WO2015136073A1

WO2015136073A1 - Macrocyclic tgf-br2 kinase inhibitors

Info

Publication number: WO2015136073A1
Application number: PCT/EP2015/055294
Authority: WO
Inventors: Jan Marie Cyriel Jozef Hoflack; Cyril BERTHET; Pascal André René BENDERITTER; Petra Marcella Françoise BLOM; Sylvie Gomez; Mourad DAOUBI
Original assignee: Oncodesign Sa
Priority date: 2014-03-14
Filing date: 2015-03-13
Publication date: 2015-09-17

Abstract

The present invention relates to macrocyclic compounds and compositions containing said compounds acting as kinase inhibitors, in particular as inhibitors of Transforming Growth Factor beta Receptor 2 (TGF-β R2) and/or mutants thereof, for use in the diagnosis, prevention and/or treatment of TGF-β R2 -kinase associated diseases. Moreover, the present invention provides methods of using said compounds, for instance as a medicine or diagnostic agent.

Description

Macrocyclic TGF- R2 kinase inhibitors

Field of the invention

The present invention relates to macrocyclic compounds and compositions containing said compounds acting as kinase inhibitors, in particular as inhibitors of Transforming Growth Factor beta Receptor 2 (TGF- R2) and/or mutants thereof, for use in the diagnosis, prevention and/or treatment of TGF- R2 -kinase associated diseases. Moreover, the present invention provides methods of using said compounds, for instance as a medicine or diagnostic agent.

Background of the invention

Transforming growth factor beta (TGF-β) is a member of a large family of dimeric polypeptide growth factors that includes, for example, activins, inhibins, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs) and mullerian inhibiting substance (MIS). Three isoforms of TGF-β (TGF-βΙ , TGF^2, and TGF^3) have been identified in mammals, and are present in most cells, along with their receptors. Each isoform is expressed in both a tissue-specific and developmental^ regulated fashion (Eur. Cytokine. Netw. (1996) 7: 363). The TGF-β family regulates a wide range of crucial cell growth and differentiation events, including early embryonic patterning and morphogenesis, sexual organ and bone/cartilage formation, wound healing and immunosuppression (Handbook of Experimental Pharmacology (1990): 419-472).

The spectrum of TGF-β cellular functions is pleiotropic and includes: apoptosis, proliferation, differentiation, mobility and cell adhesion. TGF-β binds at high affinity to the type II receptor (TGF- R2), a constitutively active serine/threonine kinase. The ligand-bound type II receptor phosphorylates the TGF-β type I receptor (TGF- R1 , also named ALK5), which allows the type I receptor to recruit and phosphorylate downstream signalling molecules, Smad2 or Smad3 (Mol. Cell. (2001 ) 8: 671 -682). Phosphorylated Smad2 or Smad3 can then complex with Smad4, and the entire hetero-Smad complex translocates to the nucleus and regulates transcription of various TGF-β responsive genes (J. Ann. Rev .Biochem. Med. (1998) 67: 773). TGF-β can also signal independently of Smads, through a non-canonical pathway. These non-Smad pathways include various branches of MAP kinase (MAPK) pathways, Rho- like GTPase signalling pathways, and phosphatidylinositol-3-kinase (PI3K)/AKT pathways (Cell Research (2009) 19:128-139).

TGF-β signalling is implicated in numerous conditions and diseases, including cancer, cardiovascular, bone, CNS, PNS, inflammatory and neurodegenerative disorders. Pathological overexpression of TGF-β is known to be associated with a number of undesirable effects, leading ultimately to the development of serious pathogenic conditions (N. Engl. J. (2000) 1350). In particular, pathological overexpression of TGF-β may cause excessive accumulation of extracellular matrix (ECM), inhibition of cell proliferation and immunosuppression.

Excessive accumulation of ECM is known to lead to fibrotic diseases such as tumour fibrosis, radiation-induced fibrosis, and fibrosis of the liver, kidney, lung, bowel, heart, pancreas, peritoneum or other organs. Fibrosis can lead to pathologic conditions such as cirrhosis, idiopathic pulmonary fibrosis, glomerulosclerosis and hypertrophic scars.

TGF-β also takes on a key function in the formation of cancer (Nature Genetics (2001 ) 29: 1 17-129; J. Clin. One (2005) 23: 2078-2093). At early stages of the development of cancer, TGF-β counters the formation of cancer. This tumour-suppressant action is based principally on the ability of TGF-β to inhibit the division of epithelial cells. By contrast, TGF-β promotes cancer growth and the formation of metastases at late tumour stages. This can be attributed to the fact that most epithelial tumours develop a resistance to the growth-inhibiting action of TGF-β, and TGF-β simultaneously supports growth of the cancer cells via other mechanisms. These mechanisms include promotion of angiogenesis, the immunosuppressant action, which supports tumour cells in avoiding the control function of the immune system (immunosurveillance), and promotion of invasiveness and the formation of metastases. The formation of an invasive phenotype is associated with an epithelial-to-mesenchymal transition (EMT) that allows the tumour cells to become invasive and migratory. The dual tumour suppression/tumour promotion roles of TGF-β have been most clearly elucidated in a transgenic system overexpressing TGF-β in keratinocytes. While the transgenics were more resistant to formation of benign skin lesions, the rate of metastatic conversion in the transgenics was dramatically increased (Cell (1996) 86: 531 -42). The production of TGF-βΙ by malignant cells in primary tumours appears to increase with advancing stages of tumour progression. Studies in many of the major epithelial cancers suggest that the increased production of TGF-β by human cancers occurs as a relatively late event during tumour progression. Further, this tumour-associated TGF-β provides the tumour cells with a selective advantage and promotes tumour progression. The effects of TGF-β on cell/cell and cell/stroma interactions result in a greater propensity for invasion and metastasis.

The important role played by TGF-β in the promotion of cancer growth is also demonstrated by investigations which show a correlation between strong TGF-β expression and a poor prognosis. Increased TGF-β level has been found in patients with prostate, breast, intestinal and lung cancer (Prostate (1998) 37: 19-29; Cancer (2001 ) 91 : 964-971 ; Cancer Epidemiol Biomarkers Prev. (1995) 4: 549-54). As mentioned above, the secretion of TGF-β by malignant cells may represent a significant tumour escape mechanism from host immunosurveillance, since it is a potent inhibitor of the clonal expansion of activated lymphocytes. Establishment of a leukocyte sub-population with disrupted TGF-β signalling in the tumour-bearing host offers a potential means for immunotherapy of cancer (Prostate (2000) 45:167-172). Cancer therapeutic modalities, such as radiation therapy and chemotherapy, induce the production of activated TGF-β in the tumour, thereby selecting outgrowth of malignant cells that are resistant to TGF-β growth inhibitory effects. Thus, these anti-cancer treatments might increase the risk of stimulating the development of tumours with enhanced growth and invasiveness (J. Clin. Invest. (2007) 1 17: 1305-1313). In this situation, agents targeting TGF- β-mediated signal transduction might be a very effective therapeutic strategy. The resistance of tumour cells to TGF-β has been shown to negate many of the cytotoxic effects of radiation therapy and chemotherapy, and the treatment-dependent activation of TGF-β in the stroma may even be detrimental as it can make the microenvironment more conducive to tumour progression and contribute to tissue damage leading to fibrosis. The development of TGF-β signal transduction inhibitors is likely to benefit the treatment of progressed cancer alone and in combination with other therapies.

The key role of TGF^R2 itself was shown in tumour cell lines which express a defective TGF^R2 receptor and exhibit reduced tumour and metastatic growth (Curr. Biol. (1998) 8: 1243-1252; J. Clin. Invest. (1999) 103: 197-206; Int. J. Cancer (2001 ) 91 :76-82). On the other hand, it has been demonstrated that activation of TGF^R2, correlated with MED12 suppression, is sufficient to induce a drug resistance to chemotherapy in colon cancer patients and to gefitinib in lung cancer (Cell (2012) 151 : 937-950). Inhibition of TGF^R signalling restores drug responsiveness in MED12 knockdown cells, suggesting a strategy to treat drug-resistant tumours that have lost MED12 and overexpressed TGF^R2.

Related to its role in the ECM regulation, TGF^R2 mutations have been associated to several connective tissue disorders (referring to a group of disease involving the protein-rich tissue that supports organs and other parts of the body), notably characterized by manifestations in the cardiovascular, skeletal, cartilage, and ocular systems. Among this group of diseases, TGF^R2 mutations have been identified in Loeys-Dietz syndrome, Marfan syndrome, heritable thoracic aortic disorders such as familial thoracic aortic aneurysm and aortic dissection or abdominal aortic aneurysm (Nature Genetics (2005) 37: 275 - 281 ; N Engl J Med (2006) 355: 788-798; Hum Mutat. (2006) 27: 770-777; European J. Hum. Genetics (2010) 18: 240-244). Although most described TGF^R2 mutations are nonsense or misense, an increase TGF-β signalling is generally observed and the pathology are clearly associated to TGF-β pathway. Similarly TGF^R2 frameshift mutations have been associated with hereditary nonpolyposis colon cancer and colorectal cancer with high levels of microsatellite instability, and JGF^ signaling remains active despite the presence of frameshift mutations in the TGF^R2 gene, because the mutated gene still expresses a functional protein (Gastroenterology (2015) Feb 28: S0016-5085). Strategies to inhibit TGF-β signalling, and TGF^R2 in particular, represent a therapeutic option to be evaluated. Other connective tissue disorders associated with excessive TGF-β signalling could be of interest for TGF^R2 targeting therapies, this list includes, but not limited to, Peyronie's disease, Ehlers-Danlos syndrome, Osteogenesis imperfecta, Stickler syndrome, Alport syndrome and congenital contractural arachnodactylyl. Owing to the cancer-promoting actions of TGF-β described above, inhibition of the TGF-β signalling pathway, for example via inhibition of TGF^R2, is a potential therapeutic concept. It has been shown in numerous preclinical trials that interruption of the TGF-β signalling pathway does indeed inhibit cancer growth. Treatment with soluble TGF^R2 reduces the formation of metastases in transgenic mice, which develop invasive breast cancer in the course of time (J. Clin. Invest. (2002) 109: 1551 -1559; J. Clin. Invest. (2002) 109: 1607-1615). Inhibition of the TGF^R2 receptor by overexpression of a dominant negative TGF^R2 receptor has previously been shown to prevent liver fibrosis and dysfunction in rat models (Proc. Natl. Acad. Sci, 1999, 96(5), 2345), and also to prevent progression of established liver fibrosis (Hepatology, 2000, 32, 247).

Compounds of the present invention may be useful in treating the fibrosis associated with various liver-related conditions such as hepatitis B virus (HBV), hepatitis C virus (HCV), alcohol-induced hepatitis, haemochromatosis and primary biliary cirrhosis. In addition, inhibition of angiogenesis is important for tumour growth and metastasis, and treatment of inflammatory diseases like rheumatoid arthritis and psoriasis, or diseases of the eye, like macular degeneration and diabetic retinopathy.

There is a continuing need for new kinase inhibitors targeting the TGF pathway, and it was therefore an object of the present invention to provide a potent, selective, small molecule inhibitor of TGF- R2 kinase activity. Such inhibitors can block specifically TGF- R2 signalling and thereby provide a therapeutic benefit in connective tissue disorders, fibrotic disorders, autoimmune disorders, non-hematological cancers, virus infection, and other diseases characterized by fibrosis and/or dysregulated TGF-β activity. We have now found that the macrocyclic pyrazolopyrimidines and imidazopyridazines and pharmaceutically acceptable compositions according to this invention are useful for the treatment of several disorders associated with TGF- R2 kinase activity (i.e. TGF- R2-kinase associated diseases).

For the determination of certain stages in the signal transduction cascade, interacting compounds can be utilized in order to modulate the signal (e.g. Stephens et al., Biochemical J., 2000, 351 , 95-105). The compounds according to the present invention can also be used as reagents for testing kinase-dependent signal transduction pathways in animals and/or cell culture models or in the clinical diseases mentioned in this application.

SUMMARY OF THE INVENTION

We have surprisingly found that the macrocyclic compounds described herein act as TGF- R2 kinase inhibitors, and are thus very useful in the prevention and/or treatment of TGF- βR2-kinase associated diseases. In a first objective, the present invention provides a compound of Formula I or stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, solvate thereof,

Wherein

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

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

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

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

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

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

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

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

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

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

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

wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -C₃.₆cycloalkyl, -Ar-ι, -Het₉, and -NR₂₃R₂₄; R₆ is selected from -C_1-6alkyl, -S0₂, -S0₂-Ci_-6alkyl, -S0₂-C₃.₆cycloalkyl, -(C=0),

ealkyl, -(C=0)-C₂-₆alkenyl, -(C=0)-0-C₁.₆alkyl, -(C=0)-Het₆, -(C=0)-Ar₆, -(C=0)-C₃_ ecycloalkyl, -(C=0)-NR₃₁R₃₂, -(C=0)-NR₃₁-(C=0)-R₃₂, -(C=S), -(C=S)-C₁.₆alkyl, -(C=S)-C₂. 6alkenyl, -(C=S)-0-C₁.₆alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃.₆cycloalkyl, -(C=S)- NR₃₁R₃₂, -(C=S)-NR₃₁-(C=S)-R₃₂, -Het₆, -Ar₆, and -C₃.₆cycloalkyl;

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

wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from

1 to 3 substituents selected from -Ci_₆alkyl, =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₁₂, -Arn , and -NR₅₃R₅4, -(C=0)-NR₅₃R₅4, -NR₅5(C=0)-NR₅₃R54, -(C=S)-NR₅₃R₅4, and -

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

Rg, Rio, Rii, Ri₂, R"i₃, Ri₄, Ri5. Ri6. Ri7. Ri8. Ri9. R20. R21. R22. R23. R24. R25. R26. R27. R28. R29.

R30, R31 , R32, R33, R34, R35, R36, R37, R38, R39, R40, R44, R45, R46, R47, R48, R49, R50, R53, R54 and R₅₅ are each independently selected from -H, -halo, =0, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci-₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -

O-d-ealkyl, -S-d.₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅iR₅₂;

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

Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

R₄₂ is selected from -H, -OH, -halo, -Ci.₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -NR₄₆R₄₇, -C₃.

₆cycloalkyl, -Ar_g and -Het₈;

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

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

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

NR₅-(C=S)-0-, and -CHR₈- ;

X-i is selected from -Ci_₆alkyl-, -0-Ci.₆alkyl-, -S-d_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-

NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NR₃-d_₆alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-d_ 6alkyl-,

-0-Ci.₆alkyl-0-Ci.₆alkyl- and -d_₆alkyl-NR₃-d-₆alkyl-; wherein each of said -d_₆alkyl- is optionally and independently substituted with from 1 to

3 substituents selected from -halo, -OH, -d_₆alkyl, -0-d_₆alkyl, -S-d_₆alkyl, -phenyl, and

-NR₃₇R₃₈;

X₂ is selected from -Ci_₆alkyl-, -0-Ci.₆alkyl-, -S-Ci.₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl- NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NRz-C^ealkyl-, -NR₂-S0₂-, -NR₂-(C=0)-d_ ₆alkyl-,

-0-Ci_-6alkyl-0-Ci_-6alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -d-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl Y is selected from a direct bond, -CHR₄₂-, -0-, -S-, and -NR₄₃-;

Ar-ι , Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, Ar₁₀ and Ar-n are each independently a 5- to 10- membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar-ι , Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι , Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and Het₁₂ are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι , Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0,

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

Z-i , Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N; and

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

for use in the diagnosis, prevention and/or treatment of TGF- R2-kinase associated disorder, more in particular for the treatment of a TGF- R2-kinase associated connective tissue disorders. In a first embodiment the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein

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

- (C=S)-C₁.₆alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂₈, -(C=S)-NR₂₇R₂₈, -C₃.₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃. 6cycloalkyl, -(C=S)-C₃.₆cycloalkyl, and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₃, -Ar₂, and -NR₁₃R₁₄; R₃ is selected from -H, -halo, -OH, -C_1-6alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl,

-

(C=S)-C₁.₆alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-N R₂₉R₃o, -(C=S)-N R₂₉R₃o,

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

₆cycloalkyl, -(C=S)-C₃.₆cycloalkyl and -S0₂-Ci_₆alkyl; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Het₂, -Ar₃, and -N R₁₅R₁₆;

R₄ is independently selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -N R₁₇R₁₈,

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

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

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

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

N R₃₁ R₃₂, -(C=S)-N R₃₁-(C=S)-R₃₂, -Het₆, -Ar₆, and -C₃.₆cycloalkyl;

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

Het₆, -Ar₆, -N R₂₅R₂₆, -(C=0)-N R₂₅R₂₆, -N R₃₃(C=0)-N R₂₅R₂₆, -(C=S)-N R₂₅R₂₆, and - N R₃₃(C=S)-N R₂₅R₂₆; and

wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_₆alkyl, =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₁₂, -Arn , and -N R₅₃R₅4, -(C=0)-N R₅₃R₅4, -N R₅5(C=0)-N R₅₃R54, -(C=S)-N R₅₃R₅4, and -

Rg, R-io, Ri i , Ri₂, Ri₃, Ri4. Ri5. Ri6, Ri7> ie> Ri9> R20, R21 , R22, R25, R∑6. R27, R∑8. R29, R30. R31 .

R32, R33, R37, R38, R39, R40, R53, R54 and R₅₅ are each independently selected from -H, - halo, =0, -OH, -C_1-6alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to

3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -

Het₇, -Ar₅ and -N R₅i R₅₂;

Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

R₄₃ is -H;

A is selected from -(CH₂)_n-Y-(CH₂)_m-, -N R₆,-;

X-i is selected from -0-Ci_₆alkyl-, -N R₃-Ci_₆alkyl-, -(C=0)-N R₃-Ci_₆alkyl-; wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl, and -N R₃₇R₃₈; X₂ is selected from -0-Ci_₆alkyl-, -N R₂-Ci_₆alkyl-, -(C=0)-N R₂-Ci_₆alkyl-; wherein each of said -Ci_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -N R₃₉R₄₀;

Y is -N R₄₃-;

Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and - NR₁₉R₂o; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι, Het₂, Het₃, Het₄, Het₆, Het₇, Het₁₀, and Het₁₂ are each independently a 4- to 10- membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι, Het₂, Het₃, Het₄, Het₆, Het₇, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0,

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

Z-i, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N; and

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

for use in the diagnosis, prevention and/or treatment of TGF- R2-kinase associated connective tissue disorders.

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

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

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

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

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

R₄ is independently selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -NR₁₇R₁₈, -C₃.₆cycloalkyl, -Ar₈ and -Het₄; R₆ is selected from -C_1-6alkyl, -S0₂, -S0₂-Ci_-6alkyl, -S0₂-C₃.₆cycloalkyl, -(C=0),

ealkyl, -(C=0)-C₂-₆alkenyl, -(C=0)-0-C₁.₆alkyl, -(C=0)-Het₆, -(C=0)-Ar₆, -(C=0)-C₃_ ecycloalkyl, -(C=0)-NR₃₁ R₃₂, -(C=0)-NR₃₁-(C=0)-R₃₂, -(C=S), -(C=S)-C₁.₆alkyl, -(C=S)-C₂. 6alkenyl, -(C=S)-0-C₁.₆alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃.₆cycloalkyl, -(C=S)- NR₃₁ R₃₂, -(C=S)-NR₃₁-(C=S)-R₃₂, -Het₆, -Ar₆, and -C₃.₆cycloalkyl;

1 to 3 substituents selected from -Ci_₆alkyl, =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₁₂, -Arn , and -NR₅₃R₅4, -(C=0)-NR₅₃R₅4, -N R₅5(C=0)-NR₅₃R54, -(C=S)-NR₅₃R₅4, and -

Rg, Rio, Rl 1 , Rl₂, Rl₃, Rl4, Rl5, Rl6, l7> l8> Rl9> R20, ¾1 > R∑2, R∑5, ¾6> R∑7, ^28, R∑9, R30, 3I > R₃₂, R₃₃, R₃₇, R₃8, R₃9, R40, R53, R54 and R₅₅ are each independently selected from -H, - halo, =0, -OH, -C_1-6alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, - Het₇, -Ar₅ and -NR₅i R₅₂;

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

R₄₃ is -H;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci_₆alkyl-,

wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl, and -NR₃₇R₃₈; X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-,

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

or at least X₂ is

Y is -NR₄₃-;

Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -

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

Het-ι , Het₂, Het₃, Het₄, Het₆, Het₇, Het₁₀, and Het₁₂ are each independently a 4- to 10- membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι , Het₂, Het₃, Het₄, Het₆, Het₇, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d.

₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0,

and -NR21 R22; wherein each of said -

Ci-₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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

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

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

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

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

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

R₆ is -Ci_₆alkyl optionally substituted with from 1 to 3 substituents selected from =0, -halo, - OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, - NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; and

R₉, R10, R11 , Ri₂, Ri₃, Ri₄, Ri5. R16. Ri7> R18. Ri9. R20, R21. R22. R25. R26. R27. R∑₈. R29. R30. R33.

R37, R3₈, R39, and R₄₀ are each independently selected from -H, -halo, =0, -OH, -Ci_ 6alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁R₅₂; R₅₁ and R₅₂ are each independently selected from -H, -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-

Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

R₄₃ is -H;

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

Xi is selected from -0-Ci_₆alkyl-, -NR₃-Ci.₆alkyl-,

wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl, and -NR₃7R₃₈; X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-,

wherein each of said -Ci_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R₄₀; wherein at least is

or at least X₂ is

Y is -NR₄₃-;

Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι, Het₂, Het₃, HeU, Het₇, and Het₁₀, are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι, Het₂, Het₃, HeU, Het₇, and Het₁₀, is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0,

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

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

R-i and R₄₁ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S- Ci_₆alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN, -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR₁₂, -0-Ci_₆alkyl, and -S-Ci_ 6alkyl; R₂ is selected from -H, -halo, -OH, -d-₆alkyl; wherein said -Ci_₆alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₃, - Ar₂, and -NR₁₃R₁₄;

R₃ is selected from -H, -halo, -OH, -Ci_₆alkyl; wherein said -Ci_₆alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.

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

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

R₆ is -Ci-₆alkyl optionally substituted with from 1 to 3 substituents selected from =0, -halo, - OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂6, -(C=0)-NR₂₅R₂₆, -

NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-N R₂₅R₂₆; and

Rg, R-io, Rl 1 , Rl₂, Rl₃, Rl4. Rl5. Rl6, Rl7> Rl8> Rl9, R∑0. R∑1. R∑2. R∑5. R∑6. R37. R38. R39, R40, are each independently selected from -H, -halo, =0, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_

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

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

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

R₄₃ is -H;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci_₆alkyl-,

wherein each of said -Ci_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl, and -NR₃₇R₃₈; X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-,

wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃gR₄₀; wherein at least is

or at least X₂ is

Y is -NR₄₃-;

Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -N R-igR₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι , Het₂, Het₃, HeU, Het₇, and Het₁₀, are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι , Het₂, Het₃, HeU, Het₇, and Het₁₀, is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0,

and -NR₂₁ R₂₂; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo; Ζ-ι, Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N; and m and n are each independently 1 , 2, 3, or 4;

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

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

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

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

R₇ is selected from -H, -OH, -halo, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₉, -Ar-, , -C₃. ecycloalkyl, -S0₂-Ar -S0₂, -SO^d-ealkyl, -(C=0), -(C=0)-C₁.₆alkyl, -(C=S), -(C=S)- C^alkyl, -0-(C=0)-C₁.₆alkyl, -0-(C=S)-C₁.₆alkyl, -(C=0)-0-C₁.₆alkyl, and .(C=S)-0-

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

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

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

6alkyl, -(C=0)-C₂-₆alkenyl, -(C=0)-0-C₁.₆alkyl, -(C=0)-Het₆, -(C=0)-Ar₆, -(C=0)-NR₃₁R₃₂, -

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

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

Het₆, -Ar₆, and -C₃.₆cycloalkyl;

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

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

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

Rg, R10, R11 , Ri₂, Ri₃, Ri₄, R15, R16, R17, R18, R19, R20, R21 , R22, R23, R24, R25, R26, R27, R28, R29, R30, R31 , R32, R33, R34, R35, R36, R37, R38, R39, R40, R44, R45, R46, R47, R48, R49, R50, R53, R54 and R₅₅ are each independently selected from -H, -halo, =0, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, - 0-Ci.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁R₅₂;

Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

6cycloalkyl, -Ar₉ and -Het₈;

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

A is selected from -(CH₂)_n-Y-(CH₂)_m-, -(C=0)-, -(C=S)-, -(C=N)-R₄₉-, -(S0₂)-, -S0₂-NR₅-, - (C=0)-NR₅-, -(C=S)-NR₅-, -NR₅-(C=0)-NR₇-, -NR₅-(C=S)-NR₇-, -NR₆,-, -NR₅-(C=0)-0-, - NR₅-(C=S)-0-, and -CHR₈- ; Χ-ι is selected from -C_1-6alkyl-, -0-Ci_-6alkyl-, -S-Ci_-6alkyl-, -(C=0)-, -NR₃-(C=0)-, -C_1-6alkyl- NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NR₃-d_₆alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-d_ 6alkyl-,

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

X₂ is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl- NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-d_₆alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-d_ 6alkyl-,

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

wherein at least is

or at least X₂ is

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

Ar-ι , Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, Ar₁₀ and Ar-n are each independently a 5- to 10- membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar-ι , Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d. 6alkyl, -0-d_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂₀; wherein each of said -d_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι , Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and Het₁₂ are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι , Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_₆alkyl, -Od_₆alkyl, -Sd_₆alkyl, =0, -(C=0)-d_₆alkyl, and -NR₂₁R₂₂; wherein each of said -d_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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

for use in the diagnosis, prevention and/or treatment of a TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and non-hematological cancers.

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

R-i and R₄₁ are each independently selected from -H, -halo, -OH, -d_₆alkyl, -0-d_₆alkyl, -S- d_₆alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN, -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι ; wherein each of said -d_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R₁₂, -0-Ci_₆alkyl, and -S-Ci_ 6alkyl;

- (C=S)-C₁.₆alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-N R₂₇R28, -(C=S)-NR₂₇R28, -C₃-₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.

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

- (C=S)-C₁.₆alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=O)-N R₂₉R₃₀, -(C=S)-NR₂₉R₃₀,

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

6alkyl, -(C=S)-C₂.₆alkenyl, -(C=S)-0-C₁.₆alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃. ecycloalkyl, -(C=S)-NR₃₁ R₃₂, -(C=S)-NR₃₁-(C=S)-R₃₂, -Het₆, -Ar₆, and -C₃.₆cycloalkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to

3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, - Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-N R₂₅R₂₆, -(C=S)-N R₂₅R₂₆, and -NR₃₃(C=S)- NR₂₅R₂₆; and

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

Het₁₂, -Arn , and -NR₅₃R₅4, -(C=0)-NR₅₃R₅4, -N R₅5(C=0)-NR₅₃R54, -(C=S)-NR₅₃R₅4, and -

Rg, R10, R11 , R"|₂, Rl₃, Rl4, Rl5, Rl6, Rl7> Rl8, Rl9, R20, R∑1 , R∑2, R∑5, R∑6, R27, R28, R∑9, R30, R3I ,

R32, R33, R37, R38, R39, R40, R53, R54 and R₅₅ are each independently selected from -H, - halo, =0, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, - Het₇, -Ar₅ and -NR₅i R₅₂;

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

R₄₃ is -H;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci_₆alkyl-,

wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl, and -NR₃₇R₃₈; X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci.₆alkyl-,

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

or at least X₂ is

Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and - NR₁₉R₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι , Het₂, Het₃, Het₄, Het₆, Het₇, Het₁₀, and Het₁₂ are each independently a 4- to 10- membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι , Het₂, Het₃, Het₄, Het₆, Het₇, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_

₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0,

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

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

R₃ is selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - (C=S)-C₁.₆alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=O)-NR₂₉R₃₀, -(C=S)-NR₂₉R₃₀, -C₃-₆cycloalkyl -Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃. 6cycloalkyl, -(C=S)-C₃.₆cycloalkyl and -S0₂-Ci.₆alkyl; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

R₆ is -Ci_₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH, - 0-Ci.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, - NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-N R₂₅R₂₆; and

Rg, Rio, Rl 1 , Rl₂, Rl₃, Rl4. Rl5. Rl6. Rl7> l8> Rl9> R20, ¾1 > R∑2, R∑5, ¾6> R∑7, ^28. R∑9, R30. R33.

R37, R38, R39, and R₄o are each independently selected from -H, -halo, =0, -OH, -Ci_ 6alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-C_1-6alkyl, -S-C_1-6alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅i R₅₂; R₅i and R₅₂ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S- Ci-₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

R₄₃ is -H;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci_₆alkyl-,

or at least X₂ is

Y is -NR₄₃-;

Het-ι , Het₂, Het₃, HeU, Het₇, and Het₁₀, are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι , Het₂, Het₃, HeU, Het₇, and Het₁₀, is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl,

=0,

m and n are each independently 1 , 2, 3, or 4; for use in the diagnosis, prevention and/or treatment of a TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and non-hematological cancers. In yet a further embodiment, the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein

R-i and R₄₁ are each independently selected from -H, -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S- Ci_-6alkyl, -N R₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN , -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι ; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R₁₂, -0-Ci_₆alkyl, and -S-Ci_ 6alkyl;

R₂ is selected from -H, -halo, -OH, -Ci_₆alkyl; wherein said -Ci_₆alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₃, -

Ar₂, and -NR₁₃R₁₄;

R₃ is selected from -H, -halo, -OH, -Ci_₆alkyl; wherein said -Ci_₆alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃. 6cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

Rg, R10, R11 , R"i₂, Ri₃, Ri₄, R15. R16, R17, ie_> Ri9_> R20, R21 , R22, R25. R26. R33. R37. R38. R39. ^and R₄₀ are each independently selected from -H , -halo, =0, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S- Ci-₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1. 6alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅₂;

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

R ₃ is -H;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci_₆alkyl-,

or at least X₂ is -(C=0)-NR₂-Ci_₆alkyl- Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂o; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι, Het₂, Het₃, HeU, Het₇, and Het₁₀, are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι, Het₂, Het₃, HeU, Het₇, and Het₁₀, is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl,

=0,

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

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

Wherein

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

R₂ is selected from -H, -halo, -OH, -Ci_₆alkyl; wherein said -Ci_₆alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₃, - Ar₂, and -NR₁₃R₁₄; R₃ is selected from -H, -halo, -OH, -d-₆alkyl; wherein said -Ci_₆alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃. 6cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

R₆ is -Ci_₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH, - 0-Ci.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂6, -(C=0)-NR₂₅R₂6, - NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-N R₂₅R₂₆; or

R₆ is -Ci_₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH, - 0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -

NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-N R₂₅R₂₆; or

Rg, Rio, Rl 1 , Rl₂, R"|₃, Rl4. Rl5. Rl6. Rl7> Rl8> Rl9> F¾0, f¾1 > f¾2> f¾5> f¾6> ¾3> ¾7> ¾8> ¾9> ^and

R₄o are each independently selected from -H , -halo, =0, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-

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

Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

R₄₃ is -H;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci_₆alkyl-,

wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl, and -NR₃₇R₃₈; X₂ is -(C=0)-N R₂-Ci_₆alkyl-; wherein each of said -Ci_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl,

-S-Ci-₆alkyl, -phenyl and -NR₃₉R₄₀;

Y is -NR₄₃-;

Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo; Het-ι , Het₂, Het₃, HeU, Het₇, and Het₁₀, are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι , Het₂, Het₃, HeU, Het₇, and Het₁₀, is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0,

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

Wherein

R-i and R₄₁ are each independently selected from -H, -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S- Ci_-6alkyl, -N R₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN , -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι ; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R₁₂, -0-Ci_₆alkyl, and -S-Ci_

₆alkyl;

wherein at least one of R-i and R₄₁ is not -H;

R₆ is -Ci_₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH, - 0-Ci.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, - NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-N R₂₅R₂₆; or

Rg, R10, R11 , Ri₂, R"i₃, Ri₄, R15. R16. Ri7> R18. Ri9. R20, R21. R22. R25. R26. R33. R37. R38. R39. ^and R₄₀ are each independently selected from -H , -halo, =0, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S- Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1-

R₅₁ and R₅₂ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S- Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀; R₄₃ is -H;

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

Xi is

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

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci.₆alkyl-,

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

Y is -NR₄₃-;

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

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

Wherein

R-i and R₄₁ are each -H R₂ is selected from -H , -halo, -OH , -d-₆alkyl; wherein said -Ci_₆alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_₆alkyl, -S-Ci_₆alkyl , -Het₃, -Ar₂, and;

R₃ is selected from -H , -halo, -OH , -Ci_₆alkyl; wherein said -Ci_₆alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_₆alkyl , -S-Ci_₆alkyl, -C₃.

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

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

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

R₆ is -C₂ alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_ 6alkyl, -S-Ci_₆alkyl , -C₃.₆cycloalkyl , -Het₆, -Ar₆, -N R₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-

NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; or R₆ is -C₃.₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆, - (C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆

Rg, Rio, Ri i , R"i₂, Ri5. Ri6. Ri7> Ri8. Ri9, R20, R21 , R22. R25. R26. R33. R37. R38. R39. ^and R40 ^are each independently selected from -H , -halo, =0, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -O-C1- 6alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl , -Het₇, -Ar₅ and -NR₅₁ R₅₂;

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

R₄₃ is -H ;

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

Xi is

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

-S-Ci_₆alkyl , -phenyl, and -NR₃₇R₃₈; and wherein *-(C=0)- of

is attached to the ring defined by Z Z₅

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-,

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

Y is -NR₄₃-;

Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -Ci_₆alkyl , -0-Ci_₆alkyl, -S-Ci_₆alkyl , and -NR₁₉R₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo; Het-ι , Het₂, Het₃, HeU, Het₇, and Het₁₀, are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι , Het₂, Het₃, HeU, Het₇, and Het₁₀, is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0,

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

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

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

The present invention also provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predru salt, hydrate, N-oxide form, or solvate thereof,

Wherein

R-i and R₄₁ are each independently selected from -H, -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S- Ci_₆alkyl, -N R₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN , -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι ; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R₁₂, -0-Ci_₆alkyl, and -S-Ci_ 6alkyl;

R₂ is selected from -H, -halo, -OH, -Ci_₆alkyl; wherein said -Ci_₆alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₃, - Ar₂, and -NR₁₃R₁₄;

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

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

Rg, R10, R11 , Ri₂, Ri₃, R"i₄, R15. R16, R17, R18, R19, R20, R21. R22. R25. R26. R33. R37. R38. R39. and R₄₀ are each independently selected from -H , -halo, =0, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S- Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1- 6alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅₂;

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

R ₃ is -H;

A is selected from -(CH₂)_n-Y-(CH₂)_m-, -NR₆,-; Χ-ι is selected from -0-Ci_₆alkyl-, -NR₃-Ci.₆alkyl-,

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

X₂ is

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

Y is -NR₄₃-;

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

for use in human or veterinary medicine, more in particular for use in the diagnosis, prevention and/or treatment of a TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and cancers.

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

Wherein

Ai is N and A₂ is C; R-ι and R₄₁ are each independently selected from -H, -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S- Ci_-6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN, -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι ; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R₁₂, -0-Ci_₆alkyl, and -S-Ci_ 6alkyl;

wherein at least one of R-i and R₄₁ is not -H;

R₆ is -Ci_₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH, - 0-Ci.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, - NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; or

R₆ is -Ci-₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH, - 0-Ci.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, - NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; or

Rg, R-io, R11 , Ri₂, Ri₃, Ri₄, Ri5. R16. Ri7> R18. Ri9. R20, R21. R22. R25. R26. R33. R37. R38. R39. and R₄₀ are each independently selected from -H , -halo, =0, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S- Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1- 6alkyl, -S-d-ealkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅i R₅₂;

Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

R ₃ is -H;

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

Xi is

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

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-,

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

Y is -NR₄₃-;

Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂o; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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

Wherein

R₂ is selected from -H, -halo, -OH, -Ci_₆alkyl; wherein said -Ci_₆alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₃, -Ar₂, and;

R₃ is selected from -H, -halo, -OH, -Ci_₆alkyl; wherein said -Ci_₆alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.

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

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

R₆ is -C₂ alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -O-C₁-

₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)- NR₂₅R₂6, -(C=S)-NR₂₅R₂6, and -NR₃3(C=S)-NR₂5R26; or R₆ is -C₃.₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂6, -(C=0)-NR₂₅R₂₆, -NR₃3(C=0)-NR₂₅R₂₆, -

Rg, R10, R11 , Rl₂, Rl5. Rl6. Rl7_> Rl8_> Rl9_> R20, R2I > R∑2, R∑5, R∑6. R33, R37, R38, R39, R40 3Γβ each independently selected from -H, -halo, =0, -OH , -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁R₅₂;

R₄₃ is -H;

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

Xi is

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

-S-Ci_₆alkyl, -phenyl, and -NR₃₇R₃₈; and wherein *-(C=0)- of

is attached to the ring defined by Z Z₅

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-,

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

Y is -NR₄₃-;

=0,

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

In a further aspect, the present invention provides a compound according to the present invention for use in the diagnosis, prevention and/or treatment of a TGF- R2-kinase associated disease; wherein the pyrazolopyrimidine or the imidazopyridazine moiety is linked to the aryl or heteroaryl moiety at position Z₄ or Z₅, in accordance with the numbering as provided in Formula I. In yet a further aspect, the present invention provides a compound according to the present invention for use in the diagnosis, prevention and/or treatment of a TGF- R2-kinase associated disease; wherein R-i is linked to the aryl or heteroaryl moiety at position Z-i , Z₂ or Z₃, in accordance with the numbering as provided in Formula I.

The present invention further provides a pharmaceutical composition for use in the prevention and/or treatment of a TGF- R2-kinase associated disease comprising a compound according to this invention. Furthermore, the present invention provides the use of a compound or composition according to this invention, suitable for inhibiting the activity of a kinase; in particular a TGF- R2 kinase; or for the diagnosis, prevention and/or treatment of a TGF- R2-kinase associated disease.

Finally, the present invention provides a method for prevention and/or treatment of a TGF- R2-kinase associated disease; said method comprising administering to a subject in need thereof a compound or a composition according to the present invention.

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

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

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

Wherein

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

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

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

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

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

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

-

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

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

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

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

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

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

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

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

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

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

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

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

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

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

Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and - NR₃₃(C=S)-NR₂₅R₂₆; and

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

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

Rg, R-io, Rl 1 , Rl2> Rl3. l4> l5> l6> l7> Rl8> Rl9> R∑0. R∑1 . R∑2. R∑₃. R∑4. R∑5. R∑6. R∑7. R∑8. R∑9.

R₃o, R₃i , R₃2, R₃₃, R₃4, R₃5, R₃6, R₃7, R₃8, R₃₉, R40, R44, R45, R46, R47, R48, R49, R50, Rs₃, R54 and R₅₅ are each independently selected from -H, -halo, =0, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -

0-Ci_-6alkyl, -S-C_1-6alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅i R₅₂;

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

R₄₂ is selected from -H, -OH, -halo, -C_1-6alkyl, -0-Ci_-6alkyl, -S-Ci_-6alkyl, -NR₄₆R₄7, -C₃.

6cycloalkyl, -Ar_g and -Het₈;

R₄₃ is selected from -H, -Ci_₆alkyl, and -C₃.₆cycloalkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci_-6alkyl, -S-C_1-6alkyl, -Het₅, -C₃.₆cycloalkyl -Ar₄, and -NR44R45;

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

NR₅-(C=S)-0-, and -CHR₈- ;

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

-0-Ci_-6alkyl-0-Ci_-6alkyl- and -Ci.₆alkyl-NR₃-Ci.₆alkyl-; wherein each of said -Ci_₆alkyl- is optionally and independently substituted with from 1 to

3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl, and -NR₃₇R₃₈;

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

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

Ar-ι , Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, Ar₁₀ and Ar-n are each independently a 5- to 10- membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar-ι , Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d. 6alkyl, -0-d_₆alkyl, -S-d_₆alkyl, and -NR₁₉R₂₀; wherein each of said -d_₆alkyl is optionally and independently substituted with from 1 to 3 -halo; Het-ι, Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and Het₁₂ are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι, Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and Het-i2 is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C_1-6alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0,

and -NR₂iR₂₂; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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

for use in the diagnosis, prevention and/or treatment of TGF- R2-kinase associated disorder, more in particular for a TGF- R2-kinase associated connective tissue disorder.

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

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

Preferably, X-i is such as the left part of the possible values of X-i (i.e. in particular -O- from - 0-Ci_₆alkyl-, -S- from -S-Ci_₆alkyl-, -NR₃- from -NR₃-(C=0)- and -NR₃-Ci_₆alky-, -S0₂- from - S0₂-NR₃-, etc) is attached to the Z Z₅ aryl or heteroaryl moiety. Alternatively, X-i is such as the right part of the possible values of X-i (i.e. in particular -Ci_₆alkyl- from -0-Ci_₆alkyl-, -S- Ci_₆alkyl- and -NR₃-Ci_₆alkyl-; -(C=0)- from -NR₃-(C=0)-, -(NR₃)- from -S0₂-NR₃-, etc) is attached to the Z Z₅ aryl or heteroaryl moiety.

Preferably, X₂ is such as the left part of the possible values of X₂ (i.e. in particular -O- from - 0-Ci_₆alkyl-, -S- from -S-Ci_₆alkyl-, -(C=0)- from -(C=0)-NR₂-, -NR₂- from -NR₂-Ci_₆alkyl-, - S0₂- from -S0₂-NR₂- etc) is attached to the pyrazolopyrimidine moiety. Alternatively, X₂ is such as the right part of the possible values of X₂ (i.e. in particular -Ci_₆alkyl- from -0-Ci_ ₆alkyl-, -S-Ci_₆alkyl- and -NR₂-Ci_₆alkyl-, -NR₂- from -(C=0)-NR₂- and -S0₂-NR₂-, etc) is attached to the pyrazolopyrimidine moiety.

The same principle applies to all the radicals of the invention unless specified otherwise. When describing the compounds of the invention, the terms used are to be construed in accordance with the following definitions, unless a context dictates otherwise:

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

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

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

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

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

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

Exemplary heterocyclic groups include piperidinyl, azetidinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidyl, succinimidyl, 3H- indolyl, isoindolinyl, chromenyl, isochromanyl, xanthenyl, 2H-pyrrolyl, 1 -pyrrolinyl, 2- pyrrolinyl, 3- pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 4aH-carbazolyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyranyl, dihydro-2H-pyranyl, 4H- pyranyl, 3,4-dihydro- 2H-pyranyl, phthalazinyl, oxetanyl, thietanyl, 3-dioxolanyl, 1 ,3-dioxanyl, 2,5-dioximidazolidinyl, 2,2,4-piperidonyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrehydrothienyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1 , 3-dioxolanyl, 1 ,4-oxathianyl, 1 ,4-dithianyl, 1 ,3,5-trioxanyl, 6H-1 ,2,5-thiadiazinyl, 21-1-1 ,5,2- dithiazinyl, 2H-oxocinyl, 1 H-pyrrolizinyl, tetrahydro- 1 ,1 -dioxothienyl, N- formylpiperazinyl, and morpholinyl; in particular pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, dioxolanyl, dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl, thiazolidinyl, tetrahydropyranyl, and tetrahydrofuranyl.

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

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

The aryl ring can optionally be substituted by one or more substituents. An "optionally substituted aryl" refers to an aryl having optionally one or more substituents (for example 1 to 5 substituents, for example 1 , 2, 3 or 4) at any available point of attachment, selected from those defined above for substituted alkyl. Where a carbon atom in an aryl group is replaced with a heteroatom, the resultant ring is referred to herein as a heteroaryl ring.

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

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

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

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

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

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

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

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

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

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

The terms described above and others used in the specification are well understood to those in the art.

In a particular embodiment, the present invention provides compounds of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof; for use in the diagnosis, prevention and/or treatment of a connective tissue disorder; wherein one or more of the following applies:

Ri and R₄₁ are each independently selected from -H , -halo, -OH , -d-₆alkyl, -0-Ci_₆alkyl , -S- Ci_₆alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN, -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι ; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -NR-nR₁₂, -0-Ci_₆alkyl, and -S-Ci_ 6alkyl; R₂ is selected from -H , -halo, -OH , -C_1-6alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl,

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

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

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

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

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

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

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

1 to 3 substituents selected from -Ci_₆alkyl, =0, -halo, -OH , -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₁₂, -Arn , and -NR₅₃R₅₄,

and -

R₉, R-io, Rii , Ri₂, Ri₃, R"i₄, Ri5. Ri6. Ri7> Ri8. Ri9. R20, R21 , R22. R23. R24. R25. R26. R2₇. R28. R29.

R30, R31 , R32, R33, R34, R35, R36, R3₇, R38, R39, R40, R44, R45, R46, R4₇, R48, R49, R50, R53, R54 and R₅₅ are each independently selected from -H , -halo, =0, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl , -C₃.₆cycloalkyl , -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -

R₅₁ and R₅₂ are each independently selected from -H, -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-

Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

₆cycloalkyl, -Ar₉ and -Het₈;

NR₅-(C=S)-0-, and -CHR₈- ;

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

-0-Ci_₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₃-Ci.₆alkyl-; wherein each of said -Ci_₆alkyl- is optionally and independently substituted with from 1 to

3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl, and

-NR₃₇R₃₈;

X₂ is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl- NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-d_₆alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-d_

₆alkyl-,

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

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

Ar-ι , Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, Ar₁₀ and Ar-n are each independently a 5- to 10- membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar-ι , Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d. 6alkyl, -0-d_₆alkyl, -S-d_₆alkyl, and -NR₁₉R₂₀; wherein each of said -d_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

m and n are each independently 1 , 2, 3, or 4. In particular, X-i, and X₂ as used herein, represent biradicals, which taken together with the radicals to which they are attached form a macrocyclic pyrazolopyrimidine compound. Said biradicals may be present in either of both directions in the macrocyclic pyrazolopyrimidine, but are preferably present in the direction as described below:

Referring to formula I :

X-i is selected from the list comprising *-Ci_₆alkyl-, *-0-Ci_₆alkyl-, *-S-Ci_₆alkyl-, *- (C=0)-, -NR₃-(C=0)-, *-d_₆alkyl-NR₃-, *-NR₃-, *-(C=0)-, *-NR₃-(C=0)-NR₄₈-, *-NR₃-d_ 6alkyl-, *-NR₃-S0₂-, *-NR₃-(C=0)-d_₆alkyl-, *-(C=0)-NR₃-C₁.₆alkyl-, *-0-d_₆alkyl-0-d_ 6alkyl- and *-Ci.₆alkyl-NR₃-Ci.₆alkyl-; wherein said biradical is preferably attached to the aryl or heteroaryl moiety via *;

X₂ is selected from the list comprising *-Ci_₆alkyl-, *-0-Ci_₆alkyl-, *-S-Ci_₆alkyl-, *- (C=0)-, *-NR₂-(C=0)-, ^*-Ci_-6alkyl-NR₂-, *-NR₂-, *-(C=0)-, *-NR₂-(C=O)-NR₅₀-, *-N R₂-d_ 6alkyl-, *-NR₂-S0₂-, *-NR₂-(C=0)-d_₆alkyl-, *-(C=0)-NR₂-d_₆alkyl-, *-0-d_₆alkyl-0-d_ 6alkyl- and *-d-₆alkyl-NR₂-d-₆alkyl-; wherein said biradical is preferably attached to the pyrazolopyrimidine moiety via *;

In a preferred embodiment, the present invention provides compounds of formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, for use in the diagnosis, prevention and/or treatment of a connective tissue disorder wherein :

R-i and R₄₁ are each independently selected from -H , -halo, -OH , -d_₆alkyl, -0-d.₆alkyl , -S- Ci-₆alkyl, -N R₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN , -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι; wherein each of said -d_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -NR-n R₁₂, -0-d_₆alkyl, and -S-C-i. 6alkyl;

R₂ is selected from -H , -halo, -OH , -d_₆alkyl, -0-Ci.₆alkyl, -S-d_₆alkyl,

- (C=S)-d_₆alkyl, -(C=0)-0-d_₆alkyl, -(C=S)-0-d_₆alkyl, -(C=0)-N R₂₇R₂₈, -(C=S)-NR₂₇R₂₈, -C₃.₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.

₆cycloalkyl, -(C=S)-C₃.₆cycloalkyl, and -S0₂-d_₆alkyl; wherein each of said -d_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH , -0-d_₆alkyl, -S-d_₆alkyl, -Het₃, -Ar₂, and -NR₁₃R₁₄;

R₃ is selected from -H , -halo, -OH , -d_₆alkyl, -0-d_₆alkyl, -S-Ci.₆alkyl,

- (C=S)-d_₆alkyl, -(C=0)-0-d_₆alkyl, -(C=S)-0-d_₆alkyl, -(C=O)-N R₂₉R₃₀, -(C=S)-NR₂₉R₃₀,

-C₃.₆cycloalkyl -Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃. 6cycloalkyl, -(C=S)-C₃.₆cycloalkyl and -S0₂-Ci_₆alkyl; wherein each of said -d_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH , -0-d-₆alkyl, -S-d_₆alkyl, -C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆; R₄ is independently selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -NR₁₇R₁₈,

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

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

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

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

NR₃₃(C=S)-NR₂₅R₂₆; and

wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_₆alkyl, =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₁₂, -Arn , and -NR₅₃R₅4, -(C=0)-NR₅₃R₅4, -N R₅5(C=0)-NR₅₃R54, -(C=S)-NR₅₃R₅4, and -

Rg, Rio, Ri i , Ri₂, R"i₃, Ri4, Ri5, Ri6, Ri7, R18, Ri9, R20, R21 , R22, R25, R26, R27, R28, R29, R30, R31 , R32, R33, R37, R38, R39, R40, R53, R54 and R₅₅ are each independently selected from -H, - halo, =0, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -

Het₇, -Ar₅ and -NR₅i R₅₂;

R₄₃ is -H;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci.₆alkyl-,

wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃gR₄o;

Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and - NR-igR₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι , Het₂, Het₃, Het₄, Het₆, Het₇, Het₁₀, and Het₁₂ are each independently a 4- to 10- membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι, Het₂, Het₃, Het₄, Het₆, Het₇, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d. 6alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0,

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

In a further embodiment, the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, for use in the diagnosis, prevention and/or treatment of a connective tissue disorder wherein

-

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

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

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

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

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

wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -d-₆alkyl, =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₁₂, -Arn , and -NR₅₃R₅4, -(C=0)-NR₅₃R₅4, -N R₅5(C=0)-NR₅₃R54, -(C=S)-NR₅₃R₅4, and -

Rg, Rio, Rl 1 , Rl₂, Rl₃, Rl4, Rl5, Rl6, l7> l8> Rl9> R20, ¾1 > R∑2, R∑5, ¾6> R∑7, ^28, R∑9, R30, 3I >

R32, R33, R37, R38, R39, R40, R53, R54 and R₅5 are each independently selected from -H, - halo, =0, -OH, -C_1-6alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to

3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, - Het₇, -Ar₅ and -NR₅i R₅₂;

R₄₃ is -H;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci_₆alkyl-,

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

or at least X₂ is

Y is -NR₄₃-;

Het-ι , Het₂, Het₃, Het₄, Het₆, Het₇, Het₁₀, and Het₁₂ are each independently a 4- to 10- membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι , Het₂, Het₃, Het₄, Het₆, Het₇, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0,

and -NR₂₁ R₂₂; wherein each of said -

Ci-₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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

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

₆alkyl;

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

R₆ is -Ci-₆alkyl optionally substituted with from 1 to 3 substituents selected from =0, -halo, - OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, - NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; and

Rg, R-io, Rl 1 , Rl₂, Rl₃, Rl₄, Rl5, Rl6, Rl7> Rl8, Rl9, R20, R∑1 , R∑2, R∑5, R∑6, R∑7, R2₈, R∑9, R30, R33, R₃₇, R₃₈, R₃₉, and R₄₀ are each independently selected from -H, -halo, =0, -OH, -Ci_

₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C^alkyl, -S-C^alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅iR₅₂; R₅₁ and R₅₂ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S- Ci-₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

R ₃ is -H;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci_₆alkyl-,

or at least X₂ is

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

-C₃.₆cycloalkyl, -Ar₈ and -Het₄; R₆ is -Ci-₆alkyl optionally substituted with from 1 to 3 substituents selected from =0, -halo, - OH, -0-Ci_-6alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂6, -(C=0)-NR₂₅R₂6, -

and -NR₃3(C=S)-NR₂₅R₂₆; and

Rg, Rio, Rl 1 , Rl₂, Rl3. Rl4. Rl5. Rl6. Rl7> Rl8, Rl9, R∑0. R∑1. R∑2. R∑5. R∑6. R37. R38. R39, R40, are each independently selected from -H, -halo, =0, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_

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

R₄₃ is -H;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci_₆alkyl-,

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

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-,

or at least X₂ is

Y is -NR₄₃-;

Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

=0,

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

In a further aspect, the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, for use in the diagnosis, prevention and/or treatment of a TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and non-hematological cancers.

R-i and R₄₁ are each independently selected from -H, -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl , -S- Ci_-6alkyl, -N R₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN , -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR-12, -0-Ci_₆alkyl, and -S-Ci_ 6alkyl;

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

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

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

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

R₅ is selected from -OH , -halo, -Ci_₆alkyl, -0-Ci_₆alkyl , -S-Ci_₆alkyl, -Het₉, -Ar-ι, -C₃.₆cycloalkyl, -SOz-An , -SO2, -SOz-CLealkyl, -(C=0), -(C=0)-C₁.₆alkyl, -(C=S), -(C=S)-C₁.₆alkyl, -O-

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

R₇ is selected from -H, -OH , -halo, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₉, -Ar-, , -C₃. ecycloalkyl, -S0₂-Ar -S0₂, -SOz-C^alkyl, -(C=0), -(C=0)-C₁.₆alkyl, -(C=S), -(C=S)- C^alkyl, -0-(C=0)-C₁.₆alkyl, -0-(C=S)-C₁.₆alkyl, -(C=0)-0-C₁.₆alkyl , and .(C=S)-0-

Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar-ι, -Het₉, and -NR₂₃R2₄; R₆ is selected from -C_1-6alkyl, -S0₂, -S0₂-Ci_-6alkyl, -S0₂-C₃.₆cycloalkyl, -(C=0),

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

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

Rg, Rio, Ri i , Ri₂, Ri₃, Ri₄, Ri5. Ri6. Ri7. Ri8. Ri9. R20, R21. R22. R23. R24. R25. R26. R27. R28. R29.

R30, R31 , R32, R33, R34, R35, R36, R37, R38, R39, R40, R44, R45, R46, R47, R48, R49, R50, R53, R54 and R₅₅ are each independently selected from -H, -halo, =0, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -

O-d-ealkyl, -S-d.₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅i R₅₂;

Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

₆cycloalkyl, -Ar_g and -Het₈;

NR₅-(C=S)-0-, and -CHR₈- ;

X-i is selected from -Ci_₆alkyl-, -0-Ci.₆alkyl-, -S-Ci.₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-

NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NR₃-d_₆alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-d_ 6alkyl-, -(C=0)-NR₃-d_₆alkyl-, -0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₃-Ci.₆alkyl-; wherein each of said -d_₆alkyl- is optionally and independently substituted with from 1 to

-NR₃₇R₃₈;

X₂ is selected from -Ci_₆alkyl-, -0-Ci.₆alkyl-, -S-d_₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl- NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NRz-C^ealkyl-, -NR₂-S0₂-, -NR₂-(C=0)-d_ ₆alkyl-,

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

or at least X₂ is

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

Ar-ι , Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, Ar₁₀ and Ar-n are each independently a 5- to 10- membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar-ι , Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_

₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι , Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and Het₁₂ are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι , Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and

Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0,

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

In a further embodiment, the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, for use in the diagnosis, prevention and/or treatment of a TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and non-hematological cancers.

Wherein one or more of the following applies:

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

R₃ is selected from -H , -halo, -OH , -C_1-6alkyl, -0-Ci_-6alkyl, -S-Ci_-6alkyl,

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

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

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

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

R₇ is selected from -H , -OH , -halo, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₉, -Ar-, , -C₃. ecycloalkyl, -S0₂-Ar -S0₂, -S0₂-d-6alkyl, -(C=0), -(C=0)-C₁.₆alkyl, -(C=S), -(C=S)- d_₆alkyl, -0-(C=0)-d_₆alkyl, -0-(C=S)-d_₆alkyl, -(C=0)-0-d_₆alkyl , and .(C=S)-0- d_₆alkyl; wherein each of said -d_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-d_₆alkyl, -S-d_₆alkyl,

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

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

₆alkyl, -(C=0)-C₂.₆alkenyl , -(C=0)-0-d_₆alkyl, -(C=0)-Het₆, -(C=0)-Ar₆, -(C=0)-NR₃₁R₃₂, - (C=0)-NR₃₁-(C=0)-R₃₂, -(C=S), -(C=S)-d_₆alkyl, -(C=S)-C₂.₆alkenyl, -(C=S)-0-d_₆alkyl, -

Het₆, -Ar₆, and -C₃.₆cycloalkyl;

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

NR₂₅R₂₆; and

wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -d_₆alkyl, =0, -halo, -OH , -0-d_₆alkyl, -S-d_₆alkyl, - Het₁₂, -Arn , and -NR₅₃R₅4, -(C=0)-NR₅₃R₅4, -NR₅5(C=0)-NR₅₃R54, -(C=S)-NR₅₃R₅4, and -

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

R₉, Rio, Rii , R"i₂, Ri₃, Ri4. Ri5. Ri6. Ri7> R18. Ri9. R20. R21. R∑2. R∑3. R∑4. R25. R26. R27. R28. R29.

R₃o, R31 , R₃2, R33. R34. R35. R36. R37. R38. R39. R40, R44. R45. R46. R47. R48, R49. R50. R53. R54 and R₅₅ are each independently selected from -H, -halo, =0, -OH, -d-₆alkyl, -0-Ci_₆alkyl,

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

R₅i and R₅₂ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-

Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

R₄₂ is selected from -H, -OH, -halo, -Ci.₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -NR₄₆R₄7, -C₃.

₆cycloalkyl, -Ar₉ and -Het₈;

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

NR₅-(C=S)-0-, and -CHR₈- ;

Xi is selected from -Ci_₆alkyl-, -0-d_₆alkyl-, -S-Ci.₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl-

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

₆alkyl-,

3 substituents selected from -halo, -OH, -d_₆alkyl, -0-d_₆alkyl, -S-d_₆alkyl, -phenyl, and -NR₃₇R₃₈;

X₂ is selected from -Ci_₆alkyl-, -0-Ci.₆alkyl-, -S-Ci.₆alkyl-, -(C=0)-, -NR₂-(C=0)-, -Ci_₆alkyl- NR₂-, -NR₂-, -(C=0)-, -NR₂-(C=O)-NR₅₀-, -NR₂-d_₆alkyl-, -NR₂-S0₂-, -NR₂-(C=0)-d_ 6alkyl-,

-0-Ci.₆alkyl-0-Ci.₆alkyl- and -Ci.₆alkyl-NR₂-Ci.₆alkyl-; wherein each of said -d_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_₆alkyl, -0-d_₆alkyl, -S-d_₆alkyl, -phenyl and -NR₃₉R₄₀;

wherein at least is -(C=0)-NR₃-d.₆alkyl- or at least X₂ is -(C=0)-NR₂-d.₆alkyl-;

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

Het-ι , Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and Het₁₂ are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι , Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_₆alkyl, -Od_₆alkyl, -Sd_₆alkyl, =0, -(C=0)-d_₆alkyl, and -NR₂₁R₂₂; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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

In a particular embodiment, the present invention provides compounds of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof; for use in the diagnosis, prevention and/or treatment of a TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and non-hematological cancers; wherein

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

6alkyl, -(C=S)-C₂.₆alkenyl, -(C=S)-0-C₁.₆alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃. ecycloalkyl, -(C=S)-NR₃₁R₃₂, -(C=S)-NR₃₁-(C=S)-R₃₂, -Het₆, -Ar₆, and -C₃.₆cycloalkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, - Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)- NR₂₅R₂₆; and

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

Rg, R-io, Rl 1 , Rl2> Rl3> l4> l5> l6> l7> l8> Rl9> R20, ¾1 > R∑2, R∑5, ¾6> f¾7> R28, R∑9, R30, 3I >

R32, R33, R37, R38, R39, R40, R53, R54 and R₅₅ are each independently selected from -H, - halo, =0, -OH, -C_1-6alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, - Het₇, -Ar₅ and -NR₅i R₅₂;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci_₆alkyl-,

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-,

or at least X₂ is

Y is -NR₄₃-;

₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0,

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

In yet a further embodiment, the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, for use in the diagnosis, prevention and/or treatment of a TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and non-hematological cancers; wherein

R-i and R₄₁ are each independently selected from -H , -halo, -OH , -d-₆alkyl, -0-Ci_₆alkyl , -S- Ci_₆alkyl, -N R₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN , -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -NR-nR₁₂, -0-Ci_₆alkyl, and -S-Ci_

₆alkyl;

- (C=S)-C₁.₆alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-N R₂₇R28, -(C=S)-NR₂₇R28, -C₃-₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃. 6cycloalkyl, -(C=S)-C₃.₆cycloalkyl, and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH , -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₃, -Ar₂, and -NR₁₃R₁₄;

- (C=S)-C₁.₆alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=O)-N R₂₉R₃₀, -(C=S)-NR₂₉R₃₀, -C₃.₆cycloalkyl -Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃.

R₆ is -Ci_₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH , - 0-Ci.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, - NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-N R₂₅R₂₆; and

R₉, R10, R11 , Ri₂, R"i₃, Ri₄, R15, R16, Ri7> R18, Ri9, R20, R21 , R22, R25, R26, R27, R28, R29, R30, R33, R₃₇, R₃₈, R₃9, and R₄₀ are each independently selected from -H , -halo, =0, -OH , -Ci_

₆alkyl, -0-Ci_₆alkyl , -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -O-C^alkyl, -S-C^alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅iR₅₂;

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

R ₃ is -H ;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci_₆alkyl-,

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

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-,

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

or at least X₂ is

Y is -NR₄₃-; Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂o; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

m and n are each independently 1 , 2, 3, or 4. In yet a further embodiment, the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, for use in the diagnosis, prevention and/or treatment of a TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and non-hematological cancers; wherein

R-i and R₄₁ are each independently selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S- Ci_₆alkyl, -N R₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN , -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι ; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R₁₂, -0-Ci_₆alkyl, and -S-Ci_ 6alkyl;

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

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

R₆ is -Ci_₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH, - 0-d.ealkyl, -S-C^alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -

Rg, Rio, Ri i , Ri₂, Ri₃, R"i₄, Ri5. Ri6. Ri7> Ri8. Ri9, R20, R21 , R22. R25. R26. R33. R37. R38. R39. and

R₄₀ are each independently selected from -H , -halo, =0, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-

₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁R₅2;

Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

R₄₃ is -H;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci.₆alkyl-,

or at least X₂ is

Y is -NR₄₃-;

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

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

₆alkyl;

Rg, R10, R11 , Ri₂, Ri₃, R"i₄, R15. R16. Ri7> Ri8> Ri9> R20, R21 , R22, R25. R26. R33. R37. R38. R39. and R₄₀ are each independently selected from -H , -halo, =0, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S- Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1. 6alkyl, -S-Ci_-6alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅i R₅₂;

Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

R ₃ is -H;

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

Xi is selected from -0-Ci_₆alkyl-, -NR₃-Ci_₆alkyl-,

wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl, and -NR₃₇R₃₈; X₂ is

Y is -NR₄₃-;

Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂o; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo; Het-ι, Het₂, Het₃, HeU, Het₇, and Het₁₀, are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι, Het₂, Het₃, HeU, Het₇, and Het₁₀, is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0,

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

Wherein

wherein at least one of R-i and R₄₁ is not -H;

Ar₂, and -NR₁₃R₁₄;

R₄ is independently selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -NR₁₇R₁₈, -C₃.₆cycloalkyl, -Ar₈ and -Het₄; R₆ is -Ci-₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH, - 0-Ci_-6alkyl, -S-Ci_-6alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂6, -(C=0)-NR₂₅R₂6, -

and -NR₃3(C=S)-N R₂₅R₂₆; or

R₆ is -Ci-₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH, - 0-Ci_-6alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -

and -NR₃3(C=S)-N R₂₅R₂₆; or

Rg, Rio, Rl 1 , Rl₂, Rl3. Rl4. Rl5. Rl6. Rl7> Rl8> Rl9> F¾0, f¾1 > f¾2> f¾5> f¾6> ¾3> ¾7> ¾8> ¾9> and

R₄o are each independently selected from -H , -halo, =0, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-

Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

R₄₃ is -H;

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

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

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-,

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

Wherein

R₂ is selected from -H, -halo, -OH, -d-₆alkyl; wherein said -Ci_₆alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₃, -Ar₂, and;

R₃ is selected from -H, -halo, -OH, -Ci_₆alkyl; wherein said -Ci_₆alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃. 6cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

R₆ is -C₂ alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_ 6alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -N R₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)- NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; or R₆ is -C₃.₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆, -

(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆

Rg, Rio, Rl 1 , R"|₂, Rl5. Rl6. l7> Rl8, Rl9, R20, R∑1. R∑2, R∑5, R∑6. R33, R37, R38, R39, R40 3Γβ each independently selected from -H, -halo, =0, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_

Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀;

R₄₃ is -H;

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

Xi is

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

is attached to the ring defined by Z Z₅

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci.₆alkyl-,

wherein each of said

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

=0,

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

Wherein

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

Ar₂, and -NR₁₃R₁₄;

and -NR₃3(C=S)-NR₂₅R₂₆; or

Rg, Rio, Rii, Ri₂, Ri3. Ri4. R-is, Ri6, Ri7> i8> i9> R20, 21 > R22, R25, R26. R33, R37, R38. R39, and R₄₀ are each independently selected from -H , -halo, =0, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S- Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_

₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁R₅₂;

R₄₃ is -H;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci.₆alkyl-,

wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl, and -NR₃7R₃₈; X₂ is

-S-Ci-₆alkyl, -phenyl and -NR₃₉R4o;

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

for use in human or veterinary medicine, more in particular for use in the diagnosis, prevention and/or treatment of a TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and cancers. In yet a further embodiment, the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug , salt, hydrate, N-oxide form, or solvate thereof,

Wherein

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

wherein at least one of R-i and R₄₁ is not -H ;

R₂ is selected from -H , -halo, -OH , -Ci_₆alkyl; wherein said -Ci_₆alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₃, - Ar₂, and -NR₁₃R₁₄;

R₃ is selected from -H , -halo, -OH , -Ci_₆alkyl; wherein said -Ci_₆alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_₆alkyl , -S-Ci_₆alkyl, -C₃. 6cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

R₆ is -Ci-₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH , - 0-Ci.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, - NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; or

Rg, R10, R11 , Ri₂, Ri₃, Ri₄, Ri5. R16. Ri7> R18. Ri9. R20, R21. R22. R25. R26. R33. R37. R38. R39. and R₄₀ are each independently selected from -H , -halo, =0, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S- Ci_₆alkyl, -C₃.₆cycloalkyl , -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -O-C1- 6alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl , -Het₇, -Ar₅ and -NR₅₁R₅₂;

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

Ci_₆alkyl, -C₃.₆cycloalkyl , -Ar₁₀ and -Het₁₀;

R ₃ is -H ;

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

Xi is

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

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-,

wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl , -phenyl and -NR₃₉R₄₀; Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂o; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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

Wherein

R₃ is selected from -H, -halo, -OH, -Ci_₆alkyl; wherein said -Ci_₆alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃. 6cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆; R₄ is independently selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -NR₁₇R₁₈,

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

R₆ is -C₂ alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_

₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂6, -NR₃₃(C=0)- NR₂₅R₂6, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; or R₆ is -C₃.₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_

₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆, -

(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆

Rg, Rio, Rl1, Rl₂, Rl5. Rl6. l7> Rl8, Rl9, R20, R∑1. R∑2. R∑5. R∑6. R33. R37. R38. R39. R40 3Γβ each independently selected from -H, -halo, =0, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_

R₄₃ is -H;

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

Xi is

wherein each of said -Ci_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl, and -NR₃₇R₃₈; and wherein *-(C=0)- of

is attached to the ring defined by Z Z₅

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-,

wherein each of said -Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -phenyl and -NR₃₉R₄₀; Y is -NR₄₃-;

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

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

In particular in the compounds according to this invention, the pyrazolopyrimidine or the imidazopyridazine moiety is linked to the aryl or heteroaryl moiety at position Z₄ or Z₅, in accordance with the numbering as provided in Formula I. Furthermore, the R-i of the compounds according to this invention is preferably linked to the aryl or heteroaryl moiety at position Z-i , Z₂ or Z₃, in accordance with the numbering as provided in Formula I. In a particular embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention, for use in the prevention and/or treatment of a TGF- R2-kinase associated disorders. In a specific embodiment, the present invention provides a pharmaceutical composition for use in the prevention and/or treatment of the TGF- R2-kinase associated disease as defined herein, said composition comprising a compound according to the present invention.

In the context of the present invention, the most interesting compounds are compounds according to formula I, or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof wherein the following restrictions apply:

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

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

6alkyl, -(C=S)-C₂.₆alkenyl, -(C=S)-0-C₁.₆alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃_ ecycloalkyl, -(C=S)-NR₃₁R₃₂, -(C=S)-NR₃₁-(C=S)-R₃₂, -Het₆, -Ar₆, and -C₃.₆cycloalkyl; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, - Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)- NR₂₅R₂₆; and

and at least X-, is

or at least X₂ is

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 the following restrictions apply:

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

6alkyl, -(C=S)-C₂.₆alkenyl, -(C=S)-0-C₁.₆alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃. ecycloalkyl, -(C=S)-NR₃₁R₃₂, -(C=S)-NR₃₁-(C=S)-R₃₂, -Het₆, -Ar₆, and -C₃.₆cycloalkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to

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

X₂ is -(C=0)-NR₂-C₁.₆alkyl- is selected from -0-Ci.₆alkyl-, -NR₃-Ci.₆alkyl-,

in particular -O-d. 6alkyl-

Another 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 the following restrictions apply:

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

At least one of R-i and R₄₁ is not -H

6alkyl, -(C=S)-C₂.₆alkenyl, -(C=S)-0-C₁.₆alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃. ecycloalkyl, -(C=S)-NR₃₁R₃₂, -(C=S)-NR₃₁-(C=S)-R₃₂, -Het₆, -Ar₆, and -C₃.₆cycloalkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, - Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-

NR₂₅R₂₆; and

is -(C=0)-NR₃-C₁.₆alkyl-

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-,

in particular -NH-C-,.

6alkyl- Yet another 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 the following restrictions apply:

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

R₆ is -C₂ alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_ 6alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)- NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; or R₆ is -C₃.₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_ ₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂6, -(C=0)-NR₂₅R₂6, -NR₃3(C=0)-NR₂₅R₂₆, -

Xi is , wherein *-(C=0)- is attached to the ring defined by Z Z₅

X₂ is s

elected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-, particular -ΝΗ-C·,.

₆alkyl-

In a further embodiment, the present invention provides the use of a compound, or a pharmaceutical composition as defined herein, for inhibiting the activity of a kinase, more in particular for inhibiting the activity of a TGF- R2 kinase.

The present invention also provides a method for the prevention and/or treatment of a TGF- R2-kinase associated disease, i.e. connective tissue disorders; said method comprising administering to a subject in need thereof a compound of formula I or a composition comprising such compound, wherein

Wherein

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

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

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

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

is selected from -H, -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - (C=S)-C₁.₆alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=O)-NR₂₉R₃₀, -(C=S)-NR₂₉R₃₀, -C₃-₆cycloalkyl -Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃.

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

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

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

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

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

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

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

NR₃₃(C=S)-NR₂₅R₂₆; and

R₈ is selected from -NR₃₄-(C=0)-R₃₅, -NR₃₄-(C=S)-R₃₅, -NR₃₆-(C=0)-NR₃₄R₃₅, -N R₃₆-(C=S)- NR₃₄R₃₅, -NR₃₄-(S0₂)-R₃₅, -NR₃₄-(C=0)-0-R₃₅, -NR₃₄-(C=S)-0-R₃₅, -0-(C=0)-NR₃₄R₃₅, and -0-(C=S)-N R₃₄R₃₅;

Rg, Rio, Ri i , Ri₂, Ri₃, R"i₄, Ri5, Ri6, Ri7_> Ri8, Ri9, R20, R21 , R22, R23, R24, R25, R26, R27, R28, R29, R₃o, R31 , R₃₂, R₃₃, R₃4, R₃5, R36, R37, R38, R39, R40, R44, R45, R46, R47, R48, R49, R50, R53, R54 and R₅₅ are each independently selected from -H, -halo, =0, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, - O-d-ealkyl, -S-C^alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅i R₅₂;

6cycloalkyl, -Ar₉ and -Het₈; R₄₃ is selected from -H, -d-₆alkyl, and -C₃.₆cycloalkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci_-6alkyl, -S-C_1-6alkyl, -Het₅, -C₃.₆cycloalkyl -Ar₄, and -NR44R45;

NR₅-(C=S)-0-, and -CHR₈- ;

X-i is selected from -Ci_₆alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -Ci_₆alkyl- NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NR₃-d_₆alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-d_ 6alkyl-,

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

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

The present invention also provides a method for the prevention and/or treatment of a TGF- R2-kinase associated disease selecte from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and non-hematological cancers; said method comprising administering to a subject in need thereof a compound of formula I or a composition comprising such compound, wherein

R-i and R₄₁ are each independently selected from -H, -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl , -S- Ci_₆alkyl, -N R₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN , -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR₁₂, -0-Ci_₆alkyl, and -S-Ci_

₆alkyl;

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

R₇ is selected from -H, -OH , -halo, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₉, -Ar-, , -C₃. ecycloalkyl, -S0₂-Ar -S0₂, -SO^d-ealkyl, -(C=0), -(C=0)-C₁.₆alkyl, -(C=S), -(C=S)- d-ealkyl, -0-(C=0)-C₁.₆alkyl, -0-(C=S)-C₁.₆alkyl, -(C=0)-0-C₁.₆alkyl , and .(C=S)-0- Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_₆alkyl, -S-Ci_₆alkyl,

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

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

Het₆, -Ar₆, and -C₃.₆cycloalkyl;

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

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

Rg, R-io, R11 , R12, Rl3, Rl4, Rl5, Rl6, Rl7> Rl8> Rl9> F¾0, f¾1 > f¾2> f¾3> f¾4> f¾5> ¾6> R∑7, R28, R∑9, R30, R3I , R32, R33, R34, R35, R36, R37, R38, R39, R40, R44, R45, R46, R47, R48, R49, R50, R53, R54 and R₅₅ are each independently selected from -H, -halo, =0, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl,

-S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, - 0-Ci_-6alkyl, -S-Ci_-6alkyl, -C_3-6cycloalkyl, -Het₇, -Ar₅ and -NR₅₁R₅₂;

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

R₄₂ is selected from -H, -OH, -halo, -C_1-6alkyl, -0-Ci_-6alkyl, -S-Ci_-6alkyl, -NR₄₆R₄₇, -C₃.

₆cycloalkyl, -Ar_g and -Het₈;

R₄₃ is selected from -H, -Ci_₆alkyl, and -C₃.₆cycloalkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci_-6alkyl, -S-C_1-6alkyl, -Het₅, -C₃.₆cycloalkyl -Ar₄, and -NR₄₄R₄₅;

(C=0)-NR₅-, -(C=S)-NR₅-, -NR₅-(C=0)-NR₇-, -NR₅-(C=S)-NR₇-, -NR₆,-, -NR₅-(C=0)-0-, - NR₅-(C=S)-0-, and -CHR₈- ;

X-i is selected from -C_1-6alkyl-, -0-Ci_₆alkyl-, -S-Ci_₆alkyl-, -(C=0)-, -NR₃-(C=0)-, -C_1-6alkyl-

NR₃-, -NR₃-, -(C=0)-, -NR₃-(C=0)-NR₄₈-, -NR₃-Ci_-6alkyl-, -NR₃-S0₂-, -NR₃-(C=0)-d.

₆alkyl-,

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

-NR₃₇R₃₈;

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

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

wherein at least is

or at least X₂ is

Y is selected from a direct bond, -CHR₄₂-, -0-, -S-, and -NR₄₃-; Ar-ι, Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, Ar₁₀ and Ar-n are each independently a 5- to 10- membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar-ι, Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d. 6alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂o; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι, Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and Het₁₂ are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι, Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0, and -NR₂₁R₂₂; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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

The present invention also provides a method for the prevention and/or treatment of a TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and cancers; said method comprising administering to a subject in need thereof a compound of formula I or a composition comprising such compound, wherein

R₆ is -Ci-₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH, - 0-Ci.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, - NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; or R₆ is -Ci-₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH, - 0-Ci_-6alkyl, -S-Ci_-6alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂6, -(C=0)-NR₂₅R₂6, -

and -NR₃3(C=S)-NR₂₅R₂₆; or

Rg, Rio, Rl 1 , Rl2> Rl3> Rl4> Rl5> Rl6> Rl7> Rl8> Rl9> F¾0, f¾1 > f¾2> f¾5> f¾6> ¾3> ¾7> ¾8> ¾9> and

R₄o are each independently selected from -H , -halo, =0, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S- Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁R₅₂;

R₄₃ is -H;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci_₆alkyl-,

X₂ is

Y is -NR₄₃-;

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

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

wherein at least one of R-i and R₄₁ is not -H;

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

R₆ is -Ci_₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH, - 0-Ci.₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂6, -(C=0)-NR₂₅R₂₆, - NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-N R₂₅R₂₆; or

Rg, R10, R11 , Ri₂, R"i₃, Ri₄, R15. R16. Ri7> R18. Ri9. R20, R21. R22. R25. R26. R33. R37. R38. R39. ^and R₄₀ are each independently selected from -H , -halo, =0, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-

Ci-₆alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1- 6alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁ R₅₂;

R ₃ is -H;

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

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

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-,

Y is -NR₄₃-;

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

m and n are each independently 1 , 2, 3, or 4. The present invention also provides a method for the prevention and/or treatment of a TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and cancers; said method comprising administering to a subject in need thereof a compound of formula I or a composition comprising such compound, wherein

R₆ is -C₂ alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -O-C1- 6alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)- NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; or R₆ is -C₃.₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆, - (C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆

Rg, R10, R11 , R"i₂, Ri5. R16. Ri7> R18. Ri9. R20, R21 , R22. R25. R26. R33. R37. R38. R39. and R40 ^are each independently selected from -H, -halo, =0, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1- 6alkyl, -S-Ci_-6alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅i R₅₂;

R₄₃ is -H;

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

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

is attached to the ring defined by Z Z₅

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci.₆alkyl-,

Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₇,

Ar₈, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo; Het-ι , Het₂, Het₃, HeU, Het₇, and Het₁₀, are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι , Het₂, Het₃, HeU, Het₇, and Het₁₀, is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0,

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

The present invention also provides a method for the prevention and/or treatment of a TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and cancers; said method comprising administering to a subject in need thereof a compound selected from the list comprising

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

Compounds of formula (I) a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, are inhibitors of TGF^R2 kinase activity and are thus believed to be of potential use in the prevention and/or treatment of TGF^R2 kinase associated disorders, more in particular for the treatment of connective tissue disorders, fibrotic disorders, autoimmune disorders, and non-hematological cancers.

In the context of the present invention, a connective tissue disorder or disease is any disease that has the connective tissues of the body as a target of pathology. Preferably, the connective tissue disorders to be treated with the compounds and composition of the present invention, are heritable connective tissue disorders and associated with excessive TGF-β signalling, such as for example selected from the list comprising Marfan syndrome, Marfan syndrome type 2, Loeys-Dietz syndrome, Peyronie's disease, Ehlers-Danlos syndrome, Osteogenesis imperfecta, Stickler syndrome, Alport syndrome and congenital contractural arachnodactylyl, familial thoracic aortic aneurysm and aortic dissection. In the context of the present invention, a fibrotic disorder is related to the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This can be a reactive, benign, or pathological state and acts as a deposit of connective tissue, which can obliterate the architecture and function of the underlying organ or tissue. Preferably, the fibrotic disorders to be treated with the compounds and composition of the present invention, are for example selected from the list comprising, idiopathic pulmonary fibrosis, cystic lung fibrosis, liver cirrhosis, endomyocardial fibrosis, nephrogenic systemic fibrosis, keloid, scleroderma/systemic sclerosis. In the context of the present invention, an autoimmune disorder is an abnormal immune response against substances and tissues normally present in the body. Preferably, the autoimmune disorders to be treated with the compounds and composition of the present invention, are for example selected from the list comprising rheumatoid arthritis, psoriasis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, the autoimmune disorders include also the autoimmune response targeting cancer cells.

In the context of the present invention, a non-hematological cancer is a proliferative disorders that does not have an origin in the blood or bone marrow. Preferably, the non-hematological cancers to be treated with the compounds and composition of the present invention, are for example selected from the list comprising hereditary nonpolyposis colon cancer, glioma, lung cancer, liver cancer and prancreatic cancer.

In the invention, particular preference is given to compounds of Formula I or any subgroup thereof that in the inhibition assay for TGF^R2 described below inhibit kinase activity with an IC₅₀ value of less than 10 μΜ, preferably less than 1 μΜ, most preferably less than 100 nM.

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

The term "TGF^R2 kinase-mediated condition" or "disease", as used herein, means any disease or other deleterious condition in which the TGF^R2 kinase and/or mutants thereof is/are known to play a role. The term "TGF^R2 kinase-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with a TGF^R2 kinase inhibitor. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which the TGF^R2 kinase is known to play a role.

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

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

Generally, for pharmaceutical use, the compounds of the inventions may be formulated as a pharmaceutical preparation or pharmaceutical composition comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds. By means of non-limiting examples, such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc.. Such suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is again made to for instance US-A-6, 372,778, US-A-6,369,086, US- A-6,369,087 and US-A-6,372,733, as well as to the standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.

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

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

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

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

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

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

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

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

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

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

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

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

When administered by nasal aerosol or inhalation, these compositions may be prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of the invention or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents. If required, the formulation can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant. For subcutaneous administration, the compound according to the invention, if desired with the substances customary therefore such as solubilizers, emulsifiers or further auxiliaries are brought into solution, suspension, or emulsion. The compounds of the invention can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations. Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, in addition also sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of the various solvents mentioned. The injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1 ,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

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

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

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

EXAMPLES

A. Compound synthesis and phvsicochemical properties

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

As indicated herein before, the present invention provides compounds according to formula I, for use in the diagnosis, prevention and/or treatment of TGF- R2-kinase associated diseases:

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

In general the compounds of formula (I) can be prepared as shown in scheme 1 below wherein a pyrazolo[1 ,5-a]pyrimidine or a imidazo[2,1 -f|pyridazine of formula (II) is converted by reaction with a compound of formula (III) into a compound of formula (IV), which is then reacted with a (hetero-) aryl of formula (V) to form a compound of formula (VI). The compound of formula (VI) can then be optionally deprotected if desired before cyclisation to form a compound of formula (VII). The compound of formula (VII) can be optionally converted into a compound of general formula (I).

Scheme 1

In the above scheme:

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

X₃ and X₄ together with the functional moiety to which they are attached represent an unprotected or a protected functional group which upon reaction (after deprotection) produce together X-i as defined in formula I; E represents a suitable functional group that can be used to form a direct bond between the (hetero-)aryl group and the scaffold.

D represents a functional group such as A or a protected functional group, which upon further reaction and/or deprotection produces a functional group such as A as defined in formula I; In the above reaction of the compound of formula (II) with the compound of formula (III) the leaving groups LGi and LG₂ are advantageously a halo group such as a chlorine or a bromine group. The reaction can be affected by a substitution for example by treating the compound of formula (II) with the compound of formula (III) in an organic solvent such as acetonitrile with an appropriate base such as for example Ν,Ν-diisopropylethylamine at an elevated temperature for example under reflux.

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

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

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

The resulting compound of formula (VI) can optionally be treated to remove any desired protecting groups for example silyl ether groups such as tert-butyldimethylsilyl groups can be converted to the parent free hydroxy group. Such deprotection can be effected in a conventional manner for example using tetrabutylammonium fluoride in tetrahydrofuran at room temperature. The resulting compound of formula (VI) can also optionally be treated to remove any desired protecting groups for example benzyl groups can be removed in a conventional manner for example using hydrogen gas and palladium on activated charcoal (10%) in a solvent such as methanol at a temperature such as room temperature. The compound of formula (VI) can optionally be treated to remove any desired protecting groups for example tert-butyloxycarbonylamino groups can be converted to the parent free amino group. Such deprotection can be effected in a conventional manner for example by treatment under acidic conditions for example using a 4N hydrochloric acid solution in a solvent such as tetrahydrofuran at for example room temperature.

The cyclisation of the compound of formula (VI) can be effected for example by treatment with 0-(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) and N,N- diisopropylethylamine in a solvent such as Ν,Ν-dimethylformamide or N,N-dimethylacetamide at for example room temperature.

The resulting compound of formula (VII) can optionally be treated to remove any desired protecting groups for example tert-butyloxycarbonylamino groups can be converted to the parent free amino group. Such deprotection can be effected in a conventional manner for example by treatment under acidic conditions for example using a 4N hydrochloric acid solution in tetrahydrofuran at room temperature.

The deprotected compound can optionally be treated to form an compound of formula (I). The reaction can advantageously be affected by treatment with an aldehyde under conditions using a base and a reducing agent such as sodium triacetoxyborohydride in a solvent such as methanol.

Compounds A9, K80, K81 , K82, K83, K84, K85, K86, K87 and K102 may be prepared according to the synthesis described in Scheme 1 .

Scheme 2

In the above scheme:

LGi represents a suitable leaving or functional groups;

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

X₅ and X₆ together with the functional moiety to which they are attached represent an unprotected or a protected functional group, which, upon reaction (after deprotection), produce together X₂ as defined in formula I;

E represents a suitable functional group that can be used to form a direct bond between the (hetero-)aryl group and the scaffold. D represents a functional group such as A or a protected functional group, which upon further reaction and/or deprotection produces a functional group such as A as defined in formula I;

In the above reaction of the compound of formula (IX) the leaving group LGi is advantageously a halo group such as chlorine or a bromine group, which could be obtained by bromination of the commercially available compound of formula (VIII).

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

The reaction of the resulting compound of formula (X) with a compound of formula (XI) which can be advantageously effected under Williamson conditions using a base such as potassium carbonate in a solvent such as acetonitrile at an elevated temperature such as under reflux. This reaction can also be effected under Mitsunobu conditions using for example diisopropyl azodicarboxylate and triphenylphosphine in a solvent such as tetrahydrofuran at an elevated temperature such as 90°C.

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

The cyclisation of the compound of formula (XII) can be effected for example by treatment with 0-(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) and Ν,Ν-diisopropylethylamine in a solvent such as Ν,Ν-dimethylformamide at for example room temperature.

In the above scheme:

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

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

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

In the above reaction of the compound of formula (IX) the leaving group LGi is advantageously a halo group such as chlorine or a bromine group, which could be obtained by bromination of the commercially available compound of formula (VIII). The boronic acid or boronate derivative of formula (XV) can be obtained from the compound of formula (XIII) through a Mitsunobu reaction using for example diisopropyl azodicarboxylate and triphenylphosphine in a solvent such as tetrahydrofuran, followed by conversion of LG2 of compound (XIV) into the corresponding boronic acid or boronate ester.

The reaction of the compound (IX) with a (hetero-)aryl compound of formula (XV) is advantageously effected through the coupling of a boronic acid E or boronic ester E derivative of the (hetero-)aryl compound (XV) under Suzuki conditions using for example tetrakis(triphenylphosphine)palladium(0), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) and potassium phosphate tribasic in a solvent mixture such as N,N- dimethylacetamide/water at an elevated temperature for example 100°C.

The cyclisation of the compound of formula (XVI) can be effected for example by treatment with 0-(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) and Ν,Ν-diisopropylethylamine in a solvent such as Ν,Ν-dimethylacetamide at for example room temperature.

The deprotected compound can optionally be treated to form an compound of formula (I). The reaction can advantageously be affected by treatment with an aldehyde under conditions using a base and a reducing agent such as sodium triacetoxyborohydride in a solvent such as methanol. Compounds K89, K90, K91 , K92, K93, K94, K95, K96, K97, K98, K100 and K101 may be prepared according to the synthesis described in Scheme 3.

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

Preparation of example A9

Example A9 is prepared following general scheme 1 and according to the procedures described in the patent application WO2013/045653 A1 to obtain example 9.

Preparation of example K79

Example K79 was prepared according to general scheme 2.

Preparation of intermediate 1

2-((2-Aminoethyl)amino)ethan-1 -ol (2.0 g, 19.2 mmol) (10.0 g, 84.62 mmol) and di-ierf-butyl dicarbonate (9.26 g, 40.32 mmol) were dissolved in dichloromethane (57 ml) and the mixture was was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The compound was used in the next step without further purification.

Preparation of intermediate 2

A mixture of pyrazolo[1 ,5-a]pyrimidine-5-carboxylic acid (10.0 g, 61 .30 mmol) and N- bromosuccinimide (1 1 .45 g, 64.36 mmol) in acetonitrile (184 ml) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the compound was used without further purification in the next step.

Preparation of intermediate 3

A mixture of 1 ,4-dioxane and water (3:1 , 183 ml) was degased by bubbling nitrogen through the mixture. Intermediate 2 (30.65 mmol), 3-hydroxyphenylboronic acid (5.07 g, 36.78 mmol) and potassium phosphate (32.53 g, 153.25 mmol) were added. Tetrakis(triphenylphosphine)palladium(0) (71 1 mg, 0.613 mmol), and 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) (1 .168 g, 2.45 mmol) were added and the suspension was stirred at 85 °C under nitrogen atmosphere for 18 hours. More 3- hydroxyphenylboronic acid (2.53 g, 18.39 mmol), yetrakis(triphenylphosphine)palladium(0) (355 mg, 0.306 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) (584 mg, 1 .22 mmol) were added and the mixture was stirred at 85 °C for 5 hours. The solvent was removed under reduced pressure and the residu was dissolved in ethyl acetate. The organic layer was washed with a 1 N sodium hydroxide solution. The water layer was acidified and the formed solid was filtered and dried under reduced pressure. The filtrate was extracted with ethyl acetate. The organic layer was dried, filtered and the solvent was removed under reduce pressure. The solid fractions were combined and without further purification used in the next step.

LCMS method 2: MH⁺ = 256, RT = 2.037 min Preparation of intermediate 4

A suspension of intermediate 3 (30.65 mmol), methyl iodide (2.86 ml, 45.98 mmol) and potassium bicarbonate (4.6 g, 45.97 mmol) in N,N-dimethylformamide (92 ml) was stirred at room temperature for 18 hours. More methyl iodide (6.0 eq) and potassium biocarbonate (4.5 eq) were added and the mixture was stirred at room temperature for another 72 hours. The solvent was removed under reduced pressure, ethyl acetate was added and washed with water. The formed solid was filtered and dried under reduced pressure (167 mg). The organic layer was dried, filtered and the solvent was removed under reduce pressure. Dichloromethane was added and the formed solid was filtered and dried under reduced pressure. The solid fractions were combined and without further purification used in the next step.

Yield: 5.56 g of intermediate 4 (67%)

LCMS method 1 : MH⁺ = 270, RT = 0.598 min Preparation of intermediate 5

To a suspension of intermediate 4 (3.0 g, 1 1 .14 mmol), the intermediate 1 (5.08 g, 16.71 mmol) and triphenylphosphine (4.38 g, 16.71 mmol) in a mixture of dry tetrahydrofuran (33 ml) and dry N,N-dimethylformamide (6 ml) was added diisopropyl azodicarboxylate (3.31 ml, 16.71 mmol). The suspension was stirred at room temperature for 15 hours. More diisopropyl azodicarboxylate (1 .05 eq) and triphenylphosphine (1 .8 eq) were added and the mixture was stirred at room temperature for 27 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried, filtered and the solvent was removed under reduce pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 50% ethyl acetate). The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 3.25 g of intermediate 5 (52%)

LCMS method 1 : MH⁺ = 578 (MW+Na), RT = 1 .281 min

Preparation of intermediate 6

To a solution of intermediate 5 (3.25 g, 5.85 mmol) in tetrahydrofuran (17.5 ml) was added a 6N hydrochloric acid solution (5.85 mmol, 12 ml/mmol). The reaction mixture was stirred at 60 °C for 3 hours. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. A mixture of toluene/tetrahydrofuran (1 :1 ) was added and evaporated under reduced pressure. Toluene was added three times and evaporated under reduced pressure three times. The compound was dried under vacuum and used without any further purification in the next step.

LCMS method 1 : MH⁺ = 342, RT = 0.226 min Preparation of intermediate 7

A solution of intermediate 6 (5.85 mmol) in N,N-dimethylformamide (146 ml) was added drop wise to a solution of 0-(benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (6.67 g, 17.55 mmol) and triethylamine (15.12 ml, 1 17.0 mmol) in N,N-dimethylformamide (440ml) at room temperature over a period of 5 hours. The solvent was removed under reduced pressure. Ethyl acetate was added and the organic layer was washed with an aqueous saturated sodium carbonate solution. The organic layer was dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using dichloromethane and methanol as eluents (gradient elution from 0% to 5% methanol). The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 671 mg of intermediate 7 (35%)

LCMS method 1 : MH⁺ = 324, RT = 1 .685 min

Preparation of example K79

A 4N hydrochloric acid solution in 1 ,4-dioxane (863 μΙ, 3.45 mmol) was added to a solution of intermediate 7 (745 mg, 2.3 mmol) in a mixture of dichloromethane and methanol (4:1 ) (70 ml). The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. Diethyl ether was added. The solid was filtered and dried under vacuum at 60°C for 24 hours to lead the title compound in 802mg (97% yield).

Yield: 802 mg of example K79 (97%)

LCMS method 2: MH⁺ = 324, RT = 1 .742 Preparation of example K80

Example K80 is prepared following general scheme 1 and according to the procedures described to obtain exam le K84.

Example K81 is prepared following general scheme 1 and according to the procedures described to obtain example K84.

Preparation of example K82

Example K82 is prepared following general scheme 1 and according to the proced described to obtain example K84.

Preparation of example K83

Example K83 is prepared following general scheme 1 and according to the proced described to obtain example K84.

Preparation of example K84 The Example K84 was prepared according to general scheme 1 . tert-Butyl N-[2-[(3- bromopyrazolo[1 ,5-a]pyrimidin-5-yl)amino]ethyl]-N-[2-[tert- butyl(dimethyl)silyl]oxyethyl]carbamate is made according to the procedures described in the patent application WO2013/045653 A1 to obtain intermediate 23. Preparation of intermediate 8

Acetic acid (6 ml/mmol, 400 ml, 64.15 mmol) was added drop wise at 0°C to a solution of tert- butyl N-[2-[(3-bromopyrazolo[1 ,5-a]pyrimidin-5-yl)amino]ethyl]-N-[2-[tert- butyl(dimethyl)silyl]oxyethyl]carbamate (39.43 g, 64.15 mmol) in a mixture of water (200 ml) and tetrahydrofuran (200 ml). The reaction mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and the residu was diluted with ethyl acetate. An aqueous saturated sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried, filtered and the solvent was removed under reduced pressure. The product was used without further purification in the next step.

LCMS method 1 : MH⁺ = 400 (MW-Boc), RT = 1 .084 min Preparation of intermediate 9

Diisopropyl azodicarboxylate (10.86 g, 55.16 mmol) was added drop wise at 0°C to a mixture of intermediate 8 (18.40 g, 36.77 mmol), isoindoline-1 ,3-dione (8.12 g, 55.16 mmol) and triphenylphosphine (14.47 g, 55.16 mmol) in dry tetrahydrofuran (200 ml). The solvent was removed under reduced pressure and the product was used without further purification in the next step.

LCMS method 1 : MH⁺ = 529 (MW-Boc), RT = 1 .294 min Preparation of intermediate 10

A mixture of intermediate 9 (54.36 mmol) and hydrazine hydrate (64%, 14.5 g, 271 .80 mmol) in ethanol (700 ml) was stirred at 50°C overnight. The reaction mixture was cooled, filtered and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with 1 N sodium hydroxide and brine. The organic layer was dried, filtered and the solvent was removed under reduced pressure. The product was used without further purification in the next step.

LCMS method 1 : MH⁺ = 499, RT = 0.503 min Preparation of intermediate 1 1

To a solution of intermediate 10 (25.0 g, 50.06 mmol) in dichloromethane (15 ml) were added triethylamine (20.88 ml, 150.18 mmol) and di-iert-butyl dicarbonate (12.02 g, 55.07 mmol). The mixture was was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents eluents (gradient elution from 0% to 10% ethyl acetate), followed by dichloromethane and methanol (gradient elution from 0% to 10% methanol). The product fractions were collected and the solvent was removed under reduced pressure.

LCMS method 1 : MH⁺ = 499 (MW-Boc), RT = 1 .323 min

Preparation of intermediate 12

A mixture of 1 ,4-dioxane and water (3:1 , 15 ml) was degassed by bubbling nitrogen gas through the mixture. Intermediate 1 1 (3.00 g, 5.00 mmol) and (3-methoxycarbonyl-5-methyl- phenyl)boronic acid (1 .79 g, 6.50 mmol) were dissolved. 2-Dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl (Xphos) (143 mg, 0.30 mmol), tetrakis(triphenylphosphine)palladium(0) (1 16 mg, 0.10 mmol), and potassium phosphate tribasic (5.03 g, 5 eq.) were added and the mixture was stirred under nitrogen gas at 90°C for 16 hours. The reaction mixture was cooled, passed over celite and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using dichloromethane and methanol as eluents (gradient elution from 0% to 10% methanol). The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 3.00 g of intermediate 12 (90%)

LCMS method 1 : MH⁺ = 569 (MW-Boc), RT = 1 .419 min Preparation of intermediate 13

Intermediate 12 (3 g, 4.49 mmol) was dissolved in a 4N hydrochloric acid solution in 1 ,4- dioxane (10 ml). Two drops of water were added and the mixture was stirred at 70°C for 16 hours. Then a 35% aqueous solution of hydrochloric acid was added and the reaction mixture was stirred at 100°C for 2 hours. The solvent was removed under reduced pressure and the residue was used in the next step without further purification.

LCMS method 1 : MH⁺ = 355, RT = 0.336 min Preparation of intermediate 14

0-(Benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) (5.69 g, 15.00 mmol) and N,N-diisopropylethylamine (17.23 ml, 100.00 mmol) were dissolved in N,N- dimethylacetamide (75 ml/mmol). A solution of intermediate 13 (5.00 mmol) in N,N- dimethylacetamide (15 ml) was added drop wise at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction mixture was used as such in the next step.

LCMS method 1 : MH⁺ = 337, RT = 0.366 min

Preparation of intermediate 15

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

To a solution of intermediate 14 (5.00 mmol) and triethylamine (13.86 ml, 100.00 mmol) in dichloromethane (15 ml) was added di-ierf-butyl dicarbonate (21 .82 g, 100.00 mmol). The mixture was was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents eluents, followed by dichloromethane and methanol. The product fractions were collected and the solvent was removed under reduced pressure.

LCMS method 1 : MH⁺ = 437 (MW-Boc), RT = 0.927 min

Preparation of intermediate 16

Intermediate 15 (5.00 mmol) was dissolved in a 4N hydrochloric acid solution in 1 ,4-dioxane (10 ml). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and the compound was precipitated in acetonitrile. The compound was obtained as the hydrochloric acid salt.

Yield: 500 mg of intermediate 16 (30%)

LCMS method 2: MH⁺ = 337, RT = 1 .574 min Preparation of example K84

Intermediate 16 (150 mg, 0.56 mmol), formaldehyde (37% aqueous solution, 1 10 μΙ, 1 .35 mmol) and triethylamine (187 μΙ, 1 .35 mmol) were dissolved in methanol (1 .35 ml) and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (286 mg, 1 .35 mmol) was added and the mixture was stirred at room temperature for 16 hours. A saturated aqueous sodium bicarbonate solution was added and the aqueous layer was extracted with ethyl acetate. The organic layer was dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using dichloromethane and methanol as eluents. The product fractions were collected and the solvent was evaporated.

Yield: 70 mg of example K84 (44%)

LCMS method 2: MH⁺ = 351 , RT = 1 .612 min

Preparation of example K85 Example K85 is prepared following general scheme 1 and according to the procedures used for the synthesis of Example K84.

Preparation of example K86

Example K86 is prepared following general scheme 1 .

Preparation of intermediate 17

4-Hydroxy-8,1 1 ,14, 18,19,22-hexaazatetracyclo[13.5.2.1²,⁶.0^l8,²¹]tricosa- 1 (21 ),2(23),3,5,15(22),16,19-heptaen-7-one (100 mg, 0.30 mmol), 2-[tert- butyl(dimethyl)silyl]oxyacetaldehyde (63 mg, 0.36 mmol) and triethylamine (125 μΙ, 0.90 mmol) were dissolved in methanol (0.90 ml) and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (191 mg, 0.90 mmol) was added and the mixture was stirred at room temperature for 16 hours. A saturated aqueous sodium bicarbonate solution was added and the aqueous layer was extracted with ethyl acetate. The organic layer was dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using dichloromethane and methanol as eluents. The product fractions were collected and the solvent was evaporated.

Yield: 60 mg of intermediate 17 (40%)

LCMS method 1 : MH⁺ = 497, RT = 0.719 min

Preparation of example K86

Acetic acid (6 ml/mmol, 5 μΙ, 0.09 mmol) was added to a solution of intermediate 17 (45 mg, 0.09 mmol) in a mixture of water (0.13 ml) and tetrahydrofuran (0.13 ml). The reaction mixture was stirred at room temperature overnight. A 1 N sodium hydroxide solution was added until slightly basic pH and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using dichloromethane and methanol as eluents (gradient elution from 0% to 5% methanol). The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 7 mg of example K86 (20%)

LCMS method 2: MH⁺ = 383, RT = 1 .716 min Preparation of example K87

Example K87 is prepared following general scheme 1 and according to the procedures used for the synthesis of Example K86.

Preparation of example K88

Example K88 is prepared following general scheme 2.

Example K79 (200 mg, 0.62 mmol), formaldehyde (37% aqueous solution, 150 μΙ, 1 .86 mmol) and triethylamine (259 μΙ, 1 .86 mmol) were dissolved in dichloroethane (1 .86 ml) and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (197 mg, 0.93 mmol) was added and the mixture was stirred at room temperature for 16 hours. A saturated aqueous sodium bicarbonate solution was added and the aqueous layer was extracted with ethyl acetate. The organic layer was dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 50% ethyl acetate). The product fractions were collected and the solvent was evaporated.

Yield: 46 mg of example K88 (22%)

LCMS method 3: MH⁺ = 338, RT = 1 .673 min

Preparation of example K89

Example K89 is prepared following general scheme 3.

Preparation of intermediate 18

To a solution of 2-(3-aminopropylamino)ethanol (10.0 g, 84.62 mmol) in dichloromethane (178 ml) was added drop wise di-iert-butyl dicarbonate (38.78 g, 177.70 mmol). The mixture was was stirred at room temperature overnight. The solvent was removed under reduced pressure. The compound was used in the next step without further purification.

Yield: 19.1 g of intermediate 18 (71 %)

LCMS method 1 : MH⁺ = 341 , RT = 0.815 min

Preparation of intermediate 19

To a solution of intermediate 18 (10.0 g, 31 .41 mmol), 3-bromophenol (3.33 g, 31 .41 mmol) and triphenylphosphine (1 1 .53 g, 43.97 mmol) in tetrahydrofuran (94 ml) was added drop wise diisopropyl azodicarboxylate (8.66 g, 43.97 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 20% ethyl acetate). The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 8.34 g of intermediate 19 (56%)

LCMS method 1 : MH⁺ = 495/497, RT = 1 .310 min Preparation of intermediate 20

Ethyl pyrazolo[1 ,5-a]pyrimidine-5-carboxylate (2.55 g, 13.34 mmol) and /v-bromosuccinimide (2.61 g, 14.67 mmol) in acetonitrile (78 ml) was stirred at room temperature for 2 days. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 20% ethyl acetate). The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 3.196 g of intermediate 20 (89%)

LCMS method 1 : MH⁺ = 272, RT = 0.639 min

Preparation of intermediate 21

Intermediate 19 (8.00 g, 16.90 mmol), bis(pinacolato)diboron (5.15 g, 16.90 mmol) and potassium carbonate (4.976 g, 50.70 mmol) were dissolved in 1 ,4-dioxane (85 ml) and the mixture was degassed by bubbling nitrogen through the solution. [1 ,1 - Bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (686 mg, 0.84 mmol) was added and the reaction mixture was stirred at 85°C for 8 hours. The mixture was cooled and filtered over celite. The sovlent was removed under reduced pressure and the residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 30% ethyl acetate). The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 7.234 g of intermediate 21 (82%)

LCMS method 1 : MH⁺ = 543, RT = 1 .395 min Preparation of intermediate 22

Intermediate 21 (2.50 g, 4.80 mmol), intermediate 20 (1 .296 g, 4.80 mmol), 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) (458 mg, 0.96 mmol) and potassium phosphate tribasic (3.00 g, 3 eq.) were dissolved in a mixture of N,N- dimethylacetamide and water (4:1 , 14.4 ml). The mixture was degassed by bubbling nitrogen through the solution. Tetrakis(triphenylphosphine)palladium(0) (557 mg, 0.48 mmol) was added and the mixture is stirred at 100°C overnight. More tetrakis(triphenylphosphine)palladium(0) (557 mg, 0.48 mmol) and 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl (Xphos) (458 mg, 0.96 mmol) were added and the mixture was stirred for 5 days. The reaction mixture was filtered over celite and the solvent was removed under reduced pressure. The compound was used in the next step without further purification.

Preparation of intermediate 23

Cesium carbonate (1 .877 g, 5.76 mmol) was added to a solution of intermediate 22 (4.80 mmol) in N,N-dimethylacetamide (28.8 ml). Ethyl iodide (595 μΙ, 5.76 mmol) was added drop wise and the reaction mixture was stirred at room temperature overnight. Ethylacetate was added and the organic layer was extracted with water. The organic layer was dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents. The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 2.70 g of intermediate 23 (96%)

LCMS method 1 : MH⁺ = 606, RT = 1 .283 min

Preparation of intermediate 24

A 4N hydrochloric acid solution in 1 ,4-dioxane (15 ml) was added to intermediate 23 (2.60 g, 4.45 mmol) and the mixture was stirred at room temperature overnight. Water (20 ml) and a couple of drops of concentrated hydrochloric acid solution were added and the reaction mixture was stirred at 100°C for 2 hours. The solvent was removed under reduced pressure and the product was used without further purification in the next step.

LCMS method 1 : MH⁺ = 356, RT = 0.213 min

Preparation of intermediate 25

0-(Benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) (5.06 g, 13.35 mmol) and N,N-diisopropylethylamine (15.50 ml, 89.00 mmol) were dissolved in N,N- dimethylacetamide (31 1 ml). A solution of Intermediate 24 (4.45 mmol) in N,N- dimethylacetamide (133 ml) was added drop wise at room temperature. After the addition was completed, a saturated aqueous sodium bicarbonate solution was added and the water phase was extracted with ethyl acetate. The combined organic layers were dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using dichloromethane and methanol as eluents (gradient elution from 0% to 3% methanol). The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 746 mg of intermediate 25 (50%)

LCMS method 1 : MH⁺ = 338, RT = 0.370 min Preparation of intermediate 26

Intermediate 25 was protected with a t-butoxycarbonyl group to enable the purification of the compound.

To a solution of intermediate 25 (535 mg, 1 .59 mmol) and triethylamine (333 μΙ, 2.39 mmol) in dichloromethane (10 ml) was added di-ierf-butyl dicarbonate (417 mg, 1 .91 mmol). The mixture was was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents eluents. The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 353 mg of intermediate 26 (51 %)

LCMS method 1 : MH⁺ = 438, RT = 1 .034 min

Preparation of example K89

A 4N hydrochloric acid solution in 1 ,4-dioxane (4 ml) was added to Intermediate 41 (353 mg, 0.83 mmol) and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The compound was obtained as the hydrochloric acid salt.

Yield: 270 mg of example K89 (99%)

LCMS method 2: MH⁺ = 338, RT = 1 .640 min

Preparation of example K90

Example K90 is prepared following general scheme 3.

Example K89 (210 mg, 0.59 mmol), formaldehyde (37% aqueous solution, 150 μΙ, 1 .86 mmol) and triethylamine (299 μΙ, 2.15 mmol) were dissolved in dichloroethane (3.60 ml) and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (167 mg, 0.83 mmol) was added and the mixture was stirred at room temperature for 16 hours. Dichloromethane was added and the organic layer was extracted with a saturated aqueous sodium bicarbonate solution. The organic layer was dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 50% ethyl acetate). The product fractions were collected and the solvent was evaporated.

Yield: 50 mg of example K90 (24%)

LCMS method 2: MH⁺ = 352, RT = 1 .629 min

Preparation of example K91

Example K91 is prepared following general scheme 3 and according to the procedures used for the synthesis of Example K89.

Preparation of example K92

Example K92 is prepared following general scheme 3.

Preparation of intermediate 27

A solution of N-(3-bromophenyl)-2-nitro-benzenesulfonamide (20.76 g, 58.13 mmol), tert-butyl N-(2-bromoethyl)carbamate (14.33 g, 63.94 mmol) and cesium carbonate (28.41 g, 87.20 mmol) in N,N-dimethylacetamide (175 ml) was stirred at 60°C for 16 hours. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried, filtered and the solvent was removed under reduced pressure. The compound was used in the next step without any further purification.

Yield: 7.90 g of intermediate 27 (27%)

LCMS method 1 : MH⁺ = 521 , RT = 1 .105 min Preparation of intermediate 28

A suspension of intermediate 27 (7.90 g, 15.79 mmol) in a 4N hydrochloric acid solution in 1 - 4-dioxane (30 ml) was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The compound was obtained as the hydrochloric acid salt and was used in the next step without further purification.

LCMS method 1 : MH⁺ = 400, RT = 1 .105 min

Preparation of intermediate 29

2-Nitrobenzenesulfonyl chloride (3.85 g, 17.37) mmol was added portionwise at 0°C to a solution of intermediate 28 (15.79 mmol) and triethylamine (6.58 ml, 47.37 mmol) in dichloromethane (70 ml). The reaction mixture was allowed to warm up to room temperature and stirred for 16 hours. Water was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 30% ethyl acetate). The product fractions were collected and the solvent was removed under reduced pressure.

LCMS method 1 : MH⁺ = 484 (MW-Boc), RT = 1 .050 min Preparation of intermediate 30

A solution of intermediate 29 (15.79 mmol), tert-butyl N-(2-bromoethyl)carbamate (3.893 g, 17.37 mmol) and cesium carbonate (5.66 g, 17.37 mmol) in N,N-dimethylacetamide (50 ml) was stirred at 60°C for 16 hours. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 30% ethyl acetate). The product fractions were collected and the solvent was removed under reduced pressure. Yield: 5.99 g of intermediate 30 (52%)

LCMS method 1 : MH⁺ = 628 (MW-Boc), RT = 1 .190 min

Preparation of intermediate 31

Intermediate 30 (5.70 g, 7.82 mmol) and bis(pinacolato)diboron (2.58 g, 3.73 mmol) were dissolved in 1 ,4-dioxane (30 ml) and the mixture was degassed by bubbling nitrogen through the solution. Potassium carbonate (2.30 g, 23.46 mmol) and [1 ,1 - bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (384 mg, 0.47 mmol) were added and the reaction mixture was stirred at 90°C for 16 hours. The mixture was cooled and filtered over celite. The sovlent was removed under reduced pressure and the residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 30% ethyl acetate). The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 2.71 g of intermediate 31 (45%)

LCMS method 1 : MH⁺ = 676 (MW-Boc), RT = 1 .279 min Preparation of intermediate 32

To a solution of intermediate 1 (4.03 g, 16.66 mmol) in a mixture of tetrahydrofuran and tert- butanol (1 :1 , 100 ml) were added 4-(dimethylamino)pyridine (1 .22 ml, 10.00 mmol) and di- iert-butyl dicarbonate (7.27 g, 33.32 mmol). The mixture was stirred at 90°C for 4 hours. The mixture was cooled to room temperature and water water was added. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 30% ethyl acetate). The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 4.36 g of intermediate 32 (88%)

LCMS method 1 : MH⁺ = 242 (MW-tBu), RT = 0.858 min Preparation of intermediate 33

Intermediate 32 (2.70 g, 3.48 mmol) was dissolved in a mixture of N,N-dimethylacetamide and water (4:1 , 20.0 ml) and the solution was degassed by bubbling nitrogen through. Intermediate 31 (829 mg, 2.78 mmol), tetrakis(triphenylphosphine)palladium(0) (406 mg, 0.35 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) (334 mg, 0.70 mmol) and potassium phosphate tribasic (2.21 g, 10.44 mmol) were added while bubbling nitrogen gas through the mixture. The reaction mixture is stirred at 90°C for 12 hours. The mixture was cooled to room temperature and solvent was removed under reduced pressure. Ethyl acetate was added and the organic layer was extracted with water. The organic layer was dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using dichloromethane and methanol as eluents (gradient elution from 0% to 10% methanol). The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 520 mg of intermediate 33 (18%)

LCMS method 1 : MH⁺ = 71 1 (MW-Boc), RT = 1 .033 min

Preparation of intermediate 34

Intermediate 33 (520 mg, 0.64 mmol) was suspended in a 4N hydrochloric acid solution in 1 ,4-dioxane (5 ml) and the mixture was stirred at room temperature for 96 hours. The solvent was removed under reduced pressure. The compound was obtained as the hydrochloric acid salt. The compound was used in the next step without any further purification.

LCMS method 2: MH⁺ = 71 1 , RT = 0.701 min

Preparation of intermediate 35

0-(Benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) (728 mg, 1 .92 mmol) and N,N-diisopropylethylamine (2.23 ml, 12.80 mmol) were dissolved in N,N- dimethylacetamide (65 ml) and the mixture was stirred at room temperature for 10 minutes. A solution of intermediate 34 (0.64 mmol) in N,N-dimethylacetamide (65 ml) was added drop wise at room temperature and the reaction mixture was stirred at room temperature for 5 minutes. A saturated aqueous sodium bicarbonate solution was added and the water phase was extracted with ethyl acetate. The combined organic layers were dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 100% ethyl acetate). The product fractions were collected and the solvent was removed under reduced pressure.

Preparation of intermediate 36

Intermediate 35 (500 mg, 0.74 mmol) was dissolved N,N-dimethylformamide (1 ml). Cesium carbonate (410 mg, 1 .26 mmol) and thiophenol (130 μΙ, 1 .26 mmol) were added and the mixture was stirred at room temperature for 16 hours. Di-iert-butyl dicarbonate (392 mg, 1 .80 mmol) was added and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried, filtered and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography over silica gel using heptane and ethyl acetate as eluents (gradient elution from 0% to 100% ethyl acetate). The product fractions were collected and the solvent was removed under reduced pressure.

Yield: 25 mg of intermediate 36 (8%)

LCMS method 1 : MH⁺ = 423, RT = 1 .381 min

Preparation of example K92

Intermediate 36 (25 mg, 0.06 mmol) was dissolved in a 4N hydrochloric acid solution in 1 ,4- dioxane (180 μΙ) and the mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The compound was obtained as the hydrochloric acid salt.

Yield: 12 mg of example K92 (62%)

LCMS method 2: MH⁺ = 323, RT = 0.387 min

Preparation of example K93

Example K93 is prepared following general scheme 3 and according to the procedures used for the synthesis of Example K90.

Preparation of example K94

Example K94 is prepared following general scheme 3 and according to the procedures used for the synthesis of Example K89.

Preparation of example K95

Example K95 is prepared following general scheme 3 and according to the procedures used for the synthesis of Example K90.

Preparation of example K96

Example K96 is prepared following general scheme 3 and according to the procedures used for the synthesis of Example K89.

Preparation of example K97

Example K97 is prepared following general scheme 3 and according to the procedures used for the synthesis of example K89 and example K92.

Preparation of example K98

Example K98 is prepared following general scheme 3 and according to the procedures used for the synthesis of example K89 and example K92.

Preparation of example K99

Example K99 is prepared following general scheme 3 and according to the procedures used for the synthesis of example K89 and example K92.

Preparation of example K100

Example K100 is prepared following general scheme 3 and according to the procedures used for the synthesis of Example K89.

Preparation of example K101

Example K101 is prepared following general scheme 3 and according to the procedures used for the synthesis of example K89 and example K92.

Preparation of example K102

Example K102 is prepared following general scheme 1 and according to the procedures used for the synthesis of intermediate 16.

Table 1

Compound A9, Example A9 Compound K79, Example K79

Compound K80, Example K80 Compound K81 , Example K81

Compound K82, Example K82 Compound K83, Example K83

Compound identification

Melting points

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

Melting point method

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

Table 2: Melting points

COMPOUND N° MELTING POINT (°C)

K79 >300

K80 ND*

K81 246.7

K82 ND* K83 253.3

K84 >300

K85 >300

K86 295.2

K87 235

K88 225,0

K89 >300

K90 168.1

K91 >300

K92 >300

K93 223.2

K94 293.9

K95 231.7

K96 >300

K97 >300

K98 273.6

K99 163.0

K100 284.3

K101 286.8

K102 296.9

* Not determined

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

General procedure LCMS

All analyses were performed using an Agilent 61 10 series LC/MSD quadrupole coupled to an Agilent 1290 series liquid chromatography (LC) system consisting of a binary pump with degasser, autosampler, thermostated column compartment and diode array detector. The mass spectrometer (MS) was operated with an atmospheric pressure electro-spray ionisation (API-ES) source in positive ion mode. The capillary voltage was set to 3000 V, the fragmentor voltage to 70 V and the quadrupole temperature was maintained at 100°C. The drying gas flow and temperature values were 12.0 L/min and 350°C respectively. Nitrogen was used as the nebulizer gas, at a pressure of 35 psig. Data acquisition was performed with Agilent Chemstation software. LCMS method 1

In addition to the general procedure LCMS: Analyses were carried out on a Phenomenex Kinetex C18 column (50 mm long x 2.1 mm i.d.; 1 .7 μιη particles) at 60°C, with a flow rate of

1 .5 mL/min. A gradient elution was performed from 90% (water + 0.1 % formic acid) / 10% Acetonitrile to 10% (water + 0.1 % formic acid) / 90% acetonitrile in 1 .50 minutes, then the final mobile phase composition was held for an additional 0.40 min. The standard injection volume was 2 μί. Acquisition ranges were set to 254 nm for the UV-PDA detector and 80-800 m/z for the MS detector. LCMS method 2

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

LCMS method 3

In addition to the general procedure LCMS: Analyses were carried out on a YMC pack ODS- AQ C18 column (50 mm long x 4.6 mm I.D..; 3 μιη particle size) at 35 °C, with a flow rate of

2.6 mL/min. A gradient elution was performed using ISET 2V1 .0 Emulated Agilent Pump G1312A V1 .0 from 94.51 % (Water + 0.1 % Formic acid)/5.49% Acetonitrile to 5% (Water + 0.1 % Formic acid)/95% Acetonitrile in 4.8 min; the resulting composition was held for 1 .0 min; from 5% (Water + 0.1 % formic acid)/95% Acetonitrile to 95% (Water + 0.1 % formic acid)/5% Acetonitrile in 0.2 min. The standard injection volume was 2 μί. Acquisition ranges were set to 190-400 nm for the UV-PDA detector and 100-1000 m/z for the TOF-MS detector.

Table 3: LCMS data

COMPOUND MASS (MH)⁺ RETENTION LCMS

NUMBER PEAK TIME (min) METHOD

K79 324.1 1 .697 2

K80 381 .2 1 .544 2

K81 379.2 1 .702 2

K82 ND* ND* ND*

K83 350.7 1 .448 2

K84 351 1 .612 2 K85 353 1 .169 2

K86 383 1 .224 2

K87 395 1 .447 2

K88 338 1 .673 3

K89 338 1 .640 2

K90 352 1 .878 2

K91 338 1 .718 2

K92 323 0.387 2

K93 352 1 .647 3

K94 338 1 .803 2

K95 352 2.063 2

K96 342 1 .746 2

K97 324 1 .304 3

K98 338 1 .553 3

K99 349 3.380 3

K100 360 1 .740 3

K101 338 1 .653 3

K102 341 .2 1 .587 2

* Not determined

B. Kinase Activity Assay

The inhibition of TGF^R2 kinase was assessed using TGF^R2 recombinant protein in an in vitro peptide-based kinase assay.

Protocol

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

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

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

5 μΙ of test sample in 10% DMSO

10 μ I of enzyme/substrate mixture

The assay for TGF^R2 contains 70 mM HEPES-NaOH pH 7.5, 3 mM MgCI₂, 3 mM MnCI₂, 3 μΜ Na-orthovanadate, 1 .2 mM DTT, 50 μg/ml PEG20000, ATP (0,1 μΜ), [γ-³³Ρ]-ΑΤΡ (approx. 8 x 10⁰⁵ cpm per well), protein kinase TGF^R2 (0,9 nM) and substrate (S6P), 4,0 μg/50 μΙ). The kinase is obtained from Carna Biosciences Inc. The reaction cocktails were incubated at 30° C for 60 minutes. The reaction was stopped with 50 μΙ of 2 % (v/v) H₃P0₄, plates were aspirated and washed two times with 200 μΙ 0.9 % (w/v) NaCI. Incorporation of ³³Pi (counting of "cpm") was determined with a microplate scintillation counter.

Compounds

The compounds are dissolved to 10 mM in DMSO. Where needed, solutions are sonicated in a bath sonicator.

Table 4 provides the plC₅₀ values and % Remaining activity values at two concentrations (1 μΜ and 0,1 μΜ) of the compounds according to the invention, obtained using the above mentioned kinase assay.

Table 4

Compound N° IC₅₀ for TGF- R2 %Remaining %Remaining

TGF- R2 TGF- R2

activity at 1 μΜ activity at 0,1

μΜ

A9 +++ ** **

K79 +++ ** **

K80 +++ ** **

K81 +++ ** **

K82 ND* ND* ND*

K83 +++ ** **

K84 +++ ** **

K85 +++ ** **

K86 +++ ** **

K87 +++ ** **

K88 +++ ** **

K89 +++ ** *

K90 +++ ** **

K91 +++ ND* ND*

K92 ++ ** *

K93 +++ ** **

K94 +++ ** **

K95 +++ ND* ND*

K96 +++ ** **

K97 +++ ** **

K98 ++ ** * K99 +++ ** **

K100 +++ ** *

K101 +++ ** **

K102 ++ ** * + indicates an IC50 > 1 μΜ, ++ indicates an IC50 of between 100 nM and 1 μΜ, and +++ indicates an IC50 < 100nM

* indicates a % remaining kinase activity above 50%, ** indicates a % remaining kinase activity below 50%

ND* = Not determined

Claims

C LAI MS

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

Wherein

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

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

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

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

wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Ar-ι, -Het₉, and -NR₂₃R₂₄; R₆ is selected from -C_1-6alkyl, -S0₂, -S0₂-Ci_-6alkyl, -S0₂-C₃.₆cycloalkyl, -(C=0),

- (C=0)-C₂-₆alkenyl, -(C=0)-0-C₁.₆alkyl, -(C=0)-Het₆, -(C=0)-Ar₆, -(C=0)-C₃-₆cycloalkyl, -(C=0)- NR31 R32, -(C=0)-NR₃₁-(C=0)-R₃₂, -(C=S), -(C=S)-C₁.₆alkyl, -(C=S)-C₂_₆alkenyl, -(C=S)-0-d_ 6alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃-₆cycloalkyl, -(C=S)-NR₃₁ R₃₂, -(C=S)-NR₃₁-(C=S)-R₃₂, -Het₆, -Ar₆, and -C₃.₆cycloalkyl;

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

wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_₆alkyl, =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₁₂, -Ar-n , and -N R53R54, -(C=0)-NR₅₃R₅4, -NR₅5(C=0)-NR₅₃R54, -(C=S)-NR₅₃R₅4, and -NR₅₅(C=S)-

Rg, R10, R11, Rl₂, Rl₃, Rl4. Rl5. Rl6. Rl7> l8> Rl9> R20, ¾1 > R∑2, R∑3. R∑4. R∑5. R∑6. R∑7. R∑8. R∑9, R30.

R31 . R32. R33. R34. R35. R36. R37. R38. R39. R40, R44. R45. R46. R47. R48, R49. R50. R53. R54 and R55 are each independently selected from -H, -halo, =0, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_₆alkyl, -S-Ci_₆alkyl, - C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁R₅₂;

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

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

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

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

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

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

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

0-, and -CHR₈- ;

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

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

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

Ar-ι , Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, Ar₁₀ and Ar-n are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar-ι , Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and - NR₁₉R₂o; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι , Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and Het₁₂ are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι , Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0,

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

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

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

Wherein

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

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

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=O)-N R₂₉R₃₀, -(C=S)-NR₂₉R₃₀, -C₃.₆cycloalkyl -Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl and -S0₂-Ci_₆alkyl; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

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

wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, - Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-N R₂₅R₂₆, and -NR₃₃(C=S)- NR₂₅R₂₆; and

Rg, R10, R11 , Ri₂, Ri₃, Ri4. Ri 5. R16. Ri7> i8> i9> R20, R21 , R22, R25, R∑6. R27, R∑8. R29, R30. R31 . R32.

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

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

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci_₆alkyl-,

wherein each of said -Ci_

₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from

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

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-,

wherein each of said

Ci-₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from

-halo, -OH, -Ci.₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -phenyl and -NR₃₉R₄o; Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar-io and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂o; wherein each of said -Ci-₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι, Het₂, Het₃, He , Het₆, Het₇, Het₁₀, and Het₁₂ are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι, Het₂, Het₃, Het₄, Het₆, Het₇, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0, -

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

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

Wherein

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

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

R₂ is selected from -H, -halo, -OH, -C_{1 6}alkyl, -0-C-,.₆alkyl, -S-C-,.₆alkyl, -(C=0)-C-,.₆alkyl, -(C=S)-C-,_ 6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂₈, -(C=S)-NR₂₇R₂₈, -C₃.₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-C-|.₆alkyl; wherein each of said -C-i_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - Het₃, -Ar₂, and -N Ri ₃Ri₄;

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-N R₂₉R₃o, -(C=S)-N R₂₉R₃₀, -C₃.₆cycloalkyl -Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl and -S0₂-Ci_₆alkyl; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₂, -Ar₃, and -N R₁₅R₁₆;

R₄ is independently selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -N R₁₇R₁₈, -C₃.₆cycloalkyl, -Ar₈ and -Het₄;

- (C=0)-C₂.₆alkenyl, -(C=0)-0-C₁.₆alkyl, -(C=0)-Het₆, -(C=0)-Ar₆, -(C=0)-C₃.₆cycloalkyl, -(C=0)- N R₃i R₃₂, -(C=0)-N R₃₁ -(C=0)-R₃₂, -(C=S), -(C=S)-C₁.₆alkyl, -(C=S)-C₂.₆alkenyl, -(C=S)-0-d_ 6alkyl, -(C=S)-Het₆, -(C=S)-Ar₆, -(C=S)-C₃.₆cycloalkyl, -(C=S)-N R₃₁ R₃₂, -(C=S)-N R₃₁-(C=S)-R₃₂, -Het₆, -Ar₆, and -C₃.₆cycloalkyl;

wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, - Ar₆, -N R₂₅R₂₆, -(C=0)-N R₂₅R₂₆, -N R₃₃(C=0)-N R₂₅R₂₆, -(C=S)-N R₂₅R₂₆, and -N R₃₃(C=S)- N R₂₅R₂₆; and

wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_₆alkyl, =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₁₂, -Ar-n , and -N R53R54, -(C=0)-N R₅₃R₅4, -N R₅5(C=0)-N R₅₃R54, -(C=S)-N R₅₃R₅4, and -N R₅₅(C=S)-

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

A is selected from -(CH₂)_n-Y-(CH₂)_m-, -N R₆-;

X-i is selected from -0-Ci_₆alkyl-, -N R₃-Ci_₆alkyl-, -(C=0)-N R₃-Ci_₆alkyl-; wherein each of said -Ci_

-halo, -OH, -Ci.₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -phenyl, and -N R₃₇R₃₈;

X₂ is selected from -0-Ci_₆alkyl-, -N R₂-Ci_₆alkyl-, -(C=0)-N R₂-Ci_₆alkyl-; wherein each of said

-halo, -OH, -Ci.₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -phenyl and -N R₃₉R₄o;

wherein at least is -(C=0)-N R₃-Ci.₆alkyl- or at least X₂ is -(C=0)-N R₂-Ci.₆alkyl-;

Y is -N R₄₃-; Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar-ιο and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂o; wherein each of said -Ci-₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-ι , Het₂, Het₃, He , Het₆, Het₇, Het₁₀, and Het₁₂ are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι , Het₂, Het₃, Het₄, Het₆, Het₇, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0, -

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

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

Wherein

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

R₂ is selected from -H, -halo, -OH, -C_{1 6}alkyl, -0-C-,.₆alkyl, -S-C-,.₆alkyl, -(C=0)-C-,.₆alkyl, -(C=S)-C-,_ 6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-NR₂₇R₂₈, -(C=S)-NR₂₇R₂₈, -C₃.₆cycloalkyl, -Het₃, -Ar₂, -(C=0)-Het₃, -(C=S)-Het₃, -(C=0)-Ar₂, -(C=S)-Ar₂, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl, and -S0₂-C-|.₆alkyl; wherein each of said -C-i_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-C-i_₆alkyl, -S-C-i_₆alkyl, - Het₃, -Ar₂, and -NRi₃R_M; R₃ is selected from -H, -halo, -OH, -C_1-6alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl,

6alkyl, -(C=0)-0-C₁.₆alkyl, -(C=S)-0-C₁.₆alkyl, -(C=0)-N R₂₉R₃o, -(C=S)-NR₂₉R₃o, -C₃-₆cycloalkyl -Het₂, -Ar₃, -(C=0)-Het₂, -(C=S)-Het₂, -(C=0)-Ar₃, -(C=S)-Ar₃, -(C=0)-C₃.₆cycloalkyl, -(C=S)-C₃. 6cycloalkyl and -S0₂-Ci_₆alkyl; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₂, -Ar₃, and -NR₁₅R₁₆;

R₆ is -Ci_₆alkyl optionally substituted with from 1 to 3 substituents selected from =0, -halo, -OH, - 0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)- NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; and

Rg, Rio, Rl 1 , Rl₂, Rl₃, Rl4. Rl 5. Rl6, l > l8> Rl9> R20, ¾1 > R∑2, R∑5, R∑6. R∑7. R∑8. R∑9. R30. R33. R37.

R₃₈, R₃₉, and R₄₀ are each independently selected from -H, -halo, =0, -OH, -Ci_₆alkyl, -O-C1.

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

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

R₄₃ is -H;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci_₆alkyl-,

wherein each of said -Ci_

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

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-,

wherein each of said

-halo, -OH, -Ci_-6alkyl, -0-Ci_-6alkyl, -S-Ci_-6alkyl, -phenyl and -NR₃₉R₄o;

wherein at least is

or at least X₂ is

Y is -NR₄₃-;

Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar-ιο being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂₀; wherein each of said -Ci_ 6alkyl is optionally and independently substituted with from 1 to 3 -halo;

Z-i , Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N; and m and n are each independently 1 , 2, 3, or 4;

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

Wherein

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

R₂ is selected from -H , -halo, -OH, -Ci_₆alkyl; wherein said -Ci_₆alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₃, -Ar₂, and -

R₃ is selected from -H , -halo, -OH, -Ci_₆alkyl; wherein said -Ci_₆alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, - Het₂, -Ar₃, and -NRi₅Ri₆;

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

R₆ is -Ci-₆alkyl optionally substituted with from 1 to 3 substituents selected from =0, -halo, -OH, -

0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-

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

Rg, R-io, Ri i , Ri₂, Ri₃, Ri₄, Ri5. Ri6. Ri7> Ri8. Ri9, R20, R21 , R22, R25. R26. R37. R38. R39. ^and R40, ^are each independently selected from -H, -halo, =0, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.

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

-C₃.₆cycloalkyl, -Het₇, -Ar₅ and -N R₅₁ R₅₂;

₆alkyl, -C₃.₆cycloalkyl, -Ar₁₀ and -Het₁₀; R₄₃ is -H;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci.₆alkyl-,

wherein each of said -d.

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

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci.₆alkyl-,

wherein each of said

-halo, -OH, -Ci.₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -phenyl and -NR₃₉R₄o;

wherein at least is

or at least X₂ is

Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂₀; wherein each of said -Ci-₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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

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

Wherein

Ai is N and A₂ is C; R-ι and R₄₁ are each independently selected from -H, -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_ 6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN, -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι ; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R₁₂, -0-Ci_₆alkyl, and -S-Ci_₆alkyl;

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

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

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

R₇ is selected from -H, -OH, -halo, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₉, -Ar-ι , -C₃.₆cycloalkyl, - SOz-A^ , -SO2, -S0₂-d_₆alkyl, -(C=0), -(C=0)-C₁.₆alkyl, -(C=S), -(C=S)-C₁.₆alkyl, -0-(C=0)-d_ 6alkyl,

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

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

wherein each of said -C₃.₆cycloalkyl is optionally and independently substituted with from 1 to 3 substituents selected from -Ci_₆alkyl, =0, -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₁₂, -Ar-n , and -N R53R54, -(C=0)-NR₅₃R₅4, -NR₅5(C=0)-NR₅3R54, -(C=S)-NR₅₃R₅4, and -NR₅₅(C=S)-

Rg, R10, R11, R12. Ri₃. Ri4. Ri5. R16. Ri7. R18. Ri9. R20, R21 , R22, R∑₃. R24, R25, R26. R27. R28. R29. R₃0.

R₃i. R₃2. R₃₃. R₃4. R₃5. R₃6. R₃7. R₃8, R₃9, R40, R44. R45. R46. R47. R48, R49. R50. Rs₃, R54 and R55 are each independently selected from -H, -halo, =0, -OH , -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_₆alkyl, -S-Ci_₆alkyl, - C₃.₆cycloalkyl, -Het₇, -Ar₅ and -NR₅₁R₅2;

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

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

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

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

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

0-, and -CHR₈- ;

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

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

wherein at least is

or at least X₂ is

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

Ar-ι, Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, Ar₁₀ and Ar-n are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar-ι, Ar₂, Ar₃, Ar₄, Ar₅, Ar₆, Ar₇, Ar₈, Ar₉, and Ar₁₀ being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and - NR₁₉R₂₀; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo; Het-ι, Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and Het₁₂ are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι, Het₂, Het₃, Het₄, Het₅, Het₆, Het₇, Het₈, Het₉, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d. 6alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0,

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

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

Wherein

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

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

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

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

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

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

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

-

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

wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, - NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-N R₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; and

Rg, R10, R11 , R"|₂, Rl₃, R14. Rl 5. Rl6. Rl7> l8> Rl9> R20, ¾1 > R∑2, R∑5, R∑6. R∑7. R∑8. R∑9. R30. 3I > R32.

R₄₃ is -H;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci_₆alkyl-,

wherein each of said -Ci_

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-,

wherein each of said

wherein at least is

or at least X₂ is

Y is -NR₄₃-;

Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar₁₀ and Ar-n are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₆, Ar₇, Ar₈, Ar-ιο and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C-i_₆alkyl, -0-C-i_₆alkyl, -S-C-i_₆alkyl, and -NR₁₉R₂₀; wherein each of said -Ci-₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

Het-i , Het₂, Het₃, He , Het₆, Het₇, Het₁₀, and Het₁₂ are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-i , Het₂, Het₃, Het₄, Het₆, Het₇, Het₁₀, and Het₁₂ is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0, -

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

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

Wherein

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

R₄ is independently selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -NR₁₇R₁₈, -C₃.₆cycloalkyl, -Ar₈ and -Het₄; R₆ is -Ci-₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_ 6alkyl, -S-Ci_-6alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂6, -(C=0)-NR₂₅R₂6, -NR₃3(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃3(C=S)-NR₂₅R₂₆; and

Rg, Rio, Rl1, R"|₂, Rl3. Rl4. Rl5, Rl6, l > l8> l9> R∑0. R∑1 , R∑2. R∑5. R∑6. R∑7. R∑8. R∑9. R30. R33. R37.

R₃₈, R₃₉, and R₄₀ are each independently selected from -H, -halo, =0, -OH, -d-₆alkyl, -O-C1.

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

R₄₃ is -H;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci_₆alkyl-,

wherein each of said -Ci_

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-,

wherein each of said

wherein at least is

or at least X₂ is

Y is -NR₄₃-;

Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar-io being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂₀; wherein each of said -Ci_ 6alkyl is optionally and independently substituted with from 1 to 3 -halo;

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

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

Wherein

R-i and R₄₁ are each independently selected from -H, -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_

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

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

R₆ is -Ci-₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH , -O-C1-

₆alkyl, -S-Ci.₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆,

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

Rg, R10, R11, Ri₂, R"i₃, Ri₄, R15. R16. Ri7> Ri8> Ri9> R20, R21 , R22, R25. R26. R33. R37. R38. R39. ^and R40 are each independently selected from -H, -halo, =0, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -

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

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

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

R₄₃ is -H;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci_₆alkyl-,

wherein each of said -Ci_

6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci.₆alkyl, -0-Ci.₆alkyl, -S-Ci.₆alkyl, -phenyl, and -NR₃₇R₃₈; X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci.₆alkyl-,

wherein each of said

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

wherein at least is

or at least X₂ is

Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar₁₀ are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar₂, Ar₃, Ar₅, Ar₇, Ar₈, and Ar-io being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, and -NR₁₉R₂₀; wherein each of said -Ci_ 6alkyl is optionally and independently substituted with from 1 to 3 -halo;

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

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

Wherein

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

6alkyl, -NR₉R₁₀, -(C=0)-R₄, -(C=S)-R₄, -S0₂-R₄, -CN, -NR₉-S0₂-R₄, -C₃.₆cycloalkyl, -Ar₇ and -Het-ι; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR₁₂, -0-Ci_₆alkyl, and -S-Ci_₆alkyl; R₂ is selected from -H , -halo, -OH, -d-₆alkyl; wherein said -Ci_₆alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₃, -Ar₂, and -

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

R₆ is -Ci_₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH , -O-C1-

₆alkyl, -S-Ci_-6alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂6, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆,

-(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; or

R₆ is -Ci_₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH , -O-C1.

₆alkyl, -S-Ci_-6alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆,

-(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; or

Rg, R10, R11 , Rl₂, Rl₃, Rl4. Rl5. Rl6. Rl7_> l8_> Rl9_> R20, f¾1 _> R∑2, R∑5, ¾6> ^33. R37, R38. R39. and R40 are each independently selected from -H, -halo, =0, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -N R₅₁ R₅₂;

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

R₄₃ is -H;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci_₆alkyl-,

wherein each of said -Ci_

X₂ is -(C=0)-N R₂-Ci_₆alkyl-; wherein each of said -Ci_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-

Ci-₆alkyl, -phenyl and -N R₃₉R₄₀;

Y is -NR₄₃-;

Het-ι , Het₂, Het₃, HeU, Het₇, and Het₁₀, are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι , Het₂, Het₃, HeU, Het₇, and Het₁₀, is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0, -(C=0)-Ci_₆alkyl, and -NR21 R22; wherein each of said -d-₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

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

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

Wherein

wherein at least one of R-i and R₄₁ is not -H;

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

-(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; or

Rg, R10, R11 , Ri₂, Ri₃, Ri₄, Ri5, R16, Ri7> R18, Ri9, R20, R21 , R22, R25, R26, R33, R37, R38, R39, ^and R40 are each independently selected from -H, -halo, =0, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -

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

R₅₁ and R₅₂ are each independently selected from -H, -halo, -OH, -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_

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

R₄₃ is -H;

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

Xi is

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

Ci-₆alkyl, -phenyl, and -NR₃7R₃₈;

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-,

wherein each of said

Y is -NR,

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

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

Wherein

Ai is N and A₂ is C; R-ι and R₄₁ are each -H

R₂ is selected from -H , -halo, -OH, -d-₆alkyl; wherein said -Ci_₆alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -Het₃, -Ar₂, and;

R₃ is selected from -H , -halo, -OH, -Ci_₆alkyl; wherein said -Ci_₆alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₂, - Ar₃, and -NR₁₅R₁₆;

R₆ is -C₂ alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂₆, -(C=0)-N R₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆, - (C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; or R₆ is -C₃.₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₆, - Ar₆, -NR₂₅R₂₆, -(C=0)-NR₂₅R₂₆, -NR₃₃(C=0)-NR₂₅R₂₆, -(C=S)-N R₂₅R₂₆, and -NR₃₃(C=S)-

Rg, R-io, Ri i , Ri₂, Ri5. Ri6. Ri7> Rie> Ri9> R20, R21 > R22, R25, R26. R33, R37, R38. R39, ^and R40 ^are each independently selected from -H, -halo, =0, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃. 6cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -N R₅₁ R₅₂;

R₄₃ is -H;

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

Xi is

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

is attached to the ring defined by Z Z₅

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-,

wherein each of said

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

Y is -NR₄₃-;

Het-ι , Het₂, Het₃, HeU, Het₇, and Het₁₀, are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het-ι , Het₂, Het₃, HeU, Het₇, and Het₁₀, is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -OCi_₆alkyl, -SCi_₆alkyl, =0, -(C=0)-Ci_₆alkyl, and -NR21R22; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 -halo;

ZL Z₂, Z₃, Z₄ and Z₅ are each independently selected from C and N; and

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

. A compound selected from the list comprising:

14. A compound as defined in anyone of claims 10-13 for use in human or veterinary medicine.

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

Wherein

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

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

-(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; or

R₆ is -Ci-₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH , -O-C1.

-(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; or

Rg, R10, R11 , R"|₂, Rl₃, Rl4. Rl5. Rl6. Rl7_> l8_> Rl9_> R20, ¾1 _> R∑2, R∑5, ¾6> ^33. R37, R38. R39. and R40 are each independently selected from -H, -halo, =0, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -N R₅₁ R₅₂;

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

R₄₃ is -H;

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

X-i is selected from -0-Ci_₆alkyl-, -NR₃-Ci_₆alkyl-,

wherein each of said -Ci_

X₂ is -(C=0)-N R₂-Ci-₆alkyl-; wherein each of said -Ci_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-

Ci-₆alkyl, -phenyl and -N R₃₉R₄₀;

Y is -NR₄₃-;

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

for use in the diagnosis, prevention and/or treatment of a TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and cancers.

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

Wherein

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

wherein at least one of R-i and R₄₁ is not -H;

-C₃.₆cycloalkyl, -Ar₈ and -Het₄;

R₆ is -Ci-₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH , -O-C₁-

-(C=S)-NR₂₅R₂₆, and -NR₃₃(C=S)-NR₂₅R₂₆; or R₆ is -Ci-₆alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_ 6alkyl, -S-Ci_-6alkyl, -C₃.₆cycloalkyl, -Het₆, -Ar₆, -NR₂₅R₂6, -(C=0)-NR₂₅R₂6, -NR₃3(C=0)-NR₂₅R₂₆, -(C=S)-NR₂₅R₂₆, and -NR₃3(C=S)-NR₂₅R₂₆; or

Rg, Rio, Ri i , R"i₂, Ri3. Ri4. R-is, Ri6, Ri7> i8> i9> R20, R21 , R22, R25, R∑6. R33, R37, R38. R39, ^and R40 are each independently selected from -H, -halo, =0, -OH , -d-₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, - C₃.₆cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -N R₅₁ R₅₂;

R₄₃ is -H;

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

Xi is -(C=0)-N R₃-Ci_₆alkyl-; wherein each of said -Ci_₆alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_₆alkyl, -0-Ci_₆alkyl, -S-

Ci-₆alkyl, -phenyl, and -NR₃₇R₃₈;

X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci_₆alkyl-,

wherein each of said

Y is -NR₄₃-;

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

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

Wherein

Rg, R-io, Ri i , Ri₂, Ri5. Ri6. Ri7> Rie> Ri9> R20, R21 > R22, R25, R26. R33, R37, R38. R39, and R40 are each independently selected from -H, -halo, =0, -OH , -Ci_₆alkyl, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃. 6cycloalkyl, -Ar₅ and -Het₇; wherein each of said -Ci_₆alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_₆alkyl, -S-Ci_₆alkyl, -C₃.₆cycloalkyl, -Het₇, -Ar₅ and -N R₅₁ R₅₂;

R₄₃ is -H;

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

Xi is

is attached to the ring defined by Z Z₅ X₂ is selected from -0-Ci_₆alkyl-, -NR₂-Ci.₆alkyl-,

wherein each of said

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

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

18. A compound as defined in claim 13, for use in the diagnosis, prevention and/or treatment of a TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and cancers.

19. A compound as defined in anyone of claims 10-12 or a compound for use as defined in any one of claims 1 to 9 or 15-17; wherein the pyrazolopyrimidine or the imidazopyridazine moiety is linked to the aryl or heteroaryl moiety at position Z₄ or Z₅, in accordance with the numbering as provided in Formula I.

20. A compound as defined in anyone of claims 10-12 or a compound for use as defined in any one of claims 1 to 9 or 15-17; wherein R-i is linked to the aryl or heteroaryl moiety at position Z-i, Z₂ or Z₃, in accordance with the numbering as provided in Formula I.

21 . A pharmaceutical composition comprising a compound as defined in any one of claims 1 -5 or 13, for use in the prevention and/or treatment of a connective tissue disorder.

22. A pharmaceutical composition comprising a compound as defined in any one of claims 6-9 or 13, for use in the prevention and/or treatment of a TGF R2-associated disorder, selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and non-hematological cancers.

23. A pharmaceutical composition comprising a compound as defined in any one of claims 10-13.

24. A pharmaceutical composition comprising a compound as defined in any one of claims 10-18, for use in the prevention and/or treatment of a TGF R2-associated disorder, selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and cancers.

25. Use of a compound as defined in any one of claims 1 to 18, or a pharmaceutical composition as defined in anyone of claims 21 -24, for inhibiting the activity of a TGF- R2 kinase.

23. A method for the prevention and/or treatment of a TGF R2-associated connective tissue disorder; said method comprising administering to a subject in need thereof a compound as defined in anyone of claims 1 to 5 or 13; or a pharmaceutical composition as defined in claim 21 .

24. A method for the prevention and/or treatment of a TGF R2-associated disorder, selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and non-hematological cancers; said method comprising administering to a subject in need thereof a compound as defined in one of claims 6-9 or 13 or a pharmaceutical composition as defined in claim 22.

25. A method for the prevention and/or treatment of a TGF R2-associated disorder, selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and cancers; said method comprising administering to a subject in need thereof a compound as defined in one of claims 10-18 or a pharmaceutical composition as defined in claim 24.