, 1H), 3.87 (s, 3H), 3.69 (s, 2H), 3.68 (s, 2H), 3.44 (dd, J= 10.3, 6.9 Hz, 8H), 2.59-2.55 (m, 4H), 2.50-2.45 (m, 4H);13C NMR (101 MHz, MeOD) 5 162.6, 159.7, 157.8, 149.2, 148.3, 141.2, 139.8, 139.3, 138.5, 137.6, 134.8, 131.3, 131.0, 130.9, 129.9, 127.0, 126.5, 126.3, 124.5, 123.8, 123.2, 121.7, 121.3, 120.6, 118.7, 111.9, 59.1, 55.4, 54.7, 52.4, 52.2, 43.4, 42.8; IR (ATR) [cm4]: 3314, 2924, 1696, 1522, 1456, 1396, 1227, 1028, 789, 723, 689; LC-MS (DAD / ESI): tR= 4.81 min, calculated for C37H40Cl2N8O4(m / z) [M+FA-H]’ 775.25; found [M+FA-H]’ 775.43; HRMS (ESI): calculated for C37H40Cl2N8O4[m / z] [M+H]+731.2622; found [M+H]+731.2619.

[0240] EXAMPLE 12. N-(2,2'-dichloro-4"-((dimethylamino)methyl)-3"-methoxy-[l,r:3',l"-terphenyl]-3-yl)- 5-((dimethylamino)methyl)picolinamide (12)

[0241] During the synthesis PROCEDURE 6 was used

[0242] Step 1: N-(2,2’-dichloro-4”-(hydroxymethyl)-3”-methoxy-[l,r:3',l"-terphenyl]-3-yl)-5-

[0243] (hydroxymethyl)picolinamide 6e (0.10 g, 0.19 mmol, 1.0 eq.), SOC12(0.08 ml, 1.50 mmol, 6.0 eq.), anhydrous DMF (5 drops), anhydrous DCM (5 mL).

[0244] Step 2: Propan-2-amine (0.03 g, 0.3 mmol, 6.0 eq.), / V^V-diisopropylethylamine (0.05 ml, 0.2 mmol, 4 eq.), anhydrous DMF (3 mL). Product 12 was obtained as a colorless precipitate with 49% (0.03 g) yield. Rf= 0.42 (SiO2, CHCl3 / MeOH / 7M NH3in MeOH, 5 / 1 / 0, 1 v / v / v); 'H NMR (400 MHz, MeOD) (400 MHz, CDCl3 / MeOD-d4) 5 8.65 (d, J= 1.8 Hz, 1H), 8.59 (dd, J= 8.3, 1.3 Hz, 1H), 8.21 (d, J= 8.0 Hz, 1H), 8.01 (dd, J = 8.0, 1.9 Hz, 1H), 7.47-7.41 (m, 3H), 7.34-7.27 (m, 2H), 7.12 (dd, J = 7.6, 1.4 Hz, 1H), 7.06-7.03 (m, 1H), 7.01 (m, J= 7.6, 1.3 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 2H), 3.84 (s, 12), 2.93-2.80 (m, 2H), 1.15-1.11 (m, 12H);13C NMR (101 MHz, CDCl3 / MeOD-d4) 5 162.0, 156.8, 148.0, 147.4, 140.6, 139.9, 139.2, 138.8, 138.6, 137.1, 134.1, 130.7, 130.3, 129.3, 129.0, 126.3, 125.8, 125.6, 125.2, 122.5, 121.2, 120.9, 119.9, 111.1, 54.1, 47.2, 47.0, 45.0, 20.6, 20.2; IR (ATR) [cm’1]: 3310, 2963, 1685, 1522, 1456, 1395, 1226, 1033, 789, 723, 689; LC-MS (DAD / ESI): tR= 5.42 min, calculated for C33H36C12N4O2(m / z) [M+2H]2+296.12; found [M+2H]2+296.30; HRMS (ESI): calculated for C33H36C12N4O2[m / z] [M+H]+591.2288; found [M+H]+591.2284. EXAMPLE 13. Methyl ((6-((2,2'-dichloro-3"-methoxy-4”-((((S)-l-methoxy-4-(methylthio)-l- oxobutan-2-yl)amino)methyl)- [1 ,1 ' :3' ,1 "-terphenyl] -3-yl)carbamoyl)pyri din-3- yl)methyl)-L- methionate (13)

[0245] During the synthesis PROCEDURE 6 was used

[0246] Step 1: N-(2,2’-dichloro-4”-(hydroxymethyl)-3”-methoxy-[l,r:3',l"-terphenyl]-3-yl)-5-

[0247] (hydroxymethyl)picolinamide 6e (0.25 g, 0.49 mmol, 1.0 eq.), SOCh (0.21 ml, 2.90 mmol, 6.0 eq.), anhydrous DMF (5 drops), anhydrous DCM (5 mL).

[0248] Step 2: Methyl L-methionate hydrochloride (0.38 g, 2.45 mmol, 5.0 eq.), triethylamine (0.27 ml, 1.96 mmol, 4.0 eq.), anhydrous DMF (5 mL). Product 13 was obtained as a colorless precipitate with 17% (0.07 g) yield.

[0249] Rf= 0.67 (SiO2, CHCl3 / MeOH / 7M NH3in MeOH, 5 / 1 / 0, 1 v / v / v); 'H NMR (600 MHz, CDC13) 5 10.73 (s, 1H), 8.65 (dd, J = 8.3, 1.4 Hz, 1H), 8.54 (s, 1H), 8.18 (d, 1H), 7.83 (dd, J = 13.9, 7.0 Hz, 1H), 7.35 (d, 1H), 7.32 (d, J = 2.7 Hz, 1H), 7.31 (d, J = 1.9 Hz, 1H), 7.26 (d, J = 7.7 Hz, 1H), 7.20 (dd, J = 5.2, 3.1 Hz, 1H), 7.03 (dd, J = 7.6, 1.5 Hz, 1H), 6.96 (dd, J = 7.6, 1.2 Hz, 1H), 6.91 (d, J = 1.3 Hz, 1H), 3.90 (d, J = 14.0 Hz, 1H), 3.80 (s, 3H), 3.75 (d, 1H), 3.70 (d, 1H), 3.68 (s, 3H), 3.65 (d, 1H), 3.59 (s, 3H), 3.39 (dd, J = 7.5, 5.7 Hz, 1H), 3.35 (dd, J = 8.5, 4.9 Hz, 1H), 2.58-2.52 (m, J = 15.5, 7.7, 4.0 Hz, 4H), 2.01 (s, 3H), 2.01 (s, 3H), 1.92-1.86 (m, 4H), 1.84-1.81 (m, J = 13.7, 6.6 Hz, 1H), 1.78-1.75 (m, 1H);13C NMR (151 MHz, CDC13) 5 175.4, 162.4, 157.1, 148.7, 148.3, 141.2, 139.8, 139.5, 139.4, 138.9, 137.4, 135.1, 131.8, 131.0, 130.0, 129.3, 127.3, 127.2, 126.4, 126.0, 123.1, 122.2, 121.6, 120.5, 111.8, 60.0, 59.5, 55.5, 52.1, 51.8, 49.3, 47.4, 32.9, 32.8, 30.6, 30.5, 15.5, 15.4; IR (ATR) [cm ]: 3318, 2918, 2851, 2361, 1733, 1694, 1598, 1526, 1475, 1397, 1300, 1227, 1200, 1170, 1128, 1035, 860, 793, 770, 724, 691; LC-MS (DAD / ESI): tR= 7. 12 min, calculated for ^ChN^sSz (m / z) [M+2H]2+400. 11; found [M+2H]2+400.34; HRMS (ESI): calculated for CM^CLN^SSZ [m / z] [M+H]+799.2152; found [M+H]+799.2153.

[0250] EXAMPLE 14. N-(2,2'-dichloro-4”-((((S)-l-hydroxy-3-(4-hydroxyphenyl)propan-2- yl)amino)methyl)-3"-methoxy-[l,r:3',l"-terphenyl]-3-yl)-5-((((S)-l-hydroxy-3-(4- hydroxyphenyl)propan-2-yl)amino)methyl)picolinamide (14)

[0251] During the synthesis PROCEDURE 6 was used

[0252] Step 1: N-(2,2’-dichloro-4”-(hydroxymethyl)-3”-methoxy-[l,r:3',l"-terphenyl]-3-yl)-5-

[0253] (hydroxymethyl)picolinamide 6e (0.30 g, 0.59 mmol, 1.0 eq.), SOC12(0.26 ml, 3.50 mmol, 6.0 eq.), anhydrous DMF (5 drops), anhydrous DCM (5 mL).

[0254] Step 2: L-tyrosinol (0.55 g, 2.35 mmol, 4.0 eq.), triethylamine (0.33 ml, 2.35 mmol, 4.0 eq.), anhydrous DMF (5 mL). Product 14 was obtained as a brown precipitate with 19% (0. 10 g) yield.

[0255] Rf= 0.33 (SiO2, CHCl3 / MeOH / 7M NH3in MeOH, 5 / 1 / 0, 1 v / v / v); 'H NMR (600 MHz, MeOD-d4) 5 8.58 (dd, J = 8.3, 1.0 Hz, 1H), 8.56 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.87 (dd, J = 8.0, 1.7 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.46-7.44 (m, 1H), 7.42 (dd, J = 8.3, 1.5 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.31 (dd, J = 7.1, 2.1 Hz, 1H), 7.11 (ddd, J = 7.5, 4.2, 1.4 Hz, 1H), 7.05 (d, J = 7.1 Hz, 2H), 7.03-6.99 (m, 4H), 6.76-6.71 (m, 4H), 4. 17 (d, J = 13. 1 Hz, 1H), 4.10 (d, J = 13.2 Hz, 1H), 3.93 (s, 2H), 3.78 (s, 3H), 3.74- 3.68 (m, J = 13.0, 6.6 Hz, 2H), 3.63-3.57 (m, 2H), 3.47 (dd, J = 11.1, 6.0 Hz, 1H), 3.17-3.11 (m, 1H), 2.87-2.83 (m, 2H), 2.83-2.81 (m, 1H), 2.71-2.66 (m, 2H);13C NMR (151 MHz, MeOD-d4) 5 171.5,

[0256] 162.9, 157.7, 156.6, 156.0, 155.7, 155.8, 149.1, 148.7, 148.5, 148.4, 148.3, 142.1, 142.2, 141.2, 140.2,

[0257] 139.3, 139.2, 139.1, 137.7, 134.8, 131.3, 131.0, 130.7, 130.3, 130.1, 129.9, 129.8, 129.2, 127.4, 127.2,

[0258] 126.7, 126.4, 123.2, 121.8, 121.7, 121.5, 120.6, 115.3, 115.0, 112.2, 62.4, 60.2, 60.0, 54.8, 54.8, 45.4,

[0259] 36.2, 34.2; IR (ATR) [cm ]: 3320 , 2917, 2849, 2362, 1734, 1694, 1598, 1526, 1475, 1457, 1397, 1300, 1227, 1201, 1170, 1128, 1035, 793, 770, 724, 691; LC-MS (DAD / ESI): tR= 5.34 min, calculated for C45H44Cl2N4O6(m / z) [M-H]’ 805.25; found [M-H]’ 805.48; HRMS (ESI): calculated for C45H44C12N4O6[m / z] [M+2H]2+404.1392; found [M+2H]2+404.1391.

[0260] EXAMPLE 15. N-(2,2'-dichloro-4”-(((2-hydroxyethyl)(methyl)amino)methyl)-3"-methoxy-

[0261] [1,1 ' :3', 1' ’-terphenyl] -3-yl)-5-(((2-hydroxyethyl)(methyl)amino)methyl)picolinamide (15)

[0262] During the synthesis PROCEDURE 6 was used

[0263] Step 1: N-(2,2’-dichloro-4”-(hydroxymethyl)-3”-methoxy-[l,r:3',l"-terphenyl]-3-yl)-5-

[0264] (hydroxymethyl)picolinamide 6e (0.30 g, 0.59 mmol, 1.0 eq.), SOC12(0.43 ml, 5.90 mmol, 10.0 eq.), anhydrous DMF (5 drops), anhydrous DCM (6 mL). Step 2: 2-(methylamine)ethanol (0.28 g, 3.53 mmol, 6 eq.), A / A'-diisopropylcthylaminc (0.41 ml, 2.36 mmol, 4 eq.), anhydrous DMF (6 mL). Product 15 was obtained as a colorless precipitate with 65% (0.03 g) yield.

[0265] Rf= 0.38 (SiO2, CHCh / MeOH, 9 / 1 v / v); 'H NMR (600 MHz, CDC13) 5 10.82 (s, 1H), 8.73 (dd, J= 8.3, 1.5 Hz, 1H), 8.59 (d, J= 1.5 Hz, 1H), 8.27 (d, J= 7.9 Hz, 1H), 7.86 (dd, J= 8.0, 2.0 Hz, 1H), 7.44-7.36 (m, 3H), 7.30 (d, J = 7.6 Hz, 1H), 7.27 (dd, J = 7.2, 2.0 Hz, 1H), 7.11 (dd, J = 7.6, 1.5 Hz, 1H), 7.04 (dd, J = 1.6, 1.5 Hz, 1H), 7.01 (d, J= 1.4 Hz, 1H), 3.87 (s, 3H), 3.70-3.64 (m, 6H), 3.61 (s, 2H), 2.68- 2.65 (m, 2H), 2.65-2.62 (m, 2H), 2.28 (s, 3H), 2.25 (s, 3H).;13C NMR (101 MHz, CDC13) 5 162.4,

[0266] 157.5, 149.0, 148.9, 141.3, 140.0, 139.6, 139.5, 138.1, 137.8, 135.2, 131.9, 131.1, 130.5, 130.1, 127.2,

[0267] 126.5, 126.3, 126.1, 123.2, 122.4, 121.6, 120.6, 112.2, 59.5, 59.0, 58.8, 58.7, 58.7, 55.9, 55.6, 42.2, 41.7; LC-MS (DAD / ESI): tR= 4.87 min, calculated for C35H40CI2N4O4 (m / z) [M+2H]2+312.11; found [M+2H]2+312.22; HRMS (ESI): calculated for C35H40Cl2N4O4[m / z] [M+H]+623.2186; found [M+H]+623.2185.

[0268] BIOACTIVITY IN A CLASSIC CELL-BASED IBC (Immune Checkpoint Blockade) ASSAY

[0269] In order to verify bioactivity, cellular experiments were carried out on a group of final compounds 1-14 First, the classic PD-1 / PD-L1 checkpoint blockade assay (ICB) was performed. In the standard assay configuration, Jurkat effector T cells (Jurkat-EC) are activated by the T-cell receptor (TCR) using an artificial TCR activator molecule (TCRAct). However, activation is inhibited by human PD-L1 exposed simultaneously with TCRAct on the surface of CHO / TCRAct / PD-Ll cells. Blockade of the PD-l / PD- L1 immune checkpoint with therapeutic antibodies (such as durvalumab) or molecules (such as the well- characterized and potent small molecule Compound A(Park et al. 2021)) may restore maximal activation of Jurkat-ECs.

[0270] In the assay, all compounds demonstrated dose-dependent restoration of Jurkat T cell activation, indicating effective blockade of the PD- 1 / PD-L 1 immune checkpoint. In the conducted experiments, activities similar to the bioactivity of one of the strongest molecules based on the structure of biphenyl, Compound A, are observed(Park et al. 2021). For all tested molecules, as well as for Compound A, toxic effects were observed at concentrations above 1 pM.

[0271] The results of the obtained bioactivities are shown in Table 1.

[0272] Table 1. Bioactivity of compounds used in ICB tests.

[0273] 6, 7 AND 8 BLOCK ENDOGENOUS HUMAN PD-L1 IN CELLULAR CONTEXT

[0274] In the second assay configuration, CHO / TCRAct / PD-Ll hamster cells were replaced with human tumor cells of the RKO line with overexpression of the TCR activator molecule (RKO / TCRAct cells). RKO cells are known to express high levels of the endogenous human PD-L1 protein, and thus are suitable to provide inhibition of T cell activation by PD- 1. In the assay, human Jurkat-EC cells were contacted with RKO / TCRAct cells in the presence of the tested molecules, and reactivation of the former was monitored and presented as % of the maximum blockade of PD-1 / PD-L1, where the maximum blockade refers to the activation at saturated concentration of Compound A.

[0275] Similar to the results obtained in a classic ICB assay, 6, 7 and 8 restored the activation of Jurkat-ECs cells to the maximum level defined as 100% blockade of PD-1 / PD-L1. In addition, in this system, compound 6 exhibited safe reactivation of Jurkat-ECs to a concentration of 3.1 pM, indicating less toxicity to treated cells and providing a promising therapeutic window for further studies.

[0276] To rule out the possibility that the tested molecules increase the activation of Jurkat-ECs independently of the PD-1 / PD-L1 immune checkpoint, the ICB assay was performed in parallel on two CHO cell lines. Both cell lines expressed the TCRAct molecule and were able to activate Jurkat-ECs, but only one overexpressed human PD-L1. Increased Jurkat-ECs activation was observed only when PD-L1 was present and not in the absence of PD-L1, suggesting that blockade of the PD-1 / PD-L1 interaction underlies the mechanism of increased T cell activation by 6, 7, and 8.

[0277] ACTIVITY OF COMPOUNDS AGAINST PRIMARY LYMPHOCYTES

[0278] The conventional ICB assay is based on artificial Jurkat-EC cells, acting as T cell substitutes. To assess the potential of the compounds to reactivate primary T cells blocked by PD-L1, a modified assay called the T cell activation assay (TCA) was performed. In this procedure, human peripheral blood primary mononuclear cells (PBMCs) freshly isolated from healthy donors are contacted with pre-seeded CHO / TCRAct / PD-Ll cells either alone or in the presence of PD-1 / PD-L1 blockers, and T cell activation is monitored by flow cytometry analysis. In the experiment, CD4+ helper T cells and CD8+ cytotoxic T cells were analyzed separately for activation / depletion marker expression on T cell surface (PD-1). Contact of PBMCs with CHO / TCRAct / PD-Ll -stimulating cells resulted in a significant increase in PD- 1 expression on both T cell types. Importantly, the percentage of activated T cells was significantly higher in the presence of the known PD-L1 -blocking antibody, durvalumab, as evidenced by an increased percentage of PD-1+ cells. This reflects the reactivation of T cells with PD-1 / PD-L1 blockade. Similar to the therapeutic antibody, the presence of compound 6 led to an increase in the activation of the T cell population, manifested by a significant increase in the percentage of PD-1 -positive cells.

[0279] In particular, the conducted assays showed that compound 6 increased the elimination of cancer cells by primary lymphocytes

[0280] In the fourth experimental system, advanced co-culture of tumor cells of the RKO / TCRAct cell line with human peripheral blood primary mononuclear cells (PBMCs) isolated from healthy donors was performed. PBMC cells just before co-culture were stained with a fluorescent dye of the "dilution dye" type in order to track the rate of their proliferation. Co-culture was carried out for 5 days in the presence of 6, a carrier of this compound (DMSO) or a control antibody (durvalumab), then a life / dead staining procedure was carried out along with the determination of the presence of several T cell surface markers (for appropriate gating and tracking of their activation), and then flow cytometry measurement was performed to determine cancer cell mortality of RKO / TCRAct.

[0281] In the presence of a carrier (DMSO), the viability of RKO / TCRAct cells was 85%, and the percentage of terminally dead cells was 13%. In the presence of durvalumab, the viability of RKO / TCRAct cells was observed at the level of 39% of 60% of terminally dead cells, which proves that the model is sensitive to blocking the PD-L1 protein. In the presence of compound 6, the percentage of dead cells was doubled compared to control (increase from 13% to 25%), while the percentage of living cells was 74%, which is an intermediate result between positive and negative control. At the same time, for both durvalumab and compound 6, an increase in PMBC proliferation and a strong increase in expression of the PD-1 protein on their surface, which, as mentioned in the previous chapter, is a determinant of lymphocyte activation in the presence of compounds blocking the PD-1 / PD-L1 checkpoint, were observed. The data obtained in this model confirm the therapeutic potential of compound 6, manifested by an increase in lymphocyte activation and an increase in their impact on the decrease in the viability of cancer cells in vitro.

[0282] ANALYSIS OF ADME PROPERTIES In order to determine the expected half-life of the tested compounds, affecting their usefulness in in vivo studies, the stability of compounds 6 and 8 was checked by incubation in a buffer or by conducting an experiment aimed at verifying microsomal stability. The following results were obtained:

[0283] 6 - stable in buffer, unstable in microsomes (45% of compound after 45 min)

[0284] 8 - stable in buffer, stable in microsomes (98% of compound after 45 min) The permeability of the compound through lipid membrane structures is an important parameter determining the bioavailability of the organic compound and its potential penetration from the digestive system into the bloodstream. In order to determine the permeability, a parallel artificial membrane penetration test (PAMPA, Parallel Artificial Membrane Permeation Assay) was performed. The following results were obtained:

[0285] SUMMARY AND CONCLUSIONS

[0286] Modulation of the immune response by inhibiting checkpoint receptors with antibodies is currently a recognized and effective cancer-fighting method known as immunooncology. The use of small molecule inhibitors instead of protein inhibitors would be another milestone in cancer therapies due to the frequent and numerous adverse immune effects caused by the antibodies used. Better pharmacokinetics and much lower production costs caused great interest of the world of science and pharmaceutical companies in small-molecule inhibitors against checkpoint receptors, i.e. PD-1 / PD-L1, manifested by many publications and patents in this field(Guzik et al. 2019).

[0287] The compounds presented herein represent a new group of small molecule PD- 1 / PD-L 1 inhibitors based on the N-terphenylpicolinamide core, characterized by very high activity in in vitro assays using artificial and native cell lines. Therefore, they are excellent candidates for in vivo preclinical studies.

[0288] ABBREVIATIONS USED:

[0289] Anhydr., anhydrous

[0290] AcOEt, ethyl acetate;

[0291] AcOH, acetic acid;

[0292] CHCI3, chloroform;

[0293] DMSO, dimethyl sulfoxide

[0294] DCM, dichloromethane;

[0295] DMF, dimethylformamide; DMSO, dimethyl sulfoxide;

[0296] HTRF, Homogenous Time Resolved Fluorescence

[0297] DIPEA, diisopropylethylamine;

[0298] MeOH, methanol;

[0299] ACN, acetonitrile;

[0300] MgSCh, magnesium sulphate;

[0301] NMR, Nuclear Magnetic Resonance Spectroscopy;

[0302] PD-1, Programmed Death 1;

[0303] PD-L1, Programmed Death Ligand;

[0304] THF, tetrahydrofuran;

[0305] TLC, thin-layer chromatography;

[0306] TMS, tetramethylsilane;

[0307] REFERENCES:

[0308] Alsaab HO, Sau S, Alzhrani R, Tatiparti K, Bhise K, Kashaw SK, Iyer AK. 2017. PD-1 and PD-L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome. Front Pharmacol. 8. https: / / doi.org / 10.3389 / fphar.2017.00561

[0309] Chakraborty SRT. 2012. The difficulties in cancer treatment. Ecancermedicalscience. 6.

[0310] Couzin-Frankel J. 2013. Cancer Immunotherapy. Science (1979). 342(6165): 1432-1433. https: / / doi.Org / 10. l 126 / science.342.6165. 1432

[0311] Guzik K, Tomala M, Muszak D, Konieczny M, Hec A, Blaszkiewicz U, Pustula M, Butera R, Domling A, Holak TA. 2019. Development of the Inhibitors That Target the PD-1 / PD-L1 Interaction — A Brief Look at Progress on Small Molecules, Peptides and Macrocycles. Molecules. 24(l l):2071. https: / / doi.org / 10.3390 / molecules24112071

[0312] Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, Okazaki T, Tokura Y. 2010. Tumor cell expression of programmed cell death- 1 ligand 1 is a prognostic factor for malignant melanoma. Cancer. 116(7): 1757-1766. https: / / doi.org / 10.1002 / cncr.24899

[0313] Ledford H, Else H, Warren M. 2018. Cancer immunologists scoop medicine Nobel prize. Nature. 562(7725). https: / / doi.org / 10.1038 / d41586-018-06751-0

[0314] Park J-J, Thi EP, Carpio VH, Bi Y, Cole AG, Dorsey BD, Fan K, Harasym T, lott CL, Kadhim S, et al. 2021. Checkpoint inhibition through small molecule-induced internalization of programmed deathligand 1. Nat Commun. 12(1): 1222. https: / / doi.org / 10.1038 / s41467-021-21410-l

[0315] Schuster M, Nechansky A, Kircheis R. 2006. Cancer immunotherapy. Biotechnol J. 1(2): 138-147. https: / / doi.org / 10.1002 / biot.200500044

[0316] Wu P, Wu D, Li L, Chai Y, Huang J. 2015. PD-L1 and Survival in Solid Tumors: A Meta-Analysis. PLoS One. 10(6):e0131403. https: / / doi.org / 10.1371 / joumal.pone.0131403

Claims

Claims1. A compound of Formula 1:Formula 1 wherein: R1is a substituent selected from: -H, -F, -Cl, -Br, -CH3,-O-alkyl, -NH-alkyl, -N-dialkyl, -CN, -NO2;R2is a substituent selected independently from:or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 characterized in that it is selected from the group comprising:N-(2'-chloro-4"-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-3"-methoxy- [l,r:3',l"-terphenyl]-3-yl)-5-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2- yl)amino)methyl)picolinamide,N-(2'-chloro-4”-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-2,3"-dimethoxy- [l,r:3',r’-terphenyl]-3-yl)-5-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2- yl)amino)methyl)picolinamide,N-(2'-chloro-4”-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-3"-methoxy-2- methyl-[l,r:3',l”-terphenyl]-3-yl)-5-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2- yl)amino)methyl)picolinamide,N-(2'-chloro-4"-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-2-fluoro-3"-methoxy- [l,r:3',l"-terphenyl]-3-yl)-5-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2- yl)amino)methyl)picolinamide,N-(2'-chloro-4”-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-2-(dimethylamino)- 3"-methoxy-[l,r:3',r’-terphenyl]-3-yl)-5-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2- yl)amino)methyl)picolinamide,N-(2,2'-dichloro-4”-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)amino)methyl)-3"-methoxy- [l,r:3',r’-terphenyl]-3-yl)-5-(((l,3-dihydroxy-2-(hydroxymethyl)propan-2- yl)amino)methyl)picolinamide,N-(2,2'-dichloro-4”-(((l,3-dihydroxypropan-2-yl)amino)methyl)-3"-methoxy-[l,r:3',l"-terphenyl]-3- yl)-5 -((( 1 ,3 -dihydroxypropan-2-yl)amino)methyl)picolinamide,N-(2,2'-dichloro-4"-(((2-hydroxyethyl)amino)methyl)-3"-methoxy-[l,r:3',l"-terphenyl]-3-yl)-5-(((2- hydroxyethyl)amino)methyl)picolin amide,N-(2,2'-dichloro-4"-(((l-hydroxy-2-methylpropan-2-yl)amino)methyl)-3"-methoxy-[l,r:3',l"- terphenyl]-3-yl)-5-(((l-hydroxy-2-methylpropan-2-yl)amino)methyl)picolinamide,N-(2,2'-dichloro-4"-(((2-(dimethylamino)ethyl)amino)methyl)-3"-methoxy-[l,r:3',l"-terphenyl]-3-yl)- 5-(((2-(dimethylamino)ethyl)amino)methyl)picolinamide,4-((6-((4”-((4-carbamoyl-piperazin-l-yl)methyl)-2,2'-dichloro-3"-methoxy-[l,r:3',l"-terphenyl]-3- yl)carbamoyl)pyridin-3-yl)methyl)piperazine- 1 -carboxamide,N-(2,2'-dichloro-4"-((dimethylamino)methyl)-3"-methoxy-[l,r:3',l"-terphenyl]-3-yl)-5- ((dimethylamino)methyl)picolinamide, methyl ((6-((2,2'-dichloro-3"-methoxy-4"-((((S)-l-methoxy-4-(methylthio)-l-oxobutan-2- yl)amino)methyl)-[l,r:3',l"-terphenyl]-3-yl)carbamoyl)pyridin-3-yl)methyl)-L-methionate,N-(2,2'-dichloro-4”-((((S)-l-hydroxy-3-(4-hydroxyphenyl)propan-2-yl)amino)methyl)-3"-methoxy-[ 1 , 1' :3', 1' ’-terphenyl] -3-yl)-5-((((S)- 1 -hydroxy-3-(4-hydroxyphenyl)propan-2- yl)amino)methyl)picolinamide, or their pharmaceutically acceptable salts.

3. The compound according to claims 1-2 for use in pharmacy, especially in the treatment or prevention of cancer.

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