BORONIC ACID DERIVATIVES
1 Assignment
0 Petitions
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.
3 Citations
42 Claims
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1-22. -22. (canceled)
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23. A compound of formula (I)
- View Dependent Claims (24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41)
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24. The compound according claim 23, 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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25. The compound according to claim 23, wherein:
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LX denotes —
CH2—
, —
O—
CH2—
, —
O—
CH2—
CH2—
, —
S—
CH2—
, —
S—
CH2—
CH2—
wherein in each case, independently from one another, 1 to 4 H atoms may be replaced by Hal, R3a, OR4a, (CH2)r-A2, Ar2 and/or Het2;or one H atom or CH2 group may be replaced by cyclopropyl, cyclobutyl or cyclopentyl; LY denotes (CH2)m, wherein 1 to 4 H atoms may be replaced by Hal, R3b, OR4b; 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-A2;
wherein in case of disubstitution substituents are in 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-, 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, SOR3a, NR4aR4b, Ar2, Het2, (CH2)r—
SR3a, (CH2)r—
N(R4a)2 and/or (CH2)r-A2; andderivatives, 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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26. The compound according to claim 23, wherein:
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LX denotes —
CH2—
, —
O—
CH2—
, —
O—
CH2—
CH2—
, —
S—
CH2—
, —
S—
CH2—
CH2—
, wherein in each case, independently from one another, 1 to 4 H atoms may be replaced by Hal, R3a, OR4a, (CH2)r-A2, phenyl, tolyl, ethylphenyl, fluorophenyl, chlorophenyl, bromophenyl, aminophenyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidyl, morpholinyl and/or piperidinyl,or one H or CH2 group may be replaced by cyclopropyl, cyclobutyl or cyclopentyl; LY denotes CH2 or CH2—
CH2 wherein 1 to 4 H atoms may be replaced by Hal, R3b, OR4b;Cyc 1- or 2-naphthyl, 2- or 3-benzofuryl, 2,3-dihydrobenzofuran-2- or 3-yl, benzothiophen-2- or 3-yl 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-A2;q, r denote each, independently from one another, 1, 2 or 3; 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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27. The compound according to claim 23, 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 denotes —
CH2—
, —
O—
CH2—
, —
O—
CH2—
CH2—
, —
S—
CH2—
, —
S—
CH2—
CH2—
, wherein in each case, independently from one another, 1 to 4 H atoms may be replaced by Hal, R3a, OR4a and/or (CH2)r-A2;or one H atom or CH2 group may be replaced by cyclopropyl, cyclobutyl or cyclopentyl; LY denotes —
CH2—
or —
CH2—
CH2—
;X denotes phenyl, pyridinyl, pyridazinyl, pyrimidyl, pyrazinyl or triazinyl, each independently from one another unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal, N3, A1, CN, OH, NR4aR4b, Ar1, Het1, OA1, OAr1, OHet1, COA1, COAr1, COHet1, CONR4aR4b, NR4aCOR3a, NR4aSO2R3a, SO2R3a, SOR3a, NR4aCOOR3a, OCONR3aR4a, O—
(CH2)q-A1 and/or (CH2)r-A2;Y denotes Cyc; R3a, R3b and R3c denote each, independently from one another, linear or branched C1-C4-alkyl, wherein 1 to 5 H atoms may be replaced by Hal, OH and/or OAlk; A1 denotes C1-C6-alkyl or C3-C6-cycloalkyl, each independently from each other, unsubstituted or mono- or disubstituted by Hal, CN, R3a, SR3a, OR4a and/or (CH2)r-A2, wherein 1 or 2 CH2 groups of the C3-C6-cycloalkyl group may be replaced by O, C═
O and/or N;Alk denotes methyl, ethyl, n-propyl or isopropyl; Cyc 1- or 2-naphthyl, 2- or 3-benzofuryl, 2,3-dihydrobenzofuran-2- or 3-yl, benzothiophen-2- or 3-yl 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-A2;q, r denote each, independently from one another, 0, 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.
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28. The compound according to claim 27, wherein Cyc denotes unsubstituted or mono- or disubstituted 1- or 2-naphthyl or 2-, 3-benzothiophenyl, wherein the substituents are selected from the group consisting of Hal, CN, R3a, OR3a, CONR4aR4b, NR3aCOR3b, SO2R3a, SOR3a, NR4aR4b, Ar2, Het2, (CH2)r—
- SR3a, (CH2)r—
N(R4a)2 and/or (CH2)r-A2;or Cyc is a residue according to formula (Fa7) or (Fb7)
- SR3a, (CH2)r—
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29. The compound according to claim 28, wherein Cyc denotes unsubstituted or mono- or disubstituted 1- or 2-naphthyl or 2-, 3-benzothiophenyl, 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)r—
- SR3a, (CH2)r—
N(R4a)2 and/or (CH2)r-A2;or Cyc is a residue according to formula (Fa7) or (S)-(Fb7)
- SR3a, (CH2)r—
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30. The compound according to claim 28, wherein Cyc denotes 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;
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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 30, wherein the stereogenic center at the carbon atom adjacent to the boronic acid residue shows an (R)-configuration
LX denotes — - CH2—
, —
CH2—
CH2—
, —
CH2—
O—
, —
CH2—
CH2—
CH2—
, —
CH2—
OCH2—
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;
or wherein 1 H atom or CH2 group may be replaced by cyclopropyl; 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; andX denotes phenyl, pyridinyl, pyridazinyl, pyrazinyl or triazinyl, each independently from one another unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by Hal, N3, A1, CN, OH, NR4aR4b, Ar1, Het1, OA1, OAr1, OHet1, COA1, COAr1, COHet1, CONR4aR4b, NR4aCOR3a, NR4aSO2R3a, SO2R3a, SOR3a, NR4aCOOR3a, OCONR3aR4a, O—
(CH2)q-A1 and/or (CH2)r-A2;Y 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 A1 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)r-A2; and Ar1 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-di fluoro-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, independently from one another, 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; andCyc unsubstituted or mono- or disubstituted 1- or 2-naphthyl, 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)r—
SR3a, (CH2)r—
N(R4a)2 and/or (CH2)r-A2,or residue according to formula (Fa7), (Fb7) or (S)-(Fb7), wherein; Ga denotes F, Cl, Br, 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;Gb denotes H, F, Cl, Br, 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;Ka, Kb denote each, independently from one another, H, F, Cl, Br, 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;A2 denotes OH, OCH3, OCH2CH3, OCF3, O—
CH2—
CH2—
OH or O—
CH2—
CH2—
OCH3;r 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.
- CH2—
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32. The compound according to claim 23, wherein the boronic acid residue shows an (R)-configuration
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;
or wherein 1 H atom or CH2 group may be replaced by cyclopropyl; 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; andX denotes phenyl, pyridinyl, pyridazinyl, pyrazinyl or triazinyl, each independently from one another unsubstituted or mono-, di- or trisubstituted by OH, CN, methy, ethyl, isopropyl, CF3, CF2CF3, OCH3, OCH2CH3, O—
CH2—
CH2—
OH, COmorpholinyl, COpiperazinyl, CON(CH3)2, CON(C2H5)2, CH2—
OCH3, and/or O—
CH2—
CH2—
OCH3;Y 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 A1 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; Cyc denotes unsubstituted or mono- or disubstituted 1- or 2-naphthyl, wherein the substituents selected from the group consisting of Hal, CN, R3a, OR3a, CONHR3a, CONR3bR3a, CONH2, NR3aCOR3b, SO2R3a, SOR3a, NHR3a, N(R3a)2, CH2—
Z, CH2—
SR3a, CH2— and
N(R4a)2;or a residue according to formula (Fa7) or (S)-(Fb7); 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; A2 denotes OH, OCH3, OCH2CH3, OCF3, O—
CH2—
CH2—
OH or O—
CH2—
CH2—
OCH3;r 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.
- CH2—
-
33. The compound according to claim 23, wherein Cyc is unsubstituted or mono or disubstituted by Hal, R3a or OR3a.
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34. The compound according to claim 23, wherein Cyc is unsubstituted or mono or disubstituted by F, Cl, CH3, C2H5, C2F5, OCH3, OC2H5, CF3, OCF3, OC2F5.
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35. The compound according to claim 23, said compound being 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)-1-[[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-difluoro-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]-acetyl]-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; [(1S)-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-(dimethylcarbamoyl)phenyl]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-[(3S)-2,3-dihydrobenzofuran-3-yl]ethyl]boronic acid; [(1R)-2-[(3R)-2,3-dihydrobenzofuran-3-yl]-1-[[(2S)-2-[2-(dimethylcarbamoyl)phenyl]propanoyl]amino]ethyl]boronic acid; [(1R)-2-[(3S)-2,3-dihydrobenzofuran-3-yl]-1-[[(2S)-2-[2-(dimethylcarbamoyl)phenyl]propanoyl]amino]ethyl]boronic acid; [(1R)-2-(benzofuran-2-yl)-1-[[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-pyridyeacetyl]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]-1-[[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-[(3S)-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-[(3S)-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; [(1R)-2-[(3 S)-2,3-dihydrobenzofuran-3-yl]-1-(3-phenoxypropanoylamino)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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36. 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)
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37. A pharmaceutical composition comprising at least one compound according to claim 23 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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38. The pharmaceutical composition according to claim 37 that further comprises 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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39. A method of treating medical conditions that are affected by inhibiting LMP7 comprising administering a compound according to claim 23 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 a subject in need of treatment.
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40. The method according to claim 39, wherein said medical condition is an immunoregulatory abnormality or hematological malignancies.
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41. The method according to claim 40, 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, sclerodenna, 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
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24. The compound according claim 23, wherein:
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42. 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, 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 31/69 Boron compoundsA61P 11/00 Drugs for disorders of the ...A61P 11/06 AntiasthmaticsA61P 17/06 AntipsoriaticsA61P 19/02 for joint disorders, e.g. a...A61P 29/00 Non-central analgesic, anti...A61P 35/00 Antineoplastic agentsA61P 35/02 specific for leukemiaA61P 37/06 Immunosuppressants, e.g. dr...C07F 5/025 Boronic and borinic acid co...