Small molecule inhibitors of galectin-3

Patent metadata

Field	Value
Publication number	US-2022185800-A1
Application number	US-202017439845-A
Country	US
Kind code	A1
Filing date	Mar 25, 2020
Priority date	Mar 26, 2019
Publication date	Jun 16, 2022
Grant date	—

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

1 . A compound of Formula (I):

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

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 selected from phenyl, pyridinyl and benzothiazolyl; and wherein each ring moiety is 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;
R 1 and R 1a are independently H or C 1-4 alkyl; and
R 2 is independently selected from hydroxy, C 1-4 alkoxy, C 1-4 haloalkoxy, —OCH 2 C(O)OH, —OCH 2 C(O)N(C 1-2 alkyl)(CH 2 ) 2 NH(C 1-4 alkyl), —OCH 2 C(O)—(C 3-6 cycloalkyl), and —OCH 2 C(O)NH(C 1-4 alkyl).

2 . The compound of claim 1 , wherein:
Ar 1 is independently

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;
Ar 3 is independently selected from phenyl, pyridinyl and benzothiazolyl; and wherein each ring moiety is 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;
R 1a is independently H or C 1-4 alkyl; and
R 2 is independently selected from hydroxy, C 1-4 alkoxy, C 1-4 haloalkoxy, —OCH 2 C(O)OH, and —OCH 2 C(O)N(C 1-2 alkyl)(CH 2 ) 2 NH(C 1-4 alkyl).

3 . The compound of claim 2 , wherein:
Ar 1 is independently

Ar 2 is independently phenyl substituted with 1 to 5 substituents selected from F, Cl and Br;
Ar 3 is independently phenyl, benzothiazolyl or quinolinyl; and wherein each ring moiety is substituted with 0 to 3 substituents selected from Cl, CH 3 , CF 3 , and —OCF 3 ; and
R 2 is independently selected from hydroxy, —OCH 3 , —OCH 2 CHF 2 , —OCH 2 CF 3 , —OCH 2 CF 2 CHF 2 , —OCH 2 C(O)OH, and —OCH 2 C(O)N(CH 3 )(CH 2 ) 2 NH(CH 3 ).

4 . The compound of claim 3 , wherein:
Ar 2 is independently selected from:

5 . The compound of claim 4 , wherein:
Ar 3 is independently selected from:

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

or a pharmaceutically acceptable salt thereof, wherein:
Ar 2 is independently phenyl or naphthyl; and wherein each ring moiety is substituted with 1 to 4 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 selected from phenyl, pyridinyl and benzothiazolyl; and wherein each ring moiety is 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;
R 1 is independently C 1-4 alkyl; and
R 2 is independently selected from hydroxy, C 1-4 alkoxy, —OCH 2 C(O)—(C 3-6 cycloalkyl), and —OCH 2 C(O)NH(C 1-4 alkyl).

7 . The compound of claim 6 , wherein:
Ar 2 is independently phenyl or naphthyl; and wherein each ring moiety is substituted with 1 to 3 substituents selected from cyano, F, Cl, Br, CH 3 , and —OCH 3 ; Ar 3 is independently selected from phenyl, pyridinyl and benzothiazolyl; and wherein each ring moiety is substituted with 0 to 3 substituents selected from Cl, CF 3 , —OCF 3 , and cyclopropyl; R 1 is CH 3 ; and R 2 is independently selected from hydroxy, —OCH 3 , —OCH 2 C(O)-(cyclopropyl), and —OCH 2 C(O)NH(CH 3 ).

8 . The compound of claim 7 , wherein:
Ar 2 is independently selected from:

9 . The compound of claim 8 , wherein:
Ar 2 is independently selected from:

10 . The compound of claim 9 , wherein R 2 is hydroxy.

11 . A compound of claim 1 , wherein the compound is selected from Examples 1 to 73 or a pharmaceutically acceptable salt thereof.

12 . 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.

13 . (canceled)

14 . A method for treating fibrosis of organs (including liver, kidney, lung, heart and skin), liver diseases and conditions (including 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 (including 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 (including psoriasis, nephropathy, and pneumonia), gastrointestinal tract diseases and conditions (including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and abnormal pancreatic secretion), renal diseases and conditions, urinary tract-associated diseases and conditions (including 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 (including obstruction of lower urinary tract), inflammatory diseases and conditions of lower urinary tract (including dysuria and frequent urination), pancreatic diseases and conditions, abnormal angiogenesis-associated diseases and conditions (including arterial obstruction), scleroderma, brain-associated diseases and conditions (including cerebral infarction and cerebral hemorrhage), neuropathic pain and peripheral neuropathy, ocular diseases and conditions (including age-related macular degeneration (AMD), diabetic retinopathy, proliferative vitreoretinopathy (PVR), cicatricial pemphigoid, and glaucoma filtration surgery scarring) comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof of claim 1 , to a patient.

15 . The method of claim 14 where the disease or condition is renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis, or systemic sclerosis.

Assignees

• Bristol Myers Squibb Co

Inventors

• Liu Chunjian
• Yoon David S
• Wang Wei
• Feng Jianxin
• Ellsworth Bruce A
• Regueiro-Ren Alicia

Classifications

• C07H19/056

  Triazole or tetrazole radicals · CPC title

• C07H17/02

  Heterocyclic radicals containing only nitrogen as ring hetero atoms · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P13/12

  of the kidneys · CPC title

• C07D417/14 Primary

  containing three or more hetero rings · CPC title