MX2008004668A

MX2008004668A - Use of pyrazolo [1 , 5 -a]pyrimidine derivatives for inhibiting protein kinases methods for inhibiting protein kinases

Info

Publication number: MX2008004668A
Application number: MXMX/A/2008/004668A
Authority: MX
Inventors: Timothy J Guzi; Kamil Paruch; Michael P Dwyer; David A Parry
Original assignee: Schering Corporation
Priority date: 2005-10-06
Filing date: 2008-04-07
Publication date: 2008-09-02

Abstract

The present invention provides methods for inhibiting protein kinases selected from the group consisting of AKT, Checkpoint kinase, Aurora kinase, Pirn kinases, and tyrosine kinase using pyrazolo[1 ,5-a]pyrimidine compounds and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with protein kinases using such compounds.

Description

USE OF PIRAZOLOM DERIVATIVES .5-A1PIRIM1D1NA TO INHIBIT PROTEIN KINASES FIELD OF THE INVENTION The present invention relates to methods for inhibiting, regulating or modulating Akt kinases, check point kinases, Aurora kinases, Pim kinases, and / or tyrosine kinases using pyrazolo [1,5-ajpyrimidine compounds or pharmaceutical compositions containing the compounds , and methods of treatment using the compounds or compositions to treat diseases such as, for example, cancer, inflammation, arthritis, viral diseases, neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, and fungal diseases.

BACKGROUND OF THE INVENTION Protein kinases are a family of enzymes that catalyze the phosphorylation of proteins, in particular the hydroxyl group of specific residues of tyrosine, serine or threonine in proteins. Protein kinases are pivotal in the regulation of a wide variety of cellular processes, including metabolism, cell proliferation, cell differentiation, and cell survival. Uncontrolled proliferation is a hallmark of cancer cells, and can be manifested by deregulation of the cell division cycle in one or two ways - by making hyperactive stimulatory genes or inactive inhibitory genes. Protein kinase inhibitors, regulators or modulators alter the function of kinases such as Akt kinases, checkpoint kinases (CHK) (e.g., CHK-1, CHK-2 etc.), Aurora kinases, Pim kinases. (e.g., Pim-1, Pim-2, Pim-3, etc.), tyrosine kinases and the like. Checkpoint kinases prevent cell cycle progression at inappropriate times, such as in response to DNA damage, and maintain the metabolic balance of the cells while the cells are stopped, and in some cases may induce apoptosis (programmed cell death) ) when the requirements of the verification point have not been met. Checkpoint control can occur in the G1 phase (before DNA synthesis) and in G2, before entering mitosis. A series of checkpoints monitor the integrity of the genome and, upon detecting DNA damage, this block cell cycle progression of "DNA checkpoints" in phases G1 and G2, and slow progression through the S phase This action allows the DNA repair processes to complete their tasks before the genome replication and the subsequent separation of this genetic material into new daughter cells takes place. Inactivation of CHK1 has been shown to transduce signals from the DNA damage sensory complex to inhibit the activation of cyclin B / Cdc2 kinase, which promotes mitotic entry, and nullifies G2 arrest induced by DNA damage inflicted either by anticancer agents or endogenous DNA damage, and results in preferential death of defective cells from resulting checkpoint. See, e.g., Peng et al., Science, 277, 1501-1505 (1997); Sanchez et al., Science, 277, 1497-1501 (1997), Nurse, Cell, 91, 865-867 (1997); Weinert, Science, 277, 1450-1451 (1997); Walworth et al., Nature, 363, 368-371 (1993); and Al-Khodairy et al., Molec. Biol. Cell., 5, 147-160 (1994). Selective manipulation of checkpoint control in cancer cells could allow widespread use in cancer chemotherapeutic and radiotherapy regimens and, in addition, may offer a common hallmark of human genomic "instability" of human cancer to be exploited as the selective basis for the destruction of cancer cells. A number of factors make CHK1 a pivotal target in DNA damage checkpoint control. The elucidation of inhibitors of these functionally related kinases and kinases such as CDS1 / CHK2, a kinase that has recently been found to cooperate with CHK1 in the regulation of S phase progression (see Zeng et al., Nature, 395, 507-510). (1998); Matsuoka, Science, 282, 1893-1897 (1998)), could provide new valuable therapeutic entities for the treatment of cancer. Another group of kinases are tyrosine kinases. Tyrosine kinases can be of the receptor type (which have extracellular, transmembrane and intracellular domains) or of the non-receptor type (being completely intracellular). Tyrosine kinases of the receptor type are composed of a large number of transmembrane receptors with diverse biological activity.

In fact, approximately 20 different subfamilies of receptor-type tyrosine kinases have been identified. A subfamily of tyrosine kinase, designated the HER subfamily, is composed of EGFR (HER1), HER2, HER3 and HER4. The igandos of this subfamily of receptors identified so far include epithelial growth factor, TGF-alpha, anfiregulin, HB-EGF, betacellulin and heregulin. Another subfamily of these receptor-type tyrosine kinases is the insulin subfamily, which includes INS-R, IGF-IR, IR, and IR-R. The PDGF subfamily includes PDGF-alpha and beta receptors, CSFIR, c-kit and FLK-II. The FLK family is composed of the kinase insert domain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and tyrosine kinase-1 similar to fms (flt-1). For a detailed discussion of receptor-type tyrosine kinases, see Plowman et al., DN & P 7 (6): 334-339, 1994. At least one of the non-receptor protein tyrosine kinases, namely LCK, is thought to mediate T cell transduction of a signal from the interaction of a cell surface protein (Cd4) with an interlaced anti-Cd4 antibody. A more detailed discussion of non-receptor tyrosine kinases is provided in Bolen, Oncogene, 8, 2025-2031 (1993). Tyrosine kinases of the non-receptor type are also composed of numerous subfamilies, including Src, Frk, Btk, Csk, Abl, Zap70, Fes / Fps, Fak, Jak, Ack, and LIMK. Each of these subfamilies is further subdivided into variable receptors. For example, the Src subfamily is one of the largest and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk. The Src subfamily of enzymes has been linked to oncogenesis. For a more detailed discussion of tyrosine kinases of the non-receptor type, see Bolen, Oncogene, 8: 2025-2031 (1993). In addition to their role in cell cycle control, protein kinases also play a crucial role in angiogenesis, which is the mechanism by which new capillaries are formed from existing vessels. When required, the vascular system has the potential to generate new capillary networks in order to maintain the proper functioning of tissues and organs. In the adult, however, angiogenesis is very limited, occurring only in the process of wound healing and neovascularization of the endometrium during menstruation. On the other hand, unwanted angiogenesis is a hallmark of several diseases, such as retinopathies, psoriasis, rheumatoid arthritis, age-related macular degeneration, and cancer (solid tumors). The protein kinases that have been shown to be involved in the angiogenic process include three members of the growth factor receptor tyrosine kinase family; VEGF-R2 (vascular endothelial growth factor receptor 2, also known as KDR (kinase insert domain receptor) and as FLK 1); FGF-R (fibroblast growth factor receptor); and TEK (also known as Tie-2). VEGF-R2, which is expressed only in endothelial cells, binds to the potent angiogenic growth factor VEGF and mediates subsequent signal transduction through the activation of its intracellular kinase activity. Therefore, direct inhibition of VEGF-R2 kinase activity is expected to result in reduced angiogenesis even in the presence of exogenous VEGA (see Strawn et al, Cancer Research, 56, 3540-3545 (1996)) , as shown with VEGF-R2 mutants that are not capable of mediating signal transduction. Millauer et al, Cancer Research, 56, 1615-1620 (1996). In addition, VEGF-R2 appears to have no function in the adult beyond that of mediating the angiogenic activity of VEGF. Therefore, it would be expected that a selective inhibitor of VEGF-R2 kinase activity exhibited little toxicity. Similarly, FGFR binds to the angiogenic growth factors aFGF and bFGF and mediates the subsequent intracellular signal transduction. Recently, it has been suggested that growth factors such as bFGF may play a critical role in inducing angiogenesis in solid tumors that have reached a certain size. Yoshiji et al., Cancer Research, 57, 3924-3928 (1997). Unlike VEGF-R2, however, FGF-R is expressed in a number of different cell types throughout the body and may or may not play important roles in other normal physiological processes in the adult. However, it has been reported that systemic administration of a small molecule inhibitor of FGF-R kinase activity blocks bFGF-induced angigogenesis in mice without evident toxicity. Mohammad et al., EMBO Journal, 17, 5996-5904 (1998). TEK (also known as Tie-2) is another receptor tyrosine kinase expressed only in endothelial cells that has been shown to play a role in angiogenesis. The binding of angiopoietin-1 factor results in autophosphorylation of the kinase domain of TEK and results in a signal transduction process that appears to mediate the interaction of endothelial cells with peri-endothelial support cells, thus facilitating vessel maturation newly formed blood, the angiopoietin-2 factor, on the other hand, seems to antagonize the action of angiopoietin-1 on TEK and alters angiogenesis. Maisonpierre et al., Science, 277, 55-60 (1997). Pim-1 is a small serine / threonine kinase. The elevated expression levels of Pim-1 have been detected in lymphoid and myeloid malignancies, and recently Pim-1 was identified as a prognostic marker in prostate cancer. K. Peltola, "Signaling in Cancer: Pim-1 Kinase and its Partners", Annales Universitatis Turkuensis, Sarja - Ser. D Osa - Tom. 616, (August 30, 2005), http://kiriasto.utu.fi/iulkaisupalvelut/annaalit/ 2004 / D616.html. Pim-1 acts as a cellular survival factor and can prevent apoptosis in malignant cells. K. Petersen Shay et al., Molecular Cancer Research 3: 170-181 (2005). References of interest with respect to the present invention are: A. Bullock et al, J. Med. Chem., 48 (2005), 7604-7614; A. Bullock et al, J. Biol. Chem., 280 No. 50 (2005), 41675-41682; D. Williamson et al, J. Bioorg. Med. Chem. Lett., 15 (2005), 863-867; and patents and patent applications: US2006 / 0135526; WO2003 / 095455; WO2006 / 044958; US2006 / 0135514; US2004 / 081013; US2006 / 0053568; WO2001 / 23388; WO2004 / 087707; WO2003 / 093297; WO2002 / 070494; U.S. 6,313,124; FR2874821; WO2005 / 070431; US2005 / 0222171; US2005 / 0107386; and JP2006 / 160628.

The pyrazolopyrimidines are known. For example, WO92 / 18504, WO02 / 50079, WO95 / 35298, WO02 / 40485, EP94304104.6, EP0628559 (equivalent to US Patents 5,602,136, 5,602,137 and 5,571, 813), U.S. 6,383,790, Chem. Pharm. Bull., (1999) 47 928, J. Med. Chem., (1977) 20, 296, J. Med. Chem., (1976) 19 517 and Chem. Pharm. Bull., (1962) 10 620 describe various pyrazolopyrimidines. Other publications of interest include: patents of E.U.A. Nos. 5,688,949 and 6,313,124, WO 98/54093, WO 03/101993, WO 03/091256, WO 04/089416 and DE 10223917. The following patents and patent applications describe various types of pyrazolopyrimidines and are incorporated herein in their entirety by reference : (i) Series No. 11/245401 filed on October 6, 2005 and published as US 2006/0128725 on June 15, 2006), (ii) Series No. 10/654546, filed on February 11, 2004, and published as US 2004/0209878 on October 21, 2004, (iii) Series No. 11/244772, filed on October 6, 2005, and published as US 2006/0041131 on February 23, 2006, (iv) Series No. 11/244776, filed on October 6, 2005, and published as US 2006/0040958 on February 23, 2006, (v) Series No. 10/654163 filed on September 3, 2003, published as US 2004 / 0102452 on May 27, 2004, and granted as US 7,084,271 on August 1, 2006; and (vi) Series No. 10/653868 filed on September 3, 2003, published as US 2004/0116442 on June 17, 2004, and issued as U.S. 7,074,924 on July 11, 2006. In addition, (vii) Proxy Cases Nos. OC01617K3, (viii) OC06284US01, (ix) OC01618K2, and (x) OC01619K2, all four of common property and being presented on the same date as the present, are also incorporated herein in their entirety by reference. The descriptions in the above references (i) to (x) cited above in this paragraph should be considered part of the present invention. There is a need for methods to inhibit protein kinases to treat or prevent disease states associated with abnormal cell proliferation. Moreover, it is desirable for many methods to use kinase inhibitors that possess both high affinity for the target kinase and high selectivity versus other protein kinases. Useful small molecule compounds that can be easily synthesized and are potent inhibitors of cell proliferation are those, for example, that are inhibitors of one or more protein kinases, such as Akt (e.g., Akt-1, Akt-2). , Akt-3), CHK1, CHK2, VEGF (VEGF-R2), Aurora (e.g., Aurora-1, Aurora-2, Aurora-3 etc.), Pim-1 and both receptor and non-receptor tyrosine kinases. receiver.

BRIEF DESCRIPTION OF THE INVENTION In its many embodiments, the present invention provides methods to inhibit, regulate or modulate Akt kinases, checkpoint kinases, Aurora kinases, Pim-1 kinases and / or tyrosine kinases using pyrazolo [1,5-a] pyrimidine compounds or Pharmaceutical compositions including said compounds and methods of treatment, prevention, inhibition or alleviation of one or more diseases associated with said protein kinases using said compounds or pharmaceutical compositions. In one aspect, the present invention provides a method for inhibiting the activity of one or more kinases in a patient, wherein the kinases are selected from the group consisting of Akt kinases, check point kinases (e.g., CHK- 1, CHK-2 etc.), Pim kinases and Aurora kinases (e.g., Aurora-1, Aurora-2, Aurora-3 etc.), the method comprises: administering a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt, solvate, ester, isomer or prodrug of the compound, to a patient in need thereof, the compound being represented by any of the following structural formulas I to VI, as well as the various compounds in the patents and patent applications cited for the compounds of formulas I to VI, as well as the compounds described in co-pending Serial No. patent applications (Attomey Docket No.OC01617K3, OC01618K2 and OC01619K2) filed on the same date as the present: I. Of the application with Series No. 11/245401 filed on October 6, 2005 and published as US 2006/0128725 on June 15, 2006), a compound or pharmaceutically acceptable salts, solvates, esters, isomers or prodrugs of said compound, the compound having the general structure shown in formula I: RY? > 2 HR Formula I wherein: R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide of said heteroaryl), - (CHR5) n- aryl, - (CHR5) n-heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl and heteroaryl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen , alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (RR5) P-R9, -N (R5) Boc, - (CR4R5) POR5, -C (O2) R5 , -C (0) R5, -C (0) NR5R10, -SO3H7 -SR10, -S (O2) R7, -S (O2) NR5R10, -N (R5) S (02) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R10; R2 is selected from the group consisting of H, R9, alkyl, alkenyl, alkynyl, CF3, heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R9 groups which can be the same or different and are independently selected from the list of R9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazole groups , aryl fused with an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazole groups, heteroaryl fused with an aryl group or heteroaryl, wherein one or more of the aryl and / or one or more of the heteroaryl in the definitions indicated above for R2 may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consists of halogen, -CN, -OR5, -SR5, -S (O2) R6, -S (O2) NR5R6, -NR5R6, -C (O) NR5R6, CF3, alkyl, aryl and OCF3; R3 is selected from the group consisting of H, halogen, -NR5R6, -OR6, -SR6, -C (O) N (R5R6), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 may be unsubstituted or optionally independently substituted with one or more portions that may be be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) pOR5, -OR5, -NR5R6, - (CR4R5) PNR5R6, -C (O2) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (O2) R7, -N (R5) C (O) R7, -N (R5) C (R4R5) nN (R5R6) and -N (R5) C (O) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion; R 4 is H, halogen or alkyl; R5 is H, alkyl, aryl, heteroaryl, arylalkyl or cycloalkyl; R6 is selected from the group consisting of H, Boc, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl , heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN , -OR5, -NR5R10, -C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) pOR5, -C (O2) R5, -C (0) R5, -C (O) NR5R10, -SO3H, -SR10, -S (O2) R7, -S (O2) NR5R10, -N (R5) S (02) R7, -N (R5) C (O) R7 and -N (R5) C (O ) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3 > OCF3, CN, -OR5, -NR4R5, -C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) pOR5, -C (02) R5, -C (O) NR R5, -C ( 0) R5, -SO3H, -SR5, -S (O2) R7, -S (O2) NR4R5, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) ) C (O) NR R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C ( O2) R5, -C (O) NR5R10, -C (0) R5, -SR10, -S (O2) R10, -S (O2) NR5R10, -N (R5) S (O2) R10, -N (R5 ) C (O) R10 and -N (R5) C (O) NR5R10; R8 is selected from the group consisting of R6, -OR6, -C (O) NR5R10, -S (O2) NR5R10, -C (O) R7, -C (= N-CN) -NH2 > -C (= NH) -NHR5, heterocyclyl, and -S (O2) R7; R9 is selected from the group consisting of halogen, -CN, -NR5R10, -SCN, -NO2, -C (O) R5, -C (O2) R6, -C (O) NR5R10, -OR6, -SR6, - S (02) R7, -S (O2) NR5R10, -N (R5) S (O2) R7, -N (R5) C (0) R7 and -N (R5) C (O) NR5R10; m is 0 to 4; n is 1 to 4; and p is 1 to 4, with the proviso that when R2 is phenyl, R3 is not alkyl, alkynyl or halogen, and that when R is aryl, R is not provided that when R is arylalkyl, then any heteroaryl substituent on the aryl of said arylalkyl contains at least three heteroatoms; II. of the application Series No. 11/244772, filed on October 6, 2005, and published as US 2006/0041131 on February 23, 1006, a compound or pharmaceutically acceptable salts, solvates, esters, isomers or prodrugs of said compound, said compound having the general structure shown in formula II: Formula 11 or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound, wherein: R is an aryl, wherein said aryl is either unsubstituted or optionally substituted or fused with one or more heteroaryl; R2 is selected from the group consisting of R9, alkyl, alkynyl, alkynylalkyl, cycloalkyl, -CF3, -C (O2) R6, aryl, arylalkyl, heteroarylalkyl, heterocyclyl, alkyl substituted with 1-6 R9 groups which groups can be the same or different with each R9 being independently selected, aryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, - (CH2) m-N -8 and ^ CH2) m- N-R ° -arilc N-R8 aryl N-RB heteroaryl substituted with 0-3 aryl or heteroaryl groups which may be the same or different and are independently selected from alkyl, phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups; R3 is selected from the group consisting of H, halogen, -NR5R6, -C (O) NR5R6, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each being independently selected portion from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) n oR 5, -OR 5, -NR5R6, - (CR4R5) nNR5R6, -C (O2) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (02) R6, -S (O2) NR5R6, -N (R5) S (O2) R7, -N ( R5) C (O) R7 and -N (R5) C (0) NR5R6; R 4 is H, halogen or alkyl; R5 is H or alkyl; R6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl can be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -N (R5) Boc, - (CR4R5) nOR5, -C (O2) R5, -C (O) R5, -C (O) NR5R10, -SO3H, -SR10, -S (O2) R7, -S ( O2) NR5R10, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl can be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR4R5, -N (R5) Boc, - (CR4R5) nOR5, -C (O2) R5, -C (O) NR4R5, -C (O) R5, -SO3H, -SR5, -S (02) R7, -S ( O2) NR4R5, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR4R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR6R10, -CH2OR5, -C (02) R5, -C (0) NR5R10, -C (O) R5, -SR10, -S (O2) R10, -S (O2) NR5R10, --N (R5) S (02) R10, -N (R5) C (O) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -C (O) NR5R10, -S (02) NR5R10, -C (O) R7 and -S (O2) R7; R9 is selected from the group consisting of halogen, CN, -NR5R10, -C (O2) R6, -C (O) NR5R10, -OR6, -SR6, -S (O2) R7, -S (O2) NR5R10, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R10; m is 0 to 4, and n is 1 to 4, with the following conditions: (i) that when R is an unsubstituted phenyl, then R2 is not alkyl, -C (O2) R6, aryl or cycloalkyl, and (ii) that when R is a phenyl substituted with a hydroxyl group, then R2 is halogen only; lll. of the application Series No. 11/244776, filed on October 6, 2005, and published as US 2006/0040958 on February 23, 1006, a compound or pharmaceutically acceptable salts, solvates, esters, isomers or prodrugs of said compound, said compound having the general structure shown in formula III: Formula III wherein: R is heteroaryl, wherein said heteroaryl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R6, -C (R4R5) nOR5, -C (02 ) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (O2) R7, -S (O2) NR5R6, -N (R5) S (02) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6; R2 is selected from the group consisting of R9, alkyl, alkynyl, aryl, heteroaryl, CF3, heterocyclylalkyl, alkynylalkyl, cycloalkyl, -C (0) OR4, alkyl substituted with 1-6 R9 groups which can be the same or different and are independently selected from the list of R9 shown below, / \ - (CHa) "\ - < CH2) m-rg ^ N-R8 V N-RB -aryl- -N N -R8 N / \ 'aril0 ^ N-Rβ wherein the aryl in the definitions given above for R may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, CN, -OR5, SR5, -CH2OR5, -C (O) R5, -SO3H, -S (O2) R6, -S (O2) NR5R6, -NR5R6, -C (0) NR5R6, -CF3, and -OCF3; R3 is selected from the group consisting of H, halogen, -NR5R6, - C (O) OR4, -C (O) NR5R6, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each being independently selected portion from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) n oR 5, -OR 5, -NR5R6, - (CR4R5) nNR5R6, -C (O2) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (02) R6, -S (O2) NR5R6, -N (R5) S (O2) R7, -N ( R5) C (O) R7 and -N (R5) C (O) NR5R6; R 4 is H, halogen or alkyl; R5 is H or alkyl; R6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -N (R5) Boc, - (CR R5) nOR5, -C (O2) R5, -C (O) R5, -C (O) NR5R10, -SO3H, -SR10, -S (02) R7, -S (02 ) NR5R10, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl may be not substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR4R5, -N ( R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) NR4R5, -C (O) R5, -SO3H, -SR5, -S (O2) R7, -S (O2) NR R5, -N (R5) S (02) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR4R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl for R7 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C (02) R5, -C (O) NR5R10, -C (O) R5, -SR10, -S (O2) R10, -S (O2) NR5R10, -N (R5) S (02) R10, -N (R5) C (O ) R10 and -N (R5) C (O) NR5R10; R8 is selected from the group consisting of R6, -C (O) NR5R10, -CH2OR4, -C (O) OR6, -C (O) R7 and -S (O2) R7; R9 is selected from the group consisting of halogen, -CN, -NR5R6, - (CH2) nOR4, -C (O2) R6, -C (O) NR5R6, -OR6, -SR6, -S (02) R7, - S (O2) NR5R6, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (0) NR5R6; m is 0 to 4; and n is 1 to 4; IV. of the application Series No. 10/654163 filed on September 3, 2003, published as US 2004/0102452 on May 27, 2004, and granted as U.S. 7,084,271 on August 1, 2006, a compound or pharmaceutically acceptable salts, solvates, esters, isomers or prodrugs of said compound, said compound having the general structure shown in formula IV: Formula IV wherein: Q is selected from the group consisting of -S (O2) NR6R7-, -C (0) NR6R7- and -C (O) OR7-; R2 is selected from the group consisting of R9, alkyl, alkynyl, alkynylalkyl, cycloalkyl, -CF3, -C (02) R6, aryl, arylalkyl, heteroarylalkyl, heterocyclyl, alkyl substituted with 1-6 R9 groups which can be the same or different and are independently selected from the list of R9 shown below, - (CH2.} n V N-R8 aryl - N N -RB \ aryl-d N-R8 wherein the aryl in the definitions indicated above for R2 may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, CN, -OR5, SR5, -S (O2) R6, -S (O2) NR5R6, -NR5R6, -C (O) NR5R6, CF3, alkyl, aryl and OCF3; R3 is selected from the group consisting of H, halogen, alkyl, alkynyl, -C (O) NR, 5DDR6D, -C (O) OR *, -NR 5 ° cR6D, cycloalkyl, cycloalkylalkyl, aryl arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each being independently selected portion from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) n oR 5, -OR 5, -NR5R6, - (CR4R5) nNR5R6, -C (O2) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (02) R6, -S (O2) NR5R6, -N (R5) S (02) R7, -N ( R5) C (O) R7 and -N (R5) C (0) NR5R6; R 4 is H, halogen or alkyl; R5 is H or alkyl; R6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl may be not substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, - N (R5) Boc, - (CR R5) nOR5, -C (O2) R5, -C (O) R5, -C (0) NR5R10, -SO3H, -SR10, -S (02) R7, -S ( O2) NR5R10, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (0) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can being unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR4R5 , -N (R5) Boc, - (CRR5) nOR5, -C (02) R5, -C (O) NR4R5, -C (0) R5, -SO3H, -SR5, -S (O2) R7, - S (O2) NR4R5, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C (02) R5, -C (0) NR5R10, -C (O) R5, -SR10, -S (O2) R10, -S (O2) NR5R10, -N (R5) S (02) R10, -N (R5) C (O) R10 and -N (R5) C (O) NR5R10; R8 is selected from the group consisting of R6, -C (O) NR5R10, -S (02) NR5R10, -C (O) R7 and -S (O2) R7; R9 is selected from the group consisting of halogen, CN, -NR5R10, -C (O2) R6, -C (O) NR5R10, -OR6, -SR6, -S (O2) R7, -S (O2) NR5R10, - N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R10; m is 0 to 4, and n is 1 to 4; V. of the application Series No. 10/653868 filed on September 3, 2003, published as US 2004/0116442 on June 17, 2004, and granted as U.S. 7,074,924 on July 1, 2006, a compound or pharmaceutically acceptable salts, solvates, esters, isomers or prodrugs of said compound, said compound having the general structure shown in formula V: wherein: Q is -S (02) - or -C (O) -; R is aryl or heteroaryl, wherein said aryl or heteroaryl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, CN, -OR5, SR5, -S (O2) R6, -S (O2) NR5R6, NR5R6, -C (O) NR5R6, CF3, alkyl, aryl and OCF3; R2 is selected from the group consisting of CN, NR5R6, -C (O2) R6, -C (0) NR5R6, -OR6, -SR6, -S (O2) R7, -S (O2) NR5R6, -N (R5 ) S (02) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6; alkynyl, heteroaryl, CF3, heterocyclyl, alkynylalkyl, cycloalkyl, alkyl substituted with 1-6 R9 groups which may be the same or different and are independently selected from the list of R9 shown below, R3 is selected from the group consisting of H, halogen, -NR5R6, -C (O) NR5R6, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 may be substituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) nOR5, -OR5, -NR5R6, - (CR R5) nNR5R6, - C (O2) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6; R 4 is H, halogen or alkyl; R5 is H or alkyl; R6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, - N (R5) Boc, - (CR4R5) nOR5, -C (O2) R5, -C (O) R5, -C (O) NR5R10, -S03H, -SR10, - S (O2) R7, -S (O2) NR5R10, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR4R5, - N (R5) Boc, - (CR R5) nOR5, -C (O2) R5, -C (O) NR4R5, -C (O) R5, -SO3H, -SR5, -S (O2) R7, -S (O2) NR4R5, -N (R5) S (02) R7, -N (R5) C (O) R7 and -N (R5) C (0) NR R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen , alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C (02) R5, -C (O) NR5R10, -C (O) R5, -SR10, -S (O2 ) R10, -S (O2) NR5R10, --N (R5) S (O2) R10, -N (R5) C (O) R10 and -N (R5) C (O) NR5R10; R8 is selected from the group consisting of R6, -C (O) NR5R10, -S (O2) NR5R10, -C (O) R7 and -S (O2) R7; R9 is selected from the group consisting of halogen, CN, -NR5R10, -C (O2) R6, -C (O) NR5R10, -OR6, -SR6, -S (O2) R7, -S (O2) NR5R10, - N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R10; m is 0 to 4, and n is 1 to 4; and I saw. of the copending application Serial No. (attorney-in-fact case No. OC06284US01) filed on the same date as the present one, a compound or pharmaceutically acceptable salts, solvates, esters, isomers or prodrugs of said compound, said compound having the general structure shown in Formula VI: Formula VI or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein: R 2 is selected from the group consisting of halo; -CF3; -CN; -SR6; -NO2; -NR5R6a; -C (O) R6; -S (O2) R7; -S (O2) NR5R10; -N (R5) S (02) R7; -N (R5) C (O) NR5R10; I rent; alkenyl; alkynyl; heterocyclyl; heterocyclylalkyl; halo; halogenoalkyl; cycloalkyl; aril; Arylalkyl; arylalkenyl; arylalkynyl; heteroarylalkyl; alkynylalkyl; aryl fused with an aryl or heteroaryl group; heteroaryl; heteroaryl fused with an aryl or heteroaryl group; - (CH ^ - ^ - R '(CH2) mv "d V ilo d1 N-R ° -aryl-N-ar N-R8 X N-Rβ wherein each of the alkyl, alkenyl, alkynyl, heterocyclyl, heterocyclylalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, and alkynylalkyl groups and the heterocyclic portions shown immediately above for R2 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) POR5, -OR5 , -NR5R6, - (CR5R1) PN R5R6, -C (O2) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (02) R6, -S (O2) NR5R6, - N (R5) S (O2) R7, -C (= N-OH), -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion; R3 is selected from the group consisting of H; -NR5R6a; -OR6b; -SR6; CF3; -C (O) N (R5R6); I rent; alkenyl, alkynyl; cycloalkyl; aril; Arylalkyl; heterocyclyl; heterocyclylalkyl; heteroaryl; heteroarylalkyl; wherein each of the alkyl, alkynyl groups; cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and the heterocyclic portions whose structures are shown immediately above for R3 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) POR5, -OR5, -NR5R6, - (CR5R1) pNR5R6, -C (O2) R5, - C (O) R5, -C (O) NR5R6, -C (= N-OH), -SR6, -S (O2) R6, -S (O2) NR5R6, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion; R4 is selected from the group consisting of -CF3; -CN; -NR5R6a; - (CR5R11) pC (O2) R6; - (CR5R11) pC (O) NR5R10; -C (O) -N (R5R10); -OR6b; -SR6; -S (O2) R7; -S (O2) NR5R10; -C (O) R6; -N (R5) S (O2) R7; -N (R5) C (0) R7; -N (R5) C (O) NR5R10; alkenyl; alkenyl (substituted with alkoxy); hydroxyalkyl; alkynyl; heterocyclyl; heterocyclylalkyl; aril; aryl fused with an aryl or heteroaryl group; heteroaryl; heteroaryl fused with an aryl or heteroaryl group; substituted alkyl; cycloalkyl; wherein each of the alkyl, cycloalkyl groups; heterocyclyl, heterocyclylalkyl, aryl, fused aryl, heteroaryl, and fused heteroaryl of R 4 may be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (O2) R5, -C (O) R5, -C ( R5) (= N-OR5), -C (O) NR5R6, -SR6, -S (O2) R6, -S (O2) NR5R6, -N (R5) S (02) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion, and wherein the substituted alkyl group of R4 is independently substituted with one or more of the above portions; R5 is H, alkyl, aryl or cycloalkyl; R6 is selected from the group consisting of H, alkyl, alkenyl, aryl, aryl, alkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3 >; CN, -OR5, -NR5R10, -C (R5R11) pR9, -N (R5) Boc, - (CR5R11) POR5, -C (O2) R5, -C (0) R5, -C (= N- OH), -C (O) NR5R10, -SO3H, -SR10, -S (02) R7, -S (O2) NR5R10, -N (R5) S (02) R7, -N (R5) C (O) R7 and -N (R5) C (0) NR5R10; R6a is selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R5R11) P-R9, -N (R5) Boc, - (CR5R11) POR5, -C (O2) R5, -C (0) R5, -C (= N-OH) , -C (O) NR5R10, -SO3H, -SR10, -S (O2) R7, -S (O2) NR5R10, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R10; R6b is selected from the group consisting of alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can being unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, -CF3, -OCF3, -CN, -OR5 , -NR5R10, -C (R5R11) P-R9, -N (R5) Boc, - (CR5R11) pOR5, -C (O2) R5, -C (0) R5, -C (O) NR5R10, -SO3H, -SR10, -S (O2) R7, -S (O2) NR5R10, -N (R5) S (02) R7, -N (R5) C (O) R7, -C (= N-OH), and - N (R5) C (O) NR5R10; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, wherein each of the alkyl, cycloalkyl, heteroarylalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl groups, heteroarylalkenyl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5 , -NR5R10, -CH2OR5, -C (02) R5, -C (0) NR5R10, -C (= N-OH), -C (O) R5, -SR10, -S (O2) R10, -S ( O2) NR5R10, -N (R5) S (O2) R10, -N (R5) C (O) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -OR6, -NR5R6, -C (O) NR5R10, -S (O2) NR5R10, -C (O) R7, -C (= N-CN) -NH2, -C (= NH) -NHR5, heterocyclyl, -S (O2) R7, and R9 is selected from the group consisting of halogen, -CN, -NR5R10, -C (O2) R6, -C (O) NR5R10, -C (= N-OH), -OR6, -SR6, -S (02) R7, -S (02) NR5R10, -N (R5) S (O2) R7, -N (R5) C (0) R7 and -N (R5) C (O) NR5R10; and R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted by one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R11, -C (R5R11) P-R9, -N (R5) Boc, - (CR5R11) pOR5, -C (O2) R5, -C (O) NR5R11, -C (0) R5, -C (= N-OH), -SO3H, -SR5, -S (O2) R7, -S (O2) NR5R11, -N (R5) S (02) R7, -N (R5) C (O) R7 and -N ( R5) C (O) NR5R11; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each of the cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R11 is H, halogen or alkyl; m is 0 to 4; n is 1 to 4; and p is 1 to 4; with the proviso that (1) when R2 is alkyl, carboxyl, phenyl or cycloalkyl, then R3 is selected from the group consisting of -NR5R6a; -C (O) N (R5R6); alkynyl; Arylalkyl; heterocyclyl; heterocyclylalkyl; heteroaryl; heteroarylalkyl; wherein each of the alkynyl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl groups, and the heterocyclic portions whose structures are shown immediately above for R3 are unsubstituted or are independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of -CN, -NR5R6, - (CR5R11) PNR5R6, -C (O) NR5R6, -S (O2) NR5R6, -N (R5) S (O2) R7, -N ( R5) C (O) R7 and -N (R5) C (O) NR5R6; (2) when R2 is halogen, then R3 is selected from the group consisting of -OR6b; -SR6; -C (O) N (R5R6); cycloalkyl; heterocyclyl; heterocyclylalkyl; wherein each of the cycloalkyl, heterocyclyl, heterocyclylalkyl, and heterocyclic portions whose structures are shown immediately before for R3 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R1) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (02) R5, -C (O) R5, -C (O) NR6R6, -SR6, -S (O2) R6, -S (O2) NR5R6, -N (R5) S (02) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion; and (3) when R2 is NH2, R3 is not methyl. The compounds described in copending patent application No. series (case of proxy No. OC01617K3) filed the same date as the present generically fall within the formula I. The compounds described in co-pending patent application No. series (case of Proxy No. OC01618K2) filed on the same date as the present one generically fall within formula II. The compounds described in co-pending patent application No. series (case of proxy No. OC01619K2) filed on the same date as the present generically fall within formula III. The various preferred modalities and modalities described in the patents and patent applications described above for the compounds of the formulas I to VI, as well as for the compounds described in co-pending patent applications No. (cases of proxy No. OC01617K3, OC01618K2 and OC01619K2) filed on the same date as the present one, are equally applicable in the practice of the methods of the present invention. In another aspect, the present invention provides a method for treating or slowing the progression of a disease associated with one or more kinases in a patient in need of treatment, wherein the kinases are selected from the group consisting of Akt, check point kinases, Pim kinases and Aurora kinases, the method comprises administering a therapeutically effective amount of at least one compound of any of the formula I to VI above, or a pharmaceutically acceptable salt, solvate, isomer or ester thereof. In another aspect, the present invention provides a method for treating one or more diseases associated with a kinase selected from the group consisting of Akt kinases, check point kinases, Pim kinases and Aurora kinases, which comprises administering to a patient in need of said kinase. treating an amount of a first compound of any of the above formula I to VI or a pharmaceutically acceptable salt, solvate, ester, isomer or prodrug thereof; and an amount of at least one second compound, said second compound being an anti-cancer agent; wherein the amounts of the first compound and the second compound result in a therapeutic effect. In another aspect, the present invention provides a method for treating, or slowing the progression of, a disease associated with a kinase selected from the group consisting of Akt kinases, checkpoint kinases, Pim kinases and Aurora kinases in a patient. The same need, which comprises administering a therapeutically effective amount of a pharmaceutical composition comprising in combination at least one pharmaceutically acceptable carrier and at least one compound of any of the formula I to VI above or a salt, solvate, ester, isomer or pharmaceutically acceptable prodrug thereof. In another aspect, the present invention provides a method for inhibiting the activity of at least one tyrosine kinase in a patient, the method comprising administering a therapeutically effective amount of at least one compound, or a salt, solvate, ester, isomer or pharmaceutically acceptable prodrug thereof to a patient in need thereof, the compound being represented by any of the structural formulas I to VI, as well as the various compounds in the patents and patent applications cited above for the compounds of the formulas I to VI, as well as the compounds described in the co-pending patent applications Nos. (Cases of proxy No. OC01617K3, OC01618K2 and OC01619K2) presented on the same date as the present one. In another aspect, the present invention provides a method of treating, or slowing down the progression of, a tyrosine kinase-associated disease in a patient in need of such inhibition, the method comprising administering to a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt, solvate, ester, isomer or prodrug thereof to a patient in need thereof, the compound being represented by any of the structural formulas I to VI, as well as the various compounds in the cited patents and patent applications. above for the compounds of formulas I to VI, as well as the compounds described in copending patent applications Nos. series (case of proxy No. OC016 7K3, OC01618K2 and OC01619K2) presented on the same date as the present one. In another aspect, the present invention provides a method for treating one or more diseases associated with tyrosine kinases, which comprises administering to a mammal in need of such treatment an amount of a first compound, which is a compound of any of the structural formulas I a VI, or a pharmaceutically acceptable salt, solvate, ester, isomer or prodrug thereof; and an amount of at least one second compound, the second compound being an anticancer agent; wherein the amounts of the first compound and the second compound result in a therapeutic effect. In another aspect, the present invention provides a method for treating, or slowing the progression of, a disease associated with one or more tyrosine kinases in a patient in need thereof, which comprises administering a therapeutically effective amount of a pharmaceutical composition that comprises in combination at least one pharmaceutically acceptable carrier and at least one compound of any of the structural formulas I to VI, or a pharmaceutically acceptable salt, solvate, ester, isomer or prodrug thereof. The methods of the present invention can be useful in the treatment and prevention of proliferative diseases, for example, cancer, inflammation and arthritis, neurodegenerative diseases such as Alzheimer's disease, cardiovascular diseases, viral diseases and fungal diseases.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides methods for inhibiting, regulating or modulating Akt kinases, checkpoint kinases, Aurora kinases, Pim kinases, and / or tyrosine kinases using pyrazolo [1,5-ajpyrimidinium compounds of any of structural formulas I to VI or pharmaceutical compositions including said compounds, as well as the various compounds in the patents and patent applications cited above for the compounds of the formulas I to VI, as well as the compounds described in co-pending patent applications Nos. (cases of proxy No. OC01617K3, OC01618K2 and OC01619K2) filed on the same date as the present, and methods of treatment, prevention, inhibition or alleviation of one or more diseases associated with Akt kinases, checkpoint kinases, Aurora kinases, kinases Pim and / or tyrosine kinases using said compounds or pharmaceutical compositions, as described above and with additional additional detail. The above methods may be useful in the therapy of proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurological / neurodegenerative disorders, arthritis, inflammation, antiproliferative (e.g., ocular retinopathy), neuronal, alopecia and disease cardiovascular. Many of these diseases and disorders are listed in U.S. 6,413,974 cited above, incorporated herein by reference. More specifically, the compounds of the formulas I to VI, as well as the various compounds in the patents and patent applications cited above for the compounds of the formulas I to VI, as well as the compounds described in the co-pending patent applications series Nos. (Proxy Cases Nos. OC01617K3, OC01618K2 and OC01619K2) filed on the same date as the present may be useful in the treatment of a variety of cancers, including (but not limited to) the following: carcinoma, including bladder, breast , colon, kidney, liver, lung, including small cell lung cancer, non-small cell lung cancer, head and neck, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate and skin, including carcinoma of the squamous cells; Hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma, and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; and other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctantoma, cancer of the thyroid follicle, and Kaposi's sarcoma. The methods of the present invention may also be useful in the treatment of any disease process that exhibits abnormal proliferation of the cells, e.g., benign prostatic hyperplasia, familial adenomatosis, polyposis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis. , glomerulonephritis, restenosis after angioplasty or vascular surgery, hypertrophic scar formation, inflammatory bowel disease, transplant rejection, endotoxic shock, and fungal infections. The compounds of the formulas I to VI, as well as the various compounds in the patents and patent applications cited above for the compounds of the formulas I to VI, as well as the compounds described in the co-pending patent applications Nos. (Cases of empowered Nos. OC01617K3, OC01618K2 and OC01619K2) filed on the same date as the present may also be useful in the treatment of Alzheimer's disease. The compounds of the formulas I to VI, as well as the various compounds in the patents and patent applications cited above for the compounds of the formulas I to VI, as well as the compounds described in co-pending patent applications Nos. (Cases of empowered Nos. OC01617K3, OC01618K2 and OC01619K2) filed on the same date as this one, can induce or inhibit apoptosis. The apoptotic response is aberrant in a variety of human diseases. The compounds of formulas I to VI, as well as the various compounds in the patents and patent applications cited above for the compounds of the formulas I to VI, as well as the compounds described in co-pending patent applications Nos. (case of proxy No. OC01617K3, OC01618K2 and OC01619K2 ) presented on the same date as the present, as modulators of apoptosis, may be useful in the treatment of cancer (including but not limited to those types mentioned above), viral infections (including but not limited to herpes viruses, poxviruses, Epstein-Barr, Sindbis virus and adenovirus), prevention of AIDS development in HIV-infected individuals, autoimmune diseases (including but not limited to systemic lupus erythematosus, autoimmune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and diabetes mellitus) autoimmune), neurodegenerative disorders (including but not limited to Al's disease) zheimer, dementia related to AIDS, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration), myelodysplastic syndrome, aplastic anemia, ischemic injury associated with myocardial infarctions, cerebral vascular accident and reperfusion injury, arrhythmia, atherosclerosis, toxin-induced or alcohol-related liver diseases, hematological diseases (including but not limited to chronic anemia and aplastic anemia), degenerative diseases of the musculoskeletal system (including but not limited to osteoporosis and arthritis) aspirin-sensitive rhinosinusitis, fibrosis cystic disease, multiple sclerosis, kidney disease and cancer pain. The compounds of the formulas I to VI, as well as the various compounds in the patents and patent applications cited above for the compounds of the formulas I to VI, as well as the compounds described in co-pending patent applications Nos. (Cases of Proxy No. OC01617K3, OC01618K2 and OC01619K2) filed on the same date as the present one, may also be useful in the chemoprevention of cancer. Chemoprevention is defined as the inhibition of the development of invasive cancer either by blocking the mutagenic event of onset or by blocking the progression of pre-malignant cells that have already undergone attack or by inhibiting tumor recurrence. The compounds of the formulas I to VI, as well as the various compounds in the patents and patent applications cited above for the compounds of the formulas I to VI, as well as the compounds described in co-pending patent applications Nos. (Cases of empowered Nos. OC01617K3, OC01618K2 and OC01619K2) filed on the same date as the present one, may also be useful in the inhibition of angiogenesis and tumor metastasis. A preferred dose is from about 0.001 to 500 mg / kg of body weight / day of the compound of formulas I to VI, as well as any of the various compounds in the patents and patent applications cited above for the compounds of the formulas I to VI, as well as the compounds described in co-pending patent applications Nos. (Cases of attorney-in-fact Nos. OC01617K3, OC01618K2 and OC01619K2) filed on the same date as the present one. An especially preferred dose is from about 0.01 to 25 mg / kg of body weight / day of the compound, or a pharmaceutically acceptable salt, solvate or ester of the compound. The compounds of this invention may also be useful in combination (administered together with or sequentially in any desired order) with one or more of anti-cancer treatments such as radiation therapy, and / or one or more anticancer agents other than the compounds of the formulas I to VI, as well as the various compounds in the patents and patent applications cited above for the compounds of the formulas I to VI, as well as the compounds described in co-pending patent applications Nos. (Cases of proxy No. OC01617K3, OC01618K2 and OC01619K2) presented on the same date as the present one. The compounds of the present invention may be present in the same dose unit as the anticancer agent or in separate dose units. Non-limiting examples of the compounds of the formula I useful in the practice of the present methods include those shown on pages 5-56 and 117-1058 of the aforementioned US 2006/0128725, some of which are listed below : or a pharmaceutically acceptable salt, solvate, ester, isomer or prodrug thereof. Non-limiting examples of additional compounds of the formula I useful in practicing the present methods include those shown on pages 4-52 and 60-983 of the aforementioned US 2004/0209878, some of which are listed below : or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. Non-limiting examples of compounds of the co-pending patent application No. series (attorney-in-fact case No. OC01617K3) filed on the same date as the present one suitable in the methods of the present invention include: ?? or a pharmaceutically acceptable salt, solvate, ester, isomer or prodrug thereof. Non-limiting examples of compounds belonging to formula II suitable in the methods of the present invention include those shown on pages 4-14 and 42-79 of the aforementioned US 2006/0041131, some of which are listed below: or a pharmaceutically acceptable salt, solvate, ester, isomer or prodrug thereof. Non-limiting examples of compounds of formula II of co-pending patent application No. series (attorney-in-fact No. OC01618K2) filed on the same date as the present one suitable in the methods of the present invention include: or a pharmaceutically acceptable salt, solvate, ester, isomer or prodrug thereof. Non-limiting examples of the compounds of the formula III in the practice of the methods of the present invention include those shown on pages 4-12 and 42-60 of the aforementioned US 2006/0040958, some of which are listed continuation: or a pharmaceutically acceptable salt, solvate, ester, isomer or prodrug thereof. Non-limiting examples of compounds of formula III of the co-pending patent application No. series (case of proxy No. OC01619K2) filed the same date as the present suitable in the methods of the present invention include: or a pharmaceutically acceptable salt, solvate, ester, isomer or prodrug thereof. Non-limiting examples of compounds of formula IV suitable in the practice of the methods of the present invention include those shown in col. 5-10 et al. 61-72 of U.S. 7,084,271 mentioned above, some of which are shown below: or a pharmaceutically acceptable salt, solvate, ester, isomer or prodrug thereof. Non-limiting examples of compounds of formula V suitable in the practice of the methods of the present invention include those of col. 6- col. 15 et al. 69- col. 87 of U.S. 7,074,924 mentioned above, some of which are shown below: or a pharmaceutically acceptable salt, solvate, ester, isomer or prodrug thereof. Non-limiting examples of compounds of formula VI of the co-pending patent application No. (case of proxy No.

OC06284US01) filed on the same date as the present one, suitable in the methods of the present invention include: or a pharmaceutically acceptable salt, solvate, ester, isomer or prodrug thereof. As indicated above, the compounds of the formula VI are described in the co-pending patent application No. series (case of proxy No. OC06284US01) filed on the same date as the present one. In some embodiments of the compound of formula VI, R2 is selected from the group consisting of -CF3; -CN; -NO2; -NR5R6a; -C (0) R6; -S (O2) R7; -S (O2) NR5R10; -N (R5) S (O2) R7; -N (R5) C (O) NR5R10; I rent; alkenyl; alkynyl; heterocyclyl; heterocyclylalkyl; halogen; halogenoalkyl; cycloalkyl; aril; Arylalkyl; arylalkenyl; arylalkynyl; heteroarylalkyl; alkynylalkyl; aryl fused with an aryl or heteroaryl group; heteroaryl; heteroaryl fused with an aryl or heteroaryl group; -aplo - N-R8 \ - aplo- ^ N_R8 dd and wherein each of the alkyl, alkenyl, alkynyl groups, heterocyclyl, heterocyclylalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl and alkynylalkyl of R2 can be replaced or optionally independently substituted with one or more portions that can be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R1) PNR5R6, -C (O2) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (O2) R6, -S (O2) NR5R6, -N ( R5) S (O2) R7, -N (R5) C (O) R7, -C (= N-OH), and -N (R5) C (O) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion.

In other embodiments of the compound of formula VI, R2 is select from the group consisting of -CF3; -CN; -NO2; -NR5R6a; -C (O) R6; -S (O2) R7; -S (O2) NR5R10; -N (R5) S (O2) R7; -N (R5) C (O) NR5R10; alkenyl; alkynyl; heterocyclyl; heterocyclylalkyl; halogen; halogenoalkyl; cycloalkyl; aril; Arylalkyl; arylalkenyl; arylalkynyl; heteroarylalkyl; alkynylalkyl; aryl fused with an aryl or heteroaryl group; heteroaryl; heteroaryl fused with an aryl or heteroaryl group; substituted alkyl; . { aryl - N N -R8 aryl r_? N-R8? Y \-/ . wherein each of the alkenyl, alkynyl, heterocyclyl, heterocyclylalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, and alkynylalkyl groups of R2 can be unsubstituted or optionally independently substituted with one or more portions which can be same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, -C (= N -OH), - (CR5R11) PNR5R6, -C (O2) R5, -C (O) R5, -C (0) NR5R6, -SR6, -S (O2) R6, -S (O2) NR5R6, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion and substituted alkyl is independently substituted with one or more of the above portions. In other embodiments of the compound of formula VI, R 2 is selected from the group consisting of halogen; -NO2; -NR5R6a; -C (O) R6; -SR6; -N (R5) C (O) NR5R10; I rent; alkenyl; alkynyl; aril; arylalquinyl; heteroaryl; wherein each of the alkyl, alkenyl, alkynyl, aryl, arylalkynyl, and heteroaryl groups of R2 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consists of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (02) R5, -C (O ) R5, -C (O) NR5R6, -SR6, -S (O2) R6, -S (O2) NR5R6, -N (R5) S (02) R7, -N (R5) C (O) R7, - C (= N-OH), and -N (R5) C (O) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion.

In other embodiments of the compound of formula VI, R 2 is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, indanyl, 1,2-benzopyranyl, 3,4-dihydro-1,2-benzopyranyl or tetralinyl, then R3 is selected from the group consisting of -NR5R6a with the proviso that R5 and R6a are not C4 alkyl or C3-C6 cycloalkyl; -C (O) N (R5R6); aril; Arylalkyl; heterocyclyl; heterocyclylalkyl; heteroaryl; heteroarylalkyl; substituted alkyl; wherein each of the aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, substituted alkyl groups and the heterocyclic portions whose structures are shown immediately above for R3 may be unsubstituted or optionally independently substituted with one or more portions which may be same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR11R1) pOR5, ORD, -NR, 5DDR6D, -C (O2) RD, -C (O) RD, -C (O) NR 5s [R- > 6b, -SRD, -S (O2) R6, -C (= N-OH), -S (O2) NR5R6, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion. In other embodiments of the compound of the formula VI, R 2 is aryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are each independently selected from the group consisting of phenyl, pyridyl, thiophenyl, furanyl and thiazole groups . In other embodiments of the compound of formula VI, R 2 is heteroaryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are each independently selected from the group consisting of phenyl, pyridyl, thiophenyl, furanyl and thiazole groups . In other embodiments of the compound of the formula VI, R 2 is selected from the group consisting of heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl. In other embodiments of the compound of formula VI, R2 is selected from the group consisting of In some embodiments of the compound of formula VI, R3 is selected from the group consisting of H; -NR5R6a; -OR6b; -SR6; -C (O) N (R5R6); alkynyl; cycloalkyl; aril; Arylalkyl; heterocyclyl; heterocyclylalkyl; heteroaryl; heteroarylalkyl; wherein each of the alkynyl groups; cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and the heterocyclic portions whose structures are shown immediately above for R3 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) POR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (O2) R5, - C (O) R5, -C (O) NR5R6, -SR6, -C (= N-OH), -S (O2) R6, -S (O2) NR5R6, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion. In other embodiments of the compound of formula VI, R3 is selected from the group consisting of H; -NR5R6a; -OR6b; -SR6; -C (O) N (R5R6); alkynyl; cycloalkyl; aril; Arylalkyl; heterocyclyl; heterocyclylalkyl; heteroaryl; heteroarylalkyl; substituted alkyl; wherein each of the alkynyl groups; cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and the heterocyclic portions whose structures are shown immediately above for R3 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR R6, - (CR5R11) PNR5R6, -C (O2) R5, -C (O) R5, -C (O) NR5R6, -SR6, -C (= N-OH), -S (O2) R6, -S (O2) NR5R6, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion, and wherein the substituted alkyl is substituted with one or more of the above portions. In other embodiments of the compound of formula VI, R3 is selected from the group consisting of -NR5R6a; -OR6b; -SR6; -C (O) N (R5R6); I rent; aril; Arylalkyl; heterocyclyl; heterocyclylalkyl; heteroaryl; heteroaplalkyl, wherein each of the alkyl, ring, aplakyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroalalkyl groups, and the heterocyclic portions whose structures are shown immediately before for R3 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aplo, cycloalkyl, -CF3, -CN, -OCF3, - (CR 1R11) pOR5, -C (= N-OH), -OR5 , -NR5R6, - (CRR11) PNR5R6, -C (O2) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (O2) R6, -S (O2) NR5R6, - N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring In a further embodiment of the compound of formula VI, R3 is selected from the group consisting of -NR5R6a, -C (O) N (R5R6), alkyl, alkyl, cycloalkyl, aplo, aplakyl, heterocyclyl, heterocyclylalkyl, hetero aplo, heteroaplalkyl, substituted alkyl, wherein each of the cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, substituted alkyl groups and the heterocyclic portions whose structures are shown immediately above for R3 is independently substituted with one or more portions which may be the same or different , each portion being independently selected from the group consisting of -CN, -NR5R6, -C (= N-OH), - (CR5R11) PNR5R6, -C (O) NR5R6, -S (O2) NR5R6, -N (R5 ) S (02) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6. In other embodiments of the compound of formula VI, R3 is selected from the group consisting of -NR5R6a; -C (O) N (R5R6); wherein each of the heterocyclic portions whose structures are shown immediately above for R3 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl , aryl, cycloalkyl, CF3, CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, -C (= N-OH), - (CR5R11) PNR5R6, -C (O2) R5, -C (O ) R5, -C (O) NR5R6, -SR6, -S (O2) R6, -S (O2) NR5R6, -N (R5) S (O2) R7, -N (R5) C (O) R7 and - N (R5) C (O) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion. In other embodiments of the compound of formula VI, R3 is -NR5R6a, with the proviso that R5 is aryl and R6a is selected from the group consisting of alkenyl, aryl, arylalkyl, arylalkenyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R5R11) pOR9, -N (R5) Boc, - (CR5R11) pOR5, -C (O2) R5, -C (O) R5, -C (O) NR5R10, -SO3H, -SR10, -S (02) R7, -S (O2) NR5R10, -N (R5) S (O2) R7, -C ( = N-OH), -N (R5) C (O) R7 and -N (R5) C (O) NR5R10. In other embodiments of the compound of formula VI, R3 is selected from the group consisting of In other embodiments of the compound of formula VI, R3 is selected from the group consisting of In other embodiments of the compound of formula VI, R 4 is selected from the group consisting of -CF 3; -NR5R6a; - (CR5R11) pC (02) R6; -C (0) -N (R5R10); -OR6b; -SR6; -S (O2) R7; -S (O2) NR5R10; -N (R5) S (02) R7; -N (R5) C (O) R7; -N (R5) C (O) NR5R10; heterocyclyl; heterocyclylalkyl; aril; aryl fused with an aryl or heteroaryl group; heteroaryl; heteroaryl fused with an aryl or heteroaryl group; substituted alkyl; - aryl- N N-R8 aplo ^ ^ e In other embodiments of the compound of formula VI, R 4 is selected from the group consisting of -CF 3; -CN; -NR5R6a; -OR6b; -SR6; -S (O2) R7; -C (O) -N (R5R10); -S (O2) NR5R10; -N (R5) S (O2) R7; -N (R5) C (0) R7; -N (R5) C (O) NR5R10; heterocyclyl; heterocyclylalkyl; aril; fused aryl; heteroaryl; fused heteroaryl; j- (CH2) m-N N- R8 In other embodiments of the compound of formula VI, R4 is selected from the group consisting of: - (CR5R11) pC (02) R6; - (CR5R11) p-C (0) -NR5R10; -C (O) -N (R5R10); hydroxyalkyl; aril; - (CH2) m-N N- RB \ N-R8 I aplo- N N -R8 - aplo ^. N_R8 wherein one or more of the aryl and / or one or more of the heteroaryl groups of R4 may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen , -CN, -OR5, -SR5, -S (O2) R6, -S (O2) NR5R6, -NR5R6, -C (O) NR5R6, CF3, alkyl, aryl and OCF3. In other embodiments of the compound of the formula VI, R 4 is aryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are each independently selected from the group consisting of phenyl, pyridyl, thiophenyl, furanyl and thiazole groups . In other embodiments of the compound of formula VI, R 4 is heteroaryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are each independently selected from the group consisting of phenyl, pyridyl, thiophenyl, furanyl and thiazolo. In other embodiments of the compound of formula VI, R 4 is selected from the group consisting of In other embodiments of the compound of the formula VI, R "is substituted alkyl which is independently substituted with one or more of the following poricones: halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11 ) pOR5, -OR5, -NR5R6, - (CR5R11) PN R5R6, -C (02) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (O2) R6, -C ( = N-OH), -S (O2) NR5R6, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, with the proviso that that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a portion -OR 5. In another embodiment, the compound of formula VI is a compound of the formula: wherein R is heteroaryl, R is heterocyclyl and R4 is heteroaryl, wherein each of said heteroaryl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from a group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (O2) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (02) R6, -C (= N-OH), -S (O2) NR5R6, -N (R5) S (O2) R7, - N (R5) C (O) R7 and -N (R5) C (O) NR5R6, wherein R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is a pyrazolyl, R 3 is piperidinyl and R 4 is pyrazolyl, wherein each of said pyrazolyl and piperidinyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected. of the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (O2) R5, - C (O) R5, -C (O) NR5R6, -SR6, -S (02) R6, -C (= N-OH), -S (O2) NR5R6, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, wherein R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is 1-methyl-pyrazol-4-yl, R 3 is piperidin-3-yl, and R 4 is pyridin-4-yl. In another embodiment, this invention provides a compound of the formula: wherein R 2 is 1-methyl-pyrazol-4-yl, R 3 is piperidin-3-yl, and R 4 is thien-3-ylyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is heteroaryl, R 3 is heterocyclyl, and R 4 is alkynyl, wherein each of said heteroaryl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from a group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (O2) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (O2) R6, -C (= N-OH), -S (O2) NR5R6, -N (R5) S (O2) R7, - N (R5) C (O) R7 and -N (R5) C (0) NR5R6, wherein R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is pyrazolyl, R 3 is piperidinyl and R 4 is propynyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R is 1-methyl-pyrazol-4-yl, R is piperidin-3-yl and R is propinyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R is heteroaryl, R is heterocyclyl and R is alkenyl (substituted with alkoxy), wherein each of said heteroaryl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PN R5R6, -C ( O2) R5, -C (O) R5, -C (= N-OH), -C (0) NR5R6, -SR6, -S (O2) R6, -S (O2) NR5R6, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, wherein R5, R6, R1, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is pyrazolyl, R 3 is piperidinyl and R 4 is alkenyl (substituted with alkoxy). In another embodiment, the compound of formula VI is a compound of the formula: where R) 2 e "" s 1-me * t; i, l- "p; i, r_azo, l-4 A-: i? lo", D R3 is p; iper; id, j; in " -3-: iilo ~. Y. C R > 4 is 3- (methoxy) propylene-1-yl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is heteroaryl, R 3 is heterocyclyl, and R 4 is cycloalkyl, wherein each of said heteroaryl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected. of the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (O2) R5, - C (O) R5, -C (O) NR5R6, -SR6, -S (02) R6, -C (= N-OH), -S (O2) NR5R6, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, wherein R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is pyrazolyl, R3 is piperidinyl and R4 is cyclopropyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is 1-methyl-pyrazol-4-yl, R 3 is piperidin-3-yl and R 4 is cyclopropyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R. 2 is heteroaryl, R is heterocyclyl and R is cyano, wherein each of said heteroaryl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR1R1) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (O2) R5, -C (O) R5, -C (0) NR5R6, -SR6, -S (O2) R6, -C (= N-OH), -S (O2) NR5R6, -N (R5) S (O2) ) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, wherein R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is pyrazolyl, R3 is piperidinyl and R4 is cyano. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is 1-methyl-pyrazol-4-yl, R 3 is piperidin-3-yl and R 4 is cyano. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is heteroaryl, R 3 is heterocyclyl, and R 4 is hydroxyalkyl, wherein each of said heteroaryl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from a group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3) - (CR 1R11) pOR5, -OR5, -NR5R6, - (CR5R1) PNR5R6, -C (O2) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (02) R6, -C (= N-OH), -S (O2) NR5R6, -N (R5) S (O2) R7 , -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, wherein R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is pyrazolyl, R 3 is piperidinyl and R 4 is 1-hydroxyethyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is 1-methyl-pyrazol-4-yl, R 3 is piperidin-3-yl and R 4 is 1-hydroxyethyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is heteroaryl, R 3 is heterocyclyl and R 4 is -C (O) R 6, wherein each of said heteroaryl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (O2 ) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (O2) R6, -C (= N-OH), -S (O2) NR5R6, -N (R5) S ( O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, wherein R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R is pyrazolyl, R is piperidinyl and R is methylcarbonyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is 1-methyl-pyrazol-4-yl, R 3 is piperidin-3-yl and R 4 is methylcarbonyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is heteroaryl, R 3 is heterocyclyl and R 4 is aryl, wherein each of said aryl, heteroaryl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR 1R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (O2) R5 , -C (O) R5, -C (O) NR5R6, -SR6, -S (O2) R6, -C (= N-OH), -S (O2) NR5R6, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, wherein R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R is pyrazolyl, R is piperidinyl and R is phenyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is 1-methyl-pyrazol-4-yl, R 3 is piperidin-3-yl and R 4 is phenyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R is heteroaryl, R3 is heterocyclyl and R4 is heteroaryl, wherein each of said heteroaryl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the a group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R1) pOR5, -OR5, -NR5R6, - (CR5R11) PN R5R6, -C (O2) R5, - C (O) R5, -C (O) NR5R6, -SR6, -S (02) R6, -C (= N-OH), -S (O2) NR5R6, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, wherein R5, R6, R1, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is pyrazolyl, R3 is piperidinyl and R4 is furanyl. In another embodiment, the compound of formula VI is a compound of the formula: where R? 2? e, s 1-methyl-pyrazol-4-yl, 1 R33 is piperidin-3-yl and R is furan-3-yl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is heteroaryl, R 3 is heterocyclyl, and R 4 is heteroaryl, wherein each of said heteroaryl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from a group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (O2) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (02) R6, -C (= N-OH), -S (O2) NR5R6, -N (R5) S (O2) R7, - N (R5) C (O) R7 and -N (R5) C (O) NR5R6, wherein R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is pyrazolyl, R3 is piperidinyl and R4 is pyridyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is 1-methyl-pyrazol-4-yl, R 3 is piperidin-3-yl and R 4 is pyrid-3-yl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is heteroaryl, R 3 is heterocyclyl and R 4 is alkenyl, wherein each of said alkenyl, heteroaryl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - < CR11R11) pOR5, -OR5, -NR5R6, - (CR5R1) PNR5R6, -C (O2) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (02) R6, -C ( = N-OH), -S (O2) NR5R6, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, wherein R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is pyrazolyl, R3 is piperidinyl and R4 is alkenyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is 1-methyl-pyrazol-4-yl, R 3 is piperidin-3-yl and R 4 is -C (= CH 2) -CH 3. In another embodiment, the compound of formula VI is a compound of the formula: wherein R is heteroaryl, R is heterocyclyl and R is heteroaryl, wherein each of said heteroaryl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from a group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (O2) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (O2) R6, -C (= N-OH), -S (O2) NR5R6, -N (R5) S (02) R7, - N (R5) C (0) R7 and -N (R5) C (0) NR5R6, wherein R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is pyrazolyl, R 3 is piperidinyl and R 4 is pyrazolyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is 1-methyl-pyrazol-4-yl, R 3 is piperidin-3-yl and R 4 is 1-hydroxyethyl-pyrazol-4-yl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is heteroaryl, R 3 is heterocyclyl and R 4 is heteroaryl, wherein each of said heteroaryl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from a group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR1 R11) pOR5, -OR5, -NR5R6, - (CR5R11) pN R5R6, -C (O2) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (02) R6, -C (= N-OH), -S (O2) NR5R6, -N (R5) S (O2) R7 , -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, wherein R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R is pyrazolyl, R is piperidinyl and R is thienyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is 1-methyl-pyrazol-4-yl, R 3 is piperidin-3-yl and R 4 is thien-2-yl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is heteroaryl, R3 is heterocyclyl and R4 is alkyl, wherein each of said alkyl, heteroaryl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR 1R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (O2) R5 , -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -C (= N-OH), -S (O2) NR5R6, -N (R5) S (O2) R7, -N (R5) C (0) R7 and -N (R5) C (O) NR5R6, wherein R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R is pyrazolyl, Rd is piperidinyl and R is ethyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is 1-methyl-pyrazol-4-yl, R 3 is piperidin-3-yl and R 4 is ethyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is heteroaryl, R 3 is heterocyclyl and R 4 is an oxime, wherein each of said heteroaryl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected of the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PN R5R6, -C (02) R5, -C (0) R5, -C (O) NR5R6, -SR6, -S (02) R6, -C (= N-OH), -S (O2) NR5R6, -N (R5) S (O2) R7 , -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, wherein R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is pyrazolyl, R3 is piperidinyl and R4 is an oxime. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is 1-methyl-pyrazol-4-yl, R3 is piperidin-3-yl and R4 is -C (= N-OH) -CH3. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is heteroaryl, R 3 is heterocyclyl and R 4 is a ketone, wherein each of said heteroaryl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected of the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3 > - (CR 1R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (O2) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (O2) R6, -C (= N-OH), -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6, in where R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is pyrazolyl, R3 is piperidinyl and R4 is a ketone. In another embodiment, the compound of formula VI is a compound of the formula: wherein R > 2 e _s 1-methyl-pytazol-4-yl, D R3 is piperidin-3-yl and R is -C (0) -CH2-CH3. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is heteroaryl, R3 is heterocyclyl and R4 is a ketone, wherein each of said aryl, heteroaryl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R1) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -C (= N-OH), -S (O2) NR5R6, -N (R5) S (O2) ) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6, wherein R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R is pyrazolyl, R is piperidinyl and R is a ketone. In another embodiment, the compound of formula VI is a compound of the formula: where R) 2 e "s, 1-methyl-pyrazole-4-i; l" o ", R D3 e _s" p "i: p -er ..i¡dji; n. -3-yl and R D4 is benzylcarbonyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is halogen, R3 is alkyl and R4 is an amide, wherein said alkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PN R5R6, -C (02) R5, -C (0) R5, -C (= N-OH), -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5 ) C (0) R7 and -N (R5) C (0) NR5R6, wherein R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is bromine, R3 is alkyl and R4 is an amide. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is bromine, R3 is methyl and R4 is -CH2-C (0) -NH 12; - In another embodiment, the compound of the formula VI is a compound of the formula: wherein R is halogen, R is alkyl and R is an amide, wherein said alkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PN R5R6, -C (02) R5, -C (0) R5, -C (= N-OH), -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5 ) C (0) R7 and -N (R5) C (0) NR5R6, wherein R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is bromine, R3 is alkyl and R4 is an amide. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 'is bromine, RJ is methyl and Rq is -CH2-C (0) -NHCH3.

In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is halogen, R3 is alkyl and R4 is a hydroxyalkyl, wherein said alkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (02) R5, -C (0) R5 , -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -C (= N-OH), -N (R5) C (0) R7 and -N (R5) C (0) NR5R6, wherein R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is bromine, R3 is alkyl and R4 is a hydroxyalkyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is bromine, R3 is methyl and R4 is 2-hydroxyethyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is halogen, R3 is alkyl and R4 is an amide, wherein said alkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR 1R11) pOR5, -OR5, -NR5R6, - (CR5R11) PN R5R6, -C (02) R5, -C (0 ) R5, -C (= N-OH), -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N ( R5) C (0) R7 and -N (R5) C (0) NR5R6, wherein R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is bromine, R3 is alkyl and R4 is an amide. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is bromine, R3 is methyl and R4 is -CH2-CH2-C (0) -NHCH3. In another embodiment, the compound of formula VI is a compound of the formula: where R, 2 is i ha, logene, D R3 is i heterooc-il? l: i? lo ". Y. r R- > 4 is aryl, wherein each of said aryl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PN R5R6, -C (O2) R5, -C (O) R5, -C (O ) NR5R6, -SR6, -S (O2) R6, -S (O2) NR5R6, -N (R5) S (02) R7, -C (= N-OH), -N (R5) C (0) R7 and -N (R5) C (0) NR5R6, wherein R5, R6, R1, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is bromine, R3 is pyrrolidinyl and R4 is an aryl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is bromine, R3 is 3-amino-pyrrolidin-1-yl and R4 is phenyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is halogen, R3 is heterocyclyl and R4 is alkyl, wherein each of said alkyl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the a group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) pNR5R6, -C (02) R5, -C (0) R5, -C (0) NR5R6, -C (= N-OH), -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, - N (R5) C (0) R7 and -N (R5) C (0) NR5R6, wherein R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is bromine, R3 is pyrrolidinyl and R4 is an alkyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is bromine, R3 is 3-amino-pyrrolidin-1-yl and R is ethyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is halogen, R * is heterocyclyl and R4 is alkyl, wherein each of said alkyl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected of the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (02) R5, - C (0) R5, -C (O) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -C (= N-OH), -N (R5) C (0) R7 and -N (R5) C (0) NR5R6, wherein R5, R6, R11, and p are as defined above. In another embodiment, the compound of formula VI is a compound of the formula: wherein R2 is bromine, R3 is pyrrolidinyl and R4 is an alkyl. In another embodiment, the compound of formula VI is a compound of the formula: wherein R 2 is bromine, R 3 is 3-amino-pyrrolidin-1-yl and R 4 is methyl. As used before, and throughout this description, the following terms, unless otherwise indicated, should be understood to have the following meanings: "Patient" or "subject" includes both humans and animals. "Mammal" means humans and other mammalian animals. "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched chain and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain from about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain from about 1 to about 6 carbon atoms in the chain.

Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having from about 1 to about 6 carbon atoms in the chain which may be straight or branched chain.

"Alkyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino , -NH (alkyl), -NH (cycloalkyl), -N (alkyl) 2, carboxy and -C (0) 0 -alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl. "Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched chain and comprising from about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have from about 2 to about 12 carbon atoms in the chain; and most preferably from about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means from about 2 to about 6 carbon atoms in the chain which may be straight or branched chain. "Alkenyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, cyano, alkoxy and -S (alkyl) . Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl. "Alkylene" means a difunctional group obtained by the removal of a hydrogen atom from an alkyl group defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene. "Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched chain and comprising from about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have from about 2 to about 12 carbon atoms in the chain; and most preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means from about 2 to about 6 carbon atoms in the chain which may be straight or branched chain. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. "Alkynyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl. "Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as described above. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The binding to the progenitor portion is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl. "Aryl" means an aromatic monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms, preferably from about 6 to about 10 carbon atoms. The aryl group may be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising from about 5 to about 14 ring atoms, preferably from about 5 to about 10 ring atoms, in which one or more of the ring atoms is a distinct element carbon, for example, nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain from about 5 to about 6 ring atoms. The "heteroaryl" may be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or aunt before the heteroaryl root name means that at least one of a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isotazolyl, oxazolyl, tazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,4- tadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo [1,2-a] pyridinyl, imidazo [2,1-btazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,4-triazinyl, benzotazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like. "Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as described above. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The binding to the progenitor portion is through the alkyl. "Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as described above. Preferred alkylaryls comprise a lower alkyl group. A non-limiting example of a suitable alkylaryl group is tolyl. The union to the progenitor portion is through the aril. "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising from about 3 to about 10 carbon atoms, preferably from about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain from about 5 to about 7 ring atoms. The cycloalkyl may be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like. "Cycloalkylalkyl" means a cycloalkyl portion are as defined above linked through an alkyl moiety (defined above) to a parent nucleus. Non-limiting examples of suitable cycloalkylalkyl include cyclohexylmethyl, adamantylmethyl and the like. "Cycloalkenyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms containing at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain from about 5 to about 7 ring atoms. The cycloalkenyl may be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like. A non-limiting example of a suitable multiclyclic cycloalkenyl is norbornylenyl. "Cycloalkenylalkyl" means a cycloalkenyl moiety as defined above linked through an alkyl moiety (defined above) to a parent nucleus. Non-limiting examples of suitable cycloalkenylalkyl include cyclopentenylmethyl, cyclohexenylmethyl and the like. "Halogen" or "halo" means fluorine, chlorine, bromine or iodine. Fluoro, chloro and bromo are preferred.

"Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system that, for example, replaces a hydrogen available in the ring system. The ring system substituents may be the same or different, each independently being selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy , aryloxy, aralkoxy, acyl, aroyl, halogen, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, -C (= N-CN ) -NH2, -C (= NH) -NH2, -C (= NH) -NH (alkyl), Y ^ N-, Y? Y2N-alkyl-, Y ^ N ^ O) -, Y ^ NSO;, - and -S02NY1Y2, wherein Y and Y2 may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" can also mean a single portion that simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) in a ring system. Examples of said portions are methylenedioxy, ethylenedioxy, -C (CH3) 2- and the like forming portions such as, for example: "Heteroarylalkyl" means a heteroaryl portion as defined above linked by an alkyl moiety (defined above) to a parent nucleus. Non-limiting examples of suitable heteroarylalkyl include 2-pyridinylmethyl, quinolinylmethyl and the like. "Heterocyclyl" means a saturated non-aromatic monocyclic or multicyclic ring system comprising from about 3 to about 10 ring atoms, preferably from about 5 to about 10 ring atoms, in which one or more of the atoms in the system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and / or sulfur atoms present in the system. Preferred heterocyclyls contain from about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclic root name means that at least one nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, a group -N (Boc), -N (CBz), -N (Tos) and the like; said protections are also considered part of this invention. The heterocyclyl may be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl may be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of non-limiting monocyclic heterocyclic rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like. "Heterocyclylalkyl" means a heterocyclyl moiety, as defined above, linked through an alkyl moiety (defined above) to a parent nucleus. Non-limiting examples of suitable heterocyclylalkyl include piperidinylmethyl, piperazinylmethyl and the like. "Heterocyclenyl" means a non-aromatic monocyclic or multicyclic ring system comprising from about 3 to about 10 ring atoms, preferably from about 5 to about 10 ring atoms, in which one or more of the atoms in the system is a element other than carbon, for example, nitrogen, oxygen or sulfur atom, alone or in combination, and containing at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and / or sulfur atoms present in the system. Preferred heterocyclenyl rings contain from about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least one nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can optionally be oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable heterocyclenyl groups include 1, 2,3,4-tetrahydropyridino, 1,2-dihydropyridyl, 1, 4-dihydropyridyl, 1, 2,3,6-tetrahydropyridino, 1, 4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazole, dihydrooxazole, dihydrooxadiazole, dihydrotazole, 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo [2.2.1] heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like. "Heterocyclenylalkyl" means a heterocyclenyl moiety as defined above linked through an alkyl moiety (defined above) to a parent nucleus. It should be noted that in ring systems containing heteroatoms of this invention, there are no hydroxyl groups on carbon atoms adjacent to an N, O or S, just as there are no N or S groups on carbon adjacent to another heteroatom. Therefore, for example, in the ring: there is no -OH attached directly to carbons marked 2 and 5. It should be noted that the tautomeric forms such as, for example, the portions: they are considered equivalent in certain embodiments of this invention. "Acyl" means a group H-C (O) -, alkyl-C (O) - or cycloalkyl-C (O) -, in which the various groups are as described above. The binding to the progenitor part is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl. "Aroyl" means an aryl-C (O) - group in which the aryl group is as described above. The binding to the progenitor portion is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1-naphthoyl. "Alkoxy" means an alkyl-O- group in which the alkyl group is as described above. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The binding to the progenitor portion is through the oxygen of the ether. "Aryloxy" means an aryl-O- group in which the aryl group is as described above. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The binding to the progenitor portion is through the oxygen of the ether. "Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as described above. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The binding to the progenitor portion is through the oxygen of the ether. "Alkylthio" means an alkyl-S- group in which the alkyl group is as described above. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The binding to the progenitor portion is through sulfur. "Arylthio" means an aryl-S- group in which the aryl group is as described above. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The binding to the progenitor portion is through sulfur. "Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as described above. A non-limiting example of a suitable aralkylthio group is benzylthio. The binding to the progenitor portion is through sulfur. "Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The binding to the progenitor portion is through the carbonyl. "Aryloxycarbonyl" means an aryl-O-C (O) - group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The binding to the progenitor portion is through the carbonyl. "Aralkoxycarbonyl" means an aralkyl-O-C (O) - group. A non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The binding to the progenitor portion is through the carbonyl. "Alkylsulfonyl" means an alkyl-S (02) - group. Preferred groups are those in which the alkyl group is lower alkyl. The binding to the progenitor portion is through the sulfonyl. "Arylsulfonyl" means an aryl-S (02) - group. The binding to the progenitor portion is through the sulfonyl.

"Hydroxyalkyl" means an HO-alkyl- group in which alkyl is as defined above. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection of the indicated group, provided that the normal valence of the designated atom under the existing circumstances is not exceeded, and that the substitution results in a stable compound . Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity of a reaction mixture, and formulation into an effective therapeutic agent. The term "optionally substituted" means optional substitution with the groups, radicals or specified portions. The term "purified", "in purified form", "isolated", or "in isolated and purified form" for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof. same. Therefore, the term "purified", "in purified form", "isolated", or "in isolated and purified form" for a compound refers to the physical state of said compound after being obtained from a described purification process or procedures here or well known to the person skilled in the art, in sufficient purity to be characterized by standard analytical techniques described herein or well known to the person skilled in the art. It should also be noted that any carbon as well as heteroatom with valences not satisfied in the text, schemes, examples and tables here is assumed to have a sufficient number of hydrogen atom (s) to satisfy the valences. When a functional group in a compound is called "protected", this means that the group is in modified form to avoid unwanted side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those skilled in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York. When any variable (eg, aryl, heterocycle, R2, etc.) occurs more than once in any constituent or in formula I, its definition in each occurrence is independent of its definition in each other occurrence. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from the combination of the specified ingredients in the specified amounts.

The compounds of formulas I-VI can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention encompass both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent binding, including hydrogen bonding. In certain cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" covers both solvates in the solution phase and solvates that can be isolated. Non-limiting examples of suitable solvates include ethanolates, methanolates and the like. "Hydrates" is a solvate in which the solvent molecule is H20. One or more compounds of the invention may also exist as, or optionally converge to, a solvate. The preparation of solvates is generally known. Therefore, for example, M. Caira et al, J. Pharmaceutical Sci., 93 (3), 601-611 (2004) describe the preparation of the fluconazole antifungal solvates in ethyl acetate as well as water. Similar preparations of solvates, hemisolvate, hydrates and the like are described in E. C. van Tonder et al, AAPS PharmSciTech., 5 (1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). A typical, non-limiting procedure involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a temperature higher than room temperature, and cooling the solution at a sufficient rate to form crystals which then They are isolated by standard methods. Analytical techniques such as, for example, R.R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate). "Effective amount" or "therapeutically effective amount" describes an amount of compound or composition of the present invention effective to inhibit the above-indicated diseases and thereby produce the desired therapeutic, relieving, inhibiting or preventive effect. The compounds of the formulas I-VI can form salts that are also within the scope of this invention. The reference to a compound of the formulas I-VI herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt (s)", as used herein, denotes acid salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. Further, when a compound of the formulas I-VI contains both a basic portion, such as, but not limited to a pyridine or imidazole, and an acid portion, such as, but not limited to a carboxylic acid, zwitterions ("internal salts") ") can be formed and included within the term" salt (s) "as used herein. The pharmaceutically acceptable salts (ie, physiologically acceptable, non-toxic) are preferred, although other salts are also useful. The salts of the compounds of the formulas I-VI can be formed, for example, by reacting a compound of the formulas I-VI with an amount of acid or base, such as an equivalent amount, in a medium such as one in the which salt is precipitated or in an aqueous medium followed by lyophilization. As used before, and throughout this description, the following terms, unless otherwise indicated, should be understood to have the following meanings: "Patient" includes both humans and animals. "Mammal" means humans and other mammalian animals. "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched chain and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain from about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain from about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having from about 1 to about 6 carbon atoms in the chain which may be straight or branched chain.

"Alkyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino , -NH (alkyl), -NH (cycloalkyl), -N (alkyl) 2, carboxy, oxime (v.gr. = N-OH)), and -C (0) 0-alkyl.

Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl. "Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched chain and comprising from about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have from about 2 to about 12 carbon atoms in the chain; and most preferably from about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means from about 2 to about 6 carbon atoms in the chain which may be straight or branched chain. "Alkenyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, cyano, alkoxy and -S (alkyl) . Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl. "Alkylene" means a difunctional group obtained by the removal of a hydrogen atom from an alkyl group defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene. "Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched chain and comprising from about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have from about 2 to about 12 carbon atoms in the chain; and most preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means from about 2 to about 6 carbon atoms in the chain which may be straight or branched chain. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. "Alkynyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl. "Aryl" means an aromatic monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms, preferably from about 6 to about 10 carbon atoms. The aryl group may be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. "Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising from about 5 to about 14 ring atoms, preferably from about 5 to about 10 ring atoms, in which one or more of the ring atoms is a distinct element carbon, for example, nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain from about 5 to about 6 ring atoms. The "heteroaryl" may be optionally substituted by one or more "ring system substituents" which may be the same or different, and they are as defined here. The prefix aza, oxa or thia before the heteroaryl root name means that at least one of a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isotazolyl, oxazolyl, tazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,4- tadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo [1,2- a] pyridinyl, imidazo [2,1-btazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazole, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,4-triazinyl, benzotazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.

"Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as described above. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The binding to the progenitor portion is through the alkyl. "Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as described above. Preferred alkylaryls comprise a lower alkyl group. A non-limiting example of a suitable alkylaryl group is tolyl. The union to the progenitor portion is through the aril. "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising from about 3 to about 10 carbon atoms, preferably from about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain from about 5 to about 7 ring atoms. The cycloalkyl may be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like. "Cycloalkylalkyl" means a cycloalkyl portion are as defined above linked through an alkyl moiety (defined above) to a parent nucleus. Non-limiting examples of suitable cycloalkylalkyl include cyclohexylmethyl, adamantylmethyl and the like. "Cycloalkenyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms containing at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain from about 5 to about 7 ring atoms. The cycloalkenyl may be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like. A non-limiting example of a suitable multiciclic cycloalkenyl is norbornylenyl. "Cycloalkenylalkyl" means a cycloalkenyl moiety as defined above linked through an alkyl moiety (defined above) to a parent nucleus. Non-limiting examples of suitable cycloalkenylalkyl include cyclopentenylmethyl, cyclohexenylmethyl and the like. "Halogen" or "halo" means fluorine, chlorine, bromine or iodine. Fluoro, chloro and bromo are preferred. "Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system that, for example, replaces a hydrogen available in the ring system. The ring system substituents may be the same or different, each independently being selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy , aryloxy, aralkoxy, acyl, aroyl, halogen, nitro, cyano, carboxy, alkoxycarbonyl, oxime (e.g., -C (= N-OH)), aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, -C (= N-CN) -NH2, -C (= NH) -NH2, -C (= NH) -NH (alkyl), Y ^ N-, Y1Y2N-alkyl -, Y ^ NCÍO) -, YÍY2NS02- and -S02NY-? Y2, where Y- \ and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl. "Ring system substituent" can also mean a single portion that simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) in a ring system. Examples of said portions are metylenedioxy, ethylenedioxy, -C (CH3) 2- and the like forming portions such as, for example: "Heteroarylalkyl" means a heteroaryl portion as defined above linked by an alkyl moiety (defined above) to a parent nucleus. Non-limiting examples of suitable heteroarylalkyl include 2-pyridinylmethyl, quinolinylmethyl and the like.

"Heterocyclyl" means a saturated non-aromatic monocyclic or multicyclic ring system comprising from about 3 to about 10 ring atoms, preferably from about 5 to about 10 ring atoms, in which one or more of the atoms in the system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and / or sulfur atoms present in the system. Preferred heterocyclyls contain from about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclic root name means that at least one nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, a group -N (Boc), -N (CBz), -N (Tos) and the like; said protections are also considered part of this invention. The heterocyclyl may be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl may be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of non-limiting monocyclic heterocyclic rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like. "Heterocyclyl" may also mean a single portion (e.g., carbonyl) that simultaneously replaces two available hydrogens on the same carbon atom in a ring system. An example of such a portion is pyrrolidone: "Heterocyclylalkyl" means a heterocyclyl moiety, as defined above, linked through an alkyl moiety (defined above) to a parent nucleus. Non-limiting examples of suitable heterocyclylalkyl include piperidinylmethyl, piperazinylmethyl and the like. "Heterocyclenyl" means a non-aromatic monocyclic or multicyclic ring system comprising from about 3 to about 10 ring atoms, preferably from about 5 to about 10 ring atoms, in which one or more of the atoms in the system is a element other than carbon, for example, nitrogen, oxygen or sulfur atom, alone or in combination, and containing at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and / or sulfur atoms present in the system. Preferred heterocyclenyl rings contain from about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least one nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can optionally be oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable heterocyclenyl groups include 1, 2,3,4-tetrahydropyridino, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1, 2,3,6-tetrahydropyridino, 1, 4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazole, dihydrooxazole, dihydrooxadiazole, dihydrotazole, 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo [2.2.1] heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like. "Heterocyclenyl" can also mean a single portion (e.g., carbonyl) that simultaneously replaces two available hydrogens on the same carbon atom in a ring system. An example of such a portion is pyrrolidinone: "Heterocyclenylalkyl" means a heterocyclenyl moiety as defined above linked through an alkyl moiety (defined above) to a parent nucleus. It should be noted that in ring systems containing heteroatoms of this invention, there are no hydroxyl groups on carbon atoms adjacent to an N, O or S, just as there are no N or S groups on carbon adjacent to another heteroatom. Therefore, for example, in the ring: there is no -OH attached directly to carbons marked 2 and 5. It should be noted that the tautomeric forms such as, for example, the portions: they are considered equivalent in certain embodiments of this invention. "Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as described above. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The binding to the progenitor portion is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl. "Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as described above. Preferred heteroalkyl contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The binding to the progenitor portion is through the alkyl. "Hydroxyalkyl" means an HO-alkyl- group in which alkyl is as defined above. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. "Acyl" means a group H-C (O) -, alkyl-C (O) - or cycloalkyl-C (O) -, in which the various groups are as described above. The binding to the progenitor part is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl. "Aroyl" means an aryl-C (O) - group in which the aryl group is as described above. The binding to the progenitor portion is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1-naphthoyl. "Alkoxy" means an alkyl-O- group in which the alkyl group is as described above. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The binding to the progenitor portion is through the oxygen of the ether. "Aryloxy" means an aryl-O- group in which the aryl group is as described above. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The binding to the progenitor portion is through the oxygen of the ether. "Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as described above. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The binding to the progenitor portion is through the oxygen of the ether. "Alkylthio" means an alkyl-S- group in which the alkyl group is as described above. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The binding to the progenitor portion is through sulfur. "Arylthio" means an aryl-S- group in which the aryl group is as described above. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The binding to the progenitor portion is through sulfur. "Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as described above. A non-limiting example of a suitable aralkylthio group is benzylthio. The binding to the progenitor portion is through sulfur. "Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The binding to the progenitor portion is through the carbonyl. "Aryloxycarbonyl" means an aryl-O-C (O) - group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The binding to the progenitor portion is through the carbonyl. "Aralkoxycarbonyl" means an aralkyl-O-C (O) - group. A non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The binding to the progenitor portion is through the carbonyl. "Alkylsulfonyl" means an alkyl-S (02) - group. Preferred groups are those in which the alkyl group is lower alkyl. The binding to the progenitor portion is through the sulfonyl.

"Arylsulfonyl" means an aryl-S (02) - group. The binding to the progenitor portion is through the sulfonyl. The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection of the indicated group, provided that the normal valence of the designated atom under the existing circumstances is not exceeded, and that the substitution results in a stable compound . Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity of a reaction mixture, and formulation into an effective therapeutic agent.The term "optionally substituted" means optional substitution. with the groups, radicals or specified portions The term "purified", "in purified form", "isolated", or "in isolated and purified form" for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof Thus, the term "purified", "in purified form", "isolated", or "in isolated and purified form" for a compound refers to the physical state of said compound after obtaining a purification procedure or procedures described herein or well known to the person skilled in the art, in sufficient purity to be characterized by anal techniques standard standards described here or well known to the person skilled in the art. It should also be noted that any carbon as well as heteroatom with valences not satisfied in the text, schemes, examples and tables here is assumed to have a sufficient number of hydrogen atom (s) to satisfy the valences. When a functional group in a compound is called "protected", this means that the group is in modified form to avoid unwanted side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those skilled in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York. When any variable (eg, aryl, heterocycle, R2, etc.) occurs more than once in any constituent or in formula I, its definition in each occurrence is independent of its definition in each other occurrence. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from the combination of the specified ingredients in the specified amounts. Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T.

Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of A. C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g., a drug precursor) that is transformed in vivo to give a compound shown above as being useful in the methods of this invention or a pharmaceutically acceptable salt, hydrate or solvate of the compound . The transformation can occur by several mechanisms (eg, by metabolic or chemical processes), such as, for example, through hydrolysis in the blood. A discussion of the use of prodrugs is provided in T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A. C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. For example, whether a compound shown above as being useful in the methods of this invention or a salt, pharmaceutically acceptable hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, alkylic CrCß), alkanoyloxymethyl (C2-C? 2), 1- (alkanoyloxy) ethyl having from 4 to 9 carbon atoms, 1-methyl-1 - (alkanoyloxy) -ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms , 1- (alkoxycarbonyloxy) ethyl having from 4 to 7 carbon atoms, 1- methyl-1- (alkoxycarbonyloxy) ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having from 3 to 9 atoms of carbon, 1- (N- (alkoxycarbonyl) amino) ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N, N-alkylamino (C1-) C2) -alkyl (C2-C3) (such as β-dimethylaminoethyl), carbamoyl- (CrC2) alkyl, N, N-dialkylcarbamoyl (CrC-2) -alkyl (C C2) and piperidino-, pyrrolidino- or morpholino-C2-C3 alkyl, and the like. Similarly, if a compound shown above as being useful in the methods of this invention contains an alcohol functional group, a prodrug can be formed by replacing the hydrogen atom of the alcohol group with a group such as, for example, alkanoyloxymethyl (CrC6) ), 1- (alkanoyloxy (C6)) ethyl, 1-methyl-1- ((C6) alkanoyloxy) ethyl, alkoxycarbonyloxymethyl (CrC6), N-alkoxycarbonyloaminomethyl (CrC6), succinoyl, alkanoyl (Cr-C6), a -amino-alkanoylCi.C), arylacyl and a-aminoacyl, or a-aminoacylo-a-aminoacyl, wherein each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, P (0) (OH ) 2, -P (0) (0-C6 alkyl) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group from the hemiacetal form of a carbohydrate), and the like. If a compound shown above to be useful in the methods of this invention incorporates an amine functional group, a prodrug can be formed by replacing a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO -carbonyl, NRR'-carbonyl wherein R and R 'are each independently alkyl (C -? - C? o), cycloalkyl (C3-C), benzyl, or R-carbonyl is a natural a-aminoacyl or a-aminoacyl natural, -C (OH) C (O) OY1 wherein Y1 is H, alkyl of (d-C6) or benzyl, -C (OY2) Y3 wherein Y2 is alkyl (CC) and Y3 is alkyl (C6) , carboxy-alkyl (CrC6), amino-alkyl (C? -C) or mono-N- or di-N, N-alkylaminoalkyl (C C6), -C (Y4) Y5 wherein Y4 is H or methyl and Y5 is mono-N- or di-N, N-alkylaminomorpholino (CrC6), piperidin-1-yl or pyrrolidin-1-yl, and the like. One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention encompass both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" covers both solvates in the solution phase and solvates that can be isolated. Non-limiting examples of suitable solvates include ethanolates, methanolates and the like. "Hydrates" is a solvate in which the solvent molecule is H20. One or more compounds shown above as being useful in the methods of this invention of the invention can optionally be converted to a solvate. The preparation of solvates is generally known. Therefore, for example, M. Caira et al, J. Pharmaceutical Sci, 93 (3), 601-611 (2004) describe the preparation of the fluconazole antifungal solvates in ethyl acetate as well as water. Similar preparations of solvates, hemisolvate, hydrates and the like are described in E. C. van Tonder et al., AAPS PharmSciTech., 5 (1), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). A typical, non-limiting procedure involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a temperature higher than room temperature, and cooling the solution at a sufficient rate to form crystals which then They are isolated by standard methods. Analytical techniques such as, for example, R.R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate). "Effective amount" or "therapeutically effective amount" describes an amount of compound or composition of the present invention effective to inhibit the above-indicated diseases and thereby produce the desired therapeutic, relieving, inhibiting or preventive effect. The compounds shown above as being useful in the methods of this invention can form salts that are also within the scope of this invention. The reference to a compound shown above as being useful in the methods of this invention is understood to include reference to salts thereof, unless otherwise indicated.

The term "salt (s)", as used herein, denotes acid salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. Further, when a compound shown above as being useful in the methods of this invention contains both a basic portion, such as, but not limited to a pyridine or imidazole, and an acid portion, such as, but not limited to a carboxylic acid, zwitterions ("internal salts") can be formed and included within the term "salt (s)" as used herein. Pharmaceutically acceptable salts (ie, physiologically acceptable, non-toxic) are preferred, although other salts are also useful. Salts of the compounds shown above as being useful in the methods of this invention can be formed, for example, by reacting a compound shown above as being useful in the methods of this invention with an amount of acid or base, such as an amount equivalent, in a medium such as one in which the salt is precipitated or in an aqueous medium followed by lyophilization. Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, iodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. In addition, acids which are generally considered suitable for the formation of pharmaceutically useful salts of basic pharmaceutical compounds are described, for example, in P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food &Drug Administration, Washington, D.C. on their website). These descriptions are incorporated herein by reference to the same. Illustrative basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g., organic amines) such as dicyclohexylamines, t -butylamines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen containing groups may be quartered with agents such as lower alkyl halides (e.g., methyl, ethyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl and dibutyl), long chain halides (e.g., decyl, lauryl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. All such acid salts and basic salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acidic and basic salts are considered equivalent to the free forms of the corresponding compounds for the purposes of the invention. The pharmaceutically acceptable esters of the present compounds include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl portion of the carboxylic acid moiety of the ester group is selected from alkyl straight or branched chain (e.g., acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (e.g., methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenoxymethyl), aryl ( for example, phenyl optionally substituted with, for example, halogen, C? -4 alquilo alkyl, or C C1- alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (e.g., methanesulfonyl); (3) amino acid esters (e.g., L-valyl or L-isoleucyl); (4) phosphonate esters and (5) esters of mono-, di- or triphosphate. The phosphate esters can be further esterified, for example, by a C-α-20 alcohol or a reactive derivative thereof, or by a 2,3-diacyl (C 6-24) -glycerol. The compounds of the formulas I to VI, as well as the compounds described in co-pending patent applications Nos. (Cases of attorney-in-fact Nos. OC01617K3, OC01618K2 and OC01619K2) filed on the same date as the present one, and salts, solvates, esters and prodrugs thereof, may exist in their tautomeric form (for example, as an amide ether or imino). All of these tautomeric forms are contemplated herein as part of the present invention. The compounds of the formulas I to VI, as well as the compounds described in co-pending patent applications Nos. (Cases of proxy No. OC01617K3, OC01618K2 and OC01619K2) filed on the same date as the present may contain asymmetric or chiral centers, and , therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of formulas I to VI, as well as the compounds described in co-pending patent applications Nos. (Cases of proxy No. OC01617K3, OC01618K2 and OC01619K2) filed on the same date as the present one, as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention encompasses all geometric and positional isomers. For example, if a compound of the formulas I to VI, as well as the compounds described in co-pending patent applications Nos. (Cases of proxy No. OC01617K3, OC01618K2 and OC01619K2) presented on the same date as the present incorporate a double bond or a fused ring, both the cis and trans forms, as well as mixtures, are encompassed within the scope of the invention. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physicochemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. The enantiomers can be separated by conversion of the enantiomeric forms to diastereomeric forms by reaction with an appropriate optimally active compound (e.g., chiral auxiliaries such as a chiral alcohol or acid chloride from Mosher), separating the diastereomers and converting (v. gr., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of the formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. The enantiomers can also be separated using chiral HPLC column. It is also possible that the compounds shown above as being useful in the methods of this invention can exist in different tautomeric forms, and such forms are encompassed within the scope of the invention. Also, for example, all forms of keto-enol and imine-enamine of the compounds are included in the invention. All stereoisomers (e.g., geometric isomers, optical isomers and the like) of the present compounds (including those of salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those may exist due to asymmetric carbons in various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are included within the scope of this invention, as positional isomers (such as , for example, 4-pyridyl and 3-pyridyl). (For example, if a compound shown above as being useful in the methods of this invention incorporates a double bond or a fused ring, both the cis and trans forms, as well as mixtures, are encompassed within the scope of the invention. for example, all forms of keto-enol and imine-enamine of the compounds are included in the invention.) The individual stereoisomers of the compounds of the invention, for example, may be substantially free of other isomers, or may be mixed, for example, as racemates or with all others, or others selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the recommendations of lUPAC 1974. The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to is also applied to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds. The present invention also encompasses isotopically-labeled compounds of the present invention which are identical to those mentioned herein, except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include hydrogen isotopes, carbon, nitrogen, oxygen, phosphorus, fluorine and dorio, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, and 36CI, respectively. Certain isotopically-labeled compounds of compounds of the formulas I to VI, as well as the compounds described in the co-pending patent applications No. series (attorney-in-fact cases Nos. OC01617K3, OC01618K2 and OC01619K2) filed on the same date as the present one (v.gr) ., those marked with 3H and 14C) are useful in tests of distribution of compound and / or substrate tissue. Tritiated (ie, 3H) and carbon-14 (ie, 1 C) isotopes are particularly preferred for their ease of preparation and detection ability. In addition, replacement with heavier isotopes such as deuterium (i.e., 2H) can give certain therapeutic advantages that result in greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements) and therefore can be preferred in some circumstances. Isotopically-labeled compounds shown above as being useful in the methods of this invention can generally be prepared following procedures analogous to those described in the schemes and / or examples given below, using an appropriate isotopically-labeled agent instead of a non-reactive agent. isotopically marked Polymorphic forms of the compounds shown above as being useful in the methods of this invention, and of the salts, solvates, esters and prodrugs of the compounds shown above as being useful in the methods of this invention, are intended to be included herein invention. The compounds according to the invention can have pharmacological properties; in particular, the compounds of the formulas I to VI, as well as the compounds described in co-pending patent applications Nos. (cases of proxy No. OC01617K3, OC01618K2 and OC01619K2) filed on the same date as the present may be inhibitors, regulators or protein kinase modulators. Non-limiting examples of protein kinases that can be inhibited, regulated or modulated include CHK cinases, such as CHK1 and CHK2, Akt kinases, Pimin cinases, tyrosine cinases, such as the HER subfamily (including, for example, EGFR (HER1), HER2, HER3 and HER4), the insulin subfamily (including, for example, INS-R, IGF-IR, IR, and IR-R), the subfamily of PDGF (including, for example, PDGF-alpha and beta receptors, CSFIR, c-kit and FLK-II), the FLK family (including, for example, kinase insert domain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and the kinase similar to fms-1 (flt-1)), non-receptor protein tyrosine kinases, for example LCK, Src, Frk, Btk, Csk, Abl, Zap70, Fes / Fps, Fak, Jak , Ack, and LIMK, tyrosine kinases of growth factor receptor such as VEGF-R2, FGF-R, TEK, and the like. The compounds of the formulas I to VI, as well as the compounds described in copending patent applications series Nos. (Case of proxy No. OC01617K3, OC01618K2 and OC01619K2) filed on the same date as the present may be inhibitors of protein cinases such as , for example, checkpoint inhibitors such as CHK1, CHK2 and the like. Preferred compounds can have Cl50 values of less than about 5 μm, preferably about 0.001 to about 1.0 μm, and most preferably about 0.001 to about 0.1 μm. For example, the compounds shown in Table 1 exhibited CHK1 inhibitory activity (Cl50) of the values shown therein. The test methods are described in the examples discussed below.

TABLE 1 In any of the above methods, the compounds of the formulas I to VI, as well as the compounds described in co-pending patent applications Nos. (Cases of proxy No. OC01617K3, OC01618K2 and OC01619K2) filed on the same date as the present may be co-administered with one or more anticancer agents that are chemically different from the compounds of the formulas I to VI, as well as the compounds described in the co-pending patent applications.

Nos. (Proxy cases Nos. OC01617K3, OC01618K2 and OC01619K2) filed the same date as the present one, that is, they contain different atoms, dispositions of atoms, etc. Non-limiting examples of suitable anticancer agents include cytostatic agents, cytotoxic agents (such as for example, but not limited to, DNA interactive agents (such as cisplatin or doxorubicin)); taxanes (e.g., taxotero, taxol); topoisomerase II inhibitors (such as etoposide); topoisomerase I inhibitors (such as irinotecan (or CPT-11), camptostar, or topotecan); interacting agents with tubulin (such as paclitaxel, docetaxel or the epothilones); hormonal agents (such as tamoxifen); thymidylate synthase inhibitors (such as 5-fluorouracil); antimetabolites (such as methotrexate); alkylating agents (such as temozolomide (TEMODAR ™ from Schering-Plow Corporation, Kenilworth, New Jersey), cyclophosphamide); famesyl transferase protein inhibitors (such as, SARASAR ™ (4- [2- [4 - [(11 R) -3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridin-11-yl] - 1-piperidinyl] -2-oxoethyl] -1-piperidinecarboxamide, or SCH 66336 from Schering-Plow Corporation, Kenilworth, New Jersey), tipifarnib (Zarnestra® or R115777 from Janssen Pharmaceuticals), L778.123 (a farnesyl transferase protein inhibitor from Merck &Company, Whitehouse Station, New Jersey), BMS 214662 (a farnesyl transferase protein inhibitor from Bristol-Myers Squibb Pharmaceuticals, Princeton, New Jersey) signal transduction inhibitors (such as, Iressa (from Astra Zeneca Pharmaceuticals, England), Tarceva (EGFR kinase inhibitors), antibodies to EGFR (e.g., C225), GLEEVEC ™ (C-abl kinase inhibitor), Novartis Pharmaceuticals, East Hanover, New Jersey), interferons such as, for example, intron (from Schering-Plow Corporation), Peg-lntron (from Schering-Plow Corporation); it's about hormone therapy; aromatase combinations; ara-C, adriamycin, Citoxan, Clofarabine (Clolar® from Genzyme Oncology, Cambridge, Massachusetts), cladribine (Leustat® from Janssen-Cilag Ltd.), afídicolon, rituxan (from Genentech / Biogen Idee), sunitiníb (Sutent® from Pfizer ), dasatinib (or BMS-354825 from Bristol-Myers Squibb), tezacitabine (from Aventis Pharma), SmM, fludarabine (from Trigan Oncology Associates), pentostatin (from BC Cancer Agency), triapine (from Vion Pharmaceuticals), didox (from Bioseeker Group), trimidox (from ALS Therapy Development Foundation), amidox, 3-AP (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), MDL-101, 731 ((E) -2'-deoxy-2 '- (fluoromethylene) citidine) and gemcitabine. Other anticancer agents (also known as antineoplastics) include but are not limited to uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Citarabine, 6-Mercaptopurine , 6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, oxaliplatin (ELOXATIN ™ from Sanofi- Synthelabo Pharmaceuticals, France), Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxicoformycin, Mithomycin-C, L-Asparaginase, Teniposide 17a-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrol acetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesterone acetate, Leuprolide, Flutamide, Toremifene, Goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine , Droloxafine, Hexamethylmelamine, Avastin, Herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Profimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melfalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225 and Campat . If formulated as a fixed dose, said combination products use the compounds of this invention within the dose range described herein and the other pharmaceutically active agent or treatment within their dose range. For example, it has been found that the CDC2 inhibitor olomucine acts synergistically with known cytotoxic agents in the induction of apoptosis (J. Cell Sci, (1995) 108. 2897. The compounds of the formulas I to VI can also be administered sequentially with known anticancer or cytotoxic agents when a combination formulation is inappropriate The invention is not limited to any particular sequence of administration; compounds of the formulas I to VI, as well as the compounds described in co-pending patent applications Nos. (cases of attorney-in-fact Nos. OC01617K3, OC01618K2 and OC01619K2) filed on the same date as the present may be administered either before, during or after the administration of the known anticancer or cytotoxic agent (s) listed above. For example, the cytotoxic activity of the cyclin-dependent kinase inhibitor flavopiridol is affected by the sequence of administration with anticancer agents. Cancer Research, (1997) 57, 3375. Such techniques are within the ability of those skilled in the art as well as physicians and should be considered as part of this invention. Accordingly, in one aspect, the methods of this invention include combinations comprising an amount of at least one compound of any of formulas I to VI, as well as the compounds described in the co-pending patent applications Nos. proxied Nos. OC01617K3, OC01618K2 and OC01619K2) filed on the same date as the present, or a pharmaceutically acceptable salt or solvate thereof, and an amount of one or more anticancer treatments and / or anticancer agents listed above wherein the amounts of the compounds / treatments result in a desired therapeutic effect. Another aspect of the present invention is a method for inhibiting one or more check point kinases in a patient in need thereof, which comprises administering to the patient a therapeutically effective amount of at least one compound of any of formulas I to VI , as well as the compounds described in co-pending patent applications Nos. (cases of attorney-in-fact Nos. OC01617K3, OC01618K2 and OC01619K2) filed the same date as the present one or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. Another aspect of the present invention is a method for treating, or slowing the progression of, a disease associated with one or more checkpoint kinases in a patient in need thereof, which comprises administering a therapeutically effective amount of minus a compound of any of formulas 1 to VI, as well as the compounds described in the co-pending patent applications Nos. (cases of attorney-in-fact Nos. OC01617K3, OC01618K2 and OC01619K2) filed on the same date as the present one or a salt, solvate , pharmaceutically acceptable ester or prodrug thereof. Yet another aspect of the present invention is a method for treating one or more diseases associated with kinase checkpoint, which comprises administering to a mammal in need of such treatment an amount of a first compound, which is a compound of any of the formulas I to VI, as well as the compounds described in co-pending patent applications Nos. (cases of proxy No. OC01617K3, OC01618K2 and OC01619K2) filed on the same date as the present one, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and an amount of at least one second compound, the second compound being an anticancer agent, wherein the amounts of the first compound and the second compound result in a therapeutic effect. Another aspect of the present invention is a method for treating, or slowing down the progression of, a disease associated with one or more check point kinases in a patient in need thereof, which comprises administering a therapeutically effective amount of a composition. Pharmaceutical comprising in combination at least one pharmaceutically acceptable carrier and at least one compound of any of the formulas I to VI, as well as the compounds described in co-pending patent applications Nos. (cases of proxy) Nos. OC01617K3, OC01618K2 and OC01619K2) filed on the same date as the present one, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. In the above methods, the checkpoint kinase to be inhibited may be CHK1 and / or CHK2. In the tyrosine kinase treatment methods described above, the tyrosine kinase can be VEGFR2, EGFR, HER2, SRC, JAK and / or TEK. The pharmacological properties of the compounds of this invention can be confirmed by a number of pharmacological tests.

The illustrated pharmacological tests described below have been carried out with compounds according to the invention and their salts, solvates, esters or prodrugs. This invention is also directed to methods using pharmaceutical compositions comprising at least one compound of any of the formulas I to VI, as well as the compounds described in co-pending patent applications No. (cases of proxy No. OC01617K3, OC01618K2 and OC01619K2) filed on the same date as the present, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound and at least one pharmaceutically acceptable carrier. To prepare pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be composed of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions can be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th edition, (1990), Mack Publishing Co., Easton, Pennsylvania. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or the addition of sweeteners and opacifiers for solutions, suspensions and oral emulsions. Liquid form preparations may also include solutions for intranasal administration. Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen. Also included are solid form preparations which are intended to be converted, shortly before use, into liquid form preparations for either oral or parenteral administration. Said liquid forms include solutions, suspensions and emulsions. The compounds of the invention can also be delivered transdermally. The transdermal compositions can take the form of cracks, lotions, aerosols and / or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose. The compounds of this invention can also be delivered subcutaneously. Preferably, the compound is administered orally or intravenously. Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate amounts of the active component, e.g., an effective amount to achieve the desired purpose. The amount of active compound in a unit dose of preparation can be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, most preferably from about 1 mg to about 25 mg, in accordance with particular application. The actual dose used can be varied depending on the requirements of the patient and the severity of the condition being treated. The determination of the appropriate dosage regimen for a particular situation is within the scope of the art. For convenience, the total daily dose can be divided and administered in portions during the day as required. The amount and frequency of administration of the compounds of the invention and / or the pharmaceutically acceptable salts thereof will be regulated in accordance with the physician's judgment considering factors such as age, condition and size of the patient as well as the severity of the symptoms that are being treated. A typical recommended daily dose regimen for oral administration may vary from about 1 mg / day to about 500 mg / day, preferably 1 mg / day to 200 mg / day, in two to four divided doses. The methods of the present invention can use an equipment comprising a therapeutically effective amount of at least one compound of the formulas I-VI, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound and a pharmaceutically carrier, vehicle or diluent. acceptable. The methods of the present invention can use an equipment comprising an amount of at least one compound of any of the formulas I to VI, as well as the compounds described in co-pending patent applications Nos. (Proxy case No. OC01617K3 , OC01618K2 and OC01619K2) filed on the same date as the present, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound and an amount of at least one anti-cancer therapy and / or anticancer agent listed above, wherein the amounts of the two or more ingredients result in a desired therapeutic effect. The invention described herein as illustrated by the following preparations and examples which should not be considered to limit the scope of the description. Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art. Where NMR data are presented, 1H spectra were obtained in either a Varian VXR-200 (200 MHz, 1 H), Varian Gemini-300 (300 MHz) or XL-400 (400 MHz) and reported as ppm below Me4Si with number of protons, multiplicities and coupling constants in Hertz indicated parentéticalmante. Where CL / MS data are presented, analyzes are performed using an Applied Biosystems API-100 mass spectrometer and Shimadzu SCL-10A CL column: Altech platinum C18, 3 microns, 33mm x 7mm ID; gradient flow: 0 min - 10% CH3CN, 5 min - 95% CH3CN, 7 min - 95% CH3CN, 7.5 min - 10% CH3CN, 9 min - stopping. The retention time and the observed parent ion are given. The following solvents and reagents can be referred to by their abbreviations in parentheses: Thin layer chromatography: CCD dichloromethane: CH2Cl2 ethyl acetate: AcOEt or EtOAc methanol: MeOH trifluoroacetate: TFA triethylamine: Et3N or TEA butoxycarbonyl: n-Boc or Boc spectroscopy nuclear magnetic resonance: NMR liquid chromatography / mass spectrometry: LC / MS high resolution mass spectrometry: HRMS milliliters: ml millimoles: mmoles microliters: μl grams: g milligrams: mg ambient temperature or temperature (room): approximately 25 ° C. dimethoxyethane: DME The preparation of the compounds of the formula VI (in the copending application No. series (case of proxy No. OC06284US01 filed on the same date as the present one) is illustrated below: PREPARED EXAMPLE 1 SO2 (18.5 ml) was slowly added under N2 to a stirred mixture of the acid (50.0 g, 218 mmol) and pyridine (44.0 ml) in anhydrous CH2Cl2 (300 ml). The mixture was stirred at 25 ° C for 20 min, then Meldrum acid (35.0 g, 243 mmol) and DMAP (66.6 g, 546 mmol) were added and the mixture was stirred under N2 for 1 hr. Then, Et 2 O (2 L) was added, the mixture was washed with 1 M HCl (3 × 500 ml), brine (500 ml), and the organic layer was dried over Na 2 SO 4, filtered, and the solvent was evaporated. The residue was dissolved in MeOH (580 ml), and the mixture was refluxed for 4 hr. The solvent was evaporated and the residue was purified by column chromatography on silica gel with 10: 1 CH2Cl2 / EtOAc as eluent. A pale yellow oil was obtained (26.5 g, 43%).

PREPARED EXAMPLE 2 A mixture of the beta-ketoester of preparative example 1 (20.0 g, 70. 1 mmol) and 3-aminopyrazole (5.40 g, 65.0 mmol) in anhydrous toluene (60 ml) was stirred and refluxed under N2 for 24 hr. The solvent was evaporated and the residue was purified by column chromatography on silica gel with 20: 1 of CH CI2 / MeOH as eluent. A white solid was obtained (15.0 g, 73%). LC-MS: 319 [M + H].

PREPARED EXAMPLE 3-4 Essentially by the same procedure set forth in Preparative Example 2, combining 3-aminopyrazole with the corresponding beta-ketoesters, the compounds given in column 1 of Table 1A were prepared.

TABLE 1A PREPARED EXAMPLE 5 A solution of Br2 (1.06 g, 6.67 mmol) in CH2Cl2 (5 mL) was added under N2 to a stirred solution of the product of Preparative Example 2 (2.12 g, 6.67 mmol) in t-BuNH2 (20 mL). The mixture was stirred for 18 hr, the solvents were evaporated, and the residue was purified by column chromatography on silica gel with CH2Cl2 / MeOH 20: 1 as eluent. A slightly gray solid was obtained (1.98 g, 75%). LC-MS: 399 [M + H].

PREPARED EXAMPLE 6 A mixture of the product from Preparative Example 5 (1.40 g, 3.53 mmol), N, N-dimethylaniline (853 mg, 7.06 mmol), and POCI3 (6 mL) was stirred at 50CC for 3 days. The excess of POCI3 was evaporated and the residue was purified by column chromatography on silica gel with CH2Cl2 / EtOAc 20: 1 as eluent. A colorless solid foam (830 mg, 57%) was obtained. LC-MS: 417 [M + H].

PREPARATORY EXAMPLE 7-8 Essentially by the same procedure set forth in preparative example 6, the compounds given in column 1 of table 2 were prepared.

TABLE 2 PREPARED EXAMPLE 9 A solution of NBS (2.66 g, 14.9 mmoles) in anhydrous CH3CN (20 ml) was added under N2 to a stirred solution of the product from preparative example 8 (4.00 g, 14.9 mmol) in anhydrous CH3CN (60 ml). The mixture was stirred for 18 hr, the solvents were evaporated, and the residue was purified by column chromatography on silica gel with 30: 1 CH2Cl2 / EtOAc as eluent. A light yellow solid foam (4.90 g, 94%) was obtained. LC-MS: 348 [M + H].

PREPARED EXAMPLE 10 A mixture of the product of Preparative Example 7 (1.00 g, 3.95 mmol), 2.0 M NH3 in 2-propanol (20.0 mL), and conc. (5.0 ml) was stirred in a closed pressure vessel at 90 ° C for 20 hr. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 7: 1 CH2Cl2 / 7N NH3 in MeOH as eluent. A pale yellow solid was obtained (225 mg, 28%). LC-MS: 235 [M + H].

Mp = 181-182 ° C.

PREPARED EXAMPLE 11 A solution of NBS (356 mg, 2.00 mmol) in anhydrous CH3CN (20 mL) was added under N2 to a stirred solution of the product of Preparative Example 10 (468 mg, 2.00 mmol) in anhydrous CH3CN (10 mL) and CH2Cl2 (10 mL). ml). The mixture was stirred for 4 h, the solvents were evaporated, and the residue was purified by column chromatography on silica gel with 2: 1 CH2Cl2 / EtOAc as eluent. A white solid was obtained (530 mg, 85%). LC-MS: 313 [M]. Mp = 150-152 ° C.

PREPARED EXAMPLE 12 A mixture of the product of preparative example 11 (100 mg, 0. 32 mmol), 2.0 M NH3 in 2-propanol (2.0 mL), and conc. Aqueous NH4OH. (0.5 ml) was stirred in a closed pressure vessel at 80 ° C for 24 hr. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 10: 1 CH2Cl2 / MeOH as eluent. A white solid was obtained (13 mg, 14%). LC-MS: 284 [M +]. Mp = 209-211 ° C.

PREPARED EXAMPLE 13 A mixture of the product of preparative example 11 (100 mg, 0. 32 mmoles) and 2.0 M Me2NH in THF (5.0 ml) was stirred in a closed pressure vessel at 60 ° C for 72 hr. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 10: 1 CH2Cl2 / MeOH as eluent. A white solid was obtained (5 mg, 5%). LC-MS: 313 [M + H]. Mp = 215-217 ° C.

PREPARED EXAMPLE 14 Essentially by the same procedure set forth in Preparative Example 13, only using MeNH2 solution in THF, the compound given below was prepared.

White solid. LC-MS: 298 [M +]. Mp = 222-224 ° C.

PREPARATION EXAMPLE 15 A mixture of the product of preparative example 11 (200 mg, 0. 64 mmol) and ethylenediamine (0.10 ml) in dioxane (2.0 ml) was stirred under N2 to 90X for 24 hr. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 4: 1 CH 2 Cl 2 / 7N NH 3 in MeOH as eluent. A white solid was obtained (101 mg, 48%). LC-MS: 329 [M + 2H]. Mp = 215-217 ° C.

PREPARED EXAMPLE 16 A mixture of the product of Preparative Example 11 (200 mg, 0.64 mmol) and 1-methylpiperazine (0.40 mL) was stirred under N2 at 100 ° C for 72 hr. The excess of 1-methylpiperazine was evaporated and the residue was purified by column chromatography on silica gel with 20: 1 CH2Cl2 / 7N NH3 in MeOH as eluent. A white solid was obtained (155 mg, 66%). LC-MS: 367 [M +]. Mp = 122-125X.

PREPARED EXAMPLE 17 1.0 M LiAIH4 in THF (0.22 ml) was added at 0 ° C to a stirred solution of the product of preparative example 11 (150 mg, 0.48 mmol) in THF (8.0 ml). The mixture was stirred for 30 min at 0 ° C, then more 1.0 M LiAlH4 in THF (0.80 ml) was added. The mixture was stirred at 0 ° C for 20 min, then quenched with MeOH (4 mL). The solvents were evaporated and the residue was purified by column chromatography on silica gel with 20: 1 CH2Cl2 / MeOH as eluent. A white solid was obtained (59 mg, 45%). LC-MS: 271 [M +], Pf = 234-236X.

PREPARED EXAMPLE 18 A mixture of the product from Preparative Example 9 (500 mg, 1.45 mmol), 2.0 M NH3 in 2-propanol (10.0 mL), and conc. Aqueous NH4OH. (2.5 ml) was stirred in a closed pressure vessel at 70 ° C for 24 hr. The solvents were evaporated and the residue was purified by column chromatography on silica gel with CH2Cl2 / MeOH 8: 1 as eluent. A white solid was obtained (151 mg, 35%). LC-MS: 299 [M + H]. Mp = 211-213 ° C.

PREPARED EXAMPLE 19 A mixture of the product of preparative example 2 (12.50 g, 39.3 mmol), N, N-dimethylaniline (15.5 ml), and POCI3 (125 ml) was stirred at 25X for 4 days. The excess of POCI3 was evaporated and the residue was poured into saturated aqueous NaHCO3 (600 ml). The mixture was extracted with CH2Cl2 (3x200 ml), the combined extracts were dried over Na2SO, filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel with CH2Cl2 / EtOAc 8: 1 as eluent. A pale yellow wax was obtained (9.41 g, 71%). LC-MS: 337 [M +].

PREPARED EXAMPLE 20 A mixture of the product from Preparative Example 19 (8.00 g, 23.8 mmol), 2.0 M NH3 in 2-propanol (50 mL), and conc. Aqueous NH OH. (5 ml) was stirred in a closed pressure vessel at 70X for 28 hr. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 10: 1 CH2Cl2 / MeOH as eluent. A white solid was obtained (7.40 g, 98%). LC-MS: 318 [M + H].

PREPARED EXAMPLE 21 A solution of Br2 (15.2 g, 95.2 mmol) in dry CH2Cl2 (100 mL) was added dropwise to a stirred solution of the amine of Preparative Example 20 (30.2 g, 95.2 mmol) in ter-BuNH2 (300 mL) and CH2Cl2 (100 ml). The mixture was stirred at 25X for 20 h, the solvents were evaporated and the residue was purified by column chromatography on silica gel with 40: 1 CH2Cl2 / MeOH as eluent. A white solid was obtained (29.8 g, 79%). LC-MS: 396 [M +].

PREPARED EXAMPLE 22 A mixture of the product from Preparative Example 21 (2.50 g, 6.31 mmol), SEMCl (3.69 g, 22.1 mmol), and diisopropylethylamine (5.70 g, 44.2 mmol) in dry 1,2-dichloroethane (20 mL) was stirred and set at reflux under N2 for 6 hr. The mixture was then poured into saturated aqueous NaHCO3 solution (250 ml), extracted with CH2Cl2 (3x50 ml), dried over Na2SO4, and filtered. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 80: 1 CH2Cl2 / EtOAc as eluent. A slightly yellow oil was obtained (1.60 g, 39%).

PREPARED EXAMPLE 23 A mixture of the product of Preparative Example 22 (200 mg, 0.31 mmol), 2-thienylboronic acid (59 mg, 0.46 mmol), Pd [PPh3] 4 (35 mg, 0.03 mmol), and Na 2 CO 3 (99 mg, 0.93 mmol) in 1,2-dimethoxyethane (3 ml) and H20 (0.6 ml) was stirred and refluxed under N2 for 72 hr. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 10: 1 hexane / EtOAc as eluent. A slightly yellow wax was obtained (54 mg, 27%).

PREPARED EXAMPLE 24 A solution of NBS (13 mg, 0.075 mmol) in anhydrous CH3CN (1 mL) was added under N2 to a stirred solution of the product of Preparative Example 23 (53 mg, 0.080 mmol) in anhydrous CH3CN (1 mL). The mixture was stirred for 1 hr, the solvents were evaporated, and the residue was purified by column chromatography on silica gel with 10: 1 hexane / EtOAc as eluent. A slightly yellow wax was obtained (36 mg, 66%).

PREPARATORY EXAMPLE 25 A mixture of the product of Preparative Example 24 (35 mg, 0.048 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) -1 H-pyrazole (15 mg, 0.071 mmol), Pd [PPh3] 4 (6 mg, 0.005 mmol), and Na 2 CO 3 (20 mg, 0.071 mmol) in 1,2-dimethoxyethane (1.5 ml) and H 2 O (0.3 ml) were stirred and dried. refluxed under N2 for 20 hr. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 2: 1 hexane / EtOAc as eluent. A yellow wax was obtained (10 mg, 29%).

PREPARED EXAMPLE 26 A mixture of the product from preparative example 25 (10 mg) and aqueous 3N HCl (0.5 ml) in EtOH (0.5 ml) was stirred at 60X for 1.5 hr. The solvents were evaporated, Na 2 CO 3 (100 mg) and 6: 1 mixture of CH 2 Cl 2 / MeOH (0.5 ml) were added to the residue and the mixture was stirred under N 2 for 15 min. It was then loaded onto a column and purified by column chromatography on silica gel with 10: 1 CH2Cl2 / 7N NH3 in MeOH as eluent. A white solid was obtained (4 mg, 80%). LC-MS: 380 [M + H]. Pf = 241-243X.

PREPARED EXAMPLE 27-36 Essentially by the same sequence of procedures set forth in the preparative examples 23-26 only using different boron reagents given in column 1 for the Suzuki couplings with the intermediate of preparative example 22, the compounds given in column 2 of the box 3 TABLE 3 PREPARED EXAMPLE 37 A mixture of the product of preparative example 22 (400 mg, 0.62 mmol), vinyl boronate (143 mg, 0.93 mmol), Pd [PPh3] (68 mg, 0.06 mmol), and Na2C03 (262 mg, 2.48 mmol) in 1,2-dimethoxyethane (6 ml) and H20 (1.2 ml) was stirred and refluxed under N2 for 48 hr. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 6: 1 hexane / EtOAc as eluent. A slightly yellow wax was obtained (312 mg, 85%).

PREPARED EXAMPLE 38 A mixture of the product from preparative example 37 (150 mg) and 10% Pd / C (70 mg) in EtOAc (5 ml) was stirred under H 2 atmosphere for 72 hr. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 5: 1 hexane / EtOAc as eluent. A slightly yellow wax was obtained (118 mg, 79%).

PREPARED EXAMPLE 39 Essentially by the same sequence of procedures set forth in preparative examples 24-26 starting from the compound of Preparative Example 38, the title compound was prepared. LC-MS: 326 [M + H]. Pf = 76-78X.

PREPARATORY EXAMPLE 40 A mixture of the product from Preparative Example 20 (2.00 g, 6.30 mmol), SEMCl (3.69 g, 22.10 mmol), and diisopropylethylamine (5.70 g, 44.20 mmol) in dry 1,2-dichloroethane (20 mL) was stirred and set at reflux under N2 for 2 hr. The mixture was then poured into saturated aqueous NaHCO 3 solution (100 ml), extracted with CH 2 Cl 2 (3x30 ml), dried over Na 2 SO, and filtered. The solvents were evaporated and the residue was purified by column chromatography on silica gel with CH2Cl2 / EtOAc 15: 1 as eluent. A slightly yellow oil was obtained (2.76 g, 76%).

PREPARED EXAMPLE 41 A solution of N-iodosuccinimide (0.90 g, 4.00 mmol) in anhydrous CH3CN (10 mL) was added under N2 to a stirred solution of the product of Preparative Example 40 (2.50 g, 4.33 mmol) in anhydrous CH3CN (10 mL). The mixture was stirred for 1 hr, the solvents were evaporated, and the residue was purified by column chromatography on silica gel with CH2Cl2 / EtOAc 40: 1 as eluent. A slightly yellow wax was obtained (2.57 g, 92%).

PREPARED EXAMPLE 42 A mixture of the product of preparative example 41 (1.50 g, 2.13 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) -1 H-pyrazole (0.89 g, 4.26 mmol), PdCI2dppf.CH2CI2 (171 mg, 0.21 mmol), and K3P04 (1.81 g, 8.52 mmol) in 1,2-dimethoxyethane (30 mL) and H20 (6 mL) was stirred and set at reflux under N2 for 3 hr. The solvents were evaporated and the residue was purified by column chromatography on silica gel with CH2Cl2 / EtOAc 5: 1 as eluent. A yellow wax was obtained (1.13 g, 81%).

PREPARED EXAMPLE 43 A mixture of the product of preparative example 42 (1.00 g) and aqueous 3N HCl (20 ml) in EtOH (20 ml) was stirred at 60X for 1.5 hr. The solvents were evaporated, Na 2 CO 3 (2.0 g) and 6: 1 mixture of CH 2 Cl 2 / MeOH (20 ml) was added to the residue and the mixture was stirred under N 2 for 15 min. It was then loaded onto a column and purified by column chromatography on silica gel with 6: 1 CH2Cl2 / 7N NH3 in MeOH as eluent. A white solid was obtained (405 mg, 90%). LC-MS: 298 [M + H].

PREPARED EXAMPLE 44 Boc20 (441 mg, 2.02 mmol) was added to a stirred solution of the product of Preparative Example 43 (500 mg, 1.68 mmol) and triethylamine (2.0 mL) in anhydrous CH 2 Cl 2 (10 mL). The mixture was stirred at 25X for 18 hr, then it was emptied into saturated aqueous NaHCO3 solution (60 ml), extracted with CH2Cl2 (3x10 ml), dried over Na2SO4, and filtered. The solvents were evaporated and the residue was purified by column chromatography on silica gel with CH2Cl2 / MeOH 20: 1 as eluent. A pale yellow solid (670 mg, 100%) was obtained. LC-MS: 398 [M + H].

PREPARED EXAMPLE 45 A solution of Br2 (191 mg, 1.19 mmol) in dry CH2Cl2 (4 mL) was added dropwise to a stirred solution of the product of Preparative Example 44 (500 mg, 1.26 mmol) in ter-BuNH2 (10 mL) and CH2Cl2 (5 ml).

The mixture was stirred at 25X for 20 h, the solvents were evaporated and the residue was purified by column chromatography on silica gel with 1: 1 CH2Cl2 / EtOAc as eluent. A white solid was obtained (415 mg, 73%). LC-MS: 476 [M +].

PREPARED EXAMPLE 46 A mixture of the product of Preparative Example 45 (410 mg, 0.86 mmol), SEMCl (503 mg, 3.01 mmol), and diisopropylethylamine (777 mg, 6.02 mmol) in dry 1,2-dichloroethane (4 mL) was stirred and stirred. refluxed under N2 for 20 hr. The mixture was then poured into saturated aqueous NaHCO3 solution (60 ml), extracted with CH2Cl2 (3x10 ml), dried over Na2SO4, and filtered. The solvents were evaporated and the residue was purified by column chromatography on silica gel with CH2Cl2 / EtOAc 7: 1 as eluent. A slightly yellow wax was obtained (214 mg, 34%).

PREPARED EXAMPLE 47 A mixture of the product of Preparative Example 46 (100 mg, 0.14 mmol), tributyltin cyanide (63 mg, 0.20 mmol), and Pd [PPh3] 4 (16 mg, 0.014 mmol) in anhydrous dioxane (2 mL) was stirred at 100X under N2 for 20 hr. Then, bis (tri-t-butylphosphine) palladium (40 mg, 0.078 mmol) was added to the mixture and the mixture was stirred at 100X under N2 for an additional 24 hr. The solvent was evaporated and the residue was purified by column chromatography on silica gel with 6: 1 hexane / EtOAc as eluent. A slightly yellow wax was obtained (48 mg, 51%). LC-MS: 683 [M + H].

PREPARED EXAMPLE 48 A mixture of the product from Preparative Example 47 (48 mg) and aqueous 3N HCl (1.0 mL) in EtOH (1.0 mL) was stirred at 60X for 1 hr. The solvents were evaporated, Na2CO3 (200 mg) and 6: 1 mixture of CH2Cl2 / MeOH (1.0 ml) were added to the residue and the mixture was stirred under N2 for 15 min. It was then loaded onto a column and purified by column chromatography on silica gel with 8: 1 CH2Cl2 / 7N NH3 in MeOH as eluent. A white solid was obtained (13 mg, 57%). LC-MS: 323 [M + H]. Pf = 101-105X.

PREPARED EXAMPLE 49 A mixture of the product from Preparative Example 46 (400 mg, 0.54 mmol), tributyl (1-ethoxyvinyl) tin (294 mg, 0.81 mmol), and Pd [PPh3] 4 (62 mg, 0.054 mmol) in anhydrous dioxane ( 8 ml) was stirred at 100X under N2 for 72 hr. The solvent was evaporated and the residue was purified by column chromatography on silica gel with CH2Cl2 / EtOAc 6: 1 as eluent. A slightly yellow wax was obtained (326 mg, 83%).

PREPARED EXAMPLE 50-51 Essentially by the same procedures set forth in preparative example 49, only using different tin reagents given in column 1 for Stille couplings with the intermediate of preparative example 46, the compounds given in column 2 of table 4 were prepared.

TABLE 4 PREPARED EXAMPLE 52 A mixture of the product from Preparative Example 49 (320 mg) and aqueous 3N HCl (3 mL) in EtOH (3 mL) was stirred at 60X for 1.5 hr. The solvents were evaporated, NaHCO3 (2.0 g) and a 6: 1 mixture were added.

CH2Cl2 / MeOH (7 ml) to the residue and the mixture was stirred under N2 for 15 min.

It was then loaded onto a column and purified by column chromatography on silica gel with 12: 1 CH2Cl2 / 7N NH3 in MeOH as eluent. A white solid was obtained (120 mg, 81%). LC-MS: 340 [M + H]. Pf = 93-97X.

PREPARATIVE EXAMPLE 53a (isomer 1) and 53b (isomer 2) Compound 53 (isomer 53a and isomer 53b) NaBH (16 mg, 0.44 mmol) was added to a stirred solution of the product from Preparative Example 52 (30 mg, 0.088 mmol) in anhydrous MeOH (3 mL). The mixture was stirred under N2 for 60 min, then the solvent was evaporated and the residue was purified by preparative CCD chromatography on silica gel with 5: 1 CH2Cl2 / 7N NH3 in MeOH as eluent. Two isomers were obtained. Isomer 1 (less polar): white solid (5 mg); Mp = 130-133X; LC-MS: 342 [M + H]. Isomer 2 (more polar): white solid (6 mg); Mp = 199-202X; LC-MS: 342 [M + H].

PREPARED EXAMPLE 54 A mixture of the product of Preparative Example 52 (40 mg, 0.12 mmol), NH 2 OH.HCl (10 mg, 0.14 mmol), and triethylamine (0.20 mL) in 1,2-dichloroethane (1 mL) and MeOH (1 mL) were added. stirred in a closed flask at 25X for 20 hr. The solvent was evaporated and the residue was purified by preparative CCD chromatography on silica gel with 5: 1 CH2Cl2 / 7N NH3 in MeOH as eluent. A slightly yellow solid was obtained (10 mg, 24%). LC-MS: 355 [M + H]. Pf = 228-230X.

PREPARATORY EXAMPLE 55 A mixture of the product from Preparative Example 51 (55 mg) and aqueous 3N HCl (2.8 mL) in EtOH (2.8 mL) was stirred at 60X for 1.5 hr. The solvents were evaporated, Na2CO3 (0.3 g) and 6: 1 mixture of CH2Cl2 / MeOH (4 ml) were added to the residue and the mixture was stirred under N2 for 15 min. Then, it was loaded on a preparative CCD plate and purified by preparative CCD on silica gel with 10: 1 CH2Cl2 / 7N NH3 in MeOH as eluent. A yellow wax was obtained (12 mg, 48%). LC-MS: 354 [M + H].

PREPARED EXAMPLE 56 The compound was prepared essentially by the same procedure as that given in preparative example 55, starting from the product of preparative example 50. Yellow wax. LC-MS: 416 [M + H].

PREPARED EXAMPLE 57 A mixture of the product of Preparative Example 51 (64 mg) in TFA (0.5 ml) and H20 (0.5 ml) was stirred at 25X for 1 hr. Toluene (5 ml) was added to the mixture and the solvents were evaporated. NaHCO3 (0.3 g) and 6: 1 mixture of CH2Cl2 / MeOH (4 ml) were added to the residue and the mixture was stirred under N2 for 15 min. Then, it was loaded on a preparative CCD plate and purified by preparative CCD on silica gel with 10: 1 CH2Cl2 / 7N NH3 in MeOH as eluent. White semi-solid was obtained (13 mg, 42%). LC-MS: 336 [M + H].

PREPARED EXAMPLE 58 A mixture of the product from preparative example 45 (1.0 eq.), Chloromethylethyl ether (4.0 eq.), And diisopropylethylamine (8.0 eq.) In dry 1,2-dichloroethane was stirred and refluxed under N2 for 20 hr. The mixture was then poured into saturated aqueous NaHC 3 solution, extracted with CH 2 Cl 2, dried over Na 2 SO, and filtered. The solvents were evaporated and the residue was purified by column chromatography on silica gel with CH2Cl2 / EtOAc 7: 1 as eluent.

PREPARED EXAMPLE 59 A mixture of the product of preparative example 58 (1.0 eq.), CF3SiEt3 (3.6 eq.), KF (3.6 eq.), And Cul (4.5 eq.) In DMF was stirred in a closed pressure vessel at 80X for 3 days. . CH 2 Cl 2 was added, the mixture was filtered through Celite, the solvent was evaporated, and the residue was subjected to chromatography to give the product.

PREPARATORY EXAMPLE 60 A mixture of the product of Preparative Example 59 and aqueous 3N HCl and EtOH was stirred at 60X for 1.5 hr. The solvents were evaporated, NaHCO 3 and a 6: 1 mixture of CH 2 Cl 2 / MeOH were added to the residue and the mixture was stirred under N 2 for 15 min. Then, it was loaded on a preparative CCD plate and purified by preparative CCD on silica gel with 10: 1 CH2Cl2 / 7N NH3 in MeOH as eluent.

PREPARED EXAMPLE 61 Diethylphenyl malonate (2.0 g, 8.5 mmol), 3-aminopyrazole (0.7 g, 1.0 eq.) And tri-? / -butylamine (2.2 ml, 1.1 eq.) Was heated at 180X for 4 hours. The reaction mixture was cooled to room temperature and suspended in EtOAc overnight. The mixture was filtered and dried under vacuum to give a white solid (2.98 g). This solid was dissolved in POCI3 (20 ml) and dimethylaniline (4 ml) was added and the reaction mixture was heated to reflux overnight. The resulting solution was cooled to room temperature and emptied on ice (400 g). The resulting mixture was extracted with EtOAc (3 x 100 ml). The combined organics were washed with H20 (5 x 150 ml) and brine, dried over Na2SO4, filtered and combined under vacuum. The crude product was purified by flash chromatography using a solution of 8% EtOAc in hexanes as eluent to give a tan solid (0.35 g, 16% yield).

PREPARED EXAMPLES 62-63 Following the procedure set forth in Preparative Example 1 but using the commercially available substituted diethyl malonates (as indicated) in Table 4.1 with 3-aminopyrazole, substituted pyrazolo [1, 5-a] pyrimidine adducts were prepared (Products) .

TABLE 4.1 PREPARED EXAMPLE 64 To a solution of 5,7-dichloro adduct (0.35 g, 1.33 mmol) of Preparative Example 61 in CH3CN to OX was added NBS (0.26 g, 1.46 mmol) in a single portion. The mixture was stirred for 3 hours at OX and concentrated under reduced pressure. The crude product was partitioned between Et20 (7 ml) and H20 (2 ml) and the layers were separated. The organic layer was washed sequentially with H20 (1 x 2 ml) and brine (2 x 2 ml). The organic layer was dried (MgSO 4), filtered and concentrated under reduced pressure to give an off white solid (0.42 g, 90% yield) which was used without further purification. LC-MS [M + H] = 344.0; 95% purity.

PREPARED EXAMPLES 65-66 Following the procedure set forth in Preparative Example 64, but using the 5,7-dichloro adducts (as indicated) in Table 4.1, substituted pyrazolo [1, 5-a] pyrimidine adducts (Products) were prepared.

TABLE 4.2 PREPARED EXAMPLE 67 To a pressure tube loaded with the 5,7-dichloro adduct (0.40 g, 1. 16 mmol) of Preparative Example 64 and a stir bar, 2M NH 3 in IPA (5 mL) and conc NH 4 OH was added. (2 ml). The tube was sealed and heated to 80X. The mixture was stirred for 12 hr, cooled to t.a., and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (6 x 1000 μM plates) using a 30: 1 mixture of CH 2 Cl 2 / MeOH (7M NH 3) as eluent to give (0.15 g, 41% yield) as a white solid , pf > 210X LC-MS: 325.1 [M + H] EXAMPLES 68-69 Following the procedure set forth in Example 67 but using the 5,7-dichloro adducts (as indicated) in Table 4.2, substituted pyrazolo [1, 5-a] pyrimidine adducts (Products) were prepared in Table 4.3.

TABLE 4.3 PREPARED EXAMPLE 70 To a mixture of 7-amino adduct (0.10 g, 0.31 mmol) from Example 67 in NMP (1.5 mL) at rt, NaHC 3 (78 mg, 0.93 mmol) was added followed by (S) - (-) - 3 - (Boc-amino) pyrrolidine (86 mg, 0.46 mmol). The mixture was added with a reflux condenser and heated to 140X. The mixture was stirred for 14 hr, cooled to t.a., and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (6 x 1000 μM plates) using a 35: 1 mixture of CH 2 Cl 2 / MeOH as eluent to give (68 mg, 46% yield) as a yellow / brown solid. LC-MS [M + H] = 475.1; 92% purity.

PREPARED EXAMPLES 71-72 Following the procedure set forth in Preparative Example 70 but using the 5,7-dichloro adducts (as indicated) in Table 4.3, substituted pyrazolo [1, 5-a] pyrimidine adducts (Products) were prepared in Table 4.4.

TABLE 4.4 EXAMPLE 73 Boc To a mixture of 7-amino adduct (68 mg, 0.14 mmol) of Preparative Example 70 in CH2Cl2 (2 mL) to OX was added TFA (0.5 mL) dropwise. The resulting mixture was stirred for 12 hr at t.a. and concentrated under reduced pressure. The crude material was partitioned between EtOAc (5 ml) and Na 2 C 3 aq. sat (2 ml) and the layers separated. The aqueous layer was extracted with EtOAc (2 x 5 ml) and the organic layers were combined. The organic layer was washed with brine (x 3 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (4 x 1000 μM plates) using a 15: 1 mixture of CH2Cl2 / MeOH (7M NH3) as eluent to give (40 mg, 46% yield) as a color solid clear cinnamon, mp 167-170X; LC-MS: 375 [M + H] EXAMPLES 74-75 Following the procedure set forth in Example 73, but using the Boc adducts (as indicated) in Table 4.4, substituted pyrazolo [1, 5-a] pyrimidine adducts (Products) were prepared in Table 4.5.

TABLE 4.5 The preparation of the compounds of the co-pending application No. series (case of proxy No. OC01617K3 filed on the same date as the present one) is illustrated below: PREPARED EXAMPLE X-10-C SO2 (18.5 ml) was slowly added under N2 to a stirred mixture of the acid (50.0 g, 218 mmol) and pyridine (44.0 ml) in anhydrous CH2Cl2 (300 ml). The mixture was stirred at 25X for 20 min, then Meldrum acid (35.0 g, 243 mmol) and DMAP (66.6 g, 546 mmol) were added and the mixture was stirred under N2 for 1 hr. Then, Et 2 O (2 L) was added, the mixture was washed with 1 M HCl (3 × 500 ml), brine (500 ml), and the organic layer was dried over Na 2 SO 4, filtered, and the solvent was evaporated. The residue was dissolved in MeOH (580 ml), and the mixture was refluxed for 4 hr. The solvent was evaporated and the residue was purified by column chromatography on silica gel with 10: 1 CH2Cl2 / EtOAc as eluent. A pale yellow oil was obtained (26.5 g, 43%).

PREPARATIVE EXAMPLE X-20-C A mixture of the beta-ketoester of preparative example X-10-C (20.0 g, 70.1 mmol) and 3-aminopyrazole (5.40 g, 65.0 mmol) in anhydrous toluene (60 ml) was stirred and refluxed under N2 for 24 hours. hr. The solvent was evaporated and the residue was purified by column chromatography on silica gel with CH2Cl2 / MeOH 20: 1 as eluent. A white solid was obtained (15.0 g, 73%). LC-MS: 319 [M + H].

PREPARED EXAMPLE X-30-C A mixture of the product of preparative example X-20-C (12.50 g, 39.3 mmol), N, N-dimethylaniline (15.5 ml), and POCI3 (125 ml) was stirred at 25X for 4 days. The excess of POCI3 was evaporated and the residue was poured into saturated aqueous NaHCO3 (600 ml). The mixture was extracted with CH2Cl2 (3x200 ml), the combined extracts were dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel with CH2Cl2 / EtOAc 8: 1 as eluent. A pale yellow wax was obtained (9.41 g, 71%). LC-MS: 337 [M +].

PREPARED EXAMPLE X-40-C A mixture of the product of preparative example X-30-C (8.00 g, 23. 8 mmol), 2.0 M NH3 in 2-propanol (50 mL), and conc. (5 ml) was stirred in a closed pressure vessel at 70X for 28 hr. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 10: 1 CH2Cl2 / MeOH as eluent. A white solid was obtained (7.40 g, 98%). LC-MS: 318 [M + H].

PREPARED EXAMPLE X-50-C A mixture of the product of preparative example X-40-C (2.00 g, 6.30 mmol), SEMCl (3.69 g, 22.10 mmol), and diisopropylethylamine (5.70 g, 44.20 mmol) in dry 1,2-dichloroethane (20 ml) was stirred and refluxed under N2 for 2 hr. The mixture was then poured into saturated aqueous NaHCO3 solution (100 ml), extracted with CH2Cl2 (3x30 ml), dried over Na2SO4, and filtered. The solvents were evaporated and the residue was purified by column chromatography on silica gel with CH2Cl2 / EtOAc 15: 1 as eluent. A slightly yellow oil was obtained (2.76 g, 76%).

PREPARED EXAMPLE X-60-C A solution of N-iodosuccinimide (0.90 g, 4.00 mmol) in anhydrous CH3CN (10 mL) was added under N2 to a stirred solution of the product of Preparative Example 50-C (2.50 g, 4.33 mmol) in anhydrous CH3CN (10 mL). . The mixture was stirred for 1 hr, the solvents were evaporated, and the residue was purified by column chromatography on silica gel with CH2Cl2 / EtOAc 40: 1 as eluent. A slightly yellow wax was obtained (2.57 g, 92%).

PREPARED EXAMPLE X-61-C Essentially, by the same procedure set forth in preparative example X-60-C, only that substituting NBS for NIS, the above compound was prepared.

PREPARED EXAMPLE X-70-C A mixture of the product of preparative example X-60-C (1.50 g, 2.13 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) - 1 H-pírazolo (0.89 g, 4.26 mmol), PdCI2dppf.CH2CI2 (171 mg, 0.21 mmol), and K3PO4 (1.81 g, 8.52 mmol) in 1,2-dimethoxyethane (30 mL) and H2O (6 mL) was stirred and refluxed under N2 for 3 hr. The solvents were evaporated and the residue was purified by column chromatography on silica gel with CH2Cl2 / EtOAc 5: 1 as eluent. A yellow wax was obtained (1.13 g, 81%).

PREPARED EXAMPLE X-80-C A mixture of the product from preparative example X-70-C (1.00 g) and aqueous 3N HCl (20 ml) in EtOH (20 ml) was stirred at 60X for 1.5 hr. The solvents were evaporated, Na 2 CO 3 (2.0 g) and 6: 1 mixture of CH 2 Cl 2 / MeOH (20 ml) were added to the residue and the mixture was stirred under N 2 for 15 min. It was then loaded onto a column and purified by column chromatography on silica gel with 6: 1 CH2Cl2 / 7N NH3 in MeOH as eluent. A white solid was obtained (405 mg, 90%). LC-MS: 298 [M + H].

PREPARED EXAMPLE X-90-C Boc 2 O (441 mg, 2.02 mmol) was added to a stirred solution of the product from Preparative Example X-80-C (500 mg, 1.68 mmol) and triethylamine (2.0 mL) in anhydrous CH 2 Cl 2 (10 mL). The mixture was stirred at 25X for 18 hr, then it was emptied into saturated aqueous NaHCO3 solution (60 ml), extracted with CH2Cl2 (3x10 ml), dried over Na2SO4, and filtered. The solvents were evaporated and the residue was purified by column chromatography on silica gel with CH2Cl2 / MeOH 20: 1 as eluent. A pale yellow solid (670 mg, 100%) was obtained. LC-MS: 398 [M + H].

EXAMPLE PREPARATIVE X-100-C A solution of Br2 (191 mg, 1.19 mmol) in dry CH2Cl2 (4 mL) was added dropwise to a stirred solution of the product of Preparative Example X-90-C (500 mg, 1.26 mmol) in ter-BuNH2 (10 mg). ml) and CH2Cl2 (5 ml). The mixture was stirred at 25X for 20 h, the solvents were evaporated and the residue was purified by column chromatography on silica gel with 1: 1 CH2Cl2 / EtOAc as eluent. A white solid was obtained (415 mg, 73%). LC-MS: 476 [M +].

PREPARED EXAMPLE X-110-C To a 3-iodine adduct in solution (0.40 g, 0.57 mmol) of preparative example X-60-C in a mixture of DME / H20 (15 ml / 3 ml) at t.a. 4-hydroxymethylphenylboronic acid (0.17 g, 1.14 mmol), Na2CO3 (0.18 g, 1.70 mmol), and PdCI2 (dppf) (46 mg, 0.057 mmol) were added. The mixture was degassed under 6 x vacuum and filled with N2 and heated to 95X. The mixture was stirred for 5 h, cooled to t.a., and concentrated under reduced pressure. The crude residue was partitioned between CH2Cl2 (10 ml) and water (3 ml) and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2 x 10 ml) and the organic layers were combined. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (6 x 1000 μM plates) using a 3: 1 mixture of hexanes / EtOAc as eluent to give (0.38 g, 96% yield) as a yellow semi-solid. LC-MS: = 684.4 [M + H] 98% purity.

PREPARATIVE EXAMPLES X-120-C to X-210-C Following the procedure set forth in preparative example X-110-C but using boronic acid / boronates (as indicated) in Table X-10-C and commercially available amines, pyrazolo adducts [1, 5-a] were prepared substituted pyrimidine (Products).

TABLE X-10-C PREPARED EXAMPLE X-220-C To a pressure tube loaded with 3-bromo-5,7-dichloropyrazolo [1,5-a] pyrimidine (3 g, 0.11 mol) and a stir bar was added NH 4 OH conc. (-90 ml) at t.a. The tube was capped, heated to 85X, and stirred for 12 hr. The mixture was cooled to t.a. and concentrated under reduced pressure. The crude product was taken up in water (70 ml) and filtered. The ppt was washed sequentially with water (1 x 50 ml) and Et20 (1 x 50 ml). The crude product was placed under high vacuum to give 2.4 g (88% yield) of a yellow solid. LC-MS: 249.1 [M + H]; 97% purity.

PREPARED EXAMPLE X-230-C To a mixture of 7-amino adduct (1.0 g, 4.0 mmol) of preparative example X-220-C in DCE (8 ml) at t.a. DIPEA (4.9 ml, 28.2 mmol) was added followed by SEMCl (2.2 ml, 12.1 mmol). The resulting mixture was heated to 90X and stirred for 12 hr. The mixture was cooled to t.a. and NaHCO 3 aq. sat (35 ml) was added followed by dilution with CH2Cl2 (50 ml). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3 x 50 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 7: 1 mixture of hexanes / EtOAc to give 2.0 g (97% yield) of a yellow oil.

PREPARED EXAMPLE X-240-C To a mixture of 5-chloro adduct (0.50 g, 0.98 mmol) of preparative example X-230-C in NMP (3 ml) at t.a. (S) -3- (Boc-amino) pyrrolidine (0.28 g, 1.5 mmol) was added followed by NaHCO3 (0.19 g, 2.2 mmol). (12.1 mmoles). The resulting mixture was heated to 130X and stirred. for 12 hr. The mixture was concentrated under reduced pressure, purified by preparative CCD using 8 x 1000 μM plates with a 40: 1 mixture of CH 2 Cl 2 / MeOH as eluent to give 0.51 g (79% yield) of a light yellow solid. LC-MS: 659.4 [M + H]; 94% purity.

PREPARED EXAMPLE X-250-C BocH By the same method used in the preparative example X-110-C, the 3-bromo derivative (0.42 g, 0.64 mmol) of the preparative example 240-C was treated with 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1 H-pyrazolo (0.27 g, 1.28 mmol) to give 0.10 g (24% yield) of a white semisolid. LC-MS: 659.0 [M + H]; 95% purity.

PREPARED EXAMPLE X-260-C To a solution of adduct 3-Br (0.45 g, 0.69 mmol) of preparative example X-61-C in CH 3 CN (4 ml) at t.a. 4-tributylstanyl thiazole (0.51 g, 1.37 mmol) was added followed by PdCI2 (PPh3) 2 (48 mg, 0.069 mmol). The resulting mixture was degassed under vacuum and filled with N2 six times. The mixture was equipped with a condenser and heated to 80X. The mixture was stirred for 12 h, cooled to t.a., and diluted with EtOAc (10 mL). The mixture was filtered through a pad of Celite which was washed with CH 2 Cl 2 (1 x 5 ml) and MeOH (1 x 5 ml). The resulting filtrate was concentrated under reduced pressure and placed under high vacuum. The crude product was purified by preparative thin layer chromatography (6 x 1000 μM plates) using a 40: 1 mixture of CH 2 Cl 2 / MeOH as eluent to give 0.28 g (61% yield) as an orange oil. LC-MS: = 661.4 [M + H] 71% purity.

PREPARED EXAMPLE X-270-C To a solution of 2-isobutylthiazole (5.0 ml, 35.4 mmol) in THF (100 mL) at -78X a 2 M solution of LDA (21.0 mL, 42.2 mmol) was added dropwise over 10 min. After 1 hr at this temperature, Bu3SnCl (11.5 ml, 42.4 mmol) was added dropwise. The mixture was allowed to warm gradually to t.a. for about 3 hr, after which the mixture was quenched with NH 4 Cl aq. sat (15 ml) and diluted with Et2O (70 ml). The layers were separated and the aqueous layer was extracted with Et2O (2 x 70 ml). The organic layers were combined, dried (MgSO4), filtered and concentrated under reduced pressure to give the desired compound as an orange / brown oil. MS: = 430.4 The material was collected crude for the next transformation without purification.

PREPARED EXAMPLE X-280-C Using the procedure of Preparative Example X-260-C, adduct 3-Br (0.40 g, 0.61 mmol) of Preparative Example X-61-C was treated with tributylstanyl thiazole (0.52 g, 1.22 mmol) of Preparative Example X-17 to give 0.34 g (77% yield) of an orange / brown oil. LC-MS: = 717.4 [M + H] 62% purity.

EXAMPLE X-10-C To an adduct solution (0.25 g, 0.37 mmol) of Preparative Example X-110-C in EtOH (3 mL) at t.a. 3M HCl (3 mL) was added. The resulting solution was heated to 60X and stirred for 5 hr (until complete by CCD). The mixture was cooled to t.a. and concentrated under reduced pressure. The crude material was taken up in 7M NH3 in MeOH (3 mL) and stirred for 3 hr. The mixture was concentrated under reduced pressure and purified by preparative thin layer chromatography (4 x 1000 μM plates) using a 10: 1 mixture of CH2Cl2 / MeOH (7M NH3) as eluent to give (20 mg, 17% yield ) as a whitish solid. LC-MS: = 324.2 [M + H] 99% purity.

EXAMPLES X20-C-X130-C Following the procedure set forth in Example X-10-C, the preparative examples indicated in column 2 of Table X-20-C were converted to the substituted pyrazolo [1,5-a] pyrimidine adducts shown in column 3 of the table X-20-C TABLE X-20-C EXAMPLE X-140-C To an adduct solution (0.28 g, 0.41 mmol) of preparative example X-170-C in water (4 ml) at t.a. TFA (4 ml) was added. The resulting solution was stirred at t.a. for 4 hr (until complete by CCD) and concentrated under reduced pressure. The crude material was taken up in 7M NH3 in MeOH (3 mL) and stirred for 3 hr. The mixture was concentrated under reduced pressure and purified by preparative thin layer chromatography (4 x 1000 μM plates) using a 10: 1 mixture of CH 2 Cl 2 / MeOH (7M NH 3) as eluent to give (60 mg, 46% yield) ) as a yellow solid, mp 167-169X; LC-MS: = 319.2 [M + H] 99% pure.

EXAMPLES X150-C -X160-C Following the procedure set forth in Example X-140-C, the compounds in column 2 of Table 30-C were converted to the substituted pyrazolo [1, 5-a] pyrimidine adducts (column 3) found in Table X-30 -C.

TABLE X-30-C PREPARED EXAMPLE X-290-C A solution of NBS (4.03 g, 22.7 mmol) in anhydrous CH3CN (40 ml) was added under N 2 to a stirred solution of the product of preparative example X-30-C (7.63 g, 22.7 mmol) in anhydrous CH 3 CN (60 ml) and CH 2 Cl 2 (20 ml). The mixture was stirred for 2 h, the solvents were evaporated, and the residue was purified by column chromatography on silica gel with CH2Cl2 / EtOAc 20: 1 as eluent. A light yellow solid foam (9.20 g, 97%) was obtained.

PREPARED EXAMPLE X-300-C Essentially by the same procedure set forth in preparative example X-290-C, the reaction of the 7-Cl adduct of preparative example X-30-C with N-iodosuccinimide gave the title compound.

PREPARED EXAMPLE X-310-C A mixture of the product of preparative example X-290-C (8.00 g, 19.3 mmol) and MeONa (2.16 g, 40.0 mmol) in anhydrous MeOH (100 mL) was stirred for 20 hr. Then, CH2Cl2 (200 mL) was added, the mixture was filtered through Celite, the solvent was evaporated, and the residue was purified by column chromatography on silica gel with 2: 1 CH2Cl2 / EtOAc as eluent. A white solid was obtained (7.75 g, 98%).

PREPARED EXAMPLE X-320-C Essentially by the same procedure set forth in Preparative Example X-310-C, starting from the compound of Preparative Example X-300-C, the title compound was prepared.

PREPARED EXAMPLE X-330-C To a solution of adduct 3-Br (0.25 g, 0.61 mmol) of preparative example X-310-C in CH 3 CN (3 ml) at t.a. 5-Tributylstanylthiazole (0.46 g, 1.22 mmol) was added followed by PdCI2 (PPh3) 2 (43 mg, 0.069 mmol). The resulting mixture was degassed under suction vacuum and filled with N2 six times. The mixture was equipped with a condenser and heated to 80X. The mixture was stirred for 12 hr, was cooled to t.a., and diluted with EtOAc (10 mL). The mixture was filtered through a pad of Celite which was washed with EtOAc (3 x 5 ml), CH2Cl2 (1 x 5 ml) and MeOH (1 x 5 ml). The resulting filtrate was concentrated under reduced pressure and placed under high vacuum. The crude product was purified by preparative thin layer chromatography (6 x 1000 μM plates) using a 20: 1 mixture of CH 2 Cl 2 / MeOH as eluent to give 0.19 g (75% yield) as a yellow semi-solid. LC-MS: = 416.2 [M + H] 66% purity.

PREPARED EXAMPLE X-340-C To a solution of adduct 3-1 (0.40 g, 0.87 mmol) of Preparative Example X-320-C in dioxane (3 mL) at t.a. 2-tributylstanilitiazole (0.40 g, 1.09 mmol) was added followed by Pd (PPh3) 4 (63 mg, 0.055 mmol). The mixture was fitted with a condenser and heated to 90X and stirred at this temperature for 12 hr. The mixture was cooled to t.a. and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (6 x 1000 μM plates) using a 20: 1 mixture of CH 2 Cl 2 / MeOH as eluent to give 0.16 g (45% yield) as a yellow semi-solid. LC-MS: = 411.2 [M + H] 84% purity.

PREPARED EXAMPLE X-350-C To a pressure tube charged with 7-ruthoxy adduct (0.18 g, 0.45 mmol) of Preparative Example X-330-C and a stir bar was added 7M NH3 in MeOH (5 mL). The tube was capped, heated to 80X, and stirred for 72 hr. The mixture was cooled to t.a., concentrated under reduced pressure, and placed under high vacuum. The crude material was purified by preparative thin layer chromatography (4 x 1000 μM plates) using a 20: 1 mixture of CH 2 Cl 2 / MeOH (7M NH 3) as eluent to give 120 mg (66% yield) as a yellow semi-solid. whitish solid. MS = 401.2 [M + H].

PREPARED EXAMPLE X-360-C In an analogous manner as described in Preparative Example X-350-C, the 7-methoxy adduct (0.16 g, 0.39 mmol) of Preparative Example X-340-C was converted to 52 mg (34% yield) of the compound of the title. LC-MS: = 396.2 [M + H] 74% purity.

EXAMPLE X-170-C To a Boc adduct mixture (0.12 g, 0.30 mmol) of preparative example X-350-C in CH2Cl2 (2 ml) at t.a. TFA (0.4 ml) was added dropwise. The resulting mixture was stirred for 12 h, concentrated under reduced pressure, and placed under high vacuum to remove traces of volatile compounds. The resulting semi-solid was dissolved in 7M NH3 in MeOH (5 mL), stirred for 4 h, and concentrated under reduced pressure. The crude material was purified by preparative thin layer chromatography (4 x 1000 μM plates) using a 6: 1 mixture of CH2Cl2 / MeOH (7M NH3) as eluent to give 67 mg (75% yield) of a white solid , mp 162-165X; MS = 301.2 [M + H].

EXAMPLE X-180-C To a piperidine adduct mixture (41 mg, 0.12 mmol) of Example X-170-C in CH3CN (2 mL) at t.a. NBS (22 mg, 0.12 mmol) was added in one portion. The resulting mixture was stirred for a 2 hr and t.a. for 1 hr. The mixture was concentrated under reduced pressure and placed under high vacuum to remove traces of volatile compounds. The crude material was purified by preparative thin layer chromatography (4 x 1000 μM plates) using a 12: 1 mixture of CH 2 Cl 2 / MeOH (NH 3 7) as eluent to give 27 mg (54% yield) of a tan solid. clear, mp 109-1 12X; MS = 418.2 [M + H]; 85% purity.

EXAMPLES X190-C -X220-C Following the procedure set forth in Example X-180-C using the compounds in column 2 of Table X-40-C, the substituted 6-Br pyrazolo [1,5-a] pyrimidine adducts were prepared in column 3 of the Table X-40-C.

TABLE X-40-C PREPARED EXAMPLE X-360-C In an analogous manner as described in example X-180-C, the 7-amino adduct (40 mg, 0.10 mmol) of preparative example X-360-C was converted to 40 mg (83% yield) of the above compound . LC-MS: = 476.3 [M + H] 98% pure.

EXAMPLE X-230-C In an analogous manner as described in example X-170-C, the 7-amino adduct (20 mg, 0.10 mmol) of preparative example X-360-C was converted to 15 mg (94% yield) of a solid pale yellow, mp 144-146X; LC-MS: = 374.1 [M + H] 90% purity.

PREPARED EXAMPLE X-370-C To a 3-H adduct solution (0.50 g, 0.87 mmol) of Preparative Example X-50-C in DMF (5.4 mL) at 0X was added POCI3 (0.13 mL, 1.39 mmol) dropwise. The resulting solution was stirred at t.a. for 12 hr and then cooled again to 0X. Carefully add 1 N NaOH (5 ml) and CH2CI2 (10 ml), the layers separated. The aqueous layer was extracted with CH2Cl2 (2 x 10 ml) and the organic layers were combined. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by preparative thin layer chromatography (6 x 1000 μM plates) using a 2: 1 mixture of hexanes / EtOAc to give 90 mg (17% yield) of a light yellow semi-solid. MS = 606.3 [M + H].

PREPARED EXAMPLE X-380-C To a solution of 3-formyl adduct (90 mg, 0.15 mmol) of Preparative Example X-370-C in MeOH (1.5 mL) at t.a. Tos-Mic (29 mg, 0.15 mmol) and K2CO3 (21 mg, 0.15 mmol) were added. The mixture was added with a condenser and heated to reflux. After 4 hr, the mixture was cooled to t.a. and concentrated under reduced pressure. The resulting semi-solid was partitioned between CH2Cl2 (3 mL) and water (1 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 10 mL). The organic layers were combined and washed with brine (x 5 ml). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by preparative thin layer chromatography (4 x 1000 μM plates) using a 40: 1 mixture of CH 2 Cl 2 / MeOH (7M NH 3) to give 67 mg (69% yield) of an orange / brown solid. LC-MS = 606.3 [M + H] 93% purity.

PREPARED EXAMPLE X-390-C To a round bottom flask loaded with adduct 3-1 (0.25 g, 0.35 mmol) of preparative example X-60-C, KCN (26 mg, 0.40 mmol), Cul (20 mg, 0.035 mmol), Pd (PPh3) 4 (8 mg, 0.035 mmol) and stir bar, degassed THF (9 mL) was added. The mixture was heated to reflux and stirred for 5 h (until complete by CCD). The mixture was cooled to t.a. and was diluted with EtOAc (5 mL). The mixture was filtered through a pad of Celite which was subsequently washed with EtOAc (2 x 5 ml). The resulting filtrate was washed sequentially with water (2 x 2 ml) and brine (2 x 2 ml). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by preparative thin layer chromatography (4 x 1000 μM plates) using a 50: 1 mixture of CH 2 Cl 2 / MeOH to give 169 mg (80% yield) of a light yellow semi-solid. LC-MS = 606.3 [M + H]; 94% purity.

PREPARED EXAMPLE X-400-C To a 3-CN adduct solution (0.15 g, 0.25 mmol) of Preparative Example X-390-C was added NaHC 3 (84 mg, 1.0 mmol) and hydroxylamine hydrochloride (35 mg, 0.50 mmol). The mixture was added with a condenser and heated to reflux and stirred for 12 hr at this temperature. The mixture was cooled to t.a. and it was filtered through a glass funnel concreted with medium. The resulting ppt was washed with MeOH (2 mL) and the resulting filtrate was concentrated under reduced pressure to give 155 mg (97% yield) of a yellow solid. LC-MS = 636.3 [M + H]; 80% purity. This material was carried without further purification.

PREPARED EXAMPLE X-410-C A solution of amido oxime adduct (0.17 g, 0.25 mmol) of preparative example X-400-C in triethyl orthoformate (3 ml) was heated at 80X for 12 hr. The mixture was cooled to t.a. after which PPTS (94 mg, 0.38 mmol) was added and the mixture re-heated to 80X and stirred for 4 hr. The mixture was cooled to t.a. and concentrated under reduced pressure. The crude material was purified by preparative thin layer chromatography (6 x 1000 μM plates) using a 50: 1 mixture of CH 2 Cl 2 / MeOH to give 110 mg (68% yield) of a light yellow semi-solid. LC-MS = 646.4 [M + H]; 65% purity.

PREPARED EXAMPLE X-420-C To a mixture of Boc derivative (3.0 g, 7.3 mmol) of preparative example X-310-C in DME / H20 (16 ml / 4 ml) was added 1-methyl-4- (4,4,5,5- tetramethyl-1, 3,2-dioxaborolan-2-yl) -1 / - / - pyrazolo (2.8 g, 13.5 mmol) and Na 2 CO 3 (3.9 g, 36.4 mmol). N2 was bubbled through the solution for 20 min with stirring after which PdCI2 (PPh3) 2 (0.39 g, 0.47 mmol) was added. The mixture was heated to 110X and stirred for 12 hr. The mixture was cooled to t.a., concentrated under reduced pressure and placed under high vacuum. The crude product was purified by flash chromatography using a 30: 1 mixture of CH2Cl2 / MeOH as eluent to give 1.57 g (52% yield) as an orange / brown solid.

LC-MS: = 413.2 [M + H] 97% purity.

EXAMPLE PREPARATIVE 420-C In an analogous manner as described in preparative example X-350-C, the 7-methoxy adduct or (2.0 g, 4.8 mmol) of preparative example X-420-C was converted to 600 mg (32% yield) of the composed of the title. LC-MS: = 398.2 [M + H]; 93% purity.

PREPARED EXAMPLE X-430-C To a solution of Boc adduct (0.60 g, 1.51 mmol) of preparative example X-420-C in CH 2 Cl 2 (10 ml) at t.a. DMAP (0.21 g, 1.7 mmol) was added followed by BoC2O (0.36 g, 1.7 mmol). The mixture was allowed to warm to t.a. and stirred for 12 hr. The mixture was washed with water (2 x 3 ml) and brine (2 x 3 ml). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by preparative CCD using 6 x 1000 mM plates with 20: 1 CH2Cl2 / MeOH (7N NH3) as eluent to give 0.35 g (47% yield) as an off-white solid. LC-MS: = 498.3 [M + H]; 99% purity.

PREPARED EXAMPLE X-440-C To a solution of Boc adduct (0.10 g, 0.20 mmol) of preparative example X-430-C in CH3CN (3 ml) at t.a. K2C03 (55 mg, 0.40 mmol) was added followed by Etl (24 μL, 0.31 mmol). The mixture was stirred at t.a. for 12 hr and filtered through a concreted glass funnel. The ppt was washed with CH3CN (10 mL) and the filtrate was concentrated under reduced pressure. The crude material was purified by preparative CCD using 2 x 1000 mM plates with 1: 2 hexanes / EtOAc as eluent to give 70 mg (67% yield) as an off-white solid. LC-MS: = 526.3 [M + H]; > 85% purity.

PREPARED EXAMPLE X-450-C Using the procedure in preparative example X-440-C, the Boc adduct (0.12 g, 0.24 mmol) of preparative example 430-C was treated with cyclopentylmethyl iodide (0.11 g, 0.48 mmol) to give 50 mg (40% strength). yield) of the title compound. LC-MS: = 580.3 [M + H]; 89% purity.

PREPARED EXAMPLE X-460-C Using the procedure in preparative example X-440-C, the Boc adduct (0.10 g, 0.20 mmol) of preparative example X-430-C was treated with 2-iodopropane (30 μl, 0.30 mmol) to give 75 mg (32 μg). % yield) of the title compound. LC-MS: = 540.3 [M + H]; 23% purity.

PREPARED EXAMPLE X-470-C 3-Amino-4-bromopyrazolo (5 g, 30.9 mmol) and 4-methoxybenzyl chloride (21 g, 134 mmol, 4.3 equiv.) Were combined in anhydrous DMF (25 mL) and added dropwise to a stirred suspension. of sodium hydride (60% dispersion in mineral oil, 6.25 g, 156 mmol, 5 equiv.) in anhydrous DMF (50 ml). The resulting suspension was stirred 2 days at room temperature. Water (300 ml) was added slowly and the resulting mixture was extracted with ether (4 x 350 ml). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was dissolved in dichloromethane and purified by silica gel chromatography using a gradient of 10% to 20% ethyl acetate-hexanes. The product, a white solid, was obtained as a 60:40 mixture of the 1-benzylated-1 H product and the 2-benzylated-2H product (total 14.96 g, 93% yield).

PREPARED EXAMPLE X-480-C The compound of preparative example X-470-C (10 g, 19.15 mmol) and 1-methyl-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1 / - / - pyrazolo (11.95 g, 57.42 mmol, 3.0 equiv.) were combined in 120 ml dimethoxyethane. 2M sodium carbonate solution (30 ml, 60 mmol, 3.1 equiv.) Was added followed by tetrakis (triphenylphosphine) palladium (O) (2.36 g, 2.04 mmol, 0.11 equiv.). The mixture was stirred 16 hours at 90X. After cooling to room temperature, water (200 ml) and brine (50 ml) were added and the mixture was extracted with ethyl acetate (2 x 200 ml). The extracts were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was dissolved in dichloromethane and purified by silica gel chromatography using a gradient from 33% to 66% ethyl acetate-hexanes. The 1-benzylated-1H product (Rf = 0.27 in 66% ethyl acetate-hexanes) was eluted first, followed by the 2-benzylated-2H product (Rf = 0.19 in 66% ethyl acetate-hexanes). The product was obtained as a yellow solid (total 5.60 g, 56% yield) with an isomeric ratio of 62:38.

PREPARED EXAMPLE X-490-C The compound of Preparative Example X-80-C (4.3 g, 8.22 mmol) was dissolved in trifluoroacetic acid (70 mL) and stirred for 17 hours at reflux. After cooling, the trifluoroacetic acid was removed under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (100 ml), methanol (50 ml) and 4N aqueous sodium hydroxide solution (25 ml, 100 mmol, 12 equiv.). The mixture was stirred 4 hours at 70 ° C, then cooled to room temperature. The mixture was concentrated and the residue was suspended in brine (100 ml) and water (40 ml). This mixture was extracted with 20% isopropanol in ethyl acetate (8 x 100 ml). The extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was dissolved in 10% methanol in dichloromethane and purified by silica gel chromatography using 10% methanol-dichloromethane followed by 10% 7N ammonia in methanol-dichloromethane. The product was obtained as a tan to coffee solid (1.03 g, 77% yield).

PREPARED EXAMPLE X-490-C To a solution of aminopyrazole (0.74 g, 4.5 mmol) of preparative example X-490-C in toluene (40 ml) in a pressure tube at t.a. β-ketoester (1.5 g, 5.0 mmol) of Preparative Example X-10-C was added. The pressure tube was capped and heated to 110X and stirred for 12 hr. The mixture was cooled to t.a. and concentrated under reduced pressure. The material was collected raw for the next transformation. LC-MS: = 399.2 [M + H]; 70% purity.

PREPARED EXAMPLE X-500-C To a solution of 7-hydroxyl adduct (1.84 g, 4.5 mmol) of preparative example X-490-C in POCI3 (13 mL, 0.14 mol) at t.a. was added? /,? / - dimethylaniline (2 mL, 15.8 mmol). The resulting solution was stirred at t.a. for 12 hr (until complete by CCD) and concentrated under reduced pressure. The crude material was cooled to OX and treated with CH2Cl2 (50 mL) and aq NaHCO3. sat (10 ml). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 50 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 1: 1 mixture of hexanes / CH 2 Cl 2 as eluent to give 1.4 g (96% yield) of a brown semi-solid. LC-MS: = 317.2 [M + H]; 95% purity.

PREPARED EXAMPLE X-510-C To a solution of 7-chloro adduct (30 mg, 0.072 mmol) of preparative example X-500-C in dioxane (1 ml) was added DIPEA (25 μl, 0.14 mmol) followed by cyclohexylamine (13 μl, 0.11 mmol). The mixture was heated to 90X and stirred for 3 hr (until complete by CCD). The mixture was cooled to t.a., concentrated under reduced pressure, and placed under high vacuum. The crude product was purified by flash chromatography using a 20: 1 mixture of CH2Cl2 / MeOH to give 24 mg (69% yield) of an orange semi-solid. MS = 480.3 [M + H].

PREPARATION EXAMPLES X520-C-X560-C Following the procedure set forth in Preparative Example X-510-C but using the amines in column 2 of Table X-50-C, substituted pyrazolo [1, 5-a] pyrimidine adducts were prepared in column 3 of Table X -50-C.

TABLE X-50-C PREPARED EXAMPLE X-570-C To a solution of 7-methoxy adduct (0.10 g, 0.24 mmol) of Preparative Example X-420-C in dioxane (1 mL) was added benzylamine (0.13 mL, 1.2 mmol). The mixture was heated to 90X and stirred for 72 hr (until complete by CCD). The mixture was cooled to t.a., concentrated under reduced pressure, and placed under high vacuum. The crude product was purified by flash chromatography using a 20: 1 mixture of CH2Cl2 / MeOH to give 25 mg (21% yield) of an orange semi-solid. LC-MS = 488.3 [M + H]; 65% purity.

PREPARED EXAMPLE X-580-C To a solution of ethanolamine (26 μL, 0.44 mmol) in dry DMSO (2 mL) at t.a. 60% NaH in oil (17 mg, 0.44 mmol) was added in one portion. The resulting mixture was stirred for 15 min at t.a. after which the 7-methoxy adduct (0.09 g, 0.22 mmole) of preparative example X-420-C was added in a single portion. The mixture was stirred for 72 hr at t.a. and was quenched with NH4CI aq. sat (1 ml). The mixture was extracted with a mixture of 10% IPA / CH2CI2 (3 x 5 ml) and the organic layers were combined. The organic layer was washed with brine (1 x 3 ml), dried (Na 2 SO), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 20: 1 mixture of CH2Cl2 / MeOH (7M NH3) to give 120 mg (81% yield) of an orange semi-solid. LC-MS = 442.2 [M + H]; 85% purity.

PREPARED EXAMPLE X-590-C To a solution of Boc adduct (25 mg, 0.054 mmol) of preparative example X-540-C in CH 2 Cl 2 (5 ml) at t.a. f-BuNH2 (0.17 ml, 1.60 mmol) was added. The mixture was stirred for 15 min after which Br2 (2.5 mL, 0.048 mmol) was added dropwise and the reaction was stirred for 10 min (until complete by CCD). The mixture was concentrated to dryness and the crude product was purified by preparative thin layer chromatography using 2 x 1000 mM plates with a 99: 1 mixture of CH2Cl2 / MeOH (7M NH3) as eluent to give 27 mg (92% yield) of an orange semi-solid. LC-MS = 545.3 [M + H], 86% purity.

EXAMPLES PREPARATIONS X600-C -X620-C Following the procedure set forth in Preparative Example 590-C but using the corresponding Boc precursors in column 2 of Table X-60-C, substituted pyrazolo [1, 5-a] pyrimidine adducts were prepared in column 3 of Table X -60-C.

TABLE X-60-C EXAMPLE X-240-C To a mixture of Boc adduct (23 mg, 0.048 mmol) of preparative example X-520-C in CH 2 Cl 2 (1 ml) at t.a. TFA (0.25 ml) was added dropwise. The resulting mixture was stirred for 2 h, concentrated under reduced pressure, and placed under high vacuum to remove traces of volatile compounds. The resulting semi-solid was dissolved in 7M NH3 in MeOH (5 mL), stirred for 4 h, and concentrated under reduced pressure. The crude material was purified by preparative thin layer chromatography (4 x 1000 μM plates) using a 6: 1 mixture of CH 2 Cl 2 / MeOH (7M NH 3) as eluent to give 14 mg (77% yield) of a yellow solid. pale, mp 131-133X; MS = 380.2 [M + H].

EXAMPLES X250-C -X370-C Following the procedure set forth in Example X-240-C using the Boc precursors indicated in column 2 of Table X-70-C, the substituted pyrazolo [1, 5-a] pyrimidine adducts were prepared in column 3 of the table X-70-C TABLE X-70-C EXAMPLE X-380-C To a mixture of ethyl adduct (65 mg, 0.20 mmol) of Example 24 in CH 3 CN (3 mL) at t.a. NBS (32 mg, 0.18 mmol) was added in a single portion. The resulting mixture was stirred for 1 h, concentrated under reduced pressure, and placed under high vacuum to remove traces of volatile compounds. The crude material was purified by preparative thin layer chromatography (2 x 1000 μM plates) using a 10: 1 mixture of CH2Cl2 / MeOH (7M NH3) as eluent to give 3 mg (3% yield) of a yellow-brown solid. . LC-MS = 484.3 [M + H]; > 80% purity.

PREPARED EXAMPLE X-700-C A mixture of the product from preparative example X-60-C (1.50 g, 2.13 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) - 1 H-pírazolo (0.89 g, 4.26 mmol), PdCI2dppf.CH2CI2 (171 mg, 0.21 mmol), and K3PO4 (1.81 g, 8.52 mmol) in 1,2-dimethoxyethane (30 mL) and H2O (6 mL) were stirred and refluxed under N2 for 3 hr. The solvents were evaporated and the residue was purified by column chromatography on silica gel with CH2Cl2 / EtOAc 5: 1 as eluent. A yellow wax was obtained (1.13 g, 81%).

PREPARED EXAMPLE X-710-C A mixture of 4,4,5,5-tetramethyl-2- (1 H -pyrazol-4-yl) -1,2,2-dioxaborlane (0.50 g, 2.58 mmol), 2- (bromomethyl) benzonitrile (0.63 g) , 3.21 mmol), and K2CO3 (1.06 g, 7.68 mmol) in acetonitrile (60 ml) was stirred and refluxed under N2 for 72 hr. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 2: 1 CH2Cl2 / EtOAc as eluent. A yellow wax was obtained (0.75 g, 94%). LC-MS: 310 [M + H].

PREPARED EXAMPLE X720-C-X770-C Essentially by the same procedures set forth in the preparative example X-710-C, only using different alkylating agents given in column 1, the compounds given in column 2 of table X-100-C were prepared. TABLE X-100-C EXAMPLE X-400-C A mixture of the product from preparative example X-700-C (1.00 g) and aqueous 3N HCl (20 ml) in EtOH (20 ml) was stirred at 60X for 1.5 hr. The solvents were evaporated, Na 2 CO 3 (2.0 g) and 6: 1 mixture of CH 2 Cl 2 / MeOH (20 ml) were added to the residue and the mixture was stirred under N 2 for 15 min. It was then loaded onto a column and purified by column chromatography on silica gel with 6: 1 CH2Cl2 / 7N NH3 in MeOH as eluent. A white solid was obtained (405 mg, 90%). LC-MS: 298 [M + H].

EXAMPLES X410-C-X530-C Essentially by the same procedures set forth in preparative example X-700-C and example 400-C, only using different boron reagents given in column 1 for Suzuki couplings with the intermediate of preparative example X-60-C , the compounds given in column 2 of Table X-110-C were prepared.

TABLE X-110-C PREPARED EXAMPLE X-770-C A mixture of the product from Example X-400-C (0.30 g, 1.00 mmol) and (tert-butyldimethylsilyloxy) acetaldehyde (0.17 g, 1.00 mmol) in CH2Cl2 (5 mL) and MeOH (1 mL) was stirred at 25X for 18 h. hr. NaBH (OAc) 3 (0.36 g, 1.7 mmol) was then added and the mixture was stirred for 1 hr. The solvents were evaporated and the mixture was purified by column chromatography on silica gel with 10: 1 CH2Cl2 / MeOH as eluent. A waxy solid was obtained (60 mg, 13%). LC-MS: 456 [M +].

EXAMPLE X-540-C Essentially by the same procedure set forth in Example X-400-C, starting from the compound of Preparative Example X-770-C, the title compound was prepared. Waxy solid. LC-MS: 342 [M + H].

EXAMPLE X-550-C A solution of N-iodosuccinimide (33 mg, 0.15 mmol) in anhydrous CH3CN (2 mL) was added under N2 to a stirred solution of the product of Example 400-C (50 mg, 0.17 mmol) in anhydrous CH3CN < (3 ml) and CH2Cl2 (5 ml). The mixture was stirred for 1 hr, the solvents were evaporated, and the residue was purified by column chromatography on silica gel with 15: 1 CH2Cl2 / 7N NH3 in MeOH as eluent. A white solid was obtained (52 mg, 83%). LC-MS: 424 [M + H]. Pf = 99-101 X.

PREPARED EXAMPLE X-780-C A mixture of the product of preparative example X-60-C (703 mg, 1.00 mmol), boronate (299 mg, 1.30 mmol), PdCI2dppf.CH2CI2 (82 mg, 0.10 mmol), and K3P0 (848 mg, 4.00 mmol) in 1,2-dimethoxyethane (20 ml) and H20 (4 ml) was stirred and refluxed under N2 for 3 hr. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 10: 1 CH2Cl2 / EtOAc as eluent. A yellow wax was obtained (430 mg, 63%). LC-MS: 680 [M + H].

EXAMPLE X-560-C A mixture of the product from preparative example X-780-C (200 mg) and TFA (5 ml) in H20 (5 ml) was stirred at 25X for 1.5 hr. The solvents were evaporated, Na 2 CO 3 (1.0 g) and 6: 1 mixture of CH 2 Cl 2 / MeOH (3 ml) was added to the residue and the mixture was stirred under N 2 for 15 min. It was then loaded onto a column and purified by column chromatography on silica gel with 6: 1 CH2Cl2 / 7N NH3 in MeOH as eluent. A white solid was obtained (70 mg, 75%). Mp = 270-272X. LC-MS: 320 [M + H].

EXAMPLE X-570-C A solution of NBS (32 mg, 0.18 mmol) in anhydrous CH3CN (3 mL) was added under N2 to a stirred solution of the product of Example 560-C (65 mg, 0.20 mmol) in anhydrous CH3CN (3 mL) and MeOH ( 9 ml). The mixture was stirred for 24 hr, the solvents were evaporated, and the residue was purified by column chromatography on silica gel with 8: 1 CH 2 Cl 2 / NH 3 7 in MeOH as eluent. A white solid was obtained (27 mg, 38%). Pf = 200-203X. LC-MS: 399 [M + H].

EXAMPLE X-580-C Essentially by the same procedures set forth in Preparative Example X-570-C, starting from the compound of Example 410-C, the above compound was prepared. Pale yellow solid. Pf = 64-67X.

LC-MS: 363 [M + H].

EXAMPLE X-590-C Essentially by the same procedures set forth in Example X-570-C, starting from the compound of Example 420-C, the above compound was prepared. White solid. Mp = 66-69 ° C. LC-MS: 406 [M +].

EXAMPLES X590-C - X630-C Essentially by the same procedure set forth in Example X-570-C, starting from the compounds in column 1 of Table X-120C, the compounds were prepared in column 2 of Table X-120C.

TABLE X-120-C PREPARED EXAMPLE X-790-C A mixture of the product of the preparative example X-60-C (1.50 g, 2.13 mmol), the boronate of formylfuran (0.732 g, 3.30 mmol), PdCI2dppf.CH2CI2 (171 mg, 0.21 mmol), and K3P04 (1.81 g, 8.52 mmoles) in 1,2-dimethoxyethane (30 ml) and H20 (6 ml) was stirred and refluxed under N2 for 3 hr. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 4: 1 hexane / EtOAc as eluent. A yellow wax was obtained (890 mg, 62%). LC-MS: 672 [M + H].

PREPARED EXAMPLE X-800-C A mixture of the product of preparative example X-790-C (440 mg, 0.65 mmol), NH2OH.HCl (50 mg, 0.72 mmol), and triethylamine (1.0 ml) in 1,2-dichloroethane (3 ml) and MeOH ( 3 ml) was stirred in a closed flask at 25X for 1 hr. The solvent was evaporated and the residue was chromatographed on silica gel with 3: 1 hexane / EtOAc as eluent. A slightly yellow wax was obtained (310 mg, 69%). LC-MS: 687 [M + H].

PREPARED EXAMPLE X-810-C Trifluoroacetic anhydride (92 mg, 0.44 mmol) was added to OX under N2 to a stirred solution of the product of Preparative Example X-800-C (300 mg, 0.44 mmol) in anhydrous CH2Cl2 (5 mL) and triethylamine (0.5 mL). The mixture was stirred for 1.5 hr, then it was emptied into saturated aqueous NaHCO3 solution (50 ml), extracted with CH2Cl2 (3x10 ml), dried over Na2SO4, and filtered. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 7: 1 hexane / EtOAc as eluent. A slightly yellow wax was obtained (192 mg, 65%). LC-MS: 669 [M + H].

EXAMPLE X-640-C Essentially by the same procedures set forth in Preparative Example X-780-C, starting from the compound of Preparative Example 810-C, the above compound was prepared. White solid. Mp = 188-191 X. LC-MS: 309 [M + H].

EXAMPLE X-650-C Essentially by the same procedures set forth in Example X-570-C, starting from the compound of Example 640-C, the above compound was prepared. White solid. LC-MS: 387 [M + H].

EXAMPLE X-660-C Essentially by the same procedures set forth in Example X-570-C, starting from the compound of Example X-640-C and using N-chlorosuccinimide instead of N-bromosuccinimide, the above compound was prepared. White solid. LC-MS: 343 [M + H].

EXAMPLE X-670-C Essentially by the same procedures set forth in Preparative Example X-560-C, starting from the compound of Preparative Example X-800-C, the above compound was prepared. White solid. LC-MS: 327 [M + H].

EXAMPLE X-680-C A solution of LiAIH (1.0 M, 1.5 mL, 1.5 mmol) in THF was added under N2 to a stirred solution of the product of Preparative Example X-520-C (70 mg, 0.16 mmol) in anhydrous THF (5 mL). The mixture was stirred for 24 hr, and then MeOH (0.5 ml) was added. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 5: 1 CH2Cl2 / 7N NH3 in MeOH as eluent. A yellow wax was obtained (22 mg, 35%). LC-MS: 404 [M + H].

PREPARED EXAMPLE X-820-C A mixture of the product from preparative example X-40-C (1.00 g, 3.15 mmol), Boc20 (0.757 g, 3.47 mmol), 4-dimethylaminopyridine (0.040 g, 0.33 mmol) and TEA (2.0 mL) in dry CH2Cl2 (20 ml) was stirred under N2 for 2 hr. The mixture was then poured into saturated aqueous NaHCO 3 solution (100 ml), extracted with CH 2 Cl 2 (3x30 ml), dried over Na 2 SO, and filtered. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 2: 1 hexane / EtOAc as eluent. A white solid was obtained (0.94 g, 71%). LC-MS: 418 [M + H].

PREPARED EXAMPLE X-830-C A mixture of the product of preparative example X-820-C (460 mg, 1.10 mmol), SEMCl (276 mg, 1.65 mmol), and diisopropylethylamine (426 mg, 3.30 mmol) in dry 1,2-dichloroethane (5 ml) was stirred and refluxed under N2 for 2 hr. The mixture was then poured into saturated aqueous NaHCO3 solution (50 ml), extracted with CH2Cl2 (3x10 ml), dried over Na2SO4, and filtered. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 2: 1 hexane / EtOAc as eluent. A slightly yellow wax was obtained (500 mg, 83%). LC-MS: 548 [M + H].

PREPARED EXAMPLE X-840-C A solution of NBS (71 mg, 0.40 mmol) in anhydrous CH3CN (2 mL) was added under N2 to a stirred solution of the product from Preparative Example X-830-C (240 mg, 0.44 mmol) in anhydrous CH3CN (3 mL) . The mixture was stirred for 1 hr, the solvents were evaporated, and the residue was purified by column chromatography on silica gel with 5: 1 hexane / EtOAc as eluent. A colorless waxy solid (231 mg, 92%) was obtained. LC-MS: 628 [M + H].

PREPARED EXAMPLE X-850-C A mixture of 4,4,5,5-tetramethyl-2- (1 H -pyrazol-4-yl) -1,2,2-dioxaborolane (5.48 g), SEMCl (5.2 ml), and K2C03 (5.85 g) in NMP (50 ml) was stirred under N2 for 1 hr. The reaction mixture was diluted with EtOAc, rinsed with H20, brine, and dried over Na2SO4. The mixture was filtered, the solvents were evaporated and the residue was used directly in the next step.

PREPARED EXAMPLE X-860-C A mixture of the product of preparative example X-850-C (774 mg, 1.23 mmol), boronate of preparative example X-1650 (520 mg, 1.60 mmol), PdCI2dppf.CH2CI2 (100 mg, 0.123 mmol), and K3PO4 ( 1.04 g, 4.92 mmol) in 1,2-dimethoxyethane (18 ml) and H2O (6 ml) was stirred and refluxed under N2 for 5 hr. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 4: 1 hexane / EtOAc as eluent. A yellow wax was obtained (528 mg, 58%). LC-MS: 744 [M + H].

EXAMPLE X-690-C A mixture of the product from preparative example X-860-C (520 mg) and aqueous 3N HCl (6 ml) in EtOH (12 ml) was stirred at 60X for 1.5 hr.

Solvents were evaporated, NaHCO 3 (1.0 g) and 6: 1 mixture of CH 2 Cl 2 / MeOH (10 ml) were added to the residue and the mixture was stirred under N 2 for 15 min. It was then loaded onto a column and purified by column chromatography on silica gel with 2: 1 CH2Cl2 / 7N NH3 in MeOH as eluent. A white solid was obtained (60 mg, 30%). LC-MS: 284 [M + H].

EXAMPLES X700-C and X710-C The racemic product of preparative example X-690-C was separated on a semi-preparative Chiralcel AD column. Chromatography with 80:20 mobile phase of hexane / 2-propanol with 0.2% diethylamine gave two isomers: Example 700-C: rapid elution (isomer 1): white solid; LCMS: 284 [M + H] Example 710-C: slow elution (isomer 2): white solid; LC-MS: 284 [M + H].

EXAMPLE X-720-C A solution of NBS (3.7 mg, 0.021 mmol) in anhydrous CH3CN (0.2 mL) was added under N2 to a stirred solution of isomer 2 from Example 710-C (7 mg, 0.024 mmol) in anhydrous MeOH (2 mL). The mixture was stirred for 18 hr, the solvents were evaporated, and the residue was purified by preparative thin layer chromatography on silica gel with 7: 1 CH2Cl2 / 7N NH3 in MeOH as eluent. A white solid was obtained (3.5 mg, 46%). LC-MS: 362 [M + H].

PREPARED EXAMPLE X-800-C Sodium hydride (60% dispersion in mineral oil, 1.57 g, 39.3 mmol, 3.04 equiv.) Was suspended in anhydrous ethyl ether (60 ml) and cooled to 0X. To this suspension was added ethyl formate (1.55 ml, 19.19 mmoles, 1.48 equiv.) And ethanol (1.50 ml, 25.72 mmoles, 1.99 equiv.), Followed by solid 4-pyridylacetonitrile hydrochloride (2.00 g, 12.95 mmoles) in small portions for several minutes. The suspension was then stirred 16 hours, warming to room temperature. Ethanol (3 ml) was added to quench the reaction, and the resulting suspension was filtered and washed with ethyl ether. After drying under vacuum, a light pink solid (2.7211 g) was obtained. This solid was suspended in ethanol (30 ml) and acetic acid (3 ml) and hydrazine monohydrate (2.0 ml, 41.23 mmol, 3.18 equiv.) Were added. The mixture was then heated to reflux overnight. After cooling, the heterogeneous mixture was concentrated under reduced pressure and the crude solid was suspended in 6.5% methanol-dichloromethane, loaded on a silica gel chromatography column and purified using 6.5% to 20% methanol-dichloromethane . An orange oily solid was obtained (0.645 g, 31% yield).

PREPARED EXAMPLE X-810-C Pyridine-2,3-dicarboxylic anhydride (24 g, 161 mmol) was suspended in anhydrous pyridine (20 ml) and re-butanol (30 ml) and stirred at 40X for 16 hours. After cooling, the suspension was concentrated under reduced pressure at 50X for at least 30 minutes, and then dried under vacuum for 3 hours. The crude intermediate (53 g), which included pyridine (21% by weight) and rer-butanol (8% by weight), was dissolved in methanol (300 ml) and dichloromethane (100 ml) and treated with trimethylsilyldiazomethane (2M solution in hexanes, 165 ml, 330 mmol, 2.05 equiv.). The resulting orange solution was stirred 16 hours at room temperature, concentrated under reduced pressure (50X), and the crude product was dissolved in dichloromethane (120 ml) and purified on an Isco Redisep 330g chromatography column eluting with 75% acetate of ethylhexanes. The product, a brown oil (21.3 g, 56% yield), consisted of 80% 2-tert-butyl 3-methyl pyridine-2,3-dicarboxylate and 20% 2-methyl pyridine-2,3- 3-tert-butyl dicarboxylate.

PREPARED EXAMPLE X-820-C 4- (Methoxycarbonyl) pyridine-2-carboxylic acid (24.63 g, 136 mmol) was suspended in tert-butanol (250 ml) and pyridine (75 ml) and cooled in an ice-water bath. 4-Toluenesulfonyl chloride (62.11 g, 326 mmol, 2.39 equiv.) Was added in one portion and the mixture was stirred 30 minutes in the ice-water bath, then 2 hours at room temperature. The mixture was then slowly poured into a stirred mixture of saturated aqueous sodium bicarbonate (1 L) and ethyl ether (500 mL). The resulting two-phase mixture was then extracted with ethyl ether (3 x 1 L). The extracts were combined, washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (25.37 g, 79%) was used without further purification.

PREPARED EXAMPLE X-830-C The compound of preparative example X-820-C (25.36 g, 107 mmol) was dissolved in glacial acetic acid (120 ml) and hydrogenated at 2.81-3.51 kg / cm2 for 3 days with 10% palladium on carbon catalyst ( 2.50 g, 2.34 mmoles, 0.022 equiv.). The mixture was filtered through a pad of Celite which was then washed with methanol. The combined filtrates were concentrated under reduced pressure until only excess acetic acid remained. The residue was dissolved in water (500 ml) and solid sodium carbonate (55 g) was added to bring the pH to 8. This solution was extracted with dichloromethane (2 x 500 ml), and the extracts were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a yellow oil (25.98 g, 100% yield).

PREPARED EXAMPLE X-840-C -o- Essentially by the same procedure as that set forth in Preparative Example X-830-C, only using the compound of Preparative Example 810-C, the above compound was prepared in 96% yield (mixture of 80:20 isomers) .

PREPARED EXAMPLE X-850-C The compound of Preparative Example X-830-C (25.97 g, 106.9 mmol) and triethylamine (20 mL, 143 mmol, 1.34 equiv.) Were combined in dichloromethane (200 mL) and cooled to 0X. Benzyl chloroformate (18.5 ml, 130 mmol, 1.21 equiv.) Was added slowly and the mixture was stirred 2 days at room temperature. The mixture was diluted with water (200 ml) and extracted with dichloromethane (2 x 200 ml). The combined extracts were washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (41.69 g) was loaded onto an Isco Redisep 750-gram chromatography column and purified using the ISCO Combiflash Companion XL system, which ran a gradient of 10% to 20% ethyl acetate-hexanes. A colorless oil was obtained (19.66 g, 49% yield).

PREPARED EXAMPLE X-860-C Essentially by the same procedure as that set forth in the preparative example X-850-C, only using the compound of the preparative example X-840-C, the above piperidine was prepared in 82% yield.

PREPARED EXAMPLE X-870-C Methyl 4-oxo-piperidinecarboxylate hydrochloride (7.51 g, 38.79 mmol) was suspended in dichloromethane (100 ml) and cooled to OX. Triethylamine (19 ml, 136 mmol, 3.5 equiv.) Was added slowly followed by benzyl chloroformate (11 ml, 77 mmol, 1.99 equiv.). The mixture was stirred 3 days at room temperature, and then diluted with water (100 ml) and the two phases were separated. The aqueous phase was then extracted with dichloromethane (100 ml), the two organic extracts were combined and washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting yellow oil was purified by chromatography on an Analogix SF40-240 Column using an Analogix Intelliflash 280 system, running a gradient of 15% to 30% ethyl acetate-hexanes. The product was obtained as a colorless oil (6.40 g, 57% yield).

PREPARED EXAMPLE X-880-C The keto ester of preparative example X-870-C (6.39 g, 22.0 mmol), ethylene glycol (12 ml, 215 mmol, 9.8 equiv.) And 4-toluenesulfonic acid monohydrate (0.640 g, 3.36 mmol, 0.15 equiv.) Were heated together in benzene (90 ml) at reflux with a Dean-Stark trap for 12 hours. After cooling, saturated aqueous sodium bicarbonate (75 ml) was added and the two phases were mixed and separated. The aqueous phase was extracted with ethyl ether (75 ml), and the ether and benzene layers were combined and washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. A colorless oil was obtained (7.17 g, 98% yield), which was used without further purification.

PREPARED EXAMPLE X-890-C 3-amino-1-cyclohexanecarboxylic acid (1503 g, 10.50 mmol, 87% cis by NMR) was suspended in anhydrous methanol (20 ml) and thionyl chloride (0.80 ml, 10.99 mmol, 1.05 equiv.) Was added dropwise for 3 minutes, resulting in a clear yellow homogeneous solution. After stirring 1 hour at room temperature, the solution was concentrated under reduced pressure to give a viscous, colorless oil. This oil was dissolved in anhydrous dichloromethane (20 ml) and triethylamine (3.70 ml, 26.55 mmol, 2.53 equiv.) Was added followed by di-tert-butyl dicarbonate (2.78 g, 12.74 mmol, 1.21 equiv.). The resulting suspension was stirred 15 hours at room temperature and then diluted with water (20 ml), mixed and separated in two phases. The aqueous phase was further extracted with ethyl acetate (2 x 20 ml). The organic phases were combined, washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was obtained as a white solid (2607 g, 97% yield) which is 90% cis by NMR.

PREPARED EXAMPLE X-900-C -Methyl-2-pyrrolidinone (5.09 g, 51.35 mmol) was stirred 15 hours in 6N aqueous hydrochloric acid (75 ml) at 100X. The solution was concentrated under reduced pressure to give a white solid which was redissolved in methanol (100 ml) to which thionyl chloride (3.75 ml, 51.54 mmoles, 1.00 equiv.) Was added slowly. After 1 hour at room temperature, the solution was concentrated under reduced pressure and the resulting crude ester was redissolved in anhydrous dichloromethane (100 ml). Triethylamine (21.5 ml, 154 mmol, 3.00 equiv.) Was added followed by di-re-butyl dicarbonate (16.88 g, 77.3 mmol, 1.51 equiv.), And the resulting solution was stirred 2 days at room temperature. The opaque yellow solution was diluted with water (100 ml), and the two phases were mixed and separated. The aqueous phase was extracted with dichloromethane (2 x 100 ml), and the combined extracts were washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give an orange oil (11.13 g, 94%). of performance.) PREPARED EXAMPLE X-910-C A solution of the ester (1.23 g, 5.05 mmol) in THF (20 ml) at -78X was treated with LIHMDS (6.1 ml of a 1.0M solution in THF, 1.2 equiv.) Dropwise. The solution was stirred at -78X for 1 hr and treated with CH3I (0.38 ml, 1.2 equiv.) Dropwise. The solution was stirred at -78X for 2 hr and at 25X for 1 hr. The solution was quenched by the addition of saturated NH CI (100 ml). The aqueous layer was extracted with Et2O (3 x 25 ml). The combined organic layer was dried (MgSO), filtered and concentrated under reduced pressure. The residue was purified by an Analogix purification system using a RediSep 40g column (25% ethyl acetate-hexanes) to provide a white solid (1.08 g, 83%).

EXAMPLES PREPARATION X920-C-X930-C Essentially by the same procedure set forth in Preparative Example X-910-C, the compounds given in column 2 of Table X-200-C were prepared.

TABLE X-200-C PREPARED EXAMPLE X-940-C The compound of Preparative Example X-850-C (2024 g, 5.37 mmol) was stirred 16 hours at room temperature in a mixture of 2N aqueous sodium hydroxide (6.5 ml., 13 mmol, 2.42 equiv.), Methanol (8 ml) and tetrahydrofuran (15 ml). Then 4N aqueous hydrochloric acid (3 ml) was added to bring the pH to 2-3, the mixture was diluted with water (50 ml) and extracted with ethyl acetate (3 x 50 ml). The combined extracts were washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a light yellow oil (1857 g, 95% yield).

EXAMPLES PREPARATION X950-C-X980-C Essentially by the same procedure set forth in Preparative Example X-940-C, the compounds given in column 2 of Table X-210-C were prepared.

TABLE X-210-C PREPARED EXAMPLE X-990-C An ester solution of Preparative Example X-910-C (1.08 g, 4.20 mmol) in EtOH (16.8 mL) at 25X was treated with NaOH (0.050 g, 3 equiv.). The solution was heated to 70X for 3 hr. The solution was cooled to 25X and concentrated under reduced pressure. The residue was dissolved in H20 (50 ml). The aqueous layer was washed with Et20 (2 x 30 ml). The aqueous layer was acidified to pH = 1 with 1 M HCl. The aqueous layer was extracted with Et20 (2 x 30 mL) and the organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was used directly in the next reaction.

EXAMPLES PREPARATION X1000-C and X1010-C Essentially by the same procedure set forth in Preparative Example X-990-C, the compounds given in column 2 of Table X-220-C were prepared. ', TABLE X-220-C PREPARED EXAMPLE X-1020-C The acid of preparative example X-940-C (1898 g, 5.23 mmol) and 1,1 '-carbonyldiimidazole (1.045 g, 6.44 mmol, 1.23 equiv.) Was stirred 16 hours at room temperature in anhydrous THF (20 mL). In a separate flask, anhydrous ethyl acetate (1.10 ml, 11.26 mmol, 2.15 equiv.) Was added dropwise to a solution of lithium bis (trimethylsilylamide) (11 ml of 1.0M / THF, 11 mmol, 2.10 equiv. ) in anhydrous THF (20 ml) at -78X. After stirring 1 hour at -78X, the crude acylimidazole solution was added dropwise. The solution was stirred four hours, heating to 5X, and then quenched with saturated ammonium chloride solution (50 ml) and water (10 ml). This mixture was extracted with ethyl ether (2 x 60 ml), and the combined extracts were washed with saturated sodium bicarbonate, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product (2.17 g) was used without further purification.

PREPARED EXAMPLE X-1030-C The aminopyrazol from preparative example X-800-C (2.39 g, 14.94 mmol) and ethyl acetoacetate (2.50 ml, 19.61 mmol, 1.31 equiv.) Were combined in glacial acetic acid (15 ml) and stirred at reflux for 14 hours. After cooling, the slurry was diluted with ethyl ether, filtered and the resulting solid was washed with additional ethyl ether. After drying under vacuum overnight at 55X, an orange solid was obtained (2687 g, 80% yield).

PREPARED EXAMPLE X-1040-C The β-ketoester of preparative example X-1020-C (1516 g, 3.50 mmol) and pyrazolo XY (0.457 g, 2.80 mmol) were stirred for 24 hours in a sealed tube heated to 115X. After cooling to room temperature, the dark brown solution was concentrated under reduced pressure to crude product (1.8434 g, -80% pure) which was used without purification.

PREPARED EXAMPLE X-1050-C Phosphorus oxychloride (25 ml) was added to the compound of preparative example X-1030-C (2683 g, 11.87 mmol) to give a green suspension, to which was added? /,? / -dimethylaniline (6.25 ml, 49.31 mmoles) , 4.15 equiv.) Resulting in a yellow-brown suspension. This suspension was heated at 105X for 1.5 hours, then cooled to room temperature. The reaction was quenched by slowly adding a vigorously stirred mixture of ice (200 g), water (100 ml) and sodium carbonate (90 g). After the ice was finished melting, the resulting dark red suspension was extracted with ethyl acetate (200 ml). The organic extract was then washed with water (200 ml) and with brine (100 ml), and then dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude red solid thus obtained was dissolved in dichloromethane and purified by chromatography on silica gel using a gradient from 0% to 100% ethyl acetate-dichloromethane followed by 0.5% to 5% methanol-ethyl acetate. A yellow-brown solid was obtained (1014 g, 35% yield).

PREPARED EXAMPLE X-1060-C Phosphorus oxychloride (10 ml) was added to the crude compound of preparative example X-1020-C (0.861 g, 1.40 mmol) to give a green suspension, to which was added? /,? / - dimethylaniline (0.55 ml, 4.34 mmoles, 3.10 equiv.) resulting in a dark brown suspension.

This suspension was stirred 2 days at room temperature, and then diluted with dichloromethane and concentrated under reduced pressure. The residue was redissolved in ethyl acetate (10 ml) and added to a stirred mixture of ice (75 g), 2M aqueous sodium carbonate (75 ml) and ethyl acetate (25 ml).

After the ice was finished melting, the resulting dark red suspension was extracted with ethyl acetate (3 x 100 ml). The combined extracts were then washed with water (200 ml) and with brine (100 ml), and subsequently dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude red oil thus obtained was dissolved in dichloromethane and purified by chromatography on silica gel using a gradient of 33% to 100% ethyl acetate-hexane. An orange oil was obtained (0.395 g, 51% yield).

PREPARED EXAMPLE X-1070-C The chlorine compound of preparative example X-1060-C (0.397 g, 0.721 mmol) in 7N ammonia in methanol (8 ml) was stirred for 16 hours in a sealed tube at 55X and then 21 hours at 80X. After cooling, a white precipitate formed and this was dissolved with the addition of dichloromethane (5 ml). The solution was concentrated and the resulting yellow solid was dissolved in 20% acetonitrile-dichloromethane and purified by silica gel chromatography using a gradient from 20% to 75% acetonitrile-dichloromethane. A white solid was obtained (0.282 g, 74% yield).; PREPARED EXAMPLE X-1080-C The chlorine compound of Preparative Example X-1050-C (0.100 g, 0.410 mmol), 4-amino-1-Boc-piperidine (0.137 g, 0.684 mmol, 1.67 equiv.) And triethylamine (0.25 mL, 1.79 mmol, 4.37 equiv.) were dissolved in anhydrous 1,4-dioxane (5 ml) and the resulting solution was stirred 15 hours at 95X. After cooling, the solution was concentrated under reduced pressure to give a yellow solid. This solid was dissolved in dichloromethane and purified by silica gel chromatography using 5% methanol-dichloromethane. A yellow solid was obtained (0.1145 g, 68% yield). LCMS: 409 [MH +]. 13 C NMR (CDCl 3) d 161.14, 154.58, 149.49, 146.33, 145.27, 141. 64, 140.97, 119.79, 105.65, 86.68, 80.10, 67.07, 49.42, 31.72, 28.39, 25.52.

PREPARED EXAMPLE X-1090-C Essentially by the same procedure as that set forth in preparative example X-1080-C, the foregoing was prepared, using N-oc-propanediamine.

EXAMPLES PREPARATIONS X1100-C and X1110-C Essentially by the same procedure set forth in preparative example X-1080-C, using N-Boc-ethanolamine, the above compounds, preparative example 1100-C and preparative example X-1110-C were prepared. X-1100-C: CLEM: 270 [MH +]. 13C NMR (CD3OD) d 162.51, 149.43, 148.26, 147.47, 142.95, 121.03, 105.46, 87.73, 60.84, 44.92, 25.33. XXb: LCMS: 370 [MH +]. 13C NMR (CDCI3) d 161.25, 153.31, 149.37, 146.32, 141.79, 141.06, 119.91, 105.55, 86.51, 83.13, 64.29, 41.26, 27.66, 25.52.

PREPARED EXAMPLE X-1120-C The compound of Preparative Example X-1100-C (0.031 g, 0.115 mmol) was dissolved in anhydrous dichloromethane (3 mL) and triethylamine (0.10 mL, 0.717 mmol, 6.23 equiv.) And acetic anhydride (0.03 mL, 0.32 mmol) were added. , 2.78 equiv.). The solution was stirred 2 days at room temperature and then concentrated under reduced pressure to give a yellow solid which was dissolved in dichloromethane and purified by silica gel chromatography using a gradient from 5% to 10% methanol-dichioromethane. A yellow solid was obtained (0.034 g, 95% yield). LCMS: 312 [MH +]. 13 C NMR (CDCl 3) d 170.97, 161.18, 149.63, 146.29, 141.79, 140.75, 1 19.98, 105.66, 86.46, 62.09, 41.12, 25.50, 20.79.

PREPARED EXAMPLE X-1130-C A solution of acid (10.0 g, 43.62 mmol) in THF (132 ml) was treated with 1,1'-carbonyldiimidazole (7.78 g, 1.1 equiv.). The solution was stirred at 25X for 18 h. In a separate flask was added LiHMDS (96 ml of a 1.0M solution in THF, 2.2 equiv.) In THF (132 ml). The solution was cooled to -78X and treated with CH3CN (5.0 mL, 2.2 equiv.) Dropwise. The solution was stirred at -78X for 1 hr. To this solution, the acylimidazole solution was added dropwise over 10 minutes. The solution was stirred at -78X for 2 hr and allowed to warm to 25X and stirring was continued for 15 hr. The solution was quenched by the addition of saturated NH 4 Cl (500 mL). The aqueous layer was extracted with Et20 (3 x 100 ml). The combined organic layer was dried (MgSO), filtered and concentrated under reduced pressure. The residue was purified by an Analogix purification system using a RediSep 40g column (gradient 0-50% ethyl acetate-hexanes) to provide XX (4.4 g, 40%) as a pale yellow oil.

PREPARED EXAMPLES X1140-C-X1350-C Essentially by the same procedure set forth in preparative example X-1130-C, the compounds given in column 2 of Table X-230-C were prepared.

TABLE X-230-C PREPARED EXAMPLE X-1360-C A solution of beta-ketonitrile from preparative example X-1 130-C (7.96 g, 22.11 mmol) and bispyrazolo from preparative example X-490-C (3.87 g, 23.73 mmol) in toluene (50 ml) was heated at 115X for 40 hr. The solution was cooled to 25X and MeOH was added to solubilize the precipitate. The solution was concentrated under reduced pressure. Purification by an Analogix purification system using an Analogix SF40-240g column (gradient 0-50% acetone-CH2Cl2) gave a pale yellow solid (7.17 g, 82%).

PREPARATION EXAMPLES X1370-C-X1540-C Essentially by the same procedure set forth in Preparative Example X-1360-C, the compounds given in column 2 of Table X-240-C were prepared. TABLE X-240-C PREPARED EXAMPLE X-1550-C The ß-keto nitrile from preparative example X-1330-C (0.638 g, 2.53 mmol), bispyrazol from preparative example X-490-C (0.414 g, 2.54 mmol, 1.00 equiv.), And anhydrous magnesium sulfate (0.4965 g) , 4.14 mmol, 1.63 equiv.) Were combined in methanol (5 ml) and the resulting suspension was stirred vigorously for two days at room temperature. The suspension was then diluted with dichloromethane, filtered to remove the magnesium sulfate, and the filtrate was concentrated under reduced pressure to give a tan solid. This was suspended in dichloromethane and loaded onto an Isco Redisep RS-40 column using an Analogix DASI-65-YES-50 silica module to retain undissolved solids from the column. The product was purified using an Analogix Intelliflash 280 system running a gradient of 10% to 70% acetone-dichloromethane. The product was obtained as an off-white solid (0.725 g, 72% yield).

PREPARED EXAMPLE X1560-C and X1570-C Using essentially the same procedure set forth in the preparative example X-1550-C, only replacing the appropriate β-keto nitriles, the compounds shown in column 2 of Table X-250-C were prepared.

TABLE X-250-C EXAMPLE X-800-C The compound of preparative example X-1500-C (0.116 g, 0.218 mmol) was dissolved in 50% ethanol-ethyl acetate (5 ml) and hydrogenated using the Thales Nanotechnology H-Cube hydrogenation reactor with a cartridge of 10% palladium-on-carbon catalyst at 1 ml / minute, hydrogen pressure of 50 bar and room temperature. The product solution was concentrated and purified by silica gel chromatography using a gradient of 4% to 7.5% 7N ammonia in methanol-dichloromethane. A white solid was obtained (0.040 g, 46% yield).

LCMS: 398 [MH +]. 13C NMR (CDCI3) d 172.61, 164.07, 147.21, 144.47, 140.72, 135.93, 127.30, 113.39, 101.40, 87.21, 81.50, 57.10, 46.98, 40.44, 38.44, 27.96, 27.85, 25.28.

EXAMPLE X-810-C The compound of Preparative Example X-1500-C (0.120 g, 0.226 mmol) was stirred in 1.25 M HCl / methanol (10 mL) in a sealed tube at 85X for 24 hours. After cooling, the solution was concentrated and the resulting oil was redissolved in methanol (4 ml). Half of this solution was then diluted with glacial acetic acid (0.5 ml) and hydrogenated using the Thales Nanotechnology H-Cube hydrogenation reactor with a catalyst cartridge of 10% palladium-on-carbon at 1 ml / minute, hydrogen of 50 bar and room temperature. The product solution was concentrated and the residue redissolved in 7N ammonia in methanol (5 ml) and concentrated again. The resulting white solid was loaded onto a 5-gram Isco Redisep chromatography column and purified using an Analogix Intelliflash 280 system running a gradient from 0% to 10% methanol-dichloromethane followed by 5% to 15% 7N ammonia in methanol- dichloromethane. The product was a colorless oil (0.018 g, 46% yield). LCMS: 356 [MH +]. 13C NMR (CDCI3) d 171.15, 162.63, 147.89, 143.87, 141.23, 136.15, 127.26, 1 12.96, 101.37, 87.03, 55.95, 52.63, 46.45, 38.43, 37.77, 27.35, 23.67.

PREPARED EXAMPLE X-1580-C The compound of Preparative Example X-1500-C (2.33 g, 4.39 mmol) was dissolved in 1.25 M HCl in methanol solution (30 mL) and stirred 16 hours at 85X in a sealed tube. After cooling, the solution was concentrated under reduced pressure and the resulting oil was redissolved in a mixture of 7N ammonia in methanol and dichloromethane. After stirring for a few minutes, the resulting white suspension was loaded onto an Analogix SF40-115 g column using a DASI-65-frit module to trap the insoluble inorganic matter of the column body. The column was run using an Analogix lntelliflash-280 system running a gradient of 0% to 5% methanol-dichloromethane. The product was obtained as a light brown solid (1.838 g, 85% yield).

PREPARED EXAMPLE X-1590-C Essentially by the same procedure set forth in the preparative example X-1580-C, only replacing the methyl ester of the preparative example X-1520-C, the tert-butyl ester was prepared in 70% yield.

PREPARED EXAMPLE X-1600-C The compound of preparative example X-1520-C (1894 g, 3,874 mmol) was dissolved in methanol (75 ml), to which di-tert-butyl dicarbonate (2.535 g, 11.62 mmol, 3.00 equiv.) Was then added and 10% palladium on carbon (1,220 g, 1.15 mmoles, 0.30 equiv.). The mixture was hydrogenated in a Parr vessel for 3 days at 3.65 kg / cm2. After filtering through Celite and washing with methanol, then dichloromethane, the combined filtrates were combined and concentrated under reduced pressure.

The residue was dissolved in methanol and purified on an Analogix SF40-150 column using Analogix lntelliflash-280 running a gradient from 0% to 10% methanol-dichloromethane. The product was obtained as a yellow solid (1.510 g, 86% yield).

PREPARED EXAMPLE X-1610-C Essentially by the same procedure set forth in the preparative example X-1600-C, only replacing the methyl ester of the preparative example X-1590-C, the above compound was prepared in 81% yield.

PREPARED EXAMPLE X-1620-C The ester of preparative example X-1600-C (0.356 g, 0.781 mmol) in anhydrous THF (6 mL) was treated with lithium triethylborohydride (1 M solution in THF, 4.6 mL, 4.6 mmol, 5.89 equiv.) And stirred 14 hours at room temperature. The solution was then diluted with methanol and concentrated. The residue was suspended in dichloromethane, loaded on an Isco Redisep-40 gram column and purified with an Analogix lntelliflash-280 system running a gradient from 0% to 5% methanol-dichloromethane. The product was obtained as a white solid (0.282 g, 85% yield).

PREPARED EXAMPLE X-1630-C Essentially by the same procedure described in the preparatory example X-1620-C, two products of the methyl ester of preparative example X-1610-C were obtained. The alcohol (53% yield) was obtained as a mixture of cis and trans isomers, while the cyclic carbamate (18% yield) consisted only of trans isomer. LCMS 354 [MH +]. 1 H NMR (CDCl 3) d 8.16 (s, 1 H), 7.93 (s, 1 H), 7.86 (s, 1 H), 5.99 (s, 1 H), 5.96 (s, 2 H), 4.48 (t, J = 8.8 Hz, 1 H), 4.25 (m, 1 H), 4.06 (m, 1 H), 3.98 (s, 3 H), 3.95 (m, 1 H), 2.90 (m, 1 H), 2.65 (m, 1 H), 2.18 (m, 1 H), 1.6-1.9 (m, 3H).

PREPARED EXAMPLE X-1640-C The ester of preparative example X-1600-C (0.182 g, 0.400 mmol), di-tert-butyl dicarbonate (0.263 g, 1.20 mmol, 3 equiv.) And N, N-dimethylamine pyridine (0.149 g, 1.22 mmol, 3 equiv.) were stirred together in THF (2 ml) at room temperature for 14 hours. The resulting solution was then concentrated under reduced pressure, and the residue was dissolved in dichloromethane and purified by chromatography on an Isco Redísep-12 gram column using an Analogix Intelliflash 280 system running 1% methanol-dichloromethane. A yellow oil was obtained (0.245 g, 94% yield).

PREPARED EXAMPLE X-1650-C The ester of preparative example X-1640-C (0.255 g, 0.374 mmol) in anhydrous THF (5 ml) was treated with lithium triethylborohydride (1 M solution in THF, 2.5 ml, 2.5 mmol, 6.68 equiv.) And stirred 14 hours at room temperature. The solution was then diluted with saturated aqueous ammonium chloride (10 ml) and water (1 ml) and extracted with ethyl acetate (2 x 15 ml). The combined extracts were washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting yellow solid was suspended in dichloromethane, loaded onto an Isco Redisep-4 gram column and purified using an Analogix Intelliflash-280 system running a gradient from 0% to 30% methanol-dichloromethane. The product was obtained as a yellow oil (0.172 g, 87% yield).

PREPARED EXAMPLE X-1660-C The alcohol of preparative example X-1650-C (0.086 g, 0.162 mmol) was dissolved in anhydrous THF (1 ml) and sodium hydride (60% dispersion in mineral oil, 0.019 g, 0.475 mmol, 2.93 equiv) was added. . The resulting suspension was stirred 1.5 hours at room temperature, then iodomethane (0.11 ml, 0.161 mmol, 0.99 equiv.) Was added, the mixture was stirred 16 hours at room temperature. Water (3 ml) and brine (1 ml) were added and the mixture was extracted with ethyl acetate (3 x 3 ml). The combined extract was concentrated under reduced pressure, and the residue was dissolved in dichloromethane and purified by chromatography on an Analogix SF12-4 column using an Analogix Intelliflash 280 system running a gradient of 10% to 50% acetone-dichloromethane. The product was obtained as a yellow oil (0.018 g, 21% yield).

PREPARED EXAMPLE X-1670-C The alcohol of preparative example X-1660-C (0.160 g, 0.298 mmol) in dichloromethane (5 ml) was slowly added to a suspension of Dess-Martin periodinane (0.267 g, 0.629 mmol, 2.11 equiv.) In dichloromethane (2 g). ml). The resulting solution was stirred 2.5 hours at room temperature, before it was quenched by the addition of 2N aqueous sodium hydroxide (10 ml) and ethyl ether (10 ml). The two-phase mixture was stirred vigorously for 1 hour, and then the two layers were separated, and the aqueous phase was extracted with ethyl ether (10 ml). The ether extracts were combined, washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a yellow solid (0.091 g, 57% yield) which was used without further purification.

PREPARED EXAMPLE X-1680-C The aldehyde from preparative example X-1670-C (0.086 g, 0.164 mmol), 2,4-dimethoxybenzylamine (0.05 ml, 0.333 mmol, 2.03 equiv.), And sodium cyanoborohydride (0.031 g, 0.493 mmol, 3.01 equiv.) were combined in methanol (2 ml) and acetic acid (0.025 ml, 0.440 mmol, 2.66 equiv.) was added to achieve a pH of 5 to 6. The resulting solution was stirred 3 days at room temperature. Water (10 ml) and saturated aqueous potassium carbonate (1 ml) were added and the mixture was extracted with dichloromethane (3 x 10 ml). The extracts were combined and concentrated under reduced pressure to give a crude oil which was purified by chromatography on an Isco Redisep 4-gram column using an Analogix Intelliflash 280 system running a gradient from 0% to 10% methanol-dichloromethane. The product was obtained as a yellow oil (0.090 g, 82% yield) PREPARED EXAMPLE X-1690-C Essentially by the same procedure set forth in preparative example X-1680-C, the above secondary amine was prepared using methylamine (2M solution in THF, 3.67 equiv.). The product was obtained as a yellow solid (0.014 g, 22% yield).

PREPARED EXAMPLE X-1700-C The ester of preparative example X-1600-C (0.125 g, 0.275 mmol) was stirred for 4.5 hours at room temperature in a mixture of THF (2 ml), methanol (1 ml) and 2N aqueous sodium hydroxide (0.50 ml, 1.0 mmoles, 3.6 equiv.). After adding 2N aqueous hydrochloric acid (0.50 ml) and water (5 ml), the mixture was extracted with ethyl acetate (6 x 5 ml). The combined extracts were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a yellow solid (0.116 g, 92% yield).

PREPARED EXAMPLE X-1710-C The acid of preparative example X-1700-C (0.114 g, 0.258 mmol),? / - (3-dimethylaminopropyl) -? / '- ethylcarbodiimide hydrochloride (0.075 g, 0.391 mmol, 1.52 equiv.), 1-hydroxybenzotriazole ( 0.056 g, 0.411 mmoles, 1.59 equiv.), Triethylamine (0.12 ml, 0.861 mmol, 3.34 equiv.) And isopropylamine (0.04 ml, 0.467 mmol, 1.81 equiv.) Were combined in anhydrous dichloromethane (5.0 ml) and anhydrous DMF (0.12 equiv.). ml) and stirred at room temperature for 16 hours. The crude reaction mixture was then loaded directly onto a 4-gram Isco Redisep chromatography column and purified using an Analogix Intelliflash 280 system running a gradient from 0% to 3% methanol-dichloromethane. The product was obtained as a yellow oil (0.100 g, 81% yield).

PREPARED EXAMPLES X1720-C-X1760-C Essentially by the same procedure set forth in Preparative Example X-1710-C, the compounds given in column 2 of Table X-260-C were prepared.

TABLE X-260-C PREPARED EXAMPLE X-1770-C Essentially by the same procedure set forth in the preparative example X-1620-C, only using the compound of the preparative example X-1760-C (0.037 g, 0.069 mmol), the above alcohol was obtained as a colorless oil (0.025 g, 72% yield).

PREPARED EXAMPLE X-1780-C The ester of preparative example X-1760-C (0.037 g, 0.069 mmol) was stirred for 15 hours at 95X in a tube sealed with 7N ammonia in methanol (3 mL). After cooling, the solution was concentrated under reduced pressure and purified by chromatography on an Isco Redisep-4 grams column using an Analogix Intelliflash 280 system running a gradient from 0% to 10% methanol-dichloromethane. The product was obtained as a yellow solid (0.024 g, 70% yield).

PREPARED EXAMPLE X-1790-C The ester of preparative example X-1640-C (0.211 g, 0.322 mmol) was dissolved anhydrous THF (3.5 ml) and cooled to -20X. Calcium hydrochloride, O-dimethylhydroxylamine (0.043 g, 0.441 mmol, 1.37 equiv.) Was added slowly in one portion followed by methylmagnesium chloride (3M solution in THF, 0.35 mL, 1.05 mmol, 3.26 equiv.) By syringe. After stirring for 1 hour, it was warmed to -5X, additional methylmagnesium chloride (3M solution in THF, 0.70 ml, 2.10 mmol, 6.52 equiv.) Was added and the mixture was stirred for 15 hours while warming to room temperature. At this point, CCD (20% methanol-dichloromethane) indicated the continued presence of starting material. An additional portion of α /, 0-dimethylhydroxylamine hydrochloride (0.052 g, 0.533 mmol, 1.66 equiv.) Was added followed by methylmagnesium chloride (3M solution in THF, 0.40 mL, 1.20 mmol, 3.73 equiv.). After stirring 1.5 hours at room temperature, additional methylmagnesium chloride (3M solution in THF, 0.70 ml, 2.10 mmol, 6.52 equiv.) Was added. The mixture was stirred 3 hours at room temperature and then quenched with saturated aqueous ammonium chloride (10 ml) and water (2 ml) and extracted with ethyl acetate (3 x 15 ml). The combined extracts were washed with brine, dried with anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by chromatography on an Isco Redisep-12g column using an Analogix Intelliflash 280 system running a gradient from 0% to 20% acetone-dichloromethane. The product was obtained as a partially solidified yellow oil (0.113 g, 66% yield).

PREPARED EXAMPLE X-1800-C The ketone from preparative example X-1790-C (0.056 g, 0.104 mmol) in anhydrous THF (3 ml) was treated with lithium triethylborohydride (solution 1 in THF, 0.35 ml, 0.35 mmol, 3.37 equiv.) And stirred at room temperature. hours at room temperature. Then water (2 ml) was added and the resulting solution was concentrated under reduced pressure. The resulting oily residue was dissolved in methanol and concentrated again to give a yellow solid. This was suspended in 10% methanol-dichloromethane (1.5 ml), loaded onto an Isco Redisep-4g chromatography column and purified using an Analogix Intelliflash 280 system running a gradient from 0% to 35% acetone-dichloromethane. The product was obtained as a yellow oil (0.048 g, 85% yield).

PREPARED EXAMPLE X-1810-C The ketone from preparative example X-1790-C (0.066 g, 0.122 mmol), hydroxylamine hydrochloride (0.023 g, 0.334 mmol, 2.74 equiv.) And sodium acetate (0.023 g, 0.274 mmol, 2.25 equiv.) Were shaken. hours in ethanol (5 ml) at 70X. After cooling, the mixture was concentrated under reduced pressure, and the crude solid was suspended in dichloromethane and purified by chromatography on an Isco Redisep-4g column using an Analogix Intelliflash 280 system running a gradient from 0% to 20% acetone. dichloromethane. The product was obtained as a yellow oil (total 0.0566 g, 84% yield) in an E.Z ratio of 87:13, of which 0.037 g was obtained as pure E-isomer.

PREPARED EXAMPLE X-1820-C Essentially by the same procedure set forth in preparative example X-1810-C, methyl oxime was prepared using methoxylamine hydrochloride. The product was obtained as a yellow oil in 81% yield which was considered to have a 90:10 ratio of product E to Z. This mixture was used without further purification in the next step.

EXAMPLE X-820-C The alcohol of preparative example X-1650-C (0.067 g, 0.156 mmol) in anhydrous dichloromethane (2 ml) was treated with triethylamine (0.025 ml, 0.179 mmol, 1.15 equiv.) And methanesulfonyl chloride (0.03 ml, 0.388 mmol, 2.49 equiv.) And stirred 14 hours at room temperature. The resulting yellow-white suspension was treated with additional triethylamine (0.10 ml, 0.717 mmol, 4.60 equiv.), At which point it became homogeneous, and then heated for 4 hours at 40X. After cooling, the solution was diluted with water (7 ml) and extracted with ethyl acetate (3 x 7 ml). The combined extracts were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude orange solid was dissolved in dichloromethane and purified by chromatography on an Isco Redisep 4-gram column using an Analogix Intelliflash 280 system running at 5% methanol-dichloromethane. The product was obtained as a yellow oil (0.023 g, 41% yield). LCMS: 354 [MH +]. 13 C NMR (CDCl 3) d 161.74, 157.61, 147.16, 144.96, 136.56, 127.12, 1 13.82, 102.53, 86.95, 69.05, 54.49, 43.62, 42.79, 38.76, 30.67, 26.68.

PREPARED EXAMPLE X-1830-C The alcohol of preparative example X-1650-C (0.050 g, 0.117 mmol) was dissolved in anhydrous dichloromethane (1 ml) and triethylamine (0.04 ml, 0.287 mmol, 2.45 equiv.) And acetic anhydride (0.015 ml, 0.159 mmol) were added. , 1.35 equiv.). The solution was 15 hours at room temperature. The solution was then concentrated under reduced pressure to give a yellow solid which was dissolved in dichloromethane and purified by chromatography on an Isco Redisep 4-gram column using an Analogix Intelliflash 280 system running a gradient of 0% to 5% methanol-dichloromethane . A yellow oil was obtained (0.051 g, 94% yield).

EXAMPLE X-830-C The ester of preparative example X-1640-C (0.103 g, 0.227 mmol) was dissolved in 7N ammonia in methanol (10 ml) in a sealed tube and stirred 15 hours at 120X followed by 22 hours at 160X. After cooling, the solution was concentrated under reduced pressure to give an orange gummy solid which was dissolved in 25% acetonitrile-water (1.0 ml) and purified by reverse phase HPLC on a Waters PrepLC 25mm column running a gradient of 5 mm. % to 50% acetonitrile-water. The product was obtained as a yellow oil (0.024 g, 26% yield). CLEM 341 [MH +]. 13 C NMR (CD3OD) d 161.70, 149.97, 146.25, 142.43, 137.51, 128.49, 115.42, 102.33, 87.25, 58.67, 47.92, 41.75, 38.87, 30.35, 28.61.

EXAMPLE X-840-C The ketal of preparative example X-1510-C (0.075 g, 0.153 mmol) was hydrogenated at 3.86 kg / cm2 for 20 hours in methanol (20 ml), 10% palladium on carbon (0.055 g, 0.052 mmol, 0.34 was added. equiv.). The suspension was filtered through Celite, the Celite was washed with methanol and dichloromethane, and the combined filtrates were concentrated under reduced pressure. The crude residue was dissolved in 5% methanol-dichloromethane and purified by chromatography on an Isco Redísep-4g column using an Analogix Intelliflash 280 system running a gradient from 0% to 10% of 7N ammonia in methanol-dichloromethane. The product was obtained as a colorless oil (0.0125 g, 23% yield). LCMS: 356 [MH +]. 13 C NMR (CDCl 3) d 160.09, 146.21, 144.36, 140.83, 136.27, 126.88, 113.56, 108.44, 101.81, 89.65, 64.82, 64.52, 51.60, 49.33, 48.49, 44.10, 38.81.

PREPARED EXAMPLE X-1840-C ? / - Bromosuccinimide (0.017 g, 1.0 equiv.) In CH3CN (0.5 mL) was added dropwise to a solution of the compound of Preparative Example X-1570-C (0.050 g, 0.097 mmol) in anhydrous acetonitrile (0.5 mL) and CH2CI2 (0.5 ml) and the mixture was stirred for 0.5 hours at 25X. The solution was concentrated and purified by preparative chromatography (20% acetone-CH 2 Cl 2) to give (0.054 g, 94.4%) of a cream colored solid.

PREPARATIVE EXAMPLES X1850-C -X2030-C Essentially by the same procedure set forth in Preparative Example X-1840-C, the compounds given in column 2 of Table X-270-C were prepared.

TABLE X-270-C EXAMPLE X-850-C A solution of the compound of Preparative Example X-1360-C (0.25 g, 0.63 mmol) in CH 2 Cl 2 (6 mL) and trifluoroacetic acid (2 mL) was stirred at 25X for 1 hr. The solution was concentrated under reduced pressure and the residue was diluted with CH2Cl2 (10 mL), 1 N NaOH (1 mL) and saturated aqueous K2CO3 (30 mL). The aqueous layer was further extracted with CH 2 Cl 2 (3 x 10 ml). The combined organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by preparative thin layer chromatography (10% 7N NH3 in MeOH-CH2Cl2) gave XX (0.16 g, 85%) as a white solid. 1 H NMR (CD 3 OD) d 8.20 (s, 1 H), 8.05 (s, 1 H), 7.96 (s, 1 H), 6.06 (s, 1 H), 3.94 (s, 3 H), 3.29-3.22 (m , 1H), 3.10-3.03 (m, 1 H), 2.99-2.93 (m, 1 H), 2.88-2.80 (m, 1 H), 2.73-2.66 (m, 1 H), 2.14-2.09 (m, 1 H), 1.89-1.79 (m, 2H), 1.71-1.60 (m, 1 H); MH + = 298.

EXAMPLES X860-C-X1600-C Essentially by the same procedure set forth in Example X-850-C, the compounds given in column 2 of Table X-280-C were prepared.

TABLE X-280-C EXAMPLES X1610-C and X1620-C The compound of Preparative Example X-1680-C (0.094 g, 0.139 mmol) was stirred 15 hours at room temperature in dichloromethane (3 mL) and trifluoroacetic acid (3 mL). A portion of this solution (0.4 ml) was removed, concentrated under reduced pressure and purified by reverse phase HPLC on a Waters PrepLC 25mm column running a gradient of 5% at 50% acetonitrile-water. Example X-1610-C, the DMB-protected amine, was obtained as a yellow oil (0.012 g, 18% yield). CLEM 477 [MH +]. 13C NMR (CD3OD) d 163.71, 163.03, 160.26, 150.27, 145.53, 142.89, 137.63, 132.48, 128.70, 116.99, 115.20, 105.75, 102.40, 99.46, 87.46, 55.99, 55.10, 49.93, 47.39, 38.96, 28.14, 24.93. The remainder of the deprotection reaction was heated at 60 ° C for 15 hours and an additional amount of trifluoroacetic acid (2 ml) was added. After cooling, this solution was also concentrated and purified by reverse phase HPLC as before. Example X-1620-C, the completely deprotected amine was obtained as a yellow oil (0.026 g, 57% yield). LCMS 327 [MH +]. 13C NMR (CD3OD) d 162.30, 150.42, 145.51, 142.96, 137.59, 128.83, 115.12, 102.45, 87.24, 54.77, 47.50, 42.50, 41.64, 38.94, 38.16, 27.13, 24.51.

PREPARED EXAMPLE X-2040-C A solution of the monoprotected piperazine (0.075 g, 0.17 mmol) in CH2Cl2 (1.6 ml) and acetic acid (0.1 ml) at 25 ° C was treated with 3,3-dimethylbutyraldehyde (0.03 ml, 3 equiv.) Followed by triacetoxyborohydride. sodium (0.11 g, 3 equiv.). The solution was stirred at 25 ° C overnight. The solution was concentrated and purified by preparative chromatography (5% MeOH-EtOAc) to give pure product (0.050 g, 56%).

PREPARATIVE EXAMPLES X2050-C and X2060-C Essentially by the same procedure set forth in preparative example X-2040-C, the compounds given in column 2 of Table X-300-C were prepared.

TABLE X-300-C PREPARED EXAMPLE X-2070-C A solution of the monoprotected piperazine (0.067 g, 0.15 mmole) in THF (1.5 ml) at 25 ° C was treated with triethylamine (0.043 ml, 2.0 equiv.) Followed by acetyl chloride (0.014 ml, 1.3 equiv.). The solution was stirred at 25 ° C overnight. The solution was concentrated and purified by preparative chromatography (5% MeOH-EtOAc) to give pure product (0.058 g, 79%).

EXAMPLE X-1630-C A mixture of the compound of Preparative Example X-2040-C (0.050 g, 0.097 mmol) in EtOAc (1 mL) and MeOH (1 mL) was treated with Pd / C and stirred under a hydrogen atmosphere overnight: The mixture was filtered through a pad of Celite and concentrated. Purification by preparative chromatography (10% 7N NH3 in MeOH-EtOAc) gave product (0.032 g, 87%). 1 H NMR (CD 3 OD) d 8.22 (s, 1 H), 8.14 (s, 1 H), 7.96 (s, 1 H), 6.31 (s, 1 H), 3.94 (s, 3 H), 3.39 (dd, J = 10.2 Hz, J = 2.9 Hz, 1 H), 3.16-2.78 (m, 5H), 2.65-2.58 (m, 1 H), 2.35-2.28 (m, 1 H), 2.21-2.13 (m, 1 H) ), 1.62-1.54 (m, 1 H), 1.40-1.33 (m, 1 H), 0.75 (s, 9H); MH + = 383.; EXAMPLES X1640-C-X1660-C Essentially by the same procedure set forth in Example X-1630-C, the compounds given in column 2 of Table X-310-C were prepared.

TABLE X-310-C EXAMPLES X1670-C-X1700-C Essentially by the same procedure set forth in the preparative example X-2040-C, only using the appropriate amine, the compounds given in column 2 of Table X-320-C were prepared.

TABLE X-320-C EXAMPLE X-1710-C Essentially by the same procedure set forth in Example X-2070-C, the compounds given in column 2 of Table X-330-C were prepared.

BOX 330-C EXAMPLE X-1720-C A solution of the compound of example X-1260-C (0.075 g, 0.19 mmol) in DMF (3.8 ml) was treated with triethylamine (0.054 ml, 2.0 equiv.) Followed by 0.015 ml methanesulfonyl chloride, 1.0 equiv.). The solution was stirred at 25 ° C for 19 h. The solution was concentrated under reduced pressure and purified by preparative chromatography (10% 7N NH3 in MeOH-CH2Cl2) to give product (0.0135 g, 14%).

EXAMPLE X-1730-C A solution of the compound of Example X-1150-C (0.050 g, 0.14 mmol) in CH2Cl2 (0.75 mL) and MeOH (0.75 mL) was stirred at: 25 ° C for 3 hr.

NaBH 4 (0.01 g, 1.1 equiv.) Was added and stirring was continued for 17 hr.

The solution was concentrated and purified by preparative chromatography (10% 7N NH3 in MeOH-CH2Cl2) to give (0.035 g, 65%) a clear orange solid. 1 H NMR (CD3OD) d 8.21 (s, 1 H), 8.03 (s, 1 H) and 7.96 (s, 1 H), 3.94 (s, 3H), 3.19-3.17 (m, 4H), 2.75 (q, J = 15.4 Hz, J = 6.8 Hz, 2H), 1.92-1.85 (t, J = 7.2 Hz, 3H); MH + = 364/366.

EXAMPLES X1740-C -X1770-C • Essentially by the same procedure set forth in Example X-1730-C, the compounds given in column 2 of Table X-400-C were prepared.

TABLE X-400-C EXAMPLE X1780-C and X1790-C Compound of example compound X-1530-C (0.047 g, 151 mmol), sodium cyanoborohydride (0.019 g, 0.302 mmol, 2 equiv.) And acetaldehyde (0.01 ml, 0.178 mmol, 1.18 equiv.) Were dissolved in methanol (5 ml), and acetic acid (2 drops) was added to reach a pH of about 6. The mixture was stirred 15 hours at room temperature in a sealed vial. The mixture was concentrated under a stream of nitrogen to a volume of about 1 ml, diluted with dichloromethane (6 ml) and loaded onto a 12-gram Isco Redisep column, and partially purified using Analogix Intelliflash 280 running at a gradient of 5. % to 50% of 7N ammonia in methanol-dichloromethane. The fractions containing the products were combined, concentrated under reduced pressure, d were purified by reverse phase HPLC on a Waters PrepLC 25mm column running a gradient of 5% to 20% acetonitrile-water. Example X-1780-C (0.031 g, 61% yield) and example X-1790-C (0.015 g, 26% yield) were obtained as colorless oils. LCMS 340 [MH +], 13 C NMR (CD3OD) d 165.74, 149.77, 146.51, 142.31, 137.56, 128. 48, 1 15.57, 101.94, 87.15, 57.89, 45.52, 41.09, 38.89, 35.52, 32.64, 29.99, 25.10, 1.82; and LCMS 368 [MH +], 13 C NMR (CD3OD) d 165.63, 149.82, 146.49, 142.38, 128.56, 115.52, 101.97, 87.05, 63.16, 46.60, 46.00, 38.88, 33.30, 32.43, 27.36, 25.44, 10.70, respectively.

EXAMPLES X1800-C and X1810-C Essentially by the same procedure set forth in example X-1780-C, the compounds in column 2 of Table X-410-C were prepared from the compound BOB using acetone and 2- (tert-butyldimethylsilyloxy) acetaldehyde, respectively.

TABLE X-410-C EXAMPLE X-1820-C The compound of Example X-1810-C (0.060 g, 0.128 mmol) in anhydrous THF (3 mL) was treated with tetrabutylammonium fluoride (1 M solution in THF, 0.25 mL, 0.25 mmol, 1.95 equiv.) And the stirred for 12 hours at room temperature. The solution was then diluted with methanol and dichloromethane and concentrated under reduced pressure. The resulting colorless oil was purified by reverse phase HPLC on a Waters PrepLC 25mm column running a gradient of 5% to 20% acetonitrile-water. The product was obtained as a white solid (0.038 g, 83% yield). LCMS 356 [MH +]. 13C NMR (CD3OD) d 165.80, 149.78, 146.50, 142.29, 137.55, 128.51, 115.55, 101.94, 87.08, 58.22, 58.18, 47.84, 45.66, 38.87, 35.33, 32.63, 29.78, 25.20. The preparation of the compounds in the copending application No. series (Proxy case No. OC01618K2 presented the same as the present one) is illustrated below: 'PREPARATIVE EXAMPLE Y-10-C SO2 (18.5 ml) was slowly added under N2 to a stirred mixture of the acid (50.0 g, 218 mmol) and pyridine (44.0 ml) in anhydrous CH2Cl2 (60 ml). The mixture was stirred at 25 ° C for 20 min, then Meldrum acid (35.0 g, 243 mmol) and DMAP (66.6 g, 546 mmol) were added and the mixture was stirred under N2 for 1 hr. Then Et20 (2 L) was added, the mixture was washed with 1 M HCl (3 x 500 ml), brine (500 ml), and the organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The residue was dissolved in MeOH (580 ml), and the mixture was refluxed for 4 hr. The solvent was evaporated and the residue was purified by column chromatography on silica gel with 10: 1 CH2Cl2 / EtOAc as eluent. A pale yellow oil was obtained (26.5 g, 43%).

PREPARATIVE EXAMPLE Y-20-C A mixture of the β-ketoester of preparative example Y-10-C (20.0 g, 70.1 mmol) and 3-amynopyrazole (5.40 g, 65.0 mmol) in anhydrous toluene (60 ml) was stirred and refluxed under N2 for 24 hours. hr. The solvent was evaporated and the residue was purified by column chromatography on silica gel with CH2Cl2 / MeOH 20: 1 as eluent. A white solid was obtained (15.0 g, 73%).

PREPARATIVE EXAMPLE Y-30-C A mixture of the product of preparative example Y-20-C (12.50 g, 39.3 mmol),? /,? / - dimethylaniline (15.5 ml), and POCI3 (125 ml) was stirred at 25 ° C for 4 days. The excess of POCI3 was evaporated and the residue was poured into saturated aqueous NaHCO3 (600 ml). The mixture was extracted with CH2Cl2 (3x200 ml), the combined extracts were dried over Na2SO, filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel with CH2Cl2 / EtOAc 8: 1 as eluent. A pale yellow wax was obtained (9.41 g, 71%).

PREPARATIVE EXAMPLE Y-40-C A solution of NBS (4.03 g, 22.7 mmol) in anhydrous CH3CN (40 mL) was added under N2 to a stirred solution of the product of Preparative Example 30-C (7.63 g, 22.7 mmol) in anhydrous CH3CN (60 mL) and CH2Cl2 (20 ml). The mixture was stirred for 2 h, the solvents were evaporated, and the residue was purified by column chromatography on silica gel with CH2Cl2 / EtOAc 20: 1 as eluent. Light yellow solid foam (9.20 g, 97%) was obtained.

PREPARATIVE EXAMPLE Y-50-C A mixture of the product from preparative example Y-40-C (8.00 g, 19.3 mmol) and NaOMe (2.16 g, 40.0 mmol) in anhydrous MeOH (100 mL) was stirred for 20 hr. Then CH2Cl2 (200 ml) was added, the mixture was filtered through Celite, the solvent was evaporated, and the residue was purified by column chromatography on silica gel with 2: 1 CH2Cl2 / EtOAc as eluent. A white solid was obtained (7.75 g, 98%).

PREPARATIVE EXAMPLE Y-60-C To a mixture of Boc derivative (3.0 g, 7.3 mmol) of preparative example Y-50-C in DME / H2O (16 ml / 4 ml) was added 1-methyl-4- (4,4,5,5-tetramethyl) -1, 3,2-dioxaborolan-2-yl) -1 H-pyrazolo (2.8 g, 13.5 mmol) and Na 2 CO 3 (3.9 g, 36.4 mmol). N2 was bubbled through the solution for 20 min with stirring after which PdCI2 (PPh3) 2 (0.39 g, 0.47 mmol) was added. The mixture was heated to 110 ° C and stirred for 12 hr. The mixture was cooled to t.a., concentrated under reduced pressure and placed under high vacuum. The crude product was purified by flash chromatography using a 30: 1 mixture of CH2Cl2 / MeOH as eluent to give 1.57 g (52% yield) as an orange / brown solid. LC-MS: = 413.2 [[M + H] 97% purity. \ PREPARATIVE EXAMPLE Y-70-C To a solution of aniline (0.044 ml, 0.49 mmol) in dry DMSO (2 ml) at t.a. 60% NaH in oil (20 mg, 0.49 mmol) was added in one portion. The resulting mixture was stirred for 30 min at t.a. after which the 7-methoxy adduct (0.10 g, 0.24 mmol) of preparative example Y-60-C was added in a single portion. The mixture was stirred for 12 hr at RT, cooled to RT and quenched with NH4CI aq. sat (2 ml). The mixture was extracted with a mixture of 10% IPA / CH 2 Cl 2 (3 x 10 ml) and the organic layers were combined. The organic layer was washed with brine (1 x 5 ml), dried (Na 2 SO), filtered and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (6 x 1000 μM plates) using a 12: 1 mixture of CH 2 Cl 2 / MeOH as eluent to give (60 mg, 53% yield) as a yellow semi-solid. LC-MS: = 474.4 [M + H] 94% purity.

PREPARATIVE EXAMPLES Y80-C -Y90-C Following the procedure outlined in the preparative example Y-70-C but using the commercially available heteroarylamines (as indicated) in the table Y-10-C with the 7-methoxy adduct of the preparative example Y-60-C, substituted pyrazolo [1, 5-a] pyrimidine adducts were prepared (Products).

TABLE Y-10-C PREPARATIVE EXAMPLE Y-100-C 3-Amino-4-bromopyrazolo (5 g, 30.9 mmol) and 4-methoxybenzyl chloride (21 g, 134 mmol, 4.3 equiv.) Were combined in anhydrous DMF (25 mL) and added dropwise to a stirred suspension. of sodium hydride (60% dispersion in mineral oil, 6.25 g, 156 mmol, 5 equiv.) in anhydrous DMF (50 ml). The resulting suspension was stirred 2 days at room temperature. Water (300 ml) was added slowly and the resulting mixture was extracted with ether (4 x 350 ml). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was dissolved in dichloromethane and purified by silica gel chromatography using a gradient of 10% to 20% ethyl acetate-hexanes. The product, a white solid, was obtained as a 60:40 mixture of the 1-benzylated-1 H product and the 2-benzylated-2H product (total 14.96 g, 93% yield).

PREPARATIVE EXAMPLE Y-110-C The compound of Preparative Example Y-100-C (10 g, 19.15 mmol) and 1-methyl-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1 H -pirazolo (11.95 g, 57.42 mmol, 3.0 equiv.) Were combined in 120 ml dimethoxyethane. 2M sodium carbonate solution (30 ml, 60 mmol, 3.1 equiv.) Was added followed by tetrakis (triphenylphosphine) palladium (0) (2.36 g, 2.04 mmol, 0.11 equiv.). The mixture was stirred 16 hours at 90 ° C. After cooling to room temperature, water (200 ml) and brine (50 ml) were added and the mixture was extracted with ethyl acetate (2 x 200 ml). The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was dissolved in dichloromethane and purified by silica gel chromatography using a gradient from 33% to 66% ethyl acetate-hexanes. The 1-benzylated-1 H product (Rf = 0.27 in 66% ethyl acetate-hexanes) was eluted first, followed by the 2-benzylated-2H product (Rf = 0.19 in 66% ethyl acetate-hexanes). The product was obtained as a yellow solid (total 5.60 g, 56% yield) with an isomeric ratio of 62:38.

PREPARED EXAMPLE Y-120-C! The compound of Preparative Example Y-110-C (4.3 g, 8.22 mmol) was dissolved in trifluoroacetic acid (70 mL) and stirred for 17 hours at reflux. After cooling, the trifluoroacetic acid was removed under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (100 ml), methanol (50 ml) and 4N aqueous sodium hydroxide solution (25 ml, 100 mmol, 12 equiv.). The mixture was stirred 4 hours at 70 ° C, then cooled to room temperature. The mixture was concentrated and the residue was suspended in brine (100 ml) and water (40 ml). This mixture was extracted with 20% isopropanol in ethyl acetate (8 x 100 ml). The extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was dissolved in 10% methanol in dichloromethane and purified by silica gel chromatography using 10% methanol-dichloromethane followed by 10% 7N ammonia in methanol-dichloromethane. The product was obtained as a tan to coffee solid (1.03 g, 77% yield).

PREPARATIVE EXAMPLE Y-130-C To a solution of aminopyrazole (0.74 g, 4.5 mmol) of Preparative Example Y-120-C in toluene (40 mL) in a pressure tube at t.a. β-ketoester (1.5 g, 5.0 mmol) of Preparative Example 1 was added. The pressure tube was capped and heated to 110 ° C and stirred for 12 hr. The mixture was cooled to t.a. and concentrated under reduced pressure. The material was collected in raw I for the next transformation. LC-MS: = 399.2 [M + H]; 70% purity.

PREPARATIVE EXAMPLE Y-140-C To a solution of 7-hydroxyl adduct (1.84 g, 4.5 mmol) of preparative example Y-130-C in POCI3 (13 mL, 0.14 mol) at t.a. N, N-dimethylaniline (2 ml, 15.8 mmol) was added. The resulting solution was stirred at t.a. for 12 hr (until complete by CCD) and concentrated under reduced pressure. The crude material was cooled to 0 ° C and treated with CH 2 Cl 2 (50 mL) and aq NaHCO 3. sat (10 ml). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 50 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 1: 1 mixture of hexanes / CH2Cl2 as eluent to give 1.4 g (96% yield) of a brown semisolid. LC-MS: = 317.2 [M + H]; 95% purity.

PREPARATIVE EXAMPLE Y-150-C To a solution of 4-amino-? /,? / - dimethylbenzenesulfonamide (96 mg, 0.48 mmol) in dry DMSO (2 mL) at t.a. 60% NaH in oil (20 mg, 0.49 mmol) was added in one portion. The resulting mixture was stirred for 20 min at t.a. after which the 7-chloro adduct (0.10 g, 0.24 mmol) of preparative example Y-140-C was added in a single portion. The mixture was stirred for 12 hr at RT, cooled to RT and quenched with NH4CI aq. sat (2 ml). The mixture was extracted with a mixture of 10% IPA / CH 2 Cl 2 (3 x 10 ml) and the organic layers were combined. The organic layer was washed with brine (1 x 5 ml), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was diluted with water (10 ml) and the resulting solid was filtered and washed with water (50 ml). The resulting ppt was placed under high vacuum to give 0.13 g (98% yield) of a dark yellow solid. LC-MS: = 581.3 [M + H] 90% purity.

PREPARATIVE EXAMPLES Y150-C-Y190-C Following the procedure set forth in the preparative example Y-150-C but using the commercially available heteroarylamines (as indicated) in Table Y-20-C with the 7-chloro adduct of preparative example Y-140-C, substituted pyrazolo [1,5-a] pyrimidine adducts (Products) were prepared.

BOX Y-20-C EXAMPLE Y-10-C To a Boc adduct solution (60 mg, 0.13 mmol) of Preparative Example Y-70-C in CH 2 Cl 2 (3 mL) at t.a. TFA (1 ml) was added. The resulting solution was stirred at t.a. for 5 hr (until complete by CCD) and concentrated under reduced pressure. The crude material was taken up in 2M NH3 in MeOH (3 mL) and stirred for 12 hr. The mixture was concentrated under reduced pressure and purified by preparative thin layer chromatography (4 x 1000 μM plates) using a 6: 1 mixture of CH 2 Cl 2 / MeOH (7M NH 3) as eluent to give (5 mg, 10% yield) as a yellow solid. Mp 131-134 ° C; LC-MS: = 374.2 [M + H] > 90% purity.

EXAMPLES Y20-C - Y90-C Following the procedure set forth in Example Y-10-C using the appropriate Boc derivatives shown in column 2 of Table Y-30-C, the final substituted pyrazolo [1, 5-a] pyrimidine adducts were prepared (Products) .

TABLE Y-30-C The preparation of the compounds in the copending application No. series (Proxy Case No. OC01619K2 filed on the same date as the present one) is illustrated below: PREPARED EXAMPLE Z-10-C SO2 (18.5 ml) was slowly added under N2 to a stirred mixture of the acid (50.0 g, 218 mmol) and pyridine (44.0 ml) in anhydrous CH2Cl2 (60 ml). The mixture was stirred at 25 ° C for 20 min, then Meldrum acid (35.0 g, 243 mmol) and DMAP (66.6 g, 546 mmol) were added and the mixture was stirred under N2 for 1 hr. Then, Et20 (2 I) was added, the mixture was washed with 1 M HCl (3 x 500 ml), brine (500 ml), and the organic layer was dried over Na2SO4, filtered, and the solvent was evaporated. The residue was dissolved in MeOH (580 ml), and the mixture was refluxed for 4 hr. The solvent was evaporated and the residue was purified by column chromatography on silica gel with 10: 1 CH2Cl2 / EtOAc as eluent. A pale yellow oil was obtained (26.5 g, 43%).

PREPARED EXAMPLE Z-20-C A mixture of the β-ketoester of preparative example Z-10-C (20.0 g, 70.1 mmol) and 3-aminopyrazole (5.40 g, 65.0 mmol) in anhydrous toluene (60 ml) was stirred and refluxed under N2 for 24 hours. hr. The solvent was evaporated and the residue was purified by column chromatography on silica gel with CH2Cl2 / MeOH 20: 1 as eluent. A white solid was obtained (15.0 g, 73%).

PREPARED EXAMPLE Z-30-C The known compound was prepared according to the procedure documented in J. Heterocyclic Chem. 1986, 23, 349.

PREPARED EXAMPLE Z-40-C A mixture of the product from Preparative Example Z-20-C (12.50 g, 39.3 mmol),? /,? / -dimethylaniline (15.5 mL), and POCI3 (125 mL) was stirred at 25 ° C for 4 days. The excess of POCI3 was evaporated and the residue was poured into saturated aqueous NaHCO3 (600 ml). The mixture was extracted with CH2Cl2 (3x200 ml), the combined extracts were dried over Na2SO4, filtered, and the solvent was evaporated. The residue was purified by column chromatography on silica gel with CH2Cl2 / EtOAc 8: 1 as eluent. A pale yellow wax was obtained (9.41 g, 71%).

PREPARED EXAMPLE Z-50-C The known compound was prepared according to the procedure documented in J. Med. Chem. 1981, 24 (5), 610-613.

PREPARED EXAMPLE Z-60-C A solution of NBS (4.03 g, 22.7 mmol) in anhydrous CH3CN (40 ml) was added under N 2 to a stirred solution of the product of preparative example Z-40-C (7.63 g, 22.7 mmol) in anhydrous CH 3 CN (60 ml) and CH 2 Cl 2 (20 ml). The mixture was stirred for 2 h, the solvents were evaporated, and the residue was purified by column chromatography on silica gel with CH2Cl2 / EtOAc 20: 1 as eluent. A light yellow solid foam (9.20 g, 97%) was obtained. I PREPARATIVE EXAMPLE Z-70-C Essentially by the same procedure set forth in Preparative Example Z-60-C, the 7-chloro adduct (1.2 g, 7.5 mmol) of Preparative Example 50-C was treated with NBS (1.5 g, 8.2 mmol) to give 1.2 g ( 69% yield) of a yellow solid. MS = 233.9 [M + H].

PREPARED EXAMPLE Z-80-C A mixture of the product from Preparative Example Z-60-C (8.00 g, 19.3 mmol) and NaOMe (2.16 g, 40.0 mmol) in anhydrous MeOH (100 mL) was stirred for 20 hr. Then CH2Cl2 (200 ml) was added, the mixture was filtered through Celite, the solvent was evaporated, and the residue was purified by column chromatography on silica gel with 2: 1 CH2Cl2 / EtOAc as eluent. A white solid was obtained (7.75 g, 98%).

PREPARED EXAMPLE Z-90-C Essentially by the same procedure set forth in preparative example Z-80-C, the 7-chloro adduct (1.6 g, 6.9 mmol) of preparative example 70-C was treated with NaOMe (0.74 g, 13.8 mmol) to give 1.5 g ( 95% yield) of a yellow / orange solid. LC-MS = 228.1 [M + H]; 97% purity.

PREPARED EXAMPLE Z-100-C To a mixture of Boc derivative (3.0 g, 7.3 mmol) of preparative example Z-80-C in DME / H2O (16 ml / 4 ml) was added 1-methyl-4- (4,4,5,5-tetramethyl) -1, 3,2-dioxaborolan-2yl) -1H-pyrazolo (2.8 g, 13.5 mmol) and Na2CO3 (3.9 g, 36.4 mmol). N2 was bubbled through the solution for 20 min with stirring, after which PdCI2 (PPh3) 2 (0.39 g, 0.47 mmol) was added. The mixture was heated to 110 ° C and stirred for 12 hr. The mixture was cooled to t.a., concentrated under reduced pressure and placed under high vacuum. The crude product was purified by flash chromatography using a 30: 1 mixture of CH2Cl2 / MeOH as eluent to give 1.57 g (52% yield) as an orange / brown solid. LC-MS: = 413.2 [M + H] 97% purity.

PREPARED EXAMPLE Z-110-C Essentially by the same procedure set forth in Preparative Example Z-100-C, the 7-methoxy adduct (0.80 g, 3.5 mmol) of Preparative Example 90-C was converted to 0.68 g (84% yield) of an orange solid. EM = 230.2. [M + H] PREPARED EXAMPLE Z-120-C To a solution of adduct 3-Br (0.27 g, 0.67 mmol) of preparative example Z-80-C in CH 3 CN (4 ml) at t.a. 4-tributylstanyl thiazole (0.50 g, 1.34 mmol) was added followed by PdCI2 (PPh3) 2 (47 mg, 0.067 mmol). The resulting mixture was degassed under suction vacuum and filled with N2 six times. The mixture was equipped with a condenser and heated to 85 ° C. The mixture was stirred for 12 h, cooled to t.a., and diluted with EtOAc (10 mL). The mixture was filtered through a pad of Celite which was washed with EtOAc (3 x 5 ml), CH2Cl2 (1 x 5 ml) and MeOH (1 x 5 ml). The resulting filtrate was concentrated under reduced pressure and placed under high vacuum. The crude product was purified by preparative thin layer chromatography (6 x 1000 μM plates) using a 20: 1 mixture of CH 2 Cl 2 / MeOH as eluent to give 0.26 g (93% yield) as an orange oil. LC-MS: = 416.2 [M + H] 61% purity.

PREPARED EXAMPLE Z-130-C To a solution of 5-amino-3-methylisothiazole hydrochloride (0.15 g, 0.97 mmol) in dry DMSO (1.5 mL) at t.a. 60% NaH in oil (46 mg, 1.94 mmol) was added in one portion. The resulting mixture was stirred for 15 min at t.a. after which the 7-methoxy adduct (0.20 g, 0.48 mmole) of preparative example Z-100-C was added in a single portion. The mixture was stirred for 12 hr at RT, cooled to RT, and quenched with NH CI aq. sat (3 ml). The mixture was extracted with a mixture of 10% IPA CH2CI2 (3 x 20 ml) and the organic layers were combined. The organic layer was washed with brine (1 x 10 ml), dried (Na 2 SO), filtered and concentrated under reduced pressure. The crude product was diluted with water (2 ml) and the resulting ppt was filtered and washed with water (2 x 1 ml). The ppt was dried under high vacuum to give 0.22 g (93% yield) of a red / orange solid. LC-MS: = 495.3 [M + H] 99% purity.

PREPARED EXAMPLE Z-140-C Essentially by the same procedure set forth in preparative example Z-130-C, the 7-methoxy adduct (0.28 g, 0.69 mmol) of Preparative Example Z-120-C was converted to 70 mg (20% yield) of a orange semisolid MS = 498.1 [M + H].

EXAMPLE Z-10-C Essentially by the same procedure set forth in Preparative Example Z-130-C, the 7-methoxy adduct (0.15 g, 0.66 mmol) of Preparative Example Z-110-C was converted to 56 mg (27% yield) of a solid yellow, mp 152-155 ° C; LC-MS = 312.2. [M + H]; 85% purity.

PREPARATIVE EXAMPLES Z150-C - Z230-C Following the procedure set forth in Preparative Example Z-130-C but using the commercially available heteroarylamines (as indicated) in Table Z-10-C with the 7-r-ethoxy adduct of Preparative Example Z-100-C, prepared the substituted pyrazolo [1, 5-a] pyrimidine adducts (Products).

TABLE Z-10-C PREPARED EXAMPLE Z-231-C 3-Amino-4-bromopyrazolo (5 g, 30.9 mmol) and 4-methoxybenzyl chloride (21 g), 134 mmol, 4.3 equiv.) Were combined in anhydrous DMF (25 ml) and added dropwise to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 6.25 g, 156 mmol, 5 equiv.) in anhydrous DMF (50 ml). The resulting suspension was stirred 2 days at room temperature. Water (300 ml) was added slowly and the resulting mixture was extracted with ether (4 x 350 ml). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was dissolved in dichloromethane and purified by silica gel chromatography using a gradient of 10% to 20% ethyl acetate-hexanes. The product, a white solid, was obtained as a 60:40 mixture of the 1-benzylated-1 H product and the 2-benzylated-2H product (total 14.96 g, 93% yield).

PREPARED EXAMPLE Z-232-C (PMBfe The compound of preparative example Z-231-C (10 g, 19.15 mmol) and 1-methyl-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) - 1 H-pyrazolo (11.95 g, 57.42 mmol, 3.0 equiv.) Were combined in 120 ml dimethoxyethane. 2M sodium carbonate solution (30 ml, 60 mmol, 3.1 equiv.) Was added followed by tetrakis (triphenylphosphine) palladium (o) (2.36 g, 2.04 mmol, 0.11 equiv.). The mixture was stirred 16 hours at 90 ° C. After cooling to room temperature, water (200 ml) and brine (50 ml) were added and the mixture was extracted with ethyl acetate (2 x 200 ml). The extracts were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was dissolved in dichloromethane and purified by silica gel chromatography using a gradient from 33% to 66% ethyl acetate-hexanes. The 1-benzylated-1 H product (Rf = 0.27 in 66% ethyl acetate-hexanes) was eluted first, followed by the 2-benzylated-2H product (Rf = 0.19 in 66% ethyl acetate-hexanes). The product was obtained as a yellow solid (total 5.60 g, 56% yield) with an isomeric ratio of 62:38.

PREPARED EXAMPLE Z-233-C The compound of Preparative Example Z-232-C (4.3 g, 8.22 mmol) was dissolved in trifluoroacetic acid (70 ml) and stirred at reflux for 17 hours. After cooling, the trifluoroacetic acid was removed under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (100 ml), methanol (50 ml) and 4N aqueous sodium hydroxide solution (25 ml, 100 mmol, 12 equiv.). The mixture was stirred 4 hours at 70 ° C, then cooled to room temperature. The mixture was concentrated and the residue was suspended in brine (100 ml) and water (40 ml). This mixture was extracted with 20% isopropanol in ethyl acetate (8 x 100 ml). The extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was dissolved in 10% methanol in dichloromethane and purified by silica gel chromatography using 10% methanol-dichloromethane followed by 10% 7N ammonia in methanol-dichloromethane. The product was obtained as a tan to coffee solid (1.03 g, 77% yield).

PREPARED EXAMPLE Z-240-C To a solution of aminopyrazole (0.74 g, 4.5 mmol) of Preparative Example Z-233-C in toluene (40 mL) in a pressure tube at t.a. β-ketoester (1.5 g, 5.0 mmol) of Preparative Example Z-10-C was added. The pressure tube was capped and heated to 110 ° C and stirred for 12 hr. The mixture was cooled to t.a. and concentrated under reduced pressure. The material was collected raw to the next transformation. LC-MS: = 399.2 [M + H]; 70% purity.

PREPARED EXAMPLE Z-250-C To a solution of 7-hydroxyl adduct (1.84 g, 4.5 mmol) of preparative example Z-240-C in POCI3 (13 mL, 0.14 mol) at t.a. N, N-dimethylaniline (2 ml, 15.8 mmol) was added. The resulting solution was stirred at t.a. for 12 hr (until complete by CCD) and concentrated under reduced pressure. The crude material was cooled to 0 ° C and treated with CH 2 Cl 2 (50 mL) and aq NaHCO 3. sat (10 ml). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2 x 50 mL). The organic layers were combined, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 1: 1 mixture of hexanes / CH 2 Cl 2 as eluent to give 1.4 g (96% yield) of a brown semi-solid. LC-MS: = 317.2 [M + H]; 95% purity.

PREPARED EXAMPLE Z-251 -C Essentially by the same procedures set forth to make the compound of Preparative Example Z-250-C, only starting with thiomorpholinecarboxylic acid, the above compound was prepared.

PREPARED EXAMPLE Z-260-C To a solution of 4-methylthiophene-2-carboxylic acid (5.0 g, 35.2 mmol) in f-BuOH (60 mL) was added DPPA (7.6 mL, 35.2 mmol) and Et3N (4.9 mL, 35.2 mmol). The resulting mixture was heated to reflux and stirred for 48 h. The mixture was cooled to t.a. and concentrated under reduced pressure. The crude material was purified by flash chromatography using a 3: 1 mixture of hexanes / CH 2 Cl 2 as eluent to give 4.2 g (56% yield) as an orange oil. The Boc derivative from the previous step (0.5 g, 2.3 mmol) was treated with 4M HCl / dioxane (25 ml) and heated to 70 ° C. The mixture was stirred for 12 h, cooled to t.a., and concentrated under reduced pressure to give 0.32 g (93% yield) of the title compound. This matepal was used directly in subsequent coupling reactions.

PREPARED EXAMPLE Z-270-C Essentially by the same procedure set forth in Preparative Example Z-130-C, the 7-chloro adduct (0.15 g, 0.35 mmol) of Preparative Example 250-C was treated with 2-amino-4-methylthiophene hydrochloride (0.32 g, 2.1 mmole) of Preparative Example Z-260-C to give 110 mg (64% yield) of a yellow semi-solid. LC-MS = 494.3 [M + H]; 80% purity.

PREPARED EXAMPLE Z-280-C Essentially by the same procedure set forth in Preparative Example Z-130-C, the 7-chloro adduct (0.40 g, 0.96 mmol) of Preparative Example Z-60-C was treated with 5-amino-3-methylisothiazole hydrochloride. (0.28 g, 1.9 mmol) to give 430 mg (91% yield) of a yellow semi-solid. LC-MS = 495.3 [M + H]; 80% purity.

EXAMPLE Z-20-C Essentially by the same procedure set forth in preparative example Z-130-C, the 7-chloro adduct (0.12 g, 0.49 mmole) was treated with 5-amino-3-methylisothiazole hydrochloride (0.15 g, 0.98 mmol) to give 38 mg (24% yield) of an orange solid, mp 165-167 ° C; LC-MS = 323.2 [M + H]; 98% purity.

PREPARED EXAMPLE Z-290-C Following the procedure outlined in the preparative example Z-130-C but using the commercially available heteroarylamine (as indicated) in Table 20-C with the 7-chloro adduct of Preparative Example Z-250-C, substituted pyrazolo [1, 5-a] pyrimidine adducts (Products) were prepared.

TABLE Z-20-C PREPARED EXAMPLE Z-300-C To a solution of Boc adduct (54 mg, 0.11 mmol) of Preparative Example Z-130-C in CH 2 Cl 2 (5 mL) at t.a. / -BuNH2 (0.41 ml, 3.9 mmol) was added. The mixture was stirred for 15 min after which Br2 (5 μl, 0.099 mmol) was added dropwise and the reaction was stirred for 1.5 hr (until complete by CCD). The mixture was concentrated to dryness and the crude product was purified by preparative thin layer chromatography using 4 x 1000 μM plates with a 24: 1 mixture of CH 2 Cl 2 / MeOH as eluent to give 25 mg (35% yield) of the Title. LC-MS = 653.4 [M + H]; 99% purity.

EXAMPLE Z-30-C To a mixture of pyrazolo adduct (120 mg, 0.24 mmol) of Preparative Example Z-130-C in CH 2 Cl 2 (2 mL) at 0 ° C was added TFA (0.6 mL) dropwise. The resulting mixture was stirred for 3 hr at t a. and concentrated under reduced pressure. The crude material was dissolved in 7M NH3 in MeOH (3 mL) and stirred for 2 hr. The mixture was concentrated under reduced pressure and placed under high vacuum. The crude product was purified by preparative thin layer chromatography (4 x 1000 μM plates) using a 10: 1 mixture of CH 2 Cl 2 / MeOH (7M NH 3) as eluent to give 20 mg (21% yield) as a corn colored solid. mp 167-170 ° C: LC-MS: = 395.2 [M + H] 95% purity.

EXAMPLES Z-40-C -Z170-C Following the procedure set forth in example Z-30-C using the appropriate Boc derivatives shown in column 2, substituted pyrazolo [1, 5-a] pyrimidine adducts (Products) were prepared in Table Z-30-C. I TABLE Z-30-C EXAMPLES Z180-C and Z190-C mg of example 30-C was injected into a semi-preparative Chiralcel AD column. Chromatography with mobile phase 70:30 hexane / 2-propanol with 0.2% diethylamine gave two isomers: rapid elution (isomer 1) Example Z-180-C: 7 mg, yellow solid; LC-MS: 395.2 [M + H]; purity 99% and slower elution (isomer 2) Example 190-C: 8 mg, yellow solid; LC-MS: 395.2 [M + H]; 99% purity.

EXAMPLES Z200-C and Z210-C Part A To a solution of 7-chloro-pyrazolo [1,5-a] pyrimidine (0.66 g) in DMSO (10 ml) was added sodium methanethiolate (0.45 g) in one portion. The resulting suspension was heated at 90 ° C for 16 hr, allowed to cool and then extracted with ethyl acetate (3 x 50 ml). The organic phase was washed with water, brine and then dried (sodium sulfate). Purification by chromatography (silica gel, 25% ethyl acetate in hexanes) gave the title compound as a yellow-orange solid (0.42 g). 1 H-NMR (400 MHz, DMSO-d 6) d 8.81 (dd, 1 H), 8.08 (dd, 1 H), 6.90 (d, 1 H), 6.50 (dd, 1 H), 2.55 (s, 3H) . LCMS: MH + = 166.

Part B To a solution of 7-methylsulfanyl-pyrazolo [1,5-a] pyrimidine (0.42 g, 2.54 mmoles, 1.00 equiv) in acetonitrile (12 ml) at t.a. N-iodosuccinimide (0.6 g, 2.7 mmol, 1.05 equiv) was added in one portion. After 30 min at t.a., the reaction was concentrated to give the title compound as a yellow-orange solid. The product was used in the next step without purification. 1 H-NMR (400 MHz, DMSO-d 6) d 8.83 (d, 1 H, J = 8.0 Hz), 8.17 (s, 1 H), 6.98 (d, 1 H, J = 8.0 Hz), 2.55 (s, 3H). LCMS: MH + = 292.

Part C A mixture of 3-iodo-7-methylsulfanyl-pyrazolo [1,5-a] pyrimidine (0.21 g, 0.73 mmol, 1.00 equiv), boronate (0.31 g, 0.95 mmol, 1.3 equiv), PdCI2 (dppf) ( 0.059 g, 0.07 mmol, 10 mol%) and potassium phosphate monohydrate (0.34 g, 1.5 mmol, 2.0 equiv) in 1, 2-DME (6 ml) and water (1 ml) was stirred under argon at 100 ° C for 12 hr. The mixture was allowed to cool to t.a. and then it was partitioned between ethyl acetate and water, washed with brine and dried (sodium sulfate). Purification by chromatography (silica gel, 20% ethyl acetate in hexanes) gave 0.2 g of the title compound. LCMS: MH + = 362.

Part DA a solution of 7-methylsulfanyl-3- [1- (2-trimethylsilyl-ethoxymethyl) -1H-pyrazol-4-yl] -pyrazolo [1,5-a] pymidine (0.2 g, 0.55 mmol, 1.00 equiv) in DCM (10 ml) at ta m-CPBA (0.25 g, 1.1 mmol, 2.0 equiv) was added in one portion. The resulting mixture was allowed to stir for 30 min at t.a. and then he concentrated. The residue was partitioned between ethyl acetate and water and the organic phase was washed with aqueous sodium bicarbonate (2 x), brine and dried (sodium sulfate). Concentration gave the title compound as an orange solid which was used directly in the next step.

Part E To a solution of isothiazole (1.15 equiv) in DMSO (2 ml) was added NaH (2.65 equiv). The resulting suspension was stirred 5 min, then sulfone (1 equiv) from Part D was added. The reaction was quenched with NH CI aq. Saturated and extracted with ethyl acetate. The crude residue was treated with 2N HCl dioxane at 50 ° C for 10 min, concentrated, purified by Prep-CL and then converted to the hydrochloride salt. By means of the procedures outlined in Part A-E, the compounds shown in column 2 of Table Z-40-C were prepared.

TABLE Z-40-C PREPARED EXAMPLE Z-310-C To a pyrazolo suspension of Preparative Example Z-233-C (4.0 g, 24.5 mmol, 1.00 equiv), dimethylmalonate (3.1 mL, 27.0 mmol, 1.1 equiv) in EtOH (74 mL) at t.a. 25% NaOMe in MeOH (11.2 ml) was added. The mixture was heated to reflux overnight (16 hr), allowed to cool to t.a. and then he concentrated. The residue was dissolved in a minimum amount of water (-100 ml) and then treated with 1 N HCl until the pH was -2-3. The resulting ppt was collected by filtration and dried to give the title compound as a tan solid (4.9 g, 87%). LCMS: MH + = 232.

EXAMPLE Z-320-C A suspension of 5,7-dihydroxypylazolopyrimidine from preparative example Z-310-C (4.2 g, 18.2 mmol, 1.00 equiv),? / ,? -dietílanilina (9 ml) and PCI5 (1.94 g, 9.32 mmol, 0.5 equiv) in POCI3 (170 ml was heated to 120 ° C in a sealed container for 20 h. After the solution was allowed to cool, the volatiles were The residue was dissolved in DCM and then carefully added to aq sodium bicarbonate The organic phase was rinsed with water, brine and dried The concentration and purification by flash chromatography (silica gel) gave the compound of the title as a bright yellow solid (3.7 g, 76%) LCMS: MH + = 268.

PREPARED EXAMPLE Z-330-C To a solution of aminoisothiazole (0.66 g, 2.0 equiv) in DMSO (30 mL) at t.a. NaH (0.29 g of 60% dispersion in oil, 2.5 equiv) was added in one portion. After approx. 10 min, the compound of preparative example Z-320-C (0.78 g, 1.00 equiv) was added in one portion. After 30 min at t.a., the reaction was quenched with ac ammonium chloride. sat And then it was extracted with 10% IPA DCM (twice). The combined organic layers were washed with water, brine and dried (sodium sulfate). After concentration, the residue was purified by column chromatography (silica gel, 80% EtOAc / hexane? EtOAc) to give the title compound 2 as a yellow solid 0.85 g (86%). 1 H-NMR (400 MHz, DMSO-d 6) d 11.63 (bs, 1H), 8.59 (s, 1 H), 8.11 (s, 1 H), 7.91 (d, 1 H), 7.32 (s, 1 H) , 6.63 (s, 1 H), 3.91 (s, 3H) and 2.41 (s, 3H). HPLC-MS tR = 1.64Min (UV 254nm). Mass calculated for formula C14H12CIN7S 345.06, observed LC / MS m / z 346.0 (M + H).

PREPARED EXAMPLE Z-340-C Essentially by the same procedure set forth in preparative example Z-330-C, the compound shown above was prepared.

EXAMPLE Z-220-C To a solution of the compound of the preparative example Z-330-C (0.03 g, 0.087 mmol) in DMSO (1 ml) in a sealed tube vessel was added 3-aminoazetidine (3 equiv) and triethylamine (5 equiv). The tube was sealed and heated by a microwave at 125 ° C for 60 min. The LC-MS analysis indicated that the reaction was complete. Purification by Prep-CL and conversion to hydrochloride salt gave compound 2. HPLC-MS tR = 2.58 Min (UV 254nm). Mass calculated for formula C17H19N9S 381.15, observed LC / MS m / z 382.1 (M + H).

EXAMPLES Z230-C -Z430-C Essentially by the same procedure outlined in Example Z-220-C, only by substituting the appropriate amine, the compounds shown in column 2 of Table Z-50-C were prepared.

TABLE Z-50-C EXAMPLE Z 440-C Part A: To the compound 1 (2.1 g, 24.1 mmol) in DCM (150 ml) was added triethylamine (1.2 equiv). The resulting solution was cooled to 0 ° C (ice bath) and stirred at 0 ° C for 10 min, then benzyl chloroformate (1.2 equiv) was added. The reaction mixture was stirred at 0 ° C for 60 min, during which time the LC-MS analysis indicated that the reaction was complete. After concentration, the residue was purified by column chromatography (SiO2, 60% ethyl acetate / hexanes) to give compound 2 as a clear oil 4.0 g (75%).

Part B: A solution of compound 2 (1 g, 4.52 mmol) and triphenyphosphine (1.1 equiv) in anhydrous THF (30 ml) was treated at 0 ° C with diisopropyl azodicarboxylate (1.1 equiv) for 10 min, thioacetic acid was added (1.1 equiv) and the reaction mixture was allowed to slowly warm to room temperature. The reaction mixture was stirred at t.a. overnight. After concentration, the residue was purified by column chromatography (SiO2, 40% ethyl acetate / hexanes) gave compound 3 as a clear oil 1.2 g (95%).

Part C: A solution of compound 3 (1.2 g, 4.26 mmol) in methanol (30 ml) was treated with potassium carbonate (1.2 equiv). The resulting solution was stirred at t.a. for 16 hr, during which time the LC-MS analysis indicated that the reaction was complete. After concentration, the residue was purified by column chromatography (SiO2, 40% ethyl acetate / hexanes) to give compound 4 as a clear oil 0.26 g (26%).

Part D: Compound 5 was synthesized by the synthesis method described in preparative example 3 (Part A). To compound 5 (0.29 g, 0.84 mmol) in dichloroethane (10 mL) was added DIEA (1.2 equiv) at t.a. The resulting solution was stirred at t.a. for 10 min, and then 2- (trimethylsilyl) -ethoxymethyl chloride (1.2 equiv) was added. The resulting mixture was stirred at t.a. for 4 hr, during which time the LC-MS analysis indicated that the reaction was complete. After concentration, the residue was purified by column chromatography (S02, 80% ethyl acetate / hexanes) gave compound 6 as an orange oil 0.17 g (43%).

Part E: A mixture of compound 7 (35 mg, 0.074 mmol, 1 equivalent), compound 4 (1.4 equivalents), PdCI2 (dppf) (0.07 equiv), sodium f-butoxide (1.1 equiv) in 1,2-dimethoxyethane (1 ml) was stirred at 85 ° C under Ar for 16 hr. The reaction mixture was cooled to t.a., filtered through Celite and the filtrate was concentrated. The residue was again taken up in ethyl acetate and washed with water, brine, dried over anhydrous sodium sulfate and concentrated to give crude compound 7, which was used in the next step directly without further purification. I Part F: To a solution of compound 7 in THF (2 mL) was added 4N HCl in dioxane (2 mL) at t.a. The resulting solution was heated at 60 ° C for 60 min, during which time the LC-MS analysis indicated that the reaction was complete. The mixture was cooled to 25 ° C and concentrated. Purification by Prep-CL and conversion to the hydrochloride salt gave compound 8, example 440-C. HPLC-MS t R = 3.10 Min (UV 254 nm).

Mass calculated for formula C18H20N8S2 412.13, observed LC / MS m / z 413.0 (M + H).

PREPARED EXAMPLE Z-631-C Essentially by the same procedure set forth in preparative example Z-60-C, using N-iodosuccinimide in place of N-bromosuccinimide, the title compound was prepared.

PREPARED EXAMPLE Z-641-C Essentially by the same procedure set forth in Preparative Example Z-80-C, starting from the compound of Preparative Example Z-631-C, the title compound was prepared.

PREPARED EXAMPLE Z-645-C A mixture of the product from preparative example Z-631-C (2.40 g, 5.20 mmol), 5-amino-3-methylisothiazole hydrochloride (1.0.1 g, 6.70 mmol) and K2C03 (2.15 g, 15.60 mmol) in anhydrous CH3CN (30 ml) was stirred and refluxed under N2 for 72 hr. Then CH2Cl2 (200 ml) was added, the mixture was filtered through Celite, the solvent was evaporated, and the residue was purified by column chromatography on silica gel with 10: 1 CH2Cl2 / EtOAc as eluent. A canary yellow solid was obtained (580 mg, 21%). LC-MS: 541 [M + H].

PREPARED EXAMPLE Z-646-C Boc20 (305 mg, 1.40 mmol) was added to a stirred solution of the product of Preparative Example Z-645-C (580 mg, 1.07 mmol) and 4-dimethylaminopyridine (146 mg, 1.20 mmol) in anhydrous CH2C! 2 (10 ml. ). The mixture was stirred at 25 ° C for 2 h, then it was drained into saturated aqueous NaHCO 3 solution (60 ml), extracted with CH 2 Cl 2 (3x10 ml), dried over Na 2 SO 4, and filtered. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 25: 1 CH2Cl2 / EtOAc as eluent. A canary yellow solid was obtained (420 mg, 61%).

PREPARED EXAMPLE Z-647-C A mixture of the product of preparative example Z-646-C (400 mg, 0.63 mmol), the boronate (208 mg, 0.94 mmol), PdCI2dppf.CH2CI2 (49 mg, 0.06 mmol), and K3P04 (530 mg, 2.50 mmol) in 1,2-dimethoxyethane (10 ml) and H20 (2 ml) was stirred and refluxed under N2 for 2 hr. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 2: 1 hexane / EtOAc as eluent. A pale yellow solid was obtained (42 mg, 11%). LC-MS: 609 [M + H].

PREPARED EXAMPLE Z-648-C A mixture of the product from preparative example Z-647-C (42 mg, 0.069 mmol), NH2OH.HCl (7 mg, 0.10 mmol), and triethylamine (0.2 ml) in CH2Cl2 (1 ml) and MeOH (1 ml) were stirred in a closed flask at 25 ° C for 4 hr. The solvent was evaporated and the residue was chromatographed on silica gel with 2: 1 hexane / EtOAc as eluent. A yellow solid was obtained (30 mg, 70%).

PREPARED EXAMPLE Z-650-C A mixture of the product of preparative example Z-641-C (300 mg, 0.66 mmol), 3-furylboronic acid (110 mg, 0.98 mmol), PdCI2dppf.CH2CI2 (54 mg, 0.06 mmole), and K3P0 (560 mg, 2.64 mmole) in 1,2-dimethoxyethane (10 ml) and H20 (2 ml) was stirred and refluxed under N2 for 5 hr. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 25: 1 CH2Cl2 / MeOH as eluent. A pale yellow solid was obtained (175 mg, 67%). LC-MS: 399 [M + H].

PREPARED EXAMPLES Z651-C -Z652-C Essentially by the same procedure set forth in the preparative example Z-650-C, only using different boron reagents given in column 1 for the Suzuki couplings with the intermediate of the preparative example Z-641-C, the given compounds were prepared in column 2 of table Z-100-C.

TABLE Z-100-C PREPARED EXAMPLE Z-655-C A mixture of the product from Preparative Example Z-652-C (3.82 g, 9.00 mmol), NH2OH.HCl (750 mg, 10.76 mmol), and triethylamine (4.0 mL) in CH2Cl2 (30 mL) and MeOH (30 mL) were stirred in a closed flask at 25 ° C for 3 hr. The solvent was evaporated and the residue was chromatographed on silica gel with CH2Cl2 / MeOH 20: 1 as eluent. A slightly yellow solid was obtained (2.20 g, 56%). LC-MS: 442 [M + H].

PREPARED EXAMPLE Z-656-C Trifluoroacetic anhydride (1.05 g, 5.00 mmol) was added at 0 ° C under N2 to a stirred solution of the product of Preparative Example Z-655-C (2.20 g, 5.00 mmol) in anhydrous CH2Cl2 (30 mL) and triethylamine (4 mL). ). The mixture was stirred for 2 hr, then it was emptied into saturated aqueous NaHCO3 solution (200 ml), extracted with CH2Cl2 (3x40 ml), dried over Na2SO4, and filtered. The solvents were evaporated and the residue was purified by column chromatography on silica gel with 50: 1 CH2Cl2 / MeOH as eluent. A slightly yellow solid was obtained (1.66 g, 79%). LC-MS: 424 [M + H].

PREPARED EXAMPLE Z-660-C Anhydrous DMSO (2 ml) was added under N2 to a mixture of 5-amino-3-methylisothiazole hydrochloride (58 mg, 0.38 mmol) and 60% NaH (30 mg, 0.76 mmol). The mixture was stirred at 25 ° C for 0.5 hr, then a solution of the product from Preparative Example Z-650-C (170 mg, 0.42 mmol) was added and the resulting mixture was stirred at 25 ° C for 18 hr. The mixture was poured into brine (100 ml), extracted with a 10: 1 mixture of EtOAc / CH2Cl2 (3x30 ml), washed with brine (2x50 ml), dried over Na2SO4, and filtered. The solvents were evaporated and the residue was purified by column chromatography on silica gel with CH2Cl2 / MeOH 20: 1 as eluent. A yellow solid was obtained (74 mg, 48%). LC-MS: 481 [M + H].

PREPARED EXAMPLE Z661-C and Z662-C Essentially by the same procedure set forth in the preparative example Z-660-C, only using different starting materials given in column 1, the compounds given in column 2 of table Z-110-C were prepared.

TABLE Z-110-C EXAMPLE Z-500-C A mixture of the product of preparative example Z-660-C (74 mg) in TFA (21 ml) and H2O (2 ml) was stirred at 25 ° C under N2 for 5 hr. The solvents were evaporated, to the residue was added NaHC 3 (200 mg) and 6: 1 CH 2 Cl / MeOH (1 ml), and the mixture was stirred at 25 ° C under N 2 for 0.5 hr. The mixture was loaded onto a column and purified by column chromatography on silica gel with 4: 1 CH2Cl2 / 7N NH3 in MeOH as eluent. A pale yellow solid was obtained (30 mg, 51%). LC-MS: 381 [M + H]. Mp = 115-118 ° C.

EXAMPLE Z510-C -Z530-C Essentially by the same procedure set forth in Example Z-500-C, only using different starting materials given in column 1, the compounds given in column 2 of Table Z-120-C were prepared.

TABLE Z-120-C EXAMPLE Z540-C and Z550-C isomer 1 20 mg of the product of example Z-520-C was dissolved in hot 2-propanol (3 ml), the solution was allowed to cool to 25 ° C, hexane (1 ml) was added, the solution was filtered and the filtrate was filtered. was injected into a semi-preparative Chiralcel AD column. Chromatography with mobile phase 75:25 hexane / 2-propanol with 0.2% diethylamine gave two isomers: rapid elution (isomer 1): 5 mg, pale yellow solid; LC-MS: 406 [M + H]; Mp = 188-190X and slow elution (isomer 2): 5 mg, pale yellow solid; LC-MS: 406 [M + H]; Mp = 187-190 ° C.

Tests Tests of CHK1 SPA An in vitro test was developed using recombinant His-CHK1 expressed in the baculovirus expression system as a source of enzyme and a biotinylated peptide based on CDC25C as a substrate (biotin-RSGLYRSPSMPENLNRPR).

Materials and Reagents: 1) C-terminal biotinylated peptide substrate CDC25C Ser 216 (25 mg), stored at -20 ° C, Custom Synthesis from Research Genetics: biotin- RSGLYRSPSMPENLNRPR 2595.4 PM 2) His-CHK1 In House lot P976, 235 μg / ml, stored at -80 ° C. 3) D-PBS (without CaCl and MgCl): GIBCO, Cat. # 14190-144 4) SPA spheres: Amersham, Cat. # SPQ0032: 500 mg / vial 10 ml of D-PBS is added to 500 mg of spheres SPA to make a working concentration of 50 mg / ml. It is stored at 4 ° C. It is used after 2 weeks after hydration. 5) White 96-well microplate with bonded GF / B filter: Packard, Cat. # 6005177 6) Top-seal 96-well adhesive plastic: Perkin Elmer, Cat. # 6005185 7) Non-bonded white polystyrene plate 96 wells: Corning, Cat. # 6005177 8) MgCl2: Sigma, Cat. # M-8266 9) DTT: Promega, Cat. # V3155 10) ATP, stored at 4 ° C: Sigma, Cat. # A-5394 11)? 33P- ATP, 1000-3000 Ci / mMol: Amersham, Cat. # AH9968 12) NaCI: Fisher Scientific, Cat. # BP358-212 13) H3P04 85% Fisher, Cat. # A242-500 14) Tris-HCL pH 8.0: Bio -Whittaker, Cat. # 16-015V 15) Staurosporine, 100 μg: CALBIOCHEM, Cat. # 569397 16) Hypure cell culture-grade water, 500 ml: HyClone, Cat. # SH30529.02 Reaction mixtures 1) Regulator of kinase pH. 50 mM Tris pH 8.0; 10 mM MgCl2; 1 mM DTT 2) His-CHK1, In House Lot P976, MW ~ 30KDa, stored at -80 ° C. 6 nM is required to give positive controls of -5,000 CPM.

For 1 plate (100 rxn): 8 μl of 235 μg / ml (7.83 μM) of supply are diluted in 2 ml of kinase pH regulator. This makes a mixture of 31 nM. 20 μl / well are added. This makes a final reaction concentration of 6 nM. , 3) Biotinylated peptide CDC25C. Dilute CDC25C to 1 mg / ml (385 μM) supply and store at -20 ° C. For 1 plate (100 rxn): dilute 10 μl of 1 mg / ml of peptide supply in 2 ml of the kinase pH regulator. This gives a mixture of 1,925 μM. 20 μl / rxn are added. This makes a final reaction concentration of 385 nM. 4) ATP mixture. For 1 plate (100 rxn): 10 μl of ATP supply is diluted 1 mM (cold) and 2 μl of fresh P33-ATP (20 uCi) in 5 ml of kinase pH regulator. This gives a solution of 2 uM of ATP (cold); 50 μl / well is added to start the reaction. The final volume is 100 μl / rxn so the final reaction concentrations will be 1 μM of ATP (cold) and 0.2 μCi / rxn.

) Detention solution: For 1 plate add: To 10 ml of washing pH regulator 2 (2M NaC1 1% H3P04): 1 ml suspension of SPA spheres (50 mg); HE add 100 μl / well 6) Wash pH regulator 1: 2 M NaCl 7) Wash pH regulator 2: 2 M NaCl, 1% H3P04 Test procedure: Component of concentration Volume final test CHK1 6 nm 20 μl / rxn Compound 10 μl / rxn (10% DMSO) CDC25C 0.385 μM 20 μl / rxn? 33P-ATP 0.2 μCi / rnx 50 μl / rxn cold ATP 1 μM Spheres of 0.05 mg / rxn 100 μl / rxn * SPA detention solution 200 μl / rxn ** * Total reaction volume for testing. ** Reaction volume end at the end of the reaction (after the addition of the solution of detention). 1) The compounds are diluted to desired concentrations in water / 10% DMSO - this will give a final concentration of DMSO of 1% in rxn. μl / rxn is supplied to appropriate wells. 10 μl of 10% DMSO are added for positive (CHK1 + CDC25C + ATP) and negative (CHK1 + ATP only) control wells. 2) The enzyme is thawed on ice - enzyme is diluted to the appropriate concentration in the kinase pH regulator (see reaction mixtures) and 20 μl is supplied to each well 3) the biotinylated substrate is thawed on ice and diluted in regulator of kinase pH (see reaction mixtures). 20 μl / well is added except for negative control wells. Instead, 20 μl of the kinase pH buffer is added to these wells. 4) ATP (cold) and P33-ATP are diluted in kinase pH regulator (see reaction mixtures). 50 μl / well is added to start the reaction. 5) Let the reaction work for 2 hours at room temperature. 6) Stop the reaction by adding 100 μl of SPA spheres / stop solution (see reaction mixtures): and allow to incubate for 15 minutes before harvesting 7) Place a Packard GF / B filter plate with white on the vacuum filter device (Packard plate harvester) and 200 ml of water is sucked, moistening the em. 8) The blank is collected and put on the Packard filter plate GF / B 9) The reaction is aspirated through the filter plate. 10) Washed: 200 ml of each wash; 1X with 2M NaCl; 1 X with 2M NaCl / 1% H3P04. 11) Allow the filter plate to dry 15 min. 12) Apply TopSeal-A adhesive over the top of the filter plate. 13) Filter plate is operated in Top Count Values: Data mode: CPM Radionuclide: SPA manual: P33 Scintillator: Liq / plast Power range: low Clsn Determinations: Dose-response curves were plotted from inhibition data generated, each in duplicate, from 8-point dilutions of inhibitory compounds. The compound concentration was plotted against% kinase activity, calculated by CPM of treated samples divided by CPM from untreated samples. To generate IC 50 values, the dose-response curves were then fitted to a standard sigmoidal curve and the IC 50 values were derived by non-linear regression analysis. The Cl 50 values for a non-limiting list of illustrative compounds useful in the methods of the present invention determined in accordance with the above method were shown above. Several compounds useful in the present invention showed not only excellent check point kinase inhibitory activity (e.g., CHK-1) but also a surprisingly high ratio of checkpoint kinase inhibition (e.g., CHK-1) versus cyclin-dependent kinase inhibition (such as, for example CDK1 or CDK2) showing a high selectivity in directing the kinase. Thus, for example, several compounds showed inhibition of CHK-1 at least five times their respective inhibition of CDK (e.g., CDK2). Several compounds showed inhibition of CHK-1 at least ten times their CDK inhibition (e.g., CDK2) respectively. Several compounds showed inhibition of CHK-1 at least fifty times their respective CDK inhibition (e.g., CDK2). Certain pyrazolopyrimidine compounds showed inhibition of CHK-1 at least five times their respective CDK inhibition (e.g., CDK2). certain pyrazolopyrimidines exhibited inhibition of CHK-1 at least ten times their respective CDK inhibition (e.g., CDK2). Certain compounds of pyrazolopyrimidinium compounds exhibited inhibition of CHK-1 at least fifty times their respective CDK inhibition (e.g., CDK2). The activities of CDK (e.g., CDK1 and CDK2) of the various compounds useful in the methods of the present invention are described in the aforementioned published and copending patent applications, including, for example, attorney-in-fact case No. OC06284 and OC01617K3 that are incorporated into it by reference. One skilled in the art would find those high desirable selectivities under certain circumstances. Although the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those skilled in the art. It is intended that all such alternatives, modifications and variations fall within the spirit and scope of the present invention.

Claims

NOVELTY OF THE INVENTION CLAIMS 1. - The use of a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting the activity of one or more kinases in a patient, in wherein the kinases are selected from the group consisting of check point kinases, Pim kinases, and Aurora kinases, and the compound selected from the group consisting of the compounds represented by any of the following structural formulas I to VI: I. Formula I wherein: R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide of said heteroaryl), - (CHRVaryl. -CHRVheteroaryl, - (CHR5) n-N I G? N -R8 - < CHR5) n-N - < CHR 55) n-N O \ O wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl and heteroaryl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen , alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) pOR5, -C (O2) R5, -C (0) R5, -C (0) NR5R10, -S03H7 -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R2 is selected from the group consisting of H, R9, alkyl, alkenyl, alkynyl, CF3, heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R9 groups which can be the same or different and are independently selected from the list of R9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazole groups , aryl fused with an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazole groups, heteroaryl fused with an aryl group or heteroaryl, - < CH2) m-N N- R8 wherein one or more of the aryl and / or one or more of the heteroaryl in the definitions indicated above for R2 may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consists of halogen, -CN, -OR5, -SR5, -S (02) R6, -S (02) NR5R6, -NR5R6, -C (0) NR5R6, CF3, alkyl, aryl and OCF3; R3 is selected from the group consisting of H, halogen, -NR5R6, -OR6, -SR6, -C (0) N (R5R6), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 can be unsubstituted or optionally independently substituted with one or more portions that can be be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, -OR5, -NR5R6, - (CR4R5) PNR5R6, -C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0 ) R7, -N (R5) C (R4R5) nN (R5R6) and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a portion - OR5; R 4 is H, halogen or alkyl; R5 is H, alkyl, aryl, heteroaryl, arylalkyl or cycloalkyl; R6 is selected from the group consisting of H, Boc, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, | heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R4R5) P-R9, -N (R5) Boc, - (CRR5) pOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -SO3H, -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR4R5, - C (R4R5) P-R9, -N (R5) Boc, - (CRR5) pOR5, -C (02) R5, -C (0) NR R5, -C (0) R5, -SO3H, -SR5, -S (02) R7, -S (02) NR4R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR4R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (¡i) R5 and R6 in the -NR5R6 portion, may be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C ( 02) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02) R10, -S (02) NR5R10, -N (R5) S (02) R10, -N (R5 ) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -OR6, -C (0) NR5R10, -S (02) NR5R10, -C (0) R7, -C (= N-CN) -NH2 > -C (= NH) -NHR5, heterocyclyl, and -S (02) R7; R9 is selected from the group consisting of halogen, -CN, -NR5R10, -SCN, -N02, -C (0) R5, -C (02) R6, -C (0) NR5R10, -OR6, -SR6, - S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; m is 0 to 4; n is 1 to 4; and p is 1 to 4, with the proviso that when R2 is phenyl, R3 is not alkyl, alkynyl or halogen, and that when R2 is aryl, R is not i (CHR5) n NR5R8 provided that when R is arylalkyl, then any heteroaryl substituent on the aryl of said arylalkyl contains at least three heteroatoms; II. Formula ll wherein: R is an aryl, wherein said aryl is either unsubstituted or optionally substituted or fused with one or more heteroaryl; R2 is selected from the group consisting of R9, alkyl, alkynyl, alkynylalkyl, cycloalkyl, -CF3, -C (02) R6, aryl, arylalkyl, heteroarylalkyl, heterocyclyl, alkyl substituted with 1-6 R9 groups which groups can be the same or different with each R9 being independently selected, aryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups, - (CH2) m-N N-R8 \ - N-R "-arilc N-RB J aril ° r N-R8 heteroaryl substituted with 0-3 aryl or heteroaryl groups which may be the same or different and are independently selected from alkyl, phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups; R3 is selected from the group consisting of H, halogen, -NR5R6, -C (0) NR5R6, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each being independently selected portion from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) n oR 5, -OR 5, -NR5R6, - (CR4R5) nNR5R6, -C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N ( R5) C (0) R7 and -N (R5) C (0) NR5R6; R 4 is H, halogen or alkyl; R5 is H or alkyl; R6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl can be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10 -N (R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -S03H, -SR10 -S (02) R7, -S (02) NR5R10 , -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10 R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl it and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, - OR5, -NR4R5, -N (R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) NR4R5, -C (0) R5, -S03H, -SR5, -S (02) R7, -S (02) NR4R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR4R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR6R10, -CH2OR5, -C (02) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02) R10, -S (02) NR5R10, -N (R5) S (02) R10, -N (R5) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -C (0) NR5R10, -S (02) NR5R10, -C (0) R7 and -S (02) R7; R9 is selected from the group consisting of halogen, CN, -NR5R10, -C (02) R6, -C (0) NR5R10, -OR6, -SR6, -S (02) R7, -S (02) NR5R10, - N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; m is 0 to 4, and n is 1 to 4, with the following conditions: (i) that when R is an unsubstituted phenyl, then R2 is not alkyl, -C (02) R6, aryl or cycloalkyl, and (i) ) that when R is a phenyl substituted with a hydroxyl group, then R2 is halogen only; Formula lll wherein: R is heteroaryl, wherein said heteroaryl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R6, -C (R4R5) nOR5, -C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (O2) R7, -S (O2) NR5R6, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6; R2 is selected from the group consisting of R9, alkyl, alkynyl, aryl, heteroaryl, CF3, heterocyclylalkyl, alkynylalkyl, cycloalkyl, -C (0) OR4, alkyl substituted with 1-6 R9 groups which may be the same or different and select independently from the list of R9 shown below, \ - (CH2) m- N N- R8 \ N-R8 I aryl - N-R8 • aariplo0d N-R1 8 wherein the aryl in the definitions indicated above for R2 may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, CN, -OR5, SRS, -CH2ORD, -C (0) R °, -S03H, -S (02) R, -S (02) NRsRb, -NRbR, -C (0) NR5R6, -CF3, and -OCF3; R3 is selected from the group consisting of H, halogen, -NR5R6, -C (0) OR4, -C (0) NR5R6, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroaryl alkyl for R3 and the heterocyclyl moieties whose structures are shown immediately before for R3 may be substituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) nOR5, -OR5, -NR5R6, - (CR R5) nNR5R6, - C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6; R 4 is H, halogen or alkyl; R5 is H or alkyl; R6 is selected from the group consisting of H, alkyl, aryl, aplaxyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, - N (R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -SO3H, -SR10, -S (02) R7, -S (02 ) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroalalkyl may be substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR4R5, -N ( R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) NR4R5, -C (0) R5, -SO3H, -SR5, -S (02) R7, -S (02) NR4R5 , -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR4R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl for R7 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C (02) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02) R10, -S (02) NR5R10, -N (R5) S (02) R1 °, -N (R5) C ( 0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -C (0) NR5R10, -CH2OR4, -C (0) OR6, -C (0) R7 and -S (02) R7; R9 is selected from the group consisting of halogen, -CN, -NR5R6, - (CH2) nOR4, -C (02) R6, -C (0) NR5R6, -OR6, -SR6, -S (02) R7, - S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6; m is 0 to 4; and n is 1 to 4; IV. Formula IV wherein: Q is selected from the group consisting of -S (02) NR6R7-, -C (0) NR6R7- and -C (0) OR7-; R2 is selected from the group consisting of R9, alkyl, alkynyl, alkynylalkyl, cycloalkyl, -CF3, -C (02) R6, aryl, arylalkyl, heteroarylalkyl, heterocyclyl, alkyl substituted with 1-6 R9 groups which may be the same or different and are independently selected from the list of R9 shown below, '(CH2) p / \ V N-R8-aryl-N N-aryl-; N-RB wherein the aryl in the definitions indicated above for R2 may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, CN, -OR5 , SR5, -S (02) R6, -S (02) NR5R6, -NR5R6, -C (0) NR5R6, CF3, alkyl, aryl and OCF3; R3 is selected from the group consisting of H, halogen, alkyl, alkynyl, -C (0) NR, 5DnR6 °, -C (0) OR, -NR) 53 | R- > 6 °, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 may be substituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) nOR5, -OR5, -NR5R6, - (CR4R5) nNR5R6, -C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N ( R5) C (0) R7 and -N (R5) C (0) NR5R6; R 4 is H, halogen or alkyl; R5 is H or alkyl; R6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10-N ( R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -S03H, -SR10 -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10 R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl cycloalkyl, heterocyclyl , heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5 , -NR4R5, -N (R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) NR R5, -C (0) R5, -S03H, -SR5, -S (02) R7, -S (02) NR4R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR4R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, may be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C (02) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02) R10, -S (02) NR5R10, -N (R5) S (02) R10,, -N (R5) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -C (O) NR5R10, -S (O2) NR5R10, -C (O) R7 and -S (O2) R7; R9 is selected from the group consisting of halogen, CN, -NR5R10, -C (O2) R6, -C (0) NR5R10, -OR6, -SR6, -S (02) R7, -S (02) NR5R10, - N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; m is 0 to 4, and n is 1 to 4; V. Formula V wherein: Q is -S (02) - or -C (O) -; R is aryl or heteroaryl, wherein said aryl or heteroaryl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, CN, -OR5, SR5, -S (02) R6, -S (02) NR5R6, NR5R6, -C (0) NR5R6, CF3, alkyl, aryl and OCF3; R2 is selected from the group consisting of CN, NR5R6, -C (02) R6, -C (0) NR5R6, -OR6, -SR6, -S (02) R7, -S (02) NR5R6, -N (R5 ) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6; alkynyl, heteroaryl, CF3, heterocyclyl, alkynylalkyl, cycloalkyl, alkyl substituted with 1-6 R9 groups which may be the same or different and are independently selected from the list of R9 shown below, Í- (CHa) "r-N N- R V d N-R8 - aryl - N N -R8 R3 is selected from the group consisting of H, halogen, -NR5R6, -C (0) NR5R6, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroalalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 may be substituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) nOR5, -OR5, -NR5R6, - (CR4R5) nNR5R6, -C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N ( R5) C (0) R7 and -N (R5) C (0) NR5R6; R 4 is H, halogen or alkyl; R5 is H or alkyl; R6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroalalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10-N ( R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -S03H, -SR10 -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and; -N (R5) C (0) NR5R10 R10 is selected from the group consisting of H, alkyl, aryl, aplaxyl cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR4R5, -N (R5) Boc, - (CR4R5) nOR5, -C (O2) R5, -C (0) NR4R5, -C (0) R5, -S03H, -SR5, -S (02) R7, -S (02) NR4R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR4R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (¡i) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroaplalkyl, aryl, heteroaryl and arylalkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C (02) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02) R10, -S (02) NR5R10, -N (R5) S (02) R10, -N (R5) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -C (0) NR5R10, -S (02) NR5R10, -C (0) R7 and -S (02) R7; R9 is selected from the group consisting of halogen, CN, -NR5R10, -C (02) R6, -C (0) NR5R10, -OR6, -SR6, -S (02) R7, -S (02) NR5R1 °, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; m is 0 to 4, and n is 1 to 4; and I saw. or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein: R2 is selected from the group consisting of halo; -CF3; -CN; -SR6; -N02; -NR5R6a; -C (0) R6; -S (02) R7; -S (02) NR5R10; -N (R5) S (02) R7; -N (R5) C (0) NR5R10; I rent; alkenyl; alkynyl; heterocyclic; heterocyclylalkyl; halo; halogenoalkyl; cycloalkyl; aril; Arylalkyl; arylalkenyl; arylalkynyl; heteroarylalkyl; alkynylalkyl; aryl fused with an aryl or heteroaryl group; heteroaryl; heteropole fused to an aryl or heteroaryl group; wherein each of the alkyl, alkenyl, alkynyl, heterocyclyl, heterocyclylalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, and alkynylalkyl groups and the heterocyclic portions shown immediately above for R2 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5 , -NR5R6, - (CR5R1) PN R5R6, -C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, - N (R5) S (02) R7, -C (= N-OH), -N (R5) C (0) R7 and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion; R3 is selected from the group consisting of H; -NR5R6a; -OR6b; -SR6; CF3; -C (0) N (R5R6); I rent; alkenyl, alkynyl; cycloalkyl; aril; aplaxyl; heterocyclyl; heterocyclylalkyl; heteroaryl; heteroarylalkyl; wherein each of the alkyl, alkynyl groups; cycloalkyl, aryl, aplakyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and the heterocyclic portions whose structures are shown immediately before for R3 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (O2) R5, -C (O) R5, -C (0) NR5R6, -C (= N-OH), -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6, with the proviso that no adjacent carbon a nitrogen atom in a heterocyclyl ring carries a -OR5 portion; R4 is selected from the group consisting of -CF3; -CN; -NR ^ 63; - (CR5R11) pC (02) R6; - (CR5R11) pC (0) NR5R10; -C (0) -N (R5R10); -OR6b; -SR6; -S (02) R7; -S (02) NR5R10; -C (0) R6; -N (R5) S (02) R7; -N (R5) C (0) R7; -N (R5) C (0) NR5R10; alkenyl; alkenyl (substituted with alkoxy); hydroxyalkyl; alkynyl; heterocyclyl; heterocyclylalkyl; aril; aryl fused with an aryl or heteroaryl group; heteroaryl; heteroaryl fused with an aryl or heteroaryl group; substituted alkyl; cycloalkyl; wherein each of the alkyl, cycloalkyl groups; heterocyclyl, heterocyclylalkyl, aryl, fused aryl, heteroaryl, and fused heteroaryl of R 4 may be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (02) R5, -C (0) R5, -C ( R5) (= N-OR5), -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion, and wherein the substituted alkyl group of R4 is independently substituted with one or more of the above portions; R5 is H, alkyl, aryl or cycloalkyl; R6 is selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R5R1) P-R9, -N (R5) Boc, - (CR5R11) pOR5 , -C (02) R5, -C (0) R5, -C (= N-OH), -C (0) NR5R10, -S03H, -SR10, -S (02) R7, -S (02) NR5R1 °, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R6a is selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R5R11) P-R9, -N (R5) Boc, - (CR5R11) pOR5, -C (02) R5, -C (0) R5, -C (= N-OH) , -C (0) NR5R10, -S03H, -SR10, -S (02) R7, -S (02) NR5R1 °, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R6b is selected from the group consisting of alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaplo, and heteroarylalkyl, wherein each of the alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl can being unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, -CF3, -OCF3, -CN, -OR5 , -NR5R10, -C (R5R1) P-R9, -N (R5) Boc, - (CR5R11) pOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -SO3H , -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7, -C (= N-OH), and -N (R5) C (0) NR5R10; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, where each alkyl, cycloalkyl, heteroarylalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroaryl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each being independently selected portion from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5 , -NR5R10, ^ CH2OR5, -C (02) R5, -C (0) NR5R10, -C (= N-OH), -C (0) R5, -SR10, -S (02) R1 °, -S (02) NR5R10, -N (R5) S (02) R10, -N (R5) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -OR6, -NR5R6, -C (0) NR5R10, -S (02) NR5R10, -C (0) R7, -C (= N-CN) -NH2, -C (= NH) -NHR5, heterocyclyl, -S (02) R7, and R9 is selected from the group consisting of halogen, -CN, -NR5R10, -C (02) R6, -C (0) NR5R10, -C (= N-OH), -OR6, -SR6, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; and R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted by one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R11, -C (R5R1) P-R9, -N (R5) Boc, - (CR5R11) pOR5, -C (O2) R5, -C (O) NR5R11, -C (O) R5, -C (= N-OH), -SO3H, -SR5, -S (O2) R7, -S (O2) NR5R11, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N ( R5) C (O) NR5R11; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each of the cycloalkyl or heterocyclyl port being unsubstituted or optionally independently being substituted with one or more R9 groups; R11 is H, halogen or alkyl; m is 0 to 4; n is 1 to 4; and p is 1 to 4; with the proviso that (1) when R2 is alkyl, carboxyl, phenyl or cycloalkyl, then R3 is selected from the group consisting of -NR5R6a; -C (0) N (R5R6); alkynyl; Arylalkyl; heterocyclyl; heterocyclylalkyl; heteroaryl; heteroarylalkyl; wherein each of the alkynyl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl groups, and the heterocyclic portions whose structures are shown immediately above for R3 are unsubstituted or are independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of -CN, -NR5R6, - (CR5R11) PNR5R6, -C (0) NR5R6, -S (02) NR5R6, -N (R5) S (02) R7, -N ( R5) C (0) R7 and -N (R5) C (0) NR5R6; (2) when R2 is halogen, then R3 is selected from the group consisting of -OR6b; -SR6; -C (0) N (R5R6); cycloalkyl; heterocyclyl; heterocyclylalkyl; wherein each of the cycloalkyl, heterocyclyl, heterocyclylalkyl, and heterocyclic portions whose structures are shown immediately before for R3 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R1) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (02) R5, -C (0) R5, -C (0) NR6R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclic ring carries a -OR5 portion; and (3) when R2 is NH2, R3 is not methyl.
2. The use of a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for treating, or slowing the progression of, a disease by inhibiting one or more cineses in a patient, wherein the kinases are selected from the group consisting of check point cinases, Pim kinases, and Aurora kinases, the compound being selected from the group consisting of the compounds represented by any of the following structural formulas I to VI: I. Formula I wherein: R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide of said heteroaryl), - (CHR5) n-aryl, - (CHR5) n-heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl and heteroaryl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen , alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) pOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -S03H7 -SR10, -S (O2) R7, -S (O2) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R2 is selected from the group consisting of H, R9, alkyl, alkenyl, alkynyl, CF3, heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R9 groups which can be the same or different and are independently selected from the list of R9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazole groups , aryl fused with an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazole groups, heteroaryl fused with an aryl group or heteroaryl, wherein one or more of the aryl and / or one or more of the heteroaryl in the definitions indicated above for R2 may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consists of halogen, -CN, -OR5, -SR5, -S (02) R6, -S (02) NR5R6, -NR5R6, -C (0) NR5R6, CF3, alkyl, aryl and OCF3; R3 is selected from the group consisting of H, halogen, -NR5R6, -OR6, -SR6, -C (0) N (R5R6), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 may be unsubstituted or optionally independently substituted with one or more portions which may be be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) pOR5, -OR5, -NR5R6, - (CR4R5) PNR5R6, - C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7, -N (R5) C (R R5) nN (R5R6) and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion; R 4 is H, halogen or alkyl; R5 is H, alkyl, aryl, heteroaryl, arylalkyl or cycloalkyl; R6 is selected from the group consisting of H, Boc, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl , heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN , -OR5, -NR5R10, -C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) pOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -SO3H, -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0 ) NR5R10; R10 is selected from! a group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR4R5, -C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) pOR5, -C (02) R5, -C (0) NR4R5, -C (0) R5, -S03H, -SR5, -S (02) R7 , -S (02) NR4R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR4R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C ( 02) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02) R10, -S (02) NR5R1 °, -N (R5) S (02) R10, -N ( R5) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -OR6, -C (0) NR5R10, -S (02) NR5R10, -C (0) R7, -C (= N-jCN) -NH. -C (= NH) -NHR5, heterocyclyl, and -S (02) R7; R9 is selected from the group consisting of halogen, -CN, -NR5R10, -SCN, -NO2, -C (O) R5, -C (O2) R6, -C (O) NR5R10, -OR8, -SR6, - S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7. -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; m is 0 to 4; n is 1 to 4; and p is 1 to 4, with the proviso that when R2 is phenyl, R3 is not alkyl, alkynyl or halogen, and that when R2 is aryl, R is not S (CHR5) "NR5R8 provided that when R is arylalkyl, then any heteroaryl substituent on the aryl of said arylalkyl contains at least three heteroatoms; II. Formula II or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound, wherein: R is an aryl, wherein said aryl is either not substituted or optionally substituted or fused with one or more heteroaryl; R2 is selected from the group consisting of R9, alkyl, alkynyl, alkynylalkyl, cycloalkyl, -CF3, -C (02) R6, aryl, arylalkyl, heteroarylalkyl, heterocyclyl, alkyl substituted with 1-6 R9 groups said groups may be the same or different with each R9 being independently selected, aryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazol, aryl r ~ \\ - N-RB and heteroaryl substituted with 0-3 aryl or heteroaryl groups which may be same or different and are independently selected from alkyl groups, phenyl, pyridyl, thiophenyl, furanyl and thiazole; R3 is selected from the group that consists of H, halogen, -NR5R6, -C (0) NR5R6, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each being independently selected portion from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) "OR5, -OR5, -NR5R6, - (CR4R5) nNR5R6, - C (02) R5, -C (0) R5, -C (0) NR5R6, '-SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, - N (R5) C (0) R7 and -N (R5) C (0) NR5R6; R 4 is H, halogen or alkyl; R5 is H or alkyl; R6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each being independently selected portion from the group consisting of halogen, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10 -N (R5) Boc, - (CR R5) nOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -S03H, -SR10 -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10 R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl cycloalkyl , heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each being independently selected portion from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5 , -NR4R5, -N (R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) NR4R5, -C (0) R5, -S03H, -SR5, -S (02) R7 , -S (02) NR4R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR4R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR6R10, -CH2OR5, -C (02) R5, -C (Q) NR5R10, -C (0) R5, -SR10, -S (02) R10, -S (02) NR5R10, -N (R5) S (02) R10, -N (R5) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -C (0) NR5R10, S (02) NR5R10, -C (0) R7 and -S (02) R7; R9 is selected from the group consisting of halogen, CN, -NR5R10, -C (02) R6, -C (0) NR5R10, -OR6, -SR6, -S (02) R7, -S (02) NR5R10, - N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; m is 0 to 4, and n is 1 to 4, with the following conditions: (i) that when R is an unsubstituted phenyl, then R2 is not alkyl, -C (02) R6, aryl or cycloalkyl, and (ii) that when R is a phenyl substituted with a hydroxy group, then R2 is halogen only; lll. Formula III, wherein: R is heteroaryl, wherein said heteroaryl may be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl , cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R6, -C (R4R5) nOR5, -C (O2) R5, -C (O) R5, -C (O) NR5R6, -SR6, -S (O2 ) R7, -S (O2) NR5R6, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR5R6; R2 is selected from the group consisting of R9, alkyl, alkynyl, aryl, heteroaryl, CF3, heterocyclylalkyl, alkynylalkyl, cycloalkyl, -C (0) OR4, alkyl substituted with 1-6 R9 groups which can be the same or different and are select independently from the list of R9 shown below, i / \. ,, (CH2) m v \ > / \ \ - (CH2) m- N N- R8 \ N-R8 1 aryl - N N -R8 wherein the aryl in the definitions indicated above for R2 may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, CN, -OR5, SR5, -CH2OR5, -C (0) R5, -SO3H, -S (02) R6, -S (02) NR5R6, -NR5R6, -C (0) NR5R6, -CF3, and -OCF3; R3 is selected from the group consisting of H, halogen, -NR5R6, -C (0) OR4, -C (0) NR5R6, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each being independently selected portion from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) n oR 5, -OR 5, -NR5R6, - (CR4R5) nNR5R6, -C (02) R5, -C (0) R5, -C (0) NR5R6,; -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6; R 4 is H, halogen or alkyl; R5 is H or alkyl; R6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -N (R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -SO3H, -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl may be not substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR4R5, -N ( R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) NR4R5, -C (0) R5, -S03H, -SR5, -S (02) R7, -S (02) NR R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR4R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl for R7 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl , CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C (02) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02) R10, -S ( 02) NR5R10, -N (R5) S (02) R10, -N (R5) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -C (0) NR5R10, -CH2OR4, -C (0) OR6, -C (0) R7 and -S (02) R7; R9 is selected from the group consisting of halogen, -CN, -NR5R6, - (CH2) nOR4, -C (02) R6, -C (0) NR5R6, -OR6, -SR6, -S (02) R7, - S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6; m is 0 to 4; and n is 1 to 4; IV. Formula IV wherein: Q is selected from the group consisting of -S (02) NR6R7-, -C (0) NR6R7- and -C (0) OR7-; R2 is selected from the group consisting of R9, alkyl, alkynyl, alkynylalkyl, cycloalkyl, -CF3, -C (02) R6, aryl, arylalkyl, heteroarylalkyl, heterocyclyl, alkyl substituted with 1-6 R9 groups which may be the same or different and are independently selected from the list of R9 shown below, - (CH2) mN NR ° V and (CH2) n. ^ aplod ^ _R8 dN -R "-anlo - N N-RB \ ~ wherein the aryl in the definitions indicated above for R2 may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, CN, -OR5, SR5, -S (02) R6, -S (02) NR5R6, -NR5R6, -C (0) NR5R6, CF3, alkyl, aryl and OCF3; R3 is selected from the group consisting of H, halogen, alkyl, alkynyl, -C (0) NR5R6, -C (0) OR4, -NR5R6, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 may be substituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) nOR5, -OR5, -NR5R6, - (CR4R5) nNR5R6, -C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N ( R5) C (0) R7 and -N (R5) C (0) NR5R6; R 4 is H, halogen or alkyl; R5 is H or alkyl; R6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10-N ( R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -S03H, -SR10 -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10 R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl cycloalkyl, heterocyclyl , heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5 , -NR4R5, -N (R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) NR4R5, -C (0) R5, -S03H, -SR5, -S (02) R7 , -S (02) NR4R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (i) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C (02) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02) R10, -S (02) NR5R10, -N (R5) S (02) R10, -N (R5) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -C (0) NR5R10, S (02) NR5R10, -C (0) R7 and -S (02) R7; R9 is selected from the group consisting of halogen, CN, -NR5R10, -C (02) R6, -C (0) NR5R10, -OR6, -SR6, -S (02) R7, -S (02) NR5R10, N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; m is 0 to 4, and n is 1 to 4; V. wherein: Q is -S (02) - or -C (O) -; R is aryl or heteroaryl, wherein said aryl or heteroaryl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, CN, -OR5, SR5, -S (02) R6, -S (02) NR5R6, NR5R6, -C (0) NR5R6, CF3, alkyl, aryl and OCF3; R2 is selected from the group consisting of CN, NR5R6, -C (02) R6, -C (0) NR5R6, -OR6, -SR6, -S (02) R7, -S (02) NR5R6, -N (R5 ) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6; alkynyl, heteroaryl, CF3, heterocyclyl, alkynylalkyl, cycloalkyl, alkyl substituted with 1-6 R9 groups which may be the same or different and are independently selected from the list of R9 shown below, - (CH2) m-N N- Rß '(CH2) m / - \ V N-R8 N-R ° and • aryl- N-Rβ R3 is selected from the group consisting of H, halogen, -NR5R6, -C (0) NR5R6, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 may be substituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) nOR5, -OR5, -NR5R6, - (CR4R5) nNR5R6, -C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N ( R5) C (0) R7 and -N (R5) C (0) NR5R6; R 4 is H, halogen or alkyl; R5 is H or alkyl; R6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10-N ( R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -SO3H, -SR10 -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10 R 0 is selected from the group consisting of H, alkyl, aryl, arylalkyl cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl may be unsubstituted or optionally substituted by one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR R5, -N (R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) NR4R5, -C (0) R5, -S03H, -SR5, -S (02) R7 , -S (02) NR4R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR4R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C (02) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02) R10, -S (02) NR5R10, -N (R5) S (02) R10, -N (R5) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -C (0) NR5R10, -S (02) NR5R10, -C (0) R7 and -S (02) R7; R9 is selected from the group consisting of halogen, CN, -NR5R10, -C (02) R6, -C (0) NR5R10, -OR6, -SR6, -S (02) R7, -S (02) NR5R10, - N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; m is 0 to 4, and n is 1 to 4; and I saw. Formula VI or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein: R2 is selected from the group consisting of halo; -CF3; -CN; -SR6; -N02; -NR5R6a; -C (0) R6; -S (02) R7; -S (02) NR5R10; -N (R5) S (02) R7; -N (R5) C (0) NR5R10; I rent; alkenyl; alkynyl; heterocyclyl; heterocyclylalkyl; halo; halogenoalkyl; cycloalkyl; aril; Arylalkyl; arylalkenyl; arylalkynyl; heteroarylalkyl; alkynylalkyl; aryl fused with an aryl or heteroaryl group; heteroaryl; heteroaryl fused with an aryl or heteroaryl group; - (CH2) m-N N-RB - (CH2) m ~ d V N-R ° - aryl-aryl N-RB wherein each of the alkyl, alkenyl, alkynyl, heterocyclyl, heterocyclylalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, arylalkyl, heteroarylalkyl, and alkynylalkyl groups and the heterocyclic portions shown immediately above for R2 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) POR5, -OR5 , -NR5R6, - (CR5R1) PN R5R6, -C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, - N (R5) S (02) R7, -C (= N-OH), -N (R5) C (0) R7 and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion; R3 is selected from the group consisting of H; -NR5R6a; -OR6b; -SR6; CF3; -C (0) N (R5R6); I rent; alkenyl, alkynyl; cycloalkyl; aril; Arylalkyl; heterocyclyl; heterocyclylalkyl; heteroaryl; heteroarylalkyl; wherein each of the alkyl, alkynyl groups; cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and the heterocyclic portions whose structures are shown immediately above for R3 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR 1R1) POR5, -OR5, -NR5R6, - (CR5R11) pNR5R6, -C (O2) R5, -C (O) R5, -C (O) NR5R6, -C (= N-OH), -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7 , -N (R5) C (0) R7 and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion; R4 is selected from the group consisting of -CF3; -CN; -NR5R6a; - (CR5R11) pC (02) R6; - (CR5R11) pC (0) NR5R10; -C (0) -N (R5R10); -OR6b; -SR6; -S (02) R7; -S (02) NR5R10; -C (0) R6; -N (R5) S (02) R7; -N (R5) C (0) R7; -N (R5) C (0) NR5R10; alkenyl; alkenyl (substituted with alkoxy); hydroxyalkyl; alkynyl; heterocyclic; heterocyclylalkyl; aril; aryl fused with an aryl or heteroaryl group; heteroaryl; heteroaryl fused with an aryl or heteroaryl group; substituted alkyl; cycloalkyl; wherein each of the alkyl, cycloalkyl groups; heterocyclyl, heterocyclylalkyl, aryl, fused aryl, heteroaryl, and fused heteroaryl of R 4 may be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (02) R5, -C (0) R5, -C ( R5) (= N-OR5), -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion, and wherein the substituted alkyl group of R4 is independently substituted with one or more of the above portions; R5 is H, alkyl, aryl or cycloalkyl; R6 is selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups may be unsubstituted or optionally substituted with one or more portions that they may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R5R11) p-R9, -N ( R5) Boc - (CR5R11) POR5, -C (02) R5, -C (0) R5, -C (= N-OH), -C (0) NR5R10, -S03H, -SR10 -S (02) R7 , -S (02) NR5R1 °, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10 R6a is selected from the group consisting of alkyl , alkenyl, aryl, arylalkyl arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl groups , heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN , -OR5, -NR5R10, -C (R5R11) P-R9, -N (R5) Boc, - (CR5R11) POR5, -C (02) R5, -C (0) R5, -C (= N-OH ), -C (0) NR5R10, -S03H, -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R6b is selected from the group consisting of alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can being unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, -CF3, -OCF3, -CN, -OR5 , -NR5R10, -C (R5R11) P-R9, -N (R5) Boc, - (CR5R1) pOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -S03H, -SR10, -S (02) R7, -S (O2) NR5R10, -N (R5) S (O2) R7, -N (R5) C (O) R7, -C (= N-OH), and - N (R5) C (O) NR5R10; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, wherein each of the alkyl, cycloalkyl, heteroarylalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5 , -NR5R10, -CH2OR5, -C (02) R5, -C (0) NR5R10, -C (= N-OH), -C (0) R5, -SR10, -S (02) R10, -S ( 02) NR5R10, -N (R5) S (02) R10, -N (R5) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -OR6, -NR5R6, -C (0) NR5R10, -S (02) NR5R10, -C (0) R7, -C (= N-CN) -NH2, -C (= NH) -NHR5, heterocyclyl, -S (02) R7, and R9 is selected from the group consisting of halogen, -CN, -NR5R10, -C (02) R6, -C (0) NR5R10, -C (= N-OH), -OR6, -SR6, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; and R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R11, -C (R5R11) P-R9, -N (R5) Boc, - (CR5R11) pOR5, -C (02) R5, -C (0) NR5R11, -C (0) R5, -C (= N-OH), -S03H, -SR5, -S (02) R7, -S (02) NR5R11, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N ( R5) C (0) NR5R11; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each of the cycloalkyl or heterocyclyl bearing unsubstituted or optionally independently being substituted with one or more R9 groups; R11 is H, halogen or alkyl; m is 0 to 4; n is 1 to 4; and p is 1 to 4; with the proviso that (1) when R2 is alkyl, carboxyl, phenyl or cycloalkyl, then R3 is selected from the group consisting of -NR5R6a; -C (0) N (R5R6); alkynyl; Arylalkyl; heterocyclyl; heterocyclylalkyl; heteroaryl; heteroarylalkyl; wherein each of the alkynyl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl groups, and the heterocyclic portions whose structures are shown immediately above for R3 are unsubstituted or are independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of -CN, -NR5R6, - (CR5R11) PNR5R6, -C (0) NR5R6, -S (02) NR5R6, -N (R5) S (02) R7, -N ( R5) C (0) R7 and -N (R5) C (0) NR5R6; (2) when R2 is halogen, then R3 is selected from the group consisting of -OR} 6Db ° .; -SR j6. , -C (0) N (R> 5 ° DR6 °); cycloalkyl; heterocyclyl; heterocyclylalkyl; wherein each of the cycloalkyl, heterocyclyl, heterocyclylalkyl groups, and the heterocyclic portions whose structures are shown immediately above for R3 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected of the group consisting of halogen, alkyl, aryl, cycloalkyl, • CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (02) R5, -C ( 0) R5, -C (0) NR6R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion; and (3) when R2 is NH2, R3 is not methyl.
3. The use of a combination of (i) a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, and (ii) an anti-cancer agent, for the manufacture of a medicament useful for treating, or slowing the progression of, a disease by inhibiting one or more kinases in a patient, wherein the kinases are selected from the group consisting of check point kinases, Pim kinases, and Aurora kinases, in wherein the first compound is selected from the group consisting of the compounds represented by any of the following structural formulas I to VI: I. H 'Formula I wherein: R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylayl. neteroaryalkyl (including N-oxide of said heteroaryl), - (CHR5) n-ary, - (CHR5) n-heteroaryl. - (CHRV - N- Rß (CHRV-N, - (CHR5) n-N I / "? C wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl and heteroaryl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen , aikile, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R4R5) P-R9, -N (R5) Boc, - (CR R5) POR5, -C (02) R5 , -C (0) R5, -C (0) NR5R10, -S03H7 -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R2 is selected from the group consisting of H, R9, alkyl, alkenyl, alkynyl, CF3, heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R9 groups which can they are the same or different and are independently selected from the list of R9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanüo and thiazolo groups , aryl fused with an aryl or heteroaryl group. heteroaryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazol groups, heteroaryl fused with an aryl or heteroaryl group, wherein one or more of the aryl and / or one or more of the heteroaryl in the definitions indicated above for R2 may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consists of halogen, -CN, -OR5, -SR5, -S (O2) R6, -S (O2) NR5R6, -NR5R6, -C (O) NR5R6, CF3, alkyl, aryl and OCF3; R is selected from the group consisting of H, halogen, -NR5R6, -OR6, -SR6, -C (0) N (R5R6), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 may be unsubstituted or optionally independently substituted with one or more portions which may be be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) pOR5, -OR5, -NR5R6, - (CR4R5) PNR5R6, - C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7, -N (R5) C (R4R5) nN (R5R6) and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a ring of heterocyclyl carries a -OR5 portion; R 4 is H, halogen or alkyl; R5 is H, alkyl, aryl, heteroaryl, arylalkyl or cycloalkyl; R6 is selected from the group consisting of H, Boc, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, aplakyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) pOR5, -C (02) R5, -C (0) R5, -C (0) NR5R , ü, -SO3H, -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R6) C (0) R7 and -N (R5) C (0) NR5R1 °; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkio, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, 'CN, -OR5, -NR4R5, -C (R R5) P-R9. -N (R5) Boc, - (CR4R5) pOR5, -C (02) R5, -C (0) NR4R5, -C (0) R5, -S03H, -SR5, -S (02) R7, -S ( 02) NR4R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR4R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C ( 02) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02) R10, -S (02) NR5R10, -N (R5) S (02) R10, -N (R5 ) C (0) R1C and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -OR6, -C (O) NR5R10, -S (02) NR5R10, -C (0) R7, -C (= N-CN) -NH2 > -C (= NH) -NHR5, heterocyclyl, and -S (02) R7; R9 is selected from the group consisting of halogen, -CN, -NR5R10, -SCN, -N02, -C (0) R5, -C (02) R6, -C (0) NR5R10, -OR6, -SR6, - S (02) R7, -S (02) NR5R1 °, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; m is 0 to 4; n is 1 to 4; and p is 1 to 4, with the proviso that when R2 is phenyl, R3 is not alkyl, alkynyl or halogen, and that when R2 is aryl, R is not S (CHR5) n NR5R8 provided that when R is arylalkyl, then any substituent of heteroaryl in the aryl of said arylalkyl contains at least three heteroatoms; II. Formula II or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound, wherein: R is an aryl, wherein said aryl is either not substituted or optionally substituted or fused with one or more heteroaryl; R2 is selected from the group consisting of R9, alkyl, alkynyl, alkynylalkyl, cycloalkyl, -CF3, -C (02) R6, aryl, arylalkyl, heteroarylalkyl, heterocyclyl, alkyl substituted with 1-6 R9 groups said groups may be the same or different with each R9 being independently selected, aryl substituted by 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazol, '(CH2) p - (CH2) m - N N - R V N - RB - aryl - N N - R1 8 y - • aarnilOo dd N - R8 heteroaryl substituted with 0-3 aryl or heteroaryl groups which may be same or different and are independently selected from alkyl, phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups; R3 is selected from the group consisting of H, halogen, -NR5R6, -C (0) NR5R6, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each being independently selected portion from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) n oR 5, -OR 5, -NR5R6, - (CR4R) nNR5R6, -C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N ( R5) C (0) R7 and -N (R5) C (0) NR5R6; R 4 is H, halogen or alkyl; R5 is H or alkyl; R6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each being independently selected portion from the group consisting of halogen, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10 -N (R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -S03H, -SR10 -S (02) R7, -S (02) NR5R10 , -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10 R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl oy heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each being independently selected portion from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5 , -NR4R5, -N (R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) NR4R5, -C (0) R5, -S03H, -SR5, -S (02) R7 , -S (02) NR4R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR4R5; or optionally (i) R5 and R10 in -NR5R10, or (ii) R5 and R6 in the NR5R6 portion portion, can be joined together to form a cycloalkyl or heterocyclyl portion, with each of said cycloalkyl or heterocyclyl portion being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen , alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR6R10, -CH2OR5, -C (02) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02 ) R10, -S (02) NR5R10, -N (R5) S (02) R10,, -N (R5) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -C (0) NR5R10, -S (02) NR5R10, -C (0) R7 and -S (02) R7; R9 is selected from the group consisting of halogen, CN, -NR5R10, -C (02) R6, -C (0) NR5R10, -OR6, -SR6, -S (02) R7, -S (02) NR5R1 °, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; m is 0 to 4, and n is 1 to 4, with the following conditions: (i) that when R is an unsubstituted phenyl, then R2 is not alkyl, -C (02) R6, aryl or cycloalkyl, and (ii) that when R is a phenyl substituted with a hydroxyl group, then R2 is halogen only; lll. Formula lll wherein: R is heteroaryl, wherein said heteroaryl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R6, -C (R4R5) nOR5, -C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R7, -S (02) NR5R6, -N (R5) S (02) R7, '-N (R5) C (0) R7 and -N (R5) C (0) NR5R6; R2 is selected from the group consisting of R9, alkyl, alkynyl, aryl, heteroaryl, CF3, heterocyclylalkyl, alkynylalkyl, cycloalkyl, -C (0) OR4, alkyl substituted with 1-6 R9 groups which may be the same or different and select independently from the list of R9 shown below, - < CH2) m ~ -aryl-N N-R8-v ^ arylod N-R " wherein the aryl in the definitions indicated above for R2 may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of, halogen, CN, -OR5, SR5 , -CH2OR5, -C (0) R5, -S03H, -S (02) R6, -S (02) NR5R6, -NR5R6, -C (0) NR5R6, -CF3, and -OCF3; R3 is selected from the group consisting of H, halogen, -NR5R6, -C (0) OR4, -C (0) NR5R6, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each being independently selected portion from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) n oR 5, -OR 5, -NR5R6, - (CR4R5) nNR5R6, -C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N ( R5) C (0) R7 and -N (R5) C (0) NR5R6; R 4 is H, halogen or alkyl; R5 is H or alkyl; R6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -N (R5) Boc, - (CR R5) nOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -S03H, -SR10, -S (02) R7, -S (02 ) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl may be not substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR4R5, -N ( R5) Boc, - (CR R5) nOR5, -C (02) R5, -C (0) NR R5, -C (0) R5, -S03H, -SR5, -S (02) R7, -S (02 ) NR4R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl for R7 can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C (O2) R5, -C (O) NR5R10, -C (0) R5, -SR10, -S (02) R10, -S (02) NR5R10, -N (R5) S (02) R10, -N (R5) C (0 ) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -C (0) NR5R10, -CH2OR4, -C (0) OR6, -C (0) R7 and -S (02) R7; R9 is selected from the group consisting of halogen, -CN, -NR5R6, - (CH2) nOR4, -C (02) R6, -C (0) NR5R6, -OR6, -SR6, -S (02) R7, - S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6; m is 0 to 4; and n is 1 to 4; IV. tf H-f Formula IV wherein: Q is selected from the group consisting of -S (02) NR6R7-, -C (0) NR6R7- and -C (0) OR7-; R2 is selected from the group consisting of R9, alkyl, alkynyl, alkynylalkyl, cycloalkyl, -CF3, -C (02) R6, aryl, arylalkyl, heteroarylalkyl, heterocyclyl, alkyl substituted with 1-6 R9 groups which may be the same or different and are independently selected from the list of R9 shown below, - (CH2) m-N N- RB - (CH2.}. P V ila N-RB -aryl - N N-Ra NT • ar N --Ro »' wherein the aryl in the definitions indicated above for R2 may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, CN, -OR5, SR5, -S (02) R6, -S (02) NR5R6, -NR5R6, -C (0) NR5R6, CF3, alkyl, aryl and OCF3; R3 is selected from the group consisting of H, halogen, alkyl, alkynyl, -C (0) NR5R6, -C (0) OR4, -NR5R6, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) nOR5, -OR5, -NR5R6, - (CR R5) nNR5R6, - C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6; R 4 is H, halogen or alkyl; R5 is H or alkyl; R6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl may be not substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR °, -NR 5 ° RD 10, -N (R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -S03H, -SR10, -S (02) R7 , -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can being unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR4R5 , -N (R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (O) NR R5, -C (O) R5, -SO3H, -SR5, -S (O2) R7, - S (O2) NR R5, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR4R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C (02) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02) R10, -S (02) NR5R10, -N (R5) S (02) R10, -N (R5) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -C (0) NR5R10, -S (02) NR5R10, -C (0) R7 and -S (02) R7; R9 is selected from the group consisting of halogen, CN, -NR5R10, -C (02) R6, -C (0) NR5R10, -OR6, -SR6, -S (02) R7, -S (02) NR5R10, - N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; m is 0 to 4, and n is 1 to 4; V. I order V wherein: Q is -S (02) - or -C (O) -; R is aryl or heteroaryl, wherein said aryl or heteroaryl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, CN, -OR5, SR5, -S (02) R6, -S (02) NR5R6, NR5R6, -C (0) NR5R6, CF3, alkylo, aryl and OCF3; R2 is selected from the group consisting of CN, NR5R6, -C (02) R6, -C (0) NR5R6, -OR6, -SR6, -S (02) R7, -S (02) NR5R6, -N (R5 ) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6; alkynyl, heteroaryl, CF3, heterocyclyl, alkynylalkyl, cycloalkyl, alkyl substituted with 1-6 R9 groups which may be the same or different and are independently selected from the list of R9 shown below, - (CH2) mN N- Re- ( CH2) "V NR ° rile N-RB • aryl- \ N-R8 R is selected from the group consisting of H, halogen, -NR5R6, -C (0) NR5R6, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 may be substituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) nOR5, -OR5, -NR5R6, - (CR4R5) nNR5R6, -C (02) R5, -C (0) R5, -C (0) NR5R6,, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6; R 4 is H, halogen or alkyl; R5 is H or alkyl; R6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10-N ( R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -S03H, -SR10 -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10 R 0 is selected from the group consisting of H, alkyl, aryl, arylalkyl cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl ilo and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, - OR5, -NR4R5, -N (R5) Boc, - (CR4R5) n0R5, -C (02) R5, -C (0) NR4R5, -C (0) R5, -S03H, -SR5, -S (02) R7, -S (02) NR4R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3) CN, -OR5, -NR5R10, -CH2OR5, -C (02) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02) R1 °, -S (02) NR5R1 °, -N (R5) S (02) R1 °, -N (R5) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -C (0) NR > 5 ° DR1? 0 ?, -S (02) NR > 5th rR > 1? 0 ?, -C (0) R7 and -S (02) R7; R9 is selected from the group consisting of halogen, CN, -NR5R10, -C (O2) R6, -C (O) NR5R10, -OR6, -SR6, -S (O2) R7, -S (02) NR5R10, - N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; m is 0 to 4, and n is 1 to 4; and I saw. Formula VI 'or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein: R2 is selected from the group consisting of halo; -CF3; -CN; -SR6; -N02; -NR5R6a; -C (0) R6; -S (02) R7; -S (02) NR5R10; -N (R5) S (02) R7; -N (R5) C (0) NR5R10; I rent; alkenyl; alkynyl; heterocyclyl; heterocyclylalkyl; halo; halogenoalkyl; cycloalkyl; aril; Arylalkyl; arylalkenyl; arylalkynyl; heteroarylalkyl; alkynylalkyl; aryl fused with an aryl or heteroaryl group; heteroaryl; heteroaryl fused with an aryl or heteroaryl group, wherein each of the alkyl, alkenyl, alkynyl, heterocyclyl, heterocyclylalkyl, haloalkyl, cycloalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, and alkynylalkyl groups and the heterocyclic portions shown immediately above for R2 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) POR5, -OR5 , -NR5R6, - (CR5R11) PN R5R6, -C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, - N (R5) S (02) R7, -C (= N-OH), -N (R5) C (0) R7 and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion; R3 is selected from the group consisting of H; -NR5R6a; -OR6b; -SR6; CF3; -C (0) N (R5R6); I rent; alkenyl, alkynyl; cycloalkyl; aril; Arylalkyl; heterocyclyl; heterocyclylalkyl; heteroaryl; heteroarylalkyl; wherein each of the alkyl, alkynyl groups; cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and the heterocyclic portions whose structures are shown immediately above for R3 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (02) R5, - C (0) R5, -C (0) NR5R6, -C (= N-OH), -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, . -N (R5) C (0) R7 and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion; R4 is selected from the group consisting of -CF3; -CN; -NR5R6a; - (CR5R11) pC (02) R6; - (CR5R11) pC (0) NR5R10; -C (0) -N (R5R1 °); -OR6b; -SR6; -S (02) R7; -S (02) NR5R10; -C (0) R6; -N (R5) S (02) R7; -N (R5) C (0) R7; -N (R5) C (0) NR5R10; alkenyl; alkenyl (substituted with alkoxy); hydroxyalkyl; alkynyl; heterocyclyl; heterocyclylalkyl; aril; aryl fused with an aryl or heteroaryl group; heteroaryl; heteroaryl fused with an aryl or heteroaryl group; substituted alkyl; cycloalkyl; -aryl- N ^^ -R8 V aril ° N-Ra \ _d and wherein each of the alkyl, cycloalkyl groups; heterocyclyl, heterocyclylalkyl, aryl, fused aryl, heteroaryl and fused heterparyl of R4 may be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (02) R5, -C (0) R5, -C ( R5) (= N-OR5), -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion, and wherein the substituted alkyl group of R4 is independently substituted with one or more of the previous portions; R5 is H, alkyl, aryl or cycloalkyl; R6 is selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN , -OR5, -NR5R10, -C (R5R11) P-R9, -N (R5) Boc - (CR5R11) pOR5, -C (02) R5, -C (0) R5, -C (= N-OH) , -C (0) NR5R10, -S03H, -SR10 -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and - N (R5) C (0) NR5R10 R6a is selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each d The alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R5R11) P-R9, -N (R5) Boc, - (CR5R1) POR5, -C (02 ) R5, -C (0) R5, -C (= N-OH), -C (0) NR5R10, -S03H, -SR10, -S (02) R7, -S (02) NR5R10, -N (R5 ) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R6b is selected from the group consisting of alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can being unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, -CF3, -OCF3, -CN, -OR5 , -NR5R10, -C (R5R11) P-R9, -N (R5) Boc, - (CR5R11) pOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -SO3H, -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7, -C (= N-OH), and - N (R5) C (0) NR5R10; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, wherein each of the alkyl, cycloalkyl, heteroarylalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5 , -NR5R10, -CH2OR5, -C (02) R5, -C (0) NR5R10, -C (= N-OH), -C (0) R5, -SR10, -S (02) R10, -S ( 02) NR5R10, -N (R5) S (02) R10, -N (R5) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -OR6, -NR5R6, -C (0) NR5R10, -S (02) NR5R10, -C (0) R7, -C (= N-CN) -NH2, -C (= NH) -NHR5, heterocyclyl, -S (02) R7, and R9 is selected from the group consisting of halogen, -CN, -NR5R10, -C (02) R6, -C (0) NR5R10, -C (= N-OH), -OR6, -SR6, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; and R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R11, -C (R5R11) P-R9, -N (R5) Boc, - (CR5R11) pOR5, -C (02) R5, -C (0) NR5R11, -C (0) R5, -C (= N-OH), -S03H, -SR5, -S (02) R7, -S (02) NR5R11, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N ( R5) C (0) NR5R11; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each of the cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R11 is H, halogen or alkyl; m is 0 to 4; n is 1 to 4; and p is 1 to 4; with the proviso that (1) when R2 is alkyl, carboxyl, phenyl or cycloalkyl, then R3 is selected from the group consisting of -NR5R6a; -C (0) N (R5R6); alkynyl; Arylalkyl; heterocyclyl; heterocyclylalkyl; heteroaryl; heteroarylalkyl; wherein each of the alkynyl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl groups, and the heterocyclic portions whose structures are shown immediately above for R3 are unsubstituted or are independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of -CN, -NR5R6, - (CR5R11) PNR5R6, -C (0) NR5R6, -S (02) NR5R6, -N (R5) S (02) R7, -N ( R5) C (0) R7 and -N (R5) C (0) NR5R6; (2) when R2 is halogen, then R3 is selected from the group consisting of -OR) 6b. , -S cnR6. , -C (0) N (R> 50rR-> 6 °); cycloalkyl; heterocyclyl; heterocyclylalkyl; wherein each of the cycloalkyl, heterocyclic, heterocyclylalkyl, and heterocyclic portions whose structures are shown immediately above for R3 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (02) R5, -C (0) R5, -C (0) NR6R6, -SR6, - -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6, with : the condition that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 moiety; and (3) when R2 is NH2, R3 does not ^ is methyl.
4. The use of a pharmaceutical composition comprising (i) by. at least one pharmaceutically acceptable vehicle, and (ii) an amount Therapeutically effective of at least one compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the - manufacture of a medicament useful for treating, or slowing the progression of, a disease by inhibiting one or more kinases in a patient, said kinases being selected from the group consisting of check point kinases, Pim kinases, and Aurora kinases , wherein said compound is selected from the group consisting of the compounds represented by any of the following structural formulas I to VI: I. Formula I wherein: R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide of said heteroaryl), - (CHR5) n-aryl, - ( CHR5) n-heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl and heteroaryl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) POR5, -C (02) R5 , -C (0) R5, -C (0) NR5R10, -S03H7 -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R2 is selected from the group consisting of H, R9, alkyl, alkenyl, alkynyl, CF3, heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R9 groups which can be the same or different and are independently selected from the list of R9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazole groups , aryl fused with an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazole groups, heteroaryl fused with an aryl group or heteroaryl, f- (CH2) m-N N- Rß wherein one or more of the aryl and / or one or more of the heteroaryl in the definitions indicated above for R2 may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consists of halogen, -CN, -OR5, -SR5, -S (02) R6, -S (02) NR5R6, -NR5R ^, -C (0) NR5R6, CF3, alkyl, aryl and OCF3; R3 is selected from the group consisting of H, halogen, -NR5R6, -OR6, -SR6, -C (0) N (R5R6), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) pOR5, -OR5, -NR5R6, - (CR4R5) PNR5R6, -C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N ( R5) C (0) R7, -N (R5) C (R R5) nN (R5R6) and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a ring from hetero cyclyl carries a portion -OR5; R 4 is H, halogen or alkyl; R5 is H, alkyl, aryl, heteroaryl, arylalkyl or cycloalkyl; R6 is selected from the group consisting of H, Boc, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl , heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN , -OR5, -NR5R10, -C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) pOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -S03H, -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0 ) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR4R5, - C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) pOR5, -C (02) R5, -C (0) NR4R5, -C (0) R5, -SO3H, -SR5, -S (02) R7, -S (02) NR R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C ( 02) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02) R10, -S (02) NR5R1 °, -N (R5) S (02) R10, -N ( R5) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -OR6, -C (0) NR5R10, -S (02) NR5R10, -C (0) R7, -C (= N-CN) -NH2 > -C (= NH) -NHR5, heterocyclyl, and -S (02) R7; R9 is selected from the group consisting of halogen, -CN, -NR5R10, -SCN, -N02, -C (0) R5, -C (02) R6, -C (0) NR5R10, -OR6, -SR6, - S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; m is 0 to 4; n is 1 to 4; and p is 1 to 4, with the proviso that when R2 is phenyl, R3 is not alkyl, alkynyl or halogen, and that when R2 is aryl, R is not S (CHR5) n NR5R8 provided that when R is arylalkyl, then any heteroaryl substituent on the aryl of said arylalkyl contains at least three heteroatoms; II. Formula II or a pharmaceutically acceptable salt, solvate, ester or prodrug of said compound, wherein: R is an aryl, wherein said aryl is either not substituted or optionally substituted or fused with one or more heteroaryl; R2 is selected from the group consisting of R9, alkyl, alkynyl, alkynylalkyl, cycloalkyl, -CF3, -C (02) R6, aryl, arylalkyl, heteroarylalkyl, heterocyclyl, alkyl substituted with 1-6 R9 groups said groups may be the same or different with each R9 being independently selected, aryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazol, , / \ - _ / (CHjJfn \? / \ '.}. - (CH2) m- N N- R8 \ d N-R8 \ aryl - N N-R8 ARÍI ° V ^ -R8 - y heteroaryl substituted with 0-3 aryl or heteroaryl groups which may be same or different and are independently selected from alkyl groups, phenyl, pyridyl, thiophenyl, furanyl and thiazolo; R3 is selected from the group that consists of H, halogen, -NR5R6, -C (0) NR5R6, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each being independently selected portion from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) n oR 5, -OR 5, -NR5R6, - (CR4R5) nNR5R6, -C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N ( R5) C (0) R7 and -N (R5) C (0) NR5R6; R 4 is H, halogen or alkyl; R5 is H or alkyl; R6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each being independently selected portion from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -N (R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -S03H, -SR10, -S (02) R7, -S ( 02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl can be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR R5 , -N (R5) Boc, - (CR4R5) nOR5, -C (O2) R5, -C (O) NR4R5, -C (O) R5, -SO3H, -SR5, -S (O2) R7, -S (O2) NR R5, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (O) NR4R5; or optionally (i) R5 and R 0 in -NR5R10, or (ii) R5 and R6 in the NR5R6 portion portion, can be joined together to form a cycloalkyl or heterocyclyl portion, with each of said cycloalkyl or heterocyclyl portion being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl may be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen , alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR6R10, -CH2OR5, -C (02) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02 ) R10, -S (02) NR5R10, -N (R5) S (02) R10, -N (R5) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -C (0) NR5R10, -S (02) NR5R10, -C (0) R7 and -S (02) R7; R9 is selected from the group consisting of halogen, CN, -NR5R10, -C (02) R6, -C (0) NR5R10, -OR6, -SR6, -S (02) R7, -S (02) NR5R10, - N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; m is 0 to 4, and n is 1 to 4, with the following conditions: (i) that when R is an unsubstituted phenyl, then R2 is not alkyl, -C (02) R6, aryl or cycloalkyl, and (ii) that when R is a phenyl substituted with a hydroxyl group, then R2 is halogen only; lll. Formula lll wherein: R is heteroaryl, wherein said heteroaryl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R6, -C (R4R5) nOR5, -C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R7, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6; R2 is selected from the group consisting of R9, alkyl, alkynyl, aryl, heteroaryl, CF3, heterocyclylalkyl, alkynylalkyl, cycloalkyl, -C (0) OR4, alkyl substituted with 1-6 R9 groups which may be the same or different and select independently from the list of R9 shown below, r ~ \ '(CH2) p (CH2) m-N N- R V N -DR8 -aryl - N N -R8 arylod \ N-RB wherein the aryl in the definitions given above for R may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, CN, -OR5, SR5, -CH2OR5, -C (0) R5, -SO3H, -S (02) R6, -S (02) NR5R6, -NR5R6, -C (0) NR5R6, -CF3, and -OCF3; R3 is selected from the group consisting of H, halogen, -NR5R6, -C (0) OR4, -C (0) NR5R6, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 can be substituted or optionally independently substituted with one or more moieties which can be the same or different, each being independently selected portion from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR R 5) n oR 5, -OR 5, -NR5R6, - (CR4R5) nNR5R6, - C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6; R 4 is H, halogen or alkyl; R5 is H or alkyl; R6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterociclilalquilp, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -N (R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -S03H, -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl may be not substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR4R5, -N ( R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) NR R5, -C (0) R5, -S03H, -SR5, -S (02) R7, -S (02) NR4R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR4R5; or optionally (i) R5 and R 0 in -NR5R10, or (ii) R5 and R6 in the NR5R6 portion portion, can be joined together to form a cycloalkyl or heterocyclyl portion, with each of said cycloalkyl or heterocyclyl portion being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl for R7 can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C (02) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02) R10, -S (02) NR5R10, -N (R5) S (02) R10, -N (R5) C (0 ) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -C (0) NR5R10, -CH2OR4, -C (0) OR6, -C (0) R7 and -S (02) R7; R9 is selected from the group consisting of halogen, -CN, -NR5R6, - (CH2) nOR4, -C (02) R6, -C (0) NR5R6, -OR6, -SR6, -S (02) R7, - S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6; m is 0 to 4; and n is 1 to 4; IV. Formula IV wherein: Q is selected from the group consisting of -S (02) NR6R7-, -C (0) NR6R7- and -C (0) OR7-; R2 is selected from the group consisting of R9, alkyl, alkynyl, alkynylalkyl, cycloalkyl, -CF3, -C (02) R6, aryl, arylalkyl, heteroarylalkyl, heterocyclyl, alkyl substituted with 1-6 R9 groups which may be the same or different and are independently selected from the list of R9 shown below, / - (CH2) ~ -N N- and (CH2) m? -R8 j - aryl-rT -R8 wherein the aryl in the definitions indicated above for R2 may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, CN, -OR5, SR5, -S (02) R6, -S (02) NR5R6, -NR5R6, -C (0) NR5R6, CF3, alkyl, aryl, and OCF3; R3 is selected from the group consisting of H, halogen, alkyl, alkynyl, -C (0) NR5R6, -C (0) OR4, -NR5R6, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 may be substituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) nOR5, -OR5, -NR5R6, - (CR4R5) nNR5R6, -C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N ( R5) C (0) R7 and -N (R5) C (0) NR5R6; R 4 is H, halogen or alkyl; R5 is H or alkyl; R6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl may be not unsubstituted or optionally substituted with one or more moieties which can be the same or different, each being independently selected portion from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, - N (R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -S03H, -SR10, -S (02) R7, -S (02) ) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each being independently selected portion from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR4R5 , -N (R5) Boc, - (CRR5) nOR5, -C (02) R5, -C (0) NR4R5, -C (0) R5, -S03H, -SR5, -S (02) R7, - S (02) NR4R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR4R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C (02) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02) R10, -S (02) NR5R1 °, -N (R5) S (02) R10, -N (R5) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -C (0) NR5R10, -S (02) NR5R10, -C (0) R7 and -S (02) R7; R9 is selected from the group consisting of halogen, CN, -NR5R10, -C (02) R6, -C (0) ÑR5R10, -OR6, -SR6, -S (02) R7, -S (02) NR5R10, - N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; m is 0 to 4, and n is 1 to 4; V. Formula V wherein: Q is -S (02) - or -C (O) -; R is aryl or heteroaryl, wherein said aryl or heteroaryl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, CN, -OR5, SR5, -S (02) R6, -S (02) NR5R6, NR5R6, -C (0) NR5R6, CF3, alkyl, aryl and OCF3; R2 is selected from the group consisting of CN, NR5R6, -C (02) R6, -C (0) NR5R6, -OR6, -SR6, -S (O2) R7, -S (O2) NR5R6, -N (R5 ) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6; alkynyl, heteroaryl, CF3, heterocyclyl, alkynylalkyl, cycloalkyl, alkyl substituted with 1-6 R9 groups which may be the same or different and are independently selected from the list of R9 shown below, - (CHz) ™, V -aryl- / - \ N-RH N-R8 \ N-R ° R3 is selected from the group consisting of H, halogen, -NR5R6, -C (0) NR5R6, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 may be substituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CRR5) nOR5, -OR5, -NR5R6, - (CR4R5) nNR5R6, - C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6; R 4 is H, halogen or alkyl; R5 is H or alkyl; R6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl may be substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR3, -NR 5 ° DR10, -N (R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -S03H, -SR10, -S (02) R7, - S (02) NR5R1 °, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR4R5, - N (R5) Boc, - (CR4R5) nOR5, -C (02) R5, -C (0) NR R5, -C (0) R5, -S03H, -SR5, -S (02) R7, -S ( 02) NR4R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR4R5; or optionally (i) R5 and R10 in -NR5R10, or (ii) R5 and R6 in the NR5R6 portion portion, can be joined together to form a cycloalkyl or heterocyclyl portion, with each of said cycloalkyl or heterocyclyl portion being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C (02) R5, -C (0) NR5R10, -C (0) R5, -SR 10S (02) R, 110U, -SY ^ NR) 5 ^ r- > 110", -N (R3) S (02) R 110U, -N (RD) C (0) R TU -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -C (0) NR5R10, -S (02) NR5R10, -C (0) R7 and -S (02) R7; R9 is selected from the group consisting of halogen, CN, -NR5R10, -C (02) R6, -C (0) NR5R10, -OR6, -SR6, -S (02) R7, -S (02) NR5R10, - N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; m is 0 to 4, and n is 1 to 4; and I saw. Formula VI or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, wherein: R 2 is selected from the group consisting of halo; -CF3; -CN; -SR6; -N02; -NR5R6a; -C (0) R6; -S (02) R7; -S (02) NR5R10; -N (R5) S (02) R7; -N (R5) C (0) NR5R10; I rent; alkenyl; alkyne; heterocyclic; heterocyclylalkyl; halo; halogenoalkyl; cycloalkyl; aril; Arylalkyl; arylalkenyl; arylalkynyl; heteroarylalkyl; alkynylalkyl; aryl fused with an aryl or heteroaryl group; heteroaryl; heteroaryl fused with an aryl or heteroaryl group; - (CH 2) mN N-R 8 - (CH 2) p V N-R 8 -aryl- N-R 8"aryl ° N-R B V 7 and wherein each of the alkyl, alkenyl, alkynyl, heterocyclyl, heterocyclylalkyl, haloalkyl groups , cycloalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, and alkynylalkyl and the heterocyclic portions shown immediately above for R2 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected of the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PN R5R6, -C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -C (= N-OH) , -N (R5) C (0) R7 and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5; R3 portion is selected from the group consisting of H; -NR5R6a; -OR6 b; -SR6; CF3; -C (0) N (R5R6); I rent; alkenyl, alkynyl; cycloalkyl; aril; Arylalkyl; heterocyclyl; heterocyclylalkyl; heteroaryl; heteroarylalkyl; wherein each of the alkyl, alkynyl groups; cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, and the heterocyclic portions whose structures are shown immediately above for R3 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (02) R5, - C (0) R5, -C (0) NR5R6, -C (= N-OH), -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclic ring carries a -OR5 portion; R4 is selected from the group consisting of -CF3; -CN; -NR5R6a; - (CR5R 1) pC (02) R6; - (CR5R11) pC (0) NR5R10; -C (0) -N (R5R10); -OR6b; -SR6; -S (02) R7; -S (02) NR5R10; -C (0) R6; -N (R5) S (02) R7; -N (R5) C (0) R7; -N (R5) C (0) NR5R10; alkenyl; alkenyl (substituted with alkoxy); hydroxyalkyl; alkynyl; heterocyclyl; heterocyclylalkyl; aril; aryl fused with an aryl or heteroaryl group; heteroaryl; heteroaryl fused with an aryl or heteroaryl group; substituted alkyl; cycloalkyl; wherein each of the alkyl, cycloalkyl groups; heterocyclyl, heterocyclylalkyl, aryl, fused aryl, heteroaryl, and fused heteroaryl of R 4 may be unsubstituted or optionally substituted independently with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, heteroaryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R1) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (02) R5, -C (0) R5, -C (R5) (= N-OR5), -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR ^ R6, -N (R5) S (02) R7, -N ( R5) C (0) R7 and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion, and wherein the substituted alkyl group of R4 is independently substituted with one or more of the above portions; R5 is H, alkyl, aryl or cycloalkyl; R6 is selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R5R11) P-R9, -N (R5) Boc, - (CR5R11) pOR5, -C (02) R5, -C (0) R5, -C (= N- OH), -C (0) NR5R10, -S03H, -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R6a is selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R5R11) P-R9, -N (R5) Boc, - (CR5R11) POR5, -C (02) R5, -C (0) R5, -C (= N-OH) , -C (0) NR5R10, -S03H, -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R6 is selected from the group consisting of alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkenyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl groups can being unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, -CF3, -OCF3, -CN, -OR5 , -NR5R10, -C (R5R11) P-R9, -N (R5) Boc, - (CR5R11) pOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -SO3H, -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7, -C (= N-OH), and - N (R5) C (0) NR5R10; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl, and heterocyclyl, wherein each of the alkyl, cycloalkyl, heteroarylalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl and heterocyclyl can be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5 , -NR5R10, -CH2OR5, -C (02) R5, -C (0) NR5R10, -C (= N-OH), -C (0) R5, -SR10, -S (02) R10, -S ( 02) NR5R1 °, -N (R5) S (02) R10, -N (R5) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -OR6, -NR5R6, -C (0) NR5R10, -S (02) NR5R10, -C (0) R7, -C (= N-CN) -NH2, -C (= NH) -NHR5, heterocyclyl, -S (02) R7, and R9 is selected from the group consisting of halogen, -CN, -NR5R10, -C (02) R6, -C (0) NR5R10, -C (= N-OH), -OR6, -SR6, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; and R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of the alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3 > OCF3, CN, -OR5, -NR5R11, -C (R5R11) P-R9, -N (R5) Boc, - (CR5R11) pOR5, -C (02) R5, -C (0) NR5R11, -C (0 ) R5, -C (= N-OH), -SO3H, -SR5, -S (02) R7, -S (02) NR5R11, -N (R5) S (02) R7, -N (R5) C ( 0) R7 and -N (R5) C (0) NR5R11; or optionally (i) R5 and R0 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each of the cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R1 is H, halogen or alkyl; m is 0 to 4; n is 1 to 4; and p is 1 to 4; with the proviso that (1) when R2 is alkyl, carboxyl, phenyl or cycloalkyl, then R3 is selected from the group consisting of -NR5R6a; -C (0) N (R5R6); alkyne; Arylalkyl; heterocyclyl; heterocyclylalkyl; heteroaryl; heteroarylalkyl; wherein each of the alkynyl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl groups, and the heterocyclic portions whose structures are shown immediately above for R3 are unsubstituted or are independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of -CN, -NR5R6, - (CR5R11) PNR5R6, -C (0) NR5R6, -S (02) NR5R6, -N (R5) S (02) R7, -N ( R5) C (0) R7 and -N (R5) C (0) NR5R6; (2) when R2 is halogen, then R3 is selected from the group consisting of -OR > 6DbD .; -SR > 6., cycloalkyl; heterocyclyl; heterocyclylalkyl; wherein each of the cycloalkyl, heterocyclyl, heterocyclylalkyl, and heterocyclic portions whose structures are shown immediately above for R3 may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, -CF3, -CN, -OCF3, - (CR11R11) pOR5, -OR5, -NR5R6, - (CR5R11) PNR5R6, -C (02) R5, -C (0) R5, -C (0) NR6R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion; and (3) when R2 is NH2, R3 is not methyl. 5. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula I is selected from the group consisting of: 6 -. 6 - The use as claimed in any of claims 1 to 4, wherein the compound of the formula I is selected from the group consisting of: 7. The use as claimed in any of claims 1 to 4, wherein the compound of the formula I is selected from the group consisting of: ?? fifteen 8. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula VI is selected from the group consisting of: 0. - The use as claimed in any of the claims to 4, wherein the compound of the formula I is: 10. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula I is: 11. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula I is: 12. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula I is: 13. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula I is: 14. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula I is: fifteen - . 15. The use as claimed in any of claims 1 to 4, wherein the compound of the formula I is: 16. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula I is: 17. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula I is: 18. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula I is: 19. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula I is: 20. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula I is: 21. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula I is: 22. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula I is: 23. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula I is: 24 -. 24. The use as claimed in any of claims 1 to 4, wherein the compound of the formula I is: The use as claimed in any of claims 1 to 4, wherein the compound of the formula VI is: 26. - The use as claimed in any of claims 1 to 4, wherein the compound of formula VI is: 27. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula II is: 28. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula II is: 29. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula II is: 30. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula II is: 31 -. 31 - The use as claimed in any of claims 1 to 4, wherein the compound of the formula III is: 32. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula III is: 33. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula III is: 34. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula III is: 35. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula III is: 36. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula III is: 37. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula III is: 38. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula III is: 39. - The use as claimed in any of claims 1 to 4, wherein the compound of the formula III is: 40. - The use as claimed in claim 3, wherein one or more anticancer agents are selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, ihnotecan, camptostar, topotecan, paclitaxel, docetaxel, epjotilones, tamoxifen, 5-fluorouracyl, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778.123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec, intron, ara-C, adhamycin, Citoxan, gemcitabine, mustard uracil, Chloromethane, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylene-thiophosphoramide, Busulfan, Carmustine, Lomustine, Streptozocine, Dacarbazine, Floxuridine, Citarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine Phosphate, Oxaliplatin, Leucovirin, ELOXATIN ™, Pentostatine , Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxicoformycin, Mitomycin-C, L-Asparaginase , Teniposide 17a-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, dromostanolone propionate, Testolactone, megestrol acetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisen, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesterone acetate, Leuprolide, Flutamide, Toremifene, Goserelin, 1 Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine , Mitotane, Mytoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, Herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab , Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225, Campat, Clofarabine, Cladribin, Affidicolon, Rituxan, Sunitinib, Dasatinib, Tezacitabine, SmM, Fludarabine, Pentostatin, Triapin, Didox, Trimidox, Amidox, 3-AP, and MDL-101, 731. 41. The use as claimed in any one of claims 1 to 4, wherein the kinase checkpoint is CHK1. 42. The use as claimed in any of claims 1 to 4, wherein the kinase checkpoint is CHK2. 43.- The use of a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting the activity of a checkpoint kinase, the compound being represented by structural formula I: Formula I wherein: R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide of said heteroaryl), - (CHR5) n-aryl, - (CHR5) n-heteroahlo, wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl and heteroaryl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR > 5 DDR1'0 ?, -C (02) R °, -C (0) R3, -C (0) NR5R10, -S03H7 -SR10, -S (02) R7, -S (02) NR5R10, -N (R5 ) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R2 is selected from the group consisting of H, R9, alkyl, alkenyl, alkynyl, CF3, heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R9 groups which can be the same or different and are independently selected from the list of R9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazole groups , aryl fused with an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazole groups, heteroaryl fused with an aryl group or heteroaryl, - < CH2) m-N N-R8 wherein one or more of the aryl and / or one or more of the heteroaryl in the definitions indicated above for R2 may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consists of halogen, -CN, -OR5, -SR5, -S (02) R6, -S (02) NR5R6, -NR5R6, -C (0) NR5R6, CF3, alkyl, aryl and OCF3; R3 is selected from the group consisting of H, halogen, -NR5R6, -OR6, -SR6, -C (0) N (R5R6), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 can be unsubstituted or optionally independently substituted with one or more portions that can be be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (GR4R5) pOR5, -OR5, -NR5R6, - (CR4R5) PNR5R6, - C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7, -N (R5) C (R4R5) nN (R5R6) and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a ring of heterocyclyl carries a -OR5 portion; R 4 is H, halogen or alkyl; R5 is H, alkyl, aryl, heteroaryl, arylalkyl or cycloalkyl; R6 is selected from the group consisting of H, Boc, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl , heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN , -OR5, -NR5R10, -C (R4R5) P-R9, -N (R5) Boc, - (CRR5) pOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10 , -S03H, -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C ( 0) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR4R5, -C (R4R5) P-R9, - N (R5) Boc, - (CR4R5) pOR5, -C (02) R5, -C (0) NR4R5, -C (0) R5, -S03H, -SR5, -S (02) R7, -S (02 ) NR4R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR4R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3 > OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C (02) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02) R10, -S (02) NR5R10 , -N (R5) S (02) R10, -N (R5) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -OR6, -C (0) NR5R10, -S (02) NR5R °, -C (0) R7, -C (= N-CN) -NH2, -C (= NH) -NHR5, heterocyclyl, and -S (02) R7; R9 is selected from the group consisting of halogen, -CN, -NR5R10, -SCN, -NO2 > -C (O) R5, -C (O2) R6, -C (O) NR5R10, -OR6, -SR6, -S (O2) R7, -S (O2) NR5R10, -N (R5) S (O2) R7, -N (R5) C (O) R7 and -N (R5) C (0) NR5R10; m is 0 to 4; n is 1 to 4; and p is 1 to 4, with the proviso that when R2 is phenyl, R3 is not alkyl, alkynyl or halogen, and that when R2 is aryl, R is not 1 (CHR5) n NR5R8 provided that when R is arylalkyl, then any heteroaryl substituent in the aryl of said arylalkyl contains at least three heteroatoms. 44.- The use of a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for treating, or slowing down the progression of, a disease by inhibiting a checkpoint kinase, the compound being represented by structural formula I: Formula I wherein: R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide of said heteroaryl), - (CHR5) n-aryl, - ( CHR5) n-heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl and heteroaryl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen , alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) POR5, -C (02) R5, -0 (O) R5, -C (0) NR5R10, -S03H7 -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R2 is selected from the group consisting of H, R9, alkyl, alkenyl, alkynyl, CF3, heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R9 groups which can be the same or different and are independently selected from the list of R9 shown below, aryl substituted with 1-3 arylo or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazole groups , aryl fused with an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazole groups, heteroaryl fused with an aryl group or heteroaryl, - < CH2), "- N N-R8 \ N-R8 - aryl- N N -R8 - aplo N-RB N, N / y wherein one or more of the aryl and / or one or more of the heteroaryl in the definitions indicated above for R2 may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consists of halogen, -CN, -OR5, -SR5, -S (02) R6, -S (02) NR5R6, -NR5R6, -C (0) NR5R6, CF3, alkyl, aryl and OCF3; R3 is selected from the group consisting of H, halogen, -NR5R6, -OR6, -SR6, -C (0) N (R5R6), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 may be unsubstituted or optionally independently substituted with one or more portions which may be be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) pOR5, -OR5, -NR5R6, - (CR4R5) PNR5R6, - C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7, -N (R5) C (R4R5) nN (R5R6) and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a ring of heterocyclyl carries a -OR5 portion; R 4 is H, halogen or alkyl; R5 is H, alkyl, aryl, heteroaryl, arylalkyl or cycloalkyl; R6 is selected from the group consisting of H, Boc, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R4R5) P-R9. -N (R5) Boc, - (CR4R5) pOR5, -C (O2) R5, -C (O) R5, -C (O) NR5R10, -SO3H, -SR10, -S (O2) R7, -S ( O2) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR4R5, - C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) pOR5, -C (02) R5, -C (0) NR4R5, -C (0) R5, -S03H, -SR5, -S (02) R7, -S (02) NR4R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR4R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, may be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, CH2OR5, -C (02 ) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02) R10, -S (02) NR5R10, -N (R5) S (02) R10, -N (R5) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -OR6, -C (0) NR5R10, -S (02) NR5R10, -C (0) R7, -C (= N-CN) -NH2, -C (= NH ) -NHR5, heterocyclyl, and -S (02) R7; R9 is selected from the group consisting of halogen, -CN, -NR5R10, -SCN, -N02, -C (0) R5, -C (02) R6, -C (0) NR5R10, -OR6, -SR6, - S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7,; -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; m is 0 to 4; n is 1 to 4; and p is 1 to 4, with the proviso that when R2 is phenyl, R3 is not alkyl, alkynyl or halogen, and that when R2 is aryl, R is not S (CHR5) - NR5R8 provided that when R is arylalkyl, then any heteroaryl substituent on the aryl of said aplakyl contains at least three heteroatoms. 45.- The use of a combination of (i) a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, and (ii) an anti-cancer agent, for the manufacture of a medicament useful for treating a disease by inhibiting a check point kinase, wherein the compound is a compound of formula I: Formula I wherein: R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide of said heteroaryl), - (CHR5) n-aryl, - (CHR5) n-heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl and heteroaryl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen , alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) pOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -S03H7 -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R2 is selected from the group consisting of H, R9, alkyl, alkenyl, alkynyl, CF3, heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R9 groups which can be the same or different and are independently selected from the list of R9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazole groups , aryl fused with an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazole groups, heteroaryl fused with an aryl group or heteroaryl, - < CH2) m-N N-R8 wherein one or more of the aryl and / or one or more of the heteroaryl in the definitions indicated above for R2 may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consists of halogen, -CN, -OR5, -SR5, -S (02) R6, -S (02) NR5R6, -NR5R6, -C (0) NR5R6, CF3, alkyl, aryl and OCF3; R3 is selected from the group consisting of H, halogen, -NR5R6, -OR6, -SR6, -C (0) N (R5R6), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and heterocyclyl moieties whose structures are shown immediately before for R3 can be unsubstituted or optionally independently substituted with one or more portions that can be be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CR4R5) pOR5, -OR5, -NR5R6, - (CR4R5) PNR5R6, - C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7, -N (R5) C (R4R5) nN (R5R6) and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a ring of heterocyclyl carries a -OR5 portion; R 4 is H, halogen or alkyl; R5 is H, alkyl, aryl, hetefoaryl, arylalkyl or cycloalkyl; R6 is selected from the group consisting of H, Boc, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group which consists of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (RR5) P-R9, -N (R5) Boc, - (CR4R5) pOR5 ,? -C (O2) R5, -C (0) R5, -C (0) NR5R10, -S03H, -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR4R5, - C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) pOR5, -C (02) R5, -C (0) NR4R5, -C (0) R5, -S03H, -SR5, -S (02) R7, -S (02) NR4R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR4R5; or optionally (i) R5 and R10 in -NR5R10, or (ii) R5 and R6 in the NR5R6 portion portion, can be joined together to form a cycloalkyl or heterocyclyl portion, with each of said cycloalkyl or heterocyclyl portion being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heterparyl, arylalkyl, heteroarylalkyl, heteroarylalkenyl and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C ( 02) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02) R10, -S (02) NR5R1 ', -N (R5) S (02) R10, -N (R5) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -OR6, -C (0) NR5R10, -S (02) NR5R10, -C (0) R7, -C (= N-CN) -NH2 > -C (= NH) -NHR5, heterocyclyl, and -S (02) R7; R9 is selected from the group consisting of halogen, -CN, -NR5R10, -SCN, -N02, -C (0) R5, -C (02) R6, -C (0) NR5R10, -OR6, -SR6, - S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7,! -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; m is 0 to 4; n is 1 to 4; and p is 1 to 4, with the proviso that when R2 is phenyl, R3 is not alkyl, alkynyl or halogen, and that when R2 is aryl, R is not S (CHR5) p NRSR8 provided that when R is arylalkyl, then any heteroaryl substituent on the aryl of said arylalkyl contains at least three heteroatoms. 46.- The use of a pharmaceutical composition comprising (!) A therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, and (ii) a pharmaceutically acceptable carrier, for the making a medicament useful for treating, or slowing the progression of, a disease by inhibiting a check point kinase, wherein the compound is a compound of formula I: Formula I wherein: R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide of said heteroaryl), - (CHR5) n-aryl, - (CHR5) n-heteroaryl,, (C Rs) Jrh ^ V - (CHR5) n NR5R8 wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl and heteroaryl can be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R R5) P-R9, -N (R5) Boc, - (CR4R5) POR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -S03H7 -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R2 is selected from the group consisting of H, R9, alkyl, alkenyl, alkynyl, CF3, heterocyclyl, heterocyclylalkyl, halogen, halogenoalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R9 groups which can be the same or different and are independently selected from the list of R9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which they can be the same or different and are selected independently of phenyl, pyridyl, thiophenyl, furanyl and thiazole groups, aryl fused with a group aryl or heteroaryl, heteroaryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazole groups, heteroaryl fused with an aryl or heteroaryl group, - (CH2) ra-N N- Rß • (CH2) p V N-R8 -aryl-N N - RR - - aplo-. -RB wherein one or more of the aryl and / or one or more of the heteroaryl in the definitions indicated above for R2 may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consists of halogen, -CN, -OR5, -SR5, -S (02) R6, -S (02) NR5R6, -NR5R6, -C (0) NR5R6, CF3, alkyl, aryl and OCF3; R3 is selected from the group consisting of H, halogen, -NR5R6, -OR6, -SR6, -C (0) N (R5R6), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 may be unsubstituted or optionally independently substituted with one or more portions which may be be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3) - (CR4R5) pOR5, -OR5, -NR5R6, - (CR4R5) PNR5R6, - C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, -N (R5) C (0) R7, -N (R5) C (R4R5) nN (R5R6) and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a ring of heterocyclyl carries a -OR5 portion; R 4 is H, halogen or alkyl; R5 is H, alkyl, aryl, heteroaryl, arylalkyl or cycloalkyl; R6 is selected from the group consisting of H, Boc, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) pOR5, -C (02) R5, -C (0) R5, -C (0) NR5R10 , -S03H, -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C ( 0) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR4R5, - C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) pOR5, -C (02) R5, -C (0) NR4R5, -C (0) R5, -S03H, -SR5, -S (02) R7, -S (02) NR4R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR4R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C ( 02) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02) R10, -S (02) NR5R10, -N (R5) S (02) R10, -N (R5 ) C (0) R10 and -N (R5) C (0) NR5R10; R8 is selected from the group consisting of R6, -OR6, -C (0) NR5R10, -S (02) NR5R10, -C (0) R7, -C (= N-CN) -NH2 > -C (= NH) -NHR5, heterocyclyl, and -S (02) R7; R9 is selected from the group consisting of halogen, -CN, -NR5R10, -SCN, -N02, -C (0) R5, -C (02) R6, -C (0) NR5R10, -OR6, -SR6, - S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; m is 0 to 4; n is 1 to 4; and p is 1 to 4, with the proviso that when R2 is phenyl, R3 is not alkyl, alkynyl or halogen, and that when R2 is aryl, R is not í (CHR5) - NR5R8 provided that when R is arylalkyl, then any heteroaryl substituent on the aryl of said arylalkyl contains at least three heteroatoms. 47.- The use as claimed in any of claims 2, 3, 4, 44, 45 or 46, wherein the disease is a proliferative disease, autoimmune disease, viral disease, fungal disease, neurological / neurodegenerative disorder, arthritis, inflammation, antiproliferative disease, neuronal, alopecia or cardiovascular disease. 48. - The use as claimed in claim 47, wherein the disease is a proliferative disease. 49. The use as claimed in claim 48, wherein the proliferative disease is selected from the group consisting of: cancer bladder, breast, colon, kidney, liver, lung, small cell lung cancer, lung cancer cells not small, head and neck, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate and skin, squamous cell carcinoma; i leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma, and Burkett's lymphoma; acute and chronic myelogenous leukemia, myelodysplasia syndrome, promyelocytic leukemia; fibrosarcoma, rhabdomyosarcoma; astrocytoma, neuroblastoma, glioma and schwannomas; melanoma, seminoma; teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoxanthoma, follicular thyroid cancer and Kaposi's sarcoma. 50.- The use as claimed in claim 48, wherein the medication is also adapted to be administrable with radiation therapy. 51. The use as claimed in claim 45, wherein one or more anticancer agents are selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, taxotero, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel , epothilones, tamoxifen, R115777, L778.123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec, intron, ara-C, adriamycin, Citoxan, gemcitabine, uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenenethophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocine, Dacarbazine, Floxuridine, Citarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine Phosphate, Oxaliplatin, Leucovirin, ELOXATIN ™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin , Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxicoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17a-Etinylestradiol, Dethylstilbestrol, Testosterone , Prednisone, Fluoxymesterone, dromostanolone propionate, Testolactone, megestrol acetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesterone acetate, Leuprolide, Flutamide, Toremifene, Goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, Herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225, Campat, Clofarabine, Cladribine, Affydicolon, Rituxan, Sunitinib, Dasatinib, Tezacitabine, SmM, Fludarabine, Pentostatin, Triapine, Didox, Trimidox, Amidox, 3-AP, and MDL -101, 731. 101, 731. The use of a therapeutically effective amount of at least one compound of any of the formulas I-VI in claim 1, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a useful medicament to treat cancer 53. The use as claimed in claim 52, wherein said cancer is selected from the group consisting of: cancer bladder, breast, colon, kidney, liver, lung, small cell lung cancer, non-small cell lung cancer , head and neck, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate and skin, squamous cell carcinoma; leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma, and Burkett's lymphoma; acute and chronic myelogenous leukemia, medalodysplasia syndrome, promyelocytic leukemia; fibrosarcoma, rhabdomyosarcoma; astrocytoma, neuroblastoma, glioma and schwannomas; melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoxanthoma, follicular thyroid cancer and Kaposí's sarcoma. 54.- The use of a combination (i) a compound of formula I, or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and (i) an anticancer agent, for the manufacture of a medicament useful for treating a cancer, wherein said compound of formula I is: I. Formula wherein: R is H, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl (including N-oxide of said heteroaryl), - (CHR5) n-aryl, - ( CHR5) n-heteroaryl, ^ (CHR5) ^ -, N --DR8 '- (CHR5) n NR6R8 -2 - (CHRs) n-N G? I N Rß - (CHR5) n-N - (CHR .5) n- G? O \ O wherein each of said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl and heteroaryl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen , alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) POR5, -C (02) R5, -C (0) R5, -C (0) NR5R10, -S03H7 -SR10, -S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; R2 is selected from the group consisting of H, R9, alkyl, alkenyl, alkynyl, CF3, heterocyclyl, heterocyclylalkyl, halogen, haloalkyl, aryl, arylalkyl, heteroarylalkyl, alkynylalkyl, cycloalkyl, heteroaryl, alkyl substituted with 1-6 R9 groups which can be the same or different and are independently selected from the list of R9 shown below, aryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazole groups , aryl fused with an aryl or heteroaryl group, heteroaryl substituted with 1-3 aryl or heteroaryl groups which may be the same or different and are independently selected from phenyl, pyridyl, thiophenyl, furanyl and thiazole groups, heteroaryl fused with an aryl group or heteroaryl, J- < CH2), n-N N- R8 wherein one or more of the aryl and / or one or more of the heteroaryl in the definitions indicated above for R2 may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consists of halogen, -CN, -OR5, -SR5, -S (02) R6, -S (02) NR5R6, -NR5R6, -C (0) NR5R6, CF3, alkyl, aryl and OCF3; R3 is selected from the group consisting of H, halogen, -NR5R6, -OR6, -SR6, -C (0) N (R5R6), alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R3 and the heterocyclyl moieties whose structures are shown immediately above for R3 may be unsubstituted or optionally independently substituted with one or more portions which may be be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, CN, -OCF3, - (CRR5) pOR5, -OR5, -NR5R6, - (CR4R5) PNR5R6, -C (02) R5, -C (0) R5, -C (0) NR5R6, -SR6, -S (02) R6, -S (02) NR5R6, -N (R5) S (02) R7, - N (R5) C (0) R7, -N (R5) C (R R5) nN (R5R6) and -N (R5) C (0) NR5R6, with the proviso that no carbon adjacent to a nitrogen atom in a heterocyclyl ring carries a -OR5 portion; R 4 is H, halogen or alkyl; R5 is H, alkyl, aryl, heteroaryl, arylalkyl or cycloalkyl; R6 is selected from the group consisting of H, Boc, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl , heteroaryl, and heteroarylalkyl may be unsubstituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN , -OR5, -NR5R10, -C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) pOR5, -C (02) R5, -C (0) R5, -C (O) NR5R10, -SO3H, -SR10, -S (O2) R7, -S (O2) NR5R10, -N (R5) S (O2) R7, -N (R5) C (0) R7 and -N (R5) C (0 ) NR5R10; R10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl may be substituted or optionally substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, heterocyclylalkyl, CF3, OCF3, CN, -OR5, -NR4R5, - C (R4R5) P-R9, -N (R5) Boc, - (CR4R5) pOR5, -C (02) R5, -C (0) NR4R5, -C (0) R5, -S03H, -SR5, -S (02) R7, -S (02) NR4R5, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR4R5; or optionally (i) R5 and R10 in the -NR5R10 portion, or (ii) R5 and R6 in the -NR5R6 portion, can be linked together to form a cycloalkyl or heterocyclyl moiety, with each said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R9 groups; R7 is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl and heterocyclyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl may be unsubstituted or optionally independently substituted with one or more portions which may be the same or different, each portion being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF3, OCF3, CN, -OR5, -NR5R10, -CH2OR5, -C ( 02) R5, -C (0) NR5R10, -C (0) R5, -SR10, -S (02) R10, -S (O2) NR5R10, -N (R5) S (02) R10, -N (R5 ) C (O) R10 and -N (R5) C (O) NR5R10; R8 is selected from the group consisting of R6, -OR6, -C (O) NR5R10, -S (O2) NR5R10, -C (0) R7, -C (= N-CN) -NH2 > -C (= NH) -NHR5, heterocyclyl, and -S (02) R7; R9 is selected from the group consisting of halogen, -CN, -NR5R10, -SCN, -N02, -C (0) R5, -C (02) R6, -C (0) NR5R10, -OR6, -SR6, - S (02) R7, -S (02) NR5R10, -N (R5) S (02) R7, -N (R5) C (0) R7 and -N (R5) C (0) NR5R10; m is 0 to 4; n is 1 to 4; and p is 1 to 4, with the proviso that when R2 is phenyl, R3 is not alkyl, alkynyl or halogen, and that when R2 is aryl, R is not. S (CHR5) - NR5R8 provided that when R is arylalkyl, then any heteroaryl substituent on the aryl of said arylalkyl contains at least three heteroatoms. 55.- The use as claimed in claim 5, wherein the medication is also adapted to be administrable with radiation therapy. 56. The use as claimed in claim 54, wherein said anticancer agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, taxotero, taxol, etoposide, rinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778.123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec, intron, ara-C, adriamycin, Citoxan, gemcitabine, mustard uracil, Chloromethane, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Trilethylenemelamine, Triethylenenetofosforamine, Busulfan, Carmustine, Lomustine, Streptozocine, Dacarbazine, Floxuridine, Citarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine Phosphate, Oxaliplast, Leucovirin, ELOXATIN ™, Pentostatine , Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitramycin, Deoxicoformycin, Mitomycin-C, L-Asparagine sa, Teniposide 17a-Ethinylestradiol, Diethylsilbesterol, Testosterone, Prednisone, Fluoximemesterone, Dromostanolone propionate, Testolactone, Megestrol acetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesterone acetate, Leuprolide, Flutamide, Toremifene , Goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, Herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer , Erbitux, Liposomal, Totepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225, Campat, Clofarabine, cladríbíne, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine, SmM, fludarabine, pentostatin, triapina , didox, trimidox, amidox, 3-AP, and MDL-101, 731. The use of a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting the activity of a checkpoint kinase, The compound being selected from the group consisting of: 58. - The use of a combination of (i) a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, and (i) a pharmaceutically acceptable carrier, for the manufacture of a drug useful for inhibiting a checkpoint kinase, wherein the compound is selected from the group consisting of: 59. - The use of a combination of (i) a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, and (i) an anti-cancer agent, for the manufacture of a medicament useful for treating a prolifferative disease, wherein said compound is selected from the group consisting of: 60. - The use as claimed in claim 59, wherein the medicament is further adapted to be administrable with radiation therapy. 61.- The use as claimed in claim 59, wherein said anticancer agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, rinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphatide, SCH 66336, R115777, L778.123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec, intron, ara-C, adriamycin, Citoxan, gemcitabine, uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylene melamine, Triethylenenethophosphoramine, Busulfan, Carmustine, Lomustine, streptozocine, Dacarbazine, Floxuridine, Citarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN ™, Pentostatine, Vínblastine, Vincristíne, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin , Deoxicoformicin, Mitomycin-C, L-Asparaginase, Teniposide 17a-Ethinylestradiol, Diethylestilbestrol, Testosterone, Prednisone, Fluoxymesterone, dromostanolone propionate, Testolactone, megestrol acetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisone, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesterone acetate, Leuprolide, Flutamide, Toremifene, Goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, Herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Totepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Fulvestrant, Ifosfomide, Rituximab, C225, Campat, Clofarabine, cladribine, aphidicol, rituxan, suntintinib, dasatinib, tezacitabine, SmM, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP, and MDL -101, 731. 62.- The use of a pharmaceutical composition comprising a combination of (i) a therapeutically effective amount of at least one compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, and (i) a carrier pharmaceutically acceptable, for the manufacture of a medicament useful for treating, or slowing down the progression of, a proliferative disease in a patient, wherein said compound is selected from the group consisting of: 63. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 64. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 65. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 66. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 67. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 68. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 69. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 70. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 71. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 72. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 73. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 74. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 75. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 76. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 77. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 78. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 79. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 80. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 81. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 82. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 83. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 84. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 85. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 86. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 87. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 88. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 89. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 90. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 91. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 92. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 93. - The use of a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound, for the manufacture of a medicament useful for inhibiting a checkpoint kinase, wherein said compound has the formula: 94. A compound that exhibits inhibition of CHK-1 which is at least five times the inhibition of CDK2 of the compound. 95.- A compound that has inhibition of CHK-1 that is at least ten times the inhibition of CDK2 of the compound. 96.- A compound that exhibits inhibition of CHK-1 that is at least fifty times the inhibition of CDK2 of the compound. 97. A pyrazolopyrimidinium compound having inhibition of CHK-1 which is at least five times the inhibition of CDK2 of the compound. 98.- A pyrazolopyrimidinium compound exhibiting CHK-1 inhbition that is at least ten times the inhibition of CDK2 of the compound. 99.- A pyrazolopyrimidinium compound having CHK-1 inhbition that is at least fifty times the inhibition of CDK2 of the compound.