Pyrazolo[1,5-A] pyrimidine derivatives

FIELD OF THE INVENTION

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.

BACKGROUND ART

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.

DISCLOSURE OF THE INVENTION

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:

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wherein R¹is 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;

R²is hydrogen, halogen, —CN, —NO₂, —CHO, -G-R⁷[G is a bond, —C(═O)— or —O—C(═O)—; and R⁷is 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, —OR⁸(R⁸is 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), —NR⁹R¹⁰(R⁹is as defined for R⁸; R¹⁰is 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 —OCH₃), —R¹¹(R¹¹is 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 R⁷is C6-C14 optionally substituted aryl or optionally substituted heteroaryl, then G is not a bond], —NR⁹C(═O)R¹²(R⁹is as defined for R⁸; R¹²is 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), —NR⁹C(═X)OR¹³(R⁹and R¹³, which may be the same or different, are as defined for R⁸; X is O, S, N—CN or NH), —NR⁹C(═X)NR¹³R¹⁴(R⁹, R¹³and R¹⁴, which may be the same or different, are as defined for R⁸; X is O, S, N—CN or NH), —NR⁹SO₂R¹³(R⁹and R¹³, which may be the same or different, are as defined for R⁸), —SR⁹(R⁹is as defined for R⁸) or —S(O) _mR⁹(R⁹is as defined for R⁸; m is 1 or 2);

R³is 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, —NO₂, —CHO, -G-R¹⁵{G is a bond, —C(═O)— or —O—C(═O)—; R¹⁵is 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, —OR¹⁶(R¹⁶is as defined for R⁸) or —NR¹⁷R¹⁸(R¹⁷and R¹⁸, which may be the same or different, are as defined for R⁸)}, —NR¹⁷C(═O)R¹⁹(R¹⁷is as defined for R⁸; R¹⁹is as defined for R¹²), —NR¹⁷C(═X)OR¹⁸(R¹⁷and R¹⁸, which may be the same or different, are as defined for R⁸; X is O, S, N—CN or NH), —NR¹⁷C(═X)NR¹⁸R²⁰(R¹⁷, R¹⁸and R²⁰, which may be the same or different, are as defined for R⁸; X is O, S, N—CN or NH), —NR¹⁷SO₂R¹⁸(R¹⁷and R¹⁸, which may be the same or different, are as defined for R⁸), —S(O)_mR¹⁷(R¹⁷is as defined for R⁸; m is 0, 1 or 2) and —SO₂NR²¹R²²(R²¹and R²², which may be the same or different, are as defined for R⁸; R²¹and R²²together 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, —NO₂, —CHO, -G-R²³{G is a bond, —C(═O)— or —O—C(═O)—; R²³is as defined for R¹⁵}, —NR²⁴C(═O)R²⁵(R²⁴is as defined for R⁸; R²⁵is as defined for R¹²), —NR²⁴C(═X)OR²⁶(R²⁴and R²⁶, which may be the same or different, are as defined for R⁸; X is O, S, N—CN or NH), —NR²⁴C(═X)NR²⁶R²⁷(R²⁴, R²⁶and R²⁷, which may be the same or different, are as defined for R⁸; X is O, S, N—CN or NH), —NR²⁴SO₂R²⁶(wherein R²⁴and R²⁶, which may be the same or different, are as defined for R⁸), —S(O)_mR²⁴(R²⁴is as defined for R⁸; m is 0, 1 or 2) and —SO₂NR²⁸R²⁹(R²⁸and R²⁹, which may be the same or different, are as defined for R⁸; R²⁸and R²⁹together 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;

R⁴is 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, —OR³⁰(R³⁰is as defined for R⁸), —SR³⁰(R³⁰is as defined for R⁸), —NR³⁰R³¹(R³⁰and R³¹, which may be the same or different, are as defined for R⁸), —NR³⁰C(═O)R³²(R³⁰is as defined for R⁸; and R³²is as defined for R¹²), —NR³⁰C(═X)OR³¹(R³⁰and R³¹, which may be the same or different, are as defined R⁸; X is O, S, N—CN or NH), —NR³⁰C(═X)NR³¹R³³(R³⁰, R³¹and R³³, which may be the same or different, are as defined for R⁸; X is O, S, N—CN or NH) or —NR³⁰SO₂R³¹(R³⁰and R³¹, which may be the same or different, are as defined for R⁸);

R⁵is 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, —NO₂, —CHO, -G-R³⁴{G is a bond, —C(═O)— or —O—C(═O)—; R³⁴is as defined for R¹⁵}, —NR³⁵C(═O)R³⁶(R³⁵is as defined for R⁸; R³⁶is as defined for R¹²), —NR³⁵C(═X)OR³⁷(R³⁵and R³⁷, which may be the same or different, are as defined for R⁸; X is O, S, N—CN or NH ), —NR³⁵C(═X)NR³⁷R³⁸(R³⁵, R³⁷and R³⁸, which may be the same or different, are as defined for R⁸; X is O, S, N—CN or NH) and —NR³⁵SO₂R³⁷(R³⁵and R³⁷, which may be the same or different, are as defined for R⁸)], unsubstituted heterocyclyl, substituted heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO₂, —CHO, -G-R³⁹{G is a bond, —C(═O)— or, —O—C(═O)—; R³⁹is as defined for R¹⁵}, —NR⁴⁰C(═O)R⁴¹(R⁴⁰is as defined for R⁸; R⁴¹is as defined for R¹²), —NR⁴⁰C(═X)OR⁴²(R⁴⁰and R⁴², which may be the same or different, are as defined for R⁸; X is O, S, N—CN or NH), —NR⁴⁰C(═X)NR⁴²R⁴³(R⁴⁰, R⁴²and R⁴³, which may be the same or different, are as defined for R⁸; X is O, S, N—CN or NH) and —NR⁴⁰SO₂R⁴²(R⁴⁰and R⁴², which may be the same or different, are as defined for R⁸)], optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkenyl, optionally substituted heterocyclylalkenyl, optionally substituted arylalkynyl, optionally substituted heterocyclylalkynyl or —NR⁴⁴R⁴⁵(R⁴⁴and R⁴⁵, which may be the same or different, are C1-C8 optionally substituted alkyl; R⁴⁴and R⁴⁵together 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);

R⁶is 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 R¹, R²and R⁴are not all H;

that R⁴is not pentafluorophenyl;

that R⁵is 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:

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wherein R^1bis 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^2bis hydrogen, halogen, —CN, —NO₂, —CHO or -G-R⁵²{G is a bond, —C(═O)— or —O—C(═O)—; and R⁵²is 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, —OR⁵³(R⁵³is 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), —NR⁵⁴R⁵⁵, —NR⁵⁴C(═O)R⁵⁵, —SR⁵⁴, optionally substituted aryl or optionally substituted heteroaryl; provided that when R⁵²is optionally substituted aryl or optionally substituted heteroaryl then G is not a bond; wherein R⁵⁴and R⁵⁵, which may be the same or different, are as defined for R⁵³; or wherein R⁵⁴and R⁵⁵together form an optionally substituted ring that optionally contains one or more heteroatoms selected from N, O and S};

R^3bis 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^4bis 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, —OR⁵⁶, —SR⁵⁶, —NR⁵⁶R⁵⁷or —NR⁵⁶C(═O)R⁵⁷;

wherein R⁵⁶and R⁵⁷, which may be the same or different, are as defined for R⁵³; or

wherein R⁵⁶and R⁵⁷together form an optionally substituted ring which optionally contains one or more heteroatoms;

R^5bis 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^6bis 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^2band R^4bare not all H;

that R^4bis not pentafluorophenyl;

that R^5bis 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;

(3) The compound as (1) wherein R¹is hydrogen or C1-C8 optionally substituted alkyl.

(4) The compound as (1) wherein R¹is hydrogen.

(5) The compound as any one of (1), (3) or (4) wherein R²is —NO₂, —OC(═O)R⁷, —CO₂R⁸or —CONR⁹R¹⁰; wherein R⁷, R⁸, R⁹and R¹⁰are as defined in claim 1.

(6) The compound as any one of (1), (3) or (4) wherein R²is —NR⁹C(═O)R¹², —NR⁹C(═X)OR¹³, —NR⁹C(═X)NR¹³R¹⁴, —NR⁹SO₂R¹³, —SR⁹or —S(O)_mR⁹; wherein R⁹, R¹², R¹³, R¹⁴and X are as defined in claim 1; m is 1 or 2.

(7) The compound as any one of (1), (3) or (4) wherein R²is 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 R²is hydrogen, halogen, —CN or —SCH₃.

(9) The compound as any one of (1), (3) or (4) wherein R²is halogen.

(10) The compound as any one of (1), (3) or (4) wherein R²is F.

(11) The compound as any one of (1), (3) or (4) wherein R²is hydrogen.

(12) The compound as any one of (1), (3) to (11) wherein R³is 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 R³is C6-C14 substituted aryl.

(14) The compound as any one of (1), (3) to (11) wherein R³is C6-C14 substituted aryl {As substituents of C6-C14 aryl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO₂, -G-R¹⁵, —NR¹⁷C(═O)R¹⁹and —S(O)_mR¹⁷; wherein R¹⁵, R¹⁷, R¹⁹or 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 R³is C6-C14 substituted aryl [As substituents of C6-C14 aryl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO₂, -G-R¹⁵{G is a bond or —C(═O)—; R¹⁵is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, —OR¹⁶or —NR¹⁷R¹⁸}, —NR¹⁷C(═O)R¹⁹and S(O)_mR¹⁷; wherein R¹⁶, R¹⁷, R¹⁸or R¹⁹are as defined in claim 1; m is 0, 1 or 2.].

(16) The compound as any one of (1), (3) to (11) wherein R³is C6-C14 substituted aryl [As substituents of C6-C14 aryl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO₂, -G-R¹⁵{G is a bond; R¹⁵is C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, —OR¹⁶or —NR¹⁷R¹⁸}, —NR¹⁷C(═O)R¹⁹and S(O)_mR¹⁷; wherein R¹⁶, R¹⁷, R¹⁸or R¹⁹are as defined in claim 1; m is 0, 1 or 2.].

(17) The compound as any one of (1), (3) to (11) wherein R³is C6-C14 substituted aryl [As substituents of C6-C14 aryl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO₂, -G-R¹⁵{G is a bond or —C(═O)—; R¹⁵is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, —OR¹⁶or —NR¹⁷R¹⁸}, —NR¹⁷C(═O)R¹⁹and S(O)_mR¹⁷; wherein R¹⁶, R¹⁷, R¹⁸or R¹⁹are as defined in claim 1; m is 0, 1 or 2.].

(18) The compound as any one of (1), (3) to (11) wherein R³is C6-C14 substituted aryl [As substituents of C6-C14 aryl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO₂, -G-R¹⁵{G is a bond or —C(═O)—; R¹⁵is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, —OR¹⁶or —NR¹⁷R¹⁸}, —NR¹⁷C(═O)R¹⁹and S(O)_mR¹⁷; wherein R¹⁶, R¹⁷, R¹⁸or R¹⁹, 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 R³is C6-C14 substituted aryl [As substituents of C6-C14 aryl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO₂and -G-R¹⁵{G is —C(═O)—; R¹⁵is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, —OR¹⁶or —NR¹⁷R¹⁸}; wherein R¹⁶, R¹⁷or R¹⁸are as defined in claim 1.].

(20) The compound as any one of (1), (3) to (11) wherein R³is unsubstituted heterocyclyl.

(21) The compound as any one of (1), (3) to (11) wherein R³is substituted heterocyclyl.

(22) The compound as any one of (1), (3) to (11) wherein R³is substituted heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO₂, -G-R²³, —NR²⁴C(═O)R²⁵and —S(O)_mR²⁴; wherein R²³, R²⁴, R²⁵or 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 R³is unsubstituted bicyclic heteroaryl.

(24) The compound as any one of (1), (3) to (11) wherein R³is substituted bicyclic heteroaryl [As substituents of bicyclic heteroaryl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO₂, -G-R²³, —NR²⁴C(═O)R²⁵and —S(O)_mR²⁴; wherein R²³, R²⁴, R²⁵or 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 R⁴is halogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, —OR³⁰; wherein R³⁰is as defined in claim 1.

(26) The compound as any one of (1), (3) to (24) wherein R⁴is C1-C8 optionally substituted alkyl.

(27) The compound as any one of (1), (3) to (24) wherein R⁴is methyl.

(28) The compound as any one of (1), (3) to (24) wherein R⁴is hydrogen.

(29) The compound as any one of (1), (3) to (28) wherein R⁵is C3-C8 substituted cycloalkyl, unsubstituted heterocyclyl or substituted heterocyclyl.

(30) The compound as any one of (1), (3) to (28) wherein R⁵is 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 —NR¹⁷R¹⁸; wherein R¹⁷or R¹⁸is as defined in claim 1].

(31) The compound as any one of (1), (3) to (28) wherein R⁵is 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 —NR¹⁷R¹⁸; wherein R¹⁷or R¹⁸is as defined in claim 1].

(32) The compound as any one of (1), (3) to (28) wherein R⁵is 4-amino-cyclohexyl.

(33) The compound as any one of (1), (3) to (28) wherein R⁵is 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 —NR¹⁷R¹⁸; wherein R¹⁷or R¹⁸is as defined in claim 1]

(34) The compound as any one of (1), (3) to (28) wherein R⁵is 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 R⁵is 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 R⁵is 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 R⁶is hydrogen.

(38) The compound as any one of (1), (3) to (36) wherein R⁶is C1-C8 optionally substituted alkyl or optionally substituted arylalkyl.

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

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wherein R¹-R⁶are as defined in claim 1; R⁵⁸is C1-C8 optionally substituted alkyl or optionally substituted arylalkyl;

with the provisos:

that R¹, R²and R⁴are not all H.

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

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wherein R¹-R⁴are as defined in claim 1; R⁵⁸is C1-C8 optionally substituted alkyl or optionally substituted arylalkyl;

with the provisos:

that R¹, R²and R⁴are not all H.

(41) A compound of the formula IV:

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wherein R¹-R⁴are as defined in claim 1;

with the provisos:

that R¹, R²and R⁴are not all H;

that R⁴is not optionally substituted aryl or optionally substituted heteroaryl.

(42) The compound as any one of (39), (40) or (41) wherein R¹is hydrogen;

(43) The compound as any one of (39), (40) or (41) wherein R²is hydrogen, halogen, —CN, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, —OR⁸(R⁸is hydrogen or C1-C8 optionally substituted alkyl), —NR⁹R¹⁰(R⁹and R¹⁰, which may be the same or different, hydrogen or C1-C8 optionally substituted alkyl), —C(═O)NR⁹R¹⁰(R⁹and R¹⁰, 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), —NR⁹C(═O)R¹²(R⁹is hydrogen or C1-C8 optionally substituted alkyl; R¹²is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl), —NR⁹C(═O)OR¹³(R⁹is hydrogen or C1-C8 optionally substituted alkyl; R¹³is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl), —NR⁹C(═O)NR¹³R¹⁴(R⁹and R¹³, which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl; R¹⁴is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl), —NR⁹SO₂R¹³(R⁹is hydrogen or C1-C8 optionally substituted alkyl; R¹³is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl), —SR⁹(R⁹is hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl) or —SO₂R⁹(R⁹is 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 R³is substituted phenyl [As substituents of phenyl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO₂, C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkynyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, —OR¹⁶(R¹⁶is hydrogen, C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl), —NR¹⁷R¹⁸(R¹⁷and R¹⁸, which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl) and —C(═O)NR¹⁷R¹⁸(R¹⁷and R¹⁸, 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, —NO₂, C1-C8 optionally substituted alkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, —OR¹⁶(R¹⁶is hydrogen, C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl), —NR¹⁷R¹⁸(R¹⁷and R¹⁸, which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl), —NHC(═O)R¹⁹(R¹⁹is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl) and —SR¹⁷(R¹⁷is C1-C8 optionally substituted alkyl)].

(45) The compound as any one of (39), (40) or (41) wherein R⁴is hydrogen, methyl or ethyl.

(46) The compound as (39) wherein R⁵is 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 —NH₂], 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 —NH₂].

(47) The compound as (39) wherein R⁶is hydrogen.

(48) The compound as any one of (39), (40) or (41) wherein R⁵⁸is tert-butyl or benzyl.

(49) The compound as (39) wherein R¹is hydrogen; R²is hydrogen, —CN, —SCH₃, —NH₂, —COOH or COCF₃; R³is substituted phenyl (As substituents of phenyl may be mentioned one or more selected from the group consisting of halogen, —CN, —OH, —OCH₃, —OEt, —COOH); R⁴is hydrogen or —CH₃; R⁵is 4-amino-cyclohexyl or piperidin-3-yl; R⁶is hydrogen; R⁵⁸is tert-butyl;

with the provisos that R¹, R²and R⁴are not all H.

(50) The compound as (40) wherein R¹is hydrogen; R²is hydrogen, —CN, —SCH₃, —NH₂, —COOH or COCF₃; R³is substituted phenyl (As substituents of phenyl may be mentioned one or more selected from the group consisting of halogen, —CN, —OH, —OCH₃, —OEt, —COOH); R⁴is hydrogen or —CH₃; R⁵⁸is tert-butyl; with the provisos that R¹, R²and R⁴are not all H

(51) The compound as (41) wherein R¹is hydrogen; R²is hydrogen, —CN, —SCH₃, —NH₂, —COOH or COCF₃; R³is substituted phenyl (As substituents of phenyl may be mentioned one or more selected from the group consisting of halogen, —CN, —OH, —OCH₃, —OEt, —COOH); R⁴is hydrogen or —CH₃; with the provisos that R¹, R²and R⁴are 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.

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

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is reacted with a compound of the formula R⁵R⁶NH.

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

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is reacted with a compound of the formula R⁵R⁶NH.

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

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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

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is reacted with a compound of the formula R³NH₂or R³NH(COCH₃).

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

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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

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is reacted with a compound of the formula R⁴CH(CO₂Me)₂or R⁴CH(CO₂Et)₂.

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

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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

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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

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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

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is reacted with a compound of the formula (CF₃CO)₂O.

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

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is reacted with hydroxide for a hydrolysis of ester group; R⁶⁷is 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

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is reacted with a compound of the formula R⁹R¹⁰in 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

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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

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is reacted with a compound of the formula R¹²COCl, R¹²COOH, R¹⁰SO₂Cl, R¹⁰NCO or R¹⁰NCS.

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

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is condensed with an alcohol derivative under Mitsunobu conditions; Ar¹represents 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

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is reacted with a boronic acid derivative in the presence of metal catalysis under Suzuki-Miyaura coupling conditions; Ar¹represents 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

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is reacted with a 1-alkyne in the presence of metal catalyst under Sonogashira coupling conditions; Ar¹represents 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

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is reacted with a compound of the formula R¹⁶R¹⁷NH in the presence of a peptide coupling agent; Ar¹represents 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

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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

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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

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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

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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

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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

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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.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the p38 MAPK cascade.

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

BEST MODE FOR CARRYING OUT THE INVENTION

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

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R²is hydrogen, halogen, —CN, —NO₂, —CHO, -G-R⁷[G is a bond, —C(═O)— or —O—C(═O)—; and R⁷is 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, —OR⁸(R⁸is 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), —NR⁹R¹⁰(R⁹is as defined for R⁸; R¹⁰is 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 —OCH₃), —R¹¹(R¹¹is 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 R⁷is C6-C14 optionally substituted aryl or optionally substituted heteroaryl, then G is not a bond], —NR⁹C(═O)R¹²(R⁹is as defined for R⁸; R¹²is 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), —NR⁹C(═X)OR¹³(R and R¹³, which may be the same or different, are as defined for R⁸; X is O, S, N—CN or NH), —NR⁹C(═X)NR¹³R¹⁴(R⁹, R¹³and R¹⁴, which may be the same or different, are as defined for R⁸; X is O, S, N—CN or NH), —NR⁹SO₂R¹³(R⁹and R¹³, which may be the same or different, are as defined for R⁸), —SR⁹(R⁹is as defined for R⁸) or —S(O)_mR⁹(R⁹is as defined for R⁸; m is 1 or 2);

R²³is as defined for R¹⁵}, —NR²⁴C(═O)R²⁵(R²⁴is as defined for R⁸; R²⁵is as defined for R¹²), —NR²⁴C(═X)OR²⁶(R²⁴and R²⁶, which may be the same or different, are as defined for R⁸; X is O, S, N—CN or NH), —NR²⁴C(═X)NR²⁶R²⁷(R²⁴, R²⁶and R²⁷, which may be the same or different, are as defined for R⁸; X is O, S, N—CN or NH), —NR²⁴SO₂R²⁶(wherein R²⁴and R²⁶, which may be the same or different, are as defined for R⁸), —S(O)_mR²⁴(R²⁴is as defined for R⁸; m is 0, 1 or 2) and —SO₂NR²⁸R²⁹(R²⁸and R²⁹, which may be the same or different, are as defined for R⁸; R²⁸and R²⁹together 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;

and R³²is as defined for R¹²), —NR³⁰C(═X)OR³¹(R³⁰and R³¹, which may be the same or different, are as defined R⁸; X is O, S, N—CN or NH), —NR³⁰C(═X)NR³¹R³³(R³⁰, R³¹and R³³, which may be the same or different, are as defined for R⁸; X is O, S, N—CN or NH) or —NR³⁰SO₂R³¹(R³⁰and R³¹, which may be the same or different, are as defined for R⁸);

R⁵is 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, —NO₂, —CHO, -G-R³⁴{G is a bond, —C(═O)— or —O—C(═O)—; R³⁴is as defined for R¹⁵}, —NR³⁵C(═O)R³⁶(R³⁵is as defined for R⁸; R³⁶is as defined for R¹²), —NR³⁵C(═X)OR³⁷R³⁵and R³⁷, which may be the same or different, are as defined for R⁸; X is O, S, N—CN or NH), —NR³⁵C(═X)NR³⁷R³⁸(R³⁵, R³⁷and R³⁸, which may be the same or different, are as defined for R⁸; X is O, S, N—CN or HH) and —NR³⁵SO₂R³⁷(R³⁵and R³⁷, which may be the same or different, are as defined for R⁸)], unsubstituted heterocyclyl, substituted heterocyclyl [As substituents of heterocyclyl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO₂, —CHO, -G-R³⁹{G is a bond, —C(═O)— or —O—C(═O)—; R³⁹is as defined for R¹⁵}, —NR⁴⁰C(═O)R⁴¹(R⁴⁰is as defined for R⁸; R⁴¹is as defined for R¹²), —NR⁴⁰C(═X)OR⁴²(R⁴⁰and R⁴², which may be the same or different, are as defined for R⁸; X is O, S, N—CN or NH), —NR⁴⁰C(═X)NR⁴²R⁴³(R⁴⁰, R⁴²and R⁴³, which may be the same or different, are as defined for R^8;X is O, S, N—CN or NH) and —NR⁴⁰SO₂R⁴²(R⁴⁰and R⁴², which may be the same or different, are as defined for R⁸)], optionally substituted arylalkyl, optionally substituted heterocyclylalkyl, optionally substituted arylalkenyl, optionally substituted heterocyclylalkenyl, optionally substituted arylalkynyl, optionally substituted heterocyclylalkynyl or —NR⁴⁴R⁴⁵(R⁴⁴and R⁴⁵, which may be the same or different, are C1-C8 optionally substituted alkyl; R⁴⁴and R⁴⁵together 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);

with the provisos:

that R¹, R²and R⁴are not all H;

that R⁴is not pentafluorophenyl;

that R⁵is 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;

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, —NO₂, —CHO, -G-R⁴⁶{G is a bond, —C(═O)—, or —O—C(═O)—; R⁴⁶is 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, —OR⁴⁷or —NR⁴⁷R⁴⁸}, —NR⁴⁷C(═O)R⁴⁸, —NR⁴⁷C(═O)OR⁴⁸, —NR⁴⁷C(═O)NR⁴⁸R⁴⁹, —NR⁴⁷SO₂R⁴⁸, —S(O)_mR⁴⁷, —NR⁴⁷SO₂R⁴⁸or —SO₂NR⁴⁷R⁴⁸; wherein optionally substituted C1-C8 alkyl means C1-C8 alkyl which may be optionally substituted with one or more F, Cl, Br, I, —CN, —NO₂, —CHO, heterocyclyl, —OR⁴⁷, —NR⁴⁷R⁴⁸, —NR⁴⁷C(═O)R⁴⁸, —COOR⁴⁷, —CONR⁴⁷R⁴⁸and —S(O)_mR⁴⁷;

wherein optionally substituted C2-C8 alkenyl means C2-C8 alkenyl which may be optionally substituted with one or more F, Cl, Br, I, —CN, —NO₂, —CHO, heterocyclyl, —OR⁵⁰, —NR⁵⁰R⁵¹, —NR⁵⁰C(═O)R⁵¹, —COOR⁵⁰, —CONR⁵⁰R⁵¹and —S(O)_mR⁵⁰;

wherein optionally substituted C2-C8 alkynyl means C2-C8 alkynyl which may be optionally substituted with one or more F, Cl, Br, I, —CN, —NO₂, —CHO, heterocyclyl, —OR⁵⁰, —NR⁵⁰R⁵¹, —NR⁵⁰C(═O)R⁵¹, —COOR⁵⁰, —CONR⁵⁰R⁵¹and —S(O)_mR⁵⁰;

wherein optionally substituted C3-C8 cycloalkyl means C3-C8 cycloalkyl which may be optionally substituted with one or more F, Cl, Br, I, —CN, —NO₂, —CHO, heterocyclyl, —OR⁵⁰, —NR⁵⁰R⁵¹, —NR⁵⁰C(═O)R⁵¹, —COOR⁵⁰, —CONR⁵⁰R⁵¹and —S(O)_mR⁵⁰;

wherein optionally substituted C6-C14 aryl means C6-C14 aryl which may be optionally substituted with one or more F, Cl, Br, I, —CN, —NO₂, —CHO, heterocyclyl, —OR⁵⁰, —NR⁵⁰R⁵¹, —NR⁵⁰C(═O)R⁵¹, —COOR⁵⁰, —CONR⁵⁰R⁵¹and —S(O)_mR⁵⁰;

wherein optionally substituted heterocyclyl means heterocyclyl which may be optionally substituted with one or more F, Cl, Br, I, —CN, —NO₂, —CHO, heterocyclyl, —OR⁵⁰, —NR⁵⁰R⁵¹, —NR⁵⁰C(═O)R⁵¹, —COOR⁵⁰, —CONR⁵⁰R⁵¹and —S(O)_mR⁵⁰;

R⁴⁷, R⁴⁸, R⁴⁹, R⁵⁰and R⁵¹, 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.

R¹is preferably hydrogen or C1-C6 optionally substituted alkyl. More preferably R¹is hydrogen.

R²is preferably selected from hydrogen, halogen, —CN, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, —OR⁸(R⁸is hydrogen or C1-C8 optionally substituted alkyl), —NR⁹R¹⁰(R⁹and R¹⁰, which may be the same or different, hydrogen or C1-C8 optionally substituted alkyl), —C(═O)NR⁹R¹⁰(R⁹and R¹⁰, 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), —NR⁹C(═O)R¹²(R⁹is hydrogen or C1-C8 optionally substituted alkyl; R¹²is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl), —NR⁹C(═O)OR¹³(R⁹is hydrogen or C1-C8 optionally substituted alkyl; R¹³is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl), —NR⁹C(═O)NR¹³R¹⁴(R⁹and R¹³, which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl; R¹⁴is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl), —NR⁹SO₂R¹³(R⁹is hydrogen or C1-C8 optionally substituted alkyl; R¹³is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl), —SR⁹(R⁹is hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl) or —SO₂R⁹(R⁹is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl).

More preferably R²is hydrogen, halogen, —CN or —SCH₃. Still more preferably R²is hydrogen;

R³is 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, —NO₂, -G-R¹⁵{G is a bond or —C(═O)—; R¹⁵is 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, —OR¹⁶(R¹⁶is hydrogen, C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl) or —NR¹⁷R¹⁸(R¹⁷and R¹⁸, 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)}, —NR¹⁷C(═O)R¹⁹(R¹⁷is hydrogen or C1-C8 optionally substituted alkyl; R¹⁹is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl) and —S(O)_mR¹⁷(R¹⁷is 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, —NO₂, -G-R²³{G is a bond or —C(═O)—; R²³is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, —OR¹⁶(R¹⁶is hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl) or —NR¹⁷R¹⁸(R¹⁷and R¹⁸, 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)}, —NR²⁴C(═O)R²⁵(R²⁴is hydrogen or C1-C8 optionally substituted alkyl; R²⁵is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl) and —S(O)_mR²⁴(R²⁴is C1-C8 optionally substituted alkyl or C3-C8 optionally substituted cycloalkyl; m is 0 or 2)].

More preferably R³is substituted phenyl [As substituents of phenyl may be mentioned one or more selected from the group consisting of halogen, —CN, —NO₂, C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkynyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, —OR¹⁶(R¹⁶is hydrogen, C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl), —NR¹⁷R¹⁸(R¹⁷and R¹⁸, which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl) and —C(═O)NR¹⁷R¹⁸(R¹⁷and R¹⁸, 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, —NO₂, C1-C8 optionally substituted alkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, —OR¹⁶(R¹⁶is hydrogen, C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl), —NR¹⁷R¹⁸(R¹⁷and R¹⁸, which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl), —NHC(═O)R¹⁹(R¹⁹is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl) and —SR¹⁷(R¹⁷is C1-C8 optionally substituted alkyl)].

R⁴is preferably selected from hydrogen, C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, optionally substituted aryl. More preferably R⁴is hydrogen, methyl or ethyl.

R⁵is 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, —OR³⁰(R³⁰is hydrogen or C1-C8 optionally substituted alkyl), —NR³⁰R³¹(R³⁰and R³¹, which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl) and —NHC(═O)R³²(R³²is 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, —OR¹⁶(R¹⁶is hydrogen or C1-C8 optionally substituted alkyl), —NR¹⁷R¹⁸(R¹⁷and R¹⁸, which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl) and —NHC(═O)R⁴¹(R⁴¹is C1-C8 optionally substituted alkyl, C3-C8 substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl)].

More preferably R⁵is 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 —NH₂], 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 —NH₂].

Still more preferably R⁵is 4-amino-cyclohexyl, piperidin-3-yl, piperidin-4-yl or pyrrolidin-3-yl.

R⁶is preferably selected from hydrogen and C1-C8 optionally substituted alkyl. More preferably R⁶is hydrogen.

As preferred combinations of the groups mentioned as preferred examples of R¹-R⁶in formula I according to the invention, there may be mentioned the following combinations 1) to 10).

1) In formula I, wherein R¹is hydrogen, R²is hydrogen, R³is C6-C14 aryl group substituted by C6-C14 optionally substituted aryl or optionally substituted heterocyclyl [wherein C6-C14 aryl group as R³may be substituted by one or more substituents selected from the group consisting of halogen, —CN, —NO₂, C1-C8 optionally substituted alkyl, —OR¹⁶(R¹⁶is hydrogen, C1-C8 optionally substituted alkyl), —NR¹⁷R¹⁸(R¹⁷and R¹⁸, which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl)], R⁴is C1-C8 optionally substituted alkyl, R⁵is 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 —NH₂], 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 —NH₂] and R6 is hydrogen.

2) In formula I, wherein R¹is hydrogen, R²is hydrogen, R³is C6-C14 aryl group substituted by —OR¹⁶(R¹⁶is C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl) [wherein C6-C14 aryl group as R³may be substituted by one or more substituents selected from the group consisting of halogen, —CN, —NO₂, C1-C8 optionally substituted alkyl, —OR¹⁶(R¹⁶is hydrogen, C1-C8 optionally substituted alkyl), —NR¹⁷R¹⁸(R¹⁷and R¹⁸, which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl)], R⁴is C1-C8 optionally substituted alkyl, R⁵is 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 —NH₂], 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 —NH₂] and R6 is hydrogen.

3) In formula I, wherein R¹is hydrogen, R²is hydrogen, R³is C6-C14 aryl group substituted by -G-R¹⁵{G is —(CO)—; R¹⁵is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, —OR¹⁶(R¹⁶is hydrogen, C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl) or —NR¹⁷R¹⁸(R¹⁷and R¹⁸, 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 R³may be substituted by one or more substituents selected from the group consisting of halogen, —CN, —NO₂, C1-C8 optionally substituted alkyl, —OR¹⁶(R¹⁶is hydrogen, C1-C8 optionally substituted alkyl), —NR¹⁷R¹⁸(R¹⁷and R¹⁸, which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl)], R⁴is C1-C8 optionally substituted alkyl, R⁵is 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 —NH₂], 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 —NH₂] and R6 is hydrogen.

4) In formula I, wherein R¹is hydrogen, R²is hydrogen, R³is 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, —NO₂, C1-C8 optionally substituted allyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, —OR¹⁶(R¹⁶is hydrogen, C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl), —NR¹⁷R¹⁸(R¹⁷and R¹⁸, which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl), —NH(CO)R¹⁹(R¹⁹is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl) and —SR¹⁷(R¹⁷is C1-C8 optionally substituted alkyl)], R⁴is C1-C8 optionally substituted alkyl, R⁵is 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 —NH₂], 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 —NH₂] and R6 is hydrogen.

5) In formula I, wherein R¹is hydrogen, R²is F, R³is C6-C14 aryl group substituted by C6-C14 optionally substituted aryl or optionally substituted heterocyclyl [wherein C6-C14 aryl group as R³may be substituted by one or more substituents selected from the group consisting of halogen, —CN, —NO₂, C1-C8 optionally substituted alkyl, —OR¹⁶(R¹⁶is hydrogen, C1-C8 optionally substituted alkyl), —NR¹⁷R¹⁸(R¹⁷and R¹⁸, which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl)], R⁴is hydrogen, R⁵is 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 —NH₂], 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 —NH₂] and R6 is hydrogen.

6) In formula I, wherein R¹is hydrogen, R²is F, R³is C6-C14 aryl group substituted by —OR¹⁶(R¹⁶is C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl) [wherein C6-C14 aryl group as R³may be substituted by one or more substituents selected from the group consisting of halogen, —CN, —NO₂, C1-C8 optionally substituted alkyl, —OR¹⁶(R¹⁶is hydrogen, C1-C8 optionally substituted alkyl), —NR¹⁷R¹⁸(R¹⁷and R¹⁸, which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl)], R⁴is hydrogen, R⁵is 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 —NH₂], 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 —NH₂] and R6 is hydrogen.

7) In formula I, wherein R¹is hydrogen, R²is F, R³is C6-C14 aryl group substituted by -G-R¹⁵{G is —(CO)—; R¹⁵is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, —OR¹⁶(R¹⁶is hydrogen, C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl) or —NR¹⁷R¹⁸(R¹⁷and R¹⁸, 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 R³may be substituted by one or more substituents selected from the group consisting of halogen, —CN, —NO₂, C1-C8 optionally substituted alkyl, —OR¹⁶(R¹⁶is hydrogen, C1-C8 optionally substituted alkyl), —NR¹⁷R¹⁸(R¹⁷and R¹⁸, which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl)], R⁴is hydrogen, R⁵is 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 —NH₂], 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 —NH₂] and R6 is hydrogen.

8) In formula I wherein R¹is hydrogen, R²is F, R³is 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, —NO₂, C1-C8 optionally substituted alkyl, C6-C14 optionally substituted aryl, optionally substituted heterocyclyl, —OR¹⁶(R¹⁶is hydrogen, C1-C8 optionally substituted alkyl, optionally substituted arylalkyl or optionally substituted heterocyclylalkyl), —NR¹⁷R¹⁸(R¹⁷and R¹⁸, which may be the same or different, are hydrogen or C1-C8 optionally substituted alkyl), —NH(CO)R¹⁹(R¹⁹is C1-C8 optionally substituted alkyl, C3-C8 optionally substituted cycloalkyl, C6-C14 optionally substituted aryl or optionally substituted heterocyclyl) and —SR¹⁷(R¹⁷is C1-C8 optionally substituted alkyl)], R⁴is hydrogen, R⁵is 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 —NH₂], 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 —NH₂] and R6 is hydrogen.

9) In formula I, wherein R¹is hydrogen, R²is halogen, —CN or —SCH₃, R³is C6-C14 optionally substituted aryl, optionally substituted bicyclic heteroaryl, R⁴is hydrogen, R⁵is 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 —NH₂], 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 —NH₂] and R6 is hydrogen.

10) In formula I, wherein R¹is hydrogen, R²is halogen or —CN, R³is C6-C14 optionally substituted aryl, optionally substituted bicyclic heteroaryl, R⁴is C1-C8 optionally substituted alkyl, R⁵is 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 —NH₂], 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 —NH₂] 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.

TABLE A

Compound

No.
R¹
R²
R⁴
R³
NR⁵R⁶

1
H
CN
H

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2
H
Br
H

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3
Me
H
H

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4
t-Bu
H
H

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5
Ph
H
H

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6
Me
Br
H

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7
H
Cl
H

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8
t-Bu
Br
H

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9
H
COOEt
H

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10
H
H
Me

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11
H
H
n-Pr

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12
H
H
Ph

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13
H
Br
H

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14
H
Br
n-Pr

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15
H
H
Me

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16
H
H
Et

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17
H
H

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18
H
Br
Me

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19
H
H

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20
H
Br
Me

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21
H
H
Ph
Me

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22
H
H

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23
H
H
Et

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24
H
H

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25
H
H
Et

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26
H
H
Et

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27
H
H
Et

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28
H
H
Et

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29
H
H
Et

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30
H
H
Et

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31
H
H
Et

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32
H
H
Me

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33
H
H
Et

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34
H
H
Et

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35
H
H
Et

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36
H
H
Et

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37
H
H
Et

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38
H
H
Et

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39
H
H
Et

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40
H
H
Et

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41
H
H
Et

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42
H
H
Et

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43
H
H
Et

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44
H
H
Et

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45
H
H
Et

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46
H
H
Et

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47
H
I
H

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48
H
I
H

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49
H
I
H

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50
H
Br
H

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51
H
H

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52
H
H

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53
H
H

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54
H
H
Et

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55
H
H
Et

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56
H
H
Et

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57
H
H
Et

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58
H
H
Et

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59
H
H
Et

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60
H
H
Et

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61
H
H
Et

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62
H
H
Et

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63
H
H
Et

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64
H
CN
H

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65
H
H
Me

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66
H
H
Me

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67
H
H
Me

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68
H
H
Me

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69
H
H
Et

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70
H
H
Et

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71
H
H
Et

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72
H
H
Et

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73
H
H
Et

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74
H
H
Et

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75
H
H
Et

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76
H
H
Me

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77
H
H
Me

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78
H
SMe
H

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79
H
H
Me

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80
H
H
Me

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81
H
H
Me

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82
H
H
Me

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83
H
H
Me

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84
H
H
Me

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85
H
H
Me

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86
H
H
Me

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87
H
H
Me

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88
H
H
Me

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89
H
H
Me

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90
H
H
Me

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91
H
H
Me

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92
H

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93
H
H
Et

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94
H

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95
H
H
Me

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96
H
H
Me

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97
H
H
Me

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98
H
H
Me

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99
H
H
Me

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100
H
H
Me
t-Bu

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101
H
H
Me

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102
H
H
Me
Ph

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103
H
H
Me

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104
H
H
Me

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105
H
H
Me

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106
H
H
Me

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107
H
H
Me

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108
H
H
Me

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109
H
H
Me

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110
H
H
Me

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111
H
H
Me

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112
H
H
Me

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113
H
H
Et

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114
H
H
i-Pr

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115
H
H
i-Pr

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116
H
H
Et

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117
H
H
Et

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118
H
H
Me

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119
H
H
Me

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120
H
H
Me
Ph

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121
H
H
Me

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122
H
H
Me

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123
H
H
Me

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124
H
H
Et

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125
H
H
Et

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126
H
H
Me

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127
H
H
Me

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128
H
H
Et

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129
H
H
Me

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130
H
H
Me

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131
H
H
Me

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132
H

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133
H
H
Me

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134
H
H
Me

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135
H
H
Me

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136
H
H
Et

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137
H
H
Et

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138
H
H
Me

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139
H
H
Et

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140
H
H

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141
H
H
Et

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142
H
H
Me

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143
H
H
Me

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144
H
H
Me

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145
H
H
Me

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146
H
H
Me

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147
H
H
Me

embedded image

148
H
H
Me

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149
H
H
Me

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150
H
H
Me

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151
H
H
Et

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152
H
H
Me

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153
H
H
Me

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154
H
Et
Me

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155
H
H
Me

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156
H
H
Me

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157
H
H
Ph

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158
H
Et
Me

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159
H
H
Et

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160
H
H
Et

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161
H
H
Me

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162
H
H
Me

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163
H

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164
H

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165
H
i-Pr
Me

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166
H
i-Pr
Me

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167
H
H
Et
Ph

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168
H
H
Et

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169
H
Cl
Et

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170
H
CN
H

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171
H
H
OMe

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172
H
H
OMe

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173
H
H
OMe

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174
H
H
Me

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175
H
H
Et

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176
H
H
Me

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177
H
H
Me

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178
H
H
Me

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179
H
H
Me

embedded image

180
H
H
Me

embedded image

181
H
H
Me

embedded image

182
H
H
Me

embedded image

183
H
H
Me

embedded image

184
H
H
Me

embedded image

185
H
H
Me

embedded image

186
H
H
Me

embedded image

187
H
H
Me

embedded image

188
H
H
Me

embedded image

189
H
H
Me

embedded image

190
H
H
Me

embedded image

191
H
H
Me

embedded image

192
H
H
Me

embedded image

193
H
H
Me

embedded image

194
H
H
Me

embedded image

195
H
H
Me

embedded image

196
H
H
Me

embedded image

197
H
H
Me

embedded image

198
H
H
Me

embedded image

199
H
H
Me

embedded image

200
H
H
Me

embedded image

201
H
H
Me

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202
H
H
Me

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203
H
H
Me

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204
H
H
Me

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Compound

No.
R¹
R²
R⁴
R³
NR⁵R⁶

205
H
H
Me

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206
H
H
Me

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207
H
H
Me

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208
H
H
Me

embedded image

209
H
H
Me

embedded image

210
H
H
Me

embedded image

211
H
H
Me

embedded image

212
H
H
Me

embedded image

213
H
H
Me

embedded image

214
H
H
Me

embedded image

215
H
H
Me

embedded image

216
H
H
Me

embedded image

217
H
H
Me

embedded image

218
H
H
Me

embedded image

219
H
H
Me

embedded image

220
H
H
Me

embedded image

221
H
H
Me

embedded image

222
H
H
Me

embedded image

223
H
H
Me

embedded image

224
H
H
Me

embedded image

225
H
H
Me

embedded image

226
H
H
Me

embedded image

227
H
H
Me

embedded image

228
H
H
Me

embedded image

229
H
H
Me

embedded image

230
H
H
Me

embedded image

231
H
H
Me

embedded image

232
H
H
Me

embedded image

233
H
H
Me

embedded image

234
H
H
Me

embedded image

235
H
H
Me

embedded image

236
H
H
Me

embedded image

237
H
H
Me

embedded image

238
H
H
Me

embedded image

239
H
H
Me

embedded image

240
H
H
Me

embedded image

241
H
H
Me

embedded image

242
H
H
Me

embedded image

243
H
H
Me

embedded image

244
H
H

embedded image

245
H
H

embedded image

246
H
H
Me

embedded image

247
H
H
Me

embedded image

248
H
H
Me

embedded image

249
H
H
Me

embedded image

250
H
H
Me

embedded image

251
H
H
Me

embedded image

252
H
H
Me

embedded image

253
H
H
Me

embedded image

254
H
H
Me

embedded image

255
H
H
Me

embedded image

256
H
H
Me

embedded image

257
H
H
Me

embedded image

258
H
H
Me

embedded image

259
H
H
Me

embedded image

260
H
H
Me

embedded image

261
H
H
Me

embedded image

262
H
H
Me

embedded image

263
H
H
Me

embedded image

264
H
H
Me

embedded image

265
H
H
Me

embedded image

266
H
H
Me

embedded image

267
H
H
Me

embedded image

268
H
H
Me

embedded image

269
H
H
Me

embedded image

270
H
H
Me

embedded image

271
H
H
Me

embedded image

272
H
H
Me

embedded image

273
H
H
Me

embedded image

274
H
H
Me

embedded image

275
H
H
Me

embedded image

276
H
H
Me

embedded image

277
H
H
Me

embedded image

278
H
H
Me

embedded image

279
H
H
Me

embedded image

280
H
H
Me

embedded image

281
H
H
Me

embedded image

282
H
H
Me

embedded image

283
H
H
Me

embedded image

284
H
H
Me

embedded image

285
H
H
Me

embedded image

286
H
H
Me

embedded image

287
H
H
Me

embedded image

288
H
H
Me

embedded image

289
H
H
Me

embedded image

290
H
H
Me

embedded image

291
H
H
Me

embedded image

292
H
H
Me

embedded image

293
H
CN
Me

embedded image

294
H
CN
Me

embedded image

295
H
CN
Me

embedded image

296
H
H
Me

embedded image

297
H
I
H

embedded image

298
H
H
Me

embedded image

299
H
H
Me

embedded image

300
H
H
Me

embedded image

301
H
H
Me

embedded image

302
H
H
Me

embedded image

303
H
H
Me

embedded image

304
H
H
Me

embedded image

305
H
H
Me

embedded image

306
H
H
Me

embedded image

307
H
H
Me

embedded image

308
H
H
Me

embedded image

309
H
H
Me

embedded image

310
H
H
Me

embedded image

311
H
H
Me

embedded image

312
H
H
Me

embedded image

313
H
H
Me

embedded image

314
H
H
Me

embedded image

315
H
H
Me

embedded image

316
H
H
Me

embedded image

317
H
H
Me

embedded image

318
H
H
Me

embedded image

319
H
H
Me

embedded image

320
H
H
Me

embedded image

321
H
H
Me

embedded image

322
H
H
Me

embedded image

323
H
H
Me

embedded image

324
H
H
Me

embedded image

325
H

embedded image

326
H

embedded image

327
H
COOH
Me

embedded image

328
H

embedded image

329
H

embedded image

330
H

embedded image

331
H

embedded image

332
H

embedded image

333
H

embedded image

334
H

embedded image

335
H

embedded image

336
H

embedded image

337
H

embedded image

338
H

embedded image

339
H

embedded image

340
H
H
Me

embedded image

341
H
H
Me

embedded image

342
H
H
Me

embedded image

343
H
NH₂
Me

embedded image

344
H

embedded image

345
H

embedded image

346
H

embedded image

347
H

embedded image

348
H

embedded image

349
H

embedded image

350
H
H
Me

embedded image

351
H
H
Me

embedded image

352
H
H
Me

embedded image

353
H
H
Me

embedded image

354
H
H
Me

embedded image

355
H
H
Me

embedded image

356
H
H
Me

embedded image

357
H
H
Me

embedded image

358
H

embedded image

359
H

embedded image

360
H

embedded image

361
H

embedded image

362
H

embedded image

363
H

embedded image

364
H

embedded image

365
H

embedded image

366
H
H
Me

embedded image

367
H
H
Me

embedded image

368
H
H
Me

embedded image

369
H
H
Me

embedded image

370
H
H
Me

embedded image

371
H
H
Me

embedded image

372
H
H
Me

embedded image

373
H
H
Me

embedded image

374
H
H
Me

embedded image

375
H
H
Me

embedded image

376
H
H
Me

embedded image

377
H
H
Me

embedded image

378
H

embedded image

379
H

embedded image

380
H

embedded image

381
H

embedded image

382
H

embedded image

383
H

embedded image

384
H

embedded image

385
H

embedded image

386
H

embedded image

387
H

embedded image

388
H

embedded image

389
H

embedded image

390
H

embedded image

391
H

embedded image

392
H

embedded image

393
H
H
Me

embedded image

394
H
H
Me

embedded image

395
H
H
Me

embedded image

396
H
H
Me

embedded image

397
H
H
Me

embedded image

398
H
H
Me

embedded image

399
H
H
Me

embedded image

400
H
H
Me

embedded image

401
H
H
Me

embedded image

402
H
H
Me

embedded image

403
H
H
Me

embedded image

404
H
H
Me

embedded image

405
H
H
Me

embedded image

406
H
H
Me

embedded image

407
H
H
Me

embedded image

408
H
H
Me

embedded image

409
H
H
Me

embedded image

410
H
H
Me

embedded image

411
H
H
Me

embedded image

412
H
H
Me

embedded image

413
H
Me
Me

embedded image

414
H
Me
Me

embedded image

415
H

embedded image

416
H

embedded image

417
H

embedded image

418
H
H
Me

embedded image

419
H
H
Me

embedded image

420
H
H
Me

embedded image

421
H
H
Me

embedded image

422
H
H
Me

embedded image

423
H
H
Me

embedded image

424
H
H
Me

embedded image

425
H
OMe
Me

embedded image

426
H

embedded image

427
H

embedded image

428
H

embedded image

429
H

embedded image

430
H

embedded image

431
H

embedded image

432
H

embedded image

433
H

embedded image

434
H

embedded image

435
H

embedded image

436
H

embedded image

437
H

embedded image

438
H

embedded image

439
H

embedded image

440
H
COOH
Me

embedded image

441
H
F
Me

embedded image

442
H
H
Me

embedded image

443
H
H
Me

embedded image

444
H
H
Me

embedded image

445
H
H
Me

embedded image

446
H
H
Me

embedded image

447
H
H
Me

embedded image

448
H
H
Me

embedded image

449
H
H
Me

embedded image

450
H
H
Me

embedded image

451
H
H
Me

embedded image

452
H
H
Me

embedded image

453
H
H
Me

embedded image

454
H
H
Me

embedded image

455
H
H
Me

embedded image

456
H
H
Me

embedded image

Compound

No.
R¹
R²
R⁴
R³
NR⁵R⁶

457
H
H
Me

embedded image

458
H
H
Me

embedded image

459
H
H
Me

embedded image

460
H
H
Me

embedded image

461
H
H
Me

embedded image

462
H
H
Me

embedded image

463
H
H
Me

embedded image

464
H
H
Me

embedded image

465
H
H
Me

embedded image

466
H
H
Me

embedded image

467
H
H
Me

embedded image

468
H
H
Me

embedded image

469
H
H
Me

embedded image

470
H
H
Me

embedded image

471
H
H
Me

embedded image

472
H
H
Me

embedded image

473
H
H
Me

embedded image

474
H
H
Me

embedded image

475
H
H
Me

embedded image

476
H
H
Me

embedded image

477
H
H
Me

embedded image

478
H
H
Me

embedded image

479
H
H
Me

embedded image

480
H
H
Me

embedded image

481
H
H
Me

embedded image

482
H
H
Me

embedded image

483
H
H
Me

embedded image

484
H
H
Me

embedded image

485
H
H
Me

embedded image

486
H
H
Me

embedded image

487
H
H
Me

embedded image

488
H
H
Me

embedded image

489
H
H
Me

embedded image

490
H
H
Me

embedded image

491
H
H
Me

embedded image

492
H
H
Me

embedded image

493
H
H
Me

embedded image

494
H
H
Me

embedded image

495
H
H
Me

embedded image

496
H
H
Me

embedded image

497
H
H
Me

embedded image

498
H
H
Me

embedded image

499
H
H
Me

embedded image

500
H
H
Me

embedded image

501
H
H
Me

embedded image

502
H
H
Me

embedded image

503
H
H
Me

embedded image

504
H
H
Me

embedded image

505
H
H
Me

embedded image

506
H
H
Me

embedded image

507
H
H
Me

embedded image

508
H
H
Me

embedded image

509
H
H
Me

embedded image

510
H
H
Me

embedded image

511
H
H
Me

embedded image

512
H
H
Me

embedded image

513
H
H
Me

embedded image

514
H
H
Me

embedded image

515
H
H
Me

embedded image

516
H
H
Me

embedded image

517
H
H
Me

embedded image

518
H
H
Me

embedded image

519
H
H
Me

embedded image

520
H
H
Me

embedded image

521
H
H
Me

embedded image

522
H
H
Me

embedded image

523
H
H
Me

embedded image

524
H

embedded image

525
Me

embedded image

526
H

embedded image

OMe

527
H

embedded image

528
H

embedded image

529
H

embedded image

530
H

embedded image

531
H

embedded image

532
H

embedded image

533
H

embedded image

534
H

embedded image

OMe

535
H

embedded image

536
H

embedded image

537
H

embedded image

538
H

embedded image

539
H

embedded image

540
H

embedded image

541
H

embedded image

542
H

embedded image

543
Me

embedded image

OMe

544
H

embedded image

545
H

embedded image

546
H

embedded image

547
H

embedded image

548
H

embedded image

549
H

embedded image

550
H

embedded image

551
H

embedded image

552
H

embedded image

553
H

embedded image

OMe

554
H

embedded image

555
H

embedded image

556
H

embedded image

557
H

embedded image

558
Me

embedded image

OMe

559
H

embedded image

560
H

embedded image

561
H

embedded image

562
H

embedded image

563
H

embedded image

564
H

embedded image

565
H

embedded image

566
H

embedded image

567
H

embedded image

568
H

embedded image

H
Ph

embedded image

569
H
H
Me

embedded image

570
H
H
Me

embedded image

571
H
F

embedded image

572
H
Br
H

embedded image

573
H

embedded image

574
H
F
Et

embedded image

575
H
H
Me

embedded image

576
H

embedded image

577
H
F
Me

embedded image

578
H
H
Me

embedded image

579
H
H
Me

embedded image

580
H

embedded image

581
H
Br
H

embedded image

582
H
H
Me

embedded image

583
H

embedded image

584
H
F
H

embedded image

585
H
F
OMe

embedded image

586
H
Me
H

embedded image

587
H
F
Me

embedded image

588
H

embedded image

589
H
F
OMe

embedded image

590
H
H

embedded image

591
H

embedded image

592
H
F

embedded image

593
H
F
H

embedded image

594
H
Me

embedded image

595
H

embedded image

596
H
F
H

embedded image

597
H
F
H

embedded image

598
H
F
H

embedded image

599
H
H
OMe

embedded image

600
H

embedded image

601
H
F
Me

embedded image

602
H
F
Me

embedded image

603
H

embedded image

604
H
H
Me

embedded image

605
H
F
Me

embedded image

606
H
F
Me

embedded image

607
H
F
H

embedded image

608
H
H
Et

embedded image

609
H

embedded image

610
H
NH₂

embedded image

611
H
F
Me

embedded image

612
H

embedded image

613
H
F
H

embedded image

614
H
Me
Me

embedded image

615
H
F
H

embedded image

616
H
H
Me

embedded image

617
H
H
Me

embedded image

618
H
H

embedded image

619
H
H
Me

embedded image

620
H
F
Me

embedded image

621
H
NH₂
H

embedded image

622
H
F
Et

embedded image

623
H
H
Me

embedded image

624
H
NH₂
H

embedded image

625
H
F

embedded image

626
H

embedded image

627
H
Br
Me

embedded image

628
H
H

embedded image

629
H
H
Me

embedded image

630
H
H
Me

embedded image

631
H
H
Me

embedded image

632
H
H
Me

embedded image

633
H
H
Me

embedded image

634
H
H
Me

embedded image

635
H
H
Me

embedded image

636
H
H
Me

embedded image

637
H
H
Me

embedded image

638
H
H
Me

embedded image

639
H
H
Me

embedded image

640
H
H
Me

embedded image

641
H
H
Me

embedded image

642
H
H
Me

embedded image

643
H
H
Me

embedded image

644
H
H
Me

embedded image

645
H
H
Me

embedded image

646
H
H
Me

embedded image

647
H
H
Me

embedded image

648
H
H
Me

embedded image

649
H
H
Me

embedded image

650
H
F
Me

embedded image

651
H
F
Me

embedded image

652
H
H
Et

embedded image

653
H
H
Me

embedded image

654
H
H
Me

embedded image

655
H
H
Me

embedded image

656
H
H
Me

embedded image

657
H
F
Me

embedded image

658
H
H
Me

embedded image

659
H
F
Me

embedded image

660
H
H
Me

embedded image

661
H
H
Me

embedded image

662
H
F
Me

embedded image

663
H
H
Me

embedded image

664
H
F
Me

embedded image

665
H
F
Me

embedded image

666
H
F
Et

embedded image

667
H
H
Me

embedded image

668
H
F
Me

embedded image

669
H
H
Me

embedded image

670
H
H
Me

embedded image

671
H
F
Me

embedded image

672
H
H
Me

embedded image

673
H
F
Me

embedded image

674
H
H
Me

embedded image

675
H
H
Me

embedded image

676
H
H
Me

embedded image

677
H
H
Me

embedded image

678
H
F
Me

embedded image

679
H
H
Me

embedded image

680
H
H
Me

embedded image

681
H
H
Me

embedded image

682
H
H
Me

embedded image

683
H
F
Me

embedded image

684
H
H
Me

embedded image

685
H
H
Me

embedded image

686
H
H
Me

embedded image

687
H
H
Me

embedded image

688
H
H
Me

embedded image

689
H
H
Me

embedded image

690
H
H
Me

embedded image

691
H
F
Me

embedded image

692
H
H
Me

embedded image

693
H
F
Et

embedded image

694
H
H
Me

embedded image

695
H
F
Me

embedded image

696
H
H
Me

embedded image

697
H
F
Me

embedded image

698
H
H
Me

embedded image

699
H
F
Me

embedded image

700
H
H
Me

embedded image

701
H
F
Me

embedded image

702
H
H
Et

embedded image

703
H
F
Me

embedded image

704
H
H
Me

embedded image

705
H
F
Et

embedded image

706
H
H
Me

embedded image

707
H
F
Me

embedded image

708
H

embedded image

709
H
Cl
H

embedded image

710
H
Cl
H

embedded image

711
H
Cl
H

embedded image

712
H
Cl
H

embedded image

713
H
Cl
H

embedded image

714
H
Cl
H

embedded image

715
H
Cl
H

embedded image

716
H
Cl
Me

embedded image

717
H
Cl
H

embedded image

718
H
Cl
H

embedded image

719
H
Br
H

embedded image

720
H
Br
H

embedded image

721
H
Br
H

embedded image

722
H
Br
H

embedded image

723
H
Br
H

embedded image

724
H
Br
H

embedded image

725
H
Br
H

embedded image

726
H
Br
H

embedded image

727
H
I
H

embedded image

728
H
I
H

embedded image

729
H
I
H

embedded image

730
H
I
H

embedded image

731
H
I
H

embedded image

732
H

embedded image

733
H

embedded image

734
H
Me
H

embedded image

735
H
Me
H

embedded image

736
H

embedded image

737
H

embedded image

738
H

embedded image

739
H
CN
H

embedded image

740
H
CN
H

embedded image

741
H
CN
H

embedded image

742
H
CN
H

embedded image

743
H
CN
H

embedded image

744
H
CN
H

embedded image

745
H
CN
H

embedded image

746
H
CN
H

embedded image

747
H

embedded image

748
H

embedded image

749
H

embedded image

750
H
SMe
H

embedded image

751
H
SMe
H

embedded image

752
H
SMe
H

embedded image

753
H
SMe
H

embedded image

754
H
SMe
H

embedded image

755
H
SMe
H

embedded image

756
H
SMe
H

embedded image

757
H
SMe
H

embedded image

758
H
OMe
H

embedded image

759
H
H
Me

embedded image

760
H
H
Me

embedded image

761
H
H
Me

embedded image

762
H

embedded image

763
H

embedded image

764
H

embedded image

765
H

embedded image

766
H

embedded image

767
H

embedded image

768
H

embedded image

769
H

embedded image

770
H

embedded image

771
H

embedded image

772
H
H
Me

embedded image

773
H
H
Me

embedded image

774
H
H
Me

embedded image

775
H
H
Me

embedded image

776
H
H
Me

embedded image

777
H
H
Me

embedded image

778
H
H
Me

embedded image

779
H
H
Me

embedded image

780
H
H
Me

embedded image

781
H
H
Me

embedded image

782
H
H
Me

embedded image

783
H
H
Me

embedded image

784
H
H
Me

embedded image

785
H
H
Me

embedded image

786
H
H
Me

embedded image

787
H
H
Me

embedded image

788
H
H
Me

embedded image

789
H
H
Me

embedded image

790
H

embedded image

791
H

embedded image

792
H
H
Me

embedded image

793
H
H
Me

embedded image

794
H
H
Me

embedded image

795
H
H
Me

embedded image

796
H
H
Me

embedded image

797
H
H
Me

embedded image

798
H
H
Me

embedded image

799
H
H
Me

embedded image

800
H
H
Me

embedded image

801
H
H
Me

embedded image

802
H
H
Me

embedded image

803
H
H
Me

embedded image

804
H
H
Me

embedded image

805
H
H
Me

embedded image

806
F
F
Me

embedded image

807
H
H
Me

embedded image

808
H
H
Me

embedded image

809
H
H
Me

embedded image

810
H
H
Me

embedded image

811
H
H
Me

embedded image

812
H
H
Me

embedded image

813
H
H
Me

embedded image

814
H
H
Me

embedded image

815
H

embedded image

816
H

embedded image

817
H

embedded image

818
H

embedded image

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

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wherein R¹-R⁶are as defined for formula I above; R⁴⁵is C1-C8 optionally substituted alkyl or optionally substituted arylalkyl;

with the provisos:

that R¹, R²and R⁴are not all H;

R⁴⁵is preferably tert-butyl or benzyl.

2) A compound of the formula III-01

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wherein R¹-R⁶are as defined for formula I above; R⁴⁵is C1-C8 optionally substituted alkyl or optionally substituted arylalkyl;

with the provisos:

that R¹, R²and R⁴are not all H;

R⁴⁵is preferably tert-butyl or benzyl.

3) A compound of the formula IV

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wherein R¹-R⁶are as defined for formula I above;

with the provisos:

that R¹, R²and R⁴are not all H;

that R⁴is 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:

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wherein R¹-R⁶are as defined for formula I above;

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wherein R¹-R⁶are 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 R¹-R⁶are as defined above:

1) reacting a compound of the formula II

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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

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with a compound of the formula R⁵R⁶NH 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

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with a compound of the formula R⁵R⁶NH

4) reacting a compound of the formula IV

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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

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with a compound of the formula R³NH₂or R³NHAc in the presence of base e.g. triethylamine and sodium hydride

6) reacting a compound of the formula VI

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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

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with a compound of the formula R⁴CH(CO₂Me)₂or R⁴CH(CO₂Et)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

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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

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

10) reacting a compound of the formula V-01

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

11) reacting a compound of the formula IV-01

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with a Grignard reagent e.g. methyl magnesium chloride

12) reacting a compound of the formula II-01

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with an acylating agent e.g. trifluoroacetic anhydride

13) reacting a compound of the formula II-01

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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

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with aqueous sodium hydroxide for the hydrolysis of ester group in compound; R⁶⁷is methyl or ethyl

15) reacting a compound of the formula II-04

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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

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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

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with a compound of the formula R¹²COCl, R¹²COOH, R¹⁰SO₂Cl, R¹⁰NCO or R¹⁰NCS

18) reacting a compound of the formula II-13

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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.); Ar¹represents C6-C14 optionally substituted aryl or optionally substituted heteroaryl

19) reacting a compound of the formula II-15

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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.); Ar¹represents C6-C14 optionally substituted aryl or optionally substituted heteroaryl

20) reacting a compound of the formula II-15

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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.); Ar¹represents C6-C14 optionally substituted aryl or optionally substituted heteroaryl

21) reacting a compound of the formula II-18

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with a compound of the formula R¹⁶R¹⁷NH in the presence of peptide coupling agent; Ar¹represents C6-C14 optionally substituted aryl or optionally substituted heteroaryl

22) reacting a compound of the formula II-20

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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

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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

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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

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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

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with H₂in the presence of Pd(OH)₂—C or alpha-chloroethyl chloroformate followed by methanol for removal of R⁶⁰group from a compound (for example as described in Protective Groups in Organic Synthesis, 3rd Ed, John Wiley & Sons Inc); R⁶⁰is benzyl or p-MeO-benzyl; n is 1, 2 or 3

27) reacting a compound of the formula I-28

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with halogenating agent e.g. iodine monochloride

28) reacting a compound of the formula V-04

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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.

EXAMPLES

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 ¹H 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)

Example 1

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (VI)]

To a stirred solution of sodium ethoxide (50 mmol) in ethanol (100 mL) was added the appropriately 2-substituted malonic acid diester (20 mmol) and appropriately substituted 3-aminopyrazole (VII) (20 mmol). The mixture was heated at reflux for 18 h, during which a precipitate formed.* The reaction was cooled to room temperature and the mixture was filtered through an A4 sinter (whilst washing with a minimum of cool ethanol). The residue was dried under vacuum. The dried precipitate was dissolved in water (ca. 100 mL) and the resulting solution was acidified (pH 2) with concentrated HCl. This rendered a pale-white precipitate (VI), which was filtered and dried. Typical unoptimised yields ranged from 20-40%. * In several cases where the substituent was an alkyl chain, little or no precipitate was formed. In these situations, the ethanol was removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The aqueous phase was acidified (pH 2) with concentrated HCl and back-extracted with ethyl acetate. The organic phase was washed (water and saturated aqueous NaCl) and dried (MgSO₄) to give the desired bis-hydroxy compound (VI).

(VI)

Compound

mp

No.
R¹
R²
R⁴
(° C.)

VI-01
Me
H
H
240 (d)

VI-02
H
H
Ph
285

VI-03
H
H
Et
260

Example 2

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (V)]

To a suspension of bis-hydroxy compound (VI) (2 g) in N,N-dimethylaniline (2 mL) was added phosphorous oxychloride (or phenyl phosphonic dichloride) (20 mL). The mixture was heated at reflux for 18 h, and excess phosphorus oxychloride (or phenyl phosphonic dichloride) was removed in vacuo. The residue was poured onto ice (50 g) and extracted with CH₂Cl₂(5×). The organic phase was adsorbed onto neutral (activity I) alumina and chromatographed (typically using petrol→30% ethyl acetate/petrol as eluent). To gave the appropriately substituted 5,7-dichloropyrazolo[1,5-a]pyrimidine intermediate (V) in yields of ca. 40% values.

(V)

Compound

mp (° C.) or

No
R¹
R²
R⁴

¹H-NMR (400 MHz, CDCl₃) d (ppm)

V-07
Me
H
H
92-95

V-08
H
H
Ph
182-186

V-09
H
H
Et
60-62

V-10
H
H
Me
2.55(s, 3H, CH₃), 6.7(s, 1H, Het-H),

8.12 (s, 1H, Het-H).

Example 3

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (V-02)]

A solution of the 5,7-dichloropyrazolo[1,5-a]pyrimidine (V-01) (0.01 mol) in chloroform (50 mL) was treated with N-chlorosuccinimide, N-bromosuccinimide or iodine monochloride (0.011 mol) at room temperature. The mixture was boiled under reflux until all solids were dissolved and no starting material remained (by TLC). The mixture was poured onto ice/water and the organic layer was separated, washed with aqueous Na₂CO₃, dried over MgSO₄, and the solvent removed in vacuo. The residual material was purified by chromatography over silica gel to provide the 3-halo-5,7-dichloropyrazolo[1,5-a]pyrimidine (V-02).

Compound

No.
R¹
R²
R⁴

¹H-NMR (400 MHz, CDCl₃) d(ppm)

V-11
H
Br
H
8.2(s, 1H, Het-H), 7.05(s, 1H, Het-H).

V-12
H
I
H
8.15(s, 1H, Het-H), 2.60(s, 3H, 6-Me).

Example 4

[General Procedures for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (V-03)]

Synthesis of {5,7-dichloro(pyrazolo[1,5-a]pyramidin-7-yl)}thiocarbonitrile.

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To a solution of powdered potassium thiocyanate (2.66 g) in acetic acid (20 mL) was added slowly a solution of bromine (0.72 mL) in acetic acid (3 mL) whilst maintaining the temperature between 10-15° C. 5,7-Dichloropyrazolo[1,5-a]pyrimidine (2.5 g) in acetic acid (30 mL) was added and the resulting solution was stirred at 15° C. for 30 min and then room temperature for 3 h after which, the solvent was removed under reduced pressure. Water and ethyl acetate were added and the product was extracted with ethyl acetate (3×). The combined organic phase was dried (Na₂SO₄), evaporated and subjected to flash chromatography to give the title compound (780 mg, 73% pure by ¹H-NMR); ¹H-NMR (400 MHz, CDCl₃) d(ppm): 8.27 (1H, s, 2-H), 7.10 (1H, s, 6-H).

Example 5

[General Procedures for the Synthesis of Pyrazolo[1,5a]pyrimidines of General Formula (V-04)]

Synthesis of 5,7-dichloro-6-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde.

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To N,N-dimethyl formamide (9 mL) under nitrogen at room temperature was added POCl₃(3mL) and the resulting slurry was stirred for 5 min. 5,7-Dichloro-6-methylpyrazolo[1,5-a]pyrimidine (5 g) was slowly added and resulting thick mixture was heated at 70° C. for 3 h. The mixture was poured onto ice and basified with sodium hydroxide (5 g). The residue was filtered and the dried precipitate chromatographed on silica gel (eluting with CH₂Cl₂→20% ethyl acetate/CH₂Cl₂) to give the title compound (3.74 g); mp 137-139° C.

Example 6

[General Procedures for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (V-05)]

Synthesis of {5,7-dichloro-6-methyl(pyrazolo[1,5-a]pyrimidin-3-yl)}methanol.

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To 5,7-dichloro-6-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde (200 mg) in ethanol (20 mL) was added sodium borohydride (70 mg) and the reaction mixture was stirred at room temperature for 15 min. Saturated aqueous NH₄Cl (1 mL) was added and the reaction mixture was stirred for a further 10 min then the solvent was removed under reduced pressure. Water and ethyl acetate were added and the product was extracted with ethyl acetate (3×). The combined organic phase was washed (water, saturated aqueous NaCl) and dried (MgSO₄) to give the title compound (150 mg); ¹H-NMR (400 MHz, CDCl₃) d(ppm): 8.22 (1H, s, 2-H), 4.90 (1H, s, CH₂OH).

Example 7

[General Procedures for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (V-06)]

Synthesis of 2-{5,7-dichloro-6-methyl(pyrazolo[1,5-a]pyrimidin-3-yl)}-1,3-dioxane.

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To 5,7-dichloro-6-methylpyrazolo[1,5-a]pyrimidine-3-carbaldehyde (290 mg) in toluene (40 mL) was added pyridinium p-toluenesulfonate (60 mg) and propan-1,3-diol. The mixture was then heated under reflux for 2 h, with azeotropic removal of water. The solution was cooled and evaporated under reduced pressure. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether ⅔ as eluent to give the title compound (310 mg) as a white solid; ¹H-NMR (400 MHz, CDCl₃) d(ppm): 8.32 (1H, s, 2-H), 5.97 (1H, s, CHO₂R), 4.25 (2H, br dd, OCH_eq), 4.05 (2H, br t, OCH_ax), 2.50 (3H, s, 6-Me), 2.25 (1H, m, CCH_eqHC), 1.48 (1H, br d, CCHH_axC).

Example 8

[General Procedures for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (IV) and (IV-01)]

a) To a solution of (appropriately substituted) 5,7-dichloropyrazolo[1,5-a]pyrimidine (V) or {5,7-dichloro(pyrazolo[1,5-a]pyramidin-7-yl)}thiocarbonitrile and triethylamine (2 equivalents) in 2-propanol (20 mL) was added the amine R³NH₂(1 or 1.1 equivalents) and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was then partitioned between water and CH₂Cl₂. The organic phase was washed twice with water and the combined aqueous phases back-extracted with CH₂Cl₂. The organic layer was combined, washed with saturated aqueous NaCl and dried over Na₂SO₄. Removal of the solvent in vacuo yielded the precursor (IV). [Purification performed—normally the products did not require any further purification, if they did, they were recrystallised. Analysis performed—¹H-NMR, HPLC and MS].

Should the above room-temperature reaction not occur satisfactorily, the following may be applied:

b) To a solution of the 5,7-dichloropyrazolo[1,5-a]pyrimidine (V) (2 g) in 2-propanol (25 mL) containing N,N-diisopropylethylamine (2 equivalents) was added the amine R³NH₂(1.2 equivalents). The reaction was heated overnight at 80° C. and the solvent removed in vacuo. The residue was partitioned between water and CH₂Cl₂and the organic phase was washed with water, saturated aqueous NaCl and dried over MgSO₄. Removal of the solvent in vacuo yielded the product (IV).

c) To a stirred suspension of sodium hydride (50 mmol) in N,N-dimethylformamide (30 mL) was added appropriately substituted aniline derivative (25 mmol) and then appropriately substituted 5,7-dichloropyrazolo[1,5-a]pyrimidine (V) (25 mmol) in tetrahydrofuran (50 mL). The resulting mixture was stirred at 50° C. for 2 h. The reaction was quenched with saturated aqueous NH₄Cl. After extraction with ethyl acetate, the combined organic layer was washed with saturated aqueous NaCl and dried over MgSO₄. The solvent was removed in vacuo to give the crude title compound (IV). Typical unoptimised yields for d) 60-80%.

d) To a solution of 2-chloroacetanilide (2.2 mmol) in toluene (3 mL) at room temperature was added sodium hydride (3 mmol) after the addition the mixture was heated until effervescence ceased and the solution became homogenous. The appropriately substituted 5,7-dichloropyrazolo[1,5-a]pyrimidine (V) (1 mmol) was added and the mixture heated at reflux for 5 h. (The solution became heterogeneous during this time). Upon cooling, acetic acid (1 mL) and water (1 mL) were cautiously added and the mixture was stirred for 15 min. The solvent was removed in vacuo and the residual acetic acid removed by azeotropic evaporation with toluene (3×). The residue was partitioned between water and ethyl acetate. The organic phase was washed (water and saturated aqueous NaCl) and dried. The solvent was removed in vacuo and the residue was chromatographed to afford the desired compound (IV). Typical unoptimised yields for c) 50-70%. The Rf of starting material (V) and product (IV) are chromatographically indistinguishable, making complete reaction difficult to determine. It appears that at least 5 h is required for significant reaction to occur.

(IV)

Compound

mp (° C.) or

No.
R¹
R²
R⁴
R³

¹H-NMR (400 MHz) d (ppm)

IV-03
H
H
Me

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(CDCl₃) 1.91(s, 3H, CH₃), 6.5(s, 1H, Het-H), 7.05(d, 1H, ArH), 7.15(t, 1H, ArH), 7.27(t, 1H, ArH), 7.45(d, 1H, ArH).

IV-04
H
Cl
H

embedded image

184-186

IV-05
H
COOEt
CH₃

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(DMSO-d6) 1.27-1.35(m, 6H), 1.78(s, 3H), 4.02(q, J=6.84Hz, 2H), 4.27(q, J=7.08Hz, 2H), 6.92(d, J=8.80Hz, 2H), 7.15(d, J=8.80Hz, 2H), 8.62(s, 1H), 9.95(s, 1H).

IV-06
H
CN
H

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(CDCl₃) 8.31(s, 1H), 7.48(dd, J=2.44, 6.24Hz, 1H), 7.35(m, 1H), 6.33(s, 1H).

IV-07
H
H
CH₃

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(CDCl₃) 8.07(s, 1H), 8.00(d, J=2.2Hz, 1H), 7.46-7.35(m, 5H), 7.12(d, J=9.04Hz, 2H), 7.00(d, J=9.04Hz, 2H), 6.49(d, J=2.2Hz, 1H), 5.09(s, 2H), 1.90(s, 3H).

IV-08
H
H
CH₃

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(CDCl₃) 8.01(d, J=2.2Hz, 1H), 7.98(brs, 1H), 7.18(m, 2H), 7.01(m, 1H), 6.54(d, J=2.2Hz, 1H), 1.96(s, 3H).

IV-09
H
CN
CH₃

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(CDCl₃) 8.25(s, 1H), 8.16(brs, 1H), 7.14(d, J=8.8Hz, 2H), 6.94(d, J=8.8Hz, 2H), 4.07(q, J=7.08Hz, 2H), 1.89(s, 3H), 1.45 (t, J=6.84Hz, 3H).

Example 9

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (IV-02)]

Synthesis of (3-chloro-4-fluorophenyl) {5-chloro-3-methylthio(pyrazolo[1,5-a]pyrimidin-7-yl)}amine.

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Methyl magnesium chloride (0.25 mL, 3M solution) was added cautiously to a solution of {5-chloro-7-[(3-chloro-4-fluorophenyl)amino]-6-methyl(pyrazolo[1,5-a]pyrimidin-3-yl)}thiocarbonitrile (100 mg) in dry tetrahydrofuran (5 mL) while maintaining the temperature between 0-4° C. for 2 h. Acetic acid (2 equivalents.) was added and the solvent was removed under reduced pressure. Water and ethyl acetate were added and the product was extracted with ethyl acetate (3×). The combined organic phase was dried (Na₂SO₄) and evaporated to give the title compound (98 mg); mp 156-158° C.

Example 10

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (III)]

To a solution of the precursor (IV) formed above (2 g) in 1,4-dioxane (10 mL) was added di-tert-butyl dicarbonate (2 equivalents) in 1,4-dioxane (10 mL) followed by a catalytic amount of 4-dimethylaminopyridine. The reaction was stirred at room temperature overnight and if starting material was detected by TLC, the reaction was left for longer. The mixture was concentrated in vacuo and the residue was then partitioned between water and CH₂Cl₂. The organic phase was washed with 10% citric acid, water and saturated aqueous NaCl and then dried over MgSO₄. Removal of the solvent in vacuo gave the Boc protected intermediate (III). [Purification performed—filter column to remove any residual 4-dimethylaminopyridine. Analysis performed—¹H-NMR, HPLC and MS].

(III)

Compound

mp (° C.) or

No.
R¹
R²
R⁴
R³

¹H-NMR (400 MHz) d (ppm)

III-01
H
H
Me

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(CDCl₃) 1.94(br s, 9H, C(CH₃)₃), 2.55(s, 3H, CH₃), 6.68(s, 1H, Het-H), 7.05(d, 1H, ArH), 7.15(t, 1H, ArH), 7.24(t, 1H, ArH), 7.5(d, 1H, ArH), 8.12(s, 1H, Het-H).

III-02
H
Br
H

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136-138

III-03
H
Cl
H

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130-132

III-04
H
COOEt
CH₃

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(DMSO-d6) 1.10-1.50(m, 15H), 2.22(s, 3H), 3.98(q, J=7.08Hz, 2H), 4.30(q, J=7.08Hz, 2H), 6.87(d, J=8.80Hz, 2H), 7.22(d, J=9.04Hz, 2H), 8.68 (brs, 1H).

III-05
H
H
CH₃

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(CDCl₃) 8.12(d, J=2.2Hz, 1H), 7.78(d, J=8.8Hz, 1H), 7.73 (br, 1H), 7.31(br, 1H), 6.69(d, J=2.2Hz, 1H), 2.78(s, 3H), 2.31(brs, 3H), 1.35(brs, 9H).

III-06
H
H
CH₃

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(CDCl₃) 8.12(d, J=2.2Hz, 1H), 7.78(d, J=8.8Hz, 1H), 7.71(br, 1H), 7.31(br, 1H), 6.69(d, J=2.2Hz, 1H), 3.34(q, J=7.56Hz, 1H), 2.31(brs, 3H), 1.47 (t, J=7.32Hz, 3H), 1.35(brs, 9H).

III-07
H
H
CH₃

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(CDCl₃) 8.12(d, J=2.2Hz, 1H), 7.79(d, J=8.8Hz, 1H), 7.82(br, 1H), 7.31(br, 1H), 6.69(d, J=2.2Hz, 1H), 4.06 (sevenfold, J=6.84Hz, 1H), 2.32(brs, 3H), 1.49(d, J=6.84Hz, 6H), 1.35 (brs, 9H).

III-08
H
CH₃
CH₃

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(CDCl₃) 7.94(s, 1H), 7.17(d, J=9.04Hz, 2H), 6.80(d, 2H), 3.98(q, J=7.08Hz, 2H), 2.35(brs, 3H), 2.29(brs, 3H), 1.38(t, J=7.08Hz, 3H), 1.25(brs, 9H).

III-09
H
H
CH₃

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(CDCl₃) 8.09(d, J=2.44Hz, 1H), 7.98(d, J=9.04Hz, 2H), 7.27(d, J=8.53Hz, 2H), 6.69(d, 1H), 3.89(s, 3H), 2.24 (s, 3H), 1.36(s, 9H).

Example 11

[General Procedures for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (II)]

a) An intimate mixture (III) (100 mg) and amine (HNR⁵R⁶) (1.5 g) were heated together at 80-85° C. for 18 h, then cooled. The crude material was then partitioned between ethyl acetate and saturated aqueous NaHCO₃. The organic phase was then separated, washed with water and dried over MgSO₄and concentrated in vacuo. The crude material was then subjected to column chromatography over silica gel. CH₂Cl₂was used as eluent, then gradient elution up to 95% CH₂Cl₂+5% (10 M NH₃in methanol). Typical purified yield 20 mg.

b) A solution of the Boc intermediate (III) (0.248 mmol), the amine (HNR⁵R⁶) (0.496 mmol), copper iodide (0.496 mmol), and potassium carbonate (0.496 mmol) in DMSO (0.8 mL) was stirred at 85° C. for 2 days. The reaction mixture was cooled to room temperature, followed by quenched with saturated aqueous NH₄Cl. The mixture was extracted with Et₂O. The combined extract was washed with saturated aqueous NaCl, dried over Na₂SO₄, filtered, and evaporated. The residue was purified by column chromatography (5˜10% MeOH—CH₂Cl₂) to give the title compound (II).

c) Synthesis of 4-{7-[tert-Butoxycarbonyl-(4-ethoxy-phenyl)-amino]-6-methyl-pyrazolo[1,5-a]pyrimidin-5-ylamino}-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester

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A solution of the Boc intermediate (0.248 mmol), the (S)-4-amino L-proline (114 mg, 0.496 mmol), copper iodide (94.4 mg, 0.496 mmol) and potassium carbonate (68.5 mg, 0.496 mmol) in DMSO (0.8 mL) was stirred at 85° C. for 2 days. The reaction mixture was cooled to room temperature, followed by quenched with saturated aqueous NH₄Cl. The mixture was extracted with Et₂O. The combined extract was washed with saturated aqueous NaCl, dried over Na₂SO₄, filtered, and evaporated. The residue was purified by column chromatography (5˜10% MeOH—CH₂Cl₂) to give coupling compound (66.0 mg, 44.6%). The title compound was obtained.

The ¹H-NMR for this compound was shown bellow.

¹H-NMR (400 MHz, CD₃OD) d(ppm): 1.25 (t, J=7.1 Hz, 3H), 1.34 (s, 18H), 1.95 (m, 1H), 2.56 (m, 1H), 3.44 (m, 1H), 3.69 (m, 1H), 3.89 (q, J=7.1 Hz, 2H), 4.16 (m, 1H), 6.05 (m, 1H, 6.74 (d, J=7.1 Hz, 2H), 7.14 (d, J=8.5 Hz, 2H), 7.68 (s, 1H).

(II)

Compound

No.
R¹
R²
R⁴
R³
NR⁵R⁶

¹H-NMR (400 MHz) d (ppm)

II-26
H
COOEt
CH₃

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(DMSO-d6) 1.03-1.51(m, 19H), 1.74-2.08(m, 7H), 2.50-2.58(m, 1H), 3.96(q, J=7.08Hz, 2H), 4.01-4.13(m, 1H), 4.19(q, J=7.08Hz, 2H), 6.85 (d, J=9.04Hz, 2H), 6.91(d, J=7.32Hz, 1H), 7.18(d, J=8.56Hz, 2H), 8.17(brs, 1H).

Example 12

[General Procedures for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (I)]

a) An intimate mixture of the Boc intermediate (III) (100 mg) and the amine (HNR⁵R⁶) (1.5 g) were heated together at 80-85° C. for 90 min, then cooled. The crude material was then partitioned between CH₂Cl₂and saturated aqueous NaHCO₃. The organic phase was then separated and washed with water, dried over MgSO₄and concentrated in vacuo. The crude material dissolved in CH₂Cl₂(10 mL) and trifluoroacetic acid (5 mL). The mixture was stirred for 1 h at room temperature, then evaporated in vacuo. The residue was partitioned between saturated aqueous NaHCO₃and CH₂Cl₂, the organic phase was separated, dried over MgSO₄then subjected to column chromatography over silica gel. CH₂Cl₂was used as eluent, then gradient elution up to 95% CH₂Cl₂+5% (10 M NH₃in methanol). Typical purified yield 20 mg.

b) The Boc intermediate (III) (0.1 mmol) was dissolved in toluene (1 ml) and the amine (HNR⁵R⁶) (1.2 equivalents) was added. Tris(dibenzylideneacetone)dipalladium (0) (2 mol %), 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (4 mol %) and sodium tert-butoxide (1.2 equivalents) were added sequentially under an atmosphere of nitrogen. The reaction was heated and agitated overnight at 80° C. following which the reaction was filtered through a 0.45 micron filter. The solvent was removed in vacuo and the residue was resuspended in CH₂Cl₂(0.2 mL). Trifluoroacetic acid (0.8 mL) was added and the reactions allowed to stand for 1 h at room temperature. The mixture was evaporated to dryness, in vacuo, and the resultant residue was dissolved in N,N-dimethylformamide (1 mL), filtered and purified by preparative HPLC to give the product (I). [Analysis performed—LC/MS)].

Example 13

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (I-01)]

Synthesis of 1-{5-[(trans-4-aminocyclohexyl)amino]-7-[(4-iodophenyl)amino]-6-methyl(pyrazolo[1,5-a]pyrimidin-3-yl)}-2,2,2-trifluoroethan-1-one (Compound NO: 417).

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To a solution of N-{5-[(trans-4-aminocyclohexyl)amino]-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)}(tert-butoxy)-N-(4-iodophenyl)carboxamide (50 mg) in 1,2-dichloroethane (1.8 mL) was added trifluoroacetic anhydride (1.8 mL). The resulting mixture was stirred at 45° C. for 3 h and then the solvent was removed in vacuo. The residue was dissolved in CH₂Cl₂(1.25 mL). To this stirred solution was added trifluoroacetic acid (0.53 mL). The resulting mixture was stirred at room temperature for 3 h, and then the solvent was removed in vacuo. The residue was dissolved in tetrahydrofuran (1.6 mL) and methanol (0.18 mL). To this stirred solution was added 2 mol/L aqueous NaOH (0.18 mL). The resulting mixture was stirred at room temperature for 15 h. The reaction was quenched with aqueous 1N HCl. After extraction with CH₂Cl₂, the combined organic layer was washed with saturated aqueous NaCl, dried over Na₂SO₄and then the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (33.0 mg, yield 41% as 3 trifluoroacetic acids salt) as a white solid. The ¹H-NMR, HPLC retention time and ESI/MS data for this compound are shown below.

¹H-NMR (400 MHz, DMSO-d₆) d(ppm): 1.38-1.56 (m, 4H), 1.79 (s, 3H), 1.97-2.12(m, 4H), 3.04(brs, 1H), 4.09(brs, 1H), 6.73(d, J=8.52 Hz, 2H), 7.11(d, J=7.32 Hz, 1H), 7.57(d, J=8.04 Hz, 2H), 7.86(brs, 3H), 8.34(s, 1H), 9.27(s, 1H).

HPLC retention time (method A): 14.7 min.

ESI/MS: 559.3 (M+H, C₂₁H₂₂F₃IN₆O).

Example 14

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (I-02)]

Synthesis of {5-[(trans-4-aminocyclohexyl)amino]-3-fluoro-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)}(4-iodophenyl)amine (Compound NO: 441).

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N-{5-[(trans-4-aminocyclohexyl)amino]-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)}(tert-butoxy)-N-(4-iodophenyl)carboxamide (20 mg) was dissolved in tetrahydrofuran (300 μL). To this solution was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2,2,2]octane bis(tetrafluoroborate) (63 mg). The resulting mixture was stirred for 19 h at 40° C. The reaction was quenched with saturated aqueous NaHCO₃. After extraction with CH₂Cl₂, the combined organic layer was washed with saturated aqueous NaCl, dried over Na₂SO₄, and the solvent was removed in vacuo to give the crude Boc protected intermediate. This crude product was used in the next reaction without further purification.

The crude product was dissolved in CH₂Cl₂(2.0 mL). To this solution was added trifluoroacetic acid (0.2 mL). After stirring for 4 h, the solvent was removed in vacuo. The residue was purified on preparative TLC to give the title compound (1.5 mg, 9% yield). The ¹H-NMR, HPLC retention time and ESI/MS data for this compound are shown below.

¹H-NMR (400 MHz, CDCl₃) d(ppm): 1.25(m, 2H), 1.36(m, 2H), 1.72(s, 3H), 1.99(m, 2H), 2.22(m, 2H), 2.72(m, 1H), 4.14(m, 1H), 6.73(m, 2H), 7.32(brs, 1H), 7.60(m, 2H), 7.69(d, J=3.40 Hz, 1H).

HPLC retention time (method A): 12.9 min.

ESI/MS: 481.4 (M+H, C₁₉H₂₃FIN₆).

Example 15

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (II-04)]

Synthesis of 5-({trans-4-[(tert-butoxy)carbonylamino]cyclohexyl}amino)-7-[(tert-butoxy)-N-(4-ethoxyphenyl)carbonylamino]-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid.

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To a stirred suspension of ethyl 5-({trans-4-[(tert-butoxy)carbonylamino]cyclohexyl}amino)-7-[(tert-butoxy)-N-(4-ethoxyphenyl)carbonylamino]-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (5.55 g) in 2-propanol (136 mL) was added 2 mol/L aqueous NaOH (34 mL). The resulting mixture was stirred at 50° C. for 40 h, and then at 80° C. for 4 h. The mixture was acidified (pH 4) with 1 mol/L aqueous HCl and concentrated in vacuo. The residue was suspended in water (150 mL) and slowly stirred for 1 h. The precipitate was filtered and dried in vacuo to give the title compound (5.35 g, yield 78%) as a white solid. The ¹H-NMR and ESI/MS data for this compound are shown below.

¹H-NMR (400 MHz, DMSO-d₆) d(ppm): 1.19-1.28(br, 4H), 1.29(t, J=7.08 Hz, 3H), 1.38(s, 18H), 1.73-1.86(br, 2H), 1.86-2.04(br, 5H), 3.15-3.33(m, 1H), 3.97(q, J=7.08 Hz, 2H), 4.02-4.08(m, 1H), 6.43(brs, 1H), 6.82(d, J=8.80 Hz, 1H), 6.86(d, J=8.76 Hz, 2H), 7.20(d, J=7.80 Hz, 2H), 7.93(brs, 1H).

ESI/MS: 625.5 (M+H, C₃₂H₄₄N₆O₇).

Example 16

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (II-05)]

Synthesis of 5-({trans-4-[(tert-butoxy)carbonylamino]cyclohexyl}amino)-7-[(tert-butoxy)-N-(4-ethoxyphenyl)carbonylamino]-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide.

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To a stirred solution of 5-({trans-4-[(tert-butoxy)carbonylamino]cyclohexyl}amino)-7-[(tert-butoxy)-N-(4-ethoxyphenyl)carbonylamino]-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.25 g) in N,N-dimethylformamide (20 mL) were added ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (1.92 g), N-hydoroxybenzotriazole monohydrate (0.31 g), triethylamine (2.8 mL) and ammonia (5.0 mL, 2.0 mol/L in methanol). The resulting mixture was stirred at room temperature for 24 h. The reaction was quenched with saturated aqueous NaCl. After extraction with CH₂Cl₂, the combined organic layer was washed with water, dried over MgSO₄, and the solvent was removed in vacuo to give the crude title compound (1.25 g) as a white solid. This crude product was used in the next reaction without further purification. ESI/MS data for this compound are shown below.

ESI/MS: 624.6 (M+H, C₃₂H₄₅N₇O₆).

Example 17

[General Procedure for the Synthesis of Pyrazolo[1,5a]pyrimidines of General Formula (II-07)]

Synthesis of N-[5-({trans-4-[(tert-butoxy)carbonylamino]cyclohexyl}amino)-7-[(tert-butoxy)-N-(4-ethoxyphenyl)carbonylamino]-6-methyl(pyrazolo[1,5-a]pyrimidin-3-yl)](phenylmethoxyl)carboxamide.

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To a stirred solution of crude 5-({trans-4-[(tert-butoxy)carbonylamino]cyclohexyl}amino)-7-[(tert-butoxy)-N-(4-ethoxyphenyl)carbonylamino]-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide (1.25 g) in benzyl alcohol (5.0 mL) was added potassium tert-butoxide (0.561 g). The resulting mixture was stirred at room temperature for 10 min. and then at 0° C. for 10 min. To this stirred solution was added iodobenzene diacetate (0.773 g), stirred at 0° C. for 10 min., and allowed to warm room temperature. The resulting mixture was stirred at room temperature for 12 h. The reaction was quenched with saturated aqueous NaCl. After extraction with CH₂Cl₂, the combined organic layer was dried over MgSO₄, and solvent was removed in vacuo to give the crude title compound (1.46 g) as pale red oil. This crude product was used in the next reaction without further purification. The ¹H-NMR and ESI/MS data for this compound are shown below.

¹H-NMR (400 MHz, DMSO-d₆) d(ppm): 1.18-1.30(brs, 4H), 1.29(t, J=7.08 Hz, 3H), 1.38(s, 18H), 1.75-1.86(m,2H), 1.87-1.97(m, 2H), 2.00(brs, 3H), 3.15-3.28(m, 1H), 3.97(t, J=7.08 Hz, 2H), 3.85-4.10(m, 1H), 5.12(s, 2H), 6.43-6.53(m, 1H), 6.75(d, J=7.56 Hz, 2H), 6.86(d, J=8.80 Hz, 2H), 7.15-7.50(m, 7H), 7.83(brs, 1H), 8.86(brs, 1H).

ESI/MS: 730.7 (M+H, C₃₉H₅₁N₇O₇).

Example 18

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (II-08)]

Synthesis of N-[3-amino-5-({trans-4-[(tert-butoxy)carbonylamino]cyclohexyl}amino)-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)](tert-butoxy)-N-(4-ethoxyphenyl)carboxamide.

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To a stirred solution of the crude N-[5-({trans-4-[(tert-butoxy)carbonylamino]cyclohexyl}amino)-7-[(tert-butoxy)-N-(4-ethoxyphenyl)carbonylamino]-6-methyl(pyrazolo[1,5-a]pyrimidin-3-yl)](phenylmethoxyl)carboxamide (1.46 g) in ethanol (100 mL) and acetic acid (0.46 mL) was added Pd/C (0.29 g, 10% on carbon). The resulting mixture was stirred at room temperature for 2 days under hydrogen atmosphere, and Pd/C was filtered off. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (elute with ethyl acetate/n-hexane=3/1) to give the title compound (0.560 g, yield 47% for 2 steps) as a pale yellow solid. The ¹H-NMR and ESI/MS data for this compound are shown below.

¹H-NMR (400 MHz, DMSO-d₆) d(ppm): 1.20-1.35(brs, 4H), 1.29(t, J=7.08 Hz, 3H), 1.38(s, 18H), 1.75-1.90(brs, 3H), 1.90-2.05(m, 4H), 3.22(brs, 1H), 3.92-4.00(m, 3H), 6.21(brs, 1H), 6.77(d, J=8.04 Hz, 1H), 6.83-6.87(m, 3H), 7.20(brs, 3H), 7.45(brs, 1H).

ESI/MS: 596.6 (M+H, C₃₁H₄₅N₇O₅).

Example 19

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (I-09)]

Synthesis of N-{5-[(trans-4-aminocyclohexyl)amino]-7-[(4-ethoxyphenyl)amino]-6-methyl(pyrazolo[1,5-a]pyrimidin-3-yl)}acetamide (Compound NO: 378).

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To acetyl chloride (7.1 μL) were added N-[3-amino-5-({trans-4-[(tert-butoxy)carbonylamino]cyclohexyl}amino)-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)](tert-butoxy)-N-(4-ethoxyphenyl)carboxamide (14.9 mg) in CH₂Cl₂(250 μL) and triethylamine (13.9 μL). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous NaCl. After extraction with CH₂Cl₂, the solvent was removed in vacuo to give the crude di-Boc protected intermediate. This crude product was used in the nest reaction without further purification.

The crude product was dissolved in CH₂Cl₂(175 μL). To this solution was added trifluoroacetic acid (75 μL). The resulting mixture was stirred at room temperature for 2 h, and then the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (9.04 mg, yield 46% as 3 trifluoroacetic acids salt) as a white solid. The ¹H-NMR, HPLC retention time and ESI/MS data for this compound are shown below.

¹H-NMR (400 MHz, DMSO-d₆) d(ppm): 1.30(t, J=6.84 Hz, 3H), 1.32-1.55 (m, 4H), 1.63 (s, 3H), 1.85-2.05(m, 4H), 2.05(s, 3H), 3.00(brs, 1H), 3.97(q, J=6.80 Hz, 2H), 4.05(brs, 1H), 6.24(brs, 1H), 6.85(d, J=9.00 Hz, 2H), 6.90(d, J=8.80 Hz, 2H), 7.78(brs, 3H), 8.00(s, 1H), 8.54(brs, 1H), 9.40(brs, 1H).

HPLC retention time (method A): 8.4 min.

ESI/MS: 438.4 (M+H, C₂₃H₃₁N₇O₂).

Example 20

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (I-10)]

Synthesis of {5-[(trans-4-aminocyclohexyl)amino]-7-[(4-ethoxyphenyl)amino]-6-methyl(pyrazolo[1,5-a]pyrimidin-3-yl)}(methylsulfonyl)amine (Compound No: 386).

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To methanesulfonyl chloride (11.5 mg) were added N-[3-amino-5-({trans-4-[(tert-butoxy)carbonylamino]cyclohexyl}amino)-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)](tert-butoxy)-N-(4-ethoxyphenyl)carboxamide (14.9 mg) in CH₂Cl₂(250 μL) and triethylamine (13.9 μL). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous NaCl. After extraction with CH₂Cl₂, the solvent was removed in vacuo to give the crude di-Boc protected intermediate. This crude product was used in the next reaction without further purification.

The crude product was dissolved in CH₂Cl₂(175 μL). To this solution was added trifluoroacetic acid (75 μL). The resulting mixture was stirred at room temperature for 2 h, and then the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (2.43 mg, yield 12% as 3 trifluoroacetic acids salt) as a white solid. The ¹H-NMR, HPLC retention time and ESI/MS data for this compound are shown below.

¹H-NMR (400 MHz, DMSO-d₆) d(ppm): 1.26(t, J=7.08 Hz, 3H), 1.30-1.45 (m, 4H), 1.60 (s, 3H), 1.87-2.03(m, 4H), 2.93(brs, 1H), 3.06(s,3H), 3.85-3.98(m, 3H), 6.24(d, J=7.32 Hz, 1H), 6.81(d, J=9.28 Hz, 2H), 6.86(d, J=9.04 Hz, 2H), 7.68(s, 1H), 7.72(brs, 3H), 8.56(s, 1H), 8.75(s, 1H).

HPLC retention time (method A): 10.5 min.

ESI/MS: 474.4 (M+H, C₂₂H₃₁N₇O₃S).

Example 21

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (I-11)]

Synthesis of N-{5-[(trans-4-aminocyclohexyl)amino]-7-[(4-ethoxyphenyl)amino]-6-methyl(pyrazolo[1,5-a]pyrimidin-3-yl)}(phenylamino)carboxamide (Compound NO: 389).

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To phenyl isocyanate (11.9 mg) were added N-[3-amino-5-({trans-4-[(tert-butoxy)carbonylamino]cyclohexyl}amino)-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)](tert-butoxy)-N-(4-ethoxyphenyl)carboxamide (14.9 mg) in CH₂Cl₂(250 μL) and triethylamine (13.9 μL). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous NaCl. After extraction with CH₂Cl₂, the solvent was removed in vacuo to give the crude di-Boc protected intermediate. This crude product was used in the next reaction without further purification.

The crude product was dissolved in CH₂Cl₂(175 μL). To this stirred solution was added trifluoroacetic acid (75 μL). The resulting nature was stirred at room temperature for 2 h, and then the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (6.59 mg, yield 31% as 3 trifluoroacetic acids salt) as a white solid. The ¹H-NMR, HPLC retention time and ESI/MS data for this compound are shown below.

¹H-NMR (400 MHz, DMSO-d₆) d(ppm): 1.30(t, J=7.08 Hz, 3H), 1.36-1.47(m, 4H), 1.65(s, 3H), 1.90-2.10(m, 4H), 2.98(brs, 1H), 3.97(q, J=7.08 Hz, 2H, 4.03(brs, 1H), 6.13(brs, 1H), 6.82-6.96(m, 5H), 7.25(t, J=8.28 Hz, 2H), 7.45(d, J=7.60 Hz, 2H), 7.76(brs, 3H), 7.86(brs, 1H), 7.95(s, 1H), 8.58(brs, 1H), 8.76(brs, 1H).

HPLC retention time (method A): 10.9 min.

ESI/MS: 515.6 (M+H, C₂₈H₃₄N₈O₂).

Example 22

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (I-12)]

Synthesis of ({5-[(trans-4-aminocyclohexyl)amino]-7-[(4-ethoxyphenyl)amino]-6-methyl(pyrazolo[1,5-a]pyrimidin-3-yl)}amino)(methylamino)methane-1-thione (Compound No: 390).

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To methyl thioisocyanate (7.3 mg) were added N-[3-amino-5-({trans-4-[(tert-butoxy)carbonylamino]cyclohexyl}amino)-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)](tert-butoxy)-N-(4-ethoxyphenyl)carboxamide (14.9 mg) in CH₂Cl₂(250 μL) and triethylamine (13.9 μL). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated aqueous NaCl. After extraction with CH₂Cl₂, the solvent was removed in vacuo to give the crude di-Boc protected intermediate. This crude product was used in the next reaction without further purification.

The crude product was dissolved in CH₂Cl₂(175 μL). To this stirred solution was added trifluoroacetic acid (75 μL). The resulting mixture was stirred at room temperature for 2 h, and then the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (8.32 mg, yield 41% as 3 trifluoroacetic acids salt) as a white solid. The ¹H-NMR, HPLC retention time and ESI/MS data for this compound are shown below.

¹H-NMR (400 MHz, DMSO-d₆) d(ppm): 1.30(t, J=6.84 Hz, 3H), 1.33-1.50(m, 4H), 1.64(s, 3H), 1.88-2.05(m, 4H), 2.91(d, J=4.40 Hz, 3H), 2.98(brs, 1H), 3.88(brs, 1H), 3.97(q, J=6.80 Hz, 2H), 6.27(d, J=7.08 Hz, 1H), 6.80-6.95(m, 4H), 7.67(s, 1H), 7.70-7.90(m, 4H), 8.61(s, 1H), 9.06(s, 1H).

HPLC retention time (method A): 10.3 min.

ESI/MS: 469.4 (M+H, C₂₃H₃₂N₈OS).

Example 23

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (I-14)]

Synthesis of {5-[(trans-4-aminocyclohexyl)amino]-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)}[4-(methylethoxy)phenyl]amine (Compound NO: 197).

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A solution of N-{5-[(4-aminocyclohexyl)amino]-6-methyl(8-hydropyrazolo[1,5-a]pyrimidin-7-yl)}(tert-butoxy)-N-[4-(phenylmethoxy)phenyl]carboxamide (3.68 g) and Pd/C (0.78 g, 10% on carbon) in methanol (140 mL) was stirred under hydrogen atmosphere for 23 h. The catalyst was filtered off and the solvent was removed in vacuo to give the crude intermediate (2.93 g) as a pale brown solid. This crude intermediate was used in the next reaction without further purification.

A suspension of crude intermediate (22.7 mg), 2-propanol (19 μL) and polymer-supported triphenylphosphine resin (3.0 mmol/g, 83.5 mg) in CH₂Cl₂(1.0 mL) was shaken for 0.5 h at room temperature. To this suspension was added a solution of diisopropylazodicarboxylate (39.3 μL) in CH₂Cl₂(1.1 mL) and then shaken at room temperature for 10 h. The reaction mixture was filtrated and the residual resin was washed with CH₂Cl₂(3×1.0 mL). The combined filtrate was evaporated in vacuo to give the crude Boc protected intermediate. This crude product was used in the next reaction without further purification.

The crude product was dissolved in CH₂Cl₂(1.0 mL). To this solution was added trifluoroacetic acid (0.87 mL). The resulting mixture was stirred at room temperature for 2.3 h and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (7.3 mg, 37% yield as 3 trifluoroacetic acids salt). The HPLC retention time and ESI/MS data for this compound are shown below.

HPLC retention time (method A): 7.6 min.

ESI/MS: 395.0 (M+H, C₂₂H₃₀N₆O).

Synthesis of {5-[(trans-4-aminocyclohexyl)amino]-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)}[3-(2-piperazinylethoxy)phenyl]amine (Compound NO: 259)

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A solution of N-{5-[(4-aminocyclohexyl)amino]-6-methyl(8-hydropyrazolo[1,5-a]pyrimidin-7-yl)}(tert-butoxy)-N-[3-(phenylmethoxy)phenyl]carboxamide (11.6 g) and Pd/C (0.62 g, 10% on carbon) in methanol (150 mL) was stirred under hydrogen atmosphere for 23 h. The catalyst was filtered off and the solvent was removed in vacuo to give the crude intermediate (10.7 g) as a pale brown solid. This crude intermediate was used in the next reaction without further purification.

A suspension of crude intermediate (33.9 mg), 4-(2-hydroxyethyl)piperazinecarboxylate (86.4 mg) and polymer-supported triphenylphosphine resin (3.0 mmol/g, 125 mg) in CH₂Cl₂(1.75 mL) was shaken for 0.5 h at room temperature. To this suspension was added a solution of diisopropylazodicarboxylate (59.0 μL) in CH₂Cl₂(1.0 mL) and then shaken at room temperature for 17.5 h. The reaction mixture was filtrated and the residual resin was washed with CH₂Cl₂(3×1.0 mL). The combined filtrate was evaporated in vacuo to give the crude Boc protected intermediate. This crude product was used in the next reaction without further purification.

The crude product was dissolved in CH₂Cl₂(1.0 mL). To this solution was added trifluoroacetic acid (0.87 mL). The resulting mixture was stirred at room temperature for 2.3 h and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (20.6 mg, 34% yield as 3 trifluoroacetic acids salt). The HPLC retention time and ESI/MS data for this compound are shown below.

HPLC retention time (method B): 2.3 min.

ESI/MS: 465.7 (M+H, C₂₅H₃₆N₈O).

Example 24

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (I-16)]

Synthesis of {5-[(trans-4-aminocyclohexyl)amino]-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)}(4-phenylphenyl)amine (Compound NO: 284).

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A mixture of N-{5-[(trans-4-aminocyclohexyl)amino]-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)}(tert-butoxy)-N-(4-iodophenyl)carboxamide (30 mg), phenylboronic acid (7.2 mg), Na₂CO₃(67.8 mg), palladium (II) acetate (3.6 mg) and triphenylphosphine (12.5 mg) in it-propanol (1.08 mL) and H₂O (0.217 mL) was stirred for 19.3 h at 80° C. The reaction mixture was filtrated and the filtrate was evaporated in vacuo to give the crude Boc protected intermediate. This crude product was used in the next reaction without further purification.

The crude product was dissolved in CH₂Cl₂(1.0 mL). To this solution was added trifluoroacetic acid (0.87 mL). The resulting mixture was stirred for 1.8 h, the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (9.1 mg, 23% yield as 3 trifluoroacetic acids salt). The HPLC retention time and ESI/MS data for this compound are shown below.

HPLC retention time (method B): 10.8 min.

ESI/MS: 413.3 (M+H, C₂₅H₂₈N₆).

Synthesis of {5-[(trans-4-aminocyclohexyl)amino]-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)}(3-(3-pyridyl)phenyl)amine (Compound NO: 450).

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The title compound and Boc protected intermediate were synthesised in the same manner as above using N-{5-[(trans-4-aminocyclohexyl)amino]-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)}(tert-butoxy)-N-(3-iodophenyl)carboxamide, pyridine-3-boronic acid, Na₂CO₃palladium (II) acetate and triphenylphosphine. The title compound (6.1 mg, 15% yield as 3 trifluoroacetic acids salt) was obtained. The HPLC retention time and ESI/MS data for this compound are shown below.

HPLC retention time (method A): 6.0 min.

ESI/MS: 414.1 (M+H, C₂₄H₂₇N₇).

Example 25

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (I-17)]

Synthesis of {5-[(trans-4-aminocyclohexyl)amino]-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)}[4-(2-phenylethynyl)phenyl]amine (Compound NO: 375).

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To a mixture of N-{5-[(trans-4-aminocyclohexyl)amino]-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)}(tert-butoxy)-N-(4-iodophenyl)carboxamide (30 mg), palladium (II) acetate (6.0 mg), triphenylphosphine (7.0 mg) in tetrahydrofuran (0.5 mL) was added ethynylbenzene (17.6 μL) and triethylamine (26 μL). The resulting mixture was stirred for 15 min. To this mixture was added cupper (I) iodide (3.0 mg) and stired for 1 h at 50° C. The reaction mixture was filtrated and the filtrate was evaporated in vacuo to give the crude Boc protected intermediate. This crude product was used in the next reaction without further purification.

The crude product was dissolved in CH₂Cl₂(1.0 mL). To this solution was added trifluoroacetic acid (0.87 mL). After stirring for 4 h, the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (11.4 mg, 27% yield as 3 trifluoroacetic acids salt). The HPLC retention time and ESI/MS data for this compound are shown below.

HPLC retention time (method A): 12.7 min.

ESI/MS: 437.2 (M+H, C₂₇H₂₈N₆).

Example 26

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (I-19)]

Synthesis of 4-({5-[(trans-4-aminocyclohexyl)amino]-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)}amino)phenyl pyrrolidinyl ketone (Compound No.792).

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To a stirred solution of 4-{(tert-butoxy)-N-[5-({trans-4-[(tert-butoxy)carbonylamino]cyclohexyl}amino)-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)]carbonylamino}benzoic acid (50 mg) in N,N-dimethylformamide (1.0 mL) was added carbonyldiimidazole (69 mg) and stirred at room temperature for 30 minutes. The resulting mixture was added to pyrrolidine (100 μL) and stirred at room temperature for 15 h. The reaction was quenched with saturated aqueous NaCl. After extraction with CH₂Cl₂, the solvent was removed in vacuo to give the crude di-Boc protected intermediate. This crude product was used in the next reaction without further purification.

The crude product was dissolved in CH₂Cl₂(700 μL). To this stirred solution was added trifluoroacetic acid (300 μL). The resulting mixture was stirred at room temperature for 2 h, and then the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (39.43 mg, yield 59% as 3 trifluoroacetic acids salt) as a white solid. The ¹H-NMR, HPLC retention time and ESI/MS data for this compound are shown below.

¹H-NMR (400 MHz, DMSO-d₆) d(ppm): 1.37-1.53 (m, 4H), 1.73-1.88 (m, 7H), 1.92-2.07 (m, 4H), 2.95-3.05 (m, 1H), 3.43 (t, J=6.60 Hz, 4H), 3.89-4.00 (m, 1H), 6.07 (s, 1H), 6.49 (brs, 1H), 6.86 (d, J=8.28 Hz, 2H), 7.45 (d, J=8.56 Hz, 2H), 7.73-7.91 (m, 4H), 9.18 (brs, 1H).

HPLC retention time (method A): 6.9 min.

ESI/MS: 434.1 (M+H, C₂₄H₃₁N₇O).

Example 27

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (I-21)]

Synthesis of 1-{5-[(trans-4-aminocyclohexyl)amino]-7-[(4-ethoxyphenyl)amino]-6-methyl(pyrazolo[1,5-a]pyridin-3-yl)}pentan-1-one (Compound NO:362).

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(tert-Butoxy)-N-[5-({trans-4-[(tert-butoxy)carbonylamino]cyclohexyl}amino)-3-(N-methoxy-N-methylcarbamoyl)-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)]-N-(4-ethoxyphenyl)carboxamide (33.4 mg) was dissolved in tetrahydrofuran (500 μL) and stirred at −7° C. for 5 min under nitrogen atmosphere. To this stirred solution was added n-butyl lithium (61.5 μL, 2.44 M in n-hexane). The resulting mixture was stirred at −78° C. for 1 h, allowed to warm at room temperature and then stirred at room temperature for 23 h. The reaction was quenched with saturated aqueous NH₄Cl. After extraction with ethyl acetate, the combined organic layer was washed with saturated aqueous NaCl, dried over Na₂SO₄and then the solvent was removed in vacuo to give the crude di-Boc protected intermediate. This crude product was used in the next reaction without further purification.

The crude product was dissolved in CH₂Cl₂(175 μL). To this stirred solution was added trifluoroacetic acid (75 μL). The resulting mixture was stirred at room temperature for 2 h, and then the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (2.93 mg, yield 6% for 2 steps as 3 trifluoroacetic acids salt) as a white solid. The ¹H-NMR, HPLC retention time and ESI/MS data for this compound are shown below.

¹H-NMR (400 MHz, DMSO-d₆) d(ppm): 0.91(t, J=7.32 Hz, 3H), 1.30(t, J=7.04 Hz, 3H), 1.32-1.52(m, 6H), 1.57-1.67 (m, 5H), 1.90-2.15(m, 4H), 2.96-3.06(m, 3H), 3.92-4.03(m, 3H), 6.57(d, J=7.32 Hz, 1H), 6.85(d, J=9.04 Hz, 2H), 6.92(d, J=9.00 Hz, 2H), 7.75-7.90(m, 3H), 8.14(s, 1H), 8.78(s, 1H).

HPLC retention time (method A): 14.2 min.

ESI/MS: 465.2 (M+H, C₂₆H₃₆N₆O₂).

Example 28

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (I-23)]

Synthesis of {5-[(trans-4-aminocyclohexyl)amino]-6-methyl-[3-benzylamino](pyrazolo[1,5-a]pyrimidin-7-yl)}(4-ethoxyphenyl)amine (Compound No. 436).

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To sodium hydride (1.2 mg) was added N-[5-({trans-4-[(tert-butoxy)carbonylamino]cyclohexyl}amino)-7-[(tert-butoxy)-N-(4-ethoxyphenyl)carbonylamino]-6-methyl(pyrazolo[1,5-a]pyrimidin-3-yl)]-2,2,2-trifluoroacetamide (20.8 mg) in tetrahydrofuran (300 μL). The resulting mixture was stirred at room temperature for 1 h, to this solution was added benzyl bromide (4.3 μL) and then stirred at room temperature for 15 h. The reaction was quenched with saturated aqueous NaCl. After extraction with CH₂Cl₂, the solvent was removed in vacuo. The residue was dissolved in CH₂Cl₂(210 μL). To this stirred solution was added trifluoroacetic acid (90 μL). The resulting mixture was stirred at room temperature for 2 h, and then the solvent was removed in vacuo. The residue was dissolved in methanol (300 μL). To this stirred solution was added aqueous 2 mol/L NaOH (75 μL). The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous NaCl. After extraction with CH₂Cl₂, the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (12.79 mg, yield 52% as 3 trifluoroacetic acids salt) as a white solid. The ¹H-NMR, HPLC retention time and ESI/MS data for this compound are shown below.

¹H-NMR (400 MHz, DMSO-d₆) d(ppm): 1.30(t, J=7.08 Hz, 3H), 1.38-1.55(m, 4H), 1.65(s, 3H), 1.95-2.13(m, 4H), 3.02(brs, 1H), 3.92-4.05(m, 3H), 4.62(s, 2H), 6.50(d, J=7.02 Hz, 1H), 6.85(d, J=9.28 Hz, 2H), 6.89(d, J=9.28 Hz, 2H), 7.38-7.46(m, 5H), 7.80(s, 1H), 7.88-7.97(m, 3H), 8.73(s, 1H).

HPLC retention time (method A): 11.2 min.

ESI/MS: 486.4 (M+H, C₂₈H₃₅N₇O).

Synthesis of [5-[(trans-4-aminocyclohexyl)amino]-3-({[3-(difluoromethoxy)phenyl]methyl}amino)-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)](4-ethoxyphenyl)amine (Compound No. 791).

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To a solution of 3-(difluoromethoxy)benzaldehyde (5.1 mg) in 1,2-dichloroethane (340 μL) and acetic acid (35 μL) were added N-[3-amino-5-({trans-4-[(tert-butoxy)carbonylamino]cyclohexyl}amino)-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)](tert-butoxy)-N-(4-ethoxyphenyl)carboxamide (22.4 mg). The resulting mixture was stirred at 70° C. for 30 min. To this solution was added sodium tetrahydroborate (20 mg) and stirred at room temperature for 10 min. The reaction was quenched with water. After extraction with CH₂Cl₂, the combined organic layer was washed with saturated aqueous NaCl and the solvent was removed in vacuo to give the crude di-Boc protected intermediate. This crude product was used in the next reaction without further purification.

The crude product was dissolved in CH₂Cl₂(280 μL). To this stirred solution was added trifluoroacetic acid (120 μL). The resulting mixture was stirred at room temperature for 2 h, and then the solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (15.58 mg, yield 46% as 3 trifluoroacetic acids salt) as a white solid. The ¹H-NMR, HPLC retention time and ESI/MS data for this compound are shown below.

¹H-NMR (400 MHz, DMSO-d₆) d(ppm): 1.30(t, J=6.84 Hz, 3H), 1.35-1.52(m, 4H), 1.65(s, 3H), 1.95-2.12(m, 4H), 3.01(m, 1H), 3.92-4.00(m, 3H), 4.63(s, 2H), 6.40-6.47(m, 1H), 6.82-6.90(m, 4H), 7.16-7.30(m, 4H), 7.45(t, J=8.04 Hz, 1H), 7.76(brs, 1H), 7.85(brs, 3H), 8.69(brs, 1H).

HPLC retention time (method A): 10.9 min.

ESI/MS: 552.1 (M+H, C₂₉H₃₅F₂N₇O₂).

Example 29

[General Procedure for the Synthesis of Pyrazolo[1,5a-]pyrimidines of General Formula (I-25)]

Synthesis of {7-[(4-ethoxyphenyl)amino]-6-methyl(pyrazolo[1,5-a]pyrimidin-5-yl)}methyl-3-piperidylamine (Compound NO: 340).

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To a solution of tert-butyl 3-({7-[(tert-butoxy)-N-(4-ethoxyphenyl)carbonylamino]-6-methyl(pyrazolo[1,5-a]pyrimidin-5-yl)}methylamino)piperidinecarboxylate (22.3 mg) in N,N-dimethylformamide (0.5 mL) was added sodium hydride (>60% w/w in oil, 3.1 mg). The resulting mixture was stirred at room temperature for 10 min. To this solution was added methyl iodide (3.7 μL) and the resulting mixture was stirred for further 15 h. The reaction was quenched with water. After extraction with CH₂Cl₂, the combined organic layer was washed with saturated aqueous NaCl, dried over Na₂SO₄, and the solvent was removed in vacuo to give the crude di-Boc protected intermediate. This crude product was used in the next reaction without further purification.

The crude product was dissolved in CH₂Cl₂(1.0 mL). To this solution was added trifluoroacetic acid (0.87 mL) and stirred for 5.5 h. The solvent was removed in vacuo. The residue was purified on preparative TLC to give the title compound (14.6 mg, 64% yield). The ¹H-NMR, HPLC retention time and ESI/MS data for this compound are shown below.

¹H-NMR (400 MHz, DMSO-d₆) d(ppm): 1.42(t, 3H), 1.78(s, 3H), 1.81(m, 3H), 1.96(m, 1H), 2.57(m, 1H), 2.86(s, 3H), 2.89(m, 1H), 3.08(m, 1H), 3.24(m, 1H), 3.49(m, 1H), 3.99(q, 2H), 5.30(brs, 1H), 6.24(d, J=2.2 Hz, 1H), 6.91(m, 2H), 6.98(m, 2H), 7.68(brs, 1H), 7.85(d, J=2.2 Hz, 1H) HPLC retention time (method A): 9.8 min.

ESI/MS: 381.2 (M+H, C₂₁H₂₈N₆O).

Example 30

[General Procedure for the Synthesis of Pyrazolo[1,5a-]pyrimidines of General Formula (I-27)]

Synthesis of {5-[((3S)(3-piperidyl))amino]-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)}(4-ethoxyphenyl)amine (Compound NO: 193).

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To a stirred solution of N-(5-{[(3S)-1-benzyl(3-piperidyl)]amino}-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl))(tert-butoxy)-N-(4-ethoxyphenyl)carboxamide (272 mg) in CH2Cl2 (2 mL) was added trifluoroacetic acid (2 mL). After stirring at room temperature for 3 h, the reaction mixture was poured into the saturated aqueous NaHCO₃and extracted with CH₂Cl₂. The combined extract was washed with saturated aqueous NaCl, dried over Na₂SO₄, filtered, and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (96% CH₂Cl₂+4% (2 M NH₃in methanol) was used as eluent, then gradient elution up to 90% CH₂Cl₂+10% (2.0 M NH₃in methanol)) to give the intermediate (237 mg).

A solution of this intermediate in ethanol (2 mL) was hydrogenated under hydrogen atmosphere in the presence of Pd(OH)₂/C (125 mg, 10% on carbon). After stirring for 5 h, the reaction mixture was filtered, and evaporated in vacuo. The crude residue was purified by column chromatography (96% CH₂Cl₂+4% (2.0 M NH₃in methanol)) to give the title compound (107 mg, 60%). The 1H-NMR, HPLC retention time and ESI/MS data for this compound are shown below.

1H-NMR (400 MHz, CDCl3) d(ppm): 7.76 (d, J=2.2 Hz, 1H), 7.49 (s, 1H), 7.00 (d, J=9.0 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 6.11 (d, J=2.2 Hz, 1H), 4.95 (m, 1H), 4.27 (m, 1H), 4.02 (q, J=7.1 Hz, 2H), 3.20 (m, 1H), 2.83 (m, 2H), 2.71 (dd, J=6.2 Hz, 11.4 Hz, 1H), 1.87 (m, 1H), 1.71 (m, 2H), 1.71 (s, 3H), 1.56 (m, 1H), 1.49 (t, J=7.1 Hz, 3H).

HPLC retention time (method A): 8.0 min.

ESI/MS: 367.4 (M+H, C₂₀H₂₆N₆O).

Synthesis of [5-(azaperhydroepin-3-ylamino)-6-methyl(pyrazolo[1,5-a]pyrimidin-7-yl)](4-ethoxyphenyl)amine (Compound No: 272).

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To a solution of (tert-butoxy)-N-(4-ethoxyphenyl)-N-(6-mrthyl-5-{[1-benzylazaperhydoepin-3-yl]amino}(pyrazolo[1,5-a]pyrimidine-7-yl))carboxamide (6.6 mg) in CH₂Cl₂(0.5 mL) was added trifluoroacetic acid (0.3 mL) at 0° C. After stirring for 16 h at room temperature, the reaction mixture was poured into saturated aqueous NaHCO₃and extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous NaCl, dried over Na₂SO₄, filtered, and evaporated in vacuo. The residue was purified on preparative TLC to give the intermediate (5.0 mg, 91%).

To a stirred solution of this intermediate (2.0 mg) in CH₂Cl₂(0.3 mL) was added α-chloroethyl chloroformate (2 μL) at 0° C. After stirring for 0.5 h, to the reaction mixture was added saturated aqueous NaHCO₃and then extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous NaCl, dried over Na₂SO₄, filtered, and evaporated in vacuo. The residue was dissolved in methanol (0.5 mL). After reflux for 4 h, the reaction mixture was cooled to room temperature and then evaporated in vacuo. The residue was purified on preparative TLC (90% CH₂Cl₂+10% (2.0 M NH₃in methanol)) to give the title compound (0.9 mg, 59%). The HPLC retention time and ESI/MS data for this compound are shown below.

HPLC retention time (method A): 4.4 min.

ESI/MS: 381.4 (M+H, C₂₁H₂₈N₆O).

Example 31

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (I-29)]

Synthesis of {5-[(trans-4-aminocyclohexyl)amino]-3-iodo(pyrazolo[1,5-a]pyrimidin-7-yl)}[(3-chlorophenyl)methyl]amine (Compound NO: 297).

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To a stirred solution of {5-[(trans-4-aminocyclohexyl)amino](pyrazolo[1,5-a]pyrimidin-7-yl)}[(3-chlorophenyl)methyl]amine (41.8 mg) in CH₂Cl₂(565 μL) was added ICl (169 μL, 1.0 M in CH₂Cl₂), and the resulting mixture was stirred at room temperature for 4 h in the dark. The reaction was quenched with saturated aqueous Na₂S₂O₃. The resulting precipitate was collected by filtration. After extraction of filtrate by CH₂Cl₂, the combined organic layer was washed with saturated aqueous NaCl. To this solution, the precipitate collected above was dissolved, and the solvent was removed in vacuo. The residue was purified by preparative HPLC, and the fraction contained the title compound was basified (pH 9) with saturated aqueous NaHCO₃. After extraction with CH₂Cl₂, combined organic layer was dried over Na₂SO₄. The solvent was removed in vacuo, and the title compound (23.11 mg, 41% yield) was obtained as a white solid. The ¹H-NMR, HPLC retention time and ESI/MS data for this compound are shown below.

¹H-NMR (270 MHz, DMSO-d₆) d(ppm): 1.00-1.40(m, 4H), 1.70-2.00(m, 4H), 2.71(m, 1H), 3.65(m, 1H), 4.44(brs, 2H), 5.10(s, 1H), 6.76(d, J=7.83 Hz, 1H), 7.10-7.50(m, 4H), 7.81(s, 1H), 8.05(brs, 1H).

HPLC retention time (method A): 7.6 min.

ESI/MS: 497.4 (M+H, C₁₉H₂₂ClIN₆).

Example 32

[General Procedure for the Synthesis of Pyrazolo[1,5-a]pyrimidines of General Formula (I-31)]

To a solution of pyrazolo[1,5-a]pyrimidine (I-30) (50 mg) in tetrahydrofuran (5 ml) was added cyclohexanone (1.1 equivalents) and the reaction was heated for 16 h at 60° C. To the cooled mixture was then added sodium cyanoborohydride (5 equivalents) and stirred at room temperature for 2 h. The mixture was evaporated to dryness, in vacuo, and the resultant residue dissolved in water and ethyl acetate. The organic layer was separated, dried over MgSO₄then subjected to column chromatography over silica gel. The eluent was CH₂Cl₂, then gradient elution up to 95% CH₂Cl₂+5% (10 M NH₃in methanol) to give pyrazolo[1,5-a]pyrimidine of General Formula (I-31).

Example 33

Synthesis of 7-N-(4-Ethoxy-phenyl)-6-methyl-5-N-(4-propyl-piperidin-3-yl)-pyrazolo[1,5-a]pyrimidine-5,7-diamine (Compound NO:814)

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To a stirred solution of 4-allyl 3-oxopiperidine (3.39 g, 12.4 mmol) in tetrahydrofuran (31 mL) was added a solution of lithium tris sec-buyul hydrobororate in tetrahydrofuran (15 mL; 1M solution ) at −78° C. After stirring at −78° C. for 3 h, the mixture was acidified with 1 N HCl and extracted with AcOEt. The combined extract was washed with saturated aqueous NaHCO₃, followed by saturated aqueous NaCl. The organic layer was dried over Na₂SO₄, filtered and evaporated in vacuo. The residue was purified by column chromatography (20% AcOEt-hexane) to give 4-Allyl-3-hydroxy-piperidine-1-carboxylic acid benzyl ester (3.12 g).

¹H-NMR (400 MHz, CDCl₃) d(ppm): 7.35 (m, 5H), 5.79 (m, 1H), 5.13 (m, 2H), 5.09 (m, 1H, 5.04 (m, 1H), 4.22 (br, 2H), 3.83 (m, 1H), 2.92 (m, 1H), 2.77 (br, 1H), 2.21 (m, 1H), 2.05 (m, 1H), 1.57 (m, 2H), 1.48 (br, 1H).

To a stirred solution of 4-Allyl-3-hydroxy-piperidine-1-carboxylic acid benzyl ester (293 mg, 1.06 mmol) were added triphenyl phosphine(362 mg, 1.38 mmol), a solution of diethyl azodicarboxylate in toluene (0.6 ml, 1.38 immol; 40% solution) and DPPA (297 μL, 1.38 mmol). After stirring for 4 h, the mixture was evaporated and the residue was purified by column chromatography (15% AcOEt-hexane)to give 4-Allyl-3-azido-piperidine-1-carboxylic acid benzyl ester.

To a stirred solution of above residue in tetrahydrofuran (3.5 mL)-H₂O (0.35 mL) was added triphenyl phosphine (417 mg, 1.59 mmol). The mixture was stirred under reflux for 16 h, added NaSO₄, filtered and evaporated. The crude mixture was purified by column chromatography to give 4-Allyl-3-amino-piperidine-1-carboxylic acid benzyl ester (118 mg, 41% in 2 steps).

¹H-NMR (400 MHz, CD₃OD) d(ppm): 7.2 (m, 5H), 5.71 (m, 1H), 5.00 (s, 2H), 4.99 (m, 1H), 4.93 (m, 1H), 4.05 (m, 1H), 3.96 (m, 1H), 2.70 (br, 1H), 2.47 (br, 1H), 2.39 (m, 1H), 2.30 (m, 1H), 1.84 (m, 1H), 1.66 (m, 1H), 1.24 (m, 1H), 1.04 (m, 1H).

4-Allyl-3-[7-(4ethoxy-phenylamino)-6-methyl-pyrazolo[1,5-a]pyrimidin-5-ylamino]-piperidine-1-carboxylic acid benzyl ester was prepared by Example 12.

A solution of 4-Allyl-3-[7-(4-ethoxy-phenylamino)-6-methyl-pyrazolo[1,5-a]pyrimidin-5-ylamino]-piperidine-1-carboxylic acid benzyl ester (3.1 mg) in EtOH (1.5 mL) was hydrogenated in the presence of 10% palladium on carbon (7.5 mg) for 45 min. The mixture was filtered through a pad of Celite and evapotrated. The residue was purified on preparative TLC to give the title compound (1.4 mg).

¹H-NMR (400 MHz, CDCl₃) d(ppm): 7.77 (d, J=2.2 Hz, 1H), 7.51 (s, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.86 (d, J=9.04 Hz, 2H), 6.10 (d, J=2.2 Hz, 1H), 4.45 (br, 1H), 4.05 (m, 1H), 4.02 (q, J=6.84 Hz, 2H), 3.47 (dd, 1H), 3.09 (m, 1H), 2.68 (m, 1H), 2.48 (m, 1H), 2.02 (m, 1H), 1.91-1.43 (m, 3H), 1.69 (s, 3H), 1.42 (t, J=6.84 Hz, 3H), 1.26 (m, 2H), 0.89 (t, J=7.08 Hz, 3H).

Example 34

The compounds of the invention listed in Table B below were synthesized according to the respective methods in Examples 1 to 33 using the corresponding starting materials and reagents. The numbers assigned to each of the compounds in Table B correspond to the Compound Nos. of the compounds listed as specific examples in Table A above. 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-d₆or CDCl₃) of selected compounds of the invention were measured. The data for the chemical shifts (d: ppm) and coupling constants (J: Hz) are shown in Table B. The “HPLC retention time” are the retention time for the compounds in HPLC analysis carried out under the condition of the Method A, B, C or D above. The “method of preparation” in Table B are the example numbers of the corresponding methods in witch the compounds were synthesized.

TABLE B

HPLC

Retention

Method

Compound
ESI/MS
Time
HPLC

of

No.
M+H
M−H
(min.)
Method
Mp(° C.)
1H-NMR(400 MHz) d(ppm)
Preparation

1
400.2

9.5
A

(DMSO-d6)
12

8.31(s, 1H), 7.61(dd, 1H),

7.49(t, 1H), 7.39(m, 1H), 7.27(d,

1H), 5.59(s, 1H), 3.94(m, 1H),

2.49(m, 1H), 1.88(m, 2H),

1.76(m, 2h), 1.15(m, 4H).

2
455

10.2
A
222-225

12

3
389

102-105(d)

12

4
431

102-105(d)

12

5
451

198-200(d)

12

6
469

12.1
A
224-226(d)

12

7
409

11.2
A
227-230(d)

12

8
509

234-237(d)

12

9
447

221-223

12

10
389

9.4
A
229-232

12

11
417

10.3
A
196-198
((DMSO-d6)
12

7.76(s, 1H), 7.31(t, 1H),

6.95(d, 1H), 6.71(m, 1H), 6.30(d,

2H), 6.09(s, 1H), 4.05(m, 1H),

2.60(m, 2H), 2.52(m, 2H),

1.95(m, 2H), 1.85(m, 2H), 1.45(m,

4H), 1.20(m, 2H), 0.90(t, 2H).

12
451

10.9
A
Gum

12

13
469
467
10.5
A
Gum

12

14
495

13.2
A
188-191

12

15
371

9.1
A
87-92(d)
(CDCl₃)
12

7.79(s, 1H), 7.42(d, 2H),

7.15(t, 1H), 6.98(t, 1H), 6.80(d,

1H), 6.25(s, 1H), 4.35(m, 1H),

4.18(m, 1H), 2.71(m, 1H),

2.21(m, 2H), 1.92(m, 1H), 1.72(s,

3H), 1.35(m, 2H), 1.25(m,

2H).

16
385
383
9.4
A
174-176(d)
(CDCl₃)
12

7.79(s, 1H), 7.41(d, 1H),

7.15(t, 1H), 6.98(t, 1H), 7.87(d,

1H), 6.13(s, 1H), 4.42(d, 1H),

4.10(m, 1H), 2.70(m, 1H),

2.28(q, 2H), 2.20(m, 2H), 1.19(m,

2H), 3.37(m, 2H), 1.25(m,

2H), 1.00(t, 3H).

17
397

9.9
A
153-155

12

18
469
467

213-216

12

19
415
413
10.3
A
176-178
(CDCl₃)
12

7.75(s, 1H), 7.55(bs, 1H),

7.10(m, 2H), 6.92(m, 1H), 6.13(s,

1H), 5.65(m, 1H), 5.18(d, 1H),

5.15(d, 1H), 4.62(d, 1H),

4.02(m, 1H), 3.00(d, 2H), 2.70(m,

1H), 2.18(m, 2H), 1.90(m,

2H), 1.45(bs, 2H), 1.32(m,

2H), 1.10(m, 2H).

20
449

220-222

12

21
337

Gum

12

22
447

11.3
A
Gum

12

23
403
401
9.5
A
Gum

12

24
465
463
10.9
A
Gum
(CDCl₃)
12

7.80(s, 1H), 7.49(s, 1H),

7.25(m, 3H), 7.09(m, 3H), 6.90(m,

2H), 6.18(s, 1H), 4.21(d, 1H),

3.90(m, 1H), 2.55(m, 1H),

2.03(s, 2H), 1.97(d, 2H), 1.80(d,

2H), 1.28(m, 1H), 1.25(m,

2H), 0.85(m, 2H).

25
369
367
7.7
A
Gum
(CDCl₃)
12

7.88(s, 1H), 7.15(m, 2H),

7.04(m, 2H), 6.95(m, 1H), 6.12(s,

1H), 4.40(d, 2H), 4.10(m, 1H),

2.71(m, 1H), 2.28(q, 2H),

2.20(d, 2H), 1.90(d, 2H),

1.20~1.50(m, 6H), 0.90(t, 3H).

26
385
383
8.9
A
Gum
(CDCl₃)
12

7.87(s, 1H), 7.25(d, 2H),

6.95(d, 2H), 6.12(s, 1H), 4.40(m,

1H), 4.10(m, 1H), 2.70(m,

1H), 2.25(q, 2H), 2.20(d, 2H),

2.05(d, 1H), 1.96(d, 2H),

1.53(bs, 2H), 1.45~1.15(m, 4H),

0.97(t, 3H).

27
380

7.7
A
202-204
(CDCl₃)
12

7.75(s, 1H), 7.28(d, 1H),

7.20(t, 1H), 6.65(m, 2H), 6.59(s,

1H), 6.12(s, 1H), 4.40(m, 1H),

4.10(m, 1H), 3.80(s, 3H),

2.71(m, 1H), 2.32(q, 2H), 2.21(d,

2H), 1.95(d, 2H), 1.58~1.18(m,

6H), 1.02(t, 3H).

28
381

7.9
A
Gum
(CDCl₃)
12

7.75(s, 1H), 7.42(bs, 1H),

7.11(d, 2H), 6.82(d, 2H), 6.12(s,

1H), 4.31(d, 1H), 4.08(m, 1H),

3.81(s, 3H), 2.70(m, 1H),

2.20(m, 3H), 1.92(m, 2H), 1.60(bs,

2H), 1.35(m, 2H), 1.20(m,

2H), 0.90(t, 3H).

29
365

8.4
A
176-178
(CDCl₃)
12

7.75(s, 1H), 7.21(d, 1H),

7.18(s, 1H), 7.12(m, 1H), 7.03(d,

1H), 6.10(s, 1H), 4.30(d, 1H),

4.09(m, 1H), 2.70(m, 1H),

2.35(s, 3H), 2.21(m, 2H), 2.11(q,

2H), 1.92(d, 2H), 1.40(bs, 2H),

1.35(m, 2H), 1.21(m, 2H),

0.85(t, 3H).

30
379

10.5
A
Gum

12

31
395

9.8
A
131-133

12

32
381

9.0
A
163-165

12

33
443

11.2
A
147-149
(CDCl₃)
12

7.75(s, 1H), 7.50(bs, 1H),

7.30(t, 2H), 7.1(m, 3H), 7.02(d,

2H), 6.98(d, 2H), 6.11(s, 1H),

4.35(d, 1H), 4.11(m, 1H),

2.70(m, 1H), 2.29(q, 2H), 2.25(m,

2H), 1.95(m, 2H), 1.50(bs,

2H), 1.35(m, 2H), 1.25(m,

2H), 0.95(t, 3H).

34
394

6.1
A
60-62
(CDCl₃)
12

7.75(s, 1H), 7.35(s, 1H),

7.12(t, 1H), 6.49(d, 1H), 6.39(m,

2H), 6.12(s, 1H), 4.35(d, 1H),

4.08(m, 1H), 2.92(s, 6H),

2.70(m, 1H), 2.29(q, 2H), 2.20(m,

2H), 1.90(m, 2H), 1.46(bs,

2H), 1.36(m, 2H), 1.22(m,

2H), 0.95(t, 3H).

35
457

11.3
A
120-122
(CDCl₃)
12

7.78(s, 1H), 7.48~7.29(m, 5H),

7.10(d, 2H), 6.90(d, 2H),

6.12(s, 1H), 5.30(s, 1H),

5.05(s, 2H), 4.30(d, 1H), 4.10(m,

1H), 2.70(m, 1H), 2.20(m,

4H), 1.80(m, 2H), 1.35(m,

4H), 1.25(m, 2H), 0.90(t, 3H).

36
397

9.5
A
190-192
(CDCl₃)
12

7.75(s, 1H), 7.35(bs, 1H),

7.20(d, 2H), 6.98(d, 2H), 6.12(s,

1H), 4.41(d, 1H), 4.15(m, 1H),

2.72(m, 1H), 2.49(s, 3H),

2.24(m, 4H), 1.95(d, 2H), 1.50(bs,

2H), 1.40(m, 2H), 1.27(m,

2H), 0.96(t, 3H).

37
385

7.5
A
183-184

12

38
399

9.8
A
63-65

12

39
379

127-129

12

40
417

9.4
A
Gum

12

41
315

6.5
A
Gum

12

42
381

Gum

12

43
389
387
10.7
A
Gum
(CDCl₃)
12

7.76(s, 1H), 7.20(s, 1H),

7.10(m, 2H), 6.95(m, 1H), 6.12(s,

1H), 4.30(br, 1H), 3.12(m,

1H), 2.85(m, 2H), 2.75(m,

1H), 2.32(q, 2H), 1.90~1.50(m,

6H), 1.03(t, 3H).

44
389
387
9.2
A
148-154

12

45
371
369

Gum

12

46
329
327
7.8
A
91-93

12

47
483
481
10.5
A
Gum

12

48
493
491
9.4
A
240-241

12

49

499

153-155

12

50
441-444
437-439
11.4
A
Gum

12

51
411
409
7.2
A
65-68

12

52
441
439

162-165
(CDCl₃)
12

7.76(s, 1H), 7.40(s, 1H),

6.78(d, 1H), 6.70(s, 1H), 6.68(d,

1H), 6.11(s, 1H), 5.55(m, 1H),

4.05(m, 1H), 3.88(s, 3H),

3.82(s, 3H), 3.41(m, 1H), 2.69(m,

1H), 2.32(m, 2H), 2.18(m,

2H), 2.0(m, 2H), 1.92(m, 2H),

1.45(t, 2H), 1.40~1.15(m, 6H).

53
453
451
10.2
A
116-118

12

54
441
439

166-168

12

55
415
413

189-192
(CDCl₃)
12

7.75(s, 1H), 7.39(s, 1H),

7.14(s, 1H), 7.02(d, 1H), 6.87(d,

1H), 6.12(s, 1H), 4.32(d, 1H),

4.10(m, 1H), 3.90(s, 3H),

2.71(m, 1H), 2.20(m, 4H), 1.94(d,

2H), 1.45~1.15(m, 6H), 0.92(t,

3H).

56
423
421
11.9
A
144-148

12

57
457
455

102-104

12

58
411
409

181-185

12

59
429-432
427-430
9.7
A
197-199
(CDCl₃)
12

7.76(s, 1H), 7.32(s, 1H),

7.21(d, 1H), 7.15(d, 1H), 6.95(d,

1H), 6.15(s, 1H), 4.41(d, 1H),

4.10(m, 1H), 2.75(m, 1H),

2.27(q, 2H), 2.22(m, 2H), 1.93(m,

2H), 1.42(br, 2H),

1.40~1.20(m, 4H), 1.00(t, 3H).

60
477
475
9.5
A
199-201
(CDCl₃)
12

7.76(s, 1H), 7.49(bs, 1H),

7.35(d, 1H), 7.30(s, 1H),

7.00~6.90(m, 2H), 6.15(s, 1H), 4.42(d,

1H), 4.08(m, 1H), 2.71(m,

1H), 2.32(q, 2H), 2.20(m, 2H),

1.92(m, 2H), 1.55(bs, 2H),

1.42~1.20(m, 4H), 1.01(t, 3H).

61
395
393

150-152
(CDCl₃)
12

7.76(s, 1H), 7.32(s, 1H),

7.17(t, 1H), 6.60(d, 1H), 6.55(s,

1H), 6.13(s, 1H), 4.38(d, 1H),

4.08(m, 1H), 3.98(q, 2H),

2.70(m, 1H), 2.31(q, 2H), 2.20(m,

2H), 1.92(m, 2H), 1.46(br,

2H), 1.38(q, 3H),

1.38~1.19(m, 4H), 0.95(q, 3H).

62
397

Gum

12

63
443

Gum
(CDCl₃)
12

7.77(s, 1H), 7.33(s, 1H),

7.15(d, 2H), 7.05(d, 2H), 6.95(d,

2H), 6.90(d, 2H), 6.13(s, 1H),

5.19(br, 1H), 4.28(m, 1H),

3.19(dd, 1H), 2.83(m, 1H), 2.72(m,

2H), 2.31(s, 3H), 2.30(q, 2H),

1.90~1.50(m, 5H), 0.97(t, 3H).

64
392.3

6.4
A

(CDCl₃)
12

8.00(s, 1H), 7.53(br, 1H),

7.23(d, 2H), 6.96(d, 2H), 5.29(s,

1H), 4.65(m, 1H), 4.06(q, 2H),

3.71(s, 3H), 2.67(m, 1H),

2.06(m, 2H), 1.89(m, 2H), 1.56(br,

2H), 1.45(t, 3H), 1.28~1.14(m,

4H).

65
383

8.5
A
185-187
(CDCl₃)
12

7.80(s, 1H), 7.50(s, 1H),

7.25(d, 2H), 6.98(d, 2H), 6.15(s,

1H), 4.30(m, 1H), 4.10(m,

1H), 2.75(m, 1H), 2.50(s, 3H),

2.22(m, 2H), 1.92(m, 2H),

1.72(s, 3H), 1.48~1.18(m, 6H).

66
438
436

Gum

12

67
409

8.7
A
Gum

12

68
409
407

59-60

12

69
452

Gum

12

70
423

Gum
(CDCl₃)
12

7.95(d, 2H), 7.75(s, 1H),

7.40(bs, 1H), 6.95(d, 2H), 6.15(s,

1H), 4.45(d, 1H), 4.35(q, 2H),

4.10(q, 2H), 2.86(m, 1H),

2.30(q, 2H), 2.25(m, 2H), 2.18(bs,

2H), 2.03(s, 3H), 1.95(m, 2H),

1.37(m, 4H), 1.28(t, 3H),

1.00(t, 3H).

71
423

Gum
(CDCl₃)
12

7.78(s, 1H), 7.77(d, 1H),

7.65(s, 1H), 7.38(t, 1H), 7.25(s,

1H), 7.20(d, 1H), 6.13(s, 1H),

4.41(m, 1H), 4.40(q, 2H),

4.10(m, 1H), 2.71(m, 1H), 2.21(m,

4H), 1.12(m, 2H), 1.51(bs,

2H), 1.39(t, 3H), 1.39~1.20(m,

4H), 1.98(t, 3H).

72
365

Gum
(DMSO-d6)
12

8.35(bs, 1H), 7.65(s, 1H),

7.08(t, 1H), 6.65(d, 1H), 6.60(s,

1H), 6.52(d, 1H), 6.18(d, 1H),

5.95(s, 1H), 3.95(m, 1H),

2.41(m, 2H), 2.20(s, 3H), 1.86(m,

2H), 1.78(m, 2H), 1.40(m,

2H), 1.18(m, 2H), 0.90(t, 3H).

73
433

Gum

12

74
457

Gum

12

75
443

Gum

12

76
365

9.0
A
148-149
(CDCl₃)
12

7.77(s, 1H), 7.48(s, 1H),

7.07(d, 1H), 6.82(s, 1H), 6.76(d,

1H), 6.14(s, 1H), 4.25(d, 1H),

4.10(m, 1H), 2.72(m, 1H),

2.23(s, 3H), 2.21(m, 2H), 1.90(m,

2H), 1.70(s, 3H), 1.45(br, 2H),

1.45~1.20(m, 4H).

77
415

9.0
A
215-216
(CDCl₃)
12

7.78(s, 1H), 7.43(s, 1H),

7.19(d, 2H), 7.10(s, 1H), 6.90(m,

1H), 6.10(s, 1H), 4.31(d, 1H),

4.10(m, 1H), 2.85(m, 1H),

2.23(m, 2H), 1.92(m, 2H), 1.78(s,

3H), 1.45~1.20(m, 6H).

78
421
419

225-235

12

79
357
355

120-160

12

80
355

7.3
A
Gum

12

81
381

146-148
(CDCl₃)
12

7.75(s, 1H), 7.50(bs, 1H),

7.18(t, 1H), 6.60(d, 1H), 6.52(d,

1H), 6.50(s, 1H), 6.12(s, 1H),

4.12(m, 1H), 4.05(m, 1H),

4.00(m, 2H), 2.72(bs, 1H), 2.20(m,

2H), 1.93(m, 2H), 1.72(s, 3H),

1.49(m, 4H).

82
366

Gum

12

83
463

8.7
A
134-136
(CDCl₃)
12

7.76(s, 1H), 7.42(s, 1H),

7.38(d, 1H), 7.25(s, 1H), 7.02(t,

1H), 6.92(d, 1H), 6.15(s, 1H),

4.32(d, 1H), 4.08(m, 1H),

2.75(m, 1H), 2.23(m, 2H), 1.95(m,

1H), 1.75(s, 3H), 1.60(br, 2H),

1.40(m, 2H), 1.25(m, 2H).

84
405
403

198-200
(CDCl₃)
12

7.80(bs, 1H), 7.78(s, 1H),

7.51(d, 2H), 6.92(d, 2H), 6.18(s,

1H), 4.37(d, 1H), 4.10(m, 1H),

2.62(m, 1H), 2.21(m, 2H),

1.95(m, 2H), 1.75(s, 3H), 1.51(bs,

2H), 1.32(m, 2H), 1.28(m,

2H).

85
371

8.5
A
209-212
(CDCl₃)
12

7.75(s, 1H), 7.46(bs, 1H),

7.25(s, 1H), 7.20(t, 1H), 7.02(d,

1H), 6.92(s, 1H), 6.85(d, 1H),

6.15(s, 1H), 4.31(d, 1H),

4.06(m, 1H), 2.72(m, 1H), 2.20(m,

2H), 1.92(m, 2H), 1.75(s, 3H),

1.52(bs, 2H), 1.32(m, 2H),

1.25(m, 2H).

86
331

138-145

12

87
303

Gum

12

88
353
351
5.9
A
145-150

12

89
351

13.4
B
Gum
(CDCl₃)
12

7.76(s, 1H), 7.45(s, 1H),

7.27(s, 2H), 7.08(d, 1H), 6.82(s,

1H), 6.72(d, 1H), 6.10(s, 1H),

4.98(m, 1H), 4.3(m, 1H),

3.2(d, 1H), 2.82(m, 2H), 2.71(m,

1H), 2.29(m, 1H), 2.20(s, 3H),

1.83(m, 1H), 1.80~1.50(m,

2H), 1.25(s, 2H).

90
391
389

Gum
(CDCl₃)
12

7.80(s, 1H), 7.55(d, 2H),

7.50(s, 1H), 7.00(d, 2H), 6.15(s,

1H), 5.20(m, 1H),

91
367

Gum
(CDCl₃)
12

7.76(s, 1H), 7.42(s, 1H),

7.20(t, 1H), 6.61(d, 1H), 6.60(m,

2H), 6.50(s, 1H), 6.12(s, 1H),

4.25(d, 1H), 4.05(m, 1H),

3.78(s, 3H), 2.75(m, 1H), 2.22(m,

2H), 1.95(m, 2H), 1.75(s, 3H),

1.50~1.12(m, 6H).

92
411

101-104

12

93
468

Gum

12

94
467
465

120-130

12

95
367

5.3
A
200-202
(DMSO-d6)
12

7.50(s, 1H), 7.00(d, 2H),

6.65(d, 2H), 5.75(d, 2H), 5.53(s,

1H), 5.51(s, 1H), 4.82(bs, 1H),

4.20(s, 2H), 3.75(m, 1H),

3.00(br, 2H), 2.35(m, 1H), 2.30(s, 2H),

1.71(m, 2H), 1.51(d, 2H),

1.50(s, 3H), 1.15(m, 2H),

0.95(m, 2H).

96

158-162
(CDCl₃)
12

7.76(s, 1H), 7.52(bs, 1H),

7.27(d, 2H), 6.95(d, 2H), 6.15(s,

1H), 4.32(d, 1H), 4.10(m, 1H),

3.82(s, 2H), 2.72(m, 1H),

2.22(m, 2H), 1.95(m, 2H), 1.70(bs,

4H), 1.35(m, 2H), 1.23(m,

2H).

97
367

97-100
(CDCl₃)
12

7.73(s, 1H), 7.57(bs, 1H),

7.25(t, 1H), 7.02(d, 1H), 6.95(s,

1H), 6.86(d, 1H), 6.13(s, 1H),

4.52(s, 2H), 4.32(d, 1H),

4.05(d, 1H), 2.70(m, 1H), 2.20(m,

2H), 1.90(m, 2H), 1.73(s, 3H),

1.33(m, 2H), 1.20(m, 2H).

98
377
375
7.4
A
205-207

12

99
401

Gum

12

100
317

Gum

12

101
392
390

Gum

12

102
337

7.1
A
96-99
(CDCl₃)
12

7.80(s, 1H), 7.50(bs, 1H),

7.40(t, 2H), 7.08(t, 1H), 7.00(d,

2H), 6.15(s, 1H), 4.28(d, 1H),

4.09(m, 1H), 2.75(m, 1H),

2.22(m, 2H), 1.98(m, 2H), 1.72(s,

3H), 1.35(m, 2H), 1.25(m,

2H).

103
463

9.2
A
105-108
(CDCl₃).
12

7.78(s, 1H), 7.60(d, 2H),

7.46(bs, 1H), 6.75(d, 2H), 6.15(s,

1H), 4.30(d, 1H), 4.09(m, 1H),

2.78(m, 1H), 2.23(m, 2H),

1.95(m, 2H), 1.87(bs, 2H), 1.75(s,

3H), 1.41(m, 2H), 1.28(m,

2H).

104
449

10.2
A
Gum
(CDCl₃)
12

7.74(s, 1H), 7.45(s, 1H),

7.38(d, 1H), 7.30(s, 1H), 7.05(t,

1H), 6.95(d, 1H), 6.15(s, 1H),

5.10(m, 1H), 4.30(m, 1H),

3.20(dd, 1H), 2.82(m, 2H), 2.72(m,

1H), 1.90(m, 1H), 1.80(s, 3H),

1.75(m, 2H), 1.43(m, 1H).

105
449
447

Gum

12

106
357

9.3
A
Gum

12

107
376
374
7.2
A
207-209
(CDCl₃)
12

8.70(bs, 1H), 7.80(s, 1H),

7.70(bs, 1H), 7.35(s, 1H), 7.20(s,

1H), 6.95(d, 1H), 6.45(s, 1H),

6.15(s, 1H), 4.22(d, 1H),

4.05(m, 1H), 3.45(s, 3H), 2.71(m,

1H), 2.20(d, 2H), 1.90(d, 2H),

1.51(s, 3H), 1.35(m, 2H),

1.24(m, 2H).

108
374

Gum

12

109
388

Gum

12

110
319

Gum

12

111
408

95-99
(CDCl₃)
12

7.78(s, 1H), 7.72(d, 1H),

7.62(s, 1H), 7.57(s, 1H), 7.05(d,

1H), 6.15(s, 1H), 4.25(d, 1H),

4.07(m, 1H), 2.82(s, 3H),

2.70(m, 1H), 2.21(m, 2H), 1.95(m,

2H), 1.75(s, 3H), 1.50(bs, 2H),

1.35(m, 2H), 1.25(m, 2H).

112
394

6.1
A
100-108

12

113
449
447

181-183

12

114
409

10.0
A
Gum

12

115
417

165-168
(CDCl₃)
12

7.76(s, 1H), 7.19(bs, 1H),

7.05(m, 2H), 6.90(m, 1H), 6.14(s,

1H), 4.55(d, 1H), 4.10(m, 1H),

3.05(m, 1H), 2.73(m, 2H),

1.95(m, 2H), 1.50(d, 1H), 1.45(m,

2H), 1.30(m, 2H), 1.23(d, 6H),

1.0(dd, 1H).

116
434

Gum

12

117
436

140-142

12

118
403

210-215
(CDCl₃)
12

7.80(d, 2H), 7.50(s, 1H),

7.35(d, 2H), 7.25(d, 2H), 6.17(s,

1H), 7.05(d, 2H), 6.15(s, 1H),

4.31(d, 1H), 4.09(m, 1H),

2.71(m, 1H), 2.20(m, 2H), 1.90(m,

2H), 1.75(s, 3H), 1.40(m, 2H),

1.25(m, 4H).

119
338

Gum

12

120
323

Gum

12

121
353
351

100-105

12

122
402

Gum

12

123
378
376

155-156

12

124
449
447

Gum
(CDCl₃)
12

7.78(s, 1H), 7.44(s, 1H),

7.08(d, 2H), 6.89(d, 2H), 6.10(s,

1H), 4.30(d, 1H), 4.10(m, 1H),

3.18(m, 3H), 2.71(m, 1H),

2.59(m, 3H), 2.36(s, 3H), 2.19(m,

3H), 1.92(m, 1H), 1.60(br,

2H), 1.34(m, 2H), 1.20(m,

2H), 0.88(t, 3H).

125
434
432

Gum

12

126
395
393

68-72
(CDCl3)
12

7.78(s, 1H), 7.44(s, 1H),

6.80(d, 1H), 6.55(s, 1H), 6.13(d,

1H), 4.24(s, 4H), 4.22(m, 1H),

4.05(m, 1H), 2.72(m, 1H),

2.21(m, 2H), 1.94(m, 2H), 1.71(s,

3H), 1.40~1.15(m, 6H).

127
377
375

60-75

12

128
435
433

Gum

12

129
420
418

58-66
(CDCl3)
12

7.78(s, 1H), 7.50(s, 1H),

6.97(d, 2H), 6.90(d, 2H), 6.20(s,

1H), 4.20(d, 1H), 4.07(m, 1H),

3.12(m, 4H), 2.72(m, 1H),

2.20(m, 2H), 1.94(m, 2H), 1.72(m,

2H), 1.64(s, 3H), 1.55(m, 2H),

1.45(m, 2H), 1.35(m, 2H),

1.25(m, 2H).

130
408
406

Gum

12

131
377
375

Gum
(CDCl₃)
12

8.00(s, 1H), 7.79(s, 1H),

7.66(d, 1H), 6.91(d, 1H), 6.89(s,

1H), 7.78(m, 1H), 6.65(m,

1H), 6.15(s, 1H), 5.32(s, 1H),

4.44(d, 1H), 4.12(m, 1H),

3.15(m, 1H), 2.75(m, 1H), 2.15(m,

4H), 1.92(m, 2H), 1.81(s, 3H),

1.35(m, 2H), 1.22(m, 4H).

132
495

70-75

12

133
361

180-183

12

134
381

Gum

12

135
361
359

Gum

12

136

571

90-93

32

137
457
455

Gum
(CDCl₃)
12

7.85(d, 1H), 7.75(s, 1H),

6.95(s, 1H), 6.85(d, 1H), 6.18(s,

1H), 4.50(d, 1H), 4.35(q, 2H),

4.12(m, 1H), 2.73(m, 1H),

2.31(q, 2H), 2.22(m, 2H), 1.92(m,

2H), 1.42(t, H), 1.42~1.1.20(m,

4H), 1.10(t, 3H).

138
395

64-67

12

139
418
416

Gum

12

140
473

Gum
(CDCl₃)
12

7.75(s, 1H), 7.70(s, 1H),

6.87(d, 2H), 6.64(d, 2H), 6.60(d,

2H), 6.41(d, 2H), 6.15(s, 1H),

4.22(d, 1H), 4.05(m, 1H),

3.90(q, 2H), 3.72(s, 3H), 2.60(m,

1H), 2.08(m, 2H), 1.81(m,

2H), 1.38(t, 3H), 1.25(m, 2H),

1.00(m, 2H).

141
412

70-74

12

142
367
365

80-85

12

143
396

Gum

12

144
396

Gum

12

145
393

236-240

12

146
393
391

210-215

12

147
459

230-234

12

148
390
388

Gum
(CDCl₃)
12

8.02(bs, 1H), 7.78(s, 1H),

7.66(s, 1H), 7.20(d, 1H), 6.88(d,

1H), 6.19(s, 1H), 6.13(s, 1H),

4.20(d, 1H), 4.05(m, 1H),

2.70(m, 1H), 2.44(s, 3H), 2.20(m,

2H), 1.93(m, 2H), 1.60(s, 3H),

1.42(brs, 2H), 1.32(m, 2H),

1.23(m, 2H).

149
376

Gum
(CDCl₃)
12

8.46(bs, 1H), 7.80(s, 1H),

7.70(s, 1H), 7.22(d, 1H), 7.19(s,

1H), 7.10(t, 1H), 6.68(d, 1H),

6.50(s, 1H), 6.18(s, 1H),

4.25(d, 1H), 4.10(m, 1H), 2.71(m,

1H), 2.21(m, 2H), 1.92(m,

2H), 1.67(s, 3H), 1.52(bs, 2H),

1.38(m, 2H), 1.28(m, 2H).

150
421

Gum

12

151

392

206-210

12

152
375
373

Gum

12

153

374

116-125
(CDCl₃)
12

8.58(bs, 1H), 7.80(s, 1H),

7.70(s, 1H), 7.55(d, 1H), 7.19(d,

1H), 7.07(s, 1H), 6.90(d, 1H),

6.55(s, 1H), 6.15(s, 1H),

4.25(d, 1H), 4.05(m, 1H), 2.72(m,

1H), 2.20(m, 2H), 1.93(m,

2H), 1.62(s, 3H), 1.60(bs, 2H),

1.40(m, 2H), 1.26(m, 2H).

154
409

204-205

12

155
408

210-215
(CDCl₃)
12

7.85(d, 1h), 7.78(s, 1H),

7.65(s, 1H), 7.39(s, 1H), 7.10(d,

1H), 6.15(s, 1H), 4.30(d, 1H),

4.08(m, 1H), 2.80(s, 3H),

2.70(m, 1H), 2.22(m, 2H), 1.92(m,

2H), 1.70(s, 3H), 1.35(m, 2H),

1.25(m, 2H).

156
341

Gum
(CDCl₃)
12

7.78(s, 1H), 7.40(bs, 1H),

7.13(m, 1H), 7.03(m, 1H), 7.01(m,

1H), 6.89(t, 1H), 6.13(s, 1H),

5.10(m, 1H), 4.28(m, 1H),

3.18(m, 1H), 2.82(m, 2H), 2.72(m,

1H), 1.87(m, 1H), 1.81(s, 3H),

1.75(m, 2H), 1.68(m, 1H),

1.59(m, 1H).

157
363

120-123

12

158
395

64-65

12

159
429

184-187
(CDCl₃)
12

7.78(s, 1H), 7.15(m, 4H),

6.98(d, 1H), 6.15(s, 1H), 4.40(d,

1H), 4.10(m, 1H), 2.72(m,

1H), 2.28(q, 2H), 2.20(m, 2H),

1.92(m, 2H), 1.40(m, 2H),

1.25(m, 2H), 1.01(t, 3H).

160
415

Gum

12

161
326
324

114-116

12

162
324
322

92-94

12

163
421
419

68-69

12

164
407
405

55-60

12

165
423
421

63-65

12

166
409
407

63-66

12

167
351

Gum

12

168
477

104-106

12

169
497

Gum

12

170
382.2

7.1
A

(DMSO-d6)
12

8.34(s, 1H), 7.66(dd, 1H),

7.52(dd, 1H), 7.47(td, 1H), 7.41(td,

1H), 7.32(d, 1H), 5.06(s, 1H),

3.77(m, 1H), 2.99(m, 1H),

1.94(m, 4H), 1.40(m, 2H), 1.19(m,

2H).

171
391

Gum

12

172
405

Gum

12

173
383

Gum
(CDCl₃)
12

7.79(s, 1H), 7.52(s, 1H),

7.15(d, 2H), 6.85(d, 2H), 6.10(s,

1H), 5.50(m, 1H), 4.15(m,

1H), 4.05(q, 2H), 3.20(s, 3H),

2.90(m, 1H), 2.75(m, 2H),

2.62(m, 1H), 2.30(m, 1H), 1.95(m,

1H), 1.75~1.53(m, 3H), 1.42(t,

2H).

174
379
377

Gum
(CDCl₃)
12

7.85(d, 1H), 7.78(s, 1H),

7.59(bs, 1H), 7.07(d, 1H), 6.93(s,

1H), 5.30(m, 1H), 5.22(s, 2H),

4.35(m, 1H), 3.15(dd, 1H),

2.88(m, 3H), 2.00~1.82(m,

4H), 1.92(s, 3H), 1.62(m, 1H).

175
394
392

Gum
(CDCl₃)
12

7.78(s, 1H), 7.70(d, 2H),

7.50(bs, 1H), 6.90(d, 2H), 6.70(m,

1H), 6.15(s, 1H), 4.45(d, 1H),

4.08(m, 1H), 3.15(m, 1H),

2.75(m, 2H), 2.32(q, 2H), 2.22(m,

2H), 1.95(m, 2H),

1.52~1.18(m, 6H), 1.03(t, 3H).

176
443.3

8.9
A

(DMSO-d6)
12

7.80(s, 1H), 7.45~7.32(m, 5H),

6.95(s, 1H), 6.05(s, 1H),

5.06(s, 2H), 3.90(m, 1H), 2.98(m,

1H), 1.98(m, 4H), 1.62(s, 3H),

1.43(t, 4H).

177
393.3

9.0
A

12

178
380.3

5.8
B

12

179
421.3

8.1
A

12

180
385.3

7.6
A

12

181
315.3

5.9
A

12

182
319.4

7.4
B

12

183
331.4

7.4
A

12

184
351.3

6.7
A

12

185
372.3

5.2
B

12

186
381.3

11.4
B

12

187
367.3

6.6
B

12

188
357.3

8.6
B

12

189
381.3

9.6
B

12

190
395.3

10.7
B

(CDCl₃)
12

7.72(d, 1H), 7.11(d, 2H),

6.83(dd, 2H), 6.05(d, 1H), 5.82(t,

1H), 4.12(d, 1H). 4.04(m, 1H),

3.78(s, 3H), 3.68(q, 2H),

2.89(t, 2H), 2.70(m, 1H), 2.19(m,

1H), 2.17(m, 1H), 2.04(s, 3H),

1.93(m, 1H), 1.90(m, 1H),

1.52(br, 2H), 1.34(m, 2H), 1.23(m,

2H).

191
375.2

12.7
B

12

192
381.3

10.8
B

12

194
395.7

8.9
B

12

195
382.7

8.1
B

12

196
353.3

5.0
B

(DMSO-d6)
23

9.33(br, 1H), 7.83(s, 1H),

6.89(d, 2H), 6.71(d, 2H),

6.08(bs, 1H), 3.88(m, 1H), 2.98(m,

1H), 1.97(m, 4H), 1.58(s, 3H),

1.43(m, 4H).

198
367.3

7.4
A

12

199
415.2

7.1
A

23

200
411.3

5.9
A

23

201
395.3

7.9
A

23

202
435.3

9.1
A

23

203
367.3

5.9
A

23

204
458.3

4.8
A

23

205
458.3

5.2
A

23

206
458.3

6.4
A

23

207
473.3

7.6
A

23

208
473.2

8.6
A

23

209
457.3

8.1
A

23

210
457.2

7.9
A

23

211
477.2

9.5
A

23

212
477.2

9.4
A

23

213
477.2

9.3
A

23

214
435.3

9.6
A

23

215
463.3

10.9
A

23

216
421.3

8.6
A

23

217
450.3

5.4
C

23

218
450.3

5.4
C

23

219
437.3

6.4
A

23

220
444.2

4.4
B

23

221
466.3

3.8
B

23

222
444.2

4.3
B

23

223
464.2

4.3
B

23

224
444.2

4.8
B

23

225
458.2

4.4
B

23

226
464.2

4.6
B

23

227
464.2

4.4
B

23

228
458.1

4.5
B

23

229
422.7

4.7
C

23

230
465.7

3.9
C

23

231
464.8

6.3
C

23

232
450.7

6.1
C

23

233
450.7

6.3
C

23

234
447.7

5.2
C

23

235
436.7

5.3
C

23

236
436.7

5.3
C

23

237
449.7

14.1
C

23

238
463.3

10.1
B

23

239
421.3

8.0
B

23

240
435.3

8.9
B

23

241
435.3

8.6
B

23

242
449.3

9.6
B

23

243
443.3

8.2
B

23

244
435.4

8.2
B

12

245
421.4

9.2
B

12

246
458.4

5.3
B

23

247
477.3

9.1
B

23

248
477.3

9.1
B

23

249
437.4

6.2
B

23

250
477.3

8.9
B

23

251
450.7

6.3
C

23

252
473.2

8.2
B

23

253
457.2

8.6
B

23

254
457.2

8.4
B

23

255
464.8

7.0
C

23

256
437.7

9.1
C

23

257
427.7

5.9
C

23

258
436.7

3.9
B

23

260
464.7

4.7
B

23

261
450.7

4.5
B

23

262
436.7

4.0
B

23

263
450.7

4.1
B

23

264
464.7

4.8
B

23

265
450.7

4.5
B

23

266
422.7

3.4
B

23

267
447.7

3.9
B

23

268
450.7

3.9
B

23

269
464.7

4.3
B

23

270
464.7

4.5
B

23

271
501.7

5.4
A

12

273
444.7

6.8
C

23

274
444.7

7.0
C

23

275
444.7

7.6
C

23

276
458.7

5.1
B

23

277
466.7

5.9
C

23

278
464.7

6.8
C

23

279
458.7

7.1
C

23

280
458.7

7.0
C

23

281
437.7

10.4
C

23

282
427.7

6.9
C

23

283
435.7

7.2
A

12

285
443.3

11.1
B

24

286
443.3

11.1
B

24

287
443.3

11.1
B

24

288
428.3

6.8
B

24

289
469.2

12.8
B

24

290
453.2

12.2
B

24

291
419.2

10.6
B

24

292
469.2

12.5
B

24

293
406.3

12.7
B

12

294
392.3

11.9
B

12

295
414.2

11.8
B

12

296
381.3

9.6
A

12

298
457.3

9.8
A

12

299
414.4

5.3
B

24

300
414.4

5.5
B

24

301
428.3

6.4
B

24

302
447.2

11.8
B

24

303
431.3

11.0
B

24

304
431.3

11.0
B

24

305
431.3

10.8
B

24

306
429.2

8.6
B

24

307
429.2

8.9
B

24

308
429.2

9.3
B

24

309
403.3

9.7
B

24

310
447.2

9.1
D

24

311
415.3

5.9
D

24

312
447.3

11.8
B

24

313
447.3

11.1
B

24

314
456.3

7.5
B

24

315
456.4

7.3
B

24

316
497.3

12.4
B

24

317
497.3

12.3
B

24

318
438.3

9.8
B

24

319
438.3

9.9
B

24

320
427.4

11.5
B

24

321
427.4

11.2
B

24

322
427.4

11.5
B

24

323
481.3

11.6
B

24

324
481.3

12.0
B

24

325
463.4

9.4
A

12

326
449.4

11.5
A

12

327
425.3

8.3
A

15

328
453.3

9.6
A

12

329
424.2

7.9
A

16

330
438.3

8.1
A

16

331
452.3

8.4
A

16

332
482.3

8.4
A

16

333
495.3

7.2
A

16

334
481.3

7.9
A

16

335
500.3

10.0
A

16

336
514.3

9.5
A

16

337
452.3

7.3
A

16

338
478.3

7.6
A

16

339
464.3

8.4
A

16

341
395.2

11.1
A

29

342
457.2

12.7
A

29

343
501.2

9.3
A

18

344
509.3

9.5
A

16

345
535.4

10.1
A

16

346

16

347
507.3

9.5
A

16

348
514.3

12.1
A

16

349
543.3

10.6
A

16

350
481.3

10.0
A

24

351
505.3

7.2
A

24

352
443.3

6.6
A

24

353
443.3

6.8
A

24

354
457.3

8.4
A

24

355
461.3

7.5
A

24

356
457.4

9.2
A

24

357
433.3

10.5
D

24

358
521.3

9.8
A

16

359
501.2

11.5
A

16

360
501.2

10.6
A

16

361
501.2

10.6
A

16

363
454.3

8.6
A

19

364
468.2

9.5
A

19

365
530.2

13.2
A

17

366
370.3

14.1
A

12

367
384.2

15.2
A

12

368
382.2

14.0
A

12

369
418.2

13.8
A

12

370
342.3

11.2
A

12

371
356.2

12.6
A

12

372
418.2

14.8
A

12

373
391.2

7.3
A

25

374
404.3

5.3
A

25

376

25

377
390.3

4.6
A

25

379
452.2

9.2
A

19

380
464.2

9.6
A

(DMSO-d6)
19

9.66(brs, 1H), 8.65(brs, 1H),

7.94(s, 1H), 7.76(brs, 3H),

6.87(d, 2H9, 6.81(d, 2H),

4.07~3.87(m, 3H), 2.96(brs,

1H), 2.05~1.80(m, 4H), 1.59(s,

3H), 1.50~1.35(m, 4H), 1.26(t,

3H), 0.79~0.65(m, 4H).

381
496.2

9.5
A

19

382
498.2

9.3
A

19

383
500.2

10.7
A

(DMSO-d6)
19

9.76(brs, 1H), 8.67(brs, 1H),

7.97-8.03(m, 3H), 7.72(brs,

3H), 7.46-7.63(m, 3H),

6.82-6.96(m, 4H),

3.92-4.03(m, 3H), 2.97(brs, 1H),

1.90-2.08(m, 4H), 1.66(s, 3H),

1.35-1.48(m, 4H), 1.31(t, 3H).

384
514.2

10.5
A

(DMSO-d6)
19

9.44(brs, 1H), 8.56(brs, 1H),

7.94(s, 1H), 7.76(brs, 3H),

7.18-7.35(m, 5H),

6.78-6.87(m, 4H), 6.13(brs, 1H),

4.02(brs, 1H), 3.93(q, 2H), 3.64(s,

2H), 2.96(brs, 1H),

1.89-2.03(m, 4H), 1.60(s, 3H),

1.32-1.48(m, 4H), 1.26(t, 3H).

385
492.1

11.8
A

19

387
536.1

12.3
A

20

388
481.2

9.3
A

(DMSO-d6)
21

8.66(brs, 1H), 7.70-7.80(m,

4H), 6.78-6.90(m, 2H),

6.30(brs, 1H), 3.82-3.97(m, 3H),

2.90-3.05(m, 3H),

1.88-2.02(m, 4H), 1.58(s, 3H),

1.32-1.46(m, 6H), 1.26(t, 3H), 0.82(t,

3H).

391
531.1

12.3
A

22

392
468.2

9.7
A

16

393
328.3

9.5
A

12

394
342.3

9.7
A

12

395
356.2

10.2
A

12

396
404.2

13.3
A

12

397
416.3

13.6
A

12

398
416.3

13.2
A

12

399
356.3

10.8
A

12

400
327.2

9.0
A

12

401
341.2

9.0
A

12

402
341.2

8.4
A

12

403
369.2

10.3
A

12

404
355.3

8.0
A

12

405
381.2

10.2
A

12

406
381.2

11.0
A

12

407
381.2

9.1
A

12

408
357.2

8.1
A

12

409
394.2

8.6
A

30

410
353.3

9.1
A

30

411
443.2

12.9
A

12

412
353.3

8.9
A

30

413
395.3

8.7
A

(CDCl₃) 8.25(s, 1H), 8.21(bs,
12

1H), 7.61(s, 1H), 7.06(d, 2H),

6.88(d, 2H), 4.23(m, 1H),

4.02(q, 2H), 3.11(m, 1H), 2.15(s,

3H), 2.11(m, 4H), 1.62(s, 3H),

1.61(m, 4H), 1.41(t, 3H).

414
381.3

9.9
A

(CDCl₃)
12

10.3(br, 1H), 10.1(br, 1H),

8.32(s, 1H), 7.68(s, 1H), 7.06(d,

2H), 6.91(d, 2H), 4.95(m, 1H),

4.05(q, 2H), 3.48(m, 2H),

3.28(m, 1H), 2.94(m, 1H),

2.35(s, 3H), 2.05(m, 2H), 1.99(m,

2H), 1.68(s, 3H), 1.44(t, 3H).

415
471.3

12.4
A

(CDCl₃)
12

8.21(br, 2H), 8.14(s, 1H),

7.51(s, 1H), 7.22(s, 2H), 7.21(s,

2H), 7.13(m, 1H), 7.02(d, 2H),

6.87(d, 2H), 4.13(m, 1H),

4.01(q, 2H), 3.99(s, 2H), 3.09(m,

1H), 2.07(m, 4H), 1.61(m, 1H),

1.60(s, 3H), 1.44(m, 1H),

1.41(t, 3H).

416
457.2

1.7
A

(CDCl₃)
12

10.2(br, 1H), 9.91(br, 1H),

8.26(s, 1H), 7.58(s, 1H), 7.43(br,

1H), 7.31-7.16(m, 5H), 7.05(d,

2H), 6.89(d, 2H), 4.92(m, 1H),

4.22(s, 2H), 4.03(q, 2H),

3.44(m, 2H), 3.22(m, 1H),

2.98(m, 1H), 2.35(s, 2H),

2.06-1.99(m, 4H), 1.68(s, 3H), 1.42(t,

3H).

418
443.2

12.4
A

12

419
457.2

12.0
A

24

420
457.2

11.0
A

24

421
433.2

11.3
A

24

422
403.3

6.5
A

24

423
452.2

11.0
A

24

424
438.3

14.3
A

12

425
411.2

9.0
A

(CDCl₃)
12

7.61(1H, s), 7.42(brs, 1H),

6.97(m, 2H), 6.85(m, 2H),

4.14(m, 1H), 4.02(q, 2H),

3.98(s, 3H), 2.73(m, 1H),

2.22(m, 2H), 1.94(m, 2H),

1.65(s, 3H), 1.42(t, 3H), 1.35(m,

2H), 1.23(m, 2H).

426
424.5

10.4
A

(DMSO-d6)
16

8.93(s, 1H), 8.74(brs, 2H),

8.12(s, 1H), 7.73(d, 1H),

6.95(d, 2H), 6.86(d, 2H), 6.69(d,

1H), 4.39(brs, 1H), 3.98(q,

2H), 3.38~3.47(m, 1H),

3.21~3.30(m, 1H),

2.93~3.03(m, 1H), 2.82~3.03(m, 4H),

1.99~2.09(m, 1H),

1.88~1.97(m, 1H), 1.57~1.83(m, 4H),

1.31(t, 3H).

427
438.6

10.9
A

16

428
464.6

13.1
A

16

429
468.5

11.4
A

16

430
481.6

9.0
A

16

431
486.6

14.4
A

(DMSO-d6)
16

9.05(s, 1H), 8.70~8.90(m, 2H),

8.26(s, 1H), 7.68(d, 2H),

7.37(t, 2H), 7.09(t, 1H), 6.99(d,

2H), 6.88(d, 2H), 6.81(d, 1H),

4.45~4.55(m, 1H), 3.99(q, 2H),

3.37~3.45(m, 1H),

3.15~3.30(m, 2H), 2.87~2.98(m, 1H),

2.18~2.27(m, 1H),

1.88~2.00(m, 1H), 1.55~1.82(m, 5H),

1.31(t, 3H).

432
487.5

12.7
A

16

433
487.5

11.0
A

((DMSO-d6)
16

9.07(s, 1H), 8.85(d, 1H),

8.72(brs, 2H), 8.35(dd, 1H),

8.25~8.32(m, 2H),

7.47~7.52(m, 1H), 6.99(d, 2H), 6.88(d,

2H), 6.82(d, 1H), 4.48~4.60(m,

1H), 3.99(q, 2H), 3.33~3.42(m,

1H), 3.12~3.30(m, 2H),

2.85~2.97(m, 1H),

2.17~2.25(m, 1H), 1.89~2.00(m, 1H),

1.57~1.80(m, 5H), 1.31(t, 3H).

434
487.6

10.0
A

((DMSO-d6)
16

9.14(s, 1H), 8.68~8.82(m, 2H),

8.65(d, 2H), 8.39(s, 1H),

8.00(d, 2H), 6.98(d, 2H),

6.83~6.92(m, 3H), 4.48~4.58(m, 1H),

3.99(q, 2H), 3.36~3.45(m, 1H),

3.15~3.25(m, 2H),

2.89~3.01(m, 1H), 2.12~2.21(m, 1H),

1.88~1.98(m, 1H),

1.62~1.77(m, 5H), 1.31(t, 3H).

435
500.6

12.4
A

((DMSO-d6)
16

8.96(s, 1H), 8.54~8.75(m, 2H),

8.27~8.34(m, 1H), 8.16(s, 1H),

7.30~7.35(m, 4H),

7.22~7.29(m, 1H), 6.96(d, 2H), 6.87(d,

2H), 6.68(d, 1H), 4.77(dd, 1H),

4.41(dd, 1H), 4.25~4.35(m,

1H), 3.98(q, 2H), 2.98~3.27(m,

3H), 2.79~2.92(m, 1H),

1.83~1.92(m, 1H),

1.38~1.75(m, 6H), 1.31(t, 3H).

437
410.6

10.1
A

28

438
454.6

9.9
A

28

439
439.6

14.8
A

59Db0011 ((DMSO-d6)
12

8.65~8.90(m, 3H), 8.19(s, 1H),

6.94(d, 2H), 6.87(d, 2H),

6.63(d, 1H), 4.36~4.46(m, 1H),

4.16~4.26(m, 2H), 3.99(q, 2H),

3.40~3.48(m, 1H),

3.06~3.24(m, 2H), 2.85~2.97(m, 1H),

1.86~2.10(m, 2H),

1.62~1.78(m, 5H), 1.27~1.35(m, 6H).

440
411.6

11.1
A

59Db0021 ((DMSO-d6)
15

8.87~8.97(brs, 1H),

8.58~8.78(m, 2H), 8.16(s, 1H),

6.82~6.97(m, 4H), 6.70(d, 1H),

4.31~4.45(m, 1H), 3.98(q, 2H),

3.35~3.45(m, 1H), 2.74~3.25(m, 3H),

1.86~2.03(s, 3H),

1.60~1.77(m, 5H), 1.31(t, 3H).

442
414.1

7.0
A

24

443
405

13.1
A

24

444
414.1

7.9
A

24

445
429.1

9.8
A

24

446
413.1

11.1
A

24

447
428.1

7.3
A

24

448
428.1

7.6
A

24

449
414.1

5.7
A

24

451
461

10.1
A

24

452
381.1

9.3
A

12

453
416

7.5
A

12

454
384.1

9.5
A

12

455
383.1

10.2
A

12

456
427.1

10.8
A

12

457
413.1

12.8
A

12

458
416

10.9
A

12

459
423

12.2
A

12

460
394.1

6.0
B

Ex. 26

462
420

7.2
B

Ex. 26

463
448

9.9
B

Ex. 26

465
476.1

13.0
B

Ex. 26

466
424.1

4.6
A

Ex. 26

467
438

7.0
B

Ex. 26

468
464

8.7
B

Ex. 26

469
451.1

5.5
B

Ex. 26

470
477.1

6.5
B

Ex. 26

471
493.1

6.1
B

Ex. 26

472
426

7.8
B

Ex. 26

473
462

10.2
B

Ex. 26

474
442

8.7
B

Ex. 26

475
454

9.6
B

Ex. 26

476
465

6.3
B

Ex. 26

477
437.1

6.1
B

Ex. 26

478
452

7.5
B

Ex. 26

480
465.1

5.9
B

Ex. 26

481
507.1

5.9
B

Ex. 26

483
480.1

10.6
B

Ex. 26

488
474

11.5
B

Ex. 26

489
474

12.0
B

Ex. 26

490
474

12.3
B

Ex. 26

492
481.1

11.8
B

Ex. 26

493
481.1

11.8
B

Ex. 26

494
486.1

12.4
B

Ex. 26

495
486.1

11.2
B

Ex. 26

496
486.1

10.8
B

Ex. 26

503
499.1

9.9
B

Ex. 26

504
499.1

7.4
B

Ex. 26

505
499.1

7.9
B

Ex. 26

506
507

8.1
B

Ex. 26

510
470.1

9.3
A

Ex. 26

511
460

9.4
B

Ex. 26

512
476

10.3
B

Ex. 26

513
471.1

4.3
A

Ex. 26

514
471

6.2
B

Ex. 26

515
471

5.8
B

Ex. 26

518
484

12.3
B

Ex. 26

519
485

6.5
B

Ex. 26

520
485

6.5
B

Ex. 26

521
488.1

6.1
B

Ex. 26

522
474.1

6.3
B

Ex. 26

759
452.1

5.5
A

Ex. 23

760
430

6.5
A

Ex. 23

761
397

9.4
A

Ex. 23

762
459

10.9
A

(CDCl₃)
Ex. 12

8.04(s, 1H), 7.87(brs, 2H),

7.54(brs, 1H), 6.99(d, J=8.8Hz,

2H), 6.85(d, J=9.0Hz, 2H),

4.02(q, J=7.0Hz, 2H),

3.60~4.30(m, 3H), 3.26(s, 3H),

3.15~3.30(m, 1H), 2.10~2.30(m,

4H), 1.50~1.75(m, 2H), 1.60(s,

3H), 1.42(t, J=6.9Hz, 3H),

1.30~1.50(m, 2H).

763
445.1

11.7
A

(CDCl₃)
Ex. 12

9.33(brs, 1H), 8.80(brs, 1H),

8.07(s, 1H), 7.63(brs, 1H),

7.03(d, J=8.8Hz, 2H), 6.89(d,

J=8.8Hz, 2H), 5.20~5.60(m,

1H), 4.52(brs, 1H), 4.04(q,

J=7.0Hz, 2H), 3.60~3.70(m,

1H), 3.20(s, 3H), 3.15~3.30(m,

3H), 2.00~2.15(m, 2H),

1.80~2.00(m, 2H), 1.65(s, 3H),

1.43(t, J=7.0Hz, 3H).

764
490

12.0
A

Ex. 16

765
490

10.7
A

Ex. 16

766
491

11.2
A

Ex. 16

767
492

12.8
A

Ex. 16

768
468.1

11.9
A

Ex. 16

769
482.1

10.7
A

Ex. 16

770
454

11.2
A

Ex. 16

771
468.1

11.1
A

Ex. 16

772
397

10.0
A

(CDCl₃)
Ex. 12

8.42(s, 1H), 7.84(s, 1H),

7.74(m, 1H), 7.11(d, J=8.8Hz,

2H), 6.91(d, J=8.8Hz, 2H),

6.36(s, 1H), 5.06(m, 1H),

4.48(m, 1H), 4.04(q, J=6.84, 2H),

3.87(m, 1H), 3.63(m, 1H),

2.98(m, 1H), 2.42(m, 1H), 1.42(t, J=6.86Hz,

3H).

773
447

10.0
A

Ex. 24

774
395.1

9.4
A

Ex. 12

775
430

6.3
A

Ex. 12

776
456

11.1
B

Ex. 26

777
397

8.4
A

Ex. 12

778
441

10.0
A

Ex. 12

779
415

5.5
A

Ex. 12

780
427.1

11.8
A

Ex. 12

781
430

9.4
A

Ex. 12

782
437

12.6
A

Ex. 12

783
401.1

10.2
A

Ex. 12

784
454.2

11.2
A

Ex. 12

785
455

11.4
A

Ex. 12

786
458.1

10.7
A

Ex. 12

787
484

12.1
A

Ex. 12

788
379.1

6.7
A

Ex. 12

789
361.1

8.6
A

Ex. 12

790
516.1

10.2
A

Ex. 28

791
552.1

10.9
A

Ex. 28

792
434.1

6.9
A

Ex. 26

793
450.1

10.5
B

Ex. 26

794
408.1

7.2
B

Ex. 26

795
398

8.4
A

Ex. 12

796
442.1

11.1
A

Ex. 12

797
387.1

11.9
A

Ex. 12

798
437.2

12.6
A

Ex. 12

799
440.2

12.0
A

Ex. 12

800
441.0

12.6
A

Ex. 12

801
444.1

10.9
A

Ex. 12

802
470.1

12.8
A

Ex. 12

803
365.2

8.1
A

Ex. 12

804
347.1

9.8
A

Ex. 12

805
374.1

4.5
A

Ex. 12

806
498.9

15.1
A

(CD₃OD)
Ex. 14

7.61~7.58(m, 2H), 7.38~7.29(m,

2H), 4.05~4.00(m, 1H),

3.09~3.07(m, 1H), 2.21~2.18(m,

2H), 2.13~2.09(m, 2H), 1.99(s,

3H), 1.58~1.49(m, 2H),

1.43~1.34(m, 2H).

807
440.0

8.722
A

(CD₃OD)
Ex. 12

7.96(s, 1H), 7.82(d, 1H),

7.71(d, 1H), 7.32(dd, 1H), 3.92(m,

2H), 3.16(m, 2H), 2.81(s, 3H),

2.15(m, 4H), 1.68(s, 3H),

1.66(m, 4H).

808
454.0

10.3
A

(CD₃OD)
Ex. 12

7.96(s, 1H), 7.83(d, 1H),

7.71(d, 1H), 7.32(dd, 1H), 3.84(m,

2H), 3.38(q, 2H), 3.16(m, 2H),

2.16(m, 4H), 1.68(s, 3H),

1.66(m, 4H), 1.49(t, 3H).

809
468.0

11.8
A

(CD₃OD)
Ex. 12

7.96(s, 1H), 7.84(d, 1H),

7.71(d, 1H), 7.32(dd, 1H), 4.09(m,

1H), 3.92(m, 2H), 3.16(m,

2H), 2.81(s, 3H), 2.15(m, 4H),

1.68(s, 3H), 1.66(m, 4H).

810
426.0

9.6
A

(CD₃OD)
Ex. 12

7.84(s, 1H), 7.75(d, 1H),

7.46(d, 1H), 7.16(dd, 1H), 4.42(m,

1H), 3.64(m, 1H), 3.38(m, 1H),

3.30(m, 2H), 2.97(m, 1H),

2.79(s, 3H), 2.16(m, 1H),

2.07(m, 1H), 1.89(m, 1H), 1.80(s,

3H).

811
440.0

10.7
A

(CD₃OD)
Ex. 12

7.87(s, 1H), 7.77(d, 1H),

7.50(d, 1H), 7.19(dd, 1H), 4.39(m,

1H), 3.64(m, 1H), 3.38(m, 1H),

3.36(q, 2H), 3.30(m, 2H),

2.98(m, 1H), 2.79(s, 3H),

2.17(m, 1H), 2.08(m, 1H), 1.89(m,

1H), 1.78(s, 3H), 1.47(t, 3H).

812
454.0

11.9
A

(CD₃OD)
Ex. 12

7.88(s, 1H), 7.79(d, 1H),

7.51(d, 1H), 7.20(dd, 1H), 4.39(m,

1H), 4.04(m, 1H), 3.65(m, 1H),

3.38(m, 1H), 3.00(m, 2H),

2.98(m, 1H), 2.17(m, 1H),

2.09(m, 1H), 1.92(m, 1H), 1.78(s,

3H), 1.49(d, 6H).

813
541.2

16.1
A

(CDCl₃)
Ex. 12

7.79(d, J=2.2Hz, 1H), 7.54(s,

1H), 7.37~7.29(m, 5H), 7.00(d,

J=8.8Hz, 2H), 6.86(d, J=9.04Hz,

2H), 6.09(brs, 1H),

5.79(m, 1H), 5.14(d, J=2.72Hz,

2H), 5.04(s, 1H), 5.01(m,

1H), 4.44(br, 1H), 4.26(br,

1H), 4.12(br, 1H), 4.02(q, J=6.84Hz,

2H), 2.94(br, 1H),

2.76(br, 1H), 2.41(m, 1H),

2.06(m, 1H), 1.83(br, 1H), 1.64(s,

3H), 1.42(t, J=7.08Hz, 3H).

815
449.4

13.9
A

Ex. 12

816
435.5

13.7
A

Ex. 12

817
499.3

15.6
A

Ex. 12

818
485.2

14.9
A

Ex. 12

Example 35

[General Procedure for Measurement of MAPKAP-K2 Enzyme Activity Inhibition]

(Compound Preparation)

Compounds were dissolved in DMSO at a concentration of 10 mM and stored in aliquots at −20° C. Compounds in DMSO from these stock aliquots were diluted in DMSO to produce the required range of 30× stock solutions. These stock solutions were then subjected to 1:3, dilutions in order to prepare the required range of 10× stock solutions and 5 μL of each solution was used per 50 μL reaction. A final DMSO concentration of 3% was maintained throughout all compound dilution series to maximise compound solubility. Compounds were routinely tested at final concentrations ranging from 300 μM to 0.001 μM, but may have been tested at lower concentrations depending upon their activity.

(MAPKAP-K2 Assay)

The kinase reaction was conducted in a round-bottomed polypropylene 96-well plate. MAPKAP-Kinase 2 was diluted to 0.5 mU/μL in diluent buffer (50 mM Tris/HCl. pH7.5, 0.1 mM EGTA, 0.1% (v/v) β-mercaptoethanol, 1 mg/mL BSA). 5 μ custom character compound or 30% DMSO was added to each well followed by 25 μ substrate cocktail (final concentration: 10 μM ATP, 30 μM peptide (KKLNRTLSVA), 0.5 μCi 33P-γ-ATP in 50 mM Tris pH7.5, 0.1 mM EGTA, 10 mM Mg-acetate and 0.1% β-mercaptoethanol). The reaction was initiated with the addition of 20 μL enzyme solution per well or 20 μL diluent buffer without enzyme. The plate was shaken for 10 seconds and then left at room temperature for 30 minutes. The reaction was terminated with 50 μL 150 mM phosphoric acid. 90 μL of the reaction mixture was then transferred into a 96-well P81 filter plate (Whatmann) and incubated at room temperature for 5 minutes. The filter plate was then washed 4 times with 200 μL 75 mM phosphoric acid per well on a plate vacuum manifold (Millipore) and dried in an oven for 2-3 hours. Packard MicroScint ‘0’ (30 μL) was then added to each well, the plate was mixed for 30 minutes and subjected to liquid scintillation counting on a Packard TopCount.

After adding 25 μL of peptide substrate solution [60 μM substrate peptide, 20 μM ATP, 50 mM Tris buffer (pH 7.5), 0.1 mM EGTA, 0.1% β-mercaptoethanol, 20 mM magnesium acetate, 0.1 μCi [γ-33P]ATP (specific activity: approximately 110 TBq/mmol)] to 5 μL of the test compound using 5% dimethylsulfoxide as the solvent, reaction was initiated by further addition of 20 μL of a MAPKAP-K2 enzyme solution [10 mU recombinant human MAPKAP-K2, 50 mM Tris buffer (pH 7.5), 0.1 mM EGTA, 0.1 % β-mercaptoethanol, 0.1% BSA]. After conducting the reaction for 30 minutes at room temperature, an equivalent volume of a 200 mM phosphoric acid solution was added to suspend the reaction, and 90 μL of the reaction product was adsorbed onto a MultiScreen PH plate (Millipore) and rinsed with a 100 mM phosphoric acid solution. After drying the plate, 30 μL of MicroScint-O (Packard BioScience) was added, and the cpm was measured with a scintillation counter to determine the inhibiting activity. Substrate peptide is Lys-Lys-Leu-Asn-Arg-Thr-Leu-Ser-Val-Ala.

(Interpretation)

% Control=(X−B)/(Tot−B)×100

% Inhibition=100−% Contr

X=cpm of the test compound wells

B=cpm of wells without enzyme

Tot=cpm of wells with DMSO vehicle only

(MAPKAP-K2 Inhibitory Activity)

The efficacy of the compounds in Table A against MAPKAP-K2 is shown in Table C below.

(The activity is presented as +, ++, or +++ representing active, more active and very active based on assays conducted at typically 1-100 μM).

TABLE C

Compound No
activity

1
++

2
++

7
++

10
+++

11
+++

12
+++

13
+

14
++

15
+++

16
+++

17
+++

18
++

19
+++

20
++

21
++

22
++

23
+++

24
+++

25
+++

26
+++

27
+++

28
+++

29
+++

30
+++

31
+++

32
+++

33
+++

34
+++

35
+++

36
+++

37
+++

38
++

39
++

40
++

41
++

42
++

43
+++

44
++

45
++

46
++

47
++

48
++

49
++

50
++

51
+++

52
+++

53
+++

54
++

55
+++

56
+++

57
+++

58
++

59
+++

60
+++

61
+++

62
++

63
+++

64
+++

65
+++

66
++

67
+++

68
+++

69
++

70
+++

71
++

72
+++

73
++

74
++

75
++

76
+++

77
+++

79
++

80
+++

81
+++

82
++

83
+++

84
+++

85
+++

86
++

87
++

88
+++

89
+++

90
+++

91
++

93
++

94
++

95
+++

96
+++

97
+++

98
+++

100
++

102
+++

103
+++

104
+++

105
+++

106
+++

107
+++

110
+

111
+++

112
+++

113
++

114
+++

115
+++

116
++

117
++

118
+++

119
+

120
++

121
++

122
++

124
++

125
++

126
+++

127
+

128
++

129
+++

130
++

131
+++

135
+

137
+++

139
+

140
+++

141
++

142
+

145
++

146
++

148
+++

149
+++

150
+++

151
++

152
++

153
+++

155
+++

156
+++

157
++

159
+++

160
++

167
++

168
++

169
++

170
+++

171
++

172
++

173
+++

174
+++

175
+++

176
+++

177
++

178
+++

179
+++

180
++

181
++

182
+

183
++

184
++

187
++

190
+

191
+++

192
++

193
+++

195
+

196
+++

197
+++

198
+++

199
+++

200
+++

201
+++

202
+++

203
+++

204
++

205
+++

206
++

207
++

208
+++

209
++

210
++

211
+++

212
++

213
+++

214
+++

215
++

216
+++

217
++

218
+++

219
+++

220
++

221
+++

222
+++

223
+++

224
+++

225
+++

226
+++

227
++

228
+++

229
+++

230
+++

231
++

232
+++

233
++

234
+++

235
++

236
++

237
++

238
++

239
++

240
++

241
++

242
++

243
++

244
++

245
+++

246
++

247
++

248
++

249
++

250
++

251
+++

252
++

253
+++

254
+++

255
++

256
+++

257
++

258
++

259
++

260
++

261
++

262
++

263
++

264
++

265
++

266
++

267
++

268
++

269
++

270
++

272
++

273
++

274
++

275
++

276
++

277
++

278
++

279
++

280
++

281
++

282
+++

284
+++

285
+++

286
+++

287
+++

288
+++

289
+++

290
+++

291
+++

292
++

293
+++

294
++

295
+++

297
++

299
+++

300
+++

301
+++

302
+++

303
+++

304
+++

305
+++

306
+++

307
+++

308
+++

309
+++

310
++

311
+++

312
+++

313
++

314
+++

315
+++

316
+++

317
+++

318
+++

319
+++

320
+++

321
+++

322
+++

323
++

324
+++

325
+

327
+++

329
+

330
++

331
+

332
++

333
+

335
++

336
+

337
+

338
+

340
+

341
+

343
++

347
+

349
+

350
+++

351
+++

352
+++

353
+++

354
+++

355
+++

356
+++

357
+++

358
+

359
++

360
++

361
+++

362
++

364
+

365
+

373
+++

374
+++

375
+++

376
+++

377
+++

378
+

379
+

381
+

382
+

383
+

384
++

385
++

386
+

387
+

389
++

391
+

393
+

394
+

400
++

401
++

402
++

403
++

404
++

406
+

407
+

408
++

409
+++

410
+++

411
++

412
++

413
++

414
++

415
+

417
+

418
++

419
+++

420
++

421
+++

422
+++

423
+++

424
+

427
+

428
+

429
++

430
+

431
++

432
++

433
+

434
++

435
++

436
+

437
+

438
++

440
+++

441
+++

442
+++

443
+++

444
+++

445
+++

446
+++

447
+++

448
+++

449
+++

450
+++

451
+++

452
+++

453
+++

454
++

455
++

456
+++

457
+++

458
++

459
+++

460
+++

462
+++

463
+++

465
+++

466
+++

467
+++

468
+++

469
+++

470
+++

471
+++

472
+++

473
+++

474
+++

475
+++

476
+++

477
+++

478
+++

480
+++

481
+++

483
+++

488
+++

489
+++

490
+++

492
+++

493
+++

494
+++

495
+++

496
+++

503
+++

504
++

505
+++

506
+++

510
+++

511
+++

512
+++

513
+++

514
+++

515
+++

518
+++

519
+++

520
+++

521
+++

522
+++

759
+++

760
+++

761
+++

764
++

765
++

766
+

767
++

768
+

769
++

772
++

773
+++

774
+++

775
+++

776
+++

777
++

778
+++

779
+++

780
+++

781
++

782
+++

783
++

784
+++

785
+++

786
+++

787
+++

788
+++

789
+++

790
+

792
+++

793
+++

794
+++

795
++

797
++

799
+++

800
+++

801
+++

802
+++

803
+++

804
+++

805
++

806
+

807
+++

808
+++

809
+++

810
+++

811
+++

812
+++

814
++

Example 36

[General Procedure for Measurement of CDK-1 Enzyme Activity Inhibition]

(Compound Preparation)

Compounds were dissolved in DMSO at a concentration of 10 mM and stored in aliquots at −20° C. Compounds in DMSO from these stock aliquots were diluted in DMSO to produce the required range of 30× stock solutions. These stock solutions were then subjected to 1:3 dilutions in order to prepare the required range of 10× stock solutions and 5 μL of each solution was used per 50 μL reaction. A final DMSO concentration of 3% was maintained throughout all compound dilution series to maximise compound solubility. Compounds were routinely tested at final concentrations ranging from 300 μM to 0.001 μM, but may have been tested at lower concentrations depending upon their activity.

(CDK-1 Assay)

The kinase reaction was conducted in a round-bottomed polypropylene 96-well plate. CDK-1 was diluted to 0.5 U/μL in diluent buffer (50 mM Tris/HCl. pH7.5, 0.1 mM EGTA, 0.1% (v/v) β-mercaptoethanol, 1 mg/mL BSA). 5 μL compound or 30% DMSO was added to each well followed by 25 μL substrate cocktail (final concentration: 10 μM ATP, 50 μM peptide (HSTPPKKKAK), 0.5 μCi ³³P-γ-ATP in 50 mM Tris-HCl (pH 7.5), 1 mM EGTA, 2 mM DTT, 10 mM MgCl₂, 0.01% Brij-35). The reaction was initiated with the addition of 20 μL enzyme solution per well or 20 μL of diluent buffer without enzyme. The plate was shaken for 10 seconds and then left at room temperature for 15 minutes. The reaction was terminated with 50 μL 150 mM phosphoric acid. 90 μL of the reaction mixture was then transferred into a 96-well P81 filter plate (Whatmann) and incubated at room temperature for 5 minutes. The filter plate was then washed 4 times with 200 μL 75 mM phosphoric acid per well on a plate vacuum manifold (Millipore) and dried in an oven for 2-3 hours. Packard MicroScint ‘0’ (30 μL) was then added to each well, the plate was miffed for 30 minutes and subjected to liquid scintillation counting on a Packard TopCount.

(Interpretation)

% Control=(X−B)/(Tot−B)×100

% Inhibition=100−% Control

X=cpm of the test compound wells

B=cpm of wells without enzyme

Tot=cpm of wells with DMSO vehicle only

(CD K-1 Inhibitory Activity)

Compounds that inhibit CDK-1 (IC₅₀<100 μM) are; 2, 7, 9, 10, 11, 12, 14, 15, 16, 17, 18, 19, 23, 24, 26, 27, 28, 29,30, 31, 32, 33, 35 and 36.

Example 37

[General Procedure for Measurement of CDK-2 Enzyme Activity Inhibition]

(Compound Preparation)

Compounds were dissolved in DMSO at a concentration of 10 mM and stored in aliquots at −20° C. Compounds in DMSO from these stock aliquots were diluted in DMSO to produce the required range of 30× stock solutions. These stock solutions were then subjected to 1:3 dilutions in order to prepare the required range of 10× stock solutions and 5 μL of each solution was used per 50 μL reaction. A final DMSO concentration of 3% was maintained throughout all compound dilution series to maximise compound solubility. Compounds were routinely tested at final concentrations ranging from 300 μM to 0.001 μM, but may have been tested at lower concentrations depending upon their activity.

(CDK-2 Assay)

a) The kinase reaction was conducted in a round-bottomed polypropylene 96-well plate. CDK-2 was diluted to 0.5 ng/μL in diluent buffer (50 mM Tris/HCl. pH7.5, 0.1 mM EGTA, 0.1% (v/v) β-mercaptoethanol, 1 mg/ml BSA). 5 μL compound or 30% DMSO was added to each well followed by 25 μL substrate cocktail (final 10 μM ATP, 0.1 mg/ml Histone type III-S, 0.2 μCi ³³P-γ-ATP in 50 mM Tris-HCl (pH 7.5), 1 mM EGTA, 2 mM DTT, 10 mM MgCl₂, 0.01% Brij-35). The reaction was initiated with the addition of 20 μL enzyme solution per well or 20 μL of diluent buffer without enzyme. The plate was shaken for 10 seconds and then left at room temperature for 60 minutes. The reaction was terminated with 50 μL 150 mM phosphoric acid. 90 μL of the reaction mixture was then transferred into a 96-well P81 filter plate (Whatmann) and incubated at room temperature for 5 minutes. The filter plate was then washed 4 times with 200 μL 75 mM phosphoric acid per well on a plate vacuum manifold (Millipore) and dried in an oven for 2-3 hours. Packard MicroScint ‘0’ (30 μL) was then added to each well, the plate was mixed for 30 minutes and subjected to liquid scintillation counting on a Packard TopCount.

After adding 25 μL of substrate solution [0.2 mg/ml Histone type III-S, 20 μM ATP, 100 mM Tris buffer (pH 7.5), 2 mM EGTA, 4 mM DTT, 0.02% polyoxyethylene lauryl ether (23 Lauryl Ether; Brij 35), 20 mM magnesium chloride, 0.2 μCi [γ-³³P]ATP (specific activity: approximately 110 TBq/mmol)] to 5 μL of the test compound using 5% dimethylsulfoxide as the solvent, reaction was initiated by fulrther addition of 20 μL of a CDK2 enzyme solution [2.5 mU recombinant human CDK2/cyclin A, 50 mM Tris buffer (pH 7.5), 0.1 mM EGTA, 0.1% β-mercaptoethanol, 0.1% BSA]. After conducting the reaction for 15 minutes at room temperature, an equivalent volume of a 70% trichloroacetic acid (TCA) solution was added to suspend the reaction, and 90 μL of the reaction product was adsorbed onto a MultiScreen HV plate (Millipore) and rinsed with a 25% TCA solution. After drying the plate, 30 μL of MicroScint-O (Packard BioScience) was added, and the cpm was measured with a scintillation counter to determine the inhibiting activity.

(Interpretation)

% Control=(X−B)/(Tot−B)×100

% Inhibition=100−% Control

X=cpm of the test compound wells

B=cpm of wells without enzyme

Tot=cpm of wells with DMSO vehicle only

(CDK-2 Inhibitory Activity)

Compounds that inhibit CDK-2 (IC₅₀<100 μM) are; 1, 2, 6, 7, 10, 11, 12, 13, 14, 15, 16, 23, 28, 31, 32, 35, 37, 38, 41, 42, 43, 44, 46, 47, 48, 49, 50, 51, 52, 53, 55, 56, 57, 58, 59, 60, 61, 63, 64, 65, 68, 70, 71, 72, 74, 75, 76, 77, 78, 80, 81, 83, 84, 85, 86, 87, 88, 89, 91, 92, 93, 95, 97, 98, 102, 103, 105, 107, 111, 112, 113, 114, 115, 116, 118, 125, 126, 128, 129, 131, 137, 140, 148, 149, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 175, 176, 178, 179, 191, 193, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 203, 211, 212, 213, 214, 215, 216, 217, 219, 221, 222, 223, 224, 225, 226, 228, 229, 231, 234, 237, 238, 239, 240, 243, 246, 247, 248, 250, 251, 252, 253, 254, 256, 267, 274, 282, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 297, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 333, 335, 340, 341, 343, 350, 351, 352, 353, 354, 355, 356, 357, 359, 360, 361, 362, 366, 368, 371, 410, 411, 412, 417, 418, 419, 420, 421, 422, 423, 425, 437, 441, 442, 443, 444, 445, 460, 463, 511, 514, 762, 764, 765, 772, 773, 776, 778 and 785.

INDUSTRIAL APPLICABILITY

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.

Number	Date	Country	Kind
0304665.3	Feb 2003	GB	national
0329446.9	Dec 2003	GB	national

Number	Date	Country
0 591 528	Apr 1994	EP
628559	Dec 1994	EP
0941994	Sep 1999	EP
1505068	Sep 2005	EP
9854093	Dec 1998	WO
0053605	Sep 2000	WO
WO 04000844	Dec 2003	WO
WO 2004022559	Mar 2004	WO
WO 2004022560	Mar 2004	WO
WO 2004022561	Mar 2004	WO
WO 2004022562	Mar 2004	WO
WO 2004026229	Apr 2004	WO
2005077954	Aug 2005	WO

Pyrazolo[1,5-A] pyrimidine derivatives

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