# US 11,026,947 B2 · ALK2 inhibitors and methods for inhibiting BMP signaling

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- Number: US 11,026,947 B2
- Document ID: US11026947B2
- Status: Granted
- Kind: B2
- Application number: 16/608,489
- Filed: 2018-04-26
- Published: 2020-06-11
- Granted: 2021-06-08
- Earliest claimed: 2017-04-27
- Assignees: The Brigham and Women's Hospital, Inc.; The United States of America, as represented by the Secretary, Dept. of Health and Human Services
- Applicants: The Brigham and Women's Hospital, Inc.; The United States of America, As Represented By The Secretary, Department Of Health And Human Services
- Inventors: Paul B. Yu; Wenwei Huang; Philip Edward Sanderson; Jian-Kang Jiang; Khalida Shamim; Wei Zheng; Xiuli Huang; Gregory Tawa; Arthur Lee; Asaf Alimardanov; Junfeng Huang
- Web page: https://patentgrep.com/patent/US11026947B2

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/551: having two nitrogen atoms, e.g. dilazep
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- 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
- C07F 9/6561: containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

The present invention provides small-molecule inhibitors of BMP signaling and compositions and methods for inhibiting BMP signaling. These compounds and compositions may be used to modulate cell growth, differentiation, proliferation, and apoptosis, and thus may be useful for treating diseases or conditions associated with BMP signaling, including inflammation, cardiovascular disease, hematological disease, cancer, and bone disorders, as well as for modulating cellular differentiation and/or proliferation. These compounds and compositions may also be used to treat subjects with Sjögren's syndrome, or diffuse intrinsic pontine glioma (DIPG).

## Claims

### Claim 1

A compound of formula (I):
or a pharmaceutically acceptable salt and/or prodrug thereof, wherein
A1 is NR4a or CR4bR5;
B1 is N or CR2;
Z1 is N or CR3;
R1 is selected from cycloalkyl, aryl, heteroaryl, and heterocyclyl;
R2 is H, CN, NO2, alkyl, or amino;
R3 is selected from H, CN, NO2, alkyl, alkoxy, heterocyclyloxy, heteroaryloxy, aryloxy, cycloalkyloxy, carbonyl, amino, amido, sulfonyl, sulfonamido, cycloalkyl, aryl, heterocyclyl, and heteroaryl;
R4a is selected from alkyl, alkenyl, alkynyl, carbonyl, O−, alkoxycarbonyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl;
R4b is selected from halo, CN, NO2, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, heterocyclyloxy, heteroaryloxy, aryloxy, cycloalkyloxy, amino, amido, carbonyl, alkoxycarbonyl, carboxy, sulfonyl, sulfonamido, thio, cycloalkyl, aryl, heterocyclyl, and heteroaryl;
R5 is selected from H, halo, hydroxy and alkyl, or
R4b and R5 together with A1 form a ring selected from cycloalkyl and heterocyclyl;
each R6 is independently selected from H, halo, CN, NO2, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, heterocyclyloxy, heteroaryloxy, aryl oxy, cycloalkyloxy, amino, amido, carbonyl, alkoxycarbonyl, carboxy, sulfonyl, sulfonamido, thio, cycloalkyl, aryl, heterocyclyl, and heteroaryl and oxo;
n is 0 or 1;
m is 0 or 1; and
x is 0, 1, 2, 3, or 4.

### Claim 2 (depends on 1)

The compound of claim 1:
or a pharmaceutically acceptable salt and/or prodrug thereof, wherein
A1 is NR4a or CR4bR5;
B1 is N or CR2;
Z1 is N or CR3;
R1 is selected from aryl, heteroaryl, and heterocyclyl;
R2 is H or amino;
R3 is H or heterocyclyloxy;
R4a is selected from alkyl, O−, aryl, heterocyclyl, and heteroaryl;
R4b is selected from alkyl, alkoxy, amino, aryl, heterocyclyl, and heteroaryl;
R5 is selected from H and alkyl, or
R4b and R5 together with A1 form a ring selected from cycloalkyl and heterocyclyl;
each R6 is independently selected from H, halo, alkyl and oxo;
n is 0 or 1;
m is 0 or 1; and
x is 0, 1, 2, 3, or 4.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R1 is selected from H, aryl, 5-6 membered heteroaryl,
wherein:
each E is independently selected from N and CR1d;
each G is independently selected from N and CR1e;
K1 is N or CH;
K2 is NH or S;
M is N or CR1a;
R1a is selected from H, halo, alkyl, haloalkyl, and amido;
R1b is selected from H, halo, CN, alkyl, haloalkyl, hydroxy, alkoxy, and haloalkoxy;
R1c is selected from H, halo, CN, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino and amido, or
R1b and R1c together with the carbon atoms to which they are attached form a heterocyclyl;
R1d is selected from H, CN, alkyl, haloalkyl, hydroxy, amido and sulfonamido;
R1c is selected from H, alkyl and amino; and
R1g is H or halo.

### Claim 4 (depends on 2)

The compound of claim 2, wherein
R4a is selected from alkyl, O−, heterocyclyl, and heteroaryl;
R4b is selected from alkyl, alkoxy, amino, amido, heterocyclyl, and heteroaryl;
R5 is selected from H and alkyl, or
R4b and R5 together with A1 form a heterocyclyl; and
each R6 is independently selected from H, halo, and alkyl; and
x is 0 or 1.

### Claim 5 (depends on 4)

The compound of claim 4, wherein R1 is selected from H, aryl, 5-6 membered heteroaryl,
wherein:
each E is independently selected from N and CR1d;
each G is independently selected from N and CR1e;
K1 is N or CH;
K2 is NH or S;
M is CR1a;
R1a is selected from H and amido;
R1b is selected from H, halo, alkyl, and alkoxy;
R1c is selected from H, alkyl, and alkoxy, or
R1b and R1c together with the carbon atoms to which they are attached form a heterocyclyl;
R1d is selected from H, alkyl, hydroxy, amido and sulfonamido;
R1e is selected from H, alkyl and amino;
R1f is H; and
R1g is H.

### Claim 6

A compound having a formula selected from:
or a pharmaceutically acceptable salt and/or prodrug thereof.

### Claim 7

A compound having a formula selected from:
or a pharmaceutically acceptable salt and/or prodrug thereof.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt and/or prodrug thereof, and one or more pharmaceutically acceptable excipients.

### Claim 9 (depends on 1)

A method for treating the formation of abnormal bone in a soft tissue of a subject, the method comprising: administering to the subject a therapeutically effective amount of one or more compounds of claim 1.

### Claim 10 (depends on 9)

The method of claim 9, wherein the subject is determined to
a) have or be at risk of having abnormal bone formation prior to treatment; and/or
b) have been subjected to a musculoskeletal trauma, a spinal cord injury or a central nervous system injury.

### Claim 11 (depends on 9)

The method of claim 9, wherein the formation of abnormal bone is associated with a heterotopic ossification disease.

### Claim 12 (depends on 11)

The method of claim 11, wherein the heterotopic ossification disease is selected from acquired heterotopic ossification, fibrodysplasia ossificans progressiva, anklyosing spondylosis, traumatic heterotopic ossification, burn- or blast-injury associated heterotopic ossification, and joint replacement surgery associated heterotopic ossification.

### Claim 13 (depends on 9)

The method of claim 9, further comprising administering at least one additional agent to the subject.

### Claim 14 (depends on 13)

The method of claim 13, wherein the at least one additional agent comprises a corticosteroid, a non-steroidal anti-inflammatory drug (NSAID), a lipoxygenase inhibitor, a leukotriene inhibitor, a mast cell stabilizing agent, an anti-histamine, a TNF inhibitor, an IL-23 blocker, an inhibitor of IL-1 signaling, and/or an anti-inflammatory agent selected from one or more of an inhibitor of the activity of substance P; an inhibitor of the secretion of substance P; an inhibitor of the effects of substance P; an inhibitor of the activity of histamine; an inhibitor of the secretion of histamine; an inhibitor of the effects of histamine; an inhibitor of mast cell function; an inhibitor of Toll-like receptor signaling; an inhibitor of MyD88; an inhibitor of TRIF; apyrase; and an agent to catalyze hydrolysis of ATP.

### Claim 15 (depends on 13)

The method of claim 13, wherein the at least one additional agent comprises an anti-inflammatory agent selected from one or more of an inhibitor of the activity of substance P; an inhibitor of the secretion of substance P; an inhibitor of the effects of substance P; an inhibitor of the activity of histamine; an inhibitor of the secretion of histamine; an inhibitor of the effects of histamine; an inhibitor of mast cell function; an inhibitor of Toll-like receptor signaling; an inhibitor of MyD88; an inhibitor of TRIF; apyrase; and an agent to catalyze hydrolysis of ATP.

### Claim 16 (depends on 13)

The method of claim 13, wherein the at least one additional agent comprises
a) an anti-growth factor agent selected from one or more of an inhibitor of PDGF ligands; an inhibitor of PDGF-AA; an inhibitor of PDGF-BB; an inhibitor of PDGFR-alpha receptor function; an inhibitor of PDGFR-beta receptor function; a neutralizing antibody against Activin A; a neutralizing antibody against Activin B; a neutralizing antibody against Activin A ligands; a neutralizing antibody against Activin B ligands; a neutralizing antibody against heterodimeric ligands containing Inhibin bA subunits encoded by the INHBA; a neutralizing antibody against heterodimeric ligands containing Inhibin bB subunits encoded by the INHBB gene; a ligand trap of BMP ligands; a ligand trap of Activin ligands; a ligand trap of soluble extracellular domains of a type II Activin receptor ActRIIA; a ligand trap of soluble extracellular domains of a type II Activin receptor ActRIIB; a ligand trap of soluble extracellular domains of a BMP type I receptor ALK2; a ligand trap of soluble extracellular domains of a BMP type I receptor ALK3; and a ligand trap of soluble extracellular domains of a BMP type I receptor ALK6; and/or
b) an anti-osteogenic signaling agent or an anti-chondrogenic signaling agent selected from one or more of a RAR-gamma agonist; a nonselective RAR agonist; an agent that inhibits the activity of osteogenic transcription factor Runx2; an agent that inhibits the expression of osteogenic transcription factor Runx2; an agent that promotes the degradation of osteogenic transcription factor Runx2; an agent that inhibits the activity of chondrogenic transcription factor Sox9; an agent that inhibits the expression of chondrogenic transcription factor Sox9; an agent that promotes the degradation of chondrogenic transcription factor Sox9; an inhibitor of HIF-1 alpha activity; and an inhibitor of HIF-1 alpha expression.

### Claim 17 (depends on 1)

A method for treating abnormal bone in a soft tissue of a subject, the method comprising: administering a therapeutically effective amount of an inhibitor of a BMP type I serine-threonine kinase receptor to the subject, wherein the inhibitor of a BMP type I serine-threonine kinase receptor is one or more compounds of claim 1.

### Claim 18 (depends on 1)

A method of treating a subject with Sjogren's syndrome, comprising:
administering to the subject a therapeutically effective amount of an inhibitor of BMP6, thereby treating the subject with Sjogren's syndrome, wherein the inhibitor is one or more compounds of claim 1.

### Claim 19 (depends on 1)

A method for treating a subject with diffuse intrinsic pontine glioma (DIPG), comprising administering to the subject a therapeutically effective amount of one or more compounds of claim 1, thereby treating the subject with diffuse intrinsic pontine glioma (DIPG).

### Claim 20 (depends on 1)

A method for treating a subject having a cancer selected from adenocarcinoma, prostate carcinoma, breast carcinoma, renal cell carcinoma, bone metastasis, lung metastasis, osteosarcoma, and multiple myeloma, comprising administering to the subject a therapeutically effective amount of one or more compounds of claim 1, thereby treating the subject with cancer.

### Claim 21

A compound having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 22

A compound having the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 23

A compound having the structure:
or a pharmaceutically acceptable salt thereof.