Inhibitors of activin receptor-like kinase

Patent metadata

Field	Value
Publication number	US-12595265-B2
Application number	US-202318137228-A
Country	US
Kind code	B2
Filing date	Apr 20, 2023
Priority date	Apr 15, 2016
Publication date	Apr 7, 2026
Grant date	Apr 7, 2026

Abstract

Described herein are compounds that inhibit ALK2 and its mutants, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions.

First claim

The invention claimed is:

1 . A method of inhibiting aberrant ALK2 activity in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
ring A is phenyl or heteroaryl, wherein ring A is optionally substituted with 1, 2, or 3 independently selected substituents selected from halo, ═O,

cyano, —OR c , —NR d R e , —S(O) k R c , —NR c S(O) 2 R c , —S(O) 2 NR d R e , —C(═O)OR c , —OC(═O)OR c , —OC(═O)R c , —OC(═S)OR c , —C(═S)OR c , —O(C═S)R c , —C(═O)NR d R e , —NR c C(═O)R c , —C(═S)NR d R e , —NR c C(═S)R c , —NR c (C═O)OR c , —O(C═O)NR d R e , —NR c (C═S)OR c , —O(C═S)NR d R e , —NR c (C═O)NR d R e , —N R c (C═S)NR d R e , —C(═S)R c , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, carbocyclyl,
(C 1 -C 6 -alkylene)-carbocyclyl, (C 1 -C 6 -heteroalkylene)-carbocyclyl, heterocyclyl, (C 1 -C 6 -alkylene)-heterocyclyl, (C 1 -C 6 -heteroalkylene)-heterocyclyl, aryl, (C 1 -C 6 -alkylene)-aryl, (C 1 -C 6 -heteroalkylene)-aryl, heteroaryl, (C 1 -C 6 -alkylene)-heteroaryl, and (C 1 -C 6 -heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more of halo, OR c , —NO 2 ,
cyano, —NR c C(═O)R c , —NR d R e , —S(O) k R c , —C(═O)OR c , —C(═O)NR d R e , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 heteroalkyl in addition to R 2 ;
R 1 is selected from NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —C(O)—C 1 -C 4 alkyl, carbocyclyl, heterocyclyl, —O—(C 0 -C 4 alkylene)-carbocyclyl, —O—(C 0 -C 4 alkylene)-heterocyclyl, —NH—(C 0 -C 4 alkylene)-carbocyclyl, —NH-phenyl, —NH—O—(C 1 -C 4 alkyl), —S-heterocyclyl, —S—(C 0 -C 3 alkylene)-(O-containing heterocyclyl), and —NH—(C 0 -C 4 alkylene)-heterocyclyl,
wherein each alkyl, alkylene, carbocyclyl, and heterocyclyl portion of R 1 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, ═O, cyano, —OR c , —NR d R e , —S(O) k R c , —NR c S(O) 2 R c , —S(O) 2 NR d R e , —C(═O)OR c , —OC(═O)OR c , —OC(═O)R c , —OC(═S)OR c , —C(═S)OR c , —O(C═S)R c , —C(═O)NR d R e , —NR c C(═O)R c , —C(═S)NR d R e , —NR c C(═S)R c , —NR c (C═O)OR c , —O(C═O)NR d R e , —NR c (C═S)OR c , —O(C═S)NR d R e , —NR c (C═O)NR d R e , —N R c (C═S)NR d R e , —C(═S)R c , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, carbocyclyl, (C 1 -C 6 -alkylene)-carbocyclyl, (C 1 -C 6 -heteroalkylene)-carbocyclyl, heterocyclyl, (C 1 -C 6 -alkylene)-heterocyclyl, (C 1 -C 6 -heteroalkylene)-heterocyclyl, aryl, (C 1 -C 6 -alkylene)-aryl, (C 1 -C 6 -heteroalkylene)-aryl, heteroaryl, (C 1 -C 6 -alkylene)-heteroaryl, and (C 1 -C 6 -heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more of halo, OR c , —NO 2 ,

cyano, —NR c C(═O)R c , —NR d R e , —S(O) k R c , —C(═O)OR c , —C(═O)NR d R e , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 heteroalkyl;
wherein any phenyl portion of R 1 is optionally substituted with 1, 2, or 3 substituents, wherein each optional substituent is independently selected from deuterium, halo, cyano, acetyl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —O—C 1 -C 4 alkyl, —C 1 -C 4 alkylene-O—C 1 -C 4 alkyl, heteroaryl, phenyl, cycloalkyl, —COOH, and —OH, wherein each of said heteroaryl, phenyl, and cycloalkyl are optionally substituted with one or more of halo, OR c , —NO 2 ,

cyano, —NR c C(═O)R c , —NR d R e , —S(O) k R c , —C(═O)OR c , —C(═O)NR d R e , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 heteroalkyl;
or
R 1 is taken together with one R 3 to form a saturated ring fused to the piperazine ring in formula (I), and wherein the ring formed by R 1 and R 3 is optionally substituted with 1, 2, or 3 substituents independently selected from halo, ═O,

cyano, —OR c , —NR d R e , —S(O) k R c , —NR c S(O) 2 R c , —S(O) 2 NR d R e , —C(═O)OR c , —OC(═O)OR c , —OC(═O)R c , —OC(═S)OR c , —C(═S)OR c , —O(C═S)R c , —C(═O)NR d R e , —NR c C(═O)R c , —C(═S)NR d R e , —NR c C(═S)R c , —NR c (C═O)OR c , —O(C═O)NR d R e , —NR c (C═S)OR c , —O(C═S)NR d R e , —NR c (C═O)NR d R e , —N R c (C═S)NR d R e , —C(═S)R c , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, carbocyclyl,
(C 1 -C 6 -alkylene)-carbocyclyl, (C 1 -C 6 -heteroalkylene)-carbocyclyl, heterocyclyl, (C 1 -C 6 -alkylene)-heterocyclyl, (C 1 -C 6 -heteroalkylene)-heterocyclyl, aryl, (C 1 -C 6 -alkylene)-aryl, (C 1 -C 6 -heteroalkylene)-aryl, heteroaryl, (C 1 -C 6 -alkylene)-heteroaryl, and (C 1 -C 6 -heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more of halo, OR c , —NO 2 ,
cyano, —NR c C(═O)R c , —NR d R e , —S(O) k R c , —C(═O)OR c , —C(═O)NR d R e , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 heteroalkyl;
if ring A is phenyl, then R 2 is selected from halo, C 1 -C 6 alkyl, heterocyclyl, cycloalkyl, —NH—(C 0 -C 4 alkylene)-heterocyclyl, —(C 1 -C 4 alkylene)-heterocyclyl, —(C 1 -C 4 alkylene)-NH-heterocyclyl, and —O—(C 0 -C 4 alkylene)-heterocyclyl, wherein any heterocyclyl, cycloalkyl, alkyl, or alkylene portion of R 2 is optionally substituted with 1, 2, 3, or substituents independently selected from halo, ═O,

cyano, —OR c , —NR d R e , —S(O) k R c , —NR c S(O) 2 R c , —S(O) 2 NR d R e , —C(═O)OR c , —OC(═O)OR c , —OC(═O)R c , —OC(═S)OR c , —C(═S)OR c , —O(C═S)R c , —C(═O)NR d R e , —NR c C(═O)R c , —C(═S)NR d R e , —NR c C(═S)R c , —NR c (C═O)OR c , —O(C═O)NR d R e , —NR c (C═S)OR c , —O(C═S)NR d R e , —NR c (C═O)NR d R e , —N R c (C═S)NR d R e , —C(═S)R c , —C(═O)R c , C 1 -C 6 alkyl,
C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, carbocyclyl, (C 1 -C 6 -alkylene)-carbocyclyl, (C 1 -C 6 -heteroalkylene)-carbocyclyl, heterocyclyl, (C 1 -C 6 -alkylene)-heterocyclyl, (C 1 -C 6 -heteroalkylene)-heterocyclyl, aryl, (C 1 -C 6 -alkylene)-aryl, (C 1 -C 6 -heteroalkylene)-aryl, heteroaryl, (C 1 -C 6 -alkylene)-heteroaryl, and (C 1 -C 6 -heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more of halo, OR c , —NO 2 ,
cyano, —NR c C(═O)R c , —NR d R e , —S(O) k R c , —C(═O)OR c , —C(═O)NR d R e , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or
C 1 -C 6 heteroalkyl; or R 2 is taken together with any ring atom in ring A to form a cycloalkyl or saturated heterocyclyl ring that is fused to ring A, and wherein the ring formed by R 2 and the ring atom in ring A is optionally substituted with 1, 2, or 3 substituents independently selected from halo, ═O,
cyano, —OR c , —NR d R e , —S(O) k R c , —NR c S(O) 2 R c , —S(O) 2 NR d R e , —C(═O)OR c , —OC(═O)OR c , —OC(═O)R c , —OC(═S)OR c , —C(═S)OR c , —O(C═S)R c , —C(═O)NR d R e , —NR c C(═O)R c , —C(═S)NR d R e , —NR c C(═S)R c , —NR c (C═O)OR c , —O(C═O)NR d R e , —NR c (C═S)OR c , —O(C═S)NR d R e ,
—NR c (C═O)NR d R e , —NR c (C═S)NR d R e , —C(═S)R c , —C(═O)R c , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, carbocyclyl, (C 1 -C 6 -alkylene)-carbocyclyl, (C 1 -C 6 -heteroalkylene)-carbocyclyl, heterocyclyl, (C 1 -C 6 -alkylene)-heterocyclyl, (C 1 -C 6 -heteroalkylene)-heterocyclyl, aryl, (C 1 -C 6 -alkylene)-aryl, (C 1 -C 6 -heteroalkylene)-aryl, heteroaryl, (C 1 -C 6 -alkylene)-heteroaryl, and (C 1 -C 6 -heteroalkyle

Assignees

• Blueprint Medicines Corp

Inventors

• Brooijmans Natasja
• Brubaker Jason D
• Fleming Paul E
• Hodous Brian Lewis
• Kim Joseph L
• Williams Brett D
• Wilson Douglas
• Wilson Kevin J
• Cronin Mark

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K31/5383

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/5025

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title