# Patent

## Title
Indazole benzimidazole compounds

## Abstract

Organic compounds having the structure I are provided where the variables have the values described herein.




Pharmaceutical formulations and medicaments include the organic compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and may be prepared by mixing the organic compound or a pharmaceutically acceptable salt of the organic compound with a carrier and water. A method of treating a patient includes administering a pharmaceutical formulation or medicament according to the invention to a patient in need thereof.

## Background
CROSS REFERENCES TO RELATED APPLICATIONS
This application claims priority to U.S. Provisional Application No. 60/302,791 filed on Jul. 3, 2001, the entire disclosure of which is incorporated by reference herein and for all purposes.


FIELD OF THE INVENTION
This invention pertains generally to methods and compositions for treating a variety of patients and cell subjects. More particularly, the present invention provides novel compositions of matter and methods for angiogenesis inhibition, treating cancer, treating diabetes, stimulating insulin-dependent processes, treating Alzheimer's disease, treating central nervous system disorders, prolonging immune responses, reducing the splitting of centrosomes, blocking DNA repair, modulating cell cycle arrest, and inhibiting enzymes such as serine/threonine kinases and tyrosine kinases. The present invention thus has application in the areas of oncology, diabetes, immunology, and medicinal chemistry.
BACKGROUND OF THE INVENTION
Capillaries reach into almost all tissues of the human body and supply tissues with oxygen and nutrients as well as removing harmful waste products. Under typical conditions, the endothelial cells lining capillaries do not divide, and capillaries, therefore, do not normally increase in number or size in a human adult. Under certain normal conditions, however, such as when a tissue is damaged, or during certain parts of the menstrual cycle, capillaries begin to proliferate rapidly. This process of forming new capillaries from pre-existing blood vessels is known as angiogenesis or neovascularization. See Folkman, J. Scientific American 275, 150–154 (1996). Angiogenesis during wound healing is an example of pathophysiological neovascularization during adult life. During wound healing, the additional capillaries provide a supply of oxygen and nutrients, promote granulation tissue, and aid in waste removal. After termination of the healing process, the capillaries normally regress. Lymboussaki, A. “Vascular Endothelial Growth Factors and their Receptors in Embryos, Adults, and in Tumors” Academic Dissertation, University of Helsinki, Molecular/Cancer Biology Laboratory and Department of Pathology, Haartman Institute, (1999).
Angiogenesis also plays an important role in the growth of cancer cells. It is known that once a nest of cancer cells reaches a certain size, roughly 1 to 2 mm in diameter, the cancer cells must develop a blood supply in order for the tumor to grow larger as diffusion will not be sufficient to supply the cancer cells with enough oxygen and nutrients. A compound that inhibits angiogenesis will thus act to retard or halt the growth of cancer cells.
Receptor tyrosine kinases (RTKs) are polypeptides that regulate developmental cell growth and differentiation and remodeling and regeneration of adult tissues. Mustonen, T. et al., J. Cell Biology 129, 895–898 (1995); van der Geer, P. et al. Ann Rev. Cell Biol. 10, 251–337 (1994). Polypeptide ligands known as growth factors or cytokines, are known to activate RTKs. Signaling involves ligand binding and a shift in conformation in the external domain of the receptor resulting in its dimerization. Lymboussaki, A. “Vascular Endothelial Growth Factors and their Receptors in Embryos, Adults, and in Tumors” Academic Dissertation, University of Helsinki, Molecular/Cancer Biology Laboratory and Department of Pathology, Haartman Institute, (1999); Ullrich, A. et al., Cell 61, 203–212 (1990). Binding of the ligand to the RTK results in receptor trans-phosphorylation at specific tyrosine residues and activation of the catalytic domains for the phosphorylation of cytoplasmic substrates. Id.
Two subfamilies of RTKs are specific to the vascular endothelium. These include the VEGF subfamily and the Tie receptor subfamily. Class III RTKs include VEGFR-1, VEGFR-2, and VEGFR-3. Shibuya, M. et al., Oncogene 5, 519–525 (1990); Terman, B. et al., Oncogene 6, 1677–1683 (1991); Aprelikova, O. et al., Cancer Res. 52, 746–748 (1992).
A number of substances have been identified that promote angiogenesis. These include angiopoietin-1, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). VEGF was first described as a protein able to induce vascular permeability and endothelial cell proliferation and was identified as a major inducer of angiogenesis and vasculogenesis. Ferrara, N. et al., Endocrinol. Rev. 18, 4–25 (1997). VEGF is known to specifically bind to RTKs including VEGFR-1 and VEGFR-2. DeVries, C. et al., Science 255, 989–991 (1992); Quinn, T. et al., Proc. Natl. Acad. Sci. 90, 7533–7537 (1993). It is now known that VEGF stimulates the migration and proliferation of endothelial cells and induces angiogenesis both in vitro and in vivo. Connolly, D. et al., J. Biol. Chem. 264, 20017–20024 (1989); Connolly, D. et al., J. Clin. Invest. 84, 1470–1478 (1989); Ferrara, N. et al., Endocrino. Rew. 18, 4–25 (1997); Leung, D. et al., Science 246, 1306–1309 (1989); Plouet, J. et al., EMBO J 8, 3801–3806 (1989).
Because angiogenesis is known to be critical to the growth of cancer and to be controlled by VEGF and VEGF-RTK, substantial efforts have been undertaken to develop compounds which inhibit or retard angiogenesis and inhibit VEGF-RTK.
Platelet derived growth factor receptor kinase (PDGFRK) is another type of RTK. PDGF expression has been shown in a number of different solid tumors, from glioblastomas to prostate carcinomas. In these various tumor types, the biologicical role of PDGF signaling can vary from autocrine stimulation of cancer cell growth to more subtle paracrine interactions involving adjacent stroma and angiogenesis. Therefore, inhibiting the PDGFR kinase activity with small molecules may interfere with tumor growth and angiogenesis.
Tie-2 is a membrane RTK. Upon binding to its ligand, Tie-2 is activated and phosphorylates its downstream signal proteins. Tie-2 kinase activity may then trigger a pathway of cellular response that leads to stabilization of vascular vessels in cancer. Therefore, blocking kinase activity of Tie-2, in synergy with blockage of activity of other angiogenic kinases such as VEGF and bFGF receptor kinases, may be effective in cutting off the blood supply to cancer cells and in treating the disease.
Glycogen synthase kinase 3 (GSK-3) is a serine/threonine kinase for which two isoforms, α and β, have been identified. Woodgett, Trends Biochem. Sci., 16:177–81 (1991). Both GSK-3 isoforms are constitutively active in resting cells. GSK-3 was originally identified as a kinase that inhibits glycogen synthase by direct phosphorylation. Upon insulin activation, GSK-3 is inactivated, thereby allowing the activation of glycogen synthase and possibly other insulin-dependent events, such glucose transport. Subsequently, it has been shown that GSK-3 activity is also inactivated by other growth factors that, like insulin, signal through receptor tyrosine kinases (RTKs). Examples of such signaling molecules include IGF-1 and EGF. Saito et al., Biochem. J., 303:27–31 (1994); Welsh et al., Biochem. J. 294:625–29 (1993); and Cross et al., Biochem. J., 303:21–26 (1994).
Agents that inhibit GSK-3 activity are useful in the treatment of disorders that are mediated by GSK-3 activity. In addition, inhibition of GSK-3 mimics the activation of growth factor signaling pathways and consequently GSK-3 inhibitors are useful in the treatment of diseases in which such pathways are insufficiently active. Examples of diseases that can be treated with GSK-3 inhibitors are described below.
Type 2 diabetes is an increasingly prevalent disease of aging. It is initially characterized by decreased sensitivity to insulin and a compensatory elevation in circulating insulin concentrations, the latter of which is required to maintain normal blood glucose levels. Increased insulin levels are caused by increased secretion from the pancreatic beta cells, and the resulting hyperinsulinemia is associated with cardiovascular complications of diabetes. As insulin resistance worsens, the demand on the pancreatic beta cells steadily increases until the pancreas can no longer provide adequate levels of insulin, resulting in elevated levels of glucose in the blood. Ultimately, overt hyperglycemia and hyperlipidemia occur, leading to the devastating long-term complications associated with diabetes, including cardiovascular disease, renal failure and blindness. The exact mechanism(s) causing type 2 diabetes are unknown, but result in impaired glucose transport into skeletal muscle and increased hepatic glucose production, in addition to inadequate insulin response. Dietary modifications are often ineffective, therefore the majority of patients ultimately require pharmaceutical intervention in an effort to prevent and/or slow the progression of the complications of the disease. Many patients can be treated with one or more of the many oral anti-diabetic agents available, including sulfonylureas, to increase insulin secretion. Examples of sulfonylurea drugs include metformin for suppression of hepatic glucose production, and troglitazone, an insulin-sensitizing medication. Despite the utility of these agents, 30–40% of diabetics are not adequately controlled using these medications and require subcutaneous insulin injections. Additionally, each of these therapies has associated side effects. For example, sulfonylureas can cause hypoglycemia and troglitazone can cause severe hepatoxicity. Presently, there is a need for new and improved drugs for the treatment of prediabetic and diabetic patients.
As described above, GSK-3 inhibition stimulates insulin-dependent processes and is consequently useful in the treatment of type 2 diabetes. Recent data obtained using lithium salts provides evidence for this notion. The lithium ion has recently been reported to inhibit GSK-3 activity. Klein et al., PNAS 93:8455–9 (1996). Since 1924, lithium has been reported to have antidiabetic effects including the ability to reduce plasma glucose levels, increase glycogen uptake, potentiate insulin, up-regulate glucose synthase activity and to stimulate glycogen synthesis in skin, muscle and fat cells. However, lithium has not been widely accepted for use in the inhibition of GSK-3 activity, possibly because of its documented effects on molecular targets other than GSK-3. The purine analog 5-iodotubercidin, also a GSK-3 inhibitor, likewise stimulates glycogen synthesis and antagonizes inactivation of glycogen synthase by glucagon and vasopressin in rat liver cells. Fluckiger-Isler et al., Biochem J. 292:85–91 (1993); and Massillon et al., Biochem J. 299:123–8 (1994). However, this compound has also been shown to inhibit other serine/threonine and tyrosine kinases. Massillon et al., Biochem J. 299:123–8 (1994).
GSK-3 is also involved in biological pathways relating to Alzheimer's disease (AD). The characteristic pathological features of AD are extracellular plaques of an abnormally processed form of the amyloid precursor protein (APP), so called β-amyloid peptide (β-AP) and the development of intracellular neurofibrillary tangles containing paired helical filaments (PHF) that consist largely of hyperphosphorylated tau protein. GSK-3 is one of a number of kinases that have been found to phosphorylate tau protein in vitro on the abnormal sites characteristic of PHF tau, and is the only kinase also demonstrated to do this in living cells and in animals. Lovestone et al., Current Biology 4:1077–86 (1994); and Brownlees et al., Neuroreport 8: 3251–3255 (1997). Furthermore, the GSK-3 kinase inhibitor, LiCl, blocks tau hyperphosphorylation in cells. Stambolic et al., Current Biology 6:1664–8 (1996). Thus GSK-3 activity may contribute to the generation of neurofibrillary tangles and consequently to disease progression. Recently it has been shown that GSK-3β associates with another key protein in AD pathogenesis, presenillin 1 (PS1). Takashima et., PNAS 95:9637–9641(1998). Mutations in the PS1 gene lead to increased production of β-AP, but the authors also demonstrate that the mutant PS1 proteins bind more tightly to GSK-3β and potentiate the phosphorylation of tau, which is bound to the same region of PS1.
It has also been shown that another GSK-3 substrate, β-catenin, binds to PS1. Zhong et al., Nature 395:698–702 (1998). Cytosolic β-catenin is targeted for degradation upon phosphorylation by GSK-3 and reduced β-catenin activity is associated with increased sensitivity of neuronal cells to β-AP induced neuronal apoptosis. Consequently, increased association of GSK-3β with mutant PS1 may account for the reduced levels of β-catenin that have been observed in the brains of PS1-mutant AD patients and to the disease related increase in neuronal cell-death. Consistent with these observations, it has been shown that injection of GSK-3 antisense but not sense, blocks the pathological effects of β-AP on neurons in vitro, resulting in a 24 hour delay in the onset of cell death and increased cell survival at 1 hr from 12 to 35%. Takashima et al., PNAS 90:7789–93. (1993). In these latter studies, the effects on cell-death are preceded (within 3–6 hours of β-AP administration) by a doubling of intracellular GSK-3 activity, suggesting that in addition to genetic mechanisms that increase the proximity of GSK-3 to its substrates, β-AP may actually increase GSK-3 activity. Further evidence for a role for GSK-3 in AD is provided by the observation that the protein expression level (but, in this case, not specific activity) of GSK-3 is increased by 50% in postsynaptosomal supernatants of AD vs. normal brain tissue. Pei et al., J. Neuropathol Exp., 56:70–78 (1997). Thus, specific inhibitors of GSK-3 should slow the progression of Alzheimer's Disease.
In addition to the effects of lithium described above, there is a long history of the use of lithium to treat bipolar disorder (manic depressive syndrome). This clinical response to lithium may reflect an involvement of GSK-3 activity in the etiology of bipolar disorder, in which case GSK-3 inhibitors could be relevant to that indication. In support of this notion it was recently shown that valproate, another drug commonly used in the treatment of bipolar disorder, is also a GSK-3 inhibitor. Chen et al., J. Neurochemistry, 72:1327–1330 (1999). One mechanism by which lithium and other GSK-3 inhibitors may act to treat bipolar disorder is to increase the survival of neurons subjected to aberrantly high levels of excitation induced by the neurotransmitter, glutamate. Nonaka et al., PNAS 95: 2642–2647 (1998). Glutamate-induced neuronal excitotoxicity is also believed to be a major cause of neurodegeneration associated with acute damage, such as in cerebral ischemia, traumatic brain injury and bacterial infection. Furthermore it is believed that excessive glutamate signaling is a factor in the chronic neuronal damage seen in diseases such as Alzheimer's, Huntingdon's, Parkinson's, AIDS associated dementia, amyotrophic lateral sclerosis (AML) and multiple sclerosis (MS). Thomas, J. Am. Geriatr. Soc. 43: 1279–89 (1995). Consequently, GSK-3 inhibitors should provide a useful treatment in these and other neurodegenerative disorders.
GSK-3 phosphorylates transcription factor NF-AT and promotes its export from the nucleus, in opposition to the effect of calcineurin. Beals et al., Science 275:1930–33 (1997). Thus, GSK-3 blocks early immune response gene activation via NF-AT, and GSK-3 inhibitors may tend to permit or prolong activation of immune responses. Thus, GSK-3 inhibitors are believed to prolong and potentiate the immunostimulatory effects of certain cytokines, and such an effect may enhance the potential of those cytokines for tumor immunotherapy or indeed for immunotherapy in general.
Lithium has other biological effects. It is a potent stimulator of hematopoiesis, both in vitro and in vivo. Hammond et al., Blood 55: 26–28 (1980). In dogs, lithium carbonate eliminated recurrent neutropenia and normalized other blood cell counts. Doukas et al. Exp. Hematol. 14: 215–221 (1986). If these effects of lithium are mediated through the inhibition of GSK-3, GSK-3 inhibitors may have even broader applications. Since inhibitors of GSK-3 are useful in the treatment of many diseases, the identification of new inhibitors of GSK-3 would be highly desirable.
NEK-2 is a mammalian serine threonine kinase, which is structurally related to the NimA kinase from the fungus Aspergillus nidulans. Mutations in NimA result in G2 phase arrest of cells and overexpression of wt NimA results in premature chromatin condensation, even when ectopically expressed in mammalian cells. Both protein and kinase levels peak in S/G2 phase of the cell cycle. NimA also appears to be required for the localization of cdk1/cyclinB complex to the nucleus and spindle pole body. Histone H3 has been shown to be an in vitro substrate for the kinase, and if this is also the case in vivo, it may explain the role of the kinase in chromosome condensation. Six NimA kinases have been identified to date in mammals, and of these, NEK-2 appears to be the most closely related to NimA. It's activity is also cell cycle regulated, peaking in S/G2 phase. Overexpression of NEK-2, however, does not affect chromatin condensation but instead results in a pronounced splitting of centrosomes, possibly due to the loss of centriole/centriole adhesion. There is evidence that NEK-2 is regulated by phosphorylation and can interact with protein phosphatase PP1. NEK-2 is ubiquitously expressed and appears to be most abundant in testis. Hyseq cluster 374113, containing only NEK-2 sequences shows dramatic overexpression of NEK-2 in lymph node metastasis (13.3×) and in primary tumor (6.5×). Inhibition of NEK-2 by antisense oligonucleotides inhibited cell proliferation and reduced the capability of cells to grow in soft agar. In addition, increased cell death was observed in these cells both in the presence and absence of cisplatin.
Ultraviolet light, ionizing radiation, environmental agents and cytotoxic drugs can result in damage to cellular DNA integrity. When such damage occurs during DNA replication or cell division it is potentially catastrophic and may result in cell death. The cellular response is to arrest the cell cycle at one of two checkpoints (G1/S or G2/M) to either permit DNA repair or initiate apoptosis.




The G1/S checkpoint is regulated by the p53 transcriptional activator protein and the absence of this critical protein is often an important step in tumorigenesis, thus defining p53 as a tumor suppressor. In fact, nearly 50% of all cancers are p53 defective due to mutation. T. Soussi, Ann. N.Y. Acad Sci., 910, 121 (2001). In response to DNA damage, checkpoint kinase 2 (CHK-2) phosphorylates p53 and this results in stabilization of the protein and an elevation in p53 levels. A. Hirao et al., Science, 287, 1824 (2000). Consequently, negative cell cycle regulators, such as p21Waf1/Cip1, are activated and halt the cell cycle at the G1/S checkpoint. B. Vogelstein et al., Nature, 408, 307 (2000).
The G2/M checkpoint is monitored by the serine/threonine checkpoint kinase 1 (CHK-1). Upon DNA damage, the protein kinase ATR (ataxia-telangiectasia mutated—rad53 related kinase) is activated. H. Zhao et al., Mol. Cell Biol., 21, 4129 (2001); Q. Liu et al., Genes Dev., 14, 1448 (2000). SATR-dependent phosphorylation of CHK-1 promotes its phosphorylation of cdc25 and Wee1 and ultimately inactivation of cdc 2. Thus, CHK-1 phosphorylation of cdc25c targets it for nuclear export to the cytoplasm and as a result the cdc25c phosphatase is rendered unavailable to activate cdc 2 by dephosphorylation. Y. Sanchez et al., Science, 277, 1497 (1997); C. Y. Peng et al., Science, 277, 1501 (1997); T. A. Chen et al., Nature, 401, 616 (1999); and A. Lopez-Girona et al., Nature, 397, 172 (1999). In addition, CHK-1 activates the protein kinase Weel, which phosphorylates and inactivates cdc 2. J. Lee et al. Mol. Biol. Cell, 12, 551 (2001); L. L. Parker et al., Science, 257, 1955 (1992). These dual pathways thus converge to result in cell cycle arrest. Because cell cycle arrest is a potential mechanism by which tumor cells can overcome the damage induced by cytotoxic agents, abrogation of these checkpoints with novel therapeutic agents should increase the sensitivity of tumors to chemotherapy. The presence of two checkpoints, coupled with the tumor specific abrogation of one of these by p53 mutations in 50% of cancers, can be exploited to design tumor-selective agents. Thus, in p53 minus tumors, therapeutic inhibition of G2/M arrest leaves cancerous cells no options for DNA damage repair and results in apoptosis. Normal cells have wild type p53 and retain an intact G1/S checkpoint. Thus these cells have an opportunity to correct DNA damage and survive. One approach to the design of chemosensitizers that abrogate the G2/M checkpoint is to identify inhibitors of the key G2/M regulatory kinase, CHK-1.




The synthesis of various quinoline derivatives is disclosed in WO 97/48694. These compounds are disclosed as capable of binding to nuclear hormone receptors and being useful for stimulating osteoblast proliferation and bone growth. The compounds are also disclosed as being useful in the treatment or prevention of diseases associated with nuclear hormone receptor families.
Various quinoline derivatives in which the benzene ring of the quinolone is substituted with a sulfur group are disclosed in WO 92/18483. These compounds are disclosed as being useful in pharmaceutical formulations and as medicaments.
Various indolyl substituted compounds have recently been disclosed in WO 01/29025, and various benzimidazolyl substituted compounds have recently been disclosed in WO 01/28993. Such compounds are reportedly capable of inhibiting, modulating and/or regulating signal transduction of both receptor-type and non-receptor type tyrosine kinases. Neither of the PCT publications discloses benzimidazole-substituted indazoles.
Various indazole compounds and pharmaceutical formulations containing them are disclosed in WO 01/02369 and recently published WO 01/53268. Such compositions are purportedly useful for mediating tyrosine kinase signal transduction and thereby modulating and/or inhibiting cell proliferation. Some of the disclosed compounds include the benzimidazole group. Various benzimidazoles substituted with —C(═O)—NH2 are disclosed in WO 00/68206 as useful as inhibitors of the enzyme poly(ADP-ribose)polymerase and for use in producing medicaments.
A continuing need exists for compounds that inhibit the proliferation of capillaries, inhibit the growth of tumors, treat cancer, treat diabetes, stimulate insulin-dependent processes, treat Alzheimer's disease, treat central nervous system disorders, prolong immune responses, reduce the splitting of centrosomes, block DNA repair, modulate cell cycle arrest, and/or inhibit enzymes such as flt-1 (VEGFR2), KDR (VEGFR2), Flk-1, bFGFR, GSK-3, NEK-2, CHK-1, Tie-2, PDGF, and cdc 2, and pharmaceutical formulations and medicaments that contain such compounds. A need also exists for methods for administering such compounds, pharmaceutical formulations, and medicaments to patients or subjects in need thereof.
SUMMARY OF THE INVENTION
The present invention provides compounds, pharmaceutical formulations and medicaments including the compounds, methods of preparing the pharmaceutical formulations, medicaments, and compounds, and methods of treating patients with the pharmaceutical formulations and compounds.
The present invention provides compounds having the structure I. The invention also provides tautomers of the compounds, pharmaceutically acceptable salts of the compounds, and pharmaceutically acceptable salts of the tautomers. Structure I has the following formula:




where, in a first group of compounds:

Z1, Z2, Z3, and Z4 are selected independently from C or N;
R1—R8 are selected independently from the group consisting of —H, —F, —Cl, —Br, —C≡N, —NO2, —CF3, —CO2H, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)O-aryl groups, substituted and unsubstituted —C(═O)O-heteroaryl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted alkylheterocyclyl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heteroaryl groups, substituted and unsubstituted —C(═O)—N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted —C(═O)—N(alkyl)(heterocyclyl) groups, substituted and unsubstituted —C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heteroaryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heteroaryl groups, and substituted and unsubstituted heterocyclyl groups;
R9 is —H, —C(═O)-alkyl, or —C(═O)-aryl; and
R10 is —H, —C(═O)-alkyl, or —C(═O)-aryl.
More particular embodiments of the compounds of the invention having the general structure shown in I above are provided in a second group of compounds. The second group of compounds are those for which:
Z1, Z2, Z3, and Z4 are independently selected from C or N;
R1 is selected from —H, —F, —Cl, and —Br;
R2 is selected from —H, —F, —Cl, —Br, —C≡N, —NO2, —CO2H, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)O-aryl groups, substituted and unsubstituted —C(═O)O-heteroaryl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted heterocyclylalkoxy groups;
R3 is selected from —H, —F, —Cl, —Br, and substituted and unsubstituted alkoxy groups;
R4 is —H;
R5 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R5 is absent if Z1 is N;
R6 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, and substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups; or R6 is absent if Z2 is N;
R7 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, and substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups; or R7 is absent if Z3 is N;
R8 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R8 is absent if Z4 is N;
R9 is —H; and
R10 is —H. In some embodiments of the second group of compounds, at least one of R1, R2, R3, R5, R6, R7 or R8 is not —H. In other such embodiments, at least two of R1, R2, R3, R5, R6, R7 or R8 are not —H.
In some embodiments of the second group of compounds, R3 is selected from —F, —Cl, —Br, and substituted and unsubstituted alkoxy groups.
Other more particular embodiments of the compounds of the invention having the general structure shown in I above are provided. Such compounds form a third group of compounds for which:
Z1, Z2, Z3, and Z4 are independently selected from C or N;
R1 is selected from —H, —F, —Cl, —Br, —NO2, —C═N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R2 is selected from —H, —F, —Cl, —Br, —C≡N, —NO2, —CO2H, —OH, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)O-aryl groups, substituted and unsubstituted —C(═O)O-heteroaryl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, and substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups, substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted akoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted heterocyclyloxy, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-(H)—C(═O)-alkyl-heterocyclyl groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms;
R3 is selected from —H, —F, —Cl, —Br, —CF3, —C≡N, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)—O-alkyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted saturated heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted saturated heterocycyl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-(alkyl)-C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-(alkyl)-C(═O)-alkyl-heterocyclyl groups;
R4 is —H, —F, —Br, —Cl, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-(H)—C(═O)-alkyl-heterocyclyl groups;
R5 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R5 is absent if Z1 is N;
R6 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups; or R6 is absent if Z2 is N;
R7 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups; or R7 is absent if Z3 is N;
R8 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R8 is absent if Z4 is N;
R9 is —H; and
R10 is selected from the group consisting of —H, and substituted or unsubstituted alkyl groups. In some such embodiments of the third group of compounds, at least one of R1, R2, R3, R4, R5, R6, R7 or R8 is not —H. In other such embodiments, at least two of R1, R2, R3, R4, R5, R6, R7 or R8 are not —H.
In another embodiment of the third group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is selected from —H, —F, —Cl, and —OMe.
In another embodiment of the third group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is selected from the group consisting of —F, —Cl, —Br, —CF3, —C≡N, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, and substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms.
In another embodiment of the third group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is selected from the group consisting of substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, and substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups. In some such embodiments, R3 is a substituted or unsubstituted —N(H)C(═O)N(H)CH2CH3 group, a substituted or unsubstituted —N(H)C(═O)N(H)CH(CH3)2 group, a substituted or unsubstituted —N(H)C(═O)N(H)C(CH3)3 group, or a substituted or unsubstituted —N(H)C(═O)N(H)-aryl group or the like. In some such embodiments, R3 is a substituted or unsubstituted —N(H)C(═O)N(H)-aryl group such as, but not limited to, a —N(H)C(═O)N(H)-(2-methoxyphenyl) group, a-N(H)C(═O)N(H)-(trifluoromethylphenyl) group, or the like.
In another embodiment of the third group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —F, —Cl, or —OMe.
In some embodiments of the third group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and if R3 is H, at least one of R6 or R7 is selected from the group consisting of —CO2H, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted alkoxyalkoxy groups, substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted cycloalkylheterocyclyl groups, substituted and unsubstituted saturated heterocyclyloxy groups, substituted and unsubstituted —N(H)-alkyl groups, substituted and unsubstituted —N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted —N(H)-alkyl-aryl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups. In some such embodiments, if R3 is H, at least one of R6 or R7 is selected from the group consisting of —CO2H, substituted and unsubstituted saturated heterocyclyloxy groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups.
In another embodiment of the third group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is selected from a first group of compounds; or Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is selected from the first group of compounds, the first group of compounds comprising members selected from the group consisting of —CO2H, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted alkoxyalkoxy groups, substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted cycloalkylheterocyclyl groups, substituted and unsubstituted saturated heterocyclyloxy groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, substituted and unsubstituted heterocyclylamino groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, —C(═O)N(H)-heteroaryl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups.
In another embodiment of the third group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values defined in the previous embodiments, Z2 is C, and R6 is a substituted or unsubstituted heterocyclyl group. In some embodiments of the third group of compounds where R6 is a heterocyclyl group, the heterocyclyl group is selected from substituted or unsubstituted pyrrolidinyl groups, substituted and unsubstituted pyridyl groups, substituted and unsubstituted morpholinyl groups, substituted and unsubstituted piperazinyl groups, substituted and unsubstituted piperidinyl groups, substituted and unsubstituted pyrazolyl groups, substituted and unsubstituted pyrrolyl groups substituted and unsubstituted imidazolyl groups, substituted and unsubstituted 1-aza-4-oxacycloheptane groups, substituted and unsubstituted 1,4-diazacycloheptane groups, substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups, substituted and unsubstituted 1,4-diazabicyclo[2.2.2]octane groups, substituted or unsubstituted 1,4-diazabicyclo[4.3.0]nonane group, and substituted or unsubstituted 1,4-diazacycloheptane groups. In still other embodiments of the third group of compounds where R6 is a heterocyclyl group, the heterocyclyl group is an unsubstituted morpholine group; a dialkyl substituted morpholinyl group such as, but not limited to, a dimethyl substituted morpholinyl group, and the like, such as, but not limited to, a 3,5-dimethyl substituted morpholinyl group; a hydroxy substituted morpholinyl group; a hydroxyalkyl substituted morpholinyl group; an aryl substituted morpholinyl group; an aminoalkyl substituted morpholinyl group including dialkylaminoalkyl substituted morpholinyl groups such as, but not limited to, dimethylaminomethyl substituted morpholinyl groups and the like such as, but not limited to, a morpholinyl group that is substituted on a ring carbon bonded to the ring O atom with a dimethylaminomethyl group and is substituted with a methyl group on the carbon bonded to the ring N atom which carbon is not bonded to the carbon bearing the dimethylaminomethyl group and the like; a heterocyclyl substituted morpholinyl group; an unsubstituted piperazine group; a dialkyl substituted piperazinyl group such as, but not limited to, a dimethyl substituted piperazinyl group, and the like such as a 3,5-dimethyl substituted piperazinyl group and the like; a monoalkyl substituted piperazinyl group such as a 3-alkyl substituted piperazinyl group, an N-alkyl substituted piperazinyl group, and the like such as, but not limited to, a 3-methyl substituted piperazinyl group, a N-alkyl substituted piperazinyl group, such as, but not limited to, N-methyl, N-ethyl, N-isopropyl substituted piperazinyl groups and the like; a hydroxyalkyl substituted piperazinyl group such as, but not limited to, hydroxyethyl and hydroxymethyl substituted piperazinyl groups and the like such as, but not limited to, N-hydroxyethyl substituted piperazinyl groups and the like; an aryl substituted piperazinyl group; a heterocyclyl substituted piperazinyl group such as, but not limited to, 2-, 3-, and 4-(2-, 3-, and 4-piperidinyl) substituted piperazinyl groups and 2-, 3-, and 4-(2-, 3-, and 4-pyridyl) substituted piperazinyl groups and the like; a —CH2C(═O)O-alkyl substituted piperazinyl group; a —C(═O)-alkyl substituted piperazinyl group such as, but not limited to, a —C(═O)-ethyl or a —C(═O)-methyl substituted piperazinyl group, and the like such as a piperazinyl group where the —C(═O)-ethyl or the —C(═O)-methyl substitution is on one of the piperazinyl N atoms and the other N atom is bonded to Z2, and the like; a —C(═O)O-alkyl substituted piperazinyl group such as, but not limited to, a —C(═O)—O-ethyl or a —C(═O)—O-methyl substituted piperazinyl group, and the like such as a piperazinyl group where the —C(═O)—O-ethyl or the —C(═O)—O-methyl substitution is on one of the piperazinyl N atoms and the other N atom is bonded to Z2, and the like; a cycloalkyl substituted piperazinyl group such as, but not limited to, a cyclohexyl and cyclopentyl substituted piperazinyl group and the like such as, but not limited to, a N-cyclohexyl substituted piperazinyl group and the like; an unsubstituted piperidine group; an alkyl substituted piperidinyl group such as, but not limited to, 2-, 3-, and 4-alkyl substituted piperidinyl groups, and the like such as, but not limited to, 2-, 3-, and 4-hydroxyalkyl substituted piperidinyl groups and the like such as, but not limited to, 2-, 3-, and 4-hydroxymethyl substituted piperidinyl groups and the like; a hydroxy substituted piperidinyl group such as 2-, 3-, and 4-hydroxy substituted piperidinyl groups; a hydroxyalkyl substituted piperidinyl group; an aryl substituted piperidinyl group such as, but not limited to, a 4-aryl substituted piperidinyl group and the like such as, but not limited to, a piperidinyl group that is substituted in the 4 position with both an aryl group and a hydroxy group and the like such as, but not limited to, a piperidinyl group that is substituted in the 4 position with both a hydroxy group and a phenyl group; a cycloalkyl substituted piperidinyl group; a heterocyclyl substituted piperidinyl group such as, but not limited to, a piperidinyl substituted piperidinyl group and the like such as, but not limited to, 4-piperidinyl substituted piperidinyl groups, 4-(2(3H)-benzimidazolone) substituted piperidinyl group, and the like; an unsubstituted pyrrolidinyl group; an alkyl substituted pyrrolidinyl group such as, but not limited to, a methyl substituted pyrrolidinyl group, a heterocyclylalkyl substituted pyrrolidinyl group, and the like such as, but not limited to, a 2-methyl substituted pyrrolidinyl group, a 2-pyrrolidinylmethyl substituted pyrrolidinyl group, and the like; an amino substituted pyrrolidinyl group such as, but not limited to, a dialkylamino substituted pyrrolidinyl group such as, but not limited to, 2- and 3-dialkylamino substituted pyrrolidinyl groups and the like such as, but not limited to, 2- and 3-substituted N,N-dimethylamino substituted pyrrolidinyl groups and the like such as, but not limited to, a pyrrolidinyl group that is substituted with both an alkyl group and an N,N-dimethylamino group and the like such as, but not limited to, a pyrrolidinyl group that is substituted with a methyl group in the 2 position and with a N,N-dimethylamino group in the 4 position; a hydroxy substituted pyrrolidinyl group such as, but not limited to, 2- and 3-hydroxy substituted pyrrolidinyl groups; a heterocyclylalkyl substituted pyrrolidinyl group; substituted and unsubstituted pyrrolyl groups; substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups; an alkyl substituted 2,5-diazabicyclo[2.2.1]heptane group such as, but not limited to, a N-methyl substituted 2,5-diazabicyclo[2.2.1]heptane group and the like; a substituted or unsubstituted 1,4-diazabicyclo[4.3.0]nonane group; and a substituted or unsubstituted 1,4-diazacycloheptane group such as, but not limited to, an alkyl substituted 1,4-diazacycloheptane group and the like, such as, but not limited to, an N-alkyl substituted 1,4-diazacycloheptane substituted group and the like such as, but not limited to, a N-methyl substituted 1,4-diazacycloheptane group and the like. In still other embodiments of the third group of compounds where R6 is a substituted or unsubstituted heterocyclyl group, R7 is —H.
In another embodiment of the third group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is a substituted or unsubstituted heterocyclyl group. In some embodiments of the third group of compounds where R7 is a heterocyclyl group, the heterocyclyl group is selected from substituted or unsubstituted pyrrolidinyl groups, substituted and unsubstituted pyridyl groups, substituted and unsubstituted morpholinyl groups, substituted and unsubstituted piperazinyl groups, substituted and unsubstituted piperidinyl groups, substituted and unsubstituted pyrazolyl groups, substituted and unsubstituted pyrrolyl groups, substituted and unsubstituted imidazolyl groups, substituted and unsubstituted 1-aza-4-oxacycloheptane groups, substituted and unsubstituted 1,4-diazacycloheptane groups, substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups, substituted and unsubstituted 1,4-diazabicyclo[2.2.2]octane groups, substituted or unsubstituted 1,4-diazabicyclo[4.3.0]nonane group, and substituted or unsubstituted 1,4-diazacycloheptane groups. In still other embodiments of the third group of compounds where R7 is a heterocyclyl group, the heterocyclyl group is an unsubstituted morpholine group; a dialkyl substituted morpholinyl group such as, but not limited to, a dimethyl substituted morpholinyl group, and the like, such as, but not limited to, a 3,5-dimethyl substituted morpholinyl group; a hydroxy substituted morpholinyl group; a hydroxyalkyl substituted morpholinyl group; an aryl substituted morpholinyl group; an aminoalkyl substituted morpholinyl group including dialkylaminoalkyl substituted morpholinyl groups such as, but not limited to, dimethylaminomethyl substituted morpholinyl groups and the like such as, but not limited to, a morpholinyl group that is substituted on a ring carbon bonded to the ring O atom with a dimethylaminomethyl group and is substituted with a methyl group on the carbon bonded to the ring N atom which carbon is not bonded to the carbon bearing the dimethylaminomethyl group and the like; a heterocyclyl substituted morpholinyl group; an unsubstituted piperazine group; a dialkyl substituted piperazinyl group such as, but not limited to, a dimethyl substituted piperazinyl group, and the like such as a 3,5-dimethyl substituted piperazinyl group and the like; a monoalkyl substituted piperazinyl group such as a 3-alkyl substituted piperazinyl group, an N-alkyl substituted piperazinyl group, and the like such as, but not limited to, a 3-methyl substituted piperazinyl group, a N-alkyl substituted piperazinyl group, such as, but not limited to, N-methyl, N-ethyl, N-isopropyl substituted piperazinyl groups and the like; a hydroxyalkyl substituted piperazinyl group such as, but not limited to, hydroxyethyl and hydroxymethyl substituted piperazinyl groups and the like such as, but not limited to, N-hydroxyethyl substituted piperazinyl groups and the like; an aryl substituted piperazinyl group; a heterocyclyl substituted piperazinyl group such as, but not limited to, 2-, 3-, and 4-(2-, 3-, and 4-piperidinyl) substituted piperazinyl groups and 2-, 3-, and 4-(2-, 3-, and 4-pyridyl) substituted piperazinyl groups and the like; a —CH2C(═O)O-alkyl substituted piperazinyl group; a —C(═O)-alkyl substituted piperazinyl group such as, but not limited to, a —C(═O)-ethyl or a —C(═O)-methyl substituted piperazinyl group, and the like such as a piperazinyl group where the —C(═O)-ethyl or the —C(═O)-methyl substitution is on one of the piperazinyl N atoms and the other N atom is bonded to Z3, and the like; a —C(═O)O-alkyl substituted piperazinyl group such as, but not limited to, a —C(═O)—O-ethyl or a —C(═O)—O-methyl substituted piperazinyl group, and the like such as a piperazinyl group where the —C(═O)—O-ethyl or the —C(═O)—O-methyl substitution is on one of the piperazinyl N atoms and the other N atom is bonded to Z3, and the like; a cycloalkyl substituted piperazinyl group such as, but not limited to, a cyclohexyl and cyclopentyl substituted piperazinyl group and the like such as, but not limited to, a N-cyclohexyl substituted piperazinyl group and the like; an unsubstituted piperidine group; an alkyl substituted piperidinyl group such as, but not limited to, 2-, 3-, and 4-alkyl substituted piperidinyl groups, and the like such as, but not limited to, 2-, 3-, and 4-hydroxyalkyl substituted piperidinyl groups and the like such as, but not limited to, 2-, 3-, and 4-hydroxymethyl substituted piperidinyl groups and the like; a hydroxy substituted piperidinyl group such as 2-, 3-, and 4-hydroxy substituted piperidinyl groups; a hydroxyalkyl substituted piperidinyl group; an aryl substituted piperidinyl group such as, but not limited to, a 4-aryl substituted piperidinyl group and the like such as, but not limited to, a piperidinyl group that is substituted in the 4 position with both an aryl group and a hydroxy group and the like such as, but not limited to, a piperidinyl group that is substituted in the 4 position with both a hydroxy group and a phenyl group; a cycloalkyl substituted piperidinyl group; a heterocyclyl substituted piperidinyl group such as, but not limited to, a piperidinyl substituted piperidinyl group and the like such as, but not limited to, 4-piperidinyl substituted piperidinyl groups, 4-(2(3H)-benzimidazolone) substituted piperidinyl group, and the like; an unsubstituted pyrrolidinyl group; an alkyl substituted pyrrolidinyl group such as, but not limited to, a methyl substituted pyrrolidinyl group, a heterocyclylalkyl substituted pyrrolidinyl group, and the like such as, but not limited to, a 2-methyl substituted pyrrolidinyl group, a 2-pyrrolidinylmethyl substituted pyrrolidinyl group, and the like; an amino substituted pyrrolidinyl group such as, but not limited to, a dialkylamino substituted pyrrolidinyl group such as, but not limited to, 2- and 3-dialkylamino substituted pyrrolidinyl groups and the like such as, but not limited to, 2- and 3-substituted N,N-dimethylamino substituted pyrrolidinyl groups and the like such as, but not limited to, a pyrrolidinyl group that is substituted with both an alkyl group and an N,N-dimethylamino group and the like such as, but not limited to, a pyrrolidinyl group that is substituted with a methyl group in the 2 position and with a N,N-dimethylamino group in the 4 position; a hydroxy substituted pyrrolidinyl group such as, but not limited to, 2- and 3-hydroxy substituted pyrrolidinyl groups; a heterocyclylalkyl substituted pyrrolidinyl group; substituted and unsubstituted pyrrolyl groups; substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups; an alkyl substituted 2,5-diazabicyclo[2.2.1]heptane group such as, but not limited to, a N-methyl substituted 2,5-diazabicyclo[2.2.1]heptane group and the like; a substituted or unsubstituted 1,4-diazabicyclo[4.3.0]nonane group; and a substituted or unsubstituted 1,4-diazacycloheptane group such as, but not limited to, an alkyl substituted 1,4-diazacycloheptane group and the like, such as, but not limited to, an N-alkyl substituted 1,4-diazacycloheptane substituted group and the like such as, but not limited to, a N-methyl substituted 1,4-diazacycloheptane group and the like. In still other embodiments of the third group of compounds where R7 is a substituted or unsubstituted heterocyclyl group, R6 is —H.
Other more particular embodiments of the compounds of the invention having the general structure shown in I above are provided. Such compounds form a fourth group of compounds for which:
Z1, Z2, Z3, and Z4 are independently selected from C or N;
R1 is selected from —H, —F, —Cl, —Br, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, and substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R2 is selected from —H, —F, —Cl, —Br, —C≡N, —NO2, —CO2H, —OH, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)O-aryl groups, substituted and unsubstituted —C(═O)O-heteroaryl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups, substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted akoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted heterocyclyloxy, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms;
R3 is selected from —H, —F, —Cl, —Br, —CF3, —C≡N, —NO2, —CO2H, substituted and unsubstituted —C(═O)—O-alkyl groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy group, substituted and unsubstituted heterocycyl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups;
R4 is —H, —F, —Br, —Cl, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R5 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R5 is absent if Z1 is N;
R6 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups; or R6 is absent if Z2 is N;
R7 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups; or R7 is absent if Z3 is N;
R8 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R8 is absent if Z4 is N;
R9 is —H; and
R10 is selected from the group consisting of —H, and substituted and unsubstituted alkyl groups. In some such embodiments of the fourth group of compounds, at least one of R1, R2, R3, R4, R5, R6, R7 or R8 is not —H. In other such embodiments, at least two of R1, R2, R3, R4, R5, R6, R7 or R8 are not —H.
In some embodiments of the fourth group of compounds, R1 is an unsubstituted —NH2 group or is a substituted or unsubstituted heterocyclylamino group such as, but not limited to, substituted and unsubstituted pyrroldinylalkylamino groups and the like, such as, but not limited to, substituted and unsubstituted pyrrolidinylmethylamino groups and the like such as, but not limited to, —N(H)—CH2-(2-pyrrolidinyl) groups and the like.
In another embodiment of the fourth group of compounds, R2 is selected from the group consisting of substituted and unsubstituted thiazolylalkylamino groups, substituted and unsubstituted pyrrolidinylalkylamino groups, and substituted and unsubstituted aminoalkylamino groups. In other such embodiments, R2 is selected from the group consisting of —N(H)—CH2-(2-thiazolyl) groups, —N(H)—CH2-(2-pyrroldinyl groups), —N(H)—CH2CH2CH2—N(H)(alkyl) groups, and —NH—CH2CH2CH2—N(alkyl)2 groups. In still other such embodiments, R2 is selected from the group consisting of —N(H)—CH2-(2-thiazolyl) groups, —N(H)—CH2-(2-pyrroldinyl groups), —N(H)—CH2CH2CH2—N(H)(CH3) groups, and —NH—CH2CH2CH2—N(CH3)2 groups.
In another embodiment of the fourth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is selected from the group consisting of —F, —Cl, —Br, —CF3, —C≡N, —NO2, —CO2H, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups and substituted and unsubstituted —C(═O)N(H)-alkyl-heterocyclyl groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms.
In another embodiment of the fourth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is selected from the group consisting of substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, and substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups. In some such embodiments, R3 is a substituted or unsubstituted —N(H)C(═O)N(H)CH2CH3 group, a substituted or unsubstituted —N(H)C(═O)N(H)CH(CH3)2 group, a substituted or unsubstituted —N(H)C(═O)N(H)C(CH3)3 group, or a substituted or unsubstituted —N(H)C(═O)N(H)-aryl group or the like. In some such embodiments, R3 is a substituted or unsubstituted —N(H)C(═O)N(H)-aryl group such as, but not limited to, a —N(H)C(═O)N(H)-(2-methoxyphenyl) group, a-N(H)C(═O)N(H)-(trifluoromethylphenyl) group, or the like.
In other embodiments of the fourth group of compounds, R3 is selected from the group consisting of substituted and unsubstituted thiazolylalkylamino groups, substituted and unsubstituted benzimidazolylalkylamino groups, substituted and unsubstituted imidazolylalkylamino groups, substituted and unsubstituted furanylalkylamino groups, and substituted and unsubstituted arylalkylamino groups. In some such embodiments, R3 is selected from the group consisting of (2-thiazolyl)alkylamino groups, 1-(3-methylbenzimidazolyl)alkylamino groups, 4-(2-phenylimidazolyl)alkylamino groups, 4-(2-ethyl-5-methylimidazolyl)alkylamino groups, (2-furanyl)alkylamino groups, phenylalkylamino groups, and 1-(2-fluoro-5-alkoxyphenyl)alkylamino groups. In still other such embodiments, R3 is selected-from the group consisting of —N(H)—CH2-(2-thiazolyl) groups, —N(H)—CH2-(1-(3-methylbenzimidazolyl)) groups, —N(H)—CH2-(4-(2-phenylimidazolyl)) groups, —N(H)—CH2-(4-(2-ethyl-5-methylimidazolyl)) groups, —N(H)—CH2-(2-furanyl) groups, —N(H)—CH2-phenyl groups, and —N(H)—CH2-(1-(2-fluoro-5-alkoxyphenyl)) groups.
In still another embodiment, R1 is selected from the group consisting of unsubstituted —NH2 groups, and substituted and unsubstituted pyrrolidinylalkylamino groups; R2 is selected from the group consisting of substituted and unsubstituted thiazolylalkylamino groups, substituted and unsubstituted pyrrolidinylalkylamino groups, and substituted and unsubstituted aminoalkylamino groups; and/or R3 is selected from the group consisting of substituted and unsubstituted thiazolylalkylamino groups, substituted and unsubstituted benzimidazolylalkylamino groups, substituted and unsubstituted imidazolylalkylamino groups, substituted and unsubstituted furanylalkylamino groups, and substituted and unsubstituted arylalkylamino groups. In such compounds, Z1–Z4, R4, R5, R6, R7, R8, R9, and R10 can have any of the other values described in any of the other embodiments of any of the groups of compounds.
In another embodiment of the fourth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is selected from a first group; or Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is selected from the first group, the first group comprising members selected from the group consisting of —Br, —CO2H, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted alkoxyalkoxy groups, substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted cycloalkylheterocyclyl groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, substituted and unsubstituted heterocyclylamino groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups. In some such embodiments, R3 is selected from the group consisting of —F, —Cl, —Br, —CF3, —C≡N, —NO2, —CO2H, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, and substituted and unsubstituted —C(═O)N(H)-alkyl-heterocyclyl groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms.
Other more particular embodiments of the compounds of the invention having the general structure shown in I above are provided. Such compounds form a fifth group of compounds for which:
Z1, Z2, Z3, and Z4 are independently selected from C or N;
R1 is selected from —H, —F, —Cl, —Br, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, and substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R2 is selected from —H, —F, —Cl, —Br, —C≡N, —NO2, —CO2H, —OH, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)O-aryl groups, substituted and unsubstituted —C(═O)O-heteroaryl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups, substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted akoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted heterocyclyloxy, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms;
R3 is selected from —F, —Cl, —Br, —CF3, —C≡N, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted saturated heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted saturated heterocycyl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, and substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups;
R4 is —H, —F, —Br, —Cl, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R5 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R5 is absent if Z1 is N;
R6 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups; or R6 is absent if Z2 is N;
R7 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups; or R7 is absent if Z3 is N;
R8 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R8 is absent if Z4 is N;
R9 is —H; and
R10 is selected from the group consisting of —H, and substituted and unsubstituted alkyl groups.
Other more particular embodiments of the compounds of the invention having the general structure shown in I above are provided. Such compounds form a sixth group of compounds for which:
Z1, Z2, Z3, and Z4 are independently selected from C or N;
R1 is selected from —H, —F, —Cl, —Br, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R2 is selected from —F, —Cl, —Br, —C≡N, —CO2H, —OH, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)O-aryl groups, substituted and unsubstituted —C(═O)O-heteroaryl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups, substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted heterocyclyloxy, and substituted and unsubstituted heterocyclylalkoxy groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms;
R3 is selected from —H, —F, —Cl, —Br, —CF3, —C≡N, —NO2, —CO2H, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—O-alkyl groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy group, substituted and unsubstituted heterocycyl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)NH-alkyl groups, substituted and unsubstituted —C(═O)N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R4 is —H, —F, —Br, —Cl, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R5 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R5 is absent if Z1 is N;
R6 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups; or R6 is absent if Z2 is N;
R7 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups; or R7 is absent if Z3 is N;
R8 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R8 is absent if Z4 is N;
R9 is —H; and
R10 is selected from the group consisting of —H, and substituted and unsubstituted alkyl groups.
Other more particular embodiments of the compounds of the invention having the general structure shown in I above are provided. Such compounds form a seventh group of compounds for which:
Z1, Z2, Z3, and Z4 are independently selected from C or N;
R1 is selected from —H, —F, —Cl, —Br, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R2 is selected from —H, —F, —Cl, —Br, —C≡N, —NO2, —CO2H, —OH, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)O-aryl groups, substituted and unsubstituted —C(═O)O-heteroaryl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups, substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted akoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted heterocyclyloxy, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms;
R3 is selected from —H, —F, —Cl, —Br, —CF3, —C≡N, —NO2, —CO2H, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—O-alkyl groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy group, substituted and unsubstituted heterocycyl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R4 is —H, —F, —Br, —Cl, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl) aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R5 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R5 is absent if Z1 is N;
R6 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups; or R6 is absent if Z2 is N;
R7 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups; or R7 is absent if Z3 is N;
R8 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R8 is absent if Z4 is N;
R9 is —H;
R10 is selected from the group consisting of —H, and substituted and unsubstituted alkyl groups; and
at least one of Z2 or Z3 is C and at least one of R6 or R7 is selected from the group consisting of substituted and unsubstituted piperidinyl substituted heterocyclyl groups, substituted and unsubstituted heterocyclyl substituted piperidinyl groups, substituted and unsubstituted hydroxymethyl substituted piperidinyl groups, dimethylaminoalkyl substituted pyrrolidinyl groups, substituted and unsubstituted 3-alkyl substituted piperazinyl groups, substituted and unsubstituted 3,5-dialkyl substituted piperazinyl groups, substituted and unsubstituted N-hydroxyalkyl substituted piperazinyl groups, substituted and unsubstituted 1,4-diazacycloheptyl groups, substituted and unsubstituted 1-aza-4-oxacycloheptyl groups, substituted and unsubstituted N-ethylpiperazinyl groups, substituted and unsubstituted N-isopropylpiperazinyl groups, substituted and unsubstituted N-sec-butylpiperazinyl groups, substituted and unsubstituted N-2-pyridyl substituted piperazinyl groups, substituted and unsubstituted N-3-pyridyl substituted piperazinyl groups, substituted and unsubstituted N-4-pyridyl substituted piperazinyl groups, substituted and unsubstituted N(H)—CH2-pyridyl groups, substituted and unsubstituted imidazolyl groups, substituted and unsubstituted 3-alkyl substituted morpholinyl groups, substituted and unsubstituted 3,5-dialkyl substituted morpholinyl groups, dialkylamino substituted pyrrolidinyl groups, pyrrolidinyl groups substituted with both dialkylamino and alkyl groups, substituted and unsubstituted 4-hydroxy substituted piperidinyl groups, substituted and unsubstituted 4-aryl substituted piperidinyl groups, substituted and unsubstituted 4-hydroxy-4-phenyl substituted piperidinyl groups, substituted and unsubstituted cyclohexylpiperazinyl groups, substituted and unsubstituted cyclopentylpiperazinyl groups, substituted and unsubstituted N-alkyl substituted diazabicycloalkane groups, substituted and unsubstituted —N(CH3)(N-alkyl(4-piperidinyl)) groups, substituted and unsubstituted piperazinyl groups further substituted with a —C(═O)-alkyl group on one of the N atoms of the piperazinyl group, substituted and unsubstituted —N(H)CH2CH2CH2-imidazolyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-pyrrolidinyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-morpholinyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-piperazinyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-piperidinyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-pyridyl groups, substituted and unsubstituted —N(H)CH2CH2-imidazolyl groups, substituted and unsubstituted —N(H)CH2CH2-pyrrolidinyl groups, substituted and unsubstituted —N(H)CH2CH2-morpholinyl groups, substituted and unsubstituted —N(H)CH2CH2-piperazinyl groups, substituted and unsubstituted —N(H)CH2CH2-piperidinyl groups, substituted and unsubstituted —N(H)CH2CH2-pyridyl groups, substituted and unsubstituted cyclobutylpiperazinyl groups, substituted and unsubstituted —OCH2-pyrrolidinyl groups, substituted and unsubstituted —OCH2CH2-pyrrolidinyl groups, substituted and unsubstituted —OCH2CH2CH2-pyrrolidinyl groups, substituted and unsubstituted piperazinyl groups further substituted with a —CH2C(═O)—O-alkyl group bonded to one of the N atoms of the piperazinyl group, substituted and unsubstituted piperazinyl groups further substituted with a —C(═O)—O-alkyl group bonded to one of the N atoms of the piperazinyl group, substituted and unsubstituted hydroxypyrrolidinyl groups, substituted and unsubstituted hydroxypiperidinyl groups, substituted and unsubstituted —OCH2-pyridyl groups, substituted and unsubstituted piperidinylamino groups, substituted and unsubstituted pyridyloxy groups with a —C(═O)—N(H)(alkyl) group bonded to a carbon atom of the pyridine ring of the pyridyloxy group, and substituted and unsubstituted pyridyloxy groups with a —C(═O)—N(alkyl)2 group bonded to a carbon atom of the pyridine ring of the pyridyloxy group.
The invention further provides many other embodiments of compounds having the formula I and embodiments of the first, second, third, fourth, fifth, sixth, and seventh groups of compounds having the formula I.
Pharmaceutical formulations according to the present invention are provided which include any of the compounds described above in combination with a pharmaceutically acceptable carrier.
The invention further provides methods for synthesizing the compounds of formula I according to the first through seventh groups.
A method of treating a patient is also provided which includes administering an effective amount of the pharmaceutical formulation according to the present invention to a patient in need thereof.
A method for inhibiting tumor growth in a patient is provided and includes administering an effective amount of a compound according to the invention to a patient having a tumor.
A method for inhibiting the proliferation of capillaries in a patient in need is still further provided and includes administering an effective amount of a compound according to the present invention to a patient in need.
Various other methods for inhibiting enzymes and treating patients and cells are further disclosed in the following detailed description.
Further objects, features and advantages of the invention will be apparent from the following detailed description.


DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel class of compounds which act as inhibitors of receptor tyrosine kinases, including inhibitors of bFGF, VEGF-RTK, KDR, Flk-1, GSK-3, NEK-2, CHK-1, Tie-2, PDGF, and cdc 2. These compounds can be formulated into pharmaceutical formulations that are useful in treating patients with a need for such inhibitors (e.g., those suffering from cancer). The compounds described herein are also useful for reducing capillary proliferation and in the treatment of cancer and other medical or cellular conditions in human and cell subjects.
The following abbreviations and definitions are used throughout this application:
“VEGF” is an abbreviation that stands for vascular endothelial growth factor.
“RTK” is an abbreviation that stands for receptor tyrosine kinase.
“VEGF-RTK” is an abbreviation that stands for vascular endothelial growth factor receptor tyrosine kinase.
“Flt-1” is an abbreviation that stands for fms-like tyrosine kinase-1, also known as vascular endothelial growth factor receptor-1 or VEGFR1.
“KDR” is an abbreviation that stands for kinase-insert domain tyrosine kinase, also known as vascular endothelial growth factor receptor-2 or VEGFR2.
“bFGF” is an abbreviation that stands for basic fibroblast growth factor.
“bFGFR” is an abbreviation that stands for basic fibroblast growth factor receptor.
“GSK-3” is an abbreviation that stands for glycogen synthase kinase 3.
“NEK-2” is an abbreviation that stands for NIM-A related kinase.
“NIM-A” is an abbreviation that stands for never in mitosis.
“CHK 1” is an abbreviation that stands for checkpoint kinase 1.
“Cdc 2” is an abbreviation that stands for cell division cycle 2.
“Tie-2” is an abbreviation that stands for tyrosine kinase with Ig and EGF homology domains.
“PDGF” is an abbreviation that stands for platelet derived growth factor.
“Flk-1” is an abbreviation that stands for fetal liver tyrosine kinase 1.
“AD” is an abbreviation that stands for Alzheimer Disease.
“APP” is an abbreviation that stands for amyloid precursor protein.
“PHF” is an abbreviation that stands for paired helical filaments.
“PS 1” is an abbreviation that stands for presenellin 1.
“MS” is an abbreviation that stands for multiple sclerosis.
“AML” is an abbreviation that stands for amyotropic lateral sclerosis.
Generally, reference to a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
The phrase “unsubstituted alkyl” refers to alkyl groups that do not contain heteroatoms. Thus the phrase includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The phrase also includes branched chain isomers of straight chain alkyl groups, including but not limited to, the following which are provided by way of example: —CH(CH3)2, —CH(CH3)(CH2CH3), —CH(CH2CH3)2, —C(CH3)3, —C(CH2CH3)3, —CH2CH(CH3)2, —CH2CH(CH3)(CH2CH3), —CH2CH(CH2CH3)2, —CH2C(CH3)3, —CH2C(CH2CH3)3, —CH(CH3)CH(CH3)(CH2CH3), —CH2CH2CH(CH3)2, —CH2CH2CH(CH3)(CH2CH3), —CH2CH2CH(CH2CH3)2, —CH2CH2C(CH3)3, —CH2CH2C(CH2CH3)3, —CH(CH3)CH2CH(CH3)2, —CH(CH3)CH(CH3)CH(CH3)2, —CH(CH2CH3)CH(CH3)CH(CH3)(CH2CH3), and others. The phrase also includes cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted with straight and branched chain alkyl groups as defined above. Thus the phrase unsubstituted alkyl groups includes primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. Unsubstituted alkyl groups may be bonded to one or more carbon atom(s), oxygen atom(s), and/or nitrogen atom(s) in the parent compound. Preferred unsubstituted alkyl groups include straight and branched chain alkyl groups and cyclic alkyl groups having 1 to 20 carbon atoms. More preferred such unsubstituted alkyl groups have from 1 to 10 carbon atoms while even more preferred such groups have from 1 to 8, from 1 to 6 or from 1 to 4 carbon atoms. Other preferred unsubstituted alkyl groups include straight and branched chain alkyl groups having from 1 to 3 carbon atoms and include methyl, ethyl, propyl, and —CH(CH3)2.
The phrase “substituted alkyl” refers to an unsubstituted alkyl group as defined above in which one or more bonds to a carbon(s) or hydrogen(s) are replaced by a bond to non-hydrogen and non-carbon atoms such as, but not limited to, a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, and ester groups; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as in trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. Substituted alkyl groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom is replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; nitrogen in groups such as imines, oximes, hydrazones, and nitriles. Substituted alkyl groups further include alkyl groups in which one or more bonds to a carbon(s) or hydrogen(s) atoms is replaced by a bond to an aryl, heterocyclyl group, or cycloalkyl group. Preferred substituted alkyl groups include, among others, alkyl groups in which one or more bonds to a carbon or hydrogen atom is/are replaced by one or more bonds to fluorine atoms. Another preferred substituted alkyl group is the trifluoromethyl group and other alkyl groups that contain the trifluoromethyl group. Other preferred substituted alkyl groups include those in which one or more bonds to a carbon or hydrogen atom is replaced by a bond to an oxygen atom such that the substituted alkyl group contains a hydroxyl, alkoxy, or aryloxy group. Still other preferred substituted alkyl groups include alkyl groups that have an amine, or a substituted or unsubstituted alkylamine, dialkylamine, arylamine, (alkyl)(aryl)amine, diarylamine, heterocyclylamine, diheterocyclylamine, (alkyl)(heterocyclyl)amine, or (aryl)(heterocyclyl)amine group.
The phrase “unsubstituted aryl” refers to aryl groups that do not contain heteroatoms. Thus the phrase includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphthenyl by way of example. Although the phrase “unsubstituted aryl” includes groups containing condensed rings such as naphthalene, it does not include aryl groups that have other groups such as alkyl or halo groups bonded to one of the ring members as aryl groups such as tolyl are substituted aryl groups. A preferred unsubstituted aryl group is phenyl. Unsubstituted aryl groups may be bonded to one or more carbon atom(s), oxygen atom(s), and/or nitrogen atom(s) in the parent compound.
The phrase “substituted aryl group” has the same meaning with respect to unsubstituted aryl groups that substituted alkyl groups had with respect to unsubstituted alkyl groups. A substituted aryl group includes aryl groups in which one of the aromatic carbons is bonded to a non-carbon or non-hydrogen atom and also includes aryl groups in which one or more aromatic carbons of the aryl group is bonded to a substituted and/or unsubstituted alkyl group. Thus, the phrase “substituted aryl” includes, but is not limited to tolyl, and hydroxyphenyl among others.
The phrase “unsubstituted arylalkyl” refers to unsubstituted alkyl groups as defined above in which a hydrogen or carbon bond of the unsubstituted alkyl group is replaced with a bond to an aryl group as defined above. For example, methyl (—CH3) is an unsubstituted alkyl group. If a hydrogen atom of the methyl group is replaced by a bond to a phenyl group, such as if the carbon of the methyl were bonded to a carbon of benzene, then the compound is an unsubstituted arylalkyl group. Thus the phrase includes, but is not limited to, groups such as benzyl, diphenylmethyl, —CH(C6H5)(CH3), and —CH2CH2(C6H5) among others.
The phrase “substituted arylalkyl” has the same meaning with respect to unsubstituted arylalkyl groups that substituted aryl groups had with respect to unsubstituted aryl groups. However, a substituted arylalkyl group also includes groups in which a carbon or hydrogen bond of the alkyl part of the group is replaced by a bond to a non-carbon or a non-hydrogen atom. Examples of substituted arylalkyl groups include, but are not limited to, —CH2C(═O)(C6H5), and —CH2(2-methylphenyl) among others.
The phrase “unsubstituted heterocyclyl” refers to both aromatic and nonaromatic ring compounds containing 3 or more ring members of which one or more is a heteroatom such as, but not limited to, N, O, and S. Although the phrase “unsubstituted heterocyclyl” includes condensed heterocyclic rings such as benzimidazolyl and indazolyl, it does not include heterocyclyl groups that have other groups such as alkyl or halo groups bonded to one of the ring members because compounds such as 2-methylbenzimidazolyl are substituted heterocyclyl groups. Examples of heterocyclyl groups include, but are not limited to: unsaturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl etc.), tetrazolyl, (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl; condensed unsaturated heterocyclic groups containing 1 to 4 nitrogen atoms such as, but not limited to, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl; unsaturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, morpholinyl; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl, benzoxazinyl (e.g. 2H-1,4-benzoxazinyl etc.); unsaturated 3 to 8 membered rings containing 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolyl, isothiazolyl, thiadiazolyl (e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolodinyl; saturated and unsaturated 3 to 8 membered rings containing 1 to 2 sulfur atoms such as, but not limited to, thienyl, dihydrodithiinyl, dihydrodithionyl, tetrahydrothiophene, tetrahydrothiopyran; unsaturated condensed heterocyclic rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, benzothiazolyl, benzothiadiazolyl, benzothiazinyl (e.g. 2H-1,4-benzothiazinyl, etc.), dihydrobenzothiazinyl (e.g. 2H-3,4-dihydrobenzothiazinyl, etc.), unsaturated 3 to 8 membered rings containing oxygen atoms such as, but not limited to furanyl (the furan group); unsaturated condensed heterocyclic rings containing 1 to 2 oxygen atoms such as benzodioxolyl (e.g. 1,3-benzodioxoyl, etc.); unsaturated 3 to 8 membered rings containing an oxygen atom and 1 to 2 sulfur atoms such as, but not limited to, dihydrooxathiinyl; saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms such as 1,4-oxathiane; unsaturated condensed rings containing 1 to 2 sulfur atoms such as benzothienyl, benzodithiinyl; and unsaturated condensed heterocyclic rings containing an oxygen atom and 1 to 2 oxygen atoms such as benzoxathiinyl. Heterocyclyl group also include those described above in which one or more S atoms in the ring is double bonded to one or two oxygen atoms (sulfoxides and sulfones). For example, heterocyclyl groups include tetrahydrothiophene, tetrahydrothiophene oxide, and tetrahydrothiophene 1,1-dioxide. Preferred heterocyclyl groups contain 5 or 6 ring members. More preferred heterocyclyl groups include morpholine, piperazine, piperidine, pyrrolidine, pyridine, 2,5-diazabicyclo[2.2.1]heptane, 1-4-diazacycloheptane, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiomorpholine, pyrrole, homopiperazine, oxazolidin-2-one, pyrrolidin-2-one, oxazole, thiazole, isoxazole, furan, and tetrahydrofuran.
The phrase “substituted heterocyclyl” refers to an unsubstituted heterocyclyl group as defined above in which one of the ring members is bonded to a non-hydrogen atom such as described above with respect to substituted alkyl groups and substituted aryl groups. Examples, include, but are not limited to, 2-methylbenzimidazolyl, 5-methylbenzimidazolyl, 5-chlorobenzthiazolyl, 1-methyl piperazinyl, 1-ethylpiperazinyl, 1-isopropylpiperazinyl, 4-(piperidinyl)piperidinyl, 2,6-dimethylpiperazinyl, 3,5-dimethylpiperazinyl, 2,6-dimethylmorpholinyl, dimethyl[(5-methylmorpholin-2-yl)methyl]amine, dimethyl(morpholin-2-ylmethyl)amine, 5-methyl-2-(dimethylaminomethyl)-1-oxa-4-azacycloheptyl, 1-methyl-1,4-diazabicycloheptane, hydroxyalkylpiperazinyl, dialkylaminopyrrolidinyl, alkylpyrrolidinyl, and 2-chloropyridyl among others.
The phrase “unsubstituted heteroaryl” refers to an unsubstituted heterocyclyl group as defined above which is aromatic. Pyridine is just one example of such a group.
The phrase “substituted heteroaryl” refers to an unsubstituted heteroaryl group as defined above in which a ring member of the heteroaryl group is bonded to a non-hydrogen atom.
The phrase “unsubstituted arylheterocyclyl” refers to heterocyclyl groups as defined above in which a ring member of a heterocyclyl group is bonded to an otherwise unsubstituted aryl group as defined above. For example, piperazine is a heterocyclyl group. If a nitrogen or carbon atom of the piperazinyl group is bonded to an unsubstituted aryl group, then the compound is an unsubstituted arylheterocyclyl group if the heterocyclyl group is also unsubstituted save for its point of attachment to the parent compound.
The phrase “substituted arylheterocyclyl” refers to heterocyclyl groups as defined above in which a ring member of a heterocyclyl group is bonded to an aryl group as defined above. For example, piperazine is a heterocyclyl group. If a nitrogen or carbon atom of the piperazinyl group is bonded to an aryl group, then the compound is a substituted arylheterocyclyl group if the aryl group is otherwise substituted and/or the heterocyclyl group is also substituted in addition to its point of attachment to the parent compound.
The phrase “unsubstituted cycloalkylheterocyclyl” refers to heterocyclyl groups as defined above in which a ring member of a heterocyclyl group is bonded to an otherwise unsubstituted cycloalkyl group.
For example, piperazine is a heterocyclyl group. If a nitrogen or carbon atom of the piperazinyl group is bonded to an unsubstituted cycloalkyl group, then the compound is an unsubstituted cycloalkylheterocyclyl group if the heterocyclyl group is also unsubstituted save for its point of attachment to the parent compound. Unsubstituted cycloalkylheterocyclyl groups include, but are not limited to N-cyclohexylpiperazinyl groups, 4-(cyclohexyl)piperidinyl groups, 4-cyclopentylpiperidinyl groups, and the like.
The phrase “substituted cycloalkylheterocyclyl” refers to heterocyclyl groups as defined above in which a ring member of a heterocyclyl group is bonded to a cycloalkyl group as defined above. For example, piperazine is a heterocyclyl group. If a nitrogen or carbon atom of the piperazinyl group is bonded to a cycloalkyl group, then the compound is a substituted cycloalkylheterocyclyl group if the cycloalkyl group is otherwise substituted and/or the heterocyclyl group is also substituted in addition to its point of attachment to the parent compound.
The phrase “unsubstituted heterocyclylheterocyclyl” refers to heterocyclyl groups as defined above in which a ring member of a first heterocyclyl group is bonded to a second otherwise unsubstituted heterocyclyl group as defined above. For example, piperazine is a heterocyclyl group. If a nitrogen or carbon atom of the piperazinyl group is bonded to a second unsubstituted heterocyclyl group, then the compound is an unsubstituted heterocyclylheterocyclyl group if the first heterocyclyl group is otherwise unsubstituted save for its point of attachment to the parent compound. Unsubstituted heterocyclylheterocyclyl groups include, among others piperidinylpiperidinyl groups and the like such as, but not limited to, 4-(piperidinyl)piperidinyl.
The phrase “substituted heterocyclylheterocyclyl” refers to heterocyclyl groups as defined above in which a ring member of a first heterocyclyl group is bonded to a second heterocyclyl group as defined above. For example, piperazine is a heterocyclyl group. If a nitrogen or carbon atom of the piperazinyl group is bonded to a second heterocyclyl group, then the compound is a substituted heterocyclylheterocyclyl group if the second heterocyclyl group is otherwise substituted and/or the first heterocyclyl group is also substituted in addition to its point of attachment to the parent compound.
The phrase “unsubstituted heterocyclylalkyl” refers to unsubstituted alkyl groups as defined above in which a hydrogen or carbon bond of the unsubstituted alkyl group is replaced with a bond to a an otherwise unsubstituted heterocyclyl group as defined above. For example, methyl (—CH3) is an unsubstituted alkyl group. If a hydrogen atom of the methyl group is replaced by a bond to an unsubstituted heterocyclyl group, such as if the carbon of the methyl were bonded to carbon 2 of pyridine (one of the carbons bonded to the N of the pyridine) or carbons 3 or 4 of the pyridine, then the compound is an unsubstituted heterocyclylalkyl group.
The phrase “substituted heterocyclylalkyl” has the same meaning with respect to unsubstituted heterocyclylalkyl groups that substituted arylalkyl groups had with respect to unsubstituted arylalkyl groups. However, a substituted heterocyclylalkyl group also includes groups in which a non-hydrogen atom is bonded to a heteroatom in the heterocyclyl group of the heterocyclylalkyl group such as, but not limited to, a nitrogen atom in the piperidine ring of a piperidinylalkyl group.
The phrase “unsubstituted alkoxy” refers to an —O-alkyl group where the alkyl group is otherwise unsubstituted. Examples of unsubstituted alkoxy groups include, but are not limited to methoxy, ethoxy, n-propoxy, i-propoxy, and n-butoxy groups.
The phrase “substituted alkoxy” refers to an —O-alkyl group where the alkyl group is otherwise substituted.
The phrase “unsubstituted aryloxy” refers to an —O-aryl group where the aryl group is otherwise unsubstituted. Examples of unsubstituted aryloxy groups include, but are not limited to, phenyloxy, and naphthyloxy groups.
The phrase “substituted aryloxy” refers to an —O-aryl group where the aryl group is otherwise substituted. Examples of such groups include 4-chlorophenyloxy and 2-methylphenyloxy groups.
The phrase “unsubstituted heterocyclyloxy” refers to an —O-heterocyclyl group where the heterocyclyl group is otherwise unsubstituted.
The phrase “substituted heterocyclyloxy” refers to an —O-heterocyclyl group where the heterocyclyl group is otherwise substituted.
The phrase “unsubstituted arylalkoxy” refers to an arylalkyl-O— group where the alkyl group of the arylalkyl group is bonded to the O atom and the arylalkyl group is otherwise unsubstituted.
The phrase “substituted arylalkoxy” refers to an arylalkyl-O— group where the alkyl group of the arylalkyl group is bonded to the O atom and the arylalkyl group is otherwise substituted.
The phrase “unsubstituted heterocyclylalkoxy” refers to a heterocyclylalkyl-O— group where the alkyl group of the heterocycylalkyl group is bonded to the O atom and the heterocyclylalkyl group is otherwise unsubstituted.
The phrase “substituted heterocyclylalkoxy” refers to an heterocyclylalkyl-O— group where the alkyl group of the heterocycylalkyl group is bonded to the O atom and the heterocyclylalkyl group is otherwise substituted.
The phrase “unsubstituted alkoxyalkoxy” refers to an —O-alkyl-O-alkyl group where both of the alkyl groups are otherwise unsubstituted.
The phrase “substituted alkoxyalkoxy” refers to an —O-alkyl-O-alkyl group where one or both of the alkyl groups are otherwise substituted.
The phrase “unsubstituted amino” refers to —NH2. 
The phrase “substituted amino” refers to an amino group in which one or more bonds to the hydrogen atoms of the amino group are replaced by bonds to non-hydrogen atom. Examples of substituted amino groups include, but are not limited to, substituted and unsubstituted alkylamino groups, heterocyclylamino groups, arylamino groups, dialkylamino groups, diheterocyclylamino groups, diarylamino groups, (alkyl)(heterocycyl)amino groups, (alkyl)(aryl)amino groups, and (heterocyclyl)(aryl) groups.
The phrase “unsubstituted alkylamino” refers to an amino group in which one of the bonds to one of the hydrogen atoms in the amino group is replaced with a bond to an otherwise unsubstituted alkyl group as defined above. Examples of unsubstituted alkylamino groups include, but are not limited to, methylamino, ethylamino, i-propylamino, n-propylamino, butylamino, and cyclohexylamino groups.
The phrase “substituted alkylamino” refers to an amino group in which one of the bonds to one of the hydrogen atoms in the amino group is replaced with a bond to an otherwise substituted alkyl group as defined above.
The phrase “unsubstituted heterocyclylamino” refers to an amino group in which one of the bonds to one of the hydrogen atoms in the amino group is replaced with a bond to an otherwise unsubstituted heterocyclyl group as defined above.
The phrase “substituted heterocyclylamino” refers to an amino group in which one of the bonds to one of the hydrogen atoms in the amino group is replaced with a bond to an otherwise substituted heterocyclyl group as defined above.
The phrase “unsubstituted dialkylamino” refers to an amino group in which the bonds to the two hydrogen atoms in the amino group are replaced with bonds to two alkyl groups which may be the same or different and which are otherwise unsubstituted alkyl groups as defined above. Examples of unsubstituted dialkylamino groups include, but are not limited to, dimethylamino groups, (methyl)(ethyl)amino groups, and (methyl)(cyclohexyl)amino groups where the parentheses in groups such as (methyl)(cyclohexyl)amino group indicate that the methyl group is bonded to the nitrogen atom of the amino group and the cyclohexyl group is bonded to the nitrogen atom of the amino group.
The phrase “substituted dialkylamino” refers to an amino group in which the bonds to the two hydrogen atoms in the amino group are replaced with bonds to two alkyl groups which may be the same or different. Furthermore, in substituted dialkylamino groups, at least one of two alkyl groups is an otherwise substituted alkyl group as defined above.
The phrase “unsubstituted (alkyl)(heterocyclyl)amino” refers to an amino group in which one of the bonds to one of the hydrogen atoms of the amino group is replaced by a bond to an otherwise unsubstituted alkyl group as defined above and the bond to the other hydrogen atom of the amino group is replaced by a bond to an otherwise unsubstituted heterocyclyl group. Examples of unsubstituted (alkyl)(heterocyclyl)amino groups include, but are not limited to, (methyl)(pyridyl)amino groups, (methyl)(morpholinyl)amino groups, and (methyl)(piperidinyl)amino groups.
The phrase “substituted (alkyl)(heterocyclyl)amino” refers to an amino group in which one of the bonds to one of the hydrogen atoms of the amino group is replaced by a bond to an otherwise substituted or unsubstituted alkyl group as defined above and the bond to the other hydrogen atom of the amino group is replaced by a bond to an otherwise substituted or unsubstituted heterocyclyl group. However, if the bond to one of the hydrogen atoms in the amino group is replaced by a bond to an otherwise unsubstituted alkyl group, then the bond to the other hydrogen atom of the amino group is replaced by a bond to an otherwise substituted heterocyclyl group. The reverse is also true so that the alkyl group and/or the heterocyclyl group is substituted in a substituted (alkyl)(heterocyclyl)amino group.
The phrase “unsubstituted heterocyclylalkylamino” refers to an amino group in which a bond to one of the hydrogen atoms in the amino group is replaced with a bond to the alkyl group of an otherwise unsubstituted heterocyclylalkyl group. Examples of unsubstituted heterocyclylalkylamino groups include, but are not limited to, 3-pyridylmethylamino, 1-piperidinylmethylamino, and 4-morpholinylmethylamino groups.
The phrase “substituted heterocyclylalkylamino” refers to an amino group in which a bond to one of the hydrogen atoms in the amino group is replaced with a bond to the alkyl group of an otherwise substituted heterocyclylalkyl group.
The phrase “unsubstituted arylalkylamino” refers to an amino group in which a bond to one of the hydrogen atoms in the amino group is replaced with a bond to the alkyl group of an otherwise unsubstituted arylalkyl group. Examples of unsubstituted arylalkylamino groups include, but are not limited to, phenylmethylamino, and naphthylethylamino groups.
The phrase “substituted arylalkylamino” refers to an amino group in which a bond to one of the hydrogen atoms in the amino group is replaced with a bond to the alkyl group of an otherwise substituted arylalkyl group.
The term “protected” with respect to hydroxyl groups, amine groups, and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction with a protecting group known to those skilled in the art such as those set forth in Protective Groups in Organic Synthesis, Greene, T., John Wiley & Sons, New York, N.Y., (1st Edition, 1981) which can be added or removed using the procedures set forth therein. Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate. Examples of protected amine groups include, but are not limited to, amides such as, formamide, acetamide, trifluoroacetamide, and benzamide; imides, such as phthalimide, and dithiosuccinimide; and others. Examples of protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
A “pharmaceutically acceptable salt” includes a salt with an inorganic base, organic base, inorganic acid, organic acid, or basic or acidic amino acid. As salts of inorganic bases, the invention includes, for example, alkali metals such as sodium or potassium; alkaline earth metals such as calcium and magnesium or aluminum; and ammonia. As salts of organic bases, the invention includes, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, and triethanolamine. As salts of inorganic acids, the instant invention includes, for example, hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid. As salts of organic acids, the instant invention includes, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. As salts of basic amino acids, the instant invention includes, for example, arginine, lysine and ornithine. Acidic amino acids include, for example, aspartic acid and glutamic acid.
The present invention provides compounds, pharmaceutical formulations including the compounds, methods of preparing the pharmaceutical formulations, and methods of treating patients with the pharmaceutical formulations and compounds.
The present invention provides compounds having the structure I.
The invention also provides tautomers of the compounds, pharmaceutically acceptable salts of the compounds, and pharmaceutically acceptable salts of the tautomers. Structure I has the following formula:




where, in the first group of compounds:

Z1, Z2, Z3, and Z4 are selected independently from C or N;
R1–R8 are selected independently from the group consisting of —H, —F, —Cl, —Br, —C≡N, —NO2, —CF3, —CO2H, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)O-aryl groups, substituted and unsubstituted —C(═O)O-heteroaryl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted alkylheterocyclyl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heteroaryl groups, substituted and unsubstituted —C(═O)—N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted —C(═O)—N(alkyl)(heterocyclyl) groups, substituted and unsubstituted —C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heteroaryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups, substituted and unsubstituted aryl groups, substituted and unsubstituted heteroaryl groups, and substituted and unsubstituted heterocyclyl groups;
R9 is —H, —C(═O)-alkyl, or —C(═O)-aryl; and
R10 is —H, —C(═O)-alkyl, or —C(═O)-aryl.
More particular embodiments of the compounds of the invention having the general structure shown in I above are provided. The second group of compounds are those for which:
Z1, Z2, Z3, and Z4 are independently selected from C or N;
R1 is selected from —H, —F, —Cl, and —Br;
R2 is selected from —H, —F, —Cl, —Br, —C≡N, —NO2, —CO2H, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)O-aryl groups, substituted and unsubstituted —C(═O)O-heteroaryl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted heterocyclylalkoxy groups;
R3 is selected from —H, —F, —Cl, —Br, and substituted and unsubstituted alkoxy groups;
R4 is —H;
R5 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R5 is absent if Z1 is N;
R6 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, and substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups; or R6 is absent if Z2 is N;
R7 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, and substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups; or R7 is absent if Z3 is N;
R8 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R8 is absent if Z4 is N;
R9 is —H; and
R10 is —H. In some embodiments of the second group of compounds, at least one of R1, R2, R3, R5, R6, R7 or R8 is not —H. In other such embodiments, at least two of R1, R2, R3, R5, R6, R7 or R8 are not —H.
In one embodiment of the second group of compounds, each of Z1, Z2, Z3, and Z4 are C.
In another embodiment of the second group of compounds, Z1 is N and each of Z2, Z3, and Z4 are C.
In another embodiment of the second group of compounds, Z1 and Z3 are both N and Z2 and Z4 are both C.
In another embodiment of the second group of compounds, Z3 is N and each of Z1, Z2, and Z4 are C.
In another embodiment of the second group of compounds, Z1–Z4 have any of the values in previous embodiments, and R1 is selected from —H, —F, —Cl, and —Br.
In another embodiment of the second group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is selected from —H, —F, —Cl, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted heterocyclylalkoxy groups.
In another embodiment of the second group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is —H.
In another embodiment of the second group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is an unsubstituted alkoxy group having from 1 to 4 carbon atoms.
In another embodiment of the second group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is —OMe.
In another embodiment of the second group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is —O-i-Pr.
In another embodiment of the second group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted arylalkoxy group.
In another embodiment of the second group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a benzyloxy group.
In another embodiment of the second group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is an unsubstituted alkyl group having from 1 to 4 carbon atoms.
In another embodiment of the second group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a methyl group.
In another embodiment of the second group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is selected from —H, —F, —Cl, and —OMe.
In another embodiment of the second group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is selected from —F, —Cl, —Br, and substituted and unsubstituted alkoxy groups.
In another embodiment of the second group of compounds, Z1 –Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —H.
In another embodiment of the second group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —F.
In another embodiment of the second group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —Cl.
In another embodiment of the second group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —OMe.
In another embodiment of the second group of compounds, Z2–Z4, R1, R2, and R3 have any of the values in previous embodiments, Z1 is C, and R5 is H.
In another embodiment of the second group of compounds, Z2–Z4, R1, R2, and R3 have any of the values in previous embodiments, Z1 is C, and R5 is —CH3. 
In another embodiment of the second group of compounds, Z2–Z4, R1, R2, and R3 have any of the values in previous embodiments, Z1 is C, and R5 is morpholine.
In another embodiment of the second group of compounds, Z1–Z3, R1, R2, and R3 have any of the values in previous embodiments, Z4 is C, and R8 is H.
In another embodiment of the second group of compounds, Z1–Z3, R1, R2, and R3 have any of the values in previous embodiments, Z4 is C, and R8 is —CH3. 
In another embodiment of the second group of compounds, Z1–Z3, R1, R2, and R3 have any of the values in previous embodiments, Z4 is C, and R8 is morpholine.
In another embodiment of the second group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is selected from —Br, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, and substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups. In still other such embodiments, R6 has the values described in the preceding sentence and R7 is —H.
In another embodiment of the second group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is an alkoxy group having from 1–6 carbon atoms. In still other such embodiments, R6 is a methoxy group. In still other such embodiments where R6 is an alkoxy group having from 1–6 carbon atoms such as a methoxy group, R7 is —H.
In another embodiment of the second group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is an alkyl group having from 1–6 carbon atoms. In still other such embodiments, R6 is a methyl group. In still other such embodiments where R6 is an alkyl group having from 1–6 carbon atoms such as a methyl group, R7 is —H.
In another embodiment of the second group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is a substituted alkoxy group having the formula —OCH2(CH2)mR11 where m is an integer selected from 0, 1, or 2 and R11 is selected from substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. In still other such embodiments, R11 is selected from substituted alkoxy groups. In still other such embodiments, R11 is selected from substituted and unsubstituted heterocyclyl groups selected from pyrrolidinyl groups, pyridyl groups, morpholinyl groups, piperazinyl groups, and piperidinyl groups. In still other such embodiments where R6 is a substituted alkoxy group having the formula —OCH2(CH2)mR11, R7 is —H.
In another embodiment of the second group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is a substituted amino group having the formula —N(R12)CH2(CH2)mR13 where m is an integer selected from 0, 1, or 2, R13 is selected from substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups, and R12 is —H or a substituted or unsubstituted alkyl group. In some such embodiments R12 is H. In other embodiments R12 is a —CH3 group. In still other such embodiments, R13 is selected from substituted alkoxy groups. In still other such embodiments, R13 is selected from substituted and unsubstituted heterocyclyl groups selected from pyrrolidinyl groups, pyridyl groups, morpholinyl groups, piperazinyl groups, and piperidinyl groups.
In still other embodiments of the second group of compounds where R6 is a substituted amino group having the formula —N(R12)CH2(CH2)mR13, R7 is —H.
In another embodiment of the second group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values defined in the previous embodiments, Z2 is C, and R6 is a substituted or unsubstituted heterocyclyl group. In some embodiments of the second group of compounds where R6 is a heterocyclyl group, the heterocyclyl group is selected from substituted or unsubstituted pyrrolidinyl groups, substituted and unsubstituted pyridyl groups, substituted and unsubstituted morpholinyl groups, substituted and unsubstituted piperazinyl groups, substituted and unsubstituted piperidinyl groups, substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups, and substituted and unsubstituted 1,4-diazabicyclo[2.2.2]octane groups. In other embodiments of the second group of compounds where R6 is a heterocyclyl group, the heterocyclyl group is an unsubstituted morpholine group, a dialkyl substituted morpholinyl group, an unsubstituted piperazine group, a dialkyl substituted piperazinyl group, a monoalkyl substituted piperazinyl group, an aryl substituted piperazinyl group, a —CH2C(═O)O-alkyl substituted piperazinyl group, a —C(═O)-alkyl substituted piperazinyl group, a —C(═O)O-alkyl substituted piperazinyl group, a cycloalkyl substituted piperazinyl group, an unsubstituted piperidine group, an aryl substituted piperidinyl group, a cycloalkyl substituted piperidinyl group, a piperidinyl substituted piperidinyl group, a dialkylamino substituted pyrrolidinyl group, an unsubstituted 2,5-diazabicyclo[2.2.1]heptane group, and an alkyl substituted 2,5-diazabicyclo[2.2.1]heptane group. In still other embodiments of the second group of compounds where R6 is a substituted or unsubstituted heterocyclyl group, R7 is —H.
In another embodiment of the second group of compounds, Z1, Z2, Z4, R, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is selected from substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, and substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups. In still other such embodiments, R7 has the values described in the preceding sentence and R6 is —H.
In another embodiment of the second group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is an alkoxy group having from 1–6 carbon atoms. In still other such embodiments, R7 is a methoxy group. In still other embodiments of the second group of compounds where R7 is an alkoxy group having from 1–6 carbon atoms such as a methoxy group, R6 is —H.
In another embodiment of the second group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is an alkyl group having from 1–6 carbon atoms. In still other such embodiments, R7 is a methyl group. In still other embodiments of the second group of compounds where R7 is an alkyl group having from 1–6 carbon atoms such as a methyl group, R6 is —H.
In another embodiment of the second group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is a substituted alkoxy group having the formula —OCH2(CH2)nR14 where n is an integer selected from 0, 1, or 2 and R14 is selected from substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. In still other such embodiments, R14 is selected from substituted alkoxy groups. In still other such embodiments, R14 is selected from substituted and unsubstituted heterocyclyl groups selected from pyrrolidinyl groups, pyridyl groups, morpholinyl groups, piperazinyl groups, and piperidinyl groups. In still other embodiments of the second group of compounds where R7 is a substituted alkoxy group having the formula —OCH2(CH2)nR14, R6 is —H.
In another embodiment of the second group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is a substituted amino group having the formula —N(R15)CH2(CH2)nR16 where n is an integer selected from 0, 1, or 2, R16 is selected from substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups, and R15 is selected from —H and alkyl groups. In some such embodiments, R15 is a —H group. In other such embodiments, R15 is a —CH3 group. In still other such embodiments, R16 is selected from substituted alkoxy groups. In still other such embodiments, R16 is selected from substituted and unsubstituted heterocyclyl groups selected from pyrrolidinyl groups, pyridyl groups, morpholinyl groups, piperazinyl groups, and piperidinyl groups.
In still other embodiments of the second group of compounds where R7 is a substituted amino group having the formula —N(R15)CH2(CH2)nR16, R6 is —H.
In another embodiment of the second group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is a substituted or unsubstituted heterocyclyl group. In some such embodiments where R7 is a heterocyclyl group, the heterocyclyl group is selected from substituted or unsubstituted pyrrolidinyl groups, substituted and unsubstituted pyridyl groups, substituted and unsubstituted morpholinyl groups, substituted and unsubstituted piperazinyl groups, substituted and unsubstituted piperidinyl groups, substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups, and substituted and unsubstituted 1,4-diazabicyclo[2.2.2]octane groups. In still other embodiments of the second group of compounds where R7 is a heterocyclyl group, the heterocyclyl group is an unsubstituted morpholine group, a dialkyl substituted morpholinyl group, an unsubstituted piperazine group, a dialkyl substituted piperazinyl group, a monoalkyl substituted piperazinyl group, an aryl substituted piperazinyl group, a —CH2C(═O)O-alkyl substituted piperazinyl group, a —C(═O)-alkyl substituted piperazinyl group, a —C(═O)O-alkyl substituted piperazinyl group, a cycloalkyl substituted piperazinyl group, an unsubstituted piperidine group, an aryl substituted piperidinyl group, a cycloalkyl substituted piperidinyl group, a piperidinyl substituted piperidinyl group, a dialkylamino substituted pyrrolidinyl group, an unsubstituted 2,5-diazabicyclo[2.2.1]heptane group, and an alkyl substituted 2,5-diazabicyclo[2.2.1]heptane group. In still other embodiments of the second group of compounds where R7 is a substituted or unsubstituted heterocyclyl group, R6 is —H.
Other more particular embodiments of the compounds of the invention having the general structure shown in I above are provided. Such compounds form a third group of compounds for which:
Z1, Z2, Z3, and Z4 are independently selected from C or N;
R1 is selected from —H, —F, —Cl, —Br, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R2 is selected from —H, —F, —Cl, —Br, —C≡N, —NO2, —CO2H, —OH, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)O-aryl groups, substituted and unsubstituted —C(═O)O-heteroaryl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups, substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted akoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted heterocyclyloxy, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms;
R3 is selected from —H, —F, —Cl, —Br, —CF3, —C≡N, substituted and unsubstituted alkyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—O-alkyl groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted saturated heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted saturated heterocycyl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups;
R4 is —H, —F, —Br, —Cl, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R5 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R5 is absent if Z1 is N;
R6 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups; or R6 is absent if Z2 is N;
R7 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups; or R7 is absent if Z3 is N;
R8 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R8 is absent if Z4 is N;
R9 is —H; and
R10 is selected from the group consisting of —H, and substituted and unsubstituted alkyl groups. In some such embodiments of the third group of compounds, at least one of R1, R2, R3, R4, R5, R6, R7 or R8 is not —H. In other such embodiments, at least two of R1, R2, R3, R4, R5, R6, R7 or R8 are not —H. In some embodiments, R10 is —H. In other embodiments, R10 is an unsubstituted alkyl group having from 1 to 6 carbon atoms such as a methyl, ethyl, propyl, i-propyl group, or the like. In some such embodiments, R10 is a —CH3 group.
In one embodiment of the third group of compounds, each of Z1, Z2, Z3, and Z4 are C.
In another embodiment of the third group of compounds, Z1 is N and each of Z2, Z3 and Z4 are C.
In another embodiment of the third group of compounds, Zand Z3 are both N and Z2 and Z4 are both C.
In another embodiment of the third group of compounds, Z3 is N and each of Z1, Z2, and Z4 are C.
In another embodiment of the third group of compounds, Z1–Z4 have any of the values in previous embodiments, and R1 is selected from —H, —F, —Cl, and —Br.
In another embodiment of the third group of compounds, Z1–Z4 have any of the values in previous embodiments, and R1 is a substituted and unsubstituted heterocyclylamino group. In some such embodiments, R1 is a substituted and unsubstituted heteroarylamino groups. In some embodiments, R1 is a substituted and unsubstituted heterocyclylamino group such as, but not limited to, substituted and unsubstituted pyrroldinylalkylamino groups and the like, such as, but not limited to, substituted and unsubstituted pyrrolidinylmethylamino groups and the like.
In another embodiment of the third group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is selected from —H, —F, —Cl, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted heterocyclyloxy, and substituted and unsubstituted heterocyclylalkoxy groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms.
In another embodiment of the third group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is —H.
In another embodiment of the third group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is an unsubstituted alkoxy group having from 1 to 4 carbon atoms.
In another embodiment of the third group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a —OMe, —OEt, —O-i-Pr, or —OCH2CH(CH3)2 group.
In another embodiment of the third group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted arylalkoxy, a substituted or unsubstituted aryloxy group, or a substituted or unsubstituted heterocyclyoxy group.
In another embodiment of the third group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted benzyloxy group, a substituted or unsubstituted phenoxy group, or a substituted or unsubstituted pyridyloxy group.
In another embodiment of the third group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is an unsubstituted alkyl group having from 1 to 4 carbon atoms.
In another embodiment of the third group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a methyl group.
In another embodiment of the third group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted —N(H)C(═O)—N(H)-alkyl-aryl group.
In another embodiment of the third group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted amino group selected from the group consisting of substituted and unsubstituted alkylamino groups, dialkylamino groups, cycloalkylamino groups, heterocyclylamino groups, heterocyclylalkylamino groups, arylalkylamino groups, arylalkoxyarylmethylamino groups, and aryloxyarylalkylamino groups. In some embodiments, the substituted and unsubstituted alkylamino groups are substituted and unsubstituted aminoalkylamino groups such as, but not limited to, dialkylaminoalkylamino and the like. In some such embodiments the substituted and unsubstituted heterocyclylalkylamino groups are substituted and unsubstituted heteroarylalkylamino groups. In some embodiments, the heterocyclylalkylamino groups include, but are not limited to, substituted and unsubstituted pyrrolidinylalkylamino groups such as, but not limited to, substituted and unsubstituted pyrrolidinylmethylalkylamino groups and the like; substituted and unsubstituted thiazolylalkylamino groups such as, but not limited to substituted and unsubstituted thiazolylmethylamino groups and the like; substituted and unsubstituted imidazolylalkylamino groups such as, but not limited to, imidazolylmethylamino groups and the like; substituted and unsubstituted furanylalkylamino groups such as, but not limited to, substituted and unsubstituted furanylmethylamino groups, and the like; and the like. In other such embodiments, the heterocyclylamino groups are substituted and unsubstituted heteroarylamino groups. In other such embodiments, the substituted and unsubstituted heterocyclylamino groups are substituted and unsubstituted arylalkylheterocyclylamino groups.
In another embodiment of the third group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted amino group selected from the group consisting of isopropylamino groups, 3-(N,N-dimethylamino)propylamino groups, pyrrolidinylmethylamino groups, arylmethylamino groups, arylalkoxyarylmethylamino groups, aryloxyarylmethylamino groups, and pyridylmethylamino groups, and pyridylamino groups.
In another embodiment of the third group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted heterocyclyl groups. In some such embodiments R2 is a substituted or unsubstituted benzimidazolyl group or is a substituted or unsubstituted pyrazolyl group.
In another embodiment of the third group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms.
In another embodiment of the third group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is selected from —H, —F, —Cl, and —OMe.
In another embodiment of the third group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —H.
In another embodiment of the third group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is selected from the group consisting of —F, —Cl, —Br, —CF3, —C≡N, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, and substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms.
In another embodiment of the third group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is selected from the group consisting of substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, and substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups. In some such embodiments, R3 is a substituted or unsubstituted —N(H)C(═O)N(H)CH2CH3 group, a substituted or unsubstituted —N(H)C(═O)N(H)CH(CH3)2 group, a substituted or unsubstituted —N(H)C(═O)N(H)C(CH3)3 group, or a substituted or unsubstituted —N(H)C(═O)N(H)-aryl group or the like. In some such embodiments, R3 is a substituted or unsubstituted —N(H)C(═O)N(H)-aryl group such as, but not limited to, a —N(H)C(═O)N(H)-(2-methoxyphenyl) group, a—N(H)C(═O)N(H)-(trifluoromethylphenyl) group, or the like.
In another embodiment of the third group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —F.
In another embodiment of the third group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —Cl.
In another embodiment of the third group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —OMe.
In some embodiments of the third group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and if R3 is H, at least one of R6 or R7 is selected from the group consisting of —CO2H, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted alkoxyalkoxy groups, substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted cycloalkylheterocyclyl groups, substituted and unsubstituted saturated heterocyclyloxy groups, substituted and unsubstituted —N(H)-alkyl groups, substituted and unsubstituted —N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted —N(H)-alkyl-aryl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups. In some such embodiments, if R3 is H, at least one of R6 or R7 is selected from the group consisting of —CO2H, substituted and unsubstituted saturated heterocyclyloxy groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups.
In another embodiment of the third group of compounds, Z2–Z4, R1, R2, and R3 have any of the values in previous embodiments, Z1 is C, and R5 is H. In some such embodiments, R8 is also H.
In another embodiment of the third group of compounds, Z2–Z4, R1, R2, and R3 have any of the values in previous embodiments, Z1 is C, and R5 is —CH3.
In another embodiment of the third group of compounds, Z2–Z4, R1, R2, and R3 have any of the values in previous embodiments, Z1 is C, and R5 is morpholine.
In another embodiment of the third group of compounds, Z1–Z3, R1, R2, and R3 have any of the values in previous embodiments, Z4 is C, and R8 is H.
In another embodiment of the third group of compounds, Z1–Z3, R1, R2, and R3 have any of the values in previous embodiments, Z4 is C, and R8 is —CH3.
In another embodiment of the third group of compounds, Z1–Z3, R1, R2, and R3 have any of the values in previous embodiments, Z4 is C, and R8 is morpholine.
In another embodiment of the third group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is selected from a first group of compounds; or Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is selected from the first group of compounds, the first group of compounds comprising members selected from the group consisting of —CO2H, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted alkoxyalkoxy groups, substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted cycloalkylheterocyclyl groups, substituted and unsubstituted saturated heterocyclyloxy groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, substituted and unsubstituted heterocyclylamino groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, —C(═O)N(H)-heteroaryl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups.
In another embodiment of the third group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is selected from —Br, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, substituted and unsubstituted —C(═O)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, and substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups. In still other embodiments, R6 has the values described in the preceding sentence and R7 is —H.
In another embodiment of the third group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is an alkoxy group having from 1–6 carbon atoms. In still other such embodiments, R6 is a methoxy group. In still other embodiments of the third group of compounds where R6 is an alkoxy group having from 1–6 carbon atoms such as a methoxy group, R7 is —H.
In another embodiment of the third group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is an alkyl group having from 1–6 carbon atoms. In still other such embodiments, R6 is a methyl group. In still other embodiments of the third group of compounds where R6 is an alkyl group having from 1–6 carbon atoms such as a methyl group, R7 is —H.
In another embodiment of the third group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is a substituted alkoxy group having the formula —OCH2(CH2)mR11 where m is an integer selected from 0, 1, or 2 and R11 is selected from substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. In still other such embodiments, R11 is selected from substituted alkoxy groups such as, but not limited to methoxy groups, ethoxy groups, propoxy groups, and the like. In still other such embodiments, R11 is selected from substituted and unsubstituted heterocyclyl groups selected from pyrrolidinyl groups, pyridyl groups, morpholinyl groups, piperazinyl groups, and piperidinyl groups. In still other embodiments where R6 is a substituted alkoxy group having the formula —OCH2(CH2)mR11, R7 is —H. In still other embodiments, R6 is a pyrrolidinylalkoxy groups, such as but not limited to, a pyrrolidinylpropoxy group or the like; an alkoxyethoxy group such as, but not limited to, a methoxyethoxy group or the like; or a substituted or unsubstituted pyridinylalkoxy group such as, but not limited to, (3-pyridinyl)methoxy groups, or the like.
In another embodiment of the third group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is a substituted amino group having the formula —N(R12)(CH2)pR13 where p is an integer selected from 0, 1, 2, or 3, R13 is selected from substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups, and R12 is selected from —H or substituted and unsubstituted alkyl groups such as, but not limited to, methyl, ethyl, propyl, and isopropyl. In some such embodiments, R13 is selected from substituted amino groups such as alkylamino groups and dialkylamino groups, such as, but not limited to, dimethylamino, diethylamino, dipropylamino, (methyl)(ethyl)amino, (ethyl)(propyl)amino, (methyl)(propyl)amino groups, and the like. In some such embodiments, R12 is a CH3 group. In still other such embodiments, R13 is selected from substituted alkoxy groups. In still other such embodiments, R13 is selected from substituted and unsubstituted heterocyclyl groups such as those selected from pyrrolidinyl groups, pyrazolyl groups, pyridyl groups, morpholinyl groups, piperazinyl groups, piperidinyl groups, and the like. In some embodiments, R6 is selected from —N(H)(3-piperidinyl) groups, —N(H)(4-piperidinyl) groups, —N(H)(4-(2-methoxymethylpyrrolidinyl)) groups, —N(CH3)(4-(1-methylpiperidinyl)) groups, —N(H)CH2(2-pyridyl) groups, —N(H)CH2(3-pyridyl) groups, —N(H)CH2(4-pyridyl) groups, —N(H)CH2CH2(2-pyridyl) groups, —N(H)CH2CH2(3-pyridyl) groups, —N(H)CH2CH2(4-pyridyl) groups, —N(CH3)CH2CH2(2-pyridyl) groups —N(H)CH2CH2(4-piperidinyl) groups, —N(H)CH2CH2(4-morpholinyl) groups, —N(H)CH2CH2CH2(1-imidazolyl) groups, —N(H)CH2CH2CH2(1-(4-methylpiperazinyl)) groups, —N(H)CH2CH2CH2(4-morpholinyl) groups, —N(H)CH2CH2CH2(1-imidazolyl) groups, —N(H)CH2CH2CH2(1-pyrrolidinyl) groups, —N(CH3)CH2CH2CH2(diethylamino) groups, and the like.
In still other embodiments of the third group of compounds where R6 is a substituted amino group having the formula —N(R12)(CH2)pR13, R7 is —H.
In another embodiment of the third group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is a substituted amino group having the formula —N(R12)(CH2)pR13 or the formula —N(R12)C(H)(alkyl)((CH2)pR13) where p is an integer selected from 0, 1, 2, or 3, R13 is selected from a methyl group, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups such as —N(H)(alkyl) groups, —N(alkyl)2 groups and the like, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups, and R12 is selected from —H; substituted and unsubstituted alkyl groups such as, but not limited to, methyl, ethyl, propyl, and isopropyl groups; —C(═O)-alkyl groups such as —C(═O)—CH3 groups and the like; —C(═O)-alkyl-N(H)(alkyl) groups such as —C(═O)—CH2—N(H)(alkyl) groups and the like; —C(═O)-alkyl-N(alkyl)2 groups such as —C(═O)—CH2—N(alkyl)2 groups and the like; —C(═O)-alkyl-N(R12a′)(R12b′) groups such as —C(═O)—CH2—N(alkyl)2 groups and the like —C(═O)-alkyl-heterocyclyl groups such as —C(═O)—CH2-heterocyclyl groups and the like such as —C(═O)—CH2-(1-piperazinyl) groups and the like; —C(═O)-heterocyclyl groups; —C(═O)-aryl groups; —C(═O)-alkyl-O-alkyl groups such as —C(═O)—CH2—O-alkyl groups; —C(═O)-alkyl-S-alkyl groups such as —C(═O)—CH2—S-alkyl groups and the like; and the like where R12a′ is selected from —H, and substituted and unsubstituted alkyl groups, and R12b′ is selected from —H, —SO2-alkyl, —SO2-aryl, —C(═O)-alkyl, —C(═O)-aryl, heterocyclyl groups such as 2-pyridyl groups and the like, heterocyclylalkyl groups, arylalkyl groups, alkyl groups, and —C(═O)-alkyl-halogen groups.
In another embodiment of the third group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values defined in the previous embodiments, Z2 is C, and R6 is a substituted or unsubstituted heterocyclyl group. In some embodiments of the third group of compounds where R6 is a heterocyclyl group, the heterocyclyl group is selected from substituted or unsubstituted pyrrolidinyl groups, substituted and unsubstituted pyridyl groups, substituted and unsubstituted morpholinyl groups, substituted and unsubstituted piperazinyl groups, substituted and unsubstituted piperidinyl groups, substituted and unsubstituted pyrazolyl groups, substituted and unsubstituted pyrrolyl groups, substituted and unsubstituted imidazolyl groups, substituted and unsubstituted 1-aza-4-oxacycloheptane groups, substituted and unsubstituted 1,4-diazacycloheptane groups, substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups, substituted and unsubstituted 1,4-diazabicyclo[2.2.2]octane groups, substituted or unsubstituted 1,4-diazabicyclo[4.3.0]nonane group, and substituted or unsubstituted 1,4-diazacycloheptane groups. In still other embodiments of the third group of compounds where R6 is a heterocyclyl group, the heterocyclyl group is an unsubstituted morpholine group; a dialkyl substituted morpholinyl group such as, but not limited to, a dimethyl substituted morpholinyl group, and the like, such as, but not limited to, a 3,5-dimethyl substituted morpholinyl group; a hydroxy substituted morpholinyl group; a hydroxyalkyl substituted morpholinyl group; an aryl substituted morpholinyl group; an aminoalkyl substituted morpholinyl group including dialkylaminoalkyl substituted morpholinyl groups such as, but not limited to, dimethylaminomethyl substituted morpholinyl groups and the like such as, but not limited to, a morpholinyl group that is substituted on a ring carbon bonded to the ring O atom with a dimethylaminomethyl group and is substituted with a methyl group on the carbon bonded to the ring N atom which carbon is not bonded to the carbon bearing the dimethylaminomethyl group and the like; a heterocyclyl substituted morpholinyl group; an unsubstituted piperazine group; a dialkyl substituted piperazinyl group such as, but not limited to, a dimethyl substituted piperazinyl group, and the like such as a 3,5-dimethyl substituted piperazinyl group and the like; a monoalkyl substituted piperazinyl group such as a 3-alkyl substituted piperazinyl group, an N-alkyl substituted piperazinyl group, and the like such as, but not limited to, a 3-methyl substituted piperazinyl group, a N-alkyl substituted piperazinyl group, such as, but not limited to, N-methyl, N-ethyl, N-isopropyl substituted piperazinyl groups and the like; a hydroxyalkyl substituted piperazinyl group such as, but not limited to, hydroxyethyl and hydroxymethyl substituted piperazinyl groups and the like such as, but not limited to, N-hydroxyethyl substituted piperazinyl groups and the like; an aryl substituted piperazinyl group; a heterocyclyl substituted piperazinyl group such as, but not limited to, 2-, 3-, and 4-(2-, 3-, and 4-piperidinyl) substituted piperazinyl groups and 2-, 3-, and 4-(2-, 3-, and 4-pyridyl) substituted piperazinyl groups and the like; a —CH2C(═O)O-alkyl substituted piperazinyl group; a —C(═O)-alkyl substituted piperazinyl group such as, but not limited to, a —C(═O)-ethyl or a —C(═O)-methyl substituted piperazinyl group, and the like such as a piperazinyl group where the —C(═O)-ethyl or the —C(═O)-methyl substitution is on one of the piperazinyl N atoms and the other N atom is bonded to Z2, and the like; a —C(═O)O-alkyl substituted piperazinyl group such as, but not limited to, a —C(═O)—O-ethyl or a —C(═O)—O-methyl substituted piperazinyl group, and the like such as a piperazinyl group where the —C(═O)—O-ethyl or the —C(═O)—O-methyl substitution is on one of the piperazinyl N atoms and the other N atom is bonded to Z2, and the like; a cycloalkyl substituted piperazinyl group such as, but not limited to, a cyclohexyl and cyclopentyl substituted piperazinyl group and the like such as, but not limited to, a N-cyclohexyl substituted piperazinyl group and the like; an unsubstituted piperidine group; an alkyl substituted piperidinyl group such as, but not limited to, 2-, 3-, and 4-alkyl substituted piperidinyl groups, and the like such as, but not limited to, 2-, 3-, and 4-hydroxyalkyl substituted piperidinyl groups and the like such as, but not limited to, 2-, 3-, and 4-hydroxymethyl substituted piperidinyl groups and the like; a hydroxy substituted piperidinyl group such as 2-, 3-, and 4-hydroxy substituted piperidinyl groups; a hydroxyalkyl substituted piperidinyl group; an aryl substituted piperidinyl group such as, but not limited to, a 4-aryl substituted piperidinyl group and the like such as, but not limited to, a piperidinyl group that is substituted in the 4 position with both an aryl group and a hydroxy group and the like such as, but not limited to, a piperidinyl group that is substituted in the 4 position with both a hydroxy group and a phenyl group; a cycloalkyl substituted piperidinyl group; a heterocyclyl substituted piperidinyl group such as, but not limited to, a piperidinyl substituted piperidinyl group and the like such as, but not limited to, 4-piperidinyl substituted piperidinyl groups, 4-(2(3H)-benzimidazolone) substituted piperidinyl group, and the like; an unsubstituted pyrrolidinyl group; an alkyl substituted pyrrolidinyl group such as, but not limited to, a methyl substituted pyrrolidinyl group, a heterocyclylalkyl substituted pyrrolidinyl group, and the like such as, but not limited to, a 2-methyl substituted pyrrolidinyl group, a 2-pyrrolidinylmethyl substituted pyrrolidinyl group, and the like; an amino substituted pyrrolidinyl group such as, but not limited to, a dialkylamino substituted pyrrolidinyl group such as, but not limited to, 2- and 3-dialkylamino substituted pyrrolidinyl groups and the like such as, but not limited to, 2- and 3-substituted N,N-dimethylamino substituted pyrrolidinyl groups and the like such as, but not limited to, a pyrrolidinyl group that is substituted with both an alkyl group and an N,N-dimethylamino group and the like such as, but not limited to, a pyrrolidinyl group that is substituted with a methyl group in the 2 position and with a N,N-dimethylamino group in the 4 position; a hydroxy substituted pyrrolidinyl group such as, but not limited to, 2- and 3-hydroxy substituted pyrrolidinyl groups; a heterocyclylalkyl substituted pyrrolidinyl group; substituted and unsubstituted pyrrolyl groups; substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups; an alkyl substituted 2,5-diazabicyclo[2.2.1]heptane group such as, but not limited to, a N-methyl substituted 2,5-diazabicyclo[2.2.1]heptane group and the like; a substituted or unsubstituted 1,4-diazabicyclo[4.3.0]nonane group; and a substituted or unsubstituted 1,4-diazacycloheptane group such as, but not limited to, an alkyl substituted 1,4-diazacycloheptane group and the like, such as, but not limited to, an N-alkyl substituted 1,4-diazacycloheptane substituted group and the like such as, but not limited to, a N-methyl substituted 1,4-diazacycloheptane group and the like. In still other embodiments of the third group of compounds where R6 is a substituted or unsubstituted heterocyclyl group, R7 is —H.
In another embodiment of the third group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is selected from substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, substituted and unsubstituted —C(═O)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, and substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups. In still other such embodiments, R7 has the values described in the preceding sentence and R6 is —H.
In another embodiment of the third group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is an alkoxy group having from 1–6 carbon atoms. In still other such embodiments, R7 is a methoxy group. In still other embodiments of the third group of compounds where R7 is an alkoxy group having from 1–6 carbon atoms such as a methoxy group, R6 is —H.
In another embodiment of the third group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is an alkyl group having from 1–6 carbon atoms. In still other such embodiments, R7 is a methyl group. In still other embodiments of the third group of compounds where R7 is an alkyl group having from 1–6 carbon atoms such as a methyl group, R6 is —H.
In another embodiment of the third group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is a substituted alkoxy group having the formula —OCH2(CH2)nR14 where n is an integer selected from 0, 1, or 2 and R14 is selected from substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. In some embodiments, R14 is selected from substituted alkoxy groups such as, but not limited to methoxy groups, ethoxy groups, propoxy groups, and the like. In still other such embodiments, R14 is selected from substituted and unsubstituted heterocyclyl groups selected from pyrrolidinyl groups, pyridyl groups, morpholinyl groups, piperazinyl groups, and piperidinyl groups. In still other embodiments of the third group of compounds where R7 is a substituted alkoxy group having the formula —OCH2(CH2)nR14, R6 is —H. In still other embodiments, R7 is a pyrrolidinylalkoxy groups, such as but not limited to, a pyrrolidinylpropoxy group or the like; an alkoxyethoxy group such as, but not limited to, a methoxyethoxy group or the like; or a substituted or unsubstituted pyridinylalkoxy group such as, but not limited to, (3-pyridinyl)methoxy groups, or the like.
In another embodiment of the third group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is a substituted amino group having the formula —N(R15)(CH2)qR16 where q is an integer selected from 0, 1, 2, or 3 and R16 is selected from substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups, and R15 is —H or a substituted or unsubstituted alkyl groups, such as, but not limited to, methyl, ethyl, propyl, and isopropyl groups. In some such embodiments, R16 is selected from substituted amino groups such as alkylamino groups and dialkylamino groups, such as, but not limited to, dimethylamino, diethylamino, dipropylamino, (methyl)(ethyl)amino, (ethyl)(propyl)amino, (methyl)(propyl)amino groups, and the like. In some such embodiments, R15 is a CH3 group. In still other such embodiments, R16 is selected from substituted alkoxy groups. In still other such embodiments, R16 is selected from substituted and unsubstituted heterocyclyl groups such as those selected from pyrrolidinyl groups, pyrazolyl groups, pyridyl groups, morpholinyl groups, piperazinyl groups, piperidinyl groups, and the like. In some embodiments, R7 is selected from —N(H)(3-piperidinyl) groups, —N(H)(4-piperidinyl) groups, —N(H)(4-(2-methoxymethylpyrrolidinyl)) groups, —N(CH3)(4-(1-methylpiperidinyl)) groups, —N(H)CH2(2-pyridyl) groups, —N(H)CH2(3-pyridyl) groups, —N(H)CH2(4-pyridyl) groups, —N(H)CH2CH2(2-pyridyl) groups, —N(H)CH2CH2(3-pyridyl) groups, —N(H)CH2CH2(4-pyridyl) groups, —N(CH3)CH2CH2(2-pyridyl) groups —N(H)CH2CH2(4-piperidinyl) groups, —N(H)CH2CH2(4-morpholinyl) groups, —N(H)CH2CH2CH2(1-imidazolyl) groups, —N(H)CH2CH2CH2(1-(4-methylpiperazinyl)) groups, —N(H)CH2CH2CH2(4-morpholinyl) groups, —N(H)CH2CH2CH2(1-imidazolyl) groups, —N(H)CH2CH2CH2(1-pyrrolidinyl) groups, —N(CH3)CH2CH2CH2(diethylamino) groups, and the like.
In still other embodiments of the third group of compounds where R7 is a substituted amino group having the formula—N(R15)(CH2)qR16, R6 is —H.
In another embodiment of the third group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is a substituted amino group having the formula —N(R15)(CH2)qR16 or the formula —N(R15)C(H)(alkyl)((CH2)qR16) where q is an integer selected from 0, 1, 2, or 3, R16 is selected from a methyl group, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups such as —N(H)(alkyl) groups, —N(alkyl)2 groups and the like, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups, and R15 is selected from —H; substituted and unsubstituted alkyl groups such as, but not limited to, methyl, ethyl, propyl, and isopropyl groups; —C(═O)-alkyl groups such as —C(═O)—CH3 groups and the like; —C(═O)-alkyl-N(H)(alkyl) groups such as —C(═O)—CH2—N(H)(alkyl) groups and the like; —C(═O)-alkyl-N(alkyl)2 groups such as —C(═O)—CH2—N(alkyl)2 groups and the like; —C(═O)-alkyl-N(R15a′)(R15b′) groups such as —C(═O)—CH2—N(alkyl)2 groups and the like —C(═O)-alkyl-heterocyclyl groups such as —C(═O)—CH2-heterocyclyl groups and the like such as —C(═O)—CH2-(1-piperazinyl) groups and the like; —C(═O)-heterocyclyl groups; —C(═O)-aryl groups; —C(═O)-alkyl-O-alkyl groups such as —C(═O)—CH2—O-alkyl groups; —C(═O)-alkyl-S-alkyl groups such as —C(═O)—CH2—S-alkyl groups and the like; and the like where R15a′ is selected from —H, and substituted and unsubstituted alkyl groups, and R15b′ is selected from —H, —SO2-alkyl, —SO2-aryl, —C(═O)-alkyl, —C(═O)-aryl, heterocyclyl groups such as 2-pyridyl groups and the like, heterocyclylalkyl groups, arylalkyl groups, alkyl groups, and —C(═O)-alkyl-halogen groups.
In another embodiment of the third group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is a substituted or unsubstituted heterocyclyl group. In some embodiments of the third group of compounds where R7 is a heterocyclyl group, the heterocyclyl group is selected from substituted or unsubstituted pyrrolidinyl groups, substituted and unsubstituted pyridyl groups, substituted and unsubstituted morpholinyl groups, substituted and unsubstituted piperazinyl groups, substituted and unsubstituted piperidinyl groups, substituted and unsubstituted pyrazolyl groups, substituted and unsubstituted pyrrolyl groups, substituted and unsubstituted imidazolyl groups, substituted and unsubstituted 1-aza-4-oxacycloheptane groups, substituted and unsubstituted 1,4-diazacycloheptane groups, substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups, substituted and unsubstituted 1,4-diazabicyclo[2.2.2]octane groups, substituted or unsubstituted 1,4-diazabicyclo[4.3.0]nonane group, and substituted or unsubstituted 1,4-diazacycloheptane groups. In still other embodiments of the third group of compounds where R7 is a heterocyclyl group, the heterocyclyl group is an unsubstituted morpholine group; a dialkyl substituted morpholinyl group such as, but not limited to, a dimethyl substituted morpholinyl group, and the like, such as, but not limited to, a 3,5-dimethyl substituted morpholinyl group; a hydroxy substituted morpholinyl group; a hydroxyalkyl substituted morpholinyl group; an aryl substituted morpholinyl group; an aminoalkyl substituted morpholinyl group including dialkylaminoalkyl substituted morpholinyl groups such as, but not limited to, dimethylaminomethyl substituted morpholinyl groups and the like such as, but not limited to, a morpholinyl group that is substituted on a ring carbon bonded to the ring O atom with a dimethylaminomethyl group and is substituted with a methyl group on the carbon bonded to the ring N atom which carbon is not bonded to the carbon bearing the dimethylaminomethyl group and the like; a heterocyclyl substituted morpholinyl group; an unsubstituted piperazine group; a dialkyl substituted piperazinyl group such as, but not limited to, a dimethyl substituted piperazinyl group, and the like such as a 3,5-dimethyl substituted piperazinyl group and the like; a monoalkyl substituted piperazinyl group such as a 3-alkyl substituted piperazinyl group, an N-alkyl substituted piperazinyl group, and the like such as, but not limited to, a 3-methyl substituted piperazinyl group, a N-alkyl substituted piperazinyl group, such as, but not limited to, N-methyl, N-ethyl, N-isopropyl substituted piperazinyl groups and the like; a hydroxyalkyl substituted piperazinyl group such as, but not limited to, hydroxyethyl and hydroxymethyl substituted piperazinyl groups and the like such as, but not limited to, N-hydroxyethyl substituted piperazinyl groups and the like; an aryl substituted piperazinyl group; a heterocyclyl substituted piperazinyl group such as, but not limited to, 2-, 3-, and 4-(2-, 3-, and 4-piperidinyl) substituted piperazinyl groups and 2-, 3-, and 4-(2-, 3-, and 4-pyridyl) substituted piperazinyl groups and the like; a —CH2C(═O)O-alkyl substituted piperazinyl group; a —C(═O)-alkyl substituted piperazinyl group such as, but not limited to, a —C(═O)-ethyl or a —C(═O)-methyl substituted piperazinyl group, and the like such as a piperazinyl group where the —C(═O)-ethyl or the —C(═O)-methyl substitution is on one of the piperazinyl N atoms and the other N atom is bonded to Z3, and the like; a —C(═O)O-alkyl substituted piperazinyl group such as, but not limited to, a —C(═O)—O-ethyl or a —C(═O)—O-methyl substituted piperazinyl group, and the like such as a piperazinyl group where the —C(═O)—O-ethyl or the —C(═O)—O-methyl substitution is on one of the piperazinyl N atoms and the other N atom is bonded to Z3, and the like; a cycloalkyl substituted piperazinyl group such as, but not limited to, a cyclohexyl and cyclopentyl substituted piperazinyl group and the like such as, but not limited to, a N-cyclohexyl substituted piperazinyl group and the like; an unsubstituted piperidine group; an alkyl substituted piperidinyl group such as, but not limited to, 2-, 3-, and 4-alkyl substituted piperidinyl groups, and the like such as, but not limited to, 2-, 3-, and 4-hydroxyalkyl substituted piperidinyl groups and the like such as, but not limited to, 2-, 3-, and 4-hydroxymethyl substituted piperidinyl groups and the like; a hydroxy substituted piperidinyl group such as 2-, 3-, and 4-hydroxy substituted piperidinyl groups; a hydroxyalkyl substituted piperidinyl group; an aryl substituted piperidinyl group such as, but not limited to, a 4-aryl substituted piperidinyl group and the like such as, but not limited to, a piperidinyl group that is substituted in the 4 position with both an aryl group and a hydroxy group and the like such as, but not limited to, a piperidinyl group that is substituted in the 4 position with both a hydroxy group and a phenyl group; a cycloalkyl substituted piperidinyl group; a heterocyclyl substituted piperidinyl group such as, but not limited to, a piperidinyl substituted piperidinyl group and the like such as, but not limited to, 4-piperidinyl substituted piperidinyl groups, 4-(2(3H)-benzimidazolone) substituted piperidinyl group, and the like; an unsubstituted pyrrolidinyl group; an alkyl substituted pyrrolidinyl group such as, but not limited to, a methyl substituted pyrrolidinyl group, a heterocyclylalkyl substituted pyrrolidinyl group, and the like such as, but not limited to, a 2-methyl substituted pyrrolidinyl group, a 2-pyrrolidinylmethyl substituted pyrrolidinyl group, and the like; an amino substituted pyrrolidinyl group such as, but not limited to, a dialkylamino substituted pyrrolidinyl group such as, but not limited to, 2- and 3-dialkylamino substituted pyrrolidinyl groups and the like such as, but not limited to, 2- and 3-substituted N,N-dimethylamino substituted pyrrolidinyl groups and the like such as, but not limited to, a pyrrolidinyl group that is substituted with both an alkyl group and an N,N-dimethylamino group and the like such as, but not limited to, a pyrrolidinyl group that is substituted with a methyl group in the 2 position and with a N,N-dimethylamino group in the 4 position; a hydroxy substituted pyrrolidinyl group such as, but not limited to, 2- and 3-hydroxy substituted pyrrolidinyl groups; a heterocyclylalkyl substituted pyrrolidinyl group; substituted and unsubstituted pyrrolyl groups; substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups; an alkyl substituted 2,5-diazabicyclo[2.2.1]heptane group such as, but not limited to, a N-methyl substituted 2,5-diazabicyclo[2.2.1]heptane group and the like; a substituted or unsubstituted 1,4-diazabicyclo[4.3.0]nonane group; and a substituted or unsubstituted 1,4-diazacycloheptane group such as, but not limited to, an alkyl substituted 1,4-diazacycloheptane group and the like, such as, but not limited to, an N-alkyl substituted 1,4-diazacycloheptane substituted group and the like such as, but not limited to, a N-methyl substituted 1,4-diazacycloheptane group and the like. In still other embodiments of the third group of compounds where R7 is a substituted or unsubstituted heterocyclyl group, R6 is —H.
In another embodiment of the third group of compounds, Z1–Z4, R1, R2, and R3 have any of the values in previous embodiments, and one of R6 or R7 is a substituted or unsubstituted pyridyloxy group. In some such embodiments, one of R6 or R7 is substituted or unsubstituted 2-pyridyloxy group, a 3-pyridyloxy group, or a 4-pyridyloxy group. In other such embodiments, one of R6 or R7 is a (2—N-alkylamido-4-pyridyl)oxy group such as a (2-N-methylamido-4-pyridyl)oxy group or the like; or a (5-N-alkylamido-3-pyridyl)oxy group such as a (5-N-methylamido-3-pyridyl)oxy group, or the like.
Other more particular embodiments of the compounds of the invention having the general structure shown in I above are provided. Such compounds form a fourth group of compounds for which:
Z1, Z2, Z3, and Z4 are independently selected from C or N;
R1 is selected from —H, —F, —Cl, —Br, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R2 is selected from —H, —F, —Cl, —Br, —C≡N, —NO2, —CO2H, —OH, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)O-aryl groups, substituted and unsubstituted —C(═O)O-heteroaryl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups, substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted akoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted heterocyclyloxy, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms;
R3 is selected from —H, —F, —Cl, —Br, —CF3, —C≡N, —NO2, —CO2H, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—O-alkyl groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy group, substituted and unsubstituted heterocycyl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups;
R4 is —H, —F, —Br, —Cl, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R5 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R5 is absent if Z1 is N;
R6 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups; or R6 is absent if Z2 is N;
R7 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups; or R7 is absent if Z3 is N;
R8 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R8 is absent if Z4 is N;
R9 is —H; and
R10 is selected from the group consisting of —H, and substituted and unsubstituted alkyl groups. In some such embodiments of the fourth group of compounds, at least one of R1, R2, R3, R4, R5, R6, R7 or R8 is not —H. In other such embodiments, at least two of R1, R2, R3, R4, R5, R6, R7 or R8 are not —H. In some embodiments, R10 is —H. In other embodiments, R10 is an unsubstituted alkyl group having from 1 to 6 carbon atoms such as a methyl, ethyl, propyl, i-propyl group, or the like. In some such embodiments, R10 is a —CH3 group
In one embodiment of the fourth group of compounds, each of Z1, Z2, Z3, and Z4 are C.
In another embodiment of the fourth group of compounds, Z1 is N and each of Z2, Z3, and Z4 are C.
In another embodiment of the fourth group of compounds, Z1 and Z3 are both N and Z2 and Z4 are both C.
In another embodiment of the fourth group of compounds, Z3 is N and each of Z1, Z2, and Z4 are C.
In another embodiment of the fourth group of compounds, Z1–Z4 have any of the values in previous embodiments, and R1 is selected from —H, —F, —Cl, and —Br.
In another embodiment of the fourth group of compounds, Z1–Z4 have any of the values in previous embodiments, and R1 is a substituted and unsubstituted heterocyclylamino group. In some such embodiments, R1 is a substituted and unsubstituted heteroarylamino groups. In some embodiments, R1 is an unsubstituted —NH2 group or is a substituted or unsubstituted heterocyclylamino group such as, but not limited to, substituted and unsubstituted pyrroldinylalkylamino groups and the like, such as, but not limited to, substituted and unsubstituted pyrrolidinylmethylamino groups and the like such as, but not limited to, —N(H)—CH2-(2-pyrrolidinyl) groups and the like.
In another embodiment of the fourth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is selected from —H, —F, —Cl, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted heterocyclyloxy, and substituted and unsubstituted heterocyclylalkoxy groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms. In another embodiment of the fourth group of compounds, R2 is selected from the group consisting of substituted and unsubstituted thiazolylalkylamino groups, substituted and unsubstituted pyrrolidinylalkylamino groups, and substituted and unsubstituted aminoalkylamino groups. In other such embodiments, R2 is selected from the group consisting of —N(H)—CH2-(2-thiazolyl) groups, —N(H)—CH2-(2-pyrroldinyl groups), —N(H)—CH2CH2CH2—N(H)(alkyl) groups, and —NH—CH2CH2CH2—N(alkyl)2 groups. In still other such embodiments, R2 is selected from the group consisting of —N(H)—CH2-(2-thiazolyl) groups, —N(H)—CH2-(2-pyrroldinyl groups), —N(H)—CH2CH2CH2—N(H)(CH3) groups, and —NH—CH2CH2CH2—N(CH3)2 groups.
In another embodiment of the fourth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is —H.
In another embodiment of the fourth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is an unsubstituted alkoxy group having from 1 to 4 carbon atoms.
In another embodiment of the fourth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a —OMe, —OEt, —O-i-Pr, or —OCH2CH(CH3)2 group.
In another embodiment of the fourth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted arylalkoxy, a substituted or unsubstituted aryloxy group, or a substituted or unsubstituted heterocyclyoxy group.
In another embodiment of the fourth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted benzyloxy group, a substituted or unsubstituted phenoxy group, or a substituted or unsubstituted pyridyloxy group.
In another embodiment of the fourth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is an unsubstituted alkyl group having from 1 to 4 carbon atoms.
In another embodiment of the fourth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a methyl group.
In another embodiment of the fourth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted —N(H)C(═O)—N(H)-alkyl-aryl group.
In another embodiment of the fourth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted amino group selected from the group consisting of substituted and unsubstituted alkylamino groups, dialkylamino groups, cycloalkylamino groups, heterocyclylamino groups, heterocyclylalkylamino groups, arylalkylamino groups, arylalkoxyarylmethylamino groups, and aryloxyarylalkylamino groups. In some embodiments, the substituted and unsubstituted alkylamino groups are substituted and unsubstituted aminoalkylamino groups such as, but not limited to, dialkylaminoalkylamino and the like. In some such embodiments the substituted and unsubstituted heterocyclylalkylamino groups are substituted and unsubstituted heteroarylalkylamino groups. In some embodiments, the heterocyclylalkylamino groups include, but are not limited to, substituted and unsubstituted pyrrolidinylalkylamino groups such as, but not limited to, substituted and unsubstituted pyrrolidinylmethylalkylamino groups and the like; substituted and unsubstituted thiazolylalkylamino groups such as, but not limited to substituted and unsubstituted thiazolylmethylamino groups and the like; substituted and unsubstituted imidazolylalkylamino groups such as, but not limited to, imidazolylmethylamino groups and the like; substituted and unsubstituted furanylalkylamino groups such as, but not limited to, substituted and unsubstituted furanylmethylamino groups, and the like; and the like. In other such embodiments, the heterocyclylamino groups are substituted and unsubstituted heteroarylamino groups. In other such embodiments, the substituted and unsubstituted heterocyclylamino groups are substituted and unsubstituted arylalkylheterocyclylamino groups.
In another embodiment of the fourth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted amino group selected from the group consisting of isopropylamino groups, 3-(N,N-dimethylamino)propylamino groups, pyrrolidinylmethylamino groups, arylmethylamino groups, arylalkoxyarylmethylamino groups, aryloxyarylmethylamino groups, and pyridylmethylamino groups, and pyridylamino groups.
In another embodiment of the fourth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted heterocyclyl groups. In some such embodiments R2 is a substituted or unsubstituted benzimidazolyl group or is a substituted or unsubstituted pyrazolyl group.
In another embodiment of the fourth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms.
In another embodiment of the fourth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is selected from —H, —F, —Cl, and —OMe.
In another embodiment of the fourth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —H.
In another embodiment of the fourth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is selected from the group consisting of —F, —Cl, —Br, —CF3, —C≡N, —NO2, —CO2H, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups and substituted and unsubstituted —C(═O)N(H)-alkyl-heterocyclyl groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms.
In another embodiment of the fourth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is selected from the group consisting of substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, and substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups. In some such embodiments, R3 is a substituted or unsubstituted —N(H)C(═O)N(H)CH2CH3 group, a substituted or unsubstituted —N(H)C(═O)N(H)CH(CH3)2 group, a substituted or unsubstituted —N(H)C(═O)N(H)C(CH3)3 group, or a substituted or unsubstituted —N(H)C(═O)N(H)-aryl group or the like. In some such embodiments, R3 is a substituted or unsubstituted —N(H)C(═O)N(H)-aryl group such as, but not limited to, a —N(H)C(═O)N(H)-(2-methoxyphenyl) group, a —N(H)C(═O)N(H)-(trifluoromethylphenyl) group, or the like.
In another embodiment of the fourth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is a substituted amino group selected from substituted or unsubstituted arylalkylamino groups such as, but not limited to, phenylalkylamino groups, (halo)(alkoxy)arylalkylamino groups, such as, but not limited to 2-fluoro-5-methoxyphenylmethylamino groups, monoalkoxyarylalkylamino groups, dialkoxyarylalkylamino groups, and the like, such as, but not limited to, 2,5-dialkoxyarylalkylamino groups and the like such as, but not limited to 2,5-dialkoxyarylmethylamino groups, substituted and unsubstituted arylalkoxyarylalkylamino groups such as, but not limited to substituted and unsubstituted arylalkoxyarylmethylamino groups and the like, such as, but not limited to, substituted and unsubstituted arylmethoxyarylmethylamino groups and the like, such as, but not limited to substituted and unsubstituted fluoroarylmethoxyarylmethylamino groups and the like, such as, but not limited to, substituted and unsubstituted 4-fluorophenylmethoxyphenyl-methylamino groups and the like; substituted and unsubstituted heterocyclylalkylamino groups including heteroarylalkylamino groups such as, but not limited to substituted and unsubstituted thiazolylalkylamino groups, benzimidazolylalkylamino groups such as, but not limited to N-methylbenzimidazolylalkylamino groups and the like, imidazolylalkylamino groups such as, but not limited to phenylimidazolylalkylamino groups, ethylmethylimidazolylalkylamino groups, and the like, substituted and unsubstituted quinolinylalkylamino groups, such as, but not limited to substituted and unsubstituted quinolinylmethylamino groups and the like, such as, but not limited to alkoxyquinolinylmethylamino groups and the like, such as, but not limited to substituted and unsubstituted 4-alkoxy-2-quinolinylmethylamino groups and the like, and furanylalkylamino groups, and the like. In other embodiments of the fourth group of compounds, R3 is selected from the group consisting of substituted and unsubstituted thiazolylalkylamino groups, substituted and unsubstituted benzimidazolylalkylamino groups, substituted and unsubstituted imidazolylalkylamino groups, substituted and unsubstituted furanylalkylamino groups, and substituted and unsubstituted arylalkylamino groups. In some such embodiments, R3 is selected from the group consisting of (2-thiazolyl)alkylamino groups, 1-(3-methylbenzimidazolyl)alkylamino groups, 4-(2-phenylimidazolyl)alkylamino groups, 4-(2-ethyl-5-methylimidazolyl)alkylamino groups, (2-furanyl)alkylamino groups, phenylalkylamino groups, and 1-(2-fluoro-5-alkoxyphenyl)alkylamino groups. In still other such embodiments, R3 is selected from the group consisting of —N(H)—CH2-(2-thiazolyl) groups, —N(H)—CH2-(1-(3-methylbenzimidazolyl)) groups, —N(H)—CH2-(4-(2-phenylimidazolyl)) groups, —N(H)—CH2-(4-(2-ethyl-5-methylimidazolyl)) groups, —N(H)—CH2-(2-furanyl) groups, —N(H)—CH2-phenyl groups, and —N(H)—CH2-(1-(2-fluoro-5-alkoxyphenyl)) groups. In still another embodiment, R1 is selected from the group consisting of unsubstituted —NH2 groups, and substituted and unsubstituted pyrrolidinylalkylamino groups; R2 is selected from the group consisting of substituted and unsubstituted thiazolylalkylamino groups, substituted and unsubstituted pyrrolidinylalkylamino groups, and substituted and unsubstituted aminoalkylamino groups; and/or R3 is selected from the group consisting of substituted and unsubstituted thiazolylalkylamino groups, substituted and unsubstituted benzimidazolylalkylamino groups, substituted and unsubstituted imidazolylalkylamino groups, substituted and unsubstituted furanylalkylamino groups, and substituted and unsubstituted arylalkylamino groups. In such compounds, Z1–Z4, R4, R5, R6, R7, R8, R9, and R10 can have any of the other values described in any of the other embodiments of any of the groups of compounds.
In another embodiment of the fourth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —F.
In another embodiment of the fourth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —Cl.
In another embodiment of the fourth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —OMe.
In another embodiment of the fourth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is a substituted and unsubstituted —C(═O)N(H)-alkyl-heterocyclyl groups where the heterocyclyl group of the —C(═O)N(H)-alkyl-heterocyclyl groups is selected from the group consisting of morpholinyl, piperazinyl, and piperidinyl groups.
In another embodiment of the fourth group of compounds, Z2–Z4, R1, R2, and R3 have any of the values in previous embodiments, Z1 is C, and R5 is H. In some such embodiments, R8 is also H.
In another embodiment of the fourth group of compounds, Z2–Z4, R1, R2, and R3 have any of the values in previous embodiments, Z1 is C, and R5 is —CH3. 
In another embodiment of the fourth group of compounds, Z2–Z4, R1, R2, and R3 have any of the values in previous embodiments, Z1 is C, and R5 is morpholine.
In another embodiment of the fourth group of compounds, Z1–Z3, R1, R2, and R3 have any of the values in previous embodiments, Z4 is C, and R8 is H.
In another embodiment of the fourth group of compounds, Z1–Z3, R1, R2, and R3 have any of the values in previous embodiments, Z4 is C, and R8 is —CH3. 
In another embodiment of the fourth group of compounds, Z1–Z3, R1, R2, and R3 have any of the values in previous embodiments, Z4 is C, and R8 is morpholine.
In another embodiment of the fourth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is selected from a first group; or Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is selected from the first group, the first group comprising members selected from the group consisting of —Br, —CO2H, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted alkoxyalkoxy groups, substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted cycloalkylheterocyclyl groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, substituted and unsubstituted heterocyclylamino groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups. In some such embodiments, R3 is selected from the group consisting of —F, —Cl, —Br, —CF3, —C≡N, —NO2, —CO2H, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, and substituted and unsubstituted —C(═O)N(H)-alkyl-heterocyclyl groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms.
In another embodiment of the fourth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is selected from —Br, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, substituted and unsubstituted —C(═O)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, and substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups. In still other embodiments, R6 has the values described in the preceding sentence and R7 is —H.
In another embodiment of the fourth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is an alkoxy group having from 1–6 carbon atoms. In still other such embodiments, R6 is a methoxy group. In still other embodiments of the fourth group of compounds where R6 is an alkoxy group having from 1–6 carbon atoms such as a methoxy group, R7 is —H.
In another embodiment of the fourth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is an alkyl group having from 1–6 carbon atoms. In still other such embodiments, R6 is a methyl group. In still other embodiments of the fourth group of compounds where R6 is an alkyl group having from 1–6 carbon atoms such as a methyl group, R7 is —H.
In another embodiment of the fourth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is a substituted alkoxy group having the formula —OCH2(CH2)mR11 where m is an integer selected from 0, 1, or 2 and R11 is selected from substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. In still other such embodiments, R11 is selected from substituted alkoxy groups such as, but not limited to methoxy groups, ethoxy groups, propoxy groups, and the like. In still other such embodiments, R11 is selected from substituted and unsubstituted heterocyclyl groups selected from pyrrolidinyl groups, pyridyl groups, morpholinyl groups, piperazinyl groups, and piperidinyl groups. In still other embodiments where R6 is a substituted alkoxy group having the formula —OCH2(CH2)mR11, R7 is —H. In still other embodiments, R6 is a pyrrolidinylalkoxy groups, such as but not limited to, a pyrrolidinylpropoxy group or the like; an alkoxyethoxy group such as, but not limited to, a methoxyethoxy group or the like; or a substituted or unsubstituted pyridinylalkoxy group such as, but not limited to, (3-pyridinyl)methoxy groups, or the like.
In another embodiment of the fourth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is a substituted amino group having the formula —N(R12)(CH2)pR13 where p is an integer selected from 0, 1, 2, or 3, R13 is selected from substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups, and R12 is selected from —H or substituted and unsubstituted alkyl groups such as, but not limited to, methyl, ethyl, propyl, and isopropyl. In some such embodiments, R13 is selected from substituted amino groups such as alkylamino groups and dialkylamino groups, such as, but not limited to, dimethylamino, diethylamino, dipropylamino, (methyl)(ethyl)amino, (ethyl)(propyl)amino, (methyl)(propyl)amino groups, and the like. In some such embodiments, R12 is a CH3 group. In still other such embodiments, R13 is selected from substituted alkoxy groups. In still other such embodiments, R13 is selected from substituted and unsubstituted heterocyclyl groups such as those selected from pyrrolidinyl groups, pyrazolyl groups, pyridyl groups, morpholinyl groups, piperazinyl groups, piperidinyl groups, and the like. In some embodiments, R6 is selected from —N(H)(3-piperidinyl) groups, —N(H)(4-piperidinyl) groups, —N(H)(4-(2-methoxymethylpyrrolidinyl)) groups, —N(CH3)(4-(1-methylpiperidinyl)) groups, —N(H)CH2(2-pyridyl) groups, —N(H)CH2(3-pyridyl) groups, —N(H)CH2(4-pyridyl) groups, —N(H)CH2CH2(2-pyridyl) groups, —N(H)CH2CH2(3-pyridyl) groups, —N(H)CH2CH2(4-pyridyl) groups, —N(CH3)CH2CH2(2-pyridyl) groups —N(H)CH2CH2(4-piperidinyl) groups, —N(H)CH2CH2(4-morpholinyl) groups, —N(H)CH2CH2CH2(1-imidazolyl) groups, —N(H)CH2CH2CH2(1-(4-methylpiperazinyl)) groups, —N(H)CH2CH2CH2(4-morpholinyl) groups, —N(H)CH2CH2CH2(1-imidazolyl) groups, —N(H)CH2CH2CH2(1-pyrrolidinyl) groups, —N(CH3)CH2CH2CH2(diethylamino) groups, and the like.
In still other embodiments of the fourth group of compounds where R6 is a substituted amino group having the formula —N(R12)(CH2)pR13, R7 is —H.
In another embodiment of the fourth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is a substituted amino group having the formula —N(R12)(CH2)pR13 or the formula —N(R12)C(H)(alkyl)((CH2)pR13) where p is an integer selected from 0, 1, 2, or 3, R13 is selected from a methyl group, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups such as —N(H)(alkyl) groups, —N(alkyl)2 groups and the like, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups, and R12 is selected from —H; substituted and unsubstituted alkyl groups such as, but not limited to, methyl, ethyl, propyl, and isopropyl groups; —C(═O)-alkyl groups such as —C(═O)—CH3 groups and the like; —C(═O)-alkyl-N(H)(alkyl) groups such as —C(═O)—CH2—N(H)(alkyl) groups and the like; —C(═O)-alkyl-N(alkyl)2 groups such as —C(═O)—CH2—N(alkyl)2 groups and the like; —C(═O)-alkyl-N(R12a′)(R12b′) groups such as —C(═O)—CH2—N(alkyl)2 groups and the like —C(═O)-alkyl-heterocyclyl groups such as —C(═O)—CH2-heterocyclyl groups and the like such as —C(═O)—CH2-(1-piperazinyl) groups and the like; —C(═O)-heterocyclyl groups; —C(═O)-aryl groups; —C(═O)-alkyl-O-alkyl groups such as —C(═O)—CH2—O-alkyl groups; —C(═O)-alkyl-S-alkyl groups such as —C(═O)—CH2—S-alkyl groups and the like; and the like where R12a′ is selected from —H, and substituted and unsubstituted alkyl groups, and R12b′ is selected from —H, —SO2-alkyl, —SO2-aryl, —C(═O)-alkyl, —C(═O)-aryl, heterocyclyl groups such as 2-pyridyl groups and the like, heterocyclylalkyl groups, arylalkyl groups, alkyl groups, and —C(═O)-alkyl-halogen groups.
In another embodiment of the fourth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values defined in the previous embodiments, Z2 is C, and R6 is a substituted or unsubstituted heterocyclyl group. In some embodiments of the fourth group of compounds where R6 is a heterocyclyl group, the heterocyclyl group is selected from substituted or unsubstituted pyrrolidinyl groups, substituted and unsubstituted pyridyl groups, substituted and unsubstituted morpholinyl groups, substituted and unsubstituted piperazinyl groups, substituted and unsubstituted piperidinyl groups, substituted and unsubstituted pyrazolyl groups, substituted and unsubstituted pyrrolyl groups, substituted and unsubstituted imidazolyl groups, substituted and unsubstituted 1-aza-4-oxacycloheptane groups, substituted and unsubstituted 1,4-diazacycloheptane groups, substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups, substituted and unsubstituted 1,4-diazabicyclo[2.2.2]octane groups, substituted or unsubstituted 1,4-diazabicyclo[4.3.0]nonane group, and substituted or unsubstituted 1,4-diazacycloheptane groups. In still other embodiments of the fourth group of compounds where R6 is a heterocyclyl group, the heterocyclyl group is an unsubstituted morpholine group; a dialkyl substituted morpholinyl group such as, but not limited to, a dimethyl substituted morpholinyl group, and the like, such as, but not limited to, a 3,5-dimethyl substituted morpholinyl group; a hydroxy substituted morpholinyl group; a hydroxyalkyl substituted morpholinyl group; an aryl substituted morpholinyl group; an aminoalkyl substituted morpholinyl group including dialkylaminoalkyl substituted morpholinyl groups such as, but not limited to, dimethylaminomethyl substituted morpholinyl groups and the like such as, but not limited to, a morpholinyl group that is substituted on a ring carbon bonded to the ring O atom with a dimethylaminomethyl group and is substituted with a methyl group on the carbon bonded to the ring N atom which carbon is not bonded to the carbon bearing the dimethylaminomethyl group and the like; a heterocyclyl substituted morpholinyl group; an unsubstituted piperazine group; a dialkyl substituted piperazinyl group such as, but not limited to, a dimethyl substituted piperazinyl group, and the like such as a 3,5-dimethyl substituted piperazinyl group and the like; a monoalkyl substituted piperazinyl group such as a 3-alkyl substituted piperazinyl group, an N-alkyl substituted piperazinyl group, and the like such as, but not limited to, a 3-methyl substituted piperazinyl group, a N-alkyl substituted piperazinyl group, such as, but not limited to, N-methyl, N-ethyl, N-isopropyl substituted piperazinyl groups and the like; a hydroxyalkyl substituted piperazinyl group such as, but not limited to, hydroxyethyl and hydroxymethyl substituted piperazinyl groups and the like such as, but not limited to, N-hydroxyethyl substituted piperazinyl groups and the like; an aryl substituted piperazinyl group; a heterocyclyl substituted piperazinyl group such as, but not limited to, 2-, 3-, and 4-(2-, 3-, and 4-piperidinyl) substituted piperazinyl groups and 2-, 3-, and 4-(2-, 3-, and 4-pyridyl) substituted piperazinyl groups and the like; a —CH2C(═O)O-alkyl substituted piperazinyl group; a —C(═O)-alkyl substituted piperazinyl group such as, but not limited to, a —C(═O)-ethyl or a —C(═O)-methyl substituted piperazinyl group, and the like such as a piperazinyl group where the —C(═O)-ethyl or the —C(═O)-methyl substitution is on one of the piperazinyl N atoms and the other N atom is bonded to Z2, and the like; a —C(═O)O-alkyl substituted piperazinyl group such as, but not limited to, a —C(═O)—O-ethyl or a —C(═O)—O-methyl substituted piperazinyl group, and the like such as a piperazinyl group where the —C(═O)—O-ethyl or the —C(═O)—O-methyl substitution is on one of the piperazinyl N atoms and the other N atom is bonded to Z2, and the like; a cycloalkyl substituted piperazinyl group such as, but not limited to, a cyclohexyl and cyclopentyl substituted piperazinyl group and the like such as, but not limited to, a N-cyclohexyl substituted piperazinyl group and the like; an unsubstituted piperidine group; an alkyl substituted piperidinyl group such as, but not limited to, 2-, 3-, and 4-alkyl substituted piperidinyl groups, and the like such as, but not limited to, 2-, 3-, and 4-hydroxyalkyl substituted piperidinyl groups and the like such as, but not limited to, 2-, 3-, and 4-hydroxymethyl substituted piperidinyl groups and the like; a hydroxy substituted piperidinyl group such as 2-, 3-, and 4-hydroxy substituted piperidinyl groups; a hydroxyalkyl substituted piperidinyl group; an aryl substituted piperidinyl group such as, but not limited to, a 4-aryl substituted piperidinyl group and the like such as, but not limited to, a piperidinyl group that is substituted in the 4 position with both an aryl group and a hydroxy group and the like such as, but not limited to, a piperidinyl group that is substituted in the 4 position with both a hydroxy group and a phenyl group; a cycloalkyl substituted piperidinyl group; a heterocyclyl substituted piperidinyl group such as, but not limited to, a piperidinyl substituted piperidinyl group and the like such as, but not limited to, 4-piperidinyl substituted piperidinyl groups, 4-(2(3H)-benzimidazolone) substituted piperidinyl group, and the like; an unsubstituted pyrrolidinyl group; an alkyl substituted pyrrolidinyl group such as, but not limited to, a methyl substituted pyrrolidinyl group, a heterocyclylalkyl substituted pyrrolidinyl group, and the like such as, but not limited to, a 2-methyl substituted pyrrolidinyl group, a 2-pyrrolidinylmethyl substituted pyrrolidinyl group, and the like; an amino substituted pyrrolidinyl group such as, but not limited to, a dialkylamino substituted pyrrolidinyl group such as, but not limited to, 2- and 3-dialkylamino substituted pyrrolidinyl groups and the like such as, but not limited to, 2- and 3-substituted N,N-dimethylamino substituted pyrrolidinyl groups and the like such as, but not limited to, a pyrrolidinyl group that is substituted with both an alkyl group and an N,N-dimethylamino group and the like such as, but not limited to, a pyrrolidinyl group that is substituted with a methyl group in the 2 position and with a N,N-dimethylamino group in the 4 position; a hydroxy substituted pyrrolidinyl group such as, but not limited to, 2- and 3-hydroxy substituted pyrrolidinyl groups; a heterocyclylalkyl substituted pyrrolidinyl group; substituted and unsubstituted pyrrolyl groups; substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups; an alkyl substituted 2,5-diazabicyclo[2.2.1]heptane group such as, but not limited to, a N-methyl substituted 2,5-diazabicyclo[2.2.1]heptane group and the like; a substituted or unsubstituted 1,4-diazabicyclo[4.3.0]nonane group; and a substituted or unsubstituted 1,4-diazacycloheptane group such as, but not limited to, an alkyl substituted 1,4-diazacycloheptane group and the like, such as, but not limited to, an N-alkyl substituted 1,4-diazacycloheptane substituted group and the like such as, but not limited to, a N-methyl substituted 1,4-diazacycloheptane group and the like. In still other embodiments of the fourth group of compounds where R6 is a substituted or unsubstituted heterocyclyl group, R7 is —H.
In another embodiment of the fourth group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is selected from substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, substituted and unsubstituted —C(═O)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, and substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups. In still other such embodiments, R7 has the values described in the preceding sentence and R6 is —H.
In another embodiment of the fourth group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is an alkoxy group having from 1–6 carbon atoms. In still other such embodiments, R7 is a methoxy group. In still other embodiments of the fourth group of compounds where R7 is an alkoxy group having from 1–6 carbon atoms such as a methoxy group, R6 is —H.
In another embodiment of the fourth group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is an alkyl group having from 1–6 carbon atoms. In still other such embodiments, R7 is a methyl group. In still other embodiments of the fourth group of compounds where R7 is an alkyl group having from 1–6 carbon atoms such as a methyl group, R6 is —H.
In another embodiment of the fourth group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is a substituted alkoxy group having the formula —OCH2(CH2)nR14 where n is an integer selected from 0, 1, or 2 and R14 is selected from substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. In some embodiments, R14 is selected from substituted alkoxy groups such as, but not limited to methoxy groups, ethoxy groups, propoxy groups, and the like. In still other such embodiments, R14 is selected from substituted and unsubstituted heterocyclyl groups selected from pyrrolidinyl groups, pyridyl groups, morpholinyl groups, piperazinyl groups, and piperidinyl groups. In still other embodiments of the fourth group of compounds where R7 is a substituted alkoxy group having the formula —OCH2(CH2)nR14, R6 is —H. In still other embodiments, R7 is a pyrrolidinylalkoxy groups, such as but not limited to, a pyrrolidinylpropoxy group or the like; an alkoxyethoxy group such as, but not limited to, a methoxyethoxy group or the like; or a substituted or unsubstituted pyridinylalkoxy group such as, but not limited to, (3-pyridinyl)methoxy groups, or the like.
In another embodiment of the fourth group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is a substituted amino group having the formula —N(R15)(CH2)qR16 where q is an integer selected from 0, 1, 2, or 3 and R16 is selected from substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups, and R15 is —H or a substituted or unsubstituted alkyl groups, such as, but not limited to, methyl, ethyl, propyl, and isopropyl groups. In some such embodiments, R16 is selected from substituted amino groups such as alkylamino groups and dialkylamino groups, such as, but not limited to, dimethylamino, diethylamino, dipropylamino, (methyl)(ethyl)amino, (ethyl)(propyl)amino, (methyl)(propyl)amino groups, and the like. In some such embodiments, R15 is a CH3 group. In still other such embodiments, R16 is selected from substituted alkoxy groups. In still other such embodiments, R16 is selected from substituted and unsubstituted heterocyclyl groups such as those selected from pyrrolidinyl groups, pyrazolyl groups, pyridyl groups, morpholinyl groups, piperazinyl groups, piperidinyl groups, and the like. In some embodiments, R7 is selected from —N(H)(3-piperidinyl) groups, —N(H)(4-piperidinyl) groups, —N(H)(4-(2-methoxymethylpyrrolidinyl)) groups, —N(CH3)(4-(1-methylpiperidinyl)) groups, —N(H)CH2(2-pyridyl) groups, —N(H)CH2(3-pyridyl) groups, —N(H)CH2(4-pyridyl) groups, —N(H)CH2CH2(2-pyridyl) groups, —N(H)CH2CH2(3-pyridyl) groups, —N(H)CH2CH2(4-pyridyl) groups, —N(CH3)CH2CH2(2-pyridyl) groups, —N(H)CH2CH2(4-piperidinyl) groups, —N(H)CH2CH2(4-morpholinyl) groups, —N(H)CH2CH2CH2(1-imidazolyl) groups, —N(H)CH2CH2CH2(1-(4-methylpiperazinyl)) groups, —N(H)CH2CH2CH2(4-morpholinyl) groups, —N(H)CH2CH2CH2(1-imidazolyl) groups, —N(H)CH2CH2CH2(1-pyrrolidinyl) groups, —N(CH3)CH2CH2CH2(diethylamino) groups, and the like.
In still other embodiments of the fourth group of compounds where R7 is a substituted amino group having the formula —N(R15)(CH2)qR16, R6 is —H.
In another embodiment of the fourth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is a substituted amino group having the formula —N(R15)(CH2)qR16 or the formula —N(R15)C(H)(alkyl)((CH2)qR16) where q is an integer selected from 0, 1, 2, or 3, R16 is selected from a methyl group, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups such as —N(H)(alkyl) groups, —N(alkyl)2 groups and the like, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups, and R15 is selected from —H; substituted and unsubstituted alkyl groups such as, but not limited to, methyl, ethyl, propyl, and isopropyl groups; —C(═O)-alkyl groups such as —C(═O)—CH3 groups and the like; —C(═O)-alkyl-N(H)(alkyl) groups such as —C(═O)—CH2—N(H)(alkyl) groups and the like; —C(═O)-alkyl-N(alkyl)2 groups such as —C(═O)—CH2—N(alkyl)2 groups and the like; —C(═O)-alkyl-N(R15a′)(R15b′) groups such as —C(═O)—CH2—N(alkyl)2 groups and the like —C(═O)-alkyl-heterocyclyl groups such as —C(═O)—CH2-heterocyclyl groups and the like such as —C(═O)—CH2-(1-piperazinyl) groups and the like; —C(═O)-heterocyclyl groups; —C(═O)-aryl groups; —C(═O)-alkyl-O-alkyl groups such as —C(═O)—CH2—O-alkyl groups; —C(═O)-alkyl-S-alkyl groups such as —C(═O)—CH2—S-alkyl groups and the like; and the like where R15a′ is selected from —H, and substituted and unsubstituted alkyl groups, and R15b′ is selected from —H, —SO2-alkyl, —SO2-aryl, —C(═O)-alkyl, —C(═O)-aryl, heterocyclyl groups such as 2-pyridyl groups and the like, heterocyclylalkyl groups, arylalkyl groups, alkyl groups, and —C(═O)-alkyl-halogen groups.
In another embodiment of the fourth group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is a substituted or unsubstituted heterocyclyl group. In some embodiments of the fourth group of compounds where R7 is a heterocyclyl group, the heterocyclyl group is selected from substituted or unsubstituted pyrrolidinyl groups, substituted and unsubstituted pyridyl groups, substituted and unsubstituted morpholinyl groups, substituted and unsubstituted piperazinyl groups, substituted and unsubstituted piperidinyl groups, substituted and unsubstituted pyrazolyl groups, substituted and unsubstituted pyrrolyl groups, substituted and unsubstituted imidazolyl groups, substituted and unsubstituted 1-aza-4-oxacycloheptane groups, substituted and unsubstituted 1,4-diazacycloheptane groups, substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups, substituted and unsubstituted 1,4-diazabicyclo[2.2.2]octane groups, substituted or unsubstituted 1,4-diazabicyclo[4.3.0]nonane group, and substituted or unsubstituted 1,4-diazacycloheptane groups. In still other embodiments of the fourth group of compounds where R7 is a heterocyclyl group, the heterocyclyl group is an unsubstituted morpholine group; a dialkyl substituted morpholinyl group such as, but not limited to, a dimethyl substituted morpholinyl group, and the like, such as, but not limited to, a 3,5-dimethyl substituted morpholinyl group; a hydroxy substituted morpholinyl group; a hydroxyalkyl substituted morpholinyl group; an aryl substituted morpholinyl group; an aminoalkyl substituted morpholinyl group including dialkylaminoalkyl substituted morpholinyl groups such as, but not limited to, dimethylaminomethyl substituted morpholinyl groups and the like such as, but not limited to, a morpholinyl group that is substituted on a ring carbon bonded to the ring O atom with a dimethylaminomethyl group and is substituted with a methyl group on the carbon bonded to the ring N atom which carbon is not bonded to the carbon bearing the dimethylaminomethyl group and the like; a heterocyclyl substituted morpholinyl group; an unsubstituted piperazine group; a dialkyl substituted piperazinyl group such as, but not limited to, a dimethyl substituted piperazinyl group, and the like such as a 3,5-dimethyl substituted piperazinyl group and the like; a monoalkyl substituted piperazinyl group such as a 3-alkyl substituted piperazinyl group, an N-alkyl substituted piperazinyl group, and the like such as, but not limited to, a 3-methyl substituted piperazinyl group, a N-alkyl substituted piperazinyl group, such as, but not limited to, N-methyl, N-ethyl, N-isopropyl substituted piperazinyl groups and the like; a hydroxyalkyl substituted piperazinyl group such as, but not limited to, hydroxyethyl and hydroxymethyl substituted piperazinyl groups and the like such as, but not limited to, N-hydroxyethyl substituted piperazinyl groups and the like; an aryl substituted piperazinyl group; a heterocyclyl substituted piperazinyl group such as, but not limited to, 2-, 3-, and 4-(2-, 3-, and 4-piperidinyl) substituted piperazinyl groups and 2-, 3-, and 4-(2-, 3-, and 4-pyridyl) substituted piperazinyl groups and the like; a —CH2C(═O)O-alkyl substituted piperazinyl group; a —C(═O)-alkyl substituted piperazinyl group such as, but not limited to, a —C(═O)-ethyl or a —C(═O)-methyl substituted piperazinyl group, and the like such as a piperazinyl group where the —C(═O)-ethyl or the —C(═O)-methyl substitution is on one of the piperazinyl N atoms and the other N atom is bonded to Z3, and the like; a —C(═O)O-alkyl substituted piperazinyl group such as, but not limited to, a —C(═O)—O-ethyl or a —C(═O)—O-methyl substituted piperazinyl group, and the like such as a piperazinyl group where the —C(═O)—O-ethyl or the —C(═O)—O-methyl substitution is on one of the piperazinyl N atoms and the other N atom is bonded to Z3, and the like; a cycloalkyl substituted piperazinyl group such as, but not limited to, a cyclohexyl and cyclopentyl substituted piperazinyl group and the like such as, but not limited to, a N-cyclohexyl substituted piperazinyl group and the like; an unsubstituted piperidine group; an alkyl substituted piperidinyl group such as, but not limited to, 2-, 3-, and 4-alkyl substituted piperidinyl groups, and the like such as, but not limited to, 2-, 3-, and 4-hydroxyalkyl substituted piperidinyl groups and the like such as, but not limited to, 2-, 3-, and 4-hydroxymethyl substituted piperidinyl groups and the like; a hydroxy substituted piperidinyl group such as 2-, 3-, and 4-hydroxy substituted piperidinyl groups; a hydroxyalkyl substituted piperidinyl group; an aryl substituted piperidinyl group such as, but not limited to, a 4-aryl substituted piperidinyl group and the like such as, but not limited to, a piperidinyl group that is substituted in the 4 position with both an aryl group and a hydroxy group and the like such as, but not limited to, a piperidinyl group that is substituted in the 4 position with both a hydroxy group and a phenyl group; a cycloalkyl substituted piperidinyl group; a heterocyclyl substituted piperidinyl group such as, but not limited to, a piperidinyl substituted piperidinyl group and the like such as, but not limited to, 4-piperidinyl substituted piperidinyl groups, 4-(2(3H)-benzimidazolone) substituted piperidinyl group, and the like; an unsubstituted pyrrolidinyl group; an alkyl substituted pyrrolidinyl group such as, but not limited to, a methyl substituted pyrrolidinyl group, a heterocyclylalkyl substituted pyrrolidinyl group, and the like such as, but not limited to, a 2-methyl substituted pyrrolidinyl group, a 2-pyrrolidinylmethyl substituted pyrrolidinyl group, and the like; an amino substituted pyrrolidinyl group such as, but not limited to, a dialkylamino substituted pyrrolidinyl group such as, but not limited to, 2- and 3-dialkylamino substituted pyrrolidinyl groups and the like such as, but not limited to, 2- and 3-substituted N,N-dimethylamino substituted pyrrolidinyl groups and the like such as, but not limited to, a pyrrolidinyl group that is substituted with both an alkyl group and an N,N-dimethylamino group and the like such as, but not limited to, a pyrrolidinyl group that is substituted with a methyl group in the 2 position and with a N,N-dimethylamino group in the 4 position; a hydroxy substituted pyrrolidinyl group such as, but not limited to, 2- and 3-hydroxy substituted pyrrolidinyl groups; a heterocyclylalkyl substituted pyrrolidinyl group; substituted and unsubstituted pyrrolyl groups; substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups; an alkyl substituted 2,5-diazabicyclo[2.2.1]heptane group such as, but not limited to, a N-methyl substituted 2,5-diazabicyclo[2.2.1]heptane group and the like; a substituted or unsubstituted 1,4-diazabicyclo[4.3.0]nonane group; and a substituted or unsubstituted 1,4-diazacycloheptane group such as, but not limited to, an alkyl substituted 1,4-diazacycloheptane group and the like, such as, but not limited to, an N-alkyl substituted 1,4-diazacycloheptane substituted group and the like such as, but not limited to, a N-methyl substituted 1,4-diazacycloheptane group and the like. In still other embodiments of the fourth group of compounds where R7 is a substituted or unsubstituted heterocyclyl group, R6 is —H.
In another embodiment of the fourth group of compounds, Z1–Z4, R1, R2, and R3 have any of the values in previous embodiments, and one of R6 or R7 is a substituted or unsubstituted pyridyloxy group. In some such embodiments, one of R6 or R7 is substituted or unsubstituted 2-pyridyloxy group, a 3-pyridyloxy group, or a 4-pyridyloxy group. In other such embodiments, one of R6 or R7 is a (2-N-alkylamido-4-pyridyl)oxy group such as a (2-N-methylamido-4-pyridyl)oxy group or the like; or a (5-N-alkylamido-3-pyridyl)oxy group such as a (5-N-methylamido-3-pyridyl)oxy group, or the like.
Other more particular embodiments of the compounds of the invention having the general structure shown in I above are provided. Such compounds form a fifth group of compounds for which:
Z1, Z2, Z3, and Z4 are independently selected from C or N;
R1 is selected from —H, —F, —Cl, —Br, —NO2, —C—N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R2 is selected from —H, —F, —Cl, —Br, —C≡N, —NO2, —CO2H, —OH, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)O-aryl groups, substituted and unsubstituted —C(═O)O-heteroaryl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups, substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted akoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted heterocyclyloxy, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms;
R3 is selected from —F, —Cl, —Br, —CF3, —C≡N, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted saturated heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted saturated heterocycyl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, and substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups;
R4 is —H, —F, —Br, —Cl, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R5 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R5 is absent if Z1 is N;
R6 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups; or R6 is absent if Z2 is N;
R7 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups; or R7 is absent if Z3 is N;
R8 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R8 is absent if Z4 is N;
R9 is —H; and
R10 is selected from the group consisting of —H, and substituted and unsubstituted alkyl groups.
In some embodiments, R10 is —H. In other embodiments, R10 is an unsubstituted alkyl group having from 1 to 6 carbon atoms such as a methyl, ethyl, propyl, i-propyl group, or the like. In some such embodiments, R10 is a —CH3 group.
In one embodiment of the fifth group of compounds, each of Z1, Z2, Z3, and Z4 are C.
In another embodiment of the fifth group of compounds, Z1 is N and each of Z2, Z3, and Z4 are C.
In another embodiment of the fifth group of compounds, Z1 and Z3 are both N and Z2 and Z4 are both C.
In another embodiment of the fifth group of compounds, Z3 is N and each of Z1, Z2, and Z4 are C.
In another embodiment of the fifth group of compounds, Z1–Z4 have any of the values in previous embodiments, and R1 is selected from —H, —F, —Cl, and —Br.
In another embodiment of the fifth group of compounds, Z1–Z4 have any of the values in previous embodiments, and R1 is a substituted and unsubstituted heterocyclylamino group. In some such embodiments, R1 is a substituted and unsubstituted heteroarylamino groups. In some embodiments, R1 is a substituted and unsubstituted heterocyclylamino group such as, but not limited to, substituted and unsubstituted pyrroldinylalkylamino groups and the like, such as, but not limited to, substituted and unsubstituted pyrrolidinylmethylamino groups and the like.
In another embodiment of the fifth group of compounds, Z1 –Z4 and R1 have any of the values in previous embodiments, and R2 is selected from —H, —F, —Cl, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted heterocyclyloxy, and substituted and unsubstituted heterocyclylalkoxy groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms.
In another embodiment of the fifth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is —H.
In another embodiment of the fifth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is an unsubstituted alkoxy group having from 1 to 4 carbon atoms.
In another embodiment of the fifth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a —OMe, —OEt, —O-i-Pr, or —OCH2CH(CH3)2 group.
In another embodiment of the fifth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted arylalkoxy, a substituted or unsubstituted aryloxy group, or a substituted or unsubstituted heterocyclyoxy group.
In another embodiment of the fifth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted benzyloxy group, a substituted or unsubstituted phenoxy group, or a substituted or unsubstituted pyridyloxy group.
In another embodiment of the fifth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is an unsubstituted alkyl group having from 1 to 4 carbon atoms.
In another embodiment of the fifth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a methyl group.
In another embodiment of the fifth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted —N(H)C(═O)—N(H)-alkyl-aryl group.
In another embodiment of the fifth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted amino group selected from the group consisting of substituted and unsubstituted alkylamino groups, dialkylamino groups, cycloalkylamino groups, heterocyclylamino groups, heterocyclylalkylamino groups, arylalkylamino groups, arylalkoxyarylmethylamino groups, and aryloxyarylalkylamino groups. In some embodiments, the substituted and unsubstituted alkylamino groups are substituted and unsubstituted aminoalkylamino groups such as, but not limited to, dialkylaminoalkylamino and the like. In some such embodiments the substituted and unsubstituted heterocyclylalkylamino groups are substituted and unsubstituted heteroarylalkylamino groups. In some embodiments, the heterocyclylalkylamino groups include, but are not limited to, substituted and unsubstituted pyrrolidinylalkylamino groups such as, but not limited to, substituted and unsubstituted pyrrolidinylmethylalkylamino groups and the like; substituted and unsubstituted thiazolylalkylamino groups such as, but not limited to substituted and unsubstituted thiazolylmethylamino groups and the like; substituted and unsubstituted imidazolylalkylamino groups such as, but not limited to, imidazolylmethylamino groups and the like; substituted and unsubstituted furanylalkylamino groups such as, but not limited to, substituted and unsubstituted furanylmethylamino groups, and the like; and the like. In other such embodiments, the heterocyclylamino groups are substituted and unsubstituted heteroarylamino groups. In other such embodiments, the substituted and unsubstituted heterocyclylamino groups are substituted and unsubstituted arylalkylheterocyclylamino groups.
In another embodiment of the fifth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted amino group selected from the group consisting of isopropylamino groups, 3-(N,N-dimethylamino)propylamino groups, pyrrolidinylmethylamino groups, arylmethylamino groups, arylalkoxyarylmethylamino groups, aryloxyarylmethylamino groups, and pyridylmethylamino groups, and pyridylamino groups.
In another embodiment of the fifth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted heterocyclyl groups. In some such embodiments R2 is a substituted or unsubstituted benzimidazolyl group or is a substituted or unsubstituted pyrazolyl group.
In another embodiment of the fifth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms.
In another embodiment of the fifth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is selected from —F, —Cl, and —OMe.
In another embodiment of the fifth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is selected from the group consisting of substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, and substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups. In some such embodiments, R3 is a substituted or unsubstituted —N(H)C(═O)N(H)CH2CH3 group, a substituted or unsubstituted —N(H)C(═O)N(H)CH(CH3)2 group, a substituted or unsubstituted —N(H)C(═O)N(H)C(CH3)3 group, or a substituted or unsubstituted —N(H)C(═O)N(H)-aryl group or the like. In some such embodiments, R3 is a substituted or unsubstituted —N(H)C(═O)N(H)-aryl group such as, but not limited to, a —N(H)C(═O)N(H)-(2-methoxyphenyl) group, a-N(H)C(═O)N(H)-(trifluoromethylphenyl) group, or the like.
In another embodiment of the fifth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —F.
In another embodiment of the fifth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —Cl.
In another embodiment of the fifth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —OMe.
In some embodiments of the fifth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and at least one of R6 or R7 is selected from the group consisting of —CO2H, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted alkoxyalkoxy groups, substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted cycloalkylheterocyclyl groups, substituted and unsubstituted saturated heterocyclyloxy groups, substituted and unsubstituted —N(H)-alkyl groups, substituted and unsubstituted —N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted —N(H)-alkyl-aryl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups. In some such embodiments, at least one of R6 or R7 is selected from the group consisting of —CO2H, substituted and unsubstituted saturated heterocyclyloxy groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups. In another embodiments of the fifth group of compounds, at least one of R6 or R7 is selected from the group consisting of substituted and unsubstituted piperidinyl substituted heterocyclyl groups, substituted and unsubstituted heterocyclyl substituted piperidinyl groups, substituted and unsubstituted hydroxymethyl substituted piperidinyl groups, dimethylaminoalkyl substituted pyrrolidinyl groups, substituted and unsubstituted 3-alkyl substituted piperazinyl groups, substituted and unsubstituted 3,5-dialkyl substituted piperazinyl groups, substituted and unsubstituted N-hydroxyalkyl substituted piperazinyl groups, substituted and unsubstituted N-alkyl substituted 1,4-diazacycloheptyl groups, substituted and unsubstituted N-ethylpiperazinyl groups, substituted and unsubstituted N-isopropylpiperazinyl groups, substituted and unsubstituted N-sec-butylpiperazinyl groups, unsubstituted piperazinyl groups, substituted and unsubstituted N-2-pyridyl substituted piperazinyl groups, substituted and unsubstituted N-3-pyridyl substituted piperazinyl groups, substituted and unsubstituted N-4-pyridyl substituted piperazinyl groups, substituted and unsubstituted N(H)—CH2-pyridyl groups, substituted and unsubstituted imidazolyl groups, substituted and unsubstituted morpholinyl groups, substituted and unsubstituted 3-alkyl substituted morpholinyl groups, substituted and unsubstituted 3,5-dialkyl substituted morpholinyl groups, dialkylamino substituted pyrrolidinyl groups, pyrrolidinyl groups substituted with both dialkylamino and alkyl groups, substituted and unsubstituted 4-hydroxy substituted piperidinyl groups, substituted and unsubstituted 4-aryl substituted piperidinyl groups, substituted and unsubstituted 4-hydroxy-4-phenyl substituted piperidinyl groups, substituted and unsubstituted cyclohexylpiperazinyl groups, substituted and unsubstituted cyclopentylpiperazinyl groups, substituted and unsubstituted N-alkyl substituted diazabicycloalkane groups, substituted and unsubstituted —N(CH3)(N-alkyl(4-piperidinyl)) groups, substituted and unsubstituted piperazinyl groups further substituted with a —C(═O)-alkyl group on one of the N atoms of the piperazinyl group, substituted and unsubstituted —N(H)CH2CH2CH2-imidazolyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-pyrrolidinyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-morpholinyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-piperazinyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-piperidinyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-pyridyl groups, substituted and unsubstituted —N(H)CH2CH2-imidazolyl groups, substituted and unsubstituted —N(H)CH2CH2-pyrrolidinyl groups, substituted and unsubstituted —N(H)CH2CH2-morpholinyl groups, substituted and unsubstituted —N(H)CH2CH2-piperazinyl groups, substituted and unsubstituted —N(H)CH2CH2-piperidinyl groups, substituted and unsubstituted —N(H)CH2CH2-pyridyl groups, substituted and unsubstituted 1-aza-4-oxacycloheptane groups, and substituted and unsubstituted 1,4-diazacycloheptane groups. In other embodiments, at least one of R6 or R7 is selected from the group consisting of piperidinyl substituted piperidinyl groups such as 4-piperidinylpiperidinyl groups or the like, 4-hydroxymethylpiperidinyl groups, 3-dimethylaminomethylpyrrolidinyl groups, 3-alkyl substituted piperazinyl groups, 3,5-dialkyl substituted piperazinyl groups, N-hydroxyethylpiperazinyl groups, N-hydroxymethylpiperazinyl groups, N-hydroxypropylpiperazinyl groups, N-methyl substituted 1,4-diazacycloheptyl groups, N-ethylpiperazinyl groups, N-isopropylpiperazinyl groups, N-sec-butylpiperazinyl groups, unsubstituted piperazinyl groups, N-(2-pyridyl)piperazinyl groups, N-(3-pyridyl)piperazinyl groups, N-(4-pyridyl)piperazinyl groups, N(H)—CH2-pyridyl groups, imidazolyl groups, unsubstituted morpholinyl groups, 3-alkylmorpholinyl groups, 3,5-dialkylmorpholinyl groups, 2-dimethylaminopyrrolidinyl groups, 2-methyl-4-dialkylaminopyrroldinyl groups, 4-hydroxypiperidinyl groups, 4-arylpiperidinyl groups, 4-hydroxy-4-phenylpiperidinyl groups, cyclohexylpiperazinyl groups, cyclopentylpiperazinyl groups, N-methyl substituted diazabicycloalkane groups, —N(CH3)(N-alkyl(4-piperidinyl)) groups, piperazinyl groups further substituted with a —C(═O)-methyl group on one of the N atoms of the piperazinyl group, —N(H)CH2CH2CH2-imidazolyl groups, —N(H)CH2CH2CH2-pyrrolidinyl groups, —N(H)CH2CH2CH2-morpholinyl groups, —N(H)CH2CH2CH2-piperazinyl groups, —N(H)CH2CH2CH2-piperidinyl groups, and —N(H)CH2CH2CH2-pyridyl groups. In some such embodiments, at least one of R6 or R7 is selected from the group consisting of 4-piperidinylpiperidinyl groups, 4-hydroxymethylpiperidinyl groups, 3-dimethylaminomethylpyrrolidinyl groups, 3,5-dimethyl substituted piperazinyl groups, N-methyl substituted 1,4-diazacycloheptyl groups, N-(2-pyridyl)piperazinyl groups, N(H)—CH2-(4-pyridyl) groups, imidazolyl groups, unsubstituted morpholinyl groups, 3-methylmorpholinyl groups, 3,5-dimethylmorpholinyl groups, 2-dimethylaminopyrrolidinyl groups, 2-methyl-4-dimethylaminopyrroldinyl groups, 4-hydroxy-4-phenylpiperidinyl groups, cyclohexylpiperazinyl groups, N-methyl substituted diazabicycloalkane groups, —N(CH3)(N-methyl(4-piperidinyl)) groups, piperazinyl groups further substituted with a —C(═O)-methyl group on one of the N atoms of the piperazinyl group, —N(H)CH2CH2CH2-imidazolyl groups, —N(H)CH2CH2CH2-pyrrolidinyl groups, —N(H)CH2CH2CH2-morpholinyl groups, —N(H)CH2CH2CH2-piperazinyl groups, —N(H)CH2CH2CH2-piperidinyl groups, and —N(H)CH2CH2CH2-pyridyl groups.
In another embodiment of the fifth group of compounds, Z2–Z4, R1, R2, and R3 have any of the values in previous embodiments, Z1 is C, and R5 is H. In some such embodiments, R8 is also H.
In another embodiment of the fifth group of compounds, Z2–Z4, R1, R2, and R3 have any of the values in previous embodiments, Z8 is C, and R5 is —CH3.
In another embodiment of the fifth group of compounds, Z2–Z4, R1, R2, and R3 have any of the values in previous embodiments, Z1 is C, and R5 is morpholine.
In another embodiment of the fifth group of compounds, Z1–Z3, R1, R2, and R3 have any of the values in previous embodiments, Z4 is C, and R8 is H.
In another embodiment of the fifth group of compounds, Z1–Z3, R1, R2, and R3 have any of the values in previous embodiments, Z4 is C, and R8 is —CH3.
In another embodiment of the fifth group of compounds, Z1–Z3, R1, R2, and R3 have any of the values in previous embodiments, Z4 is C, and R8 is morpholine.
In another embodiment of the fifth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is selected from a first group of compounds; or Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is selected from the first group of compounds, the first group of compounds comprising members selected from the group consisting of —CO2H, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted alkoxyalkoxy groups, substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted cycloalkylheterocyclyl groups, substituted and unsubstituted saturated heterocyclyloxy groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, substituted and unsubstituted heterocyclylamino groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, —C(═O)N(H)-heteroaryl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups.
In another embodiment of the fifth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is selected from —Br, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, substituted and unsubstituted —C(═O)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, and substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups. In still other embodiments, R6 has the values described in the preceding sentence and R7 is —H.
In another embodiment of the fifth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is an alkoxy group having from 1–6 carbon atoms. In still other such embodiments, R6 is a methoxy group. In still other embodiments of the fifth group of compounds where R6 is an alkoxy group having from 1–6 carbon atoms such as a methoxy group, R7 is —H.
In another embodiment of the fifth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is an alkyl group having from 1–6 carbon atoms. In still other such embodiments, R6 is a methyl group. In still other embodiments of the fifth group of compounds where R6 is an alkyl group having from 1–6 carbon atoms such as a methyl group, R7 is —H.
In another embodiment of the fifth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is a substituted alkoxy group having the formula —OCH2(CH2)mR11 where m is an integer selected from 0, 1, or 2 and R11 is selected from substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. In still other such embodiments, R11 is selected from substituted alkoxy groups such as, but not limited to methoxy groups, ethoxy groups, propoxy groups, and the like. In still other such embodiments, R11 is selected from substituted and unsubstituted heterocyclyl groups selected from pyrrolidinyl groups, pyridyl groups, morpholinyl groups, piperazinyl groups, and piperidinyl groups. In still other embodiments where R6 is a substituted alkoxy group having the formula —OCH2(CH2)mR11, R7 is —H. In still other embodiments, R6 is a pyrrolidinylalkoxy groups, such as but not limited to, a pyrrolidinylpropoxy group or the like; an alkoxyethoxy group such as, but not limited to, a methoxyethoxy group or the like; or a substituted or unsubstituted pyridinylalkoxy group such as, but not limited to, (3-pyridinyl)methoxy groups, or the like.
In another embodiment of the fifth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is a substituted amino group having the formula —N(R12)(CH2)pR13 where p is an integer selected from 0, 1, 2, or 3, R13 is selected from substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups, and R12 is selected from —H or substituted and unsubstituted alkyl groups such as, but not limited to, methyl, ethyl, propyl, and isopropyl. In some such embodiments, R13 is selected from substituted amino groups such as alkylamino groups and dialkylamino groups, such as, but not limited to, dimethylamino, diethylamino, dipropylamino, (methyl)(ethyl)amino, (ethyl)(propyl)amino, (methyl)(propyl)amino groups, and the like. In some such embodiments, R12 is a CH3 group. In still other such embodiments, R13 is selected from substituted alkoxy groups. In still other such embodiments, R13 is selected from substituted and unsubstituted heterocyclyl groups such as those selected from pyrrolidinyl groups, pyrazolyl groups, pyridyl groups, morpholinyl groups, piperazinyl groups, piperidinyl groups, and the like. In some embodiments, R6 is selected from —N(H)(3-piperidinyl) groups, —N(H)(4-piperidinyl) groups, —N(H)(4-(2-methoxymethylpyrrolidinyl)) groups, —N(CH3)(4-(1-methylpiperidinyl)) groups, —N(H)CH2(2-pyridyl) groups, —N(H)CH2(3-pyridyl) groups, —N(H)CH2(4-pyridyl) groups, —N(H)CH2CH2(2-pyridyl) groups, —N(H)CH2CH2(3-pyridyl) groups, —N(H)CH2CH2(4-pyridyl) groups, —N(CH3)CH2CH2(2-pyridyl) groups —N(H)CH2CH2(4-piperidinyl) groups, —N(H)CH2CH2(4-morpholinyl) groups, —N(H)CH2CH2CH2(1-imidazolyl) groups, —N(H)CH2CH2CH2(1-(4-methylpiperazinyl)) groups, —N(H)CH2CH2CH2(4-morpholinyl) groups, —N(H)CH2CH2CH2(1-imidazolyl) groups, —N(H)CH2CH2CH2(1-pyrrolidinyl) groups, —N(CH3)CH2CH2CH2(diethylamino) groups, and the like.
In still other embodiments of the fifth group of compounds where R6 is a substituted amino group having the formula —N(R12)(CH2)pR13, R7 is —H.
In another embodiment of the fifth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is a substituted amino group having the formula —N(R12)(CH2)pR13 or the formula —N(R12)C(H)(alkyl)((CH2)pR13) where p is an integer selected from 0, 1, 2, or 3, R13 is selected from a methyl group, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups such as —N(H)(alkyl) groups, —N(alkyl)2 groups and the like, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups, and R12 is selected from —H; substituted and unsubstituted alkyl groups such as, but not limited to, methyl, ethyl, propyl, and isopropyl groups; —C(═O)-alkyl groups such as —C(═O)—CH3 groups and the like; —C(═O)-alkyl-N(H)(alkyl) groups such as —C(═O)—CH2—N(H)(alkyl) groups and the like; —C(═O)-alkyl-N(alkyl)2 groups such as —C(═O)—CH2—N(alkyl)2 groups and the like; —C(═O)-alkyl-N(R12a′)(R12b′) groups such as —C(═O)—CH2—N(alkyl)2 groups and the like —C(═O)-alkyl-heterocyclyl groups such as —C(═O)—CH2-heterocyclyl groups and the like such as —C(═O)—CH2-(1-piperazinyl) groups and the like; —C(═O)-heterocyclyl groups; —C(═O)-aryl groups; —C(═O)-alkyl-O-alkyl groups such as —C(═O)—CH2—-O-alkyl groups; —C(═O)-alkyl-S-alkyl groups such as —C(═O)—CH2—S-alkyl groups and the like; and the like where R12a′ is selected from —H, and substituted and unsubstituted alkyl groups, and R12b′ is selected from —H, —SO2-alkyl, —SO2-aryl, —C(═O)-alkyl, —C(═O)-aryl, heterocyclyl groups such as 2-pyridyl groups and the like, heterocyclylalkyl groups, arylalkyl groups, alkyl groups, and —C(═O)-alkyl-halogen groups.
In another embodiment of the fifth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values defined in the previous embodiments, Z2 is C, and R6 is a substituted or unsubstituted heterocyclyl group. In some embodiments of the fifth group of compounds where R6 is a heterocyclyl group, the heterocyclyl group is selected from substituted or unsubstituted pyrrolidinyl groups, substituted and unsubstituted pyridyl groups, substituted and unsubstituted morpholinyl groups, substituted and unsubstituted piperazinyl groups, substituted and unsubstituted piperidinyl groups, substituted and unsubstituted pyrazolyl groups, substituted and unsubstituted pyrrolyl groups, substituted and unsubstituted imidazolyl groups, substituted and unsubstituted 1,4-diazacycloheptane groups, substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups, substituted and unsubstituted 1,4-diazabicyclo[2.2.2]octane groups, substituted or unsubstituted 1,4-diazabicyclo[4.3.0]nonane group, and substituted or unsubstituted 1,4-diazacycloheptane groups. In still other embodiments of the fifth group of compounds where R6 is a heterocyclyl group, the heterocyclyl group is an unsubstituted morpholine group; a dialkyl substituted morpholinyl group such as, but not limited to, a dimethyl substituted morpholinyl group, and the like, such as, but not limited to, a 3,5-dimethyl substituted morpholinyl group; a hydroxy substituted morpholinyl group; a hydroxyalkyl substituted morpholinyl group; an aryl substituted morpholinyl group; an aminoalkyl substituted morpholinyl group including dialkylaminoalkyl substituted morpholinyl groups such as, but not limited to, dimethylaminomethyl substituted morpholinyl groups and the like such as, but not limited to, a morpholinyl group that is substituted on a ring carbon bonded to the ring O atom with a dimethylaminomethyl group and is substituted with a methyl group on the carbon bonded to the ring N atom which carbon is not bonded to the carbon bearing the dimethylaminomethyl group and the like; a heterocyclyl substituted morpholinyl group; an unsubstituted piperazine group; a dialkyl substituted piperazinyl group such as, but not limited to, a dimethyl substituted piperazinyl group, and the like such as a 3,5-dimethyl substituted piperazinyl group and the like; a monoalkyl substituted piperazinyl group such as a 3-alkyl substituted piperazinyl group, an N-alkyl substituted piperazinyl group, and the like such as, but not limited to, a 3-methyl substituted piperazinyl group, a N-alkyl substituted piperazinyl group, such as, but not limited to, N-methyl, N-ethyl, N-isopropyl substituted piperazinyl groups and the like; a hydroxyalkyl substituted piperazinyl group such as, but not limited to, hydroxyethyl and hydroxymethyl substituted piperazinyl groups and the like such as, but not limited to, N-hydroxyethyl substituted piperazinyl groups and the like; an aryl substituted piperazinyl group; a heterocyclyl substituted piperazinyl group such as, but not limited to, 2-, 3-, and 4-(2-, 3-, and 4-piperidinyl) substituted piperazinyl groups and 2-, 3-, and 4-(2-, 3-, and 4-pyridyl) substituted piperazinyl groups and the like; a —CH2C(═O)O-alkyl substituted piperazinyl group; a —C(═O)-alkyl substituted piperazinyl group such as, but not limited to, a —C(═O)-ethyl or a —C(═O)-methyl substituted piperazinyl group, and the like such as a piperazinyl group where the —C(═O)-ethyl or the —C(═O)-methyl substitution is on one of the piperazinyl N atoms and the other N atom is bonded to Z2, and the like; a —C(═O)O-alkyl substituted piperazinyl group such as, but not limited to, a —C(═O)—O-ethyl or a —C(═O)—O-methyl substituted piperazinyl group, and the like such as a piperazinyl group where the —C(═O)—O-ethyl or the —C(═O)—O-methyl substitution is on one of the piperazinyl N atoms and the other N atom is bonded to Z2, and the like; a cycloalkyl substituted piperazinyl group such as, but not limited to, a cyclohexyl and cyclopentyl substituted piperazinyl group and the like such as, but not limited to, a N-cyclohexyl substituted piperazinyl group and the like; an unsubstituted piperidine group; an alkyl substituted piperidinyl group such as, but not limited to, 2-, 3-, and 4-alkyl substituted piperidinyl groups, and the like such as, but not limited to, 2-, 3-, and 4-hydroxyalkyl substituted piperidinyl groups and the like such as, but not limited to, 2-, 3-, and 4-hydroxymethyl substituted piperidinyl groups and the like; a hydroxy substituted piperidinyl group such as 2-, 3-, and 4-hydroxy substituted piperidinyl groups; a hydroxyalkyl substituted piperidinyl group; an aryl substituted piperidinyl group such as, but not limited to, a 4-aryl substituted piperidinyl group and the like such as, but not limited to, a piperidinyl group that is substituted in the 4 position with both an aryl group and a hydroxy group and the like such as, but not limited to, a piperidinyl group that is substituted in the 4 position with both a hydroxy group and a phenyl group; a cycloalkyl substituted piperidinyl group; a heterocyclyl substituted piperidinyl group such as, but not limited to, a piperidinyl substituted piperidinyl group and the like such as, but not limited to, 4-piperidinyl substituted piperidinyl groups, 4-(2(3H)-benzimidazolone) substituted piperidinyl group, and the like; an unsubstituted pyrrolidinyl group; an alkyl substituted pyrrolidinyl group such as, but not limited to, a methyl substituted pyrrolidinyl group, a heterocyclylalkyl substituted pyrrolidinyl group, and the like such as, but not limited to, a 2-methyl substituted pyrrolidinyl group, a 2-pyrrolidinylmethyl substituted pyrrolidinyl group, and the like; an amino substituted pyrrolidinyl group such as, but not limited to, a dialkylamino substituted pyrrolidinyl group such as, but not limited to, 2- and 3-dialkylamino substituted pyrrolidinyl groups and the like such as, but not limited to, 2- and 3-substituted N,N-dimethylamino substituted pyrrolidinyl groups and the like such as, but not limited to, a pyrrolidinyl group that is substituted with both an alkyl group and an N,N-dimethylamino group and the like such as, but not limited to, a pyrrolidinyl group that is substituted with a methyl group in the 2 position and with a N,N-dimethylamino group in the 4 position; a hydroxy substituted pyrrolidinyl group such as, but not limited to, 2- and 3-hydroxy substituted pyrrolidinyl groups; a heterocyclylalkyl substituted pyrrolidinyl group; substituted and unsubstituted pyrrolyl groups; substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups; an alkyl substituted 2,5-diazabicyclo[2.2.1]heptane group such as, but not limited to, a N-methyl substituted 2,5-diazabicyclo[2.2.1]heptane group and the like; a substituted or unsubstituted 1,4-diazabicyclo[4.3.0]nonane group; and a substituted or unsubstituted 1,4-diazacycloheptane group such as, but not limited to, an alkyl substituted 1,4-diazacycloheptane group and the like, such as, but not limited to, an N-alkyl substituted 1,4-diazacycloheptane substituted group and the like such as, but not limited to, a N-methyl substituted 1,4-diazacycloheptane group and the like. In still other embodiments of the fifth group of compounds where R6 is a substituted or unsubstituted heterocyclyl group, R7 is —H.
In another embodiment of the fifth group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is selected from substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, substituted and unsubstituted —C(═O)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, and substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups. In still other such embodiments, R7 has the values described in the preceding sentence and R6 is —H.
In another embodiment of the fifth group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is an alkoxy group having from 1–6 carbon atoms. In still other such embodiments, R7 is a methoxy group. In still other embodiments of the fifth group of compounds where R7 is an alkoxy group having from 1–6 carbon atoms such as a methoxy group, R6 is —H.
In another embodiment of the fifth group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is an alkyl group having from 1–6 carbon atoms. In still other such embodiments, R7 is a methyl group. In still other embodiments of the fifth group of compounds where R7 is an alkyl group having from 1–6 carbon atoms such as a methyl group, R6 is —H.
In another embodiment of the fifth group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is a substituted alkoxy group having the formula —OCH2(CH2)nR14 where n is an integer selected from 0, 1, or 2 and R14 is selected from substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. In some embodiments, R14 is selected from substituted alkoxy groups such as, but not limited to methoxy groups, ethoxy groups, propoxy groups, and the like. In still other such embodiments, R14 is selected from substituted and unsubstituted heterocyclyl groups selected from pyrrolidinyl groups, pyridyl groups, morpholinyl groups, piperazinyl groups, and piperidinyl groups. In still other embodiments of the fifth group of compounds where R7 is a substituted alkoxy group having the formula —OCH2(CH2)nR14, R6 is —H. In still other embodiments, R7 is a pyrrolidinylalkoxy groups, such as but not limited to, a pyrrolidinylpropoxy group or the like; an alkoxyethoxy group such as, but not limited to, a methoxyethoxy group or the like; or a substituted or unsubstituted pyridinylalkoxy group such as, but not limited to, (3-pyridinyl)methoxy groups, or the like.
In another embodiment of the fifth group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is a substituted amino group having the formula —N(R15)(CH2)qR16 where q is an integer selected from 0, 1, 2, or 3 and R16 is selected from substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups, and R15 is —H or a substituted or unsubstituted alkyl groups, such as, but not limited to, methyl, ethyl, propyl, and isopropyl groups. In some such embodiments, R16 is selected from substituted amino groups such as alkylamino groups and dialkylamino groups, such as, but not limited to, dimethylamino, diethylamino, dipropylamino, (methyl)(ethyl)amino, (ethyl)(propyl)amino, (methyl)(propyl)amino groups, and the like. In some such embodiments, R15 is a CH3 group. In still other such embodiments, R16 is selected from substituted alkoxy groups. In still other such embodiments, R16 is selected from substituted and unsubstituted heterocyclyl groups such as those selected from pyrrolidinyl groups, pyrazolyl groups, pyridyl groups, morpholinyl groups, piperazinyl groups, piperidinyl groups, and the like. In some embodiments, R7 is selected from —N(H)(3-piperidinyl) groups, —N(H)(4-piperidinyl) groups, —N(H)(4-(2-methoxymethylpyrrolidinyl)) groups, —N(CH3)(4-(1-methylpiperidinyl)) groups, —N(H)CH2(2-pyridyl) groups, —N(H)CH2(3-pyridyl) groups, —N(H)CH2(4-pyridyl) groups, —N(H)CH2CH2(2-pyridyl) groups, —N(H)CH2CH2(3-pyridyl) groups, —N(H)CH2CH2(4-pyridyl) groups, —N(CH3)CH2CH2(2-pyridyl) groups —N(H)CH2CH2(4-piperidinyl) groups, —N(H)CH2CH2(4-morpholinyl) groups, —N(H)CH2CH2CH2(1-imidazolyl) groups, —N(H)CH2CH2CH2(1-(4-methylpiperazinyl)) groups, —N(H)CH2CH2CH2(4-morpholinyl) groups, —N(H)CH2CH2CH2(1-imidazolyl) groups, —N(H)CH2CH2CH2(1-pyrrolidinyl) groups, —N(CH3)CH2CH2CH2(diethylamino) groups, and the like.
In still other embodiments of the fifth group of compounds where R7 is a substituted amino group having the formula-N(R15)(CH2)qR16, R6 is —H.
In another embodiment of the fifth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is a substituted amino group having the formula —N(R15)(CH2)qR16 or the formula —N(R15)C(H)(alkyl)((CH2)qR16) where q is an integer selected from 0, 1, 2, or 3, R16 is selected from a methyl group, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups such as —N(H)(alkyl) groups, —N(alkyl)2 groups and the like, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups, and R15 is selected from —H; substituted and unsubstituted alkyl groups such as, but not limited to, methyl, ethyl, propyl, and isopropyl groups; —C(═O)-alkyl groups such as —C(═O)—CH3 groups and the like; —C(═O)-alkyl-N(H)(alkyl) groups such as —C(═O)—CH2—N(H)(alkyl) groups and the like; —C(═O)-alkyl-N(alkyl)2 groups such as —C(═O)—CH2—N(alkyl)2 groups and the like; —C(═O)-alkyl-N(R15a′)(R15b′) groups such as —C(═O)—CH2—N(alkyl)2 groups and the like —C(═O)-alkyl-heterocyclyl groups such as —C(═O)—CH2-heterocyclyl groups and the like such as —C(═O)—CH2-(1-piperazinyl) groups and the like; —C(═O)-heterocyclyl groups; —C(═O)-aryl groups; —C(═O)-alkyl-O-alkyl groups such as —C(═O)—CH2—O-alkyl groups; —C(═O)-alkyl-S-alkyl groups such as —C(═O)—CH2—S-alkyl groups and the like; and the like where R15a′ is selected from —H, and substituted and unsubstituted alkyl groups, and R15b′ is selected from —H, —SO2-alkyl, —SO2-aryl, —C(═O)-alkyl, —C(═O)-aryl, heterocyclyl groups such as 2-pyridyl groups and the like, heterocyclylalkyl groups, arylalkyl groups, alkyl groups, and —C(═O)-alkyl-halogen groups.
In another embodiment of the fifth group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is a substituted or unsubstituted heterocyclyl group. In some embodiments of the fifth group of compounds where R7 is a heterocyclyl group, the heterocyclyl group is selected from substituted or unsubstituted pyrrolidinyl groups, substituted and unsubstituted pyridyl groups, substituted and unsubstituted morpholinyl groups, substituted and unsubstituted piperazinyl groups, substituted and unsubstituted piperidinyl groups, substituted and unsubstituted pyrazolyl groups, substituted and unsubstituted pyrrolyl groups, substituted and unsubstituted imidazolyl groups, and substituted and unsubstituted 1-aza-4-oxacycloheptane groups, substituted and unsubstituted 1,4-diazacycloheptane groups, substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups, substituted and unsubstituted 1,4-diazabicyclo[2.2.2]octane groups, substituted or unsubstituted 1,4-diazabicyclo[4.3.0]nonane group, and substituted or unsubstituted 1,4-diazacycloheptane groups. In still other embodiments of the fifth group of compounds where R7 is a heterocyclyl group, the heterocyclyl group is an unsubstituted morpholine group; a dialkyl substituted morpholinyl group such as, but not limited to, a dimethyl substituted morpholinyl group, and the like, such as, but not limited to, a 3,5-dimethyl substituted morpholinyl group; a hydroxy substituted morpholinyl group; a hydroxyalkyl substituted morpholinyl group; an aryl substituted morpholinyl group; an aminoalkyl substituted morpholinyl group including dialkylaminoalkyl substituted morpholinyl groups such as, but not limited to, dimethylaminomethyl substituted morpholinyl groups and the like such as, but not limited to, a morpholinyl group that is substituted on a ring carbon bonded to the ring O atom with a dimethylaminomethyl group and is substituted with a methyl group on the carbon bonded to the ring N atom which carbon is not bonded to the carbon bearing the dimethylaminomethyl group and the like; a heterocyclyl substituted morpholinyl group; an unsubstituted piperazine group; a dialkyl substituted piperazinyl group such as, but not limited to, a dimethyl substituted piperazinyl group, and the like such as a 3,5-dimethyl substituted piperazinyl group and the like; a monoalkyl substituted piperazinyl group such as a 3-alkyl substituted piperazinyl group, an N-alkyl substituted piperazinyl group, and the like such as, but not limited to, a 3-methyl substituted piperazinyl group, a N-alkyl substituted piperazinyl group, such as, but not limited to, N-methyl, N-ethyl, N-isopropyl substituted piperazinyl groups and the like; a hydroxyalkyl substituted piperazinyl group such as, but not limited to, hydroxyethyl and hydroxymethyl substituted piperazinyl groups and the like such as, but not limited to, N-hydroxyethyl substituted piperazinyl groups and the like; an aryl substituted piperazinyl group; a heterocyclyl substituted piperazinyl group such as, but not limited to, 2-, 3-, and 4-(2-, 3-, and 4-piperidinyl) substituted piperazinyl groups and 2-, 3-, and 4-(2-, 3-, and 4-pyridyl) substituted piperazinyl groups and the like; a —CH2C(═O)O-alkyl substituted piperazinyl group; a —C(═O)-alkyl substituted piperazinyl group such as, but not limited to, a —C(═O)-ethyl or a —C(═O)-methyl substituted piperazinyl group, and the like such as a piperazinyl group where the —C(═O)-ethyl or the —C(═O)-methyl substitution is on one of the piperazinyl N atoms and the other N atom is bonded to Z3, and the like; a —C(═O)O-alkyl substituted piperazinyl group such as, but not limited to, a —C(═O)—O-ethyl or a —C(═O)—O-methyl substituted piperazinyl group, and the like such as a piperazinyl group where the —C(═O)—O-ethyl or the —C(═O)—O-methyl substitution is on one of the piperazinyl N atoms and the other N atom is bonded to Z3, and the like; a cycloalkyl substituted piperazinyl group such as, but not limited to, a cyclohexyl and cyclopentyl substituted piperazinyl group and the like such as, but not limited to, a N-cyclohexyl substituted piperazinyl group and the like; an unsubstituted piperidine group; an alkyl substituted piperidinyl group such as, but not limited to, 2-, 3-, and 4-alkyl substituted piperidinyl groups, and the like such as, but not limited to, 2-, 3-, and 4-hydroxyalkyl substituted piperidinyl groups and the like such as, but not limited to, 2-, 3-, and 4-hydroxymethyl substituted piperidinyl groups and the like; a hydroxy substituted piperidinyl group such as 2-, 3-, and 4-hydroxy substituted piperidinyl groups; a hydroxyalkyl substituted piperidinyl group; an aryl substituted piperidinyl group such as, but not limited to, a 4-aryl substituted piperidinyl group and the like such as, but not limited to, a piperidinyl group that is substituted in the 4 position with both an aryl group and a hydroxy group and the like such as, but not limited to, a piperidinyl group that is substituted in the 4 position with both a hydroxy group and a phenyl group; a cycloalkyl substituted piperidinyl group; a heterocyclyl substituted piperidinyl group such as, but not limited to, a piperidinyl substituted piperidinyl group and the like such as, but not limited to, 4-piperidinyl substituted piperidinyl groups, 4-(2(3H)-benzimidazolone) substituted piperidinyl group, and the like; an unsubstituted pyrrolidinyl group; an alkyl substituted pyrrolidinyl group such as, but not limited to, a methyl substituted pyrrolidinyl group, a heterocyclylalkyl substituted pyrrolidinyl group, and the like such as, but not limited to, a 2-methyl substituted pyrrolidinyl group, a 2-pyrrolidinylmethyl substituted pyrrolidinyl group, and the like; an amino substituted pyrrolidinyl group such as, but not limited to, a dialkylamino substituted pyrrolidinyl group such as, but not limited to, 2- and 3-dialkylamino substituted pyrrolidinyl groups and the like such as, but not limited to, 2- and 3-substituted N,N-dimethylamino substituted pyrrolidinyl groups and the like such as, but not limited to, a pyrrolidinyl group that is substituted with both an alkyl group and an N,N-dimethylamino group and the like such as, but not limited to, a pyrrolidinyl group that is substituted with a methyl group in the 2 position and with a N,N-dimethylamino group in the 4 position; a hydroxy substituted pyrrolidinyl group such as, but not limited to, 2- and 3-hydroxy substituted pyrrolidinyl groups; a heterocyclylalkyl substituted pyrrolidinyl group; substituted and unsubstituted pyrrolyl groups; substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups; an alkyl substituted 2,5-diazabicyclo[2.2.1]heptane group such as, but not limited to, a N-methyl substituted 2,5-diazabicyclo[2.2.1]heptane group and the like; a substituted or unsubstituted 1,4-diazabicyclo[4.3.0]nonane group; and a substituted or unsubstituted 1,4-diazacycloheptane group such as, but not limited to, an alkyl substituted 1,4-diazacycloheptane group and the like, such as, but not limited to, an N-alkyl substituted 1,4-diazacycloheptane substituted group and the like such as, but not limited to, a N-methyl substituted 1,4-diazacycloheptane group and the like. In still other embodiments of the fifth group of compounds where R7 is a substituted or unsubstituted heterocyclyl group, R6 is —H.
In another embodiment of the fifth group of compounds, Z1–Z4, R1, R2, and R3 have any of the values in previous embodiments, and one of R6 or R7 is a substituted or unsubstituted pyridyloxy group. In some such embodiments, one of R6 or R7 is substituted or unsubstituted 2-pyridyloxy group, a 3-pyridyloxy group, or a 4-pyridyloxy group. In other such embodiments, one of R6 or R7 is a (2-N-alkylamido-4-pyridyl)oxy group such as a (2-N-methylamido-4-pyridyl)oxy group or the like; or a (5-N-alkylamido-3-pyridyl)oxy group such as a (5-N-methylamido-3-pyridyl)oxy group, or the like.
Other more particular embodiments of the compounds of the invention having the general structure shown in I above are provided. Such compounds form a sixth group of compounds for which:
Z1, Z2, Z3, and Z4 are independently selected from C or N;
R1 is selected from —H, —F, —Cl, —Br, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R2 is selected from —F, —Cl, —Br, —C≡N, —CO2H, —OH, substituted and unsubstituted guanidinyl groups,substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)O-aryl groups, substituted and unsubstituted —C(═O)O-heteroaryl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups, substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted heterocyclyloxy, and substituted and unsubstituted heterocyclylalkoxy groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms;
R3 is selected from —H, —F, —Cl, —Br, —CF3, —C≡N, —NO2, —CO2H, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—O-alkyl groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy group, substituted and unsubstituted heterocycyl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R4 is —H, —F, —Br, —Cl, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R5 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R5 is absent if Z1 is N;
R6 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups; or R6 is absent if Z2 is N;
R7 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups; or R7 is absent if Z3 is N;
R8 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R8 is absent if Z4 is N;
R9 is —H; and
R10 is selected from the group consisting of —H, and substituted and unsubstituted alkyl groups.
In some embodiments, R10 is —H. In other embodiments, R10 is an unsubstituted alkyl group having from 1 to 6 carbon atoms such as a methyl, ethyl, propyl, i-propyl group, or the like. In some such embodiments, R10 is a —CH3 group.
In one embodiment of the sixth group of compounds, each of Z1, Z2, Z3, and Z4 are C.
In another embodiment of the sixth group of compounds, Z1 is N and each of Z2, Z3, and Z4 are C.
In another embodiment of the sixth group of compounds, Z1 and Z3 are both N and Z2 and Z4 are both C.
In another embodiment of the sixth group of compounds, Z3 is N and each of Z1, Z2, and Z4 are C.
In another embodiment of the sixth group of compounds, Z1–Z4 have any of the values in previous embodiments, and R1 is selected from —H, —F, —Cl, and —Br.
In another embodiment of the sixth group of compounds, Z1–Z4 have any of the values in previous embodiments, and R1 is a substituted and unsubstituted heterocyclylamino group. In some such embodiments, R1 is a substituted and unsubstituted heteroarylamino groups. In some embodiments, R1 is a substituted and unsubstituted heterocyclylamino group such as, but not limited to, substituted and unsubstituted pyrroldinylalkylamino groups and the like, such as, but not limited to, substituted and unsubstituted pyrrolidinylmethylamino groups and the like.
In another embodiment of the sixth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is an unsubstituted alkoxy group having from 1 to 4 carbon atoms.
In another embodiment of the sixth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a —OMe, —OEt, —O-i-Pr, or —OCH2CH(CH3)2 group.
In another embodiment of the sixth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted arylalkoxy, a substituted or unsubstituted aryloxy group, or a substituted or unsubstituted heterocyclyloxy group.
In another embodiment of the sixth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted benzyloxy group, a substituted or unsubstituted phenoxy group, or a substituted or unsubstituted pyridyloxy group.
In another embodiment of the sixth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted —N(H)C(═O)—N(H)-alkyl-aryl group such as, but not limited to, a —N(H)C(═O)—N(H)—CH2-aryl group, a —N(H)C(═O)—N(H)—CH2CH2-aryl group, or the like such as a —N(H)C(═O)—N(H)—CH2-phenyl group, or a —N(H)C(═O)—N(H)—CH2CH2-phenyl group, or the like.
In another embodiment of the sixth group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms.
In another embodiment of the sixth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is selected from —H, —F, —Cl, and —OMe.
In another embodiment of the sixth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —H.
In another embodiment of the sixth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is selected from the group consisting of —F, —Cl, —Br, —CF3, —C≡N, —NO2, —CO2H, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups and substituted and unsubstituted —C(═O)N(H)-alkyl-heterocyclyl groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms.
In another embodiment of the sixth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is selected from the group consisting of substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, and substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups. In some such embodiments, R3 is a substituted or unsubstituted —N(H)C(═O)N(H)CH2CH3 group, a substituted or unsubstituted —N(H)C(═O)N(H)CH(CH3)2 group, a substituted or unsubstituted —N(H)C(═O)N(H)C(CH3)3 group, or a substituted or unsubstituted —N(H)C(═O)N(H)-aryl group or the like. In some such embodiments, R3 is a substituted or unsubstituted —N(H)C(═O)N(H)-aryl group such as, but not limited to, a —N(H)C(═O)N(H)-(2-methoxyphenyl) group, a-N(H)C(═O)N(H)-(trifluoromethylphenyl) group, or the like.
In another embodiment of the sixth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is a substituted amino group selected from substituted or unsubstituted arylalkylamino groups such as, but not limited to, phenylalkylamino groups, (halo)(alkoxy)arylalkylamino groups, such as, but not limited to 2-fluoro-5-methoxyphenylmethylamino groups, monoalkoxyarylalkylamino groups, dialkoxyarylalkylamino groups, and the like, such as, but not limited to, 2,5-dialkoxyarylalkylamino groups and the like such as, but not limited to 2,5-dialkoxyarylmethylamino groups, substituted and unsubstituted arylalkoxyarylalkylamino groups such as, but not limited to substituted and unsubstituted arylalkoxyarylmethylamino groups and the like, such as, but not limited to, substituted and unsubstituted arylmethoxyarylmethylamino groups and the like, such as, but not limited to substituted and unsubstituted fluoroarylmethoxyarylmethylamino groups and the like, such as, but not limited to, substituted and unsubstituted 4-fluorophenylmethoxyphenyl-methylamino groups and the like; substituted and unsubstituted heterocyclylalkylamino groups including heteroarylalkylamino groups such as, but not limited to substituted and unsubstituted thiazolylalkylamino groups, benzimidazolylalkylamino groups such as, but not limited to N-methylbenzimidazolylalkylamino groups and the like, imidazolylalkylamino groups such as, but not limited to phenylimidazolylalkylamino groups, ethylmethylimidazolylalkylamino groups, and the like, substituted and unsubstituted quinolinylalkylamino groups, such as, but not limited to substituted and unsubstituted quinolinylmethylamino groups and the like, such as, but not limited to alkoxyquinolinylmethylamino groups and the like, such as, but not limited to substituted and unsubstituted 4-alkoxy-2-quinolinylmethylamino groups and the like, and furanylalkylamino groups, and the like.
In another embodiment of the sixth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —F.
In another embodiment of the sixth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —Cl.
In another embodiment of the sixth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —OMe.
In another embodiment of the sixth group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is a substituted and unsubstituted —C(═O)N(H)-alkyl-heterocyclyl groups where the heterocyclyl group of the —C(═O)N(H)-alkyl-heterocyclyl groups is selected from the group consisting of morpholinyl, piperazinyl, and piperidinyl groups.
In another embodiment of the sixth group of compounds, Z2–Z4, R1, R2, and R3 have any of the values in previous embodiments, Z1 is C, and R5 is H. In some such embodiments, R8 is also H.
In another embodiment of the sixth group of compounds, Z2–Z4, R1, R2, and R3 have any of the values in previous embodiments, Z1 is C, and R5 is —CH3.
In another embodiment of the sixth group of compounds, Z2–Z4, R1, R2, and R3 have any of the values in previous embodiments, Z1 is C, and R5 is morpholine.
In another embodiment of the sixth group of compounds, Z1–Z3, R1, R2, and R3 have any of the values in previous embodiments, Z4 is C, and R8 is H.
In another embodiment of the sixth group of compounds, Z1–Z3, R1, R2, and R3 have any of the values in previous embodiments, Z4 is C, and R8 is —CH3.
In another embodiment of the sixth group of compounds, Z1–Z3, R1, R2, and R3 have any of the values in previous embodiments, Z4 is C, and R8 is morpholine.
In another embodiment of the sixth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is selected from a first group; or Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is selected from the first group, the first group comprising members selected from the group consisting of —Br, —CO2H, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted alkoxyalkoxy groups, substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted cycloalkylheterocyclyl groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, substituted and unsubstituted heterocyclylamino groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups. In some such embodiments, R3 is selected from the group consisting of —F, —Cl, —Br, —CF3, —C≡N, —NO2, —CO2H, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, and substituted and unsubstituted —C(═O)N(H)-alkyl-heterocyclyl groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms. In another embodiments of the sixth group of compounds, at least one of Z2 or Z3 is C and at least one of R6 or R7 is selected from the group consisting of substituted and unsubstituted piperidinyl substituted heterocyclyl groups, substituted and unsubstituted heterocyclyl substituted piperidinyl groups, substituted and unsubstituted hydroxymethyl substituted piperidinyl groups, dimethylaminoalkyl substituted pyrrolidinyl groups, substituted and unsubstituted 3-alkyl substituted piperazinyl groups, substituted and unsubstituted 3,5-dialkyl substituted piperazinyl groups, substituted and unsubstituted N-hydroxyalkyl substituted piperazinyl groups, substituted and unsubstituted N-alkyl substituted 1,4-diazacycloheptyl groups, substituted and unsubstituted N-ethylpiperazinyl groups, substituted and unsubstituted N-isopropylpiperazinyl groups, substituted and unsubstituted N-sec-butylpiperazinyl groups, unsubstituted piperazinyl groups, substituted and unsubstituted N-2-pyridyl substituted piperazinyl groups, substituted and unsubstituted N-3-pyridyl substituted piperazinyl groups, substituted and unsubstituted N-4-pyridyl substituted piperazinyl groups, substituted and unsubstituted N(H)—CH2-pyridyl groups, substituted and unsubstituted imidazolyl groups, substituted and unsubstituted morpholinyl groups, substituted and unsubstituted 3-alkyl substituted morpholinyl groups, substituted and unsubstituted 3,5-dialkyl substituted morpholinyl groups, dialkylamino substituted pyrrolidinyl groups, pyrrolidinyl groups substituted with both dialkylamino and alkyl groups, substituted and unsubstituted 4-hydroxy substituted piperidinyl groups, substituted and unsubstituted 4-aryl substituted piperidinyl groups, substituted and unsubstituted 4-hydroxy-4-phenyl substituted piperidinyl groups, substituted and unsubstituted cyclohexylpiperazinyl groups, substituted and unsubstituted cyclopentylpiperazinyl groups, substituted and unsubstituted N-alkyl substituted diazabicycloalkane groups, substituted and unsubstituted —N(CH3)(N-alkyl(4-piperidinyl)) groups, substituted and unsubstituted piperazinyl groups further substituted with a —C(═O)-alkyl group on one of the N atoms of the piperazinyl group, substituted and unsubstituted —N(H)CH2CH2CH2-imidazolyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-pyrrolidinyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-morpholinyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-piperazinyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-piperidinyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-pyridyl groups, substituted and unsubstituted —N(H)CH2CH2-imidazolyl groups, substituted and unsubstituted —N(H)CH2CH2-pyrrolidinyl groups, substituted and unsubstituted —N(H)CH2CH2-morpholinyl groups, substituted and unsubstituted —N(H)CH2CH2-piperazinyl groups, substituted and unsubstituted —N(H)CH2CH2-piperidinyl groups, substituted and unsubstituted —N(H)CH2CH2-pyridyl groups, substituted and unsubstituted 1-aza-4-oxacycloheptane groups, and substituted and unsubstituted 1,4-diazacycloheptane groups. In other embodiments, at least one of R6 or R7 is selected from the group consisting of piperidinyl substituted piperidinyl groups such as 4-piperidinylpiperidinyl groups or the like, 4-hydroxymethylpiperidinyl groups, 3-dimethylaminomethylpyrrolidinyl groups, 3-alkyl substituted piperazinyl groups, 3,5-dialkyl substituted piperazinyl groups, N-hydroxyethylpiperazinyl groups, N-hydroxymethylpiperazinyl groups, N-hydroxypropylpiperazinyl groups, N-methyl substituted 1,4-diazacycloheptyl groups, N-ethylpiperazinyl groups, N-isopropylpiperazinyl groups, N-sec-butylpiperazinyl groups, unsubstituted piperazinyl groups, N-(2-pyridyl)piperazinyl groups, N-(3-pyridyl)piperazinyl groups, N-(4-pyridyl)piperazinyl groups, N(H)—CH2-pyridyl groups, imidazolyl groups, unsubstituted morpholinyl groups, 3-alkylmorpholinyl groups, 3,5-dialkylmorpholinyl groups, 2-dimethylaminopyrrolidinyl groups, 2-methyl-4-dialkylaminopyrroldinyl groups, 4-hydroxypiperidinyl groups, 4-arylpiperidinyl groups, 4-hydroxy-4-phenylpiperidinyl groups, cyclohexylpiperazinyl groups, cyclopentylpiperazinyl groups, N-methyl substituted diazabicycloalkane groups, —N(CH3)(N-alkyl(4-piperidinyl)) groups, piperazinyl groups further substituted with a —C(═O)-methyl group on one of the N atoms of the piperazinyl group, —N(H)CH2CH2CH2-imidazolyl groups, —N(H)CH2CH2CH2-pyrrolidinyl groups, —N(H)CH2CH2CH2-morpholinyl groups, —N(H)CH2CH2CH2-piperazinyl groups, —N(H)CH2CH2CH2-piperidinyl groups, and —N(H)CH2CH2CH2-pyridyl groups. In some such embodiments, at least one of R6 or R7 is selected from the group consisting of 4-piperidinylpiperidinyl groups, 4-hydroxymethylpiperidinyl groups, 3-dimethylaminomethylpyrrolidinyl groups, 3,5-dimethyl substituted piperazinyl groups, N-methyl substituted 1,4-diazacycloheptyl groups, N-(2-pyridyl)piperazinyl groups, N(H)—CH2-(4-pyridyl) groups, imidazolyl groups, unsubstituted morpholinyl groups, 3-methylmorpholinyl groups, 3,5-dimethylmorpholinyl groups, 2-dimethylaminopyrrolidinyl groups, 2-methyl-4-dimethylaminopyrroldinyl groups, 4-hydroxy-4-phenylpiperidinyl groups, cyclohexylpiperazinyl groups, N-methyl substituted diazabicycloalkane groups, —N(CH3)(N-methyl(4-piperidinyl)) groups, piperazinyl groups further substituted with a —C(═O)-methyl group on one of the N atoms of the piperazinyl group, —N(H)CH2CH2CH2-imidazolyl groups, —N(H)CH2CH2CH2-pyrrolidinyl groups, —N(H)CH2CH2CH2-morpholinyl groups, —N(H)CH2CH2CH2-piperazinyl groups, —N(H)CH2CH2CH2-piperidinyl groups, and —N(H)CH2CH2CH2-pyridyl groups.
In another embodiment of the sixth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is selected from —Br, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, substituted and unsubstituted —C(═O)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, and substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups. In still other embodiments, R6 has the values described in the preceding sentence and R7 is —H.
In another embodiment of the sixth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is an alkoxy group having from 1–6 carbon atoms. In still other such embodiments, R6 is a methoxy group. In still other embodiments of the sixth group of compounds where R6 is an alkoxy group having from 1–6 carbon atoms such as a methoxy group, R7 is —H.
In another embodiment of the sixth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is an alkyl group having from 1–6 carbon atoms. In still other such embodiments, R6 is a methyl group. In still other embodiments of the sixth group of compounds where R6 is an alkyl group having from 1–6 carbon atoms such as a methyl group, R7 is —H.
In another embodiment of the sixth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is a substituted alkoxy group having the formula —OCH2(CH2)mR11 where m is an integer selected from 0, 1, or 2 and R11 is selected from substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. In still other such embodiments, R11 is selected from substituted alkoxy groups such as, but not limited to methoxy groups, ethoxy groups, propoxy groups, and the like. In still other such embodiments, R11 is selected from substituted and unsubstituted heterocyclyl groups selected from pyrrolidinyl groups, pyridyl groups, morpholinyl groups, piperazinyl groups, and piperidinyl groups. In still other embodiments where R6 is a substituted alkoxy group having the formula —OCH2(CH2)mR11, R7 is —H. In still other embodiments, R6 is a pyrrolidinylalkoxy groups, such as but not limited to, a pyrrolidinylpropoxy group or the like; an alkoxyethoxy group such as, but not limited to, a methoxyethoxy group or the like; or a substituted or unsubstituted pyridinylalkoxy group such as, but not limited to, (3-pyridinyl)methoxy groups, or the like.
In another embodiment of the sixth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, z2 is C, and R6 is a substituted amino group having the formula —N(R12)(CH2)pR13 where p is an integer selected from 0, 1, 2, or 3, R13 is selected from substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups, and R12 is selected from —H or substituted and unsubstituted alkyl groups such as, but not limited to, methyl, ethyl, propyl, and isopropyl. In some such embodiments, R13 is selected from substituted amino groups such as alkylamino groups and dialkylamino groups, such as, but not limited to, dimethylamino, diethylamino, dipropylamino, (methyl)(ethyl)amino, (ethyl)(propyl)amino, (methyl)(propyl)amino groups, and the like. In some such embodiments, R12 is a CH3 group. In still other such embodiments, R13 is selected from substituted alkoxy groups. In still other such embodiments, R13 is selected from substituted and unsubstituted heterocyclyl groups such as those selected from pyrrolidinyl groups, pyrazolyl groups, pyridyl groups, morpholinyl groups, piperazinyl groups, piperidinyl groups, and the like. In some embodiments, R6 is selected from —N(H)(3-piperidinyl) groups, —N(H)(4-piperidinyl) groups, —N(H)(4-(2-methoxymethylpyrrolidinyl)) groups, —N(CH3)(4-(1-methylpiperidinyl)) groups, —N(H)CH2(2-pyridyl) groups, —N(H)CH2(3-pyridyl) groups, —N(H)CH2(4-pyridyl) groups, —N(H)CH2CH2(2-pyridyl) groups, —N(H)CH2CH2(3-pyridyl) groups, —N(H)CH2CH2(4-pyridyl) groups, —N(CH3)CH2CH2(2-pyridyl) groups —N(H)CH2CH2(4-piperidinyl) groups, —N(H)CH2CH2(4-morpholinyl) groups, —N(H)CH2CH2CH2(1-imidazolyl) groups, —N(H)CH2CH2CH2(1-(4-methylpiperazinyl)) groups, —N(H)CH2CH2CH2(4-morpholinyl) groups, —N(H)CH2CH2CH2(1-imidazolyl) groups, —N(H)CH2CH2CH2(1-pyrrolidinyl) groups, —N(CH3)CH2CH2CH2(diethylamino) groups, and the like.
In still other embodiments of the sixth group of compounds where R6 is a substituted amino group having the formula —N(R12)(CH2)pR13, R7 is —H.
In another embodiment of the sixth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z2 is C, and R6 is a substituted amino group having the formula —N(R12)(CH2)pR13 or the formula —N(R12)C(H)(alkyl)((CH2)pR13) where p is an integer selected from 0, 1, 2, or 3, R13 is selected from a methyl group, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups such as —N(H)(alkyl) groups, —N(alkyl)2 groups and the like, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups, and R12 is selected from —H; substituted and unsubstituted alkyl groups such as, but not limited to, methyl, ethyl, propyl, and isopropyl groups; —C(═O)-alkyl groups such as —C(═O)—CH3 groups and the like; —C(═O)-alkyl-N(H)(alkyl) groups such as —C(═O)—CH2—N(H)(alkyl) groups and the like; —C(═O)-alkyl-N(alkyl)2 groups such as —C(═O)—CH2—N(alkyl)2 groups and the like; —C(═O)-alkyl-N(R12a′)(R12b′) groups such as —C(═O)—CH2—N(alkyl)2 groups and the like —C(═O)-alkyl-heterocyclyl groups such as —C(═O)—CH2-heterocyclyl groups and the like such as —C(═O)—CH2-(1-piperazinyl) groups and the like; —C(═O)-heterocyclyl groups; —C(═O)-aryl groups; —C(═O)-alkyl-O-alkyl groups such as —C(═O)—CH2—O-alkyl groups; —C(═O)-alkyl-S-alkyl groups such as —C(═O)—CH2—S-alkyl groups and the like; and the like where R12a′ is selected from —H, and substituted and unsubstituted alkyl groups, and R12b′ is selected from —H, —SO2-alkyl, —SO2-aryl, —C(═O)-alkyl, —C(═O)-aryl, heterocyclyl groups such as 2-pyridyl groups and the like, heterocyclylalkyl groups, arylalkyl groups, alkyl groups, and —C(═O)-alkyl-halogen groups.
In another embodiment of the sixth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values defined in the previous embodiments, Z2 is C, and R6 is a substituted or unsubstituted heterocyclyl group. In some embodiments of the sixth group of compounds where R6 is a heterocyclyl group, the heterocyclyl group is selected from substituted or unsubstituted pyrrolidinyl groups, substituted and unsubstituted pyridyl groups, substituted and unsubstituted morpholinyl groups, substituted and unsubstituted piperazinyl groups, substituted and unsubstituted piperidinyl groups, substituted and unsubstituted pyrazolyl groups, substituted and unsubstituted pyrrolyl groups, substituted and unsubstituted imidazolyl groups, substituted and unsubstituted 1-aza-4-oxacycloheptane groups, substituted and unsubstituted 1,4-diazacycloheptane groups, substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups, substituted and unsubstituted 1,4-diazabicyclo[2.2.2]octane groups, substituted or unsubstituted 1,4-diazabicyclo[4.3.0]nonane group, and substituted or unsubstituted 1,4-diazacycloheptane groups. In still other embodiments of the sixth group of compounds where R6 is a heterocyclyl group, the heterocyclyl group is an unsubstituted morpholine group; a dialkyl substituted morpholinyl group such as, but not limited to, a dimethyl substituted morpholinyl group, and the like, such as, but not limited to, a 3,5-dimethyl substituted morpholinyl group; a hydroxy substituted morpholinyl group; a hydroxyalkyl substituted morpholinyl group; an aryl substituted morpholinyl group; an aminoalkyl substituted morpholinyl group including dialkylaminoalkyl substituted morpholinyl groups such as, but not limited to, dimethylaminomethyl substituted morpholinyl groups and the like such as, but not limited to, a morpholinyl group that is substituted on a ring carbon bonded to the ring O atom with a dimethylaminomethyl group and is substituted with a methyl group on the carbon bonded to the ring N atom which carbon is not bonded to the carbon bearing the dimethylaminomethyl group and the like; a heterocyclyl substituted morpholinyl group; an unsubstituted piperazine group; a dialkyl substituted piperazinyl group such as, but not limited to, a dimethyl substituted piperazinyl group, and the like such as a 3,5-dimethyl substituted piperazinyl group and the like; a monoalkyl substituted piperazinyl group such as a 3-alkyl substituted piperazinyl group, an N-alkyl substituted piperazinyl group, and the like such as, but not limited to, a 3-methyl substituted piperazinyl group, a N-alkyl substituted piperazinyl group, such as, but not limited to, N-methyl, N-ethyl, N-isopropyl substituted piperazinyl groups and the like; a hydroxyalkyl substituted piperazinyl group such as, but not limited to, hydroxyethyl and hydroxymethyl substituted piperazinyl groups and the like such as, but not limited to, N-hydroxyethyl substituted piperazinyl groups and the like; an aryl substituted piperazinyl group; a heterocyclyl substituted piperazinyl group such as, but not limited to, 2-, 3-, and 4-(2-, 3-, and 4-piperidinyl) substituted piperazinyl groups and 2-, 3-, and 4-(2-, 3-, and 4-pyridyl) substituted piperazinyl groups and the like; a —CH2C(═O)O-alkyl substituted piperazinyl group; a —C(═O)-alkyl substituted piperazinyl group such as, but not limited to, a —C(═O)-ethyl or a —C(═O)-methyl substituted piperazinyl group, and the like such as a piperazinyl group where the —C(═O)-ethyl or the —C(═O)-methyl substitution is on one of the piperazinyl N atoms and the other N atom is bonded to Z2, and the like; a —C(═O)O-alkyl substituted piperazinyl group such as, but not limited to, a —C(═O)—O-ethyl or a —C(═O)—O-methyl substituted piperazinyl group, and the like such as a piperazinyl group where the —C(═O)—O-ethyl or the —C(═O)—O-methyl substitution is on one of the piperazinyl N atoms and the other N atom is bonded to Z2, and the like; a cycloalkyl substituted piperazinyl group such as, but not limited to, a cyclohexyl and cyclopentyl substituted piperazinyl group and the like such as, but not limited to, a N-cyclohexyl substituted piperazinyl group and the like; an unsubstituted piperidine group; an alkyl substituted piperidinyl group such as, but not limited to, 2-, 3-, and 4-alkyl substituted piperidinyl groups, and the like such as, but not limited to, 2-, 3-, and 4-hydroxyalkyl substituted piperidinyl groups and the like such as, but not limited to, 2-, 3-, and 4-hydroxymethyl substituted piperidinyl groups and the like; a hydroxy substituted piperidinyl group such as 2-, 3-, and 4-hydroxy substituted piperidinyl groups; a hydroxyalkyl substituted piperidinyl group; an aryl substituted piperidinyl group such as, but not limited to, a 4-aryl substituted piperidinyl group and the like such as, but not limited to, a piperidinyl group that is substituted in the 4 position with both an aryl group and a hydroxy group and the like such as, but not limited to, a piperidinyl group that is substituted in the 4 position with both a hydroxy group and a phenyl group; a cycloalkyl substituted piperidinyl group; a heterocyclyl substituted piperidinyl group such as, but not limited to, a piperidinyl substituted piperidinyl group and the like such as, but not limited to, 4-piperidinyl substituted piperidinyl groups, 4-(2(3H)-benzimidazolone) substituted piperidinyl group, and the like; an unsubstituted pyrrolidinyl group; an alkyl substituted pyrrolidinyl group such as, but not limited to, a methyl substituted pyrrolidinyl group, a heterocyclylalkyl substituted pyrrolidinyl group, and the like such as, but not limited to, a 2-methyl substituted pyrrolidinyl group, a 2-pyrrolidinylmethyl substituted pyrrolidinyl group, and the like; an amino substituted pyrrolidinyl group such as, but not limited to, a dialkylamino substituted pyrrolidinyl group such as, but not limited to, 2- and 3-dialkylamino substituted pyrrolidinyl groups and the like such as, but not limited to, 2- and 3-substituted N,N-dimethylamino substituted pyrrolidinyl groups and the like such as, but not limited to, a pyrrolidinyl group that is substituted with both an alkyl group and an N,N-dimethylamino group and the like such as, but not limited to, a pyrrolidinyl group that is substituted with a methyl group in the 2 position and with a N,N-dimethylamino group in the 4 position; a hydroxy substituted pyrrolidinyl group such as, but not limited to, 2- and 3-hydroxy substituted pyrrolidinyl groups; a heterocyclylalkyl substituted pyrrolidinyl group; substituted and unsubstituted pyrrolyl groups; substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups; an alkyl substituted 2,5-diazabicyclo[2.2.1]heptane group such as, but not limited to, a N-methyl substituted 2,5-diazabicyclo[2.2.1]heptane group and the like; a substituted or unsubstituted 1,4-diazabicyclo[4.3.0]nonane group; and a substituted or unsubstituted 1,4-diazacycloheptane group such as, but not limited to, an alkyl substituted 1,4-diazacycloheptane group and the like, such as, but not limited to, an N-alkyl substituted 1,4-diazacycloheptane substituted group and the like such as, but not limited to, a N-methyl substituted 1,4-diazacycloheptane group and the like. In still other embodiments of the sixth group of compounds where R6 is a substituted or unsubstituted heterocyclyl group, R7 is —H.
In another embodiment of the sixth group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is selected from substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, substituted and unsubstituted —C(═O)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, and substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups. In still other such embodiments, R7 has the values described in the preceding sentence and R6 is —H.
In another embodiment of the sixth group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is an alkoxy group having from 1–6 carbon atoms. In still other such embodiments, R7 is a methoxy group. In still other embodiments of the sixth group of compounds where R7 is an alkoxy group having from 1–6 carbon atoms such as a methoxy group, R6 is —H.
In another embodiment of the sixth group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is an alkyl group having from 1–6 carbon atoms. In still other such embodiments, R7 is a methyl group. In still other embodiments of the sixth group of compounds where R7 is an alkyl group having from 1–6 carbon atoms such as a methyl group, R6 is —H.
In another embodiment of the sixth group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is a substituted alkoxy group having the formula —OCH2(CH2)nR14 where n is an integer selected from 0, 1, or 2 and R14 is selected from substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups. In some embodiments, R14 is selected from substituted alkoxy groups such as, but not limited to methoxy groups, ethoxy groups, propoxy groups, and the like. In still other such embodiments, R14 is selected from substituted and unsubstituted heterocyclyl groups selected from pyrrolidinyl groups, pyridyl groups, morpholinyl groups, piperazinyl groups, and piperidinyl groups. In still other embodiments of the sixth group of compounds where R7 is a substituted alkoxy group having the formula —OCH2(CH2)nR14, R6 is —H. In still other embodiments, R7 is a pyrrolidinylalkoxy groups, such as but not limited to, a pyrrolidinylpropoxy group or the like; an alkoxyethoxy group such as, but not limited to, a methoxyethoxy group or the like; or a substituted or unsubstituted pyridinylalkoxy group such as, but not limited to, (3-pyridinyl)methoxy groups, or the like.
In another embodiment of the sixth group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is a substituted amino group having the formula —N(R15)(CH2)qR16 where q is an integer selected from 0, 1, 2, or 3 and R16 is selected from substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups, and R15 is —H or a substituted or unsubstituted alkyl groups, such as, but not limited to, methyl, ethyl, propyl, and isopropyl groups. In some such embodiments, R16 is selected from substituted amino groups such as alkylamino groups and dialkylamino groups, such as, but not limited to, dimethylamino, diethylamino, dipropylamino, (methyl)(ethyl)amino, (ethyl)(propyl)amino, (methyl)(propyl)amino groups, and the like. In some such embodiments, R15 is a CH3 group. In still other such embodiments, R16 is selected from substituted alkoxy groups. In still other such embodiments, R16 is selected from substituted and unsubstituted heterocyclyl groups such as those selected from pyrrolidinyl groups, pyrazolyl groups, pyridyl groups, morpholinyl groups, piperazinyl groups, piperidinyl groups, and the like. In some embodiments, R7 is selected from —N(H)(3-piperidinyl) groups, —N(H)(4-piperidinyl) groups, —N(H)(4-(2-methoxymethylpyrrolidinyl)) groups, —N(CH3)(4-(1-methylpiperidinyl)) groups, —N(H)CH2(2-pyridyl) groups, —N(H)CH2(3-pyridyl) groups, —N(H)CH2(4-pyridyl) groups, —N(H)CH2CH2(2-pyridyl) groups, —N(H)CH2CH2(3-pyridyl) groups, —N(H)CH2CH2(4-pyridyl) groups, —N(CH3)CH2CH2(2-pyridyl) groups —N(H)CH2CH2(4-piperidinyl) groups, —N(H)CH2CH2(4-morpholinyl) groups, —N(H)CH2CH2CH2(1-imidazolyl) groups, —N(H)CH2CH2CH2(1-(4-methylpiperazinyl)) groups, —N(H)CH2CH2CH2(4-morpholinyl) groups, —N(H)CH2CH2CH2(1-imidazolyl) groups, —N(H)CH2CH2CH2(1-pyrrolidinyl) groups, —N(CH3)CH2CH2CH2(diethylamino) groups, and the like.
In still other embodiments of the sixth group of compounds where R7 is a substituted amino group having the formula —N(R15)(CH2)qR16, R6 is —H.
In another embodiment of the sixth group of compounds, Z1, Z3, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is a substituted amino group having the formula —N(R15)(CH2)qR16 or the formula —N(R15)C(H)(alkyl)((CH2)qR16) where q is an integer selected from 0, 1, 2, or 3, R16 is selected from a methyl group, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups such as —N(H)(alkyl) groups, —N(alkyl)2 groups and the like, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups, and R15 is selected from —H; substituted and unsubstituted alkyl groups such as, but not limited to, methyl, ethyl, propyl, and isopropyl groups; —C(═O)-alkyl groups such as —C(═O)—CH3 groups and the like; —C(═O)-alkyl-N(H)(alkyl) groups such as —C(═O)—CH2—N(H)(alkyl) groups and the like; —C(═O)-alkyl-N(alkyl)2 groups such as —C(═O)—CH2—N(alkyl)2 groups and the like; —C(═O)-alkyl-N(R15a′)(R15b′) groups such as —C(═O)—CH2—N(alkyl)2 groups and the like —C(═O)-alkyl-heterocyclyl groups such as —C(═O)—CH2-heterocyclyl groups and the like such as —C(═O)—CH2-(1-piperazinyl) groups and the like; —C(═O)-heterocyclyl groups; —C(═O)-aryl groups; —C(═O)-alkyl-O-alkyl groups such as —C(═O)—CH2-O-alkyl groups; —C(═O)-alkyl-S-alkyl groups such as —C(═O)—CH2-S-alkyl groups and the like; and the like where R15a′ is selected from —H, and substituted and unsubstituted alkyl groups, and R15b′ is selected from —H, —SO2-alkyl, —SO2-aryl, —C(═O)-alkyl, —C(═O)-aryl, heterocyclyl groups such as 2-pyridyl groups and the like, heterocyclylalkyl groups, arylalkyl groups, alkyl groups, and —C(═O)-alkyl-halogen groups.
In another embodiment of the sixth group of compounds, Z1, Z2, Z4, R1, R2, R3, R5, and R8 have any of the values in previous embodiments, Z3 is C, and R7 is a substituted or unsubstituted heterocyclyl group. In some embodiments of the sixth group of compounds where R7 is a heterocyclyl group, the heterocyclyl group is selected from substituted or unsubstituted pyrrolidinyl groups, substituted and unsubstituted pyridyl groups, substituted and unsubstituted morpholinyl groups, substituted and unsubstituted piperazinyl groups, substituted and unsubstituted piperidinyl groups, substituted and unsubstituted pyrazolyl groups, substituted and unsubstituted imidazolyl groups, substituted and unsubstituted 1-aza-4-oxacycloheptane groups, substituted and unsubstituted pyrrolyl groups, substituted and unsubstituted 1,4-diazacycloheptane groups, substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups, substituted and unsubstituted 1,4-diazabicyclo[2.2.2]octane groups, substituted or unsubstituted 1,4-diazabicyclo[4.3.0]nonane group, and substituted or unsubstituted 1,4-diazacycloheptane groups. In still other embodiments of the sixth group of compounds where R7 is a heterocyclyl group, the heterocyclyl group is an unsubstituted morpholine group; a dialkyl substituted morpholinyl group such as, but not limited to, a dimethyl substituted morpholinyl group, and the like, such as, but not limited to, a 3,5-dimethyl substituted morpholinyl group; a hydroxy substituted morpholinyl group; a hydroxyalkyl substituted morpholinyl group; an aryl substituted morpholinyl group; an aminoalkyl substituted morpholinyl group including dialkylaminoalkyl substituted morpholinyl groups such as, but not limited to, dimethylaminomethyl substituted morpholinyl groups and the like such as, but not limited to, a morpholinyl group that is substituted on a ring carbon bonded to the ring O atom with a dimethylaminomethyl group and is substituted with a methyl group on the carbon bonded to the ring N atom which carbon is not bonded to the carbon bearing the dimethylaminomethyl group and the like; a heterocyclyl substituted morpholinyl group; an unsubstituted piperazine group; a dialkyl substituted piperazinyl group such as, but not limited to, a dimethyl substituted piperazinyl group, and the like such as a 3,5-dimethyl substituted piperazinyl group and the like; a monoalkyl substituted piperazinyl group such as a 3-alkyl substituted piperazinyl group, an N-alkyl substituted piperazinyl group, and the like such as, but not limited to, a 3-methyl substituted piperazinyl group, a N-alkyl substituted piperazinyl group, such as, but not limited to, N-methyl, N-ethyl, N-isopropyl substituted piperazinyl groups and the like; a hydroxyalkyl substituted piperazinyl group such as, but not limited to, hydroxyethyl and hydroxymethyl substituted piperazinyl groups and the like such as, but not limited to, N-hydroxyethyl substituted piperazinyl groups and the like; an aryl substituted piperazinyl group; a heterocyclyl substituted piperazinyl group such as, but not limited to, 2-, 3-, and 4-(2-, 3-, and 4-piperidinyl) substituted piperazinyl groups and 2-, 3-, and 4-(2-, 3-, and 4-pyridyl) substituted piperazinyl groups and the like; a —CH2C(═O)O-alkyl substituted piperazinyl group; a —C(═O)-alkyl substituted piperazinyl group such as, but not limited to, a —C(═O)-ethyl or a —C(═O)-methyl substituted piperazinyl group, and the like such as a piperazinyl group where the —C(═O)-ethyl or the —C(═O)-methyl substitution is on one of the piperazinyl N atoms and the other N atom is bonded to Z3, and the like; a —C(═O)O-alkyl substituted piperazinyl group such as, but not limited to, a —C(═O)—O-ethyl or a —C(═O)—O-methyl substituted piperazinyl group, and the like such as a piperazinyl group where the —C(═O)—O-ethyl or the —C(═O)—O-methyl substitution is on one of the piperazinyl N atoms and the other N atom is bonded to Z3, and the like; a cycloalkyl substituted piperazinyl group such as, but not limited to, a cyclohexyl and cyclopentyl substituted piperazinyl group and the like such as, but not limited to, a N-cyclohexyl substituted piperazinyl group and the like; an unsubstituted piperidine group; an alkyl substituted piperidinyl group such as, but not limited to, 2-, 3-, and 4-alkyl substituted piperidinyl groups, and the like such as, but not limited to, 2-, 3-, and 4-hydroxyalkyl substituted piperidinyl groups and the like such as, but not limited to, 2-, 3-, and 4-hydroxymethyl substituted piperidinyl groups and the like; a hydroxy substituted piperidinyl group such as 2-, 3-, and 4-hydroxy substituted piperidinyl groups; a hydroxyalkyl substituted piperidinyl group; an aryl substituted piperidinyl group such as, but not limited to, a 4-aryl substituted piperidinyl group and the like such as, but not limited to, a piperidinyl group that is substituted in the 4 position with both an aryl group and a hydroxy group and the like such as, but not limited to, a piperidinyl group that is substituted in the 4 position with both a hydroxy group and a phenyl group; a cycloalkyl substituted piperidinyl group; a heterocyclyl substituted piperidinyl group such as, but not limited to, a piperidinyl substituted piperidinyl group and the like such as, but not limited to, 4-piperidinyl substituted piperidinyl groups, 4-(2(3H)-benzimidazolone) substituted piperidinyl group, and the like; an unsubstituted pyrrolidinyl group; an alkyl substituted pyrrolidinyl group such as, but not limited to, a methyl substituted pyrrolidinyl group, a heterocyclylalkyl substituted pyrrolidinyl group, and the like such as, but not limited to, a 2-methyl substituted pyrrolidinyl group, a 2-pyrrolidinylmethyl substituted pyrrolidinyl group, and the like; an amino substituted pyrrolidinyl group such as, but not limited to, a dialkylamino substituted pyrrolidinyl group such as, but not limited to, 2- and 3-dialkylamino substituted pyrrolidinyl groups and the like such as, but not limited to, 2- and 3-substituted N,N-dimethylamino substituted pyrrolidinyl groups and the like such as, but not limited to, a pyrrolidinyl group that is substituted with both an alkyl group and an N,N-dimethylamino group and the like such as, but not limited to, a pyrrolidinyl group that is substituted with a methyl group in the 2 position and with a N,N-dimethylamino group in the 4 position; a hydroxy substituted pyrrolidinyl group such as, but not limited to, 2- and 3-hydroxy substituted pyrrolidinyl groups; a heterocyclylalkyl substituted pyrrolidinyl group; substituted and unsubstituted pyrrolyl groups; substituted and unsubstituted 2,5-diazabicyclo[2.2.1]heptane groups; an alkyl substituted 2,5-diazabicyclo[2.2.1]heptane group such as, but not limited to, a N-methyl substituted 2,5-diazabicyclo[2.2.1]heptane group and the like; a substituted or unsubstituted 1,4-diazabicyclo[4.3.0]nonane group; and a substituted or unsubstituted 1,4-diazacycloheptane group such as, but not limited to, an alkyl substituted 1,4-diazacycloheptane group and the like, such as, but not limited to, an N-alkyl substituted 1,4-diazacycloheptane substituted group and the like such as, but not limited to, a N-methyl substituted 1,4-diazacycloheptane group and the like. In still other embodiments of the sixth group of compounds where R7 is a substituted or unsubstituted heterocyclyl group, R6 is —H.
In another embodiment of the sixth group of compounds, Z1–Z4, R1, R2, and R3 have any of the values in previous embodiments, and one of R6 or R7 is a substituted or unsubstituted pyridyloxy group. In some such embodiments, one of R6 or R7 is substituted or unsubstituted 2-pyridyloxy group, a 3-pyridyloxy group, or a 4-pyridyloxy group. In other such embodiments, one of R6 or R7 is a (2-N-alkylamido-4-pyridyl)oxy group such as a (2-N-methylamido-4-pyridyl)oxy group or the like; or a (5-N-alkylamido-3-pyridyl)oxy group such as a (5-N-methylamido-3-pyridyl)oxy group, or the like.
Other more particular embodiments of the compounds of the invention having the general structure shown in I above are provided. Such compounds form a seventh group of compounds for which:
Z1, Z2, Z3, and Z4 are independently selected from C or N;
R1 is selected from —H, —F, —Cl, —Br, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R2 is selected from —H, —F, —Cl, —Br, —C≡N, —NO2, —CO2H, —OH, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)O-aryl groups, substituted and unsubstituted —C(═O)O-heteroaryl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups, substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted akoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted heterocyclyloxy, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms;
R3 is selected from —H, —F, —Cl, —Br, —CF3, —C≡N, —NO2, —CO2H, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—O-alkyl groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy group, substituted and unsubstituted heterocycyl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R4 is —H, —F, —Br, —Cl, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R5 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R5 is absent if Z1 is N;
R6 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups; or R6 is absent if Z2 is N;
R7 is selected from —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups; or R7 is absent if Z3 is N;
R8 is selected from —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups, or R8 is absent if Z4 is N;
R9 is —H;
R10 is selected from the group consisting of —H, and substituted and unsubstituted alkyl groups; and
at least one of Z2 or Z3 is C and at least one of R6 or R7 is selected from the group consisting of substituted and unsubstituted piperidinyl substituted heterocyclyl groups, substituted and unsubstituted heterocyclyl substituted piperidinyl groups, substituted and unsubstituted hydroxymethyl substituted piperidinyl groups, dimethylaminoalkyl substituted pyrrolidinyl groups, substituted and unsubstituted 3-alkyl substituted piperazinyl groups, substituted and unsubstituted 3,5-dialkyl substituted piperazinyl groups, substituted and unsubstituted N-hydroxyalkyl substituted piperazinyl groups, substituted and unsubstituted 1,4-diazacycloheptyl groups, substituted and unsubstituted 1-aza-4-oxacycloheptyl groups, substituted and unsubstituted N-ethylpiperazinyl groups, substituted and unsubstituted N-isopropylpiperazinyl groups, substituted and unsubstituted N-sec-butylpiperazinyl groups, substituted and unsubstituted N-2-pyridyl substituted piperazinyl groups, substituted and unsubstituted N-3-pyridyl substituted piperazinyl groups, substituted and unsubstituted N-4-pyridyl substituted piperazinyl groups, substituted and unsubstituted N(H)—CH2-pyridyl groups, substituted and unsubstituted imidazolyl groups, substituted and unsubstituted 3-alkyl substituted morpholinyl groups, substituted and unsubstituted 3,5-dialkyl substituted morpholinyl groups, dialkylamino substituted pyrrolidinyl groups, pyrrolidinyl groups substituted with both dialkylamino and alkyl groups, substituted and unsubstituted 4-hydroxy substituted piperidinyl groups, substituted and unsubstituted 4-aryl substituted piperidinyl groups, substituted and unsubstituted 4-hydroxy-4-phenyl substituted piperidinyl groups, substituted and unsubstituted cyclohexylpiperazinyl groups, substituted and unsubstituted cyclopentylpiperazinyl groups, substituted and unsubstituted N-alkyl substituted diazabicycloalkane groups, substituted and unsubstituted —N(CH3)(N-alkyl(4-piperidinyl)) groups, substituted and unsubstituted piperazinyl groups further substituted with a —C(═O)-alkyl group on one of the N atoms of the piperazinyl group, substituted and unsubstituted —N(H)CH2CH2CH2-imidazolyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-pyrrolidinyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-morpholinyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-piperazinyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-piperidinyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-pyridyl groups, substituted and unsubstituted —N(H)CH2CH2-imidazolyl groups, substituted and unsubstituted —N(H)CH2CH2-pyrrolidinyl groups, substituted and unsubstituted —N(H)CH2CH2-morpholinyl groups, substituted and unsubstituted —N(H)CH2CH2-piperazinyl groups, substituted and unsubstituted —N(H)CH2CH2-piperidinyl groups, substituted and unsubstituted —N(H)CH2CH2-pyridyl groups, substituted and unsubstituted cyclobutylpiperazinyl groups, substituted and unsubstituted —OCH2-pyrrolidinyl groups, substituted and unsubstituted —OCH2CH2-pyrrolidinyl groups, substituted and unsubstituted —OCH2CH2CH2-pyrrolidinyl groups, substituted and unsubstituted piperazinyl groups further substituted with a —CH2C(═O)—O-alkyl group bonded to one of the N atoms of the piperazinyl group, substituted and unsubstituted piperazinyl groups further substituted with a —C(═O)—O-alkyl group bonded to one of the N atoms of the piperazinyl group, substituted and unsubstituted hydroxypyrrolidinyl groups, substituted and unsubstituted hydroxypiperidinyl groups, substituted and unsubstituted —OCH2-pyridyl groups, substituted and unsubstituted piperidinylamino groups, substituted and unsubstituted pyridyloxy groups with a —C(═O)—N(H)(alkyl) group bonded to a carbon atom of the pyridine ring of the pyridyloxy group, and substituted and unsubstituted pyridyloxy groups with a —C(═O)—N(alkyl)2 group bonded to a carbon atom of the pyridine ring of the pyridyloxy group.
In some embodiments, R10 is —H. In other embodiments, R10 is an unsubstituted alkyl group having from 1 to 6 carbon atoms such as a methyl, ethyl, propyl, i-propyl group, or the like. In some such embodiments, R10 is a —CH3 group.
In one embodiment of the seventh group of compounds, each of Z1, Z2, Z3, and Z4 are C.
In another embodiment of the seventh group of compounds, Z1 is N and each of Z2, Z3, and Z4 are C.
In another embodiment of the seventh group of compounds, Z1 and Z3 are both N and Z2 and Z4 are both C.
In another embodiment of the seventh group of compounds, Z3 is N and each of Z1, Z2, and Z4 are C.
In another embodiment of the seventh group of compounds, Z1–Z4 have any of the values in previous embodiments, and R1 is selected from —H, —F, —Cl, and —Br.
In another embodiment of the seventh group of compounds, Z1–Z4 have any of the values in previous embodiments, and R1 is a substituted and unsubstituted heterocyclylamino group. In some such embodiments, R1 is a substituted and unsubstituted heteroarylamino groups. In some embodiments, R1 is a substituted and unsubstituted heterocyclylamino group such as, but not limited to, substituted and unsubstituted pyrroldinylalkylamino groups and the like, such as, but not limited to, substituted and unsubstituted pyrrolidinylmethylamino groups and the like.
In another embodiment of the seventh group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is selected from —H, —F, —Cl, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted heterocyclyloxy, and substituted and unsubstituted heterocyclylalkoxy groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms.
In another embodiment of the seventh group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is —H.
In another embodiment of the seventh group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is an unsubstituted alkoxy group having from 1 to 4 carbon atoms.
In another embodiment of the seventh group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a —OMe, —OEt, —O-i-Pr, or —OCH2CH(CH3)2 group.
In another embodiment of the seventh group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted arylalkoxy, a substituted or unsubstituted aryloxy group, or a substituted or unsubstituted heterocyclyoxy group.
In another embodiment of the seventh group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted benzyloxy group, a substituted or unsubstituted phenoxy group, or a substituted or unsubstituted pyridyloxy group.
In another embodiment of the seventh group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is an unsubstituted alkyl group having from 1 to 4 carbon atoms.
In another embodiment of the seventh group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a methyl group.
In another embodiment of the seventh group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted —N(H)C(═O)—N(H)-alkyl-aryl group.
In another embodiment of the seventh group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted amino group selected from the group consisting of substituted and unsubstituted alkylamino groups, dialkylamino groups, cycloalkylamino groups, heterocyclylamino groups, heterocyclylalkylamino groups, arylalkylamino groups, arylalkoxyarylmethylamino groups, and aryloxyarylalkylamino groups. In some embodiments, the substituted and unsubstituted alkylamino groups are substituted and unsubstituted aminoalkylamino groups such as, but not limited to, dialkylaminoalkylamino and the like. In some such embodiments the substituted and unsubstituted heterocyclylalkylamino groups are substituted and unsubstituted heteroarylalkylamino groups. In some embodiments, the heterocyclylalkylamino groups include, but are not limited to, substituted and unsubstituted pyrrolidinylalkylamino groups such as, but not limited to, substituted and unsubstituted pyrrolidinylmethylalkylamino groups and the like; substituted and unsubstituted thiazolylalkylamino groups such as, but not limited to substituted and unsubstituted thiazolylmethylamino groups and the like; substituted and unsubstituted imidazolylalkylamino groups such as, but not limited to, imidazolylmethylamino groups and the like; substituted and unsubstituted furanylalkylamino groups such as, but not limited to, substituted and unsubstituted furanylmethylamino groups, and the like; and the like. In other such embodiments, the heterocyclylamino groups are substituted and unsubstituted heteroarylamino groups. In other such embodiments, the substituted and unsubstituted heterocyclylamino groups are substituted and unsubstituted arylalkylheterocyclylamino groups.
In another embodiment of the seventh group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted amino group selected from the group consisting of isopropylamino groups, 3-(N,N-dimethylamino)propylamino groups, pyrrolidinylmethylamino groups, arylmethylamino groups, arylalkoxyarylmethylamino groups, aryloxyarylmethylamino groups, and pyridylmethylamino groups, and pyridylamino groups.
In another embodiment of the seventh group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 is a substituted or unsubstituted heterocyclyl groups. In some such embodiments R2 is a substituted or unsubstituted benzimidazolyl group or is a substituted or unsubstituted pyrazolyl group.
In another embodiment of the seventh group of compounds, Z1–Z4 and R1 have any of the values in previous embodiments, and R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms.
In another embodiment of the seventh group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is selected from —H, —F, —Cl, and —OMe.
In another embodiment of the seventh group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —H.
In another embodiment of the seventh group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is selected from the group consisting of —F, —Cl, —Br, —CF3, —C≡N, —NO2, —CO2H, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups and substituted and unsubstituted —C(═O)N(H)-alkyl-heterocyclyl groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms.
In another embodiment of the seventh group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is selected from the group consisting of substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, and substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups. In some such embodiments, R3 is a substituted or unsubstituted —N(H)C(═O)N(H)CH2CH3 group, a substituted or unsubstituted —N(H)C(═O)N(H)CH(CH3)2 group, a substituted or unsubstituted —N(H)C(═O)N(H)C(CH3)3 group, or a substituted or unsubstituted —N(H)C(═O)N(H)-aryl group or the like. In some such embodiments, R3 is a substituted or unsubstituted —N(H)C(═O)N(H)-aryl group such as, but not limited to, a —N(H)C(═O)N(H)-(2-methoxyphenyl) group, a—N(H)C(═O)N(H)-(trifluoromethylphenyl) group, or the like.
In another embodiment of the seventh group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is a substituted amino group selected from substituted or unsubstituted arylalkylamino groups such as, but not limited to, phenylalkylamino groups, (halo)(alkoxy)arylalkylamino groups, such as, but not limited to 2-fluoro-5-methoxyphenylmethylamino groups, monoalkoxyarylalkylamino groups, dialkoxyarylalkylamino groups, and the like, such as, but not limited to, 2,5-dialkoxyarylalkylamino groups and the like such as, but not limited to 2,5-dialkoxyarylmethylamino groups, substituted and unsubstituted arylalkoxyarylalkylamino groups such as, but not limited to substituted and unsubstituted arylalkoxyarylmethylamino groups and the like, such as, but not limited to, substituted and unsubstituted arylmethoxyarylmethylamino groups and the like, such as, but not limited to substituted and unsubstituted fluoroarylmethoxyarylmethylamino groups and the like, such as, but not limited to, substituted and unsubstituted 4-fluorophenylmethoxyphenyl-methylamino groups and the like; substituted and unsubstituted heterocyclylalkylamino groups including heteroarylalkylamino groups such as, but not limited to substituted and unsubstituted thiazolylalkylamino groups, benzimidazolylalkylamino groups such as, but not limited to N-methylbenzimidazolylalkylamino groups and the like, imidazolylalkylamino groups such as, but not limited to phenylimidazolylalkylamino groups, ethylmethylimidazolylalkylamino groups, and the like, substituted and unsubstituted quinolinylalkylamino groups, such as, but not limited to substituted and unsubstituted quinolinylmethylamino groups and the like, such as, but not limited to alkoxyquinolinylmethylamino groups and the like, such as, but not limited to substituted and unsubstituted 4-alkoxy-2-quinolinylmethylamino groups and the like, and furanylalkylamino groups, and the like.
In another embodiment of the seventh group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —F.
In another embodiment of the seventh group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —Cl.
In another embodiment of the seventh group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is —OMe.
In another embodiment of the seventh group of compounds, Z1–Z4, R1, and R2 have any of the values in previous embodiments, and R3 is a substituted and unsubstituted —C(═O)N(H)-alkyl-heterocyclyl groups where the heterocyclyl group of the —C(═O)N(H)-alkyl-heterocyclyl groups is selected from the group consisting of morpholinyl, piperazinyl, and piperidinyl groups.
In another embodiment of the seventh group of compounds, Z2–Z4, R1, R2, and R3 have any of the values in previous embodiments, Z1 is C, and R5 is H. In some such embodiments, R8 is also H.
In another embodiment of the seventh group of compounds, Z2–Z4, R1, R2, and R3 have any of the values in previous embodiments, Z1 is C, and R5 is —CH3. 
In another embodiment of the seventh group of compounds, Z2–Z4, R1, R2, and R3 have any of the values in previous embodiments, Z1 is C, and R5 is morpholine.
In another embodiment of the seventh group of compounds, Z1–Z3, R1, R2, and R3 have any of the values in previous embodiments, Z4 is C, and R8 is H.
In another embodiment of the seventh group of compounds, Z1–Z3, R1, R2, and R3 have any of the values in previous embodiments, Z4 is C, and R8 is —CH3.
In another embodiment of the seventh group of compounds, Z1–Z3, R1, R2, and R3 have any of the values in previous embodiments, Z4 is C, and R8 is morpholine.
In another embodiment of the seventh group of compounds, at least one of R6 or R7 is selected from the group consisting of piperidinyl substituted piperidinyl groups such as 4-piperidinylpiperidinyl groups or the like, 4-hydroxymethylpiperidinyl groups, 3-dimethylaminomethylpyrrolidinyl groups, 3-alkyl substituted piperazinyl groups, 3,5-dialkyl substituted piperazinyl groups, N-hydroxyethylpiperazinyl groups, N-hydroxymethylpiperazinyl groups, N-hydroxypropylpiperazinyl groups, N-methyl substituted 1,4-diazacycloheptyl groups, N-ethylpiperazinyl groups, N-isopropylpiperazinyl groups, N-sec-butylpiperazinyl groups, unsubstituted piperazinyl groups, N-(2-pyridyl)piperazinyl groups, N-(3-pyridyl)piperazinyl groups, N-(4-pyridyl)piperazinyl groups, N(H)—CH2-pyridyl groups, imidazolyl groups, unsubstituted morpholinyl groups, 3-alkylmorpholinyl groups, 3,5-dialkylmorpholinyl groups, 2-dimethylaminopyrrolidinyl groups, 2-methyl-4-dialkylaminopyrroldinyl groups, 4-hydroxypiperidinyl groups, 4-arylpiperidinyl groups, 4-hydroxy-4-phenylpiperidinyl groups, cyclohexylpiperazinyl groups, cyclopentylpiperazinyl groups, N-methyl substituted diazabicycloalkane groups, —N(CH3)(N-alkyl(4-piperidinyl)) groups, piperazinyl groups further substituted with a —C(═O)-methyl group on one of the N atoms of the piperazinyl group, —N(H)CH2CH2CH2-imidazolyl groups, —N(H)CH2CH2CH2-pyrrolidinyl groups, —N(H)CH2CH2CH2-morpholinyl groups, —N(H)CH2CH2CH2-piperazinyl groups, —N(H)CH2CH2CH2-piperidinyl groups, and —N(H)CH2CH2CH2-pyridyl groups. In some such embodiments, at least one of R6 or R7 is selected from the group consisting of 4-piperidinylpiperidinyl groups, 4-hydroxymethylpiperidinyl groups, 3-dimethylaminomethylpyrrolidinyl groups, 3,5-dimethyl substituted piperazinyl groups, N-methyl substituted 1,4-diazacycloheptyl groups, N-(2-pyridyl)piperazinyl groups, N(H)—CH2-(4-pyridyl) groups, imidazolyl groups, unsubstituted morpholinyl groups, 3-methylmorpholinyl groups, 3,5-dimethylmorpholinyl groups, 2-dimethylaminopyrrolidinyl groups, 2-methyl-4-dimethylaminopyrroldinyl groups, 4-hydroxy-4-phenylpiperidinyl groups, cyclohexylpiperazinyl groups, N-methyl substituted diazabicycloalkane groups, —N(CH3)(N-methyl(4-piperidinyl)) groups, piperazinyl groups further substituted with a —C(═O)-methyl group on one of the N atoms of the piperazinyl group, —N(H)CH2CH2CH2-imidazolyl groups, —N(H)CH2CH2CH2-pyrrolidinyl groups, —N(H)CH2CH2CH2-morpholinyl groups, —N(H)CH2CH2CH2-piperazinyl groups, —N(H)CH2CH2CH2-piperidinyl groups, and —N(H)CH2CH2CH2-pyridyl groups.
The heterocyclic groups of the present invention may be attached in various ways. For example, where R6 is a heterocyclyl group such as morpholine, the morpholine may be attached to Z2 as shown below in Structures II, III, and IV.




As a further example, where R6 is a piperazine group, the piperazine may be attached to Z2 as shown below in Structures V, VI, VII, and VIII.




As a further example, where R6 is a pyrrolidinyl group, then the pyrrolidinyl group may be attached to Z2 as shown below in structures IX, X, and XI.





The indazole benzimidazoles of the present invention may generally be assembled by coupling a suitably substituted indazole fragment with a suitably substituted 2-amino aniline or 2-nitro aniline compound. In one method, shown in Scheme 1, an indazole-3-carboxylic acid is reacted with POCl3 to form a dimer. The resulting dione is then heated in the presence of a suitably substituted diamine to form the desired indazole benzimidazole adduct. If a nitro aniline is used in place of the diamine, an additional reduction and cyclodehydration step is required to effect the ring closure. Alternatively a diamine having one protected amine group may be reacted in place of the diamine. Formation of the indazole benzimidazole by this procedure will include a deprotection and cyclodehydration to afford the desired indazole benzimidazole compound. These reactions may be conducted in aromatic solvents such as toluene and non-nucleophilic bases such as trialkylamines such as triethylamine may be employed.




Therefore, according to one embodiment, the invention provides a method for synthesizing a substituted or unsubstituted indazole benzimidazole. The method includes: (a) reacting a dimer formed from two molecules of an indazole-3-carboxylic acid, wherein the six membered benzene ring of the indazole-3-carboxylic acid may be substituted or unsubstituted, with an amino compound selected from the group consisting of:

    
    
        (i) a diaminobenzene derivative comprising a benzene ring and at least two amine groups bonded to adjacent carbon atoms in the benzene ring, wherein the benzene ring may be further substituted or may comprise 1,2-diaminobenzene, and further wherein the substituted or unsubstituted indazole benzimidazole is formed by reaction with the dimer;
        (ii) a nitroaminobenzene derivative comprising a benzene ring, at least one nitro group, and at least one amine group, wherein the at least one amine group is bonded to a carbon atom in the benzene ring that is adjacent to another carbon atom in the benzene ring to which the at least one nitro group is bonded, further wherein the benzene ring may be further substituted or may comprise 1-amino-2-nitrobenzene, and further wherein an amide comprising a nitro group is formed by reaction with the dimer;
        (iii) a first (protected amino)(amino)benzene derivative comprising a benzene ring, at least one protected amine group, and at least one —NH2 group, wherein the at least one protected amine group is bonded to a first carbon atom in the benzene ring that is adjacent to a second carbon atom in the benzene ring to which the at least one —NH2 group is bonded, further wherein the benzene ring may be further substituted or may only include H atoms bonded to the four other carbon atoms of the benzene ring, and further wherein an amide comprising at least one protected amine group is formed by reaction with the dimer; and
        (iv) a second (protected amino)(amino)benzene derivative comprising a benzene ring, at least one protected amine group, and at least one —NH2 group, wherein the at least one protected amine group is bonded to a first carbon atom in the benzene ring that is adjacent to a second carbon atom in the benzene ring to which the at least one —NH2 group is bonded, further wherein the benzene ring may be further substituted or may only include H atoms bonded to the four other carbon atoms of the benzene ring, further wherein the protected amine group comprises a protecting group that is removed during the reaction with the dimer such that the substituted or unsubstituted indazole benzimidazole is formed by the reaction with the dimer,

wherein, if the dimer is reacted with the nitroaminobenzene derivative, the method further comprises (b):

    
    


(b) reducing the nitro group of the amide comprising the nitro group and cyclodehydrating to form the substituted or unsubstituted indazole benzimidazole;
and further wherein, if the dimer is reacted with the first (protected amino)(amino)benzene derivative, then the method further comprises (c):
(c) removing the protecting group from the amide comprising the at least one protected amine group and cyclodehydrating to form the substituted or unsubstituted benzimidazole.
In some embodiments, the dimer is reacted with the diaminobenzene derivative, the nitroaminobenzene derivative, the first (protected amino)(amino)benzene derivative, or the second (protected amino)(amino)benzene derivative in a toluene solution which may be a refluxing toluene solution in some embodiments. In some embodiments, the the dimer is reacted with the diaminobenzene derivative, the nitroaminobenzene derivative, the first (protected amino)(amino)benzene derivative, or the second (protected amino)(amino)benzene derivative at a temperature of greater than 85° C. whereas in other embodiments, the temperature ranges from about 95° C. to about 111° C., from about 95° C. to about 105° C., or from about 98° C. to about 110° C.
In some embodiments, the method includes reacting the dimer with a salt such as hydrochloride, hydrobromide, dihydrochloride, dihydrobromide, or the like salt of the diaminobenzene derivative, the nitroaminobenzene derivative, the first (protected amino)(amino)benzene derivative, or the second (protected amino)(amino)benzene derivative. In other embodiments, the diaminobenzene derivative, the nitroaminobenzene derivative, the first (protected amino)(amino)benzene derivative, or the second (protected amino)(amino)benzene derivative is reacted with the dimer in the presence of a base such as, but not limited to, triethylamine, tripropylamine, tributylamine, ethyldipropylamine, propyldiethylamine, or the like.
In some embodiments, the method includes reacting the indazole-3-carboxylic acid with a reagent affecting the conversion of the acid to an acid halide or anhydride such as, but not limited to, cyanuric fluoride, tetramethylfluoroformamidinium hexafluorophosphate, cyanuric chloride, SOCl2, PCl3, PCl5, PBr3, PBr5, POCl3, carbonyl diimidazole/HCl, Oxalyl chloride, and carbodiimides, followed by in situ dimerization.
In some embodiments in which the nitroaminobenzene derivative is reacted with the dimer, the method includes reducing the nitro group of the amide with hydrogen using a hydrogenation catalyst such as, but not limited to, Pd on carbon, Pt on carbon, or the like. In some such embodiments, the catalyst is Pd on carbon. In some such embodiments, the reduced product is cyclodehydrated by treating the reduced product with an acid such as, but not limited to, acetic acid. In some cases the reduced product is cyclodehydrated by treating the reduced product with sodium acetate and acetic acid and heating such as at a reflux temperature. In some embodiments in which the first (protected amino)(amino)benzene derivative is reacted with the dimer, cyclodehydrating includes reacting the amine formed by removal of the protecting group with an acid such as, but not limited to, acetic acid. In some cases the amine formed by removal of the protecting group is cyclodehydrated by treating the reduced product with sodium acetate and acetic acid and heating such as at a reflux temperature. In some cases, the amide comprising the protected amine group formed by reaction of the first (protected amino)(amino)benzene derivative with the dimer is removed and the product is cyclodehydrated, in one procedure, using an acid. Most commonly used protective groups for amines are stable to the reaction with the dimer. Boc may come off during the reaction with the dimer, but only if the temperature is maintained at from 130–150° C. or higher. Examples of protective groups for the amines that are stable upon reaction with the dimer include, but are not limited to, carbamates such as, but not limited to, methyl ethyl, t-butyl, benzyl, and 9-fluorenylmethyl carbamates and the like; amides such as, but not limited to, acetamide, chloroacetamide, trifluoroacetamide, benzamide and the like; sulfonamides such as, but not limited to, benzenesulfonamide, p-toluenesulfonamide, trifluoromethanesulfonamide, and the like; and groups such as, but not limited to, N-allyl, N-benzyl, N-o-nitrobenzyl, N-p-methoxybenzyl, N-2,4-dimethoxybenzyl, N-triphenylmethyl, SEM, and the like. Groups which are sensitive to acids such as, but not limited to, N-2,4-dimethoxybenzyl, N-triphenylmethyl, may come off during cyclodehydration when it is performed in refluxing AcOH. If the cyclodehydration is performed in the presence of a non nucleophilic base such as triethylamine, some carbamates such as, but not limited to, 9-fluorenylmethyl carbamate and 2,4-dichlorobenzyl carbamate may be cleaved.
In some embodiments, the indazole-3-carboxylic acid used to form the dimer has the formula XII where R1, R2, R3, R4, and R9 have any of the values set forth above with respect to the first, second, third, fourth, fifth, sixth, and seventh group of compounds having the formula I. Compound XII has the following structure.




In some embodiments, the dimer is a compound having the formula XIII where R1, R2, R3, and R4 have any of the values set forth above with respect to the first, second, third, fourth, fifth, sixth, and seventh group of compounds having the formula I. With respect to the indazole-3-carboxylic acid of formula XII and the dimer of formula XIII, one skilled in the art will recognize that certain nucleophilic R1 through R4 groups may need to be protected with suitable protecting groups prior to formation of the dimer or prior to reaction with the the diaminobenzene derivative, the nitroaminobenzene derivative, the first (protected amino)(amino)benzene derivative, or the second (protected amino)(amino)benzene derivative. Compound of formula XIII have the following structure.




In some embodiments in which the diaminobenzene derivative is reacted with the dimer, the diaminobenzene derivative is a compound having the formula XIV where R5, R6, R7, and R8 have any of the values set forth above with respect to the first, second, third, fourth, fifth, sixth, and seventh group of compounds having the formula I. One skilled in the art will recognize that certain nucleophilic R5 through R8 groups may need to be protected with suitable protecting groups for reaction with the dimer. Compounds of formula XIV has the following structure.




In some embodiments in which the nitroaminobenzene derivative is reacted with the dimer, the diaminobenzene derivative is a compound having the formula XVA or XVB where R5, R6, R7, and R8 have any of the values set forth above with respect to the first, second, third, fourth, fifth, sixth, and seventh group of compounds having the formula I. One skilled in the art will recognize that certain nucleophilic R5 through R8 groups may need to be protected with suitable protecting groups for reaction with the dimer. Compounds of formula XVA and XVB have the following structures.




The indazole fragment may also be constructed from suitably substituted indoles via a nitrosation reaction to form a suitably substituted indazole-3-carbaldehyde as the key coupling precursor (Scheme 2). This strategy affords considerable flexibility in the synthesis of functionalized indazole benzimidazoles. By using appropriately substituted indole, 1,2-diaminobenzene, or 1,2-diaminoheteroaryl starting materials, many of which are commercially available or may be easily made by one of skill in the art, a wide variety of desired indazole benzimidazole compounds may be synthesized. Without being bound to hypothesis, it is believed that a hemiaminal intermediate compound is initially obtained which is then cyclooxidized to provide the substituted and unsubstituted indazole benzimidazole compounds of the invention. The suitably substituted indazole-3-carbaldehyde may alternatively be reacted with a suitably substituted monoprotected substituted or unsubstituted 1,2-diaminobenzene to form an imine that includes the protecting group. The intermediate imine product may then be deprotected and oxidatively cyclized to produce the desired indazole benzimidazole product. The suitably substituted indazole-3-carbaldehyde may also be reacted with a suitably substituted benzene bearing at least two amine groups one of which is protected with a suitable protecting group that provides a protected benzimidazole indazole product. Removal of the protecting group in such embodiments affords the indazole benzimidazole product. In another embodiment, the indazole-3-carbaldehyde may be reacted with a monoprotected substituted or unsubstituted 1,2-diaminobenzene derivative in a reaction in which the protecting group is lost and the indazole benzimidazole is formed. Generally, the O2 for the oxidative cyclization step comes from that dissolved in the solvent in the reaction vessel. In one alternative embodiment, O2 may be bubbled through the reaction mixture. In other embodiments, compounds which provide a source for O2 such as nitrobenzene may be used in the oxidative cyclization to form the indazole benzimidazole product.




In one embodiment, the invention provides a first alternative method for synthesizing a substituted or unsubstituted indazole benzimidazole. The method includes reacting a substituted or unsubstituted indazole-3-carbaldehyde with an amino compound selected from the group consisting of:

    
    
        (i) a diaminobenzene derivative comprising a benzene ring and at least two amine groups bonded to adjacent carbon atoms in the benzene ring, wherein the benzene ring may be further substituted or may comprise 1,2-diaminobenzene, and further wherein the substituted or unsubstituted indazole benzimidazole is formed by reaction with the substituted or unsubstituted indazole-3-carbaldehyde;
        (ii) a first (protected amino)(amino)benzene derivative comprising a benzene ring, at least one protected amine group, and at least one —NH2 group, wherein the at least one protected amine group is bonded to a first carbon atom in the benzene ring that is adjacent to a second carbon atom in the benzene ring to which the at least one —NH2 group is bonded, further wherein the benzene ring may be further substituted or may only include H atoms bonded to the four other carbon atoms of the benzene ring, and further wherein a N-protected substituted or unsubstituted indazole benzimidazole is formed by reaction with the substituted or unsubstituted indazole-3-carbaldehyde;
        (iii) a second (protected amino)(amino)benzene derivative comprising a benzene ring, at least one protected amine group, and at least one —NH2 group, wherein the at least one protected amine group is bonded to a first carbon atom in the benzene ring that is adjacent to a second carbon atom in the benzene ring to which the at least one —NH2 group is bonded, further wherein the benzene ring may be further substituted or may only include H atoms bonded to the four other carbon atoms of the benzene ring, and further wherein an imine comprising at least one protected amine group is formed by reaction with the substituted or unsubstituted indazole-3-carbaldehyde; and
        (iv) a third (protected amino)(amino)benzene derivative comprising a benzene ring, at least one protected amine group, and at least one —NH2 group, wherein the at least one protected amine group is bonded to a first carbon atom in the benzene ring that is adjacent to a second carbon atom in the benzene ring to which the at least one —NH2 group is bonded, further wherein the benzene ring may be further substituted or may only include H atoms bonded to the four other carbon atoms of the benzene ring, further wherein the protected amine group comprises a protecting group that is removed during the reaction with the substituted or unsubstituted indazole-3-carbaldehyde such that the substituted or unsubstituted indazole benzimidazole is formed by the reaction with the substituted or unsubstituted indazole-3-carbaldehyde,

wherein, if the substituted or unsubstituted indazole-3-carbaldehyde is reacted with the first (protected amino)(amino)benzene derivative, the method further comprises (b):

    
    


(b) removing the protecting group from the N-protected substituted or unsubstituted indazole benzimidazole to form the substituted or unsubstituted indazole benzimidazole;
and further wherein, if the substituted or unsubstituted indazole-3-carbaldehyde is reacted with the second (protected amino)(amino)benzene derivative, then the method further comprises (c):
(c) removing the protecting group from the imine comprising the at least one protected amine group and oxidatively cyclizing to form the substituted or unsubstituted benzimidazole.
In other embodiments, the diaminobenzene derivative, the first (protected amino)(amino)benzene derivative, the second (protected amino)(amino)benzene derivative, or the third (protected amino)(amino)benzene derivative is reacted with the indazole-3-carbaldehyde in the presence of a base such as, but not limited to, triethylamine, tripropylamine, tributylamine, ethyldipropylamine, propyldiethylamine, or the like.
In some embodiments of the first alternative methods, the method includes reacting the indazole-3-carbaldehyde with the diaminobenzene derivative, the first (protected amino)(amino)benzene derivative, the second (protected amino)(amino)benzene derivative, or the third (protected amino)(amino)benzene derivative in an aromatic solvent such as toluene, an alcohol solvent such as ethanol, or a combination of these such as a 3:1 toluene ethanol mixture. In other embodiments, the diaminobenzene derivative, the first (protected amino)(amino)benzene derivative, the second (protected amino)(amino)benzene derivative, or the third (protected amino)(amino)benzene derivative is reacted with the indazole-3-carbaldehyde at a temperature of greater than 85° C. whereas in other embodiments, the temperature ranges from about 95° C. to about 111° C., from about 95° C. to about 105° C., or from about 98° C. to about 110° C.
In some embodiments in which the first (protected amino)(amino)benzene derivative is reacted with the indazole-3-carbaldehyde to produce the N-protected indazole benzimidazole, the protected amino group is protected with a protecting group such as Bn, SEM, and the like. In some embodiments in which the second (protected amino)(amino)benzene derivative is reacted with the indazole-3-carbaldehyde to produce the imine, the protected amino group is protected with a protecting group such as Fmoc, Boc, and the like. In some embodiments in which the third (protected amino)(amino)benzene derivative is reacted with the indazole-3-carbaldehyde to produce the indazole benzimidazole, the protected amino group is protected with a protecting group such as TMS, TES, and the like.
In some embodiments, the indazole-3-carbaldehyde used to form the indazole benzimidazole is a compound having the formula XVI where R1, R2, R3, and R4 have any of the values set forth above with respect to the first, second, third, fourth, fifth, sixth, and seventh group of compounds having the formula I. Compound XVI has the following structure.




In some embodiments in which the diaminobenzene derivative is reacted with the indazole-3-carbaldehyde, the diaminobenzene derivative is a compound having the formula XIV as set forth above where R5, R6, R7, and R8 have any of the values set forth above with respect to the first, second, third, fourth, fifth, sixth, and seventh group of compounds having the formula I. One skilled in the art will recognize that certain nucleophilic R5 through R8 groups may need to be protected with suitable protecting groups for reaction with the indazole-3-carbaldehyde. In addition, certain R1–R4 groups such as —OH may require protection during reaction of the substituted indole with NaNO2/HCl and during reaction with the diamine in toluene. Groups such as —OH may be protected with a suitable protecting groups such as Cbz which may then be removed after the indazole-3-carbaldehyde has been reacted with the diamine. Such transformation are well within the realm of those skilled in the art.
In some embodiments of the first alternative method of forming a substituted or unsubstituted indazole benzimidazole, the indazole-3-carbaldehyde, such as compounds of formula XVI, are formed by reacting a suitably substituted indole with NaNO2. In such procedures, the reaction is generally conducted in the dark. The reaction may be protected from light by, for example, covering the reaction vessel with an opaque material such as aluminum foil or the like. In such procedures, a substituted or unsubstituted indole is generally added to a reaction vessel that includes an aqueous solution of NaNO2 at an acidic pH such as at a pH ranging from at or about 2 to a pH of at or about 3. In one embodiment, the pH is at or about 2.5. The NaNO2 solution is generally made acidic by adding an acid such as HCl or HBr although other acids may be employed for this purpose An organic solvent such as dioxane or tetrahydrofuran may be added to the aqueous NaNO2 solution along with the indole or prior to adding the indole. Generally, the indole is added slowly to the reaction vessel that contains the NaNO2 solution. Suitable indoles for use in the synthesis of the indazole-3-carbaldehydes typically are compounds having the formula XVII where R1 through R4 have any of the values set forth above with respect to the first, second, third, fourth, fifth, sixth, and seventh groups of compound of formula I. Compounds of formula XVII have the following structure.




A wide variety of indoles are commercially available for use in preparing the indazole-3-carbaldehydes of formula XVI. Examples of R1 groups in commercially available indoles include, but are not limited to, —H, —F, —Cl, —CH3, —CF3, —OMe, —CO2Me, —CO2Et, —OBn, —C≡N, and the like. Examples of R2 groups of commercially available indoles include, but are not limited to, —H, —F, —Cl, —Br, —OMe, —CF3, and the like. Examples of R3 groups of commercially available indoles include, but are not limited to, —H, —F, —Cl, —OMe, —OBn, —CF3, —C≡N, and the like. Examples of R4 groups of commercially available indoles include, but are not limited to, —H, —F, —Cl, —Br, -Et, —OMe, —CO2Me, —CO2Et, —OBn, —NO2, and the like.
Scheme 3 illustrates just a few of the methods that may be used to produce a variety of 1,2-diamino benzenes. Halo (X=halogen) nitroanilines may be reacted with a wide variety of nucleophiles (Nu−) such as alcohols and amines to produce functionalized nitroanilines which may subsequently be reduced to diamines. The alcohol moiety of a nitroamino phenol may be modified using known methods to introduce a broad range of substituents into a diamine for subsequent inclusion in an indazole benzimidazole compound.




In addition to the above schemes, it should be noted that various groups, including, but not limited to, hydroxyl groups and amine groups may be introduced into the indazole benzimidazole compounds of the present invention as protected groups using traditional protecting group chemistry. The use of standard protecting groups and the removal of such groups is well known in the art and various such groups may be used to prepare compounds in accordance with the present invention.
The instant invention also provides for compositions which may be prepared by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like to treat or ameliorate a variety of disorders related to the activity of VEGF-RTK, more particularly angiogenesis associated with cancer or related to the activity of KDR, Flt-1, Flk-1, bFGFR, GSK-3, NEK-2, CHK-1, cdc 2, Tie-2, and PDGF. The compositoins of the inventions may be used to create formulations and to inhibit tyrosine kinases and serine/threonine kinases. Such compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. The instant compositions can be formulated for various routes of administration, for example, by oral administration, by nasal administration, by rectal administration, subcutaneous injection, intravenous injection, intramuscular injections, or intraperitoneal injection. The following dosage forms are given by way of example and should not be construed as limiting the instant invention.
For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive such as a starch or other additive. Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Optionally, oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art.
Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water. Pharmaceutical formulations and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration.
As noted above, suspensions may include oils. Such oil include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension formulations.
For nasal administration, the pharmaceutical formulations and medicaments may be a spray or aerosol containing an appropriate solvent(s) and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. A propellant for an aerosol formulation may include compressed air, nitrogen, carbon dioxide, or a hydrocarbon based low boiling solvent.
Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Preferably, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.
For injection, the pharmaceutical formulation and/or medicament may be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
For rectal administration, the pharmaceutical formulations and medicaments may be in the form of a suppository, an ointment, an enema, a tablet or a cream for release of compound in the intestines, sigmoid flexure and/or rectum. Rectal suppositories are prepared by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers of the compound, with acceptable vehicles, for example, cocoa butter or polyethylene glycol, which is present in a solid phase at normal storing temperatures, and present in a liquid phase at those temperatures suitable to release a drug inside the body, such as in the rectum. Oils may also be employed in the preparation of formulations of the soft gelatin type and suppositories. Water, saline, aqueous dextrose and related sugar solutions, and glycerols may be employed in the preparation of suspension formulations which may also contain suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as buffers and preservatives.
Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carries are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.
The formulations of the invention may be designed to be short-acting, fast-releasing, long-acting, and sustained-releasing as described below. Thus, the pharmaceutical formulations may also be formulated for controlled release or for slow release.
The instant compositions may also comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the pharmaceutical formulations and medicaments may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants may employ known inert materials such as silicones and biodegradable polymers.
Specific dosages may be adjusted depending on conditions of disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant invention.
A therapeutically effective dose may vary depending upon the route of administration and dosage form. The preferred compound or compounds of the instant invention is a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD50 and ED50. The LD50 is the dose lethal to 50% of the population and the ED50 is the dose therapeutically effective in 50% of the population. The LD50 and ED50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals.
“Treating” within the context of the instant invention, means an alleviation of symptoms associated with a disorder or disease, or halt of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder. For example, within the context of treating patients in need of an inhibitor of VEGF-RTK, successful treatment may include a reduction in the proliferation of capillaries feeding a tumor or diseased tissue, an alleviation of symptoms related to a cancerous growth or tumor, proliferation of capillaries, or diseased tissue, a halting in capillary proliferation, or a halting in the progression of a disease such as cancer or in the growth of cancerous cells. Treatment may also include administering the pharmaceutical formulations of the present invention in combination with other therapies. For example, the compounds and pharmaceutical formulations of the present invention may be administered before, during, or after surgical procedure and/or radiation therapy. The compounds of the invention can also be administered in conjunction with other anti-cancer drugs including those used in antisense and gene therapy. Appropriate combinations can be determined by those of skill in the oncology and medicine arts.
Pharmaceutical formulations and medicaments according to the invention include any of the compounds described above in combination with a pharmaceutically acceptable carrier. Thus, the compounds of the invention may be used to prepare medicaments and pharmaceutical formulations. In some such embodiments, the medicaments and pharmaceutical formulations comprise any of the compounds of any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh group of compounds of formula I or pharmaceutically acceptable salts thereof. The invention also provides for the use of any of the compounds of any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh group of compounds of formula I or pharmaceutically acceptable salts thereof for the inhibition of an enzyme such as flt-1 (VEGFR1), KDR (VEGFR2), Flk-1, bFGFR, GSK-3, CHK-1, NEK-2, cdc 2, or for the treatment of a disease or condition associated with any of these enzymes as described in greater detail below. The invention also provides the use of any of the compounds of any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh group of compounds of formula I or pharmaceutically acceptable salts thereof for the manufacture of enzyme inhibition agent such as a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, a pharmaceutical formulation, or a medicament that inhibits enzymes such as flt-1 (VEGFR1), KDR (VEGFR2), Flk-1, bFGFR, GSK-3, CHK-1, NEK-2, cdc 2, PDGF, and Tie-2 or treats a disease or condition associated with any of these enzymes as described in greater detail below.
A method of treating a patient in need of an inhibitor of vascular endothelial growth factor receptor tyrosine kinase includes administering an effective amount of a pharmaceutical formulation, a medicament according to the invention or any of the compounds of any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh group of compounds of formula I to a patient in need thereof.
A method for inhibiting tumor growth in a patient includes administering an effective amount of the compound, a pharmaceutically acceptable salt thereof of any of the of the first, second, third, fourth, fifth, sixth, and/or seventh groups of compounds of formula I, or a medicament to a patient having a tumor.
A method for inhibiting angiogenesis and tumor growth in a patient includes administering an effective amount of the compound or a pharmaceutically acceptable salt thereof according to a patient in need.
The invention provides a method of treating a subject with various tumor types. The method includes administering to the subject, such as a human subject, a compound according to any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh group of compounds or a pharmaceutically acceptable salt thereof of formula I to the subject. In some such embodiments, the method includes a method of treating a cancer patient.
The invention provides a method of inhibiting an enzyme such as a serine/threonine kinase. The method includes administering to a subject, such as a human subject, a mammalian subject, or a cell subject, a compound according to any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh group of compounds or a pharmaceutically acceptable salt thereof of formula I to the subject. In some such embodiments, the serine/threonine kinase is GSK-3. In other such embodiments, the serine/threonine kinase is CHK-1. In other such embodiments, the serine/threonine kinase is NEK-2.
The invention provides a method of inhibiting an enzyme such as a tyrosine kinase. The method includes administering to a subject, such as a human subject, a mammalian subject, or a cell subject, a compound according to any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh group of compounds or a pharmaceutically acceptable salt thereof of formula I to the subject. In some such embodiments, the tyrosine kinase is VEGF.
The invention provides a method of treating a subject with type II diabetes. The method includes administering to the subject, such as a human subject, a compound according to any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh group of compounds or a pharmaceutically acceptable salt thereof of formula I to the subject. In some such embodiments, the method includes a method of treating a prediabetic or diabetic patient.
The invention provides a method of stimulating insulin-dependent processes in a patient. The method includes administering to the patient, such as a human patient, a compound according to any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh group of compounds of formula I, or a pharmaceutically acceptable salt thereof, to the subject. In some such embodiments, the method includes a method of reducing plasma glucose levels, increasing glycogen uptake, potentiating insulin, upregulating glucose synthase activity, and stimulating glycogen synthesis such as in skin, muscle, and fat cells.
The invention provides a method of treating a subject with Alzheimer's disease. The method includes administering to the subject, such as a human subject, a compound according to any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh group of compounds of formula I, or a pharmaceutically acceptable salt thereof, to the subject. In some such embodiments, the method includes reducing tau hyperphosphorylation, reducing the generation of neurofibrillary tangles, and slowing the progression of Alzheimer's disease.
The invention provides a method of treating a subject with a central nervous system disorder. The method includes administering to the subject, such as a human subject, a compound according to any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh group of compounds of formula I, or a pharmaceutically acceptable salt thereof, to the subject. In some such embodiments, the method includes a method of treating bipolar disorder; increasing the survival of neurons subjected to aberrantly high levels of excitation induced by glutamate; reducing neurodegeneration asscociated with acute damage such as in cerebral ischemia, traumatic brain injury, and bacterial injury; and reducing chronic neuronal damage associated with Alzheimer's disease, Huntington's disease, Parkinson's disease, AIDS associated dementia, amyotrophic lateral sclerosis (AML) and multiple sclerosis.
The invention provides a method of prolonging an immune response in a subject. The method includes administering to the subject, such as a human subject, a compound according to any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh group of compounds of formula I, or a pharmaceutically acceptable salt thereof, to the subject. In some such embodiments, the method includes prolonging and/or potentiating immunostimulatory effects of cytokines, and enhancing the potential of cytokines for immunotherapy such as tumor immunotherapy.
The invention provides a method of reducing the splitting of centrosomes in the cells of a subject. The method includes administering to the subject, such as a human subject, a compound according to any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh group of compounds of formula I, or a pharmaceutically acceptable salt thereof, to the subject. In some such embodiments, the subject is a cancer patient.
The invention provides a method of blocking DNA repair in a cancer cell of a cancer patient. The method includes administering to the patient, such as a human patient, a compound according to any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh group of compounds of formula I, or a pharmaceutically acceptable salt thereof, to the patient.
The invention provides a method of promoting phosphorylation of cdc25 and Wee1 in a patient. The method includes administering to the patient, such as a human patient, a compound according to any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh group of compounds of formula I, or a pharmaceutically acceptable salt thereof, to the patient.
The invention provides a method of modulating and/or preventing cell cycle arrest in a cell. The method includes contacting the cell with a compound according to any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh group of compounds of formula I, or a pharmaceutically acceptable salt thereof. In one method, the cells are defective in the p53 gene and/or have p53 mutations and/or are deficient in p53. In some embodiments, the cells are cancer cells such as those deficient in p53. In some embodiments, arrest at the G2/M checkpoint is prevented or inhibited. In some embodiments, the method includes treating a patient, such as a human patient with any of the compounds of the invention, and in some such further embodiments, the method further includes treating the patient with another therapeutic agent such as a chemotherapeutic agent or with radiation or heat.
A method of preparing pharmaceutical formulations and medicaments includes mixing any of the above-described compounds with a pharmaceutically acceptable carrier.
The present invention, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.
EXAMPLES
Nomenclature for the Example compounds was provided using ACD Name version 5.07 software (Nov. 14, 2001) available from Advanced Chemistry Development, Inc., Chemlnnovation NamExpert+NomenclatorTM brand software available from ChemInnovation Software, Inc., and AutoNom version 2.2 available in the ChemOffice® Ultra software package version 7.0 available from CambridgeSoft Corporation (Cambridge, Mass.). Some of the compounds and starting materials were named using standard IUPAC nomenclature.
The following abbreviations are used throughout the application with respect to chemical terminology:













AcOH:
Acetic acid


ATP:
Adenosine triphosphate


BINAP:
2,2′-Bis(diphenylphosphino)-1,1′-binaplhthyl


Boc:
N-tert-Butoxycarbonyl


Bn:
Benzyl


BSA:
Bovine Serum Albumin


Cbz:
Carbobenzyloxy


DEAD:
Diethyl azodicarboxylate


DIEA:
Diisopropylethylamine


DMA:
N,N-Dimethylacetamide


DMAP:
4-Dimethylaminopyridine


DMF:
N,N-Dimethylformamide


DMSO:
Dimethylsulfoxide


dppf:
1,1′(diphenylphosphino)ferrocene


DTT:
DL-Dithiothreitol


ED50:
Dose therapeutically effective in 50% of the population


EDC or EDCI:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide



hydrochloride


EDTA:
Ethylene diamine tetraacetic acid


EtOAc:
Ethyl acetate


EtOH:
Ethanol


Fmoc:
9-fluorenylmethyl


HBTU:
O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium



hexafluorophosphate


HPLC:
High Pressure Liquid Chromatography


IC50 value:
The concentration of an inhibitor that causes a 50%



reduction in a measured activity.


KHMDS:
Potassium bis(trimethylsilyl)amide


LC/MS:
Liquid Chromatography/Mass Chromatography


LiHMDS:
Lithium bis(trimethylsilyl)amide


MeOH:
Methanol


NMP:
N-methylpyrrolidone


Pd(dba)2:
Bis(dibenzylideneacetone)Palladium


PPTS:
Pyridinium p-toluenesulfonate


Pyr:
Pyridine


SEMCl:
2-(Trimethylsilyl)ethoxymethyl chloride


TBAF:
Tetrabutylammonium fluoride


TEA:
Triethylamine


TES:
Triethylsilyl


TFAA:
Trifluoroacetic anhydride


THF:
Tetrahydrofuran


TMS:
Trimethylsilyl









Purification and Characterization of Compounds
Compounds of the present invention were characterized by high performance liquid chromatography (HPLC) using a Waters Millenium chromatography system with a 2690 Separation Module (Milford, Mass.). The analytical columns were Alltima C-18 reversed phase, 4.6×250 mm from Alltech (Deerfield, Ill.). A gradient elution was used, typically starting with 5% acetonitrile/95% water and progressing to 100% acetonitrile over a period of 40 minutes. All solvents contained 0.1% trifluoroacetic acid (TFA). Compounds were detected by ultraviolet light (UV) absorption at either 220 or 254 nm. HPLC solvents were from Burdick and Jackson (Muskegan, Mich.), or Fisher Scientific (Pittsburg, Pa.). In some instances, purity was assessed by thin layer chromatography (TLC) using glass or plastic backed silica gel plates, such as, for example, Baker-Flex Silica Gel 1B2-F flexible sheets. TLC results were readily detected visually under ultraviolet light, or by employing well known iodine vapor and other various staining techniques.
Mass spectrometric analysis was performed on one of two LCMS instruments: a Waters System (Alliance HT HPLC and a Micromass ZQ mass spectrometer; Column: Eclipse XDB-C18, 2.1×50 mm; Solvent system: 5–95% acetonitrile in water with 0.05% TFA; Flow rate 0.8 mL/min; Molecular weight range 150–850; Cone Voltage 20 V; Column temperature 40° C.) or a Hewlett Packard System (Series 1100 HPLC; Column: Eclipse XDB-C18, 2.1×50 mm; Solvent system: 1–95% acetonitrile in water with 0.05%TFA; Flow rate 0.4 mL/min; Molecular weight range 150–850; Cone Voltage 50 V; Column temperature 30° C.). All masses are reported as those of the protonated parent ions.
GCMS analysis was performed on a Hewlet Packard instrument (HP6890 Series gas chromatograph with a Mass Selective Detector 5973; Injector volume: 1 μL; Initial column temperature: 50° C.; Final column temperature: 250° C.; Ramp time: 20 minutes; Gas flow rate: 1 mL/min; Column: 5% Phenyl Methyl Siloxane, Model #HP 190915-443, Dimensions: 30.0m×25 μm×0.25 μm).
Preparative separations were carried out using either a Flash 40 chromatography system and KP-Sil, 60A (Biotage, Charlottesville, Va.), or by HPLC using a C-18 reversed phase column. Typical solvents employed for the Flash 40 Biotage system were dichloromethane, methanol, ethyl acetate, hexane and triethyl amine. Typical solvents employed for the reverse phase HPLC were varying concentrations of acetonitrile and water with 0.1% trifluoroacetic acid.
Various functionalized aryl diamines were obtained from commercial sources, prepared by methods know to those of skilled in the art, or were prepared by the following general methods:
Method 1




2,4-Difluoronitrobenzene (1.0 equivalent) was placed in a dry round-bottomed flask equipped with a dry ice condenser charged with acetone and dry ice. Ammonia was condensed into the flask and the resulting solution was stirred at reflux for 7 hours. A yellow precipitate formed within 1 hour. After 7 hours, the condenser was removed and the liquid ammonia was allowed to evaporate over several hours. The crude product was purified by flash chromatography on silica gel (85:15 hexanes:ethyl acetate, product at Rf=0.32, contaminant at Rf=0.51); GC/MS (m/z) 156.1 (M+), Rt 11.16 minutes.
The resulting 5-fluoro-2-nitrophenylamine (1.0 equivalent) and an amine (1.1 equivalents) e.g. N-methyl piperazine, were dissolved in N-methylpyrrolidinone and triethylamine (2.0 equivalents) was added. The reaction mixture was heated at 100° C. for 3 hours. The solution was then cooled to room temperature and diluted with water. The resulting precipitate was filtered and dried under vacuum to provide the 2-amino-4-dialkylamino nitrobenzene or 4-dialkylamino nitroaniline. Alternatively, the same product may be obtained by the reaction of commercially available 5-chloro-2-nitrophenylamine (1.0 equivalent) and an amine (5 equivalents; neat). The two are heated at 130° C. for 1–2 days and the product is isolated in an identical manner. LC/MS (m/z) 237.1 (MH+), Rt 1.304 minutes.
The nitroamine (1.0 equivalent) and 10% Pd/C (0.1 equivalents) were suspended in anhydrous ethanol at room temperature. The reaction flask was evacuated and subsequently filled with H2. The resulting mixture was then stirred under a hydrogen atmosphere overnight. The resulting solution was filtered through Celite and concentrated under vacuum to provide the crude product which was used without further purification.
Method 2




A round bottom flask was charged with 2,3-difluoro-6-nitrophenylamine (1 equivalent) and enough NMP to make a viscous slurry. An amine (5 equivalents), e.g. N-methyl piperazine, was added and the solution was heated at 100° C. After 2 hours, the solution was cooled and poured into water. A bright yellow solid formed which was filtered and dried. The nitroamine was reduced as in Method 1 to provide the crude product which was used without further purification. LC/MS (m/z) 225.1 (MH+), Rt 0.335 minutes.
Method 3




To a 0.1 M DMF solution of 1,3-difluoro-2-nitrobenzene was added Et3N (2 equivalents) followed by an amine (1 equivalent), e.g. morpholine. The mixture was stirred for 18 hours and then diluted with water and extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated. LC/MS (m/z): 227.2 (MH+), Rt 2.522 minutes Ammonia was condensed into a bomb containing the crude product. The bomb was sealed and heated to 100° C. (over 400 psi). After 72 hours the bomb was allowed to cool and the ammonia was evaporated to provide a reddish solid. The nitroamine was reduced as in Method 1 to provide the crude product which was used without further purification. LC/MS (m/z) 194.1 (MH+), Rt 1.199 minutes.
Method 4




To a stirred N-methylpyrrolidinone solution containing NaH (1.3 equivalents) was added an alcohol (1.0 equivalent), e.g. 2-methoxyethanol. The resulting mixture was then stirred for 30 minutes. A slurry of 5-fluoro-2-nitrophenylamine in N-methylpyrrolidinone was then added slowly. The mixture was then heated to 100° C. After 2 hours, the reaction mixture was cooled and water was added. The mixture was then filtered and the solid was washed with water and purified by silica gel chromatography (1:1 ethyl acetate:hexane). LC/MS (m/z) 213.2 (MH+), Rt 2.24 minutes. The nitroamine was reduced as in Method 1 to provide the crude product which was used without further purification. LC/MS (m/z) 183.1 (MH+), Rt 0.984 minutes.
Method 5




Diisopropyl azodicarboxylate (1.1 equivalents) was added dropwise to a stirred solution of 4-amino-3-nitrophenol (1.0 equivalent), triphenylphosphine (1.1 equivalents), and an alcohol, e.g. N-(2-hydroxyethyl)morpholine (1.0 equivalent), in tetrahydrofuran at 0° C. The mixture was allowed to warm to room temperature and stirred for 18 hours. The solvent was evaporated, and the product was purified by silica gel chromatography (98:2 CH2Cl2:methanol) to yield 4-(2-morpholin-4-ylethoxy)-2-nitrophenylamine as a dark reddish-brown oil. LC/MS (m/z) 268.0 (MH+), Rt 1.01 minutes. The nitroamine was reduced as in Method 1 to give the crude product which was used without further purification. LC/MS (m/z) 238.3 (MH+), Rt 0.295 minutes.
Method 6




To a flask charged with 4-amino-3-nitrophenol (1 equivalent), K2CO3 (2 equivalents), and 2-butanone was added an alkyl dibromide, e.g. 1,3-dibromopropane (1.5 equivalents). The resulting mixture was then heated at 80° C. for 18 hours. After cooling, the mixture was filtered, concentrated, and diluted with water. The solution was then extracted with CH2Cl2 (3×) and the combined organic layers were concentrated to give a solid that was then washed with pentane. LC/MS (m/z) 275.1 (MH+), Rt 2.74 minutes.
An acetonitrile solution of the bromide prepared above, an amine, e.g. pyrrolidine (5 equivalents), CS2CO3 (2 equivalents) and Bu4NI (0.1 equivalents) was heated at 70° C. for 48 hours. The reaction mixture was cooled, filtered, and concentrated. The residue was dissolved in CH2Cl2, washed with water, and concentrated to give the desired nitroamine, e.g. 2-nitro-4-(3-pyrrolidin-1-ylpropoxy)phenylamine. LC/MS (m/z) 266.2 (MH+), Rt 1.51 minutes. The nitroamine was reduced as in Method 1 to provide the crude product which was used without further purification.
Method 7




To a suspension of 6-chloro-3-nitropyridin-2-amine (1 equivalent) in acetonitrile was added an amine, e.g. morpholine (4 equivalents). The resulting reaction mixture was stirred at 70° C. for 5 hours. The solvent was evaporated under reduced pressure, and the residue triturated with ether to provide the desired compound as a bright yellow powder. LC/MS (m/z) 225.0 (MH+), Rt 1.79 minutes. The nitroamine was reduced as in Method 1 to provide the crude product which was used without further purification.
Method 8
Synthesis of {[(5S,2R)-4-(3-Amino-4-nitrophenyl)-5-methylmorpholin-2-yl]methyl}dimethylamine and {[(5S,2R)-4-(3,4-diaminophenyl)-5-methylmorpholin-2-yl]methyl}dimethylamine
Step 1. Synthesis of (2S)-[benzylamino]propan-1-ol




A mixture of (2S)-2-amino propanol (1.2 equivalents), benzaldehyde (1 equivalent), NaHCO3 (1.5 equivalents) and MeOH, was heated at reflux for 4 hours and then cooled to 0° C. Sodium borohydride (5.0 equivalents)was then added over 1 hour while the reaction was vigorously stirred. The reaction mixture was stirred at room temperature for 4 hours and then filtered over Celite. The filtrate was concentrated, and the residue was dissolved in CH2Cl2. The solution was washed successively with water (×2) and brine (×1). The organic extracts were collected and dried over Na2SO4. The solvent was evaporated to give the desired product as a white solid. GC/MS: 134 (100%, M+—CH2OH), Rt=11.57 minutes.
Step 2. Synthesis of (2S,5S)-2-(chloromethyl)-5-methyl-4-benzylmorpholine




A mixture of (2S)-2-[benzylamino]propan-1-ol (1 equivalent) and epichlorohydrin (1 equivalent) was stirred at room temperature overnight. The mixture was cooled down to 0° C. and cold trifluoromethanesulfonic acid (4 equivalents) was added. The flask was equipped with a reflux condenser and the mixture was stirred at 160° C. overnight. The reaction mixture was cooled to room temperature, diluted with CH2Cl2 and quenched with ice water. The mixture was then made basic (pH=12) with a 30% NaOH solution. The two phases were separated, and the aqueous phase was extracted with CH2Cl2. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to afford a dark brown oil. The crude product contained an equimolar mixture of (2R,5S)-2-(chloromethyl)-5-methyl-4-benzylmorpholine (cis diastereoisomer) and (2S,5S)-2-(chloromethyl)-5-methyl-4-benzylmorpholine (trans diastereoisomer), which were separated by chromatography on silica gel (ethyl acetate/hexanes 1:20 to 1:8). (2S,5S)-2-(chloromethyl)-5-methyl-4-benzyl morpholine was obtained as the isomer with the lower Rf. GC/MS: 239 (15%, M+), Rt=15.08 minutes; LC/MS (m/z): 240.0 (MH+), Rt 1.56 minutes.
Step 3. Synthesis of {[(5S,2R)-5-methyl-4-benzylmorpholin-2-yl]methyl}dimethylamine




A mixture of (2S,5S)-2-(chloromethyl)-5-methyl-4-benzylmorpholine (1 equivalent) and dimethylamine (5 equivalents) in ethanol, was heated at 150° C. for 36 hours in a sealed high pressure vessel. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was taken up in 1 N HCl, and the solution was washed with CH2Cl2. The water phase was made basic with a 30% aq. NaOH solution (pH=12) and extracted with CH2Cl2. The organic extracts were collected and dried over Na2SO4. Evaporation of the solvent under reduced pressure afforded (2S,5S)-2-[dimethylamino(methyl)]-5-methyl-4-benzylmorpholine as a yellow oil. GC/MS: 247 (2%, M-H), 204 (55%, M-NMe2), Rt=15.5 min; LC/MS (m/z): 249.2 (MH+), Rt 0.72 minutes.
Step 4. Synthesis of [((2S,5S)-5-methylmorpholin-2-yl)methyl]dimethylamine




{[(5S,2R)-5-methyl-4-benzylmorpholin-2-yl]methyl}dimethylamine (1 equivalent), was dissolved in EtOH and the solution was transferred to a stainless steel high pressure vessel equipped with a pressure gauge. 10% Pd/C was added (10 wt. %), and the vessel charged with H2. The reaction mixture was stirred at 130° C. and 200 psi of H2 overnight. The reaction mixture was cooled to room temperature, filtered over a pad of Celite, and then evaporated. The desired amine was obtained in quantitative yield as a pale yellow oil. GC/MS: 128 (10%, M+−2×CH3), 58 (100%, NHCH2CHO), Rt=8.16 minutes.
Step 5. Synthesis of {[(5S,2R)-4-(3-amino-4-nitrophenyl)-5-methylmorpholin-2-yl]methyl}dimethylamine




A mixture of 5-fluoro-2-nitroaniline (1.1 equivalents), [((2S,5S)-5-methylmorpholin-2-yl)methyl]dimethylamine (1 equivalent), triethylamine (3 equivalents), and N-methylpyrrolidinone was heated at 140° C. for 48 hours in a sealed high pressure vessel. The reaction mixture was then cooled to 25° C. and dissolved in CH2Cl2. The solution was washed with water (×2) and dried over Na2SO4. Purification via chromatography on silica gel (10% MeOH in dichloromethane) afforded the desired product as a dark yellow foam. LC/MS (m/z) 295.2 (MH+) Rt 1.55 minutes.
Step 6. Synthesis of {[(5S,2R)-4-(3,4-Diaminophenyl)-5-methylmorpholin-2-yl]methyl}dimethylamine




The nitroaniline produced in Step 5 was reduced using the method set forth in Method 1 to provide the crude title compound which was used without further purification.
Method 9
Synthesis of 1,2-diamino-3-methyl-4-fluorobenzene
Step 1. Synthesis of N-(3-fluoro-2-methylphenyl)acetamide




1-amino-3-fluoro-2-methylbenzene (1 equivalent) was dissolved in CH2Cl2 and acetic anhydride (2.0 equivalents) was added slowly. The solution was stirred at room temperature for 4 hours. The reaction mixture was then quenched with water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with H2O, a 10% HCl solution, H2O, and brine. It was then dried over Na2SO4 and concentrated in vacuo, to yield N-(3-fluoro-2-methylphenyl)acetamide as a pink solid. LC/MS (m/z) 168.2 (MH+), Rt 1.91 minutes.
Step 2. Synthesis of 1-amino-3-fluoro-2-methyl-6-nitrobenzene




A mixture of HNO3/H2SO4 (1:1, 60% HNO3:conc. H2SO4) cooled to 0° C. was added dropwise to N-(3-fluoro-2-methylphenyl)acetamide to form a 0.16 M solution. The solution was stirred at 0° C. for 10 minutes and then at room temperature for 30 minutes. The solution was then diluted with water and made basic (pH=10) by addition of 6 N NaOH. The mixture was then extracted CH2Cl2 (3×), dried over Na2SO4, and concentrated in vacuo to yield 1-amino-3-fluoro-2-methyl-6-nitrobenzene (the acetyl group was removed during basic work up). LC/MS (m/z) 171.1 (MH+), Rt 1.87 minutes.
Step 3. Synthesis of 1,2-diamino-4-fluoro-3-methylbenzene




Reduction of the nitro group on 1-amino-3-fluoro-2-methyl-6-nitrobenzene was carried out as described in Method 1 to yield the title compound. LC/MS (m/z) 141.1 (MH+), Rt 0.43 minutes.
Method 10
Synthesis of 4-(4-dimethylamino-2-methylpyrrolidin-1-yl)-1,2-diaminobenzene
Step 1. Synthesis of (2S,4S)-4-dimethylamino-2-methylpyrrolidine




(2S,4S)-4-dimethylamino-2-methylpyrrolidine was synthesized from the Boc-protected cis-4-hydroxy-D-proline methyl ester (available from Bachem) as described in T. Rosen, D. T. W. Chu, I. M. Lico, P. B. Gernandes, K. Marsh, L. Shen, V. G. Cepa, A. G. Pernet, J. Med. Chem., 1988, 31(8), 1598–1611.
Step 2. Synthesis of 3-[(2S,4S)-4-dimethylamino-2-methylpyrrolidin-1-yl]-1-amino-6-nitrobenzene




(2S,4S)-4-dimethylamino-2-methylpyrrolidine (1.0 equivalent) and 1-amino-3-fluoro-6-nitrobenzene (1.2 equivalents) were dissolved in N-methylpyrrolidinone, and Et3N (5.0 equivalents) was added. The solution was heated for 5 hours at 100° C. The solution was then cooled and diluted with water. The aqueous layer was extracted with ethyl acetate. The organic layer was then washed twice with H2O, once with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by column chromatography (1:1 ethyl acetate:hexane to 1:20 MeOH:ethyl acetate to 1:1 MeOH: ethyl acetate to give the title compound as a yellow gum. LC/MS (m/z) 265.2 (MH+), Rt 1.65 minutes.
Step 3. Synthesis of 4-[(2S,4S)-4-dimethylamino-2-methylpyrrolidin-1-yl]-1,2-diaminobenzene




3-[(2S,4S)-4-Dimethylamino-2-methylpyrrolidin-1-yl]-1-amino-6-nitrobenzene was reduced as in Method 1 to afford the title compound. LC/MS (m/z) 235.4 (MH+), Rt 0.37 minutes.
Example 1
3-(1H-Benzimidazol-2-yl)-1H-indazole
Synthesis of 11a,5a-Dihydro-1H-indazolo[2′,3′-2,1]piperazino[4,5-b]1H-indazole-6,12-dione
Indazole-3-carboxylic acid (1.0 equivalents) was dissolved in phosphorus oxychloride (0.05 equivalents) and refluxed. After 4 hours, the mixture was cooled and concentrated in vacuo. The resulting dione was washed three times with benzene, dried, and isolated as a red solid. LC/MS (m/z) 289.1 (MH+), Rt 2.90 minutes. Synthesis of 3-(1H-Benzimidazol-2-yl)-1H-indazole
A toluene solution containing 11a,5a-dihydro-1H-indazolo[2′,3′-2,1]piperazino[4,5-b]1H-indazole-6,12-dione (1.0 equivalent) and phenylenediamine (1.5 equivalents), was heated to 100° C. After 18 hours, the solvent was evaporated and the residue was washed repeatedly with water, followed by methanol, and then filtered. Purification by reverse phase preparatory HPLC gave the title compound as a yellow solid. LC/MS (m/z) 235.3 (MH+), Rt 1.90 minutes.
Example 2
3-(6-Methoxy-1H-benzimidazol-2-yl)-1H-indazole
Procedure 1
A solution of 11a,5a-dihydro-1H-indazolo[2′,3′-2,1]piperazino[4,5-b]1H-indazole-6,12-dione (1.0 equivalent) from Example 1 and 4-methoxy-o-phenylenediamine dihydrochloride (1.5 equivalents) in toluene was heated to 100° C. After 36 hours, the solvent was evaporated and the residue was washed repeatedly with water. The filtrate lyophilized, and the recovered material was purified by reverse phase HPLC yielding the title compound as a grey solid. LC/MS (m/z) 265.3 (MH+), Rt 2.04 minutes.
Procedure 2
A solution containing of 11a,5a-dihydro-1H-indazolo[2′,3′-2,1]piperazino[4,5-b] 1H-indazole-6,12-dione (1.0 equivalent) from Example 1, and 4-methoxy-o-phenylenediamine dihydrochloride (1.5 equivalents) in toluene was heated at reflux. After two days, the solvent was evaporated and the residue was washed repeatedly with water. The filtrate was frozen and lyophilized, and the recovered material was purified by reverse phase HPLC yielding the title compound as a grey solid. LC/MS (m/z) 265.3 (MH+), Rt 2.04 minutes.
Example 3
3-{6-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]-1H-benzimidazol-2-yl}-1H-indazole
Synthesis of 1H-Indazol-3-yl-N-[5-((6S,2R)-2,6-dimethylmorpholin-4-yl)-2-nitrophenyl]carboxamide
A toluene solution containing 5-[cis-(6S,2R)-2,6-dimethylmorpholin-4-yl)]-2-nitroaniline (2.0 equivalents; synthesized following the procedure described in Method 1 starting from 2,6-cis-dimethylmorpholine and omitting the reduction step), 11a,5a-dihydro-1H-indazolo[2′,3′-2, 1]piperazino[4,5-b]1H-indazole-6,12-dione from Example 1 (1.0 equivalent), and Et3N (2.1 equivalents) was heated at reflux for two days. The resulting mixture was then cooled and filtered. The crude material was washed with methanol to provide a brown solid LC/MS (m/z) 396.1 (MH+), Rt 3.44 minutes.
Synthesis of 1H-Indazol-3-yl-N-[5-((6S,2R)-2,6-dimethylmorpholin-4-yl)-2-aminophenyl]carboxamide
To a solution of 1H-indazol-3-yl-N-[5-((6S,2R)-2,6-dimethyl-morpholin-4-yl)-2-nitrophenyl]carboxamide (1.0 equivalent) in ethanol was added 10% Pd/C (0.5 equivalents). The reaction vessel was repeatedly purged with nitrogen, and then the reaction was stirred under a hydrogen atmosphere (1 atm) for 18 hours. The product was filtered through Celite with ethanol. The solvent was removed to provide a brown solid which was used without purification. LC/MS (m/z) 366.2 (MH+), Rt 2.19 minutes.
Synthesis of 3-{6-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]-1H-benzimidazol-2-yl}-1H-indazole
1H-Indazol-3-yl-N-[5-((6S,2R)-2,6-dimethyl-morpholin-4-yl)-2-aminophenyl]carboxamide (1.0 equivalent) was dissolved in acetic acid, and sodium acetate (1.1 equivalents) was added. The solution was heated at reflux for 1 hour and then cooled. The acetic acid was removed, and the residue was triturated with ethyl acetate and filtered. The filtrate was concentrated to provide a green foam which was purified by reverse phase HPLC. LC/MS (m/z) 348.1 (MH+), Rt 2.23 minutes.
Example 4
5-Chloro-3-(5-methyl-1H-benzimidazol-2-yl)-1H-indazole
Procedure 1
A 0.25 M aqueous solution of NaNO2 (1.0 equivalent) was brought to a pH of 2.5 by the addition of dilute HCl. Dioxane was added to the solution (10% by volume). The flask was protected from light with aluminum foil and 5-chloroindole (1.0 equivalent) was added slowly. The solution was stirred vigorously for 2 hours. The solution was then extracted with three portions of ethyl acetate. The organic layers were combined, washed with water, dried over MgSO4, filtered, and concentrated. The product was purified by flash chromatography (ethyl acetate:hexane, 1:1, v/v) yielding 5-chloro-1H-indazole-3-carbaldehyde as a purple solid. LC/MS (m/z) 181.3 (MH+), Rt 2.7 minutes.
A flask was charged with 5-chloro-1H-indazole-3-carbaldehyde (1.0 equivalent) and 3,4-diaminotoluene (1.0 equivalent) in toluene and ethanol (approximately 3:1). The flask was heated to 100° C. for 18 hours. The solvent was evaporated, and the residue purified by reverse phase HPLC to provide the desired product as a white solid. LC/MS (m/z) 283.1 (MH+), Rt 2.5 minutes.
Procedure 2
A 0.05 M solution of NaNO2 (1.0 equivalent) was brought to a pH of 2.5 with the addition of dilute HCl. The flask was protected from light with foil and 5-chloroindole (1.0 equivalent) was added slowly. The solution was left to stir vigorously for 2 hours. The solution was then filtered and extracted with three portions of ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The product was purified by flash chromatography (ethyl acetate:hexane, 1:1, v/v) yielding a purple solid. LC/MS (m/z) 181.3 (MH+), Rt 2.7 minutes.
A flask was charged with 5-chloro-1H-indazole-3-carbaldehyde (1.0 equivalent) and 3,4-diaminotoluene (1.0 equivalent) in toluene and EtOH. The reaction mixture was heated to 100° C. for 18 hours. The solvent was then evaporated, and the residue was purified by reverse phase HPLC yielding a white solid. LC/MS (m/z) 283.1 (MH+), Rt 2.5 minutes.
Examples 5–670
Examples 5–670 were synthesized following the indole modification and coupling procedure of Example 4. The aryl diamine and the indole precursors are readily recognizable by one skilled in the art and are commercially available from Aldrich (Milwaukee, Wis.) or Acros Organics (Pittsburgh, Pa). 5-Fluoro-6-chloroindole, 6-(trifluoromethyl)indole, 6-nitroindole, and 5-carbethoxyindole may be obtained from Biosynth International (Naperville, Ill.). 5,6-Difluoroindole and 4,6-difluoroindole may be obtained from Asymchem International, Inc. (Durham, N.C.). 5,6-Methylenedioxyindole may be obtained from Maybridge Chemical Company Ltd. (Cornwall, UK). N-(4-Morpholinoethyl)indole-6-carboxamide may be obtained from Peakdale Molecular (High Peak, UK). The preparation for some of the compounds employed is described in the various methods disclosed herein.














LC/MS




(m/z)


Example
Name
(MH+)

















5
3-(5-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-indazole
320.1


6
5-chloro-3-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1H-
382.1



benzimidazol-2-yl}-1H-indazole


7
3-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1H-
366.2



benzimidazol-2-yl}-5-fluoro-1H-indazole


8
3-{5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-
347.2



benzimidazol-2-yl}-1H-indazole


9
3-{5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-
365.2



benzimidazol-2-yl}-5-fluoro-1H-indazole


10
3-[5-(3-pyrrolidin-1-ylpropoxy)-1H-benzimidazol-2-yl]-1H-
362.3



indazole


11
5-fluoro-3-[5-(3-pyrrolidin-1-ylpropoxy)-1H-benzimidazol-
380.1



2-yl]-1H-indazole


12
6-fluoro-3-[5-(3-pyrrolidin-1-ylpropoxy)-1H-benzimidazol-
380.1



2-yl]-1H-indazole


13
6-chloro-3-[5-(3-pyrrolidin-1-ylpropoxy)-1H-benzimidazol-
396.1



2-yl]-1H-indazole


14
3-[5-(3-pyrrolidin-1-ylpropoxy)-1H-benzimidazol-2-yl]-1H-
387.2



indazole-5-carbonitrile


15
3-[5-(2-methoxyethoxy)-1H-benzimidazol-2-yl]-1H-indazole
309.2


16
5-fluoro-3-[5-(2-methoxyethoxy)-1H-benzimidazol-2-yl]-1H-indazole
327.2


17
6-fluoro-3-[5-(2-methoxyethoxy)-1H-benzimidazol-2-yl]-
327.2



1H-indazole


18
3-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1H-
366.3



benzimidazol-2-yl}-6-fluoro-1H-indazole


19
6-chloro-3-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1H-
382.3



benzimidazol-2-yl}-1H-indazole


20
ethyl {4-[2-(1H-indazol-3-yl)-1H-benzimidazol-5-
405.3



yl]piperazin-1-yl}acetate


21
(3S)-1-[2-(1H-indazol-3-yl)-1H-benzimidazol-5-yl]-N,N-
347.1



dimethylpyrrolidin-3-amine


22
2-(1H-indazol-3-yl)-5-morpholin-4-yl-1H-imidazo[4,5-b]pyridine
321.3


23
2-(6-fluoro-1H-indazol-3-yl)-5-morpholin-4-yl-1H-
339.1



imidazo[4,5-b]pyridine


24
2-(5-methoxy-1H-indazol-3-yl)-5-morpholin-4-yl-1H-
351.3



imidazo[4,5-b]pyridine


25
3-(5-morpholin-4-yl-1H-imidazo[4,5-b]pyridin-2-yl)-1H-
346.3



indazole-5-carbonitrile


26
5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(1H-indazol-3-yl)-
348.2



1H-imidazo[4,5-b]pyridine


27
5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(6-fluoro-1H-
366.2



indazol-3-yl)-1H-imidazo[4,5-b]pyridine


28
5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(5-methoxy-1H-
378.3



indazol-3-yl)-1H-imidazo[4,5-b]pyridine


29
3-[6-(pyridin-3-ylmethoxy)-1H-benzimidazol-2-yl]-1H-
342.2



indazole


30
6-fluoro-3-[6-(pyridin-3-ylmethoxy)-1H-benzimidazol-2-yl]-
359.8



1H-indazole


31
6-chloro-5-fluoro-3-[6-(pyridin-3-ylmethoxy)-1H-
393.8



benzimidazol-2-yl]-1H-indazole


32
4,6-difluoro-3-[6-(pyridin-3-ylmethoxy)-1H-benzimidazol-
377.9



2-yl]-1H-indazole


33
3-[6-(pyridin-3-ylmethoxy)-1H-benzimidazol-2-yl]-1H-
367.1



indazole-5-carbonitrile


34
6-fluoro-3-[6-(pyridin-4-ylmethoxy)-1H-benzimidazol-2-yl]-
360.2



1H-indazole


35
4,6-difluoro-3-[6-(pyridin-4-ylmethoxy)-1H-benzimidazol-
377.2



2-yl]-1H-indazole


36
1′-[2-(1H-indazol-3-yl)-1H-benzimidazol-6-yl]-1,4′-
401.3



bipiperidine


37
1′-[2-(6-fluoro-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-
419.3



1,4′-bipiperidine


38
1′-[2-(6-chloro-5-fluoro-1H-indazol-3-yl)-1H-benzimidazol-
453.3



6-yl]-1,4′-bipiperidine


39
1′-[2-(4,6-difluoro-1H-indazol-3-yl)-1H-benzimidazol-6-
437.2



yl]-1,4′-bipiperidine


40
3-[6-(4-cyclohexylpiperazin-1-yl)-1H-benzimidazol-2-yl]-
401.3



1H-indazole


41
3-[6-(4-cyclohexylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
419.3



fluoro-1H-indazole


42
6-chloro-3-[6-(4-cyclohexylpiperazin-1-yl)-1H-
453.3



benzimidazol-2-yl]-5-fluoro-1H-indazole


43
3-[6-(4-cyclohexylpiperazin-1-yl)-1H-benzimidazol-2-yl]-
437.2



4,6-difluoro-1H-indazole


44
3-[6-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-
361.2



indazole


45
3-[6-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
379.2



fluoro-1H-indazole


46
3-[5-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4,6-
397.2



difluoro-1H-indazole


47
3-[6-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
413.1



chloro-5-fluoro-1H-indazole


48
2-(1H-indazol-3-yl)-N-methyl-N-(1-methylpiperidin-4-yl)-
362.2



1H-benzimidazol-6-amine


49
2-(6-fluoro-1H-indazol-3-yl)-N-methyl-N-(1-
379.2



methylpiperidin-4-yl)-1H-benzimidazol-6-amine


50
2-(4,6-difluoro-1H-indazol-3-yl)-N-methyl-N-(1-
397.2



methylpiperidin-4-yl)-1H-benzimidazol-6-amine


51
2-(6-chloro-5-fluoro-1H-indazol-3-yl)-N-methyl-N-(1-
413.2



methylpiperidin-4-yl)-1H-benzimidazol-6-amine


52
2-(5-fluoro-1H-indazol-3-yl)-N-methyl-N-(1-
379.2



methylpiperidin-4-yl)-1H-benzimidazol-6-amine


53
2-(4-chloro-1H-indazol-3-yl)-N-methyl-N-(1-
395.2



methylpiperidin-4-yl)-1H-benzimidazol-6-amine


54
2-(4-fluoro-1H-indazol-3-yl)-N-methyl-N-(1-
379.3



methylpiperidin-4-yl)-1H-benzimidazol-6-amine


55
3-[6-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-1H-
345.2



benzimidazol-2-yl]-1H-indazole


56
6-fluoro-3-[6-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-
363.2



1H-benzimidazol-2-yl]-1H-indazole


57
4,6-difluoro-3-[6-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-
381.2



yl)-1H-benzimidazol-2-yl]-1H-indazole


58
6-chloro-5-fluoro-3-[6-(5-methyl-2,5-
397.2



diazabicyclo[2.2.1]hept-2-yl)-1H-benzimidazol-2-yl]-1H-



indazole


59
5-fluoro-3-[6-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-
363.2



1H-benzimidazol-2-yl]-1H-indazole


60
4-chloro-3-[6-(5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-
379.2



1H-benzimidazol-2-yl]-1H-indazole


61
4-fluoro-3-[6-(5-methyl-2,5-diazabicyclo [2.2.1]hept-2-yl)-
363.2



1H-benzimidazol-2-yl]-1H-indazole


62
3-[6-(4-isopropylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-
361.3



indazole


63
6-fluoro-3-[6-(4-isopropylpiperazin-1-yl)-1H-benzimidazol-
379.3



2-yl]-1H-indazole


64
6-chloro-5-fluoro-3-[6-(4-isopropylpiperazin-1-yl)-1H-
413.2



benzimidazol-2-yl]-1H-indazole


65
5-fluoro-3-[6-(4-isopropylpiperazin-1-yl)-1H-benzimidazol-
379.3



2-yl]-1H-indazole


66
4-fluoro-3-[6-(4-isopropylpiperazin-1-yl)-1H-benzimidazol-
395.2



2-yl]-1H-indazole


67
4-fluoro-3-[6-(4-isopropylpiperazin-1-yl)-1H-benzimidazol-
379.3



2-yl]-1H-indazole


68
5,6-difluoro-3-[6-(4-isopropylpiperazin-1-yl)-1H-
397.2



benzimidazol-2-yl]-1H-indazole


69
4-{[2-(1H-indazol-3-yl)-1H-benzimidazol-6-yl]oxy}-N-
385.1



methylpyridine-2-carboxamide


70
4-{[2-(5-methoxy-1H-indazol-3-yl)-1H-benzimidazol-6-
415.2



yl]oxy}-N-methylpyridine-2-carboxamide


71
4-{[2-(6-chloro-5-fluoro-1H-indazol-3-yl)-1H-
437.1



benzimidazol-6-yl]oxy}-N-methylpyridine-2-carboxamide


72
4-{[2-(5-fluoro-1H-indazol-3-yl)-1H-benzimidazol-6-
403.1



yl]oxy}-N-methylpyridine-2-carboxamide


73
4-{[2-(4-fluoro-1H-indazol-3-yl)-1H-benzimidazol-6-
403.1



yl]oxy}-N-methylpyridine-2-carboxamide


74
4-{[2-(6-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-
419.1



yl]oxy}-N-methylpyridine-2-carboxamide


75
6-methoxy-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-
363.1



2-yl]-1H-indazole


76
3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-
333.1



indazole


77
5-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
367.1



yl]-1H-indazole


78
5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
351.1



yl]-1H-indazole


79
5-methoxy-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-
363.1



2-yl]-1H-indazole


80
2-(1H-indazol-3-yl)-3H-imidazo[4,5-b]pyridine
236.1


81
3-[4-chloro-6-(trifluoromethyl)-1H-benzimidazol-2-yl]-1H-
337.1



indazole


82
2-(1H-indazol-3-yl)-1H-benzimdazole-6-carboxylic acid
279.1


83
3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5-
378.2



nitro-1H-indazole


84
methyl 3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
391.1



yl]-1H-indazole-5-carboxylate


85
3-(5-fluoro-6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-
338.2



indazole


86
3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-
358.4



indazole-5-carbonitrile


87
4,6-difluoro-3-[5-(4-methylpiperazin-1-yl)-1H-
369.1



benzimidazol-2-yl]-1H-indazole


88
6-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
351.1



yl]-1H-indazole


89
6-chloro-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-
385.1



benzimidazol-2-yl]-1H-indazole


90
5-chloro-3-[5-(2-methoxyethoxy)-1H-benzimidazol-2-yl]-
343.2



1H-indazole


91
4,6-difluoro-3-[5-(2-methoxyethoxy)-1H-benzimidazol-2-
345.2



yl]-1H-indazole


92
6-chloro-5-fluoro-3-[5-(2-methoxyethoxy)-1H-
361.1



benzimidazol-2-yl]-1H-indazole


93
3-[5-(2-methoxyethoxy)-1H-benzimidazol-2-yl]-1H-
334.1



indazole-5-carbonitrile


94
1-[2-(6-chloro-5-fluoro-1H-indazol-3-yl)-4-methyl-1H-
353.2



benzimidazol-5-yl]-N,N-dimethylpyrrolidin-3-amine


95
1-[2-(5-methoxy-1H-indazol-3-yl)-4-methyl-1H-
391.3



benzimidazol-5-yl]-N,N-dimethylpyrrolidin-3-amine


96
1-[2-(1H-indazol-3-yl)-4-methyl-1H-benzimidazol-5-yl]-
361.3



N,N-dimethylpyrrolidin-3-amine


97
1-[2-(6-chloro-5-fluoro-1H-indazol-3-yl)-4-methyl-1H-
413.2



benzimidazol-5-yl]-N,N-dimethylpyrrolidin-3-amine


98
3-(5-morpholin-4-yl-1H-imidazo[4,5-b]pyridin-2-yl)-1H-
365.2



indazole-5-carboxylic acid


99
2-(4,6-difluoro-1H-indazol-3-yl)-5-morpholin-4-yl-1H-
357.2



imidazo[4,5-b]pyridine


100
2-(6-chloro-5-fluoro-1H-indazol-3-yl)-5-morpholin-4-yl-1H-
373.2



imidazo [4,5-b]pyridine


101
ethyl 4-[2-(5,6-difluoro-1H-indazol-3-yl)-1H-benzimidazol-
427.2



5-yl]piperazine-1-carboxylate


102
ethyl 4-[2-(6-fluoro-1H-indazol-3-yl)-1H-benzimidazol-5-
409.2



yl]piperazine-1-carboxylate


103
ethyl 4-[2-(1H-indazol-3-yl)-1H-benzimidazol-5-
391.2



yl]piperazine-1-carboxylate


104
ethyl 4-[2-(4-fluoro-1H-indazol-3-yl)-1H-benzimidazol-5-
409.2



yl]piperazine-1-carboxylate


105
1′-{2-[5-(benzyloxy)-1H-indazol-3-yl]-1H-benzimidazol-5-
507.4



yl}-1,4′-bipiperidine


106
1′-[2-(4-bromo-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-
479.0



1,4′-bipiperidine


107
1′-[2-(5-methyl-1H-indazol-3-yl)-1H-benzimidazol-5-yl]-
415.0



1,4′-bipiperidine


108
1′-[2-(4-fluoro-1H-indazol-3-yl)-1H-benzimidazol-5-yl]-
419.0



1,4′-bipiperidine


109
1′-[2-(4-chloro-1H-indazol-3-yl)-1H-benzimidazol-5-yl]-
435.0



1,4′-bipiperidine


110
1′-]2-(5-nitro-1H-indazol-3-yl)-1H-benzimidazol-5-yl]-1,4′-
446.0



bipiperidine


111
3-[4-fluoro-5-(4-methylpiperazine-1-yl)-1H-benzimidazol-2-
351.0



yl]-1H-indazole


112
4-fluoro-3-[4-fluoro-5-(4-methylpiperazin-1-yl)-1H-
369.0



benzimidazol-2-yl]-1H-indazole


113
4-chloro-3-[4-fluoro-5-(4-methylpiperazin-1-yl)-1H-
385.0



benzimidazol-2-yl]-1H-indazole


114
5-fluoro-3-[4-fluoro-5-(4-methylpiperazin-1-yl)-1H-
369.0



benzimidazol-2-yl]-1H-indazole


115
6-fluoro-3-[4-fluoro-5-(4-methylpiperazin-1-yl)-1H-
369.0



benzimidazol-2-yl]-1H-indazole


116
3-[4-fluoro-5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-
381.0



yl]-5-(methyloxy)-1H-indazole


117
6-chloro-5-fluoro-3-[4-fluoro-5-(4-methylpiperazin-1-yl)-
403.0



1H-benzimidazol-2-yl]-1H-indazole


118
5,6-difluoro-3-[4-fluoro-5-(4-methylpiperazin-1-yl)-1H-
387.0



benzimidazol-2-yl]-1H-indazole


119
4-{[2-(4-bromo-1H-indazol-3-yl)-1H-benzimidazol-6-
464.3



yl]oxy}-N-methylpyridine-2-carboxamide


120
3-(7-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-indazole
320.4


121
4-fluoro-3-(7-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-
338.4



indazole


122
5-methyl-3-(7-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-
334.4



indazole


123
5-fluoro-3-(7-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-
338.4



indazole


124
6-chloro-3-(7-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-
354.8



indazole


125
5-methoxy-3-(7-morpholin-4-yl-1H-benzimidazol-2-yl)-
350.4



1H-indazole


126
5,6-difluoro-3-(4-morpholin-4-yl-1H-benzimidazol-2-yl)-
356.3



1H-indazole


127
6-chloro-5-fluoro-3-(4-morpholin-4-yl-1H-benzimidazol-
372.8



2-yl)-1H-indazole


128
2-(1H-indazo1-3-yl)-N-(pyridin-4-ylmethyl)-1H-
341.4



benzimidazol-6-amine


129
2-(5-methoxy-1H-indazol-3-yl)-N-(pyridin-4-ylmethyl)-
371.4



1H-benzimidazol-6-amine


130
2-(6-chloro-5-fluoro-1H-indazol-3-yl)-N-(pyridin-4-
393.8



ylmethyl)-1H-benzimidazol-6-amine


131
2-(5-fluoro-1H-indazol-3-yl)-N-(pyridin-4-ylmethyl)-1H-
359.4



benzimidazol-6-amine


132
2-(4-bromo-1H-indazo1-3-yl)-N-(pyridin-4-ylmethyl)-1H-
420.3



benzimidazol-6-amine


133
2-(4-fluoro-1H-indazo1-3-yl)-N-(pyridin-4-ylmethyl)-1H-
359.4



benzimidazol-6-amine


134
2-(6-chloro-1H-indazol-3-yl)-N-(pyridin-4-ylmethyl)-1H-
375.8



benzimidazol-6-amine


135
2-(1H-indazol-3-yl)-N-(2-pyridin-2-ylethyl)-1H-
355.4



benzimidazol-6-amine


136
2-(5-methoxy-1H-indazol-3-yl)-N-(2-pyridin-2-ylethyl)-
385.4



1H-benzimidazol-6-amine


137
2-(6-chloro-5-fluoro-1H-indazol-3-yl)-N-(2-pyridin-2-
407.9



ylethyl)-1H-benzimidazol-6-amine


138
2-(5-fluoro-1H-indazo1-3-yl)-N-(2-pyridin-2-ylethyl)-1H-
373.4



benzimidazol-6-amine


139
2-(4-fluoro-1H-indazol-3-yl)-N-(2-pyridin-2-ylethyl-1H-
373.4



benzimidazol-6-amine


140
2-(6-chloro-1H-indazol-3-yl)-N-(2-pyridin-2-ylethyl)-1H-
389.9



benzimidazol-6-amine


141
2-(1H-indazol-3-yl)-N-(pyridin-3-ylmethyl)-1H-
341.4



benzimidazol-6-amine


142
2-(5-methoxy-1H-indazol-3-yl)-N-(pyridin-3-ylmethyl)-
371.4



1H-benzimidazol-6-amine


143
2-(6-chloro-5-fluoro-1H-indazol-3-yl)-N-(pyridin-3-
393.8



ylmethyl)-1H-benzimidazol-6-amine


144
2-(5-fluoro-1H-indazol-3-yl)-N-(pyridin-3-ylmethyl)-1H-
359.4



benzimidazol-6-amine


145
2-(1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine
236.2


146
2-(6-chloro-5-fluoro-1H-indazol-3-yl)-3H-imidazo[4,5-
288.7



c]pyridine


147
2-(5-fluoro-1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine
254.2


148
2-(6-chloro-1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine
270.7


149
2-(6-fluoro-1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine
254.2


150
2-(5-chloro-1H-indazol-3-yl)-3H-imidazo[4,5-c]pyridine
270.7


151
4-fluoro-3-[6-(3-pyrrolidin-1-ylpropoxy)-1H-
380.4



benzimidazol-2-yl]-1H-indazole


152
5-isopropoxy-3-[6-(3-pyrrolidin-1-ylpropoxy)-1H-
420.5



benzimidazol-2-yl]-1H-indazole


153
5-methoxy-3-[6-(3-pyrrolidin-1-ylpropoxy)-1H-
392.5



benzimidazol-2-yl]-1H-indazole


154
5-chloro-3-[6-(3-pyrrolidin-1-ylpropoxy)-1H-
396.9



benzimidazol-2-yl]-1H-indazole


155
4,6-difluoro-3-[6-(3-pyrrolidin-1-ylpropoxy)-1H-
398.4



benzimidazol-2-yl]-1H-indazole


156
6-chloro-5-fluoro-3-[6-(3-pyrrolidin-1-ylpropoxy)-1H-
414.9



benzimidazol-2-yl]-1H-indazole


157
3-[6-(1,4′-bipiperidin-1′-yl)-1H-benzimidazol-2-yl]-N-(2-
557.7



morpholin-4-ylethyl)-1H-indazole-6-carboxamide


158
1′-[2-(6-nitro-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-
446.5



1,4′-bipiperidine


159
3-[6-(1,4′-bipiperidin-1′-yl)-1H-benzimidazol-2-yl]-1H-
426.5



indazole-5-carbonitrile


160
methyl 3-[6-(1,4′-bipiperidin-1′-yl)-1H-benzimidazol-2-
459.6



yl]-1H-indazole-5-carboxylate


161
1′-[2-(5-phenoxy-1H-indazol-3-yl)-1H-benzimidazol-6-
493.6



yl]-1,4′-bipiperidine


162
2-(4-fluoro-1H-indazol-3-yl)-N-(pyridin-3-ylmethyl)-1H-
359.4



benzimidazol-6-amine


163
2-(6-chloro-1H-indazol-3-yl)-N-(pyridin-3-ylmethyl)-1H-
375.8



benzimidazol-6-amine


164
2-(5-isopropoxy-1H-indazol-3-yl)-N-(pyridin-3-ylmethyl)-
399.5



1H-benzimidazol-6-amine


165
8-(5-fluoro-1H-indazol-3-yl)-9H-purine
255.2


166
8-(6-fluoro-1H-indazol-3-yl)-9H-purine
255.2


167
6-bromo-2-(5-methoxy-1H-indazol-3-yl)-3H-imidazo[4,5-
345.2



b]pyridine


168
6-bromo-2-(5-fluoro-1H-indazol-3-yl)-3H-imidazo[4,5-
333.1



b]pyridine


169
6-bromo-2-(4-bromo-1H-indazol-3-yl)-3H-imidazo[4,5-
394.0



b]pyridine


170
8-(6-chloro-1H-indazol-3-yl)-6-methyl-9H-purine
285.7


171
8-(5-isopropoxy-1H-indazol-3-yl)-6-methyl-9H-purine
309.3


172
N-{3-[6-(1,4′-bipiperidin-1′-yl)-1H-benzimidazol-2-yl]-
487.6



1H-indazol-5-yl}-N′-ethylurea


173
1′-[2-(1H-indazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-yl]-
402.5



1,4′-bipiperidine


174
1′-[2-(4-bromo-1H-indazo1-3-yl)-3H-imidazo[4,5-
481.4



b]pyridin-5-yl]-1,4′-bipiperidine


175
1′-[2-(5-chloro-1H-indazol-3-yl)-3H-imidazo[4,5-
437.0



b]pyridin-5-yl]-1,4′-bipiperidine


176
1′-[2-(5-nitro-1H-indazol-3-yl)-3H-imidazo[4,5-b]pyridin-
447.5



5-yl]-1,4′-bipiperidine


177
1′-[2-(5-isopropoxy-1H-indazol-3-yl)-3H-indazo[4,5-
460.6



b]pyridin-5-yl]-1,4′-bipiperidine


178
8-(1H-indazol-3-yl)-6-methyl-9H-purine
251.3


179
8-(5-methoxy-1H-indazol-3-yl)-6-methyl-9H-purine
281.3


180
8-(5-fluoro-1H-indazol-3-yl)-6-methyl-9H-purine
269.3


181
3-(5-fluoro-4-methyl-1H-benzimidazol-2-yl)-1H-indazole
267.3


182
3-(5-fluoro-4-methyl-1H-benzimidazol-2-yl)-5-methoxy-
297.3



1H-indazole


183
3-(5-fluoro-4-methyl-1H-benzimidazol-2-yl)-N-(2-
423.5



morpholin-4-ylethyl)-1H-indazole-6-carboxamide


184
3-[6-(1,4′-bipiperidin-1′-yl)-1H-benzimidazol-2-yl]-N-(5-
538.6



nitropyridin-2-yl)-1H-indazol-5-amine


185
1-{1-[2-(1H-indazol-3-yl)-1H-benzimidazol-5-
450.5



yl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one


186
1-{1-[2-(4-bromo-1H-indazol-3-yl)-1H-benzimidazol-5-
529.4



yl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one


187
1-{1-[2-(5-fluoro-1H-indazol-3-yl)-1H-benzimidazol-5-
468.5



yl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one


188
1-{1-[2-(5-methoxy-1H-indazol-3-yl)-1H-benzimidazol-5-
480.5



yl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one


189
1-{1-[2-(5-nitro-1H-indazol-3-yl)-1H-benzimidazol-5-
495.5



yl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one


190
2-{4-[2-(5-fluoro-1H-indazol-3-yl)-1H-benzimidazol-6-
381.4



yl]piperazin-1-yl}ethanol


191
2-{4-[2-(5-methoxy-1H-indazol-3-yl)-1H-benzimidazol-6-
393.5



yl]piperazin-1-yl}ethanol


192
2-{4-[2-(5-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-
397.9



yl]piperazin-1-yl}ethanol


193
2-{4-[2-(5-nitro-1H-indazol-3-yl)-1H-benzimidazol-6-
408.4



yl[piperazin-1-yl}ethanol


194
methyl 3-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-1H-
421.5



benzimidazol-2-yl}-1H-indazole-5-carboxylate


195
2-{4-[2-(5-isopropoxy-1H-indazol-3-yl)-1H-benzimidazol-
421.5



6-yl]piperazin-1-yl}ethanol


196
2-{4-[2-(6-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-
397.9



yl]piperazin-1-yl}ethanol


197
2-{4-[2-(5-ethoxy-1H-indazol-3-yl)-1H-benzimidazol-6-
407.5



yl]piperazin-1-yl}ethanol


198
2-{4-[2-(5-phenoxy-1H-indazol-3-yl)-1H-benzimidazol-6-
455.5



yl]piperazin-1-yl}ethanol


199
2-{4-[2-(6-nitro-1H-indazol-3-yl)-1H-benzimidazol-6-
408.4



yl]piperazin-1-yl}ethanol


200
3-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-1H-benzimidazol-
519.6



2-yl}-N-(2-morpholin-4-ylethyl)-1H-indazole-6-



carboxamide


201
2-(6-chloro-1H-indazol-3-yl)-N-piperidin-3-yl-1H-
367.9



benzimidazol-6-amine


202
2-(6-chloro-1H-indazol-3-yl)-N-[(5R)-5-
397.9



(methoxymethyl)pyrrolidin-3-yl]-1H-benzimidazol-6-



amine


203
6-chloro-3-{5-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-
421.9



yl]-1H-benzimidazol-2-yl}-1H-indazole


204
6-fluoro-3-{5-[2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-
405.5



yl]-1H-benzimidazol-2-yl}-1H-indazole


205
5-(benzyloxy)-3-{5-[(2S)-2-(pyrrolidin-1-
493.6



ylmethyl)pyrrolidin-1-yl]-1H-benzimidazol-2-yl}-1H-



indazole


206
5-methoxy-3-{5-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-
417.5



1-yl]-1H-benzimidazol-2-yl}-1H-indazole


207
2-(1H-indazol-3-yl)-N-(2-pyridin-3-ylethyl)-1H-
355.4



benzimidazol-5-amine


208
2-(5-fluoro-1H-indazol-3-yl)-N-(2-pyridin-3-ylethyl)-1H-
373.4



benzimidazol-5-amine


209
2-(5-methoxy-1H-indazol-3-yl)-N-(2-pyridin-3-ylethyl)-
385.4



1H-benzimidazol-5-amine


210
2-(5-chloro-1H-indazol-3-yl)-N-(2-pyridin-3-ylethyl)-1H-
389.9



benzimidazol-6-amine


211
2-(5-nitro-1H-indazol-3-yl)-N-(2-pyridin-3-ylethyl)-1H-
400.4



benzimidazol-6-amine


212
methyl 3-{6-[(2-pyridin-3-ylethyl)amino]-1H-
413.5



benzimidazol-2-yl}-1H-indazole-5-carboxylate


213
2-(5-isopropoxy-1H-indazol-3-yl)-N-(2-pyridin-3-ylethyl)-
413.5



1H-benzimidazol-6-amine


214
2-(6-fluoro-1H-indazol-3-yl)-N-(2-pyridin-3-ylethyl)-1H-
373.4



benzimidazol-6-amine


215
2-(6-chloro-1H-indazol-3-yl)-N-(2-pyridin-3-ylethyl)-1H-
389.9



benzimidazol-6-amine


216
2-(6-methoxy-1H-indazol-3-yl)-N-(2-pyridin-3-ylethyl)-
385.4



1H-benzimidazol-6-amine


217
2-(5-ethoxy-1H-indazol-3-yl)-N-(2-pyridin-3-ylethyl)-1H-
399.5



benzimidazol-6-amine


218
2-(5-phenoxy-1H-indazol-3-yl)-N-(2-pyridin-3-ylethyl)-
447.5



1H-benzimidazol-6-amine


219
2-(6-nitro-1H-indazol-3-yl)-N-(2-pyridin-3-ylethyl)-1H-
400.4



benzimidazol-6-amine


220
2-(5-chloro-1H-indazol-3-yl)-N-[3-(1H-imidazol-1-
392.9



yl)propyl]-1H-benzimidazol-6-amine


221
N-[3-(1H-imidazol-1-yl)propyl]-2-(5-methoxy-1H-indazol-
388.4



3-yl)-1H-benzimidazol-6-amine


222
N-[3-(1H-imidazol-1-yl)propyl]-2-(5-nitro-1H-indazol-3-
403.4



yl)-1H-benzimidazol-6-amine


223
methyl 3-(6-{[3-(1H-imidazol-1-yl)propyl]amino}-1H-
416.5



benzimidazol-2-yl)-1H-indazole-5-carboxylate


224
3-(6-{[3-(1H-imidazol-1-yl)propyl]amino}-1H-
383.4



benzimidazol-2-yl)-1H-indazole-5-carbonitrile


225
2-[5-(benzyloxy)-1H-indazol-3-yl]-N-[3-(1H-imidazol-1-
464.5



yl)propyl]-1H-benzimidazol-6-amine


226
N-[3-(1H-imidazol-1-yl)propyl]-2-(5-isopropoxy-1H-
416.5



indazol-3-yl)-1H-benzimidazol-6-amine


227
2-(6-fluoro-1H-indazol-3-yl)-N-[3-(1H-imidazol-1-
376.4



yl)propyl]-1H-benzimidazol-6-amine


228
2-(6-chloro-1H-indazol-3-yl)-N-[3-(1H-imidazol-1-
392.9



yl)propyl]-1H-benzimidazol-6-amine


229
2-(5-ethoxy-1H-indazol-3-yl)-N-[3-(1H-imidazol-1-
402.5



yl)propyl]-1H-benzimidazol-6-amine


230
N-[3-(1H-imidazol-1-yl)propyl]-2-(6-nitro-1H-indazol-3-
403.4



yl)-1H-benzimidazol-6-amine


231
2-(1H-indazol-3-yl)-N-(2-morpholin-4-ylethyl)-1H-
363.4



benzimidazol-6-amine


232
2-(5-chloro-1H-indazol-3-yl)-N-(2-morpholin-4-ylethyl)-
397.9



1H-benzimidazol-6-amine


233
2-(5-methoxy-1H-indazol-3-yl)-N-(2-morpholin-4-
393.5



ylethyl)-1H-benzimidazol-6-amine


234
2-[5-(benzyloxy)-1H-indazol-3-yl]-N-(2-morpholin-4-
469.6



ylethyl)-1H-benzimidazol-6-amine


235
2-(6-fluoro-1H-indazol-3-yl)-N-(2-morpholin-4-ylethyl)-
381.4



1H-benzimidazol-6-amine


236
2-(6-chloro-1H-indazol-3-yl)-N-(2-morpholin-4-ylethyl)-
397.9



1H-benzimidazol-6-amine


237
2-(5-ethoxy-1H-indazol-3-yl)-N-(2-morpholin-4-ylethyl)-
407.5



1H-benzimidazol-6-amine


238
N-(2-morpholin-4-ylethyl)-2-(6-nitro-1H-indazol-3-yl)-
408.4



1H-benzimidazol-6-amine


239
5-chloro-3-[6-(4-isopropylpiperazin-1-yl)-1H-
395.9



benzimidazol-2-yl]-1H-indazole


240
5-bromo-3-[6-(4-isopropylpiperazin-1-yl)-1H-
440.4



benzimidazol-2-yl]-1H-indazole


241
3-[6-(4-isopropylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5-
391.5



methoxy-1H-indazole


242
3-[6-(4-isopropylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5-
406.5



nitro-1H-indazole


243
methyl 3-[6-(4-isopropylpiperazin-1-yl)-1H-benzimidazol-
419.5



2-yl]-1H-indazole-5-carboxylate


244
5-(benzyloxy)-3-[6-(4-isopropylpiperazin-1-yl)-1H-
467.6



benzimidazol-2-yl]-1H-indazole


245
6-chloro-3-[6-(4-isopropylpiperazin-1-yl)-1H-
395.9



benzimidazol-2-yl]-1H-indazole


246
3-[6-(4-isopropylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
391.5



methoxy-1H-indazole


247
5-ethoxy-3-[6-(4-isopropylpiperazin-1-yl)-1H-
405.5



benzimidazol-2-yl]-1H-indazole


248
3-[6-(4-isopropylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
406.5



nitro-1H-indazole


249
5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(5-fluoro-1H-
366.4



indazol-3-yl)-3H-imidazo[4,5-b]pyridine


250
2-(5-chloro-1H-indazol-3-yl)-5-[(3R,5S)-3,5-
382.9



dimethylpiperazin-1-yl]-3H-imidazo[4,5-b]pyridine


251
5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(5-nitro-1H-
393.4



indazol-3-yl)-3H-imidazo[4,5-b]pyridine


252
2-(6-chloro-1H-indazol-3-yl)-5-[(3R,5S)-3,5-
382.9



dimethylpiperazin-1-yl]-3H-imidazo[4,5-b]pyridine


253
5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(6-nitro-1H-
393.4



indazol-3-yl)-3H-imidazo[4,5-b]pyridine


254
2-(5-fluoro-1H-indazol-3-yl)-N-[3-(4-methylpiperazin-1-
408.5



yl)propyl]-1H-benzimidazol-6-amine


255
2-(5-chloro-1H-indazol-3-yl)-N-[3-(4-methylpiperazin-1-
424.9



yl)propyl]-1H-benzimidazol-6-amine


256
2-(5-bromo-1H-indazol-3-yl)-N-[3-(4-methylpiperazin-1-
469.4



yl)propyl]-1H-benzimidazol-6-amine


257
2-(5-methoxy-1H-indazol-3-yl)-N-[3-(4-methylpiperazin-
420.5



1-yl)propyl]-1H-benzimidazol-6-amine


258
N-[3-(4-methylpiperazin-1-yl)propyl]-2-(5-nitro-1H-
435.5



indazol-3-yl)-1H-benzimidazol-6-amine


259
methyl 3-(6-{[3-(4-methylpiperazin-1-yl)propyl]amino}-
448.5



1H-benzimidazol-2-yl)-1H-indazole-5-carboxylate


260
2-[5-(benzyloxy)-1H-indazol-3-yl]-N-[3-(4-
496.6



methylpiperazin-1-yl)propyl]-1H-benzimidazol-6-amine


261
2-(6-fluoro-1H-indazol-3-yl)-N-[3-(4-methylpiperazin-1-
408.5



yl)propyl]-1H-benzimidazol-6-amine


262
2-(6-chloro-1H-indazol-3-yl)-N-[3-(4-methylpiperazin-1-
424.9



yl)propyl]-1H-benzimidazol-6-amine


263
2-(5-ethoxy-1H-indazol-3-yl)-N-[3-(4-methylpiperazin-1-
434.6



yl)propyl]-1H-benzimidazol-6-amine


264
N-[3-(4-methylpiperazin-1-yl)propyl]-2-(6-nitro-1H-
435.5



indazol-3-yl)-1H-benzimidazol-6-amine


265
2-(5-methoxy-1H-indazo1-3-yl)-N-(pyridin-2-ylmethyl)-
359.4



1H-benzimidazol-6-amine


266
2-(5-chloro-1H-indazol-3-yl)-N-(pyridin-2-ylmethyl)-1H-
375.8



benzimidazol-6-amine


267
2-(5-methoxy-1H-indazol-3-yl)-N-(pyridin-2-ylmethyl)-
371.4



1H-benzimidazol-6-amine


268
2-(5-nitro-1H-indazol-3-yl)-N-(pyridin-2-ylmethyl)-1H-
386.4



benzimidazol-6-amine


269
methyl 3-{6-[(pyridin-2-ylmethyl)amino]-1H-
399.4



benzimidazol-2-yl}-1H-indazole-5-carboxylate


270
2-(6-fluoro-1H-indazol-3-yl)-N-(pyridin-2-ylmethyl)-1H-
359.4



benzimidazol-6-amine


271
2-(5-ethoxy-1H-indazol-3-yl)-N-(pyridin-2-ylmethyl)-1H-
385.4



benzimidazol-6-amine


272
2-(6-nitro-1H-indazol-3-yl)-N-(pyridin-2-ylmethyl)-1H-
386.4



benzimidazol-6-amine


273
2-(5-fluoro-1H-indazol-3-yl)-N-piperidin-3-yl-1H-
351.4



benzimidazol-5-amine


274
methyl 3-[5-(piperidin-3-ylamino)-1H-benzimidazol-2-yl]-
391.4



1H-indazole-5-carboxylate


275
2-(5,6-difluoro-1H-indazol-3-yl)-N-piperidin-3-yl-1H-
369.4



benzimidazol-5-amine


276
3-[5-(piperidin-3-ylamino)-1H-benzimidazol-2-yl]-1H-
358.4



indazole-6-carbonitrile


277
2-(6-fluoro-1H-indazol-3-yl)-N-piperidin-3-yl-1H-
351.4



benzimidazol-5-amine


278
2-(5-chloro-1H-indazol-3-yl)-1H-benzimidazole-6-
313.7



carboxylic acid


279
2-[5-(benzyloxy)-1H-indazol-3-yl]-1H-benzimidazole-6-
385.4



carboxylic acid


280
3-(6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-indazole
319.4


281
5-chloro-3-(6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-
353.8



indazole


282
5-bromo-3-(6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-
398.3



indazole


283
5-methoxy-3-(6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-
349.4



indazole


284
5-nitro-3-(6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-
364.4



indazole


285
methyl 3-(6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-
377.4



indazole-5-carboxylate


286
5-(benzyloxy)-3-(6-piperazin-1-yl-1H-benzimidazol-2-yl)-
425.5



1H-indazole


287
5-isopropoxy-3-(6-piperazin-1-yl-1H-benzimidazol-2-yl)-
377.5



1H-indazole


288
6-fluoro-3-(6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-
337.4



indazole


289
6-chloro-3-(6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-
353.8



indazole


290
6-methoxy-3-(6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-
349.4



indazole


291
5-ethoxy-3-(6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-
363.4



indazole


292
6-nitro-3-(6-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-
364.4



indazole


293
2-(5-methyl-1H-indazol-3-yl)-N-piperidin-3-yl-1H-
347.4



benzimidazol-5-amine


294
1-[2-(5-fluoro-1H-indazol-3-yl)-1H-benzimidazol-6-
352.4



yl]piperidin-4-ol


295
1-[2-(5-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-
368.8



yl]piperidin-4-ol


296
1-[2-(5-bromo-1H-indazol-3-yl)-1H-benzimidazol-6-
413.3



yl]piperidin-4-ol


297
1-[2-(5-methoxy-1H-indazol-3-yl)-1H-benzimidazol-6-
364.4



yl]piperidin-4-ol


298
1-[2-(5-nitro-1H-indazol-3-yl)-1H-benzimidazol-6-
379.4



yl]piperidin-4-ol


299
methyl 3-[6-(4-hydroxypiperidin-1-yl)-1H-benzimidazol-
392.4



2-yl]-1H-indazole-5-carboxylate


300
1-{2-[5-(benzyloxy)-1H-indazol-3-yl]-1H-benzimidazol-6-
440.5



yl}piperidin-4-ol


301
1-[2-(6-fluoro-1H-indazol-3-yl)-1H-benzimidazol-6-
352.4



yl]piperidin-4-ol


302
1-[2-(6-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-
368.8



yl]piperidin-4-ol


303
1-[2-(6-nitro-1H-indazol-3-yl)-1H-benzimidazol-6-
379.4



yl]piperidin-4-ol


304
2-(5-fluoro-1H-indazol-3-yl)-N-(2-piperidin-1-ylethyl)-
379.5



1H-benzimidazol-6-amine


305
2-(1H-indazol-3-yl)-N-methyl-N-(2-pyridin-2-ylethyl)-1H-
369.4



benzimidazol-6-amine


306
2-(5-fluoro-1H-indazol-3-yl)-N-methyl-N-(2-pyridin-2-
387.4



ylethyl)-1H-benzimidazol-6-amine


307
2-(5-chloro-1H-indazol-3-yl)-N-methyl-N-(2-pyridin-2-
403.9



ylethyl)-1H-benzimidazol-6-amine


308
2-(5-methoxy-1H-indazol-3-yl)-N-methyl-N-(2-pyridin-2-
399.5



ylethyl)-1H-benzimidazol-6-amine


309
2-(6-fluoro-1H-indazol-3-yl)-N-methyl-N-(2-pyridin-2-
387.4



ylethyl)-1H-benzimidazol-6-amine


310
2-(6-chloro-1H-indazol-3-yl)-N-methyl-N-(2-pyridin-2-
403.9



ylethyl)-1H-benzimidazol-6-amine


311
2-(6-methoxy-1H-indazol-3-yl)-N-methyl-N-(2-pyridin-2-
399.5



ylethyl)-1H-benzimidazol-6-amine


312
2-(5-ethoxy-1H-indazol-3-yl)-N-methyl-N-(2-pyridin-2-
413.5



ylethyl)-1H-benzimidazol-6-amine


313
N-methyl-2-(6-nitro-1H-indazol-3-yl)-N-(2-pyridin-2-
414.4



ylethyl)-1H-benzimidazol-6-amine


314
N-{3-[6-(1,4′-bipiperidin-l′-yl)-1H-benzimidazol-2-yl]-
595.7



1H-indazol-5-yl}-N′-(2,4-dimethoxyphenyl)urea


315
2-(5-chloro-1H-indazol-3-yl)-N-methyl-N-(1-
395.9



methylpiperidin-4-yl)-1H-benzimidazol-6-amine


316
2-(5-bromo-1H-indazol-3-yl)-N-methyl-N-(1-
440.4



methylpiperidin-4-yl)-1H-benzimidazol-6-amine


317
2-(5-methoxy-1H-indazol-3-yl)-N-methyl-N-(1-
391.5



methylpiperidin-4-yl)-1H-benzimidazol-6-amine


318
N-methyl-N-(1-methylpiperidin-4-yl)-2-(5-nitro-1H-
406.5



indazol-3-yl)-1H-benzimidazol-6-amine


319
methyl 3-{6-[methyl(1-methylpiperidin-4-yl)amino]-1H-
419.5



benzimidazol-2-yl}-1H-indazole-5-carboxylate


320
N-methyl-2-(5-methyl-1H-indazol-3-yl)-N-(1-
375.5



methylpiperidin-4-yl)-1H-benzimidazol-6-amine


321
2-[5-(benzyloxy)-1H-indazol-3-yl]-N-methyl-N-(1-
467.6



methylpiperidin-4-yl)-1H-benzimidazol-6-amine


322
2-(6-chloro-1H-indazol-3-yl)-N-methyl-N-(1-
395.9



methylpiperidin-4-yl)-1H-benzimidazol-6-amine


323
2-(6-methoxy-1H-indazol-3-yl)-N-methyl-N-(1-
391.5



methylpiperidin-4-yl)-1H-benzimidazol-6-amine


324
2-(5-ethoxy-1H-indazol-3-yl)-N-methyl-N-(1-
405.5



methylpiperidin-4-yl)-1H-benzimidazol-6-amine


325
N-methyl-N-(1-methylpiperidin-4-yl)-2-(6-nitro-1H-
406.5



indazol-3-yl)-1H-benzimidazol-6-amine


326
2-(1H-[1,3]dioxolol[4,5-f]indazol-3-yl)-N-methyl-N-(1-
405.5



methylpiperidin-4-yl)-1H-benzimidazol-6-amine


327
N-methyl-2-(7-methyl-1H-indazol-3-yl)-N-(1-
375.5



methylpiperidin-4-yl)-1H-benzimidazol-6-amine


328
N-(1-benzylpiperidin-4-yl)-2-(5-methoxy-1H-indazol-3-
453.6



yl)-1H-benzimidazol-6-amine


329
N-(1-benzylpiperidin-4-yl)-2-(6-fluoro-1H-indazol-3-yl)-
441.5



1H-benzimidazol-6-amine


330
2-(6-chloro-1H-indazol-3-yl)-N-(2-pyridin-4-ylethyl)-1H-
389.9



benzimidazol-5-amine


331
1-[2-(1H-indazol-3-yl)-1H-benzimidazol-6-yl]piperidin-3-
334.4



ol


332
1-[2-(5-fluoro-1H-indazol-3-yl)-1H-benzimidazol-6-
352.4



yl]piperidin-3-ol


333
1-[2-(5-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-
368.8



yl]piperidin-3-ol


334
1-[2-(5-bromo-1H-indazol-3-yl)-1H-benzimidazol-6-
413.3



yl]piperidin-3-ol


335
1-[2-(5-methoxy-1H-indazol-3-yl)-1H-benzimidazol-6-
364.4



yl]piperidin-3-ol


336
1-[2-(5-nitro-1H-indazol-3-yl)-1H-benzimidazol-6-
379.4



yl]piperidin-3-ol


337
methyl 3-[6-(3-hydroxypiperidin-1-yl)-1H-benzimidazol-
392.4



2-yl]-1H-indazole-5-carboxylate


338
1-[2-(5-methyl-1H-indazol-3-yl)-1H-benzimidazol-6-
348.4



yl]piperidin-3-ol


339
1-{2-[5-(benzyloxy)-1H-indazol-3-yl]-1H-benzimidazol-6-
440.5



yl}piperidin-3-ol


340
1-[2-(6-fluoro-1H-indazol-3-yl)-1H-benzimidazol-6-
352.4



yl]piperidin-3-ol


341
1-[2-(6-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-
368.8



yl]piperidin-3-ol


342
1-[2-(6-methoxy-1H-indazol-3-yl)-1H-benzimidazol-6-
364.4



yl]piperidin-3-ol


343
1-[2-(5-ethoxy-1H-indazol-3-yl)-1H-benzimidazol-6-
378.4



yl]piperidin-3-ol


344
1-[2-(6-nitro-1H-indazol-3-yl)-1H-benzimidazol-6-
379.4



yl]piperidin-3-ol


345
1-[2-(1H-[1,3]dioxolo[4,5-f]indazol-3-yl)-1H-
378.4



benzimidazol-6-yl]piperidin-3-ol


346
1-[2-(7-methyl-1H-indazol-3-yl)-1H-benzimidazol-6-
348.4



yl]piperidin-3-ol


347
(3R)-1-[2-(5-fluoro-1H-indazol-3-yl)-1H-benzimidazol-6-
338.4



yl]pyrrolidin-3-ol


348
(3R)-1-[2-(5-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-
354.8



yl]pyrrolidin-3-ol


349
(3R)-1-[2-(5-bromo-1H-indazol-3-yl)-1H-benzimidazol-6-
399.3



yl]pyrrolidin-3-ol


350
(3R)-1-[2-(5-methoxy-1H-indazol-3-yl)-1H-benzimidazol-
350.4



6-yl]pyrrolidm-3-ol


351
(3R)-1-[2-(5-nitro-1H-indazol-3-yl)-1H-benzimidazol-6-
365.4



yl]pyrrolidin-3-ol


352
(3R)-1-[2-(6-fluoro-1H-indazol-3-yl)-1H-benzimidazol-6-
378.4



yl]pyrrolidin-3-ol


353
(3R)-1-[2-(5-methyl-1H-indazol-3-yl)-1H-benzimidazol-6-
334.4



yl]pyrrolidin-3-ol


354
(3R)-1-{2-[5-(benzyloxy)-1H-indazol-3-yl]-1H-
426.5



benzimidazol-6-yl}pyrrolidin-3-ol


355
(3R)-1-[2-(6-fluoro-1H-indazol-3-yl)-1H-benzimidazol-6-
338.4



yl]pyrrolidin-3-ol


356
(3R)-1-[2-(6-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-
354.8



yl]pyrrolidin-3-ol


357
(3R)-1-[2-(6-methoxy-1H-indazol-3-yl)-1H-benzimidazol-
350.4



6-yl]pyrrolidin-3-ol


358
(3R)-1-[2-(5-ethoxy-1H-indazol-3-yl)-1H-benzimidazol-6-
364.4



yl]pyrrolidin-3-ol


359
(3R)-1-[2-(6-nitro-1H-indazol-3-yl)-1H-benzimidazol-6-
365.4



yl]pyrrolidin-3-ol


360
(3R)-1-[2-(1H-[1,3]dioxolo[4,5-f]indazol-3-yl)-1H-
364.4



benzimidazol-6-yl]pyrrolidin-3-ol


361
(3R)-1-[2-(7-methyl-1H-indazol-3-yl)-1H-benzimidazol-6-
334.4



yl]pyrrolidin-3-ol


362
6-fluoro-3-{6-[(4-methylpiperazin-1-yl)carbonyl]-1H-
379.4



benzimidazol-2-yl}-1H-indazole


363
1′-{[2-(6-fluoro-1H-indazol-3-yl)-1H-benzimidazol-6-
447.5



yl]carbonyl}-1,4′-bipiperidine


364
6-fluoro-3-[6-(morpholin-4-ylcarbonyl)-1H-benzimidazol-
366.4



2-yl]-1H-indazole


365
2-(6-fluoro-1H-indazol-3-yl)-N-methyl-N-(1-
407.5



methylpiperidin-4-yl)-1H-benzimidazole-6-carboxamide


366
3-(6-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]carbonyl}-1H-
394.4



benzimidazol-2-yl)-6-fluoro-1H-indazole


367
2-(6-fluoro-1H-indazol-3-yl)-N-methyl-N-(1-
393.4



methylpyrrolidin-3-yl)-1H-benzimidazole-6-carboxamide


368
(3S,5S)-1-[2-(6-fluoro-1H-indazol-3-yl)-1H-benzimidazol-
379.5



5-yl]-N,N,5-trimethylpyrrolidin-3-amine


369
1-[2-(1H-indazol-3-yl)-1H-benzimidazol-6-yl]-4-
410.5



phenylpiperidin-4-ol


370
1-[2-(5-fluoro-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-4-
428.5



phenylpiperidin-4-ol


371
1-[2-(5-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-4-
444.9



phenylpiperidin-4-ol


372
1-[2-(5-bromo-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-4-
489.4



phenylpiperidin-4-ol


373
1-[2-(5-methoxy-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-
440.5



4-phenylpiperidin-4-ol


374
1-[2-(5-nitro-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-4-
455.5



phenylpiperidin-4-ol


375
methyl 3-[6-(4-hydroxy-4-phenylpiperidin-1-yl)-1H-
468.5



benzimidazol-2-yl]-1H-indazole-5-carboxylate


376
1-[2-(5-methyl-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-4-
424.5



phenylpiperidin-4-ol


377
1-{2-[5-(benzyloxy)-1H-indazol-3-yl]-1H-benzimidazol-6-
516.6



yl}-4-phenylpiperidin-4-ol


378
1-[2-(6-fluoro-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-4-
428.5



phenylpiperidin-4-ol


379
1-[2-(6-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-4-
444.9



phenylpiperidm-4-ol


380
1-[2-(6-methoxy-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-
440.5



4-phenylpiperidin-4-ol


381
1-[2-(5-ethoxy-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-4-
454.5



phenylpiperidin-4-ol


382
1-[2-(6-nitro-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-4-
455.5



phenylpiperidin-4-ol


383
1-[2-(1H-[1,3]dioxolo[4,5-f]indazol-3-yl)-1H-
454.5



benzimidazol-6-yl]-4-phenylpiperidin-4-ol


384
1-[2-(7-methyl-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-4-
424.5



phenylpiperidin-4-ol


385
1-[2-(7-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-4-
444.9



phenylpiperidin-4-ol


386
1-[2-(1H-indazol-3-yl)-1H-benzimidazol-6-yl]-N,N-
347.4



dimethylpyrrolidin-3-amine


387
1-[2-(5-fluoro-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-
365.4



N,N-dimethylpyrrolidin-3-amine


388
1-[2-(5-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-
381.9



N,N-dimethylpyrrolidin-3-amine


389
1-[2-(5-bromo-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-
426.3



N,N-dimethylpyrrolidin-3-amine


390
1-[2-(5-methoxy-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-
377.5



N,N-dimethylpyrrolidin-3-amine


391
N,N-dimethyl-1-[2-(5-nitro-1H-indazol-3-yl)-1H-
392.4



benzimidazol-6-yl]pyrrolidin-3-amine


392
methyl 3-{6-[3-(dimethylamino)pyrrolidin-1-yl]-1H-
405.5



benzimidazol-2-yl}-1H-indazole-5-carboxylate


393
1-{2-[5-(benzyloxy)-1H-indazol-3-yl]-1H-benzimidazol-6-
453.6



yl}-N,N-dimethylpyrrolidin-3-amine


394
1-[2-(6-fluoro-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-
365.4



N,N-dimethylpyrrolidin-3-amine


395
1-[2-(6-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-
381.9



N,N-dimethylpyrrolidin-3-amine


396
1-[2-(6-methoxy-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-
377.5



N,N-dimethylpyrrolidin-3-amine


397
1-[2-(5-ethoxy-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-
391.5



N,N-dimethylpyrrolidin-3-amine


398
N,N-dimethyl-1-[2-(6-nitro-1H-indazol-3-yl)-1H-
392.4



benzimidazol-6-yl]pyrrolidin-3-amine


399
N,N-dimethyl-1-[2-(7-methyl-1H-indazol-3-yl)-1H-
361.5



benzimidazol-6-yl]pyrrolidin-3-amine


400
1-[2-(7-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-
381.9



N,N-dimethylpyrrolidin-3-amine


401
5-fluoro-3-(6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-
338.4



indazole


402
5-chloro-3-(6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-
354.8



indazole


403
5-bromo-3-(6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-
399.3



indazole


404
5-methoxy-3-(6-morpholin-4-yl-1H-benzimidazol-2-yl)-
350.4



1H-indazole


405
3-(6-morpholin-4-yl-1H-benzimidazol-2-yl)-5-nitro-1H-
365.4



indazole


406
methyl 3-(6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-
378.4



indazole-5-carboxylate


407
5-methyl-3-(6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-
334.4



indazole


408
5-(benzyloxy)-3-(6-morpholin-4-yl-1H-benzimidazol-2-
426.5



yl)-1H-indazole


409
6-fluoro-3-(6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-
338.4



indazole


410
6-chloro-3-(6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-
354.8



indazole


411
6-methoxy-3-(6-morpholin-4-yl-1H-benzimidazol-2-yl)-
350.4



1H-indazole


412
5-ethoxy-3-(6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-
364.4



indazole


413
3-(6-morpholin-4-yl-1H-benzimidazol-2-yl)-6-nitro-1H-
365.4



indazole


414
3-(6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-
364.4



[1,3]dioxolo[4,5-f]indazole


415
7-methyl-3-(6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-
334.4



indazole


416
7-chloro-3-(6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-
354.8



indazole


417
N-({(2R,5S)-4-[2-(6-chloro-1H-indazol-3-yl)-1H-
425.9



benzimidazol-5-yl]-5-methylmorpholin-2-yl}methyl)-N,N-



dimethylamine


418
N-(3,4-dimethoxybenzyl)-3-[6-(4-methylpiperazin-1-yl)-
498.6



1H-benzimidazol-2-yl]-1H-indazol-5-amine


419
N-[4-(benzyloxy)-3-methoxybenzyl]-3-[6-(4-
574.7



methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-indazol-



5-amine


420
3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-N-
530.6



(4-phenoxybenzyl)-1H-indazol-5-amine


421
3-[6-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5-
379.4



fluoro-1H-indazole


422
3-[6-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5-
395.9



chloro-1H-indazole


423
3-[6-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5-
440.3



bromo-1H-indazole


424
3-[6-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5-
406.4



nitro-1H-indazole


425
methyl 3-[6-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-
419.5



yl]-1H-indazole-5-carboxylate


426
3-[6-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5-
375.4



methyl-1H-indazole


427
3-[6-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5-
467.5



(benzyloxy)-1H-indazole


428
3-[6-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
395.9



chloro-1H-indazole


429
3-[6-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
391.4



methoxy-1H-indazole


430
3-[6-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5-
405.5



ethoxy-1H-indazole


431
3-[6-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
406.4



nitro-1H-indazole


432
3-[6-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-
405.4



[1,3]dioxolo[4,5-f]indazole


433
3-[6-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-yl]-7-
375.4



methyl-1H-indazole


434
3-[6-(4-acetylpiperazin-1-yl)-1H-benzimidazol-2-yl]-7-
395.9



chloro-1H-indazole


435
3-[6-(1,4′-bipiperidin-1′-yl)-1H-benzimidazol-2-yl]-N-[(2-
542.1



chloropyridin-3-yl)methyl]-1H-indazol-5-amine


436
2-(5-fluoro-1H-indazol-3-yl)-N-(2-pyridin-4-ylethyl)-1H-
373.4



benzimidazol-6-amine


437
2-(5-chloro-1H-indazol-3-yl)-N-(2-pyridin-4-ylethyl)-1H-
389.9



benzimidazol-6-amine


438
2-(5-methoxy-1H-indazol-3-yl)-N-(2-pyridin-4-ylethyl)-
385.4



1H-benzimidazol-6-amine


439
2-(5-nitro-1H-indazol-3-yl)-N-(2-pyridin-4-ylethyl)-1H-
400.4



benzimidazol-6-amine


440
methyl 3-{6-[(2-pyridin-4-ylethyl)amino]-1H-
413.5



benzimidazol-2-yl}-1H-indazole-5-carboxylate


441
2-(6-fluoro-1H-indazol-3-yl)-N-(2-pyridin-4-ylethyl)-1H-
373.4



benzimidazol-6-amine


442
2-(6-chloro-1H-indazol-3-yl)-N-(2-pyridin-4-ylethyl)-1H-
389.9



benzimidazol-6-amine


443
2-(6-methoxy-1H-indazol-3-yl)-N-(2-pyridin-4-ylethyl)-
385.4



1H-benzimidazol-6-amine


444
2-(5-ethoxy-1H-indazol-3-yl)-N-(2-pyridin-4-ylethyl)-1H-
399.5



benzimidazol-6-amine


445
2-(6-nitro-1H-indazol-3-yl)-N-(2-pyridin-4-ylethyl)-1H-
400.4



benzimidazol-6-amine


446
2-(5-methyl-1H-indazol-3-yl)-N-(2-pyridin-4-ylethyl)-1H-
369.4



benzimidazol-6-amine


447
2-(1H-[1,3]dioxolo[4,5-f]indazol-3-yl)-N-(2-pyridin-4-
399.4



ylethyl)-1H-benzimidazol-6-amine


448
2-(5-methyl-1H-indazol-3-yl)-N-(3-morpholin-4-ylpropyl)-
389.9



1H-benzimidazol-6-amine


449
2-(1H-indazol-3-yl)-N-(3-morpholin-4-ylpropyl)-1H-
377.5



benzimidazol-6-amine


450
2-(5-fluoro-1H-indazol-3-yl)-N-(3-morpholin-4-ylpropyl-
395.5



1H-benzimidazol-6-amine


451
2-(5-chloro-1H-indazol-3-yl)-N-(3-morpholin-4-ylpropyl)-
411.9



1H-benzimidazol-6-amine


452
2-(5-bromo-1H-indazol-3-yl)-N-(3-morpholin-4-ylpropyl)-
456.4



1H-benzimidazol-6-amine


453
2-(5-methoxy-1H-indazol-3-yl)-N-(3-morpholin-4-
407.5



ylpropyl)-1H-benzimidazol-6-amine


454
N-(3-morpholin-4-ylpropyl)-2-(5-nitro-1H-indazol-3-yl)-
422.5



1H-benzimidazol-6-amine


455
methyl 3-{6-[(3-morpholin-4-ylpropyl)amino]-1H-
435.5



benzimidazol-2-yl}-1H-indazole-5-carboxylate


456
2-(5-methyl-1H-indazol-3-yl)-N-(3-morpholin-4-ylpropyl)-
391.5



1H-benzimidazol-6-amine


457
2-[5-(benzyloxy)-1H-indazol-3-yl]-N-(3-morpholin-4-
483.6



ylpropyl)-1H-benzimidazol-6-amine


458
2-(6-fluoro-1H-indazol-3-yl)-N-(3-morpholin-4-ylpropyl)-
395.5



1H-benzimidazol-6-amine


459
2-(6-chloro-1H-indazol-3-yl)-N-(3-morpholin-4-ylpropyl)-
411.9



1H-benzimidazol-6-amine


460
2-(6-methoxy-1H-indazol-3-yl)-N-(3-morpholin-4-
407.5



ylpropyl)-1H-benzimidazol-6-amine


461
2-(5-ethoxy-1H-indazol-3-yl)-N-(3-morpholin-4-ylpropyl)-
421.5



1H-benzimidazol-6-amine


462
N-(3-morpho1in-4-ylpropyl)-2-(6-nitro-1H-indazol-3-yl)-
422.5



1H-benzimidazol-6-amine


463
2-(1H-[1,3]dioxolo[4,5-f]indazol-3-yl)-N-(3-morpholin-4-
421.5



ylpropyl)-1H-benzimidazol-6-amine


464
2-(7-chloro-1H-indazol-3-yl)-N-(3-morpholin-4-ylpropyl)-
411.9



1H-benzimidazol-6-amine


465
N-(3-morpholin-4-ylpropyl)-2-[6-(trifluoromethyl)-1H-
445.5



indazol-3-yl]-1H-benzimidazol-6-amine


466
3,5-bis(1H-benzimidazol-2-yl)-1H-indazole
351.4


467
{1-[2-(1H-indazol-3-yl)-1H-benzimidazol-6-yl]piperidin-
348.4



4-yl}methanol


468
{1-[2-(5-fluoro-1H-indazol-3-yl)-1H-benzimidazol-6-
366.4



yl]piperidin-4-yl}methanol


469
{1-[2-(5-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-
382.9



yl]piperidin-4-yl}methanol


470
{1-[2-(5-bromo-1H-indazol-3-yl)-1H-benzimidazol-6-
427.3



yl]piperidin-4-yl}methanol


471
{1-[2-(5-methoxy-1H-indazol-3-yl)-1H-benzimidazol-6-
378.4



yl]piperidin-4-yl}methanol


472
{1-[2-(5-nitro-1H-indazol-3-yl)-1H-benzimidazol-6-
393.4



yl]piperidin-4-yl}methanol


473
methyl 3-{6-[4-(hydroxymethyl)piperidin-1-yl]-1H-
406.5



benzimidazol-2-yl}-1H-indazole-5-carboxylate


474
{1-[2-(5-methyl-1H-indazol-3-yl)-1H-benzimidazol-6-
362.4



yl]piperidin-4-yl}methanol


475
(1-{2-[5-(benzyloxy)-1H-indazol-3-yl]-1H-benzimidazol-
454.5



6-yl}piperidin-4-yl)methanol


476
{1-[2-(6-fluoro-1H-indazol-3-yl)-1H-benzimidazol-6-
366.4



yl]piperidin-4-yl}methanol


477
{1-[2-(6-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-
382.9



yl]piperidin-4-yl}methanol


478
{1-[2-(6-methoxy-1H-indazol-3-yl)-1H-benzimidazol-6-
378.4



yl]piperidin-4-yl}methanol


479
{1-[2-(5-ethoxy-1H-indazol-3-yl)-1H-benzimidazol-6-
392.5



yl]piperidin-4-yl}methanol


480
{1-[2-(6-nitro-1H-indazol-3-yl)-1H-benzimidazol-6-
393.4



yl]piperidin-4-yl}methanol


481
{1-[2-(1H-[1,3]dioxolo[4,5-f]indazol-3-yl)-1H-
392.4



benzimidazol-6-yl]piperidin-4-yl}methanol


482
{1-[2-(7-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-
382.9



yl]piperidin-4-yl}methanol


483
(1-{2-[6-(trifluoromethyl)-1H-indazol-3-yl]-1H-
416.4



benzimidazol-6-yl}piperidin-4-yl)methanol


484
3-(1H-benzimidazol-2-yl)-5-(benzyloxy)-1H-indazole
341.4


485
5-(1H-benzimidazol-2-yl)-3-[5-(4-methylpiperazin-yl)-
449.5



1H-benzimidazol-2-yl]-1H-indazole


486
N-({1-[2-(6-fluoro-1H-indazol-3-yl)-1H-benzimidazol-6-
379.5



yl]pyrrolidin-3-yl}methyl)-N,N-dimethylamine


487
3-(1H-benzimidazol-2-yl)-1H-[1,3]dioxolo[4,5-f]indazole
279.3


488
3-(1H-benzimidazol-2-yl)-6-chloro-1H-indazole
269.7


489
3-(1H-benzimidazol-2-yl)-6-fluoro-1H-indazole
253.3


490
3-(1H-benzimidazol-2-yl)-1H-indazole-6-carbonitrile
260.3


491
3-(1H-benzimidazol-2-yl)-6-nitro-1H-indazole
280.3


492
3-(1H-benzimidazol-2-yl)-N-(2-morpholin-4-ylethyl)-1H-
391.4



indazole-6-carboxamide


493
6-fluoro-3-{6-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-
377.4



2(1H)-yl]-1H-benzimidazol-2-yl}-1H-indazole


494
5-chloro-3-{5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-
381.9



benzimidazol-2-yl}-1H-indazole


495
5-bromo-3-{5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-
426.3



benzimidazol-2-yl}-1H-indazole


496
3-{5[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-
377.5



benzimidazol-2-yl}-5-methoxy-1H-indazole


497
3-{[5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-
392.4



benzimidazol-2-yl}-5-nitro-1H-indazole


498
methyl 3-{5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-
405.5



benzimidazol-2-yl}-1H-indazole-5-carboxylate


499
3-{5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-
361.5



benzimidazol-2-yl}-5-methyl-1H-indazole


500
5-(benzyloxy)-3-{5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-
453.6



1H-benzimidazol-2-yl}-1H-indazole


501
3-{5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-
365.4



benzimidazol-2-yl}-6-fluoro-1H-indazole


502
3-{5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-
381.9



benzimidazol-2-yl}-6-nitro-1H-indazole


503
3-{5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-
377.5



benzimidazol-2-yl}-6-methoxy-1H-indazole


504
5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-2-(1H-pyrazol-3-
297.4



yl)-1H-benzimidazole


505
3-{5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-
391.5



benzimidazol-2-yl}-5-ethoxy-1H-indazole


506
3-{5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-
392.4



benzimidazol-2-yl}-6-nitro-1H-indazole


507
3-{5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-
391.4



benzimidazol-2-yl}-1H-[1,3]dioxolo[4,5-f]indazole


508
7-chloro-3-{5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-
381.9



benzimidazol-2-yl}-1H-indazole


509
3-{5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-
391.5



benzimidazol-2-yl}-5-methoxy-4-methyl-1H-indazole


510
3-{5-[(3R,5S)-3,5-dimethylpiperazin-1-yl]-1H-
372.4



benzimidazol-2-yl}-1H-indazole-6-carbonitrile


511
5-fluoro-3-(5-methyl-1H-benzimidazol-2-yl)-1H-indazole
267.3


512
5-methoxy-3-(5-methyl-1H-benzimidazol-2-yl)-1H-
279.3



indazole


513
methyl 3-(5-methyl-1H-benzimidazol-2-yl)-1H-indazole-5-
307.3



carboxylate


514
3-(5-methyl-1H-benzimidazol-2-yl)-1H-indazole-5-
274.3



carbonitrile


515
3-[6-(4-methyl-1,4-diazepan-1-yl)-1H-benzimidazol-2-yl]-
347.4



1H-indazole


516
5-fluoro-3-[6-(4-methyl-1,4-diazepan-1-yl)-1H-
365.4



benzimidazol-2-yl]-1H-indazole


517
5-chloro-3-[6-(4-methyl-1,4-diazepan-1-yl)-1H-
381.9



benzimidazol-2-yl]-1H-indazole


518
5-bromo-3-[6-(4-methyl-1,4-diazepan-1-yl)-1H-
426.3



benzimidazol-2-yl]-1H-indazole


519
5-methoxy-3-[6-(4-methyl-1,4-diazepan-1-yl)-1H-
377.5



benzimidazol-2-yl]-1H-indazole


520
3-[6-(4-methyl-1,4-diazepan-1-yl)-1H-benzimidazol-2-yl]-
392.4



5-nitro-1H-indazole


521
methyl 3-[6-(4-methyl-1,4-diazepan-1-yl)-1H-
405.5



benzimidazol-2-yl]-1H-indazole-5-carboxylate


522
5-methyl-3-[6-(4-methyl-1,4-diazepan-1-yl)-1H-
361.5



benzimidazol-2-yl]-1H-indazole


523
5-(benzyloxy)-3-[6-(4-methyl-1,4-diazepan-1-yl)-1H-
453.6



benzimidazol-2-yl]-1H-indazole


524
6-fluoro-3-[6-(4-methyl-1,4-diazepan-1-yl)-1H-
365.4



benzimidazol-2-yl]-1H-indazole


525
6-chloro-3-[6-(4-methyl-1,4-diazepan-1-yl)-1H-
381.9



benzimidazol-2-yl]-1H-indazole


526
6-methoxy-3-[6-(4-methyl-1,4-diazepan-1-yl)-1H-
377.5



benzimidazol-2-yl]-1H-indazole


527
5-ethoxy-3-[6-(4-methyl-1,4-diazepan-1-yl)-1H-
391.5



benzimidazol-2-yl]-1H-indazole


528
3-[6-(4-methyl-1,4-diazepan-1-yl)-1H-benzimidazol-2-yl]-
392.4



6-nitro-1H-indazole


529
3-[6-(4-methyl-1,4-diazepan-1-yl)-1H-benzimidazol-2-yl]-
391.4



1H-[1,3]dioxolo[4,5-f]indazole


530
7-chloro-3-[6-(4-methyl-1,4-diazepan-1-yl)-1H-
381.9



benzimidazol-2-yl]-1H-indazole


531
3-[6-(4-methyl-1,4-diazepan-1-yl)-1H-benzimidazol-2-yl]-
372.4



1H-indazole-6-carbonitrile


532
5-(benzyloxy)-3-[6-(4-methylpiperazin-1-yl)-1H-
439.5



benzimidazol-2-yl]-1H-indazole


533
5-isopropoxy-3-[6-(4-methylpiperazin-1-yl)-1H-
391.5



benzimidazol-2-yl]-1H-indazole


534
3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5-
471.5



[(5-nitropyridin-2-yl)oxy]-1H-indazole


535
5-methyl-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-
347.4



2-yl]-1H-indazole


536
5-ethoxy-3-[6-(4-methylpiperazin-yl)-1H-benzimidazol-
377.5



2-yl]-1H-indazole


537
5-isobutoxy-3-[6-(4-methylpiperazin-1-yl)-1H-
405.5



benzimidazol-2-yl]-1H-indazole


538
3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
378.4



nitro-1H-indazole


539
N-isopropyl-3-[6-(4-methylpiperazin-1-yl)-1H-
390.5



benzimidazol-2-yl]-1H-indazol-6-amine


540
5-bromo-3-(5-methyl-1H-benzimidazol-2-yl)-1H-indazole
328.2


541
3-(1H-benzimidazol-2-yl)-5-nitro-1H-indazole
280.3


542
methyl 3-(1H-benzimidazol-2-yl)-1H-indazole-5-
293.3



carboxylate


543
6-chloro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-
367.9



2-yl]-1H-indazole


544
3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
378.4



nitro-1H-indazole


545
3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-
358.4



indazole-6-carbonitrile


546
3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-
377.4



indazole-6-carboxylic acid


547
3-(1H-benzimidazol-2-yl)-6-methyl-1H-indazole
249.3


548
5-methyl-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-
347.4



2-yl]-1H-indazole


549
3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-
377.4



[1,3]dioxolo[4,5-f]indazole


550
3-(1H-benzimidazol-2-yl)-1H-indazol-6-amine
250.3


551
3-(1H-benzimidazol-2-yl)-1H-indazole-6-carboxylic acid
279.3


552
3-(1H-benzimidazol-2-yl)-6-methox-1H-indazole
265.3


553
3-(1H-benzimidazol-2-yl)-1H-indazole-5-carboxylic acid
279.3


554
3-(1H-benzimidazol-2-yl)-5-chloro-1H-indazole
269.7


555
3-(5-chloro-1H-benzimidazol-2-yl)-5-fluoro-1H-indazole
287.7


556
3-(5-chloro-1H-benzimidazol-2-yl)-5-methoxy-1H-
299.7



indazole


557
3-(1H-benzimidazol-2-yl)-5-bromo-1H-indazole
314.2


558
3-(1H-benzimidazol-2-yl)-5-fluoro-1H-indazole
253.3


559
3-(1H-benzimidazol-2-yl)-1H-indazole-5-carbonitrile
260.3


560
6-bromo-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-
412.3



2-yl]-1H-indazole


561
5-bromo-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-
412.3



2-yl]-1H-indazole


562
3-[6-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-
347.4



indazole


563
3-[6-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5-
365.4



fluoro-1H-indazole


564
5-chloro-3-[6-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-
381.9



yl]-1H-indazole


565
5-bromo-3-[6-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-
426.3



yl]-1H-indazole


566
3-[6-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5-
377.5



methoxy-1H-indazole


567
3-[6-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5-
392.4



nitro-1H-indazole


568
methyl 3-[6-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-
405.5



yl]-1H-indazole-5-carboxylate


569
3-[6-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5-
361.5



methyl-1H-indazole


570
5-(benzyloxy)-3-[6-(4-ethylpiperazin-1-yl)-1H-
453.6



benzimidazol-2-yl]-1H-indazole


571
3-[6-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
365.4



fluoro-1H-indazole


572
6-chloro-3-[6-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-
381.9



yl]-1H-indazole


573
3-[6-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
377.5



methoxy-1H-indazole


574
5-ethoxy-3-[6-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-
391.5



yl]-1H-indazole


575
3-[6-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-6-
392.4



nitro-1H-indazole


576
3-[6-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-
391.4



[1,3]dioxolo[4,5-f]indazole


577
7-chloro-3-[6-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-
381.9



yl]-1H-indazole


578
3-[6-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-5-
391.5



methoxy-4-methyl-1H-indazole


579
3-[6-(4-ethylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-
372.4



indazole-6-carbonitrile


580
3-[6-(4-cyclohexylpiperazin-1-yl)-1H-benzimidazol-2-yl]-
419.5



5-fluoro-1H-indazole


581
5-chloro-3-[6-(4-cyclohexylpiperazin-1-yl)-1H-
436.0



benzimidazol-2-yl]-1H-indazole


582
5-bromo-3-[6-(4-cyclohexylpiperazin-1-yl)-1H-
480.4



benzimidazol-2-yl]-1H-indazole


583
3-[6-(4-cyclohexylpiperazin-1-yl)-1H-benzimidazol-2-yl]-
431.6



5-methoxy-1H-indazole


584
3-[6-4-cyclohexylpiperazin-1-yl)-1H-benzimidazol-2-yl]-
446.5



5-nitro-1H-indazole


585
methyl 3-[6-(4-cyclohexylpiperazin-1-yl)-1H-
459.6



benzimidazol-2-yl]-1H-indazole-5-carboxylate


586
3-[6-(4-cyclohexylpiperazin-1-yl)-1H-benzimidazol-2-yl]-
415.6



5-methyl-1H-indazole


587
5-(benzyloxy)-3-[6-(4-cyclohexylpiperazin-1-yl)-1H-
507.7



benzimidazol-2-yl]-1H-indazole


588
6-chloro-3-[6-(4-cyclohexylpiperazin-1-yl)-1H-
436.0



benzimidazol-2-yl]-1H-indazole


589
3-[6-(4-cyclohexylpiperazin-1-yl)-1H-benzimidazol-2-yl]-
431.6



6-methoxy-1H-indazole


590
3-[6-(4-cyclohexylpiperazin-1-yl)-1H-benzimidazol-2-yl]-
445.6



5-ethoxy-1H-indazole


591
3-[6-(4-cyclohexylpiperazin-1-yl)-1H-benzimidazol-2-yl]-
446.5



6-nitro-1H-indazole


592
3-[6-(4-cyclohexylpiperazin-1-yl)-1H-benzimidazol-2-yl]-
445.5



1H-[1,3]dioxolo[4,5-f]indazole


593
7-chloro-3-[6-(4-cyclohexylpiperazin-1-yl)-1H-
436.0



benzimidazol-2-yl]-1H-indazole


594
3-[6-(4-cyclohexylpiperazin-1-yl)-1H-benzimidazol-2-yl]-
445.6



5-methoxy-4-methyl-1H-indazole


595
3-[6-(4-cyclohexylpiperazin-1-yl)-1H-benzimidazol-2-yl]-
426.5



1H-indazole-6-carbonitrile


596
3-(5-chloro-1H-benzimidazol-2-yl)-5-nitro-1H-indazole
314.7


597
3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-
377.4



indazole-5-carboxylic acid


598
3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-4-
378.4



nitro-1H-indazole


599
3-[6-(4-pyridin-2-ylpiperazin-1-yl)-1H-benzimidazol-2-
396.5



yl]-1H-indazole


600
5-fluoro-3-[6-(4-pyridin-2-ylpiperazin-1-yl)-1H-
414.5



benzimidazol-2-yl]-1H-indazole


601
5-chloro-3-[6-(4-pyridin-2-ylpiperazin-1-yl)-1H-
430.9



benzimidazol-2-yl]-1H-indazole


602
5-bromo-3-[6-(4-pyridin-2-ylpiperazin-1-yl)-1H-
475.4



benzimidazol-2-yl]-1H-indazole


603
5-methoxy-3-[6-(4-pyridin-2-ylpiperazin-1-yl)-1H-
426.5



benzimidazol-2-yl]-1H-indazole


604
5-nitro-3-[6-(4-pyridin-2-ylpiperazin-1-yl)-1H-
441.5



benzimidazol-2-yl]-1H-indazole


605
methyl 3-[6-(4-pyridin-2-ylpiperazin-1-yl)-1H-
454.5



benzimidazol-2-yl]-1H-indazole-5-carboxylate


606
5-methyl-3-[6-(4-pyridin-2-ylpiperazin-1-yl)-1H-
410.5



benzimidazol-2-yl]-1H-indazole


607
5-(benzyloxy)-3-[6-(4-pyridin-2-ylpiperazin-1-yl)-1H-
502.6



benzimidazol-2-yl]-1H-indazole


608
6-fluoro-3-[6-(4-pyridin-2-ylpiperazin-1-yl)-1H-
414.5



benzimidazol-2-yl]-1H-indazole


609
6-chloro-3-[6-(4-pyridin-2-ylpiperazin-1-yl)-1H-
430.9



benzimidazol-2-yl]-1H-indazole


610
5-ethoxy-3-[6-(4-pyridin-2-ylpiperazin-1-yl)-1H-
440.5



benzimidazol-2-yl]-1H-indazole


611
3-[6-(4-pyridin-2-ylpiperazin-1-yl)-1H-benzimidazol-2-
440.5



yl]-1H-[1,3]dioxolo[4,5-f]indazole


612
7-chloro-3-[6-(4-pyridin-2-ylpiperazin-1-yl)-1H-
430.9



benzimidazol-2-yl]-1H-indazole


613
3-[6-(4-pyridin-2-ylpiperazin-1-yl)-1H-benzimidazol-2-
421.5



yl]-1H-indazole-6-carbonitrile


614
3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-N-
431.6



[(2S)-pyrrolidin-2-ylmethyl]-1H-indazol-4-amine


615
3-(6-chloro-1H-benzimidazol-2-yl)-1H-indazole-5-
294.7



carbonitrile


616
methyl 3-(6-chloro-1H-benzimidazol-2-yl)-1H-indazole-5-
327.7



carboxylate


617
N′-[3-(1H-benzimidazol-2-yl)-1H-indazol-5-yl]-N,N-
335.4



dimethyipropane-1,3-diamine


618
5-chloro-3-(6-chloro-1H-benzimidazol-2-yl)-1H-indazole
304.2


619
5-bromo-3-(5-chloro-1H-benzimidazol-2-yl)-1H-indazole
348.6


620
N-({4-[2-(5-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-
411.9



yl]morpholin-2-yl}methyl)-N,N-dimethylamine


621
N-({4-[2-(5-bromo-1H-indazol-3-yl)-1H-benzimidazol-6-
456.4



yl]morpholin-2-yl}methyl)-N,N-dimethylamine


622
N,N-dimethyl-N-({4-[2-(5-nitro-1H-indazol-3-yl)-1H-
422.5



benzimidazol-6-yl]morpholin-2-yl}methyl)amine


623
methyl 3-(6-{2-[(dimethylamino)methyl]morpholin-4-yl}-
435.5



1H-benzimidazol-2-yl)-1H-indazole-5-carboxylate


624
N-[(4-{2-[5-(benzyloxy)-1H-indazol-3-yl]-1H-
483.6



benzimidazol-6-yl}morpholin-2-yl)methyl]-N,N-



dimethylamine


625
N-({4-[2-(6-fluoro-1H-indazol-3-yl)-1H-benzimidazol-6-
395.5



yl]morpholin-2-yl}methyl)-N,N-dimethylamine


626
N-({4-[2-(6-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-
411.9



yl]morpholin-2-yl}methyl)-N,N-dimethylamine


627
3-(6-{2-[(dimethylamino)methyl]morpholin-4-yl}-1H-
402.5



benzimidazol-2-yl)-1H-indazole-6-carbonitrile


628
2-(5-chloro-1H-indazol-3-yl)-N-(pyridin-4-ylmethyl)-1H-
375.8



benzimidazol-6-amine


629
2-(5-bromo-1H-indazol-3-yl)-N-(pyridin-4-ylmethyl)-1H-
MW!



benzimidazol-6-amine


630
2-(5-nitro-1H-indazol-3-yl)-N-(pyridin-4-ylmethyl)-1H-
386.4



benzimidazol-6-amine


631
2-(5-methyl-1H-indazol-3-yl)-N-(pyridin-4-ylmethyl)-1H-
355.4



benzimidazol-6-amine


632
2-[5-(benzyloxy)-1H-indazol-3-yl]-N-(pyridin-4-
447.5



ylmethyl)-1H-benzimidazol-6-amine


633
2-(6-fluoro-1H-indazol-3-yl)-N-(pyridin-4-ylmethyl)-1H-
359.4



benzimidazol-6-amine


634
2-(7-chloro-1H-indazol-3-yl)-N-(pyridin-4-ylmethyl)-1H-
375.8



benzimidazol-6-amine


635
3-{6-[(pyridin-4-ylmethyl) amino]-1H-benzimidazol-2-yl}-
366.4



1H-indazole-6-carbonitrile


636
3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-
348.4



indazol-4-amine


637
N-({(2S,5S)-4-[2-(6-fluoro-1H-indazol-3-yl)-1H-
409.5



benzimidazol-6-yl]-5-methylmorpholin-2-yl}methyl)-N,N-



dimethylamine


638
N-({(2S,5S)-4-[2-(6-chloro-1H-indazol-3-yl)-1H-
425.9



benzimidazol-6-yl]-5-methylmorpholin-2-yl}methyl)-N,N-



dimethylamine


639
3-[6-(1H-imidazol-1-yl)-1H-benzimidazol-2-yl]-1H-
301.3



indazole


640
5-fluoro-3-[6-(1H-imidazol-1-yl)-1H-benzimidazol-2-yl]-
319.3



1H-indazole


641
5-chloro-3-[6-(1H-imidazol-1-yl)-1H-benzimidazol-2-yl]-
335.8



1H-indazole


642
5-bromo-3-[6-(1H-imidazol-1-yl)-1H-benzimidazol-2-yl]-
380.2



1H-indazole


643
3-[6-(1H-imidazol-1-yl)-1H-benzimidazol-2-yl]-5-
331.4



methoxy-1H-indazole


644
3-[6-(1H-imidazol-1-yl)-1H-benzimidazol-2-yl]-5-nitro-
346.3



1H-indazole


645
methyl 3-[6-(1H-imidazol-1-yl)-1H-benzimidazol-2-yl]-
359.4



1H-indazole-5-carboxylate


646
3-[6-(1H-imidazol-1-yl)-1H-benzimidazol-2-yl]-5-methyl-
315.4



1H-indazole


647
5-(benzyloxy)-3-[6-(1H-imidazol-1-yl)-1H-benzimidazol-
407.4



2-yl]-1H-indazole


648
6-fluoro-3-[6-(1H-imidazol-1-yl)-1H-benzimidazol-2-yl]-
319.3



1H-indazole


649
6-chloro-3-[6-(1H-imidazol-1-yl)-1H-benzimidazol-2-yl]-
335.8



1H-indazole


650
5-ethoxy-3-[6-(1H-imidazol-1-yl)-1H-benzimidazol-2-yl]-
345.4



1H-indazole


651
3-[6-(1H-imidazol-1-yl)-1H-benzimidazol-2-yl]-1H-
345.3



[1,3]dioxolo[4,5-f]indazole


652
7-chloro-3-[6-(1H-imidazol-1-yl)-1H-benzimidazol-2-yl]-
335.8



1H-indazole


653
3-[6-(1H-imidazol-1-yl)-1H-benzimidazol-2-yl]-1H-
326.3



indazole-6-carbonitrile


654
2-(5-fluoro-1H-indazol-3-yl)-N-(3-pyrrolidin-1-ylpropyl)-
379.5



1H-benzimidazol-6-amine


655
2-(5-chloro-1H-indazol-3-yl)-N-(3-pyrrolidin-1-ylpropyl)-
395.9



1H-benzimidazol-6-amine


656
2-(5-methoxy-1H-indazol-3-yl)-N-(3-pyrrolidin-1-
391.5



ylpropyl)-1H-benzimidazol-6-amine


657
2-(5-nitro-1H-indazol-3-yl)-N-(3-pyrrolidin-1-ylpropyl)-
406.5



1H-benzimidazol-6-amine


658
2-(5-methyl-1H-indazol-3-yl)-N-(3-pyrrolidin-1-ylpropyl)-
375.5



1H-benzimidazol-6-amine


659
2-[5-(benzyloxy)-1H-indazol-3-yl]-N-(3-pyrrolidin-1-
467.6



ylpropyl)-1H-benzimidazol-6-amine


660
2-(6-fluoro-1H-indazol-3-yl)-N-(3-pyrrolidin-1-ylpropyl)-
379.5



1H-benzimidazol-6-amine


661
2-(6-chloro-1H-indazol-3-yl)-N-(3-pyrrolidin-1-ylpropyl)-
395.9



1H-benzimidazol-6-amine


662
2-(5-ethoxy-1H-indazol-3-yl)-N-(3-pyrrolidin-1-ylpropyl)-
405.5



1H-benzimidazol-6-amine


663
2-(1H-[1,3]dioxolo[4,5-f]indazol-3-yl)-N-(3-pyrrolidin-1-
405.5



ylpropyl)-1H-benzimidazol-6-amine


664
2-(7-chloro-1H-indazol-3-yl)-N-(3-pyrrolidin-1-ylpropyl)-
395.9



1H-benzimidazol-6-amine


665
N,N-diethyl-N′-[2-(5-fluoro-1H-indazol-3-yl)-1H-
395.5



benzimidazol-6-yl]-N′-methylpropane-1,3-diamine


666
N-[2-(5-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-
412.0



N′,N′-diethyl-N-methylpropane-1,3-diamine


667
N,N-diethyl-N′-[2-(5-nitro-1H-indazol-3-yl)-
422.5



1H-benzimidazol-6-yl]propane-1,3-diamine


668
N-{2-[5-(benzyloxy)-1H-indazol-3-yl]-1H-benzimidazol-6-
483.6



yl}-N′,N′-diethyl-N-methylpropane-1,3-diamine


669
N,N-diethyl-N′-[2-(6-fluoro-1H-indazol-3-yl)-1H-
395.5



benzimidazol-6-yl]-N′-methylpropane-1,3-diamine


670
N-[2-(7-chloro-1H-indazol-3-yl)-1H-benzimidazol-6-yl]-
412.0



N′,N′-diethyl-N-methylpropane-1,3-diamine









Example 671
3-[6-(1,4′-Bipiperidin-1′-yl)-1H-benzimidazol-2-yl]-1H-indazol-5-amine
To a solution of the product produced in Example 110 (1.0 eq) in ethanol:ethyl acetate (1:1) was added 10% Pd/C (0.5 eq). The reaction vessel was repeatedly purged with nitrogen and then stirred under a hydrogen atmosphere (1 atm) for 48 hours. The product was filtered through Celite with ethanol. The solvent was removed to provide a brown solid which was used without purification. LC/MS (m/z) 416.1 (MH+), Rt 1.30 minutes.
Examples 672–684
Examples 672–684 were synthesized from amino substituted indazole benzimidazoles and isocyanates, using the procedure set forth below for the synthesis of various compounds which include a urea substituent.
Example 672
N-{3-[6-(1,4′-Bipiperidin-1′-yl)-1H-benzimidazol-2-yl]-1H-indazol-5-yl}-N′-phenylurea
Benzimidazol-2-yl-1H-indazole-5-ylamine was dissolved in THF and and phenylisocyanate (1.1 equivalents) was added. The mixture was shaken overnight, the solution was concentrated, and the resulting residue was purified by preparatory HPLC. LC/MS (m/z) 535.6 (MH+), Rt 1.93 minutes.
















LC/MS (m/z)


Example

Name
(MH+)







673

1′-[2-(6-chloro-1H-indazol-3-yl)-3H-
437.0




imidazo[4,5-b]pyridin-5-yl]-1,4′-




bipiperidine


674

N-{3-[6-(1,4′-bipiperidin-1′-yl)-
501.6




1H-benzimidazol-2-yl]-1H-indazol-5-




yl}-N′-isopropylurea


675

N-benzyl-N′-{3-[6-(1,4′-
549.7




bipiperidin-1′-yl)-1H-benzimidazol-




2-yl]-1H-indazol-5-yl}urea


676

N-{3-[6-(1,4′-bipiperidin-
595.7




1′-yl)-1H-benzimidazol-2-yl]-1H-




indazol-5-yl}-N′-(2,4-




dimethoxyphenyl)urea


677

N-{3-[6-(1,4′-bipiperidin-
515.7




1′-yl)-1H-benzimidazol-2-yl]-1H-




indazol-5-yl}-N′-(tert-butyl)urea


678

N-[3-(1H-benzimidazol-2-yl)-1H-
349.4




indazol-5-yl]-N′-(tert-butyl)urea


679

N-(tert-butyl)-N′-{3-[6-
447.6




(4-methylpiperazin-1-yl)-1H-




benzimidazol-2-yl]-1H-indazol-




5-yl}urea


680

N-isopropyl-N′-{3-[6-(4-
433.5




methylpiperazin-1-yl)-1H-benzimidazol-




2-yl]-1H-indazol-6-yl}urea


681

N-(tert-butyl)-N′-{3-[6-(4-
447.6




methylpiperazin-1-yl)-1H-benzimidazol-




2-yl]-1H-indazol-6-yl}urea


682

N-ethyl-N′-{3-[6-(4-
419.5




methylpiperazin-1-yl)-1H-benzimidazol-




2-yl]-1H-indazol-6-yl}urea


683

N-(2-methoxyphenyl)-N′-{3-[6-(4-
497.6




methylpiperazin-1-yl)-1H-benzimidazol-




2-yl]-1H-indazol-6-yl}urea


684

N-{3-[6-(4-methylpiperazin-1-yl)-1H-
535.5




benzimidazol-2-yl]-1H-indazol-6-yl}-




N′-[3-(trifluoromethyl)phenyl]urea









Examples 685–689
Examples 685–689 were synthesized from amino substituted indazole-benzimidazoles and acyl halides or sulfonyl halides, using the coupling procedures set forth below for the synthesis of various compounds that include the —N(H)—C(═O)—R or the —N(H)—(SO2)—R′ group.
Example 685
N-{3-[6-(1,4′-Bipiperidin-1′-yl)-1H-benzimidazol-2-yl]-1H-indazol-5-yl}benzaniide
Benzimidazol-2-yl-1H-indazole-5-ylamine was dissolved in CH2Cl2 and benzoyl chloride (1.1 equivalent) was added followed by diisopropylethylamine (1.1 equivalent). The resulting mixture was allowed to stir overnight. The solution was then concentrated and the resulting residue was purified by preparatory HPLC. LC/MS (m/z) 520.6 (MH+), Rt 1.86 minutes
Example 688
N-{3-[6-(1,4′-Bipiperidin-1′-yl)-1H-benzimidazol-2-yl]-1H-indazol-5-yl}methanesulfonamide
3-Benzimidazol-2-yl-1H-indazole-5-ylamine (1 equivalent), methanesulfonyl chloride (1.1 equivalent), and diisopropylethylamine (2 equivalents) in CH2Cl2 were stirred for 18 hours. The solvent was evaporated, and the resulting residue was purified by preparatory HPLC. LC/MS (m/z) 494.6 (MH+), Rt 2.35 minutes.














LC/MS (m/z)


Example
Name
(MH+)







686
N-{3-[6-(1,4′-bipiperidin-1′-
458.6



yl)-1H-benzimidazol-2-yl]-1H-indazol-



5-yl}acetamide


687
N-{3-[6-(1,4′-bipiperidin-1′-yl)-
510.6



1H-benzimidazol-2-yl]-1H-indazol-5-



yl}-2-furamide


689
N-{3-[6-(4-methylpiperazin-1-yl)-
440.2



1H-benzimidazol-2-yl]-1H-indazol-6-



yl}ethanesulfonamide









Examples 690–726
Examples 690–726 were synthesized from amino substituted indazole-benzimidazoles and carbonyl compounds, using the procedure set forth below for Example 710.
Example 710
3-(1H-Benzimidazol-2-yl)-N-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-amine
3-Benzimidazol-2-yl-1H-indazole-5-ylamine (1 equivalent), 2-thiazolecarboxaldehyde(1.1 equivalent), BH3: pyridine (10 equivalents, 8 M in pyridine) in AcOH:MeOH:CH2Cl2 (1:2:2) were stirred for 18 hours at room temperature. The solvent was removed, and the residue was purified by preparatory HPLC. LC/MS (m/z) 347.1 (MH+), Rt 1.93 minutes.














LC/MS (m/z)


Example
Name
(MH+)







690
3-[6-(1,4′-bipiperidin-1′-
509.7



yl)-1H-benzimidazol-2-yl]-



N-[(3-methyl-1H-pyrazol-4-



yl)methyl]-1H-indazol-5-



amine


691
3-[6-(1,4′-bipiperidin-
495.6



1′-yl)-1H-benzimidazol-2-yl]-



N-(2-furylmethyl)-1H-indazol-5-amine


692
3-[6-(1,4′-bipiperidin-
547.7



1′-yl)-1H-benzimidazol-2-yl]-



N-(2,3-dihydro-1-benzofuran-5-



ylmethyl)-1H-indazol-5-amine


693
3-[6-(1,4′-bipiperidin-
495.6



1′-yl)-1H-benzimidazol-2-



yl]-N-(1H-imidazol-2-



ylmethyl)-1H-indazol-5-amine


694
3-[6-(1,4′-bipiperidin-
512.7



1′-yl)-1H-benzimidazol-2-



yl]-N-(1,3-thiazol-2-



ylmethyl)-1H-indazol-5-amine


695
3-[6-(1,4′-bipiperidin-
535.7



1′-yl)-1H-benzimidazol-2-yl]-



N-(3-methoxybenzyl)-1H-



indazol-5-amine


696
3-[6-(1,4′-bipiperidin-
498.7



1′-yl)-1H-benzimidazol-2-



yl]-N-[(2S)-pyrrolidin-2-



ylmethyl]-1H-indazol-5-amine


697
3-[6-(1,4′-bipiperidin-
552.7



1′-yl)-1H-benzimidazol-2-yl]-



N-({5-[(dimethylamino)methyl]-



2-furyl}methyl)-1H-



indazol-5-amine


698
3-[6-(1,4′-bipiperidin-
524.7



1′-yl)-1H-benzimidazol-2-yl]-



N-[(3,5-dimethylisoxazol-



4-yl)methyl]-1H-indazol-5-



amine


699
N-(1H-l,2,3-benzotriazol-5-
546.7



ylmethyl)-3-[6-(1,4′-



bipiperidin-1′-yl)-1H-



benzimidazol-2-yl]-1H-indazol-



5-amine


700
N-(1H-benzimidazol-5-ylmethyl)-
545.7



3-[6-(1,4′-bipiperidin-1′-



yl)-1H-benzimidazol-2-yl]-1H-



indazol-5-amine


701
3-[6-(1,4′-bipiperidin-
558.1



1′-yl)-1H-benzimidazol-2-



yl]-N-[(5-chloro-1,3-dimethyl-



1H-pyrazol-4-yl)methyl]-



1H-indazol-5-amine


702
3-[6-(1,4′-bipiperidin-
544.1



1′-yl)-1H-benzimidazol-2-



yl]-N-[(4-chloro-1-methyl-



1H-pyrazol-3-yl)methyl]-1H-



indazol-5-amine


703
3-[6-(1,4′-bipiperidin-
537.7



1′-yl)-1H-benzimidazol-2-



yl]-N-[(2-ethyl-4-methyl-



1H-imidazol-5-yl)methyl]-1H-



indazol-5-amine


704
N-(1-(N-hydroxycarbamoyl)(1S,2R)-
385.4



2-hydroxypropyl){4-[4-(N-



ethylcarbamoyl)phenyl]phen-



nyl}carboxamide


705
N-{4-[(4-fluorobenzyl)
561.7



oxy]benzyl}-3-[6-(4-



methylpiperazin-1-yl)-1H-



benzimidazol-2-yl]-1H-



indazol-6-amine


706
N-(1H-benzimidazol-2-ylmethyl)-
545.7



3-[6-(1,4′-bipiperidin-



1′-yl)-1H-benzimidazol-2-



yl]-1H-indazol-5-amine


707
N-benzyl-3-[6-(1,4′-
505.7



bipiperidin-1′-yl)-1H-



benzimidazol-2-yl]-1H-



indazol-5-amine


708
3-[6-(1,4′-bipiperidin-
511.7



1′-yl)-1H-benzimidazol-2-



yl]-N-(cyclohexylmethyl)-



1H-indazol-5-amine


709
N-(1-benzylpiperidin-4-yl)-
588.8



3-[6-(1,4′-bipiperidin-



1′-yl)-1H-benzimidazol-



2-yl]-1H-indazol-5-amine


711
3-(1H-benzimidazol-2-yl)-N-
332.4



[(2S)-pyrrolidin-2-



ylmethyl]-1H-indazol-5-amine


712
3-[6-(4-methylpiperazin-
444.6



1-yl)-1H-benzimidazol-2-yl]-



N-(1,3-thiazol-2-ylmethyl)-



1H-indazol-5-amine


713
3-[6-(4-methylpiperazin-1-
430.6



yl)-1H-benzimidazol-2-yl]-



N-[(2S)-pyrrolidin-2-



ylmethyl]-1H-indazol-5-amine


714
N-(2,5-dimethoxybenzyl)-3-
497.6



[6-(4-methylpiperazin-1-



yl)-1H-benzimidazol-2-



yl]-1H-indazol-6-amine


715
3-[6-(4-methylpiperazin-
444.6



1-yl)-1H-benzimidazol-2-yl]-



N-(1,3-thiazol-2-ylmethyl)-



1H-indazol-6-amine


716
N-[(1-methyl-1H-benzimidazol-
491.6



2-yl)methyl]-3-[6-(4-



methylpiperazin-1-yl)-1H-



benzimidazol-2-yl]-1H-



indazol-6-amine


717
3-[6-(4-methylpiperazin-1-
503.6



yl)-1H-benzimidazol-2-yl]-



N-[(2-phenyl-1H-imidazol-



4-yl)methyl]-1H-indazol-6-



amine


718
N-benzyl-3-[6-(4-
437.5



methylpiperazin-1-yl)-1H-



benzimidazol-2-yl]-1H-



indazol-6-amine


719
N-[(2-ethyl-4-methyl-1H-
469.6



imidazol-5-yl)methyl]-3-



[6-(4-methylpiperazin-1-



yl)-1H-benzimidazol-2-yl]-



1H-indazol-6-amine


720
N-(2-furylmethyl)-3-[6-
427.5



(4-methylpiperazin-1-yl)-1H-



benzimidazol-2-yl]-1H-



indazol-6-amine


721
N-[(4-methoxyquinolin-2-
518.6



yl)methyl]-3-[6-(4-



methylpiperazin-1-yl)-1H-



benzimidazol-2-yl]-1H-



indazol-6-amine


722
3-[6-(4-methylpiperazin-1-
444.6



yl)-1H-benzimidazol-2-yl]-



N-(1-methylpiperidin-4-yl)-



1H-indazol-6-amine


723
N-(2-fluoro-5-methoxybenzyl)-
485.6



3-[6-(4-methylpiperazin-1-



yl)-1H-benzimidazol-2-yl]-



1H-indazol-6-amine


724
N-{3-[6-(4-
441.5



methylpiperazin-1-yl)-1H-



benzimidazol-2-yl]-1H-



indazol-6-yl}-2-furamide


725
N-{3-[6-(4-
442.5



methylpiperazin-1-yl)-



1H-benzimidazol-2-yl]-1H-



indazol-6-yl}-1,3-oxazole-



5-carboxamide


726
N-{3-[6-(4-
389.5



methylpiperazin-1-yl)-1H-



benzimidazol-2-yl]-1H-



indazol-6-yl}acetamide









Example 727
Synthesis of [(1Z)-2-aza-1-(4-methylpiperazinyl)-2-phenylvinyl]{3-[6-(4-piperidylpiperidyl)benzimidazol-2-yl](1H-indazol-5-yl)}amine
3-[6-(4-piperidylpiperidyl)benzimidazol-2-yl]-1H-indazole-5-ylamine was dissolved in THF and shaken with benzenisothiocyanate (1.1 equivalents) for 18 hours. EDC-HCl (1.1 equivalents) and N-methylpiperazine (3 equivalents) were then added. The resulting solution was shaken for 18 hours. The solvent was then evaporated, and the residue was purified by preparatory HPLC to give [(1Z)-2-aza-1-(4-methyl-piperazinyl)-2-phenylvinyl]{3-[6-(4-piperidylpiperidyl)benzimidazol-2-yl-](1H-indazol-5-yl)}amine. LC/MS (m/z) 617.5 (MH+), Rt 2.65 minutes.
Example 728
Synthesis of N′-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-N,N-dimethyl-propane-1,3-diamine
Synthesis of 5-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazole
A reaction mixture of 3-benzimidazol-2-yl-5-bromo-1H-indazole in CH2Cl2and aqueous 50% NaOH solution was cooled to 0° C. and charged with SEMCl (2.2 equivalents). The reaction was stirred overnight and the cooling bath was gradually allowed to warm to room temperature. The reaction was partitioned between water and methylene chloride and the layers separated. The aqueous phase was extracted with CH2Cl2 (3×) and the organic extracts were combined and washed with brine. The resulting crude residue was purified by flash chromatography to give 5-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazole. LC/MS (m/z) 573.1 (MH+), Rt 4.29 minutes.
Synthesis of N,N-Dimethyl-N′-{1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoiniidazol-2-yl]-1H-indazol-5-yl}-propane-1,3-diamine
To a solution of 5-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazole in dry toluene was added Pd2(dba)3 (0.02 equivalents), (R)-BINAP (0.06 equivalents), N,N dimethyl propyldiamine (1.6 equivalents), and sodium t-butoxide (1.2 equivalents). The resulting reaction mixture was subjected to microwave irradiation (≈300 watts, 120° C., 10 minutes). The crude reaction product was purified by chromatography to furnish N,N-Dimethyl-N′-{1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazol-5-yl}-propane-1,3-diamine. LC/MS (m/z) 595.3 (MH+), Rt 2.95 minutes.
Synthesis of N′-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-N,N-dimethyl-propane-1,3-diamine
A solution of N,N-dimethyl-N′-{1-(2-trimethylsilanyl-ethoxymethyl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-indazol-5-yl}-propane-1,3-diamine in THF was treated with ethylene diamine (20 equivalents) and tetrabutylammonium fluoride (20 equivalents) and heated at 70° C. overnight. The resulting crude residue was purified by reverse phase HPLC to N′-[3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-yl]-N,N-dimethyl-propane-1,3-diamine. LC/MS (m/z) 335.1 (MH+), Rt 1.30 minutes.
Example 729
2-{4-[2-(5-Ethoxy-1H-indazol-3-yl)-3H-benzimidazol-5-yl]-piperazin-1-yl}-ethanol
Synthesis of 5-Ethoxyindole




5-Hydroxyindole (1.0 equivalents) was dissolved in dry, degassed acetone. EtBr (5.0 equivalents) and CS2CO3 (2.5 equivalents) were added, and the resulting solution was stirred for 18 hours. The reaction mixture was filtered through a Celite plug. The solvent was evaporated and the product purified by flash chromatography (MeOH:CH2Cl2, 5:95) to yield the desired indole ether title compound. LC/MS (m/z) 162.1 (MH+), Rt 2.45 minutes.
Synthesis of 5-Ethoxy-1H-indazole-3-carbaldehyde




The formation of 5-ethoxy-1H-indazole-3-carbaldehyde from 5-ethoxyindole was carried out using the procedures described above in Example 4. LC/MS (m/z) 191.1 (MH+), Rt 2.14 minutes.
Synthesis of 2-{4-[2-(5-Ethoxy-1H-indazol-3-yl)-3H-benzimidazol-5-yl]-piperazin-1-yl}-ethanol
The formation of 2-{4-[2-(5-ethoxy-1H-indazol-3-yl)-3H-benzimidazol-5-yl]-piperazin-1-yl}-ethanol was carried out using 5-ethoxy-1H-indazole-3-carbaldehyde and 2-[4-(3,4-diaminophenyl)-piperazin-1-yl]-ethanol using the method described above in Example 4. LC/MS (m/z) 407.3, (MH+), Rt 2.65 minutes.
Example 730
3-[6-(4-Methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-5-(5-nitro-pyridin-2-yloxy)-1H-indazole
Synthesis of 5-(5-Nitro-pyridin-2-yloxy)-1H-indole




NaH (1.1 equivalents) was added to a solution of 5-hydroxyindole (1.0 equivalent) in NMP. The resulting mixture stirred for 2 hours at room temperature. 2-Chloro-5-nitropyridine (1.1 equivalents) was added and the solution was heated to 100° C. for 2 hours. The solution was cooled and poured into water. The aqueous layer was extracted with EtOAc three times. The organic layers were then combined and concentrated to yield the desired indole heteroaryl ether 5-(5-nitro-pyridin-2-yloxy)-1H-indole.
Synthesis of 5-(5-Nitro-pyridin-2-yloxy)-1H-indazole-3-carbaldehyde




The formation of 5-(5-nitro-pyridin-2-yloxy)-1H-indazole-3-carbaldehyde from 5-(5-nitro-pyridin-2-yloxy)-1H-indole was carried using the method described above in Example 4. LC/MS (m/z) 285.2 (MH+), Rt 2.43 minutes.
Synthesis of 3-[6-(4-Methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-5-(5-nitro-pyridin-2-yloxy)-1H-indazole-
The title compound was synthesized from 5-(5-nitro-pyridin-2-yloxy)-1H-indazole-3-carbaldehyde and 4-(4-methyl-piperazin-1-yl)-benzene-1,2-diamine using the method described above in Example 4. LC/MS (m/z) 471.3 (MH+), Rt 2.94 minutes.
Example 731
3-(1H-Benzoimidazol-2-yl)-1H-indazol-5-ol
A solution of 5-hydroxyindole (1.0 equivalent), benzyl chloroformate (1.1 equivalents), and diisopropylethylamine (2.0 equivalents) in CH2Cl2 was stirred for 18 hours. The solution is concentrated to yield the desired CBz protected indole ether. The product is then reacted with NaNO2 in HCl and dioxane as previously described, followed by reaction with phenylenediamine in EtOH and toluene using the methods described above to yield the Cbz protected indazole benzimidazole. The Cbz-protected product is deprotected using 10% Pd/C and H2 to provide the desired 5-hydroxyindole benzimidazole.
Example 732
4-[2-(5-Fluoro-1H-indazol-3-yl)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid methylamide
Synthesis of 4-(4-Amino-3-nitro-phenoxy)-pyridine-2-carboxylic acid methylamide




A mixture containing 4-amino-3-nitrophenol (1 equivalent) and potassium bis(trimethylsilyl)amide (2 equivalents) was stirred in dimethylformamide for 2 hours at room temperature. [4-chloro-(2-pyridiyl)]-N-methylcarboxamide (1 equivalent) and potassium carbonate (1.5 equivalents) were added to the mixture, and the reaction was stirred at 90° C. for 3 days. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated, washed with brine (2×), dried, filtered, and concentrated to give brown solid. LC/MS (m/z) 289.2 (MH+), Rt 2.18 minutes.
Synthesis of 4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carboxylic acid methylamide




A solution of 4-(4-amino-3-nitro-phenoxy)-pyridine-2-carboxylic acid methylamide (1 equivalent) in CH2Cl2 was treated with trifluoroacetic anhydride (1 equivalent) and stirred for 10 minutes at 0° C. The mixture was quenched with a saturated NaHCO3 solution. The organic layer was separated and washed with water and brine, dried, and evaporated to yield the trifluoroacetamide.
To the solution of the trifluoroacetamide (1 equivalent) in a mixture of toluene:acetonitrile (approximately 4:1) and sodium hydroxide solution (50%) was added benzyltrimethylammonium chloride (1 equivalent) and dimethyl sulfate (1.5 equivalents). The biphasic mixture was stirred overnight at room temperature. The mixture was evaporated and then taken up in ethyl acetate, washed with water (2×) and brine (2×), dried, and evaporated to yield the title compound as a reddish orange solid. LC/MS (m/z) 303.3 (MH+), Rt 2.42 minutes.
Synthesis of 4-(3-Amino-4-methylamino-phenoxy)-pyridine-2-carboxylic Acid Methylamide




4-(4-Methylamino-3-nitro-phenoxy)-pyridine-2-carboxylic acid methylamide was reduced using the hydrogenation procedure described in Method 1. LC/MS (m/z) 273.3 (MH+), Rt 1.63 minutes.
Synthesis of 4-[2-(5-Fluoro-1H-indazol-3-yl)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid methylamide
The title compound was synthesized from 5-fluoro-1H-indazole-3-carbaldehyde and 4-(3-amino-4-methylamino-phenoxy)-pyridine-2-carboxylic acid methylamide as described above in Example 4. LC/MS (m/z) 417.4 (MH+), Rt 3.62 minutes.
Example 733
4-[2-(5-Fluoro-1H-indazol-3-yl)-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid methylamide
Synthesis of 4-(3,4-Diamino-phenoxy)-pyridine-2-carboxylic acid methylamide




4-(4-Amino-3-nitro-phenoxy)-pyridine-2-carboxylic acid methylamide was reduced using the hydrogenation procedure described in Method 1. LC/MS (m/z) 259.2 (MH+), Rt 1.32 minutes.
Synthesis of 4-[2-(5-Fluoro-1H-indazol-3-yl)-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid methylamide
The title compound was synthesized from 5-fluoro-1H-indazole-3-carbaldehyde and 4-(3,4-diamino-phenoxy)-pyridine-2-carboxylic acid methylamide using the method described above in Example 4. LC/MS (m/z) 403.1 (MH+), Rt 2.26 minutes.
Examples 734–741
The compounds in the following table are synthesized using the procedures described above.











Example
Name







734
{4-[2-(5-methoxy-1H-indazol-3-yl)-3H-



benzoimidazol-5-yl]-5-methyl-morpholin-



2-ylmethyl}-dimethyl-amine


735
{4-[2-(5-isopropoxy-1H-indazol-3-yl)-



3H-benzoimidazol-5-yl]-5-methyl-morpholin-



2-ylmethyl}-dimethyl-amine


736
{4-[2-(5-benzyloxy-1H-indazol-3-yl)-3H-



benzoimidazol-5-yl]-5-methyl-morpholin-2-



ylmethyl}-dimethyl-amine


737
dimethyl-(5-methyl-4-{2-[5-(1-methyl-



piperidin-3-yloxy)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-morpholin-2-ylmethyl)-



amine


738
1′-[2-(5-methoxy-1H-indazol-3-yl)-3H-



benzoimidazol-5-yl]-



[1,4′]bipiperidinyl


739
1′-[2-(5-isopropoxy-1H-indazol-3-yl)-



3H-benzoimidazol-5-yl]-



[1,4′]bipiperidinyl


740
3-[6-(4-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-5-(1-methyl-



piperidin-3-yloxy)-1H-indazole


741
1′-{2-[5-(1-methyl-piperidin-



3-yloxy)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-



[1,4′]bipiperidinyl









Example 742
1′-[2-(4-Ethoxy-1H-indazol-3-yl)-3H-benzoiniidazol-5-yl]-[1,4′]bipiperidinyl
Synthesis of 4-Ethoxy-1H-indole




4-Hydroxyindole (1.0 equivalents) is dissolved in dry, degassed acetone. EtBr (5.0 equivalents) and Cs2CO3 (2.5 equivalents) are added, and the resulting solution is stirred for 18 hours. The reaction mixture is filtered through a Celite plug. The solvent is evaporated, and the product is purified by flash chromatography (MeOH:CH2Cl2, 5:95) to yield the title compound.
Synthesis of 4-Ethoxy-1H-indazole-3-carbaldehyde




The formation of the title compound from 4-ethoxy-1H-indole is carried out using the procedure described above in Example 4.
Synthesis of 1′-[2-(4-Ethoxy-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]-[1,4′]bipiperidinyl
The formation of the title compound is carried out using 4-ethoxy-1H-indazole-3-carbaldehyde and 4-[1,4′]bipiperidinyl-1′-yl-benzene-1,2-diamine using the method described above in Example 4.
Examples 743–754
The compounds in the following table are synthesized using the procedures described above.












Example

Name







743

{4-[2-(4-methoxy-1H-indazol-




3-yl)-3H-benzoimidazol-5-yl]-5-




methyl-morpholin-2-ylmethyl}-




dimethyl-amine


744

{4-[2-(4-isopropoxy-1H-




indazol-3-yl)-3H-benzoimidazol-




5-yl]-5-methyl-morpholin-2-




ylmethyl}-dimethyl-amine


745

{4-[2-(4-benzyloxy-1H-indazol-




3-yl)-3H-benzoimidazol-5-yl]-5-




methyl-morpholin-2-ylmethyl}-




dimethyl-amine


746

(4-{2-[4-(1-ethyl-piperidin-




3-yloxy)-1H-indazol-3-yl]-3H-




benzoimidazol-5-yl}-5-methyl-




morpholin-2-ylmethyl)-dimethyl-




amine


747

4-methoxy-3-[6-(4-methyl-piperazin-




1-yl)-1H-benzoimidazol-2-yl]-




1H-indazole


748

4-isopropoxy-3-[6-(4-methyl-




piperazin-1-yl)-1H-benzoimidazol-2-




yl]-1H-indazole


749

4-benzyloxy-3-[6-(4-methyl-




piperazin-1-yl)-1H-benzoimidazol-2-




yl]-1H-indazole


750

4-(1-ethyl-piperidin-3-yloxy)-3-




[6-(4-methyl-piperazin-1-yl)-1H-




benzoimidazol-2-yl]-1H-indazole


751

1′-[2-(4-methoxy-1H-indazol-




3-yl)-3H-benzoimidazol-5-yl]-




[1,4′]bipiperidinyl


752

1′-[2-(4-isopropoxy-1H-




indazol-3-yl)-3H-benzoimidazol-




5-yl]-[1,4′]bipiperidinyl


753

1′-[2-(4-benzyloxy-1H-indazol-




3-yl)-3H-benzoimidazol-5-yl]-




[1,4′]bipiperidinyl


754

1′-{2-[4-(1-ethyl-piperidin-




3-yloxy)-1H-indazol-3-yl]-3H-




benzoimidazol-5-yl}-




[1,4′]bipiperidinyl









Example 755
1′-[2-(6-Ethoxy-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]-[1,4′]bipiperidinyl
Synthesis of 6-Ethoxy-1H-indole




6-Hydroxyindole (1.0 equivalents) is dissolved in dry, degassed acetone. EtBr (5.0 equivalents) and Cs2CO3 (2.5 equivalents) are added, and the resulting solution is stirred for 18 hours. The reaction mixture is filtered through a Celite plug. The solvent is evaporated, and the product is purified by flash chromatography (MeOH:CH2Cl2, 5:95) to yield the title compound.
Synthesis of 6-Ethoxy-1H-indazole-3-carbaldehyde




The formation of the title compound from 6-ethoxy-1H-indole is carried out using the procedure described above in Example 4.
Synthesis of 1′-[2-(6-Ethoxy-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]-[1,4′]bipiperidinyl
The formation of the title compound is carried out using 6-ethoxy-1H-indazole-3-carbaldehyde and 4-[1,4′]bipiperidinyl-1′-yl-benzene-1,2-diamine using the method described above in Example 4.
Examples 756–767
The compounds in the following table are synthesized using the procedures described above.











Example
Name







756
{4-[2-(6-methoxy-1H-indazol-3-



yl)-3H-benzoimidazol-5-yl]-5-



methyl-morpholin-2-ylmethyl}-



dimethyl-amine


757
{4-[2-(6-isopropoxy-1H-indazol-



3-yl)-3H-benzoimidazol-5-yl]-5-



methyl-morpholin-2-ylmethyl}-



dimethyl-amine


758
{4-[2-(6-benzyloxy-1H-indazol-



3-yl)-3H-benzoimidazol-5-yl]-5-



methyl-morpholin-2-ylmethyl}-



dimethyl-amine


759
(4-{2-[6-(1-ethyl-piperidin-



3-yloxy)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-5-methyl-



morpholin-2-ylmethyl)-dimethyl-



amine


760
6-methoxy-3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-



2-yl]-1H-indazole


761
6-isopropoxy-3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-2-



yl]-1H-indazole


762
6-benzyloxy-3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-2-



yl]-1H-indazole


763
6-(1-ethyl-piperidin-3-yloxy)-3-



[6-(4-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


764
1′-[2-(6-methoxy-1H-indazol-



3-yl)-3H-benzoimidazol-5-yl]-



[1,4′]bipiperidinyl


765
1′-[2-(6-isopropoxy-1H-indazol-



3-yl)-3H-benzoimidazol-5-yl]-



[1,4′]bipiperidinyl


766
1′-[2-(6-benzyloxy-1H-indazol-



3-yl)-3H-benzoimidazol-5-yl]-



[1,4′]bipiperidinyl


767
1′-{2-[6-(1-ethyl-piperidin-



3-yloxy)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-



[1,4′]bipiperidinyl









Example 768
1′-[2-(7-Ethoxy-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]-
Synthesis of 7-Ethoxy-1H-indole




7-Hydroxyindole (1.0 equivalents) is dissolved in dry, degassed acetone. EtBr (5.0 equivalents) and Cs2CO3 (2.5 equivalents) are added, and the resulting solution is stirred for 18 hours. The reaction mixture is filtered through a Celite plug. The solvent is evaporated, and the product is purified by flash chromatography (MeOH:CH2Cl2, 5:95) to yield the title compound.
Synthesis of 7-Ethoxy-1H-indazole-3-carbaldehyde




The formation of the title compound from 7-ethoxy-1H-indole is carried out using the procedure described above in Example 4.
Synthesis of 1′-[2-(7-Ethoxy-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]-[1,4′]bipiperidinyl
The formation of the title compound is carried out using 7-ethoxy-1H-indazole-3-carbaldehyde and 4-[1,4′]bipiperidinyl-1′-yl-benzene-1,2-diamine using the method described above in Example 4.
Examples 769–780
The compounds in the following table are synthesized using the procedures described above.











Example
Name







769
{4-[2-(7-methoxy-1H-indazol-3-



yl)-3H-benzoimidazol-5-yl]-5-



methyl-morpholin-2-ylmethyl}-



dimethyl-amine


770
{4-[2-(7-isopropoxy-1H-indazol-



3-yl)-3H-benzoimidazol-5-yl]-5-



methyl-morpholin-2-ylmethyl}-



dimethyl-amine


771
{4-[2-(7-benzyloxy-1H-indazol-



3-yl)-3H-benzoimidazol-5-yl]-5-



methyl-morpholin-2-ylmethyl}-



dimethyl-amine


772
(4-{2-[7-(1-ethyl-piperidin-



3-yloxy)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-5-methyl-



morpholin-2-ylmethyl)-dimethyl-



amine


773
7-methoxy-3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-



2-yl]-1H-indazole


774
7-isopropoxy-3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-2-



yl]-1H-indazole


775
7-benzyloxy-3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-2-



yl]-1H-indazole


776
7-(1-ethyl-piperidin-3-yloxy)-3-



[6-(4-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


777
1′-[2-(7-methoxy-1H-indazol-3-



yl)-3H-benzoimidazol-5-yl]-



[1,4′]bipiperidinyl


778
1′-[2-(7-isopropoxy-1H-indazol-



3-yl)-3H-benzoimidazol-5-yl]-



[1,4′]bipiperidinyl


779
1′-[2-(7-benzyloxy-1H-indazol-



3-yl)-3H-benzoimidazol-5-yl]-



l,4′]bipiperidinyl


780
1′-{2-[7-(1-ethyl-piperidin-



3-yloxy)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-



[1,4′]bipiperidinyl









Examples 781–792
The compounds in the following table are synthesized using the procedures described in Example 730











Example
Name







781
dimethyl-(5-methyl-4-{2-[5-



(pyridin-2-yloxy)-1H-indazol-3-



yl]-3H-benzoimidazol-5-yl}-



morpholin-2-ylmethyl)-amine


782
(4-{2-[5-(3-methoxy-pyridin-



2-yloxy)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-5-methyl-



morpholin-2-ylmethyl)-dimethyl-



amine


783
2-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-



5-yloxy}-nicotinonitrile


784
dimethyl-(5-methyl-4-{2-[5-



(4-methyl-pyridin-2-yloxy)-1H-indazol-



3-yl]-3H-benzoimidazol-5-yl}-



morpholin-2-ylmethyl)-amine


785
3-[6-(4-methyl-piperazin-1-yl)-



1H-benzoimidazol-2-yl]-5-(pyridin-2-



yloxy)-1H-indazole


786
5-(3-methoxy-pyridin-2-yloxy)-3-



[6-(4-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


787
2-{3-[6-(4-methyl-piperazin-



1-yl)-1H-benzoimidazol-2-yl]-1H-



indazol-5-yloxy}-nicotinonitrile


788
3-[6-(4-methyl-piperazin-1-yl)-



1H-benzoimidazol-2-yl]-5-(4-methyl-



pyridin-2-yloxy)-1H-indazole


789
1′-{2-[5-(pyridin-2-yloxy)-



1H-indazol-3-yl]-3H-benzoimidazol-5-



yl}-[1,4′]bipiperidinyl


790
1′-{2-[5-(3-methoxy-pyridin-



2-yloxy)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-



[1,4′]bipiperidinyl


791
2-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-5-yloxy]-nicotinonitrile


792
1′-{2-[5-(4-methyl-pyridin-2-



yloxy)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-



[1,4′]bipiperidinyl









Example 793
3-[6-(4-Methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-4-(5-nitro-pyridin-2-yloxy)-1H-indazole
Synthesis of 4-(5-Nitropyridin-2-yloxy)-1H-indole




NaH (1.1 equivalents) is added to a solution of 4-hydroxyindole (1.0 equivalent) in NMP. The resulting mixture is stirred for 2 hours at room temperature. 2-Chloro-5-nitropyridine (1.1 equivalents) is added and the solution is heated to 100° C. for 2 hours. The solution is cooled and poured into water. The aqueous layer is extracted with EtOAc three times. The organic layers are combined and concentrated to yield the title compound.
Synthesis of 4-(5-Nitro-pyridin-2-yloxy)-1H-indazole-3-carbaldehyde




The formation of the title compound from 4-(5-nitropyridin-2-yloxy)-1H-indole is carried out using the procedure described above in Example 4.
Synthesis of 3-[6-(4-Methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-4-(5-nitro-pyridin-2-yloxy)-1H-indazole
The formation of the title compound is carried out using 4-(5-nitropyridin-2-yloxy)-1H-indazole-3-carbaldehyde and 4-(4-methylpiperazin-1-yl)-benzene-1,2-diamine using the method described above in Example 4.
Examples 794–805
The compounds in the following table are synthesized using the procedures described above.











Example
Name







794
dimethyl-(5-methyl-4-{2-[4-



(pyridin-2-yloxy)-1H-indazol-3-



yl]-3H-benzoimidazol-5-yl}-



morpholin-2-ylmethyl)-amine


795
(4-{2-[4-(3-methoxy-pyridin-2-



yloxy)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-5-methyl-



morpholin-2-ylmethyl)-dimethyl-



amine


796
2-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-4-



yloxy}-nicotinonitrile


797
dimethyl-(5-methyl-4-{2-[4-



(4-methyl-pyridin-2-yloxy)-1H-indazol-



3-yl]-3H-benzoimidazol-5-yl}-



morpholin-2-ylmethyl)-amine


798
3-[6-(4-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-4-(pyridin-2-



yloxy)-1H-indazole


799
4-(3-methoxy-pyridin-2-yloxy)-3-



[6-(4-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


800
2-{3-[6-(4-methyl-piperazin-1-



yl)-1H-benzoimidazol-2-yl]-1H-



indazol-4-yloxy}-nicotinonitrile


801
3-[6-(4-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-4-(4-methyl-



pyridin-2-yloxy)-1H-indazole


802
1′-{2-[4-(pyridin-2-yloxy)-1H-



indazol-3-yl]-3H-benzoimidazol-5-



yl}-[1,4′]bipiperidinyl


803
1′-{2-[4-(3-methoxy-pyridin-2-



yloxy)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-



[1,4′]bipiperidinyl


804
2-[3-(6-[1,4′]Bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-4-yloxy]-nicotinonitrile


805
1′-{2-[4-(4-Methyl-pyridin-2-



yloxy)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-



[1,4′]bipiperidinyl









Example 806
3-[6-(4-Methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-6-(5-nitro-pyridin-2-yloxy)-1H-indazole
Synthesis of 6-(5-Nitropyridin-2-yloxy)-1H-indole




NaH (1.1 equivalents) is added to a solution of 6-hydroxyindole (1.0 equivalent) in NMP. The resulting mixture is stirred for 2 hours at room temperature. 2-Chloro-5-nitropyridine (1.1 equivalents) is added and the solution is heated to 100° C. for 2 hours. The solution is cooled and poured into water. The aqueous layer is extracted with EtOAc three times. The organic layers are combined and concentrated to yield the titled compound.
Synthesis of 6-(5-Nitropyridin-2-yloxy)-1H-indazole-3-carbaldehyde




The formation of the title compound from 6-(5-nitropyridin-2-yloxy)-1H-indole is carried out using the procedure described in Example 4.
Synthesis of 3-[6-(4-Methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-6-(5-nitro-pyridin-2-yloxy)-1H-indazole
The formation of the title compound is carried out using 6-(5-nitropyridin-2-yloxy)-1H-indazole-3-carbaldehyde and 4-(4-methylpiperazin-1-yl)-benzene-1,2-diamine using the method described above in Example 4.
Examples 807–818
The compounds in the following table are synthesized using the procedures described above.











Example
Name







807
dimethyl-(5-methyl-4-{2-[6-



(pyridin-2-yloxy)-1H-indazol-3-



yl]-3H-benzoimidazol-5-yl}-



morpholin-2-ylmethyl)-amine


808
(4-{2-[6-(3-methoxy-pyridin-



2-yloxy)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-5-methyl-



morpholin-2-ylmethyl)-dimethyl-



amine


809
2-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-



6-yloxy}-nicotinonitrile


810
dimethyl-(5-methyl-4-{2-[6-(4-



methyl-pyridin-2-yloxy)-1H-indazol-



3-yl]-3H-benzoimidazol-5-yl}-



morpholin-2-ylmethyl)-amine


811
3-[6-(4-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-6-(pyridin-2-



yloxy)-1H-indazole


812
6-(3-methoxy-pyridin-2-yloxy)-3-



[6-(4-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


813
2-{3-[6-(4-methyl-piperazin-1-



yl)-1H-benzoimidazol-2-yl]-1H-



indazol-6-yloxy}-nicotinonitrile


814
3-[6-(4-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-6-(4-methyl-



pyridin-2-yloxy)-1H-indazole


815
1′-{2-[6-(pyridin-2-yloxy)-1H-



indazol-3-yl]-3H-benzoimidazol-5-



yl}-[1,4′]bipiperidinyl


816
1′-{2-[6-(3-methoxy-pyridin-2-



yloxy)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-



[1,4′]bipiperidinyl


817
2-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-6-yloxy]-nicotinonitrile


818
1′-{2-[6-(4-methyl-pyridin-



2-yloxy)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-



[1,4′]bipiperidinyl









Example 819
3-[6-(4-Methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-7-(5-nitro-pyridin-2-yloxy)-1H-indazole
Synthesis of 7-(5-Nitropyridin-2-yloxy)-1H-indole




NaH (1.1 equivalents) is added to a solution of 7-hydroxyindole (1.0 equivalent) in NMP. The resulting mixture is stirred for 2 hours at room temperature. 2-Chloro-5-nitropyridine (1.1 equivalents) is added and the solution is heated to 100° C. for 2 hours. The solution is cooled and poured into water. The aqueous layer is extracted with EtOAc three times. The organic layers are combined and concentrated to yield the desired indole heteroaryl ether.
Synthesis of 7-(5-Nitropyridin-2-yloxy)-1H-indazole-3-carbaldehyde




The formation of the title compound from 7-(5-nitropyridin-2-yloxy)-1H-indole is carried out using the procedure described above in Example 4.
Synthesis of 3-[6-(4-Methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-7-(5-nitro-pyridin-2-yloxy)-1H-indazole
The formation of the title compound is carried out using 7-(5-nitropyridin-2-yloxy)-1H-indazole-3-carbaldehyde and 4-(4-methylpiperazin-1-yl)-benzene-1,2-diamine using the method described above in Example 4.
Examples 820–831
The compounds in the following table are synthesized using the procedures described above.











Example
Name







820
dimethyl-(5-methyl-4-{2-[7-(pyridin-



2-yloxy)-1H-indazol-3-yl]-3H-benzoimidazol-



5-yl}-morpholin-2-ylmethyl)-amine


821
(4-{2-[7-(3-methoxy-pyridin-2-yloxy)-1H-



indazol-3-yl]-3H-benzoimidazol-5-yl}-5-



methyl-morpholin-2-ylmethyl)-dimethyl-amine


822
2-{3-[6-(2-dimethylaminomethyl-5-methyl-



morpholin-4-yl)-1H-benzoimidazol-2-yl]-1H-



indazol-7-yloxy}-nicotinonitrile


823
dimethyl-(5-methyl-4-{2-[7-(4-methyl-



pyridin-2-yloxy)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-morpholin-2-



ylmethyl)-amine


824
3-[6-(4-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-7-(pyridin-2-



yloxy)-1H-indazole


825
7-(3-methoxy-pyridin-2-yloxy)-3-[6-(4-



methyl-piperazin-1-yl)-1H-benzoimidazol-



2-yl]-1H-indazole


826
2-{3-[6-(4-methyl-piperazin-1-yl)-



1H-benzoimidazol-2-yl]-1H-indazol-7-



yloxy}-nicotinonitrile


827
3-[6-(4-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-7-(4-methyl-



pyridin-2-yloxy)-1H-indazole


828
1′-{2-[7-(pyridin-2-yloxy)-1H-



indazol-3-yl]-3H-benzoimidazol-5-



yl}-[1,4′]bipiperidinyl


829
1′-{2-[7-(3-methoxy-pyridin-2-



yloxy)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-



[1,4′]bipiperidinyl


830
2-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-7-yloxy]-nicotinonitrile


831
1′-{2-[7-(4-methyl-pyridin-2-



yloxy)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-



[1,4′]bipiperidinyl









Examples 832–842
The compounds in the following table are synthesized using the procedures described in Example 685.











Example
Name







832
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-5-



yl}-acetamide


833
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-5-



yl}-2,2-dimethyl-propionamide


834
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-5-



yl}-2,4-difluoro-benzamide


835
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-5-



yl}-2-methoxy-benzamide


836
N-{3-[6-(4-methyl-piperazin-1-



yl)-1H-benzoimidazol-2-yl]-1H-



indazol-5-yl}-acetamide


837
2,2-dimethyl-N-{3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-



2-yl]-1H-indazol-5-yl}-propionamide


838
2,4-difluoro-N-{3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-



2-yl]-1H-indazol-5-yl}-benzamide


839
2-methoxy-N-{3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-2-



yl]-1H-indazol-5-yl}-benzamide


840
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-5-yl]-2,2-dimethyl-propionamide


841
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-5-yl]-2,4-difluoro-benzamide


842
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-5-yl]-2-methoxy-benzamide









Examples 843–854
The compounds in the following table are synthesized using the procedures described in Example 688.











Example
Name







843
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-5-



yl}-C,C,C-trifluoro-



methanesulfonamide


844
thiophene-2-sulfonic acid{3-[6-



(2-dimethylaminomethyl-5-methyl-



morpholin-4-yl)-1H-benzoimidazol-2-



yl]-1H-indazol-5-yl}-amide


845
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-5-



yl}-benzenesulfonamide


846
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-5-



yl}-4-methoxy-benzenesulfonamide


847
C,C,C-trifluoro-N-{3-[6-(4-



methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-



5-yl}-methanesulfonamide


848
thiophene-2-sulfonic acid{3-[6-



(4-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-5-



yl}-amide


849
N-{3-[6-(4-methyl-piperazin-1-



yl)-1H-benzoimidazol-2-yl]-1H-



indazol-5-yl}-benzenesulfonamide


850
4-methoxy-N-{3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-2-



yl]-1H-indazol-5-yl}-



benzenesulfonamide


851
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-5-yl]-C,C,C-trifluoro-



methanesulfonamide


852
thiophene-2-sulfonic acid[3-(6-



[1,4′]bipiperidinyl-1′-yl-1H-



benzoimidazol-2-yl)-1H-indazol-5-



yl]-amide


853
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-5-yl]-benzenesulfonamide


854
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-5-yl]-4-methoxy-



benzenesulfonamide









Examples 855–865
The compounds in the following table are synthesized using the procedures described in Example 685 using 3-benzimidazol-2-yl-1H-indazol-6-ylamine as the starting material.











Example
Name







855
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-6-



yl}-acetamide


856
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-6-



yl}-2,2-dimethyl-propionamide


857
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-6-



yl}-2,4-difluoro-benzamide


858
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-6-



yl}-2-methoxy-benzamide


859
2,2-dimethyl-N-{3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-



2-yl]-1H-indazol-6-yl}-propionamide


860
2,4-difluoro-N-{3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-



2-yl]-1H-indazol-6-yl}-benzamide


861
2-methoxy-N-{3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-2-



yl]-1H-indazol-6-yl}-benzamide


862
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-6-yl]-acetamide


863
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-6-yl]-2,2-dimethyl-propionamide


864
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-6-yl]-2,4-difluoro-benzamide


865
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-6-yl]-2-methoxy-benzamide









Examples 866–877
The compounds in the following table are synthesized using the procedures described in Example 688 using 3-benzimidazol-2-yl-1H-indazol-6-ylamine as the starting material.











Example
Name







866
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-6-



yl}-C,C,C-trifluoro-



methanesulfonamide


867
thiophene-2-sulfonic acid {3-[6-



(2-dimethylaminomethyl-5-methyl-



morpholin-4-yl)-1H-benzoimidazol-2-



yl]-1H-indazol-6-yl}-amide


868
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-6-



yl}-benzenesulfonamide


869
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-6-



yl}-4-methoxy-



benzenesulfonamide


870
C,C,C-trifluoro-N-{3-[6-(4-



methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-6-



yl}-methanesulfonamide


871
thiophene-2-sulfonic acid {3-[6-



(4-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-6-



yl}-amide


872
N-{3-[6-(4-methyl-piperazin-1-



yl)-1H-benzoimidazol-2-yl]-1H-



indazol-6-yl}-benzenesulfonamide


873
4-methoxy-N-{3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-2-



yl]-1H-indazol-6-yl}-



benzenesulfonamide


874
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-6-yl]-C,C,C-trifluoro-



methanesulfonamide


875
Thiophene-2-sulfonic acid [3-(6-



[1,4′]bipiperidinyl-1′-yl-



1H-benzoimidazol-2-yl)-1H-indazol-6-



yl]-amide


876
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-6-yl]-benzenesulfonamide


877
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-6-yl]-4-methoxy-benzenesulfonamide









Example 878
N-{3-[6-(4-Methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-4-yl}-benzamide
3-[6-(4-Methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-4-ylamine is dissolved in CH2Cl2 and benzoyl chloride (1.1 equivalent) is added followed by diisopropylethylamine (1.1 equivalent). The resulting mixture is stirred overnight. The solution is then concentrated and the resulting residue is purified by preparatory HPLC to provide the title compound.
Examples 879–890
The compounds in the following table are synthesized using the procedures described above.











Example
Name







879
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-4-



yl}-acetamide


880
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-4-



yl}-2,2-dimethyl-propionamide


881
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-4-



yl}-2,4-difluoro-benzamide


882
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-4-



yl}-2-methoxy-benzamide


883
N-{3-[6-(4-methyl-piperazin-1-



yl)-1H-benzoimidazol-2-yl]-1H-



indazol-4-yl}-acetamide


884
2,2-dimethyl-N-{3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-



2-yl]-1H-indazol-4-yl}-propionamide


885
2,4-difluoro-N-{3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-



2-yl]-1H-indazol-4-yl}-benzamide


886
2-methoxy-N-{3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-2-



yl]-1H-indazol-4-yl}-benzamide


887
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-4-yl]-acetamide


888
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-4-yl]-2,2-dimethyl-propionamide


889
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-4-yl]-2,4-difluoro-benzamide


890
N-[3-(6-[1,4′]Bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-4-yl]-2-methoxy-benzamide









Example 891
N-{3-[6-(4-Methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-4-yl}-methanesulfonamide
3-[6-(4-Methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-4-ylamine (1 equivalent), methanesulfonyl chloride (1.1 equivalent), and diisopropylethylamine (2 equivalents) in CH2Cl2 are stirred for 18 hours. The solvent is evaporated, and the resulting residue is purified by preparatory HPLC to provide the title compound.
Examples 892–903
The compounds in the following table are synthesized using the procedures described above.











Example
Name







892
N-{3-[6-(2-dimethylaminomethyl-5-



methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-4-



yl}-C,C,C-trifluoro-



methanesulfonamide


893
thiophene-2-sulfonic acid {3-



[6-(2-dimethylaminomethyl-5-methyl-



morpholin-4-yl)-1H-benzoimidazol-



2-yl]-1H-indazol-4-yl}-amide


894
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-



4-yl}-benzenesulfonamide


895
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-4-



yl}-4-methoxy-benzenesulfonamide


896
C,C,C-trifluoro-N-{3-[6-(4-



methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-4-



yl}-methanesulfonamide


897
thiophene-2-sulfonic acid {3-[6-



(4-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-4-



yl}-amide


898
N-{3-[6-(4-methyl-piperazin-1-



yl)-1H-benzoimidazol-2-yl]-1H-



indazol-4-yl}-benzenesulfonamide


899
4-methoxy-N-{3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-2-



yl]-1H-indazol-4-yl}-



benzenesulfonamide


900
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-4-yl]-C,C,C-trifluoro-



methanesulfonamide


901
thiophene-2-sulfonic acid [3-(6-



[1,4′]bipiperidinyl-1′-



yl-1H-benzoimidazol-2-yl)-1H-indazol-



4-yl]-amide


902
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-4-yl]-benzenesulfonamide


903
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-4-yl]-4-methoxy-



benzenesulfonamide









Example 904
3-[6-(4-Methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-7-nitro-1H-indazole
Synthesis of 7-Nitro-1H-indazole-3-carbaldehyde




The formation of 7-nitro-1H-indazole-3-carbaldehyde is carried out from the commercially available 7-nitroindole using the method described above in Example 4.
Synthesis of 3-[6-(4-Methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-7-nitro-1H-indazole
The formation of the title compound from 7-nitro-1H-indazole-3-carbaldehyde and 4-(4-methylpiperazin-1-yl)benzene-1,2-diamine is carried out using the procedure described above in Example 4.
Example 905
3-[6-(4-Methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-7-ylamine
The title compound is obtained by reducing the nitro group of 3-[6-(4-methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-7-nitro-1H-indazole of Example 742 using the method described in Method 1.
Example 906
N-{3-[6-(4-Methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-7-yl}-benzamide
The 3-[6-(4-methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-7-ylamine of Example 743 is dissolved in CH2Cl2 and benzoyl chloride (1.1 equivalent) is added followed by diisopropylethylamine (1.1 equivalent). The resulting mixture is stirred overnight. The solution is then concentrated and the resulting residue is purified by preparatory HPLC to provide the title compound.
Examples 907–918
The compounds in the following table are synthesized using the procedures described above.











Example
Name







907
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-7-



yl}-acetamide


908
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-7-



yl}-2,2-dimethyl-propionamide


909
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-7-



yl}-2,4-difluoro-benzamide


910
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-7-



yl}-2-methoxy-benzamide


911
N-{3-[6-(4-methyl-piperazin-1-



yl)-1H-benzoimidazol-2-yl]-1H-



indazol-7-yl}-acetamide


912
2,2-dimethyl-N-{3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-



2-yl]-1H-indazol-7-yl}-propionamide


913
2,4-difluoro-N-{3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-



2-yl]-1H-indazol-7-yl}-benzamide


914
2-methoxy-N-{3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-2-



yl]-1H-indazol-7-yl}-benzamide


915
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-7-yl]-acetamide


916
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-7-yl]-2,2-dimethyl-propionamide


917
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-7-yl]-2,4-difluoro-benzamide


918
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-7-yl]-2-methoxy-benzamide









Example 919
N-{3-[6-(4-Methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-7-yl}-methanesulfonamide
3-[6-(4-methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-7-ylamine (1 equivalent), methanesulfonyl chloride (1.1 equivalent), and diisopropylethylamine (2 equivalents) in CH2Cl2 are stirred for 18 hours. The solvent is evaporated, and the resulting residue is purified by preparatory HPLC to provide the title compound.
Examples 920–931
The compounds in the following table are synthesized using the procedures described above.











Example
Name







920
N-{3-[6-(2-dimethylaminomethyl-5-



methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-7-



yl}-C,C,C-trifluoro-



methanesulfonamide


921
thiophene-2-sulfonic acid {3-[6-



(2-dimethylaminomethyl-5-methyl-



morpholin-4-yl)-1H-benzoimidazol-2-



yl]-1H-indazol-7-yl}-amide


922
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-7-



yl}-benzenesulfonamide


923
N-{3-[6-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-7-



yl}-4-methoxy-



benzenesulfonamide


924
C,C,C-trifluoro-N-{3-[6-(4-



methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-7-



yl}-methanesulfonamide


925
thiophene-2-sulfonic acid {3-[6-



(4-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazol-7-



yl}-amide


926
N-{3-[6-(4-methyl-piperazin-1-



yl)-1H-benzoimidazol-2-yl]-1H-



indazol-7-yl}-benzenesulfonamide


927
4-methoxy-N-{3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-2-



yl]-1H-indazol-7-yl}-



benzenesulfonamide


928
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-7-yl]-C,C,C-trifluoro-



methanesulfonamide


929
thiophene-2-sulfonic acid [3-(6-



[1,4′]bipiperidinyl-1′-



yl-1H-benzoimidazol-2-yl)-1H-indazol-



7-yl]-amide


930
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-7-yl]-benzenesulfonamide


931
N-[3-(6-[1,4′]bipiperidinyl-



1′-yl-1H-benzoimidazol-2-yl)-1H-



indazol-7-yl]-4-methoxy-



benzenesulfonamide









Example 932
({(2R,5S)-4-[2-(6-Fluoro(1H-indazol-3-yl))benzimidazol-6-yl]-5-methylmorpholin-2-yl}methyl)diethylamine
Synthesis of {[(2R,5S)-5-Methyl-4-benzylmorpholin-2-yl]methyl}diethylamine




The title compound is obtained from (2S,5S)-2-(chloromethyl)-5-methyl-4-benzylmorpholine (see Method 8 Steps 1 and 2) displacing the chloride with diethylamine under the same reaction conditions used in Method 8 Step 3.
Synthesis of [((2S,5S)-5-Methylmorpholin-2-yl)methyl]diethylamine




The formation of the title compound is carried out using the same procedure described in Method 8 Step 4 from {[(5S,2R)-5-methyl-4-benzylmorpholin-2-yl]methyl}diethylamine.
Synthesis of {[(2R,5S)-4-(3-Amino-4-nitrophenyl)-5-methylmorpholin-2yl]methyl}diethylamine




The formation of the title compound is carried out using the same procedure described in Method 8 Step 5 using [((2S,5S)-5-methylmorpholin-2-yl)methyl]diethylamine and 5-fluoro-2-nitro-phenylamine.
Synthesis of {[(2R,5S)-4-(3,4-Diaminophenyl)-5-methylmorpholin-2-yl]methyl}diethylamine




The formation of the title compound is carried out using the same procedure described in Method 8 Step 6 {[(2R,5S)-4-(3-amino-4-nitrophenyl)-5-methylmorpholin-2yl]methyl}diethylamine.
Synthesis of ({(2R,5S)-4-[2-(6-Fluoro(1H-indazol-3-yl))benzimidazol-6-yl]-5-methylmorpholin-2-yl}methyl)diethylamine
The title compund is synthesized according to the general procedure described in Example 4 with {[(2R,5S)-4-(3,4-diaminophenyl)-5-methylmorpholin-2-yl]methyl}diethylamine and 6-fluoro-1H-indazole-3-carbaldehyde.
Examples 933–940
The compounds in the following table are synthesized using the procedures described above in Example 932.











Example
Name







933
(2R,5S)-diethyl-{4-[2-(6-



fluoro-1H-indazol-3-yl)-3H-



benzoimidazol-5-yl]-5-methyl-



morpholin-2-ylmethyl}-amine


934
(2R,5S)-{4-[2-(6-fluoro-1H-



indazol-3-yl)-3H-benzoimidazol-



5-yl]-5-methyl-morpholin-2-



ylmethyl}-isopropyl-methyl-amine


935
(2R,5S)-{4-[2-(6-chloro-1H-



indazol-3-yl)-3H-benzoimidazol-



5-yl]-5-methyl-morpholin-2-



ylmethyl}-diethyl-amine


936
(2R,5S)-{4-[2-(6-chloro-1H-



indazol-3-yl)-3H-benzoimidazol-



5-yl]-5-methyl-morpholin-2-



ylmethyl}-isopropyl-methyl-amine


937
(2R,5S)-diethyl-{4-[2-(5-



methoxy-1H-indazol-3-yl)-3H-



benzoimidazol-5-yl]-5-methyl-



morpholin-2-ylmethyl}-amine


938
(2R,5S)-isopropyl-{4-[2-(5-



methoxy-1H-indazol-3-yl)-3H-



benzoimidazol-5-yl]-5-methyl-



morpholin-2-ylmethyl}-methyl-amine


939
(2R,5S)-3-[6-(2-azetidin-1-



ylmethyl-5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-6-fluoro-



1H-indazole


940
(2R,5S)-6-fluoro-3-[6-(5-methyl-



2-pyrrolidin-1-ylmethyl-morpholin-



4-yl)-1H-benzoimidazol-2-yl]-



1H-indazole









Examples 941–964
The compounds in the following table are synthesized using the procedures described above in Example 932 starting from the appropriate (2S,5R)-2-(chloromethyl)-5-methyl-4-benzylmorpholine, (2R,5S)-2-(chloromethyl)-5-methyl-4-benzylmorpholine, or (2R,5R)-2-(chloromethyl)-5-methyl-4-benzylmorpholine.











Example
Name







941
(2S,5S)-diethyl-{4-[2-(6-fluoro-



1H-indazol-3-yl)-3H-benzoimidazol-



5-yl]-5-methyl-morpholin-2-



ylmethyl}-amine


942
(2S,5S)-{4-[2-(6-fluoro-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-5-methyl-morpholin-2-



ylmethyl}-isopropyl-methyl-amine


943
(2S,5S)-{4-[2-(6-chloro-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-5-methyl-morpholin-2-



ylmethyl}-diethyl-amine


944
(2S,5S)-{4-[2-(6-chloro-



1H-indazol-3-yl)-3H-benzoimidazol-



5-yl]-5-methyl-morpholin-2-



ylmethyl}-isopropyl-methyl-amine


945
(2S,5S)-diethyl-{4-[2-(5-



methoxy-1H-indazol-3-yl)-3H-



benzoimidazol-5-yl]-5-methyl-



morpholin-2-ylmethyl}-amine


946
(2S,5S)-isopropyl-{4-[2-(5-



methoxy-1H-indazol-3-yl)-3H-



benzoimidazol-5-yl]-5-methyl-



morpholin-2-ylmethyl}-methyl-amine


947
(2S,5S)-3-[6-(2-azetidin-1-



ylmethyl-5-methyl-morpholin-4-



yl)-1H-benzoimidazol-2-yl]-6-



fluoro-1H-indazole


948
(2S,5S)-6-fluoro-3-[6-(5-methyl-



2-pyrrolidin-1-ylmethyl-morpholin-



4-yl)-1H-benzoimidazol-2-yl]-



1H-indazole


949
(2S,5R)-diethyl-{4-[2-(6-



fluoro-1H-indazol-3-yl)-3H-



benzoimidazol-5-yl]-5-methyl-



morpholin-2-ylmethyl}-amine


950
(2S,5R)-{4-[2-(6-fluoro-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-5-methyl-morpholin-2-



ylmethyl}-isopropyl-methyl-amine


951
(2S,5R)-{4-[2-(6-chloro-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-5-methyl-morpholin-2-



ylmethyl}-diethyl-amine


952
(2S,5R)-{4-[2-(6-chloro-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-5-methyl-morpholin-2-



ylmethyl}-isopropyl-methyl-amine


953
(2S,5R)-diethyl-{4-[2-(5-



methoxy-1H-indazol-3-yl)-3H-



benzoimidazol-5-yl]-5-methyl-



morpholin-2-ylmethyl}-amine


954
(2S,5R)-isopropyl-{4-[2-(5-



methoxy-1H-indazol-3-yl)-3H-



benzoimidazol-5-yl]-5-methyl-



morpholin-2-ylmethyl}-methyl-amine


955
(2S,5R)-3-[6-(2-azetidin-1-



ylmethyl-5-methyl-morpholin-4-yl)-



1H-benzoimidazol-2-yl]-6-fluoro-



1H-indazole


956
(2S,5R)-6-fluoro-3-[6-(5-methyl-



2-pyrrolidin-1-ylmethyl-morpholin-



4-yl)-1H-benzoimidazol-2-yl]-1H-



indazole


957
(2R,5R)-diethyl-{4-[2-(6-



fluoro-1H-indazol-3-yl)-3H-



benzoimidazol-5-yl]-5-methyl-



morpholin-2-ylmethyl}-amine


958
(2R,5R)-{4-[2-(6-fluoro-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-5-methyl-morpholin-2-



ylmethyl}-isopropyl-methyl-amine


959
(2R,5R)-{4-[2-(6-chloro-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-5-methyl-morpholin-2-



ylmethyl}-diethyl-amine


960
(2R,5R)-{4-[2-(6-chloro-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-5-methyl-morpholin-2-



ylmethyl}-isopropyl-methyl-amine


961
(2R,5R)-diethyl-{4-[2-(5-



methoxy-1H-indazol-3-yl)-3H-



benzoimidazol-5-yl]-5-methyl-



morpholin-2-ylmethyl}-amine


962
(2R,5R)-isopropyl-{4-[2-(5-



methoxy-1H-indazol-3-yl)-3H-



benzoimidazol-5-yl]-5-methyl-



morpholin-2-ylmethyl}-methyl-amine


963
(2R,5R)-3-[6-(2-azetidin-1-



ylmethyl-5-methyl-morpholin-4-yl)-



1H-benzoimidazol-2-yl]-6-fluoro-



1H-indazole


964
(2R,5R)-6-fluoro-3-[6-(5-



methyl-2-pyrrolidin-1-ylmethyl-



morpholin-4-yl)-1H-benzoimidazol-



2-yl]-1H-indazole









Examples 965–972
The compounds in the following table are synthesized using the procedures described above in Example 932 using (S)-(+)-2-amino-1-butanol or (R)-(−)-2-amino-1-butanol and performing the displacement on the chloromethyl intermediate with dimethylamine or diethylamine.











Example
Name







965
(2R,5S)-{5-ethyl-4-[2-(6-



fluoro-1H-indazol-3-yl)-3H-



benzoimidazol-5-yl]-morpholin-



2-ylmethyl}-dimethyl-amine


966
(2R,5S)-diethyl-{5-ethyl-4-



[2-(6-fluoro-1H-indazol-3-yl)-



3H-benzoimidazol-5-yl]-



morpholin-2-ylmethyl}-amine


967
(2R,5R)-{5-ethyl-4-[2-(6-



fluoro-1H-indazol-3-yl)-3H-



benzoimidazol-5-yl]-morpholin-



2-ylmethyl}-dimethyl-amine


968
(2R-5R)-diethyl-{5-ethyl-4-



[2-(6-fluoro-1H-indazol-3-yl)-



3H-benzoimidazol-5-yl]-



morpholin-2-ylmethyl}-amine


969
(2S,5S)-{5-ethyl-4-[2-(6-



fluoro-1H-indazol-3-yl)-3H-



benzoimidazol-5-yl]-morpholin-



2-ylmethyl}-dimethyl-amine


970
(2S-5S)-diethyl-{5-ethyl-4-



[2-(6-fluoro-1H-indazol-3-yl)-



3H-benzoimidazol-5-yl]-



morpholin-2-ylmethyl}-amine


971
(2S,5R)-{5-ethyl-4-[2-(6-



fluoro-1H-indazol-3-yl)-3H-



benzoimidazol-5-yl]-morpholin-



2-ylmethyl}-dimethyl-amine


972
(2S-5R)-diethyl-{5-ethyl-4-



[2-(6-fluoro-1H-indazol-3-yl)-



3H-benzoimidazol-5-yl]-



morpholin-2-ylmethyl}-amine









Examples 973–983
The following compounds are synthesized as previously described using 4-amino-1-propanol as a starting material and performing the displacement on the chloromethyl intermediate with commercially available secondary amines.











Example
Name







973
{4-[2-(6-fluoro-1H-indazol-



3-yl)-3H-benzoimidazol-5-yl]-



[1,4]oxazepan-2-ylmethyl}-



dimethyl-amine


974
diethyl-{4-[2-(6-fluoro-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-[1,4]oxazepan-2-



ylmethyl}-amine


975
{4-[2-(6-chloro-1H-indazol-3-



yl)-3H-benzoimidazol-5-yl]-



[1,4]oxazepan-2-ylmethyl}-



dimethyl-amine


976
{4-[2-(6-chloro-1H-indazol-3-



yl)-3H-benzoimidazol-5-yl]-



[1,4]oxazepan-2-ylmethyl}-



diethyl-amine


977
diethyl-{4-[2-(5-methoxy-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-[1,4]oxazepan-2-



ylmethyl}-amine


978
{4-[2-(5-chloro-1H-indazol-3-



yl)-3H-benzoimidazol-5-yl]-



[1,4]oxazepan-2-ylmethyl}-



diethyl-amine


979
diethyl-{4-[2-(5-fluoro-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-[1,4]oxazepan-2-



ylmethyl}-amine


980
diethyl-{4-[2-(5-phenoxy-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-[1,4]oxazepan-2-



ylmethyl}-amine


981
{4-[2-(6-fluoro-1H-indazol-3-



yl)-3H-benzoimidazol-5-yl]-



[1,4]oxazepan-2-ylmethyl}-



isopropyl-methyl-amine


982
3-[6-(2-azetidin-1-ylmethyl-



[1,4]oxazepan-4-yl)-1H-



benzoimidazol-2-yl]-6-



fluoro-1H-indazole


983
6-fluoro-3-[6-(2-pyrrolidin-1-



ylmethyl-[1,4]oxazepan-4-yl)-1H-



benzoimidazol-2-yl]-1H-indazole









Example 984
3-[6-((3S)-3,4-Dimethylpiperazinyl)benzimidazol-2-yl]-6-fluoro-1H-indazole
Synthesis of (3S)-3-Methylpiperazine-1-carboxylic acid tert-butyl ester




To a stirred solution of (2S)-2-methylpiperazine (2 equivalents) in added. The mixture was stirred at −10° C. for two minutes, and subsequently quenched with saturated aqueous NaHCO3. The two phases were separated, and the organic layer was extracted with methylene chloride. The organic extracts were collected, dried over Na2SO4, and concentrated to give the desired product. LC/MS (m/z) 201.0 (MH+), Rt 1.67 minutes.
Synthesis of (2S)-1,2-Dimethyl-piperazine




(3S)-3-Methylpiperazine-1-carboxylic acid tert-butyl ester (1 equivalent) and paraformaldehyde (5 equivalents) were dissolved in a mixture of MeOH and AcOH (5:1) on molecular sieves. NaCNBH3 (4 equivalents) was added to the suspension at 25° C. The slurry was subsequently heated to 80° C. After 10 hours, the mixture was cooled, filtered, and concentrated. The residue was dissolved in dichloromethane and washed with saturated aqueous NaHCO3. The organic solution was dried (Na2SO4), and concentrated. The tert-butoxycarbonyl group was removed by treating the crude amine with saturated HCl in MeOH at room temperature for 30 minutes. The mixture was then concentrated and excess HCl was removed in-vacuo. The desired (2S)-1,2-dimethylpiperazine was thus obtained as the bis HCl salt. LC/MS (m/z) 115.0 (MH+), Rt 0.33 minutes.
Synthesis of 5-(3S)-(3,4-Dimethyl-piperazin-1-yl)-2-nitro-phenylamine




The title compound was prepared from (2S)-1,2-dimethylpiperazine using the procedure described in Method 8 Step 5. LC/MS (m/z) 251.3 (MH+), Rt 1.48 minutes.
Synthesis of 4-(3S)-(3,4-Dimethyl-piperazin-1-yl)-benzene-1,2-diamine




The title compound was prepared by reducing 5-(3S)-(3,4-dimethyl-piperazin-1-yl)-2-nitro-phenylamine using the procedure described in Method 8 Step 6.
Synthesis of 3-[6-(3S)-(3,4-Dimethyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-6-fluoro-1H-indazole
The title compound is synthesized from 4-(3S)-(3,4-dimethyl-piperazin-1-yl)-benzene-1,2-diamine using the procedure described in Example 4.
Examples 985–988
The following compounds are synthesized as previously described using of 4-(3S)-(3,4-dimethyl-piperazin-1-yl)-benzene-1,2-diamine.











Example
Name







985
5-chloro-3-[6-(3S)-(3,4-dimethyl-



piperazin-1-yl)-1H-benzoimidazol-



2-yl]-1H-indazole


986
6-chloro-3-[6-(3S)-(3,4-dimethyl-



piperazin-1-yl)-1H-benzoimidazol-



2-yl]-1H-indazole


987
3-[6-(3S)-(3,4-dimethyl-piperazin-



1-yl)-1H-benzoimidazol-2-yl]-5-



methoxy-1H-indazole


988
3-[6-(3S)-(3,4-Dimethyl-piperazin-



1-yl)-1H-benzoimidazol-2-yl]-5-



fluoro-1H-indazole









Examples 989–993
The following compounds are synthesized as previously described in Example 984 starting from (2R)-2-methylpiperazine.











Example
Name







989
5-chloro-3-[6-(3R)-(3,4-dimethyl-



piperazin-1-yl)-1H-benzoimidazol-



2-yl]-1H-indazole


990
6-chloro-3-[6-(3R)-(3,4-dimethyl-



piperazin-1-yl)-1H-benzoimidazol-



2-yl]-1H-indazole


991
3-[6-(3R)-(3,4-dimethyl-piperazin-



1-yl)-1H-benzoimidazol-2-yl]-6-



fluoro-1H-indazole


992
3-[6-(3R)-(3,4-dimethyl-piperazin-



1-yl)-1H-benzoimidazol-2-yl]-5-



fluoro-1H-indazole


993
3-[6-(3R)-(3,4-dimethyl-piperazin-



1-yl)-1H-benzoimidazol-2-yl]-5-



methoxy-1H-indazole









Example 994
6-Chloro-3-[6-((2S)-2-methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazole
Synthesis of tert-Butyl (3S)-4-(3-amino-4-nitrophenyl)-3-methylpiperazinecarboxylate




The title compound was synthesized as described in Method 8 Step 5 from tert-butyl (3S)-3-methylpiperazine carboxylate (see Example 984). LC/MS (m/z) 281.3 (MH+), Rt 2.90 minutes.
Synthesis of tert-butyl (3S)-4-(3,4-diaminophenyl)-3-methylpiperazinecarboxylate




The title compound is synthesized as described in Method 8 Step 6 using tert-butyl (3S)-4-(3-amino-4-nitrophenyl)-3-methylpiperazinecarboxylate.
Synthesis of 6-Chloro-3-[6-((2S)-2-methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazole
The title compound is synthesized from (3S)-4-(3,4-diaminophenyl)-3-methylpiperazinecarboxylate using the procedure described in Example 4. The tert-butoxycarbonyl protecting groups is removed by treatment with saturated HCl in MeOH.
Example 995
3-[6-((2S)-2,4-dimethylpiperazinyl)benzimidazol-2-yl]-6-chloro-1H-indazole
Synthesis of 3-[6-((2S)-2,4-dimethylpiperazinyl)benzimidazol-2-yl]-6-chloro-1H-indazole
3-[6-((2S)-2-methylpiperazinyl)benzimidazol-2-yl]-6-chloro-1H-indazole (1 equivalent) is dissolved in a mixture of MeOH and acetic acid (10: 1), on molecular sieves. Paraformaldehyde (10 equivalents) is added in one portion. The reaction mixture is stirred at room temperature overnight then solid NaCNBH3 is added in small portions. The reaction mixture is refluxed for 5 hours, cooled to room temperature, filtered, and concentrated under reduced pressure. The residue is dissolved in dichloromethane and washed with saturated aqueous NaHCO3. The organic solution is dried over Na2SO4, and the solvent removed under reduced pressure to afford the desired product.
Examples 996–1005
The following compounds are synthesized from: 3-[6-((2S)-2-methylpiperazinyl)benzimidazol-2-yl]-6-chloro-1H-indazole and 3-[6-((2R)-2-methylpiperazinyl)benzimidazol-2-yl]-6-chloro-1H-indazole according to the procedures described above in examples 994 and 995.











Example
Name
















996
6-chloro-3-[6-((2S)-4-ethyl-



2-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


997
6-chloro-3-[6-((2S)-4-isopropyl-



2-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


998
6-chloro-3-[6-((2S)-4-cyclobutyl-



2-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


999
6-chloro-3-[6-((2R)-2,4-dimethyl-



piperazin-1-yl)-1H-benzoimidazol-



2-yl]-1H-indazole


1000
6-chloro-3-[6-((2R)-4-ethyl-2-



methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1001
6-chloro-3-[6-((2R)-4-isopropyl-



2-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1002
6-chloro-3-[6-((2R)-4-cyclobutyl-



2-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1003
6-fluoro-3-[6-((2S)-4-isopropyl-



2-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1004
5-chloro-3-[6-((2S)-4-isopropyl-



2-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1005
3-[6-((2S)-4-isopropyl-2-methyl-



piperazin-1-yl)-1H-benzoimidazol-



2-yl]-5-methoxy-1H-indazole









Example 1006
({4-[2-(6-Fluoro(1H-indazol-3-yl))benzimidazol-6-yl]-1-methylpiperazin-2-yl}methyl)dimethylamine
Synthesis of 1,4-Bisbenzyl-2-(chloromethyl)piperazine




The title compound was synthesized as previously described in U.S. Pat. No. 4,940,710 incorporated herein by reference.
Synthesis of {[1,4-Bisbenzylpiperazin-2-yl]methyl}dimethylamine




A mixture of 1,4-bisbenzyl-2-(chloromethyl)piperazine (1 equivalent) and dimethylamine (5 equivalents) in ethanol, was heated at 150° C. for 36 hours in a sealed high pressure vessel. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was taken up in 1 N HCl, and the solution was washed with CH2Cl2. The water phase was made basic with a 30% aqueous NaOH solution (pH=12) and extracted with CH2Cl2. The organic extracts were collected and dried over Na2SO4. Evaporation of the solvent under reduced pressure afforded {[1,4-bisbenzylpiperazin-2-yl]methyl}dimethylamine. LC/MS (m/z): 324.3 (MH+), Rt 1.76 minutes.
Synthesis of Dimethyl(piperazin-2-ylmethyl)amine




{[1,4-bisbenzylpiperazin-2-yl]methyl}dimethylamine (1 equivalent), was dissolved in EtOH and the solution was transferred to a stainless steel high pressure vessel equipped with a pressure gauge. 10% Pd/C was added (10 wt. %), and the vessel charged with H2. The reaction mixture was stirred at 130° C. and 200 psi of H2 overnight. The reaction mixture was cooled to room temperature, filtered over a pad of Celite, and then evaporated. The desired amine was obtained in quantitative yield as a pale yellow oil. GC/MS: 143 (10%, M+), Rt=14.3 minutes.
Synthesis of tert-butyl 3-[(dimethylamino)methyl]piperazine-carboxylate




The title compound was synthesized from dimethyl(piperazin-2-ylmethyl)amine using the procedure described in example 984. GC/MS: 170 (20%, M+-tBuO), Rt=13.5 minutes.
Synthesis of Dimethyl[(1-methylpiperazin-2-yl)methyl]amine




The title compound was synthesized from tert-butyl 3-[(dimethylamino)methyl]piperazinecarboxylate using the procedure described in example 984. Purification by column chromatography on silica gel afforded the Boc protected amine which was treated with HCl in MeOH to afford the desired product. LC/MS (m/z): 158.1 (MH+), Rt 0.27 minutes.
Synthesis of {[4-(3-amino-4-nitrophenyl)-1-methylpiperazin-2-yl]methyl}dimethylamine




The title compound was synthesized from dimethyl[(1-methylpiperazin-2-yl)methyl]amine using the procedure described in Method 8 Step 5. LC/MS (m/z): 294.1 (MH+), Rt 1.11 minutes.
Synthesis of {[4-(3,4-diaminophenyl)-1-methylpiperazin-2-yl]methyl}dimethylamine




The title compound is synthesized from {[4-(3-amino-4-nitrophenyl)-1-methylpiperazin-2-yl]methyl}dimethylamine using the procedure described in Method 8 Step 6.
Synthesis of ({4-[2-(6-fluoro(1H-indazol-3-yl))benzimidazol-6-yl]-1-methylpiperazin-2-yl}methyl)dimethylamine
The title compound is synthesized from {[4-(3,4-diaminophenyl)-1-methylpiperazin-2-yl]methyl}dimethylamine using the procedure described in Example 4.
Examples 1007–1012
The following compounds are synthesized according to the procedure described above in Example 1006.











Example
Name







1007
{4-[2-(6-chloro-1H-indazol-3-



yl)-3H-benzoimidazol-5-yl]-1-methyl-



piperazin-2-ylmethyl}-dimethyl-amine


1008
{4-[2-(5-methoxy-1H-indazol-3-



yl)-3H-benzoimidazol-5-yl]-1-methyl-



piperazin-2-ylmethyl}-dimethyl-amine


1009
{4-[2-(5-benzyloxy-1H-indazol-3-



yl)-3H-benzoimidazol-5-yl]-1-methyl-



piperazin-2-ylmethyl}-dimethyl-amine


1010
{4-[2-(6-chloro-1H-indazol-3-



yl)-3H-benzoimidazol-5-yl]-1-ethyl-



piperazin-2-ylmethyl}-dimethyl-amine


1011
Diethyl-{4-[2-(6-fluoro-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-1-methyl-piperazin-2-



ylmethyl}-amine


1012
Diethyl-{1-ethyl-4-[2-(6-



fluoro-1H-indazol-3-yl)-3H-benzoimidazol-



5-yl]-piperazin-2-ylmethyl}-amine









Example 1013
3-(6-(1,4-Diazaperhydroepinyl)benzimidazol-2-yl)-6-fluoro-1H-indazole
Synthesis of tert-Butyl 4-(3-amino-4-nitrophenyl)-1,4-diazaperhydroepinecarboxylate




The title compound is synthesized from commercially available Boc-homopiperazine according to the procedure described in Method 1.
Synthesis of 3-(6-(1,4-Diazaperhydroepinyl)benzimidazol-2-yl)-6-fluoro-1H-indazole
The title compound is synthesized from tert-butyl 4-(3-amino-4-nitrophenyl)-1,4-diazaperhydroepinecarboxylate after the nitro group has been reduced according to the procedure described in Example 4. The tert-butoxycarbonyl is removed treating with saturated HCl in MeOH.
Example 1014
6-Fluoro-3-[6-(4-methyl(1,4-diazaperhydroepinyl))benzimidazol-2-yl]-1H-indazole
Synthesis of 6-Fluoro-3-[6-(4-methyl(1,4-diazaperhydroepinyl))-benzimidazol-2-yl]-1H-indazole
The title compound is synthesized from 3-(6-(1,4-diazaperhydro-epinyl)benzimidazol-2-yl)-6-fluoro-1H-indazole according to the procedure in Examples 984 and 985.
Examples 1015–1018
The following compounds are synthesized according to the procedure described above in Example 1014 using an appropriate carbonyl compound.











Example
Name







1015
6-Fluoro-3-[6-(4-ethyl(1,4-



diazaperhydroepinyl))-benzimidazol-2-



yl]-1H-indazole


1016
6-Fluoro-3-[6-(4-



isopropyl(1,4-



diazaperhydroepinyl))-benzimidazol-



2-yl]-1H-indazole


1017
6-Fluoro-3-[6-(4-



cyclobutyl(1,4-diazaperhydroepinyl))-



benzimidazol-2-yl]-1H-indazole









Example 1019
2-(6-Fluoro(1H-indazol-3-yl))-6-(1-methyl(3-piperidyloxy))-benzimidazole
Synthesis of 4-(1-Methyl-3-piperidyloxy)phenylamine




KHMDS (1.1 equivalent) was added to a THF solution of 1-methylpiperidin-3-ol (1 equivalent) at 0° C. and stirred until H2 evolution ceased. 1-fluoro-4-nitrobenzene (1 equivalent) was then added and the solution was allowed to warm to room temperature. After 2 hours, water was added and the mixture was extracted with EtOAc (3×). The combined organic extracts were dried over Na2SO4, and concentrated in vacuo to give a bright yellow oil which was directly used in the reduction step. The oil (1 equivalent) and a catalytic amount of 10% Pd/C were suspended in anhydrous EtOH at room temperature. The reaction flask was evacuated and subsequently filled with H2. After stirring for 18 hours, the mixture was filtered through Celite, and the solvent was concentrated in vacuo to yield 4-(1-methyl-3-piperidyloxy)phenylamine. LC/MS (m/z) 207.2 (MH+), Rt 0.47 minutes.
Synthesis of N-[4-(1-Methyl-3-piperidyloxy)phenyl]acetamide




4-(1-methyl-3-piperidyloxy)phenylamine (1 equivalent) was dissolved in CH2Cl2 and a catalytic amount of DMAP was added. Acetic anhydride (1.3 equivalents) was added slowly, and the solution was stirred at room temperature overnight. The reaction was then quenched with water and the aqueous layer was extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo, to yield N-[4-(1-methyl-3-piperidyloxy)phenyl]acetamide as a yellow oil. LC/MS (m/z) 249.3 (MH+), Rt 1.24 minutes.
Synthesis of N-[4-(1-Methyl(3-piperidyloxy))-2-nitrophenyl]-acetamide




A mixture of HNO3/H2SO4 (1:1, 60% HNO3: concentrated H2SO4) cooled to 0° C. was added dropwise to N-[4-(1-methyl-3-piperidyloxy)phenyl]-acetamide to form a 0.16 M solution. The solution was stirred at 0° C. for 10 minutes and then at room temperature for 30 minutes. The solution was then diluted with water and made basic (pH=10) with 6 N NaOH. The mixture was then extracted with CH2Cl2 (5×), dried over Na2SO4, and concentrated in vacuo to yield N-[4-(1-methyl(3-piperidyloxy))-2-nitrophenyl]acetamide. LC/MS (m/z) 294.0 (MH+), Rt 1.24 minutes.
Synthesis of 4-(1-Methyl(3-piperidyloxy))-2-nitrophenylamine




N-[4-(1-methyl(3-piperidyloxy))-2-nitrophenyl]acetamide was dissolved in 1:1 MeOH : 6N NaOH (aq) solution (0.03 M). After stirring at room temperature for 2 hours, MeOH was removed in vacuo. The remaining solution was extracted with EtOAc (3×). The combined organic extracts were then dried over Na2SO4 and concentrated in vacuo to give 4-(1-methyl(3-piperidyloxy))-2-nitrophenylamine.
Synthesis of 4-(1-Methyl-3-piperidyloxy)benzene-1,2-diamine




The title compound is synthesized from 4-(1-methyl(3-piperidyloxy))-2-nitrophenylamine using the procedure described in Method 1.
Synthesis of 2-(6-fluoro(1H-indazol-3-yl))-6-(1-methyl(3-piperidyloxy))benzimidazole
The title compound is synthesized from 4-(1-Methyl-3-piperidyloxy)benzene-1,2-diamine using the procedure described in Example 4.
Examples 1020–1023
The following compounds are synthesized according to the procedure described above in Example 1019.











Example
Name







1020
6-chloro-3-[6-(1-methyl-piperidin-



3-yloxy)-1H-benzoimidazol-2-yl]-



1H-indazole


1021
5-methoxy-3-[6-(1-methyl-piperidin-



3-yloxy)-1H-benzoimidazol-2-



yl]-1H-indazole


1022
5-benzyloxy-3-[6-(1-methyl-piperidin-



3-yloxy)-1H-benzoimidazol-



2-yl]-1H-indazole


1023
3-[6-(1-methyl-piperidin-3-yloxy)-



1H-benzoimidazol-2-yl]-1H-5,7-



dioxa-1,2-diaza-s-indacene









Example 1024
[2-(1H-Indazol-3-yl)-3H-benzoimidazol-5-yl]-methyl-amine
Synthesis of N1-Methyl-4-nitro-benzene-1,3-diamine




The title compound was synthesized according to the procedure described in Method 1. LC/MS (m/z) 168.3 (MH+), Rt 1.78 minutes.
Synthesis of N4-Methylbenzene-1,2,4-triamine




The title compound is synthesized by reducing N1-methyl-4-nitro-benzene-1,3-diamine using the procedure described above in Method 8 Step 6.
Synthesis of [2-(1H-Indazol-3-yl)-3H-benzoimidazol-5-yl]-methyl-triamine
The title compound is synthesized from N4-methylbenzene-1,2,4-triamine using the procedure described above in Example 4.
Examples 1025–1033
The following nitroaniline compounds were synthesized according to the procedure described above in Example 1024 starting from the appropriate commercially available amine. The spirocyclic materials used to prepare some of the examples in the following table were synthesized using the procedure following the table.















LC/MS





(m/z)
Rt


Example
Name
(MH+)
(minutes)







1025
N1-(2-dimethylamino-1-
239.4
1.53



methyl-ethyl)-4-nitro-



benzene-1,3-diamine


1026
4-nitro-N1-(2-piperidin-
265.1
1.45



1-yl-ethyl)-benzene-



1,3-diamine


1027
N1-(1-benzyl-piperidin-4-
294.5
1.71



yl)-4-nitro-benzene-



1,3-diamine


1028
N1-(1-ethyl-pyrrolidin-3-
265.1
1.39



ylmethyl)-4-nitro-



benzene-1,3-diamine


1029
N1-[3-(4-methyl-
294.5
1.38



piperazin-1-yl)-



propyl]-4-nitro-



benzene-1,3-diamine


1030
N1-methyl-N1-(1-
265.1
1.40



methyl-piperidin-



4-yl)-4-nitro-



benzene-1,3-diamine


1031
N1-(2-dimethylamino-
239.2
1.48



ethyl)-N1-methyl-4-



nitro-benzene-



1,3-diamine


1032
5-(9-isopropyl-1-
335.3
1.87



oxa-4,9-diaza-



spiro[5.5]undec-



4-yl)-2-nitro-



phenylamine


1033
5-(2-isopropyl-5-oxa-
309.1
1.60



2,8-diaza-



spiro[3.5]non-



8-yl)-2-nitro-



phenylamine









Preparation of Spirocycle Nitroanilines
The spirocyclic nitroanilines of Examples 1032 and 1033 were synthesized according to the following procedure. The synthesis of Example 1033 is provided below. The synthesis of Example 1032 was carried out in an analogous manner starting from 5-oxa-2,8-diaza-spiro[3.5]nonan-7-one.
Synthesis of 9-Isopropyl-1-oxa-4,9-diaza-spiro[5.5]undecan-3-one




1-Oxa-4,9-diaza-spiro[5.5]undecan-3-one was dissolved in MeOH and treated with acetone (6 equivalents) and NaCNBH3 (4 equivalents). To the reaction mixture was added acetic acid (3 equivalents). The reaction was heated at 50° C. for 6 hours and then cooled to room temperature. The reaction was then poured into an aqueous NaHCO3 solution and extracted with EtOAc (3×). The combined fractions were dried over MgSO4 and concentrated to provide the title compound as a yellow oil that was purified by chromatography (10% MeOH/CH2Cl2). LC/MS (m/z) 213.1 (MH+), Rt=1.38 minutes.
Synthesis of 9-Isopropyl-1-oxa-4,9-diaza-spiro[5.5]undecane




9-Isopropyl-1-oxa-4,9-diaza-spiro[5.5]undecan-3-one was dissolved in THF and LiAlH4 (5 equivalents) was added. The reaction was heated at reflux for 4 hours and then cooled to room temperature. NaF (20 equivalents) and water (5 equivalents) were added and the reaction was stirred vigorously for 1 hour. The resulting precipitate was filtered away and the filtrate was concentrated to provide the title compound as a colorless oil. GC/MS (m/z) 198, Rt=12.57 minutes.
Synthesis of 5-(9-Isopropyl-1-oxa-4,9-diaza-spiro[5.5]undec-4-yl)-2-nitro-phenylamine




The title compound was synthesized from 9-isopropyl-1-oxa-4,9-diaza-spiro[5.5]undecane using the procedure described above in Method 2.
Various indazole benzimidazoles are synthesized following the procedure of Example 4 using the nitroanilines of Examples 1024–1033 in combination with a indazole-3-carbaldehyde of formula XVI where R1, R2, R3, and R4 have any of the values described above. For example, various indazole benzimidazoles are synthesized by reacting the nitroanilines of Examples 1024–1033 with 5-fluoroindazole, 5-chloroindazole, 6-fluoroindazole, 6-chloroindazole, 5-methoxyindazole, 6-methoxyindazole, 5-ethoxyindazole, and 6-ethoxyindazole 3-carbaldehydes.
Indazole benzimidazole compounds prepared from the nitroanilines of Examples 1024–1029 are reacted with an acyl halide such as acetyl chloride to provide benzimidazole indazoles with an amide group. In an acetylation procedure, a DMA solution of an indazole benzimidazole (1 equivalent) prepared from a nitroaniline of Examples 1024–1029 is added to a room temperature solution of acetyl chloride (1.5 equivalents) in THF over 15 minutes. After this time, triethylamine (4 equivalents) is added dropwise and the reaction mixture is stirred for 2 hours at room temperature. The reaction is then partitioned between EtOAc and water. Aqueous layers are extracted with EtOAc (2×) and the combined extractions are washed with water once. Drying over anhydrous MgSO4 and concentration provides an oil that is purified by reverse phase HPLC to provide the desired product.
Indazole benzimidazole compounds prepared from the nitroanilines of Examples 1024–1029 are reacted with an acyl halide such as bromoacetyl chloride to provide benzimidazole indazoles with an amide group that includes a bromide for further reaction. In such an acetylation procedure, a DMA solution of an indazole benzimidazole (1 equivalent) prepared from a nitroaniline of Examples 1024–1029 is added to a room temperature solution of bromoacetyl chloride (1.5 equivalents) in THF over 15 minutes. After this time, triethylamine (4 equivalents) is added dropwise and the reaction mixture is stirred for 2 hours at room temperature. The reaction is then partitioned between EtOAc and water. Aqueous layers are extracted with EtOAc (2×) and the combined extractions are washed with water once. Drying over anhydrous MgSO4 and concentration provides an oil that is purified by reverse phase HPLC to provide the desired product.
An indazole benzimidazole compound that has been reacted with a bromoacetyl chloride such as described in the preceding paragraph is further functionalized by reaction with an amine. In such a reaction, the bromoacetylated product resulting from the reaction of the bromoacetyl chloride with an indazole benzimidazole prepared from the nitroanilines of Examples 1024–1029 is suspended in a desired amine such as, but not limited to, N-methylpiperazine, morpholine, and piperidine and the reaction is heated at reflux for 1 hour. The reaction is concentrated and the residue is purified via reverse phase HPLC to provide the desired product in which the bromide has been displaced by the amine.
Example 1034
5-Fluoro-3-[5-fluoro-6-(4-isopropyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazole
Synthesis of 4-Fluoro-5-(4-isopropyl-piperazin-1-yl)-2-nitro-phenylamine




4,5-Difluoro-2-nitrophenylamine (1.0 equivalent) and N-isopropyl piperazine were heated at 100° C. for 3 hours. The solution was then cooled to room temperature and diluted with water. The resulting precipitate was filtered and dried under vacuum to provide title compound product. LC/MS (m/z) 283.2 (MH+), Rt 1.56 minutes.
Synthesis of 4-Fluoro-5-(4-isopropyl-piperazin-1-yl)-benzene-1,2-diamine




Reduction of 4-fluoro-5-(4-isopropyl-piperazin-1-yl)-2-nitro-phenylamine is carried out using the procedures described in Method 1 to afford the title product.
Synthesis of 5-Fluoro-3-[5-fluoro-6-(4-isopropyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazole
The title compound was synthesized as described in Example 4 from 4-fluoro-5-(4-isopropyl-piperazin-1-yl)-benzene-1,2-diamine and 5-fluoro-1H-indazole-3-carbaldehyde. LC/MS (m/z) 397.5 (MH+), Rt 2.78 minutes.
Example 1035
3,5-Bis-(1H-benzoimidazol-2-yl)-1H-indazole
Synthesis of 1H-Indazole-3,5-dicarbaldehyde




The title compound was synthesized as described in Example 4 from the commercially available 5-formylindole. LC/MS (m/z) 175.3 (MH+), Rt 1.80 min.
Synthesis of 3,5-Bis-(1H-benzoimidazol-2-yl)-1H-indazole
The title compound was synthesized from 1H-Indazole-3,5-dicarbaldehyde and 1,2-diaminobenzene using the methods described in Example 4 except that an excess of 1,2-diaminobenzene was used. LC/MS m/z 351.2 (MH+), Rt 2.03 minutes.
Example 1036
5-(1H-Benzoimidazol-2-yl)-3-[6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazole
Synthesis of 5-(1H-Benzoimidazol-2-yl)-3-[6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazole
The title compound was synthesized as described in Example 4 in three steps. First, 1H-indole-5-carbaldehyde is reacted with 1,2-diaminobenzene in toluene and ethanol. The product of the first reaction is then reacted with NaNO2 in dioxane with aqueous HCl. The 5-benzimidazole 3-carbaldehyde thus obtained is then reacted with 4-(4-methyl-piperazin-1-yl)-benzene-1,2-diamine to produce the title compound. LC/MS m/z 449.3 (MH+), Rt 1.71 minutes.
Example 1037
1′-[2-(4-Ethoxymethyl-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]
[1,4′]bipiperidinyl
Synthesis of 4-Ethoxymethyl-1H-indole




Indole-4-methanol (1.0 equivalent) in THF is added to NaH (1.2 equivalents) in THF at 0° C. EtBr (5.0 equivalents) is added, and the resulting solution is warmed to room temperature and then heated at 50° C. for 9 hours. The reaction mixture is quenched with H2O, extracted with EtOAc. The organic layer is dried over Na2SO4, filtered and concentrated. The organic layer is dried over Na2SO4, filtered, and concentrated. The product is purified by flash chromatography (MeOH:CH2Cl2, 5:95) to yield the desired indole ether title compound.
Synthesis of 4-Ethoxymethyl-1H-indazole-3-carbaldehyde




The formation of 4-ethoxymethyl-1H-indazole-3-carbaldehyde from 4-ethoxymethyl-1H-indole is carried out as described in Example 4.
Synthesis of 1′-[2-(4-Ethoxymethyl-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]-[1,4′]bipiperidinyl
The title compound is formed by reaction of 4-ethoxymethyl-1H-indazole-3-carbaldehyde with 4-[1,4′]bipiperidinyl-1′-yl-benzene-1,2-diamine and is carried out as described in Example 4.
Examples 1038–1046
The following compounds are synthesized according to the procedure described above in Example 1037 using the appropriate starting materials.











Example
Name







1038
{4-[2-(4-methoxymethyl-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-5-methyl-morpholin-2-



ylmethyl}-dimethyl-amine


1039
{4-[2-(4-benzyloxymethyl-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-5-methyl-morpholin-2-



ylmethyl}-dimethyl-amine


1040
{4-[2-(4-isopropoxymethyl-



1H-indazol-3-yl)-3H-benzoimidazol-



5-yl]-5-methyl-moipholin-2-



ylmethyl}-dimethyl-amine


1041
4-methoxymethyl-3-[6-(4-methyl-



piperazin-1-yl)-1H-benzoimidazol-



2-yl]-1H-indazole


1042
4-benzyloxymethyl-3-[6-(4-



methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1043
4-isopropoxymethyl-3-[6-(4-



methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1044
1′-[2-(4-methoxymethyl-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-[1,4′]bipiperidinyl


1045
1′-[2-(4-benzyloxymethyl-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-[1,4′]bipiperidinyl


1046
1′-[2-(4-isopropoxymethyl-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-[1,4′]bipiperidinyl









Example 1047
1′-[2-(5-Ethoxymethyl-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]-[1,4 ′]bipiperidinyl
Synthesis of 5-Ethoxymethyl-1H-indole




Indole-5-methanol (1.0 equivalent)in THF is added to NaH (1.2 equivalents) in THF at 0° C. EtBr (5.0 equivalents) is added, and the resulting solution is warmed to room temperature and then heated at 50° C. for 9 hours. The reaction mixture is then quenched with H2O, extracted with EtOAc. The organic layer is dried over Na2SO4, filtered and concentrated. The product is purified by flash chromatography (MeOH:CH2Cl2, 5:95) to yield the desired indole ether title compound.
Synthesis of 5-Ethoxymethyl-1H-indazole-3-carbaldehyde




The formation of 5-ethoxymethyl-1H-indazole-3-carbaldehyde from 5-ethoxymethyl-1H-indole is carried out as described in Example 4.
Synthesis of 1′-[2-(5-Ethoxymethyl-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]-[1,4′]bipiperidinyl
The title compound is formed by reaction of 5-ethoxymethyl-l1H-indazole-3-carbaldehyde with 4-[1,4′]bipiperidinyl-1′-yl-benzene-1,2-diamine and is carried out as described in Example 4.
Examples 1048–1056
The following compounds are synthesized according to the procedure described above in Example 1047 using the appropriate starting materials.











Example
Name







1048
{4-[2-(5-methoxymethyl-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-5-methyl-morpholin-2-



ylmethyl}-dimethyl-amine


1049
{4-[2-(5-benzyloxymethyl-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-5-methyl-morpholin-2-



ylmethyl}-dimethyl-amine


1050
{4-[2-(5-isopropoxymethyl-



1H-indazol-3-yl)-3H-benzoimidazol-



5-yl]-5-methyl-morpholin-2-



ylmethyl}-dimethyl-amine


1051
5-methoxymethyl-3-[6-(4-



methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1052
5-benzyloxymethyl-3-[6-(4-



methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1053
5-isopropoxymethyl-3-[6-(4-



methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1054
1′-[2-(5-methoxymethyl-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-[1,4′]bipiperidinyl


1055
1′-[2-(5-benzyloxymethyl-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-[1,4′]bipiperidinyl


1056
1′-[2-(5-isopropoxymethyl-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-[1,4′]bipiperidinyl









Example 1057
1′-[2-(6-Ethoxymethyl-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]-[1,4 ′]bipiperidinyl
Synthesis of 6-Ethoxymethyl-1H-indole




Indole-6-methanol (1.0 equivalent)in THF is added to NaH (1.2 equivalents) in THF at 0° C. EtBr (5.0 equivalents) is added, and the resulting solution is warmed to room temperature and then heated at 50° C. for 9 hours. The reaction mixture is then quenched with H2O, extracted with EtOAc. The organic layer is dried over Na2SO4, filtered and concentrated. The product is purified by flash chromatography (MeOH:CH2Cl2, 5:95) to yield the desired indole ether title compound.
Synthesis of 6-Ethoxymethyl-1H-indazole-3-carbaldehyde




The formation of 6-ethoxymethyl-1H-indazole-3-carbaldehyde from 6-ethoxymethyl-1H-indole is carried out as described in Example 4.
Synthesis of 1′-[2-(6-Ethoxymethyl-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]-[1,4′]bipiperidinyl
The title compound is formed by reaction of 6-ethoxymethyl-l1H-indazole-3-carbaldehyde with 4-[1,4′]bipiperidinyl-1′-yl-benzene-1,2-diamine and is carried out as described in Example 4.
Examples 1058–1066
The following compounds are synthesized according to the procedure described above in Example 1057 using the appropriate starting materials.











Example
Name







1058
{4-[2-(6-methoxymethyl-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-5-methyl-morpholin-2-



ylmethyl}-dimethyl-amine


1059
{4-[2-(6-benzyloxymethyl-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-5-methyl-morpholin-2-



ylmethyl}-dimethyl-amine


1060
{4-[2-(6-isopropoxymethyl-



1H-indazol-3-yl)-3H-benzoimidazol-



5-yl]-5-methyl-morpholin-2-



ylmethyl}-dimethyl-amine


1061
6-methoxymethyl-3-[6-(4-



methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1062
6-benzyloxymethyl-3-[6-(4-



methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1063
6-isopropoxymethyl-3-[6-(4-



methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1064
1′-[2-(6-methoxymethyl-



1H-indazol-3-yl)-3H-benzoimidazol-5-



yl]-[1,4′]bipiperidinyl


1065
1′-[2-(6-benzyloxymethyl-



1H-indazol-3-yl)-3H-benzoimidazol-5-



yl]-[1,4′]bipiperidinyl


1066
1′-[2-(6-isopropoxymethyl-



1H-indazol-3-yl)-3H-benzoimidazol-5-



yl]-[1,4′]bipiperidinyl









Example 1067
1′-[2-(7-Ethoxymethyl-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]-[1,4′]bipiperidinyl
Synthesis of 7-Ethoxymethyl-1H-indole




Indole-7-methanol (1.0 equivalent)in THF is added to NaH (1.2 equivalents) in THF at 0° C. EtBr (5.0 equivalents) is added, and the resulting solution is warmed to room temperature and then heated at 50° C. for 9 hours. The reaction mixture is then quenched with H2O, extracted with EtOAc. The organic layer is dried over Na2SO4, filtered and concentrated. The product is purified by flash chromatography (MeOH:CH2Cl2, 5:95) to yield the desired indole ether title compound.
Synthesis of 7-Ethoxymethyl-1H-indazole-3-carbaldehyde




The formation of 7-ethoxymethyl-1H-indazole-3-carbaldehyde from 7-ethoxymethyl-1H-indole is carried out as described in Example 4.
Synthesis of 1′-[2-(7-Ethoxymethyl-1H-indazol-3-yl)-3H-benzoimidazol-5-yl]-[1,4 ′]bipiperidinyl
The title compound is formed by reaction of 7-ethoxymethyl-1H-indazole-3-carbaldehyde with 4-[1,4′]bipiperidinyl-1′-yl-benzene-1,2-diamine and is carried out as described in Example 4.
Examples 1068–1076
The following compounds are synthesized according to the procedure described above in Example 1067 using the appropriate starting materials.











Example
Name







1068
{4-[2-(7-methoxymethyl-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-5-methyl-morpholin-2-



ylmethyl}-dimethyl-amine


1069
{4-[2-(7-benzyloxymethyl-1H-



indazol-3-yl)-3H-benzoimidazol-5-



yl]-5-methyl-morpholin-2-



ylmethyl}-dimethyl-amine


1070
{4-[2-(7-isopropoxymethyl-



1H-indazol-3-yl)-3H-benzoimidazol-5-



yl]-5-methyl-morpholin-2-



ylmethyl}-dimethyl-amine


1071
7-methoxymethyl-3-[6-(4-



methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1072
7-benzyloxymethyl-3-[6-(4-



methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1073
7-isopropoxymethyl-3-[6-(4-



methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1074
1′-[2-(7-methoxymethyl-



1H-indazol-3-yl)-3H-benzoimidazol-5-



yl]-[1,4′]bipiperidinyl


1075
1′-[2-(7-benzyloxymethyl-



1H-indazol-3-yl)-3H-benzoimidazol-5-



yl]-[1,4′]bipiperidinyl


1076
1′-[2-(7-isopropoxymethyl-



1H-indazol-3-yl)-3H-benzoimidazol-5-



yl]-[1,4′]bipiperidinyl









Example 1077
3-(1H-Benzoimidazol-2-yl)-1H-indazol-4-ol
A solution of 4-hydroxyindole (1.0 equivalent), benzyl chloroformate (1.1 equivalents), and diisopropylethylamine (2.0 equivalents) in CH2Cl2 is stirred for 18 hours. The solution is concentrated to yield the desired CBz protected indole ether. The product is then reacted with NaNO2 in HCl and dioxane as described in Example 4, followed by reaction with phenylenediamine in EtOH and toluene using the methods described above to yield the Cbz protected indazole benzimidazole. The Cbz-protected product is deprotected using 10% Pd/C and H2 to provide the desired 4-hydroxyindole benzimidazole.
Example 1078
3-(1H-Benzoimidazol-2-yl)-1H-indazol-6-ol
A solution of 6-hydroxyindole (1.0 equivalent), benzyl chloroformate (1.1 equivalents), and diisopropylethylamine (2.0 equivalents) in CH2Cl2 is stirred for 18 hours. The solution is concentrated to yield the desired CBz protected indole ether. The product is then reacted with NaNO2 in HCl and dioxane as described in Example 4, followed by reaction with phenylenediamine in EtOH and toluene using the methods described above to yield the Cbz protected indazole benzimidazole. The Cbz-protected product is deprotected using 10% Pd/C and H2 to provide the desired 6-hydroxyindole benzimidazole.
Example 1079
3-(1H-Benzoimidazol-2-yl)-1H-indazol-7-ol
A solution of 7-hydroxyindole (1.0 equivalent), benzyl chloroformate (1.1 equivalents), and diisopropylethylamine (2.0 equivalents) in CH2Cl2 is stirred for 18 hours. The solution is concentrated to yield the desired CBz protected indole ether. The product is then reacted with NaNO2 in HCl and dioxane as described in Example 4, followed by reaction with phenylenediamine in EtOH and toluene using the methods described above to yield the Cbz protected indazole benzimidazole. The Cbz-protected product is deprotected using 10% Pd/C and H2 to provide the desired 7-hydroxyindole benzimidazole.
Examples 1080–1095
The following compounds are synthesized according to the procedures described above using the appropriate starting materials.











Example
Name







1080
3-[5-(4-methyl-piperazin-1-yl)-



1H-benzoimidazol-2-yl]-1H-



indazol-4-ol


1081
3-[5-(4-isopropyl-piperazin-1-



yl)-1H-benzoimidazol-2-yl]-1H-



indazol-4-ol


1082
3-[5-(2,4-dimethyl-piperazin-



1-yl)-1H-benzoimidazol-2-yl]-



1H-indazol-4-ol


1083
3-[5-(2-dimethylaminomethyl-



5-methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-



indazol-4-ol


1084
3-[5-(4-methyl-piperazin-1-



yl)-1H-benzoimidazol-2-yl]-



1H-indazol-5-ol


1085
3-[5-(4-isopropyl-piperazin-1-



yl)-1H-benzoimidazol-2-yl]-1H-



indazol-5-ol


1086
3-[5-(2,4-dimethyl-piperazin-1-



yl)-1H-benzoimidazol-2-yl]-1H-



indazol-5-ol


1087
3-[5-(2-dimethylaminomethyl-5-



methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-



indazol-5-ol


1088
3-[5-(4-methyl-piperazin-1-yl)-



1H-benzoimidazol-2-yl]-1H-



indazol-6-ol


1089
3-[5-(4-isopropyl-piperazin-1-



yl)-1H-benzoimidazol-2-yl]-1H-



indazol-6-ol


1090
3-[5-(2,4-dimethyl-piperazin-1-



yl)-1H-benzoimidazol-2-yl]-1H-



indazol-6-ol


1091
3-[5-(2-dimethylaminomethyl-5-



methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-



indazol-6-ol


1092
3-[5-(4-methyl-piperazin-1-yl)-



1H-benzoimidazol-2-yl]-1H-



indazol-7-ol


1093
3-[5-(4-isopropyl-piperazin-1-



yl)-1H-benzoimidazol-2-yl]-1H-



indazol-7-ol


1094
3-[5-(2,4-dimethyl-piperazin-1-



yl)-1H-benzoimidazol-2-yl]-1H-



indazol-7-ol


1095
3-[5-(2-dimethylaminomethyl-5-



methyl-morpholin-4-yl)-1H-



benzoimidazol-2-yl]-1H-



indazol-7-ol









Example 1096
5-[5-(4-Methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-3-[6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazole
The synthesis of the title compound is carried out using 1H-indazole-3,5-dicarbaldehyde and 4-(4-methylpiperazin-1-yl)-benzene-1,2-diamine and the methods described in Example 4 except that an excess of the 4-(4-methylpiperazin-1-yl)-benzene-1,2-diamine is used.
Example 1097
5-(1H-Benzoimidazol-2-yl)-3-[6-(4-isopropyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazole
Synthesis of 5-(1H-Benzoimidazol-2-yl)-3-[6-(4-isopropyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazole
The synthesis of the title compound is carried out as described in Example 1036 from 4-(4-isopropyl-piperazin-1-yl)-benzene-1,2-diamine to produce the title compound.
Examples 1098–1106
The following compounds are synthesized according to the procedures described above using the appropriate starting materials.











Example
Name







1098
[4-(2-{3-[6-(2-



dimethylaminomethyl-5-methyl-



morpholin-4-yl)-1H-benzoimidazol-



2-yl]-1H-indazol-5-yl}-1H-



benzoimidazol-5-yl)-5-methyl-



morpholin-2-ylmethyl]-



dimethyl-amine


1099
5-[5-(2,4-dimethyl-piperazin-1-



yl)-1H-benzoimidazol-2-yl]-3-



[6-(2,4-dimethyl-piperazin-1-



yl)-1H-benzoimidazol-2-yl]-1H-



indazole


1100
3-(1H-benzoimidazol-2-yl)-5-[5-



(2,4-dimethyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1101
5-[5-(4-isopropyl-2-methyl-



piperazin-1-yl)-1H-benzoimidazol-2-



yl]-3-[6-(4-isopropyl-2-methyl-



piperazin-1-yl)-1H-benzoimidazol-



2-yl]-1H-indazole


1102
(4-{2-[5-(1H-benzoimidazol-2-



yl)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-5-methyl-



morpholin-2-ylmethyl)-dimethyl-



amine


1103
3-(1H-benzoimidazol-2-yl)-5-[5-



(4-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1104
5-(1H-benzoimidazol-2-yl)-3-[6-



(2,4-dimethyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1105
5-(1H-benzoimidazol-2-yl)-3-[6-



(4-isopropyl-2-methyl-piperazin-



1-yl)-1H-benzoimidazol-2-yl]-



1H-indazole


1106
(4-{2-[3-(1H-benzoimidazol-



2-yl)-1H-indazol-5-yl]-1H-



benzoimidazol-5-yl}-5-methyl-



morpholin-2-ylmethyl)-dimethyl-



amine









Example 1107
3,4-Bis-(1H-benzoimidazol-2-yl)-1H-indazole
Synthesis of 1H-Indazole-3,4-dicarbaldehyde




The commercially available 1H-indole-4-carbaldehyde is reacted with NaNO2 in the presence of HCl and H2O in dioxane to produce the title pound.
Synthesis of 3,4-Bis-(1H-benzoimidazol-2-yl)-1H-indazole
The title compound is prepared using the procedure described in Example 4 from 1H-indazole-3,4-dicarbaldehyde and an excess of 1,2-diaminobenzene.
Example 1108
4-(1H-Benzoimidazol-2-yl)-3-[6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazole
Synthesis of 4-(1H-Benzoimidazol-2-yl)-3-[6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazole
The synthesis of the title compound is carried out as described in 1036 from 4-benzimidazole-3-indazole carbaldehyde and 4-(4-methylpiperazin-1-yl)-benzene-1,2-diamine to produce the title compound.
Examples 1109–1115
The following compounds are synthesized according to the procedures described above in Example 1108 using the appropriate starting materials.











Example
Name







1109
4-(1H-benzoimidazol-2-yl)-3-[6-



(4-isopropyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1110
4-(1H-benzoimidazol-2-yl)-3-[6-



(2,4-dimethyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1111
(4-{2-[4-(1H-benzoimidazol-



2-yl)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-5-methyl-



morpholin-2-ylmethyl)-dimethyl-



amine


1112
3-(1H-benzoimidazol-2-yl)-4-[6-



(4-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1113
3-(1H-benzoimidazol-2-yl)-4-[6-



(4-isopropyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1114
3-(1H-benzoimidazol-2-yl)-4-[6-



(2,4-dimethyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1115
(4-{2-[3-(1H-benzoimidazol-2-



yl)-1H-indazol-4-yl]-3H-



benzoimidazol-5-yl}-5-methyl-



morpholin-2-ylmethyl)-dimethyl-



amine









Example 1116
3,6-Bis-(1H-benzoimidazol-2-yl)-1H-indazole
Synthesis of 1H-Indazole-3,6-dicarbaldehyde




The synthesis of the title compound is carried out from 1H-indole-6-carbaldehyde by reacting it with NaNO2 in dioxane with aqueous HCl using the method described in Example 4.
Synthesis of 3,6-Bis-(1H-benzoimidazol-2-yl)-1H-indazole
The synthesis of the title compound is carried out from 1H-Indazole-3,6-dicarbaldehyde by reacting it with an excess of 1,2-diaminobenzene using the method described in Example 4.
Example 1117
6-(1H-Benzoimidazol-2-yl)-3-[6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazole
Synthesis of 6-(1H-Benzoimidazol-2-yl)-3-[6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazole
The synthesis of the title compound is carried out as described in 1036 from 6-benzimidazole-3-indazole carbaldehyde and 4-(4-methylpiperazin-1-yl)-benzene-1,2-diamine to produce the title compound.
Examples 1118–1124
The following compounds are synthesized according to the procedures described above in Example 1108 using the appropriate starting materials.











Example
Name







1118
6-(1H-benzoimidazol-2-yl)-3-[6-



(4-isopropyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1119
6-(1H-benzoimidazol-2-yl)-3-[6-



(2,4-dimethyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1120
(4-{2-[6-(1H-benzoimidazol-2-



yl)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-5-methyl-



morpholin-2-ylmethyl)-dimethyl-



amine


1121
3-(1H-benzoimidazol-2-yl)-6-[5-



(4-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1122
3-(1H-benzoimidazol-2-yl)-6-[5-



(4-isopropyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1123
3-(1H-benzoimidazol-2-yl)-6-[5-



(2,4-dimethyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1124
3-(1H-benzoimidazol-2-yl)-6-[5-



(2-isobutyl-5-methyl-morpholin-



4-yl)-1H-benzoimidazol-2-yl]-1H-



indazole









Example 1125
3,7-Bis-(1H-benzoimidazol-2-yl)-1H-indazole
Synthesis of 1H-Indazole-3,7-dicarbaldehyde




The synthesis of the title compound is carried out from 1H-indole-7-carbaldehyde by reacting it with NaNO2 in dioxane with aqueous HCl using the method described in Example 4.
Synthesis of 3,7-Bis-(1H-benzoimidazol-2-yl)-1H-indazole
The synthesis of the title compound is carried out from 1H-indazole-3,7-dicarbaldehyde by reacting it with an excess of 1,2-diaminobenzene using the method described in Example 4.
Example 1126
7-(1H-Benzoimidazol-2-yl)-3-[6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazole
Synthesis of 7-(1H-Benzoimidazol-2-yl)-3-[6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazole
The synthesis of the title compound is carried out as described 1036 from 7-benzimidazole-3 indazolecarbaldehyde and 4-(4-methylpiperazin-1-yl)-benzene-1,2-diamine to produce the title compound.
Examples 1127–1133
The following compounds are synthesized according to the procedures described above in Example 1108 using the appropriate starting materials.











Example
Name







1127
7-(1H-benzoimidazol-2-yl)-3-[6-



(4-isopropyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1128
7-(1H-benzoimidazol-2-yl)-3-[6-



(2,4-dimethyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1129
(4-{2-[7-(1H-benzoimidazol-2-



yl)-1H-indazol-3-yl]-3H-



benzoimidazol-5-yl}-5-methyl-



morpholin-2-ylmethyl)-dimethyl-



amine


1130
3-(1H-benzoimidazol-2-yl)-7-[5-



(4-methyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1131
3-(1H-benzoimidazol-2-yl)-7-[5-



(4-isopropyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1132
3-(1H-benzoimidazol-2-yl)-7-[5-



(2,4-dimethyl-piperazin-1-yl)-1H-



benzoimidazol-2-yl]-1H-indazole


1133
3-(1H-benzoimidazol-2-yl)-7-[5-



(2-isobutyl-5-methyl-morpholin-



4-yl)-1H-benzoimidazol-2-yl]-



1H-indazole









Examples 1134–1160
Examples 1134–1160 were using the procedure set forth above in Example 732 for the synthesis of indazole benzimidazoles.














LC/MS m/z


Example
Name
(MH+)







1134
4-{[2-(5-fluoro-1H-
417.4



indazol-3-yl)-1-methyl-1H-



benzimidazol-5-yl]oxy}-



N-methylpyridine-2-



carboxamide


1135
4-{[2-(5-methoxy-1H-
429.4



indazol-3-yl)-1-methyl-1H-



benzimidazol-5-yl]oxy}-



N-methylpyridine-2-



carboxamide


1136
Methyl 3-[1-methyl-5-
457.5



({2-



[(methylamino)carbonyl]pyridin-



4-yl}oxy)-1H-



benzimidazol-2-yl]-



1H-indazole-5-carboxylate


1137
N-methyl-4-{[1-
413.5



methyl-2-(5-methyl-



1H-indazol-3-yl)-



1H-benzimidazol-5-



yl]oxy}pyridine-



2-carboxamide


1138
4-({2-[5-
505.5



(benzyloxy)-1H-indazol-



3-yl]-1-methyl-1H-



benzimidazol-5-



yl}oxy)-N-



methylpyridine-2-



carboxamide


1139
4-{[2-(6-fluoro-
417.4



1H-indazol-3-yl)-1-



methyl-1H-



benzimidazol-5-



yl]oxy}-N-



methylpyridine-2-



carboxamide


1140
4-{[2-(6-chloro-
433.9



1H-indazol-3-yl)-1-



methyl-1H-



benzimidazol-5-



yl]oxy}-N-



methylpyridine-2-



carboxamide


1141
4-{[2-(5,6-
435.4



difluoro-1H-indazol-



3-yl)-1-methyl-1H-



benzimidazol-5-



yl]oxy}-N-



methylpyridine-2-



carboxamide


1142
4-{[2-(6-chloro-
451.9



5-fluoro-1H-indazol-



3-yl)-1-methyl-1H-



benzimidazol-5-



yl]oxy}-N-



methylpyridine-2-



carboxamide


1143
4-{[2-(1H-
443.4



[1,3]dioxolo[4,



5-f]indazol-3-yl)-1-



methyl-1H-benzimidazol-



5-yl]oxy}-N-



methylpyridine-2-



carboxamide


1144
4-{[2-(5-chloro-
419.8



1H-indazol-3-yl)-1H-



benzimidazol-6-



yl]oxy}-N-



methylpyridine-2-



carboxamide


1145
4-{[2-(5-bromo-1H-
464.3



indazol-3-yl)-1H-



benzimidazol-6-



yl]oxy}-N-



methylpyridine-2-



carboxamide


1146
Methyl 3-[6-({2-
443.4



[(methylamino)carbonyl]pyridin



-4-yl}oxy)-1H-



benzimidazol-2-yl]-



1H-indazole-5-



carboxylate


1147
N-methyl-4-{[2-
399.4



(5-methyl-1H-indazol-



3-yl)-1H-



benzimidazol-6-



yl]oxy}pyridine-



2-carboxamide


1148
4-({2-[5-
491.5



(benzyloxy)-1H-



indazol-3-yl]-1H-



benzimidazol-6-



yl}oxy)-N-



methylpyridine-2-



carboxamide


1149
4-{[2-(6-
403.4



fluoro-1H-indazol-



3-yl)-1H-



benzimidazol-6-



yl]oxy}-N-



methylpyridine-2-



carboxamide


1150
4-{[2-(5,6-
421.4



difluoro-1H-indazol-



3-yl)-1H-benzimidazol-



6-yl]oxy}-N-



methylpyridine-2-



carboxamide


1151
4-{[2-(1H-
429.4



[1,3]dioxolo[4,5-



f]indazol-3-yl)-



1H-benzimidazol-6-



yl]oxy}-N-



methylpyridine-2-



carboxamide


1152
4-{[2-(7-chloro-
419.8



1H-indazol-3-yl)-1H-



benzimidazol-6-



yl]oxy}-N-



methylpyridine-2-



carboxamide


1153
4-{[2-(6-cyano-
410.4



1H-indazol-3-yl)-1H-



benzimidazol-6-



yl]oxy}-N-



methylpyridine-2-



carboxamide


1154
4-{[2-(5-
457.5



isobutoxy-1H-



indazol-3-yl)-1H-



benzimidazol-



6-yl]oxy}-N-



methylpyridine-2-



carboxamide


1155
5-fluoro-3-[5-
397.4



fluoro-6-(4-



isopropylpiperazin-



1-yl)-1H-



benzimidazol-2-



yl]-1H-indazole


1156
3-[5-fluoro-6-
393.5



(4-isopropylpiperazin-



1-yl)-1H-



benzimidazol-2-yl]-



5-methyl-1H-indazole


1157
5-(benzyloxy)-3-[5-
485.6



fluoro-6-(4-



isopropylpiperazin-



1-yl)-1H-benzimidazol-



2-yl]-1H-indazole


1158
6-fluoro-3-[5-
397.4



fluoro-6-(4-



isopropylpiperazin-



1-yl)-1H-benzimidazol-



2-yl]-1H-indazole


1159
6-chloro-3-[5-
413.9



fluoro-6-(4-



isopropylpiperazin-



1-yl)-1H-



benzimidazol-2-



yl]-1H-indazole


1160
3-[5-fluoro-6-(4-
423.5



isopropylpiperazin-1-



yl)-1H-benzimidazol-



2-yl]-1H-



[1,3]dioxolo[4,5-



f]indazole









Example 1161
8-[2-(1H-Indazol-3-yl)-1H-benzoimidazol-5-yl]-1,4-dioxa-8-aza-spiro[4.5]decane
Synthesis of 5-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-2-nitro-phenylamine




The title compound was synthesized as described in Method 10, Step 2 from 1,4-dioxa-8-aza-spiro[4.5]decane and 5-fluoro-2-nitrophenylamine. LC/MS (m/z) 280.3 (MH+), Rt 2.41 minutes.
Synthesis of 8-[2-(1H-Indazol-3-yl)-1H-benzoiniidazol-5-yl]-1,4-dioxa-8-aza-spiro[4.5]decane
5-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-2-nitro-phenylamine was reduced to produce 4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzene-1,2-diamine using the procedures described above. The reduced 1,2-diaminobenzene product is heated in toluene and EtOH at 100° C. overnight with indazole-3-carbaldehyde (1.0 equivalent) to give the title compound.
Example 1162
{1-[2-(1H-Indazol-3-yl)-1H-benzoimidazol-5-yl]-piperidin-4-yl}-dimethyl-amine
Synthesis of {1-[2-(1H-Indazol-3-yl)-1H-benzoimidazol-5-yl]-piperidin-4-yl}-dimethyl-amine
The dioxolane protecting group of 8-[2-(1H-indazol-3-yl)-1H-benzoimidazol-5-yl]-1,4-dioxa-8-aza-spiro[4.5]decane is removed with PPTS (1.15 equivalents) in acetone in the microwave ( ̃300 watts, 150° C., 11 minutes) to give the ketone. The ketone is reacted with dimethylamine and BH3:pyridine (10 equivalents) in AcOH:MeOH:CH2Cl2 as described in Example 710 to yield the title compound.
Examples 1163–1199
The following compounds are synthesized according to the procedures described in Examples 1161 and 1162 using the appropriate starting materials.











Example
Name







1163
{1-[2-(5-chloro(1H-indazol-3-yl))benzimidazol-5-yl](4-



piperidyl)}dimethylamine


1164
{1-[2-(5-fluoro(1H-indazol-3-yl))benzimidazol-5-yl](4-



piperidyl)}dimethylamine


1165
{1-[2-(5-methoxy(1H-indazol-3-yl))benzimidazol-5-yl](4-



piperidyl)}dimethylamine


1166
5-chloro-3-[5-(4-pyrrolidinylpiperidyl)benzimidazol-



2-yl]-1H-indazole


1167
5-fluoro-3-[5-(4-pyrrolidinylpiperidyl)benzimidazol-



2-yl]-1H-indazole


1168
5-methoxy-3-[5-(4-pyrrolidinylpiperidyl)benzimidazol-



2-yl]-1H-indazole


1169
{1-[2-(6-chloro(1H-indazol-3-yl))benzimidazol-5-yl](4-



piperidyl)}dimethylamine


1170
{1-[2-(6-fluoro(1H-indazol-3-yl))benzimidazol-5-yl](4-



piperidyl)}dimethylamine


1171
{1-[2-(6-methoxy(1H-indazol-3-yl))benzimidazol-5-yl](4-



piperidyl)}dimethylamine


1172
6-chloro-3-[5-(4-pyrrolidinylpiperidyl)benzimidazol-



2-yl]-1H-indazole


1173
6-fluoro-3-[5-(4-pyrrolidinylpiperidyl)benzimidazol-



2-yl]-1H-indazole


1174
6-methoxy-3-[5-(4-pyrrolidinylpiperidyl)benzimidazol-



2-yl]-1H-indazole


1175
5-chloro-3-{5-[4-(4-methylpiperazinyl)piperidyl]



benzimidazol-2-yl}-1H-indazole


1176
5-fluoro-3-{5-[4-(4-methylpiperazinyl)piperidyl]



benzimidazol-2-yl}-1H-indazole


1177
5-methoxy-3-{5-[4-(4-methylpiperazinyl)piperidyl]



benzimidazol-2-yl}-1H-indazole


1178
4-{1-[2-(5-chloro-1H-indazol-3-yl)benzimidazol-5-yl]-4-



piperidyl}morpholine


1179
4-{1-[2-(5-fluoro-1H-indazol-3-yl)benzimidazol-5-yl]-4-



piperidyl}morpholine


1180
5-methoxy-3-[5-(4-morpholin-4-ylpiperidyl)



benzimidazol-2-yl]-1H-indazole


1181
6-chloro-3-{5-[4-(4-methylpiperazinyl)piperidyl]



benzimidazol-2-yl}-1H-indazole


1182
6-fluoro-3-{5-[4-(4-methylpiperazinyl)piperidyl]



benzimidazol-2-yl}-1H-indazole


1183
6-methoxy-3-{5-[4-(4-methylpiperazinyl)piperidyl]



benzimidazol-2-yl}-1H-indazole


1184
4-{1-[2-(6-chloro-1H-indazol-3-yl)benzimidazol-5-yl]-4-



piperidyl}morpholine


1185
4-{1-[2-(6-fluoro-1H-indazol-3-yl)benzimidazol-5-yl]-4-



piperidyl}morpholine


1186
6-methoxy-3-[5-(4-morpholin-4-ylpiperidyl)benzimidazol-



2-yl]-1H-indazole


1187
{1′-[2-(1H-Indazol-3-yl)-1H-benzoimidazol-5-yl]-



[1,4′]bipiperidinyl-4-yl}-dimethyl-amine


1188
{1′-[2-(5-chloro-1H-indazol-3-yl)-1H-benzoimidazol-5-yl]-



[1,4′]bipiperidinyl-4-yl}-dimethyl-amine


1189
{1′-[2-(5-fluoro-1H-indazol-3-yl)-1H-benzoimidazol-5-yl]-



[1,4′]bipiperidinyl-4-yl}-dimethyl-amine


1190
{1′-[2-(5-methoxy-1H-indazol-3-yl)-1H-benzoimidazol-5-yl]-



[1,4′]bipiperidinyl-4-yl}-dimethyl-amine


1191
1′-[2-(5-chloro-1H-indazol-3-yl)-1H-benzoimidazol-5-yl]-4-



pyrrolidin-1-yl-[1,4′]bipiperidinyl


1192
1′-[2-(5-fluoro-1H-indazol-3-yl)-1H-benzoimidazol-5-yl]-4-



pyrrolidin-1-yl-[1,4′]bipiperidinyl


1193
1′-[2-(5-methoxy-1H-indazol-3-yl)-1H-benzoimidazol-



5-yl]-4-pyrrolidin-1-yl-[1,4′]bipiperidinyl


1194
{1′-[2-(6-chloro-1H-indazol-3-yl)-1H-benzoimidazol-5-yl]-



[1,4′]bipiperidinyl-4-yl}-dimethyl-amine


1195
{1′-[2-(6-fluoro-1H-indazol-3-yl)-1H-benzoimidazol-5-yl]-



[1,4′]bipiperidiny1-4-yl}-dimethy1-amine


1196
{1′-[2-(6-methoxy-1H-indazol-3-yl)-1H-benzoimidazol-



5-yl]-[1,4′]bipiperidinyl-4-yl}-dimethyl-amine


1197
1′-[2-(6-chloro-1H-indazol-3-yl)-1H-benzoimidazol-



5-yl]-4-pyrrolidin-1-yl-[1,4′]bipiperidinyl


1198
1′-[2-(6-fluoro-1H-indazol-3-yl)-1H-benzoimidazol-



5-yl]-4-pyrrolidin-1-yl-[1,4′]bipiperidinyl


1199
1′-[2-(6-methoxy-1H-indazol-3-yl)-1H-benzoimidazol-



5-yl]-4-pyrrolidin-1-yl-[1,4′]bipiperidinyl









Assay Procedures
In Vitro Kinase Assays for Receptor Tyrosine Kinases
The kinase activity of various protein tyrosine kinases can be measured by providing ATP and a suitable peptide or protein tyrosine-containing substrate, and assaying the transfer of phosphate moiety to the tyrosine residue. Recombinant proteins corresponding to the cytoplasmic domains of the fit-1 (VEGER1), Flk-1, Tie-2, PDGE, and bFGF receptors were expressed in Sf9 insect cells using a Baculovirus expression system (InVitrogen) and purified via Glu antibody interaction (for Glu-epitope tagged constructs) or by Metal Ion Chromatography (for His6 (SEQ ID NO: 1) tagged constructs). For each assay, test compounds were serially diluted in DMSO then mixed with an appropriate kinase reaction buffer plus ATP. Kinase protein and an appropriate biotinylated peptide substrate were added to give a final volume of 50–100 μL, reactions were incubated for 1–3 hours at room temperature and stopped by the addition of 25–50 μL of 45 mM EDTA, 50 mM Hepes pH 7.5. Stopped reaction mix (75 μL) was transferred to a streptavidin coated microtiter plate (Boehringer Mannheim) and incubated for 1 hour. Phosphorylated peptide product was measured with the DELFIA time-resolved fluorescence system (Wallac or PE Biosciences), using a Eu-labeled anti-phosphotyrosine antibody PT66 with the modification that the DELFIA assay buffer was supplemented with 1 mM MgCl2 for the antibody dilution. Time resolved fluorescence was read on a Wallac 1232 DELFIA fluorometer or a PE Victor II multiple signal reader. The concentration of each compound for 50% inhibition (IC50) was calculated by non-linear regression using XL Fit data analysis software.
In Vitro Kinase Assays for Serine/Threonine Kinases
Fit-1, Flk-1, Tie-2, and bFGFR kinases were assayed in 50 mM Hepes pH 7.0, 2 mM MgCl2, 10 mM MnCl2, 1 mM NaF, 1 mM DTT, 1 mg/mI BSA, 2 μM ATP, and 0.20–0.50 μM corresponding biotinylated peptide substrate. FIt-1, FIk-1, Tie-2, and bFGFR kinases were added at 0.1 μg/mL, 0.05 μg/mL, or 0.1 μg/mL respectively. For the PDGFR kinase assay, 120 μg/mL enzyme with the same buffer conditions as above was used except for changing ATP and peptide substrate concentrations to 1.4 μM ATP, and 0.25 μM biotin-GGLFDDPSYVNVQNL-NH2 (SEQ ID NO: 2) peptide substrate.
Each of the compounds produced in Examples 1–728 was synthesized and assayed using the procedures described above. The majority of the exemplary compounds displayed an IC50 value of less than 10 μM with respect to VEGFR1, Flk-1, bFGF, Tie-2, CHK-1, cdc2, GSK-3, NEK-2, and PDGF. In addition, many of the exemplary compounds exhibited IC50 values in the nM range and showed potent activity with respect to VEGFR1, Flk-1, bFGF, Tie-2, CHK-1, cdc2, GSK-3, NEK-2, and PDGF with IC50 values of less than 1 μM. The other examples also exhibited such activity with respect to VEGFR1, Flk-1, bFGF, Tie-2, CHK-1, cdc2, GSK-3, NEK-2, and PDGF or will be shown to exhibit such activity. The exemplary compounds also exhibit inhibition activity with respect to KDR.
Each of Examples 1–728 and many of the other examples exhibited activity in one or more important assays. Many of the other exemplary compounds will be shown to exhibit activity in these assays. For this reason, each of the Exemplary compounds is both individually preferred and is preferred as a group. One, two, or more compounds of the invention may be used in combination in pharmaceutical formulations, medicaments, and in methods of treating subjects. Furthermore, each of the R1–R10 groups of the exemplary compounds is preferred individually and as a member of a group.
In one embodiment, the invention provides a method of inhibiting flt-1 (VEGFR1). The method includes administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh groups of compounds of formula I to a subject, such as a human, in need thereof.
In one embodiment, the invention provides a method of inhibiting KDR (VEGFR2). The method includes administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh groups of compounds of formula I to a subject, such as a human, in need thereof.
In one embodiment, the invention provides a method of inhibiting Flk-1. The method includes administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh groups of compounds of formula I to a subject, such as a human, in need thereof.
In one embodiment, the invention provides a method of inhibiting bFGFR. The method includes administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh groups of compounds of formula I to a subject, such as a human, in need thereof.
In one embodiment, the invention provides a method of inhibiting GSK-3. The method includes administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh groups of compounds of formula I to a subject, such as a human, in need thereof.
In one embodiment, the invention provides a method of inhibiting NEK-2. The method includes administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh groups of compounds of formula I to a subject, such as a human, in need thereof.
In one embodiment, the invention provides a method of inhibiting CHK-1. The method includes administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh groups of compounds of formula I to a subject, such as a human, in need thereof.
In one embodiment, the invention provides a method of inhibiting cdc 2. The method includes administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh groups of compounds of formula I to a subject, such as a human, in need thereof.
In one embodiment, the invention provides a method of inhibiting Tie-2. The method includes administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh groups of compounds of formula I to a subject, such as a human, in need thereof.
In one embodiment, the invention provides a method of inhibiting PDGF. The method includes administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh groups of compounds of formula I to a subject, such as a human, in need thereof.
In one embodiment, the invention provides a method of inhibiting bFGF. The method includes administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh groups of compounds of formula I to a subject, such as a human, in need thereof.
In one embodiment, the invention provides a method of inhibiting a serine/threonine kinase. The method includes administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh groups of compounds of formula I to a subject, such as a human, in need thereof.
In one embodiment, the invention provides a method of inhibiting a tyrosine kinase. The method includes administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any of the embodiments of the first, second, third, fourth, fifth, sixth, and/or seventh groups of compounds of formula I to a subject, such as a human, in need thereof.
It should be understood that the organic compounds according to the invention may exhibit the phenomenon of tautomerism. As the chemical structures within this specification can only represent one of the possible tautomeric forms, it should be understood that the invention encompasses any tautomeric form of the drawn structure.
It is understood that the invention is not limited to the embodiments set forth herein for illustration, but embraces all such forms thereof as come within the scope of the following claims.

## Claims

1. A compound having the structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable salt of the tautomer



wherein
Z1, Z2, Z3, and Z4 are C;
R1 is selected from the group consisting of —H, —F, —Cl, —Br, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R2 is selected from the group consisting of —H, —F, —Cl, —Br, —C≡N, —NO2, —CO2H, —OH, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)O-aryl groups, substituted and unsubstituted —C(═O)O-heteroaryl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups, substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted akoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted heterocyclyloxy, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms;
R3 is selected from the group consisting of —H, —F, —Cl, —Br, —CF3, —C≡N, —NO2, —CO2H, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—O-alkyl groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy group, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R4 is selected from the group consisting of —H, —F, —Br, —Cl, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R5 is selected from the group consisting of —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups;
R6 is selected from the group consisting of —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups;
R7 is selected from the group consisting of —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups;
R8 is selected from the group consisting of —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups;
R9 is —H; and
R10 is selected from the group consisting of —H, and substituted and unsubstituted alkyl groups,
and further wherein at least one of R6 or R7 is selected from the group consisting of —Br, —CO2H, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted alkoxyalkoxy groups, substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted cycloalkylheterocyclyl groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, substituted and unsubstituted heterocyclylamino groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups.

2. The compound of claim 1, wherein R3 is selected from the group consisting of —F, —Cl, —Br, —CF3, —C≡N, —NO2, —CO2H, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, and substituted and unsubstituted —C(═O)N(H)-alkyl-heterocyclyl groups.

3. The compound of claim 1, wherein R3 is selected from the group consisting of —F, —Cl, —Br, —CF3, —C≡N, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, and substituted and unsubstituted —C(═O)N(H)-alkyl-heterocyclyl groups.

4. The compound of claim 1, wherein R1 is selected from —H, —F, —Cl, or —Br.

5. The compound of claim 1, wherein R2 is selected from the group consisting of —H, —F, —Cl, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted heterocyclyloxy, and substituted and unsubstituted heterocyclylalkoxy groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms.

6. The compound of claim 1, wherein R2 is H.

7. The compound of claim 1, wherein R2 is an unsubstituted alkoxy group having from 1 to 4 carbon atoms, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryloxy group, or a substituted or unsubstituted heteroaryloxy group.

8. The compound of claim 1, wherein R3 is selected from the group consisting of —H, —F, —Cl, and —OMe.

9. The compound of claim 1, wherein R5 or R8 is selected from —H, a —CH3 group, or a morpholine group.

10. The compound of claim 1, wherein R6 is selected from the group consisting of —Br, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, substituted and unsubstituted —C(═O)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, and substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups.

11. The compound of claim 1, wherein R6 is an alkoxy group having from 1–6 carbon atoms or an alkyl group having from 1–6 carbon atoms.

12. The compound of claim 1, wherein R6 is a substituted alkoxy group having the formula —OCH2(CH2)mR11 where m is an integer selected from the group consisting of 0, 1, and 2 and R11 is selected from the group consisting of substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups.

13. The compound of claim 1, wherein R6 is a substituted amino group having the formula —N(R12)(CH2)pR13 where p is an integer selected from 0, 1, 2, or 3, R13 is selected from the group consisting of substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups, and R12 is selected from the group consisting of —H, and substituted and unsubstituted alkyl groups.

14. The compound of claim 1, wherein R6 is a substituted or unsubstituted heterocyclyl group.

15. The compound of claim 1, wherein at least one of R6 or R7 is —H.

16. The compound of claim 1, wherein R7 is selected from the group consisting of substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, substituted and unsubstituted —C(═O)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, and substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups.

17. The compound of claim 1, wherein R7 is an alkoxy group having from 1–6 carbon atoms or an alkyl group having from 1–6 carbon atoms.

18. The compound of claim 1, wherein R7 is a substituted alkoxy group having the formula —OCH2(CH2)nR14 where n is an integer selected from 0, 1, or 2 and R14 is selected from the group consisting of substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups.

19. The compound of claim 1, wherein R7 is a substituted amino group having the formula —N(R15)(CH2)qR16 where q is an integer selected from 0, 1, 2, or 3, R16 is selected from the group consisting of substituted and unsubstituted alkoxy groups, substituted and unsubstituted aryl groups, and substituted and unsubstituted heterocyclyl groups, and R15 is selected from the group consisting of —H, and substituted and unsubstituted alkyl groups.

20. The compound of claim 1, wherein R7 is a substituted or unsubstituted heterocyclyl group.

21. The compound of claim 1, wherein R3 is selected from —F, —Cl, or —OMe.

22. The compound of claim 1, wherein R2 is a substituted or unsubstituted amino group selected from the group consisting of substituted and unsubstituted alkylamino groups, dialkylamino groups, heterocyclylamino, heterocyclylalkylamino groups, heterocyclylamino groups, arylalkylamino groups, arylalkoxyarylmethylamino groups, and aryloxyarylalkylamino groups.

23. The compound of claim 1, wherein R3 is selected from the group consisting of substituted and unsubstituted —C(═O)N(H)-alkyl-heterocyclyl groups where the heterocyclyl group of the —C(═O)N(H)-alkyl-heterocyclyl groups is selected from the group consisting of morpholinyl, piperazinyl, and piperidinyl groups.

24. A compound having the structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable salt of the tautomer



wherein
Z1, Z2, Z3, and Z4 are C;
R1 is selected from the group consisting of —H, —F, —Cl, —Br, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R2 is selected from the group consisting of —H, —F, —Cl, —Br, —C≡N, —NO2, —CO2H, —OH, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)O-aryl groups, substituted and unsubstituted —C(═O)O-heteroaryl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups, substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted akoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted heterocyclyloxy, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms;
R3 is selected from the group consisting of —F, —Cl, —Br, —CF3, —C≡N, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted saturated heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted saturated heterocyclyl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, and substituted and unsubstituted —N(H)C(═O)N(H)-aryl;
R4 is selected from the group consisting of —H, —F, —Br, —Cl, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R5 is selected from the group consisting of —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups;
R6 is selected from the group consisting of —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups;
R7 is selected from the group consisting of —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups;
R8 is selected from the group consisting of —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups;
R9 is —H; and
R10 is selected from the group consisting of —H, and substituted and unsubstituted alkyl groups.

25. A compound having the structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable salt of the tautomer



wherein p1 Z1, Z2, Z3, and Z4 are C;
R1 is selected from the group consisting of —H, —F, —Cl, —Br, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R2 is selected from the group consisting of —F, —Cl, —Br, —C≡N, —CO2H, —OH, substituted and unsubstituted guanidinyl groups,substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)O-aryl groups, substituted and unsubstituted —C(═O)O-heteroaryl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)C(═O)N(H)-heterocyclyl groups,substituted and unsubstituted —N(H)—(SO2)-alkyl groups, substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted heterocyclyloxy, and substituted and unsubstituted heterocyclylalkoxy groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms;
R3 is selected from the group consisting of —H, —F, —Cl, —Br, —CF3, —C≡N, —NO2, —CO2H, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—O-alkyl groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy group, substituted and unsubstituted heterocycyl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R4 is selected from the group consisting of —H1-F, —Br, —Cl, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R5 is selected from the group consisting of —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups;
R6 is selected from the group consisting of —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups;
R7 is selected from the group consisting of —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups;
R8 is selected from the group consisting of —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups;
R9 is —H; and
R10 is selected from the group consisting of —H, and substituted and unsubstituted alkyl groups.

26. A compound having the structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable salt of the tautomer



wherein
Z1, Z2, Z3, and Z4 are C;
R1 is selected from the group consisting of —H, —F, —Cl, —Br, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R2 is selected from the group consisting of —H, —F, —Cl, —Br, —C≡N, —NO2, —CO2H, —OH, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)O-aryl groups, substituted and unsubstituted —C(═O)O-heteroaryl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups, substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted akoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted heterocyclyloxy, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms;
R3 is selected from the group consisting of —H, —F, —Cl, —Br, —CF3, —C≡N, —NO2, —CO2H, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—O-alkyl groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy group, substituted and unsubstituted heterocycyl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R4 is selected from the group consisting of —H, —F, —Br, —Cl, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R5 is selected from the group consisting of —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups;
R6 is selected from the group consisting of —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups;
R7 is selected from the group consisting of —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups;
R8 is selected from the group consisting of —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups;
R9 is —H; and
R10 is selected from the group consisting of —H, and substituted and unsubstituted alkyl groups,
and further wherein at least one of R6 or R7 is selected from the group consisting of substituted and unsubstituted piperidinyl substituted heterocyclyl groups, substituted and unsubstituted heterocyclyl substituted piperidinyl groups, substituted and unsubstituted hydroxymethyl substituted piperidinyl groups, dimethylaminoalkyl substituted pyrrolidinyl groups, substituted and unsubstituted 3-alkyl substituted piperazinyl groups, substituted and unsubstituted 3,5-dialkyl substituted piperazinyl groups, substituted and unsubstituted N-hydroxyalkyl substituted piperazinyl groups, substituted and unsubstituted 1,4-diazacycloheptyl groups, substituted and unsubstituted 1-aza-4-oxacycloheptane groups, substituted and unsubstituted N-ethylpiperazinyl groups, substituted and unsubstituted N-isopropylpiperazinyl groups, substituted and unsubstituted N-sec-butylpiperazinyl groups, substituted and unsubstituted N-2-pyridyl substituted piperazinyl groups, substituted and unsubstituted N-3-pyridyl substituted piperazinyl groups, substituted and unsubstituted N-4-pyridyl substituted piperazinyl groups, substituted and unsubstituted N(H)—CH2-pyridyl groups, substituted and unsubstituted imidazolyl groups, substituted and unsubstituted 3-alkyl substituted morpholinyl groups, substituted and unsubstituted 3,5-dialkyl substituted morpholinyl groups, dialkylamino substituted pyrrolidinyl groups, pyrrolidinyl groups substituted with both dialkylamino and alkyl groups, substituted and unsubstituted 4-hydroxy substituted piperidinyl groups, substituted and unsubstituted 4-aryl substituted piperidinyl groups, substituted and unsubstituted 4-hydroxy-4-phenyl substituted piperidinyl groups, substituted and unsubstituted cyclohexylpiperazinyl groups, substituted and unsubstituted cyclopentylpiperazinyl groups, substituted and unsubstituted N-alkyl substituted diazabicycloalkane groups, substituted and unsubstituted —N(CH3)(N-alkyl(4-piperidinyl)) groups, substituted and unsubstituted piperazinyl groups further substituted with a —C(═O)-alkyl group bonded to one of the N atoms of the piperazinyl group, substituted and unsubstituted —N(H)CH2CH2CH2-imidazolyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-pyrrolidinyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-morpholinyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-piperazinyl groups, substituted and unsubstituted —N(H)CH2CH2-piperazinyl groups, substituted and unsubstituted —N(H)CH2CH2-piperidinyl groups, substituted and unsubstituted —N(H)CH2CH2-imidazolyl groups, substituted and unsubstituted —N(H)CH2CH2-pyrrolidinyl groups, substituted and unsubstituted —N(H)CH2CH2-morpholinyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-piperazinyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-piperidinyl groups, substituted and unsubstituted —N(H)CH2CH2CH2-pyridyl groups, substituted and unsubstituted cyclobutylpiperazinyl groups, substituted and unsubstituted —OCH2-pyrrolidinyl groups, substituted and unsubstituted —OCH2CH2-pyrrolidinyl groups, substituted and unsubstituted -OCH2CH2CH2-pyrrolidinyl groups, substituted and unsubstituted piperazinyl groups further substituted with a —CH2C(═O)—O-alkyl group bonded to one of the N atoms of the piperazinyl group, substituted and unsubstituted piperazinyl groups further substituted with a —C(═O)—O-alkyl group bonded to one of the N atoms of the piperazinyl group, substituted and unsubstituted hydroxypyrrolidinyl groups, substituted and unsubstituted hydroxypiperidinyl groups, substituted and unsubstituted —OCH2-pyridyl groups, substituted and unsubstituted piperidinylamino groups, substituted and unsubstituted pyridyloxy groups with a —C(═O)—N(H)(alkyl) group bonded to a carbon atom of the pyridine ring of the pyridyloxy group, and substituted and unsubstituted pyridyloxy groups with a —C(═O)—N(alkyl)2 group bonded to a carbon atom of the pyridine ring of the pyridyloxy group.

27. A compound having the structure I, a tautomer of the compound, a pharmaceutically acceptable salt of the compound, or a pharmaceutically acceptable salt of the tautomer



wherein
Z1, Z2, Z3, and Z4 are C;
R1 is selected from the group consisting of —H, —F, —Cl, —Br, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R2 is selected from the group consisting of —H, —F, —Cl, —Br, —C—N, —NO2, —CO2H, —OH, substituted and unsubstituted guanidinyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted —C(═O)O-alkyl groups, substituted and unsubstituted —C(═O)O-aryl groups, substituted and unsubstituted —C(═O)O-heteroaryl groups, substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)-aryl groups, substituted and unsubstituted —N(H)C(═O)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —N(H)C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups, substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted akoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted heterocyclyloxy, substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups; or R2 and R3 are a group of formula —OCH2O— such that R2 and R3 define a fused 5-membered ring that includes 2 oxygen atoms;
R3 is selected from the group consisting of —H, —F, —Cl, —Br, —CF3, —C≡N, —NO2, —CO2H, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—O-alkyl groups, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy group, substituted and unsubstituted heterocycyl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—(SO2)-alkyl groups substituted and unsubstituted —N(H)—(SO2)-aryl groups, —N(H)—(SO2)—CF3 groups, substituted and unsubstituted —N(H)—(SO2)-heterocyclyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-alkyl groups, substituted and unsubstituted —N(H)C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R4 is the group consisting of —H, —F, —Br, —Cl, —NO2, —C≡N, —C(═O)—O-alkyl groups, —OH, substituted and unsubstituted arylalkoxy groups, substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted alkoxyalkyl groups, substituted and unsubstituted arylalkoxyalkyl groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted —N(H)—C(═O)-aryl groups, substituted and unsubstituted —N(H)—C(═O)-alkyl groups, substituted and unsubstituted —N(H)—SO2-alkyl groups, substituted and unsubstituted —N(H)—SO2-aryl groups, —N(H)—SO2—CF3 groups, substituted and unsubstituted —N(H)—SO2-heterocyclyl groups, substituted and unsubstituted heterocyclyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted —C(═O)—N(H)-alkyl groups, substituted and unsubstituted —C(═O)—N(H)-alkyl-heterocyclyl groups, substituted and unsubstituted (alkyl)(alkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclyl)aminoalkyl groups substituted and unsubstituted (alkyl)(arylalkyl)aminoalkyl groups, substituted and unsubstituted (alkyl)(heterocyclylalkyl)aminoalkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-aryl groups, substituted and unsubstituted -alkyl-N(alkyl)-C(═O)-alkyl-heterocyclyl groups, substituted and unsubstituted alkylaminoalkyl groups, substituted and unsubstituted arylaminoalkyl groups, substituted and unsubstituted heterocyclylaminoalkyl groups substituted and unsubstituted arylalkylaminoalkyl groups, substituted and unsubstituted heterocyclylalkylaminoalkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-aryl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-heterocyclyl groups, substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-aryl groups, and substituted and unsubstituted -alkyl-N(H)—C(═O)-alkyl-heterocyclyl groups;
R5 is selected from the group consisting of —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups;
R6 is selected from the group consisting of —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups;
R7 is selected from the group consisting of —H, —F, —Cl, —Br, —CF3, —CO2H, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups including substituted and unsubstituted heterocyclylalkoxy groups, substituted and unsubstituted arylalkoxy groups, and substituted and unsubstituted alkoxyalkoxy groups; substituted and unsubstituted heterocyclyl groups including substituted and unsubstituted heterocyclylheterocyclyl groups, substituted and unsubstituted arylheterocyclyl groups, substituted and unsubstituted alkylheterocyclyl groups, and substituted and unsubstituted cycloalkylheterocyclyl groups; substituted and unsubstituted heterocyclyloxy groups, substituted and unsubstituted aryloxy groups, substituted and unsubstituted amino groups including substituted and unsubstituted dialkylamino groups, substituted and unsubstituted (alkyl)(heterocyclyl)amino groups, substituted and unsubstituted heterocyclylalkylamino groups, substituted and unsubstituted arylalkylamino groups, and substituted and unsubstituted heterocyclylamino groups; substituted and unsubstituted —C(═O)N(H)-alkyl groups, substituted and unsubstituted —C(═O)N(H)-aryl groups, substituted and unsubstituted —C(═O)N(H)-heterocyclyl groups, substituted and unsubstituted —C(═O)N(alkyl)(heterocyclyl) groups, and substituted and unsubstituted —C(═O)-heterocyclyl groups;
R8 is selected from the group consisting of —H, —F, —Cl, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkylamino groups, substituted and unsubstituted dialkylamino groups, and substituted and unsubstituted heterocyclyl groups;
R9 is —H; and
R10 is selected from the group consisting of —H, and substituted and unsubstituted alkyl groups,
and further wherein at least one of the following is true:
(i) R1 is selected from the group consisting of unsubstituted —NH2 groups, and substituted and unsubstituted pyrrolidinylalkylamino groups;
(ii) R2 is selected from the group consisting of substituted and unsubstituted thiazolylalkylamino groups, substituted and unsubstituted pyrrolidinylalkylamino groups, and substituted and unsubstituted aminoalkylamino groups; or
(iii) R3 is selected from the group consisting of substituted and unsubstituted thiazolylalkylamino groups, substituted and unsubstituted benzimidazolylalkylamino groups, substituted and unsubstituted imidazolylalkylamino groups, substituted and unsubstituted furanylalkylamino groups, and substituted and unsubstituted arylalkylamino groups.