Pyrazolo[1,5-A] pyrimidine derivatives

This is a national stage of Application No. PCT/JP2004/002522 filed Mar. 1, 2004, which claims benefit of priority to U.S. Provisional App. No. 60/500,695, filed Sep. 8, 2003.

The present invention relates to novel compounds, their use in the inhibition of protein kinases, their use in medicine and particularly in the prevention and/or treatment of a wide variety of diseases including inflammatory disorders, cancer, angiogenesis, diabetes and neurological disorders. The invention also provides processes for the manufacture of said compounds, compositions containing them and processes for manufacturing such compositions.

Protein kinases are a family of enzymes that catalyse the phosphorylation of hydroxyl groups in proteins. Approximately 2% of the genes encoded by the human genome are predicted to encode protein kinases. The phosphorylation of specific tyrosine, serine, or threonine residues on a target protein can dramatically alter its function in several ways including activating or inhibiting enzymatic activity, creating or blocking binding sites for other proteins, altering subcellular localisation or controlling protein stability. Consequently, protein kinases are pivotal in the regulation of a wide variety of cellular processes, including metabolism, proliferation, differentiation and survival (Hunter, T. Cell, 1995, 80, 224-236). Of the many different cellular functions known to require the actions of protein kinases, some represent targets for therapeutic intervention for certain disease (Cohen, P. Nature Rev. Drug Disc., 2002, 1,309-315).

It is known that several diseases arise from, or involve, aberrant protein kinase activity. In humans, protein tyrosine kinases are known to have a significant role in the development of many diseases including diabetes, cancer and have also been linked to a wide variety of congenital syndromes (Robertson, S. C. Trends Genet. 2000, 16, 265-271). Serine/threonine kinases also represent a class of enzymes, inhibitors of which are likely to have relevance to the treatment of cancer, diabetes and a variety of inflammatory disorders (Adams, J. L. et al. Prog. Med. Chem. 2001, 38, 1-60).

One of the principal mechanisms by which cellular regulation is affected is through the transduction of extracellular signals across the membrane that in turn modulate biochemical pathways within the cell. Protein phosphorylation represents one course by which intracellular signals are propagated from molecule to molecule resulting finally in cellular responses. These signal transduction cascades are regulated and often overlapping as evidenced by the existence of many protein kinases as well as phosphatases. It is currently believed that a number of disease and/or disorders are a result of either aberrant activation or inhibition in the molecular components of kinase cascades.

Three potential mechanisms for inhibition of protein kinases have been identified thus far. These include a pseudo-substrate mechanism, an adenine mimetic mechanism and the locking of the enzyme into an inactive conformation by using surfaces other than the active site (Taylor, S. S. Curr. Opin. Chem. Biol. 1997, 1, 219-226). The majority of inhibitors identified/designed to date act at the ATP-binding site. Such ATP-competitive inhibitors have demonstrated selectivity by virtue of their ability to target the more poorly conserved areas of the ATP-binding site (Wang, Z. et al. Structure 1998, 6, 1117-1128).

There exists a need for the provision of further compounds that are inhibitors of protein kinases.

MAPKAP-K2 (mitogen-activated protein kinase-activated protein kinase 2) is a serine/threonine kinase that operates immediately downstream of the p38 kinase in the stress-induced MAPK pathway ( FIG. 1 ).

The p38 kinase pathway is involved in transducing the effects of a variety of stress-related extracellular stimuli such as heat shock, UV light, bacterial lipopolysaccharide, and pro-inflammatory cytokines. Activation of this pathway results in the phosphorylation of transcription and initiation factors, and affects cell division, apoptosis, invasiveness of cultured cells and the inflammatory response (Martin-Blanco, Bioessays 22, 637-645 (2000)).

p38 kinase itself activates a number of protein kinases other than the MAPKAP kinases such as Mnk1/2, PRAK and MSK1 ( FIG. 1 ). The specific and/or overlapping functions of the majority of these targets have yet to be resolved. This pathway has been of particular interest for the discovery of new anti-inflammatory agents. Previous strategies to intervene this pathway have involved the development of selective inhibitors of p38 kinase. Such inhibitors are effective both for inhibiting pro-inflammatory cytokine production in cell-based models and animal models of chronic inflammations (Lee et al., Immunopharmacology 47, 185-201 (2000)). p38 kinase knockout mouse is embryonic lethal. And cells derived from such embryos have demonstrated a number of abnormalities in fundamental cell responses. These observations indicate that caution should be paid to the long-term therapy with p38 kinase inhibitors.

An alternative strategy for the development of anti-inflammatory agents could be the inhibition of this pathway at the level of MAPKAP-K2. Human MAPKAP-K2 has two proline-rich domains at its N-terminus followed by the kinase domain and the C-terminal regulatory domain. This kinase has low homology with other serine/threonine kinases except MAPKAP-K3 and -K4. The C-terminal regulatory domain contains a bipartite nuclear localisation signal and a nuclear export signal. The crystal structure of inactive MAPKAP-K2 has been resolved (Meng, W. et al. J. Biol. Chem. 277, 37401-37405 (2002)). Activation of MAPKAP-K2 by p38 kinase occurs via selective phosphorylation of threonine residues 222 and 334 (Stokoe et al., EMBO J. 11, 3985-3994 (1992)). MAPKAP-K2 has an amphiphilic A-helix motif located within its C-terminal region that is likely to block the binding of substrates. The dual phosphorylation by p38 kinase has been proposed to reposition this motif resulting in enhanced catalytic activity (You-Li et al., J. Biol. Chem. 270, 202-206 (1995)). MAPKAP-K2 is present in the nucleus of unstimulated cells, and translocates to the cytoplasm upon cell stimulation. This kinase is known to phosphorylate a number of nuclear transcription factors as well as cytosolic proteins such as heat shock proteins and 5-lipoxygenase (Stokoe et al., FEBS Lett. 313, 307-313 (1992), Werz, et al., Proc. Natl. Acad. Sci. USA 97, 5261-5266 (2000), Heidenreich, et al., J. Biol. Chem. 274, 14434-14443 (1999), Tan, et al., EMBO J. 15, 4629-4642 (1996), Neufeld, J. Biol. Chem. 275, 20239-20242 (2000)). All such substrates contain a unique amino acid motif (XX-Hyd-XRXXSXX, where Hyd is a bulky hydrophobic residue) that is required for efficient phosphorylation by MAPKAP-K2 (Stokoe et al., Biochem. J. 296, 843-849 (1993)).

Currently MAPKAP-K2 is the only p38 kinase substrate for which a specific function has been identified. A specific role for MAPKAP-K2 in mediating the inflammatory response has been strongly indicated by the phenotype of the MAPKAP-K2-deficient mouse (MAPKAP-K2 −/− ) (Kotlyarov, et al., Nature Cell Biol. 1, 94-97 (1999)). This mouse is viable and normal except for a significantly reduced inflammatory response. Recently it has also been shown that MAPKAP-K2 deficiency results in a marked neuroprotection from ischaemic brain injury (Wang et al., J. Biol Chem. 277, 43968-43972 (2002)). MAPKAP-K2 is believed to regulate the translation and/or stability of important pro-inflammatory cytokine mRNAs. It is thought to function via phosphorylation of proteins that bind to the AU-rich elements found within untranslated regions of these cytokines. The identity of these proteins is currently under investigation.

MAPKAP-K2 therefore represents an intervention point in the stress-induced kinase cascade for perturbation of the inflammatory response.

As a result of much diligent research directed toward achieving the object stated above, the present inventors have completed the present invention upon discovering that the novel Pyrazolo[1,5-a]pyrimidine derivatives represented by formula I below and their pharmaceutically acceptable salts exhibit excellent kinase inhibiting activity.

In other words, the present invention provides as follows:

(1) A Compound of Formula I:

wherein R 1 is hydrogen, C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkenyl, C2-C8 optionally substituted alkynyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkenyl, optionally substituted heterocyclylalkenyl, optionally substituted arylalkynyl or optionally substituted heterocyclylalkynyl;

R 2 is hydrogen, halogen, —CN, —NO 2 , —CHO, -G-R 7 [G is a bond, —C(═O)— or —O—C(═O)—; and R 7 is C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkenyl, C2-C8 optionally substituted alkynyl, C3-C8 optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkenyl, optionally substituted heterocyclylalkenyl, optionally substituted arylalkynyl, optionally substituted heterocyclylalkynyl, —OR 8 (R 8 is hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl), —NR 9 R 10 (R 9 is as defined for R 8 ; R 10 is hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heterocyclylalkyl or —OCH 3 ), —R 11 (R 11 is an optionally substituted saturated heterocyclyl with 5 to 7 members containing one to four heteroatoms selected from N, O and S), C6-C14 optionally substituted aryl or optionally substituted heteroaryl; provided that when R 7 is C6-C14 optionally substituted aryl or optionally substituted heteroaryl, then G is not a bond], —NR 9 C(═O)R 12 (R 9 is as defined for R 8 ; R 12 is hydrogen, C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkenyl, C2-C8 optionally substituted alkynyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkenyl, optionally substituted heterocyclylalkenyl, optionally substituted arylalkynyl or optionally substituted heterocyclylalkynyl), —NR 9 C(═X)OR 13 (R 9 and R 13 , which may be the same or different, are as defined for R 8 ; X is O, S, N—CN or NH), —NR 9 C(═X)NR 13 R 14 (R 9 , R 13 and R 14 , which may be the same or different, are as defined for R 8 ; X is O, S, N—CN or NH), —NR 9 SO 2 R 13 (R 9 and R 13 , which may be the same or different, are as defined for R 8 ), —SR 9 (R 9 is as defined for R 8 ) or —S(O) m R 9 (R 9 is as defined for R 8 ; m is 1 or 2);

R 3 is C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkenyl, C2-C8 optionally substituted alkynyl, C3-C8 optionally substituted cycloalkyl, C6-C14 unsubstituted aryl, C6-C14 substituted aryl [As substituents of C6-C14 aryl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , —CHO, -G-R 15 {G is a bond, —C(═O)— or —O—C(═O)—; R 15 is C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkenyl, C2-C8 optionally substituted alkynyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkenyl, optionally substituted heterocyclylalkenyl, optionally substituted arylalkynyl, optionally substituted heterocyclylalkynyl, —OR 16 (R 16 is as defined for R 8 ) or —NR 17 R 18 (R 17 and R 18 , which may be the same or different, are as defined for R 8 )}, —NR 17 C(═O)R 19 (R 17 is as defined for R 8 ; R 19 is as defined for R 12 ), —NR 17 C(═X)OR 18 (R 17 and R 18 , which may be the same or different, are as defined for R 8 ; X is O, S, N—CN or NH), —NR 17 C(═X)NR 18 R 20 (R 17 , R 18 and R 20 , which may be the same or different, are as defined for R 8 ; X is O, S, N—CN or NH), —NR 17 SO 2 R 18 (R 17 and R 18 , which may be the same or different, are as defined for R 8 ), —S(O) m R 17 (R 17 is as defined for R 8 ; m is 0, 1 or 2) and —SO 2 NR 21 R 22 (R 21 and R 22 , which may be the same or different, are as defined for R 8 ; R 21 and R 22 together may be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, the said monocyclic or bicyclic heterocycle may optionally be substituted with one or more substituents)], unsubstituted heterocyclyl, substituted heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , —CHO, -G-R 23 {G is a bond, —C(═O)— or —O—C(═O)—; R 23 is as defined for R 15 }, —NR 24 C(═O)R 25 (R 24 is as defined for R 8 ; R 25 is as defined for R 12 ), —NR 24 C(═X)OR 26 (R 24 and R 26 , which may be the same or different, are as defined for R 8 ; X is O, S, N—CN or NH), —NR 24 C(═X)NR 26 R 27 (R 24 , R 26 and R 27 , which may be the same or different, are as defined for R 8 ; X is O, S, N—CN or NH), —NR 24 SO 2 R 26 (wherein R 24 and R 26 , which may be the same or different, are as defined for R 8 ), —S(O) m R 24 (R 24 is as defined for R 8 ; m is 0, 1 or 2) and —SO 2 NR 28 R 29 (R 28 and R 29 , which may be the same or different, are as defined for R 8 ; R 28 and R 29 together may be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, the said monocyclic or bicyclic heterocycle may optionally be substituted with one or more substituents)], optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkenyl, optionally substituted heterocyclylalkenyl, optionally substituted arylalkynyl or optionally substituted heterocyclylalkynyl;

R 4 is hydrogen, halogen, C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkenyl, C2-C8 optionally substituted alkynyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkenyl, optionally substituted heterocyclylalkenyl, optionally substituted arylalkynyl, optionally substituted heterocyclylalkynyl, —OR 30 (R 30 is as defined for R 8 ), —SR 30 (R 30 is as defined for R 8 ), —NR 30 R 31 (R 30 and R 31 , which may be the same or different, are as defined for R 8 ), —NR 30 C(═O)R 32 (R 30 is as defined for R 8 ; and R 32 is as defined for R 12 ), —NR 30 C(═X)OR 31 (R 30 and R 31 , which may be the same or different, are as defined R 8 ; X is O, S, N—CN or NH), —NR 30 C(═X)NR 31 R 33 (R 30 , R 31 and R 33 , which may be the same or different, are as defined for R 8 ; X is O, S, N—CN or NH) or —NR 30 SO 2 R 31 (R 30 and R 31 , which may be the same or different, are as defined for R 8 );

R 5 is C1-C8 substituted alkyl, C2-C8 optionally substituted alkenyl, C2-C8 optionally substituted alkynyl, C3-C8 substituted cycloalkyl [As substituents of C3-C8 cycloalkyl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , —CHO, -G-R 34 {G is a bond, —C(═O)— or —O—C(═O)—; R 34 is as defined for R 15 }, —NR 35 C(═O)R 36 (R 35 is as defined for R 8 ; R 36 is as defined for R 12 ), —NR 35 C(═X)OR 37 (R 35 and R 37 , which may be the same or different, are as defined for R 8 ; X is O, S, N—CN or NH ), —NR 35 C(═X)NR 37 R 38 (R 35 , R 37 and R 38 , which may be the same or different, are as defined for R 8 ; X is O, S, N—CN or NH) and —NR 35 SO 2 R 37 (R 35 and R 37 , which may be the same or different, are as defined for R 8 )], unsubstituted heterocyclyl, substituted heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , —CHO, -G-R 39 {G is a bond, —C(═O)— or, —O—C(═O)—; R 39 is as defined for R 15 }, —NR 40 C(═O)R 41 (R 40 is as defined for R 8 ; R 41 is as defined for R 12 ), —NR 40 C(═X)OR 42 (R 40 and R 42 , which may be the same or different, are as defined for R 8 ; X is O, S, N—CN or NH), —NR 40 C(═X)NR 42 R 43 (R 40 , R 42 and R 43 , which may be the same or different, are as defined for R 8 ; X is O, S, N—CN or NH) and —NR 40 SO 2 R 42 (R 40 and R 42 , which may be the same or different, are as defined for R 8 )], optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkenyl, optionally substituted heterocyclylalkenyl, optionally substituted arylalkynyl, optionally substituted heterocyclylalkynyl or —NR 44 R 45 (R 44 and R 45 , which may be the same or different, are C1-C8 optionally substituted alkyl; R 44 and R 45 together may be taken together with the nitrogen to which they are attached to form a mono heterocycle with 5-7 members and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, the said mono heterocycle may optionally be substituted with one or more substituents);

R 6 is hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl;

with the provisos:

that R 1 , R 2 and R 4 are not all H;

that R 4 is not pentafluorophenyl;

that R 5 is not a group represented as the following (a):

(a) C1-C6 alkyl or C3-C6 cycloalkyl, in which an alkyl group or a cycloalkyl group optionally may be substituted by phenyl or by one or more fluoro substituents;

and pharmaceutically acceptable salts, and other pharmaceutically acceptable biohydrolyzable derivatives thereof, including esters, amides, carbamates, carbonates, ureides, solvates, hydrates, affinity reagents or prodrugs.

(2) A compound of formula I-b:

wherein R 1b is hydrogen, C1-C6 optionally substituted alkyl, C2-C6 optionally substituted alkenyl, C2-C6 optionally substituted alkynyl, C3-C8 optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted arylalkenyl, optionally substituted heteroarylalkenyl, optionally substituted arylalkynyl or optionally substituted heteroarylalkynyl;

R 2b is hydrogen, halogen, —CN, —NO 2 , —CHO or -G-R 52 {G is a bond, —C(═O)— or —O—C(═O)—; and R 52 is C1-C6 optionally substituted alkyl, C2-C6 optionally substituted alkenyl, C2-C6 optionally substituted alkynyl, C3-C8 optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted arylalkenyl, optionally substituted heteroarylalkenyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkynyl, —OR 53 (R 53 is hydrogen, C1-C6 optionally substituted alkyl, C2-C6 optionally substituted alkenyl, C2-C6 optionally substituted alkynyl, C3-C8 optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted arylalkenyl, optionally substituted heteroarylalkenyl, optionally substituted arylalkynyl or optionally substituted heteroarylalkynyl), —NR 54 R 55 , —NR 54 C(═O)R 55 , —SR 54 , optionally substituted aryl or optionally substituted heteroaryl; provided that when R 52 is optionally substituted aryl or optionally substituted heteroaryl then G is not a bond; wherein R 54 and R 55 , which may be the same or different, are as defined for R 53 ; or wherein R 54 and R 55 together form an optionally substituted ring that optionally contains one or more heteroatoms selected from N, O and S};

R 3b is C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkenyl, C2-C8 optionally substituted alkynyl, C3-C8 optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted arylalkenyl, optionally substituted heteroarylalkenyl, optionally substituted arylalkynyl or optionally substituted heteroarylalkynyl;

R 4b is hydrogen, halogen, C1-C6 optionally substituted alkyl, C2-C6 optionally substituted alkenyl, C2-C6 optionally substituted alkynyl, C3-C8 optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted arylalkenyl, optionally substituted heteroarylalkenyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkynyl, —OR 56 , —SR 56 , —NR 56 R 57 or —NR 56 C(═O)R 57 ;

wherein R 56 and R 57 , which may be the same or different, are as defined for R 53 ; or

wherein R 56 and R 57 together form an optionally substituted ring which optionally contains one or more heteroatoms;

R 5b is C1-C6 substituted alkyl, C2-C6 optionally substituted alkenyl, C2-C6 optionally substituted alkynyl, C3-C8 substituted cycloalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl;

R 6b is hydrogen, C1-C6 optionally substituted alkyl, C2-C6 optionally substituted alkenyl, C2-C6 optionally substituted alkynyl or C3-C8 optionally substituted cycloalkyl;

with the provisos:

that R 1b , R 2b and R 4b are not all H;

that R 4b is not pentafluorophenyl;

that R 5b is not a group represented as the following (a):

(a) C1-C6 alkyl or C3-C6 cycloalkyl, in which an alkyl group optionally may be substituted by phenyl or by one or more fluoro substituents;

and pharmaceutically acceptable salts, and other pharmaceutically acceptable biohydrolyzable derivatives thereof, including esters, amides, carbamates, carbonates, ureides, solvates, hydrates, affinity reagents or prodrugs.

(3) The compound as (1) wherein R 1 is hydrogen or C1-C8 optionally substituted alkyl.

(4) The compound as (1) wherein R 1 is hydrogen.

(5) The compound as any one of (1), (3) or (4) wherein R 2 is —NO 2 , —OC(═O)R 7 , —CO 2 R 8 or —CONR 9 R 10 ; wherein R 7 , R 8 , R 9 and R 10 are as defined in claim 1 .

(6) The compound as any one of (1), (3) or (4) wherein R 2 is —NR 9 C(═O)R 12 , —NR 9 C(═X)OR 13 , —NR 9 C(═X)NR 13 R 14 , —NR 9 SO 2 R 13 , —SR 9 or —S(O) m R 9 ; wherein R 9 , R 12 , R 13 , R 14 and X are as defined in claim 1 ; m is 1 or 2.

(7) The compound as any one of (1), (3) or (4) wherein R 2 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl or optionally substituted arylalkyl.

(8) The compound as any one of (1), (3) or (4) wherein R 2 is hydrogen, halogen, —CN or —SCH 3 .

(9) The compound as any one of (1), (3) or (4) wherein R 2 is halogen.

(10) The compound as any one of (1), (3) or (4) wherein R 2 is F.

(11) The compound as any one of (1), (3) or (4) wherein R 2 is hydrogen.

(12) The compound as any one of (1), (3) to (11) wherein R 3 is C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkenyl, C2-C8 optionally substituted alkynyl, C3-C8 optionally substituted cycloalkyl, C6-C14 unsubstituted aryl, C6-C14 substituted aryl, unsubstituted heteroaryl, substituted heteroaryl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl.

(13) The compound as any one of (1), (3) to (11) wherein R 3 is C6-C14 substituted aryl.

(14) The compound as any one of (1), (3) to (11) wherein R 3 is C6-C14 substituted aryl {As substituents of C6-C14 aryl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , -G-R 15 , —NR 17 C(═O)R 19 and —S(O) m R 17 ; wherein R 15 , R 17 , R 19 or G are as defined in claim 1 ; m is 0, 1 or 2.}.

(15) The compound as any one of (1), (3) to (11) wherein R 3 is C6-C14 substituted aryl [As substituents of C6-C14 aryl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , -G-R 15 {G is a bond or —C(═O)—; R 15 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, —OR 16 or —NR 17 R 18 }, —NR 17 C(═O)R 19 and S(O) m R 17 ; wherein R 16 , R 17 , R 18 or R 19 are as defined in claim 1 ; m is 0, 1 or 2.].

(16) The compound as any one of (1), (3) to (11) wherein R 3 is C6-C14 substituted aryl [As substituents of C6-C14 aryl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , -G-R 15 {G is a bond; R 15 is C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —OR 16 or —NR 17 R 18 }, —NR 17 C(═O)R 19 and S(O) m R 17 ; wherein R 16 , R 17 , R 18 or R 19 are as defined in claim 1 ; m is 0, 1 or 2.].

(17) The compound as any one of (1), (3) to (11) wherein R 3 is C6-C14 substituted aryl [As substituents of C6-C14 aryl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , -G-R 15 {G is a bond or —C(═O)—; R 15 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, —OR 16 or —NR 17 R 18 }, —NR 17 C(═O)R 19 and S(O) m R 17 ; wherein R 16 , R 17 , R 18 or R 19 are as defined in claim 1 ; m is 0, 1 or 2.].

(18) The compound as any one of (1), (3) to (11) wherein R 3 is C6-C14 substituted aryl [As substituents of C6-C14 aryl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , -G-R 15 {G is a bond or —C(═O)—; R 15 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, —OR 16 or —NR 17 R 18 }, —NR 17 C(═O)R 19 and S(O) m R 17 ; wherein R 16 , R 17 , R 18 or R 19 , which may be the same or different, are hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl; m is 0, 1 or 2.].

(19) The compound as any one of (1), (3) to (11) wherein R 3 is C6-C14 substituted aryl [As substituents of C6-C14 aryl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 and -G-R 15 {G is —C(═O)—; R 15 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, —OR 16 or —NR 17 R 18 }; wherein R 16 , R 17 or R 18 are as defined in claim 1 .].

(20) The compound as any one of (1), (3) to (11) wherein R 3 is unsubstituted heterocyclyl.

(21) The compound as any one of (1), (3) to (11) wherein R 3 is substituted heterocyclyl.

(22) The compound as any one of (1), (3) to (11) wherein R 3 is substituted heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , -G-R 23 , —NR 24 C(═O)R 25 and —S(O) m R 24 ; wherein R 23 , R 24 , R 25 or G are as defined in claim 1 ; m is 0, 1 or 2.].

(23) The compound as any one of (1), (3) to (11) wherein R 3 is unsubstituted bicyclic heteroaryl.

(24) The compound as any one of (1), (3) to (11) wherein R 3 is substituted bicyclic heteroaryl [As substituents of bicyclic heteroaryl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , -G-R 23 , —NR 24 C(═O)R 25 and —S(O) m R 24 ; wherein R 23 , R 24 , R 25 or G are as defined in claim 1 ; m is 0, 1 or 2.].

(25) The compound as any one of (1), (3) to (24) wherein R 4 is halogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, —OR 30 ; wherein R 30 is as defined in claim 1 .

(26) The compound as any one of (1), (3) to (24) wherein R 4 is C1-C8 optionally substituted alkyl.

(27) The compound as any one of (1), (3) to (24) wherein R 4 is methyl.

(28) The compound as any one of (1), (3) to (24) wherein R 4 is hydrogen.

(29) The compound as any one of (1), (3) to (28) wherein R 5 is C3-C8 substituted cycloalkyl, unsubstituted heterocyclyl or substituted heterocyclyl.

(30) The compound as any one of (1), (3) to (28) wherein R 5 is C3-C8 substituted cycloalkyl [As substituents of cycloalkyl may be mentioned one or more selected from the group consisting of halogen, —CN, C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkenyl, C3-C8 optionally substituted cycloalkyl and —NR 17 R 18 ; wherein R 17 or R 18 is as defined in claim 1 ].

(31) The compound as any one of (1), (3) to (28) wherein R 5 is substituted cyclohexyl [As substituents of cyclohexyl may be mentioned one or more selected from the group consisting of halogen, —CN, C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkenyl, C3-C8 optionally substituted cycloalkyl and —NR 17 R 18 ; wherein R 17 or R 18 is as defined in claim 1 ].

(32) The compound as any one of (1), (3) to (28) wherein R 5 is 4-amino-cyclohexyl.

(33) The compound as any one of (1), (3) to (28) wherein R 5 is unsubstituted heterocyclyl or substituted heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, —CN, C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkenyl, C3-C8 optionally substituted cycloalkyl and —NR 17 R 18 ; wherein R 17 or R 18 is as defined in claim 1 ]

(34) The compound as any one of (1), (3) to (28) wherein R 5 is unsubstituted piperidin-3-yl, unsubstituted piperidin-4-yl or unsubstituted pyrrolidin-3-yl.

(35) The compound as any one of (1), (3) to (28) wherein R 5 is substituted piperidin-3-yl, substituted piperidin-4-yl or substituted pyrrolidin-3-yl.

(36) The compound as any one of (1), (3) to (28) wherein R 5 is substituted piperidin-3-yl, substituted piperidin-4-yl or substituted pyrrolidin-3-yl [As their substituents may be mentioned one or more selected from the group consisting of halogen, —CN, C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkenyl and C3-C8 optionally substituted cycloalkyl]

(37) The compound as any one of (1), (3) to (36) wherein R 6 is hydrogen.

(38) The compound as any one of (1), (3) to (36) wherein R 6 is C1-C8 optionally substituted alkyl or optionally substituted arylalkyl.

(39) A compound of the formula II-26:

wherein R 1 -R 6 are as defined in claim 1 ; R 58 is C1-C8 optionally substituted alkyl or optionally substituted arylalkyl;

with the provisos:

that R 1 , R 2 and R 4 are not all H.

(40) A compound of the formula III-01:

wherein R 1 -R 4 are as defined in claim 1 ; R 58 is C1-C8 optionally substituted alkyl or optionally substituted arylalkyl;

with the provisos:

that R 1 , R 2 and R 4 are not all H.

(41) A compound of the formula IV:

wherein R 1 -R 4 are as defined in claim 1 ;

with the provisos:

that R 1 , R 2 and R 4 are not all H;

that R 4 is not optionally substituted aryl or optionally substituted heteroaryl.

(42) The compound as any one of (39), (40) or (41) wherein R 1 is hydrogen;

(43) The compound as any one of (39), (40) or (41) wherein R 2 is hydrogen, halogen, —CN, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, —OR 8 (R 8 is hydrogen or C1-C8 optionally substituted alkyl), —NR 9 R 10 (R 9 and R 10 , which may be the same or different, hydrogen or C1-C8 optionally substituted alkyl), —C(═O)NR 9 R 10 (R 9 and R 10 , which may be the same or different, are hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl), —NR 9 C(═O)R 12 (R 9 is hydrogen or C1-C8 optionally substituted alkyl; R 12 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl), —NR 9 C(═O)OR 13 (R 9 is hydrogen or C1-C8 optionally substituted alkyl; R 13 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl), —NR 9 C(═O)NR 13 R 14 (R 9 and R 13 , which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl; R 14 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl), —NR 9 SO 2 R 13 (R 9 is hydrogen or C1-C8 optionally substituted alkyl; R 13 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl), —SR 9 (R 9 is hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl) or —SO 2 R 9 (R 9 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl).

(44) The compound as any one of (39), (40) or (41) wherein R 3 is substituted phenyl [As substituents of phenyl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkynyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, —OR 16 (R 16 is hydrogen, C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl), —NR 17 R 18 (R 17 and R 18 , which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl) and —C(═O)NR 17 R 18 (R 17 and R 18 , which may be the same or different, are hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl)], unsubstituted bicyclic heteroaryl, substituted bicyclic heteroaryl [As substituents of bicyclic heteroaryl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , C1-C8 optionally substituted alkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, —OR 16 (R 16 is hydrogen, C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl), —NR 17 R 18 (R 17 and R 18 , which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl), —NHC(═O)R 19 (R 19 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl) and —SR 17 (R 17 is C1-C8 optionally substituted alkyl)].

(45) The compound as any one of (39), (40) or (41) wherein R 4 is hydrogen, methyl or ethyl.

(46) The compound as (39) wherein R 5 is preferably selected from cyclohexyl [As substituents of cyclohexyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ], unsubstituted saturated heterocyclyl or substituted saturated heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ].

(47) The compound as (39) wherein R 6 is hydrogen.

(48) The compound as any one of (39), (40) or (41) wherein R 58 is tert-butyl or benzyl.

(49) The compound as (39) wherein R 1 is hydrogen; R 2 is hydrogen, —CN, —SCH 3 , —NH 2 , —COOH or COCF 3 ; R 3 is substituted phenyl (As substituents of phenyl may be mentioned one or more selected from the group consisting of halogen, —CN, —OH, —OCH 3 , —OEt, —COOH); R 4 is hydrogen or —CH 3 ; R 5 is 4-amino-cyclohexyl or piperidin-3-yl; R 6 is hydrogen; R 58 is tert-butyl;

with the provisos that R 1 , R 2 and R 4 are not all H.

(50) The compound as (40) wherein R 1 is hydrogen; R 2 is hydrogen, —CN, —SCH 3 , —NH 2 , —COOH or COCF 3 ; R 3 is substituted phenyl (As substituents of phenyl may be mentioned one or more selected from the group consisting of halogen, —CN, —OH, —OCH 3 , —OEt, —COOH); R 4 is hydrogen or —CH 3 ; R 58 is tert-butyl; with the provisos that R 1 , R 2 and R 4 are not all H

(51) The compound as (41) wherein R 1 is hydrogen; R 2 is hydrogen, —CN, —SCH 3 , —NH 2 , —COOH or COCF 3 ; R 3 is substituted phenyl (As substituents of phenyl may be mentioned one or more selected from the group consisting of halogen, —CN, —OH, —OCH 3 , —OEt, —COOH); R 4 is hydrogen or —CH 3 ; with the provisos that R 1 , R 2 and R 4 are not all H.

(52) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein removal of Boc protecting group from compound II.

(53) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound III

is reacted with a compound of the formula R 5 R 6 NH.

(54) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound IV

is reacted with a compound of the formula R 5 R 6 NH.

(55) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound IV

is reacted with di-tert-butyl dicarbonate.

(56) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound V

is reacted with a compound of the formula R 3 NH 2 or R 3 NH(COCH 3 ).

(57) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound VI

is reacted with phosphorus oxychloride or phenyl phosphonic dichloride.

(58) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound VII

is reacted with a compound of the formula R 4 CH(CO 2 Me) 2 or R 4 CH(CO 2 Et) 2 .

(59) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound V-01

is reacted with a halogenating, thiocyanating or acylating agent.

(60) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound IV-01

is reacted with a Grignard reagent.

(61) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound II-01

is reacted with a halogenating agent.

(62) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound II-01

is reacted with a compound of the formula (CF 3 CO) 2 O.

(63) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound II-03

is reacted with hydroxide for a hydrolysis of ester group; R 67 is methyl or ethyl.

(64) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound II-04

is reacted with a compound of the formula R 9 R 10 in the presence of a peptide coupling agent.

(65) A process for the manufacture of a compound -as defined in any one of (1), (3) to (38) wherein compound II-06

is rearranged via isocyanate intermediate under Hofmann rearrangement conditions, followed by removal of carbonate.

(66) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound II-08

is reacted with a compound of the formula R 12 COCl, R 12 COOH, R 10 SO 2 Cl, R 10 NCO or R 10 NCS.

(67) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound II-13

is condensed with an alcohol derivative under Mitsunobu conditions; Ar 1 represents C6-C14 optionally substituted aryl or optionally substituted heteroaryl.

(68) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound II-15

is reacted with a boronic acid derivative in the presence of metal catalysis under Suzuki-Miyaura coupling conditions; Ar 1 represents C6-C14 optionally substituted aryl or optionally substituted heteroaryl.

(69) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound II-15

is reacted with a 1-alkyne in the presence of metal catalyst under Sonogashira coupling conditions; Ar 1 represents C6-C14 optionally substituted aryl or optionally substituted heteroaryl.

(70) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound II-18

is reacted with a compound of the formula R 16 R 17 NH in the presence of a peptide coupling agent; Ar 1 represents C6-C14 optionally substituted aryl or optionally substituted heteroaryl.

(71) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound II-20

is reacted with an alkyl lithium reagent.

(72) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound II-22

is reacted with alkyl halide, followed by removal of trifluoroacetyl group.

(73) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound II-08

is reacted with an aldehyde in the presence of reducing agent.

(74) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound II-24

is reacted with alkyl halide in the presence of sodium hydride

(75) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound I-26

is reacted with hydrogen in the presence of Palladium on activated carbon or with chloroformate followed by methanol; R60 is benzyl or p-MeO-benzyl; n is 1, 2 or 3.

(76) A process for the manufacture of a compound as defined in any one of (1), (3) to (38) wherein compound V-04

is reacted with reducing agent or diol derivative for formation of acetal.

(77) A composition comprising a compound as defined in any one of (1), (3) to (38) in combination with a pharmaceutically acceptable carrier, diluent or excipient.

(78) The composition as (77) further comprising one or more active agents.

(79) A process for the manufacture of a composition as defined in (77) or (78) comprising combining a compound as defined in any one of (1), (3) to (38) with the pharmaceutically acceptable carrier or diluent, optionally with an additional active agent.

(80) A compound as defined in any one of (1), (3) to (38), or a composition as defined in any one of (77) or (78), for use in medicine.

(81) A compound as defined in any one of (1), (3) to (38), or a composition as defined in any one of (77) or (78), for inhibiting protein kinase.

(82) A compound as defined in any one of (1), (3) to (38), or a composition as defined in any one of (77) or (78), for selectively inhibiting MAPKAP-K2.

(83) A compound as defined in any one of (1), (3) to (38), or a composition as defined in any one of (77) or (78), for selectively inhibiting CDK.

(84) A compound as defined in any one of (1), (3) to (38), or a composition as defined in any one of (77) or (78), for use in the prevention or treatment of a protein kinase-mediated disorder.

(85) The compound or composition as (84), wherein the disorder is a neurodegenerative/neurological disorder (including dementia), inflammatory disease, a disorder linked to apoptosis, particularly neuronal apoptosis, stroke, sepsis, autoimmune disease, destructive bone disorder, proliferative disorder, diabetes, cancer, tumour growth, infectious disease, allergy, ischemia reperfusion injury, heart attack, angiogenic disorder, organ hypoxia, vascular hyperplasia, cardiac hypertrophy and/or thrombin induced platelet aggregation.

(86) The compound or composition as (84), wherein the disorder is inflammatory disease and/or autoimmune disease.

(87) The compound or composition as (84), wherein the disorder is autoimmune disease.

(88) The compound or composition as (87), wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, glomerulonephritis, scleroderma, Sjogren's syndrome, juvenile rheumatoid arthritis, psoriatic arthritis, chronic thyroiditis, Graves's disease, autoimmune gastritis, diabetes, autoimmune haemolytis anaemia, autoimmune neutropaenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, ulcerative colitis, Crohn's disease, psoriasis or graft vs host disease.

(89) The compound or composition as (87), wherein the autoimmune disease is rheumatoid arthritis, psoriasis, ankylosing spondylitis, juvenile rheumatoid arthritis, psoriatic arthritis or Crohn's disease.

(90) A method of treating or preventing a protein kinase-mediated disorder in an individual, which method comprises administering to said individual a compound as claimed in any one of (1), (3) to (38) or a composition as defined in (77) or (78).

(91) The method as (90) wherein the individual is in need of the treatment or prevention of the disorder.

(92) The method as (90) or (91) wherein the disorder is a neurodegenerative/neurological disorder (including dementia), inflammatory disease, a disorder linked to apoptosis, particularly neuronal apoptosis, stroke, sepsis, autoimmune disease, destructive bone disorder, proliferative disorder, diabetes, cancer, tumour growth, infectious disease, allergy, ischemia reperfusion injury, heart attack, angiogenic disorder, organ hypoxia, vascular hyperplasia, cardiac hypertrophy and/or thrombin induced platelet aggregation.

(93) The method as (90) or (91) wherein the disorder is autoimmune disease.

(94) The method as (93) wherein the autoimmune disease is rheumatoid arthritis, psoriasis, ankylosing spondylitis, juvenile rheumatoid arthritis, psoriatic arthritis or Crohn's disease.

(95) The method as (90) to (94) wherein one or more active agent is administered to the individual simultaneously, subsequently or sequentially to administering the compound.

(96) Use of a compound as defined in any one of (1), (3) to (38) in the manufacture of a medicament for the prevention or treatment of a protein kinase-mediated disorder.

(97) Use as (96) wherein the disorder is a neurodegenerative/neurological disorder (including dementia), inflammatory disease, a disorder linked to apoptosis, particularly neuronal apoptosis, stroke, sepsis, autoimmune disease, destructive bone disorder, proliferative disorder, diabetes, cancer, tumour growth, infectious disease, allergy, ischemia reperfusion injury, heart attack, angiogenic disorder, organ hypoxia, vascular hyperplasia, cardiac hypertrophy and/or thrombin induced platelet aggregation.

(98) Use as (96) wherein the disorder is autoimmune disease.

(99) Use as (98) wherein the autoimmune disease is rheumatoid arthritis, psoriasis, ankylosing spondylitis, juvenile rheumatoid arthritis, psoriatic arthritis or Crohn's disease.

(100) Use as (96) or (97) wherein one or more active agent is administered to the individual simultaneously, subsequently or sequentially to administering the compound.

(101) An assay for determining the activity of the compounds as defined in any one of (1), (3) to (38), comprising providing a system for assaying the activity and assaying the activity of a compound as defined in any one of (1), (3) to (38).

(102) The assay as (101) wherein the assay is for the protein kinase inhibiting activity of the compound.

(103) A method of inhibiting the activity or function of a protein kinase, which method comprises exposing a protein kinase to a compound as defined in any one of (1), (3) to (38) or a composition as defined in (77) or (78).

(104) The method as (103) which is performed in a research model, in vitro, in silico or in vivo such as in an animal model.

FIG. 1 shows the p38 MAPK cascade.

FIGS. 2-8 show general reaction schemes for the preparation of compounds of Formula I.

In a first aspect the invention provides a compound of formula I:

wherein R 1 is hydrogen, C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkenyl, C2-C8 optionally substituted alkynyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkenyl, optionally substituted heterocyclylalkenyl, optionally substituted arylalkynyl or optionally substituted heterocyclylalkynyl;

R 2 is hydrogen, halogen, —CN, —NO 2 , —CHO, -G-R 7 [G is a bond, —C(═O)— or —O—C(═O)—; and R 7 is C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkenyl, C2-C8 optionally substituted alkynyl, C3-C8 optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkenyl, optionally substituted heterocyclylalkenyl, optionally substituted arylalkynyl, optionally substituted heterocyclylalkynyl, —OR 8 (R 8 is hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl), —NR 9 R 10 (R 9 is as defined for R 8 ; R 10 is hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heterocyclylalkyl or —OCH 3 ), —R 11 (R 11 is an optionally substituted saturated heterocyclyl with 5 to 7 members containing one to four heteroatoms selected from N, O and S), C6-C14 optionally substituted aryl or optionally substituted heteroaryl; provided that when R 7 is C6-C14 optionally substituted aryl or optionally substituted heteroaryl, then G is not a bond], —NR 9 C(═O)R 12 (R 9 is as defined for R 8 ; R 12 is hydrogen, C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkenyl, C2-C8 optionally substituted alkynyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkenyl, optionally substituted heterocyclylalkenyl, optionally substituted arylalkynyl or optionally substituted heterocyclylalkynyl), —NR 9 C(═X)OR 13 (R and R 13 , which may be the same or different, are as defined for R 8 ; X is O, S, N—CN or NH), —NR 9 C(═X)NR 13 R 14 (R 9 , R 13 and R 14 , which may be the same or different, are as defined for R 8 ; X is O, S, N—CN or NH), —NR 9 SO 2 R 13 (R 9 and R 13 , which may be the same or different, are as defined for R 8 ), —SR 9 (R 9 is as defined for R 8 ) or —S(O) m R 9 (R 9 is as defined for R 8 ; m is 1 or 2);

R 3 is C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkenyl, C2-C8 optionally substituted alkynyl, C3-C8 optionally substituted cycloalkyl, C6-C14 unsubstituted aryl, C6-C14 substituted aryl [As substituents of C6-C14 aryl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , —CHO, -G-R 15 {G is a bond, —C(═O)— or —O—C(═O)—; R 15 is C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkenyl, C2-C8 optionally substituted alkynyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkenyl, optionally substituted heterocyclylalkenyl, optionally substituted arylalkynyl, optionally substituted heterocyclylalknyl, —OR 16 (R 16 is as defined for R 8 ) or —NR 17 R 18 (R 17 and R 18 , which may be the same or different, are as defined for R 8 )}, —NR 17 C(═O)R 19 (R 17 is as defined for R 8 ; R 19 is as defined for R 12 ), —NR 17 C(═X)OR 18 (R 17 and R 18 , which may be the same or different, are as defined for R 8 ; X is O, S, N—CN or NH), —NR 17 C(═X)NR 18 R 20 (R 17 , R 18 and R 20 , which may be the same or different, are as defined for R 8 ; X is O, S, N—CN or NH), —NR 17 SO 2 R 18 (R 17 and R 18 , which may be the same or different, are as defined for R 8 ), —S(O) m R 17 (R 17 is as defined for R 8 ; m is 0, 1 or 2) and —SO 2 NR 21 R 22 (R 21 and R 22 , which may be the same or different, are as defined for R 8 ; R 21 and R 22 together may be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, the said monocyclic or bicyclic heterocycle may optionally be substituted with one or more substituents)], unsubstituted heterocyclyl, substituted heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , —CHO, -G-R 23 {G is a bond, —C(═O)— or —O—C(═O)—;

R 23 is as defined for R 15 }, —NR 24 C(═O)R 25 (R 24 is as defined for R 8 ; R 25 is as defined for R 12 ), —NR 24 C(═X)OR 26 (R 24 and R 26 , which may be the same or different, are as defined for R 8 ; X is O, S, N—CN or NH), —NR 24 C(═X)NR 26 R 27 (R 24 , R 26 and R 27 , which may be the same or different, are as defined for R 8 ; X is O, S, N—CN or NH), —NR 24 SO 2 R 26 (wherein R 24 and R 26 , which may be the same or different, are as defined for R 8 ), —S(O) m R 24 (R 24 is as defined for R 8 ; m is 0, 1 or 2) and —SO 2 NR 28 R 29 (R 28 and R 29 , which may be the same or different, are as defined for R 8 ; R 28 and R 29 together may be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, the said monocyclic or bicyclic heterocycle may optionally be substituted with one or more substituents)], optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkenyl, optionally substituted heterocyclylalkenyl, optionally substituted arylalkynyl or optionally substituted heterocyclylalkynyl;

R 4 is hydrogen, halogen, C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkenyl, C2-C8 optionally substituted alkynyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkenyl, optionally substituted heterocyclylalkenyl, optionally substituted arylalkynyl, optionally substituted heterocyclylalkynyl, —OR 30 (R 30 is as defined for R 8 ), —SR 30 (R 30 is as defined for R 8 ), —NR 30 R 31 (R 30 and R 31 , which may be the same or different, are as defined for R 8 ), —NR 30 C(═O)R 32 (R 30 is as defined for R 8 ;

and R 32 is as defined for R 12 ), —NR 30 C(═X)OR 31 (R 30 and R 31 , which may be the same or different, are as defined R 8 ; X is O, S, N—CN or NH), —NR 30 C(═X)NR 31 R 33 (R 30 , R 31 and R 33 , which may be the same or different, are as defined for R 8 ; X is O, S, N—CN or NH) or —NR 30 SO 2 R 31 (R 30 and R 31 , which may be the same or different, are as defined for R 8 );

R 5 is C1-C8 substituted alkyl, C2-C8 optionally substituted alkenyl, C2-C8 optionally substituted alkynyl, C3-C8 substituted cycloalkyl [As substituents of C3-C8 cycloalkyl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , —CHO, -G-R 34 {G is a bond, —C(═O)— or —O—C(═O)—; R 34 is as defined for R 15 }, —NR 35 C(═O)R 36 (R 35 is as defined for R 8 ; R 36 is as defined for R 12 ), —NR 35 C(═X)OR 37 R 35 and R 37 , which may be the same or different, are as defined for R 8 ; X is O, S, N—CN or NH), —NR 35 C(═X)NR 37 R 38 (R 35 , R 37 and R 38 , which may be the same or different, are as defined for R 8 ; X is O, S, N—CN or HH) and —NR 35 SO 2 R 37 (R 35 and R 37 , which may be the same or different, are as defined for R 8 )], unsubstituted heterocyclyl, substituted heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , —CHO, -G-R 39 {G is a bond, —C(═O)— or —O—C(═O)—; R 39 is as defined for R 15 }, —NR 40 C(═O)R 41 (R 40 is as defined for R 8 ; R 41 is as defined for R 12 ), —NR 40 C(═X)OR 42 (R 40 and R 42 , which may be the same or different, are as defined for R 8 ; X is O, S, N—CN or NH), —NR 40 C(═X)NR 42 R 43 (R 40 , R 42 and R 43 , which may be the same or different, are as defined for R 8; X is O, S, N—CN or NH) and —NR 40 SO 2 R 42 (R 40 and R 42 , which may be the same or different, are as defined for R 8 )], optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkenyl, optionally substituted heterocyclylalkenyl, optionally substituted arylalkynyl, optionally substituted heterocyclylalkynyl or —NR 44 R 45 (R 44 and R 45 , which may be the same or different, are C1-C8 optionally substituted alkyl; R 44 and R 45 together may be taken together with the nitrogen to which they are attached to form a mono heterocycle with 5-7 members and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, the said mono heterocycle may optionally be substituted with one or more substituents);

R 6 is hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl;

with the provisos:

that R 1 , R 2 and R 4 are not all H;

that R 4 is not pentafluorophenyl;

that R 5 is not a group represented as the following (a):

(a) C1-C6 alkyl or C3-C6 cycloalkyl, in which an alkyl group or a cycloalkyl group optionally may be substituted by phenyl or by one or more fluoro substituents;

and pharmaceutically acceptable salts, and other pharmaceutically acceptable biohydrolyzable derivatives thereof, including esters, amides, carbamates, carbonates, ureides, solvates, hydrates, affinity reagents or prodrugs thereof.

For the purposes of this invention, alkyl relates to both straight chain or branched alkyl radicals of 1 to 8 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 2-methylpentyl, 4-methylpentyl, 1-ethylbutyl, n-hexyl, n-heptyl, 2-methylhexyl, 5-methylhexyl, 1,1-dimethylpentyl, 6-methylheptyl and n-octyl.

The term “cycloalkyl” means a cycloalkyl radical of 3 to 8 carbon atoms including but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term “alkenyl” means a straight chain, branched or ring structured alkenyl radical of 2 to 8 carbon atoms and containing one or more carbon-carbon double bonds and includes, but is not limited to, vinyl, allyl, isopropenyl, 1-propenyl, 2-butenyl, 1-butenyl, 2-methyl-1-propenyl, 2-methyl-3-pentenyl, 1-pentenyl, 2-pentenyl, 4-methyl-1-pentenyl, 1-hexenyl, 2-hexenyl, 2-cyclopentenyl, 2-cyclohexenyl, 2-heptenyl, 2-octenyl, 3-cyclopentenyl, 1,3-butadienyl and 1,5-hexadienyl. When they have cis and trans geometrical isomers, both isomers are included.

The term “alkynyl” means a straight chain or branched alkynyl radical of 2 to 8 carbon atoms and containing one or more carbon-carbon triple bonds and includes, but is not limited to, ethynyl, 2-propynyl, 1-propynyl, 1-butynyl, 2-butynyl, 3-hexynyl, 3-methyl-1-butynyl, 3,3-dimethyl-1-butynyl, 3-pentynyl, 2-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 1-methyl-3-pentynyl, 1-methyl-3-hexynyl, 2-heptynyl and 2-octynyl.

“Aryl” means an aromatic 6-10 membered hydrocarbon containing one ring or being fused to one or more saturated or unsaturated rings including, but not limited to, phenyl, naphthyl, anthracenyl, 5-indanyl and 5,6,7,8-tetrahydro-2-naphthyl.

“Heteroaryl” means an aromatic 5-10 membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O or S and containing one ring or being fused to one or more saturated or unsaturated rings. Examples of heteroaryl include, but are not limited to, monovalent group including furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, triazole, thiadiazole, oxadiazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, benzofuran, dibenzofuran, benzothiophene, indole, benzimidazole, benzothiazole, benzoxazole, quinoline, isoquinoline, quinazoline, quinoxaline, purine, pteridine, phenoxazine and phenozine.

“Saturated heterocyclyl” means a 3-10 membered saturated ring containing 1 to 4 heteroatoms selected from N, O or S and containing one ring or being fused to one or more saturated rings; the saturated heterocyclyl is fully saturated. Examples of saturated heterocyclyl include, but are not limited to, monovalent group including piperidine, piperazine, morpholine, pyrrolidine, imidazolidine, pyrazolidine and quinuclidine.

“Heterocyclyl” means a 3-10 membered ring system containing 1 to 4 heteroatoms selected from N, O or S. The heterocyclyl system can contain one ring or may be fused to one or more saturated or unsaturated rings; the heterocyclyl can be fully saturated, partially saturated or unsaturated and includes, but is not limited to, heteroaryl and saturated heterocyclyl; the heterocyclyl can contain one or two —(C═O)— or —(C═S)— groups. Examples of heterocyclyl include, but are not limited to, monovalent group including furan, thiophene, pyrrole, pyrroline, pyrrolidine, oxazole, oxazolidine, isoxazolidine, thiazole, thiazolidine, isothiazole, isothiazolidine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, triazole, thiadiazole, oxadiazole, tetrazole, pyran, tetrahydropyran, thiopyran, tetrahydrothiopyran, pyridine, pyrazine, pyrimidine, pyridazine, benzofuran, dibenzofuran, benzothiophene, indole, benzimidazole, benzothiazole, benzoxazole, chromane, isochromane, quinoline, decahydroquinoline, isoquinoline, quinazoline, quinoxaline, purine, pteridine, azetidine, morpholine, thiomorpholine, piperidine, homopiperidine, piperazine, homopiperazine, indoline, isoindoline, phenoxazine, phenazine, phenothiazine, quinuclidine, acridine, carbazole, cinnoline, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, indolizine, indazole, isoindole, isoxazole, napthyridine, oxathiazole, oxathiazolidine, oxazine, oxadiazine, phthalazine, quinolizine, tetrahydrofuran, tetrazine, thiadiazine, thiatriazole, thiazine, thianaphthalene, triazine, 1,3-dioxane, 2,5-dihydrofuran, oxazoline, trithiane, piperidin-2-one, 3H-isobenzofuran-1-one, epsilon-caprolactam, 2-furanone, 2-pyrrolidone, tetrahydro-3H-pyrazol-3-one, piperazin-2-one, coumarin, tetrahydro-2-pyrimidinone, glutarimide and morpholine-3,5-dione.

“Arylalkyl” used herein is a group comprising a combination of the aryl and the alkyl. Examples thereof include, but are not limited to, benzyl, phenethyl, (2-naphthyl)-methyl, 3-phenylpropyl, 4-phenylbutyl and 5-(1-naphthyl) pentyl.

“Heterocyclylalkyl” is a group comprising a combination of the heterocyclyl and the alkyl. Examples thereof include, but are not limited to, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 3-furilmethyl, 2-(3-indolyl)ethyl, 2-morpholinoethyl, 2-piperidinoethyl, 2-(4-pyridyl)-ethyl, 3-(1-piperadinyl)-propyl, 3-(2-thienyl)-propyl, and 2-(1-imidazole)ethyl.

“Arylalkenyl” is a group comprising a combination of the aryl and the alkenyl. Examples thereof include, but are not limited to, styryl, cinnamyl and 4-phenyl-2-butenyl. When they have cis and trans geometrical isomers, both isomers are included.

“Heterocyclylalkenyl” used herein is a group comprising a combination of the heterocyclyl and the alkenyl. Examples thereof include, but are not limited to, (3-pyridyl)vinyl, 3-(3-thienyl)propene-2-yl, 3-(4-morpholinyl)-1-propenyl and 4-(1-piperidyl)-2-butenyl. When they have cis and trans geometrical isomers, both isomers are included.

“Arylalkynyl” used herein is a group comprising a combination of the aryl and the alkynyl. Examples thereof include, but are not limited to, phenylethynyl and 4-phenyl-2-butynyl.

“Heterocyclylalkynyl” used herein is a group comprising a combination of the heterocyclyl and the alkynyl. Examples thereof include, but are not limited to, 4-(4pyridyl)-2-butynyl and 5-(1-piperazinyl)-2-pentynyl.

Halogen means F, Cl, Br or I.

Suitable substituents include F, Cl, Br, I, —CN, —NO 2 , —CHO, -G-R 46 {G is a bond, —C(═O)—, or —O—C(═O)—; R 46 is optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C14 aryl, optionally substituted heterocyclyl, —OR 47 or —NR 47 R 48 }, —NR 47 C(═O)R 48 , —NR 47 C(═O)OR 48 , —NR 47 C(═O)NR 48 R 49 , —NR 47 SO 2 R 48 , —S(O) m R 47 , —NR 47 SO 2 R 48 or —SO 2 NR 47 R 48 ; wherein optionally substituted C1-C8 alkyl means C1-C8 alkyl which may be optionally substituted with one or more F, Cl, Br, I, —CN, —NO 2 , —CHO, heterocyclyl, —OR 47 , —NR 47 R 48 , —NR 47 C(═O)R 48 , —COOR 47 , —CONR 47 R 48 and —S(O) m R 47 ;

wherein optionally substituted C2-C8 alkenyl means C2-C8 alkenyl which may be optionally substituted with one or more F, Cl, Br, I, —CN, —NO 2 , —CHO, heterocyclyl, —OR 50 , —NR 50 R 51 , —NR 50 C(═O)R 51 , —COOR 50 , —CONR 50 R 51 and —S(O) m R 50 ;

wherein optionally substituted C2-C8 alkynyl means C2-C8 alkynyl which may be optionally substituted with one or more F, Cl, Br, I, —CN, —NO 2 , —CHO, heterocyclyl, —OR 50 , —NR 50 R 51 , —NR 50 C(═O)R 51 , —COOR 50 , —CONR 50 R 51 and —S(O) m R 50 ;

wherein optionally substituted C3-C8 cycloalkyl means C3-C8 cycloalkyl which may be optionally substituted with one or more F, Cl, Br, I, —CN, —NO 2 , —CHO, heterocyclyl, —OR 50 , —NR 50 R 51 , —NR 50 C(═O)R 51 , —COOR 50 , —CONR 50 R 51 and —S(O) m R 50 ;

wherein optionally substituted C6-C14 aryl means C6-C14 aryl which may be optionally substituted with one or more F, Cl, Br, I, —CN, —NO 2 , —CHO, heterocyclyl, —OR 50 , —NR 50 R 51 , —NR 50 C(═O)R 51 , —COOR 50 , —CONR 50 R 51 and —S(O) m R 50 ;

wherein optionally substituted heterocyclyl means heterocyclyl which may be optionally substituted with one or more F, Cl, Br, I, —CN, —NO 2 , —CHO, heterocyclyl, —OR 50 , —NR 50 R 51 , —NR 50 C(═O)R 51 , —COOR 50 , —CONR 50 R 51 and —S(O) m R 50 ;

R 47 , R 48 , R 49 , R 50 and R 51 , which may be the same or different, are hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, heterocyclyl, arylalkyl or heterocyclylalkyl; m=0, 1 or 2.

R 1 is preferably hydrogen or C1-C6 optionally substituted alkyl. More preferably R 1 is hydrogen.

R 2 is preferably selected from hydrogen, halogen, —CN, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, —OR 8 (R 8 is hydrogen or C1-C8 optionally substituted alkyl), —NR 9 R 10 (R 9 and R 10 , which may be the same or different, hydrogen or C1-C8 optionally substituted alkyl), —C(═O)NR 9 R 10 (R 9 and R 10 , which may be the same or different, are hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl), —NR 9 C(═O)R 12 (R 9 is hydrogen or C1-C8 optionally substituted alkyl; R 12 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl), —NR 9 C(═O)OR 13 (R 9 is hydrogen or C1-C8 optionally substituted alkyl; R 13 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl), —NR 9 C(═O)NR 13 R 14 (R 9 and R 13 , which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl; R 14 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl), —NR 9 SO 2 R 13 (R 9 is hydrogen or C1-C8 optionally substituted alkyl; R 13 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl), —SR 9 (R 9 is hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl) or —SO 2 R 9 (R 9 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl).

More preferably R 2 is hydrogen, halogen, —CN or —SCH 3 . Still more preferably R 2 is hydrogen;

R 3 is preferably selected from C6-C14 substituted aryl [As substituents of C6-C14 aryl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , -G-R 15 {G is a bond or —C(═O)—; R 15 is C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkenyl, C2-C8 optionally substituted alkynyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, —OR 16 (R 16 is hydrogen, C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl) or —NR 17 R 18 (R 17 and R 18 , which may be the same or different, are hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl)}, —NR 17 C(═O)R 19 (R 17 is hydrogen or C1-C8 optionally substituted alkyl; R 19 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl) and —S(O) m R 17 (R 17 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl; m is 0 or 2)], unsubstituted heterocyclyl, substituted heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , -G-R 23 {G is a bond or —C(═O)—; R 23 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, —OR 16 (R 16 is hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl) or —NR 17 R 18 (R 17 and R 18 , which may be the same or different, are hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl)}, —NR 24 C(═O)R 25 (R 24 is hydrogen or C1-C8 optionally substituted alkyl; R 25 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl) and —S(O) m R 24 (R 24 is C1-C8 optionally substituted alkyl or C3-C8 optionally substituted cycloalkyl; m is 0 or 2)].

More preferably R 3 is substituted phenyl [As substituents of phenyl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkynyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, —OR 16 (R 16 is hydrogen, C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl), —NR 17 R 18 (R 17 and R 18 , which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl) and —C(═O)NR 17 R 18 (R 17 and R 18 , which may be the same or different, are hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl)], unsubstituted bicyclic heteroaryl, substituted bicyclic heteroaryl [As substituents of bicyclic heteroaryl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , C1-C8 optionally substituted alkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, —OR 16 (R 16 is hydrogen, C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl), —NR 17 R 18 (R 17 and R 18 , which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl), —NHC(═O)R 19 (R 19 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl) and —SR 17 (R 17 is C1-C8 optionally substituted alkyl)].

R 4 is preferably selected from hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, optionally substituted aryl. More preferably R 4 is hydrogen, methyl or ethyl.

R 5 is preferably selected from C3-C8 substituted cycloalkyl [As substituents of C3-C8 cycloalkyl may be mentioned one or more selected from the group consisting of halogen, —CN, C1-C8 optionally substituted alkyl, —OR 30 (R 30 is hydrogen or C1-C8 optionally substituted alkyl), —NR 30 R 31 (R 30 and R 31 , which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl) and —NHC(═O)R 32 (R 32 is C1-C8 optionally substituted alkyl, C3-C8 substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl)], unsubstituted heterocyclyl, substituted heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, —CN, C1-C8 optionally substituted alkyl, —OR 16 (R 16 is hydrogen or C1-C8 optionally substituted alkyl), —NR 17 R 18 (R 17 and R 18 , which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl) and —NHC(═O)R 41 (R 41 is C1-C8 optionally substituted alkyl, C3-C8 substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl)].

More preferably R 5 is preferably selected from cyclohexyl [As substituents of cyclohexyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl —OH and —NH 2 ], unsubstituted saturated heterocyclyl or substituted saturated heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl —OH and —NH 2 ].

Still more preferably R 5 is 4-amino-cyclohexyl, piperidin-3-yl, piperidin-4-yl or pyrrolidin-3-yl.

R 6 is preferably selected from hydrogen and C1-C8 optionally substituted alkyl. More preferably R 6 is hydrogen.

As preferred combinations of the groups mentioned as preferred examples of R 1 -R 6 in formula I according to the invention, there may be mentioned the following combinations 1) to 10).

1) In formula I, wherein R 1 is hydrogen, R 2 is hydrogen, R 3 is C6-C14 aryl group substituted by C6-C14 optionally substituted aryl or optionally substituted heterocyclyl [wherein C6-C14 aryl group as R 3 may be substituted by one or more substituents selected from the group consisting of halogen, —CN, —NO 2 , C1-C8 optionally substituted alkyl, —OR 16 (R 16 is hydrogen, C1-C8 optionally substituted alkyl), —NR 17 R 18 (R 17 and R 18 , which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl)], R 4 is C1-C8 optionally substituted alkyl, R 5 is cyclohexyl [As substituents of cyclohexyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ], unsubstituted saturated heterocyclyl or substituted saturated heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ] and R6 is hydrogen.

2) In formula I, wherein R 1 is hydrogen, R 2 is hydrogen, R 3 is C6-C14 aryl group substituted by —OR 16 (R 16 is C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl) [wherein C6-C14 aryl group as R 3 may be substituted by one or more substituents selected from the group consisting of halogen, —CN, —NO 2 , C1-C8 optionally substituted alkyl, —OR 16 (R 16 is hydrogen, C1-C8 optionally substituted alkyl), —NR 17 R 18 (R 17 and R 18 , which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl)], R 4 is C1-C8 optionally substituted alkyl, R 5 is cyclohexyl [As substituents of cyclohexyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ], unsubstituted saturated heterocyclyl or substituted saturated heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ] and R6 is hydrogen.

3) In formula I, wherein R 1 is hydrogen, R 2 is hydrogen, R 3 is C6-C14 aryl group substituted by -G-R 15 {G is —(CO)—; R 15 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, —OR 16 (R 16 is hydrogen, C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl) or —NR 17 R 18 (R 17 and R 18 , which may be the same or different, are hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl)} [wherein C6-C14 aryl group as R 3 may be substituted by one or more substituents selected from the group consisting of halogen, —CN, —NO 2 , C1-C8 optionally substituted alkyl, —OR 16 (R 16 is hydrogen, C1-C8 optionally substituted alkyl), —NR 17 R 18 (R 17 and R 18 , which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl)], R 4 is C1-C8 optionally substituted alkyl, R 5 is cyclohexyl [As substituents of cyclohexyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ], unsubstituted saturated heterocyclyl or substituted saturated heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ] and R6 is hydrogen.

4) In formula I, wherein R 1 is hydrogen, R 2 is hydrogen, R 3 is unsubstituted bicyclic heteroaryl or substituted bicyclic heteroaryl [As substituents of bicyclic heteroaryl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , C1-C8 optionally substituted allyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, —OR 16 (R 16 is hydrogen, C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl), —NR 17 R 18 (R 17 and R 18 , which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl), —NH(CO)R 19 (R 19 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl) and —SR 17 (R 17 is C1-C8 optionally substituted alkyl)], R 4 is C1-C8 optionally substituted alkyl, R 5 is cyclohexyl [As substituents of cyclohexyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ], unsubstituted saturated heterocyclyl or substituted saturated heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ] and R6 is hydrogen.

5) In formula I, wherein R 1 is hydrogen, R 2 is F, R 3 is C6-C14 aryl group substituted by C6-C14 optionally substituted aryl or optionally substituted heterocyclyl [wherein C6-C14 aryl group as R 3 may be substituted by one or more substituents selected from the group consisting of halogen, —CN, —NO 2 , C1-C8 optionally substituted alkyl, —OR 16 (R 16 is hydrogen, C1-C8 optionally substituted alkyl), —NR 17 R 18 (R 17 and R 18 , which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl)], R 4 is hydrogen, R 5 is cyclohexyl [As substituents of cyclohexyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ], unsubstituted saturated heterocyclyl or substituted saturated heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ] and R6 is hydrogen.

6) In formula I, wherein R 1 is hydrogen, R 2 is F, R 3 is C6-C14 aryl group substituted by —OR 16 (R 16 is C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl) [wherein C6-C14 aryl group as R 3 may be substituted by one or more substituents selected from the group consisting of halogen, —CN, —NO 2 , C1-C8 optionally substituted alkyl, —OR 16 (R 16 is hydrogen, C1-C8 optionally substituted alkyl), —NR 17 R 18 (R 17 and R 18 , which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl)], R 4 is hydrogen, R 5 is cyclohexyl [As substituents of cyclohexyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ], unsubstituted saturated heterocyclyl or substituted saturated heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ] and R6 is hydrogen.

7) In formula I, wherein R 1 is hydrogen, R 2 is F, R 3 is C6-C14 aryl group substituted by -G-R 15 {G is —(CO)—; R 15 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, —OR 16 (R 16 is hydrogen, C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl) or —NR 17 R 18 (R 17 and R 18 , which may be the same or different, are hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl)} [wherein C6-C14 aryl group as R 3 may be substituted by one or more substituents selected from the group consisting of halogen, —CN, —NO 2 , C1-C8 optionally substituted alkyl, —OR 16 (R 16 is hydrogen, C1-C8 optionally substituted alkyl), —NR 17 R 18 (R 17 and R 18 , which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl)], R 4 is hydrogen, R 5 is cyclohexyl [As substituents of cyclohexyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ], unsubstituted saturated heterocyclyl or substituted saturated heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ] and R6 is hydrogen.

8) In formula I wherein R 1 is hydrogen, R 2 is F, R 3 is unsubstituted bicyclic heteroaryl or substituted bicyclic heteroaryl [As substituents of bicyclic heteroaryl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO 2 , C1-C8 optionally substituted alkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, —OR 16 (R 16 is hydrogen, C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl), —NR 17 R 18 (R 17 and R 18 , which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl), —NH(CO)R 19 (R 19 is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl) and —SR 17 (R 17 is C1-C8 optionally substituted alkyl)], R 4 is hydrogen, R 5 is cyclohexyl [As substituents of cyclohexyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ], unsubstituted saturated heterocyclyl or substituted saturated heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ] and R6 is hydrogen.

9) In formula I, wherein R 1 is hydrogen, R 2 is halogen, —CN or —SCH 3 , R 3 is C6-C14 optionally substituted aryl, optionally substituted bicyclic heteroaryl, R 4 is hydrogen, R 5 is cyclohexyl [As substituents of cyclohexyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ], unsubstituted saturated heterocyclyl or substituted saturated heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ] and R6 is hydrogen.

10) In formula I, wherein R 1 is hydrogen, R 2 is halogen or —CN, R 3 is C6-C14 optionally substituted aryl, optionally substituted bicyclic heteroaryl, R 4 is C1-C8 optionally substituted alkyl, R 5 is cyclohexyl [As substituents of cyclohexyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ], unsubstituted saturated heterocyclyl or substituted saturated heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, C1-C8 optionally substituted alkyl, —OH and —NH 2 ] and R6 is hydrogen.

The compounds of the first aspect may be provided as a salt, preferably as a pharmaceutically acceptable salt of the compounds of formula I. Examples of pharmaceutically acceptable salts of these compounds include those derived from organic acids such as acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, methanesulphonic acid, benzenesulphonic acid, trifluoroacetic acid and p-toluenesulphonic acid, mineral acids such as hydrochloric and sulphuric acid and the like, giving methanesulphonate, benzenesulphonate, p-toluenesulphonate, hydrochloride and sulphate, and the like, respectively or those derived from bases such as organic and inorganic bases. Examples of suitable inorganic bases for the formation of salts of compounds for this invention include the hydroxides, carbonates, and bicarbonates of ammonia, lithium, sodium, calcium, potassium, aluminium, iron, magnesium, zinc and the like. Salts can also be formed with suitable organic bases. Such bases suitable for the formation of pharmaceutically acceptable base addition salts with compounds of the present invention include organic bases which are non-toxic and strong enough to form salts. Such organic bases are already well known in the art and may include amino acids such as arginine and lysine, mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and trimethylamine, guanidine; N-methylglucosamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; tris(hydroxymethyl) aminomethane; and the like.

Salts may be prepared in a conventional manner using methods well known in the art. Acid addition salts of said basic compounds may be prepared by dissolving the free base compounds of the invention in aqueous or aqueous alcohol solution or other suitable solvents containing the required acid. Where a compound of the invention contains an acidic function, a base salt of said compound may be prepared by reacting said compound with a suitable base. The acid or base salt may separate directly or can be obtained by concentrating the solution e.g. by evaporation. The compounds of this invention may also exist in solvated or hydrated forms.

The invention also extends to a prodrug of the aforementioned compounds such as an ester or amide thereof. A prodrug is any compound that may be converted under physiological conditions or by solvolysis to any of the compounds of the invention or to a pharmaceutically acceptable salt of the compounds of the invention. A prodrug may be inactive when administered to a subject but is converted in vivo to an active compound of the invention.

The compounds of the invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. The compounds of the invention may exist in trans or cis form. The first aspect of the invention covers all of these compounds.

As specific examples of compounds of the formula I above there may be mentioned compounds listed in Table A below.

Wherein “Me”, “Et”, “n-Pr”, “i-Pr”, “n-Bu”, “t-Bu” and “Ph” mean “methyl group”, “ethyl group”, “n-propyl group”, “isopropyl group”; “n-butyl group”, “tert-butyl group” and “phenyl group” respectively.

In a second aspect, the present invention provides a compound of formula II-26, III-01 and IV which are useful as synthetic intermediates for a compound of formula I:

1) A compound of the formula II-26

wherein R 1 -R 6 are as defined for formula I above; R 45 is C1-C8 optionally substituted alkyl or optionally substituted arylalkyl;

with the provisos:

that R 1 , R 2 and R 4 are not all H;

R 45 is preferably tert-butyl or benzyl.

2) A compound of the formula III-01

wherein R 1 -R 6 are as defined for formula I above; R 45 is C1-C8 optionally substituted alkyl or optionally substituted arylalkyl;

with the provisos:

that R 1 , R 2 and R 4 are not all H;

R 45 is preferably tert-butyl or benzyl.

3) A compound of the formula IV

wherein R 1 -R 6 are as defined for formula I above;

with the provisos:

that R 1 , R 2 and R 4 are not all H;

that R 4 is not optionally substituted aryl or optionally substituted heteroaryl.

The pyrazolo[1,5-a]pyrimidine derivatives represented by formula I above exist as tautomers represented by the following formula X and XI:

wherein R 1 -R 6 are as defined for formula I above;

wherein R 1 -R 6 are as defined for formula I above;

These tautomers are also encompassed within the scope of the present invention.

In a third aspect, the present invention provides a process for the manufacture of a compound of the invention by reaction of a compound of formula II, III, IV, V, VI, VII, V-01, IV-01, II-01, II-03, II-04, II-06, II-08, II-13, II-15, II-18, II-20, II-22, II24, I-26, I-28 or V-04 as follows, wherein R 1 -R 6 are as defined above:

1) reacting a compound of the formula II

with acid e.g. trifluoroacetic acid for removal of t-butoxycarbonyl groups of a compound (for example as described in Protective Groups in Organic Synthesis, 3rd Ed, John Wiley & Sons Inc)

2) reacting a compound of the formula III

with a compound of the formula R 5 R 6 NH either in the absence or presence of transition metal catalyst under e.g. Buchwald conditions (for example as described in J. Am. Chem. Soc. 1994, 116, 7901.)

3) reacting a compound of the formula IV

with a compound of the formula R 5 R 6 NH

4) reacting a compound of the formula IV

with a compound of the formula di t-butyl dicarbonate (for example as described in Protective Groups in Organic Synthesis, 3rd Ed, John Wiley & Sons Inc)

5) reacting a compound of the formula V

with a compound of the formula R 3 NH 2 or R 3 NHAc in the presence of base e.g. triethylamine and sodium hydride

6) reacting a compound of the formula VI

with a halogenating agent e.g. phosphorus oxychloride or phenyl phosphonic dichloride (for example as described in U.S. Pat. No. 3,907,799 (CA 1975, 84, 4998p), J. Med. Chem. 1977, 20, 296, Montash Chem. 1986, 117, 1305.)

7) reacting a compound of the formula VII

with a compound of the formula R 4 CH(CO 2 Me) 2 or R 4 CH(CO 2 Et) 2 (for example as described in J. Med. Chem 1976, 19, 296 and J. Med. Chem. 1977, 20, 296.)

8) reacting a compound of the formula V-01

with a halogenating agent e.g. N-chlorosuccinimide, N-bromosuccinimide (for example as described in J. Med. Chem. 1976, 19, 517.) or iodine monochloride

9) reacting a compound of the formula V-01

with a thiocyanating agent e.g. combination of potassium thiocyanate and bromine

10) reacting a compound of the formula V-01

with an acylating agent e.g. dimethyl formamide/phosphorus oxychloride or acetyl chloride/aluminium trichloride

11) reacting a compound of the formula IV-01

with a Grignard reagent e.g. methyl magnesium chloride

12) reacting a compound of the formula II-01

with an acylating agent e.g. trifluoroacetic anhydride

13) reacting a compound of the formula II-01

with fluorinating agent e.g. 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (J. Chem. Soc. Perkin 1, 1996, 2069.)

14) reacting a compound of the formula II-03

with aqueous sodium hydroxide for the hydrolysis of ester group in compound; R 67 is methyl or ethyl

15) reacting a compound of the formula II-04

with amine derivatives in the presence of peptide coupling agent e.g. ethyl-3-(3′-dimethylaminopropyl) carbodiimide hydrochloride, N-hydoroxybenzotriazole monohydrate and triethylamine

16) reacting a compound of the formula II-06

with oxidizing agent e.g. iodosobenzene diacetate for Hofmann rearrangement in the presence of benzyl alcohol (for example as described in J. Org. Chem. 1979, 44, 1746 and Synthesis 1981, 266.), followed by removal of the benzyloxy carbonyl group by hydrogenolysis in the presence of palladium on carbon (for example as described in Protective Groups in Organic Synthesis, 3rd Ed, John Wiley & Sons Inc)

17) reacting a compound of the formula II-08

with a compound of the formula R 12 COCl, R 12 COOH, R 10 SO 2 Cl, R 10 NCO or R 10 NCS

18) reacting a compound of the formula II-13

with alcohol derivatives in the presence of e.g. diisopropyl azodicarboxylate and polymer supported triphenylphosphine under e.g. Mitsunobu conditions (for example as described in Synthesis 1981, 1.); Ar 1 represents C6-C14 optionally substituted aryl or optionally substituted heteroaryl

19) reacting a compound of the formula II-15

with boronic acid derivatives in the presence of transition metal catalyst under e.g. Suzuki coupling conditions (for example as described in Chem. Rev. 1995, 95, 2457.); Ar 1 represents C6-C14 optionally substituted aryl or optionally substituted heteroaryl

20) reacting a compound of the formula II-15

with a 1-alkyne in the presence of transition metal catalyst under Sonogashira coupling conditions (Synthesis 1980, 627, and Comprehensive Organic Synthesis, Vol. 3, p. 521, 1991.); Ar 1 represents C6-C14 optionally substituted aryl or optionally substituted heteroaryl

21) reacting a compound of the formula II-18

with a compound of the formula R 16 R 17 NH in the presence of peptide coupling agent; Ar 1 represents C6-C14 optionally substituted aryl or optionally substituted heteroaryl

22) reacting a compound of the formula II-20

with an alkyl lithium e.g. n-butyl lithium under Weinreb conditions (for example as described in Tetrahedron Lett. 1981, 22, 3815.)

23) reacting a compound of the formula II-22

with alkyl halide e.g. methyl iodide in the presence of base, followed by trifluoroacetic acid and sodium hydroxide, respectively, for removal of t-butoxycarbonyl and trifluoroacetyl group from a compound

24) reacting a compound of the formula II-08

with an aldehyde e.g. benzyl aldehyde in the presence of reducing agent e.g. sodium acetoxyborohydride

25) reacting a compound of the formula II-24

with alkyl halide e.g. methyl iodide in the presence of base e.g. sodium hydride

26) reacting a compound of the formula I-26

with H 2 in the presence of Pd(OH) 2 —C or alpha-chloroethyl chloroformate followed by methanol for removal of R 60 group from a compound (for example as described in Protective Groups in Organic Synthesis, 3rd Ed, John Wiley & Sons Inc); R 60 is benzyl or p-MeO-benzyl; n is 1, 2 or 3

27) reacting a compound of the formula I-28

with halogenating agent e.g. iodine monochloride

28) reacting a compound of the formula V-04

with reducing agent e.g. sodium borohydride or with diol derivative e.g. propane 1,3-diol and ethane 1,2-diol for formation of acetal.

A compound of formula I may undergo one or more further reactions to provide a different compound of formula I. For example, a compound may undergo a reduction, oxidation, elimination, substitution and/or addition reaction.

FIG. 2-8 shows a general reaction scheme for the preparation of compounds of Formula I.

The compounds of formula V, VI, VII and VIII are either known or can be prepared by methods analogous to those known for preparing analogous known compounds.

Other methods will be apparent to the chemist skilled in the art, as will the methods for preparing starting materials and intermediates. The Examples also make apparent various methods of preparing compounds of the invention as well as starting materials and intermediates.

In a fourth aspect, the present invention provides a composition comprising a compound of the invention in combination with a pharmaceutically acceptable carrier, diluent or excipient.

The composition may also comprise one or more additional active agents, such as an anti-inflammatory agent (for example a p38 inhibitor, glutamate receptor antagonist, or a calcium channel antagonist), a chemotherapeutic agent and/or an antiproliferative agent.

Suitable carriers and/or diluents are well known in the art and include pharmaceutical grade starch, mannitol, lactose, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, (or other sugar), magnesium carbonate, gelatin, oil, alcohol, detergents, emulsifiers or water (preferably sterile). The composition may be a mixed preparation of a composition or may be a combined preparation for simultaneous, separate or sequential use (including administration).

The composition according to the invention for use in the aforementioned indications may be administered by any convenient method, for example by oral (including by inhalation), parenteral, mucosal (e.g. buccal, sublingual, nasal), rectal or transdermal administration and the compositions adapted accordingly.

For oral administration, the composition can be formulated as liquids or solids, for example solutions, syrups, suspensions or emulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solution of the compound or physiologically acceptable salt in a suitable aqueous or non-aqueous liquid carrier(s) for example water, ethanol, glycerine, polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and microcrystalline cellulose.

A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, powders, granules or pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

Compositions for oral administration may be designed to protect the active ingredient against degradation as it passes through the alimentary tract, for example by an outer coating of the formulation on a tablet or capsule.

Typical parenteral compositions consist of a solution or suspension of the compound or physiologically acceptable salt in a sterile aqueous or non-aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

Compositions for nasal or oral administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a pharmaceutically acceptable propellant. The aerosol dosage forms can also take the form of a pump-atomiser.

Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

Compositions for rectal or vaginal administration are conveniently in the form of suppositories (containing a conventional suppository base such as cocoa butter), pessaries, vaginal tabs, foams or enemas.

Compositions suitable for transdermal administration include ointments, gels, patches and injections including powder injections.

Conveniently the composition is in unit dose form such as a tablet, capsule or ampoule.

In a fifth aspect, the present invention provides a process for the manufacture of a composition according of the invention which comprises admixing one or more compounds of the invention with one more pharmaceutically acceptable excipients, carriers or diluents. The manufacture can be carried out by standard techniques well known in the art and involves combining a compound according to the first aspect of the invention and the pharmaceutically acceptable carrier or diluent. The composition may be in any form including a tablet, a liquid, a capsule, and a powder or in the form of a food product, e.g. a functional food. In the latter case the food product itself may act as the pharmaceutically acceptable carrier.

In a sixth aspect, the present invention provides a compound or composition of the invention, for use in medicine.

The compounds of the present invention are inhibitors of protein kinases such as mitogen-activated protein kinases, particularly mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2), or cyclin dependent kinases (CDK) e.g., CDK1 and CDK2. Preferably, the compounds of the invention inhibit MAPKAP-K2 or CDK selectively (i.e., the compounds of the present invention show greater activity against one kinase than the other). For the purpose of this invention, an inhibitor is any compound which reduces or prevents the activity of a protein kinase.

The compounds are therefore useful for conditions for which inhibition of protein kinase activity is beneficial. Thus, preferably, this aspect provides a compound of the first aspect, or a composition of the third aspect of the present invention, for the prevention or treatment of a protein kinase-mediated disorder. The compounds of the first aspect of the invention may thus be used for the inhibition of protein kinase.

A “protein kinase-mediated disorder” is any disease or deleterious condition in which protein kinase plays a role. Examples include neurological disorder (including dementia), inflammatory disease, a disorder linked to apoptosis, particularly neuronal apoptosis; stroke, sepsis, autoimmune disease, destructive bone disorder, proliferative disorder, cancer, tumour growth, infectious disease, allergy, ischemia reperfusion injury, heart attack, angiogenic disorder, organ hypoxia, vascular hyperplasia, cardiac hypertrophy and thrombin induced platelet aggregation.

The compounds of the present invention are particularly useful for the prevention or treatment of a neurodegenerative disorder. In particular, the neurodegenerative disorder results from apoptosis and/or inflammation. Examples of neurodegenerative disorders are: dementia; Alzheimer's disease; Parkinson's disease; Amyotrophic Lateral Sclerosis; Huntington's disease; senile chorea; Sydenham's chorea; hypoglycemia; head and spinal cord trauma including traumatic head injury; acute and chronic pain; epilepsy and seizures; olivopontocerebellar dementia; neuronal cell death; hypoxia-related neurodegeneration; acute hypoxia; glutamate toxicity including glutamate neurotoxicity; cerebral ischemia; dementia linked to meningitis and/or neurosis; cerebrovascular dementia; or dementia in an HIV-infected patient.

The compounds of the invention can also be used to prevent or treat disorders resulting from inflammation. These include, for example, inflammatory bowel disorder, bronchitis, asthma, acute pancreatitis, chronic pancreatitis, allergies of various types, and possibly Alzheimer's disease. Autoimmune diseases which may also be treated or prevented by the compounds of the present invention include rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, psoriatic arthritis, glomerulonephritis, scleroderma, chronic thyroiditis, Graves's disease, autoimmune gastritis, diabetes, autoimmune haemolytis anaemia, autoimmune neutropaenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, ulcerative colitis, Crohn's disease, psoriasis or graft vs host disease.

A compound of the present invention may be administered simultaneously, subsequently or sequentially with one or more other active agent, such as an anti-inflammatory agent e.g. p38 inhibitor, glutamate receptor antagonist, calcium channel antagonist, a chemotherapeutic agent or an antiproliferative agent. For example, for acute treatment, a p38 inhibitor may be administered to a patient prior to administering a compound of the present invention.

The compounds of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 2000 mg, preferably between 30 mg and 1000 mg, e.g. between 10 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the compound of the formula I, or a physiologically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.

In a seventh aspect, the present invention provides a method of treating or preventing a protein kinase-mediated disorder in an individual, which method comprises administering to said individual one or more compounds of the invention or a composition of the invention. The active compound is preferably administered in a cumulative effective amount. The individual may be in need of the treatment or prevention. Any of the protein kinase-mediated disorders listed above in relation to the fifth aspect may be the subject of treatment or prevention according to the sixth aspect. One or more other active agent may be administered to the individual simultaneously, subsequently or sequentially to administering the compound. The other active agent may be an anti-inflammatory agent such as a p38 inhibitor, glutamate receptor antagonist, calcium channel antagonist, a chemotherapeutic agent or an antiproliferative agent.

In an eighth aspect, the present invention provides the use of a compound of the invention in the manufacture of a medicament for the prevention or treatment of a protein kinase-mediated disorder. The medicament may be used for treatment or prevention of any of the protein kinase-mediated disorders listed above in relation to the fifth aspect. Again, the compounds of the present invention may be administered simultaneously, subsequently or sequentially with one or more other active agent such as a p38 inhibitor.

In a ninth aspect, the present invention provides an assay for determining the activity of the compounds of the present invention, comprising providing a system for assaying the activity and assaying the activity of the compound. Preferably the assay is for the protein kinase inhibiting activity of the compound. The compounds of the invention may be assayed in vitro, in vivo, in silico, or in a primary cell culture or a cell line. In vitro assays include assays that determine inhibition of the kinase activity of activated protein kinase. Alternatively, in vitro assays may quantitate the ability of a compound to bind protein kinase and may be measured either by radiolabelling the compound prior to binding, then isolating the inhibitor/protein kinase complex and determining the amount of the radiolabel bound or by running a competition experiment where new inhibitors are incubated with protein kinase bound to known radioligands. An example of an assay which may be used is Scintillation Proximity Assay (SPA), preferably using radiolabelled ATP. Another example is ELISA. Any type or isoform of protein kinase may be used in these assays.

In a tenth aspect, the present invention provides a method of inhibiting the activity or function of a protein kinase, which method comprises exposing a protein kinase to a compound or a composition of the invention. The method may be performed in a research model, in vitro, in silico, or in vivo such as in an animal model. A suitable animal model may be a kainic acid model in rat or mice, traumatic brain injury model in rat, or MPTP in mice for neurodegenerative disorder and a collagen induced arthritis model in rat or mice, type II collagen-antibodies induced arthritis in mice, or a LPS induced endotoxin shock model in mice for inflammatory disease.

All features of each of the aspects apply to all other aspects mutatis mutandis.

The invention will now be explained in greater detail by the following examples, with the understanding that the scope of the invention is not in any sense restricted by these examples. The numbers assigned to each of the compounds in the examples correspond to the Compound Nos. of the compounds listed as specific examples in Tables A above. Structures of isolated novel compounds were confirmed by 1 H NMR and/or other appropriate analyses.

Compounds were characterised by mass spectrometry using single quadrupole instrumentation with an electrospray source. M+H indicates values obtained for compound molecular mass (M) with proton (H) capture and M−H compound molecular mass (M) with proton (H) loss. Melting points (mp) are uncorrected; (d) denotes decomposition at or near the melting point. Compounds which were not solids were gums. The 1H-NMR spectra (400 MHz, DMSO-d6 or CDCl3) of selected compounds of the invention were measured. The data for the chemical shifts (d: ppm) and coupling constants (J: Hz) are shown. The “HPLC retention time” data for the compounds synthesized in the examples are the retention time for the compounds in HPLC analysis carried out under the following conditions.

HPLC (High Performance Liquid Chromatography) Conditions

System: Hewlett-Packard 1100 HPLC

Column: Cadenza CD-C18 (Imtakt) 100 mm×4.6 mmf

[Method A]

Solvent: A: H2O/acetonitrile=95/5

0.05% TFA (trifluoroacetic acid) B: H2O/acetonitrile=5/95 0.05% TFA (trifluoroacetic acid)

Flow rate: 1.0 mL/min

Gradient:

0-1 min, solvent B: 10% solvent A: 90%

1-13 min, solvent B: 10%→70% solvent A: 90%→30%

13-14 min, solvent B: 70%→100% solvent A: 30%→0%

14-16 min, solvent B: 100% solvent A: 0%

16-19 min, solvent B: 100%→10% solvent A: 0%→90%

Calculation of purity: Area % of UV absorption (254 nm)

[Method B]

Solvent: A: H2O/acetonitrile=95/5

0.05% TFA (trifluoroacetic acid) B: H2O/acetonitrile=5/95 0.05% TFA (trifluoroacetic acid)

Flow rate: 1.0 mL/min

Gradient:

0-1 min, solvent B: 5% solvent A: 95%

1-13 min, solvent B: 5%→55% solvent A: 95%→45%

13-14 min, solvent B; 55%→100% solvent A: 45%→0%

14-17 min, solvent B: 100% solvent A: 0%

17-18 min, solvent B: 100%→5% solvent A: 0%→95%

Calculation of purity: Area % of UV absorption (254 nm)

[Method C]

Solvent: A: H2O/acetonitrile=95/5

0.05% TFA (trifluoroacetic acid) B: H2O/acetonitrile=5/95 0.05% TFA (trifluoroacetic acid)

Flow rate: 1.5 mL/min

Gradient:

0-1 min, solvent B: 2% solvent A: 98%

1-9 min, solvent B: 2%→30% solvent A: 98%→70%

9-13 min, solvent B: 30%→100% solvent A: 70%→0%

13-16 min, solvent B: 100% solvent A: 0%

16-17.5min, solvent B: 100%→2% solvent A: 0%→98%

Calculation of purity: Area % of UV absorption (254 nm)

[Method D]

Solvent: A: H2O/acetonitrile=95/5

0.1% NEt3 (triethyl amine) B: H2O/acetonitrile=5/95 0.1% NEt3 (triethyl amine)

Flow rate: 1.5 mL/min

Gradient:

0-1 min, solvent B: 10% solvent A: 90%

1-14 min, solvent B: 10%→100% solvent A: 90%→0%

14-16 min, solvent B: 100% solvent A: 0%

16-17 min, solvent B: 100%→10% solvent A: 0%→90%

17-20min, solvent B: 10 solvent A: 90%

Calculation of purity: Area % of UV absorption (254 nm)

The Pyrazolo[1,5-a]pyrimidine derivatives represented by formula I and their pharmaceutically acceptable salts exhibit excellent kinase inhibiting activity (particularly MAPKAP-K2 inhibiting activity). Drugs comprising the compounds as effective ingredients are therefore expected to be useful as therapeutic or prophylactic agents for a protein kinase mediated disorder in which kinase is implicated, such as such as inflammatory disease, autoimmune disease, destructive bone disorder, cancer and/or tumour growth.