Galectin-3 inhibitors

Patent metadata

Field	Value
Publication number	US-12291522-B2
Application number	US-202117927426-A
Country	US
Kind code	B2
Filing date	May 27, 2021
Priority date	May 28, 2020
Publication date	May 6, 2025
Grant date	May 6, 2025

Abstract

The present disclosure relates to compounds of Formula (I), which inhibit Gal-3, and include pharmaceutically acceptable salts, compositions comprising such compounds, and methods using and making such compounds and compositions.

First claim

We claim:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
Ar 1 is independently

Ar 2 is independently phenyl or naphthyl; and wherein each ring moiety is substituted with 1 to 5 substituents selected from cyano, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
Ar 3 is independently phenyl, pyridinyl, quinolone, isoquinoline, or benzothaizolyl, wherein each ring moiety is substituted with 0 to 3 substituents selected from cyano, halogen, C 1-4 alkyl, C 1-4 haloalkyl;
R 1 and R 1a are independently H or C 1-4 alkyl;
R 2 is independently —C(═O)NR 3 R 4 or —OR 4 ;
R 3 is independently H, C 1-4 alkyl, or C 1-4 haloalkyl;
R 4 is independently -(L 1 ) 1-4 -L 2 -C(═O)NHR 5 , -(L 1 ) 1-4 -L 2 -NHC(═O)R 5 ,
(L 1 ) 1-4 -NHC(═O)-L 2 -OR 5 ,

althernatively, —NR 3 R 4 is independently

L 1 is independently C 1-3 alkylene or —C 1-3 alkylene-O—;
L 2 is independently a bond or C 1-3 alkylene;
L 3 is independently —O—, —CH 2 —, —CH 2 O—, —OCH 2 —, or —CH 2 OCH 2 —;
Ar 4 is independently phenylene or pyridinylene; and wherein each ring moiety is substituted with 0 to 2 substituents selected from cyano, halogen, C 1-4 alkyl,
C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;
R 5 is independently

R 6 is independently H or C 1-4 alkyl;
R 7 is independently indolyl substituted with 0 to 2 substituents selected from cyano, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy; and
Ar 5 is independently phenylene or pyridinylene; and wherein each ring moiety is substituted with a thiazolyl substituted with 0 to 2 substituents selected from cyano, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy.

2. A compound of claim 1 , wherein:
Ar 1 is

Ar 2 is independently phenyl substituted with 1 to 5 substituents selected from cyano, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy; and
Ar 3 is independently phenyl substituted with 0 to 3 substituents selected from cyano, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy and C 3-6 cycloalkyl.

3. A compound of claim 2 , wherein:
Ar 2 is independently phenyl substituted with 1 to 4 substituents selected from F, Cl and Br;
Ar 3 is independently phenyl substituted with 0 to 3 substituents selected from Cl, CH 3 , CF 3 , and —OCF 3 ;
R 3 is independently H, C 1-3 alkyl, or C 1-3 haloalkyl;
R 4 is independently -L 1 -L 2 -C(═O)NHR 5 , -(L 1 ) 1-3 -L 2 -NHC(═O)R 5 ,
(L 1 ) 1-3 -NHC(═O)-L 2 -OR 5 ,

and
althernatively, —NR 3 R 4 is independently

4. A compound of claim 3 , wherein:
Ar 2 is independently

5. A compound of claim 4 , wherein:
Ar 3 is independently

6. A compound of claim 1 , wherein the compound is of Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein:
R 3 is independently H or —CH 2 Cl;
R 4 is independently —CH 2 CH 2 OCH 2 C(═O)NHR 5 , —(CH 2 CH 2 O) 1-3 (CH 2 ) 1-2 NHC(═O)R 5 , —(CH 2 CH 2 O) 1-3 (CH 2 ) 2 NHC(═O)CH 2 OR 5 ,

althernatively, —NR 3 R 4 is independently

R 5 is independently

and
R 6 is independently H or CH 3 .

7. A compound of claim 1 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

8. A composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of claim 1 , and one or more pharmaceutically acceptable carriers.

9. A method for treating fibrosis of organs selected from liver, kidney, lung, heart and skin; liver diseases and conditions selected from acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), liver hypofunction, and hepatic blood flow disorder; cell proliferative diseases, cancers, and conditions selected from solid tumor, solid tumor metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, chronic lymphocytic leukemia (CLL)) and invasive metastasis of cancer cell; inflammatory diseases and conditions selected from psoriasis, nephropathy, and pneumonia; gastrointestinal tract diseases and conditions selected from irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and abnormal pancreatic secretion; renal diseases and conditions, urinary tract-associated diseases and conditions selected from benign prostatic hyperplasia or symptoms associated with neuropathic bladder disease, spinal cord tumor, hernia of intervertebral disk, spinal canal stenosis, and symptoms derived from diabetes; lower urinary tract diseases and conditions of obstruction of lower urinary tract; inflammatory diseases and conditions of lower urinary tract selected from dysuria and frequent urination; pancreatic diseases and conditions, abnormal angiogenesis-associated diseases and conditions of arterial obstruction; scleroderma, brain-associated diseases and conditions selected from cerebral infarction and cerebral hemorrhage; neuropathic pain and peripheral neuropathy, ocular diseases and cond

Assignees

• Bristol Myers Squibb Co

Inventors

• Liu Chunjian
• Wang Wei
• Ellsworth Bruce A
• Balog James Aaron
• Regueiro-Ren Alicia

Classifications

• C07H19/056

  Triazole or tetrazole radicals · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• A61P13/12

  of the kidneys · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title