Substituted boronic acids and boronate esters as immunoproteasome inhibitors

A process for the preparation of a compound of formula (I):

• wherein the compound of formula (I) is represented by formula (Ia) and/or formula (Ib):
• wherein:
• LX denotes —CH2—, —O(CH2)n—, —S(CH2)p— or —(CH2)pS—, where 1, 2, 3, 4 or 5 H atoms may be independently replaced by Hal, N3, R3a, OR4a, (CH2)rA2, (CH2)rAr2 or (CH2)rHet2;
• LY denotes —CH2—;
• X denotes an aromatic 6-membered carbocyclyl or aromatic 6-membered heterocyclyl, each optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from Hal, A1, N3, CN, OH, NR4aR4bAr1, Het1, OA1, OAr1, OHet1, C(O)A1, C(O)Ar1, C(O)Het1, C(O)NR4aR4b, NR4aC(O)R3a, NR4aS(O)2R3a, S(O)2R3a, S(O)R3a, NR4aC(O)2R3a, OC(O)NR3aR4a, O(CH2)qA1, (CH2)rSR3a, (CH2)rN(R4a)2 or (CH2)rA2;
• Y denotes Cyc;
• R1 and R2 each independently denote C1-C6 alkyl;
• or
• R1 and R2, together with the oxygen atoms to which they are attached, form a residue according to formula (CE):
• R3a and R3b each independently denote linear or branched C1-C6 alkyl, where 1, 2, 3, 4 or 5 H atoms may be independently replaced by Hal, OH or OAlk;
• R4a and R4b each independently denote H or R3a;
• or
• R4a and R4b, together with the nitrogen atom to which they are attached, form a nitrogen-containing heterocyclyl comprising 3, 4, 5 or 6 carbon atoms;
• A1 denotes linear or branched C1-C6 alkyl or C3-C6 cycloalkyl, each optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from Hal, CN, R3a, SR3a, OR4a or (CH2)rA2, where 1, 2 or 3 CH2 groups of C3-C6 cycloalkyl may be independently replaced by O, C(O) or N;
• A2 denotes OR4a;
• Alk denotes linear or branched C1-C6 alkyl;
• Ar1 denotes phenyl, optionally substituted by 1, 2 or 3 substituents selected from Hal, NO2, CN, R3aOR4a, C(O)NR4aR4b, NR4aC(O)R3b, S(O)2R3a, S(O)R3a, NR4aR4b, Ar2, Het2 or (CH2)rA2;
• Het1 denotes a saturated, unsaturated or aromatic 5- or 6-membered heterocyclyl comprising 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S, where each heterocyclyl may be optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from Hal, NO2, CN, R3a, OR4a, C(O)NR4aR4b, NR4aC(O)R3b, S(O)2R3a, S(O)R3a, NR4aR4b, Ar2, Het2 or (CH2)rA2;
• Ar2 denotes phenyl, biphenyl or naphthyl, each optionally and independently substituted by 1, 2 or 3 substituents selected from Hal, CN, R3a, OR4a, C(O)NR4aR4b, NR4aC(O)R3b, S(O)2R3a, S(O)R3a, NR4aR4b or (CH2)qA2;
• Het2 denotes a saturated, unsaturated or aromatic 5- or 6-membered heterocyclyl comprising 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S, optionally substituted by 1, 2 or 3 substituents selected from Hal, CN, R3a, OR4a, C(O)NHR3a, NR3aC(O)R3b, S(O)2R3a, S(O)R3a, NR4aR4b or (CH2)qA2;
• Cyc denotes a monocyclic or bicyclic, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered carbocyclyl or heterocyclyl, each optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from Hal, CN, R3a, OR3a, C(O)NR4aR4b, NR3aC(O)R3b, S(O)2R3a, S(O)R3a, NR4aR4b, Ar2, Het2, (CH2)rSR3a, (CH2)rN(R4a)2 or (CH2)rA2, where the monocyclic carbocyclyl is aromatic and at least one ring of the bicyclic carbocyclyl or heterocyclyl is aromatic, and further where the heterocyclyl comprises 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S;
• n denotes 1, 2, 3, 4, 5 or 6;
• p denotes 1, 2, 3, 4, 5 or 6;
• q denotes 0, 1, 2, 3 or 4;
• r denotes 0, 1, 2, 3 or 4;
• and
• Hal denotes F, Cl, Br or I;
• with the proviso that when LX denotes —O(CH2)n—, the oxygen atom of LX is bonded to X;
• wherein the process comprises the following steps:
• (i) reacting a compound of formula (III):
• wherein:
• LX denotes —CH2—, —O(CH2)n—, —S(CH2)p— or —(CH2)pS—, where 1, 2, 3, 4 or 5 H atoms may be independently replaced by Hal, N3, R3a, OR4a, (CH2)rA2, (CH2)rAr2 or (CH2)rHet2;
• X denotes an aromatic 6-membered carbocyclyl or aromatic 6-membered heterocyclyl, each optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from Hal, A1, N3, CN, OH, NR4aR4b, Ar1, Het1, OA1, OAr1, OHet1, C(O)A1, C(O)Ar1, C(O)Het1, C(O)NR4aR4b, NR4aC(O)R3a, NR4aS(O)2R3a, S(O)2R3a, S(O)R3a, NR4aC(O)2R3a, OC(O)NR3aR4a, O(CH2)qA1, (CH2)rSR3a, (CH2)rN(R4a)2 or (CH2)rA2;
• R3a and R3b each independently denote linear or branched C1-C6 alkyl, where 1, 2, 3, 4 or 5 H atoms may be independently replaced by Hal, OH or OAlk;
• R4a and R4b each independently denote H or R3a;
• or
• R4a and R4b, together with the nitrogen atom to which they are attached, form a nitrogen-containing heterocyclyl comprising 3, 4, 5 or 6 carbon atoms;
• A2 denotes OR4a;
• Alk denotes linear or branched C1-C6 alkyl;
• Ar2 denotes phenyl, biphenyl or naphthyl, each optionally and independently substituted by 1, 2 or 3 substituents selected from Hal, CN, R3a, OR4a, C(O)NR4aR4b, NR4aC(O)R3b, S(O)2R3a, S(O)R3a, NR4aR4b or (CH2)qA2;
• Het2 denotes a saturated, unsaturated or aromatic 5- or 6-membered heterocyclyl comprising 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S, optionally substituted by 1, 2 or 3 substituents selected from Hal, CN, R3a, OR4a, C(O)NHR3a, NR3aC(O)R3b, S(O)2R3a, S(O)R3a, NR4aR4b or (CH2)qA2;
• n denotes 1, 2, 3, 4, 5 or 6;
• p denotes 1, 2, 3, 4, 5 or 6;
• q denotes 0, 1, 2, 3 or 4;
• r denotes 0, 1, 2, 3 or 4;
• and
• Hal denotes F, Cl, Br or I;
• with the proviso that when LX denotes —O(CH2)n—, the oxygen atom of LX is bonded to X;
• with a compound of formula (IV):
• wherein:
• LY denotes —CH2—;
• Y denotes Cyc;
• R1 and R2 each independently denote C1-C6 alkyl;
• or
• R1 and R2, together with the oxygen atoms to which they are attached, form a residue according to formula (CE):
• R3a and R3b each independently denote linear or branched C1-C6 alkyl, where 1, 2, 3, 4 or 5 H atoms may be independently replaced by Hal, OH or OAlk;
• R4a and R4b each independently denote H or R3a;
• or
• R4a and R4b, together with the nitrogen atom to which they are attached, form a nitrogen-containing heterocyclyl comprising 3, 4, 5 or 6 carbon atoms;
• A2 denotes OR4a;
• Ar2 denotes phenyl, biphenyl or naphthyl, each optionally and independently substituted by 1, 2 or 3 substituents selected from Hal, CN, R3a, OR4a, C(O)NR4aR4b, NR4aC(O)R3b, S(O)2R3a, S(O)R3a, NR4aR4b or (CH2)qA2;
• Het2 denotes a saturated, unsaturated or aromatic 5- or 6-membered heterocyclyl comprising 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S, optionally substituted by 1, 2 or 3 substituents selected from Hal, CN, R3a, OR4a, C(O)NHR3a, NR3aC(O)R3b, S(O)2R3a, S(O)R3a, NR4aR4b or (CH2)qA2;
• Cyc denotes a monocyclic or bicyclic, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered carbocyclyl or heterocyclyl, each optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from Hal, CN, R3a, OR3a, C(O)NR4aR4b, NR3aC(O)R3b, S(O)2R3a, S(O)R3a, NR4aR4b, Ar2, Het2, (CH2)rSR3a, (CH2)rN(R4a)2 or (CH2)rA2, where the monocyclic carbocyclyl is aromatic and at least one ring of the bicyclic carbocyclyl or heterocyclyl is aromatic, and further where the heterocyclyl comprises 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S;
• q denotes 0, 1, 2, 3 or 4;
• r denotes 0, 1, 2, 3 or 4;
• and
• Hal denotes F, Cl, Br or I;
• to provide a compound of formula (Ib):
• wherein:
• LX denotes —CH2—, —O(CH2)n—, —S(CH2)p— or —(CH2)pS—, where 1, 2, 3, 4 or 5 H atoms may be independently replaced by Hal, N3, R3a, OR4a, (CH2)rA2, (CH2)rAr2 or (CH2)rHet2;
• LY denotes —CH2—;
• X denotes an aromatic 6-membered carbocyclyl or aromatic 6-membered heterocyclyl, each optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from Hal, A1, N3, CN, OH, NR4aR4b, Ar1, Het1, OA1, OAr1, OHet1, C(O)A1, C(O)Ar1, C(O)Het1, C(O)NR4aR4b, NR4aC(O)R3a, NR4aS(O)2R3a, S(O)2R3a, S(O)R3a, NR4aC(O)2R3a, OC(O)NR3aR4a, O(CH2)qA1, (CH2)rSR3a, (CH2)rN(R4a)2 or (CH2)rA2;
• Y denotes Cyc;
• R1 and R2 each independently denote C1-C6 alkyl;
• or
• R1 and R2, together with the oxygen atoms to which they are attached, form a residue according to formula (CE):
• R3a and R3b each independently denote linear or branched C1-C6 alkyl, where 1, 2, 3, 4 or 5 H atoms may be independently replaced by Hal, OH or OAlk;
• R4a and R4b each independently denote H or R3a;
• or
• R4a and R4b, together with the nitrogen atom to which they are attached, form a nitrogen-containing heterocyclyl comprising 3, 4, 5 or 6 carbon atoms;
• A1 denotes linear or branched C1-C6 alkyl or C3-C6 cycloalkyl, each optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from Hal, CN, R3a, SR3a, OR4a or (CH2)rA2, where 1, 2 or 3 CH2 groups of C3-C6 cycloalkyl may be independently replaced by O, C(O) or N;
• A2 denotes OR4a;
• Alk denotes linear or branched C1-C6 alkyl;
• Ar1 denotes phenyl, optionally substituted by 1, 2 or 3 substituents selected from Hal, NO2, CN, R3a, OR4a, C(O)NR4aR4b, NR4aC(O)R3b, S(O)2R3a, S(O)R3a, NR4aR4b, Ar2, Het2 or (CH2)rA2;
• Het1 denotes a saturated, unsaturated or aromatic 5- or 6-membered heterocyclyl comprising 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S, where each heterocyclyl may be optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from Hal, NO2, CN, R3a, OR4a, C(O)NR4aR4b, NR4aC(O)R3b, S(O)2R3a, S(O)R3a, NR4aR4b, Ar2, Het2 or (CH2)rA2;
• Ar2 denotes phenyl, biphenyl or naphthyl, each optionally and independently substituted by 1, 2 or 3 substituents selected from Hal, CN, R3a, OR4a, C(O)NR4aR4b, NR4aC(O)R3b, S(O)2R3a S(O)R3a, NR4aR4b or (CH2)qA2;
• Het2 denotes a saturated, unsaturated or aromatic 5- or 6-membered heterocyclyl comprising 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S, optionally substituted by 1, 2 or 3 substituents selected from Hal, CN, R3a, OR4a, C(O)NHR3a, NR3aC(O)R3b, S(O)2R3a, S(O)R3a, NR4aR4b or (CH2)qA2;
• Cyc denotes a monocyclic or bicyclic, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered carbocyclyl or heterocyclyl, each optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from Hal, CN, R3a, OR3a, C(O)NR4aR4b, NR3aC(O)R3b, S(O)2R3a, S(O)R3a, NR4aR4b, Ar2, Het2, (CH2)rSR3a, (CH2)rN(R4a)2 or (CH2)rA2, where the monocyclic carbocyclyl is aromatic and at least one ring of the bicyclic carbocyclyl or heterocyclyl is aromatic, and further where the heterocyclyl comprises 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S;
• n denotes 1, 2, 3, 4, 5 or 6;
• p denotes 1, 2, 3, 4, 5 or 6;
• q denotes 0, 1, 2, 3 or 4;
• r denotes 0, 1, 2, 3 or 4;
• and
• Hal denotes F, Cl, Br or I;
• with the proviso that when LX denotes —O(CH2)n—, the oxygen atom of LX is bonded to X;
• and
• (ii) reacting the compound of formula (Ib) above with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid and trifluoroacetic acid, or a combination thereof, optionally in the presence of an excess of a small molecular weight boronic acid, to provide a compound of formula (Ia):
• wherein:
• LX denotes —CH2—, —O(CH2)n—, —S(CH2)p— or —(CH2)pS—, where 1, 2, 3, 4 or 5 H atoms may be independently replaced by Hal, N3, R3a, OR4a, (CH2)rA2, (CH2)rAr2 or (CH2)rHet2;
• LY denotes —CH2—;
• X denotes an aromatic 6-membered carbocyclyl or aromatic 6-membered heterocyclyl, each optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from Hal, A1, N3, CN, OH, NR4aR4b, Ar1, Het1, OA1, OAr1, OHet1, C(O)A1, C(O)Ar1, C(O)Het1, C(O)NR4aR4b, NR4aC(O)R3a, NR4aS(O)2R3a, S(O)2R3a, S(O)R3a, NR4aC(O)2R3a, OC(O)NR3aR4a, O(CH2)qA1, (CH2)rSR3a, (CH2)rN(R4a)2 or (CH2)rA2;
• Y denotes Cyc;
• R3a and R3b each independently denote linear or branched C1-C6 alkyl, where 1, 2, 3, 4 or 5 H atoms may be independently replaced by Hal, OH or OAlk;
• R4a and R4b each independently denote H or R3a;
• or
• R4a and R4b, together with the nitrogen atom to which they are attached, form a nitrogen-containing heterocyclyl comprising 3, 4, 5 or 6 carbon atoms;
• A1 denotes linear or branched C1-C6 alkyl or C3-C6 cycloalkyl, each optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from Hal, CN, R3a, SR3a, OR4a or (CH2)rA2, where 1, 2 or 3 CH2 groups of C3-C6 cycloalkyl may be independently replaced by O, C(O) or N;
• A2 denotes OR4a;
• Alk denotes linear or branched C1-C6 alkyl;
• Ar1 denotes phenyl, optionally substituted by 1, 2 or 3 substituents selected from Hal, NO2, CN, R3a, OR4a, C(O)NR4aR4b, NR4aC(O)R3b, S(O)2R3a, S(O)R3a, NR4aR4b, Ar2, Het2 or (CH2)rA2;
• Het1 denotes a saturated, unsaturated or aromatic 5- or 6-membered heterocyclyl comprising 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S, where each heterocyclyl may be optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from Hal, NO2, CN, R3a, OR4a, C(O)NR4aR4b, NR4aC(O)R3b, S(O)2R3a, S(O)R3a, NR4aR4b, Ar2, Het2 or (CH2)rA2;
• Ar2 denotes phenyl, biphenyl or naphthyl, each optionally and independently substituted by 1, 2 or 3 substituents selected from Hal, CN, R3a, OR4a, C(O)NR4aR4b, NR4aC(O)R3b, S(O)2R3a, S(O)R3a, NR4aR4b or (CH2)qA2;
• Het2 denotes a saturated, unsaturated or aromatic 5- or 6-membered heterocyclyl comprising 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S, optionally substituted by 1, 2 or 3 substituents selected from Hal, CN, R3a, OR4a, C(O)NHR3a, NR3aC(O)R3b, S(O)2R3a, S(O)R3a, NR4aR4b or (CH2)qA2;
• Cyc denotes a monocyclic or bicyclic, 4-, 5-, 6-, 7-, 8-, 9- or 10-membered carbocyclyl or heterocyclyl, each optionally and independently substituted by 1, 2, 3, 4 or 5 substituents selected from Hal, CN, R3a, OR3a, C(O)NR4aR4b, NR3aC(O)R3b, S(O)2R3a, S(O)R3a, NR4aR4b, Ar2, Het2, (CH2)rSR3a, (CH2)rN(R4a)2 or (CH2)rA2, where the monocyclic carbocyclyl is aromatic and at least one ring of the bicyclic carbocyclyl or heterocyclyl is aromatic, and further where the heterocyclyl comprises 1, 2 or 3 heteroatoms independently selected from the group consisting of N, O and S;
• n denotes 1, 2, 3, 4, 5 or 6;
• p denotes 1, 2, 3, 4, 5 or 6;
• q denotes 0, 1, 2, 3 or 4;
• r denotes 0, 1, 2, 3 or 4;
• and
• Hal denotes F, Cl, Br or I;
• with the proviso that when LX denotes —O(CH2)n—, the oxygen atom of LX is bonded to X.

A compound selected from the group consisting of:

• [(1R)-1-[[2-[(3,5-dichloro-2-pyridyl)oxy]acetyl]amino]-2-phenyl-ethyl]boronic acid;
• [(1R)-2-phenyl-1-[[2-(2-pyridyloxy)acetyl]amino]ethyl]boronic acid;
• [(1R)-1-[(2-phenoxyacetyl)amino]-2-phenyl-ethyl]boronic acid;
• [(1R)-1-(3-phenoxypropanoylamino)-2-(p-tolyl)ethyl]boronic acid;
• [(1R)-1-[3-(4-methoxyphenoxy)propanoylamino]-2-(p-tolyl)ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[(2-phenylacetyl)amino]-ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[3-(4-methylphenoxy)propanoylamino]-ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-(3-pyridyl)acetyl]amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-(4-cyanophenyl)acetyl]amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-(4-methoxyphenyl)acetyl]amino]-ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-(3-pyridyloxy)acetyl]amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-(6-methoxy-2-pyridyl)acetyl]amino]-ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-(5-ethoxy-2-pyridyl)acetyl]amino]-ethyl]boronic acid;
• [(1R)-1-[(2-phenylacetyl)amino]-2-(p-tolyl)ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-(3-methoxyphenyl)acetyl]amino]-ethyl]boronic acid;
• [(1R)-1-[[(2R)-2-hydroxy-2-phenyl-acetyl]amino]-2-(p-tolyl)ethyl]-boronic acid;
• [(1R)-1-[[(2S)-2-hydroxy-2-phenyl-acetyl]amino]-2-(p-tolyl)ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[(2-pyrazin-2-ylacetyl)amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-(4-pyridyl)acetyl]amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[(2-pyrimidin-2-ylacetyl)amino]ethyl]-boronic acid;
• [(1R)-1-[[2-(4-acetamidophenyl)acetyl]amino]-2-(p-tolyl)ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-(3,4,5-trifluorophenyl)acetyl]amino]-ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[(2,2-difluoro-2-phenyl-acetyl)amino]-ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-[2-(trifluoromethyl)phenyl]acetyl]amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-(2,6-dichlorophenyl)acetyl]-amino]-ethyl]boronic acid;
• [(1R)-[[2-(4-acetamidophenyl)acetyl]amino]-2-(benzofuran-3-yl)ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-(2-methoxyphenyl)acetyl]amino]-ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-[2-(trifluoromethoxy)phenyl]acetyl]amino]-ethyl]boronic acid;
• [(1R)-2-(2,4-dimethylphenyl)-1-[(2-phenylacetyl)amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-[4-(methoxymethyl)phenyl]acetyl]amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-[3-(3-hydroxypropoxy)phenyl]acetyl]amino]ethyl]-boronic acid;
• [(1R)-1-[[2-(3-acetamidophenyl)acetyl]amino]-2-(benzofuran-3-yl)ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[(2S)-2-methoxy-2-phenyl-acetyl]amino]ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[(2R)-2-methoxy-2-phenyl-acetyl]amino]ethyl]boronic acid;
• [(1R)-2-(2,4-dimethylphenyl)-1-[[2-(2,6-dimethylphenyl)acetyl]-amino]ethyl]boronic acid;
• [(1R)-2-(2,4-dimethylphenyl)-1-[(1-phenylcyclopropanecarbonyl)amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[(2S)-2-phenylpropanoyl]amino]ethyl]-boronic acid;
• [(1R)-1-[[2-(4-acetamidophenyl)acetyl]amino]-2-(2,4-dimethylphenyl)ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-[4-(2-hydroxyethoxy)phenyl]acetyl]amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-[4-(3-hydroxypropoxy)-phenyl]acetyl]amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-[3-(2-hydroxyethoxy)phenyl]acetyl]amino]ethyl]-boronic acid;
• [(1R)-1-[[2-(2,6-dimethoxyphenyl)acetyl]amino]-2-(2,4-dimethylphenyl)ethyl]-boronic acid;
• [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[4-(2-oxopyrrolidin-1-yl)phenyl]acetyl]-amino]ethyl]boronic acid;
• [(1R)-1-[[2-(4-dimethylaminophenyl)acetyl]amino]-2-(2,4-dimethylphenyl)ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[(2R)-2-phenylpropanoyl]amino]ethyl]-boronic acid;
• [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[4-(methanesulfonamido)phenyl]acetyl]-amino]ethyl]boronic acid;
• [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[4-[(2-methoxyacetyl)amino]phenyl]acetyl]-amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-[2-(methoxymethyl)phenyl]acetyl]amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-[3-(methoxymethyl)phenyl]acetyl]-amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-[2-(2-hydroxyethoxy)phenyl]acetyl]amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2,2-di fluoro-2-(4-methoxyphenyl)acetyl]amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-(3,4,5-trimethoxyphenyl)acetyl]amino]ethyl]-boronic acid;
• [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[4-[(2,2,2-trifluoroacetyl)amino]phenyl]amino]ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-(2-tetrahydropyran-4-yloxyphenyl)acetyl]amino]-ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-[2-(3-hydroxypropoxy)phenyl]-acetyl]amino]-ethyl]boronic acid;
• [(1S)-2-(benzofuran-3-yl)-1-[[(2S)-3-hydroxy-2-phenyl-propanoyl]-amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[(2S)-3-hydroxy-2-phenyl-propanoyl]-amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-(2,5-dimethoxyphenyl)acetyl]-amino]ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[(2R)-3-hydroxy-2-phenyl-propanoyl]-amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-(2,3,4-trimethoxyphenyl)acetyl]amino]ethyl]-boronic acid;
• [(1S)-2-(benzofuran-3-yl)-1-[[2-[2-(3-hydroxypropoxy)phenyl]acetyl]amino]ethyl]-boronic acid;
• [(1S)-2-(benzofuran-3-yl)-1-[[(2R)-3-hydroxy-2-phenyl-propanoyl]amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-[2-(morpholine-4-carbonyl)phenyl]acetyl]amino]ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-[4-(2-oxopyrrolidin-1-yl)phenyl]-acetyl]amino]-ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-[2-(ethylcarbamoyl)phenyl]acetyl]amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-[2-(dimethylcarbamoyl)phenyl]acetyl]amino]-ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-(4-phenylphenyl)acetyl]amino]ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[(2,2-diphenylacetyl)amino]ethyl]boronic acid;
• [(1 S)-2-(benzofuran-3-yl)-1-[[2-(4-phenylphenyl)acetyl]amino]ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[(2R)-2-ethoxy-2-phenyl-acetyl]amino]ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[3-(4-methoxyphenyl)-2-phenyl-propanoyl]amino]-ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-[3-(ethoxycarbonylamino)phenyl]-acetyl]amino]-ethyl]boronic acid;
• [(1R)-2-(2-chlorobenzofuran-3-yl)-1-[(2-phenylacetyl)amino]ethyl]-boronic acid;
• [(1R)-2-(2,3-dihydrobenzofuran-3-yl)-1-[(2-phenylacetyl)amino]-ethyl]boronic acid;
• [(1R)-2-(7-methylbenzofuran-3-yl)-1-[(2-phenylacetyl)amino]-ethyl]boronic acid;
• [(1R)-1-[[(2R)-2-methoxy-2-phenyl-acetyl]amino]-2-(7-methylbenzofuran-3-yl)ethyl]boronic acid;
• [(1R)-2-(7-methyl-2,3-dihydrobenzofuran-3-yl)-1-[(2-phenylacetyl)amino]ethyl]boronic acid;
• [(1R)-1-[[2-(2,5-dimethoxyphenyl)acetyl]amino]-2-(7-methylbenzofuran-3-yl)ethyl]boronic acid;
• [(1R)-1-[[(2S)-3-hydroxy-2-phenyl-propanoyl]amino]-2-(7-methylbenzofuran-3-yl)ethyl]boronic acid;
• [(1S)-1-[[(2S)-3-hydroxy-2-phenyl-propanoyl]amino]-2-(7-methylbenzofuran-3-yl)ethyl]boronic acid;
• [(1S)-1-[[2-(4-methoxyphenyl)acetyl]amino]-2-(7-methylbenzofuran-3-yl)ethyl]boronic acid;
• [(1R)-1-[[2-(4-methoxyphenyl)acetyl]amino]-2-(7-methylbenzofuran-3-yl)ethyl]boronic acid;
• [(1R)-1-[[(2R)-3-hydroxy-2-phenyl-propanoyl]amino]-2-(7-methylbenzofuran-3-yl)ethyl]boronic acid;
• [(1S)-1-[[(2R)-3-hydroxy-2-phenyl-propanoyl]amino]-2-(7-methylbenzofuran-3-yl)ethyl]boronic acid;
• [(1R)-2-(7-chlorobenzofuran-3-yl)-1-[(2-phenylacetyl)amino]ethyl]boronic acid;
• [(1R)-1-[3-(5-methoxy-2-pyridyl)propanoylamino]-2-(7-methyl-2,3-dihydrobenzofuran-3-yl)ethyl]boronic acid;
• [(1S)-1-[3-(5-methoxy-2-pyridyl)propanoylamino]-2-(7-methyl-2,3-dihydrobenzofuran-3-yl)ethyl]boronic acid;
• [(1R)-1-[[2-(4-methoxyphenyl)acetyl]amino]-2-[(3R)-7-methyl-2,3-dihydrobenzofuran-3-yl]ethyl]boronic acid;
• [(1R)-1-[[2-(4-methoxyphenyl)acetyl]amino]-2-[(3S)-7-methyl-2,3-dihydrobenzofuran-3-yl]ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-(2-cyanophenyl)acetyl]amino]ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-[4-(1-hydroxy-1-methyl-ethyl)phenyl]acetyl]amino]-ethyl]boronic acid;
• [(1R)-2-(7-methoxybenzofuran-3-yl)-1-[(2-phenylacetyl)amino]ethyl]boronic acid;
• [(1R)-1-[[(2R)-2-methoxy-2-phenyl-acetyl]amino]-2-(7-methyl-2,3-dihydrobenzofuran-3-yl)ethyl]boronic acid;
• [(1R)-2-(6,7-dimethylbenzofuran-3-yl)-1-[(2-phenylacetyl)amino]ethyl]boronic acid;
• [(1R)-2-(6,7-dimethylbenzofuran-3-yl)-1-[3-(5-methoxy-2-pyridyl)propanoylamino]-ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[(2S)-2-[2-(dimethylcarbamoyl)phenyl]propanoyl]amino]ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[(2R)-2-[2-(dimethylcarbamoyl)phenyl]propanoyl]amino]-ethyl]boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-(2-phenylphenyl)acetyl]amino]ethyl]boronic acid;
• [(1R)-2-[(3S)-2,3-dihydrobenzofuran-3-yl]-1-[[(2R)-2-[2-(dimethylcarbamoyl)phenyl]-propanoyl]amino]ethyl]boronic acid;
• [(1R)-1-[[2-[2-(dimethylcarbamoyephenyl]acetyl]amino]-2-(7-methyl-2,3-dihydrobenzofuran-3-yl)ethyl]boronic acid;
• [(1R)-2-(6,7-dimethyl-2,3-dihydrobenzofuran-3-yl)-1-[(2-phenylacetyl)amino]ethyl]-boronic acid;
• [(1R)-2-(6,7-dimethyl-2,3-dihydrobenzofuran-3-yl)-1-[3-(5-methoxy-2-pyridyl)-propanoylamino]ethyl]boronic acid;
• [(1R)-1-[[2-(2-acetamidophenyl)acetyl]amino]-2-(benzofuran-3-yl)ethyl]boronic acid;
• [(1R)-1-[[2-(2-cyanophenyl)acetyl]amino]-2-(7-methylbenzofuran-3-yl)ethyl]boronic acid;
• [(1R)-1-[[2-(2-cyanophenyl)acetyl]amino]-2-[(3 S)-2,3-dihydrobenzofuran-3-yl]ethyl]-boronic acid;
• [(1R)-2-[(3R)-2,3-dihydrobenzofuran-3-yl]-1-[[(2S)-2-[2-(dimethylcarbamoyephenyl]-propanoyl]amino]ethyl]boronic acid;
• [(1R)-2-[(3 S)-2,3-dihydrobenzofuran-3-yl]-1-[[(2S)-2-[2-(dimethylcarbamoyephenyl]-propanoyl]amino]ethyl]boronic acid;
• [(1R)-2-(benzofuran-2-yl)-14 [2-(4-methoxyphenyl)acetyl]amino]ethyl]boronic acid;
• [(1R)-1-[[(2R)-2-ethoxy-2-phenyl-acetyl]amino]-2-(7-methyl-2,3-dihydrobenzofuran-3-yl)ethyl]boronic acid;
• [(1R)-2-(benzofuran-2-yl)-1-[(2-phenylacetyl)amino]ethyl]boronic acid;
• (1R)-2-(2,3-dihydrobenzofuran-3-yl)-1-[[(2R)-2-ethoxy-2-phenyl-acetyl]amino]ethyl]-boronic acid;
• [2-(benzofuran-3-yl)-1-[[2-(2-pyridyl)acetyl]amino]ethyl]boronic acid;
• [(1R)-2-(7-chlorobenzofuran-3-yl)-1-[[2-(5-ethoxy-2-pyridyl)acetyl]amino]ethyl]boronic acid;
• [(1R)-2-[(3S)-2,3-dihydrobenzofuran-3-yl]-1-[[2-(4-methoxyphenyl)acetyl]amino]ethyl]-boronic acid;
• [(1R)-2-[(3R)-2,3-dihydrobenzofuran-3-yl]-1-[[2-(4-methoxyphenyl)acetyl]amino]ethyl]-boronic acid;
• [(1R)-2-(7-chlorobenzofuran-3-yl)-1-[[2-(2-cyanophenyl)acetyl]amino]ethyl]boronic acid;
• [(1S)-2-[(3S)-2,3-dihydrobenzofuran-3-yl]-14 [2-(4-methoxyphenyl)acetyl]amino]ethyl]-boronic acid;
• [(1S)-2-[(3R)-2,3-dihydrobenzofuran-3-yl]-1-[[2-(4-methoxyphenyl)acetyl]amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-[3-(morpholine-4-carbonyl)-2-pyridyl]acetyl]amino]-ethyl]boronic acid;
• [(1R)-2-[(3S)-7-methoxy-2,3-dihydrobenzofuran-3-yl]-1-[[2-(4-methoxyphenyl)acetyl]-amino]ethyl]boronic acid;
• [2-(7-fluorobenzofuran-3-yl)-1-[(2-phenylacetyl)amino]ethyl]boronic acid;
• [(1R)-2-[(3R)-2,3-dihydrobenzofuran-3-yl]-1-[[2-(4-methoxyphenyl)acetyl]amino]ethyl]-boronic acid;
• [(1R)-2-(benzofuran-3-yl)-1-[[2-(3-cyanophenyl)acetyl]amino]ethyl]boronic acid;
• [(1R)-2-[(3 S)-7-methyl-2,3-dihydrobenzofuran-3-yl]-1-[(2-phenylacetyl)amino]ethyl]-boronic acid;
• [(1R)-2-(7-fluorobenzofuran-3-yl)-1-[(2-phenylacetyl)amino]ethyl]boronic acid;
• [(1R)-2-(6-chloro-7-methyl-benzofuran-3-yl)-1-[(2-phenylacetyl)amino]ethyl]boronic acid;
• [(1R)-2-[(3R)-7-methyl-2,3-dihydrobenzofuran-3-yl]-1-[(2-phenylacetyl)amino]ethyl]-boronic acid;
• [(1R)-2-(4,7-dimethylbenzofuran-3-yl)-1-[(2-phenylacetyl)amino]ethyl]boronic acid;
• [(1R)-2-(4,7-dimethylbenzofuran-3-yl)-1-[[2-(4-methoxyphenyl)acetyl]amino]ethyl]-boronic acid;
• [(1R)-1-[[2-(2-cyanophenyl)acetyl]amino]-2-[(3S)-7-methyl-2,3-dihydrobenzofuran-3-yl]ethyl]boronic acid;
• [(1R)-2-[(3 S)-2,3-dihydrobenzofuran-3-yl]-1-[[2-(5-ethoxy-2-pyridyl)acetyl]amino]-ethyl]boronic acid;
• [(1R)-2-[(3S)-7-chloro-2,3-dihydrobenzofuran-3-yl]-1-[(2-phenylacetyl)amino]ethyl]-boronic acid;
• [(1R)-2-[(3R)-7-chloro-2,3-dihydrobenzofuran-3-yl]-1-[(2-phenylacetyl)amino]ethyl]-boronic acid;
• [(1R)-2-[(3S)-7-chloro-2,3-dihydrobenzofuran-3-yl]-1-[[2-(2-cyanophenyl)acetyl]-amino]ethyl]boronic acid;
• [(1R)-2-[(3R)-7-chloro-2,3-dihydrobenzofuran-3-yl]-1-[[2-(2-cyanophenyl)acetyl]-amino]ethyl]boronic acid;
• and
• [(1R)-2-[(3S)-2,3-dihydrobenzofuran-3-yl]-1-(3-phenoxypropanoylamino)ethyl]boronic acid, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.