Protein kinase modulators and method of use

This application claims the benefit of U.S. Provisional Application No. 60/569,193 filed May 7, 2004 and U.S. patent application Ser. No. 11/126,000 filed May 5, 2005 now issued as U.S. Pat. No. 7,880,000, both specifications of which are hereby incorporated by reference herein.

The invention relates to the field of pharmaceutical agents and, more specifically, is directed to compounds, compositions, uses and methods for treating angiogenesis and cancer.

Protein kinases represent a large family of enzymes, which catalyze the phosphorylation of target protein substrates. The phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate. Common points of attachment for the phosphate group to the protein substrate include, for example, a tyrosine, serine or threonine residue. For example, protein tyrosine kinases (PTKs) are enzymes, which catalyze the phosphorylation of specific tyrosine residues in cellular proteins. Examples of kinases in the protein kinase family include, without limitation, ab1, Akt, Aurora-A, Aurora-B, bcr-ab1, Blk, Brk, Btk, c-kit, c-Met, c-src, c-fms, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK, Yes, and Zap70. Due to their activity in numerous cellular processes, protein kinases have emerged as important therapeutic targets.

Protein kinases play a central role in the regulation and maintenance of a wide variety of cellular processes and cellular function. For example, kinase activity acts as molecular switches regulating cell proliferation, activation, and/or differentiation. Uncontrolled or excessive kinase activity has been observed in many disease states including benign and malignant proliferation disorders as well as diseases resulting from inappropriate activation of the immune system (autoimmune disorders), allograff rejection, and graft vs host disease. In addition, endothelial cell specific receptor PTKs, such as VEGF-2, Tie-2 and Lck mediate the angiogenic process and are, therefore, involved in supporting the progression of cancers and other diseases involving uncontrolled vascularization.

Angiogenesis is the process of developing new blood vessels, particularly capillaries, from pre-existing vasculature and is an essential component of embryogenesis, normal physiological growth, repair, and tumor expansion. Angiogenesis remodels small vessels into larger conduit vessels, a physiologically important aspect of vascular growth in adult tissues. Vascular growth is required for beneficial processes such as tissue repair, wound healing, recovery from tissue ischemia and menstrual cycling.

Certain diseases and/or pathological conditions develop as a result of, or are known to be associated with, the regulation and/or deregulation of angiogenesis. For example, ocular neovascularisation such as retinopathies (including diabetic retinopathy), age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, and arteriosclerosis have been found to be caused, in part, due the loss of regulation and/or maintenance of vascular growth. Inflammatory diseases such as a rheumatoid or rheumatic inflammatory disease, and especially arthritis (including rheumatoid arthritis) where new capillary blood vessels invade the joint and destroy cartilage, have been associated with angiogenesis. In addition, chronic inflammatory disorders such as chronic asthma, arterial or post-transplantational atherosclerosis, endometriosis, and neoplastic diseases including so-called solid tumors and liquid tumors (for example, leukemias), have been found to be linked to the regulation and control of angiogenesis.

The involvement of angiogenesis in major diseases has lead to the identification and development of various targets for inhibiting angiogenesis. These targets relate to various receptors, enzymes, and other proteins in the angiogenic process or cascade of events leading to angiogenesis, such as, for example, activation of endothelial cells by an angiogenic signal, synthesis and release of degradative enzymes, endothelial cell migration, proliferation of endothelial cells, and formation of capillary tubules.

One target identified in the cascade of events leading to angiogenesis is the Tie receptor family. The Tie-1 and Tie-2 receptors are single-transmembrane, tyrosine kinase receptors (Tie stands for tyrosine kinase receptors with immunoglobulin and EGF homology domains). Tie-2 is an endothelial cell specific receptor tyrosine kinase, which is involved in angiogenic processes, such as vessel branching, sprouting, remodeling, maturation and stability. Tie-2 is the first mammalian receptor for which both agonist ligand(s) (for example, Angiopoietin-1 (“Ang1”) which binds to and stimulates phosphorylation and signal transduction of Tie-2), and context dependent agonist/antagonist ligand(s) (for example, Angiopoietin-2 (“Ang2”)) have been identified. Knock out and transgenic manipulation of the expression of Tie-2 and its ligands indicates that tight spacial and temporal control of Tie-2 signaling is important for the proper development of new vascularization.

Biological models suggest that the stimulation of Tie-2 by the Ang1 ligand 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 Ang1 stimulation of Tie-2 or the inhibition of Tie-2 autophosphorylation 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 death, especially in the absence of growth/survival stimuli.

Recently, upregulation of Tie-2 expression has been found in the vascular synovial pannus of arthritic joints of humans, consistent with the role in inappropriate neovascularization. This finding suggests 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 would, therefore, be useful in treating such disorders, as well as in other instances of improper neovascularization. However, with the recent recognition of Ang3 and Ang4 as additional Tie-2 binding ligands, targeting a Tie-2 ligand-receptor interaction as an anti-angiogenic therapeutic approach is less favorable. Accordingly, a Tie-2 receptor kinase inhibition approach has become a strategy of choice.

Another angiogenic factor responsible for regulating the growth and differentiation of the vascular system and its components, both during embryonic development and normal growth, as well as in a wide number of pathological anomalies and diseases, is Vascular Endothelial Growth Factor (“VEGF”; originally termed “Vascular Permeability Factor”, VPF), along with its cellular receptors (see G. Breier et al., Trends in Cell Biology, 6:454-456 (1996)).

VEGF is a dimeric, disulfide-linked 46-kDa glycoprotein related to “Platelet-Derived Growth Factor” (PDGF). It is produced by normal cell lines and tumor cell lines; is an endothelial cell-specific mitogen; shows angiogenic activity in in vivo test systems (e.g. rabbit cornea); is chemotactic for endothelial cells and monocytes; and induces plasminogen activators in endothelial cells, which are involved in the proteolytic degradation of extracellular matrix during the formation of capillaries. A number of isoforms of VEGF are known, which show comparable biological activity, but differ in the type of cells that secrete them and in their heparin-binding capacity. In addition, there are other members of the VEGF family, such as “Placenta Growth Factor” (PlGF) and VEGF-C.

VEGF receptors (VEGFR) are also transmembrane receptor tyrosine kinases. They are characterized by an extracellular domain with seven immunoglobulin-like domains and an intracellular tyrosine kinase domain. Various types of VEGF receptor are known, e.g. VEGFR-1 (also known as flt-1), VEGFR-2 (also known as KDR), and VEGFR-3.

A large number of human tumors, especially gliomas and carcinomas, express high levels of VEGF and its receptors. This has led to the belief that the VEGF released by tumor cells stimulates the growth of blood capillaries and the proliferation of tumor endothelium in a paracrine manner, and through the improved blood supply, accelerate tumor growth. Increased VEGF expression could explain the occurrence of cerebral edema in patients with glioma. Direct evidence of the role of VEGF as a tumor angiogenesis factor in vivo has been shown in studies in which VEGF expression or VEGF activity was inhibited. This was achieved with anti-VEGF antibodies, with dominant-negative VEGFR-2 mutants, which inhibited signal transduction, and with antisense-VEGF RNA techniques. All approaches led to a reduction in the growth of glioma cell lines or other tumor cell lines in vivo as a result of inhibited tumor angiogenesis.

VEGF's are unique in that they are the primary angiogenic growth factors known to contribute to vascular hyperpermeability and the formation of edema. Indeed, vascular hyperpermeability and edema that is associated with the expression or administration of many other growth factors appears to be mediated via VEGF production.

Inflammatory cytokines stimulate VEGF production. Hypoxia results in a marked upregulation of VEGF in numerous tissues, hence situations involving infarct, occlusion, ischemia, anemia, or circulatory impairment typically invoke VEGF/VPF-mediated responses. Vascular hyperpermeability, associated edema, altered transendothelial exchange and macromolecular extravasation, which is often accompanied by diapedesis, can result in excessive matrix deposition, aberrant stromal proliferation, fibrosis, etc. Hence, VEGF-mediated hyperpermeability can significantly contribute to disorders with these etiologic features. As such, the regulation of angiogenesis via the VEGF receptor activity has become an important therapeutic target.

Angiogenesis is regarded as an absolute prerequisite for tumors that grow beyond a diameter of about 1-2 mm. Up to this size, oxygen and nutrients may be supplied to the tumor cells by diffusion. Every tumor, regardless of its origin and its cause, is thus dependent on angiogenesis for its growth after it has reached a certain size.

Three principal mechanisms play an important part in the activity of angiogenesis inhibitors against tumors: 1) Inhibition of the growth of vessels, especially capillaries, into vascular resting tumors, with the result that there is no net tumor growth owing to the balance that is achieved between cell death and proliferation; 2) Prevention of the migration of tumor cells owing to the absence of blood flow to and from tumors; and 3) Inhibition of endothelial cell proliferation, thus avoiding the paracrine growth-stimulating effect exerted on the surrounding tissue by the endothelial cells which normally line the vessels. See R. Connell and J. Beebe, Exp. Opin. Ther. Patents, 11:77-114 (2001).

The inhibition of vascular growth in this context has also shown beneficial effects in preclinical animal models. For example, inhibition of angiogenesis by blocking vascular endothelial growth factor or its receptor has resulted in inhibition of tumor growth and in retinopathy. Also, the development of pathological pannus tissue in rheumatoid arthritis involves angiogenesis and might be blocked by inhibitors of angiogenesis.

The ability to stimulate vascular growth has potential utility for treatment of ischemia-induced pathologies such as myocardial infarction, coronary artery disease, peripheral vascular disease, and stroke. The sprouting of new vessels and/or the expansion of small vessels in ischemic tissues prevents ischemic tissue death and induces tissue repair. Regulating angiogenesis by inhibiting certain recognized pathways in this process would therefore, be useful in treating diseases, such as ocular neovascularization, including retinopathy, age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, inflammatory disease rheumatoid arthritis, chronic inflammatory disorders such as chronic asthma, arterial or post-transplantational atherosclerosis, endometriosis, and neoplastic diseases such as leukemias, otherwise known to be associated with deregulated angiogenesis. Treatment of malaria and related viral diseases may also be mediated by HGF and cMet.

Other receptor tyrosine kinases such as FGFR-1, PDGFR, FLK-1 (Fetal Liver Kinase-1) and c-Met have also been suggested to play a role in angiogenesis. C-met is a unique receptor tyrosine kinase, which comprises, in its native form, a 190 kDa heterodimeric (a disulfide-linked 50 kDa α-chain and a 145 kDa β-chain) membrane-spanning tyrosine kinase protein (Proc. Natl. Acad. Sci. USA, 84:6379-6383 (1987)). C-Met is mainly expressed in epithelial cells and stimulation of c-Met leads to scattering, angiogenesis, proliferation and metastasis. (See Cytokine and Growth Factor Reviews, 13:41-59 (2002)). The ligand for c-Met is hepatocyte growth factor (also known as scatter factor, HGF and SF). HGF is a heterodimeric protein secreted by cells of mesodermal origin (Nature, 327:239-242 (1987); J. Cell Biol., 111:2097-2108 (1990)).

Various biological activities have been described for HGF through interaction with c-met (Hepatocyte Growth Factor-Scatter Factor (HGF-SF) and the c-Met Receptor, Goldberg and Rosen, eds., Birkhauser Verlag-Basel, 67-79 (1993). The biological effect of HGF/SF may depend in part on the target cell. HGF induces a spectrum of biological activities in epithelial cells, including mitogenesis, stimulation of cell motility and promotion of matrix invasion (Biochem. Biophys. Res. Comm., 122:1450-1459 (1984); Proc. Natl. Acad. Sci. U.S.A., 88:415-419 (1991)). It stimulates the motility and invasiveness of carcinoma cells, the former having been implicated in the migration of cells required for metastasis. HGF can also act as a “scatter factor”, an activity that promotes the dissociation of epithelial and vascular endothelial cells (Nature, 327:239-242 (1987); J. Cell Biol., 111:2097-2108 (1990); EMBO J., 10:2867-2878 (1991); Proc. Natl. Acad. Sci. USA, 90:649-653 (1993)). Therefore, HGF is thought to be important in tumor invasion (Hepatocyte Growth Factor-Scatter Factor (HGF-SF) and the C-Met Receptor, Goldberg and Rosen, eds., Birkhauser Verlag-Basel, 131-165 (1993)).

HGF and c-Met are expressed at abnormally high levels in a large variety of solid tumors. High levels of HGF and/or c-Met have been observed in liver, breast, pancreas, lung, kidney, bladder, ovary, brain, prostate, gallbladder and myeloma tumors in addition to many others. The role of HGF/c-Met in metastasis has been investigated in mice using cell lines transformed with HGF/c-Met (J. Mol. Med., 74:505-513 (1996)). Over-expression of the c-Met oncogene has also been suggested to play a role in the pathogenesis and progression of thyroid tumors derived from follicular epithelium (Oncogene, 7:2549-2553 (1992)). HGF is a morphogen (Development, 110:1271-1284 (1990); Cell, 66:697-711 (1991)) and a potent angiogenic factor (J. Cell Biol., 119:629-641 (1992)).

Recent work on the relationship between inhibition of angiogenesis and the suppression or reversion of tumor progression shows great promise in the treatment of cancer (Nature, 390:404-407 (1997)), especially the use of multiple angiogenesis inhibitors compared to the effect of a single inhibitor. Angiogenesis can be stimulated by HGF, as well as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF).

Elevated levels of HGF and c-Met have also been observed in non-oncological settings, such as hypertension, myocardial infarction and rheumatoid arthritis. It has been observed that levels of HGF increase in the plasma of patients with hepatic failure (Gohda et al., supra) and in the plasma (Hepatol., 13:734-750 (1991)) or serum (J. Biochem., 109:8-13 (1991)) of animals with experimentally induced liver damage. HGF has also been shown to be a mitogen for certain cell types, including melanocytes, renal tubular cells, keratinocytes, certain endothelial cells and cells of epithelial origin (Biochem. Biophys. Res. Commun., 176:45-51 (1991); Biochem. Biophys. Res. Commun., 174:831-838 (1991); Biochem., 30:9768-9780 (1991); Proc. Natl. Acad. Sci. USA, 88:415-419 (1991)). Both HGF and the c-Met protooncogene have been postulated to play a role in microglial reactions to CNS injuries (Oncogene, 8:219-222 (1993)).

In view of the role of HGF and/or c-Met in potentiating or promoting such diseases or pathological conditions, it would be useful to have a means of substantially reducing or inhibiting one or more of the biological effects of HGF and its receptor. Thus, a compound that reduces the effect of HGF would be a useful compound.

Non-receptor tyrosine kinases represent a collection of cellular enzymes, which lack extracellular activity and transmembrane sequences. Examples of non-receptor tyrosine kinases identified include over twenty-four individual kinases, comprising eleven (11) subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, jak, Ack, and LIMK). Src is thought to be the largest family including Src, TES, FYN, Lyn, Lck, blk, Fgr, and Yrk. The Src subfamily has been linked to oncogenesis and immune responses. See Bohlen, Oncogene, 8:2025-2031 (1993), which disclosure is incorporated herein by reference in its entirety. These kinases have also been found to be involved in cellular signaling pathways in numerous pathogenic conditions, including cancer, psoriasis, and other hyper-proliferative disorders or hyper-immune responses. Thus, it would be useful to inhibit the activity of non-receptor kinases as well.

Many classes of compounds have been proposed to generally or specifically inhibit kinase activity. For example, the Kirin publication WO 03/000660 describes substituted phenyl compounds, U.S. Pat. No. 6,143,764 describes substituted quinolines, WO 02/32872 describes substituted quinolines, and WO 00/47212 describes substituted quinazoline derivatives. However, there is always a need to improve the pharmacokinetic and pharmacodynamic profile of kinase inhibitor compounds for improved physiological efficacy and enhanced treatment of kinase-related pathological conditions and/or disease states. Further, there is a need to treat disease states associated with angiogenesis such as cancer, rheumatoid arthritis, and other conditions where active angiogenesis is undesirable.

The present invention provides a new class of compounds useful in treating pathological conditions and/or disease states related to kinase activity and, in particular, in treating active angiogenesis and related diseases, including cancer and rheumatoid arthritis. In one embodiment of the invention, the compounds, including pharmaceutically acceptable salts thereof, are generally defined by Formula I

wherein A, B, D, E, G, H 1-5 and R 1-4 are defined herein.

In another embodiment, the invention provides compounds of Formulas II and III, which are similar in structure to Formula I above.

The invention also provides processes for making compounds of Formulas I-III, as well as intermediates useful in such processes.

The compounds provided by the invention have kinase modulatory activity and, in particular, inhibitory activity, including, without limitation, Tie-2, Lck, KDR, c-Met and/or Aurora kinase inhibitory activity.

To this end, the invention further provides the use of these compounds, as well as their pharmaceutically acceptable salts, in the preparation and manufacture of a medicament for therapeutic, prophylactic, acute or chronic treatment of an angiogenesis mediated disease state, including those described previously. These compounds are also useful in the manufacture of anti-cancer medicaments. More particularly, these compounds are useful in the manufacture of a medicament to attenuate or prevent disorders through inhibition of Tie-2, Lck, KDR, c-Met and/or Aurora kinase activity. For example, in one embodiment, the invention provides a pharmaceutical composition comprising a therapeutically-effective amount of a compound of Formula I, II or III in association with a least one pharmaceutically-acceptable carrier, adjuvant or diluent.

Further, the invention provides a method of treating angiogenesis related disorders in a subject inflicted with, or susceptible to, such disorder, the method comprising administering to the subject a therapeutically-effective amount of a compound of Formula I, II or III.

In one embodiment of the invention, compounds useful for treating angiogenesis related disorders, including cancer and inflammation, are defined by Formula I:

and pharmaceutically acceptable salts thereof, wherein

A is N or CR 10 ;

B is N or CR 11 ;

D is N or CR 12 ;

E is N or CH;

G is NR 13 , O, S, C(O), S(O), SO 2 , CR 13 R 13 or CR 13 R 14 ;

H 1 is N or CR 5 ;

H 2 is N or CR 6 ;

H 3 is N or CR 7 ;

H 4 is N or CR 8 ;

H 5 is N or CR 9 ;

R 1 is H, halo, haloalkyl, NO 2 , CN, NR 13 R 13 , OR 13 , SR 13 , (CHR 13 ) n R 13 , or R 15 ; alternatively R 1 taken together with R 10 forms a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N and S, and the ring optionally substituted independently with 1-3 substituents of R 13 , halo, haloalkyl, oxo, NO 2 , CN, SR 13 , OR 13 , OC(O)R 13 , COOR 13 , C(O)R 13 , C(O)NR 13 R 13 , NR 13 R 13 , NR 13 R 14 or NR 14 R 14 ;

R 2 is H, halo, haloalkyl, oxo, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 or C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, wherein the C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl is optionally substituted with one or more substituents of R 13 ; alternatively R 2 taken together with R 11 forms a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N and S, and the ring optionally substituted independently with 1-3 substituents of R 13 , halo, haloalkyl, oxo, NO 2 , CN, SR 13 , OR 13 , OC(O)R 13 , COOR 13 , C(O)R 13 , C(O)NR 13 R 13 , NR 13 R 13 , NR 13 R 14 or NR 14 R 14 ;

each of R 3 and R 4 , independently, is H, halo, haloalkyl, oxo, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 ; NR 13 C(O)R 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, wherein the C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl is optionally substituted independently with one or more substituents of R 13 ; alternatively, either of R 3 or R 4 , independently, taken together with R 12 forms a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and the ring optionally substituted independently with 1-3 substituents of R 13 ;

each of R 5 and R 6 , independently, is H, halo, haloalkyl, oxo, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, wherein the C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl is optionally substituted independently with one or more substituents of R 13 ; alternatively R 5 taken together with R 6 forms a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and the ring optionally substituted independently with 1-3 substituents of R 13 ;

each of R 7 and R 8 , independently, is R 13 , halo, haloalkyl, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 16 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)NR 13 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C(S)R 13 , C(S)NR 13 R 13 , C(S)NR 13 R 14 , NR 13 C(S)R 13 , NR 13 C(S)R 14 , NR 13 C(S)NR 13 R 13 , NR 13 C(S)NR 13 R 14 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , S(O) 2 NR 13 R 14 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 or NR 13 S(O) 2 R 14 ;

each of R 9 , R 10 , R 11 and R 12 , independently, is H, R 13 , halo, haloalkyl, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 16 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)NR 13 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C(S)R 13 , C(S)NR 13 R 13 , C(S)NR 13 R 14 , NR 13 C(S)R 13 , NR 13 C(S)R 14 , NR 13 C(S)NR 13 R 13 , NR 13 C(S)NR 13 R 14 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , S(O) 2 NR 13 R 14 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 or NR 13 S(O) 2 R 14 ;

each R 13 , independently, is H, C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl, C 4-8 cycloalkenyl, R 15 or R 16 , each of which is optionally substituted with one or more substituents of R 15 , R 16 or R 17 ;

R 14 is C(O)R 18 , COOR 18 , S(O) 2 R 18 or R 16 ; alternatively R 14 taken together with R 13 forms a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N and S, and the ring optionally substituted independently with 1-3 substituents of oxo, halo, haloalkyl, NO 2 , CN, R 17 or R 18 ;

R 15 is halo, haloalkyl, oxo, NO 2 , CN, SR 18 , OR 18 , OC(O)R 18 , NR 16 R 18 , NR 18 R 18 , COOR 16 , C(O)R 16 , COOR 18 , C(O)R 18 , C(O)NR 16 R 18 , C(O)NR 18 R 18 , S(O) 2 NR 16 R 18 , S(O) 2 NR 18 R 18 , S(O) 2 R 16 , S(O) 2 R 18 , C(O)C(O)R 18 , NR 18 C(O)NR 16 R 18 , NR 18 C(O)NR 18 R 18 , NR 18 C(O)C(O)R 18 , NR 18 C(O)R 16 , NR 18 C(O)R 18 , NR 18 (COOR 16 ), NR 18 (COOR 18 ), NR 18 S(O) 2 NR 16 R 18 , NR 18 S(O) 2 NR 18 R 18 , NR 18 S(O) 2 R 18 , NR 18 S(O) 2 R 16 , NR 18 C(O)C(O)NR 16 R 18 or NR 18 C(O)C(O)NR 18 R 18 ;

R 16 is a saturated or unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, the ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, the heteroatoms selected from O, N, or S, wherein 0, 1, 2 or 3 atoms of each ring is optionally substituted independently with 1-3 substituents of R 17 , R 20 , C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, each of which is optionally substituted with one or more substituents of R 17 , R 18 or R 20 ;

R 17 is halo, haloalkyl, oxo, NO 2 , CN, SR 18 , OR 18 , OC(O)R 18 , NR 18 R 18 , NR 18 R 20 , COOR 18 , C(O)R 18 , COOR 20 , C(O)R 20 , C(O)NR 18 R 18 , C(O)NR 18 R 20 , S(O) 2 NR 18 R 18 , S(O) 2 NR 18 R 20 , S(O) 2 R 18 , S(O) 2 R 20 , C(O)C(O)R 18 , NR 18 C(O)NR 18 R 18 , NR 18 C(O)NR 18 R 20 , NR 18 C(O)C(O)R 18 , NR 18 C(O)R 18 , NR 18 C(O)R 20 , NR 18 (COOR 18 ), NR 18 (COOR 20 ), NR 18 S(O) 2 NR 18 R 18 , NR 18 S(O) 2 NR 18 R 20 , NR 18 S(O) 2 R 18 , NR 18 S(O) 2 R 20 , NR 18 C(O)C(O)NR 18 R 18 or NR 18 C(O)C(O)NR 18 R 20 ;

each R 18 , independently, is H, C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl, C 4-8 cycloalkenyl, R 18 or R 20 , each of which is optionally substituted with 1-3 substituents of R 21 ;

R 19 , independently, is C(O)R 20 , C(O)R 21 , COOR 20 , COOR 21 , S(O) 2 R 20 or S(O) 2 R 21 ;

R 20 is a saturated or unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, the ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, the heteroatoms selected from O, N, or S, wherein 0, 1, 2 or 3 atoms of each ring is optionally substituted independently with 1-3 substituents of R 21 ;

each R 21 , independently, is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO 2 , NH 2 , acetyl, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl, C 1-10 -thioalkoxyl or a saturated or partially or fully unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein each of the C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl, C 1-10 -thioalkoxyl and ring of said ring system is optionally substituted independently with 1-3 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl; and

n is 0, 1, 2, 3, 4 or 5,

provided that (1) when A is N, then B is not N, and when B is N, then A is not N; (2) no more than one of H 1 , H 2 , H 3 , H 4 and H 5 is N; (3) when either of R 1 or R 2 is substituted or unsubstituted NH-phenyl, then no more than four of R 5 , R 6 , R 7 , R 8 and R 9 is H; and (4) when R 1 is Phenyl, then neither of R 6 and R 8 is, independently, NO 2 .

Accordingly, the above embodiment of the present invention does not encompass triazine D-ring compounds, wherein both A and B are N, respectively. Triazine D-ring compounds (Formula III) of the present invention are described in another embodiment hereinbelow. In addition, the above embodiment does not include compounds wherein either of R 1 or R 2 is an amine-linked aniline and all five of R 5 , R 6 , R 7 , R 8 and R 9 are H, respectively. Finally, the above embodiment does not include compounds wherein R 1 is Phenyl, and either of R 6 and R 8 is, independently, NO 2 .

In another embodiment, the compounds of Formula I include N as A and CR 11 as B, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include N as B and CR 10 as A, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include CR 10 as A and CR 11 as B, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include N as D, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include CR 12 as D, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include CH as E, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include CR 12 as D and N as E, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include CR 12 as D, N as E, and H, halo, NO 2 , CN, C 1-10 alkyl or C 1-10 alkoxyl as R 2 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include NR 13 , O, CHR 13 , S, C(O), S(O) or SO 2 as G, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include NR 13 , O, CHR 13 , S, C(O), S(O) or SO 2 and as G and H, halo, NO 2 , CN, C 1-10 alkyl or C 1-10 alkoxyl as R 2 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include NR 13 as G, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include O as G, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include CHR 13 as G, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include S as G, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include C(O) as G, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include S(O) as G, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include SO 2 as G, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H as each of R 3 , R 4 and R 9 , and CH or CR 12 as D, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H as each of R 3 , R 4 and R 9 , CH or CR 12 as D, and H, halo, NO 2 , CN, C 1-10 alkyl or C 1-10 alkoxyl as R 2 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H as each of R 3 , R 4 and R 9 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include CH or CR 12 as D, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include N or CR 5 as H 1 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include N or CR 6 as H 2 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include N or CR 7 as H 3 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include N or CR 8 as H 4 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include N or CR 9 as H 5 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include N or CR 5 as H 1 , N or CR 6 as H 2 , CR 7 as H 3 , N or CR 8 as H 4 , and N or CR 9 as H 5 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include N or CR 5 as H 1 , N or CR 6 as H 2 , N or CR 7 as H 3 , CR 8 as H 4 , and N or CR 9 as H 5 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include CR 5 as H 1 , CR 6 as H 2 , CR 7 as H 3 , CR 8 as H 4 , and CR 9 as H 5 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include CR 5 as H 1 , CR 6 as H 2 , CR 7 as H 3 , CR 8 as H 4 , and CR 9 as H 5 , and each of CR 5 , CR 6 , CR 7 , CR 8 and CR 9 , independently, is not hydrogen (H), in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include R 15 as R 1 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo, haloalkyl, NO 2 , CN, NR 13 R 13 , OR 13 , SR 13 , or (CHR 13 ) n R 13 as R 1 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, NR 13 R 13 , OR 13 , SR 13 or CH 2 R 13 as R 1 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include C 1-10 alkyl, C 1-10 alkoxyl, C 1-10 alkyl-amino-, aryl-amino-, aryl, heteroaryl, heterocyclyl, heteroaryl-amino-, aryl-alkyl-amino-, heterocyclyl-alkyl-amino- and heteroaryl-alkyl-amino- as R 1 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include R 1 taken together with R 10 to form a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N and S, and the ring optionally substituted independently with 1-3 substituents of R 13 , halo, haloalkyl, oxo, NO 2 , CN, SR 13 , OR 13 , OC(O)R 13 , COOR 13 , C(O)R 13 , C(O)NR 13 R 13 , NR 13 R 13 or NR 13 R 14 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo, haloalkyl, oxo, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 or C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, wherein the C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl is optionally substituted with one or more substituents of R 13 , as R 2 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo, haloalkyl, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , C 1-10 alkyl, C 1-10 alkenyl or C 1-10 alkynyl, wherein the C 1-10 alkyl, C 1-10 alkenyl and C 1-10 alkynyl, is optionally substituted with one or more substituents of R 13 , as R 2 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include C 1-10 alkyl, C 1-10 alkoxyl, C 1-10 alkyl-amino-, aryl-amino-, aryl, heteroaryl, heterocyclyl, heteroaryl-amino-, aryl-alkyl-amino-, heterocyclyl-alkyl-amino- and heteroaryl-alkyl-amino- as R 2 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H as R 2 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include R 2 taken together with R 11 to form a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N and S, and the ring optionally substituted independently with 1-3 substituents of R 13 , halo, haloalkyl, oxo, NO 2 , CN, SR 13 , OR 13 , OC(O)R 13 , COOR 13 , C(O)R 13 , C(O)NR 13 R 13 , NR 13 R 13 , NR 13 R 14 or NR 14 R 14 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo, haloalkyl, oxo, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 or C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, wherein the C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl is optionally substituted with one or more substituents of R 13 , as each R 3 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo, haloalkyl, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , C 1-10 alkyl, C 1-10 alkenyl or C 1-10 alkynyl, wherein the C 1-10 alkyl, C 1-10 alkenyl and C 1-10 alkynyl, is optionally substituted with one or more substituents of R 13 , as R 3 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include C 1-10 alkyl, C 1-10 alkoxyl, C 1-10 alkyl-amino-, aryl-amino-, aryl, heteroaryl, heterocyclyl, heteroaryl-amino-, aryl-alkyl-amino-, heterocyclyl-alkyl-amino- and heteroaryl-alkyl-amino- as R 3 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H as R 3 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include R 3 taken together with R 12 to form a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and the ring optionally substituted independently with 1-3 substituents of R 13 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo, haloalkyl, oxo, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 or C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, wherein the C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl is optionally substituted with one or more substituents of R 13 , as each R 4 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo, haloalkyl, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , C 1-10 alkyl, C 1-10 alkenyl or C 1-10 alkynyl, wherein the C 1-10 alkyl, C 1-10 alkenyl and C 1-10 alkynyl, is optionally substituted with one or more substituents of R 13 , as R 4 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include C 1-10 alkyl, C 1-10 alkoxyl, C 1-10 alkyl-amino-, aryl-amino-, aryl, heteroaryl, heterocyclyl, heteroaryl-amino-, aryl-alkyl-amino-, heterocyclyl-alkyl-amino- and heteroaryl-alkyl-amino- as R 4 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula include H as R 4 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include R 4 taken together with R 12 to form a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and the ring optionally substituted independently with 1-3 substituents of R 13 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo, haloalkyl, oxo, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 or C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, wherein the C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl is optionally substituted with one or more substituents of R 13 , as R 5 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, Cl, Br, F, I, CF 3 , CF 2 CF 3 , NO 2 , CN, acetyl, oxo, haloalkyl, haloalkoxyl, CN, OH, SH, NO 2 , NH 2 , acetyl, C 1-10 -alkylamino-, benzyl or phenyl as R 5 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo, haloalkyl, oxo, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 or C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, wherein the C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl is optionally substituted with one or more substituents of R 13 , as R 6 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, Cl, Br, F, I, CF 3 , CF 2 CF 3 , NO 2 , CN, acetyl, oxo, haloalkyl, haloalkoxyl, CN, OH, SH, NO 2 , NH 2 , acetyl, C 1-10 -alkylamino-, benzyl or phenyl as R 6 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include R 5 taken together with R 6 to form a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and the ring optionally substituted independently with 1-3 substituents of R 13 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)NR 13 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C(S)R 13 , C(S)NR 13 R 13 , C(S)NR 13 R 14 , NR 13 C(S)R 13 , NR 13 C(S)R 14 , NR 13 C(S)NR 13 R 13 NR 13 C(S)NR 13 R 14 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , S(O) 2 NR 13 R 14 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , C 1-10 alkyl optionally substituted with one or more substituents of R 15 or R 16 , or C 1-10 alkenyl optionally substituted with one or more substituents of R 15 or R 16 , as R 7 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include SR 13 , OR 13 , NR 13 R 13 , C(O)R 13 , COOR 13 , C(O)NR 13 R 13 , NR 13 C(O)R 13 , NR 13 (COOR 13 ), NR 13 C(O)NR 13 R 13 , C(S)R 13 , C(S)NR 13 R 13 , NR 13 C(S)R 13 , NR 13 C(S)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 or C 1-10 alkyl substituted with SR 13 , OR 13 , NR 13 R 13 , C(O)R 13 , COOR 13 , C(O)NR 13 R 13 , NR 13 C(O)R 13 , NR 13 (COOR 13 ), NR 13 C(O)NR 13 R 13 , C(S)R 13 , C(S)NR 13 R 13 , NR 13 C(S)R 13 , NR 13 C(S)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 as R 7 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo, haloalkyl, haloalkoxyl, CN, OH, NO 2 , NH 2 , SH, acetyl, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl or C 1-10 -thioalkoxyl as R 7 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo, haloalkyl, C 1-10 -alkyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino- or C 1-10 -alkoxyl as R 7 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)NR 13 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C(S)R 13 , C(S)NR 13 R 13 , C(S)NR 13 R 14 , NR 13 C(S)R 13 , NR 13 C(S)R 14 , NR 13 C(S)NR 13 R 13 , NR 13 C(S)NR 13 R 14 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , S(O) 2 NR 13 R 14 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , C 1-10 alkyl optionally substituted with one or more substituents of R 15 or R 16 , or C 1-10 alkenyl optionally substituted with one or more substituents of R 15 or R 16 , as R 8 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include SR 13 , OR 13 , NR 13 R 13 , C(O)R 13 , COOR 13 , C(O)NR 13 R 13 , NR 13 C(O)R 13 , NR 13 (COOR 13 ), NR 13 C(O)NR 13 R 13 , C(S)R 13 , C(S)NR 13 R 13 , NR 13 C(S)R 13 , NR 13 C(S)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 or C 1-10 alkyl substituted with SR 13 , OR 13 , NR 13 R 13 , C(O)R 13 , COOR 13 , C(O)NR 13 R 13 , NR 13 C(O)R 13 , NR 13 (COOR 13 ), NR 13 C(O)NR 13 R 13 , C(S)R 13 , C(S)NR 13 R 13 , NR 13 C(S)R 13 , NR 13 C(S)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 as R 8 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo, haloalkyl, haloalkoxyl, CN, OH, NO 2 , NH 2 , SH, acetyl, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 dialkylamino-, C 1-10 -alkoxyl or C 1-10 -thioalkoxyl as R 8 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo, haloalkyl, C 1-10 -alkyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino- or C 1-10 -alkoxyl as R 8 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, R 13 , halo, haloalkyl, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 16 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)NR 13 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C(S)R 13 , C(S)NR 13 R 13 , C(S)NR 13 R 14 , NR 13 C(S)R 13 , NR 13 C(S)R 14 , NR 13 C(S)NR 13 R 13 , NR 13 C(S)NR 13 R 14 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , S(O) 2 NR 13 R 14 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 or NR 13 S(O) 2 R 14 as R 9 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula include H, R 13 , halo, haloalkyl, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 or C(O)R 13 as R 9 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H as R 9 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, R 13 , halo, haloalkyl, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 16 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)NR 13 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C(S)R 13 , C(S)NR 13 R 13 , C(S)NR 13 R 14 , NR 13 C(S)R 13 , NR 13 C(S)R 14 , NR 13 C(S)NR 13 R 13 , NR 13 C(S)NR 13 R 14 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , S(O) 2 NR 13 R 14 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 or NR 13 S(O) 2 R 14 as R 10 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H as R 10 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, R 13 , halo, haloalkyl, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 16 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)NR 13 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C(S)R 13 , C(S)NR 13 R 13 , C(S)NR 13 R 14 , NR 13 C(S)R 13 , NR 13 C(S)R 14 , NR 13 C(S)NR 13 R 13 , NR 13 C(S)NR 13 R 14 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , S(O) 2 NR 13 R 14 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 or NR 13 S(O) 2 R 14 as R 11 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H as R 11 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, R 13 , halo, haloalkyl, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 16 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)NR 13 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C(S)R 13 , C(S)NR 13 R 13 , C(S)NR 13 R 13 , NR 13 C(S)R 13 , NR 13 C(S)R 14 , NR 13 C(S)NR 13 R 13 , NR 13 C(S)NR 13 R 14 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , S(O) 2 NR 13 R 14 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 or NR 13 S(O) 2 R 14 as R 12 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo, haloalkyl, NO 2 , CN, acetyl, C 1-10 -alkyl, SR 13 , OR 13 , NR 13 R 13 , C(O)R 13 , COOR 13 , C(O)NR 13 R 13 , NR 13 C(O)R 13 , NR 13 C(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , S(O) 2 NR 13 R 14 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 or R 16 optionally substituted with 1-3 substituents of R 17 , R 18 or R 20 as R 12 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo, haloalkyl, oxo, NO 2 , CN, or C 1-10 alkyl, C 1-10 alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyrrolyl, pyranyl, phenyl, naphthyl, benzyl, furanyl, pyrrolyl, thiophenyl, indolyl, imidazolyl, pyrazolyl, oxazolyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl, benzothiozolyl, piperidinyl, piperazinyl, morpholinyl, each of which is optionally independently substituted with 1-3 substituents of R 13 , as R 12 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, R 13 , halo, haloalkyl, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 or C(O)R 13 as R 12 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl, C 4-8 cycloalkenyl, R 15 or R 16 , each of which is optionally substituted with one or more substituents of R 15 , R 16 or R 18 , as R 13 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, phenyl, pyridyl, pyrimidinyl, triazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl, 2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl, benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, 2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl, cycloheptyl, pyranyl, naphthyl or benzyl, each of which is optionally independently substituted with 1-3 substituents of R 15 , R 16 or R 18 , as R 13 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, C(O)R 18 , COOR 18 , S(O) 2 R 18 or R 16 , as R 14 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include R 14 taken together with R 13 to form a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N and S, and the ring optionally substituted independently with 1-3 substituents of oxo, halo, haloalkyl, NO 2 , CN, R 17 or R 18 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo, haloalkyl, oxo, NO 2 , CN, SR 18 , OR 18 , OC(O)R 18 , NR 16 R 18 , NR 18 R 18 , COOR 18 , C(O)R 16 , COOR 18 , C(O)R 18 , C(O)NR 16 R 18 , C(O)NR 18 R 18 , S(O) 2 NR 16 R 18 , S(O) 2 NR 18 R 18 , S(O) 2 R 16 , S(O) 2 R 18 , C(O)C(O)R 18 , NR 18 C(O)NR 16 R 18 , NR 18 C(O)NR 18 R 18 , NR 18 C(O)C(O)R 18 , NR 18 C(O)R 16 , NR 18 C(O)R 18 , NR 18 (COOR 16 ), NR 18 (COOR 18 ), NR 18 S(O) 2 NR 16 R 18 , NR 18 S(O) 2 NR 18 R 18 , NR 18 S(O) 2 R 18 , NR 18 S(O) 2 R 16 , NR 18 C(O)C(O)NR 16 R 18 or NR 18 C(O)C(O)NR 18 R 18 as R 15 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include a saturated or unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, the ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, the heteroatoms selected from O, N, or S, wherein 0, 1, 2 or 3 atoms of each ring is optionally substituted independently with 1-3 substituents of R 17 , R 20 , C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, each of which is optionally substituted with one or more substituents of R 17 , R 18 or R 20 , as R 16 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include phenyl, pyridyl, pyrimidinyl, triazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl, 2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl, benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, 2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl, cycloheptyl, pyranyl or naphthyl, each of which is optionally substituted independently with 1-3 substituents of R 17 , R 18 or R 20 , as R 16 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include halo, haloalkyl, oxo, NO 2 , CN, SR 18 , OR 18 , OC(O)R 18 , NR 18 R 18 , NR 18 R 20 , COOR 18 , C(O)R 18 , COOR 20 , C(O)R 20 , C(O)NR 18 R 18 , C(O)NR 18 R 20 , S(O) 2 NR 18 R 18 , S(O) 2 NR 18 R 20 , S(O) 2 R 18 , S(O) 2 R 20 , C(O)C(O)R 18 , NR 18 C(O)NR 18 R 18 , NR 18 C(O)NR 18 R 20 , NR 18 C(O)C(O)R 18 , NR 18 C(O)R 18 , NR 18 C(O)R 20 , NR 18 (COOR 18 ), NR 18 (COOR 20 ), NR 18 S(O) 2 NR 18 R 18 , NR 18 S(O) 2 NR 18 R 20 , NR 18 S(O) 2 R 18 , NR 18 S(O) 2 R 20 , NR 18 C(O)C(O)NR 18 R 18 or NR 18 C(O)C(O)NR 18 R 20 as R 17 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl, C 4-8 cycloalkenyl, R 19 or R 20 , each of which is optionally substituted with 1-3 substituents of R 21 , as R 18 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, hexyl, acetyl or C 1-10 -alkoxyl, each of which is optionally independently substituted with 1-3 substituents of R 21 , as R 18 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include C(O)R 20 , C(O)R 21 , COOR 20 , COOR 21 , S(O) 2 R 20 or S(O) 2 R 21 as R 19 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include a saturated or unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, the ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, the heteroatoms selected from O, N, or S, wherein 0, 1, 2 or 3 atoms of each ring is optionally substituted independently with 1-3 substituents of R 21 as R 20 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include phenyl, pyridyl, pyrimidinyl, triazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl, 2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl, benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, 2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl, cycloheptyl, pyranyl or naphthyl, each of which is optionally substituted independently with 1-3 substituents of R 21 , as R 20 , in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I include H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO 2 , NH 2 , acetyl, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl, C 1-10 -thioalkoxyl or a saturated or partially or fully unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein each of the C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl, C 1-10 -thioalkoxyl and ring of said ring system is optionally substituted independently with 1-3 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl as each R 21 , in conjunction with any of the above or below embodiments.

In yet another embodiment of the invention, compounds useful for treating angiogenesis and cancer are generally defined of Formula II:

and pharmaceutically acceptable salts thereof, wherein

A is N or CR 10 ;

B is N or CR 11 ;

D is N or CR 12 ;

G is NR 13 , O, S, C(O), S(O), SO 2 , CR 13 R 13 or CR 13 R 14 ;

R 1 is H, halo, haloalkyl, NO 2 , CN, NR 13 R 13 , OR 13 , SR 13 , (CHR 13 ) n R 13 or R 15 ; alternatively R 1 taken together with R 10 forms a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N and S, and the ring optionally substituted independently with 1-3 substituents of R 13 , halo, haloalkyl, oxo, NO 2 , CN, SR 13 , OR 13 , OC(O)R 13 , COOR 13 , C(O)R 13 , C(O)NR 13 R 13 , NR 13 R 13 or NR 13 R 14 ;

R 2 is H, halo, haloalkyl, oxo, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, wherein the C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl is optionally substituted with one or more substituents of R 13 ; alternatively R 2 taken together with R 11 forms a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N and S, and the ring optionally substituted independently with 1-3 substituents of R 13 , halo, haloalkyl, oxo, NO 2 , CN, SR 13 , OR 13 , OC(O)R 13 , COOR 13 , C(O)R 13 , C(O)NR 13 R 13 , NR 13 R 13 , NR 13 R 14 or NR 14 R 14 ;

each of R 3 and R 4 , independently, is H, halo, haloalkyl, oxo, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , NR 13 C(O)C(O)NR 13 R 13 or NR 13 C(O)C(O)NR 13 R 14 , C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, wherein the C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl is optionally substituted with one or more substituents of R 13 ; alternatively, either of R 3 or R 4 , independently, taken together with R 12 forms a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and the ring optionally substituted independently with 1-3 substituents of R 13 ;

each of R 5 and R 6 , independently, is H, halo, haloalkyl, oxo, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, wherein the C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl is optionally substituted independently with one or more substituents of R 13 ; alternatively R 5 taken together with R 6 forms a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and the ring optionally substituted independently with 1-3 substituents of R 13 ;

one of R 7 and R 8 is SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)NR 13 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C(S)R 13 , C(S)NR 13 R 13 , C(S)NR 13 R 14 , NR 13 C(S)R 13 , NR 13 C(S)R 14 , NR 13 C(S)NR 13 R 13 , NR 13 C(S)NR 13 R 14 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , S(O) 2 NR 13 R 14 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , C 1-10 alkyl optionally substituted with one or more substituents of R 15 or R 16 , or C 1-10 alkenyl optionally substituted with one or more substituents of R 15 or R 16 ; and

the other of R 7 and R 8 is H, halo, haloalkyl, haloalkoxyl, CN, OH, NO 2 , NH 2 , SH, acetyl, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl or C 1-10 -thioalkoxyl;

each of R 9 , R 10 , R 11 and R 12 , independently, is H, R 13 , halo, haloalkyl, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O) NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 16 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)NR 13 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C(S)R 13 , C(S)NR 13 R 13 , C(S)NR 13 R 14 , NR 13 C(S)R 13 , NR 13 C(S)R 14 , NR 13 C(S)NR 13 R 13 , NR 13 C(S)NR 13 R 14 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , S(O) 2 NR 13 R 14 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 or NR 13 S(O) 2 R 14 ;

each R 13 , independently, is H, C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl, C 4-8 cycloalkenyl, R 15 or R 16 , each of which is optionally substituted with one or more substituents of R 15 , R 16 or R 18 ;

R 14 is C(O)R 18 , COOR 18 , S(O) 2 R 18 or R 16 ;

R 15 is halo, haloalkyl, NO 2 , CN, SR 18 , OR 18 , OC(O)R 18 , NR 16 R 18 , NR 18 R 18 , COOR 16 , C(O)R 16 , COOR 18 , C(O)R 18 , C(O)NR 16 R 18 , C(O)NR 18 R 18 , S(O) 2 NR 16 R 18 , S(O) 2 NR 18 R 18 , S(O) 2 R 16 , S(O) 2 R 18 , C(O)C(O)R 18 , NR 18 C(O)NR 16 R 18 , NR 18 C(O)NR 18 R 18 , NR 18 C(O)C(O)R 18 , NR 18 C(O)R 16 , NR 18 C(O)R 18 , NR 18 (COOR 16 ), NR 18 (COOR 18 ), NR 18 S(O) 2 NR 16 R 18 , NR 18 S(O) 2 NR 18 R 18 , NR 18 S(O) 2 R 18 , NR 18 S(O) 2 R 16 , NR 18 C(O)C(O)NR 16 R 18 or NR 18 C(O)C(O)NR 18 R 18 ;

R 16 is a saturated or unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, the ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, the heteroatoms selected from O, N, or S, wherein 0, 1, 2 or 3 atoms of each ring is optionally substituted independently with 1-3 substituents of R 17 , R 20 , C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, each of which is optionally substituted with one or more substituents of R 17 , R 18 or R 20 ;

R 17 is halo, haloalkyl, oxo, NO 2 , CN, SR 18 , OR 18 , OC(O)R 18 , NR 18 R 18 , NR 18 R 20 , COOR 18 , C(O)R 18 , COOR 20 , C(O)R 20 , C(O)NR 18 R 18 , C(O)NR 18 R 20 , S(O) 2 NR 18 R 18 , S(O) 2 NR 18 R 20 , S(O) 2 R 18 , S(O) 2 R 20 , C(O)C(O)R 18 , NR 18 C(O)NR 18 R 18 , NR 18 C(O)NR 18 R 20 , NR 18 C(O)C(O)R 18 , NR 18 C(O)R 18 , NR 18 C(O)R 20 , NR 18 (COOR 18 ), NR 18 (COOR 20 ), NR 18 S(O) 2 NR 18 R 18 , NR 18 S(O) 2 NR 18 R 20 , NR 18 S(O) 2 R 18 , NR 18 S(O) 2 R 20 , NR 18 C(O)C(O)NR 18 R 18 or NR 18 C(O)C(O)NR 18 R 20 ;

each R 18 , independently, is H, C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl, C 4-8 cycloalkenyl, R 19 or R 20 , each of which is optionally substituted with 1-3 substituents of R 21 ;

R 19 , independently, is C(O)R 20 , C(O)R 21 , COOR 20 , COOR 21 , S(O) 2 R 20 or S(O) 2 R 21 ;

R 20 is a saturated or unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, the ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, the heteroatoms selected from O, N, or S, wherein 0, 1, 2 or 3 atoms of each ring is optionally substituted independently with 1-3 substituents of C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, each of which is optionally substituted with one or more substituents of R 21 ;

each R 21 , independently, is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO 2 , NH 2 , acetyl, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl, C 1-10 -thioalkoxyl or a saturated or partially or fully unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein each of the C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl, C 1-10 -thioalkoxyl and ring of said ring system is optionally substituted independently with 1-3 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl; and

n is 0, 1, 2, 3, 4 or 5,

provided that (1) when A is N, then B is not N, and when B is N, then A is not N; (2) when either of R 1 or R 2 is substituted or unsubstituted NH-phenyl, then no more than four of R 5 , R 6 , R 7 , R 8 and R 9 is H; and (3) when R 1 is phenyl, then neither of R 6 and R 8 is, independently, NO 2 .

In another embodiment, the invention includes compounds of Formula II, wherein:

A is N;

B is CR 11 ;

D is CR 12 ;

G is NR 13 , O or S;

R 1 is H, NR 13 R 13 , OR 13 , SR 13 or CH 2 R 13 ;

R 2 is H, halo, NO 2 , CN; C 1-10 alkyl or C 1-10 alkoxyl;

each of R 3 and R 4 , independently, is H, halo, haloalkyl, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, wherein the C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl is optionally substituted independently with one or more substituents of R 13 ; alternatively, either of R 3 or R 4 , independently, taken together with R 12 forms a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and the ring optionally substituted independently with 1-3 substituents of R 13 ;

each of R 5 and R 6 , independently, is H, halo, haloalkyl, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, wherein the C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl is optionally substituted independently with one or more substituents of R 13 ; alternatively R 5 taken together with R 6 forms a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and the ring optionally substituted independently with 1-3 substituents of R 13 ;

one of R 7 and R 8 is SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)NR 13 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C(S)R 13 , C(S)NR 13 R 13 , C(S)NR 13 R 14 , NR 13 C(S)R 13 , NR 13 C(S)R 14 , NR 13 C(S)NR 13 R 13 , NR 13 C(S)NR 13 R 14 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , S(O) 2 NR 13 R 14 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 or C 1-10 alkyl optionally substituted with one or more substituents of R 15 or R 16 ;

the other of R 7 and R 8 is H, halo, haloalkyl, haloalkoxyl, CN, OH, NO 2 , NH 2 , acetyl, C 1-10 -alkyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl or C 1-10 -thioalkoxyl;

R 9 is H;

R 11 is H;

R 12 is H, halo, haloalkyl, NO 2 , CN, acetyl, C 1-10 -alkyl, SR 13 , OR 13 , NR 13 R 13 , C(O)R 13 , COOR 13 , C(O)NR 13 R 13 , NR 13 C(O)R 13 , NR 13 C(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , S(O) 2 NR 13 R 14 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 or R 16 optionally substituted with 1-3 substituents of R 17 , R 18 or R 20 ;

each R 13 , independently, is H, C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl, C 4-8 cycloalkenyl, R 15 or R 16 , each of which is optionally substituted with one or more substituents of R 15 , R 16 or R 18 ;

R 14 is C(O)R 18 , COOR 18 , S(O) 2 R 18 or R 16 ;

R 15 is halo, haloalkyl, oxo, NO 2 , CN, SR 18 , OR 18 , OC(O)R 18 , NR 16 R 18 , NR 18 R 18 , COOR 16 , C(O)R 16 , COOR 18 , C(O)R 18 , C(O)NR 16 R 18 , C(O)NR 18 R 18 , S(O) 2 NR 16 R 18 , S(O) 2 NR 18 R 18 , S(O) 2 R 16 , S(O) 2 R 18 , C(O)C(O)R 18 , NR 18 C(O)NR 16 R 18 , NR 18 C(O)NR 18 R 18 , NR 18 C(O)C(O)R 18 , NR 18 C(O)R 16 , NR 18 C(O)R 18 , NR 18 (COOR 16 ), NR 18 (COOR 18 ), NR 18 S(O) 2 NR 16 R 18 , NR 18 S(O) 2 NR 18 R 18 , NR 18 S(O) 2 R 18 , NR 18 S(O) 2 R 16 , NR 18 C(O)C(O)NR 16 R 18 or NR 18 C(O)C(O)NR 18 R 18 ;

R 16 is a saturated or unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, the ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, the heteroatoms selected from O, N, or S, wherein 0, 1, 2 or 3 atoms of each ring is optionally substituted independently with 1-3 substituents of R 17 , R 20 , C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, each of which is optionally substituted with one or more substituents of R 17 , R 18 or R 20 ;

R 17 is halo, haloalkyl, NO 2 , CN, SR 18 , OR 18 , OC(O)R 18 , NR 18 R 18 , NR 18 R 20 , COOR 18 , C(O)R 18 , COOR 20 , C(O)R 20 , C(O)NR 18 R 18 , C(O)NR 18 R 20 , S(O) 2 NR 18 R 18 , S(O) 2 NR 18 R 20 , S(O) 2 R 18 , S(O) 2 R 20 , C(O)C(O)R 18 , NR 18 C(O)NR 18 R 18 , NR 18 C(O)NR 18 R 20 , NR 18 C(O)C(O)R 18 , NR 18 C(O)R 18 , NR 18 C(O)R 20 , NR 18 (COOR 18 ), NR 18 (COOR 20 ), NR 18 S(O) 2 NR 18 R 18 , NR 18 S(O) 2 NR 18 R 20 , NR 18 S(O) 2 R 18 , NR 18 S(O) 2 R 20 , NR 18 C(O)C(O)NR 18 R 18 or NR 18 C(O)C(O)NR 18 R 20 ;

each R 18 , independently, is H, C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl, C 4-8 cycloalkenyl, R 19 or R 20 , each of which is optionally substituted with 1-3 substituents of R 21 ;

R 19 , independently, is C(O)R 20 , C(O)R 21 , COOR 20 , COOR 21 , S(O) 2 R 20 or S(O) 2 R 21 ;

R 20 is a saturated or unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, the ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, the heteroatoms selected from O, N, or S, wherein 0, 1, 2 or 3 atoms of each ring is optionally substituted independently with 1-3 substituents of C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, each of which is optionally substituted with one or more substituents of R 21 ;

each R 21 , independently, is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO 2 , NH 2 , acetyl, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl, C 1-10 -thioalkoxyl or a saturated or partially or fully unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein each of the C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl, C 1-10 -thioalkoxyl and ring of said ring system is optionally substituted independently with 1-3 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl; and

n is 0, 1, 2 or 3.

In another embodiment, the invention includes compounds of Formula II, wherein:

A is CR 10 ;

B is N;

D is CR 12 ;

G is NR 13 , O or S;

R 1 is H, NR 13 R 13 , OR 13 , SR 13 or CH 2 R 13 ; alternatively R 1 taken together with R 10 forms a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N and S, and the ring optionally substituted independently with 1-3 substituents of R 13 , halo, haloalkyl, oxo, NO 2 , CN, SR 13 , OR 13 , OC(O)R 13 , COOR 13 , C(O)R 13 , C(O)NR 13 R 13 , NR 13 R 13 or NR 33 R 14 ;

R 2 is H, halo, NO 2 , CN, C 1-10 alkyl or C 1-10 alkoxyl;

each of R 3 and R 4 , independently, is H, halo, haloalkyl, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, wherein the C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl is optionally substituted independently with one or more substituents of R 13 ; alternatively, either of R 3 or R 4 , independently, taken together with R 12 forms a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and the ring optionally substituted independently with 1-3 substituents of R 13 ;

each of R 5 and R 6 , independently, is H, halo, haloalkyl, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, wherein the C 1-10 alkyl, C 1-10 alkenyl C 1-10 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl is optionally substituted independently with one or more substituents of R 13 ; alternatively R 5 taken together with R 6 forms a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and the ring optionally substituted independently with 1-3 substituents of R 13 ;

one of R 7 and R 8 is SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)NR 13 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C(S)R 13 , C(S)NR 13 R 13 , C(S)NR 13 R 14 , NR 13 C(S)R 13 , NR 13 C(S)R 14 , NR 13 C(S)NR 13 R 13 , NR 13 C(S)NR 13 R 14 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , S(O) 2 NR 13 R 14 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 or C 1-10 alkyl optionally substituted with one or more substituents of R 15 or R 16 ;

the other of R 7 and R 8 is H, halo, haloalkyl, haloalkoxyl, CN, OH, NO 2 , NH 2 , acetyl, C 1-10 -alkyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl or C 1-10 -thioalkoxyl;

R 9 is H;

R 10 is H;

R 12 is H, halo, haloalkyl, NO 2 , CN, acetyl, C 1-10 -alkyl, SR 13 , OR 13 , NR 13 R 13 , C(O)R 13 , COOR 13 , C(O)NR 13 R 13 , NR 13 C(O)R 13 , NR 13 C(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , S(O) 2 NR 13 R 14 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 or R 16 optionally substituted with 1-3 substituents of R 17 , R 18 or R 20 ;

each R 13 , independently, is H, C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl, C 4-8 cycloalkenyl, R 15 or R 16 , each of which is optionally substituted with one or more substituents of R 15 , R 16 or R 18 ;

R 14 is C(O)R 18 , COOR 18 , S(O) 2 R 18 or R 16 ;

R 15 is halo, haloalkyl, oxo, NO 2 , CN, SR 18 , OR 18 , OC(O)R 18 , NR 16 R 18 , NR 18 R 18 , COOR 16 , C(O)R 16 , COOR 18 , C(O)R 18 , C(O)NR 16 R 18 , C(O)NR 18 R 18 , S(O) 2 NR 16 R 18 , S(O) 2 NR 18 R 18 , S(O) 2 R 16 , S(O) 2 R 18 , C(O)C(O)R 18 , NR 18 C(O)NR 16 R 18 , NR 18 C(O)NR 18 R 18 , NR 18 C(O)C(O)R 18 , NR 18 C(O)R 16 , NR 18 C(O)R 18 , NR 18 (COOR 16 ), NR 18 (COOR 18 ), NR 18 S(O) 2 NR 16 R 18 , NR 18 S(O) 2 R 18 R 18 , NR 18 S(O) 2 R 18 , NR 18 S(O) 2 R 16 , NR 18 C(O)C(O)NR 16 R 18 or NR 18 C(O)C(O)NR 18 R 18 ;

R 16 is a saturated or unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, the ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, the heteroatoms selected from O, N, or S, wherein 0, 1, 2 or 3 atoms of each ring is optionally substituted independently with 1-3 substituents of R 17 , R 20 , C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, each of which is optionally substituted with one or more substituents of R 17 , R 18 or R 20 ;

R 17 is halo, haloalkyl, oxo, NO 2 , CN, SR 18 , OR 18 , OC(O)R 18 , NR 18 R 18 , NR 18 R 20 , COOR 18 , C(O)R 18 , COOR 20 , C(O)R 20 , C(O)NR 18 R 18 , C(O)NR 18 R 20 , S(O) 2 NR 18 R 18 , S(O) 2 NR 18 R 20 , S(O) 2 R 18 , S(O) 2 R 20 , C(O)C(O)R 18 , NR 18 C(O)NR 18 R 18 , NR 18 C(O)NR 18 R 20 , NR 18 C(O)C(O)R 18 , NR 18 C(O)R 18 , NR 18 C(O)R 20 , NR 18 (COOR 18 ), NR 18 (COOR 20 ), NR 18 S(O) 2 NR 18 R 18 , NR 18 S(O) 2 NR 18 R 20 , NR 18 S(O) 2 R 18 , NR 18 S(O) 2 R 20 , NR 18 C(O)C(O)NR 18 R 18 or NR 18 C(O)C(O)NR 18 R 20 ;

each R 18 , independently, is H, C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl, C 4-8 cycloalkenyl, R 19 or R 20 , each of which is optionally substituted with 1-3 substituents of R 21 ;

R 19 , independently, is C(O)R 20 , C(O)R 21 , COOR 20 , COOR 21 , S(O) 2 R 20 or S(O) 2 R 21 ;

R 20 is a saturated or unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, the ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, the heteroatoms selected from O, N, or S, wherein 0, 1, 2 or 3 atoms of each ring is optionally substituted independently with 1-3 substituents of C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, each of which is optionally substituted with one or more substituents of R 21 ;

each R 21 , independently, is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO 2 , NH 2 , acetyl, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl, C 1-10 -thioalkoxyl or a saturated or partially or fully unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein each of the C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl, C 1-10 -thioalkoxyl and ring of said ring system is optionally substituted independently with 1-3 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl; and

n is 0, 1, 2 or 3.

In another embodiment, the invention includes compounds of Formula II, wherein:

R 7 is SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)NR 13 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C(S)R 13 , C(S)NR 13 R 13 , C(S)NR 13 R 14 , NR 13 C(S)R 13 , NR 13 C(S)R 14 , NR 13 C(S)NR 13 R 13 , NR 13 C(S)NR 13 R 14 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , S(O) 2 NR 13 R 14 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , C 1-10 alkyl optionally substituted with one or more substituents of R 15 or R 16 , or C 1-10 alkenyl optionally substituted with one or more substituents of R 15 or R 16 ; and

R 8 is H, halo, haloalkyl, haloalkoxyl, CN, OH, NO 2 , NH 2 , SH, acetyl, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl or C 1-10 -thioalkoxyl.

In another embodiment, the invention includes compounds of Formula II, wherein:

R 7 is. H, halo, haloalkyl, haloalkoxyl, CN, OH, NO 2 , NH 2 , SH, acetyl, C 1-10 alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl or C 1-10 -thioalkoxyl; and

R 8 is SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 16 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)NR 13 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C(S)R 13 , C(S)NR 13 R 13 , C(S)NR 13 R 14 , NR 13 C(S)R 13 , NR 13 C(S)R 14 , NR 13 C(S)NR 13 R 13 , NR 13 C(S)NR 13 R 14 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , S(O) 2 NR 13 R 14 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , C 1-10 alkyl optionally substituted with one or more substituents of R 15 or R 16 , or C 1-10 alkenyl optionally substituted with one or more substituents of R 15 or R 16 .

In another embodiment, the invention includes compounds of Formula II, wherein:

A is N;

B is CR 11 ;

D is N or CR 12 ;

G is NR 13 , O or S;

R 1 is H, NR 13 R 13 , OR 13 , SR 13 or CH 2 R 13 ;

R 2 is H;

each of R 3 and R 4 , independently, is H, halo, haloalkyl, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, wherein the C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl is optionally substituted independently with one or more substituents of R 13 ;

each of R 5 and R 6 , independently, is H, halo, haloalkyl, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, wherein the C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl is optionally substituted independently with one or more substituents of R 13 ; alternatively R 5 taken together with R 6 forms a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and the ring optionally substituted independently with 1-3 substituents of R 13 ;

one of R 7 and R 8 is NR 13 R 13 , C(O)R 13 , COOR 13 , C(O)NR 13 R 13 , NR 13 C(O)R 13 , NR 13 (COOR 13 ), NR 13 C(O)NR 13 R 13 , C(S)NR 13 R 13 , NR 13 C(S)R 13 , NR 13 C(S)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 or C 1-10 alkyl optionally substituted with one or more substituents of NR 18 R 18 , C(O)R 18 , COOR 18 , C(O)NR 18 R 18 , NR 13 C(O)R 18 , NR 18 (COOR 18 ), NR 18 C(O)NR 18 R 18 , C(S)NR 18 R 18 , NR 18 C(S)R 18 , NR 18 C(S)NR 18 R 18 , S(O) 2 R 18 , S(O) 2 NR 18 R 18 , NR 18 S(O) 2 NR 18 R 18 , NR 18 S(O) 2 R 18 ;

the other of R 7 and R 8 is H, halo, haloalkyl, haloalkoxyl, CN, OH, NO 2 , NH 2 , acetyl, C 1-10 -alkyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl or C 1-10 -thioalkoxyl;

R 9 is H;

R 11 is H;

R 12 is H, halo, haloalkyl, oxo, NO 2 , CN, or C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyrrolyl, pyranyl, phenyl, naphthyl, benzyl, furanyl, pyrrolyl, thiophenyl, indolyl, imidazolyl, pyrazolyl, oxazolyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl, benzothiozolyl, piperidinyl, piperazinyl, morpholinyl, each of which is optionally independently substituted with 1-3 substituents of R 13 ;

each R 13 , independently, is H, C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, phenyl, pyridyl, pyrimidinyl, triazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl, 2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl, benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, 2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl, cycloheptyl, pyranyl, naphthyl or benzyl, each of which is optionally independently substituted with 1-5 substituents of R 15 , R 16 or R 18 ;

R 15 is halo, haloalkyl, oxo, NO 2 , CN, SR 18 , OR 18 , OC(O)R 18 , NR 16 R 18 , NR 18 R 18 , COOR 16 , C(O)R 16 , COOR 18 , C(O)R 18 , C(O)NR 16 R 18 , C(O)NR 18 R 18 , S(O) 2 NR 16 R 18 , S(O) 2 NR 18 R 18 , S(O) 2 R 16 , S(O) 2 R 18 , C(O)C(O)R 18 , NR 18 C(O)NR 16 R 18 , NR 18 C(O)NR 18 R 18 , NR 18 C(O)C(O)R 18 , NR 18 C(O)R 16 , NR 18 C(O)R 18 , NR 18 (COOR 16 ), NR 18 (COOR 18 ), NR 18 S(O) 2 NR 16 R 18 , NR 18 S(O) 2 NR 18 R 18 , NR 18 S(O) 2 R 18 , NR 18 S(O) 2 R 16 , NR 18 C(O)C(O)NR 16 R 18 or NR 18 C(O)C(O)NR 18 R 18 ;

R 16 is phenyl, pyridyl, pyrimidinyl, triazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl, 2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl, benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, 2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl, cycloheptyl, pyranyl or naphthyl, each of which is optionally substituted independently with 1-3 substituents of R 17 , R 18 or R 20 ;

R 17 is halo, haloalkyl, oxo, NO 2 , CN, SR 18 , OR 18 , OC(O)R 18 , NR 18 R 18 , NR 18 R 20 , COOR 18 , C(O)R 18 , COOR 20 , C(O)R 20 , C(O)NR 18 R 18 , C(O)NR 18 R 20 , S(O) 2 NR 18 R 18 , S(O) 2 NR 18 R 20 , S(O) 2 R 18 , S(O) 2 R 20 , C(O)C(O)R 18 , NR 18 C(O)NR 18 R 18 , NR 18 C(O)NR 18 R 20 , NR 18 C(O)C(O)R 18 , NR 18 C(O)R 18 , NR 18 C(O)R 20 , NR 18 (COOR 18 ), NR 18 (COOR 20 ), NR 18 S(O) 2 NR 18 R 18 , NR 18 S(O) 2 NR 18 R 20 , NR 18 S(O) 2 R 18 , NR 18 S(O) 2 R 20 , NR 18 C(O)C(O)NR 18 R 18 or NR 18 C(O)C(O)NR 18 R 20 ;

each R 18 , independently, is H, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, hexyl, acetyl or C 1-10 -alkoxyl, each of which is optionally independently substituted with 1-3 substituents of R 21 ;

R 20 is phenyl, pyridyl, pyrimidinyl, triazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl, 2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl, benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, 2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl, cycloheptyl, pyranyl or naphthyl, each of which is optionally substituted independently with 1-3 substituents of R 21 ;

each R 21 , independently, is H, Cl, Br, F, I, CF, CF 2 CF 3 , NO 2 , CN; acetyl, oxo, haloalkyl, haloalkoxyl, CN, OH, SH, NO 2 , NH 2 , acetyl, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl, C 1-10 -thioalkoxyl or a saturated or partially or fully unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein each of the C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl, C 1-10 -thioalkoxyl and ring of said ring system is optionally substituted independently with 1-3 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl; and

n is 0, 1, 2 or 3.

The embodiments for various of the elements described herein above with respect to compounds of Formula I also apply to compounds of Formula II, where appropriate, as will be appreciated by those skilled in the art.

In another embodiment, the invention includes compounds of Formula III, wherein:

and pharmaceutically acceptable salts thereof, wherein

D is N or CR 12 ;

G is O, S, C(O), S(O), SO 2 or (CHR 13 ) m ;

R 1 is H, halo, haloalkyl, NO 2 , CN, NR 13 R 13 , OR 13 , SR 13 , or (CHR 13 ) n R 13 ;

R 2 is H, halo, haloalkyl, oxo, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, wherein the C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl is optionally substituted with one or more substituents of R 13 ;

each of R 3 and R 4 , independently, is H, halo, haloalkyl, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, wherein the C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl is optionally substituted independently with one or more substituents of R 13 ; alternatively, either of R 3 or R 4 , independently, taken together with R 12 forms a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and the ring optionally substituted independently with 1-3 substituents of R 13 ;

each of R 5 and R 6 , independently, is H, halo, haloalkyl, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 , NR 13 R 14 , C(O)R 13 , COOR 13 , OC(O)R 13 , C(O)C(O)R 13 , C(O)NR 13 R 13 , C(O)NR 13 R 14 , NR 13 C(O)R 13 , NR 13 C(O)R 14 , NR 13 C(O)NR 13 R 13 , NR 13 C(O)C(O)R 13 , NR 13 (COOR 13 ), OC(O)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 , NR 13 S(O) 2 R 14 , NR 13 C(O)C(O)NR 13 R 13 , NR 13 C(O)C(O)NR 13 R 14 , C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl or C 4-8 cycloalkenyl, wherein the C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl and C 4-8 cycloalkenyl is optionally substituted independently with one or more substituents of R 13 ; alternatively R 5 taken together with R 6 forms a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N, or S, and the ring optionally substituted independently with 1-3 substituents of R 13 ;

one of R 7 and R 8 is SR 13 , OR 13 , NR 13 R 13 , C(O)R 13 , COOR 13 , C(O)NR 13 R 13 , NR 13 C(O)R 13 , NR 13 (COOR 13 ), NR 13 C(O)NR 13 R 13 , C(S)NR 13 R 13 , NR 13 C(S)R 13 , NR 13 C(S)NR 13 R 13 , S(O) 2 R 13 , S(O) 2 NR 13 R 13 , NR 13 S(O) 2 NR 13 R 13 , NR 13 S(O) 2 R 13 or C 1-10 alkyl optionally substituted with one or more substituents of SR 13 , OR 13 , NR 18 R 18 , C(O)R 18 , COOR 18 , C(O)NR 18 R 18 , NR 13 C(O)R 18 , NR 18 (COOR 18 ), NR 18 C(O)NR 18 R 18 , C(S)NR 18 R 18 , NR 18 C(S)R 18 , NR 18 C(S)NR 18 R 18 , S(O) 2 R 18 , S(O) 2 NR 18 R 18 , NR 18 S(O) 2 NR 18 R 18 , NR 18 S(O) 2 R 18 ;

the other of R 7 and R 8 is H, halo, haloalkyl, haloalkoxyl, CN, OH, NO 2 , NH 2 , acetyl, C 1-10 -alkyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl or C 1-10 -thioalkoxyl;

each of R 9 and R 12 , independently, is H, R 13 , halo, haloalkyl, NO 2 , CN, SR 13 , OR 13 , NR 13 R 13 or C(O)R 13 ;

each R 13 , independently, is H, C 1-10 alkyl, C 1-10 alkenyl, C 1-10 alkynyl, C 3-8 cycloalkyl, C 4-8 cycloalkenyl, R 15 or R 16 , each of which is optionally substituted with 1-5 substituents of R 15 , R 16 or R 17 ;

R 14 is C(O)R 18 , COOR 18 , S(O) 2 R 18 or R 16 ; alternatively R 14 taken together with R 13 forms a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N and S, and the ring optionally substituted independently with 1-3 substituents of oxo, halo, haloalkyl, NO 2 , CN, R 17 or R 18 ;

R 15 is halo, haloalkyl, oxo, NO 2 , CN, SR 18 , OR 18 , OC(O)R 18 , NR 16 R 18 , NR 18 R 18 , COOR 16 , C(O)R 16 , COOR 18 , C(O)R 18 , C(O)NR 16 R 18 , C(O)NR 18 R 18 , S(O) 2 NR 16 R 18 , S(O) 2 NR 18 R 18 , S(O) 2 R 16 , S(O) 2 R 18 , C(O)C(O)R 18 , NR 18 C(O)NR 16 R 18 , NR 18 C(O)NR 18 R 18 , NR 18 C(O)C(O)R 18 , NR 18 C(O)R 16 , NR 18 C(O)R 18 , NR 18 (COOR 16 ), NR 18 (COOR 18 ), NR 18 S(O) 2 NR 16 R 18 , NR 18 S(O) 2 NR 18 R 18 , NR 18 S(O) 2 R 18 , NR 18 S(O) 2 R 16 , NR 18 C(O)C(O)NR 16 R 18 or NR 18 C(O)C(O)NR 18 R 18 ;

R 16 is phenyl, pyridyl, pyrimidinyl, triazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl, 2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl, benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, 2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl, cycloheptyl, pyranyl or naphthyl, each of which is optionally substituted independently with 1-3 substituents of R 17 , R 18 or R 20 ;

R 17 is halo, haloalkyl, oxo, NO 2 , CN, SR 18 , OR 18 , OC(O)R 18 , NR 18 R 18 , NR 18 R 20 , COOR 18 , C(O)R 18 , COOR 20 , C(O)R 20 , C(O)NR 18 R 18 , C(O)NR 18 R 20 , S(O) 2 NR 18 R 18 , S(O) 2 NR 18 R 20 , S(O) 2 R 18 , S(O) 2 R 20 , C(O)C(O)R 18 , NR 18 C(O)NR 18 R 18 , NR 18 C(O)NR 18 R 20 , NR 18 C(O)C(O)R 18 , NR 18 C(O)R 18 , NR 18 C(O)R 20 , NR 18 (COOR 18 ), NR 18 (COOR 20 ), NR 18 S(O) 2 NR 18 R 18 , NR 18 S(O) 2 NR 18 R 20 , NR 18 S(O) 2 R 18 , NR 18 S(O) 2 R 20 , NR 18 C(O)C(O)NR 18 R 18 or NR 18 C(O)C(O)NR 18 R 20 ;

each R 18 , independently, is H, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, hexyl, acetyl or C 1-10 -alkoxyl, each of which is optionally independently substituted with 1-3 substituents of R 21 ;

R 20 is phenyl, pyridyl, pyrimidinyl, triazinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, benzothiazolyl, oxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, isoxazolyl, isothiazolyl, indolyl, azaindolyl, 2,3-dihydroindolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, imidazo-pyridinyl, purinyl, benzotriazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl, 2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl, cyclohexyl, cycloheptyl, pyranyl or naphthyl, each of which is optionally substituted independently with 1-3 substituents of R 21 ;

each R 21 , independently, is H, Cl, Br, F, I, CF, CF 2 CF 3 , NO 2 , CN; acetyl, oxo, haloalkyl, haloalkoxyl, CN, OH, SH, NO 2 , NH 2 , acetyl, C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl, C 1-10 -thioalkoxyl or a saturated or partially or fully unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein each of the C 1-10 -alkyl, C 2-10 -alkenyl, C 2-10 -alkynyl, C 3-10 -cycloalkyl, C 4-10 -cycloalkenyl, C 1-10 -alkylamino-, C 1-10 -dialkylamino-, C 1-10 -alkoxyl, C 1-10 -thioalkoxyl and ring of said ring system is optionally substituted independently with 1-3 substituents of halo, haloalkyl, CN, NO 2 , NH 2 , OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl; and

n is 0, 1, 2 or 3,

provided that (1) when either of R 1 or R 2 is substituted or unsubstituted NH-phenyl, then no more than four of R 5 , R 6 , R 7 , R 8 and R 9 is H; and (4) when R 1 is Phenyl, then neither of R 6 and R 8 is, independently, NO 2 .

The embodiments for various of the elements described herein above with respect to compounds of Formula I also apply to compounds of Formula III, where appropriate, as will be appreciated by those skilled in the art.

In yet another embodiment, Formulas I, II and III include the exemplary compounds and derivatives, prodrugs, solvates, tautomers and pharmaceutically acceptable salt forms thereof, intermediates related thereto, which are described in the Examples herein.

The following definitions should further assist in understanding the invention and its scope as described herein.

The terms “agonist” and “agonistic” when used herein refer to or describe a molecule which is capable of, directly or indirectly, substantially inducing, promoting or enhancing biological activity of a biological molecule, such as an enzyme or receptor, including Tie-2 and Lck.

“Angiogenesis” is defined as any alteration of an existing vascular bed or the formation of new vasculature which benefits tissue perfusion. This includes the formation of new vessels by sprouting of endothelial cells from existing blood vessels or the remodeling of existing vessels to alter size, maturity, direction and/or flow properties to improve blood perfusion of tissue.

The terms “cancer” and “cancerous” when used herein refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, without limitation, carcinoma, lymphoma, sarcoma, blastoma and leukemia. More particular examples of such cancers include squamous cell carcinoma, lung cancer, pancreatic cancer, cervical cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, and head and neck cancer. While the term “cancer” as used herein is not limited to any one specific form of the disease, it is believed that the methods of the invention will be particularly effective for cancers which are found to be accompanied by unregulated levels of Tie-2, and similar kinases, in the mammal.

The terms “treat”, “treating,” “treatment,” and “therapy” as used herein refer to therapy, including without limitation, curative therapy, prophylactic therapy, and preventative therapy. Prophylactic treatment generally constitutes either preventing the onset of disorders altogether or delaying the onset of a pre-clinically evident stage of disorders in individuals.

The term “mammal” as used herein refers to any mammal classified as a mammal, including humans, cows, horses, dogs and cats. In one embodiment of the invention, the mammal is a human.

A “pharmaceutically-acceptable derivative” denotes any salt (also referred to as “pharmaceutically-acceptable salt”), ester of a compound of this invention, or any other compound which upon administration to a patient is capable of providing (directly or indirectly) a compound of this invention, or a metabolite or residue thereof, characterized by the ability to inhibit angiogenesis.

The phrase “therapeutically-effective” is intended to quantify the amount of each agent, which will achieve the goal of improvement in disorder severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies. For example, effective neoplastic therapeutic agents prolong the survivability of the patient, inhibit the rapidly-proliferating cell growth associated with the neoplasm, or effect a regression of the neoplasm.

The terms “ring” and “ring system” refer to a one or more rings, typically fused together where more than one ring, comprising the delineated number of atoms, said atoms being carbon or, where indicated, a heteroatom such as nitrogen, oxygen or sulfur. The ring itself, as well as any substitutents thereon, may be attached at any atom that allows a stable compound to be formed. The term “nonaromatic” ring or ring system refers to the fact that at least one, but not necessarily all, rings in a bicyclic or tricyclic ring system is nonaromatic.

“Leaving groups” generally refer to groups that are displaceable by a nucleophile. Such leaving groups are known in the art. Examples of leaving groups include, but are not limited to, halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylate, tosylate), sulfides (e.g., SCH 3 ), N-hydroxsuccinimide, N-hydroxybenzotriazole, and the like. Nucleophiles are species that are capable of attacking a molecule at the point of attachment of the leaving group causing displacement of the leaving group. Nucleophiles are known in the art. Examples of nucleophilic groups include, but are not limited to, amines, thiols, alcohols, Grignard reagents, anionic species (e.g., alkoxides, amides, carbanions) and the like.

The term “H” denotes a single hydrogen atom. This radical may be attached, for example, to an oxygen atom to form a hydroxyl radical.

Where the term “alkyl” is used, either alone or within other terms such as “haloalkyl” and “alkylamino”, it embraces linear or branched radicals preferably having alpha to beta number of carbon atoms. For example a C 1 -C 10 alkyl is an alkyl comprising 1 to 10 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like. It is contemplated herein that alkyl radicals may be optionally substituted with various substituents, where indicated. The term “alkylenyl” embraces bridging divalent alkyl radicals such as methylenyl and ethylenyl.

The term “alkenyl”, alone or in combination, embraces linear or branched radicals having at least one carbon.carbon double bond of two or more carbon atoms. Included within alkenyl radicals are “lower alkenyl” radicals having two to about six carbon atoms and, for example, those radicals having two to about four carbon atoms. Examples of alkenyl radicals include, without limitation, ethenyl, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms “alkenyl” and “lower alkenyl”, embrace radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations, as appreciated by those of ordinary skill in the art. It is contemplated herein that alkenyl radicals may be optionally substituted with various substituents, where indicated.

The term “alkynyl”, alone or in combination, denotes linear or branched radicals having at least one carbon-carbon triple bond and having two or more carbon atoms. Examples of alkynyl radicals include “lower alkynyl” radicals having two to about six carbon atoms and, for example, lower alkynyl radicals having two to about four carbon atoms. Examples of such radicals include, without limitation, ethynyl, propynyl (propargyl), butynyl, and the like. It is contemplated herein that alkynyl radicals may be optionally substituted with various substituents, where indicated.

The term “halo”, alone or in combination, means halogens such as fluorine, chlorine, bromine or iodine atoms.

The term “haloalkyl”, alone or in combination, embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. For example, this term includes monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals such as a perhaloalkyl. A monohaloalkyl radical, for example, may have either an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. “Lower haloalkyl” embraces radicals having 1-6 carbon atoms and, for example, lower haloalkyl radicals having one to three carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. “Perfluoroalkyl”, as used herein, refers to alkyl radicals having all hydrogen atoms replaced with fluoro atoms. Examples include trifluoromethyl and pentafluoroethyl.

The term “hydroxyalkyl”, alone or in combination, embraces linear or branched alkyl radicals having one or more carbon atoms any one of which may be substituted with one or more hydroxyl radicals. The term hydroxyalkyl radicals include “lower hydroxyalkyl” radicals having one to six carbon atoms and one to three hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.

The term “alkoxy”, alone or in combination, embraces linear or branched oxy-containing radicals each having alkyl portions of alpha to beta number of carbon atoms. For example, a C 1-10 alkoxy radical indicates an alkoxide having one to ten carbon atoms, arranged in a linear or branched fashion, attached to an oxygen atom. The term alkoxy radicals include “lower alkoxy” radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide “haloalkoxy” radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.

The term “partially or fully saturated” as used herein, refers to a moiety, linear, branched or cyclic in nature, having no atom-atom double or triple bonds, and one or more atom-atom double or triple bonds, arranged such that wherein the structure is cyclic, the ring structure is not aromatic, as appreciated by those skilled in the art.

The term “fully unsaturated” as used herein, refers to a moiety having double or triple bonds, arranged in a manner such that the structure is aromatic, as appreciated by those skilled in the art.

The term “aryl”, alone or in combination, means a carbocyclic aromatic moiety containing one, two or even three rings wherein such rings may be attached together in a fused manner. Thus the term “aryl” embraces aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, anthracenyl, and indanyl. Said “aryl” group may have 1 to 3 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino, and the like. Phenyl substituted with —O—CH 2 —O— forms an aryl benzodioxolyl substituent. Aryl as used herein, implies a fully unsaturated ring.

The term “heterocycles” or “heterocyclic radicals”, alone or in combination, embraces saturated, partially saturated and unsaturated heteroatom-containing ring radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. This term does not include rings containing —O—O—, —O—S— or —S—S— portions. Said “heterocycle” may have 1 to 3 substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, amino and lower alkylamino.

Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl]; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl.

Examples of unsaturated heterocyclic radicals, also referred to herein as “heteroaryl” radicals, include unsaturated 5 to 6 membered heteromonocyclyl group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

The term “heterocycle” also embraces radicals where heterocyclic radicals are fused/condensed with aryl radicals: unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturated and unsaturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms [e.g. benzofuryl, benzothienyl, 2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Examples of heterocyclic radicals include five to ten membered fused or unfused radicals. Further examples of heteroaryl radicals include quinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl. Other examples of heteroaryl radicals are 5- or 6-membered heteroaryl, containing one or two heteroatoms selected from sulfur, nitrogen and oxygen, such as thienyl, furyl, pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl radicals.

Examples of non-nitrogen containing heteroaryl include, without limitation, pyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzofuryl, benzothienyl, and the like.

Examples of partially saturated and saturated heterocyclyl include, without limitation, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryl and dihydrothiazolyl, and the like.

The term “sulfonyl”, whether used alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals —SO 2 —.

The terms “sulfamyl,” “aminosulfonyl” and “sulfonamidyl,” denotes a sulfonyl radical substituted with an amine radical, forming a sulfonamide (—SO 2 NH 2 ).

The terms “carboxy” or “carboxyl”, whether used alone or with other terms, such as “carboxyalkyl”, denotes —CO 2 H.

The term “carbonyl”, whether used alone or with other terms, such as “aminocarbonyl”, denotes —(C═O)—.

The term “aminocarbonyl” denotes an amide group of the formula —C(═O)NH 2 .

The term “aralkyl” embraces aryl-substituted alkyl radicals. Examples of aralkyl radicals include “lower aralkyl” radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.

The term “alkylthio” embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. An example of “alkylthio” is methylthio, (CH 3 S—).

The term “aminoalkyl” and “diaminoalkyl” embraces “N-alkylamino” and “N,N-dialkylamino”, respectively, where amino groups are independently substituted with one alkyl radical and with two alkyl radicals, respectively. Examples of alkylamino radicals include “lower alkylamino” radicals having one or two alkyl radicals of one to six carbon atoms, attached to a nitrogen atom. Suitable alkylamino radicals may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino and the like.

The term “C 1-10 alkyl-amino-” denotes amino groups, which have been substituted with one or two alkyl radicals, such as N-methylamino. The alkylamino radicals may be further substituted on the alkyl portion of the radical.

The term “aryl-alkyl-amino-” or “aralkylamino” denotes amino groups, which have been substituted with one or two aryl-substituted-alkyl radicals, such as benzyl-amino. The aralkyl-amino radicals may be further substituted on the aryl or alkyl portion of the radical.

The term “heterocyclyl-alkyl-amino-” denotes amino groups, which have been substituted with one or two heterocyclyl-substituted-alkyl radicals, such as piperidyl-methyl-amino. The heterocyclyl-alkyl-amino radicals may be further substituted on the heterocycle or alkyl portion of the radical.

The term “heteroaryl-alkyl-amino-” or “heteroaralkylamino” denotes amino groups, which have been substituted with one or two heteroaryl-substituted-alkyl radicals, such as pyrimidyl-amino. The heteroaralkyl-amino radicals may be further substituted on the heteroaryl or alkyl portion of the radical.

The term “arylamino” denotes amino groups, which have been substituted with one or two aryl radicals, such as N-phenylamine. The arylamino radicals may be further substituted on the aryl ring portion of the radical.

The term “heteroarylamino” denotes amino groups, which have been substituted with one or two heteroaryl radicals, such as N-thienylamino. The “heteroarylamino” radicals may be further substituted on the heteroaryl ring portion of the radical.

The term “cycloalkyl” includes saturated carbocyclic groups. Examples of cycloalkyl groups include C 3 -C 6 rings, such as compounds including, cyclopentyl, cyclopropyl, and cyclohexyl.

The term “cycloalkenyl” includes carbocyclic groups having one or more carbon-carbon double bonds including “cycloalkyldienyl” compounds. Examples of cycloalkenyl groups include C 3 -C 6 rings, such as compounds including, without limitation, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cycloheptadienyl.

The term “comprising” is meant to be open ended, including the indicated component(s) but not excluding other elements.

The terms “Formula I”, “Formula II” and “Formula III” include any sub formulas.

The present invention comprises processes for the preparation of a compound of Formulae I and II.

Also included in the family of compounds of Formulas I-III are the pharmaceutically-acceptable salts thereof. The term “pharmaceutically-acceptable salts” embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts of compounds of Formulas I-III may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Suitable exemplary organic acids include, without limitation, aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, adipic, butyric, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic, digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic, glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic, nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic, persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic, tartaric, thiocyanic, mesylic, undecanoic, stearic, algenic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid.

Suitable pharmaceutically-acceptable base addition salts of compounds of Formulas I-III include, without limitation, metallic salts such as salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts made from organic bases including primary, secondary, tertiary amines and substituted amines including cyclic amines such as caffeine, arginine, diethylamine, N-ethyl piperidine, aistidine, glucamine, isopropylamine, lysine, morpholine, N-ethyl morpholine, piperazine, piperidine, triethylamine, trimethylamine. All of these salts may be prepared by conventional means from the corresponding compound of the invention by reacting, for example, the appropriate acid or base with the compound of Formulas I-III. When a basic group and an acid group are present in the same molecule, a compound of Formulas I-III may also form internal salts.

General Synthetic Procedures

The compounds of the invention can be synthesized according to the following procedures of Schemes 1-13, wherein the substituents are as defined for Formulas I-III, above, except where further noted. The synthetic methods described below are merely exemplary, and the compounds of the invention may be synthesized by alternate routes as appreciated by persons of ordinary skill in the art.

The following list of abbreviations used throughout the specification represent the following:

BSA—bovine serum albumin Cs 2 CO 3 —cesium carbonate CHCl 3 —chloroform CH 2 Cl 2 , DCM—dichloromethane, methylene chloride DIBAL—diisobutylaluminum hydride DIEA, (iPr 2 NEt—diisopropylethylamine DME—dimethoxyethane DMF—dimethylformamide DMAP—4-dimethylaminopyridine DMSO—dimethylsulfoxide dppa—diphenylphosphoryl azide EDC—1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Et 2 O—diethyl ether EtOAc ethyl acetate FBS—fetal bovine serum G, gm—gram h, hr—hour HBr—hydrobromic acid HCl—hydrochloric acid HOBt—1-hydroxybenzotriazole hydrate H 2 —hydrogen H 2 O 2 —hydrogen peroxide HATU—O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate HPLC—high pressure liquid chromatography IPA, IpOH—isopropyl alcohol K 2 CO 3 —potassium carbonate MCPBA—meta-chloroperbenzoic acid MgSO 4 —magnesium sulfate MeOH—methanol N 2 —nitrogen NaHCO 3 —sodium bicarbonate NaOH—sodium hydroxide NaH—sodium hydride Na 2 SO 4 —sodium sulfate NH 4 Cl—ammonium chloride NH 4 OH—ammonium chloride NMP—N-methylpyrrolidinone P(t-bu) 3 —tri(tert-butyl)phosphine PBS—phosphate buffered saline Pd/C—palladium on carbon Pd(PPh 3 ) 4 —palladium(0)triphenylphosphine tetrakis Pd(PhCN) 2 Cl 2 —palladium di-cyanophenyl dichloride Pd(OAc) 2 —palladium acetate Pd 2 (dba) 3 —bis(dibenzylideneacetone) palladium PyBop—benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium hexafluorophosphate RT—room temperature rac-BINAP—2,2′-Bis(diphenylphosphine)-1,1′-binaphthyl TBTU—O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate TEA, Et 3 N—triethylamine TFA—trifluoroacetic acid THF—tetrahydrofuran

The biaryl ring system (3), including substituted or unsubstituted pyridyl-pyridines, pyridyl-pyrimidines and pyridyl triazines (all where D=C 12 and E=N) and generally referred to herein as the C-D ring portion of the compounds of Formulas I-III, can be prepared according to the method generally described in Scheme 1. As shown, Suzuki coupling methodology utilizing an aryl halide (1) where X is a halide such as iodide, bromide or chloride, and an aryl borinate (2) in the presence of palladium, such as Pd(PPh 3 ) 4 , and a weak base, such as a Na 2 CO 3 , K 2 CO 3 or NaHCO 3 in a polar solvent such as DME can be used to synthesize compound (3). LG is a leaving group, such as F or Cl. Similarly, other known aryl coupling methods, such as use of stannanes, zincates and copper coupling techniques are also suitable to prepare compound (3).

In a similar manner, phenyl-pyridines, phenyl-pyrimidines and phenyl-triazine C-D rings (all where both D and E=N) of the compounds of Formulas I-III, can also be prepared according to the Suzuki or other metalation chemistry methods, wherein the aryl borinate (2) is a desirably substituted phenyl borinate, as described in Scheme 1.

Alternatively, amino-substituted pyridyl pyrimidines C-D ring systems (8) can be prepared according to the method shown in scheme 2.

Chloro-nicotinic acid chlorides (4) can be treated with dimethylmalonate in the presence of a suitable base and MgCl to form intermediate (5). Compound (5) can be cyclized to form the hydroxyl-substituted pyrimidyl-pyridine compound (6), in the presence of suitable base and formamidine acetate. Desirable amino-R 1 groups can be installed at the 3 position of the 4,6-pyrimidine D-ring by simply treating compound (7) with a primary or secondary amine, having the desired substitution, with heat under conditions milder than those required to displace the pyridyl chloride of compound (6). Further, compound (6) can be treated with p-toluene sulfonyl chloride, or other similar activating reagents to render the pyrimidine hydroxyl group into a suitable leaving group (LG) for displacement with a desired, sufficiently reactive nucleophile, including amines, sulfur, and oxygen nucleophiles. Also, compound (6) may be treated with a base sufficiently strong to deprotonate the hydroxyl proton in order to alkylate the hydroxyl group, thereby forming an ether, alkoxy moiety, and the like. Further, compound (6) can be converted to the corresponding thiol utilizing reactions and techniques known in the art. This thiol (not shown0 may then be converted to corresponding thio-linked R 1 groups. In addition, compound (7) can be treated with ammonia to give the amino adduct, which then can be alkylated, acylated, or otherwise substituted with a desired group. Such methods are known to those skilled in the art, and are described in Jerry March's Advanced Organic Chemistry, 4 th edition (1992), which disclosure is hereby incorporated by reference in its entirety.

The 2,4-regioisomer of the above pyridyl-pyrimidines can also be made using the following Scheme 3.

Compound (10) can be made by treating the acid chloride of compound (9a) (ring C) and converting it to the corresponding methyl ketone (9b) followed by treatment with dimethyl formamide dimethylacetal to obtain the corresponding enaminone (9c). Then substituted guanidine.HCl can be treated with a suitable base, such as sodium methoxide, for a time period prior to exposing the guanidine mixture to the enaminone (9c) to form the pyridyl pyrimidine (10). This method allows desired R 1 groups to be installed prior to ring closure. Care must be taken to restrict the R 1 groups in this method to those, which would not interfere with or react during formation of intermediates 9a-9c and also ring closure to form compound (10), as appreciated by persons of ordinary skill in the art.

Alternatively, compound (9c) can be treated with guanidine.HCl in the presence of NaOH in isopropanol to afford the corresponding 3-amino-pyrimidine D ring (not shown, where R 1 is NH 2 ). The R 1 position of this intermediated can be modified using reductive alkylation methods with corresponding aldehydes, acylation methods, and other groups, by methods appreciated by persons of ordinary skill in the art, to install the desired groups at this position on the D ring of compounds of Formulas I and II. Alternatively, the 3-aminopyrimidine may be converted to 3-fluoropyrimidine with use of t-butyl nitrate and HF.pyridine, and the fluoride then displaced with a desired R 1 group such as NH 2 R, OR and SR. This latter technique may also be used to convert amino-triazines to the corresponding fluoro-triazines.

Similarly, pyridyl-triazines C-D biaryl ring systems can be made using the method of scheme 4.

In a manner similar to the method illustrated and described in Scheme 2, desirable amino-R 1 groups can be installed at the 3 position of a triazine D ring by treating compound (15) with a primary or secondary amine, having the desired substitution, with heat under conditions less strenuous than required to displace the pyridyl chloride of compound (15).

The C-D ring portion of the compounds of Formulas I-III can be attached to the B ring of compound (17—see scheme 5 below) by a number of conventional methods known in the art, as disclosed in March. Suitable methods are illustrated in schemes 5 and 6 below.

As shown in Scheme 5, compound (18) comprising biaryl ethers and thiols (where G=O and S, respectively) can be prepared by reacting compound (16) (where LG is a leaving group, such as a halide) with a nucleophilic phenyl compound (17) wherein G is a suitable nucleophile, such as NHR or NH 2 (Scheme 6), OH, SH or carbon nucleophile, sufficient to displace the chloride from ring C of compound (16). For example, phenols (G=O) and thiols (G=S) can be coupled with activated aryl chlorides to form the biaryl ethers and thiols (compound 18) using weak bases such as TEA, or inorganic bases such as Cs 2 CO 3 , in DMSO at elevated temperatures, such as ranging form about 70° C. to about 130° C. Similarly, this transformation can also be carried out in NMP at about 200° C. in a microwave.

Anilines (compound 17) can be coupled with activated aryl chlorides (compound 16) to form biaryl anilines (compound 18) using Pd catalysis or NEt 3 .TFA under suitable conditions, which may or may not require the input of heat.

Alternatively, and with reference to Scheme 2, where certain R 1 and/or R 2 groups hinder or limit the ability to couple ring C to ring B via the nucleophilic displacement method described above, the B-C ring coupling can be effected from intermediate compound (6) in Scheme 2 as follows in Scheme 7.

As shown, compound (6) can first be reacted with the desired B ring nucleophilic species prior to converting the pyrimidyl hydroxyl group to the corresponding chloride for subsequent displacement with an amine, or other desired R 1 group.

Compounds of the invention (Formulas I-III) wherein D is CR 12 can be prepared by the general method shown in scheme 8.

As shown, commercially available 2-hydroxynicotinic acid can be iodinated and subjected to thionyl chloride according to the procedure disclosed in Elworthy et al., J. Med. Chem, 40(17):2674-2687 (1997), which disclosure is incorporated herein by reference in its entirety. Conversion of the iodinated intermediate (compound 22) to the corresponding pyrimidine (compound 23) proceeds as described above in Scheme 2. After displacement of the pyridyl chloride (compound 23) with an aniline (compound 17) to form compound (24), Pd(0) mediated-coupling with an aryl boronate in the presence of mild base, such as sodium or potassium carbonate or bicarbonate, in toluene affords compound (25), an aryl pyridyl pyrimidine. Compound (25) can also be prepared using corresponding stannanes or zincates, as known in the art. Alternatively, desired R 12 groups may be installed onto the C-ring via the iodide, using conventional methods (not shown), as appreciated by those skilled in the art.

Alternatively, the desired aryl group can be installed on ring C (compound 20) even before building the D-C ring piece of compounds of Formulas I-III. For example, Church et al. describes the synthesis of 5-aryl-2-chloropyridines from phenylacetic acids in J. Org. Chem., 60:3750-3758 (1995), which disclosure is incorporated herein by reference in its entirety. The general method described in Church is shown in Scheme 9 below.

After formation of the methyl ketone intermediate (not shown) by grignard addition to compound (27), elaboration to the pyrimidine and addition of aniline to the chloropyridine may proceed as described before. The method of Scheme 9 can also be used to provide desirable R 1 and R 2 groups at the 3 or 5-positions, respectively, of a pyrimidine D ring.

The final moieties of the compounds of the invention, generally defined in Formulas I-III, can be attached to the ring B of intermediate compounds (18), (20), (25) and (29) described above, and intermediates (30) and (32) illustrated below, by the general methods described in schemes 10-13 below.

As shown, amides can be prepared according to the method illustrated in Scheme 10. Substituted primary and secondary amines can be coupled with a free acid of ring B using a suitable coupling reagent, such as EDC, TBTU, HBTU, HOBT, DCC, HATU and others known in the art, via the corresponding acid-chloride or other acid halide. The acid-halide in compound (30) is designated as C(O)—X, where X is a suitable halide such as a chloride or fluoride. An acid chloride can be formed by reacting the free acid with oxalyl chloride, POCl 3 or similar reagent in a suitable solvent. The amide bond may also be effected using other known, conventional acid activated leaving groups. Such reactions generally proceed well in an inert, non-nucleophilic solvent(s), such as DMF, DMSO, CH 2 CL 2 and the like, at ambient temperatures. Poor solubility of the coupling reagent and/or the intermediates may generally require use of polar solvents. In some cases, depending upon the particular substrate or intermediates (30) and/or the amine starting material, heat may be necessary to effect the transformation and/or a higher yield. While Scheme 10 illustrates compound (31) having the amide corresponding to R 7 or R 8 , the invention is not so limited and such method is applicable to ring B having a free acid at any of positions R 5 , R 6 , R 7 , R 8 or R 9 , respectively. Further, while Scheme 10 illustrates an NHR 13 R 13 substituted amine, other amine substitutions are contemplated herein, such as NHR 13 R 14 substituted amines are also suitable.

As shown, reverse amides can be prepared according to the method illustrated in Scheme 11. Substituted free carboxylic acids may be coupled with the amine of compound (32) utilizing common coupling reagents and methods, such as those described in Scheme 10, to form the corresponding amide. Heat may be used where necessary. As in Scheme 10, Scheme 11 is not limited to compounds wherein the amide corresponds to positions R 7 or R 8 in Formulas I-III. Such method is also applicable to ring B having a free amine at any of positions R 5 , R 6 , R 7 , R 8 or R 9 , respectively, and to the carboxylic acid having groups other than R 13 , such as R 14 , R 15 and R 16 substituted acids, are also suitable.

As shown, ureas and thioureas (compound 34 wherein X═O and S, respectively) can be prepared according to the method illustrated in Scheme 12. The desired isocyanates and isothiocyanates are coupled with the amine (32) to form the desired ureas or thioureas (35).

The coupling reaction generally proceeds in an inert, non-nucleophilic, anhydrous solvent, such as DMF, CHCL 3 CH 2 Cl 2 , toluene and the like, at mild conditions, such as at room temperature. Further, the amine of compound (32) may be present in any of the R group positions corresponding to those in Formulas I-III for ring B, and not just corresponding to R 7 and R 8 as shown. Also, the method is not limited to R 13 , but also encompasses groups covered under R 14 , R 15 , and R 18 , as described above.

As shown, sulfonamides (37) can be prepared according to the method illustrated in Scheme 13. Anilines (32) are coupled with substituted sulfonyl chlorides (36) in the presence of a weak base, such as a tertiary amine or pyridine, in inert, non-nucleophilic, anhydrous solvents, such as DMF, CHCL 3 CH 2 Cl 2 , toluene and the like, at mild conditions, such as at room temperature, to form the desired sulfonamide (37). In some cases, depending upon the particular intermediates (32) and/or (36), their concentration in the solvent medium and independent reactivity, heat may be necessary to effect the transformation and/or a higher yield.

In addition, the methods described in schemes 10-13 are also applicable to pyridyl B rings (not shown). The specific examples described herein further illustrate amide, urea, carbamate, carbonate, and the like couplings between desired A rings and desired B rings, or desired B-C or B-C-D ring moieties.

Further, as described in schemes 10-12, the substitutions of compounds (36) and (37) are not limited to R 13 as shown, and encompass other groups as well, such as R 14 , R 15 , R 16 , and R 18 groups. The various R 13 substitutions in Schemes 10-13 and R 14 , R 15 , R 16 and R 18 group substitutions in compounds of Formulas I-III can be prepared by the general synthetic organic methods described in March Advanced Organic Chemistry and by methods published in the chemical literature, as appreciated by those of ordinary skill in the art. Further, the synthesis of various R 13 , R 14 , R 15 , R 16 and R 18 group substitutions are described in the synthesis of the following exemplary compounds of Formulas I-III.

To enhance the understanding of the invention described herein, the following examples are set forth. It should be appreciated that these examples are merely for illustrative purposes only and are not to be construed as limiting the scope of this invention in any manner.

Analytical Methods:

Unless otherwise indicated, all HPLC analyses were run on a Agilent Model 1100 system with an Agilent Technologies Zorbax SB-C 8 (5μ) reverse phase column (4.6×150 mm; Part no. 883975-906) run at 30° C. with a flow rate of about 1.50 mL/min. The mobile phase used solvent A (H 2 O/0.1% TFA) and solvent B (AcCN/0.1% TFA) with a 11 min gradient from 5% to 100% AcCN. The gradient was followed by a 2 min return to 5% AcCN and about a 2.5 minute re-equilibration (flush).

LC-MS Method:

Samples were run on a Agilent model-1100 LC-MSD system with an Agilent Technologies XDB-C 8 (3.5μ) reverse phase column (4.6×75 mm) at 30° C. The flow rate was constant and ranged from about 0.75 mL/min to about 1.0 mL/min.

The mobile phase used a mixture of solvent A (H 2 O/0.1% HOAc) and solvent B (AcCN/0.1% HOAc) with a 9 min time period for a gradient from 10% to 90% solvent B. The gradient was followed by a 0.5 min period to return to 10% solvent B and a 2.5 min 10% solvent B re-equilibration (flush) of the column.

Preparative HPLC Method:

Where indicated, compounds of interest were purified via reverse phase HPLC using a Gilson workstation with a 20×50 mm column at 20 mL/min. The mobile phase used a mixture of solvent A (H 2 O/0.1% TFA) and solvent B (AcCN/0.1% TFA) with a 10 min gradient from 5% to 100% solvent B. The gradient is followed by a 2 min return to 5% AcCN.

Proton NMR Spectra:

Unless otherwise indicated, all 1 H NMR spectra were run on a Varian series Mercury 300 MHz or on a Bruker 400 MHz instrument. Where so characterized, all observed protons are reported as parts-per-million (ppm) downfield from tetramethylsilane (TMS) or other internal reference in the appropriate solvent indicated.

The following examples represent exemplary methods of synthesizing or preparing desired structural moieties or pieces of the compounds of Formulas I-III, including exemplary A rings, B rings, A-B rings, C-D rings, B-C-D rings and fragments thereof. It should be appreciated that these methods are merely representative examples and other conventional, known or developed alternative methods may also be utilized. These structural moieties will assist in understanding how the many complete compound examples of Formulas I-III described herein below were made.

To 1-chloromethyl-2-nitro-4-trifluoromethyl-benzene (1.5 g, 6.2 mmol), N-methylpiperazine (0.83 mL, 7.5 mmol), and THF (31 mL) was added NaHCO 3 (1.43 g, 17.1 mmol). The mixture was heated overnight at 75° C. in a sealed tube. The cooled reaction was filtered, concentrated, diluted with CH 2 Cl 2 , and extracted with water and brine. The organic layer was dried over Na 2 SO 4 , filtered and concentrated to yield 1-methyl-4-(2-nitro-4-trifluoromethyl-benzyl)-piperazine.

To 1-methyl-4-(2-nitro-4-trifluoromethyl-benzyl)-piperazine (543 mg, 1.8 mmol) in MeOH (18 mL) was added 10% Pd/C (95 mg, 0.09 mmol). The mixture was stirred under an atmosphere of hydrogen at RT for 2 h. The resulting mixture was filtered through a pad of Celite and concentrated to yield 2-(4-methyl-piperazin-1-ylmethyl)-5-trifluoromethyl-phenylamine. MS m/z=274 [M+1] + . Calc'd for C 13 H 18 F 3 N 3 : 273.30.

The following Examples 9-13 were synthesized in a manner an analogous to that described in Example 8:

To N-(4-bromo-2-nitro-phenyl)-N,N′,N′-trimethyl-propane-1,3-diamine (940 mg, 2.97 mmol), Pd(PhCN) 2 Cl 2 (34 mg, 0.09 mmol), CuI (11 mg, 0.06 mmol) and dioxane (4 mL) was added P(tBu) 3 .HBF 4 (53 mg, 0.18 mmol), iPr 2 NH (0.50 mL, 3.6 mmol) and (trimethylsilyl)acetylene (0.49 mL, 3.6 mmol). The mixture was stirred for 3.5 h at RT, diluted with MeOH and stirred at RT with excess saturated aqueous K 2 CO 3 for 2 h. The mixture was filtered through a pad of activated charcoal and concentrated to yield N-(4-ethynyl-2-nitro-phenyl)-N,N′, N′-trimethyl-propane-1,3-diamine. MS m/z=262 [M+1] + . Calc'd for C 14 H 19 N 3 O 2 : 261.33.

To N-(4-ethynyl-2-nitro-phenyl)-N,N′,N′-trimethyl-propane-1,3-diamine (730 mg, 2.79 mmol), EtOH (40 mL) and THF (13 mL) was added concentrated HCl (1.0 mL) and iron metal (10.6 g, 191 mmol). A reflux condenser was attached and the mixture was heated overnight at 90° C. The cooled mixture was filtered through a pad of Celite, concentrated and purified by flash chromatography (90:10:1 CH 2 Cl 2 /MeOH/NH 4 OH) to yield N 1 -(3-dimethylamino-propyl)-4-ethynyl-N 1 -methyl-benzene-1,2-diamine. MS m/z=232 [M+1] + . Calc'd for C 14 H 21 N 3 : 231.34.

Synthesis of N 1 -(3-Dimethylamino-propyl)-N 1 -methyl-4-pentafluoroethylbenzene-1,2-diamine

To a round bottom flask at 0° C. was added 4-Bromo-1-fluoro-2-nitrobenzene (10 g, 45.46 mmol) and N,N,N′-Trimethyl-propane-1,3-diamine (6.99 mL, 47.7 mmol). The reaction was allowed to warm to RT and stirred for 16 h. The reaction was extracted into EtOAc, washed once with saturated aqueous NaHCO 3 , twice with water, and then dried over Mg 2 SO 4 . The organic layer was filtered and concentrated to yield the title compound as a bright orange solid. MS (M+H) + =316, 318; Calc'd 316.19 for C 12 H 18 BrN 3 O 2 .

To a pressure vessel was added N-(4-Bromo-2-nitro-phenyl)-N,N′, N′-trimethyl-propane-1,3-diamine (Step 1, 5.0 g, 15.8 mmol), copper powder (10.0 g, 158 mmol), and 20 mL DMSO. Pentafluoroethyl iodide (7.8 g, 31.6 mmol) was bubbled in and the vessel sealed. The mixture was then heated to 120° C. and vigorously stirred for 22 h. The reaction was cooled to 0° C. and filtered through a Buchner funnel, rinsing with EtOAc. The filtrate was then washed once with saturated aqueous NaHCO 3 , twice with water, once with brine, and then dried over Mg 2 SO 4 . The crude mixture was then purified by silica gel chromatography using a 10% MeOH/CH 2 Cl 2 gradient to yield the title compound as a brown oil. MS (M+H) + =356; Calc'd 355.30 for C 14 H 18 F 5 N 3 O 2 .

Step 3. Preparation of N 1 -(3-Dimethylamino-propyl)-N 1 -methyl-4-pentafluoroethylbenzene-1,2-diamine

N,N,N′-Trimethyl-N′-(2-nitro-4-pentafluoroethyl-phenyl)-propane-1,3-diamine (Step 2, 800 mg, 2.25 mmol) was dissolved in 15 mL MeOH. Palladium (120 mg, 0.307 mmol, 10% w/w on carbon) was added, a balloon containing hydrogen was inserted, and the reaction was stirred at RT for 18 h. The solution was then filtered through a pad of Celite and concentrated, yielding viscous brown oil. The crude mixture was purified using reverse phase chromatography to give the title compound as reddish-brown oil. MS (M+H) + =326; Calc'd 325.32 for C 14 H 20 F 5 N 3 .

Synthesis of 4-tert-Butyl-N 1 -(3-dimethylamino-propyl)-N 1 -methyl-benzene-1,2-diamine

To a sealed tube was added Pd(OAc) 2 (105 mg 0.469 mmol), NaO t Bu (1.35 g, 14.07 mmol), 1-Bromo-4-tert-butylbenzene (2.0 g, 9.38 mmol), N,N,N′-Trimethyl-propane-1,3-diamine (1.65 mL, 11.26 mmol), P( i BuNCH 2 CH 2 ) 3 N (133 μL, 0.375 mmol), and 5 mL toluene. The solution was heated to 80° C. for 1 h, cooled to RT, filtered through a pad of silica gel (rinsing with 10% MeOH/CH 2 Cl 2 ), and concentrated in vacuo to yield the title compound (2.0 g, 86%) as a dark brown oil. MS (M+H) + =249; Calc'd 248.41 for C 16 H 28 N 2 .

Nitronium-tetrafluoroborate (2.14 g, 16.10 mmol) was dissolved in 40 mL aceonitrile, cooled to 0° C. and stirred for 15 min. A solution of N-(4-tert-Butyl-phenyl)-N,N′,N′-trimethyl-propane-1,3-diamine (Step 1, 2.0 g, 8.05 mmol) in 40 mL acetonitrile was added drop-wise over 10 min. The solution was stirred for 30 min at 0° C., warmed to RT, and stirred an additional 16 h. The reaction was extracted into EtOAc, washed twice with water, once with brine, dried over Mg 2 SO 4 , filtered, and concentrated in vacuo to yield a crude mixture that was purified by silica gel chromatography using a 10% MeOH/CH 2 Cl 2 gradient to give the title compound as a brown oil. The correct regioisomer was determined to be the only product by H-NMR analysis. MS (M+H) + =294; Calc'd 293.40 for C 16 H 27 N 3 O 2 .

N-(4-tert-Butyl-2-nitro-phenyl)-N,N′,N′-trimethyl-propane-1,3-diamine (Step 2, 200 mg, 0.682 mmol) was dissolved in 7 mL MeOH. Palladium (66 mg, 0.062 mmol, 10% w/w on carbon) was added, a balloon containing hydrogen was inserted, and the reaction was stirred at RT for 18 h. The solution was then filtered through a pad of Celite and concentrated, yielding the title compound as a dark brown solid. MS (M+H) + =264; Calc'd 263.42 for C 16 H 29 N 3 .

N1-(3-(dimethylamino)propyl)-4-isopropyl-N1-methylbenzene-1,2-diamine

Example 17 was synthesized in a manner analogous to the method described in Example 16. MS (M+H) + =250; Calc'd 249.40 for C 15 H 27 N 3 .

Synthesis of 2-(4-Methyl-piperazin-1-yl)-5-trifluoromethyl-phenylamine

Example 18 was prepared in accordance to a procedure described in Collins, et. al., Tetrahedron, 48, No. 37, pp 7887-7898, 1992. To a solution of 1-Fluoro-2-nitro-4-trifluoromethyl-benzene (1.0 g, 4.78 mmol) in dry THF (24 mL) was added 1-Methyl-piperazine (0.64 mL, 5.74 mmol). The solution turned bright yellow. NaHCO 3 (1.1 g, 13 mmol) was added and the reaction was stirred at room temperature and monitored by LCMS. The reaction was filtered and concentrated before being taken up in CH 2 Cl 2 and H 2 O. The organic layer was separated, dried with MgSO 4 , filtered, and concentrated to afford the title compound as an orange-brown oil.

To 1-Methyl-4-(2-nitro-4-trifluoromethyl-phenyl)-piperazine (1.46 g, 5.05 mmol) in dry MeOH (50 mL) was added Pd/C (10%, 535 mg). H 2 gas was bubbled through the solution at room temperature overnight with vigorous stirring. The reaction mixture was filtered through celite to provide, after concentration, the desired product as a white solid. MS (M+H) + =260; Calc'd 259.28 for C 12 H 16 F 3 N 3 .

The following Examples 19-24 were synthesized in a manner analogous to that described in Example 18.

To a round bottom flask at 0° C. was added 4-Bromo-1-fluoro-2-nitrobenzene (10 g, 45 mmol) and N,N,N′-Trimethyl-propane-1,3-diamine (6.99 ml, 47.7 mmol). The reaction was allowed to warm to RT and stirred for 16 h. The reaction was extracted into EtOAc, washed once with saturated aqueous NaHCO 3 , twice with water, and then dried over Mg 2 SO 4 . The organic layer was filtered and concentrated to yield the title compound as a bright orange solid. MS (M+H + )=316, 318; Calc'd for C 12 H 18 BrN 3 O 2 =316.19.

To a pressure vessel was added 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (900 mg, 5.36 mmol), potassium phosphate (3.0 g, 14 mmol), and 0.82 mL water. After stirring at RT for 15 minutes, N-(4-Bromo-2-nitro-phenyl)-N,N′,N′-trimethyl-propane-1,3-diamine (Step 1, 1.30 g, 4.12 mmol), palladium acetate (92 mg, 0.412 mmol), tricyclohexylphosphine (231 mg 0.824 mmol), and 21 ml toluene were added. The reaction was sealed and stirred at 80° C. for 19 h. The reaction was then cooled to RT, quenched with EtOAc and extracted into water, washed once with brine, and then dried over Mg 2 SO 4 . The crude mixture was then purified by reverse phase chromatography to yield the title compound as a dark red-brown oil. MS (M+H + )=278; Calc'd for C 15 H 23 N 3 O 2 =277.36.

4-cyclopropyl-N-(3-(dimethylamino)propyl)-N-methyl-2-nitrobenzenamine (Step 2, 600 mg, 2.16 mmol) was dissolved in 22 mL MeOH. Palladium (115 mg, 0.108 mmol, 10% w/w on carbon) was added, a balloon containing hydrogen was inserted, and the reaction was stirred at RT for 18 h. The solution was then filtered through a pad of Celite and concentrated, yielding the title compound as viscous red-brown oil. MS (M+H + )=248; Calc'd for C 15 H 25 N 3 =247.38.

Synthesis of 2-(2-Pyrrolidin-1-yl-ethoxy)-5-trifluoromethyl-phenylamine

To a suspension of NaH (60%, 248 mg, 6.21 mmol) in dry THF was added 2-Pyrrolidin-1-yl-ethanol (0.68 mL, 5.74 mmol). Bubbling was observed. The reaction was stirred for 5 minutes, at which time 1-Fluoro-2-nitro-4-trifluoromethyl-benzene (0.67 mL, 4.79 mmol) was added. The solution turned red, and LCMS indicated completion of the reaction. The reaction was quenched by addition of H 2 O, and the mixture was extracted with EtOAc, dried with MgSO 4 , filtered, and concentrated to afford the title compound as an orange oil.

To a solution of 1-[2-(2-Nitro-4-trifluoromethyl-phenoxy)-ethyl]-pyrrolidine (1.70 g, 5.59 mmol) in dry MeOH (56 mL) was added Pd/C (10%, 350 mg). H 2 gas was bubbled through the solution, which was then stirred vigorously under an atmosphere of H 2 . After completion of the reaction by LCMS, the mixture was filtered through celite and concentrated to afford the desired product as a yellow/orange oil. MS (M+H) + =275; Calc'd 274.29 for C 13 H 17 F 3 N 2 O.

N,N-dimethyl-3-(2-nitro-4-(trifluoromethyl)phenoxy)propan-1-amine

Example 30 was synthesized in a manner analogous to that described in Example 29. MS (m/z): 263 (M+H) + . Calc'd for C 12 H 17 F 3 N 2 O 3 : 262.27.

Synthesis of (S)-1-(2-amino-4-(trifluoromethyl)phenyl)-N,N-dimethylpiperidin-3-amine

To a light yellow solution of (S)-tert-butyl 3-aminopiperidine-1-carboxylate (0.52 g, 2.6 mmol) in 25 ml MeOH was added sodium cyanoborohydride (0.33 g, 5.2 mmol), AcOH (0.74 ml, 13 mmol), and formaldehyde (37 wt. % solution in water, 1.0 ml). After stirring approximately 12 h, the reaction was quenched by the addition of 5 mL saturated aqueous sodium bicarbonate. The volatile organic solvents were removed in vacuo, and water and EtOAc was added. The organic layer was removed, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried with Na 2 SO 4 , filtered, and concentrated to give a yellow oil. The resulting material was treated with 4 ml 4N HCl in dioxane at 0° C. After 2 h, the solution was concentrated in vacuo to give a light yellow solid. This solid was treated with 1-fluoro-2-nitro-4-trifluoromethyl-benzene (0.37 mL, 2.6 mmol), sodium bicarbonate (1.0 g, 13 mmol), and 5 ml dry THF. The mixture was heated to 75° C. with a water-cooled reflux condenser for 12 h. The mixture was allowed to cool to ambient temperature, was filtered through a fritted funnel, and concentrated to give the desired product as an orange oil. MS (m/z): 318.0 (M+H) + . Calc'd for C 14 H 18 F 3 N 3 O 2 : 317.31.

(S)—N,N-Dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-amine (0.82 g, 2.6 mmol) was reduced with Pd/C (10%, 0.27 g) in 10 ml methanol. After approximately 12 h, the reaction was flushed with nitrogen and filtered through a pad of celite, rinsing with methanol. Removal of the solvent in vacuo gave the title compound as an orange-red oil. MS (m/z): 288.2 (M+H) + . Calc'd for C 14 H 20 F 3 N 3 : 287.32.

Synthesis of (S)-3-((1-methylpyrrolidin-2-yl)methoxy)-5-(trifluoromethyl)benzenamine

The title compound was synthesized by a method similar to that described in WO 2002066470 A1.

Synthesis of 2-(2-Dimethylamino-1,1-dimethyl-ethyl)-5-trifluoromethyl-phenylamine

The title compound was synthesized according to a method described in Prasad, G., J. Org. Chem. 1991, 56, 7188-7190. To a yellow-brown solution of (2-Nitro-4-trifluoromethyl-phenyl)-acetonitrile (2.5 g, 11 mmol), 18-crown-6 (0.72 g, 2.7 mmol), and methyl iodide (1.5 mL, 24 mmol) in dry THF under nitrogen at −78 degrees C. was added potassium tert-butoxide (2.7 g, 24 mmol) in one portion. The reaction immediately became a deep purple color. The reaction was allowed to stir for 2 h at −78 degrees C., and was then warmed to ambient temperature. A water-cooled reflux condenser was added and the solution heated to 70 degrees C. under nitrogen. Over 40 minutes, the color changed from dark purple to cloudy gray. The mixture was allowed to cool to room temperature, and was concentrated in vacuo. The resulting material was partitioned between 1 N HCl and EtOAc. The organic layer was washed once with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a brown oil which was judged to be primarily monoalkylated nitrile. The crude material was resubjected to the reaction conditions using 18-crown-6 (0.72 mg, 2.7 mmol), methyl iodide (0.75 mL, 12 mmol), and potassium tert-butoxide (1.4 g, 12 mmol) as before, with the following modifications: the reaction was allowed to stir only 10 min. at −78 degrees C. before being warmed to room temperature, and the reaction vessel was sealed and heated to 70 degrees C. for 2 h. Upon cooling to room temperature, the reaction was quenched and worked up as before. Purification by flash chromatography afforded the desired product as a light brown solid. MS (M+H) + =259; Calc'd 258.20 for C 11 H 9 F 3 N 2 O 2 .

To the solid 2-methyl-2-(2-nitro-4-trifluoromethyl-phenyl)-propionitrile (1.0 g, 3.9 mmol) in a 250 mL round-bottom flask at 0 degrees C. was added a solution of borane in THF (47 mL of a 1 M solution in THF, 47 mmol). The orange-yellow solution was allowed to warm to room temperature and stir for 6 h. The solution was then cooled to 0 degrees C., and was quenched by the careful dropwise addition of 6 N HCl. After gas evolution ceased, a total of 47 mL 6N HCl was added, resulting in a white precipitate. The mixture was concentrated in vacuo to % the original volume, and was basified at 0 degrees C. with 6N NaOH. The mixture was extracted with a 100 mL portion of ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give a yellow oil. Purification by flash chromatography provided the desired product which contained minor impurities by NMR. MS m/z 263=[M+H] + . Calc'd for C 11 H 13 F 3 N 2 O 2 : 262.23.

To a solution of 2-Methyl-2-(2-nitro-4-trifluoromethyl-phenyl)-propylamine (0.76 g, 2.9 mmol) in methanol (29 mL) at 0 degrees C. was added formaldehyde (0.60 mL of a 37 wt solution in water, excess), acetic acid (0.83 mL, 14.5 mmol), and sodium cyanoborohydride (0.36 g, 5.8 mmol). The homogeneous yellow solution was allowed to warm to room temperature and was stirred overnight. After approximately 12 h, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate until basic. The mixture was concentrated in vacuo, and the resulting material was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed once with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a yellow oil which contained solid material. The oil was dissolved in dichloromethane and filtered through a plug of cotton. Purification by flash chromatography provided the title compound as a yellow oil. MS m/z 291=[M+H] + . Calc'd for C 13 H 17 F 3 N 2 O 2 : 290.29.

A 50 mL round-bottom flask containing dimethyl-[2-methyl-2-(2-nitro-4-trifluoromethyl-phenyl)-propyl]-amine (0.61 g, 2.1 mmol) was charged with 10% palladium on carbon (0.23 g, 0.21 mmol) under nitrogen. Ethyl acetate (5 mL) and methanol (5 mL) were added sequentially via syringe. The atmosphere was replaced with hydrogen, and the reaction was stirred rapidly under 1 atm hydrogen overnight. After approximately 12 h, the reaction was flushed with nitrogen and filtered through a pad of celite, rinsing with methanol. Removal of the solvent in vacuo gave the title compound as a clear and colorless oil. MS m/z 261=[M+H] + . Calc'd for C 13 H 19 F 3 N 2 : 260.30.

Synthesis of (3-amino-5-(trifluoromethyl)phenyl)(4-methylpiperazin-1-yl)methanone

A solution of thionyl chloride (30 ml) and 3-nitro-5-(trifluoromethyl)benzoic acid (10 g) was heated to reflux for 2 h. The reaction mixture was concentrated under reduced pressure and treated with toluene (10 ml) which was then removed under reduced pressure to afford 3-nitro-5-(trifluoromethyl)benzoyl chloride.

To a solution of 3-nitro-5-(trifluoromethyl)benzoyl chloride (2.35 g, 9.3 mmol) in CH 2 Cl 2 (40 ml) at room temperature was added N-methylpiperazine (1.26 ml, 9.3 mmol) and the mixture was allowed to stir for 30 min. The reaction was concentrated under reduced pressure, taken up in 1 M HCl (50 ml) and the aqueous layer was washed with Et 2 O (2×20 ml). The aqueous layer was basified to a pH of about 9 with 6 N NaOH, and the aqueous layer was extracted with Et 2 O (3×50 ml). The organic extracts were combined and washed with water (1×20 ml) followed by brine (1×20 ml), and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (4-methylpiperazin-1-yl)(3-nitro-5-trifluoromethyl)phenyl)-methanone as a tan oil, which was used without further purification.

To an argon purged solution of (4-methylpiperazin-1-yl(3-nitro-5-trifluoromethyl)phenyl)-methanone (1.03 g, 3.25 mmol) was added Pd/C (344 mg, 0.32 mmol, 10%). The mixture was placed under an atmosphere of H 2 at RT for 5 h. The reaction was purged with argon and filtered through Celite. The filtrate was concentrated under reduced pressure to afford (3-amino-5-(trifluoromethyl)phenyl)(4-methylpiperazin-1-yl)methanone as an off-white solid. MS m/z=288 [M+H] + . Calc'd for C 13 H 16 F 3 N 3 O: 287.3.

Synthesis of 3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)-benzenamine

To LAH (1.84 g, 48.5 mmol) in THF (50 ml) at room temperature was added (4-methylpiperazin-1-yl)(3-nitro-5-trifluoromethyl)phenyl)-methanone (1.54 g, 4.85 mmol) in THF (10 ml). The resulting mixture was refluxed for 5 h. The reaction mixture was cooled to 0° C. at which point water (1.84 ml), 15% aq. NaOH (1.84 ml and water (3.68 ml) were successively added. The resulting mixture was allowed to stir at room temperature for 1 h. The mixture was filtered through Celite, concentrated under reduced pressure and purified via flash chromatography (silica gel, 0 to 25% MeOH in CH 2 Cl 2 , gradient elution) to afford 3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzenamine as a colorless oil. MS m/z=274 [M+H] + . Calc'd for C 13 H 18 F 3 N 3 : 273.30.

Synthesis of (3-amino-5-(trifluoromethyl)phenyl)(sulfonylmorpholino)methanone

3-Nitro-5-(trifluoromethyl)benzoic acid (2.96 g, 12.6 mmol) was allowed to reflux in thionyl chloride (6 mL) for 6 h. The resulting solution was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting solid was taken up in CH 2 Cl 2 (20 mL) and i Pr 2 NEt (2.6 mL, 15.1 mmol) and thiomorpholine (1.4 mL, 13.8 mmol) was added. The reaction was stirred at RT for 1 h and then diluted with CH 2 Cl 2 (50 mL). The organic layer was washed with aq. HCl (1 M, 25 mL), 9% aq. Na 2 CO 3 (25 mL), brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (3-nitro-5-(trifluoromethyl)phenyl)(thiomorpholino)-methanone.

To a solution of (3-nitro-5-(trifluoromethyl)phenyl)-(thiomorpholino)methanone (1.56 g, 4.88 mmol) in EtOH (50 mL) was added a solution containing ammonium molybdate tetrahydrate (602 mg, 0.49 mmol) and hydrogen peroxide (30%, 4.2 mL, 43.92 mmol). The resulting mixture was allowed to stir overnight. Once the reaction was complete, as observed by TLC (1:1 hexanes:EtOAc), it was poured onto water (100 mL). The aqueous layer was extracted with CH 2 Cl 2 (3×50 mL). The combined organic layers were washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (3-nitro-5-(trifluoromethyl)phenyl)(sulfonylmorpholino)methanone.

To an argon purged solution of (3-nitro-5-(trifluoromethyl)phenyl)-(sulfonylmorpholino) methanone (658 mg, 1.87 mmol) in EtOH (20 mL) was added Pd/C (198 mg, 0.187 mmol, 10%). The resulting mixture was allowed to stir under an atmosphere of hydrogen gas for 3 days. The reaction was purged with argon, filtered through Celite and concentrated under reduced pressure to afford (3-amino-5-(trifluoromethyl)phenyl)-(sulfonylmorpholino)methanone which was used without further purification. MS m/z=323 [M+H] + . Calc'd for C 12 H 13 F 3 N 2 O 3 S: 322.

Synthesis of (S)-tert-butyl 2-((3-amino-5-(trifluoromethyl)phenoxy)methyl)pyrrolidine-1-carboxylate

To a solution of 1-methoxy-3-nitro-5-(trifluoromethyl)benzene (1.0 g, 4.5 mmol) in dichloromethane (10 ml) was added pyridine hydrochloride salt (4.0 g, 35 mmol). After addition dichloromethane was removed under vacuum and the resulting solid mixture was heated at 200° C. overnight in an open reaction flask. After cooling to RT, 10% HCl (50 ml) was added and the mixture was extracted with EtOAc (3×50 ml). The combined organic layer was washed with brine (50 ml) and dried over Na 2 SO 4 . Solvent was removed under vacuum and the residue was purified by flash column chromatography on the silica gel (hexane/EtOAc=3:1) to afford the title compound as a white solid.

Step 2. Preparation of (S)-tert-butyl 2-((3-nitro-5-(trifluoromethyl)phenoxy)methyl)pyrrolidine-1-carboxylate

To a solution of 3-nitro-5-(trifluoromethyl)phenol (1.4 g, 6.7 mmol) in benzene (50 ml) was added (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.4 g, 6.7 mmol) and triphenylphosphine (1.78 g, 6.7 mmol). Then diisopropyl azodicarboxylate (1.4 g, 6.7 mmol) was added dropwise to the mixture at RT. The resulting mixture was stirred at RT overnight and then solvent was removed under vacuum. The product was purified by flash column chromatography on the silica gel (EtOAc/hexane=5→25%) resulting in an off-white solid.

Step 3. Preparation of (S)-tert-butyl 2-((3-amino-5-(trifluoromethyl)phenoxy)methyl)pyrrolidine-1-carboxylate

A mixture of (S)-tert-butyl 2-((3-nitro-5-(trifluoromethyl)phenoxy)methyl)pyrrolidine-1-carboxylate (2.0 g, 5.1 mmol) and Pd/C (10%, 150 mg) in EtOH (30 ml) was stirred under H 2 (1 atm) for 5 hr. The mixture was filtered through Celite and washed with MeOH. Evaporation of solvent gave the title product as a light amber oil. MS m/z=361 [M+H] + . Calc'd for C 17 H 23 F 3 N 2 O 3 : 360.38.

The following Examples 37-24 were synthesized in a manner analogous to that described in Example 36.

To a mixture of 3-nitro-5-(trifluoromethyl)phenol (2.10 g, 10.1 mmol) and cesium carbonate (4.00 g, 12.2 mmol) in acetonenitrile (50 ml) was added 2-chloroethyl p-toluenesulfonate (2.9 g, 12 mmol) slowly. The resulting mixture was stirred at RT for 5 hr, poured into water (100 ml) and then extracted with EtOAc (3×80 ml). The combined organic layer was washed with brine (100 ml) and dried over Na 2 SO 4 . Solvent was removed under vacuum and the residue was purified by flash column chromatography on the silica gel (hexane/EtOAc=5 to 25%) to afford the desired compound.

Prepared in an analogous manner to Step 3 for (S)-tert-butyl 2-((3-amino-5-(trifluoromethyl)phenoxy)methyl)pyrrolidine-1-carboxylate of Example 37.

Synthesis of 2-((2-iminooxazolidin-3-yl)methyl)-5-(trifluoromethyl)benzenamine

In a sealed tube, added 1-(chloromethyl)-2-nitro-4-(trifluoromethyl)benzene (2.0 g, 8.4 mmol), tetrahydrofuran (8.4 mL), and 2-aminoethanol (5.0 mL, 83.5 mmol). Stirred the mixture at room temperature for 45 minutes. Extracted the mixture into ethyl acetate, washed 2 times with water, 1 time with brine solution, dried over magnesium sulfate, filtered, concentrated to yield 2-(2-nitro-4-(trifluoromethyl)benzylamino)ethanol. MS (M+H) + =265; Calc'd 264.21 for C 10 H 11 F 3 N 2 O 3 .

In a sealed tube, added 2-(2-nitro-4-(trifluoromethyl)benzylamino)ethanol (Step 1, 1.10 g, 4.16 mmol), cyanogen bromide (1.32 g, 12.4 mmol), and tetrahydrofuran (4.2 mL). Stirred at room temperature for 56 hours. Concentrated down to yield 3-(2-nitro-4-(trifluoromethyl)benzyl)oxazolidin-2-imine. MS (M+H) + =290; Calc'd 289.22 for C 11 H 10 F 3 N 3 O 3 .

In a 100 mL round bottom flask, added palladium (110 mg, 0.10 mmol, 10% w/w on carbon), methanol (20 mL), and 3-(2-nitro-4-(trifluoromethyl)benzyl)oxazolidin-2-imine (Step 2, 600 mg, 2.07 mmol). Attached a balloon containing hydrogen, stirred at room temperature for 22 hours. Filtered through a pad of Celite, concentrated down to yield 2-((2-iminooxazolidin-3-yl)methyl)-5-(trifluoromethyl)benzenamine as a waxy orange-yellow solid. MS (M+H) + =260; Calc'd 259.22 for C 11 H 12 F 3 N 3 O.

Synthesis of (S)-3-(3-(dimethylamino)pyrrolidin-1-yl)benzoic acid

A mixture of methyl 3-bromobenzoate (1.0 g, 4.7 mmol), 2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl (0.037 g, 0.093 mmol), tris(dibenzylidineacetone)dipalladium (0) (0.021 g, 0.023 mmol), anhydrous K 3 PO 4 (1.4 g, 6.5 mmol) in 9.3 mL toluene under argon was added (S)—N,N-dimethylpyrrolidin-3-amine (0.71 mL, 5.6 mmol). The reaction was sealed and heated to 80 deg. C. for 3 days. The reaction was cooled to ambient temperature, was diluted with ethyl acetate, and filtered through celite. The filtrate was concentrated in vacuo to give a brown oil, which was further purified by silica gel chromatography, using 90/10/1 dichloromethane/methanol/sat'd ammonium hydroxide as eluent to give (S)-methyl 3-(3-(dimethylamino)pyrrolidin-1-yl)benzoate as a light brown oil.

To a solution of (S)-methyl 3-(3-(dimethylamino)pyrrolidin-1-yl)benzoate (0.555 g, 2.24 mmol) in MeOH (2.5 mL) was added 1N NaOH (2.5 mL). The reaction was sealed and heated to 70 deg. C. for 1 h. The reaction was cooled to ambient temperature and was concentrated to % the volume in vacuo. Water was added, followed by 1N HCl until pH 5-6 is obtained. The resulting thick oily mixture was extracted seven times with dichloromethane. The aqueous layer was concentrated in vacuo to a solid, which was rinsed with 1:1 MeOH/MC and filtered. The filtrate was concentrated in vacuo to give (S)-3-(3′-(dimethylamino)pyrrolidin-1-yl)benzoic acid as a yellow solid. MS m/z=235 [M+1] + . Calc'd for C 13 H 18 N 2 O 2 : 234.29.

Synthesis of 2-(methylamino)-4-tert-pentylphenol

2-Amino-4-tert-pentylphenol (5.00 g, 27.8 mmol) and potassium carbonate (3.88 g, 28.1 mmol) were mixed at RT for 2.5 hours in DMF (15 mL). Methyl iodide (1.20 mL, 19.3 mmol) was added and the mixture was stirred overnight at RT. Diluted the mixture with EtOAc and extracted with aqueous sodium bicarbonate and water. Dried the organic layers over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (10-15% MTBE/hexanes). Concentrated the product fractions to yield the title compound.

The following Examples 44-47 describe representative syntheses of exemplary A-B rings.

Synthesis of 3-Amino-N-(3-isopropyl-phenyl)-4-methyl-benzamide

To a solution of 4-methyl-3-nitro-benzoyl chloride (2.00 g, 0.010 mol) in THF (30 mL), in a water bath-cooled 100 mL round bottom flask, was added 3-isopropyl-phenylamine (1.35 g, 0.010 mol) dropwise. The reaction was allowed to stir at room temperature for 1 hour before being concentrated. The mixture was taken up in EtOAc and washed with NaHCO 3 (aq., conc.) and then brine. The solution was dried over MgSO 4 , filtered, and concentrated to yield the title compound as an orange oil that solidifies upon standing. MS m/z 299=[M+H] + . Calc'd for C 17 H 18 N 2 O 3 : 298.34.

To N-(3-Isopropyl-phenyl)-4-methyl-3-nitro-benzamide (3.00 g, 0.010 mol) dissolved in EtOAc (60 mL) in a 100 mL round bottom flask was added Pd/C (10%, 250 mg). The flask was capped with a rubber septum and flushed with H 2 gas through a balloon/needle. Positive H 2 pressure was applied through the balloon/needle and reaction was stirred vigorously at room temperature for 3 days. TLC indicated clean conversion of starting material. The reaction was filtered through a pad of sand/celite. After concentration, the mixture was purified by silica gel chromatography to afford a slightly orange oil. Trituration with a mixture of hexanes and EtOAc afforded the title compound as an off-white solid. MS m/z 269=[M+H] + . Calc'd for C 17 H 20 N 2 O: 268.36.

Potassium tert-butoxide (7.92 g, 70.5 mmol) was dissolved in THF (150 mL) and cooled to −78° C. 2-Fluoro-5-methoxybenzoic acid (3.00 g, 17.6 mmol) in THF (100 mL) was added followed by n-butyl lithium (2.5 N in hexanes, 28.2 mL, 70.5 mmol). After 40 minutes, iodomethane (2.2 mL, 35.4 mmol) was added and allowed to stir at −78° C. for 70 minutes before warming to room temperature. The reaction was quenched with saturated ammonium chloride (100 mL) and extracted with ether. The aqueous layer was acidified using 6 N HCl then extracted with ether. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was purified by Gilson reverse-phase HPLC (acidic mobile phase) to yield 2-fluoro-5-methoxy-4-methylbenzoic acid as a white solid. MS m/z=185 [M+1] + . Calc'd for C 9 H 9 FO 3 : 184.20.

To 2-fluoro-5-methoxy-4-methylbenzoic acid (650 mg, 3.53 mmol) was added 49% aqueous HBr (6.5 mL) and glacial acetic acid (5.5 mL). The mixture was heated overnight at 140° C., cooled to RT, diluted with ice water and extracted with EtOAc. The organic layer was dried over Na 2 SO 4 , filtered and concentrated to yield 2-fluoro-5-hydroxy-4-methylbenzoic acid. MS m/z=171 [M+1] + . Calc'd for C 8 H 7 FO 3 : 170.20.

The title compound was prepared according to the procedure described in J. Med. Chem. 1994, 37, 636-646. To 4-methyl-benzene-1,3-diamine (4.93 g, 40.4 mmol), MeOH (220 mL) and triethylamine (5.1 mL, 36.7 mmol) was added di-tert-butyl dicarbonate (8.00 g, 36.7 mmol). The mixture was stirred overnight at RT and concentrated. The residue was dissolved in EtOAc and extracted with 10% aqueous NaHCO 3 . The organic layer was dried over Na 2 SO 4 , filtered and concentrated about 90% of the way. At this point the product which precipitated out of solution, was filtered and washed with EtOAc to yield (3-amino-4-methyl-phenyl)-carbamic acid tert-butyl ester.

Step 2. Preparation of [4-methyl-3-(3-pyrimidin-4-yl-pyridin-2-ylamino)-phenyl]-carbamic acid tert-butyl ester

The title compound was prepared according to the procedure described in Tetrahedron 2001, 51, 7027-7034. Pd(OAc) 2 (47 mg, 0.21 mmol), and rac-BINAP (131 mg, 0.21 mmol) were stirred in toluene (12 mL) at RT for 12 minutes. This mixture was added to 4-(2-chloro-pyridin-3-yl)-pyrimidine (1.01 g, 5.24 mmol), (3-amino-4-methyl-phenyl)-carbamic acid tert-butyl ester (1.63 g, 7.34 mmol), and K 2 CO 3 (14.5 g, 105 mmol) in toluene (40 mL). The mixture was heated overnight at 130° C. in a sealed tube. The cooled reaction was filtered through a pad of Celite, partially concentrated and the resulting solid was filtered to yield [4-methyl-3-(3-pyrimidin-4-yl-pyridin-2-ylamino)-phenyl]-carbamic acid tert-butyl ester.

The title compound was prepared according to the procedure described in J. Am. Chem. Soc. 1993, 115, 905-916. To [4-methyl-3-(3-pyrimidin-4-yl-pyridin-2-ylamino)-phenyl]-carbamic acid tert-butyl ester (550 mg, 1.46 mmol) was added CH 2 Cl 2 (15 mL) and TFA (3.0 mL). The mixture was stirred for 3 h at 0° C., diluted with EtOAc and extracted with 50% aqueous Na 2 CO 3 . The organic layer was dried over Na 2 SO 4 , filtered and concentrated to yield 4-methyl-N 3 -(3-pyrimidin-4-yl-pyridin-2-yl)-benzene-1,3-diamine. MS m/z=278 [M+1] + . Calc'd for C 16 H 15 FN 5 : 277.33.

To a solution of 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.00 g, 9.09 mmol) in DMF was added Potassium carbonate (2.51 g, 18.2 mmol) and 1-fluoro-4-nitrobenzene (0.964 ml, 9.09 mmol). The reaction was flushed with nitrogen, sealed, and heated to 120 deg. C. After 18 h, water was added and the mixture extracted twice with EtOAc. The organic layer was dried over Na 2 SO 4 , filtered, and concentrated in vacuo. Purify by silica gel chromatography, eluting with 0-15% EtOAc/hexanes to give 4,4,5,5-tetramethyl-2-(2-(4-nitrophenoxy)phenyl)-1,3,2-dioxaborolane as a white solid. MS m/z=342 [M+1] + . Calc'd for C 18 H 20 BNO 5 : 341.17.

To a mixture of 4,4,5,5-tetramethyl-2-(2-(4-nitrophenoxy)phenyl)-1,3,2-dioxaborolane (0.936 g, 2.7 mmol), Pd(dppf)Cl 2 (0.10 g, 0.14 mmol) in dioxane and Sodium carbonate (2.0 M in water, 2.7 ml, 5.5 mmol) was added 4-chloro-2-methylthiopyrimidine (0.38 ml, 3.3 mmol). The brown mixture was sealed and heated to 80 deg. C. overnight. In the morning the reaction was partitioned between EtOAc/1N NaOH. The aqueous layer was extracted once with EtOAc. The combined organics were dried over anhyd. Na 2 SO 4 , filtered, and concentrated to a brown oil. This material was treated with CH 2 Cl 2 and purified by silica gel chromatography eluting with 0-25% EtOAc/hexane. The product-containing fractions were concentrated to afford 2-(methylthio)-4-(2-(4-nitrophenoxy)phenyl)pyrimidine as a clear oil. MS m/z=340 [M+1] + . Calc'd for C 17 H 13 N 3 O 3 : 339.37.

To a stirring solution of 2-(methylthio)-4-(2-(4-nitrophenoxy)phenyl)pyrimidine (0.819 g, 2.4 mmol) at 0 deg. C. was added a yellow solution of ammonium molybdate tetrahydrate (0.30 g, 0.24 mmol) in hydrogen peroxide 30% (1.8 ml, 22 mmol) via pipette. The solution was allowed to warm to ambient temperature at which point a yellow precipitate formed. Let stir 2 h. The desired product predominated, with a small amount of sulfoxide present. Placed in 0 deg. C. freezer overnight. In the morning, continue stirring at room temperature. After approximately 4 h, the reaction was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give 2-(methylsulfonyl)-4-(2-(4-nitrophenoxy)phenyl)pyrimidine. The material was used without further purification. MS m/z=372 [M+1] + . Calc'd for C 17 H 13 N 3 SO 5 : 371.37.

To a mixture of methylamine hydrochloride (0.863 g, 12.8 mmol), 2-(methylsulfonyl)-4-(2-(4-nitrophenoxy)phenyl)pyrimidine (0.791 g, 2.13 mmol) in iPrOH was added n,n-diisopropylethylamine (2.60 ml, 14.9 mmol). The reaction was sealed and heated to 70 deg. C. overnight. The resulting clear yellow solution was judged complete by LCMS in the morning. The reaction was cooled to ambient temperature, resulting in the formation of white crystals. Filter, rinsing with isopropanol. Concentrate filtrate, partition between EtOAc and 1N NaOH. Dry over anhyd. Na 2 SO 4 , filter, concentrate to give N-methyl-4-(2-(4-nitrophenoxy)phenyl)pyrimidin-2-amine as a light yellow solid. MS m/z=323 [M+1] + . Calc'd for C 17 H 14 N 4 O 3 : 322.32.

To N-methyl-4-(2-(4-nitrophenoxy)phenyl)pyrimidin-2-amine (0.667 g, 2.1 mmol) and palladium, 10 wt. % on activated carbon, wet (0.44 g, 0.41 mmol) in a 100 mL round bottom flask was added MeOH under nitrogen via syringe. The atmosphere was replaced with hydrogen from a balloon and the mixture stirred rapidly for 24 h. The reaction was flushed with nitrogen, and filtered through celite rinsing with 100 mL MeOH. The filtrate was concentrated in vacuo to give 4-(2-(4-aminophenoxy)phenyl)-N-methylpyrimidin-2-amine as a light yellow solid. MS m/z=293 [M+1] + . Calc'd for C 17 H 16 N 4 O: 292.34.

The following Examples 65-80 describe representative syntheses of exemplary C-D rings.

Synthesis of 2-chloro-4-(2-chloro-pyridin-3-yl)-[1,3,5]triazine

2-Chloro-3-cyanopyridine (5.0 g, 36 mmol) was dissolved in dry EtOH (100 mL) at 0° C. HCl was bubbled through the mixture for three hours and the mixture was sealed and refrigerated (about 8° C.) overnight. After concentration, the residue was stirred with ammonium acetate (5.5 g) in 100 mL IpOH. After 12 h, the pH was adjusted to 9 (from 4) using concentrated NH 4 OH solution, and stirring continued two more days. The mixture was concentrated and purified by flash chromatography (10:1:0.1 CH 2 Cl 2 /MeOH/NH 4 OH). Trituration in hot tBuOMe/IpOH removed some residual amide side-product to provide the title compound as a white solid.

2-Chloro-nicotinamidine (Step 1) was suspended in 10 mL IpOH with 500 mg solid cyanamide and the stirring solids were dissolved by addition of 5% aqueous NaHCO 3 (30 mL). After two days stirring, the amino-(2-chloro-pyridin-3-yl)-methylcyanamide was isolated by EtOAc extraction of the aqueous reaction mixture followed by flash chromatography using 95:5:0.5 CH 2 Cl 2 /MeOH/NH 4 OH. MS m/z=181 [M+H] + . Calc'd for C 7 H 6 N 4 Cl: 181.03.

Amino-(2-chloro-pyridin-3-yl)-methylcyanamide (3.5 g) was added as a solid to a stirring, 0° C. solution of POCl 3 (2.3 ml, 25 mmol) and DMF (1.9 mL, 25 mmol) in 100 mL AcCN. The clear solution was stirred at RT for 1 h. Toluene (40 mL) was added and the mixture was concentrated. The residue was immediately filtered through a 200 g plug of silica (loading in 10:1 CH 2 Cl 2 /IpOH, eluting with 10:1->4:1 hexane/t-BuOMe). Concentration provided 2-chloro-4-(2-chloro-pyridin-3-yl)-[1,3,5]triazine as a white solid. MS m/z=227 [M+H] + . Calc'd for C 8 H 4 Cl 2 N 4 : 225.98.

Synthesis of [4-(2-Chloro-pyridin-3-yl)-[1,3,5]triazin-2-yl]-methyl-amine

To 2-chloro-4-(2-chloro-pyridin-3-yl)-[1,3,5]triazine (10.0 g, 44.0 mmol) in 55 ml of methylene chloride was added methylamine (45 ml, 88.0 mmol) as a 2.0 M solution in THF at 0° C. After stirring at room temperature for 18 h, the mixture was diluted with acetone and filtered through a plug of silica gel and concentrated to yield the title compound. MS m/z=222 [M+H] + . Calc'd for C 9 H 8 ClN 5 : 221.65.

Synthesis of 4-(2-Chloro-pyridin-3-yl)-pyrimidine

1-(2-Chloro-pyridin-3-yl)-ethanone ([Kuo, D. L. Tetrahedron, 48, 42, 9233-9236] (21.7 g, 139 mmol) in 46 mL N,N-dimethylformamide, dimethyl acetal (42 g, 350 mmol) was heated under a drying tube at 85° C. for 1.5 h and concentrated. The residue was purified by suction filtration chromatography (using 150 g silica in a Buchner funnel, with rapid collection of fractions eluting with 10:1 and then 5:1 CH 2 Cl 2 /IpOH) to provide the title compound as a yellow solid. MS m/z=211 [M+H] + . Calc'd for C 10 H 11 ClN 2 O: 210.66.

Sodium methoxide was generated over a period of 1.5 h by the intermittent addition of small chunks of sodium metal (8.3 g total, 360 mmol) to 400 mL dry methanol under N 2 at room temperature, using a bath of 500 mL IpOH at room temperature as a heat sink. Formamidine acetate (42.7 g, 410 mmol) was added, followed ten minutes later by the enaminone (30.6 g, 146 mmol). The reaction was stirred overnight under a N 2 -filled balloon at an internal temperature of 40° C. After 20 h, the mixture was stirred at 48° C. for 4 h. Additional formamidine acetate (7.0 g) was added and the mixture was stirred overnight at 44° C. The mixture was concentrated by rotary evaporator, taken up in ethyl acetate and extracted with saturated aqueous NaHCO 3 . The aqueous layer was back-extracted with EtOAc. The combined organic layers (1.2 L) were dried over Na 2 SO 4 and concentrated. The residue was purified by flash vacuum filtration chromatography (300 g silica) in 3:1 to 2:1 hexane/EtOAc to provide a solid white title compound. MS m/z=192 [M+H] + . Calc'd for C 9 H 6 ClN 3 : 191.62.

Synthesis of 4-(5-bromo-2-chloropyridin-3-yl)pyrimidine

5-Bromo-2-chloronicotinic acid (10.0 g, 42.3 mmol) was treated with thionyl chloride (10.0 mL, 137 mmol) and heated to 50° C. for 18 hours. The volatiles were removed and the resulting crude acyl chloride was treated with 80 mL anhydrous THF, trimethylsilylacetylene (5.98 mL, 42.3 mmol), and copper iodide (322 mg, 1.79 mmol). The suspension was sparged with argon for 30 seconds then dichloropalladium bistriphenylphosphine (594 mg, 0.846 mmol) was added followed by triethylamine (6.18 mL, 44.4 mmol). After a brief exotherm, the reaction mixture was stirred at ambient temperature for 1 hour before addition of formamidine hydrochloride (4.09 g, 50.8 mmol), sodium carbonate monohydrate (15.7 g, 127 mmol), and methanol (100 mL). After stirring at ambient temperature (mild exotherm) for 15 minutes, the reaction was heated to reflux for 3 hours. The mixture was then allowed to cool before it was filtered through Celite and concentrated in vacuo. The resulting oil was purified by column chromatography using 10-70% EtOAc/hexanes and triturated with diethyl ether to afford the title compound as a tan, crystalline solid. MS m/z=270 (M+H) + . Calc'd for C 9 H 5 BrClN 3 : 270.52.

Synthesis of 4-(2-chloropyridin-3-yl)-N-methylpyrimidin-2-amine

1-(2-Chloro-pyridin-3-yl)-ethanone [Kuo, D. L. Tetrahedron, 48, 42, 9233-9236] (21.7 g, 139 mmol) in 46 mL N,N-dimethylformamide, dimethyl acetal (42 g, 350 mmol) was heated under a drying tube at 85° C. for 1.5 h and concentrated. The residue was purified by suction filtration chromatography (using 150 g silica in a Buchner funnel, with rapid collection of fractions eluting with 10:1 and then 5:1 CH 2 Cl 2 /IpOH) to provide the title compound as a yellow solid. MS m/z=211 [M+H] + . Calc'd for C 10 H 11 ClN 2 O: 210.66.

Sodium metal (3.40 g, 148 mmol) was added over ˜10 minutes to 180 mL of MeOH at RT and allowed to stir for an additional 30 minutes to generate sodium methoxide. Methyl guanidine HCl (20.0 g, 182 mmol) was added and the resulting mixture was stirred for 30 minutes before 1-(2-Chloro-pyridin-3-yl)-3-dimethylamino-propenone (12.0 g, 57 mmol) was added. An air condenser was attached and the mixture was heated to 50° C. for 23 hours. Part of the MeOH was removed by rotary evaporation and the resulting solid was filtered and washed with saturated sodium bicarbonate and water. The title compound was obtained as a fluffy white solid after drying. MS m/z=221 [M+H] + . Calc'd for C 10 H 9 ClN 4 : 220.66.

Synthesis of 4-(2-Chloropyridin-3-yl)-2-(methylthio)pyrimidine

The 5 L reactor was purged with Argon then charged with 4-chloro-2-methyl-thiopyrimidine (111 mL, 953 mmol) and 2-chloropyridine-3-boronic acid (100 g, 635 mmol). The reactor was put under vacuum and filled with Argon. This was repeated two more times. Ethylene glycol dimethyl ether (500 mL) was added to the mixture followed by Pd(PPh 3 ) 4 (58.7 g, 50.8 mmol). The reactor was put under vacuum and filled with Argon. This was repeated two more times then more ethylene glycol dimethyl ether (1500 mL) was added. A solution of sodium bicarbonate (1M soln, 1300 mL) was added to the stirred reaction mixture. A small exotherm was observed. The reaction mixture was stirred and refluxed for 2.75 h then gradually cooled to 25° C. The mixture was diluted with ethyl acetate (1500 mL) and vigorously stirred. The layers were allowed to separate and the aqueous phase was removed. The organic phase was washed with water (1000 mL), then brine (1000 mL), dried over magnesium sulfate and filtered. The solvents were removed under vacuum to afford the crude product as a light yellow solid. The crude product was separated by column chromatography using a mixture of ethanol and dichloromethane. The title compound was obtained as a fluffy white solid and slurried in ethyl acetate to remove traces of an impurity. MS m/z=238 [M+H] + . Calc'd for C 10 H 8 ClN 3 S: 237.71.

Synthesis of 4-(2-Chloropyridin-3-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine

In a 25 mL Erlynmeyer flask, combined hydrogen peroxide (0.50 mL, 21 mmol) and ammonium molybdate tetrahydrate (52 mg, 0.042 mmol) to give deep yellow solution. In a second 25 mL round bottom flask, combined 4-(2-chloropyridin-3-yl)-2-(methylthio)pyrimidine (100 mg, 0.421 mmol) and methanol (5.0 mL). The hydrogen peroxide solution was slowly added to the MeOH solution. The mixture was stirred at room temperature for 1 hour. Concentrated MeOH until a light yellow solid crashed out, filtered, washed with water, and dried to yield 4-(2-chloropyridin-3-yl)-2-(methylsulfonyl)pyrimidine as light yellow solid. MS (M+H) + =270.0, 271.9; Calc'd 269.71 for C 10 H 8 ClN 3 O 2 S.

Step 2. Preparation of 4-(2-chloropyridin-3-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine

In a 48 mL sealed pressure vessel, was added 4-(4-methylpiperazin-1-yl)benzenamine (0.851 g, 4.45 mmol), potassium carbonate (1.03 g, 7.42 mmol), N,N-dimethylformamide (10 mL) and 4-(2-chloropyridin-3-yl)-2-(methylsulfonyl)pyrimidine (Step 1, 1.0 g). the vessel was heated to 70° C. for 22 hours, cooled to room temperature, diluted with water, extracted into ethyl acetate, washed 1× with water and 1× with NaCl solution. The organics were dried over magnesium sulfate, filtered through fritted Buchner funnel, and concentrated. The crude was chromatographed on silica gel using 15-60% 90:10:1 (CH 2 Cl 2 :MeOH:NH 4 OH/CH 2 Cl 2 ) as a gradient. Concentrated the product fractions to yield 4-(2-chloropyridin-3-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine as a brown solid. MS (M+H) + =381. Calc'd 380.87 for C 20 H 21 ClN 6 .

Sodium hydride (880 mg, 22 mmol, 1.1 equiv, 60% in mineral oil) was washed with 15 mL of dry hexanes under an argon atmosphere. Most of the hexanes were removed and replaced with 40 mL of THF. 4-Chloro-7-azaindole was added portionwise into the sodium hydride suspension. The suspension was stirred until the gas evolution ceased. Triisopropylchlorosilane (3 g, 20 mmol, 1 equiv) was added via syringe. The reaction was placed in a preheated oil bath at 80° C. and monitored by LC-MS and TLC. After 3 hours, the reaction was cooled to room temperature. The reaction was quenched slowly with saturated NH 4 Cl. The product was extracted with hexanes and Et 2 O. The organic layers were combined, washed with brine, dried over MgSO 4 , and concentrated. The residue was passed through a plug of silica gel with an aid of hexanes to remove the baseline spots. The filtrate was concentrated to afford 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine as a viscous colorless oil.

4-Chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (5.03 g, 16.3 mmol, 1 equiv), 2-chloropyridine-3-boronic acid (4.36 g, 27.7 mmol, 1.7 equiv), palladium acetate (183 mg, 0.815 mmol, 5 mol %), 2-(dicyclohexylphosphino)biphenyl (571 mg, 1.63 mmol, 10 mol %), and finely ground anhydrous K 3 PO 4 (10.4 g, 48.9 mmol, 3 equiv) were added into a sealed tube. The tube was purged with argon for 5 minutes. Dioxane (30 mL) was added via syringe under a positive argon flow. The tube was sealed and the reaction was stirred at room temperature for 5 minutes. Then the tube was placed in a preheated oil bath at 110° C. for 2 h. The reaction was cooled down to room temperature. The content was filtered through a plug of celite with an aid of diethyl ether. The filtrated was concentrated under reduced pressure. The crude was purified by column chromatography using a mixture of 95:5 Hex:Et 2 O as eluent. The product, 4-(2-chloropyridine-3-yl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3,b]pyridine was obtained as a light yellow solid. 1 H′NMR (Varian, 300 MHz, CDCl 3 ): 8.35 (d, J=4.7 Hz, 1H), 8.30-8.28 (m, 1H), 8.10-8.03 (m, 1H), 7.40-7.30 (m, 2H), 7.15 (dd, J=4.3, 1.7 Hz, 1H), 6.54 (dd, J=3.6, 1.9 Hz, 1H), 1.89 (sept, J=7.4 Hz, 3H), 1.15 (d, J=7.4 Hz, 18H).

To 2-fluoro-4-iodopyridine (500 mg, 2.2 mmol) and cesium carbonate (730 mg, 2.2 mmol) was added THF (5 mL) and MeOH (0.091 mL, 2.2 mmol). The resulting mixture was heated to 50° C. for 24 hours in a sealed tube. The cooled mixture was diluted with water and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and concentrated to yield the title compound. MS m/z=236 [M+1] + . Calc'd for C 6 H 6 INO: 235.03.

To 4-iodo-2-methoxypyridine (834 mg, 3.55 mmol), 2-chloropyridine-3-boronic acid (838 mg, 5.32 mmol), Na 2 CO 3 (1.13 g, 10.7 mmol), Pd(OAc) 2 (40 mg, 0.18 mmol) and P(tBu) 3 ·HBF 4 (104 mg, 0.36 mmol) was added dioxane (12 mL) and water (4 mL). The mixture was heated overnight at 100° C. in a sealed tube. The resulting mixture was diluted with EtOAc and extracted with water and brine. The organic layer was dried over Na 2 SO 4 , filtered and concentrated. The resulting solid was triturated with MeOH and dried to yield the title compound. MS m/z=221 [M+1] + . Calc'd for C 21 H 9 ClN 2 O: 220.66.

Synthesis of N-(4-(2-chloropyridin-3-yl)pyrimidin-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

In an argon purged 500 mL round bottom flask placed in an isopropanol bath (used as a heat sink), added sodium metal (3.40 g, 148 mmol) slowly to methanol (180 mL). Stirred at RT for 30 minutes. Added guanidine hydrochloride (17.0 g, 182 mmol), stirred at RT for 30 minutes, added (E)-1-(2-chloropyridin-3-yl)-3-(dimethylamino)prop-2-en-1-one (12.0 g, 57.0 mmol), attached air condenser, and heated to 50° C. for 24 hours. Removed approximately half of the methanol by rotary evaporation. Filtered solids onto side-armed flask under vacuum, then washed with saturated NaHCO 3 and H 2 O, air dried to yield 4-(2-chloropyridin-3-yl)pyrimidin-2-amine as off-white solid. MS (M+H) + =206. Calc'd′206.63 for C 9 H 7 ClN 4 .

In a 50 mL round bottom flask, dissolved 4-(4-methylpiperazin-1-yl)benzoic acid (1.00 g, 4.50 mmol) in dichloromethane (5.0 mL). Added oxalyl chloride (1.2 mL, 9.1 mmol) and N,N-dimethylformamide (2 drops). Stirred at RT for 2 hours. Concentrated and isolated 4-(4-methylpiperazin-1-yl)benzoyl chloride as an off-white solid. LC/MS of methyl ester (quenched with methanol) revealed an MS (M+H) + of 235; Calc'd 234.29 for C 13 H 18 N 2 O 2 (methyl ester).

Step 3. Preparation of N-(4-(2-chloropyridin-3-yl)pyrimidin-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

In a 48 mL sealed pressure vessel, added 4-(2-chloropyridin-3-yl)pyrimidin-2-amine (Step 1, 0.72 g, 3.5 mmol), 4-(4-methylpiperazin-1-yl)benzoyl chloride (1.0 g, 4.2 mmol), chloroform (5.0 mL), and N,N-diisopropylethylamine (0.73 mL, 4.2 mmol). The mixture was stirred at 50° C. for 17 hours, and concentrated to yield N-(4-(2-chloropyridin-3-yl)pyrimidin-2-yl)-4-(4-methylpiperazin-1-yl)benzamide as a light brown solid. MS (M+H) + =409; Calc'd 408.88 for C 21 H 21 ClN 6 O.

The following, more specific, representative methods (designated herein as methods A-Q) were used to complete synthesis of exemplary compounds of Formulas I-III. The tabulated list of compounds following each representative A-Q method were synthesized by that method. For example, Examples 81a-197 were made by method A.

Method A

Synthesis of 4-Fluoro-3-(3-pyrimidin-4-yl-pyridin-2-ylamino)-N-[3-(tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-phenyl]-benzamide

4-(2-Chloro-pyridin-3-yl)-pyrimidine (240 mg, 1.2 mmol), 3-amino-4-fluorobenzoic acid (217 mg, 1.40 mmol), and 340 mg Et 3 N-TFA salt were mixed together in a sealed tube under argon. (The liquid Et 3 N-TFA reagent was generated by adding 2.5 mL TFA dropwise to a 0° C. solution of 3 mL Et 3 N in isopropanol, then concentrating by rotary evaporator followed by 30 minutes under high vacuum.). The mixture was melted at 95° C., and heating was continued overnight. The residue was triturated with a small amount of methanol and filtered to obtain the title compound as a solid. MS m/z=311 [M+H] + . Calc'd for C 16 H 11 FN 4 O 2 : 310.29.

Step 2. Preparation of 4-Fluoro-3-(3-pyrimidin-4-yl-pyridin-2-ylamino)-N-[3-(tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-phenyl]-benzamide

4-Fluoro-3-(3-pyrimidin-4-yl-pyridin-2-ylamino)-benzoic acid (142 mg, 0.46 mmol, azeotropically-dried from xylenes) was suspended in 4 mL dry DMF under N 2 . EDC (105 mg, 0.55 mmol) and DMAP (0.45 mmol) was added, and the mixture was stirred at 68° C. for ten minutes. After cooling, azeotropically-dried 3-(tetrahydro-furan-2-ylmethoxy)-5-trifluoromethyl-phenylamine (synthesized according to general procedures described U.S. Pat. Pub. 2003203922A1) in 3 mL DMF was added to the mixture, which was then stirred under N 2 at 68° C. for 18 h. Concentration, trituration with methanol, and filtration provided a yellow solid. Further purification was provided by flash chromatography (1:1:1 CH 2 Cl 2 /hexanes/t-BuOMe to 1% 10:1 MeOH in 1:1:1 CH 2 Cl 2 /hexanes/t-BuOMe). After concentration, trituration again with methanol provided the title compound as a yellow solid. MS m/z=554 [M+H] + . Calc'd for C 28 H 23 F 4 N5O 3 : 553.52.

Method B

Synthesis of 3-((3-(5-Fluoro-2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)amino)-4-methyl-N-(3-(1-methylethyl)phenyl)benzamide

To 2,4-dichloro-5-fluoropyrimidine (500 mg, 2.99 mmol), 2-chloropyridine-3-boronic acid (707 mg, 4.49 mmol), Pd(PPh 3 ) 4 (346 mg, 0.30 mmol) was added DME (9.0 mL) and 1 M NaHCO 3 (3.0 mL). The mixture was heated overnight in a sealed tube at 80° C., cooled to RT, diluted with EtOAc, and washed with water and saturated Na 2 CO 3 . The organic layer was dried over Na 2 SO 4 , filtered, concentrated and purified by reverse-phase HPLC to provide 2-chloro-4-(2-chloro-pyridin-3-yl)-5-fluoro-pyrimidine. MS m/z=244, 246 [M] + and [M+2] + . Calc'd for C 9 H 4 Cl 2 FN 3 : 244.06.

To 2-chloro-4-(2-chloro-pyridin-3-yl)-5-fluoro-pyrimidine (178 mg, 0.73 mmol) and methylamine hydrochloride (74 mg, 1.1 mmol) was added K 2 CO 3 (202 mg, 1.46 mmol) and DMSO (1.5 mL). The mixture was heated overnight in a sealed tube at 55° C. The mixture was cooled to RT, diluted with EtOAc and water, then neutralized with TFA (pH˜6-7). The organic layer was washed several times with water, dried over Na 2 SO 4 , filtered and concentrated to yield [4-(2-chloro-pyridin-3-yl)-5-fluoro-pyrimidin-2-yl]-methyl-amine. MS m/z=239 [M+1] + . Calc'd for C 10 H 8 ClFN 4 : 238.65.

Step 3. Preparation of 3-((3-(5-fluoro-2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)amino)-4-methyl-N-(3-(1-methylethyl)phenyl)benzamide

[4-(2-Chloro-pyridin-3-yl)-5-fluoro-pyrimidin-2-yl]-methyl-amine (62 mg, 0.26 mmol), 3-amino-N-(3-isopropyl-phenyl)-4-methyl-benzamide (84 mg, 0.31 mmol), Pd(OAc) 2 (6 mg, 0.03 mmol), rac-BINAP (16 mg, 0.03 mmol) and K 2 CO 3 (719 mg, 5.2 mmol) in toluene (3.0 mL) were reacted overnight at 130° C. The reaction was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na 2 SO 4 , filter, concentrated and purified by reverse-phase HPLC (Gilson, acidic mobile phase) yielding the title compound. MS m/z=471 [M+1] + . Calc'd for C 27 H 27 FN 6 O: 470.55.

To 3,4-dichlorobenzoic acid (200 mg, 1.05 mmol), 2,4-diaminotoluene (513 mg, 4.20 mmol), and EDC (403 mg, 2.10 mmol) was added CH 2 Cl 2 (40 mL). The mixture was stirred overnight at RT, concentrated, diluted with EtOAc and extracted with water. The organic layer was dried over Na 2 SO 4 , filtered, concentrated, and purified by flash chromatography (n-Hexanes→50% EtOAc/n-Hexanes) yielding N-(3-amino-4-methyl-phenyl)-3,4-dichloro-benzamide. MS m/z=295, 297 [M] + and [M+2] + . Calc'd for C 14 H 12 Cl 2 N 2 O: 295.17.

Step 2. Preparation of 3,4-dichloro-N-(4-methyl-3-((3-(4-pyrimidinyl)-2-pyridinyl)amino)phenyl)benzamide

4-(2-Chloro-pyridin-3-yl)-pyrimidine (60 mg, 0.30 mmol), N-(3-amino-4-methyl-phenyl)-3,4-dichloro-benzamide (107 mg, 0.36 mmol), Pd(OAc) 2 (4 mg, 0.012 mmol), rac-BINAP (8 mg, 0.012 mmol) and K 2 CO 3 (829 mg, 6.0 mmol) in toluene (3.0 mL) were reacted overnight at 130° C. The reaction was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na 2 SO 4 , filter, concentrated and purified by reverse-phase HPLC (Gilson, acidic mobile phase) yielding the title compound. MS m/z=450, 452 [M] + and [M+2] + . Calc'd for C 23 H 17 Cl 2 N 5 O: 450.33.

Method E

Synthesis of N-(2-fluoro-5-((3-(4-pyrimidinyl)-2-pyridinyl)amino)phenyl)-3-(trifluoromethyl)benzamide

4-(2-Chloro-pyridin-3-yl)-pyrimidine (60 mg, 0.30 mmol), 4-fluoro-3-nitrobenzenamine (56 mg, 0.36 mmol), Pd(OAc) 2 (4 mg, 0.012 mmol), rac-BINAP (8 mg, 0.012 mmol) and K 2 CO 3 (829 mg, 6.0 mmol) in toluene (3.0 mL) were reacted overnight at 130° C. The reaction was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na 2 SO 4 , filter, concentrated and purified by silica gel chromatography (0-100% EtOAc/hexanes) yielding the title compound. MS m/z=312 [M+1] + . Calc'd for C 15 H 10 FN 5 O 2 : 311.28.

N-(4-fluoro-3-nitrophenyl)-3-(pyrimidin-4-yl)pyridin-2-amine (62 mg, 0.20 mmol) was dissolved in THF (6 mL) and treated with Pd/C (5% Pd, 102 mg). The atmosphere was purged with hydrogen and the reaction was stirred under a balloon of H 2 for 2.5 days at RT. The mixture was filtered through a pad of Celite, concentrated and purified by silica gel chromatography (0-100% EtOAc/hexanes) to yield the title compound as a bright yellow solid. MS m/z=282 [M+1] + . Calc'd for C 15 H 12 FN 5 : 281.30.

Step 3. Preparation of N-(2-fluoro-5-((3-(4-pyrimidinyl)-2-pyridinyl)amino)phenyl)-3-(trifluoromethyl)benzamide

To 4-fluoro-N 1 -(3-(pyrimidin-4-yl)pyridin-2-yl)benzene-1,3-diamine (25 mg, 0.089 mmol) in CH 2 Cl 2 (1.5 mL) was added 3-(trifluoromethyl)benzoyl chloride (21 mg, 0.098 mmol). The mixture was stirred overnight at RT. The crude material was purified by preparative TLC (100% EtOAc), which yielded the title compound as a yellow solid. MS m/z=454 [M+1] + . Calc'd for C 23 H 15 F 4 N 5 : 453.40.

Method F

Synthesis of 4-methyl-N-(3-(2-(4-methylpiperazin-1-yl)ethoxy)-5-(trifluoromethyl)phenyl)-3-(3-(pyrimidin-4-yl)pyridin-2-ylamino)benzamide

A mixture of N-(3-(2-chloroethoxy)-5-(trifluoromethyl)phenyl)-4-methyl-3-(3-(pyrimidin-4-yl)pyridin-2-ylamino)benzamide (200 mg, 0.38 mmol), 1-methylpiperazine (76 mg, 0.76 mmol) and sodium iodide (catalytic amount) in DMF (5 ml) was heated at 100° C. for 20 hr. After cooling to RT, water (50 ml) was added and the mixture was extracted with EtOAc (3×50 ml). The combined organic layer was washed with brine (3×50 ml) and dried over Na 2 SO 4 . The solvent was removed in vacuo and the product was purified by flash column chromatography eluting with MeOH(NH3)/DCM (1 to 5%) to afford the title compound as a light yellow solid. MS m/z=592 [M+1] + . Calc'd for C 31 H 32 F 3 N 7 O 2 : 591.6.

Method G

Synthesis of 3-(3-(pyrimidin-4-yl)pyridin-2-ylamino)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)phenyl)benzamide

3-Nitro-4-(trifluoromethyl)benzoic acid (10 g, 43 mmol) was taken up in 100 ml of ethanol and sulfuric acid (11 ml) was added to the mixture. The reaction was heated to reflux for 12 hours. The volatiles were removed in vacuo. The residue obtained was diluted with ethyl acetate and water. The layers were separated and the organic layer was washed with an aqueous solution of saturated sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate and the volatiles removed in vacuo to give ethyl 3-nitro-4-(trifluoromethyl)benzoate a clear yellow oil.

Ethyl 3-nitro-4-(trifluoromethyl)benzoate (11.58 g, 44 mmol) was taken up in EtOH (150 ml) and vacuum purged. Then, under a nitrogen atmosphere, Pd/C (1.15 g) was added. The mixture was stirred at RT overnight under a hydrogen atmosphere using a balloon. The reaction was filtered through a pad of celite and the filtrate reduced under reduced pressure to give ethyl 3-amino-4-(trifluoromethyl)benzoate a white solid.

4-(2-Chloropyridin-3-yl)pyrimidine (1.5 g, 7.8 mmol), ethyl 3-amino-4-(trifluoromethyl)benzoate (2.0 g, 8.6 mmol), Sodium tert-butoxide (1.1 g, 12 mmol), rac-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.49 g, 0.78 mmol) were all mixed together in toluene (25 ml) and degassed under vacuum. Nitrogen was bubbled into the reaction for 5 minutes and then Palladium (II) acetate (0.088 g, 0.39 mmol) was added. The mixture was heated to 80° C. and stirred overnight. The reaction was diluted with ethyl acetate and washed with an aqueous saturated solution of sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient 5 to 40% ethyl acetate in hexanes to afford ethyl 3-(3-(pyrimidin-4-yl)pyridin-2-ylamino)-4-(trifluoromethyl)benzoate as a brown solid. MS m/z=389 [M+1] + . Calc'd for C 19 H 15 F 3 N 4 O 2 : 388.11.

Ethyl 3-(3-(pyrimidin-4-yl)pyridin-2-ylamino)-4-(trifluoromethyl)benzoate (2.50 g, 6 mmol) was suspended in EtOH (30 ml) and treated with 5N Sodium hydroxide (4 ml). The mixture was stirred at reflux overnight. The reaction was cooled down and the volatiles removed in vacuo. The residue was washed with diluted acetic acid (10:1 water:acetic acid) and then washed with water, to give 3-(3-(pyrimidin-4-yl)pyridin-2-ylamino)-4-(trifluoromethyl)benzoic acid as a yellow solid, after drying in a vacuum oven at 60° C. overnight. MS m/z=361 [M+1] + . Calc'd for C 17 H 11 F 3 N 4 O 2 : 360.08.

Step 5. Preparation of 3-(3-(pyrimidin-4-yl)pyridin-2-ylamino)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)phenyl)benzamide

3-(3-(Pyrimidin-4-yl)pyridin-2-ylamino)-4-(trifluoromethyl)benzoic acid (0.13 g, 0.36 mmol), 3-(trifluoromethyl)benzenamine (0.070 g, 0.43 mmol), TBTU (0.14 g, 0.43 mmol), DIPEA (0.13 ml, 0.72 mmol) were all mixed together in a 25 ml flask containing 3 ml of DMF. The mixture was stirred together at room temperature for 16 hours. The reaction was then diluted with an aqueous saturated solution of sodium bicarbonate and extracted with DCM. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and the purified by column chromatography on silica gel using a gradient of 30 to 80% EtOAc in hexanes to give 3-(3-(pyrimidin-4-yl)pyridin-2-ylamino)-4-(trifluoromethyl)-N-(3-(trifluoromethyl)phenyl)benzamide as an off-white solid. MS m/z=504 [M+1] + . Calc'd for C 24 H 15 F 6 N 5 O: 503.12.

Method H

Synthesis of N-((1R)-1-Cyclohexylethyl)-2-fluoro-5-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)benzamide

To a solution of 2-fluoro-5-[3-(2-methylamino-pyrimidin-4-yl)-pyridin-2-yloxy]-benzoyl chloride hydrochloride (86 mg, 0.22 mmol) in THF (2.0 mL) was added (R)-1-cyclohexyl-ethylamine (0.029 mL, 0.20 mmol). The mixture was stirred overnight at RT, quenched with excess NEt 3 , concentrated and purified by preparative TLC (100% EtOAc) to yield N-((1R)-1-cyclohexylethyl)-2-fluoro-5-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)benzamide. MS m/z=450 [M+1] + . Calc'd for C 25 H 28 FN 5 O 2 : 449.53.

Method I

Synthesis of 4-Methyl-3-((3-(6-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)-N-(3-(trifluoromethyl)phenyl)benzamide

4-Chloro-6-(2-chloro-pyridin-3-yl)-pyrimidine (450 mg, 1.99 mmol), methylamine hydrochloride (202 mg, 2.99 mmol), K 2 CO 3 (550 mg, 3.98 mmol) and DMSO (3.0 mL) were combined. The mixture was heated overnight at 80° C. in a sealed tube. The cooled mixture was diluted with water (300 mL) and the resulting solid was filtered, washed with water and dried to yield the title compound. MS m/z=221 [M+1] + . Calc'd for C 10 H 9 ClN 4 : 220.66.

Step 2. Preparation of 4-methyl-3-((3-(6-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)-N-(3-(trifluoromethyl)phenyl)benzamide

[6-(2-Chloro-pyridin-3-yl)-pyrimidin-4-yl]-methyl-amine (55 mg, 0.25 mmol), 3-hydroxy-4-methyl-N-(3-trifluoromethyl-phenyl)-benzamide (81 mg, 0.27 mmol), Cs 2 CO 3 (162 mg, 0.50 mmol) and DMSO (0.8 mL) were combined. The mixture was heated overnight at 125° C. in a sealed tube. The resulting mixture was cooled to RT, diluted with water and extracted with EtOAc. The aqueous layer was neutralized (pH˜7) with TFA and extracted with EtOAc. The organic layer was dried over Na 2 SO 4 , filtered and concentrated to yield the title compound. MS m/z=480 [M+1] + . Calc'd for C 25 H 20 F 3 N 5 O 2 : 479.47.

Method J

To 3-methyl-4-(3-(pyrimidin-4-yl)pyridin-2-yloxy)benzenamine (93 mg, 0.33 mmol) in CH 2 Cl 2 (8 mL) was added saturated sodium bicarbonate (4 mL) followed 5 minutes later by phosgene (20% solution in toluene, 0.27 mL, 0.50 mmol). The mixture was stirred for 15 minutes at RT, diluted with CH 2 Cl 2 and extracted with water. The organic layer was dried over sodium sulfate, filtered, concentrated and used without purification.

Step 2. Preparation of N-(2-((3-(dimethylamino)propyl)(methyl)amino)-5-(trifluoromethyl)phenyl)-N′-(3-methyl-4-((3-(4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)urea

To 4-(2-(4-isocyanato-2-methylphenoxy)pyridin-3-yl)pyrimidine (93 mg, 0.33 mmol) in toluene (3 mL) was added N 1 -(3-(dimethylamino)propyl)-N 1 -methyl-4-(trifluoromethyl)benzene-1,2-diamine (82 mg, 0.30 mmol). The mixture was stirred for 2.5 days at RT, then concentrated and purified by semi-preparative HPLC (Gilson, acidic mobile phase) to yield the title compound as an off-white solid. MS m/z=580 [M+H] + . Calc'd for C 30 H 32 F 3 N 7 O 2 : 579.63.

Synthesis of N-(5-Cyclohexyl-2-(methyloxy)phenyl)-N′-(3-methyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)urea

To 5-cyclohexyl-2-methoxy-phenylamine (106 mg, 0.49 mmol), CH 2 Cl 2 (10 mL) and saturated NaHCO 3 (5 mL) was added a 20% solution of COCl 2 in toluene (0.39 mL) directly to the organic layer. The mixture was stirred for 15 min at RT, diluted with CH 2 Cl 2 and extracted with water. The organic layer was dried over Na 2 SO 4 , filtered and concentrated to yield 4-cyclohexyl-2-isocyanato-1-methoxy-benzene.

4-Amino-2-methyl-phenol (84 mg, 0.68 mmol), Cs 2 CO 3 (665 mg, 2.04 mmol) and NMP (2.5 mL) were combined. The mixture was heated for 5 minutes at 100° C., cooled to RT and [4-(2-chloro-pyridin-3-yl)-pyrimidin-2-yl]-methyl-amine (150 mg, 0.68 mmol) was added. The mixture was heated in the microwave to 210° C. for 20 minutes, cooled, filtered through a plug of cotton and purified by reverse-phase HPLC (Gilson, acidic mobile phase) to yield the title compound. MS m/z=308 [M+1] + . Calc'd for C 17 H 17 N 5 O: 307.36.

Step 3. Preparation of N-(5-cyclohexyl-2-(methyloxy)phenyl)-N′-(3-methyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)urea

To 4-cyclohexyl-2-isocyanato-1-methoxy-benzene (56 mg, 0.24 mmol) in toluene (3.0 mL) was added {4-[2-(4-amino-2-methyl-phenoxy)-pyridin-3-yl]-pyrimidin-2-yl}-methyl-amine (46 mg, 0.15 mmol). The mixture was stirred overnight at RT, concentrated and purified by preparative TLC (50% EtOAc/CH 2 Cl 2 ) to yield N-(5-cyclohexyl-2-(methyloxy)phenyl)-N′-(3-methyl-4-((3-(2-(methylamino)-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)urea. MS m/z=539 [M+1] + . Calc'd for C 31 H 34 N 6 O 3 : 538.66.

[Note: there are many commercially available isocyanates which may also be reacted in a manner analogous that described in method J, and sulfonyl chlorides can also be added in an analogous fashion to that described in Method C.]

Method K

2,6-Dimethyl-3-nitrobenzenamine (10.4 g, 62.6 mmol) was dissolved in 75% sulfuric acid (200 ml). Mixture cooled to 0° C. and treated with a solution of sodium nitrite (4.53 g, 65.7 mmol) in concentrated sulfuric acid (25.0 ml). After the mixture had been stirred for 1 hour at this temperature, water (200 ml) was added and the mixture warmed to 60° C. until the evolution of gas ceased. The mixture was allowed to cool to room temperature and then filtered to afford 2,6-dimethyl-3-nitrophenol. MS m/z=168 (M+H) + . Calc'd for C 8 H 9 NO 3 : 169.18.

Dissolved 2,6-dimethyl-3-nitrophenol (1.96 g, 11.7 mmol) and 4-(2-chloropyridin-3-yl)pyrimidine (1.50 g, 7.83 mmol) in dimethylsulfoxide (15.0 ml) and added cesium carbonate (5.10 g, 15.7 mmol). Reaction mixture was heated to 120° C. in a sealed tube for 8 hours. Reaction mixture was then allowed to cool to room temperature and then poured into 250 mL of rapidly stirring water in an Erlenmeyer flask. After 10 minutes, the opaque brown aqueous solution was cooled to 0° C. and allowed to stand for 10 minutes, then filtered. The precipitate was collected as the title compound. MS m/z=323 (M+H) + . Calc'd for C 17 H 16 N 4 O 3 : 324.34.

Added tin(II) chloride dihydrate (6.13 g, 27.1 mmol) to a stirring solution/suspension of 4-(2-(2,6-dimethyl-3-nitrophenoxy)pyridin-3-yl)pyrimidine (1.75 g, 5.43 mmol) in methanol (20.0 ml). Heated reaction mixture to 65° C. for 1.25 hours. Filtered hot suspension through Celite which was washed with 20 mL MeOH and 200 mL EtOAc. The organic solution was then extracted with 3×100 1N HCl. The acidic aqueous phase was then basified with 5N NaOH and allowed to stand for 5 minutes. The aqueous phase was then extracted with 3×150 mL portions of CHCl 3 which was collected as a bright red-orange solution, dried over sodium sulfate and concentrated in vacuo to afford a brown solid. This was purified by column chromatography (10-100% (2.0 M NH 3 in MeOH) in dichloromethane) and concentrated to afford 2,4-dimethyl-3-(3-(pyrimidin-4-yl)pyridin-2-yloxy)benzenamine as a bright red-orange solid. MS m/z=293 (M+H) + . Calc'd for C 17 H 16 N 4 O: 292.34.

Step 4. Preparation of N-(2,4-dimethyl-3-(3-(pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-3-(trifluoromethyl)benzamide

Dissolved 2,4-dimethyl-3-(3-(pyrimidin-4-yl)pyridin-2-yloxy)benzenamine (100 mg, 0.342 mmol) in dichloromethane (1.0 mL), added 3-(trifluoromethyl)benzoyl chloride (107 mg, 0.513 mmol) and triethylamine (0.12 mL). Stirred at ambient temp for 4 hours and then concentrated and purified by reverse-phase HPLC (Gilson, acidic mobile phase) to yield the title compound. MS m/z=465 (M+H) + . Calc'd for C 25 H 19 F 3 N 4 O 2 : 464.45.

Method Q

To NaH (60% dispersion in mineral oil) (0.734, 18.3 mmol) in THF (100 mL) at 0° C. was added dropwise a solution of 2-fluoro-4-nitrobenzenamine (2.20 g, 14.1 mmol) in THF (25 mL). The solution turned deep red in color and was stirred at 0° C. for 1 hour. A solution of 2,3-dichlorobenzene-1-sulfonyl chloride (3.80 g, 15.5 mmol) in THF (25 mL) was then added dropwise, at which point the reaction turned orange/yellow in color. The mixture was allowed to warm to room temperature and then was stirred for and additional 30 minutes. The reaction was quenched by addition of NH 4 Cl (aq., sat.), and then concentrated. The mixture was partitioned between water and ethyl acetate. The organics were dried with MgSO 4 , filtered, and concentrated to afford 2,3-dichloro-N-(2-fluoro-4-nitrophenyl)benzenesulfonamide.

To a solution of 2,3-dichloro-N-(2-fluoro-4-nitrophenyl)benzenesulfonamide (5.0 g, 13.7 mmol) and Raney Nickel (0.600 g) in THF (200 mL) was applied positive H 2 pressure through a balloon/needle. The reaction was stirred at room temperature for 4 hours and then filtered. The mixture was concentrated and triturated with CH 2 Cl 2 to afford N-(4-amino-2-fluorophenyl)-2,3-dichlorobenzenesulfonamide as a grey solid.

Step 4. Preparation of 2,3-dichloro-N-(2-fluoro-4-(3-(pyrimidin-4-yl)pyridin-2-ylamino)phenyl)benzenesulfonamide

To N-(4-amino-2-fluorophenyl)-2,3-dichlorobenzenesulfonamide (0.150 g, 0.45 mmol) and 4-(2-chloropyridin-3-yl)pyrimidine (0.086 g, 0.45 mmol) was added NEt 3 .TFA. The mixture was heated at 100° C. CH 2 Cl 2 /MeOH was added, producing a yellow precipitate, which was filtered. Trituration with a further portion of CH 2 Cl 2 /MeOH, followed by filtration, afforded 2,3-dichloro-N-(2-fluoro-4-(3-(pyrimidin-4-yl)pyridin-2-ylamino)phenyl)benzenesulfonamide as an orange solid. MS m/z=491 [M+H] + . Calc'd for C 21 H 14 Cl 2 FN 5 O 2 S: 490.35.