EA034601B1 - Process for producing boronic acids - Google Patents

Abstract

The present invention provides novel processes for producing boronic acids of formula (v), wherein ring A isBoronic acids are useful as proteasome inhibitors.

Description

Technical field

The present invention relates to a new method for producing boronic acids, suitable for use as proteasome inhibitors.

State of the art

Boronic acids exhibit a number of pharmaceutically useful types of biological activity. US Pat. No. 4,499,082 (1985) to Shenvi et al. Shows that peptide boronic acids are inhibitors of certain proteolytic enzymes. Kettner (Kettner) and Shenvi (Shenvi) in US patent No. 5187157 (1993), 5242904 (1993) and 5250720 (1993) proposed a class of peptide boronic acids that inhibit trypsin-like proteases. Kliman (Kleeman) et al. In US Pat. No. 5,169,841 (1992) propose N-terminal modified peptide boronic acids that inhibit the action of renin. Kinder et al. In US Pat. No. 5,106,948 (1992) indicate that certain boronic acid compounds inhibit the growth of cancer cells. Bakhovchin (Bachovchin) with coauthors in the publication of international application WO 07/0005991 describes compounds of peptide boronic acids that inhibit fibroblast activating protein.

Boronic acids are promising inhibitors of the proteasome, which is a multicatalytic protease responsible for most of the processes of intracellular protein renewal. Adams et al. US Pat. No. 5,780,454 (1998) describe peptide boronic esters and acids suitable for use as proteasome inhibitors. This work also describes the use of boronic esters and acids to reduce the rate of breakdown of muscle proteins, decrease the activity of NF-kB in the cell, decrease the rate of breakdown of p53 protein in the cell, suppress the breakdown of cyclins in the cell, suppress the growth of cancer cells and inhibit NFκΒ-dependent cell adhesion . Furet et al. In WO 02/096933; Chatterjee et al. In WO 05/016859 and Bernadini et al. In WO 05/021558 and WO 06/08660 additional boronic esters and acids are proposed which have been reported to have proteasome inhibitory activity.

Ciechanover, Cell, 79: 13-21 (1994), indicates that a proteasome is a proteolytic component of the ubiquitin-proteasome pathway in which proteins bind to many ubiquitin molecules, resulting in subsequent degradation of these proteins. Kishanover also indicated that the ubiquitin-proteasome pathway plays a key role in a number of important physiological processes. In the work of Rivett (Rivett) with co-authors, Biochem. J. 291: 1 (1993), it is indicated that the proteasome exhibits trypsin, chymotrypsin and peptidyl-glutamyl peptidase activity. The catalytic core of the 26S proteasome is the 20S proteasome. McCormack et al., Biochemistry 37: 7792 (1998), describe a variety of peptide substrates, including Suc-Leu-LeuVal-Tyr-AMC, Z-Leu-Leu-Arg-AMC, and Z-Leu-Leu-Glu- 2NA, where Suc is N-succinyl, AMS is 7-amino-4-methylcoumarin, and 2NA is 2-naphthylamine, which are cleaved by the 20S proteasome.

Proteasome inhibition is an important new cancer treatment strategy. King et al., Science 274: 1652-1659 (1996), showed that the ubiquitin-proteasome pathway plays an important role in cell ring regulation, tumor growth, and metastasis. The authors showed that a number of key regulatory proteins, including cyclins and cyclin-dependent kinases p21 and p27 ^KSF1 , are continuously degraded during the course of the cell ring along the ubiquitin-proteasome pathway. Timely decomposition of these proteins is required to advance the cell along the cell ring and its mitotic division.

In addition, the ubiquitin-proteasome pathway is necessary for the regulation of transcription. Palombella et al., Cell, 78: 773 (1994), showed that activation of the transcription factor NF-kB is regulated by proteasome-mediated degradation of the IkB inhibitory protein. In turn, NF-kB plays a central role in the regulation of genes involved in immune and inflammatory responses. Reed et al., Immunity 2: 493-506 (1995), show that the ubiquitin-proteasome pathway is necessary for the expression of cell adhesion molecules such as E-selectin, ICAM-I, and VCAM-I. Zetter, Seminars in Cancer Biology 4: 219-229 (1993), showed that cell adhesion molecules are involved in tumor metastasis and angiogenesis in vivo, directing the adhesion and extravasation of tumor cells to and from the vascular system to distant tissues inside the body. In addition, Beg and Baltimore, Science 274: 782 (1996), showed that NFkB is an anti-apoptotic control factor, and inhibition of NFkB activation makes cells more sensitive to environmental influences and cytotoxic agents.

The VELCADE® proteasome inhibitor (bortezomib; No. 2-pyrazinecarbonyl-E-phenylalanine-bleicinboronic acid) is the first proteasome inhibitor officially approved for use. Mitsiades et al., Current Drug Targets, 7: 1341 (2006), provide an overview of clinical trials that allowed permission to use boron 1,034,601 tezomib for treating patients with multiple myeloma who received at least one previously known drug. Fisher et al., J. Clin. Oncol., 30: 4867, an international multicenter phase II clinical trial is described that confirms the activity of bortezomib in patients with recurrent or refractory lymphoma from mantle cells. In Ishii et al., Anti-Cancer Agents in Medicinal Chemistry, 7: 359 (2007), and Roccaro et al., Curr. Pharm. Biotech., 7: 1341 (2006), discusses a number of molecular mechanisms that may contribute to the antitumor activity of bortezomib.

As can be seen from the above sources, the proteasome is an important target for therapeutic intervention. Therefore, there is still a need for new and / or improved proteasome inhibitors.

Description of the invention

The present invention provides methods for producing boronic acids, which are effective proteasome inhibitors. These compounds are suitable for suppressing the activity of proteasomes in vitro and in vivo and are particularly suitable for the treatment of various diseases associated with cell proliferation.

The invention relates to a method for producing a compound of formula (v)

where the ring A represents including:

(1) reacting a compound of formula (i) with a compound of formula (ii) to produce a compound of formula (iiia)

wherein PG is a protecting group selected from an acyl group and a urethane group;

(2) removing the protective group of a compound of formula (iiia) to give a compound of formula (iii)

(3) reacting a compound of formula (iii) with a compound of formula (viii) to obtain a compound of formula (iv)

(4) removing the protective group of a compound of formula (iv) to obtain a compound of formula (v); where Z ¹ and Z ² together with the boron atom to which they are attached form

where X ₁ ^- represents CF3CO2 ^- and X2 ^- represents Cl ^- . The invention also relates to a method for producing a compound of formula (v)

where the ring A represents including:

(1a) reacting a compound of formula (viii) with a compound of formula (vi) to obtain a compound of formula (viia)

- 2,034,601 where PG is a protecting group selected from an acyl group and a urethane group;

(2a) removing the protective group of a compound of formula (viia) to give a compound of formula (vii);

viia vii (3 a) reacting a compound of formula (vii) with a compound of formula (i) to obtain formula (iv)

and (4) removing the protective group of a compound of formula (iv) to give a compound of formula (v), wherein Z ¹ and Z ² together with the boron atom to which they are attached form

CH ₃

НзС * d <СНз ау ⁷ _; where X ₁ ^- represents CF3CO2 ^- and X2 ^- represents Cl ^- .

As used herein, the term “boronic acid” refers to a chemical compound containing fragment B (OH) ₂ . In some embodiments, boronic acids can form oligomeric anhydrides by dehydrating a boronic acid fragment. For example, Snyder et al., J. Am. Chem. Soc. 80: 3611 (1958), oligomeric arylboronic acids are described.

General synthesis methodology

A method of obtaining a compound of formula (v) is shown in scheme 1 below.

Scheme 1

The reaction of combining compound (i) with N-protected glycine (ii) followed by removal of the N-terminal protecting groups provides compound (iii). Examples of suitable protecting groups (PGs) include, without limitation, acyl protecting groups, for example, formyl, acetyl (Ac), succinyl (Suc) and methoxy succinyl; and urethane protecting groups, for example, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) and fluorenylmethoxycarbonyl (Fmoc). The peptide coupling reaction can be carried out by first converting a carboxylic acid fragment in the composition of compound (ii) into an activated ester, for example, O - ^ - hydroxysuccinimide) ether, followed by treatment with compound (i). Alternatively, the activated ester can be prepared in situ by contacting a carboxylic acid with an agent used in a peptide coupling reaction. Examples of suitable agents used in a peptide coupling reaction include, but are not limited to, carbodiimide agents, for example, dicyclohexylcarbodiimide (DCC) or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC); phosphonium agents, for example benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP); and uronium agents, for example, tetrafluoroborate O- (1Hbenzotriazol-1-yl) -HHN, No.-tetramethyluronium (TBTU).

Then, a coupling reaction of compound (iii) with substituted benzoic acid (ArCO ₂ H) was carried out to give compound (iv). The conditions of the peptide coupling reaction described above for the coupling reaction of compounds (i) and (ii) are also suitable for carrying out the coupling reaction of compound (iii) with ArCO ₂ H. Removal of the protecting groups from the boronic acid fragment then leads to the formation of compound (v) . The deprotection step is preferably carried out by transesterification in a two-phase mixture containing boronic ester (iv), an organic boronic acid acceptor, lower alkanol, C ₅ . ₈ hydrocarbon solvent and aqueous mineral acid.

Scheme 2

Alternatively, the sequence of coupling reactions can be reversed, as shown in Scheme 2. Thus, O-protected glycine (vi) is first coupled with substituted benzoic acid (ArCO ₂ H) and then the ether is hydrolyzed to give compound (vii) . The coupling reaction with compound (i) is then carried out and the protective groups are removed from boronic acid as described above for Scheme 1 to give compound (v).

For a more complete understanding of the present invention, the following examples of obtaining and conducting research are given below. These examples illustrate the preparation or study of specific compounds and in no way limit the present invention.

Examples

Abbreviations:

DCM - methylene chloride;

DIEA - diisopropylethylamine;

EDCI - Y- (3-dimethylaminopropyl) -Y'-ethylcarbodiimide hydrochloride;

EtOAc - ethyl acetate;

h - hours;

HPLC - high performance liquid chromatography;

TBTU - tetrafluoroborate ortho-benzotriazol-1-yl-y, y, y ', y'-tetramethyluronium;

HOBt - 1-hydroxybenzotriazole hydrate;

LC-MS - liquid chromatography - mass spectrometry;

min - minutes;

tr is the retention time from the spectra of the diode array.

LC-MS analytical methods

Spectra were obtained on a Symmetry C18 column of 3.5 μm -4.6x50 mm using the following gradient: Solvent A: 2% isopropyl alcohol, 98% water, 10 mM NH ₄ OAc.

Solvent B: 75% acetonitrile, 25% methanol, 10 mM NH ₄ OAc.

Time [min] Flow [ml / min] % solvent B 0, 0 10 fifty 3,5 10 100, 0 4.9 1,0 100, 0 fifty 1,0 fifty

Example 1. Synthesis of [(1H) -1 - ({[(2,3-difluorobenzoyl) amino] acetyl} amino) -3-methylbutyl) boronic acid · 20 D-mannitol (I-1)

- 4,034,601

Step 1. Methyl [(2,3-difluorobenzoyl) amino] acetate.

To a solution of 2,3-difluorobenzoic acid (0.190 g, 1.2 mmol) in tetrahydrofuran (5 ml) was added glycine methyl ester hydrochloride (0.150 g, 1.2 mmol), HOBt (0.162 g, 1.2 mmol), DIEA (0.209 ml, 1.2 mmol) and EDCI (0.252 g, 1.3 mmol). The reaction mixture was allowed to stir overnight. The reaction was quenched with saturated sodium bicarbonate and the product was separated in DCM. Separation of the organic layer and then removal of the solvent made it possible to obtain methyl [(2,3difluorobenzoyl) amino] acetate, which was used in the next step without purification.

Step 2. [(2,3-Difluorobenzoyl) amino] acetic acid.

To a solution of methyl [(2,3-difluorobenzoyl) amino] acetate (0.250 g, 1.1 mmol) in methanol (7 ml) was added lithium hydroxide (0.053 g, 2.2 mmol) and water (3 ml). The reaction mixture was allowed to stir overnight. The mixture was diluted with water (20 ml) and acidified with 1N HCl (5 ml). The product was separated in DCM / methanol (4: 1). The organic layer was dried over sodium sulfate and the solvent was removed to obtain [(2,3-difluorobenzoyl) amino] acetic acid, which was used in the next step without purification.

Step 3. 2,3-Difluoro-N- [2 - ({(1R) -3-methyl-1 - [(3aR, 4R, 6R, 7aS) -3a, 5,5-trimethylhexahydro-4,6-methane -

1,3,2-benzodioxaborol-2-yl] butyl} amino) -2-oxoethyl] benzamide.

To a solution of [(2,3-difluorobenzoyl) amino] acetic acid (0.205 g, 0.95 mmol) in dimethylformamide (10 ml) was added TBTU (0.337 g, 1.0 mmol) and (1R) -3-methyl-1 - [(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-4,6-methane-1,3,2-benzodioxaborol-2-yl] butan-1-amine as trifluoroacetate salt (0.362 g , 0.95 mmol). The mixture was allowed to cool to 0 ° C and DIEA (0.498 ml, 2.9 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction was quenched with water (100 ml) and the product was separated in DCM. The organic layer was dried over sodium sulfate and the solvent was removed to give 2,3-difluoro-N- [2 - ({(1R) -3-methyl-1 - [(3aR, 4R, 6R, 7aS) -3a, 5.5trimethylhexahydro -4,6-methan-1,3,2-benzodioxaborol-2-yl] butyl} amino) -2-oxoethyl] benzamide.

Step 4. [(^) - 1 - ({((2,3-Difluorobenzoyl) amino) acetyl} amino) -3-methylbutyl] boronic acid.

To a solution of 2,3-difluoro-N- [2 - ({(1R) -3-methyl-1 - [(3aR, 4R, 6R, 7aS) -3a, 5,5-trimethylhexahydro-4,6methane-1, 3,2-benzodioxaborol-2-yl] butyl} amino) -2-oxoethyl] benzamide (0.536 g, 1.2 mmol) in methanol / 1N HCl (1: 1) (1.5 ml) heptanol (1 ml) was added ) and isobutyl borate (0.207 g, 2.0 mmol). The reaction mixture was allowed to stir overnight. The heptanol layer was separated and the methanol / HCl layer was concentrated. The crude product was purified by reverse phase HPLC to give [(1R) -1 ({(2,3-difluorobenzoyl) amino) acetyl} amino) -3-methylbutyl] boronic acid.

Step 5. [(^) - 1 - ({((2,3-Difluorobenzoyl) amino) acetyl} amino) -3-methylbutyl1boronic acid · 20 D-mannitol (I-1).

To a solution of [(^) - 1 - ({((2,3-difluorobenzoyl) amino) acetyl} amino) -3-methylbutyl] boronic acid (0.085 g, 0.26 mmol) in tert-butyl alcohol (2 ml) and water (5 ml) was added D-mannitol (0.943 g, 5.2 mmol). The solution was heated and allowed to mix until the solids were completely dissolved. The solution was then frozen and the solvent was removed by lyophilization to obtain [(1R) -1 - ({(2,3difluorobenzoyl) amino) acetyl} amino) -3-methylbutyl] boronic acid · 20 D-mannitol (I-1) (0, 98 g, 97%).

Example 2. Synthesis of [(^) - 1 - ({((2-bromobenzoyl) amino) acetyl} amino) -3-methylbutyl] boronic acid · 20 D-mannitol (I-5)

Vg Oh

Step 1. tert-Butyl- [2 - ({(1R) -3-methyl-1 - [(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-4,6-methane-1,3 , 2benzodioxaborol-2-yl] butyl} amino) -2-oxoethyl] carbamate.

To the mixture (1R) -3-methyl-1 - [(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-4,6-methane-1,3,2-benzodioxaborol-2-yl] butane -1-amine as trifluoroacetate salt (4.9 g, 10.8 mmol), N- (tert-butoxycarbonyl) glycine (1.98 g, 11.3 mmol) and TBTU (3.81 g, 11.9 mmol) in DCM (100 ml), a solution of DIEA (5.64 ml, 32.4 mmol) in DCM (25 ml) was added dropwise over 15 minutes. The reaction mixture was allowed to stir overnight and concentrated. The crude product was purified by column chromatography to give tert-butyl- [2 - ({(1R) -3-methyl-1 - [(3aS, 4S, 6S, 7aR) -3a, 5.5-5 034601 trimethylhexahydro-4 , 6-methan-1,3,2-benzodioxaborol-2-yl] butyl} amino) -2-oxoethyl] carbamate (2.5 g,

55%).

Step 2. 2-amino-N - [(1R) -3-methyl-1 - [(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-4,6-methane-1,3,2benzodioxaboron -2-yl] butyl} acetamide.

To a solution of tert-butyl- [2 - ({(1R) -3-methyl-1 - [(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-4,6-methane-

1.3.2-benzodioxaborol-2-yl] butyl} amino) -2-oxoethyl] carbamate (2.5 g, 5.9 mmol) in DCM (15 ml) was added 4M HCl in dioxane (5.9 ml). The reaction mixture was allowed to stir for 2 hours and concentrated to give 2-amino-N - [(1R) -3-methyl-1 - [(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-4 , 6methane-1,3,2-benzodioxaborol-2-yl] butyl} acetamide, which was used in the next step without purification.

Step 3. 2-Bromo-N- [2 - ({(1R) -3-methyl-1 - [(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-4,6-methane-1 , 3.2benzodioxaborol-2-yl] butyl} amino) -2-oxoethyl] benzamide.

To a solution of 2-bromobenzoic acid (0.124 g, 0.62 mmol) in DCM (2.25 ml) was added EDCI (0.119 g, 0.62 mmol), HOBt (0.084 g, 0.62 mmol), N-methylmorpholine ( 0.185 ml, 1.68 mmol) and 2-amino-X- | (1E) 3-methyl-1 - [(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-4,6-methane- 1,3,2-benzodioxaborol-2-yl] butyl} acetamide (0.2 g, 0.56 mmol). The reaction mixture was allowed to stir for 2 hours and concentrated. The precipitate was diluted with water and extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO ₄ , filtered and concentrated. The crude product was purified by column chromatography to give 2-bromo ^ - | 2 - ({(1I) -3-methyl-1 [(3aS, 4S, 6S, 7aR) -3a, 5.5-trimethylhexahydro-4.6 -methane-1,3,2-benzodioxaborol-2-yl] butyl} amino) -2oxoethyl] benzamide (0.22 g, 78%).

Step 4. [(^) - 1 - ({[((2-Bromobenzoyl) amino] acetyl} amino) -3-methylbutyl] boronic acid.

To a solution of 2-bromo-N- [2 - ({(1R) -3-methyl-1 - [(3aS, 4S, 6S, 7aR) -3a, 5,5-trimethylhexahydro-4,6-methane-

1.3.2-benzodioxaborol-2-yl] butyl} amino) -2-oxoethyl] benzamide (0.220 g, 0.44 mmol) in methanol / hexane (1: 1) (2.2 ml) was added 1N HCl (1 ml 1.0 mmol) and isobutyl borate (0.078 g, 0.76 mmol). The reaction mixture was allowed to stir overnight. The reaction mixture was concentrated and purified by reverse phase HPLC to give [(^) - 1 - ({[(2-bromobenzoyl) amino] acetyl} amino) -3-methylbutyl] boronic acid (0.119 g, 73%).

Step 5. [(^) - 1 - ({((2-Bromobenzoyl) amino) acetyl} amino) -3-methylbutyl] boronic acid · 20 D mannitol (I-5).

To a solution of [(^) - 1 - ({[(2-bromobenzoyl) amino] acetyl} amino) -3-methylbutyl] boronic acid (0.103 g, 0.28 mmol) in tert-butyl alcohol (9 ml) and water (15 ml) was added D-mannitol (1.01 g, 5.5 mmol). The solution was heated and allowed to mix until the solids were completely dissolved. The solution was then frozen and the solvent was removed by lyophilization to give [(1R) -1 - ({(2bromobenzoyl) amino) acetyl} amino) -3-methylbutyl] boronic acid · 20 D-mannitol (I-5) (0.92 g , 84%).

The compounds in the following table were obtained from suitable starting materials in a manner analogous to the method described in example 1 or 2:

1-1 LC-MS: ER-327.3, tr = 3.36 min. 1-2 LC-MS: Er- 343-2, tr = 3.62 min 1-3 LC-MS: Er- 327.3 tr = 3.49 min 1-4 LC-MS: Er- 327.2 tr = 327 minutes 1-5 LC-MS: Er- 369.2 tr = 3.30 min H NMR (300 MHz, d ₄ -MeOD) 8: 7.62 (dd,: LH), 7.28- 7.50 (m, ZN), 4 , 19 (s, 2H), 2, 70-2.78 (m, 1H), 1.57-1, 71 ( m, 1H), 1.26-1.40 (m, 2Η) and 0.89 (D, 6H). 1-6 LC-MS: Er- 309.1, tr = 3.14 min 1-7 LC-MS: Er- 343.2 tr = 3.30 min 1-8 LC-MS: Er- 309.3, tr = 3.23 min 1-9 LC-MS: Er- 327.3 tr = 3.49 min 1-10 LC-MS: Er- 325.2, tr = 3,58 min 1-11 LC-MS: Er- 359.2 tr - 3.66 min % NMR (300 MHz, d ₄ MeOD) 8: 7, 62 (s, 1H) 7.49 (d, 2H), 4 , 23 (s, 2H), 2.74-2 , 82 (m -, 1H), 1.62-1.78 (m, 1H) , 1 30-1.45 (m, 2H) and 0.95 (d, 6H) • 1-12 LC-MS: Er- 359.2 tr = 3.95 min 1-13 LC-MS: Er- 309.2 tr = 3.34 min 1-14 LC-MS: Er- 343.2 tr = 3.44 min 1-15 LC-MS: Er- 359.2 tr = 3.26 min

- 6,034,601

1-16 LC-MS: Er- 325.2, tr = 3.20 min 1-17 LC-MS: Er- 327.3 tr = 3, 39 min 1-18 LC-MS: Er- 343.2 tr - 3, 58 min 1-19 LC-MS: Er- 325.1 tr - 3, 51 min 1-20 LC-MS: Er- 359.2 tr = 3, 54 min 1-21 LC-MS: Er- 359.2 tr = 3, 99 min

Example 2. The study using the proteasome 20S.

To 1 μl of the test compound dissolved in DMSO in a 384-well black microtiter plate was added 25 μl of the buffer used in this study at 37 ° C containing human PA28 activator (Boston Biochem, final concentration 12 nM) with Ac-WLA-AMC ( β5 selective substrate) (final concentration 15 μM), and then 25 μl of the buffer used in this study at 37 ° C containing 20S human proteasomes (Boston Biochem, final concentration 0.25 nM) was added. The buffer used in the study contained 20 mM HEPES, 0.5 mM EDTA and 0.01% BSA, pH 7.4. The progress of the reaction was monitored using a BMG Galaxy plate reader (37 ° C, excitation at 380 nm, emission at 460 nm, gain 20). Percent inhibition was calculated relative to control samples with 0% inhibition (DMSO) and 100% inhibition (10 μM bortezomib).

During this study, all compounds I-1 through I-21 showed IC ₅₀ values of less than 50 nM.

Although the present invention has been described above with some details intended to provide clarity and a more complete understanding of the invention, the specific embodiments given are illustrative and do not limit the present invention. After reviewing the present description, it will be obvious to a person skilled in the art that various possible changes in form and content are also within the scope of the present invention, the scope of which is determined to a greater extent by the attached claims than by specific embodiments.

Patent and scientific literature referred to in the present description, characterize the information available to specialists in this field of technology. Unless otherwise specified, all technical and scientific terms used in this description have the meanings usually implied by the average person skilled in the technical field to which the present invention relates. The contents of patents, patent applications and sources referenced herein are hereby incorporated by reference to the same extent as if it were specifically and individually indicated for each of these documents that this document is incorporated by reference. In case of discrepancies, the present description, including definitions, will be decisive.

Claims (14)

(1) reacting a compound of formula (i) with a compound of formula (ii) to produce a compound of formula (iiia) where PG is a protective group selected from an acyl group and a urethane group; 1. The method of obtaining the compounds of formula (v) where the ring A represents ^{C |} / including: 2. The method according to claim 1, wherein the interaction in steps (1) and (3) is carried out in the presence of a peptide coupling agent. (2) removing the protective group of a compound of formula (iiia) to obtain a compound of formula (iii) 3. The method of claim 2, wherein the peptide coupling agent is selected from a carbodiimide agent, a phosphonium agent, and a uronium agent. (3) reacting a compound of formula (iii) with a compound of formula (viii) to produce a compound of formula (iv) 4. The method according to claim 3, where the peptide coupling agent is selected from dicyclohexylcarbodiimide (DCC), 1 (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC), benzotriazole-1yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), tetrafluoroborate O- ( -benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium (TBTU) and N-hydroxybenzotriazole (HOBt). (4) removing the protective group of a compound of formula (iv) to obtain a compound of formula (v); where Z ¹ and Z ² together with the boron atom to which they are attached form where X ₁ ^- represents CF3CO2 ^- and X ₂ ^- represents Cl ^- . 5. The method according to claim 1, where the interaction in stages (1) and (3) is carried out in the presence of a solvent. 6. The method according to claim 5, where the solvent is selected from dichloromethane, tetrahydrofuran and dimethylformamide. 7. The method according to claim 1, where the protective group is selected from formyl, acetyl, succinyl, methoxy succinyl; tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) and fluorenylmethoxycarbonyl (Fmoc). - 7 034601 - 8 034601 where Xf represents CF ₃ CO ₂ 'and X ₂ ^- represents Cl ^- . 8. The method of obtaining the compounds of formula (v) where the ring A represents including: (1a) reacting a compound of formula (viii) with a compound of formula (vi) to obtain a compound of formula (viia) where PG is a protective group selected from an acyl group and a urethane group; (vii); (2a) removing the protective group of a compound of formula (viia) to give a compound of formula (iv) (3a) reacting a compound of formula (vii) with a compound of formula (i) to obtain the formula and (4) removing the protective group of a compound of formula (iv) to give a compound of formula (v), wherein Z ¹ and Z ² together with the boron atom to which they are attached form 9. The method of claim 8, where the interaction in stages (1A) and (3a) is carried out in the presence of a peptide coupling agent. 10. The method of claim 9, wherein the peptide coupling agent is selected from a carbodiimide agent, a phosphonium agent, and a uronium agent. 11. The method of claim 10, wherein the peptide coupling agent is selected from dicyclohexylcarbodiimide (DCC), 1 (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC), benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), tetrafluoroborate (1H-benzotriazol-1-yl) -X, X, X ', X'-tetramethyluronium (TBTU) and N-hydroxybenzotriazole (HOBt). 12. The method according to claim 8, where the interaction in stages (1A) and (3a) is carried out in the presence of a solvent. 13. The method according to item 12, where the solvent is selected from dichloromethane, tetrahydrofuran and dimethylformamide. 14. The method of claim 8, where the protective group is selected from formyl, acetyl, succinyl, methoxysuccinyl; tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) and fluorenylmethoxycarbonyl (Fmoc).