WO2016146651A1 - Inhibiteurs macrocycliques de récepteur kinase de type activine - Google Patents

Inhibiteurs macrocycliques de récepteur kinase de type activine Download PDF

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WO2016146651A1
WO2016146651A1 PCT/EP2016/055628 EP2016055628W WO2016146651A1 WO 2016146651 A1 WO2016146651 A1 WO 2016146651A1 EP 2016055628 W EP2016055628 W EP 2016055628W WO 2016146651 A1 WO2016146651 A1 WO 2016146651A1
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alkyl
het
halo
cycloalkyl
optionally
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PCT/EP2016/055628
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Jan Marie Cyriel Jozef Hoflack
Cyril BERTHET
Pascal André René BENDERITTER
Petra Marcella Françoise BLOM
Sylvie Gomez
Mourad DAOUBI
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Oncodesign Sa
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems

Definitions

  • 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.
  • the present invention provides methods of using said compounds, for instance as a medicine or diagnostic agent.
  • Bone morphogenetic proteins are multi-functional growth factors that belong to the Transforming Growth Factor beta (TGFbeta) superfamily.
  • TGFbeta Transforming Growth Factor beta
  • 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.
  • 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.
  • 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.
  • BMPs Many disorders have been linked to either the BMPs or the molecules functioning downstream of BMP signalling pathway, such as ALK1 and/or ALK2.
  • Fibrodysplasia Ossificans Progressiva also known as Myositis Ossificans Progressiva
  • FOP Fibrodysplasia Ossificans Progressiva
  • 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.
  • 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.
  • 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.
  • EMT epithelial-mesenchymal transition
  • EndMT has 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.
  • 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.
  • 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
  • inflammatory diseases characterized in increased BMP-signalling and/or dysregulated ALK1 /ALK2 kinase activities.
  • 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.
  • 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,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6 alkyl;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -d- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Ar- ⁇ , -Het 9 , and -NR23R24;
  • Rg R-io, R11, Ri 2 , Ri 3 , Ri 4 , Ri5.
  • R20. R21. R22. R23. R24. R25. R26. R27. R28. R29. R30.
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_
  • R 42 is selected from -H, -OH, -halo, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 46 R 47 , -C 3 . 6 cycloalkyl, -Ar 9 and -Het 8 ;
  • R 43 is selected from -H -Ci_ 6 alkyl, and -C 3 . 6 cycloalkyl; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1- 6alkyl, -S-Ci_ 6 alkyl, -Het 5 , -C 3 . 6 cycloalkyl -Ar 4 , and -NR 44 R 45 ;
  • -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR 39 R4o;
  • Y is selected from a direct bond, -CHR 42 -, -0-, -S-, and -NR 43 -;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , Ar 10 and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci- 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • an Activin-like receptor kinase associated disease selected from anemia-related disorders or disorders characterized by abnormal bone formation.
  • 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
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6 alkyl;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NRi 3 Ri 4 ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -d- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -d_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, - ⁇ , -Het 9 , and -NR 23 R 24 ;
  • each of said -d_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-d_ 6 alkyl, -S-d_ 6 alkyl, -C 3 . 6 cycloalkyl, -Het 7 , -Ar 5 and -NR 51 R 52 ;
  • R51 and R 52 are each independently selected from -H, -halo, -OH, -d_ 6 alkyl, -0-d_ 6 alkyl, -S-Ci_
  • R 43 is selected from -H -d_ 6 alkyl, and -C 3 . 6 cycloalkyl; wherein each of said -d. 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1-
  • 6 alkyl-, -(C 0)- NR 3 -Ci_ 6 alkyl-, -0-Ci. 6 alkyl-0-Ci. 6 alkyl- and -Ci. 6 alkyl-NR 3 -Ci.
  • each of said -Ci_ 6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • Y is -NR 43 -;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-
  • Ci- 6 alkyl, and -NR 19 R 20 wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • 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
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6 alkyl;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -d- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NRi 3 R M ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 ,
  • Rg Rio, Rl 1 , Rl 2 , Rl 3 , Rl4, Rl5, Rl6, l > l8> Rl9> R20, 3 ⁇ 41 > R ⁇ 2, R ⁇ 5, R ⁇ 6, R ⁇ 7, R28, R ⁇ 9, R30, 3I > R32,
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • R 43 is selected from -H -Ci_ 6 alkyl, and -C 3 . 6 cycloalkyl; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6alkyl, -S-Ci_ 6 alkyl, -Het 5 , -C 3 . 6 cycloalkyl -Ar 4 , and -NR44R45;
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 -;
  • -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR 39 R4o;
  • Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said
  • Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and - NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i, Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • an Activin-like receptor kinase associated disease selected from the list comprising anemia-related disorders or disorders characterized by abnormal bone formation.
  • 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
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6 alkyl;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NRi 3 Ri 4 ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -d- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_
  • A is selected from -NR 6 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and - NR 19 R 2 o; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • an Activin-like receptor kinase associated disease selected from the list comprising anemia-related disorders or disorders characterized by abnormal bone formation.
  • 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 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NRi 3 R M ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 ,
  • R 6 is selected from -Ci_ 6 alkyl, -S0 2 , -S0 2 -Ci. 6 alkyl, -S0 2 -C 3 . 6 cycloalkyl, -Het 6 , -Ar 6 , and -C 3 .
  • Rg R10, R11 , Rl 2 , R"
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • R 43 is selected from -H -Ci_ 6 alkyl, and -C 3 . 6 cycloalkyl; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6alkyl, -S-Ci_ 6 alkyl, -Het 5 , -C 3 . 6 cycloalkyl -Ar 4 , and -NR44R45;
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 -;
  • Y is -NR 43 -;
  • Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C-i_ 6 alkyl, -0-C-i_ 6 alkyl, -S-C-i_ 6 alkyl, and - NR 19 R 20 ; wherein each of said -C-i_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • an Activin-like receptor kinase associated disease selected from the list comprising anemia-related disorders or disorders characterized by abnormal bone formation.
  • 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
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6 alkyl;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NRi 3 R M ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 ,
  • 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, - ⁇ , -Het 9 , and -NR 23 R 2 ;
  • Rg R10, R11 , R12, Rl3, Rl4, Rl5, Rl6, Rl > Rl8, Rl9, R20, R ⁇ 1 , R ⁇ 2, R ⁇ 3, R ⁇ 4, R ⁇ 7, R2 8 , R ⁇ 9, R30, R37, R3 8 ,
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 - halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • an Activin-like receptor kinase associated disease selected from the list comprising anemia-related disorders or disorders characterized by abnormal bone formation.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein
  • a 2 is C, and A-i is N;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6 alkyl;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NR 13 R 14 ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -d_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, - ⁇ , -Het 9 , and -NR 23 R 2 ;
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_
  • Xi is -Ci- 6 alkyl-NR 3 -Ci- 6 alkyl-; wherein each of said -Ci_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci- 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • Z-i, Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • an Activin-like receptor kinase associated disease selected from the list comprising anemia-related disorders or disorders characterized by abnormal bone formation.
  • 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
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -NR-nR 12 , and -S-Ci_ 6 alkyl;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NRi 3 Ri 4 ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -d- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • Rg Rio, Rl 1 , Rl 2 , Rl 3 , Rl4.
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_
  • A is -NR 6 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and - NR 19 R 2 o; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • 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.
  • 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
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6 alkyl;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ; R 5 is selected from -H, -OH, -halo, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 9 , -Ar- ⁇ , -C 3 .
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_
  • Xi is -Ci- 6 alkyl-NR 3 -Ci- 6 alkyl-; wherein each of said -Ci_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci_ 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 - halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • 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 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NRi 3 R M ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, - Ar 8 and -Het 4 ;
  • R 5 i and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • A is -NR 6 -;
  • 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci. 6 alkyl, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR 39 R 40 ;
  • Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C-i_ 6 alkyl, -0-C-i_ 6 alkyl, -S-C-i_ 6 alkyl, and - NR 19 R 20 ; wherein each of said -C-i_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Het-i , Het 2 , Het 3 , Het 4 , Het 6 , Het 7 , Het 10 , and Het 12 are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4.
  • 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
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6 alkyl;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NR 13 R 14 ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 ,
  • each of said -d_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, - ⁇ , -Het 9 , and -NR 23 R 2 ;
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • Xi is -Ci- 6 alkyl-NR 3 -Ci- 6 alkyl-; wherein each of said -Ci_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci- 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • 6 alkyl-, -(C 0)- NR 2 -Ci_ 6 alkyl-, -0-Ci. 6 alkyl-0-Ci. 6 alkyl- and -Ci. 6 alkyl-NR 2 -Ci.
  • each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR39R40;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 - halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n are each independently 1 , 2, 3, or 4.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein
  • R-i and R 41 are not simultaneously -H
  • R 2 is selected from -H, -halo, -OH, -C 1-6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -d- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, - Ar 8 and -Het 4 ;
  • each of said - Ci- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, -Het 7 , -Ar 5 and -NR 51 R 52 ;
  • R51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • A is -NR 6 -;
  • 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci. 6 alkyl, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and - NR 19 R 2 o; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Het- ⁇ , Het 2 , Het 3 , Het 4 , Het 6 , Het 7 , Het 10 , and Het 12 are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • 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.
  • 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
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6 alkyl;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NRi 3 R M ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -d_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, - ⁇ , -Het 9 , and -NR 23 R 24 ;
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_
  • Xi is -Ci. 6 alkyl-NR 3 -Ci. 6 alkyl-; wherein each of said -Ci_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-
  • -d_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_ 6 alkyl, -0-d_ 6 alkyl, -S-d_ 6 alkyl, -phenyl and -NR 39 R 40 ;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_ 6 alkyl, -0-d_ 6 alkyl, -S-d_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -d_ 6 alkyl is optionally and independently substituted with from 1 to 3 - halo;
  • Het- ⁇ , Het 2 , Het 3 , Het 4 , Het 7 , Het 9 , and Het 10 are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N; and m and n are each independently 1 , 2, 3, or 4;
  • 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.
  • the present invention provides a compound selected from the list comprising:
  • the present invention provides a compound selected from the list comprising:
  • the present invention provides a compound according to the present invention for use in the diagnosis, prevention and/or treatment of an Activin-like receptor kinase associated disease; wherein the pyrazolopyrimidine or the imidazopyridazine moiety is linked to the aryl or heteroaryl moiety at position Z 4 or Z 5 , in accordance with the numbering as provided in Formula I.
  • the present invention provides a compound according to the present invention for use in the diagnosis, prevention and/or treatment of an Activin-like receptor kinase associated disease; wherein R-i is linked to the aryl or heteroaryl moiety at position Z-i , Z 2 or Z 3 , in accordance with the numbering as provided in Formula I.
  • the present invention further provides a pharmaceutical composition for use in the prevention and/or treatment of an ALK1 or ALK2-kinase associated disease comprising a compound according to this invention.
  • 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.
  • 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.
  • 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,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6 alkyl;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NRi 3 R M ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 ,
  • R 5 and R 7 are each independently selected from -H, -OH, -halo, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • Rg R-io, Rii, Ri 2 , Ri 3 , R"i 4 , Ri5. Ri6. Ri7. Ri8. Ri9.
  • R20 R21. R22. R23. R24. R25. R26. R27. R28. R29. R30.
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_
  • R 42 is selected from -H, -OH, -halo, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 46 R 47 , -C 3 . 6 cycloalkyl,
  • R 43 is selected from -H -Ci_ 6 alkyl, and -C 3 . 6 cycloalkyl; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1- 6alkyl, -S-Ci_ 6 alkyl, -Het 5 , -C 3 . 6 cycloalkyl -Ar 4 , and -NR 44 R 45 ;
  • 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci. 6 alkyl, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR 39 R 40 ;
  • Y is selected from a direct bond, -CHR 42 -, -0-, -S-, and -NR 43 -;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , Ar 10 and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar-i, Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci- 6 alkyl, and -NR 19 R 2 o; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i, Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • an Activin-like receptor kinase associated disease selected from anemia-related disorders or disorders characterized by abnormal bone formation.
  • radicals can be read both ways.
  • A is such as the right part of the possible values of A (i.e.
  • X-i is such as the right part of the possible values of X-i (i.e.
  • X 2 is such as the left part of the possible values of X 2 (i.e.
  • X 2 is such as the right part of the possible values of X 2 (i.e.
  • alkyl by itself or as part of another substituent refers to fully saturated hydrocarbon radicals.
  • 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.
  • the subscript refers to the number of carbon atoms that the named group may contain.
  • d- 6 alkyl means an alkyl of one to six carbon atoms.
  • alkyl groups are methyl, ethyl, n-propyl, i-propyl, butyl, and its isomers (e.g.
  • 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.
  • 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.
  • substituents include -halo, -OH, primary and secondary amides, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, heteroaryl, aryl, and the like.
  • 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.
  • alkyl groups as defined are divalent, i.e., with two single bonds for attachment to two other groups, they are termed "alkylene” groups.
  • alkylene groups includes methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene, 1 ,2- dimethylethylene, pentamethylene and hexamethylene.
  • 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 C 3 alkylene group may be for example *-CH 2 CH 2 CH 2 -*, *-CH(-CH 2 CH 3 )-*, or *-CH 2 CH(-CH 3 )-*. Likewise a C 3 cycloalkylene group may be
  • heterocycle refers 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.
  • 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-dihydr
  • 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.
  • aryl 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-indany
  • 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.
  • heteroaryl ring where a carbon atom in an aryl group is replaced with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring.
  • heteroaryl 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,
  • 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.
  • 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.
  • substituted 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • isotopes that can be incorporated into compounds of formula (I) are isotopes of hydrogen, carbon, nitrogen, fluorine, such as 3 H, C, 3 N, 4 C, 5 0 and 8 F.
  • Such isotopically-labelled compounds of formula (I) are useful in drug and/or substrate tissue distribution assays.
  • C and 8 F 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.
  • 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.
  • a compound means one compound or more than one compound.
  • 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:
  • each of said -d- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6 alkyl;
  • R 2 is selected from -H, -halo, -OH, -C 1-6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NRi 3 R M ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 ,
  • R 5 and R 7 are each independently selected from -H, -OH, -halo, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 9 R10, R11 , Ri 2 , R"i 3 , Ri 4 , R15. R16. Ri7 > R18. Ri9.
  • R20. R21. R22. R23. R24. R25. R26. R2 7 . R28. R29. R30.
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Het 7 , -Ar 5 and -NR 51 R 52 ;
  • R 5 i and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • R 42 is selected from -H, -OH, -halo, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 46 R 4 7, -C 3 . 6 cycloalkyl, -Ar 9 and -Het 8 ;
  • R 43 is selected from -H -Ci_ 6 alkyl, and -C 3 . 6 cycloalkyl; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_
  • Y is selected from a direct bond, -CHR 42 -, -0-, -S-, and -NR 43 -;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , Ar 10 and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci- 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Het- ⁇ , Het 2 , Het 3 , Het 4 , Het 5 , Het 6 , Het 7 , Het 8 , Het 9 , Het 10 , and Het 12 are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het- ⁇ , Het 2 , Het 3 , He , Het 5 , Het 6 , Het 7 , Het 8 , Het 9 , Het 10 , and Het 12 is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d.
  • each of said -d- 6alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i, Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n 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.
  • X-i, and X 2 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:
  • 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 R 41 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_
  • R 2 is selected from -H, -halo, -OH, -C 1-6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -d_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, - ⁇ , -Het 9 , and -NR 23 R 24 ;
  • Rg, Rio, Rl 1 , Rl 2 , Rl 3 , 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, R 3 i , R 32 , R 33 , R 37 , R 38 , R 3 9, R40, R44, R45, R48, R50, R53, R54 and R 55 are each independently selected from -H , -halo, 0, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 .
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Het 7 , -Ar 5 and -NR 51 R 52 ;
  • R51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_
  • R 43 is selected from -H -Ci_ 6 alkyl, and -C 3 . 6 cycloalkyl; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1-
  • 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_ 6 alkyl, -0-d_ 6 alkyl, -S-d_ 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • 6 alkyl-, -(C 0)- NR 2 -Ci_ 6 alkyl-, -0-Ci. 6 alkyl-0-Ci. 6 alkyl- and -Ci. 6 alkyl-NR 2 -Ci.
  • each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR39R40;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-
  • Ci- 6 alkyl, and -NR 19 R 20 wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n are each independently 1 , 2, 3, or 4.
  • 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 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NRi 3 R M ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl , -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl , -Het 7 , -Ar 5 and -NR 51 R 52 ; R51 and R 52 are each independently selected from -H , -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 . 6 cycloalkyl , -Ar 10 and -Het 10 ;
  • R 43 is selected from -H -Ci_ 6 alkyl, and -C 3 . 6 cycloalkyl ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -O-C1- 6alkyl, -S-Ci_ 6 alkyl, -Het 5 , -C 3 . 6 cycloalkyl -Ar 4 , and -NR44R45;
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 -;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n are each independently 1 , 2, 3, or 4.
  • 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 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NRi 3 R M ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH , -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl , -NR 17 R 18 ,
  • R 5 i and R 52 are each independently selected from -H , -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 . 6 cycloalkyl , -Ar 10 and -Het 10 ;
  • A is selected from -NR 6 -;
  • 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -Ci -6 alkyl , -0-Ci -6 alkyl , -S-Ci -6 alkyl, -phenyl , and -NR 37 R 38 ;
  • -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -Ci_ 6 alkyl , -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl , -phenyl and -NR 39 R 40 ;
  • Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -C-i_ 6 alkyl, -0-C-i_ 6 alkyl , -S-C-i_ 6 alkyl, and - NR 19 R 20 ; wherein each of said -C-i_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n are each independently 1 , 2, 3, or 4.
  • 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
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6 alkyl;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NRi 3 R M ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 ,
  • R 6 is selected from -Ci_ 6 alkyl, -S0 2 , -S0 2 -Ci_ 6 alkyl, -S0 2 -C 3 . 6 cycloalkyl, -Het 6 , -Ar 6 , and -C 3 .
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Het 6 , -Ar 6 , -
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_
  • R 43 is selected from -H -Ci_ 6 alkyl, and -C 3 . 6 cycloalkyl; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6alkyl, -S-Ci_ 6 alkyl, -Het 5 , -C 3 . 6 cycloalkyl -Ar 4 , and -NR44R45;
  • A is selected from -(CH 2 )n-Y-(CH 2 )m-, -NR 6 -;
  • Y is -NR 43 -;
  • Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and - NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4.
  • 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
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6 alkyl;
  • R 2 is selected from -H , -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -
  • R 3 is selected from -H , -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl , -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -d_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH , -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, - ⁇ , -Het 9 , and -NR 23 R 2 ;
  • R 9 R-io, R11 , Ri 2 , Ri 3 , Ri 4 , R15. R16. Ri7> R18. Ri9.
  • R51 and R 52 are each independently selected from -H , -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 . 6 cycloalkyl , -Ar 10 and -Het 10 ;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 - halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n are each independently 1 , 2, 3, or 4.
  • 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
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6 alkyl;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NRi 3 R M ;
  • R 3 is selected from -H, -halo, -OH, -C 1-6 alkyl, -0-Ci -6 alkyl, -S-Ci -6 alkyl,
  • each of said -d- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -d_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, - ⁇ , -Het 9 , and -NR 23 R 24 ;
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • Xi is -Ci- 6 alkyl-NR 3 -Ci- 6 alkyl-; wherein each of said -Ci_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci_ 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_ 6 alkyl, -0-d_ 6 alkyl, -S-d_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -d_ 6 alkyl is optionally and independently substituted with from 1 to 3 - halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n are each independently 1 , 2, 3, or 4.
  • 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 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NRi 3 R M ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 ,
  • 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, R 3 0, R 3 1 , R 3 2,
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • A is -NR 6 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and - NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4.
  • 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 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NRi 3 R M ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said - Ci- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, - ⁇ , -Het 9 , and -NR 23 R 2 ;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, - OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Het 7 , -Ar 5 and -NR 51 R 52 ;
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • Xi is -Ci-6alkyl-NR 3 -Ci-6alkyl-; wherein each of said -d- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci- 6 alkyl, -phenyl, and -NR 3 7R 38 ;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 - halo;
  • Z-i, Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n are each independently 1 , 2, 3, or 4.
  • 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;
  • R 2 is selected from -H, -halo, -OH, -C 1-6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -d- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NRi 3 R M ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, - Ar 8 and -Het 4 ;
  • Ci- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, -Het 7 , -Ar 5 and -NR 51 R 52 ;
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • A is -NR 6 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and - NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n are each independently 1 , 2, 3, or 4.
  • 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
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6 alkyl;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NR 13 R 14 ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -d_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, - ⁇ , -Het 9 , and -NR 23 R 24 ;
  • 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.
  • R 5 i and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • Xi is -Ci- 6 alkyl-NR 3 -Ci- 6 alkyl-; wherein each of said -Ci_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci- 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 - halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4.
  • 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 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NRi 3 R M ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, - Ar 8 and -Het 4 ;
  • each of said - Ci- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci. 6 alkyl, -S-d- 6 alkyl, -C 3 . 6 cycloalkyl, -Het 7 , -Ar 5 and -NR 51 R 52 ;
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • A is -NR 6 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n are each independently 1 , 2, 3, or 4.
  • 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:
  • a 2 is C, and A-i is N;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6 alkyl;
  • R 2 is selected from -H , -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -
  • R 3 is selected from -H , -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl , -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -d_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH , -0-d- 6 alkyl, -S-d_ 6 alkyl, -C 3 . 6 cycloalkyl, - ⁇ , -Het 9 , and -NR 23 R 2 ;
  • 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.
  • R 5 i and R 52 are each independently selected from -H , -halo, -OH , -d_ 6 alkyl, -0-d_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 . 6 cycloalkyl , -Ar 10 and -Het 10 ;
  • Xi is -Ci.6alkyl-NR 3 -Ci. 6 alkyl-; wherein each of said -d_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -d_ 6 alkyl , -0-d_ 6 alkyl, -S- Ci_ 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • each of said -d_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -d_ 6 alkyl , -0-d_ 6 alkyl, -S-d_ 6 alkyl , -phenyl and -NR 39 R 40 ;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 2 o; wherein each of said
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n are each independently 1 , 2, 3, or 4.
  • 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:
  • the pyrazolopyrimidine or the imidazopyridazine moiety is linked to the aryl or heteroaryl moiety at position Z 4 or Z 5 , in accordance with the numbering as provided in Formula I.
  • the R-i of the compounds according to this invention is preferably linked to the aryl or heteroaryl moiety at position Z-i , Z 2 or Z 3 , in accordance with the numbering as provided in Formula I.
  • the present invention 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.
  • 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.
  • 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 -(CH 2 )n-Y-(CH 2 )m-, -NR 6 -; and Y is -NR 43 -. 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 -(CH 2 )n-Y-(CH 2 )m-, -NR 6 -;
  • R 43 is selected from -H -Ci_ 6 alkyl, and -C 3 . 6 cycloalkyl; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1- 6alkyl, -S-Ci_ 6 alkyl, -Het 5 , -C 3 . 6 cycloalkyl -Ar 4 , and -NR44R45;
  • Xi is -0-Ci_ 6 alkyl-
  • X 2 is -NR 2 -Ci. 6 alkyl.
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 -;
  • R 6 is selected from -Ci_ 6 alkyl, -S0 2 , -S0 2 -Ci_ 6 alkyl, -S0 2 -C 3 . 6 cycloalkyl, -Het 6 , -Ar 6 , and -C 3 .
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1- 6alkyl, -S-Ci_ 6 alkyl, -Het 5 , -C 3 . 6 cycloalkyl -Ar 4 , and -NR44R45.
  • Compound having a central external amide are compounds wherein the following restrictions apply: A is -NR 6 -;
  • X-i is -O-C1- 6alkyl- and X 2 is -NR 2 -Ci. 6 alkyl.
  • 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, - ⁇ , -Het 9 , and -NR 23 R 24 ;
  • compounds having a central internal amide preferably also:
  • Xi is -Ci- 6 alkyl-NR 3 -Ci- 6 alkyl-; wherein each of said -d- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci- 6 alkyl, -phenyl, and -NR 3 7R 38 ; and
  • X 2 is -N R 2 -Ci. 6 alkyl.
  • 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
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NRi 3 R M ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Ar- ⁇ , -Het 9 , and -NR23R24;
  • Rg R10, R11, Ri 2 , R"i 3 , Ri 4 , R15. R16. Ri7. R18. Ri9.
  • R20 R21. R22. R23. R24. R25. R26. R27. R28. R29. R30.
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Het 7 , -Ar 5 and -NR 51 R 52 ;
  • R51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_
  • R 42 is selected from -H, -OH, -halo, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 46 R 47 , -C 3 . 6 cycloalkyl, -Ar 9 and -Het 8 ;
  • R 43 is selected from -H -Ci_ 6 alkyl, and -C 3 . 6 cycloalkyl; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1-
  • Y is selected from a direct bond, -CHR 42 -, -0-, -S-, and -NR 43 -;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , Ar 10 and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-
  • Ci- 6 alkyl, and -NR 19 R 20 wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • 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
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -NR-n R 12 , and -S-Ci_ 6 alkyl;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NRi 3 R M ;
  • R 3 is selected from -H, -halo, -OH, -C 1-6 alkyl, -0-Ci -6 alkyl, -S-Ci -6 alkyl,
  • each of said -d- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • A is -NR 6 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C-i_ 6 alkyl, -0-C-i_ 6 alkyl, -S-C-i_ 6 alkyl, and - NR-19R20; wherein each of said -d- 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • 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 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, - Het 3 , -Ar 2 , and -NRi 3 R M ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, - Ar 8 and -Het 4 ;
  • each of said - Ci- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, -Het 7 , -Ar 5 and -NR 51 R 52 ;
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • A is -NR 6 -;
  • X 2 is selected from -C-
  • Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C-i_ 6 alkyl, -0-C-i_ 6 alkyl, -S-C-i_ 6 alkyl, and -
  • each of said -C-i_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;

Abstract

La présente invention concerne des composés macrocycliques et des compositions contenant lesdits composés agissant en tant qu'inhibiteurs de la kinase, en particulier en tant qu'inhibiteurs de récepteurs kinases de type Activine, plus particulièrement ALK1 et/ou ALK2 et/ou des mutants de ceux-ci, destinés au diagnostic, à la prévention et/ou au traitement des maladies associées à l'ALK1-kinase et/ou à l'ALK2-kinase. En outre, la présente invention fournit des procédés d'utilisation desdits composés, par exemple à titre de médicaments ou d'agents de diagnostic.
PCT/EP2016/055628 2015-03-16 2016-03-16 Inhibiteurs macrocycliques de récepteur kinase de type activine WO2016146651A1 (fr)

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US10752594B2 (en) 2013-03-14 2020-08-25 Sumitomo Dainippon Pharma Oncology, Inc. JAK1 and ALK2 inhibitors and methods for their use
US11040038B2 (en) 2018-07-26 2021-06-22 Sumitomo Dainippon Pharma Oncology, Inc. Methods for treating diseases associated with abnormal ACVR1 expression and ACVR1 inhibitors for use in the same

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