Boronic acid derivatives

Patent metadata

Field	Value
Publication number	US-11858951-B2
Application number	US-202217649411-A
Country	US
Kind code	B2
Filing date	Jan 31, 2022
Priority date	Aug 24, 2017
Publication date	Jan 2, 2024
Grant date	Jan 2, 2024

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 method for treatment of an immunoregulatory abnormality or a cancer, the method comprising:
administering a compound of formula (I) tautomer, or stereoisomer thereof, as well as a pharmaceutically acceptable salt of each of the foregoing, including a mixture thereof in all ratios, to a patient in need thereof,

wherein in the compound of formula (I):
LY denotes (CH 2 ) m , wherein 1 to 4H 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 S 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/or SO 2 R 5a ; and wherein 1, 2 or 3 of the 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/or 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 of 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 of 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 5H 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 of 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 of 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 , 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;
wherein the immunoregulatory abnormality is an autoimmune or chronic inflammatory disease selected from the group consisting of systemic lupus erythematosus, chronic rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, amyotrophic lateral sclerosis, atherosclerosis, scleroderma, autoimmune hepatitis, Sjogren Syndrome, lupus nephritis, glomerulonephritis, Rheumatoid Arthritis, Psoriasis, Myasthenia Gravis, Immunoglobulin A nephropathy, Vasculitis, Transplant rejection, Myositis, Henoch-Schönlein Purpura, and asthma;
wherein the cancer is a hematological malignancy or a solid tumor,
wherein said hematological malignancy is a disease selected from the group consisting of multiple myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma, plasmacytoma, follicular lymphoma, immunocytoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, and myeloid leukemia; and
wherein the solid tumor is selected from the group consisting of inflammatory breast and colon cancer, lung cancer, head and neck cancer, prostate cancer, pancreas cancer, bladder cancer, renal cancer, hepatocellular cancer, and gastric cancer.

2. The method of claim 1 , wherein in the compound of formula (I),
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 2H atoms may be replaced by at least one selected from the group consisting of Hal, R 3a , and OR 4a .

3. The method of claim 1 , wherein in the compound of formula (I),
T 1 , T 2 , T 3 , T 4 , T 5 , T 6 , T 7 , T 8 , and T 9 denote O.

4. The method of claim 1 , wherein in the compound of formula (I),
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),

Assignees

• Merck Patent Gmbh

Inventors

• Klein Markus
• Schadt Oliver
• Esdar Christina

Classifications

• C07F5/025 Primary

  Boronic and borinic acid compounds · CPC title

• A61K31/69

  Boron compounds · CPC title

• A61K45/06

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

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title