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Title:
COMPOUNDS THAT INTERACT WITH KINASES
Document Type and Number:
WIPO Patent Application WO/2004/022572
Kind Code:
A1
Abstract:
A method of inhibiting or effecting the activity of protein kinase activity which comprises contacting a protein kinase with a compound of formula (I) being a derivative of a furanose or pyranose form of a monosaccharide, or a pharmaceutically acceptable salt thereof.

Inventors:
MEUTERMANS WIM (AU)
SCHAFER KARL (AU)
WEST MICHAEL LEO (AU)
MULDOON CRAIG (AU)
FOLEY FIONA (AU)
BOULOC NATALIE (GB)
TOMETZKI GERALD (AU)
Application Number:
PCT/AU2003/001146
Publication Date:
March 18, 2004
Filing Date:
September 05, 2003
Export Citation:
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Assignee:
ALCHEMIA PTY LTD (AU)
MEUTERMANS WIM (AU)
SCHAFER KARL (AU)
WEST MICHAEL LEO (AU)
MULDOON CRAIG (AU)
FOLEY FIONA (AU)
BOULOC NATALIE (GB)
TOMETZKI GERALD (AU)
International Classes:
A61K31/7056; A61K31/7076; A61K31/708; A61P9/00; A61P29/00; C07H17/02; C07H17/08; (IPC1-7): C07H17/02; C07H17/08; A61K31/7056; A61K31/7076; A61K31/4184; A61P9/00; A61P29/00
Domestic Patent References:
WO1996040705A11996-12-19
WO2001032653A12001-05-10
WO1999041266A11999-08-19
Foreign References:
EP1106609A22001-06-13
Other References:
CHEMICAL ABSTRACTS, vol. 125, Columbus, Ohio, US; abstract no. 125:196213, WALCZAK K. ET AL.: "Synthesis of reversed azole nucleosides under the Mitsunobu reaction conditions" XP008095088
See also references of EP 1546167A4
Attorney, Agent or Firm:
CULLEN & CO. (239 George Street Brisbane, Queensland 4000, AU)
Download PDF:
Claims:
Claims :
1. A method of inhibiting or effecting protein kinase activity which comprises contacting a protein kinase with a compound of formula I being a derivative of a furanose or pyranose form of a monosaccharide, or a pharmaceutically acceptable salt thereof formula I Wherein; n is 1 or 2, X is selected from the group consisting of: OR1, an unsubstituted 5 or 6 membered heterocyclic moiety, a substituted 5 or 6 membered heterocyclic moiety, an unsubstituted 9 or 10 membered heterobicyclic moiety and a substituted 9 or 10 membered heterobicyclic moiety, R1 is selected from the group consisting of: C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl, Y is selected from the group consisting of an unsubstituted 5 or 6 membered heterocyclic moiety; a substituted 5 or 6 membered heterocyclic moiety, an unsubstituted 9 or 10 membered heterobicyclic moiety and a substituted 9 or 10 membered heterobicyclic moiety; an amino acid, a dipeptide, and R6 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl or C3 to C14 heteroarylalkyl, with the proviso that R6, R7 and R8 are not all H, R9 is selected from H, or (CO)R6, R7, R8, R11, R12, R14, are independently selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 to C14 arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to C14 arylalkyl and C6 to C14 heteroarylalkyl, R13 is selected from the group consisting of : unsubstituted phenyl unsubstituted benzyl, substituted phenyl, substituted benzyl, H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 to C14 arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to C14 arylalkyl or C6 to C14 heteroarylalkyl,SR6 andOR6, R15 is absent or is at least one substituent on the aromatic ring which are independently selected from the group consisting of: OH, NO, NO2, NH2, N3, halogen, CF3, CHF2, CH2F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, alkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl and thioheteroaryl.
2. The method of claim 1, wherein R1 is substituted, cyclic or cyclic, branched and/or linear.
3. The method of claim 1, wherein R7 and R8 combine to form a cyclic structure.
4. The method of claim 1, wherein R6 and one of R7 or R8 combine to form a cyclic structure.
5. The method of claim 1, wherein R11 and R12 combine to form a cyclic structure,.
6. The method of claim 1, wherein X is selected from: OR1, R1 and R3 are independently selected from the group consisting of: C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl, R4 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl, R5 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl or C3 to C14 heteroarylalkyl, C1 to C7 acyl, C6 to C14 arylacyl, and C3 to C14 heteroarylacyl, R2 is selected from the group consisting of : (C=O)R3, (C=O)OR4, and (C=O)NHR4, Y is selected from: 7 The method of claim 6, wherein at least one of R1 to R5 is substituted, cyclic or cyclic, branched and/or linear.
7. The method of claim 6, wherein R7 and R8 combine to form a cyclic structure.
8. The method of claim 6, wherein R6 and one of R7 or R8 combine to form a cyclic structure.
9. The method of claim 6, wherein R11 and R12 combine to form a cyclic structure.
10. The method of claim 1 and claim 6 wherein at least one of R1R14 is substituted and these substituents and the substituents on the substituted 5 or 6 membered heterocyclic moiety and the substituted 9 or 10 membered heterobicyclic moiety are selected from the group consisting of: OH, NO, NO2, NH2, N3, halogen, CF3, CHF2, CH2F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, alkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted.
11. The method of claim 1 wherein the group X is.
12. The method of claim 1, wherein the group X is.
13. The method of claim 1, wherein X isOR1.
14. The method of claim 12 wherein the group Y is A.
15. The method of claim 13 wherein the group Y is A.
16. The method of claim 12 wherein Y is B.
17. The method of claim 13, wherein Y is B.
18. The method of claim 12, wherein Y is c.
19. The method of claim 13 wherein Y is c.
20. The method of claim 12, wherein Y is D.
21. The method of claim 13, wherein Y is D.
22. The method of claim 12, wherein Y is E.
23. The method of claim 13, wherein Y is E.
24. The method of claim 12, wherein Y is F.
25. The method of claim 13, wherein Y is F.
26. The method of claim 12, wherein Y is.
27. The method of claim 13, wherein Y is.
28. The method of claim 1 wherein the protein kinase is a serine or threonine kinase.
29. The method of claim 1 wherein the protein kinase is a tyrosine kinase.
30. The method of claim 1 wherein the protein kinase is one or more of the isoforms of protein kinase C.
31. The method of claim 1 wherein the protein kinase is Tie2, also known as TEK, HPK6, TIE2, VMCM, VMCM1.
32. The method of claim 1 wherein the protein kinase is cKit also known as SCFR, CD117, PBT.
33. The method of claim 1 wherein the protein kinase is VEGF R2/KDR also known as VEGFR2, VEGFR2, VEGFR, Hs. KDR, Hs. 12337, FLK1, FLK1.
34. The method of claim 1 wherein the protein kinase is EGFR also known as ERBB1, ERBB, EGFRvill.
35. The method of claim 1 wherein the protein kinase is Abl also known as cab1, cABL, JTK7, p150, ABL1.
36. The method of claim 1 wherein the protein kinase is MET also known as HGFR, CMET, RCCP2.
37. The method of claim 1 wherein the protein kinase is, CDK2 also known as p34CDK2, p33CDK2, p33CDK2.
38. The method of claim 1 wherein the protein kinase is PDGF also known as PDGFR1, PDGFR, PDGFRbeta, JTK12, CD140B, PDGFRB.
39. The method of claim 1 wherein the protein kinase is FGFR1 also known as NSAM, LOC51033, FLT2, FLJ14326, CEK, CFGR, BFGFR, H5, H4, H3, H2, FLG.
40. The method of claim 1 wherein the protein kinase is P38 MAP Kinase also known as p38alpha, p38ALPHA, SAPK2a, SAPK2A, PRKM15, PRKM14, Mxi2, MX12, Exip, EXIP, CSPB1, CSBP2, CSBP1, p38, RK, P38, MAPK14.
41. A compound of formula I which is a derivative of a furanose form of a monosaccharide of general formula 1, formula I Wherein; n is 1, X is selected from: OR1, R1 and R3 are independently selected from the group consisting of: C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl, R4 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl, R5 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl or C3 to C14 heteroarylalkyl, C1 to C7 acyl, C6 to C14 arylacyl, and C3 to C14 heteroarylacyl, R2 is selected from (C=O)R3, (C=O)OR4, (C=O)NHR4, Y is selected from the group consisting of: R6 is selected from the group consisting of H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl, with the proviso that R6, R7 and R8 are not all H, R9 is selected from H, or (CO)R6, R7, R8, R11, R12, R14, are independently selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 to C14 arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to C14 arylalkyl or C6 to C14 heteroarylalkyl, R13 is selected from the group consisting of: unsubstituted phenyl, unsubstituted benzyl, substituted phenyl, substituted benzyl, H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 to C14 arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to C14 arylalkyl or C6 to C14 heteroarylalkyl,SR6 orOR6, R15 is absent or is at least one substituent on the aromatic ring which is independently selected from the group consisting of: OH, NO, N02, NH2, N3, halogen, CF3, CHF2, CH2F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, alkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl.
42. The compound of claim 42, wherein R7 and R8 combine to form a cyclic structure.
43. The compound of claim 42, wherein R6 and one of R7 or R8 combine to form a cyclic structure.
44. The compound of claim 42, wherein R11 and R12 combine to form a cyclic structure.
45. The compound of claim 42, wherein the groups R1, R2, R3, R4 and R5 are optionally substituted, cyclic or cyclic, branched and/or linear.
46. The compound of claim 42, wherein R2 and R3 combine to form a ring structure.
47. The compound of claim 42, wherein the groups R4 and R5 combine to form a ring structure.
48. A compound of claim 42 in which at least one of R1 to R14 is substituted with a substituent selected from the group, OH, NO, N02, NH2, N3, halogen, CF3, CHF2, CH2F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoalkyl, alkyl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted,.
49. The compound of claim 42 in which the group X is.
50. The compound of claim 42 in which the group X is.
51. The compound of claim 42 in which the group X isOR1.
52. The compound of claim 50 wherein Y is A.
53. The compound of claim 51 wherein Y is.
54. The compound of claim 50, wherein Y is.
55. The compound of claim 51, wherein Y is B.
56. The compound of claim 50, wherein Y is c.
57. The compound of claim 51, wherein Y is c.
58. The compound claim 50, wherein Y is.
59. The compound claim 51, wherein Y is D.
60. The compound of claim 50, wherein Y is E.
61. The compound of claim 51, wherein Y is.
62. The compound of claim 50, wherein Y is F.
63. The compound of claim 51, wherein Y is F.
64. The compound claim 50, wherein Y is.
65. The compound claim 51, wherein Y is.
Description:
Compounds that Interact with Kinases FIELD OF THE INVENTION The invention is directed to classes of biologically active compounds that interact in a pharmaceutically significant manner with protein kinases, and particularly to provide compounds suitable for the treatment of disorders mediated by protein kinase activity. The invention is also directed to treatment of the above mentioned disorders. The invention is also directed to the preparation of novel compounds per se.

BACKGROUND OF THE INVENTION The drug discovery landscape has been transformed by the genomics revolution. Advances in the understanding of biomolecular pathways and the roles they play in disease is generating vast numbers of targets for therapeutic intervention. Protein kinases now represent an extensive and important class of therapeutic targets.

Kinases are key components in almost all signal transduction pathways, modulating extracellular and intracellular signalling processes that mediate events such as cell growth and differentiation, metabolism and apoptosis. Kinases do this by catalysing the transfer of a phosphate group from ATP to protein substrates. The pivotal role of kinases is emphasized by the fact that kinases represent the third most populous domain in the proteome.

Kinases have been implicated in many diseases. Twenty percent of oncogenes code for tyrosine kinases. Kinases play pivotal roles in many leukemias, tumours and other proliferative disorders. Other states involving kinases include inflammatory disorders such as psoriasis, cardiovascular diseases such as restenosis, viral induced diseases such as Kaposi's sarcoma, circulatory diseases such as atherosclerosis and fibroproliferative diseases. Specific kinases are often implicated in particular disease states and therefore present themselves as potential targets for therapeutic intervention.

The kinase family includes serine/threonine kinases and tyrosine

kinases, with the amino acid referring to the particular residue on a protein substrate that is phosphorylated. The tyrosine kinases can be further divided into receptor tyrosine kinases and non-receptor tyrosine kinases.

Considering the rate of generation and nature of the targets currently being deconvoluted by biologists, there is a need for the development of drug candidates, designed in a rational manner to purposely interact with selected targets, such as the kinases.

From a drug discovery perspective, carbohydrate pyranose and furanose rings and their derivatives are well suited as templates. Each sugar represents a three-dimensional scaffold to which a variety of substituents can be attached, usually via a scaffold hydroxyl group, although occasionally a scaffold carboxyl or amino group may be present for substitution. By varying the substituents, their relative position on the sugar scaffold, and the type of sugar to which the substituents are coupled, numerous highly diverse structures are obtainable. An important feature to note with carbohydrates, is that molecular diversity is achieved not only in the type of substituents, but also in the three dimensional presentation. The different stereoisomers of carbohydrates that occur naturally, offer the inherent structural advantage of providing alternative presentation of substituents. We have developed a system that allows the chemical synthesis of highly structurally and functionally diverse derivatised carbohydrate and tetrahydropyran structures, of both natural and unnatural origin. The diversity accessible is particularly augmented by the juxtaposition of both structural and functional aspects of the molecules.

A number of kinase inhibitors have appeared in the scientific literature to date. Many have entered human clinical trials and in two cases, Gleevac and Iressa, approval for the treatment of various tumours has been granted (Cohen, P. , Nature Tev. Drug Discovery, 1,309-316, 2002). The specificity of published kinase inhibitors varies widely and it is apparent from the study of Gleevac that specificity for a single kinase is not a prerequisite for the inhibitor becoming a useful drug, indeed the inhibition of more than one kinase may be an advantage for therapeutic intervention. Despite some promiscuity in the target kinase being acceptable, it is generally considered desirable to have

good selectivity for the target kinase (s) over more general"housekeeping" kinases. Thus selectivity and inhibitor potency must be assessed on a case by case basis.

The level of inhibition in cell based assays also shows considerable variation from approximately 0.1 micromolar to over 100 micromolar as exemplified by the following table (a more detailed study can be found in: Davies et. al., Biochem. J. , 351,95-105, 2000; and Bain et. al., Biochem. J., 371,199-204, 2003). It is frequently the case that the most potent inhibitor is not the most suitable inhibitor for therapeutic purposes. Inhibitor Top 5 kinases inhibited concentration kinase and residual activity ML-9 MSK-1 ROCK-II SmMLCK S6K1 CDK2 100 µM 14% 23% 25% 27% 38% LY 294002 P13K CK2 PHK GSK3p SGK 50 uM 13% 18% 44% 53% 72% HA1077 ROCK-II PRK2 MSK1 S6K1 PKA 20 uM 7% 15% 19% 32% 35% PP2 LCK CDK2 CK1 SAPK2a MKK1 10M1% 3% 6% 21 % 55% Ro-31-8220 MAPKAPK1 b MSK1 PKCa GSK3ß S6K1 1 uM 2% 2% 3% 5% 6% MSK-1 = mitogen and stress activated protein kinase 1; ROCK-IN = Who associated coiled coil forming protein kinase II ; SmMLCK = smooth myosin light chain kinase; S6K1 = p70 S6 kinase; CDK2 = cyclin dependant kinase 2; Pi3K = phosphoinositide 3 kinase; CK2 = casein kinase 2; PHK = phosphorylase kinase; GSK3ß = glycogen synthetase kinase 3p ; SGK = serum and glucocortin induced kinase; PRK2 = PKC related kinase 2; PKA = protein kinase A; LCK = T cell specific kinase; CK1 = casien kinase 1; SAPK2a = p38 kinase; MKK1 = mitogen activated protein kinase 1; MAPKAP-K1 b = mitogen activated protein kinase activated protein kinase 1 b ; PKCa = protein kinase C alpha.

It will be clearly understood that, if a prior art publication is referred to herein, this reference does not constitute an admission that the publication forms part of the common general knowledge in the art in Australia or in any other country.

SUMMARY OF THE INVENTION Using the axioms of this drug discovery methodology, we synthesised several novel classes of chemotypes in an effort to develop drug candidates against kinase targets.

Kinases selected examples from the three different classes; serine/threonin kinase, tyrosine receptor kinase and tyrosine non-receptor kinase have been explored to determine the generality of the current invention. Compounds were tested within the industry standard concentration range described above and have revealed potent and selective inhibitors against each selected kinase target.

It is a general object of the invention to provide compounds suitable for the treatment of disorders mediated by protein kinase activity and in the treatment of the above mentioned disorders.

It is an optional object of the invention to provide a pharmaceutical formulation comprising at least one compound as described herein or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutical acceptable carriers, diluents or excipients.

It is a further optional object of the invention to provide a method of treatment of a human or animal subject suffering from a disorder mediated by aberrant protein kinase activity which method comprises administering to the human or animal subject an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof.

It is a further object of the invention to prepare novel compounds per se In one form, the invention comprises method of inhibiting or effecting protein kinase activity which comprises contacting a protein kinase with a compound of formula I being a derivative of a furanose or pyranose form of a monosaccharide, or a pharmaceutical acceptable derivative thereof

formula I Wherein; n is 1 or 2, X is selected from the group consisting of: OR1, an unsubstituted 5 or 6 membered heterocyclic moiety, a substituted 5 or 6 membered heterocyclic moiety, an unsubstituted 9 or 10 membered heterobicyclic moiety and a substituted 9 or 10 membered heterobicyclic moiety, R1 is selected from the group consisting of: C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl, Y is selected from the group consisting of: an unsubstituted 5 or 6 membered heterocyclic moiety; a substituted 5 or 6 membered heterocyclic moiety, an unsubstituted 9 or 10 membered heterobicyclic moiety and a substituted 9 or 10 membered heterobicyclic moiety; an amino acid, a dipeptide, and

R6 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl or C3 to C14 heteroarylalkyl, with the proviso that R6, R7 and R8 are not all H, R9 is selected from H, or- (CO)-R6, R7, R8, R11, R12, R14, are independently selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 to C14 arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to C14 arylalkyl and C6 to C14 heteroarylalkyl, R13 is selected from the group consisting of : unsubstituted phenyl unsubstituted benzyl, substituted phenyl, substituted benzyl, H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 to C14 arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to C14 arylalkyl or C6 to C14 heteroarylalkyl,-S-R6 and-O-R6, R15 is absent or is at least one substituent on the aromatic ring which are independently selected from the group consisting of: OH, NO, N02, NH2, N3, halogen, CF3, CHF2, CH2F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, alkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl and thioheteroaryl.

R1 may be substituted, cyclic or cyclic, branched and/or linear.

R7 and R8 may combine to form a cyclic structure. R6 and one of R7 or R8 may combine to form a cyclic structure.

R11 and R12 may combine to form a cyclic structure, X may be selected from: OR1,

R1 and R3 are independently selected from the group consisting of: C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl, R4 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl, R5 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl or C3 to C14 heteroarylalkyl, C1 to C7 acyl, C6 to C14 arylacyl, and C3 to C14 heteroarylacyl, R2 is selected from the group consisting of :- (C=O)-R3,- (C=O)-OR4, and- (C=O)-NH-R4, Y is selected from:

At least one of R1-R14 may be substituted and these substituents and the substituents on the substituted 5 or 6 membered heterocyclic moiety and the substituted 9 or 10 membered heterobicyclic moiety may be selected from the group consisting of: OH, NO, N02, NH2, N3, halogen, CF3, CHF2, CH2F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl,

aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoalkyl, alkyl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted.

X may comprise X may comprise X may comprise-OR1 Y may comprise A as described above.

Y may comprise B as described above.

Y may comprise C as described above.

Y may comprise D as described above.

Y may comprise E as described above.

Y may describe F as described above.

Y may comprise G as described above.

The protein kinase may comprise a serine or threonine kinase.

The protein kinase may comprise a tyrosine kinase.

The protein kinase may comprise one or more of the isoforms of protein kinase C.

The protein kinase may comprise Tie-2, also known as TEK, HPK-6, TIE-2 VMCM, VMCM1.

The protein kinase may comprise c-Kit also known as SCFR, CD117, PBT.

The protein kinase may comprise VEGF-R2/KDR also known as VEGFR2, VEGFR-2, VEGFR, Hs. KDR, Hs. 12337, FLK1, FLK-1.

The protein kinase may comprise EGF-R also known as ERBB1, ERBB, EGFRvl l l.

The protein kinase may comprise Ab also known as c-ab1, c-ABL, JTK7, p150, ABL1.

The protein kinase may comprise MET also known as HGFR, C-MET, RCCP2.

The protein kinase may comprise, CDK2 also known as p34CDK2, p33CDK2, p33CDK2.

The protein kinase may comprise PDGF also known as PDGFR1, PDGFR, PDGF-R-beta, JTK12, CD140B, PDGFRB.

The protein kinase may comprise kinase, FGFR-1 also known as N-SAM, LOC51033, FLT2, FLJ14326, CEK, C-FGR, BFGFR, H5, H4, H3, H2, FLG.

The protein kinase may comprise P38 MAP Kinase also known as p38alpha p38ALPHA, SAPK2a, SAPK2A, PRKM15, PRKM14, Mxi2, MXI2, Exip, EXIP, CSPB1, CSBP2, CSBP1, p38, RK, P38, MAPK14.

In another form, the invention comprises a compound of formula I which is a derivative of a furanose form of a monosaccharide of general formula 1, formula I Wherein; n is 1, X is selected from: OR1,

R1 and R3 are independently selected from the group consisting of: C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl, R4 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl, R5 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl or C3 to C14 heteroarylalkyl, C1 to C7 acyl, C6 to C14 arylacyl, and C3 to C14 heteroarylacyl, R2 is selected from- (C=O)-R3,- (C=O)-OR4,- (C=O)-NH-R4, Y is selected from the group consisting of:

R6 is selected from the group consisting of H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl, with the proviso that R6, R7 and R8 are not all H, R9 is selected from H, or- (CO)-R6,

R7, R8, R11, R12, R14, are independently selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 to C14 arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to C14 arylalkyl or C6 to C14 heteroarylalkyl, R13 is selected from the group consisting of: unsubstituted phenyl, unsubstituted benzyl, substituted phenyl, substituted benzyl, H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 to C14 arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to C14 arylalkyl or C6 to C14 heteroarylalkyl,-S-R6 or-O-R6, R15 is absent or is at least one substituent on the aromatic ring which is independently selected from the group consisting of: OH, NO, N02, NH2, N3, halogen, CF3, CHF2, CH2F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, alkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl.

R7 and R8 may combine to form a cyclic structure.

R6 and one of R7 or R8 may combine to form a cyclic structure.

R11 and R12 may combine to form a cyclic structure.

R1, R2, R3, R4 and R5 are optionally substituted, cyclic or cyclic, branched and/or linear.

R2 and R3 may combine to form a ring structure.

R4 and R5 may combine to form a ring structure.

At least one of R1 to R5 may be substituted with a substituent selected from the group, OH, NO, NOs, NH2, N3, halogen, CF3, CHF2, CH2F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid,

carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, alkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted, X may be or-OR1.

Y may comprise A as described above.

Y may comprise B as described above.

Y may comprise C as described above.

Y may comprise D as described above.

Y may comprise E as described above.

Y may comprise F as described above.

Y may comprise G as described above.

The compounds of the invention may be mixed with a pharmaceutical

acceptable carrier, adjuvant, or vehicle which may comprise a-toxic carrier, adjuvant, or vehicle that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof.

The pharmaceutical derivative may comprise a salt, ester, salt of an ester or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention, although no limitation is meant thereby.

Compounds of the invention may be administered orally such as by means of a tabled, powder, liquid, emulsion, dispersion and the like ; by inhalation; topically such as by means of a cream, ointment, salve etc; and as a suppository, although no limitation is meant thereby.

BEST MODE General Methods General Method 1-Amide bond formation: To a solution of an acid in DMF (0.3 ml, 0.35 M, 1.0 equiv. ) at room temperature was added a solution of HBTU in DMF (0.3 ml, 0.42 M, 1.2 equiv. ) followed by DIPEA (2.5 equiv. ).

After 10 min. , a solution of the desired amine in DMF (0.3 ml, 0.37 M, 1.05 equiv. ) was added. The resulting solution was stirred at room temperature for 2.5 h, then diluted with DCM (8 ml) and washed with 10 % citric acid (2 x 5 ml), saturated NaHCO3 (2 x 5 ml), brine (5 ml) and water (5 ml). The solvent was removed in vacuo.

General Method 2-Ester Hydrolysis : A solution of the ester (0.1 mmoles) in THF (0.5 ml) was treated with a solution of lithium hydroxide in water (0.5 ml, 0.45 M, 2.1 equiv. ). The resulting mixture was stirred at room temperature overnight, then evaporated to dryness under reduced pressure to provide the

corresponding carboxyllic acid as the lithium salt. The residue is redissolved in either ethyl acetate or dichloromethane and washed with a small quantity of 10% citric acid solution, followed by drying of the organic layer and removal of the solvents in vacuo to yield the desired carboxylic acid. In cognate experiments sodium hydroxide or potassium hydroxide has been substituted for lithium hydroxide to for the corresponding sodium or potassium salts in comparable yields. Methanol and dioxane have been substituted for THF as the reaction solvent with comparable results.

General Method 3a-Removal of acid labile protecting groups (isopropvlidene and BOC)-solution phase: The compound was dissolved in acetonitrile and treated with 90/10 trifluoroacetic acid-water (2ml) and monitored by t. l. c for reaction completeness. Reaction times vary considerably from 15 minutes at RT to 6 hours at RT. When complete, the mixture was concentrated under reduced pressure and co-evaporating from acetonitrile. The crude products were resuspended in water-acetonitrile and lyophilised then purificatied by reverse phase C-18 HPLC using a solvent gradient of water/acetonitrile to afford the desired product as white solids. In cognate experiments, 50/50 trifluoroacetic acid-water has been used with similar efficiency.

General Method 3b-Removal of acid labile protecting-groups (isopropylidene and BOC) and cleavage from resin-solid phase: The resin bound compound (approx. 200mg of resin) was washed with DCM (2x 2mL) then treated with TFA/DCM 1: 1 (1 mL) for 15 mins. The resin was filtered and washed with acetonitrile (1 ml) (filtrates collected). This procedure was repeated for a second cycle. The filtrates were evaporated under a stream of nitrogen. The residue was redissolved in water (1 ml) and agitated for 3h. After this time, the solution was lyophilised to afford the crude products which were purified as described above.

General Method 4-removal of an Fmoc protecting group : The Fmoc protected compound on resin (12 g of resin, 0.7 mmol/g, 8.4 mmol) was

washed with DMF (2 x 120 ml), then treated with 20 % piperidine in DMF (120 ml) and shaken at r. t. for 30 min. The resin was drained and washed with DMF (2 x 120 ml). The reaction was repeated and the resin was drained, washed with DMF (2 x 120 ml), DCM (2 x 120 ml), MeOH (2 x 120 ml) and ether (2 x 120 ml), and dried in vacuo for 2 h.

General Method 5-couplinq of fluoro-nitro-benzoic acid: Resin bound substrate was washed under N2 with dry DCM (1 x 80 mi, 1 x 60 ml). To a solution of 4-fluoro-3-nitrobenzoic acid (9.3 g, FW 185.09, 50.2 mmol, 6 equiv. ) in dry DCM (60 ml) and dry DMF (9 ml) at r. t. and under N2 was added 1, 3-diisopropylcarbodiimide (DIC, 3.9 ml, d 0.806, FW 126.20, 24.9 mmol, 3 equiv. ). The solution was stirred for 10 min. , then added to the resin followed by 4- (dimethylamino) pyridine (DMAP, 102 mg, FW 122.17, 0.83 mmol, 0.1 equiv. ). The resin was then shaken at r. t. for 3 h, drained, washed with DMF (4 x 120 ml), DCM (3 x 120 ml) and ether (2 x 120 ml), and dried in vacuo overnight. The coupling procedure may be repeated in the event of a positive ninhydrin test.

General Method 6-nucleophillic aromatic displacment : Resin bound 3- nitro-4-fluoro-benzoate XI (200 mg, 0.14 mmol) was washed under N2 with dry DMF (2 ml) or dry DMSO (2 ml), then treated with a solution of the nucleophile (0.42 mmol, 3 equiv. ) and diisopropylamine (DIPEA, 0.146 mi, d 0.742, FW, 129.25, 0.84 mmol, 6 equiv. ) in dry DMF (2 ml) or dry DMSO (2 ml) and shaken at r. t. o/n. The resin was drained and washed with DMF (3 x 2 ml) and DCM (3 x 2 ml). In the case of DMSO as solvent, the reaction was warmed to 60 oC. The nucleophile may be any suitable primary or secondary aliphatic or aromatic amine, or a thiol. In an alternative experiment, the nucleophile was bound to the solid support and treated with an excess of ortho-fluoro-nitrobenzyl derivatives under similar conditions.

General Method 7-reduction of an aromatic nitro group : The resin bound substrate (0.14 mmol) was washed with DMF (2 x 2 ml) and then suspended in DMF (0.7 ml) to which was added a solution of SnC12. 2H20 in DMF (0.7 ml,

2 M, 1.40 mmol, 10 equiv. ). The resin was shaken at r. t. o/n, then washed with DMF (5 x 2 ml), DCM (3 x 2 ml) and MeOH (5 x 2 ml).

General Method 8 preparation and reaction of an acid chloride : Resin bound substrate (0.14 mmol) was washed with DCM (2 x 2 ml) and then under N2 with dry DCM (2 x 2 ml). A suspension of the of sugar-acid building blocks (0.42 mmol, 3 equiv. ) in dry DCM (2 ml) was treated with triphosgene (42 mg, FW 296.75, 0.14 mmol, 1 equiv.) followed by collidine (0.159 ml, d 0.917, FW 121.18, 1.20 mmol, 8.6 equiv. ). An effervescence was observed and a solution formed. After 1 min. , this solution was added to the resin bound substrate and the resin was shaken at r. t. for 3 h. The resin was drained and washed with DCM (5 x 2 ml) and MeOH (3 x 2 ml).

General Method 9 cleavage of adenosine N-benzovl aroup : The adenosine-containing products were treated with saturated ammonia in methanol (4 ml) at r. t. o/n. The solvent was removed in vacuo and the product was again treated with sat NH3 in MeOH at r. t. o/n. The solvent was removed in vacuo and compounds purified as described above. In an alternative proceedure, 1 M hydrazine hydrate in DMF was substituted for methanolic ammonia. The latter procedure is particularly useful for benzoate removal on solid support.

General Method 10-benzimidazole svnthesis : Resin bound substrate (approx. 200mg, 0. 14mmol) was treated with a solution of an aldehyde (5.0 equivalents) in N-methylpyrrolidine (NMP) (4ml) and heated to 45-50°C overnight. The resins were subsequently washed with DMF (3x4mL), DCM (3x4mL), MeOH (3x4mL), ether (3x4mL) and dried in vacuo overnight.

General Method 11-Cesium carboxylate coupling : The cesium salt of the Boc protected amino acid is made by dissolving the amino acid in methanol (5ml/mmol) and water (0. 5ml/mmol) and adding an aqueous solution of 20% Cs2CO3 until pH 7 is reached. The solvent is removed in vacuo and the material is freeze-dried overnight to give a white powder. The resin is treated

with the cesium salt (5eq) in dry DMF (4ml/g of resin) and stirred at 50°C for 24 hours. The resin is drained and washed with DMF, DMF/H20 (1: 1; x 3), MeOH/H20 (1: 1; x 3) and MeOH (x 3) and then dried in vacuo.

General Method 12-Reductive amination: 6 eq of aldehyde is dissolved in TMOF/THF (1: 1; 2ml) and added to the resin (200mg) and shaken at room temperature for 3-4 hours. The resin is drained and a solution of NaCNBH3 (2eq) in THF/MeOH/AcOH (9: 1: 0.1 ; 2ml) is added to the resin and shaken overnight at room temperature. The resin is then drained and washed with THF/MeOH (1: 3; x 3, DMF/MeOH (1: 3; x 3), DCM/MeOH (1: 3; x 3) and DCM.

General Method 13-Urea formation: In a gloved box, the resin is swelled in 10% DIPEA/DCM, a solution of triphosgene (2eq in 1. 2ml of dry DCM) was added to the resin in two batches and shaken for 1 hour. The resin is washed with dry DCM (1 ml x 2) and a solution of the amine (1.1 eq) and DIPEA (2.2eq) in 1. 5m1 of dry DCM was added and shaken for 30 minutes. The resin is drained and washed with DMF (x 3), DCM (x 3) and MeOH (x 3) and dried.

General Method 14 base catalysed ring closure : The resin was treated with a solution of MeOH/NEt3 (9: 1; 2ml) and heated to 60°C overnight. The resin is drained (collecting the filtrate) and washed with MeOH, (1 ml), DCM (1 ml), MeOH (1 ml) and DCM (1 ml). The filtrates are combined and the solvent removed in vacuo. The process is then repeated.

General Method 15-Thiourea formation: Resin bound substrate was washed under N2 with dry THF (3 x 30 mL) then thiocarbonyl diimidazole (2.49g, 14 mmol) in dry THF (70 mL, conc = 0.2M) was added and the resin was shaken at rt for 12h. The resin was filtered, washed with THF (3 x 30 mL), DMF (2 x 30 mL), DCM (2 x 30 ml), DCM/MeOH (30 mL), MeOH (30 mL) and dried in vacuo.

General Method 16-S alkylation of an isothiourea: The reactions were

performed in Bodhan Miniblocks. The resin bound thiourea compound resin (200 mg) was washed under N2 with dry DMF (2 x 2 mL). Alkyl halide R1X (0.7 mmol) in dry DMF (1 mL) was added followed by DIPEA (1.4 mmol) in dry DMF (1 mL). The resin was shaken at rt for 12h, then washed with DMF (3 x 2 mL), DCM (3 x 2 mL), DCM/MeOH 1: 1 (2 x 2 mL), MeOH (2 x 2 mL).

General Method 17-bromoacetylation : To bromoacetic acid (7.76g) in dry DCM (40 mL) was added slowly DIC (4.4 mL) at 0 °C. The solution was stirred at 0°C for 30 mins. The solution was syringed out leaving the precipitated urea.

Resin bound substrate was washed under N2 with dry DMF then swollen in dry DMF (1 mL). The bromoacetic anhydride solution in dry DCM (1 ml) was added and the resin was shaken at rt for 1 hrs. The resin was filtered, washed with dry DMF (3x 3 mL) under N2 (glove box) and dry DCM (2 x 3 mL). Excess DCM was drained applying positive pressure of N2. The resin was carried through the next step immediately.

General Method 18-N-alkvlation : Bromoacetylated resin produced by general method 17 is added to a sugar amine building block (5eq) in DMF (1 mL). The resin was shaken at rt for 16h then filtered, washed with DMF, DCM, DCM/MeOH and dried in vacuo.

General Method 19-Dichloro-Nitropyrimidine addition: The resin was swelled in NMP and a solution of 4, 6-Dichloro-5-nitropyrimidine (5eq) and DIPEA (10eq) in NMP (1 !/100mg resin) was added and shaken at room temperature overnight (solution turned deep orange-red). The resin was drained under nitrogen and washed with dry DMF and dry DCM until filtrate is colourless and dried in vacuo.

General Method 20-Nitro reduction: The resin was swelled in DCM (1. 5ml/100mg) and a solution of K2C03 (10eq) and Na2S204 (8eq) in H20 (0. 75ml/100mg) was added. Viologen (0.4eq) was then added turning the solution deep blue. The resin was then shaken vigourously for 72 hours. The

resin was then drained and washed with an aqueous solution of 1% AcOH, THF, DMF and DCM and dried in vacuo.

General Method 21-Aldehvde cyclisation : A solution of the aldehyde (5eq) in NMP with 1% AcOH (800µl/100mg resin) was added to the dry resin in a test tube. The tube was sealed but allowed to vent with a needle in the top.

The resin was heated at 100°C overnight. The resin was filtered and washed with DMF, DCM and MeOH and dried in vacuo.

General Method 22-Acid Chloride Acylation : Resin bound substrate was washed under N2 with dry DCM then swollen in DIPEA (20eq)/DCM (1 mL). A solution of acid chloride (10eq) in DCM (1ml) was added and the resin was shaken at rt for 24h. The resin was washed with DMF, DMF/MeOH, DCM, DCM/MeOH, MeOH and dried in vacuo.

General Method 23-Reaction with the isocyanates and the resin cleavage : The resin was taken up in DCE and cooled to 0 °C followed by isocyanate (4 eq) addition. After 30 minutes, 10% TFA/DCM was added followed by shaking for 1 hour at room temperature. The resin was filtered and washed with DCM. The filtrate was concentrated under reduced pressure to afford the crude residue.

General Method 24-Biological assays : Compounds were tested in vitro as follows.

Recombinant protein kinases, which were expressed as fusion proteins in SF9 insect cells or E. coli, were used for all in vitro assays. The purity and identity of each kinase was checked by SDS-PAGE/silver staining and by western blot analysis with specific antibodies.

All kinase assays except for p38a (see below) were performed in 96- well micro-titre plates. The assay components included assay buffer, ATP, test compound, enzyme and substrate.

The assay for all enzymes (except for the PKC. see below contained 60 mM HEPES-NaOH, pH7. 5, 3 mM MgCl2, 3 mM MnCl2, 3 tM Na- orthovanadate, 1 mM DTT, 0.1 µM [γ-33P]-ATP (approx. 5x105 cpm per well).

The assay for the PKCs contained 60 mM HEPES-NaOH, pH 7.5, 1 mM EDTA, 1.25 mM EGTA, 5 mM MgCl2, 1.32 mM Cal2, 5 pg/m ! Phosphatidylserine, 1 µg/ml 1.2 Dioleyl-glycerol, 1.2 mM DTT, 50 µg/ml PEG20000, 0.1 µM [γ-33P]-ATP (approx. 5 x105 cpm per well).

The table below details the amounts of enzyme and substrate that were used per well : &num Kinase Screenpool &num Enzyme Substrate Substra te (ngl50, u1) (ngl50, u1, 1 KIT 1 50 Poly (Glu, Tyr) 4 1 125 2 EGF-R 4 50 Poly (Glu, Tyr) 4 1 125 3 TIE2 3 100 Poly (Glu, Tyr) 4:1 125 4 PDGF-3 100 Poly (Glu, Tyr) 4 1 500 Ralpha 5 FGF-R1 1 75 Poly (Glu, Tyr) 4 1 500 6 CDK2/CycA 2 10 Histone H1 250 7 MET 7 100 Poly (Glu, Tyr) 4:1 125 8 VEGF-R2 2 50 Poly (Glu, Tyr) 4 : 1 125 9 ABL 1 10 Poly (Ala, Glu, Lys, 250 Tyr) 6 2 :5:1 10 PKC-beta1 1 13 Histone H1 500 The reaction cocktails were incubated at 30°C for 80 minutes. The reaction was stopped with 50 pl of 2% (v/v) H3PO4, plates were aspirated and washed twice with 200 lli of H20 or 0.9% (w/v) NaCl. Incorporation of 33Pj was determined with a microplate scintillation counter.

The mitogen-activated protein kinase p38a assays were done in a proprietary microassay NanoCarrierT 2080 format. In these assays phosphorylation was detected by a phospho-substrate specific monoclonal antibody in an indirect competition assay. The degree of binding of the antibody to the phospho-substrate was measured by fluorescence

polarization using 2D-FIDA anisotrophy. In these experiments the final concentration of the enzyme was 1.6nM and the substrate was 2, uM.

All data is presented as residual activity, which is the activity of the enzyme in the presence of the stipulated concentration of inhibitor or compound. 100% activity is the maximum activity of the enzyme in the absence of any inhibitor or compound.

In all experiments the Z'value was calculated according to Zhang et al (J-H Zhang, T. D. Y Chung, K. R. Oldenburg (1999) Journal of Biomolecular Screening 4: 67-73) using the standard deviations and mean values of the positive and negative controls.

Z'= 1- (3*Stdevneg + 3*Stdevpos)/ (Meanpos-Meanneg) Only data where the Z'value was >0.5 was used.

Example 1: (1-a) General Method 1, (1-b) General Method 2, (1-c) General Method 3.

Analysis of some typical example compounds Isomer A: proton (400 MHz: DMSO) 2.38 (dt, J 5.0, 6H, CH2CH2), 2.65 (d, J 15.0 Hz, 1 H, CH3), 3.85-3. 95 (m, 2H, H2 or H3 or H4), 4.05 (dd, J 3.0, 8.0 Hz, 1H, H5a), 4.10 (dd, J 3. 0,8. 0 Hz, 1H, H5b), 4.30 (m, 1H, CH), 4.65 (dd, J 5. 0, 5.0 Hz, 1H, H2 or H3 or H4), 5.87 (d, J 4.0 Hz, 1H, H1), 8.30 (s, 1H, ArH), 8. 45 (s, 1 H, ArH).

Isomer B: proton (400 MHz: DMSO) 2.42 (dt, J 5.0, 6H, CH2CH2), 2.75 (d, J 15.0 Hz, 1H, CH3), 3. 85-3. 95 (m, 2H, H2 or H3 or H4), 4.05 (dd, J 3.0, 8.0 Hz, 1H, H5a), 4.10 (dd, J 3. 0,8. 0 Hz, 1H, H5b), 4.30 (m, 1H, CH), 4.65 (dd, J5. 0,

5.0 Hz, 1 H, H2 or H3 or H4), 5.92 (d, J 4.0 Hz, 1 H, H 1), 8.35 (s, 1 H, ArH), 8.50 (s, 1 H, ArH).

Example 2: R1=phenyl, R1=propyl (2-a) General Method 1, (2-b) General Method 2, (2-c) General Method 3.

Analysis of some typical example compounds proton (400 MHz: D2O) 2.36-2. 55 (m, 5H, alkyl H), 2.57-2. 76 (m, 1 H, alkyl H), 3.31-3. 48 (m, 2H, H5), 3.98-4. 07 (m, 1H, H4), 4.45-4. 56 (m, 2H, H3, NCHCO), 4.69-4. 75 (m, 2H, H2), 5.57 (d, J2. 4 Hz, 1H, H1), 7.32-7. 40 (m, 2H, PhH), 7.41-7. 53 (m, 3H, PhH). proton (400 MHz: D20) 2.26-2. 40 (m, 4H, alkyl H), 2.73 (dd, J 14.0, 8.0 Hz,

1 H, CHaPh), 2.88 (dd, J 14.0, 6.2 Hz, 1 H, CHbPh), 3.30 (dd, J 14.6, 4.6 Hz, 1 H, H5a), 3.42 (dd, J 14.6, 3.8 Hz, 1 H, H5b), 3.96-4. 02 (m, 1 H, H4), 4.26 (t, J 5.8 Hz, 1 H, H3), 4.36 (t, J 7. 4 Hz, 1 H, NCHCO), 5.52 (d, J 2. 8 Hz, 1 H, H1), 7.02-7. 20 (m, 5H, PhH), 7.35 (d, J 6. 4 Hz, 2H, PhH), 7.42-7. 54 (m, 3H, PhH). proton (400 MHz: D20) 1.76-1. 87 (m, 1 H, alkyl H), 1.96-2. 08 (m, 1 H, alkyl H), 2.30-2. 41 (m, 6H, alkyl H), 3.43 (d, J 4. 4 Hz, 2H, H5), 4.06 (q, J 5. 2 Hz, 1 H, H4), 4.26 (dd, J 9. 0,5. 2 Hz, 1 H, H3), 4.40 (t, J 5. 6 Hz, 1 H, NCHCO), 4.69- 4.74 (m, 1H, H2), 5.54 (d, J3. 2 Hz, 1H, H1), 7.2. 8-7. 48 (m, 8H, PhH), 7.65 (s, 1H, PhH). proton (400 MHz: D20) 0.77 (t, J 7.4 Hz, 3H, CH2CH3), 1.42-1. 56 (m, 2H, CH2CH3), 2.37-2. 53 (m, 5H, alkyl H), 2.58 (dd, J 15.4, 5.4 Hz, 1 H, alkyl H), 2.89 (t, J 7. 6 Hz, 2H, ArCH2), 3.30-3. 46 (m, 2H, H5), 4.07-4. 15 (m, 1 H, H4), 4.42-4. 53 (m, 2H, H3, NCHCO), 4.70-4. 75 (m, 2H, H2), 5.87 (d, J 2. 8 Hz, 1 H, H1).

proton (400 MHz : D20) 0.78 (t, J 7.2 Hz, 3H, CH2CH3), 1.38-1. 46 (m, 2H, CH2CH3), 2.34 (bs, 4H, alkyl H), 2.70 (t, J 10.2 Hz, 1 H, ArCHa), 2.74-2. 96 (m, 3H, ArCHb, CH2Ph), 3.25-3. 45 (m, 2H, H5), 4.02-4. 12 (m, 1H, H4), 4.18-4. 25 (m, 2H, H3), 4.29-4. 38 (m, 1H, NCHCO), 5.83 (bs, 1H, H1), 6.99-7. 20 (m, 5H, PhH).

51 proton (400 MHz: D20) 0.73 (t, J 7. 4 Hz, 3H, CH2CH3), 1.36-1. 50 (m, 2H, CH2CH3), 1.73-1. 85 (m, 1 H, alkyl H), 1.88-2. 03 (m, 1 H, alkyl H), 2.28-2. 45 (m, 6H, alkyl H), 2.84 (q, J 7. 5 Hz, 2H, ArCH2), 3.42 (d, J 4. 4 Hz, 2H, H5), 4.10- 4.20 (m, 2H, H3, H4), 4.38 (t, J 5. 4 Hz, 1 H, NCHCO), 5.84 (d, J 2. 8 Hz, 1 H, H1), 7.34-7. 52 (m, 3H, ArH), 7.65 (s, 1H, ArH).

Some typical peptide arms IIa-IIr used in step a of examples 1 and 2 Example 3: 3N-Fmoc (a) 3 NH2 H 3_I 3_II b) 0 0 RINK N Ar (d) 3-IV/N Ar (d 3-III NO2 H NO2 NOs"NOs e) | (C) 0 0 RINK O >3N JA R1-< O@N J H ~ z ~/r H,, Ar H I \ R E H I \ Ar NH2 H NO2 H NHs"N02 H°2CLt 7 R2 V (g) - IX, X, XI, (shown below) 0 N o RINK } HJ9t R1 3-VII NR' (h) H2NOC N'R' 0 0 3 N R 0 HO OH HO OH O R2

(3-a) General Method 4, (3-b) General Method 5, (3-c) General Method 6 (using reagents ArNH2 and DMSO), (3-d) General Method 6 (using reagents ArCH2NH2 and DMF as solvent), (3-e) General Method 7, (3-f) General Method 7, (3-g) General Method 8, (3-h) General Method 3b, effects ring closure, deprotection and cleavage from resin, (3-i) General Method 9, only required for adenine containing compounds.

Blocks IX, X and XI

Analysis of a typical example compound 355 proton (400 MHz: d6 DMSO) 4.92 (q, J 4.4 Hz, 1 H, H2 or H3), 4. 98 (q, J 5.1 Hz, 1 H, H2 or H3), 5.33 (d, J 4.0 Hz, 1 H, H4), 5.54 (d, J 16.8 Hz, 1 H, CHaPh), 5.62 (d, J 17.2 Hz, 1 H, CHbPh), 5.77 (d, J 5.3 Hz, 1 H, OH), 5.80 (d, J 5.4 Hz, 1H, OH), 6.10 (d, J5. 3 Hz, 1H, H1), 6.96 (d, J7. 9 Hz, 1H, PhH), 7.09 (t, J7. 8 Hz, 1 H, PhH), 7.24 (bs, 2H, NH2), 7.27 (bs, 1 H, PhH), 7.29 (s, 1 H, CONHa), 7.36 (d, J 8.9 Hz, 1 H, PhH), 7.47 (d, J 8.3 Hz, 1 H, ArH), 7.78 (dd, J 8.5, 1.6 Hz, 1 H, ArH), 7.98 (bs, 2H, ArH, CONHb), 8.31 (d, J 1.2 Hz, 1 H, ArH), 8.37 (s, 1 H, ArH).

Example 4:

(4-c) General Method 6 using a sugar amine, (4-d) General Method 7, (4-e) General Method 10, (4-f) General Method 3b, (4-g) General Method 9, only required for adenine containing compounds.

Exemplary Aldehydes used in step 4-e.

Benzaldehyde, 3-Bromobenzaldehyde, m-Tolualdehyde, 2- Methoxybenzaldehyde, p-Tolualdehyde, 4-Dimethylaminobenzaldehyde, 4- Cyanobenzaldehyde, 1,2, 3, 6-tetrahydrobenzaldehyde, Indole-3- carboxaldehyde, 2-naphthaldehyde, 3-methyl thiophene-2-carboxaldehyde, cyclohexane carboxaldehyde, pyrrole-2-carboxaldedhyde, phenyl acetaldehyde, 4- (2-pyridyl) benzaldehyde, a, a, a-trifluoro-o-tolualdehyde, 2,5- dimethylbenzaldeyde, 3, 5-difluorobenzaldehyde, 2-fluorobenzaldehyde, 4- fluoro-3- (trifluoromethyl) benzaldehyde.

Example 5:

(5-a) General Method 1, (5-b) General Method 4, (5-c) General Method 6, (5- d) General Method 7, (5-e) General Method 3b Analysis of some typical example compounds

proton (400 MHz: d6 DMSO) 2.41 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 4.34-4. 53 (m, 4H, H2, H3, H4, H5a), 4.75 (d, J 13.2 Hz, 1H, H5b), 5.80 (s, 1H, H1), 6.97 (d, J 8. 8 Hz, 2H, ArH), 7.39-7. 47 (m, 2H, ArH), 7.51 (bs, 1 H, NHa), 7. 57-7. 67 (m, 3H, ArH), 7.69-7. 75 (m, 1 H, ArH), 7.79 (bs, 1 H, NHb).

proton (400 MHz: d6 DMSO) 0.77 (t, J 7.4 Hz, 3H, CH2CH3), 1.40 (q, J 7.1 Hz, 2H, CH2CH3), 2.37 (s, 3H, ArCH3), 2.84-2. 98 (m, 2H, ArCH2), 4.38-4. 52 (m, 4H, H2, H3, H4, H5a), 4.70 (bd, J 14.4 Hz, 1H, H5b), 5.80 (s, 1H, H1), 6. 85 (d, J 8.0 Hz, 2H, ArH), 7.27 (bs, 2H, NHa, ArH), 7.48-7. 60 (m, 4H, ArH), 7.78 (bs, 1H, NHb). proton (400 MHz: d6 DMSO) 3.77 (s, 3H, OCH3), 4.35-4. 46 (m, 3H, H2, H3, H4), 4.57 (bdd, J 14.8, 6.4 Hz, 1H, H5a), 4.84 (bd, J 14.8 Hz, 1H, H5b), 5.05 (d, J 11.6 Hz, 1 H, OCHa), 5.11 (d, J 11.6 Hz, 1 H, OCHb), 5.34 (s, 1 H, H1), 6.96-7. 04 (m, 4H, ArH), 7.20 (d, J 8. 8 Hz, 2H, ArH), 7.30-7. 46 (m, 7H, ArH), 7.54 (bs, 1 H, NHa), 7.60 (d, J 8. 8 Hz, 2H, ArH), 7.63-7. 68 (m, 1 H, ArH), 7.71- 7.78 (m, 1 H, ArH), 7.90 (bs, 1 H, NHb).

Example 6 :

Conditions : (a) general method 5 (b) general method 6; (c) general method 7, general method 10; (d) general method 9 for adenosine containing compounds only, general method 3b.

Example 7: Bzo 0 CN-NaOM-e Ho 0 CN 2, 2-dimethoxyproppneHO 0 CN BzO OBz Ho OH 2SO4, acetone 7-I 7-I MsCI PY 1 r 0 0 0 N3e_H BrCH2C02Me N3<CN NaN3 MsO~CN cyme Zn/THF oo DMF o , >< 7-VI Ln,, nr o, ><o o<o HCI 7-V 7-IV THF N3eco2Me BzCI, p, y N3tzco2Me BuOCOCN N/sCHICO2tBU U lu HO OH BzO OBz [Cu (acac) 2] Bzo OBZ 5 mol % 7-IX 7-vni 7-VII 7-VIII 5 mol % 7-IX 1) R'NHNH2 83 2) H+ pi'al "''N-N"\-N N3wCO2H TFA N3 ° w oztau E :-co2Me DCM : co2Me BzO OBz BzO OBz /7-XI 7-X /1) HBTU, DIPEA, DMF . N-N 0 N-N 0 N-N o R sN_N o THF BZC OBz HO OH 7-XIII 7-XII 1) HBTU, DIPEA, DMF ) (2) R2NH2 Rl\ N-N o Ri\N-N o N-N N NH--o N3< 4NHs BzCi, py N wNHX N3 -CONHR2--CONHR2 BzO OBz 7 XV HÕ OH 7 FIV DTT Ri R N-N 0 H. NY-0 | DTT BzO OBz 7-XVI BzO OBZ 7 XVI Example 8:

(8-a) General Method 11, (8-b) General Method 3b, (8-c) General Method 12, (8-d) General Method 13, (8-e) General Method 14, (8-f) General Method 3a, (8-g) General Method 9 for adenosine containing compounds.

Analysis of some typical example compounds

Isomer 1: proton NMR (400MHz, d6-DMSO): 8 : 8.46 (s, 1 H, H-6); 8.26 (d, 1 H, H-8); 7.93 (s, 2H, NH2); 7.37-7. 31 (m, 6h); 7.15-7. 08 (m, 5H); 6.92 (d, 1H, J=6Hz); 5.86

(d, 1 H, J=5.6Hz, H-1); 4.70-4. 64 (m, 2H, containing H-2 and Hß1ald) ; 4.39 (d, 1H, J=16Hz, Hß2ald) ; 4.20 (t, 1 H, J= 4.8Hz, Ha) ; 4.04-3. 96 (m, 2H, containing H-3, H-5A); 3.59 (d, 1 H, J=6.8Hz, H-4); 2.97 (m, 2H, containing Hpi, Hß2).

Isomer 2 : proton NMR (400MHz, d6-DMSO) : # : 8.42 (s, 1H, H-6); 8.22 (d, 1H, H-8); 7.75 (s, 2H, NH2); 7.38-7. 30 (m, 6h); 7.17-7. 11 (m, 5H); 6.98-6. 96 (m, 1H, J=6Hz); 5.82 (d, 1 H, J=5.6Hz, H-1); 4.72-4. 64 (m, 2H, containing H-2 and Hpia, d) ; 4.40 (d, 1H, J=16.4Hz, Hß2ald) ; 4.21 (t, 1H, J= 4. 4Hz, Ha) ; 4.08 (t, 1H, J=4. 4Hz, H- 3); 3.97 (q, 1H, J=6.4, 10. 4Hz, H-5A); 3.65 (dd, 1H, J=6.4, 14.4Hz, H-4); 3.54 (dd, 1 H, J=7.6, 14.4, H-5A); 2.98 (d, 2H, J=4.8Hz containing Hpi, Hp2).

221 Isomer 1: proton NMR (400MHz, d6-DMSO) : # : 8.48 (s, 1H, H-6); 8.27 (s, 1H, H-8); 7.45 (d, 1 H, J=4.4Hz) ; 7.40 (d, 1 H, J=4.8Hz) ; 7.24-7. 09 (m, 4H); 7.05-7. 02 (m, 1 H) ; 6.97-6. 91 (m, 2H); 5.84 (d, 1 H, J=6.4Hz, H-1); 4.86 (d, 1H, J=16Hz, Hß1ald); 4.66-4. 63 (m, 1H, H-2); 4.45 (d, 1H, J=16Hz, Hß2ald); 4.21 (t, 1H, J=4.4Hz, Hα); 4.03 (t, 1H, J=3.6Hz, H-3); 3.98-3. 92 (m, 1H, H-5A); 3.19 (q, 1H, J=5.2, 9.2Hz Hß1) ; 3.05-3. 01 (m, 1H, Hß2).

Isomer 2 : proton NMR (400MHz, d6-DMSO) : # : 8.47 (s, 1H, H-6); 8.26 (s, 1H, H-8); 7.44 (d, 1H, J=4Hz); 7.41 (d, 1H, J=4.8Hz) ; 7.24-7. 09 (m, 4H); 7.05-7. 02 (m, 1H) ; 6.97-6. 91 (m, 2H); 5.82 (d, 1H, J=6.4Hz, H-1); 4.88 (d, 1H, J=16Hz, Hß1ald) ; 4.66-4. 63 (m, 1H, H-2); 4.45 (d, 1H, J=16Hz, Hß2ald); 4. 22 (t, 1 H, J=4. 4Hz, Ha) ; 4.06 (t, 1 H, J=4Hz, H-3); 3.98-3. 92 (m, 1 H, H-5A); 3.22 (q, 1H, J=5.2, 9.2Hz Hpi) ; 3.05-3. 01 (m, 1H, Hß2).

proton NMR (400MHz, d6-DMSO): a : 8.37 (s, 1H, H-6); 8.12 (s, 1H, H-8); 7.63 (t, 4H, J=8.4Hz) ; 7.46 (t, 2H, J=7.6Hz) ; 7.36-7. 27 (m, 5H); 5.87 (d, 1 H, J=5.6Hz, H-1) ; 5.53 (d, 1 H, J=6.4Hz) ; 5.35 (d, 1 H, J=4.8), 4.78 (q, 1 H, J=5.2, 10.4Hz) ; 4.51 (s, 2H), 4.17-4. 08 (m, 2H); 3.92 (s, 2H); 3.82-3. 77 (m, 1H) ; 3.70-3. 64 (m, 1 H).

proton NMR (400MHz, d6-DMSO) : # : 7.78 (s, 1 H) ; 7.42 (s, 1 H) ; 7.08 (d, 1 H, J=4Hz); 6.88 (d, 1 H, J=3.6Hz) ; 5.77 (d, 1 H, J=2.8Hz) ; 4.62-4. 60 (m, 1 H) ; 4.54 (s, 2H); 4.39 (t, 1 H, J=5.2Hz) ; 4.16 (q, 1 H, J=6,11. 6Hz); 3. 85 (d, 2H, J=5.2Hz) ; 3.62-3. 57 (m, 1 H) ; 3.53-3. 48 (m, 1 H) ; 3.02-2. 90 (m, 3H); 1.54-1. 48 (m, 2H); 0.86-0. 83 (m, 3H).

Isomer 1:

proton NMR (400MHz, d6-DMSO): 8 : 8.40 (s, 1H) ; 8.18 (s, 1H) ; 7.62 (s, 2H); 7.56 (d, 2H, J=7.6Hz) ; 7.44 (t, 2H, J= 3.6Hz) ; 7.37 (t, 3H, J=8.4Hz) ; 7.27-7. 25 (m, 3H); 7.20-7. 18 (m, 2H); 7.08 (d, 2H, J=8Hz); 5.87 (d, 1H, J=5.6Hz) ; 4.76 (d, 1H, J=15. 6Hz); 4.67 (t, 1H, J= 5.6Hz) ; 4.30 (d, 1H, J=15. 6Hz); 4.23 (t, 1H, J=4. 4Hz); 4.04-4. 00 (m, 2H); 3.70-3. 59 (m, 2H); 3.18-3. 04 (m, 2H).

Isomer 2 : proton NMR (400MHz, d6-DMSO) : 8 : 8.39 (s, 1 H) ; 8.20 (s, 1 H) ; 7.81 (s, 2H); 7.61 (d, 2H, J=7.2Hz) ; 7.52 (d, 2H, J= 8Hz); 7.45 (t, 3H, J=7.2Hz) ; 7.35-7. 26 (m, 5H); 7.21 (dd, 4H, J=6.8, 15.6) ; 5.83 (d, 1 H, J=6Hz); 4.78 (d, 1 H, J=15. 6Hz); 4.69 (t, 1 H, J=5.2Hz) ; 4.30 (d, 1 H, J= 15.6Hz) ; 4.25 (t, 1 H, J=4.4Hz) ; 4.11 (t, 1 H, J=4.4Hz) ; 4.02-3. 98 (m, 2H); 3.21-3. 06 (m, 2H); 3.18- 3.04 (m, 2H).

750 Isomer 1 proton NMR (400MHz, d6-DMSO) : a : 8.46 (s, 1 H) ; 8.25 (s, 1 H) ; 7.63 (d, 4H, J=7.2Hz) ; 7.52 (t, 2H, J= 7.6Hz) ; 7.44-7. 36 (m, 5H); 7.28 (d, 2H, J=8.4Hz) ; 7.16 (d, 2H, J=8.4Hz) ; 5.95 (d, 1H, J=5.6Hz) ; 4.79-4. 73 (m, 2H); 4.40-4. 33 (m, 2H); 4.13-4. 07 (m, 2H); 3.78-3. 70 (m, 2H); 3.26-3. 11 (m, 2H).

Isomer 2 proton NMR (400MHz, d6-DMSO) : 5 : 8.26 (s, 1 H) ; 8.07 (s, 1 H) ; 7.55 (d, 2H, J=7.4Hz) ; 7.45 (d, 2H, J=8.4Hz) ; 7.39 (t, 5H, J= 7.6Hz) ; 7.30 (d, 2H, J=8Hz); 7.17 (d, 2H, J=8.4Hz) ; 7.11 (d, 2H, J=8.4Hz) ; 5.77 (d, 1 H, J=5.6Hz) ; 5.50 (s, 1 H) ; 5.26 (s, 1 H) ; 4.67-4. 63 (m, 2H); 4.25-4. 22 (m, 2H); 4.06 (t, 1 H, J=8Hz); 3.95 (q, 1H, J=6.8, 10.4Hz) ; 3.67-3. 48 (m, 2H); 3.18-2. 99 (m, 2H).

Example 9: C-NHz = RINK amide PS resin Non Ho i 0 0 0 0 9-Ia : R1=P 9-Ib : R1=Pr N-N y- /'n/* N-M o N-N N o o N R O O (b R/ H O I \ 9-II X 0 0 HN 9-ici HZN N-N RZ N_N Rz H2N_, y', 0 H2N 0 O N/\ ON (C) R N I f R / 0 0 (d) Ho OH RX d\ 9-IV 9-V

Conditions : (a) general method 1; (b) (i) MsCl, DCM, (ii) Tryptamine derivative, DMF (c) R3CHO, 25% TFA/DCM, rt; (d) general method 3b.

Example 10:

Conditions : (a) (i) general method 4, (ii) o-nitrobenzenesulfonyl chloride, DCM, DIPEA, 3 hours, RT; (b) PPh3, aminoalcohol, DEAD, 24 hr; (c) (i) general method 4, (ii) general method 12; (d) (i) Na+PhS-, DMF, 12 hours, RT (ii) general method 13 where the amine is intramolecular, (e) general method 3b.

Example 11:

Conditions : (a) DMF, DIPEA ; (b) general method 1; (c) general method 3b; (d) reflux in toluene.

Example 12:

Conditions : (a) aldehyde, TMOF/THF; (b) general method 4; (c) general method 12; (d) ) (i) Na+PhS-, DMF, (ii) general method 13 where the second amine is intramolecular ; (e) general method 3b Example 13:

Conditions : (a) R2-Isothiocyanate, DCM; (b) Bromoketone, DMF; (c) general method 3b Example 14:

Conditions : (a) R2CHO, TMOF, THF; (b) R3-CO-CI, NEt3 ; (c) general method 3b.

Example 15:

Conditions : (a) Epoxide, DIEA, DMF; (b) CDI, DCM; (c) general method 3b.

Example 16:

Conditions : (a) R3-CO-CO-R4, NH40Ac, R2-CHO ; (b) general method 3b Example 17:

Conditions : (a) R2CHO, TMOF, THF; (b) mercapto acetic acid; (c) general method 3b.

Example 18 : Intermediate from example 4 (4-lit a, c, d) (a) o HNd Y Ra HN-/\-/ (b) s oo is-i HN HAN 0 Ra N=/\-/ _ - .... 0 R3 HAN N Ra (d) N \-J zizi /3 HAN N N 0ra 1 8-IV S HO OH R3

(18-a) General Method 15, (18-b) General Method 16, (18-c) General Method 9, hydrazine/DMF conditions for adenosine containing compounds only, (18- d) General Method 3b Exemplary yield and crude product purity Ra=adenosine Purity of Compound crude cpds (%, by ELSD) yield (%) 86 96 33 87 92 33 88 84 31 89 98 31 90 97 27 91 96 46 92 92 35 93 87 28 94 86 34 95 98 40 96 85 33 97 95 35 98 94 45 99 97 39 100 98 39 101 96 40 102 98 47 103 63 23 104 90 38 105 96 31 106 95 49 107 98 46 108 41 18 109 89 38 110 89 41 111 81 18 112 20 12 113 15 8 114 35 12 115 95 22 116 84 42 117 97 39 118 88 34 119 77 25 120 92 44 Analysis of some typical example compounds

18-1 proton (400MHz, d6-DMSO) : 8.29 (s, 1H, H-8), 8.11 (s, 1H, H-2), 8.00 (d, 1H, J = 1.5 Hz, Ar-H), 7.87 (broad s, 1 H, NH), 7.61 (dd, 1 H, J = 1.5, 8.6 Hz, Ar-H), 7.41 (d, 1 H, J = 8.6 Hz, ArH), 7.30 (broad s, 2H, NH), 7.21 (broad s, 1 H, NH), 5.86 (d, 1H, J = 5.1 Hz, H'-1), 5.61 (d, 1H, J = 6.0 Hz, OH), 5.45 (d, 1H, J = 5.4 Hz, OH), 4.72 (qua, 1 H, J = 5.2 Hz, H'-2 or H'-3), 4.54 (dd, J = 15.2, 4.7 Hz, H'-5), 4.47 (dd, 1 H, J = 15.2, 7.4 Hz, H'-5), 4.31 (qua, 1 H, J = 4.7 Hz, H'-3 or H'-2), 4.29 (dt, 1 H, J = 4.7, 7.4 Hz). carbon (100MHz, d6-DMSO) : 168.7, 156.6, 154.8, 153.2, 149.8, 142.9, 140.4, 139.3, 128.4, 121.9, 119.8, 117.6, 109.8, 88.5, 82.7, 73.5, 71.8, 46.9.

115 proton (400MHz, d6-DMSO) : 8.38 (s, 1H, H-8), 8.15 (s, 1H, H-2), 7.95 (broad s, 1 H, NH), 7.64 (d, 1 H, J = 1. 5 Hz, Ar-H), 7.54 (dd, 1 H, J = 1. 5,8. 3 Hz, Ar-H), 7.31 (d, 1H, J = 8. 5 Hz, Ar-H), 7.30 (broad s, 1 H, NH), 7.25 (broad s, 1 H, NH), 5.85 (d, 1H, J = 6. 3 Hz, H'-1), 5.54 (d, 1H, J = 6.2 Hz, OH), 5.38 (d, 1H, J = 5.1 Hz, OH), 4. 82 (qua, 1H, J = 5.8 Hz, H'-3 or H'-2), 4.70 (dd, 1H, J = 4.6, 13.8 Hz, H'-5), 4.49-4. 38 (m, 2H, H'-5 + H'-4), 4.35 (m, 1H, H'), 2.10 (s, 3H, CH3). carbon (100MHz, d6-DMSO) : 170.2, 167.9, 156.6, 153.2, 150.0, 140.4, 135.9, 131.1, 129.6, 122.3, 119.8, 110.0, 109.7, 87.8, 82.4, 73.2, 71.9, 46.9, 31.5.

116 proton (400MHz, d6-DMSO) : 8.30 (s, 1H, H-8), 8.11 (s, 1H, H-1), 8.08 (d, 1H, J = 1.5 Hz, Ar-H), 7.59 (broad s, 1 H, NH), 7.63 (dd, 1 H, J = 1.5, 8.3 Hz, Ar-H), 7.43 (d, 1H, J = 8.3 Hz, Ar-H), 7.31 (broad s, 2H, NH2), 7.22 (broad s, 1H, NH), 5. 87 (d, 1 H, J = 5.0 Hz, H'-1), 5.63 (d, 1 H, J = 5.8 Hz, OH), 5.46 (d, 1 H, J = 5.4 Hz, OH), 4.75 (qua, 1H, J = 5.0 Hz, H'-2 or H'-3), 4.54 (dd, 1H, J = 4.7, 15.3 Hz, H'-5), 4.48 (dd, 1H, J = 7.6, 15.3 Hz, H'-5), 4.34 (qua, 1H, J = 4.7 Hz, H'-2 or H'-3), 4.25 (dt, 1H, J = 4.7, 7.4 Hz, H'-4), 3.24 (qua, 2H, J = 7.3 Hz, CH2), 1.32 (t, 3H, J = 7.3 Hz, CH3).

carbon (100MHz, d6-DMSO) : 168.7, 156.6, 153.8, 153.2, 149.8, 143.0, 140.4, 139.1, 128.4, 121.9, 119.8, 117.6, 109.9, 88. 5,82. 7,73. 4,71. 8,46. 9,27. 2, 15.6.

Yield and puritv of crude products Ra = Purity of Crude cpds (%, by Compound# R ELSD) yield 121 Ph 96.9 38 122 Ph 94.8 5 123 Ph 96.7 31 124 Ph 97.8 34 125 Ph 50.6 38 126 Ph 97.3 21 127 Ph 98.3 41 128 Ph 97.7 26 129 Ph 97.7 14 130 Ph 96.7 28 131 Ph 91.1 23 132 Ph 97.9 39 133 Ph 96.9 36 134 Ph 89.0 31 135 Ph 97.5 33 136 Ph 96.4 22 137 Ph 97.0 30 138 Ph 96.7 28 139 Ph 84.6 23 140 Ph 83. 3 24 141 Ph 97.1 28 142 Ph 97.0 27 143 Ph 95.3 35 144 Ph 72.8 25 145 Ph 88.6 30 146 Ph 85.7 8 147 Ph 66.3 23 148 Ph 68.1 25 149 Ph 26.1 15 150 Ph 97.7 7 151 Ph 99.1 5 152 Ph 97.8 6 153 Ph 48.4 17 154 Ph 95.6 26 155 Ph 96.0 31 156 Ph 74.50 2 157 Ph 7.9 3 158 Ph 53.6 17 159 Pr 96.4 12 160 Pr 98.2 37 161 Pr 96.8 20 162 Pr 96.9 36 163 Pr 97.4 19 164 Pr 96.4 36 165 Pr 96.7 27 166 Pr 97.2 24 167 Pr 96.8 17 168 Pr 95.0 33 169 Pr 82.1 15 170 Pr 95.8 34 171 Pr 97.0 37 172 Pr 97.4 23 173 Pr 96. 8 33 174 Pr 96.9 37 175 Pr 96.9 41 176 Pr 96.9 28 177 Pr 89.9 7 178 Pr 98.2 35 179 Pr 97.3 37 180 Pr 96.4 36 181 Pr 93.7 28 182 Pr 80.7 26 183 Pr 96.6 36 184 Pr 97.7 36 185 Pr 60.2 21 186 Pr 86.9 33 187 Pr 39.7 15 188 Pr 97.2 2 189 Pr 99.5 60 190 Pr 98.4 4 191 Pr 60.0 5 192 Pr 96.0 34 193 Pr 96.7 36 194 Pr 95.4 12 195 Pr 17.0 2 196 Pr 80.5 11 Analysis of a typical example compounds

138 proton (400MHz, d6-DMSO) : 8.13 (d, 1H, J = 1.3 Hz, Ar-H), 8.09 (d, 1H, J = 8.7 Hz, Ar-H), 7.93 (broad s, 1 H, NH), 7.86 (broad s, 1 H, NH), 7.70 (dd, 1 H, J = 1.3, 8.4 Hz, Ar-H), 7.64 (d, 1H, J = 8.7 Hz, Ar-H), 7.50-7. 30 (m, 5H, Ar-H), 7.28 (d, 1 H, J = 8.5 Hz, Ar-H), 7.25 (broad s, 1H, NH), 5.75 (d, 1H, J = 5.48 Hz, OH), 5.53 (d, 1H, J = 6.4 Hz, OH), 5.37 (d, 1H, J = 1.7 Hz, H'-1), 4.75- 4.60 (m, 3H, CH + CH2), 4.54-4. 40 (m, 2H, CH), 4. 30-4. 23 (m, 2H, CH).

Carbon (100MHz, d6-DMSO) : 167,6, 161.1, 152.2, 146.2 145.3, 141.8, 138.9, 138.2, 138.1, 129.9, 129.7, 129.4, 127.8, 127.7, 125.0, 123.2, 121.3, 116.9, 108.8, 89.7, 82.3, 74., 71.8, 46.3, 34.7.

Example 19:

(19-a) General Method 17, (19-b) General Method 18, (19-c) General Method 9 for adenosine containing compounds only, (19-d) General Method 3b. R\, pu W 0. 1% formic acid N CH3CN/H2o N 20-, *,-N 0 R'0 2 N NH HÒ OH NH2 H4O HÕ OH 19-111 19-IV Retention time, observed mass, yield Compound 2 components 19-lit and 19-IV 312 Rt= 4.24min (M+H) +=516 (26%), Rt= 4.75min (M+H) +=544 (72%) 313 Rt= 4.80min (M+H) +=550 (3%), Rt= 5.28min (M+H) +=578 (72%) 314 Rt= 4.52min (M+H) +=546 (23%), Rt= 4.96min (M+H) +=574 74% 315 Rt= 4. 70min (M+H) +=530 (11 %), Rt= 5.17min (M+H) +=558 (88%) 316 Rt= 4.69min (M+H) = (2%), Rt= 5.23 min (M+H)+= (19% 317 Rt= 5.82min (M+H) +=572 (22%), Rt= 6.26min (M+H) +=544 (78%) 318 Rt=4. 81min (M+H) +=596 (73%), Rt=5.40min (M+H) +=624 (27%) 319 Rt=4.68min (M+H) =530 (2%), Rt=5.15min M+H)+=558 (98% 320 Rt=5.92min (M+H) =608 (25%), Rt=6.37min (M+H) +=636 (75%) 321 Rt=5.97 min (M+H) +=622 (52%), Rt= 6.48min (M+H) +=650 (48%) 322 Rt= 5.74min (M+H) +=592 (43%), Rt=6.27min (M+H) +=620 (57%) 323 Rt= 5. 15min (M+H) +=569 (14%), Rt= 5.98min (M+H) += 597 (86%) 324 Rt= 5.63min (M+H) +=603 (46%), Rt= 6.62min (M+H) += 631 (52%) 325 Rt= 5.34min (M+H) =599 (23%), Rt= 6.20min (M+H) +=627 (77%) 326 Rt= 5.51 min (M+H) +=583 (38%), Rt= 6.38min (M+H) +=611 (62%) 327 Rt= 5.58min (M+H) =603 (90%), Rt= 6.46min (M+H) +=631 (8%) 328 Rt= 6.54min (M+H) +=625 (55%), Rt= 7. 41 min (M+H) +=653 (45%) 329 Rt= 5.77min (M+H) +=647 (31%), Rt= 6.66min (M+H) +=677 (55%) 330 Rt= 5. 59min (M+H) +=612 (28%), Rt=6.20 min (M+H) +=640 (61%) 331 Rt= 5.51 min (M+H) +=583 (22%), Rt= 6.31 min M+H)+=611 (78% 332 Rt= 6.57min (M+H) +=661 (42%), Rt= 7.50min (M+H) +=689 (58%) 333 Rt= 6.75min (M+H) +=675 (38%), Rt=7.62 min (M+H) +=703 (60%) 334 Rt=6.56min (M+H) +=645 (55%), Rt= 7.38min M+H)+=673 (44% 335 Rt= 5.03min (M+H) +=535 (17%), Rt= 5.77min (M+H) +=563 (82%) 335 Rt= 5.58min (M+H) +=569 (11 %), Rt= 6.35min M+H)+=597 (87% 336 Rt= 5.26min (M+H) +=565 (15%), Rt= 6. 0min (M+H) +=593 (84%) 337 Rt= 5.33min (M+H) +=5. 49 (12%), Rt= 6.04min (M+H) +=577 (88%) 338 Rt= 5. 41 min (M+H) +=569 (79%), Rt= 6.27min M+H)+=597 (5% 339 Rt= 6.44min (M+H) +=591 (36%), Rt= 7.29min (M+H) += 619 (64%) 340 Rt= 5.67 (M+H) +=615 (18%), Rt= 6.46min (M+H) +=643 (79%) 341 Rt=6. 51 min (M+H) +=591 (8%) 342 Rt= 5.37min (M+H) +=549 (25%), Rt= 6.20min (M+H) +=577 75% 343 Rt= 6.54min (M+H) +=627 (19%), Rt= 7.40min (M+H) +=655 (81%) 344 Rt= 6.64min (M+H) +=641 (30%), Rt= 7.52min (M+H) +=669 (69%) 345 Rt=6.41 min (M+H) +=611 (58%), Rt=7.26 min (M+H) +=639 (42%)

Example 20:

(20-a) General Method 12, (20-b) General Method 19, (20-c) General Method 6, (20-d) General Method 20, (20-e) General Method 21, (20-f) General Method 9 for adenosine containing compounds only, then General Method 3b for all compounds.

Analysis of some typical example compounds:

proton NMR (400MHz, d6-DMSO) : 8 : 8.37 (s, 1 H) ; 8.24 (s, 1 H) ; 7.57 (d, 2H, J=8.8Hz) ; 7.35 (d, 2H, J=7.2Hz) ; 7.30 (t, 2H, J=7.6Hz) ; 7.21 (t, 2H, J=7.2Hz), 6.77 (d, 2H, J=8.8Hz), 5.81 (d, 1 H, J=4.4Hz) ; 4.71-4. 63 (m, 3H), 4.64 (t, 1 H, J=4.8Hz) ; 4.46-4. 38 (m, 2H); 4.33-4. 30 (m, 1 H), 3.76 (s, 3H).

726 Beta isomer: proton NMR (400MHz, d6-DMSO) : 5 : 8.27 (s, 1 H), 7.88 (s, 1 H), 7.55-7. 41 (m, 6H); 7.28 (dd, 2H, J=1.2, 7.6Hz) ; 6.84 (d, 2H, J=8. 8Hz) ; 5.31 (d, 1 H, J=2Hz); 4.66 (d, 1 H, J=11. 2Hz); 4.51 (s, 1 H) ; 4.41-4. 32 (m, 3H); 3.97-3. 88 (m, 3H); 2.98 (s, 3H); 1.73-1. 66 (m, 2H); 1.39-1. 26 (m, 12H); 0.87-0. 84 (m, 3H).

Alpha isomer: proton NMR (400MHz, d6-DMSO) : 8 : 8.25 (s, 1 H), 7.82 (d, 3H, J=8.4Hz) ; 7.51- 7.46 (m, 6H) ; 7.11 (d, 2H, J=8. 8Hz) ; 5.43 (d, 1 H, J=4. 4Hz) ; 4.91 (s, 1 H) ; 4.37 (s, 1 H) ; 4.23 (q, 1 H, J=5.6, 8.8Hz) ; 4.06 (t, 2H, J=6.4Hz) ; 3.79 (s, 3H); 1.77- 1.70 (m, 2H); 1.44-1. 26 (m, 12H); 0.87-0. 84 (m, 3H).

Example 21:

(21-a) General Method 12, (21-b) General Method 6, (21-c) General Method 7, (21-d) General Method 1 or 22, (21-e) General Method 9, (21-f) General Method 3-b then General Method 3a.

Analysis of some typical example compounds:

920 proton (400MHz, d6-DMSO) : 8. 36 (s, 1H, H-8), 8.25 (s, 1H, H-2), 7.88 (s, 2H, ArCH), 7.62 (d, 2H, J= 8.8Hz, ArCH), 6.84 (d, 2H, J=8.8Hz, ArCH), 5.85 (d, 1H, J= 3.6Hz, H'-1), 4.73 (dd, 1H, J=3.5, 15.8Hz, CH), 4.57-4. 64 (m, 2H, CH2), 4.36 (t, 1 H, J= 5.6 Hz, CH), 4.22 (m, 1 H, H'-4), 3.80 (s, 3H, OCH3).

Example 22:

(22-a) General Method 1, general method 4 (22-b) General Method 12, (22-c) General Method 23, (22-d) General Method 9, (22-e) General Method 3-a.

Analysis of some typical example compounds:

Isomer1 : proton NMR (400MHz, d6-DMSO): 8 : 8.48 (s, 1H) ; 8.17 (s, 1H) ; 7.39-7. 22 (m, 6H); 7.11 (d, 2H, J=7.6Hz) ; 6. 86 (d, 2H, J=6.8Hz) ; 5.93 (d, 1H, J=4.8Hz) ; 4.67 (t, 1 H, J=4.8Hz) ; 4.59 (t, 1 H, J=3.6Hz) ; 4.34 (t, 1 H, J=5.2Hz) ; 4.22 (q, 1 H, J=4.8, 10Hz) ; 4.00 (dd, 1H, J=6.8, 15.2Hz) ; 3.76 (dd, 1H, J=7.6, 14.8Hz) ; 3.26 (dd, 1H, J=4.4, 14Hz); 3.05 (dd, 1H, J=3.6, 14.4Hz).

Isomer2 : proton NMR (400MHz, d6-DMSO) : 8 : 8.59 (s, 1 H) ; 8.31 (s, 1 H) ; 7.38-7. 23 (m, 5H); 7.11-7. 06 (m, 3H); 6.88 (d, 2H, J=6.8Hz) ; 5.97 (d, 1 H, J=6Hz); 4.84 (t, 1H, J=4.8Hz) ; 4.50 (t, 1H, J=3.6Hz) ; 4.25-4. 22 (m, 2H); 4.14 (dd, 1H, J=3.6, 14.8Hz) ; 3.23 (dd, 1H, J=5.2, 14.4Hz) ; 3.00 (dd, 1H, J=2.8, 14Hz).

935 Isomer 1: proton NMR (400MHz, d6-DMSO) : 8 : 10.94 (s, 1 H) ; 8.59 (s, 1 H) ; 8.26 (s, 1 H) ; 7.48 (d, 1H, J=8Hz); 7.32-7. 26 (m, 4H); 7.10 (s, 1H) ; 7.06 (t, 1H, J=7.6Hz) ; 6.93 (t, 1 H, J=7.6Hz) ; 6.69-6. 67 (m, 2H); 5.95 (d, 1 H, J=5.2Hz) ; 4.66 (t, 1 H, J=5.6Hz) ; 4.54 (t, 1 H, J=3.2Hz) ; 4.33 (t, 1 H, J=4.8Hz) ; 4.25 (q, 1 H, J=5.2, 10.8Hz) ; 4.00 (dd, 1H, J=6.4, 15.2Hz) ; 3.76 (dd, 1H, J=4,14. 8Hz); 3.37-3. 25 (m, 2H).

Isomer 2 : proton NMR (400MHz, d6-DMSO) : 8 : 10.95 (s, 1 H) ; 8.68 (s, 1 H) ; 7.43 (d, 1 H, J=8Hz); 7.32 (d, 2H, J=8Hz); 7.27-7. 25 (m, 2H); 7.09 (s, 1 H) ; 7.06 (t, 1 H, J=8Hz); 6.92 (t, 1 H, J=8Hz); 6.70 (dd, 2H, J=3.6, 7.6Hz) ; 5.99 (d, 1 H, J=5.6Hz) ; 4.81 (t, 1 H, J=5.2Hz) ; 4.47 (t, 1 H, J=3.2Hz) ; 4.29-4. 22 (m, 2H); 4.12 (dd, 1H, J=4.4, 14.8Hz) ; 3.68 (dd, 1H, J=8.4, 14.8Hz) ; 3.36 (dd, 1H, J=5.2, 15.2Hz) ; 3.24 (dd, 1 H, J=2.4, 15.2Hz).

948 Isomer 1: proton NMR (400MHz, d6-DMSO) : 8 : 8.96 (s, 1 H) ; 8.49 (s, 1 H) ; 8.03 (s, 1 H) ; 7.73 (d, 2H, J=10.8Hz) ; 7.67 (d, 2H, J=7.2Hz) ; 7.49 (t, 2H, J=7.6Hz) ; 7.40- 7.35 (m, 2H); 7.34 (d, 2H, J=8.4Hz) ; 5.95 (d, 1 H, J=5.6Hz) ; 4.70 (t, 1 H, J=5.2Hz) ; 4.65 (t, 1 H, J=4.4Hz) ; 4.31 (t, 1 H, J=4.8Hz) ; 4.27-4. 23 (m, 1 H) ; 3.95 (dd, 1H, J=7.6, 15.2Hz) ; 3.77 (dd, 1H, J=4,14. 8Hz); 3.26-3. 24 (m, 2H).

Isomer 2 : proton NMR (400MHz, d6-DMSO) : 5 : 8.97 (s, 1 H) ; 8.51 (s, 1 H) ; 7.82 (s, 1 H) ; 7.73 (d, 2H, J=8.8Hz) ; 7.67 (d, 2H, J=7.2Hz) ; 7.49 (t, 2H, J=7.2Hz) ; 7.40-7. 35 (m, 2H); 7.25 (d, 2H, J=8.4Hz) ; 5.95 (d, 1 H, J=5.6Hz) ; 4.79 (t, 1 H, J=4.8Hz) ; 4.62 (t, 1H, J=5.6Hz) ; 4.27-4. 22 (m, 2H); 4.16 (dd, 1H, J=4,14. 8Hz); 3.33- 3.21 (m, 2H). Example 23: Part A

(23-a) General Method 1, (23-b) General Method 4, (23-c) General Method 6, (23-d) General Method 10, (23-e) General Method 4 or General Method 20, (23-f) General Method 12. (23-g) General Method 9. (23-h) General Method 3a.

Part B

(23-i) General Method 22, (23j) General Method 3-a Part-C

(23-k) General Method 7, (23-I) General Method 17, followed by treatment of the resins with a 1.43 Molar solution (-10 equivalents) of piperazine in dry DMF at room temperature overnight. The resin was then drained, washed (2 x DMF and 3 x DCM) and then dried in vacuo, General Method 12; (23-m) General Method 3-a.

Analysis of a typical example compounds:

968 proton (400 MHz: d6 DMSO) 3.79 (s, 3H, OCH3), 4.30 (bs, 2H, H2, H3), 4.43 (bd, J 6.0 Hz, 3H, H4, NCH2Ph), 4.65 (dd, J 15.6, 6.2 Hz, 1 H, H5a), 4.91 (d, J 14. 8 Hz, 1 H, H5b), 5.35 (s, 1H, H1), 6.64 (d, J 8. 8 Hz, 2H, ArH), 6.98 (d, J 8. 8 Hz, 2H, ArH), 7.19 (d, J 8. 8 Hz, 2H, ArH), 7.22-7. 36 (m, 5H, ArH, NHa), 7.42- 7.56 (m, 5H, ArH), 7.71 (t, J 7. 6 Hz, 2H, ArH), 7.82 (bs, 1H, NHb).

proton (400 MHz: d6 DMSO) 4.24-4. 31 (m, 1 H, H4), 4.38 (dd, J 7.4, 5.0 Hz, 1 H, H3), 4.47 (dd, J 4. 4,1. 6 Hz, 1 H, H2), 4.50 (dd, J 15.6, 7.6 Hz, 1 H, H5a), 4.76 (dd, J 15.6, 2.8 Hz, 1 H, H5b), 5.33 (d, J 1.2 Hz, 1 H, H 1), 7.29 (dd, J 7. 8, 1.4 Hz, 2H, ArH), 7.40-7. 62 (m, 8H, ArH, ArCONHa), 7.68 (d, J 8. 4 Hz, 2H, ArH), 7.83 (s, 1 H, ArCONHb), 7.88 (d, J 8.8 Hz, 2H, ArH), 7.91-7. 99 (m, 3H, ArH), 10.46 (s, 1 H, ArNHCOPh).

Example 24:

(24-a) General Method 1, (24-b) General Method 4, (24-c) General Method 12, (24-d) General Method 13, (24-e) General Method 3-b.

Analysis of some typical example compounds:

954 proton (d6-DMSO, 400MHz) : 8. 51 (s, 1H, H-2/8), 8.31 (s, 1H, H-2/8), 7.60- 7.05 (m, 8H, ArCH), 5.86 (d, 1H, J=5.6, Hz, H'-1), 4.67 (t, 1H, J=5.5Hz, H'- 2/3), 4.64 (d, 1H, JAB=16.1Hz, HA-), 4.39 (d, 1H, JAB=16.1Hz, HB-), 4.34 (t, 1H, J=5. 1Hz, H-2/3), 4.09 (t, 1H, J=4.2Hz,), 3.99 (m, 1H, H'-4), 3.67 (dd, 1H, J=5.8Hz, 14. 0Hz, HA), 3.58 (dd, 1H, J=7.6, 14. 0Hz, HB), 3.14 (dd, 1H, J=5.1, 14.4Hz, H'-5A), 3.02 (dd, 1H, J=4.6, 14.4Hz, H'-5B).

proton (d6-DMSO, 400MHz) : 8.48 (s, 1 H, H-2/8), 8.29 (s, 1 H, H-2/8), 7.57- 7.00 (m, 8H, ArCH), 5.88 (d, 1 H, J=5.8Hz, H'-1), 4.68 (t, J=5.2Hz, H'-), 4.60 (d, 1H, JAB=16. 1Hz, H-), 4.38 (d, 1H, JAB=16.1Hz, H), 4.34 (t, 1H, J=5. 1Hz, H- ), 4.07 (t, 1H, J=4.6Hz, H), 4.01 (m, 1H, H'-4), 3.64 (d, 2H, AB system, H-), 3.12 (dd, 1H, J=5.2, 14.6Hz, HA-), 3.01 (dd, 1H, J=4.4, 14.6Hz, HB-).

Exemplary compounds of the Invention : The substructures A-H listed below are substituents in the field R1 in the libraries of compounds that follow.

Others substiuents referred to in the following libraries may be subsequently found in the text at the end of examples.

Example 25: R1 R2 R (on Comp. ISOMER arm IIa-1 L and D H 2 A IIb-1 L and D H 3 A IIC-1 L and D H 4 A IId-1 L and D H IIe-1 L H 6 A lie-1 D H 7 A llf-1 L and D H A IIg-1 L and D H 9 A IIh-1 L and D H 10 A IIi-1 L and D H 11 A IIj-1 L and D H 12 A IIk-1 L and D H 13 A III-1 L and D H 14 A IIo-1 L H 15 A IIo-1 D H 16 B IIa-1 L and D methyl 17 B lib-1 L and D methyl 18 B IIc-1 L and D methyl 19 B IId-1 L and D methyl 20 B IIe-1 L and D H 21 B IIf-1 L and D H 22 B IIh-1 L and D methyl 23 B L and D ethyl 24 B L and D ethyl 25 B IIk-1 L and D methyl 26 B IIr-1 L and D methyl L and D methyl 28 B IIo-1 L and D methyl 29 B lip-1 L and D meth I 30 B IIq-1 L and D methyl Example 26: R (on Com. R1 R2 Isomer arm) 31 c IIa-1 L and D H 32 c IIb-1 L and D H 33 D llb-1 L and D H 34 c c-1 LandD H 35 c IId-1 L and D H 36 D lid-1 L and D H 37 D lie-1 L and D H 38 c lle-1 L and D H 39 D IIf-1 L and D H 40 c lof-1 L and D H 41 D IIg-1 L and D H 42 c IIh-1 L and D H 43 D lih-1 L and D H 44 c IIi-1 L H 45 D IIi-1 L H 46 C IIj-1 L H 47 D IIj-1 L H 48 c IIK-1 L and D H 49 D lik-1 L and D H 50 C IIr-1 L H 51 D IIr-1 L H 52 C III-1 L H 53 D III-1 L H 54 c IIn-1 L H 55 D IIn-1 L H 56 c IIo-1 L H 57 D IIo-1 L H 58 c IIp-1 L H 59 D IIp-1 L H 60 c IIq-1 L H 61 D IIq-1 L H 62 C IIb-1 L H 63 D IIb-1 L H 64 lie-1 L H 65 D IIe-1 L H Example 27: Comp. R1 R2 R3 R4 66 A a4 v2 El 67 A ß7 v2 #1 68 A ß6 v2 #1 69 A #5 v2 XI 70 A #4 #2 #1 71 A a4 v2 a4 72 A ß7 v2 a4 73 A ß6 0 v2 a4 74 A #5 v2 a4 75 A K4 v2 a4 76 A a4 al El 77 A p7 al El 78 A ß6 al #1 79 A #5 al XI 80 A K4 al XI 81 A a4 al al 82 A ß7 α1 al 83 A ß6 al al 84 A #5 α1 α1 85 A #4 α1 al 5 Example 28 : Comp. R1 R2 86 A PI 87 A 1 88 A 2 89 A 82 90 A #1 91 A Kl 92 A 7cul 93 A ml 94 A s2 95 A #1 96 A 3 97 A y2 98 A y3 99 A 82 100 A s3 101 A K2 102 A #2 103 A s4 104 A 4 105 A 4 106 A 5 107 A 1 108 A #3 109 A 2 110 A vl 111 A v2 112 A V3 113 A v4 114 A #1 115 A v5 116 A V6 117 A s5 118 A #6 119 A V7 120 A Xl Example 29: Comp. R1 R2 121 C α1 122 C PI 123 C 1 124 C 2 125 C 81 126 C #1 127 C #1 128 C 7Cl 129 C Cul 130 C #2 131 C ol 132 C ß3 133 C 2 134 C 3 135 C #2 137 C S3 137 C #2 138 C #2 139 C s4 140 C 4 141 C 4 142 C 5 143 C 1 144 C 7i3 145 C 2 146 C vl 147 C v2 148 C v3 149 C v4 150 C #1 151 C v5 152 C v6 153 C #1 154 C #5 155 C s6 156 C #2 157 C V7 158 C 1 159 D al ß1 161 D 1 162 D 2 163 D 81 164 D 165 D Kl 166 D nl 167 D #1 168 D s2 169 D al 170 D 3 171 D 2 172 D y3 173 D 82 174 D s3 175 D K2 176 D #2 177 D #4 178 D 4 179 D y4 180 D 5 181 D 1 182 D 7t3 183 D 2 184 D #1 185 D v2 186 D v3 187 D v4 188 D #1 189 D v5 190 D v6 191 D pi 192 D #5 193 D s6 194 D p2 195 D v7 196 D X1 Example 30: Comp. R1 R2 R3 197 A #4 #1 198 A PI 1 199 A 1 1 200 A #5 #1 201 A #2 #1 202 A ai 203 A α2 #1 204 A 1 1 205 A #1 #1 206 A #2 #1 207 A jazz 208 A #7 #1 209 A 3 #1 210 A y2 oxyl 211 A 5 1 212 A #4 al 213 A PI al 214 A 1 al 215 A s5 al 216 A s2 al 217 A al al 218 A a2 al 219 A 1 al 220 A #1 al 221 A #2 al 222 A s7 al 223 A 3 al 224 A 2 α1 225 A y5 al 226 C #4 #1 227 C 1 #1 228 C 1 1 229 C s5 #1 230 C 1 1 231 C #1 #1 232 C #2 #1 233 C 2 234 C #7 #1 235 C 3 #1 236 C 2 #1 237 C 5 #1 238 C 1 al 239 C #5 α1 240 C s2 al 241 C al al 242 C a2 al 243 C 11 al 244 C #1 al 245 c #2 al 246 C 2 al 247 C s7 al 248 C µ3 al 249 C y2 al 250 C γ5 al 251 D #4 al 252 D PI al 253 D s2 1 254 D al 1 Example 31 : Comp. R1 R2 255 A #2 256 A 3 257 A 6 258 A #1 259 A #8 260 A X2 261 A 3 262 A X4 263 A v8 264 A 8 265 A #5 266 A 4 267 A 5 268 A T3 269 A a3 270 A #4 271 A #3 272 A 9 273 A 6 274 C 2 275 C 6 276 C 1 277 C 01 278 C 2 279 C x3 280 C 4 281 C v8 282 C 8 283 C #5 284 C 4 285 C 5 286 C T3 287 C a3 288 C #4 289 C #3 290 C 9 291 C 6 292 D o2 293 D 2 294 D 6 295 D 1 296 D #1 297 D #8 298 D 2 299 D 3 300 D 4 301 D v8 302 D ß8 303 D #5 304 D µ4 305 D 5 306 D T3 307 D a3 308 D T4 309 D #3 310 D 9 311 D u6 Example 32:

Comp. R1 R2 R3 312 A #2 a4 313 A #2 6 314 A E2 5 315 A #2 s9 316 A X2 7 317 A #2 s10 318 A 1 #2 319 A #2 Ell 320 A #2 6 321 A oxyl 4 322 A #2 #3 323 C #2 a4 324 C #2 6 325 C #2 5 326 C E2 #9 327 C 1 7 328 C 1 s10 329 C E2 02 330 C #2 43 331 C E2 #11 332 C E2 6 333 C #2 #4 334 C 1 #3 335 D E2 a4 336 D #2 6 337 D #2 #5 338 D #2 e9 339 D 1 7 340 D #2 slO 341 D E2 #2 342 D #2 Ell 343 D 2 6 344 D #2 #4 345 D 1 o3 Example 33:

Comp. R1 R2 346 A X5 347 D X5 348 A #9 349 D s9 350 A 6 351 D 7 352 A al 353 C al 354 D al 355 A #3 356 C #3 357 D #3 358 A y3 359 C y3 360 D 3 361 A 04 362 C #4 363 D #4 364 A 1 365 C 1 366 D 1 367 A s3 368 C s3 369 D s3 370 A XI 371 C XI 372 D XI 373 A ES 374 C #5 375 D #5 376 A Kl 377 C Kl 378 D Kl 379 A #1 380 C #1 381 D #1 382 A #2 383 C K2 384 D K2 385 A a5 386 C a5 387 D a5 388 A 10 389 C 10 390 D 10 391 A y6 392 C y6 393 D y6 394 A v2 395 C v2 396 D #2 Example 34: Comp. R1 R2 397 A #1 398 C 61 399 D 61 400 A a4 401 A E ; ll 402 A X8 403 A s9 404 A 3 405 A #2 406 A a6 407 A 7 408 A 3 409 A T4 410 A a7 411 A 8 412 A al 413 A #10 414 A K3 415 A #12 416 A 7 417 A γ8 418 A 9 419 C a4 420 C #11 421 C 8 422 C #9 423 C 3 424 C #2 425 C α6 426 _ C, u7 427 C 03 428 C T4 429 C a7 430 C 6 431 C al 432 C s10 433 C K3 434 C #12 435 C 7 436 C 8 437 C 9 438 D a4 439 D s11 440 D 8 441 D s9 442 D 3 443 D co2 444 D a6 445 D 7 446 D 3 447 D T4 448 D a7 449 D 8 450 D al 451 D s10 451 D #3 453 D #12 454 D y7 455 D y8 456 D y9 Example 35:

Comp. R1 R2 457 D #1 458 D P8. 459 D #3 460 D µ6 461 D Example 36:

Comp. R1 R2 462 D s2 463 D al 464 D 82 465 D 4 466 D #1 Example 37:: Compound No. R1 R2 R3 467 E 3 #3 468 E 6 #3 469 E 2 #3 470 E 3 1 471 E 6 1 472 E #3 1 473 E #4 #1 474 E X2 1 475 C 3 1 476 C 6 1 477 C #3 1 478 C 4 1 479 C 2 #1 480 A 3 #1 481 A 6 1 482 A #3 1 483 A 4 1 484 A 2 #1 Example 38: Compound No R1 R2 R3 485 A 5 1 486 A 9 #1 487 A 7 #1 488 A 10 #1 489 A X11 1 490 A 12 #1 491 A 13 #1 492 A 14 #1 493 A X15 Mil 494 A 16 #1 495 A X17 1 496 A 18 #1 497 A 19 1 498 A Mil 499 A #4 oxyl 500 A x20 1 501 A 44 1 502 A 11 #1 503 A 21 # 1 504 A #22 #1 505 C 5 1 506 C 9 #1 507 C 7 #1 508 C 10 oxyl 509 C 11 1 510 C 12 1 511 C 13 #1 512 C 14 # 1 513 C IS 1 514 C 16 1 515 C 17 oxyl 516 C #18 #1 517 C 19 #1 518 C 23 oxyl 519 C #4 1 520 C 20 1 521 C 44 1 522 C 11 vl 523 C 21 #1 524 C 22 1 525 D 5 1 526 D 9 527 D 7 #1 528 D 10 #1 529 D xii Wl 530 D 12 #1 531 D 13 1 532 D 14 1 533 D 15 1 534 D xl6 oxyl 535 D 17 #1 536 D 18 oxyl 537 D 19 1 538 D 23 #1 539 D o4 1 540 D 20 #1 541 D 4 1 542 D ß11 #1 543 D 21 #1 544 D #22 545 A 5 #1 546 A X9 X9-1 547 A 7 #7-1 548 A 10 #10-1 549 A 11 11-1 550 A 12 #12-1 551 A 13 13-1 552 A 14 14-1 553 A 15 715-1 554 A 16 #16-1 555 A 17 17-1 556 A X18 18-1 557 A 19 #19-1 558 A 23 #23-1 559 A a4 #4-1 560 A x20 20-1 561 A 4 # 4-1 562 A Pll 4 563 A 22 22-1 564 C 5 XI 565 C X9 X9-1 566 C 7 7-1 567 C 10 #10-1 568 C 11 Xll-1 569 C 12 #12-1 570 C 13 #13-1 571 C 714 714-1 572 C 15 #15-1 573 C 16 #16-1 574 C 17 #17-1 575 C 18 #18-1 576 C 19 #19-1 577 C 23 #23-1 578 C or4 a4-1 579 C 20 #20-1 580 C 44 44-1 581 C 11 4 582 C 22 22-1 583 D #5 #1 584 D 9 9-1 585 D 7 7-1 586 D 10 #10-1 587 D 11 #11-1 588 D 12 12-1 589 D 13 #13-1 590 D 14 #14-1 591 D 15 15-1 592 D 16 16-1 593 D X17 17-1 594 D 18 #18-1 595 D X19 19-1 596 D 23 23-1 597 D a4 #4-1 598 D 4 4-1 599 D 11 ß4 600 D x22 x22- Example 39:

Compound No R1 R2 R3 601 A 41 al 602 A s5 al 603 A s2 al 604 A il al 605 A T2 al 606 A 3 al 607 E #2 α1 608 E 2 al 609 E 3 α1 610 E 5 al Example 40: Compound No R1 R2 R3 R4 R5 611 C 4 #1 612 F 5 #1 613 D x5 #1 614 C 5 #1 615 G X5 #1 616 H 5 #1 617 F 5 #5 618 D 5 #5 619 C 5 #5 620 G 5 #5 621 H 5 #5 622 F 5 #1 #5 623 D 5 #1 #5 624 C 5 #1 #5 625 G 5 #1 #5 626 H X5 v5 627 F 5 ß12 628 D 5 ß12 ß12 629 C 5 ß12 ß12 630 G X5 pl2 631 H 5 ß12 ß12 632 F 18 #1 633 D 18 #1 634 C 18 #1 635 G 18 #1 636 H 18 #1 637 F 18 #5 638 D 18 #5 639 C 18 #5 640 G 18 #5 641 H 18 #5 642 F 18 #1 #5 643 D 18 #1 #5 644 C 18 #1 #5 645 G 18 #1 #5 646 H 18 #1 #5 647 F 18 ß12 p 12 648 D 18 ß12 ßl2 649 C Xl8 ß12 pi2 650 G 18 ß12 ß12 651 H 18 ß12 ß12 652 F 4 #1 #1 653 D 4 #1 #1 654 G 4 #1 #1 655 H 4 #1 #1 656 F 4 #5 #1 657 D X4 K5 Vl 658 C X4 K5 659 G 4 #5 #1 660 H 4 #5 #1 661 F 4 #1 #5 662 D 4 #1 #5 663 C 4 #1 v5 664 G 4 #1 #5 665 H 4 #1 #5 666 F 4 ß12 ß12 667 D 4 ß12 ß12 668 C 4 ß12 ß12 669 G 4 ß12 ß12 670 H 4 ß12 ß12 671 F 5 #1 #1 #1 672 D X5 XI #1 #1 673 C 5 #1 #1 #1 674 G #5 #1 #1 #1 675 H 5 #1 #1 #1 676 F 5 #1 #5 #1 677 D X5 #1 #5 #1 678 C 5 #1 #5 1 679 G X5 #1 #5 #1 680 H X5 #1 #5 #1 681 F 5 #1 #1 #5 682 D X5 Xl Wl v5 683 C X5 #1 #1 #5 684 G 5 xl 1 #5 685 H #5 #1 #1 #5 686 D #5 #1 ß12 ß12 687 C #1 ß12 688 G #1 ß12 ß12 689 H 5 xl Pl2 pl2 690 F 18 #18-1 #1 691 C 18 #18-1 #1 #1 692 G 18 #18-1 #1 #1 693 H 18 #18-1 #1 694 H 18 #18-1 #5 695 F 18 #18-1 #1 v5 696 C 18 #18-1 #1 v5 697 D 18 #18-1 #1 v5 698 G 18 #18-1 #1 #5 699 H 18 #18-1 #1 #5 700 F 18 #18-1 ß12 ß12 701 D 18 #18-1 ß12 ß12 702 C 18 #18-1 ß12 ß12 703 G 18 #18-1 ß12 ß12 704 H 18 #18-1 ß12 705 F 4 #24 #1 706 C 4 #24 #1 707 G 4 x24 y l 708 H 4 #24 #1 709 F 4 #24 #5 710 D X4 #24 #5 711 C 4 x24 x5 712 H #4 #24 #5 713 D 4 #24 #1 714 F 4 #24 ß12 Example 41 : Compound No. R1 R2 R3 715 A X5 al 716 C 5 al 717 A X3 al 718 C #3 al 719 A #3 α1 720 C #3 al 721 A X5 v5 722 C X5 v5 723 C X5 v5 724 A X3 v5 725 C X3 v5 726 C X3 v5 727 A #3 v5 728 C a3 v5 729 C a3 v5 Example 42:

Compound No R1 R2 R3 730 A 2 al 731 A s5 al 732 A 3 al 733 A 19 α1 734 A 1 al 735 A 10 α1 736 A 5 al 737 A al al 738 A 4-1 al 739 A 10 al 740 A 2 al 741 A a4 al 742 A a8 al 743 A 2 2 744 A #5 2 745 A 3 2 746 A 19 ß2 747 A 1 ß2 748 A 10 2 749 A 45 2 750 A al 2 751 A 4-1 2 752 A lilo 2 753 A 2 ß2 754 A a4 2 755 A a8 2 756 A p2 #5 757 A #5 #5 758 A 3 #5 759 A 19 #5 760 A X1 s5 761 A 10 #5 762 A 45 s5 763 A al s5 764 A 4-1 s5 765 A µ10 #5 766 A 2 #5 767 A a4 s5 768 A a8 zu 769 A 2 #1 770 A #5 #1 771 A 3 #1 772 A Xi 773 A 10 #1 774 A al 775 A 4-1 #1 776 A 10 #1 777 A 2 #1 778 A a4 41 779 A a8 41 780 A ß2 #1 781 A 2 45 782 A #5 #1 783 A #5 5 784 A 3 oxyl 785 A 3 5 786 A XI 1 787 A 1 5 788 A 10 vl 789 A 10 45 790 A 45 1 791 A 5 45 792 A al 1 793 A al 45 794 A 4-1 1 795 A 10 1 796 A 10 45 797 A 2 #1 798 A 2 #5 799 A a8 45 800 A a8 5 801 A 2 wu 802 A #5 #1 803 A 3 #1 804 A 19 #1 805 A 1 #1 806 A 19 1 807 A 19 45 808 A 2 #1 809 A 10 1 810 A 2 γ1 811 A a4 1 812 A a8 1 813 A 2 #2 814 A #5 #2 815 A 3 #2 816 A 19 #2 817 A 1 #2 818 A 10 #2 819 A 5 K2 820 A #1 #2 821 A 4-1 #2 822 A 10 #2 823 A 2 #2 824 A α4 #2 825 A a8 K2 826 A 2 #2 827 A e5 r2 828 A 3 #2 829 A 19 #2 830 A 1 #2 831 A 10 #2 832 A 5 #2 833 A #1 #2 834 A 4-1 T2 835 A 10 T2 836 A 2 #2 837 A a4 #2 838 A a8 #2 839 A P2 r2 840 A s5 2 841 A 3 2 842 A 19 µ2 843 A 1 µ2 844 A 10 2 845 A 5 p2 846 A 2 µ2 847 A 4-1 µ2 848 A p10 p2 849 A 2 µ2 850 A a4 2 851 A a8 2 852 A 2 1 853 A 85 1 854 A 3 1 855 A 19 #1 856 A X 1 X 1 857 A 10 1 858 A 5 #1 859 A al 1 860 A 4-1 XI 861 A 2 1 862 A a4 XI 863 A a8 XI 864 A 2 #4 865 A #5 #4 866 A 3 #4 867 A 19 #4 868 A 1 #4 869 A 10 #4 870 A 5 #4 871 A al #4 872 A 4-1 #4 873 A nul0 E4 874 A 2 #4 875 A a4 #4 876 A a8 24 877 A al vl 878 A al v2 879 A al v9 880 A v4 al 881 A v4 2 882 A v4 T2 883 A v4 il 884 A 1 v4 885 A 7-1 al 886 A 7-1 2 887 A 7-1 #2 888 A 7-1 Tl 889 A 7-1 #1 890 A 10 su 891 A X5 #1 892 A al #1 893 A 4-1 #1 894 A 10 #1 895 A a4 #1 896 A a8 #1 897 A 2 1 898 A #5 yl 899 A 3 1 900 A 19 γ1 901 A 1 y1 902 A 10 γ1 903 A 45 1 904 A al yl 905 A 4-1 y1 906 A 11 #1 907 A 11 #2 908 A v4 3 909 A al al 910 A #1 ß2 911 A al s5 Example 43: Compound No R1 R2 R3 R4 912 A 4 #1 913 A 5 #1 914 A 18 #1 1 915 A _X5 #1 #5 916 A 18 #1 #5 917 A 5 #5 918 A 4 #5 919 A 18 #5 #1 920 A 5 ß12 ß12 921 A X4 P12 pi2 922 A 18 ß12 ß12 Example 44: Compound No R1 R2 R3 923 A al a4 924 A al 925 A al s9 926 A al K6 927 A al #3 928 A al #8 929 A 1 a4 930 A #1 ß6 931 A 1 s9 932 A 1 933 A 1 #3 934 A 1 x8 935 A 7-1 a4 936 A 7-1 937 A 7-1 e9 938 A 7-1 #6 939 A 7-1 s3 940 A 7-1 % 8 941 A 13 a4 942 A #13 ß6 943 A 13 #9 944 A 13 945 A 13 a3 946 A 13 X8 947 A al a4 948 A α1 ß6 949 A µ7-1 α4 905 A µ7-1 ß6 951 A 7-1 952 A 13 #3 953 A µ13 Example 45: Compound No R1 R2 R3 954 A 4 al 955 A 2 al 956 A 83 al 957 A 2 al 958 A 1 al 959 A ß3 al 960 A 4 al 961 A 2 al 962 A #3 al 963 A 2 al 964 A 1 al 965 A 3 al Example 46:

Compound No R1 R2 R3 R4 966 C al #1 1 967 G al zu 1 968 H al #1 1 969 C al #5 #1 970 G α1 #5 #1 971 H al #5 #1 972 C al V1 v5 973 G al 1 #5 974 H α1 #1 #5 975 C al ß12 ß12 976 G al ß12 12 977 h al ß12 ß12 Example 47: Compound No. R1 R2 R3 978 A #2 a2-1 979 A 2 2-1 980 A 6 2 981 A #1 #3 982 A #8 #1 983 A 8 3 984 A #5 #1 985 A r3 il 986 A a3 a3-1 987 A #4 T2 988 A a3 al 989 C 2 2-1 990 C X3 3-1 991 C 4 4-1 992 C v8 vl 993 C 5 µ5-1 994 C #3 il 995 C T4 #2 996 C 6 6-1 997 D a2 o2-l 998 D 2 2-1 999 D 6 2 1000 D 1 1-1 X4-1 (#24 1001 D 4 1002 D v8 vl 1003 D T4 T2 1004 D #3 #1 1005 D 9 9-1 1006 D 6 6-1 1007 A 2 #2-1 Example 48:

Compound No. R1 R2 R3 1008 A a4 al 1009 A Cl1 #3 1010 A 8 8-1 1011 A #9 #5 1012 A #2 el 1013 A #6 a6-1 1014 A #3 #2 1015 A #4 #5 1016 A a7 a7-1 1017 A al a5 1018 A #10 #2 1019 A K3 K7 1020 A #12 #7 1021 A 7 4 1022 A 8 vs-l 1023 A y9 5 1024 C a4 al 1025 C 61 #3 1026 C #11 #3 1027 C 8 8-1 1028 C #9 #5 1029 C #3 su 1030 C a6 a6-1 1031 C zu 1032 C r4 T5 1033 C a7 a7-1 1034 C al a5 1035 C E10 #2 1036 C K3 K7 1037 C el2 #7 1038 C 7 4 1039 C 8 8-1 1040 C γ9 α5 1041 D a4 al 1042 D #1 #3 1043 D #11 #3 1044 D 8 8-1 1045 D #9 #5 1046 D s2 #1 1047 D a6 a6-1 1048 D 3 2 1049 D a7 a7-1 1050 D E10 s2 1051 D #3 #7 1052 D #12 #7 1053 D 7 4 1054 D 8 γ8-1 1055 D 9 5 Example 49: Selected activity data tested at 25 micromolar except! tested at 2.5 micromolar. compound number EGF-R c-Kit VEGF ABL MET PDGFalpha CDK2 Tie2 PKC P38 100695258 10988106704280 146 94 53 101 115 78 127 270 71 142 212 23 12 10 41 46 38 25 1 26 223 22 109 11 24 31 17 40 0 10 24615683027282613 279 66 17 31 6 72 85 20 12 80 345 58 40 54 74 87 82 67 41 65 456969296 107 103 113 28 91 104 - 466 84 55 72 110 102 104 114 88 87 486! 24 45 96 100 488 ! 34 13682100 508! 12 17 16 100 528 ! 12 44 26 101 604 27 13 18 49 46 46 30 3 50 100 605 20 18 14 55 54 56 26 5 27 100 658 ! 20 55 5 99 659 ! 1763894 668! 16 1 669! 11 34 1 97 670! 9 23 1 718! 7 8 1 7251 610 912 88 38 44 96 88 96 119 72 96 70

Blank = not determined.

The following lists examples of compound numbers that demonstrate activity EGF-R inhibitors at 25 micromolar : 470,471, 472,478, 480,604, 605,611, 100,198, 205,207, 209,212, 213,214, 215, 216, 218,211, 220,221, 222, 223,224, 225,227, 233,235, 238,240, 241,246, 248,254, 273,279, 291, 334,345, 350,386, 391,392, 393: c-Kit inhibitors at 25 micromolar : 470,471, 472,473, 474, 480, 482,483, 484, 604,605, 611,912, 486,488, 501,504, 508,528, 606,607, 608,609, 610, 654,657, 658,659, 660,663, 664,665, 666,667, 668, 669, 670, 99,100, 103, 104, 108,109, 110,122, 125,127, 130,131, 132,133, 135,136, 137, 138,139, 140,143, 144,145, 146,148, 154,155, 163,168, 169,170, 173, 174,175, 177,178, 180, 181,183, 184,186, 192,193, 198,204, 205,207, 209,212, 213,214, 217,218, 211,220, 221,222, 225,227, 233,235, 238, 240,241, 246,248, 254,: 228,242, 244,245, 247,250, 252,253, 260,261, 262,271, 264,273, 279,282, 286,289, 291,299, 309,321, 322,332, 333, 334,345, 346,362, 370,377, 378,379, 386,398, 403,404, 408,427, 458, 459,460, 462,463, 464, 465,466 : VEGF-R2 inhibitors at 25 micromolar : 472,478,, 480,482, 483,484, 604, 605,611, 912,486, 505,508, 528,604, 605,606, 608,658, 659,660, 667,

668,669, 670,100, 198,205, 207,209, 211,212, 214,215, 216,218, 220, 221,222, 223,224, 225,227, 233,235, 238,244, 246,252, 254,256, 271, 273,279, 291,345, 370,371, 379,403, 466: ABL inhibitors at 25 micromolar : 470,478, 480,604, 605,611, 107,127, 135, 152,156, 157,158, 159,191, 207,212, 214,215, 220,221, 223,224, 225, 233,246, 273,279, 291,299, 330,334, 345,397 : MET inhibitors at 25 micromolar : 470,480, 604,605, 207,212, 214,217, 220, 221,223, 224,225, 233,238, 246,279, 291: PDGF-Ralpha inhibitors at 25 micromolar : 470,604, 605,207, 212, 214,215, 220,221, 223,224, 225,233, 246,202, 271,321, 334,370 : CDK2 inhibitors at 25 micromolar : 470,472, 478,604, 605,611, 32,100, 205, 207,209, 212,213, 214,215, 216,218, 219,220, 221,222, 223,224, 225, 233,246, 273,279, 291,334, 345,456 : Tie2 inhibitors at 25 micromlar : 470,471, 472,474, 478, 480,604, 605,611, 912,508, 528,534, 535,604, 605,606, 607,608, 609,610, 654,657, 658, 659,660, 667,668, 669,670, 71,91, 92,99, 100,101, 103,104, 106,107, 108,109, 113,114, 127,131, 135,136, 138,139, 143,144, 145,146, 151, 152,153, 154,155, 160,168, 177,178, 183,192, 198,205, 207,209, 211, 212,217, 214,215, 216,218, 220,221, 222,223, 224,225, 227,231, 233, 235,238, 240,241, 244,246, 248,250, 252,254, 256,271, 273,279, 291, 333,334, 345,376, 379,446, 457,459 : PK-C inhibitors at 25 micromolar : 470,471, 472,474, 478,480, 604,605, 611,2, 205,207, 209,212, 213,214, 215,216, 218,219, 220,221, 222,223, 224,225, 233,246, 299,321, 333,334, 345,379 : FGF-R1 inhibitors at 25 micromolar : 604,605, 611,100, 104,198, 205,207, 211,212, 214,215, 216,217, 218,220, 221,222, 223,224, 225,227, 233, 238,246, 248,254, 273,279, 291,345 : Tables of Substituents:

Throughout the specification and the claims (if present), unless the context requires otherwise, the term"comprise", or variations such as "comprises"or"comprising", will be understood to apply the inclusion of the stated integer or group of integers but not the exclusion of any other integer or group of integers.

It should be appreciated that various other changes and modifications can be made to any embodiment described without departing from the spirit and scope of the invention