# US 12,595,265 B2 · Inhibitors of activin receptor-like kinase

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- Number: US 12,595,265 B2
- Document ID: US12595265B2
- Status: Granted
- Kind: B2
- Application number: 18/137,228
- Filed: 2023-04-20
- Published: 2024-05-16
- Granted: 2026-04-07
- Earliest claimed: 2016-04-15
- Assignees: Blueprint Medicines Corporation
- Applicants: Blueprint Medicines Corporation
- Inventors: Natasja Brooijmans; Jason D. Brubaker; Paul E. Fleming; Brian Lewis Hodous; Joseph L. Kim; Brett D. Williams; Douglas Wilson; Kevin J. Wilson; Mark Cronin
- Web page: https://patentgrep.com/patent/US12595265B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61K 31/5025: ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/5383: ortho- or peri-condensed with heterocyclic ring systems
- A61P 19/00: Drugs for skeletal disorders
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 519/00: 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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

### Claim 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, —ORc, —NRdRe, —S(O)kRc, —NRcS(O)2Rc, —S(O)2NRdRe, —C(═O)ORc, —OC(═O)ORc, —OC(═O)Rc, —OC(═S)ORc, —C(═S)ORc, —O(C═S)Rc, —C(═O)NRdRe, —NRcC(═O)Rc, —C(═S)NRdRe, —NRcC(═S)Rc, —NRc(C═O)ORc, —O(C═O)NRdRe, —NRc(C═S)ORc, —O(C═S)NRdRe, —NRc(C═O)NRdRe, —N Rc(C═S)NRdRe, —C(═S)Rc, —C(═O)Rc, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, carbocyclyl,
(C1-C6-alkylene)-carbocyclyl, (C1-C6-heteroalkylene)-carbocyclyl, heterocyclyl, (C1-C6-alkylene)-heterocyclyl, (C1-C6-heteroalkylene)-heterocyclyl, aryl, (C1-C6-alkylene)-aryl, (C1-C6-heteroalkylene)-aryl, heteroaryl, (C1-C6-alkylene)-heteroaryl, and (C1-C6-heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more of halo, ORc, —NO2,
cyano, —NRcC(═O)Rc, —NRdRe, —S(O)kRc, —C(═O)ORc, —C(═O)NRdRe, —C(═O)Rc, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl in addition to R2;
R1 is selected from NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 alkyl, —O—C1-C6 alkyl, —C(O)—C1-C4 alkyl, carbocyclyl, heterocyclyl, —O—(C0-C4 alkylene)-carbocyclyl, —O—(C0-C4 alkylene)-heterocyclyl, —NH—(C0-C4 alkylene)-carbocyclyl, —NH-phenyl, —NH—O—(C1-C4 alkyl), —S-heterocyclyl, —S—(C0-C3 alkylene)-(O-containing heterocyclyl), and —NH—(C0-C4 alkylene)-heterocyclyl,
wherein each alkyl, alkylene, carbocyclyl, and heterocyclyl portion of R1 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, ═O, cyano, —ORc, —NRdRe, —S(O)kRc, —NRcS(O)2Rc, —S(O)2NRdRe, —C(═O)ORc, —OC(═O)ORc, —OC(═O)Rc, —OC(═S)ORc, —C(═S)ORc, —O(C═S)Rc, —C(═O)NRdRe, —NRcC(═O)Rc, —C(═S)NRdRe, —NRcC(═S)Rc, —NRc(C═O)ORc, —O(C═O)NRdRe, —NRc(C═S)ORc, —O(C═S)NRdRe, —NRc(C═O)NRdRe, —N Rc(C═S)NRdRe, —C(═S)Rc, —C(═O)Rc, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, carbocyclyl, (C1-C6-alkylene)-carbocyclyl, (C1-C6-heteroalkylene)-carbocyclyl, heterocyclyl, (C1-C6-alkylene)-heterocyclyl, (C1-C6-heteroalkylene)-heterocyclyl, aryl, (C1-C6-alkylene)-aryl, (C1-C6-heteroalkylene)-aryl, heteroaryl, (C1-C6-alkylene)-heteroaryl, and (C1-C6-heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more of halo, ORc, —NO2,
cyano, —NRcC(═O)Rc, —NRdRe, —S(O)kRc, —C(═O)ORc, —C(═O)NRdRe, —C(═O)Rc, C1-C6 alkyl, C1-C6haloalkyl, or C1-C6 heteroalkyl;
wherein any phenyl portion of R1 is optionally substituted with 1, 2, or 3 substituents, wherein each optional substituent is independently selected from deuterium, halo, cyano, acetyl, C1-C4 alkyl, C1-C4 haloalkyl, —O—C1-C4 alkyl, —C1-C4 alkylene-O—C1-C4 alkyl, heteroaryl, phenyl, cycloalkyl, —COOH, and —OH, wherein each of said heteroaryl, phenyl, and cycloalkyl are optionally substituted with one or more of halo, ORc, —NO2,
cyano, —NRcC(═O)Rc, —NRdRe, —S(O)kRc, —C(═O)ORc, —C(═O)NRdRe, —C(═O)Rc, C1-C6 alkyl, C1-C6haloalkyl, or C1-C6 heteroalkyl;
or
R1 is taken together with one R3 to form a saturated ring fused to the piperazine ring in formula (I), and wherein the ring formed by R1 and R3 is optionally substituted with 1, 2, or 3 substituents independently selected from halo, ═O,
cyano, —ORc, —NRdRe, —S(O)kRc, —NRcS(O)2Rc, —S(O)2NRdRe, —C(═O)ORc, —OC(═O)ORc, —OC(═O)Rc, —OC(═S)ORc, —C(═S)ORc, —O(C═S)Rc, —C(═O)NRdRe, —NRcC(═O)Rc, —C(═S)NRdRe, —NRcC(═S)Rc, —NRc(C═O)ORc, —O(C═O)NRdRe, —NRc(C═S)ORc, —O(C═S)NRdRe, —NRc(C═O)NRdRe, —N Rc(C═S)NRdRe, —C(═S)Rc, —C(═O)Rc, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, carbocyclyl,
(C1-C6-alkylene)-carbocyclyl, (C1-C6-heteroalkylene)-carbocyclyl, heterocyclyl, (C1-C6-alkylene)-heterocyclyl, (C1-C6-heteroalkylene)-heterocyclyl, aryl, (C1-C6-alkylene)-aryl, (C1-C6-heteroalkylene)-aryl, heteroaryl, (C1-C6-alkylene)-heteroaryl, and (C1-C6-heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more of halo, ORc, —NO2,
cyano, —NRcC(═O)Rc, —NRdRe, —S(O)kRc, —C(═O)ORc, —C(═O)NRdRe, —C(═O)Rc, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl;
if ring A is phenyl, then R2 is selected from halo, C1-C6 alkyl, heterocyclyl, cycloalkyl, —NH—(C0-C4 alkylene)-heterocyclyl, —(C1-C4 alkylene)-heterocyclyl, —(C1-C4 alkylene)-NH-heterocyclyl, and —O—(C0-C4 alkylene)-heterocyclyl, wherein any heterocyclyl, cycloalkyl, alkyl, or alkylene portion of R2 is optionally substituted with 1, 2, 3, or substituents independently selected from halo, ═O,
cyano, —ORc, —NRdRe, —S(O)kRc, —NRcS(O)2Rc, —S(O)2NRdRe, —C(═O)ORc, —OC(═O)ORc, —OC(═O)Rc, —OC(═S)ORc, —C(═S)ORc, —O(C═S)Rc, —C(═O)NRdRe, —NRcC(═O)Rc, —C(═S)NRdRe, —NRcC(═S)Rc, —NRc(C═O)ORc, —O(C═O)NRdRe, —NRc(C═S)ORc, —O(C═S)NRdRe, —NRc(C═O)NRdRe, —N Rc(C═S)NRdRe, —C(═S)Rc, —C(═O)Rc, C1-C6 alkyl,
C1-C6 haloalkyl, C1-C6 heteroalkyl, carbocyclyl, (C1-C6-alkylene)-carbocyclyl, (C1-C6-heteroalkylene)-carbocyclyl, heterocyclyl, (C1-C6-alkylene)-heterocyclyl, (C1-C6-heteroalkylene)-heterocyclyl, aryl, (C1-C6-alkylene)-aryl, (C1-C6-heteroalkylene)-aryl, heteroaryl, (C1-C6-alkylene)-heteroaryl, and (C1-C6-heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more of halo, ORc, —NO2,
cyano, —NRcC(═O)Rc, —NRdRe, —S(O)kRc, —C(═O)ORc, —C(═O)NRdRe, —C(═O)Rc, C1-C6 alkyl, C1-C6 haloalkyl, or
C1-C6 heteroalkyl; or R2 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 R2 and the ring atom in ring A is optionally substituted with 1, 2, or 3 substituents independently selected from halo, ═O,
cyano, —ORc, —NRdRe, —S(O)kRc, —NRcS(O)2Rc, —S(O)2NRdRe, —C(═O)ORc, —OC(═O)ORc, —OC(═O)Rc, —OC(═S)ORc, —C(═S)ORc, —O(C═S)Rc, —C(═O)NRdRe, —NRcC(═O)Rc, —C(═S)NRdRe, —NRcC(═S)Rc, —NRc(C═O)ORc, —O(C═O)NRdRe, —NRc(C═S)ORc, —O(C═S)NRdRe,
—NRc(C═O)NRdRe, —NRc(C═S)NRdRe, —C(═S)Rc, —C(═O)Rc, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, carbocyclyl, (C1-C6-alkylene)-carbocyclyl, (C1-C6-heteroalkylene)-carbocyclyl, heterocyclyl, (C1-C6-alkylene)-heterocyclyl, (C1-C6-heteroalkylene)-heterocyclyl, aryl, (C1-C6-alkylene)-aryl, (C1-C6-heteroalkylene)-aryl, heteroaryl, (C1-C6-alkylene)-heteroaryl, and (C1-C6-heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more of halo, ORc, —NO2,
cyano, —NRcC(═O)Rc, —NRdRe, —S(O)kRc, —C(═O)ORc, —C(═O)NRdRe, —C(═O)Rc, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl;
if ring A is heteroaryl, then R2 is selected from halo, C1-C6 alkyl, heterocyclyl, cycloalkyl, —NH—(C0-C4 alkylene)-heterocyclyl, —(C1-C4 alkylene)-heterocyclyl,
—(C1-C4 alkylene)-NH-heterocyclyl, and —O—(C0-C4 alkylene)-heterocyclyl, wherein any heterocyclyl, cycloalkyl, alkyl, or alkylene portion of R2 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, ═O,
cyano, —ORc, —NRdRe, —S(O)kRc, —NRcS(O)2Rc, —S(O)2NRdRe, —C(═O)ORc, —OC(═O)ORc, —OC(═O)Rc, —OC(═S)ORc, —C(═S)ORc, —O(C═S)Rc, —C(═O)NRdRe, —NRcC(═O)Rc, —C(═S)NRdRe, —NRcC(═S)Rc, —NRc(C═O)ORc, —O(C═O)NRdRe, —NRc(C═S)ORc, —O(C═S)NRdRe, —NRc(C═O)NRdRe, —N Rc(C═S)NRdRe, —C(═S)Rc, —C(═O)Rc, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, carbocyclyl,
(C1-C6-alkylene)-carbocyclyl, (C1-C6-heteroalkylene)-carbocyclyl, heterocyclyl, (C1-C6-alkylene)-heterocyclyl, (C1-C6-heteroalkylene)-heterocyclyl, aryl, (C1-C6-alkylene)-aryl, (C1-C6-heteroalkylene)-aryl, heteroaryl, (C1-C6-alkylene)-heteroaryl, and (C1-C6-heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more of halo, ORc, —NO2,
cyano, —NRcC(═O)Rc, —NRdRe, —S(O)kRc, —C(═O)ORc, —C(═O)NRdRe, —C(═O)Rc, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl; or R2 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 R2 and the ring atom in ring A is optionally substituted with 1, 2, or 3 substituents independently selected from halo, ═O,
cyano, —ORc, —NRdRe, —S(O)kRc, —NRcS(O)2Rc, —S(O)2NRdRe, —C(═O)ORc, —OC(═O)ORc, —OC(═O)Rc, —OC(═S)ORc, —C(═S)ORc, —O(C═S)Rc, —C(═O)NRdRe, —NRcC(═O)Rc, —C(═S)NRdRe, —NRcC(═S)Rc, —NRc(C═O)ORc, —O(C═O)NRdRe, —NRc(C═S)ORc, —O(C═S)NRdRe,
—NRc(C═O)NRdRe, —NRc(C═S)NRdRe, —C(═S)Rc, —C(═O)Rc, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, carbocyclyl, (C1-C6-alkylene)-carbocyclyl, (C1-C6-heteroalkylene)-carbocyclyl, heterocyclyl, (C1-C6-alkylene)-heterocyclyl, (C1-C6-heteroalkylene)-heterocyclyl, aryl, (C1-C6-alkylene)-aryl, (C1-C6-heteroalkylene)-aryl, heteroaryl, (C1-C6-alkylene)-heteroaryl, and (C1-C6-heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more of halo, ORc, —NO2,
cyano, —NRcC(═O)Rc, —NRdRe, —S(O)kRc, —C(═O)ORc, —C(═O)NRdRe, —C(═O)Rc, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl;
each R3 is independently selected from C1-C4 alkyl and C1-C4 haloalkyl;
each Rc is selected from hydrogen, hydroxy, C1-C6 alkyl, C1-C6 heteroalkyl, carbocyclyl, (C1-C6-alkylene)-carbocyclyl, (C1-C6-heteroalkylene)-carbocyclyl, heterocyclyl, (C1-C6-alkylene)-heterocyclyl, (C1-C6-heteroalkylene)-heterocyclyl, aryl, (C1-C6-alkylene)-aryl, (C1-C6-heteroalkylene)-aryl, heteroaryl, (C1-C6-alkylene)-heteroaryl, or (C1-C6-heteroalkylene)-heteroaryl, each of which is optionally substituted with one or more of halo, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
each Rd and Re are independently selected from hydrogen, C1-C6 alkyl, or C1-C6 heteroalkyl;
each k is independently 0, 1, or 2; and
n is 0, 1, 2, or 3.

### Claim 2 (depends on 1)

The method of claim 1, wherein:
n is 0; or
n is 1 and R3 is selected from methyl, ethyl, and CHF2.

### Claim 3 (depends on 1)

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 R2; and
ring A is optionally substituted with 1, 2, or 3 substituents independently selected from halo, ═O,
cyano, —ORc, —NRdRe, —S(O)kRc, —NRcS(O)2Rc, —S(O)2NRdRe, —C(═O)ORc, —OC(═O)ORc, —OC(═O)Rc, —OC(═S)ORc, —C(═S)ORc, —O(C═S)Rc, —C(═O)NRdRe, —NRcC(═O)Rc, —C(═S)NRdRe, —NRcC(═S)Rc, —NRc(C═O)ORc, —O(C═O)NRdRe, —NRc(C═S)ORc, —O(C═S)NRdRe,
—NRc(C═O)NRdRe, —NRc(C═S)NRdRe, —C(═S)Rc, —C(═O)Rc, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, carbocyclyl, (C1-C6-alkylene)-carbocyclyl, (C1-C6-heteroalkylene)-carbocyclyl, heterocyclyl, (C1-C6-alkylene)-heterocyclyl, (C1-C6-heteroalkylene)-heterocyclyl, aryl, (C1-C6-alkylene)-aryl, (C1-C6-heteroalkylene)-aryl, heteroaryl, (C1-C6-alkylene)-heteroaryl, and (C1-C6-heteroalkylene)-heteroaryl, wherein each of said alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more of halo, ORc, —NO2,
cyano, —NRcC(═O)Rc, —NRdRe, —S(O)kRc, —C(═O)ORc, —C(═O)NRdRe, —C(═O)Rc, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl in addition to R2.

### Claim 4 (depends on 3)

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

### Claim 5 (depends on 1)

The method of claim 1, wherein ring A is optionally substituted with 1 or 2 substituents in addition to R2, wherein each optional substituent is independently selected from cyano, halo, methyl, and OCHF2.

### Claim 6 (depends on 1)

The method of claim 1, wherein:
R1 is selected from —C(O)—(C1-C3 alkyl), C1-C3 alkyl, —O—(C1-C5 alkyl), —NH(C1-C5 alkyl), —N(C1-C4 alkyl)2, —NH—(C3-C6 cycloalkyl), C3-C6 cycloalkyl, —O—(C3-C6 cycloalkyl), —O—(C1-C3 alkylene)-(C3-C6 cycloalkyl), —(C1-C3 alkylene)-(C3-C6 cycloalkyl), —O—(C0-C3 alkylene)-(O-containing heterocyclyl), —NH—(C0-C3 alkylene)-(0-containing heterocyclyl), an O-containing heterocyclyl, an N-containing heterocyclyl, —O—(C0-C3 alkylene)-(N-containing heterocyclyl), —S—(C0-C3 alkylene)-(0-containing heterocyclyl), —NH—O—(C1-C3 alkyl), and —NH-phenyl, wherein:
any alkyl, cycloalkyl, phenyl, or heterocyclyl portion of R1 is optionally substituted with 1, 2, or 3 substituents, wherein each optional substituent is independently selected from deuterium, halo, cyano, acetyl, C1-C4 alkyl, C1-C4 haloalkyl, —O—C1-C4 alkyl, —C1-C4 alkylene-O—C1-C4 alkyl, heteroaryl, phenyl, cycloalkyl, —C00H, and —OH, wherein each of said heteroaryl, phenyl, and cycloalkyl are optionally substituted with one or more of halo, ORc, —NO2,
cyano, —NRcC(═O)Rc, —NRdRe, —S(O)kRc, —C(═O)ORc, —C(═O)NRdRe, —C(═O)Rc, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl; or
R1 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.

### Claim 7 (depends on 1)

The method of claim 1, wherein:
R2 is selected from halo, cycloalkyl, heterocyclyl, —O—(C0-C4 alkylene)-heterocyclyl, —(C1-C3 alkylene)-heterocyclyl, —(C1-C3 alkylene)-NH—(C1-C3 alkyl), -(hydroxy-substituted C1-C3 alkylene)-NH—(C1-C3 alkyl), C1-C4 alkyl substituted with both hydroxy and one or more of amino, C1-C4 alkylamino or di-C1-C4 alkylamino cyano-substituted C1-C4 alkyl, hydroxy, —S(O)2—C1-C4 alkyl, and -(amino substituted C1-C3 alkylene)-heterocyclyl; or
R2 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, —NH2, —NH(C1-C4 alkyl), —NH—C(O)—O—(C1-C4 alkyl), ═O, —C(O)—C1-C4 alkyl, —C1-C4 alkyl, deuterated C1-C4 alkyl, —C1-C4 haloalkyl, hydroxy-substituted —C1-C4 alkyl, —O—C1-C4 alkyl, —O—C1-C4 haloalkyl, —(C1-C4 alkylene)-O—(C1-C4 alkyl), -(amino substituted C1-C4 alkylene)-O—(C1-C4 alkyl), —(C1-C4 alkylene)-O—(C1-C4 haloalkyl), —C(O)—O—C1-C4 alkyl, —COOH, C3-C6 cycloalkyl, heterocyclyl, and —NH-heterocyclyl, wherein each said heterocyclyl is optionally substituted with one or more of halo, ORc, —NO2,
cyano, —NRcC(═O)Rc, —NRdRe, —S(O)kRc, —C(═O)ORc, —C(═O)NRdRe, —C(═O)Rc, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 heteroalkyl.

### Claim 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(R13) or N;
R11 is selected from: —NH—(C3-C4 cycloalkyl); —NH—C1-C3 alkyl; —O—C3-C4 cycloalkyl; —O—(C1-C3 alkyl) optionally substituted with one or more substituents selected from fluoro, hydroxy, cyano, and deuterium; and —O—(O-containing heterocycle);
R12 is selected from:
piperidin-3-yl optionally 3-substituted with C1-C3 alkoxy, fluoro, C1-C3 alkyl, or cyano; and
piperidin-4-yl optionally 4-substituted with C1-C3 alkoxy, fluoro, C1-C3 alkyl, and cyano, wherein:
R12 is additionally optionally 1-substituted with C1-C5 alkyl optionally substituted with one or more hydroxy and/or one or more —NH2;
R3 is selected from hydrogen, cyano, and fluoro; and
R14 is fluoro.

### Claim 9 (depends on 8)

The method of claim 8, wherein the compound is a compound of formula (IIa):
or a pharmaceutically acceptable salt thereof, wherein:
X is C(R13) or N;
R11 is selected from: —NH—(C3-C4 cycloalkyl); —NH—C1-C3 alkyl; —O—C3-C4 cycloalkyl; —O—(C1-C3 alkyl) optionally substituted with one or more substituents selected from fluoro, hydroxy, cyano, and deuterium; and —O—(O-containing heterocycle);
R13 is selected from hydrogen, cyano, and fluoro;
R14 is fluoro;
R15 is selected from hydrogen, C1-C3 alkoxy, fluoro, C1-C3 alkyl, and cyano; and
R16 is hydrogen or C1-C5 alkyl optionally substituted with one or more hydroxy and/or one or more —NH2.

### Claim 10 (depends on 8)

The method of claim 8, wherein the compound is a compound of formula (IIb):
or a pharmaceutically acceptable salt thereof, wherein:
X is C(R13) or N;
R11 is selected from: —NH—(C3-C4 cycloalkyl); —NH—C1-C3 alkyl; —O—C3-C4 cycloalkyl; —O—(C1-C3 alkyl) optionally substituted with one or more substituents selected from fluoro, hydroxy, cyano, and deuterium; and —O—(O-containing heterocycle);
R13 is selected from hydrogen, cyano, and fluoro;
R14 is fluoro;
R15 is selected from hydrogen, C1-C3 alkoxy, fluoro, C1-C3 alkyl, and cyano; and
R16 is hydrogen or C1-C5 alkyl optionally substituted with one or more hydroxy and/or one or more —NH2.

### Claim 11 (depends on 10)

The method of claim 10, wherein the compound is a compound of formula (IIb-1):
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 10)

The method of claim 10, wherein the compound is a compound of formula (IIb-2):
or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 8)

The method of claim 8, wherein R14 is absent.

### Claim 14 (depends on 8)

The method of claim 8, wherein R13 is hydrogen.

### Claim 15 (depends on 8)

The method of claim 8, wherein R11 is selected from:
—NH—C1-C3 alkyl;
—O—C1-C3 alkyl optionally substituted with one or more substituents selected from fluoro, hydroxy, cyano, and deuterium;
oxetan-3-yloxy; and
tetrahydrofuran-3-yloxy.

### Claim 16 (depends on 1)

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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### Claim 17 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 26 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 27 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 28 (depends on 1)

The method of claim 1, wherein the compound is
or a pharmaceutically acceptable salt thereof.

### Claim 29 (depends on 1)

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.

### Claim 30 (depends on 29)

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

### Claim 31 (depends on 1)

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