WO2015136073A1 - Inhibiteurs macrocycliques de la kinase tgf-br2 - Google Patents

Inhibiteurs macrocycliques de la kinase tgf-br2 Download PDF

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WO2015136073A1
WO2015136073A1 PCT/EP2015/055294 EP2015055294W WO2015136073A1 WO 2015136073 A1 WO2015136073 A1 WO 2015136073A1 EP 2015055294 W EP2015055294 W EP 2015055294W WO 2015136073 A1 WO2015136073 A1 WO 2015136073A1
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alkyl
het
halo
optionally
cycloalkyl
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PCT/EP2015/055294
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Jan Marie Cyriel Jozef Hoflack
Cyril BERTHET
Pascal André René BENDERITTER
Petra Marcella Françoise BLOM
Sylvie Gomez
Mourad DAOUBI
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Oncodesign Sa
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue

Definitions

  • 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.
  • TGF- R2 Transforming Growth Factor beta Receptor 2
  • the present invention provides methods of using said compounds, for instance as a medicine or diagnostic agent.
  • TGF- ⁇ Transforming growth factor beta
  • BMPs bone morphogenetic proteins
  • GDFs growth and differentiation factors
  • MIS mullerian inhibiting substance
  • TGF- ⁇ The spectrum of TGF- ⁇ cellular functions is pleiotropic and includes: apoptosis, proliferation, differentiation, mobility and cell adhesion.
  • TGF- ⁇ binds at high affinity to the type II receptor (TGF- R2), a constitutively active serine/threonine kinase.
  • TGF- R1 The ligand-bound type II receptor phosphorylates the TGF- ⁇ 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).
  • TGF- ⁇ responsive genes J. Ann. Rev .Biochem. Med. (1998) 67: 773).
  • TGF- ⁇ 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).
  • MAPK MAP kinase
  • Rho- like GTPase signalling pathways Rho- like GTPase signalling pathways
  • PI3K phosphatidylinositol-3-kinase
  • TGF- ⁇ signalling is implicated in numerous conditions and diseases, including cancer, cardiovascular, bone, CNS, PNS, inflammatory and neurodegenerative disorders.
  • Pathological overexpression of TGF- ⁇ 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).
  • pathological overexpression of TGF- ⁇ may cause excessive accumulation of extracellular matrix (ECM), inhibition of cell proliferation and immunosuppression.
  • ECM extracellular matrix
  • ECM 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- ⁇ 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- ⁇ counters the formation of cancer. This tumour-suppressant action is based principally on the ability of TGF- ⁇ to inhibit the division of epithelial cells. By contrast, TGF- ⁇ 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- ⁇ , and TGF- ⁇ simultaneously supports growth of the cancer cells via other mechanisms.
  • TGF- ⁇ epithelial-to-mesenchymal transition
  • TGF- ⁇ The production of TGF- ⁇ by malignant cells in primary tumours appears to increase with advancing stages of tumour progression.
  • TGF- ⁇ The important role played by TGF- ⁇ in the promotion of cancer growth is also demonstrated by investigations which show a correlation between strong TGF- ⁇ expression and a poor prognosis.
  • Increased TGF- ⁇ 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).
  • the secretion of TGF- ⁇ 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.
  • tumour cells The resistance of tumour cells to TGF- ⁇ has been shown to negate many of the cytotoxic effects of radiation therapy and chemotherapy, and the treatment-dependent activation of TGF- ⁇ 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.
  • TGF- ⁇ signal transduction inhibitors The development of TGF- ⁇ signal transduction inhibitors is likely to benefit the treatment of progressed cancer alone and in combination with other therapies.
  • TGF ⁇ R2 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).
  • 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.
  • 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.
  • 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.
  • TGF ⁇ R2 nonsense or misense
  • an increase TGF- ⁇ signalling is generally observed and the pathology are clearly associated to TGF- ⁇ pathway.
  • 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- ⁇ signalling, and TGF ⁇ R2 in particular represent a therapeutic option to be evaluated.
  • TGF ⁇ R2 targeting therapies include, but not limited to, Peyronie's disease, Ehlers-Danlos syndrome, Osteogenesis imperfecta, Stickler syndrome, Alport syndrome and congenital contractural arachnodactylyl.
  • Peyronie's disease Ehlers-Danlos syndrome
  • Osteogenesis imperfecta Stickler syndrome
  • Alport syndrome congenital contractural arachnodactylyl.
  • inhibition of the TGF- ⁇ 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- ⁇ 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.
  • 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.
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • alcohol-induced hepatitis haemochromatosis
  • haemochromatosis haemochromatosis
  • primary biliary cirrhosis hepatitis B virus
  • 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.
  • TGF- R2 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- ⁇ activity.
  • 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).
  • 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.
  • the macrocyclic compounds described herein act as TGF- R2 kinase inhibitors, and are thus very useful in the prevention and/or treatment of TGF- ⁇ R2-kinase associated diseases.
  • the present invention provides a compound of Formula I or stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, solvate thereof,
  • A-i and A 2 are selected from C and N; wherein when A-i is C, then A 2 is N; and wherein when
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -Ar 2 , and -NR 13 R 14 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 .
  • R 6 cycloalkyl, -Ar- ⁇ , -Het 9 , and -NR 23 R 24 ;
  • R 6 is selected from -C 1-6 alkyl, -S0 2 , -S0 2 -Ci -6 alkyl, -S0 2 -C 3 .
  • each of said -C 3 . 6 cycloalkyl is optionally and independently substituted with from
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-
  • R 42 is selected from -H, -OH, -halo, -Ci. 6 alkyl, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -NR 46 R 47 , -C 3 .
  • R 43 is selected from -H, -Ci_ 6 alkyl, and -C 3 . 6 cycloalkyl; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -O-d-ealkyl, -S-d-ealkyl, -Het 5 , -C 3 . 6 cycloalkyl -Ar 4 , and -NR 44 R 45 ;
  • each of said -d- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl Y is selected from a direct bond, -CHR 42 -, -0-, -S-, and -NR 43 -;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , Ar 10 and Ar-n are each independently a 5- to 10- membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein
  • A-i and A 2 are selected from C and N; wherein when A-i is C, then A 2 is N; and wherein when
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • 6cycloalkyl, -(C S)-C 3 .
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -Ar 2 , and -NR 13 R 14 ;
  • R 3 is selected from -H, -halo, -OH, -C 1-6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -
  • each of said -d- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, -Het 2 , -Ar 3 , and -N R 15 R 16 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -N R 17 R 18 ,
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-
  • R 43 is -H
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -N R 6 ,-;
  • Y is -N R 43 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and - NR 19 R 2 o; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i, Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • TGF- R2-kinase associated connective tissue disorders for use in the diagnosis, prevention and/or treatment of TGF- R2-kinase associated connective tissue disorders.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein
  • A-i and A 2 are selected from C and N; wherein when A-i is C, then A 2 is N; and wherein when A 2 is C, then is N;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • 6cycloalkyl, -(C S)-C 3 .
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -Ar 2 , and -NR 13 R 14 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -C 3 . 6 cycloalkyl is optionally and independently substituted with from
  • Rg, Rio, Rl 1 , Rl 2 , Rl 3 , Rl4, Rl5, Rl6, l7> l8> Rl9> R20, 3 ⁇ 41 > R ⁇ 2, R ⁇ 5, 3 ⁇ 46> R ⁇ 7, ⁇ 28, R ⁇ 9, R30, 3I > R 32 , R 33 , R 37 , R 3 8, R 3 9, R40, R53, R54 and R 55 are each independently selected from -H, - halo, 0, -OH, -C 1-6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 .
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, - Het 7 , -Ar 5 and -NR 5 i R 52 ;
  • R 5 i and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • R 43 is -H
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 -;
  • X-i is selected from -0-Ci_ 6 alkyl-, -NR 3 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR 39 R 40 ; wherein at least X-,
  • Y is -NR 43 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Het- ⁇ , Het 2 , Het 3 , Het 4 , Het 6 , Het 7 , Het 10 , and Het 12 are each independently a 4- to 10- membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het- ⁇ , Het 2 , Het 3 , Het 4 , Het 6 , Het 7 , Het 10 , and Het 12 is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d.
  • Ci- 6 alkyl is optionally and independently substituted with from 1 to 3 -halo
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • TGF- R2-kinase associated connective tissue disorders for use in the diagnosis, prevention and/or treatment of TGF- R2-kinase associated connective tissue disorders.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein
  • A-i and A 2 are selected from C and N; wherein when A-i is C, then A 2 is N; and wherein when
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -Ar 2 , and -NR 13 R 14 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 ,
  • R 9 R10, R11 , Ri 2 , Ri 3 , Ri 4 , Ri5.
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-
  • R 43 is -H
  • A is selected from -(CH 2 )n-Y-(CH 2 )m-, -NR 6 ,-;
  • Xi is selected from -0-Ci_ 6 alkyl-, -NR 3 -Ci. 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl, and -NR 3 7R 38 ;
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci_ 6 alkyl-, wherein each of said -Ci_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR 39 R 40 ; wherein at least is or at least
  • Y is -NR 43 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 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 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • TGF- R2-kinase associated connective tissue disorders for use in the diagnosis, prevention and/or treatment of TGF- R2-kinase associated connective tissue disorders.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein
  • A-i and A 2 are selected from C and N; wherein when A-i is C, then A 2 is N; and wherein when
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • R 2 is selected from -H, -halo, -OH, -d- 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , - Ar 2 , and -NR 13 R 14 ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 .
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 ,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-
  • R 43 is -H
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 ,-;
  • X-i is selected from -0-Ci_ 6 alkyl-, -NR 3 -Ci_ 6 alkyl-, wherein each of said -Ci_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR 3 gR 40 ; wherein at least is or
  • Y is -NR 43 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -N R-igR 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • TGF- R2-kinase associated connective tissue disorders for use in the diagnosis, prevention and/or treatment of TGF- R2-kinase associated connective tissue disorders.
  • 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
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -Ar 2 , and -NR 13 R 14 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Ar- ⁇ , -
  • Ci- 6 alkyl wherein each of said -d- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from-halo, -OH , -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Het 6 , -
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, - 0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, -Het 7 , -Ar 5 and -NR 51 R 52 ;
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-
  • R 42 is selected from -H, -OH, -halo, -Ci. 6 alkyl, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -NR 46 R 47 , -C 3 .
  • R 43 is selected from -H, -Ci_ 6 alkyl, and -C 3 . 6 cycloalkyl; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -O-d-ealkyl, -S-C ⁇ alkyl, -Het 5 , -C 3 . 6 cycloalkyl -Ar 4 , and -NR 44 R 45 ;
  • each of said -Ci_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl, and
  • Y is selected from a direct bond, -CHR 42 -, -0-, -S-, and -NR 43 -;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , Ar 10 and Ar-n are each independently a 5- to 10- membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d.
  • each of said -d_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and non-hematological cancers.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein
  • each of said -d_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • each of said -d- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -Ar 2 , and -NR 13 R 14 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • Rg R10, R11 , R"
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • R 43 is -H
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 ,-;
  • X-i is selected from -0-Ci_ 6 alkyl-, -NR 3 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci.
  • each of said -Ci_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR 39 R4o; wherein at least is or at least X 2 is
  • Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and - NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Het- ⁇ , Het 2 , Het 3 , Het 4 , Het 6 , Het 7 , Het 10 , and Het 12 are each independently a 4- to 10- membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het- ⁇ , Het 2 , Het 3 , Het 4 , Het 6 , Het 7 , Het 10 , and Het 12 is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_
  • each of said - Ci- 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and non-hematological cancers.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -Ar 2 , and -NR 13 R 14 ;
  • each of said -d- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • Rg Rio, Rl 1 , Rl 2 , Rl 3 , Rl4.
  • R 5 i and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci- 6 alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • R 43 is -H
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 ,-;
  • X-i is selected from -0-Ci_ 6 alkyl-, -NR 3 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR 39 R 40 ; wherein at least X-,
  • Y is -NR 43 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 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 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Het- ⁇ , Het 2 , Het 3 , HeU, Het 7 , and Het 10 are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het- ⁇ , Het 2 , Het 3 , HeU, Het 7 , and Het 10 , is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -OCi_ 6 alkyl, -SCi_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4; 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.
  • a TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and non-hematological cancers.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, wherein
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • R51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • R 3 is -H
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 ,-;
  • X-i is selected from -0-Ci_ 6 alkyl-, -NR 3 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR 39 R 40 ; wherein at least X-,
  • Het- ⁇ , Het 2 , Het 3 , HeU, Het 7 , and Het 10 are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het- ⁇ , Het 2 , Het 3 , HeU, Het 7 , and Het 10 , is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -OCi_ 6 alkyl, -SCi_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and non-hematological cancers.
  • 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,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , - Ar 2 , and -NR 13 R 14 ;
  • R 3 is selected from -H, -halo, -OH, -d- 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-
  • R 43 is -H
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 ,-;
  • X-i is selected from -0-Ci_ 6 alkyl-, -NR 3 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • Y is -NR 43 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 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 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo; Het- ⁇ , Het 2 , Het 3 , HeU, Het 7 , and Het 10 , are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het- ⁇ , Het 2
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R 12 , -0-Ci_ 6 alkyl, and -S-Ci_
  • R-i and R 41 are not -H;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1-
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ; R 43 is -H;
  • A is selected from -(CH 2 )n-Y-(CH 2 )m-, -NR 6 ,-;
  • Xi is wherein each of said -d- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci- 6 alkyl, -phenyl, and -NR 3 7R 38 ;
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci. 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR 39 R4o;
  • Y is -NR 43 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 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 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo; Het- ⁇ , Het 2 , Het 3 , HeU, Het 7 , and Het 10 , are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het- ⁇ , Het 2
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n are each independently 1 , 2, 3, or 4.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof,
  • R-i and R 41 are each -H
  • R 2 is selected from -H , -halo, -OH , -d- 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl , -Het 3 , -Ar 2 , and;
  • R 3 is selected from -H , -halo, -OH , -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_ 6 alkyl , -S-Ci_ 6 alkyl, -C 3 .
  • R 4 is independently selected from -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl , -NR 17 R 18 ,
  • R 6 is -C 3 .
  • 6 alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 .
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -O-C1- 6alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl , -Het 7 , -Ar 5 and -NR 51 R 52 ;
  • R51 and R 52 are each independently selected from -H , -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci_ 6 alkyl, -C 3 . 6 cycloalkyl , -Ar 10 and -Het 10 ;
  • R 43 is -H ;
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 ,-;
  • Xi is wherein each of said -Ci_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl,
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl , -phenyl and -NR 39 R 40 ;
  • Y is -NR 43 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 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 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -Ci_ 6 alkyl , -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl , and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo; Het- ⁇ , Het 2 , Het 3 , HeU, Het 7 , and Het 10 , are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het- ⁇ , He
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n are each independently 1 , 2, 3, or 4.
  • the present invention provides a compound 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,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , - Ar 2 , and -NR 13 R 14 ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 .
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 ,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1- 6alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Het 7 , -Ar 5 and -NR 51 R 52 ;
  • R51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci- 6 alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • R 3 is -H
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 ,-; ⁇ - ⁇ is selected from -0-Ci_ 6 alkyl-, -NR 3 -Ci. 6 alkyl-, wherein each of said -Ci_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl, and -NR 3 7R 38 ;
  • X 2 is wherein each of said -Ci_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci- 6 alkyl, -phenyl and -NR 39 R 40 ;
  • Y is -NR 43 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 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 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and cancers.
  • 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,
  • Ai is N and A 2 is C;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • R-i and R 41 are not -H;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , - Ar 2 , and -NR 13 R 14 ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C1- 6alkyl, -S-d-ealkyl, -C 3 . 6 cycloalkyl, -Het 7 , -Ar 5 and -NR 5 i R 52 ;
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-
  • R 3 is -H
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 ,-;
  • Xi is wherein each of said -Ci_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci- 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR 39 R 40 ;
  • Y is -NR 43 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 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 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 2 o; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and cancers.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof,
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -Ar 2 , and;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 .
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 ,
  • R 6 is -C 2 alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -O-C 1 -
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Het 7 , -Ar 5 and -NR 51 R 52 ;
  • R 5 i and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • R 43 is -H
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 ,-;
  • Xi is wherein each of said -Ci_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl,
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci_ 6 alkyl-, wherein each of said -Ci_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR 39 R 40 ;
  • Y is -NR 43 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 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 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Het- ⁇ , Het 2 , Het 3 , HeU, Het 7 , and Het 10 are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het- ⁇ , Het 2 , Het 3 , HeU, Het 7 , and Het 10 , is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -OCi_ 6 alkyl, -SCi_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and cancers.
  • TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and cancers.
  • 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 Z 4 or Z 5 , in accordance with the numbering as provided in Formula I.
  • the present invention provides a compound according to the present invention for use in the diagnosis, prevention and/or treatment of a TGF- R2-kinase associated disease; wherein R-i is linked to the aryl or heteroaryl moiety at position Z-i , Z 2 or Z 3 , in accordance with the numbering as provided in Formula I.
  • the present invention further provides a pharmaceutical composition for use in the prevention and/or treatment of 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.
  • 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.
  • 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,
  • A-i and A 2 are selected from C and N ; wherein when A-i is C, then A 2 is N ; and wherein when
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH , -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -Ar 2 , and -NR 13 R 14 ;
  • R 3 is selected from -H , -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH , -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl , -NR 17 R 18 ,
  • R 5 and R 7 are each independently selected from -H , -OH , -halo, -Ci_ 6 alkyl , -0-Ci_ 6 alkyl , -S-Ci_
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_ 6 alkyl, -S-Ci_
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci- 6 alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • R 42 is selected from -H, -OH, -halo, -C 1-6 alkyl, -0-Ci -6 alkyl, -S-Ci -6 alkyl, -NR 46 R 4 7, -C 3 .
  • R 43 is selected from -H, -Ci_ 6 alkyl, and -C 3 . 6 cycloalkyl; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci -6 alkyl, -S-C 1-6 alkyl, -Het 5 , -C 3 . 6 cycloalkyl -Ar 4 , and -NR44R45;
  • Y is selected from a direct bond, -CHR 42 -, -0-, -S-, and -NR 43 -;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , Ar 10 and Ar-n are each independently a 5- to 10- membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d.
  • each of said -d_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Het- ⁇ , Het 2 , Het 3 , Het 4 , Het 5 , Het 6 , Het 7 , Het 8 , Het 9 , Het 10 , and Het 12 are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het- ⁇ , Het 2 , Het 3 , Het 4 , Het 5 , Het 6 , Het 7 , Het 8 , Het 9 , Het 10 , and Het-i2 is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -C 1-6 alkyl, -OCi_ 6 alkyl,
  • Z-i, Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • TGF- R2-kinase associated disorder 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.
  • radicals can be read both ways.
  • A is such as the right part of the possible values of A (i.e.
  • X-i is such as the right part of the possible values of X-i (i.e.
  • X 2 is such as the right part of the possible values of X 2 (i.e.
  • alkyi by itself or as part of another substituent refers to fully saturated hydrocarbon radicals.
  • 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.
  • the subscript refers to the number of carbon atoms that the named group may contain.
  • d- 6 alkyl means an alkyi of one to six carbon atoms.
  • alkyi groups are methyl, ethyl, n-propyl, i-propyl, butyl, and its isomers (e.g.
  • C C 6 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.
  • 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.
  • substituents include -halo, -OH, primary and secondary amides, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, heteroaryl, aryl, and the like.
  • cycloalkyl by itself or as part of another substituent is a cyclic 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.
  • alkyi groups as defined are divalent, i.e., with two single bonds for attachment to two other groups, they are termed "alkylene" groups.
  • alkylene groups includes methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, ethylethylene, 1 ,2-dimethylethylene, pentamethylene and hexamethylene.
  • alkylene groups of this invention preferably comprise the same number of carbon atoms as their 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 C 3 alkylene group may be for example *-CH 2 CH 2 CH 2 -*, *-CH(-CH 2 CH 3 )-*, or *-CH 2 CH(-CH 3 )-*.
  • 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.
  • 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-d
  • 8-10 membered heterocyclic groups are also meant to include spiro-groups, which are bicyclic compounds with both rings connected through a single atom, such as for example spiro[4.5]decane, which is a spiro compound consisting of a cyclohexane ring and a cyclopentane ring.
  • aryl refers to a polyunsaturated, aromatic hydrocarbyl group having from 5-10 atoms.
  • Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated herein.
  • Non-limiting examples of aryl comprise phenyl, biphenylyl, biphenylenyl, 5- or 6-tetralinyl, 1 -, 2-, 3-, 4-, 5-, 6-, 7-, or 8-azulenyl, 1 - or 2- naphthyl, 1 -, 2-, or 3-indenyl, 1 -, 2-, or 9-anthryl, 1 - 2-, 3-, 4-, or 5-acenaphtylenyl, 3-, 4-, or 5- acenaphtenyl, 1 -, 2-, 3-, 4-, or 10-phenanthryl, 1 - or 2-pentalenyl, 1 , 2-, 3-, or 4-fluorenyl, 4- or 5-indanyl,
  • 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.
  • heteroaryl refers but is not limited to 5 to 10 carbon-atom aromatic rings in which one or more carbon atoms can be replaced by oxygen, nitrogen or sulfur atoms.
  • Non-limiting examples of such heteroaryl include: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1 - b][1 ,3]thiazolyl, thieno[
  • an “optionally substituted heteroaryl” refers to a heteroaryl having optionally one or more substituents (for example 1 to 4 substituents, for example 1 , 2, 3 or 4), selected from those defined above for substituted alkyl.
  • halo or halogen as a group or part of a group is generic for fluoro, chloro, bromo, or iodo, as well as any suitable isotope thereof.
  • substituted is meant to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group, provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic and/or diagnostic agent.
  • groups may be optionally substituted, such groups may be substituted once or more, and preferably once, twice or thrice.
  • Substituents may be selected from, those defined above for substituted alkyl.
  • alkyl, aryl, or cycloalkyl each being optionally substituted with” or “alkyl, aryl, or cycloalkyl, optionally substituted with” refers to optionally substituted alkyl, optionally substituted aryl and optionally substituted cycloalkyl.
  • the compounds of the invention may exist in the form of different isomers and/or tautomers, including but not limited to geometrical isomers, conformational isomers, E/Z-isomers, stereochemical isomers (i.e. enantiomers and diastereoisomers) and isomers that correspond to the presence of the same substituents on different positions of the rings present in the compounds of the invention. All such possible isomers, tautomers and mixtures thereof are included within the scope of the invention.
  • the invention includes isotopically-labelled compounds and salts, which are identical to compounds of formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes that can be incorporated into compounds of formula (I) are isotopes of hydrogen, carbon, nitrogen , fluorine, such as 3 H , C, 3 N , 4 C, 5 0 and 8 F.
  • Such isotopically-labelled compounds of formula (I) are useful in drug and/or substrate tissue distribution assays.
  • C and 8 F isotopes are particularly useful in PET (Positron Emission Tomography).
  • PET is useful as a diagnostic or treatment follow-up tool that can be applied in a translational manner in a preclinical and clinical setting. It also has applications in PK determination of compounds, including biodistribution .
  • Isotopically labeled compounds of formula (I) can generally be prepared by carrying out the procedures disclosed below, by substituting a readily available non- isotopically labeled reagent with an isotopically labeled reagent.
  • the term "compounds of the invention” or a similar term is meant to include the compounds of general Formula I and any subgroup thereof. This term also refers to the compounds as depicted in Table 1 , their derivatives, /v-oxides, salts, solvates, hydrates, stereoisomeric forms, racemic mixtures, tautomeric forms, optical isomers, analogues, pro-drugs, esters, and metabolites, as well as their quaternized nitrogen analogues.
  • the v-oxide forms of said compounds are meant to comprise compounds wherein one or several nitrogen atoms are oxidized to the so-called /v-oxide.
  • a compound means one compound or more than one compound .
  • the present invention provides compounds of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof; for use in the diagnosis, prevention and/or treatment of a connective tissue disorder; wherein one or more of the following applies:
  • A-i and A 2 are selected from C and N ; wherein when A-i is C, then A 2 is N ; and wherein when
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • each of said -d- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH , -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -Ar 2 , and -NR 13 R 14 ;
  • R 4 is independently selected from -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl , -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_ 6 alkyl, -S-Ci_ 6alkyl, -C 3 . 6 cycloalkyl , -Ar- ⁇ , -Het 9 , and -NR 23 R 24 ;
  • each of said -C 3 . 6 cycloalkyl is optionally and independently substituted with from
  • R 9 R-io, Rii , Ri 2 , Ri 3 , R"i 4 , Ri5. Ri6. Ri7> Ri8. Ri9.
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-
  • R 42 is selected from -H, -OH, -halo, -C 1-6 alkyl, -0-Ci -6 alkyl, -S-Ci -6 alkyl, -NR 46 R 4 7, -C 3 .
  • R 43 is selected from -H, -Ci_ 6 alkyl, and -C 3 . 6 cycloalkyl; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci -6 alkyl, -S-C 1-6 alkyl, -Het 5 , -C 3 . 6 cycloalkyl -Ar 4 , and -NR44R45;
  • each of said -d_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_ 6 alkyl, -0-d_ 6 alkyl, -S-d_ 6 alkyl, -phenyl and -NR 39 R 40 ;
  • Y is selected from a direct bond, -CHR 42 -, -0-, -S-, and -NR 43 -;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , Ar 10 and Ar-n are each independently a 5- to 10- membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d.
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4.
  • X-i, and X 2 as used herein represent biradicals, which taken together with the radicals to which they are attached form a macrocyclic pyrazolopyrimidine compound.
  • Said biradicals may be present in either of both directions in the macrocyclic pyrazolopyrimidine, but are preferably present in the direction as described below:
  • the present invention provides compounds of formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, for use in the diagnosis, prevention and/or treatment of a connective tissue disorder wherein :
  • A-i and A 2 are selected from C and N ; wherein when A-i is C, then A 2 is N ; and wherein when
  • each of said -d_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -NR-n R 12 , -0-d_ 6 alkyl, and -S-C-i. 6alkyl;
  • each of said -d_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH , -0-d_ 6 alkyl, -S-d_ 6 alkyl, -Het 3 , -Ar 2 , and -NR 13 R 14 ;
  • each of said -d_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH , -0-d- 6 alkyl, -S-d_ 6 alkyl, -C 3 . 6 cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 ,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • R 43 is -H
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 ,-;
  • X-i is selected from -0-Ci_ 6 alkyl-, -NR 3 -Ci. 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl, and -NR 3 7R 38 ;
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR 3 gR 4 o;
  • Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and - NR-igR 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Het- ⁇ , Het 2 , Het 3 , Het 4 , Het 6 , Het 7 , Het 10 , and Het 12 are each independently a 4- to 10- membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het- ⁇ , Het 2 , Het 3 , Het 4 , Het 6 , Het 7 , Het 10 , and Het 12 is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d.
  • Z-i, Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n are each independently 1 , 2, 3, or 4.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, for use in the diagnosis, prevention and/or treatment of a connective tissue disorder wherein
  • A-i and A 2 are selected from C and N; wherein when A-i is C, then A 2 is N; and wherein when
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -Ar 2 , and -NR 13 R 14 ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 ,
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci- 6 alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • R 43 is -H
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 -;
  • X-i is selected from -0-Ci_ 6 alkyl-, -NR 3 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR 39 R 40 ; wherein at least is or at least
  • Y is -NR 43 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and - NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Ci- 6 alkyl is optionally and independently substituted with from 1 to 3 -halo
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, for use in the diagnosis, prevention and/or treatment of a connective tissue disorder wherein
  • A-i and A 2 are selected from C and N; wherein when A-i is C, then A 2 is N; and wherein when
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -Ar 2 , and -NR 13 R 14 ;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -Ci_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -O-C ⁇ alkyl, -S-C ⁇ alkyl, -C 3 .
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci- 6 alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • R 3 is -H
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 ,-;
  • X-i is selected from -0-Ci_ 6 alkyl-, -NR 3 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci.
  • each of said -Ci_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR 39 R4o; wherein at least is or at least X 2 is
  • Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 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 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, for use in the diagnosis, prevention and/or treatment of a connective tissue disorder wherein
  • A-i and A 2 are selected from C and N; wherein when A-i is C, then A 2 is N; and wherein when A 2 is C, then is N;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , - Ar 2 , and -NR 13 R 14 ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 .
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 ,
  • Rg, Rio, Rl 1 , Rl 2 , 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- 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Het 7 , -Ar 5 and -NR 51 R 52 ;
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci- 6 alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • R 43 is -H
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 ,-;
  • X-i is selected from -0-Ci_ 6 alkyl-, -NR 3 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR 3 gR 40 ; wherein at least is or at least X 2 is
  • Y is -NR 43 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 are each independently a 5- to 10-membered aromatic heterocycle optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Het- ⁇ , Het 2 , Het 3 , HeU, Het 7 , and Het 10 are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het- ⁇ , Het 2 , Het 3 , HeU, Het 7 , and Het 10 , is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -OCi_ 6 alkyl, -SCi_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i, Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n are each independently 1 , 2, 3, or 4.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, for use in the diagnosis, prevention and/or treatment of a TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and non-hematological cancers.
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR-12, -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH , -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -Ar 2 , and -NR 13 R 14 ;
  • R 4 is independently selected from -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl , -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_ 6 alkyl , -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Ar- ⁇ , -
  • Ci_ 6 alkyl wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Ar- ⁇ , -Het 9 , and -NR 23 R2 4 ; R 6 is selected from -C 1-6 alkyl, -S0 2 , -S0 2 -Ci -6 alkyl, -S0 2 -C 3 .
  • each of said -C 3 . 6 cycloalkyl is optionally and independently substituted with from
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-
  • R 42 is selected from -H, -OH, -halo, -Ci. 6 alkyl, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -NR 46 R 47 , -C 3 .
  • R 43 is selected from -H, -Ci_ 6 alkyl, and -C 3 . 6 cycloalkyl; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -O-d-ealkyl, -S-d-ealkyl, -Het 5 , -C 3 . 6 cycloalkyl -Ar 4 , and -NR 44 R 45 ;
  • Y is selected from a direct bond, -CHR 42 -, -0-, -S-, and -NR 43 -;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , Ar 10 and Ar-n are each independently a 5- to 10- membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Het- ⁇ , Het 2 , Het 3 , Het 4 , Het 5 , Het 6 , Het 7 , Het 8 , Het 9 , Het 10 , and Het 12 are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het- ⁇ , Het 2 , Het 3 , Het 4 , Het 5 , Het 6 , Het 7 , Het 8 , Het 9 , Het 10 , and
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, for use in the diagnosis, prevention and/or treatment of a TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and non-hematological cancers.
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • 6cycloalkyl, -(C S)-C 3 .
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH , -0-Ci -6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -Ar 2 , and -NR 13 R 14 ;
  • each of said -d- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH , -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl , -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_ 6 alkyl , -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Ar- ⁇ , -
  • each of said -d_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -0-d_ 6 alkyl, -S-d_ 6 alkyl,
  • 6 alkyl, -(C 0)-C 2 .
  • 6 alkenyl, -(C S)-0-d_ 6 alkyl, -
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -
  • R 5 i and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-
  • R 42 is selected from -H, -OH, -halo, -Ci. 6 alkyl, -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -NR 46 R 4 7, -C 3 .
  • R 43 is selected from -H, -Ci_ 6 alkyl, and -C 3 . 6 cycloalkyl; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -O-d-ealkyl, -S-d. 6 alkyl, -Het 5 , -C 3 . 6 cycloalkyl -Ar 4 , and -NR 44 R 45 ;
  • each of said -d_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d_ 6 alkyl, -0-d_ 6 alkyl, -S-d_ 6 alkyl, -phenyl and -NR 39 R 40 ;
  • Y is selected from a direct bond, -CHR 42 -, -0-, -S-, and -NR 43 -;
  • Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , Ar 10 and Ar-n are each independently a 5- to 10- membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar- ⁇ , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 9 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d.
  • Z-i, Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n are each independently 1 , 2, 3, or 4.
  • the present invention provides 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
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -Ar 2 , and -NR 13 R 14 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • R51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci- 6 alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • A is selected from -(CH 2 )n-Y-(CH 2 )m-, -NR 6 ,-;
  • X-i is selected from -0-Ci_ 6 alkyl-, -NR 3 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR 39 R 40 ; wherein at least is or at least X 2 is
  • Y is -NR 43 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n are each independently a 5- to 10-membered aryl optionally comprising 1 or 2 heteroatoms selected from O, N and S; each of said Ar 2 , Ar 3 , Ar 5 , Ar 6 , Ar 7 , Ar 8 , Ar 10 and Ar-n being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and - NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Het- ⁇ , Het 2 , Het 3 , Het 4 , Het 6 , Het 7 , Het 10 , and Het 12 are each independently a 4- to 10- membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het- ⁇ , Het 2 , Het 3 , Het 4 , Het 6 , Het 7 , Het 10 , and Het 12 is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_
  • each of said - Ci- 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n are each independently 1 , 2, 3, or 4.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, for use in the diagnosis, prevention and/or treatment of a TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and non-hematological cancers; wherein
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH , -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -Ar 2 , and -NR 13 R 14 ;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from - halo, -OH , -0-Ci. 6 alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl , -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -Ci_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -O-C ⁇ alkyl, -S-C ⁇ alkyl, -C 3 . 6 cycloalkyl, -Het 7 , -Ar 5 and -NR 5 iR 52 ;
  • R 51 and R 52 are each independently selected from -H , -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci_ 6 alkyl, -C 3 . 6 cycloalkyl , -Ar 10 and -Het 10 ;
  • R 3 is -H ;
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 ,-;
  • X-i is selected from -0-Ci_ 6 alkyl-, -NR 3 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl , -phenyl and -NR 39 R 40 ; wherein at least is or at least X 2 is
  • Y is -NR 43 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 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 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 2 o; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof, for use in the diagnosis, prevention and/or treatment of a TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and non-hematological cancers; wherein
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , - Ar 2 , and -NR 13 R 14 ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 .
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 ,
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-
  • R 43 is -H
  • A is selected from -(CH 2 )n-Y-(CH 2 )m-, -NR 6 ,-;
  • X-i is selected from -0-Ci_ 6 alkyl-, -NR 3 -Ci. 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl, and -NR 3 7R 38 ;
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR 39 R 40 ; wherein at least is or at
  • Y is -NR 43 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 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 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo; Het- ⁇ , Het 2 , Het 3 , HeU, Het 7 , and Het 10 , are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het- ⁇ , Het 2
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n are each independently 1 , 2, 3, or 4.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-n R 12 , -0-Ci_ 6 alkyl, and -S-Ci_
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , - Ar 2 , and -NR 13 R 14 ;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-
  • R 3 is -H
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 ,-;
  • Xi is selected from -0-Ci_ 6 alkyl-, -NR 3 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl, and -NR 37 R 38 ;
  • X 2 is wherein each of said -Ci_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci- 6 alkyl, -phenyl and -NR 39 R 40 ;
  • Y is -NR 43 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 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 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 2 o; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo; Het- ⁇ , Het 2 , Het 3 , HeU, Het 7 , and Het 10 , are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het- ⁇ , Het 2 , He
  • Z-i, Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n are each independently 1 , 2, 3, or 4.
  • the 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,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • R-i and R 41 are not -H;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ; R 6 is -Ci- 6 alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -OH, - 0-Ci -6 alkyl, -S-Ci -6 alkyl, -C 3 .
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-
  • R 43 is -H
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 ,-;
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR 39 R4o;
  • Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 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 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo; Het- ⁇ , Het 2 , Het 3 , HeU, Het 7 , and Het 10 , are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het- ⁇ , Het 2
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof,
  • R 2 is selected from -H, -halo, -OH, -d- 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -Ar 2 , and;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-
  • R 43 is -H
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 ,-;
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci. 6 alkyl-, wherein each of said
  • -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR39R40;
  • Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 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 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Het- ⁇ , Het 2 , Het 3 , HeU, Het 7 , and Het 10 are each independently a 4- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and S, wherein each of said Het- ⁇ , Het 2 , Het 3 , HeU, Het 7 , and Het 10 , is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -OCi_ 6 alkyl, -SCi_ 6 alkyl,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n are each independently 1 , 2, 3, or 4.
  • the present invention provides a compound 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,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • R 43 is -H
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 ,-;
  • X-i is selected from -0-Ci_ 6 alkyl-, -NR 3 -Ci. 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl, and -NR 3 7R 38 ;
  • X 2 is wherein each of said -Ci_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl,
  • Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 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 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i, Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug , salt, hydrate, N-oxide form, or solvate thereof,
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -NR-nR 12 , -0-Ci_ 6 alkyl, and -S-Ci_ 6alkyl;
  • R-i and R 41 are not -H ;
  • R 2 is selected from -H , -halo, -OH , -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , - Ar 2 , and -NR 13 R 14 ;
  • R 3 is selected from -H , -halo, -OH , -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -OH , -0-Ci_ 6 alkyl , -S-Ci_ 6 alkyl, -C 3 . 6cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ;
  • R 4 is independently selected from -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl , -NR 17 R 18 , -C 3 . 6 cycloalkyl, -Ar 8 and -Het 4 ;
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -O-C1- 6alkyl, -S-Ci. 6 alkyl, -C 3 . 6 cycloalkyl , -Het 7 , -Ar 5 and -NR 51 R 52 ;
  • R 51 and R 52 are each independently selected from -H , -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-
  • R 3 is -H ;
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 ,-;
  • Xi is wherein each of said -Ci_ 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci- 6 alkyl , -phenyl, and -NR 37 R 38 ;
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH , -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl , -phenyl and -NR 39 R 40 ;
  • Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 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 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and cancers.
  • the present invention provides a compound of Formula I or a stereoisomer, tautomer, racemic, metabolite, pro- or predrug, salt, hydrate, N-oxide form, or solvate thereof,
  • R 2 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -Het 3 , -Ar 2 , and;
  • R 3 is selected from -H, -halo, -OH, -Ci_ 6 alkyl; wherein said -Ci_ 6 alkyl is optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 . 6cycloalkyl, -Het 2 , -Ar 3 , and -NR 15 R 16 ; R 4 is independently selected from -halo, -OH, -d- 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -NR 17 R 18 ,
  • R 6 is -C 2 alkyl optionally substituted with from 1 to 3 substituents selected from -halo, -0-Ci_
  • each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6alkyl, -S-Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Het 7 , -Ar 5 and -NR 51 R 52 ;
  • R 51 and R 52 are each independently selected from -H, -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S- Ci_ 6 alkyl, -C 3 . 6 cycloalkyl, -Ar 10 and -Het 10 ;
  • R 43 is -H
  • A is selected from -(CH 2 ) n -Y-(CH 2 ) m -, -NR 6 ,-;
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci_ 6 alkyl-, wherein each of said -Ci- 6 alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -phenyl and -NR 39 R 40 ; Y is -NR 43 -;
  • Ar 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 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 2 , Ar 3 , Ar 5 , Ar 7 , Ar 8 , and Ar 10 being optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -Ci_ 6 alkyl, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, and -NR 19 R 20 ; wherein each of said -Ci_ 6 alkyl is optionally and independently substituted with from 1 to 3 -halo;
  • Z-i , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C and N;
  • n and n are each independently 1 , 2, 3, or 4;
  • TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and cancers.
  • the present invention provides a compound selected from the list comprising:
  • TGF- R2-kinase associated disease selected from the list comprising connective tissue disorders, fibrotic disorders, autoimmune disorders, and cancers.
  • the pyrazolopyrimidine or the imidazopyridazine moiety is linked to the aryl or heteroaryl moiety at position Z 4 or Z 5 , in accordance with the numbering as provided in Formula I.
  • the R-i of the compounds according to this invention is preferably linked to the aryl or heteroaryl moiety at position Z-i , Z 2 or Z 3 , in accordance with the numbering as provided in Formula I.
  • the present invention provides a pharmaceutical composition comprising a compound of the present invention, for use in the prevention and/or treatment of a TGF- R2-kinase associated disorders.
  • 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.
  • 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 -(CH 2 )n-NH-(CH 2 )m-, -NR 6 ,-;
  • each of said -d- 6 alkyl is optionally and independently substituted with from 1 to 3 substituents selected from -halo, -OH, -0-Ci_ 6 alkyl, -S-Ci_ 6 alkyl, -C 3 .
  • 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 -(CH 2 ) n -NH-(CH 2 ) m -, -NR 6 ,-;
  • 6 alkyl- is selected from -0-Ci. 6 alkyl-, -NR 3 -Ci. 6 alkyl-, 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 -(CH 2 ) n -NH-(CH 2 ) m -, -NR 6 ,-;
  • At least one of R-i and R 41 is not -H
  • X 2 is selected from -0-Ci_ 6 alkyl-, -NR 2 -Ci_ 6 alkyl-, in particular -NH-C-,.
  • A is selected from -(CH 2 ) n -NH-(CH 2 ) m -, -NR 6 ,-;
  • X 2 is s elected from -0-Ci_ 6 alkyl-, -NR 2 -Ci_ 6 alkyl-, particular - ⁇ -C ⁇ ,.
  • 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

Abstract

L'invention concerne des composés macrocycliques et des compositions contenant ces composés agissant en tant qu'inhibiteurs de kinase, en particulier en tant qu'inhibiteurs du bêta-récepteur 2 de facteur de croissance transformant (TGF-β R2) et/ou de ses mutants, pour une utilisation dans le diagnostic, la prévention et/ou le traitement de maladies associées à la kinase TGF-β R2. De plus, l'invention concerne des méthodes d'utilisation desdits composés, par exemple en tant que médicament ou agent de diagnostic.
PCT/EP2015/055294 2014-03-14 2015-03-13 Inhibiteurs macrocycliques de la kinase tgf-br2 WO2015136073A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021152165A1 (fr) * 2020-01-31 2021-08-05 Oncodesign S.A. Inhibiteurs macrocycliques de la rip2-kinase

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013045653A1 (fr) * 2011-09-30 2013-04-04 Oncodesign S.A. Inhibiteurs de kinase flt3 macrocycliques
WO2013046029A1 (fr) * 2011-09-30 2013-04-04 Ipsen Pharma S.A.S. Inhibiteurs macrocycliques de la kinase lrrk2

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013045653A1 (fr) * 2011-09-30 2013-04-04 Oncodesign S.A. Inhibiteurs de kinase flt3 macrocycliques
WO2013046029A1 (fr) * 2011-09-30 2013-04-04 Ipsen Pharma S.A.S. Inhibiteurs macrocycliques de la kinase lrrk2

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021152165A1 (fr) * 2020-01-31 2021-08-05 Oncodesign S.A. Inhibiteurs macrocycliques de la rip2-kinase
CN115698020A (zh) * 2020-01-31 2023-02-03 昂科迪塞恩精密医药公司(Opm) 大环rip2-激酶抑制剂

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