BR112020003368B1 - BORONIC ACID DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR USES, AND PHARMACEUTICAL FORMULATION - Google Patents

Abstract

The present invention relates to boronic a-amino acid derivatives. These compounds are useful for inhibiting immunoproteasome (LMP7) activity and for the treatment and/or prevention of medical conditions affected by immunoproteasome activity, such as inflammatory and autoimmune diseases, neurodegenerative diseases, proliferative diseases and cancer.

Description

Field of Invention

[0001] The present invention relates to boronic a-amino acid derivatives. These compounds are useful for inhibiting immunoproteasome (LMP7) activity and for the treatment and/or prevention of medical conditions affected by immunoproteasome activity, such as inflammatory and autoimmune diseases, neurodegenerative diseases, proliferative diseases and cancer. In particular, the compounds of the present invention are selective inhibitors of the immunoproteasome.

Background of the invention

[0002] The proteasome (also known as macropain, multicatalytic protease, and 20S protease) is a high molecular weight multisubunit protease that has been identified in all species examined, from archaea to humans. The enzyme has a native molecular weight of approximately 650,000 and, as revealed by electron microscopy, a distinctive cylinder-shaped morphology (Rivett, (1989) Arch. Biochem. Biophys. 268: 1-8; and Orlowski, (1990) Biochemistry 29: 10289-10297). Proteasome subunits range in molecular weight from 20,000 to 35,000 and are homologous to each other but not to any other known protease.

[0003] The 20S proteasome is a cylindrical-shaped multicatalytic protease complex of 700 kDa, composed of 28 subunits, classified into α and β types, arranged in 4 stacked heptameric rings. In yeast and other eukaryotes, 7 different α subunits form the outer rings and 7 different β subunits comprise the inner rings. The a-subunits serve as binding sites for the 19S (PA700) and 1IS (PR68) regulatory complexes, as well as a physical barrier to the internal proteolytic chamber formed by the two rings of the β-subunit. Thus, in vivo, the proteasome is believed to exist as a 26S particle ("the 26S proteasome"). In vivo experiments have shown that inhibition of the 20S form of the proteasome can be easily correlated with inhibition of the 26S proteasome.

[0004] Cleavage of the amino-terminal prosequences of the β-subunits during particle formation exposes amino-terminal threonine residues, which serve as catalytic nucleophiles. The subunits responsible for catalytic activity in the proteasome thus have an amino terminal nucleophilic residue, and these subunits belong to the family of N-terminal nucleophilic (Ntn) ATTY REF: 26500-0023WO1 hydrolases (where the N-terminal nucleophilic residue is, for example, (e.g., Cys, Ser, Thr, and other nucleophilic moieties). This family includes, for example, penicillin G acylase (PGA), penicillin V acylase (PVA), glutamine PRPP amidotransferase (GAT) and bacterial glycosyl paraginase. In addition to the ubiquitously expressed β subunits, higher vertebrates also possess three interferon Y-inducible β subunits (LMP7, LMP2, and MECL1), which replace their normal counterparts, β5, β1, and β2, respectively. When all three IFN-γ inducible subunits are present, the proteasome is referred to as an "immunoproteasome". Thus, eukaryotic cells can possess two forms of proteasomes in varying proportions.

[0005] Through the use of different peptide substrates, three main proteolytic activities have been defined for the 20S eukaryote proteasomes: chymotrypsin-like activity (CT-L), which cleaves after large hydrophobic residues; trypsin-like activity (T-L), which cleaves after basic residues; and hydrolysis activity of peptidylglutamyl peptide (PGPH), which cleaves after acidic residues. Two additional, less characterized activities have also been attributed to the proteasome: the activity of BrAAP, which cleaves after branched-chain amino acids; and SNAAP activity, which cleaves after small neutral amino acids. Although both forms of the proteasome possess all five enzyme activities, differences in the extent of activities between the forms have been described based on specific substrates. For both forms of the proteasome, the main proteolytic activities of the proteasome appear to be contributed by different catalytic sites in the 20S core.

[0006] In eukaryotes, protein degradation is predominantly mediated by the ubiquitin pathway, in which proteins targeted for destruction are linked to the 76-amino acid polypeptide ubiquitin. Once targeted, ubiquitinated proteins serve as substrates for the 26S proteasome, which cleaves proteins into short peptides through the action of its three main proteolytic activities. While playing a general role in intracellular protein turnover, proteasome-mediated degradation also plays a key role in many processes such as major histocompatibility complex (MHC) class I presentation, apoptosis and cell viability, antigen processing, cell activation, NF-KB and pro-inflammatory signal transduction.

[0007] Proteasome activity is high in muscle-wasting diseases that involve protein breakdown, such as muscular dystrophy, cancer, and AIDS. Evidence also suggests a possible role for the proteasome in antigen processing for MHC class I molecules (Goldberg, et al. (1992) Nature 357: 375-379).

[0008] Proteasomes are involved in neurodegenerative diseases and disorders such as amyotrophic lateral sclerosis (ALS), (J Biol Chem 2003, Allen S et al., Exp Neurol 2005, Puttaparthi k et al.), Sjogren's Syndrome (Arthritis & Rheumatism, 2006, Egerer T et al.), systemic lupus erythematosus and lupus nephritis (SLE/LN), (Arthritis & rheuma 2011, Ichikawa et al. al., J Immunol, 2010, Lang VR et al., Nat Med , 2008, Neubert K et al), glomerulonephritis (J Am Soc nephrol 2011, Bontscho et al.), rheumatoid arthritis (Clin Exp Rheumatol, 2009, Van der Heiden JW et al.), inflammatory bowel disease (IBD), ulcerative colitis , Crohn's disease, (Gut 2010, Schmidt N et al., J Immunol 2010, Basler M et al., Clin Exp Immunol, 2009, Inoue S et al. .), multiple sclerosis (Eur J Immunol 2008, Fissolo N et al. al., J Mol Med 2003, Elliott PJ et al., J. Neuroimmunol 2001, Hosseini et al., J. Autoimmun 2000, Vanderlugt CL et al.), amyotrophic lateral sclerosis (ALS), (Exp Neurol 2005, Puttaparthi et al. al., J Biol Chem 2003, Allen S et al.), osteoarthritis (Pain 2011, Ahmed et al., Biomed Mater Eng 2008, Etienne S et al.), Atherosclerosis (J Cardiovasc Pharmaco In 2010, Feng B et al. , Psoriasis (Genes & Immunity, 2007, Kramer U et al.), Myasthenia Gravis (J Immunol, 2011, Gomez AM et al.), dermal fibrosis (Thorax 2011, Mutlu GM et al. Inflammation 2011, Koca SS et al., Faseb J 2006, Fineschi S et al.), Renal fibrosis (Nefrologia 2011 Sakairi T et al.), Cardiac fibrosis (Biochem Pharmacol 2011, May et al.,) Hepatic fibrosis (Am J Physiol gastrointest Liver Physiol 2006, Anan A et al.), Pulmonary fibrosis (Faseb J 2006, Fineschi S et al.), Immunoglobulin A nephropathy (IGa nephropathy), (Kidney Int, 2009, Coppo R et al.), (Kidney Int, 2009, Coppo R et al.), Vasculitis (J Am Soc nephrol 2011, Bontscho et al.), Transplant rejection (Nephrol Dial transplant 2011, Waiser J et al.), Hematologic neoplasms (Br J Haematol 2011, singh AV et al., Curr Cancer Drug Target 2011) , Chen D et al.) and asthma.

[0009] However, it should be noted that commercially available proteasome inhibitors inhibit both constitutive and immunoforms of the proteasome. Even bortezomib, the FDA-approved proteasome inhibitor for the treatment of patients with relapsed multiple myeloma, does not distinguish between the two forms (Altun et al., Cancer Res 65: 7896, 2005). Furthermore, bortezomib use is associated with treatment-emergent painful peripheral neuropathy (PN), this in vitro bortezomib-induced neurodegeneration occurs via a proteasome-independent mechanism, and that bortezomib inhibits several non-proteasomal targets in vitro and in vitro. alive (Clin. Cancer Res, 17(9), May 1, 2011).

[0010] In addition to conventional proteasome inhibitors, a new approach may be the specific targeting of the specific hematological immunoproteasome, thereby increasing overall efficacy and reducing off-target negative effects. It has been demonstrated that the specific immunoproteasome inhibitor could exhibit greater efficiency in cells of hematological origin (Curr Cancer Drug Targets, 11(3), March 2011).

[0011] Thus, there is a need to provide new proteasome inhibitors that are selective for a specific form of the proteasome. In particular, there is a need to provide selective immunoproteasome inhibitors, which could be used as therapeutic agents for the treatment of, for example, SLE or other immunological or autoimmune disorders in the context of rheumatoid arthritis. Selective immunoproteasome inhibitors are useful for minimizing unwanted side effects mediated by inhibition of the constitutive proteasome or other non-proteasome targets.

[0012] WO 2013/092979 A1 describes boronic acid derivatives, which show selectivity in relation to the inhibition of LMP7 activity. However, the extent of selectivity, which is achievable with the described types of compounds, is limited, particularly with regard to splitting the inhibitory activity of the constitutive proteasome.

[0013] Non-specific proteasome and immunoproteasome inhibitors such as bortezomib and carfilzomib have demonstrated their clinical value in the indication of multiple myeloma. Although this non-specific profile, targeting key components in the immunoproteasome and the constitutive proteasome, is considered beneficial in terms of target inhibition and clinical efficacy, this non-specific profile limits the clinical applicability of these agents, inducing pronounced side effects such as thrombocytopenia, neutropenia and as well as peripheral neuropathy. To some extent, this side effect profile can be attributed to broad inhibition of catalytic activity, especially the combined inhibition of constitutive and imoproteasome β5 subunits. The approach to introduce more selective inhibitors of the immunoproteasome (and especially the β5i subunit of the immunoproteasome) in order to reduce major side effects was described for example in 2011 by Singh et al. (Br. J. Hematology 152(2): 155-163 ) for PR-924, a 100-fold selective inhibitor of the LMP7 subunit of the immunoproteasome. The authors demonstrated the presence of high levels of immunoproteasome expression in multiple myeloma. The authors also described the effect of a selective inhibitor of the LMP7 subunit in inducing cell death in MM cell lines, as well as in primary cells from CD138+ MM patients without decreasing the viability of control PBMCs from healthy volunteers, which can be considered a proof of concept. In addition to the concept of a reduced side effect profile for selective β5i inhibitors, another group has demonstrated the efficacy of selective β5i inhibition on the viability of bortezomib-resistant cell lines, underlining the value and potential perspective for the application of selective LMP7 inhibitors. for hematologic malignancies (D. Niewerth et al./Biochemical Pharmacology 89 (2014) 43-51).

[0014] WO 2016/050356, WO 2016/050355, WO 2016/050359 and WO 2016/050358 describe compounds that inhibit immunoproteasome (LMP7) activity and provide a significant breakdown of constitutive proteasome inhibitory activity.

[0015] Surprisingly, it was found that the amino boronic acid derivatives of the present invention provide a particularly high split to constitutive proteasome inhibitory activity. Furthermore, they show good results in view of plasma protein binding, CYP inhibition, PK profile and oral bioavailability.

Description of the invention

[0016] The present invention provides compounds of Formula (I) where LY denotes (CH2)m, where 1 to 4 H atoms can be replaced by Hal, R3a and/or OR4a, and/or where one CH2 group can be replaced by O, S, SO or SO2; X denotes a heterobicycle or heterotricycle of Formula (xa), (xb), (xc), (xd), (xe), (xf), (xg), (xh) or (xi) each independently of the other , unsubstituted or mono-, di- or trisubstituted by Hal, NO2, CN, R5a, OR5a, CONR5aR5b, NR5aCOR5b, SO2R5a, SOR5a, SO2NR5aR5b, NR5aSO2R5b, NR5aR5b, (CH2)q-R6, COR5a and/or SO2R5a, and wherein 1, 2 or 3 of the cyclic CH2 groups may be replaced by CR4aR4b, C=O, O, S, NR5a, SO and/or SO2; (optional substituents of (xa) - (xi) not shown) Y denotes P1, P2 or P3; P1 denotes a linear or branched C1-C6-alkyl or C3-C8-cycloalkyl, each of which, independently of one another, is unsubstituted or mono-, di-, tri- or tetra-substituted by Hal, CN, R3a, OR3a and/or (CH2)q-R6; P2 denotes phenyl or a 5-, 6- or 7-membered monocyclic aromatic heterocycle, each of which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal, CN, R3a, OH, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a , SOR3a, NR4aR4b, Ar2, Het2, (CH2)q-SR3a, (CH2)q-N(R4a)2 and/or (CH2)q-R6, wherein the heterocyclic system contains 1, 2 or 3 N atoms , O and/or S; P3 denotes an 8-, 9- or 10-membered bicyclic hydrocarbon or heterocycle, each independently of the other unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal, CN, R3a, OH, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2, (CH2)q-SR3a, (CH2)qN(R4a)2 and/or (CH2)q-R6, wherein at least one ring of the hydrocarbon or bicyclic heterocycle is aromatic , and in which the heterocyclic system contains 1, 2 or 3 N, O and/or S atoms; Cy1, Cy2, Cy3, Cy4 and Cy5 each independently of one another denote Ar1 or Het1; R1, R2 each independently of the other denotes H or C1-C6-alkyl, or R1 and R2 together form a residue according to Formula (EC) R3a, R3b each independently of one another denote linear or branched C1-C6-alkyl or C3-C8-cycloalkyl, in which 1 to 5 H atoms may be replaced by Hal, CN, OH and/or OAlk; R4a, R4b each independently of one another denote H or R3a; or R4a and R4b together form a C3-C8 alkylene group; R5a, R5b each independently of one another denote H, R3a, Ar2 or Het2; R6 denotes OH or OR3a; T1, T2, T3, T4, T5, T6, T7, T8 and T9 each denote, independently of one another, O, SO, C=O; Alk denotes straight or branched C1-C6-alkyl; Ar1 represents an aromatic 6-membered carbocycle; Het1 represents a saturated, unsaturated or aromatic 5- or 6-membered heterocycle having 1 to 4 N, O and/or S atoms; Ar2 denotes phenyl which is unsubstituted or mono- or disubstituted by Hal, NO2, CN, R3a, OR3a, CONHR3a, NR3aCOR3b, SO2R3a, SOR3a, NH2, NHR3a, N(R3a)2 and/or (CH2)q- R6; Het2 denotes a saturated, unsaturated or aromatic 5- or 6-membered heterocycle having 1 to 4 N, O and/or S atoms, which is unsubstituted or mono- or disubstituted by Hal, NO2, CN, R3a, OH, OR3a , CONHR3a, NR3aCOR3b, SO2R3a, SOR3a, NH2, NHR3a, N(R3a)2, (CH2)q-R6 and/or oxo (=O); q denotes 1, 2, 3, 4, 5 or 6; m denotes 0, 1 or 2; Hal denotes F, Cl, Br or I; and prodrugs, solvates, tautomers, oligomers, adducts and stereoisomers thereof, as well as the pharmaceutically acceptable salts of each of the foregoing, including their mixtures in all ratios.

[0017] The compounds of the present invention are inhibitors of the LMP7 immunoproteasome subunit. They show particularly high selectivity for LMP7 over Beta5 (cP) and good properties in terms of solubility, plasma protein binding, CYP inhibition, CYP inhibition, PK profile and oral bioavailability.

[0018] It is known that derivatives of boronic acid, such as compounds of Formula (I), in which R1 and R2 denote H-shaped oligomers (boronic acids. Edited by Dennis G. Hall, Copyright © 2005 WILEY-VCH Verlag , GmbH & Co. KGaA, Weinheim, ISBN 3-52730991-8). Such oligomers (in particular, but not limited to dimers or trimers) of the compounds of Formula (I) are included in this invention. The known cyclic trimers of boronic acids have, for example, the following structure:

[0019] Boronic acid derivatives, such as the compounds of Formula (I), in which R1 and R2 denote H, are also known to form adducts by reaction with aliphatic or aromatic alcohols, diols, sugars, sugar alcohols, a- hydroxy acids or nucleophiles containing one, two or three N-/O-containing functional groups (e.g. -NH2, -CONH2 or C=NH, -OH, -COOH) in which three functional groups are present, one of the three heteroatoms may form a coordinating link ("Boronics Acids” Edited by Dennis G. Hall, 2nd Edition, Copyright © 2011 WILEY-VCH Verlag, GmbH & Co. KGaA, Weinheim, ISBN 978-3-527-32598-6; WO2013128419; WO2009154737) Adduct formation is particularly rapid with pre-assembled diols The present invention includes such adducts (in particular esters or heterocyclic derivatives) of boronic acid compounds of Formula (I).

[0020] It should be noted that the compounds of the present invention possess a stereogenic center on the carbon atom adjacent to the boronic acid residue; has been indicated with an asterisk (*) in Formula (I)* below:

[0021] The compounds according to Formula (I) thus exhibit two different configurations at this stereogenic center, ie the (R) configuration and the (S) configuration. Thus, the compounds of the present invention can be present enantiopure or as a racemic (1:1) mixture of the two enantiomers of Formula (R)-(I) and (S)-(I).

[0022] The compounds of Formula (I) may also be present in a mixture in which one of the (R)-(I) or (S)-(I) enantiomers is present in excess over the other, for example, 60 :40, 70:30, 80:20, 90:10, 95:5 or similar. In a particular embodiment of the present invention, the Formula (R)-(I) stereoisomer of the compound of Formula (Ia) and the Formula (S)-(I) stereoisomer of the compound of Formula (Ia) are present in a relationship from (R)-(I) to (S)-(I) of at least 90 parts of (R)-(I) to not more than 10 parts of (S)-(I), preferably at least 95 (R)-(I) to not more than 5 (S)-(I), more preferably from at least 99 (R)-(I) to not more than 1 (S)-(I), even more preferably from at least 99.5 (R)-(I) to not more than 0.5 (S)-(I). In another particular embodiment of the present invention, the Formula (S)-(I) stereoisomer of the compound of Formula (Ia) and the Formula (R)-(I) stereoisomer of the compound of Formula (Ia) are present in a relationship from (S)-(I) to (R)-(I) of at least 90 (S)-(I) to not more than 10 (R)-(I), preferably at least 95 (S)-( I) to not more than 5 (R)-(I), more preferably from at least 99 (S)-(I) to not more than 1 (R)-(I), even more preferably from at least 99.5 (S)-(I) to not more than 0.5 (R)-(I).

[0023] The enriched or pure stereoisomers of Formulas (R)-(I) and (S)-(I) can be obtained by usual methods known in the art and by the specific methods described below. One particular method to obtain them is preparative column chromatography such as HPLC or SFC using chiral column material.

[0024] Particular preferred embodiments of the present invention comprise compounds of Formula (R)-(I), wherein the stereogenic center on the carbon atom adjacent to the boronic acid residue has an (R) configuration:

[0025] The compounds according to Formula (I) may also carry other stereogenic centers located on carbon atoms other than the carbon atom adjacent to the boronic acid residue. All of these stereogenic centers can occur in either the (R) or (S) configuration.

[0026] In particular, the compounds of the present invention have other stereogenic centers on the carbon atom of the substituent X, which is directly attached to the carbon atom of the amide group CONH shown in Formula (I)) and on carbon atoms adjacent to the bridged atom; these stereogenic centers are shown, for example, in Formula (xa*) below, where they are indicated with an asterisk (*): (optional substituents of (xa*) not shown)

[0027] The possible stereoisomers of (xa*) are shown below:

[0028] Compounds according to Formula (I) thereby also exhibit two different configurations at these stereogenic centers, ie, the (R) configuration and the (S) configuration. The compounds of the present invention may have an (R) or (S) configuration at each of these stereogenic centers or the compounds are present in a racemic (1:1) mixture of two stereoisomers. The compounds of Formula (I) may also be present in a mixture in which one of the stereoisomers is present in excess of the other, for example 60:40, 70:30, 80:20, 90:10, 95:5 or similar.

[0029] Above and below, in cases where a chemical structure with a stereogenic center is shown and no specific stereochemistry is indicated, the structure includes all possible stereoisomers as well as their mixtures. For example, the present invention includes the acid stereoisomers [(1R)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2R,4R) -7-oxabicyclo[2.2.1]-heptan-2-yl]-formamido}ethyl]boronic acid, [(1R)-2-[(3S)-2,3-dihydro-1-benzofuran- 3-yl]-1-{[(1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid, [(1R)-2-[(3S)- 2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2S,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid [(1R)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,2R,4S)-7-oxabicyclo[2.2.1]heptan -2-yl]formamido}ethyl]boronic acid, [(1S)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2S, 4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]-boronic acid, [(1S)-2-[(3S)-2,3-dihydro-1-benzofuran -3-yl]-1-{[(1R,2R,4S)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]-boronic acid, [(1R)-2-[(3R )-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2S,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid , [(1R)-2-[(3R)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,2R,4S)-7-oxabicyclo[2.2.1] acid ]heptan-2-yl]formamido}ethyl]boronic acid, [(1S)-2-[(3R)-2,3-dihydro-1-benzofuran-3-yl]-1-{[( 1S,2S,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]-boronic acid, [(1S)-2-[(3R)-2,3-dihydro-1 -benzofuran-3-yl]-1-{[(1R,2R,4S)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid, [(1S)-2- [(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido }ethyl]boronic acid, [(1S)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,2S,4S)-7-oxabicyclo [2.2.1]heptan-2-yl]formamido}ethyl]-boronic acid, [(1R)-2-[(3R)-2,3-dihydro-1-benzofuran-3-yl]- 1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid, [(1R)-2-[(3R)-2,3-di -hydro-1-benzofuran-3-yl]-1-{[(1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid, [(1S)- 2-[(3R)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl] formamido}ethyl]-boronic acid as well as [(1S)-2-[(3R)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,2S ,4S)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]-boronic acid. Another exemplary set of stereoisomers included in the present invention is represented by the following stereoisomers, [(1R)-2-(1-benzofuran-3-yl)-1-{[(1S,2R,4R)-7-oxabicyclo acid [2.2.1]heptan-2-yl]formamido}ethyl]boronic acid, [(1S)-2-(1-benzofuran-3-yl)-1-{[(1S, 2R,4R)-7-oxabicyclo [2.2.1]heptan-2-yl]formamido}ethyl]boronic acid, [(1R)-2-(1-benzofuran-3-yl)-1-{[(1R,2S,4S)-7-oxabicyclo [2.2.1] heptan-2-yl]formamido}ethyl]boronic acid, [(1S)-2-(1-benzofuran-3-yl)-1-{[(1R,2S, 4S)-7-oxabicyclo [2.2.1]heptan-2-yl]formamido}ethyl]boronic acid, [(1R)-2-(1-benzofuran-3-yl)-1-{[(1S,2S,4R)-7-oxabicyclo [2.2.1]heptan-2-yl]formamido}ethyl]boronic acid, [(1S)-2-(1-benzofuran-3-yl)-1-{[(1S,2S,4R)-7 -oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid, [(1R)-2-(1-benzofuran-3-yl)-1-{[(1R,2R,4S)-7 -oxabicyclo[2.2.1]heptan-2-yl]formido}ethyl]boronic acid and [(1S)-2-(1-benzofuran-3-yl)-1-{[(1R,2R,4S) -7- oxabicyclo[2.2.1]heptan-2-yl]formamide}ethyl]boronic acid. The different stereoisomers of a given compound are useful for the analytical characterization of a specific sample (eg for quality control purposes) via NMR, HPLC, SFC or any other suitable analytical method. Thus, another aspect of the present invention relates to the use of stereoisomers of compounds according to Formula (I) in analytical characterization methods.

[0030] In general, all residues of the compounds described herein that occur more than once can be identical or different, that is, they are independent of each other. Above and below, residues and parameters have the meanings indicated for Formula (I), unless expressly indicated otherwise. Therefore, the invention relates in particular to the compounds of Formula (I) in which at least one of said residues has one of the preferred meanings indicated below. Furthermore, all specific embodiments described below shall include derivatives, prodrugs, solvates, tautomers or stereoisomers thereof, as well as the physiologically acceptable salts of each of the foregoing, including mixtures thereof in all ratios.

[0031] The heterobicycles or heterotricycles of Formula (xa), (xb), (xc), (xd), (xe), (xf), (xg), (xh) and (xi) may be unsubstituted or mono -, di- or tri-substituted by Hal, NO2, CN, R5a, OR5a, CONR5aR5b, NR5aCOR5b, SO2R5a, SOR5a, SO2NR5aR5b, NR5aSO2R5b, NR5aR5b, (SO2)q-R6, COR5a and/or SO2R5a. If the heterobicycles or heterotricycles of Formula (xe), (xf), (xg), (xh) and (xi) are substituted, one or more substituents may be attached to one of the bridged rings or one of the fused rings Cy1, Cy2 , Cy3, Cy4 and Cy5. This includes, for example, compounds in which a substituent is attached to the bridged ring and a substituent is attached to the fused Cy1, Cy2, Cy3, Cy4 or Cy5 ring. In case one of the fused rings Cy1, Cy2, Cy3, Cy4 and Cy5 contains one or more CH2 groups, these groups are understood to be part of the "cyclic CH2 groups" of heterobicycles or heterotricycles of Formula (xe), (xf), ( xg), (xh) and (xi), which can be replaced by CR4aR4b, C=O, O, S, NR5a, SO or SO2. Thus, if 1, 2 or 3 of the cyclic CH2 groups of heterobicycles or heterotricycles of Formula (xe), (xf), (xg), (xh) and (xi) are replaced by CR4aR4b, C=O, O, S, NR5a, SO or SO2 these cyclic CH2 can be part of the bridged ring and/or the fused rings Cy1, Cy2, Cy3, Cy4 and Cy5. This includes, for example, compounds in which a CH2 group on the bridged ring is replaced and a CH2 on the fused Cy1, Cy2, Cy3, Cy4 or Cy5 ring is replaced.

[0032] In case Y is P3, wherein at least one of the two rings of the hydrocarbon or bicyclic heterocycle is an aromatic ring, the other ring may be a saturated, unsaturated or aromatic ring. In specific examples of such embodiments P3 and the adjacent group LY are linked together through the aromatic ring of P3. In other embodiments, P3 and the adjacent group LY are linked to each other via the saturated or unsaturated ring of P3. In case P3 is a bicyclic heterocycle, it preferably contains 1 or 2 heteroatoms selected from N, O and/or S. In case P2 is an aromatic monocyclic heterocycle that preferably contains 1 or 2 heteroatoms selected from N, O and/or S .

[0033] In case Y is P2 and P2 is phenyl, it is preferably unsubstituted or mono-, di- or trisubstituted by Hal, CN, R3a, OH, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2 , (CH2)q-SR3a, (CH2)qN(R4a)2 and/or (CH2)q-R6. Particularly preferred are embodiments in which P2 denotes a di- or tri-substituted phenyl. In those embodiments in which P2 indicates a monosubstituted phenyl, the substituent is preferably in the 3 or 4 position. In those embodiments in which P2 indicates a disubstituted phenyl, the two substituents are preferably in the 2,3-, 2,4-, 2,5 position or 3,4 (more preferably at the 2,4 or 3,4 position). And in those embodiments, in which P2 indicates a trisubstituted phenyl, the three substituents are preferably in the 2, 3, 4 position of the aromatic ring.

[0034] In case P2 indicates a monocyclic heterocycle, this heterocycle may be saturated, unsaturated or aromatic.

[0035] In modalities where m indicates 0, LY is absent.

[0036] In the context of the present invention, "C1-C6-alkyl" means an alkyl moiety having 1, 2, 3, 4, 5 or 6 carbon atoms and being straight or branched chain. The term "C3-C6 cycloalkyl " refers to saturated cyclic hydrocarbon groups having 3, 4, 5 or 6 carbon atoms.

[0037] The term "unsubstituted" means that the corresponding radical, group or moiety has no substituents other than H; the term "substituted", which applies to one or more hydrogens, explicit or implicit in the structure, means that the corresponding radical, group or fraction has one or more substituents other than H. When a radical has a plurality of substituents, i.e. , at least two, and a selection of multiple substituents is specified, the substituents are selected independently of one another and need not be identical.

[0038] The term "carbocycle" means a ring system in which all ring members are carbon atoms.

[0039] The term "heterocycle" means a ring system, in which some of the ring members are heteroatoms such as N, O or S.

[0040] The group "NRR'" is an amino group, where R and R' are, for example, each independently of the other H or residues of linear or branched C1-C6 alkyl (particularly methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, sec-butyl or tert-butyl, pentyl, hexyl).

[0041] The group "SO" as for example included in SOR5a, is the group in which S and O are connected through a double bond (S = O).

[0042] The "CO" group, as for example included in COR4a, is the group in which C and O are connected through a double bond (C=O).

[0043] The term "alkylene" refers to a divalent alkyl group. An "alkylene group" is a (poly)methylene group (-(CH 2 )x-).

[0044] The oxo group (=O) is a substituent, which can occur for example in saturated cyclic residues or, as far as possible, in a (partially) unsaturated ring, as in particular Het1 and Het2. In preferred embodiments, the Het1 and Het2 heterocycles optionally carry one or two oxo groups.

[0045] When used herein, the term "unsaturated" means that a fraction has one or more units of unsaturation. When used herein with reference to any rings, cyclic systems, cyclic moieties, and the like, the term "partially unsaturated" refers to a cyclic moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass cyclic moieties with one more double or triple bond.

[0046] In the context of the present invention, notations such as "O-CH3" and "OCH3" or "CH2CH2" and "-CH2-CH2-" have the same meaning and are used interchangeably.

[0047] When used herein, in Structural Formulas, arrows or links with vertical dotted lines are used to indicate the point of attachment to an adjacent group. For example, the arrow in (xa) shows the point of attachment to the adjacent C=O group.

[0048] Particularly important embodiments of the present invention include compounds of Formula (I), wherein R1, R2 each independently of one another denote H or C1-C4 alkyl or R1 and R2 together form a residue according to Formula (CE); and LY denotes CH2 or CH2CH2, where 1 to 2 H atoms can be replaced by Hal, R3a, OR4a (preferably 1 to 2 H atoms can be replaced by F, Cl, CH3, CH2CF3, CH2CHF2, CH2F, CHF2 , CF3, OCH3 and/or OCF3, and more preferably LY denotes CH2 or CH2CH2).

[0049] Specific embodiments include compounds of Formula (I), wherein T1, T2, T3, T4, T5, T6, T7, T8 and T9 denote O.

[0050] Other specific embodiments comprise compounds according to Formula (I), wherein P1 denotes a linear or branched C1-C6-alkyl or C3-C8-cycloalkyl, each of which, independently of one another, is unsubstituted mono-, di- or trisubstituted with Hal, CN, R3a, OR3a, and/or (CH2)q-R6; P2 denotes phenyl, pyridyl, pyrrolyl, furanyl, thiophenyl, pyrimidyl, pyrazinyl or pyridazinyl, each independently of one another unsubstituted mono-, di- or trisubstituted by Hal, CN, R3a, OH, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2, (CH2)q-SR3a, (CH2)q-N(R4a)2 and/or (CH2)q-R6; It is

[0051] P3 denotes a bicyclic residue of Formula (ya), (yb), (yc), (yd), (ye), (yf), (yg), (yh), (yi), (yj), (yk), (yl), (ym), (yn), (yp) or (yp), each independently of the other unsubstituted mono-, dior trisubstituted by Hal, CN, R3a, OH, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2, (CH2)q-SR3a, (CH2)qN(R4a)2 and/or (CH2)q-R6: (optional substituents of (ia) - (ip) not shown) wherein Ea denotes O, S, N(Alk) or CH=CH; Eb denotes O, S, N(Alk), CH2, CH2CH2, OCH2, SCH2, or N(Alk)CH2.

[0052] In other embodiments of the invention, the residues of a compound of Formula (I) are defined as follows:

[0053] R3a, R3b each, independently of one another, denote linear or branched C1-C4-alkyl or C3-C6 cycloalkyl, in which 1 to 3 H atoms can be replaced by F, Cl and/or in which 1 or 2 H atoms can be replaced by CN, OH, OCH3 and/or OC2H5.

[0054] Additional embodiments of the invention comprise compounds according to Formula (I) wherein Y indicates P2 or P3.

[0055] Other specific embodiments comprise compounds according to Formula (I), wherein

[0056] X is a heterobicycle or heterotricycle of the formula (xa1), (xb1), (xc1), (xd1), (xe1), (xf1), (xg1), (xh1) or (xi1), each of which independently of one another, unsubstituted or mono-, di- or trisubstituted by Hal, NO2, CN, R5a, OR5a, CONR5aR5b, NR5aCOR5b, SO2R5a, SOR5a, SO2NR5aR5b, NR5aSO2R5b, NR5aR5b, (CH2)q-R6, COR5a and/ or SO2R5a, and in which 1 of the cyclic CH2 groups can be replaced by CR4aR4b, C=O, O, S, NR5a, SO and/or SO2: (optional substituents of (xa1) - (xi1) not shown)

[0057] Other specific embodiments comprise compounds according to Formula (I), wherein

[0058] X is a heterobicycle or heterotricycle of Formula (xa), (xb), (xc), (xd), (xe), (xf), (xg), (xh) or (xi) each independently each other, unsubstituted or mono- or disubstituted by F, Cl, CH3, C2H5, CF3, OCH3, OC2H5,COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 and/or N( C2H5)2, and in which 1 or 2 of the cyclic CH2 groups can be replaced by C(CH3)2, C(C2H5)2, C=O, O, S, NH, NR3a, SO and/or SO2 (where R3a is preferably methyl, ethyl, propyl, isopropyl or cyclopropyl).

[0059] Important embodiments comprise compounds of Formula (I), wherein X is a heterobicycle or heterotricycle of Formula (xa1), (xb1), (xc1), (xd1), (xe1), (xf1), (xg1) , (xh1) or (xi1), each independently of the other unsubstituted or mono-, disubstituted by F, Cl, CH3, C2H5, CF3, OCH3, OC2H5,COCF3, SCH3, SC2H5, CH2OCH3, N(CH3 )2, CH2N(CH3)2 and/or N(C2H5).

[0060] Many specific embodiments comprise compounds of Formula (I), wherein X is a heterobicycle or heterotricycle selected from the following group:

[0061] Other embodiments comprise compounds of Formula (I), wherein P3 denotes unsubstituted or mono- or disubstituted 1- or 2-naphthyl, wherein the optional substituents are selected from the group consisting of Hal, CN, R3a, OH, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2, (CH2)q-SR3a, (CH2)qN(R4a)2, and/or (CH2)q-R6, or (P3 is) one residue according to Formula (Ra) or (Rb): where Ga, Gb each independently denote H, Hal, CN, R3a, OR3a, CONHR3a, CONR3bR3a, CONH2, NR3aCOR3b, SO2R3a, SOR3a, NHR3a, N(R3a)2, (CH2)q-SR3a , (CH2)qN(R4a)2 and/or (CH2)q-R6; Ka, Kb each denote, independently of one another, H, Hal, CN, R3a, OR3a, CONHR3a, CONR3bR3a, CONH2, NR3aCOR3b, SO2R3a, SOR3a, NHR3a, N(R3a)2, (CH2)q-SR3a, ( CH2)qN(R4a)2 and/or (CH2)q-R6; Ea denotes O, S, N(Alk) or CH=CH; Eb denotes O, S, N(Alk), CH2, CH2-CH2, O-CH2, S-CH2, or N(Alk)CH2.

[0062] The residue according to Formula (Rb) has a stereogenic center at the carbon atom close to LY; has been indicated with an asterisk (*) in Formula (Rb)* below:

[0063] Residues according to Formula (Rb) thus exhibit two different configurations at this stereogenic center, ie, the (R) configuration and the (S) configuration. Thus, the compounds of the present invention may be present enantiopure or as a racemic (1:1) mixture of the two enantiomers of Formula (R)-(Rb) and (S)-(Rb).

[0064] Compounds of Formula (I) which include residues according to Formula (Rb) may also be present in a mixture in which one of the (R)-(Rb) or (S)-(Rb) enantiomers is present in excess of the other, for example 60:40, 70:30, 80:20, 90:10, 95:5 or the like. In a particular embodiment of the present invention, the Formula (R)-(Rb) stereoisomer of the compound of Formula (I) and the Formula (S)-(Rb) stereoisomer of the compound of Formula (I) are present in a relationship from (R)-(Rb) to (S)-(Rb) of at least 90 parts of (R)-(Rb) and not more than 10 parts of (S)-(Rb), preferably at least 95 ( R)-(Rb) to not more than 5 (S)-(Rb), more preferably at least 99 (R)-(Rb) to not more than 1 (S)-(Rb), even more preferably at least less than 99.5 (R)-(Rb) to not more than 0.5 (S)-(Rb). In another particular embodiment of the present invention, the Formula (S)-(Rb) stereoisomer of the Formula (Rb) compound and the Formula (R)-(Rb) stereoisomer of the Formula (I) compound are present in a relationship from (S)-(Rb) to (R)-(Rb) of at least 90 (S)-(Rb) and not more than 10 (R)-(Rb), preferably at least 95 (S)-( Rb) to not more than 5 (R)-(Rb), more preferably at least 99 (S)-(Rb) to not more than 1 (R)-(Rb), even more preferably at least 99.5 (S)-(Rb) to not more than 0.5 (R)-(Rb).

[0065] Particularly preferred embodiments of the present invention comprise compounds of Formula (I), wherein P3 is a residue of Formula (S)-(Rb) (which has an (S) configuration on the carbon attached to LY).

[0066] Specific embodiments comprise compounds according to Formula (I), wherein: P2 denotes unsubstituted or mono- or disubstituted or unsubstituted 2- or 3-thienyl or 3-, 4-, 2,3-, 2,4-, 2,5-, 3,4- or 2,3,4-substituted, in which case the optional substituents are independently selected from the group consisting of Hal, CN, R3a, OH, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2, (CH2)q-SR3a, (CH2)q-N(R4a)2 and (CH2)q-R6; P3 denotes unsubstituted or mono- or disubstituted 1- or 2-naphthyl, wherein the optional substituents are selected from the group consisting of Hal, CN, R3a, OH, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b , Ar2, Het2, (CH2)q-SR3a, (CH2)q-N(R4a)2e/or (CH2)q-R6, or (P3 is) a residue according to Formula (Ra) or (Rb) (preferably P3 is a residue according to Formula (Ra) or (S)-(Rb)); Ga, Gb each denote, independently of one another, H, Hal, CN, R3a, OR3a, CONHR3a, CONR3bR3a, CONH2, NR3aCOR3b, SO2R3a, SOR3a, NHR3a, N(R3a)2, (CH2)q-SR3a, ( CH2)q-N(R4a)2e/or (CH2)q-R6; Ka, Kb each denote, independently of one another, H, Hal, CN, R3a, OR3a, CONHR3a, CONR3bR3a, CONH2, NR3aCOR3b, SO2R3a, SOR3a, NHR3a, N(R3a)2, (CH2)q-SR3a, ( CH2)q-N(R4a)2e/or (CH2)q-R6; Ea denotes O, S, N(Alk) or CH=CH; Eb denotes O, S, N(Alk), CH2, CH2-CH2, OCH2, SCH2, or N(Alk)CH2.

[0067] Other specific embodiments comprise compounds of Formula (I), wherein: P2 denotes unsubstituted or mono- or disubstituted or unsubstituted 2- or 3-thienyl or 3-, 4-, 2,3-, 2, 4-, 2,5-, 3,4- or 2,3,4-substituted, in which case the optional substituents are independently selected from the group consisting of Hal, CN, R7a, OR7a, CONHR7a, CONR7bR7a, CONH2, NR7aCOR7b, SO2R7a, SOR7a, NHR7a, N(R7a)2, (CH2)p-SR7a, (CH2)p-N(R7a)2, and/or (CH2)p-R8; P3 is a residue according to Formula (Ra) or (Rb) (preferably P3 is a residue according to Formula (Ra) or (S)-(Rb)); Ga, Gb each denote, independently of one another, H, Hal, CN, R7a, OR7a, CONHR7a, CONR7bR7a, CONH2, NR7aCOR7b, SO2R7a, SOR7a, NHR7a, N(R7a)2, (CH2)p-SR7a, ( CH2)p-N(R7a)2e/or (CH2)p-R8; Ka, Kb denote each independently of one another H, Hal, CN, R7a, OR7a, CONHR7a, CONR7bR7a, CONH2, NR7aCOR7b, SO2R7a, SOR7a, NHR7a, N(R7a)2, (CH2)p-SR7a, ( CH2)p-N(R7a)2 and/or (CH2)p-R8; R7a, R7b each denote, independently of one another, linear or branched C1-C3-alkyl, in which 1 to 3 H atoms can be replaced by Hal; and R8 denotes OH or OR7a; and p denotes 1 or 2.

[0068] Even more specific embodiments comprise compounds according to Formula (I), wherein: P2 denotes unsubstituted or mono- or disubstituted or unsubstituted 2- or 3-thienyl or 3-, 4-, 2,3 phenyl -, 2,4-, 2,5-, 3,4- or 2,3,4-substituted, wherein the optional substituents are selected from the group consisting of F, Cl, CN, CH3, C2H5, CF3, OCH3, OC2H5, COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 or N(C2H5)2; P3 is a residue according to Formula (Ra) or (Rb) (preferably P3 is a residue according to Formula (Ra) or (S)-(Rb)); Ga, Gb each denote, independently of one another, H, F, Cl, CN, CH3, C2H5, CF3, OCH3, OC2H5, COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 or N(C2H5)2; Ka, Kb each denote, independently of one another, H, F, Cl, CN, CH3, C2H5, CF3, OCH3, OC2H5, COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 or N(C2H5)2.

[0069] Particular embodiments comprise compounds of Formula (I), wherein P3 is a residue according to Formula (Ra) or (Rb), and wherein Ea, Eb each independently of one another denote O or S Particularly preferred embodiments comprise compounds of Formula (I), wherein P3 is a residue according to Formula (Fa) or (Fb):

[0070] In such embodiments, the stereogenic center at the carbon atom at position 3 of the dihydrofuranyl (Fb) residue preferably shows an (S) configuration, that is, the residue is an (S)-(Fb)* residue of (3S)-2,3-dihydrobenzofuran-3-yl (optionally substituted): (optional substituents not shown).

[0071] Thus, other very specific embodiments of the invention, the present invention comprises compounds according to Formula (I), wherein P2 denotes unsubstituted 2- or 3-thienyl or mono- or disubstituted or unsubstituted or 3-phenyl , 4-, 2,3-, 2,4-, 2,5-, 3,4- or 2,3,4-substituted, wherein the optional substituents are selected from the group consisting of Hal, CN , R3a, OH, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2, (CH2)q-SR3a, (CH2)q-N(R4a)2e/or (CH2)q-R6; P3 denotes a residue according to Formula (Fa) or (S)-(Fb); Ga, Gb each denote, independently of one another, H, Hal, CN, R3a, OH, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2, (CH2)q-SR3a, (CH2)q-N( R4a)2 and/or (CH2)q-R6; and Ka, Kb each denote, independently of one another, H, Hal, CN, R3a, OH, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2, (CH2)q-SR3a, (CH2)q-N (R4a)2 and/or (CH2)q-R6.

[0072] Other very specific embodiments of the invention, the present invention comprises compounds according to Formula (I), wherein: P2 denotes unsubstituted or mono- or disubstituted or unsubstituted 2- or 3-thienyl or 3- phenyl, 4-, 2,3-, 2,4-, 2,5-, 3,4- or 2,3,4-substituted, wherein the optional substituents are selected from the group consisting of H, Hal, CN, R7a, OR7a, CONHR7a, CONR7bR7a, CONH2, NR7aCOR7b, SO2R7a, SOR7a, NHR7a, N(R7a)2, (CH2)p-SR7a, (CH2)pN(R7a)2 and/or (CH2)p-R8 ; P3 denotes a residue according to Formula (Fa) or (S)-(Fb); Ga, Gb each denote, independently of one another, H, Hal, CN, R7a, OR7a, CONHR7a, CONR7bR7a, CONH2, NR7aCOR7b, SO2R7a, SOR7a, NHR7a, N(R7a)2, (CH2)p-SR7a, ( CH2)pN(R7a)2 and/or (CH2)p-R8; Ka, Kb denote each independently of one another H, Hal, CN, R7a, OR7a, CONHR7a, CONR7bR7a, CONH2, NR7aCOR7b, SO2R7a, SOR7a, NHR7a, N(R7a)2, (CH2)p-SR7a, ( CH2)pN(R7a)2 and/or (CH2)p-R8;

[0073] R7a, R7b each denote, independently of one another, C1-C3-linear or branched alkyl, in which 1 to 3 H atoms may be replaced by Hal; and R8 denotes OH or OR7a; and p denotes 1 or 2.

[0074] Other very specific embodiments of the present invention comprise compounds according to Formula (I), wherein: P2 denotes unsubstituted or mono- or disubstituted or unsubstituted 2- or 3-thienyl or 3-, 4-, phenyl 2,3-, 2,4-, 2,5-, 3,4- or 2,3,4-substituted, wherein the optional substituents are selected from the group consisting of F, Cl, CN, CH3 , C2H5, CF3, OCH3, OC2H5, COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 or N(C2H5)2; P3 denotes a residue according to Formula (Fa) or (S)-(Fb), Ga, Gb each independently of one another denote H, F, Cl, CN, CH3, C2H5, CF3, OCH3, OC2H5 , COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 or N(C2H5)2; and Ka, Kb denote each independently of the other H, F, Cl, CN, CH3, C2H5, CF3, OCH3, OC2H5, COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 or N(C2H5)2.

[0075] Particular embodiments of the present invention comprise compounds according to Formula (I), wherein Y denotes P2 or P3, preferably Y denotes P3.

[0076] Specific embodiments of the present invention comprise compounds according to Formula (I) in which LY denotes CH2 or CH2CH2, in which 1 to 2 H atoms can be replaced by Hal, R7a, OH and/or OR7a, and/ or in which a CH2 group can be replaced by O or S; X is a heterobicycle or heterotricycle of formula (xa), (xb), (xc), (xd), (xe), (xf), (xg), (xh) or (xi) each independently of the other , unsubstituted or mono- or disubstituted by F, Cl, CH3, C2H5, CF3, OCH3, OC2H5, COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 and/or N(C2H5)2 , and wherein 1 of the cyclic CH2 groups may be replaced by C(CH3)2, C(C2H5)2, C=O, O, S, NCH3, SO or SO2; Y denotes P2 or P3 (preferably P3); P2 denotes unsubstituted or mono- or disubstituted or unsubstituted 2- or 3-thienyl or 3-, 4-, 2,3-, 2,4-, 2,5-, 3,4- or 2,3 phenyl, 4-substituted, wherein the optional substituents are selected from the group consisting of H, Hal, CN, R7a, OR7a, CONHR7a, CONR7bR7a, CONH2, NR7aCOR7b, SO2R7a, SOR7a, NHR7a, N(R7a)2, ( CH2)p-SR7a, (CH2)pN(R7a)2 and/or (CH2)p-R8; P3 denotes a residue according to Formula (Fa) or (S)-(Fb); Ga, Gb each denote, independently of one another, H, Hal, CN, R7a, OR7a, CONHR7a, CONR7bR7a, CONH2, NR7aCOR7b, SO2R7a, SOR7a, NHR7a, N(R7a)2, (CH2)p-SR7a, ( CH2)pN(R7a)2 and/or (CH2)p-R8;

[0077] Ka, Kb denote each independently of one another H, Hal, CN, R7a, OR7a, CONHR7a, CONR7bR7a, CONH2, NR7aCOR7b, SO2R7a, SOR7a, NHR7a, N(R7a)2, (CH2)p- SR7a, (CH2)p-N(R7a)2 and/or (CH2)p-R8; R7a, R7b each denote, independently of one another, linear or branched C1-C3-alkyl, in which 1 to 3 H atoms can be replaced by Hal; and R8 denotes OH or OR7a; and p denotes 1 or 2.

[0078] Cy1, Cy2, Cy3, Cy4, Cy5 each independently of one another denote Ar1 or Het1; R1, R2 each independently of the other denote H or C1-C6-alkyl, or R1 and R2 together form a residue according to Formula (EC); T1, T2, T3, T4, T5, T6, T7, T8 and T9 each denote O; Hal denotes F, Cl or Br.

[0079] Many other specific embodiments of the present invention comprise compounds according to Formula (R)-(I)-(S)-(Fb) or (R)-(I)-(Fa): where Ga, Gb each independently denote H, Hal, CN, R7a, OR7a, CONHR7a, CONR7bR7a, CONH2, NR7aCOR7b, SO2R7a, SOR7a, NHR7a, N(R7a)2, (CH2)p-SR7a , (CH2)p-N(R7a)2e/or (CH2)p-R8; Ka, Kb denote each independently of one another H, Hal, CN, R7a, OR7a, CONHR7a, CONR7bR7a, CONH2, NR7aCOR7b, SO2R7a, SOR7a, NHR7a, N(R7a)2, (CH2)p-SR7a, ( CH2)pN(R7a)2 and/or (CH2)p-R8; X is a heterobicycle or heterotricycle of the formula ((xa1), (xb1), (xc1), (xd1), (xe1), (xf1), (xg1), (xh1) or (xi1) each, independently of the other, unsubstituted or mono- or disubstituted by F, Cl, CH3, C2H5, CF3, OCH3, OC2H5, COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 and/or N(C2H5) 2, in which 1 of the cyclic groups CH2 may be replaced by C(CH3)2, C(C2H5)2, C=O, O, S, NCH3, SO or SO2; R1, R2 denotes H or C1-C4-alkyl R1 and R2 together form a residue according to Formula (EC); R7a, R7b each denote, independently of one another, C1-C3-linear or branched alkyl, in which 1 to 3 H atoms can be replaced by Hal ; R8 denotes OH or OR7a; ep denotes 1 or 2.

[0080] In general, residues included in compounds according to Formula (I) as described above may have the following meaning: LY preferably denotes -CH2- or -CH2-CH2- where 1 to 4 H atoms may being replaced by Hal and/or 1 H atom can be replaced by Hal, R3a and/or OR4a, and/or where 1 or 2 non-adjacent CH2 groups can be replaced by O, SO and/or SO2. More preferably, LY denotes -CH2- or -CH2-CH2-, where 1 to 4 H atoms can be replaced by F or Cl and/or 1 or 2 H atoms can be replaced by OH, methyl, ethyl, isopropyl , CF3, CF2CF3, OCH3, OCH2CH3, OCH2CH2OH and/or CH2OCH3 and/or in which 1 CH2 group of LY can be replaced by O.

[0081] R1, R2 preferably each independently denote H or methyl, ethyl, n-propyl or isopropyl or R1 and R2 together form a residue according to Formula (EC) as described above. More preferably R1, R2 denote H, methyl or ethyl and particularly preferably R1, R2 denote H.

[0082] In the embodiments in which R3a or R3b represents a linear or branched C1-C6 alkyl, they preferably denote each, independently of one another, methyl, ethyl, n-propyl or isopropyl linear or branched, in which 1 to 5 atoms of H can be replaced by F, Cl, CN, OH and OAlqu, where Alk is preferably methyl or ethyl. More preferably R3a and R3b each denote, independently of one another, methyl, ethyl, n-propyl or isopropyl, in which 1, 2 or 3 H atoms are replaced by F, Cl, OH, OCH3, OC2H5 or OCH(CH3 )two.

[0083] In the embodiments in which R3a or R3b independently of one another represents the cyclic alkyl group (cycloalkyl), they preferably denote independently of one another cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is unsubstituted or mono-, di- or trisubstituted by Hal (preferably F or Cl), methyl, ethyl, n-propyl, OH, CN, OCH3 or OC2H5.

[0084] R4a and R4b preferably each independently denote one another, preferably H, methyl, moreover ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl or pentyl, wherein 1, 2 or 3 H atoms are replaced by F, Cl, OH, OCH3, OC2H5 or OCH(CH3)2 or R4a and R4b of together a C3-C6 alkylene group.

[0085] Y may denote phenyl, 1- or 2-naphthyl, 4- or 5-indanyl, 1-, 2, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4 -, 5- or 6-azulenyl, 1- or 2-tetrahydronaphthaline 5- or 6-yl, 2- or 3-furyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2,3-dihydrobenzofuran-2- or 3-yl, 2- or 3-thienyl, 2- or 3-benzothienyl, 2-, 3-, 4-, 5-, 6- or 7-benzothiophenyl, methylenedioxyphenyl, benzodioxan-6- or 7-yl or 3,4-dihydro-1,5-benzodioxepin-6- or -7-yl, each independently of the other, unsubstituted, mono-, disubstituted or trisubstituted by Hal ( preferably F or Cl), CN, R3a, OH, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2, (CH2)q-SR3a, (CH2)q-N(R4a)2 and/or (CH2)q -R6. In particular, Y may denote phenyl, 1- or 2-naphthyl 2-, 3-, 4-, 5-, 6- or 7-benzofuryl 2,3-dihydrobenzofuran-2- or 3-yl, 2- or 3-thienyl, 2- or 3-benzothienyl or benzodioxan-6- or 7-yl, each independently of the other, unsubstituted, mono-, disubstituted or trisubstituted by F, Cl, CN, CH3, C2H5, CF3, OCH3 , OC2H5, COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 or N(C2H5)2. In the case where Y denotes a disubstituted phenyl, the substituents are preferably in the 2,4-, 2,5- or 3,4 position, more preferably in the 2,4- or 3,4 position. In the case where Y denotes a trisubstituted phenyl, the substituents are preferably in the 2,3,4 position.

[0086] In particular, Y may denote o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o -, m- or p-tert-butylphenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl , o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-trifluoromethyl-phenyl, o-, m- or p-trichloromethyl-phenyl, o-, m- or p-(methylsulfonyl)phenyl, o-, m- or p-phenoxyphenyl, o-, m- or p-methoxymethyl-phenyl, also preferably 2,4-, 2,5-, 2,6- or 3,4 -dimethylphenyl, 2,4-, 2,5- or 3,4-difluorophenyl, 2,4-, 2,5- or 3,4-dichlorophenyl, 2,4-, 2,5- or 3,4-dibromophenyl , 2,5- or 3,4-dimethoxyphenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2, 3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trifluorophenyl, 2,3,4-, 2,3,5-, 2, 3,6-, 2,4,6- or 3,4,5-trimethylphenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3, 4,5-tris-trifluoromethyl-phenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-tristrichloromethyl-phenyl, 2, 3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trimethoxymethyl-phenyl, 2,4,6-trimethoxyphenyl, p-iodophenyl, 2- fluoro-3-chlorophenyl, 2-fluoro-3-bromophenyl, 2,3-difluoro-4-bromophenyl, 3-bromo-3-methoxyphenyl, 2-chloro-3-methoxyphenyl, 2-fluoro-3-methoxyphenyl, 2- chloro-3-acetamidophenyl, 2-fluoro-3-methoxyphenyl, 2-chloro-3-acetamidophenyl, 2,3-dimethyl-4-chlorophenyl, 2,3-dimethyl-4-fluorophenyl.

[0087] Y may likewise denote 1- or 2-naphthyl, 4- or 5-indanyl, 1-, 2-, 4-, 5- or 6-azulenyl, 1- or 2-tetrahydronaphthalin 5- or 6-yl, 2- or 3-furyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothiophenyl, methylenedioxyphenyl , benzodioxan-6- or 7-yl or 3,4-dihydro-1,5-benzodioxepin-6- or -7-yl. Particular preferred substituents of Y are selected from the group comprising, Cl, CN, CH3, C2H5, CF3, OCH3, OC2H5, COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 or N (C2H5)2.

[0088] Ar2 preferably denotes phenyl, which is unsubstituted or mono- or disubstituted by Hal, CN, R3a, OR3a, CONHR3a, NH2, NHR3a and/or N(R3a)2. Thus, Ar2 preferably denotes e.g. phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl , o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o, m- or p- (N-methylamino)phenyl, o-, m- or p-(N-methylaminocarbonyl)-phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p -ethoxyphenyl, o-, m- or p-(N,N-dimethylamino)phenyl, o-, m- or p-(N-ethylamino)phenyl, o-, m- or p-(N,N- diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-cyanophenyl.

[0089] Het2 preferably denotes a saturated, unsaturated or aromatic 5- or 6-membered heterocycle having 1 to 4 N, O and/or S atoms, which is unsubstituted or mono- or disubstituted by Hal, CN, R3a, OR3a , CONHR3a, NH2, NHR3a and/or N(R3a)2. Thus, Het2 can for example denote 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3 -, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl , 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, imidazolyl, morpholinyl or piperazinyl.

[0090] Alk preferably denotes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, pentyl or hexyl, more preferably methyl, ethyl, propyl or isopropyl, more preferably methyl, ethyl, n-propyl or isopropyl.

[0091] Hal preferably denotes F, Cl or Br, more preferably F or Cl.

[0092] m preferably denotes 0, 1 or 2, plus 1 or 2 and most preferably 1.

[0093] q denotes preferably 0, 1, 2, 3 or 4 and even more preferably 0, 1 or 2.

[0094] Particular embodiments of the present invention include compounds selected from the group consisting of: [(1R)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-acid 1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,2S,4S)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1R)-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamide}-2-(thiophen-3-yl)ethyl]boronic acid; [(1R)-2-(1-benzofuran-3-yl)-1-{[(1R,8S)-11-oxatricyclo[6.2.1.02,7]undeca-2(7),3,5- acid trien-1-yl]formamide}ethyl]boronic acid; [(1S)-2-(1-benzofuran-3-yl)-1-{[(1R,8S)-11-oxatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien acid -1-yl]formamide}ethyl]boronic acid; [(1R)-2-(1-benzofuran-3-yl)-1-{[(1S,8R)-11-oxatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien acid -1-yl]formamide}ethyl]boronic acid; [(1S)-2-(1-benzofuran-3-yl)-1-{[(1S,8R)-11-oxatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien acid -1-yl]formamide}ethyl]boronic acid; [(1R)-2-(1-benzofuran-3-yl)-1-{[(1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid; [(1R)-2-(1-benzofuran-3-yl)-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid; [(1R)-2-(1-benzofuran-3-yl)-1-{[(1R,2R,4S)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid; [(1S)-2-(1-benzofuran-3-yl)-1-{[(1R,2R,4S)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid; [(1R)-2-(7-chloro-1-benzofuran-3-yl)-1-{[(1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-yl]formamide} acid ethyl]boronic; [(1R)-2-(7-chloro-1-benzofuran-3-yl)-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamide} acid ethyl]boronic; [(1R)-2-[(3R)-7-methyl-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2R, 4R)-7-oxabicyclo[ acid] 2.2.1]heptan-2-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3S)-7-methyl-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2R, 4R)-7-oxabicyclo[ acid 2.2.1]heptan-2-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,8S)-11-oxa-tricyclo[6.2.1.02, 7]undeca-2(7),3,5-trien-1-yl]formamide}ethyl]boronic acid; [(1R)-2-(1-benzofuran-3-yl)-1-{[(1S,6S,7R)-3-cyclopropyl-4-oxo-10-oxa-3-azatricyclo[5.2.1.01, 5]dec-8-en-6-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,8R)-11-oxa-tricyclo[6.2.1.02, 7]undeca-2(7),3,5-trien-1-yl]formamide}ethyl]boronic acid; [(1R)-2-(7-methyl-1-benzofuran-3-yl)-1-{[(1R,8S)-11-oxatricyclo[6.2.1.02.7]undeca-2,4,6- acid trien-1-yl]formamide}ethyl]boronic acid; [(1R)-2-(7-methyl-1-benzofuran-3-yl)-1-{[(1S,8R)-11-oxatricyclo[6.2.1.02.7]undeca-2,4,6- acid trien-1-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,8R)-8-methyl-11-oxatricyclo[6.2. 1.02.7]undeca-2,4,6-trien-1-yl]formamide}ethyl]boronic acid; [(1R)-2-(1-benzofuran-3-yl)-1-{[(1R,8S)-11-oxatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien acid -9-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,8S)-8-methyl-11-oxatricyclo[6.2. 1.02.7]undeca-2,4,6-trien-1-yl]formamide}ethyl]boronic acid; [(1R)-2-(1-benzofuran-3-yl)-1-{[(1S,8R)-11-oxatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien acid -9-yl]formamide}ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid; [(1R)-2-cyclohexyl-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid; [(1R)-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamide}-3-phenylpropyl]boronic acid; [(1R)-3-methyl-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}butyl]boronic acid; [(1S)-2-(1-benzofuran-3-yl)-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid; [(1S)-2-(1-benzofuran-3-yl)-1-{[(1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid; [(1R)-2-(1-benzofuran-3-yl)-1-{[(1S,2S,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid; [(1S)-2-(1-benzofuran-3-yl)-1-{[(1S,2S,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid; [(1R)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2S,4R)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,2R,4S)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1S)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2S,4R)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1S)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,2R,4S)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3R)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2S,4R)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3R)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,2R,4S)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1S)-2-[(3R)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2S,4R)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1S)-2-[(3R)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,2R,4S)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1S)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1S)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,2S,4S)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3R)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3R)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,2S,4S)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1S)-2-[(3R)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1S)-2-[(3R)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,2S,4S)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic; and prodrugs, solvates, tautomers, oligomers, adducts or stereoisomers thereof, as well as the pharmaceutically acceptable salts of each of the foregoing, including their mixtures in all ratios.

[0095] The term solvates of the compounds is understood as additions of inert solvent molecules in the compounds that form due to their force of mutual attraction. Solvates are, for example, mono- or dihydrates or alkoxides.

[0096] It is understood that the invention also relates to solvates of the salts.

[0097] The term pharmaceutically acceptable derivatives is understood to mean, for example, the salts of the compounds according to the invention and also so-called prodrug compounds.

[0098] When used herein and unless otherwise indicated, the term "prodrug" means a derivative of a compound of Formula (I) that can hydrolyze, oxidize or otherwise react under biological conditions (in vitro or in vivo ) to provide an active compound, particularly a compound of Formula (I). Examples of prodrugs include, but are not limited to, derivatives and metabolites of a compound of Formula (I) that include biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates , biohydrolyzable ureides and biohydrolyzable phosphate analogues. In certain embodiments, prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid. Carboxylate esters are conveniently formed by esterification of any of the carboxylic acid moieties present in the molecule. Prodrugs can typically be prepared using well known methods, such as those described by Burger's Medicinal Chemistry and Drug Discovery, 6th ed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).

[0099] The expression "effective amount" denotes an amount of a drug or pharmaceutical active ingredient that causes in a tissue, system, animal or human being a biological or medical response that is sought or desired, for example, by a researcher or doctor.

[00100] In addition, the expression "therapeutically effective amount" denotes an amount that, compared to a corresponding individual who did not receive that amount, has the following consequence: better treatment, cure, prevention or elimination of a disease, syndrome, condition , illness, disorder, or side effects, or a reduction in the progression of a disease, illness, or disorder.

[00101] The term "therapeutically effective amount" also encompasses amounts that are effective to enhance normal physiological function.

[00102] The invention also refers to the use of mixtures of the compounds of Formula (I), for example, mixtures of two diastereomers, for example, in the proportion 1:1, 1: 2, 1: 3, 1: 4, 1 : 5 1:10, 1:100 or 1:1000.

[00103] "Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment in which the compound is found and may differ depending on, for example, whether the compound is a solid or whether it is in an organic or aqueous solution.

[00104] The invention further comprises a process for the preparation of a compound of Formula (I) as described above and its pharmaceutically acceptable salts, tautomers and stereoisomers, characterized by a compound of Formula (III) is coupled with a compound of Formula (VI) wherein all residues of Formula (III) and Formula (IV) are as defined above and wherein the obtained compound of Formula (Ib) can subsequently be converted into a compound of Formula (Ia) by treatment with HCl, HBr, HI and/or TFA, in the presence or absence of an excess of a small molecular weight boronic acid

[00105] The following abbreviations refer to the abbreviations used below: AcOH (acetic acid), ACN (acetonitrile), BINAP (2,2'-bis (disphenylphosphino)-1,1'-binaphthalene), dba (dibenzylidene acetone) , tBu (tert-butyl), tBuOK (potassium tert-butoxide), CDI (1,1'-Carbonyldiimidazole), DBU (1,8-dizabicyclo[5.4.0]undec-7-ene), DCC (dicyclo- hexylcarbodiimide), DCM (dichloromethane), DIAD (diisobutylazodicarboxylate), DIC (diisopropylcarbodiimide), DIEA (diisopropylethylamine), DMA (dimethylacetamide), DMAP (4-dimethylaminopyridine), DMSO (dimethylsulfoxide), DMF (N ,N-dimethylformamide), EDC.HCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), EtOAc or EE (ethyl acetate), EtOH (ethanol), g (gram), cHex (cyclohexane ), HATU (dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluorophosphate), HOBt (N-hydroxybenzotriazole), HPLC ( high performance liquid chromatography), hr (hour), MHz (Megahertz), MeOH (methanol), min (minute), mL (milliliter), mmol (millimolar), mM (millimolar), mp (melting point), MS (mass spectrometry), MW (microwave), NMM (N-methyl morpholine), NMR (nuclear magnetic resonance), NBS (N-bromosuccinimide), PBS (phosphate buffered saline), PMB (para-methoxybenzyl) , PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), rt (room temperature), TBAF (tetrabutylammonium fluoride), TBTU (N,N,N',N'-tetramethyl-O-(benzotriazole- 1-yl)uronium), T3P (T3P (propane phosphonic acid anhydride), TEA (triethylamine), TFA (trifluoroacetic acid), THF (tetrahydrofuran), PetEther (petroleum ether), TBME (tert-butylmethyl ether) , TLC (thin layer chromatography), TMS (trimethylsilyl), TMSI (trimethylsilyl iodide), UV (ultraviolet).

[00106] Generally, compounds of Formula (I), in which all residues are defined as above, can be obtained from a compound of Formula (III), as described in Scheme 1.Scheme 1:

[00107] The first step consists of reacting a compound of Formula (III), in which X is defined as above, with a compound of Formula (IV), in which R1, R2, LY and Y are defined as above. The reaction is carried out using conditions and methods well known to those skilled in the art for the preparation of amides of a carboxylic acid with standard coupling agents, such as, but not limited to, HATU, TBTU, 1-alkyl-2- polymer supported chloropyridinium (polymer supported Mukaiiama reagent), 1-methyl-2-chloropyridinium iodide (Mukaiiama reagent), a carbodiimide (such as DCC, DIC, EDC) and HOBt, PiBOP® and other such well known reagents by those skilled in the art, preferably TBTU, in the presence or absence of bases such as TEA, DIEA, NMM, polymer-supported morpholine, preferably DIEA, in a suitable solvent such as DCM, THF or DMF, at a temperature between -10° C and 50°C, preferably at 0°C, for a few hours, for example one hour to 24 h. Alternatively, compounds of Formula (III) can be converted to carboxylic acid derivatives such as acyl halides or anhydrides by methods well known to those skilled in the art, such as, but not limited to, treatment with SOCl2, POCl3, PCl5 , (COCl) 2 , in the presence or absence of catalytic amounts of DMF, in the presence or absence of a suitable solvent, such as toluene, DCM, THF, at a temperature rising from 20°C to 100°C, preferably at 50°C, for a few hours, for example, one hour to 24 h. Conversion of the carboxylic acid derivatives into compounds of Formula (I) can be achieved using conditions and methods well known to those skilled in the art for the preparation of amides from a carboxylic acid derivative (e.g. acyl chloride) with alkyl amines, in the presence of bases such as TEA, DIEA, NMM in a suitable solvent, such as DCM, THF or DMF, at a temperature increasing from 20°C to 100°C, preferably at 50°C, for a few hours , for example, one hour to 24 h.

[00108] In the process described above, the reaction between the compound of Formula (III) and the compound of Formula (IV) is preferably carried out in the presence of a coupling agent selected from HATU, TBTU, 1-alkyl- Polymer supported 2-chloropyridinium (polymer supported Mukaiiama reagent), 1-methyl-2-chloropyridinium iodide (Mukaiyama reagent), a carbodiimide.

[00109] Compounds of Formula (Ia), in which X, LY and Y are defined as above and in which R1 and R2 are H, can be prepared from compounds of Formula (Ib), using methods well known to those those skilled in the art for the hydrolysis of boronic esters, such as, but not limited to, treatment with HCl, HBr, HI, TFA, in the presence or absence of an excess of a low molecular weight boronic acid, such as, however, not limited to, iBuB(OH)2 (Scheme 2) Scheme 2:

[00110] The compounds of Formula (III) or (IV) are commercially available or can be prepared by methods well known to those skilled in the art.

[00111] In general, the compounds of Formula (IV) are, for example, accessible by the following scheme 3a:

[00112] The synthesis of compounds of Formula (IV) is further described in WO 2016/050356, WO 2016/050355, WO 2016/050359 and WO 2016/050358.

[00113] The compounds of Formula (III) are, for example, accessible by the routines described in Schemes 4, 5 and 6: Scheme 4:

[00114] By similar approaches, substituted 7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acids can also be synthesized.Scheme 5:

[00115] By similar approaches, substituted 11-oxatricyclo[6.2.1.02,7]undeca-2,4,6,9-tetraene-9-carboxylic acids can also be synthesized. Scheme 6:

[00116] By similar approaches from substituted furan-2-carboxylic acids, substituted 11-oxatricyclo[6.2.1.02,7]undeca-2,4,6-triene-1-carboxylic acids can be synthesized. Substituted anthranilic acids can also be used to synthesize the corresponding compounds which carry additional substituents on the aromatic moiety.

[00117] If the above set of general synthetic methods is not applicable to obtain compounds according to Formula (I) and/or intermediates necessary for the synthesis of compounds of Formula (I), suitable methods of preparation known to a skilled person in the technique, should be used.

[00118] In general, the synthetic routes for any individual compounds of Formula (I) will depend on the specific substituents of each molecule and the immediate availability of the necessary Intermediates; again such factors being appreciated by those skilled in the art. For all methods of protection and deprotection, see Philip J. Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and Theodora W. Greene and Peter GM Wuts in "Protective Groups in Organic Synthesis", Wiley Interscience , 3rd edition, 1999.

[00119] The compounds of this invention can be isolated in association with solvent molecules by crystallization from the evaporation of an appropriate solvent. Pharmaceutically acceptable acid addition salts of the compounds of Formula (I), which contain a basic center, may be prepared in conventional manner. For example, a solution of the free base can be treated with a suitable acid, neat or in a suitable solution, and the resulting salt isolated by filtration or by vacuum evaporation of the reaction solvent. Pharmaceutically acceptable base addition salts can be obtained in an analogous manner by treating a solution of compounds of Formula (I), which contain an acidic centre, with a suitable base. Both types of salts can be formed or interconverted using ion exchange resin techniques.

[00120] Depending on the conditions used, reaction times are generally between a few minutes and 14 days, and the reaction temperature is between about -30°C and 140°C, usually between -10°C and 90°C, in particular between about 0°C and about 70°C.

[00121] The compounds of Formula (I) can furthermore be obtained by freeing the compounds of Formula (I) from one of its functional derivatives by treatment with a solvating or hydrolyzing agent.

[00122] The preferred starting materials for solvolysis or hydrogenolysis are those that conform to Formula (I) but contain corresponding protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups , preferably those carrying an amino protecting group rather than an H atom bonded to an N atom, in particular those carrying an R'-N group, where R' denotes an amino protecting group rather than an HN group, and/or those that carry a hydroxyl protecting group instead of the H atom of a hydroxyl group, e.g. those that fit Formula (I) but carry a -COOR group, "where R" denotes a protecting group hydroxyl, rather than a -COOH group.

[00123] It is also possible that a plurality of protected amino and/or hydroxyl groups - identical or different - is present in the starting material molecule. If the protective groups present are different from each other, they can, in many cases, be selectively cleaved.

[00124] The term "amino protecting group" is known in general terms and refers to groups that are suitable for protecting (blocking) an amino group against chemical reactions, however, which are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protecting groups are removed after the desired reaction (or reaction sequence), their type and size are also not crucial; however, preference is given to those having 1-20, in particular 1-8, carbon atoms. The term "acyl group" is to be understood in the broadest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and, in particular, alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl, such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and tolyl; aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl) and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl and FMOC; and arylsulfonyl, such as Mtr. Preferred amino protecting groups are BOC and Mtr, in addition CBZ, Fmoc, benzyl and acetyl.

[00125] The term "hydroxyl protecting group" is also known in general terms and refers to groups that are suitable for protecting a hydroxyl group against chemical reactions, but are easy to remove after the desired chemical reaction has been carried out elsewhere of the molecule. Typical of such groups are the aforementioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups. The nature and size of the hydroxyl protecting groups are not crucial as they are removed again after the desired chemical reaction or reaction sequence; preference is given to groups having 1-20, in particular 1-10, carbon atoms. Examples of hydroxyl protecting groups are, inter alia, benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, where benzyl and tert-butyl are particularly preferred.

[00126] The term "solvates of the compounds" is taken to mean adducts of inert solvent molecules in the compounds which form due to their force of mutual attraction. Solvates are, for example, mono- or dihydrates or alcoholates.

[00127] The compounds of Formula (I) are released from their functional derivatives - depending on the protecting group used - for example using strong acids, advantageously using TFA or perchloric acid, however also using other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid, or sulfonic acids such as benzene or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as THF or dioxane, amides such as DMF, halogenated hydrocarbons such as DCM, furthermore also alcohols such as methanol, ethanol or isopropanol and water. Furthermore, mixtures of the above-mentioned solvents are suitable. TFA is preferably used in excess without adding another solvent, and perchloric acid is preferably used in the form of a mixture of acetic acid and 70% perchloric acid in the ratio of 9:1. Reaction temperatures for the cleavage are advantageously between about 0 and about 50°C, preferably between 15 and 30°C (room temperature).

[00128] The BOC, OBut and Mtr groups can, for example, be cleaved preferably using TFA in DCM or using approximately 3 to 5N HCl in dioxane at 15-30°C, and the FMOC group can be cleaved using approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°C.

[00129] Protecting groups that can be removed hydrogenolytically (for example, CBZ, benzyl or the release of the amidino group from its oxadiazole derivative) can be cleaved, for example, by treatment with hydrogen in the presence of a catalyst (for example, a catalyst of a noble metal, such as palladium, advantageously on a support, such as carbon). Suitable solvents here are those indicated above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is generally carried out at temperatures between about 0 and 100°C and pressures between about 1 and 200 bar, preferably between 20-30°C and 1-10 bar. Hydrogenolysis of the CBZ group is successful, for example, in 5-10% Pd/C in methanol or using ammonium formate (instead of hydrogen) in Pd/C in methanol/DMF at 20-30°C.

[00130] Examples of suitable inert solvents are hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, trifluoromethylbenzene, chloroform or DCM; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or ethylene glycol monoethyl ether or dimethyl ether (diglyme); ketones, such as acetone or butanone; amides such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides such as dimethylsulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters, such as EtOAc, or mixtures of said solvents.

[00131] Esters can be saponified, for example, using LiOH, NaOH or KOH in water, water/THF, water/THF/ethanol or water/dioxane, at temperatures between 0 and 100°C. Furthermore, the ester can be hydrolyzed, for example, using acetic acid, TFA or HCl.

[00132] Furthermore, free amino groups can be acylated in conventional manner using an acyl chloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide or reacted with CH3-C(=NH)-OEt, advantageously in a inert solvent such as DCM or THF and/or in the presence of a base such as triethylamine or pyridine at temperatures between -60°C and +30°C.

[00133] Throughout the report, the term leaving group preferably denotes Cl, Br, I or a reactively modified OH group, such as, for example, an activated ester, an imidazolide or alkylsulfonyloxy with 1 to 6 carbon atoms (preferably, methylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxy having 6 to 10 carbon atoms (preferably phenyl or p-tolylsulfonyloxy).

[00134] Radicals of this type for activation of the carboxyl group in typical acylation reactions are described in the literature (for example, in standard works such as Houben-Weila, Metoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag , Stuttgart).

[00135] The activated esters are advantageously formed in situ, for example by adding HOBt or N-hydroxysuccinimide.

Pharmaceutical salts and other forms

[00136] Said compounds of Formula (I) can be used in their final form without salt. On the other hand, the present invention also relates to the use of these compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases by procedures known in the art. Pharmaceutically acceptable salt forms of the compounds of Formula (I) are prepared for the most part by conventional methods. If the compound of Formula (I) contains an acidic center such as a carboxyl group, one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding base addition salt. Such bases are, for example, alkali metal hydroxides, including potassium hydroxide and sodium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; and various organic bases, such as piperidine, diethanolamine, and N-methyl-glycamine (meglumine), benzathine, choline, diethanolamine, ethylenediamine, benetamine, diethylamine, piperazine, lysine, L-arginine, ammonia, triethanolamine, betaine, ethanolamine, morpholine, and tromethamine . In the case of certain compounds of Formula I, which contain a basic center, acid addition salts can be formed by treating these compounds with pharmaceutically acceptable organic and inorganic acids, for example hydrogen halides such as hydrogen chloride or hydrogen bromide, other mineral acids and their corresponding salts such as sulfate, nitrate or phosphate and the like, and alkyl monoaryl sulfonates such as methanesulfonate, ethanesulfonate, toluenesulfonate and benzenesulfonate and other organic acids and corresponding salts thereof such as carbonate, acetate, trifluoroacetate, tartrate, maleate , succinate, citrate, benzoate, salicylate, ascorbate and the like. Accordingly, pharmaceutically acceptable acid addition salts of the compounds of Formula (I) include the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, bisulfite, bromide, camphorate, camphorsulfonate, caprate, caprylate, chloride, chlorobenzoate, citrate, cyclamate, cinnamate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, glycolate, fumarate, galacterate (of mucic acid), galacturonate, glycoheptanoate, gluconate, glutamate, glycerophosphate , hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2 - naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate, pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate, however, these do not represent a restriction. Both types of salts can be formed or interconverted preferably using ion exchange resin techniques.

[00137] In addition, the base salts of the compounds of Formula (I) include salts of aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II ), potassium, sodium and zinc, however, this is not intended to represent a restriction. Of the salts mentioned above, preference is given to ammonium; the alkali metal salts of sodium and potassium and the alkaline earth metal salts of calcium and magnesium. Salts of the compounds of Formula (I) which are derived from pharmaceutically acceptable non-toxic organic bases include salts of primary, secondary and tertiary amines, substituted amines, including also naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example example arginine, betaine, caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glycamine , glucosamine, histidine, hydrabamine, isopropylamine, lidocaine, lysine, meglumine (N-methyl-D-glycamine), morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine and tris( hydroxymethyl)methylamine (tromethamine), however, these are not intended to represent a restriction.

[00138] The compounds of Formula (I) of the present invention that contain nitrogen-containing basic groups can be quaternized using agents such as (C1-C4)-alkyl halides, for example, methyl, ethyl, isopropyl and tert. -butyl; di(C1-C4)alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (C10-C18)alkyl halides, for example decyl, dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide; and aryl-(C1-C4)alkyl halides, for example benzyl chloride and phenethyl bromide. Both water and oil soluble compounds of Formula (I) can be prepared using such salts.

[00139] The above-mentioned pharmaceutical salts that are preferred include acetate, trifluoroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate , sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, however, these are not intended to represent a restriction.

[00140] The acid addition salts of the basic compounds of Formula (I) are prepared by bringing the free base form into contact with a sufficient amount of the desired acid, causing the salt to form in a conventional manner. The free base can be regenerated by bringing the salt form into contact with a base and isolating the free base in conventional manner. The free base forms differ in some respect from the corresponding salt forms with respect to certain physical properties, such as solubility in polar solvents; for purposes of the invention, however, the salts otherwise correspond to the respective free base forms.

[00141] As mentioned, the pharmaceutically acceptable base addition salts of the compounds of Formula (I) are formed with metals or amines, such as alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glycamine and procaine.

[00142] The base addition salts of acidic compounds of Formula (I) are prepared by bringing the free acid form into contact with a sufficient amount of the desired base, causing the salt to form in a conventional manner. The free acid can be regenerated by contacting the salt form with an acid and isolating the free acid in conventional manner. The free acid forms differ in some respect from the corresponding salt forms with respect to certain physical properties, such as solubility in polar solvents; for purposes of the invention, however, the salts otherwise correspond to the respective free acid forms.

[00143] If a compound of Formula (I) contains more than one group that is capable of forming pharmaceutically acceptable salts of this type, Formula (I) also encompasses multiple salts. Typical multiple salt forms include, for example, bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium and trihydrochloride, however, these are not intended to represent a restriction.

[00144] With regard to the above, it can be seen that the term "pharmaceutically acceptable salt" in the present connection is considered an active ingredient comprising a compound of Formula (I) in the form of one of its salts, in particular if this salt form imparts improved pharmacokinetic properties to the active ingredient compared to the free form of the active ingredient or any other salt form of the active ingredient previously used. The pharmaceutically acceptable salt form of the active ingredient can also for the first time provide this active ingredient with a desired pharmacokinetic property that it did not have before and can even have a positive influence on the pharmacodynamics of this active ingredient in relation to its therapeutic efficacy in the body.

[00145] Due to their molecular structure, the compounds of Formula (I) are chiral and can occur according to various enantiomeric forms. They can therefore exist in racemic or optically active form.

[00146] Since the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers. In these cases, the final product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to those skilled in the art or even employed as such in the synthesis.

[00147] In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids such as (R) and (S) forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g. N- benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids. Also advantageous is the resolution of the chromatographic enantiomer with the aid of an optically active resolving agent (eg dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers immobilized on silica gel). Suitable eluents for this purpose are mixtures of aqueous or alcoholic solvents, such as, for example, hexane/isopropanol/acetonitrile, for example, in the ratio 82:15:3.

isotopes

[00148] Furthermore, a compound of Formula (I) is intended to include isotope-tagged forms. An isotope-labeled form of a compound of Formula (I) is identical to that compound except that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or mass number different from the atomic mass or number mass of the atom that usually occurs naturally. Examples of isotopes which are readily commercially available and which can be incorporated into a compound of Formula (I) by well known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F and 36CI, respectively. A compound of Formula (I), a prodrug, or a pharmaceutically acceptable salt of any containing one or more of the aforementioned isotopes and/or other isotopes of other atoms, is intended to form part of the present invention. An isotope-labelled compound of Formula (I) can be utilized in a number of beneficial ways. For example, an isotope-labelled compound of Formula (I) into which, for example, a radioisotope such as 3 H or 14 C has been incorporated, is suitable for drug and/or substrate tissue distribution assays. These radioisotopes, i.e. trictium (3H) and carbon-14 (14C), are particularly preferred due to simple preparation and excellent detectability. The incorporation of heavier isotopes, eg deuterium (2H), into a compound of Formula (I) has therapeutic advantages due to the greater metabolic stability of this isotope-tagged compound. The higher metabolic stability translates directly into an increased half-life in vivo or at lower doses, which under most circumstances would represent a preferred embodiment of the present invention. An isotope-labelled compound of Formula (I) can generally be prepared by carrying out the procedures described in the synthesis schemes and the related description, in the example part and in the preparation part of the present text, substituting a non-isotope-labeled reagent for an isotope-labelled reagent. labeled with readily available isotope.

[00149] Deuterium (2H) can also be incorporated into a compound of Formula (I) in order to manipulate the oxidative metabolism of the compound through the primary kinetic isotope effect. The primary kinetic isotopic effect is a change in the rate for a chemical reaction that results from the exchange of isotopic nuclei, which in turn is caused by the change in the ground state energies required for the formation of covalent bonds following this isotopic exchange. Switching to a heavier isotope generally results in a decrease in the ground state energy for a chemical bond and therefore causes a reduction in the rate of rate limiting bond breaking. If bond disruption occurs at or near a saddle point region along the coordinate of a multiple-product reaction, product delivery rates can be altered substantially. For explanation: if deuterium is bonded to a carbon atom in a non-exchangeable position, rate differences of kM/kD = 2-7 are typical. If this rate difference is successfully applied to a compound of Formula (I) susceptible to oxidation, the in vivo profile of this compound can be drastically modified and results in improved pharmacokinetic properties.

[00150] When researching and developing therapeutic agents, the person skilled in the art tries to optimize the pharmacokinetic parameters while maintaining the desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. Currently available in vitro liver microsomal assays provide valuable information on the course of oxidative metabolism of this type, which in turn allows rational design of deuterated compounds of Formula (I) with improved stability through resistance to such oxidative metabolism. . Significant improvements in the pharmacokinetic profiles of the compounds of Formula (I) are thereby obtained, and can be expressed quantitatively in terms of increases in in vivo half-life (t1/2), concentration at maximum therapeutic effect (Cmax), area under the dose-response curve (AUC) and F; and in terms of reduced clearance, dose and material costs.

[00151] The following is intended to illustrate the above: a compound of Formula (I) that has multiple potential sites of attack for oxidative metabolism, for example, benzylic hydrogen atoms and hydrogen atoms bonded to a nitrogen atom, is prepared as a series of analogues in which various combinations of hydrogen atoms are replaced by deuterium atoms, such that some, most, or all of these hydrogen atoms have been replaced by deuterium atoms. Half-life measurements allow you to favorably and accurately determine the extent to which the improvement in resistance to oxidative metabolism has improved. Thus, it is determined that the half-life of the parent compound can be prolonged by up to 100% as a result of deuterium-hydrogen exchanges of this type.

[00152] Deuterium-hydrogen exchange in a compound of Formula (I) can also be used to achieve a favorable modification of the metabolite spectrum of the starting compound in order to decrease or eliminate unwanted toxic metabolites. For example, if a toxic metabolite arises through oxidative carbon-hydrogen bond (CH) cleavage, it can reasonably be assumed that the deuterated analog will greatly decrease or eliminate production of the undesired metabolite, even though the specific oxidation is not a step of rate determination. Additional prior art information regarding deuterium-hydrogen exchange can be found, for example, in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette et al., Biochemistry 33(10) 2927-2937, 1994, and Jarman et al. Carcinogenesis 16(4), 683688, 1993.

[00153] The present invention relates to a pharmaceutical formulation (preferably for use in the treatment of an immunoregulatory abnormality or a cancer) comprising at least one compound of Formula (I) (particularly a therapeutically effective amount of a compound of Formula (I) ), and/or a prodrug, solvate, tautomer, oligomer, adduct or stereoisomer thereof, as well as a pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, as an active ingredient, together with a pharmaceutically acceptable carrier acceptable.

[00154] For the purposes of the present invention, the term "pharmaceutical formulation" refers to a composition or product comprising one or more active ingredients and one or more inert ingredients that make up the vehicle, as well as any product that results, directly or indirectly, from the combination, complexation or aggregation of any two or more ingredients, or from the dissociation of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. Accordingly, the pharmaceutical formulations of the present invention encompass any composition made by mixing at least one compound of the present invention and a pharmaceutically acceptable carrier, excipient or vehicle.

[00155] The pharmaceutical formulations of the present invention also cover any composition that further comprises a second active ingredient and/or a prodrug or solvate thereof, as well as a pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios , wherein this second active ingredient is different from a compound of Formula (I) in which all residues are defined above.

[00156] The pharmaceutical formulations according to the present invention can be used as drugs in human and veterinary medicine.

[00157] For the purposes of the present invention, an immunoregulatory abnormality is preferably an autoimmune or chronic inflammatory disease selected from the group consisting of: systemic lupus erythematosus, chronic rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS ), atherosclerosis, scleroderma, autoimmune hepatitis, Sjogren's Syndrome, lupus nephritis, glomerulonephritis, Rheumatoid Arthritis, Psoriasis, Myasthenia Gravis, Immunoglobulin A nephropathy, Vasculitis, Transplant Rejection, Myositis, Henoch-Schonlein Purpura and asthma; the cancer is preferably a hematological malignancy or a solid tumor, wherein the hematological malignancy is preferably a disease selected from the group of malignant B-cell and T/NK non-Hodgkin lymphoma, such as: multiple myeloma, lining cell lymphoma, diffuse large B-cell lymphoma, plasmacytoma, follicular lymphoma, immunocytoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, and myeloid leukemia; and wherein the solid tumor is preferably a disease selected from the group of: inflammatory breast, liver and colon cancer, lung cancer, head and neck cancer, prostate cancer, pancreatic cancer, bladder cancer, kidney cancer , hepatocellular cancer and gastric cancer.

[00158] Pharmaceutical formulations can be administered in the form of dosage units, which comprise a predetermined amount of active ingredient per dosage unit. Such a unit may comprise, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of a compound according to the invention, depending on the disease condition treated, the method of administration and the age, weight and condition of the patient, or pharmaceutical formulations may be administered in the form of dosage units comprising a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those comprising a daily or partial dose, as indicated above, or corresponding fraction thereof of an active ingredient. Furthermore, pharmaceutical formulations of this type can be prepared using a process, which is generally known in the pharmaceutical art.

[00159] The pharmaceutical formulations can be adapted for administration by any suitable method desired, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous) methods , intramuscularly, intravenously or intradermally). Such formulations can be prepared using all procedures known in the pharmaceutical art, for example by combining the active ingredient with the excipient(s) or adjuvant(s).

[00160] Pharmaceutical formulations adapted for oral administration can be administered as separate units, such as, for example, capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

[00161] Thus, for example, in the case of oral administration in the form of a tablet or capsule, the active ingredient component can be combined with an oral, non-toxic and pharmaceutically acceptable inert excipient, such as, for example, ethanol, glycerol, water and the like. Powders are prepared by grinding the compound to a suitable fine size and mixing it with a similarly ground pharmaceutical excipient, such as, for example, an edible carbohydrate, such as, for example, starch or mannitol. A flavor, preservative, dispersant and colorant may likewise be present.

[00162] Capsules are produced by preparing a powder mixture as described above and filling the gelatin shells formed therewith. Glidants and lubricants, such as, for example, highly dispersed silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form, can be added to the powder mixture before the filling operation. A disintegrant or solubilizer, such as, for example, agar-agar, calcium carbonate or sodium carbonate, can also be added in order to improve the availability of the medicine after the capsule is taken.

[00163] Furthermore, if desired or necessary, suitable binders, lubricants and disintegrants, as well as colorants, can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners made from corn, natural and synthetic rubber such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or dry-pressing the mixture, adding a lubricant and disintegrant, and pressing the entire mixture to produce tablets. A powder blend is prepared by mixing the suitably ground compound with a diluent or base as described above and optionally with a binder such as carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone, a dissolution retarder such as for example paraffin, an absorption accelerator such as for example a quaternary salt and/or an absorbent such as for example bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder such as syrup, starch paste, acadia mucilage or cellulose solutions or polymer materials and pressing it through a sieve. As an alternative to granulating, the powder mixture can be passed through a tabletting machine, producing unevenly shaped lumps which are broken up to form granules. The granules can be lubricated by adding stearic acid, a stearate salt, talc or mineral oil to prevent sticking to tablet molds. The lubricated mixture is then pressed to produce tablets. The active ingredients can also be combined with a free-flowing inert excipient and then pressed directly to produce tablets without performing granulation or dry pressing steps. A clear or opaque protective layer consisting of a sealing layer of shellac, a layer of sugar or polymeric material, and a glossy layer of wax may be present. Dyes can be added to these coatings to be able to differentiate between different dosage units.

[00164] Oral liquids, such as, for example, solution, syrups and elixirs, can be prepared in the form of dosage units, so that a given amount comprises a prespecified amount of the compounds. Syrups can be prepared by dissolving the compounds in an aqueous solution with a suitable flavor, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compounds in a non-toxic vehicle. Solubilizers and emulsifiers, such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives, such as, for example, peppermint oil or natural sweeteners or saccharin, or other artificial sweeteners, and the like, may also be added.

[00165] Dosage unit formulations for oral administration may, if desired, be encapsulated in microcapsules. The formulation can also be prepared in such a way that the release is prolonged or delayed, such as, for example, by coating or embedding particulate material in polymers, wax and the like.

[00166] The compounds of Formula (I) and their salts, solvates and physiologically functional derivatives thereof and the other active ingredients can also be administered in the form of liposome delivery systems, such as, for example, small unilamellar vesicles, large vesicles unilamellar and multilamellar vesicles. Liposomes can be formed from various phospholipids, such as, for example, cholesterol, stearylamine or phosphatidylcholines.

[00167] The compounds of Formula (I) and the salts, solvates and their physiologically functional derivatives thereof and the other active ingredients can also be delivered using monoclonal antibodies as individual vehicles to which the compound molecules are coupled. The compounds can also be coupled to soluble polymers as carriers for targeted drugs. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamidophenol, polyhydroxyethylaspartamidophenol or polyethylene oxide polylysine substituted with palmitoyl radicals. The compounds may furthermore be coupled with a class of biodegradable polymers that are suitable for achieving controlled release of a drug, for example polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydroxypyrans, polycyanoacrylates and hydrogel crosslinked or amphipathic block copolymers.

[00168] Pharmaceutical formulations adapted for transdermal administration can be administered as independent patches for close and prolonged contact with the recipient's epidermis. Thus, for example, the active ingredient can be released from the patch by iontophoresis, as described in general terms in Pharmaceutical Research, 3(6), 318 (1986).

[00169] Pharmaceutical compounds adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

[00170] For the treatment of the eye or other external tissue, for example mouth and skin, the formulations are preferably applied as a topical ointment or cream. In the case of formulation to produce an ointment, the active ingredient may be employed with a paraffinic or water-miscible cream base. Alternatively, the active ingredient can be formulated to produce a cream with an oil-in-water cream base or a water-in-oil base.

[00171] Pharmaceutical formulations adapted for topical application to the eye include eye drops, in which the active ingredient is dissolved or suspended in a suitable vehicle, in particular an aqueous solvent.

[00172] Pharmaceutical formulations adapted for topical application in the mouth include lozenges, lozenges and mouthwashes.

[00173] Pharmaceutical formulations adapted for rectal administration can be administered in the form of suppositories or enemas.

[00174] Pharmaceutical formulations adapted for nasal administration in which the carrier substance is a solid comprise a coarse powder having a particle size, for example in the range of 20 to 500 microns, which is administered in the manner in which the inhalation is taken , i.e., by rapid inhalation through the nasal passages from a container containing the powder held close to the nose. Formulations suitable for administration as a nasal spray or nasal drops with a liquid carrier substance include water or oil solutions of active ingredients.

[00175] Pharmaceutical formulations adapted for administration by inhalation include finely particulate powders or mists, which can be generated by various types of pressurized dispensers with aerosols, nebulizers or insufflators.

[00176] Pharmaceutical formulations adapted for vaginal administration can be administered as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

[00177] Pharmaceutical formulations adapted for parenteral administration include sterile aqueous and non-aqueous injection solutions comprising antioxidants, buffers, bacteriostats and solutes, whereby the formulation is made isotonic with the blood of the recipient to be treated; and aqueous and non-aqueous sterile suspensions, which may comprise suspending media and thickeners. The formulations may be administered in single or multi-dose containers, e.g. ampoules and vials sealed and stored in the freeze-dried (lyophilized) state, so that only the addition of the sterile vehicle liquid, e.g. water for injection purposes , just before use is required.

[00178] Solutions and suspensions for injection prepared according to the recipe can be prepared from sterile powders, granules and tablets.

[00179] It goes without saying that, in addition to the constituents particularly mentioned above, the formulations may also comprise other agents usual in the art with respect to the particular type of formulation; thus, for example, formulations which are suitable for oral administration may comprise flavors.

[00180] The compositions/formulations according to the invention can be used as drugs in human and veterinary medicine.

[00181] A therapeutically effective amount of a compound of Formula (I) and the other active ingredient depends on a number of factors, including, for example, the age and weight of the animal, the precise condition of the disease requiring treatment and its severity, the nature of the formulation and the method of administration and is ultimately determined by the treating physician or veterinarian. However, an effective amount of a compound is generally in the range of 0.1 to 100 mg/kg of recipient (mammal) body weight per day and particularly typically in the range of 1 to 10 mg/kg of body weight per day. Thus, the actual amount per day for an adult mammal weighing 70 kg is generally between 70 and 700 mg, where this amount may be given as a single dose per day or usually in a series of partial doses (such as two, three, four, five or six) a day, so that the total daily dose is the same. An effective amount of a salt or solvate or a physiologically functional derivative thereof can be determined as a fraction of the effective amount of the compound per se.

[00182] The invention also relates to a compound according to Formula (I) or any specific embodiment described above and/or their products, solvates, tautomers, oligomers, adducts or stereoisomers thereof, as well as the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios, for use in the prevention and/or treatment of medical conditions affected by LMP7 inhibition.

[00183] The invention relates to a compound according to Formula (I) or any specific embodiment described above and/or a prodrug, solvate, tautomers, oligomers, adducts or stereoisomers thereof, as well as the pharmaceutically acceptable salts of each one of the foregoing, including mixtures thereof in all ratios, for use in the treatment and/or prophylaxis (prevention) of an immunoregulatory abnormality or cancer (including, in particular, haematological malignancy and solid tumours).

[00184] The present invention also relates to a method of treating an individual suffering from an immunoregulatory abnormality or a cancer, comprising administering to said individual compounds of Formula (I) in an amount that is effective for the treatment of the said immunoregulatory abnormality or a cancer. The present invention preferably relates to a method of treating a subject suffering from an autoimmune or chronic inflammatory disease, hematological malignancy or a solid tumor.

[00185] The described compounds of Formula (I) can be administered and/or used in combination with other known therapeutic agents (active ingredients), including anticancer agents. When used herein, the term "anti-cancer agent" refers to any agent that is administered to a cancer patient for the purpose of treating the cancer.

[00186] The anticancer treatment defined above may be applied as a monotherapy or may involve, in addition to the compounds of Formula (I) described herein, conventional surgery or radiotherapy or medicinal therapy. Such medicinal therapy, for example, chemotherapy or targeted therapy, may include one or more, but preferably one, of the following antitumour agents: Alkylating agents such as altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosylate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechlorethamine, carboquone; apaziquone, fotemustine, glyphosphamide, palifosfamide, pipobromane, trofosfamide, uramustine, TH-3024, VAL-0834; Platinum compounds such as carboplatin, cisplatin, eptaplatin, myriplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin; DNA altering agents such as anrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; ansacrine, brostalicin, pixantrone, laromustine1,3; Topoisomerase inhibitors such as etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; ammonafide, belotecan, elliptinium acetate, vorelaxin; Microtubule modifiers such as cabazitaxel, docetaxel, eribulin, Ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; fosbretabulin, thesistaxel; Antimetabolites such as asparaginase3, azacitidine, calcium levofolinate, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, delarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxyfluridine, elacitarabine, raltitrexed, sapacitabine, tegafur2,3, trimetrexate; Anticancer antibiotics such as bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunurrobicin, plicamycin; aclarubicin, peplomycin, pirarubicin; Hormones/Antagonists such as abarelix, abiraterone, bicalutamide, buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone, estradiol, fluocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilostane, triptorelin, diethylstilbestrol; acolbifen, danazol, deslorelin, epitiostanol, orteronel, enzalutamide1,3; Aromatase inhibitors such as aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestane; Small molecule kinase inhibitors such as crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tipifarnib, tivantinib, tivozanib, trametinib, pimasertib, brivanib alaninate, cediranib, apatinib4, cabozantinib S-malate1,3, ibrutinib1,3, icotinib4, buparlisib2, cipatinib4, cobimetinib1,3, idelalisib1,3, fedratinib1, XL-6474; Photosensitizers such as methoxsalen3; porfimer sodium, talaporfin, temoporfin; Antibodies such as alemtuzumab, besilesomab, brentuximab vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, pertuzumab2,3; catumaxomab, elotuzumab, bevacizumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab, nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab, matuzumab, dalotuzumab1, 2,3, onartuzumab1,3 racotumomab1, tabalumab1,3 , EMD-5257974, nivolumab1,3; Cytokines such as aldesleukin, interferon alfa2, interferon alfa2a3, interferon alfa2b2,3; celmoleucine, tasonermin, teceleucine, oprelvekin1,3, recombinant interferon beta-1a4; Drug Conjugates such as denileucim diftitox, ibritumomab tiuxethane, iobenguan I123, prednimustine, trastuzumab emtansine, estramustine, gentuzumab, ozogamicin, aflibercept; cintredecim besudotox, edotreotide, inotuzumab ozogamicin, naptumomab stafenatox, oportuzumab monatox, technetium (99mTc)arcitumomab1,3, vintafolid1,3; Vaccines such as sipuleucel3; vitespen3, emepepimut-S3, oncoVAX4, rindopepimut3, troVax4, MGN-16014, MGN-17034; Miscellaneous alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid, imiquimod, lenalidomide, lentinan, metyrosine, mifamurtide, pamidronic acid, pegaspargase, pentostatin, sipuleucel3, sizofirane, tamibarotene, temsirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid, vorinostat; celecoxib, cilengitide, entinostat, etanidazole, ganetspib, idronoxil, iniparib, ixazomib, lonidamine, nimorazol, panobinostat, peretinoin, plitidepsin, pomalidomide, procodazole, ridaforolimus, tasquinimod, telotristat, thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, val spodar, gendicin4, picibanil4, reolisin4, retaspimycin hydrochloride1,3, trebananib2,3, virulizine4, carfilzomib1,3, endostatin4, immucotel4, belinostate3, MGN-17034; 1 Prop. INN (Proposed International Non-Proprietary Name) 2 Rec. INN (Recommended International Non-Proprietary Names) 3 USAN (United States Adopted Name) 4no INN.

[00187] The invention also relates to the use of compounds of Formula (I) and related Formulas in combination with at least one other active drug ingredient, preferably drugs used in the treatment of multiple sclerosis, such as cladribine or another coagent such as interferon, for example pegylated or non-pegylated interferons, preferably interferon beta and/or with compounds that improve vascular function or in combination with immunomodulatory agents, for example Fingolimod; cyclosporins, rapamycins or ascomycins, or their immunosuppressive analogues, for example, cyclosporin A, cyclosporin G, FK-506, ABT-281, ASM981, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin, etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine; mycophenolic acid; mycophenolate mofetil; 15- deoxyspergualine; diflucortolone valerate; difluprednado; Alclomethasone Dipropionate; ancinonide; ansacrine; asparaginase; azathioprine; basiliximab; beclomethasone dipropionate; betamethasone; betamethasone acetate; betamethasone dipropionate; betamethasone sodium phosphate; betamethasone valerate; budesonide; captopril; chlormethine hydrochloride; cladribine; clobetasol propionate; cortisone acetate; cortivazol; cyclophosphamide; cytarabine; daclizumab; dactinomycin; desonide; deoxymethasone; dexamethasone; dexamethasone acetate; dexamethasone isonicotinate; dexamethasone sodium metasulfobenzoate; dexamethasone phosphate; dexamethasone tebutate, dichlorisone acetate; doxorubicin hydrochloride; epirubicin hydrochloride; fluchlorolone acetonide; fludrocortisone acetate; fludroxycortide; flumethasone pivalate; flunisolide; fluocinolone acetonide; fluocinonide; fluocortolone; fluocortolone hexanoate; fluocortolone pivalate; fluorometholone; flupredniden acetate; fluticasone propionate; gemcitabine hydrochloride; halcinonide; hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone hemisuccinate; melphalan; meprednisone; mercaptopurine; methylprednisolone; methylprednisolone acetate; methylprednisolone hemisuccinate; misoprostol; Muromonab-cd3; mycophenolate mofetil; paramethasone acetate; prednazoline, prednisolone; prednisolone acetate; prednisolone caproate; prednisolone sodium metasulfobenzoate; prednisolone sodium phosphate; prednisone; prednilidene; rifampicin; rifampicin sodium; tacrolimus; teriflunomide; thalidomide; thiotepa; thixocortol pivalate; triamcinolone; acetonide triamcinolone hemisuccinate; triamcinolone benetonide; triamcinolone diacetate; triamcinolone hexacetonide; immunosuppressive monoclonal antibodies, for example monoclonal antibodies to leukocyte receptors, for example MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD40, CD45 or CD58 or their ligands; or other immunomodulatory compounds, for example CTLA41g, or other adhesion molecule inhibitors, for example mAbs or low molecular weight inhibitors, including Selectin antagonists and VLA-4 antagonists. A preferred composition is with Ciclosporin A, FK506, rapamycin or 40-(2-hydroxy)ethyl-rapamycin and Fingolimod. These other medicinal products, such as interferon beta, may be administered concomitantly or sequentially, for example subcutaneously, intramuscularly or orally.

[00188] The invention also relates to the use of compounds of Formula (I) and related Formulas in combination with at least one other active drug ingredient, preferably drugs used in the treatment of cancer (such as in particular anticancer and/or antitumor agents described above).

[00189] The present invention also relates to a set (kit) consisting of separate packages of (a) an effective amount of a compound of Formula (I) and/or a prodrug, solvate, tautomer, oligomer, adduct or stereoisomer of same, as well as a pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, and (b) an effective amount of another active drug ingredient.

[00190] The compounds of the present invention can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials, and are further exemplified by the following specific examples.

[00191] Furthermore, using the procedures described herein, in conjunction with common knowledge in the art, additional compounds of the present invention claimed herein can be readily prepared. The compounds illustrated in the examples should not, however, be interpreted as forming the only genus considered as the invention. The examples further illustrate details for preparing the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[00192] The starting materials for the preparation of the compounds of the present invention can be prepared by methods as described in the examples or by methods known per se, as described in the synthetic organic chemistry literature and known to those skilled in the art, or they can be obtained commercially.

[00193] The synthesis of the compounds of Formula (IV) is described in WO 2016/050356, WO 2016/050355, WO 2016/050359 and WO 2016/050358. Examples LCMS: Method A: Agilent 70108359 - Chromolith Speed Rod RP18e 50- 4.6mm; polar.m; 2.4 mL/min; 220nm; buffer A: 0.05% HCOOH/H2O, buffer B: 0.04% HCOOH/ACN; 0.0-2.8 min 100% to 4% Buffer B; 2.8-3.3 min 100% Buffer B; 3.3-3.4 min 100%-4% buffer B. Method B: Waters XBrigde C8 3.5 µm; 4.6x50mm; EliteLa Chrom 70173815; 8.1 min; 2 mL/min; 215nm; Buffer A: 0.05% TFA/H2O; Buffer B: 0.04% TFA/ACN; 0.0-0.2 min 5% Buffer B; 0.2-8.5 min 5% -100% Buffer B; 8.5-10.0 min 99% to 5% buffer. RT: Retention time.

[00194] The invention will be illustrated, but not limited, by reference to the specific embodiments described in the examples below. Unless otherwise indicated in the schematics, variables have the same meaning as described above.

[00195] Unless otherwise specified, all starting materials are obtained from commercial suppliers and used without further purifications. Unless otherwise specified, all temperatures are expressed in oC and all reactions are carried out at room temperature. The compounds can be purified by common means, such as in particular silica chromatography or preparative HPLC.

[00196] Unless otherwise stated, all structures listed below, where no specific stereochemistry is indicated, refer to mixtures of stereoisomers.Intermediate 1: Step 1: 2-(2,4-Dimethyl-benzyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

[00197] To a solution of 1-Bromomethyl-2,4-dimethyl-benzene (25.00 g; 114.40 mmol; 1.00 eq.) in degassed Dioxane (250.00 mL), Bis(pinacolato)diboron (35.21 g; 137.28 mmol; 1.20 eq.), dry K2CO3 (47.91 g; 343.19 mmol; 3.00 eq.) and Tetracis(triphenylphosphine)palladium(0) (6623 mg; 5.72 mmol; 0.05 eq.) are added. The reaction mixture is then heated at 100°C under a nitrogen atmosphere for 16 h. The reaction mixture is diluted with dichloromethane and passed through celite. The filtrate is concentrated. The residue is dissolved in ethyl acetate and washed with brine. The organic layer is dried over anhydrous Na2SO4, filtered and concentrated. The crude product is purified by column chromatography using 1% ethyl acetate in petroleum ether to obtain 2-(2,4-dimethyl-benzyl)-4,4,5,5-tetramethyl-[1,3,2 ]dioxaborolane (11.50 g; 37.84 mmol; 33.1%) as colorless liquid.

[00198] 1H NMR (400 MHz, CDCl3) δ 7.04-7.02 (m, 1H), 6.95-6.93 (m, 1H), 6.92-6.90 (m, 1H), 2.28 (s, 3H), 2.25 (s, 3H), 2.23 (s, 2H), 1.24 (s, 12H).Step 2: (1S,2S ,6R,8S)-4-(2,4-Dimethyl-benzyl)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane

[00199] To an ice-cold solution of 2-(2,4-dimethyl-benzyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (24.00 g; 79.3 mmol ; 1.0 eq.) In Diethyl ether (240.00 mL) under nitrogen atmosphere, (1S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol (20.68 g; 119.07 mmol; 1.50 eq.) is added and the reaction mixture is stirred at room temperature for 14 h. TLC analysis showed completion of the reaction. The reaction mixture is washed with brine. The organic layer is dried over anhydrous Na2SO4 and concentrated. The crude product is purified by flash column chromatography using 2% ethyl acetate in petroleum ether to obtain (1S,2S,6R,8S)-4-(2,4-Dimethyl-benzyl)-2,9,9 -trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane (28.00 g; 82.96 mmol; 90.0%) as a colorless oil.

[00200] 1H NMR (400 MHz, CDCl3): δ 7.05-7.03 (m, 1 H), 6.95-6.94 (m, 1 H), 6.92-6.90 (m , 1H), 4.27-4.25 (m, 1H), 2.33-2.30 (m, 9H), 2.27-2.17 (m, 1H), 2.05 (t, J = 5.76 Hz, 1 H), 1.90-1.89 (m, 1 H), 1.84-1.80 (m, 1 H), 1.38 (s, 3 H ), 1.28 (s, 3H), 1.11-1.09 (m, 1H), 0.91 (s, 3H)

[00201] GCMS: m/z: 298.3. Step 3: (1S,2S,6R,8S)-4-[(S)-1-Chloro-2-(2,4-dimethyl-phenyl)-ethyl]-2,9,9-trimethyl-3,5 -dioxa-4-bora-tricyclo[6.1.1.02.6]decane

[00202] Dichloromethane (37.33 mL; 583.45 mmol; 3.00 eq.) in Tetrahydrofuran (140.00 mL) is collected in an RB flask (round bottom flask) under a positive pressure of nitrogen and cooled to -99°C using a liquid nitrogen-ethanol mixture. To this, n-butyllithium (1.6 M in THF) (133.71 mL; 213.93 mmol) is added dropwise through the sides of the RB flask (at an average rate, the addition took about 35 min). So that the internal temperature is maintained between -92°C and -102°C. After addition, the reaction mixture is stirred for 25 minutes. During the course of the reaction, a white precipitate forms (the internal temperature is maintained between -90°C and -96°C). Then a solution of (1S,2S,6R,8S)-4-(2,4-Dimethyl-benzyl)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1. 1.02.6]decane (58.00 g; 194.5 mmol) in THF (300.00 mL) is added dropwise through the sides of the RB flask (about 40 min) so that the internal temperature is maintained between -94°C and -100°C. After addition, the reaction mixture is stirred for 10 min. Then zinc chloride (0.5 M in THF) (388.97 mL; 194.48 mmol) is added dropwise down the sides of the RB flask (at an average rate, the addition took about 35 min) so that the internal temperature is maintained between -94°C and -99°C. The reaction mixture is then slowly allowed to reach 20°C and stirred at 20°C for 2.5 h. An aliquot of the reaction mixture is processed and analyzed by 1H NMR which showed completion of the reaction. The reaction mixture is concentrated (bath temperature 30°C). The residue is partitioned between diethyl ether and saturated NH4Cl solution. The organic layer is dried over anhydrous Na 2 SO 4 and concentrated (bath temperature 30°C) to afford (1S,2S,6R,8S)-4-[(S)-1-Chloro-2-(2,4-dimethyl -phenyl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane (75.70 g; 154.83 mmol; 79.6%) as a white solid.

[00203] 1H NMR (400 MHz, CDCl3): δ 7.12 (d, J = 7.64 Hz, 1 H), 6.98 (s, 1 H), 6.96 (d, J = 7, 68 Hz, 1H), 4.38-4.36 (m, 1H), 3.67-3.62 (m, 1H), 3.18-3.11 (m, 2H), 2 .40-2.36 (m, 2H), 2.32 (s, 3H), 2.30 (s, 3H), 2.23-2.20 (m, 1H), 2.08 (t, J = 5.96 Hz, 1 H), 1.93-1.87 (m, 2 H), 1.36 (s, 3 H), 1.30 (s, 3 H), 1, 14-1.11 (m, 1H), 0.84 (s, 3H). 7.18-7.08 (m, 5H), 4.37 (dd, J=1.32, 8.74Hz, 1H), 3.77-3.75 (m, 1H), 3.673 .63 (m, 1H), 3.19-3.17 (m, 1H), 3.10-3.08 (m, 1H), 2.36-2.31 (m, 5H) , 2.09 (t, J = 5.84 Hz, 1 H), 1.93-1.86 (m, 4 H), 1.39 (s, 3 H), 1.30 (s, 3 H ), 1.13-1.10 (m, 1H), 0.84 (s, 3H).

[00204] GCMS: m/z: 346.3. Step 4: (1S,2S,6R,8S)-4-[(R)-2-(2,4-Dimethyl-phenyl)-1-(1,1,1,3,3,3-hexamethyl -disilazane-2-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane

[00205] A solution of (1S,2S,6R,8S)-4-[(S)-1-Chloro-2-(2,4-dimethyl-phenyl)-ethyl]-2,9,9-trimethyl- 3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane (75.70 g; 218.35 mmol; 1.00 eq.) in THF (400.00 mL) under a positive pressure of atmosphere of nitrogen is cooled to -78°C. To this is added a solution of (bistrimethylsilyl)amide (1.0 M in THF) (262 mL; 262 mmol; 1.20 eq.) dropwise over a period of 30 minutes. The reaction mixture is allowed to come to room temperature and stirred at room temperature for 18 h. The reaction mixture is evaporated at a temperature of 30°C. The residue is triturated with hexane and the solid formed is filtered. The filtrate is allowed to stand for some time under vacuum and any solids, if formed, are filtered again. The filtrate is concentrated at a temperature of 30°C to obtain (1S,2S,6R,8S)-4-[(R)-2-(2,4-Dimethyl-phenyl)-1-(1,1,1 ,3,3,3-hexamethyl-disilazan-2-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane (80.10 g; 169.84 mmol; 77.8%; brown oil).

[00206] 1H NMR (400 MHz, CDCl3): δ: 7.06 (d, J = 7.64 Hz, 1 H), 6.94 (s, 1 H), 6.90 (d, J = 7 .80 Hz, 1H), 4.29-4.27 (m, 1H), 3.15-3.10 (m, 1H), 2.87-2.83 (m, 1H), 2.58-2.53 (m, 1H), 2.34-2.32 (m, 2H), 2.30 (s, 3H), 2.28 (s, 3H), 2, 15-2.13 (m, 1H), 2.03 (t, J = 5.88 Hz, 1H), 1.90-1.88 (m, 1H), 1.81-1.77 (m, 1H), 1.39 (s, 3H), 1.32 (s, 3H), 1.01-0.98 (m, 1H), 0.93 (s, 3H) , 0.85 (s, 3H), 0.09 (s, 18H). Step 5: (R)-2-(2,4-Dimethyl-phenyl)-1-((1S,2S,6R) Hydrochloride ,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]dec-4-yl)-ethylamine

[00207] A stirred solution of (1S,2S,6R,8S)-4-[(R)-2-(2,4-Dimethyl-phenyl)-1-(1,1,1,3,3 ,3-hexamethyl-disilazan-2-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane (80.10 g; 169. 84 mmol; 1.00 eq.) in diethyl ether (400.00 mL) under a nitrogen atmosphere is cooled to -10°C. To this 2M solution of hydrochloric acid in diethyl ether (212.30 mL; 424.59 mmol; 2.50 eq.) is added dropwise. The reaction mixture is stirred at room temperature for 2 h. The reaction mixture is evaporated under reduced pressure to obtain (R)-2-(2,4-dimethyl-phenyl)-1-((1S,2S,6R,8S)-2,9,9-trimethyl-phenyl) hydrochloride. 3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]dec-4-yl)-ethylamine (63.00 g; 72.61 mmol; 42.8%; brown solid).

[00208] 1H NMR (400 MHz, DMSO-d6): δ 8.19 (s, 3 H), 7.05 (d, J =7.68 Hz, 1 H), 6.95 (s, 1 H ), 6.90 (d, J = 8.16 Hz, 1 H), 4.31 (dd, J = 1.80, 8.76 Hz, 1 H), 3.02-3.00 (m, 1H), 2.99-2.92 (m, 1H), 2.87-2.84 (m, 1H), 2.26-2.24 (m, 3H), 2.26 ( s, 3H), 2.24 (s, 3H), 2.03-2.00 (m, 1H), 1.91 (t, J = 5.68 Hz, 1H), 1.82 -1.80 (m, 1H), 1.71-1.66 (m, 1H), 1.31 (s, 3H), 1.21 (s, 3H), 0.98-0 .96 (m, 1H), 0.77 (s, 3H).

[00209] By similar sequences described for intermediate 1, the following compounds can be prepared where the group Y denotes one of the following groups: Intermediate 2: Step 1: benzofuran-3-ylmethanol

[00210] A solution of 1-Benzofuran-3-carbaldehyde (5 g, 34.2 mmol) in methanol (50 mL) is cooled with ice and sodium borohydride (1.9 g, 51.3 mmol) is added in portions. The reaction mixture is stirred at room temperature for 1 h. The reaction mixture is concentrated and the residue is partitioned between saturated ammonium chloride and ethyl acetate. The organic layer is separated, dried over sodium sulfate and concentrated (5.0 g, colorless liquid, 98%).1H NMR (400 MHz, CDCl3): δ 7.70-7.68 (m, 1H), 7.62 (s, 1H), 7.527.50 (m, 1H), 7.36-7.26 (m, 2H), 4.86 (s, 2H). Step 2: 3-(bromomethyl )benzofuran

[00211] A cold (0°C) solution of benzofuran-3-ylmethanol (5.0 g, 33.7 mmol) in diethyl ether (50 mL) is treated with phosphorus tribromide (1.1 mL, 11.2 mmol) and the reaction mixture is stirred at 0 °C for 30 min. The reaction mixture is then poured onto ice and extracted with ether. The organic layer is dried over sodium sulfate and concentrated (7.1 g, yellow liquid, 100%).

[00212] 1H NMR (400 MHz, CDCl3): δ 7.74-7.71 (m, 2H), 7.53 (s, 1H), 7.39-7.31 (m, 2H) , 4.65 (s, 2H). Step 3: 2-(benzofuran-3-ylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[00213] A solution of 3-(bromomethyl)benzofuran (7.1 g, 33.8 mmol) in degassed 1,4-dioxane (70 mL) is treated with bis(pinacolato)diboron (10.3 g, 40, 5 mmol), potassium carbonate (13.9 g, 101.0 mmol), tetracis(triphenylphosphine)palladium(0) (1.9 g, 1.7 mmol) and the mixture heated at 100 °C for 12 h. The vial contents are cooled to room temperature and filtered through a bed of celite. The filtrate is concentrated and the crude product is purified by flash column chromatography on silica gel, eluting with 2-5% ethyl acetate in petroleum ether to give the title compound (6.1 g, 69%) as yellow oil.

[00214] 1H NMR (400 MHz, CDCl3) δ 7.57-7.52 (m, 2H), 7.46-7.44 (m, 1H), 7.30-7.21 (m, 2H), 2.23 (s, 2H), 1.29 (s, 12H).Step 4: 2-(benzofuran-3-ylmethyl)boronic acid pinanediol ester

[00215] A solution of 2-(benzofuran-3-ylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.1 g, 23.6 mmol) in diethyl ether (60 mL ) is treated with (1S,2S,3R,5S)-(+)-pinanediol (6.0 g, 35.4 mmol). The reaction mixture is stirred at room temperature for 12 h, then the mixture is washed twice with water, then with brine and dried over anhydrous sodium sulfate, then concentrated. The crude product is purified by flash column chromatography on silica gel, eluting with 5% ethyl acetate in petroleum ether, to give the title compound (6.3 g, 82%).

[00216] 1H NMR (400 MHz, CDCl3): δ 7.58-7.56 (m, 1 H), 7.55-7.53 (m, 1 H), 7.46-7.44 (m , 1H), 7.28-7.23 (m, 2H), 4.33 (dd, J = 1.88, 8.76 Hz, 1H), 2.34-2.32 (m, 1H), 2.28 (s, 2H), 2.22-2.21 (m, 1H), 2.08 (t, J = 5.88 Hz, 1H), 1.42 (s , 3H), 1.29 (s, 3H), 1.13 (d, J = 10.92 Hz, 1H), 0.85 (s, 3H). GCMS: m/z: 310.Step 5: [(1S)-1-chloro-2-(benzofuran-3-ylmethyl)boronic acid (+)-pinanediol ester

[00217] To a cooled (-100°C) mixture of dichloromethane (6.3 mL, 60.9 mmol) and anhydrous tetrahydrofuran (36 mL) is added n-butyl lithium (1.6 M in hexanes, 14 .0 mL, (22.3 mmol) over 20 min by stirring for 20 min at -100°C, a solution of (+)-pinanediol ester of 2-(benzofuran-3-ylmethyl)boronic acid (6, 3 g, 20.3 mmol) in anhydrous THF (22 mL) is added over 20 min. Then a solution of zinc chloride (0.5 M in THF, 36.5 mL, 18.2 mmol) is added at -100 °C over 30 min. The mixture is allowed to reach room temperature and is stirred for 18 h and concentrated. To the resulting oil is added diethyl ether and saturated ammonium chloride. The organic layer is dried over sodium sulfate anhydrous sodium and concentrated in vacuo (residue: 7.3 g, 99%).

[00218] 1H NMR (400 MHz, DMSO-d6): δ 7.60-7.57 (m, 2H), 7.49 7.47 (m, 1H), 7.31-7.25 ( m, 2H), 4.36-4.34 (m, 1H), 3.31-3.29 (m, 1H), 3.24-3.22 (m, 1H), 2, 35-2.31 (m, 1H), 2.14-2.12 (m, 1H), 2.06 (t, J = 5.84 Hz, 1H), 1.90-1.86 (m, 2H), 1.42 (s, 3H), 1.04 (d, J = 11.04 Hz, 1H), 0.85 (s, 3H). GCMS: m/z: 358.2. Step 6: [(1R)-1-[bis(trimethylsilyl)amino]-2-(benzofuran-3-ylmethyl)boronic acid (+)-pinanediol ester

[00219] To a cooled solution (-78°C) of (+)-pinanediol ester of [(1S)-1-chloro-2-(benzofuran-3-ylmethyl)boronic acid (7,3), ester of pinanediol (7.3 g, 20.3 mmol) in 40 mL tetrahydrofuran is added lithium bis(trimethylsilyl)amide (1M in THF, 25.5 mL, 25.5 mmol). The mixture is left at room temperature, stirred for 18 h and concentrated to dryness. To the resulting residue is added hexane, and then the precipitated solid is filtered. The filtrate is concentrated to yield the required crude product (6.7 g, 68%).

[00220] 1H NMR (400 MHz, CDCl3): δ 7.60-7.59 (m, 1 H), 7.50-7.45 (m, 2 H), 7.28-7.24 (m , 2H), 4.31 (dd, J = 1.56, 8.70 Hz, 1H), 3.183.14 (m, 1H), 2.92-2.90 (m, 1H), 2.75-2.72 (m, 1H), 2.34-2.30 (m, 1H), 2.15-2.14 (m, 1H), 2.03 (t, J = 5.68 Hz, 1H), 1.88-1.80 (m, 2H), 1.39 (s, 3H), 1.30 (s, 3H), 1.01 (d, J = 10.88 Hz, 1H), 0.84 (s, 3H), 0.09 (s, 18H). Step 7: [(1R)-1-(1R)-1- amino-2-(benzofuran-3-ylmethyl)boronic

[00221] A cooled solution (0°C) of (+)-pinanediol ester of [(1R)-1-[bis(trimethylsilyl)amino]-2-(benzofuran-3-ylmethyl)boronic acid (6.7 g, 13.9 mmol) in diethyl ether (30 mL) is treated with trifluoroacetic acid (3.2 mL, 41.7 mmol) dropwise. The reaction mixture is then stirred at room temperature for 3 h. Precipitation is seen. The reaction mixture is cooled to 0°C and filtered. The filtered solid is washed with cold ether and dried under vacuum to give the title compound (2.3 g, white solid, 36%).

[00222] 1H NMR (400 MHz, DMSO-d6): δ 7.66 (s, 1 H), 7.61-7.60 (m, 1 H), 7.47-7.45 (m, 1 H), 7.29-7.20 (m, 2H), 4.30-4.28 (m, 1H), 3.27-3.16 (m, 3H), 2.25-2 .13 (m, 3H), 1.94 (t, J = 5.56 Hz, 1H), 1.861.81 (m, 2H), 1.25 (s, 6H), 1.01 ( d, J = 8.00 Hz, 1H), 0.75 (s, 3H). Intermediate 3: 2-(7-methyl-benzofuran-3-yl)-1-((1S,2S, 6R) hydrochloride ,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylamine Step 1: 7-Methyl-benzofuran-3-carboxylic acid ethyl ester

[00223] To a solution of 2-hydroxy-3-methyl-benzaldehyde (20.00 g; 139.55 mmol; 1.00 eq.) in dichloromethane (120 mL) is added tetrafluoroboric acid diethyl ether complex (1 .88 mL; 13.96 mmol; 0.10 eq.). To the resulting dark red mixture, ethyldiazoacetate (31.70 mL; 300.04 mmol; 2.15 eq.) in dichloromethane (80 mL) is added dropwise slowly at 25-30 °C (internal temperature) for about 50 min. After 16 h, concentrated H2SO4 is added. The reaction mixture is stirred for 30 min. The reaction mixture is then neutralized with solid NaHCO 3 , filtered through celite and the filtrate concentrated to obtain a crude residue. The residue is purified by column chromatography using 2% ethyl acetate in petroleum ether to give 7-methyl-benzofuran-3-carboxylic acid ethyl ester (19.00 g; 86.83 mmol; 62.2%; yellow oil).

[00224] HPLC (method A): RT 4.98 min (HPLC purity 93%) 1H NMR, 400 MHz, CDCl3: 8.27 (s, 1 H), 7.88-7.90 (m, 1 H), 7.25-7.29 (m, 1H), 7.17 (d, J = 7.32 Hz, 1H), 4.39-4.45 (m, 2H), 2, 55 (s, 3H), 1.44 (t, J = 7.16 Hz, 3H). Step 2: (7-methyl-benzofuran-3-yl)-methanol

[00225] To a solution of 7-methyl-benzofuran-3-carboxylic acid ethyl ester (19.00 g; 86.83 mmol; 1.00 eq.) in dichloromethane (190.00 mL) under nitrogen is added hydride of diisobutyl aluminum (1.0 M in toluene) (191.03 mL; 191.03 mmol; 2.20 eq.) dropwise at -78 °C. The reaction mixture is allowed to come to room temperature and stirred for 1 h. The reaction mixture is cooled with an ice bath and quenched with a 1.5N aqueous HCl solution. The resulting mixture (which had the sticky solid mass suspended in solvent) is diluted with ethyl acetate and filtered through celite. The celite pad is washed thoroughly with ethyl acetate and dichloromethane. The filtrate is evaporated to obtain a crude residue. The solid remaining on the celite bed is taken and triturated with ethyl acetate and filtered. The filtrate is mixed with the crude residue and evaporated. The residue thus obtained is taken up in ethyl acetate and washed with a 1.5 N aqueous HCl solution and brine. The organic layer is dried over anhydrous Na2SO4 and concentrated. The residue obtained is purified by flash column chromatography using 40-50% ethyl acetate in petroleum ether as eluent to obtain (7-methyl-benzofuran-3-yl)-methanol (8.20 g; 48.40 mmol ; 55.7%; light yellow oil).

[00226] HPLC (method A): RT 3.33 min. (HPLC purity 95.7%). 1H NMR, 400 MHz, CDCl3: 7.64 (s, 1H), 7.50-7.52 (m, 1H), 7.17-7.21 (m, 1H), 7.14 ( d, J = 7.20 Hz, 1H), 4.86-4.86 (m, 2H), 2.54 (s, 3H). Step 3: 3-(bromomethyl)-7-methyl-benzofuran

[00227] To an ice-cold solution of (7-methyl-benzofuran-3-yl)-methanol (8.20 g; 48.40 mmol; 1.00 eq.) in diethyl ether (82.00 mL) under nitrogen atmosphere, phosphorus tribromide (1.53 mL; 16.12 mmol; 0.33 eq.) is added dropwise and the reaction mixture is stirred under ice-cold conditions for 30 minutes. The reaction mixture is poured onto ice and extracted with diethyl ether. The organic layer is dried over anhydrous Na 2 SO 4 and concentrated to give 3-Bromomethyl-7-methyl-benzofuran (10.00 g; 44.43 mmol; 91.8%; colorless oil).

[00228] 1H NMR, 400 MHz, CDCl3: 7.71 (s, 1 H), 7.53-7.55 (m, 1 H), 7.21-7.25 (m, 1 H), 7 .16 (d, J = 7.32 Hz, 1H), 4.65 (s, 2H), 2.48 (s, 3H). Step 4: 7-Methyl-3-(4,4,5, 5-tetramethyl-[1,3,2]dioxaborolan-2-ylmethyl)-benzofuran

[00229] To a solution of 3-bromomethyl-7-methyl-benzofuran (10.00 g; 44.43 mmol; 1.00 eq.) in degassed dioxane-1,4 (100.00 mL) are added bis( pinacolate)diboron (13.68 g; 53.31 mmol; 1.20) eq.), dry K2CO3 (18.61 g; 133.28 mmol; 3.00 eq.) and tetracis(triphenylphosphine)palladium ( 0) (2.57 g; 2.22 mmol; 0.05 eq.). The reaction mixture is then heated at 100°C under a nitrogen atmosphere for 16 h. The reaction mixture is diluted with dichloromethane and filtered through celite. The filtrate is concentrated. The residue is dissolved in ethyl acetate and washed with brine. The organic layer is dried over anhydrous Na2SO4 and concentrated. The crude product is purified by column chromatography using 2% ethyl acetate in petroleum ether to obtain 7-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2- ylmethyl)-benzofuran (5.00 g; 18.37 mmol; 41.4%; colorless liquid).

[00230] 1H NMR, 400 MHz, DMSO-d6: 7.65 (s, 1H), 7.33-7.35 (m, 1H), 7.07-7.13 (m, 2H) , 2.43 (s, 3H), 2.13 (s, 2H), 1.16 (s, 12H). Step 5: Trimethyl-4-(7-methyl-benzofuran-3-ylmethyl)-3 ,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane

[00231] To an ice-cold solution of 7-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-ylmethyl)-benzofuran (5.00 g; 18.37 mmol; 1.00 eq.) in Et2O (50.00 mL) under nitrogen atmosphere is added 1S,2S,3R,5S-(+)-2,3-pinane diol (4.69 g; 27 .56 mmol; 1.50 eq.) and the reaction mixture is stirred at room temperature for 14 h. TLC analysis showed completion of the reaction. The reaction mixture is washed with brine. The organic layer is dried over anhydrous Na2SO4 and concentrated. The crude product is purified by flash column chromatography using 2% ethyl acetate in petroleum ether to obtain (1S,2S,6R,8S)-2,9,9-trimethyl-4-(7-methyl-benzofuran- 3-ylmethyl)-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane (5.00 g; 13.00 mmol; 70.7%; colorless liquid). GCMS: m/z: 324.2

[00232] 1H NMR, 400 MHz, CDCl3: 7.53-7.55 (m, 1 H), 7.39-7.40 (m, 1 H), 7.12-7.27 (m, 1 H), 7.06-7.08 (m, 1H), 4.31-4.34 (m, 1H), 2.53 (s, 3H), 2.30-2.37 (m , 1H), 2.26 (s, 2H), 2.18-2.23 (m, 1H), 2.07 (t, J = 5.76 Hz, 1H), 1.84- 1.93 (m, 2H), 1.42 (s, 3H), 1.29 (s, 3H), 1.121.15 (m, 1H), 0.85 (s, 3H).Step 6: (1S,2S,6R,8S)-4-[1-Chloro-2-(7-methyl-benzofuran-3-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa- 4-bora-tricyclo[6.1.1.02.6]decane

[00233] Dichloromethane (2.96 mL; 46.26 mmol; 3.00 eq.) in THF (40 mL) is collected in an RB vial under a positive pressure of nitrogen and cooled to -95°C using the liquid mixture of nitrogen-ethanol. To this n-butyllithium (1.6 M in hexanes) (10.60 mL; 16.96 mmol; 1.10 eq.) is added dropwise through the sides of the RB flask (at an average rate, addition took about 30 min) so that the internal temperature is maintained between -95°C and -100°C. After addition, the reaction mixture is stirred for 20 minutes. During the course of the reaction, a white precipitate forms (the internal temperature is maintained between -95°C and -100°C). Then, a solution of (1S,2S,6R,8S)-2,9,9-trimethyl-4-(7-methyl-benzofuran-3-ylmethyl)-3,5-dioxa-4-bora-tricyclo[ 6.1.1.02.6]decane (5.00 g; 15.42 mmol; 1.00 eq.) in THF (20 mL) is added dropwise down the sides of the RB flask (about 25 min) so that the internal temperature is maintained between -95°C and -100°C. After the addition, immediately zinc chloride (0.5 M in THF) (27.76 mL; 13.88 mmol; 0.90 eq.) is added dropwise through the sides of the RB flask (at an average rate , the addition took about 45 minutes) so that the internal temperature is maintained between -95°C and -100°C. The reaction mixture is then slowly allowed to come to room temperature and stirred at room temperature for 16 h. The reaction mixture is concentrated (bath temperature 30°C). The residue is partitioned between diethyl ether and saturated NH4Cl solution. The organic layer is separated, dried over anhydrous Na 2 SO 4 and concentrated (bath temperature 30°C) to afford (1S,2S,6R,8S)-4-[1-Chloro-2-(7-methyl-benzofuran-3 -yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane (5.90 g; 15.83 mmol; 102.7%; brown liquid). 1H NMR, 400 MHz, CDCl3: 7.57 (s, 1H), 7.42-7.44 (m, 1H), 7.27 (s, 1H), 7.09-7.18 ( m, 1H), 4.34-4.36 (m, 1H), 3.74-3.76 (m, 1H), 3.283.30 (m, 1H), 3.20-3, 22 (m, 1H), 2.52 (s, 3H), 2.32-2.34 (m, 1H), 2.07 (t, J = 5.88 Hz, 1H), 1 .85-1.91 (m, 2H), 1.42 (s, 3H), 1.29 (s, 3H), 1.06-1.09 (m, 1H), 0.85 (s, 3H). Step 7: ((1S,2S,6R,8S)-4-[1-(1,1,1,3,3,3-hexamethyl-disilazan-2-yl)-2-( 7-methyl-benzofuran-3-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane

[00234] A solution of (1S,2S,6R,8S)-4-[1-Chloro-2-(7-methyl-benzofuran-3-yl)-ethyl]-2,9,9-trimethyl- 3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane (5.90 g; 15.83 mmol; 1.00 eq.) in THF (40.00 mL) under a positive pressure of atmosphere of nitrogen is cooled to -78°C. To this is added a solution of lithium (bistrimethylsilyl)amide (1.0 M in THF) (17.41 mL; 17.41 mmol; 1.10 eq.) dropwise over a period of 30 minutes. The reaction mixture is allowed to come to room temperature and stirred at room temperature for 18 h. The reaction mixture is evaporated at 30°C. The residue is triturated with n-hexane and the solid formed is filtered. The filtrate is concentrated at 30°C to obtain (1S,2S,6R, 8S)-4-[1-(1,1,1,3,3,3-hexamethyl-disilazan-2-yl)-2-( 7-Methyl-benzofuran-3-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane (6.00 g; 12.06 mmol; 76.2%; dark brown oil).

[00235] 1H NMR, 400 MHz, CDCl3: 7.50 (s, 1H), 7.41-7.43 (m, 1H), 7.12-7.16 (m, 1H), 7 .06-7.08 (m, 1H), 4.29-4.32 (m, 1H), 3.17-3.09 (m, 1H), 2.70-2.89 (m , 1H), 2.52-2.70 (m, 1H), 2.52 (s, 3H), 2.282.31 (m, 1H), 2.14-2.14 (m, 1H). H), 2.03 (t, J = 5.68 Hz, 1 H), 1.78-1.89 (m, 2 H), 1.39 (s, 3 H), 1.31 (s, 3H), 1.01-1.04 (m, 1H), 0.90-0.92 (m, 2H), 0.88 (s, 3H), 0.12 (s, 18H) .Step 8: 2-(7-methyl-benzofuran-3-yl)-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricycle [ 6.1.1.02.6] dec-4-yl)-ethylamine hydrochloride

[00236] A stirred solution of (1S,2S,6R,8S)-4-[1-(1,1,1,3,3,3-hexamethyl-disilazan-2-yl)-2-(7-methyl -benzofuran-3-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane (6.00 g; 12.06 mmol; 1 .00 eq.) in diethyl ether (60.00 mL) under a nitrogen atmosphere is cooled to -10°C. To this, 2M solution of hydrochloric acid in diethyl ether (15.07 mL; 30.14 mmol; 2.50 eq.) is added dropwise. The reaction mixture is stirred at room temperature for 2 h. The reaction mixture is evaporated at 30°C. To the residue, diethyl ether (20 mL) is added, and the formed solid is filtered, washed with cold diethyl ether and dried under vacuum to obtain 2-(7-methyl-benzofuran-3-yl)-1-((1S, 2S, 6R, 8S)-2,9,9-Trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]dec-4-yl)-ethylamine hydrochloride (3.50 g; 8 .98 mmol; 74.5%; orange-brown solid).

[00237] 1H NMR, 400 MHz, DMSO-d6: 8.09 (s, 3H), 7.83 (s, 1H), 7.52-7.53 (m, 1H), 7.12 -7.19 (m, 2H), 4.39 (dd, J = 1.84, 8.62 Hz, 1H), 3.07-3.13 (m, 1H), 3.03- 3.07 (m, 2H), 2.43 (s, 4H), 2.28-2.30 (m, 1H), 2.07-2.08 (m, 1H), 1, 92 (t, J = 5.68 Hz, 1 H), 1.82-1.84 (m, 1 H), 1.71-1.75 (m, 1 H), 1.19-1.25 (m, 8H), 1.00-1.08 (m, 1H), 0.78 (s, 3H). Intermediate 4: 2-(7-Chloro-benzofuran-3-yl)-1-((1S,2S, 6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.02.6]dec-4-yl)ethylamine Step 1: 7-Chloro-benzofuran-3-carboxylic acid ethyl ester:

[00238] To a solution of 3-chloro-2-hydroxy-benzaldehyde (25.00 g; 156.48 mmol; 1.00 eq.) in dichloromethane (250 mL), tetrafluoroboric acid diethyl ether complex ( 2.11 mL; 15.65 mmol; 0.10 eq.). To the resulting dark red mixture is added ethyldiazoacetate (35.55 mL; 336.44 mmol; 2.15 eq.) taken in dichloromethane (50 mL) dropwise slowly at 25-30°C (internal temperature) for about 50 min. After 16 h, concentrated H2SO4 is added. The reaction mixture is stirred for 15 minutes. The reaction mixture is then neutralized with solid NaHCO 3 , filtered through celite and the filtrate concentrated to obtain a crude residue. The residue is purified by column chromatography using 2% ethyl acetate in petroleum ether to afford 7-chloro-benzofuran-3-carboxylic acid ethyl ester 2 (18.20 g; 81.02 mmol; 51.8% ; colorless liquid).

[00239] 1H NMR, 400 MHz, DMSO-d6: 8.88 (s, 1H), 7.95-7.93 (m, 1H), 7.57-7.55 (m, 1H), 7.42 (t, J = 7.8 Hz, 1H), 4.38-4.33 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H). Step 2: (7-Chloro-benzofuran-3-yl)-methanol:

[00240] To a stirred solution of 7-chloro-benzofuran-3-carboxylic acid ethyl ester (450 g; 2.0089 mol; 1.00 eq.) in DCM (4500 mL) at -78°C is added hydride of 1.0 M diisobutyl aluminum in toluene (4017 mL; 4.0178 mol; 2.20 eq.). The reaction mixture is then slowly allowed to come to room temperature and stirred at room temperature for 2 h. Upon completion of the reaction as confirmed by TLC, the reaction mixture is quenched with 1.5N HCL (500 mL), passed through celite and washed with DCM (2000 mL). The filtrate is washed with brine solution (1 x 2000 mL). The organic layer is separated, dried over Na2SO4, filtered and concentrated in vacuo. The crude product is subjected to column chromatography and eluted with 15% ethyl acetate in petroleum ether to afford (7-Chloro-benzofuran-3-yl)-methanol 3 (365 g; 2.0054 mol; 99.8 %; white solid foam).

[00241] 1H NMR, 400 MHz, DMSO-d6: 7.99 (s, 1 H), 7.66 (dd, J = 1.0, 7.8 Hz, 1 H), 7.41 (dd, J = 0.8, 7.8 Hz, 1 H), 7.26 (t, J = 7.8 Hz, 1 H), 5.24 (t, J = 5.6 Hz, 1 H), 4 .63-4.62 (m, 2H). Step 3: 3-Bromomethyl-7-chloro-benzofuran:

[00242] To an ice-cooled solution of (7-chloro-benzofuran-3-yl)-methanol (365 g; 2.0054 mol; 1.00 eq.) in diethyl ether (3650 mL) is added phosphorus tribromide (62.2 mL; 0.6618 mol; 0.33 eq.) dropwise under a nitrogen atmosphere. The reaction mixture is stirred under cooling in an ice bath for 30 minutes. Subsequently, the reaction mixture is poured onto ice and extracted with diethyl ether. The organic layer is dried over anhydrous Na 2 SO 4 , filtered and concentrated to give 3-bromomethyl-7-chloro-benzofuran (480 g; 1.9591 mol; 97.71%; white solid).

[00243] 1H NMR, 400 MHz, DMSO-d6: 8.29 (s, 1 H), 7.72 (dd, J =1.0, 7.8 Hz, 1 H), 7.49 (dd, J = 0.8, 7.8 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 4.90 (s, 2H). Step 4: 7-Chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-ylmethyl)-benzofuran:

[00244] To a solution of 3-bromomethyl-7-chloro-benzofuran (480 g; 1.9591 mol; 1.00 eq.) in degassed dioxane-1,4-1,4 (4800 mL) are added bis( pinacolate)diboron (596.9 g; 2.3510 mol; 1.20 eq.), dry potassium acetate (576.8 g; 5.877 mol; 3.00 eq.) and [1,1'-bis(diphenylphosphine) )ferrocene]dichloropalladium(II), complexed with dichloromethane (70.33 g; 0.0979 mol; 0.05 eq.). The reaction mixture is then heated at 100°C under a nitrogen atmosphere overnight. The reaction mixture is diluted with dichloromethane and passed through celite. The filtrate is concentrated. The residue is dissolved in ethyl acetate and washed with brine (1000 mL x 1). The organic layer is dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material is purified by column chromatography using 2% ethyl acetate in petroleum ether to obtain 7-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2- ylmethyl)-benzofuran (480 g; 1.6438 mol; 83.9%; yellow semi-solid).

[00245] GCMS: m/z: 292 (Column: DB-5 ms (15 m x 0.25 mm x 0.25 μm); Carrier gas: helium, flow rate: 2.0 mL/min).

[00246] 1H NMR, 400 MHz, DMSO-d6: 7.79 (s, 1 H), 7.52 (dd, J =1.0, 7.8 Hz, 1 H), 7.38 (dd, J = 0.8, 7.8 Hz, 1H), 7.27-7.23 (m, 1H), 2.17 (s, 2H), 1.18 (s, 12H). Step 5 : (1S,2S,6R,8S)-4-(7-Chloro-benzofuran-3-yl-methyl)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6,1 ,1,02,6]decane:

[00247] To an ice-cold solution of 7-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-ylmethyl)-benzofuran (480 g; 1, 6438 mol; 1.00 eq.) in diethyl ether (5000 mL) and under nitrogen atmosphere is added 1S,2S,3R,5S-(+)-2,3-pinane diol (335.7 g; 1.9726 mol; 1.20 eq.). The reaction mixture is stirred at room temperature for 16 h. The reaction mixture is washed with water (2000 mL x 1) and brine (1500 mL x 1). The organic layer is dried over anhydrous Na2SO4, filtered and concentrated. The crude material is purified by flash chromatography using 1% ethyl acetate in petroleum ether to provide (1S,2S,6R,8S)-4-(7-chloro-benzofuran-3-yl-methyl)-2,9 ,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane (520 g; 1.510 mol; 91.9%; pale yellow semi-solid). GCMS: m/z: 344 (Column: HP-5 MS (12 m x 0.20 D mm x 0.33 μm); Carrier gas: helium, flow rate: 2.0 mL/min)

[00248] 1H NMR, 400 MHz, DMSO-d6: 7.80 (s, 1 H), 7.54 (dd, J = 0.9, 7.8 Hz, 1 H), 7.38 (dd, J = 0.7, 7.8 Hz, 1 H), 7.24 (t, J = 7.8 Hz, 1 H), 4.33 (t, J = 6.9 Hz, 1 H), 2 .29-2.24 (m, 3H), 2.14-2.10 (m, 1H), 1.93 (t, J = 5.4 Hz, 1H), 1.84 -1, 81 (m, 1H), 1.70-1.65 (m, 1H), 1.31 (s, 3H), 1.21 (s, 3H), 0.98 (d, J = 10.72 Hz, 1H), 0.78 (s, 3H). Step 6: (1S,2S,6R,8S)-4-[(S)-1-Chloro-2-(7-chloro-benzofuran) -3-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane:

[00249] Dichloromethane (95.7 mL; 1.499 mol; 3.00 eq.) in THF (1200 mL) is collected in an RB vial under a positive pressure of nitrogen and cooled to -95°C using the liquid mixture of nitrogen-ethanol. To this, n-butyllithium (1.6 M in THF) (343.6 mL; 0.549 mol; 1.10 eq.) is added dropwise through the side neck of the RB flask (at an average rate, addition took about 45 min) so that the internal temperature is maintained between -95°C and -100°C. After addition, the reaction mixture is stirred for 30 minutes. During the course of the reaction, a white precipitate forms (the internal temperature is maintained between -95°C and -100°C). Then, a solution of (1S,2S,6R,8S)-4-(7-chloro-benzofuran-3-ylmethyl)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1 .1.02.6] decane (172 g; 0.4999 mol; 1.00 eq.) in THF (500 mL) is added dropwise through the side neck of the RB flask (about 25 min) so that the temperature internal temperature is again maintained between -95°C and -100°C. After addition is complete, zinc chloride (0.5 M in THF) (1599.6 mL; 0.7998 mol; 1.6 eq.) is immediately added dropwise through the side neck of the RB flask ( at an average rate, the addition takes about 40 min.) so that the internal temperature is maintained between -95°C and -100°C. The reaction mixture is then slowly allowed to reach -5°C and stirred at -5°C for 1.5 h. The reaction mixture is quenched by adding saturated NH4Cl solution (500 mL). The reaction mixture is concentrated in vacuo (bath temperature 30°C). The residue is partitioned between diethyl ether and saturated NH4Cl solution. The organic layer is separated, dried over anhydrous Na 2 SO 4 and concentrated (bath temperature 30°C) to afford (1S,2S,6R,8S)-4-[(S)-1-chloro-2-(7-chloro -benzofuran-3-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane (205 g; 0.5214 mol; 104.5 %; orange oil).

[00250] GCMS: m/z: 392 (Column: ZB-1MS (10 m x 0.101D mm x 0.1 μm); Carrier gas: helium, flow rate: 2.0 mL/min)

[00251] 1H NMR, 400 MHz, CDCl3: 7.64 (s, 1 H), 7.50 (d, J = 8.00 Hz, 1 H), 7.33-7.31 (m, 1 H ), 7.23-7.21 (m, 1H), 4.36-4.34 (m, 1H), 3.29-3.27 (m, 1H), 3.22-3, 20 (m, 1H), 2.34-2.32 (m, 1H), 2.15-2.14 (m, 1H), 2.06 (t, J = 5.60 Hz, 1H ) ), 1.91-1.83 (m, 7 H), 1.36 (s, 3 H), 1.29 (s, 3 H), 1.05-1.02 (m, 1 H) , 0.85 (s, 3H). Step 7: (1S,2S,6R,8S)-4-[(R)-2-(7-Chloro-benzofuran-3-yl)-1-(1,1,1,3,3,3-hexamethyl -disilazan-2-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane:

[00252] A solution of (1S,2S,6R,8S)-4-[(S)-1-chloro-2-(7-chloro-benzofuran-3-yl)-ethyl]-2,9,9- trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6] decane (205 g; 0.5214 mol; 1.00 eq.) in THF (2050 mL) under a positive pressure of nitrogen atmosphere is cooled to -78°C. To this, a solution of lithium (bis-trimethylsilyl)amide (1.0 M in THF) (625 mL; 0.6257 mol; 1.20 eq.) is added dropwise over a period of of 30 minutes. The reaction mixture is allowed to come to room temperature and stirred at room temperature for 18 h. The solvent of the reaction mixture is evaporated at 30°C. The residue is triturated with hexane and the solid formed is filtered. The filtrate is allowed to stand for some time under vacuum and any solids, if formed, are filtered again. The filtrate is concentrated at 30°C to obtain (1S,2S, 6R,8S)-4-[(R)-2-(7-chloro-benzofuran-3-yl)-1-(1,1,1, 3,3,3-hexamethyl-disilazan-2-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane (180 g; 0 .3481 mol; 66.7%; orange oil).1H NMR, 400 MHz, CDCl3: 7.63 (s, 1H), 7.51-7.49 (m, 1H), 7.29-7 .27 (m, 1H), 7.19-7.15 (m, 1H), 4.32-4.29 (m, 1H), 3.63-3.61 (m, 1H) , 3.14-3.12 (m, 1H), 2.87-2.85 (m, 1H), 2.26-2.24 (m, 1H), 2.14-2.12 (m, 1H), 1.88-1.86 (m, 1H), 1.88-1.76 (m, 2H), 1.33 (s, 3H), 1.30 (s , 3H), 1.02-0.99 (m, 1H), 0.85 (s, 3H), 0.07 (s, 18H). Step 8: (R)-2-( hydrochloride 7-chloro-benzofuran-3-yl)-1-((1S,2S, 6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6] dec-4-yl)-ethylamine:

[00253] A stirred solution of (1S,2S,6R,8S)-4-[(R)-2-(7-chloro-benzofuran-3-yl)-1-(1,1,1,3,3 ,3-hexamethyl-disilazan-2-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane (180 g; 0.348 mol) in diethyl ether (1800 mL) under a nitrogen atmosphere is cooled to -10°C. To this solution, hydrochloric acid in diethyl ether (2.0 M concentration; 435.2 mL; 0.870 mol; 2.50 eq.) is added dropwise. The reaction mixture is stirred at room temperature for 2 h (solid precipitation is observed during the course of the reaction). The reaction mixture is evaporated to dryness, and the solid obtained is triturated with diethyl ether (500 ml) and subsequently filtered. The filter cake is washed with diethyl ether (3 x 300 mL) and dried under vacuum to provide (R)-2-(7-chloro-benzofuran-3-yl)-1-((1S,2S,6R, 8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]dec-4-yl)-ethylamine (81.5 g; 0.1992 mol; 57. 2%; off-white solid).

[00254] 1H NMR, 400 MHz, CDCl3: 8.09 (s, 3 H), 7.97 (s, 1 H), 7.73 (dd, J = 1.52 Hz, 7.76 Hz, 1 H), 7.44 (d, J = 7.76 Hz, 1 H), 7.31 (d, J = 7.80 Hz, 1 H), 4.42-4.40 (m, 1 H) , 3.16-3.07 (m, 3H), 2.32-2.27 (m, 1H), 2.10-2.04 (m, 1H), 1.93 (t, J = 5.56 Hz, 1 H), 1.83-1.71 (m, 2 H), 1.27 (s, 3 H), 1.25 (s, 3 H), 1.08-1, 02 (m, 1H), 0.79 (s, 3H). Intermediate 5: (R)-2-(2,3-Dihydro-benzofuran-3-yl)-1-((1S, 2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylamine Step 1: (1S,2S,6R ,8S)-4-(2,3-Dihydro-benzofuran-3-ylmethyl)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane

[00255] To a solution of (1S,2S,6R,8S)-4-Benzofuran-3-ylmethyl-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6 ]decane (5.00 g; 10.72 mmol; 1.00 eq.) in methanol (100.00 mL) in a small clave is added palladium on carbon (10% by weight) (2.28 g; 2. 14 mmol; 0.20 eq.). The contents are hydrogenated under a H2 pressure of 5 kg/cm2 for 3 h. TLC analysis revealed complete conversion. The reaction mixture is filtered through celite and the filtrate is evaporated. The crude oil is purified by Biotage-isolera column chromatography (C18 column; mobile phase: ACN/H2O; 50:50 isocratic) to obtain a (1S,2S,6R,8S)-4-(2,3-di- hydro-benzofuran-3-ylmethyl)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane (4.10 g; 13.13 mmol; 122.5 %; pale yellow liquid). GCMS: m/z: 312.3. Step 2: (1S,2S,6R,8S)-4-[1-Chloro-2-(7-methyl-benzofuran-3-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa -4-bora-tricyclo[6.1.1.02.6]decane

[00256] Dichloromethane (2.46 mL; 38.44 mmol; 3.00 eq.) in THF (40.00 mL) is collected in an RB flask under positive nitrogen pressure and cooled to -95°C using the liquid mixture of nitrogen-ethanol. To this, n-butyllithium (1.6 M in THF) (8.81 mL; 14.09 mmol; 1.10 eq.) is added dropwise down the sides of the RB flask (at an average rate, addition took about 20 min). So that the internal temperature is maintained between -95°C and -100°C. After addition, the reaction mixture is stirred for 25 minutes. During the course of the reaction, a white precipitate forms (the internal temperature is maintained between -95°C and -100°C). Then, a solution of (1S,2S,6R,8S)-4-(2,3-Dihydro-benzofuran-3-ylmethyl)-2,9,9-trimethyl-3,5-dioxa-4 -bora-tricyclo[6.1.1.02.6]decane (4.00 g; 12.81 mmol; 1.00 eq.) in THF (15.00 mL) is added dropwise down the sides of the RB flask (about 25 min) so that the internal temperature is maintained between -95°C and -100°C. After the addition, immediately zinc chloride (0.5 M in THF) (25.62 mL; 12.81 mmol; 1.00 eq.) is added dropwise through the sides of the RB flask (at an average rate , the addition took about 25 min) so that the internal temperature is maintained between -95°C and -100°C. The reaction mixture is then slowly allowed to come to room temperature and stirred at room temperature for 18 h. The reaction mixture is concentrated (bath temperature 30°C). The residue is partitioned between diethyl ether and saturated NH4Cl solution. The organic layer is dried over anhydrous Na2SO4 and concentrated (bath temperature 30°C) to give (1S,2S,6R,8S)-4-[(S)-1-Chloro-2-(2,3-di- hydro-benzofuran-3-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane (4.60 g; 12.75 mmol; 99.5%; yellow oil).

[00257] 1H NMR, 400 MHz, CDCl3: 7.29 (d, J = 6.72 Hz, 1 H), 7.21 7.10 (m, 1 H), 6.90-6.77 (m , 2H), 4.68-4.65 (m, 1H), 4.32-4.29 (m, 2H), 3.65-3.60 (m, 1H), 2.40 -2.08 (m, 4H), 1.94-1.85 (m, 2H), 1.42 (s, 3H), 1.33 (s, 3H), 1.22 (s , 3H), 1.17-1.15 (m, 1H), 0.86 (s, 3H). Step 3: (1S,2S,6R,8S)-4-[(R)-2- (2,3-Dihydro-benzofuran-3-yl)-1-(1,1,1,3,3,3-hexamethyl-disilazan-2-yl)-ethyl]-2,9,9-trimethyl -3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane

[00258] A solution of (1S,2S,6R,8S)-4-[(S)-1-Chloro-2-(2,3-dihydro-benzofuran-3-yl)-ethyl]-2, 9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane (4.60 g; 12.75 mmol; 1.00 eq.) in THF (45.00 mL) under a positive pressure of nitrogen atmosphere is cooled to -78°C. To this, a solution of lithium (bistrimethylsilyl)amide (1.0 M in THF) (16.58 mL; 16.58 mmol; 1.30 eq.) is added dropwise over a period of 30 minutes. The reaction mixture is allowed to come to room temperature and stirred at room temperature for 18 h. The reaction mixture is evaporated at 30°C. The residue is triturated with hexane and the solid formed is filtered. The filtrate is allowed to stand for some time under vacuum and any solids, if formed, are filtered again. The filtrate is concentrated at 30°C to obtain (1S,2S,6R,8S)-4-[(R)-2-(2,3-Dihydro-benzofuran-3-yl)-1-(1, 1,1,3,3,3-hexamethyl-disilazan-2-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane ( 3.77 g; 7.76 mmol; 60.9%; yellow oil).

[00259] 1H NMR, 400 MHz, CDCl3: 7.22-7.10 (m, 2 H), 6.90-6.79 (m, 2 H), 4.62-4.59 (m, 1 H), 4.33-4.27 (m, 1H), 2.34-2.20 (m, 2H), 2.072.05 (m, 1H), 1.94-1.84 (m , 2H), 1.40 (s, 3H), 1.30 (s, 3H), 1.15-1.13 (m, 1H), 0.86 (s, 3H), 0 ,10 (s, 18H). Step 4: (R)-2-(2,3-Dihydro-benzofuran-3-yl)-1-((1S, 2S,6R,8S)-2, Hydrochloride, 9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]dec-4-yl)-ethylamine

[00260] A stirred solution of (1S,2S,6R,8S)-4-[(R)-2-(2,3-Dihydro-benzofuran-3-yl)-1-(1,1,1 ,3,3,3-hexamethyl-disilazan-2-yl)-ethyl]-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]decane (3.77 g; 7.76 mmol; 1.00 eq.) in Et2O (35.00 mL) under a nitrogen atmosphere is cooled to -10°C. To this, 2N HCl in diethyl ether (9.70 mL; 19.41 mmol; 2.50 eq.) is added dropwise. The reaction mixture is stirred at room temperature for 2 h. The reaction mixture is evaporated to dryness under reduced pressure to obtain a solid. The formed solid is triturated with diethyl ether, filtered, washed with diethyl ether and dried under vacuum to obtain (R)-2-(2,3-Dihydro-benzofuran-3-yl)-1-((1S ,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylamine (2.30 g; 5. 25 mm; yield 67.7%; pale brown solid). The analysis showed the presence of isomers (~ 65.50 % + 20.75 %) at the indicated position (*).LCMS: 4.73 min, 86.25 % (max), 80.47 % (220 nm), 342.20 (M+1).

[00261] 1H NMR, 400 MHz, DMSO-d6: 8.11 (s, 3 H), 7.23-7.19 (m, 1 H), 7.13-7.10 (m, 1 H) , 6.85 (t, J = 7.40 Hz, 1 H), 6.77 (d, J = 8.04 Hz, 1 H), 4.61-4.57 (m, 1 H), 4 .48-4.45 (m, 1H), 4.25-4.22 (m, 1H), 3.683.62 (m, 1H), 2.90-2.85 (m, 1H) , 2.34-2.32 (m, 1H), 2.19-2.17 (m, 1H), 2.02-1.99 (m, 2H), 1.89-1.77 (m, 3H), 1.39 (s, 3H), 1.25 (s, 3H), 1.17-1.14 (m, 1H), 0.82 (s, 3H).

[00262] By similar sequences described for intermediates 2-4, other examples of the following portion can be prepared

[00263] such as in particular compounds in which the group Y denotes one of the following groups: Intermediate Acid 1: (1S,2R,4R)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid Step 1: (1S,2R,4R)-7 acid (R)-1-phenyl ethyl ester -oxa-bicyclo[2.2.1]heptane-2-carboxylic acid

[00264] To a solution of 7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid (4.680 g; 31.276 mmol, racemic) in dry dichloromethane (max. 0.005% H2O) SeccoSolv® (100 mL) (R)-1-phenyl-ethanol (4.623 mL; 37.531 mmol), 4-(dimethylamino)pyridine for synthesis (DMAP) (3.821 g; 31.276 mmol) and (3-dimethylamino- propyl)-ethyl-carbodiimide (EDCI) (6.730 g; 34.404 mmol) under stirring at 0°C. Thereafter, the clear reaction solution is stirred overnight at room temperature. After completion of ester formation, the reaction is quenched by addition of sat. NH4Cl(aq) solution. Then the mixture is extracted twice with CH2Cl2. The organic layer is washed three times with sat. NaHCO 3 (aq) solution. and brine, dried over Na2SO4, filtered and evaporated to dryness. The crude product is purified by flash chromatography (silica gel; n-heptane/ethyl acetate 0-30% ethyl acetate) to obtain 7.496 g (30.43 mmol, 97.3%) of a colorless oil (HPLC : pure mixture of diastereomers 100 %).

[00265] The mixture of diastereomers is separated by preparative chiral HPLC (Chiralcel OD-H; n-heptane/2-propanol 95:5; 220 nm) to obtain (R)-1-phenyl-ethyl ester (1R, 2S,4S)-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid (3.22 g, colorless oil, 41.8% yield, 100% chiral HPLC) and (R)-1-phenyl- (1S,2R,4R)-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (3.14 g, oil, 40.7% yield on 100% chiral HPLC) Step 2 : (1S,2R,4R)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid

[00266] To a solution of (R)-1-phenyl-ethyl ester of (1S, 2R, 4R)-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid (46.74 g; 182. 75 mmol; 1.00 eq.) in THF (233.70 mL), palladium on carbon (10% w/w) (1.94 g; 1.83 mmol; 0.01 eq.) is added. The content is hydrogenated under an atmosphere of H2 at 50°C and 5 bar pressure for 16 h. Upon completion of the hydrogenation, the reaction mixture is filtered through celite, the filtrate is evaporated to dryness and taken up in pentane. The organic layer is extracted three times with water. Subsequently, the aqueous layer is lyophilized to obtain (1S,2R,4R)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (22.62 g; 159.09 mmol; yield 87.1%) as a colorless solid.

[00267] TLC: Chloroform/methanol (9.5/0.5) Rf 0.5. 1H-NMR 400 MHz, DMSO-d6: 12.16 (s, 1 H), 4.66 (d, J = 4.4 Hz, 1 H), 4.54 (t, J = 4.4 Hz, 1H), 2.57 (d, J = 35.2 Hz, 1H), 1.91-1.86 (m, 1H), 1.65-1.37 (m, 4H), 1 .34-1.33 (m, 1H). Optical rotation [α]20 D = +31.9°; αD20 = +0.0644° (ethanol, 20.16 mg/10 mL). Intermediate Acid 2: (1R,2S,4S)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid

[00268] To a solution of (R)-1-phenyl-ethyl ester of (1R, 2S, 4S)-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid (4.52 g; 17, 98 mmol; 1.00 eq.) in THF (22.60 mL) palladium on carbon (10% w/w) (0.19 g; 0.18 mmol; 0.01 eq.) is added. The contents are hydrogenated under an atmosphere of H2 at 50°C for 12 h. TLC analysis revealed that the start is complete. The reaction mixture is filtered through Celite and the filtrate is evaporated to obtain (1R, 2S, 4S)-7-Oxa-bicyclo[2.2.1]heptane-2-carboxylic acid (2.10 g; 14.77 mmol ; 82.1%; off-white solid)

[00269] 1H-NMR 400 MHz, DMSO-d6: 12.16 (s, 1 H), 4.66 (d, J =4.4 Hz, 1 H), 4.54 (t, J = 4, 4 Hz, 1 H), 2.57 (d, J = 35.2 Hz, 1 H), 1.911.86 (m, 1 H), 1.65-1.37 (m, 4 H), 1, 34-1.33 (m, 1H). Acid Intermediate 3: (1S,8R)-8-Methyl-11-oxa-tricyclo[6.2.1.02.7]undeca-2,4,6 acid (salt) -triene-1-carboxylic acid Step 1: 8-Methyl-11-oxa-tricyclo[6.2.1.02.7]undeca-2,4,6,9-tetraene-1-carboxylic acid methyl ester

[00270] Isopentyl nitrite (3.64 mL; 27.12 mmol) is added to a solution of 3.72 g of anthranilic acid (27.12 mmol) and trifluoroacetic acid (0.26 mL; 3.39 mmol) in 45 mL of dry THF at 0°C. The resulting solution is stirred vigorously for a few minutes at 0°C and then warmed to room temperature. After stirring for 1 h at room temperature, the color of the suspension turned yellow. The brown solid is filtered and washed with dry THF before transferring it to a flask containing a solution of 5-methyl-furan-2-carboxylic acid methyl ester (2.00 g; 13.56 mmol) in ethylene glycol-ether dimethyl for synthesis (45.00 mL). The resulting mixture is then gradually heated to 100°C until decomposition is complete and stirred for a further hour at 100°C. After evaporation of the solvent, the reaction mixture is purified by flash chromatography (silica gel; gradient EE/heptane; 0-25% EE) to obtain 8-methyl-11-oxa-tricyclo[6.2.1.02, 7]Undeca-2,4,6,9-tetraene-1-carboxylic acid (1.82 g; 53.7%; yellow gum) as a 1:1 mixture of stereoisomers.

[00271] LCMS, method A: (M + H) 217.0; Tr 2.03 min. Step 2: (1S,8R)-8-Methyl-11-oxa-tricyclo[6.2.1.02,7]undeca-2,4,6-triene-1-carboxylic acid methyl ester and (1R, 8S)-8-methyl-11-oxa-tricyclo[6.2.1.02.7]undeca-2,4,6-triene-1-carboxylic acid

[00272] 8-Methyl-11-oxa-tricyclo[6.2.1.02.7] undeca-2,4,6,9-tetraene-1-carboxylic acid methyl ester (1.82 g, 7.28 mmol) in 18 mL of EE is hydrogenated at room temperature and normal pressure using 500 mg of Pd/C (54% water) until the reaction is complete. The reaction mixture is filtered and the filtrate is concentrated. The residual sticky oil (mixture of stereoisomers) is separated using chiral preparative SFC (Chiral Cel OD-H; CO 2 /2-propanol 58.5: 1.5; 220 nm) to obtain (1S, 8R)-acid methyl ester 8-Methyl-11-oxa-tricyclo[6.2.1.02.7]undeca-2,4,6-triene-1-carboxylic acid (439 mg, 25.3% yield) and (1R, 8S)-acid methyl ester 8-Methyl-11-oxa-tricyclo[6.2.1.02.7]undeca-2,4,6-triene-1-carboxylic acid (449 mg, 25.9% yield), both as colorless oils.

[00273] LCMS, Method A: (M + H) not detected; Rt 2.09 min (same for both compounds). Step 3: Lithium (salt) of (1S,8R)-8-methyl-11-oxa-tricyclo[6.2.1.02.7]undeca-2,4,6-triene-1-carboxylic acid

[00274] (1S, 8R)-8-Methyl-11-oxa-tricyclo[6.2.1.02.7]undeca-2,4,6-triene-1-carboxylic acid methyl ester (0.439 g; 1.84 mmol ) is absorbed in 5 mL of deionized water and 2.5 mL of THF. LiOH (44 mg, 1.84 mmol) is added, the mixture is stirred under argon at room temperature for 1 h and evaporated to yield the title compound, which is used without further purification.

[00275] LCMS, Method A: (M-Li+H-18) 187; Rt 1.71 min. Acid Intermediate 4: Lithium (1R,8S)-8-methyl-11-oxa-tricyclo[6.2.1.02.7]undeca-2,4,6-triene-1-carboxylic acid

[00276] (1R, 8S)-8-Methyl-11-oxa-tricyclo[6.2.1.02,7]undeca-2,4,6-triene-1-carboxylic acid methyl ester (purity 91%; 0.449 g; 1.88 mmol) is captured in 5 mL of deionized water and 2.5 mL of THF. LiOH (45 mg, 1.88 mmol) is added, the mixture is stirred under argon at room temperature for 1 h and evaporated to give the title compound.

[00277] LCMS, method A: (M-Li+ H-18) 187; Rt 1.71 min. Acid intermediate 5: (1S,8R)-11-oxa-tricyclo[6.2.1.02,7]undeca-2,4,6-triene-9-carboxylic acid Step 1: Furan-3-carboxylic acid (R)-1-Phenyl-ethyl ester

[00278] To a solution of 3-furancarboxylic acid (2.00 g; 17.84 mmol) in 40 mL of dry dichloromethane is added (R)-1-phenylethanol (2.64 mL; 21.41 mmol) , 4-dimethylamino-pyridine (2.18 g; 17.85 mmol) and (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (3.84 g; 19.63 mmol) under argon atmosphere at 0°C . The clear reaction solution is stirred without further cooling for 3 h. The reaction solution is quenched with sat. and extracted with dichloromethane. The organic layer is washed 3x with sat. NaHCO 3 solution. and brine, dried over Na2SO4 and filtered. After evaporation of the solvent, the reaction mixture is purified by flash chromatography (silica gel; gradient EE/heptane; 0-30% EE) to obtain furan-3-carboxylic acid (R)-1-phenyl-ethyl ester (3.55 g; 90% yield; yellow oil). LCMS, method A: (M + H) not detected; Rt 2.46 min.Step 2: (1R,8R)-11-oxa-tricyclo[6.2.1.02.7]undeca-2,4,6,9-tetraene acid (R)-1-phenyl-ethyl ester (1S,8S)-11-oxa-tricyclo[6.2.1.02.7]undeca-2,4,6,9-tetraene-9-carboxylic acid -9-carboxylic and (R)-1-phenyl-ethyl ester

[00279] Isopentyl nitrite (1.91 mL; 14.18 mmol) is added to a solution of anthranilic acid (1.94 g, 14.18 mmol) and trifluoroacetic acid (0.137 mL; 1.77 mmol) in 22 mL THF dried at 0°C. The resulting solution is stirred vigorously for a few minutes at 0°C and then warmed to room temperature. After stirring for 1 h at room temperature, the color of the suspension turned yellow. The liquid is decanted off and the remaining brown solid is washed with dry THF before transferring it to a flask containing a solution of (R)-1-phenyl-ethyl ester of furan-3-carboxylic acid (1.60 g ;7.09 mmol) in ethylene glycol dimethyl ether for synthesis (22 mL). The resulting mixture is then gradually heated to 100°C until decomposition is complete and stirred for a further hour at 100°C. After evaporation of the solvent, the reaction mixture is purified by flash chromatography (silica gel; EE/heptane gradient; 0-35% EE) to obtain 677mg of (R)-1-phenyl-ethyl ester of 11- oxa-tricyclo[6.2.1.02.7]undeca-2,4,6,9-tetraene-9-carboxylic oxane (677 mg, colorless oil) as a mixture of diastereomers. This mixture is separated using chiral preparative HPLC (Chiral Pak AD; n-heptan/ethanol 1:1; 220 nm) to obtain (1R, 8R)-11-oxa-tricyclo acid (R)-1-phenyl-ethyl ester [6.2.1.02.7]undeca-2,4,6,9-tetraene-9-carboxylic acid (190 mg, chiral HPLC >97%; Rt 7.73 min) and (R)-1-phenyl-ethyl ester (1S,8S)-11-oxa-tricyclo[6.2.1.02.7]undeca-2,4,6,9-tetraene-9-carboxylic acid (180 mg; chiral HPLC >96%; Rt 12.53 min) . Step 3: (1S,8R)-11-oxa-tricyclo[6.2.1.02.7]undeca-2,4,6-triene-9-carboxylic acid (R)-1-phenyl-ethyl ester

[00280] A solution of (R)-1-phenyl-ethyl ester (1S,8S)-11-oxa-tricyclo[6.2.1.02,7]undeca-2,4,6,9-tetraene-9- carboxylic acid (0.470 g, 1.190 mmol) in 10 mL of THF is hydrogenated at room temperature and normal pressure using 500 mg of Pd/C (54% water) until the reaction is complete. The reaction mixture is filtered, the filtrate is concentrated and purified by flash chromatography (silica gel; EE/heptane gradient; 0-60% EE) to obtain (R)-1-phenyl-ethyl ester (1S ,8R)-11-oxa-tricyclo[6.2.1.02.7]undeca-2,4,6-triene-9-carboxylic acid (184 mg) as a colorless oil.

[00281] LCMS, method A: (M + H) not detected; Rt 2.51 min. Step 4: (1S,8R)-11-oxa-tricyclo[6.2.1.02.7]undeca-2,4,6-triene-9-carboxylic acid

[00282] A solution of (R)-1-phenyl-ethyl ester of (1S, 8R)-11-oxa-tricyclo[6.2.1.02.7]undeca-2,4,6-triene-9-carboxylic acid ( 0.184g, 0.626 mmol) in 10 mL of THF is hydrogenated at room temperature and normal pressure using 200 mg of Pd/C (54% water) overnight. The reaction mixture is filtered and the filtrate is evaporated to obtain 130 mg of (1S, 8R)-11-Oxa-tricyclo[6.2.1.02.7]undeca-2,4,6-triene-9-carboxylic acid as a white solid.LCMS, method A: (M-18) 174; Rt 1.42 min. Acid intermediate 6: (1R,8S)-11-oxa-tricyclo[6.2.1.02.7]undeca-2,4,6-triene-9-carboxylic acid Step 1: (1R,8S)-11-oxa-tricyclo[6.2.1.02.7]undeca-2,4,6-triene-9-carboxylic acid (R)-1-phenyl-ethyl ester

[00283] A solution of (R)-1-phenyl-ethyl ester of acid (1R, 8R)-11-oxa-tricyclo[6.2.1.02,7]undeca-2,4,6,9-tetraene-9- carboxylic acid (0.470 g, 76% purity, 1.22 mmol) in 10 mL of THF is hydrogenated at room temperature and normal pressure using 100 mg of Pd/C (54% water) until the reaction is complete (5 min) . The reaction mixture is filtered, the filtrate is concentrated and purified by flash chromatography (silica gel; EE/heptane gradient; 0-50% EE) to obtain (R)-1-phenyl ethyl ester (1R ,8S)-11-Oxa-tricyclo[6.2.1.02.7]undeca-2,4,6-triene-9-carboxylic acid (107 mg, 30% yield) as colorless wax. LCMS, Method A: (M + H ) not detected; Rt 2.52 min. Step 2: (1R,8S)-11-oxa-tricyclo[6.2.1.02.7]undeca-2,4,6-triene-9-carboxylic acid

[00284] A solution of (R)-1-phenyl-ethyl ester of (1S, 8R)-11-oxa-tricyclo[6.2.1.02,7]undeca-2,4,6-triene-9-carboxylic acid ( 0.107g, 0.364 mmol) in 10 mL of THF is hydrogenated at room temperature and normal pressure using 100 mg of Pd/C (54% water) overnight. The reaction mixture is filtered, and the filtrate is evaporated to obtain (1R, 8S)-11-oxa-tricyclo[6.2.1.02.7]undeca-2,4,6-triene-9-carboxylic acid (69 mg; 92% yield) as a white solid. LCMS, method A: (M + H) not detected; Rt 1.36 min. Example 1: [(1R)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2R,4R)-7-oxabicyclo[2.2] acid .1]heptan-2-yl]formamide}ethyl]boronic acid (Compound No. 1) Step 1: [(R)-2-(S)-2,3-Dihydro-benzofuran-3-yl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3 (1S,2R,4R)-7-oxa-bicyclo[2.2.1]heptane- acid ,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-amide 2-carboxylic

[00285] To a hydrochloride solution of (R)-2-(S)-2,3-Dihydro-benzofuran-3-yl-1-((1S,2S,6R,8S)-2, 9,9-Trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]dec-4-yl)-ethylamine (0.250 g; 0.66 mmol) in 5 mL of dry DMF is added to -15°C and argon atmosphere, (1S,2R,4R)-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid (0.113 g; 0.79 mmol), ethyl-diisopropyl-amine (0.34 mL; 1.99 mmol) and TBTU (0.70 g; 2.18 mmol). The yellow reaction solution is stirred 1 h at -10°C, then 1 h at room temperature. The reaction solution is ice-cooled and diluted with ethyl acetate. After separation, the organic phase is washed with brine and saturated NaHCO 3 solution, dried over sodium sulfate, filtered and concentrated in vacuo (bath temperature 30°C). The orange oil obtained is first purified by flash chromatography (silica gel; heptane/EE gradient, 0-100% EE) to produce a mixture of diastereomers, which is separated using chiral SFC (ChiralPak AD, CO2:Methanol (88: 12 )). 122 mg of the title compound (yield 39.6%) are obtained as a colorless oil. LCMS, method A: (M + H) 466.2; Rt 2.49 min Step 2: [(1R)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2R,4R)- 7-oxabicyclo[2.2.1]heptan-2-yl]formamide}ethyl]boronic acid (Compound No. 1)

[00286] To a biphasic acid system (1S, 2R, 4R)-7-Oxa-bicyclo[2.2.1]heptane-2-carboxylic acid[(R)-2-(S)-2,3-dihydro -benzofuran-3-yl-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02.6]dec-4- yl)-ethyl]-amide (0.206 g; 0.44 mmol) in 27 mL of n-pentane and 20.6 mL of methanol is added at 0°C isobutylboronic acid (0.180 g; 1.77 mmol) and HCl 2N (1.99 mL; 3.98 mmol). The reaction is stirred at room temperature overnight. The pentane phase is separated, and the methanolic aqueous phase is washed 5x with pentane. The methanolic phase is concentrated in vacuo, diluted with ice water and made basic with 1N NaOH. It is then extracted with DCM (2x). The aqueous phase is acidified with 1N HCl and extracted with DCM (5x). This organic phase is dried over Na2SO4, filtered and evaporated. The residue is taken up in acetonitrile/water and lyophilized to give 104 mg (yield: 71%) of the title compound as a white solid.

[00287] 1H NMR (500 MHz, DMSO-d6/D2O) d 7.23 - 7.20 (m, 1H), 7.13 - 7.09 (m, 1H), 6.86 (td, J = 7.4, 1.0 Hz, 1 H), 6.76 (d, J = 7.8 Hz, 1 H), 4.60 (d, J = 4.7 Hz, 1 H), 4 .59 - 4.53 (m, 2H), 4.21 (dd, J = 9.0, 6.7 Hz, 1H), 3.47 - 3.38 (m, 1H), 2, 94 - 2.89 (m, 1H), 2.59 (dd, J = 9.0, 4.9 Hz, 1H), 1.91 - 1.84 (m, 2H), 1.71 (dd, J = 12.0, 9.1 Hz, 1H), 1.64 - 1.42 (m, 5H).

[00288] LCMS Method A: (M+H) 314.2; Rt 1.57 min Example 2: [(1R)-2-(1-benzofuran-3-yl)-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan- 2-yl]formamide}ethyl]boronic acid (Compound No. 9) Step 1: [(R)-2-(Benzofuran-3-yl)-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricycle (1S,2R, 4R)-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid [6.1.1.02,6]dec-4-yl)-ethyl]-amide

[00289] To a solution of (1S, 2R, 4R)-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid (1.87 g; 13.18 mmol), [dimethylamino-( [1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium (HATU) (4.62 g; 14.37 mmol) and 4-methyl-morpholine (3 .29 mL; 29.94 mmol) in 70 mL of dry DMF is added under ice-cooling and an argon atmosphere (R)-2-(benzofuran-3-yl)-1-((1S,2S,6R) hydrochloride , 8S)-2,9,9-Trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02.6]dec-4-yl)-ethylamine (4.50 g; 11.98 mmol). The yellow solution is stirred for 2.5 h at room temperature. The reaction mixture is poured into 500 ml of saturated NaHCO3 solution, cooled on ice and stirred for 15 min. The precipitate is collected by vacuum filtration and washed with water. The solid obtained is triturated with acetonitrile, diluted with MTB-ether and aspirated to yield [(R)-2-(benzofuran-3-yl)-1-((1S,2S,6R,8S)-2,9,9 (1S, 2R, 4R)-7-oxa-bicyclo[2.2. 1]heptane-2-carboxylic acid (3.26 g, yield: 58.8%) as a white solid (purity 100%).

[00290] LCMS Method A: (M+H) 464.2; Rt 2.57 min Step 2: [(1R)-2-(1-benzofuran-3-yl)-1-{[(1S,2R,4R)-7-oxabi-cyclo[2.2.1]heptan- 2-yl]formamide}ethyl]boronic

[00291] To a biphasic system of [(R)-2-benzofuran-3-yl-1-((1S,2S, 6R,8S)-2,9,9-trimethyl-3,5-dioxa-4- Bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-amide (1S, 2R, 4R)-7-Oxa-bicyclo[2.2.1]heptane-2-carboxylic acid (ee = 97 %, 3.45 mmol; 1.60 g) in 150 mL of n-pentane and 50 mL of methanol are added at 0°C isobutylboronic acid (13.81 mmol; 1.41 g) and 1N hydrochloric acid ( 15.54 mmol; 15.54 mL). The reaction is stirred at room temperature overnight. The pentane phase is separated and the methanolic phase is washed with pentane (3x 80 mL). The methanolic phase is concentrated (bath temperature below 30°C) in vacuo, diluted with ice water and basified with 1N NaOH (pH 11-12). This basic solution is extracted with DCM (3 x 80 mL). The aqueous phase is acidified with 1N HCl (pH 2) and extracted with DCM (5x 80 mL) again. The combined organic phases are dried over Na2SO4, filtered and evaporated. The residue is taken up in acetonitrile/water and lyophilized to afford 0.697 g (61.3% yield) of the title compound as a white solid.

[00292] Analytical data: see table 2 Example 3: [(1R)-2-(7-chloro-1-benzofuran-3-yl)-1-{[(1S,2R, 4R)-7-oxabicyclo acid [2.2.1]heptan-2-yl]formamide}ethyl]boronic acid (Compound No. 13) Step 1: [(R)-2-(7-Chloro-benzofuran-3-yl)-1-((1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4 (1S,2R,4R)-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid-bora-tricyclo[6.1.1.02.6]dec-4-yl)-ethyl]-amide

[00293] To a solution of (1S, 2R, 4R)-7-oxa-bicyclo[2.2.1] heptane-2-carboxylic acid (3.77 g; 26.55 mmol), [dimethylamino-( [1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium (HATU) (9.30 g; 28.97 mmol) and 4-methyl-morpholine (6 63 mL; 60.34 mmol) in 148 mL of dry DMF is added under ice-cooling and an argon atmosphere (R)-2-(7-chloro-benzofuran-3-yl)-1-((1S ,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethylamine (9.90 g; 24. 14mmol). The yellow solution is stirred for 3 h at room temperature. The reaction mixture is poured into 1 L of saturated NaHCO3 solution, cooled in ice, and stirred for 15 min. The precipitate is collected by vacuum filtration and washed with water. The solid obtained is triturated with acetonitrile, diluted with MTB-ether and aspirated to yield [(R)-2-(7-chloro-benzofuran-3-yl)-1-((1S,2S,6R,8S)-2 (1S, 2R, 4R)-7-oxa-acid ,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-amide bicyclo[2.2.1]heptane-2-carboxylic acid (6.9 g, yield: 56.6%) as a white solid (purity 95%). LCMS, method A: (M+H) 498.2; Rt 2.70 min Step 2: [(1R)-2-(7-chloro-1-benzofuran-3-yl)-1-{[(1S, 2R, 4R)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid (Compound No. 13)

[00294] To a biphasic system of [(R)-2-(7-chloro-benzofuran-3-yl)-1- ((1S,2S,6R,8S)-2,9,9-trimethyl-3, (1S,2R,4R)-7-oxa-bicyclo[2.2.1]heptane-2 acid 5-dioxa-4-bora-tricyclo[6.1.1.02.6]dec-4-yl)-ethyl]-amide -carboxylic acid (ee = 99%, 12.39 mmol; 6.26 g) in 220 mL of n-pentane and 125 mL of methanol are added at 0°C isobutylboronic acid (37.17 mmol; 3.79 g) and 1N hydrochloric acid (55.760 mmol; 55.760 mL). The reaction is stirred at room temperature overnight. The pentane phase is separated and the methanolic phase is washed with pentane (3 x 200 mL). The methanolic phase is concentrated (bath temperature below 30°C) in vacuo, diluted with 200 ml of ice water and basified with 1N NaOH (pH 12-13). This basic solution is extracted with DCM (3x 200 mL). The aqueous phase is acidified with 1N HCl (pH 2-3) and extracted with DCM (5 x 220 mL) again. The combined organic phases are dried over Na2SO4, filtered and evaporated. The residue is taken up in acetonitrile/water and lyophilized to yield 3.277 g of the title compound as a white solid.

[00295] 1H NMR (500 MHz, DMSO-d6/D2O) d 7.78 (s, 1 H), 7.64 - 7.60 (m, 1 H), 7.42 - 7.39 (m, 1H), 7.29 (t, J = 7.8 Hz, 1H), 4.54 - 4.50 (m, 1H), 4.48 - 4.45 (m, 1H), 3 .15 - 3.09 (m, 1H), 2.89 (dd, J = 14.9, 5.8 Hz, 1H), 2.77 (dd, J = 14.9, 8.4) Hz, 1H), 2.50 (dd, J = 9.0, 4.9 Hz, 1H), 1.82 - 1.75 (m, 1H), 1.65 (dd, J = 11 .9, 9.0 Hz, 1H), 1.58 - 1.49 (m, 2H), 1.49 - 1.39 (m, 2H).

[00296] Waters XBridge C8 3.5 µm 4.6 x 50 mm (A19/533 - La Chrom Elite; 70173815); 8.1 min; 2 mL/min; 215 nm; Buffer A:TFA/H2O 0.05%; Buffer B: 0.04% TFA/ACN; 0.0-0.2 min 5% Buffer B; 0.2-8.1 min 5% -100% Buffer B; 8.1-10.0 min 100% -5% Buffer B: %; Tr 4.24 min.

[00297] UPLC MS Waters Acquity UPLC; CORTECS C18 1.6 µm 50-2.1 mm; A: H2O+ 0.05% HCOOH; B: MeCN+ 0.04% HCOOH; T: 30°C; Flow: 0.9 mL/min; 2% -> 100% B: 0 -> 1.0 min; 100% B: 1.0 -> 1.3 min: 346.1 [M + H-H 2 O]; RT 0.61 min.

[00298] From commercially available acids (or acids synthesized by saponification of commercially available esters) or acids described in the literature, the following compounds were synthesized according to example 1 or 2, steps 1 and 2:

Biological activity Determination of LMP7 activity:

[00299] Measurement of LMP7 inhibition is performed in 384-well format, based on fluorescence intensity assay.

[00300] Purified human immunoproteasome (0.25 nM) and compounds serially diluted in DMSO (concentration range 30 μM to 15 pM) or controls are incubated for 20 minutes or 120 minutes (long incubation) at 25°C in buffer of assay containing 50 mM Tris pH 7.4, 0.03% SDS, 1 mM EDTA and 1% DMSO. The reaction is initiated by the addition of the fluorogenic peptide substrate, Suc-LLVY-AMC (Bachem I-1395), at a concentration of 40 µM. After 60 minutes of incubation at 37°C, fluorescence intensity is measured at λex = 350 nm and λem = 450 nm with a fluorescence reader (Perkin Elmer Envision reader or equivalent).

[00301] The LMP7 activity of the compounds is summarized in Table 3. Unless otherwise indicated, results are obtained after incubation for 20 minutes.

Determination of Beta5 activity:

[00302] Measurement of Beta5 inhibition is performed in 384-well format based on fluorescence intensity assay.

[00303] Purified human constitutive proteasome (1.25 nM) and compounds serially diluted in DMSO (concentration range from 30 μM to 15 pM) or controls are incubated for 20 minutes or 120 minutes (long incubation) at 25°C in assay buffer containing 50 mM Tris pH 7.4, 0.03% SDS, 1 mM EDTA and 1% DMSO. The reaction is initiated by the addition of the fluorogenic peptide substrate, Suc-LLVY-AMC (Bachem I-1395), at a concentration of 40 µM. After 60 minutes of incubation at 37°C, fluorescence intensity is measured at λex = 350 nm and λem = 450 nm with a fluorescence reader (Perkin Elmer Envision reader or equivalent).

[00304] Table 3 shows the Beta5 activity of the compounds according to the invention and their selectivity for LMP7 versus Beta5. Unless otherwise indicated, results are obtained after incubating for 20 minutes. *: 5 μM< IC50 < 3.0*10-5M, **: 0.5 μM <ICδ0< 5 μM, ***: 0.05 μM <ICδ0< 0.5 μM, ****: IC50< 0.05 μM, +: Selectivity < 100, ++: 100 < Selectivity < 300, +++: 300 < Selectivity < 500, ++++: 500 < Selectivity < 700, +++++: Selectivity > 700, nma,: no measurable activity in range of specified concentration; according to the method described above, "long incubation" means that the sample is incubated for 120 min.

[00305] The following examples refer to drugs:

Example A: Injection vials

[00306] A solution of 100 g of an active ingredient of Formula (I) and 5 g of disodium hydrogen phosphate in 3 L of double-distilled water is adjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered, transferred to injection vials , lyophilized under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of active ingredient.

Example B: Suppositories

[00307] A mixture of 20 g of an active ingredient of Formula (I) with 100 g of soy lecithin and 1400 g of cocoa butter is melted, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C: Solution

[00308] A solution is prepared from 1 g of an active ingredient of Formula I, 9.38 g of NaH2PO42 H2O, 28.48 g of Na2HPO4 . 12 H2O and 0.1 g of benzalkonium chloride in 940 mL of double-distilled water. The pH is adjusted to 6.8, and the solution is made up to 1 liter and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: Ointment

[00309] 500 mg of an active ingredient of Formula (I) is mixed with 99.5 g of Vaseline under aseptic conditions.

Example E: Pills

[00310] A mixture of 1 kg of active ingredient of Formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed in a conventional manner to produce tablets so that each tablet contains 10 mg of active ingredient.

Example F: Drageas

[00311] The tablets are compressed analogously to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Example G: Capsules

[00312] 2 kg of active ingredient of Formula (I) are introduced into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.

Example H: Ampoules

[00313] A solution of 1 kg of active ingredient of Formula (I) in 60 L of bidistilled water is sterile filtered, transferred into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

Claims (19)

1. Compound, characterized by the fact that it presents Formula (I), in which LY denotes (CH2)m, where 1 to 4 H atoms can be replaced by Hal, R3a and/or OR4a, and/or where one CH2 group can be replaced by O, S, SO or SO2; X denotes a heterobicycle or heterotricycle of Formula (xa), (xb), (xc), (xd), (xe), (xf), (xg), (xh) or (xi), each of which, independently of the other, unsubstituted or mono-, di- or trisubstituted by Hal, NO2, CN, R5a, OR5a, CONR5aR5b, NR5aCOR5b, SO2R5a, SOR5a, SO2NR5aR5b, NR5aSO2R5b, NR5aR5b, (CH2)q-R6, COR5a and/or SO2R5a, and where 1, 2 or 3 of the cyclic CH2 groups can be replaced by CR4aR4b, C=O, O, S, NR5a, SO and/or SO2: Y denotes P1, P2 or P3; P1 denotes a linear or branched C1-C6-alkyl or C3-C8-cycloalkyl, each of which, independently of one another, is unsubstituted or mono-, di-, tri- or tetra-substituted by Hal, CN, R3a, OR3a, and/ or (CH2)q-R6; P2 denotes phenyl or a 5-, 6- or 7-membered monocyclic aromatic heterocycle, each of which is unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal, CN, R3a, OH, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a , SOR3a, NR4aR4b, Ar2, Het2, (CH2)q-SR3a, (CH2)q-N(R4a)2 and/or (CH2)q-R6, wherein the heterocyclic system contains 1, 2 or 3 N atoms , O and/or S; P3 denotes an 8-, 9- or 10-membered bicyclic hydrocarbon or heterocycle, each independently of the other unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal, CN, R3a, OH, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2, (CH2)q-SR3a, (CH2)qN(R4a)2 and/or (CH2)q-R6, wherein at least one ring of the hydrocarbon or bicyclic heterocycle is aromatic , and in which the heterocyclic system contains 1, 2 or 3 N, O and/or S atoms; Cy1, Cy2, Cy3, Cy4 and Cy5 each independently of one another denote Ar1 or Het1; R1, R2 each independently of the other denote H or C1-C6-alkyl, or R1 and R2 together form a residue according to Formula (EC) R3a, R3b each independently of one another denote linear or branched C1-C6-alkyl or C3-C8-cycloalkyl, in which 1 to 5 H atoms may be replaced by Hal, CN, OH and/or OAlk; R4a, R4b each independently of one another denote H or R3a; or R4a and R4b together form a C3-C8 alkylene group; R5a, R5b each independently of one another denote H, R3a, Ar2 or Het2; R6 denotes OH or OR3a; T1, T2, T3, T4, T5, T6, T7, T8 and T9 each denote, independently of one another, O, SO, C=O; Alk denotes straight or branched C1-C6-alkyl; Ar1 represents an aromatic 6-membered carbocycle; Het1 represents a saturated, unsaturated or aromatic 5- or 6-membered heterocycle having 1 to 4 N, O and/or S atoms; Ar2 denotes phenyl which is unsubstituted or mono- or disubstituted by Hal, NO2, CN, R3a, OR3a, CONHR3a, NR3aCOR3b, SO2R3a, SOR3a, NH2, NHR3a, N(R3a)2 and/or (CH2)q- R6; Het2 denotes a saturated, unsaturated or aromatic 5- or 6-membered heterocycle having 1 to 4 N, O and/or S atoms, which is unsubstituted or mono- or disubstituted by Hal, NO2, CN, R3a, OH, OR3a , CONHR3a, NR3aCOR3b, SO2R3a, SOR3a, NH2, NHR3a, N(R3a)2, (CH2)q-R6 and/or oxo (=O); q denotes 1, 2, 3, 4, 5 or 6; m denotes 0, 1 or 2; Hal denotes F, Cl, Br or I; and the pharmaceutically acceptable salts thereof. 2. Compound of formula (I), according to claim 1, characterized in that: R1, R2 each denote, independently of one another, H or C1-C4-alkyl or R1 and R2 together form a residue of according to Formula (EC); and LY denotes CH2 or CH2CH2, where 1 to 2 H atoms may be replaced by Hal, R3a, OR4a; and pharmaceutically acceptable salts thereof. 3. Compound of Formula (I), according to claim 1 or 2, characterized by the fact that: T1, T2, T3, T4, T5, T6, T7, T8 and T9 denotes O; and the pharmaceutically acceptable salts thereof. 4. Compound of formula (I), according to any one of claims 1 to 3, characterized in that: P1 denotes a linear or branched C1-C6-alkyl or C3-C8-cycloalkyl, each one independently of the other, unsubstituted mono-, di-, or trisubstituted by Hal, CN, R3a, OR3a, and/or (CH2)q-R6; P2 denotes phenyl, pyridyl, pyrrolyl, furanyl, thiophenyl, pyrimidyl, pyrazinyl or pyridazinyl, each independently of the other unsubstituted mono-, di- or trisubstituted by Hal, CN, R3a, OH, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2, (CH2)q-SR3a, (CH2)qN(R4a)2 and/or (CH2)q-R6; and P3 denotes a bicyclic residue of Formula (ya), (yb), (yc), (yd), (ye), (yf), (yg), (yh), (yi), (yj), (yk ), (yl), (ym), (yn), (yo) or (yp), each independently of the other unsubstituted mono-, dior trisubstituted by Hal, CN, R3a, OH, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2, (CH2)q-SR3a, (CH2)qN(R4a)2 and/or (CH2)q-R6: in which Ea denotes O, S, N(Alk) or CH=CH; Eb denotes O, S, N(Alk), CH2, CH2-CH2, O-CH2, S-CH2 or N(Alk)CH2; and the pharmaceutically acceptable salts thereof. 5. Compound of formula (I), according to any one of claims 1 to 4, characterized in that: R3a, R3b each denote, independently of one another, C1-C4-alkyl or C3-C6 cycloalkyl linear or branched, in which 1 to 3 H atoms can be replaced by F, Cl and/or and in which 1 or 2 H atoms can be replaced by CN, OH, OCH3, and/or OC2H5; and the pharmaceutically acceptable salts of same. 6. Compound of formula (I), according to any one of claims 1 to 5, characterized in that Y indicates P2 or P3 and the pharmaceutically acceptable salts thereof. 7. Compound of Formula (I), according to any one of Claims 1 to 6, characterized in that the stereogenic center on the carbon atom adjacent to the boronic acid residue has a configuration (R), according to Formula (R)-(I), and the pharmaceutically acceptable salts thereof. 8. Compound of Formula (I) according to any of claims 1 to 7, characterized in that: X is a heterobicycle or heterotricycle of Formula (xa1), (xb1), (xc1), (xd1), (xe1) ), (xf1), (xg1), (xh1) or (xi1), each independently of the other unsubstituted or mono-, di- or trisubstituted by Hal, NO2, CN, R5a, OR5a, CONR5aR5b, NR5aCOR5b , SO2R5a, SOR5a, SO2NR5aR5b, NR5aSO2R5b, NR5aR5b, (CH2)q-R6, COR5a and/or SO2R5a, and wherein 1 of the cyclic groups CH2 may be replaced by CR4aR4b, C=O, O, S, NR5a, SO and /or SO2: the pharmaceutically acceptable salts thereof. 9. Compound of Formula (I), according to any one of Claims 1 to 7, characterized in that: X is a heterobicycle or heterotricycle of Formula (xa), (xb), (xc), (xd), (xe), (xf), (xg), (xh) or (xi), each independently of the other unsubstituted or mono-, disubstituted by F, Cl, CH3, C2H5, CF3, OCH3, OC2H5, COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 and/or N(C2H5); and the pharmaceutically acceptable salts thereof. 10. Compound of Formula (I), according to claim 8, characterized in that: X is a heterobicycle or heterotricycle of Formula (xa1), (xb1), (xc1), (xd1), (xe1), (xf1), (xg1), (xh1) or (xi1), each independently of the other unsubstituted or mono-, disubstituted by F, Cl, CH3, C2H5, CF3, OCH3, OC2H5,COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 and/or N(C2H5); and the pharmaceutically acceptable salts thereof. 11. Compound of Formula (I), according to any one of claims 1 to 10, characterized in that: P3 denotes unsubstituted or mono- or disubstituted 1- or 2-naphthyl, in which the optional substituents are selected from from a group consisting of Hal, CN, R3a, OH, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2, (CH2)q-SR3a, (CH2)qN(R4a)2, and/or (CH2) )q-R6, or P3 is a residue according to Formula (Ra) or (Rb): in which Ga, Gb each independently denote H, Hal, CN, R3a, OR3a, CONHR3a, CONR3bR3a, CONH2, NR3aCOR3b, SO2 R3a, SOR3a, NHR3a, N(R3a)2, (CH2)q- SR3a, (CH2)qN(R4a)2 and/or (CH2)q-R6; Ka, Kb each denote, independently of one another, H, Hal, CN, R3a, OR3a, CONHR3a, CONR3bR3a, CONH2, NR3aCOR3b, SO2R3a, SOR3a, NHR3a, N(R3a)2, (CH2)q-SR3a, ( CH2)qN(R4a)2 and/or (CH2)q-R6; Ea denotes O, S, N(Alk) or CH=CH; and Eb denotes O, S, N(Alk), CH2, CH2-CH2, O-CH2, S-CH2, or N(Alk)CH2. 12. Compound of formula (I), according to claim 11, characterized in that: Ea, Eb each denote O or S, and the pharmaceutically acceptable salts thereof. 13. Compound of Formula (I), according to claim 11 or 12, characterized in that: P3 is a residue according to Formula (Fa) or (Fb): and the pharmaceutically acceptable salts thereof. 14. Compound of Formula (I), according to claim 13, characterized in that: P2 denotes 2- or 3-thienyl unsubstituted or mono- or disubstituted or unsubstituted or phenyl 3-, 4-, 2, 3-, 2,4-, 2,5-, 3,4- or 2,3,4-substituted, wherein the optional substituents are selected from the group consisting of Hal, CN, R3a, OH, OR3a , CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2, (CH2)q-SR3a, (CH2)qN(R4a)2e/or (CH2)q-R6; P3 denotes a residue according to Formula (Fa) or (S)-(Fb), Ga, Gb each denote, independently of one another, H, Hal, CN, R3a, OH, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2, (CH2)q-SR3a, (CH2)qN( R4a)2 and/or (CH2)q-R6; Ka, Kb each denote, independently of one another, H, Hal, CN, R3a, OH, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2, (CH2)q-SR3a, (CH2)qN( R4a)2 and/or (CH2)q-R6; and the pharmaceutically acceptable salts thereof. 15. Compound of Formula (I), according to claim 14, characterized in that: P2 denotes 2- or 3-thienyl unsubstituted or mono- or disubstituted or unsubstituted or phenyl 3-, 4-, 2, 3-, 2,4-, 2,5-, 3,4- or 2,3,4-substituted, wherein the optional substituents are selected from the group consisting of F, Cl, CN, CH3, C2H5 , CF3, OCH3, OC2H5, COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 or N(C2H5)2; P3 denotes a residue according to Formula (Fa) or (S)-(Fb), Ga, Gb each independently of one another denote H, F, Cl, CN, CH3, C2H5, CF3, OCH3, OC2H5 , COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 or N(C2H5)2; Ka, Kb each denote, independently of one another, H, F, Cl, CN, CH3, C2H5, CF3, OCH3, OC2H5, COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 or N(C2H5)2; and the pharmaceutically acceptable salts thereof. 16. Compound according to claim 1, characterized in that it is selected from the group consisting of: acid [(1R)-2-[(3S)-2,3-dihydro-1-benzofuran -3-yl]-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,2S,4S)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1R)-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamide}-2-(thiophen-3-yl)ethyl]boronic acid; [(1R)-2-(1-benzofuran-3-yl)-1-{[(1R,8S)-11-oxatricyclo[6.2.1.02,7]undeca-2(7),3,5- acid trien-1-yl]formamide}ethyl]boronic acid; [(1S)-2-(1-benzofuran-3-yl)-1-{[(1R,8S)-11-oxatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien acid -1-yl]formamide}ethyl]boronic acid; [(1R)-2-(1-benzofuran-3-yl)-1-{[(1S,8R)-11-oxatricyclo[6.2.1.02,7]undeca-2(7),3,5- acid trien-1-yl]formamide}ethyl]boronic acid; [(1S)-2-(1-benzofuran-3-yl)-1-{[(1S,8R)-11-oxatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien acid -1-yl]formamide}ethyl]boronic acid; [(1R)-2-(1-benzofuran-3-yl)-1-{[(1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid; [(1R)-2-(1-benzofuran-3-yl)-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid; [(1R)-2-(1-benzofuran-3-yl)-1-{[(1R,2R,4S)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid; [(1S)-2-(1-benzofuran-3-yl)-1-{[(1R,2R,4S)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid; [(1R)-2-(7-chloro-1-benzofuran-3-yl)-1-{[(1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-yl]formamide} acid ethyl]boronic; [(1R)-2-(7-chloro-1-benzofuran-3-yl)-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamide} acid ethyl]boronic; [(1R)-2-[(3R)-7-methyl-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2R, 4R)-7-oxabicyclo[ acid] 2.2.1]heptan-2-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3S)-7-methyl-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2R, 4R)-7-oxabicyclo[ acid 2.2.1]heptan-2-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,8S)-11-oxatricyclo[6.2.1.02.7] acid undeca-2(7),3,5-trien-1-yl]formamide}ethyl]boronic acid; [(1R)-2-(1-benzofuran-3-yl)-1-{[(1S,6S,7R)-3-cyclopropyl-4-oxo-10-oxa-3-azatricyclo[5,2, 1,01,5]dec-8-en-6-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,8R)-11-oxatricyclo[6.2.1.02.7] acid undeca-2(7),3,5-trien-1-yl]formamide}ethyl]boronic acid; [(1R)-2-(7-methyl-1-benzofuran-3-yl)-1-{[(1R,8S)-11-oxatricyclo[6.2.1.02.7]undeca-2,4,6- acid trien-1-yl]formamide}ethyl]boronic acid; [(1R)-2-(7-methyl-1-benzofuran-3-yl)-1-{[(1S,8R)-11-oxatricyclo[6.2.1.02.7]undeca-2,4,6- acid trien-1-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,8R)-8-methyl-11-oxatricyclo[6.2. 1.02.7]undeca-2,4,6-trien-1-yl]formamide}ethyl]boronic acid; [(1R)-2-(1-benzofuran-3-yl)-1-{[(1R,8S)-11-oxatricyclo[6.2.1.02,7]undeca-2(7),3,5- acid trien-9-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,8S)-8-methyl-11-oxatricyclo[6.2. 1.02.7]undeca-2,4,6-trien-1-yl]formamide}ethyl]boronic acid; [(1R)-2-(1-benzofuran-3-yl)-1-{[(1S,8R)-11-oxatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien acid -9-yl]formamide}ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid; [(1R)-2-cyclohexyl-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamide}ethyl]boronic acid; [(1R)-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamide}-3-phenylpropyl]boronic acid; [(1R)-3-methyl-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}butyl]boronic acid; [(1S)-2-(1-benzofuran-3-yl)-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid; [(1S)-2-(1-benzofuran-3-yl)-1-{[(1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid; [(1R)-2-(1-benzofuran-3-yl)-1-{[(1S,2S,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid; [(1S)-2-(1-benzofuran-3-yl)-1-{[(1S,2S,4R)-7-oxabicyclo[2.2.1]heptan-2-yl]formamido}ethyl]boronic acid; [(1R)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2S,4R)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,2R,4S)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1S)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2S,4R)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1S)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,2R,4S)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3R)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2S,4R)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3R)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,2R,4S)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1S)-2-[(3R)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2S,4R)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1S)-2-[(3R)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,2R,4S)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1S)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1S)-2-[(3S)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,2S,4S)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3R)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1R)-2-[(3R)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,2S,4S)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1S)-2-[(3R)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1S,2R,4R)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; [(1S)-2-[(3R)-2,3-dihydro-1-benzofuran-3-yl]-1-{[(1R,2S,4S)-7-oxabicyclo[2.2.1] acid heptan-2-yl]formamide}ethyl]boronic acid; and the pharmaceutically acceptable salts thereof. 17. Process for preparing the compound of Formula (I) as defined in any one of claims 1 to 16, and the pharmaceutically acceptable salts thereof, characterized in that the compound of Formula (III), is coupled with a compound of Formula (VI), wherein all residues of Formula (III) and Formula (IV) are as defined in any one of claims 1 to 15 and wherein the obtained compound of Formula (Ib) can subsequently be converted into a compound of Formula (Ia), by treatment with HCl, HBr, HI and/or TFA, in the presence or absence of excess of a small molecular weight boronic acid, 18. Pharmaceutical formulation, characterized in that it comprises at least one compound, as defined in any one of claims 1 to 16, and/or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable vehicle. 19. Use of a compound of Formula (I), as defined in any one of claims 1 to 16, or pharmaceutically acceptable salts thereof, characterized in that it is in the manufacture of a pharmaceutical formulation for the prevention and/or treatment of an immunoregulatory or cancerous abnormality, such as in particular a haematological malignancy or a solid tumour; where the immunoregulatory abnormality is an autoimmune or chronic inflammatory disease selected from the group consisting of: systemic lupus erythematosus, chronic rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), atherosclerosis, scleroderma, autoimmune hepatitis, Sjogren's Syndrome, Lupus Nephritis, Glomerulonephritis, Rheumatoid Arthritis, Psoriasis, Myasthenia Gravis, Immunoglobulin A Nephropathy, Vasculitis, Transplant Rejection, Myositis, Henoch-Schonlein Purpura, and asthma; and wherein hematologic malignancy is a disease selected from the group consisting of: multiple myeloma, lining cell lymphoma, diffuse large B-cell lymphoma, plasmacytoma, follicular lymphoma, immunocytoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, and leukemia myeloid; and wherein the solid tumor is selected from a group consisting of: inflammatory breast and colon cancer, lung cancer, head and neck cancer, prostate cancer, pancreatic cancer, bladder cancer, kidney cancer, cancer hepatocellular and gastric cancer.