ALK2 inhibitors and methods for inhibiting BMP signaling

1. A compound of formula (I):

or a pharmaceutically acceptable salt and/or prodrug thereof, wherein

A 1 is NR 4a or CR 4b R 5 ;

B 1 is N or CR 2 ;

Z 1 is N or CR 3 ;

R 1 is selected from cycloalkyl, aryl, heteroaryl, and heterocyclyl;

R 2 is H, CN, NO 2 , alkyl, or amino;

R 3 is selected from H, CN, NO 2 , alkyl, alkoxy, heterocyclyloxy, heteroaryloxy, aryloxy, cycloalkyloxy, carbonyl, amino, amido, sulfonyl, sulfonamido, cycloalkyl, aryl, heterocyclyl, and heteroaryl;

R 4a is selected from alkyl, alkenyl, alkynyl, carbonyl, O − , alkoxycarbonyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl;

R 4b is selected from halo, CN, NO 2 , hydroxy, alkyl, alkenyl, alkynyl, alkoxy, heterocyclyloxy, heteroaryloxy, aryloxy, cycloalkyloxy, amino, amido, carbonyl, alkoxycarbonyl, carboxy, sulfonyl, sulfonamido, thio, cycloalkyl, aryl, heterocyclyl, and heteroaryl;

R 5 is selected from H, halo, hydroxy and alkyl, or

R 4b and R 5 together with A 1 form a ring selected from cycloalkyl and heterocyclyl;

each R 6 is independently selected from H, halo, CN, NO 2 , 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.

2. The compound of claim 1 :

or a pharmaceutically acceptable salt and/or prodrug thereof, wherein

A 1 is NR 4a or CR 4b R 5 ;

B 1 is N or CR 2 ;

Z 1 is N or CR 3 ;

R 1 is selected from aryl, heteroaryl, and heterocyclyl;

R 2 is H or amino;

R 3 is H or heterocyclyloxy;

R 4a is selected from alkyl, O − , aryl, heterocyclyl, and heteroaryl;

R 4b is selected from alkyl, alkoxy, amino, aryl, heterocyclyl, and heteroaryl;

R 5 is selected from H and alkyl, or

R 4b and R 5 together with A 1 form a ring selected from cycloalkyl and heterocyclyl;

each R 6 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.

3. The compound of claim 1 , wherein R 1 is selected from H, aryl, 5-6 membered heteroaryl,

wherein:

each E is independently selected from N and CR 1d ;

each G is independently selected from N and CR 1e ;

K 1 is N or CH;

K 2 is NH or S;

M is N or CR 1a ;

R 1a is selected from H, halo, alkyl, haloalkyl, and amido;

R 1b is selected from H, halo, CN, alkyl, haloalkyl, hydroxy, alkoxy, and haloalkoxy;

R 1c is selected from H, halo, CN, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, amino and amido, or

R 1b and R 1c together with the carbon atoms to which they are attached form a heterocyclyl;

R 1d is selected from H, CN, alkyl, haloalkyl, hydroxy, amido and sulfonamido;

R 1c is selected from H, alkyl and amino; and

R 1g is H or halo.

4. The compound of claim 2 , wherein

R 4a is selected from alkyl, O − , heterocyclyl, and heteroaryl;

R 4b is selected from alkyl, alkoxy, amino, amido, heterocyclyl, and heteroaryl;

R 5 is selected from H and alkyl, or

R 4b and R 5 together with A 1 form a heterocyclyl; and

each R 6 is independently selected from H, halo, and alkyl; and

x is 0 or 1.

5. The compound of claim 4 , wherein R 1 is selected from H, aryl, 5-6 membered heteroaryl,

wherein:

each E is independently selected from N and CR 1d ;

each G is independently selected from N and CR 1e ;

K 1 is N or CH;

K 2 is NH or S;

M is CR 1a ;

R 1a is selected from H and amido;

R 1b is selected from H, halo, alkyl, and alkoxy;

R 1c is selected from H, alkyl, and alkoxy, or

R 1b and R 1c together with the carbon atoms to which they are attached form a heterocyclyl;

R 1d is selected from H, alkyl, hydroxy, amido and sulfonamido;

R 1e is selected from H, alkyl and amino;

R 1f is H; and

R 1g is H.

6. A compound having a formula selected from:

or a pharmaceutically acceptable salt and/or prodrug thereof.

7. A compound having a formula selected from:

or a pharmaceutically acceptable salt and/or prodrug thereof.

8. 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.

9. 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 .

10. 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.

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

12. 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.

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

14. 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.

15. 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.

16. 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.

17. 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 .

18. 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 .

19. 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).

20. 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.

21. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

22. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

23. A compound having the structure:

or a pharmaceutically acceptable salt thereof.