Title of Invention

IMIDAZOPYRAZINE TYROSINE KINASE INHIBITORS

Abstract Compounds of the formula (I) and pharmaceutically acceptable salts thereof, wherein Q<1 >and R<1> are defined herein, inhibit the IGF-1R enzyme and are useful for the treatment and/or prevention of various diseases and conditions that respond to treatment by inhibition of tyrosine kinases.
Full Text

IMTOAZOPYORAZINE TYROSINE KINASE INHIBITORS
BACKGROUND OF THE INVENTION
[1] The present invention is directed to novel imidazopyrazines, their salts,
and compositions comprising them. In particular, the present invention is directed to imidazopyrazines as novel tyrosine kinase inhibitors that inhibit tyrosine kinase enzymes in animals., including humans, for the treatment and/or prevention of various diseases and conditions such as cancer.
[2] Phosphoryi transferases are a large family of enzymes that transfer
phosphorous-containing groups from one substrate to another. Kinases are a class of ^ enzymes that function in the catalysis of phosphoryi transfer. The phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate. Almost all kinases contain, a similar 250-300 amino acid catalytic domain. Protein kinases, with at least 400 identified, constitute the largest subfamily of structurally related phosphoryi transferases and are responsible for the control of a wide variety of signal transduction processes within the cell. The protein kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein- serine/threonine, etc.). Protein kinase sequence motifs have been identified that generally correspond to each of these kinase families. Lipid kinases (e.g. PI3K) constitute a separate group of kinases with structural similarity to protein kinases. [3] The "kinase domain" appears in a number of polypeptides which serve
a variety of functions. Sucli polypeptides include, for example, transmembrahe receptors, intracellular receptor associated polypeptides, cytoplasmic located polypeptides, nuclear located polypeptides and subcellular located polypeptides. The activity of protein kinases can be regulated by a variety of mechanisms and any individual protein might be regulated by more than one mechanism. Such mechanisms include, for example, autqphosphoryiation, transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions, protein- polynucleotide interactions, ligand binding, and post-translational modification. [4] Phosphorylation of target proteins occurs in response to a variety of
extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stresses, etc. Protein and lipid

kinases regulate many different cell processes by aHrffpg phosphate groups to targets such as proteins or lipids. Such cell processes include, for example, proliferation, growth, differentiation, metabolism, cell cycle events, apqptosis, motility, transcription, translation and other signaling processes. Kinase catalyzed phosphorylation acts as molecular on/off switches to modulate or regulate the biological function of the target protein. Thus, protein and lipid kinases can function in signaling pathways to activate or inactivate, or modulate the activity (either directly or indirectly) of the targets. These targets may include, for example, metabolic enzymes, regulatory proteins, receptors, cytoskeletal proteins, ion channels or pumps, or transcription factors.
[5] A partial list of protein kinases includes abl, AKT, bcr-abl, Blk, Brie,
Btk, c-kit, c-met, c-src, CDK1, CDK2, CDK3, CDK4, CDKS, CDK6, CDK7, CDK8, CDK9, CDK10, cRafl, CSFir, CSK, EGHt, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGJR5, Fgr, flt-I, Fps, Fik, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PK, PKC, PYK2, ron, tie, tie2, TRK, Yes, and Zap70. Thus, protdn kiriases represent a large family of proteins which play a central role in the regulation of a wide variety of cellular processes, maintaining control over cellular function. Uncontrolled signaling due to defective control of protein phosphorylation has been implicated in a number of diseases and disease conditions, including for example, inflammation, cancer, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS), cardiovascular disease, dermatology, and angiogenesis. [6] Initial interest in protein kinases as pharmacological targets was
stimulated by findings that many viral oacogenes encode structurally modified cellular protein kinases with constitutive enzyme activity. One early exaniple was the Rous sarcoma virus (RSV) or avian sarcoma virus (AS V), which caused highly malignant tumors of the same type or sarcomas within infected chickens. Subsequently, deregulated protein kinase activity, resulting from a variety of mechanisms, has been implicated in the pafhophysiology of a number of important human disorders including, for example, cancer, CNS conditions, and immunologically related diseases. The development of selective protein kinase inhibitors that can block the disease pathologies and/or symptoms resulting from aberrant protein kinase activity has therefore become an important therapeutic target

[7] Protein tyrosine kinases (PTKs) are enzymes that catalyse the
phosphoryiation of specific tyrosine residues in cellular proteins. Suchpost- translational modification of the substrate proteins, often enzymes themselves, acts as a molecular switch regulating cell proliferation, activation or differentiation (for review, see Schlessinger and Ullrich, 1992, Neuron 9:383-391). Aberrant or excessive PTK activity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune system (e.g., autoimmune disorders), allograft rejection, and graft vs. host disease. In addition, endothelial-cell specific receptor PTKs such as KDR and Tie-2 mediate the angiogenic process, and are thus involved in supporting the progression of cancers and other diseases involving inappropriate vascularization (e.g., diabetic retmopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, retinopathy of prematurity, infantile hemangiomas). [8] Tyrosine kinases can. be of the receptor-type (having extracellular,
transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular). The Receptor Tyrosine Kinases (RTKs) comprise a large family of transmembrane receptors with at least nineteen distinct RTK subfamilies having diverse biological activities. The RTK family includes receptors that are crucial for the growth and differentiation of a variety of cell types (Yarden and Ullrich, Ann. Rev. Biochem. 57:433-478,1988; Ullrich and Schlessinger, Cell 61:243-254,1990). The intrinsic function of RTKs is activated upon ligand binding, which results in phosphoryiation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses (Ullrich. & Schlessinger, 1990, Cell 61:203-212). Thus, RTK mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), typically followed by receptor dimerization, stimulation of the intrinsic protein tyxosine kinase activity and receptor trans- phosphoryiation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response such as cell division, differentiation, metabolic effects, and changes in the extracellular microenvironmeat (see Schlessinger and Ullrich, 1992, Neuron 9:1-20). [9] Proteins with SH2 (sre homology -2) or phosphotyrosine binding
(PTB) domains bind activated tyrosiue kinase receptors and their substrates with high

affinity to propagate signals into celL Both of the domains recognize phosphotyrosne. (Fantl et alt 1992, Cell 69:413-423; Songyang et al., 1994, Mol CelL BioL 145777-2785; Songyang et al, 1993, Cell 72:767-778; and Koch et alt 1991, Science 252:668-678; Shoelson, Curr Opiru Chem. BioL (1997), 1(2), 227-234; Cowburn, Curr Opin. Struct BioL (1997), 7(6), 835-838)- Several intracelklar substrate proteins that associate with RTKs have been identified. They may be divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack such a domain but serve as adapters and associate with catalytically active molecules (Songyangtf al., 1993, Cell 72:767-778). The specificity of the interactions between receptors or proteins and SH2 or PTB domains of their substrates is determined by the arnzno acid residnes immediately surrounding the phosphoryiated tyrosme residue. For example, differences in the binding affinities between SID domains and the axnino acid sequences surrounding the phosphotyrosine residues on particular receptors correlate with the observed differences in their substrate phosphorylation profiles (Songyang e* al, 1993, Cell 72:767-778). Observations suggest that the function of each receptor tyrosine kinase is determined not only by its pattern of expression and ligand availability but also by the array of downstream signal transduction pathways that are activated by a particular receptor as well as the timing and duration of those stimuli. Thus, phosphorylation provides an important regulatory step which determines the selectivity of signaling pathways recruited by specific growth factor receptors, as well as differentiation factor receptors.
[10] Several receptor tyrosme kinases such as FGFR-1, PDGFR, Tie-2 and
c-Met, and growth factors that bind thereto, have been suggested to play a role in angiogenesis, although some may promote angiogenesis indirectly (Mustonen and Alitalo,/. Cell BioL 129:895-898,1995). One such receptor tyrosine kinase, known as "fetal liver kinase 1" (FLJL-1), is a member of the type HI subclass of RTKs. Human FLK-1 is also known as Trinase insert domain-containing receptor" (KDR) (Terman et aL, Oncogene 6:1677-83,1991). It is also called "vascular endothelial cell growth factor receptor 2" (VEGFR-2) since it binds vascular endothelial cell growth factor (VEGF) with high affinity. The mtrrine version of FIX-l/VEGFR-2 1 has also been called NYK. (Oelrichs et al, Oncogene 8(1):11-15,1993). Numerous studies (such as those reported in Millaner et al., supra), suggest that VEGF and FLK-

l/KIJR/VEGFR-2 are a ligand-receptor pair that play an important role in the proliferation of vascular eadothelial cells (vasculogenesis), and the formation and sprouting of blood vessels (angiogenesis). A^ccordingly, VEGF plays a role in the stimulation of both normal and pathological angiogenesis (Jakeman et al., Endocrinology 133:848-859,1993; Kolch et aL, Breast Cancer Research and Treatment 36:139-155,1995; Fsrrara et at, Endocrine Reviews 18(1); 4-25,1997; Ferrara et aL, Regulation of Angiogenesis (ed, L D. Goldberg and E.M. Rosen), 209-232,1997). In addition, VEGF has been implicated in the control and enhancement of vascular pemieabflity (Connolly, et aL, 1. BioL Chem. 264:20017-20024,1989; Brown et al, Regulation of Angiogenesis (ed. LD. Goldberg and EM. Rosen), 233-269,1997). '
[11] Another type III subclass RTK1 related to FLK-1/KDR (DeVries et aL
Science 255:989-991,1992; Shibuya et al., Oncogene 5:519-524,1990) is "fins-like tyrosine kinase-F (Flt-1), also called Vascular endothelial cell growth factor receptor 1" (VEGFR-1). Members of the FLK-l/KDR/VEGFR-2 and Flt-l/VEGPR-1 subfamilies are expressed primarily on endothelial cells. These subclass members are specifically stimulated by members of the VEGF family of ligands (Klagsbum and D'Amore, CytoMne & Growth Factor Reviews 7:259270,1996). VEGF binds to Flt-1 with higher affinity than to FLK-1/KDR and is mitogenic toward vascular endothelial cells (Terman et aL, 1992, supra; Mustonen et aL supra; DeVries et al., supra). Flt-1 is believed to be essential for endothelial organization during vascular development Flt-1 expression is associated with early vascular development in mouse embryos, and with neovascularization during wound healing (Mustonen and Alitalo, supra). Expression of Flt-1 inmonocytes, osteoclasts, and osteoblasts, as well as in adult tissues such as kidney glomeruii suggests an additional function for this receptor that is no related to cell growth (Mustonen and Alitalo, supra). [12] Placenta growth factor (P1GF) has an amino acid sequence that
exhibits significant homology to the VEGF sequence (Park et al, 1. Biol Chem. 269:25646-54,1994; Magionee* al. Oncogene 8:925-31,1993). As with VEGF, different species of PIGF arise from alternative splicing of mRNA, and the protein exists in dimeric fonn (Park et al., supra). P1GF-1 and P1GF-2 bind to Flt-1 with high affinity, and P1GF-2 also avidly binds to neuropilin-1 (Migdal et al., 1. Biol. Chem. 273 (35): 22272-22278), but neither binds to FLK-17KDR (Park et al, supra).

P1GF has been reported to potentiate both the vascular permeability and mitogenic effect of VEGF on endotheKal cells when VEGF is present at low concentrations (purportedly due to heterodimer formation) (Park et aL, supra). [13] VEGF-B is thought to play a role in the regulation of extracellular
matrix degradation, cell adhesion, and migration through modulation of the expression and activity of urokinase type plasminogen activator and plasmiaogen activator inhibitor 1 (Pepper et aL, Proa NatL AcadL ScL U. S. A (1998), 95(20):11709-11714).
[14] VEGEF-C can also bind KDR/VEGFR-2 and stimulate proliferation and
migration of endothelial cells in vitro and angiogenesis in in vivo models (Lymboussaki etal.Am. JPathoL (1998), 153(2):395-403; Witzenbichler et aL, Am. J. PathoL (1998), 153(2), 381-394). The transgenic overexpression of VEGF-C causes proliferation and enlargement of only lymphatic vessels, while blood vessels are unaffected. Unlike VEGF, the expression of VEGF-C is not induced by hypoxia (Ristimaki etal, J. BioL Chem. (1998), 273(14), 8413-8418), [15] Structurally similar to VEGF-C, VEGF-D is reported to bind and
activate at least two VEGFRs, VEGFR-3/Flt-4 and KDR/VEGFR-2. It was originally cloned as a c-fos inducible mitogen for fibroblasts and is most prominently expressed in the mesenchymal cells of the lung and skin (Achen et alt Proc. Natl AcacL Set U S. A (1998), 95(2), 548-553 and references therein). VEGF, VEGF-C and VEGF-D have been claimed to induce increases in vascular permeability in vivo in a Miles assay when injected into cutaneous tissue CPCT/US97/14696; WO98/07832, Witzenbichler et al., supra). The physiological role and significance of these ligands in modulating vascular hyperpenneability and endothelial responses in tissues where they are expressed remains uncertain.
[16] Tie-2 (TEK) is a member of a recently discovered family of
endothelial cell specific RTKs involved in critical angiogenic processes such as vessel branching, sprouting, remodeling, maturation and stability. Tie-2 is the first mammalian RTK for which both agonist ligands (e.g^ Angiopoietinl ("Angl"), which stimulates receptor autophosphoryfetion and signal transaction), and antagonist ligands (e.g., Angiopoietm2 ("Ang2")), have been identified. The current model suggests that stimulation of Tie-2 kmase by the Angl Kgand is directly involved in the branching, sprouting and outgrowth of new vessels, and recruitment and interaction of

periendothelial support cells important in maintaining vessel integrity and inducing quiescence. The absence of Angl stimulation of Tie-2 or the inhibition of Tie-2 autophosphoryiation by Ang2, which is produced at high levels at sites of vascular regression, may cause a loss in vascular structure and matrix contacts resulting in endothelial cell death, especially in the absence of growth/survival stimuli. Recently, significant ^regulation of Tie-2 expression has been found within the vascular synovial panxms of arthritic joints of humans, consistent with a role in the inappropriate neovascwiarizatiop, suggesting that Tie-2 plays a role in the progression of rheumatoid arthritis. Point mutations producing constitutively activated forms of Tie-2 have been identified in association with human venous malformation disorders. Tie-2 inhibitors are, thereM, useful in treating such disorders, and in other situations of inappropriate neovascularization.
[17] Non-receptor tyrosine kinases represent a collection of cellular
enzymes which lack extracellular and transmembrane sequences (see, Bohlen, 1993, Oncogene 8:2025-2031). Over twenty-four individual non-receptor tyrosine kinases, comprising eleven (11) subfamilies (Sic, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack and LIMK) have been identified. The Src subfamily of non-receptor tyrosine kinases is comprised of the largest number of PTKs and include Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yik. The Src subfamily of enzymes has been linked to oncogenesis and immune responses.
[18] Plk-1 is a serine/threonine kinase which is an important regulator of
cell cycle progression. It plays critical roles in the assembly and the dynamic function of the mitotic spindle apparatus. Plk -1 and related kinases have also been shown to be closely involved in the activation and inactivation of other cell cycle regulators, such as cyclin-dependent kinases. High levels of PBc-l expression are associated with cell proliferation activities. It is often found in malignant tumors of various origins. Inhibitors of PBc-l are expected to block cancer cell proliferation by disrupting processes involving mitotic spindles and inappropriately activated cyclin-dependent kinases.
[19] Cdc2 (cdkl Ycyclin B is another serine/tbreonine kinase enzyme which
belongs to the cyclin-dependenl kinase (cdks) family. These enzymes are involved in the critical transition between various phases of cell cycle progression. It is believed that uncontrolled cell proliferation, the hallmaxk of cancer, is dependent upon elevated

cdk activities in these cells. The loss of control of cdk regulation is a frequent event in hypeiproliferative diseases and cancer (Pines, Current Opinion in Cell Biology, 4:144-148 (1992); Lees, Current Opinion in Cell Biology, 7:773-780 (1995); Hunter and Pines, Cell, 79:573-582 (1994)). The inhibition of elevated cdk activities in cancer cells by cdc2/cyclin B kinase inhibitors could suppress proliferation and may restore the normal control of cell cycle progression.
[20] Malignant cells are associated with the loss of control over one or more
cell cycle elements. These elements range from cell surface receptors to the regulators of transcription and translation, including the insulin-like growth factors, insulin growth fector-I (IOM) and insulin growth fector-2 (IGF-2). [M J. Ellis, "The Insulin-Like Growth Factor Network and Breast Cancer", Breast Cancer, Molecular Genetics, Pafhogenesis and Therapeuttes, Humana Press 1999], The insulin growth factor system consists of families of ligauds, inmifri growth factor binding proteins, and receptors,
[21] A major physiological role of the IGF-1 system is the promotion of
normal growth and regeneration, and overexpressed IGF-IR can initiate mitogenesis and promote ligand-dependent neoplastic transformation. Furthermore, IGF-IR plays an important role in the establishment and maintenance of the malignant phenotype. ■ [22] IGF-IR exists as a heterodimer, with several disulfide bridges. The
tyrosine kinase catalytic site and the ATP binding site are located on the cytoplasmic portion of the beta subunit Unlike the epidermal growth factor (EGF) receptor, no mutant oncogenic forms of fee IGF-IR have been identified. However, several oncogenes have been demonstrated to affect IGF-1 and IGF-IR expression. The correlation between a reduction of IGF-IR expression and resistance to transformation has been seen. Exposure of cells to the mRNA antisense to IGF-IR RNA prevents soft agar growth of several human tumor cell lines. [23] Apoptosis is a ubiquitous physiological process used to eliminate
damaged or unwanted cells in muMcelluIar organisms. Disregulation of apoptosis is believed to be involved in the pathogenesis of many human diseases. The fixture of apoptotic cell death has been implicated in various cancers, as well as autoimmune disorders. Conversely, increased apoptosis is associated with a variety of diseases involving cell loss such as neurodegenerative disorders and AIDS. As such, regulators of apoptosis have become an important therapeutic target It is now

established that a major mode of tumor survival is escape from apoptosis. IGF-IR abrogates progression into apoptosis, both in vivo and in vitro. It has also been shown that a decrease in the level of IGF-IR below wild-type levels causes apoptosis of tumor cells in vivo. The ability of IGF-IR disruption to cause apoptosis appears to be diminished in normal, non-tumorigenic cells.
[24] Inappropriately high protein Irinase activity- has been implicated in
many diseases resulting from abnormal cellular function. This might arise either directly or indirectly, by failure of the proper control mechanisms for the kinase, related to mutation, over-expression or inappropriate activation of the enzyme; or by over- or underproduction of cytokines or growth factors also participating in the transduction of signals upstream or downstream of the kinase. In all of these instances, selective inhibition of the action of the kinase might be expected to have a beneficial effect
[25] The type 1 insulin-like growth factor receptor (IGF-IR) is a
transmembrane RTK that binds primarily to IGF-1 but also to 1GF-II and insulin with lower affinity. Binding of IGF-1 to its receptor results in receptor oligomerization, activation of tyrosine kinase, intennolecular receptor autophosphorylation and phosphorylation of cellular substrates (major substrates are IRS1 and She). The ligand-activated IGF-IR induces mitogenic activity in normal cells and plays an important role in abnormal growth.
[26] Several clinical reports underline the important role of the IGF-1
pathway in human tumor development 1) IGF-IR overexpression is frequently found in various tumors (breast, colon, lung, sarcoma.) and is often associated with an aggressive phenotype. 2) High circulating IGF1 concentrations are strongly correlated with prostate, lung and breast cancer risk. Furthermore, IGF-IR is required for establishment and maintenance of the transformed phenotype in vitro and in vivo (BasergaR. Exp. CelL Res., 1999,253,1-6). The kinase activity of IGF-IR is essential for the transforming activity of several oncogeaes: EGFR, PDGFR, SV40 T antigen, activated Ras, Ra£ and v-Src. The expression of IGF-IR in normal fibroblasts induces neoplastic phenotypes, which can then foim tumors in vivo. IGF-IR expression plays an important role in anchorage-independent growth. IGF-IR has also been shown to protect cells from chemotherapy-, radiation-, and cytokme-induced apoptosis. Conversely, inhibition of endogenous IGF-IR by dominant

negative IGF-1R, triple helix formation or antisense expression vector has been shown to repress transforming activity in vitro and tmnor growth in animal models, . [27] Many of fee tyrosine kinases, whe&er an RTK or non-receptor
tyrosine 1rina.se, have been found to be involved in cellular signaling pathways involved in numerous pathogenic conditions, including cancer, psoriasis, and other hyperproHferative disorders or hyper-immune responses. Therefore, much research is ongoing for inhibitors of kinases involved in mediating or v^^^^v^g disease states to treat such diseases. Examples of such kmase research include, for example: (1) inhibition of c-Src (Bric&eD, Critical Reviews in Oneogenesis, 3:401-406 (1992); Courtneidge, Seminars in Cancer Biology, 5:236-246 (1994), raf (Powis, Pharmacology & Therapeutics, 62-51-95 (1994)) and the cyclin-dependent kinases (CDKs) 1,2 and 4 in cancer (Pines, Current Opinion in Cell Biology, 4:144-148 (1992); Lees, Current Opinion in Cell Biology, 7:773-780 (1995); Hunter and Pines, Cell 79:573-582 (1994)), (2) inhibition of CDK2 or PDGF-R kinase in restenosis (Buchdunger et aL, Proceedings of the National Academy of Science USA, 92:2258- 2262 (1995)), (3) inhibition of CDK5 and GSK3 kinases in Alzhehners (Hosoi et aL, Journal of Biochemistry (Tokyo), 117:741-749 (1995); Aplin et aL, Journal of Neurochemistry, 67:699-707 (1996), (4) inhibition of c-Src kinase in osteoporosis (Tanaka et al, Nature, 383:528-531 (1996), (5) inhibition of GSK-3 kinase in type-2 diabetes (Borthwick et ah, Biochemical & Biophysical Research Communications, 210:738-745 (1995), (6) inhibition of the p38 kinase in inflammation (Badger et aL, The Journal of Pharmacology and Experimental Therapeutics, 279:1453-1461 (1996)), (7) inhibition of VEGF-R1-3 and TBE-1 and 2 kinases in diseases which involve angiogenesis (Shawver et aL, Drug Discovery Today, 2:50-63 (1997)), (8) inhibition of UL97 kinase in viral infections (He et aL, Journal of Virology, 71:405- 411 (1997)), (9) inhibition of CSF-1R kinase in bone and hematopoetic diseases (Myers et. aL, Bioorganic & Medicinal Chemistry Letters, 7:421-424 (1997), and (10) inhibition of Lck kinase in autoimmune diseases and transplant rejection (Myers et al., Bioorganic & Medicinal Chemistry Letters, 7:417-420 (1997)). [28] Inhibitors of certain kinases may be useful in the treatment of diseases
when the kinase is not misregulated, but it nonetheless essential for maintenance of the disease state. la this case, inhibition of the kinase activity would act either as a cure or palliative for these diseases. For example, many viruses, such as human

papilloma virus, disrupt the cell cycle and drive cells into the S-phase of the cell cycle (Vousden, FASEB Journal, 7:8720879 (1993)). Preventing cells from entering DNA synthesis after viral infection by inhibition of essential S-phase initiating activities such as CDK2, may disrupt the virus life cycle by preventing virus replication. This same principle may be used to protect normal cells of the body from toxicity of cycle- specific chemotherapeutic agents (Stone et aL, Cancer Research, 56:3199-3202 (l996);lteh&etaLtJ of CDK 2 or 4 will prevent progression into the cycle in normal cells and limit the toxicity of cytotoxics which act in S-phase, G2 or mitosis.
[29] Furthermore, CDK2/cyclin E activity has also been shown to regulate
NF-kB. Inhibition of CDK2 activity stimulates NF-kB-dependent gene expression, an event mediated through interactions with the p300 co-activator (Perkins et al7 Science, 275:523-527 (1997)). NF-kB regulates genes involved in inflammatory responses (such as hematopoetic growth factors, chemoldnes and leukocyte adhesion molecules) (Baeuerle and Henkel, Annual Review of Immunology, 12:141-179 (1994)) and maybe involved in the suppression of apqptotic signals within the cell (Beg and Baltimore, Science, 274:782-784 (1996); Wang et aL, Science, 274:784-787 (1996); Van Antwerp et aL, Science, 274:787-789 (1996). Thus, inhibition of CDK2 may suppress apoptosis induced by cytotoxic drugs via a mechanism which involves NF- kB and be useful where regulation of NF-kB plays a role in etiology of disease. [30] A further example of the usefulness of kinase inhibition is fungal
infections: Aspergillosis is a common infection in immxxne-compromised patients (Armstrong, Clinical Infectious Diseases, 16: 1-7(1993)). Inhibition of the Aspergillus kinases Cdc2/CDC28 or Nim A (Osmani et aL, EMBO Journal, 10:2669-2679 (1991); Osmani et al, Cell, 67:283-291 (1991)) may cause arrest or death in the fungi, effectively treating these infections.
[31] The identification of effective small compounds which specifically
inhibit signal transduction and cellular proliferation by modulating the activity of receptor and non-receptor tyrosine and serine/threonine kinases to regulate and modulate abnormal or inappropriate cell proliferation, differentiation, or metabolism is therefore desirable. In particular, the identification of methods and compounds that specifically inhibit the function of a tyrosine kinase which is essential for angiogenic processes or the formation of vascular hyperpermeability leading to edema, ascites,

effusions, exudates, and macromolecular extravasation and matrix deposition as well as associated disorders would be beneficial
[32] In view of the importance of PTKs to the control, regulation, and
modulation of cell proliferation and the diseases and disorders associated with abnormal cell proliferation, many attempts have been made to identify receptor and non-receptor tyrosinc ktnase inhibitors using a variety of approaches, including the use of mutant ligands (U.S. Patent No. 4,966,849), soluble receptors and antibodies (International Patent Publication No. WO 94/10202; Kendall & Thomas, 1994, Proc NatL Acad Sci 90:10705-09; KsmetaL, 1993, Nature 362:841-844), RNA ligands (Jeffinek, et aL, Biochemistry 33:1045056; Takano, et aL, 1993, Mol Bio. Cell 4:358A; Kinsella, et aL 1992, Exp. Cell lies. 199:56-62; Wright, et al9 1992,1. Cellular Phys, 152:448-57) and tyrosine kinase inhibitors (International Patent Publication Nos. WO 94/03427; WO 92/21660; WO 91/15495; ^WO 94/14808; US. Patent No. 5,330,992; Mariani, etal», 1994, Froc. Am. Assoc Cancer Res. 35:2268), [33] More recently, attempts have been made to identify small molecules
which act as tyrosine kinase inhibitors. Bis-, mono-cyclic, bicyclic or heterocyclic aiyl compounds (International Patent Publication No. WO 92/20642) and vinylene-azaindole derivatives (International Patent Publication No. WO 94/14808) have been described generally as tyrosine kinase inhibitors. Styryl compounds (U.S. Patent No. 5,217,999), styryl-substitutedpyridyi compounds (U.S. Patent No. 5,302,606), certain quinazoline derivatives (EP Application No, 0566266 Al; Expert Opin. Ther. Pat (1998), 8(4): 475-478), selenoindoles and selenides (International Patent Publication No. WO 94/03427), tricyclic polyfcydroxylic compounds (International Patent Publication No. WO 92/21660) and benzylphosphonic acid compounds (international Patent Publication No. WO 91/15495) have been described as compounds for use as tyrosine kinase inhibitors for use in the treatment of cancer. Axulixiocinnolines (PCT WO97/34876) and quinazoline derivative compounds (Metnatioaal Patent Publication No. WO 97/22596; International Patent Publication No. WO97/42187) have been described as inhibitors of angiogmesis and vascular permeability, BisOndolytnaleimide) compounds have been described as inhibiting particular PKC serine/threordne kinase isofbnns whose signal transducing function is associated with altered vascular permeability in VEGF-related diseases (International Patent Publication Nos. WO 97/40830 and WO 97/40831).

[34] IGF-1R performs important roles in cell division, development, and
metabolism, and in its activated state, plays a role in oncogenesis and suppression of apoptosis. IGF-1R is known to be overexpressed in a number of cancer cell lines (IGF-1R overexpression is linked to acromegaly and to cancer of the prostate). By contrast, down-regulation of IGF-1R expression has been shown to result in the inhibition of tumorigenesis and an increased apoptosis of tumor cells. [35] Memational Patent Publication Nos. WO03/018021 andWO
03/018022 describe pyrinridines for treating IGF-1R related disorders, International Patent Publication Nos. WO 02/102804 and WO 02/102805 describe cyclolignans and cyclolignans as IGF-1R inhibitors, International Patent Publication No. WO 02/092599 describes pyrrolopyrkaidiiies for the treatment of a disease which responds to an inhibition of the IGF-1R tyrosme kznase, International Patent Publication No. WO 01/72751 describes pynolopyrimidines as tyrosine kinase inliibitors. International Patent Publication No. WO 00/71129 describes pyrrolotriazine inhibitors of kinases. International Patent Publication No. WO 97/28161 describes pyirolo [2,3-d]pyrimidines and their use as tyrosine kinase inhibitors.
[36] Panizas, et aL describes tyiphostms with in vitro and in vivo IGF-1R
inhibitory activity (Endocrinology, 138:1427-1433 (1997)), and International Patent Publication No. WO 00/35455 describes heteroaryl-aryl ureas as IGF-1R inhibitors. International Patent Publication No. WO 03/048133 describes pyrimidine derivatives as modulators of IGF-1R. International Patent Publication No. WO 03/024967 describes chemical compounds with inhibitory effects towards kinase proteins. International Patent Publication No. WO 03/068265 describes methods and compositions for treating hyperproliferative conditions. International Patent Publication No. WO 00/17203 describes pyrrolopyrimidines as protein kinase inhibitors. Japanese Patent Publication No. JP 07/133280 describes a cephem compound, its production and antimicrobial composition. A. Albert et aL, Journal of the Chemical Society, II: 1540-1547 (1970) describes pteridine studies and pteridines unsubstituted in the 4-position, a synfliesis from pyrazines via 3,4-dhydropteridines. A. Albert et aL, Chenu Biol Pteridines Proc. Int. Symp., 4th, 4: 1-5 (1969) describes a synthesis of pteridines (unsubstituted in the 4-position) from pyrazines, via 3-4-dihydropteridines.

SUMMARY OF THE INVENTION
[37] The present invention relates to compounds of Formula L

[38] or a pharmaceufically acceptable salt thereof The compounds of
Formula I inhibit the IGF-1R enzyme and are useful for the treatment and/or prevention of various diseases and conditions that respond to treatment by inhibition oflGF-lR. The compounds of this invention are useful as inhibitors of serine/threonine and tyrosine Idnases. In particular, compounds of this invention are useful as inhibitors of tyrosine kinases that are important in hyperproliferative diseases, especially cancer.
DETAILED DESCRIPTION OF THE INVENTION
[39] The present invention relates to a compound of Formula I:

[40] or a phannaceutically acceptable salt thereof, wherein:



















[65] X1 and Y1 are each independently equal to -O-, -NR7-S
[66] and the other variables are described as above for Formula L
[67] In another embodiment of this second aspect, a compound is
represented by Fonnula I, or a phannaceotically acceptable salt thereof wherein R1 is
cycloalkyl, optionally substituted by one or more Gn substituents; wherein Q1 is aryl1
or heteroaryl1, any of which is substituted by one to five independent G1 substituents;
[68] at least one of said G1 substituents is ^V-CY1)*-*4;
[69] X1 and Y1 are each independently equal to -O- or -CR^R6-;
[70] and the other variables are described as above for Formula L
[71] In another embodiment of this second aspect, a compound is
represented by Fonnula I, or a phannaceutically acceptable salt thereof wherein R1 is
cycloalkyl, optionally substituted by one or more Gn substituents; Q1 is aryl1 or
heteroaryl1, any of which is substituted by one to five independent G1 substituents;
[72] at least one of said G1 substituents is -(X^K^V-R4;
[73] X1 and Y1 are each independently equal to -O- or -CH2-;
[74] and the other variables are described as above for Fonnula L
[75] In another embodiment of this second aspect, a compound is
represented By Formula I, or a phannaceutically acceptable salt thereof! wherein R1 is
cycloalkyl, optionally substituted by one or more Gn substituents; Q1 is aiyl1 or
heteroaryl1, any of which is substituted by one to five independent G1 substituents;
[76] at least one of said G1 substituents is -(X^-O^V-R4;
[77] R4 is H, alky!, aryi, heteroaryl, cycloalkyl, heterocyclyl, cycloalkenyl,
or heterocycloalkenyl, any of which is optionally substituted by one or more
independent G41 substituents;
[78] and the other variables are described as above for Fonnula L
[79] In another embodiment of this second aspect, a compound is
represented by Foinrula I, or a phannaceutically acceptable salt thereof wherein Rx is
cycloalkyl, optionally substituted by one or more Gu substituents; Q1 is aiyl1 or
heteroaiyi1, any of which is substituted by one to five independent G1 substituents;
[80] at least one of said Gl substituents is -^XV-CY^-R4;
[81] R* is aryl or heteroaryi, optionally substituted by one or more
independent G41 substituents;











optionally substituted by one or more Gu substituents; Q1 is aryl1 or heteroaryi1, any
of which is substituted by one to five independent G2 substitucnts;
[131] at least one of said G1 substituents is ^V [132] X1 and Y1 are each independently equal to -O- or -CH2-;
[133] and the other variables are described as above for Formula L
[134] In another embodiment of tins third aspect, a compound is represented
by Formula I, or a pharmaceutically acceptable salt thereof, wherein R is aryl,
optionally substituted by one or more Gu substituents; Q1 is aryl1 or heteroaryi1, any
of which is substituted by one to five independent G1 substitucnts;
[135] at least one of said G1 substituenis is -(X^-O^^-R4;
[136] R4 is H, alkyi, aryi, heteroaryi, cycloalkyi, heterocyclyi, cycloalkenyl,
or heterocycloalkenyi, any of which is optionally substituted by one or more
independent G41 substituents;
[137] and the other variables are described as above for Formula L
[138] In another embodiment of this third aspect, a compound is represented
by Formula I, or a phannaceutically acceptable salt thereof wherein R1 is aryl,
optionally substituted by one or more Gu substituents; Q1 is aryl1 or heteroaiyl1, any
of which is substituted by one to five independent Gl substituents;
[139] at least one of said G1 substituents is -(X^-^V-R4;
[140] R4 is aryl or heteroaryi, optionally substituted by one or more
independent G41 substituents;
[141] and the other variables are described as above for Formula I.
[142] In another embodiment of tins third aspect, a compound is represented
by Formula I, or a pharmaceutically acceptable salt thereof wherein R1 is aryl,
optionally substituted by one or more Gu substituents; Q1 is aryl1 or heteroaryi1, any
of which is.substituted by one to five independent G1 substituents;
[143] at least one of said G1 substituents is -{X^HY'V-R4;
[144] R4 is aryl or heteroaryi, optionally substituted by one or more G41
substituents;
[145] and the other variables are described as above for Formula I.
[146] In another embodiment of this third aspect, a compound is represented
by Formula I, or a pharmaceutically acceptable salt thereof wherein









[184] wherein at least one of said G1 substituents is -(X^-Qf^-R4;
[185] R4 is H, alkyl, aryl, heteoaryi, cycloalkyi, heterocyclyl, cycloalkenyl,
or heterocycloaDcenyi, any of which is optionally substituted by one or more
independent G41 substituents;
[186] and the other variables are described as above for Formula L
[187] In another embodiment of this fourth aspect, a compound is
represented by Formula I, or a pharmaceufically acceptable salt thereof, wherein R1 is
heterocyclyi, optionally substituted by one or more G11 substrtoenls; Q1 is aryl1 or
heteroaxyi1, any of which is substituted by one to five independent G1 substituents;
[188] wherein at least one of said G1 substitaents is -(X^-O^W-R4;
[189] R4 is aryl or heteroaryl, optionally substituted by one or more
independent G substituents;
[190] and the other variables are described as above for Formula L
[191] In another embodiment of this fourth aspect, a compound is
represented by Formula I, or a phannaceuticaUy acceptable salt thereof wherein Q1 is
aryl1 or heteroaryl1, any of which is substituted by one to five independent G1
substituents;
[192] wherein at least one of said G1 substituents is -(XV-CY^-R4;
[193] R4 is aryl or heteroaryl, optionally substituted by one or more G41
substituents;
[194] and the other variables are described as above for Formula I.
[195] In another embodiment of this fourth aspect, a compound is
represented by Formula I, or a pharmaceuticafly acceptable salt thereof wherein
[196] R1 is heterocyclyi represented by the structural formula:

[197] and the other variables are described as above for Formula L
[198] In another embodiment of this fourth aspect, a compound is
represented by Formula I, or a phaxmaceutically acceptable salt thereof wherein [ 199] R1 is heterocyclyi represented by the structural formula:





























[274J The present invention includes a method of inhibiting protein kinase
activity wherein the activity of said protein kinase influences angiogenesis, vascular
permeability, immune response, cellular apoptosis, tumor growth, or inflammation
comprising administering a compound of Formula I or a pbannaceuticaHy acceptable
salt thereof
[275] The present invention includes a method of treating a patient having a
condition which is mediated by protein kinase activity, said method comprising
administering to the patient a therapeutically effective amount of a compound of
Formula 1 or a pharmaceutically acceptable salt thereof
[276] The present invention includes a method of treating a patient having a
condition which is mediated by IGF-1R activity, said method comprising
administering to the patient a therapeutically effective amount of a compound of
Formula I or a pharmaceutically acceptable salt thereof
[277] The present invention includes a method of treating a patient having a
hypexproliferative disorder, said method comprising administering to the patient a
therapeutically effective amount of a compound of Formula I or a pharmaceutically
acceptable salt thereof
[278] The present invention includes a method of treating a patient having a
condition which is mediated by protein kinase activity wherein the activity of said
protein kinase influences angiogenesis, vascular permeability, immune response,
cellular apoptosis, tumor growth, or inflammation, said method comprising
administering to the patient a therapeutically effective amount of a compound of
Formula I or a pharmaceutically acceptable salt thereof.
[279] The presort invention includes a method of treating a patient having a
condition which is mediated by protem kinase activity wherein the protein kinase is a
protein serine/threanme kinase or a protein tyrosine kinase, said method comprising
administering to the patient a therapeutically effective amount of a compound of
Formula I or a pharmaceutically acceptable salt thereof
[280] The present invention includes a method of treating a patient having a
condition which is mediated by protein kinase activrty wherein the condition mediated
by protean kinase activity is one or more ulcers, said method comprising
administering to the patient a therapeutically effective amount of a compound of
Formula I or a pharmaceutically acceptable salt thereof

[281] The present invention includes a method of treating a patient having a
condition which is mediated by protein kinase activity wherein the condition mediated by protein kinase activity is one or more ulcers wherem the ulcer or ulcers are caused by a bacterial or fimgal infection; or the ulcer or ulcers are Mooren ulcers; or the ulcer or ulcers are a symptom of ulcerative colitis, said method comprising administering to the patient a therapeuiically effective amount of a compound of Formula I or a phannaceutically acceptable salt thereof
[282] The present invention includes a method of treating a patient having a
condition which is mediated by protein kinase activity wherem the condition mediated by protein kinase activity is Lyme disease, sepsis or infection by Herpes simplex, Herpes Zoster, human immunodeficiency virus, parapoxvirus, protozoa, or toxoplasmosis, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a phannaceutically acceptable salt thereof.
[283] The present invention includes a method of treating a patient having a
condition which is mediated by protein kinase activity wherein the condition mediated by protein kinase activity is Lyme disease, sepsis or infection by Heipes simplex, Herpes Zoster, human immunodeficiency virus, parapoxvirus, protozoa, or toxoplasmosis, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a phannaceutically acceptable salt thereof.
[284] The present invention includes a method of treating a patient having a
condition which is mediated by protein kinase activity wherein the condition mediated by protein kinase activity is von EBppel Iindau disease, pernphigoid, psoriasis, Pagefs disease, or polycystic kidney disease, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a phannaceutically acceptable salt thereof
[285] The present invention includes a method of treating a patient having a
condition which is mediated by protein kinase activity wherem the condition mediated by protein kinase activity is fibrosis, sarcoidosis, cirrhosis, thyroiditis, hyperviscosity syndrome, Oslcr-Weber-Rendu disease, chronic occlusive pulmonary disease, asthma, exudtaes, ascites, pleural effusions, pulmonary edema, cerebral edema or edema following bums, trauma, radiation, stroke, hypoxia, or ischemia, said method

comprising administering to the patient a iherapetitically effective amount of a compound of Formula I or a phannaceutically acceptable salt thereof [286] The present invention includes a method of treating a patient having a
condition which is mediated by protein kinase activity wherein the condition mediated by protein kinase activity is ovarian byperstimulation syndrome, pieeclainpsia, menometronhagia, or endometriosis, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a phannaceutically acceptable salt thereof.
[287] The present invention includes a method of treating a patient having a
condition which is mediated by protein kinase activity wherein the condition mediated by protein kinase-activity is chronic inflammation, systemic lupus, glomerulonephritis, synovitis, inflammatory bowel disease, Grohn's disease, glomerulonephritis, rheumatoid arthritis and osteoarfhritis, multiple sclerosis, or graft rejection, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a phannaceutically acceptable salt thereof
[288] The present invention includes a method of treating a patient having a
condition which is mediated by protein kinase activity wherein the condition mediated by protein kinase activity is sickle cell anaemia, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a phannaceutically acceptable salt thereof
[289] The present invention includes a method of treating a patient having a
condition which is mediated by protein kinase activity wherein the condition mediated by protein kinase activity is an ocular condition, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a phannaceutically acceptable salt thereof
[290] The present invention includes a method of treating a patient having a
condition which is mediated by protein kinase activity wherein the condition mediated by protein kinase activity is an ocular condition wherem the ocular condition is ocular or macular edema, ocular neovascular disease, seleritis, radial keratotomy, uveitis, vitritis, myopia, optic pits, chronic retinal detachment, post-laser treatment complications, conjunctivitis, Stargardfs disease, Eales disease, retmopafliy, or macular degeneration, said method comprising administering to the patient a

fherapeutically effective amount of a compound of Formula I or a phannaceuticaUy acceptable salt thereof
[291] The present invention, includes a method of treating a patient having a
condition wMch is mediated by protein kinase activity wherein the condition, mediated by protein kinase activity is a cardiovascular condition, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a phannaceuticaUy acceptable salt thereof
[292] The present invention includes a method of treating a patient having a
condition which is mediated by protein kinase activity wherein the condition mediated by protein kinase activity is atherosclerosis, restenosis, ischemia/reperfusion injury, vascular occlusion, venous malformation, or carotid obstructive disease, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a phannaceuticaUy acceptable salt thereof [293] The present invention includes a method of treating a patient having a
condition which is mediated by protein kinase activity wherein the condition mediated by protein kinase activity is cancer, said method comprising administering to the patient a tberapeutically effective amount of a compound of Formula I or a phannaceuticaUy acceptable salt thereof.
[294] The present invention includes a method of treating a patient having a
condition which is mediated by protein kinase activity wherein the condition mediated by protein kinase activity is cancer wherein the cancer is a solid tumor, a sarcoma, fibrosarcoma, osteoma, melanoma, retinoblastoma, a rhabdomyosarcoma, glioblastoma, neuroblastoma, teratocarcinoma, an hematopoietic malignancy, or malignant ascites, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a phannaceuticaUy acceptable salt thereof.
[295] The present invention includes a method of treating a patient having a
condition which is mediated by protein kinase activity wherein the condition mediated by protein kinase activity is cancer wherein the cancer is Kaposi's sarcoma, Hodgkin's disease, lymphoma, myeloma, or leukemia, said method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a phannaceuticaUy acceptable salt thereof

[296] The present invention includes a method of treating a patient having a
condition which is mediated by protein kinase activity wherein the condition mediated
by protein kinase activity is Crow-Fukase (POEMS) syndrome or a diabetic condition,
said method comprising administering to the patient a therapeutically effective
amount of a compound of Formula 1 or a pharmacentically acceptable salt thereof
[297] The present invention includes a method of treating a patient having a
condition which is mediated by protein kinase activity wherein the condition mediated
by protein kinase activity is Crow-Fukase (POEMS) syndrome or a diabetic condition
wherein the diabetic condition is insulin-dependent diabetes mellitus glaucoma,
diabetic retinopathy, or microangiopathy, said method comprising administering to
the patient a therapeutically effective amount of a compound of Formula I or a
pharmaceutically acceptable salt thereof
[298] The present invention includes a method of treating a patient having a
condition which is mediated by protein kinase activity wherein the protein kinase
activity is involved in T cell activation, B cell activation, mast cell degranulation,
monocyte activation, signal transduction, apoptosis, the potentiation of an
inflammatory response or a combination thereof said method comprising
administering to the patient a therapeutically effective amount of a compound of
Formula I or a pharmaceutically acceptable salt thereof.
[299] The present invention includes a composition comprising a compound
according to Formula I, or a pharmaceutically acceptable salt thereof; and a
pharmaceutically acceptable carrier.
[300] The present invention includes a composition comprising a compound
according to Formula I, or a pharmaceutically acceptable salt thereof; and an anti-
neoplastic, anti-tumor, anti-angiogenic, or chemothetapeutic agent
[301 ] The present invention includes a composition comprising a compound
according to Formula I, or a pharmaceutically acceptable salt thereof; and a cytotoxic
cancer therapeutic agent
[302] The present invention includes a composition comprising a compound
according to Formula I, or a phannaceutically acceptable salt thereof; and an
angiogenesis inhibiting cancer therapeutic agent
[303] The present invention includes a method of treating a patient having a
condition which is mediated by protein kinase activity, said method comprising

administering to the patient a tlierapeuticaUy effective amount of a pharmaceutical composition comprising a compound according to Formula I, or a phannaceutically acceptable salt thereof, and a pharmaceotically acceptable carrier.
[304] Unless otherwise stated, the connections of compound name moieties
are at the rightmost recited moiety. That is, die substrtuent name starts with a
terminal moiety, continues with any bridging moieties, and ends with the connecting
moiety. For example, hetaiylthioCi^alkyi has a heteroaiyi group connected through a
thio sulfur to a CM alkyl that connects to the chemical species bearing the substitueat.
[305] As used herein, for example, 'Qwalkyi" is used to mean an alkyl
having 0-4 carbons - that is, 0,1,2,3, or 4 carbons in a straight or branched
configuration. An alkyl having no carbon is hydrogen when the alkyl is a terminal
group. An alkyi having no carbon is a direct bond when the alkyl is abridging
(connecting) group.
[306] In all embodiments of this invention, the term "alkyl" includes both
branched and straight chain alkyl groups. Typical alkyl groups are methyl, ethyl, n-
propyl, isopropyl, n-butyl, sec-butyl, isobutyl, terf-butyl, n-pentyl, isopentyl, n-hexyl,
H-heptyl, isooctyi, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl,
eicosyl and the like.
[307] The term "halo" refers to fluoro, chloro, bromo or iodo.
[308] Tie term "haloaDcyr refers to an alkyl group substituted with one or
more halo groups, for example chloromethyl, 2-bromoethyi, 3-iodopropyl,
trifluoromethyl, perfluoropropyl, 8-chlorononyl and the Eke.
[309] The term "cycloalkyl" refers to a cyclic aliphatic ring structure,
optionally substituted with alkyl, hydroxy and halo, such as cyclopropyl,
methylcyclopropyi, cyclobutyi, cyclopentyl, 2-hydroxycyclopeolyi, cyclohexyl, 4-
chlorocyclohexyl, cycloheptyl, cyclooctyl and the like.
[310] The term "alkylcarbonyioxyalkyr refers to an ester moiety, for
example acetoxymethyl, n-butyryloxyethyi and the like.
[311] The term "alkynylcarbonyr refers to an alkynylketo functionality, for
example propynoyi and the like.

[312] The term "hydroxyalkyr refers to an alkyl group substituted with one
or more hydroxy groups, for example hydroxymethyl, 23-^ydroxybutyl and the
like.
[313] The term "alkyisulfonyialkyT refers to an alkyi group substituted with
an aBcylsulfonyl moiety, for example mesyimefhyi, isopropylsulfonyiethyl and the
like.
[314] The term "alkyisulfonyT refers to a sulfbnyi moiety substituted with an
alkyl group, for example mesyi, n-propyisulfonyl and the like.
[315] The term "acetyiarninoalkyr refers to an alkyl group substituted with
an amide moiety, for example acetylaminomethyl and the like.
[316] The term "acetyiaminoalkenyiw refers to an alkenyl group substituted
with an amide moiety, for example 2-(acetyiamino)vinyi and the like.
[317] The term "aflcenyT refers to an ethylenically tmsaturated hydrocarbon
group, straight or branched chain, having 1 or 2 ethylenic bonds, for example vinyl,
ally!, 1-butenyl, 2-butenyl, isoprope&yl, 2-pentenyi and the like.
[318] The term "haloalkenyl11 refers to an alkenyl group substituted with one
or more halo groups.
[319] The term "cycloaBcenyl" refers to a cyclic aliphatic ring structure,
optionally substituted with alkyl, hydroxy and halo, having 1 or 2 ethylenic bonds
such as methylcyclopropenyl, trifluoromethylcyclopropenyl, cyclopentenyl,
cyclohexenyl, 1,4-cyclohexadienyi and the like.
[320] The term " alkynyl" refers to an unsaturated hydrocarbon group,
straight or branched, having 1 or 2 acetylenic bonds, for example ethynyl, propargyl
and the like.
[321] The term "haloalkynyT refers to an alkynyl group substituted with one
or more halo groups.
[322] The term "aBcylcaibonyi" refers to an alkylketo functionality, for
example acetyi, n-butyryl and the Kke.
[323] The term "alksnyicaibonyin refers to an aBcenyBceto functionality, for
example, propenoyl and the like.
[324] The term "aryT refers to phenyi or naphthyl which may be optionally
substituted Typical aryl substituents include, but are not limited to, phenyl, 4-
chlorophenyl, 4-fluorophenyi, 4-bromophenyi, 3-nitrophenyl, 2HEnethoxyphenyl, 2-

methylphenyi, 3-methyphenyI, 4-mefeyiphenyi, 4-ethyiphenyi, 2-methyi-3-methoxyphenyl, 2,4-dibrom0phenyl, 3,5-^IifhiorophenyI, 3,5-dimethylphGnyl, 2,4,6-trichloropheiiyl, 4-methoxyphenyl, naphthyl, 2-chloronaphthyl, 2,4-dimethoxyphenyl, 4^trifluoromethyl)phenyl and 2-iodo-4-methylphenyL
[325] The term "aryi^refers to phenyi which may be optionally substituted.
Typical aryi1 substituents include, but are not limited to, phenyi, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 3-nitrophenyl,2-methoxyphenjd, 2-methylphenyl, 3-methyphe&yl, 4-mefliylphenyl, 4-ethyiphenyl, 2-me£hyi-3-methoxyphenyl, 2,4-dibromophenyi, 3^-difluarophenyl, 3,5-dimefliy^)hen5d, 2,4,6-trichloiophenyl, 4-meflioxyphenjd, 2,4-dimethoxyphaayi, 4-(trifluorometh>i)phQi)4 and 2-iodo-4-
[326] The tenns "hetooar^" or iehstaryT9 refer to a substituted or
unsubstituted 5- or 6-membered unsaturated ring containing one, two, three or four heteroatoms, preferably one or two heteroatoms independently selected from oxygen, nitrogen and sulfur or to a bicyclic unsaturated ring system containing up to 10 atoms including one heteroatom selected from oxygen, nitrogen and sulfur. Examples of hetaryls include, but are not limited to, 2-, 3- or 4-pyridinyl, pyrazinyl, 2-, 4-, or 5- pyrrmidinyl, pyridazinyl, triazolyl, tetrazolyl, imidazolyl, 2- or 3-tfaienyl, 2- or 3- furyl, pyrrolyl, oxazolyl, isoxazoljd, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzotriazolyl, benzofiiranyl, and benzothienyl. The heterocyclic ring may be optionally substituted with up to two substituents. [327] The terms "heteroaryl1" or "hetaryl1" refer to a substituted or
unsubstituted 5- or 6-membered unsaturated ring containing one, two, three or four heteroatoms, preferably one or two heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of hetaryls include, but are not limited to, 2-, 3- or 4-pyridinyl, pyrazfnyl, 2-, 4-, or 5-pyrimidinyl, pyridazinyl, triazolyi, tetrazolyl, imidazolyl, 2- or 3-thienyl, 2- or 3-foryl, pyrrolyl, oxazolyi, isoxazolyi, thiazolyi, isothiazolyl, oxadiazolyi, and thiadiazolyl. The heterocyclic ring may be optionally substituted with up to two substituents.
[328] The terms "aryi-alkyr or "arylalkyi" are used to describe a group
wherein the alkyi chain can be branched or straight chain with the aryl portion, as defined hereinbefore, forming a bridging portion of the aryl-alkyi moiety. Examples of axyi-alkyi groups include, but are not limited to, optionally substituted benzyl,

phenethyi, phenpropyl and phenbutyl such as 4-chlorobenzyl, 2,4-dibromobenzyl, 2-
methylbenzyl, 2-(3-fluorophenyl)e&yi, 2^4-methyIphenyl)ethyl,2-(4-
(trifhioromethyOphenyOethyl, 2-(2-methoxyphenyl)efliyi, 2-(3-nitrophenyI)ethyl, 2-
(2,4-dichlonjphenji)ethyl, 2^3,5-dimefhoxyphmyl)e&yI, 3-phenyipropyi, 3-(3-
chlorophenyl)prqpyi, 3^2-methy^henyl)pn>pyI, 3 (trifluoromefliyi)phenyl)propyl, 3-(2,4-dichlorophenyi)propyi, 4-phenyIbuiyl, 4-(4-
chlorpphenyl)butyi, 4-(2-me1ky3phenyi)butyi, 4-(2,4-dichlorophflaayi)butyl3 4-(2-
methoxphenyl)butyl and 10-phenyldecyI.
[329] The terms "aryl-cycloalkyr or "arylcycloalkyr are used to describe a
group wherein the aryl group is attached to a cycloalkyl group, for example
phenyicyclqpentyi and the like.
[330] The terms "aryl-alkenyi" or "arylalfasiyr are used to describe a group
wherein the alkenyl chain can be branched or straight chain with the aryl portion, as
defined hereinbefore, forming a bridging portion of the araDcenyi moiety, for example
styryl (2-phenylvinyl), phenprqpenyl and the like.
[331 ] The terms "aiyl-alkynyl" or "arylalkynyl" are used to describe a group
wherein the alkynyl chain can be branched or straight chain with the aryl portion, as
defined hereinbefore, forming a bridging portion of the aryl-alkynyl moiety, for
example 3-phenyl-l-propynyl and the like.
[332] The terms "aryl-oxy" or "aryloxy" are used to describe a terminal aiyl
group attached to a bridging oxygen atom. Typical aryi-oxy groups include phenoxy,
3,4slichlorophenoxy and the like.
[333] The terms "aryl-oxyalkyl" or "aiyioxyaBcyT are used to describe a
group wherein an alkyl group is substituted with an aryi-oxy group, for example
pentafluorophenoxymethyl and the like.
[334] The terms tshetaryt-oxy" or Tieteroaryl-oxy11 or "hetaryloxy* or
"heteroaryloxy" are used to describe a terminal hetaryl group attached to a bridging
oxygen atom. Typical hetaryi-oxy groups include 4,6^imethoxypyrimidin-2-3doxy
and the like.
[335] The terns "hetarylalkyl" or "heteroai)dalk}dn or "hetaryl-alkyr or
'fteteroaryl-aDcyr are used to describe a group wherein the alkyl chain can be branched or straight chain with the heteroaiyi portion, as defined hereinbefore,

forming a bridging portion of the heteroaralkyl moiety, for example 3-furylmethyl, thenyi, fur&ryi and the like.
[336] The terms "hetarylalkenyl" or Tieteroarylalkenyr or or **heteroaryl-alkenyin are used to describe a grotip herein the alkenyl chain can be branched or straight chain with the heteroaryl portion, as defined hereinbefore, fonning a bridging portion of the heteroaralkenyl moiety, for example 3-(4-pyridyl)-1-propenyL
[337] The teems 'TietarylalkynyT or "heteroaryblkynyl" or
"hetaryl-alkynyr or "heteroaryl-alkynyf are used to describe a group wherein the aflcynyl chain can be branched or straight chain with the heteroaryi portion, as defined hereinbefore, fonning a bridging portion of the heteroaralkynyl moiety, for example 4-(2*tfaienyl)-l-biitynyL
[338] The term "heterocyclyT refers to a substituted or unsubstituted 5 or 6
membered saturated ring containing one, two or three heteroatoms, preferably one or two heteroatoms independently selected from oxygen, nitrogen and sulfur or to a bicyclic ring system containing up to 10 atoms including one heteroatom selected from oxygen, nitrogen and sulfur wherein the ring containing the heteroatom is saturated. Examples of heterocyclyls include, but are not limited to, tetrahydrofuranyl, tetrahydrofuryi, pyrrolidinyl, piperidinyl, 4-pyranyi, tetrahydropyranyi, thiolanyl, morpholinyl, piperazinyl, dioxolanyl, dioxanyl, indolinyl, 5-methyl-6-chromanyl and
\ G 1
[339] The terms "heterocyclylalkyr or "heterocycljd-alkjd" are used to
describe a group wherein the alkyl chain can be branched or straight chain with the heterocyclyl portion, as defined hereinabove, fonning a bridging portion of the heterocyclyialkyi moiety, for example 3-piperidinylmethyl and the like. [340] The terms "heterocyclyialkenyr or "heterocyclyi-alkenyr are used to
describe a group wherein the aDcenyi chain can be branched or straight chain with the heterocyclyl portion, as defined hereinbefore, forming a bridging portion of the beterocyclylalkenyl moiety, for example 2-morpholinyl-l-propenyL

[341] The terms ^eteocyclylalkynyT or "heterocyclyl-alkynyl" are usea 10
describe a group wherein the alkynyl chain, can be branched or straight chain with the
hetoocyclyl portion, as defined hereinbefore, forming a bridging portion of the
heterocyclyialkynyi moiety, for example 2-pyrrolidin)i-l-butynyL
[342] The term "caiboxyiaBcyT includes both branched and straight chain
alkyi groups as defined hereinbefore attached to a carboxyi (-COOH) group.
[343] The term "caxboxyLaDcenyT includes both branched and straight chain
alkenyl groups as defined hereinbefore attached to a carboxyi (-COOH) group,
[344] The term "caiboxyialkynyi11 includes both branched and straight chain
aflcynyl groups as defined hereinbefore attached to a carboxyi (-COOH) group.
[345] The term "caiboxyicycloaDcyr refers to a carboxyi (-COOH) group
attached to a cyclic aliphatic ring structure as defined hereinbefore.
[346] The term "carboxylcycloaBcenyr refers to a carboxyl (-COOEQ group
attached to a cyclic aliphatic ring structure having 1 or 2 ethylenic bonds as defined
hereinbefore.
[347] The terms "cycloalkyialkyT or "cycloalkyi-alkyr refer to a cycloalkyl
group as defined hereinbefore attached to an alkyi group, for example
cyclopropylmethyl, cyclohexylethyl and the like.
[348] The terms "cycloalkylaDcenyl" or "cycloalkyl-aJkenyr refer to a
cycloalkyl group as defined hereinbefore attached to an alkenyl group, for example
cyclohexylvinyl, cycloheptyiallyl and the like.
[349] The terms "cycloalkylalkynyl" or "cycloaDcyl-aBcynyT refer to a
cycloalkyl group as defined hereinbefore attached to an alkynyl group, for example
cyclopropyipropargyl, 4-cyclopentjd-2-butynyl and the like.
[350] The terms "cycloaDcenyialkyl" or "cycloalkenyl-alkyr refer to a
cycloaBcenyl group as defined hereinbefore attached to an alkyi group, for example 2-
(cyclopenten-l-yl)ethyl and the like.
[351] The terras "cycloaDcenyialkenyr or "cycloalkenji-alkeayr1 refer to a
cycloaDcenyl group as defined hereinbefore attached to an alkenyl group, for example
l-(cyclohexen-3-yl)aIlyi and the like.

[352] The terms "cycloalkenylalkynyl" or "cycloalkenyl-alkynyi11 refer to a
cycloalkeiiyi group as defined hereinbefore attached to an altynyi group, for example
Hcyclohexen-3-yl)propargyi and the Hkc
[353] The term "cartoxylcycloalkyla&yr refers to a carboxyi (-COOH)
group attached to the cycloalkyl ting portion of a cycloalkylaDcyi group as defined
hereinbefore.
[354] The team "caiboxjdcycloaDcylalkeDyi" refers to a caiboxyi (-COOH)
group attached to the cycloalkyl ring portion of a cycloalkylalkenyl group as defined
hereinbefore.
[355] The term "carboxylcycloalkylalkynyr refers to a caiboxyl (-COOH)
group attached to the cycloalkyl ring portion of a cycloalkyiaDcynyi group as defined
hereinbefore.
[356] The term "carboxylcycloalkenylalkjd" refers to a caiboxyl (-COOH)
group attached to the cycloalkenyl ring portion of a cycloalkenyialkyi group as
defined hereinbefore.
[357] The term "carboxylcycloalkenylalkenyP1 refers to a cafboxyi (-COOH)
group attached to the cycloalkenyl ring portion of a cycloalkenylalkenyl group as
defined hereinbefore.
[358] The term "carboxylcycloalkenylalkynyl" refers to a caiboxyl (-COOH)
group attached to the cycloalkenyl ring portion of a cycloalkenylalkynyl group as
defined hereinbefore.
[359] The term "alkoxy" includes both branched and straight chain terminal
alkyl groups attached to a bridging oxygen atom. Typical alkoxy groups include
methoxy, ethoxy, 71-propoxy, isopropoxy, tert-butoxy and the like.
[360] The term "haloalkoxy11 refers to an alkoxy group substituted with one
or more halo groups, for example chloromethoxy, trifluoromethoxy, difluoromethoxy,
perfhioroisobutoxy and tiie like.
[361] The term "altoxyalkoxyaJkyT refers to an alkyl group substituted with
an alkoxy moiety which is in turn substituted with a second alkoxy moiety, for
example methoxymethoxymethji, isopropoxymethoxyethyl and the like.
[362] The term nalkytthion includes both branched and straight chain alkyl
groups attached to a bridging sulfur atom, for example methyithio.

[363] The term "haloaftylflrio" refers to an alkyithio group substituted with
one or more halo groups, for example triflaoromethylfeio.
[364] The term "alkoxyalkyT refers to an alkyi group substituted with an
alkoxy group, for example isopropoxymethyL
[365] The term "aBcoxyalkenyT refers to an alkenyl group substituted with
an aDcoxy group, for example 3-methoxyaIlyL
[366] The term "aJkoxyaBcynyT refers to an alkynyl group substituted with
an alkoxy group, for example 3-methoxypiopargyL
[367] The term llalkoxycarbonyiaIkylM iefers to a straight chain or branched
alkyi substituted with an aflcoxycaxbonyl, for example e&oxycarbonyimefhyi, 2-
(methoxycarbonyl)propyl and the Kke.
[368] The term "alkoxycarbonylaDcenyT refers to a straight chain or
branched alkenyl as defined hereinbefore substituted with an aBcoxycarbonyl, for
example 4-(ethoxycarbonyl)-2-bi2tenyl and the like.
[369] The term "alkoxycaAonylalkynyT refers to a straight chain or
branched alkynyl as defined hereinbefore substituted with an alkoxycarbonyl, for
example 4-(ethoxycarbonyl)-2«butynyl and the like.
[370] The term "haloalkoxyalkyF refers to a straight chain or branched alkyi
as defined hereinbefore substituted with, a haloalkoxy, for example 2-
chloroethoxymethyl, trifluoromefhoxymethyl and the like.
[371 ] The term "haloaDcoxyalkenyl11 refers to a straight chain or branched
alkenyl as defined hereinbefore substituted with a haloalkoxy, for example 4-
(chloromethoxy)-2-butenyl and the like.
[372] The term "haloaJkoxyalkynyT refers to a straight chain or branched
alkynyl as defined hereinbefore substituted with a haloalkoxy, for example 4-(2-
fluoroethoxy)-2-butynyi and the like.
[373] The term "aflcylthioalkyr refers to a straight chain or branched alkyi as
defined hereinbefore substituted with an alkyithio group, for example
mefhyltbiomethyl, 3-(isobutyithio)heptyi and the like.
[374] The term "alkyithioalkenyi" refers to a straight chain or branched
alkenyl as defined hereinbefore substituted with an alkyithio group, for example 4-
(methyltfaio)-2-butenyi and the Eke.

[375] The term "alkylthioalkynyl11 refers to a straight chain or branched
alkynyl as defined hereinbefore substituted with an alkyitfaio group, for example 4~
(ethylthio)-2-lratynyi and the like.
[376] The term "haloalkylthioalkyr refers to a straight chain or branched
aBcyi as defined hereinbefore substituted with an haloaBcyfthio group, for example 2-
cMoroetiiylthioinethyl, trifluoromefhyltbiometiiyl and the like.
[377] The texm "haloalkyiUrioalkexLyr refers to a straight chain or branched
alkenyi as defined hereinbefore substituted with an haloalkyithio group, for example
4^cUoix)ine5thyl1hio)-2-butenyi and the Eke.
[378] The term "hatoalkyifcioaJkynyr refers to a straight chain or branched
alkynyi as defined hereinbefore substituted wifh a haloaDcyifliio -group, for example 4-
(2-fhioroefhyltMo)-2-butyiiyi and the like.
[379] The tenn "dialkoxyphosphorylalkyP refers to two straight chain or
branched alkoxy groups as defined hereinbefore attached to a pentavalent
phosphorous atom, containing an oxo substituent, which is in turn attached to an
alkyl, for example diethoxyphosphorylmethyl.
[380] The term "oligomer" refers to a low-molecular weight polymer, whose
number average molecular weight is typically less than about 5000 g/mol, and whose
degree of polymerization (average number of monomer units per chain) is greater than
one and typically equal to or less than about 50.
[381] Compounds described herein contain one or more asymmetric centers
and may thus give rise to diastereomers and optical isomers. The present invention
includes all such possible diastereomers as well as their racemic mixtures, their
substantially pure resolved enantiomers, all possible geometric isomers, and
phannaceutically acceptable salts thereof The above Formula I is shown without a
definitive stereochemistry at certain positions. The present invention includes all
stereoisomers of Formula I and phannaceutically acceptable salts thereof Further,
mixtures of stereoisomers as well as isolated specific stereoisomers axe also included.
During the course of the synthetic procedures used to prepare such compounds, or in
using racemization or epimerization procedures known to those skilled in the art, the
products of such procedures can be a mixture of stereoisomers.

[382] The invention also encompasses a pharmaceutical composition that is
comprised of a compound of Formula I in combination with a pharmaceutically acceptable carrier.
[3 83] Preferably the composition is comprised of a phannaceutically
acceptable earner and a non-toxic therapeutically effective amount of a compound of Formula I as described above (or a phannaceutically acceptable salt thereof). [384] Moreover, within this preferred embodiment, the invention
encompasses a pharmaceutical composition for the treatment of disease by inhibiting kinases, comprising a phannaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of Formula I as described above (or a phannaceutically acceptable salt thereof).
[385] The term phannaceutically acceptable salts" refers to salts prepared
from pharmaceutically acceptable non-toxic bases or adds. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium slats. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, argmine, betaine, caffeine, choline, N1,NJ-dibenzylethylenediamine, diethyiamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-e&yimoipholine, N-ethylpiperidine, glucamine, ghxeosamine, histidine, hydrabamine, isopropylkmine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triefhylaineine, trimetbylamine, tiipropyiamine, tromethamine and 1iie like.
[386] When the compound of the present invention is basic, its
corresponding salt can be conveniently prepared from phannaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for

example, acetic, benzenesulfbrric, benzoic, caznphorsulfonic, citric, efhanesulfonic, formic, fumaric, gtuconic, ghxtaxnic, hydrobromic, hydrochloric, iseflrionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartanc, p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic, formic, hydrochloric, maleic, phosphoric, sul&ric and tartanc acids. Particularly preferred are formic and hydrochloric add [3 87] The pharmaceutical compositions of the present invention comprise a
compound represented by Formula I (or a pharmaceutically acceptable salt thereof) as an active ingredient, a phannaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
[3 88] In practice, the compounds represented by Formula I, or a prodrug, or
a metabolite, or a pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The earner may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula I, or a phannaceutically acceptable salt thereof may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the

compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
[389] Thus, the pharmaceutical compositions of this invention may include a
pharmaceutically acceptable carrier and a compound, or a phannaceutically acceptable salt, of Formula L The compounds of Formula I, or phannaceutically acceptable salts thereof can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds. [390] The pharmaceutical carrier employed can be, for example, a solid,
liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.
[391] In preparing the compositions for oral dosage form, any convenient
pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.
[392] A tablet containing the composition of tins invention may be prepared
by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient

[393] For example, a formulation intended for the oral administration to
humans may contain from about 0.5mg to about Sg of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about Img to about 2g of the active ingredient, typically 25mg, 50mg, lOOmg, 200m& 300mg, 400mg, 500m& 600mg, 800mg, or lOOOmg. [394] Pharmaceutical compositions of the present invention suitable for
parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropyicellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms. [395] Pharmaceutical compositions of the present invention suitable for
injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof [396] Pharmaceutical compositions of the present invention can be in a form
suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. TTiese formulations may be prepared, utilizing a compound represented by Formula I of this invention, or a phannaceotically acceptable salt thereof via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with aboat 5wt% to about 10wt% of the compound, to produce a cream or ointment having a desired consistency.
[397] Pharmaceutical compositions of this invention can be in a form
suitable for rectal administration wherein the earner is a solid. It is preferable that the

mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in fee art The suppositories may be conveniently formed by first admixing the composition with the softened or melted carriers) followed by chilling and shaping in molds.
[398] In addition to the aforementioned carrier ingredients, the
pharmaceutical formulations described above may include, as appropriate, one or more additional canier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including aati-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation . isotonic with the blood of fee intended recipient Compositions containing a compound described by Formula I, or phannaceuticaUy acceptable salts thereof may also be prepared in powder or liquid concentrate form.
[399] ' Generally, dosage levels on fee order of from about O.Olmg/kg to
about 15Qmg/kg of body weight per day are useful in fee treatment of fee above- indicated conditions, or alternatively about 0.5mg to about 1% per patient per day. For example, inflammation, cancer, allergy/asthma, disease and conditions of fee immune system, disease and conditions of fee central nervous system (CNS), cardiovascular disease, dermatology, and angiogenesis may be effectively treated by fee administration of from about 0.01 to 50mg of fee compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day. [400] It is understood, however, feat fee specific dose level for any particular
patient will depend upon a variety of fectors including fee age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and fee severity of fee particular disease undergoing therapy. [401] Compounds described herein contain one or more asymmetric centers
and may feus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and phannaceutically acceptable salts thereof The above Formula I is shown without a definitive stereochemistry at certain positions. The present invention includes all stereoisomers of Formula I and phannaceutically acceptable salts thereof Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included During fee course of fee synthetic procedures used to prepare such compounds, or in

using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers. [402] The invention also encompasses a pharmaceutical composition that is
comprised of a compound of Formula I in combination with a pharmaceutically acceptable carrier.
[403] Preferably the composition is comprised of a pharmaceutically
acceptable carrier and a non-toxic thexapeutically effective amount of a compound of Formula I as described above, or a phannaceotically acceptable salt thereof [404] Moreover, within this prefexed embodiment, the invention
encompasses a pharmaceutical composition for the treatment of disease by inhibiting tyrosine kinase enzymes, resulting in cell proliferation, growth, differentiation, metabolism, cell cycle events, apoptosis, motility, transcription, phosphoryiation, translation and other signaling processes, comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of formula I as described above (or a pharmaceutically acceptable salt thereof). [405] The term "phannaceutically acceptable salts" refers to salts prepared
from phannaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from phannaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium slats. Salts derived from phannaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines. Other phannaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, argmine, betaine, caffeine, choline, N*,N'-dibenzyIethylenediamine, diethylamine, 2-diefhyiaminoethanol, 2-dimethjdaminoethanol, ethanolamine, ethylenediamine, N-ethyhnorpholine, N-ethyipiperidine, giucanrine, gtucosamine, Mstidine, hydrabamine, isopropylamine, lysine, methyiglucamine, morpholine, piperazine, piperidine, polyamine resins,

procaine, purines, theobromine, triethylameine, trimethylamine, tripropyiamine, trometh antfnft and the like.
[406] When the compound of the present invention is basic, its
corresponding salt can be conveniently prepared from phannaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphotsulfonic, citric, e&anesulfomc, fumaric, gluconic, glutamic, bydrobromic, hydrochloric, isethiomc, lactic, maleic, malic, mandelic, methanesulfonic, mode, nitric, pamoic, pantothemc, phosphoric, succicic, sulfuric, taitaric, p-tohaenesulfanic add and the like. Particularly preferred are citric, hydrobramic, hydrochloric, maleic, phosphoric, sulforic and tartaric acids. [407] The pharmaceutical compositions of the present invention comprise a
compound represented by formula I, or a phannaceutically acceptable salt thereof as an active ingredient, a phannaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
[408] In practice, the compounds represented by Formula I, or
phannaceutically acceptable salts thereof of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The earner may take a wide variety of forms depending on the fonn of preparation desired for administration. E.gM oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as anon-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound represented by Formula I, or a pharmaceuttically acceptable salt thereof may also be administered by controlled

release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In -general, the compositions are prepared by uniformly and intimately aflmrring the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
[409] Thus, the pharmaceutical compositions of this invention may include a
phazmaceutically acceptable carrier and a compound or a phannaceuticaUy acceptable salt of Formula L The compounds of Formula I, orphannaceuticafly acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
[410] The pharmaceutical carrier employed can be, for example, a solid,
liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.
[411] In preparing the compositions for oral dosage form, any convenient
pharmaceutical media may be employed For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystaUine cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.
[412] A tablet containing the composition of this invention may be prepared
by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent Molded tablets may be made by molding in a suitable machine, a mixture of

the powdered compound moistened wife an inert liquid diluent Each tablet preferably contains from about 0.05mg to about 5g of fee active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of fee active ingredient
[413] For example, a formulation intended for fee oral administration to
humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of fee total composition. Unit dosage forms will generally contain between from about lmg to about 2g of fee active ingredient, typically 25mg, 50m& lOQmg, 20Qmg, 300mg, 400mgt 500mg, 600mg, SOOmg, or lOOOmg. [414] Pharmaceutical compositions of fee present invention suitable for
parenteral administration maybe prepared as solutions or suspensions of fee active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms. [415] Pharmaceutical compositions of the present invention suitable for
injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fimgi* The carrier can be a solvent or dispersion medium containing, for example, water, effaanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof [416] Pharmaceutical compositions of the present invention can be in a form
suitable for topical sue such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention, or a pharmaceotically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with

about 5wt% to about 10wt% of the compound, to produce a cream or ointment having a desired consistency.
[417] Pharmaceutical compositions of tins invention can be in a form
suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art He suppositories maybe conveniently formed by first admixing the composition with the softened or melted carriers) followed by chilling and shaping in molds.
[418] In addition to the aforementioned earner ingredients, the
pharmaceutical formulations described above may include, as appropriate, one or more additional earner ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient Compositions containing a compound described by Formula I, or pharmaceutically acceptable salts thereof may also be prepared in powder or liquid concentrate form.
[419] Generally, dosage levels on the order of from about O.Olmg/kg to
about 150tng/kg of body weight per day are useful in the treatment of the above- indicated conditions, or alternatively about 0.5mg to about 7g per patient per day. For example, inflammation, cancer, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS), cardiovascular disease, dermatology, and angiogenesis may be effectively treated by the administration of from about 0.01 to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 3>5g per patient per day. [420] It is understood, however, that the specific dose level for any particular
patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
BIOLOGICAL ASSAYS
[421] The efficacy of the Examples of the invention, compounds of Formula
I, as inhibitors of insulin-like growth factor-1 receptor (IGF-1R) were demonstrated and confirmed by a number of pharmacological in vitro assays. The following assays

and their respective methods have been carried out with the compounds according to the invention- Activity possessed by compounds of Formula I may be demonstrated in vivo.
In vitro tvrosiae kmase assay
[422] The IGF-1R inhibitory of a compound of formula I can be shown in a
tyrosine kinase assay using purified GST fusion protein containing the cytoplasmic kinase domain of human IGF-1R expressed in Sf9 cells. This assay is carried out in a final volume of 90 ]\L containing 1-lOOnM (depending on the specific activity) in an ImmuIon-4 96-well plate (Thenno Labsystems) pre-coated with 1 fig/well of substrate poly-glu-tyr (4:1 ratio) in kinase buffer (5QmM Hepes, pH 7.4,125mM Nad, 24mM
MgCk lrnM MnCl2> 1% glycerol, 200pM Na3VC>4, and 2mM DTT). The enzymatic
reaction was initiated by addition of ATP at a final concentration of IOOJOM. After incubation at room temperature for 30 minutes, the plates were washed with 2mM Imidazole buffered saline with 0.02% Tweea-20. Then the plate was incubated with anti-phospliotyrosine mouse monoclonal antibody pY-20 conjugated with horse radish peroxidase (HRP) (Calbiochem) at 167ng/mL diluted in phosphate buffered saline (PBS) containing 3% bovine serum albumin (BS A), 0.5% Tween-20 and 200^M Na3VO4 for 2 hours at room temperature. Following 3X 250|iL washes, the bound anti-phosphotyrosine antibody was detected by incubation with lOOfil/well ABTS (Kirkegaard & Perry Labs, Inc.) for 30 minutes at room temperature. The reaction was stopped by the addition of 100(il /well 1 % SDS, and the phosphotyrosine dependent signal was measured by a plate reader at 405/490 nm.
[423] Examples 1-21 showed inhibition of IGF-1R. Examples 1-21 showed
efficacy and activity by inhibiting IGF-1R in the biochemical assay with IC50 values
less than 15 JJM. Preferably the IC50 value is less than 5jxM. More advantageously,
the IC50 value is less than ipM. Even more advantageously, the IC50 value is less
than200nM.
[424] The most preferred Examples are selective towards IGF-1R.

CeD-based antophosphotvrosine Assay
[425] NIH 3T3 cells stably expressing full-length human IGF- 1R were
seeded at lxlO4 cells/well in 0.1 ml Dulbecco's TnTnfnrai essential medium (DMEM) supplemented with 10% fetal calf serum (FCS) per well in 96-weH plates. On Day 2, fee medium is replaced with starvation medium (DMEM containing 0.5% FCS) for 2 hours and a compound was diluted in 100% dimethyl sulfbadde (DMSO), added to the cells at six final concentrations in di^licates (20,6.6,2.2,0.74,025 and 0.082|iM), and incubated at 37°C for additional 2 hours. Following addition of recombinant human IGF-1 (100 ng/mL) at 37°C for 15 minutes, the media was then removed and the cells were washed once with PBS (phosphate-buffered saline), then Iysed with cold TGH buffer (1 % Triton-100,10% giycerol, 50mM Hepes [pH 7.4]) supplemented with 150mM NaO, 1.5mM MgCl, imM EDTA and fresh protease and phosphatase inhibitors [10p,g/ml leupeptin, 25^ig/ml aprotinin, imM phcnyl methyl suiphonyl fluoride (PMSF), and 200yM Na3VC>4]. Cell lysates were transferred to a 96-well microlite2 plate (Corning CoStar #3922) coated with 10ng>well of IGF-1R , antibody (Calbiochem, Cat#GR31L) and incubated at 4°C overnight Following washing wifh TGE buffer, the plate was incubated with anti-phosphotyrosine mouse monoclonal antibody pY-20 conjugated with horse radish peroxidase (HRP) for 2 hours at room temperature. The autophosphotyrosine was then detected by addition of Super Signal ELBA. Femto Maximum Sensitivity Substrate (Pierce) and chemiluminescence was read on a Wallac Victor21420 Multilabel Counter. The IC50 curves of the compounds were plotted using an Excelpit program. [426] The following Examples showed efficacy and activity by inhibiting
IGF-1R in the above assay with IC50 values between lOOyM - about 8nM, with selectivity over insulin receptor expected to be in arange from 1-15 fold. The selectivity is preferably 5 fold, even more preferably the selectivity is 10 fold. Preferably the IC50 value is less than 5pM. More advantageously, the IC50 value is less than ipM. Even more advantageously, the IC50 value is less than 200nML TnsnHn receptor autophosphotyrosine assays are performed essentially as described above for IGF-1R cell-based assays, but use insulin (10 nM) as activating ligand and an insulin receptor antibody as capture antibody with HepG2 cells expressing endogenous human insulin receptor.

EXPERIMENTAL
[427] Schemes 1-13 below, as well as the Examples that follow, show how to
synthesize compounds of this invention and utilize die following abbreviations: Me for methyl, Et for ethyl, *Pr or *Pr for isopropyl, n-Bu for n-butyl, t-Bu for tert-bviyi, Ac for acetyl, Pb for phenyi, 4C1-Ph or (4CI)Ph for 4-chlorqphenyi, 4Me-Ph or (4Me)Ph for 4-methylphenyl, (p-CH3O)Ph forp-methoxyphenyl, (p~NC>2)Fh &>ip-nitrophenyl, 4Br-Ph or (4Br)Ph for 4-bromqphenyl, 2-CF3-Ph or (2CF3)Ph for 2-trifluoromethylphenyi, DMAP for 4-(dinetJiyiainino)pyridme, DCC for 1^-dicyclohexylcarbodiimide, EDC for 1^3-dimeth>daminopropyi)-3^&yicaitK5d^^ hydrochloride, HOBt for 1-hydioxybenzotriazole, HOAt for l-hydroxy-7-azabenzotriazole, CDI for l,l'-carbon)ddiiinidazole, NMO for 4-methybnorpholiae N-oxide, DEAD for die&l)1 azodicarboxylate, DIAD for diisopropyi azodicafboxylate, DBAD for di-tert-but3d azodicaiboxjdat^ HPFC for high performance Hash chromaiography, rt for room temperature, mill for minute, h for hour, and Bn for benzyL
[428] Accordingly, the following are compounds which are useful as
intermediates in the formation of IGF-1R inhibiting Examples. [429] ! The compounds of Formula I of this invention and the intermediates used in the synthesis of the compounds of this invention were prepared according to the following methods. Method A was used when preparing compounds of Formula I as shown below in Scheme 1: Method A:
[430] where Q1 and R1 are as defined previously for compound of Formula L
[431 ] la a typical preparation of compounds of Formula I, compound of
Formula H was reacted with ammonia in a suitable solvent Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran

(THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile; alcoholics such as methanol, ethanol, isopropanol, trifluotoethanol, and the like; and chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents were used, however, the preferred solvent was isopropanoi. The above process was carried out at temperatures between about -78 °C and about 120 °C. Preferably, the reaction was carried out between 80 °C and about 100 °C. Th-e above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or Iowa1 amounts were used if desired. [432] The compounds of Formula II of Scheme 1 were prepared as shown
below in Scheme 2.

[433] where Q1 and R1 are as defined previously for compound of Formula L
[434] In a typical preparation of a compound of Formula II, an intermediate
of Formula UI was treated -with POCI3 in a suitable solvent at a suitable reaction temperature. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; and chlorinated solvents such as mefhyiene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents were used. The prefe^ed solvent was methyiene chloride. The above process was carried out at temperatures between about -78 °C and about 120 °C. Preferably, the reaction was carried out between 40 °C and about 70 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if

desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired,
[435]
[436] The compounds of Formula IH of Scheme 2 were prepared as shown
below in Scheme 3:
Scheme 3
[437] where Q1 and R1 are as defined previously for compound of Formula I
and A1 = OH, aUcoxy, or a leaving group such as chloro or inridazole. [438] In a typical preparation, of a compound of Formula UI, a compound of
Formula IV and compound of Formula V were reacted under suitable amide coupling conditions. Suitable conditions include but are not limited to treating compounds of Formula IV and V (when A1 = OH) with coupling reagents such as DCC or EDC in conjunction with DMAP, HOBt, HO At and the like. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofiiran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulfoxide (DMSO); acetonitrile; halogenated solvents such as chloroform or methylene chloride. If desired, mixtures of these solvents were used, however the preferred solvent was methylene chloride. The above process was carried out at temperatures between about 0 °C and about 80 °C. Preferably, the reaction was carried out between 22 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. Additionally, other suitable reaction conditions for the conversion of RNH2 to CONHR can be found in Larock, E- C. Comprehensive Organic Transformations, 2nd e&; Wiley and Sons: New Yoric, 1999, pp 1941-1949.

[439] The compounds of Formula IV of Scheme 3 were prepared as shown
below in Scheme 4:

[440] where Ql is as defined previously for compound ofFonrmla I and A2 =
phthalimido or N.
[441 ] In a typical preparation, of a compound of Formula IV, a compound of
Formula VI is reacted under suitable reaction conditions in a suitable solvent When A = phthalimido, suitable conditions include treatment of compound of Formula VI with hydrazine in a suitable solvent. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofuran (THF), glyme, and the like; dimethylformamide (DMF); dimethyl sulftmde (DMSO); acetonitrile; halogenated solvents such as chloroform or methylene chloride; alcoholic solvents such as methanol and ethanol. If desired, mixtures of these solvents may be used, however the preferred solvent was ethanoL The above process was carried out at temperatures between about 0 °C and about 80 °C. Preferably, the reaction was carried out between 22 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. [442] The compounds of Formula IV of Scheme 3 can alternatively be
prepared as shown below in Scheme 4a:


[443] where Q1 is as defined previously for compound of Formula L
[444] in a typical preparation, of a compound of Formula IV, an aldehyde
Q1-CHO was reacted under suitable reaction conditions in a suitable solvent with lithium hexamefcyidisilazidc to give an #-TMS mme Q1-O=&-Si(CH3)3, Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydro&ran (THF), glyme, and the like. The preferred solvent was THF. The above process was carried out at temperatures between about -78 °C and about 20 °C. The preferred temperature was about 0 °C The inline Q!- [445] The compounds of Formula VI of Scheme 4 were prepared as shown
below in Scheme 5:


[446] where Q is as defined previously for compound of Formula I and A -
phthaliinido or N[447] la a typical preparation of a compound of Formula VI (when A2 =
phfhalimido), a compound of Formula VH was reacted with a phthalimide under typical Mitsunobu conditions in a suitable solvent in the presence of suitable reactants. Suitable solvents for use in the above process included, bat were not limited to, ethers such as tetrahydro&ran (THF), glyme, and the like; dimethytfannamide pMF); dimethyl sulfoxide (DMSO); acetonitrile (CH3CN); chlorinated solvents such as mefhyiene chloride (CB2CI2) or chloroform (CHG3). If desired, mixtures of these solvents were used, however, the preferred solvent was THF. Suitable reactants for use in the above process included, but were not limited to, triphenylphosphine and the like and an azodicarboxylate (DIAD, DEAD, DBAD). The desired reactants were triphenylphosphine and DIAD. The above process may be carried out at temperatures between about -78 °C and about 100 °C. Preferably, the reaction was carried out at 22 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired. Generally, one equivalent of triphenylphospine, DIAD and phfhalimide was used per equivalent of compound of Formula VIL The compounds of Formula VH were prepared according to known procedures (Pie, N.; et aL Tetrahedron, 1998,54,9701-9710) from aldehydes Q1—CHO. Additionally, compound of Formula VII can be reacted with Ts2O, Ms2O, Tf2O, TsCl, MsCl, or SOC12 in which the hydroxy group is converted to a leaving group such as its respective tosyiate, mesylate triflate or halogen such as chloro and subsequently reacted with an amine equivalent such as NH(Boc)2, phthalimide, or azide. Conversion of the amine equivalents by known methods such as by treating under acidic conditions (NHCBoch), with hydrazine

(phthalimide) as shown in. Scheme 4, or with triphenylphosphine/water (azide) will afford the desired axnine as shown in Scheme 4.
[448] Ths compounds of Formula I-A (compounds of Fonnula I where R1 =
Z—CONR2R3) were prepared as shown below in Scheme 6:

[449] where Q1, R2, and R3 are as defined previously for compound of
Fonnula I and A3 - hydrogen or alkyl such as methyl or ethyl. [450] In a typical preparation of compound of Fonnula I-A (compounds of
Formula I where R1 = Z—CONR2R3), when A3 « alkyl and R2 and R3 were both equal to H, reaction of compound of Formula II-A with ammonia in a suitable solvent, afforded compound of Fonnula I-A. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydro&ran (THF), glyme, and the like; dimethylformamide pMF); dimethyl sulfoxide (DMSO); acetonitrile; alcoholics such as methanol, ethanol, isopropanol, trifluoroethanol, and the like; and chlorinated solvents such as methylene chloride (CH2CI2) or chloroform (CHQ3). If desired, mixtures of these solvents were used, however, the preferred solvent was isopropanoL The above process was carried out at temperatures between about -78 °C and about 120 °C. Preferably, the reaction was carried out between 80 °C and about 100 °C* The above process to produce compounds of the present invention was preferably earned out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equrmolar amounts of reactants were preferably used although higher or lower amounts were used if desired. Additionally, in a typical preparation of compound, of Fonnula I-A (compounds of Formula I where R1 - Z—CONR^R3), compound of Fonnula II-A (compounds of Formula II where R1



lithium aluminum hydride in a suitable solvent, such as THF to afford compound of Formula II-B (compounds of Formula II where R1 = Z—CH2OH). Subsequent treatment of compound of Formula II-B (compounds of Formula II where R1 = Z— CH2OH) with ammonia in a suitable solvent, afforded wrnpound of Formula I-B (compounds of Formula I where Rl » Z—CH2OH). Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydro&ran (THF), glyme, and the like; dimethylfonnarnide (DMF); dimethyl sulfoxide (DMSO); acetonitrile; alcoholics such as methanol, ethanol, isopropanol, trifluoroethanol, and the like; and chlorinated solvents such as meihyiene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents were -used. The preferred solvent was isopropaaoL The above process was carried oat at temperatures between about -78 °C and about 120 °C. Preferably, the reaction was earned out between 80 °C and about 100 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower
pressures were used if desired. Substantially, equimolar amounts of reactants were t preferably used although higher or lower amounts were used if desired.
[454] The compounds of Formula n~B (compounds of Formula II where R1
= Z^CH2OH), n-C (compounds of Formula II where R1 = Z^-CH2A4), II-D (oompounds of Formula II where R1 = Z—^A5(R2)(R3)d), I-B (compounds of Formula I where R1 = Z—CH2OH) and I-C (compounds of Formula I where R1 == Z— A (R )(R )a) were prepared as shown below in Scheme 8:





, and I-C" (compounds of Formula I where R1 = Z—CEb—N(R2)(R3)), the hydroxy group of compound of Formula I-B (compounds of Formula I where R = Z—CH2OH) was converted to A2, a phihalimide group, following the procedures as described in Scheme 5 fin: the conversion of compound of Formula VII to compound of Formula VL Reaction of compound of Formula I-C* under conditions described in Scheme 4 afforded compound of Formula I-C". Reaction of compound of Formula I- C" with but not limited to various alkylating agents, various aldehydes/ketones under reductive animation conditions, various acylating agents such as acetic anhydride, benzoyi chlorides, or with caiboxyiic acids in the presence of EDC or DCC with HOBT or HOAT, or with sulphonylating agents such as Ts2O or MeSC^Cl afforded compounds of Formula I-C' * \ For example, in a typical preparation of compounds of Formula I-C" (compounds of Formula I where R1 = Z^-CHT—NO^XR3)), a compound of Formula I-C" is treated with a suitable acylating agent in the presence of a suitable base in a suitable solvent. Suitable solvents for use in the above process included, but were not limited to, ethers such as tetrahydrofiiran (THF), glyme, and the like; and chlorinated solvents such as naethylene chloride (CH2CI2) or chloroform (CHCI3). If desired, mixtures of these solvents were used, however, the preferred solvent was chloroform. Suitable bases for use in the above process included, but were not limited to, trialkylamines such as diisopropylethylaznine, triefhylamine, or resion bound trialkylamines such as PS-DEEA. The preferred base was PS-DIEA. In the case where the suitable acylating agent was acetic anhydride, Hie conversion of compound of Formula I-C" to compound of Formula I-C'" where R2 = H and R3 = COCH3 was accomplished. The above process was carried out at temperatures between about -78 DC and about 120 °C. Preferably, the reaction was carried out between 0 °C and about 20 °C. The above process to produce compounds of the present invention was preferably carried out at about atmospheric pressure although higher or lower pressures were used if desired. Substantially, equimolar amounts of reactants were preferably used although higher or lower amounts were used if desired [460] The compounds of Formula I-D (compounds of Formula I where R1 =
Z —H and Z is a heterocyclyi ring containing a nitrogen atom connected to H) and I-E (compounds of Formula I where R1 = Z2—R2 and Z2 is a heterocyclyi ring containing a nitrogen atom connected to R ) were prepared as shown below in Scheme 9:

















[485] c) C^3-Beaiz3doxy-phen3d>^
(confound of Formula IV where Q1 = Ph-(3-0Bn)): 2-[(3-Beozjioxy-phenyIH3-cMoro-pyrazin-2-yl>'methyi]-isoindole-l,3«dioiie (compound of Formula VI where Qz - Pb-(3-OBn) and A2=phfhaKmido) (2.76 g, 6.05 mmol) was dissolved in EtOH (12 mL) andCHaCb (4mL) charged with N2H4 (0.57 mL, 18J6mmoI) and allowed to react for 16 h at rL The white precipitate that was formed was filtered and washed with EtOAc. The filtrate and organic washings were concentrated rn vacwo, and purified via HPFC using a 100 g Jones silica gd column (50% EtOAc: Hex to 5% MeOH: CR2Cl2) to yield the desired product as a reddish oil; XHNMR(CDCl3,400 MHz) 5 5.04 (s, 2H), 5.52 (s, 1H), 6.85-6.98 (m, 2H), 721-726 (m, 2H), 730-7.41 (m, 5H), 8.26 (d, 1H, J= 2.5 Hz), 8.52 (d, 1H, J = 2.5 Hz); MS (ES) 326.25 (M+l), 328.23 (M+3), 329.24 (M+4). An alternative preparation of ftris conq>ound is as follows: To a solution of 3-benzyloxybenzaldehyde (compound of Foimula Ql-CHO where Q1 = Ph-(3-OBn) (1.00 g, 4.71 mmol) in dry THF (5 mL), cooled by ice/water, was added UHMDS (1 M solution in THF; 4.8 mL, 4.8 mmol). After 30 min at 0 °C, this solution of (3-BenzyloxybenzyHdene)-trime1hylsilylamiiie (compound of Formula Ql-C=N-Si(CH3)3 where Q1 = Ph-(3-OBn) was cooled by CQ2(s)/acetone, To a solution of 2,2,6,6-tetramethylpiperidine (0.90 mL, 0,75 g, 5.3 mmol) in dry THF (10 mL)5 cooled by CO2(s)/acetone, was added wBuLi (2.5 M in hexanes; 2.2 mL, 5.5 mmol). The cooling bath was replaced with an iceAvater bath for 15 mfr^ and then the solution was re-cooled to -78 °C. After 15 min, 2~chlon?pyrazin£ (0.39 mL, 0.50 g,
4.4 mmol) was added The cooled solution of (3-Benzyioxybenzyiidene)- trimethylsilylamine (vide supra) was transferred into this solution of lithiochloropyrazme 2 by cannula 30 min later, and the mixture is stirred at -78 °C for
2.4 h and at 0 °C for 0.5 h. The reaction was quenched by adding water and EtOAc. The mixture was filtered through Celite, the layers were separated, the aqueous layer was extracted with EtOAc (4x30 mL), and the combined EtOAc extracts were washed with water and brine and dried over MgSO^ The crude material was adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Plasfamaster, 50 g /150 mL cartridge, eluting with hexanes:EtOAc 4:1 (1-44) -» 1:1 (45-64) -* EtOAc (65-97)], yielding the target compound as an orange foam.































yield the desired product as a light yellow solid; lH NMR (CDC13,400 MHz) 5 2.61-2.68 (m, 2H), 2.94-3.01 (m, 2H), 3.36 (q, 1H, J* 8.0 Hz), 4.42 (q, 1H, •/= 7.3 Hz), 5.15 (s, 2H), 7.00-7.09 (m, 1H), 7.30-747 (m, 9H), 7.56 (d, 1H, /= 5.0 Hz); MS (ES) 407.2 (M+l), 409.2 (M+3).
[552]
[553] b) 3-[l-(3-Benzyloxy-phefcyl)-8^Moro-iinic^
cyclobutanone (compound of Formula II-F where Z3 = 3-cyclobutyl and Q1 = Ph-(3-OBn)): 3-Oxo-cyclobutanecarboxyfic Acid [(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyi]-amide (compound of Fonnula IE where R1 = 3-cyclobutanone and Q1 = Ph-(3-OBn)) (614.0 mg, 1.5 mmol) was dissolved in POCI3 (8.0 mL) and CH2CI2 (2.0 • mL) and allowed to stir at 55 °C for 24 h. The reaction mixture was concentrated in vacuo to a yellow solid, dissolved in cold EtOAc and neutralized with cold sat NaHCO3- The aqueous layer was extracted with EtOAc (3x) and the combined organic layers were dried over Na2SC>4, filtered and concentrated in vacuo. Purification via HPFC using a 20 g Jones silica gel column (50% EtOActHex to 1% MeOH:CH2Cl2) followed by a recrystalizafion from hot EtOH yielded the desired product as a light yellow solid; lH NMR (CDCI3,400 MHz) 5 3.61-3.68 (m, 2H), 3.86-3.95 (in, 3H), 5.15 (s, 2H), 7.00-7.09 (m, 1H), 7.30-7.47 (m, 9H), 7.61 (d, 1H, J = 5,0 Hz); MS (ES) 404.2 (M+l), 4062 (M+3). Alternatively, 3-[H3-Benzyloxy-phenyl)-8-cUoro-iraida2»[l^-a]pyrazm-3-5d]-cyclobu±anone can be prepared from 1-(3-benzyioxyphenyl)-8-cUoro-3-(3-merthylmec^lobutjd)-iim (Example 44b) as follows: To a solution of l-(3-bmzyloxyphenyl)-8-chloro-3-(3-methylcnecyclobutyl)-imidazo[l^-fl]pyrazine (100 mg, 0^5 mmol) in THF (3 mL) and water (1 mL) were added NMO (0.1 mL, 0.5 mmol, 50% aq. solution) and K2OsO4«H2O (5 mg, 0.013 mmol). The resulting mixture was stirred at rt overnight. TLC showed the reaction was complete. The reaction was quenched with Na2SO3 (160 mg, 1.25 mmol), then diluted with EtOAc (40 mL) and water (5 mL), washed with brine (20 mL), and dried over anhydrous sodium sulfete. The filtrate was











































mmol) in dry CH2Q2 (10 mL), cooled to 0 °C, cyclobutanecarbonyl chloride (350 /iL, 363 mg, 3.058 mmol) was added under N2 atmosphere, the cooling bath was removed, and the reaction mixture stirred at ambient temperature for 2 h. The reaction mixture was quenched with dH2O, taken up by CH2CI2 (3x 20 mL), washed (1 x 30mL each) with 0.25M citric acid (pH 2-3), dEfeO, NaHCO3 sat aq. soL, and brine, dried over . anhydrous MgSO^ and filtered. Sample was purified by filtration through a silica gel plug with 10% EtOAc:CH2Cl2 (250 mL) and filtrate was concentrated in vacuo, yielding the title compound as a gold-colored solid; *H NMR (CDCI3, 400 MHz) 5 1.80-2.02 (m, 2H), 2.10-222 (m, 2H), 2.22-234 (m, 2H), 3.09 (quint, /= 8,4 Hz, , 1H), 6.58 (d, /- 7.6 Hz, 1H), 7.01 (d, J= 8.0 Hz, 1H), 7.24-7.36 (m, 5H), 8.33 (d, J = 2.4 Hz, 1H), 8.52 (d, 7= 2.0 Hz, 1H).
[652]
[653] c) C^3-CMoropyrazin-2-yl)-C-phenylmetiiylamine: To a solution of
2-[(3-chloropyrazin-2-yl)-pheaylmethyi]-isoindole-l,3-dione (7.70 g, 22 mmol), containing « 0.77 eq. of reduced DIAD, in EtOH (10 mL) and co-solvent CH2C12 (15 mL), N2H4 (10 mL, 7.91 g, 0.172 mol) was added and the reaction solution was stirred at it, under N2, for 1 cL The suspension was filtered, the orange solid was washed several times with CH2G2, and the filtrate was concentrated in vacuo. The residue was suspended between HC1 (2M)/EtOAc and the EtOAc layer was discarded. The aqueous layer was brought to a basic pH using NaOH and extracted with CH2C12 (5x60 mL), washed with brine (2x50 mL), dried over MgSC>4, filtered, and concentrated, giving 2.1923 g (45%; 9.9795 mmol) of the title compound, containing «0.1 eq. of reduced DIAD, as abrown oil; jH NMR (CDCI3,400 MHz) 5 2.24 (s, br, 2H), 5.56 (s, 1H), 7.26-7.38 (m, 5H), 827 (s, 1H), 8.55 (s, 1H). MS (ES+): m/z 203^/205^ (100/73) [MHf-^H3]-
[654] C^3-(Moropyrazin-2-yi)-C-phenyhnetiiylainine hydrochloride
(2-HC1): To a solution of C-(3-chloropyrazin-2-yi>C-phenylmethylainine (1.582 g, 7.20 mmol) in 1,4-dioxane (


















































[755]
[756] a) cis a7iJfra7Ly-3-[H3-Ben2yloxy-phen5^8K;UcKrc>-imida2o[l,5-
a]pyrazm-3-yl]-cyclobutane-carboxylic add methyl ester: A solution of (COC1)2 (3.17 g, 2.2 TnT^ 25.0 mmol) in dry methylene chloride (20 mL) was charged with a solution of DMSO (3.90 g, 50.0 rnmol) in methylene chloride (10 mL) dropwise at -78 °C under nitrogen. The resulting mixture was stirred at -78 °C for 30 ruin, followed by the addition of {3-[l-(3-benzyloxyphenyI)-8-chloro-imida2o[l,5" a]pyrazin-3-yl]cyclobutyl}methanol in methylene chloride (15 mL). The mixture was stiired at -78 °C for 30 min, then quenched with Et3N (17.5 mL, 125 mmol) and slowly wanned to rt The mixture was diluted with methylene chloride (100 mL), then washed with water (30 mL), sat. aq. NaHCO3 (2 x 30 mL) and brine (30 mL), and dried over anhydrous sodium sulfate. TLC showed the reaction completed and produced the desired aldehydes (trans isomer is less polar than cis one). Evaporation afforded the crude product as a yellow oil, which was directly used to the next step. The solution of the above aldehyde in anhydrous methanol (50 mL) was charged with NIS (6.75 g, 30 mmol) and potassium carbonate (4.14 g, 30 mmol), the resulting mixture was stiired in the dark at rt overnight TLC showed the reaction almost completed. The reaction was quenched with 20 mL of water and dfluted with ethyl acetate (150 mL), then washed with sat aq. Na2S2O3 (2 x 30 mL) and brine (50 mL), and dried over anhydrous sodium sulfete. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (eluting with Hexanes:EtOAc = 70:30 -» 60:40 -> 50:50) by which the two isomers were separated. c£s-3-[l-(3-Beaizyioxy-phenyl)-8-chloro-imidazo[l,5-a]pyrazin-3-yl]^yclobutane-
2H), 7.04 (m, 1H), 7.26-7.47 (m, 9H), 7.58 (d, J= 5.0 Hz, 1H). frans-3-[H3-Benzyloxy-phaiyl)-8-chloro-iinidazo[l ^-a]pyncm-3-yI}-cyck)butane-cafboxylic acid methyl ester. yellow oil; LC-MS (ES, Pos.): m/z 448/450 (3/1) [MH4]; ^NMR (CDCfe,400 MHz) 8 2.76-2.83 (m, 2H), 2.88-2.95 (m, 2H), 333 (m, 1H), 3.77 (s, 3H), 4.03 (m, 1H), 5.14 (s, 2H), 7.05 (II^IH), 726-7.47 (m, 9H), 7 JO (d, J= 4.9 Hz, 1H).
[757]
[758] EXAMPLE 66: 3-[8-Amino-l-(3-benzyloxy-phenyl)-iniidazo[l,5-
a]pyrazin-3-yI]-l-hydroxymethyl-cyclobTitanol: To a sohition of l-(3- bcnzyioxyphe!ayl)-8KMon>-3^3-metihyleaecyclobT^ (1.0 g,
2.5 nmol) in THF (21 mL) and wata: (7 mL) were added NMO (1.0 mL, 5.0 mmol, 50% aq. solution) and K^OsCVB^O (46 mg, 0.125 mmol). The resulting mixture was stirred at rt ovenrigbt TLC showed the reaction was complete. The reaction was quendied withN^SCb (1.60 g, 12.5 mmol). Water (15 mL) was added to dissolve the salts and the organic phase was separated. The aqueous phase was extracted with EtOAc (3 x 25 mL), and the combined organic phases were washed with brine (20 mL), and dried over anhydrous sodium sulfete. The filtrate was concentrated under reduced pressure to give a yellow solid, a mixture of two isomers in ca. 3:2 ratio by *H NMR (CDC13,400 MHz). LC-MS (ES, Pos.): m/z 436/438 (3A) [MH*]. The solution of the above diol (260 mg, 0.6 mmol) in 5 mL of *PrOH was cooled to -78 °C and charged with NH3 gas for 1mm. This sealed tube was equipped with a teflon O-ring, sealed and heated at 110 °C overnight The mixture was cooled to -78 °C and the cap was removed. Themixture was diluted wiftmefcyiene chloride (30 mL) and the salt was filtered off. The filtrate was concentrated under reduced pressure andthe crude product was purified by silica gel column chromatography (100% ethyl acetate -* EtOActMeOH * 95:5 to 90:10), the title compound as a pale solid, a mixture of two isomers in ca. 3:2 ratio; LC-MS (ES, Pos.): m/z All [MH*]; TH NMR (CDC13,

400 MHz) 5 2.54-2.80 (m,4H), 2.80,3.85 (2xm, 1H, 2:3 ratio), 3.67,3.71 (2xs,2H, 3:2 ratio), 5.06 (br s, 2H), 5.14 (s, 2H), 7.03-7.45 (m, 11H).
[759]
[760] EXAMPLE 67 and 68: as- and trom-Toluene-4-^ulfonic add 3-[8-
amiao-l-(3-benzyioxy-phenyl)-^^
cyclobutyimcthyl ester A solution of 3-[8-amino-l-(3-benz3floxy-plienyI)- inndazo[l,5-a]pyrazinr3-yl]-l-hydroxyme^ (500 mg, 12 tnmol) in
dry mefhytene chloride (10 mL) and pyridine (3 mL) was charged with a solution of TS2O (470 mg, 1.44 mmol) in mefhylene chloride (3 mL) at -40 °C undo: N2 atmosphere. The mixture was slowly wanned to rt overnight TLC showed the reaction was complete. The reaction, was quenched with water (2 znL), diluted with me&ylene chloride (40 mL), washed with sat aq. NaHCC>3 (2 x 15 mL) and brine (15 mL), and dried over anhydrous sodium sulfaie. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (eluting with Hexanes:EtOAc - 50:50 -+ 30:70 -» 100% ethyl acetate, then 5% MeOH/EtOAc) afforded each pure isomer c&-Toloene-4-sulfonic acid 3-[8-amino-1^3-benzyloxy^
cyclobutylmetiiyi ester less polar isomcr, fig^xt yellow solid, LC-MS (ES, Pos.): m/z 571 |MH*]; JH NMR (C3X33,400 MHz) 5 2.46 (s, 3H), 230-2^5 (m, 2H), 2.79-2.84 (m, 2H), 3.41 (m, 1H), 4.10 (s, 2H), 5.06 (br s, 2H)» 5.14 (s, 2H), 7.03-7.11 (m, 3H), 721-723 (m, 2H)t 733-7.45 (m, SH), 7.85 (d, /= 83 Hz, 2H). iran5-Totaflne-4-sulfi>mc acid 3-[8-axmno-1^3-ben2j4oxy^h«iyi)-miida^ hydioxy-cyclobutylmetli^ csten Iigjtf yellow solid, LC-MS (ES, Pos.): m^571 [MH^; ^NMR (CDCb. 400 MHz) 5 2.37 (s, 3H), 2.60-2.70 (m, 4H), 3.85 (m, 1H), 4^4 (s, 2H), 5.08 (br s, 2H), 5.17 (s, 2H), 6^9-7.08 (m, 3H), 720-727 (m, 3H), 733-7.47 (m, 7H), 7.71 (d, J« 83 Hz, 2H).



































































[896] Flow rate O.85ml/min
0-0.3 mins lOO%A
0.3 - 425 mins 100% A to 10% A
4.25-4.40 mins 10% A to 0% A
4.40- 4.90 mins hold at 100%B
4-90-5.00 minsO%Ato 100% A
5.00 - 6.00 mins Hold at 100% A for re-equilibration
[897] Column: Waters Atlantis C18 3u 2.1x30nnn with Phcnamenex Polar
RP 4.0x2.0mm Guard column; UV Detection: 220nm; MS conditions: 80-700 amu scan; Sample cone 30V; Capillary 3 J2kV;
[898] Methods run using the following equipment
Waters 1525 Binary HPLC pump
4 x Jasco PU-1585 pumps
CTC HTS Pal Autosampler with 4 injection valves
Waters 2488 UV detector
Micromass LCT with 5 clhannel MUX inter&ce Data acquired using Masslynx V4,0 Mass-directed Pmificatioii
Micromass Platform LC MasslynxV33
Waters 600 HPLC pump Waters Reagent manager Waters 2700 Autosampler Waters Fraction Collector II








































































Documents:

1290-chenp-2006 form-3 10-08-2011.pdf

1290-CHENP-2006 AMENDED PAGES OF SPECIFICATION 10-08-2011.pdf

1290-CHENP-2006 AMENDED CLAIMS 10-08-2011.pdf

1290-CHENP-2006 CORRESPONDENCE OTHERS 29-11-2011.pdf

1290-CHENP-2006 EXAMINATION REPORT REPLY RECEIVED 10-08-2011.pdf

1290-CHENP-2006 OTHER PATENT DOCUMENT 10-08-2011.pdf

1290-CHENP-2006 CORRESPONDENCE OTHERS 05-10-2011.pdf

1290-CHENP-2006 CORRESPONDENCE OTHERS 25-10-2011.pdf

1290-CHENP-2006 FORM-1 25-10-2011.pdf

1290-CHENP-2006 FORM-13 25-10-2011.pdf

1290-CHENP-2006 FORM-2 25-10-2011.pdf

1290-CHENP-2006 FORM-3 05-10-2011.pdf

1290-CHENP-2006 POWER OF ATTORNEY 25-10-2011.pdf

1290-CHENP-2006 CORRESPONDENCE OTHERS 21-12-2010.pdf

1290-CHENP-2006 CORRESPONDENCE OTHERS 24-10-2011.pdf

1290-CHENP-2006 POWER OF ATTORNEY 24-10-2011.pdf

1290-chenp-2006-abstract.pdf

1290-chenp-2006-claims.pdf

1290-chenp-2006-correspondnece-others.pdf

1290-chenp-2006-description(complete).pdf

1290-chenp-2006-form 1.pdf

1290-chenp-2006-form 3.pdf

1290-chenp-2006-form 5.pdf

1290-chenp-2006-pct.pdf


Patent Number 249666
Indian Patent Application Number 1290/CHENP/2006
PG Journal Number 44/2011
Publication Date 04-Nov-2011
Grant Date 01-Nov-2011
Date of Filing 13-Apr-2006
Name of Patentee OSI PHARMACEUTICALS, INC.
Applicant Address 58 South Service Road, Suite 110, Melville, NY 11747
Inventors:
# Inventor's Name Inventor's Address
1 DONG, Han-Qing 1 Bioscience Park Drive, Farmingdale, NY 11735
2 FOREMAN, Kenneth 1 Bioscience Park Drive, Farmingdale, NY 11735
3 MULVIHILL, Mark, Joseph 1 Bioscience Park Drive, Farmingdale, NY 11735
4 CESARIO, Cara 4 Oak Road, New City, NY 10956
5 COX, Matthew Watlington Road, Oxford, OX4 6LT
6 BECK, Patricia, Anne 20491 Hartford Road, Dixon, MO 65459
7 NIGRO, Anthony, Innocenzo 1 Bioscience Park Drive, Farmingdale, NY 11735
8 SAROGLOU, Lydia Watlington Road, Oxford, OX4 6LT
9 STEINIG, Arno, G. 1 Bioscience Park Drive, Farmingdale, NY 11735
10 SUN, Yingchuan 1 Bioscience Park Drive, Farmingdale, NY 11735
11 WENG, Qinghua 1 Bioscience Park Drive, Farmingdale, NY 11735
12 WERNER, Douglas 1 Bioscience Park Drive, Farmingdale, NY 11735
13 WILKES, Robin Watlington Road, Oxford, OX4 6LT
14 WILLIAMS, Jonathan Watlington Road, Oxford, OX4 6LT
PCT International Classification Number A61K31/4985; C07D487/04
PCT International Application Number PCT/US2004/034219
PCT International Filing date 2004-10-14
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/511,712 2003-10-15 U.S.A.