BORONIC ACID DERIVATIVES
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Accused Products
Abstract
Compounds of formula (I) are inhibitors of LMP7 and can be employed, inter alia, for the treatment of an autoimmune disorder or hematological malignancies.
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Citations
54 Claims
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1-28. -28. (canceled)
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29. A compound of formula (I)
- View Dependent Claims (30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53)
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30. The compound according to claim 29, wherein R6 denotes Ar1, Het1 or A1.
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31. The compound according to claim 29, wherein:
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R1, R2 denote H or C1-C4-alkyl or R1 and R2 form together a residue according to formula (CE) and
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32. The compound according to claim 29, wherein:
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R5a, R5b denote each, independently from one another, H, F, Cl, methyl, ethyl, n-propyl, isopropyl, CH3, CH2CF3, CH2CHF2, CH2F, CHF2, CF3, OCH3, OCF3, OC2H5, CN, CH2CN, C2H5OCH3, CH2OCH3, OH;
or R5a and R5b form together a C3-C6-cycloalkyl residue;R6 denotes Ar1, HetAr or A1; R7, R8, R9, R10 denote each, independently from one another, H, F, Cl, (CH2)p—
CN, (CH2)p—
NR4aR4b, (CH2)p—
COOR4a, (CH2)p—
CONR4aR4b or linear or branched C1-C4-alkyl, wherein 1 to 5H atoms of the alkyl group may be replaced by Hal;A1 denotes linear or branched C1-C6-alkyl or C3-C6-cycloalkyl, each, independently from one another, unsubstituted or mono- or disubstituted by Hal, CN, Alk, OR4a and/or (CH2)r—
OR4a, and wherein 1 or 2 CH2 groups of C3-C6-cycloalkyl may be replaced by O, C═
O, and/or NR4a;p denotes 0 or 1; and 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.
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33. The compound according to claim 29, wherein:
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Cyc denotes phenyl, which is unsubstituted, mono-, di- or trisubstituted by Hal, CN, R3a, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2 (CH2)r—
SR3a, (CH2)r—
N(R4a)2 and/or (CH2)r—
OR4a;
wherein in case of monosubstitution of the phenyl residue the substituents are in 3-, or 4-position, in case of disubstitution substituents are in 2,3-, 2,4-, 2,5- or 3,4-position and in case of trisubstitution substituents are in 2,3,4-position;or 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-tetrahydronaphthalin 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 from one another, unsubstituted, mono-, disubstituted or trisubstituted by Hal, CN, R3a, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3aNR4aR4b, Ar2, Het2 (CH2)r—
SR3a, (CH2)r—
N(R4a)2 and/or (CH2)r—
OR4a;A1 denotes linear or branched C1-C6-alkyl or C3-C6-cycloalkyl, which is unsubstituted or mono-, di- or trisubstituted by Hal, Alk, CN, OR4a, and/or (CH2)r—
OR4a;r denote each, independently from one another, 0, 1, 2, 3 or 4; p denotes 0 or 1; and 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.
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34. The compound according to claim 29, wherein:
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LX is absent or denotes CH2, wherein 1 to 2H atoms may be replaced by F, Cl, CH3, C2H5, OCH3, OCF3, OC2H5; Cyc denotes phenyl, which is unsubstituted, mono-, di- or trisubstituted by Hal, CN, R3a, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2, (CH2)r—
SR3a, (CH2)r—
N(R4a)2 and/or (CH2)r—
OR4a;
wherein in case of monosubstitution of the phenyl residue the substituents are in 3-, or 4-position, in case of, in case of disubstitution substituents are in 2,3-, 2,4-, 2,5- or 3,4-position and in case of trisubstitution substituents are in 2,3,4-position;or 1- or 2-naphthyl, 2- or 3-benzofuryl, 2,3-dihydrobenzofuran-2- or 3-yl, 2- or 3-thienyl, 2- or 3-benzothienyl, or 2- or 3-indolyl, each independently from one another, unsubstituted, mono-, disubstituted or trisubstituted by Hal, CN, R3a, OR3a, CONR4aR4bNR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2, (CH2)r—
SR3a, (CH2)r—
N(R4a)2 and/or (CH2)r—
OR4a;A1 denotes linear or branched C1-C6-alkyl or C3-C6-cycloalkyl, which is unsubstituted or mono-, di- or trisubstituted by Hal, Alk, CN, OR4a, and/or (CH2)r—
OR4a;r denote each, independently from one another, 0, 1, 2, 3 or 4; p denotes 0 or 1; and 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.
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35. The compound according to claim 29, wherein:
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R1, R2 denote H or C1-C4-alkyl or R1 and R2 form together a residue according to formula (CE); LX is absent or denotes CH2, denotes CH2, wherein 1 to 2H atoms may be replaced by F, Cl, CH3, C2H5, OCH3, OCF3, OC2H5; LY denotes CH2 or CH2CH2, wherein 1 to 2H atoms may be replaced by Hal, R3b, OR4b; Y denotes Cyc; R5a, R5b denote each, independently from one another, methyl, ethyl, n-propyl, isopropyl, CH3, CH2CF3, CH2CHF2, CH2F, CHF2, CF3, OCH3, OCF3, OC2H5, CH2CN, CH2OCH3, OH;
or R5a and R5b form together a C3-C6-cycloalkyl residue;R6 denotes methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, CH2CF3, CH2CHF2, CH2F, CHF2, CF3, OCH3, OCF3, CH2CN, CH2OCH3;
or phenyl, which is unsubstituted, mono- or disubstituted by F, Cl, Br, CN, Alk, OAlk, CONR4aR4b and/or (CH2)r—
OR4a;R7, R8, R9, R10 denote each, independently from one another, C3-C6-cycloalkyl, Ar1, Het1, (CH2)1-2—
NR4aR4b, COOR4a, CN or NO2;
or linear or branched C1-C4-alkyl, wherein 1 to 5H atoms of the alkyl group may be replaced by Hal;Cyc denotes phenyl, which is unsubstituted, mono-, di- or trisubstituted by Hal, CN, R3a, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2, (CH2)r—
SR3a, (CH2)r—
N(R4a)2 and/or (CH2)r—
OR4a;
wherein in case of monosubstitution of the phenyl residue the substituents are in 3-, or 4-position, in case of disubstitution substituents are in 2,4-, or 3,4-position and in case of trisubstitution substituents are in 2,3,4-position;or 1- or 2-naphthyl, 2- or 3-benzofuryl, 2,3-dihydrobenzofuran-2- or 3-yl, 2- or 3-thienyl, 2- or 3-benzothienyl, or 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, each, independently from one another, unsubstituted, mono-, disubstituted or trisubstituted by Hal, CN, R3a, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2, (CH2)r—
SR3a, (CH2)r—
N(R4a)2 and/or (CH2)r—
OR4a;A1 denotes R3a or C3-C6-cycloalkyl, which is unsubstituted or mono-, di- or trisubstituted by Hal, Alk, CN, OR4a, and/or (CH2)r—
OR4a;r denote each, independently from one another, 0, 1, 2, 3 or 4; p denotes 0 or 1; and 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.
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36. The compound according to claim 29, wherein R7 and R9 denote each, independent from one another, H, C2H5, CF3, OCH3, OC2H5, COCF3, Cl or F;
- and R8 denotes H, F, Cl, (CH2)1-2—
CN, (CH2)1-2—
NR4aR4b, (CH2)1-2—
COOR4a, (CH2)p—
CONR4aR4b or linear or branched C1-C4-alkyl, wherein 1 to 5H atoms of the alkyl group may be replaced by Hal.
- and R8 denotes H, F, Cl, (CH2)1-2—
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37. The compound according to claim 29, wherein:
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X is a residue of formula xa); R5a, R5b denote each, H or R5a is H and R5b denotes methyl, ethyl, n-propyl, isopropyl, CH3, CH2CF3, CH2CHF2, CH2F, CHF2, CF3, OCH3, OCF3, OC2H5, CH2CN, CH2OCH3, OH; and LX is absent or CH2 or CF2 (preferably absent).
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38. The compound according to claim 29, wherein R7 and R9 denote each, independent from one another, H, Cl, F and R8 denotes C3-C6-cycloalkyl, Ar1, Het1, COOR4a, CN or NO2.
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39. The compound according to claim 29, wherein R7 and R9 denote H and R8 denotes H, CH3, C3-C6-cycloalkyl, Ar1, Het1, (CH2)1-2—
- NR4aR4b, COOR4a, CN or NO2 (CH3, CF3, OCH3, OCF3, CH2N(CH3)2, COOCH3 or COOC2H5, COOisopropyl).
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40. The compound according to claim 29, wherein R7, R8 and R9 denote H.
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41. The compound according to claim 29, wherein R7 and R9 denote H and R8 denotes C3-C6-cycloalkyl, Ar1, Het1, (CH2)1-2—
- NR4aR4b, COOR4a, CN or NO2 (preferably CH3, CF3, OCH3, OCF3, CH2N(CH3)2, COOCH3 or COOC2H5).
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42. The compound according to claim 29, wherein R6 denotes cyclopropyl, Ar1, Het1, each, independent from one another, unsubstituted, mono-, disubstituted or trisubstituted by Hal, CN, OCH3, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, CH2—
- CF3, CH2—
CHF2.
- CF3, CH2—
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43. The compound according to claim 29, wherein:
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X is a residue of formula xa); R5a, R5b denote each, H or R5a is H and R5b denotes methyl, ethyl, n-propyl, isopropyl, CH3, CH2CF3, CH2CHF2, CH2F_CHF2, CF3, OCH3, OCF3, OC2H5, CH2CN, CH2OCH3, OH; and LX is absent or CH2 or CF2 (preferably absent); Cyc denotes unsubstituted or mono- or disubstituted 2- or 3-thienyl;
unsubstituted or 3-, 4-, 2,3-, 2,4-, 2,5-, 3,4- or 2,3,4-substituted phenyl;
or unsubstituted or mono- or disubstituted 1- or 2-naphthyl, wherein in each case the substituents are each, independently from one another, selected from the group consisting of Hal, CN, R3a, OR3a, CONHR3a, CONR3bR3a, CONH2, NR3aCOR3b, SO2R3a, SOR3a, NHR3a, N(R3a)2, (CH2)r—
SR3a, (CH2)r—
N(R4a)2 and/or (CH2)r-A2;or Cyc is a residue according to formula (Fa7) or (Fb7)
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44. The compound according to claim 43, wherein Cyc denotes:
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unsubstituted or mono- or disubstituted 2- or 3-thienyl;
unsubstituted or 3-, 4-, 2,3-, 2,4-, 2,5-, 3,4- or 2,3,4-substituted phenyl;
or unsubstituted or mono- or disubstituted 1- or 2-naphthyl, wherein in each case the substituents are each, independently from one another, selected from the group consisting of Hal, CN, R3a, OR3a, CONHR3a, CONR3bR3a, CONH2, NR3aCOR3b, SO2R3a, SOR3a, NHR3a, N(R3a)2, (CH2)r—
SR3a, (CH2)r—
N(R4a)2 and/or (CH2)r-A2;or Cyc is a residue according to formula (Fa7) or (S)-(Fb7)
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45. The compound according to claim 43, wherein Cyc denotes:
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unsubstituted or 3-, 4-, 2,3-, 2,4-, 2,5-, 3,4- or 2,3,4-substituted phenyl, wherein the substituents are each, independently from one another, selected from the group consisting of Hal, CN, R3a, OR3a, CONHR3a, CONR3bR3a, CONH2, NR3aCOR3b, SO2R3a, SOR3a, NHR3a, N(R3a)2, (CH2)r—
SR3a, (CH2)r—
N(R4a)2 and/or (CH2)r-A2;or Cyc is a residue according to formula (Fa7), (Fb7) or (S)-(Fb7), wherein; Ga denotes F, Cl, CH3, C2H5, CF3, OCH3, OC2H5, COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 or N(C2H5)2; Gb denotes H, F, Cl, CH3, C2H5, CF3, OCH3, OC2H5, COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 or N(C2H5)2; Ka, Kb denote each, independently from one another, H, F, Cl, CH3, C2H5, CF3, OCH3, OC2H5, COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 or N(C2H5)2; and 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
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46. The compound according to claim 29, wherein the boronic acid residue shows an (R)-configuration
Cyc denotes unsubstituted or 3-, 4-, 2,3-, 2,4-, 2,5-, 3,4- or 2,3,4-substituted phenyl, wherein the substituents are each, independently from one another, selected from the group consisting of Hal, CN, R3a, OR3a, CONHR3a, CONR3bR3a, CONH2, NR3aCOR3b, SO2R3a, SOR3a, NHR3a, N(R3a)2, (CH2)r— - SR3a, (CH2)r—
N(R4a)2 and/or (CH2)r-A2;or Cyc is a residue according to formula (Fa7), (Fb7) or (S)-(Fb7), wherein; Ga denotes F, Cl, CH3, C2H5, CF3, OCH3, OC2H5, COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 or N(C2H5)2; Gb denotes H, F, Cl, CH3, C2H5, CF3, OCH3, OC2H5, COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 or N(C2H5)2; Ka, Kb denote each, independently from one another, H, F, Cl, CH3, C2H5, CF3, OCH3, OC2H5, COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 or N(C2H5)2; and 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.
- SR3a, (CH2)r—
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47. The compound according to claim 29, said compound being selected from the group consisting of:
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[(1R)-2-(2,4-dimethylphenyl)-1-[[2-(2-fluoro-N-prop-2-enoyl-anilino)acetyl]amino]-ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-(4-fluoro-N-prop-2-enoyl-anilino)acetyl]amino]-ethyl]boronic acid; [(1R)-1-[[2-[2-but-2-ynoyl(propyl)amino]acetyl]amino]-2-(2,4-dimethylphenyl)ethyl]-boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-(3-fluoro-N-prop-2-enoyl-anilino)acetyl]amino]-ethyl]boronic acid; [(1R)-2-(3,4-dimethylphenyl)-1-[[2-[prop-2-noyl(propyl)amino]acetyl]amino]ethyl]-boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[prop-2-enoyl(propyl)amino]acetyl]amino]ethyl]-boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-(N-prop-2-ynoylanilino)acetyl]amino]ethyl]-boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[(1-prop-2-enoylindoline-2-carbonyl)amino]ethyl]-boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[N-prop-2-enoyl-4-(trifluoromethoxy)anilino]-acetyl]amino]ethyl]boronic acid; [(1R)-2-(3,4-dimethylphenyl)-1-[[2-[methyl(vinylsulfonyl)amino]acetyl]amino]ethyl]-boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[methyl(prop-2-ynoyl)amino]acetyl]amino]-ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[ethyl(prop-2-ynoyl)amino]acetyl]amino]ethyl]-boronic acid; [(1R)-1-[[2-[[(E)-3-chloroprop-2-enoyl]-methyl-amino]acetyl]amino]-2-(2,4-dimethylphenyl)ethyl]boronic acid; [(1R)-2-(3,4-dimethylphenyl)-1 [[2-[ethyl(prop-2-enoyl)amino]acetyl]amino]ethyl]-boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[methyl(vinylsulfonyl)amino]acetyl]amino]-ethyl]boronic acid; [(1R)-2-(3,4-dimethylphenyl)-1-[[2-[methyl(prop-2-enoyl)amino]acetyl]amino]-ethyl]boronic acid; [(1R)-2-(3,4-dimethylphenyl)-1-[[2-(N-prop-2-enoylanilino)acetyl]amino]ethyl]-boronic acid; [(1R)-1-[[2-[[(Z)-but-2-enoyl]-ethyl-amino]acetyl]amino]-2-(2,4-dimethylphenyl)-ethyl]boronic acid; [(1R)-1-[[2-[but-2-ynoyl(ethyl)amino]acetyl]amino]-2-(2,4-dimethylphenyl)ethyl]j-boronic acid; [(1R)-1-[[2-[but-2-ynoyl(methyl)amino]acetyl]amino]-2-(2,4-dimethylphenyl)ethyl]-boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[ethyl-[(Z)-2-methylbut-2-enoyl]amino]acetyl]-amino]ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[ethyl-[(E)-2-methylbut-2-enoyl]amino]acetyl]-amino]ethyl]boronic acid; [(1R)-1-[[2-[[(E)-but-2-enoyl]-ethyl-amino]acetyl]amino]-2-(2,4-dimethylphenyl)-ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[ethyl(3-methylbut-2-enoyl)amino]acetyl]-amino]ethyl]boronic acid; [(1R)-2-(4-chlorophenyl)-1-[[2-[ethyl(prop-2-enoyl)amino]acetyl]amino]ethyl]-boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-(N-prop-2-enoylanilino)acetyl]amino]ethyl]-boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[isopropyl(prop-2-enoyl)amino]acetyl]amino]-ethyl]boronic acid; [(1R)-1-[[2-[ethyl(2-methylprop-2-enoyl)amino]acetyl]amino]-2-phenyl-ethyl]-boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[ethyl(vinylsulfonyl)amino]acetyl]amino]ethyl]-boronic acid; [(1R)-1-[[2-[ethyl(prop-2-enoyl)amino]acetyl]amino]-2-(4-fluorophenyl)ethyl]-boronic acid; [(1R)-1-[[2-[ethyl(prop-2-enoyl)amino]acetyl]amino]-2-(p-tolyl)ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[ethyl(2-methylprop-2-enoyl)amino]acetyl]-amino]ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[methyl(prop-2-enoyl)amino]acetyl]amino]-ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[ethyl(prop-2-enoyl)amino]acetyl]amino]ethyl]-boronic acid; [(1R)-1-[[2-[isopropyl(prop-2-enoyl)amino]acetyl]amino]-2-phenyl-ethyl]boronic acid; [(1R)-2-(benzofuran-3-yl)-1-[[2-[ethyl(prop-2-enoyl)amino]acetyl]amino]ethyl]-boronic acid; [(1R)-1-[[2-[ethyl(prop-2-enoyl)amino]acetyl]amino]-2-phenyl-ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[(2R)-1-prop-2-enoylpiperidine-2-carbonyl]amino]ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[(2S)-1-prop-2-enoylpiperidine-2-carbonyl]amino]ethyl]boronic acid; [(1R)-2-(2,4-dichlorophenyl)-1-[[2-[ethyl(prop-2-enoyl)amino]acetyl]amino]ethyl]boronic acid; [(1R)-1-[[2-(2,3-difluoro-N-prop-2-enoyl-anilino)acetyl]amino]-2-(2,4-dimethylphenyl)ethyl]boronic acid; [(1R)-1-[[2-(2,5-difluoro-N-prop-2-enoyl-anilino)acetyl]amino]-2-(2,4-dimethylphenyl)ethyl]boronic acid; [(1R)-1-[[2-(2,6-difluoro-N-prop-2-enoyl-anilino)acetyl]amino]-2-(2,4-dimethylphenyl)ethyl]boronic acid; [(1R)-1-[[2-(2-fluoro-N-prop-2-enoyl-anilino)acetyl]amino]-2-phenyl-ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[(2R)-2-(N-prop-2-enoylanilino)propanoyl]-amino]ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[(2S)-2-(N-prop-2-enoylanilino)propanoyl]-amino]ethyl]boronic acid; [(1R)-2-(3,4-dimethylphenyl)-1-[[(2R)-2-(N-prop-2-enoylanilino)propanoyl]-amino]ethyl]boronic acid; [(1R)-2-(3,4-dimethylphenyl)-1-[[(2S)-2-(N-prop-2-enoylanilino)propanoyl]-amino]ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[(2S)-2-[methyl(prop-2-enoyl)amino]-propanoyl]amino]ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[ethyl-[(E)-4-methoxy-4-oxo-but-2-enoyl]amino]acetyl]amino]ethyl]boronic acid; [(1R)-2-(2,4-dichlorophenyl)-1-[[(2R)-1-prop-2-enoylpiperidine-2-carbonyl]amino]ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[(2R)-2-[methyl(prop-2-enoyl)amino]-propanoyl]amino]ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[(2R)-1-prop-2-enoylpyrrolidine-2-carbonyl]amino]ethyl]boronic acid; [(1R)-2-(2,4-dichlorophenyl)-1-[[(2R)-1-prop-2-enoylpyrrolidine-2-carbonyl]amino]ethyl]boronic acid; [(1R)-2-(4-chlorophenyl)-1-[[2-(2-fluoro-N-prop-2-enoyl-anilino)acetyl]-amino]ethyl]boronic acid; [(1R)-1-[[2-[cyanomethyl(prop-2-enoyl)amino]acetyl]amino]-2-(2,4-dimethylphenyl)ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[prop-2-enoyl(2,2,2-trifluoroethyl)amino]acetyl]amino]ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[(2S)-1-prop-2-enoylpyrrolidine-2-carbonyl]amino]ethyl]boronic acid; [(1R)-1-[[2-[cyclopropyl(prop-2-enoyl)amino]acetyl]amino]-2-(2,4-dimethylphenyl)ethyl]boronic acid; [(1R)-2-(2,4-dichlorophenyl)-1-[[2-[prop-2-enoyl(2,2,2-trifluoroethyl)amino]-acetyl]amino]ethyl]boronic acid; [(1R)-2-(3,4-dimethylphenyl)-1-[[2-[prop-2-enoyl(2,2,2-trifluoroethyl)-amino]acetyl]amino]ethyl]boronic acid; [(1R)-1-[[2-[[(E)-4-(dimethylamino)-4-oxo-but-2-enoyl]-ethyl-amino]acetyl]-amino]-2-(2,4-dimethylphenyl)ethyl]boronic acid; [(1R)-1-[[2-[cyanomethyl(prop-2-enoyl)amino]acetyl]amino]-2-(3,4-dimethylphenyl)ethyl]boronic acid; [(1R)-1-[[2-[ethyl(prop-2-enoyl)amino]acetyl]amino]-2-[2-methyl-4-(trifluoromethyl)phenyl]ethyl]boronic acid; [(1R)-2-(3,4-dichlorophenyl)-1-[[2-[ethyl(prop-2-enoyl)amino]acetyl]-amino]ethyl]boronic acid; [(1R)-2-(3,4-dichlorophenyl)-1-[[2-[methyl(prop-2-enoyl)amino]acetyl]-amino]ethyl]boronic acid; [(1R)-1-[[2-[methyl(prop-2-enoyl)amino]acetyl]amino]-2-[2-methyl-4-(trifluoromethyl)phenyl]ethyl]boronic acid; [(1R)-2-(3,4-dimethylphenyl)-1-[[(2S)-2-[methyl(prop-2-enoyl)amino]propanoyl]amino]ethyl]boronic acid; [(1R)-1-[[2-[cyclopropyl(prop-2-enoyl)amino]acetyl]amino]-2-(3,4-dichlorophenyl)ethyl]boronic acid; [(1R)-1-[[2-[cyclopropyl(prop-2-enoyl)amino]acetyl]amino]-2-(2,4-dichlorophenyl)ethyl]boronic acid; [(1R)-1-[[2-[cyclopropyl(prop-2-enoyl)amino]acetyl]amino]-2-(3,4-dimethylphenyl)ethyl]boronic acid; [(1R)-1-[[2-[ethyl(prop-2-enoyl)amino]acetyl]amino]-2-(2,3,4-trimethylphenyl)ethyl]boronic acid; [(1S)-1-[[2-[methyl(prop-2-enoyl)amino]acetyl]amino]-2-(3-thienyl)ethyl]boronic acid; [(1R)-1-[[2-[methyl(prop-2-enoyl)amino]acetyl]amino]-2-(2,3,4-trimethylphenyl)ethyl]boronic acid; [(1R)-1-[[2-[methyl(prop-2-enoyl)amino]acetyl]amino]-2-(3-thienyl)ethyl]-boronic acid; [(1 S)-1-[[2-[ethyl(prop-2-enoyl)amino]acetyl]amino]-2-(3-thienyl)ethyl]-boronic acid; [(1R)-1l-[[2-[ethyl(prop-2-enoyl)amino]acetyl]amino]-2-(3-thienyl)ethyl]-boronic acid; [(1R)-1-[[2-(2-fluoro-N-prop-2-enoyl-anilino)acetyl]amino]-2-(3-thienyl)ethyl]boronic acid; [(1R)-1-[[2-[ethyl(prop-2-enoyl)amino]acetyl]amino]-2-(1-naphthyl)ethyl]-boronic acid; [(1R)-1-[[2-[methyl(prop-2-enoyl)amino]acetyl]amino]-2-(1-naphthyl)ethyl]-boronic acid; [(1R)-1-[[2-[ethyl(prop-2-enoyl)amino]acetyl]amino]-2-(2-naphthyl)ethyl]-boronic acid; [(1R)-1-[[2-[methyl(prop-2-enoyl)amino]acetyl]amino]-2-(2-naphthyl]-boronic acid; [(1R)-1-[[2-[2,2-difluoroethyl(prop-2-enoyl)amino]acetyl]amino]-2-(3,4-dimethylphenyl)ethyl]boronic acid; [(1R)-1-[[2-[2,2-difluoroethyl(prop-2-enoyl)amino]acetyl]amino]-2-(2,4-dimethylphenyl)ethyl]boronic acid; [(1R)-2-(2,4-dichlorophenyl)-1-[[2-[methyl(prop-2-enoyl)amino]acetyl]-amino]ethyl]boronic acid; [(1R)-2-(benzofuran-3-yl)-1-[[2-(2-fluoro-N-prop-2-enoyl-anilino)acetyl]-amino]ethyl]boronic acid; [(1R)-1-[[2-(2-chloro-N-prop-2-enoyl-anilino)acetyl]amino]-2-(2,4-dimethylphenyl)ethyl]boronic acid; [(1R)-2-(3,4-dimethylphenyl)-1-[[2-(prop-2-enoylamino)acetyl]-amino]ethyl]boronic acid; [(1R)-1-[[2-(2-chloro-N-prop-2-enoyl-anilino)acetyl]amino]-2-(3-thienyl)ethyl]boronic acid; [(1R)-1-[[2-[cyclopropyl(prop-2-enoyl)amino]acetyl]amino]-2-(3-thienyl)ethyl]boronic acid; [(1R)-1-[[2-(2-fluoro-N-prop-2-enoyl-anilino)acetyl]amino]-2-[(3R)-7-methyl-2,3-dihydrobenzofuran-3-yl]ethyl]boronic acid; [(1R)-1-[[2-(N-prop-2-enoylanilino)acetyl]amino]-2-(3-thienyl)ethyl]boronic acid; [1-[[2-(2-ethyl-N-prop-2-enoyl-anilino)acetyl]amino]-2-(3-thienyl)ethyl]-boronic acid; [(1R)-1-[[2-(3-ethyl-N-prop-2-enoyl-anilino)acetyl]amino]-2-(3-thienyl)ethyl]boronic acid; [(1R)-1-[[2-(3,5-dichloro-N-prop-2-enoyl-anilino)acetyl]amino]-2-(3-thienyl)ethyl]boronic acid; [(1R)-1-[[2-(4-ethyl-N-prop-2-enoyl-anilino)acetyl]amino]-2-(3-thienyl)ethyl]boronic acid; [(1R)-1-[[2-(3,4-dichloro-N-prop-2-enoyl-anilino)acetyl]aminol-2-(3-thienyl)ethyl]boronic acid; [(1R)-2-(3-fluorophenyl)-1-[[2-(2-fluoro-N-prop-2-enoyl-anilino)acetyl]amino]ethyl]boronic acid; [(1R)-1-[[2-(3,4-dimethoxy-N-prop-2-enoyl-anilino)acetyl]amino]-2-(3-thienyl)ethyl]boronic acid; [(1R)-2-[(3 S)-2,3-dihydrobenzofuran-3-yl]-1-[[2-(2-fluoro-N-prop-2-enoyl-anilino)acetyl]amino]ethyl]boronic acid; [(1R)-1-[[2-(2-fluoro-N-prop-2-enoyl-anilino)acetyl]amino]-3-phenyl-propyl]boronic acid; [(1R)-1-[[2-[3-(dimethylcarbamoyl)-N-prop-2-enoyl-anilino]acetyl]amino]-2-(3-thienyl)ethyl]boronic acid; [(1R)-1-[[2-[4-(dimethylcarbamoyl)-N-prop-2-enoyl-anilino]acetyl]amino]-2-(3-thienyl)ethyl]boronic acid; [(1R)-1-[[2-(4-bromo-N-prop-2-enoyl-anilino)acetyl]amino]-2-(2-thienyl)ethyl]boronic acid; [(1R)-1-[[2-[[(E)-4-(dimethylamino)but-2-enoyl]-ethyl-amino]acetyl]amino]-2-(2,4-dimethylphenyl)ethyl]boronic acid; and 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.
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48. A process for the preparation of a compound of formula (I) and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, characterized in that a compound of Formula (III)
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49. A pharmaceutical composition comprising at least one compound of claim 29 and its 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, as active ingredient, together with a pharmaceutically acceptable carrier.
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50. The pharmaceutical composition according to claim 49, said composition further comprising a second active ingredient and its 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, wherein that second active ingredient is other than a compound of formula (I).
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51. A method of treating a subject for medical conditions that are affected by inhibiting LMP7 comprising administering a compound according to claim 29 or its 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 to said subject.
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52. The method according to claim 51, wherein said medical condition being an immunoregulatory abnormality or hematological malignancies.
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53. The method according to claim 52, wherein the immunoregulatory abnormality is an autoimmune or chronic inflammatory disease selected from the group consisting of systemic lupus erythematosis, chronic rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), atherosclerosis, scleroderma, autoimmune hepatitis, Sjogren Syndrome, lupus nephritis, glomerulonephritis, Rheumatoid Arthritis, Psoriasis, Myasthenia Gravis, Imunoglobuline A nephropathy, Vasculitis, Transplant rejection, Myositis, Henoch-SchOnlein Purpura and asthma;
- and wherein the hematological malignancy is a disease selected from the group consisting of Multiple myeloma, chronic lymphoid leukemia, acute myeloid leukemia and mantle cell lymphoma.
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30. The compound according to claim 29, wherein R6 denotes Ar1, Het1 or A1.
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54. A kit consisting of separate packs of:
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(a) an effective amount of a compound of the formula (I) and/or pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios, and (b) an effective amount of a further medicament active ingredient.
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Specification
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Current AssigneeMerck Patent GmbH (Merck & Co., Inc.)
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Original AssigneeMerck Patent GmbH (Merck & Co., Inc.)
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InventorsKLEIN, MARKUS, SCHADT, OLIVER, HASELMAYER, PHILIPP, KRIER, MIREILLE
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current
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CPC Class CodesA61K 31/69 Boron compoundsA61P 1/00 Drugs for disorders of the ...A61P 1/04 for ulcers, gastritis or re...A61P 1/16 for liver or gallbladder di...A61P 11/06 AntiasthmaticsA61P 13/12 of the kidneysA61P 17/00 Drugs for dermatological di...A61P 17/06 AntipsoriaticsA61P 19/02 for joint disorders, e.g. a...A61P 21/00 Drugs for disorders of the ...A61P 21/04 for myasthenia gravisA61P 25/00 Drugs for disorders of the ...A61P 29/00 Non-central analgesic, anti...A61P 35/00 Antineoplastic agentsA61P 35/02 specific for leukemiaA61P 37/00 Drugs for immunological or ...A61P 37/02 ImmunomodulatorsA61P 37/06 Immunosuppressants, e.g. dr...A61P 43/00 Drugs for specific purposes...A61P 9/00 Drugs for disorders of the ...A61P 9/10 : for treating ischaemic or a...C07F 5/025 : Boronic and borinic acid co...