NZ730758B2 - Macrocyclic rip2 kinase inhibitors - Google Patents

Abstract

The present invention relates to macrocyclic compounds and compositions containing said compounds acting as kinase inhibitors, in particular as inhibitors of RIP2 and/or mutants thereof, for use in the diagnosis, prevention and/or treatment of RIP2-kinase associated diseases. Moreover, the present invention provides methods of using said compounds, for instance as a medicine or diagnostic agent.

Description

Macrocyclic R|P2 kinase inhibitors Field of the invention The present invention relates to macrocyclic compounds and itions ning said nds acting as kinase inhibitors, in particular as inhibitors of RIP2, and/or mutants thereof, for use in the sis, prevention and/or treatment of RIP2-kinase ated diseases. er, the present invention provides methods of using said compounds, for instance as a medicine or diagnostic agent. 1O ound of the invention Protein kinases tute a large family of structurally related enzymes that are responsible for the control of a wide variety of signal transduction processes in the cell. They have been shown to be key regulators in most ar functions ing proliferation, cell metabolism, cell survival, sis, DNA damage repair, cell motility... Uncontrolled signalling due to defective control of protein phosphorylation has been implicated in a number of diseases, including, for example, cancer, inflammation, allergies, immune diseases, CNS disorders, angiogenesis...

Amongst the es of protein s, one particular example is the Receptor-Interacting Serine/Threonine Kinases including RIP2. R|P2 (Receptor-Interacting Protein 2) is also referred to as Card-Containing sociated Kinase (CARDIAK), CARD3 (C-terminal CAspase-Recruitment Domain 3), Receptor-Interacting Protein Kinase 2 (RIPK2), or Rip-Like Interacting Clarp Kinase (RICK). R|P2 kinase is composed of an N-terminal kinase domain and a C-terminal caspase- recruitment domain (CARD) linked via an intermediate (IM) region (Curr. Med. Chem. (2005) 4, 35- 42)). The CARD domain of R|P2 kinase mediates interaction with other CARD-containing ns, such as the Nucleotide Oligomerization Domain Proteins, NOD1 and NOD2 (J. Biol. Chem. (2000) 275, 27823-27831 and EMBO reports (2001) 2, 736-742). NOD1 and NOD2 are cytoplasmic receptors which are activated by specific bacterial peptidoglycan motifs and play a key role in innate immune surveillance. Upon intracellular bacterial exposure, NOD1 or NOD2 binds to the protein kinase R|P2 to coordinate NF-KB (nuclear factor K B)-mediated cytokine responses. Once associated with NOD1/2, R|P2 undergoes autophosphorylation on Tyr 474 (Y474), and acts as a 3O molecular scaffold to bring together other kinases (TAK1, IKKoc/[S/y) involved in NF-KB and MAPK activation (Nature Reviews Immunology (2006) 6, 9-20).

Both NOD1/2 and R|P2 are NF-KB regulated genes, and as such, their activation causes a positive feedback loop in which activation of NOD1/2:RIP2 stimulates further tion and further in?ammation. Additionally, NOD1/2 and R|P2 expression are stimulated by a variety of mediators of in?ammation, including TNF (Tumor Necrosis ) and IFN (Interferon). In addition to NF-KB y activation, the NOD1/2:RIP2 complex stimulates autophagy, bacteriocidal activity, MHC Class II presentation and MAPK (Mitogen-Activated Protein Kinase) activation. Overall, this pathway modulates the innate immune system to help tailor the adaptive immune response to eradicate the offending pathogen.

Dysregulation of RIP2-dependent signaling has been linked to autoinflammatory diseases. Patients with loss-of-function NOD2 alleles are prone to the development of Crohn’s disease, an in?ammatory er of the gastrointestinal tract (Am. J. Hum. Genet. (2002) 70, 845-857 and Microbes and Infection (2009) 11, 912-918). In contrast, gain-of-function NOD2 mutations have been genetically linked to other matory diseases, such as Blau Syndrome/Early Onset Sarcoidosis (EOS), a pediatric granulomateous disease characterized by uveitis, dermatitis, and arthritis (Nature Genetics (2001) 29, 19-20 and Current tology Reports (2005) 7, 427-433). ons in NOD1 have been ated with asthma (Hum. Mol. Genet. (2005) 14, 935-941), and early-onset and extra-intestinal inflammatory bowel disease (Hum. Mol. Genet. (2005) 14, 1245- 1O 1250). Genetic and functional studies have also suggested a role for RIP2-dependent signaling in a variety of other granulomateous disorders, such as sarcoidosis (Journal of Clinical Immunology (2009) 29, 78-89) and Wegner’s Granulomatosis (Diagnostic ogy (2009) 4, 23).

The fact that both loss-of-function polymorphisms and gain-of-function mutations cause in?ammatory diseases is likely due to the fact that NOD2 functions as a rheostat to help maintain normal logic homeostasis. Lack of coordination between atory signaling pathways in?uences the development of in?ammatory disorders, and the NOD1/2:R|P2 activation equilibrium is central to this coordination. Treatments for Crohn's disease and sarcoidosis currently rely on broad, non-specific immunologic tion (e.g., corticosteroids) or on specific cytokine inhibition (e.g., anti-TNF ies) with significant costs and side s. Treatment is less than ideal, r, because not all agents are equally cious, the diseases occur over long time , and not all agents remain efficacious in the same patient. The RIP2 Y474 autophosphorylation event has been shown to be necessary for effective NOD2 signaling and does not occur in the presence of the most common loss-of-function Crohn's e-associated NOD2 allele. This autophosphorylation is inhibited by non highly selective kinase inhibitors, Gefitinib and Erlotinib, ting that RIP2's tyrosine kinase activity could be targeted specifically in the treatment of in?ammatory diseases (Genes Dev. (2010) 1, 2666-77). Several clinical cases were ed about Gefitinib or nib treatment being efficient to clear psoriasis or reduce arthritic symptoms or insulin-resistant type 2 diabetes associated with metabolic syndrome (The Oncologist (2013) 18: e3—e5). In mouse established models of chronic in?ammatory bowel diseases, inhibition of RIP2 3O ty by the small molecule 88203580 is efficacious to reduce induced-colitis (J Biol Chem. (2005) 15, 14981-14988.) None of these small molecules r, primarily and selectively targets RIP2. It was therefore an object of the present invention to e a potent, selective, small molecule inhibitor of RIP2 kinase activity which can block specifically RIP2-dependent pro- in?ammatory signaling and thereby provides a therapeutic benefit in autoinflammatory diseases characterized in increased and/or dysregulated RIP2 kinase activity.

We have now found that the macrocyclic pyrazolopyrimidines and imidazopyridazines and pharmaceutically acceptable compositions according to this invention are useful for the treatment of inflammatory disorders, in particular Crohn’s disease, bowel disease, Sarcoidosis, psoriasis, rheumatoid arthritis, asthma and insulin-resistant type 2 diabetes, ulcerative colitis, lupus, uveitis, blau syndrome, granulomatous in?ammation, in particular ’s disease, multiple sclerosis, and es associated with R|P2 kinase activity (i.e. RIP2—kinase associated diseases).

Y OF THE INVENTION We have surprisingly found that the macrocyclic compounds described herein act as R|P2 kinase inhibitors, and are thus very useful in the diagnosis, prevention and/or treatment of RIP2—kinase associated diseases.

In a first objective the present ion provides a nd of Formula | or a stereoisomer, 1O tautomer, racemic, metabolite, pro- or pre-drug, salt, hydrate, N-oxide form, or solvate thereof, Wherein R1 is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, -NR9R10, -(C=O)-R4, - (C=S)—R4, -SOz-R4, -CN, -NR9-SOZ-R4, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar1 and —Het1; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OR35, -NR11R12, -O-C1_6alkyl, and -S-C1_6alkyl; wherein when A2 is N, then R1 and R5 are not simultaneously —H; R5 is attached to Z1 or Z5 and is selected from —H, —halo, -OH, lkyl, -O-C1_6alkyl, 6alkyl, - NR6R7, -(C=O)-R8, -(C=S)—R8, -SOZ-R8, -CN, -NR6-SOZ-R8, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, - Ar5 and —Het5; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OR36, -NR23R24, -O-C1_6alkyl, and -S-C1_6alkyl; R2 is selected from —H, -halo, -OH, -C1_6alkyl, and -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, — OR27, and -NR13R14; R3 is selected from —H, -halo, -OH, -C1_6alkyl, ycloalkyl; wherein each of said -C1_6alkyl is ally and independently substituted with from 1 to 3 substituents selected from —halo, — ORzg, and -NR15R16; R4 and R8 are each independently selected from —halo, —OH, -C1_6alkyl, 6alkyl, -S-C1_6alkyl, - NR17R18, ycloalkyl, -O-Cg_6cycloalkyl, -Ar4 and -Het4; R6, R7, R9, R101 R11! R12, R13, R141 R15! R16, R17! R18, R19, R20, R21, R22, R23, R24, R31, R321R331 R34, R35 and R36 are each ndently selected from —H, -halo, =0, -OH, -C1_6alkyl, -O-C1_6alkyl, - S—C1_6alkyl, -C3_6cycloalkyl, -Ar6 and —Het6; wherein each of said -C1_6alkyl is optionally and independently tuted with from 1 to 3 substituents selected from —halo, —OH, -O-C1_6alkyl, 6alkyl, -Cg_6cycloalkyl, -Het6, -Ar6 and —NR37R38; R27 and R28, are each independently selected from —H, lkyl, -C3_6cycloalkyl and -Het2: R37 and R38, are each independently selected from —H, -halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_ 6alkyl, -C3_6cycloalkyl, -Ar7 and —Het7; X1 is ed from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NR3-C1_6alkyl-, -NR3-Cq_6alkyl-, -NR3-, and -O-; wherein each of said -C1_6alkyl- is ally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, -phenyl, and -N R33R34; 1O X2 is selected from —C1_6alkyl-, 6alkyl-, —S—C1_6alkyl-, lkyl-NRZ-C1_6alkyl-, -NR2-Cq_6alkyl-, -NR2-, and -O-; wherein each of said -C1_6alkyl- is optionally and independently substituted with from 1 to 3 substituents ed from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, -phenyl and -N R31R32; Ar1, Ar4, Ar5, Ar6, and Ar7 are each independently a 5- to 10-membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and 8; each of said An, Ar4, Ar5, Ar6, and Ar7 being optionally and independently substituted with from 1 to 3 substituents selected from — halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, and —NR19R20; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; Het1, Het2, Het4, Het5, Het6, and Het7 are each independently a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and 8; wherein each of said Het1, Het2, Het4, Het5, Het6, and Het7 is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, 6alkyl, =0, -(C=O)-C1_ 6alkyl, and -NR21R22; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; Hetg is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms ed from O, N and wherein said Hetg is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_6alkyl, and - NR21R22; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 3O to 3 -halo; wherein when R1 is —H, then at least one heteroatom of Hetg is attached to X1 Z1, 22, 23, Z4 and Z5 are each ndently selected from C and N; and A1 and A2 are each independently selected from C and N.

In a particular ment, the present ion provides a compound of Formula | or a stereoisomer, tautomer, racemic, metabolite, pro- or pre-drug, salt, hydrate, N-oxide form, or solvate thereof, wherein R1 is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, -NR9R10, -R4, - (C=S)—R4, -SOz-R4, -CN, OZ-R4, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar1 and —Het1; 40 wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 tuents selected from —halo, -OR35, -NR11R12, -O-C1_6alkyl, and -S-C1_6alkyl; wherein when A2 is N, then R1 and R5 are not simultaneously —H; R5 is attached to Z1 or Z5 and is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, - NR6R7, -(C=O)-R8, -(C=S)—R8, -SOZ-R8, -CN, -NR6-SOZ-R8, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, - Ar5 and —Het5; wherein each of said -C1_6alkyl is optionally and ndently substituted with from 1 to 3 substituents ed from —halo, -OR36, -NR23R24, -O-C1_6alkyl, and -S-C1_6alkyl; R2 is selected from —H, -halo, -OH, -C1_6alkyl, and -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, — OR27, and -NR13R14; 1O R3 is selected from —H, -halo, -OH, -C1_6alkyl, and -Cg_6cycloalkyl; wherein each of said lkyl is optionally and ndently substituted with from 1 to 3 substituents selected from —halo, — ORzg, and -NR15R16; R4 and R8 are each independently selected from —halo, —OH, -C1_6alkyl, -O-C1_6alkyl, 6alkyl, - NR17R18, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar4 and -Het4; R6, R7, R9, R101 R11! R12, R13, R141 R15! R16, R17! R18, R19, R20, R21, R22, R23, R24, R31, R321R331 R34, R35 and R36 are each independently selected from —H, -halo, =0, -OH, -C1_6alkyl, -O-C1_6alkyl, - S—C1_6alkyl, -C3_6cycloalkyl, -Ar6 and —Het6; wherein each of said lkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, —OH, -O-C1_6alkyl, -S-C1_6alkyl, -Cg_6cycloalkyl, -Het6, -Ar6 and —NR37R38; R27 and R28, are each independently selected from —H, -C1_6alkyl, -C3_6cycloalkyl and -Het2: R37 and R38, are each independently ed from —H, -halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_ 6alkyl, ycloalkyl, -Ar7 and —Het7; X1 is selected from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NR3-C1_6alkyl-, -NR3-Cq_6alkyl-, and -N R3-; X2 is selected from —O-CH2-, —S—CH2-, and -NR2-CH2-; Ar1, Ar4, Ar5, Ar6, and Ar7 are each independently a 5- to bered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and 8; each of said An, Ar4, Ar5, Ar6, and Ar7 being optionally and ndently tuted with from 1 to 3 substituents selected from — halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, and —NR19R20; wherein each of said -C1_6alkyl is 3O optionally and independently substituted with from 1 to 3 -halo; Het1, Het2, Het4, Het5, Het6, and Het7 are each ndently a 3- to 10-membered cycle having from 1 to 3 heteroatoms selected from O, N and 8; wherein each of said Het1, Het2, Het4, Het5, Het6, and Het7 is optionally and ndently substituted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_ 6alkyl, and -NR21R22; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; Hetg is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and wherein said Hetg is optionally and independently substituted with from 1 to 3 substituents 40 selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_6alkyl, and - NR21R22; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; wherein when R1 is —H, then at least one heteroatom of Hetg is ed to X1 Z1, 22, 23, Z4 and Z5 are each independently selected from C and N; and A1 and A2 are each ndently selected from C and N.

In a particular embodiment, the present invention provides a compound of Formula | or a stereoisomer, tautomer, racemic, metabolite, pro- or pre-drug, salt, hydrate, N-oxide form, or solvate thereof, wherein 1O R1 is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, -NR9R10, -(C=O)-R4, - (C=S)—R4, -SOz-R4, -CN, -N Rg-SOZ-R4, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar1 and —Het1; wherein each of said -C1_6alkyl is optionally and independently tuted with from 1 to 3 tuents selected from —halo, -OR35, -NR11R12, -O-C1_6alkyl, and -S-C1_6alkyl; wherein when A2 is N, then R1 and R5 are not simultaneously —H.

R5 is attached to Z1 or Z5 and is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, - NR6R7, -(C=O)-R8, -(C=S)—R8, -SOZ-R8, -CN, -NR6-SOZ-R8, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, - Ar5 and —Het5; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OR36, -NR23R24, -O-C1_6alkyl, and -S-C1_6alkyl; R2 is selected from —H, -halo, -OH, -C1_6alkyl, and -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is optionally and ndently tuted with from 1 to 3 substituents selected from —halo, — OR27, and -NR13R14; R3 is selected from —H, -halo, -OH, -C1_6alkyl, and -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, — ORzg, and -NR15R16; R4 and R8 are each independently selected from —halo, —OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, - NR17R18, -O-Cg_6cycloalkyl, -C3_6cycloalkyl, -Ar4 and -Het4; R6, R7, R9, R101 R11! R12, R13, R141 R15! R16, R17! R18, R19, R20, R21, R22, R23, R24, R31, R321R331 R34, R37 and R38 are each independently selected from —H, -halo, =0, -OH, -C1_6alkyl, -O-C1_6alkyl, - S—C1_6alkyl, -C3_6cycloalkyl, -Ar6 and —Het6; wherein each of said lkyl is optionally and 3O independently substituted with from 1 to 3 tuents selected from —halo, —OH, -O-C1_6alkyl, -S-C1_6alkyl, -Cg_6cycloalkyl, -Het6, -Ar6 and 36; R27 and R28, are each independently selected from —H, -C1_6alkyl, -C3_6cycloalkyl and -Het2: R37 and R38, are each independently selected from —H, -halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_ , -C3_6cycloalkyl, -Ar7 and —Het7; X1 is selected from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, lkyl-NR3-C1_6alkyl-, -NR3-Cq_6alkyl-, -NR3-, and -O-; n each of said -C1_6alkyl- is optionally and independently substituted with from 1 to 3 tuents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, -phenyl, and -N R33R34 X2 is selected from —C1_6alkyl-, —O-C1_6alkyl-, 6alkyl-, -C1_6alkyl-NRZ-C1_6alkyl-, q_6alkyl-, 40 -NR2-, and -O-; wherein each of said -C1_6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, -phenyl and -N R31R32; Ar1, Ar4, Ar5, Ar6, and Ar7 are each independently a 5- to 10-membered aromatic cycle ally comprising 1 to 3 heteroatoms selected from O, N and 8; each of said An, Ar4, Ar5, Ar6, and Ar7 being optionally and independently substituted with from 1 to 3 substituents selected from — halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, and —NR19R20; wherein each of said -C1_6alkyl is ally and independently substituted with from 1 to 3 -halo; Het1, Het2, Het4, Het5, Het6, and Het7 are each independently a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms ed from O, N and 8; wherein each of said Het1, Het2, 1O Het4, Het5, Het6, and Het7 is optionally and independently substituted with from 1 to 3 tuents selected from —halo, -OH, —C1_6alkyl, 6alkyl, 6alkyl, =0, -(C=O)-C1_ 6alkyl, and -NR21R22; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; Hetg is a bivalent 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and 8; wherein at least one of said heteroatoms is attached to X1; and n said Hetg is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_6alkyl, and -NR21R22; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 - halo; Z1, 22, 23, Z4 and Z5 are each independently selected from C and N; and A1 and A2 are each independently selected from C and N.

In a particular embodiment, the present invention provides a compound of Formula la or a stereoisomer, tautomer, racemic, metabolite, pro- or pre-drug, salt, hydrate, N-oxide form, or solvate thereof, N ,23\ /R1 N Z 22 t8 la Wherein R1 is selected from —H, —halo, -OH, lkyl, -O-C1_6alkyl, -S-Cq_6alkyl, -NR9R10, -(C=O)-R4, - 3O R4, -SOz-R4, -CN, -NR9-SOZ-R4, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar1 and —Het1; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 tuents selected from —halo, -OR35, -NR11R12, -O-C1_6alkyl, and -S-C1_6alkyl; R5 is attached to Z1 or Z5 and is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, - NR6R7, -(C=O)-R8, -(C=S)—R8, -SOZ-R8, -CN, -NR6-SOZ-R8, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, - Ar5 and —Het5; wherein each of said -C1_6alkyl is optionally and independently tuted with from 1 to 3 substituents selected from —halo, -OR36, 24, -O-C1_6alkyl, and -S-C1_6alkyl; R2 is selected from —H, -halo, -OH, -C1_6alkyl, and -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 tuents selected from —halo, — OR27, and -NR13R14; R3 is selected from —H, -halo, -OH, -C1_6alkyl, and -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, — 1O ORzg, and -NR15R16; R4 and R8 are each independently selected from —halo, —OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, - NR17R18, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar4 and -Het4; R6, R7, R9, R101 R11! R12, R13, R141 R15! R16, R17! R18, R19, R20, R21, R22, R23, R24, R29, R30, R31, R32, R33, R34, R37 and R38 are each ndently selected from —H, -halo, =0, -OH, -C1_6alkyl, -O- Cq_6alkyl, -S-C1_6alkyl, -Cg_6cycloalkyl, -Ar6 and —Het6; wherein each of said lkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, — OH, -O-C1_6alkyl, -S-C1_6alkyl, ycloalkyl, -Het6, -Ar6 and —NR35R36; R27 and R28, are each independently selected from —H, -C1_6alkyl, -C3_6cycloalkyl and -Het2: R37 and R38, are each independently selected from —H, -halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_ 6alkyl, -C3_6cycloalkyl, -Ar7 and —Het7; X1 is selected from —C1_6alkyl-, 6alkyl-, —S—C1_6alkyl-, lkyl-NR3-C1_6alkyl-, -NR3-Cq_6alkyl-, -NR3-, and -O-; wherein each of said -C1_6alkyl- is optionally and independently substituted with from 1 to 3 substituents ed from —halo, -OH, lkyl, -O-C1_6alkyl, -S-C1_6alkyl, -phenyl, and -N R33R34 X2 is selected from —C1_6alkyl-, —O-C1_6alkyl-, 6alkyl-, lkyl-NR3-C1_6alkyl-, -NR2-Cq_6alkyl-, -NR2-, and -O-; wherein each of said -C1_6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, -phenyl and -N R31R32; Ar1, Ar4, Ar5, Ar6, and Ar7 are each independently a 5- to 10-membered aromatic cycle optionally 3O comprising 1 to 3 heteroatoms selected from O, N and 8; each of said An, Ar4, Ar5, Ar6, and Ar7 being optionally and independently substituted with from 1 to 3 substituents selected from — halo, -OH, -C1_6alkyl, -O-C1_6alkyl, 6alkyl, and —NR19R20; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; Het1, Het2, Het4, Het5, Het6, and Het7 are each independently a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and 8; wherein each of said Het1, Het2, Het4, Het5, Het6, and Het7 is optionally and independently tuted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_ 6alkyl, and -NR21R22; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; Hetg is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and wherein said Hetg is optionally and independently tuted with from 1 to 3 tuents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_6alkyl, and - NR21R22; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; wherein when R1 is —H, then at least one heteroatom of Hetg is ed to X1 Z1, 22, 23, Z4 and Z5 are each independently ed from C and N. 1O In a ular embodiment, the present invention provides a compound of Formula la or a stereoisomer, tautomer, racemic, metabolite, pro- or pre-drug, salt, hydrate, N-oxide form, or solvate thereof, wherein R1 is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, -NR9R10, -R4, - (C=S)—R4, -SOz-R4, -CN, -NR9-SOZ-R4, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar1 and —Het1; wherein each of said -C1_6alkyl is optionally and independently tuted with from 1 to 3 substituents selected from —halo, -OR35, -NR11R12, -O-C1_6alkyl, and -S-C1_6alkyl; R5 is attached to Z1 or Z5 and is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, - NR6R7, -(C=O)-R8, -(C=S)—R8, -SOZ-R8, -CN, -NR6-SOZ-R8, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, - Ar5 and —Het5; wherein each of said lkyl is optionally and ndently tuted with from 1 to 3 substituents selected from —halo, -OR36, -NR23R24, 6alkyl, and -S-C1_6alkyl; R2 is selected from —H, -halo, -OH, lkyl, -C3_6cycloalkyl,; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, — OR27, and -NR13R14; R3 is selected from —H, -halo, -OH, -C1_6alkyl, -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents ed from —halo, — ORzg, and -NR15R16; R4 and R8 are each independently selected from —halo, —OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, - NR17R18, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar4 and -Het4; R6, R7, R9, R101 R11! R12, R13, R141 R15! R16, R17! R18, R19, R20, R21, R22, R23, R24, R31, R321R331 R34, 3O R35 and R36 are each independently selected from —H, -halo, =0, -OH, -C1_6alkyl, -O-C1_6alkyl, - S—C1_6alkyl, -C3_6cycloalkyl, -Ar6 and —Het6; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, —OH, -O-C1_6alkyl, -S-C1_6alkyl, -Cg_6cycloalkyl, -Het6, -Ar6 and —NR37R38; R27 and R28, are each independently selected from —H, -C1_6alkyl, -C3_6cycloalkyl and -Het2: R37 and R38, are each independently selected from —H, -halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_ 6alkyl, -C3_6cycloalkyl, -Ar7 and —Het7; X1 is selected from lkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NR3-C1_6alkyl-, -NR3-Cq_6alkyl-, and -N R3-; X2 is selected from —O-CH2-, —S—CH2-, and -NR2-CH2-; An, Ar4, Ar5, Ar6, and Ar7 are each independently a 5- to 10-membered aromatic cycle optionally comprising 1 to 3 atoms selected from O, N and 8; each of said An, Ar4, Ar5, Ar6, and Ar7 being optionally and ndently substituted with from 1 to 3 substituents selected from — halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, and 20; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; Het1, Het2, Het4, Het5, Het6, and Het7 are each independently a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and 8; wherein each of said Het1, Het2, Het4, Het5, Het6, and Het7 is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, lkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_ 1O 6alkyl, and -NR21R22; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; Hetg is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and wherein said Hetg is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_6alkyl, and - NR21R22; n each of said -C1_6alkyl is optionally and ndently substituted with from 1 to 3 -halo; wherein when R1 is —H, then at least one heteroatom of Hetg is attached to X1 Z1, 22, 23, Z4 and Z5 are each independently selected from C and N.

In a particular embodiment, the present invention provides a compound of Formula la or a stereoisomer, tautomer, racemic, lite, pro- or pre-drug, salt, hydrate, N-oxide form, or solvate thereof, wherein R1 is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, -NR9R10, -(C=O)-R4, - (C=S)—R4, -SOz-R4, -CN, -NR9-SOZ-R4, -C3_6cycloalkyl, 6cycloalkyl, -Ar1 and —Het1; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OR35, -NR11R12, -O-C1_6alkyl, and -S-C1_6alkyl; R5 is attached to Z1 or Z5 and is ed from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, 6alkyl, - NR6R7, -R8, -(C=S)—R8, -SOZ-R8, -CN, -NR6-SOZ-R8, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, - 3O Ar5 and —Het5; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OR36, -NR23R24, -O-C1_6alkyl, and -S-C1_6alkyl; R2 is ed from —H, -halo, -OH, -C1_6alkyl, and -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is optionally and ndently substituted with from 1 to 3 substituents selected from —halo, — OR27, and -NR13R14; R3 is selected from —H, -halo, -OH, -C1_6alkyl, and -Cg_6cycloalkyl; wherein each of said lkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, — ORzg, and -NR15R16; R4 and R8 are each independently selected from —halo, —OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, - NR17R18, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar4 and -Het4; R6, R7, R9, R101 R11! R12, R13, R141 R15! R16, R17! R18, R19, R20, R21, R22, R23, R24, R29, R30, R31, R32, R33, R34, R37 and R38 are each independently selected from —H, -halo, =0, -OH, lkyl, -O- Cq_6alkyl, -S-C1_6alkyl, -Cg_6cycloalkyl, -Ar6 and —Het6; wherein each of said lkyl is optionally and independently tuted with from 1 to 3 substituents selected from —halo, — OH, -O-C1_6alkyl, -S-C1_6alkyl, -C3_6cycloalkyl, -Het6, -Ar6 and —NR35R36; R27 and R28, are each independently selected from —H, -C1_6alkyl, -C3_6cycloalkyl and -Het2: R37 and R38, are each independently selected from —H, -halo, -OH, -C1_6alkyl, 6alkyl, -S-C1_ 6alkyl, -C3_6cycloalkyl, -Ar7 and —Het7; X1 is selected from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NR3-C1_6alkyl-, -NR3-Cq_6alkyl-, 1O -NR3-, and -O-; wherein each of said -C1_6alkyl- is ally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, -phenyl, and -N R33R34 X2 is selected from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NR3-C1_6alkyl-, -NR2-Cq_6alkyl-, -NR2-, and -O-; wherein each of said -C1_6alkyl- is ally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, 6alkyl, -phenyl and -N R31R32; Ar1, Ar4, Ar5, Ar6, and Ar7 are each independently a 5- to bered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and 8; each of said An, Ar4, Ar5, Ar6, and Ar7 being ally and independently substituted with from 1 to 3 substituents selected from — halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, and —NR19R20; wherein each of said -C1_6alkyl is optionally and independently tuted with from 1 to 3 -halo; Het1, Het2, Het4, Het5, Het6, and Het7 are each independently a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and 8; wherein each of said Het1, Het2, Het4, Het5, Het6, and Het7 is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_ 6alkyl, and -NR21R22; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; Hetg is a bivalent 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and 8; 3O wherein at least one of said heteroatoms is attached to X1; and wherein said Hetg is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_6alkyl, and -NR21R22; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 - halo; Z1, 22, 23, Z4 and Z5 are each independently selected from C and N.

In a particular embodiment, the t invention provides a compound of Formula la or a stereoisomer, tautomer, racemic, metabolite, pro- or pre-drug, salt, hydrate, N-oxide form, or e thereof, wherein I," ,23\ ,R1 N 24 22 R1 is selected from —halo, -C1_6alkyl and -CN; R5 is attached to Z1 and is selected from —H, —halo, -C1_6alkyl, and -C3_6cycloalkyl; R2 is selected from —H, -C1_6alkyl and -C3_6cycloalkyl; X1 is selected from —O-C1_6alkyl, and -NR3-C1_6alkyl-; X2 is -N RZ-C1_6alkyl; Hetg is a 3- to bered N-containing heterocycle; and Z1, 22, 23, Z4 and Z5 are each C. 1O In a specific embodiment the present invention provides a compound selected from the list comprising: f"/N‘\ HN N \ Compound 01, Example 01 Compound 02, Example 02 / / N’N N’N \ \ \ \ N \ N \ \\\ HN ‘\/\0 Cl 0 Compound 03 Example 03 nd 04 Example 04 \ \ \ \ d C" N\/\O F \\/\O F Compound 05, Example 05 Compound 06, Example 06 / N’N \ [\N’l‘i QWO F CH/QN\/\O Compound 07, Example 07 Compound 08, Example 08 \\/\0 CI Compound 09, Example 09 Compound 010, Example 010 [\NwN 6NH CHf\ ‘\/\O F nd 011, e 011 nd 012, Example 012 f" \ \ \ \ \ f"\ :1? N :1? N O F O F Compound 013, Example 013 Compound 014, Example 014 In yet a further aspect, the present invention provides a compound ing to the present invention; wherein R5 is linked to the aryl or heteroaryl moiety at position Z1 in accordance with the numbering as provided in Formula | or la.

In yet a further aspect, the present invention provides a compound according to the present invention; wherein said compound is the S—enantiomer.

The present invention further provides a pharmaceutical composition comprising a compound according to this invention.

In a further aspect, the present invention provides a compound or a composition according to this ion, for use as a medicine.

In a ular embodiment, the present invention provides a nd or composition according to this invention for use in the diagnosis, prevention and/or treatment of a RIP2—kinase associated disease. Said RIP2—kinase associated e may in particular be an matory disorders, more in particular selected from the list comprising: Crohn’s e, bowel disease, Sarcoidosis, psoriasis, rheumatoid arthritis, asthma, ulcerative colitis, lupus, uveitis, blau syndrome, granulomatous in?ammation, in particular behcet’s disease, multiple sclerosis and insulin-resistant type 2 diabetes. 1O Furthermore, the t invention provides the use of a nd or composition according to this ion, suitable for inhibiting the activity of a kinase; in ular a R|P2 kinase; or for the diagnosis, prevention and/or treatment of a RIP2—kinase associated disease.

Finally, the t invention provides a method for prevention and/or treatment of a RIP2—kinase associated disease; said method comprising administering to a subject in need thereof a compound or a ition according to the present invention.

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

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

As already mentioned hereinbefore, in a first aspect the present invention provides a compound of Formula | or a stereoisomer, tautomer, racemic, metabolite, pro- or pre-drug, salt, hydrate, N-oxide form, or solvate thereof, Wherein R1 is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, 6alkyl, -NR9R10, -(C=O)-R4, - R4, -SOz-R4, -CN, -NR9-SOZ-R4, -C3_6cycloalkyl, 6cycloalkyl, -Ar1 and —Het1; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OR35, -NR11R12, -O-C1_6alkyl, and -S-C1_6alkyl; wherein when A2 is N, then R1 and R5 are not simultaneously —H; R5 is attached to Z1 or Z5 and is selected from —H, —halo, -OH, lkyl, -O-C1_6alkyl, -S-C1_6alkyl, - NR6R7, -(C=O)-R8, -(C=S)—R8, -SOZ-R8, -CN, -NR6-SOZ-R8, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, - Ar5 and —Het5; n each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OR36, -NR23R24, -O-C1_6alkyl, and -S-C1_6alkyl; 1O R2 is selected from —H, -halo, -OH, -C1_6alkyl, and -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is optionally and independently tuted with from 1 to 3 substituents selected from —halo, — OR27, and -NR13R14; R3 is selected from —H, -halo, -OH, -C1_6alkyl, -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, — ORzg, and -NR15R16; R4 and R8 are each independently selected from —halo, —OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, - NR17R18, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar4 and -Het4; R6, R7, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R31, R32, R33, R34, R35 and R36 are each independently selected from —H, -halo, =0, -OH, -C1_6alkyl, -O-C1_6alkyl, - S—C1_6alkyl, -C3_6cycloalkyl, -Ar6 and —Het6; wherein each of said -C1_6alkyl is optionally and independently tuted with from 1 to 3 substituents selected from —halo, —OH, -O-C1_6alkyl, -S-C1_6alkyl, -Cg_6cycloalkyl, -Het6, -Ar6 and —NR37R38; R27 and R28, are each independently selected from —H, lkyl, -C3_6cycloalkyl and -Het2: R37 and R38, are each independently selected from —H, -halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_ 6alkyl, -C3_6cycloalkyl, -Ar7 and —Het7; X1 is selected from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NR3-C1_6alkyl-, -NR3-Cq_6alkyl-, -NR3-, and -O-; n each of said -C1_6alkyl- is optionally and independently tuted with from 1 to 3 tuents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, -phenyl, and -N ; 3O X2 is selected from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NRZ-C1_6alkyl-, -NR2-Cq_6alkyl-, -NR2-, and -O-; wherein each of said -C1_6alkyl- is optionally and independently tuted with from 1 to 3 substituents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, -phenyl and -N R31R32; Ar1, Ar4, Ar5, Ar6, and Ar7 are each independently a 5- to 10-membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and 8; each of said An, Ar4, Ar5, Ar6, and Ar7 being optionally and independently substituted with from 1 to 3 substituents selected from — halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, and —NR19R20; n each of said lkyl is optionally and independently substituted with from 1 to 3 -halo; Het1, Het2, Het4, Het5, Het6, and Het7 are each ndently a 3- to 10-membered heterocycle 40 having from 1 to 3 heteroatoms selected from O, N and 8; wherein each of said Het1, Het2, Het4, Het5, Het6, and Het7 is ally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, lkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_ , and -NR21R22; wherein each of said -C1_6alkyl is ally and ndently substituted with from 1 to 3 -halo; Hetg is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and wherein said Hetg is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_6alkyl, and - NR21R22; wherein each of said lkyl is optionally and independently substituted with from 1 1O to 3 -halo; wherein when R1 is —H, then at least one heteroatom of Hetg is attached to X1 Z1, 22, 23, Z4 and Z5 are each independently selected from C and N; and A1 and A2 are each independently selected from C and N.

Unless indicated othen/vise, all of the above radicals can be read both ways. For example, when X1 is -NR3-C1_6alkyl-, the -C1_6alkyl- may be attached to Hetg and —NR3- attached to the 21-25 aryl or heteroaryl . Alternatively, the -C1_6alkyl- may be attached to the 21-25 aryl or heteroaryl moeity and —NR3- attached to Hetg. What is called "left part" of a radical is for e when X1 is - NR3-C1_6alkyl-, -NR3-, and the "right part" is lkyl-.

Preferably, X1 is such as the left part of the possible values of X1 (i.e. in particular —0 from —O-C1_ 6alkyl, -S from —S—Cq_6alkyl, -NR3 from -N R3-C1_6alkyl, etc) is attached to the 21-25 aryl or heteroaryl moiety. Alternatively, X1 is such as the right part of the possible values of X1 (i.e. in particular (C1. 6alkyl)— from —O-C1_6alkyl, —S—C1_6alkyl and -NR3-C1_6alkyl, etc) is attached to the 21-25 aryl or heteroaryl moiety.

Preferably, X2 is such as the left part of the possible values of X2 (i.e. in particular —0 from —O-C1_ 6alkyl, -S from —S—Cq_6alkyl, -NR2 from -NR2-C1_6alkyl, etc) is attached to the pyrazolopyrimidine . Alternatively, X2 is such as the right part of the possible values of X2 (i.e. in particular (C1. 6alkyl)— from —O-C1_6alkyl, —S—C1_6alkyl and -N RZ-C1_6alkyl, etc) is attached to the pyrazolopyrimidine moiety. 3O The same principle s to all the radicals of the invention unless specified otherwise.

When describing the compounds of the invention, the terms used are to be ued in accordance with the following definitions, unless a context dictates otherwise: The term "alkyl" by itself or as part of another substituent refers to fully saturated hydrocarbon radicals. Generally, alkyl groups of this invention se from 1 to 6 carbon atoms. Alkyl groups may be linear or branched and may be substituted as indicated herein. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. Thus, for example, C1_6alkyl means an alkyl of one to six carbon atoms.

Examples of alkyl groups are , 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. C1-C6 alkyl includes all linear, branched, or cyclic alkyl groups with between 1 and 6 carbon atoms, and thus includes methyl, ethyl, n-propyl, i-propyl, butyl and its isomers (e.g. n-butyl, i-butyl and t-butyl); pentyl and its isomers, hexyl and its isomers, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term "optionally substituted alkyl" refers to an alkyl group optionally substituted with one or more substituents (for example 1 to 3 substituents, for example 1, 2 or 3 substituents or 1 to 2 substituents) at any available point of attachment. Non-limiting examples of such substituents include —halo, -OH, y and secondary amides, -O-C1_6alkyl, -S-C1_6alkyl, heteroaryl, aryl, and the like.

The term "cycloalkyl" by itself or as part of another substituent is a cyclic alkyl group, that is to say, 1O a monovalent, saturated, or unsaturated hydrocarbyl group having a cyclic structure. Cycloalkyl includes all ted or partially saturated ining 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 e but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

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

Generally, alkylene groups of this invention preferably comprise the same number of carbon atoms as their alkyl counterparts. Where an alkylene or lkylene biradical is present, connectivity to the molecular structure of which it forms part may be through a common carbon atom or different carbon atom. To illustrate this applying the asterisk nomenclature of this invention, a C3 ne group may be for example *-CHZCHZCH2-*, *-CH(-CH2CH3)-*, or *-CHZCH(-CH3)-*. se a C3 cycloalkylene group may be * The terms "heterocycle" as used herein by itself or as part of another group refer to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 6 membered monocyclic ring systems, or 8-10 membered bicyclic rings) which have at least one heteroatom in at least one carbon atom-containing ring. Each ring of the heterocyclic group containing a heteroatom may 3O 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 tuents, or for e 1, 2, 3 or 4), selected from those defined above for substituted alkyl.

Exemplary heterocyclic groups include piperidinyl, inyl, imidazolinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, azolidinyl, piperidyl, succinimidyl, 3H- indolyl, isoindolinyl, chromenyl, omanyl, xanthenyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3- pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 4aH-carbazolyl, 2-oxopiperazinyl, piperazinyl, perazinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyranyl, dihydro-2H-pyranyl, 4H-pyranyl, hydro- anyl, phthalazinyl, oxetanyl, thietanyl, 3-dioxolanyl, 1,3-dioxanyl, 2,5-dioximidazolidinyl, 2,2,4-piperidonyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl e, oxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 6H-1,2,5-thiadiazinyl, 2H-1,5,2—dithiazinyl, 2H-oxocinyl, 1H-pyrrolizinyl, tetrahydro- 1,1-dioxothienyl, N-formylpiperazinyl, and morpholinyl; in particular pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, dioxolanyl, dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl, 1O lidinyl, tetrahydropyranyl, tetrahydrofuranyl, Zb’ch_(E_ Y X_(-. ‘- ‘- ‘- r " " I . x N-.- ‘ Za\x\—/N-:- Z'a’x N-:_ I -L -L -L Zb\ ‘ N N Zc Za g : : : ‘Zb \ '— \r \‘r i E_ E_ N'E_ I N':_ N_E' N-:' I r:— I I x N-i- x N-i- xf—l fY N-'- XZY {Y N-i- Y N-:- wherein X, Y, Z, Za, Zb and Zc represent a C atom or suitable heteroatom, selected from N, O and 8-10 Membered heterocyclic groups are also meant to include spiro-groups, which are bicyclic nds 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, further suitable 8-10 membered heterocyclic groups are represented herein below: \ l WO 42087 2015/071347 jj: $5: odi- Cg g1; 9d: 9 o2S RN ._ :— ,'_ :— I I | N-E- N-E- N—:'. 028 N-:- N'E' RN N-:- 023 so2 wherein R represents a substituent selected from the list as defined for any one of Het1 to Het7.

The term "aryl" as used herein refers to a polyunsaturated, aromatic arbyl group having from -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 ryl, 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-?uorenyl, 4- or 5-indanyl, 5-, 6-, 7-, or 8- tetrahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, dibenzo[a,d]cylcoheptenyl, 1O and 1-, 2-, 3-, 4-, or 5-pyrenyl; in particular phenyl.

The aryl ring can optionally be substituted by one or more tuents. An nally substituted aryl" refers to an aryl having optionally one or more substituents (for example 1 to 5 tuents, 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 ant ring is referred to herein as a heteroaryl ring.

The term "heteroaryl" as used herein by itself or as part of another group refers but is not limited to to 10 -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, yl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl, iazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl, thieno[3,2—b]furanyl, thieno[3,2—b]thiophenyl, thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl, tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2—benzisoxazolyl, 2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2- benzoisothiazolyl, 2,1 -benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl, 2,1 ,3- benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl, thienopyridinyl, purinyl, imidazo[1,2-a]pyridinyl, pyridazin-1(6H)—yl, 2-oxopyridin-1(2H)—yl, 6-oxo-pyridazin-1(6H)—yl, 2- oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 7-azaindolyl, 6-azaindolyl, 5-azaindolyl, ndolyl.

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

The term "halo" or "halogen" as a group or part of a group is generic for , chloro, bromo, or 1O iodo, as well as any suitable isotope thereof.

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

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

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

More lly, from the above, it will be clear to the skilled person that the compounds of the invention may exist in the form of ent isomers and/or tautomers, including but not limited to geometrical isomers, conformational isomers, omers, 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 f are included within the scope of the invention.

In addition, the invention includes ically-labelled compounds and salts, which are identical to 3O compounds of a (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of formula (I) are isotopes of hydrogen, carbon, nitrogen, fluorine, such as 3H, 11C, 13N, 14C, 15O and 18F. Such isotopically-labelled compounds of a (I) are useful in drug and/or substrate tissue distribution assays. For example 11C and 18F isotopes are particularly useful in PET (Positron Emission Tomography). PET is useful as a diagnostic or treatment -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. lsotopically labeled nds of formula (I) can generally be prepared by carrying out the procedures disclosed below, by substituting a y available non-isotopically labeled t with an isotopically labeled t.

Whenever used in the present invention the term "compounds of the invention" or a similar term is meant to include the compounds of general Formula | and any subgroup thereof. This term also refers to the compounds as depicted in Table 1, their derivatives, N-oxides, salts, solvates, hydrates, stereoisomeric forms, racemic mixtures, tautomeric forms, optical isomers, analogues, pro-drugs, esters, and metabolites, as well as their quaternized en analogues. The e forms of said compounds are meant to comprise compounds wherein one or several nitrogen atoms are oxidized to the so-called N-oxide. 1O As used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. By way of example, "a compound" means one compound or more than one compound.

The terms described above and others used in the specification are well understood to those in the Preferably, compounds of Formula l are defined as such that A1 and A2 are selected from C and N; wherein when A1 is C, then A2 is N; and wherein when A2 is C, then A1 is N; provided that when A2 is N, then R1 and R5 are not simultaneously —H.

More ably, A1 is N and A2 is C. Alternatively, A2 is N and A1 is C; provided that when A2 is N, then R1 and R5 are not simultaneously —H. ably, R1 is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, -NR9R10, - (C=O)—R4, -(C=S)-R4, -SOz-R4, -CN, -NR9-SOZ-R4, -C3_6cycloalkyl, -O-C3_6cycloalkyl, -Ar1 and — Het1; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OR35, -NR11R12, -O-C1_6alkyl, and -S-C1_6alkyl.

More preferably, R1 is selected from -F, -C|, -CN, -O-C1_6alkyl, -O-C1_6cycloalkyl; wherein each of said -C1_6alkyl is ally and independently substituted with from 1 to 3 -Me, -halo, -OH, -H, - cyclopropyl, -cyclobutyl; -cycloalkyls are optionally independently tuted by -Me, -halo, - OH, -H. ably, R5 is attached to Z1 or Z5 and is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, - alkyl, -NR6R7, -(C=O)-R8, -(C=S)-R8, -SOZ-R8, -CN, -NR6-SOZ-R8, -C3_6cycloalkyl, -O-C3_ alkyl, -Ar5 and —Het5; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OR36, -NR23R24, -O-C1_6alkyl, and -S-C1_6alkyl.

More ably, R5 is selected from -F, -Cl, -CN, -C1_3alkyl, -Cg_4cycloalkyl; wherein each of said - C1_3alkyl is optionally and independently substituted with from 1 to 3 -Me, -halo, -OH, -H; wherein each of said -C3_4cycloalkyl is ally and ndently substituted with from 1 to 3 -Me, -halo, -OH, -H.

Preferably, R2 is selected from -H, -halo, -OH, -C1_6alkyl, -Cg_6cycloalkyl; wherein each of said -C1_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from — halo, —OR27, and -NR13R14.

More preferably, R2 is selected from -H, -C1_3alkyl, -C3_4cycloalkyl; wherein each of said -C1_3alkyl is 1O ally and independently tuted with from 1 to 3 -H, -Me, -halo, -OH, -NR13R14. n each of said -C3_4cycloalkyl is optionally and independently substituted with from 1 to 3 -H, -Me, -halo, -OH, -NR13R14.

Preferably, R3 is selected from —H, -halo, -OH, -C1_6alkyl, -C3_6cycloalkyl; wherein each of said -C1_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from — halo, —OR28, and -NR15R16.

More preferably, R3 is selected from Cq_3alkyl, C3_4cycloalkyl; wherein each of said -C1_3alkyl is optionally and independently substituted with from 1 to 3 -H, -Me, -halo, -OH, -NR15R16. n each of said -C3_4cycloalkyl is optionally and independently substituted with from 1 to 3 -H, -Me, -halo, -OH, -NR15R16.

Preferably, R4 and R8 are each independently selected from —halo, —OH, -C1_6alkyl, -O-C1_6alkyl, -SCq _6alkyl, -NR17R18, -Cg_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar4 and -Het4.

More preferably, R4 is selected from -C1_3alkyl, -O-C1_3alkyl, -NR17R18, -C3_4cycloalkyl, -O-C3_ 4cycloalkyl; wherein each of said Cq_3alkyl is optionally and independently substituted with from 1 to 3 -H, -Me, -halo, -OH, -NR17R18. wherein each of said -C3_4cycloalkyl is optionally and independently substituted with from 1 to 3 -H, -Me, -halo, -OH, 18.

More preferably, R8 is selected from -C1_3alkyl, -O-C1_3alkyl, -NR17R18, -C3_4cycloalkyl, -O-C3_ 4cycloalkyl; wherein each of said -C1_3alkyl is optionally and independently tuted with from 3O 1 to 3 -H, -Me, -halo, -OH, -NR17R18. wherein each of said ycloalkyl is optionally and independently tuted with from 1 to 3 -H, -Me, -halo, -OH, -NR17R18.

Preferably, R6, R7, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R31, R32, R33, R34, R35 and R36 are each independently selected from —H, -halo, =0, -OH, -C1_6alkyl, -O- Cq_6alkyl, -S-C1_6alkyl, -Cg_6cycloalkyl, -Ar6 and —Het6; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, — OH, -O-C1_6alkyl, -S-C1_6alkyl, -C3_6cycloalkyl, -Het6, -Ar6 and —NR35R36.

Preferably, R27 and R28, are each independently selected from —H, -C1_6alkyl, ycloalkyl and - Het2.

More preferably, R27 and R28, are each independently selected from —H, -C1_3alkyl, -Cg_4cycloalkyl; wherein each of said -C1_3alkyl is optionally and independently substituted with from 1 to 3 -H, - Me, -halo; and wherein each of said -C3_4cycloalkyl is optionally and independently substituted with from 1 to 3 -H, -Me, -halo.

Preferably, R37 and R38, are each independently selected from —H, -halo, -OH, -C1_6alkyl, -O-C1_ 6alkyl, -S-C1_6alkyl, -C3_6cycloalkyl, -Ar7 and —Het7. 1O More preferably, R37 and R38, are each independently selected from —H, -C1_3alkyl, or -C3_ 4cycloalkyl; wherein each of said -C1_3alkyl is optionally and ndently substituted with from 1 to 3 -H, -Me, -halo; and wherein each of said ycloalkyl is optionally and independently substituted with from 1 to 3 -H, -Me, -halo, -OH.

Preferably, X1 is selected from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, lkyl-NR3-C1_6alkyl-, - NR3-C1_6alkyl-, -NR3-, -O-; wherein each of said -C1_6alkyl- is optionally and independently substituted with from 1 to 3 tuents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S- Cq_6alkyl, -phenyl, and -NR33R34.

More preferably, X1 is selected from -O-C1_3alkyl, -NR3-C1_3alkyl-; wherein each of said -C1_3alkyl is optionally and independently substituted with from 1 to 3 -H, -halo, -CF3, -CHF2, -C1_3alkyl, -C or substituted to form a cyclopropyl, cyclobutyl or oxetane; wherein each of said cyclopropyl, cyclobutyl or e is optionally and independently substituted with from 1 to 3 -H, -Me, -halo, - Preferably, X2 is ed from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NRZ-C1_6alkyl-, - NRZ-C1_6alkyl-, -NR2-, -O-; wherein each of said -C1_6alkyl- is ally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S- Cq_6alkyl, -phenyl and -NR31R32.

More preferably, X2 is selected from —O-C1alkyl-, -NR2-C1alkyl; wherein each of said -C1alkyl is 3O optionally and independently substituted with from 1 to 2 -H, -halo, -Me or bi-substituted to form a cyclopropyl, cyclobutyl, oxetane; n each of said cyclopropyl, cyclobutyl or oxetane is optionally and independently substituted with from 1 to 3 -H, -Me, -halo, -OH Preferably, Ar1, Ar4, Ar5, Ar6, and Ar7 are each independently a 5- to bered aromatic cycle optionally sing 1 to 3 heteroatoms selected from O, N and 8; each of said An, Ar4, Ar5, Ar6, and Ar7 being optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, 6alkyl, —NR19R20; wherein each of said - C1_6alkyl is optionally and ndently substituted with from 1 to 3 —halo.

More preferably, Ar1, Ar4, Ar5, Ar6, and Ar7 are each independently selected from any 5 or 6 40 ed aromatic ring.

Preferably, Het1, Het2, Het4, Het5, Het6, and Het7 are each independently a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and 8; wherein each of said Het1, Het2, Het4, Het5, Het6, and Het7 is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, lkyl, -O-C1_6alkyl, 6alkyl, =0, -(C=O)-C1_ 6alkyl, and -NR21R22; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 —halo.

More preferably, Het1, Het2, Het4, Het5, Het6, and Het7 are each independently selected from any 5 or 6 membered saturated or unsaturated heterocycle. 1O Preferably, Hetg is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and 8; wherein said Hetg is optionally and independently substituted with from 1 to 6 substituents selected from -H, —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_6alkyl, and - NR21R22; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; wherein when R1 is —H, then at least one heteroatom of Hetg is attached to X1 More preferably, Hetg is selected from pyrrolidine or dine, and ally and independently substituted with from 1 to 6 substituents selected from -H, —halo, -OH, —C1_6alkyl, 6alkyl, -S- C1_6alkyl, =0, -(C=O)-C1_6alkyl, and -NR21R22; wherein each of said lkyl is optionally and ndently substituted with from 1 to 3 -halo.

Preferably, Z1, 22, 23, Z4 and Z5 are each independently selected from C and N.

More ably, Z1, 22, 23, Z4 and Z5 are each C.

In a particular embodiment, the present invention provides a compound of Formula | or a stereoisomer, tautomer, racemic, metabolite, pro- or pre-drug, salt, hydrate, N-oxide form, or solvate thereof; wherein one or more of the following applies: R1 is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, -NR9R10, -(C=O)-R4, - R4, -SOz-R4, -CN, -NR9-SOZ-R4, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar1 and —Het1; 3O wherein each of said -C1_6alkyl is optionally and ndently substituted with from 1 to 3 substituents selected from —halo, -OR35, -NR11R12, -O-C1_6alkyl, and -S-C1_6alkyl; wherein when A2 is N, then R1 and R5 are not aneously —H; R5 is attached to Z1 or Z5 and is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, - NR6R7, -(C=O)-R8, -(C=S)—R8, 8, -CN, -NR6-SOZ-R8, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, - Ar5 and —Het5; wherein each of said -C1_6alkyl is optionally and ndently substituted with from 1 to 3 substituents selected from —halo, -OR36, 24, -O-C1_6alkyl, and -S-C1_6alkyl; R2 is selected from —H, -halo, -OH, -C1_6alkyl, and -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, — OR27, and -NR13R14; R3 is selected from —H, -halo, -OH, -C1_6alkyl, -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, — ORzg, and -NR15R16; R4 and R8 are each independently selected from —halo, —OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, - NR17R18, -C3_6cycloalkyl, 6cycloalkyl, -Ar4 and -Het4; R6, R7, R9, R101 R11! R12, R13, R141 R15! R16, R17! R18, R19, R20, R21, R22, R23, R24, R31, R321R331 R34, R35 and R36 are each independently selected from —H, -halo, =0, -OH, -C1_6alkyl, -O-C1_6alkyl, - S—C1_6alkyl, -C3_6cycloalkyl, -Ar6 and —Het6; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, —OH, -O-C1_6alkyl, 1O -S-C1_6alkyl, -Cg_6cycloalkyl, -Het6, -Ar6 and 38; R27 and R28, are each independently selected from —H, -C1_6alkyl, -C3_6cycloalkyl and -Het2: R37 and R38, are each independently selected from —H, -halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_ 6alkyl, -C3_6cycloalkyl, -Ar7 and —Het7; X1 is selected from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NR3-C1_6alkyl-, q_6alkyl-, -NR3-, and -O-; wherein each of said lkyl- is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, l, and -N R33R34; X2 is selected from —C1_6alkyl-, 6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NRZ-C1_6alkyl-, -NR2-Cq_6alkyl-, -NR2-, and -O-; wherein each of said -C1_6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, -phenyl and -N R31R32; Ar1, Ar4, Ar5, Ar6, and Ar7 are each independently a 5- to 10-membered aromatic cycle optionally sing 1 to 3 heteroatoms selected from O, N and 8; each of said An, Ar4, Ar5, Ar6, and Ar7 being ally and ndently substituted with from 1 to 3 substituents selected from — halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, and —NR19R20; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; Het1, Het2, Het4, Het5, Het6, and Het7 are each independently a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and 8; wherein each of said Het1, Het2, Het4, Het5, Het6, and Het7 is optionally and independently substituted with from 1 to 3 3O substituents selected from —halo, -OH, lkyl, -O-C1_6alkyl, 6alkyl, =0, -(C=O)-C1_ 6alkyl, and -NR21R22; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; Hetg is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms ed from O, N and wherein said Hetg is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_6alkyl, and - NR21R22; wherein each of said -C1_6alkyl is optionally and independently tuted with from 1 to 3 -halo; wherein when R1 is —H, then at least one heteroatom of Hetg is attached to X1 40 Z1, 22, 23, Z4 and Z5 are each independently selected from C and N; and A1 and A2 are each independently selected from C and N.

In a further embodiment, the present invention provides a compound of Formula | or a stereoisomer, tautomer, racemic, metabolite, pro- or pre-drug, salt, hydrate, N-oxide form, or solvate thereof, N R 24’23‘2/2 1 062 £ R5 N Y Wherein R1 is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, -NR9R10, -R4, - (C=S)—R4, -SOz-R4, -CN, -NR9-SOZ-R4, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar1 and —Het1; 1O wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents ed from —halo, -OR35, -NR11R12, -O-C1_6alkyl, and -S-C1_6alkyl; R5 is attached to Z1 or Z5 and is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, - NR6R7, -(C=O)-R8, —R8, 8, -CN, -NR6-SOZ-R8, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, - Ar5 and —Het5; wherein each of said lkyl is optionally and independently substituted with from 1 to 3 substituents ed from —halo, -OR36, -NR23R24, -O-C1_6alkyl, and -S-C1_6alkyl; R2 is selected from —H, -halo, -OH, -C1_6alkyl, and -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, — OR27, and 14; R3 is selected from —H, -halo, -OH, -C1_6alkyl, -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, — ORzg, and -NR15R16; R4 and R8 are each independently selected from —halo, —OH, lkyl, -O-C1_6alkyl, -S-C1_6alkyl, - NR17R18, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar4 and -Het4; R6, R7, R9, R101 R11! R12, R13, R141 R15! R16, R17! R18, R19, R20, R21, R22, R23, R24, R31, R321R331 R34, R35 and R36 are each ndently selected from —H, -halo, =0, -OH, -C1_6alkyl, -O-C1_6alkyl, - alkyl, ycloalkyl, -Ar6 and —Het6; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, —OH, -O-C1_6alkyl, -S-C1_6alkyl, -Cg_6cycloalkyl, -Het6, -Ar6 and —NR37R38; R27 and R28, are each independently ed from —H, -C1_6alkyl, -C3_6cycloalkyl and -Het2: R37 and R38, are each independently ed from —H, -halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_ 6alkyl, -C3_6cycloalkyl, -Ar7 and —Het7; X1 is selected from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NR3-C1_6alkyl-, -NR3-Cq_6alkyl-, -NR3-, and -O-; wherein each of said -C1_6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, lkyl, -O-C1_6alkyl, 6alkyl, -phenyl, and -N R33R34; X2 is selected from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NRZ-C1_6alkyl-, -NR2-Cq_6alkyl-, -NR2-, and -O-; wherein each of said lkyl- is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, -phenyl and -N R31R32; Ar1, Ar4, Ar5, Ar6, and Ar7 are each independently a 5- to 10-membered aromatic cycle ally comprising 1 to 3 heteroatoms selected from O, N and 8; each of said An, Ar4, Ar5, Ar6, and Ar7 being optionally and independently tuted with from 1 to 3 substituents selected from — 1O halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, and —NR19R20; wherein each of said -C1_6alkyl is ally and independently substituted with from 1 to 3 -halo; Het1, Het2, Het4, Het5, Het6, and Het7 are each independently a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and 8; wherein each of said Het1, Het2, Het4, Het5, Het6, and Het7 is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_ 6alkyl, and -NR21R22; wherein each of said -C1_6alkyl is optionally and ndently substituted with from 1 to 3 -halo; Hetg is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and n said Hetg is optionally and ndently substituted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_6alkyl, and - NR21R22; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; wherein when R1 is —H, then at least one heteroatom of Hetg is attached to X1 Z1, 22, 23, Z4 and Z5 are each independently ed from C and N; and A1 and A2 are each independently selected from C and N provided that said compound is not In particular, X1, and X2 as used herein, represent biradicals, which taken together with the radicals to which they are attached form a macrocyclic pyrazolopyrimidine compound. Said biradicals may be present in either of both directions in the macrocyclic pyrazolopyrimidine, but are ably present in the direction as described below: ing to formula I: X1 is selected from the list comprising *—C1_6alkyl-, *—O-C1_6alkyl-, *—S—Cq_6alkyl-, *-C1_6alkyl- NR3-C1_6alkyl-, *-NR3-C1_6alkyl-, , *-O-; * wherein said biradical is preferably attached to the aryl or heteroaryl moiety via *; X2 is ed from the list comprising *—C1_6alkyl-, *—O-C1_6alkyl-, *—S—Cq_6alkyl-, *-C1_6alkyl- NRZ-C1_6alkyl-, *-NR2-C1_6alkyl-, *-NR2-, *-O-; * wherein said biradical is preferably attached to the pyrazolopyrimidine moiety via *; In yet a further embodiment, the present invention es a compound of Formula | or a stereoisomer, tautomer, racemic, metabolite, pro- or ug, salt, hydrate, N-oxide form, or solvate thereof; wherein R1 is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, -NR9R10, -(C=O)-R4, - (C=S)—R4, 4, -CN, -NR9-SOZ-R4, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar1 and —Het1; 1O wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OR35, -NR11R12, -O-C1_6alkyl, and -S-C1_6alkyl; wherein when A2 is N, then R1 and R5 are not simultaneously —H; R5 is attached to Z1 or Z5 and is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, - NR6R7, -(C=O)-R8, -(C=S)—R8, -SOZ-R8, -CN, -NR6-SOZ-R8, -C3_6cycloalkyl, 6cycloalkyl, - Ar5 and —Het5; wherein each of said -C1_6alkyl is optionally and ndently substituted with from 1 to 3 substituents selected from —halo, -OR36, -NR23R24, 6alkyl, and -S-C1_6alkyl; R2 is selected from —H, -halo, -OH, -C1_6alkyl, and -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is ally and independently substituted with from 1 to 3 substituents selected from —halo, — OR27, and -NR13R14; R3 is selected from —H, -halo, -OH, -C1_6alkyl, and -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is ally and independently substituted with from 1 to 3 substituents selected from —halo, — ORzg, and -NR15R16; R4 and R8 are each independently ed from —halo, —OH, -C1_6alkyl, -O-C1_6alkyl, 6alkyl, - NR17R18, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar4 and -Het4; R6, R7, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R31, R32, R33, R34, R35 and R36 are each independently selected from —H, -halo, =0, -OH, -C1_6alkyl, -O-C1_6alkyl, - S—C1_6alkyl, -C3_6cycloalkyl, -Ar6 and —Het6; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, —OH, 6alkyl, -S-C1_6alkyl, -Cg_6cycloalkyl, -Het6, -Ar6 and 38; 3O R27 and R28, are each independently selected from —H, -C1_6alkyl, -C3_6cycloalkyl and -Het2: R37 and R38, are each independently selected from —H, -halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_ 6alkyl, -C3_6cycloalkyl, -Ar7 and —Het7; X1 is selected from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NR3-C1_6alkyl-, -NR3-Cq_6alkyl-, and -N R3-; X2 is selected from —O-CH2-, —S—CH2-, and -NR2-CH2-; Ar1, Ar4, Ar5, Ar6, and Ar7 are each independently a 5- to 10-membered ic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and 8; each of said An, Ar4, Ar5, Ar6, and Ar7 being ally and independently substituted with from 1 to 3 substituents selected from — halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, and —NR19R20; wherein each of said -C1_6alkyl is 40 optionally and independently substituted with from 1 to 3 -halo; Het1, Het2, Het4, Het5, Het6, and Het7 are each independently a 3- to 10-membered heterocycle having from 1 to 3 atoms selected from O, N and 8; wherein each of said Het1, Het2, Het4, Het5, Het6, and Het7 is optionally and independently tuted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_ , and -NR21R22; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; Hetg is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and wherein said Hetg is optionally and independently substituted with from 1 to 3 substituents 1O selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -C1_6alkyl, and - NR21R22; wherein each of said lkyl is optionally and independently substituted with from 1 to 3 -halo; wherein when R1 is —H, then at least one heteroatom of Hetg is ed to X1 Z1, 22, 23, Z4 and Z5 are each independently selected from C and N; and A1 and A2 are each independently selected from C and N.

In another embodiment, the present invention provides a compound of Formula | or a stereoisomer, tautomer, c, metabolite, pro- or pre-drug, salt, e, N-oxide form, or solvate thereof; wherein R1 is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, -NR9R10, -(C=O)-R4, - (C=S)—R4, -SOz-R4, -CN, -NR9-SOZ-R4, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar1 and —Het1; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OR35, -NR11R12, -O-C1_6alkyl, and 6alkyl; wherein when A2 is N, then R1 and R5 are not simultaneously —H.

R5 is attached to Z1 or Z5 and is selected from —H, —halo, -OH, -C1_6alkyl, 6alkyl, -S-C1_6alkyl, - NR6R7, -(C=O)-R8, -(C=S)—R8, -SOZ-R8, -CN, OZ-R8, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, - Ar5 and —Het5; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OR36, -NR23R24, 6alkyl, and -S-C1_6alkyl; R2 is selected from —H, -halo, -OH, -C1_6alkyl, and -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is 3O optionally and independently substituted with from 1 to 3 substituents selected from —halo, — OR27, and -NR13R14; R3 is selected from —H, -halo, -OH, -C1_6alkyl, and -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, — ORzg, and -NR15R16; R4 and R8 are each independently selected from —halo, —OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, - NR17R18, 6cycloalkyl, -C3_6cycloalkyl, -Ar4 and -Het4; R6, R7, R9, R101 R11! R12, R13, R141 R15! R16, R17! R18, R19, R20, R21, R22, R23, R24, R31, R321R331 R34, R37 and R38 are each independently selected from —H, -halo, =0, -OH, -C1_6alkyl, -O-C1_6alkyl, - S—C1_6alkyl, -C3_6cycloalkyl, -Ar6 and —Het6; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, —OH, -O-C1_6alkyl, -S-C1_6alkyl, -Cg_6cycloalkyl, -Het6, -Ar6 and —NR35R36; R27 and R28, are each independently selected from —H, -C1_6alkyl, -C3_6cycloalkyl and -Het2: R37 and R38, are each independently selected from —H, -halo, -OH, -C1_6alkyl, 6alkyl, -S-C1_ 6alkyl, -C3_6cycloalkyl, -Ar7 and —Het7; X1 is selected from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NR3-C1_6alkyl-, -NR3-Cq_6alkyl-, -NR3-, and -O-; wherein each of said -C1_6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, l, and -N R33R34 1O X2 is selected from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NRZ-C1_6alkyl-, -NR2-Cq_6alkyl-, -NR2-, and -O-; n each of said -C1_6alkyl- is optionally and independently tuted with from 1 to 3 substituents selected from —halo, -OH, lkyl, -O-C1_6alkyl, -S-C1_6alkyl, -phenyl and -N R31R32; Ar1, Ar4, Ar5, Ar6, and Ar7 are each independently a 5- to 10-membered aromatic cycle optionally sing 1 to 3 atoms selected from O, N and 8; each of said An, Ar4, Ar5, Ar6, and Ar7 being optionally and independently substituted with from 1 to 3 substituents selected from — halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, and —NR19R20; wherein each of said -C1_6alkyl is ally and independently substituted with from 1 to 3 -halo; Het1, Het2, Het4, Het5, Het6, and Het7 are each independently a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms ed from O, N and 8; wherein each of said Het1, Het2, Het4, Het5, Het6, and Het7 is optionally and independently substituted with from 1 to 3 tuents ed from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_ 6alkyl, and -NR21R22; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; Hetg is a bivalent 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and 8; wherein at least one of said atoms is ed to X1; and wherein said Hetg is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_6alkyl, and -NR21R22; 3O wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 - halo; Z1, 22, 23, Z4 and Z5 are each independently selected from C and N; and A1 and A2 are each independently selected from C and N.

In a further ular embodiment, the present invention provides a compound of Formula la or a stereoisomer, tautomer, racemic, metabolite, pro- or pre-drug, salt, hydrate, N-oxide form, or solvate thereof; wherein N R1 NO 24 23‘2/2 £ R5 0 21 N Y X2 /X1 \Hetg Ia Wherein R1 is ed from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, -NR9R10, -(C=O)-R4, - (C=S)—R4, -SOz-R4, -CN, -NR9-SOZ-R4, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar1 and —Het1; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OR35, -NR11R12, 6alkyl, and 6alkyl; R5 is attached to Z1 or Z5 and is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, - NR6R7, -(C=O)-R8, -(C=S)—R8, -SOZ-R8, -CN, -NR6-SOZ-R8, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, - Ar5 and —Het5; wherein each of said -C1_6alkyl is optionally and independently substituted with 1O from 1 to 3 substituents selected from —halo, -OR36, 24, -O-C1_6alkyl, and -S-C1_6alkyl; R2 is ed from —H, -halo, -OH, -C1_6alkyl, ycloalkyl,; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, — OR27, and -NR13R14; R3 is selected from —H, -halo, -OH, -C1_6alkyl, -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents ed from —halo, — ORzg, and -NR15R16; R4 and R8 are each independently selected from —halo, —OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, - 8, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar4 and -Het4; R6, R7, R8, R9, R101 R11! R12, R13, R141 R15! R16, R17! R18, R19, R20, R21, R22, R23, R24, R27, R28, R29, R30, R31, R32, R33, R34, R35 and R36 are each independently selected from —H, -halo, =0, -OH, - Cq_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, -C3_6cycloalkyl, -Are and —Het6; wherein each of said -C1_ 6alkyl is optionally and independently tuted with from 1 to 3 substituents selected from — halo, —OH, -O-C1_6alkyl, -S-C1_6alkyl, -C3_6cycloalkyl, -Het6, -Are and —N R35R36; R27 and R28, are each independently selected from —H, lkyl, -C3_6cycloalkyl and Het2: R35 and R36, are each independently selected from —H, -halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_ 6alkyl, -C3_6cycloalkyl, -Ar7 and —Het7; X1 is selected from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NR3-C1_6alkyl-, -NR3-Cq_6alkyl-, -NR3-, -O-; n each of said -C1_6alkyl- is optionally and independently tuted with from 1 to 3 substituents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, -phenyl, and -N R33R34 X2 is selected from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NR3-C1_6alkyl-, -NR2-Cq_6alkyl-, -NR2-, -O-; wherein each of said -C1_6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, -phenyl and -N R31R32; Ar1, Ar4, Ar5, Ar6, and Ar7 are each independently a 5- to bered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and 8; each of said An, Ar4, Ar5, Ar6, and Ar7 being optionally and independently substituted with from 1 to 3 substituents selected from — halo, -OH, -C1_6alkyl, -O-C1_6alkyl, 6alkyl, —NR19R20; wherein each of said -C1_6alkyl is ally and independently tuted with from 1 to 3 -halo; Het1, Het2, Het4, Het5, Het6, and Het7 are each independently a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and 8; wherein each of said Het1, Het2, 1O Het4, Het5, Het6, and Het7 is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_ 6alkyl, and -NR21R22; wherein each of said -C1_6alkyl is optionally and independently tuted with from 1 to 3 -halo; Hetg is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and 8; n said Hetg is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_6alkyl, and - NR21R22; wherein each of said -C1_6alkyl is ally and independently substituted with from 1 to 3 -halo; wherein when R1 is —H, then at least one heteroatom of Hetg is attached to X1 Z1, 22, 23, Z4 and Z5 are each independently selected from C and N.

Preferably, compounds of a la are defined as such that Preferably, R1 is ed from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, -NR9R10, - (C=O)—R4, -(C=S)-R4, 4, -CN, -NR9-SOZ-R4, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar1 and — Het1; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 tuents selected from —halo, -OR35, -NR11R12, -O-C1_6alkyl, and -S-C1_6alkyl.

More preferably, R1 is selected from -F, -Cl, -CN, -O-C1_6alkyl, -O-C1_6cycloalkyl; wherein each of said -C1_6alkyl is ally and independently substituted with from 1 to 3 -Me, -halo, -OH, -H, 3O cyclopropyl, cyclobutyl; cycloalkyls are optionally independently substituted by -Me, -halo, -OH, Preferably, R5 is attached to Z1 or Z5 and is selected from —H, —halo, -OH, lkyl, -O-C1_6alkyl, - S—C1_6alkyl, -NR6R7, -(C=O)-R8, -(C=S)-R8, -SOZ-R8, -CN, -NR6-SOZ-R8, -C3_6cycloalkyl, -O-C3_ 6cycloalkyl, -Ar5 and —Het5; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents ed from —halo, -OR36, -NR23R24, -O-C1_6alkyl, and -S-C1_6alkyl.

More preferably, R5 is selected from -F, -Cl, -CN, -C1_3alkyl, -Cg_4cycloalkyl; wherein each of said - C1_3alkyl is optionally and independently substituted with from 1 to 3 -Me, -halo, -OH, -H; wherein each of said cloalkyl is ally and independently substituted with from 1 to 3 - Me, -halo, -OH, -H.

Preferably, R2 is selected from -H, -halo, -OH, -C1_6alkyl, -Cg_6cycloalkyl; wherein each of said -C1_ 6alkyl is ally and independently substituted with from 1 to 3 substituents selected from — halo, —OR27, and -NR13R14.

More preferably, R2 is selected from -H, -C1_3alkyl, ycloalkyl; n each of said -C1_3alkyl is 1O optionally and independently substituted with from 1 to 3 -H, -Me, -halo, -OH, -NR13R14. wherein each of said C3_4cycloalkyl is ally and independently substituted with from 1 to 3 -H, -Me, - halo, -OH, -NR13R14.

Preferably, R3 is selected from —H, -halo, -OH, -C1_6alkyl, -C3_6cycloalkyl; wherein each of said -C1_ 6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from — halo, —OR28, and 16.

More preferably, R3 is selected from Cq_3alkyl, C3_4cycloalkyl; wherein each of said -C1_3alkyl is optionally and independently substituted with from 1 to 3 -H, -Me, -halo, -OH, -NR15R16. n each of said -C3_4cycloalkyl is optionally and independently substituted with from 1 to 3 -H, -Me, -halo, -OH, -NR15R16.

Preferably, R4 and R8 are each independently selected from —halo, —OH, lkyl, 6alkyl, -SCq _6alkyl, -NR17R18, -Cg_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar4 and -Het4.

More preferably, R4 is selected from -C1_3alkyl, -O-C1_3alkyl, -NR17R18, ycloalkyl, -O-C3_ 4cycloalkyl; wherein each of said -C1_3alkyl is optionally and independently substituted with from 1 to 3 -H, -Me, -halo, -OH, -NR17R18. wherein each of said -C3_4cycloalkyl is optionally and independently substituted with from 1 to 3 -H, -Me, -halo, -OH, -NR17R18; More preferably, R8 is selected from -C1_3alkyl, -O-C1_3alkyl, -NR17R18, -C3_4cycloalkyl, -O-C3_ 4cycloalkyl; wherein each of said -C1_3alkyl is ally and independently substituted with from 3O 1 to 3 -H, -Me, -halo, -OH, -NR17R18. wherein each of said ycloalkyl is optionally and independently substituted with from 1 to 3 -H, -Me, -halo, -OH, -NR17R18.

Preferably, R6, R7, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R31, R32, R33, R34, R35, and R36 are each independently selected from —H, -halo, =0, -OH, -C1_6alkyl, -O- Cq_6alkyl, -S-C1_6alkyl, -Cg_6cycloalkyl, -Ar6 and —Het6; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, — OH, -O-C1_6alkyl, -S-C1_6alkyl, -C3_6cycloalkyl, -Het6, -Ar6 and —NR35R36.

Preferably, R27 and R28, are each ndently selected from —H, -C1_6alkyl, -C3_6cycloalkyl and - Het2.

More preferably, R27 and R28, are each ndently ed from —H, -C1_3alkyl, or -C3_ 4cycloalkyl; wherein each of said -C1_3alkyl is ally and independently substituted with from 1 to 3 -H, -Me, -halo; and wherein each of said -C3_4cycloalkyl is optionally and independently substituted with from 1 to 3 -H, -Me, -halo.

Preferably, R37 and R38, are each independently selected from —H, -halo, -OH, lkyl, -O-C1_ 6alkyl, -S-C1_6alkyl, -C3_6cycloalkyl, -Ar7 and —Het7. 1O More preferably, R37 and R38, are each independently selected from —H, -C1_3alkyl, or -C3_ 4cycloalkyl; wherein each of said -C1_3alkyl is ally and independently substituted with from 1 to 3 -H, -Me, -halo; and wherein each of said -C3_4cycloalkyl is optionally and independently substituted with from 1 to 3 -H, -Me, -halo, -OH.

Preferably, X1 is selected from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NR3-C1_6alkyl-, - _6alkyl-, -NR3-, -O-; wherein each of said -C1_6alkyl- is optionally and independently tuted with from 1 to 3 substituents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S- kyl, -phenyl, and -NR33R34.

More preferably, X1 is selected from -O-C1_3alkyl, -NR3-C1_3alkyl-; wherein each of said -C1_3alkyl is optionally and independently substituted with from 1 to 3 -H, -halo, -CF3, CHFZ, -C1_3alkyl, -C or substituted to form a cyclopropyl, cyclobutyl or oxetane; wherein each of said cyclopropyl, cyclobutyl or oxetane is optionally and independently substituted with from 1 to 3 -H, -Me, -halo, - Preferably, X2 is selected from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NRZ-C1_6alkyl-, - NRZ-C1_6alkyl-, -NR2-, -O-; wherein each of said -C1_6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, lkyl, -O-C1_6alkyl, -S- Cq_6alkyl, -phenyl and 32.

More preferably, X2 is selected from —O-C1alkyl-, -NR2-C1alkyl; wherein each of said -C1alkyl is 3O optionally and independently substituted with from 1 to 2 -H, -halo, -Me or bi-substituted to form a cyclopropyl, cyclobutyl, oxetane; wherein each of said cyclopropyl, cyclobutyl or oxetane is optionally and independently substituted with from 1 to 3 -H, -Me, -halo, -OH Preferably, Ar1, Ar4, Ar5, Ar6, and Ar7 are each ndently a 5- to 10-membered ic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and 8; each of said An, Ar4, Ar5, Ar6, and Ar7 being optionally and independently substituted with from 1 to 3 tuents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, —NR19R20; wherein each of said - C1_6alkyl is optionally and independently substituted with from 1 to 3 —halo.

More preferably, Ar1, Ar4, Ar5, Ar6, and Ar7 are each independently selected from any 5 or 6 40 membered aromatic ring.

Preferably, Het1, Het2, Het4, Het5, Het6, and Het7 are each independently a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and 8; wherein each of said Het1, Het2, Het4, Het5, Het6, and Het7 is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_ 6alkyl, and -NR21R22; wherein each of said lkyl is optionally and independently substituted with from 1 to 3 —halo.

More preferably, Het1, Het2, Het4, Het5, Het6, and Het7 are each independently selected from any 5 or 6 membered saturated or rated heterocycle. 1O Preferably, Hetg is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and 8; wherein said Hetg is optionally and independently substituted with from 1 to 6 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -C1_6alkyl, and - 2; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; wherein when R1 is —H, then at least one heteroatom of Hetg is attached to X1 More preferably, Hetg is selected from dine or pyrrolidine, and optionally and independently substituted with from 1 to 6 substituents selected from -H, —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S- C1_6alkyl, =0, -(C=O)-C1_6alkyl, and -NR21R22; n each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo.

Preferably, Z1, 22, 23, Z4 and Z5 are each independently selected from C and N.

More preferably, Z1, 22, 23, Z4 and Z5 are each C.

In a further particular embodiment, the present ion provides a compound of Formula la or a stereoisomer, tautomer, racemic, metabolite, pro- or pre-drug, salt, hydrate, N-oxide form, or solvate thereof; wherein one or more of the ing s: " ,23\ ,R1 N z 22 R1 is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, 0, -(C=O)-R4, - (C=S)—R4, -SOz-R4, -CN, -NR9-SOZ-R4, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar1 and —Het1; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OR35, -NR11R12, -O-C1_6alkyl, and -S-C1_6alkyl; R5 is attached to Z1 or Z5 and is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, - NR6R7, -(C=O)-R8, -(C=S)—R8, -SOZ-R8, -CN, -NR6-SOZ-R8, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, - Ar5 and —Het5; wherein each of said -C1_6alkyl is optionally and independently tuted with from 1 to 3 substituents selected from —halo, -OR36, -NR23R24, -O-C1_6alkyl, and 6alkyl; R2 is selected from —H, -halo, -OH, -C1_6alkyl, and -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, — OR27, and -NR13R14; R3 is selected from —H, -halo, -OH, -C1_6alkyl, and -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 tuents selected from —halo, — 1O ORzg, and -NR15R16; R4 and R8 are each independently selected from —halo, —OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, - NR17R18, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar4 and -Het4; R6, R7, R9, R101 R11! R12, R13, R141 R15! R16, R17! R18, R19, R20, R21, R22, R23, R24, R29, R30, R31, R32, R33, R34, R37 and R38 are each ndently selected from —H, -halo, =0, -OH, lkyl, -O- Cq_6alkyl, -S-C1_6alkyl, -Cg_6cycloalkyl, -Ar6 and —Het6; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 tuents selected from —halo, — OH, -O-C1_6alkyl, -S-C1_6alkyl, -C3_6cycloalkyl, -Het6, -Ar6 and —NR35R36; R27 and R28, are each independently selected from —H, -C1_6alkyl, -C3_6cycloalkyl and -Het2: R37 and R38, are each independently selected from —H, -halo, -OH, -C1_6alkyl, 6alkyl, -S-C1_ 6alkyl, -C3_6cycloalkyl, -Ar7 and —Het7; X1 is selected from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NR3-C1_6alkyl-, -NR3-Cq_6alkyl-, -NR3-, and -O-; wherein each of said -C1_6alkyl- is optionally and independently substituted with from 1 to 3 substituents ed from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, -phenyl, and -N R33R34 X2 is selected from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, lkyl-NR3-C1_6alkyl-, -NR2-Cq_6alkyl-, -NR2-, and -O-; wherein each of said -C1_6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, -phenyl and -N R31R32; Ar1, Ar4, Ar5, Ar6, and Ar7 are each independently a 5- to 10-membered aromatic cycle optionally 3O comprising 1 to 3 heteroatoms selected from O, N and 8; each of said An, Ar4, Ar5, Ar6, and Ar7 being optionally and independently substituted with from 1 to 3 substituents selected from — halo, -OH, -C1_6alkyl, 6alkyl, -S-Cq_6alkyl, and —NR19R20; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; Het1, Het2, Het4, Het5, Het6, and Het7 are each ndently a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and 8; wherein each of said Het1, Het2, Het4, Het5, Het6, and Het7 is optionally and independently tuted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -C1_ 6alkyl, and 22; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; Hetg is a 3- to bered heterocycle having from 1 to 3 heteroatoms selected from O, N and wherein said Hetg is optionally and ndently substituted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, 6alkyl, 6alkyl, =0, -(C=O)-C1_6alkyl, and - 2; wherein each of said -C1_6alkyl is optionally and ndently substituted with from 1 to 3 -halo; wherein when R1 is —H, then at least one heteroatom of Hetg is attached to X1 Z1, 22, 23, Z4 and Z5 are each independently ed from C and N. 1O In particular, X1, and X2 as used herein, represent biradicals, which taken together with the radicals to which they are attached form a macrocyclic pyrazolopyrimidine compound. Said biradicals may be present in either of both directions in the macrocyclic pyrazolopyrimidine, but are preferably present in the direction as described below: Referring to formula la: X1 is selected from the list sing *—C1_6alkyl-, *—O-C1_6alkyl-, *—S—Cq_6alkyl-, *-C1_6alkyl- NR3-C1_6alkyl-, *-NR3-C1_6alkyl-, *-NR3-, *-O-; * wherein said biradical is preferably attached to the aryl or heteroaryl moiety via *; X2 is selected from the list comprising *—C1_6alkyl-, *—O-C1_6alkyl-, *—S—Cq_6alkyl-, *-C1_6alkyl- _6alkyl-, *-NR2-C1_6alkyl-, *-NR2-, *-O-; * wherein said biradical is preferably attached to the pyrazolopyrimidine moiety via *; In still another embodiment, the present invention provides a compound of Formula la or a stereoisomer, tautomer, racemic, lite, pro- or pre-drug, salt, hydrate, N-oxide form, or solvate thereof; wherein R1 is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, -NR9R10, -(C=O)-R4, - (C=S)—R4, -SOz-R4, -CN, -NR9-SOZ-R4, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar1 and —Het1; wherein each of said -C1_6alkyl is optionally and ndently substituted with from 1 to 3 substituents selected from —halo, -OR35, -NR11R12, -O-C1_6alkyl, and -S-C1_6alkyl; R5 is attached to Z1 or Z5 and is selected from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, - 3O NR6R7, -(C=O)-R8, -(C=S)—R8, -SOZ-R8, -CN, -NR6-SOZ-R8, ycloalkyl, -O-Cg_6cycloalkyl, - Ar5 and —Het5; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OR36, -NR23R24, -O-C1_6alkyl, and -S-C1_6alkyl; R2 is selected from —H, -halo, -OH, -C1_6alkyl, ycloalkyl,; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 tuents selected from —halo, — OR27, and -NR13R14; R3 is selected from —H, -halo, -OH, -C1_6alkyl, -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is optionally and ndently substituted with from 1 to 3 substituents selected from —halo, — ORzg, and -NR15R16; R4 and R8 are each independently selected from —halo, —OH, lkyl, -O-C1_6alkyl, -S-C1_6alkyl, - 40 NR17R18, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar4 and -Het4; R6, R7, R9, R101 R11! R12, R13, R141 R15! R16, R17! R18, R19, R20, R21, R22, R23, R24, R31, 31 R34, R35 and R36 are each independently selected from —H, -halo, =0, -OH, -C1_6alkyl, -O-C1_6alkyl, - S—C1_6alkyl, ycloalkyl, -Ar6 and —Het6; wherein each of said -C1_6alkyl is ally and independently substituted with from 1 to 3 substituents selected from —halo, —OH, -O-C1_6alkyl, -S-C1_6alkyl, -Cg_6cycloalkyl, -Het6, -Ar6 and —NR37R38; R27 and R28, are each independently selected from —H, -C1_6alkyl, -C3_6cycloalkyl and -Het2: R37 and R38, are each independently selected from —H, -halo, -OH, -C1_6alkyl, 6alkyl, -S-C1_ 6alkyl, -C3_6cycloalkyl, -Ar7 and —Het7; X1 is selected from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NR3-C1_6alkyl-, -NR3-Cq_6alkyl-, 1O and -N R3-; X2 is selected from —O-CH2-, -, and -NR2-CH2-; Ar1, Ar4, Ar5, Ar6, and Ar7 are each independently a 5- to 10-membered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and 8; each of said An, Ar4, Ar5, Ar6, and Ar7 being optionally and independently substituted with from 1 to 3 substituents selected from — halo, -OH, lkyl, -O-C1_6alkyl, -S-Cq_6alkyl, and —NR19R20; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; Het1, Het2, Het4, Het5, Het6, and Het7 are each independently a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and 8; wherein each of said Het1, Het2, Het4, Het5, Het6, and Het7 is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -C1_ , and -NR21R22; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; Hetg is a 3- to 10-membered heterocycle having from 1 to 3 heteroatoms ed from O, N and wherein said Hetg is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -(C=O)-C1_6alkyl, and - NR21R22; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; wherein when R1 is —H, then at least one heteroatom of Hetg is attached to X1 3O Z1, 22, 23, Z4 and Z5 are each independently selected from C and N.

In yet a r embodiment, the present invention provides a compound of Formula la or a stereoisomer, tautomer, racemic, metabolite, pro- or pre-drug, salt, hydrate, N-oxide form, or solvate thereof; wherein R1 is ed from —H, —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, 6alkyl, -NR9R10, -(C=O)-R4, - (C=S)—R4, -SOz-R4, -CN, -NR9-SOZ-R4, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar1 and —Het1; wherein each of said -C1_6alkyl is ally and independently substituted with from 1 to 3 substituents selected from —halo, -OR35, -NR11R12, -O-C1_6alkyl, and -S-C1_6alkyl; R5 is attached to Z1 or Z5 and is selected from —H, —halo, -OH, lkyl, -O-C1_6alkyl, -S-C1_6alkyl, - 40 NR6R7, -(C=O)-R8, -(C=S)—R8, -SOZ-R8, -CN, -NR6-SOZ-R8, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, - Ar5 and —Het5; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OR36, -NR23R24, -O-C1_6alkyl, and 6alkyl; R2 is ed from —H, -halo, -OH, -C1_6alkyl, and -Cg_6cycloalkyl; wherein each of said lkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, — OR27, and -NR13R14; R3 is selected from —H, -halo, -OH, -C1_6alkyl, and -Cg_6cycloalkyl; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, — ORzg, and -NR15R16; R4 and R8 are each independently selected from —halo, —OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, - 1O NR17R18, -C3_6cycloalkyl, -O-Cg_6cycloalkyl, -Ar4 and -Het4; R6, R7, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R29, R30, R31, R32, R33, R34, R37 and R38 are each independently selected from —H, -halo, =0, -OH, -C1_6alkyl, -O- Cq_6alkyl, 6alkyl, -Cg_6cycloalkyl, -Ar6 and —Het6; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 substituents selected from —halo, — OH, -O-C1_6alkyl, -S-C1_6alkyl, -C3_6cycloalkyl, -Het6, -Ar6 and —NR35R36; R27 and R28, are each independently ed from —H, -C1_6alkyl, -C3_6cycloalkyl and -Het2: R37 and R38, are each independently selected from —H, -halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_ , -C3_6cycloalkyl, -Ar7 and —Het7; X1 is selected from —C1_6alkyl-, —O-C1_6alkyl-, —S—C1_6alkyl-, -C1_6alkyl-NR3-C1_6alkyl-, -NR3-Cq_6alkyl-, -NR3-, and -O-; n each of said -C1_6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, -phenyl, and -N R33R34 X2 is selected from —C1_6alkyl-, 6alkyl-, 6alkyl-, -C1_6alkyl-NR3-C1_6alkyl-, -NR2-Cq_6alkyl-, -NR2-, and -O-; wherein each of said -C1_6alkyl- is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, -phenyl and -N R31R32; Ar1, Ar4, Ar5, Ar6, and Ar7 are each independently a 5- to bered aromatic cycle optionally comprising 1 to 3 heteroatoms selected from O, N and 8; each of said An, Ar4, Ar5, Ar6, and Ar7 being optionally and independently substituted with from 1 to 3 substituents selected from — 3O halo, -OH, -C1_6alkyl, -O-C1_6alkyl, -S-Cq_6alkyl, and —NR19R20; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; Het1, Het2, Het4, Het5, Het6, and Het7 are each ndently a 3- to bered heterocycle having from 1 to 3 heteroatoms selected from O, N and 8; wherein each of said Het1, Het2, Het4, Het5, Het6, and Het7 is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S-C1_6alkyl, =0, -C1_ 6alkyl, and -NR21R22; wherein each of said -C1_6alkyl is optionally and independently substituted with from 1 to 3 -halo; Hetg is a bivalent 3- to 10-membered heterocycle having from 1 to 3 heteroatoms selected from O, N and 8; 40 n at least one of said heteroatoms is attached to X1; and wherein said Hetg is optionally and independently substituted with from 1 to 3 substituents selected from —halo, -OH, —C1_6alkyl, -O-C1_6alkyl, -S—C1_6alkyl, :O, -(C=O)-C1_6a|ky|, and -NR21R22; wherein each of said -C1_6alkyl is optionally and ndently substituted with from 1 to 3 - halo; Z1, 22, 23, Z4 and Z5 are each independently selected from C and N.

In yet a further embodiment, the present ion provides a compound of Formula la or a stereoisomer, tautomer, racemic, metabolite, pro- or pre-drug, salt, hydrate, N-oxide form, or solvate thereof; n 1O R1 is ed from —halo, -C1_6alkyl and -CN; R5 is ed to Z1 and is selected from —H, —halo, lkyl, and -C3_6cycloalkyl; R2 is selected from —H, -C1_6alkyl and -C3_6cycloalkyl; X1 is ed from —O-C1_6alkyl, and -NR3-C1_6alkyl-; X2 is -N RZ-C1_6alkyl; Hetg is a 3- to 10-membered N-containing heterocycle; and Z1, 22, 23, Z4 and Z5 are each C.

In yet a further embodiment, the present invention provides a compound of a la or a stereoisomer, tautomer, racemic, metabolite, pro- or pre-drug, salt, hydrate, N-oxide form, or solvate thereof; wherein R1 and R5 are both -H; R2 is selected from —H, -C1_6alkyl and ycloalkyl; X1 is selected from —O-C1_6alkyl, and -NR3-C1_6alkyl-; X2 is -N RZ-C1_6alkyl; Hetg is a 3- to 10-membered N-containing heterocycle; wherein at least one of said heteroatoms is attached to X1; and Z1, 22, 23, Z4 and Z5 are each C.

In yet a further embodiment, the present invention provides a compound of Formula la or a 3O isomer, tautomer, racemic, metabolite, pro- or pre-drug, salt, hydrate, N-oxide form, or solvate thereof; wherein R1 is selected from —H and —halo; R5 is attached to Z1 and is selected from —H, and —halo; R2 is selected from —H, and -C1_6alkyl; X1 is —O-C1_6alkyl; X2 is -N RZ-C1_6alkyl; Hetg is a 5- to 6-membered N-containing heterocycle; wherein when R1 is —H, then at least one of said atoms is attached to X1; and Z1, 22, 23, Z4 and Z5 are each C.

In a particular embodiment, the present invention provides a compound selected from the list comprising: f",N‘ HN \N \ CLO cr% Compound 01, Example 01 nd 02, Example 02 9C0 C. nd 03, Example 03 Compound 08, Example 08 Compound 09, Example 09 Compound 010, Example 010 / \ N’N \ \ N \ [LA N\/\0 0 F Compound 011, Example 011 Compound 012, e 012 f" \ \ \ \ \ f"\ :1? N :1? N F F Compound 013, Example 013 Compound 014, Example 014 In particular in the compounds according to this invention, the R5 is linked to the aryl or heteroaryl moiety at position Z1 in accordance with the numbering as provided in Formula | or la. rmore, the present invention provides a compound according to this invention, wherein said compound is the tiomer. 1O The compounds of the present invention can be prepared according to the reaction schemes ed in the examples hereinafter, but those skilled in the art will appreciate that these are only illustrative for the invention and that the compounds of this invention can be ed by any of several standard synthetic ses commonly used by those skilled in the art of organic chemistry.

The present invention further provides a pharmaceutical composition comprising a compound according to this invention.

In a further aspect, the present invention provides a compound or a composition ing to this invention, for use as a medicine.

In a particular embodiment, the present ion provides a compound or composition according to this invention for use in the diagnosis, prevention and/or treatment of a RIP2—kinase associated disease. Said inase associated disease may in particular be an inflammatory disorders, more in particular selected from the list sing: Crohn’s disease, bowel disease, Sarcoidosis, psoriasis, rheumatoid tis, asthma, tive colitis, lupus, uveitis, blau syndrome, granulomatous in?ammation, in particular behcet’s disease, multiple sclerosis and insulin-resistant type 2 diabetes.

Furthermore, the present ion es the use of a compound or composition according to this invention, suitable for inhibiting the activity of a kinase; in particular a R|P2 kinase; or for the diagnosis, prevention and/or treatment of a RIP2—kinase associated disease.

Finally, the present invention provides a method for prevention and/or treatment of a RIP2—kinase associated disease; said method sing administering to a subject in need thereof a compound or a composition according to the present invention.

METHOD OF TREATMENT Compounds of formula (I) or (la) a stereoisomer, tautomer, racemic, metabolite, pro- or pre-drug, 1O salt, e, N-oxide form, or solvate thereof, are inhibitors of R|P2 kinase activity and are thus believed to be of potential use in the diagnosis, prevention and/or treatment of inflammatory disorders, in particular Crohn’s disease, bowel disease, Sarcoidosis, psoriasis, rheumatoid tis, asthma, ulcerative colitis, lupus, s, blau syndrome, granulomatous mation, in particular behcet’s disease, multiple sclerosis and insulin-resistant type 2 diabetes.

As used herein, the terms "in?ammatory disorder" or "inflammatory disease" can refer to a disorder or disease characterized by aberrant activation of the immune system that leads to or causes enesis of several acute and c conditions including, for example, sarcoidosis, rheumatoid arthritis, inflammatory bowel e, transplant rejection, colitis, gastritis and ileitis. An in?ammatory disease can include a state in which there is a response to tissue , cell injury, an antigen, an ious disease, and/or some unknown cause. Symptoms of in?ammation may include, but are not limited to, cell infiltration and tissue swelling.

In the invention, particular preference is given to compounds of Formula | or any subgroup thereof that in the inhibition assay for R|P2 described below inhibit kinase activity with an IC50 value of less than 10 uM, preferably less than 1 uM, most preferably less than 100 nM.

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

The term "RIP2 kinase-mediated condition" or "disease", as used herein, means any disease or other deleterious condition in which the R|P2 kinase and/or mutants thereof is/are known to play a role. The term " R|P2 kinase-mediated condition" or "disease" also means those diseases or 3O ions that are alleviated by treatment with a R|P2 kinase inhibitor. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which the R|P2 kinase is known to play a role.

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

The ceutically acceptable salts of the compounds according to the invention, i.e. in the form of water-, oil-soluble, or dispersible products, include the conventional xic salts or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.

Examples of such acid addition salts include e, adipate, alginate, aspartate, benzoate, 1O benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, oxyethanesulfonate, lactate, maleate, methanesulfonate, 2—naphthalene-sulfonate, nicotinate, oxalate, palmoate, pectinate, fate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and ium salts, alkaline earth metal salts such as m and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as ne, lysine, and so forth. In addition, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain s such as decyl, lauryl, myristyl and stearyl chlorides, bromides and s, aralkyl s like benzyl and phenethyl—bromides and others. Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.

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

By means of non-limiting examples, such a formulation may be in a form suitable for oral 3O administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for administration by inhalation, by a skin patch, by an t, by a suppository, etc.. Such suitable administration forms — which may be solid, semi- solid or liquid, depending on the manner of administration — as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is again made to for instance US-A—6,372,778, US-A-6,369,086, US-A—6,369,087 and US-A-6,372,733, as well as to the standard handbooks, such as the latest edition of Remington’s ceutical Sciences.

Some preferred, but non-limiting es of such preparations include tablets, pills, powders, lozenges, s, cachets, elixirs, suspensions, emulsions, ons, , aerosols, ointments, creams, lotions, soft and hard gelatin es, suppositories, eye drops, sterile injectable ons and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with rs, excipients, and diluents that are suitable per se for such formulations, such as e, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium ate, alginates, tragacanth, gelatin, calcium te, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. The formulations can optionally contain other pharmaceutically active substances (which may or may not lead to a synergistic effect with 1O the nds of the invention) and other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, desintegrants, bulking agents, fillers, preserving agents, sweetening agents, ?avoring agents, ?ow regulators, release agents, etc.. The compositions may also be formulated so as to e rapid, sustained or delayed release of the active nd(s) contained therein, for example using liposomes or hydrophilic polymeric matrices based on natural gels or synthetic polymers. In order to enhance the solubility and/or the stability of the nds of a pharmaceutical composition according to the invention, it can be ageous to employ Cl-, [3- or odextrins or their derivatives. An interesting way of formulating the compounds in combination with a extrin or a derivative thereof has been described in EP-A-721,331. In particular, the present invention encompasses a pharmaceutical composition sing an ive amount of a nd according to the invention with a pharmaceutically acceptable cyclod extrin.

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

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

More in particular, the compositions may be formulated in a pharmaceutical formulation comprising 3O a therapeutically effective amount of particles consisting of a solid dispersion of the compounds of the invention and one or more pharmaceutically acceptable water-soluble polymers.

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

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

Yet another interesting way of formulating the compounds ing to the invention involves a pharmaceutical ition whereby the compounds are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition with good 1O bio-availability which can conveniently be manufactured and which is suitable for ing pharmaceutical dosage forms for oral administration. Materials le for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and tives thereof.

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

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

The compounds can be administered by a variety of routes including the oral, rectal, , transdermal, subcutaneous, intravenous, intramuscular or intranasal routes, ing mainly on 3O the specific preparation used and the condition to be treated or prevented, and with oral and intravenous administration usually being preferred. The at least one compound of the invention will generally be administered in an "effective amount", by which is meant any amount of a compound of a or any subgroup thereof that, upon suitable administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered. y, depending on the condition to be prevented or treated and the route of administration, such an effective amount will usually be n 0.01 to 1000 mg per kilogram body weight day of the patient per day, more often n 0.1 and 500 mg, such as between 1 and 250 mg, for example about 5, 10, 20, 50, 100, 150, 200 or 250 mg, per kilogram body weight day of the patient per day, which may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion. The amount(s) to be administered, the route of administration and the further treatment n may be determined by the treating clinician, depending on factors such as the age, gender and general condition of the patient and the nature and severity of the disease/symptoms to be treated. Reference is again made to US-A- 6,372,778,US-A-6,369,086, US-A-6,369,087 and US-A—6,372,733 and the further prior art mentioned above, as well as to the rd handbooks, such as the latest edition of Remington’s Pharmaceutical Sciences.

In accordance with the method of the t invention, said pharmaceutical composition can be administered separately at different times during the course of therapy or concurrently in divided or 1O single combination forms. The present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.

For an oral administration form, the compositions of the present ion can be mixed with suitable additives, such as excipients, stabilizers, or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions. es of suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, corn starch. In this case, the preparation can be carried out both as dry and as moist granules.

Suitable oily ents or ts are vegetable or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar ons, or mixtures thereof. Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and ants known in the art.

When administered by nasal aerosol or inhalation, these compositions may be ed according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, ing benzyl alcohol or other suitable preservatives, absorption promoters to enhance ilability, carbons, and/or other solubilizing or sing agents known in the art. Suitable pharmaceutical formulations for administration in the form of aerosols or sprays 3O are, for example, solutions, suspensions or emulsions of the compounds of the invention or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such ts. If required, the formulation can also additionally n other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant.

For subcutaneous administration, the nd according to the invention, if desired with the substances customary therefore such as solubilizers, emulsifiers or further auxiliaries are brought into solution, suspension, or emulsion. The compounds of the invention can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations.

Suitable solvents are, for example, water, physiological saline on or alcohols, e.g. ethanol, propanol, ol, in addition also sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of the various solvents mentioned. The injectable solutions or suspensions may be formulated according to known art, using suitable xic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or le dispersing or g and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

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

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

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

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

General schemes: 1O As indicated herein , the present invention in general provides compounds according to formula I, for use in the diagnosis, prevention and/or treatment of RIP2—kinase associated diseases: With nce to the general on schemes suitable for preparing said compounds, these compounds can be represented by formulas la or lb respectively, for which the general reaction schemes can be found herein below.

N(EDP? 21R N f ‘22 QN : >‘I— R5 R z 21 ON 5 Z Y21: >‘I— 1 X1 X2\He/ X2\Het8/ (Ia) (lb) In general the nds of formula (I) can be prepared as shown in scheme 1 below wherein a pyrazolo[1,5-a]pyrimidine or a imidazo[2,1-f]pyridazine of formula (II) is converted by reaction with a compound of formula (Vll) into a compound of a . The nd of formula (Vlll) can be optionally be converted into a compound of formula (IV) which is then reacted with a (hetero- )aryl of formula (V) to form a compound of formula (VI). The compound of formula (VI) can be optionally ted into a compound of general formula (I).

Scheme 1 ?ioN z" A1 O/‘LOA A1 1 3 xr'Het' —) 2 OAZO —) + )\ ik G1L N’ x5 1" N’ f; N X4 Hats 2 21R R1 LG: LG; 5 " VII "‘3' VIII \ 'V x5 X3 0I9 0goAr —> f, N’ —>x2 N’ HQ 242"?5 (247‘: X3 )=\2 R1 Heta 1\ z )\2 X4 1 R 1 1 \X1 R5 VI I In the above scheme: LG1 and LGZ each independently represent le leaving or onal ; X5 is converted into a functional group X3; X3 and X4 together with the onal moiety to which they are attached represent an unprotected or a ted functional group which upon reaction (after deprotection) produce together X1 as 1O defined in formula I; E represents a suitable functional group that can be used to form a direct bond between the (hetero-)aryl group and the scaffold.

In the above reaction of the compound of formula (II) with the compound of formula (VII) the leaving groups LG1 and LGZ are advantageously a halo group such as a chlorine or a bromine group. The reaction can be affected by a substitution for example by treating the compound of formula (II) with the compound of formula (VII) in an organic solvent such as acetonitrile with an appropriate base such as for example triethylamine at an elevated ature for example under re?ux.

Compounds of formula (Vll) can be obtained through s selective reaction steps by standard means obvious to those skilled in the art.

Compounds of formula (Vlll) can be converted to compounds of formula (IV) by reaction with a suitable protected or unprotected linker group.

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

The cyclisation of the compound of formula (VI) can be effected for example under obu conditions using for example diisopropyl arboxylate and triphenylphosphine in a solvent mixture such as 2-methyl-1,4-dioxane and toluene at an elevated temperature such as 90°C.

The free hydroxyl group could also be converted into a leaving group such as a chloride by reacting the hydroxyl group for example with thionyl chloride in the presence of a base such as pyridine in a solvent such as dichloromethane at an elevated temperature for example under reflux.

The ation of the compound of formula (VI) can be advantageously effected under Williamson conditions for example using a base such as cesium carbonate in a solvent such as N,N- dimethylformamide at an elevated temperature such as 90°C resulting in the formation of 1O compound of formula (I).

The resulting compound of formula (I) can optionally be treated to introduce a substituents such as an alkyl group.

Compounds 01, 02, 03, O4, 05, 06, O7, O8, O9, O10, O11, O12, 013 and 014 may be ed according to the synthesis described in Scheme 1.

Experimental part In obtaining the compounds described in the examples, the following experimental protocols were followed unless otherwise indicated.

Unless otherwise , on es were magnetically stirred at room temperature. Where 2O solutions were "dried", they were generally dried over a drying agent such as sodium sulfate or magnesium e. Where mixtures, solutions and extracts were "concentrated", they were typically concentrated on a rotary evaporator under reduced pressure.

For some compounds that were purified by reversed phase high-performance liquid chromatography (HPLC) the used method is described below (indicated in the compound ure with HPLC method A). When necessary, these methods can be slightly adjusted by a person skilled in the art to obtain a more optimal result for the separation.

HPLC method A The crude product was purified by reverse phase HPLC, using a Gilson semi-preparative HPLC 3O system operated by Gilson UNIPOINT software.

The purification was carried out on a Phenomenex Luna column (100 mm long x 21.2 mm id; 5 pm particles) at room ature, with a constant flow rate of 20.0 mL/min. A nt n was performed from 32% (25 mM NH4HCO3 aqueous solution) / 68% (Acetonitrile-Methanol 1:1) to 4% (25 mM NH4HCO3 aqueous solution) / 96% nitrile-Methanol 1:1) in 20 minutes. The UV detector was set to 226nm, which corresponds to the wavelenght of maximum absorbance observed for the compound.

Example 01 was prepared following general scheme 1 Step A 3-bromochloropyrazolo[1,5-a]pyrimidine (2.32g, 9.998mmol, 1.0eq), tert-butyl 2- (aminomethyl)pyrrolidinecarboxylate (2.0g, 9.98mmol, 1.0eq) and triethylamine (2.26mi, 12.97mmol, 1.3eq) were suspended in MeCN (30ml). The reaction mixture was heated at 80°C for 5h. Upon completion, monitored by TLC plate, solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 1 N HCI, s 1N NaHCO3. The organic layer was dried 1O ), filtered and concentrated to dryness. The crude was purified by flash chromatography using the following eluent: Heptane:EtOAc 100:0 to 75:25 fast tot 50:50 slow. The title compound was ed as a solid in 3.32g (84% .

MH+: 396.1/398.1 Step B The title compound from step A was stirred in 25 ml of HCI 4M in MeOH for 18h at RT. Upon completion, monitored by LCMS, solids were filtered off and washed with a small amount of MeOH yielding a first fraction of yellowish solid (1.6g). The mother liquor was concentrated yielding a second fraction ofa brownish solid (1.5g). The title compound was obtained in 3.1g (110%).

MH+: 296.1/298.1 Step C The title compound from step B (2.6g, 7.82mmol, 1.0eq), (2-bromoethoxy)(tert-butyl)dimethylsilane (2.02mi, 9.38mmol, 1.2eq) and Potassium carbonate (3.24g, mol, 3.0eq) were suspended in CH3CN and heated at 90°C for 1h. Then an additional 1.2 eq of (2-bromoethoxy)(tertbutyl )dimethylsilane was added and the reaction mixture was stirred for 1h at 90°C. Upon completion, monitored by TLC plate, the reaction e was concentrated. The residue was dissolved in EtOAc and washed with water 2x and Brine. The organic layer was dried (MgSO4), filtered, concentrated. The crude was purified by flash tography using the following eluent: DCM:MeOH 99:1 to 90:1. The product fractions were collected and concentrated to lead 2.2g of a 1O solid (62%).

MH+: 454.3/456.3 Step D The title compound from step C (2.2g, 4.84mmol, 1.0eq), Boc anhydride (1.16g, ol, 1.1eq) and DMAP (0.029g, 0.24mmol, 0.05eq) were dissolved in THF (14ml) and stirred for 1h at rt then at 65°C for 1h. Additional Boc anhydride was added and the reaction was stirred for an additional 1h at 65°C. Upon tion, monitored by TLC plate, the reaction mixture was concentrated.

The crude was ed by ?ash chromatography using the following : Heptane:EtOAC 100:0 to 50:50 fast to lead the title compound in 2.1g (78% yield).

MH+: 6062/6083 Step E A mixture of the title compound from step D (2.1g, 3.79mmol, 1.0eq), (3-hydroxyphenyl)boronic acid (0.68g, 4.93mmol, 1.3eq), XPhos (0.072g, 0.15mmol, 0.04eq) and Potassium phosphate (2.41g, 11.35mmol, 3.0eq) were dissolved in Dioxane /water 3:1 (12ml) and degassed with N2.

Palladium tetrakis (0.093g, 0.08mmol, 0.02eq) was added to the stirring mixture, which was warmed to 85°C for 3h under N2 atmosphere. Upon completion, monitored by TLC plate, the reaction mixture was diluted with EtOAc. Layers separated, organic layer was washed with water and Brine, dried (MgSO4), filtered, concentrated to dryness. The crude was purified by flash chromatography using the following eluent: OH 100:0 to 97.5:2.5. Product fractions collected and trated to s to lead the title compound in 1.98g (92% yield).

MH+: 568.4 ?n\ \ BocN N Step F 1O The title compound from step E (1 .98g, 3.49mmol, 1.0eq) was dissolved in THF (10ml), then TBAF 1M in THF (3.84mi, 1.1eq) was added. The reaction mixture was stirred for 2h at RT.

TLC: SM A present. Stirred additional 1h at rt. Upon tion, monitored by LCMS, solvent was evaporated and the residue was dissolved in EtOAc and washed with aq. sat. NaHCO3 3x. The organic layer was dried (MgSO4), filtered, concentrated to dryness.

The crude was purified by ?ash tography using the following eluent: DCM:MeOH 100:0 to 97:3 to 93:7 to obtain the title compound in 1.1g (69% yield).

MH+: 454.3 f""\ \ BocN N Step G In a pre-dried ?ask, to a stirred solution of the title compound from step F , 1.37mmol, 1.0eq) and Pyridine (0.335ml, 4.11mmol, 3.0eq) in anhydrous DCM (6ml) at 0°C under N2 atmosphere was added Thionyl chloride (0.3ml, 4.11mmol, . After addition the reaction was stirred for 30min at 0°C and then for 2 hours at RT under N2 atmosphere. The reaction mixture was concentrated and co-evaporated with toluene/DCM mixture 2x and once with toluene ng orange/brown solids. The crude was used as such in the next step.

MH+: 436.2 \ \ Step H To a stirred suspension of Cesium carbonate (2.23g, 6.85mmol, 5.0eq) in DMF (103ml; 75 ml/mmol, calculated from the title compound of step G) at 90°C was added a on of the title nd from step G (1 .37mmol) in 34ml DMF (25 ml/mmol) dropwise over 2h. Then the reaction was stirred at 90 °C for 1hour. Upon completion, monitored by LCMS, DMF was reduced under . The residue was diluted with DCM (emulsion) and washed with water once. The organic layer was concentrated to dryness. The crude was ed by ?ash chromatography using the 1O following eluent: Heptane:EtOAc 100:0 to 60:40 to lead the title compound in 350mg (58% yield over 2 steps).

Cf\/\o Stepl The title compound from step H (350mg, 0.8mmol, 1.0eq) was stirred in HCI 4M in MeOH (5ml) for 77h at RT. Upon completion, monitored by LCMS, the white solids were filtered off and washed with MeOH and dried at 45°C under vacuum to lead the first fraction. The mother liquor was concentrated and co-evaporated with EtOH. During the co-evaporation and white solid crushed out which was collected and washed with MeOH and Ether, dried at 45°C under vacuum to lead a second fraction. The fractions were combined to lead a white solid in 246mg (91% yield) MH+: 366.1 Melting point >300°C HPLC retention time: 0.443min Examples 03 to 09 and 011 to 014 were prepared following general scheme 1 and according to the procedures described in the Example 01.

Example 02 Example 02 was prepared ing the general scheme 1 \Nf" \ N\/\O Step A In a pre-dried flask, the title compound from Example 01 (82mg, 0.22mmol, 1.0eq) was dissolved in 1m| anhydrous DMF. Sodium hydride 60% (50mg, 2.2mmol, 10.0eq) was added. The reaction mixture was stirred for 30min at rt (solution), then Methyl iodide (16ul, 0.25mmol, 1.15eq) was added. The reaction mixture was stirred for 1h at rt. LCMS monitoring showed a mixture of the ed product and dimethylated product. The on mixture was quenched with water. The 1O product was extracted with DCM:MeOH 9:1 twice. The organic layer was dried (MgSO4), filtered, concentrated. The crude was purified by flash chromatography in DCM:MeOH 100:0 to 96:4. The resulting oil was triturated with DIPE and DCM and concentrated twice to lead the title nd in 25mg (32% yield).

MH+: 350.2 Retention time: 2.154min Melting point: 91 .2°C Example 010 Example 010 was prepared following the general scheme 1, more precisely following a similar procedure than for the preparation of Example 02.

N\/\O MH+: 350.2 Retention time: 1.912min g point: 198.5°C Table 1 Compound 010, Example 010 Compound 09, Example 09 Compound 013, Example 013 Compound 014, Example 014 The compounds were identified according to the analytical methods and the analytical results described in W02013/045653 A1 and W02013/046029 A1.

Table 2: g points MELTING N° P0|NT(°C) 010 198.5 011 >300 012 273,8 013 298,4 014 >300 Table 3: LCMS data COMPOUND MASS (MH)+ RETENTION LCMS NUMBER TIME (min) METHOD The inhibition of R|P2 kinase was assessed using RIP2 recombinant n in an in vitro peptide- based kinase assay.

B. Kinase Activity Assay The inhibition of R|P2 kinase was assessed using RIP2 recombinant protein in an in vitro peptide- based kinase assay.

Protocol A radiometric protein kinase assay (33PanQinase® Activity Assay) is used for ing the kinase activity. All assays are performed in 96-well FlashPlatesTM from Perkin Elmer in a 50 pl reaction volume. The reaction cocktail is pipetted in 4 steps in the following order: 10 pl of non-radioactive ATP solution (in H20) ul of assay buffer/ [y-33P]-ATP mixture pl of test sample in 10% DMSO pl of enzyme/substrate mixture The assay for R|P2 contains 70 mM HEPES-NaOH pH 7.5, 3 mM MgClz, 3 mM MnClZ, 3 pM Na- anadate, 1.2 mM DTT, 50 pg/ml PEG20000, ATP (3,0 uM), [y-33P]-ATP x. 5 x 1005 cpm per well), protein kinase R|P2 (15,7 nM) and substrate (RBER-Chktide), 2,0 pg/50 pl).

The reaction cocktails were incubated at 30° C for 60 s. The reaction was stopped with 50 pl of 2 % (v/v) H3PO4, plates were aspirated and washed two times with 200 pl 0.9 % (w/v) NaCl.

Incorporation of 33Pi (counting of "cpm") was determined with a microplate scintillation counter.

Compounds The compounds are dissolved to 10 mM in DMSO. Where needed, solutions are sonicated in a bath sonicator.

Table 4 es the plC50 values and % Remaining activity values at two concentrations (1 pM and 0,1 pM) of the compounds according to the invention, obtained using the above mentioned kinase assay.

Table 4. R|P2 biochemical affinity Compound N° IC5o for R|P2 %Remaining %Remaining R|P2 activity at R|P2 activity at + indicates an IC5O > 1uM, ++ indicates an IC5O of between 100 nM and mm and +++ indicates an IC5O < 100nM * indicates ** indicates a % remaining kinase activity above 50%, a % remaining kinase activity below 50% ND = Not determined

Claims (10)

1. A compound of formula (Ia) or a stereoisomer, tautomer, racemate, salt, hydrate, N-oxide form, or solvate thereof, R1 is ed from -H, and –halo; R5 is attached to Z1 and is selected from –H, and –halo; R2 is selected from –H, and -C1-6alkyl; X1 is selected from –O-C1-6alkyl; X2 is -NR2-C1-6alkyl; Het8 is selected from pyrrolidinyl and piperidinyl; and Z1, Z2, Z3, Z4 and Z5 are each C.

2. A compound as defined in claim 1; said compound being selected from the list consisting of: Compound O1, e O1 Compound O2, Example O2 Compound O3, Example O3 Compound O4, Example O4 Compound O5, Example O5 Compound O6, e O6 Compound O7, Example O7 Compound O8, Example O8 Compound O9, Example O9 nd O10, Example O10 Compound O11, Example O11 Compound O12, Example O12 Compound O13, Example O13 and Compound O14, Example O14.

3. A compound according to claim 1; wherein said compound is the S-enantiomer.

4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3.

5. A nd according to any one of claims 1 to 3 or a composition according to claim 4 for use as a medicine.

6. A compound according to any one of claims 1 to 3 or a composition according to claim 4 for use in the prevention and/or treatment of a inase associated disease.

7. A compound according to any one of claims 1 to 3 or a composition according to claim 4 for use in the prevention and/or ent of an inflammatory disorder,

8. A compound according to any one of claims 1 to 3 or a composition ing to claim 4 for use in the prevention and/or treatment of a disorder selected from the list consisting of Crohn’s disease, bowel disease, Sarcoidosis, psoriasis, rheumatoid arthritis, asthma, tive colitis, lupus, uveitis, blau syndrome, granulomatous inflammation.

9. A compound ing to any one of claims 1 to 3 or a composition according to claim 4 for use in the prevention and/or treatment of a disorder selected from the list consisting of behçet’s disease, multiple sclerosis and insulin-resistant type 2 diabetes.

10. In vitro use of a compound as d in any one of claims 1 to 3, for inhibiting the activity of a RIP2 kinase.