IP Library › Granted Patent US 12,595,265

Granted Patent B2

US 12,595,265 · App. 18/137,228 · Granted Apr 7, 2026

Inhibitors of activin receptor-like kinase

Inventors: Natasja Brooijmans (Cambridge, MA); Jason D. Brubaker (Cambridge, MA); Paul E. Fleming (Cambridge, MA); Brian Lewis Hodous (Cambridge, MA); Joseph L. Kim (Cambridge, MA); Brett D. Williams (Cambridge, MA); Douglas Wilson (Cambridge, MA); Kevin J. Wilson (Cambridge, MA); Mark Cronin (Cambridge, MA)

Assignee: Blueprint Medicines Corporation

C07D487/04 A61K31/5025 A61K31/5377 A61K31/5383 A61P35/00 C07D519/00

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Quick Facts

Patent No.: US 12,595,265
App. No.: 18/137,228
Granted: Apr 7, 2026
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

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

Claims (928)

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;

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, —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,

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,

—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 -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 heteroaryl, 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 4 substituents independently selected from halo, ═O,

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 saturated ring atom in ring A to form a cycloalkyl or saturated heterocyclyl ring that is fused, spirofused, or bridged 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, —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;

each R 3 is independently selected from C 1 -C 4 alkyl and C 1 -C 4 haloalkyl;

each R c is selected from hydrogen, hydroxy, C 1 -C 6 alkyl, 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, or (C 1 -C 6 -heteroalkylene)-heteroaryl, each of which is optionally substituted with one or more of halo, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;

each R d and R e are independently selected from hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 heteroalkyl;

each k is independently 0, 1, or 2; and

n is 0, 1, 2, or 3.

2 . The method of claim 1 , wherein:

n is 0; or

n is 1 and R 3 is selected from methyl, ethyl, and CHF 2 .

3 . The method of claim 1 , wherein

ring A is selected from:

wherein:

“1” represents a portion of ring A bound to a pyrrolo[1,2-b]pyridazine moiety;

“2” represents a portion of ring A bound to R 2 ; and

ring A is optionally substituted with 1, 2, or 3 substituents independently selected from halo, ═O,

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 .

4 . The method of claim 3 , wherein ring A is selected from

5 . The method of claim 1 , wherein ring A is optionally substituted with 1 or 2 substituents in addition to R 2 , wherein each optional substituent is independently selected from cyano, halo, methyl, and OCHF 2 .

6 . The method of claim 1 , wherein:

R 1 is selected from —C(O)—(C 1 -C 3 alkyl), C 1 -C 3 alkyl, —O—(C 1 -C 5 alkyl), —NH(C 1 -C 5 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH—(C 3 -C 6 cycloalkyl), C 3 -C 6 cycloalkyl, —O—(C 3 -C 6 cycloalkyl), —O—(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), —(C 1 -C 3 alkylene)-(C 3 -C 6 cycloalkyl), —O—(C 0 -C 3 alkylene)-(O-containing heterocyclyl), —NH—(C 0 -C 3 alkylene)-(0-containing heterocyclyl), an O-containing heterocyclyl, an N-containing heterocyclyl, —O—(C 0 -C 3 alkylene)-(N-containing heterocyclyl), —S—(C 0 -C 3 alkylene)-(0-containing heterocyclyl), —NH—O—(C 1 -C 3 alkyl), and —NH-phenyl, wherein:

any alkyl, cycloalkyl, phenyl, or heterocyclyl 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, —C 00 H, 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 any ring atom in the piperazine moiety of formula (I) to form a carbocyclyl or heterocyclyl ring fused to the piperazine moiety.

7 . The method of claim 1 , wherein:

R 2 is selected from halo, cycloalkyl, heterocyclyl, —O—(C 0 -C 4 alkylene)-heterocyclyl, —(C 1 -C 3 alkylene)-heterocyclyl, —(C 1 -C 3 alkylene)-NH—(C 1 -C 3 alkyl), -(hydroxy-substituted C 1 -C 3 alkylene)-NH—(C 1 -C 3 alkyl), C 1 -C 4 alkyl substituted with both hydroxy and one or more of amino, C 1 -C 4 alkylamino or di-C 1 -C 4 alkylamino cyano-substituted C 1 -C 4 alkyl, hydroxy, —S(O) 2 —C 1 -C 4 alkyl, and -(amino substituted C 1 -C 3 alkylene)-heterocyclyl; or

R 2 is taken together with a ring atom in ring A to form a heterocyclyl or a carbocyclyl that is fused to ring A, wherein any heterocyclyl or carbocyclyl is optionally substituted with 0, 1, 2, or 3 substituents, wherein:

each optional substituent is independently selected from halo, cyano, hydroxy, —NH 2 , —NH(C 1 -C 4 alkyl), —NH—C(O)—O—(C 1 -C 4 alkyl), ═O, —C(O)—C 1 -C 4 alkyl, —C 1 -C 4 alkyl, deuterated C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, hydroxy-substituted —C 1 -C 4 alkyl, —O—C 1 -C 4 alkyl, —O—C 1 -C 4 haloalkyl, —(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl), -(amino substituted C 1 -C 4 alkylene)-O—(C 1 -C 4 alkyl), —(C 1 -C 4 alkylene)-O—(C 1 -C 4 haloalkyl), —C(O)—O—C 1 -C 4 alkyl, —COOH, C 3 -C 6 cycloalkyl, heterocyclyl, and —NH-heterocyclyl, wherein each said heterocyclyl is 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.

8 . 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 (II):

or a pharmaceutically acceptable salt thereof, wherein:

X is C(R 13 ) or N;

R 11 is selected from: —NH—(C 3 -C 4 cycloalkyl); —NH—C 1 -C 3 alkyl; —O—C 3 -C 4 cycloalkyl; —O—(C 1 -C 3 alkyl) optionally substituted with one or more substituents selected from fluoro, hydroxy, cyano, and deuterium; and —O—(O-containing heterocycle);

R 12 is selected from:

piperidin-3-yl optionally 3-substituted with C 1 -C 3 alkoxy, fluoro, C 1 -C 3 alkyl, or cyano; and

piperidin-4-yl optionally 4-substituted with C 1 -C 3 alkoxy, fluoro, C 1 -C 3 alkyl, and cyano, wherein:

R 12 is additionally optionally 1-substituted with C 1 -C 5 alkyl optionally substituted with one or more hydroxy and/or one or more —NH 2 ;

R 3 is selected from hydrogen, cyano, and fluoro; and

R 14 is fluoro.

9 . The method of claim 8 , wherein the compound is a compound of formula (IIa):

or a pharmaceutically acceptable salt thereof, wherein:

X is C(R 13 ) or N;

R 13 is selected from hydrogen, cyano, and fluoro;

R 14 is fluoro;

R 15 is selected from hydrogen, C 1 -C 3 alkoxy, fluoro, C 1 -C 3 alkyl, and cyano; and

R 16 is hydrogen or C 1 -C 5 alkyl optionally substituted with one or more hydroxy and/or one or more —NH 2 .

10 . The method of claim 8 , wherein the compound is a compound of formula (IIb):

or a pharmaceutically acceptable salt thereof, wherein:

X is C(R 13 ) or N;

R 13 is selected from hydrogen, cyano, and fluoro;

R 14 is fluoro;

R 15 is selected from hydrogen, C 1 -C 3 alkoxy, fluoro, C 1 -C 3 alkyl, and cyano; and

R 16 is hydrogen or C 1 -C 5 alkyl optionally substituted with one or more hydroxy and/or one or more —NH 2 .

11 . The method of claim 10 , wherein the compound is a compound of formula (IIb-1):

or a pharmaceutically acceptable salt thereof.

12 . The method of claim 10 , wherein the compound is a compound of formula (IIb-2):

or a pharmaceutically acceptable salt thereof.

13 . The method of claim 8 , wherein R 14 is absent.

14 . The method of claim 8 , wherein R 13 is hydrogen.

15 . The method of claim 8 , wherein R 11 is selected from:

—NH—C 1 -C 3 alkyl;

—O—C 1 -C 3 alkyl optionally substituted with one or more substituents selected from fluoro, hydroxy, cyano, and deuterium;

oxetan-3-yloxy; and

tetrahydrofuran-3-yloxy.

16 . The method of claim 1 , wherein the compound selected from any one of the compounds provided below and pharmaceutically acceptable salts thereof:

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17 . The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

18 . The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

19 . The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

20 . The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

21 . The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

22 . The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

23 . The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

24 . The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

25 . The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

26 . The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

27 . The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

28 . The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

29 . The method of claim 1 , wherein the aberrant ALK2 activity is caused by a mutation in an ALK2 gene that results in the expression of an ALK2 enzyme having an amino acid modification selected from one or more of L196P, PF197-8L, R202I, R206H, Q207E, R258S, R258G, G328A, G328V, G328W, G328E, G328R, G356D, and R375P.

30 . The method of claim 29 , wherein the ALK2 enzyme has the amino acid modification R206H.

31 . The method of claim 1 , wherein the subject is suffering from fibrodysplasia ossificans progressiva or diffuse intrinsic pontine glioma.

Assignments (3)

RELEASE OF SECURITY INTEREST (REEL/FRAME 064748/0552) Recorded Jul 24, 2025

From: TAO TALENTS, LLC

To: BLUEPRINT MEDICINES CORPORATION

Reel/Frame 072249/0280 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 1, 2023

From: BROOIJMANS, NATASJA; BRUBAKER, JASON D.; FLEMING, PAUL E.; HODOUS, BRIAN LEWIS; KIM, JOSEPH L.; WAETZIG, JOSHUA D.; WILLIAMS, BRETT D.; WILSON, DOUGLAS; WILSON, KEVIN J.; CRONIN, MARK

To: BLUEPRINT MEDICINES CORPORATION

Reel/Frame 065735/0533 →

SECURITY INTEREST Recorded Aug 29, 2023

From: BLUEPRINT MEDICINES CORPORATION

To: TAO TALENTS, LLC

Reel/Frame 064748/0552 →

Continuity (6)

Continuation 16887262 · May 29, 2020

Continuation 16293317 · Mar 5, 2019

Continuation 15488257 · Apr 14, 2017

Provisional Application 62411172 · Oct 21, 2016

Provisional Application 62322948 · Apr 15, 2016

Related Publication 20240158398A1 · May 16, 2024

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