BORONIC ACID DERIVATIVES
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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
40 Claims
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1-21. -21. (canceled)
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22. A compound of formula (I)
- View Dependent Claims (23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39)
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23. The compound according to claim 22, wherein Y denotes Cyc 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;
- with the provisio that compound (R)-(2-(benzofuran-3-yl)-1-(2-(N-methylmethylsulfonamido) acetamido)ethyl)boronic acid is excluded.
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24. The compound according to claim 22, wherein Cyc denotes phenyl, which is unsubstituted, mono-, di- or trisubstituted by Hal, CN, R3a, OR3a, CONHR3a, CONR3bR3a, CONH2, NR3aCOR3b, SO2R3a, SOR3a, NHR3a, N(R3a)2, Ar2, Het2 ,(CH2)q—
- SR3a, (CH2)q—
N(R3a)2 and/or (CH2)q—
Z;or 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- or 3-thienyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2,3-dihydrobenzofuran-2- or 3-yl, 2-, 3-, 4-, 5-, 6- or 7-benzothiophenyl, benzodioxan-6- or 7-yl or 3,4-dihydro-1,5-benzodioxepin-6- or -7-yl, each, independently form one another, unsubstituted or mono-, di- or trisubstituted by Hal, CN, R3a, OR3a, CONHR3a, CONR3bR3a, CONH2, NR3aCOR3b, SO2R3a, SOR3a, NHR3a, N(R3a)2, Ar2, Het2 ,(CH2)q—
SR3a, (CH2)q—
N(R3a)2 and/or (CH2)q—
Z ; 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;
with the provisio that compound (R)-(2-(benzofuran-3-yl)-1-(2-(N-methylmethylsulfonamido) acetamido)ethyl)boronic acid is excluded.
- SR3a, (CH2)q—
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25. The compound according to claim 22, wherein:
R1, R2 denote H or C1-C4-alkyl, or R1 and R2 form together a residue according to formula (CE)
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26. The compound according to claim 22, wherein Cyc denotes 3-, 4-, 2,4-, 3,4-, or 2,3,4-substituted phenyl, wherein the substituents are selected from the group consisting of Hal, CN, R3a, OR3a, CONHR3a, CONR3bR3a, CONH2, NR3aCOR3b, SO2R3a, SOR3a, NHR3a, N(R3a)2, (CH2)q—
- SR3a, (CH2)q—
N(R3a)2 and/or (CH2)q—
Z;or 1- or 2-naphthyl, 2- or 3-thienyl, 3-benzofuryl or 2,3-dihydrobenzofuran-3-yl, each independently from one another unsubstituted or mono-, di- or trisubstituted by Hal, CN, R3a, OR3a, CONHR3a, CONR3bR3a, CONH2, NR3aCOR3b, SO2R3a, SOR3a, NHR3a, N(R3a)2, (CH2)q—
SR3a, (CH2)q—
N(R3a)2 and/or (CH2)q—
Z;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;
with the provisio that compound (R)-(2-(benzofuran-3-yl)-1-(2-(N-methylmethylsulfonamido) acetamido)ethyl)boronic acid is excluded.
- SR3a, (CH2)q—
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27. The compound according to claim 26, wherein Cyc denotes:
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2,4-, 3,4-, or 2,3,4-substituted phenyl, wherein the substituents are selected from the group consisting of Hal, CN, R3a, OR3a, CONHR3a, CONR3bR3a, CONH2, NR3aCOR3b, SO2R3a, SOR3a, NHR3a, N(R3a)2, (CH2)q—
SR3a, (CH2)q—
N(R3a)2 and/or (CH2)q—
Z;or 1- or 2-naphthyl, 2- or 3-thienyl, 3-benzofuryl or 2,3-dihydrobenzofuran-3-yl, each independently from one another unsubstituted or mono-, di- or trisubstituted by Hal, CN, R3a, OR3a, CONHR3a, CONR3bR3a, CONH2, NR3aCOR3b, SO2R3a, SOR3a, NHR3a, N(R3a)2, (CH2)q—
SR3a, (CH2)q—
N(R3a)2 and/or (CH2)q—
Z; and
wherein q denotes 1 or 2, and R3a, R3b and R3c denote each, independently from one another, linear or branched C1-C3-alkyl, wherein 1 to 5 H atoms may be replaced by F, Cl, OH and OAlk, wherein Alk is methyl or ethyl; 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;
with the provisio that compound (R)-(2-(benzofuran-3-yl)-1-(2-(N-methylmethylsulfonamido) acetamido)ethyl)boronic acid is excluded.
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28. The compound according to claim 27, wherein Cyc denotes:
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2,4-, 3,4-, or 2,3,4-substituted phenyl or unsubstituted or mono- or disubstituted 1- or 2-naphthyl, 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)q—
SR3a, (CH2)q—
N(R3a)2 and/or (CH2)q—
Z;or Cyc is a residue according to formula (Fa7) or (Fb7)
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29. The compound according to claim 28, wherein Cyc denotes:
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2,4-, 3,4-, or 2,3,4-substituted phenyl or unsubstituted or mono- or disubstituted 1- or 2-naphthyl, 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)q—
SR3a, (CH2)q—
N(R3a)2 and/or (CH2)q—
Z;or Cyc is a residue according to formula (Fa7) or (S)-(Fb7)
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30. The compound according to claim 28, wherein Cyc denotes:
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2,4-, 3,4-, or 2,3,4-substituted phenyl or unsubstituted or mono- or disubstituted 1- or 2-naphthyl, wherein the substituents are each, independently from one another, selected from the group consisting of F, Cl, CH3, C2H5, CF3, OCH3, OC2H5, COCF3, SCH3, SC2H5, CH2OCH3, N(CH3)2, CH2N(CH3)2 or N(C2H5)2; 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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31. The compound according to claim 22, wherein the stereogenic center at the carbon atom adjacent to the boronic acid residue shows an (R)-configuration;
- and wherein;
LX denotes —
CH2—
, —
CH2—
CH2—
, —
CH2—
CH2—
CH2—
, —
CH2—
CH2—
CH2—
CH2—
, —
CH2—
CH2—
O—
CH2—
wherein 1 to 4 H atoms may be replaced by F or Cl and/or 1 or 2 H atoms may be replaced by OH, methy, ethyl, isopropyl, CF3, CF2CF3, OCH3, OCH2CH3, O—
CH2—
CH2—
OH, O—
CH2—
CH2—
OCH3, phenyl, tolyl, ethylphenyl, fluorophenyl, chlorophenyl, bromophenyl, aminophenyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidyl, morpholinyl and/or piperidinyl; andLY denotes —
CH2—
or —
CH2—
CH2—
wherein 1 to 4 H atom may be replaced by F or Cl and/or 1 or 2 H atoms may be replaced by OH, methy, ethyl, isopropyl, CF3, CF2CF3, OCH3, OCH2CH3, O—
CH2—
CH2—
OH and/or O—
CH2—
CH2—
OCH3; andY denotes Cyc; and R1, R2 denote each, independently from one another H or C1-C4-alkyl, or R1 and R2 form together a residue according to formula (CE) as described above; and R3a, R3b and R3c denote each, independently from one another, linear or branched C1-C3-alkyl, wherein 1 to 5 H atoms may be replaced by F, Cl, OH and OAlk, wherein Alk is methyl or ethyl; and A denotes ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl, each unsubstituted or mono-, di-, tri- or tetrasubstituted by Hal, CN, R3a, SR3a ,OR3a, Ar1, Het1, and/or (CH2)q—
Z; andAr1 denotes 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-ethyl-amino)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-(methylsulfonyl)phenyl, o-, m- or p-methylsulfanylphenyl, o-, m- or p-cyanophenyl, o-, m- or p-(3-oxomorpholin-4-yl)phenyl, o-, m- or p-(piperidinyl)phenyl, o-, m- or p-(morpholin-4-yl)phenyl, furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or 2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-di chloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl; and Het1 denotes 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, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl or pyrazinyl, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxaneyl, 1,3-dioxane-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl or 1-, 2- or 3-piperazinyl, each unsubstituted or mono- or disubstituted by F, Cl, CH3, C2H5, CF3, OCH3, OC2H5, COCF3, SCH3, SC2H5, N(CH3)2, NHCH3, CH2N(CH3)2 and/or N(C2H5)2; and Cyc phenyl, which is unsubstituted, mono-, di- or trisubstituted by Hal, CN, R3a, OR3a, CONHR3a, CONR3bR3a, CONH2, NR3aCOR3b, SO2R3a, SOR3a, NHR3a, N(R3a)2, CH2—
Z, CH2—
SR3a, CH2—
N(R3a)2, Ar3 and/or Het3;or 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-dihydrobenzofuran-2- or 3-yl, 2-, 3-, 4-, 5-, 6- or 7-benzothiophenyl, benzodioxan-6- or 7-yl or 3,4-dihydro-1,5-benzodioxepin-6- or -7-yl, each, independently form one another, unsubstituted or mono-, di- or trisubstituted by Hal, CN, R3a, OR3a, CONHR3a, CONR3bR3a, CONH2, NR3aCOR3b, SO2R3a, SOR3a, NHR3a, N(R3a)2, CH2—
Z, CH2—
SR3a, CH2—
N(R3a)2, Ar3 and/or Het3; andAr3 denotes phenyl unsubstituted or mono- or disubstituted by F, Cl, CH3, C2H5, CF3, OCH3, OC2H5, COCF3, SCH3, SC2H5, N(CH3)2, NHCH3, CH2N(CH3)2 and/or N(C2H5)2; Het3 denotes 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, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl or pyrazinyl, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxaneyl, 1,3-dioxane-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperaziny; Z denotes OH, OCH3, OCH2CH3, OCF3, O—
CH2—
CH2—
OH or O—
CH2—
CH2—
OCH3; andq denotes 1, 2, 3 or 4; 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; with the provisio that compound (R)-(2-(benzofuran-3-yl)-1-(2-(N-methylmethylsulfonamido) acetamido)ethyl)boronic acid is excluded.
- and wherein;
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32. The compound according to claim 22, wherein the stereogenic center at the carbon atom adjacent to the boronic acid residue shows an (R)-configuration;
- and wherein;
LX denotes —
CH2—
, —
CH2—
CH2—
, —
CH2—
CH2—
CH2—
, —
CH2—
CH2—
CH2—
CH2—
, —
CH2—
CH2—
O—
CH2—
wherein 1 to 4 H atoms may he replaced by F or Cl and/or 1 or 2 H atoms may be replaced by OH, methy, ethyl, isopropyl, CF3, CF2CF3, OCH3, OCH2CH3, O—
CH2—
CH2—
OH, O—
CH2—
CH2—
OCH3, phenyl, tolyl, ethylphenyl, fluorophenyl, chlorophenyl, bromophenyl, aminophenyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidyl, morpholinyl and/or piperidinyl; andLY denotes —
CH2—
or —
CH2—
CH2—
wherein 1 to 4 H atom may be replaced by F or Cl and/or 1 or 2 H atoms may be replaced by OH, methy, ethyl, isopropyl, CF3, CF2CF3, OCH3, OCH2CH3, O—
CH2—
CH2—
OH and/or O—
CH2—
CH2—
OCH3; andY denotes Cyc; and R1, R2 denote each, independently from one another H or C1-C4-alkyl ,or R1 and R2 form together a residue according to formula (CE) as described above; and R3a, R3b and R3c denote each, independently from one another, linear or branched C1-C3-alkyl, wherein 1 to 5 H atoms may be replaced by F, Cl, OH and OAlk, wherein Alk is methyl or ethyl; and A denotes ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl or 1-ethyl-2-methylpropyl, each unsubstituted or mono-, di-, tri- or tetrasubstituted by Hal, CN, R3a, SR3a, OR3a, Ar1, Het1, and/or (CH2)q—
Z; andAr1 denotes 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-(methylsulfonyl)phenyl, o-, m- or p-methylsulfanylphenyl, o-, m- or p-cyanophenyl, o-, m- or p-(3-oxomorpholin-4-yl)phenyl, o-, m- or p-(piperidinyl)phenyl, o-, m- or p-(morpholin-4-yl)phenyl, furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or 2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl; and Het1 denotes 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, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl or pyrazinyl, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxaneyl, 1,3-dioxane-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl; and Cyc denotes 2,4-, 3,4-, or 2,3,4-substituted phenyl or unsubstituted or mono- or disubstituted 1- or 2-naphthyl, 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—
Z, CH2—
SR3a, and CH2—
N(R3a)2,or a residue according to formula (Fa7) or (S)-(Fb7)
- and wherein;
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33. The compound according to claim 22, said compound being selected from the group consisting of:
-
[(1R)-1-[3-(N-acetylanilino)propanoylamino]-2-phenyl-ethyl]boronic acid; [(1R)-1-[3-(N-ethylsulfonylanilino)propanoylamino]-2-(p-tolyl)ethyl]boronic acid; [(1R)-1-[3-(N-methylsulfonylanilino)propanoyl amino]-2-(p-tolyl)ethyl]boronic acid; [(1R)-1-[3-(benzenesulfonyl)propanoylamino]-2-(benzofuran-3-yl)ethyl]boronic acid; [(1R)-1-[3-[benzenesulfonyl(ethyl)amino]propanoylamino]-2-(p-tolyl)ethyl]boronic acid; [(1R)-1-[3-[benzenesulfonyl(isopropyl)amino]propanoylamino]-2-(p-tolyl)ethyl]-boronic acid; [(1R)-1-[3-[benzenesulfonyl(methyeamino]propanoylamino]-2-(p-tolyeethyl]-boronic acid; [(1R)-1-[3-[benzoyl(ethyl)amino]propanoylamino]-2-phenyl-ethyl]boronic acid; [(1R)-1-[3-[benzoyl(isopropyl)amino]propanoylamino]-2-phenyl-ethyl]boronic acid; [(1R)-1-[3-[benzoyl(methyl)amino]propanoylamino]-2-phenyl-ethyl]boronic acid; [(1R)-1-[3-[ethyl(ethylsulfonyl)amino]propanoylamino]-2-(p-tolyl)ethyl]boronic acid; [(1R)-1-[3-[ethyl-(2-methylbenzoyl)amino]propanoylamino]-2-phenyl-ethyl]boronic acid; [(1R)-1-[3-[ethyl-(3-methylbenzoyeamino]propanoylamino]-2-phenyl -ethyl]boronic acid; [(1R)-1-[3-[ethyl-(4-methylbenzoyl)amino]propanoylamino]-2-phenyl-ethyl]boronic acid; [(1R)-1-[3-[isopropyl(methylsulfonyl)amino]propanoylamino]-2-(p-tolyl)ethyl]-boronic acid; [(1R)-1-[[2-[benzenesulfonyl(ethyl)amino]acetyl]amino]-2-(p-tolyl)ethyl]boronic acid; [(1R)-1-[[2-[benzoyl(ethyl)amino]acetyl]amino]-2-phenyl-ethyl]boronic acid; [(1R)-1-[[5-(dimethylamino)-5-oxo-pentanoyl]amino]-2-(3-ethylphenyl)ethyl]-boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[3-[ethyl-(4-methylbenzoyl)amino]-propanoylamino]ethyl]boronic acid; [(1R)-2-(3-ethylphenyl)-1-(3-methylsulfonylpropanoylamino)ethyl]boronic acid; [(1R)-2-(3-ethylphenyl)-1-(4-methylsulfonylbutanoylamino)ethyl]boronic acid; [(1R)-2-(3-ethylphenyl)-1-(5-methylsulfonylpentanoylamino)ethyl]boronic acid; [(1R)-2-(benzofuran-3-yl)-1-(3-methylsulfonylpropanoylamino)ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[ethyl(propanoyl)amino]acetyl]amino]ethyl]-boronic acid; [(1R)-1-[3-[ethyl-(4-methoxybenzoyl)amino]propanoylamino]-2-(4-fluorophenyl)-ethyl]boronic acid; [(1R)-1-[3-[(4-chlorobenzoyl)-ethyl-amino]propanoylamino]-2-(4-fluorophenyl)-ethyl]boronic acid; [(1R)-1-[3-[ethyl -[4-(trifluoromethyl)benzoyl]amino]propanoylamino]-2-(4-fluorophenyl)ethyl]boronic acid; [(1R)-1-[3-[(4-cyanobenzoyl)-ethyl-amino]propanoylamino]-2-(4-fluorophenyl)-ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[ethyl(o-tolylsulfonyl)amino]acetyl]amino]ethyl]-boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[ethyl(p-tolylsulfonyeamino]acetyl]amino]ethyl]-boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[ethyl(m-tolylsulfonyl)amino]acetyl]amino]ethyl]-boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[methyl(p-tolylsulfonyl)amino]acetyl]amino]-ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[isopropyl(p-tolylsulfonyl)amino]acetyl]amino]-ethyl]boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-(N-propanoylanilino)acetyl]amino]-ethyl]boronic acid; [(1R)-1-[[2-[N-(benzenesulfonyl)anilino]acetyl]amino]-2-(2,4-dimethylphenyl)ethyl]-boronic acid; [(1R)-2-(2,4-dimethylphenyl)-1-[[2-[ethyl-(2-methylsulfanylacetyl)-amino]acetyl]-amino]ethyl]boronic acid; [(1R)-1-[[2-[(2-chloroacetyl)-ethyl-amino]acetyl]amino]-2-(2,4-dimethylphenyl)-ethyl]boronic acid; [(1R)-2-(benzofuran-3-yl)-1-[[3-(dimethylamino)-3-oxo-2-phenyl-propanoyl]-amino]ethyl]boronic acid; [(1R)-1-[[2-(2-fluoro-N-propanoyl-anilino)acetyl]amino]-2-(3-thienyl)ethyl]boronic acid; [(1R)-1-[[2-[methyl-[2-(trifluoromethyl)benzoyl]amino]acetyl]amino]-2-(3-thienyl)ethyl]boronic acid; [(1R)-2-[(3S)-2,3-dihydrobenzofuran-3-yl]-1-[[2-[isopropyl(p-tolylsulfonyl)amino]-acetyl]-amino]ethyl]boronic acid; [(1R)-1-[3[(4-chlorobenzoyl)-ethyl-amino]propanoylamino]-2-[(3 S)-2,3-dihydrobenzofuran-3-yl]ethyl]boronic acid; [(1R)-1-[[2-[ethyl(p-tolylsulfonyl)amino]acetyl]amino]-2-(7-methylbenzofuran-3-yl)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.
-
-
34. A process for the preparation of compounds of the formula I and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, characterised in that a compound of Formula (III)
-
35. A pharmaceutical composition comprising at least one compound according to claim 22, 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, as active ingredient, together with a pharmaceutically acceptable carrier.
-
36. The pharmaceutical composition according to claim 35, said composition further comprises a second active ingredient 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, wherein that second active ingredient is other than a compound of formula (I).
-
37. A method of treating a subject for medical conditions affected by inhibiting LMP7 comprising administering a compound according to claim 22 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.
-
38. The method according to claim 37, wherein said medical condition is an immunoregulatory abnormality or hematological malignancies.
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39. The method according to claim 38, 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-Schö
- nlein 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.
- nlein purpura and asthma; and
-
23. The compound according to claim 22, wherein Y denotes Cyc 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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40. A kit consisting of separate packs of:
-
(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
- Resources
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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, BUSCH, MICHAEL
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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 2300/00 Mixtures or combinations of...A61K 31/69 Boron compoundsA61K 45/06 Mixtures of active ingredie...A61P 11/06 AntiasthmaticsA61P 17/06 AntipsoriaticsA61P 29/00 Non-central analgesic, anti...A61P 35/00 Antineoplastic agentsA61P 35/02 specific for leukemiaC07F 5/025 Boronic and borinic acid co...