Boronic acid derivatives

Patent metadata

Field	Value
Publication number	US-11274109-B2
Application number	US-201816640669-A
Country	US
Kind code	B2
Filing date	Aug 21, 2018
Priority date	Aug 24, 2017
Publication date	Mar 15, 2022
Grant date	Mar 15, 2022

Abstract

α-amino boronic acid derivatives are useful for inhibiting the activity of immunoproteasome (LMP7) and for the treatment and/or prevention of medical conditions affected by immunoproteasome activity such as inflammatory and autoimmune diseases, neurodegenerative diseases, proliferative diseases and cancer.

First claim

The invention claimed is:

1. A compound of formula (I),

wherein
LY denotes (CH 2 ) m , wherein 1 to 4 H atoms may be replaced by at least one selected from the group consisting of Hal, R 3a and OR 4a , and/or wherein one CH 2 group may be replaced by O, S, SO or SO 2 ;
X denotes a heterobicycle or heterotricycle of formula (xa), (xb), (xc), (xd), (xe), (xf), (xg), (xh) or (xi), each, independently from one another, unsubstituted or mono-, di- or trisubstituted by at least one selected from the group consisting of Hal, NO 2 , CN, R 5a , OR 5a , CONR 5a R 5b , NR 5a COR 5b , SO 2 R 5a , SOR 5a , SO 2 NR 5a R 5b , NR 5a SO 2 R 5b , NR 5a R 5b , (CH 2 ) q —R 6 , COR 5a and SO 2 R 5a , and wherein 1, 2 or 3 of cyclic CH 2 groups may be replaced by at least one selected from the group consisting of CR 4a R 4b , C═O, O, S, NR 5a , SO and SO 2 :

Y denotes P 1 , P 2 or P 3 ;
P 1 denotes a linear or branched C 1 -C 6 -alkyl or C 3 -C 8 -cycloalkyl, each, independently from one another, unsubstituted or mono-, di-, tri- or tetrasubstituted by at least one selected from the group consisting of Hal, CN, R 3a , OR 3a , and (CH 2 ) q -R 6 ;
P 2 denotes phenyl or an aromatic monocyclic 5-, 6- or 7-membered heterocycle, each unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by at least one selected from the group consisting of Hal, CN, R 3a , OH, OR 3a , CONR 4a R 4b, NR 3a COR 3b , SO 2 R 3a , SOR 3a , NR 4a R 4b , Ar 2 , Het 2 , (CH 2 ) q —SR 3a , (CH 2 ) q —N(R 4a ) 2 and (CH 2 ) q —R 6 , wherein the heterocycle of P 2 contains 1, 2 or 3 N, O and/or S atoms;
P 3 denotes a bicyclic 8-, 9- or 10-membered hydrocarbon or heterocycle, each independently from one another unsubstituted or mono-, di-, tri-, tetra- or pentasubstituted by at least one selected from the group consisting of Hal, CN, R 3a , OH, OR 3a , CONR 4a R 4b, NR 3a COR 3b , SO 2 R 3a , SOR 3a , NR 4a R 4b , Ar 2 , Het 2 , (CH 2 ) q —SR 3a , (CH 2 ) q —N(R 4a ) 2 and (CH 2 ) q —R 6 , wherein at least one ring of the bicyclic hydrocarbon or heterocycle is aromatic, and wherein the heterocycle of P 3 contains 1, 2 or 3 N, O and/or S atoms;
Cy 1 , Cy 2 , Cy 3 , Cy 4 and Cy 5 denote each, independently from one another, Ar 1 or Het 1 ;
R 1 and R 2 denote each, independently from one another, H or C 1 -C 6 -alkyl, or R 1 and R 2 form together a residue according to formula (CE):

R 3a and R 3b denote each, independently from one another, linear or branched C 1 -C 6 -alkyl or C 3 -C 8 cycloalkyl, wherein 1 to 5 H atoms may be replaced by at least one selected from the group consisting of Hal, CN, OH and OAlk;
R 4a and R 4b denote each, independently from one another, H or R 3a , or R 4a and R 4b form together a C 3 -C 8 alkylene group;
R 5a and R 5b denote each, independently from one another, H, R 3a , Ar 2 or Het 2 ;
R 6 denotes OH or OR 3a ;
T 1 , T 2 , T 3 , T 4 , T 5 , T 6 , T 7 , T 8 and T 9 denote each, independently from one another, O, SO, or C═O;
Alk denotes linear or branched C 1 -C 6 -alkyl;
Ar 1 represents an aromatic 6-membered carbocycle;
Het 1 represents a saturated, unsaturated or aromatic 5- or 6-membered heterocycle having 1 to 4 N, O and/or S atoms;
Ar 2 denotes phenyl, which is unsubstituted or mono- or disubstituted by at least one selected from the group consisting of Hal, NO 2 , CN, R 3a , OR 3a , CONHR 3a , NR 3a COR 3b , SO 2 R 3a , SOR 3a , NH 2 , NHR 3a , N(R 3a ) 2 and (CH 2 ) q —R 6 ;
Het 2 denotes a saturated, unsaturated or aromatic 5- or 6-membered heterocycle having 1 to 4 N, O and/or S atoms, which is unsubstituted or mono- or disubstituted by at least one selected from the group consisting of Hal, NO 2 , CN, R 3a , OH, OR 3a , CONHR 3a , NR 3a COR 3b , SO 2 R 3a , SOR 3a , NH 2 , NHR 3a , N(R 3a ) 2 , (CH 2 ) q —R 6 and oxo (═O);
q denotes 1, 2, 3, 4, 5 or 6;
m denotes 0, 1 or 2; and
Hal denotes F, Cl, Br or I;
and tautomers, and stereoisomers thereof as well as the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios.

2. The compound of formula (I) according to claim 1 , wherein
R 1 and R 2 denote each, independently from one another, H or C 1 -C 4 -alkyl, or R 1 and R 2 form together a residue according to the formula (CE); and
LY denotes CH 2 or CH 2 CH 2 , wherein 1 to 2 H atoms may be replaced by at least one selected from the group consisting of Hal, R 3a , and OR 4a ;
and tautomers, and stereoisomers thereof as well as the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios.

3. The compound of formula (I) according to claim 1 , wherein
T 1 , T 2 , T 3 , T 4 , T 5 , T 6 , T 7 , T 8 and T 9 denote O;
and tautomers, and stereoisomers thereof as well as the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios.

4. The compound of formula (I) according to claim 1 , wherein
P 1 denotes a linear or branched C 1 -C 6 -alkyl or C 3 -C 8 -cycloalkyl, each, independently from one another, unsubstituted or mono-, di- or trisubstituted by at least one selected from the group consisting of Hal, CN, R 3a , OR 3a , and (CH 2 ) q —R 6 ;
P 2 denotes phenyl, pyridyl, pyrrolyl, furanyl, thiophenyl, pyrimidyl, pyranzinyl or pyridazinyl, each, independently from one another, unsubstituted or mono-, di- or trisubstituted by at least one selected from the group consisting of Hal, CN, R 3a , OH, OR 3a , CONR 4a R 4b , NR 3a COR 3b , SO 2 R 3a , SOR 3a , NR 4a R 4b , Ar 2 , Het 2 ,(CH 2 ) q —SR 3a , (CH 2 ) q —N(R 4a ) 2 and (CH 2 ) q -R 6 ; and
P 3 denotes a bicyclic residue of formula (ya), (yb), (yc), (yd), (ye), (yf), (yg), (yh), (yi), (yj), (yk), (yl), (ym), (yn), (yo) or (yp), each, independently from one another, unsubstituted or mono-, di- or trisubstituted by at least one selected from the group consisting of Hal, CN, R 3a , OH, OR 3a , CONR 4a R 4b, NR 3a COR 3b , SO 2 R 3a , SOR 3a , NR 4a R 4b , Ar 2 , Het 2 (CH 2 )q—SR 3a , (CH 2 )q —N(R 4a ) 2 and (CH 2 ) q —R 6 :

wherein
E a denotes O, S, N(Alk) or CH═CH; and
E b denotes O, S, N(Alk), CH 2 , CH 2 —CH 2 , O—CH 2 , S—CH 2 or N(Alk)CH 2 ;
and tautomers, and stereoisomers thereof as well as the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios.

5. The compound of formula (I) according to claim 1 , wherein
R 3a and R 3b denote each, independently from one another, linear or branched C 1 -C 4 -alkyl or C 3 -C 6 cycloalkyl, wherein 1 to 3 H atoms may be replaced by at least one selected from the group consisting of F and Cl, and/or wherein 1 or 2 H atoms may be replaced by at least one selected from the group consisting of CN, OH, OCH 3 , and OC 2 H 5 ;
and tautomers, and stereoisomers thereof as well as the pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all ratios.

6. The compound of formula (I) according to claim 1 , wherein
Y denotes P 2 or P 3 ;
and tautomers, and stereoisomers thereof as well as the pharmaceutically acce

Assignees

• Merck Patent Gmbh

Inventors

• Klein Markus
• Schadt Oliver
• Esdar Christina

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K9/2018

  Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates · CPC title

• A61K47/06

  Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite · CPC title

• A61K9/19

  lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} · CPC title

• A61K9/48

  Preparations in capsules, e.g. of gelatin, of chocolate {(A61K9/0004 takes precedence; bite capsules A61K9/0056)} · CPC title