FIELD OF THE INVENTION

The present invention relates to macrocyclic compounds and compositions containing said compounds acting as kinase inhibitors, in particular as inhibitors of Activin-like receptor kinases, more in particular ALK1 and/or ALK2 and/or mutants thereof, for use in the diagnosis, prevention and/or treatment of ALK1 -kinase and/or ALK2-kinase associated diseases. Moreover, the present invention provides methods of using said compounds, for instance as a medicine or diagnostic agent.

BACKGROUND TO THE INVENTION

Bone morphogenetic proteins (BMPs) are multi-functional growth factors that belong to the Transforming Growth Factor beta (TGFbeta) superfamily. The BMP family regulates a wide range of crucial cell growth and differentiation events, including early embryonic patterning and morphogenesis, notably in bone/cartilage formation. Studies from transgenic and knockout mice and from animals and humans with naturally occurring mutations in BMPs and related genes have shown that BMP signaling plays critical roles in heart, neural and cartilage development (Growth Factors (2004) 22: 233-241 ). BMPs also play an important role in postnatal bone formation.

To date, around 20 BMP family members have been identified and characterized. BMPs signal through serine/threonine kinase receptors, composed of type I and II subtypes. Three type I receptors have been shown to bind BMP ligands, type IA and IB BMP receptors (BMPR-IA or ALK3 and BMPR-IB or ALK6) and type IA activin receptor (ActR-IA, ALK2 or ACVR1 ) (Mol. Cell. Biol.

(1994) 14: 5961 -5974). Signal transduction studies have revealed that Smadl , 5 and 8 are the immediate downstream molecules of BMP receptors and play a central role in BMP signal transduction. Smad-dependant transcription leads to induction of Hox proteins, known to be essential in embryonic tissue patterning and postnatal tissue homeostasis (Ann. NY Acad. Sci.

(2006) 1068: 26-40).

Many disorders have been linked to either the BMPs or the molecules functioning downstream of BMP signalling pathway, such as ALK1 and/or ALK2.

Among them, Fibrodysplasia Ossificans Progressiva (FOP), also known as Myositis Ossificans Progressiva, is a severely disabling heritable disorder of connective tissue characterized by progressive heterotopic ossification that forms qualitatively normal bone in characteristic extraskeletal sites. The worldwide prevalence is approximately 1/2,000,000. There is no ethnic, racial, gender, or geographic predilection to FOP. Heterotopic ossification in FOP begins in childhood and can be induced by trauma, or may occur without warning. Bone formation is episodic and transforms skeletal muscles, tendons, ligaments, fascia, and aponeuroses into heterotopic bone, rendering movement impossible (Orphanet J. Rare. Dis. (201 1 ) 1 : 80). All FOP patients carry a heterozygous mutation (617G>A; R206H) in the gene ALK2. Patients with atypical forms of FOP have been described and shown to have heterozygous ALK2 missense mutations in conserved amino acids (Shore et al, Nature Genetics (2006) 38: 525-527). There is no effective treatment, and soft-tissue trauma (eg, biopsies, surgical procedures, intramuscular injections, or mandibular blocks for dental procedures) and viral illnesses are likely to induce episodes of rapidly progressive heterotopic ossification, with resultant permanent loss of motion in the affected area.

BMP signalling is also critical for both epithelial and endothelial cell plasticity in embryonic development and disease progression. Transformation of epithelial cells into mesenchymal cells (epithelial-mesenchymal transition or EMT) is a mechanism that regulates gastrulation, neural crest and somite dissociation, craniofacial development, wound healing, organ fibrosis, and tumour metastasis. Similarly, endothelial-mesenchymal transition (EndMT) is a critical aspect of endocardial cushion formation during cardiac development and recent studies have shown that EndMT plays an essential role in the tumour microenvironment by generating carcinoma- associated fibroblasts and may be an essential mediator of cancer progression. Similarly, many fibroblasts formed during cardiac and renal fibrosis have been shown to be of endothelial origin. EndMT has also been implicated in atherosclerosis, pulmonary hypertension, and wound healing. Therapeutic strategies targeting BMP-signalling provide a perspective on pharmacological interventions to mitigate several disease conditions related to EMT or EndMT.

Taking into consideration the role of ALK2 protein in the BMP signalling pathway and in postnatal tissue homeostasis, in particular its major implication in FOP, it was therefore an object of the present invention to provide a potent, selective, small molecule inhibitor of ALK2. By this means, it provides a therapeutic benefit in FOP, anemia (anemia of iron deficiency, anemia of chronic disease), cardiovascular disorders (pulmonary/vascular/systemic hypertension, atherosclerosis, Rendu-Osler disease, primary pulmonary hypertension), cancer (solid tumors, ovarian cancer, DIPG, lung cancer, prostate cancer, breast cancer, head and neck squamous cancer, hepatocellular carcinoma cancer, metastatic cancers), fibrosis, immunology/stem cell differentiation (immune modulation propagation, engraftment and differentiation of progenitor cells, transplantation), neurological disorders (spinal cord injury, treatment of demyelination) and inflammatory diseases characterized in increased BMP-signalling and/or dysregulated ALK1 /ALK2 kinase activities.

We have now found that the macrocyclic pyrazolopyrimidines and imidazopyridazines and pharmaceutically acceptable compositions according to this invention are useful for the treatment of several disorders associated with ALK1 and/or ALK2 kinase activity (i.e. ALK1 -kinase and/or ALK2-kinase associated diseases). SUMMARY OF THE INVENTION

We have surprisingly found that the macrocyclic compounds described herein act as Activin-like receptor kinase inhibitors, more in particular as ALK1 and/or ALK2 kinase inhibitors, and are thus very useful in the prevention and/or treatment of ALK1 -kinase and/or ALK2-kinase associated diseases.

In a first objective the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or redrug, salt, hydrate, N-oxide form, or solvate thereof,

Wherein

R-i and R ₄₁ are each independently selected from -H, -halo, -OH, -d- ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ 6alkyl, -NR ₉ R ₁₀ , -(C=0)-R ₄ , -(C=S)-R ₄ , -S0 ₂ -R ₄ , -CN, -NR ₉ -S0 ₂ -R ₄ , -C ₃ . ₆ cycloalkyl, -Ar ₇ and -Het-ι; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR ₁₂ , -0-Ci_ ₆ alkyl, and -S-Ci_ ₆ alkyl;

R ₂ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=0)-NR ₂₇ R ₂ 8, -(C=S)-NR ₂₇ R ₂₈ , -C ₃ - ₆ cycloalkyl, -Het ₃ , -Ar ₂ , -(C=0)-Het ₃ , -(C=S)-Het ₃ , -(C=0)-Ar ₂ , -(C=S)-Ar ₂ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ . 6cycloalkyl, and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -

Het ₃ , -Ar ₂ , and -NRi ₃ R _M ;

R ₃ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=O)-NR ₂₉ R ₃₀ , -(C=S)-NR ₂₉ R ₃₀ , -C ₃ . ₆ cycloalkyl -Het ₂ , -Ar ₃ , -(C=0)-Het ₂ , -(C=S)-Het ₂ , -(C=0)-Ar ₃ , -(C=S)-Ar ₃ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ . 6cycloalkyl and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₂ , -Ar ₃ , and -NR ₁₅ R ₁₆ ;

R ₄ is independently selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -NR ₁₇ R ₁₈ , -C ₃ . ₆ cycloalkyl, -Ar ₈ and -Het ₄ ;

R ₅ and R ₇ are each independently selected from -H, -OH, -halo, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ 6alkyl, -Het ₉ , -Ar-, , -C ₃ . ₆ cycloalkyl, -S0 ₂ -Ar-, , -S0 ₂ , -S0 ₂ -Ci_ ₆ alkyl, -(C=0), -(C=0)-Ci_ ₆ alkyl, -(C=S), -(C=S)-C ₁ . ₆ alkyl, -0-(C=0)-C ₁ . ₆ alkyl, -0-(C=S)-C ₁ . ₆ alkyl, -(C=0)-0-C ₁ . ₆ alkyl, and wherein each of said -d- ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Ar-ι, -Het ₉ , and -NR23R24;

R ₆ is selected from -Ci_ ₆ alkyl, -S0 ₂ , -S0 ₂ -Ci. ₆ alkyl, -S0 ₂ -C ₃ . ₆ cycloalkyl, -(C=0), - (C=0)-C ₂ - ₆ alkenyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=0)-Het ₆ , -(C=0)-Ar ₆ , -(C=0)-C ₃ - ₆ cycloalkyl, -(C=0)- NR31 R32, -(C=0)-NR ₃₁ -(C=0)-R ₃₂ , -(C=S), -(C=S)-C ₁ . ₆ alkyl, -(C=S)-C ₂ . ₆ alkenyl, -(C=S)-0-d_ 6alkyl, -(C=S)-Het ₆ , -(C=S)-Ar ₆ , -(C=S)-C ₃ - ₆ cycloalkyl, -(C=S)-NR ₃₁ R ₃₂ , -(C=S)-NR ₃₁ -(C=S)-R ₃₂ , -Het ₆ , -Ar ₆ , and -C ₃ . ₆ cycloalkyl;

wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from =0, -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₆ , - Ar ₆ , -NR ₂₅ R ₂₆ , -(C=0)-NR ₂₅ R ₂₆ , -NR ₃₃ (C=0)-NR ₂₅ R ₂₆ , -(C=S)-NR ₂₅ R ₂₆ , and -NR ₃₃ (C=S)- NR ₂₅ R ₂₆ ; and

wherein each of said -C ₃ . ₆ cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_ ₆ alkyl, =0, -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -Het ₁₂ , -Ar-n, and -NR ₅₃ R ₅ 4, -(C=0)-NR ₅₃ R ₅ 4, -NR ₅ 5(C=0)-NR ₅₃ R54, -(C=S)-NR ₅₃ R ₅ 4, and -NR ₅₅ (C=S)-

R ₈ is selected from -NR ₃₄ -(C=0)-R ₃₅ , -NR ₃₄ -(C=S)-R ₃₅ , -NR ₃₆ -(C=0)-NR ₃₄ R ₃₅ , -NR ₃₆ -(C=S)- NR ₃₄ R ₃₅ , -NR ₃₄ -(S0 ₂ )-R ₃₅ , -NR ₃₄ -(C=0)-0-R ₃₅ , -NR ₃₄ -(C=S)-0-R ₃₅ , -0-(C=0)-NR ₃₄ R ₃₅ , and -0-(C=S)-NR ₃₄ R ₃₅ ;

Rg, R-io, R11, Ri ₂ , Ri ₃ , Ri ₄ , Ri5. R16. Ri7. R18. Ri9. R20. R21. R22. R23. R24. R25. R26. R27. R28. R29. R30.

R31. R32. R33. R34. R35. R36. R37. R38. R39. R40, R44. R45. R46. R47. R48, R49. R50. R53. R54 and R55 are each independently selected from -H, -halo, =0, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, - C ₃ . ₆ cycloalkyl, -Ar ₅ and -Het ₇ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

-C ₃ . ₆ cycloalkyl, -Het ₇ , -Ar ₅ and -NR ₅₁ R ₅₂ ;

R ₅₁ and R ₅₂ are each independently selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_

₆ alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₁₀ and -Het ₁₀ ;

R ₄₂ is selected from -H, -OH, -halo, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -NR ₄₆ R ₄₇ , -C ₃ . ₆ cycloalkyl, -Ar ₉ and -Het ₈ ;

R ₄₃ is selected from -H -Ci_ ₆ alkyl, and -C ₃ . ₆ cycloalkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1- 6alkyl, -S-Ci_ ₆ alkyl, -Het ₅ , -C ₃ . ₆ cycloalkyl -Ar ₄ , and -NR ₄₄ R ₄₅ ;

A is selected from -(CH ₂ ) _n -Y-(CH ₂ ) _m -, -(C=0)-, -(C=S)-, -(C=N)-R ₄₉ -, -(S0 ₂ )-, -S0 ₂ -NR ₅ -, -(C=0)- NR5-, -(C=S)-NR ₅ -, -NR ₅ -(C=0)-NR ₇ -, -NR ₅ -(C=S)-NR ₇ -, -NR ₆ -, -NR ₅ -(C=0)-0-, -NR ₅ -(C=S)-0-

, and -CHR ₈ - ;

X-i is selected from -Ci_ ₆ alkyl-, -0-Ci_ ₆ alkyl-, -S-Ci_ ₆ alkyl-, -(C=0)-, -NR ₃ -(C=0)-, -Ci_ ₆ alkyl-NR ₃ -, -NR ₃ -, -(C=0)-, -NR ₃ -(C=0)-NR ₄₈ -, -NRs-C^alkyl-, -NR ₃ -S0 ₂ -, -NR ₃ -(C=0)-C ₁ . ₆ alkyl-, -(C=0)- NR ₃ -Ci_ ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -Ci. ₆ alkyl-NR ₃ -Ci. ₆ alkyl-; wherein each of said -Ci_ ₆ alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci _-6 alkyl, -0-Ci _-6 alkyl, -S-Ci _-6 alkyl, -phenyl, and -NR ₃₇ R ₃₈ ;

X ₂ is selected from -C _1-6 alkyl-, -0-Ci_ ₆ alkyl-, -S-Ci_ ₆ alkyl-, -(C=0)-, -NR ₂ -(C=0)-, -Ci. ₆ alkyl-NR ₂ -, -NR ₂ -, -(C=0)-, -NR ₂ -(C=O)-NR ₅₀ -, -NR ₂ -Ci _-6 alkyl-, -NR ₂ -S0 ₂ -, -NR ₂ -(C=0)-C ₁ . ₆ alkyl-, -(C=0)- NR ₂ -Ci_ ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -Ci. ₆ alkyl-NR ₂ -Ci. ₆ alkyl-; wherein each of said

-Ci- ₆ alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d- ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -phenyl and -NR ₃₉ R4o;

Y is selected from a direct bond, -CHR ₄₂ -, -0-, -S-, and -NR ₄₃ -;

Ar-ι , Ar ₂ , Ar ₃ , Ar ₄ , Ar ₅ , Ar ₆ , Ar ₇ , Ar ₈ , Ar ₉ , Ar ₁₀ and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar-ι , Ar ₂ , Ar ₃ , Ar ₄ , Ar ₅ , Ar ₆ , Ar ₇ , Ar ₈ , Ar ₉ , Ar ₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S- Ci- ₆ alkyl, and -NR ₁₉ R ₂₀ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι , Het ₂ , Het ₃ , Het ₄ , Het ₅ , Het ₆ , Het ₇ , Het ₈ , Het ₉ , Het ₁₀ , and Het ₁₂ are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι , Het ₂ , Het ₃ , He , Het ₅ , Het ₆ , Het ₇ , Het ₈ , Het ₉ , Het ₁₀ , and Het ₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6alkyl, -OCi_ ₆ alkyl, -SCi_ ₆ alkyl, =0, and -NR ₂₁ R ₂₂ ; wherein each of said -Ci_ 6alkyl is optionally and independently substituted with from 1 to 3 -halo;

Z-i , Z ₂ , Z ₃ , Z ₄ and Z ₅ are each independently selected from C and N; and

m and n are each independently 1 , 2, 3, or 4;

for use in the diagnosis, prevention and/or treatment of an Activin-like receptor kinase associated disease selected from anemia-related disorders or disorders characterized by abnormal bone formation.

In a first embodiment, the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein

R-i and R ₄₁ are each independently selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ 6alkyl, -NR ₉ R ₁₀ , -(C=0)-R ₄ , -(C=S)-R ₄ , -S0 ₂ -R ₄ , -CN, -NR ₉ -S0 ₂ -R ₄ , -C ₃ . ₆ cycloalkyl, -Ar ₇ and -Het-ι ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR ₁₂ , -0-Ci_ ₆ alkyl, and -S-Ci_ ₆ alkyl;

R ₂ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=0)-NR ₂₇ R ₂₈ , -(C=S)-NR ₂₇ R ₂₈ , -C ₃ . ₆ cycloalkyl, -Het ₃ , -Ar ₂ , -(C=0)-Het ₃ , -(C=S)-Het ₃ , -(C=0)-Ar ₂ , -(C=S)-Ar ₂ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ . 6cycloalkyl, and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, - Het ₃ , -Ar ₂ , and -NRi ₃ Ri ₄ ;

R ₃ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=0)-NR ₂₉ R ₃ o, -(C=S)-NR ₂₉ R ₃₀ , -C ₃ . ₆ cycloalkyl -Het ₂ , -Ar ₃ , -(C=0)-Het ₂ , -(C=S)-Het ₂ , -(C=0)-Ar ₃ , -(C=S)-Ar ₃ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ .

₆ cycloalkyl and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -d- ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₂ , -Ar ₃ , and -NR ₁₅ R ₁₆ ;

R ₄ is independently selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -NR ₁₇ R ₁₈ , -C ₃ . ₆ cycloalkyl, -Ar ₈ and -Het ₄ ;

R ₅ is selected from -H, -OH, -halo, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -Het ₉ , -Ar-ι , -C ₃ . ₆ cycloalkyl, - SOz-A^ , -S0 ₂ , -S0 ₂ -d_ ₆ alkyl, -(C=0), -(C=0)-C ₁ . ₆ alkyl, -(C=S), -(C=S)-C ₁ . ₆ alkyl, -0-(C=0)-d_ 6alkyl, wherein each of said -d_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci. ₆ alkyl, -S-Ci. ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Αη , -Het ₉ , and -NR ₂₃ R ₂₄ ;

R ₆ is selected from -Ci_ ₆ alkyl, -S0 ₂ , -S0 ₂ -Ci_ ₆ alkyl, -S0 ₂ -C ₃ . ₆ cycloalkyl, -(C=0), - (C=0)-C ₂ . ₆ alkenyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=0)-Het ₆ , -(C=0)-Ar ₆ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=0)- NR ₃ i R ₃₂ , -(C=0)-N R ₃₁ -(C=0)-R ₃₂ , -(C=S), -(C=S)-C ₁ . ₆ alkyl, -(C=S)-C ₂ . ₆ alkenyl, -(C=S)-0-d_ 6alkyl, -(C=S)-Het ₆ , -(C=S)-Ar ₆ , -(C=S)-C ₃ . ₆ cycloalkyl, -(C=S)-NR ₃₁ R ₃₂ , -(C=S)-NR ₃₁ -(C=S)-R ₃₂ , -Het ₆ , -Ar ₆ , and -C ₃ . ₆ cycloalkyl;

wherein each of said -d_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from =0, -halo, -OH, -0-d_ ₆ alkyl, -S-d_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₆ , - Ar ₆ , -NR ₂₅ R ₂₆ , -(C=0)-NR ₂₅ R ₂₆ , -NR ₃₃ (C=0)-NR ₂₅ R ₂₆ , -(C=S)-NR ₂₅ R ₂₆ , and -NR ₃₃ (C=S)- NR ₂₅ R ₂₆ ; and

wherein each of said -C ₃ . ₆ cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -d_ ₆ alkyl, =0, -halo, -OH, -0-d_ ₆ alkyl, -S-d_ ₆ alkyl, -Het ₁₂ , -Ar-n , and -NR ₅₃ R ₅₄ , and -NR ₅₅ (C=S)-

R ₉ , R10, R11 , Ri ₂ , Ri ₃ , R"i ₄ , R15, R16, Ri7 _> R18, Ri9, R20, R21 , R22, R23, R24, R25, R26, R27, R28, R29, R30, R ₃ i , R ₃₂ , R ₃₃ , R ₃₇ , R ₃₈ , R39, R40, R44, R45, R48, R50, R53, R54 and R ₅₅ are each independently selected from -H , -halo, =0, -OH, -d_ ₆ alkyl, -0-d_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₅ and -Het ₇ ; wherein each of said -d_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-d_ ₆ alkyl, -S-d_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₇ , -Ar ₅ and -NR ₅₁ R ₅₂ ;

R51 and R ₅₂ are each independently selected from -H, -halo, -OH, -d_ ₆ alkyl, -0-d_ ₆ alkyl, -S-Ci_

₆ alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₁₀ and -Het ₁₀ ;

R ₄₃ is selected from -H -d_ ₆ alkyl, and -C ₃ . ₆ cycloalkyl; wherein each of said -d. ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1-

₆ alkyl, -S-d_ ₆ alkyl, -Het ₅ , -C ₃ . ₆ cycloalkyl -Ar ₄ , and -NR ₄₄ R ₄₅ ;

A is selected from -(CH ₂ ) _n -Y-(CH ₂ ) _m -, -(C=0)-NR ₅ -, -NR ₆ -; Χ-ι is selected from -C _1-6 alkyl-, -0-Ci_ ₆ alkyl-, -S-Ci_ ₆ alkyl-, -(C=0)-, -NR ₃ -(C=0)-, -Ci. ₆ alkyl-NR ₃ -, -NR ₃ -, -(C=0)-, -NR ₃ -(C=0)-NR ₄₈ -, -NRs-d-ealkyl-, -NR ₃ -S0 ₂ -, -NR ₃ -(C=0)-C ₁ . ₆ alkyl-, -(C=0)- NR ₃ -Ci_ ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -Ci. ₆ alkyl-NR ₃ -Ci. ₆ alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci. ₆ alkyl, -S-Ci. ₆ alkyl, -phenyl, and -NR ₃₇ R ₃₈ ;

X ₂ is selected from -Ci_ ₆ alkyl-, -0-Ci_ ₆ alkyl-, -S-Ci_ ₆ alkyl-, -(C=0)-, -NR ₂ -(C=0)-, -Ci. ₆ alkyl-NR ₂ -, -NR ₂ -, -(C=0)-, -NR ₂ -(C=O)-NR ₅₀ -, -NR^d-ealkyl-, -NR ₂ -S0 ₂ -, -NR ₂ -(C=0)-C ₁ . ₆ alkyl-, -(C=0)- NR ₂ -Ci- ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -Ci. ₆ alkyl-NR ₂ -Ci. ₆ alkyl-; wherein each of said -Ci- ₆ alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci. ₆ alkyl, -0-Ci. ₆ alkyl, -S-Ci. ₆ alkyl, -phenyl and -NR ₃₉ R ₄ o;

Y is -NR ₄₃ -;

Ar-ι, Ar ₂ , Ar ₃ , Ar ₄ , Ar ₅ , Ar ₆ , Ar ₇ , Ar ₈ , Ar ₁₀ and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar-ι, Ar ₂ , Ar ₃ , Ar ₄ , Ar ₅ , Ar ₆ , Ar ₇ , Ar ₈ , Ar ₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-

Ci- ₆ alkyl, and -NR ₁₉ R ₂₀ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι, Het ₂ , Het ₃ , Het ₄ , Het ₅ , Het ₆ , Het ₇ , Het ₉ , Het ₁₀ , and Het ₁₂ are each independently a 4- to 10- membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι, Het ₂ , Het ₃ , Het ₄ , Het ₅ , Het ₆ , Het ₇ , Het ₉ , Het ₁₀ , and Het ₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, - OCi- ₆ alkyl, -SCi_ ₆ alkyl, =0, and -NR ₂₁ R ₂₂ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 -halo;

Z-i , Z ₂ , Z ₃ , Z ₄ and Z ₅ are each independently selected from C and N; and

m and n are each independently 1 , 2, 3, or 4;

for use in the diagnosis, prevention and/or treatment of an Activin-like receptor kinase associated disease selected from the list comprising anemia-related disorders or disorders characterized by abnormal bone formation. In a further embodiment, the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein

R-i and R ₄₁ are each independently selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ 6alkyl, -NR ₉ R ₁₀ , -(C=0)-R ₄ , -(C=S)-R ₄ , -S0 ₂ -R ₄ , -CN, -NR ₉ -S0 ₂ -R ₄ , -C ₃ . ₆ cycloalkyl, -Ar ₇ and

-Het-ι; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR ₁₂ , -0-Ci_ ₆ alkyl, and -S-Ci_ ₆ alkyl;

R ₂ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=0)-NR ₂₇ R ₂₈ , -(C=S)-NR ₂₇ R ₂₈ , -C ₃ . ₆ cycloalkyl, -Het ₃ , -Ar ₂ , -(C=0)-Het ₃ , -(C=S)-Het ₃ , -(C=0)-Ar ₂ , -(C=S)-Ar ₂ , -(C=0)-C ₃ - ₆ cycloalkyl, -(C=S)-C ₃ . 6cycloalkyl, and -S0 ₂ -Ci. ₆ alkyl; wherein each of said -d- ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, - Het ₃ , -Ar ₂ , and -NRi ₃ R _M ;

R ₃ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=O)-NR ₂₉ R ₃₀ , -(C=S)-NR ₂₉ R ₃₀ , -C ₃ . ₆ cycloalkyl -Het ₂ , -Ar ₃ , -(C=0)-Het ₂ , -(C=S)-Het ₂ , -(C=0)-Ar ₃ , -(C=S)-Ar ₃ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ . 6cycloalkyl and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₂ , -Ar ₃ , and -NRi ₅ Ri ₆ ;

R ₄ is independently selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -NR ₁₇ R ₁₈ ,

-C ₃ . ₆ cycloalkyl, -Ar ₈ and -Het ₄ ;

R ₆ is selected from -Ci_ ₆ alkyl, -S0 ₂ , -S0 ₂ -Ci_ ₆ alkyl, -S0 ₂ -C ₃ . ₆ cycloalkyl, -(C=0), - (C=0)-C ₂ . ₆ alkenyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=0)-Het ₆ , -(C=0)-Ar ₆ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=0)- NR ₃₁ R ₃₂ , -(C=0)-N R ₃₁ -(C=0)-R ₃₂ , -(C=S), -(C=S)-C ₁ . ₆ alkyl, -(C=S)-C ₂ . ₆ alkenyl, -(C=S)-0-d_

₆ alkyl, -(C=S)-Het ₆ , -(C=S)-Ar ₆ , -(C=S)-C ₃ . ₆ cycloalkyl, -(C=S)-NR ₃₁ R ₃₂ , -(C=S)-NR ₃₁ -(C=S)-R ₃₂ , -Het ₆ , -Ar ₆ , and -C ₃ . ₆ cycloalkyl;

wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from =0, -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₆ , - Ar ₆ , -NR ₂₅ R ₂₆ , -(C=0)-NR ₂₅ R ₂₆ , -NR ₃₃ (C=0)-NR ₂₅ R ₂₆ , -(C=S)-NR ₂₅ R ₂₆ , and -NR ₃₃ (C=S)-

NR ₂₅ R ₂₆ ; and

wherein each of said -C ₃ . ₆ cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_ ₆ alkyl, =0, -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -Het ₁₂ , -Ar-n , and -NR ₅₃ R ₅ 4, -(C=0)-NR ₅₃ R ₅ 4, -NR ₅ 5(C=0)-NR ₅₃ R54, -(C=S)-NR ₅₃ R ₅ 4, and -NR ₅₅ (C=S)-

Rg, Rio, Rl 1 , Rl ₂ , Rl ₃ , Rl4, Rl5, Rl6, l > l8> Rl9> R20, ¾1 > R∑2, R∑5, R∑6, R∑7, R28, R∑9, R30, 3I > R32,

R33, R37, R38, R39, R40, R44, R45, R48, R50, R53, R54 and R ₅₅ are each independently selected from -H, -halo, =0, -OH , -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₅ and -Het ₇ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-C _1-6 alkyl, -S-C _1-6 alkyl, -C ₃ . ₆ cycloalkyl, -Het ₇ , -Ar ₅ and -NR ₅ i R ₅₂ ;

R ₅₁ and R ₅₂ are each independently selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ 6alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₁₀ and -Het ₁₀ ;

R ₄₃ is selected from -H -Ci_ ₆ alkyl, and -C ₃ . ₆ cycloalkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6alkyl, -S-Ci_ ₆ alkyl, -Het ₅ , -C ₃ . ₆ cycloalkyl -Ar ₄ , and -NR44R45;

A is selected from -(CH ₂ ) _n -Y-(CH ₂ ) _m -, -NR ₆ -;

X-i is selected from -C _1-6 alkyl-, -0-Ci_ ₆ alkyl-, -S-Ci_ ₆ alkyl-, -(C=0)-, -NR ₃ -(C=0)-, -Ci_ ₆ alkyl-N R ₃ -, -NR3-, -(C=0)-, -NR ₃ -(C=0)-NR ₄₈ -, -NR ₃ -Ci _-6 alkyl-, -NR ₃ -S0 ₂ -, -NR ₃ -(C=0)-C ₁ . ₆ alkyl-, -(C=0)- NR ₃ -Ci_ ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -Ci. ₆ alkyl-N R ₃ -Ci. ₆ alkyl-; wherein each of said -Ci_ ₆ alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci _-6 alkyl, -0-Ci _-6 alkyl, -S-Ci _-6 alkyl, -phenyl, and -NR ₃₇ R ₃₈ ;

X ₂ is selected from -C _1-6 alkyl-, -0-Ci_ ₆ alkyl-, -S-Ci_ ₆ alkyl-, -(C=0)-, -NR ₂ -(C=0)-, -Ci. ₆ alkyl-NR ₂ -, -NR ₂ -, -(C=0)-, -NR ₂ -(C=O)-NR ₅₀ -, -NR ₂ -Ci _-6 alkyl-, -NR ₂ -S0 ₂ -, -NR ₂ -(C=0)-C ₁ . ₆ alkyl-, -(C=0)- NR ₂ -Ci_ ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -Ci. ₆ alkyl-NR ₂ -Ci. ₆ alkyl-; wherein each of said

-Ci- ₆ alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d- ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -phenyl and -NR ₃₉ R4o;

Ar ₂ , Ar ₃ , Ar ₄ , Ar ₅ , Ar ₆ , Ar ₇ , Ar ₈ , Ar ₁₀ and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said

Ar ₂ , Ar ₃ , Ar ₄ , Ar ₅ , Ar ₆ , Ar ₇ , Ar ₈ , Ar ₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, and - NR ₁₉ R ₂₀ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι, Het ₂ , Het ₃ , Het ₄ , Het ₅ , Het ₆ , Het ₇ , Het ₁₀ , and Het ₁₂ are each independently a 4- to 10- membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι, Het ₂ , Het ₃ , He , Het ₅ , Het ₆ , Het ₇ , Het ₁₀ , and Het ₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, - OCi- ₆ alkyl, -SCi_ ₆ alkyl, =0, and -NR ₂₁ R ₂₂ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 -halo;

Z-i, Z ₂ , Z ₃ , Z ₄ and Z ₅ are each independently selected from C and N; and

m and n are each independently 1 , 2, 3, or 4;

for use in the diagnosis, prevention and/or treatment of an Activin-like receptor kinase associated disease selected from the list comprising anemia-related disorders or disorders characterized by abnormal bone formation.

In a further embodiment, the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein

R-i and R ₄₁ are each independently selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ 6alkyl, -NR ₉ R ₁₀ , -(C=0)-R ₄ , -(C=S)-R ₄ , -S0 ₂ -R ₄ , -CN, -NR ₉ -S0 ₂ -R ₄ , -C ₃ . ₆ cycloalkyl, -Ar ₇ and -Het-ι; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR ₁₂ , -0-Ci_ ₆ alkyl, and -S-Ci_ ₆ alkyl;

R ₂ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=0)-NR ₂₇ R ₂₈ , -(C=S)-NR ₂₇ R ₂₈ , -C ₃ . ₆ cycloalkyl, -Het ₃ , -Ar ₂ , -(C=0)-Het ₃ , -(C=S)-Het ₃ , -(C=0)-Ar ₂ , -(C=S)-Ar ₂ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ . 6cycloalkyl, and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, - Het ₃ , -Ar ₂ , and -NRi ₃ Ri ₄ ;

R ₃ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=0)-NR ₂₉ R ₃ o, -(C=S)-NR ₂₉ R ₃₀ , -C ₃ . ₆ cycloalkyl -Het ₂ , -Ar ₃ , -(C=0)-Het ₂ , -(C=S)-Het ₂ , -(C=0)-Ar ₃ , -(C=S)-Ar ₃ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ .

₆ cycloalkyl and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -d- ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₂ , -Ar ₃ , and -NR ₁₅ R ₁₆ ;

R ₄ is independently selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -NR ₁₇ R ₁₈ , -C ₃ . ₆ cycloalkyl, -Ar ₈ and -Het ₄ ;

R ₆ is selected from -(C=0), - (C=0)-Ar ₆ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=0)-NR ₃₁ R ₃₂ , -(C=0)-NR ₃₁ -(C=0)-R ₃₂ , -(C=S), -(C=S)-d_ 6alkyl, -(C=S)-C ₂ . ₆ alkenyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=S)-Het ₆ , -(C=S)-Ar ₆ , -(C=S)-C ₃ . ₆ cycloalkyl, - (C=S)-NR ₃₁ R ₃₂ , -(C=S)-NR ₃₁ -(C=S)-R ₃₂ ;

wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from =0, -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₆ , - Ar ₆ , -NR ₂₅ R ₂₆ , -(C=0)-NR ₂₅ R ₂₆ , -NR ₃₃ (C=0)-NR ₂₅ R ₂₆ , -(C=S)-NR ₂₅ R ₂₆ , and -NR ₃₃ (C=S)- NR ₂₅ R ₂₆ ; and

wherein each of said -C ₃ . ₆ cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_ ₆ alkyl, =0, -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -Het ₁₂ , -Ar-n , and -NR ₅₃ R ₅ 4, -(C=0)-NR ₅₃ R ₅ 4, -NR ₅ 5(C=0)-NR ₅₃ R54, -(C=S)-NR ₅₃ R ₅ 4, and -NR ₅₅ (C=S)-

Rg, R10, R11 , Rl ₂ , R"| ₃ , Rl4, Rl5, Rl6, Rl7> l 8> l9> R20, 2I > R∑2, R∑5, R∑6, R∑7, R28, R∑9, R30, 3I > R32,

R33, R37, R38, R39, R40, R48, R50, R53, R54 and R55 are each independently selected from -H, - halo, =0, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₅ and -Het ₇ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₇ , -Ar ₅ and -NR ₅₁ R ₅₂ ; R ₅₁ and R ₅₂ are each independently selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_

6alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₁₀ and -Het ₁₀ ;

A is selected from -NR ₆ -;

X-i is selected from -C _1-6 alkyl-, -0-Ci _-6 alkyl-, -S-Ci _-6 alkyl-, -(C=0)-, -NR ₃ -(C=0)-, -Ci_ ₆ alkyl-NR ₃ -, -NR ₃ -, -(C=0)-, -NR ₃ -(C=0)-NR ₄₈ -, -NR ₃ -d_ ₆ alkyl-, -NR ₃ -S0 ₂ -, -NR ₃ -(C=0)-C ₁ . ₆ alkyl-, -(C=0)- NR ₃ -Ci_ ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -Ci. ₆ alkyl-NR ₃ -Ci. ₆ alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci. ₆ alkyl, -S-Ci. ₆ alkyl, -phenyl, and -NR ₃₇ R ₃₈ ;

X ₂ is selected from -Ci_ ₆ alkyl-, -0-Ci_ ₆ alkyl-, -S-Ci_ ₆ alkyl-, -(C=0)-, -NR ₂ -(C=0)-, -Ci_ ₆ alkyl-NR ₂ -, -NR ₂ -, -(C=0)-, -NR ₂ -(C=O)-NR ₅₀ -, -NR ₂ -d_ ₆ alkyl-, -NR ₂ -S0 ₂ -, -NR ₂ -(C=0)-C ₁ . ₆ alkyl-, -(C=0)- NR ₂ -Ci_ ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -Ci. ₆ alkyl-NR ₂ -Ci. ₆ alkyl-; wherein each of said -Ci- ₆ alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci. ₆ alkyl, -0-Ci. ₆ alkyl, -S-Ci. ₆ alkyl, -phenyl and -NR ₃₉ R ₄ o; Ar ₂ , Ar ₃ , Ar ₅ , Ar ₆ , Ar ₇ , Ar ₈ , Ar ₁₀ and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar ₂ , Ar ₃ , Ar ₅ , Ar ₆ , Ar ₇ , Ar ₈ , Ar ₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d- ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, and - NR ₁₉ R ₂ o; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι, Het ₂ , Het ₃ , Het ₄ , Het ₆ , Het ₇ , Het ₁₀ , and Het ₁₂ are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι, Het ₂ , Het ₃ , He , Het ₆ , Het ₇ , Het ₁₀ , and Het ₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -OCi_ ₆ alkyl, -SCi_ ₆ alkyl, =0, - and -NR ₂₁ R ₂₂ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 -halo;

Z-i , Z ₂ , Z ₃ , Z ₄ and Z ₅ are each independently selected from C and N; and

m and n are each independently 1 , 2, 3, or 4;

for use in the diagnosis, prevention and/or treatment of an Activin-like receptor kinase associated disease selected from the list comprising anemia-related disorders or disorders characterized by abnormal bone formation.

In a further embodiment, the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein

R-i and R ₄₁ are each independently selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ 6alkyl, -NR ₉ R ₁₀ , -(C=0)-R ₄ , -(C=S)-R ₄ , -S0 ₂ -R ₄ , -CN, -NR ₉ -S0 ₂ -R ₄ , -C ₃ . ₆ cycloalkyl, -Ar ₇ and -Het-ι; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to

3 substituents selected from -halo, -OH, -NR-nR ₁₂ , -0-Ci_ ₆ alkyl, and -S-Ci_ ₆ alkyl;

R ₂ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=0)-NR ₂₇ R ₂₈ , -(C=S)-NR ₂₇ R ₂₈ , -C ₃ . ₆ cycloalkyl, -Het ₃ , -Ar ₂ , -(C=0)-Het ₃ , -(C=S)-Het ₃ , -(C=0)-Ar ₂ , -(C=S)-Ar ₂ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ . 6cycloalkyl, and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, - Het ₃ , -Ar ₂ , and -NRi ₃ R _M ;

R ₃ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=O)-NR ₂₉ R ₃₀ , -(C=S)-NR ₂₉ R ₃₀ , -C ₃ . ₆ cycloalkyl -Het ₂ , -Ar ₃ , -(C=0)-Het ₂ , -(C=S)-Het ₂ , -(C=0)-Ar ₃ , -(C=S)-Ar ₃ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ .

₆ cycloalkyl and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₂ , -Ar ₃ , and -NR ₁₅ R ₁₆ ; R ₄ is independently selected from -halo, -OH, -d- ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -NR ₁₇ R ₁₈ ,

-C ₃ . ₆ cycloalkyl, -Ar ₈ and -Het ₄ ;

R ₆ is selected from -Ci_ ₆ alkyl, -S0 ₂ , -S0 ₂ -Ci. ₆ alkyl, -S0 ₂ -C ₃ . ₆ cycloalkyl, -Het ₆ , -Ar ₆ , and -C ₃ .

₆ cycloalkyl;

wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₆ , -Ar ₆ , - NR25R26, -NR ₃₃ (C=0)-NR ₂₅ R26, and -N R ₃₃ (C=S)-NR ₂₅ R26; and

wherein each of said -C ₃ . ₆ cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_ ₆ alkyl,-halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -Het ₁₂ , -Ar-n , and - NR ₅₃ R ₅ 4, -NR ₅ 5(C=0)-NR ₅₃ R54, -(C=S)-NR ₅₃ R ₅ 4, and -NR ₅ 5(C=S)-NR ₅₃ R54;

Rg, R10, R11 , Rl ₂ , R"| ₃ , Rl4. Rl5. Rl6. Rl7> l8> Rl9> R20, ¾1 > R∑2, R∑5, R∑6. R∑7. R∑8. R∑9. R30. 3I > R32.

R33, R37, R38, R39, R40, R44, R45, R48, R50, R53, R54 and R ₅₅ are each independently selected from -H, -halo, =0, -OH , -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₅ and -Het ₇ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₇ , -Ar ₅ and -NR ₅₁ R ₅₂ ;

R ₅₁ and R ₅₂ are each independently selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ 6alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₁₀ and -Het ₁₀ ;

R ₄₃ is selected from -H -Ci_ ₆ alkyl, and -C ₃ . ₆ cycloalkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6alkyl, -S-Ci_ ₆ alkyl, -Het ₅ , -C ₃ . ₆ cycloalkyl -Ar ₄ , and -NR44R45;

A is selected from -(CH ₂ ) _n -Y-(CH ₂ ) _m -, -NR ₆ -;

X-i is selected from -C _1-6 alkyl-, -0-Ci _-6 alkyl-, -S-Ci _-6 alkyl-, -(C=0)-, -NR ₃ -(C=0)-, -C-,- ₆ alkyl-N R ₃ -, -NR ₃ -, -(C=0)-, -NR ₃ -(C=0)-NR ₄₈ -, -NRs-d-ealkyl-, -NR ₃ -S0 ₂ -, -NR ₃ -(C=0)-C ₁ . ₆ alkyl-, -(C=0)- NR ₃ -Ci- ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -Ci. ₆ alkyl-N R ₃ -Ci. ₆ alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from

-halo, -OH, -Ci. ₆ alkyl, -0-Ci. ₆ alkyl, -S-Ci. ₆ alkyl, -phenyl, and -NR ₃₇ R ₃₈ ;

X ₂ is selected from -Ci_ ₆ alkyl-, -0-C-,- ₆ alkyl-, -S-C-,- ₆ alkyl-, -(C=0)-, -NR ₂ -(C=0)-, -Ci_ ₆ alkyl-N R ₂ -, -NR ₂ -, -(C=0)-, -NR ₂ -(C=O)-NR ₅₀ -, -NRz-C^alkyl-, -NR ₂ -S0 ₂ -, -NR ₂ -(C=0)-C ₁ . ₆ alkyl-, -(C=0)- NR ₂ -Ci_ ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -Ci. ₆ alkyl-NR ₂ -Ci. ₆ alkyl-; wherein each of said -Ci- ₆ alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -phenyl and -NR ₃₉ R ₄₀ ;

Y is -NR ₄₃ -;

Ar ₂ , Ar ₃ , Ar ₄ , Ar ₅ , Ar ₆ , Ar ₇ , Ar ₈ , Ar ₁₀ and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar ₂ , Ar ₃ , Ar ₄ , Ar ₅ , Ar ₆ , Ar ₇ , Ar ₈ , Ar ₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C-i_ ₆ alkyl, -0-C-i_ ₆ alkyl, -S-C-i_ ₆ alkyl, and - NR ₁₉ R ₂₀ ; wherein each of said -C-i_ ₆ alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-i , Het ₂ , Het ₃ , Het ₄ , Het ₅ , Het ₆ , Het ₇ , Het ₁₀ , and Het ₁₂ are each independently a 4- to 10- membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι , Het ₂ , Het ₃ , He , Het ₅ , Het ₆ , Het ₇ , Het ₁₀ , and Het ₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, - OCi- ₆ alkyl, -SCi_ ₆ alkyl, =0, and -NR21 R22; wherein each of said -d- ₆ alkyl is optionally and independently substituted with from 1 to 3 -halo;

Z-i , Z ₂ , Z ₃ , Z ₄ and Z ₅ are each independently selected from C and N; and

m and n are each independently 1 , 2, 3, or 4;

for use in the diagnosis, prevention and/or treatment of an Activin-like receptor kinase associated disease selected from the list comprising anemia-related disorders or disorders characterized by abnormal bone formation.

In a further embodiment, the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein

Ri and R ₄₁ are each independently selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ 6alkyl, -NR ₉ R ₁₀ , -(C=0)-R ₄ , -(C=S)-R ₄ , -S0 ₂ -R ₄ , -CN , -NR ₉ -S0 ₂ -R ₄ , -C ₃ . ₆ cycloalkyl, -Ar ₇ and -Het-ι ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R ₁₂ , -0-Ci_ ₆ alkyl, and -S-Ci_ ₆ alkyl;

R ₂ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=0)-NR ₂₇ R ₂₈ , -(C=S)-NR ₂₇ R ₂₈ , -C ₃ - ₆ cycloalkyl,

-Het ₃ , -Ar ₂ , -(C=0)-Het ₃ , -(C=S)-Het ₃ , -(C=0)-Ar ₂ , -(C=S)-Ar ₂ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ . 6cycloalkyl, and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, - Het ₃ , -Ar ₂ , and -NRi ₃ R _M ;

R ₃ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=O)-NR ₂₉ R ₃₀ , -(C=S)-NR ₂₉ R ₃₀ , -C ₃ . ₆ cycloalkyl -Het ₂ , -Ar ₃ , -(C=0)-Het ₂ , -(C=S)-Het ₂ , -(C=0)-Ar ₃ , -(C=S)-Ar ₃ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ . 6cycloalkyl and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₂ , -Ar ₃ , and -NRi ₅ Ri ₆ ;

R ₄ is independently selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -NR ₁₇ R ₁₈ ,

-C ₃ . ₆ cycloalkyl, -Ar ₈ and -Het ₄ ;

R ₅ is selected from -H, -OH, -halo, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -Het ₉ , -Ar-ι , -C ₃ . ₆ cycloalkyl, - SOz-A^ , -SO2, -SOz-C _L ealkyl, -(C=0), -(C=0)-C ₁ . ₆ alkyl, -(C=S), -(C=S)-C ₁ . ₆ alkyl, -0-(C=0)-d_ 6alkyl, wherein each of said -C-,.

₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci. ₆ alkyl, -S-Ci. ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Αη , -Het ₉ , and -NR ₂₃ R ₂ ;

Rg, R10, R11 , R12, Rl3, Rl4, Rl5, Rl6, Rl > Rl8, Rl9, R20, R∑1 , R∑2, R∑3, R∑4, R∑7, R2 ₈ , R∑9, R30, R37, R3 ₈ ,

R39, R40, R ₄₈ , and R ₅₀ , are each independently selected from -H , -halo, =0, -OH , -Ci_ ₆ alkyl, -O- Ci- ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₅ and -Het ₇ ; wherein each of said -d- ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, - OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₇ , -Ar ₅ and -NR ₅₁ R ₅₂ ;

R ₅₁ and R ₅₂ are each independently selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ 6alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₁₀ and -Het ₁₀ ;

A is selected from -(C=0)-NR ₅ -;

X-i is selected from -Ci_ ₆ alkyl-, -0-Ci_ ₆ alkyl-, -S-Ci_ ₆ alkyl-, -(C=0)-, -NR ₃ -(C=0)-, -Ci_ ₆ alkyl-NR ₃ -, -NR ₃ -, -(C=0)-, -NR ₃ -(C=0)-NR ₄₈ -, -NRs-C^alkyl-, -NR ₃ -S0 ₂ -, -NR ₃ -(C=0)-C ₁ . ₆ alkyl-, -(C=0)- NR ₃ -Ci_ ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -Ci. ₆ alkyl-NR ₃ -Ci. ₆ alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from

-halo, -OH, -Ci. ₆ alkyl, -0-Ci. ₆ alkyl, -S-Ci. ₆ alkyl, -phenyl, and -NR ₃₇ R ₃₈ ;

X ₂ is selected from -Ci_ ₆ alkyl-, -0-Ci_ ₆ alkyl-, -S-Ci_ ₆ alkyl-, -(C=0)-, -NR ₂ -(C=0)-, -Ci_ ₆ alkyl-NR ₂ -, -NR ₂ -, -(C=0)-, -NR ₂ -(C=O)-NR ₅₀ -, -NR^d-ealkyl-, -NR ₂ -S0 ₂ -, -NR ₂ -(C=0)-C ₁ . ₆ alkyl-, -(C=0)- NR ₂ -Ci_ ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -Ci. ₆ alkyl-NR ₂ -Ci. ₆ alkyl-; wherein each of said -Ci- ₆ alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -phenyl and -NR ₃₉ R ₄₀ ;

Ar-ι, Ar ₂ , Ar ₃ , Ar ₅ , Ar ₇ , Ar ₈ , and Ar ₁₀ are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar-ι, Ar ₂ , Ar ₃ , Ar ₅ , Ar ₇ , Ar ₈ , and Ar ₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, and -NR ₁₉ R ₂₀ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 - halo;

Het-ι, Het ₂ , Het ₃ , Het ₄ , Het ₇ , Het ₉ , and Het ₁₀ are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι, Het ₂ , Het ₃ , Het ₄ , Het ₇ , Het ₉ , and Het ₁₀ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -OCi_ ₆ alkyl, -SCi_ ₆ alkyl, =0, - and -NR ₂₁ R ₂₂ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 -halo;

Z-i , Z ₂ , Z ₃ , Z ₄ and Z ₅ are each independently selected from C and N; and

m and n are each independently 1 , 2, 3, or 4;

for use in the diagnosis, prevention and/or treatment of an Activin-like receptor kinase associated disease selected from the list comprising anemia-related disorders or disorders characterized by abnormal bone formation.

In a further embodiment, the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein

A ₂ is C, and A-i is N; R-ι and R ₄₁ are each independently selected from -H, -halo, -OH, -d- ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ 6alkyl, -NR ₉ R ₁₀ , -(C=0)-R ₄ , -(C=S)-R ₄ , -S0 ₂ -R ₄ , -CN, -NR ₉ -S0 ₂ -R ₄ , -C ₃ . ₆ cycloalkyl, -Ar ₇ and -Het-ι; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR ₁₂ , -0-Ci_ ₆ alkyl, and -S-Ci_ ₆ alkyl;

R ₂ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=0)-NR ₂₇ R ₂ 8, -(C=S)-NR ₂₇ R ₂₈ , -C ₃ - ₆ cycloalkyl, -Het ₃ , -Ar ₂ , -(C=0)-Het ₃ , -(C=S)-Het ₃ , -(C=0)-Ar ₂ , -(C=S)-Ar ₂ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ . 6cycloalkyl, and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, - Het ₃ , -Ar ₂ , and -NR ₁₃ R ₁₄ ;

R ₃ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=O)-NR ₂₉ R ₃₀ , -(C=S)-NR ₂₉ R ₃₀ , -C ₃ . ₆ cycloalkyl -Het ₂ , -Ar ₃ , -(C=0)-Het ₂ , -(C=S)-Het ₂ , -(C=0)-Ar ₃ , -(C=S)-Ar ₃ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ . 6cycloalkyl and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

-C ₃ . ₆ cycloalkyl, -Het ₂ , -Ar ₃ , and -NR ₁₅ R ₁₆ ;

R ₄ is independently selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -NR ₁₇ R ₁₈ , -C ₃ . ₆ cycloalkyl, -Ar ₈ and -Het ₄ ;

R ₅ is selected from -H, -OH, -halo, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -Het ₉ , -Ar-ι, -C ₃ . ₆ cycloalkyl, - SOz-A^ , -SO2, -SOz-C _L ealkyl, -(C=0), -(C=0)-C ₁ . ₆ alkyl, -(C=S), -(C=S)-C ₁ . ₆ alkyl, -0-(C=0)-d_

₆ alkyl, wherein each of said -d_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci. ₆ alkyl, -S-Ci. ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Αη , -Het ₉ , and -NR ₂₃ R ₂ ;

Rg, R10, R11, R12, Rl3, Rl4, Rl5, Rl6, Rl > Rl 8, Rl9, R20, R∑1 , R∑2, R∑3, R∑4, R∑7, R28, R∑9, R30, R37, R38, R ₃₉ , R _40, R _48, and R ₅₀ , are each independently selected from -H , -halo, =0, -OH , -Ci_ ₆ alkyl, -O-

Ci- ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₅ and -Het ₇ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, - OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₇ , -Ar ₅ and -NR ₅₁ R ₅₂ ;

R ₅₁ and R ₅₂ are each independently selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_

6alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₁₀ and -Het ₁₀ ;

A is selected from -(C=0)-NR ₅ -;

Xi is -Ci- ₆ alkyl-NR ₃ -Ci- ₆ alkyl-; wherein each of said -Ci_ ₆ alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S- Ci- ₆ alkyl, -phenyl, and -NR ₃₇ R ₃₈ ;

X ₂ is selected from -Ci_ ₆ alkyl-, -0-Ci_ ₆ alkyl-, -S-Ci_ ₆ alkyl-, -(C=0)-, -NR ₂ -(C=0)-, -Ci_ ₆ alkyl-NR ₂ -, -NR ₂ -, -(C=0)-, -NR ₂ -(C=O)-NR ₅₀ -, -NR ₂ -d_ ₆ alkyl-, -NR ₂ -S0 ₂ -, -NR ₂ -(C=0)-C ₁ . ₆ alkyl-, -(C=0)- NR ₂ -Ci_ ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -Ci. ₆ alkyl-NR ₂ -Ci. ₆ alkyl-; wherein each of said -Ci- ₆ alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -phenyl and -NR ₃₉ R ₄₀ ; Ar-ι, Ar ₂ , Ar ₃ , Ar ₅ , Ar ₇ , Ar ₈ , and Ar ₁₀ are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar-ι, Ar ₂ , Ar ₃ , Ar ₅ , Ar ₇ , Ar ₈ , and Ar ₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d- ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, and -NR ₁₉ R ₂ o; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 - halo;

Het-ι, Het ₂ , Het ₃ , Het ₄ , Het ₇ , Het ₉ , and Het ₁₀ are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι, Het ₂ , Het ₃ , Het ₄ , Het ₇ , Het ₉ , and Het ₁₀ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -OCi_ ₆ alkyl, -SCi_ ₆ alkyl, =0, - and -NR ₂₁ R ₂₂ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 -halo;

Z-i, Z ₂ , Z ₃ , Z ₄ and Z ₅ are each independently selected from C and N; and

m and n are each independently 1 , 2, 3, or 4;

for use in the diagnosis, prevention and/or treatment of an Activin-like receptor kinase associated disease selected from the list comprising anemia-related disorders or disorders characterized by abnormal bone formation.

In a further aspect, the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein

R-i and R ₄₁ are each independently selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ 6alkyl, -NR ₉ R ₁₀ , -(C=0)-R ₄ , -(C=S)-R ₄ , -S0 ₂ -R ₄ , -CN, -NR ₉ -S0 ₂ -R ₄ , -C ₃ . ₆ cycloalkyl, -Ar ₇ and

-Het-ι; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -NR-nR ₁₂ , and -S-Ci_ ₆ alkyl;

wherein R-i and R ₄₁ are not simultaneously -H

R ₂ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=0)-NR ₂₇ R ₂₈ , -(C=S)-NR ₂₇ R ₂₈ , -C ₃ . ₆ cycloalkyl,

-Het ₃ , -Ar ₂ , -(C=0)-Het ₃ , -(C=S)-Het ₃ , -(C=0)-Ar ₂ , -(C=S)-Ar ₂ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ . 6cycloalkyl, and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, - Het ₃ , -Ar ₂ , and -NRi ₃ Ri ₄ ;

R ₃ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=0)-NR ₂₉ R ₃ o, -(C=S)-NR ₂₉ R ₃₀ , -C ₃ . ₆ cycloalkyl -Het ₂ , -Ar ₃ , -(C=0)-Het ₂ , -(C=S)-Het ₂ , -(C=0)-Ar ₃ , -(C=S)-Ar ₃ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ .

₆ cycloalkyl and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -d- ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₂ , -Ar ₃ , and -NR ₁₅ R ₁₆ ;

R ₄ is independently selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -NR ₁₇ R ₁₈ , -C ₃ . ₆ cycloalkyl, -Ar ₈ and -Het ₄ ;

R ₆ is selected from -(C=0), - (C=0)-Ar ₆ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=0)-NR ₃₁ R ₃₂ , -(C=0)-NR ₃₁ -(C=0)-R ₃₂ ;

wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from =0, -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₆ , - Ar ₆ , -NR ₂₅ R ₂₆ , -(C=0)-NR ₂₅ R ₂₆ , -NR ₃₃ (C=0)-NR ₂₅ R ₂₆ , -(C=S)-NR ₂₅ R ₂₆ , and -NR ₃₃ (C=S)-

NR ₂₅ R ₂₆ ; and

wherein each of said -C ₃ . ₆ cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_ ₆ alkyl, =0, -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -Het ₁₂ , -Ar-n , and -NR ₅₃ R ₅ 4, -(C=0)-NR ₅₃ R ₅ 4, -NR ₅ 5(C=0)-NR ₅₃ R54, -(C=S)-NR ₅₃ R ₅ 4, and -NR ₅₅ (C=S)-

Rg, Rio, Rl 1 , Rl ₂ , Rl ₃ , Rl4. Rl5. Rl6, l > l8> Rl9> R20, ¾1 > R∑2, R∑5, R∑6. R∑7. R∑8. R∑9. R30. 3I > R32.

R33, R37, R38, R39, R40, R48, R50, R53, R54 and R55 are each independently selected from -H, - halo, =0, -OH, -Ci- ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₅ and -Het ₇ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₇ , -Ar ₅ and -NR ₅₁ R ₅₂ ;

R ₅₁ and R ₅₂ are each independently selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_

6alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₁₀ and -Het ₁₀ ;

A is -NR ₆ -;

X-i is selected from -C _1-6 alkyl-, -0-Ci_ ₆ alkyl-, -S-Ci_ ₆ alkyl-, -(C=0)-, -NR ₃ -(C=0)-, -Ci_ ₆ alkyl-NR ₃ -, -NR ₃ -, -(C=0)-, -NR ₃ -(C=0)-NR ₄₈ -, -NR ₃ -Ci _-6 alkyl-, -NR ₃ -S0 ₂ -, -NR ₃ -(C=0)-C ₁ . ₆ alkyl-, -(C=0)-

NR ₃ -Ci_ ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -Ci. ₆ alkyl-NR ₃ -Ci. ₆ alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci _-6 alkyl, -0-Ci _-6 alkyl, -S-Ci _-6 alkyl, -phenyl, and -NR ₃₇ R ₃₈ ;

X ₂ is selected from -C _1-6 alkyl-, -0-Ci_ ₆ alkyl-, -S-Ci_ ₆ alkyl-, -(C=0)-, -NR ₂ -(C=0)-, -Ci_ ₆ alkyl-NR ₂ -, -NR ₂ -, -(C=0)-, -NR ₂ -(C=O)-NR ₅₀ -, -NR ₂ -Ci _-6 alkyl-, -NR ₂ -S0 ₂ -, -NR ₂ -(C=0)-C ₁ . ₆ alkyl-, -(C=0)-

NR ₂ -Ci- ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -Ci. ₆ alkyl-NR ₂ -Ci. ₆ alkyl-; wherein each of said -Ci- ₆ alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -phenyl and -NR ₃₉ R ₄₀ ;

Ar ₂ , Ar ₃ , Ar ₅ , Ar ₆ , Ar ₇ , Ar ₈ , Ar ₁₀ and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar ₂ , Ar ₃ , Ar ₅ , Ar ₆ , Ar ₇ , Ar ₈ , Ar ₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d- ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, and - NR ₁₉ R ₂ o; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι, Het ₂ , Het ₃ , Het ₄ , Het ₆ , Het ₇ , Het ₁₀ , and Het ₁₂ are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι, Het ₂ , Het ₃ , He , Het ₆ , Het ₇ , Het ₁₀ , and Het ₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -OCi_ ₆ alkyl, -SCi_ ₆ alkyl, =0, - and -NR ₂₁ R ₂₂ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 -halo;

Z-i , Z ₂ , Z ₃ , Z ₄ and Z ₅ are each independently selected from C and N; and

m and n are each independently 1 , 2, 3, or 4;

for use in the diagnosis, prevention and/or treatment of an Activin-like receptor kinase associated disease selected from the list comprising disorders characterized by abnormal bone formation, vascular disorders, cardiovascular disorders, endocrine disorders, anemia-related disorders, and myel in-related disorders.

In a further embodiment, the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein

R-i and R ₄₁ are each independently selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ 6alkyl, -NR ₉ R ₁₀ , -(C=0)-R ₄ , -(C=S)-R ₄ , -S0 ₂ -R ₄ , -CN, -NR ₉ -S0 ₂ -R ₄ , -C ₃ . ₆ cycloalkyl, -Ar ₇ and -Het-ι; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR ₁₂ , -0-Ci_ ₆ alkyl, and -S-Ci_ ₆ alkyl;

R ₂ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=0)-NR ₂₇ R ₂₈ , -(C=S)-NR ₂₇ R ₂₈ , -C ₃ . ₆ cycloalkyl, -Het ₃ , -Ar ₂ , -(C=0)-Het ₃ , -(C=S)-Het ₃ , -(C=0)-Ar ₂ , -(C=S)-Ar ₂ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ . 6cycloalkyl, and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -

Het ₃ , -Ar ₂ , and -NRi ₃ R _M ;

R ₃ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=O)-NR ₂₉ R ₃₀ , -(C=S)-NR ₂₉ R ₃₀ , -C ₃ . ₆ cycloalkyl -Het ₂ , -Ar ₃ , -(C=0)-Het ₂ , -(C=S)-Het ₂ , -(C=0)-Ar ₃ , -(C=S)-Ar ₃ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ . 6cycloalkyl and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₂ , -Ar ₃ , and -NR ₁₅ R ₁₆ ;

R ₄ is independently selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -NR ₁₇ R ₁₈ , -C ₃ . ₆ cycloalkyl, -Ar ₈ and -Het ₄ ; R ₅ is selected from -H, -OH, -halo, -d- ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -Het ₉ , -Ar-ι , -C ₃ . ₆ cycloalkyl, - SOz-A^ , -S0 ₂ , -SOz-C _L ealkyl, -(C=0), -(C=0)-C ₁ . ₆ alkyl, -(C=S), -(C=S)-C ₁ . ₆ alkyl, -0-(C=0)-d_ 6alkyl, wherein each of said -C-,. 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci _-6 alkyl, -S-Ci _-6 alkyl, -C ₃ . ₆ cycloalkyl, -Αη , -Het ₉ , and -NR ₂₃ R ₂ 4;

Rg, R-io, Rl 1 , Rl2> Rl3> Rl4, Rl5, Rl6, Rl7, Rl8, Rl9> R20, f¾1 > R∑2, R∑3, R∑4, F¾7, R28, R∑9, R30, R37, R38,

R39, R ₄₀ , R ₄₈ , and R ₅₀ , are each independently selected from -H , -halo, =0, -OH , -Ci_ ₆ alkyl, -O- Ci- ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₅ and -Het ₇ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, - OH, -0-Ci _-6 alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₇ , -Ar ₅ and -NR ₅₁ R ₅₂ ;

R ₅₁ and R ₅₂ are each independently selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_

6alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₁₀ and -Het ₁₀ ;

A is selected from -(C=0)-NR ₅ -;

Xi is -Ci- ₆ alkyl-NR ₃ -Ci- ₆ alkyl-; wherein each of said -Ci_ ₆ alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S- Ci_ ₆ alkyl, -phenyl, and -NR ₃₇ R ₃₈ ;

X ₂ is selected from -C _1-6 alkyl-, -0-Ci_ ₆ alkyl-, -S-Ci_ ₆ alkyl-, -(C=0)-, -NR ₂ -(C=0)-, -Ci_ ₆ alkyl-N R ₂ -, -NR ₂ -, -(C=0)-, -NR ₂ -(C=O)-NR ₅₀ -, -NR ₂ -Ci _-6 alkyl-, -NR ₂ -S0 ₂ -, -NR ₂ -(C=0)-C ₁ . ₆ alkyl-, -(C=0)- NR ₂ -Ci- ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -Ci. ₆ alkyl-NR ₂ -Ci. ₆ alkyl-; wherein each of said -Ci- ₆ alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -phenyl and -NR ₃₉ R ₄₀ ;

Ar-ι , Ar ₂ , Ar ₃ , Ar ₅ , Ar ₇ , Ar ₈ , and Ar ₁₀ are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar-ι , Ar ₂ , Ar ₃ , Ar ₅ , Ar ₇ , Ar ₈ , and Ar ₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, and -NR ₁₉ R ₂₀ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 - halo;

Het-ι , Het ₂ , Het ₃ , Het ₄ , Het ₇ , Het ₉ , and Het ₁₀ are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι , Het ₂ , Het ₃ , Het ₄ , Het ₇ , Het ₉ , and Het ₁₀ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -OCi_ ₆ alkyl, -SCi_ ₆ alkyl, =0, - and -NR ₂₁ R ₂₂ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 -halo;

Z-i , Z ₂ , Z ₃ , Z ₄ and Z ₅ are each independently selected from C and N; and

m and n are each independently 1 , 2, 3, or 4;

for use in the diagnosis, prevention and/or treatment of an Activin-like receptor kinase associated disease selected from the list comprising disorders characterized by abnormal bone formation, vascular disorders, cardiovascular disorders, endocrine disorders, anemia-related disorders, and myel in-related disorders. ln a further aspect, the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein

Wherein

R-i and R ₄₁ are each independently selected from -H, -halo, -OH, -d- ₆ alkyl, -S-Ci_ ₆ alkyl, -NR ₉ R ₁₀ , - (C=0)-R ₄ , -(C=S)-R ₄ , -SO2-R4, -N R9-SO2-R4, -C ₃ . ₆ cycloalkyl, -Ar ₇ and -Het, ; wherein each of said -Ci- ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -NR-n R ₁₂ , and -S-Ci_ ₆ alkyl;

wherein R-i and R ₄₁ are not simultaneously -H

R ₂ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=0)-NR ₂₇ R ₂ 8, -(C=S)-NR ₂₇ R ₂ 8, -C ₃ - ₆ cycloalkyl, -Het ₃ , -Ar ₂ , -(C=0)-Het ₃ , -(C=S)-Het ₃ , -(C=0)-Ar ₂ , -(C=S)-Ar ₂ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ . 6cycloalkyl, and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, - Het ₃ , -Ar ₂ , and -NRi ₃ R _M ;

R ₃ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=O)-NR ₂₉ R ₃₀ , -(C=S)-NR ₂₉ R ₃₀ , -C ₃ . ₆ cycloalkyl -Het ₂ , -Ar ₃ , -(C=0)-Het ₂ , -(C=S)-Het ₂ , -(C=0)-Ar ₃ , -(C=S)-Ar ₃ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ .

₆ cycloalkyl and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₂ , -Ar ₃ , and -NR ₁₅ R ₁₆ ;

R ₄ is independently selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, - Ar ₈ and -Het ₄ ;

R ₆ is selected from -(C=0), - (C=0)-Ar ₆ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=0)-NR ₃₁ R ₃₂ , -(C=0)-NR ₃₁ -(C=0)-R ₃₂ ;

wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from =0, -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₆ , - Ar ₆ , -NR ₂₅ R ₂₆ , -(C=0)-NR ₂₅ R ₂₆ , -NR ₃₃ (C=0)-NR ₂₅ R ₂₆ , -(C=S)-NR ₂₅ R ₂₆ , and -NR ₃₃ (C=S)-

NR ₂₅ R ₂₆ ; and wherein each of said -C ₃ . ₆ cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -d- ₆ alkyl, =0, -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -Het ₁₂ , -Ar-n , and -NR53R54, -(C=0)-NR ₅₃ R ₅ 4, -NR ₅ 5(C=0)-NR ₅ 3R54, -(C=S)-NR ₅₃ R ₅ 4, and -NR ₅₅ (C=S)- Rg, R-io, R11 , R12, Rl3, Rl4, Rl5, Rl6, Rl9, R20, R∑1 , R∑2, R∑5, R∑6, R∑7, R28, R∑9, R30, R3I , R32, R33, R37,

R ₃₈ , R ₃₉ , R ₄₀ , R48, R50, R53, R54 and R ₅₅ are each independently selected from -H, -halo, =0, - OH, -Ci- ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₅ and -Het ₇ ; wherein each of said - Ci- ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci. ₆ alkyl, -S-Ci. ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₇ , -Ar ₅ and -NR ₅₁ R ₅₂ ;

R ₅ i and R ₅₂ are each independently selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ 6alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₁₀ and -Het ₁₀ ;

A is -NR ₆ -;

X-i is selected from -C-,- ₆ alkyl-, -0-Ci_ ₆ alkyl-, -S-C-,- ₆ alkyl-, -(C=0)-, -NR ₃ -(C=0)-, -Ci_ ₆ alkyl-N R ₃ -, -NR ₃ -, -(C=0)-, -NR ₃ -(C=0)-NR ₄₈ -, -NRs-d-ealkyl-, -NR ₃ -S0 ₂ -, -NR ₃ -(C=0)-C ₁ . ₆ alkyl-, -(C=0)- NR ₃ -Ci_ ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -Ci. ₆ alkyl-N R ₃ -Ci. ₆ alkyl-; wherein each of said -Ci_

₆ alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci. ₆ alkyl, -0-Ci. ₆ alkyl, -S-Ci. ₆ alkyl, -phenyl, and -NR ₃₇ R ₃₈ ;

X ₂ is selected from -Ci_ ₆ alkyl-, -0-d. ₆ alkyl-, -S-Ci_ ₆ alkyl-, -(C=0)-, -NR ₂ -(C=0)-, -d. ₆ alkyl-N R ₂ -, -NR ₂ -, -(C=0)-, -NR ₂ -(C=O)-NR ₅₀ -, -NR ₂ -d_ ₆ alkyl-, -NR ₂ -S0 ₂ -, -NR ₂ -(C=0)-C ₁ . ₆ alkyl-, -(C=0)- NR ₂ -Ci_ ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -Ci. ₆ alkyl-NR ₂ -Ci. ₆ alkyl-; wherein each of said

-Ci- ₆ alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -phenyl and -NR ₃₉ R ₄₀ ;

Ar ₂ , Ar ₃ , Ar ₅ , Ar ₆ , Ar ₇ , Ar ₈ , Ar ₁₀ and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar ₂ , Ar ₃ , Ar ₅ , Ar ₆ , Ar ₇ , Ar ₈ , Ar ₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C-i_ ₆ alkyl, -0-C-i_ ₆ alkyl, -S-C-i_ ₆ alkyl, and - NR ₁₉ R ₂₀ ; wherein each of said -C-i_ ₆ alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-i , Het ₂ , Het ₃ , Het ₄ , Het ₆ , Het ₇ , Het ₁₀ , and Het ₁₂ are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said

Het-i , Het ₂ , Het ₃ , He , Het ₆ , Het ₇ , Het ₁₀ , and Het ₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C-i_ ₆ alkyl, -OC-i_ ₆ alkyl, -SC-i_ ₆ alkyl, =0, - and -NR ₂₁ R ₂₂ ; wherein each of said -C-i_ ₆ alkyl is optionally and independently substituted with from 1 to 3 -halo;

Z-i , Z ₂ , Z ₃ , Z ₄ and Z ₅ are each independently selected from C and N; and

m and n are each independently 1 , 2, 3, or 4. In a further embodiment, the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein

Ri and R ₄₁ are each independently selected from -H, -halo, -OH, -d- ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ 6alkyl, -NR ₉ R ₁₀ , -(C=0)-R ₄ , -(C=S)-R ₄ , -S0 ₂ -R ₄ , -CN , -NR ₉ -S0 ₂ -R ₄ , -C ₃ . ₆ cycloalkyl, -Ar ₇ and -Het-ι ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R ₁₂ , -0-Ci_ ₆ alkyl, and -S-Ci_ ₆ alkyl;

wherein R-i and R ₄₁ are not simultaneously -H

R ₂ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=0)-NR ₂₇ R ₂ 8, -(C=S)-NR ₂₇ R ₂₈ , -C ₃ - ₆ cycloalkyl, -Het ₃ , -Ar ₂ , -(C=0)-Het ₃ , -(C=S)-Het ₃ , -(C=0)-Ar ₂ , -(C=S)-Ar ₂ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ . 6cycloalkyl, and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, - Het ₃ , -Ar ₂ , and -NR ₁₃ R ₁₄ ;

R ₃ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=O)-NR ₂₉ R ₃₀ , -(C=S)-NR ₂₉ R ₃₀ , -C ₃ . ₆ cycloalkyl -Het ₂ , -Ar ₃ , -(C=0)-Het ₂ , -(C=S)-Het ₂ , -(C=0)-Ar ₃ , -(C=S)-Ar ₃ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ . 6cycloalkyl and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

-C ₃ . ₆ cycloalkyl, -Het ₂ , -Ar ₃ , and -NR ₁₅ R ₁₆ ;

R ₄ is independently selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -NR ₁₇ R ₁₈ ,

-C ₃ . ₆ cycloalkyl, -Ar ₈ and -Het ₄ ;

R ₅ is selected from -H, -OH, -halo, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -Het ₉ , -Ar-ι , -C ₃ . ₆ cycloalkyl, - SOz-A^ , -S0 ₂ , -SOz-d-ealkyl, -(C=0), -(C=0)-C ₁ . ₆ alkyl, -(C=S), -(C=S)-C ₁ . ₆ alkyl, -0-(C=0)-d_

₆ alkyl, wherein each of said -d_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci. ₆ alkyl, -S-Ci. ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Αη , -Het ₉ , and -NR ₂₃ R ₂ ;

R ₉ , R10, R11 , Ri ₂ , Ri ₃ , Ri ₄ , Ri5, R16, Ri7, R18, Ri9, R20, R21 , R22, R23, R24, R27, R28, R29, R30, R37, R38, R ₃₉ , R ₄₀ , R ₄₈ , and R ₅₀ , are each independently selected from -H , -halo, =0, -OH , -Ci_ ₆ alkyl, -O-

Ci- ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₅ and -Het ₇ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, - OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₇ , -Ar ₅ and -NR ₅₁ R ₅₂ ;

R ₅₁ and R ₅₂ are each independently selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ 6alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₁₀ and -Het ₁₀ ;

A is selected from -(C=0)-NR ₅ -;

Xi is -Ci- ₆ alkyl-NR ₃ -Ci- ₆ alkyl-; wherein each of said -Ci_ ₆ alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S- Ci- ₆ alkyl, -phenyl, and -NR ₃₇ R ₃₈ ; X ₂ is selected from -C _1-6 alkyl-, -0-Ci_ ₆ alkyl-, -S-Ci_ ₆ alkyl-, -(C=0)-, -NR ₂ -(C=0)-, -Ci. ₆ alkyl-NR ₂ -, -NR ₂ -, -(C=0)-, -NR ₂ -(C=O)-NR ₅₀ -, -NR^d-ealkyl-, -NR ₂ -S0 ₂ -, -NR ₂ -(C=0)-C ₁ . ₆ alkyl-, -(C=0)- NR ₂ -Ci_ ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -Ci. ₆ alkyl-NR ₂ -Ci. ₆ alkyl-; wherein each of said -Ci- ₆ alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -phenyl and -NR39R40;

Ar-ι , Ar ₂ , Ar ₃ , Ar ₅ , Ar ₇ , Ar ₈ , and Ar ₁₀ are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar-ι , Ar ₂ , Ar ₃ , Ar ₅ , Ar ₇ , Ar ₈ , and Ar ₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, and -NR ₁₉ R ₂₀ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 - halo;

Het-ι , Het ₂ , Het ₃ , Het ₄ , Het ₇ , Het ₉ , and Het ₁₀ are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι , Het ₂ , Het ₃ , Het ₄ , Het ₇ , Het ₉ , and Het ₁₀ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -OCi_ ₆ alkyl, -SCi_ ₆ alkyl, =0, - and -NR ₂₁ R ₂₂ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 -halo;

Z-i , Z ₂ , Z ₃ , Z ₄ and Z ₅ are each independently selected from C and N; and

m and n are each independently 1 , 2, 3, or 4.

In a further aspect, the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein

Wherein

R-i and R ₄₁ are each independently selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -NR ₉ R ₁₀ , - (C=0)-R ₄ , -(C=S)-R ₄ , -S0 ₂ -R ₄ , -NR ₉ -S0 ₂ -R ₄ , -C ₃ . ₆ cycloalkyl, -Ar ₇ and -Het^ wherein each of said -Ci- ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -NR-n R ₁₂ , and -S-Ci_ ₆ alkyl;

wherein R-i and R ₄₁ are not simultaneously -H R ₂ is selected from -H, -halo, -OH, -C _1-6 alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=0)-NR ₂₇ R ₂ 8, -(C=S)-NR ₂₇ R ₂ 8, -C ₃ - ₆ cycloalkyl, -Het ₃ , -Ar ₂ , -(C=0)-Het ₃ , -(C=S)-Het ₃ , -(C=0)-Ar ₂ , -(C=S)-Ar ₂ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ . 6cycloalkyl, and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -d- ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -

Het ₃ , -Ar ₂ , and -NRi ₃ R _M ;

R ₃ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=O)-NR ₂₉ R ₃₀ , -(C=S)-NR ₂₉ R ₃₀ , -C ₃ . ₆ cycloalkyl -Het ₂ , -Ar ₃ , -(C=0)-Het ₂ , -(C=S)-Het ₂ , -(C=0)-Ar ₃ , -(C=S)-Ar ₃ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ . 6cycloalkyl and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₂ , -Ar ₃ , and -NR ₁₅ R ₁₆ ;

R ₄ is independently selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, - Ar ₈ and -Het ₄ ;

R ₆ is selected from -(C=0), - (C=0)-Ar ₆ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=0)-NR ₃₁ R ₃₂ , -(C=0)-NR ₃₁ -(C=0)-R ₃₂ ;

wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from =0, -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₆ , - Ar ₆ , -NR ₂₅ R ₂₆ , -(C=0)-NR ₂₅ R ₂₆ , -NR ₃₃ (C=0)-NR ₂₅ R ₂₆ , -(C=S)-NR ₂₅ R ₂₆ , and -NR ₃₃ (C=S)- NR ₂₅ R ₂₆ ; and

wherein each of said -C ₃ . ₆ cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_ ₆ alkyl, =0, -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -Het ₁₂ , -Ar-n , and -NR ₅₃ R ₅ 4, -(C=0)-NR ₅₃ R ₅ 4, -NR ₅ 5(C=0)-NR ₅₃ R54, -(C=S)-NR ₅₃ R ₅ 4, and -NR ₅₅ (C=S)- Rg, R-io, Rii , Ri ₂ , Ri ₃ , Ri4, Ri5, Ri6, Ri9, R20, R21 , R22, R25, R26, R27, R28, R29, R30, R31 , R32, R33, R37, R ₃₈ , R ₃₉ , R _40, R48, R50, R53, R54 and R ₅₅ are each independently selected from -H, -halo, =0, - OH, -Ci- ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₅ and -Het ₇ ; wherein each of said - Ci- ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci. ₆ alkyl, -S-Ci. ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₇ , -Ar ₅ and -NR ₅₁ R ₅₂ ;

R51 and R ₅₂ are each independently selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ 6alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₁₀ and -Het ₁₀ ;

A is -NR ₆ -;

X-i is selected from -Ci_ ₆ alkyl-, -0-Ci_ ₆ alkyl-, -S-Ci_ ₆ alkyl-, -(C=0)-, -NR ₃ -(C=0)-, -Ci_ ₆ alkyl-NR ₃ -, -NR ₃ -, -(C=0)-, -NR ₃ -(C=0)-NR ₄₈ -, -NRs-d-ealkyl-, -NR ₃ -S0 ₂ -, -NR ₃ -(C=0)-C ₁ . ₆ alkyl-, -(C=0)- NR ₃ -Ci_ ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -Ci. ₆ alkyl-NR ₃ -Ci. ₆ alkyl-; wherein each of said -Ci_

₆ alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci. ₆ alkyl, -0-Ci. ₆ alkyl, -S-Ci. ₆ alkyl, -phenyl, and -NR ₃₇ R ₃₈ ;

X ₂ is selected from -Ci_ ₆ alkyl-, -0-Ci_ ₆ alkyl-, -S-Ci_ ₆ alkyl-, -(C=0)-, -NR ₂ -(C=0)-, -Ci_ ₆ alkyl-NR ₂ -, -NR ₂ -, -(C=0)-, -NR ₂ -(C=O)-NR ₅₀ -, -NR ₂ -d_ ₆ alkyl-, -NR ₂ -S0 ₂ -, -NR ₂ -(C=0)-C ₁ . ₆ alkyl-, -(C=0)- NR ₂ -Ci_ ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -Ci. ₆ alkyl-NR ₂ -Ci. ₆ alkyl-; wherein each of said -Ci_ ₆ alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d- ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -phenyl and -NR ₃₉ R4o;

Ar ₂ , Ar ₃ , Ar ₅ , Ar ₆ , Ar ₇ , Ar ₈ , Ar ₁₀ and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar ₂ , Ar ₃ , Ar ₅ , Ar ₆ , Ar ₇ , Ar ₈ , Ar ₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, and - NR ₁₉ R ₂ o; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι , Het ₂ , Het ₃ , Het ₄ , Het ₆ , Het ₇ , Het ₁₀ , and Het ₁₂ are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said

Het-ι , Het ₂ , Het ₃ , He , Het ₆ , Het ₇ , Het ₁₀ , and Het ₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -OCi_ ₆ alkyl, -SCi_ ₆ alkyl, =0, - and -NR ₂₁ R ₂₂ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 -halo;

Z-i , Z ₂ , Z ₃ , Z ₄ and Z ₅ are each independently selected from C and N; and

m and n are each independently 1 , 2, 3, or 4;

for use in human or veterinary medicine; more in particular for the diagnosis, prevention and/or treatment of an Activin-like receptor kinase associated disease selected from the list comprising disorders characterized by abnormal bone formation, vascular disorders, cardiovascular disorders, endocrine disorders, anemia-related disorders, myelin-related disorders, neurological disorders and cancer.

In a further embodiment, the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein

R-i and R ₄₁ are each independently selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ 6alkyl, -NR ₉ R ₁₀ , -(C=0)-R ₄ , -(C=S)-R ₄ , -S0 ₂ -R ₄ , -CN , -NR ₉ -S0 ₂ -R ₄ , -C ₃ . ₆ cycloalkyl, -Ar ₇ and -Het-ι ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R ₁₂ , -0-Ci_ ₆ alkyl, and -S-Ci_ ₆ alkyl;

wherein R-i and R ₄₁ are not simultaneously -H

R ₂ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=0)-NR ₂₇ R ₂₈ , -(C=S)-NR ₂₇ R ₂₈ , -C ₃ . ₆ cycloalkyl, -Het ₃ , -Ar ₂ , -(C=0)-Het ₃ , -(C=S)-Het ₃ , -(C=0)-Ar ₂ , -(C=S)-Ar ₂ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ . 6cycloalkyl, and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, - Het ₃ , -Ar ₂ , and -NRi ₃ R _M ;

R ₃ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=O)-NR ₂₉ R ₃₀ , -(C=S)-NR ₂₉ R ₃₀ , -C ₃ . ₆ cycloalkyl -Het ₂ , -Ar ₃ , -(C=0)-Het ₂ , -(C=S)-Het ₂ , -(C=0)-Ar ₃ , -(C=S)-Ar ₃ , -(C=0)-C ₃ - ₆ cycloalkyl, -(C=S)-C ₃ . 6cycloalkyl and -S0 ₂ -Ci. ₆ alkyl; wherein each of said -d- ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₂ , -Ar ₃ , and -NR ₁₅ R ₁₆ ;

R ₄ is independently selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -NR ₁₇ R ₁₈ , -C ₃ . ₆ cycloalkyl, -Ar ₈ and -Het ₄ ;

R ₅ is selected from -H, -OH, -halo, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -Het ₉ , -Ar-ι , -C ₃ . ₆ cycloalkyl, - SOz-A^ , -S0 ₂ , -S0 ₂ -d_ ₆ alkyl, -(C=0), -(C=0)-C ₁ . ₆ alkyl, -(C=S), -(C=S)-C ₁ . ₆ alkyl, -0-(C=0)-d_ 6alkyl, wherein each of said -d_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci. ₆ alkyl, -S-Ci. ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Αη , -Het ₉ , and -NR ₂₃ R ₂₄ ;

Rg, R-io, Rl 1 , Rl ₂ , Rl ₃ , Rl4, Rl5, Rl6, l _> Rl8, Rl9, R20, R∑1 , R∑2, R∑3, R∑4, R∑7, R28, R∑9, R30, R37, R38,

R39, R40, R48, and R ₅₀ , are each independently selected from -H , -halo, =0, -OH , -Ci_ ₆ alkyl, -O-

Ci- ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₅ and -Het ₇ ; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -

OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, -C ₃ . ₆ cycloalkyl, -Het ₇ , -Ar ₅ and -NR ₅₁ R ₅₂ ;

R ₅₁ and R ₅₂ are each independently selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_

₆ alkyl, -C ₃ . ₆ cycloalkyl, -Ar ₁₀ and -Het ₁₀ ;

A is selected from -(C=0)-NR ₅ -;

Xi is -Ci. ₆ alkyl-NR ₃ -Ci. ₆ alkyl-; wherein each of said -Ci_ ₆ alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-

Ci- ₆ alkyl, -phenyl, and -NR ₃₇ R ₃₈ ;

X ₂ is selected from -Ci_ ₆ alkyl-, -0-Ci_ ₆ alkyl-, -S-Ci_ ₆ alkyl-, -(C=0)-, -NR ₂ -(C=0)-, -Ci_ ₆ alkyl-N R ₂ -,

-NR ₂ -, -(C=0)-, -NR ₂ -(C=O)-NR ₅₀ -, -NR ₂ -d_ ₆ alkyl-, -NR ₂ -S0 ₂ -, -NR ₂ -(C=0)-d_ ₆ alkyl-, -(C=0)- NR ₂ -Ci- ₆ alkyl-, -0-Ci. ₆ alkyl-0-Ci. ₆ alkyl- and -d- ₆ alkyl-NR ₂ -d- ₆ alkyl-; wherein each of said

-d_ ₆ alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_ ₆ alkyl, -0-d_ ₆ alkyl, -S-d_ ₆ alkyl, -phenyl and -NR ₃₉ R ₄₀ ;

Ar-ι , Ar ₂ , Ar ₃ , Ar ₅ , Ar ₇ , Ar ₈ , and Ar ₁₀ are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar-ι , Ar ₂ , Ar ₃ , Ar ₅ , Ar ₇ , Ar ₈ , and Ar ₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_ ₆ alkyl, -0-d_ ₆ alkyl, -S-d_ ₆ alkyl, and -NR ₁₉ R ₂₀ ; wherein each of said -d_ ₆ alkyl is optionally and independently substituted with from 1 to 3 - halo;

Het-ι , Het ₂ , Het ₃ , Het ₄ , Het ₇ , Het ₉ , and Het ₁₀ are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said

Het-ι , Het ₂ , Het ₃ , Het ₄ , Het ₇ , Het ₉ , and Het ₁₀ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_ ₆ alkyl, -Od_ ₆ alkyl, -Sd_ ₆ alkyl, =0, - (C=0)-d- ₆ alkyl, and -NR ₂₁ R ₂₂ ; wherein each of said -d_ ₆ alkyl is optionally and independently substituted with from 1 to 3 -halo;

Z-i , Z ₂ , Z ₃ , Z ₄ and Z ₅ are each independently selected from C and N; and m and n are each independently 1 , 2, 3, or 4;

for use in human or veterinary medicine; more in particular for the diagnosis, prevention and/or treatment of an Activin-like receptor kinase associated disease selected from the list comprising disorders characterized by abnormal bone formation, vascular disorders, cardiovascular disorders, endocrine disorders, anemia-related disorders, and myelin-related disorders, neurological disorders and cancer.

In a further embodiment, the present invention provides a compound selected from the list comprising:

In a further embodiment, the present invention provides a compound selected from the list comprising:

use in human or veterinary medicine; more in particular for use in the diagnosis, prevention and/or treatment of an Activin-like receptor kinase associated disease selected from the list comprising disorders characterized by abnormal bone formation, vascular disorders, cardiovascular disorders, endocrine disorders, anemia-related disorders, and myelin-related disorders, neurological disorders and cancer. In a further aspect, the present invention provides a compound according to the present invention for use in the diagnosis, prevention and/or treatment of an Activin-like receptor kinase associated disease; wherein the pyrazolopyrimidine or the imidazopyridazine moiety is linked to the aryl or heteroaryl moiety at position Z ₄ or Z ₅ , in accordance with the numbering as provided in Formula I.

In yet a further aspect, the present invention provides a compound according to the present invention for use in the diagnosis, prevention and/or treatment of an Activin-like receptor kinase associated disease; wherein R-i is linked to the aryl or heteroaryl moiety at position Z-i , Z ₂ or Z ₃ , in accordance with the numbering as provided in Formula I.

The present invention further provides a pharmaceutical composition for use in the prevention and/or treatment of an ALK1 or ALK2-kinase associated disease comprising a compound according to this invention. Furthermore, the present invention provides the use of a compound or composition according to this invention, suitable for inhibiting the activity of a kinase; in particular an Activin-like receptor kinase, more in particular and ALK1 or ALK2 kinase; or for the diagnosis, prevention and/or treatment of an ALK1 or ALK2-kinase associated disease. Finally, the present invention provides a method for prevention and/or treatment of an ALK1 or ALK2-kinase associated disease; said method comprising administering to a subject in need thereof a compound or a composition according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be further described. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

Unless a context dictates otherwise, asterisks are used herein to indicate the point at which a mono- or bivalent radical depicted is connected to the structure to which it relates and of which the radical forms part.

As already mentioned hereinbefore, in a first aspect the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof,

Wherein

R-i and R ₄₁ are each independently selected from -H, -halo, -OH, -d- ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ 6alkyl, -NR ₉ R ₁₀ , -(C=0)-R ₄ , -(C=S)-R ₄ , -S0 ₂ -R ₄ , -CN, -NR ₉ -S0 ₂ -R ₄ , -C ₃ . ₆ cycloalkyl, -Ar ₇ and

-Het-ι; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR ₁₂ , -0-Ci_ ₆ alkyl, and -S-Ci_ ₆ alkyl;

R ₂ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=0)-NR ₂₇ R ₂ 8, -(C=S)-NR ₂₇ R ₂₈ , -C ₃ - ₆ cycloalkyl, -Het ₃ , -Ar ₂ , -(C=0)-Het ₃ , -(C=S)-Het ₃ , -(C=0)-Ar ₂ , -(C=S)-Ar ₂ , -(C=0)-C ₃ . ₆ cycloalkyl, -(C=S)-C ₃ .

₆ cycloalkyl, and -S0 ₂ -Ci_ ₆ alkyl; wherein each of said -Ci_ ₆ alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl, - Het ₃ , -Ar ₂ , and -NRi ₃ R _M ;

R ₃ is selected from -H, -halo, -OH, -Ci_ ₆ alkyl, -0-Ci_ ₆ alkyl, -S-Ci_ ₆ alkyl,

6alkyl, -(C=0)-0-C ₁ . ₆ alkyl, -(C=S)-0-C ₁ . ₆ alkyl, -(C=O)-NR ₂₉ R ₃₀ , -(C=S)-NR ₂₉ R ₃₀ , -C ₃ . ₆ cycloalkyl