Boronic acid derivatives

Patent metadata

Field	Value
Publication number	US-10669289-B2
Application number	US-201515516427-A
Country	US
Kind code	B2
Filing date	Oct 1, 2015
Priority date	Oct 1, 2014
Publication date	Jun 2, 2020
Grant date	Jun 2, 2020

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.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein:
LX is absent;
LY denotes (CH 2 ) m ;
X denotes an α,β-unsaturated amide or sulfonamide of formula xa), xb), or xd) wherein the cyclic residues in xb) are each unsubstituted or are substituted to form a phenyl ring fused to the cycle in xb):

Q denotes C═O or SO 2 ;
Y denotes Cyc;
R 1 , R 2 denote each, independently from one another, H, methyl, ethyl, n-propyl or isopropyl or R 1 and R 2 form together a residue according to formula (CE)

R 4a , R 4b denote each, independently from one another, H or methyl, ethyl, or isopropyl wherein 1 to 3 H atoms may be replaced by Hal;
R 5a , R 5b denote each, independently from one another, H, methyl, ethyl, propyl or isopropyl;
R 6 denotes H, Ar1, Het1 or A1;
R 7 , R 8 , R 9 , and R 10 denote each, independently from one another, H, Hal, methyl optionally substituted with 1 to 3 Hal, ethyl optionally substituted with 1 to 3 Hal, CO—O—CH 3 , CO—N(CH 3 ) 2 or CH 2 —N(CH 3 ) 2 ;
A1 denotes linear or branched C1 to C3 alkyl or C1 to C3 cycloalkyl, unsubstituted or mono-, di- or trisubstituted by Hal, methyl, ethyl, n-propyl, isopropyl or CN;
Ar1 denotes phenyl, which is unsubstituted, mono-, di- or trisubstituted by Hal, R 4a , OR 4a , CONR 4a R 4b , NR 4a COR 4b , (CH 2 ) r —CONR 4a R 4b , (CH 2 ) r —NR 4a COR 4b and/or (CH 2 ) r —OR 4a ;
Het1 denotes aromatic 5- or 6-membered heterocycle having 1 to 2 N, O and/or S atoms, wherein each heterocycle may independently be unsubstituted or mono-, or disubstituted by Hal, methyl, ethyl, n-propyl, or isopropyl;
Cyc denotes phenyl, 1- or 2-naphthyl, 4- or 5-indanyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 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 each independently from one another unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by methyl, ethyl, propyl, isopropyl, Hal, Hal substituted methyl, ethyl, propyl, isopropyl or CN;
m denotes 1;
p denotes 0 or 1;
r denotes 1;
Hal denotes F, Cl, Br or I; and
tautomers or stereoisomers thereof, as well as the physiologically acceptable salts of each of the foregoing, including mixtures thereof in all ratios.

2. The compound according to claim 1 , wherein R 6 denotes Ar1, Het1 or A1.

3. The compound according to claim 1 , wherein:
R 1 , R 2 denote H, methyl, ethyl, n-propyl or isopropyl, or R 1 and R 2 form together a residue according to formula (CE)

tautomers or stereoisomers thereof, as well as the physiologically acceptable salts of each of the foregoing, including mixtures thereof in all ratios.

4. The compound according to claim 1 , wherein:
R 5a , R 5b denote each, independently from one another, H, methyl, ethyl, propyl or isopropyl;
R 6 denotes A1;
A1 denotes linear or branched C1 to C3 alkyl or C1 to C3 cycloalkyl, each, independently from one another, unsubstituted or mono-, di- or trisubstituted by Hal, methyl, ethyl, n-propyl, isopropyl or CN; and
tautomers or stereoisomers thereof, as well as the physiologically acceptable salts of each of the foregoing, including mixtures thereof in all ratios.

5. The compound according to claim 1 , wherein:
Cyc denotes phenyl, which is unsubstituted, mono-, di- or trisubstituted by methyl, ethyl, propyl, isopropyl, Hal, Hal substituted methyl, ethyl, propyl, isopropyl, or CN, 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- 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, each independently from one another, unsubstituted, mono-, disubstituted or trisubstituted by methyl, ethyl, propyl, isopropyl, Hal, Hal substituted methyl, ethyl, propyl, isopropyl, or CN;
A1 denotes linear or branched C1 to C3 alkyl or C1 to C3 cycloalkyl, unsubstituted or mono-, di- or trisubstituted by Hal or CN; and
tautomers or stereoisomers thereof, as well as the physiologically acceptable salts of each of the foregoing, including mixtures thereof in all ratios.

6. The compound according to claim 1 , wherein:
Cyc denotes phenyl, which is unsubstituted, mono-, di- or trisubstituted by Hal, methyl, ethyl, propyl, isopropyl, Hal, Hal substituted methyl, ethyl, propyl, isopropyl, or CN; 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, 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, methyl, ethyl, propyl, isopropyl, Hal, Hal substituted methyl, ethyl, propyl, isopropyl, or CN; and
tautomers or stereoisomers thereof, as well as the physiologically acceptable salts of each of the foregoing, including mixtures thereof in all ratios.

7. The compound according to claim 1 , wherein:
R 1 , R 2 denote H, methyl, ethyl, n-propyl or isopropyl, or R 1 and R 2 form together a residue according to formula (CE);
R 6 denotes methyl, ethyl, n-propyl, isopropyl, cyclopropyl, CH 2 CF 3 , CH 2 CHF 2 , CH 2 F, CHF 2 , CF 3 , CH 2 CN; or phenyl, which is unsubstituted, mono- or disubstituted by F, Cl, Br, R 4a , OR 4a , CONR 4a R 4b and/or (CH 2 ) r —OR 4a ;
Cyc denotes phenyl, which is unsubstituted, mono-, di- or trisubstituted by Hal, methyl, ethyl, propyl, isopropyl, Hal substituted methyl, ethyl, propyl, isopropyl or CN, 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, methyl, ethyl, propyl, isopropyl, Hal substituted methyl, ethyl, propyl, isopropyl or CN; and
tautomers or stereoisomers thereof, as well as the physiologically acceptable salts of each of the foregoing, including mixtures thereof in all ratios.

8. The compound according to claim 1 , wherein R 7 and R 9 denote each, independent from one another, H, Hal, methyl optionally substituted with 1 to 3 Hal, ethyl optionally substituted with 1 to 3 Hal, CO—O—CH 3 , CO—N(CH 3 ) 2 or CH 2 —N(CH 3 ) 2 .

9. The compound according to claim 1 , wherein:
X is a residue of formula xa); and
R 5a , R 5b denote each, independent from one another, H, methyl, e

Assignees

• Merck Patent Gmbh

Inventors

• Klein Markus
• Schadt Oliver
• Haselmayer Philipp
• Krier Mireille

Classifications

• A61K31/69

  Boron compounds · CPC title

• C07F5/025 Primary

  Boronic and borinic acid compounds · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title