Indazole derivatives

Patent metadata

Field	Value
Publication number	US-12552801-B2
Application number	US-202118255085-A
Country	US
Kind code	B2
Filing date	Nov 29, 2021
Priority date	Dec 1, 2020
Publication date	Feb 17, 2026
Grant date	Feb 17, 2026

Abstract

The invention provides novel compounds having the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3 and R4 are as described herein. The compound of formula (I) can be used as a medicament.

First claim

The invention claimed is:

1 . A compound of formula (I)

wherein
R 1 and R 2 are independently selected from halogen and hydrogen;
R 3 is alkyl or haloalkyl; and
R 4 is heterocycloalkyl, dialkylaminoalkyl, (alkyl) (halo) heterocycloalkyl, hydroxyalkylheterocycloalkylalkoxy, alkylheterocycloalkyl, hydroxyalkylheterocycloalkylalkylcycloalkyl or alkoxyalkylheterocycloalkyl;
or a pharmaceutically acceptable salt thereof.

2 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are independently selected from fluorine and hydrogen.

3 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein one of R 1 and R 2 is fluorine and the other one is hydrogen.

4 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is alkyl or difluoroalkyl.

5 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl or difluoromethyl.

6 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is morpholinyl, dialkylaminoalkyl, (alkyl)(halo)piperidinyl, hydroxyalkylpiperidinylalkoxy, alkylpiperidinyl, hydroxyalkylpiperidinylalkyl(bicyclo[1.1.1]pentanyl) or alkoxyalkylpiperidinyl.

7 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is morpholinyl, dimethylaminoethyl, dimethylaminomethyl, (ethyl) (fluoro) piperidinyl, hydroxymethylpiperidinylethoxy, ethylpiperidinyl, hydroxymethylpiperidinylmethyl(bicyclo[1.1.1]pentanyl) or methoxyethylpiperidinyl.

8 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; rac-2-(6-(4-(2-(dimethylamino)ethyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 2-(6-(4-((3S,4S)-1-ethyl-3-fluoropiperidin-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 2-(6-(4-((3R,4R)-1-ethyl-3-fluoropiperidin-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 2-[6-[4-[(dimethylamino)methyl]phenyl]-7-methyl-4-(trifluoromethyl) indazol-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-(1,3-thiazol-2-yl)acetamide; 2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(4-(hydroxymethyl)piperidin-1-yl)ethoxy)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(1-ethylpiperidin-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-((dimethylamino)methyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(3-((4-(hydroxymethyl)piperidin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(1-(2-methoxyethyl)piperidin-4-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(4-(hydroxymethyl)piperidin-1-yl)ethoxy)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; and 2-(7-(difluoromethyl)-6-(4-morpholinophenyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; or a pharmaceutically acceptable salt thereof.

9 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(7-methyl-6-(4-morpholinophenyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; rac-2-(6-(4-(2-(dimethylamino)ethyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; 2-[6-[4-[(dimethylamino)methyl]phenyl]-7-methyl-4-(trifluoromethyl) indazol-2-yl]-2-[rac-(6R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl]-N-(1,3-thiazol-2-yl)acetamide; 2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(4-(hydroxymethyl)piperidin-1-yl)ethoxy)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-((dimethylamino)methyl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(3-((4-(hydroxymethyl)piperidin-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-(6-(4-(2-(4-(hydroxymethyl)piperidin-1-yl)ethoxy)phenyl)-7-methyl-4-(trifluoromethyl)-2H-indazol-2-yl)-N-(thiazol-2-yl)acetamide; and 2-(7-(difluoromethyl)-6-(4-morpholinophenyl)-4-(trifluoromethyl)-2H-indazol-2-yl)-2-((R)-6-fluoro-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-N-(thiazol-2-yl)acetamide; or a pharmaceutically acceptable salt thereof.

10 . A process for the preparation of a compound of formula (I),

or a pharmaceutically acceptable salt thereof,
comprising the following steps:
(a) the reaction of a compound of formula (B1)

in a suitable solvent and in presence of a base, to arrive at a compound of formula (B2)

wherein M + is Na + , Li + or a protonated base;
(b) the reaction of the compound of formula (B2) in a suitable solvent and in presence of an acid to yield a compound of formula (B3)

 and
(c) the reaction of a compound of formula (B3) with a compound of formula (B4)

in the presence of a coupling agent and a base;
wherein
R 1 and R 2 are independently selected from halogen and hydrogen;
R 3 is alkyl or haloalkyl; and
R 4 is heterocycloalkyl, dialkylaminoalkyl, (alkyl) (halo) heterocycloalkyl, hydroxyalkylheterocycloalkylalkoxy, alkylheterocycloalkyl, hydroxyalkylheterocycloalkylalkylcycloalkyl or alkoxyalkylheterocycloalkyl; and
R is H or alkyl.

11 . A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt according to claim 1 and a therapeutically inert carrier.

12 . A method for the treatment or prophylaxis of a cancer in a patient in need thereof, comprising administering an effective amount of the compound or pharmaceutically acceptable salt according to claim 1 .

Assignees

• Hoffmann La Roche

Inventors

• Dolente Cosimo
• Goergler Annick
• Hewings David Stephen
• Jaeschke Georg
• Obst-Sander Christa Ulrike
• Ricci Antonio

Classifications

• A61K9/1652

  Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623) · CPC title

• A61K47/10

  Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers · CPC title

• A61K9/08

  Solutions {(composition of solutions A61K47/00)} · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61K9/4875

  Compounds of unknown constitution, e.g. material from plants or animals (oils, fats, waxes, shellac A61K9/4858) · CPC title