WO2016146651A1

WO2016146651A1 - Macrocyclic activin-like receptor kinase inhibitors

Info

Publication number: WO2016146651A1
Application number: PCT/EP2016/055628
Authority: WO
Inventors: Jan Marie Cyriel Jozef Hoflack; Cyril BERTHET; Pascal André René BENDERITTER; Petra Marcella Françoise BLOM; Sylvie Gomez; Mourad DAOUBI
Original assignee: Oncodesign Sa
Priority date: 2015-03-16
Filing date: 2016-03-16
Publication date: 2016-09-22

Abstract

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.

Description

MACROCYCLIC ACTIVIN-LIKE RECEPTOR KINASE INHIBITORS

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 R₄₁ are each independently selected from -H, -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN, -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR₁₂, -0-Ci_₆alkyl, and -S-Ci_₆alkyl;

R₂ is selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl,

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂8, -(C=S)-NR₂₇R₂₈, -C₃-₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -

Het₃, -Ar₂, and -NRi₃R_M;

R₃ is selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl,

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=O)-NR₂₉R₃₀, -(C=S)-NR₂₉R₃₀, -C₃.₆cycloalkyl -Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

R₄ is independently selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -NR₁₇R₁₈, -C₃.₆cycloalkyl, -Ar₈ and -Het₄;

R₅ and R₇ are each independently selected from -H, -OH, -halo, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -Het₉, -Ar-, , -C₃.₆cycloalkyl, -S0₂-Ar-, , -S0₂, -S0₂-Ci_₆alkyl, -(C=0), -(C=0)-Ci_₆alkyl, -(C=S), -(C=S)-C₁.₆alkyl, -0-(C=0)-C₁.₆alkyl, -0-(C=S)-C₁.₆alkyl, -(C=0)-0-C₁.₆alkyl, and

wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar-ι, -Het₉, and -NR23R24;

R₆ is selected from -Ci_₆alkyl, -S0₂, -S0₂-Ci.₆alkyl, -S0₂-C₃.₆cycloalkyl, -(C=0),

- (C=0)-C₂-₆alkenyl, -(C=0)-0-C₁.₆alkyl, -(C=0)-Het₆, -(C=0)-Ar₆, -(C=0)-C₃-₆cycloalkyl, -(C=0)- NR31 R32, -(C=0)-NR₃₁-(C=0)-R₃₂, -(C=S), -(C=S)-C₁.₆alkyl, -(C=S)-C₂.₆alkenyl, -(C=S)-0-d_ 6alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃-₆cycloalkyl, -(C=S)-NR₃₁R₃₂, -(C=S)-NR₃₁-(C=S)-R₃₂, -Het₆, -Ar₆, and -C₃.₆cycloalkyl;

wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, - Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)- NR₂₅R₂₆; and

wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_₆alkyl, =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₁₂, -Ar-n, and -NR₅₃R₅4, -(C=0)-NR₅₃R₅4, -NR₅5(C=0)-NR₅₃R54, -(C=S)-NR₅₃R₅4, and -NR₅₅(C=S)-

R₈ is selected from -NR₃₄-(C=0)-R₃₅, -NR₃₄-(C=S)-R₃₅, -NR₃₆-(C=0)-NR₃₄R₃₅, -NR₃₆-(C=S)- NR₃₄R₃₅, -NR₃₄-(S0₂)-R₃₅, -NR₃₄-(C=0)-0-R₃₅, -NR₃₄-(C=S)-0-R₃₅, -0-(C=0)-NR₃₄R₃₅, and -0-(C=S)-NR₃₄R₃₅;

Rg, R-io, R11, Ri₂, Ri₃, Ri₄, 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_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl,

-C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁R₅₂;

R₅₁ and R₅₂ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_

₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

R₄₂ is selected from -H, -OH, -halo, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -NR₄₆R₄₇, -C₃.₆cycloalkyl, -Ar₉ and -Het₈;

R₄₃ is selected from -H -Ci_₆alkyl, and -C₃.₆cycloalkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1- 6alkyl, -S-Ci_₆alkyl, -Het₅, -C₃.₆cycloalkyl -Ar₄, and -NR₄₄R₄₅;

A is selected from -(CH₂)_n-Y-(CH₂)_m-, -(C=0)-, -(C=S)-, -(C=N)-R₄₉-, -(S0₂)-, -S0₂-NR₅-, -(C=0)- NR5-, -(C=S)-NR₅-, -NR₅-(C=0)-NR₇-, -NR₅-(C=S)-NR₇-, -NR₆-, -NR₅-(C=0)-0-, -NR₅-(C=S)-0-

, and -CHR₈- ;

X-i is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NRs-C^alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₃-Ci.₆alkyl-; wherein each of said -Ci_ ₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_-6alkyl, -0-Ci_-6alkyl, -S-Ci_-6alkyl, -phenyl, and -NR₃₇R₃₈;

X₂ is selected from -C_1-6alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci.₆alkyl-NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-Ci_-6alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said

-Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R4o;

Y is selected from a direct bond, -CHR₄₂-, -0-, -S-, and -NR₄₃-;

Ar-ι , Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, Ar₁₀ 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 , Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S- Ci-₆alkyl, and -NR₁₉R₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι , Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and Het₁₂ 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 , Het₂, Het₃, He , Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0,

and -NR₂₁R₂₂; wherein each of said -Ci_ 6alkyl is optionally and independently substituted with from 1 to 3 -halo;

Z-i , Z₂, Z₃, Z₄ and Z₅ 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 R₄₁ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN, -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι ; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR₁₂, -0-Ci_₆alkyl, and -S-Ci_₆alkyl;

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂₈, -(C=S)-NR₂₇R₂₈, -C₃.₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₃, -Ar₂, and -NRi₃Ri₄;

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₉R₃o, -(C=S)-NR₂₉R₃₀, -C₃.₆cycloalkyl -Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃.

₆cycloalkyl and -S0₂-Ci_₆alkyl; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

R₅ is selected from -H, -OH, -halo, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₉, -Ar-ι , -C₃.₆cycloalkyl, - SOz-A^ , -S0₂, -S0₂-d_₆alkyl, -(C=0), -(C=0)-C₁.₆alkyl, -(C=S), -(C=S)-C₁.₆alkyl, -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.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Αη , -Het₉, and -NR₂₃R₂₄;

R₆ is selected from -Ci_₆alkyl, -S0₂, -S0₂-Ci_₆alkyl, -S0₂-C₃.₆cycloalkyl, -(C=0),

- (C=0)-C₂.₆alkenyl, -(C=0)-0-C₁.₆alkyl, -(C=0)-Het₆, -(C=0)-Ar₆, -(C=0)-C₃.₆cycloalkyl, -(C=0)- NR₃i R₃₂, -(C=0)-N R₃₁-(C=0)-R₃₂, -(C=S), -(C=S)-C₁.₆alkyl, -(C=S)-C₂.₆alkenyl, -(C=S)-0-d_ 6alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃.₆cycloalkyl, -(C=S)-NR₃₁ R₃₂, -(C=S)-NR₃₁-(C=S)-R₃₂, -Het₆, -Ar₆, and -C₃.₆cycloalkyl;

wherein each of said -d_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from =0, -halo, -OH, -0-d_₆alkyl, -S-d_₆alkyl, -C₃.₆cycloalkyl, -Het₆, - Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)- NR₂₅R₂₆; and

wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -d_₆alkyl, =0, -halo, -OH, -0-d_₆alkyl, -S-d_₆alkyl, -Het₁₂, -Ar-n , and -NR₅₃R₅₄,

and -NR₅₅(C=S)-

R₉, R10, R11 , Ri₂, Ri₃, R"i₄, R15, R16, Ri7_> R18, Ri9, R20, R21 , R22, R23, R24, R25, R26, R27, R28, R29, R30, R₃i , R₃₂, R₃₃, R₃₇, R₃₈, R39, R40, R44, R45, R48, R50, R53, R54 and R₅₅ are each independently selected from -H , -halo, =0, -OH, -d_₆alkyl, -0-d_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -d_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-d_₆alkyl, -S-d_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅₂;

R51 and R₅₂ are each independently selected from -H, -halo, -OH, -d_₆alkyl, -0-d_₆alkyl, -S-Ci_

₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

R₄₃ is selected from -H -d_₆alkyl, and -C₃.₆cycloalkyl; wherein each of said -d.₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1-

₆alkyl, -S-d_₆alkyl, -Het₅, -C₃.₆cycloalkyl -Ar₄, and -NR₄₄R₄₅;

A is selected from -(CH₂)_n-Y-(CH₂)_m-, -(C=0)-NR₅-, -NR₆-; Χ-ι is selected from -C_1-6alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci.₆alkyl-NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NRs-d-ealkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₃-Ci.₆alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -phenyl, and -NR₃₇R₃₈;

X₂ is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci.₆alkyl-NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR^d-ealkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci-₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci.₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -phenyl and -NR₃₉R₄o;

Y is -NR₄₃-;

Ar-ι, Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ 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, Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-

Ci-₆alkyl, and -NR₁₉R₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι, Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₉, Het₁₀, and Het₁₂ 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, Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₉, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, - OCi-₆alkyl, -SCi_₆alkyl, =0,

and -NR₂₁R₂₂; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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 R₄₁ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN, -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and

-Het-ι; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR₁₂, -0-Ci_₆alkyl, and -S-Ci_₆alkyl;

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂₈, -(C=S)-NR₂₇R₂₈, -C₃.₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃-₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-Ci.₆alkyl; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₃, -Ar₂, and -NRi₃R_M;

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=O)-NR₂₉R₃₀, -(C=S)-NR₂₉R₃₀, -C₃.₆cycloalkyl -Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NRi₅Ri₆;

R₄ is independently selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -NR₁₇R₁₈,

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

- (C=0)-C₂.₆alkenyl, -(C=0)-0-C₁.₆alkyl, -(C=0)-Het₆, -(C=0)-Ar₆, -(C=0)-C₃.₆cycloalkyl, -(C=0)- NR₃₁ R₃₂, -(C=0)-N R₃₁-(C=0)-R₃₂, -(C=S), -(C=S)-C₁.₆alkyl, -(C=S)-C₂.₆alkenyl, -(C=S)-0-d_

₆alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃.₆cycloalkyl, -(C=S)-NR₃₁ R₃₂, -(C=S)-NR₃₁-(C=S)-R₃₂, -Het₆, -Ar₆, and -C₃.₆cycloalkyl;

wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, - Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-

NR₂₅R₂₆; and

wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_₆alkyl, =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₁₂, -Ar-n , and -NR₅₃R₅4, -(C=0)-NR₅₃R₅4, -NR₅5(C=0)-NR₅₃R54, -(C=S)-NR₅₃R₅4, and -NR₅₅(C=S)-

Rg, Rio, Rl 1 , Rl₂, Rl₃, 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 R₅₅ are each independently selected from -H, -halo, =0, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-C_1-6alkyl, -S-C_1-6alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅i R₅₂;

R₅₁ and R₅₂ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

R₄₃ is selected from -H -Ci_₆alkyl, and -C₃.₆cycloalkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6alkyl, -S-Ci_₆alkyl, -Het₅, -C₃.₆cycloalkyl -Ar₄, and -NR44R45;

A is selected from -(CH₂)_n-Y-(CH₂)_m-, -NR₆-;

X-i is selected from -C_1-6alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-N R₃-, -NR3-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NR₃-Ci_-6alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-N R₃-Ci.₆alkyl-; wherein each of said -Ci_ ₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_-6alkyl, -0-Ci_-6alkyl, -S-Ci_-6alkyl, -phenyl, and -NR₃₇R₃₈;

Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ 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

Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and - NR₁₉R₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι, Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₁₀, and Het₁₂ 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, Het₂, Het₃, He , Het₅, Het₆, Het₇, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, - OCi-₆alkyl, -SCi_₆alkyl, =0,

Z-i, Z₂, Z₃, Z₄ and Z₅ 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 R₄₁ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN, -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR₁₂, -0-Ci_₆alkyl, and -S-Ci_₆alkyl;

R₆ is selected from -(C=0),

- (C=0)-Ar₆, -(C=0)-C₃.₆cycloalkyl, -(C=0)-NR₃₁R₃₂, -(C=0)-NR₃₁-(C=0)-R₃₂, -(C=S), -(C=S)-d_ 6alkyl, -(C=S)-C₂.₆alkenyl, -(C=S)-0-C₁.₆alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃.₆cycloalkyl, - (C=S)-NR₃₁R₃₂, -(C=S)-NR₃₁-(C=S)-R₃₂;

Rg, R10, R11 , Rl₂, 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_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁R₅₂; R₅₁ and R₅₂ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_

6alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

A is selected from -NR₆-;

X-i is selected from -C_1-6alkyl-, -0-Ci_-6alkyl-, -S-Ci_-6alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NR₃-d_₆alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₃-Ci.₆alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -phenyl, and -NR₃₇R₃₈;

X₂ is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl-NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-d_₆alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci.₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -phenyl and -NR₃₉R₄o; Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ 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 Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and - NR₁₉R₂o; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι, Het₂, Het₃, Het₄, Het₆, Het₇, Het₁₀, and Het₁₂ 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, Het₂, Het₃, He , Het₆, Het₇, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0, -

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

R-i and R₄₁ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN, -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to

3 substituents selected from -halo, -OH, -NR-nR₁₂, -0-Ci_₆alkyl, and -S-Ci_₆alkyl;

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂₈, -(C=S)-NR₂₇R₂₈, -C₃.₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₃, -Ar₂, and -NRi₃R_M;

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=O)-NR₂₉R₃₀, -(C=S)-NR₂₉R₃₀, -C₃.₆cycloalkyl -Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃.

₆cycloalkyl and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆; R₄ is independently selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -NR₁₇R₁₈,

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

R₆ is selected from -Ci_₆alkyl, -S0₂, -S0₂-Ci.₆alkyl, -S0₂-C₃.₆cycloalkyl, -Het₆, -Ar₆, and -C₃.

₆cycloalkyl;

wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, - NR25R26, -NR₃₃(C=0)-NR₂₅R26, and -N R₃₃(C=S)-NR₂₅R26; and

wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_₆alkyl,-halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₁₂, -Ar-n , and - NR₅₃R₅4, -NR₅5(C=0)-NR₅₃R54, -(C=S)-NR₅₃R₅4, and -NR₅5(C=S)-NR₅₃R54;

Rg, R10, R11 , Rl₂, 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 R₅₅ are each independently selected from -H, -halo, =0, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅₂;

A is selected from -(CH₂)_n-Y-(CH₂)_m-, -NR₆-;

X-i is selected from -C_1-6alkyl-, -0-Ci_-6alkyl-, -S-Ci_-6alkyl-, -(C=0)-, -NR₃-(C=0)-, -C-,-₆alkyl-N R₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NRs-d-ealkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci-₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-N R₃-Ci.₆alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from

-halo, -OH, -Ci.₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -phenyl, and -NR₃₇R₃₈;

X₂ is selected from -Ci_₆alkyl-, -0-C-,-₆alkyl-, -S-C-,-₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl-N R₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NRz-C^alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R₄₀;

Y is -NR₄₃-;

Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ 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 Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C-i_₆alkyl, -0-C-i_₆alkyl, -S-C-i_₆alkyl, and - NR₁₉R₂₀; wherein each of said -C-i_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-i , Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₁₀, and Het₁₂ 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 , Het₂, Het₃, He , Het₅, Het₆, Het₇, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, - OCi-₆alkyl, -SCi_₆alkyl, =0,

and -NR21 R22; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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

Ri and R₄₁ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN , -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι ; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R₁₂, -0-Ci_₆alkyl, and -S-Ci_₆alkyl;

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂₈, -(C=S)-NR₂₇R₂₈, -C₃-₆cycloalkyl,

-Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₃, -Ar₂, and -NRi₃R_M;

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

R₅ is selected from -H, -OH, -halo, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₉, -Ar-ι , -C₃.₆cycloalkyl, - SOz-A^ , -SO2, -SOz-C_Lealkyl, -(C=0), -(C=0)-C₁.₆alkyl, -(C=S), -(C=S)-C₁.₆alkyl, -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.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Αη , -Het₉, and -NR₂₃R₂ ;

Rg, R10, R11 , R12, Rl3, Rl4, Rl5, Rl6, Rl > Rl8, Rl9, R20, R∑1 , R∑2, R∑3, R∑4, R∑7, R2₈, R∑9, R30, R37, R3₈,

R39, R40, R₄₈, and R₅₀, are each independently selected from -H , -halo, =0, -OH , -Ci_₆alkyl, -O- Ci-₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, - OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁R₅₂;

A is selected from -(C=0)-NR₅-;

X-i is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NRs-C^alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₃-Ci.₆alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from

X₂ is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl-NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR^d-ealkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R₄₀;

Ar-ι, Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ 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, Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 - halo;

Het-ι, Het₂, Het₃, Het₄, Het₇, Het₉, and Het₁₀ 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, Het₂, Het₃, Het₄, Het₇, Het₉, and Het₁₀ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0, -

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

A₂ is C, and A-i is N; R-ι and R₄₁ are each independently selected from -H, -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN, -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR₁₂, -0-Ci_₆alkyl, and -S-Ci_₆alkyl;

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂8, -(C=S)-NR₂₇R₂₈, -C₃-₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₃, -Ar₂, and -NR₁₃R₁₄;

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=O)-NR₂₉R₃₀, -(C=S)-NR₂₉R₃₀, -C₃.₆cycloalkyl -Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl,

-C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

R₅ is selected from -H, -OH, -halo, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₉, -Ar-ι, -C₃.₆cycloalkyl, - SOz-A^ , -SO2, -SOz-C_Lealkyl, -(C=0), -(C=0)-C₁.₆alkyl, -(C=S), -(C=S)-C₁.₆alkyl, -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.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Αη , -Het₉, and -NR₂₃R₂ ;

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, R₃₉, R_40, R_48, and R₅₀, are each independently selected from -H , -halo, =0, -OH , -Ci_₆alkyl, -O-

Ci-₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, - OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁R₅₂;

6alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

A is selected from -(C=0)-NR₅-;

Xi is -Ci-₆alkyl-NR₃-Ci-₆alkyl-; wherein each of said -Ci_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S- Ci-₆alkyl, -phenyl, and -NR₃₇R₃₈;

X₂ is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl-NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-d_₆alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R₄₀; Ar-ι, Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ 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, Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂o; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 - halo;

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

-Het-ι; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -NR-nR₁₂, and -S-Ci_₆alkyl;

wherein R-i and R₄₁ are not simultaneously -H

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂₈, -(C=S)-NR₂₇R₂₈, -C₃.₆cycloalkyl,

-Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₃, -Ar₂, and -NRi₃Ri₄;

R₆ is selected from -(C=0),

- (C=0)-Ar₆, -(C=0)-C₃.₆cycloalkyl, -(C=0)-NR₃₁ R₃₂, -(C=0)-NR₃₁-(C=0)-R₃₂;

NR₂₅R₂₆; and

Rg, Rio, Rl 1 , Rl₂, Rl₃, 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-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁R₅₂;

6alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

A is -NR₆-;

X-i is selected from -C_1-6alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NR₃-Ci_-6alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)-

NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₃-Ci.₆alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_-6alkyl, -0-Ci_-6alkyl, -S-Ci_-6alkyl, -phenyl, and -NR₃₇R₃₈;

X₂ is selected from -C_1-6alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl-NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-Ci_-6alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)-

NR₂-Ci-₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R₄₀;

Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ 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 Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and - NR₁₉R₂o; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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.

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂₈, -(C=S)-NR₂₇R₂₈, -C₃.₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -

Het₃, -Ar₂, and -NRi₃R_M;

R₄ is independently selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -NR₁₇R₁₈, -C₃.₆cycloalkyl, -Ar₈ and -Het₄; R₅ is selected from -H, -OH, -halo, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₉, -Ar-ι , -C₃.₆cycloalkyl, - SOz-A^ , -S0₂, -SOz-C_Lealkyl, -(C=0), -(C=0)-C₁.₆alkyl, -(C=S), -(C=S)-C₁.₆alkyl, -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_-6alkyl, -S-Ci_-6alkyl, -C₃.₆cycloalkyl, -Αη , -Het₉, and -NR₂₃R₂4;

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, R₄₀, R₄₈, and R₅₀, are each independently selected from -H , -halo, =0, -OH , -Ci_₆alkyl, -O- Ci-₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, - OH, -0-Ci_-6alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅₂;

6alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

A is selected from -(C=0)-NR₅-;

Xi is -Ci-₆alkyl-NR₃-Ci-₆alkyl-; wherein each of said -Ci_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S- Ci_₆alkyl, -phenyl, and -NR₃₇R₃₈;

X₂ is selected from -C_1-6alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl-N R₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-Ci_-6alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci-₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R₄₀;

Ar-ι , Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ 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 , Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 - halo;

Het-ι , Het₂, Het₃, Het₄, Het₇, Het₉, and Het₁₀ 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 , Het₂, Het₃, Het₄, Het₇, Het₉, and Het₁₀ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0, -

and -NR₂₁ R₂₂; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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 R₄₁ are each independently selected from -H, -halo, -OH, -d-₆alkyl, -S-Ci_₆alkyl, -NR₉R₁₀, - (C=0)-R₄, -(C=S)-R₄, -SO2-R4, -N R9-SO2-R4, -C₃.₆cycloalkyl, -Ar₇ and -Het, ; wherein each of said -Ci-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -NR-n R₁₂, and -S-Ci_₆alkyl;

wherein R-i and R₄₁ are not simultaneously -H

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂8, -(C=S)-NR₂₇R₂8, -C₃-₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₃, -Ar₂, and -NRi₃R_M;

₆cycloalkyl and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

R₄ is independently selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, - Ar₈ and -Het₄;

R₆ is selected from -(C=0),

NR₂₅R₂₆; and wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -d-₆alkyl, =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₁₂, -Ar-n , and -NR53R54, -(C=0)-NR₅₃R₅4, -NR₅5(C=0)-NR₅3R54, -(C=S)-NR₅₃R₅4, and -NR₅₅(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,

R₃₈, R₃₉, R₄₀, R48, R50, R53, R54 and R₅₅ are each independently selected from -H, -halo, =0, - OH, -Ci-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said - Ci-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅₂;

R₅i and R₅₂ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

A is -NR₆-;

X-i is selected from -C-,-₆alkyl-, -0-Ci_₆alkyl-, -S-C-,-₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-N R₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NRs-d-ealkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-N R₃-Ci.₆alkyl-; wherein each of said -Ci_

₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci.₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -phenyl, and -NR₃₇R₃₈;

X₂ is selected from -Ci_₆alkyl-, -0-d.₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -d.₆alkyl-N R₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-d_₆alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said

-Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R₄₀;

Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ 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 Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C-i_₆alkyl, -0-C-i_₆alkyl, -S-C-i_₆alkyl, and - NR₁₉R₂₀; wherein each of said -C-i_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-i , Het₂, Het₃, Het₄, Het₆, Het₇, Het₁₀, and Het₁₂ 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 , Het₂, Het₃, He , Het₆, Het₇, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C-i_₆alkyl, -OC-i_₆alkyl, -SC-i_₆alkyl, =0, -

and -NR₂₁ R₂₂; wherein each of said -C-i_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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 R₄₁ are each independently selected from -H, -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN , -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι ; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R₁₂, -0-Ci_₆alkyl, and -S-Ci_₆alkyl;

wherein R-i and R₄₁ are not simultaneously -H

-C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

R₅ is selected from -H, -OH, -halo, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₉, -Ar-ι , -C₃.₆cycloalkyl, - SOz-A^ , -S0₂, -SOz-d-ealkyl, -(C=0), -(C=0)-C₁.₆alkyl, -(C=S), -(C=S)-C₁.₆alkyl, -0-(C=0)-d_

₆alkyl,

R₉, R10, R11 , Ri₂, Ri₃, Ri₄, Ri5, R16, Ri7, R18, Ri9, R20, R21 , R22, R23, R24, R27, R28, R29, R30, R37, R38, R₃₉, R₄₀, R₄₈, and R₅₀, are each independently selected from -H , -halo, =0, -OH , -Ci_₆alkyl, -O-

Ci-₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, - OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅₂;

A is selected from -(C=0)-NR₅-;

Xi is -Ci-₆alkyl-NR₃-Ci-₆alkyl-; wherein each of said -Ci_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S- Ci-₆alkyl, -phenyl, and -NR₃₇R₃₈; X₂ is selected from -C_1-6alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci.₆alkyl-NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR^d-ealkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR39R40;

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

Wherein

R-i and R₄₁ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -S-Ci_₆alkyl, -NR₉R₁₀, - (C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het^ wherein each of said -Ci-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -NR-n R₁₂, and -S-Ci_₆alkyl;

wherein R-i and R₄₁ are not simultaneously -H R₂ is selected from -H, -halo, -OH, -C_1-6alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl,

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂8, -(C=S)-NR₂₇R₂8, -C₃-₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-Ci_₆alkyl; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -

Het₃, -Ar₂, and -NRi₃R_M;

R₆ is selected from -(C=0),

wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_₆alkyl, =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₁₂, -Ar-n , and -NR₅₃R₅4, -(C=0)-NR₅₃R₅4, -NR₅5(C=0)-NR₅₃R54, -(C=S)-NR₅₃R₅4, and -NR₅₅(C=S)- Rg, R-io, Rii , Ri₂, Ri₃, Ri4, Ri5, Ri6, Ri9, R20, R21 , R22, R25, R26, R27, R28, R29, R30, R31 , R32, R33, R37, R₃₈, R₃₉, R_40, R48, R50, R53, R54 and R₅₅ are each independently selected from -H, -halo, =0, - OH, -Ci-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said - Ci-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁R₅₂;

R51 and R₅₂ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

A is -NR₆-;

X-i is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NRs-d-ealkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₃-Ci.₆alkyl-; wherein each of said -Ci_

X₂ is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl-NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-d_₆alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R4o;

Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ 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 Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and - NR₁₉R₂o; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι , Het₂, Het₃, Het₄, Het₆, Het₇, Het₁₀, and Het₁₂ 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 , Het₂, Het₃, He , Het₆, Het₇, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0, -

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.

R-i and R₄₁ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN , -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι ; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R₁₂, -0-Ci_₆alkyl, and -S-Ci_₆alkyl;

wherein R-i and R₄₁ are not simultaneously -H

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=O)-NR₂₉R₃₀, -(C=S)-NR₂₉R₃₀, -C₃.₆cycloalkyl -Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃-₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl and -S0₂-Ci.₆alkyl; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

Rg, R-io, Rl 1 , Rl₂, Rl₃, 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 R₅₀, are each independently selected from -H , -halo, =0, -OH , -Ci_₆alkyl, -O-

Ci-₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -

OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅₂;

₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

A is selected from -(C=0)-NR₅-;

Xi is -Ci.₆alkyl-NR₃-Ci.₆alkyl-; wherein each of said -Ci_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-

Ci-₆alkyl, -phenyl, and -NR₃₇R₃₈;

X₂ is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl-N R₂-,

-NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-d_₆alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-d_₆alkyl-, -(C=0)- NR₂-Ci-₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -d-₆alkyl-NR₂-d-₆alkyl-; wherein each of said

-d_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_₆alkyl, -0-d_₆alkyl, -S-d_₆alkyl, -phenyl and -NR₃₉R₄₀;

Ar-ι , Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ 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 , Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_₆alkyl, -0-d_₆alkyl, -S-d_₆alkyl, and -NR₁₉R₂₀; wherein each of said -d_₆alkyl is optionally and independently substituted with from 1 to 3 - halo;

Het-ι , Het₂, Het₃, Het₄, Het₇, Het₉, and Het₁₀ 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 , Het₂, Het₃, Het₄, Het₇, Het₉, and Het₁₀ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_₆alkyl, -Od_₆alkyl, -Sd_₆alkyl, =0, - (C=0)-d-₆alkyl, and -NR₂₁ R₂₂; wherein each of said -d_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Z-i , Z₂, Z₃, Z₄ and Z₅ 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:

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 Z₄ or Z₅, 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 , Z₂ or Z₃, 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 R₄₁ are each independently selected from -H, -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN, -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂8, -(C=S)-NR₂₇R₂₈, -C₃-₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃.

₆cycloalkyl, and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₃, -Ar₂, and -NRi₃R_M;

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=O)-NR₂₉R₃₀, -(C=S)-NR₂₉R₃₀, -C₃.₆cycloalkyl

-Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃.

₆cycloalkyl and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl,

-C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

R₅ and R₇ are each independently selected from -H, -OH, -halo, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_

₆alkyl, -Het₉, -Ar-, , -C₃.₆cycloalkyl, -S0₂-Ar-, , -S0₂, -S0₂-Ci_₆alkyl, -(C=0),

-(C=S), -(C=S)-C₁.₆alkyl, -0-(C=0)-C₁.₆alkyl, -0-(C=S)-C₁.₆alkyl, -(C=0)-0-C₁.₆alkyl, and

wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl,

-C₃.₆cycloalkyl, -Ar-ι, -Het₉, and -NR₂₃R₂₄;

-

(C=0)-C₂.₆alkenyl, -(C=0)-0-C₁.₆alkyl, -(C=0)-Het₆, -(C=0)-Ar₆, -(C=0)-C₃.₆cycloalkyl, -(C=0)- NR₃₁R₃₂, -(C=0)-NR₃₁-(C=0)-R₃₂, -(C=S), -(C=S)-C₁.₆alkyl, -(C=S)-C₂.₆alkenyl, -(C=S)-0-d_

₆alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃.₆cycloalkyl, -(C=S)-NR₃₁R₃₂, -(C=S)-NR₃₁-(C=S)-R₃₂,

-Het₆, -Ar₆, and -C₃.₆cycloalkyl; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, - Ar₆, -NR₂₅R₂6, -(C=0)-NR₂₅R₂6, -NR₃3(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)- NR₂₅R₂₆; and

R₈ is selected from -NR₃₄-(C=0)-R₃₅, -NR₃₄-(C=S)-R₃₅, -NR₃₆-(C=0)-NR₃₄R₃₅, -NR₃₆-(C=S)- NR₃₄R₃₅, -NR₃₄-(S0₂)-R₃₅, -NR₃₄-(C=0)-0-R₃₅, -NR₃₄-(C=S)-0-R₃₅, -0-(C=0)-NR₃₄R₃₅, and

-0-(C=S)-NR₃₄R₃₅;

Rg, R-io, Rii, Ri₂, Ri₃, R"i₄, Ri5. Ri6. Ri7. Ri8. Ri9. R20. R21. R22. R23. R24. R25. R26. R27. R28. R29. R30.

-C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁R₅₂;

₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

R₄₂ is selected from -H, -OH, -halo, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -NR₄₆R₄₇, -C₃.₆cycloalkyl,

-Ar_g and -Het₈;

A is selected from -(CH₂)_n-Y-(CH₂)_m-, -(C=0)-, -(C=S)-, -(C=N)-R₄₉-, -(S0₂)-, -S0₂-NR₅-, -(C=0)- NR₅-, -(C=S)-NR₅-, -NR₅-(C=0)-NR₇-, -NR₅-(C=S)-NR₇-, -NR₆-, -NR₅-(C=0)-0-, -NR₅-(C=S)-0- , and -CHR₈- ;

X-i is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NRs-d-ealkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci-₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₃-Ci.₆alkyl-; wherein each of said -Ci_

X₂ is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl-NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NRz-C^alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci-₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said

Y is selected from a direct bond, -CHR₄₂-, -0-, -S-, and -NR₄₃-;

Ar-ι, Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, Ar₁₀ 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-i, Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S- Ci-₆alkyl, and -NR₁₉R₂o; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι, Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and Het₁₂ 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, Het₂, Het₃, He , Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0,

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

Unless indicated otherwise, all of the above radicals can be read both ways. For example, when A is -(C=0)-NR₅-, the -(C=0)- may be attached to X₂ and -NR₅- attached to X·, . Alternatively, the - (C=0)- may be attached to X-i and -NR₅- attached to X-| . What is called "left part" of a radical is for example when A is -(C=0)-NR₅-, -(C=0)-, and the "right part" is -NR₅-.

Preferably, A is such as the left part of the possible values of A (i.e. in particular -(C=N)- from - (C=N)-R₄₉-, -(C=0)- from -(C=0)-NR₅-, -(C=S)- from -(C=S)-NR₅-, -S0₂- from -S0₂-NR₅-, etc) is attached to X-| . Alternatively, A is such as the right part of the possible values of A (i.e. in particular -R₄₉- from -(C=N)-R₄₉-, -NR₅- from -(C=0)-NR₅-, -NR₅- from -(C=S)-NR₅-, -NR₅- from -S0₂-NR₅-, etc) is attached to X-| .

Preferably, X-i is such as the left part of the possible values of X-i (i.e. in particular -O- from -0-Ci_ ₆alkyl-, -S- from -S-Ci_₆alkyl-, -NR₃- from -NR₃-(C=0)- and -NR₃-Ci_₆alky-, -S0₂- from -S0₂-NR₃-, etc) is attached to the Z Z₅ aryl or heteroaryl moiety. Alternatively, X-i is such as the right part of the possible values of X-i (i.e. in particular -Ci_₆alkyl- from -0-Ci_₆alkyl-, -S-Ci_₆alkyl- and -NR₃-Ci_ ₆alkyl-; -(C=0)- from -NR₃-(C=0)-, -(NR₃)- from -S0₂-NR₃-, etc) is attached to the Z Z₅ aryl or heteroaryl moiety. Preferably, X₂ is such as the left part of the possible values of X₂ (i.e. in particular -O- from -0-Ci_ ₆alkyl-, -S- from -S-Ci_₆alkyl-, -(C=0)- from -(C=0)-NR₂-, -NR₂- from -NR₂-Ci_₆alkyl-, -S0₂- from - S0₂-NR₂- etc) is attached to the pyrazolopyrimidine moiety. Alternatively, X₂ is such as the right part of the possible values of X₂ (i.e. in particular -Ci_₆alkyl- from -0-Ci_₆alkyl-, -S-Ci_₆alkyl- and - NR₂-Ci-₆alkyl-, -NR₂- from -(C=0)-NR₂- and -S0₂-NR₂-, etc) is attached to the pyrazolopyrimidine moiety. The same principle applies to all the radicals of the invention unless specified otherwise.

When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless a context dictates otherwise:

The term "alkyl" by itself or as part of another substituent refers to fully saturated hydrocarbon radicals. Generally, alkyl groups of this invention comprise from 1 to 6 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. Thus, for example, d-₆alkyl means an alkyl of one to six carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl, butyl, and its isomers (e.g. n-butyl, i- butyl and t-butyl); pentyl and its isomers, hexyl and its isomers. C C6 alkyl includes all linear, branched, or cyclic alkyl groups with between 1 and 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term "optionally substituted alkyl" refers to an alkyl group optionally substituted with one or more substituents (for example 1 to 3 substituents, for example 1 , 2 or 3 substituents or 1 to 2 substituents) at any available point of attachment. Non-limiting examples of such substituents include -halo, -OH, primary and secondary amides, -0-Ci_₆alkyl, -S-Ci_₆alkyl, heteroaryl, aryl, and the like.

The term "cycloalkyl" by itself or as part of another substituent is a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having a cyclic structure. Cycloalkyl includes all saturated or partially saturated (containing 1 or 2 double bonds) hydrocarbon groups having a cyclic structure. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this invention comprise from 3 to 6 atoms. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

Where alkyl groups as defined are divalent, i.e., with two single bonds for attachment to two other groups, they are termed "alkylene" groups. Non-limiting examples of alkylene groups includes methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene, 1 ,2- dimethylethylene, pentamethylene and hexamethylene.

Generally, alkylene groups of this invention preferably comprise the same number of carbon atoms as their alkyl counterparts. Where an alkylene or cycloalkylene biradical is present, connectivity to the molecular structure of which it forms part may be through a common carbon atom or different carbon atom. To illustrate this applying the asterisk nomenclature of this invention, a C₃ alkylene group may be for example *-CH₂CH₂CH₂-*, *-CH(-CH₂CH₃)-*, or *-CH₂CH(-CH₃)-*. Likewise a C₃ cycloalkylene group may be

The terms "heterocycle" as used herein by itself or as part of another group refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 6 membered monocyclic ring systems, or 8-10 membered bicyclic rings) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1 , 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms. An optionally substituted heterocyclic refers to a heterocyclic having optionally one or more substituents (for example 1 to 4 substituents, or for example 1 , 2, 3 or 4), selected from those defined above for substituted alkyl.

Exemplary heterocyclic groups include piperidinyl, azetidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, succinimidyl, 3H- indolyl, isoindolinyl, chromenyl, isochromanyl, xanthenyl, 2H-pyrrolyl, 1 -pyrrolinyl, 2-pyrrolinyl, 3- pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 4aH-carbazolyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyranyl, dihydro-2H-pyranyl, 4H-pyranyl, 3,4-dihydro- 2H-pyranyl, phthalazinyl, oxetanyl, thietanyl, 3-dioxolanyl, 1 ,3-dioxanyl, 2,5-dioximidazolidinyl,

2.2.4- piperidonyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrehydrothienyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1 , 3-dioxolanyl, 1 ,4-oxathianyl, 1 ,4-dithianyl,

1 .3.5- trioxanyl, 6H-1 ,2,5-thiadiazinyl, 2H-1 ,5,2-dithiazinyl, 2H-oxocinyl, 1 H-pyrrolizinyl, tetrahydro- 1 ,1 -dioxothienyl, N- formylpiperazinyl, and morpholinyl; in particular pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, dioxolanyl, dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, and tetrahydrofuranyl.

8-10 membered heterocyclic groups are also meant to include spiro-groups, which are bicyclic compounds with both rings connected through a single atom, such as for example spiro[4.5]decane, which is a spiro compound consisting of a cyclohexane ring and a cyclopentane ring.

The term "aryl" as used herein refers to a polyunsaturated, aromatic hydrocarbyl group having from 5-10 atoms. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein. Non-limiting examples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, 1 -, 2-, 3-, 4-, 5-, 6-, 7-, or 8-azulenyl, 1 - or 2-naphthyl, 1 -, 2-, or 3- indenyl, 1 -, 2-, or 9-anthryl, 1 - 2-, 3-, 4-, or 5-acenaphtylenyl, 3-, 4-, or 5-acenaphtenyl, 1 -, 2-, 3-, 4- , or 10-phenanthryl, 1 - or 2-pentalenyl, 1 , 2-, 3-, or 4-fluorenyl, 4- or 5-indanyl, 5-, 6-, 7-, or 8- tetrahydronaphthyl, 1 ,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl, dibenzo[a,d]cylcoheptenyl, and 1 -, 2-, 3-, 4-, or 5-pyrenyl; in particular phenyl.

The aryl ring can optionally be substituted by one or more substituents. An "optionally substituted aryl" refers to an aryl having optionally one or more substituents (for example 1 to 5 substituents, for example 1 , 2, 3 or 4) at any available point of attachment, selected from those defined above for substituted alkyl.

Where a carbon atom in an aryl group is replaced with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring.

The term "heteroaryl" as used herein by itself or as part of another group refers but is not limited to 5 to 10 carbon-atom aromatic rings in which one or more carbon atoms can be replaced by oxygen, nitrogen or sulfur atoms. Non-limiting examples of such heteroaryl, include: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1 -b][1 ,3]thiazolyl, thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl, thieno[2,3-d][1 ,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1 ,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1 ,3-benzoxazolyl, 1 ,2-benzisoxazolyl, 2,1 -benzisoxazolyl, 1 ,3-benzothiazolyl, 1 ,2- benzoisothiazolyl, 2,1 -benzoisothiazolyl, benzotriazolyl, 1 ,2,3-benzoxadiazolyl, 2,1 ,3- benzoxadiazolyl, 1 ,2,3-benzothiadiazolyl, 2,1 ,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[1 ,2-a]pyridinyl, 6-oxo-pyridazin-1 (6H)-yl, 2-oxopyridin-1 (2H)-yl, 6-oxo-pyridazin-1 (6H)-yl, 2- oxopyridin-1 (2H)-yl, 1 ,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 7-azaindolyl, 6-azaindolyl, 5-azaindolyl, 4-azaindolyl.

An "optionally substituted heteroaryl" refers to a heteroaryl having optionally one or more substituents (for example 1 to 4 substituents, for example 1 , 2, 3 or 4), selected from those defined above for substituted alkyl.

The term "halo" or "halogen" as a group or part of a group is generic for fluoro, chloro, bromo, or iodo, as well as any suitable isotope thereof.

Whenever the term "substituted" is used in the present invention, it is meant to indicate that one or more hydrogens on the atom indicated in the expression using "substituted" is replaced with a selection from the indicated group, provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic and/or diagnostic agent.

Where groups may be optionally substituted, such groups may be substituted once or more, and preferably once, twice or thrice. Substituents may be selected from, those defined above for substituted alkyl.

As used herein the terms such as "alkyl, aryl, or cycloalkyl, each being optionally substituted with" or "alkyl, aryl, or cycloalkyl, optionally substituted with" refers to optionally substituted alkyl, optionally substituted aryl and optionally substituted cycloalkyl.

More generally, from the above, it will be clear to the skilled person that the compounds of the invention may exist in the form of different isomers and/or tautomers, including but not limited to geometrical isomers, conformational isomers, E/Z-isomers, stereochemical isomers (i.e. enantiomers and diastereoisomers) and isomers that correspond to the presence of the same substituents on different positions of the rings present in the compounds of the invention. All such possible isomers, tautomers and mixtures thereof are included within the scope of the invention.

In addition, the invention includes isotopically-labelled compounds and salts, which are identical to compounds of formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of formula (I) are isotopes of hydrogen, carbon, nitrogen, fluorine, such as ³H, C, ³N, ⁴C, ⁵0 and ⁸F. Such isotopically-labelled compounds of formula (I) are useful in drug and/or substrate tissue distribution assays. For example C and ⁸F isotopes are particularly useful in PET (Positron Emission Tomography). PET is useful as a diagnostic or treatment follow-up tool that can be applied in a translational manner in a preclinical and clinical setting. It also has applications in PK determination of compounds, including biodistribution. Isotopically labeled compounds of formula (I) can generally be prepared by carrying out the procedures disclosed below, by substituting a readily available non-isotopically labeled reagent with an isotopically labeled reagent.

Whenever used in the present invention the term "compounds of the invention" or a similar term is meant to include the compounds of general Formula I and any subgroup thereof. This term also refers to the compounds as depicted in Table 1 , their derivatives, /v-oxides, salts, solvates, hydrates, stereoisomeric forms, racemic mixtures, tautomeric forms, optical isomers, analogues, pro-drugs, esters, and metabolites, as well as their quaternized nitrogen analogues. The v-oxide forms of said compounds are meant to comprise compounds wherein one or several nitrogen atoms are oxidized to the so-called /v-oxide.

As used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. By way of example, "a compound" means one compound or more than one compound.

The terms described above and others used in the specification are well understood to those in the art. a particular embodiment, the present invention provides compounds of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof; 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; wherein one or more of the following applies:

Ri and R₄₁ are each independently selected from -H, -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN, -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι ; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R₁₂, -0-Ci_₆alkyl, and -S-Ci_₆alkyl;

R₂ is selected from -H, -halo, -OH, -C_1-6alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl,

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂8, -(C=S)-NR₂₇R₂8, -C₃-₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃.

-C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

-C₃.₆cycloalkyl, -Ar-ι , -Het₉, and -NR₂₃R₂₄;

-

(C=0)-C₂.₆alkenyl, -(C=0)-0-C₁.₆alkyl, -(C=0)-Het₆, -(C=0)-Ar₆, -(C=0)-C₃.₆cycloalkyl, -(C=0)- NR₃₁ R₃₂, -(C=0)-N R₃₁-(C=0)-R₃₂, -(C=S), -(C=S)-C₁.₆alkyl, -(C=S)-C₂.₆alkenyl, -(C=S)-0-d_

₆alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃.₆cycloalkyl, -(C=S)-NR₃₁ R₃₂, -(C=S)-NR₃₁-(C=S)-R₃₂,

-Het₆, -Ar₆, and -C₃.₆cycloalkyl;

NR₂₅R₂₆; and

R₉, R10, R11 , Ri₂, R"i₃, Ri₄, R15. R16. Ri7_> R18. Ri9. R20. R21. R22. R23. R24. R25. R26. R2₇. R28. R29. R30.

R31 , R₃₂, R₃₃, R₃₄, R₃5, R₃6, R₃₇, R₃8, R₃9, R₄o, R44. R45. R46. R4₇. R48, R49. R50. R53. R54 and R55 are each independently selected from -H, -halo, =0, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁R₅₂;

R₄₂ is selected from -H, -OH, -halo, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -NR₄₆R₄7, -C₃.₆cycloalkyl, -Ar₉ and -Het₈;

R₄₃ is selected from -H -Ci_₆alkyl, and -C₃.₆cycloalkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_

₆alkyl, -S-Ci_₆alkyl, -Het₅, -C₃.₆cycloalkyl -Ar₄, and -NR₄₄R₄₅;

A is selected from -(CH₂)n-Y-(CH₂)_m-, -(C=0)-, -(C=S)-, -(C=N)-R₄₉-, -(S0₂)-, -S0₂-NR₅-, -(C=0)-

NR₅-, -(C=S)-NR₅-, -NR₅-(C=0)-NR₇-, -NR₅-(C=S)-NR₇-, -NR₆-, -NR₅-(C=0)-0-, -NR₅-(C=S)-0-

, and -CHR₈- ;

Xi is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NR₃-d_₆alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₃-Ci.₆alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci.₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -phenyl, and -NR₃₇R₃₈;

X₂ is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl-NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-d_₆alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R₄₀;

Y is selected from a direct bond, -CHR₄₂-, -0-, -S-, and -NR₄₃-;

Ar-ι, Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, Ar₁₀ 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, Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S- Ci-₆alkyl, and -NR₁₉R₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι, Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and Het₁₂ 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, Het₂, Het₃, He , Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d.

₆alkyl, -Od_₆alkyl, -Sd_₆alkyl, =0,

and -NR₂₁R₂₂; wherein each of said -d- 6alkyl is optionally and independently substituted with from 1 to 3 -halo;

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 particular, X-i, and X₂ as used herein, represent biradicals, which taken together with the radicals to which they are attached form a macrocyclic pyrazolopyrimidine compound. Said biradicals may be present in either of both directions in the macrocyclic pyrazolopyrimidine, but are preferably present in the direction as described below:

Referring to formula I:

Xi is selected from the list comprising *-Ci_₆alkyl-, *-0-Ci_₆alkyl-, *-S-Ci_₆alkyl-, *-(C=0)-, -

NR₃-(C=0)-, *-Ci_-6alkyl-NR₃-, *-NR₃-, *-(C=0)-, *-NR₃-(C=0)-NR₄₈-, *-NR₃-Ci_-6alkyl-, *-NR₃- SO2-,

*-0-Ci_-6alkyl-0-Ci_-6alkyl- and *-d_ 6alkyl-NR₃-Ci_₆alkyl-; wherein said biradical is preferably attached to the aryl or heteroaryl moiety via *;

X₂ is selected from the list comprising *-Ci_₆alkyl-, *-0-Ci_₆alkyl-, *-S-Ci_₆alkyl-, *-(C=0)-, *-

NR₂-(C=0)-, *-Ci_-6alkyl-NR₂-, *-NR₂-, *-(C=0)-, *-NR₂-(C=O)-NR₅₀-, *-NR₂-Ci_-6alkyl-, *-NR₂- SO2-,

*-0-Ci_-6alkyl-0-Ci_-6alkyl- and *-d_ 6alkyl-NR₂-Ci-₆alkyl-; wherein said biradical is preferably attached to the pyrazolopyrimidine moiety via *;

In a preferred embodiment, the present invention provides compounds of formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, 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; wherein

R-i and R₄₁ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_

6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN, -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR₁₂, -0-Ci_₆alkyl, and -S-Ci_₆alkyl;

Het₃, -Ar₂, and -NRi₃R_M;

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=O)-NR₂₉R₃₀, -(C=S)-NR₂₉R₃₀, -C₃.₆cycloalkyl -Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. ₆cycloalkyl and -S0₂-Ci.₆alkyl; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

Rg, Rio, Rl 1 , Rl₂, Rl₃, Rl4, Rl5, Rl6, l7> Rl8, Rl9, R20, R∑1 , R∑2, R∑3, R∑4, R∑5, R∑6, R∑7, R28, R∑9, R30, R₃i , R₃₂, R₃₃, R₃₇, R₃₈, R₃9, R40, R44, R45, R48, R50, R53, R54 and R₅₅ are each independently selected from -H , -halo, =0, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅₂;

R51 and R₅₂ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_

₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

R₄₃ is selected from -H -Ci_₆alkyl, and -C₃.₆cycloalkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1-

₆alkyl, -S-Ci_₆alkyl, -Het₅, -C₃.₆cycloalkyl -Ar₄, and -NR44R45;

A is selected from -(CH₂)_n-Y-(CH₂)_m-, -(C=0)-NR₅-, -NR₆-;

X-i is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-N R₃-,

-NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NR₃-d_₆alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-d_₆alkyl-, -(C=0)-

NR₃-Ci-₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -d-₆alkyl-N R₃-d-₆alkyl-; wherein each of said -d.

₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_₆alkyl, -0-d_₆alkyl, -S-d_₆alkyl, -phenyl, and -NR₃₇R₃₈; X₂ is selected from -C_1-6alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci.₆alkyl-N R₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR^d-ealkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR39R40;

Ar-ι , Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ 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 , Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-

Het-ι , Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₉, Het₁₀, and Het₁₂ 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 , Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₉, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, - OCi-₆alkyl, -SCi_₆alkyl, =0,

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, 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; wherein

R-i and R₄₁ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN , -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι ; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to

3 substituents selected from -halo, -OH, -NR-n R₁₂, -0-Ci_₆alkyl, and -S-Ci_₆alkyl;

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=O)-NR₂₉R₃₀, -(C=S)-NR₂₉R₃₀, -C₃.₆cycloalkyl -Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃-₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl and -S0₂-Ci.₆alkyl; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_₆alkyl, -S-Ci_₆alkyl , -C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

R₄ is independently selected from -halo, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl , -NR₁₇R₁₈, -C₃.₆cycloalkyl, -Ar₈ and -Het₄;

- (C=0)-C₂.₆alkenyl, -(C=0)-0-C₁.₆alkyl , -(C=0)-Het₆, -(C=0)-Ar₆, -(C=0)-C₃.₆cycloalkyl, -(C=0)- NR₃iR₃₂, -(C=0)-NR₃₁-(C=0)-R₃₂, -(C=S), -(C=S)-C₁.₆alkyl , -(C=S)-C₂.₆alkenyl, -(C=S)-0-d_ 6alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃.₆cycloalkyl, -(C=S)-NR₃₁R₃₂, -(C=S)-NR₃₁-(C=S)-R₃₂,

-Het₆, -Ar₆, and -C₃.₆cycloalkyl ;

wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from =0, -halo, -OH , -0-Ci_₆alkyl , -S-Ci_₆alkyl , -C₃.₆cycloalkyl, -Het₆, - Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)- NR₂₅R₂₆; and

wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_₆alkyl, =0, -halo, -OH , -0-Ci_₆alkyl , -S-Ci_₆alkyl, -Het₁₂, -Ar-n , and -NR₅₃R₅4, -(C=0)-NR₅₃R₅4, -NR₅5(C=0)-NR₅₃R54, -(C=S)-NR₅₃R₅4, and -NR₅₅(C=S)- Rg, R10, R11 , R"i₂, Ri₃, R14, R15, R16, Ri7> R18, Ri9, R20, R21 , R22, R25, R26, R27, R28, R29, R30, R31 , R32, R33, R37, R38, R39, R40, R44, R45, R48, R50, R53, R54 and R₅₅ are each independently selected from -H , -halo, =0, -OH , -Ci_₆alkyl , -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl , -Het₇, -Ar₅ and -NR₅₁R₅₂; R51 and R₅₂ are each independently selected from -H , -halo, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -C₃.₆cycloalkyl , -Ar₁₀ and -Het₁₀;

R₄₃ is selected from -H -Ci_₆alkyl, and -C₃.₆cycloalkyl ; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -O-C1- 6alkyl, -S-Ci_₆alkyl, -Het₅, -C₃.₆cycloalkyl -Ar₄, and -NR44R45;

A is selected from -(CH₂)_n-Y-(CH₂)_m-, -NR₆-;

X-i is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NR₃-d_₆alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₃-Ci.₆alkyl-; wherein each of said -d. 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -d_₆alkyl , -0-d_₆alkyl , -S-d_₆alkyl, -phenyl , and -NR₃₇R₃₈;

X₂ is selected from -d_₆alkyl-, -0-Ci.₆alkyl-, -S-Ci.₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci.₆alkyl-NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-d_₆alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-d_₆alkyl-, -(C=0)- NR₂-d-₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.6alkyl-NR₂-d.₆alkyl-; wherein each of said -d_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -d_₆alkyl , -0-d_₆alkyl, -S-d_₆alkyl , -phenyl and -NR₃₉R₄o; Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ 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 Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -

NR-19R20; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι , Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₁₀, and Het₁₂ 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 , Het₂, Het₃, He , Het₅, Het₆, Het₇, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, - OCi-₆alkyl, -SCi_₆alkyl, =0,

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

₆cycloalkyl and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆; R₄ is independently selected from -halo, -OH , -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl , -NR₁₇R₁₈,

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

R₆ is selected from -(C=0),

-

(C=0)-Ar₆, -(C=0)-C₃-₆cycloalkyl, -(C=0)-NR₃₁R₃₂, -(C=0)-NR₃₁-(C=0)-R₃₂, -(C=S), -(C=S)-d_ 6alkyl, -(C=S)-C₂-₆alkenyl, -(C=S)-0-C₁.₆alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃.₆cycloalkyl, -

(C=S)-NR₃₁R₃₂, -(C=S)-NR₃₁-(C=S)-R₃₂;

wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_₆alkyl, =0, -halo, -OH , -0-Ci_₆alkyl , -S-Ci_₆alkyl, -Het₁₂, -Ar-n , and -NR₅₃R₅4, -(C=0)-NR₅₃R₅4, -NR₅5(C=0)-NR₅₃R54, -(C=S)-NR₅₃R₅4, and -NR₅₅(C=S)- Rg, Rio, Rl 1 , Rl₂, Rl₃, Rl4, Rl5, Rl6, Rl7> Rl8> Rl9> R20, ¾1 > 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-₆alkyl, -0-Ci_₆alkyl , -S-Ci_₆alkyl , -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl , -Het₇, -Ar₅ and -NR₅₁R₅₂; R₅i and R₅₂ are each independently selected from -H , -halo, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -C₃.₆cycloalkyl , -Ar₁₀ and -Het₁₀;

A is selected from -NR₆-;

X-i is selected from -C_1-6alkyl-, -0-Ci_₆alkyl-, -S-Ci_-6alkyl-, -(C=0)-, -NR₃-(C=0)-, -C-,-₆alkyl-NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NR₃-Ci_-6alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₃-Ci.₆alkyl-; wherein each of said -Ci_

₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -Ci_-6alkyl , -0-Ci_-6alkyl , -S-Ci_-6alkyl, -phenyl , and -NR₃₇R₃₈;

X₂ is selected from -C_1-6alkyl-, -0-Ci_-6alkyl-, -S-Ci_-6alkyl-, -(C=0)-, -NR₂-(C=0)-, -C-,-₆alkyl-NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-Ci_-6alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said

-Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -Ci_₆alkyl , -0-Ci_₆alkyl, -S-Ci_₆alkyl , -phenyl and -NR₃₉R₄₀;

Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ 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 Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -C-i_₆alkyl, -0-C-i_₆alkyl , -S-C-i_₆alkyl, and - NR₁₉R₂₀; wherein each of said -C-i_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-i , Het₂, Het₃, Het₄, Het₆, Het₇, Het₁₀, and Het₁₂ 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 , Het₂, Het₃, He , Het₆, Het₇, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0, -

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

R-i and R₄₁ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN , -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and

-Het-ι ; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R₁₂, -0-Ci_₆alkyl, and -S-Ci_₆alkyl;

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂₈, -(C=S)-NR₂₇R₂₈, -C₃-₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃.

-C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

R₆ is selected from -Ci_₆alkyl, -S0₂, -S0₂-Ci_₆alkyl, -S0₂-C₃.₆cycloalkyl, -Het₆, -Ar₆, and -C₃.

₆cycloalkyl;

wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -

NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆, and -N R₃₃(C=S)-NR₂₅R₂₆; and

wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_₆alkyl,-halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₁₂, -Ar-n , and - NR53 54,

and -NR₅5(C=S)-NR₅₃R5₄; Rg, R-io, Rl 1 , Rl2, Rl3, Rl4, Rl5, Rl6, l > Rl8> Rl9> F¾0, 2I , R∑2, R∑5, R∑6, R∑7, R28, R∑9, R30, R3I > F¾2,

R33, R37, R38, R39, R40, R44, R45, R48, R50, R53, R54 and R₅₅ are each independently selected from -H, -halo, =0, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅2;

6alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

A is selected from -(CH₂)n-Y-(CH₂)m-, -NR₆-;

X-i is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-N R₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NRs-C^alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-N R₃-Ci.₆alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from

X₂ is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl-N R₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR^d-ealkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R₄₀;

Y is -NR₄₃-;

Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ 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 Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and - NR₁₉R₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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, 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; wherein

R-i and R₄₁ are each independently selected from -H , -halo, -OH , -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN, -NR₉-S0₂-R₄, -C₃.₆cycloalkyl , -Ar₇ and -Het-ι; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -NR-nR₁₂, -0-Ci_₆alkyl, and -S-Ci_₆alkyl;

R₂ is selected from -H , -halo, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl,

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂8, -(C=S)-NR₂₇R₂₈, -C₃-₆cycloalkyl , -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-Ci_₆alkyl ; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_₆alkyl, -S-Ci_₆alkyl, -

Het₃, -Ar₂, and -NRi₃R_M;

R₃ is selected from -H , -halo, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl,

6alkyl, -(C=0)-0-C₁.₆alkyl , -(C=S)-0-C₁.₆alkyl , -(C=O)-NR₂₉R₃₀, -(C=S)-NR₂₉R₃₀, -C₃.₆cycloalkyl -Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_₆alkyl, -S-Ci_₆alkyl , -C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

R₅ is selected from -H , -OH , -halo, -Ci_₆alkyl, -0-Ci_₆alkyl , -S-Ci_₆alkyl, -Het₉, -Ar-ι, -C₃.₆cycloalkyl, - SOz-A^ , -S0₂, -S0₂-d_₆alkyl, -(C=0), -(C=0)-C₁.₆alkyl, -(C=S), -(C=S)-C₁.₆alkyl, -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.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Αη , -Het₉, and -NR₂₃R₂ ;

R₉, R-io, R11 , Ri₂, Ri₃, Ri₄, R15. R16. Ri7> R18. Ri9. R20, R21. R22. R23. R24. R27. R28. R29. R30. R37. R38.

R39, R40, R₄8, and R₅₀, are each independently selected from -H , -halo, =0, -OH , -Ci_₆alkyl, -O- Ci-₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, - OH , -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl , -Het₇, -Ar₅ and -NR₅₁R₅₂;

R51 and R₅₂ are each independently selected from -H , -halo, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -C₃.₆cycloalkyl , -Ar₁₀ and -Het₁₀;

A is selected from -(C=0)-NR₅-;

X-i is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NR₃-d_₆alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-d_₆alkyl-, -(C=0)- NR₃-Ci-₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci-₆alkyl-NR₃-Ci.₆alkyl-; wherein each of said -d. 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci.₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -phenyl, and -NR₃₇R₃₈;

X₂ is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci.₆alkyl-N R₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR^d-ealkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)-

NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R4o;

Ar-ι , Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ 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 , Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 - halo;

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

-Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₃, -Ar₂, and -NRi₃R_M; R₃ is selected from -H, -halo, -OH, -C_1-6alkyl, -0-Ci_-6alkyl, -S-Ci_-6alkyl,

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₉R₃o, -(C=S)-NR₂₉R₃o, -C₃-₆cycloalkyl -Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl and -S0₂-Ci_₆alkyl; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl,

-C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

R₅ is selected from -H, -OH, -halo, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₉, -Ar-ι , -C₃.₆cycloalkyl, - SOz-A^ , -S0₂, -S0₂-d_₆alkyl, -(C=0), -(C=0)-C₁.₆alkyl, -(C=S), -(C=S)-C₁.₆alkyl, -0-(C=0)-d_

₆alkyl,

Rg, Rio, Rl 1 , R"|₂, Rl₃, Rl4, Rl5, Rl6, Rl7_> Rl 8, Rl₉, R20, R∑1 , R∑2, R∑3, R∑4, R∑7, R28, R∑9, R30, R37, R38, R₃₉, R_40, R_48, and R₅₀, are each independently selected from -H , -halo, =0, -OH , -Ci_₆alkyl, -O-

A is selected from -(C=0)-NR₅-;

X₂ is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl-NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-d_₆alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-d_₆alkyl-, -(C=0)- NR₂-Ci-₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-d.₆alkyl-; wherein each of said -d_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_₆alkyl, -0-d_₆alkyl, -S-d_₆alkyl, -phenyl and -NR₃₉R₄₀;

Het-ι , Het₂, Het₃, Het₄, Het₇, Het₉, and Het₁₀ 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 , Het₂, Het₃, Het₄, Het₇, Het₉, and Het₁₀ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_₆alkyl, -Od_₆alkyl, -Sd_₆alkyl, =0, -

and -NR₂₁R₂₂; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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

3 substituents selected from -halo, -NR-nR₁₂, and -S-Ci_₆alkyl;

wherein R-i and R₄₁ are not simultaneously -H

-C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

R₆ is selected from -(C=0),

-

(C=0)-Ar₆, -(C=0)-C₃.₆cycloalkyl, -(C=0)-NR₃₁R₃₂, -(C=0)-NR₃₁-(C=0)-R₃₂;

wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, -

Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-

NR₂₅R₂₆; and

wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_₆alkyl, =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₁₂, -Ar-n, and -NR53R54, -(C=0)-NR₅₃R₅4, -NR₅5(C=0)-NR₅3R54, -(C=S)-NR₅₃R₅4, and -NR₅₅(C=S)-

Rg, R10, R11 , R12, Rl3, Rl4, Rl5, Rl6, Rl7> Rl8, Rl9, R20, R∑1 , R∑2, R∑5, R∑6, R∑7, R28, R∑9, R₃0, R₃1 , R₃2,

R33, R37, R38, R39, R40, R48, R50, R53, R54 and R55 are each independently selected from -H, - halo, =0, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅2; R₅₁ and R₅₂ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

A is -NR₆-;

X-i is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-N R₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NRs-d-ealkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-N R₃-Ci.₆alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -phenyl, and -NR₃₇R₃₈;

X₂ is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl-N R₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-d_₆alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci.₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -phenyl and -NR₃₉R₄o;

Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ 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 Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and - NR₁₉R₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι , Het₂, Het₃, Het₄, Het₆, Het₇, Het₁₀, and Het₁₂ 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 , Het₂, Het₃, He , Het₆, Het₇, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0, -

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

R-i and R₄₁ are each independently selected from -H, -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN , -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι ; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂8, -(C=S)-NR₂₇R₂₈, -C₃-₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₃, -Ar₂, and -NRi₃R_M;

R₅ is selected from -H, -OH, -halo, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₉, -Ar-ι , -C₃.₆cycloalkyl, - SOz-A^ , -S0₂, -SOz-d-ealkyl, -(C=0), -(C=0)-C₁.₆alkyl, -(C=S), -(C=S)-C₁.₆alkyl, -0-(C=0)-d_ 6alkyl,

wherein each of said - Ci-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Αη , -Het₉, and -NR₂₃R₂ ;

R₉, R-io, R11 , Ri₂, Ri₃, Ri₄, Ri5, R16, Ri7> R18, Ri9, R20, R21 , R22, R23, R24, R27, R28, R29, R30, R37, R38, R39, R40, R₄8, and R₅₀, are each independently selected from -H , -halo, =0, -OH , -Ci_₆alkyl, -O- Ci-₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, - OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅₂;

A is selected from -(C=0)-NR₅-; Xi is -Ci-6alkyl-NR₃-Ci-6alkyl-; wherein each of said -d-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S- Ci-₆alkyl, -phenyl, and -NR₃7R₃₈;

X₂ is selected from -C_1-6alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci.₆alkyl-NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR^d-ealkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)-

Ar-ι, Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ 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, Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 - halo;

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

wherein R-i and R₄₁ are not simultaneously -H

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂8, -(C=S)-NR₂₇R₂8, -C₃-₆cycloalkyl,

-Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-Ci_₆alkyl; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₃, -Ar₂, and -NRi₃R_M;

R₆ is selected from -(C=0),

Rg, R10, R11 , Ri₂, R"i₃, R14, R15, R16, Ri9, R20, R21 , R22, R25, R26, R27, R28, R29, R30, R31 , R32, R33, R37, R₃₈, R₃₉, R₄₀, R48, R50, R53, R54 and R₅₅ are each independently selected from -H, -halo, =0, - OH, -Ci-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -

Ci-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅₂;

A is -NR₆-;

X-i is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-N R₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NRs-C^alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-N R₃-Ci.₆alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -phenyl, and -NR₃₇R₃₈; X₂ is selected from -C_1-6alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci.₆alkyl-N R₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR^d-ealkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR39R40;

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

wherein R-i and R₄₁ are not simultaneously -H

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂₈, -(C=S)-NR₂₇R₂₈, -C₃.₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₃, -Ar₂, and -NR₁₃R₁₄;

R₄ is independently selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -NR₁₇R₁₈, -C₃.₆cycloalkyl, -Ar₈ and -Het₄;

R₅ is selected from -H, -OH, -halo, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₉, -Ar-ι , -C₃.₆cycloalkyl, - SOz-A^ , -S0₂, -SOz-C_Lealkyl, -(C=0), -(C=0)-C₁.₆alkyl, -(C=S), -(C=S)-C₁.₆alkyl, -0-(C=0)-d_ 6alkyl,

Rg, Rio, Rl 1 , Rl2. Rl3. Rl4, Rl5, Rl6, Rl > Rl8, Rl9. R∑0. R∑1. R∑2. R∑3. R∑4. R∑7. R∑8. R∑9. R30. R37. R38.

R39, R40, R48, and R₅₀, are each independently selected from -H , -halo, =0, -OH , -Ci_₆alkyl, -O- Ci-₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, - OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅₂;

A is selected from -(C=0)-NR₅-;

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; for 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, myelin-related disorders, neurological disorders and cancer; wherein:

R-i and R₄₁ are each independently selected from -H, -halo, -OH, -d-₆alkyl, -S-Ci_₆alkyl, -NR₉R₁₀, - (C=0)-R₄, -(C=S)-R₄, -SO2-R4, -NR9-SO2-R4, -C₃.₆cycloalkyl, -Ar₇ and -Het, ; wherein each of said -Ci-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -NR-n R₁₂, and -S-Ci_₆alkyl;

wherein R-i and R₄₁ are not simultaneously -H

R₆ is selected from -(C=0),

wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_₆alkyl, =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₁₂, -Ar-n , and -NR₅₃R₅₄,

and -NR₅₅(C=S)-

Rg, R10, R11 , Ri₂, Ri₃, R"i₄, R15, R16, R19, R20, R21 , R22, R25, R26, R27, R28, R29, R30, R31 , R32, R33, R37, R₃₈, R₃₉, R₄₀, R₄8, R50, R53, R54 and R₅₅ are each independently selected from -H, -halo, =0, - OH, -Ci-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said - Ci-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci.₆alkyl, -S-d-₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁R₅₂;

A is -NR₆-;

X-i is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NRs-d-ealkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₃-Ci.₆alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from

Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ 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 Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -

NR₁₉R₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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; for 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, myelin-related disorders, neurological disorders and cancer; wherein:

A₂ is C, and A-i is N; R-ι and R₄₁ are each independently selected from -H , -halo, -OH , -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN, -NR₉-S0₂-R₄, -C₃.₆cycloalkyl , -Ar₇ and -Het-ι ; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -NR-nR₁₂, -0-Ci_₆alkyl, and -S-Ci_₆alkyl;

wherein R-i and R₄₁ are not simultaneously -H

Het₃, -Ar₂, and -NRi₃R_M;

R₅ is selected from -H , -OH , -halo, -d.₆alkyl, -0-d.₆alkyl , -S-d.₆alkyl, -Het₉, -Αη , -C₃.₆cycloalkyl, - SOz-A^ , -SO2, -S0₂-d_₆alkyl, -(C=0), -(C=0)-C₁.₆alkyl, -(C=S), -(C=S)-C₁.₆alkyl, -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-d-₆alkyl, -S-d_₆alkyl, -C₃.₆cycloalkyl, -Αη , -Het₉, and -NR₂₃R₂ ;

Rg, R10, R11 , R12. Rl3. Rl4. Rl5. Rl6, Rl > Rl8> Rl9. R∑0. R∑1. R∑2. R∑3. R∑4. R∑7. R∑8. R∑9. R30. R37. R38.

R39, R40, R₄8, and R₅₀, are each independently selected from -H , -halo, =0, -OH , -d_₆alkyl, -O- Ci-₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -d_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, - OH , -0-d_₆alkyl, -S-d_₆alkyl, -C₃.₆cycloalkyl , -Het₇, -Ar₅ and -NR₅₁R₅₂;

R₅i and R₅₂ are each independently selected from -H , -halo, -OH , -d_₆alkyl, -0-d_₆alkyl, -S-Ci_ 6alkyl, -C₃.₆cycloalkyl , -Ar₁₀ and -Het₁₀;

A is selected from -(C=0)-NR₅-;

Xi is -Ci.6alkyl-NR₃-Ci.₆alkyl-; wherein each of said -d_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -d_₆alkyl , -0-d_₆alkyl, -S- Ci_₆alkyl, -phenyl, and -NR₃₇R₃₈;

X₂ is selected from -d_₆alkyl-, -0-Ci.₆alkyl-, -S-Ci.₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci.₆alkyl-NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-d_₆alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-d_₆alkyl-, -(C=0)- NR₂-Ci-₆alkyl-, -0-d-₆alkyl-0-d-₆alkyl- and -Ci.6alkyl-NR₂-d.₆alkyl-; wherein each of said -d_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -d_₆alkyl , -0-d_₆alkyl, -S-d_₆alkyl , -phenyl and -NR₃₉R₄₀; Ar-ι, Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ 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, Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂o; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 - halo;

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

In a further embodiment, the present invention provides a compound or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, said compound being selected from the list comprising:

The present invention also provides a compound or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof; for 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; said compound being selected from the list comprising:

In particular in the compounds according to this invention, the pyrazolopyrimidine or the imidazopyridazine moiety is linked to the aryl or heteroaryl moiety at position Z₄ or Z₅, in accordance with the numbering as provided in Formula I. Furthermore, the R-i of the compounds according to this invention is preferably linked to the aryl or heteroaryl moiety at position Z-i , Z₂ or Z₃, in accordance with the numbering as provided in Formula I.

In a particular embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention, for use in the prevention and/or treatment of a Activin-like receptor kinase associated disorder; more in particular for use use in the prevention and/or treatment of a ALK1 or ALK2-kinase associated disorder.

In a specific embodiment, the present invention provides a pharmaceutical composition for use in the prevention and/or treatment of a Activin-like receptor kinase associated disorder; more in particular for use use in the prevention and/or treatment of a ALK1 or ALK2-kinase associated disorder.

In the context of the present invention, the most interesting compounds are compounds according to formula I, or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N- oxide form, or solvate thereof wherein A is selected from -(CH₂)n-Y-(CH₂)m-, -(C=0)-NR₅-, - NR₆-; and Y is -NR₄₃-. A particularly preferred group of compounds are compounds of formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof wherein A is selected from -(CH₂)n-Y-(CH₂)m-, -NR₆-; and Y is -NR₄₃-. More in particular, a preferred group of compounds are compounds of formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof wherein the following restrictions apply:

A is selected from -(CH₂)n-Y-(CH₂)m-, -NR₆-;

R₆ is selected from -C_1-6alkyl, -S0₂, -S0₂-Ci_₆alkyl, -S0₂-C₃.₆cycloalkyl, -(C=0),

- (C=0)-C₂.₆alkenyl, -(C=0)-0-C₁.₆alkyl, -(C=0)-Het₆, -(C=0)-Ar₆, -(C=0)-C₃-₆cycloalkyl, -(C=0)-

NR31 R32, -(C=0)-NR₃₁-(C=0)-R₃₂, -(C=S), -(C=S)-C₁.₆alkyl, -(C=S)-C₂.₆alkenyl, -(C=S)-0-d_ 6alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃.₆cycloalkyl, -(C=S)-NR₃₁R₃₂, -(C=S)-NR₃₁-(C=S)-R₃₂, -Het₆, -Ar₆, and -C₃.₆cycloalkyl;

Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)- NR₂₅R₂₆; and

wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_₆alkyl, =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₁₂, -Ar-n , and -NR₅₃R₅4, -(C=0)-NR₅₃R₅4, -NR₅5(C=0)-NR₅₃R54, -(C=S)-NR₅₃R₅4, and -NR₅₅(C=S)- Y is -NR₄₃-;

R₄₃ is selected from -H -Ci_₆alkyl, and -C₃.₆cycloalkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1- 6alkyl, -S-Ci_₆alkyl, -Het₅, -C₃.₆cycloalkyl -Ar₄, and -NR44R45;

Xi is -0-Ci_₆alkyl-; and

X₂ is -NR₂-Ci.₆alkyl.

In particular, we identified 2 further preferred groups of compounds, i.e. compounds having a central amine, or compounds having a central external amide.

Compound having a central amine are compounds wherein the following restrictions apply:

A is selected from -(CH₂)_n-Y-(CH₂)_m-, -NR₆-;

6cycloalkyl;

wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, - NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; and wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_₆alkyl,-halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₁₂, -Ar-n, and - NR53 54, -NR₅₅(C=0)-NR53R54, -(C=S)-NR₅₃R₅4, and -NR₅5(C=S)-NR₅3R54; R₄₃ is selected from -H -d-₆alkyl, and -C₃.₆cycloalkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1- 6alkyl, -S-Ci_₆alkyl, -Het₅, -C₃.₆cycloalkyl -Ar₄, and -NR44R45.

Compound having a central external amide are compounds wherein the following restrictions apply: A is -NR₆-;

R₆ is selected from -(C=0),

- (C=0)-Ar₆, -(C=0)-C₃-₆cycloalkyl, -(C=0)-NR₃₁R₃₂, -(C=0)-NR₃₁-(C=0)-R3₂, -(C=S), -(C=S)-d_ 6alkyl, -(C=S)-C₂.₆alkenyl, -(C=S)-0-C₁.₆alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃-₆cycloalkyl, - (C=S)-NR₃₁R₃₂, -(C=S)-NR₃₁-(C=S)-R₃₂;

In said compounds having a central amine or central external amide, preferably also X-i is -O-C1- 6alkyl- and X₂ is -NR₂-Ci.₆alkyl.

Further to said series of compounds having a central amine or central external amide, we identified a further interesting group of compounds, having a central internal amide. Said compounds are characterized by the following restrictions:

A is selected from -(C=0)-NR₅-;

R₅ is selected from -H, -OH, -halo, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₉, -Ar-ι, -C₃.₆cycloalkyl, - SOz-A^ , -SO2, -S0₂-d_₆alkyl, -(C=0), -(C=0)-C₁.₆alkyl, -(C=S), -(C=S)-C₁.₆alkyl, -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.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Αη , -Het₉, and -NR₂₃R₂₄;

It should be noted that the central internal amide, can be present in both direction, i.e. with -(C=0)- directed to the X-i or X₂ part of the molecules. In said compounds having a central internal amide, preferably also:

Xi is -Ci-₆alkyl-NR₃-Ci-₆alkyl-; wherein each of said -d-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S- Ci-₆alkyl, -phenyl, and -NR₃7R₃₈; and

X₂ is -N R₂-Ci.₆alkyl.

In a further embodiment, the present invention provides the use of a compound, or a pharmaceutical composition as defined herein, for inhibiting the activity of a kinase, more in particular for inhibiting the activity of an Activin-like receptor kinase, in particular an ALK1 or ALK2 kinase.

The present invention also provides a method for the prevention and/or treatment of an Activin-like receptor kinase associated disease selected from the list comprising disorders characterized by abnormal bone formation or anemia-related disorders; said method comprising administering to a subject in need thereof a compound of formula I or a composition comprising such compound, wherein

R₅ and R₇ are each independently selected from -H, -OH, -halo, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -Het₉, -Ar-, , -C₃.₆cycloalkyl, -S0₂-Ar-, , -S0₂, -S0₂-Ci_₆alkyl, -(C=0),

wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar-ι, -Het₉, and -NR23R24;

- (C=0)-C₂-₆alkenyl, -(C=0)-0-C₁.₆alkyl, -(C=0)-Het₆, -(C=0)-Ar₆, -(C=0)-C₃-₆cycloalkyl, -(C=0)- NR₃₁R₃₂, -(C=0)-NR₃₁-(C=0)-R₃₂, -(C=S), -(C=S)-C₁.₆alkyl, -(C=S)-C₂.₆alkenyl, -(C=S)-0-d_

₆alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃.₆cycloalkyl, -(C=S)-NR₃₁R₃₂, -(C=S)-NR₃₁-(C=S)-R₃₂, -Het₆, -Ar₆, and -C₃.₆cycloalkyl;

NR₂₅R₂₆; and

Rg, R10, R11, Ri₂, R"i₃, Ri₄, R15. 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_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁R₅₂;

6alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

A is selected from -(CH₂)_n-Y-(CH₂)_m-, -(C=0)-, -(C=S)-, -(C=N)-R₄₉-, -(S0₂)-, -S0₂-NR₅-, -(C=0)-

, and -CHR₈- ;

Xi is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NRs-d-ealkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₃-Ci.₆alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci.₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -phenyl, and -NR₃₇R₃₈; X₂ is selected from -C_1-6alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci.₆alkyl-NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR^d-ealkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR39R40;

Y is selected from a direct bond, -CHR₄₂-, -0-, -S-, and -NR₄₃-;

Ar-ι , Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, Ar₁₀ 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 , Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-

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

The present invention also provides a method for the 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; said method comprising administering to a subject in need thereof a compound of formula I or a composition comprising such compound, wherein

-Het-ι ; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -NR-n R₁₂, and -S-Ci_₆alkyl;

wherein R-i and R₄₁ are not simultaneously -H

-C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

R₆ is selected from -(C=0), -(C=0)-C-,-₆alkyl, -(C=0)-C₂.₆alkenyl, -(C=0)-0-C-,-₆alkyl, -(C=0)-Het₆, - (C=0)-Ar₆, -(C=0)-C₃.₆cycloalkyl, -(C=0)-NR₃₁ R₃₂, -(C=0)-NR₃₁-(C=0)-R₃₂;

Rg, R10, R11 , Ri₂, R"i₃, Ri4. Ri5. R16. Ri7> i 8> i9> R20, R21 , R22, R25, R∑6. R27, R28. R29. R30. R31 . R32.

R₃₃, R₃₇, R₃₈, R₃9, R40, R48, R50, R53, R54 and R₅₅ are each independently selected from -H, - halo, =0, -OH, -Ci-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅₂; R₅₁ and R₅₂ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

A is -NR₆-;

X-i is selected from -Ci_₆alkyl-, -0-C-,-₆alkyl-, -S-C-,-₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-N R₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NRs-C^alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-N R₃-Ci.₆alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from

X₂ is selected from -Ci_₆alkyl-, -0-C-,-₆alkyl-, -S-C-,-₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl-N R₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR^d-ealkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R₄₀;

Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ 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 Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C-i_₆alkyl, -0-C-i_₆alkyl, -S-C-i_₆alkyl, and - NR-19R20; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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

The present invention also provides a method for the 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; said method comprising administering to a subject in need thereof a compound of formula I or a composition comprising such compound, wherein

R-i and R₄₁ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -S-Ci_₆alkyl, -NR₉R₁₀, - (C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -N R₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-, ; wherein each of said -Ci-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -NR-n R₁₂, and -S-Ci_₆alkyl;

wherein R-i and R₄₁ are not simultaneously -H

R₆ is selected from -(C=0),

- (C=0)-Ar₆, -(C=0)-C₃.₆cycloalkyl, -(C=0)-NR₃₁ R₃₂, -(C=0)-NR₃₁-(C=0)-R₃₂; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, - Ar₆, -NR₂₅R₂6, -(C=0)-NR₂₅R₂6, -NR₃3(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)- NR₂₅R₂₆; and

Rg, R-io, Ri i , Ri₂, Ri₃, Ri4, Ri5, Ri6, Ri9, R20, R21 , R22, R25, R26, R27, R28, R29, R30, R31 , R32, R33, R37, R₃₈, R₃9, R40, R48, R50, R53, R54 and R₅₅ are each independently selected from -H, -halo, =0, -

OH, -Ci-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said - Ci-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅₂;

A is -NR₆-;

X-i is selected from -Ci_₆alkyl-, -0-C-,-₆alkyl-, -S-C-,-₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-N R₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NRs-d-ealkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-N R₃-Ci.₆alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from

X₂ is selected from -C-|.₆alkyl-, -0-Ci_₆alkyl-, -S-d.₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -d.₆alkyl-N R₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-d_₆alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R₄₀;

Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ 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 Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C-i_₆alkyl, -0-C-i_₆alkyl, -S-C-i_₆alkyl, and -

NR₁₉R₂₀; wherein each of said -C-i_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-i , Het₂, Het₃, Het₄, Het₆, Het₇, Het₁₀, and Het₁₂ 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 , Het₂, Het₃, He , Het₆, Het₇, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C-i_₆alkyl, -OC-i_₆alkyl, -SC-i_₆alkyl, =0, -

m and n are each independently 1 , 2, 3, or 4 The present invention also provides a method for the 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; said method comprising administering to a subject in need thereof a compound of formula I or a composition comprising such compound, wherein said compound is selected from the list comprisin :

The compounds of the present invention can be prepared according to the reaction schemes provided in the examples hereinafter, but those skilled in the art will appreciate that these are only illustrative for the invention and that the compounds of this invention can be prepared by any of several standard synthetic processes commonly used by those skilled in the art of organic chemistry. METHOD OF TREATMENT

Compounds of formula (I) a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, are inhibitors of ALK2 kinase activity and are thus believed to be of potential use in the prevention and/or treatment of disorders associated with abnormal bone formation (e.g. FOP), anemia-related disorders (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. 1. Disorders associated with abnormal bone formation

1 .1 Fibrodysplasia Ossificans Progressiva (FOP)

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 (G617A; 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.

1 .2 Treatment of pathologic bone formation (Myositis Ossificans)

Heterotopic ossification may occur consequently to a traumatic injury (Cushner et al, Orthop.Rev., 1992, 21 :1319-26). By analogy with genetically-related ossification in FOP, the use of ALK2 inhibitors are likely to impair the development of pathologic bone tissues.

1 .3 Treatment of ectopic or maladaptive bone formation

Osteo-differentiation may be induced by exacerbated BMP signaling, which may lead to vascular calcification (Bostrom et al, J Clin Invest, 1993, 91 :1800-9; Tyson et al, Arterioscler Thromb Vase Biol, 2003, 23:489-494). The use of ALK1 /2 inhibitors, which inhibit the BMP-induced Smad signalling (Santivale et al, PLOS One, 2013, 8(4):e62721 ), is likely to be useful for the inhibition of the calcification process and avoid heavy cardiac and vascular surgery for valve replacement.

In other cases, where bone fracture occurs, the temporary use of such kinase inhibitors may be useful in the delaying of fracture healing and avoid maladaptive bone formation in case the patient's fracture cannot be reduced in a short timeframe.

2. Anemia-related diseases

Treatment of anemia, iron deficiency and anemia of chronic disease (ACD)

Dysregulation of iron homeostasis, a hallmark of anemia, can be consecutive to different diseases such as infections, cancer and rheumatologic diseases. BMP receptor type 1 , more specifically ALK2, were shown to influence Hepcidin expression, a key iron regulator (Steinbicker et al, Blood, 201 1 , 1 18(15):4224-30). Moreover, TMPRSS6 mutation (Iron-deficiency Anemia, ISBN:978-1 - 4649-8960-5) or high inflammatory cytokine levels (Wrighting et al, Blood, 2006, 108(9):3204-9) causes the elevation of Hepcidin level through BMP signalling pathway, which may led to severe iron deficiency. Since current therapeutic options for patients with ACD (perfusion, ESAs (erythropoiesis-stimulating agents) and/or iron intake) remain moderately effective, inhibition of Hepcidin expression by ALK2 inhibitors may provide an efficient treatment option to improve quality of life (QoL) and support response to underlying disease treatment (Coyne et al, Kidney Int, 201 1 , 80(3):240-4).

3. (Cardio)-vascular-related diseases

3.1 Treatment of systemic hypertension

BMPs are known to inhibit proliferation induce apoptosis in normal human PASMC (Pulmonary Arterial Smooth Muscle Cells). However, dysregulation of BMP signaling seems involved in down regulation of voltage-gated K+ (Kv) channels activity. Such lower activity is associated with pulmonary hypertension. Evaluation of the effect of BMP-2 on Kv (Fantozzi et al, Am.J. Physiol. Lung Cell. Mol. Physiol., 2006, 291 ±993-1004), support evidence that BMP-2- mediated apoptosis may induce activation of Kv channels. Therefore, the use of ALK1 /2 inhibitors, a privileged binding partner of BMP2 (Upton et al, Mol Pharm, 2008, 73(2):539-52), may be beneficial for the treatment of pulmonary vascular medial hypertrophy.

3.2 Treatment of pulmonary hypertension

Pulmonary hypertension is a rare lung disease characterized by a narrowing of pulmonary arteries, leading to short breath, chest pain, higher heart beat and tiredness. A study demonstrated that BMP4 is selectively upregulated in hypoxic mice's lungs (Frank et al, Circ.Res., 2005, 97:496-504). Additionally, in vivo studies showed a significant reduction of hypoxia induced by Smad 1/5/8 phosphorylation in BMP4-mutated transgenic mice. Therefore, the use of ALK2 inhibitors, which inhibit BMP4-induced Smad-1/5/8 phosphorylation (Santivale et al, PLOS One, 2013, 8(4):e62721 ), may provide an efficient treatment to patients suffering from pulmonary hypertension with no current therapeutic options.

3.3 Treatment of ventricular hypertrophy

Ventricular hypertrophy is a thickening of the ventricular wall, which could be the consequence of either stress or diseases as myocardial infarction, heart failure or hypertension. Upregulation of BMP10, a known ALK1 ligand (David et al, Blood, 2007, 109(5):1953-61 ), was observed in hypertrophic card io myocytes (Nakano et al, Heart and Circ. Physiol., 2007, 293(6):H3396-403). Therefore, inhibition of ALK1 may be useful for treating pathological ventricular hypertrophy.

3.4 Primary pulmonary hypertension

Primary pulmonary hypertension (PPH) is a rare disease of the lung characterized by a narrowing of the blood vessels in the lungs leading to higher blood pressure. Genomic sequencing highlighted the critical role of ALK1 in the development of pulmonary hypertension (Harrison et al, 2003, 40:865-71 ). Therefore the use of ALK1 inhibitors may provide a therapeutic option for such disease.

3.5 Rendu-Osler disease (HHT)

Rendu-Osler disease, also known as hereditary hemorrhagic telangiectasia (HHT) is an inherited rare disorder that affects the vascular system. HHT disease consists in the development of arteriovenous malformations in the skin, mucous membranes and key organs as brain, liver and lungs. These abnormal blood vessels are usually fragile and tend to cause bleeding and subsequently anemia. Mutations in the ALK1 gene were clearly associated with the development of HHT type 2 (Nature Genetics, 1996, 13:189-95), therefore the use of ALK1 inhibitors may provide a disease-modifying agent to treat such disease.

3.6 Treatment of atherosclerosis

This vascular disease is a slowly-progressing and complex disease for which several risk factors were identified to disturb normal blood flow such as smoking, high amount of fat, high blood pressure or high amount of sugar. It consists in the narrowing of the lumina artery space by the building of a plaque constituted by different substances present in the blood (cholesterol, fat, calcium, sugar). Since recent studies, inflammatory cause is commonly accepted and BMP4 was identified as an important factor in the first step of disease development (Sorescu et al, JBC, 2003, 278:31 128-31 135). Since ALK2 is involved in the BMP signaling used by BMP4 (Santivale et al, PLOS One, 2013, 8(4):e62721 ), the use of ALK2 inhibitors may provide a potential therapeutic option to patients in addition to lifestyle changes (dietary plan, physical activity).

4. Endocrinal disorders

Polycystic ovary syndrome (PCOS)

Polycystic ovary syndrome, also known as Stein-Leventhal syndrome, is an endocrinal disorder, which is symptomatic in 5-10% of women of reproductive age. Through the analysis of ACVR1/ALK2 variants in women with PCOS, it was shown a strong correlation between ACVR1 variants and high AMH (anti-Mulerian hormone) levels (Kevenaar et al, Human reprod., 2009, 24, 1 :241 -9). This study suggests that inhibition of ALK2 may restore the regulation of folliculogenesis and be an efficient treatment for PCOS patients. 5. Neurological disorders

Treatment of spinal cord injury

The damage of a part of the spinal cord is often a permanent injury, which results in the change in different body functions (sensations, strength... ). Elevated expression of BMP2/4 (co-localized around injury site) was shown to inhibit axonal regeneration, which was reversed with the use of a BMP antagonist (Matsuura et al, J. Neurochemistry, 2008, 105(4):1471 -9). Additionally, RGMa protein was shown to play an important role in axon regeneration (Hata et al, JBC, 2006, 173(1 ):47-58) and showed to mediate BMP signaling through Smad-1 /5/8. Since ALK2 is a key regulator of Smad 1/5/8 phosphorylation, the use of ALK2 inhibitors may provide useful treatment to patients with such disabling injury.

6. Immune modulation

Optimization of Treg production - immune modulation and use in transplantation

Evidence of synergistic effect of BMP2/4 and TGFb on Foxp3+ Treg induction through Smad signaling pathway was demonstrated (Lu et al, Eur J Immunol, 2010, 40:142-52). Therefore, ALK2 inhibitors are likely to improve Treg purity and yield, which may support the development of Treg- based therapies, notably for use in transplantation (Tang et al, J Mol Cell Biol, 2012, 4(1 ):1 1 -21 ).

7. Stem cell research

Stem cell research for in vitro and in vivo applications

BMP signaling is known to be involved in the embryogenic development, particularly in the differentiation of stem cells. The use of BMP type 1 receptor inhibitors (eg. ALK1/ALK2 inhibitors) are likely to avoid embryonic stem cell differentiation to maintain their pluripotency (Okita et al, Curr Stem Cell Res Ther, 2006, 1 :103-1 1 1 ). Additionally, the use of this type of inhibitors may be useful in the process of manipulation of stem cell differentiation, directing differentiation of pluripotent or progenitor cell populations.

8. Cancer

As described above, BMP signalling plays a key role in the epithelial-mesenchymal transition or EMT, which is a mechanism that regulates tumour metastasis. Recent studies have shown that endothelial-mesenchymal transition (EndMT) plays an essential role in the tumour microenvironment by generating carcinoma-associated fibroblasts and may be an essential mediator of cancer progression. 8.1 DIPG/mHGA:

Following recent genomic studies, ALK2 activating mutations are likely to be involved in pediatric midline high-grade astrocytoma (mHGAs) (Fontebasso et al, Nature Genetics, 2014, 46:462-6) and in diffuse intrinsic pontine glioma (DIPG) (Buczkowicz et al, Nature Genetics, 2014, 46:451 -6). These studies suggest that the inhibition of ALK2 may provide a treatment to young patients with no therapeutic option.

8.2 Solid tumor cancer

Malignant solid tumors require increasing amount of nutriments to sustain growth. Angiogenesis is a physiological process, which consists in the development of new blood vessels. This mechanism is usually promoted in solid tumors and constitutes a privileged target for novel therapies (Rosen, Cancer J, 2001 , 7(3):S120-8). ALK1 was identified as critical player in the pathological development of blood vessels (Cunha et al, 201 1 , 1 17(26):6999-7006). Additionally, recent studies highlighted the potential synergies of the combination of ALK1 with VEGFR inhibitors to inhibit solid tumor angiogenesis (Bhatt et al, Clin Cancer Res, 2014, 20(1 1 ):2838-45).

8.3 Ovarian cancer

STIP1 (tumor stress-induced phosphoprotein 1 ) was identified as prognostic biomarker in ovarian cancer (Chao et al, PLOSOne, 2013, 8(2):e57084). Furthermore, this protein activates ALK2-Smad signaling pathway to promote proliferation in this type of cancer (Tsai et al, Cell Reports, 2012, 2:283-93), probably through BMP9 signaling (Inman et al, Cancer Res, 2009, 69:9259. Therefore the use of ALK2 inhibitors may provide a useful treatment against ovarian cancer.

8.4 Lung cancer

BMP7 was shown to play an important role in the proliferation of lung cancer cells (Xu et al, Chinese J Lung Cancer, 2010, 13(7):659-64). Additionally, it was shown that BMP7 activates Smad 1 signaling pathway through ALK2 (Matias-Silva et al, JBC, 1998, 273(40):25628-36). Therefore the use of ALK2 inhibitor may provide a useful treatment against lung cancer.

8.5 Breast cancer

BMP4 and BMP7 were shown to play an important role in breast cancer (Takahashi et al, J Endocrinol, 2008, 199:445-55; Alarmo et al, Breast Cancer Res & Treat, 2007, 103(2):239-46). Additionally, it was shown that BMP7 activates Smad 1 signaling pathway through ALK2 (Matias- Silva et al, JBC, 1998, 273(40):25628-36). Therefore, the use of ALK2 inhibitors, which inhibit as well BMP4-induced Smad-1/5/8 phosphorylation (Santivale et al, PLOS One, 2013, 8(4):e62721 ), may provide a useful treatment against breast cancer.

8.6 Metastatic breast and prostate cancer

Overexpression of BMP2/4/7 was observed in metastatic prostate carcinoma (Bobinac et al, Croat Med J, 2005, 46(3):389-96), whereas only BMP7 could be observed in metastatic breast carcinoma. Since BMP signaling pathway involves Smad phosphorylation, the use of ALK1 /ALK2 inhibitors may be useful to inhibit signaling from BMPs (Santivale et al, PLOS One, 2013, 8(4):e62721 , Matias-Silva et al, JBC, 1998, 273(40):25628-36) and consequently provide a treatment against metastatic prostate and breast cancer. In the invention, particular preference is given to compounds of Formula I or any subgroup thereof that in the inhibition assay for ALK2 described below inhibit kinase activity with an IC₅₀ value of less than 10 μΜ, preferably less than 1 μΜ, most preferably less than 100 nM.

Said inhibition may be effected in vitro and/or in vivo, and when effected in vivo, is preferably effected in a selective manner, as defined above.

The term "ALK2 kinase-mediated condition" or "disease", as used herein, means any disease or other deleterious condition in which the ALK2 kinase and/or mutants thereof is/are known to play a role. The term " ALK2 kinase-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with an ALK2 kinase inhibitor. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which the ALK2 kinase is known to play a role.

The term "ALK1 kinase-mediated condition" or "disease", as used herein, means any disease or other deleterious condition in which the ALK1 kinase and/or mutants thereof is/are known to play a role. The term " ALK1 kinase-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with an ALK1 kinase inhibitor. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which the ALK1 kinase is known to play a role.

For pharmaceutical use, the compounds of the invention may be used as a free acid or base, and/or in the form of a pharmaceutically acceptable acid-addition and/or base-addition salt (e.g. obtained with non-toxic organic or inorganic acid or base), in the form of a hydrate, solvate and/or complex, and/or in the form or a pro-drug or pre-drug, such as an ester. As used herein and unless otherwise stated, the term "solvate" includes any combination which may be formed by a compound of this invention with a suitable inorganic solvent (e.g. hydrates) or organic solvent, such as but not limited to alcohols, ketones, esters and the like. Such salts, hydrates, solvates, etc. and the preparation thereof will be clear to the skilled person; reference is for instance made to the salts, hydrates, solvates, etc. described in US-A-6, 372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6, 372,733.

The pharmaceutically acceptable salts of the compounds according to the invention, i.e. in the form of water-, oil-soluble, or dispersible products, include the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalene-sulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. In addition, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl-bromides and others. Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.

Generally, for pharmaceutical use, the compounds of the inventions may be formulated as a pharmaceutical preparation or pharmaceutical composition comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.

By means of non-limiting examples, such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc.. Such suitable administration forms - which may be solid, semisolid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is again made to for instance US-A-6, 372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6, 372,733, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.

Some preferred, but non-limiting examples of such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, creams, lotions, soft and hard gelatin capsules, suppositories, eye drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. The formulations can optionally contain other pharmaceutically active substances (which may or may not lead to a synergistic effect with the compounds of the invention) and other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc.. The compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein, for example using liposomes or hydrophilic polymeric matrices based on natural gels or synthetic polymers. In order to enhance the solubility and/or the stability of the compounds of a pharmaceutical composition according to the invention, it can be advantageous to employ α-, β- or γ-cyclodextrins or their derivatives. An interesting way of formulating the compounds in combination with a cyclodextrin or a derivative thereof has been described in EP-A-721 ,331 . In particular, the present invention encompasses a pharmaceutical composition comprising an effective amount of a compound according to the invention with a pharmaceutically acceptable cyclodextrin.

In addition, co-solvents such as alcohols may improve the solubility and/or the stability of the compounds. In the preparation of aqueous compositions, addition of salts of the compounds of the invention can be more suitable due to their increased water solubility.

For local administration, the compounds may advantageously be used in the form of a spray, ointment or transdermal patch or another suitable form for topical, transdermal and/or intradermal administration.

More in particular, the compositions may be formulated in a pharmaceutical formulation comprising a therapeutically effective amount of particles consisting of a solid dispersion of the compounds of the invention and one or more pharmaceutically acceptable water-soluble polymers.

The term "a solid dispersion" defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components. When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase as defined in thermodynamics, such a solid dispersion is referred to as "a solid solution". Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered.

It may further be convenient to formulate the compounds in the form of nanoparticles which have a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm. Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.

Yet another interesting way of formulating the compounds according to the invention involves a pharmaceutical composition whereby the compounds are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition with good bio-availability which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration. Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof.

The preparations may be prepared in a manner known per se, which usually involves mixing at least one compound according to the invention with the one or more pharmaceutically acceptable carriers, and, if desired, in combination with other pharmaceutical active compounds, when necessary under aseptic conditions. Reference is again made to US-A-6, 372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733 and the further prior art mentioned above, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.

The pharmaceutical preparations of the invention are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use. Generally, such unit dosages will contain between 1 and 1000 mg, and usually between 5 and 500 mg, of the at least one compound of the invention, e.g. about 10, 25, 50, 100, 200, 300 or 400 mg per unit dosage.

The compounds can be administered by a variety of routes including the oral, rectal, ocular, transdermal, subcutaneous, intravenous, intramuscular or intranasal routes, depending mainly on the specific preparation used and the condition to be treated or prevented, and with oral and intravenous administration usually being preferred. The at least one compound of the invention will generally be administered in an "effective amount", by which is meant any amount of a compound of Formula or any subgroup thereof that, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered. Usually, depending on the condition to be prevented or treated and the route of administration, such an effective amount will usually be between 0.01 to 1000 mg per kilogram body weight day of the patient per day, more often between 0.1 and 500 mg, such as between 1 and 250 mg, for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg, per kilogram body weight day of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion. The amount(s) to be administered, the route of administration and the further treatment regimen may be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease/symptoms to be treated. Reference is again made to US-A- 6,372,778, US-A-6,369,086, US-A-6,369,087 and US-A-6,372,733 and the further prior art mentioned above, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.

In accordance with the method of the present invention, said pharmaceutical composition can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.

For an oral administration form, the compositions of the present invention can be mixed with suitable additives, such as excipients, stabilizers, or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions. Examples of suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, corn starch. In this case, the preparation can be carried out both as dry and as moist granules. Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof. Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.

When administered by nasal aerosol or inhalation, these compositions may be prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of the invention or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents. If required, the formulation can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant.

For subcutaneous administration, the compound according to the invention, if desired with the substances customary therefore such as solubilizers, emulsifiers or further auxiliaries are brought into solution, suspension, or emulsion. The compounds of the invention can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations. Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, in addition also sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of the various solvents mentioned. The injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1 ,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

When rectally administered in the form of suppositories, these formulations may be prepared by mixing the compounds according to the invention with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.

In preferred embodiments, the compounds and compositions of the invention are used orally or parenterally.

The invention will now be illustrated by means of the following synthetic and biological examples, which do not limit the scope of the invention in any way. EXAMPLES

A. Compound synthesis and phvsicochemical properties

The compounds of this invention can be prepared by any of several standard synthetic processes commonly used by those skilled in the art of organic chemistry. The compounds are generally prepared from starting materials which are either commercially available or prepared by standard means obvious to those skilled in the art.

General schemes:

As indicated herein before, the present invention provides compounds according to formula I, for use in the diagnosis, prevention and/or treatment of ALK1 /ALK2-kinase associated diseases:

With reference to the general reaction schemes suitable for preparing said compounds, these compounds can be represented by formula I, for which the general reaction schemes can be found herein below.

The compounds of formula (I) can also be prepared as shown in general scheme 4 below wherein a pyrazolo[1 ,5-a]pyrimidine or a imidazo[2,1 -f|pyridazine of formula (II) is converted by reaction with a compound of formula (VIII) into a compound of formula (IX). The compound of formula (IX) can be optionally be converted into a compound of formula (XII) which is then reacted with a (hetero-)aryl of formula (XIII) to form a compound of formula (XIV). The compound of formula (XIV) can then be optionally deprotected if desired before cyclisation to form a compound of formula (VII). The compound of formula (VII) can be optionally converted into a compound of general formula (I). Scheme 1

VI VII

In the above scheme:

LGi and LG₂ each independently represent suitable leaving or functional groups;

E represents a suitable functional group that can be used to form a direct bond between the (hetero-)aryl group and the scaffold.

D represents a functional group such as A or a protected functional group, which upon further reaction and/or deprotection produces a functional group such as A as defined in formula I;

X₃ and X₄ together with the functional moiety to which they are attached represent an unprotected or a protected functional group which upon reaction (after deprotection) produce together X-i as defined in formula I;

In the above reaction of the compound of formula (II) with the compound of formula (III), the leaving groups LGi and LG₂ are advantageously a halo group such as a chlorine or a bromine group. The reaction can be affected by a substitution for example by treating the compound of formula (II) with the compound of formula (III) in an organic solvent such as acetonitrile with an appropriate base such as for example diisopropylethylamine at an elevated temperature for example under reflux.

Compounds of formula (III) can be either commercially acquired or obtained through various selective protection and deprotection steps.

The reaction of the compound with formula (V) with a (hetero-)aryl compound of formula (IV) is advantageously effected under Suzuki conditions using for example tetrakis(triphenylphosphine)palladium(0), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) and potassium phosphate tribasic in a solvent mixture such as 1 ,4-dioxane/water at an elevated temperature for example 80°C.

The resulting compound of formula (VI) can optionally be treated to remove any desired protecting groups for example tert-butyloxycarbonylamino groups can be converted to the parent free amino group and for example ester groups can be converted to the parent free carboxylic acid groups. Such deprotection can be effected in a conventional manner for example by treatment under acidic conditions for example using an aqueous 6N hydrochloric acid solution in a solvent such as acetonitrile at an elevated temperature for example 60°C.

The cyclisation of the compound of formula (VI) can be effected for example by treatment with diisopropyl azodicarboxylate and triphenylphosphine in a solvent such as toluene/MeTHF at for example 1 10°C.

The resulting compound of formula (VII) can optionally be treated to remove any desired protecting groups for example tert-butyloxycarbonylamino groups to be converted to the parent free amino group and can optionally be treated to introduce functional groups such as alkyls or acyls to form a compound of formula (I).

The resulting compound of formula (VII) can optionally be treated to reduce a functional group on the phenyl ring by a reducing agent such as lithium aluminium hydride to form a compound of formula (I).

Compounds P1 , P2 and P3 may be prepared according to the synthesis described in Scheme 1 . Scheme 2

XI VII

In the above scheme:

G and J represent functional groups or protected functional groups, which upon further reaction and/or deprotection produce a functional group such as D;

In the above reaction of the compound of formula (II) with the compound of formula (VIII), the leaving groups LGi and LG₂ are advantageously a halo group such as chlorine or bromine group. The reaction can be affected by a substitution for example by treating the compound of formula (II) with the compound of formula (VIII) in an organic solvent such as acetonitrile with an appropriate base such as for example diisopropylethylamine at an elevated temperature for example under reflux.

Compounds of formula (VIII) can be either commercially acquired or obtained through various selective protection and deprotection steps.

The reaction of the compound with formula (V) with a (hetero-)aryl compound of formula (IX) is advantageously effected under Suzuki conditions using for example tetrakis(triphenylphosphine)palladium(0), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) and potassium phosphate tribasic in a solvent mixture such as 1 ,4-dioxane/water at an elevated temperature for example 80°C.

The reaction of the compound with formula (X) with compound from formula (XI) can be effected under reducing amination conditions using for example sodium triacetoxyborohydride in presence of a base such as N,N-diisopropylethylamine.

The cyclisation of the compound of formula (XI) can be effected for example by treatment with O- (benzotriazol-1 -yl)-N,N ,N',N'-tetramethyluronium hexafluorophosphate (HBTU) and N ,N- diisopropylethylamine in a solvent such as Ν,Ν-dimethylformamide at for example room temperature.

Compounds P4, P5, P6, P7, P8, P9, P10 and P1 1 may be prepared according to the synthesis described in Scheme 2.

In the above scheme: LGi and LG₂ each independently represent suitable leaving or functional groups;

G represents a suitable functional group or protected functional group, which upon further reaction and/or deprotection produces a functional group such as K;

K and L represent functional groups or protected functional groups, which upon further reaction and/or deprotection produce a functional group such as D;

In the above reaction of the compound of formula (II) with the compound of formula (VIII) the leaving groups LGi and LG₂ are advantageously a halo group such as a chlorine or a bromine group. The reaction can be affected by a substitution for example by treating the compound of formula (II) with the compound of formula (VIII) in an organic solvent such as acetonitrile with an appropriate base such as for example diisopropylethylamine at an elevated temperature for example under reflux.

The compounds of formula (IX) can be deprotected using for example acidic conditions such as a 4N hydrochloric acid solution in methanol at room temperature.

The resulting deprotected compound can be reacted with for example 2-nitrobenzenesulfonyl chloride and triethylamine in a solvent such as dichloromethane at a temperature going from 0°C to room temperature.

The resulting compound can optionally be protected with a suitable protecting group such as a tert- butyloxycarbonylamino group in a conventional manner for example by treatment with di-tert-butyl dicarbonate in basic conditions using for example triethylamine and 4-(dimethylamino)pyridine in a solvent such as tetrahydrofuran at an elevated temperature such as under reflux.

The compound of formula (IX) can optionally be alkylated using for example iodomethane and cesium carbonate in a solvent such as Ν,Ν-dimethylformamide at a temperature such as room temperature.

The nitrobenzenesulfonyl can optionally be removed by treatment with for example thiophenol and cesium carbonate in a solvent such as Ν,Ν-dimethylformamide at for example room temperature.

The boronic ester of formula (XIII) can be obtained through for example Williamson reaction using for example potassium carbonate in a solvent such as acetonitrile at for example room temperature, followed by boronation through for example treatment with bis(pinacolato)diboron, [1 ,1 -bis(diphenylphosphino)ferrocene]dichloropalladium(ll) and potassium acetate in a solvent such as 1 ,4-dioxane at for example an elevated temperature such as 80°C. Some intermediate steps can be required to obtain the desired boronic esters.

The reaction of the compound with formula (XII) with a (hetero-)aryl compound of formula (XIII) is advantageously effected under Suzuki conditions using for example tetrakis(triphenylphosphine)palladium(0), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) and potassium phosphate tribasic in a solvent mixture such as 1 ,4-dioxane/water at an elevated temperature for example 80°C.

The resulting compound of formula (XIV) can optionally be treated to remove any desired protecting groups for example tert-butyloxycarbonylamino groups can be converted to the parent free amino group and for example ester groups can be converted to the parent free carboxylic acid groups. Such deprotection can be effected in a conventional manner for example by treatment under acidic conditions for example using an aqueous 6N hydrochloric acid solution in a solvent such as acetonitrile at an elevated temperature for example 60°C.

The cyclisation of the compound of formula (XIV) can be effected for example by treatment with O- (benzotriazol-1 -yl)-N,N ,N',N'-tetramethyluronium hexafluorophosphate (HBTU) and N ,N- diisopropylethylamine in a solvent such as Ν,Ν-dimethylformamide at for example room temperature.

The resulting compound of formula (VII) can optionally be treated to form a compound of formula (")^■

Compound B7 may be prepared according to the synthesis described in Scheme 3.

The above general processes are illustrated by the specific processes which are described in the patent applications WO2013/045653 A1 and WO2013/046029 A1 .

The compounds B7 and P1 may be prepared according to the specific methods described in the patent applications WO2013/045653 A1 and WO2013/046029 A1 .

Preparation of example P2

Preparation of intermediate 1

A solution of 3-bromo-5-chloropyrazolo[1 ,5-a]pyrimidine (15 g, 64.52 mmol), tert-butyl (2- aminoethyl)(2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate (23.64 g, 74.20 mmol) and N ,N- diisopropylethylamine (14.6 ml, 83.88mmol) in acetonitrile (200 ml) was stirred at 85°C for 10 hours. The solvent was removed under reduced pressure and the residue was dissolved in ethylacetate. The organic layer was washed with water and brine, dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 100% ethyl acetate). The product fractions were collected and the solvent was evaporated.

Yield: 32.1 g of intermediate 1 (96%)

LCMS method 1 : MH⁺ = 514/516, RT = 1 .412 min Preparation of intermediate 2

Di-tert-butyl dicarbonate (30 g, 137.26 mmol) was added to a solution of intermediate 1 (32.1 g, 62.39 mmol), triethylamine (25ml, 249.56mmol, 4.0eq) and 4-(dimethylamino)pyridine (0.38 g, 3.12 mmol) in tetrahydrofuran (200 ml). The mixture was stirred at 60°C for 4 hours. The solvent was removed under reduced pressure and the residue was dissolved in ethylacetate. The organic layer was washed with water and brine, dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 50% ethyl acetate). The product fractions were collected and the solvent was evaporated.

LCMS method 1 : MH⁺ = 636 (MW + Na), RT = 1 .659 min Preparation of intermediate 3

3-Chloro-5-hydroxybenzonitrile (230 mg, 1 .5 mmol) was dissolved in dimethoxyethane (5 ml). Bis(pinacolato)boron (419 mg, 1 .65 mmol) was added followed by tricyclohexylphosphine (40 mg, 0.15 mmol) and potassium acetate (221 mg, 2.25 mmol). The resulting suspension was purged with nitrogen, tris(dibenzylideneacetone)dipalladium(0) (37 mg, 0.04 mmol) was added and the mixture was heated in the microwave at 150°C for 1 hour. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 50% ethyl acetate). The product fractions were collected and the solvent was evaporated. The product was triturated with heptane and dried under reduced pressure.

Yield: 50 mg of intermediate 3 (70%)

LCMS method 1 : MH⁺ = 246, RT = 0.839 min

Preparation of intermediate 4

Intermediate 2 (2.0 g, 3.25 mmol) and intermediate 3 (1 .20 g, 4.88 mmol) were dissolved in a mixture of 1 ,4-dioxane/water (9:1 , 20 ml). 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) (95 mg, 0.2 mmol) and potassium phosphate tribasic (2.08 g, 9.75 mmol) were added. The reaction mixture was degassed by bubbling nitrogen gas through the mixture. Tetrakis(triphenylphosphine)palladium(0) (1 16 mg, 0.1 mmol) was added and the reaction mixture was stirred overnight under nitrogen atmosphere to 80°C. The reaction mixture was cooled to room temperature, water was added and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 50% ethyl acetate). The product fractions were collected and the solvent was evaporated. The product was triturated with diethylether and dried under reduced pressure.

Yield: 1 .427 g of intermediate 4 (67%)

LCMS method 1 : MH⁺ = 675, RT = 1 .519 min

Preparation of intermediate 5

Intermediate 4 (1 .417 g, 2.19 mmol) was dissolved in tetrahydrofuran (6.5 ml) and a 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (1 .15 ml, 4.38 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate and was washed with water. The organic layer dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 70% ethyl acetate). The product fractions were collected and the solvent was evaporated. The product was triturated with diethylether and dried under reduced pressure.

Yield: 980 mg of intermediate 5 (83%)

LCMS method 1 : MH⁺ = 561 (MW + Na), RT = 1 .045 min Preparation of intermediate 6

Diisopropyl azodicarboxylate (921 mg, 4.68 mmol) was dissolved in dry toluene (150 ml) under nitrogen atmosphere. The resulting solution was stirred at 90°C. A solution of triphenylphosphine (1 .23 g, 4.68 mmol) in toluene (50 ml) was added drop wise over a period of 1 hour and simultaneously with a suspension of intermediate 5 (840 mg, 1 .56 mmol) in 2- methyltetrahydrofuran (50 ml). The reaction mixture was stirred at 90°C for 1 hour. The mixture was cooled to room temperature, diluted with ethyl acetate and washed with water. The organic layer dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 90% ethyl acetate). The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 346 mg of intermediate 6 (42%)

LCMS method 1 : MH⁺ = 521 , RT = 1 .421 min

Preparation of intermediate 7

Intermediate 6 (346 mg, 0.66 mmol) was suspended in a 4N Hydrochloric acid in 1 ,4-dioxane (5 ml) and stirred at room temperature overnight, then at 45°C overnight. The reaction mixture was cooled to room temperature and diluted with diethyl ether. The solid was filtered and dried under reduced pressure at 50°C. The compound was obtained as the Hydrochloric acid salt.

Yield: 236 mg of intermediate 7 (100%)

LCMS method 2: MH⁺ = 321 , RT = 1 .780 min

Preparation of example P2

Intermediate 7 (55 mg, 0.15 mmol) was suspended in tetrahydrofuran. The mixture was cooled between 0°C and 5°C and lithium aluminium hydride (10 mg, 0.38 mmol) was added. The mixture was stirred at 0°C to 5°C for 1 hour and then allowed to warm to room temperature. The reaction mixture was stirred overnight at room temperature. Methanol and silica gel were added and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using dichloromethane/methanol/ammoniumhydroxide as eluents. The product fractions were collected and the solvent was removed under reduced pressure. The product was triturated with diethylether and dried under reduced pressure. Yield: 18 mg of example P2 (37%)

LCMS method 3: MH⁺ = 325, RT = 0.920 min

Preparation of example P3

3-fluoro-7-oxa-10,14,18,19,22-pentaazatetracyclo[13.5.2.1², .0¹ ,²¹]tricosa-

1 (21 ),2(23),3,5,15(22),16,19-heptaene is prepared following general scheme 1 and according to the procedures described in the patent a lication WO2014/140235 to obtain example G6.

A mixture of 3-fluoro-7-oxa-10,14,18,19,22-pentaazatetracyclo[13.5.2.1², .0¹ ,²¹]tricosa- 1 (21 ),2(23),3,5,15(22),16,19-heptaene (100 mg, 0.37 mmol), cyclobutylcarboxylic acid (40 mg, 0.41 mmol) and N,N-diisopropylethylamine (219 μΙ, 1 .29 mmol) was dissolved in N ,N- dimethylformamide (1 .1 ml). 0-(Benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) (167 mg, 0.44 mmol) was added and the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and methanol was added. The resulting solid was filtered and dried under reduced pressure.

Yield: 72 mg of example P3 (47%)

LCMS method 2: MH⁺ = 410, RT = 3.260 min

Preparation of example P4

Example P4 is prepared following general scheme 2 and according to the procedures described in the patent application WO2013/046029 for the synthesis of example 47.

Preparation of example P5

Example P5 is prepared following general scheme 2 and according to the procedures described in the patent application WO2013/046029 for the s nthesis of example 47.

Preparation of example P6

Example P6 is prepared following general scheme 2 and according to the procedures described in the patent application WO2013/046029 for the s nthesis of example 47.

Preparation of example P7

Example P7 is prepared following general scheme 2 and according to the procedures described in the patent application WO2013/046029 for the s nthesis of example 47.

Preparation of example P8

Example P8 is prepared following general scheme 2 and according to the procedures described in the patent application WO2013/046029 for the synthesis of example 47.

Preparation of example P9

Example P9 is prepared following general scheme 2 and according to the procedures described in the patent application WO2013/046029 for the synthesis of example 47.

Preparation of intermediate 8

Example P8 (140 mg, 0.38 mmol) was dissolved in a mixture dichloromethane/methanol (4:1 ; 1 .1 ml), triethylamine (159 μΙ_, 1 .14mmol) and 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (216 μΙ_, 1 .14mmol) were added and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxy borohydride (242 mg, 1 .14 mmol) was added and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the compound was without any further purification used in the next step.

Yield: 160 mg of intermediate 8 (79%)

LCMS method 2: MH⁺ = 531 , RT = 0.951 min Preparation of example P9

Intermediate 8 (160 mg, 0.3 mmol) was dissolved in a mixture of tetrahydrofuran/water (3 ml/mmol; 1 .8 ml). Acetic acid (6 ml/mmol; 1 .8 ml) was added drop wise at 0°C and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with an aqueous saturated sodium bicarbonate solution. The organic layers were dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 40% ethyl acetate). The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 19 mg of example P9 (15%)

LCMS method 2: MH⁺ = 417, RT = 1 .805 min

Preparation of example P10

Example P10 is prepared following general scheme 2

Preparation of intermediate 9

A solution of 3-bromo-5-chloropyrazolo[1 ,5-a]pyrimidine (2.0 g, 8.6mmol), 3-ethoxy-3-oxopropan-1 - aminium chloride (1 .45 g, 9.46 mmol) and N,N-diisopropylethylamine (2.25 ml, 12.9 mmol) in acetonitrile (30 ml) was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (400 ml). The organic layer was washed with an aqueous saturated sodium bicarbonate solution and water. The organic layer was dried, filtered and the solvent was removed under reduced pressure and the compound was without any further purification used in the next step.

LCMS method 1 : MH⁺ = 313/315, RT = 0.718 min

Preparation of intermediate 10

A solution of the intermediate 9 (8.6 mmol), di-tert-butyl dicarbonate (2.76 ml, 12.9 mmol), triethylamine (3.58 ml, 25.8 mmol) and 4-(dimethylamino)pyridine (210 mg, 1 .72 mmol) in 1 ,4- dioxane (30 ml) was stirred at 100°C for 12 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 15% ethyl acetate). The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 2.64 g of intermediate 10 (74%)

LCMS method 1 : MH⁺ = 413/415, RT = 1 .1 14 min

Preparation of intermediate 1 1

A solution of intermediate 10 (2.65 g, 6.41 mmol) in a mixture of 1 ,4-dioxane/water (4:1 ; 30 ml) was was degassed by bubbling nitrogen gas. 3-(Formylphenyl)boronic acid (1 .06 g, 7.05 mmol), tetrakis(triphenylphosphine)palladium(0) (371 mg, 0.32 mmol), 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl (Xphos) (305 mg, 0.64 mmol) and potassium phosphate tribasic (12.24 g, 19.23 mmol) were added under nitrogen atmosphere. The reaction mixture was stirred at 90°C for 12 hours. The solvent was removed under reduced pressure, ethyl acetate was added and the organic layer was washed with water. The organic layer was dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents. The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 1 .79 g of intermediate 1 1 (63%)

LCMS method 1 : MH⁺ = 339 (MW - Boc), RT = 1 .176 min

Preparation of intermediate 12

To a solution of intermediate 1 1 (1 .79 g, 4.08 mmol), tert-butyl (2-aminoethyl)carbamate (0.719 g, 4.49 mmol) and triethylamine (1 .70 ml, 12.24 mmol) in a mixture dichloromethane/methanol (4:1 ; 20 ml) was added sodium triacetoxyborohydride (3.89 g, 18.36 mmol) portion wise at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane and extracted with a 10% aqueous sodium bicarbonate solution. The organic layer was dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 50% ethyl acetate). The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 1 .339 g of intermediate 12 (56%)

LCMS method 1 : MH⁺ = 583, RT = 0.983 min

Preparation of intermediate 13

Intermediate 12 (1 .339 g, 2.3 mmol) was dissolved in a 4N Hydrochloric acid solution in 1 ,4- dioxane (10 ml). The reaction mixture was stirred at room temperature for 12 hours. A few drops of water and an aqueous Hydrochloric acid 37% solution were added. The mixture was stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The compound was without further purification used in the next step.

LCMS method 1 : MH⁺ = 383, RT = 0.404 min Preparation of intermediate 14

0-(Benzotriazol-1 -yl)-N,N,N',N'-tetramethyluroniurn hexafluorophosphate (HBTU) (2.617 g, 6.9 mmol) and N,N-diisopropylethylamine (8.01 ml, 46mmol) were dissolved in N,N-dimethylacetamide (70ml/mmol) and the mixture was stirred at room temperature for 10 minutes. A solution of intermediate 13 (2.3 mmol) in N,N-dimethylacetamide (69 ml) was added drop wise and the reaction mixture was stirred at room temperature for 1 hour. An aqueous saturated sodium bicarbonate solution was added and the product was extracted with n-butanol. The solvent of the combined organic layers was removed under reduced pressure and the compound was without further purification used in the next step.

LCMS method 1 : MH⁺ = 337, RT = 0.326 min

Preparation of intermediate 15

Intermediate 14 was protected with a t-butoxycarbonyl group to enable the purification of the compound.

Di-tert-butyl dicarbonate (753 μΙ, 3.45 mmol) and triethylamine (1 .6 ml, 1 1 .5 mmol) were added drop wise to a solution of intermediate 14 (2.30 mmol) in dichloromethane (20 ml). The solvent was removed under reduced pressure after the addition was completed. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate and dichloromethane and methanol as eluents. The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 563 mg of intermediate 15 (56%)

LCMS method 1 : MH⁺ = 437, RT = 0.829 min Preparation of intermediate 16

Intermediate 15 (563 mg, 1 .29 mmol) was dissolved in a 4N Hydrochloric acid solution in 1 ,4- dioxane (10 ml). The mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue was triturated with acetonitrile and filtered. The compound was without further purification used in the next step.

Yield: 89 mg of intermediate 16 (20%)

LCMS method 1 : MH⁺ = 337, RT = 1 .507 min Preparation of example P10

To a solution of intermediate 16 (459 mg, 1 .36 mmol) in methanol (4 ml) was added formaldehyde (37% in water; 552 μΙ, 6.8 mmol) then triethylamine (413 μΙ, 4.08 mmol). The mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (865 mg, 4.08 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. An aqueous saturated sodium bicarbonate solution was added and the product was extracted with dichloromethane. The combined organic layers were dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using dichloromethane and methanol as eluents (gradient elution from 0% to 10% methanol). The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 67 mg of example P10 (14%)

LCMS method 2: MH⁺ = 351 , RT = 1 .537 min Preparation of example P1 1

Preparation of intermediate 17

5-Bromo-2,3-difluorobenzaldehyde (3.56 g, 16.13 mmol), bis(pinacolato)boron (4.92 g, 19.36 mmol,) and potassium acetate (4.75 g, 48.39 mmol) were suspended in 1 ,4-dioxane (80 ml). The mixture was degassed for 10 minutes. Bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (661 mg, 0.81 mmol) was added and the mixture was heated at 85°C for 16 hours. The crude was filtered over celite and the compound was used without further purification in the next step.

Preparation of intermediate 18

To a solution of tert-butyl (2-aminoethyl)carbamate (5.0 g, 31 .21 mmol) and triethylamine (13.01 ml, 93.63 mmol) in dichloromethane (93 ml) was added 4-nitrobenzenesulfonyl chloride (7.61 g, 34.33 mmol) portion wise at 0°C. The reaction mixture was stirred at room temperature for 16 hours. Water was added and the mixture was extracted with dichloromethane. The combined organic layers were dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 40% ethyl acetate). The product fractions were collected and the solvent was evaporated.

Yield: 10.3 g of intermediate 18 (95%)

LCMS method 1 : MH⁺ = 368 (MW + Na), RT = 0.760 min Preparation of intermediate 19

To a solution of intermediate 18 (4.9 g, 14.19 mmol) in N ,N-dimethylacetamide (60 ml) was added cesium carbonate (5.08 g, 15.61 mmol). Methyl iodide (972 μΙ, 15.61 mmol) was added and the reaction mixture was stirred at 50°C for 16 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (200 ml) and washed with an aqueous saturated sodium bicarbonate solution. The organic layer was dried, filtered and the solvent was removed under reduced pressure. The compound was used without further purification in the next step.

LCMS method 1 : MH⁺ = 382, RT = 0.838 min Preparation of intermediate 20

To a solution of the intermediate 19 (14.19 mmol) in N,N-dimethylacetamide (45 ml) was added at room temperature cesium carbonate (6.94 g, 21 .29 mmol) and thiophenol (2.35 g, 21 .29 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography over silica gel using dichloromethane and methanol as eluents (gradient elution from 0% to 10% methanol). The product fractions were collected and the solvent was evaporated.

Yield: 2.2 g of intermediate 20 (88%) Preparation of intermediate 21

A mixture of 3-bromo-5-chloropyrazolo[1 ,5-a]pyrimidine (5.3 g, 22.80 mmol), intermediate 20 (4.37 g, 25.08 mmol) and N,N-diisopropylethylamine (8.84 ml, 68.40 mmol) in acetonitrile (70 ml) was stirred at 100°C for 16 hours. The mixture was cooled to room temperature and an aqueous saturated sodium bicarbonate solution was added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried, filtered and the solvent was removed under reduced pressure. The compound was without further purification used in the next step.

LCMS method 1 : MH⁺ = 370/372, RT = 0.866 min

Preparation of intermediate 22

A solution of intermediate 21 in a mixture of 1 ,4-dioxane/water (4:1 ; 20 ml) was degassed by bubbling nitrogen gas, intermediate 17 (1 .51 g, 8.15 mmol), 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl (Xphos) (0.195 g, 0.41 mmol), tetrakis(triphenylphosphine)palladium(0) (162 mg, 0.14 mmol) and potassium phosphate tribasic (7,19 g, 33.9 mmol) were added under nitrogen atmosphere. The reaction mixture was stirred at 100°C for 16 hours. The mixture was cooled to room temperature and water was added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 100% ethyl acetate). The product fractions were collected and the solvent was evaporated.

Yield: 1 .94 g of intermediate 22 (66%)

LCMS method 1 : MH⁺ = 432, RT = 1 .058 min Preparation of intermediate 23

To a solution of intermediate 22 (1 .94 g, 4.5 mmol), 3-ethoxy-3-oxopropan-1 -aminium chloride (829 mg, 5.4 mmol) and triethylamine (1 .88 mL, 13.5 mmol) in a mixture of dichloromethane/methanol (4:1 ; 13.5 ml) was added portion wise at room temperature sodium triacetoxyborohydride (2.55 g, 13.5 mmol). The mixture was stirred at room temperature for 48 hours. The reaction mixture was extracted with a mixture of dichloromethane and an aqueous saturated sodium bicarbonate solution. The organic layer was dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 100% ethyl acetate). The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 863 mg of intermediate 23 (36%)

LCMS method 1 : MH⁺ = 533, RT = 1 .062 min Preparation of intermediate 24

Intermediate 23 (863 mg, 1 .62 mmol) was dissolved in a 4N Hydrochloric acid solution in 1 ,4- dioxane (4.9 ml) at 0°C and the mixture was stirred at room temperature for 48 hours. A few drops of water and a 37% Hydrochloric acid solution were added and the reaction mixture was stirred at 100°C for 2 hours. The solvent was removed under reduced pressure. The compound was without further purification used in the next step.

LCMS method 1 : MH⁺ = 405, RT = 0.268 min Preparation of example P1 1

0-(Benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1 .84 g, 4.86 mmol) and N,N-diisopropylethylamine (5.64 ml, 32.4 mmol) were dissolved in N,N-dimethylacetamide (160 ml) The mixture was stirred at room temperature for 10 minutes. A solution of intermediate 24 (1 .62 mmol) in N ,N-dimethylacetamide (160 ml) was added drop wise and the reaction mixture was stirred at room temperature for 5 minutes. An aqueous saturated sodium bicarbonate solution was added and the water phase was extracted with ethyl acetate. The combined organic layers were dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 100% ethyl acetate). The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 350 mg of example P1 1 (56%)

LCMS method 2: MH⁺ = 387, RT = 1 .825 min

Table 1

Compound identification

Melting points

For the melting point determination of the compounds of the present invention, the following method was used.

Melting point method

For a number of compounds, melting points (m.p.) were determined in open capillary tubes on a Mettler FP62 apparatus. Melting points were measured with a temperature ranging from 50°C to 300°C , using a gradient of 10 °C/minute. The melting point value was read from a digital display and was not corrected.

Table 2: Melting points

* Not determined LCMS

For LCMS-characterization of the compounds of the present invention, the following method was used.

General procedure LCMS

All analyses were performed using an Agilent 61 10 series LC/MSD quadrupole coupled to an Agilent 1290 series liquid chromatography (LC) system consisting of a binary pump with degasser, autosampler, thermostated column compartment and diode array detector. The mass spectrometer (MS) was operated with an atmospheric pressure electro-spray ionisation (API-ES) source in positive ion mode. The capillary voltage was set to 3000 V, the fragmentor voltage to 70 V and the quadrupole temperature was maintained at 100°C. The drying gas flow and temperature values were 12.0 L/min and 350°C respectively. Nitrogen was used as the nebulizer gas, at a pressure of 35 psig. Data acquisition was performed with Agilent Chemstation software.

LCMS method 1

In addition to the general procedure LCMS: Analyses were carried out on a Phenomenex Kinetex C18 column (50 mm long x 2.1 mm i.d.; 1 .7 μιη particles) at 60°C, with a flow rate of 1 .5 mL/min. A gradient elution was performed from 90% (water + 0.1 % formic acid) / 10% Acetonitrile to 10% (water + 0.1 % formic acid) / 90% acetonitrile in 1 .50 minutes, then the final mobile phase composition was held for an additional 0.40 min. The standard injection volume was 2 μί. Acquisition ranges were set to 254 nm for the UV-PDA detector and 80-800 m/z for the MS detector.

LCMS method 2

In addition to the general procedure LCMS: Analyses were carried out on a YMC pack ODS-AQ C18 column (50 mm long x 4.6 mm i.d.; 3 μιη particles) at 35°C, with a flow rate of 2.6 mL/min. A gradient elution was performed from 95% (water + 0.1 % formic acid) / 5% Acetonitrile to 5% (water + 0.1 % formic acid) / 95% Acetonitrile in 4.80 minutes, then the final mobile phase composition was held for an additional 1 .00 min. The standard injection volume was 2 μί. Acquisition ranges were set to 190-400nm for the UV-PDA detector and 100-1400 m/z for the MS detector.

LCMS method 3

In addition to the general procedure LCMS: Analyses were carried out on a YMC pack ODS-AQ C18 column (50 mm long x 4.6 mm I.D..; 3 μιη particle size) at 35 °C, with a flow rate of 2.6 mL/min. A gradient elution was performed using ISET 2V1 .0 Emulated Agilent Pump G1312A V1 .0 from 94.51 % (Water + 0.1 % Formic acid)/5.49% Acetonitrile to 5% (Water + 0.1 % Formic acid)/95% Acetonitrile in 4.8 min; the resulting composition was held for 1 .0 min; from 5% (Water + 0.1 % formic acid)/95% Acetonitrile to 95% (Water + 0.1 % formic acid)/5% Acetonitrile in 0.2 min. The standard injection volume was 2 μί. Acquisition ranges were set to 190-400 nm for the UV- PDA detector and 100-1000 m/z for the TOF-MS detector.

Table 3: LCMS data

COMPOUND MASS (MH)⁺ RETENTION LCMS

NUMBER PEAK TIME (min) METHOD

B7 324 2.275 2

P1 451 .2 2.337 2

P2 325 0.920 3 P3 410.2 3.260 3

P4 365 1 .644 2

P5 365 1 .727 3

P6 365 1 .700 3

P7 365.1 1 .699 2

P8 372.9 1 .725 2

P9 417 1 .805 2

P10 351 1 .537 2

P1 1 387.0 1 .825 2

B. Kinase Activity Assay

The inhibition of ALK1 and ALK2 kinase was assessed using ALK1 and ALK2 recombinant protein in an in vitro peptide-based kinase assay.

Protocol

A radiometric protein kinase assay (³³PanQinase^® Activity Assay) is used for measuring the kinase activity. All assays are performed in 96-well FlashPlates™ from Perkin Elmer in a 50 μΙ reaction volume. The reaction cocktail is pipetted in 4 steps in the following order:

10 μ I of non-radioactive ATP solution (in H20)

25 μΙ of assay buffer/ [γ-³³Ρ]-ΑΤΡ mixture

5 μΙ of test sample in 10% DMSO

10 μ I of enzyme/substrate mixture

The assay contains 70 mM HEPES-NaOH pH 7.5, 3 mM MgCI₂, 3 mM MnCI₂, 3 μΜ Na- orthovanadate, 1 .2 mM DTT, 50 μg/ml PEG20000, ATP (3,0 μΜ), [γ-³³Ρ]-ΑΤΡ (approx. 5 x 10⁰⁵ cpm per well), protein kinase (5,6 nM) and substrate (GSK3(14-27)), 4,0 μg/50 μΙ).

The reaction cocktails were incubated at 30° C for 60 minutes. The reaction was stopped with 50 μΙ of 2 % (v/v) H3PO4, plates were aspirated and washed two times with 200 μΙ 0.9 % (w/v) NaCI. Incorporation of ³³Pi (counting of "cpm") was determined with a microplate scintillation counter. Compounds

The compounds are dissolved to 5 mM in DMSO. Where needed, solutions are sonicated in a bath sonicator. Table 4 provides the plC₅₀ values and % Remaining activity values at two concentrations (1 μΜ and 0,1 μΜ) of the compounds according to the invention, obtained using the above mentioned kinase assay. Table 4

+ indicates an IC50 > 1 μΜ, ++ indicates an IC50 of between 100 nM and 1 μΜ, and +++ indicates an IC50 < 100nM

* indicates a % remaining kinase activity above 50%, ** indicates a % remaining kinase activity below 50% ND = Not determined

Claims

C LAI MS

1 . A compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form or solvate thereof,

wherein:

wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar-ι, -Het₉, and -NR₂₃R₂₄;

R₆ is selected from -Ci_₆alkyl, -S0₂, -S0₂-Ci_₆alkyl, -S0₂-C₃.₆cycloalkyl, -(C=0), - (C=0)-C₂.₆alkenyl, -(C=0)-0-C₁.₆alkyl, -(C=0)-Het₆, -(C=0)-Ar₆, -(C=0)-C₃.₆cycloalkyl, -(C=0)- NR31 R32, -(C=0)-NR₃₁-(C=0)-R32, -(C=S), -(C=S)-C₁.₆alkyl, -(C=S)-C₂-₆alkenyl, -(C=S)-0-d_ 6alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃-₆cycloalkyl, -(C=S)-NR₃₁R₃₂, -(C=S)-NR₃₁-(C=S)-R3₂, -Het₆, -Ar₆, and -C₃.₆cycloalkyl;

wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, - Ar₆, -NR25R26, -(C=0)-NR₂₅R₂6, -NR₃₃(C=0)-NR₂₅R26, -(C=S)-NR₂₅R₂6, and -NR₃₃(C=S)- wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_₆alkyl, =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₁₂, -Ar-n, and -NR₅₃R₅4, -(C=0)-NR₅₃R₅4, -NR₅5(C=0)-NR₅₃R54, -(C=S)-NR₅₃R₅4, and -NR₅₅(C=S)-

R₈ is selected from -NR₃₄-(C=0)-R₃₅, -NR₃₄-(C=S)-R₃₅, -NR₃₆-(C=0)-NR₃₄R₃₅, -NR₃₆-(C=S)- NR34R35, -NR₃₄-(S0₂)-R₃5, -NR₃₄-(C=0)-0-R₃₅, -NR₃₄-(C=S)-0-R₃₅, -0-(C=0)-NR₃₄R₃₅, and -0-(C=S)-NR₃₄R₃₅;

Rg, R-io, R11, R12. Rl3. Rl4. Rl5. Rl6. Rl7> Rl 8, Rl9, R∑0. R∑1. R∑2. R∑3. R∑4. R∑5. R∑6. R∑7. R∑8. R∑9, 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_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁R₅₂;

6alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

, and -CHR₈- ;

X-i is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NRs-d-ealkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₃-Ci.₆alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci.₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -phenyl, and -NR₃₇R₃₈;

X₂ is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl-NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NRz-d-ealkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci-₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R₄₀; Y is selected from a direct bond, -CHR₄₂-, -0-, -S-, and -NR₄₃-;

Ar-ι, Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, Ar₁₀ 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, Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S- Ci-₆alkyl, and -NR₁₉R₂o; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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

2. A compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein:

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=O)-NR₂₉R₃₀, -(C=S)-NR₂₉R₃₀, -C₃.₆cycloalkyl -Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆; R₄ is independently selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -NR₁₇R₁₈, -C₃.₆cycloalkyl, -Ar₈ and -Het₄;

wherein each of said -d_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci_-6alkyl, -S-Ci_-6alkyl, -C₃.₆cycloalkyl, -Αη , -Het₉, and -NR₂₃R₂4;

R₆ is selected from -C_1-6alkyl, -S0₂, -S0₂-Ci_-6alkyl, -S0₂-C₃.₆cycloalkyl, -(C=0),

Rg, Rio, Rl 1 , Rl₂, R"|₃, Rl4. Rl5. Rl6. Rl7> l8> Rl9> R20, ¾1 > R∑2, R∑3, R∑4, R∑5. R∑6. R∑7. R∑8. R∑9. R30.

R31 , R32, R33, R37, R38, R39, R40, R44, R45, R48, R50, R53, R54 and R₅₅ are each independently selected from -H , -halo, =0, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅₂;

₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

₆alkyl, -S-Ci_₆alkyl, -Het₅, -C₃.₆cycloalkyl -Ar₄, and -NR44R45;

A is selected from -(CH₂)_n-Y-(CH₂)_m-, -(C=0)-NR₅-, -NR₆-;

X-i is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-N R₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NR₃-d_₆alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-d_₆alkyl-, -(C=0)- NR₃-d-₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-N R₃-d.₆alkyl-; wherein each of said -d. 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_₆alkyl, -0-d_₆alkyl, -S-d_₆alkyl, -phenyl, and -NR₃₇R₃₈;

X₂ is selected from -d_₆alkyl-, -0-Ci.₆alkyl-, -S-Ci.₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -d_₆alkyl-N R₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-d_₆alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-d_₆alkyl-, -(C=0)- NR₂-Ci-₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -d-₆alkyl-NR₂-d-₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R4o;

Ar-ι , Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ 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 , Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S- Ci-₆alkyl, and -NR₁₉R₂o; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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

3. A compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein:

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=O)-NR₂₉R₃₀, -(C=S)-NR₂₉R₃₀, -C₃.₆cycloalkyl -Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_₆alkyl, -S-Ci_₆alkyl ,

-C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

R₄ is independently selected from -halo, -OH , -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl , -NR₁₇R₁₈,

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

-

(C=0)-C₂.₆alkenyl, -(C=0)-0-C₁.₆alkyl , -(C=0)-Het₆, -(C=0)-Ar₆, -(C=0)-C₃.₆cycloalkyl, -(C=0)-

NR₃iR₃₂, -(C=0)-NR₃₁-(C=0)-R₃₂, -(C=S), -(C=S)-C₁.₆alkyl , -(C=S)-C₂.₆alkenyl, -(C=S)-0-d_

-Het₆, -Ar₆, and -C₃.₆cycloalkyl ;

wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_₆alkyl, =0, -halo, -OH , -0-Ci_₆alkyl , -S-Ci_₆alkyl, -Het₁₂, -Ar-n , and -NR₅₃R₅4, -(C=0)-NR₅₃R₅4, -NR₅5(C=0)-NR₅₃R54, -(C=S)-NR₅₃R₅4, and -NR₅₅(C=S)-

Rg, R-io, Rl 1 , Rl₂, Rl₃, Rl4. Rl5. Rl6, Rl7> Rl8> Rl9> F¾0, R2I > R∑2. R∑5. R∑6. R∑7. R∑8. R∑9. R30. R3I > R32.

R33, R37, R38, R39, R40, R44, R45, R48, R50, R53, R54 and R₅₅ are each independently selected from -H , -halo, =0, -OH , -Ci_₆alkyl , -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl , -Het₇, -Ar₅ and -NR₅₁R₅₂;

R₅₁ and R₅₂ are each independently selected from -H , -halo, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_

6alkyl, -C₃.₆cycloalkyl , -Ar₁₀ and -Het₁₀;

R₄₃ is selected from -H -Ci_₆alkyl, and -C₃.₆cycloalkyl ; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_ 6alkyl, -S-Ci_₆alkyl, -Het₅, -C₃.₆cycloalkyl -Ar₄, and -NR44R45;

A is selected from -(CH₂)_n-Y-(CH₂)_m-, -NR₆-;

X₂ is selected from -d_₆alkyl-, -0-Ci.₆alkyl-, -S-Ci.₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci.₆alkyl-NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-d_₆alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-d_₆alkyl-, -(C=0)- NR₂-Ci-₆alkyl-, -0-d-₆alkyl-0-d-₆alkyl- and -Ci.₆alkyl-NR₂-d.₆alkyl-; wherein each of said -d_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -d_₆alkyl , -0-d_₆alkyl, -S-d_₆alkyl , -phenyl and -NR₃₉R₄₀;

Y is -NR₄₃-; Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ 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 Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and - NR₁₉R₂o; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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

4. A compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein:

A-i and A₂ are selected from C and N; wherein when A-i is C, then A₂ is N; and wherein when A₂ is C, then A-, is N;

R-i and R₄₁ are each independently selected from -H, -halo, -OH, -C-i_₆alkyl, -0-C-i_₆alkyl, -S-C-i.

6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN, -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-i ; wherein each of said -C-i_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR₁₂, -0-C-i_₆alkyl, and -S-C-i_₆alkyl;

R₂ is selected from -H, -halo, -OH, -C-,.₆alkyl, -0-C-,.₆alkyl, -S-C-,.₆alkyl, -(C=0)-C-,.₆alkyl, -(C=S)-C-,_ 6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂₈, -(C=S)-NR₂₇R₂₈, -C₃.₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-C-|.₆alkyl; wherein each of said -C-i_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-C-i_₆alkyl, -S-C-i_₆alkyl, - Het₃, -Ar₂, and -NRi₃R_M;

R₃ is selected from -H, -halo, -OH, -C-,.₆alkyl, -0-C-,.₆alkyl, -S-C-,.₆alkyl, -(C=0)-C-,.₆alkyl, -(C=S)-C-,_ 6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=O)-NR₂₉R₃₀, -(C=S)-NR₂₉R₃₀, -C₃.₆cycloalkyl -Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl and -S0₂-C-|.₆alkyl; wherein each of said -C-i_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-C-i_₆alkyl, -S-C-i_₆alkyl, -C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R-|₆; R₄ is independently selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -NR₁₇R₁₈,

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

R₆ is selected from -(C=0),

-

(C=0)-Ar₆, -(C=0)-C₃-₆cycloalkyl, -(C=0)-NR₃₁R₃₂, -(C=0)-NR₃₁-(C=0)-R₃₂, -(C=S), -(C=S)-d_

₆alkyl, -(C=S)-C₂-₆alkenyl, -(C=S)-0-C₁.₆alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃.₆cycloalkyl, -

(C=S)-NR₃₁R₃₂, -(C=S)-NR₃₁-(C=S)-R₃₂;

Rg, Rio, Rl 1 , Rl₂, Rl₃, Rl4. Rl5. Rl6, l > l8> Rl9> R20, f¾1 > R∑2, R∑5, R∑6. R∑7. R∑8. R∑9. R30. 3I > R32.

6alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

A is selected from -NR₆-;

X-i is selected from -C_1-6alkyl-, -0-Ci_-6alkyl-, -S-Ci_-6alkyl-, -(C=0)-, -NR₃-(C=0)-, -C-,-₆alkyl-NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NR₃-Ci_-6alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₃-Ci.₆alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_-6alkyl, -0-Ci_-6alkyl, -S-Ci_-6alkyl, -phenyl, and -NR₃₇R₃₈;

X₂ is selected from -C_1-6alkyl-, -0-Ci_₆alkyl-, -S-Ci_-6alkyl-, -(C=0)-, -NR₂-(C=0)-, -C-,-₆alkyl-NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-Ci_-6alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R₄₀;

Het-i , Het₂, Het₃, Het₄, Het₆, Het₇, Het₁₀, and Het₁₂ 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, Het₂, Het₃, He , Het₆, Het₇, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0, -

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

5. A compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein:

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂₈, -(C=S)-NR₂₇R₂₈, -C₃-₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₃, -Ar₂, and -NRi₃R_M;

6cycloalkyl;

wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, - NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; and

wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_₆alkyl,-halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₁₂, -Ar-n, and - NR53 54,

and -NR₅5(C=S)-NR₅₃R5₄; Rg, R-io, Rl 1 , Rl2, Rl3, Rl4, Rl5, Rl6, l > Rl 8> Rl9> F¾0, 2I , R∑2, R∑5, R∑6, R∑7, R28, R∑9, R30, R3I > F¾2,

6alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

A is selected from -(CH₂)n-Y-(CH₂)m-, -NR₆-;

X-i is selected from -C_1-6alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-N R₃-, -NR3-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NR₃-Ci_-6alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-N R₃-Ci.₆alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_-6alkyl, -0-Ci_-6alkyl, -S-Ci_-6alkyl, -phenyl, and -NR₃₇R₃₈;

Y is -NR₄₃-;

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

6. 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 R₄₁ are each independently selected from -H, -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN , -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι ; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R₁₂, -0-Ci_₆alkyl, and -S-Ci_₆alkyl;

R₉, R10, R11 , Ri₂, Ri₃, Ri₄, Ri5. R16. Ri7> R18. Ri9. R20, R21. R22. R23. R24. R27. R28. R29. R30. R37. R38.

R39, R40, R₄8, and R₅₀, are each independently selected from -H , -halo, =0, -OH , -Ci_₆alkyl, -O- Ci-₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, - OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅₂;

A is selected from -(C=0)-NR₅-;

X-i is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-N R₄₈-, -NR₃-d_₆alkyl-, -NR₃-S0₂-, -N R₃-(C=0)-d_₆alkyl-, -(C=0)- NR₃-Ci-₆alkyl-, -0-d-₆alkyl-0-d-₆alkyl- and -Ci.₆alkyl-NR₃-d.₆alkyl-; wherein each of said -d. 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d-₆alkyl, -0-d_₆alkyl, -S-d_₆alkyl, -phenyl, and -NR₃₇R₃₈; X₂ is selected from -C_1-6alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci.₆alkyl-N R₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR^d-ealkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R4o;

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

7. A compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein:

Rg, Rio, Ri i , R"i₂, Ri₃, Ri4. Ri5. Ri6. Ri7_> Ris, Ri9, R20, R21 , R22, R23, R24, R27. R28. R29. R30. R37. R38.

R39, R40, R48, and R₅₀, are each independently selected from -H , -halo, =0, -OH , -Ci_₆alkyl, -O- Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, - OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅₂;

A is selected from -(C=0)-NR₅-;

Xi is -Ci.₆alkyl-NR₃-Ci.₆alkyl-; wherein each of said -Ci_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S- Ci-₆alkyl, -phenyl, and -NR₃₇R₃₈;

X₂ is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl-N R₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-d_₆alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-d_₆alkyl-, -(C=0)- NR₂-Ci-₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -d-₆alkyl-NR₂-d-₆alkyl-; wherein each of said -d_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_₆alkyl, -0-d_₆alkyl, -S-d_₆alkyl, -phenyl and -NR₃₉R₄₀;

Het-ι , Het₂, Het₃, Het₄, Het₇, Het₉, and Het₁₀ 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 , Het₂, Het₃, Het₄, Het₇, Het₉, and Het₁₀ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_₆alkyl, -Od_₆alkyl, -Sd_₆alkyl, =0, - (C=0)-d-₆alkyl, and -NR₂₁ R₂₂; wherein each of said -d_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

8. 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 R₄₁ are each independently selected from -H, -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN , -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι ; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -NR-n R₁₂, and -S-Ci_₆alkyl;

wherein R-i and R₄₁ are not simultaneously -H

R₆ is selected from -(C=0),

and -NR₅₅(C=S)-

R₉, R10, R11 , Ri₂, Ri₃, R"i₄, R15. R16. Ri7> R18. R19. R20, R21. R22. R25. R26. R27. R28. R29. R30. R31. R32.

R33, R37, R38, R39, R40, R48, R50, R53, R54 and R55 are each independently selected from -H, - halo, =0, -OH, -Ci-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁R₅2;

A is -NR₆-;

X-i is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NRs-C^alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₃-Ci.₆alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci.₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -phenyl, and -NR₃₇R₃₈;

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

9. A compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein:

A-i and A₂ are selected from C and N ; wherein when A-i is C, then A₂ is N ; and wherein when A₂ is C, then A-, is N ;

R₉, R-io, Ri i , Ri₂, Ri₃, R"i₄, Ri5. Ri6. Ri7> Ri8. Ri9, R20, R21 , R22. R23. R24. R27. R∑₈. R29. R30. R37. R3₈.

R39, R40, R₄₈, and R₅₀, are each independently selected from -H , -halo, =0, -OH , -Ci_₆alkyl, -O- Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, - OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅₂;

A is selected from -(C=0)-NR₅-;

Xi is -Ci-₆alkyl-NR₃-Ci-₆alkyl-; wherein each of said -Ci_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S- Ci-₆alkyl, -phenyl, and -NR₃₇R₃₈; X₂ is selected from -C_1-6alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci.₆alkyl-N R₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR^d-ealkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R4o;

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

10. 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 R₄₁ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -S-Ci_₆alkyl, -NR₉R₁₀, - (C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -N R₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het^ wherein each of said -Ci-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -NR-n R₁₂, and -S-Ci_₆alkyl;

wherein R-i and R₄₁ are not simultaneously -H

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂₈, -(C=S)-NR₂₇R₂₈, -C₃.₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₃, -Ar₂, and -NRi₃R_M; R₃ is selected from -H, -halo, -OH, -C_1-6alkyl, -0-Ci_-6alkyl, -S-Ci_-6alkyl,

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₉R₃o, -(C=S)-NR₂₉R₃o, -C₃-₆cycloalkyl -Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl and -S0₂-Ci_₆alkyl; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

R₆ is selected from -(C=0),

Rg, R10, R11 , Ri₂, Ri₃, Ri4. Ri5. R16. Ri9. R20, R21 , R22. R25. R26. R27. R28. R29. R30. R31. R32. R33. R37.

A is -NR₆-;

X-i is selected from -Ci_₆alkyl-, -0-C-,-₆alkyl-, -S-C-,-₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-N R₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NRs-d-ealkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci-₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-N R₃-Ci.₆alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci.₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -phenyl, and -NR₃₇R₃₈;

X₂ is selected from -Ci_₆alkyl-, -0-d.₆alkyl-, -S-d.₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl-N R₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-d_₆alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R₄₀;

Het-ι , Het₂, Het₃, Het₄, Het₆, Het₇, Het₁₀, and Het₁₂ 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 , Het₂, Het₃, He , Het₆, Het₇, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0, -

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

1 1 . 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 R₄₁ are not simultaneously -H

wherein each of said -C-,. 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Αη , -Het₉, and -NR₂₃R₂ ; Rg, R-io, Rl 1 , Rl2, Rl3, Rl4, Rl5, Rl6, Rl > Rl8> Rl9> F¾0, R∑1 , R∑2, R∑3, R∑4, R∑7, R28, R∑9, R30, R37, R38,

R39, R₄₀, R₄₈, and R₅₀, are each independently selected from -H , -halo, =0, -OH , -d-₆alkyl, -O- Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, - OH, -0-Ci_-6alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅₂;

6alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

A is selected from -(C=0)-NR₅-;

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

12. A compound according to anyone of claims 10-1 1 for use in human or veterinary medicine.

13. 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 R₄₁ are not simultaneously -H

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂8, -(C=S)-NR₂₇R₂8, -C₃-₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-Ci_₆alkyl; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₃, -Ar₂, and -NRi₃R_M;

R₆ is selected from -(C=0),

Rg, R10, R11 , R"i₂, Ri₃, R14. R15. R16. Ri9. R20, R21. R22. R25. R26. R27. R28. R29. R30. R31. R32. R33. R37.

A is -NR₆-;

X-i is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-N R₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NRs-C^alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-C₁.₆alkyl-, -(C=0)- NR₃-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-N R₃-Ci.₆alkyl-; wherein each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci.₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -phenyl, and -NR₃₇R₃₈; X₂ is selected from -C_1-6alkyl-, -0-Ci_-6alkyl-, -S-Ci_-6alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci.₆alkyl-NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR^d-ealkyl-, -NR₂-S0₂-, -NR₂-(C=0)-C₁.₆alkyl-, -(C=0)- NR₂-Ci_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R4o;

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, myel in-related disorders, neurological disorders and cancer.

14. 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 R₄₁ are not simultaneously -H

R₂ is selected from -H, -halo, -OH, -C-,.₆alkyl, -0-C-,.₆alkyl, -S-C-,.₆alkyl, -(C=0)-C-,.₆alkyl, -(C=S)-C-,_ 6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂₈, -(C=S)-NR₂₇R₂₈, -C₃.₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-C-|.₆alkyl; wherein each of said -C-i_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-C-i_₆alkyl, -S-C-i_₆alkyl, - Het₃, -Ar₂, and -NRi₃R_M; R₃ is selected from -H, -halo, -OH, -C_1-6alkyl, -0-Ci_-6alkyl, -S-Ci_-6alkyl,

R₉, Rio, Ri i , Ri₂, Ri₃, Ri4. Ri5. Ri6, Ri7> Ris, R-i₉, R20, R21 , R22, R23, R24, R27, R∑8. R∑9. R30. R37. R38.

A is selected from -(C=0)-NR₅-;

X₂ is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl-N R₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-d_₆alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-d_₆alkyl-, -(C=0)- NR₂-Ci-₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-d.₆alkyl-; wherein each of said -d_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_₆alkyl, -0-d_₆alkyl, -S-d_₆alkyl, -phenyl and -NR₃₉R₄₀;

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, neurological disorders and cancer.

15. A compound or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N- oxide form, or solvate thereof selected from the list comprising:

16. A compound or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N- oxide form, or solvate thereof as defined in claim 15; for use in human or veterinary medicine.

17. A compound or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N- oxide form, or solvate thereof as defined in claim 15; 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.

18. A compound for use as defined in any one of claims 1 to 9 or 12-14; wherein the pyrazolopyrimidine or the imidazopyridazine moiety is linked to the aryl or heteroaryl moiety at position Z₄ or Z₅, in accordance with the numbering as provided in Formula I.

19. A compound as defined in any one of claims 10-1 1 ; wherein the pyrazolopyrimidine or the imidazopyridazine moiety is linked to the aryl or heteroaryl moiety at position Z₄ or Z₅, in accordance with the numbering as provided in Formula I.

20. A compound for use as defined in any one of claims 1 to 9 or 12-14; wherein R-i is linked to the aryl or heteroaryl moiety at position Z-i , Z₂ or Z₃, in accordance with the numbering as provided in Formula I; more in particular at position Z-| .

21 . A compound as defined in any one of claims 10-1 1 ; wherein R-i is linked to the aryl or heteroaryl moiety at position Z-i , Z₂ or Z₃, in accordance with the numbering as provided in Formula I; more in particular at position Z-| .

22. A pharmaceutical composition for use in the prevention and/or treatment of an Activin-like receptor kinase associated disease selected from anemia-related disorders or disorders characterized by abnormal bone formation; said composition comprising a compound as defined in any one of claims 1 -7, 10-1 1 or 15.

23. A pharmaceutical composition for use in the 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; said composition comprising a compound as defined in any one of claims 8-9, 10-1 1 or 15.

24. A pharmaceutical composition for use in the 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; said composition comprising a compound as defined in any one of claims 10-1 1 , 13-14 or 15.

25. A pharmaceutical composition comprising a compound as defined in anyone of claims 10-1 1 or 15.

26. Use of a compound as defined in any one of claims 1 -15, or a pharmaceutical composition as defined in anyone of claims 22-25, for inhibiting the activity of an Activin-like receptor kinase.

27. A method for the prevention and/or treatment of an Activin-like receptor kinase associated disease selected from the list comprising disorders characterized by abnormal bone formation or anemia-related disorders; said method comprising administering to a subject in need thereof a composition comprising a compound as defined in any one of claims 1 -7, 10-1 1 or 15; or a pharmaceutical composition as defined in claim 22.

28. A method for the 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; said method comprising administering to a subject in need thereof a composition comprising a compound as defined in any one of claims 8-9, 10-1 1 or 15; or a pharmaceutical composition as defined in claim 23.

29. A method for the 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; said method comprising administering to a subject in need thereof a composition comprising a compound as defined in any one of claims 10-1 1 , 13-14 or 15; or a pharmaceutical composition as defined in claim 24.