WO2007139967A2 - Triazole compounds that modulate hsp90 activity - Google Patents

Triazole compounds that modulate hsp90 activity Download PDF

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Publication number
WO2007139967A2
WO2007139967A2 PCT/US2007/012543 US2007012543W WO2007139967A2 WO 2007139967 A2 WO2007139967 A2 WO 2007139967A2 US 2007012543 W US2007012543 W US 2007012543W WO 2007139967 A2 WO2007139967 A2 WO 2007139967A2
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Prior art keywords
optionally substituted
compound
independently
alkyl
occurrence
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PCT/US2007/012543
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French (fr)
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WO2007139967A3 (en
Inventor
Weiwen Ying
Teresa Przewloka
Junghyun Chae
Shijie Zhang
Hao Li
Zhenjian Du
David James
Dinesh U. Chimmanamada
Howard P. Ng
Kevin Foley
Zachary Demko
Lijun Sun
Dan Zhou
Shuzhen Qin
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Synta Pharmaceuticals Corp.
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Priority to PL07795379T priority Critical patent/PL2035396T3/en
Priority to DK07795379T priority patent/DK2035396T3/en
Priority to RSP20140378 priority patent/RS53446B/en
Priority to EP20070795379 priority patent/EP2035396B1/en
Priority to CA2653329A priority patent/CA2653329C/en
Priority to ES07795379.2T priority patent/ES2484042T3/en
Application filed by Synta Pharmaceuticals Corp. filed Critical Synta Pharmaceuticals Corp.
Priority to AU2007267859A priority patent/AU2007267859B2/en
Priority to SI200731480T priority patent/SI2035396T1/en
Priority to JP2009512171A priority patent/JP5441691B2/en
Publication of WO2007139967A2 publication Critical patent/WO2007139967A2/en
Publication of WO2007139967A3 publication Critical patent/WO2007139967A3/en
Priority to HRP20140704TT priority patent/HRP20140704T1/en

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Definitions

  • chemotherapeutic agents act on a specific molecular target thought to be involved in the development of the malignant phenotype.
  • a complex network of signaling pathways regulate cell proliferation, and the majority of malignant cancers are facilitated by multiple genetic abnormalities in these pathways. Therefore, it is unlikely that a therapeutic agent that acts on one molecular target will be fully effective in curing a patient who has cancer.
  • HSPs Heat shock proteins
  • HSPs are a class of chaperone proteins that are up-regulated in response to elevated temperature and other environmental stresses, such as ultraviolet light, nutrient deprivation, and oxygen deprivation. HSPs act as chaperones to other cellular proteins (called client proteins) and facilitate their proper folding and repair, and aid in the refolding of misfolded client proteins.
  • client proteins cellular proteins
  • the Hsp90 family is one of the most abundant HSP families, accounting for about 1-2% of proteins in a cell that is not under stress and increasing to about 4-6% in a cell under stress. Inhibition of Hsp90 results in degradation of its client proteins via the ubiquitin proteasome pathway.
  • Hsp90 client proteins of Hsp90 are mostly protein kinases or transcription factors involved in signal transduction, and a number of its client proteins have been shown to be involved in the progression of cancer, Examples of Hsp90 client proteins that have been implicated in the progression of cancer are described below.
  • Her-2 is a transmembrane tyrosine kinase cell surface growth factor receptor that is expressed in normal epithelial cells.
  • Her2 has an extracellular domain that interacts with extracellular growth factors and an internal tyrosine kinase portion that transmits the external growth signal to the nucleus of the cell.
  • Her2 is overexpressed in a significant proportion of malignancies, such as breast cancer, ovarian cancer, prostate cancer, and gastric cancers, and is typically associated with a poor prognosis.
  • Akt kinase is a serine/threonine kinase which is a downstream effector molecule of phosphoinositide 3-kinase and is involved in protecting the cell from apoptosis. Akt kinase is thought to be involved in the progression of cancer because it stimulates cell proliferation and suppresses apoptosis.
  • Cdk4/cyclin D complexes are involved in phosphorylation of retinoblastoma protein which is an essential step in progression of a cell through the G1 phase of the cell cycle. Disruption of Hsp90 activity has been shown to decrease the half life of newly synthesized Cdk4.
  • the Raf family of proto-oncogenes was first identified when C-raf (raf-1 ) was discovered due to its homology with v-raf, the transforming gene of the mouse sarcoma virus 3611.
  • A-raf was later discovered by screening a cDNA library under low stringency conditions using a v-raf probe, and B-raf was discovered due to its homology with C-Rmil, a transforming gene in avaian retrovirus Mill Hill No. 2.
  • the Raf family of proteins is involved in the Ras/Raf/MEK/ERK pathway, referred to herein as the "MAP kinase pathway" (MEK stands for “MAPK/ERK kinase” and ERK stands for “extracellularly regulated kinases”), which has been implicated in the genesis and progression of many human cancers through upregulation of cell division and proliferation.
  • All raf proteins are serine/theronine kinases which are capable of activating the MAP kinase pathway.
  • B-raf is far more potent at activating this pathway than A-raf or C-raf, and mutations in the gene encoding B-raf are more common in cancer.
  • B-raf mutations have been identified in 60% to 70% of malignant melanomas, 83% of anaplastic thyroid carcinoma, 35% to 69% of papillary thyroid caricinoma, 4% to 16% of colon cancer, 63% of low-grade ovarian carcinoma, 15% of Barrett's esophageal carcinoma, 4% of acute myeloid leukemia, 3-4.8% of head and neck squamous cell carcinoma, 2%-3% of non-small- cell lung cancer, 2% of gastric carcinoma, 2% of ⁇ on-Hodgkins lymphoma and has been reported in glioma, sar ⁇ ma, breast cancer, cholangiocarcinoma, and liver cancer.
  • B-raf Most mutations in B-raf that have been found in human cancers are point mutations that occur in the kinase domain and are clustered in exons 11 and 15 of the gene which contains several regulatory phosphorylation sites (S446, S447, D448, D449, T599, and S602). (Beeram, ef a/., Journal of Clinical Oncology (2005), 23(27):6771-6790). The most prevalent mutation is the T1799A transversion mutation which accounts for more than 80% of mutations in the BRAF gene and results in a V600E mutation in B-raf.
  • V600E was formerly designated V599E (the gene mutation was designated T1796A) due to a mistake in the GenBank nucleotide sequence NM 004333.
  • the corrected GenBank sequence is NT 007914 and designates the protein mutation as V600E and the gene mutation as T1799A. This corrected numbering will be used herein.
  • This mutation is thought to mimic phosphorylation in the activation segment of B-raf since it inserts a negatively charged residue near two activating phosphorylation sites, T599 and S602, and thus results in constitutively active B- raf in a Ras independent manner. (Xing, M., Endocrine-Related Cancer (2005), 12:245- 262).
  • B-raf mutants E586K and L597V were not sensitive to degradation when cells were treated with 17AAG. Therefore, it is believed that wild type B-raf in its activated form is a client protein of Hsp90 and that most mutated forms of B-raf are more dependent on Hsp90 for folding, stability and/or function than the wild type protein.
  • Raf-1 is a MAP 3-kinase (MAP3K) which when activated can phosphorylate and acitivate the serine/threonine specific protein kinases ERK1 and ERK2.
  • Activated ERKs play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration.
  • Anaplastic large-cell lymphoma is a type of non-Hodgkin's lymphoma characterized by the expression of CD30/KM antigen. ALCL normally arises from T-cells, however, a subset of cases have either a null cell or B-cell phenotype. Cases that arise from B-cells are sometimes categorized as diffuse large B-cell lymphomas.
  • ALCL case that express CD30/KM antigen also have the chromosomal translocation t(2;5)(p23;q35) which fuses the nucleophosmin (NPM/B23) gene to the anaplastic lymphoma kinse (ALK) gene and results in the oncogenetic fusion protein NPM-ALK with tyrosine kinase activity.
  • ALK rearrangements have been observed in the following percentages: 1) 30% to 50% of pleomorphic ALCL, 2) more than 80% of monomorphic ALCL, 3) 75% to 100% of small-cell cases, and 4) 60% to 100% of lymphohistiocytic ALCL.
  • NPM-ALK is able to transform both fibroblasts, hematopoietic, and primary bone marrow cell lines, and is thought to stimulate mitosis through the RAS pathway and the through activation of phospholipase C-gamma (PLC-gamma), ' and to protect against apoptosis through its activation of phosphatidylinositol 3 kinase (PI-3 kinase) survival pathway.
  • PLC-gamma phospholipase C-gamma
  • PI-3 kinase phosphatidylinositol 3 kinase
  • NPM-ALK has been shown to associate with Hsp90 and incubation of NPM-ALK expressing ALCL cells with the benzoquinone ansamycin, 17AAG, has been shown to disrupt this association resulting in increased degradation of NPM-ALK and induce cell-cycle arrest and apoptosis.
  • v-src Rous sarcoma virus
  • Hsp90 has been shown to complex with v-scr and inhibit its degradation.
  • Hsp90 is required to maintain steroid hormone receptors in a conformation capable of binding hormone with high affinity. Inhibition of the action of Hsp90 therefore is expected to be useful in treating hormone-associated malignancies such as breast cancer.
  • p53 is a tumor suppressor protein that causes cell cycle arrest and apoptosis. Mutation of the p53 gene is found in about half of all human cancers making it one of the most common genetic alterations found in cancerous cells. In addition, p53 mutation is associated with a poor prognosis. Wild-type p53 has been shown to interact with Hsp90, but mutated p53 forms a more stable association than wild-type p53 as a result of its misfolded conformations.
  • Hsp90 A stronger interaction with Hsp90 protects the mutated protein form normal proteolytic degradation and prolongs its half-life.
  • inhibition of the stabilizing effect of Hsp90 causes mutant p53 to be degraded and restores the normal transcriptional activity of wild-type p53.
  • HiMa is a hypoxia-inducible transcription factor that is up-regulated under low oxygen conditions. Under normal oxygen conditions HiMa associates with Von Hippel-Lindau (VHL) tumor suppressor protein and is degraded. Low oxygen conditions inhibit this association and allows HiMa to accumulate and complex with HiM ⁇ to form an active transcription complex that associates with hypoxia-response elements to activate the transcription of vascular endothelial growth factor (VEGF). Increased HiMa is associated with increased metastasis and a poor prognosis.
  • VHL Von Hippel-Lindau
  • VEGF vascular endothelial growth factor
  • PKs protein tyrosine kinases
  • STKs serine-threonine kinases
  • PKs protein tyrosine kinases
  • STKs serine-threonine kinases
  • Growth factor receptors with PTK activity are known as receptor tyrosine kinases.
  • Receptor tyrosine kinases are a family of tightly regulated enzymes, and the aberrant activation of various members of the family is one of the hallmarks of cancer.
  • the receptor tyrosine kinase family can be divided into subgroups that have similar structural organization and sequence similarity within the kinase domain.
  • Epidermal Growth Factor Receptor is a member of the type 1 subgroup of receptor tyrosine kinase family of growth factor receptors, which play critical roles in cellular growth, differentiation, and survival. Activation of these receptors typically occurs via specific ligand binding which results in hetero- or homodimerization between receptor family members, with subsequent autophosphorylation of the tyrosine kinase domain.
  • Specific ligands which bind to EGFR include epidermal growth factor (EGF), transforming growth factor ⁇ (TGFq, amphiregulin and some viral growth factors.
  • EGFR Activation of EGFR triggers a cascade of intracellular signaling pathways involved in both cellular proliferation (the ras/raf/MAP kinase pathway) and survival (the PI3 kinase/Akt pathway).
  • ras/raf/MAP kinase pathway the ras/raf/MAP kinase pathway
  • survival the PI3 kinase/Akt pathway
  • EGFR Aberrant or overexpression of EGFR has been associated with an adverse prognosis in a number of human cancers, including head and neck, breast, colon, prostate, lung (e.g., NSCLC, adenocarcinoma and squamous lung cancer), ovaries, gastrointestinal cancers (gastric, colon, pancreatic), renal cell cancer, bladder cancer, glioma, gynecological carcinomas, and prostate cancer.
  • overexpression of tumor EGFR has been correlated with both chemoresistance and a poor prognosis (Lei, et al., Anticancer Res. (1999), 79:221-8; Veale, et a ⁇ , Br. J. Cancer (1993); 68: 162-5, the entire teachings of each of these references are incorporated herein by reference).
  • Gefitinib a chemotherapeutic agent that inhibits the activity of EGFR
  • Gefitinib a chemotherapeutic agent that inhibits the activity of EGFR
  • EGF tyrosine kinase domain of EGFR
  • these mutants displayed two to three times higher activity than wild type EGFR.
  • wild type EGFR was internalized by the cells and down-regulated after 15 minutes, where as mutant EGFR was internalized more slowly and continued to be activated for up to three hours (Lynch, ef a/., The New England Journal of Medicine (2006), 350:2129-2139, the entire teachings of which are incorporated herein by reference).
  • Gliomas are another type of cancer that is characterized by amplification and/or mutation of the EGFR gene.
  • One of the most common mutations in the EGFR gene is a deletion of exons 2-7 which results in a truncated form of EGFR in which amino acids 6-273 of the extracellular domain are replaced with a single glycine residue.
  • This mutation is called EGFRvIII and is expressed in about half of all glioblastomas.
  • EGFRvIII is unable to bind EGF and TGFD and has constitutive, ligand-independent tyrosine kinase activity.
  • Hsp90 co-purifies with EGFRvIII indicating that Hsp90 complexes with EGFRvIII.
  • Hsp90 inhibitor geldanamycin a benzoquinone ansamycin antibiotic
  • Hsp90 inhibitor geldanamycin was able to decrease the expression of EGFRv)II indicating that interaction with Hsp90 is essential to maintain high expression levels of EGFRvIII (Lavictoire, et a!., Journal of Biological Chemistry (2003), 278(7):5292-5299, the entire teachings of which are incorporated herein by reference).
  • the members of the type III group of receptor tyrosine kinases include platelet-derived growth factor (PDGF) receptors (PDGF receptors alpha and beta), colony-stimulating factor (CSF-1) receptor (CSF-1R, c-Fms), Fms-like tyrosine kinase (FLT3), and stem cell factor receptor (c-kit).
  • PDGF platelet-derived growth factor
  • CSF-1R colony-stimulating factor receptor
  • FLT3 Fms-like tyrosine kinase
  • c-kit stem cell factor receptor
  • FILT3 is primarily expressed on immature hematopoietic progenitors and regulates their proliferation and survival.
  • Hematologic cancers also known as hematologic or hematopoietic malignancies, are cancers of the blood or bone marrow; including leukemia and lymphoma.
  • Acute myelogenous leukemia is a clonal hematopoietic stem cell leukemia that represents about 90% of all acute leukemias in adults with an incidence of 3.9 per 100,000 (See e.g., Lowenberg et al., N. Eng. J. Med 341: 1051-62 (1999) and Lopesde Menezes, et al, Clin. Cancer Res. (2005), 11(14):5281-5291, the enter teachings of both references are incorporated by reference). While chemotherapy can result in complete remissions, the long term disease-free survival rate for AML is about 14% with about 7,400 deaths from AML each year in the United States.
  • FLT3 kinase receptor mutations which result in constitutively active FLT3.
  • Two types of activating mutations have been identified in AML patients: internal tandem duplications (ITDs) and point mutation in the activating loop of the kinase domain.
  • ITDs internal tandem duplications
  • FLT3-1TD mutations are the most significant factor adversely affecting relapse rate with 64% of patients having the mutation relapsing within 5 years (see Current Pharmaceutical Design (2005), 77:3449-3457, the entire teachings of which are incorporated herein by reference).
  • the prognostic significance of FLT3 mutations in clinical studies suggests that FLT3 plays a driving role in AML and may be necessary for the development and maintenance of the disease.
  • MLL Mixed Lineage Leukemia
  • the FLT3-ITD mutation is also present in about 3% of cases of adult myelodysplastic syndrome and some cases of acute lymphocytic leukemia (ALL) (Current Pharmaceutical Design (2005), 77:3449-3457).
  • ALL acute lymphocytic leukemia
  • FLT3 has been shown to be a client protein of Hsp90, and 17AAG, a benzoquinone ansamycin antibiotic that inhibits Hsp90 activity, has been shown to disrupts the association of Flt3 with Hsp90.
  • 17AAG a benzoquinone ansamycin antibiotic that inhibits Hsp90 activity
  • the growth of leukemia cell that express either wild type FLT3 or FLT3- ITD mutations was found to be inhibited by treatment with 17"AAG (Yao, et a/., Clinical Cancer Research (2003), 9:4483-4493, the entire teachings of which are incorporated herein by reference).
  • c-Kit is a membrane type III receptor protein tyrosine kinase which binds Stem Cell Factor (SCF) to its extraellular domain.
  • SCF Stem Cell Factor
  • c-Kit has tyrosine kinase activity and is required for normal hematopoiesis.
  • mutations in c-kit can result in ligand-independent tyrosine kinase activity, autophosphorylation, and uncontrolled cell proliferation.
  • Aberrant expression and/or activation of c-Kit has been implicated in a variety of pathologic states.
  • evidence for a contribution of c-Kit to neoplastic pathology includes its association with leukemias and mast cell tumors, small cell lung cancer, testicular cancer, and some cancers of the gastrointestinal tract and central nervous system.
  • c-Kit has been implicated in playing a role in carcinogenesis of the female genital tract sarcomas of neuroectodermal origin, and Schwann cell neoplasia associated with neurofibromatosis.
  • c-Kit has been shown to be a client protein of Hsp90, and Hsp90 inhibitor 17AAG, a benzoquino ⁇ ansamycin, has been shown to induce apoptosis in Kasumi-1 cells, an acute myeloid leukemia cell line that harbors a mutation in c-kit.
  • c-Met is a receptor tyrosine kinase that is a client protein of Hsp90 and is encoded by the Met protooncogene.
  • Hepatocyte growth factor (also referred to as scatter factor (SF)) is the natural ligand of c-Met which binds to c-Met and leads to a variety of cellular responses such as proliferation, survival, angiogenesis, wound healin, tissue regeneration, scattering, motility, invasion and branching morphogenesis (Ma et a/., Cancer and Metastasis Reviews (2003), 22: 309-325).
  • c-Met and HGF are expressed in numerous tissues, although their expression is normally confined predominantly to cells of epithelial and mesenchymal origin, respectively.
  • c-Met and HGF are required for normal mammalian development and have been shown to be important in cell migration, cell proliferation and survival, morphogenic differentiation, and organization of 3-dimensional tubular structures (e.g., renal tubular cells, gland formation, etc.).
  • dysregulation of c-Met and/or HGF is believed to contribute to tumor growth, dissemination and invasion in several human cancers.
  • c-Met and/or HGF are highly expressed in numerous cancers and their expression correlates with poor prognosis (Christensen, et al., Cancer Research (2003), 63:7345- 7355),
  • c-Met receptor mutations have been shown to be expressed in a number of human cancers including hereditary and sporadic human papillary renal carcinomas, ovarian cancer, childhood hepatocellular carcinoma, metastatic head and neck squamous cell carcinomas, esophageal cancer and gastric cancer.
  • Met gene amplification and over expression of c-Met has been shown to be associated with both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), as well as colorectal cancer, and the Tpr/Met fusion protein has been shown to be present in human osteogenic sarcoma and gastric cancer. Families with germine mutations that activate c-Met kinase are prone to multiple kidney tumors as well as tumors in other tissues. Numerous studies have correlated the expression of c-Met and/or HGF with the state of disease progression of different types of cancer (including lung, colon, breast, prostate, liver, pancreas, brain, kidney, ovarian, stomach, skin, and bone cancers).
  • RTK receptor tyrosine kinases
  • BCR-ABL is an ocoprotein with tyrosine kinase activity and has been associated with chronic myelogenous leukemia (CML), with a subset of patients with acute lymphocytic leukemia (ALL) and with a subset of patients with acute myelogenous leukemia (AML).
  • CML chronic myelogenous leukemia
  • ALL acute lymphocytic leukemia
  • AML acute myelogenous leukemia
  • the BCR-ABL oncogene has been found in at least 90-95% of patients with CML, 20% of adults with ALL, 5% of children with ALL, and in about 2% of adults with AML.
  • the BCR- ABL oncoprotein is generated by the transloction of gene sequences from the c-ABL protein tyrosine kinase on chromosome 9 into the BCR sequences on chromosome 22, producing the Philadelphia chromosome.
  • the BCR-ABL gene has been shown to produce at least three alternative chimeric proteins, p230 Bcr-Abl, p210 Bcr-Abl, and p190 Bcr-Abl which have unregulated tyrosine kinase activity.
  • the p210 Bcr-Abl fusion protein is most often associated with CML, while the p190 Bcr-Abl fusion protein is most often associated with ALL Bcr-Abl has also been associated with a variety of additional hematological malignancies including granulocytic hyperplasia, myelomonocytic leukemia, lymphomas and erythroid leukemia Studies have shown that lowering the expression or activity of Bcr-Abl is effective in treating Bcr-Ab!-pos ⁇ t ⁇ ve leukemias For example, agents such as As 2 O 3 which lower Bcr-Abl expression have been shown to be highly effective against Bcr-Abl leukemias In addition, inhibition of Bcr-Abl tyrosine kinase activity by lmatinib (also known as STI571 and Gleevic) induces differentiation and apoptosis and causes eradication of Bcr-Abl positive leukemia cells both in vivo and in vitro In
  • Bcr-Abl fusion proteins exist as complexes with Hsp90 and are rapidly degraded when the action of Hsp90 is inhibited It has been shown that geldanamycin, a benzoquinone ansamycin antibiotic that disrupts the association of Bcr-Abl with Hsp90, results in proteasomal degradation of Bcr-Abl and induces apoptosis in Bcr-Abl leukemia cells
  • Hsp90 has been shown by mutational analysis to be necessary for the survival of normal eukaryotic cells
  • Hsp90 is over expressed in many tumor types indicating that it may play a significant role in the survival of cancer cells and that cancer cells may be more sensitive to inhibition of Hsp90 than normal cells
  • cancer cells typically have a large number of mutated and overexpressed oncoproteins that are dependent on Hsp90 for folding
  • tumor cells may be especially dependent on Hsp90 for survival
  • inhibition of Hsp90 causes simultaneous inhibition of a number of oncoproteins, as well as hormone receptors and transcription factors making it an attractive target for an anti-cancer agent
  • benzoquinone ansamycins a family of natural products that inhibit Hsp90, has shown evidence of therapeutic activity in clinical trials
  • benzoquinone ansamycins suffer from a number of limitations For example, they have low oral bioavailability, and their limited solubility makes them difficult to formula In addition, they are metabolized by polymorphic cytochrome P450 CYP3A4 and are a substrate for P-glycoprotein export pump involved in the development of multidrug resistance Therefore, a need exist for new therapeutics that improve the prognosis of cancer patients and that reduces or overcomes the limitations of currently used anti-cancer agents.
  • the present invention provides compounds which inhibit the activity of Hsp90 and are useful in the treatment of proliferative disorders, such as cancer.
  • the present invention provides compounds represented by structural formula (I):
  • R 1 , R 2 , and R 3 are each, independently, -OH, -SH, -NHR 7 , -OR 26 , -SR 26 , -O(CH 2 ) m OH, -O(CH 2 ) m SH, -O(CH 2 ) m NR 7 H, -S(CH 2 ) m OH, -S(CH 2 ) m SH, -S(CH 2 ) m NR 7 H,.
  • R 5 is an optionally substituted alkyl; an optionally substituted heteroaryl or an optionally substituted aryl;
  • R 6 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR 7 , -SR 7 , -NR 10 Ri 1 , -OC(O)NR 10 R 11 , -SC(O)NR 10 R 11 , -NR 7 C(O)NR 10 R 11 , -OC(O)R 7 , -SC(O)R 7 , -NR 7 C(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -NR 7 C(O)OR 7 , -OCH 2 C(O)R 7 , -SCH 2 C(
  • R 26 is a lower alkyl; p, for each occurrence, is independently, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3 or 4; or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
  • the present invention provides compounds represented by structural formula (II):
  • X 41 is O 1 S, or NR 42 ;
  • X 42 is CR 44 or N;
  • Y 40 is N or CR 43 ;
  • Y 41 is N or CR 45 ;
  • Y 42 for each occurrence, is independently N, C or CR 46 ;
  • R 40 is OH, SH, or NHR 7 ;
  • R 41 is -H, -OH, -SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl,,an alkoxy or cycloalkoxy, a haloalkoxy, -NR 10 Rn, -OR 7 , -C(O)R 7 , -C(O)OR 71 -C(S)R
  • R 43 and R 44 are, independently, -H, -OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 Rn, -NR 8 C(O)R 7 , -SR 7 , -S(O)pR 7 , -OS(O)pR 7 , -
  • R 45 for each occurrence, is independently, selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi 0 R 11 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 Rn, -NR 8 C(O)R 7 , -SR 7 , -S(O) P R 7 , -OS(O) P
  • the present invention provides compounds represented by structural formula (IV):
  • R56 is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl;
  • R5 2 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, ⁇ -butyl, n-pentyl, n-hexyl, -(CH 2 ) 2 OCH 3 , -CH 2 C(O)OH, and -C(O)N(CH 3 ) 2 ;
  • R 53 and R 54 are each, independently, -H, methyl, ethyl, or isopropyl; or R 53 and R 54 taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring; and
  • R 56 is selected from the group consisting of -H, -OH, -OCH 3 , and -OCH 2 CH 3 ; or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
  • the present invention provides compounds represented by structural formula (V);
  • R * 1 is , -NHR 7 , -NHC(O)NR 10 RI 1 , -NHC(O)R 7 , -NHC(O)OR 7 , -NHCH 2 C(O)R 7 , -NHCH 2 C(O)OR 7 , -NHCH 2 C(O)NR 10 R 1 I, -NHS(0) p R 7 , -NHS(O) p NR 10 Rii, -NHS(0) p 0R 7 , -NHC(S)R 7 , -NHC(S)OR 7 , -NHC(S)NR 10 R 11 , -NHC(NR 8 )R 7 , -NHC(NR 8 )OR 7 , or -NHC(NR 8 )NR 10 R 11 ;
  • R 2 is -OH, -SH 1 -NR 7 H 1 -OR 26 , -SR 26 , -0(CH 2 ) H1 OH,
  • R' 3 is -OH, -SH, Or -NHR 7 ;
  • R's is an optionally substituted heteroaryl or an optionally substituted aryl
  • R 7 and R 8 for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alke ⁇ yl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
  • R 10 and R 11 for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 10 and R 11 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R 26 is a lower alkyl;
  • the present invention provides compounds represented by structural formula (Vl):
  • R 6 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR 7 , -SR 7 , -NR 1O RII 1 -OC(O)NR 1 OR 1 I, -SC(O)NR 10 R 11 , -NR 7 C(O)NR 10 R 11 , -OC(O)R 7 , -SC(O)R 7 , -NR 7 C(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -NR 7 C(O)OR 7 , -OCH 2 C(O)R 7 , -SCH 2
  • the present invention provides compounds represented by structural formula (VII):
  • X 41 is O, S 1 or NR 42 ;
  • X 42 is CR 44 or N;
  • Y 40 is N or CR 43 ;
  • Y 41 is N or CR 45 ;
  • Y 42 for each occurrence, is independently N, C or CR 46 ;
  • R' 4 o is NHR 7 ;
  • R 41 is -H, -OH, -SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, -NRi 0 R 11 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -C(S)R 7 , -C(O)SR 7 , -C(S)SR 7 , -C(S)OR 7 ,
  • R 42 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, -C(O)R 7 , -(CH 2 ) m C(0)OR 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 R 11 , -S(O) P R 7 , -S(O) P OR 7 , or -S(O)pNR 10 Rii;
  • R 43 and R 44 are, independently, -H, -OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 R 11 , -NR 8 C(O)R 7 , -SR 7 , -S(O)pR 7 .
  • R 45 is -H, -OH, -SH, -NR 7 H, -OR 26 , -SR 26 , -NHR 26 , -0(CH 2 ) m 0H, -O(CH 2 ) m SH, -O(CH 2 ) m NR 7 H, -S(CH 2 ) m OH, -S(CH 2 ) m SH, -S(CH 2 ) m NR 7 H, -OC(O)NR 10 R 11 ,
  • R 46 for each occurrence, is independently, selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi 0 R 11 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 R 11 , -NR 8 C(O)R 7 , -SR 7 , -S(O) P R 7 , -OS(O)
  • the present invention provides compounds represented by structural formula (IX):
  • X 45 is CR 54 or N;
  • R 58 is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl;
  • R 52 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, -(CH 2 ) 2 OCH 3 , -CH 2 C(O)OH, and -C(O)N(CH 3 ) 2 ;
  • R 53 and Rs 4 are each, independently, -H, methyl, ethyl, or isopropyl; or R5 3 and R 54 taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring,
  • R 55 is selected from the group consisting of -H, -OH, -OCH 3 , and
  • R' 4O is defined as for formula (VII) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof
  • the present invention provides compounds represented by structural formula (Xl)
  • X is -O- or -S-
  • R' 5 is an optionally substituted heteroaryl or an optionally substituted aryl
  • R' ⁇ is -H 1 an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR 7 , -SR 7 , -NR 10 R 11 , -OC(O)NR 10 R 1 I, -SC(O)NR 10 R 11 , -NR 7 C(O)NR 10 R 1 ,, -OC(O)R 7 , -SC(O)R 7 , -NR 7 C(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -NR 7 C(O)OR 7 , -OCH 2 C(O)R 7 ,
  • R 7 and R 8 for each occurrence, is independently, -H, an optionally substituted alky], an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
  • Rio and R 11 for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
  • R' 17l R 18 , and Ri 9 are each, independently, -H 1 -C(O)R 2 ., or (alk)O(alk); provided that at least one of R' 17l R 18 , or R 19 is not -H;
  • R 22 for each occurrence is independently optionally substituted alkyl, optionally substituted aryl, -O(alk), amino, alkyl amino, or dialkyl amino; alk is a lower alkyl; p, for each occurrence, is independently 1 or 2; or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
  • the compound is not 3-(2-Hydroxy-4-methoxymethyoxy-phenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4] triazole; 3-[2-Hydroxy-4-(2-hydroxy-ethoxy)-phenyl]-4-(naphthalen-1-yl)-5-mercapto-[1 ,2,4] triazole;
  • R 70 , R' 2 , and R' 3 are, independently, -OH, -SH, or -NHR 7 ;
  • R 20 is C(O)R y ; and
  • R y is an optionally substituted alkyl; or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and
  • R' 6 is defined as for formula (Xl).
  • the present invention provides compounds represented by structural formula (XVI):
  • XVI wherein, X is -O- or -S-; Xi is O or S; R 71 and R 72 are each, independently, -H, -C(O)R 22 , or (alk)O(alk); R 22 , for each occurrence is independently optionally substituted alkyl, optionally substituted aryl, -O(alk), amino, alkyl amino, or dialkyl amino; R 23 is -C(O)R 22 or -alk-O- C(O)R 22 ; alk is a lower alkyl; and or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and R' 5 and R' ⁇ are defined as for formula (Xl).
  • the present invention provides compounds represented by structural formula (XVII):
  • R 24 and R 25 are each, independently -OH or -SH, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and R' 5 and R' 6 are defined as for formula (Xl).
  • R 23 is defined as for formula (XVI).
  • the present invention provides compounds represented by structural formula (XVIII):
  • X 41 is O, S, or NR 42 ;
  • X 42 is CR 44 or N;
  • Y 40 is N or CR 43 ;
  • Y 41 is N or CR 45 ;
  • Y 42 for each occurrence, is independently N, C or CR 46 ;
  • R 4 i is -H, -OH, -SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterooyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, -NR 10 R 11 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -C(S)R 7 , -C(O)SR 7
  • R 42 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, -C(O)R 7 ,
  • R 43 and R 44 are, independently, -H, -OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 R 11 , -NR 8 C(O)R 7 , -SR 7 , -S(O) p R 7 , -OS(O)pR 7 ,
  • R 45 is -H, -OH, -SH, -NR 7 H, -OR 26 , -SR 26 , -NHR 26 , -O(CH 2 ) m OH, -O(CH 2 ) m SH, -O(CH 2 ) m NR 7 H, -S(CH 2 ) m OH, -S(CH 2 ) m SH, -S(CH 2 ) m NR 7 H, -OC(O)NR 10 R 11 , -SC(O)NR 10 R 11 , -NR 7 C(O)NR 10 R 11 , -OC(O)R 7 , -SC(O)R 7 , -NR 7 C(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -NR 7 C(O)OR 7 , -OCH 2 C(O)R 7 , -SCH 2 C(O)R 7 , -NR 7 CH 2 C
  • R46 for each occurrence, is independently, selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyi, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR 10 R 11 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 R 11 , -NR 8 C(O)R 7 , -SR 7 , -S(O) P R 7 , -0S(0) p R 7
  • the present invention provides compounds represented by structural formula (XIX):
  • the present invention provides compounds represented by structural formula (XX):
  • X 4 5 is CR 54 or N;
  • R 56 is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl;
  • R 52 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, -(CH 2 ) 2 OCH 3 , -CH 2 C(O)OH, and -C(O)N(CH 3 ) 2 ;
  • R 53 and R 54 are each, independently, -H, methyl, ethyl, or isopropyl; or
  • R 53 and R 54 taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring;
  • R 55 is selected from the group consisting of -H 1 -OH, -OCH 3 , and OCH 2 CH 3 . or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and R 23 and X 1 are defined as for formula (XVIII).
  • the present invention provides compounds represented by structural formula (XXI):
  • XXI a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is optionally further substituted with one or two independently selected S substituents in addition to R 3 ; ring E is aromatic or non-aromatic; X 16 Js -O-, -NR 7 -, or -S-;
  • 0 R 1 and R 3 are each, independently, -OH, -SH, -NR 7 H, -OR' 2S , -SR' 26 ,
  • R 10 and R 11 are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted 0 heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 10 and R 11 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
  • R' 2 ⁇ for each occurrence is, independently, a C1-C6 alkyl; 5 R 38 and R' 39l for each occurrence, are independently H 1 an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, hitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR 10 Rn, -OR 7 , -C(O)R 7 , -C(O)OR 71 -C(S)R 7 , -C(O)SR 7 , -C(S)SR 7 ,
  • R' 4O and R 41 are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R' 4O and R' 4 i, together with the carbon atoms to which they are attached form a three to eight membered cycloalkenyl; p, for each occurrence, is, independently, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4; and k is 1 or 2.
  • the compounds represented by formula (XXI) do not include compounds in which R' s is p-chlorophenyl and rings A and E together are benzofuranyl.
  • the compounds represented by formula (XXI) do not include S-f ⁇ methoxy-e-hydroxy-benzofuran- ⁇ -ylJ ⁇ chloro-phenyO-mercapto ⁇ H-ti ⁇ . ⁇ triazole.
  • the present invention provides compounds represented by structural formula (XXVIII):
  • Ring F is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R 103 .
  • Ring G is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to -TrV 1 -T 2 -V 2 .
  • R 100 is -OH, -SH 1 -NR 7 H, -OR' 2 ⁇ ) -SR' 2B , -NHR' 26 , -O(CH 2 ) m OH, -O(CH 2 ) m SH, -O(CH 2 ) m NR 7 H, -S(CH 2 ) m OH, -S(CH 2 ) m SH, -S(CH 2 ) m NR r H, -OC(O)NR 10 Ri 1 , -SC(O)NR 10 Ri 1 , -NR 7 C(O)NR 10 RH, -OC(O)R 7 , -SC(O)R 71 -NR 7 C(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -NR 7 C(O)OR 7 , -OCH 2 C(O)R 7 , -SCH 2 C(O)R 7 , -NR 7 CH 2 C(
  • R 103 is -OH, -SH, -NR 7 H, -OR' 26 , -SR' 26 , -NHR' 26 , -O(CH 2 ) m OH, -O(CH 2 ) m SH, -O(CH 2 ) m NR 7 H, -S(CH 2 ) m OH, -S(CH 2 ) m SH, -S(CH 2 ) m NR 7 H, -OC(O)NR 10 R 11 , -SC(O)NR 10 R 11 , -NR 7 C(O)NRi 0 R 11 , -OC(O)R 7 , -SC(O)R 7 , -NR 7 C(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -NR 7 C(O)OR 7 , -OCH 2 C(O)R 71 -SCH 2 C(O)R 7 , -NR 7 CH 2
  • R 7 and R 8 for each occurrence, is independently, -H, an optionally substituted alky), an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl.
  • R 10 and Ri 1 for each occurrence, is independently -H 1 an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; or Ri 0 and R 11 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl.
  • R' 26 is a C1-C6 alkyl.
  • Ti is absent or a C1-C4 alkylene.
  • T 2 is absent or a C1-C4 alkylene
  • V 1 is absent and V 2 is -NR a R b , -NR 3 S(O) 2 R", - S(O)NR a R b , -S(O) 2 NR a R b or -C(O)NR a R b
  • T 2 is absent or a C1-C4 alkylene
  • V is -O- -S-, -N(R-)- or -C(O)N(R ' )-
  • V 2 is -S(O)NR a R b , -S(O) 2 NR a R b or -C(0)NR a R b
  • T 2 is a C2-C4 alkylene
  • V, is -O-, -S, -N(R ' )-, -C(O)O-, C(O)N(R ' )-
  • V 2 is -NR a
  • Each R is independently -H or C1-C3 alkyl.
  • Each R ** is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl.
  • R 8 and R b are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or heteroaryl, or an optionally substituted aralkyl; or R a and R b , taken together with the nitrogen to which they are attached, form an optionally substituted heteroaryl or heterocyclyl.
  • p for each occurrence, is independently, O, 1 or 2.
  • m for each occurrence, is independently, 1, 2, 3 or 4.
  • ring G is not phenyl
  • ring G is not naphtbyl or indolyl
  • the present invention provides compounds represented by a structural formula selected from (XXIX) and (XXX):
  • Ring G is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to -T 1 -V 1 -T 2 -V 2 X 14 is O, S or NR 7
  • R 100 is -OH, -SH, -NR 7 H, -OR' 26l -SR' 26 , -NHR' 2B , -O(CH 2 ) m OH, -0(CH 2 ) m SH, -O(CH 2 ) m NR 7 H, -S(CH 2 ) m OH, -S(CH 2 ) m SH, -S(CH 2 ) m NR 7 H, -OC(O)NR 10 R 11 ,
  • R 103 is -OH, -SH, -NR 7 H, -OR' ⁇ ⁇ , -SR' 2 ⁇ , -NHR' 26 , -O(CH 2 ) m OH, -0(CH 2 ) m SH, -O(CH 2 ) m NR 7 H, -S(CH 2 ) m OH, -S(CH 2 ) m SH, -S(CH 2 ) m NR 7 H, -OC(O)NR 10 R 11 , -SC(O)NR 10 R 11 , -NR 7 C(O)NR 10 R 11 , -OC(O)R 7 , -SC(O)R 7 , -NR 7 C(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -NR 7 C(O)OR 7 , -OCH 2 C(O)R 7 , -SCH 2 C(O)R 7 , -NR 7
  • R 7 and R 8 for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl or an optionally substituted heteroaralkyl
  • R 10 and Rn for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl, or R 10 and R 11 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl.
  • R 1 Z 2 is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl, a haloalkyl, -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 R 11 , -NR 8 C(O)R 7 , -S(O) P R 7 , -S(0) P OR 7 or -S(0) p NR 1D Rn.
  • R' 2 3 and R' 24 are independently -H, an optionally substituted alky, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR 10 Rn, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 Rn, -NR 8 C(O)R 7 , -SR 7 , -S(O) P R 7 , -0S(0) p R 7
  • R a and R b for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or heteroaryl, an optionally substituted aralkyl; or R a and R b , taken together with the nitrogen to which they are attached, form an optionally substituted heteroaryl or heterocyclyl.
  • T 1 is absent or a C1-C4 alkylene.
  • T 2 is absent or a C1-C4 alkylene
  • V 1 is absent and V 2 is -NR a R b , -NR 8 S(O) 2 R ** , - S(O)NR 8 R", -S(O) 2 NR 8 R" or -C(0)NR a R b
  • T 2 is absent or a C1-C4 alkylene
  • V 1 is -0-, -S-, -N(R ' )- or -C(O)N(R ' )-
  • V 2 is -S(O)NR a R b , -S(O) 2 NR a R b or -C(0)NR a R b
  • T 2 is a C2-C4 alkylene
  • V 1 is -0-, -S, -N(R * )-, -C(O)O-, C(O)N(R * )-
  • V 2 is -NR a R b , or
  • Each R** is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl.
  • p for each occurrence, is independently, O, 1 or 2.
  • m for each occurrence, is independently, 1 , 2, 3 or 4.
  • Hsp90 is necessary for the survival of normal eukaryotic cells. However, Hsp90 is over expressed in many tumor types indicating that it may play a significant role in the survival of cancer cells and that cancer cells may be more sensitive to inhibition of Hsp90 than normal cells.
  • the compounds shown in Table 1-5 or compounds of any formula herein, or tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof, are useful treating proliferative disorders such as cancer.
  • chemotherapeutic agents initially cause tumor regression, most agents that are currently used to treat cancer target only one pathway to tumor progression. Therefore, in many instances, after treatment with one or more chemotherapeutic agents, a tumor develops multidrug resistance and no longer responses positively to treatment.
  • One of the advantages of inhibiting Hsp90 activity is that several of its client proteins, which are mostly protein kinases or transcription factors involved in signal transduction, have been shown to be involved in the progression of cancer. Thus, inhibition of Hsp90 provides a method of short circuiting several pathways for tumor progression simultaneously.
  • treatment of tumors with an Hsp90 inhibitor of the invention is more likely to result in regression or elimination of the tumor, and less likely to result in the development of more aggressive multidrug resistant tumors than other currently available therapeis.
  • the present invention provides compounds disclosed herein and uses of said compounds to inhibit Hsp90 activity and for the treatment of a proliferative disorder, such as cancer.
  • the present invention encompasses the use of compounds of the invention to slow or stop the growth of cancerous cells or to reduce or eliminate cancerous cells in a subject, preferably the subject is a mammal.
  • the compounds of the invention can be used in combination with other chemotherapeutic agents and may help to prevent or reduce the development of multidrug resistant cancerous cells in a mammal.
  • the compounds of the invention may allow a reduced efficacious amount of a second chemotherapeutic agent given to a mammal, because compounds of. the invention should inhibit the development of multidrug resistant cancerous cells.
  • the compounds of the invention can be used to block, occlude, or otherwise disrupt blood flow in neovasculature. In other embodiments, the compounds of the Invention can be used to treat or inhibit angiogenesis in a subject in need thereof.
  • the present invention also relates to compounds which inhibit the activity of topoisomerase II.
  • the present invention also relates to the discovery that treatment of cells, such as peripheral blood mononuclear cells (PMBCs) that have been stimulated with an inflammatory stimulus, such as INF ⁇ /LPS or SAC, with an Hsp90 inhibitor reduces the expression of GR in the PMBCs and reduces the production of inflammatory cytokines.
  • PMBCs peripheral blood mononuclear cells
  • an Hsp90 inhibitor reduces the expression of GR in the PMBCs and reduces the production of inflammatory cytokines.
  • the present invention also relates to compounds which inhibit the activity of Hsp90 and are useful in the treatment of or prevention of infections.
  • alkyl means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms.
  • Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2- methylhexyl, 3-methylhexyl, 4-methy)hexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3- dimethylpentyl, 2,4-dimethylpenty
  • (CrC ⁇ Jalkyl) means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms.
  • Representative (Ci-C 6 )alkyl groups are those shown above having from 1 to 6 carbon atoms.
  • Alkyl groups included in compounds of this invention may be optionally substituted with one or more substituents.
  • alkenyl means a saturated straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and having at least one carbon-carbon double bond.
  • Representative straight chain and branched (C 2 -Ci 0 )alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2- methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2- heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1- decenyl, 2-decenyl, 3-decenyl and the like.
  • alkynyl means a saturated straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and having at least one carbon-carbon triple bond.
  • Representative straight chain and branched alkynyls include acetylenyl, propynyl, 1- butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl, 1-hexynyl, 2- hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1- nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 9-decynyl, and the
  • cycloalkyl means a saturated, mono- or polycyclic alkyl radical having from 3 to 20 carbon atoms.
  • Representative cycloalkyls include cyclopropyl, 1- methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, - cyclodecyl, octahydro-pentale ⁇ yl, and the like.
  • Cycloalkyl groups may be optionally substituted with one or more substituents.
  • cycloalkenyl means a mono- or poly- cyclic non-aromatic alkyl radical having at least one carbon-carbon double bond in the cyclic system and from 3 to 20 carbon atoms.
  • Representative cycloalkenyls include cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclodecenyl, cyclodecadienyl, 1, 2,3,4, 5,8-hexahydronaphthalenyl and the like. Cycloalkenyl groups may be optionally substituted with one or more substitus, cyclo
  • haloalkyl means an alkyl group, in which one or more (including all) the hydrogen radicals are replaced by a halo group, wherein each halo group is independently selected from -F, -Cl, -Br, and -I.
  • halomethyl means a methyl in which one to three hydrogen radical(s) have been replaced by a halo group.
  • Representative haloalkyl groups include trifluoromethyl, bromomethyl, 1 ,2-dichloroethyl, 4-iodobutyl, 2- fluoropentyl, and the like.
  • an "alkoxy” is an alkyl group which is attached to another moiety via an oxygen linker.
  • an “haloalkoxy” is an haloalkyl group which is attached to another moiety via an oxygen linker.
  • an "aromatic ring” or “aryl” means a hydrocarbon monocyclic or polycyclic radical in which at least one ring is aromatic.
  • suitable aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.
  • Aryl groups may be optionally substituted with one or more substituents.
  • the aryl group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, referred to herein as "(C 6 )aryl.”
  • aralkyl means an aryl group that is attached to another group by a (C r C 6 )alkylene group.
  • Representative aralkyl groups include benzyl, 2-phenyl-ethyl, naphth-3-yl-methyl and the like.
  • Aralkyl groups may be optionally substituted with one or more substituents.
  • alkylene refers to an alkyl group that has two points of attachment
  • (C r C 6 )alkylene refers to an alkylene group that has from one to six carbon atoms.
  • Straight chain (C r C 6 )alkylene groups are preferred.
  • alkytene groups include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), n-propylene (-CH 2 CH 2 CH 2 -), isopropylene (-CH 2 CH(CH 3 )-), and the like.
  • Alkylene groups may be optionally substituted with one or more substituents.
  • heterocyclyl means a monocyclic (typically having 3- to
  • a 3- to 10-membered heterocycle can contain up to 5 heteroatoms; and a 7- to 20-membered heterocycle can contain up to 7 heteroatoms.
  • a heterocycle has at least one carbon atom ring member.
  • Each heteroatom is independently selected from nitrogen, which can be oxidized (e.g., N(O)) or quaternized; oxygen; and sulfur, including sulfoxide and sulfone.
  • the heterocycle may be attached via any heteroatom or carbon atom.
  • heterocycles include morpholinyl, thiom ⁇ rpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hyda ⁇ toinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofura ⁇ yl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • a heteroatom may be substituted with a protecting group known to those of ordinary skill in the art, for example, the hydrogen on a nitrogen may be substituted with a tert-butoxycarbonyl group.
  • the heterocyclyl may be optionally substituted with one or more substituents. Only stable isomers of such substituted heterocyclic groups are contemplated in this definition,
  • heteroaryl means a monocyclic or polycyclic heteroaromatic ring comprising carbon atom ring members and one or more heteroatom ring members.
  • Each heteroatom is independently selected from nitrogen, which can be oxidized (e.g., N(O)) or quaternized; oxygen; and sulfur, including sulfoxide and sulfone.
  • heteroaryl groups include pyridyl, 1-oxo-pyridyl, furanyl, benzo[1 ,3]dioxolyl, benzo[1 ,4]diox ⁇ nyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, a isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, a triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetra
  • the heteroaromatic ring is selected from 5-8 membered monocyclic heteroaryl rings.
  • the point of attachment of a heteroaromatic or heteroaryl ring may be at either a carbon atom or a heteroatom of the heteroaromatic or heteroaryl rings.
  • Heteroaryl groups may be optionally substituted with one or more substituents.
  • (C 5 )heteroaryP means an aromatic heterocyclic ring of 5 members, wherein at least one carbon atom of the ring is replaced with a heteroatom such as, for example, oxygen, sulfur or nitrogen.
  • Representative (C 5 )heteroaryls include furanyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyrazinyl, triazolyl, thiadiazoly), and the like.
  • (C ⁇ )heteroaryl means an aromatic heterocyclic ring of 6 members, wherein at least one carbon atom of the ring is replaced with a heteroatom such as, for example, oxygen, nitrogen or sulfur.
  • Representative (C 6 )heteroaryis include pyridyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl and the like.
  • heteroarylkyl means a heteroaryl group that is attached to another group by a (C r C 6 )all ⁇ ylene.
  • Representative heteroaralkyls include 2-(pyridin-4-yl)- propyl, 2-(thien-3-yl)-ethyl, imidazol-4-yl-methyl and the like.
  • Heteroaralkyl groups may be optionally substituted with one or more substituents.
  • acetal means a substituent in which the carbon atom which forms the point of attachment to another moiety is attached two single bonded oxygen atoms, e.g., -CH(OR)(OR), wherein the R groups represent an alkyl group as described herein, or two R groups may join together to form a heterocyclyl group as described herein, for example:
  • a C2-6 acetal is a acetal in which the two R groups together comprise between 2 and 6 carbon atoms, e.g., two methyl groups, two ethyl groups, or the two R groups join together to form a 5 or 6 membered ring.
  • the term "ketal" means a substituent in which the carbon atom which forms the point of attachment to another moiety is attached two single bonded oxygen atoms and an alkyl group as defined herein, e.g., -C(OR)(OR)alkyl, wherein the R groups represent an alkyl group as described herein, or two R groups may join together to form a heterocyclyl group as described herein, for example:
  • a C2-6 ketal is a acetal in which the two R groups together comprise between 2 and 6 carbon atoms, e.g.,_two methyl groups, two ethyl groups, or the two R groups join together to form a 5 or 6 membered ring.
  • halogen or halo means -F, -Cl, -Br or -I.
  • heteroalkyl means a linear straight or branched chain alkyl group, wherein one or more of the internal carbon atoms in the chain is replaced by a heteroatom, such as, O, N or S, e.g., -[CH 2 ) x -O-[CH 2 ] y [CH 3 ] wherein x is a positive integer and y is O or a positive integer, and wherein replacement of the carbon atom does not result in a unstable compound.
  • a heteroatom such as, O, N or S
  • Suitable substituents for an alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups include are those substituents which form a stable compound of the invention without significantly adversely affecting the reactivity or biological activity of the compound of the invention.
  • substituents for an alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl include an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, optionally substituted alkoxy, -C(O)NR 28 Ra S ), -C(S)NR 28 R 29 , -C(NR 32 )NR 28 R 29 , -NR 33 C(O)R 31 ,
  • R 33 and R 31 for each occurrence is independently, H 1 an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl (preferably the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkyl are unsubstituted); and
  • R 32 for each occurrence is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, -C(O)R 33 , -C(O)NR 28 R 29 , -S(O) P R 33 , or -S(O)pNR 2a R29 (preferably the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl and heteraralkyl are unsubstituted);
  • p O 1 1 or 2;
  • h is O, 1 or 2.
  • heterocyclyl, heteroaryl, or heteroaralkyl group When a heterocyclyl, heteroaryl, or heteroaralkyl group contains a nitrogen atom, it may be substituted or unsubstituted. When a nitrogen atom in the aromatic, ring of a heteroary! group has a substituent the nitrogen may be a quaternary nitrogen.
  • the terms “subject”, “patient” and “mammal” are used interchangeably.
  • the terms “subject” and “patient” refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), preferably a mammal including a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee and a human), and more preferably a human.
  • a non-primate e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse
  • a primate e.g., a monkey, chimpanzee and a human
  • the subject is a non-huma ⁇ animal such as a farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit).
  • a farm animal e.g., a horse, cow, pig or sheep
  • a pet e.g., a dog, cat, guinea pig or rabbit
  • the subject is a human.
  • lower refers to a group having up to four atoms.
  • a “lower alkyl” refers to an alkyl radical having from 1 to 4 carbon atoms
  • “lower alkoxy” refers to "-O ⁇ CrCtJalkyi
  • a “lower alkenyl” or “lower alkynyl” refers to an alkenyl or alkynyl radical having from 2 to 4 carbon atoms, respectively.
  • contiguous linear connectivity means connected together so as to form an uninterrupted linear array or series of atoms.
  • a linker of the compounds described herein having a specified number of atoms in contiguous linear connectivity has at least that number of atoms connected together so as to form an uninterrupted chain, but may also include additional atoms that are not so connected (e.g., branches or atoms contained within a ring system).
  • linker means a diradical having from 1-6 atoms in contiguous linear connectivity (i.e., as defined above and excluding atoms present in any side chains and branches), that covalently connects the phenyl ring portion of a compound of this invention to the R x group of the compound.
  • reactive functional groups such as (without limitation) carboxy, hydroxy, thiol, and amino moieties
  • Protected derivatives are those compounds in which a reactive site or sites are blocked with one ore more protecting groups.
  • suitable protecting groups for hydroxyl groups include benzyl, methoxymethyl, allyl, trimethylsilyl, tert-butyldimethylsilyl, acetate, and the like.
  • suitable amine protecting groups include benzyloxycarbonyl, tert-butoxycarbonyl, tert-butyl, benzyl and fluorenylmethyloxy- carbonyl (Fmoc).
  • suitable thiol protecting groups include benzyl, tert-butyl, acetyl, methoxymethy) and the like.
  • Other suitable protecting groups are well known to those of ordinary skill in the art and include those found in T. W. Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.
  • compound(s) of this invention refers to a compound of formula (I)-(XL), and those set forth in Tables 1-5, or a pharmaceutically ' acceptable salt, solvate, clathrate, hydrate, polymorph or prodrug thereof, and also include protected derivatives thereof.
  • the compounds of the invention may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers ⁇ i.e., geometric isomers), enantiomers, or diastereorners.
  • the chemical structures depicted herein, including the compounds of this invention encompass all of the corresponding compounds' enantiomers, diastereomers and geometric isomers, that is, both the stereochemical ⁇ pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and isomeric mixtures (e.g., enantiomeric, diastereomeric and geometric isomeric mixtures).
  • one enantiomer, diastereomer or geometric isomer will possess superior activity or an improved toxicity or kinetic profile compared to other isomers. In those cases, such enantiomers, diastereomers and geometric isomers of compounds of this invention are preferred.
  • polymorph means solid crystalline forms of a compound of the present invention or complex thereof.
  • Different polymorphs of the same compound can exhibit different physical, chemical and/or spectroscopic properties. Different physical properties include, but are not limited to stability (e.g., to heat or light), compressibility and density (important in formulation and product manufacturing), and dissolution rates (which can affect bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical characteristics (e.g.
  • tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity).
  • Different physical properties of polymorphs can affect their processing. For example, one polymorph might be more likely to form solvates or might be more difficult to filter or wash free of impurities than another due to, for example, the shape or size distribution of particles of it.
  • hydrate means a compound of the present invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • clathrate means a compound of the present invention or a salt thereof in the form of a crystal lattice that contains spaces (e.g., channels) that have a guest molecule (e.g., a solvent or water) trapped within.
  • prodrug means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of this invention. Prodrugs may become active upon such reaction under biological conditions, or they may have activity in their unreacted forms.
  • prodrugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of formula (I)-(XL), and those set forth in Tables 1-5, that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • Other examples of prodrugs include derivatives of compounds of formula (I)-(XL), and those set forth in Tables 1-5, that comprise -NO, -NO 2 , - ONO, or -ONO 2 moieties.
  • Prodrugs can typically be prepared using well-known methods, such as those described by 1 BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5 th ed).
  • biohydrolyzable amide means an amide, ester, carbamate, carbonate, ureide, or phosphate analogue, respectively, that either: 1) does not destroy the biological activity of the compound and confers upon that compound advantageous properties in vivo, such as improved water solubility, improved circulating half-life in the blood (e.g., because of reduced metabolism of the prodrug), improved uptake, improved duration of action, or improved onset of action; or 2) is itself biologically inactive but is converted in vivo to a biologically active compound.
  • biohydrolyzable amides include, but are not limited to, lower alkyl amides, ⁇ -amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.
  • biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters.
  • biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylaminss, heterocyclic and heteroaromatic amines, and polyether amines.
  • Hsp90 includes each member of the family of heat shock proteins having a mass of about 90-kiloDaltons.
  • the highly conserved Hsp90 family includes cytosolic Hsp90 ⁇ and Hsp90 ⁇ isoforms, as well as GRP94, which is found in the endoplasmic reticulum, and HSP75/TRAP1 , which is found in the mitochondrial matrix.
  • c-Met is a receptor tyrosine kinase that is expressed in normal and malignant cells and has been identified as a proto-oncogene.
  • HGF/c-Met signaling triggers an invasive growth program that is thought to be essential in early embryonic development but when dysregulated can result malignant growth, motility, migration and invasion by a mechanism that is not yet completely understood.
  • the human Met gene is located on chromosome 7 band 7q21-q31 and spans more than 120 kb (Ma, ef a/., Cancer and Metastasis Reviews (2003), 22:309-325).
  • c-Met is a heterodimer that consists of an extracellular ⁇ -subunit and a ⁇ -subunit with a large extracellular domain, a membrane spanning segment and an intracellular tyrosine kinase domain.
  • Functional structures and domains of c-Met include 1) Sema domain at the N-terminus which includes a MRS cysteine-rich region; 2) PSI domain which is also found in plexins, semaphorins and integrins; 3) IPT repeats which are found in immunoglobulin, plexins and transcription factors; 4) transmembrane domain; 5) juxtamembrane domain; and 6) the intracellular tyrosine kinase domain at the C-termi ⁇ us.
  • Activation of c-Met signaling is dependent on phosphorylation of multiple residues on c-Met.
  • c-Met Upon binding of HGF, c-Met undergoes autophosphorylation at Y1230, Y1234, and Y1235 in the activation loop of the tyrosine kinase domain which ativates the kinase activity of c- Met.
  • Y1313 can also be phosphorylated in response to HGF binding and is important in binding PI3-K which is implicated in prosurvival signaling.
  • Phosphorylation of Y1349 and Y1356 at the C-terinus of c-Met activates the multisubstrate signal transducer docking site which has been implicated in Met-mediated signal transduction and mediates the interactions of SHC, Src, and Gab1 , while recruitment of Grb2, PI3-K, PLC- ⁇ and SHP2 is dependent on phosphorylation of Y1356 alone.
  • Regultation of cell morphogenesis is mediated via Y1365.
  • Phosphorylation of the Y1003 residue in the juxtamembrane domain mediates the binding of c-Cbl.
  • c-Cbl acts as a negative regulator protein of c-Met by promoting the polyu biqu itinization of c-Met which leads to degradation.
  • Dysregulation of HGF/c-Met signaling can be caused by 1) increased expression of HGF; 2) activating mutations which typically occur in the tyrosine kinase domain or the juxtamembrane domain of c-Met and confer constitutive kinase activity; 3) intra- chromosomal ammplification of the Met gene and over expression of c-Met; 4) chromosomal translocation such as in the Trp/Met fusion protein which results in the loss of the juxtamembra ⁇ e domain and leads to constitutive activation, and 5) alternate splicing variants c-Met mRNA which lead to loss of the juxtamembrane domain and also lead to constitutive activation
  • Activating mutation in the tyrosine kinase domain or in the juxtamembrane domain of c-Met which result in increased activation of the tyrosine kinase activity have been observed in hereditary and sporatic papillary renal carcinoma, ovarian cancer, hepatocellular carcinoma, metastatic head and neck squamous cell carcinomas, NSCLC, SCLC, glioma, breast cancer, and gastric cancer
  • somatic papillary renal cell carcinoma activating mutations have been found at amino acid residues M1268 (e g , M1268T) Y1248 (e g , Y1248D, Y1248H), Y1246 (e g , Y1246H), Y1230 (e g , Y1230C), L1213 (e g , L1213V), H1124 (e g , H1124D, H1112L, and H1112Y), and V1110 (V11101
  • the juxtamembrane of receptor tyrosine kinases has been shown to repress catalytic function and mutation in the juxtamembrane relieve this repression and can lead to oncogenesis
  • the Tpr/Met fusion protein results from replacement of the 5' region of the Met gene with Tpr which provides two strong dimerization motifs Dime ⁇ zation activates the Met kinase activity and results in transforming and metastatic properties
  • the Tpr/Met fusion protein has been found in gastric cancer and results in increased Met kinase activity
  • an alternative splicing form of Met mRNA has been found in small cell lung cancer which results in skipping the juxtamembrane domain Loss of the juxtamembrane domain leads to increased Met kinase activity and oncogenesis
  • Compounds of the invention cause the degradation of c-Met and can be used either alone or in combination with other anticancer therapies to treat patients with cancers that have jux
  • Amplification of the Met gene and overexpression of c-Met has been found in several types of cancers including gastric cancer, esophageal cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, multiple myeloma, and colorectal cancer metastases.
  • Compounds of the invention cause the degradation of c-Met and can be used either alone or in combination with other anticancer therapies to treat patients with cancers that have Met gene amplification and/or c-Met overexpression.
  • Met amplification and mutation has also been implicated as a strategy by which certain cancers become resistant to therapy (e.g., chemotherapy or radiation therapy).
  • therapy e.g., chemotherapy or radiation therapy.
  • certain non-small cell lung cancers contain an activating mutation in receptor tyrosine kinase EGFR which results in oncogenesis.
  • Most EGFR mutant NSCLCs initially respond to EGFR inhibitors such as lressa and Tarceva but the vast majority of these tumors ultimately become resistant to the drug.
  • Met amplification is a mechanisms of acquired resitance, and in particular acquired resistance to kinase inhibitors such as lressa and Tarceva (EGFR inhibitors), Gleevec (a Bcr-Abl, PDGF 1 and c-Kit inhibitor) (Engelman et al., Sciencexpress, www.sciencexpress orq / 26 April 2007/ page 1 / 10.1126/science. 1141478).
  • kinase inhibitors such as lressa and Tarceva (EGFR inhibitors), Gleevec (a Bcr-Abl, PDGF 1 and c-Kit inhibitor)
  • EGFR inhibitors EGFR inhibitors
  • Gleevec a Bcr-Abl
  • PDGF 1 and c-Kit inhibitor a Bcr-Abl
  • Compounds of the invention cause the degradation of c-Met and can be used either alone or in combination with other anticancer therapies, such as treatment with kinase inhibitor
  • c-Met associated cancer refers to any type of malignant growth or metastasis that is caused by or enhanced by dysregulation in HGF/c-Met signaling.
  • B-raf is a serine/threonine kinase that is involved in the MAP kinase pathway and is encoded by a gene located on chromosome 7q32. Ten isoforms of B-raf have been identified which are the result of splicing variants. The term “B-raf refers to all such splicing variants.
  • B-raf has three conserved regions (CR): 1) CR1 which contains a cysteine rich domain (CRD) and most of the Ras binding domain (RBD) and facilitates the binding of B- raf to Ras and recruitment to the cell membrane; 2) CR2 which is rich in serine and threonine and includes the S365 residue which is an inhibitory phosphorylation site; and 3) CR3 which contains the kinase domain including a G-loop GXGXXG motif, an activation segment and regulatory phosphorylation sites S446, S447, D448, D449, T599 and S602. B-raf is translocated to the cell membrane and activated by association with GTP-bound Ras.
  • CCD cysteine rich domain
  • RBD Ras binding domain
  • B-raf is regulated by changes in its conformation and is inactive when the activation segment is held in an inactive conformation as a result of hydrophobic interactions with the P-loop. Phosphorylation in the activation segment results in a shift to the active conformation of B-raf.
  • the activation segment and P-loop that interact with one-another and restraining the activation segment in an inactive conformation are where the majority of B-raf oncogenic mutations are clustered. This indicates that as a result of B- raf mutations the inactive B-raf conformation is destabilized thereby promoting an active B- raf conformation.
  • B-raf associated cancers are cancers in which inappropriate B-raf activity is detected.
  • B-raf associated cancers have increased B-raf activity, such as B-raf with mutations in the kinase domain that confer increased activity over that of wild type B-raf and/or constitutively active B-raf (e.g., B-raf that has activity that is not dependent on interaction with Ras).
  • Activating mutations in the kinase domain include V600E, V600D, G596R, G594V, G469A, G469E, G466V, and G464V mutations.
  • B-raf associated cancers include malignant melanomas, anaplastic thyroid carcinoma, papillary thyroid caricinoma, follicular thyroid cancer, para-follicular C-cell-derived medullary thyroid cancer, colon cancer, ovarian carcinoma, Barrett's esophageal carcinoma, acute myeloid leukemia, head and neck squamous cell carcinoma, non-small-cell lung cancer, gastric carcinoma, non-Hodgkins lymphoma, glioma, saroma, breast cancer, cholangiocarcinoma, and liver cancer in which inappropriate B-raf activity can be detected, such as increased B- raf activity of a mutant form of B-raf over that of wild type B-raf or constitutive activity of B- raf.
  • NPM-ALK refers to a fusion protein which is the result of a t(2;5)(p23;q35) translocation of the gene sequence for NPM/B23 nucleolar protein into the sequence which encodes for the tyrosine kinase ALK.
  • the NPM-ALK fusion protein contains the first 117 amino acids of the amine terminal of NPM and the C-terminal residues 1058 to 1620 of ALK.
  • NPM-ALK associated cancers refers to cancers in which the NPM-ALK fusion protein is expressed, such as ALCL and diffuse large B-cell lymphomas.
  • c-kit or "c-kit kinase” refers to a membrane receptor protein tyrosine kinase which is preferably activated upon binding Stem Cell Factor (SCF) to its extracellular domain (Yarden et al., 1987; Qiu et al., 1988).
  • SCF Stem Cell Factor
  • the full length amino acid sequence of a c- kit kinase preferably is as set forth in Yarden, ef al., 1987, EMBO J., 71:3341-3351; and Qiu, et al., 1988, EMBO J., 7:1003-1011, which are incorporated by reference herein in their entirety, including any drawings.
  • c-kit or “c-kit kinase” and include those that fall into two classes: (1) having a single amino acid substitution at codon 816 of the human c-kit kinase, or its equivalent position in other species (Ma et al., 1999, J. Invest Dermatol., 112:165-170), and (2) those which have mutations involving the putative juxtamembrane z-helix of the protein (Ma 1 ef a/., 1999, J. Biol. Chem,, 274:13399-13402). Both of these publications are incorporated by reference herein in their entirety, including any drawings.
  • Bcr-Abl is a fusion protein that results from the translocation of gene sequences from c-ABL protein tyrosine kinase on chromosome 9 into BCR sequences on chromosome 22 producing the Philiadelphia chromosome.
  • a schematic representation of human Bcr, AbI, and Bcr-Abl can be seen in Figure 1 of U.S. patent application serial number 10/193,651, filed on July 9, 2002, the entire teachings of which are incorporated herein by reference.
  • Bcr-Abl fusion proteins can vary in size from 185-230 kDa but they must contain at least the OLI domain from Bcr and the TK domain from AbI for transforming activity.
  • the most common Bcr-Abl gene products found in humans are P230 Bcr-Abl, P210 Bcr-Abl, and P190 Bcr-Abl.
  • P210 Bcr-Abl is characteristic of CML and P190 Bcr-Abl is characteristic of ALL.
  • FLT3 kinase is a tyrosine kinase receptor involved in the regulation and stimulation of cellular proliferation (see Gilliland et a/., Blood (2002), 700:1532-42, the entire teachings of which are incorporated herein by reference).
  • the FLT3 kinase has five immunoglobuli ⁇ -like domains in its extracellular region as well as an insert region of 75-100 amino acids in the middle of its cytoplasmic domain. FLT3 kinase is activated upon the binding of the FLT3 ligand, which causes receptor dimerization.
  • Normal cells that express FLT3 kinase include immature hematopoietic cells, typically CD34+ cells, placenta, gonads, and brain (see Rosnet, ef a/., Stood (1993), 82:1110-19; Small ef a/., Proc. Nati. Acad. Sci. U.S.A. (1994), 91:459-63; and Rosnet ef a/., Leukemia (1996), 10:238-48, the entire teachings of each of these references are incorporated herein by reference).
  • efficient stimulation of proliferation via FLT3 kinase typically requires other hematopoietic growth factors or interleukins.
  • FLT3 kinase also plays a critical role in immune function through its regulation of dendritic cell proliferation and dilferentiation (see McKenna ef a/., Stood (2000), 95:3489-97, the entire teachings of which are incorporated herein by reference).
  • FLT3 kinase Numerous hematologic malignancies express FLT3 kinase, the most prominent of which is AML (see Yokota ef a/., Leukemia (1997), 77:1605-09, the entire teachings of which are incorporated herein by reference).
  • Other FLT3 expressing malignancies include B- precursor cell acute lymphoblastic leukemias, myelodysplastic leukemias, T-cell acute lymphoblastic leukemias, and chronic myelogenous leukemias (see Rasko ef a/., Leukemia (1995), 9:2058-66, the entire teachings of which are incorporated herein by reference).
  • FLT3 kinase mutations associated with hematologic malignancies are activating mutations.
  • the FLT3 kinase is constitutively activated without the need for binding and dimerization by FLT3 ligand, and therefore stimulates the cell to grow continuously.
  • Two types of activating mutations have been identified: internal tandem duplications (ITDs) and point mutation in the activating loop of the kinase domain.
  • ITDs internal tandem duplications
  • FLT3 kinase refers to both wild type FLT3 kinase and mutant FLT3 kinases, such as FLT3 kinases that have activating mutations.
  • Inappropriate FLT3 activity includes, but is not limited to, enhanced FLT3 activity resulting from increased or de novo expression of FLT3 in cells, increased FLT3 expression or activity, and FLT3 mutations resulting in constitutive activation.
  • the existence of inappropriate or abnormal FLT3 ligand and FLT3 levels or activity can be determined using well known methods in the art. For example, abnormally high FLT3 levels can be determined using commercially available ELISA kits. FLT3 levels can be determined using flow cytometric analysis, immunohistochemical analysis, and in situ hybridization techniques.
  • EGFR epidermal growth factor receptor
  • EGFR epidermal growth factor receptor
  • peptide peptide
  • polypeptide having EGFR or EGFR family (e.g., HER1 , HER2, HER3, and/or HER4) activity (such as encoded by EGFR Genbank Accession Nos. shown in Table I of U.S. Patent Application Serial No. 10/923,354, filed on August 20, 2004 , the entire teachings of which are incorporated herein by reference), or any other EGFR transcript derived from a EGFR gene and/or generated by EGFR translocation.
  • EGFR epidermal growth factor receptor
  • EGFR is also meant to include other EGFR protein, peptide, or polypeptide derived from EGFR isoforms (e.g., HER1 , HER2, HER3, and/or HER4), mutant EGFR genes, splice variants of EGFR genes, and EGFR gene polymorphisms.
  • a "proliferative disorder” or a “hyperproliferative disorder,” and other equivalent terms, means a disease or medical condition involving pathological growth of cells.
  • Proliferative disorders include cancer, smooth muscle cell proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, retinopathy, e.g., diabetic retinopathy or other retinopathies, cardiac hyperplasia, reproductive system associated disorders such as benign prostatic hyperplasia and ovarian cysts, pulmonary fibrosis, endometriosis, fibromatosis, harmatomas, lymphangiomatosis, sarcoidosis, desmoid tumors,
  • Smooth muscle cell proliferation includes hyperproliferation of cells in the vasculature, for example, intimal smooth muscle cell hyperplasia, restenosis and vascular occlusion, particularly stenosis following biologically- or mechanically-mediated vascular injury, e.g., vascular injury associated with angioplasty.
  • intimal smooth muscle cell hyperplasia can include hyperplasia in smooth muscle other than the vasculature, e.g., bile duct blockage, bronchial airways of the lung in patients with asthma, in the kidneys of patients with renal interstitial fibrosis, and the like.
  • Non-cancerous proliferative disorders also include hyperproliferation of cells in the skin such as psoriasis and its varied clinical forms, Reiter's syndrome, pityriasis rubra pilaris, and hyperproliferative variants of disorders of keratinization (e.g., actinic keratosis, senile keratosis), scleroderma, and the like,
  • the proliferative disorder is cancer.
  • Cancers that can be treated or prevented by the methods of the present invention include, but are not limited to human sarcomas and carcinomas, e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medu
  • leukemias include acute and/or chronic leukemias, e.g., lymphocytic leukemia (e.g., as exemplified by the p388 (murine) cell line), large granular lymphocytic leukemia, and lymphoblastic leukemia; T-cell leukemias, e.g., T-cell leukemia (e.g., as exemplified by the CEM, Jurkat, and HSB-2 (acute), YAC-1 (murine) cell lines), T- lymphocytic leukemia, and T-lymphoblastic leukemia; B cell leukemia (e.g., as exemplified by the SB (acute) cell line) , and B-lymphocytic leukemia; mixed cell leukemias, e.g., B and T cell leukemia and B and T lymphocytic leukemia; myeloid leukemias, e.g., granulocy
  • the disclosed method is believed to be particularly effective in treating subject with non-solid tumors such as multiple myeloma.
  • the disclosed method is believed to be particularly effective against T-leukemia (e.g., as exemplified by Jurkat and CEM cell lines); B-leukemia (e.g., as exemplified by the SB cell line); promyelocytes (e.g., as exemplified by the HL-60 cell line); uterine sarcoma (e.g., as exemplified by the MES-SA cell line); monocytic leukemia (e.g., as exemplified by the THP- 1 (acute) cell line); and lymphoma (e.g., as exemplified by the U937 cell line).
  • T-leukemia e.g., as exemplified by Jurkat and CEM cell lines
  • B-leukemia e.g., as exemplified by the SB cell line
  • the disclosed method is believed to be particularly effective in treating subject with non-Hodgkin's lymphoma (NHL).
  • Lymphomas are generally classified as either Hodgkin's disease (HD) or non-Hodgkin's lymphomas (NHL).
  • NHL differs from HD by the absence of Reed-Sternberg cells. The course of NHL is less predictable than HD and is more likely to spread to areas beyond the lymph nodes. NHL can be further divided into B- cell NHL and T-cell NHL each of which can be further categorized into a variety of different subtypes.
  • B-cell NHL includes Burkitt's lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, nodal marginal zone B-cell lymphoma, plasma cell neoplasms, small lymphocytic lymphoma/chronic lymphocytic leukemia, mantle cell lymphoma, extranodal marginal zone B-cell lymphoma, and lymphoplamacytic lymphoma/Waldenstrom macroglobulinemia.
  • T-cell NHL include anaplastic large-cell lymphoma, precursor-T-cell lymphoblastic leukemia/lymphoma, unspecified peripheral T-cell lymphoma, acute lymphoblastic leukemia/lymphoma, angioimmunoblastic T-cell lymphoma, and mycosis fungoides.
  • the compounds of the invention are useful for treating NHLs, including B-cell and T-cell NHLs, since Hsp90 is upregulated in many NHLs.
  • NHLs including B-cell and T-cell NHLs
  • Hsp90 was found to be moderately to strongly over expressed in all cases of Burkitt's lymphoma (5/5, 100%), and in a subset of follicular lymphoma (17/28, 61%), diffuse large B- cell lymphoma (27/46, 59%), nodal marginal zone B-cell lymphoma (6/16, 38%), plasma cell neoplasms (14/39, 36%), small lymphocytic lymphoma/chronic lymphocytic leukemia (3/9, 33%), mantle cell lymphoma (12/38, 32%), and lymphoplamacytic lymphoma/Waldenstrom macroglobulinemia (3/10, 30%).
  • Hsp90 was found to be moderately to strongly over expressed in a subset of anaplastic large-cell lymphoma (14/24, 58%), precursor-T-cell lymphoblastic leukemia/lymphoma (20/65, 31%), unspecified peripheral T-cell lymphoma (8/43, 23%), and angioimmunoblastic T-cell lymphoma (2/17, 12%).
  • anaplastic large-cell lymphoma 14/24, 58%
  • precursor-T-cell lymphoblastic leukemia/lymphoma (20/65, 31%)
  • unspecified peripheral T-cell lymphoma 8/43, 23%)
  • angioimmunoblastic T-cell lymphoma 2/17, 12%.
  • Some of the disclosed methods can be particularly effective at treating subjects whose cancer has become "multi-drug resistant".
  • a cancer which initially responded to an anticancer drug becomes resistant to the anti-cancer drug when the anti-cancer drug is no longer effective in treating the subject with the cancer.
  • many tumors will initially respond to treatment with an anti-cancer drug by decreasing in size or even going into remission, only to develop resistance to the drug.
  • Drug resistant tumors are characterized by a resumption of their growth and/or reappearance after having seemingly gone into remission, despite the administration of increased dosages of the anti-cancer drug.
  • Cancers that have developed resistance to two or more anti-cancer drugs are said to be "multi-drug resistant". For example, it is common for cancers to become resistant to three or more anti-cancer agents, often five or more anti-cancer agents and at times ten or more anti-cancer agents.
  • c-kit associated cancer refers to a cancer which has aberrant expression and/or activation of c-kit.
  • c-Kit associated cancers include leukemias, mast cell tumors, small cell lung cancer, testicular cancer, some cancers of the gastrointestinal tract and some central nervous system.
  • c-kit has been implicated in playing a role in carcinogenesis of the female genital tract (Inoue, ef a/., 1994, Cancer Res., 54(11):3049- 3053), sarcomas of neuroectodermal origin (Ricotti, ef a/., 1998, Blood, 97:2397-2405), and Schwann cell neoplasia associated with neurofibromatosis (Ryan, ef a/., 1994, J. Neuro. Res., 37:415-432).
  • compounds of the invention are vascular targeting agents.
  • compounds of the invention are effective for blocking, occluding, or otherwise disrupting blood flow in "neovasculature.”
  • the invention provides a novel treatment for diseases involving the growth of new blood vessels ("neovasculature"), including, but not limited to: cancer; infectious diseases; autoimmune disorders; benign tumors, e.g.
  • hemangiomas acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas; artheroscleric plaques; ocular angiogenic diseases, e.g., diabetic retinopathy, retinopathy of prematurity, macular degeneration, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, rubeosis, retinoblastoma, persistent hyperplastic vitreous syndrome, choroidal neovascularization, uvietis and Pterygia (abnormal blood vessel growth) of the eye, rheumatoid arthritis, psoriasis, warts, allergic dermatitis, blistering disease, Karposi sarcoma, delayed wound healing, endometriosis, uterine bleeding, ovarian cysts, ovarian hyperstimulation, vasculogenesis, granulations, hypertrophic scars (keloids), nonunion
  • angiogenesis refers to a fundamental process of generating new blood vessels in tissues or organs
  • Angiogenesis is involved with or associated with many diseases or conditions, including, but not limited to cancer, ocular neovascular disease, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity corneal graft rejection, neovascular glaucoma, retrolental fibroplasias, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea, warts, eczema, phylectenulosis, syphilis, Mycobacteria infections, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpes zoster infections, protozoan infections
  • infection is used herein in its broadest sense and refers to any infection e.g. a viral infection or one caused by a microorganism: bacterial infection, fungal infection, or parasitic infection (e.g. protozoal, amoebic, or helminth).
  • infections may be found in a number of well known texts such as "Medical Microbiology” (Greenwood, D , Slack, R., Koherer, J., Churchill Livingstone Press, 2002); “Mims' Pathogenesis of Infectious Disease” (Mims, C, Nash, A., Stephen, J., Academic Press, 2000); “Fields” Virology. (Fields, B. N., Knipe, D.
  • Bacillus infections include, but are not limited to, infections caused by Gram Positive Bacteria including Bacillus cereus, Bacillus anthracis, Clostridium botulinum, Clostridium difficile, Clostridium tetani, Clostridium perfringens, Corynebacteria diphtheriae, Enterococcus (Streptococcus D), Listeria monocytogenes, Pneumoccoccal infections (Streptococcus pneumoniae), Staphylococcal infections and Streptococcal infections; Gram Negative Bacteria including Bacteroides, Bordetella pertussis, Brucella, Campylobacter infections, enterohaemorrhagic Escherichia coli (EHEC/E.
  • Gram Positive Bacteria including Bacillus cereus, Bacillus anthracis, Clostridium botulinum, Clostridium difficile, Clostridium tetani, Clostridium perfringens, Coryne
  • fungus refers to a distinct group of eukaryotic, spore-forming organisms with absorptive nutrition and lacking chlorophyll. It includes mushrooms, molds, and yeasts.
  • "Fungal infections” include, but are not limited to, infections caused by Alternariaretemata, Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, Aspergillus versicolor, Blastomyces dermatiditis, Candida albicans, Candida dubliensis, Candida krusei, Candida parapsilosis, Candida tropicalis, Candida glabrata, Coccidioides immitis, Cryptococcus neoformans, Epidermophyton floccosum, Histoplasma capsulatum,
  • “Parasitic infections” include, but are not limited to, infections caused by Leishmania, Toxoplasma, Plasmodia, Theileria, Acanthamoeba, Anaplasma, Giardia, Trichomonas, Trypanosoma, Coccidia, and Babesia.
  • parasitic infections include those caused by Trypanosoma cruzi, Eimeria tenella, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Cryptosporidium parvum, Naegleria fowleri, Entamoeba histolytica, Balamuthia mandrillaris, Entameoba histolytica, Schistostoma mansoni, Plasmodium falciparum, P. vivax, P. ovale P. malariae, P. berghei, Leishmania donovani, L. infantum, L. chagasi, L. mexicana, L. amazonensis, L. venezuelensis, L.
  • the term "viral infection” refers to any stage of a viral infection, including incubation phase, latent or dormant phase, acute phase, and development and maintenance of immunity towards a virus. Consequently, the term “treatment” is meant to include aspects of generating or restoring immunity of the patient's immune system, as well as aspects of suppressing or inhibiting viral replication.
  • Viral infections include, but are not limited to those caused by Adenovirus, Lassa fever virus (Arenavirus), Astrovirus, Hantavirus, Rift Valley Fever virus (Phlebovirus), Calicivirus, Ebola virus, Marburg Virus, Japanese encephalitis virus, Dengue virus, Yellow fever virus, Hepatitis C virus, Hepatitis G virus, Hepatitis B virus, Hepatitis D virus, Herpes simplex virus 1, Herpes simplex virus 2), Cytomegalovirus, Epstein Barr virus, Varicella Zoster Virus, Human Herpesvirus 7, Human Herpesvirus 8, Influenza virus, Parainfluenza virus, Rubella virus, Mumps virus, Morbillivirus, Measles virus, Respiratory Syncytial virus, Papillomaviruses, JC virus (Polyomavirus), BK virus (Polyomavirus), Parvovirus, Coxsackie virus (A and B), Hepatitis A virus, Polioviruse
  • viral infections include Adenovirus acute respiratory disease, Lassa fever, Astrovirus enteritis, Hantavirus pulmonary syndrome, Rift valley fever, Hepatitis E 1 diarrhoea, Ebola hemorrhagic fever, Marburg hemorrhagic fever, Japanese encephalitis, Dengue fever, Yellow fever, Hepatitis C, Hepatitis G, Hepatitis B, Hepatitis D, Cold sores, Genital sores, Cytomegalovirus infection, Mononucleosis, Chicken Pox, Shingles, Human Herpesvirus infection 7, Kaposi Sarcoma, Influenza, Brochiolitis, German measles, Mumps, Measles (rubeola), Measles, Brochiolitis, Papillomas (Warts), cervical cancer, Progressive multifocal leukoencephalopathy, Kidney disease, Erythema infectiosum, Viral myocarditis, meninigitis, entertitis, Hepati
  • Topoisomerase Il (“topo II”) plays important roles in DNA replication, chromosome segregation and the maintenance of the nuclear scaffold in eukaryotic cells. The enzyme acts by creating breaks in DNA, thereby allowing the DNA strands to unravel and separate. Due to the important roles of the enzyme in dividing cells, the enzyme is a highly attractive target for chemotherapeutic agents, especially in human cancers.
  • the ability of compounds to inhibit topo Il can be determined by any method known in the art such as in Example K.
  • the glucocorticoid receptor is a member of the steroid hormone nuclear receptor family which includes glucocorticoid receptors (GR), androgen receptors (AR), mineralocorticoid receptors (MR), estrogen receptors (ER), and progesterone receptors (PR).
  • Glucocorticoid receptors bind glucocorticoids such as Cortisol, corticosterone, and cortisone.
  • Immunosuppression refers to impairment of any component of the immune system resulting in decreased immune function. This impairment may be measured by any conventional means including whole blood assays of lymphocyte function, detection of lymphocyte proliferation and assessment of the expression of T cell surface antigens.
  • the antisheep red blood cell (SRBC) primary (IgM) antibody response assay (usually referred to as the plaque assay) is one specific method. This and other methods are described in Luster, M.I., Portier, C 1 Pait, D.G., White, K.L., Jr., Gennings, C 1 Munson, A.E., and Rosenthal, G.J, (1992).
  • a patient in need of immunosuppression is within the judgement of a physician, and can include patients with immune or inflammatory disorders.
  • patients that have undergone or will be undergoing an organ, tissue, bone marrow, or stem cell transplantation are in need of immunosuppression to prevent inflammation and/or rejection of the transplanted organ or tissue.
  • the term "immune disorder” and like terms means a disease, disorder or condition caused by the immune system of an animal, including autoimmune disorders.
  • Immune disorders include those diseases, disorders or conditions that have an immune component and those that are substantially or entirely immune system-mediated.
  • Autoimmune disorders are those wherein the animal's own immune system mistakenly attacks itself, thereby targeting the cells, tissues, and/or organs of the animal's own body.
  • the autoimmune reaction is directed against the nervous system in multiple sclerosis and the gut in Crohn's disease.
  • systemic lupus erythematosus affected tissues and organs may vary among individuals with the same disease.
  • One person with lupus may have affected skin and joints whereas another may have affected skin, kidney, and lungs. Ultimately, damage to certain tissues by the immune system may be permanent, as with destruction of insulin-producing cells of the pancreas in Type 1 diabetes mellitus.
  • autoimmune disorders of the nervous system e.g., multiple sclerosis, myasthenia gravis, autoimmune neuropathies such as Guillain-Barre, and autoimmune uveitis
  • autoimmune disorders of the blood e.g., autoimmune hemolytic anemia, pernicious anemia, and autoimmune thrombocytopenia
  • autoimmune disorders of the blood vessels e.g., temporal arteritis, anti-phospholipid syndrome, vasculitides such as Wegener's granulomatosis, and Behcet's disease
  • autoimmune disorders of the skin e.g., psoriasis, dermatitis herpetiformis, pemphigus vulgaris, and vitiligo
  • autoimmune disorders of the gastrointestinal system e.g., Crohn's disease, ulcerative colitis, primary biliary cirrhosis, and autoimmune hepatitis
  • Hashimoto's thyroiditis, autoimmune oophoritis and orchitis, and autoimmune disorder of the adrenal gland include connective tissue and musculoskeletal system diseases) (e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, spondyloarthropathies such as ankylosing spondylitis, and Sjogren's syndrome).
  • connective tissue and musculoskeletal system diseases e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, spondyloarthropathies such as ankylosing spondylitis, and Sjogren's syndrome.
  • other immune system mediated diseases such as graft-versus-host disease and allergic disorders, are also included in the definition of immune disorders
  • Treatment of an immune disorder refers to administering a compound represented by any of the formulas disclosed herein to a subject, who has an immune disorder, a symptom of such a disease or a predisposition towards such a disease, with the purpose to cure, relieve, alter, affect, or prevent the autoimmune disorder, the symptom of it, or the predisposition towards it.
  • allergic disorder means a disease, condition or disorder associated with an allergic response against normally innocuous substances. These substances may be found in the environment (such as indoor air pollutants and aeroallergens) or they may be non-environmental (such as those causing dermatological or food allergies). Allergens can enter the body through a number of routes, including by inhalation, ingestion, contact with the skin or injection (including by insect sting). Many allergic disorders are linked to atopy, a predisposition to generate the allergic antibody IgE. Because IgE is able to sensitize mast cells anywhere in the body, atopic individuals often express disease in more than one organ.
  • allergic disorders include any hypersensitivity that occurs upon re-exposure to the sensitizing allergen, which in turn causes the release of Inflammatory mediators.
  • Allergic disorders include without limitation, allergic rhinitis (e.g., hay fever), sinusitis, rhinosinusitis, chronic or recurrent otitis media, drug reactions, insect sting reactions, latex reactions, conjunctivitis, urticaria, anaphylaxis and anaphylactoid reactions, atopic dermatitis, asthma and food allergies.
  • the term "asthma” means a pulmonary disease, disorder or condition characterized by reversible airway obstruction, airway inflammation, and increased airway responsiveness to a variety of stimuli.
  • an "inflammatory disorder” means a disease, disorder or condition characterized by inflammation of body tissue or having an inflammatory component. These include local inflammatory responses and systemic inflammation.
  • inflammatory disorders include: transplant rejection, including skin graft rejection; chronic inflammatory disorders of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel diseases such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung disorders such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory disorders of the eye including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory disorders of the gums, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidney including uremic complications, glomerulonephritis and nephrosis; inflammatory disorders of the skin including sclerodermatitis, psoriasis and eczema; inflammatory diseases of the central nervous system, including chronic demy
  • a systemic inflammation of the body exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines.
  • shock can be induced, e.g., by a chemotherapeutic agent used in cancer chemotherapy.
  • Treatment of an inflammatory disorder refers to administering a compound or a composition of the invention to a subject, who has an inflammatory disorder, a symptom of such a disorder or a predisposition towards such a disorder, with the purpose to cure, relieve, alter, affect, or prevent the inflammatory disorder, the symptom of it, or the predisposition towards it.
  • the term "pharmaceutically acceptable salt,” is a salt formed from, for example, an acid and a basic group of one of the compounds of formula (I)-(XL), and those set forth in Tables 1-5.
  • Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, besylate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, be ⁇ zoate, glutamate, metha ⁇ esulfo ⁇ ate, ethanesulfonate, be ⁇ zenesulfonate, p-toluen
  • pharmaceutically acceptable salt also refers to a salt prepared from a compound of formula (I)-(XL) 1 and those set forth in Tables 1-5, having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base.
  • Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N- ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-
  • pharmaceutically acceptable salt also refers to a salt prepared from a compound of formula (I)-(XL), and those set forth in Tables 1-5, having a basic functional group, such as an amine functional group, and a pharmaceutically acceptable inorganic or organic acid.
  • Suitable acids include, but are not limited to, hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), nitric acid, hydrogen bisulfide, phosphoric acid, lactic acid, salicylic acid, tartaric acid, bitartratic acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • solvate is a solvate formed from the association of one or more pharmaceutically acceptable solvent molecules to one of the compounds of formula (I)-(XL), and those set forth in Tables 1-5.
  • solvate includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).
  • a pharmaceutically acceptable carrier may contain inert ingredients which do not unduly inhibit the biological activity of the compounds.
  • the pharmaceutically acceptable carriers should be biocompatible, i.e., non-toxic, non-inflammatory, non-immunogenic and devoid of other undesired reactions upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed, such as those described in Remington's Pharmaceutical Sciences, ibid.
  • Suitable pharmaceutical carriers for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing about 0.9% mg/ml benzyl alcohol), phosphate-buffered saline, Hank's solution, Ringer's-lactate and the like.
  • the term "effective amount” refers to an amount of a compound of this invention which is sufficient to reduce or ameliorate the severity, duration, progression, or onset of a disease or disorder, e.g. a proliferative disorder, prevent the advancement of a disease or disorder, e.g. a proliferative disorder, cause the regression of a disease or disorder, e.g.
  • a proliferative prevent the recurrence, development, onset or progression of a symptom associated with a disease or disorder, e.g. a proliferative disorder, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.
  • the precise amount of compound administered to a subject will depend on the mode of administration, the type and severity of the disease or condition and on the characteristics of the subject, such as genera) health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of cell proliferation, and the mode of administration. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
  • an "effective amount" of the second agent will depend on the type of drug used. Suitable dosages are known for approved agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the invention being used. In cases where no amount is expressly noted, an effective amount should be assumed.
  • the invention provides a method of preventing, treating, managing, or ameliorating a proliferative disorder or one or more symptoms thereof, said methods comprising administering to a subject in need thereof a dose of at least 150 ⁇ g/kg, preferably at least 250 ⁇ g/kg, at least 500 ⁇ g/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at least 200 mg/kg or more of one or more compounds of the invention once every day, preferably, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 10 days, once every two weeks, once every three weeks, or once a month.
  • dosages of a chemotherapeutic agents other than compounds of the invention which have been or are currently being used to prevent, treat, manage, or ameliorate a proliferative disorder, or one or more symptoms thereof, can be used in the combination therapies of the invention.
  • the recommended dosages of agents currently used for the prevention, treatment, management, or amelioration of a proliferative disorder, or one or more symptoms thereof can obtained from any reference in the art including, but not limited to, Hardman et a/., eds., 1996, Goodman & Gilman's The Pharmacological Basis Of Basis Of Therapeutics 9 th Ed, Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57 th Ed., 2003, Medical Economics Co., Inc., Montvale, NJ, which are incorporated herein by reference in its entirety.
  • the terms “treat”, “treatment” and “treating” refer to the reduction or amelioration of the progression, severity and/or duration of a disease or disorder, e.g. a proliferative disorder, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of a disease or disorder, e.g. a proliferative disorder resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as a compound of the invention).
  • the terms “treat”, “treatment” and “treating” refer to the amelioration of at least one measurable physical parameter of a disease or disorder, e.g. a proliferative disorder, such as growth of a tumor, not necessarily discernible by the patient.
  • the terms “treat”, “treatment” and “treating” refer to the inhibition of the progression of a disease or disorder, e.g. a proliferative disorder, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both.
  • the terms “treat”, “treatment” and “treating” refer to the reduction or stabilization of tumor size or cancerous cell count.
  • a compound of the invention is administered as a preventative measure to a patient, preferably a human, having a genetic predisposition to any of the disorders described herein.
  • a therapeutic agent refers to any agent(s) which can be used in the treatment, management, or amelioration of a disease or disorder, e.g. a proliferative disorder or one or more symptoms thereof.
  • the term “therapeutic agent” refers to a compound of the invention.
  • the term “therapeutic agent” refers does not refer to a compound of the invention.
  • a therapeutic agent is an agent which is known to be useful for, or has been or is currently being used for the treatment, management, prevention, or amelioration a disease or disorder, e.g. a proliferative disorder or one or more symptoms thereof.
  • the term "synergistic” refers to a combination of a compound of the invention and another therapy (e.g., a prophylactic or therapeutic agent), which is more effective than the additive effects of the therapies
  • a synergistic effect of a combination of therapies permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a subject with a disease or disorder, e g a proliferative disorder
  • the ability to utilize lower dosages of a therapy (e g , a prophylactic or therapeutic agent) and/or to administer said therapy less frequently reduces the toxicity associated with the administration of said therapy to a subject without reducing the efficacy of said therapy in the prevention, management or treatment of a disease or disorder, e g a proliferative disorder
  • a synergistic effect can result in improved efficacy of agents in the prevention, management or treatment of a disease or disorder, e g a
  • side effects encompasses unwanted and adverse effects of a therapy (e g , a prophylactic or therapeutic agent) Side effects are always unwanted, but unwanted effects are not necessarily adverse
  • An adverse effect from a therapy (e g , prophylactic or therapeutic agent) might be harmful or uncomfortable or risky
  • Side effects include, but are not limited to fever, chills, lethargy, gastrointestinal toxicities (including gastric and intestinal ulcerations and erosions), nausea, vomiting, neurotoxicities, nephrotoxicities, renal toxicities (including such conditions as papillary necrosis and chronic interstitial nephritis), hepatic toxicities (including elevated serum liver enzyme levels), myelotoxicities (including leukopenia, myelosuppression, thrombocytopenia and anemia), dry mouth, metallic taste, prolongation of gestation, weakness, somnolence, pain (including muscle pain, bone pain and headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms, akathisia, cardiovascular
  • the term "in combination” refers to the use of more than one therapies (e g , one or more prophylactic and/or therapeutic agents)
  • therapies e g , prophylactic and/or therapeutic agents
  • a first therapy e g , a prophylactic or therapeutic agent such as a compound of the invention
  • can be administered prior to e g , 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e g , 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks
  • therapies can refer to any protocol(s), method(s), and/or agent(s) that can be used in the prevention, treatment, management, or amelioration of a proliferative disorder or one or more symptoms thereof.
  • a “protocol” includes dosing schedules and dosing regimens.
  • the protocols herein are methods of use and include prophylactic and therapeutic protocols.
  • a subject is administered one or more therapies (e.g., one or more prophylactic or therapeutic agents) to "manage” a disease so as to prevent the progression or worsening of the disease.
  • therapies e.g., one or more prophylactic or therapeutic agents
  • composition that "substantially" comprises a compound means that the composition contains more than about 80% by weight, more preferably more than about 90% by weight, even more preferably more than about 95% by weight, and most preferably more than about 97% by weight of the compound.
  • a reaction that is "substantially complete” means that the reaction contains more than about 80% by weight of the desired product, more preferably more than about 90% by weight of the desired product, even more preferably more than about 95% by weight of the desired product, and most preferably more than about 97% by weight of the desired product.
  • a racemic mixture means about 50% of one enantiomer and about 50% of is corresponding enantiomer relative to a chiral center in the molecule.
  • the invention encompasses all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures of the compounds of the invention.
  • Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or diastereomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
  • the compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
  • the compounds of the invention When administered to a patient, e.g., to a non-human animal for veterinary use or for improvement of livestock, or to a human for clinical use, the compounds of the invention are administered in isolated form or as the isolated form in a pharmaceutical composition.
  • isolated means that the compounds of the invention are separated from other components of either (a) a natural source, such as a plant or cell, preferably bacterial culture, or (b) a synthetic organic chemical reaction mixture.
  • the compounds of the invention are purified via conventional techniques.
  • purified means that when isolated, the isolate contains at least 95%, preferably at least 98%, of a compound of the invention by weight of the isolate either as a mixture of stereoisomers or as a diastereomeric or enantiomeric pure isolate.
  • composition that Is "substantially free" of a compound means that the composition contains less than about 20% by weight, more preferably less than about 10% by weight, even more preferably less than about 5% by weight, and most preferably less than about 3% by weight of the compound.
  • the present invention emcompasses compounds having Formulas (I)-(XL), and those set forth in Tables 1-5, and tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof.
  • the invention provides compounds of formula (II) as set forth below:
  • the invention provides compounds of formula (III) as set forth below:
  • the invention provides compounds of formula (IV) as set forth below:
  • the invention provides compounds of formula (V) as set forth below:
  • the invention provides compounds of formula (Vl) as set forth below:
  • the invention provides compounds of formula (VII) as set forth below:
  • R' 4O , R4 1 , X 41 , X «, Y 40 , Y 41 , and Y 42 are defined as above.
  • the invention provides compounds of formula (VIII) as set forth below:
  • the invention provides compounds of formula (X) as set forth below:
  • the compound is not 3-(2-Hydroxy-4-methoxymethyoxy-phenyl)-4-(naphthalen-1 -yl)-5-mercapto-[1 ,2,4] triazole; 3-[2-Hydroxy-4-(2-hydroxy-ethoxy)-phenyl]-4-(naphthalen-1-yl)-5-mercapto-[1 ,2,4] triazole;
  • the invention provides compounds of formula (XII) as set forth below:
  • R' 6 , Ri 8 and R 19 are defined as above.
  • the invention provides compounds of formula (XIV) as set forth below:
  • the invention provides compounds of formula (XV) as set forth below:
  • the invention provides compounds of formula (XVI) as set forth below:
  • the invention provides compounds of formula (XVII) as set forth below:
  • the invention provides compounds of formula (XVIII) as set forth below:
  • R 23 , R 41 , X 1 , X 41, X 42 ,Y 40 ,Y 41 and Y 42 4 are defined as above.
  • the invention provides compounds of formula (XIX) as set forth below:
  • R23, R ⁇ »i, R 4 2, R 43 , R 4 5, Xi, and X 42 are defined as above.
  • the invention provides compounds of formula (XX) as set forth below: or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and F* 23> R52.
  • R5 3 , R 55 , R 5 6, Xi, and X 45 are defined as above.
  • the invention provides compounds of formula (XXI):
  • ring A is optionally further substituted with one or two independently selected substituents in addition to R 3 ;
  • ring E is aromatic or non-aromatic;
  • X 16 is -0-, -NR 7 -, or -S-;
  • R 1 and R 3 are each, independently, -OH, -SH, -NR 7 H, -OR' 26 , -SR' 26 , -O(CH 2 ) m OH, -O(CH 2 ) m SH, -0(CH 2 )JMR 7 H, -S(CH 2 ) m OH, -S(CH 2 ) m SH, -S(CH 2 ) m NR 7 H, -OC(O)NR 10 R 11 , -SC(O)NR 10 R 11 , -NR 7 C(O)NR 10 R 11 , -OC(O)R 7 , -SC(O)R 7 , -NR 7 C(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -NR 7 C(O)OR 7 , -OCH 2 C(O)R 7 , -SCH 2 C(O)R 7 , -NR 7 CH 2 C(O)R
  • R' 26l for each occurrence is, independently, a C1-C6 alkyl;
  • R 38 and R' 39) for each occurrence are independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR 10 Ri 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -C(S)R 7 , -C(O)SR 7 , -C(S)SR 7 ,
  • the present invention provides compounds represented by structural formula (XXVIII):
  • the present invention provides compounds represented by a structural formula selected from (XXIX) and (XXX):
  • the present invention provides compounds represented by a structural formula represented by (XXXI) or (XXXII):
  • X3 and X 4 are each, independently, N, N(O), N + (R 75 ) CH or CR 73 .
  • Each R 73 and R 74 is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalke ⁇ yl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR 10 Ri 1 , -OR 7 , -SR 7 , -C(O)R 7 , -C(O)OR 7 , -C(S)R 7 , -C(O)SR 7 , -C(S)SR 7 , -C(S)OR 7 , -C(S)NR 7 , -C
  • R 75 for each occurrence, is independently an alkyl or an aralkyl; and the values for the remainder of the variables are as described above.
  • the present invention provides compounds represented by structural formula (XXXIII) or (XXXIV):
  • R' 2 5 for each occurence is independently a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, -OH, -SH, -NHR 7 , -(CH 2 ) b OH, -(CH z ) b SH, -(CH 2 ) b NR 7 H, -OCH 3 , -SCH 3 , -NHCH 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 SH, -OCH 2 CH 2 NR 7 H, -SCH 2 CH 2 OH, -SCH 2 CH 2 SH, -SCH 2 CH 2 NR 7 H, -OC(O)NR 10 R 11 , -SC(O)NR 10 Rn, -NR 7 C(O)NR 10 Rn, -OC(O)R 7 , -SC(O)R 7 , -NR 7 C(O)R 7 , -OC(O)OR 7 , -SC
  • the present invention provides compounds represented by structural formula (XXXV):
  • the present invention provides compounds represented by structural formula (XXXVI):
  • the present invention provides compounds represented by structural formula (XXXVII):
  • the present invention provides compounds represented by structural formula (XXXVIII):
  • the present invention provides compounds represented by a structural formula selected from (XXXIX) and ((XL):
  • R 5 is represented by the following formula:
  • Rg for each occurrence, is independently a substitue ⁇ t selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR 10 R 11 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 Rn, -NR 8 C(O)R 7 , -SR 7 , -S(O
  • R 5 is represented by the following formula:
  • R 5 is represented by the following formula:
  • R 33 is a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;
  • R 34 is H, a lower alkyl, or a lower alkylcarbonyl;
  • Ring B and Ring C are optionally substituted with one or more substituents.
  • R 5 is selected from the group consisting of:
  • X 5 for each occurrence, is independently CH, CR 9 , N, N(O) 1 N + (R 17 ), provided that at least three X 6 groups are independently selected from CH and CR 9 ,
  • X7 for each occurrence, is independently CH, CR g , N, N(O), N + (R 17 ), provided that at least three X 7 groups are independently selected from CH and CRg,
  • X 8 for each occurrence, is independently CH 2 , CHR 9 , C(Rg) 2 , S, S(O)p, NR 7 , or NR 17 , X 9 , for each occurrence, is independently N or CH,
  • X 10 for each occurrence, is independently CH, CR 9 , N, N(O), N + (Ri 7 ), provided that at least one X 10 is selected from CH and CR 8 , R 9 , for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl,
  • R 17 for each occurrence, is independently -H, an alkyl, an aralkyl, -C(O)R 7 , -C(O)OR 7 , or -C(O)NR 10 R 11
  • R 5 is an optionally substituted indolyl, an optionally substituted benzoimidazolyl, an optionally substituted indazolyl, an optionally substituted 3H- ⁇ ndazolyl, an optionally substituted indolizi ⁇ yl, an optionally substituted qumoli ⁇ yl, an optionally substituted isoquinolinyl, an optionally substituted benzoxazolyl, an optionally substituted benzo[1,3]d ⁇ oxolyl, an optionally substituted benzofuryl, an optionally substituted benzothiazolyl, an optionally substituted benzo[d] ⁇ soxazolyl, an optionally substituted benzo[d] ⁇ soth ⁇ azolyl, an optionally substituted th ⁇ azolo[4,5-c]pyr ⁇ d ⁇ nyl, an optionally substituted th ⁇ azolo[5,4-c]pyr ⁇ d ⁇ nyl, an optionally substituted th ⁇ azolo[
  • R 5 is selected from the group consisting of;
  • X 11 for each occurrence, is independently CH, CR 3 , N, N(O), or N + (R 17 ), provided that at least two Xn groups are independently selected from CH and CR 9 ;
  • X 12 for each occurrence, is independently CH, CR 9 , N, N(O), N + (R 17 ), provided that at least one X 12 group is independently selected from CH and CR 9 ;
  • X 13 for each occurrence, is independently O, S 1 S(O)p, NR 7 , or NR 17 ;
  • R 9 for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alky ⁇ yi, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a hydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, -NR 10 Rn, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C
  • R 17 for each occurrence, is independently an alkyl or an aralkyl.
  • R 5 is represented by the following formula:
  • X 15, for each occurrence, is independently CH 2 , CHR 7 , or NR 7 ,
  • R 5 is represented by the following formula:
  • n is 0, 1, 2, 3, 4, or 5.
  • n is 1.
  • Z is an optionally substituted alky!, an optionally substituted alkoxy, an amino, an alkyl amino, or a dialkyl amino.
  • R 6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl.
  • R 6 is -L-R x , wherein L is an optionally substituted 1 to 6 atom linker, wherein each linker atom is independently selected from the group consisting of C, O, S or N; and R x is an optionally substituted heteroaryl or an optionally substituted aryl
  • R x is an optionally substituted phenyl, an optionally substituted indolyl, an optionally substituted benzoimidazolyl, an optionally substituted indazolyl, an optionally substituted 3W-indazolyl, an optionally substituted indolizinyl, an optionally substituted quinolinyl, an optionally substituted isoquinolinyl, an optionally substituted benzoxazolyl, an optionally substituted benzo[1 ,3]dioxolyl, an optionally substituted benzofuryl, an optionally substituted be ⁇ zothiazolyl, an optionally substituted be
  • Ri, R 2 , and R 3 are each, independently, -OH, -SH, Or -NHR 7 .
  • R 2 and R 3 are each -OH.
  • R 6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfa ⁇ yl or a C3-C6 cycloalkyl; and R-i, R 2 , and R 3 are each, independently, -OH or -SH.
  • X 41 is NR 42 and
  • X 42 IS CR4 4 .
  • X 41 is NR 42 and X 42 is N.
  • R 41 is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy. In another embodiment, in the compounds represented by formula (II), R 41 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
  • X 41 is NR 42 , and R 42 is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, -C(O)N(R 27 ) 2 , and -C(O)OH, wherein each R 27 is independently -H or a lower alkyl.
  • X 4 i is NR 42 , and R 42 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, fert-butyl, n-pentyl, n-hexyl, -C(O)OH, -(CH 2 ) m C(O)OH, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , and -C(O)N(CH 3 ) 2 .
  • R 43 and R 44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
  • X 42 is CR 44 ;
  • Y 40 is CR 43 ; and
  • R 43 and R 44 together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring.
  • R 43 and R 44 together with the carbon atoms to which they are attached form a C 5 -C 6 cycloalkenyl or a C 5 -C 8 aryl.
  • R 45 or CR 45 is selected from the group consisting of -H, -OH, -SH, -NH 2 , a lower alkoxy, a lower alkyl amino, and a lower dialkyl amino.
  • R 45 is selected from the group consisting of -H 1 -OH, methoxy and ethoxy.
  • X 41 is O.
  • R 40 is -OH or -SH.
  • X 42 is CR 44
  • R 43 and R 44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
  • X 42 is CR 44
  • R 43 and R 44 taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring.
  • R 43 and R 44 taken together with the carbon atoms to which they are attached, form a C 5 -C 6 cycloalkenyl or a C 5 -C 8 aryl.
  • X 42 is CR 44
  • X 42 is N
  • the compound is selected from the group consisting of 2-Ethyl-6-[5-mercapto-4-(1-methyl-1H-indol-5-yl)-4H-[1 ,2,4]tnazol-3-yl]-pyridine-3,5-diol, 2-[5-Hydroxy-4-(1-methyl-1 H-indol-5-yl)-4H-[1,2,4]triazol-3-yl]-6-isopropyl-pyridine-3,5- cliol,
  • R' 5 is represented by the following formula
  • R 9 for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alky ⁇ yl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR 10 Rn, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 R 11 , -NR 8 C(O)R 7 , -SR 7 , -S(
  • R' 5 is represented by the following formula
  • R'5 in the compounds represented by formula (V) or (Vl) 1 R'5 is represented by the following formula
  • R 33 is a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;
  • R 34 is H 1 a lower alkyl, or a lower alkyicarbonyl
  • Ring B and Ring C are optionally substituted with one or more substituents.
  • R's is selected from the group consisting of:
  • X 6 for each occurrence, is independently CH, CR 9 , N, N(O), N + (R 17 ), provided that at least three X 6 groups are independently selected from CH and CR 9 ;
  • X 7 for each occurrence, is independently CH, CR 9 , N, N(O), N + (R 17 ), provided that at least three X 7 groups are independently selected from CH and CR 9 ;
  • X 8 for each occurrence, is independently CH 2 , CHR 9 , C(Rg) 2 , S, S(O)p, NR 7 , or NR 17 ;
  • X 9 for each occurrence, is independently N or CH;
  • X) 0 for each occurrence, is independently CH 1 CRg, N, N(O), N + (Ri 7 ), provided that at least one X 10 is selected from CH and CR 9 ;
  • Rg for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alky), an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cya ⁇ o, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR 10 R 11 , -OR 7 , -C(O)R 7 , -
  • R 17 for each occurrence, is independently -H, an alkyl, an aralkyl, -C(O)R 7 , -C(O)OR 7 , or -C(O)NR 10 Ri 1 ,
  • R' 5 is an optionally substituted indolyl, an optionally substituted benzoimidazolyl, an optionally substituted indazolyl, an optionally substituted 3H-indazolyl, an optionally substituted indolizinyl, an optionally substituted quinolinyl, an optionally substituted isoquinoli ⁇ yl, an optionally substituted benzoxazolyl, an optionally substituted benzo[1 ,3]dioxolyl, an optionally substituted benzofuryl, an optionally substituted benzothiazolyl, an optionally substituted benzo[d]isoxazolyl, an optionally substituted benzo[d]isothiazolyl, an optionally substituted thiazolo[4,5-c]pyridinyl, an optionally substituted thiazolo[5,4-c]pyridinyl, an optionally substituted thiazolo[4,5-b
  • R' 5 is selected from the group consisting of: wherein:
  • X 11 for each occurrence, is independently CH, CR 9 , N, N(O), or N + (R 17 ), provided that at least one X 11 is N, N(O), or N + (Ri 7 ) and at least two X 1 -, groups are independently selected from CH and CR 9 ;
  • X 12 for each occurrence, is independently CH, CRg, N, N(O), N + (R 17 ), provided that at least one X 12 group is independently selected from CH and CR 9 ;
  • X 13 for each occurrence, is independently O 1 S, S(O)p, NR 7 , or NRi 7 ;
  • R 9 for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a hydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, -NRi 0 R 11 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 R 11 , -NR 8 C(O)R 7 , -SR 7 , -S
  • R' is -NHR 7 .
  • R 2 is -OH, -SH, or -NHR 7 .
  • R' 3 is
  • Z for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR 10 R 11 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -C(S)R 7 , -C(O)SR 7 , -C(S)SR 7 , -C(S)OR 7 , -C(S)NR 10 R
  • 1 1 is 1.
  • t is O.
  • R 5 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl.
  • R ⁇ is -NHR 7 ;
  • R 2 is -OH, -SH, or -NHR 7 ;
  • R' 3 is -OH or -SH;
  • R 6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl.
  • X 41 is NR 42 and X 42 is CR 44 .
  • X 41 is NR 42 and X 42 is N.
  • R 4 i is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
  • R 41 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
  • X 41 is NR 42
  • R 42 is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, -C(O)N(R Z7 ) 2 , and -C(O)OH, wherein each R 27 is independently -H or a lower alkyl.
  • X 41 is NR 42
  • R 42 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, fert-butyl, n-pentyl, n-hexyl, -C(O)OH, -(CH 2 ) m C(O)OH, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , and -C(O)N(CH 3 J 2 .
  • R 43 and R 44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
  • X 42 is CR 44 ;
  • Y 40 is CR 43 ; and
  • R 43 and R 44 together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring.
  • R 43 and R 44 together with the carbon atoms to which they are attached form a C 5 -C 8 cycloalkenyl or a C 5 -C 8 aryl.
  • R 45 or CR 45 is selected from the group consisting of -H, -OH, -SH, -NH 2 , a lower alkoxy, a lower alkyl amino, and a lower dialkyl amino.
  • R 45 is selected from the group consisting of -H, -OH, methoxy and ethoxy.
  • X 41 is O.
  • X 42 is CR 44
  • R 43 and R 44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
  • X 42 is CR 44 , and R 43 and R 44 , taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring.
  • R 43 and R 44 taken together with the carbon atoms to which they are attached, form a C 5 -C 8 cycloalkenyl or a C 5 -C 8 aryl.
  • X 42 is CR 44 . In one embodiment, in the compounds represented by formula (VIII), X 42 is N.
  • R 4 i is selected from the group consisting of -H 1 lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
  • R 41 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
  • R 112 is -H or an optionally substituted lower alkyl.
  • the compound is selected from the group consisting of
  • R' 5 is represented by the following formula:
  • R 9 is independently a substituent selected from the group consisting of an optionally substituted alky], an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR 10 Rn, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 Rn, -NR 8 C(O)R 7 , -SR 7 , -S(O) 13 R
  • R 33 is a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;
  • R 34 is H, a lower alkyl, or a lower alkylcarbonyl
  • Ring B and Ring C are optionally substituted with one or more substituents.
  • R' 5 is selected from the group consisting of:
  • X 6 for each occurrence, is independently CH, CR 9 , N, N(O), N + (R 17 ), provided that at least three X 6 groups are independently selected from CH and CR 9 ;
  • X 7 for each occurrence, is independently CH, CR 9 , N, N(O), N + (R 17 ), provided that at least three X 7 groups are independently selected from CH and CR 9 ;
  • X 8 for each occurrence, is independently CH 2 , CHR 9 , C(Rg) 2 , S, S(O)p, NR 7 , or NR 17 ;
  • X 9 for each occurrence, is independently N or CH;
  • X 10 for each occurrence, is independently CH, CR 9 , N, N(O), N + (R 17 ), provided that at least one X 10 is selected from CH and CR 3 ;
  • R 9 for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR 10 Ri 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 R 11 , -NR 8 C(O)R 7 , -SR 7 , -S(O
  • R 17 for each occurrence, is independently -H, an alkyl, an aralkyl, -C(O)R 7 , -C(O)OR 7 , or -C(O)NR 10 R 11 .
  • R's is an optionally substituted indolyl, an optionally substituted benzoimidazolyl, an optionally substituted indazolyl, an optionally substituted 3H-indazolyl, an optionally substituted indolizinyl, an optionally substituted quinolinyl, an optionally substituted isoquinolinyl, an optionally substituted benzoxazolyl, an optionally substituted benzo[1 ,3]dioxolyl, an optionally substituted benzofuryl, an optionally substituted benzothiazolyl, an optionally substituted benzo[d]isoxazolyl, an optionally substituted benzo[d]isothiazolyl, an optionally substituted thiazolo[4,5-c]pyridinyl, an optionally substituted thiazolo[5,4-c]pyridinyl, an optionally substituted thiazolo
  • R' 5 is selected from the group consisting of:
  • Xn for each occurrence, is independently CH, CR 9 , N, N(O), or N + (R 17 ), provided that at least one Xn is N, N(O), or N + (R 17 ) and at least two X 1 , groups are independently selected from CH and CR 9 ;
  • X 12 for each occurrence, is independently CH, CR 9 , N, N(O), N + (R 17 ), provided that at least one X 12 group is independently selected from CH and CR g ;
  • Xi 3 for each occurrence, is independently O, S, S(O)p, NR 7 , or NR 17 ;
  • R 9 for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally ' substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a hydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, -NR 10 R 11 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 Rn, -NR 8 C(O)R 7 , -SR 7 , -S(
  • R 17 for each occurrence, is independently an aikyl or an aralkyl.
  • R' B is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1- C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl.
  • R' 6 is -H.
  • R 19 is - H.
  • R' 5 is an optionally substituted phenyl.
  • R' 2 and R' 3 are each -OH.
  • X' is -S-S-.
  • X' is -0-0-.
  • the compound is 6,6'-(5,5'-disulfanediylbis(4-(4-(dimethylamino)phenyl)-4H-1,2,4-triazole-5,3-diyl))bis(4- isopropylbenzene-1 ,3-diol) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof.
  • X 41 is NR 42 and X 42 is CR 44 .
  • X 41 is NR 42 and X 42 is N.
  • R 41 is selected from the group consisting of -H 1 lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
  • R 4t is selected from the group consisting of -H 1 methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
  • X 41 is NR 42 , and R 42 is selected from the group consisting of -H, a lower alky), a lower cycloalkyl, -C(O)N(R 27 ) 2 , and -C(O)OH, wherein each R 27 is independently -H or a lower alky).
  • X 41 is NR 42
  • R 42 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, -C(O)OH, -(CH 2 ) m C(0)0H, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , and -C(O)N(CH 3 ) 2 .
  • R 43 and R 44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
  • X 42 is CR 44 ;
  • Y 40 is CR 43 ; and
  • R 43 and R 44 together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring.
  • R 43 and R 44 together with the carbon atoms to which they are attached form a C 5 -C 6 cycloalkenyl or a C 5 -C 8 aryl.
  • CR 45 is selected from the group consisting of -H, -OH, -SH, -NH 2 , a lower alkoxy, a lower alkyl amino, and a lower dialkyl amino.
  • R 45 is selected from the group consisting of -H, -OH, methoxy and ethoxy.
  • X 41 is O.
  • R 40 is -OH or -SH.
  • X 42 is CR 44
  • R 43 and R 44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
  • X 42 is CR 44 , and R 43 and R 44 , taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring.
  • R 43 and R 44 taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring.
  • R 43 and R 44 taken together with the carbon atoms to which they are attached, form a C 5 -C 8 cycloalkenyl or a C 5 -C 6 aryl.
  • X 42 is CR 44 .
  • the compound is selected from the group consisting of
  • the compound is selected from the group consisting of
  • R' 5 is an optionally substituted naphthyl.
  • R's is represented by the following formula:
  • Rg for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alky), an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR 10 Rn, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 R 11 , -NR 8 C(O)R 7 , -SR 7 , -S(O) P R
  • R 9 is defined as above; q is zero or an integer from 1 to 5; and u is zero or an integer from 1 to 5.
  • R' 5 is represented by the following structural formula:
  • R 33 is H, a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;
  • R 34 is H, a lower alkyl, or a lower alkylcarbonyl; and Ring B and Ring C are optionally substituted with one or more independently selected substituents.
  • R' 5 is selected from the group consisting of:
  • X 6 for each occurrence, is independently CH, CR 9 , N, N(O), N + (R 17 ), provided that at least three X 6 groups are independently selected from CH and CR 9 , X 7 , for each occurrence, is independently CH, CR 9 , N, N(O), N + (R 17 ), provided that at least three X 7 groups are independently selected from CH and CR 9 ,
  • X 8 for each occurrence, is independently CH 2 , CHR 9 , CR 9 Rg, O, S, S(O)p, NR 7 , or NR 17 ,
  • X 9 for each occurrence, is independently N or CH, Xio, for each occurrence, is independently CH, CRg 1 N, N(O), N + (R 17 ), provided that at least one X 10 is selected from CH and CR 9 ,
  • R 17 for each occurrence, is independently -H, an alkyl, an aralkyl, -C(O)R 7 , -C(O)OR 7 , or -C(O)NR 10 R 1I , wherein R 7 , R 9 , R 10 , Rn and p are defined as above
  • R's is an optionally substituted indolyl, an optionally substituted benzoimidazolyl, an optionally substituted indazolyl, an optionally substituted 3H- ⁇ ndazolyl, an optionally substituted indolizinyl, an optionally substituted quinolinyl, an optionally substituted isoqumolinyl, an optionally substituted benzoxazolyl, an optionally substituted benzo[1 ,3]dioxolyl, an optionally substituted benzofuryl, an optionally substituted benzothiazolyl, an optionally substituted benzo[d] ⁇ soxazolyl, an optionally substituted benzo[d] ⁇ soth ⁇ azolyl, an optionally substituted th ⁇ azo!o[4,5-c]py ⁇ d ⁇ nyl, an optionally substituted th ⁇ azolo[5,4-c]py ⁇ d ⁇ nyl, an optionally substituted th ⁇ azolo[5,4-c]py ⁇ d
  • R's is an optionally substituted indolyl.
  • R 5 is an indolyl represented by the following structural formula:
  • R 33 is a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;
  • R 34 is H, a lower alkyl, or a lower alkylcarbonyl
  • Ring B and Ring C are optionally substituted with one or more substituents.
  • R' 5 is selected from the group consisting of:
  • Xn for each occurrence, is independently CH, CR 9 , N, N(O), or N + (R 17 ), provided that at least one X 11 is N, N(O), or N + (R 17 ) and at least two X 11 groups are independently selected from CH and CR 9 ;
  • X 12 for each occurrence, is independently CH, CR 9 , N, N(O), N + (R 17 ), provided that at least one X 12 group is independently selected from CH and CR g ;
  • Xi 3 for each occurrence, is independently O, S, S(O)p, NR 7 , or NR 17 ; wherein R 7 , Rg and Ri 7 are defined as above.
  • R' 5 is a phenyl which is optionally substituted with from one to five substituents independently selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, -C(O)NR' 2B R' 2 9, -C(S)NR 1 Z 8 R ⁇ 9 , -C(NR' 32 )NR' 28 R' 29 , -NR 1 S0 C(O)R 1 S 1 , -NR' 3 oC(S)R' 31l -NR' 3
  • R'5 is a phenyl which is substituted with from one to five substituents independently selected from the group consisting of an alkyl, an alkoxy, a haloalkyl, an amino, an alkylamino, a dialkylamino, a cycloalkoxy, a halo, carboxy, -C(O)R 35 , -OC(O)R 1 Z6 , -C(O)OR' 26 , - NR 35 C(O)R 1 S6 , -C(O)NR 35 R 35 , -NR 35 C(O)NR 36 R 37 , -NR 35 C(NR 8 )NR 36 R 37 , -S(O) 2 R' 26 , - S(O) 2 NR 35 R 36 , -NR 35 S(O) 2 R' 26l an alkoxyalkyl, a dialkylamino, an alkoxyalkoxy, an al
  • R' 5 is represented by the following formula
  • X 16 is NR 35 and R 35 is H or a lower alkyl.
  • R 35 is H or a lower alkyl.
  • one of R' 40 or R' 41 is H and the other is a lower alkyl, a lower alkoxy, or a three to six membered cycloalkyl.
  • R' 40 and R' 4 1 are both H.
  • X 16 is -O-, -
  • NR 35 -, or -S- are independently, H or a lower alkyl.
  • X 16 is - NH- and Z' is -NR 35 -.
  • XXIII 1 Xi 6 and Z' are -O-.
  • Z' is CR 35 R 3S .
  • X 16 is NH.
  • R' 4O is H and
  • R' 41 is a lower alkyl, a lower alkoxy, or a 3 to 6 membered cycloalkyl.
  • R' 41 is H and R' 4O is a lower alkyl, a lower alkoxy, or a 3 to 6 membered cycloalkyl.
  • R' 40 and R' 41 are H.
  • the dashed line is a double bond.
  • R' 4O and R 1 M together with the carbon to which they are attached form a five or six membered cycloalkenyl.
  • X 16 is -NH-, - O-, or -S-;
  • Z' is -NR 35 -, -0-, -S- or -CR 35 R 36 -;
  • R 35 and R 36 for each occurrence, are independently, H or a lower alkyl.
  • R 38 and R' 39 are each, independently, H or a lower alkyl; X 16 is -NH-; and Z' is -NR 35 - or -O-.
  • R 38 and R' 39 are each, independently, H or a lower alkyl; X 16 is -O-; and Z' is -NR 35 - or -O-.
  • X 18 is -O-, - NH-, or -S-.
  • R 7 is H or a lower alkyl.
  • X 15 is - NH-.
  • X 16 is -O-, - NH-, or -S-.
  • R 7 is H or a lower alkyl.
  • R 1 and R 3 are each independently -OH, -SH, -NHR 7 , -OC(O)NR 10 RH, -SC(O)NR 10 R 11 , -OC(O)R 7 , -SC(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -OS(O) P R 7 , -S(O) P OR 7 , -SS(O)pR 7, -OS(O)pOR 7 , -SS(O) p OR 7, -OC(S)R 7 , -SC(S)R 7 , -OC(S)OR 7 , -SC(S)OR 7 , -OC(S)NR 10 R 1 I, -SC(S)NR 10 R 11 , -OC(NR 8 )R 7 , -SC(NR 8 )R 7 , -OC(NR 8 )OR 7 , -SC(NR 8 )OR 7 , -SC(
  • R 1 and R 3 are each, independently, -OH, -SH, or -NHR 7 .
  • Ri is -SH or -OH; and R 3 is -OH.
  • the compound is selected from the group consisting of: 3-[3-methyl-6-hydroxy-iH-indol-5-yl]- 4-(6-methoxy- ⁇ aphthalen-1-yl)-5-hydroxy-4/-/- [1,2,4]triazole;
  • Ring F is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R 103
  • Ring F is phenyl substituted with (R' 25 ) x and (R 73 Jo in addition to R 103
  • Ring F is represented by the following structural formula
  • Ring F is represented by the following structural formula
  • Ring G is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to -T 1 -Vi-Ta-V 2
  • Ring G is a six membered nitrogen containing heteroaryl substituted with T 1 -V 1 -T 2 -V 2 and optionally further substituted with one or more R 74 groups
  • Ring G is pyridyl substituted with TrV 1 -T 2 -V 2 and optionally further substituted with one or more R 74 groups.
  • Ring G is represented by the following structural formula:
  • Ring G is represented by the following structural formula:
  • Ring G is represented by a structural formula selected from:
  • Ring G is phenyl substituted with Ti-Vi-T 2 -V 2 and optionally further substituted with one or more R 74 groups.
  • Ring G is represented by a structural formula selected from:
  • Ring G is represented by a structural formula selected from:
  • R 100 is -OH, -SH, -NR 7 H, -OR 1 Z6 , -SR'a ⁇ , -NHR ⁇ 26 , -O(CH 2 ) m OH, -O(CH 2 ) m SH, -O(CH 2 ) m NR 7 H, -S(CH 2 ) m OH, -S(CH 2 ) m SH, -S(CH 2 ) m NR 7 H, -OC(O)NR 10 R 11 , -SC(O)NR 10 R 11 , -NR 7 C(O)NR 10 Rn, -OC(O)R 7 , -SC(O)R 71 -NR 7 C(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -NR 7 C(O)OR 7 , -OCH 2 C(O)R 7 , -SCH 2 C(O)R
  • R 100 is -OH 1 -SH, -NHR 7 , -OC(O)NR 10 R 11 , -SC(O)NR 10 R 11 .
  • R 10 3 is -OH, -SH, -NR 7 H, -OR 1 M1 -SR 1 M , -NHR' 26 , -O(CH 2 ) m OH, -O(CH 2 ) m SH, -O(CH 2 ) m NR 7 H, -S(CH 2 ) m OH, -S(CH 2 ) m SH, -S(CH 2 ) m NR 7 H, -OC(O)NR 10 R 11 , -SC(O)NR 10 R 11 , -NR 7 C(O)NR 10 R 11 , -OC(O)R 7 , -SC(O)R 71 -NR 7 C(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -NR 7 C(O)OR 7 ,
  • Ri 03 is -OH, -SH, -NHR 7 , -OC(O)NR 1 ORH.
  • R 103 is -OH, -SH or -NHR 7 .
  • Ri 03 is independently -SH or -OH.
  • R 73 for each occurrence is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR 10 R 11 , -OR 7 , -SR 7 , -C(O)R 7 , -C(O)OR 7 ,
  • R 73 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR 7 , -SR 7 , -NR 10 R 111 -OC(O)NR 10 R 11 , -SC(O)NR 10 R 11 , -NR 7 C(O)NR 10 R 11 , -OC(O)R 7 , -SC(O)R 7 , -NR 7 C(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -NR 7 C(O)OR 7 , -OCH 2 C(O)R 7 ,
  • R 73 is for each occurrence, is independently an optionally substituted C1-C6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C3-C6 cycloalkenyl, an optionally substituted heterocyclyl, a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, an alkoxy, an alkylsulfanyl, -OH, -SH, -NHR 7 , -(CH 2 ) b OH, -(CH 2 ) b SH, -(CH 2 ) b NR 7 H, -OCH 3 , -SCH 3 , -NHCH 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 SH, -OCH 2 CH 2 NR 7 H, -SCH 2 CH 2 NR 7 H, -SCH 2 CH 2 NR 7 H, -SCH 2 CH 2 NR 7 H, -
  • R 73 for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, -OH, -SH, -HNR 7 , -OC(O)NR 10 R 11 , -SC(O)NR 10 R 11 , -OC(O)R 7, -SC(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -OS(O) P R 7 , -S(O) P OR 7 , -SS(O) P R 7 , -OS(O) P OR 7 ,
  • R 73 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkylsulfanyl or a C3-C6 cycloalkyl. In another preferred embodiment, R 73 is cyclopropyl or
  • R 7 and R 8 for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloa.lkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl.
  • R 7 and R 8 for each occurrence Is independently -H, C1-C6 alkyl, C3-C6 cycloalkyi or aryl.
  • R 7 and R 8 for each occurrence is independently -H or C1-C3 alkyl.
  • R 10 and R 11 for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyi, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; or R 10 and R 11 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl.
  • Ri 0 and R 11 for each occurrence is independently -H, C1-C6 alkyl, C3-C6 cycloalkyi or aryl.
  • R 10 and Ri 1 for each occurrence is independently -H or C1-C3 alkyl.
  • R' 25 for each occurence is independently a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, -OH, -SH, -NHR 7 , -(CH 2 ) b OH, -(CH 2 ) b SH, -(CH 2 J b NR 7 H, -OCH 3 , -SCH 3 , -NHCH 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 SH, -OCH 2 CH 2 NR 7 H, -SCH 2 CH 2 OH, -SCH 2 CH 2 SH, -SCH 2 CH 2 NR 7 H, -OC(O)NR 10 R 11 , -SC(O)NR 10 Rii, -NR 7 C(O)NR 10 R 11 , -OC(O)R 7 , -SC(O)R 7 , -NR 7 C(O)R 7 , -OC(O)R 7 , -OC(O
  • R' 26 is a C1-C6 alkyl
  • R 74 for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR 10 R 11 , -OR 7 , -SR 7 , -C(O)R 7 , -C(O)OR 7 , -C(S)R 7 , -C(S)R 7 , -C(S)R 7 , -C(S)R 7
  • R 74 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an optionally substituted alkenyl, an
  • R 74 is a -OH, -SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl.
  • R 74 is a methyl, ethyl, propyl, isopropyl, methoxy or ethoxy.
  • T 1 is absent or a C1-C4 alkylene. In a preferred embodiment, T 1 is absent or a C1-C2 alkylene. In another preferred embodiment, T 1 is absent.
  • T 2 is absent or a C1-C4 alkylene
  • V 1 is absent and V 2 is -NR a R b , -NR 3 S(O) 2 R", -S(O)NR a R b , -S(O) 2 NR a R b or -C(0)NR a R b
  • T 2 is absent or a C1-C4 alkylene
  • V 1 is absent and V 2 is -NR a R b or -S(O) 2 NR 3 R".
  • T 2 is absent or a C1-C4 alkylene
  • Vi is absent and V 2 is -NR a R b .
  • T 2 is absent, V 1 is absent and V 2 is -NR a R b ;or
  • T 2 is absent or a C1-C4 alkylene
  • V 1 is -0-, -S-, -N(R-)- or -C(O)N(R " )- and V 2 is -S(O)NR a R b , -S(O) 2 NR 3 R" or -C(O)NR a R b .
  • T 2 is absent or a C1-C4 alkylene
  • V 1 is -0-, -S- or -N(R * )-
  • V 2 is -S(O) 2 NR 8 R".
  • T 2 is absent or a C1-C4 alkylene
  • V 1 is -O- and V 2 is -S(O) 2 NR 8 R"; or
  • T 2 is a C2-C4 alkylene, V 1 is -0-, -S, -N(R * )-, -C(O)O-, C(O)N(R-)- and V 2 is -NR a R b , or -NR 8 S(O) 2 R ** .
  • T 2 is a C2-C4 alkylene, V 1 is -0-, -S- or -N(R * )-, and V 2 is -NR a R b .
  • T 2 is a C2-C4 alkylene, V 1 is -O- and V 2 is -NR 8 R".
  • T 2 is absent or a C1-C4 alkylene
  • V 1 is absent and V 2 is -NR a R b , -NR 0 S(O) 2 R**, -S(O)NR 8 R", -S(O) 2 NR 3 R" or -C(O)NR a R b
  • T 2 is absent or a C1-C4 alkylene
  • V- is absent and V 2 is -S(O) 2 NR a R b , or -NR 8 S(O) 2 R* * .
  • T 2 is absent or a C1-C4 alkylene
  • V 1 is absent and V 2 is -S(O) 2 NR a R b , or -NR 8 S(O) 2 R**.
  • T 2 is absent, V 1 is absent and V 2 is -S(O) 2 NR a R b , or -NR 8 S(O) 2 R**; or
  • T 2 is absent or a C1-C4 alkylene, V 1 is -0-, -S-, -N(R ' )- or -C(O)N(R-)- and V 2 is -S(O)NR 8 R", -S(O) 2 NR 8 R" or -C(O)NR a R b .
  • T 2 is absent or a C1-C4 alkylene, V 1 is -0-, -S- or - N(R-)-, and V 2 is -S(O) 2 NR 8 R".
  • T 2 is absent or a C1-C4 alkylene, V 1 is -0-, and V 2 is -S(O) 2 NR 8 R"; or
  • T 2 is a C2-C4 alkylene
  • V 1 is -O-, -S, -N(R-)-, -C(O)O-, C(O)N(R-)-
  • V 2 is -NR a R b , or -NR 8 S(O) 2 R**
  • T 2 is a C2-C4 alkylene
  • V 1 is -0-, -S- or -N(R " )-
  • V 2 is -NR a R b or -NR 3 S(O) 2 R * *.
  • T 2 is a C2-C4 alkylene
  • Vi is -O-
  • V 2 is -NR a R b Or -NR 8 S(O) 2 R**.
  • Each R * is independently -H or C1-C3 alkyl.
  • R a and R b are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or heteroaryl, or an optionally substituted aralky); or R a and R b , taken together with the nitrogen to which they are attached, form an optionally substituted heteroaryl or heterocyclyl.
  • R B and R b are each independently a hydrogen, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, -COOH, C2-6 acetal, C2-6 ketal, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino and a cycloalkyl; or R a and R b taken together with the nitrogen to which they are attached form a substituted or unsubstituted ⁇ onaromatic, nitrogen-containing heterocyclyl.
  • R a and R b are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -COOH, C2-6 acetal, C2-6 ketal, amino, C1-C6 alkoxy, alkylamino and dialkylamino; or R a and R b taken together with the nitrogen to which they are attached are:
  • R a and R b are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino and a cycloalkyl; or R a and R b taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl.
  • R a and R b are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -COOH, amino, C1-C6 alkoxy, alkylamino and dialkylamino; or R a and R b taken together with the nitrogen to which they are attached are:
  • each R** is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl
  • R** is independently, -H, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, amino, a C1-C6 alkoxy, alkylamino and dialkylami ⁇ o
  • R** is independently, -H, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting
  • R' 3S is -H, a C1-C4 alkyl or a C1-C4 acyl
  • p for each occurrence, is independently, O, 1 or 2
  • m for each occurrence, is independently, 1 , 2, 3 or 4
  • m is 2 or 3
  • k is 1 , 2, 3, or 4
  • k is 1 , 2 or 3, or preferably k is 2 or 3
  • e and f for each occurrence is independently an integer from 0 to 4 In a preferred embodiment, f is 0 or 1 In a preferred embodiment, e is 0 or 1 In one embodiment of compounds of formula (XXVIII), x is O or 1 , provided that e+x is less than or equal to 4
  • V 2 is -C(O)NR R then ring G is not ⁇ aphthyl or indolyl
  • X 3 and X 4 are each, independently, N, N(O), N + (R 75 ) CH or CR 73
  • R 75 for each occurrence, is independently an alkyl or an aralkyl; and the values and preferred values for the remainder of the variables are as described above for formula (I).
  • X 3 , X 4 , X 5 and R 75 are as described immediately, above and:
  • Ring F is represented by a structural formula selected from:
  • R 73 , and R 74 for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR 10 R 11 , -OR 7 , -SR 7 , -C(O)R 7 , -C(O)OR 7 , -C(S)R 7 , -C(O)SR 7 , -C
  • R' Z s is -OH, -SH, -NHR 7l -(CH 2 ) b OH, -(CH 2 ) b SH, -(CH 2 ) b NR 7 H, -OCH 3 , -SCH 3 , -NHCH 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 SH, -OCH 2 CH 2 NR 7 H, -SCH 2 CH 2 OH, -SCH 2 CH 2 SH, -SCH 2 CH 2 NR 7 H, -OC(O)NR 10 R 11 , -SC(O)NR 10 R 11 , -NR 7 C(O)NR 10 R 11 , -OC(O)R 7 , -SC(O)R 7 , -NR 7 C(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -SC(O)OR 7 , -NR 7 C(O)
  • R 100 , R 103 and R' 2S for each occurrence is independently -OH, -SH, -NHR 7 , -OC(O)NR 10 R 111 -SC(O)NR 10 R 1 ,, -OC(O)R 7, -SC(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -OS(O) P R 7 , -S(O) P OR 7 , -SS(O) P R 7 , -OS(O) p OR 7 , -SS(O) p OR 7 , -SS(O) p OR 7 , -OC(S)R 7 , -SC(S)R 7 , -OC(S)OR 7 , -SC(S)OR 7 , -OC(S)NR 10 R 11 , -SC(S)NR 10 R 11 , -OC(NR 8 )R 7 , -SC(NR
  • R 74 is an optionally substituted alky), an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR 7 , -SR 7 , -NR 10 R 11 , -OC(O)NR 10 Ri 1 , -SC(O)NR 10 Rn, -NRyC(O)NR 10 Rn, -OC(O)R 7 , -SC(O)R 7 , -NR 7 C(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -SC(O)OR 7 , -NR 7 C(O)OR 7 , -SC(O)OR 7 ,
  • R 73 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR 7 , -SR 7 , -NR 10 R 111 -OC(O)NR 10 R 11 , -SC(O)NR 10 R 1I , -NR 7 C(O)NR 10 R 11 , -OC(O)R 7 , -SC(O)R 7 , -NR 7 C(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -NR 7 C(O)OR 7 , -NR 7 C(O)OR 7 , -NR 7 C(
  • Ring G is a six membered nitrogen containing heteroaryl substituted with T 1 -V 1 -T 2 -V 2 and optionally further substituted with one or more R 74 group.
  • Ring G is as just described; and R 73 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkylsulfanyl or a C3-C6 cycloalkyl.
  • R 100 and R 103 are each, independently, -OH, -SH or -NHR 7 ; and the values and preferred values for remainder of the variables are as described in the sixth embodiment. More preferably, R 100 and R 103 are • each, independently, -OH, -SH or -NHR 7 and;
  • R B and R b are each independently a hydrogen, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH 1 -CN, -SH, -COOH, C2-6 acetal, C2-6 ketal, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino and a cycloalkyl; or R a and R b taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic,
  • T 1 is absent or a C1 -C2 alkylene.
  • T 2 is absent or a C1-C4 alkylene, V 1 is absent and V 2 is -NR a R b or -S(O) 2 NR a R b ; or T 2 is absent or a C1-C4 alkylene, V 1 is -O-, -S- or -N(R ' )-, and V 2 is -S(O) 2 NR a R b ; or T 2 is a C2-C4 alkylene, V 1 is -0-, -S- or - N(R ' )-, and V 2 is -NR 3 R".
  • R 74 is a -OH, -SH 1 halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl.
  • R 1O o, R 1O s and R' 25 for each occurrence is independently -SH or -OH, and R 73 is cyclopropyl or isopropyl.
  • R 73 is cyclopropyl or isopropyl.
  • R 74 is a methyl, ethyl, propyl, isopropyl, methoxy or ethoxy.
  • R a and R b are each independently a hydrogen, a C1 -C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -COOH, C2-6 acetal, C2-6 ketal, amino, C1-C6 alkoxy, alkylamino and dialkylamino; or R a and R b taken together with the nitrogen to which they are attached are:
  • R' 35 is -H, a C1-C4 alkyl or a C1-C4 acyl.
  • T 1 is absent.
  • T 2 is absent or a C1-C4 alkylene, V 1 is absent and V 2 is -NR a R b .
  • Ring G is phenyl substituted with T 1 -V 1 -T 2 -V 2 and optionally further substituted with one or more R 74 group.
  • Ring G is as just described and R 73 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkylsulfanyl or a C3-C6 cycloalkyl.
  • Ri O o and R 103 are each, independently, -OH, -SH Or -NHR 7 . More preferably, R 100 and R 103 are each, independently, -OH, -SH or -NHR 7 ; and
  • R a and R b are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino and a cycloalkyl; or R a and R b taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl.
  • R** is independently, -H, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, amino, a C1- C6 alkoxy, alkylamino and dialkylamino, T 1 is absent or a C1-C2 alkylene.
  • T 2 is absent or a C1-C4 alkylene, V 1 is absent and V 2 is -S(O) 2 NR 8 R", or -NR 3 S(O) 2 R ** ; or T 2 is absent or a C1-C4 alkylene, V 1 is -0-, -S- or -N(R-)-, and V 2 is -S(0) 2 NR a R b ; or T 2 is a C2-C4 alkylene, V 1 is -0-, -S- or -N(R>, and V 2 is -NR a R b or -NR 8 S(O) 2 R".
  • R 74 is a -OH, -SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl.
  • R 74 is as just described and Rioo, R 1O a and R' 25 for each occurrence, is independently -SH or -OH, and R 73 is cyclopropyl or isopropyl.
  • R 74 is a methyl, ethyl, propyl, isopropyl, methoxy or ethoxy.
  • R 74 is as just described; and R a and R b are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -COOH, amino, C1-C6 alkoxy, alkylamino and dialkylamino; or R a and R b taken together with the nitrogen to which they are attached are:
  • R' 35 is -H, a C1-C4 alkyl or a C1-C4 acyl.
  • R** is independently, -H, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, amino, a C1-C6 alkoxy, alkylamino and dialkylamino. Ti is absent.
  • T 2 is absent or a C1-C4 alkylene
  • V 1 is absent and V 2 is -S(O) 2 NR 3 R", or -NR 3 S(O) 2 R* * .
  • R 73 is for each occurrence, is independently an optionally substituted C1-C6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C3-C6 cycloalkenyl, an optionally substituted heterocyclyl, a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, an alkoxy, an alkylsulfanyl, -OH, -SH, -NHR 7 , -(CHz) b OH, -(CH 2 ) b SH, -(CH 2 ) b NR r H, -OCH 3 , -SCH 3 , -NHCH 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 SH, -OCH 2 CH 2 NR 7 H, -SCH 2 CH 2 OH, -SCH 2 CH 2 CH 2
  • R 73 and k are as just described; and Ring F is represented by a structural formula selected from:
  • R 73 , k and Ring F are as just described; and R 1O o and R 103 are each independently -OH 1 -SH, -NHR 7 , -OC(O)NR 10 Rii.
  • R 73 , k, F, ' R 100 and R 103 are as just described; and R 74 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR 7 , -SR 7 , -NR 10 R 11 , -OC(O)NR 10 R 1I , -SC(O)NR 10 R 11 , -NR 7 C(O)NR 10 Ri 1 , -OC(O)R 7 , -SC(O)R 7 , -NR 7 C(O)R 7 , -OC(O)
  • R 73 for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, -OH, -SH, -HNR 7 ,
  • Ring G is a six membered nitrogen containing heteroaryl substituted with T 1 -V 1 -T 2 -V 2 and optionally further substituted with one or more R 74 group.
  • G is as just described; and R 73 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkylsulfanyl or a C3-C6 cycloalkyl.
  • R 73 is as just described; and Ring G is pyridyl substituted with T 1 -V 1 -T 2 -V 2 and optionally further substituted with one or more R 74 group.
  • R 73 and G are as just described; and R 100 and R 103 for each occurrence is independently, -OH, -SH, or -NHR 7 .
  • R 73 , G, R 100 and R-io 3 are as just described; and R a and R b are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, -COOH 1 C2-6 acetal, C2-6 ketal, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino and a cycloalkyl; or R a and R b taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl.
  • T 1 is absent or a C1-C2 alkylene.
  • T 2 is absent or a C1-C4 alkylene, V-, is absent and V 2 is -NR a R b or -S(O) 2 NR 3 R"; or T 2 is absent or a C1-C4 alkylene, V 1 is -0-, -S- or -N(R ' )-, and V 2 is -S(O) 2 NR 8 R"; or T 2 is a C2-C4 alkylene, V 1 is -0-, -S- or -N(R>, and V 2 is -NR a R b .
  • Ring G is represented by the following structural formula: C
  • R 74 for each occurrence is independently -OH, -SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, G1- C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl.
  • R 74 is as just described; and R 10- and R 103 for each occurrence, is independently -SH or -OH, and R 73 is cyclopropyl or isopropyl.
  • R 74 , R 100 and R 103 are as just described; and Ring G is represented by the following structural formula:
  • R 74 for each occurrence is independently methyl, ethyl, propyl, isopropyl, methoxy or ethoxy.
  • R 74 is as just described;
  • R a and R b are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, - COOH, C2-6 acetal, C2-6 ketal, amino, C1-C6 alkoxy, alkylamino and dialkylamino; or R a and R b taken together with the nitrogen to which they are attached are:
  • R' 35 is -H, a C1-C4 alkyl or a C1-C4 acyl. Ti is absent.
  • T 2 is absent or a C1-C4 alkylene, V 1 is absent and V 2 is -NR a R b .
  • 1 Ring G is phenyl substituted with Ti-V 1 -T 2 -V 2 and optionally further substituted with one or more R 74 group.
  • G is as just described and R 73 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkylsulfanyl or a C3-C6 cycloalkyl.
  • G and R 73 are as just described and Ri 00 and Ri 03 for each occurrence is independently, -OH, -SH 1 or -NHR 7 .
  • G, R 73 R 100 and R 103 are as just described and:
  • R a and R b are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino and a cycloalkyl; or R" and R b taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl.
  • R* * is independently ' , -H, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, amino, a C1- C6 alkoxy, alkylamino and dialkylamino.
  • T 1 is absent or a C1-C2 alkylene.
  • T 2 is absent or a C1-C4 alkylene, V 1 is absent and V 2 is -S(O) 2 NR 3 R", or -NR 3 S(O) 2 R"; or T 2 is absent or a C1-C4 alkylene, V 1 is -O-, -S- or -N(R * )-, and V 2 is -S(O) 2 NR a R b ; or T 2 is a C2-C4 alkylene, V 1 is -0-, -S- or -N(R>, and V 2 is -NR 3 S(O) 2 R".
  • Ring G is represented by a structural formula selected from:
  • R 74 for each occurrence is independently -OH 1 -SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl.
  • R 74 is as described above and R 100 and R 103 for each occurrence, is independently -SH or -OH, and R 73 is cyclopropyl or isopropyl.
  • R 74 for each occurrence is independently methyl, ethyl, propyl, isopropyl, methoxy or ethoxy.
  • R 74 is as described above and R" and R b are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -COOH, amino, C1-C6 alkoxy, alkylamino and dialkylamino; or R a and R b taken together with the nitrogen to which they are attached are:
  • R" 35 is -H, a C1-C4 alky I or a C1-C4 acyl.
  • R** is independently, -H, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, amino, a C1-C6 alkoxy, alkylamino and dialkylamino.
  • T 1 is absent.
  • T 2 is absent or a C1-C4 aikylene, V 1 is absent and V 2 is -S(O) z NR a R b , or -NR 3 S(O) 2 R".
  • Ring G is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to -T 1 -Vi-T 2 -V 2 .
  • Ring G is a six membered nitrogen containing heteroaryl substituted with T 1 -V 1 -T 2 -V 2 and optionally further substituted with one or more R 74 group.
  • Ring G is pyridyl substituted with T 1 -V 1 -T 2 -V 2 and optionally further substituted with one or more R7 4 group.
  • G is as just described and R' 22 is -H, an alkyl, an aralkyl, -C(O)R 7 , -C(O)OR 7 or -C(O)NR 10 Ri 1 .
  • R a and R b are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, -COOH, C2-6 acetal, C2-6 ketal, amino, a C1-C6 alkoxy, ' alkylsulfanyl, alkylamino, dialkylamino and a cycloalkyl; or R a and R b taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl.
  • T 1 is absent or a C1-C2 aikylene.
  • T 2 is absent or a C1-C4 alkylene, V 1 is absent and V 2 is -NR a R b or -S(O) 2 NR 3 R"; or T 2 is absent or a C1-C4 alkylene, V 1 is -0-, -S- or -N(R " )-, and V 2 is -S(O) 2 NR a R b ; or T 2 is a C2-C4 alkylene, V 1 is -0-, -S- or -N(R * )-, and V 2 is -NR a R b .
  • Ring G is represented by the following structural formula:
  • ring G is as just described and R 74 for each occurrence is independently -OH, -SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl.
  • Ring G is represented by the following structural formula:
  • R a and R b are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -COOH, C2-6 acetal, C2-6 ketal, amino, C1-C6 alkoxy, alkylamino and dialkylamino; or R a and R b taken together with the nitrogen to which they are attached are:
  • R' 35 is -H, a C1-C4 alkyl or a C1-C4 acyl.
  • T 1 is absent.
  • T 2 is absent or a C1-C4 alkylene, V 1 is absent and V 2 is -NR a R b .
  • Ring G is phenyl substituted with T 1 -VrT 2 -V 2 and optionally further substituted with one or more R 74 group.
  • Ring G is as just described and R1 0 0 is -OH 1 -SH, or -NHR 7 .
  • Ring G and R 1O o are as just described; and R' 22 is -H, an alkyl, an aralkyl, -C(O)R 7 , -C(O)OR 7 or -C(O)NR 10 Ru.
  • Ring G, R 100 and R' 22 are as just described and R a and R b are each independently a hydrogen, a C1-G6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino and a cycloalkyl; or R a and R b taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl.
  • R ** is independently, -H 1 a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH 1 amino, a C1- C6 alkoxy, alkylamino and dialkylamino.
  • T 1 is absent or a C1-C2 alkylene.
  • T 2 is absent or a C1-C4 alkylene, V, is absent and V 2 is -S(O) 2 NR a R b , or -NR 3 S(O) 2 R**; or T 2 is absent or a C1-C4 alkylene, V 1 is -0-, -S- or -N(R ' )-, and V 2 is -S(O) 2 NR 3 R"; or T 2 is a C2-C4 alkylene, V 1 is -0-, -S- or -N(R * )-, and V 2 is -NR 8 S(O) 2 R * *.
  • Ring G is represented by a structural formula selected from:
  • Ring G is as just described; and R 74 for each occurrence is independently -OH, -SH, halogen, cyano, a C1- C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl.
  • Ring G and R 74 are as just described and X 14 is O.
  • Ring G, R 74 and Xi 4 are as just described and: R a and R b are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, - COOH, amino, C1-C6 alkoxy, alkylamino and dialkylamino; or R a and R b taken together with the nitrogen to which they are attached are:
  • R' 35 is -H, a C1-C4 alky! or a C1-C4 acyl.
  • R** is independently, -H, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, amino, a C1-C6 alkoxy, alkylamino and dialkylamino.
  • T 1 is absent.
  • T 2 is absent or a C1-C4 alkylene
  • V is absent and V 2 is -S(O) 2 NR a R b , or -NR 3 S(O) 2
  • the compound is selected from the group consisting of: 4-(4-(6-(N-(2-methoxyethyl)-N-methylamino)pyridin-3-yl)-5-hydroxy-4H-1,2,4-triazol-3-yl)-6- isopropylbenzene-1 ,3-diol;
  • the compounds of the invention do not include the compounds disclosed in U.S. Patent Application No. 11/282,119, filed November 17, 2005.
  • Exemplary compounds of the invention are depicted in Table 1 below, including tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof.
  • Exemplary compounds of the invention are depicted in Table 2 below, including tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof.
  • Exemplary compounds of the invention are depicted in Table 3 below, including tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof.

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Abstract

The present invention relates to substituted triazole compounds and compositions comprising substituted triazole compounds. The invention further relates to methods of inhibiting the activity of Hsp90 in a subject in need thereof and methods for preventing or treating hyperproliferative disorders, such as cancer, in a subject in need thereof comprising administering to the subject a substituted triazole compound of the invention, or a composition comprising such a compound.

Description

TRIAZOLE COMPOUNDS THAT MODULATE HSP90 ACTIVITY
RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No. 60/808,276, filed May 25, 2006, U.S. Provisional Application No. 60/808,253, filed May 25, 2006, U.S. Provisional Application No. 60/808,284, filed May 25, 2006, U.S. Provisional Application No.
60/808,255, filed May 25, 2006, and U.S. Provisional Application No. 60/808,339, filed May 25, 2006, the entire teachings of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
Although tremendous advances have been made in elucidating the genomic abnormalities that cause malignant cancer cells, currently available chemotherapy remains unsatisfactory, and the prognosis for the majority of patients diagnosed with cancer remains dismal. Most chemotherapeutic agents act on a specific molecular target thought to be involved in the development of the malignant phenotype. However, a complex network of signaling pathways regulate cell proliferation, and the majority of malignant cancers are facilitated by multiple genetic abnormalities in these pathways. Therefore, it is unlikely that a therapeutic agent that acts on one molecular target will be fully effective in curing a patient who has cancer.
Heat shock proteins (HSPs) are a class of chaperone proteins that are up-regulated in response to elevated temperature and other environmental stresses, such as ultraviolet light, nutrient deprivation, and oxygen deprivation. HSPs act as chaperones to other cellular proteins (called client proteins) and facilitate their proper folding and repair, and aid in the refolding of misfolded client proteins. There are several known families of HSPs, each having its own set of client proteins. The Hsp90 family is one of the most abundant HSP families, accounting for about 1-2% of proteins in a cell that is not under stress and increasing to about 4-6% in a cell under stress. Inhibition of Hsp90 results in degradation of its client proteins via the ubiquitin proteasome pathway. Unlike other chaperone proteins, the client proteins of Hsp90 are mostly protein kinases or transcription factors involved in signal transduction, and a number of its client proteins have been shown to be involved in the progression of cancer, Examples of Hsp90 client proteins that have been implicated in the progression of cancer are described below. Her-2 is a transmembrane tyrosine kinase cell surface growth factor receptor that is expressed in normal epithelial cells. Her2 has an extracellular domain that interacts with extracellular growth factors and an internal tyrosine kinase portion that transmits the external growth signal to the nucleus of the cell. Her2 is overexpressed in a significant proportion of malignancies, such as breast cancer, ovarian cancer, prostate cancer, and gastric cancers, and is typically associated with a poor prognosis.
Akt kinase is a serine/threonine kinase which is a downstream effector molecule of phosphoinositide 3-kinase and is involved in protecting the cell from apoptosis. Akt kinase is thought to be involved in the progression of cancer because it stimulates cell proliferation and suppresses apoptosis.
Cdk4/cyclin D complexes are involved in phosphorylation of retinoblastoma protein which is an essential step in progression of a cell through the G1 phase of the cell cycle. Disruption of Hsp90 activity has been shown to decrease the half life of newly synthesized Cdk4.
The Raf family of proto-oncogenes (A-raf, B-raf and C-raf) was first identified when C-raf (raf-1 ) was discovered due to its homology with v-raf, the transforming gene of the mouse sarcoma virus 3611. A-raf was later discovered by screening a cDNA library under low stringency conditions using a v-raf probe, and B-raf was discovered due to its homology with C-Rmil, a transforming gene in avaian retrovirus Mill Hill No. 2. The Raf family of proteins is involved in the Ras/Raf/MEK/ERK pathway, referred to herein as the "MAP kinase pathway" (MEK stands for "MAPK/ERK kinase" and ERK stands for "extracellularly regulated kinases"), which has been implicated in the genesis and progression of many human cancers through upregulation of cell division and proliferation. All raf proteins are serine/theronine kinases which are capable of activating the MAP kinase pathway. However, B-raf is far more potent at activating this pathway than A-raf or C-raf, and mutations in the gene encoding B-raf are more common in cancer. For example, B-raf mutations have been identified in 60% to 70% of malignant melanomas, 83% of anaplastic thyroid carcinoma, 35% to 69% of papillary thyroid caricinoma, 4% to 16% of colon cancer, 63% of low-grade ovarian carcinoma, 15% of Barrett's esophageal carcinoma, 4% of acute myeloid leukemia, 3-4.8% of head and neck squamous cell carcinoma, 2%-3% of non-small- cell lung cancer, 2% of gastric carcinoma, 2% of πon-Hodgkins lymphoma and has been reported in glioma, sarσma, breast cancer, cholangiocarcinoma, and liver cancer. Most mutations in B-raf that have been found in human cancers are point mutations that occur in the kinase domain and are clustered in exons 11 and 15 of the gene which contains several regulatory phosphorylation sites (S446, S447, D448, D449, T599, and S602). (Beeram, ef a/., Journal of Clinical Oncology (2005), 23(27):6771-6790). The most prevalent mutation is the T1799A transversion mutation which accounts for more than 80% of mutations in the BRAF gene and results in a V600E mutation in B-raf. The V600E was formerly designated V599E (the gene mutation was designated T1796A) due to a mistake in the GenBank nucleotide sequence NM 004333. The corrected GenBank sequence is NT 007914 and designates the protein mutation as V600E and the gene mutation as T1799A. This corrected numbering will be used herein. This mutation is thought to mimic phosphorylation in the activation segment of B-raf since it inserts a negatively charged residue near two activating phosphorylation sites, T599 and S602, and thus results in constitutively active B- raf in a Ras independent manner. (Xing, M., Endocrine-Related Cancer (2005), 12:245- 262).
Treatment of cancer cells with 17AAG, an Hsp90 inhibitor, has been shown to stimulate the degradation of B-raf, and mutant forms of B-raf have been shown to be more sensitive to degradation than the wild type. For example, when melanoma cell line A375 which contain the V600E mutation was treated with 17AAG, B-raf was degraded more rapidly than in CHL cells which contained wild type B-raf. Other B-raf mutants (e.g., V600D, G469A, G469E, G596R, G466V, and G594V) were a found to be degraded more rapidly than wild type B-raf when transvected into COS cells. However, B-raf mutants E586K and L597V were not sensitive to degradation when cells were treated with 17AAG. Therefore, it is believed that wild type B-raf in its activated form is a client protein of Hsp90 and that most mutated forms of B-raf are more dependent on Hsp90 for folding, stability and/or function than the wild type protein. (Dias, et al., Cancer Res. (2005), 65(23): 10686-10691). Raf-1 is a MAP 3-kinase (MAP3K) which when activated can phosphorylate and acitivate the serine/threonine specific protein kinases ERK1 and ERK2. Activated ERKs play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration.
Anaplastic large-cell lymphoma (ALCL) is a type of non-Hodgkin's lymphoma characterized by the expression of CD30/KM antigen. ALCL normally arises from T-cells, however, a subset of cases have either a null cell or B-cell phenotype. Cases that arise from B-cells are sometimes categorized as diffuse large B-cell lymphomas. About 60% of the ALCL case that express CD30/KM antigen also have the chromosomal translocation t(2;5)(p23;q35) which fuses the nucleophosmin (NPM/B23) gene to the anaplastic lymphoma kinse (ALK) gene and results in the oncogenetic fusion protein NPM-ALK with tyrosine kinase activity. Within specific subtypes of ALCL, ALK rearrangements have been observed in the following percentages: 1) 30% to 50% of pleomorphic ALCL, 2) more than 80% of monomorphic ALCL, 3) 75% to 100% of small-cell cases, and 4) 60% to 100% of lymphohistiocytic ALCL. NPM-ALK is able to transform both fibroblasts, hematopoietic, and primary bone marrow cell lines, and is thought to stimulate mitosis through the RAS pathway and the through activation of phospholipase C-gamma (PLC-gamma),' and to protect against apoptosis through its activation of phosphatidylinositol 3 kinase (PI-3 kinase) survival pathway. (Duyster, et al., Oncogene (2001), 20:5623-5637). NPM-ALK has been shown to associate with Hsp90 and incubation of NPM-ALK expressing ALCL cells with the benzoquinone ansamycin, 17AAG, has been shown to disrupt this association resulting in increased degradation of NPM-ALK and induce cell-cycle arrest and apoptosis. (Georgakis, ef a/., Exp. Hematology (2006), 34(12):1670-1679; Bonvini, et al., Cancer Research (2002), 62:1559-1566).
The transforming protein of Rous sarcoma virus, v-src, is a prototype of an oncogene family that induces cellular transformation (i.e., tumorogenesis) by non-regulated kinase activity. Hsp90 has been shown to complex with v-scr and inhibit its degradation.
Hsp90 is required to maintain steroid hormone receptors in a conformation capable of binding hormone with high affinity. Inhibition of the action of Hsp90 therefore is expected to be useful in treating hormone-associated malignancies such as breast cancer. p53 is a tumor suppressor protein that causes cell cycle arrest and apoptosis. Mutation of the p53 gene is found in about half of all human cancers making it one of the most common genetic alterations found in cancerous cells. In addition, p53 mutation is associated with a poor prognosis. Wild-type p53 has been shown to interact with Hsp90, but mutated p53 forms a more stable association than wild-type p53 as a result of its misfolded conformations. A stronger interaction with Hsp90 protects the mutated protein form normal proteolytic degradation and prolongs its half-life. In a cell that is heterozygous for mutated and wild-type p53, inhibition of the stabilizing effect of Hsp90 causes mutant p53 to be degraded and restores the normal transcriptional activity of wild-type p53.
HiMa is a hypoxia-inducible transcription factor that is up-regulated under low oxygen conditions. Under normal oxygen conditions HiMa associates with Von Hippel-Lindau (VHL) tumor suppressor protein and is degraded. Low oxygen conditions inhibit this association and allows HiMa to accumulate and complex with HiM β to form an active transcription complex that associates with hypoxia-response elements to activate the transcription of vascular endothelial growth factor (VEGF). Increased HiMa is associated with increased metastasis and a poor prognosis.
There are two classes of PKs: protein tyrosine kinases (PTKs), which catalyze the phosphorylation of tyrosine kinase residues, and the serine-threonine kinases (STKs), which catalyze the phosphorylation of serine or threonine residues. Growth factor receptors with PTK activity are known as receptor tyrosine kinases. Receptor tyrosine kinases are a family of tightly regulated enzymes, and the aberrant activation of various members of the family is one of the hallmarks of cancer. The receptor tyrosine kinase family can be divided into subgroups that have similar structural organization and sequence similarity within the kinase domain.
Epidermal Growth Factor Receptor (EGFR) is a member of the type 1 subgroup of receptor tyrosine kinase family of growth factor receptors, which play critical roles in cellular growth, differentiation, and survival. Activation of these receptors typically occurs via specific ligand binding which results in hetero- or homodimerization between receptor family members, with subsequent autophosphorylation of the tyrosine kinase domain. Specific ligands which bind to EGFR include epidermal growth factor (EGF), transforming growth factor α (TGFq, amphiregulin and some viral growth factors. Activation of EGFR triggers a cascade of intracellular signaling pathways involved in both cellular proliferation (the ras/raf/MAP kinase pathway) and survival (the PI3 kinase/Akt pathway). Members of this family, including EGFR and HER2, have been directly implicated in cellular transformation.
A number of human malignancies are associated with aberrant or overexpression of EGFR and/or overexpression of its specific ligands (Gullick, Br. Med. Bull. (1991 ), 47:87-98; Modijtahedi and Dean, Int. J. Oncol. (1994), 4:277-96; Salomon, ef a/., Crit. Rev. Oncol. Hematol. (1995); 19:183-232, the entire teachings of each of these references are incorporated herein by reference). Aberrant or overexpression of EGFR has been associated with an adverse prognosis in a number of human cancers, including head and neck, breast, colon, prostate, lung (e.g., NSCLC, adenocarcinoma and squamous lung cancer), ovaries, gastrointestinal cancers (gastric, colon, pancreatic), renal cell cancer, bladder cancer, glioma, gynecological carcinomas, and prostate cancer. In some instances, overexpression of tumor EGFR has been correlated with both chemoresistance and a poor prognosis (Lei, et al., Anticancer Res. (1999), 79:221-8; Veale, et aλ, Br. J. Cancer (1993); 68: 162-5, the entire teachings of each of these references are incorporated herein by reference).
Gefitinib, a chemotherapeutic agent that inhibits the activity of EGFR, has been found to be highly efficacious in a subset of lung cancer patients that have mutations in the tyrosine kinase domain of EGFR. In the presence of EGF, these mutants displayed two to three times higher activity than wild type EGFR. In addition, wild type EGFR was internalized by the cells and down-regulated after 15 minutes, where as mutant EGFR was internalized more slowly and continued to be activated for up to three hours (Lynch, ef a/., The New England Journal of Medicine (2006), 350:2129-2139, the entire teachings of which are incorporated herein by reference). Gliomas are another type of cancer that is characterized by amplification and/or mutation of the EGFR gene. One of the most common mutations in the EGFR gene is a deletion of exons 2-7 which results in a truncated form of EGFR in which amino acids 6-273 of the extracellular domain are replaced with a single glycine residue. This mutation is called EGFRvIII and is expressed in about half of all glioblastomas. EGFRvIII is unable to bind EGF and TGFD and has constitutive, ligand-independent tyrosine kinase activity. Hsp90 co-purifies with EGFRvIII indicating that Hsp90 complexes with EGFRvIII. Moreover, Hsp90 inhibitor geldanamycin, a benzoquinone ansamycin antibiotic, was able to decrease the expression of EGFRv)II indicating that interaction with Hsp90 is essential to maintain high expression levels of EGFRvIII (Lavictoire, et a!., Journal of Biological Chemistry (2003), 278(7):5292-5299, the entire teachings of which are incorporated herein by reference). These results demonstrate that inhibiting the activity of Hsp90 is an effective strategy for treating cancers that are associated with inappropriate EGFR activity. The members of the type III group of receptor tyrosine kinases include platelet-derived growth factor (PDGF) receptors (PDGF receptors alpha and beta), colony-stimulating factor (CSF-1) receptor (CSF-1R, c-Fms), Fms-like tyrosine kinase (FLT3), and stem cell factor receptor (c-kit). FILT3 is primarily expressed on immature hematopoietic progenitors and regulates their proliferation and survival. Hematologic cancers, also known as hematologic or hematopoietic malignancies, are cancers of the blood or bone marrow; including leukemia and lymphoma. Acute myelogenous leukemia (AML) is a clonal hematopoietic stem cell leukemia that represents about 90% of all acute leukemias in adults with an incidence of 3.9 per 100,000 (See e.g., Lowenberg et al., N. Eng. J. Med 341: 1051-62 (1999) and Lopesde Menezes, et al, Clin. Cancer Res. (2005), 11(14):5281-5291, the enter teachings of both references are incorporated by reference). While chemotherapy can result in complete remissions, the long term disease-free survival rate for AML is about 14% with about 7,400 deaths from AML each year in the United States. Approximately 70 % of AML blasts express wild type FLT3 and about 25 % to about 35 % express FLT3 kinase receptor mutations which result in constitutively active FLT3. Two types of activating mutations have been identified in AML patients: internal tandem duplications (ITDs) and point mutation in the activating loop of the kinase domain. FLT3-ITD mutations in AML patients is indicative of a poor prognosis for survival, and in patients who are in remission, FLT3-1TD mutations are the most significant factor adversely affecting relapse rate with 64% of patients having the mutation relapsing within 5 years (see Current Pharmaceutical Design (2005), 77:3449-3457, the entire teachings of which are incorporated herein by reference). The prognostic significance of FLT3 mutations in clinical studies suggests that FLT3 plays a driving role in AML and may be necessary for the development and maintenance of the disease.
Mixed Lineage Leukemia (MLL) involve translocations of chromosome 11 band q23 (11q23) and occur in approximately 80% of infant hematological malignancies and 10 % of adult acute leukemias. Although certain 11q23 translocation have been shown to be essential to immortalization of hematopoietic progenitors in vitro, a secondary genotoxic event is required to develop leukemia. There is a strong concordance between FLT3 and MLL fusion gene expression, and the most consistently overexpressed gene in MLL is FLT3. Moreover, it has been shown that activated FLT3 together with MLL fusion gene expression induces acute leukemia with a short latency period (see Ono, et al, J. of Clinical Investigation (2005), 115:919-929, the entire teachings of which are incorporated by reference). Therefore, it is believed that FLT3 signally is involved in the development and maintenance of MLL (see Armstrong, et a/., Cancer Cell (2003), 3: 173-183, the entire teachings of which are incorporated herein by reference).
The FLT3-ITD mutation is also present in about 3% of cases of adult myelodysplastic syndrome and some cases of acute lymphocytic leukemia (ALL) (Current Pharmaceutical Design (2005), 77:3449-3457).
FLT3 has been shown to be a client protein of Hsp90, and 17AAG, a benzoquinone ansamycin antibiotic that inhibits Hsp90 activity, has been shown to disrupts the association of Flt3 with Hsp90. The growth of leukemia cell that express either wild type FLT3 or FLT3- ITD mutations was found to be inhibited by treatment with 17"AAG (Yao, et a/., Clinical Cancer Research (2003), 9:4483-4493, the entire teachings of which are incorporated herein by reference). c-Kit is a membrane type III receptor protein tyrosine kinase which binds Stem Cell Factor (SCF) to its extraellular domain. c-Kit has tyrosine kinase activity and is required for normal hematopoiesis. However, mutations in c-kit can result in ligand-independent tyrosine kinase activity, autophosphorylation, and uncontrolled cell proliferation. Aberrant expression and/or activation of c-Kit has been implicated in a variety of pathologic states. For example, evidence for a contribution of c-Kit to neoplastic pathology includes its association with leukemias and mast cell tumors, small cell lung cancer, testicular cancer, and some cancers of the gastrointestinal tract and central nervous system. In addition, c-Kit has been implicated in playing a role in carcinogenesis of the female genital tract sarcomas of neuroectodermal origin, and Schwann cell neoplasia associated with neurofibromatosis. (Yang et a/., J CHn Invest. (2003), 772:1851-1861; Viskochil, J Clin Invest. (2003), 772:1791-1793, the entire teachings of each of these reference are incorporated herein by reference). c-Kit has been shown to be a client protein of Hsp90, and Hsp90 inhibitor 17AAG, a benzoquinoπ ansamycin, has been shown to induce apoptosis in Kasumi-1 cells, an acute myeloid leukemia cell line that harbors a mutation in c-kit. c-Met is a receptor tyrosine kinase that is a client protein of Hsp90 and is encoded by the Met protooncogene. Hepatocyte growth factor (HGF) (also referred to as scatter factor (SF)) is the natural ligand of c-Met which binds to c-Met and leads to a variety of cellular responses such as proliferation, survival, angiogenesis, wound healin, tissue regeneration, scattering, motility, invasion and branching morphogenesis (Ma et a/., Cancer and Metastasis Reviews (2003), 22: 309-325). c-Met and HGF are expressed in numerous tissues, although their expression is normally confined predominantly to cells of epithelial and mesenchymal origin, respectively. c-Met and HGF are required for normal mammalian development and have been shown to be important in cell migration, cell proliferation and survival, morphogenic differentiation, and organization of 3-dimensional tubular structures (e.g., renal tubular cells, gland formation, etc.). However, dysregulation of c-Met and/or HGF is believed to contribute to tumor growth, dissemination and invasion in several human cancers. c-Met and/or HGF are highly expressed in numerous cancers and their expression correlates with poor prognosis (Christensen, et al., Cancer Research (2003), 63:7345- 7355), For example, c-Met receptor mutations have been shown to be expressed in a number of human cancers including hereditary and sporadic human papillary renal carcinomas, ovarian cancer, childhood hepatocellular carcinoma, metastatic head and neck squamous cell carcinomas, esophageal cancer and gastric cancer. Met gene amplification and over expression of c-Met has been shown to be associated with both non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), as well as colorectal cancer, and the Tpr/Met fusion protein has been shown to be present in human osteogenic sarcoma and gastric cancer. Families with germine mutations that activate c-Met kinase are prone to multiple kidney tumors as well as tumors in other tissues. Numerous studies have correlated the expression of c-Met and/or HGF with the state of disease progression of different types of cancer (including lung, colon, breast, prostate, liver, pancreas, brain, kidney, ovarian, stomach, skin, and bone cancers).
The validity of targeting receptor tyrosine kinases (RTK) that are dysregulated in human cancers is illustrated by the successes of Gleevec targeting Bcr-Abl in chronic myelogenous leukemia and c-Kit in gastroinstinal stromal tumors, Herceptin in Her-2 overexpressing breast cancers, and lressa in select NSCLC that have dysregulated EGFR. Compelling evidence exists for targeting c-Met in the treatment of human cancers and several small drug molecules that inhibit c-Met are currently in development. However, therapies that target specific RTK often work well initially for treating cancer but eventually fail due to additional mutations which allow RTK to maintain its activity in the presence of the drug. Moreover, the selective c-Met inhibitor SU11274, while highly affected against wild type c- Met and some mutants of c-Met, has been shown to be ineffective against other c-Met mutants (Berthou, et a/., Oncogene (2004), 23:5387-5393). Therefore, a need exists to develop new anticancer therapeutics that reduce the expression and/or activity of c-Met via a different mechanism than therapeutics that directly inhibit c-Met.
BCR-ABL is an ocoprotein with tyrosine kinase activity and has been associated with chronic myelogenous leukemia (CML), with a subset of patients with acute lymphocytic leukemia (ALL) and with a subset of patients with acute myelogenous leukemia (AML). In fact, the BCR-ABL oncogene has been found in at least 90-95% of patients with CML, 20% of adults with ALL, 5% of children with ALL, and in about 2% of adults with AML. The BCR- ABL oncoprotein is generated by the transloction of gene sequences from the c-ABL protein tyrosine kinase on chromosome 9 into the BCR sequences on chromosome 22, producing the Philadelphia chromosome. The BCR-ABL gene has been shown to produce at least three alternative chimeric proteins, p230 Bcr-Abl, p210 Bcr-Abl, and p190 Bcr-Abl which have unregulated tyrosine kinase activity. The p210 Bcr-Abl fusion protein is most often associated with CML, while the p190 Bcr-Abl fusion protein is most often associated with ALL Bcr-Abl has also been associated with a variety of additional hematological malignancies including granulocytic hyperplasia, myelomonocytic leukemia, lymphomas and erythroid leukemia Studies have shown that lowering the expression or activity of Bcr-Abl is effective in treating Bcr-Ab!-posιtιve leukemias For example, agents such as As2O3 which lower Bcr-Abl expression have been shown to be highly effective against Bcr-Abl leukemias In addition, inhibition of Bcr-Abl tyrosine kinase activity by lmatinib (also known as STI571 and Gleevic) induces differentiation and apoptosis and causes eradication of Bcr-Abl positive leukemia cells both in vivo and in vitro In patients with CML in the chronic phase, as well as in a blast crisis, treatment with lmatinib typically will induce remission However, in many cases, particularly in those patients who were in a blast crisis before remission, the remission is not durable because the Bcr-Abl fusion protein develops mutations that cause it to be resistence to lmatinib (See Nimmanapalli, ef a/ , Cancer Research (2001 ), 61 1799-1804, and Gorre, et al , Blood (2002), 700 3041-3044, the entire teachings of each of these references are incorporated herein by reference)
Bcr-Abl fusion proteins exist as complexes with Hsp90 and are rapidly degraded when the action of Hsp90 is inhibited It has been shown that geldanamycin, a benzoquinone ansamycin antibiotic that disrupts the association of Bcr-Abl with Hsp90, results in proteasomal degradation of Bcr-Abl and induces apoptosis in Bcr-Abl leukemia cells
Hsp90 has been shown by mutational analysis to be necessary for the survival of normal eukaryotic cells However, Hsp90 is over expressed in many tumor types indicating that it may play a significant role in the survival of cancer cells and that cancer cells may be more sensitive to inhibition of Hsp90 than normal cells For example, cancer cells typically have a large number of mutated and overexpressed oncoproteins that are dependent on Hsp90 for folding In addition, because the environment of a tumor is typically hostile due to hypoxia, nutrient deprivation, acidosis, etc , tumor cells may be especially dependent on Hsp90 for survival Moreover, inhibition of Hsp90 causes simultaneous inhibition of a number of oncoproteins, as well as hormone receptors and transcription factors making it an attractive target for an anti-cancer agent In fact, benzoquinone ansamycins, a family of natural products that inhibit Hsp90, has shown evidence of therapeutic activity in clinical trials
Although promising, benzoquinone ansamycins, and their derivatives, suffer from a number of limitations For example, they have low oral bioavailability, and their limited solubility makes them difficult to formula In addition, they are metabolized by polymorphic cytochrome P450 CYP3A4 and are a substrate for P-glycoprotein export pump involved in the development of multidrug resistance Therefore, a need exist for new therapeutics that improve the prognosis of cancer patients and that reduces or overcomes the limitations of currently used anti-cancer agents.
SUMMARY OF THE INVENTION
The present invention provides compounds which inhibit the activity of Hsp90 and are useful in the treatment of proliferative disorders, such as cancer.
In one embodiment, the present invention provides compounds represented by structural formula (I):
Figure imgf000011_0001
(I) wherein:
R1, R2, and R3 are each, independently, -OH, -SH, -NHR7, -OR26, -SR26, -O(CH2)mOH, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H,. -OC(O)NR10Rii, -SC(O)NR10RI1, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10Ri1,
-SCH2C(O)NR10R11, -NR7CH2C(O)NRi0R11, -OS(O)pR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)pR7, -OS(O)PNR10R11, -SS(O)pNR10Rn, -NR7S(O)PNR10R11, -OS(O)pOR7l -SS(O)pOR7l -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NRi0R11, -NR7C(S)NR10R1I, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7,
-OC(NR8)NR10R11, -SC(NR8)NR10Ru, -NR7C(NR8)NR10Ri i, -OP(O)(ORr)2, or -SP(O)(OR7J2;
R5 is an optionally substituted alkyl; an optionally substituted heteroaryl or an optionally substituted aryl;
R6 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR7, -SR7, -NR10Ri1, -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10Rii, -SCH2C(O)NR10Rn, -NR7CH2C(O)NR10RI1, -OS(O)PR7, -SS(0)PR7, -NR7S(O)pR7, -OS(O)PNR10R11, -SS(0)pNR10Rn, -NR7S(O)pNR10Rn, -0S(O)p0R7, -SS(0)p0R7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRB)NR10R11, -SC(NRB)NR10RII, -NR7C(NR8)NR10RII, -C(O)R7, -C(O)OR7, -C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10Rn, -C(S)SR7, -C(NRa)OR7, -C(NR8)R7, -C(NR8)NR10RH, -C(NR8)SR7, -S(0)P0R7, -S(O)11NR10R11, or -S(O)PR7; R7 and R8, for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R10 and R11, for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is independently, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3 or 4; or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
In another embodiment, the present invention provides compounds represented by structural formula (II):
Figure imgf000012_0001
(II)
wherein:
X41 is O1 S, or NR42; X42 is CR44 or N; Y40 is N or CR43; Y41 is N or CR45;
Y42, for each occurrence, is independently N, C or CR46; R40 is OH, SH, or NHR7; R41 is -H, -OH, -SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl,,an alkoxy or cycloalkoxy, a haloalkoxy, -NR10Rn, -OR7, -C(O)R7, -C(O)OR71 -C(S)R71 -C(O)SR7,
-C(S)SR7, -C(S)OR7, -C(S)NR10R11, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(O)R7, -SC(O)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NR10R11, -OC(S)NR10Ri1, -OC(NR8)NR10R11, -SC(O)NR10R11, -SC(NRB)NR10R11, -SC(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -C(O)NR10R11, -NR8C(O)R7, -NR7C(S)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(O)OR7, -NR7C(NR8)OR7, -NR7C(O)NR10R11, -NR7C(S)NR10R11, -NR7C(NR8)NR10R11, -SR7, -S(O)pR7, -OS(O)pR7, -OS(O)POR7, -OS(O)PNR10R11, -S(O)POR7, -NR8S(O)PR7, -NR7S(O)PNR10R11, -NR7S(O)pOR7, -S(O)PNR10R11, -SS(O)PR7, -SS(O)POR7, -SS(O)PNR10R11, ~OP(O)(OR7)2, or -SP(O)(OR7);,; R42 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, -C(O)R7, -(CH2)mC(O)OR7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -S(O)PR7, -S(O)POR7, or -S(O)pNR10R1i;
R43 and R44 are, independently, -H, -OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)pR7, -OS(O)pR7, -S(O)pOR7, -NR8S(O)PR7, -S(O)pNR10Rn, or R43 and R44 taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl;
R45 Js -H1 -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)WSH, -S(CH2)mNR7H, -OC(O)NR10R11, -SC(O)NR10Ri1, -NR7C(O)NR10Ri1, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11,
-SCH2C(O)NR10R1I, -NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)PNR10R1I, -SS(O)pNR10Rii, -NR7S(O)PNR10R11. -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7l -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1I, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RiI, -SC(NR8)NR10R11, or -NR7C(NR8)NR10Rn; and
R45, for each occurrence, is independently, selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi0R11, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)PR7, or -S(O)PNR10R11; or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
In another embodiment, the present invention provides compounds represented by structural formula (IV):
Figure imgf000015_0001
(IV) wherein:
;
R56 is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl;
R52 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, π-butyl, n-pentyl, n-hexyl, -(CH2)2OCH3, -CH2C(O)OH, and -C(O)N(CH3)2;
R53 and R54 are each, independently, -H, methyl, ethyl, or isopropyl; or R53 and R54 taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring; and
R56 is selected from the group consisting of -H, -OH, -OCH3, and -OCH2CH3; or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
In one embodiment, the present invention provides compounds represented by structural formula (V);
Figure imgf000015_0002
(V) wherein: R*1 is , -NHR7, -NHC(O)NR10RI 1, -NHC(O)R7, -NHC(O)OR7, -NHCH2C(O)R7, -NHCH2C(O)OR7, -NHCH2C(O)NR10R1I, -NHS(0)pR7, -NHS(O)pNR10Rii, -NHS(0)p0R7, -NHC(S)R7, -NHC(S)OR7, -NHC(S)NR10R11, -NHC(NR8)R7, -NHC(NR8)OR7, or -NHC(NR8)NR10R11; R2 is -OH, -SH1 -NR7H1 -OR26, -SR26, -0(CH2)H1OH, -0(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10R11 τ -SS(O)PNR10R11, -NR7S(O)pNR10Rii, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NRioRii, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R'3 is -OH, -SH, Or -NHR7;
R's is an optionally substituted heteroaryl or an optionally substituted aryl;
R7 and R8, for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alkeπyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a lower alkyl;
2 is a substituent; p, for each occurrence, is independently, 1 or 2; m, for each occurrence, is independently, 1, 2, 3 or 4; and t is O, 1, 2, or 3. or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof. In one aspect, the compound of formula (V) is not:
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-{1-isopropyl-iπdol-4-yl)-5-amino-[1,2,4] triazole, 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-methoxy-phenyl)-5-amino-[1,2,4] triazole, 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-arnino-[1 >2,4] triazole, 3-(2,4-Dihydroxy-phenyl)-4-phenyl-5-(sulfamoylamino)- [1,2,4] triazole,
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-1-yl)-5-ureido-[1 , 2,4] triazole, 3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(2,3-difluorophenyl)-5-ureido-[1 , 2,4] triazole, 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isoρropyl-indol-4-yl)-5-ureido-[1 ,2,4] triazole, 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(quinolin-5-yl)-5-ureido-[1,2,4] triazole, 3-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-(3-methyl-quinolin-5-yl)-5-carboxyamino-[1 ,2,4] triazole,
3-(2,4-Dihydroxy-phenyl)-4-(1-methyl-2-chloro-indol-4-yl)-5-carbamoyloxy-[1,2,4] triazole,
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-[3,5-di-(trifluoromethyl)-phenyl]-5-carbamoyloxy- [1,2,4] triazole, 3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(3-trifluoromethyl-phenyl)-5-(sulfamoylamino)- [1,2,4] triazole,
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-1-yl)-5-(sulfamoylamino)- [1 ,2,4] triazole,
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(1-isopropyl-benzoimidazol-4-yl)-5-(sulfamoylamino)- [1,2,4] triazole, or
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(3-isopropylphenyl)-5-(thiocarboxyamino)- [1 ,2,4] triazole,
In one embodiment, the present invention provides compounds represented by structural formula (Vl):
Figure imgf000017_0001
wherein R6 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR7, -SR7, -NR1ORII1 -OC(O)NR1OR1I, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Rii, -NR7CH2C(O)NRi0Rn, -OS(O)PRT, -SS(O)PR7| -NR7S(O)pR7, -OS(O)PNR10R11, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NRB)R7, -OC(NRB)OR7, -SC(NR6)OR7, -NR7C(NR8)OR7, -OC(NRe)NR10R11, -SC(NRB)NR10R11, -NR7C(NR8)NR10R11, -C(O)R7, -C(O)OR7, -C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -S(O)POR7, -S(O)PNR10R11, or -S(O)PR7. • or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and R'i> R2, R'3, and R's are defined as for formula (V).
In one embodiment, the present invention provides compounds represented by structural formula (VII):
Figure imgf000018_0001
(VII)
wherein:
X41 is O, S1 or NR42; X42 is CR44 or N; Y40 is N or CR43; Y41 is N or CR45; Y42, for each occurrence, is independently N, C or CR46; R'4o is NHR7;
R41 is -H, -OH, -SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, -NRi0R11, -OR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)NR10R11, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R1I. -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(O)R7, -SC(O)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NR10R11, -OC(S)NR10R11, -OC(NR8)NR10R11, -SC(O)NR10R11, -SC(NR8)NR10R11, -SC(S)NR10R11, -OC(NR6)R7, -SC(NR8)R7, -C(O)NR10R11, -NR8C(O)R7, -NR7C(S)R7, -NR7C(S)OR71 -NR7C(NR8)R7, -NR7C(O)OR7, -NR7C(NR8)OR7, -NR7C(O)NR10R11, -NR7C(S)NR10R11, -NR7C(NR8)NR10R11, -SR7, -S(O)pR7, -O.S(O)pR7, -OS(0)pOR7, -OS(O)PNR10R11, -S(O)POR7, -NR8S(O)PR7, -NR7S(O)pNR10Rii, -NR7S(O)POR7, -S(O)PNR10R11, -SS(O)PR7, -SS(O)POR7, -SS(O)PNR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R42 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, -C(O)R7, -(CH2)mC(0)OR7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -S(O)PR7, -S(O)POR7, or -S(O)pNR10Rii;
R43 and R44 are, independently, -H, -OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)pR7. -OS(O)pR7, -S(O)POR7, -NR8S(O)PR7, -S(O)PNR10R11, or R43 and R44 taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl;
R45 is -H, -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -0(CH2)m0H, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(O)NR10R11,
-SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(0)NR10Rn, -SCH2C(0)NRi0Rii, -NR7CH2C(O)NR10R11, -0S(0)pR7, -SS(0)pR7, -NR7S(O)PR7) -OS(O)PNR10R11, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -0S(O)p0R7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R1I, or -NR7C(NR8)NR10Rn; and
R46, for each occurrence, is independently, selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi0R11, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)pR7, or -S(O)PNR10R11. or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
In one embodiment, the present invention provides compounds represented by structural formula (IX):
Figure imgf000020_0001
(IX) wherein:
X45 is CR54 or N;
R58 is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl;
R52 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, -(CH2)2OCH3, -CH2C(O)OH, and -C(O)N(CH3)2;
R53 and Rs4 are each, independently, -H, methyl, ethyl, or isopropyl; or R53 and R54 taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring,
R55 is selected from the group consisting of -H, -OH, -OCH3, and
OCH2CH3, and
R'4O is defined as for formula (VII) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof
In one embodiment, the present invention provides compounds represented by structural formula (Xl)
Figure imgf000021_0001
(Xl) wherein
X is -O- or -S-,
R'5 is an optionally substituted heteroaryl or an optionally substituted aryl,
R'β is -H1 an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR7, -SR7, -NR10R11, -OC(O)NR10R1I, -SC(O)NR10R11, -NR7C(O)NR10R1,, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7,
-OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -OS(O)-R7, -SS(O)PR7, -NR7S(O)PR7, -OS(0)pNR10Rii, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -OS(O)pOR7l -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7,
-OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NR3)NR10R11, -C(O)R7, -C(O)OR7, -C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NRIORI1, -C(NR8)SR7, -S(O)POR7, -S(O)PNR10R11, or -S(O)PR7;
R7 and R8, for each occurrence, is independently, -H, an optionally substituted alky], an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and R11, for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R'17l R18, and Ri9 are each, independently, -H1 -C(O)R2., or (alk)O(alk); provided that at least one of R'17l R18, or R19 is not -H;
R22, for each occurrence is independently optionally substituted alkyl, optionally substituted aryl, -O(alk), amino, alkyl amino, or dialkyl amino; alk is a lower alkyl; p, for each occurrence, is independently 1 or 2; or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof. In one aspect of compounds of formula (Xl), the compound is not 3-(2-Hydroxy-4-methoxymethyoxy-phenyl)-4-(naphthalen-1-yl)-5-mercapto-[1,2,4] triazole; 3-[2-Hydroxy-4-(2-hydroxy-ethoxy)-phenyl]-4-(naphthalen-1-yl)-5-mercapto-[1 ,2,4] triazole;
3-[2,4-Di-(dimethyl-carbamoyloxy)-phenyl]-4-(naphthalen-1-yl)-5-(dimethyl- carbamoylsulfanyl)- [1,2,4] triazole;
3-(2,4-Dihydroxy~phenyl)-4-(naphthalen-1-yl)-5-(dimethylcarbamoylsulfanyl)- [1 ,2,4] triazole;
3-(2,4-Diethoxycarbonyloxy-phenyl)-4-(naphthalen-1-yl)-5-(ethoxycarbonylsulfanyl)- [1,2,4] triazole;
3-(2,4-Di-isobutyryloxy-phenyl)-4-(naphthalen-1-yl)-5-(isobutyrylsulfanyl)- [1 ,2,4] triazole; 3-[2,4-Di-(dimethyl-carbamoyloxy)-phenyl]-4-(quinolin-5-yl)-5-(dimethyl-carbamoylsulfanyl)- [1 ,2,4] triazole;
3-(2,4-Diacetoxy-phenyl)-4-(naphthalen-1 -yl)-5-(acetylsulfanyl)- [1,2,4] triazole; 3-(2,4-Diacetoxy~phenyl)-4-(naphthalen-1-yl)-5-mercapto-[1 , 2, 4] triazole; S-tZ^-Diethylcarbamoyloxy-phenylJ^-fnaphthalen-i-yO-δ-Cethylcarbamoylsulfanyi)- [1 ,2,4] triazole; a^Z^-Dihydroxy-δ-ethyl-pheny^-fS-trifluoromethyl-phenyO-δ-carbamoyloxy-li^,^ triazole; 3-(2,4-Dihydroxy-5-ethyl-pheπyl)-4-(1-methyl-indol-4-yl)-5-carbamoyloxy-[1 ,2,4] triazole;
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(8-methoxy-quinolin-5-yl)-5-carbamoyloxy-[1,2,4] triazole;
3-(2-Hydroxy-4-ethoxycarbonyoxy-5-methoxy-phenyl)-4-(1-isopropyl-benzoimidazol-4-yl)-5- hydroxy-[1 ,2,4] triazole; 3-(2-Hydroxy-4-ethoxycarbonyoxy-5-ethyl-phenyl)-4-(naphthalin-2-yl)-5-hydroxy-[1 ,2,4] triazole;
3-[2-Hydroxy-4-(dimethyl-carbamoyoxy)-5-ethyl-phenyl]-4-(naphthalin-2-yl)-5-hydroxy-[1 ,2,4] triazole;
3-[2-Hydroxy-4-(dimethyl-carbamoyoxy)-5-chloro-phenyl]-4-(quinoliπ-5-yl)-5-mercapto- [1,2,4] triazole;
' 3-[2-Hydroxy-4-(dimethyl-carbamoyoxy)-5-ethyl-phenyl]-4-(2,3-difluoro-phenyl)-5-mercapto- [1 ,2,4] triazole; or
3-[2-Hydroxy-4-isobutyryloxy-5-ethyl-phenyl]-4-(1-methyl-benzo-imidazol-4-yl)-5-hydroxy- [1 ,2,4] triazole. In another embodiment, the present invention provides compounds represented by structural formula (XIV):
Figure imgf000023_0001
(XIV) wherein: X' is -O-O- or -S-S-; R'2 and R'3 are, independently, -OH, -SH, or -NHR7; or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and R'5 and R'β are defined as for formula (Xl). In another embodiment, the present invention provides compounds represented by structural formula (XV):
Figure imgf000024_0001
(XV) wherein: R70, R'2, and R'3 are, independently, -OH, -SH, or -NHR7; R20 is C(O)Ry; and Ry is an optionally substituted alkyl; or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and R'6 is defined as for formula (Xl).
In another embodiment, the present invention provides compounds represented by structural formula (XVI):
Figure imgf000024_0002
(XVI) wherein, X is -O- or -S-; Xi is O or S; R71 and R72 are each, independently, -H, -C(O)R22, or (alk)O(alk); R22, for each occurrence is independently optionally substituted alkyl, optionally substituted aryl, -O(alk), amino, alkyl amino, or dialkyl amino; R23 is -C(O)R22 or -alk-O- C(O)R22; alk is a lower alkyl; and or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and R'5 and R'β are defined as for formula (Xl). In another embodiment, the present invention provides compounds represented by structural formula (XVII):
Figure imgf000025_0001
(XVII) wherein: R24 and R25 are each, independently -OH or -SH, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and R'5 and R'6 are defined as for formula (Xl). R23 is defined as for formula (XVI).
In another embodiment, the present invention provides compounds represented by structural formula (XVIII):
Figure imgf000025_0002
(XVlIl) wherein:
X41 is O, S, or NR42;
X42 is CR44 or N;
Y40 is N or CR43;
Y41 is N or CR45;
Y42, for each occurrence, is independently N, C or CR46; R4i is -H, -OH, -SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterooyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)NR10R1I, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NRB)OR7, -SC(O)R7, -SC(O)OR7, -SC(NR0)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NR10R11, -OC(S)NR10R11, -OC(NR8)NR10R11, -SC(O)NR10R11, -SC(NR8)NR10R11, -SC(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7,
-C(O)NR10Rn, -NR8C(O)R7, -NR7C(S)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(O)OR7, -NR7C(NR8)OR7, -NR7C(O)NR10R11, -NR7C(S)NR10R11, -NR7C(NR8)NR10R11, -SR7, -S(O)pR7, -OS(O)pR7, -OS(0)POR7, -OS(O)PNR10R11, -S(O)POR7, -NR8S(O)PR7, -NR7S(O)PNR10R11, -NR7S(O)POR7, -S(O)PNR10R11, -SS(O)PR7, -SS(O)POR7, -SS(O)PNR10R11, -OP(O)(ORT)2, or -SP(O)(OR7)2;
R42 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, -C(O)R7,
-(CH2)mC(O)OR7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -S(O)PR7, -S(O)POR7, or -S(O)pNR10Rii;
R43 and R44 are, independently, -H, -OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)pR7, -OS(O)pR7, -S(O)POR7, -NR8S(O)PR7, -S(O)PNR10R11, Or R43 and R44 taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl;
R45 is -H, -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -OS(O)pR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)PNR10R11, -SS(O)pNR10Rii, -NR7S(O)PNR10R11, -0S(0)p0R7, -SS(O)p0R7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NRB)NR10R11, or -NR7C(NR8)NR10R11; and
R46, for each occurrence, is independently, selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyi, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -0S(0)pR7, -S(0)p0R7, -NR8S(O)pR7, or -S(O)PNR10R11; or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
In another embodiment, the present invention provides compounds represented by structural formula (XIX):
Figure imgf000027_0001
(XIX)
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and R23, R41, R«, R43, R45, Xi, and X« are defined as for formula (XVIII).
In another embodiment, the present invention provides compounds represented by structural formula (XX):
Figure imgf000028_0001
(XX) wherein:
X45 is CR54 or N; R56 is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl;
R52 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, -(CH2)2OCH3, -CH2C(O)OH, and -C(O)N(CH3)2;
R53 and R54 are each, independently, -H, methyl, ethyl, or isopropyl; or
R53 and R54 taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring; and
R55 is selected from the group consisting of -H1 -OH, -OCH3, and OCH2CH3. or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and R23 and X1 are defined as for formula (XVIII). In another embodiment, the present invention provides compounds represented by structural formula (XXI):
Figure imgf000028_0002
2
- 28 -
(XXI) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is optionally further substituted with one or two independently selected S substituents in addition to R3; ring E is aromatic or non-aromatic; X16 Js -O-, -NR7-, or -S-;
Y is -(C R38R MX-, -C(O)-, -C(S)-, -C(NR8)-, -CR7=, -0-, -NR7-, -N=, or-S; Z' is -(CR38FT39)Ir1 =CR7- -0-, -S-, -NR7-, =N-, Or-CRV=CRV; 0 R1 and R3 are each, independently, -OH, -SH, -NR7H, -OR'2S, -SR'26,
-O(CH2)mOH, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(0)NR,oRii, -SC(O)NR10R11, -NR7C(O)NR10Ri1, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R1 I, 5 -SCH2C(O)NR10R1I, -NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7,
-NR7S(O)pR7, -OS(O)PNR10R11, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)pOR7, -NR7S(O)POR7) -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, 0 -OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NRB)NR1DR11, -OP(O)(OR7)Z, or -SP(O)(OR7)2; R's is an optionally substituted aryl or an optionally substituted heteroaryl; Rr and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted 5 heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted 0 heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R'2β, for each occurrence is, independently, a C1-C6 alkyl; 5 R38 and R'39l for each occurrence, are independently H1 an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, hitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR10Rn, -OR7, -C(O)R7, -C(O)OR71 -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)NR10R11, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(O)R7, -SC(O)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NR10R11, -OC(S)NR10R11, -OC(NR8)NR10R11, -SC(O)NR10R11, -SC(NR8)NR10R11, -SC(S)NR10R11, -OC(NR8)R7, ' -SC(NR8)R7, -C(O)NR10R11, -NR8C(O)R7, -NR7C(S)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(O)OR7, -NR7C(NR8)OR7, -NR7C(O)NR10R11, -NR7C(S)NR10Ri1, -NR7C(NR8)NR10R11, -SR7, -S(O)PR7, -OS(O)pR7, -OS(O)pOR7, -OS(O)PNR10R11, -S(O)POR7, -NR8S(O)PR7, -NR7S(O)PNR10R11, -NR7S(O)pOR7l -S(O)PNR10R11, -SS(O)PR7, -SS(O)POR7, -SS(O)PNR10R1 , , -OP(O)(OR7)2l or -SP(O)(OR7J2; or R38 and R'39 together with the carbon or carbon atoms to which they are attached form a three to eight membered cycloalkyl or a three to eight membered cycloalkenyl;
R'4O and R 41, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R'4O and R'4i, together with the carbon atoms to which they are attached form a three to eight membered cycloalkenyl; p, for each occurrence, is, independently, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4; and k is 1 or 2.
In some embodiments, the compounds represented by formula (XXI) do not include compounds in which R's is p-chlorophenyl and rings A and E together are benzofuranyl.
In some embodiments, the compounds represented by formula (XXI) do not include S-f^methoxy-e-hydroxy-benzofuran-δ-ylJ^^chloro-phenyO-mercapto^H-ti ^.^triazole.
In one embodiment, the present invention provides compounds represented by structural formula (XXVIII):
Figure imgf000030_0001
(XXVIII) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof. Ring F is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R103. Ring G is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to -TrV1-T2-V2.
R100 is -OH, -SH1 -NR7H, -OR'2β) -SR'2B, -NHR'26, -O(CH2)mOH, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNRrH, -OC(O)NR10Ri1, -SC(O)NR10Ri1, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R71 -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10Rn, -SCH2C(O)NR10R11, -NR7CH2C(O)NRi0R11, -OS(0)PR7, -SS(O)PR7| -S(O)POR7, -NR7S(O)pR7l -OS(O)pNR10Rn, -SS(O)pNR10R11? -NR7S(O)pNR10Rn, -OS(O)POR7, -SS(O)pOR7l -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR71 -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R1I, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, ^OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NR8)NR10R1 I, -0P(O)(OR7)2, or -SP(0)(OR7)2.
R103 is -OH, -SH, -NR7H, -OR'26, -SR'26, -NHR'26, -O(CH2)mOH, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NRi0R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R71 -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10Ri1, -SCH2C(0)NRioRii, -NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -OS(O)PNR10R11, -SS(O)PNR10R11, -NR7S(O)pNR10Rn, -OS(O)pOR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR71 -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10Ri1, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NR8)NR10Ri1, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -S(O)NHR8, -S(O)2NHR8, -OP(O)(OR7)2 or -SP(O)(OR7)2. R7 and R8, for each occurrence, is independently, -H, an optionally substituted alky), an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl. R10 and Ri1, for each occurrence, is independently -H1 an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; or Ri0 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl.
R'26 is a C1-C6 alkyl.
Ti is absent or a C1-C4 alkylene.
T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -NRaRb, -NR3S(O)2 R", - S(O)NRaRb, -S(O)2NRaRb or -C(O)NRaRb; or T2 is absent or a C1-C4 alkylene, V, is -O- -S-, -N(R-)- or -C(O)N(R')- and V2 is -S(O)NRaRb, -S(O)2NRaRb or -C(0)NRaRb; or T2 is a C2-C4 alkylene, V, is -O-, -S, -N(R')-, -C(O)O-, C(O)N(R')- and V2 is -NRaRb, or -NR9S(O)2R**.
Each R is independently -H or C1-C3 alkyl.
Each R** is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl.
R8 and Rb, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or heteroaryl, or an optionally substituted aralkyl; or Ra and Rb, taken together with the nitrogen to which they are attached, form an optionally substituted heteroaryl or heterocyclyl. p, for each occurrence, is independently, O, 1 or 2. m, for each occurrence, is independently, 1, 2, 3 or 4.
In specific embodiments, when T1, T2 and V1 are absent and V2 is -NRaRb then ring G is not phenyl, and when T1, T2 and V1 are absent and V2 is -C(0)NRaRb then ring G is not naphtbyl or indolyl.
In another embodiment, the present invention provides compounds represented by a structural formula selected from (XXIX) and (XXX):
Figure imgf000032_0001
(XXIX) (XXX) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof. Ring G is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to -T1-V1-T2-V2 X14 is O, S or NR7
R100 is -OH, -SH, -NR7H, -OR'26l -SR'26, -NHR'2B, -O(CH2)mOH, -0(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(O)NR10R11,
-SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10Rn. -SCH2C(O)NR10R1I, -NR7CH2C(O)NR10Ri1, -OS(O)PR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)PNR1OR111 -SS(O)PNR10R11, -NR7S(O)PNR10R1I, -OS(O)pOR7, -SS(0)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1I, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NRB)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NRg)NR10R11, -S(O)POR7, -OP(O)(OR7J2 or -SP(O)(OR7)2
R103 is -OH, -SH, -NR7H, -OR'∑β, -SR'2β, -NHR'26, -O(CH2)mOH, -0(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11,
-SCH2C(O)NR10R11, -NR7CH2C(O)NR10Ri1, -OS(O)PR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)PNR10R11, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7,
-OC(NR8)NRiOR11, -SC(NRe)NR10Rn, -NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -S(O)NHR8, -S(O)2NHR8, -S(O)POR7, -OP(O)(OR7)2 or -SP(O)(OR7J2
R7 and R8, for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl or an optionally substituted heteroaralkyl
R10 and Rn, for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl, or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl.
R1Z2, for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl, a haloalkyl, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -S(O)PR7, -S(0)POR7 or -S(0)pNR1DRn.
R'23 and R'24, for each occurrence, is independently -H, an optionally substituted alky, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -0S(0)pR7, -S(O)POR7, -NRBS(O)PR7 or -S(O)PNR10R11. R'26 is a C1-C6 alkyl.
Ra and Rb, for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or heteroaryl, an optionally substituted aralkyl; or Ra and Rb, taken together with the nitrogen to which they are attached, form an optionally substituted heteroaryl or heterocyclyl.
T1 is absent or a C1-C4 alkylene.
T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -NRaRb, -NR8S(O)2 R**, - S(O)NR8R", -S(O)2NR8R" or -C(0)NRaRb; or T2 is absent or a C1-C4 alkylene, V1 is -0-, -S-, -N(R')- or -C(O)N(R')- and V2 is -S(O)NRaRb, -S(O)2NRaRb or -C(0)NRaRb; or T2 is a C2-C4 alkylene, V1 is -0-, -S, -N(R*)-, -C(O)O-, C(O)N(R*)- and V2 is -NRaRb, or -NR8S(O)2R**. Each R' is independently -H or C1-C3 alkyl.
Each R** is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl. p, for each occurrence, is independently, O, 1 or 2. m, for each occurrence, is independently, 1 , 2, 3 or 4.
The compounds shown in Table 1-5 or compounds of any formula herein, or tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof, inhibit the activity of Hsp90 and, thereby facilitates the degradation of Hsp90 client proteins. Hsp90 is necessary for the survival of normal eukaryotic cells. However, Hsp90 is over expressed in many tumor types indicating that it may play a significant role in the survival of cancer cells and that cancer cells may be more sensitive to inhibition of Hsp90 than normal cells. Thus, the compounds shown in Table 1-5 or compounds of any formula herein, or tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof, are useful treating proliferative disorders such as cancer.
Although chemotherapeutic agents initially cause tumor regression, most agents that are currently used to treat cancer target only one pathway to tumor progression. Therefore, in many instances, after treatment with one or more chemotherapeutic agents, a tumor develops multidrug resistance and no longer responses positively to treatment. One of the advantages of inhibiting Hsp90 activity is that several of its client proteins, which are mostly protein kinases or transcription factors involved in signal transduction, have been shown to be involved in the progression of cancer. Thus, inhibition of Hsp90 provides a method of short circuiting several pathways for tumor progression simultaneously. Therefore, treatment of tumors with an Hsp90 inhibitor of the invention either alone, or in combination with other chemotherapeutic agents, is more likely to result in regression or elimination of the tumor, and less likely to result in the development of more aggressive multidrug resistant tumors than other currently available therapeis.
DETAILED DESCRIPTION OF THE INVENTION
A description of preferred embodiments of the invention follows.
The present invention provides compounds disclosed herein and uses of said compounds to inhibit Hsp90 activity and for the treatment of a proliferative disorder, such as cancer. In particular, the present invention encompasses the use of compounds of the invention to slow or stop the growth of cancerous cells or to reduce or eliminate cancerous cells in a subject, preferably the subject is a mammal.
In certain embodiments, the compounds of the invention can be used in combination with other chemotherapeutic agents and may help to prevent or reduce the development of multidrug resistant cancerous cells in a mammal. In this embodiment, the compounds of the invention may allow a reduced efficacious amount of a second chemotherapeutic agent given to a mammal, because compounds of. the invention should inhibit the development of multidrug resistant cancerous cells.
In certain embodiments, the compounds of the invention can be used to block, occlude, or otherwise disrupt blood flow in neovasculature. In other embodiments, the compounds of the Invention can be used to treat or inhibit angiogenesis in a subject in need thereof.
The present invention also relates to compounds which inhibit the activity of topoisomerase II.
The present invention also relates to the discovery that treatment of cells, such as peripheral blood mononuclear cells (PMBCs) that have been stimulated with an inflammatory stimulus, such as INFγ/LPS or SAC, with an Hsp90 inhibitor reduces the expression of GR in the PMBCs and reduces the production of inflammatory cytokines.
The present invention also relates to compounds which inhibit the activity of Hsp90 and are useful in the treatment of or prevention of infections.
A. Terminology
Unless otherwise specified, the below terms used herein are defined as follows:
As used herein, the term "alkyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2- methylhexyl, 3-methylhexyl, 4-methy)hexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3- dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3-dimtheylpentyl, 3,3-dimethylhexyl, 4,4- dimethylhexyl, 2-ethylpentyl, 3-ethylpeπtyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2- methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2- diethylhexyl, 3,3-diethylhexyl and the like. The term "(CrCβJalkyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms. Representative (Ci-C6)alkyl groups are those shown above having from 1 to 6 carbon atoms. Alkyl groups included in compounds of this invention may be optionally substituted with one or more substituents.
As used herein, the term "alkenyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and having at least one carbon-carbon double bond. Representative straight chain and branched (C2-Ci0)alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2- methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2- heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1- decenyl, 2-decenyl, 3-decenyl and the like. Alkeπyl groups may be optionally substituted with one or more substituents.
As used herein, the term "alkynyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and having at least one carbon-carbon triple bond. Representative straight chain and branched alkynyls include acetylenyl, propynyl, 1- butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl, 1-hexynyl, 2- hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1- nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, 9-decynyl, and the like. Alkynyl groups may be optionally substituted with one or more substituents.
As used herein, the term "cycloalkyl" means a saturated, mono- or polycyclic alkyl radical having from 3 to 20 carbon atoms. Representative cycloalkyls include cyclopropyl, 1- methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, - cyclodecyl, octahydro-pentaleπyl, and the like. Cycloalkyl groups may be optionally substituted with one or more substituents. As used herein, the term "cycloalkenyl" means a mono- or poly- cyclic non-aromatic alkyl radical having at least one carbon-carbon double bond in the cyclic system and from 3 to 20 carbon atoms. Representative cycloalkenyls include cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl, cyclononenyl, cyclononadienyl, cyclodecenyl, cyclodecadienyl, 1, 2,3,4, 5,8-hexahydronaphthalenyl and the like. Cycloalkenyl groups may be optionally substituted with one or more substituents.
As used herein, the term "haloalkyl" means an alkyl group, in which one or more (including all) the hydrogen radicals are replaced by a halo group, wherein each halo group is independently selected from -F, -Cl, -Br, and -I. The term "halomethyl" means a methyl in which one to three hydrogen radical(s) have been replaced by a halo group. Representative haloalkyl groups include trifluoromethyl, bromomethyl, 1 ,2-dichloroethyl, 4-iodobutyl, 2- fluoropentyl, and the like.
As used herein, an "alkoxy" is an alkyl group which is attached to another moiety via an oxygen linker. As used herein, an "haloalkoxy" is an haloalkyl group which is attached to another moiety via an oxygen linker.
As used herein, the term an "aromatic ring" or "aryl" means a hydrocarbon monocyclic or polycyclic radical in which at least one ring is aromatic. Examples of suitable aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Aryl groups may be optionally substituted with one or more substituents. In one embodiment, the aryl group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, referred to herein as "(C6)aryl."
As used herein, the term "aralkyl" means an aryl group that is attached to another group by a (CrC6)alkylene group. Representative aralkyl groups include benzyl, 2-phenyl-ethyl, naphth-3-yl-methyl and the like. Aralkyl groups may be optionally substituted with one or more substituents.
As used herein, the term "alkylene" refers to an alkyl group that has two points of attachment The term "(CrC6)alkylene" refers to an alkylene group that has from one to six carbon atoms. Straight chain (CrC6)alkylene groups are preferred. Non-limiting examples of alkytene groups include methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), and the like. Alkylene groups may be optionally substituted with one or more substituents.
As used herein, the term "heterαcyclyl" means a monocyclic (typically having 3- to
10-members) or a polycyclic (typically having 7- to 20-members) heterocyclic ring system which is either a saturated ring or a unsaturated non-aromatic ring. A 3- to 10-membered heterocycle can contain up to 5 heteroatoms; and a 7- to 20-membered heterocycle can contain up to 7 heteroatoms. Typically, a heterocycle has at least one carbon atom ring member. Each heteroatom is independently selected from nitrogen, which can be oxidized (e.g., N(O)) or quaternized; oxygen; and sulfur, including sulfoxide and sulfone. The heterocycle may be attached via any heteroatom or carbon atom. Representative heterocycles include morpholinyl, thiomσrpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydaπtoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuraπyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. A heteroatom may be substituted with a protecting group known to those of ordinary skill in the art, for example, the hydrogen on a nitrogen may be substituted with a tert-butoxycarbonyl group. Furthermore, the heterocyclyl may be optionally substituted with one or more substituents. Only stable isomers of such substituted heterocyclic groups are contemplated in this definition,
As used herein, the term "heteroaromatic", "heteroaryl" or like terms means a monocyclic or polycyclic heteroaromatic ring comprising carbon atom ring members and one or more heteroatom ring members. Each heteroatom is independently selected from nitrogen, which can be oxidized (e.g., N(O)) or quaternized; oxygen; and sulfur, including sulfoxide and sulfone. Representative heteroaryl groups include pyridyl, 1-oxo-pyridyl, furanyl, benzo[1 ,3]dioxolyl, benzo[1 ,4]dioxιnyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, a isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, a triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, pyrrolo[2,3]pyrimidinyl, pyrazplo[3,4]pyrimidinyl, imidazo[1 ,2-a]pyrϊdyl, and benzothienyl. In one embodiment, the heteroaromatic ring is selected from 5-8 membered monocyclic heteroaryl rings. The point of attachment of a heteroaromatic or heteroaryl ring may be at either a carbon atom or a heteroatom of the heteroaromatic or heteroaryl rings. Heteroaryl groups may be optionally substituted with one or more substituents.
As used herein, the term "(C5)heteroaryP means an aromatic heterocyclic ring of 5 members, wherein at least one carbon atom of the ring is replaced with a heteroatom such as, for example, oxygen, sulfur or nitrogen. Representative (C5)heteroaryls include furanyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyrazinyl, triazolyl, thiadiazoly), and the like.
As used herein, the term "(Cβ)heteroaryl" means an aromatic heterocyclic ring of 6 members, wherein at least one carbon atom of the ring is replaced with a heteroatom such as, for example, oxygen, nitrogen or sulfur. Representative (C6)heteroaryis include pyridyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl and the like.
As used herein, the term "heteroaralkyl" means a heteroaryl group that is attached to another group by a (CrC6)all<ylene. Representative heteroaralkyls include 2-(pyridin-4-yl)- propyl, 2-(thien-3-yl)-ethyl, imidazol-4-yl-methyl and the like. Heteroaralkyl groups may be optionally substituted with one or more substituents.
As used herein, the term " acetal" means a substituent in which the carbon atom which forms the point of attachment to another moiety is attached two single bonded oxygen atoms, e.g., -CH(OR)(OR), wherein the R groups represent an alkyl group as described herein, or two R groups may join together to form a heterocyclyl group as described herein, for example:
Figure imgf000040_0001
. A C2-6 acetal is a acetal in which the two R groups together comprise between 2 and 6 carbon atoms, e.g., two methyl groups, two ethyl groups, or the two R groups join together to form a 5 or 6 membered ring. As used herein, the term "ketal" means a substituent in which the carbon atom which forms the point of attachment to another moiety is attached two single bonded oxygen atoms and an alkyl group as defined herein, e.g., -C(OR)(OR)alkyl, wherein the R groups represent an alkyl group as described herein, or two R groups may join together to form a heterocyclyl group as described herein, for example:
Figure imgf000040_0002
and
Figure imgf000040_0003
. A C2-6 ketal is a acetal in which the two R groups together comprise between 2 and 6 carbon atoms, e.g.,_two methyl groups, two ethyl groups, or the two R groups join together to form a 5 or 6 membered ring.
As used herein, the term "halogen" or "halo" means -F, -Cl, -Br or -I.
As used herein the term "heteroalkyl" means a linear straight or branched chain alkyl group, wherein one or more of the internal carbon atoms in the chain is replaced by a heteroatom, such as, O, N or S, e.g., -[CH2)x-O-[CH2]y[CH3] wherein x is a positive integer and y is O or a positive integer, and wherein replacement of the carbon atom does not result in a unstable compound.
Suitable substituents for an alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups include are those substituents which form a stable compound of the invention without significantly adversely affecting the reactivity or biological activity of the compound of the invention. Examples of substituents for an alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroarylalkyl include an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, an optionally substituted haloalkyl, an optionally substituted heteroalkyl, optionally substituted alkoxy, -C(O)NR28RaS), -C(S)NR28R29, -C(NR32)NR28R29, -NR33C(O)R31, -NR33C(S)R31, -NR33C(NR32)R31, halo, -OR33, cyano, πitro, haloalkoxy, -C(O)R33, -C(S)R33, -C(NR32)R33, -NR28R2S, -C(O)OR33, -C(S)OR33, -C(NR32)OR331 -OC(O)R331 -OC(S)R331 -OC(NR32)R33, -NR30C(O)NR28R29, -NR33C(S)NR28R29, -NR33C(NR32)NR28R29, -OC(O)NR28R2S, -OC(S)NR28R29, -OC(NR32)NR28R29, -NR33C(O)OR31, -NR33C(S)OR31, -NR33C(NR32)OR31, -S(O)hR33l -OS(O)PR33, -NR33S(O)pR33, -S(O)pNR2BR29, -OS(O)PNR28R29, or -N R33S(O)PN R28R29 guanadino, -C(O)SR31, -C(S)SR31, -C(NR32)SR31, -OC(O)OR31, -OC(S)OR31, -OC(NR32)OR31, -SC(O)R33, -SC(O)OR31, -SC(NR32)OR31, -SC(S)R33, -SC(S)OR31, -SC(O)NR28R29, -SC(NR32)NR28R28, -SC(S)NR28R29, -SC(NR32)R33, -OS(O)POR31, -S(O)pOR31, -NR30S(O)pOR31, -SS(O)PR33, -SS(O)POR31, -SS(O)pNR28R29l -OP(O)(OR31)2, or -SP(O)(OR31)2, (preferably the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroalkyl, alkoxy, heteroaralkyl and haloalkyl are unsubstituted); wherein R28 and R29, for each occurrence is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl (preferably the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl and heteraralkyl are unsubstituted);
R33 and R31 for each occurrence is independently, H1 an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl (preferably the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl, and heteraralkyl are unsubstituted); and
R32, for each occurrence is independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, -C(O)R33, -C(O)NR28R29, -S(O)PR33, or -S(O)pNR2aR29 (preferably the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, aralkyl and heteraralkyl are unsubstituted);
p is O1 1 or 2; and
h is O, 1 or 2.
In addition, alkyl, cycloalkyl, alkylene, a heterocyclyl, and any saturated portion of a alkenyl, cycloalkenyl, alkynyl, aralkyl, and heteroaralkyl groups, may also be substituted with =0, =S, =N-R32.
When a heterocyclyl, heteroaryl, or heteroaralkyl group contains a nitrogen atom, it may be substituted or unsubstituted. When a nitrogen atom in the aromatic, ring of a heteroary! group has a substituent the nitrogen may be a quaternary nitrogen.
As used herein, the terms "subject", "patient" and "mammal" are used interchangeably. The terms "subject" and "patient" refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), preferably a mammal including a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee and a human), and more preferably a human. In one embodiment, the subject is a non-humaή animal such as a farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit). In a preferred embodiment, the subject is a human.
As used herein, the term "lower" refers to a group having up to four atoms. For example, a "lower alkyl" refers to an alkyl radical having from 1 to 4 carbon atoms, "lower alkoxy" refers to "-O^CrCtJalkyi and a "lower alkenyl" or "lower alkynyl" refers to an alkenyl or alkynyl radical having from 2 to 4 carbon atoms, respectively.
As used herein, the term "contiguous linear connectivity" means connected together so as to form an uninterrupted linear array or series of atoms. For example, a linker of the compounds described herein having a specified number of atoms in contiguous linear connectivity has at least that number of atoms connected together so as to form an uninterrupted chain, but may also include additional atoms that are not so connected (e.g., branches or atoms contained within a ring system).
As used herein, the term "linker" means a diradical having from 1-6 atoms in contiguous linear connectivity (i.e., as defined above and excluding atoms present in any side chains and branches), that covalently connects the phenyl ring portion of a compound of this invention to the Rx group of the compound. Unless indicated otherwise, the compounds of the invention containing reactive functional groups (such as (without limitation) carboxy, hydroxy, thiol, and amino moieties) also include protected derivatives thereof. "Protected derivatives" are those compounds in which a reactive site or sites are blocked with one ore more protecting groups. Examples of suitable protecting groups for hydroxyl groups include benzyl, methoxymethyl, allyl, trimethylsilyl, tert-butyldimethylsilyl, acetate, and the like. Examples of suitable amine protecting groups include benzyloxycarbonyl, tert-butoxycarbonyl, tert-butyl, benzyl and fluorenylmethyloxy- carbonyl (Fmoc). Examples of suitable thiol protecting groups include benzyl, tert-butyl, acetyl, methoxymethy) and the like. Other suitable protecting groups are well known to those of ordinary skill in the art and include those found in T. W. Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.
As used herein, the term "compound(s) of this invention" and similar terms refers to a compound of formula (I)-(XL), and those set forth in Tables 1-5, or a pharmaceutically ' acceptable salt, solvate, clathrate, hydrate, polymorph or prodrug thereof, and also include protected derivatives thereof.
The compounds of the invention may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers {i.e., geometric isomers), enantiomers, or diastereorners. According to this invention, the chemical structures depicted herein, including the compounds of this invention, encompass all of the corresponding compounds' enantiomers, diastereomers and geometric isomers, that is, both the stereochemical^ pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and isomeric mixtures (e.g., enantiomeric, diastereomeric and geometric isomeric mixtures). In some cases, one enantiomer, diastereomer or geometric isomer will possess superior activity or an improved toxicity or kinetic profile compared to other isomers. In those cases, such enantiomers, diastereomers and geometric isomers of compounds of this invention are preferred.
As used herein, the term "polymorph" means solid crystalline forms of a compound of the present invention or complex thereof. Different polymorphs of the same compound can exhibit different physical, chemical and/or spectroscopic properties. Different physical properties include, but are not limited to stability (e.g., to heat or light), compressibility and density (important in formulation and product manufacturing), and dissolution rates (which can affect bioavailability). Differences in stability can result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical characteristics (e.g. , tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). Different physical properties of polymorphs can affect their processing. For example, one polymorph might be more likely to form solvates or might be more difficult to filter or wash free of impurities than another due to, for example, the shape or size distribution of particles of it.
As used herein, the term "hydrate" means a compound of the present invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
As used herein, he term "clathrate" means a compound of the present invention or a salt thereof in the form of a crystal lattice that contains spaces (e.g., channels) that have a guest molecule (e.g., a solvent or water) trapped within.
As used herein and unless otherwise indicated, the term "prodrug" means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of this invention. Prodrugs may become active upon such reaction under biological conditions, or they may have activity in their unreacted forms. Examples of prodrugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of formula (I)-(XL), and those set forth in Tables 1-5, that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other examples of prodrugs include derivatives of compounds of formula (I)-(XL), and those set forth in Tables 1-5, that comprise -NO, -NO2, - ONO, or -ONO2 moieties. Prodrugs can typically be prepared using well-known methods, such as those described by 1 BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed).
As used herein and unless otherwise indicated, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide" and "biohydrolyzable phosphate analogue" mean an amide, ester, carbamate, carbonate, ureide, or phosphate analogue, respectively, that either: 1) does not destroy the biological activity of the compound and confers upon that compound advantageous properties in vivo, such as improved water solubility, improved circulating half-life in the blood (e.g., because of reduced metabolism of the prodrug), improved uptake, improved duration of action, or improved onset of action; or 2) is itself biologically inactive but is converted in vivo to a biologically active compound. Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylaminss, heterocyclic and heteroaromatic amines, and polyether amines.
As used herein, "Hsp90" includes each member of the family of heat shock proteins having a mass of about 90-kiloDaltons. For example, in humans the highly conserved Hsp90 family includes cytosolic Hsp90α and Hsp90β isoforms, as well as GRP94, which is found in the endoplasmic reticulum, and HSP75/TRAP1 , which is found in the mitochondrial matrix.
c-Met is a receptor tyrosine kinase that is expressed in normal and malignant cells and has been identified as a proto-oncogene. HGF/c-Met signaling triggers an invasive growth program that is thought to be essential in early embryonic development but when dysregulated can result malignant growth, motility, migration and invasion by a mechanism that is not yet completely understood. The human Met gene is located on chromosome 7 band 7q21-q31 and spans more than 120 kb (Ma, ef a/., Cancer and Metastasis Reviews (2003), 22:309-325). In wild type cells, c-Met is a heterodimer that consists of an extracellular α-subunit and a β-subunit with a large extracellular domain, a membrane spanning segment and an intracellular tyrosine kinase domain. Functional structures and domains of c-Met include 1) Sema domain at the N-terminus which includes a MRS cysteine-rich region; 2) PSI domain which is also found in plexins, semaphorins and integrins; 3) IPT repeats which are found in immunoglobulin, plexins and transcription factors; 4) transmembrane domain; 5) juxtamembrane domain; and 6) the intracellular tyrosine kinase domain at the C-termiπus.
Activation of c-Met signaling is dependent on phosphorylation of multiple residues on c-Met. Upon binding of HGF, c-Met undergoes autophosphorylation at Y1230, Y1234, and Y1235 in the activation loop of the tyrosine kinase domain which ativates the kinase activity of c- Met. Y1313 can also be phosphorylated in response to HGF binding and is important in binding PI3-K which is implicated in prosurvival signaling. Phosphorylation of Y1349 and Y1356 at the C-terinus of c-Met activates the multisubstrate signal transducer docking site which has been implicated in Met-mediated signal transduction and mediates the interactions of SHC, Src, and Gab1 , while recruitment of Grb2, PI3-K, PLC-γ and SHP2 is dependent on phosphorylation of Y1356 alone. Regultation of cell morphogenesis is mediated via Y1365. Phosphorylation of the Y1003 residue in the juxtamembrane domain mediates the binding of c-Cbl. c-Cbl acts as a negative regulator protein of c-Met by promoting the polyu biqu itinization of c-Met which leads to degradation.
Dysregulation of HGF/c-Met signaling can be caused by 1) increased expression of HGF; 2) activating mutations which typically occur in the tyrosine kinase domain or the juxtamembrane domain of c-Met and confer constitutive kinase activity; 3) intra- chromosomal ammplification of the Met gene and over expression of c-Met; 4) chromosomal translocation such as in the Trp/Met fusion protein which results in the loss of the juxtamembraπe domain and leads to constitutive activation, and 5) alternate splicing variants c-Met mRNA which lead to loss of the juxtamembrane domain and also lead to constitutive activation
Activating mutation in the tyrosine kinase domain or in the juxtamembrane domain of c-Met which result in increased activation of the tyrosine kinase activity have been observed in hereditary and sporatic papillary renal carcinoma, ovarian cancer, hepatocellular carcinoma, metastatic head and neck squamous cell carcinomas, NSCLC, SCLC, glioma, breast cancer, and gastric cancer In somatic papillary renal cell carcinoma activating mutations have been found at amino acid residues M1268 (e g , M1268T) Y1248 (e g , Y1248D, Y1248H), Y1246 (e g , Y1246H), Y1230 (e g , Y1230C), L1213 (e g , L1213V), H1124 (e g , H1124D, H1112L, and H1112Y), and V1110 (V11101) In germline papillary renal cell carcinoma activating mutations have been found at amino acid residues Y1248 (e g , Y1248C), Y1246 (e g , Y1246N), V1238 (e g , V1238I), Y1230 (e g , Y1230C and Y1230H), V1206 (e g , V1206L), M1149 (e g , M1149T), and H1112 (e g , H1112R) In hepatocellular carcinoma activating mutations have been found at amino acid residues M1268 (e g ,
M1268I), K1262 (e g , K1262R), and T1191 (e g , T1191 I) In head and neck squamous cell carcinoma activating mutations have been found at amino acid residues Y1253 (e g , Y1253D), Y1235 (e g , Y1235D), and Y1230 (e g , Y1230C and Y1230D) In glioma activating mutations have been found at amino acid residue G1137 (e g , G1137V) In NSCLC activating mutations have been found at amino acid residue T1010 (e g , T1010I) In SCLC activating mutations have been found at amino acid residues R988 (e g , R988C) and T1010 (e g , T1010I) In breast cancer activating mutations have been found at ammo acid residues T1010 (e g , T1010I) In gastric cancer activating mutations have been found at amino acid residue P1009 (e g , P1009S) Amino acids listed herein for c-Met are numbered as in Schmit, et al , Onogene (1999), 18 2343-2350 Compounds of the invention cause the degradation of c-Met and can be used either alone or in combination with other anticancer therapies to treat patients with cancers that have activating mutations in the tyrosine kinase domain or in the juxtamembrane domain of c-Met
The juxtamembrane of receptor tyrosine kinases has been shown to repress catalytic function and mutation in the juxtamembrane relieve this repression and can lead to oncogenesis The Tpr/Met fusion protein results from replacement of the 5' region of the Met gene with Tpr which provides two strong dimerization motifs Dimeπzation activates the Met kinase activity and results in transforming and metastatic properties The Tpr/Met fusion protein has been found in gastric cancer and results in increased Met kinase activity In addition, an alternative splicing form of Met mRNA has been found in small cell lung cancer which results in skipping the juxtamembrane domain Loss of the juxtamembrane domain leads to increased Met kinase activity and oncogenesis Compounds of the invention cause the degradation of c-Met and can be used either alone or in combination with other anticancer therapies to treat patients with cancers that have juxtamembrane mutations or deletions in c-Met.
Amplification of the Met gene and overexpression of c-Met has been found in several types of cancers including gastric cancer, esophageal cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, multiple myeloma, and colorectal cancer metastases. Compounds of the invention cause the degradation of c-Met and can be used either alone or in combination with other anticancer therapies to treat patients with cancers that have Met gene amplification and/or c-Met overexpression.
Met amplification and mutation has also been implicated as a strategy by which certain cancers become resistant to therapy (e.g., chemotherapy or radiation therapy). For example, certain non-small cell lung cancers contain an activating mutation in receptor tyrosine kinase EGFR which results in oncogenesis. Most EGFR mutant NSCLCs initially respond to EGFR inhibitors such as lressa and Tarceva but the vast majority of these tumors ultimately become resistant to the drug. A subset of these resistant cancers have been shown to have amplified Met, and it is thought that Met amplification is a mechanisms of acquired resitance, and in particular acquired resistance to kinase inhibitors such as lressa and Tarceva (EGFR inhibitors), Gleevec (a Bcr-Abl, PDGF1 and c-Kit inhibitor) (Engelman et al., Sciencexpress, www.sciencexpress orq / 26 April 2007/ page 1 / 10.1126/science. 1141478). Compounds of the invention cause the degradation of c-Met and can be used either alone or in combination with other anticancer therapies, such as treatment with kinase inhibitors, to treat patients with cancer that has become resistant to other anticancer therapies.
As used herein, "c-Met associated cancer" refers to any type of malignant growth or metastasis that is caused by or enhanced by dysregulation in HGF/c-Met signaling. B-raf is a serine/threonine kinase that is involved in the MAP kinase pathway and is encoded by a gene located on chromosome 7q32. Ten isoforms of B-raf have been identified which are the result of splicing variants. The term "B-raf refers to all such splicing variants. B-raf has three conserved regions (CR): 1) CR1 which contains a cysteine rich domain (CRD) and most of the Ras binding domain (RBD) and facilitates the binding of B- raf to Ras and recruitment to the cell membrane; 2) CR2 which is rich in serine and threonine and includes the S365 residue which is an inhibitory phosphorylation site; and 3) CR3 which contains the kinase domain including a G-loop GXGXXG motif, an activation segment and regulatory phosphorylation sites S446, S447, D448, D449, T599 and S602. B-raf is translocated to the cell membrane and activated by association with GTP-bound Ras. B-raf is regulated by changes in its conformation and is inactive when the activation segment is held in an inactive conformation as a result of hydrophobic interactions with the P-loop. Phosphorylation in the activation segment results in a shift to the active conformation of B-raf. Interestingly, the activation segment and P-loop that interact with one-another and restraining the activation segment in an inactive conformation, are where the majority of B-raf oncogenic mutations are clustered. This indicates that as a result of B- raf mutations the inactive B-raf conformation is destabilized thereby promoting an active B- raf conformation. (Berram, ef al., Journal of Clinical Oncology (2005), 23(27):6771-6790).
B-raf associated cancers are cancers in which inappropriate B-raf activity is detected. In one embodiment, B-raf associated cancers have increased B-raf activity, such as B-raf with mutations in the kinase domain that confer increased activity over that of wild type B-raf and/or constitutively active B-raf (e.g., B-raf that has activity that is not dependent on interaction with Ras). Activating mutations in the kinase domain include V600E, V600D, G596R, G594V, G469A, G469E, G466V, and G464V mutations. Examples of B-raf associated cancers include malignant melanomas, anaplastic thyroid carcinoma, papillary thyroid caricinoma, follicular thyroid cancer, para-follicular C-cell-derived medullary thyroid cancer, colon cancer, ovarian carcinoma, Barrett's esophageal carcinoma, acute myeloid leukemia, head and neck squamous cell carcinoma, non-small-cell lung cancer, gastric carcinoma, non-Hodgkins lymphoma, glioma, saroma, breast cancer, cholangiocarcinoma, and liver cancer in which inappropriate B-raf activity can be detected, such as increased B- raf activity of a mutant form of B-raf over that of wild type B-raf or constitutive activity of B- raf. As used herein, "NPM-ALK" refers to a fusion protein which is the result of a t(2;5)(p23;q35) translocation of the gene sequence for NPM/B23 nucleolar protein into the sequence which encodes for the tyrosine kinase ALK. Typically, the NPM-ALK fusion protein contains the first 117 amino acids of the amine terminal of NPM and the C-terminal residues 1058 to 1620 of ALK. For a schematic representation of NPM-ALK see figure 1 of Duyster, ef al., Oncogene (2001 ), 20:5623-5637, the entire teachings of which are incorporated herein by reference.
The term "NPM-ALK associated cancers" refers to cancers in which the NPM-ALK fusion protein is expressed, such as ALCL and diffuse large B-cell lymphomas.
The term "c-kit" or "c-kit kinase" refers to a membrane receptor protein tyrosine kinase which is preferably activated upon binding Stem Cell Factor (SCF) to its extracellular domain (Yarden et al., 1987; Qiu et al., 1988). The full length amino acid sequence of a c- kit kinase preferably is as set forth in Yarden, ef al., 1987, EMBO J., 71:3341-3351; and Qiu, et al., 1988, EMBO J., 7:1003-1011, which are incorporated by reference herein in their entirety, including any drawings. Mutant versions of c-kit kinase are encompassed by the term "c-kit" or "c-kit kinase" and include those that fall into two classes: (1) having a single amino acid substitution at codon 816 of the human c-kit kinase, or its equivalent position in other species (Ma et al., 1999, J. Invest Dermatol., 112:165-170), and (2) those which have mutations involving the putative juxtamembrane z-helix of the protein (Ma1 ef a/., 1999, J. Biol. Chem,, 274:13399-13402). Both of these publications are incorporated by reference herein in their entirety, including any drawings.
As used herein, "Bcr-Abl" is a fusion protein that results from the translocation of gene sequences from c-ABL protein tyrosine kinase on chromosome 9 into BCR sequences on chromosome 22 producing the Philiadelphia chromosome. A schematic representation of human Bcr, AbI, and Bcr-Abl can be seen in Figure 1 of U.S. patent application serial number 10/193,651, filed on July 9, 2002, the entire teachings of which are incorporated herein by reference. Depending on the breaking point in the Bcr gene, Bcr-Abl fusion proteins can vary in size from 185-230 kDa but they must contain at least the OLI domain from Bcr and the TK domain from AbI for transforming activity. The most common Bcr-Abl gene products found in humans are P230 Bcr-Abl, P210 Bcr-Abl, and P190 Bcr-Abl. P210 Bcr-Abl is characteristic of CML and P190 Bcr-Abl is characteristic of ALL.
FLT3 kinase is a tyrosine kinase receptor involved in the regulation and stimulation of cellular proliferation (see Gilliland et a/., Blood (2002), 700:1532-42, the entire teachings of which are incorporated herein by reference). The FLT3 kinase has five immunoglobuliπ-like domains in its extracellular region as well as an insert region of 75-100 amino acids in the middle of its cytoplasmic domain. FLT3 kinase is activated upon the binding of the FLT3 ligand, which causes receptor dimerization. Dimerization of the FLT3 kinase by FLT3 ligand activates the intracellular kinase activity as well as a cascade of downstream substrates including Statδ, Ras, phosphatidylinositol-3-kinase (PI3K), PLCD, Erk2, Akt, MAPK1 SHC, SHP2, and SHIP (see Rosnet ef a/., Acta Haematol. (1996), 95:218; Hayakawa ef a/., Oncogene (2000), 19:624; Mizuki ef a/., 8/ood (2000), 96:3907; and Gilliand ef a/., Curr. Opin. Hematol. (2002), 9: 274-81 , the entire teachings of each of these references are incorporated herein by reference). Both membrane-bound and soluble FLT3 ligand bind, dimerize, and subsequently activate the FLT3 kinase.
Normal cells that express FLT3 kinase include immature hematopoietic cells, typically CD34+ cells, placenta, gonads, and brain (see Rosnet, ef a/., Stood (1993), 82:1110-19; Small ef a/., Proc. Nati. Acad. Sci. U.S.A. (1994), 91:459-63; and Rosnet ef a/., Leukemia (1996), 10:238-48, the entire teachings of each of these references are incorporated herein by reference). However, efficient stimulation of proliferation via FLT3 kinase typically requires other hematopoietic growth factors or interleukins. FLT3 kinase also plays a critical role in immune function through its regulation of dendritic cell proliferation and dilferentiation (see McKenna ef a/., Stood (2000), 95:3489-97, the entire teachings of which are incorporated herein by reference).
Numerous hematologic malignancies express FLT3 kinase, the most prominent of which is AML (see Yokota ef a/., Leukemia (1997), 77:1605-09, the entire teachings of which are incorporated herein by reference). Other FLT3 expressing malignancies include B- precursor cell acute lymphoblastic leukemias, myelodysplastic leukemias, T-cell acute lymphoblastic leukemias, and chronic myelogenous leukemias (see Rasko ef a/., Leukemia (1995), 9:2058-66, the entire teachings of which are incorporated herein by reference). FLT3 kinase mutations associated with hematologic malignancies are activating mutations. In other words, the FLT3 kinase is constitutively activated without the need for binding and dimerization by FLT3 ligand, and therefore stimulates the cell to grow continuously. Two types of activating mutations have been identified: internal tandem duplications (ITDs) and point mutation in the activating loop of the kinase domain. As used herein, the term "FLT3 kinase" refers to both wild type FLT3 kinase and mutant FLT3 kinases, such as FLT3 kinases that have activating mutations.
Compounds provided herein are useful in treating conditions characterized by inappropriate FLT3 activity such as proliferative disorders. Inappropriate FLT3 activity includes, but is not limited to, enhanced FLT3 activity resulting from increased or de novo expression of FLT3 in cells, increased FLT3 expression or activity, and FLT3 mutations resulting in constitutive activation. The existence of inappropriate or abnormal FLT3 ligand and FLT3 levels or activity can be determined using well known methods in the art. For example, abnormally high FLT3 levels can be determined using commercially available ELISA kits. FLT3 levels can be determined using flow cytometric analysis, immunohistochemical analysis, and in situ hybridization techniques.
By "epidermal growth factor receptor" or "EGFR" as used herein is meant, any epidermal growth factor receptor (EGFR) protein, peptide, or polypeptide having EGFR or EGFR family (e.g., HER1 , HER2, HER3, and/or HER4) activity (such as encoded by EGFR Genbank Accession Nos. shown in Table I of U.S. Patent Application Serial No. 10/923,354, filed on August 20, 2004 , the entire teachings of which are incorporated herein by reference), or any other EGFR transcript derived from a EGFR gene and/or generated by EGFR translocation. The term "EGFR" is also meant to include other EGFR protein, peptide, or polypeptide derived from EGFR isoforms (e.g., HER1 , HER2, HER3, and/or HER4), mutant EGFR genes, splice variants of EGFR genes, and EGFR gene polymorphisms.
As used herein, a "proliferative disorder" or a "hyperproliferative disorder," and other equivalent terms, means a disease or medical condition involving pathological growth of cells. Proliferative disorders include cancer, smooth muscle cell proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, retinopathy, e.g., diabetic retinopathy or other retinopathies, cardiac hyperplasia, reproductive system associated disorders such as benign prostatic hyperplasia and ovarian cysts, pulmonary fibrosis, endometriosis, fibromatosis, harmatomas, lymphangiomatosis, sarcoidosis, desmoid tumors,
Smooth muscle cell proliferation includes hyperproliferation of cells in the vasculature, for example, intimal smooth muscle cell hyperplasia, restenosis and vascular occlusion, particularly stenosis following biologically- or mechanically-mediated vascular injury, e.g., vascular injury associated with angioplasty. Moreover, intimal smooth muscle cell hyperplasia can include hyperplasia in smooth muscle other than the vasculature, e.g., bile duct blockage, bronchial airways of the lung in patients with asthma, in the kidneys of patients with renal interstitial fibrosis, and the like.
Non-cancerous proliferative disorders also include hyperproliferation of cells in the skin such as psoriasis and its varied clinical forms, Reiter's syndrome, pityriasis rubra pilaris, and hyperproliferative variants of disorders of keratinization (e.g., actinic keratosis, senile keratosis), scleroderma, and the like,
In a preferred embodiment, the proliferative disorder is cancer. Cancers that can be treated or prevented by the methods of the present invention include, but are not limited to human sarcomas and carcinomas, e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma; leukemias, e.g., acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia); chronic leukemia (chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia); and polycythemia vera, lymphoma (Hodgkin's disease and non- Hodgkin's disease), multiple myeloma, Waldenstrobm's macroglobulinemia, and heavy chain disease.
Other examples of leukemias include acute and/or chronic leukemias, e.g., lymphocytic leukemia (e.g., as exemplified by the p388 (murine) cell line), large granular lymphocytic leukemia, and lymphoblastic leukemia; T-cell leukemias, e.g., T-cell leukemia (e.g., as exemplified by the CEM, Jurkat, and HSB-2 (acute), YAC-1 (murine) cell lines), T- lymphocytic leukemia, and T-lymphoblastic leukemia; B cell leukemia (e.g., as exemplified by the SB (acute) cell line) , and B-lymphocytic leukemia; mixed cell leukemias, e.g., B and T cell leukemia and B and T lymphocytic leukemia; myeloid leukemias, e.g., granulocytic leukemia, myelocytic leukemia (e.g., as exemplified by the HL-60 (promyelocyte) cell line), and myelogenous leukemia (e.g., as exemplified by the K562(chronic)cell line); neutrophilic leukemia; eosinophilic leukemia; monocytic leukemia (e.g., as exemplified by the THP- 1 (acute) cell line); myelomonocytic leukemia; Naegeli-type myeloid leukemia; and nonlymphocytic leukemia. Other examples of leukemias are described in Chapter 60 of The Chemotherapy Sourcebook, Michael C. Perry Ed., Williams & Williams (1992) and Section 36 of Holland FrIe Cancer Medicine 5th Ed., Bast et al. Eds., B.C. Decker Inc. (2000). The entire teachings of the preceding references are incorporated herein by reference.
In one embodiment, the disclosed method is believed to be particularly effective in treating subject with non-solid tumors such as multiple myeloma. In another embodiment, the disclosed method is believed to be particularly effective against T-leukemia (e.g., as exemplified by Jurkat and CEM cell lines); B-leukemia (e.g., as exemplified by the SB cell line); promyelocytes (e.g., as exemplified by the HL-60 cell line); uterine sarcoma (e.g., as exemplified by the MES-SA cell line); monocytic leukemia (e.g., as exemplified by the THP- 1 (acute) cell line); and lymphoma (e.g., as exemplified by the U937 cell line).
In one embodiment, the disclosed method is believed to be particularly effective in treating subject with non-Hodgkin's lymphoma (NHL). Lymphomas are generally classified as either Hodgkin's disease (HD) or non-Hodgkin's lymphomas (NHL). NHL differs from HD by the absence of Reed-Sternberg cells. The course of NHL is less predictable than HD and is more likely to spread to areas beyond the lymph nodes. NHL can be further divided into B- cell NHL and T-cell NHL each of which can be further categorized into a variety of different subtypes. For example, B-cell NHL includes Burkitt's lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, nodal marginal zone B-cell lymphoma, plasma cell neoplasms, small lymphocytic lymphoma/chronic lymphocytic leukemia, mantle cell lymphoma, extranodal marginal zone B-cell lymphoma, and lymphoplamacytic lymphoma/Waldenstrom macroglobulinemia. T-cell NHL include anaplastic large-cell lymphoma, precursor-T-cell lymphoblastic leukemia/lymphoma, unspecified peripheral T-cell lymphoma, acute lymphoblastic leukemia/lymphoma, angioimmunoblastic T-cell lymphoma, and mycosis fungoides.
Without wishing to be bound by any theory, it is believed that the compounds of the invention are useful for treating NHLs, including B-cell and T-cell NHLs, since Hsp90 is upregulated in many NHLs. In particular, in a survey of 412 cases of NHL in B-cell NHL, Hsp90 was found to be moderately to strongly over expressed in all cases of Burkitt's lymphoma (5/5, 100%), and in a subset of follicular lymphoma (17/28, 61%), diffuse large B- cell lymphoma (27/46, 59%), nodal marginal zone B-cell lymphoma (6/16, 38%), plasma cell neoplasms (14/39, 36%), small lymphocytic lymphoma/chronic lymphocytic leukemia (3/9, 33%), mantle cell lymphoma (12/38, 32%), and lymphoplamacytic lymphoma/Waldenstrom macroglobulinemia (3/10, 30%). In addition, in T-cell NHL, Hsp90 was found to be moderately to strongly over expressed in a subset of anaplastic large-cell lymphoma (14/24, 58%), precursor-T-cell lymphoblastic leukemia/lymphoma (20/65, 31%), unspecified peripheral T-cell lymphoma (8/43, 23%), and angioimmunoblastic T-cell lymphoma (2/17, 12%). (See Valbuena, ef a/., Modern Pathology (2005), 78:1343-1349, the entire teachings of which are incorporated herein by reference.)
Some of the disclosed methods can be particularly effective at treating subjects whose cancer has become "multi-drug resistant". A cancer which initially responded to an anticancer drug becomes resistant to the anti-cancer drug when the anti-cancer drug is no longer effective in treating the subject with the cancer. For example, many tumors will initially respond to treatment with an anti-cancer drug by decreasing in size or even going into remission, only to develop resistance to the drug. Drug resistant tumors are characterized by a resumption of their growth and/or reappearance after having seemingly gone into remission, despite the administration of increased dosages of the anti-cancer drug. Cancers that have developed resistance to two or more anti-cancer drugs are said to be "multi-drug resistant". For example, it is common for cancers to become resistant to three or more anti-cancer agents, often five or more anti-cancer agents and at times ten or more anti-cancer agents.
As used herein, the term "c-kit associated cancer" refers to a cancer which has aberrant expression and/or activation of c-kit. c-Kit associated cancers include leukemias, mast cell tumors, small cell lung cancer, testicular cancer, some cancers of the gastrointestinal tract and some central nervous system. In addition, c-kit has been implicated in playing a role in carcinogenesis of the female genital tract (Inoue, ef a/., 1994, Cancer Res., 54(11):3049- 3053), sarcomas of neuroectodermal origin (Ricotti, ef a/., 1998, Blood, 97:2397-2405), and Schwann cell neoplasia associated with neurofibromatosis (Ryan, ef a/., 1994, J. Neuro. Res., 37:415-432).
In one embodiment, compounds of the invention are vascular targeting agents. In one aspect, compounds of the invention are effective for blocking, occluding, or otherwise disrupting blood flow in "neovasculature." In one aspect, the invention provides a novel treatment for diseases involving the growth of new blood vessels ("neovasculature"), including, but not limited to: cancer; infectious diseases; autoimmune disorders; benign tumors, e.g. hemangiomas, acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas; artheroscleric plaques; ocular angiogenic diseases, e.g., diabetic retinopathy, retinopathy of prematurity, macular degeneration, corneal graft rejection, neovascular glaucoma, retrolental fibroplasia, rubeosis, retinoblastoma, persistent hyperplastic vitreous syndrome, choroidal neovascularization, uvietis and Pterygia (abnormal blood vessel growth) of the eye, rheumatoid arthritis, psoriasis, warts, allergic dermatitis, blistering disease, Karposi sarcoma, delayed wound healing, endometriosis, uterine bleeding, ovarian cysts, ovarian hyperstimulation, vasculogenesis, granulations, hypertrophic scars (keloids), nonunion fractures, scleroderma, trachoma, vascular adhesions, vascular malformations, DiGeorge syndrome, HHT, transplant arteπopathy, restinosis, obesity, myocardial angiogenesis, coronary collaterals, cerebral collaterals, arteriovenous malformations, ischemic limb angiogenesis, primary pulmonary hypertension, asthma nasal polyps, inflammatory bowel disease, periodontal disease, ascites, peritoneal adhesions, Osier- Webber Syndrome, plaque neovascularization, telangiectasia, hemophiliac joints, synovitis, osteomyelitis, osteophyte formation, angiofibroma, fibromuscular dysplasia, wound granulation, Crohn's disease, and atherosclerosis Vascular targeting can be demonstrated by any method known to those skilled in the art, such as the method described herein in Examples E and F
As used herein, the term "angiogenesis' refers to a fundamental process of generating new blood vessels in tissues or organs Angiogenesis is involved with or associated with many diseases or conditions, including, but not limited to cancer, ocular neovascular disease, age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity corneal graft rejection, neovascular glaucoma, retrolental fibroplasias, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea, warts, eczema, phylectenulosis, syphilis, Mycobacteria infections, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpes zoster infections, protozoan infections, Kaposi's sarcoma, Mooren's ulcer, Terπen's marginal degeneration, maπginal keratolysis, rheumatoid arthritis, systemic lupus, polyarteritis, trauma, Wegener's sarcoidosis, scleritis, Stevens- Johnson disease, pemphigoid, radial keratotomy, corneal graph rejection, diabetic retinopathy, macular degeneration, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Paget's disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitπtis, mycobacterial infections, Lyme's disease, systemic lupus erythematosa, retinopathy of prematurity, Eales1 disease, Behcet's disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, trauma and post-laser complications, diseases associated with rubeosis (neovasculariation of the angle), diseases caused by the abnormal proliferation of fibrovascular or fibrous tissue including all forms of proliferative vitreoretinopathy, rheumatoid arthritis, osteoarthritis, ulcerative colitis, Crohn's disease, Bartonellosis, atheroscierosis; Osler-Weber-Rendu disease; hereditary hemorrhagic telangiectasia; pulmonary hemangiomatosis; pre-eclampsia; endometriosis; fibrosis of the liver and of the kidney; developmental abnormalities (organogenesis); skin disclolorations (e.g., hemangioma, nevus flammeus, or nevus simplex); wound healing; hypertrophic scars, I.e., keloids; wound granulation; vascular adhesions; cat scratch disease (Rochele ninalia quintosa); ulcers (Helicobacter pylori); keratoconjunctivitis; gingivitis; periodontal disease; epulis; hepatitis; tonsillitis; obesity; rhinitis; laryngitis; tracheitis; bronchitis; bronchiolitis; pneumonia; interstitial pulmonary fibrosis; neurodermitis; thyroiditis; thyroid enlargement; endometriosis; glomerulonephritis; gastritis; inflammatory bone and cartilage destruction; thromboembolic disease; and Buerger's disease.
The term "infection" is used herein in its broadest sense and refers to any infection e.g. a viral infection or one caused by a microorganism: bacterial infection, fungal infection, or parasitic infection (e.g. protozoal, amoebic, or helminth). Examples of such infections may be found in a number of well known texts such as "Medical Microbiology" (Greenwood, D , Slack, R., Peutherer, J., Churchill Livingstone Press, 2002); "Mims' Pathogenesis of Infectious Disease" (Mims, C, Nash, A., Stephen, J., Academic Press, 2000); "Fields" Virology. (Fields, B. N., Knipe, D. M,, Howley, P. M., Lippincott Williams and Wilkins, 2001); and "The Sanford Guide To Antimicrobial Therapy," 26th Edition, J. P. Saπford et a/. (Antimicrobial Therapy, Inc., 1996), all of which are incorporated by reference herein in their entirety.
"Bacterial infections" include, but are not limited to, infections caused by Gram Positive Bacteria including Bacillus cereus, Bacillus anthracis, Clostridium botulinum, Clostridium difficile, Clostridium tetani, Clostridium perfringens, Corynebacteria diphtheriae, Enterococcus (Streptococcus D), Listeria monocytogenes, Pneumoccoccal infections (Streptococcus pneumoniae), Staphylococcal infections and Streptococcal infections; Gram Negative Bacteria including Bacteroides, Bordetella pertussis, Brucella, Campylobacter infections, enterohaemorrhagic Escherichia coli (EHEC/E. coli 0157: H7) enteroinvasive Escherichia coli (EIEC), enterotoxigenic Escherichia coli (ETEC), Haemophilus influenzae, Helicobacter pylori, Klebsiella pneumoniae, Legionella spp., Moraxella catarrhalis, Neisseria gonnorrhoeae, Neisseria meningitidis, Proteus spp., Pseudomonas aeruginosa, Salmonella spp., Shigella spp., Vibrio cholera and Yersinia; acid fast bacteria including Mycobacterium tuberculosis, Mycobacterium avium-intracellulare, Myobacterium johnei, Mycobacterium leprae, atypical bacteria, Chlamydia, Mycoplasma, Rickettsia, Spirochetes, Treponema pallidum, Borrelia recurrentis, Borrelia burgdorfii and Leptospira icterohemorrhagiae; or other miscellaneous bacteria, including Actinomyces and Nocardia.
The term "fungus" or "fungal" refers to a distinct group of eukaryotic, spore-forming organisms with absorptive nutrition and lacking chlorophyll. It includes mushrooms, molds, and yeasts. "Fungal infections" include, but are not limited to, infections caused by Alternaria altemata, Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, Aspergillus versicolor, Blastomyces dermatiditis, Candida albicans, Candida dubliensis, Candida krusei, Candida parapsilosis, Candida tropicalis, Candida glabrata, Coccidioides immitis, Cryptococcus neoformans, Epidermophyton floccosum, Histoplasma capsulatum,
Malassezia furfur, Microsporum canis, Mucor spp., Paracoccidioides brasiliensis, Penicillium marneffei, Pityrosporum ovale, Pneumocystis carinii, Sporothrix schenkii, Trichophyton rubrum, Trichophyton interdigitale, Trichosporon beigelii, Rhodotorula spp., Brettanomyces clausenii, Brettanomyces custerii, Brettanomyces anomalous, Brettanomyces naardenensis, Candida himilis, Candida intermedia, Candida saki, Candida solani, Candida tropicalis, Candida versatilis, Candida bechii, Candida famata, Candida lipolytica, Candida stellata, Candida vini, Debaromyces hansenii, Dekkera intermedia, Dekkera bruxellensis, Geotrichium sandidum, Hansenula fabiani, Hanseniaspora uvarum, Hansenula anomala, Hanseniaspora guillermondii Hanseniaspora vinae, Kluyveromyces lactis, Kloekera apiculata, Kluveromyces marxianus, Kluyveromyces fragilis, Metschikowia pulcherrima, Pichia guilliermodii, Pichia orientalis, Pichia fermentans, Pichia memranefaciens, Rhodotorula Saccharomyces bayanus, Saccharomyces cerevisiae, Saccharomyces dairiensis Saccharomyces exigus, Saccharomyces uinsporus, Saccharomyces uvarum, Saccharomyces oleaginosus, Saccharomyces boulardii, Saccharomycodies ludwigii, Schizosaccharomyces pombe, Torulaspora delbruekii, Torulopsis stellata, Zygoaccharomyces bailli and Zygosaccharomyces rouxii.
"Parasitic infections" include, but are not limited to, infections caused by Leishmania, Toxoplasma, Plasmodia, Theileria, Acanthamoeba, Anaplasma, Giardia, Trichomonas, Trypanosoma, Coccidia, and Babesia. For example, parasitic infections include those caused by Trypanosoma cruzi, Eimeria tenella, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Cryptosporidium parvum, Naegleria fowleri, Entamoeba histolytica, Balamuthia mandrillaris, Entameoba histolytica, Schistostoma mansoni, Plasmodium falciparum, P. vivax, P. ovale P. malariae, P. berghei, Leishmania donovani, L. infantum, L. chagasi, L. mexicana, L. amazonensis, L. venezuelensis, L. tropics, L. major, L. minor, L. aethiopica, L. Biana braziliensis, L. (V.) guyanensis, L. (V.) panamensis, L. (V.) peruviana, Trypanosoma brucei rhodesiense, T brucei gambiense, Giardia intestinalis, G. lambda, Toxoplasma gondii, Trichomonas vaginalis, Pneumocystis carinii, Acanthamoeba castellani A. culbertsoni, A. polyphaga, A. healyi, (A. astronyxis), A. hatchetti, A. rhysodes, and Trichinella spiralis. As used herein, the term "viral infection" refers to any stage of a viral infection, including incubation phase, latent or dormant phase, acute phase, and development and maintenance of immunity towards a virus. Consequently, the term "treatment" is meant to include aspects of generating or restoring immunity of the patient's immune system, as well as aspects of suppressing or inhibiting viral replication.
Viral infections include, but are not limited to those caused by Adenovirus, Lassa fever virus (Arenavirus), Astrovirus, Hantavirus, Rift Valley Fever virus (Phlebovirus), Calicivirus, Ebola virus, Marburg Virus, Japanese encephalitis virus, Dengue virus, Yellow fever virus, Hepatitis C virus, Hepatitis G virus, Hepatitis B virus, Hepatitis D virus, Herpes simplex virus 1, Herpes simplex virus 2), Cytomegalovirus, Epstein Barr virus, Varicella Zoster Virus, Human Herpesvirus 7, Human Herpesvirus 8, Influenza virus, Parainfluenza virus, Rubella virus, Mumps virus, Morbillivirus, Measles virus, Respiratory Syncytial virus, Papillomaviruses, JC virus (Polyomavirus), BK virus (Polyomavirus), Parvovirus, Coxsackie virus (A and B), Hepatitis A virus, Polioviruses, Rhinoviruses, Reovirus, Rabies Virus (Lyssavirus), Human Immunodeficiency virus 1 and 2, Human T-cell Leukemia virus.
Examples of viral infections include Adenovirus acute respiratory disease, Lassa fever, Astrovirus enteritis, Hantavirus pulmonary syndrome, Rift valley fever, Hepatitis E1 diarrhoea, Ebola hemorrhagic fever, Marburg hemorrhagic fever, Japanese encephalitis, Dengue fever, Yellow fever, Hepatitis C, Hepatitis G, Hepatitis B, Hepatitis D, Cold sores, Genital sores, Cytomegalovirus infection, Mononucleosis, Chicken Pox, Shingles, Human Herpesvirus infection 7, Kaposi Sarcoma, Influenza, Brochiolitis, German measles, Mumps, Measles (rubeola), Measles, Brochiolitis, Papillomas (Warts), cervical cancer, Progressive multifocal leukoencephalopathy, Kidney disease, Erythema infectiosum, Viral myocarditis, meninigitis, entertitis, Hepatitis, Poliomyelitis, Cold, Diarrhoea, Rabies, AIDS and Leukemia.
DNA topoisomerases are enzymes present in all cells that catalyze topological changes in DNA. Topoisomerase Il ("topo II") plays important roles in DNA replication, chromosome segregation and the maintenance of the nuclear scaffold in eukaryotic cells. The enzyme acts by creating breaks in DNA, thereby allowing the DNA strands to unravel and separate. Due to the important roles of the enzyme in dividing cells, the enzyme is a highly attractive target for chemotherapeutic agents, especially in human cancers. The ability of compounds to inhibit topo Il can be determined by any method known in the art such as in Example K.
The glucocorticoid receptor is a member of the steroid hormone nuclear receptor family which includes glucocorticoid receptors (GR), androgen receptors (AR), mineralocorticoid receptors (MR), estrogen receptors (ER), and progesterone receptors (PR). Glucocorticoid receptors bind glucocorticoids such as Cortisol, corticosterone, and cortisone.
"Immunosuppression" refers to impairment of any component of the immune system resulting in decreased immune function. This impairment may be measured by any conventional means including whole blood assays of lymphocyte function, detection of lymphocyte proliferation and assessment of the expression of T cell surface antigens. The antisheep red blood cell (SRBC) primary (IgM) antibody response assay (usually referred to as the plaque assay) is one specific method. This and other methods are described in Luster, M.I., Portier, C1 Pait, D.G., White, K.L., Jr., Gennings, C1 Munson, A.E., and Rosenthal, G.J, (1992). "Risk Assessment in Immunotoxicology I: Sensitivity and Predictability of Immune Tests." Fundam, Appl. Toxicol., 18, 200-210. Measuring the immune response to a T-cell dependent immunogen is another particularly useful assay (Dean, J. H., House, R. V., and Luster, M.I. (2001). "Immunotoxicology: Effects of, and Responses to, Drugs and Chemicals." In Principles and Methods of Toxicology: Fourth Edition (A. W. Hayes, Ed.), pp. 1415-1450, Taylor & Francis, Philadelphia, Pennsylvania). In one embodiment, a decrease in the expression of glucocorticoid receptors in PBMCs indicates impairment of immune function. A patient in need of immunosuppression is within the judgement of a physician, and can include patients with immune or inflammatory disorders. In one embodiment, patients that have undergone or will be undergoing an organ, tissue, bone marrow, or stem cell transplantation are in need of immunosuppression to prevent inflammation and/or rejection of the transplanted organ or tissue.
The compounds of this invention can be used to treat subjects with immune disorders. As used herein, the term "immune disorder" and like terms means a disease, disorder or condition caused by the immune system of an animal, including autoimmune disorders. Immune disorders include those diseases, disorders or conditions that have an immune component and those that are substantially or entirely immune system-mediated. Autoimmune disorders are those wherein the animal's own immune system mistakenly attacks itself, thereby targeting the cells, tissues, and/or organs of the animal's own body. For example, the autoimmune reaction is directed against the nervous system in multiple sclerosis and the gut in Crohn's disease. In other autoimmune disorders such as systemic lupus erythematosus (lupus), affected tissues and organs may vary among individuals with the same disease. One person with lupus may have affected skin and joints whereas another may have affected skin, kidney, and lungs. Ultimately, damage to certain tissues by the immune system may be permanent, as with destruction of insulin-producing cells of the pancreas in Type 1 diabetes mellitus. Specific autoimmune disorders that may be ameliorated using the compounds and methods of this invention include without limitation, autoimmune disorders of the nervous system (e.g., multiple sclerosis, myasthenia gravis, autoimmune neuropathies such as Guillain-Barre, and autoimmune uveitis), autoimmune disorders of the blood (e.g., autoimmune hemolytic anemia, pernicious anemia, and autoimmune thrombocytopenia), autoimmune disorders of the blood vessels (e.g., temporal arteritis, anti-phospholipid syndrome, vasculitides such as Wegener's granulomatosis, and Behcet's disease), autoimmune disorders of the skin (e.g., psoriasis, dermatitis herpetiformis, pemphigus vulgaris, and vitiligo), autoimmune disorders of the gastrointestinal system (e.g., Crohn's disease, ulcerative colitis, primary biliary cirrhosis, and autoimmune hepatitis), autoimmune disorders of the endocrine glands (e.g., Type 1 or immune-mediated diabetes mellitus, Grave's disease. Hashimoto's thyroiditis, autoimmune oophoritis and orchitis, and autoimmune disorder of the adrenal gland); and autoimmune disorders of multiple organs (including connective tissue and musculoskeletal system diseases) (e.g., rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, spondyloarthropathies such as ankylosing spondylitis, and Sjogren's syndrome). In addition, other immune system mediated diseases, such as graft-versus-host disease and allergic disorders, are also included in the definition of immune disorders herein. Because a number of immune disorders are caused by inflammation, there is some overlap between disorders that are considered immune disorders and inflammatory disorders. For the purpose of this invention, in the case of such an overlapping disorder, it may be considered either an immune disorder or an inflammatory disorder. "Treatment of an immune disorder" herein refers to administering a compound represented by any of the formulas disclosed herein to a subject, who has an immune disorder, a symptom of such a disease or a predisposition towards such a disease, with the purpose to cure, relieve, alter, affect, or prevent the autoimmune disorder, the symptom of it, or the predisposition towards it.
As used herein, the term "allergic disorder" means a disease, condition or disorder associated with an allergic response against normally innocuous substances. These substances may be found in the environment (such as indoor air pollutants and aeroallergens) or they may be non-environmental (such as those causing dermatological or food allergies). Allergens can enter the body through a number of routes, including by inhalation, ingestion, contact with the skin or injection (including by insect sting). Many allergic disorders are linked to atopy, a predisposition to generate the allergic antibody IgE. Because IgE is able to sensitize mast cells anywhere in the body, atopic individuals often express disease in more than one organ. For the purpose of this invention, allergic disorders include any hypersensitivity that occurs upon re-exposure to the sensitizing allergen, which in turn causes the release of Inflammatory mediators. Allergic disorders include without limitation, allergic rhinitis (e.g., hay fever), sinusitis, rhinosinusitis, chronic or recurrent otitis media, drug reactions, insect sting reactions, latex reactions, conjunctivitis, urticaria, anaphylaxis and anaphylactoid reactions, atopic dermatitis, asthma and food allergies.
As used herein, the term "asthma" means a pulmonary disease, disorder or condition characterized by reversible airway obstruction, airway inflammation, and increased airway responsiveness to a variety of stimuli.
Compounds represented by any of the formulas disclosed herein can be used to prevent or to treat subjects with inflammatory disorders. As used herein, an "inflammatory disorder" means a disease, disorder or condition characterized by inflammation of body tissue or having an inflammatory component. These include local inflammatory responses and systemic inflammation. Examples of such inflammatory disorders include: transplant rejection, including skin graft rejection; chronic inflammatory disorders of the joints, including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption; inflammatory bowel diseases such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease; inflammatory lung disorders such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease; inflammatory disorders of the eye including corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis; chronic inflammatory disorders of the gums, including gingivitis and periodontitis; tuberculosis; leprosy; inflammatory diseases of the kidney including uremic complications, glomerulonephritis and nephrosis; inflammatory disorders of the skin including sclerodermatitis, psoriasis and eczema; inflammatory diseases of the central nervous system, including chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS-related neurodegeneration and Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and viral or autoimmune encephalitis; autoimmune disorders, immune-complex vasculitis, systemic lupus and erythematodes; systemic lupus erythematosus (SLE); and inflammatory diseases of the heart such as cardiomyopathy, ischemic heart disease hypercholesterolemia, atherosclerosis; as well as various other diseases with significant inflammatory components, including preeclampsia; chronic liver failure, brain and spinal cord trauma. There may also be a systemic inflammation of the body, exemplified by gram-positive or gram negative shock, hemorrhagic or anaphylactic shock, or shock induced by cancer chemotherapy in response to pro-inflammatory cytokines, e.g., shock associated with pro-inflammatory cytokines. Such shock can be induced, e.g., by a chemotherapeutic agent used in cancer chemotherapy. "Treatment of an inflammatory disorder" herein refers to administering a compound or a composition of the invention to a subject, who has an inflammatory disorder, a symptom of such a disorder or a predisposition towards such a disorder, with the purpose to cure, relieve, alter, affect, or prevent the inflammatory disorder, the symptom of it, or the predisposition towards it.
As used herein, the term "pharmaceutically acceptable salt," is a salt formed from, for example, an acid and a basic group of one of the compounds of formula (I)-(XL), and those set forth in Tables 1-5. Illustrative salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, besylate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, beπzoate, glutamate, methaπesulfoπate, ethanesulfonate, beπzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3- naphthoate)) salts. The term "pharmaceutically acceptable salt" also refers to a salt prepared from a compound of formula (I)-(XL)1 and those set forth in Tables 1-5, having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N- ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-
(hydroxymethyl)methylamine, N, N,-di-lower alkyl-N-(hydroxy lower alkyl)-amιnes, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethy!)amine; N-methyl-D-glucamine; and amino acids such as arginiπe, lysine, and the like. The term "pharmaceutically acceptable salt" also refers to a salt prepared from a compound of formula (I)-(XL), and those set forth in Tables 1-5, having a basic functional group, such as an amine functional group, and a pharmaceutically acceptable inorganic or organic acid.. Suitable acids include, but are not limited to, hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), nitric acid, hydrogen bisulfide, phosphoric acid, lactic acid, salicylic acid, tartaric acid, bitartratic acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
As used herein, the term "pharmaceutically acceptable solvate," is a solvate formed from the association of one or more pharmaceutically acceptable solvent molecules to one of the compounds of formula (I)-(XL), and those set forth in Tables 1-5. The term solvate includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).
A pharmaceutically acceptable carrier may contain inert ingredients which do not unduly inhibit the biological activity of the compounds. The pharmaceutically acceptable carriers should be biocompatible, i.e., non-toxic, non-inflammatory, non-immunogenic and devoid of other undesired reactions upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed, such as those described in Remington's Pharmaceutical Sciences, ibid. Suitable pharmaceutical carriers for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing about 0.9% mg/ml benzyl alcohol), phosphate-buffered saline, Hank's solution, Ringer's-lactate and the like. Methods for encapsulating compositions (such as in a coating of hard gelatin or cyclodextran) are known in the art (Baker, ef a/., "Controlled Release of Biological Active Agents", John Wiley and Sons, 1986). As used herein, the term "effective amount" refers to an amount of a compound of this invention which is sufficient to reduce or ameliorate the severity, duration, progression, or onset of a disease or disorder, e.g. a proliferative disorder, prevent the advancement of a disease or disorder, e.g. a proliferative disorder, cause the regression of a disease or disorder, e.g. a proliferative, prevent the recurrence, development, onset or progression of a symptom associated with a disease or disorder, e.g. a proliferative disorder, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy. The precise amount of compound administered to a subject will depend on the mode of administration, the type and severity of the disease or condition and on the characteristics of the subject, such as genera) health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of cell proliferation, and the mode of administration. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When co-administered with other agents, e.g., when co-administered with an anti-cancer agent, an "effective amount" of the second agent will depend on the type of drug used. Suitable dosages are known for approved agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the invention being used. In cases where no amount is expressly noted, an effective amount should be assumed.
Non-limiting examples of an effective amount of a compound of the invention are provided herein below. In a specific embodiment, the invention provides a method of preventing, treating, managing, or ameliorating a proliferative disorder or one or more symptoms thereof, said methods comprising administering to a subject in need thereof a dose of at least 150 μg/kg, preferably at least 250 μg/kg, at least 500 μg/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at least 200 mg/kg or more of one or more compounds of the invention once every day, preferably, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 10 days, once every two weeks, once every three weeks, or once a month.
The dosages of a chemotherapeutic agents other than compounds of the invention, which have been or are currently being used to prevent, treat, manage, or ameliorate a proliferative disorder, or one or more symptoms thereof, can be used in the combination therapies of the invention. Preferably, dosages lower than those which have been or are currently being used to prevent, treat, manage, or ameliorate a proliferative disorder, or one or more symptoms thereof, are used in the combination therapies of the invention. The recommended dosages of agents currently used for the prevention, treatment, management, or amelioration of a proliferative disorder, or one or more symptoms thereof, can obtained from any reference in the art including, but not limited to, Hardman et a/., eds., 1996, Goodman & Gilman's The Pharmacological Basis Of Basis Of Therapeutics 9th Ed, Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57th Ed., 2003, Medical Economics Co., Inc., Montvale, NJ, which are incorporated herein by reference in its entirety.
As used herein, the terms "treat", "treatment" and "treating" refer to the reduction or amelioration of the progression, severity and/or duration of a disease or disorder, e.g. a proliferative disorder, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of a disease or disorder, e.g. a proliferative disorder resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as a compound of the invention). In specific embodiments, the terms "treat", "treatment" and "treating" refer to the amelioration of at least one measurable physical parameter of a disease or disorder, e.g. a proliferative disorder, such as growth of a tumor, not necessarily discernible by the patient. In other embodiments the terms "treat", "treatment" and "treating" refer to the inhibition of the progression of a disease or disorder, e.g. a proliferative disorder, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both. In other embodiments the terms "treat", "treatment" and "treating" refer to the reduction or stabilization of tumor size or cancerous cell count.
As used herein, the terms "prevent", "prevention" and "preventing" refer to the reduction in the risk of acquiring or developing a given disease or disorder, e.g. a proliferative disorder, or the reduction or inhibition of the recurrence or a disease or disorder, e.g. a proliferative disorder. In one embodiment, a compound of the invention is administered as a preventative measure to a patient, preferably a human, having a genetic predisposition to any of the disorders described herein.
As used herein, the terms "therapeutic agent" and "therapeutic agents" refer to any agent(s) which can be used in the treatment, management, or amelioration of a disease or disorder, e.g. a proliferative disorder or one or more symptoms thereof. In certain embodiments, the term "therapeutic agent" refers to a compound of the invention. In certain other embodiments, the term "therapeutic agent" refers does not refer to a compound of the invention. Preferably, a therapeutic agent is an agent which is known to be useful for, or has been or is currently being used for the treatment, management, prevention, or amelioration a disease or disorder, e.g. a proliferative disorder or one or more symptoms thereof. As used herein, the term "synergistic" refers to a combination of a compound of the invention and another therapy (e.g., a prophylactic or therapeutic agent), which is more effective than the additive effects of the therapies A synergistic effect of a combination of therapies (e g , a combination of prophylactic or therapeutic agents) permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a subject with a disease or disorder, e g a proliferative disorder The ability to utilize lower dosages of a therapy (e g , a prophylactic or therapeutic agent) and/or to administer said therapy less frequently reduces the toxicity associated with the administration of said therapy to a subject without reducing the efficacy of said therapy in the prevention, management or treatment of a disease or disorder, e g a proliferative disorder In addition, a synergistic effect can result in improved efficacy of agents in the prevention, management or treatment of a disease or disorder, e g a proliferative disorder Finally, a synergistic effect of a combination of therapies (e g , a combination of prophylactic or therapeutic agents) may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone
As used herein, the phrase "side effects" encompasses unwanted and adverse effects of a therapy (e g , a prophylactic or therapeutic agent) Side effects are always unwanted, but unwanted effects are not necessarily adverse An adverse effect from a therapy (e g , prophylactic or therapeutic agent) might be harmful or uncomfortable or risky Side effects include, but are not limited to fever, chills, lethargy, gastrointestinal toxicities (including gastric and intestinal ulcerations and erosions), nausea, vomiting, neurotoxicities, nephrotoxicities, renal toxicities (including such conditions as papillary necrosis and chronic interstitial nephritis), hepatic toxicities (including elevated serum liver enzyme levels), myelotoxicities (including leukopenia, myelosuppression, thrombocytopenia and anemia), dry mouth, metallic taste, prolongation of gestation, weakness, somnolence, pain (including muscle pain, bone pain and headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms, akathisia, cardiovascular disturbances and sexual dysfunction
As used herein, the term "in combination" refers to the use of more than one therapies (e g , one or more prophylactic and/or therapeutic agents) The use of the term "in combination" does not restrict the order in which therapies (e g , prophylactic and/or therapeutic agents) are administered to a subject with a proliferative disorder A first therapy (e g , a prophylactic or therapeutic agent such as a compound of the invention) can be administered prior to (e g , 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e g , 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e g , a prophy lactic or therapeutic agent such as an anti-cancer agent) to a subject with a proliferative disorder, such as cancer.
As used herein, the terms "therapies" and "therapy" can refer to any protocol(s), method(s), and/or agent(s) that can be used in the prevention, treatment, management, or amelioration of a proliferative disorder or one or more symptoms thereof.
A used herein, a "protocol" includes dosing schedules and dosing regimens. The protocols herein are methods of use and include prophylactic and therapeutic protocols.
As used herein, the terms "manage," "managing," and "management" refer to the beneficial effects that a subject derives from a therapy (e.g., a prophylactic or therapeutic agent), which does not result in a cure of the disease. In certain embodiments, a subject is administered one or more therapies (e.g., one or more prophylactic or therapeutic agents) to "manage" a disease so as to prevent the progression or worsening of the disease.
As used herein, a composition that "substantially" comprises a compound means that the composition contains more than about 80% by weight, more preferably more than about 90% by weight, even more preferably more than about 95% by weight, and most preferably more than about 97% by weight of the compound.
As used herein, a reaction that is "substantially complete" means that the reaction contains more than about 80% by weight of the desired product, more preferably more than about 90% by weight of the desired product, even more preferably more than about 95% by weight of the desired product, and most preferably more than about 97% by weight of the desired product.
As used herein, a racemic mixture means about 50% of one enantiomer and about 50% of is corresponding enantiomer relative to a chiral center in the molecule. The invention encompasses all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures of the compounds of the invention.
Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or diastereomers by well known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods. The compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
When administered to a patient, e.g., to a non-human animal for veterinary use or for improvement of livestock, or to a human for clinical use, the compounds of the invention are administered in isolated form or as the isolated form in a pharmaceutical composition. As used herein, "isolated" means that the compounds of the invention are separated from other components of either (a) a natural source, such as a plant or cell, preferably bacterial culture, or (b) a synthetic organic chemical reaction mixture. Preferably, the compounds of the invention are purified via conventional techniques. As used herein, "purified" means that when isolated, the isolate contains at least 95%, preferably at least 98%, of a compound of the invention by weight of the isolate either as a mixture of stereoisomers or as a diastereomeric or enantiomeric pure isolate.
As used herein, a composition that Is "substantially free" of a compound means that the composition contains less than about 20% by weight, more preferably less than about 10% by weight, even more preferably less than about 5% by weight, and most preferably less than about 3% by weight of the compound.
Only those choices and combinations of substituents that result in a stable structure are contemplated. Such choices and combinations will be apparent to those of ordinary skill in the art and may be determined without undue experimentation.
The invention can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non-limiting embodiments of the invention. B. The Compounds of the Invention
The present invention emcompasses compounds having Formulas (I)-(XL), and those set forth in Tables 1-5, and tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof.
Compounds of formulas (I)-(XL)1 and those set forth in Tables 1-5, inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formulas (I)-(XL), and those set forth in Tables 1-5, are particularly useful in treating cancer when given in combination with another anti-cancer agent. In one embodiment, the invention provides compounds of formula (I) as set forth below:
Figure imgf000067_0001
(I) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and Riι Ra, R3, R5, and R6 are defined above.
In another embodiment, the invention provides compounds of formula (II) as set forth below:
Figure imgf000067_0002
(II)
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and R40, R41, X41, X41, Y40, Y41. and Y42 are defined above. In another embodiment, the invention provides compounds of formula (III) as set forth below:
Figure imgf000068_0001
(III) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R39, R41, R42, R43, R45, and X42 are defined as above.
In another embodiment, the invention provides compounds of formula (IV) as set forth below:
Figure imgf000068_0002
(IV) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, and R39, R521 R53. R55. R561 and X45 are defined as above.
In one embodiment, the invention provides compounds of formula (V) as set forth below:
Figure imgf000069_0001
(V) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, wherein R'h R2, R'3l R'5l Z and n are defined as above. In one aspect, the compound of formula (V) is not:
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-amino-[1,2,4] triazole, 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-methoxy-phenyl)-5-amino-[1 ,2,4] triazole, 3-(2,4-Dihyd roxy-5-ethyl-phenyl)-4-(naphthalen-1 -yl)-5-amino-[1 ,2,4] triazole, 3-(2,4-Dihydroxy-phenyl)-4-phenyl-5-(sulfamoylamino)- [1 ,2,4] triazole, 3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-1-yl)-5-ureido-[1 ,2,4] triazole, 3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(2,3-difluorophenyl)-5-ureido-[1 ,2,4] triazole, 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-ureido-[1 ,2,4] triazole, 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(quinolin-5-yl)-5-ureido-[1 ,2,4] triazole,
3-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-(3-methyl-quinolin-5-yl)-5-carboxyamino-[1 ,2,4] triazole,
3-(2,4-Dihydroxy-phenyl)-4-(1-methyl~2-chloro-indol-4-yl)-5-carbamoyloxy-[1,2,4] triazole,
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-[3,5-di-(trifluoromethyl)-phenyl]-5-carbamoyloxy- [1 ,2,4] triazole,
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(3-trifluoromethyl-phenyl)-5-(sulfamoylamino)- [1 ,2,4] triazole,
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-1-yl)-5-(sulfamoylamino)- [1 ,2,4] triazole,
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(1-isopropyl-benzoimidazol-4-yl)-5-(sulfamoylamino)- [1 ,2,4] triazole, or 3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(3-isopropylphenyl)-5-(thiocarboxyamino)- [1,2,4] triazole.
In one embodiment, the invention provides compounds of formula (Vl) as set forth below:
Figure imgf000070_0001
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, wherein R\, R∑, R'3, R'5, and R6 are defined as above. In one embodiment, the invention provides compounds of formula (VII) as set forth below:
Figure imgf000070_0002
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, wherein R'4O, R41, X41, X«, Y40, Y 41, and Y42 are defined as above.
In one embodiment, the invention provides compounds of formula (VIII) as set forth below:
Figure imgf000071_0001
(VIII) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, and R'40, R41, R42, R43, R45, and X42 are defined as above. In one embodiment, the invention provides compounds of formula (IX) as set forth below:
Figure imgf000071_0002
(IX) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, and R'40, Rs2, R53, R55. R56, and X45 are defined as above.
In one embodiment, the invention provides compounds of formula (X) as set forth below:
Figure imgf000072_0001
(X) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R60, R41 and R42 are defined as above. In one embodiment, the invention provides compounds of formula (Xl) as set forth below:
Figure imgf000072_0002
(Xl) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, R'5, R'e, R'17, Ri8, R19 and X are defined above.
In one aspect of compounds of formula (Xl), the compound is not 3-(2-Hydroxy-4-methoxymethyoxy-phenyl)-4-(naphthalen-1 -yl)-5-mercapto-[1 ,2,4] triazole; 3-[2-Hydroxy-4-(2-hydroxy-ethoxy)-phenyl]-4-(naphthalen-1-yl)-5-mercapto-[1 ,2,4] triazole;
3-[2,4-Di-(dimethyl-carbamoyloxy)-phenyl]-4-(naphthalen-1-yl)-5-(dimethyl- carbamoylsulfanyl)- [1 ,2,4] triazole;
3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-1-yl)-5-(dimethylcarbamoylsulfanyl)- [1 ,2,4] triazole;
3-(2,4-Diethoxycarbonyloxy-phenyl)-4-(naphthalen-1 -yl)-5-(ethoxycarbonylsulfanyl)- [1 ,2,4] triazole;
3-(2,4-Di-isobutyryloxy-phenyl)-4-(naphthalen-1-yl)-5-(isobutyrylsulfanyl)- [1 ,2,4] triazole; 3-[2,4-Di-(dimethyl-carbamoyloxy)-phenyl]-4-(quinolin-5-yl)-5-(climethyl-carbamoylsulfanyl)- [1 ,2,4] triazole;
3-(2,4-Diacetoxy-phenyl)-4-(naphthalen-1 -yl)-5-(acetylsulfany!)- [1 ,2,4] triazole; 3-(2,4-Diacetoxy-phenyl)-4-(naphthalen-1 -yl)-5-mercapto-[1 ,2,4] triazole; 3-(2,4-Diethylcarbamoyloxy-phenyl)-4-(naphthalen-1 -yl)-5-(ethylcarbamoylsulfanyl)- [1 ,2,4] triazole;
3-(2,4-Dihydroxy-5-ethyl-pheπyl)-4-(3-trifluoromethyl-phenyl)-5-carbamoyloxy-[1 ,2,4] triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-( 1 -methyl-indol-4-yl)-5-carbamoyloxy-[1 ,2,4] triazole; 3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(8-methoxy-quinolin-5-yl)-5-carbamoyloxy-[1 ,2,4] triazole;
3-(2-Hydroxy-4-ethoxycarbonyoxy-5-methoxy-phenyl)-4-(1-isopropyl-benzoimidazol-4-yl)-5- hydroxy-[1 ,2,4] triazole;
3-(2-Hydroxy-4-ethoxycarbonyoxy-5-ethyl-phenyl)-4-(naphthalin-2-yl)-5-hydroxy-[1 ,2,4] triazole;
3-[2-Hydroxy-4-(dimethyl-carbamoyoxy)-5-ethyl-phenylH-(naphthaliπ-2-yl)-5-hydroxy-[1,2,4] triazole;
S-^-Hydroxy^dimethyl-carbamoyoxyJ-S-chloro-phenyO-^^quinolin-S-yO-δ-mercapto- [1,2,4] triazole; 3-[2-Hydroxy-4-(dimethyl-carbamoyoxy)-5-ethyl-phenyl]-4-(2,3-difluoro-phenyl)-5-mercapto- [1 ,2,4] triazole; or
3-[2-Hydroxy-4-isobutyryloxy-5-ethyl-phenyl]-4-(1-methyl-benzo-imida∑ol-4-yl)-5-hydroxy- [1 ,2,4] triazole.
In one embodiment, the invention provides compounds of formula (XII) as set forth below:
Figure imgf000074_0001
(XII) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and R'β, R1U. Ri8, and R19 are defined as above. In one embodiment, the invention provides compounds of formula (XIII) as set forth below:
Figure imgf000074_0002
(XIII)
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and R'6, Ri8 and R19 are defined as above.
In one embodiment, the invention provides compounds of formula (XIV) as set forth below:
Figure imgf000075_0001
(XIV) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and X', R'2l RJ 3, R'5 and R'6 are defined as above.
In one embodiment, the invention provides compounds of formula (XV) as set forth below:
Figure imgf000075_0002
(XV) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, R70, R'2, R'3. R's. and R20 are defined as above.
In one embodiment, the invention provides compounds of formula (XVI) as set forth below:
Figure imgf000076_0001
(XVI) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and R'_, R'6, X , Xi, R71 and R72 are defined as above.
In one embodiment, the invention provides compounds of formula (XVII) as set forth below:
Figure imgf000076_0002
(XVIl) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and R'5, R'6, R23, R24 and R25 are defined as above.
In one embodiment, the invention provides compounds of formula (XVIII) as set forth below:
Figure imgf000077_0001
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and R23, R41, X1, X41,X 42,Y40,Y 41and Y424 are defined as above.
In one embodiment, the invention provides compounds of formula (XIX) as set forth below:
Figure imgf000077_0002
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and R23, R<»i, R42, R43, R45, Xi, and X42 are defined as above.
In one embodiment, the invention provides compounds of formula (XX) as set forth below:
Figure imgf000078_0002
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, and F*23> R52. R53, R55, R56, Xi, and X45 are defined as above.
In one aspect, the invention provides compounds of formula (XXI):
Figure imgf000078_0001
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is optionally further substituted with one or two independently selected substituents in addition to R3; ring E is aromatic or non-aromatic; X16 is -0-, -NR7-, or -S-;
Y is -(CR38R1 M)Ir, -C(O)-, -C(S)-, -C(NR8)-, -CR7=, -0-, -NR7-, -N=, or -S;
Z' ιs -(CR3BR'39)k-, 3CR7-, -O-, -S-, -NR7-, =N-, Or -CRV=CRV;
R1 and R3 are each, independently, -OH, -SH, -NR7H, -OR'26, -SR'26, -O(CH2)mOH, -O(CH2)mSH, -0(CH2)JMR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Ri1, -NR7CH2C(O)NR10R11, -0S(0)pR7l -SS(0)pR7, -S(O)POR7, -NR7S(O)pR7l -OS(O)PNR10R11, -SS(O)PNR10R11, -NRTS(O)pNR10Rii, -0S(0)p0R7, -SS(0)p0R7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NR8)NR10R11, -OP(O)(OR7J2, or -SP(O)(OR7)2; R'δ is an optionally substituted aryl or an optionally substituted heteroaryl; R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; Rio and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R'26l for each occurrence is, independently, a C1-C6 alkyl; R38 and R'39) for each occurrence, are independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR10Ri1, -OR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)NR10R11, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R1I, -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(O)R7, -SC(O)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NR10R11, -OC(S)NR10R11, -OC(NR8)NR10R11, -SC(O)NR10Ri1, -SC(NR8)NR10R11, -SC(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -C(O)NRi0R11, -NR8C(O)R7, -NR7C(S)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(O)OR7, -NR7C(NR8)OR7, -NR7C(O)NR10R11, -NR7C(S)NRi0R11, -NR7C(NR8)NRI0RH, -SR7, -S(O)pR7, -0S(O)pR7, -OS(O)pOR7l -OS(O)PNR10R11, -S(O)POR7, -NRBS(O)PR7, -NR7S(O)PNR10R11, -NR7S(O)pOR7, -S(O)pNR,0Rn, -SS(O)PR7, -SS(O)POR7, -SS(O)pNR10Rn, -OP(O)(OR7)2> or -SP(O)(OR7J2; or R38 and R'39 together with the carbon or carbon atoms to which they are attached form a three to eight rnembered cycloalkyl or a three to eight membered cycloalkenyl; R'4o and R'4i, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R'4O and R'41, together with the carbon atoms to which they are attached form a three to eight membered cycloalkenyl; p, for each occurrence, is, independently, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4; and k is 1 or 2; provided that when R'5 is p-chlorophenyl, rings A and E together are not benzofuranyl.
In another embodiment, in compounds represented by formula (XXI)1 or any of the embodiments of formula (XXI) in which particular groups are disclosed, the compound is structural formula (XXII);
Figure imgf000080_0001
(XXII) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof; wherein Ri, R3, R'5, R 40, R'41 and X16 are defined as above.
In another embodiment, in compounds represented by formula (XXI), or any of the embodiments of formula (XXI) in which particular groups are disclosed, the compound is represented by structural formula (XXIII):
Figure imgf000080_0002
(XXIII) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein Ri, R3, R's, X16, and Z1 are defined as above.
In another embodiment, in compounds represented by formula (XXI), or any of the embodiments of formula (XXI) in which particular groups are disclosed, the compound is represented by structural formula (XXIV):
Figure imgf000081_0001
(XXIV) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein the dashed line is a single or a double bond; and R1, R3, R'5, R'40 and R'41 are defined as above.
In another embodiment, in compounds represented by formula (XXI), or any of the embodiments of formula (XXI) in which particular groups are disclosed, the compound is represented by structural formula (XXV):
Figure imgf000081_0002
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein R1, R3, R'5, R38, R'__, Xiβi and Z' are defined as above. In another embodiment, in compounds represented by formula (XXI), or any of the embodiments of formula (XXI) in which particular groups are disclosed, the compound is represented by structural formula (XXVI):
Figure imgf000082_0001
(XXVI) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein Ri, R3, R'5, R7 and X16 are defined as above.
In another embodiment, in compounds represented by formula (XXI), or any of the embodiments of formula (XXI) in which particular groups are disclosed, the compound is represented by structural formula (XXVIl):
Figure imgf000082_0002
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein Ri, R3, R'5, R7 and X16 is defined as above.
In one embodiment, the present invention provides compounds represented by structural formula (XXVIII):
Figure imgf000083_0001
(XXVIII) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, wherein Ring F, Ring G, R100, Rio3,Ti, T2, V1, and V2 are defined as above.
In specific embodiments of compounds of formula (XXVIII), when T1, Tz and V1 are absent and V2 is -NRaRb then ring G is not phenyl, and when T1, T2 and V1 are absent and V2 is -C(O)NRaRb then ring G is not naphthyl or indolyl.
In another embodiment, the present invention provides compounds represented by a structural formula selected from (XXIX) and (XXX):
Figure imgf000083_0002
(XXIX) (XXX) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, wherein Ring G, R100, R103, R'22, R'23, R'24, R74, f, Xu, T1, T2, V1, and V2 are defined as above.
In specific embodiments, the present invention provides compounds represented by a structural formula represented by (XXXI) or (XXXII):
Figure imgf000084_0001
(XXXI) (XXXII) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof:
X3 and X4 are each, independently, N, N(O), N+(R75) CH or CR73. X5 is O, S, NR75, CH2, CH(R73), C(R73)2, CH=CH, CH=CR73, CR73=CH, CR73=CR73, CH=N, CR73=N, CH=N(O), CR73=N(O), N=CH, N=CR73, N(O)=CH, N(O)=CR73, N+(R75)=CH, N+(R7S)=CR73, CH=N+(R75), CR73=N+(R75) or N=N, provided that at least one X3, X. or X5 is a heteroatom;
Each R73 and R74, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkeπyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR10Ri1, -OR7, -SR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)NR10R11, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(O)R7, -SC(O)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NR10Rn, -OC(S)NR10R11, -OC(NR8)NR10R11, -SC(O)NR10R11, -SC(NR8)NR10Rii, -SC(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -C(O)NR10R11, -NR7C(O)R7, -NR7C(S)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Rii, -NR7CH2C(O)NR10R11, -NR7C(NR8)OR7, -NR7C(O)NR10R11, -NR7C(S)NR10R11, -NR7C(NRS)NR10R1I, -SR7, -S(O)PR7, -0S(0)PR7, -OS(O)POR7, -OS(O)PNR10R11, -S(O)pOR7, -NR8S(O)PR7l -NR7S(O)PNR10R11, -NR7S(O)POR7, -S(O)PNR10R11, -SS(O)PR7, -SS(O)pOR7, -SS(O)PNR10R11, -OP(0)(OR7)2, or -SP(O)(OR7)2
R75, for each occurrence, is independently an alkyl or an aralkyl; and the values for the remainder of the variables are as described above. In one embodiment the present invention provides compounds represented by structural formula (XXXIII) or (XXXIV):
Figure imgf000085_0001
(XXXIII) (XXXIV). or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof; wherein
R'25 for each occurence is independently a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, -OH, -SH, -NHR7, -(CH2)bOH, -(CHz)bSH, -(CH2)bNR7H, -OCH3, -SCH3, -NHCH3, -OCH2CH2OH, -OCH2CH2SH, -OCH2CH2NR7H, -SCH2CH2OH, -SCH2CH2SH, -SCH2CH2NR7H, -OC(O)NR10R11, -SC(O)NR10Rn, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -NR7S(O)pR7, -OS(O)PNR10R11, -SS(O)pNR10R,i, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)pOR7l -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R1I, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10Rn, -NR7C(NR8)NR10R11, -C(O)R7, -C(O)OR7, -C(O)NR10Rn, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10Rn, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -S(0)POR7, -S(O)pNR10Rn, or -S(O)PR7; b is 1 , 2, 3, or 4 e and f for each occurrence, is independently an integer from O to 4; and x is O or 1 , provided that e+x is less than or equal to 4; and the values for the remainder of the variables are as described above.
In another embodiment, the present invention provides compounds represented by structural formula (XXXV):
or 1
Figure imgf000085_0002
(XXXV). or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, wherein values for the variables are as described above.
In another embodiment, the present invention provides compounds represented by structural formula (XXXVI):
or 1
Figure imgf000086_0001
(XXXVI) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof; wherein values for the variables are as described above.
In another embodiment, the present invention provides compounds represented by structural formula (XXXVII):
w 1
Figure imgf000086_0002
(XXXVII) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof; wherein values for the variables are as described above.
In another embodiment, the present invention provides compounds represented by structural formula (XXXVIII):
Cf 1
Figure imgf000087_0001
(XXXVIII) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof; wherein values for the variables are as described above.
In another embodiment, the present invention provides compounds represented by a structural formula selected from (XXXIX) and ((XL):
Figure imgf000087_0002
(XXXIX) and
Figure imgf000087_0003
(XL) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof; wherein values for the variables are as described above.
In one embodiment, in the compounds represented by formula (I), R5 is represented by the following formula:
Figure imgf000088_0001
wherein:
Rg, for each occurrence, is independently a substitueπt selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)pR7, -OS(O )pR7, -S(O)pOR7, -NR8S(O)PR7, or -S(O)PNR10R1,, -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(0R7)2; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and q is zero or an integer from 1 to 7.
In another embodiment, in the compounds represented by formula (I), R5 is represented by the following formula:
Figure imgf000088_0002
wherein: q is zero or an integer from 1 to 5; and u is zero or an integer from 1 to 5. In another embodiment, in the compounds represented by formula (I), R5 is represented by the following formula:
Figure imgf000089_0001
wherein;
R33 is a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl; R34 is H, a lower alkyl, or a lower alkylcarbonyl; and
Ring B and Ring C are optionally substituted with one or more substituents.
In another embodiment, in the compounds represented by formula (I), R5 is selected from the group consisting of:
Figure imgf000089_0002
Figure imgf000090_0001
wherein
X5, for each occurrence, is independently CH, CR9, N, N(O)1 N+(R17), provided that at least three X6 groups are independently selected from CH and CR9,
X7, for each occurrence, is independently CH, CRg, N, N(O), N+(R17), provided that at least three X7 groups are independently selected from CH and CRg,
X8, for each occurrence, is independently CH2, CHR9, C(Rg)2, S, S(O)p, NR7, or NR17, X9, for each occurrence, is independently N or CH,
X10, for each occurrence, is independently CH, CR9, N, N(O), N+(Ri7), provided that at least one X10 is selected from CH and CR8, R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl,
-NR10RiI, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)pR7, -OS(O)pR7, -S(O)POR7, -NR8S(O)PR7, or -S(O)pNR10Rii. -S(0)p0R7, -OP(0)(OR7)2, or -SP(0)(OR7)2l -S(O)POR7, -OP(O)(OR7)* or -SP(O)(OR7)2, or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring, and
R17, for each occurrence, is independently -H, an alkyl, an aralkyl, -C(O)R7, -C(O)OR7, or -C(O)NR10R11
In another embodiment, in the compounds represented by formula (I), R5 is an optionally substituted indolyl, an optionally substituted benzoimidazolyl, an optionally substituted indazolyl, an optionally substituted 3H-ιndazolyl, an optionally substituted indoliziπyl, an optionally substituted qumoliπyl, an optionally substituted isoquinolinyl, an optionally substituted benzoxazolyl, an optionally substituted benzo[1,3]dιoxolyl, an optionally substituted benzofuryl, an optionally substituted benzothiazolyl, an optionally substituted benzo[d]ιsoxazolyl, an optionally substituted benzo[d]ιsothιazolyl, an optionally substituted thιazolo[4,5-c]pyrιdιnyl, an optionally substituted thιazolo[5,4-c]pyrιdιnyl, an optionally substituted thιazolo[4,5-b]pyrιdιnyl, an optionally substituted thιazolo[5,4- b]pyrιdιnyl, an optionally substituted oxazolo[4,5-c]pyrιdιnyl, an optionally substituted oxazolo[5,4-c]pyπdιnyl, an optionally substituted oxazolo[4,5-b]pyπdιnyl, an optionally substituted oxazolo[5,4-b]pyrιdιnyl,an optionally substituted imidazopyridinyl, an optionally substituted benzothiadiazolyl, benzoxadiazolyl, an optionally substituted benzotπazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azamdolyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted imidazo[4,5-a]pyridinyl, an optionally substituted imidazo[1 ,2-a]pyridinyl, an optionally substituted 3W-imidazo[4,5-b]pyridinyl, an optionally substituted 1/-/-imidazo[4,5-b]pyridinyl, an optionally substituted 1/-/-imidazo[4,5-c]pyridinyl, an optionally substituted ZH- imidazo[4,5-c]pyridinyl, an optionally substituted pyridopyrdazinyl, and optionally substituted pyridopyrimidinyl, an optionally substituted pyrrolo[2,3]pyrimidyl, an optionally substituted pyrazolo[3,4]pyrimidyl an optionally substituted cyclopentaimidazolyl, an optionally substituted cyclopentatriazolyl, an optionally substituted pyrrolopyrazolyl, an optionally substituted pyrroloimidazolyl, an optionally substituted pyrrolotriazolyl, or an optionally substituted benzo(b)thienyl.
In another embodiment, in the compounds represented by formula (I)1 R5 is selected from the group consisting of;
Figure imgf000092_0001
wherein: X11, for each occurrence, is independently CH, CR3, N, N(O), or N+(R17), provided that at least two Xn groups are independently selected from CH and CR9;
X12, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least one X12 group is independently selected from CH and CR9;
X13, for each occurrence, is independently O, S1 S(O)p, NR7, or NR17; R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkyπyi, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a hydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Ri1, -NR6C(O)R7, -SR7, -S(O)PR7, -OS(O)pR7, -S(O)pOR7, -NR8S(O)pR7, or -S(O)PNR10R111 -S(O)POR71 -OP(O)(OR7)Z1 Or -SP(O)(OR7)2, -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(OR7)2; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
R17, for each occurrence, is independently an alkyl or an aralkyl. In another embodiment, in the compounds represented by formula (I), R5 is represented by the following formula:
Figure imgf000093_0001
wherein: X15, for each occurrence, is independently CH2, CHR7, or NR7,
In another embodiment, in the compounds represented by formula (I), R5 is represented by the following formula:
Figure imgf000093_0002
wherein: Z is a substituent; and n is 0, 1, 2, 3, 4, or 5. In one aspect, n is 1. In another aspect, n is 1 and Z is an optionally substituted alky!, an optionally substituted alkoxy, an amino, an alkyl amino, or a dialkyl amino.
In another embodiment, in the compounds represented by formula (I), R6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl.
In another embodiment, in the compounds represented by formula (I), R6 is -L-Rx, wherein L is an optionally substituted 1 to 6 atom linker, wherein each linker atom is independently selected from the group consisting of C, O, S or N; and Rx is an optionally substituted heteroaryl or an optionally substituted aryl In one aspect, Rx is an optionally substituted phenyl, an optionally substituted indolyl, an optionally substituted benzoimidazolyl, an optionally substituted indazolyl, an optionally substituted 3W-indazolyl, an optionally substituted indolizinyl, an optionally substituted quinolinyl, an optionally substituted isoquinolinyl, an optionally substituted benzoxazolyl, an optionally substituted benzo[1 ,3]dioxolyl, an optionally substituted benzofuryl, an optionally substituted beπzothiazolyl, an optionally substituted benzo[d]isoxazolyl, an optionally substituted benzo[d]isothiazo)yl, an optionally substituted thiazolo[4,5-c]pyridinyl, an optionally substituted thiazolo[5,4-c]pyridinyl, an optionally substituted thiazolo[4,5-b]pyridinyl, an optionally substituted thiazolo[5,4-b]pyridinyl, an optionally substituted oxazo)o[4,5- c]pyridinyl, an optionally substituted oxazolo[5,4-c]pyridiπyl, an optionally substituted oxazolo[4,5-b]pyridinyl, an optionally substituted oxazolo[5,4-b]pyridinyl,an optionally substituted imidazopyridinyl, an optionally substituted benzothiadiazolyl, benzoxadiazolyl, an optionally substituted benzotriazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted imidazo[4,5-a]pyridinyl, an optionally substituted imidazo[1,2-a]pyridinyl, an optionally substituted 3W-imidazo[4,5-b]pyridinyl, an optionally substituted 1/-/-imidazo[4,5-b]pyridinyl, an optionally substituted 1/-/-imidazo[4,5-c]pyridinyl, an optionally substituted 3H-imidazo[4,5-c]pyridinyl, an optionally substituted pyridopyrdazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyridopyrimidinyl, an optionally substituted pyrrolo[2,3]pyrimidyl, an optionally substituted pyrazolo[3,4]ρyrimidyl an optionally substituted cyclopentaimidazolyl, an optionally substituted cyclopentatriazolyl, an optionally substituted pyrrolopyrazolyl, an optionally substituted pyrroloimidazolyl, an optionally substituted pyrrolotriazolyl, or an optionally substituted benzo(b)thienyl. In another aspect, Rx is an optionally substituted phenyl. In one aspect, L is a C1-C4 alkylene.
In another embodiment, in the compounds represented by formula (I), Ri, R2, and R3 are each, independently, -OH, -SH, Or -NHR7.
In another embodiment, in the compounds represented by formula (I), R2 and R3 are each -OH. In another embodiment, in the compounds represented by formula (I)1 R6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfaπyl or a C3-C6 cycloalkyl; and R-i, R2, and R3 are each, independently, -OH or -SH.
In one embodiment, in the compounds represented by formula (II), X41 is NR42 and
X42 IS CR44. In another embodiment, in the compounds represented by formula (II), X41 is NR42 and X42 is N.
In another embodiment, in the compounds represented by formula (II), R41 is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy. In another embodiment, in the compounds represented by formula (II), R41 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
In another embodiment, in the compounds represented by formula (II), X41 is NR42, and R42 is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, -C(O)N(R27)2, and -C(O)OH, wherein each R27 is independently -H or a lower alkyl.
In another embodiment, in the compounds represented by formula (II), X4i is NR42, and R42 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, fert-butyl, n-pentyl, n-hexyl, -C(O)OH, -(CH2)mC(O)OH, -CH2OCH3, -CH2CH2OCH3, and -C(O)N(CH3)2.
In another embodiment, in the compounds represented by formula (II), R43 and R44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
In another embodiment, in the compounds represented by formula (II), X42 is CR44; Y40 is CR43; and R43 and R44 together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring.
In another embodiment, in the compounds represented by formula (II), R43 and R44 together with the carbon atoms to which they are attached form a C5-C6 cycloalkenyl or a C5-C8 aryl. In another embodiment, in the compounds represented by formula (II), R45 or CR45 is selected from the group consisting of -H, -OH, -SH, -NH2, a lower alkoxy, a lower alkyl amino, and a lower dialkyl amino.
In another embodiment, in the compounds represented by formula (II), R45 is selected from the group consisting of -H1 -OH, methoxy and ethoxy. In another embodiment, in the compounds represented by formula (II), X41 is O.
In another embodiment, in the compounds represented by formula (II), R40 is -OH or -SH.
In one embodiment, in the compounds represented by formula (III), X42 is CR44, and R43 and R44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. In another embodiment, in the compounds represented by formula (III), X42 is CR44, and R43 and R44, taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring.
In another embodiment, in the compounds represented by formula (111), R43 and R44, taken together with the carbon atoms to which they are attached, form a C5-C6 cycloalkenyl or a C5-C8 aryl. In another embodiment, in the compounds represented by formula (III), X42 is CR44 In another embodiment, in the compounds represented by formula (III), X42 is N
In another embodiment, the compound is selected from the group consisting of 2-Ethyl-6-[5-mercapto-4-(1-methyl-1H-indol-5-yl)-4H-[1 ,2,4]tnazol-3-yl]-pyridine-3,5-diol, 2-[5-Hydroxy-4-(1-methyl-1 H-indol-5-yl)-4H-[1,2,4]triazol-3-yl]-6-isopropyl-pyridine-3,5- cliol,
2-[4-(4-Dιmethylamιno-phenyl)-5-hydroxy-4H-[1 ,2,4]tπazol-3-yl]-6-ιsopropyl-pyπdιne-3,5- diol,
2-lsopropyl-6-[5-mercapto-4-(2-methoxy-ιndan-5-yl)-4H-[1,2,4]tπazol-3-yl]-pyrιdιne-3,5- diol,
2-[5-Mercapto-4-(4-methoxymethyl-phenyl)-4H-[1 ,2,4]tπazol-3-yl]-6-phenethyl-pyrιdιne- 3,5-dιol,
2-[4-(4-Dimethylamιnomethyl-phenyl)-5-hydroxy-4H-[1 ,2,4]trιazol-3-yl]- 6-phenethyl-pyrιdιne-3,5-dιol,
2-Ethyl-6-[5-hydroxy-4-(4-methoxy-benzyl)-4H-[1,2,4]trιazol-3-yl]-pyπdιne-3,5-dιol, 2-Cyclopropyl-6-[4-(4-dιmethylamιno-benzyl)-5-hydroxy-4H-[1 ,2,4]trιazol-3-yl]-pyπdιne- 3,5-dιol,
2-[5-Hydroxy-4-(1-methyl-2,3-dιhydro-1 H-ιndo)-5-yl)-4H-[1 ,2,4]trιazol-3-yl]-6-ιsopropyl- pyrιdιne-3,5-dιol,
2-{5-Hydroxy-4-[2-(2-methoxy-ethyl)-2,3-dιhydro-1H-ιsoιndol-5-ylHH-[1,2,4]trιazol-3-yl}- 6-ιsopropyl-pyπdιne-3,5-dιol, or
2-{5-Hydroxy-4-[2-(2-hydroxy-ethoxy)-ιndan-5-yl]-4H-[1,2,4]trιazol-3-yl}-6-ιsopropyl- pyπdιne-3,5-dιol,
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof
In one embodiment, in the compounds represented by formula (V) or (Vl)1 R'5 is represented by the following formula
Figure imgf000096_0001
wherein R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkyπyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)pR7, -OS(O)pR7> -S(O)pOR7, -NR8S(O)PR7, or -S(O)pNR10Rii, -S(0)p0R7, -OP(O)(OR7)2, or -SP(O)(OR7)2; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and q is zero or an integer from 1 to 7.
In one embodiment, in the compounds represented by formula (V) or (Vl), R'5 is represented by the following formula;
Figure imgf000097_0001
wherein: q is zero or an integer from 1 to 5; and u is zero or an integer from 1 to 5.
In one embodiment, in the compounds represented by formula (V) or (Vl)1 R'5 is represented by the following formula;
Figure imgf000097_0002
wherein: R33 is a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;
R34 is H1 a lower alkyl, or a lower alkyicarbonyl; and
Ring B and Ring C are optionally substituted with one or more substituents.
In one embodiment, in the compounds represented by formula (V) or (Vl), R's is selected from the group consisting of:
Figure imgf000098_0001
Figure imgf000099_0001
wherein'
X6, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least three X6 groups are independently selected from CH and CR9;
X7, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least three X7 groups are independently selected from CH and CR9;
X8, for each occurrence, is independently CH2, CHR9, C(Rg)2, S, S(O)p, NR7, or NR17; X9, for each occurrence, is independently N or CH;
X)0, for each occurrence, is independently CH1 CRg, N, N(O), N+(Ri7), provided that at least one X10 is selected from CH and CR9; Rg, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alky), an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyaπo, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)pR7l -S(O)pOR7l -NR8S(O)pR7l or -S(O)PNR10R11, -S(O)POR7, -OP(O)(OR7J2, or -SP(0)(OR7)2, -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(OR7)2; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
R17, for each occurrence, is independently -H, an alkyl, an aralkyl, -C(O)R7, -C(O)OR7, or -C(O)NR10Ri1,
In one embodiment, in the compounds represented by formula (V) or (Vl), R'5 is an optionally substituted indolyl, an optionally substituted benzoimidazolyl, an optionally substituted indazolyl, an optionally substituted 3H-indazolyl, an optionally substituted indolizinyl, an optionally substituted quinolinyl, an optionally substituted isoquinoliπyl, an optionally substituted benzoxazolyl, an optionally substituted benzo[1 ,3]dioxolyl, an optionally substituted benzofuryl, an optionally substituted benzothiazolyl, an optionally substituted benzo[d]isoxazolyl, an optionally substituted benzo[d]isothiazolyl, an optionally substituted thiazolo[4,5-c]pyridinyl, an optionally substituted thiazolo[5,4-c]pyridinyl, an optionally substituted thiazolo[4,5-b]pyridinyl, an optionally substituted thiazolo[5,4- b]pyridinyl, an optionally substituted oxazolo[4,5-c]pyridinyl, an optionally substituted oxazolo[5,4-c]pyridinyl, an optionally substituted oxazolo[4,5-b]pyridinyl, an optionally substituted oxazolo[5,4-b]pyridinyl,an optionally substituted imidazopyridinyl, an optionally substituted benzothiadiazolyl, benzoxadiazolyl, an optionally substituted benzotriazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaiπdolyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted imidazo[4,5-a]pyridinyl, an optionally substituted imidazo[1,2-a]pyridinyl, an optionally substituted 3H-imidazo[4,5-b]pyridinyl, an optionally substituted 1W-imidazo[4,5-b]pyridinyl, an optionally substituted 1 H-imidazo[4,5-c]pyridinyl, an optionally substituted 3H- imidazo[4,5-c]pyridinyl, an optionally substituted pyridopyrdazinyl, and optionally substituted pyridopyrimidinyl, an optionally substituted pyrrolo[2,3]pyrimidyl, an optionally substituted pyra∑olo[3,4]pyrimidyl an optionally substituted cyclopentaimidazolyl, an optionally substituted cyclopentatriazolyl, an optionally substituted pyrrolopyrazolyl, an optionally substituted pyrroloimidazolyl, an optionally substituted pyrrolotriazolyl, or an optionally substituted benzo(b)thienyl.
In one embodiment, in. the compounds represented by formula (V) or (Vl), R'5 is selected from the group consisting of:
Figure imgf000101_0001
wherein:
X11, for each occurrence, is independently CH, CR9, N, N(O), or N+(R17), provided that at least one X11 is N, N(O), or N+(Ri7) and at least two X1-, groups are independently selected from CH and CR9;
X12, for each occurrence, is independently CH, CRg, N, N(O), N+(R17), provided that at least one X12 group is independently selected from CH and CR9;
X13, for each occurrence, is independently O1 S, S(O)p, NR7, or NRi7;
R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a hydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, -NRi0R11, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)pR7, -S(O)pOR7> -NRBS(O)pR7, or -S(O)PNR10R11, -S(O)POR7, -OP(O)(ORy)2, or -SP(O)(ORy)2, -S(O)pOR7, -OP(O)(OR7J2, or -SP(O)(OR7)2; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and Ri7, for each occurrence, is independently an alkyl or an aralkyl.
In one embodiment, in the compounds represented by formula (V) or (Vl), R', is -NHR7.
In one embodiment, in the compounds represented by formula (V) or (Vl), R2 is -OH, -SH, or -NHR7. In one embodiment, in the compounds represented by formula (V) or (Vl), R'3 is
-OH or -SH.
In one embodiment, in the compounds represented by formula (V), Z, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)NR10Rn, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10Ri1, -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(O)R7, -SC(O)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NR10R1I, -OC(S)NR10Ri1, -OC(NR8)NR10R11, -SC(O)NR10R11, -SC(NR8)NR10R11, -SC(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -C(O)NR10R11, -NR8C(O)R7, -NR7C(S)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(O)OR7, -NR7C(NR8)OR7, -NR7C(O)NR10RH, -NR7C(S)NR10RH, -NR7C(NR8)NR10R11, -SR7, -S(O)PR7, -OS(O)PR7, -OS(O)pOR7, -OS(O)PNR1ORI11 -S(O)POR7, -NR8S(O)pR7, -NRrSfOJpNRioRn,
-NR7S(O)pOR7, -S(O)PNR10R11, -SS(O)PR7, -SS(O)POR7, -SS(O)PNR10R11, -OP(O)(0R7)2, or -SP(O)(OR7)2.
In one embodiment, in the compounds represented by formula (V)1 1 is 1. In one embodiment, in the compounds represented by formula (V), t is O. In one embodiment, in the compounds represented by formula (Vl), R5 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl.
In one embodiment, in the compounds represented by formula (Vl), R^ is -NHR7; R2 is -OH, -SH, or -NHR7; R'3 is -OH or -SH; and R6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl.
In one embodiment, in the compounds represented by formula (VII), X41 is NR42 and X42 is CR44.
In one embodiment, in the compounds represented by formula (VII), X41 is NR42 and X42 is N. In one embodiment, in the compounds represented by formula (VII), R4i is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
In one embodiment, in the compounds represented by formula (VII), R41 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
In one embodiment, in the compounds represented by formula (VII), X41 is NR42, and R42 is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, -C(O)N(RZ7)2, and -C(O)OH, wherein each R27 is independently -H or a lower alkyl.
In one embodiment, in the compounds represented by formula (VII), X41 is NR42, and R42 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, fert-butyl, n-pentyl, n-hexyl, -C(O)OH, -(CH2)mC(O)OH, -CH2OCH3, -CH2CH2OCH3, and -C(O)N(CH3J2.
In one embodiment, in the compounds represented by formula (VII), R43 and R44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
In one embodiment, in the compounds represented by formula (VII), X42 is CR44; Y40 is CR43; and R43 and R44 together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring.
In one embodiment, in the compounds represented by formula (VII), R43 and R44 together with the carbon atoms to which they are attached form a C5-C8 cycloalkenyl or a C5-C8 aryl.
In one embodiment, in the compounds represented by formula (VII), R45 or CR45 is selected from the group consisting of -H, -OH, -SH, -NH2, a lower alkoxy, a lower alkyl amino, and a lower dialkyl amino. In one embodiment, in the compounds represented by formula (VII)1 R45 is selected from the group consisting of -H, -OH, methoxy and ethoxy.
In one embodiment, in the compounds represented by formula (VII), X41 is O.
In one embodiment, in the compounds represented by formula (VIII), X42 is CR44, and R43 and R44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
In one embodiment, in the compounds represented by formula (VIII), X42 is CR44, and R43 and R44, taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring.
In one embodiment, in the compounds represented by formula (VIII)1 R43 and R44, taken together with the carbon atoms to which they are attached, form a C5-C8 cycloalkenyl or a C5-C8 aryl.
In one embodiment, in the compounds represented by formula (VIII), X42 is CR44. In one embodiment, in the compounds represented by formula (VIII), X42 is N.
In one embodiment, in the compounds represented by formula (X), R4i is selected from the group consisting of -H1 lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
In one embodiment, in the compounds represented by formula (X), R41 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. In one embodiment, in the compounds represented by formula (X), R112 is -H or an optionally substituted lower alkyl.
In another embodiment, the compound is selected from the group consisting of
4-lsopropyl-6-[4-(1 -methyl-1 H-indol-5-yl)-5-phenylamino-4H-[1 ,2 ,4]triazol-3-yl]-benzene-
1 ,3-diol;
4-lsopropyl-6-[4-(1-methyl-1 H-indol-5-yl)-5-methylamino-4H-[1 ,2,4]triazol-3-yl]-benzene-
1 ,3-diol;
4-lsopropyl-6-[4-(1-methyl-1 H-indol-5-yl)-5-benzylamino-4H-[1 ,2,4]triazol-3-yl]-benzene-
1 ,3-diol;
4-(5-amino-4-(1 -methyl-1 H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1,3-diol;
4-isopropyl-6-(4-(1-methyl-1 H-indol-5-yl)-5-(quinolin-6-ylamino)-4H-1 ,2,4-triazol-3- yl)benzene-1 ,3-diol;
4-(5-(3-aminophenylamino)-4-(1 -methyl-1 H-indol-5-yl)-4H-1 ,2,4-triazol-3-yl)-6- isopropylbenzene-1 ,3-diol;
4-isopropyl-6-(4-(1-methyl-1 H-indol-5-yl)-5-(3-(trifluoromethyl)phenylamino)-4H-1,2,4- triazol-3-yl)benzene-1 ,3-diol;
4-isopropyl-6-(5-(3-methoxyphenylamino)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3- yl)benzene-1 ,3-diol;
N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3- yl)benzamide;
N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1 ,2,4-triazol-3-yl)- 5-methylisoxazole-3-carboxamide;
N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1 -methyl-1 H-indol-5-yl)-4H-1 , 2, 4-triazol-3- yl)acetamide;
N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1 H-indol-5-yl)-4H-1 ,2,4-triazol-3- yl)butyramide;
N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1 H-indol-5-yl)-4H-1 ,2,4-triazol-3-yl)- 2-methoxyacetamide;
N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1 H-indol-5-yl)-4H-1 ,2,4-triazol-3- yl)isobutyramide;
N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1 -methyl-1 H-indol-5-yl)-4H-1 ,2,4-triazol-3- yl)furan-2-carboxamide;
N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1 H-indol-5-yl)-4H-1 ,2,4-triazol-3-yl)- 2-phεnylacetamide;
N-Cδ-ia.A-dihydroxy-δ-isopropylphenyH-CI-methyl-I H-indol-δ-yO^H-i ^^-triazol-a-yl)- 3,4-difluorobenzamide;
N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)- 2,2,2-trifluoroacetamide;
2-(4-chlorophenoxy)-N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1 H-indol-5-yl)- 4H-1 ,2,4-triarol-3-yl)acetamide; or
N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indo!-5-yl)-4H-1,2,4-triazol-3- yl)cyclopentanecarboxamide;
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof.
In one embodiment of the compounds represented by formula (Xl), (XVI), or (XVII), R'5 is represented by the following formula:
Figure imgf000105_0001
wherein:
R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alky], an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)13R7, -0S(O)pR7, -S(0)pOR7, -NR8S(O)PR7, or -S(O)pNR10R11τ -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(OR7)2; or two RB groups taken together with the carbon atoms to which they are attached form a fused ring; and q is zero or an integer from 1 to 7. In another embodiment of the compounds represented by formula (Xl), (XVI), or (XVII)1 R's is represented by the following formula:
Figure imgf000106_0001
wherein: q is zero or an integer from 1 to 5; and u is zero or an integer from 1 to 5 In another embodiment of the compounds represented by formula (Xl), (XVI), or
(XVII), R's is represented by the following formula:
Figure imgf000106_0002
wherein:
R33 is a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;
R34 is H, a lower alkyl, or a lower alkylcarbonyl; and
Ring B and Ring C are optionally substituted with one or more substituents.
In another embodiment of the compounds represented by formula (Xl), (XVI), or (XVII), R'5 is selected from the group consisting of:
Figure imgf000106_0003
Figure imgf000107_0001
Figure imgf000108_0001
wherein:
X6, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least three X6 groups are independently selected from CH and CR9; X7, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least three X7 groups are independently selected from CH and CR9;
X8, for each occurrence, is independently CH2, CHR9, C(Rg)2, S, S(O)p, NR7, or NR17; X9, for each occurrence, is independently N or CH;
X10, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least one X10 is selected from CH and CR3;
R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10Ri1, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -0S(O)pR7, -S(O)pOR7, -NRβS(O)pR7, or -S(O)PNR10R11, -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(OR7)2, -S(0)p0R7, -OP(O)(OR7)2, or -SP(O)(OR7)2; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
R17, for each occurrence, is independently -H, an alkyl, an aralkyl, -C(O)R7, -C(O)OR7, or -C(O)NR10R11.
In another embodiment of the compounds represented by formula (Xl), (XVI), or (XVII), R's is an optionally substituted indolyl, an optionally substituted benzoimidazolyl, an optionally substituted indazolyl, an optionally substituted 3H-indazolyl, an optionally substituted indolizinyl, an optionally substituted quinolinyl, an optionally substituted isoquinolinyl, an optionally substituted benzoxazolyl, an optionally substituted benzo[1 ,3]dioxolyl, an optionally substituted benzofuryl, an optionally substituted benzothiazolyl, an optionally substituted benzo[d]isoxazolyl, an optionally substituted benzo[d]isothiazolyl, an optionally substituted thiazolo[4,5-c]pyridinyl, an optionally substituted thiazolo[5,4-c]pyridinyl, an optionally substituted thiazolo[4,5-b]pyridinyl, an optionally substituted thiazolo[5,4-b]pyridinyl, an optionally substituted oxazolo[4,5- cjpyridinyl, an optionally substituted oxazolo[5,4-c]pyridinyl, an optionally substituted oxazolo[4,5-b]pyridinyl, an optionally substituted oxazolo[5,4-bjpyπdinyl,aπ optionally substituted imidazopyridinyl, an optionally substituted benzothiadiazolyl, benzoxadiazolyl, an optionally substituted benzotriazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted imidazo[4,5-a]pyridinyl, an optionally substituted imidazo[1,2-a]pyridinyl, an optionally substituted 3/-/-imidazo[4,5-b]pyridinyl, an optionally substituted 1/-/-imidazo[4,5-b]pyridinyl, an optionally substituted 1/-/-imidazo[4,5-c]pyridinyl, an optionally substituted 3H-imidazo[4,5-c]pyridinyi, an optionally substituted pyridopyrdazinyl, and optionally substituted pyridopyrlmidinyl, an optionally substituted pyrrolo[2,3]pyrimidyl, an optionally substituted pyrazolo[3,4]pyrimidyl an optionally substituted cyclopentaimidazolyl, an optionally substituted cyclopentatriazolyl, an optionally substituted pyrrolopyrazolyl, an optionally substituted pyrroloimidazolyl, an optionally substituted pyrrolotriazolyl, or an optionally substituted benzo(b)thιenyl.
In another embodiment of the compounds represented by formula (Xl), (XVI), or (XVII), R'5 is selected from the group consisting of:
Figure imgf000109_0001
wherein:
Xn, for each occurrence, is independently CH, CR9, N, N(O), or N+(R17), provided that at least one Xn is N, N(O), or N+(R17) and at least two X1, groups are independently selected from CH and CR9; X12, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least one X12 group is independently selected from CH and CRg;
Xi3, for each occurrence, is independently O, S, S(O)p, NR7, or NR17;
R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally'substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a hydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)pR7, -S(O)pOR7, -NR8S(O)pR7, or -S(O)PNR10R11, -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(ORy)2, -S(O)p0R7, -OP(O)(OR7)2, or -SP(O)(OR7)2; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
R17, for each occurrence, is independently an aikyl or an aralkyl.
In one embodiment of the compounds represented by formula (Xl), (XII), (XIII), (XIV), (XV), (XVI), or (XVII), R'B is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1- C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl.
In one embodiment of the compounds represented by formula (Xl), (XII), (XIII), (XIV), (XV), (XVI), or (XVII), R'6 is -H.
In one embodiment of the compounds represented by formula (XII) or (XIII), R19 is - H.
In one embodiment of the compounds represented by formula (XIV), R'5 is an optionally substituted phenyl.
In one embodiment of the compounds represented by formula (XlV), R'2 and R'3 are each -OH. In one embodiment of the compounds represented by formula (XIV), X' is -S-S-.
In one embodiment of the compounds represented by formula (XlV), X' is -0-0-.
In one embodiment of the compounds represented by formula (XIV), the compound is 6,6'-(5,5'-disulfanediylbis(4-(4-(dimethylamino)phenyl)-4H-1,2,4-triazole-5,3-diyl))bis(4- isopropylbenzene-1 ,3-diol) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof.
In one embodiment of the compounds represented by formula (XVIII), X41 is NR42 and X42 is CR44.
In another embodiment of the compounds represented by formula (XVIII), X41 is NR42 and X42 is N. In another embodiment of the compounds represented by formula (XVIII)1 R41 is selected from the group consisting of -H1 lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy. ^ In another embodiment of the compounds represented by formula (XVIIl), R4t is selected from the group consisting of -H1 methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
In another embodiment of the compounds represented by formula (XVIII), X41 is NR42, and R42 is selected from the group consisting of -H, a lower alky), a lower cycloalkyl, -C(O)N(R27)2, and -C(O)OH, wherein each R27 is independently -H or a lower alky).
In another embodiment of the compounds represented by formula (XVIII), X41 is NR42, and R42 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, -C(O)OH, -(CH2)mC(0)0H, -CH2OCH3, -CH2CH2OCH3, and -C(O)N(CH3)2.
In another embodiment of the compounds represented, by formula (XVIII), R43 and R44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
In another embodiment of the compounds represented by formula (XVIII), X42 is CR44; Y40 is CR43; and R43 and R44 together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring.
In another embodiment of the compounds represented by formula (XVIII), R43 and R44 together with the carbon atoms to which they are attached form a C5-C6 cycloalkenyl or a C5-C8 aryl. In another embodiment of the compounds represented by formula (XVIII)1 R45 or
CR45 is selected from the group consisting of -H, -OH, -SH, -NH2, a lower alkoxy, a lower alkyl amino, and a lower dialkyl amino.
In another embodiment of the compounds represented by formula (XVIII), R45 is selected from the group consisting of -H, -OH, methoxy and ethoxy. In another embodiment of the compounds represented by formula (XVIII), X41 is O.
In another embodiment of the compounds represented by formula (XVIII), R40 is -OH or -SH.
In one embodiment of the compounds represented by formula (XIX), X42 is CR44, and R43 and R44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
In another embodiment of the compounds represented by formula (XIX), X42 is CR44, and R43 and R44, taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring. - I l l -
In another embodiment of the compounds represented by formula (XIX), R43 and R44, taken together with the carbon atoms to which they are attached, form a C5-C8 cycloalkenyl or a C5-C6 aryl.
In another embodiment of the compounds represented by formula (XIX), X42 is CR44.
In another embodiment of the compounds represented by formula (XIX)1 X42 is N. In another embodiment, the compound is selected from the group consisting of
4-ethyl-6-(5-mercapto-4-(naphthalen-1 -yl)-4H-1 ,2,4-triazo!-3-yl)-1 ,3-phenylene bis(2,2- dimethylpropanoate);
4-ethyl-6-(5-mercapto-4-(naphthalen-1-yl)-4H-1 ,2,4-triazol-3-yl)-1 ,3-phenylene dibenzoate;
2-(5-mercapto-4-(naphthalen-1-yl)-4H-1 ,2,4-triazol-3-yl)-5-(2~methoxyethoxy)pheno1;
4-(5-(ethylcarbamoylthio)-4-(naphthalen-1-yl)-4H-1,2,4-triazol-3-yl)-1,3-phenylene bis(dimethylcarbamate); or
5-hydroxy-2-isopropyl-4-(5-(3-methoxypropanoyloxy)-4-(1-methyM H-indol-5-yl)-4H-
1 ,2,4-triazol-3-y!)phenyl 3-methoxypropanoate;
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In another embodiment, the compound is selected from the group consisting of
2-amino-1 -(5-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1 ,2,4-triazol-4-yl)-1 H- indol-1-yl)ethaπoπe;
1-(5-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1 ,2,4-triazol-4-yl)-1H-indol-1- yl)ethanone;
■ tert-butyl 3-(5-(3-(2,4-dihydroxy-5-isopropyIphenyl)-5-hydroxy-4H-1,2,4-triazol-4-y))-1H- indol-1 -y l)-3-oxopropylcarbamate; or
1-(5-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1 ,2,4-triazol-4-yl)-1 H-indol-1-yl)- 3-methoxypropan-1 -one;
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In another embodiment, the compound is selected from the group consisting of
3-(2,4-dihydroxy-5-isopropy lphenyl)-4-( 1 -methyl-1 H-indol-5-yl)- 1 -propionyl-1 H-1 ,2,4- triazol-5(4H)-onε;
(3-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-5-oxo-4,5~dihydro-1H- 1 ,2,4-triazol-1-yl)methyl pivalate;
(3-(2,4-dihydroxy-5-isopropylphenyl)-4-(1 -methyl-1 H-indol-5-yl)-5-oxo-4,5-dihydro-1 H- 1 ,2,4-triazol-1-yl)methyl 2-amino-3-methylbutanoate;
(3-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-5-oxo-4,5-dihydro-1H- 1 ,2,4-triazol-1-yl)methyl 2-amino-3-phenylpropanoate;
(3-(2,4-dihydroxy-5-isopropylpbenyl)-4-(1-methyl-1 H-indol-5-yl)-5-oxo-4,5-dihydro-1 H- 1 ,2,4-triazol-1-yl)methyl 2,2-bis(tert-butoxycarbonylamino)-3-methylbutanoate;
4-(1-(2-aminoacetyl)-4-(1-methyl-1 H-indo]-5-yl)-5-oxo-4,5-dihydro-1 H-1 ,2,4-triazol-3-yl)- 6-isopropyl-1,3-phenylene bis(2-aminoacetate) trihydrochloride;
4-(1-(2-aminopropanoyl)-4-(1-methyl-1H-indol-5-yl)-5-oxo-4,5-dihydro-1 H-1,2,4-triazol-3- yl)-6-isopropyl-1 ,3-phenylene bis(2-aminopropanoate) trihydrochloride; or
4-( 1-(2-amino-3-phenylpropanoyl)-4-( 1 -methyl-1 H-indol-5-yl)-5-oxo-4, 5-dihydro-1 H-1 ,2,4- triazol-3-yl)-6-isopropyl-1 ,3-phenyleπe bis(2-amino-3-phenylpropanoate) trihydrochloride; or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof.
In one embodiment, in the compounds of formula (XXI), R'5 is an optionally substituted naphthyl.
In another embodiment, in the compounds of formula (XXI), R's is represented by the following formula:
Figure imgf000113_0001
wherein:
Rg, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alky), an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(0)p0R7< -NR8S(O)pR7l or -S(O)15NR10R11, -S(O)POR7, -OP(O)(0R7)2, or -SP(O)(OR7)2; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and q is zero or an integer from 1 to 7; and R7, RB, R10, R1 I, and p are defined as above, In another embodiment, in the compounds represented by formula (XXI)1 R's is represented by one of the following formulas:
Figure imgf000114_0001
wherein R9 is defined as above; q is zero or an integer from 1 to 5; and u is zero or an integer from 1 to 5.
In another embodiment, in the compounds represented by formula (XXI), R'5 is represented by the following structural formula:
Figure imgf000114_0002
wherein:
R33 is H, a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;
R34 is H, a lower alkyl, or a lower alkylcarbonyl; and Ring B and Ring C are optionally substituted with one or more independently selected substituents.
In another embodiment, in the compounds represented by formula (XXI), R'5 is selected from the group consisting of:
Figure imgf000114_0003
Figure imgf000115_0001
Figure imgf000116_0001
wherein
X6, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least three X6 groups are independently selected from CH and CR9, X7, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least three X7 groups are independently selected from CH and CR9,
X8, for each occurrence, is independently CH2, CHR9, CR9Rg, O, S, S(O)p, NR7, or NR17,
X9, for each occurrence, is independently N or CH, Xio, for each occurrence, is independently CH, CRg1 N, N(O), N+(R17), provided that at least one X10 is selected from CH and CR9,
R17, for each occurrence, is independently -H, an alkyl, an aralkyl, -C(O)R7, -C(O)OR7, or -C(O)NR10R1I, wherein R7, R9, R10, Rn and p are defined as above
In another embodiment, in the compounds represented by formula (XXI), R's is an optionally substituted indolyl, an optionally substituted benzoimidazolyl, an optionally substituted indazolyl, an optionally substituted 3H-ιndazolyl, an optionally substituted indolizinyl, an optionally substituted quinolinyl, an optionally substituted isoqumolinyl, an optionally substituted benzoxazolyl, an optionally substituted benzo[1 ,3]dioxolyl, an optionally substituted benzofuryl, an optionally substituted benzothiazolyl, an optionally substituted benzo[d]ιsoxazolyl, an optionally substituted benzo[d]ιsothιazolyl, an optionally substituted thιazo!o[4,5-c]pyπdιnyl, an optionally substituted thιazolo[5,4-c]pyπdιnyl, an optionally substituted thιazolo[4,5-b]pyπdιnyl, an optionally substituted thιazolo[5,4- b]pyπdιnyl, an optionally substituted oxazolo[4,5-c]pyrιdιnyl, an optionally substituted oxazolo[5,4-c]pyrιdιnyl, an optionally substituted oxazolo[4,5-b]pyπdιnyl, an optionally substituted oxazolo[5,4-b]pyπdιnyl,an optionally substituted imidazopyπdinyl, an optionally substituted benzothiadiazolyl, benzoxadiazolyl, an optionally substituted benzotπazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted quiπazolinyl, an optionally substituted punnyl, an optionally substituted ιmιdazo[4,5-a]pyπdιnyl, an optionally substituted ιmιdazo[1,2-a]pyπdιnyl, an optionally substituted 3H-imidazo[4,5-b]pyndinyl, an optionally substituted 1H-ιmιdazo[4,5-b]pyπdιnyl, an optionally substituted 1H-ιmιdazo[4,5-c]pyrιdιnyl, an optionally substituted 3H- ιmιdazo[4,5-c]pyπdιnyl, an optionally substituted pyπdopyrdazinyl, and optionally substituted pyridopyπmidinyl, an optionally substituted pyrrolo[2,3]pyrιmιdyl, an optionally substituted pyrazolo[3,4]pyrimidyl an optionally substituted cyclopentaimidazolyl, an optionally substituted cyclopentatriazolyl, an optionally substituted pyrrolopyrazolyl, an optionally substituted pyrroloimidazolyl, an optionally substituted pyrrolotriazolyl, or an optionally substituted benzo(b)thienyl.
In another embodiment, in the compounds represented by formula (XXI), R's is an optionally substituted indolyl. Preferably, R5 is an indolyl represented by the following structural formula:
Figure imgf000117_0001
wherein: R33 is a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;
R34 is H, a lower alkyl, or a lower alkylcarbonyl; and
Ring B and Ring C are optionally substituted with one or more substituents.
In another embodiment, in the compounds represented by formula (XXI), R'5 is selected from the group consisting of:
Figure imgf000117_0002
wherein:
Xn, for each occurrence, is independently CH, CR9, N, N(O), or N+(R17), provided that at least one X11 is N, N(O), or N+(R17) and at least two X11 groups are independently selected from CH and CR9;
X12, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least one X12 group is independently selected from CH and CRg;
Xi3, for each occurrence, is independently O, S, S(O)p, NR7, or NR17; wherein R7, Rg and Ri7 are defined as above.
In another embodiment, in the compounds represented by formula (XXI), R'5 is a phenyl which is optionally substituted with from one to five substituents independently selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, -C(O)NR'2BR'29, -C(S)NR1Z8R^9, -C(NR'32)NR'28R'29, -NR1 S0C(O)R1S1, -NR'3oC(S)R'31l -NR'3oC(NR'32)R'31, halo, -OR'30, cyano, nitro, haloalkoxy, -C(O)R'30, -C(S)R'3O, ^(NR'azJR'ao, -NR'2BR'29, -C(O)OR'30l -C(S)OR'30, -C(NR'32)OR'30, -OC(O)R'30, -OC(S)R'30l -OC(NR'32)R'30, -NR'3DC(O)NR'28R'2g, -NR1 MC(S)NR1 Z8R1 Z9, -NR1 MC(NR1 S2)NR1 Z8R1 Z9, -OC(O)NR1Z8R^9, -OC(S)NR1S8R^9, -OC(NR1 S2)NR MR^8, -NR1 MC(O)OR1 Si, -NR'3oC(S)OR'31, -NR'3DC(NR1 32)OR1 31, -S(O)11R1 M, -OS(O)pR'30l , -NR^0S(O)PR1 M, -StO^NR^R^,
-OS(O)pNR'28R'29, or -NR'3oS(0)pNR'28R'29, wherein R'2δ and R'2g, for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R'2S and R'29 taken together with the nitrogen to which they are attached is optionally substituted heterocyclyl or optionally substituted heteroaryl; R'3O and R'31 for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R'32, for each occurrence is, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, -C(O)R'30, -C(O)NR'28R'z9, -S(O)pR'30, or -S(O)pNR'2sR'29; p, for each occurrence, is independently, 1 or 2; and h is O, 1 or 2.
In another embodiment, in the compounds represented by formula (XXI), R'5 is a phenyl which is substituted with from one to five substituents independently selected from the group consisting of an alkyl, an alkoxy, a haloalkyl, an amino, an alkylamino, a dialkylamino, a cycloalkoxy, a halo, carboxy, -C(O)R35, -OC(O)R1 Z6, -C(O)OR'26, - NR35C(O)R1 S6, -C(O)NR35R35, -NR35C(O)NR36R37, -NR35C(NR8)NR36R37, -S(O)2R'26, - S(O)2NR35R36, -NR35S(O)2R'26l an alkoxyalkyl, a dialkylamino, an alkoxyalkoxy, an alkylaminoalkyl, a dialkylaminoalkyl, an alkylaminoalkoxy, a dialkylaminoalkoxy, an alkoxyalkylaminoalkoxy, an alkoxydialkylaminoalkoxy, heterocyclyl, an alkyl substituted with a heterocyclyl, an alkoxy substituted with a heterocyclyl, or a heteroaralkyl, wherein the heterocycle and the heteroaryl are optionally substituted with a lower alkyl; wherein R35, R35, and R37, for each occurrence, are each independently, H or an alkyl; and R8 is defined as above.
In another embodiment, in the compounds represented by formula (XXI), R'5 is represented by the following formula;
Figure imgf000119_0001
wherein X8, R9 and p are defined as above; and k is 0, 1 or 2.
In one embodiment of the compounds represented by formula (XXII), X16 is NR35 and R35 is H or a lower alkyl. In another embodiment of the compounds represented by formula (XXII), one of R'40 or R'41 is H and the other is a lower alkyl, a lower alkoxy, or a three to six membered cycloalkyl.
In another embodiment of the compounds represented by formula (XXII), R'40 and R'41 are both H.
In one embodiment of the compounds represented by formula (XXIII)1 X16 is -O-, -
NR35-, or -S-; Z' is -O-, -S-, -NR35- or CR35R36; and R35 and R36, for each occurrence, are independently, H or a lower alkyl.
In another embodiment of the compounds represented by formula (XXIII), X16 is - NH- and Z' is -NR35-. In another embodiment of the compounds represented by formula (XXIII)1 Xi6 and Z' are -O-.
In another embodiment of the compounds represented by formula (XXIII), Z' is CR35R3S.
In another embodiment of the compounds represented by formula (XXIII), X16 is NH. In one embodiment of the compounds represented by formula (XXIV), R'4O is H and
R'41 is a lower alkyl, a lower alkoxy, or a 3 to 6 membered cycloalkyl.
In another embodiment of the compounds represented by formula (XXIV), R'41 is H and R'4O is a lower alkyl, a lower alkoxy, or a 3 to 6 membered cycloalkyl.
In another embodiment of the compounds represented by formula (XXIV), R'40 and R'41 are H. In another embodiment of the compounds represented by formula (XXIV), the dashed line is a double bond.
In another embodiment of the compounds represented by formula (XXIV), R'4O and R1M together with the carbon to which they are attached form a five or six membered cycloalkenyl.
In one embodiment of the compounds represented by formula (XXV), X16 is -NH-, - O-, or -S-; Z' is -NR35-, -0-, -S- or -CR35R36-; R35 and R36, for each occurrence, are independently, H or a lower alkyl.
In another embodiment of the compounds represented by formula (XXV), R38 and R'39 are each, independently, H or a lower alkyl; X16 is -NH-; and Z' is -NR35- or -O-.
In another embodiment of the compounds represented by formula (XXV), R38 and R' 39 are each, independently, H or a lower alkyl; X16 is -O-; and Z' is -NR35- or -O-.
In one embodiment of the compounds represented by formula (XXVI), X18 is -O-, - NH-, or -S-. In another embodiment of the compounds represented by formula (XXVI), R7 is H or a lower alkyl.
In another embodiment of the compounds represented by formula (XXVI), X15 is - NH-.
In one embodiment of the compounds represented by formula (XXVII), X16 is -O-, - NH-, or -S-.
In another embodiment of the compounds represented by formula (XXVII), R7 is H or a lower alkyl.
In another embodiment of the compounds represented by formula (XXVII), Xi6 is -
NH-. In another embodiment of the compounds represented by formula (XXI) through
(XXVII), R1 and R3 are each independently -OH, -SH, -NHR7, -OC(O)NR10RH, -SC(O)NR10R11, -OC(O)R7, -SC(O)R7, -OC(O)OR7, -SC(O)OR7, -OS(O)PR7, -S(O)POR7, -SS(O)pR7, -OS(O)pOR7, -SS(O)pOR7, -OC(S)R7, -SC(S)R7, -OC(S)OR7, -SC(S)OR7, -OC(S)NR10R1I, -SC(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -OP(O)(OR7)2 or -SP(O)(OR7)2.
In another embodiment of the compounds represented by formula (XXI) through (VII), R1 and R3 are each, independently, -OH, -SH, or -NHR7.
In another embodiment of the compounds represented by formula (XXI) through (VII), Ri is -SH or -OH; and R3 is -OH. In another embodiment, the compound is selected from the group consisting of: 3-[3-methyl-6-hydroxy-iH-indol-5-yl]- 4-(6-methoxy-πaphthalen-1-yl)-5-hydroxy-4/-/- [1,2,4]triazole;
3-[6-hydroxy-1 H-indol-5-yl]- 4-(1 -ethyl-1 H-indol-4-yl)-5-mercapto-4H-[1 ,2,4]triazole;
3-(2-oxo-1 ,3-dihydro-3-methyl-6-hydroxy-beπzoimidazol-5-y))-4-(2,3- dihydrobenzo[1 ,4]dioxin-5-yl)-5-mercapto-4H-[1 ,2,4]triazole;
3-(6-hydroxy-2,2-dimethyl-benzo[1 ,3]dioxol-5-yl)-4-(4-methyl-phenyl)-5-hydroxy-4/-/- [1 ,2,4]triazole;
3-(2-oxo-6-hydroxy-benzo[1 ,3]dioxol-5-yl)-4-(4-methoxy-phenyl)-5-mercapto-4H- [1 ,2,4]triazole;
3-{2-oxo-6-hydroxy-1 ,3-dihydro-indol-5-yl)-4-(3,5-dimethyl-phenyl)-5-hydroxy-4/-/- [1,2,4]triazole;
S^e-hydroxy-IH-ben∑oimidazol-S-ylH^acenaphthen-δ-yO-δ-mercapto^H- [1 ,2,4]triazole;
3-(6-hydroxy-1H-indazol-5-yl)-4-(2,3-dichloro-phenyl)-5-hydroxy-4H-[1 ,2,4]triazole;
3-(2-oxo-7-hydroxy-1H-quinolin-6-yl)-4-(quinolin-5-yl)-5-mercapto-4H-[1 ,2,4]triazole;
S-^.S-dimethyl-e-hydroxy-I H-indol-δ-yll^^a.S-dimethyl-IH-indoM-yO-δ-mercapto^H- (1,2,4]triazole;
3-(2-methyl-6-hydroxy-1W-benzoimidazo!-5-y!)-4-(4-carboxy-naphthalen-1-yl)-5- mercapto-4H-[1 ,2,4]triazole;
3-(3-isopropyl-6-hydroxy-1H-indazol-5-yl)-4-(4-dimethylcarbamoyl-πaphthalen-1-yl)-5- hydroxy-4H-[1 ,2,4]triazole;
3-(2-oxo-4-methyl-7-hydroxy-1H-quinolin-6-yl)-4-(2,3-dimethyl-4-methoxy-phenyl)-5- mercapto-4H-[1 ,2,4]triazole;
3-(2-oxo-3-ethyl-6-hydroxy-1,3-dihydro-indol-5-yl)-4-(1-isopropyl-1H-iπdol-4-yl)-5- hydroxy-4W-[1 ,2,4]tιϊazole;
3-(2-oxo-3,3-dimethyl-6-hydroxy-1 ,3-dihydro-indo!-5-yl)-4-[1-(2-methoxy-ethyl)-1H-indol- 4-yl]-5-mercapto-4H-[1 ,2,4]triazole;
3-(2-oxo-6-hydroxy-benzo[1 ,3]dioxol-5-yl)-4-(1 -isopropyl-1 H-indoi-4-yl)-5-mercapto-4H- [1 ,2,4]triazo!e;
3-(6-hydroxy-2,2-diethyl-benzo[1 ,3]dioxol-5-yl)-4-(1-dimethylcarbamoyl-1H-indol-4-yl)-5- mercapto-4W-[1 ,2,4]triazole;
3-(2-oxo-1 ,3-dihydro-3-isopropyl-6-hydroxy-benzoimidazol-5-yl)-4-(1 ,2,3-trimethyl-1 H- indol-5-yl)-5-hydroxy-4H-[1,2,4]triazole;
S-II-dimethylcarbamoyl-β-dimethylcarbamoyoxy-IW-iπdol-S-yl]- 4-(1 -ethyl-1 H-indo!-4- yl)-5-dimethylcarbamoylsulfanyl-4H-[1 ,2,4]triazole;
3-(6-ethoxycarbonyloxy-1H-benzoimidazol-5-yl)-4-(naphthalene-5-yl)-5- ethoxycarbonyloxy-4H-[1,2,4]triazole;
3-(3-cyclopropyl-6-acetoxy-1H-iπdazol-5-yl)-4-(naphthalen-1-yl)-5-acetoxy-4/-/- [1,2,4]tπa2ole,
3-(2-oxo-3,3-dιmethyl-6-hydroxy-1 ,3-d!hydro-ιndol-5-yl)-4-(naphthalen-1-yl)-5-(2- hydroxy-ethylsulfaπyMH-li ^.^tπazole,
3-(2-oxo-3-methyl-7-hydroxy-1H-quinolm-6-yl)-4-(benzothiazol-4-yl)-5-hydroxy-4M- [1 ,2,4]trιa2θle,
3-(2-oxo-6-hydroxy-benzo[1 i3]dιoxo]-5-yl)-4-[2-(1/-/-tetrazol-5-yl)-phenyl]-5-hydroxy-4H- [1 ,2,4]trιazole,
3-(6-hydroxy-2)2-dιmethyl-benzo[1 ,3]dιoxol-5-yl)-4-(9H-purιn-6-yl)-5-hydroxy-4H- [1 ,2,4]tπazole,
3-(2-oxo-1,3-dιhydro-6-hydroxy-benzoιmιdazol-5-yl)-4-phenyl-5-sυlfamoylamιno-4λ7- [1,2,4]tπazoie,
3-[3-methyl-6-hydroxy-1/-/-ιndoi-5-yl]- 4-(1-ιsopropyl-iW-ιndol-4-yl)-5-ureιdo-4H- [1 ,2,4]trιazole,
3-[3-methoxy-6-hydroxy-1H-ιndol-5-yl]- 4-(naphthalen-1-yl)-5-carbamoyloxy-4/-/- [1,2,4]trιazole,
3-(6-hydroxy-1/-/-benzoιmιdazol-5-yl)-4-(8-methoxy-quιnolιn-5-yl)-5-carbamoyloxy-4H- [1 ,2,4]trιazole,
3-(3-ιsopropyl-6-hydroxy-1/-/-ιπdazol-5-yl)-4-(1-methyl-2-chloro-1H-ιndol-4-yl)-5- carboxyamιno-4H-[1 ,2,4]tπazole,
3-(2-oxo-3-propyl-6-hydroxy-1 ,3-dιhydro-ιndol-5-yl)-4-(3-trιfluoromethyl-phenyl)-5- sulfamoylamιno-4H-[1 ,2,4]trιazole,
3-(2-oxo-7-hydroxy-1 H-quιno!ιπ-6-yl)-4-(1-ιsopropyl-i H-benzoιmιdazol-4-yl)-5- sulfamoylamιno-4H-[1,2,4]trιazole,
3-(2-oxo-6-hydroxy-benzo[1 ,3]dιoxol-5-yl)-4-( 1 -ιsopropyl-1 H-benzoιmιdazol-4-yl)-5- sulfamoyloxy-4H-[1,2,4]tπazole,
3-(6-hydroxy-benzo[1 ,3]dιoxol-5-yl)-4-(1-ιsopropyl-1 H-benzoιmιdazol-4-y))-5-hydroxy- 4H-[1 ,2,4]trιazole,
3-(2-oxo-3-methyl-6-hydroxy-1 τ3-dιhydro-ιndol-5-yl)-4-(1-ιsopropyl-7-methoxy-1W-ιndol- 4-yl)-5-mercapto-4H-[1 ,2,4]trιazole,
3-[2,3-dιmethyl-6-hydroxy-1 H-ιndol-5-yl]- 4-(1-ethyl-2-methyl-1H-benzoιmιdazol-5-yl)-5- mercapto~4H-[1 ,2,4]tπazole,
3-(2-trιfluoromethyl-6-hydroxy-1H-benzoιmιdazol-5-y])-4-(1-cyclopropylmethyl-1 /-/-ιndol- 4-yl)-5-mercapto-4/-/-[1 ,2,4]tπazole,
3-(6-hydroxy-1/-/-ιndazol-5-yl)-4-(1-methyl-3-ethyl-1W-ιndol-5-yl)-5-mercapto-4/-i'- [1,2,4]tπazole,
3-[6-hydroxy-1H-ιπdol-5-yl]- 4-(1-methyl-1H-ιndol-5-yl)-5-hydroxy-4/-/-[1 ,2,4]tπazole,
3-(2-oxo-1 ,3-dihydro-3-isopropyl-6-hydroxy-benzoimidazol-5-yl)-4-(2-methyl-7-methoxy- benzofuran-4-yl)-5-mercapto~4H-[1,2,4]trιazole, 3-(2-oxo-6-hydroxy-ben2o[1 ,3]dioxol-5-yl)-4-(2-methyl-benzooxazol-5-yl)-5-mercapto- 4H-[1,2,4]tπazole,
3-(6-hydroxy-2,2-dιmethyl-benzo[1l3]dιoxol-5-yl)-4-(1(3-dιmethyl-1/-/-ιndol-5-yl)-5- hydroxy-4H-[1 ,2,4]tπazole,
3-(2-oxo-1 ,3-dιhydro-3-methyl-6-hydroxy-benzoιmιdazol-5-yl)-4-(2-methyl-7-methoxy- benzofuran-4-yl)-5-mercapto-4H-[1 ,2,4]tnazole,
3-[3-methyl-6-hydroxy-1 H-mdol-5-yl]- 4-(1-methyl-1H-mdazol-5-yl)-5-mercapto-4/-/- [1 ,2,4]tπazole,
3-(6-hydroxy-benzo[1,3]dιoxol-5-yl)-4-( benzo[1 ,3]dioxol-5-yl)-5-mercapto-4W- [1 ,2,4]trιazole,
3-[2,3-dιmethyl-6-hydroxy-1/V-ιπdol-5-yl]- 4-(4-propyl-3,4-dιhydro-2H-benzo[1 ,4]oxazιn- β-yO-S-mercapto^H-ti^^Jtπazole, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof
In one embodiment of compounds of formula (XXVIII), Ring F is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to R103 In a preferred embodiment Ring F is phenyl substituted with (R'25)x and (R73Jo in addition to R103 In another preferred embodiment, Ring F is represented by the following structural formula
Figure imgf000123_0001
In another preferred embodiment, Ring F is represented by the following structural formula
Figure imgf000123_0002
In one embodiment of compounds of formula (XXVIII), Ring G is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to -T1-Vi-Ta-V2 In a preferred embodiment, Ring G is a six membered nitrogen containing heteroaryl substituted with T1-V1-T2-V2 and optionally further substituted with one or more R74 groups In another preferred embodiment, Ring G is pyridyl substituted with TrV1-T2-V2 and optionally further substituted with one or more R74 groups.
In another preferred embodiment, Ring G is represented by the following structural formula:
Figure imgf000124_0001
In another preferred embodiment, Ring G is represented by the following structural formula:
c
Figure imgf000124_0002
In another preferred embodiment, Ring G is represented by a structural formula selected from:
Figure imgf000124_0003
In other embodiments, Ring G is phenyl substituted with Ti-Vi-T2-V2 and optionally further substituted with one or more R74 groups. In a preferred embodiment, Ring G is represented by a structural formula selected from:
Figure imgf000124_0004
In another preferred embodiment, Ring G is represented by a structural formula selected from:
Figure imgf000125_0001
In one embodiment of compounds of formula (XXVIII), R100 is -OH, -SH, -NR7H, -OR1 Z6, -SR'aβ, -NHR^26, -O(CH2)mOH, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R71 -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10Rii, -SCH2C(O)NR10Rn, -NR7CH2C(O)NR1ORH, -OS(O)pR7> -SS(O)pR7, -S(O)POR7, -NR7S(O)PR71 -OS(O)PNR10R111 -SS(O)PNR1OR1I , -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7. -SC(S)R7, -NR7C(S)R7, -OC(S)OR71 -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1I, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NRB)NR10R11, -OP(O)(OR7)2, or -SP(0)(OR7)2. In a preferred embodiment R100 is -OH1 -SH, -NHR7, -OC(O)NR10R11, -SC(O)NR10R11. -OC(O)R7, -SC(O)R7, -OC(O)OR7, -SC(O)OR7, -OS(O)pR7, -S(O)POR7, -SS(O)PR7, -OS(O)POR7, -SS(O)POR7, -OC(S)R7, -SC(S)R7, -OC(S)OR7, -SC(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -OP(O)(OR7)2 or -SP(O)(ORy)2. In another preferred embodiment, R1Oo is -OH, -SH or -NHR7. In another preferred embodiment, R100 is -SH or -OH.
In one embodiment of compounds of formula (XXVIII), R103 is -OH, -SH, -NR7H, -OR1 M1 -SR1 M, -NHR'26, -O(CH2)mOH, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R71 -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7,
-OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R1 I, -0S(0)pR7, -SS(0)pR7, -S(0)p0R7, -NR7S(O)pR7, -OS(O)PNR10R11, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -0S(0)p0R7, -SS(0)p0R7, -NR7S(O)POR7( -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR71 -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R,,, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NRB)NR10R1 1, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -S(O)NHR8, -S(O)2NHR8, -OP(O)(OR7)2 or -SP(O)(OR7)2. In a preferred embodiment Ri03 is -OH, -SH, -NHR7, -OC(O)NR1ORH. -SC(O)NR10R11, -OC(O)R7, -SC(O)R7, -OC(O)OR7, -SC(O)OR7, -OS(O)pR7, -S(O)POR7, -SS(O)pR7, -OS(O)POR7, -SS(O)POR7, -OC(S)R7, -SC(S)R7, -OC(S)OR7, -SC(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -OC(NR6)OR7, -SC(NR8)OR7, -OP(O)(OR7)2 or -SP(O)(OR7)2. In another preferred embodiment, R103 is -OH, -SH or -NHR7. in another preferred embodiment, Ri03 is independently -SH or -OH. In one embodiment of compounds of formula (XXVIII), R73 for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR10R11, -OR7, -SR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)NR10R11, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(O)R7, -SC(O)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NR10R11, -OC(S)NR10R11, -OC(NR8)NR10R11, -SC(O)NR10R11, -SC(NR8)NR10R111 -SC(S)NR1OR111 -OC(NR8)R71 -SC(NR8)R7, -C(O)NR10R11, -NR7C(O)R7, -NR7C(S)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R1I, -NR7CH2C(O)NR10R11, -NR7C(NR8)OR7, -NR7C(O)NR10R11, -NR7C(S)NRi0R11, -NR7C(NR8)NR10R11, -SR7, -S(O)PR7, -OS(O)PR7, -OS(O)pOR7, -OS(O)PNR10R11, -S(O)POR7, -NR8S(O)PR7, -NR7S(O)PNR10R11,
-NR7S(O)POR7, -S(O)pNR,0Ri,r -SS(O)PR7, -SS(O)POR7, -SS(O)PNR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2. In a preferred embodiment, R73 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR7, -SR7, -NR10R111 -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R1,, -SCH2C(O)NRi0Rii, -NR7CH2C(O)NR10R11, -OS(O)pR7l -SS(O)PR7, -NR7S(O)pR7l -OS(O)PNR10R11, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(0)P0R7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R1I, -NR7C(S)NR,0Rii, -OC(NR8)R7, -SC(NR3)R7, -NR7C(NR6)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NR8)NR10R11, -C(O)R7, -C(O)OR7, -C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -S(0)p0R7, -S(O)PNR10R11 or -S(O)PR7. In another preferred embodiment, R73 is for each occurrence, is independently an optionally substituted C1-C6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C3-C6 cycloalkenyl, an optionally substituted heterocyclyl, a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, an alkoxy, an alkylsulfanyl, -OH, -SH, -NHR7, -(CH2)bOH, -(CH2)bSH, -(CH2)bNR7H, -OCH3, -SCH3, -NHCH3, -OCH2CH2OH, -OCH2CH2SH, -OCH2CH2NR7H, -SCH2CH2OH1 -SCH2CH2SH, -SCH2CH2NR7H, -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)PNR10R11, -SS(O)13NR10R11, -NR7S(O)PNR10R11, -OS(O)POR7> -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7,
-OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R1 I, -NR7C(NRB)NR10RI1, -C(O)R7, -C(O)OR7, -C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -S(O)pOR7, -S(O)PNR10R11, -S(O)PR7, -OP(O)(OR7)2 or-SP(0)(OR7)2. In another preferred embodiment, R73, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, -OH, -SH, -HNR7, -OC(O)NR10R11, -SC(O)NR10R11, -OC(O)R7, -SC(O)R7, -OC(O)OR7, -SC(O)OR7, -OS(O)PR7, -S(O)POR7, -SS(O)PR7, -OS(O)POR7,
-SS(O)POR7, -OC(S)R7, -SC(S)R7, -OC(S)OR7, -SC(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -OC(NR8)OR7, -SC(NR6)OR7, -OP(O)(OR7)2 or -SP(O)(OR7)2, In another preferred embodiment, R73 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkylsulfanyl or a C3-C6 cycloalkyl. In another preferred embodiment, R73 is cyclopropyl or isopropyl
In one embodiment of compounds of formula (XXVIII), R7 and R8, for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloa.lkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl. In a preferred embodiment, R7 and R8 for each occurrence, Is independently -H, C1-C6 alkyl, C3-C6 cycloalkyi or aryl. In another preferred embodiment, R7 and R8 for each occurrence, is independently -H or C1-C3 alkyl. In one embodiment of compounds of formula (XXVIII), R10 and R11, for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyi, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl. In a preferred embodiment, Ri0 and R11 for each occurrence, is independently -H, C1-C6 alkyl, C3-C6 cycloalkyi or aryl. In another preferred embodiment, R10 and Ri1 for each occurrence, is independently -H or C1-C3 alkyl. In one embodiment of compounds of formula (XXVIII), R'25 for each occurence is independently a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, -OH, -SH, -NHR7, -(CH2)bOH, -(CH2)bSH, -(CH2JbNR7H, -OCH3, -SCH3, -NHCH3, -OCH2CH2OH, -OCH2CH2SH, -OCH2CH2NR7H, -SCH2CH2OH, -SCH2CH2SH, -SCH2CH2NR7H, -OC(O)NR10R11, -SC(O)NR10Rii, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)pNR10Rii, -SS(O)PNR10R1I, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NRB)OR7, -NR7C(NRB)OR7, -OC(NR8)NR10R111 -SC(NR8)NR10R1I, -NR7C(NR8)NR10R11, -C(O)R7, -C(O)OR7, -C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -S(O)POR7, -S(O)PNR10R11, or -S(O)PR7. In a preferred embodiment, R'25 is -OH, -SH, -NHR7, -(CH2)bOH, -(CH2)bSH, -(CH2)bNR7H,
-OCH3, -SCH3, -NHCH3, -OCH2CH2OH, -OCH2CH2SH, -OCH2CH2NR7H, -SCH2CH2OH, -SCH2CH2SH, -SCH2CH2NR7H, -OC(O)NR10R11, -SC(O)NR10Ri1, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -OS(O)pR7, -SS(O)pR7, -NR7S(O)PR7, -OS(O)PNR10R11, -SS(O)PNR10R11, -NR7S(O)pNR10R11( -OS(O)POR7) -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri1, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRB)NRioRii, -SC(NR8)NR10R11, -NR7C(NR8)NR10R11, -C(O)R7, -C(O)OR7, -C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10RH, -C(NR8)SR7, -S(0)p0R7, -S(0)pNRioRii or -S(O)PR7 In another preferred embodiment, R'2S for each occurrence is independently -OH, -SH, -NHR7, -OC(O)NR10R11 -SC(O)NR10R11 -OC(O)R7, -SC(O)R7, -OC(O)OR7, -SC(O)OR7 -OS(O)PR7, -S(O)POR7, -SS(O)PR7, -OS(O)POR7, -SS(O)POR7, -OC(S)R7 -SC(S)R7, -OC(S)OR7, -SC(S)OR7 -OC(S)NR10R11 -SC(S)NR10R1I -OC(NR8)R7 -SC(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -OP(O)(OR7)2 or -SP(O)(OR7);, In another preferred embodiment, R'Zs is independently -OH, -SH or -NHR7 In another preferred embodiment, R'2s is independently -SH or -OH
In one embodiment of compounds of formula (XXVIII), R'26 is a C1-C6 alkyl In one embodiment of compounds of formula (XXVIII), R74, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR10R11, -OR7, -SR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)NR10R11, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(O)R7, -SC(O)OR7, -SC(NRa)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NR10R11, -OC(S)NR10R11, -OC(NR8)NR10R11, -SC(O)NR10R11, -SC(NR8)NR10R11, -SC(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -C(O)NR10R11, -NR7C(O)R7, -NR7C(S)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R1I, -NR7C(NR8)OR7,
-NR7C(O)NR10R11, -NR7C(S)NR10R11, -NR7C(NR8)NR10R11, -SR7, -S(O)PR7, -OS(O)PR7, -OS(O)pOR7, -OS(O)PNR10R11, -S(O)POR7, -NR8S(O)PR7, -NR7S(O)PNR10R11, -NR7S(O)pOR7, -S(O)PNR10R11, -SS(O)PR7, -SS(O)POR7, -SS(O)PNR10R11, -OP(O)(OR7)2l or -SP(O)(OR7)2 In a preferred embodiment, R74 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR7, -SR7, -NR10R11, -OC(O)NR10R11, -SC(O)NR10R1 I, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)PNR10R11, -SS(O)PNR10R11, -NR7S(O)PNR10Ri1, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R1I, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RI 1, -SC(NRa)NR)0Ri1, -NR7C(NR8)NR10R11, -C(O)R7, -C(O)OR7, -C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NRi0R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -S(O)POR7, -S(O)PNR10R11 or -S(O)PR7. In another preferred embodiment, R74 is a -OH, -SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl. In another preferred embodiment, R74 is a methyl, ethyl, propyl, isopropyl, methoxy or ethoxy.
In one embodiment of compounds of formula (XXVIII), T1 is absent or a C1-C4 alkylene. In a preferred embodiment, T1 is absent or a C1-C2 alkylene. In another preferred embodiment, T1 is absent.
In one embodiment of compounds of formula (XXVIII), T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -NRaRb, -NR3S(O)2 R", -S(O)NRaRb, -S(O)2NRaRb or -C(0)NRaRb. In a preferred embodiment, T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -NRaRb or -S(O)2NR3R". In another preferred embodiment T2 is absent or a C1-C4 alkylene, Vi is absent and V2 is -NRaRb. In another preferred embodiment T2 is absent, V1 is absent and V2 is -NRaRb;or
In one embodiment of compounds of formula (XXVIIl), T2 is absent or a C1-C4 alkylene, V1 is -0-, -S-, -N(R-)- or -C(O)N(R")- and V2 is -S(O)NRaRb, -S(O)2NR3R" or -C(O)NRaRb. In a preferred embodiment, T2 is absent or a C1-C4 alkylene, V1 is -0-, -S- or -N(R*)-, and V2 is -S(O)2NR8R". In another preferred embodiment, T2 is absent or a C1-C4 alkylene, V1 is -O- and V2 is -S(O)2NR8R"; or
In one embodiment of compounds of formula (XXVIlI), T2 is a C2-C4 alkylene, V1 is -0-, -S, -N(R*)-, -C(O)O-, C(O)N(R-)- and V2 is -NRaRb, or -NR8S(O)2R**. In a preferred embodiment, T2 is a C2-C4 alkylene, V1 is -0-, -S- or -N(R*)-, and V2 is -NRaRb. In another preferred embodiment, T2 is a C2-C4 alkylene, V1 is -O- and V2 is -NR8R".
In one embodiment of compounds of formula (XXVIII), T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -NRaRb, -NR0S(O)2 R**, -S(O)NR8R", -S(O)2NR3R" or -C(O)NRaRb. In a preferred embodiment, T2 is absent or a C1-C4 alkylene, V-, is absent and V2 is -S(O)2NRaRb, or -NR8S(O)2 R**. In another preferred embodiment, T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -S(O)2NRaRb, or -NR8S(O)2 R**. In another preferred embodiment, T2 is absent, V1 is absent and V2 is -S(O)2NRaRb, or -NR8S(O)2 R**; or
In one embodiment of compounds of formula (XXVIII), T2 is absent or a C1-C4 alkylene, V1 is -0-, -S-, -N(R')- or -C(O)N(R-)- and V2 is -S(O)NR8R", -S(O)2NR8R" or -C(O)NRaRb. In a preferred embodiment T2 is absent or a C1-C4 alkylene, V1 is -0-, -S- or - N(R-)-, and V2 is -S(O)2NR8R". In another preferred embodiment, T2 is absent or a C1-C4 alkylene, V1 is -0-, and V2 is -S(O)2NR8R"; or
In one embodiment of compounds of formula (XXVIII), T2 is a C2-C4 alkylene, V1 is -O-, -S, -N(R-)-, -C(O)O-, C(O)N(R-)- and V2 is -NRaRb, or -NR8S(O)2R**, In a preferred embodiment T2 is a C2-C4 alkylene, V1 is -0-, -S- or -N(R")-, and V2 is -NRaRb or -NR3S(O)2 R**. In another preferred embodiment T2 is a C2-C4 alkylene, Vi is -O-, and V2 is -NRaRb Or -NR8S(O)2 R**.
In one embodiment of compounds of formula (XXVIII), Each R* is independently -H or C1-C3 alkyl.
In one embodiment of compounds of formula (XXVIII), Ra and Rb, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or heteroaryl, or an optionally substituted aralky); or Ra and Rb, taken together with the nitrogen to which they are attached, form an optionally substituted heteroaryl or heterocyclyl. In a preferred embodiment, RB and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, -COOH, C2-6 acetal, C2-6 ketal, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino and a cycloalkyl; or Ra and Rb taken together with the nitrogen to which they are attached form a substituted or unsubstituted πonaromatic, nitrogen-containing heterocyclyl. In another preferred embodiment, Ra and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -COOH, C2-6 acetal, C2-6 ketal, amino, C1-C6 alkoxy, alkylamino and dialkylamino; or Ra and Rb taken together with the nitrogen to which they are attached are:
Figure imgf000131_0001
In one embodiment of compounds of formula (XXVIII), Ra and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino and a cycloalkyl; or Ra and Rb taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl. In a preferred embodiment, Ra and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -COOH, amino, C1-C6 alkoxy, alkylamino and dialkylamino; or Ra and Rb taken together with the nitrogen to which they are attached are:
Figure imgf000132_0001
In one embodiment of compounds of formula (XXVIII), each R** is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl In a preferred embodiment, R** is independently, -H, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, amino, a C1-C6 alkoxy, alkylamino and dialkylamiπo In another preferred embodiment, R** is independently, -H, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, amino, a C1- C6 alkoxy, alkylamino and dialkylammo In another preferred embodiment R** is -H or a C1-C3 alkyl
In one embodiment of compounds of formula (XXVIII), R'3S is -H, a C1-C4 alkyl or a C1-C4 acyl,
In one embodiment of compounds of formula (XXVIII), p, for each occurrence, is independently, O, 1 or 2
In one embodiment of compounds of formula (XXVIII), m, for each occurrence, is independently, 1 , 2, 3 or 4 Preferably m is 2 or 3 In one embodiment of compounds of formula (XXVIlI), k is 1 , 2, 3, or 4 Preferably k is 1 , 2 or 3, or preferably k is 2 or 3
In one embodiment of compounds of formula (XXVIII), e and f for each occurrence, is independently an integer from 0 to 4 In a preferred embodiment, f is 0 or 1 In a preferred embodiment, e is 0 or 1 In one embodiment of compounds of formula (XXVIII), x is O or 1 , provided that e+x is less than or equal to 4
In one embodiment of compounds of formula (XXVIII), when T1, T2 and V1 are absent and V2 is -NR >8πRb then ring G is not phenyl, and when T1, T2 and Vi are absent and
V2 is -C(O)NR R then ring G is not πaphthyl or indolyl In one embodiment of compounds of formula (XXXI) or (XXXII), X3 and X4 are each, independently, N, N(O), N+(R75) CH or CR73 X5 is O, S, NR75, CH2, CH(R73), C(R73)2, CH=CH, CH=CR73, CR73=CH, CR73=CR73, CH=N, CR73=N, CH=N(O), CR73=N(O), N=CH, N=CR73, N(O)=CH1 N(O)=CR73, N+(R75)=CH, N+(R75J=CR73, CH=N+(R75), CR73=N+(R75) or N=N, provided that at least one X3, X4 or X5 is a heteroatom.
In one embodiment of compounds of formula (XXXI) or (XXXII), R75, for each occurrence, is independently an alkyl or an aralkyl; and the values and preferred values for the remainder of the variables are as described above for formula (I). Preferably X3, X4, X5 and R75 are as described immediately, above and:
In one embodiment of compounds of formula (XXXI) or (XXXII), Ring F is represented by a structural formula selected from:
Figure imgf000133_0001
Figure imgf000133_0002
In one embodiment of compounds of formula (XXXI) or (XXXII), preferably, R73, and R74, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR10R11, -OR7, -SR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)NR10R11, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10RH, -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(O)R7, -SC(O)OR7, -SC(NR6)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NR10R11, -OC(S)NR10R11, -OC(NRe)NR1OR11, -SC(O)NR10R11, -SC(NR8)NR10R11, -SC(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -C(O)NR10R11, -NR7C(O)R7, -NR7C(S)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -NR7C(NR8)OR7, -NR7C(O)NR10R11, -NR7C(S)NR10R11, -NR7C(NR8)NR10R11, -SR7, -S(O)PR7, -0S(0)pR7, -OS(O)POR7, -OS(O)PNR10R11, -S(O)POR7, -NR8S(O)pR7l -NR7S(O)PNR10R11, -NR7S(O)pOR7, -S(O)PNR10R11, -SS(O)PR7, -SS(O)POR7, -SS(O)PNR10R11, -OP(O)(ORy)2, or -SP(O)(ORy)2.
In one embodiment of compounds of formula (XXXI) or (XXXII), R'Zs is -OH, -SH, -NHR7l -(CH2)bOH, -(CH2)bSH, -(CH2)bNR7H, -OCH3, -SCH3, -NHCH3, -OCH2CH2OH, -OCH2CH2SH, -OCH2CH2NR7H, -SCH2CH2OH, -SCH2CH2SH, -SCH2CH2NR7H, -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10Ri1, -OS(O)PR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)pNR10Rii, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)pOR7l -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NR8)NR10R11, -C(O)R7, -C(O)OR7,
-C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR3)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -S(O)POR7, -S(0)pNR10Rn or -S(O)PR7.
In one embodiment of compounds of formula (XXXIII) or (XXXlV)1 R100, R103 and R'2S for each occurrence is independently -OH, -SH, -NHR7, -OC(O)NR10R111 -SC(O)NR10R1 ,, -OC(O)R7, -SC(O)R7, -OC(O)OR7, -SC(O)OR7, -OS(O)PR7, -S(O)POR7, -SS(O)PR7, -OS(O)pOR7, -SS(O)pOR7, -OC(S)R7, -SC(S)R7, -OC(S)OR7, -SC(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -OP(O)(OR7)2 or -SP(O)(OR7J2.
In one embodiment of compounds of formula (XXXIII) or (XXXIV), R74 is an optionally substituted alky), an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR7, -SR7, -NR10R11, -OC(O)NR10Ri1, -SC(O)NR10Rn, -NRyC(O)NR10Rn, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NRi0Rii, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10Rn, -0S(0)pR7, -SS(0)pR7, -NR7S(O)pR7, -OS(O)PNR10R1I, -SS(O)PNR10R11, -NR7S(O)PNR10RI1, -OS(O)POR7, -SS(0)p0R7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1I, -SC(S)NR10R1I, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NRB)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NR8)NR10R11, -C(O)R7, -C(O)OR7, -C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -S(0)p0R7, -S(O)PNR10R11 or -S(O)PR7; and f is O OM .
In one embodiment of compounds of formula (XXXIII) or (XXXIV), R73 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR7, -SR7, -NR10R111 -OC(O)NR10R11, -SC(O)NR10R1I, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10Rn, -OS(O)PR7, -SS(O)PR7, -NR7S(O)pR7l -OS(O)pNR10Rn, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1I, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NR8)NR10R11, -C(O)R7, -C(O)OR7,
-C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -S(O)POR7, -S(O)PNR10R11 or -S(O)PR7.
In one embodiment of compounds of formula (XXXIII) or (XXXlV), Ring G is a six membered nitrogen containing heteroaryl substituted with T1-V1-T2-V2 and optionally further substituted with one or more R74 group.
In one embodiment of compounds of formula (XXXIII) or (XXXIV), Ring G is as just described; and R73 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkylsulfanyl or a C3-C6 cycloalkyl.
In one embodiment for compounds of formula (XXXV), the values and preferred values for the variables are as described above for formulas (XXXIII) or (XXXiV).
In one embodiment for compounds of formula (XXXV), R100 and R103 are each, independently, -OH, -SH or -NHR7; and the values and preferred values for remainder of the variables are as described in the sixth embodiment. More preferably, R100 and R103 are • each, independently, -OH, -SH or -NHR7 and; In one embodiment for compounds of formula (XXXV), RB and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH1 -CN, -SH, -COOH, C2-6 acetal, C2-6 ketal, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino and a cycloalkyl; or Ra and Rb taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl.
In one embodiment for compounds of formula (XXXV)1 T1 is absent or a C1 -C2 alkylene.
In one embodiment for compounds of formula (XXXV), T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -NRaRb or -S(O)2NRaRb; or T2 is absent or a C1-C4 alkylene, V1 is -O-, -S- or -N(R')-, and V2 is -S(O)2NRaRb; or T2 is a C2-C4 alkylene, V1 is -0-, -S- or - N(R')-, and V2 is -NR3R".
In one embodiment for compounds of formula (XXXVI), the values and preferred values for the variables are as described above for formula (XXXV). In one embodiment for compounds of formula (XXXVI), R74 is a -OH, -SH1 halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl.
In one embodiment for compounds of formula (XXXVI), R1Oo, R1Os and R'25 for each occurrence, is independently -SH or -OH, and R73 is cyclopropyl or isopropyl. In one embodiment for compounds of formula (XXXVII)1 the values and preferred values for the variables are as described above for formula (XXXVI).
In one embodiment for compounds of formula (XXXVII), R74 is a methyl, ethyl, propyl, isopropyl, methoxy or ethoxy.
In one embodiment for compounds of formula (XXXVII), Ra and Rb are each independently a hydrogen, a C1 -C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -COOH, C2-6 acetal, C2-6 ketal, amino, C1-C6 alkoxy, alkylamino and dialkylamino; or Ra and Rb taken together with the nitrogen to which they are attached are:
Figure imgf000136_0001
R'35 is -H, a C1-C4 alkyl or a C1-C4 acyl.
T1 is absent. T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -NRaRb. In one embodiment for compounds of structural formula (XXXIV), Ring G is phenyl substituted with T1-V1-T2-V2 and optionally further substituted with one or more R74 group.
In one embodiment for compounds of structural formula (XXXIV), Ring G is as just described and R73 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkylsulfanyl or a C3-C6 cycloalkyl.
In one embodiment of compounds of formula (XXXVIII), the values and preferred values for the variables are as described above for formula (XXXIV).
In one embodiment of compounds of formula (XXXVIII), RiOo and R103 are each, independently, -OH, -SH Or -NHR7. More preferably, R100 and R103 are each, independently, -OH, -SH or -NHR7; and
Ra and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino and a cycloalkyl; or Ra and Rb taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl.
R** is independently, -H, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, amino, a C1- C6 alkoxy, alkylamino and dialkylamino, T1 is absent or a C1-C2 alkylene. T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -S(O)2NR8R", or -NR3S(O)2 R**; or T2 is absent or a C1-C4 alkylene, V1 is -0-, -S- or -N(R-)-, and V2 is -S(0)2NRaRb; or T2 is a C2-C4 alkylene, V1 is -0-, -S- or -N(R>, and V2 is -NRaRb or -NR8S(O)2 R".
In one embodiment of compounds of formula (XXXVIII), R74 is a -OH, -SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl.
In one embodiment of compounds of formula (XXXVIII), R74 is as just described and Rioo, R1Oa and R'25 for each occurrence, is independently -SH or -OH, and R73 is cyclopropyl or isopropyl. In one embodiment of compounds of formula (XXXIX) and (XL), the values and preferred values for the variables are as described above for formula (XXXVIII). In one embodiment of compounds of formula (XXXIX) and (XL), R74 is a methyl, ethyl, propyl, isopropyl, methoxy or ethoxy.
In one embodiment of compounds of formula (XXXIX) and (XL), R74 is as just described; and Ra and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -COOH, amino, C1-C6 alkoxy, alkylamino and dialkylamino; or Ra and Rb taken together with the nitrogen to which they are attached are:
Figure imgf000138_0001
R'35 is -H, a C1-C4 alkyl or a C1-C4 acyl.
R** is independently, -H, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, amino, a C1-C6 alkoxy, alkylamino and dialkylamino. Ti is absent.
T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -S(O)2NR3R", or -NR3S(O)2 R**.
In one embodiment of compounds of formula (XXXI) or (XXXII), the values and preferred values for the remainder of the variables are as described above for formula (XXVlII),
In one embodiment of compounds of formula (XXXI) or (XXXII), R73 is for each occurrence, is independently an optionally substituted C1-C6 alkyl, an optionally substituted C3-C6 cycloalkyl, an optionally substituted C3-C6 cycloalkenyl, an optionally substituted heterocyclyl, a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, an alkoxy, an alkylsulfanyl, -OH, -SH, -NHR7, -(CHz)bOH, -(CH2)bSH, -(CH2)bNRrH, -OCH3, -SCH3, -NHCH3, -OCH2CH2OH, -OCH2CH2SH, -OCH2CH2NR7H, -SCH2CH2OH, -SCH2CH2SH, -SCH2CH2NR7H, -OC(O)NR10Ri1, -SC(O)NR10Ru, -NR7C(O)NR10Rn, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7,
-OCH2C(O)NR10R1I, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -NR7S(O)pR7, -OS(O)pNR10Rii, -SS(O)PNR10R1,, -NR7S(O)PNRi0R11, -OS(O)POR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NRi0Ri1, -NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7,
-OC(NR8)NR10R111 -SC(NR8)NR10Ri1, -NR7C(NR8)NR10Rii, -C(O)R7, -C(O)OR7, -C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -S(O)POR7, -S(O)PNR10R111 -S(O)PR7, -OP(0)(OR7)2 or-SP(O)(OR7)2. k is 1 , 2, 3, or 4; and
In one embodiment of compounds of formula (XXXI) or (XXXII), R73 and k are as just described; and Ring F is represented by a structural formula selected from:
Figure imgf000139_0001
Figure imgf000139_0002
In one embodiment of compounds of formula (XXXI) or (XXXII), R73, k and Ring F are as just described; and R1Oo and R103 are each independently -OH1 -SH, -NHR7, -OC(O)NR10Rii. -SC(O)NR10Ri1, -OC(O)R7, -SC(O)R7, -OC(O)OR7, -SC(O)OR7, -OS(O)PR7, -S(O)pOR7, -SS(O)pR7, -OS(0)pOR7, -SS(O)POR7, -OC(S)R7, -SC(S)R7, -OC(S)OR7, -SC(S)OR7, -OC(S)NR10Ri1, -SC(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -OP(O)(OR7)2 or -SP(O)(OR7)2.
In one embodiment of compounds of formula (XXXI) or (XXXII), R73, k, F,' R100 and R103 are as just described; and R74 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR7, -SR7, -NR10R11, -OC(O)NR10R1I, -SC(O)NR10R11, -NR7C(O)NR10Ri1, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10Ri1, -SCH2C(O)NR10R11, -NR7CH2C(0)NRioRii, -OS(0)PR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)PNR10R11, -SS(O)PNR10R11, -NR7S(O)PNR10RI1, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri1, -SC(S)NR10R1 I, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR6)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NR8)NR10RI1, -C(O)R7, -C(O)OR7, -C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -S(O)POR71 -S(O)PNR10R11 Or -S(0)pR7; and f is 0 or 1.
In one embodiment of compounds of formula (XXXI) or (XXXII), R73, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, -OH, -SH, -HNR7,
-OC(O)NR10R11, -SC(O)NR10R11. -OC(O)R7, -SC(O)R7, -OC(O)OR7, -SC(O)OR7, -OS(O)PR7, -S(O)pOR7, -SS(O)PR7, -OS(O)POR7, -SS(O)POR7, -OC(S)R7, -SC(S)R7, -OC(S)OR7, -SC(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -OP(O)(OR7)2 or -SP(O)(OR7)2. In one embodiment of compounds of formula (XXXI) or (XXXII), Ring G is a six membered nitrogen containing heteroaryl substituted with T1-V1-T2-V2 and optionally further substituted with one or more R74 group.
In one embodiment of compounds of formula (XXXI) or (XXXII), G is as just described; and R73 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkylsulfanyl or a C3-C6 cycloalkyl.
In one embodiment of compounds of formula (XXXI) or (XXXII), R73 is as just described; and Ring G is pyridyl substituted with T1-V1-T2-V2 and optionally further substituted with one or more R74 group.
In one embodiment of compounds of formula (XXXI) or (XXXIl), R73 and G are as just described; and R100 and R103 for each occurrence is independently, -OH, -SH, or -NHR7.
In one embodiment of compounds of formula (XXXI) or (XXXII), R73, G, R100 and R-io3 are as just described; and Ra and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, -COOH1 C2-6 acetal, C2-6 ketal, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino and a cycloalkyl; or Ra and Rb taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl.
T1 is absent or a C1-C2 alkylene.
T2 is absent or a C1-C4 alkylene, V-, is absent and V2 is -NRaRb or -S(O)2NR3R"; or T2 is absent or a C1-C4 alkylene, V1 is -0-, -S- or -N(R')-, and V2 is -S(O)2NR8R"; or T2 is a C2-C4 alkylene, V1 is -0-, -S- or -N(R>, and V2 is -NRaRb.
In one embodiment of compounds of formula (XXXI) or (XXXII), Ring G is represented by the following structural formula: C
Figure imgf000141_0001
In one embodiment of compounds of formula (XXXI) or (XXXII), R74 for each occurrence is independently -OH, -SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, G1- C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl.
In one embodiment of compounds of formula (XXXI) or (XXXII), R74 is as just described; and R10- and R103 for each occurrence, is independently -SH or -OH, and R73 is cyclopropyl or isopropyl.
In one embodiment of compounds of formula (XXXI) or (XXXII), R74, R100 and R103 are as just described; and Ring G is represented by the following structural formula:
c
Figure imgf000141_0002
In one embodiment of compounds of formula (XXXI) or (XXXII), R74 for each occurrence is independently methyl, ethyl, propyl, isopropyl, methoxy or ethoxy.
In one embodiment of compounds of formula (XXXI) or (XXXII), R74 is as just described; and
Ra and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, - COOH, C2-6 acetal, C2-6 ketal, amino, C1-C6 alkoxy, alkylamino and dialkylamino; or Ra and Rb taken together with the nitrogen to which they are attached are:
Figure imgf000141_0003
R'35 is -H, a C1-C4 alkyl or a C1-C4 acyl. Ti is absent.
T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -NRaRb. In one embodiment of compounds of formula (XXXI) or (XXXII)1 Ring G is phenyl substituted with Ti-V1-T2-V2 and optionally further substituted with one or more R74 group. In one embodiment of compounds of formula (XXXI) or (XXXII), G is as just described and R73 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkylsulfanyl or a C3-C6 cycloalkyl.
In one embodiment of compounds of formula (XXXI) or (XXXII), G and R73 are as just described and Ri00 and Ri03 for each occurrence is independently, -OH, -SH1 or -NHR7.
In one embodiment of compounds of formula (XXXI) or (XXXII), G, R73 R100 and R103 are as just described and:
Ra and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino and a cycloalkyl; or R" and Rb taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl.
R** is independently', -H, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, amino, a C1- C6 alkoxy, alkylamino and dialkylamino.
T1 is absent or a C1-C2 alkylene.
T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -S(O)2NR3R", or -NR3S(O)2 R"; or T2 is absent or a C1-C4 alkylene, V1 is -O-, -S- or -N(R*)-, and V2 is -S(O)2NRaRb; or T2 is a C2-C4 alkylene, V1 is -0-, -S- or -N(R>, and V2 is -NR3S(O)2 R". In one embodiment of compounds of formula (XXXI) or (XXXII), Ring G is represented by a structural formula selected from:
Figure imgf000142_0001
In one embodiment of compounds of formula (XXXI) or (XXXII)1
R74 for each occurrence is independently -OH1 -SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl.
In one embodiment of compounds of formula (XXXI) or (XXXII), R74 is as described above and R100 and R103 for each occurrence, is independently -SH or -OH, and R73 is cyclopropyl or isopropyl.
In one embodiment of compounds of formula (XXXI) or (XXXII), R74 for each occurrence is independently methyl, ethyl, propyl, isopropyl, methoxy or ethoxy.
In one embodiment of compounds of formula (XXXI) or (XXXII), R74 is as described above and R" and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -COOH, amino, C1-C6 alkoxy, alkylamino and dialkylamino; or Ra and Rb taken together with the nitrogen to which they are attached are:
Figure imgf000143_0001
R"35 is -H, a C1-C4 alky I or a C1-C4 acyl. R** is independently, -H, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, amino, a C1-C6 alkoxy, alkylamino and dialkylamino. T1 is absent.
T2 is absent or a C1-C4 aikylene, V1 is absent and V2 is -S(O)zNRaRb, or -NR3S(O)2 R".
In one embodiment of compounds of formula (XXIX) or (XXX)1 the values and preferred values for the variables are as described above for formula (XXVIII).
In one embodiment of compounds of formula (XXIX) or (XXX), Ring G is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to -T1-Vi-T2-V2.
In one embodiment of compounds of formula (XXIX) or (XXX)1 Ring G is a six membered nitrogen containing heteroaryl substituted with T1-V1-T2-V2 and optionally further substituted with one or more R74 group.
In one embodiment of compounds of formula (XXIX) or (XXX)1 G is as just described and RiOo is -OH, -SH1 or -NHR7.
In one embodiment of compounds of formula (XXIX) or (XXX), Ring G is pyridyl substituted with T1-V1-T2-V2 and optionally further substituted with one or more R74 group.
In one embodiment of compounds of formula (XXIX) or (XXX), G is as just described and R'22 is -H, an alkyl, an aralkyl, -C(O)R7, -C(O)OR7 or -C(O)NR10Ri1. In one embodiment of compounds of formula (XXIX) or (XXX), G and R'22 are as just described and Ra and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, -COOH, C2-6 acetal, C2-6 ketal, amino, a C1-C6 alkoxy,' alkylsulfanyl, alkylamino, dialkylamino and a cycloalkyl; or Ra and Rb taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl.
T1 is absent or a C1-C2 aikylene. T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -NRaRb or -S(O)2NR3R"; or T2 is absent or a C1-C4 alkylene, V1 is -0-, -S- or -N(R")-, and V2 is -S(O)2NRaRb; or T2 is a C2-C4 alkylene, V1 is -0-, -S- or -N(R*)-, and V2 is -NRaRb.
In one embodiment of compounds of formula (XXIX) or (XXX), Ring G is represented by the following structural formula:
or 1
Figure imgf000144_0001
In one embodiment of compounds of formula (XXIX) or (XXX), ring G is as just described and R74 for each occurrence is independently -OH, -SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl. In one embodiment of compounds of formula (XXIX) or (XXX), Ring G is represented by the following structural formula:
1
Figure imgf000144_0002
In one embodiment of compounds of formula (XXIX) or (XXX)1 ring G is as just described and X14 is O,
In one embodiment of compounds of formula (XXIX) or (XXX), ring G and X14 are as just described and Ra and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -COOH, C2-6 acetal, C2-6 ketal, amino, C1-C6 alkoxy, alkylamino and dialkylamino; or Ra and Rb taken together with the nitrogen to which they are attached are:
Figure imgf000144_0003
R'35 is -H, a C1-C4 alkyl or a C1-C4 acyl.
T1 is absent.
T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -NRaRb. In one embodiment of compounds of formula (XXIX) or (XXX), Ring G is phenyl substituted with T1-VrT2-V2 and optionally further substituted with one or more R74 group.
In one embodiment of compounds of formula (XXIX) or (XXX), Ring G is as just described and R100 is -OH1 -SH, or -NHR7. In one embodiment of compounds of formula (XXIX) or (XXX), Ring G and R1Oo are as just described; and R'22 is -H, an alkyl, an aralkyl, -C(O)R7, -C(O)OR7 or -C(O)NR10Ru.
In one embodiment of compounds of formula (XXIX) or (XXX), Ring G, R100 and R'22 are as just described and Ra and Rb are each independently a hydrogen, a C1-G6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino and a cycloalkyl; or Ra and Rb taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl.
R** is independently, -H1 a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH1 amino, a C1- C6 alkoxy, alkylamino and dialkylamino.
T1 is absent or a C1-C2 alkylene.
T2 is absent or a C1-C4 alkylene, V, is absent and V2 is -S(O)2NRaRb, or -NR3S(O)2 R**; or T2 is absent or a C1-C4 alkylene, V1 is -0-, -S- or -N(R')-, and V2 is -S(O)2NR3R"; or T2 is a C2-C4 alkylene, V1 is -0-, -S- or -N(R*)-, and V2 is -NR8S(O)2 R**. In one embodiment of compounds of formula (XXIX) or (XXX), Ring G is represented by a structural formula selected from:
Figure imgf000145_0001
In one embodiment of compounds of formula (XXIX) or (XXX), Ring G is as just described; and R74 for each occurrence is independently -OH, -SH, halogen, cyano, a C1- C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl.
In one embodiment of compounds of formula (XXIX) or (XXX), Ring G and R74 are as just described and X14 is O.
In one embodiment of compounds of formula (XXIX) or (XXX), Ring G, R74 and Xi4 are as just described and: Ra and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, - COOH, amino, C1-C6 alkoxy, alkylamino and dialkylamino; or Ra and Rb taken together with the nitrogen to which they are attached are:
Figure imgf000146_0001
R'35 is -H, a C1-C4 alky! or a C1-C4 acyl.
R** is independently, -H, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, amino, a C1-C6 alkoxy, alkylamino and dialkylamino.
T1 is absent.
T2 is absent or a C1-C4 alkylene, V, is absent and V2 is -S(O)2NRaRb, or -NR3S(O)2
R"
In another embodiment, the compound is selected from the group consisting of: 4-(4-(6-(N-(2-methoxyethyl)-N-methylamino)pyridin-3-yl)-5-hydroxy-4H-1,2,4-triazol-3-yl)-6- isopropylbenzene-1 ,3-diol;
4-(4-(6-(N-(2,2-dimethoxyethyl)-N-methylamino)pyridin-3-yl)-5-hydroxy-4H-1 ,2,4-triazol-3-yl)-6- isopropylbenzene-1 ,3-diol;
4-(4-(6-(N-(2,2-methoxyethyl)-N-methylamino)ρyridin-3-yl)-5-hydroxy-4H-1 ,2,4-triazol-3-yl)-6- isopropylbenzene-1 ,3-diol;
2-(N-(5-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-oxo-1H-1 ,2,4-triazol-4(5H)-yl)pyridin-2-yl)-N- methylamino)acetic acid;
4-(4-(6-(N-(2-(dimethylamino)ethyl)-N-methylamino)pyridin-3-yl)-5-hydroxy-4H-1 ,2,4-triazol-3-yl)- 6-isopropylbenzene-1 ,3-diol;
4-(4-(6-(dimethylamino)pyridin-3-yl)-5-hydroxy-4H-1 ,2,4-triazol-3-yl)-6-isopropylbenzene-1,3- diol;
4-(4-(6-(dimethylamino)pyridin-3-yl)-5-hydroxy-4H-1 ,2,4-triazol-3-yl)-6-isopropylbenzene-1 ,3-diol dihydrochloride;
4-(5-hydroxy-4-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene- 1 ,3-diol;
4-(5-hydroxy-4-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene- 1 ,3-diol dihydrochloride;
3-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1 ,2,4-triazol-4-yl)-N-(2- (dimethylamino)ethyl)-N-methylbenzenesulfonamide; 5-(3-{2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-N,N,2- trimethylbenzenesulfonamide; 5-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-2- (dimethylamino)benzenesulfonamicle;
5-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1 ,2,4-triazol-4-yl)-2-
(dimethylamiπo)benzenesulfonamide hydrochloride;
3-(3-(2,4-dihydroxy-5-isopropylpheπyl)-5-mercapto-4H-1,2,4-triazol-4-yl)ben2eπesulfonamide;
4-(5-hydroxy-4-(3-(morpholinosulfonyl)phenyl)-4H-1,2,4-triazol-3-yl)-6-isopropylben2ene-1,3- diol;
N-(4-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1 ,2,4-triazol-4-yl)phenyl)-N- methylmethanesulfonamide;
5-(3-(2,4-dibydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-N-(2-methoxyethyl)-N,2- dimethylbenzenesulfonamide;
4-(5-hydroxy-4-(6-morpho!inopyridin-3-yl)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1 ,3-diol; or
4-(5-hydroxy-4-(6-(2-morpholinoethoxy)pyridiπ-3-yl)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-
1 ,3-diol; or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof.
In one embodiment, the compounds of the invention do not include the compounds disclosed in U.S. Patent Application No. 11/282,119, filed November 17, 2005.
Exemplary compounds of the invention are depicted in Table 1 below, including tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof.
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0002
Exemplary compounds of the invention are depicted in Table 2 below, including tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof.
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Exemplary compounds of the invention are depicted in Table 3 below, including tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof.
Figure imgf000154_0002
Figure imgf000155_0001
Figure imgf000156_0001
I
Figure imgf000157_0001
-
-
Figure imgf000158_0001
Figure imgf000159_0001
Exemplary compounds of the invention are depicted in Table 4 below, including tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof.
Figure imgf000159_0002
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
,3-
Figure imgf000167_0001
Figure imgf000168_0001
, 3-
H-
Figure imgf000169_0001
Exemplary compounds of the invention are depicted in Table 5 below, including tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof.
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0002
In certain instances tautomeric forms of the disclosed compound exist, such as the tautomeric structures shown below:
Figure imgf000174_0001
Tautomer
X15 = O, S or NR7
It is to be understood that when a compound is represented by a structural formula herein, all other tautomeric forms which may exist for the compound are encompassed the structural formula. Compounds represented by formulas disclosed herein that can form analogous tautomeric structures to the one shown above are also preferred.
Similarly, prodrugs, i.e. compounds which can be metabolized or hydrolyzed in vivo to a compound of the present invention are encompassed by the present description. For example, the following embodiments of a compound of the present invention can be produced in vivo in the following reaction:
Figure imgf000175_0001
Figure imgf000175_0002
Figure imgf000175_0003
One skilled in the art will understand that other hydrolyzable protecting groups can be employed with the compounds of the present invention to obtain prodrugs encompassed by the present description.
Without wishing to be bound by any theory, it is believed that the compounds of the invention preferentially bind to Hsp90 in the tautomeric form shown above, and thereby inhibit the activity of Hsp90.
C. Methods for Making Compounds of the Invention
Compounds of the invention can be obtained via standard, well-known synthetic methodology, see e.g., March, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992. In particular, compounds of the invention can be obtained by heating a benzoic acid (1) with an aminophenyl (2) to give a phenyl benzamide (3) which can then be reacted with hydrazine to give a triazole (4) (see Scheme I below). Starting materials useful for preparing compounds of the invention and intermediates therefore, are commercially available or can be prepared from commercially available materials using known synthetic methods and reagents.
Additional methods of preparing the compounds of the invention can be found in U.S. Provisional Patent Application Serial No. 60/808,376, filed on May 25, 2006; U.S. Provisional Patent Application Serial No. 60/808,342, filed on May 25, 2006; U.S. Provisional Patent Application Serial No. 60/808,375, filed on May 25, 2006; and U.S. Provisional Patent Application Serial No. 60/902,031, filed on February 16, 2007, the entire teachings of each of these applications are incorporated herein by reference.
Reactive functional groups can be protected during one or more reaction step, then deprotected to restore the original functionality. Examples of suitable protecting groups for hydroxyl groups include benzyl, methoxymethyl, allyl, trimethylsilyl, tert-butyldimethylsilyl, acetate, and the like. Examples of suitable amine protecting groups include benzyloxycarbonyl, tert-butoxycarbonyl, tert-butyl, benzyl and fluorenylmethyloxy-carbonyl (Fmoc). Examples of suitable thiol protecting groups include benzyl, tert-butyl, acetyl, methoxymethyl and the like. Other suitable protecting groups are well known to those of ordinary skill in the art and include those found in T. W. Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.
Scheme I: Synthesis of triazole compounds of the invention
Figure imgf000177_0001
Figure imgf000177_0002
(3) (4)
Figure imgf000177_0003
In addition, compounds of the invention can also be prepared as shown below in the Schemes and Examples below.
In one embodiment, the compounds can be prepared as shown in Scheme II. A dlhydroxy benzoic acid methyl ester is reacted with benzyl chloride, to produce a Bis-benzyloxy benzoic acid methyl ester (1). The Bis-benzyloxy benzoic acid methyl ester can then be heated with LiOH to give a Bis-benzyloxy benzoic acid (2). The Bis-benzyloxy benzoic acid (2) is then reacted with an aminophenyl to produce a phenyl-benzamide (3). The phenyl- benzamide (3) is then reacted with hydrazine to give a triazol (4). The hydroxy groups can then be unprotecxted in the presence of palladium on charcoal to give the final product. Scheme Il
Figure imgf000178_0001
In another embodiment the compounds can be prepared as shown in Scheme III. A nitroaniline (1) can be reacted with propionyl chloride to yield nitro-phenyl-propionamide (2). NaH can then be added to a solution of (2) in anhydrous THF followed by iodomethane to give pure product nitro-phenyl-N-methyl-propionamide (3).
The nitro-phenyl-N-methyl-propionamide (3) and borane-methyl sulfide complex are heated to give the nitro-phenyl-methyl-propyl-amine (4). A solution of (4) in MeOH/EtOAc containing Pd-C can be subjected to hydrogenation to give the N-methyl-N-propyl-benzene- 1,3-diamine (5).
To a stirred solution of (5) in CH2CI2 can be added 1 ,1'-thiocarbonyldiimidazόle to give the (5-lsothiocyanato-2-methoxy-phenyl)-methyl-propyl-amine (6).
The isothiocyanate (6) can be reacted with the hydrazide (7) to give the intermediate (8). A solution of NaOH in water can be added to the intermediate (8), which can then be flushed with nitrogen and heated. The reaction mixture can then be cooled and acidified. The mixture can then be filtered and purified to give 4-isopropyl-6-{5-mercapto-4-[4~methoxy-3- (methyl-propyl-amino)-phenyl]-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol.
Scheme III
Figure imgf000179_0001
In another embodiment the compounds can be prepared as shown in Scheme IV. A bromo- nitrobenzene (1) can be reacted with N1, N2, Λ/2-trimethylethane-1 ,2-diamine to give N1- (nitrophenyl)-ΛΛ N2, Λ/2-trimethylethane-1 ,2-diamine (2). A solution of (2) in can be subjected to hydrogenation, passed through a short pad of celite, washed with MeOH and evaporated under reduced pressure. Thiocarbodiimidazole can then be added to (2) to give the W'-(isothiocyanato-phenyl)- )-N1, N2, Λ^-trimethylethane-i ^-diamine (3)
The isothiocyanate (3) can then be reacted with a benzoic acid hydrazide to give the final product 4-(4-{3-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)-5-mercapto-4H- 1,2,4-triazol-3-yl}-6-isopropylbenzene-1,3-diol (4).
Scheme IV
Figure imgf000180_0001
(4)
Certain compounds of the invention can be obtained by heating a hydrazide (A) with an isocyanate (X14 = O), isothiocyanate, (X14 = S) or carbodiimide (X14 = NR7) (B) in an alcohol to form intermediate (C). Intermediate (C) can be cyclized to form a triazole core (D) by heating it in an aqueous solution which includes about 2 molar equivalents of NaOH (see Scheme V below).
Scheme V: Synthesis of triazole compounds of the invention
Figure imgf000180_0002
(D)
Starting materials useful for preparing compounds of the invention and intermediates therefore, are commercially available or can be prepared from commercially available materials using known synthetic methods and reagents. For example, a hydrazide can be prepared by reacting an ester (such as 6-hydroxy-1 H-indoIe-5-carboxylic acid methyl ester) or acid chloride with hydrazine. lsocyanates and isothiocyanates (X14 is O or S, respectively) can be formed in a number of ways from compounds that have a primary amine group. For example, a primary amine can be reacted with phosgene or thiophosgene to form an isocyanate or an isothiocyanate, respectively. Alternatively, a cyanate or thiocyanate ion can be reacted with an alkyl halide to form an alkyl isocyanate or an alkyl isothiocyanate. In addition, an isothiocyanate can be prepared by reacting a diazonium salt with a thiocyanate ion. Carbodiimides (Xi4 is NR7) can be prepared by dehydration of ureas using a dehydration agent such as tosyl chloride in pyridine, POCI3, PCI5, P2Os-pyridine, and Ph3PBr2-Et3N. Other methods of preparing isocyanates, thioisocyanates, and carbodiimides can be found in March, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, the entire teachings of which are incorporated by reference. Reactive functional groups can be protected during one or more reaction step, then deprotected to restore the original functionality. Examples of suitable protecting groups for hydroxyl groups include benzyl, methoxymethyl, allyl, trimethylsilyl, tert-butyldimethylsilyl, acetate, and the like. Examples of suitable amine protecting groups include benzyloxycarbonyl, tert-butoxycarbonyl, tert-butyl, benzyl and fluorenylmethyloxy-carbonyl (Fmoc). Examples of suitable thiol protecting groups include benzyl, tert-butyl, acetyl, methoxymethyl and the like. Other suitable protecting groups are well known to those of ordinary skill in the art and include those found in T. W. Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.
An alternative method of preparing the compounds of the invention is shown in Scheme Vl. In this method, an aryl or heteroaryl amine compound (i) is stirred at about room temperature with a thiocarbonyl (ii) which has two leaving groups, Li and L2, such as imidazole-1-yl groups, to form compound (iii). Typically, the thiocarbonyl compound is present in a slight molar excess of about 1.05 eq. to about 1.3 eq. compared with compound (i). Compound (iii) is then combined with a hydrazide compound (iv) in a solvent and heated to about 5O0C to about 1000C for about 0.5 to 5 hrs to form compound (v). Typically, compound (iii) and compound (iv) can be present in about equal molar ratio or a slight excess of compound (iii), such as about 1.01 to about 1.1 molar eq. of compound (iii) compare to compound (iv). Compound (v) can then be cyclized to form a triazole compound of the invention (vi) by suspending it in aqueous solution containing about 2 molar eq. of NaOH and heating the solution to about 750C to about 11O0C for about 0.5 hr to about 2 hrs. Typically, the NaOH solution containing compound (v) is degassed before heating by bubbling an inert gas, such as nitrogen or argon, through it.
Scheme Vl: Alternative synthesis of triazole compounds of the invention
Figure imgf000182_0001
2 eq NaOIl (aq)
Figure imgf000182_0002
Figure imgf000182_0003
Another alternative method of preparing the compounds of the invention is shown in Scheme VII In this method, an aldehyde group is added to an aryl or a heteroaryl having a phenolic hydroxyl group in the position ortho to the hydroxyl group using a Vilsmeier reaction For example, diaminobenzene (vii) is reacted with 3-oxo-butyπc acid methyl ester (viii) to form 7-amιno-4-methyl-1 H-quιnolιn-2-one (ix) The amine group of 7-amιno-4- methyl-1 H-quιnolιn-2-one (ix) is converted to a diazonium salt and replaced with a hydroxy group by treating it with NaNO2 and H2SO4 in an aqueous solution to form 7-hydroxy-4- methyl-1 H-quιnolιn-2-one (x) 7-Hydroxy-4-methyl-1 H-quιnolιn-2-one (x) is then treated with POCI3 and dimethylformamide (DMF) to add an aldehyde group ortho to the phenolic hydroxyl group forming 2-oxo-7-hydroxy-4-methyl-1 ,2-dιhydro-1 H-quιnolιn-6-carbaldehyde (xi) The hydroxyl group is then protected with a hydroxyl protecting group such as a benzyl group by, for example, reacting 2-oxo-7-hydroxy-4-methyl-1 ,2-dιhydro-1 H-quιnolιn-6- carbaldehyde (xi) with benzyl chloride in the presence of a base to form 2-oxo-7-benzyloxy- 4-methyl-1 ,2-dιhydro-i H-quιnolιn-6-carbaldehyde (xii)
1-Methyl-6-amιno-ιndole is reacted with phenylchloroformate to form 1-methyl-1 H- ιndole-6-phenylcarbamate which is then heated with hydrazine in dioxane to form 1-methyl- 1 H-ιndole-6-amιnohydπzιde (xiii) 1-Methyl-1 H-ιndole-6-amιnohydrιzιde (xni) is heated with 2-oxo-7-benzyloxy-4-methyl-1 ,2-dιhydro-1 H-quιnolιn-6-carbaldehyde (xii) in and ethanol solution with a catalytic amount of acetic acid to form intermediate (xiv) Intermediate (xiv) is cychzed to form a triazole ring by heating it with a catalytic amount of (5 3) NaOH/K3Fe(CN)6 in an ethanol solution for about 4 to 10 hours to form compound (xv) The hydroxyl group of compound (xv) is deprotected by treating it with BCI3 to form a compound of the invention (xvi) Scheme VII: Alternative synthesis of triazole compounds of the invention
Figure imgf000183_0001
An indole hydrazide can also be prepared by treating a solution of 2-methoxy-4- amino-benzoic acid methyl ester (xvii) in ethanol with N-bromosuccinamide to form 2- methoxy-4-amino-5-bromo-benzoic acid methyl ester (xviii) (see Scheme VIII). A solution of 2-methoxy-4-amiπo-5-bromo-benzoic acid methyl ester (xviii) in DMF is then reacted with trimethyl-prop-1-ynyl silane (xix) in the presence of with palladium acetate, Na2CO3, triphenylphosphine and tetrabutylaminium iodide to form 6-methoxy-3-methyl-2- trimethylsilanyl-1/-/-indole-5-carboxylic acid methyl ester (xx). Compound (xx) is then treated with an aqueous HCI solution to remove the trimethylsilanyl group and form 6- methoxy-3-methyl-1H-indole-5-carboxylic acid methyl ester (xxi). Compound (xxi) is treated with NaOH in a THF/H2O solution to convert the ester to a carboxylic acid. The carboxylic acid is then activated by treating it with oxalyl chloride in dichloromethane and a catalytic amount of DMF, then the activated carboxylic acid is converted to a hydrazide by treating it with hydrazine hydrate in dichloromethane to form 6-methoxy-3-methyl-1 H-indole- 5-carboxylic acid hydrazide (xxii). Hydrazide (xxii) can be used in the method of Scheme Vor Vl to form a compound of the invention
Scheme VIII: Method of preparing a 1H-indole-hvdrazide
Figure imgf000184_0001
DMF
Figure imgf000184_0003
(xxii) CH2Cl2, -78°C-rt
Figure imgf000184_0002
In one embodiment, ring A of the compounds of the invention has a hydroxyl substituent group. In this embodiment, it is sometimes desirable to prepare a prodrug by protecting the hydroxy group with a moiety that can be hydrolyzed in vivo. Protection of the hydroxy group is expected to improve the circulating half-life of compound compounds of the invention. In addition, it is desirable that a group added to the hydroxy group increase the water solubility of the compounds of the invention. In one embodiment, 4-methyl- piperizine-1 -carbamoyl group is used to protect the hydroxy group (see Scheme IX). In this embodiment, a compound of the invention, such as compound (E), is treated with about one molar equivalents of 4-methyl-piperizine-1-carbonyl chloride (F) in the presence of a base to form compound (G) in which the hydroxy group is protected. Alternatively, the metcapto group can be protected first by reacting compound (E) with about one molar equivalent of acyl chloride in the presence of a base to form intermediate (H). Intermediate (H) can them be reacted with about one molar equivalent of 4-methyl-piperizine-1-carbonyl chloride (F) in the presence of a base, then the acetyl group can be removed by treatment with a mild acid to form compound (G).
Scheme IX: Preparation of prodrugs in which the 4-hydroxy group of compounds of the invention is protected with 4-methyl-piperizine-1 -carbamoyl.
Figure imgf000185_0001
Another prodrug of compounds of the the invention can be formed by addition of a phosphate group to an hydroxy substituent on ring A (Scheme X). In this embodiment, a compound of the invention, such as compound (E), is treated with about one molar equivalent of diisopropyl phosphoramidous acid di-t-butyl ester in the presence of tetrazole to yield compound (J). The phosphorous group is then oxidized with m-CPBA to form a phosphoric acid di-t-butyl ester group of compound K. The t-butyl groups are then hydrolyzed with trifluoroacetic acid (TFA) to yield a phosphoric acid group or compound L.
Scheme X: Preparation of prodrugs in which the 4-hvdroxy group of compounds of the invention is protected with a phosphate group.
Figure imgf000186_0001
Figure imgf000186_0002
Scheme Xl: Synthesis of Certain Triazole Compounds
Figure imgf000186_0003
Scheme XII: Synthesis of Certain Triazole Compounds
Figure imgf000187_0001
D. Uses of Compounds of the Invention
The present invention is directed to therapies which involve administering one of more compounds of the invention, and compositions comprising said compounds to a subject, preferably a human subject, to inhibit the activity of Hsp90 or to prevent, treat, manage, or ameliorate a proliferative disorder, such as cancer, or one or more symptoms thereof.
In one embodiment, the present invention is directed to treating cancers in which aberrant expression and/or activation of c-kit has been implicated as a contributing factor. The method comprises adiministering to a patient an effective amount of a compound represented by formula (I)-(XL), and those set forth in Tables 1-5.
In one embodiment, the present invention is directed to treating cancers in which expression of Bcr-Abl has been implicated as a contributing factor. The method comprises adiministering to a patient an effective amount of a compound represented by formula (I)- (XL)1 and those set forth in Tables 1-5.
In one embodiment, the present invention is directed to treating cancers in which aberrant expression and/or activation of flt-3 has been implicated as a contributing factor. The method comprises adiministering to a patient an effective amount of a compound represented by formula (I)-(XL), and those set forth in Tables 1-5.
In one embodiment, the present invention is directed to treating cancers in which aberrant expression and/or activation of EGFR has been implicated as a contributing factor. The method comprises adiministering to a patient an effective amount of a compound represented by formula (I)-(XL), and those set forth in Tables 1-5.
In one embodiment, the present invention is directed to treating cancers in which Hsp90 is over expressed compared with normal cells. The method comprises adiministering to a patient an effective amount of a compound represented by formula (I)-(XL), and those set forth in Tables 1-5. Examples of cancers in which Hsp90 is over expressed include difuse large B-cell lymphomas (DLBCL).
In one aspect, the invention provides a method of inhibiting the activity of Hsp90 in a cell, comprising administering to the cell an effective amount of a compound represented by formula (I)-(XL), and those set forth in Tables 1-5. In one embodiment, the compound is administered to a cell in a subject, preferably a mammal, and more preferably a human.
In another aspect, the invention provides a method of treating or preventing a proliferation disorder in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I)-(XL), and those set forth in Tables 1-5. In one embodiment, the compound is administered to a human to treat or prevent a proliferative disorder. In another embodiment, the proliferation disorder is cancer. In another embodiment, the compound is administered with one or more additional therapeutic agents. In a preferred embodiment, the additional therapeutic agent is an anticancer agent.
In another aspect, the invention provides a method for treating cancer in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I)-(XL), and those set forth in Tables 1-5. In one embodiment, the compound is administered to a human to treat or prevent cancer. In another embodiment, the compound is administered with one or more additional therapeutic agents. In a preferred embodiment, the one or more additional therapeutic agents are anticancer agents. In another aspect, the invention provides a method for treating a c-kit associated cancer in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I)-(XL), and those set forth in Tables 1-5. In one embodiment, the compound is administered to a human to treat or prevent the c-kit associated cancer. In another embodiment, the compound is administered with one or more additional therapeutic agents. In a preferred embodiment, the one or more additional therapeutic agents are ■ anticancer agents.
In another aspect, the invention provides a method for treating a Bcr-Abl associated cancer in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I)-(XL), and those set forth in Tables 1-5. In one embodiment, the compound is administered to a human to treat or prevent the Bcr-Abl associated cancer. In another embodiment, the compound is administered with one or more additional therapeutic agents. In a preferred embodiment, the one or more additional therapeutic agents are anticancer agents.
In another aspect, the invention provides a method for treating a flt3 associated cancer in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I)-(XL), and those set forth in Tables 1-5. In one embodiment, the compound is administered to a human to treat or prevent the flt3 associated cancer. In another embodiment, the compound is administered with one or more additional therapeutic agents. In a preferred embodiment, the one or more additional therapeutic agents are anticancer agents. In another aspect, the invention provides a method for treating an EGFR associated cancer in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I)-(XL)1 and those set forth in Tables 1-5. In one embodiment, the compound is administered to a human to treat or prevent the EGFR associated cancer. In another embodiment, the compound is administered with one or more additional therapeutic agents. In a preferred embodiment, the one or more additional therapeutic agents are anticancer agents.
In another aspect, the invention provides a method for treating a cancer in a mammal which is characterized by the upregulation of Hsp90 compared to normal cells of the same type, comprising administering to the mammal an effective amount of a compound represented by formula (I)-(XL), and those set forth in Tables 1-5. In one embodiment, the compound is administered to a human to treat or prevent the cancer associated with the upregulation of Hsp90. In another embodiment, the cancer associated with the upregulation of Hsp90 is DLBCL. In another embodiment, the compound is administered with one or more additional therapeutic agents. In a preferred embodiment, the one or more additional therapeutic agents are anticancer agents.
In another aspect, the invention provides a method for treating or inhibiting angiogenesis in a subject in need thereof, comprising administering to the subject an effective amount of a compound represented by formula (I)-(XL), and those set forth in Tables 1 -5.
In another aspect, the invention provides a method of blocking, occluding, or otherwise disrupting blood flow in neovasculature, comprising contacting the neovasculature with an effective amount of a compound represented by formula (I)-(XL), and those set forth in Tables 1-5. In one aspect, the neovasculature is in a subject and blood flow in the neovasculature is blocked, occluded, or otherwise disrupted in the subject by administering to the subject an effective amount of a compound represented by formula (I)-(XL), and those set forth in Tables 1-5. In one aspect, the subject is human. The present invention provides a method for preventing, treating, managing, or ameliorating an infection in a subject in need thereof, comprising administering an effective amount of a compound represented by formula (I)-(XL), and those set forth in Tables 1-5
In one aspect, the invention is directed to a method of treating or preventing a fungal infection
In one aspect, the invention is directed to a method of treating or preventing a yeast infection
In one aspect, the invention is directed to a method of treating or preventing a yeast infection caused by a Candida yeast In one aspect, the invention is directed to a method of treating or preventing a bacterial infection
In one aspect, the invention is directed to a method of treating or preventing abacterial infection caused by a Gram Positive Bacteria
In one aspect, the invention is directed to a method of treating or preventing abacterial infection caused by a Gram Negative Bacteria
In one aspect, the invention is directed to a method of treating or preventing a viral infection
In one aspect, the invention is directed to a method of treating or preventing a viral infection caused by an influenza virus, a herpes virus, a hepatitis virus, or an HIV virus
In one aspect the invention is directed to a method of treating or preventing a viral infection caused by influenza A virus, herpes simplex virus type 1 , hepatitis C virus, hepatitis B virus, HIV-1 virus, or Epstein-Barr Virus
In one aspect, the invention is directed to a method of treating or preventing a parasitic infection
In one aspect, the invention is directed to a method of treating or preventing a protozoal infection
In one aspect, the invention is directed to a method of treating or preventing an infection caused by Plasmodium falciparum or trypsanosoma cruzi
In one aspect, the invention is directed to a method of treating or preventing an infection caused by a leishmania protozoa In one aspect, the invention is directed to a method of treating or preventing an amoebic infection
In one aspect, the invention is directed to a method of treating or preventing a helminth infection In one aspect, the invention is directed to a method of treating or preventing an infection caused by schistostoma mansoni
In one aspect, compounds of the invention are administered in combination with one or more additional anti-infective therapeutic agents The present invention provides a method for inhibiting topoisomerase II, comprising administering an effective amount of a compound represented by formula (I)-(XL), and those set forth in Tables 1-5
In another embodiment, topoisomerase Il is associated with a disease and administering the compound will treat or prevent the disease In one aspect, the disease is a proliferative disease In another aspect, the proliferative disease is cancer In one aspect, the disease is an infection
The present invention provides a method of treating an inflammatory disorder in a subject in need thereof, comprising administering an effective amount of a compound represented by formula (I)-(XL), and those set forth in Tables 1-5 In one embodiment, the inflammatory disorder is selected from the group consisting of transplant rejection, skin graft rejection arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption, inflammatory bowel disease, ileitis, ulcerative colitis, Barrett's syndrome, Crohn's disease, asthma, adult respiratory distress syndrome, chronic obstructive airway disease, corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmitis, endophthalmitis, gingivitis, periodontitis, tuberculosis, leprosy, uremic complications, glomerulonephritis, nephrosis, sclerodermatitis, psoriasis, eczema, chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS-related neurodegeneration, Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis viral or autoimmune encephalitis, autoimmune disorders, immune-complex vasculitis, systemic lupus and erythematodes, systemic lupus erythematosus (SLE), cardiomyopathy, ischemic heart disease hypercholesterolemia, atherosclerosis, preeclampsia, chronic liver failure, brain and spinal cord trauma The present invention provides a method of treating an immune disorder in a subject in need thereof, comprising administering an effective amount of a compound represented by formula (I)-(XL), and those set forth in Tables 1-5 In one embodiment, the immune disorder is selected from the group consisting of multiple sclerosis, myasthenia gravis, Guillain-Barre, autoimmune uveitis, autoimmune hemolytic anemia, pernicious anemia, autoimmune thrombocytopenia, temporal arteritis, anti-phospholipid syndrome, vasculitides such as
Wegener's granulomatosis, Behcet's disease, psoriasis, dermatitis herpetiformis, pemphigus vulgaris, vitiligo, Crohn's disease, ulcerative colitis, primary biliary cirrhosis, autoimmune hepatitis, Type 1 or immune-mediated diabetes mellitus, Grave's disease. Hashimoto's thyroiditis, autoimmune oophoritis and orchitis, autoimmune disorder of the adrenal gland, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, ankylosing spondylitis, and Sjogren's syndrome.
The present invention provides a method of suppressing an immune response in a subject in need thereof, comprising administering an effective amount of a compound represented by formula (I)-(XL), and those set forth in Tables 1-5. In one embodiment, the subject in need of immunosuppression is a subject that has received an organ or tissue transplant, such as a skin graft, heart, kidney, lung, liver, pancreas, cornea, bowel, stomach, and the like. In another embodiment, the subject in need of immunosuppression is a subject that has received stem cell transplantation. The transplant may be a syngeneic transplant (i.e., from a donor that has the same genetic make up), an allographs transplant (i.e., from a donor of the same species) or a xenographic transplant (i.e., from a donor that is a different species).
The present invention provides a method of inhibiting the production of inflammatory cytokines, such as G-CSF, GM-CSF, IL-12, IL-1β, IL-23, lL-6, IL-8, and TNF-α, in a subject in need of such treatment. The method comprises administering to the subject an effective amount of a compound represented by formula (I)-(XL), and those set forth in Tables 1-5. 1. c-Kit Associated Cancers
SCF binding to the c-kit protects hematopoietic stem and progenitor cells from apoptosis (Lee, et al., 1997, J. Immunol., 759:3211 -3219), thereby contributing to colony formation and hematopoiesis. Expression of c-kit is frequently observed in acute myelocytic leukemia (AML) and sometimes observed in acute lymphocytic leukemia (ALL) (for reviews, see Sperling, et al., 1997, Haemal, 82:617-621; Escribano, et al., 1998, leuk. Lymph., 30:459- 466). Although c-kit is expressed in the majority of AML cells, its expression does not appear to be prognostic of disease progression (Sperling, et al, 1997, Haemat. 82:617-621). However, SCF protected AML cells from apoptosis induced by chemotherapeutic agents (Hassan, et a/., 1996, Acta. Hem., 95:257-262). Therefore, degradation of c-kit caused by the inhibition of Hsp90 by the compounds of the invention will enhance the efficacy of these agents and may induce apoptosis of AML cells.
The clonal growth of cells from patients with myelodysplastic syndrome (Sawada, et a/., 1996, Blood, 88:319-327) or chronic myelogenous leukemia (CML) (Sawai, et al., 1996, Exp. Hem., 2:116-122) was found to be significantly enhanced by SCF in combination with other cytokines. CML is characterized by expansion of Philadelphia chromosome positive cells of the marrow (Verfaillie, er a/., 1998, Leuk., 72:136-138), which appears to primarily result from inhibition of apoptotic death (Jones, 1997, Curr. Opiπ. One, 9:3-7). The product of the Philadelphia chromosome, p210.sup.BCR-ABL, has been reported to mediate inhibition of apoptosis (Bedi, et al., 1995, Stood, 86:1148-1158). Since p210.sup.BCR-ABL and the c-kit RTK both inhibit apoptosis and p62.sup.dok has been suggested as a substrate (Carpino, ef al., 1997, Ce//, 88:197-204), it is possible that clonal expansion mediated by these kinases occurs through a common signaling pathway. However, c-kit has also been reported to interact directly with p210.sup. BCR-ABL (Hallek, ef a/., 1996, Brit. J Haem., 94:5-16), which suggests that c-kit may have a more causative role in CML pathology. Therefore, degradation of c-kit caused by the inhibition of Hsp90 by the compounds of the invention will prove useful in the treatment of CML.
Normal colorectal mucosa does not express c-kit (Bellone, ef al., 1997, J. Cell Physiol., 172:1-11). However, c-kit is frequently expressed in colorectal carcinoma (Bellone, ef al.,
1997, J. Ceil Physiol., 172: 1-11), and autocrine loops of SCF and c-kit have been observed in several colon carcinoma cell lines (Toyota, ef al., 1993, Turn. Biol., 74:295-302; Lahm, ef a/., 1995, Ce// Growth & Differ., 6:1111-1118; Bellone, et al., 1997, J. Cell Physiol., 172Λ- 11). Furthermore, disruption of the autocrine loop by the use of neutralizing antibodies (Lahm, et al., 1995, Ce// Growth & Differ., 6:1111-1118) and downregulation of c-kit and/or SCF significantly inhibits cell proliferation (Lahm, et al., 1995, Ce// Growth & Differl., 6:1111- 1118; Bellone, et al., 1997, J. Cell Physiol., -/72:1-11).
SCF/c-kit autocrine loops have been observed in gastric carcinoma cell lines (Turner, ef a/., 1992, Blood, 80:374-381; Hassan, et al., 1998, Digest. Dis. Science, 43:8-14), and constitutive c-kit activation also appears to be important for gastrointestinal stromal tumors (GISTs). GISTs are the most common mesenchymal tumor of the digestive system. More than 90% of GISTs express c-kit, which is consistent with the putative origin of these tumor cells from interstitial cells of Cajal (ICCs) (Hirota, ef a/., 1998, Science, 279:577-580). The c-kit expressed in GISTs from several different patients was observed to have mutations in the intracellular juxtamembrane domain leading to constitutive activation (Hirota, et al.,
1998, Science 279:577-580). Therefore, degradation of c-kit caused by the inhibition of Hsp90 by the compounds of the invention will be an efficacious means for the treatment of these cancers.
Male germ cell tumors have been histologically categorized into seminomas, which retain germ cell characteristics, and nonseminomas which can display characteristics of embryonal differentiation. Both seminomas and nonseminomas are thought to initiate from a preinvasive stage designated carcinoma in situ (CIS) (Murty, ef al., 1998, Sem. Oncol., 25:133-144). Both c-kit and SCF have been reported to be essential for normal gonadal development during embryogenesis (Loveland, et al., 1997,' J. Endocrinol., -/53:337-344). Loss of either the receptor or the ligand resulted in animals devoid of germ cells. In postnatal testes, c-kit has been found to be expressed in Leydig cells and spermatogonia, while SCF was expressed in Sertoli cells (Loveland, ef al., 1997, J. Endocrinol., 153:337- 344). Testicular tumors develop from Leydig cells with high frequency in transgenic mice expressing human papilloma virus 16 (HPV16) E6 and E7 oncogenes (Kondoh, et ai, 1991 , J. Virol., 65:3335-3339; Kondoh, ef a/., 1994, J. UmI., 752:2151-2154). These tumors express both c-kit and SCF, and an autocrine loop may contribute to the tumorigenesis (Kondoh, ef al., 1995, Oncogene, 70:341-347) associated with cellular loss of functional p53 and the retinoblastoma gene product by association with E6 and E7 (Dyson, ef a/., 1989, Science, 243:934-937; Wemess, ef a/., 1990, Science, 248:76-79; Scheffner, ef a/., 1990, Ce//, 63:1129-1136). Defective signaling mutants of SCF (Kondoh, et al., 1995, Oncogene, 70:341-347) or c-kit (Li, ef a/., 1996, Cane. Res., 56:4343-4346) inhibited formation of testicular tumors in mice expressing HPV16 E6 and E7. Since c-kit kinase activation is pivotal to tumorigenesis in these animals, the compounds of the invention which inhibit Hsp90 and thereby cause the degradation of c-kit will be useful for preventing or treating testicular tumors associated with human papilloma virus.
Expression of c-kit on germ cell tumors shows that the receptor is expressed by the majority of carcinomas in situ and seminomas, but c-kit is expressed in only a minority of nonseminomas (Strohmeyer, et al., 1991 , Cane. Res., 57:1811-1816; Rajpert-de Meyts, βf a/., 1994, Int. J. Aπdrol., 77:85-92; Izquierdo, et al., 1995, J. Pathol., 777:253-258; Strohmeyer, ef a/., 1995, J. Urol., 753:511-515; Bokenmeyer, ef a/., 1996, J. Cance. Res., Clin. Oncol, 722:301-306; Sandlow, et al., 1996, J. Androl., 77:403-408). Therefore, degradation of c-kit caused by the inhibition of Hsp90 by the compounds of the invention will be an efficacious means for the treatment of these cancers.
SCF and c-kit are expressed throughout the central nervous system of developing rodents, and the pattern of expression suggests a role in growth, migration and differentiation of neuroectodermal cells. Expression of SCF and c-kit have also been reported in the adult brain (Hamel, et al., 1997, J. Neuro-Onc, 35:327-333). Expression of c-kit has also been observed in normal human brain tissue (Tada, et al. 1994, J. Neυro., 80:1063-1073). Glioblastoma and astrocytoma, which define the majority of intracranial tumors, arise from neoplastic transformation of astrocytes (Levin, ef a/., 1997, Principles & Practice of
Oncology, 2022-2082). Expression of c-kit has been observed in glioblastoma cell lines and tissues (Berdel, et al., 1992, Cane. Res., 52:3498-3502; Tada, et al., 1994, J. Neuro., 80:1063-1073; Stanulla, et al., 1995, Act. Neuropath., 89:158-165).
The association of c-kit with astrocytoma pathology is less clear. Reports of expression of c-kit in normal astrocytes have been made (Natali, ef al., 1992, Int. J. Cane, 52:197-201), (Tada, ef al. 1994, J. Neuro., 80:1063-1073), while others report it is not expressed (Kristt, ef al., 1993, Neuro., 33:106-115). In the former case, high levels of c-kit expression in high - 19.4 -
grade tumors were observed (Kristt, et a/., 1993, Neuro., 33:106-115), whereas in the latter case researchers were unable to detect any expression in astrocytomas. In addition, contradictory reports of c-kit and SCF expression in neuroblastomas also exist. One study found that neuroblastoma cell lines often express SCF, but rarely express c-kit. In primary tumors, c-kit was detected in about 8% of neuroblastomas, while SCF was found in 18% of tumors (Beck, et al., 1995, Blood, 86:3132-3138). In contrast, other studies (Cohen, et al., 1994, Blood, 84:3465-3472) have reported that all 14 neuroblastoma cell lines examined contained c-kit/SCF autocrine loops, and expression of both the receptor and ligand were observed in 45% of tumor samples examined. In two cell lines, anti-c-kit antibodies inhibited cell proliferation, suggesting that the SCF/c-kit autocrine loop contributed to growth (Cohen, ei al., 1994, Blood, 84:3465-3472). Therefore, degradation of c-kit caused by the inhibition of Hsp90 by the compounds of the invention will be an efficacious means for treating some cancers of the central nervous system.
2. Bcr-Abl Associated Cancers The Philadelphia chromosome which generates the fusion protein Bcr-Abl is associated with the bulk of chronic myelogenous leukemia (CML) patients (more than 95%), 10-25% of acute lymphocytic leukemia (ALL) patients, and about 2-3% of acute myelogenous leukemias (AML). In addition, Bcr-Abl is a factor in a variety of other hematological malignancies, including granulocytic hyperplasia resembling CML, myelomonocytic leukemia, lymphomas, and erythroid leukemia (see Lugo, et al., MCB (1989), 9:1263-1270; Daley, et al., Science (1990), 247:824-830; and Honda, Blood (1998), 91 :2067-2075, the entire teachings of each of these references are incorporated herein by reference).
A number of different kinds of evidence support the contention that Bcr-Abl oncoproteins, such as p210 and p185 BCR-ABL, are causative factors in these leukemias (Campbell and Arlinghaus, "Current Status of Bcr Gene Involvement with Human Leukemia", In: Advances in Cancer Research, Eds. Klein, VandeWoude, Orlando, FIa. Academic Press, Inc., 57:227- 256, 1991, the entire teachings of which are incorporated herein by reference). The malignant activity is due in large part to the Bcr-Abl protein's highly activated protein tyrosine kinase activity and its abnormal interaction with protein substrates (Arlinghaus et al., In: UCLA Symposia on Molecular and Cellular Biology New Series, Acute Lymphoblastic
Leukemia, Eds. R. P. Gale, D. Hoelzer, New York, N.Y., Alan R. Liss, Inc., 108:81-90, 1990, the entire teachings of which are incorporated herein by reference). The Bcr-Abl oncoprotein p210 Bcr-Abl is associated with both CML and ALL, whereas the smaller oncoprotein, p185 BCR-ABL, is associated with ALL patients, although some CML patients also express p185 (Campbell et al., 1991).
3. FLT3 Associated Cancers FLT3 associated cancers are cancers in which inappropriate FLT3 activity is detected FLT3 associated cancers include hematologic malignancies such as leukemia and lymphoma. In some embodiments FLT3 associated cancers include acute myelogenous leukemia (AML), B-precursor cell acute lymphoblastic leukemia, myelodysplastic leukemia, T-cell acute lymphoblastic leukemia, mixed lineage leukemia (MLL), or chronic myelogenous leukemia (CML)
4 EGFR Associated Cancers
EGFR associated cancers are cancers in which inappropriate EGFR activity (e g , overexpression of EGFR or mutation of EGFR which causes constitutive tyrosine kinase activity) has been implicated as a contributing factor Inappropriate EGFR activity has been associated with an adverse prognosis in a number of human cancers, such as neuroblastoma, intestine carcinoma such as rectum carcinoma, colon carcinoma, familiary adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tong carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroidea carcinoma, papillary thyroidea carcinoma, renal carcinoma, kidney parenchym carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors,
Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cell leukemia lymphoma, hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyo sarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma and plasmocytoma
In particular, EGFR appears to have an important role in the development of human brain tumors A high incidence of overexpression, amplification, deletion and structural rearrangement of the gene coding for EGFR has been found in biopsies of brain tumors In fact, the amplification of the EGFR gene in glioblastoma multiforme tumors is one of the most consistent genetic alterations known, with EGFR being overexpressed in approximately 40% of malignant gliomas and EGFRvIlI mutation being found in about 50% of all glioblastomas In addition to gliomas, abnormal EGFR expression has also been reported in a number of squamous epidermoid cancers and breast cancers Interestingly, evidence also suggests that many patients with tumors that over-express EGFR have a poorer prognosis than those having tumors that do not over-express EGFR,
Non-small cell lung cancer (NSCLC) includes squamous cell carcinomas, adenocarcinoma, bronchioloalveolar carcinoma (BAC), and large cell undifferentiated carcinoma. A subset of patients with NSCLC have been shown to have mutations in the tyrosine kinase domain of EGFR which is thought to be necessary for the maintenance of the disease. Treatment of this subset of patients with NSCLC with gefitinib, a tyrosine kinase inhibitor which targets EGFR1 has shown rapid and dramatic clinical response.
Consequently, therapeutic strategies that can potentially inhibit or reduce the aberrant expression of EGFR are of great interest as potential anti-cancer agents.
5. Combination Therapies and Treatment of Refractory Cancers
The prophylactic or therapeutic agents of the combination therapies of the invention can be administered sequentially or concurrently. In a specific embodiment, the combination therapies of the invention comprise one or more compounds and at least one other therapy (e.g., another prophylactic or therapeutic agent) which has the same mechanism of action as said compounds. In another specific embodiment, the combination therapies of the invention comprise one or more compounds of the invention and at least one other therapy (e.g., another prophylactic or therapeutic agent) which has a different mechanism of action than said compounds. In certain embodiments, the combination therapies of the present invention improve the prophylactic or therapeutic effect of one or more compounds of the invention by functioning together with the compounds to have an additive or synergistic effect. In certain embodiments, the combination therapies of the present invention reduce the side effects associated with the therapies (e.g., prophylactic or therapeutic agents). In certain embodiments, the combination therapies of the present invention reduce the effective dosage of one or more of the therapies.
The prophylactic or therapeutic agents of the combination therapies can be administered to a subject, preferably a human subject, in the same pharmaceutical composition. In alternative embodiments, the prophylactic or therapeutic agents of the combination therapies can be administered concurrently to a subject in separate pharmaceutical compositions. The prophylactic or therapeutic agents may be administered to a subject by the same or different routes of administration.
In a specific embodiment, a pharmaceutical composition comprising one or more compounds of the invention is administered to a subject, preferably a human, to prevent, treat, manage, or ameliorate a proliferative disorder, such as cancer, or one or more symptom thereof. In accordance with the invention, pharmaceutical compositions of the invention may also comprise one or more other agents (e.g., prophylactic or therapeutic agents which are currently being used, have been used, or are known to be useful in the prevention, treatment or amelioration of a proliferative disorder or a symptom thereof).
The invention provides methods for preventing, managing, treating or ameliorating a proliferative disorder, such as cancer, or one or more symptoms thereof in a subject refractory (either completely or partially) to existing agent therapies for such a proliferative disorder, said methods comprising administering to said subject a dose of an effective amount of one or more compounds of the invention and a dose of an effective amount of one or more therapies (e.g., one or more prophylactic or therapeutic agents useful for the prevention, treatment, management, or amelioration of a proliferative disorder or a symptom thereof). The invention also provides methods for preventing, treating, managing, or ameliorating a proliferative disorder or a symptom thereof by administering one or more compounds of the invention in combination with any other therapy(ies) to patients who have proven refractory to other therapies but are no longer on these therapies.
The compounds of the invention and/or other therapies can be administered to a subject by any route known to one of skill in the art. Examples of routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), intranasal, transdermal (topical), transmucosal, and rectal administration.
6) Agents Useful In Combination With the Compounds of the Invention
Without wishing to be bound by theory, it is believed that the compounds of the invention can be particularly effective at treating subjects whose cancer has become multi-drug resistant. Although chemotherapeutic agents initially cause tumor regression, most agents that are currently used to treat cancer target only one pathway to tumor progression. Therefore, in many instances, after treatment with one or more chemotherapeutic agents, a tumor develops multidrug resistance and no longer responds positively to treatment. One of the advantages of inhibiting Hsp90 activity is that several of its client proteins, which are mostly protein kinases or transcription factors involved in signal transduction, have been shown to be involved in the progression of cancer. Thus, inhibition of Hsp90 provides a method of short circuiting several pathways for tumor progression simultaneously. Therefore, it is believed that treatment of cancer with an Hsp90 inhibitor of the invention either alone, or in combination with other chemotherapeutic agents, is more likely to result in regression or elimination of the tumor, and less likely to result in the development of more aggressive multidrug resistant tumors than other currently available therapies.
In one embodiment, the compounds of the invention can be administered with agents that are tyrosine kinase inhibitors (e.g., gefitinib or erlotinib which inhibit EGFR tyrosine kinase activity). In another embodiment, the compounds of the invention can be administered to patients whose cancer has become resistant to a tyrosine kinase inhibitor (e g , gefitinib or erlotinib) In this embodiment, the compounds of the invention can be administered either alone or in combination with the tyrosine kinase inhibitor
In another embodiment, the compounds of the invention are useful for treating patients with hematological cancers that have become resistant to Imatinib, a chemotherapeutic agent that acts by inhibiting tyrosine kinase activity of Bcr-Abl In patients with CML in the chronic phase, as well as in a blast crisis, treatment with Imatinib typically will induce remission However, in many cases, particularly in those patients who were in a blast crisis before remission, the remission is not durable because the Bcr-Abl fusion protein develops mutations in the tyrosine kinase domain that cause it to be resistence to Imatinib (See Nimmanapalli, ef a/ , Cancer Research (2001), 67 1799-1804, and Gorre, ef a/ , Blood (2002), 100 3041-3044, the entire teachings of each of these references are incorporated herein by reference) Compounds of the invention act by inhibiting the activity of Hsp90 which disrupt Bcr-Abl/Hsp90 complexes When Bcr-Abl is not complex to Hsp90 it is rapidly degraded Therefore, compounds of the invention are effective in treating Imatinib resistant leukemias since they act through a different mechanism than Imatinib Compounds of the invention can be administered alone or with Imatinib in patients who have a Bcr-Abl associated cancer that is not resistant to Imatinib or to patients whose cancer has become resistant to Imatinib Anticancer agents that can be co-admimstered with the compounds of the invention include Taxol™, also referred to as ' paclitaxel", is a well-known anti-cancer drug which acts by enhancing and stabilizing microtubule formation, and analogs of Taxol™, such as Taxotere™ Compounds that have the basic taxane skeleton as a common structure feature, have also been shown to have the ability to arrest cells in the G2-M phases due to stabilization or inhibition of microtubules
Other anti-cancer agents that can be employed in combination with the compounds of the invention include Avastin, Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin, aldesleukin, altretamine, ambomycin, ametantrone acetate, aminoglutethimide, amsacπne, anastrozole, anthramycin, asparaginase, asperlin, azacitidine, a∑etepa, azotomycin, batimastat, beπzodepa, bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin, bleomycin sulfate, brequinar sodium, bropiπmine, busulfan, cactinomycin, calusterone, caracemide, carbetimer, carboplatin, carmustine, carubicin hydrochloride, carzelesin, cedefingol, chlorambucil, cirolemycin, cladπbine, crisnatol mesylate, cyclophosphamide, cytarabine, dacarbazine, daunorubicin hydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguanine mesylate, diaziquone, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin, edatrexate, eflornithine hydrochloride, elsamitrucin, enloplattn, enpromate, epipropidine, epirubicin hydrochloride, erbulozole, esorubicin hydrochloride, estramustine, estramustine phosphate sodium, etanidazole, etoposide, etoposide phosphate, etopπne, fadrozole hydrochloride, fazarabine, fenretinide, floxuπdine, fludarabine phosphate, fluorouracil, flurocitabine, fosquidone, fostriecin sodium, gemcitabiπe, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, ilmofosine, iπterleukin Il (including recombinant interleukin II, or rlL2), interferon alfa-2a, interferon alfa-2b, interferon alfa-n1 , interferon alfa- n3, interferon beta-I a, interferon gamma-l b, iproplatin, irinotecan hydrochloride, lanreotide acetate, letrozole, leuprolide acetate, liarozole hydrochloride, lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol, maytansine, mechlorethamine hydrochloride, megestrol acetate, melengestrol acetate, melphalan, menogaπl, mercaptopuπne, methotrexate, methotrexate sodium, metopπne, meturedepa, mitiπdomide, mitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper, mitotane, mitoxantrone hydrochloride, mycopheπolic acid, nocodazole, nogalamycin, ormaplatin, oxisuran, pegaspargase, peliomycin, pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan, piroxantrone hydrochloride, plicamycin, plomestane, porfimer sodium, porfiromycin, prednimustine, procarbazine hydrochloride, puromycin, puromycin hydrochloride, pyrazofuπn, ribopπne, rogletimide, safingol, safingol hydrochloride, semustine, simtrazene, sparfosate sodium, sparsomycin, spirogermanium hydrochloride, spiromustme, spiroplatin, streptonigrin, streptozocin, sulofenur, tahsomycin, tecogalan sodium, tegafur, teloxantrone hydrochloride, temoporfin, teniposide, teroxirone, testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin, tirapazamine, toremifenε citrate, trestolone acetate, tπciπbine phosphate, tπmetrexate, trimetrexate glucuroπate, tπptorelin, tubulozole hydrochloride, uracil mustard, uredepa, vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate, vindesine, vindesine sulfate, vinepidine sulfate, vinglycinate sulfate, vinleurosine sulfate, vinorelbine tartrate, vinrosidine sulfate, vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicin hydrochloride
Other anti-cancer drugs that can be employed in combination with the compounds of the invention include 20-epι-1 ,25 dihydroxyvitamin D3, 5-ethynyluracιl, abiraterone, aclarubicin, acylfulvene, adecypenol, adozelesin, aldesleukin, ALL-TK antagonists, altretamine, ambamustine, amidox, amifostine, aminolevulinic acid, amrubicin, amsacπne, anagrelide, anastrozole, andrographolide, angiogenesis inhibitors, antagonist D, antagonist G1 antarehx, anti-dorsalizing morphogenetic proteιn-1, antiandrogen, prostatic carcinoma, antiestrogen, antineoplaston, antisense oligonucleotides, aphidicolin glycinate, apoptosis gene modulators, apoptosis regulators, apurinic acid, ara-CDP-DL-PTBA, arginine deaminase, asulacrine, atamestane, atπmustine, axinastatin 1 , axinastatin 2, axinastatin 3, azasetron, azatoxin, azatyrosine, baccatin 111 derivatives, balanol, batimastat, BCR/ABL antagonists, benzochloπns, benzoylstaurospoπne, beta lactam derivatives, beta-alethine, betaclamycin B, betulinic acid, bFGF inhibitor, bicalutamide, bisantreπe, bisaziridinylspermine, bisnafide, bistratene A, bizelesin, breflate, bropiπmine, budotitaπe, buthionine sulfoximine, calcipotπol, calphostin C, camptothecin derivatives, canarypox IL-2, capecitabiπe, carboxamide-amino- tnazole, carboxyamidotriazole, CaRest M3, CARN 700, cartilage derived inhibitor, carzelesin, casein kinase inhibitors (ICOS), castanospermine, cecropin B, cetrorelix, chlorlns, chloroquinoxaline sulfonamide, cicaprost, cis-porphyπn, cladπbine, clomifene analogues, clotrimazole, collismycin A, collismycin B, combretastatin A4, combretastatin analogue, conagenin, crambescidin 816, crisnatol, cryptophycin 8, cryptophycin A derivatives, curacin A, cyclopentanthraquinones, cycloplatam, cypemycin, cytarabine ocfosfate, cytolytic factor, cytostatin, dacliximab, decitabine, dehydrodidemnin B1 deslorelin, dexamethasone, dexifosfamide, dexrazoxane, dexverapamil, diaziquone, didemnin B, didox, diethylnorspermine, dιhydro-5-azacytιdιne, 9- dioxamycin, diphenyl spiromustine, docosanol, dolasetron, doxifluπdine, droloxifene, dronabinol, duocarmycin SA, ebselen, ecomustine, edelfosine, edrecolomab, eflomithine, elemene, emitefur, epirubicin, epπsteπde, estramustine analogue, estrogen agonists, estrogen antagonists, etanidazole, etoposide phosphate, exemestane, fadrozole, fazarabine, fenretmide, filgrastim, finasteride, flavopiπdol, flezelastine, fluasterone, fludarabiπe, fluorodaunorunicin hydrochloride, forfenimex, formestane, fostπecin, fotemustine, gadolinium texaphyrin, gallium nitrate, galocitabine, ganirehx, gelatinase inhibitors, gemcitabine, glutathione inhibitors, hepsulfam, hereguhn, hexamethylene bisacetamide, hypericin, ibandronic acid, idarubicin, idoxifene, idramantone, ilmofosine, ilomastat, imidazoacridones, imiquimod, immunostimulant peptides, insulin-like growth factor-1 receptor inhibitor, interferon agonists, interferons interleukins, lobenguane, iododoxorubicin, ipomeanol, 4-, iroplact, irsogladine, isobengazole, isohomohalicondrin B, itasetron, jasplakinolide, kahalalide F, lamellaπn-N triacetate, lanreotide, leinamycm, lenograstim, lentinan sulfate, leptolstatin, letrozole, leukemia inhibiting factor, leukocyte alpha interferon, leuprolide+estrogen+progesterone, leuprorelin, levamisole, liarozole, linear polyamine analogue, lipophilic disacchaπde peptide, lipophilic platinum compounds, lissoclinamide 7, lobaplatin, lombricine, lometrexol, lonidamine, losoxantrone, lovastatin, loxonbine, lurtotecan, lutetium texaphyrin, lysofylline, lytic peptides, maitansme, mannostatin A, maπmastat, masoprocol, maspin, matrilysin inhibitors, matrix metalloproteinase inhibitors, menogaπl, merbarone, meterelin, methioninase, metoclopramide, MIF inhibitor, mifepristone, miltefosine, miπmostim, mismatched double stranded RNA1 mitoguazone, mitolactol, mitomycin analogues, mitonafide, mitotoxin fibroblast growth factor-saporin, mitoxantrone, mofarotene, molgramostim, monoclonal antibody, human chorionic gonadotrophin, monophosphoryl lipid A+myobacterium cell wall sk, mopidamol, multiple drug resistance gene inhibitor, multiple tumor suppressor 1 -based therapy, mustard anticancer agent, mycaperoxide B1 mycobacterial cell wall extract, myπaporone, N-acetyldinaline, N-substituted benzamides, nafarelin, nagrestip, naloxone+pentazocine, napavin, naphterpin, nartograstim, nedaplatin nemorubicin, neridronic acid, neutral endopeptidase, nilutamide, nisamycin, nitric oxide modulators, nitroxide antioxidant, nitrullyn, 06-benzylguanιne, octreotide, okicenone, oligonucleotides, onapπstone, ondansetron, ondansetron, oracin, oral cytokine inducer, ormaplatin, osaterone, oxaliplatin, oxaunomycin, palauamine, palmitoylrhizoxin, pamidronic acid, panaxytπol, panomifene, parabactin; pazelliptine, pegaspargase, peldesine, pentosan polysulfate sodium, pentostatin, pentrozole, perflubron, perfosfamide, penllyl alcohol, phenazinomycin, phenylacetate, phosphatase inhibitors, picibanil, pilocarpine hydrochloride, pirarubicin, piπtrexim, placetin A, placetin B, plasminogen activator inhibitor, platinum complex, platinum compounds, platinum-tπamine complex, porfimer sodium, porfiromycin, prednisone, propyl bis-acridone, prostaglandin J2, proteasome inhibitors, protein A-based immune modulator, protein kinase C inhibitor, protein kinase C inhibitors, microalgal, protein tyrosine phosphatase inhibitors, purine nucleoside phosphorylase inhibitors, purpuπns, pyrazoloacridine, pyπdoxylated hemoglobin polyoxyethylene conjugate, raf antagonists, raltitrexed, ramosetron, ras farnesyl protein transferase inhibitors, ras inhibitors, ras-GAP inhibitor, retelliptine demethylated, rhenium Re 186 etidronate, rhizoxin, ribozymes RII retinamide, rogletimide, rohitukine, romurtide, roquinimex, rubiginone B1, ruboxyl, safingol, saintoptn, SarCNU, sarcophytol A, sargramostim, Sdi 1 mimetics, semustme, senescence derived inhibitor 1 , sense oligonucleotides, signal transduction inhibitors, signal transduction modulators, single chain antigen-binding protein, sizofiran, sobuzoxane, sodium borocaptate, sodium phenylacetate, solverol, somatomedin binding protein, sonermin, sparfosic acid, spicamycin D, spiromustine, splenopentin, spongistatin 1 , squalamine, stem cell inhibitor, stem-ceil division inhibitors, stipiamide, stromelysin inhibitors, sulfmosine, superactive vasoactive intestinal peptide antagonist, suradista, suramin, swainsonme, synthetic glycosaminoglycans, tallimustine, tamoxifen methiodide, taυromustine, tazarotene, tecogalan sodium, tegafur, tellurapyrylium, telomerase inhibitors, temoporfin, temozolomide, teniposide, tetrachlorodecaoxide, tetrazomme, thaliblastme, thiocoraline, thrombopoietin, thrombopoietin mimetic, thymalfasin, thymopoietin receptor agonist, thymotπnaπ, thyroid stimulating hormone, tin ethyl etiopurpurm, tirapazamine, titanocene bichloride, topsentin, toremifeπe, totipotent stem cell factor, translation inhibitors, tretinoin, tπacetyluπdine, tπciπbine, tπmetrexate, tπptorelin, tropisetron, turosteπde, tyrosine kinase inhibitors, tyrphostins, UBC inhibitors, ubenimex, urogenital sinus-derived growth inhibitory factor, urokinase receptor antagonists, vapreotide, vaπolin B, vector system, erythrocyte gene therapy, velaresol, veramine, verdms, verteporfin, vinorelbine, vinxaltine, vitaxin, vorozole, zanoterone, zeniplatin, zilascorb, and zinostatin stimalamer Preferred anti-cancer drugs are 5-fluorouracιl and leucovorin
Other chemotherapeutic agents that can be employed in combination with the compounds of the invention include but are not limited to alkylating agents, antimetabolites, natural products, or hormones Examples of alkylating agents useful for the treatment or prevention of T-cell malignancies in the methods and compositions of the invention include but are not limited to, nitrogen mustards (e.g.,'mechloroethamiπe, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), or triazenes (decarbazine, efc). Examples of antimetabolites useful for the treatment or prevention of T-cell malignancies in the methods and compositions of the invention include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin). Examples of natural products useful for the treatment or prevention of T-cell malignancies in the methods and compositions of the invention include but are not limited to vinca alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha).
Examples of alkylating agents that can be employed in combination with the compounds of the invention include but are not limited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, efc), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, efc), or triazenes (decarbazine, efc). Examples of antimetabolites useful for the treatment or prevention of cancer in the methods and compositions of the invention include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin). Examples of natural products useful for the treatment or prevention of cancer in the methods and compositions of the invention include but are not limited to vinca alkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide, teniposide), antibiotics (e.g., actinomycin D, daunorubicin, doxorubicin, bleomycin, plicamycin, mitomycin), enzymes (e.g., L- asparaginase), or biological response modifiers (e.g., interferon alpha). Examples of hormones and antagonists useful for the treatment or prevention of cancer in the methods and compositions of the invention include but are not limited to adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), gonadotropin releasing hormone analog (e.g., leuprolide). Other agents that can be used in the methods and compositions of the invention for the treatment or prevention of cancer include platinum coordination complexes (e.g., cisplatin, carboblatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide). Examples of anti-cancer agents which act by arresting cells in the G2-M phases due to stabilization or inhibition of microtubules and which can be used in combination with the compounds of the invention include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10 and NSC-376128), Mivobulin isethionate (also known as CI-980), Vincristine, NSC- 639829, Discodermolide (also known as NVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1 , Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotin hydrochloride (also known as LlM 03793 and NSC-D-669356), Epothilones (such as Epothilone A, Epothilone B1 Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D (also referred to as KOS-862, dEpoB, and desoxyepothilone B ), Epothilone E, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone), Auristatin PE (also known as NSC-654663), Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF- 223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ- 268970 (Lilly/Novartis), AM-97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCI), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCI, and RPR-258062A), Vitilevuamide, Tubulysin A1 Canadensol, Centaureidin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 and WHI-261), H10 (Kansas State University), H16 (Kansas State University), Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569), Narcosine (also known as NSC-5366), Nascapine, D- 24851 (Asta Medica), A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-191), TMPN (Arizona State University), Vanadocene acetylacetonate, T- 138026 (Tularik), Monsatrol, lnanocine (also known as NSC-698666), 3- IAABE (Cytoskeleton/Mt. Sinai School of Medicine), A-204197 (Abbott), T-607 (Tularik, also known as T-900607), RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, lsoeleutherobin A, and Z-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica), D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350 (Nereus), Taccalonolide A, TUB-245 (Aveπtis), A-259754 (Abbott), Diozostatin, (-)-Phenylahistin (also known as NSCL-96F037), D-68838 (Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris, also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286 (also known as SPA- 110, trifluoroacetate salt) (Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Saπofi).
7) An it-Infective Agents Useful In Combination With the Compounds of the Invention
Other anti-fungal agents that can be co-administered with the compounds of the invention include, but are not limited to, polyene antifungals (e.g., amphotericin and nystatin), azole antifungals (e.g., ketoconazole, miconazole, fluconazole, itraconazole, posaconazole, ravuconazole, voriconazole, clotrimazole, econazole, oxiconazole, sulconazole, terconazole, butoconazole, and tioconazole), amorolfine, butenafine, naftifine, terbinafine, flucytosine, nikkomycin Z1 caspofungin, micafungin (FK463), anidulafungin (LY303366), griseofulvin, ciclopiroxolamine, tolnaftate, intrathecal, haloprogrin, and undecylenate. Other anti-bacterial agents that can be co-administered with the compounds of the invention include, but are not limited to, sulfa drugs (e.g., sulfanilamide), folic acid analogs (e.g., trimethoprim), beta-lactams (e.g., penacillin, cephalosporins), aminoglycosides (e.g., stretomycin, kanamycin, neomycin, gentamycin), tetracyclines (e.g., chlorotetracycline, oxytetracycline, and doxycycline), macrolides (e.g., erythromycin, azithromycin, and clarithromycin), lincosamides (e.g., clindamycin), streptogramins (e.g., quinupristin and dalfopristin), fluoroquinolones (e.g., ciprofloxacin, levofloxacin, and moxifloxacin), polypeptides (e.g., polymixins), rifampin, mupirocin, cycloserine, aminocyclitol (e.g., spectinomycin), glycopeptides (e.g., vancomycin), oxazolidinones (e.g., linezolid), ribosomes, chloramphenicol, fusidic acid, and metronidazole. Other anti-viral agents that can be co-administered with the compounds of the invention include, but are not limited to, Emtricitabine (FTC); Lamivudine (3TC); Carbovir; Acyclovir; Interferon; Famciclovir; Penciclovir; Zidovudine (AZT); Didanosine (ddl); Zalcitabine (ddC); Stavudine (d4T); Tenofovir DF (Viread); Abacavir (ABC); L-(-)-FMAU; L-DDA phosphate prodrugs; β-D-dioxolane nucleosides such as β-D-dioxolanyl-guanine (DG), β-D-dioxolanyl- 2,6-diaminopurine (DAPD), and β-D-dioxolanyl-6-chloropurine (ACP); non-nucleoside RT inhibitors such as Nevirapine (Viramune), MKC-442, Efavirenz (Sustiva), Delavirdine (Rescriptor); protease inhibitors such as Amprenavir, Atazanavir, Fosamprenavir, Indinavir, Kaletra, Nelfinavir, Ritonavir, Saquinavir, AZT, DMP-450; combination treatments such as Epzicom (ABC+3TC), Trizivir (ABC+3TC+AZT), Truvada (FTC+Viread); Omega IFN (BioMedicines Inc.); BILN-2061 (Boehringer Ingelheim); Summetrel (Endo Pharmaceuticals Holdings Inc.); Roferon A (F. Hoffman-La Roche); Pegasys (F. Hoffman-La Roche); Pegasys/Ribaravin (F. Hoffman-La Roche); CellCept (F. Hoffman-La Roche); Wellferon (GlaxoSmithKline); Albuferon-α (Human Genome Sciences Inc.); Levovirin (ICN Pharmaceuticals); IDN-6556 (Idun Pharmaceuticals); IP-501 (Indevus Pharmaceuticals); Actimmune (InterMune Inc.); lnfergen A (InterMune Inc.); ISIS 14803 (ISIS Pharmaceuticals Inc.); JTK-003 (Japan Tobacco Inc.); Pegasys/Ceplene (Maxim Pharmaceuticals); Ceplene (Maxim Pharmaceuticals); Civacir (Nabi Biopharmaceuticals Inc.); lntron A/Zadaxin (RegeneRx); Levovirin (Ribapharm Inc.); Viramidine (Ribapharm Inc.); Heptazyme (Ribozyme Pharmaceuticals); lntron A (Schering-Plough); PEG-lntron (Schering-Plough); Rebetron (Schering-Plough); Ribavirin (Schering-Plough); PEG-lntron/Ribavirin (Schering- Plough); Zadazim (SciClone); Rebif (Serono); IFN- β /EMZ701 (Transition Therapeutics); T67 (Tularik Inc.); VX-497 (Vertex Pharmaceuticals Inc.); VX-950/LY-570310 (Vertex
Pharmaceuticals Inc.); Omniferon (Viragen Inc.); XTL-002 (XTL Biopharmaceuticals); SCH 503034 (Schering-Plough); isatoribine and its prodrugs ANA971 and ANA975 (Anadys); R1479 (Roche Biosciences); Valopicitabine (Idenix); NIM811 (Novartis); Actilon (Coley Pharmaceuticals); Pradefovir (Metabasis Therapeutics); zanamivir; adefovir, adefovir dipivoxil, oseltamivir; vidarabine; gancyclovir; valganciclovir; amantadine; rimantadine; relenza; tamiflu; amantadine; entecavir; and pleconaril.
Other anti-parasitic agents that can be co-administered with the compounds of the invention include, but are not limited to, avermectins, milbemycins, lufenuron, imidacloprid, organophosphates, pyrethroids, sufanamides, iodquinol, diloxanide furoate, metronidazole, paromycin, azithromycin, quinacrine, furazolidone, tinidazole, omidazole, bovine, colostrum, bovine dialyzable leukocyte extract, chloroquine, chloroquine phosphate, diclazuril, eflornithine, paromomycin, pentamidine, pyrimethamine, spiramycin, trimethoprim- sulfamethoxazole, albendazole, quinine, quinidine, tetracycline, pyrimethamine-sulfadoxine, mefloquine, doxycycline, proguanil, clindamycin, suramin, melarsoprol, diminazene, nifurtimox, spiroarsoranes, ketoconazole, terbinafine, lovastatin, sodium stibobgluconate, N- methylglucamine antimonate, amphotericin B1 allopurinol, itraconazole, sulfadiazine, dapsone, trimetrexate, clarithromycin, roxithromycin, atovaquone, aprinocid, tinidazole, mepacrine hydrochloride, emetine, polyaminopropyl biguanide, paromomycin, benzimidazole, praziquantel, or albendazole. 8) Steroid or Non-Steroidal Anti-Inflammatory Agents Useful In Combination With the Compounds of the Invention
In one embodiment relating to autoimmune, allergic and inflammatory conditions, the other therapeutic agent may be a steroid or a non-steroidal anti-inflammatory agent. Particularly useful non-steroidal anti-inflammatory agents, include, but are not limited to, aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam; salicylic acid derivatives, including aspirin, sodium salicylate, choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin; para-aminophennol derivatives including acetaminophen and phenacetin; indole and indene acetic acids, including indomethacin, sulindac, and etodolac; heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac; anthrariilic acids (fenamates), including mefenamic acid, and meclofenamic acid; enolic acids, including oxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone); and alkanones, including nabumetone and pharmaceutically acceptable salts thereof and mixtures thereof. For a more detailed description of the NSAIDs, see Paul A. Insel, Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed in the Treatment of Gout, in Goodman & Gilman's The Pharmacological Basis of Therapeutics 617-57 (Perry B. Molinhoff and Raymond W. Ruddon eds., 9th ed 1996) and Glen R. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs in Remington: The Science and Practice of Pharmacy VoI Il 1196-1221 (A.R. Gennaro ed. 19th ed. 1995) which are hereby incorporated by reference in their entireties.
Of particular relevance to allergic disorders, the other therapeutic agent may be an antihistamine. Useful antihistamines include, but are not limited to, loratadine, cetirizine, fexofenadine, desloratadine, diphenhydramine, chlorpheniramine, chlorcyclizine, pyrilamine, promethazine, terfenadine, doxepin, carbinoxamine, clemastine, tripelennamine, brompheniramine, hydroxyzine, cyclizine, meclizine, cyproheptadine, phenindamine, acrivastine, azelastine, levocabastine, and mixtures thereof. For a more detailed description of antihistamines, see Goodman & Gilman's The Pharmacological Basis of Therapeutics (2001) 651-57, 10th ed).
Immunosuppressive agents include glucocorticoids, corticosteroids (such as Prednisone or Solumedrol), T cell blockers (such as cyclosporin A and FK506), purine analogs (such as azathioprine (Imuran)), pyrimidine analogs (such as cytosine arabinoside), alkylating agents (such as nitrogen mustard, phenylalanine mustard, buslfan, and cyclophosphamide), folic acid antagonsists (such as aminopterin and methotrexate), antibiotics (such as rapamycin, actinomycin D, mitomycin C, puramycin, and chloramphenicol), human IgG, antilymphocyte globulin (ALG)1 and antibodies (such as anti-CD3 (OKT3), anti-CD4 (OKT4), anti-CD5, anti- CD?, anti-IL-2 receptor, anti-alpha/beta TCR, anti-ICAM-1 , anti-CD20 (Rituxan), anti-IL-12 and antibodies to immunotoxiπs). E. Compositions and Methods for Administering Therapies
The present invention provides compositions for the treatment, prophylaxis, and amelioration of proliferative disorders, such as cancer. In a specific embodiment, a composition comprises one or more compounds of the invention, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or prodrug thereof. In another embodiment, a composition of the invention comprises one or more prophylactic or therapeutic agents other than a compound of the invention, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, prodrug thereof. In another embodiment, a composition of the invention comprises one or more compounds of the invention, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or prodrug thereof, and one or more other prophylactic or therapeutic agents. In another embodiment, the composition comprises a compound of the invention, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
In a preferred embodiment, a composition of the invention is a pharmaceutical composition or a single unit dosage form. Pharmaceutical compositions and dosage forms of the invention comprise one or more active ingredients in relative amounts and formulated in such a way that a given pharmaceutical composition or dosage form can be used to treat or prevent proliferative disorders, such as cancer. Preferred pharmaceutical compositions and dosage forms comprise a compound of formula (I)-(XL), and those set forth in Tables 1-5, or a pharmaceutically acceptable prodrug, salt, solvate, clathrate, hydrate, or prodrug thereof, optionally in combination with one or more additional active agents.
The pharmaceutical compositions can be used in therapy, e.g., to treat a mammal with an infection. In one embodiment, the pharmaceutical composition includes one or more additional therapeutic agents, such as one or more additional anti-infective agents.
In another embodiment, the present invention is the use of a compound of anyone of the formulas disclosed herein for the manufacture of a medicament for treating a mammal with an infection. In another embodiment of the present invention is a pharmaceutical composition comprising a compound represented by any one of the formulas disclosed herein and a pharmaceutically acceptable carrier. The pharmaceutical compositions can be used in therapy, e.g., to treat a mammal with an inflammatory or immune disorder. In one embodiment, the pharmaceutical composition includes one or more additional therapeutic agent, such as one or more additional anti-inflammatory agent or one or more immunosuppressant.
In another embodiment, the present invention is the use of a compound of anyone of the formulas disclosed herein for the manufacture of a medicament for treating a mammal with an inflammatory or autoimmune disorder or for treatment of a mammal in need of immunosuppression. A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), intranasal, transdermal (topical), transmucosal, and rectal administration. In a specific embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to human beings. In a preferred embodiment, a pharmaceutical composition is formulated in accordance with routine procedures for subcutaneous administration to human beings. ■ Single unit dosage forms of the invention are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial), or transdermal administration to a patient. Examples of dosage forms include, but are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; suppositories; ointments; cataplasms (poultices); pastes; powders; dressings; creams; plasters; solutions; patches; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or nonaqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to a patient; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for parenteral administration to a patient. .
The composition, shape, and type of dosage forms of the invention will typically vary depending on their use. For example, a dosage form suitable for mucosal administration may contain a smaller amount of active ingredient(s) than an oral dosage form used to treat the same indication. This aspect of the invention will be readily apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences (1990) 18th ed., Mack Publishing, Easton PA.
Typical pharmaceutical compositions and dosage forms comprise one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient. For example, oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms.
The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the decomposition of some active ingredients can be accelerated by some excipients such as lactose, or when exposed to water. Active ingredients that comprise primary or secondary amines (e.g., N-desmethylvenlafaxine and N,N-didesmethylvenlafaxine) are particularly susceptible to such accelerated decomposition. Consequently, this invention encompasses pharmaceutical compositions and dosage forms that contain little, if any, lactose. As used herein, the term "lactose-free" means that the amount of lactose present, if any, is insufficient to substantially increase the degradation rate of an active ingredient. Lactose-free compositions of the invention can comprise excipients that are well known in the art and are listed, for example, in the U.S. Pharmocopia (USP) SP (XXI)/NF (XVI). In general, lactose-free compositions comprise active ingredients, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Preferred lactose-free dosage forms comprise active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate.
This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen (1995) Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 379-80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are preferably anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected.
An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs. The invention further encompasses pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as "stabilizer" include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
1) Oral Dosage Forms
Pharmaceutical compositions of the invention that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences (1990) 18th ed., Mack Publishing, Easton PA.
Typical oral dosage forms of the invention are prepared by combining the active ingredient(s) in an admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
Examples of excipients that can be used in oral dosage forms of the invention include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. One specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103J and Starch 1500 LM.
Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. The binder or filler in pharmaceutical compositions of the invention is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
Disintegrants are used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms of the invention. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, preferably from about 1 to about 5 weight percent of disintegrant.
Disintegrants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
Lubricants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, TX), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
2) Controlled Release Dosage Forms
Active ingredients of the invention can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591 ,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.
All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled- release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds
A particular extended release formulation of this invention comprises a therapeutically or prophylactically effective amount of a compound of formula (I)-(XL), and those set forth in Tables 1-5, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, or prodrug thereof, in spheroids which further comprise microcrystalline cellulose and, optionally, hydroxypropylmethyl-cellulose coated with a mixture of ethyl cellulose and hydroxypropylmethylcellulose Such extended release formulations can be prepared according to U S Patent No 6,274,171 , the entirely of which is incorporated herein by reference
A specific controlled-release formulation of this invention comprises from about 6% to about 40% a compound of formula (I)-(XL), and those set forth in Tables 1-5, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, or prodrug thereof, by weight, about 50% to about 94% microcrystalline cellulose, NF, by weight, and optionally from about 0 25% to about 1 % by weight of hydroxypropyl-methylcellulose, USP, wherein the spheroids are coated with a film coating composition comprised of ethyl cellulose and hydroxypropylmethylcellulose
3) Parenteral Dosage Forms
Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions
Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art Examples include, but are not limited to Water for Injection USP, aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection, water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol, and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myπstate, and benzyl benzoate Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms of the invention.
4) Transdermal, Topical, and Mucosal Dosage Forms
Transdermal, topical, and mucosal dosage forms of the invention include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences (1980 & 1990) 16th and 18th eds., Mack Publishing, Easton PA and Introduction to Pharmaceutical Dosage Forms (1985) 4th ed., Lea & Febiger, Philadelphia. Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels. Further, transdermal dosage forms include "reservoir type" or "matrix type" patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients.
Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide transdermal, topical, and mucosal dosage forms encompassed by this invention are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied. With that fact in mind, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane-1 ,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form lotions, tinctures, creams, emulsions, gels or ointments, which are non-toxic and pharmaceutically acceptable. Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences (1980 & 1990) 16th and 18th eds., Mack Publishing, Easton PA. Depending on the specific tissue to be treated, additional components may be used prior to, in conjunction with, or subsequent to treatment with active ingredients of the invention. For example, penetration enhancers can be used to assist in delivering the active ingredients to the tissue. Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water- soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).
The pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied, may also be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery. In this regard, stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent. Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.
5) Dosage & Frequency of Administration
The amount of the compound or composition of the invention which will be effective in the prevention, treatment, management, or amelioration of a proliferative disorders, such as cancer, or one or more symptoms thereof, will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The frequency and dosage will also vary according to factors specific for each patient depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the patient. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. Suitable regiments can be selected by one skilled in the art by considering such factors and by following, for example, dosages reported in the literature and recommended in the Physician's Desk Reference (57th ed., 2003).
Exemplary doses of a small molecule include milligram or microgram amounts of the small molecule per kilogram of subject or sample weight (e.g., about 1 microgram per kilogram to about 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram).
In general, the recommended daily dose range of a compound of the invention for the conditions described herein lie within the range of from about 0.01 mg to about 1000 mg per day, given as a single once-a-day dose preferably as divided doses throughout a day. In one embodiment, the daily dose is administered twice daily in equally divided doses. Specifically, a daily dose range should be from about 5 mg to about 500 mg per day, more specifically, between about 10 mg and about 200 mg per day. In managing the patient, the therapy should be initiated at a lower dose, perhaps about 1 mg to about 25 mg, and increased if necessary up to about 200 mg to about 1000 mg per day as either a single dose or divided doses, depending on the patient's global response. It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in ■ conjunction with individual patient response,
Different therapeutically effective amounts may be applicable for different proliferative disorders, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat or ameliorate such proliferative disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the compounds of the invention are also encompassed by the above described dosage amounts and dose frequency schedules. Further, when a patient is administered multiple dosages of a compound of the invention, not all of the dosages need be the same. For example, the dosage administered to the patient may be increased to improve the prophylactic or therapeutic effect of the compound or it may be decreased to reduce one or more side effects that a particular patient is experiencing.
In a specific embodiment, the dosage of the composition of the invention or a compound of the invention administered to prevent, treat, manage, or ameliorate a proliferative disorders, such as cancer, or one or more symptoms thereof in a patient is 150 μg/kg, preferably 250 μg/kg, 500 μg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, or 200 mg/kg or more of a patient's body weight. In another embodiment, the dosage of the composition of the invention or a compound of the invention administered to prevent, treat, manage, or ameliorate a proliferative disorders, such as cancer, or one or more symptoms thereof in a patient is a unit dose of 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 12 mg, 0.1 mg to 10 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 to 8 mg, 0.25 mg to 7m g, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.
The dosages of prophylactic or therapeutic agents other than compounds of the invention, which have been or are currently being used to prevent, treat, manage, or proliferative disorders, such as cancer, or one or more symptoms thereof can be used in the combination therapies of the invention. Preferably, dosages lower than those which have been or are currently being used to prevent, treat, manage, or ameliorate a proliferative disorders, or one or more symptoms thereof, are used in the combination therapies of the invention. The recommended dosages of agents currently used for the prevention, treatment, management, or amelioration of a proliferative disorders, such as cancer, or one or more symptoms thereof, can obtained from any reference in the art including, but not limited to, Hardman ef a/., eds., 1996, Goodman & Gilman's The Pharmacological Basis Of Basis Of Therapeutics 91h Ed, Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57m Ed., 2003, Medical Economics Co., Inc., Montvale, NJ, which are incorporated herein by reference in its entirety.
In certain embodiments, when the compounds of the invention are administered in combination with another therapy, the therapies (e.g., prophylactic or therapeutic agents) are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours part. In one embodiment, two or more therapies (e.g., prophylactic or therapeutic agents) are administered within the same patent visit.
In certain embodiments, one or more compounds of the invention and one or more other the therapies (e.g., prophylactic or therapeutic agents) are cyclically administered. Cycling therapy involves the administration of a first therapy (e.g., a first prophylactic or therapeutic agents) for a period of time, followed by the administration of a second therapy (e.g., a second prophylactic or therapeutic agents) for a period of time, followed by the administration of a third therapy (e.g., a third prophylactic or therapeutic agents) for a period of time and so forth, and repeating this sequential administration, i.e., the cycle in order to reduce the development of resistance to one of the agents, to avoid or reduce the side effects of one of the agents, and/or to improve the efficacy of the treatment.
In certain embodiments, administration of the same compound of the invention may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, administration of the same prophylactic or therapeutic agent may be repeated and the administration may be separated by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
In a specific embodiment, the invention provides a method of preventing, treating, managing, or ameliorating a proliferative disorders, such as cancer, or one or more symptoms thereof, said methods comprising administering to a subject in need thereof a dose of at least 150 μg/kg, preferably at least 250 μg/kg, at least 500 μg/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at least 200 mg/kg or more of one or more compounds of the invention once every day, preferably, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 10 days, once every two weeks, once every three weeks, or once a month F Other Embodiments
The compounds of the invention may be used as research tools (for example, to evaluate the mechanism of action of new drug agents, to isolate new drug discovery targets using affinity chromatography, as antigens in an ELISA or EllSA-like assay, or as standards in in vitro or in vivo assays) These and other uses and embodiments of the compounds and compositions of this invention will be apparent to those of ordinary skill in the art
The invention is further defined by reference to the following examples describing in detail the preparation of compounds of the invention It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the purpose and interest of this invention The following examples are set forth to assist in understanding the invention and should not be construed as specifically limiting the invention described and claimed herein Such variations of the invention, including the substitution of all equivalents now known or later developed, which would be within the purview of those skilled in the art, and changes in formulation or minor changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein
EXAMPLES
Example 1 : 2-Ethyl-6-[5-mercapto-4-(1-methyl-1 H-ιndol-5-yl)-4H-[1 ,2,4]trιazol-3-yl]- pyrιdιne-3,5-dιol
1H-NMR (MeOD) 7 47 (d, 1 H), 7 37 (d, 1H), 7 22 (d, 1 H), 7 03 (dd, 1 H), 6 83 (s, 1 H), 6 43 (dd, 1H), 3 79 (s, 3H), 2 61 (q, 2H), 0 95 (t, 3H)1 MS expected ion = 367 2, observed ion = 368 1
2,6-dιbromo-3,5-dimethoxypyridine A flask was charged with 3,5-dιmethoxypyrιdιne (13 g, 93 mmol), water (100 mL) and concentrated hydrochloric acid (8 ml_, ~1 eq ) To a separate flask was added potassium bromide (65 g ), water (200 mL) and sulfuric acid (69 g ) To a third flask was added potassium bromate (18 g ), and water (1 2 liters) All flasks were stirred until they were homogenous To the flask with potassium bromate was added the solution containing potassium bromide, followed by the solution containing the pyridine compound The reaction was stirred for ten minutes, and a solution of sodium sulfite was added until the orange color disappeared The solid was collected by Buchner funnel, washed with water, dissolved in dichloromethane, dried over sodium sulfate, and evaporated to give 2,6-dibromo-3,5-dimethoxypyridine (23.3 g; 78 mmol).
6-Bromo-3,5-dimethoxy-pyridine-2-carbonitrile: A flask was charged with 2,6-dibromo- 3,5-dimethoxypyridine (6.0 g; 20 mmol); copper (I) cyanide (2.3 g; 1.3 eq.) and dimethylformamide (30 mL). The reaction was heated at 90 0C for two hours, and then cooled. The reaction mixture was diluted with ethyl acetate (200 mL), dichloromethane ( 100 mL) and washed with a two molar aqueous sodium chloride solution (3x200 mL). The organic layer was evaporated, and purified by column chromatography to give an approximately equimolar mixture of starting material and 6-Bromo-3,5-dimethoxy-pyridine-2- carbonitrile (1.01 g).
6-ethyl-3,5-dimethoxy-pyridine-2-carbonitrile: Impure 6-bromo-3,5-dimethoxy-pyridine-2- carbonitrile (462 mg; <1.9 mmol) was dissolved in tetrahydrofuran (20 mL) under nitrogen, and to the solution was added 1,3-bis(diphenylphosphino)propane nickel (II) chloride (105 mg; 0.19 mmol). The solution was cooled to 0 0C, and a solution of ethyl magnesium bromide (1.0 molar in THF; 2.7 mL; 1.4 eq.) was slowly added. The reaction was stirred for five minutes, and quenched with saturated aqueous ammonium chloride (10 mL). To the reaction was added ethyl acetate (40 mL) and water (40 mL). The organic layer was isolated, dried over sodium sulfate, evaporated, and purified by column chromatography to give 6-ethyl-3,5-dimethoxy-pyridine-2-carbonitrile (114 mg; 0.6 mmol). 6-Ethyl-3,5-dimethoxy-pyridine-2-carboxylic acid ethyl ester: A pressure flask was charged with 6-ethyl-3,5-dimethoxy-pyridine-2-carbonitrile (114 mg; 0.6 mmol), anhydrous ethanol (4 mL) and sulfuric acid (8 drops; ~1.1 eq.). The reaction was heated at 130 0C for six days. The reaction was then evaporated, and to the residue was added 10% aqueous sodium carbonate solution (4 mL) and dichloromethane (6 mL). The crude reaction was stirred until all solid was dissolved, and the organic layer was isolated, and purified by column chromatography to give 6-ethyl-3,5-dimethoxy-pyridine-2-carboxylic acid ethyl ester (50 mg; 0.21 mmol).
6-Ethyl-3,5-dimethoxy-pyridine-2-carboxylic acid hydrazide: A flask was charged with 6-ethyl-3,5-dimethoxy-pyridine-2-carboxylic acid ethyl ester (50 mg.; 0.21 mmol), dioxane (4 mL) and hydrazine (64 mg; 2 mmol). The reaction was heated at reflux for one hour, and all solvents were removed by evaporation. To the dried cake was added ethyl acetate (10 mL) and a 10% aqueous sodium carbonate solution (1 mL). The organic layer was isolated, dried with magnesium sulfate, and evaporated to give 6-ethyl-3,5-dimethoxy-pyridine-2- carboxylic acid hydrazide (34 mg.; 0.15 mmol). 5-isothiocyanato-1 -methyl-1 H-indole A flask was charged with 5-amιno-1 -methyl-1 H- indole (8 8 g, 60 mmol), thiocarbonyl diimidazole (10 7 g, 60 mmol) and ethyl acetate (200 ml.) The reaction was heated at 50 0C for five minutes, and after cooling, the solvent was evaporated The crude material was dissolved in dichloromethane (100 mL) and filtered through a short plug of silica gel, which was washed with another bolus of dichloromethane (100 mL) The organic eluent was evaporated to give 5-ιsothιocyanato-1 -methyl-1 H-indole (8 9g, 47 mmol)
Λ/-[6-Ethyl-3,5-dimethoxy-pyridine-2-carboxamidyl]-W'-(1-Methyl-1H-indol-5-yI)- thiourea A flask was charged with e-ethyl-S.δ-dimethoxy-pyridine^-carboxylic acid hydrazide (34 mg, 0 15 mmol), 5-ιsothιocyanato-1 -methyl-1 H-indole (28 mg, 0 15 mmol) and ethanol (2 mL) and the mixture was heated at reflux for three hours The reaction was then cooled, and the precipitate was filtered and dried to give Λ/-[6-Ethyl-3,5-dιmethoxy-pyπdιne- 2-carboxamιdyl]-Λ/'-(1-Methyl-1 H-ιndαl-5-yl)-thιourea (44 mg, 0 11 mmol)
5-(6-Ethyl-3,5-dimethoxy-pyridin-2-yl)-4-(1 -methyl-1 H-indol-5-yl)-4H-[1,2,4]triazole-3- thiol A flask was charged with Λ/-[6-ethyl-3,5-dιmethoxy-pyπdιne-2-carboxamιdyl]-/V'-(1- Methyl-1 H-ιndol-5-yl)-thιourea (41 mg, 0 10 mmol), and one normal aqueous sodium hydroxide (2 mL), and the reaction was stirred at reflux under nitrogen for three hours The reaction was then cooled, adjusted to pH=7 with one normal hydrochloric acid, and the precipitate was extracted with dichloromethane (2x6 mL) The organic layers were dried with sodium sulfate, and evaporated to give quantitative yield of 5-(6-Ethyl-3,5-dιmethoxy- pyπdιn-2-yl)-4-(1 -methyl-1 H-ιndol-5-yl)-4H-[1,2,4]tπazole-3-thιol
2-Ethyl-6-[5-mercapto-4-(1 -methyl-1 H-indol-5-yl)-4H-t1,2,4]trιazol-3-yl]-pyrιdine-3,5- diol: A flask was charged with 5-(6-Ethyl-3,5-dιmethoxy-pyrιdιn-2-yl)-4-(1-methyl-1 H-ιndol- 5-yl)-4H-[1 ,2,4]trιazole-3-thιol (30 mg, 0 08 mmol), and pyridine hydrochloride (2 g) The reaction was put under a nitrogen atmosphere, and heated to 22O0C for forty five minutes, and then cooled To the flask was then added water (10 mL) and ethyl acetate (10 mL) and the contents were stirred until all solids were dissolved The organic layer was isolated, washed with water and all solvent was evaporated under vacuum with heating to give 2- ethyl-6-[5-mercapto-4-(1-methyl-1H-ιndol-5-yl)-4H-[1 ,2,4]trιazol-3-yl]-pyπdιne-3,5-diol
Example 2: 4-lsopropyl-6-[4-(1 -methyl-1 H-ιndol-5-yl)-5-phenylamιno-4H-[1 ,2,4]trιazol-3-yl]- benzene-1,3-dιol (Compound 1a)
1H-NMR (CDCI3) 7 70 (d, 1H), 7 59 (d, 1 H), 7 50 (m, 3H), 7 29 (m, 2H), 7 22 (dd, 1H), 6 98 (m, 1 H), 6 62 (d, 1 H), 6 40 (s, 1H), 6 28 (s, 1H), 3 94 (s, 3H), 2 83 (q, 1 H), 0 57 (d, 3H), 0 44 (d, 3H) MS expected ion = 439 2, observed ion = 440 4 t5-(5-lsopropyl-2,4-dimethoxy-phenyl)-4-(1-methyl-1 H-indol-5-yl)-4H-[1,2,4]triazol-3-yl]- phenyl-amine: A flask was charged with 5-isopropyl-2,4-dimethoxy-N-(1 -methyl-1 H-indol- 5-yl)-thiobenzamide (123 mg; 0.33 mmol), dioxane (2 ml), and hydrazine (0.5 mL). The reaction was heated to 100 0C for one hour, and the solvent was removed by evaporation. To the solid cake was added ethyl acetate (10 mL) and 10% aqueous potassium carbonate (1 mL), and it was shaken until the solid was completely dissolved. The organic layer was isolated, and dried with sodium sulfate. To the crude intermediate in the organic layer was added diisopropylethylamine (86 mg, 0.66 mmol) and phenylisocyanide dichloride (88 mg; 1.5 eq.). The reaction was stirred overnight, and washed with saturated aqueous ammonium chloride, dried with sodium sulfate, and the product was purified by column chromatography to. give [5-(5-lsopropyl-2,4-dimethoxy-phenyl)-4-(1 -methyl-1 H-indol-5-yI)- 4H-[1 ,2,4]triazol-3-yl]-phenyl-amine (64 mg).
4-lsopropyl-6-[4-(1 -methyl-1 H-indol-5-yl)-5-phenylamino-4H-[1,2,4]triazol-3-yl]- benzene-1,3-diol: A flask was charged with [5-(5-lsopropyl-2,4-dimethoxy-phenyl)-4-(1- methyl-1 H-indol-5-yl)-4H-[1 ,2,4]triazol-3-yl]-phenyl-amine (27 mg; 0.06 mmol) and pyridinium chloride (2 g.). The reactants were placed under a nitrogen atmosphere, and the reaction was heated to 210 0C for 25 minutes. To the cooled reaction mixture was added dichloromethane and saturated ammonium chloride solution. The organic fraction was isolated, and the product was purified by column chromatography to give 4-lsopropyl-6-[4- (1-methyl-1H-indol-5-yl)-5-phenylamino~4H-[1,2,4]triazol-3-yll-benzene-1 ,3-diol (18 mg; 0.04 mmol.)
Example 3: 4-lsopropyl-6-[4-(1 -methyl-1 H-indol-5-yl)-5-methylamiπo-4H-[1 ,2,4]triazol-3-yl]- benzene-1 ,3-diol (Compound 2a)
1H-NMR (CDCI3): 7.60 (d, 1 H); 7.51 (d, 1 H); 7.23 (d, 1 H); 6.56 (d, 1 H); 6.41 (s, 1 H); 6.30 (s, 1 H); 3.88 (s, 3H); 3.03 (d, 3H); 2.79 (q, 1 H); 0.57 (d, 3H); 0.45 (d, 3H). MS: expected ion = 377.2; observed ion = 378.4.
Compound 2a was synthesized in a fashion analogous to Compound 1a.
Example 4: 4-lsopropyl-6-[4-(1-methyl-1H-indol-5-yl)-5-benzylamino-4H-[1,2,4]triazol-3-yl]- benzene-1,3-diol (Compound 3a) 1H-NMR (CDCI3): 7.60 (d, 1H); 7.50 (d, 1 H); 7.34-7.22 (m, 6H); 7.16 (dd, 1H); 6.56 (d, 1H); 6.41 (s, 1 H); 6.29 (s, 1H); 4.60 (d, 2H); 3.87 (s, 3H); 2.78 (q, 1 H); 0.57 (d, 3H); 0.46 (d, 3H). MS: expected ion = 453.2; observed ion = 454.4.
Compound 3a was synthesized in a fashion analogous to Compound 1a.
Example 5; N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1 H-indol-5-yi)-4H-1 ,2,4- triazol-3-yl)acetamide (Compound 11a) [δ-tδ-lsopropyl-a^-dibenzyloxy-pheπyO^-li-methyl-IH-indol-S-ylJ^H-Ii^^ltriazol-S- yl]-phenyl-amine: A flask was charged with 5-ιsopropyl-2,4-dιbenzyloxy-N-(1-methyl-1H- ιndol-5-yl)-thιobenzamιde (10 4 g, 20 mmol), dioxane (50 mL), and hydrazine hydrate (50 mL, 1 mol) The reaction was heated to 100 0C for one hour, and the solvent was removed by evaporation To the solid cake was added ethyl acetate (200 mL) and 10% aqueous potassium carbonate (100 mL), and it was shaken until the solid was completely dissolved The organic layer was isolated, and dried with sodium sulfate, and evaporated The crude intermediate was dissolved in tetrahydrofuran (200 mL), and to it was added diisopropylethylamine (6 mL, 30 mmol) and bromocyanogen (2 33 g, 1 1 eq ) The reaction was stirred overnight, and washed with saturated aqueous ammonium chloride, dried with sodium sulfate, and the product was purified by column chromatography to give [5-(5- lsopropyl-2,4-dιbenzyloxy-phenyl)-4-(1-methyl-1H-ιndol-5-yl)-4H-[1,2,4]tπazol-3-yl]-phenyl- amine (3 6 g)
N-(5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1 -methyl-1 H-indol-5-yl)-4H-1 ,2,4-triazol- 3-yl)acetamide: A flask was charged with [5-(5-lsopropyl-2,4-dιbenzyloxy-phenyl)-4-(1 - methyl-1 H-ιndol-5-yl)-4H-[1 ,2,4]tπazol-3-yl]-phenyl-amιne (0 25 mmol, 136 mg ), dimethylformamide (2 mL), and acetylimidazole (2 eq , 90 mg ), and the reaction was heated at 750C for 16 hours The solution was diluted with ethyl acetate (20 mL) and washed with water (3x10 mL), dried and the product was purified by column chromatography to give N-(5-(2,4-bιs(benzyloxy)-5-ιsopropylphenyl)-4-(1-methyl-1H-ιndol-5- yl)-4H-1 ,2,4-tπazol-3-yl)acetamιde
N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-trιazol-3- yl)acetamide A flask was charged with N-(5-(2,4-bιs(benzyloxy)-5-isopropylphenyl)-4-(1- methyl-1 H-indol-5-yl)-4H-1,2,4-trιazol-3-yl)acetamιde, tetrahydrofuran (10 mL), methanol (10 mL), 10% palladium on carbon (50 mg ) (in some cases palladium hydroxide was used) The reaction was stirred under an atmosphere of hydrogen for 16 hours, filtered through celite, and evaporated to give N-(5-(2,4-dιhydroxy-5-isopropylphenyl)-4-(1-methyl-1 H-ιndol- 5-y|)-4H-1 ,2,4-tπazol-3-yl)acetamιde 1H-NMR (CDCI3) 8 60 (br, 1H), 7 60 (d, 1H), 7 49 (d, 1 H), 7 29 (br, 1 H), 7 23 (d, 1 H), 7 14 (dd, 1 H), 6 55 (d, 1 H), 6 40 (s, 1 H), 6 38 (s, 1 H)1 3 94 (s, 3H), 2 82 (q, 1 H), 2 20 (s, 3H)1 0 47 (d, 6H) MS expected ion = 406 2, observed ion = 406 3 Example 6: N-(5-(2,4-dιhydroxy-5-ιsopropylphenyl)-4-(1 -methyl-1 H-ιndol-5-yl)-4H-1, 2,4- tπazol-3-yl)benzamιde (Compound 9a) A flask was charged with [5-(5-lsopropyl-2,4- dιbenzyloxy-phenyl)-4-(1 -methyl-1 H-ιndol-5-yl)-4H-[1 ,2,4]tπazol-3-yl]-phenyl-amιne (0 33 mmol, 183 mg ), dichloromethane (10 mL), diisopropylethylamine (3 eq , 0 2 mmol), and benzoyl chloride (2 eq , 70 mg ), and the reaction was stirred for 16 hours The organic solution was washed with saturated ammonium chloride (2x5 mL), dried and the product was purified by column chromatography to give N-(5-(2,4-bιs(benzyloxy)-5-ιsopropylphenyl)- 4-( 1 -methyl- 1 H-indo!-5-yl)-4 H- 1 ,2 ,4-triazol-3-yl)beπzamide and also N-benzoyl-N-(5-(2,4- bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1 H-indol-5-yl)-4H-1 ,2,4-triazol-3- yl)benzamide. The N-benzoyl-N-(5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(1 -methyl- 1 H- indol-5-yl)-4H-1 ,2,4-triazol-3-yl)benzamide was dissolved in methanol (5 mL), and 10% aqueous potassium carbonate (1 mL) was added, and the reaction was stirred for 16 hours. The solvent was then evaporated, and the solid was dissolved in ethyl acetate (10 mL), washed with water (2x5 mL), dried and evaporated to give more N-(5-(2,4-bis(benzyloxy)-5- isopropylphenyl)-4-(1 -methyl-1 H-indol-5-yl)-4H-1 ,2,4-triazol-3-yl)benzamide. The N-(5-(2,4- bis(benzyloxy)-5-isopropylphenyl)-4-(1-methyl-1 H-indol-5-yl)-4H-1 ,2,4-triazol-3- yl)benzamide was hydrogeπolyzed in a fashion analgous to N-(5-(2,4-dihydroxy-5- isopropylphenyl)-4-(1 -methyl-1 H-indol-5-yl)-4H-1 ,2,4-triazol-3-yl)acetarnide (Compound 4) to give N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1 H-indol-5-yl)-4H-1,2,4-triazol-3- yl)benzamide. MS: expected ion = 467.2; observed ion = 467.3.
Example 7: N-(5-(2,4- dihydroxy-5-isopropylphenyl)-4-(1 -methyl-1 H-indol-5-yl)-4H-1 , 2,4- triazol-3-yl)-5-methylisoxazole-3-carboxamide (Compound 10a): this compound was synthesized in an analogous fashion to N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl- 1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)benzamide (Compound 9a). MS: expected ion = 472.2; observed ion = 472.3.
Example 8: N-(5-(2,4- dihydroxy-5-isopropylphenyl)-4-(1-methyl-1 H-indol-5-yl)-4H-1 ,2,4- triazαl-3-yl)butyramide (Compound 12a); this compound was synthesized in an analogous fashion to N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1 -methyl-1 H-indol-5-yl)-4H-1, 2,4- triazol-3-yl)acetamide (Compound 11a) MS: expected ion = 434.2; observed ion = 434.3.
Example 9: N-(5-(2,4- dihydroxy-5-isopropylphenyl)-4-(1 -methyl-1 H-indol-5-yl)-4H-1, 2,4- triazol-3-yl)-2-methoxyacetamide (Compound 13a): this compound was synthesized in an analogous fashion to N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1 H-indol-5-yl)-4H- 1,2,4-triazol-3-yl)acetamide (Compound 11a). MS: expected ion = 436.2; observed ion = 436.3.
Example 10: N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1 H-indol-5-yl)-4H-1,2,4- triazol-3-yl)isobutyramide (Compound 14a): this compound was synthesized in an analogous fashion to N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1 -methyl-1 H-indol-5-yl)-4H- 1,2,4-triazol-3-yl)acetamide (Compound 11a). MS: expected ion = 434.2; observed ion = 434.3.
Example 11: N-(5-(2,4- dihydroxy-5-isopropylphenyl)-4-(1 -methyl-1 H-indol-5-yl)-4H-1, 2,4- triazol-3-yl)furan-2-carboxamide (Compound 15a): this compound was synthesized in an analogous fashion to N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1 H-indαl-5-yl)-4H- 1 ,2,4-triazol-3-yl)acetamide (Compound 11a). MS: expected ion = 458.2; observed ion = 458.2. Example 12: N-(5~(2,4-dihydroxy-5-isopropylphenyl)-4-(1-rnethyl-1H-indol-5-yl)-4H-1 ,2,4- triazol-3-yl)-2-phenylacetamide (Compound 16a): this compound was synthesized in an analogous fashion to N-(5~(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1 H-indol-5-yl)-4H- 1 ,2,4-triazol-3-yl)acetamide (Compound 11a). MS: expected ion = 482.2; observed ion = 482.3.
Example 13: N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1 ,2,4- triazol-3-yl)-3,4-difluorobenzamide (Compound 17a): this compound was synthesized in an analogous fashion to N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1 H-indol-5-yl)-4H- 1 ,2,4-triazol-3-yl)acetamide (Compound 11a). MS: expected ion = 504.2; observed ion = 504.2.
Example 14: N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1 ,2,4- triazol-3-yl)-2,2,2-trifluoroacetamide (Compound 18a): this compound was synthesized in an analogous fashion to N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)- 4H-1 ,2,4-triazol-3-yl)acetamide (Compound 11a). MS: expected ion = 460.2; observed ion =460.2.
Example 15: N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-iH-indol-5-yl)-4H-1 ,2,4- triazol-3-yl)cyclopentanecarboxamide (Compound 20a): this compound was synthesized in an analogous fashion to N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)- 4H-1 ,2,4-triazol-3-yl)acetamide (Compound 11a). MS: expected ion = 460.2; observed ion =460.3.
Example 16: 2-(4-chlorophenoxy)-N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1 H- indol-5-yl)-4H-1,2,4-triazol-3-yl)acetamide (Compound 19a): this compound was synthesized in an analogous fashion to N-(5-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl- 1 H-indol-5-yl)-4H-1 ,2,4-triazol-3-yl)acetamide (Compound 11a). MS: expected ion = 532.2; observed ion = 532.3.
Example 17: 4-(5-Arnino-4-(1-methyl-1H-indol-5-yl)-4H-1 ,2,4-triazol-3-yl)-6- isopropylbenzene-1 ,3-diol (Compound 4a):
5-(2,4-bismethoxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1 ,2,4-triazol-3- amiπe: This compound was synthesized in an analogous fashion to 5-(2,4-bis(benzyloxy)- 5-isopropylphenyl)-4-(1-methyl-1 H-indol-5-yl)-4H-1 ,2,4-triazol-3-amine.
(this is the final product) 1H-NMR (CDCI3): 7.52 (d, 1 H); 7.42 (d, 1 H), 7.16 (d, 1 H), 7.06 (dd, 1 H), 6.47 (d, 1 H), 6.28 (s, 1 H), 6.20 (s, 1 H), 3.80 (s, 3H); 2.73 (q, 1H); 0.40 (m, 6H). MS: expected ion = 543.3; observed ion = 543.4.
Example 18: 4-isopropyl-6-(4-(1-methyl-1 H-indol-5-yl)-5-(quinolin-6-ylamino)-4H-1 ,2,4- triazol-3-yl)benzene-1,3-diol (Compound 5a): N-(5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3- yl)quinolin-6-amiπe: A tube was charged with 5-(2,4-bismethoxy-5-isopropylphenyl)-4-(1- methyl-1 H-indol-5-yl)-4H-1,2,4-triazol-3-amine (0,25 mmol, 100 mg.), 6-bromoquinoline (0.5 mmol, 100 mg.), tris(dibenzylideneacetone) dipalladium(O), (10 mol%), cesium carbonate (1 mmol, 326 mg.), Xantphos (20 mol%), and dioxane (2 mL). The reaction is place under an atmosphere of nitrogen, and heated to 95°C for 16 hours. The crude mixture is run directly down a silica gel column for purification, giving N-(5-(5-isopropyl-2,4-dimethoxyphenyl)-4-(1- methyl-1 H-indol-5-yl)-4H-1 ,2,4-triazol-3-yl)quinolin-6-amine (114 mg.)
4-isopropyl-6-(4-(1-methyl-1H-indol-5-yl)-5-(quinolin-6-ylamino)-4H-1,2,4-triazol-3- yl)benzene-1,3-diol: A tube was charged with N-(5-(5-isopropyl-2,4-dimethoxyphenyl)-4- (1-methyl-1 H-indol-5-yl)-4H-1 ,2,4-triazol-3-yl)quinolin-6-amine (114 mg) and pyridine*HCI (4 g.), and placed under a nitrogen atmosphere. It was heated to 21O0C for 50 minutes, and then cooled. The solid was dissolved in ethyl acetate (20 mL) and washed with a saturated solution of ammonium chloride (3x20 mL). The organic layer was dried and evaporated to give 4-isopropyl-6-(4-(1 -methyl-1 H-indol-5-yl)-5-(quinolin-6-ylamino)-4H-1 ,2,4-triazol-3- yl)benzene-1 ,3-diol (42 mg). In some cases column chromatography was necessary for purification. 1H-NMR (CDCI3): 8.69 (dd, 1H); 8.50 (d, 1 H), 8.22 (d, 1 H), 7.98 (d, 1 H), 7.75 (d, 1 H), 7.63 (d, 1 H), 7.45-7.36 (m, 2H), 7.33 (d, 1 H), 7.27 (dd, 1 H), 6.64 (d, 1 H)1 6.42 (s, 1 H), 6.30 (s, 1 H), 3.98 (s, 3H); 2.83 (q, 1 H); 0.50 (m, 6H). MS: expected ion = 491.4; observed ion = 491.
Example 19: 4-(5-(3-aminophenylamino)-4-(1 -methyl-1 H-indol-5-yl)-4H-1 ,2,4-triazol-3-yl)- 6-isopropylbenzene-1 ,3-diol (Compound 6a). This compound was made in an analogous way to 4-isopropyl-6-(4-(1-methyl-1 H-indol-5-yl)-5-(quinolιn-6-ylamino)-4H-1 ,2,4-tπazol-3- yl)benzene-1 ,3-diol. (Compound 5a) Example 20: 4-isopropyl-6-(4-(1 -methyl-1 H-indol-5-yl)-5-(3-(trifluoromethyl)phenylamino)- 4H-1 ,2,4-triazol-3-yl)benzene-1 ,3-diol (Compound 7a). This compound was made in an analogous way to 4-isopropyl-6-(4-(1 -methyl-1 H-indol-5-yl)-5-(quinolin-6-ylamino)-4H-1 , 2,4- triazol-3-yl)benzene-1 ,3-diol. (Compound 5a)
Example 21 : 4-isopropyl-6-(5-(3-methoxyphenylamino)-4-(1 -methyl-1 H-indol-5-yl)-4H- 1 ,2,4-triazol-3-yl)benzene-1 ,3-diol (Compound 8a). This compound was made in an analogous way to 4-isopropyl-6-(4-(1-methyl-1 H-iπdol-5-yl)-5-(quinolin-6-ylamino)-4H-1 ,2,4- triazol-3-yl)benzene-1 ,3-diol (Compound 5a).
Example 22: Dimethyl-carbamic acid 3-dimethylcarbamoyloxy-4-(5- dimethylcarbamoylsulfanyl-4-naphthalen-1 -yl-4H-[1 ,2,4]triazol-3-yl)-phenyl ester
Figure imgf000227_0001
A mixture of E (336 mg, 1mmol) and dimethylcarbamyl chloride (430 mg, 4mmol) in pyridine (2mL) was heating at 80 0C for 2h.The solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography (CH2CI2/Me0H, 95:5) to give 350 mg (63%) of F as white solid
1H-NMR (CDCI3) δ (ppm), 7.83(d, J=8.1 Hz, 2H), 7.48-7.34(m, 4H), 7.28-7.20(m, 1H), 6.99 (d, J=1.8Hz, 1 H), 6.80(d, J=8.7Hz, 1 H), 6.62-6.58(m, 1H)1 2.94(s, 3H), 2.89(s, 3H), 2.84(s, 3H), 2.81 (s, 3H), 2.75-2.69(m, 6H); ESMS clcd for C27H2BN6O5S: 548.18; Found: 549.2 (M+H)+.
Example 23: 2-(5-Mercapto-4-naphthalen-1-yl-4H-l1,2,4]triazol-3-yl)-5-methoxymethoxy- phenol
Figure imgf000227_0002
To a stirred solution of methyl 2,4-dihydroxybenzoate (840 mg, 5.0 mmol) in 20 mL of anhydrous THF at 0 0C under the nitrogen, was added NaH (60% in oil) (200mg, 5,0 mmol). The suspension was stirred for 0.5h at 0 0C and MOMCI (0.4ml_, 5.0 mmol) was added at 0 0C. After the mixture warmed to room temperature and stirred for 1h, the reaction was quenched by ice brine and extracted with EtOAc (10OmL). The organic phase was washed with brine, dried (Na2SO4), filtered evaporated in vacuo and solid washed with hexane/EtOAc (9:1) to give pure product A (940mg g, 89% yield).
To a solution of A (430mg, 2 mmol) in dioxane (5 mL) were added 1 mL hydrazine and stirred at 85-90 0C at 2h then the solvent was removed in vacuo. The residue was dissolved in EtOAc and washed water and brine. The organic extract was dried over Na2SO4 and filtered and concentrated to a low volume and allowed to crystallize. The product B was collected as with crystals (400 mg, 94%).
To a stirred solution of 1-isothiocyanatonaphthalene (290 mg, 1.55 mmol)) in 2OmL of methanol was added hydrazide B (330mg, 1.55 mmol). The resultant mixture was then heated at 70 0C for 1 h, then cooled. Solvent was removed on rotary evaporator and the residue was treated with hexane/EtoAc (9:1). The white precipitate thus obtained was filtered, washed with ether to give C (520 mg, 84%).
To a solution of NaOH (120mg, 3mmol) in 3 mL of water was added compound C (480 mg, 1 ,2mmol). After the dissolution of the solid (1-2 min), the flask was flushed with nitrogen and heated to 110 0C for 2h. The reaction mixture was cooled, an additional 20 mL of water was added and the whole mixture was acidified with cone. HCI to pH 7. The white precipitate thus obtained was filtered, washed with water and dried. The crude product was then re- dissolved in a mixture of 10 mL of ethyl acetate, dried over anhydrous Na2SO4 and passed through a short pad of silica gel with an additional 50 mL of ethyl acetate as eluent. The filtrates were concentrated and crude product was re-precipitated in 3:1 hexane/ethyl acetate to give 380mg (85%) of D as white solid.
1H-NMR (DMSO-de) δ (ppm), 9.94(s, 1 H), 7.98(t, J=6.6 Hz, 2H), 7.6-7.45(m, 5H), 7.10(d, J=4.2 Hz1 1H)1), 6.30-6.27 (m, 2H), 5.01(s, 2H), 3.26(s, 3H); ESMS clcd for C20H17N3O3S: 379.10; Found: 380.0 (M+H)+.
Example 24: 6,6'-(5,5'-disulfanediylbis(4-(4-(dimethylamino)phenyl)-4H-1 ,2,4-triazole-5,3- diyl))bis(4-isopropylbenzene-1,3-diol) (Compound 7b)
Figure imgf000229_0001
Compound 7b
A 250 mL of round bottom flask was dried and charged with compound 12-0718 (500mg, 1.4 mmol), THF (200 mL), and catalytic amount of iodine. The mixture was kept refluxing for 5 h, and concentrated until 20 mL of solvent remained. The resulting precipitate was isolated and washed with THF (10 mL) two times to give 350 mg of pure product 6,6'-(5,5'- disulfanediylbis(4-(4-(dimethylamino)phenyl)-4H-1,2,4-triazole-5,3-diyl))bis(4- isopropylbenzene-1 ,3-diol) ( yield 70%).
1H NMR (DMSO): δ (ppm) 11.05 (s, 1H); 9.88 (s, 1 H); 9.75 (d, J= 9 Hz, 2H); 6.62 (d, J= 9 Hz, 2H); 6.48 (s, 1H); 6.37 (s, 1 H); 3.64 (m, 1 H); 2.75 (m, 6H); 0.76 (m, 6H). ESMS calcd (C38H42N8O4S2): 738.28; found: 738.2 (M+H)+
Example 25: 1-(5-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1 ,2,4-triazol-4-yl)-1 H- indol-1-yl)ethanone (Compound 9b)
Figure imgf000229_0002
Figure imgf000229_0003
Compound 9b
A mixture of compound A (300 mg, 0.56 mmol, prepared according to procedures in our previous patents), acetic acid (0.06 mL, 1.13 mmol), EDC (320 mg, 1.70 mmol) and HOBt (84 mg, 0.61 mmol) in methylene chloride (10 mL) was stirred overnight at room temperature. The reaction mixture was quenched water, extracted with methylene chloride, dried and concentrated to give a residue, which was purified by column chromatograph on silica gel (20% EA/hexane) to give the title compound B 1-(5-(3-(2,4-bis(benzyloxy)-5- isopropylphenyl)-5-hydroxy-4H-1 T2,4-triazol-4-yl)-i H-indol-1-yl)ethanone (250 mg, 78% yield)
To a solution of the compound B (250 mg, 0 44 mmol) from previous step in 1 1 EA/EtOH was added 70 mg of palladium on carbon (10% wt) The hydrogenation reaction took 2 h to give final product as a white solid (110 mg, 62% yield)
1H NMR (DMSO) δ (ppm) 11 29 (s, 1 H), 9 68 (s, 1 H), 9 58 (s, 1 H)1 7 45 - 7 36 (m, 3H), 6 94 (iti, 1H), 6 84 (S1 1H), 643 (s, 1H), 6 21 (s, 1H), 2 90 (m, 1H), 2 54 (s, 3H), 0 86 (m, 6H) ESMS calcd (C2IH20N4O4) 392 15, found 392 1 (M+H)+
Example 26: tert-butyl 3-(5-(3-(2,4-dιhydroxy-5-ιsopropylphenyl)-5-hydroxy-4H-1,2,4-tπazol- 4-yl)-1 H-ιndol-1-yl)-3-oxopropylcarbamate (Compound 10b)
1H NMR (DMSO) δ (ppm) 11 29 (s, 1 H)1 9 68 (s, 1 H), 9 57 (s, 1 H), 7 43 - 7 35 (m, 3H), 6 92 - 6 82 (m, 3H), 6 41 (s, 1H), 6 20 (s, 1H), 3 36 (m, 2H), 3 11 (m, 2H), 2 89 (m, 1H), 1 36 (m, 9H), 0 86 (m, 6H) ESMS calcd (C27H3IN5O6) 521 23, found 521 2 (M+H)+ Example 27: 5-(2,4-Dihydroxy-5-ιsopropyl-phenyl)-4-(1-methyl-1H-ιndol-5-yl)-2-propιonyl- 2,4-dιhydro-[1 ,2,4]trιazol-3-one (Compound 1 b)
Figure imgf000230_0001
a (545 mg, 1 mmol) was dissolved in CH2CI2 (10 mL) Propionyl chloride (0 13 mL, 1 2 mmol) was added drop wise followed by Et3N (0 17 mL, 1 2 mmol) The reaction mixture was stirred at r t for 30 mm and water was added The reaction mixture was extracted with EtOAc (25 mL x 3) and the combined organic layers were washed with water and brine and dried over Na2SO4 Purification of the concentrated crude product by column chromatography (EtOAc Hexane = 4 6) afforded b as a pale yellow oil (395 mg, 66%) b (390 mg, 0 65 mmol) was hydrogenated using Pd/C (10%, dry, 50 mg) and H2 balloon at 1 atm at room temperature Pd/C was filtered off through a pad of celite and the mother liquid was concentrated to give Compound 1 as a white solid (225 mg, 82%) 1H NMR (300 MHz, DMSO-d6), δ (ppm) 9 67 (s, 1 H)1 9 55 (s, 1 H), 7 47 (d, J = 1 8 Hz, 1 H), 7 43 (d, J = 8 7 Hz, 1 H), 7 40 (d, J = 3 0 Hz, 1 H)1 6 98 (dd, J = 8 7 Hz, 1 8 Hz1 1H), 6 90 (s, 1 H), 643 (d, J = 3 0 Hz, 1 H), 6 21 (s, 1 H), 3 78 (s, 3H), 2 98 (q, J = 7 2 Hz, 2H), 3 00-2 88 (m, 1 H), 1 41 (t, 3H), 0 92 (d, J = 6 9 Hz, 6H) ESMS calcd for C23H24N4O4 420 2, Found 421 2 (M+1)+
Example 28: 2,2-Dιmethyl-propιonιc acid 3-(2,4-dιhydroxy-5-ιsopropyl-phenyl)-4-(1-methyl- 1H-ιndol-5-yl)-5-oxo-4,5-dιhydro-[1,2,4]trιazol-1-ylmethylester (Compound 2b)
Compound 2b was synthesized in a similar way to Compound 1b ESMS calcd for C26H30N4O5478 2, Found 479 3 (M+1)+ Example 29 3-(2,4-dιhydroxy-5-ιsopropylphenyl)-4-(1-(3-methoxypropanoyl)-i H-indol-5-yl)- 1H-1,2,4-tπazol-5(4H)-one (Compound 11b)
Chemical Formula C23H24N4O5 Molecular Weight 436 5 H-NMR (DMSO-δB) 11 3 (s, 1 H), 9 7 (s, 1 H), 9 6 (S1 1 H),
7 4 (m, 3H), 6 9 (m, 1 H), 6 8 (s, 1 H), 6 4 (s, 1 H), 6 2 (s,1 H), 3 7 (t, J = 6 6 Hz, 2H), 3 3 (s, 3H)1 3 2 (t, J = 6 3 Hz1 2H)1 2 8 (m, 1H)1 0 86 (m, 6H)
Example 30 (3-(2,4-dιhydroxy-5-ιsopropylphenyl)-4-(1-methyl-1H-ιndol-5-yl)-5-oxo-4,5- dιhydro-1 H-1 ,2,4-tπazol-1-yl)methyl 2-amιno-3-methylbutanoate (Compound 12b)
Chemical Formula C25H3IN5O5 Molecular Weight 493 6
H-NMR (DMSO- δ 6) 9 6 (br s, 1 H), 9 4 (br s, 1 H)1 7 4 (m, 3H), 6 9 (m, 2H), 6 4 (s, 1 H), 6 2 (s,1 H), 5 8 (q, J = 10 5 Hz, 2H), 3 8 (s, 3H), 3 2 (d, J = 4 8 Hz, 1 H), 2 9 (m, 1H), 1 8 (m, 1H), 1 7 (br s, 2H), 0 95-0 82 (m, 12H)
Example 31 (3-(2,4-dιhydroxy-5-ιsopropylphenyl)-4-(1-methyl-1 H-indol-5-yl)-5-oxo-4,5- dιhydro-1H-1,2,4-trιazol-1-yl)methyl 2-amιno-3-phenylpropanoate (Compound 13b)
Chemical Formula C30H31N5O5 Molecular Weight 541 6 H-NMR (DMSO- δ6) 9 6 (br s, 1H)1 9 4 (br S1 1 H), 7 4 (m, 3H), 7 2 (m, 5H)1 6 9 (m, 2H), 6 4 (d, J = 3 Hz1 1 H), 6 2 (s,1H), 5 8 (s, 2H), 3 8 (s, 3H), 3 6 (t, J = 6 6 Hz, 1H), 2 9 (m, 3H)1 1 8 (br s, 2H)1 O 94 (m, 6H)
Example 32 Preparation of Compound 6d
The compound was prepared as shown in Scheme Xl above N2,N2-dιmethylpyrιdιne-2,5-dιamιne (2 75g, 20mmol) in 50 ml CH2CI2 was added to the solution N.N'-carbonyldiimidazole (CDI) (4 Og , 25 mmol) in 100ml CH2CI2, and the solution was mix at room temperature (RT) for 1h Solvents were removed on rotary evaporator and the residue was dissolved in 50 ml dioxane and treated with hydrazine (6 5 ml , 200mmol, 10eq) at RT to 450C for 1h The reaction mixture was subjected to EtOAc/aqueous workup to remove excess hydrazine The aqueous solution was extracted with CH2CI2 The organic layer was dried over Na2SO4, filtered evaporated in vacuo gave A as light brown solid.
To a stirred solution of the hydrazide A (1.95g, 10 mmol) in 6OmL of MeOH was added the 2,4-bis(benzyloxy)-5-isopropylbenzaldehyde B ( 3.61 g ,10 mmol ). The resultant mixture was then heated at 70 0C for 1h, then cooled. The white precipitate thus obtained was filtered, washed with ether (2 X 50 mL) and vacuum dried to give 4.84 g (90%) of C as a white solid.
To a solution of compound C (3.5 g, 6.5 mmol) in 100 mL of EtOH was added 10.7g
(32.5 mmol) of K3Fe(CN)6 and 1.6g (40 mmol) of NaOH . After the dissolution of the solid (1-2 min), the flask was flushed with nitrogen and heated to 110 0C for 8h. The reaction mixture was cooled, and then filtered over Celite, washed EtOH and evaporated to dryness.
To the oily residue was added 50 ml water and the mixture was acidified with cone. HCI to pH 7-8. The white precipitate thus obtained was filtered, washed with water and dried. The crude product was then re-dissolved in a mixture of 25 mL of ethyl acetate and methanol (9:1), dried over anhydrous Na2SO4 and passed through a short pad of silica gel with an additional 150 mL of ethyl acetate as eluent The filtrates were concentrated and crude product was re-precipitated to give D (2.60 g, 74.7%) as an off-white solid.
A solution of compound D (2.14 g, 4.0 mmol) in 200 mL of MeOH/EtOAc (1 :1 ) containing 5% w/w of Pd-C (10%) was subjected to hydrogenation (1 atm, balloon, (3 h). The contents of the flask were passed through a short pad of celite and washed with EtOAc.
The filtrate was evaporated under reduced pressure to give 1.3 g (91.5%) of compound 6d. 1H-NMR (DMSO-de) δ (ppm), 11.83(s, 1 H), 9.57(s. 1H), 9.39(s, 1 H), 7.90(d,
J=2.1Hz, 1 H), 7.29 (d, .7=9.0 Hz1 1 H), 6.88(s, 1 H), 6.59(d, J=8.7 Hz, 1 H), 6.23(s, 1 H), 3.0-
2.90(m, 1H), 2.97(s, 3H), 1.01(d, J=6.9 Hz, 6H);
The compounds prepared in Examples 33-41 and 50 were prepared according to the procedure outlined in Exmaple 32.
Example 33: Compound 1d
1H-NMR (DMSO-d6) δ (ppm), 11.87(s, 1 H), 9.61(s, 1H), 9.43(s, 1 H), 7.81 (d, J=2.7Hz, 1 H), 7.11 (d, J=9.0 Hz1 1 H), 6.88(s, 1 H), 6.59(d, J=9.0 Hz, 1 H), 6.26(s, 1 H), 3.65(t, J=SA Hz,
2H), 3.43(t, J=5.4 Hz, 2H), 3.20(s, 3H), 3.0-2.90(m, 1 H), 2.96(s, 3H), 0.99(d, J=6.9 Hz, 6H); ESMS clcd for C20H25N5O4: 399.19; Found: 400.1 (M+H)+.
Example 34: Compound 3d 1H-NMR (DMSO-dB) δ (ppm), 12.08(s, 1 H)1 9.80(bs, 2H), 7.89-7.92(m, 2H), 7.58(d, J=2.7 Hz, 1H), 7.52 (d, J=2.7 Hz, 1H), 7.04(s, 1H), 6.29(s, 1H), 4.2-3.2(m, 4H), 3.55(s, 3H), 3.10- 3.0(m, 1H), 2.92(s, 3H), 1.09(d, J=6.6 Hz, 6H); ESMS clcd for C20H25N5O5: 415.19; Found: 416.1 (M+H)+. Example 35: Compound 6d
1H-NMR (DMSO-d6) δ (ppm), 11.83(8, 1H)1 9.57(3, 1H), 9.39(s, 1H), 7.90(d, J=2.1Hz, 1H), 7.29 (d, J=9.0 Hz, 1H), 6.88(s, 1H)1 6.59(d, J=8.7 Hz, 1 H), 6.23(s, 1H), 3.0-2.90(m, 1H), 2.97(s, 3H), 1.01(d, J=6.9 Hz, 6H); ESMS clcd for C18H2IN5O3: 355.16; Found: 356.1 (M+H)+.
Example 36: Compound 5d
1H-NMR (DMSO-d6) δ (ppm), 11.85(s, 1H), 9.59(s, 1 H), 9.44 (s, 1 H), 7.82(d, J=2.1 Hz, 1 H), 7.28 (d, J=9.0 Hz, 1 H), 6.87(s, 1H), 6.56(d, J=9.0 Hz, 1 H), 6.26(s, 1 H), 3.57(t, J=6.9 Hz, 2H), 3.02-2.90(m, 1H), 2.97(s, 3H), 2.35(t, J=6.6 Hz, 2H), 2.15(s, 6H), 1.01(d, J=6,9 Hz, 6H);
ESMS clcd for C21H26N6O3: 412.22; Found: 413.1 (M+H)+.
Example 37: Compound 4d
ESMS clcd for C19H21N5O5: 399.15; Found: 400.1 (M+H)+.
Example 38: Compound 2d ESMS clcd for C21H27N5O5: 429.20; Found: 430.1 (M+H)+.
Example 39: Compound 7d
ESMS clcd for C18H23CI2N5O3: 427.12; Found: 356.1 (M+H)+.
Example 40: Compound 8d
ESMS clcd for C21H26N6O3: 410.21; Found: 411.1 (M+H)+.
Example 41: Compound 9d
ESMS clcd for C21H28CI2 N6O3: 482.16; Found: 411.1 (M+H)+.
Example 42: Procedure: Compound 11d
The compound was prepared as shown in Scheme XII above.
To a solution of 2-Methyl-5-nitrobenzenesulphonyl chloride (4.8g, 20 mmol) in 50 mL THF at 0°C was slowly added dimethylamine (20 mL,, 40 mmol)(2.0 M solution in THF). The mixture was stirred for 1h at O0C and then warmed to room temperature. The solution was treated with 50 mL of water and extracted with ethyl acetate, washed with brine dried over Na2SO4, filtered, and after evaporated to dryness to yield the 4.78g (98%)of the amine A. A solution of compound A (3.66 g, 15 mmol) in MeOH/EtOAc (1:1) (250 mL) containing 5% w/w of Pd-C (10%) was subjected to hydrogenation (1 atm, balloon) overnight. The contents of the flask were passed through a short pad of celite and washed with EtOAc. The filtrate was evaporated under reduced pressure to give 3.0 g (93%) of compound B. Compound B (2 15g, lOmmol) in 50 ml CH2CI2 was added to the solution N1N'- carbonyldiimidazole (CDI) (2 Og , 12 5 mmol) in 100ml CH2CI2, and the solution was mix at RT for 1 h Solvent were removed on rotary evaporator and the residue was dissolved in 50 ml dioxane and treated with hydrazine (3 25 mL, lOOmmol, 10eq) at RT to 450C for 1h The reaction mixture was subjected to EtOAc/aqueous workup to remove excess hydrazine The aqueous solution was extracted with CH2CI2 The organic layer was dried over Na2SO4, filtered evaporated in vacuo gave compound C as off-white solid (2 06g, 76%)
To a stirred solution of the hydrazide C (1 36g, 5 mmol) in 5OmL of MeOH was added the 2,4-bιs(benzyloxy)-5-ιsopropylbenzaldehyde D (1 8 g ,5 mmol ) The resultant mixture was then heated at 70 0C for 1h, then cooled The white precipitate thus obtained was filtered, washed with ether (2 X 50 mL) and vacuum dried to give 2 76 g (90%) of E as a white solid
To a solution of compound E (2 46 g , 4 0 mmol) in 100 mL of EtOH was added (7 9g 24 0 mmol) of K3Fe(CN)6 and 1 2g (30 mmol) of NaOH After the dissolution of the solid (1-2 mm), the flask was flushed with nitrogen and heated to 110 0C for 8h The reaction mixture was cooled, and then filtered over Celite , washed EtOH and evaporated to dryness To the oily residue was added 50 ml water and the mixture was acidified with cone HCI to pH 7-8 The white precipitate thus obtained was filtered, washed with water and dried The crude product was then re-dissolved in a mixture of 25 mL of ethyl acetate and methanol (9 1), dried over anhydrous Na2SO4 and passed through a short pad of silica gel with an additional 150 mL of ethyl acetate as eluent The filtrates were concentrated and crude product was re-precipitated to give F (1 76 g, 72%) as an off-white solid
A solution of compound F (1 3O g, 2 12 mmol) in 150 mL of MeOH/EtOAc (1 1 ) containing 5% w/w of Pd-C (10%) was subjected to hydrogenation (1 atm, balloon, (3 h) The contents of the flask were passed through a short pad of celite and washed with EtOAc The filtrate was evaporated under reduced pressure to give 0 87 g (95%) of Compound 11d 1H-NMR (DMSO-d6) δ (ppm), 11 99(s, 1 H), 9 59(s, 1 H), 9 34 (s, 1 H), 7 5-7 37(m, 3H), 7 01 (S, 1 H)), 6 21(s, 1 H), 3 02-2 90(m, 1 H), 2 52-2 49(m, 9H), 1 07 (d, J=6 9 Hz, 6H), ESMS clcd for C20H24N4O5S 432 15, Found 433 2 (M+1 )+
The compounds prepared in Examples 43-49 were prepared according to the procedure outlined in Example 42
Example 43 Compound ed
1H-NMR (DMSO-d6) δ (ppm), 12 06(s, 1 H), 9 65(s, 1 H), 9 48 (s, 1 H), 7 75(d, J=2 4Hz, 1 H), 7 54 (d, J=8 4 Hz, 1H), 7 31 (d, J=8 7 Hz, 1 H), 7 12(s, 2H)), 6 83(s, 1H), 6 28(s, 1H)1 3 02- 2 90(m, 1 H), 2 66(s, 6H), 0 99(d, J=Q 9 Hz, 6H), ESMS clcd for Ci9H23N5O5S 433 14, Found 434 2 (M+1)+ Example 44: Compound 11d
1H-NMR (DMSO-dg) δ (ppm), 11.99(s, 1 H), 9.59(s, 1 H)1 9.34 (s, 1H), 7.5-7.37(m, 3H), 7.01(s, 1 H)), 6.21(s, 1 H)1 3.02-2.90(m, 1 H), 2.52-2.49(m, 9H), 1.07 (d, J=6.9 Hz1 6H); ESMS clcd for C20H24N4O6S: 432.15; Found: 433.2 (M+1)+. Example 45: Compound 18d
1H-NMR (DMSOd6) δ (ppm), 11.99(s, 1 H), 9.61(s, 1 H), 9.38 (s, 1 H), 7.5-7.34(m, 3H), 7.01(s, 1H)), 6.21(s, 1H), 3.40-3.34(m, 2H), 3,17(s, 1H)1 3.08-3.00(m, 3H),2.59(s, 3H)1 2.50(S1 3H), 1.08(d. J=6.9 Hz, 6H); ESMS clcd for C22H28N4O6S: 476.17; Found: 477.2 (M+1)+. Example 46: Compound 14d
ESMS clcd for C17H18N4O4S: 406.08; Found: 407.1 (M+1 )+.
Example 47: Compound 15d
ESMS clcd for C21H24N4O6S: 460.14; Found: 461.2 (M+1)+.
Example 48: Compound 1Od ESMS clcd for C22H29N6O6S: 475.19; Found: 476.2 (M+1)+.
Example 49: Compound 17d
ESMS clcd for C19H22N4O5S: 418.13; Found: 419.2 (M+1)+.
Example 50: 4-(5-hydroxy-4-(6-morpholinopyridin-3-yl)-4H-1 ,2,4-tria∑ol-3-yl)-6- isopropylbenzene-1 ,3-diol (Compound 19d) 1H-NMR (DMSO-d6) δ (ppm), 11.89(s, 1 H), 9.60(s, 1H), 9.41 (s, 1 H)1 7.87(s, 1 H), 7.35(d,d J=2.7, J=9.0 Hz, 1H)), 6.92 (s, 1 H), 6.81(d, J=9.0 Hz, 1 H), 6.24(s, 1 H), 3.67-3.64 (m, 4H), 3.43-3.40(m, 4H), 3.08-2.95(m, 1H), 1.04 (d, J=6.9 Hz, 6H);
ESMS clcd for C20H23N5O4: 397.18; Found: 398.3 (M+1)+.
Example 51 : 4-(5-hydroxy-4-(6-(2-morpholinoethoxy)pyridin-3-yl)-4H-1 ,2,4-triazol-3-yl)-6- isopropylbenzene-1,3-diol (Compound 2Od)
1H-NMR (DMSO-d6) δ (ppm), 11.96(s, 1 H)1 9.64(s, 1 H)1 9.40 (s, 1 H), 7.90(s, 1H)1 7.53 (d,d J=2.7, J=9.0 Hz1 1H)), 6.94 (s, 1H), 6.84(d, J=9.0 Hz, 1H)1 6.25(s, 1 H), 4.40- 4.32(m,2H),3.60-3.52 (m, 4H), 3.08-2.95(m, 1 H), 2.68-2.60(m,2H), 2.48-2.38(m, 4H), 1.05 (d, J=6.9 Hz1 6H); ESMS clcd for C22H27N5O6: 441.20; Found: 442.4 (M+1)+.
Example A: Inhibition of Hsp90 Hsp90 protein is obtained from Stressgen (Cat#SPP-770). Assay buffer: 100 mM Tris-HCI, Ph7.4, 20 mM KCI, 6 mM MgCI2. Malachite green (0.0812% w/v) (M9636) and polyviny alcohol USP (2.32% w/v) (P1097) are obtained from Sigma. A Malachite Green Assay (see Methods MoI Med, 2003, 85:149 for method details) is used for examination of ATPase activity of Hsp90 protein. Briefly, Hsp90 protein in assay buffer (100 mM Tris-HCI, Ph7.4, 20 mM KCI, 6 mM MgCI2) is mixed with ATP alone (negative control) or in the presence of Geldanamycin (a positive control) or a compound of the invention in a 96-well plate. Malachite green reagent is added to the reaction. The mixtures are incubated at 37 0C for 4 hours and sodium citrate buffer (34% w/v sodium citrate) is added to the reaction. The plate is read by an ELISA reader with an absorbance at 620 nm.
Example B: Degradation of Hsp90 Client Proteins via Inhibition of Hsp90 Activity
A. Cells and Cell Culture
Human high-Her2 breast carcinoma BT474 (HTB-20), SK-BR-3 (HTB-30) and MCF-7 breast carcinoma (HTB-22) from American Type Culture Collection, VA, USA were grown in Dulbecco's modified Eagle's medium with 4 mM L-glutamine and antibiotics (100lU/ml penicillin and 100 ug/ml streptomycine;GibcoBRL). To obtain exponential cell growth, cells were trypsinized, counted and seeded at a cell density of 0.5x106 cells /ml regularly, every 3 days. All experiments were performed on day 1 after cell passage.
B. Degradation of Her2 in Cells after Treatment with a Compound of the Invention
1. Method 1
BT-474 cells are treated with 0.5μM, 2μM, or 5μM of 17AAG (a positive control) or 0.5μM, 2μM, or 5μM of a compound of the invention overnight in DMEM medium. After treatment, each cytoplasmic sample is prepared from 1x10B cells by incubation of cell lysis buffer (#9803, cell Signaling Technology) on ice for 10 minutes. The resulting supernatant used as the cytosol fractions is dissolved with sample buffer for SDS-PAGE and run on a SDS- PAGE gel, blotted onto a nitrocellulose membrane by using semi-dry transfer. Non-specific binding to nitrocellulose is blocked with 5% skim milk in TBS with 0.5% Tween at room temperature for 1 hour, then probed with anti-Her2/ErB2 mAb (rabbit IgG, #2242, Cell Signaling) and anti-Tubulin (T9026, Sigma) as housekeeping control protein. HRP- conjugated goat anti-rabbit IgG (H+L) and HRP-conjugated horse anti-mouse IgG (H+L) are used as secondary Ab (#7074, #7076, Cell Signaling) and LumiGLO reagent, 2Ox Peroxide (#7003, Cell Signaling) is used for visualization.
Her2, an Hsp90 client protein, is expected to be degraded when cells are treated with compounds of the invention. 0.5μM of 17AAG, a known Hsp90 inhibitor which is used as a positive control, causes partial degradation of Her2. 2. Method 2
MV-4-11 cells (20,000 cells/well) were cultured in 96-well plates and maintained at 37 0C for several hours. The cells were treated with a compound of the invention or 17AAG (a positive control) at various concentrations and incubated at 37 0C for 72 hours. Cell survival was measured with Cell Counting Kit-8 (Dojindo Laboratories, Cat. # CK04).
The IC60 range for Her2 degradation by compounds of the invention are lised below in Tables 6-9.
Tables 6-9: ICS0 range of compounds of the invention for inhibition of Hsp90
Table 6
Figure imgf000237_0001
Table 8
Figure imgf000238_0001
Table 9
Figure imgf000238_0002
Figure imgf000239_0001
Fluorescent Staining of Her2 on the Surface of Cells Treated with a Compound of the Invention
After treatment with a compound of the invention, cells are washed twice with 1xPBS/1%FBS, and then stained with anti-Her2- FITC (#340553, BD) for 30 min at 40C. Cells are then washed three times in FACS buffer before the fixation in 0.5 ml 1 % paraformadehydrede. Data is acquired on a FACSCalibur system. Isotype-matched controls were used to establish the non-specific staining of samples and to set the fluorescent markers. A total 10,000 events are recorded from each sample. Data are analysed by using CellQuest software (BD Biosciences).
D. Apoptosis analysis
After treatment with the compounds of the invention, cells are washed once with 1xPBS/1 %FBS, and then stained in binding buffer with FITC-conjugated Annexin V and Propidium iodide (Pl) (all obtained from BD Biosciences) for 30 min at 4°C. Flow cytometric analysis is performed with FACSCalibur (BD Biosciences) and a total 10,000 events are recorded from each sample. Data is analyzed by using CellQuest software (BD Biosciences). The relative fluorescence is calculated after subtraction of the fluorescence of control.
E. Degradation of c-Kit in Cells after Treatment with a Compound of the Invention Two leukemia cell lines, HEL92.1.7 and Kasumi-1, are used for testing c-kit degradation induced by Hsp90 inhibitors of the invention. The cells (3X105 per well) are treated with 17AAG (0.5 μM), or a compound of the invention for about 18 h. The cells are collected and centrifuged (SORVALL RT 6000D) at 1200 rpm for 5 min. The supematants are discarded, and the cells are washed one time with 1X PBS. After centrifugation the cells are stained with FITC conjugated c-kit antibody (MBL International, Cat# K0105-4) in 100 ml 1X PBS at 40C for 1 h. The samples are read and analysized with FACSCalibur flow cytomεter (Becton Dicknson). c-Kit, a tyrosine kinase receptor and one of the Hsp90 client proteins, is selected and used in a FACS-based degradation assay. Compounds of the invention are expected to induce c-kit degradation in a dose-dependent manner. Compounds of the invention are expected to be effective in the treatment of c-kit associated tumors, such as leukemias, mast cell tumors, small cell lung cancer, testicular cancer, some cancers of the gastrointestinal tract (including GIST), and some central nervous system.
The results of the FACS analysis can be confirmed with Western blot analysis. F. Degradation of c-Met in Cells after Treatment with a Compound of the Invention
The ability of the Hsp90 inhibitors of the invention to induce the degradation of c-Met, an Hsp90 client protein that is expressed at high levels in several types of non-small cell lung cancer can be examined. NCI-M 993 (ATCC, cat# CRL-5909) are seeded in 6-well plates at 5 X 105 cells/well. The cells are treated with 17AAG (100 nM or 400 nM) or a compound of the invention (100 nM or 400 nM), and cell lysis is prepared 24 h after treatment. Equal amount of proteins are used for Western blot analysis. The compounds of the invention are expected to potently induce degradation of c-Met in this cell line due to inhibition of Hsp90.
Example C: Anti-tumor Activity Against the Human Tumor Cell Line MDA-MB- 435S in a nude Mouse Xenograft Model
The human tumor cell line, MDA-MB-435S (ATCC #HTB-129; G. Ellison, et al., MoI. Pathol. 55:294-299, 2002), is obtained from the American Type Culture Collection (Manassus, Virginia, USA). The cell line is cultured in growth media prepared from 50% Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI Media 1640, 10% fetal bovine serum (FBS), 1 % 100X L-glutamine, 1% 100X Penicillin-Streptomycin, 1 % 100X sodium pyruvate and 1% 100X MEM non-essential amino acids. FBS is obtained from Sigma-Aldrich Corp. (St, Louis, Missouri, USA), and all other reagents are obtained from Invitrogen Corp. (Carlsbad, California, USA). Approximately 4-5 x 10(6) cells that have been cryopreserved in liquid nitrogen are rapidly thawed at 370C and transferred to a 175 cm2 tissue culture flask containing 50 ml of growth media and then incubated at 370C in a 5% CO2 incubator. The growth media is replaced every 2-3 days until the flask becames 90% confluent, typically in 5-7 days. To passage and expand the cell line, a 90% confluent flask is washed with 10 ml of room temperature phosphate buffered saline (PBS) and the cells are disassociated by adding 5 ml 1X Trypsin-EDTA (Invitrogen) and incubating at 370C until the cells detach from the surface of the flask. To inactivate the trypsin, 5 ml of growth media is added and then the contents of the flask are centrifuged to pellet the cells. The supernatant is aspirated and the cell pellet is resuspended in 10 ml of growth media and the cell number determined using a hemocytometer. Approximately 1-3 x 10(6) cells per flask are seeded into 175 cm2 flasks containing 50 ml of growth media and incubated at 370C in a 5% CO2 incubator. When the flasks reach 90% confluence, the above passaging process is repeated until sufficient cells have been obtained for implantation into mice.
Six to eight week old, female Crl:CD-1-πuBR (nude) mice are obtained from Charles River Laboratories (Wilmington, Massachusetts, USA). Animals are housed 4-5/cage in micro- isolators, with a 12hr/12hr light/dark cycle, acclimated for at least 1 week prior to use and fed normal laboratory chow ad libitum. Studies are conducted on animals between 7 and 12 weeks of age at implantation. To implant tumor cells into nude mice, the cells are trypsinized as above, washed' in PBS and resusupended at a concentration of 50 x 10(6) cells/ml in PBS. Using a 27 gauge needle and 1 cc syringe, 0.1 ml of the cell suspension is injected into the corpus adiposum of nude mice. The corpus adiposum is a fat body located in the ventral abdominal vicera in the right quadrant of the abdomen at the juncture of the os coxae (pelvic bone) and the os femoris (femur). Tumors are then permitted to develop in vivo until they reach approximately 150 mm3 in volume, which typically requires 2-3 weeks following implantation. Tumor volumes (V) are calculated by caliper measurement of the width (W), length (L) and thickness (T) of tumors using the following formula: V = 0.5326 x (L x W x T). Animals are randomized into treatment groups so that the average tumor volumes of each group are similar at the start of dosing. Sock solutions of test compounds are prepared by dissolving the appropriate amounts of each compound in dimethyl sulfoxide (DMSO) by sonication in an ultrasonic water bath. Stock solutions are prepared at the start of the study, stored at -2O0C and diluted fresh each day for dosing. A solution of 20% Cremophore RH40 (polyoxyl 40 hydrogenated castor oil; BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany) in 80% D5W (5% dextrose in water; Abbott Laboratories, North Chicago, Illinois, USA) is also prepared by first heating 100% Cremophore RH40 at 50-600C until liquefied and clear, diluting 1 :5 with 100% D5W, reheating again until clear and then mixing well. This solution is stored at room temperature for up to 3 months prior to use. To prepare formulations for daily dosing, DMSO stock solutions are diluted 1:10 with 20% Cremophore RH40. The final formulation for dosing contains 10% DMSO, 18% Cremophore RH40, 3.6% dextrose and 68.4% water and the appropriate amount of test article. Animals are intraperitoneal (IP) injected with this solution at 10 ml per kg body weight on a schedule of 5 days per week (Monday thru Friday, with no dosing on Saturday and Sunday) for 3 weeks.
Compounds of the invention are expected to result in decreased the growth rate of MDA- MB-435S cells in nude mice to a greater extent than a dose of 100 mg/kg body weight of the Hsp90 inhibitor 17-AAG.
Example D: Anti-tumor Activity Against Human Tumor Cells in a nude Mouse Xenograft Model The human squamous non-small cell lung cancer cell line, RERF-LC-AI (RCB0444; S.
Kyoizumi, et al., Cancer. Res. 45:3274-3281 , 1985), is obtained from the Riken Cell Bank (Tsukuba, Ibaraki, Japan). The cell line is cultured in growth media prepared from 50% Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI Media 1640, 10% fetal bovine serum (FBS), 1% 100X L-glutamine, 1% 100X penicillin-streptomycin, 1 % 100X sodium pyruvate and 1% 100X MEM non-essential amino acids. FBS is obtained from American Type Culture Collection (Manassas, Virginia, USA) and all other reagents are obtained from Invitrogen Corp. (Carlsbad, California, USA). Approximately 4-5 x 10(6) cells that have been cryopreserved in liquid nitrogen are rapidly thawed at 370C and transferred to a 175 cm2 tissue culture flask containing 50 ml of growth media and then incubated at 370C in a 5% CO2 incubator.
The growth media is replaced every 2-3 days until the flask becomes 90% confluent, typically in 5-7 days. To passage and expand the cell line, a 90% confluent flask is washed with 10 ml of room temperature phosphate buffered saline (PBS) and the cells are disassociated by adding 5 ml 1X trypsin-EDTA (Invitrogen) and incubating at 370C until the cells detach from the surface of the flask. To inactivate the trypsin, 5 ml of growth media is added and then the contents of the flask are centrifuged to pellet the cells. The supernatant is aspirated and the cell pellet is resuspended in 10 ml of growth media and the cell number determined using a hemocytometer. Approximately 1-3 x 10(6) cells per flask are seeded into 175 cm2 flasks containing 50 ml of growth media and incubated at 370C in a 5% CO2 incubator. When the flasks reach 90% confluence, the above passaging process is repeated until sufficient cells have been obtained for implantation into mice. Seven to eight week old, female Crl:CD-1-πι/BR (nude) mice are obtained from Charles River Laboratories (Wilmington, Massachusetts, USA). Animals are housed 4-5/cage in micro-isolators, with a 12hr/12hr light/dark cycle, acclimated for at least 1 week prior to use and fed normal laboratory chow ad libitum. Studies are conducted on animals between 8 and 12 weeks of age at implantation. To implant RERF-LC-AI tumor cells into nude mice, the cells are trypsinized as above, washed in PBS and resuspended at a concentration of 50 x 10(6) cells/ml in 50% non-supplemented RPMI Media 1640 and 50% Matrigel Basement Membrane Matrix (#354234; BD Biosciences; Bedford, Massachusetts, USA). Using a 27 gauge needle and 1 cc syringe, 0.1 ml of the cell suspension is injected subcutaneously into the flank of each nude mouse. Tumor volumes (V) are calculated by caliper measurement of the width (W), length (L) and thickness (T) of tumors using the following formula: V = 0.5236 x (L x W x T).
In vivo passaged RERF-LC-AI tumor cells (RERF-LC-AIIVP) are isolated to improve the rate of tumor implantation relative to the parental cell line in nude mice. RERF-LC-AI tumors are permitted to develop in vivo until they reach approximately 250 mm3 in volume, which requires approximately 3 weeks following implantation. Mice are euthanized via CO2 asphyxiation and their exteriors sterilized with 70% ethanol in a laminar flow hood. Using sterile technique, tumors are excised and diced in 50 ml PBS using a scalpel blade. A single cell suspension is prepared using a 55 ml Wheaton Safe-Grind tissue grinder (catalog #62400-358; VWR International, West Chester, Pennsylvania, USA) by plunging the pestle, up and down 4-5 times without twisting. The suspension is strained through a 70 μM nylon cell strainer and then centrifuged to pellet the cells. The resulting pellet is resuspended in 0.1 M NH4CI to lyse contaminating red blood cells and then immediately centrifuged to pellet the cells. The cell pellet is resuspended in growth media and seeded into 175 cm2 flasks containing 50 ml of growth media at 1-3 tumors/flask or approximately 10 x 10(6) cells/flask. After overnight incubation at 370C in a 5% CO2 incubator, nonadherent cells are removed by rinsing two times with PBS and then the cultures are fed with fresh growth media. When the flasks reach 90% confluence, the above passaging process is repeated until sufficient cells havr been obtained for implantation into mice,
RERF-LC-AIIVP cells are then implanted as above and tumors are permitted to develop in vivo until the majority reached an average of 100-200 mm3 in tumor volume, which typically requires 2-3 weeks following implantation. Animals with oblong or very small or large tumors are discarded, and only animals carrying tumors that display consistent growth rates are selected for studies. Animals are randomized into treatment groups so that the average tumor volumes of each group are similar at the start of dosing.
The HSP90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), can be employed as a positive control (Albany Molecular Research, Albany, New York, USA). Stock solutions of test articles are prepared by dissolving the appropriate amounts of each compound in dimethyl sulfoxide (DMSO) by sonication in an ultrasonic water bath. Stock solutions are prepared weekly, stored at -2O0C and diluted fresh each day for dosing. A solution of 20% Cremophore RH40 (polyoxyl 40 hydrogenated castor oil; BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany) in 80% D5W (5% dextrose in water; Abbott Laboratories, North Chicago, Illinois, USA) is also prepared by first heating 100% Cremophore RH40 at 50-600C until liquefied and clear, diluting 1:5 with 100% D5W, reheating again until clear and then mixing well. This solution is stored at room temperature for up to 3 months prior to use. To prepare formulations for daily dosing, DMSO stock solutions are diluted 1 : 10 with 20% Cremophore RH40. The final formulation for dosing contains 10% DMSO, 18% Cremophore RH40, 3.6% dextrose, 68.4% water and the appropriate amount of test article. Animals are intraperitoneal^ (i.p.) injected with this solution at 10 ml per kg body weight on a schedule of 5 days per week (Monday, Tuesday, Wednesday, Thursday and Friday, with no dosing on Saturday and Sunday) for a total of 15 doses.
Treatment with compounds of the invention is expected to result in the decreased growth rate of RERF-LC-AIIVP human lung tumor cells in nude mice.
Example E: Necrosis in a nude Mouse Tumor Model
The mouse mammary carcinoma cell line, EMT6 (ATCC #CRL-2755), is obtained from the American Type Culture Collection (ATCC; Manassas, Virginia, USA). The cell line is cultured in growth media prepared from 50% Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI Media 1640, .10% fetal bovine serum (FBS), 1% 100X L-glutamine, 1% 100X Penicillin-Streptomycin, 1% 100X sodium pyruvate and 1% 100X MEM nonessential amino acids. FBS is obtained from ATCC and all other reagents are obtained from Invitrogen Corp. (Carlsbad, California, USA). Approximately 4-5 x 10(6) cells that have been cryopreserved in liquid nitrogen are rapidly thawed at 37 0C and transferred to a 175 cm2 tissue culture flask containing 50 ml of growth media and then incubated at 370C in a 5% CO2 incubator. The growth media is replaced every 2-3 days until the flask became 90% confluent, typically in 5-7 days. To passage and expand the cell line, a 90% confluent flask is washed with 10 ml of room temperature phosphate buffered saline (PBS) and the cells are disassociated by adding 5 ml 1X Trypsin-EDTA (Invitrogen) and incubating at 37 0C until the cells detach from the surface of the flask. To inactivate the trypsin, 5 ml of growth media is added and then the contents of the flask are centrifuged to pellet the cells. The supernatant is aspirated and the cell pellet is resuspended in 10 ml of growth media and the cell number determined using a hemocytometer. Approximately 1-3 x 10(6) cells per flask are seeded into 175 cm2 flasks containing 50 ml of growth media and incubated at 37 0C in a 5% CO2 incubator. When the flasks reach 90% confluence, the above passaging process is repeated until sufficient cells have been obtained for implantation into mice.
Seven to eight week old, female Crl:CD-1-m/BR (nude) mice are obtained from Charles River Laboratories (Wilmington, Massachusetts, USA). Animals are housed 4-5/cage in micro-isolators, with a 12hr/12hr light/dark cycle, acclimated for at least 1 week prior to use and fed normal laboratory chow ad libitum. Studies are conducted on animals between 8 and 10 weeks of age at implantation. To implant EMT6 tumor cells into nude mice, the cells are trypsinized as above, washed in PBS and resusupended at a concentration of 10 x 10(6) cells/ml in PBS. Using a 27 gauge needle and 1 cc syringe, 0.1 ml of the cell suspension is injected subcutaneously into the flank of each nude mouse.
Tumors are then permitted to develop in vivo until the majority reached 75-125 mm3 in tumor volume, which typically requires 1 week following implantation. Animals with oblong, very small or large tumors are discarded, and only animals carrying tumors that display consistent growth rates are selected for studies. Tumor volumes (V) are calculated by caliper measurement of the width (W), length (L) and thickness (T) of tumors using the following formula: V = 0.5236 x (L x W x T). Animals are randomized into treatment groups so that each group had median tumor volumes of ~100 mm3 at the start of dosing.
To formulate a compound of the invention in DRD, a stock solution of the test article is prepared by dissolving an appropriate amount of the compound in dimethyl sulfoxide (DMSO) by sonication in an ultrasonic water bath. A solution of 20% Cremophore RH40 (polyoxyl 40 hydrogenated castor oil; BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany) in 5% dextrose in water (Abbott Laboratories, North Chicago, Illinois, USA) is also prepared by first heating 100% Cremophore RH40 at 50-600C until liquefied and clear, diluting 1 :5 with 100% D5W, reheating again until clear and then mixing well. This solution is stored at room temperature for up to 3 months prior to use. To prepare a DRD formulatioπ for dosing, the DMSO stock solution is diluted 1 10 with 20% Cremophore RH40 The final DRD formulation for dosing contains 10% DMSO, 18% Cremophore RH40, 3 6% dextrose, 68 4% water and the appropriate amount of test article
Tumor-bearing animals are given a single intravenous (i v ) bolus injections of either DRD vehicle or a compound of the invention formulated in DRD, both at 10 mL per kg body weight Then, 4-24 hr after drug treatment, tumors are excised, cut in half and fixed overnight in 10% neutral-buffered formalin Each tumor is embedded in paraffin with the cut surfaces placed downwards in the block, and rough cut until a complete section is obtained From each tumor, 5 μM serial sections are prepared and stained with hematoxylin and eosin Slides are evaluated manually using light microscopy with a 10 x 10 square gπdded reticle The percentage of necrosis in a tumor is quantified at 200X magnification by scoring the total number of grid squares containing necrosis and the total number of grid squares containing viable tumor cells
It is expected that compounds of the invention will result in an increase in necrotic tissue in the center of EMT6 tumors relative to the baseline necrosis observed in vehicle treated tumors As would be expected for a vascular targeting mechanism of action, rapid onset of necrosis is consistent with there being a loss of blood flow to tumors resulting in hypoxia and tumor cell death
Example F: Vascular Disrupting Activities in a nude Mouse Tumor Model The mouse mammary carcinoma cell line, EMT6 (ATCC #CRL-2755), is obtained from the American Type Culture Collection (ATCC, Manassas, Virginia, USA) The cell line is cultured in growth media prepared from 50% Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI Media 1640, 10% fetal bovine serum (FBS), 1% 100X L-glutamine, 1% 100X Penicillin-Streptomycin, 1% 100X sodium pyruvate and 1% 100X MEM non- essential amino acids FBS is obtained from ATCC and all other reagents are obtained from Invitrogen Corp (Carlsbad, California, USA) Approximately 4-5 x 106 cells that have been cryopreserved in liquid nitrogen are rapidly thawed at 370C and transferred to a 175 cm2 tissue culture flask containing 50 mL of growth media and then incubated at 370C in a 5% CO2 incubator The growth media is replaced every 2-3 days until the flask became 90% confluent, typically in 5-7 days To passage and expand the cell line, a 90% confluent flask is washed with 10 mL of room temperature phosphate buffered saline (PBS) and the cells are disassociated by adding 5 mL 1X Trypsin-EDTA (Invitrogen) and incubating at 37°C until the cells detach from the surface of the flask To inactivate the trypsin, 5 mL of growth media is added and then the contents of the flask are centrifuged to pellet the cells The supernatant is aspirated and the cell pellet is resuspended in 10 mL of growth media and the cell number determined using a hemocytometer Approximately 1-3 x 106 cells per flask are seeded into 175 cm2 flasks containing 50 mL of growth media and incubated at 370C in a 5% CO2 incubator. When the flasks reach 90% confluence, the above passaging process is repeated until sufficient cells have been obtained for implantation into mice.
Seven to eight week old, female Crl:CD-1-m/BR (nude) mice are obtained from Charles River Laboratories (Wilmington, Massachusetts, USA). Animals are housed 4-5/cage in micro-isolators, with a 12hr/12hr light/dark cycle, acclimated for at least 1 week prior to use and fed normal laboratory chow ad libitum. Studies are conducted on animals between 8 and 10 weeks of age at implantation. To implant EMT6 tumor cells into nude mice, the cells are trypsinized as above, washed in PBS and resusupended at a concentration of 10 x 10B cells/mL in PBS. Using a 27 gauge needle and 1 cc syringe, 0.1 mL of the cell suspension is injected subcutaneously into the flank of each nude mouse.
For the Evans Blue dye assay, tumors are permitted to develop in vivo until the majority reach 40-90 mm3 in tumor volume (to minimize the extent of tumor necrosis), which typically require 4-6 days following implantation. Animals with visibly necrotic, oblong, very small or very large tumors are discarded and only animals carrying tumors that display consistent growth rates are selected for use. Tumor volumes (V) are calculated by caliper measurement of the width (W), length (L) and thickness (T) of tumors using the following formula: V = 0.5236 x (L x W x T). Animals are randomized into treatment groups so that at the start of dosing each group have median tumor volumes of ~125 mm3 or ~55 mm3 for the Evans Blue dye assay. To formulate compounds of the invention for dosing, the appropriate amount of compound is dissolved in 5% dextrose in water (D5W; Abbott Laboratories, North Chicago, Illinois, USA). Vehicle-treated animals are dosed with D5W.
To conduct the Evans Blue dye assay, tumor-bearing animals are dosed with vehicle or test article at 0 hr, and then i.v. injected with 100 μL of a 1% (w/v) Evan's Blue dye (Sigma #E-2129; St. Louis, Missouri, USA) solution in 0.9% NaCI at +1 hr. Tumors are excised at + 4 hr, weighed and the tissue disassociated by incubation in 50 μL 1 N KOH at 60 0C for 16 hr. To extract the dye, 125 μL of a 0.6 N phosphoric acid and 325μL acetone are added, and the samples vigorously vortexed and then microcentrifuged at 3000 RPM for 15 min to pellet cell debris. The optical absorbance of 200 μL of supernatant is then measured at 620 nM in a Triad spectrophotometer (Dynex Technologies, Chantilly, Virginia, USA). Background OD62O values from similarly sized groups of vehicle or test article-treated animals that have not been injected with dye are subtracted as background. OD620 values are then normalized for tumor weight and dye uptake is calculated relative to vehicle-treated tumors. To examine the vascular disrupting activity of a compound of the invention, the Evans Blue dye assay is employed as a measurement of tumor blood volume (Graff ef a/., Eur J Cancer 36:1433-1440, 2000). Evans Blue dye makes a complex with serum albumin by electrostatic interaction between the sulphonic acid group of the dye and the terminal cationic nitrogens of the lysine residues in albumin. The dye leaves the circulation very slowly, principally by diffusion into extravascular tissues while still bound to albumin. Albumin-dye complex taken up by tumors is located in the extracellular space of non- necrotic tissue, and intracellular uptake and uptake in necrotic regions is negligible. The amount of dye present in a tumor is a measurement of the tumor blood volume and microvessel permeability. Compounds of the invention are expected to result in substantially decreased tumor dye uptake relative to vehicle-treated animals. Such a decrease in dye penetration into the tumor is consistent with there being a loss of blood flow to tumors due to blockage of tumor vasculature, consistent with a vascular disrupting mechanism of action.
Example G: Inhibition of the Production of Inflammatory Cytokines in Human PBMCs
Human PBMC are isolated using Ficoll 400 and diatrizoate sodium (density1.077 g/ml) solution and purified with RosetteSep (StemCell Technologies). The PBMCs are primed with human IFN-γ (800 U/ml,.Pierce Biotechnology #R-IFNG-50), seeded at
0.5x106/100μL/well in 96-well U-bottom plate with culture medium (RPM1 1640, 10% FBS, 1 % Pen/Strep), and incubated in 370C for overnight. The cells are then stimulated with 1μg/ml of LPS (Lipopolysaccharide, Sigma#L2654-1MG) or 0.025% of SAC (Staphylococcus Aureus Cowan, Calbiochem-Novabiochem Corp. #507858), and treated with a test compound at different concentrations with final DMSO concentration less than 0.5% for 16-18 hrs. About 180μl/well of supernatant is collected and measured using ELISA kit or Bio-plex (Bio-Rad) to determine the levels of cytokine production. The cell survival is determined using Cell Counting Kit-8 (Dojindo Molecular Technologies, Inc.). Compounds of the invention are expected to broadly inhibit the production of proinflammatory cytokines.
Example H: Suppression of Glucocorticoid Receptor Levels in Rat and Human PBMCs
Cell Preparation:
Whole blood samples from healthy human volunteers and male SD rats are collected and the PBMCs are isolated immediately as follows. 5 ml of whole blood is diluted with an equal volume of sterile 1x PBS. The diluted blood is overlayed carefully into a sterile centrifuge tube without disturbing the bottom layer that containing 5 ml of Ficoll-paque plus density gradient solution. The layered blood is centrifuged at 1500 x g for 30 minutes at room temperature. The middle thin layer containing PBMCs is carefully removed, transferred to another sterile centrifuge tube, and washed twice with PBS to remove Percoll. Isolated rat and human PBMCs are cultured in 10%fetal bovine serum/DMEM. Treatment
The rat and human PBMCs are treated with DMSO (control), compounds of the invention, or 17-DMAG at concentrations of 0, 1 , 5, 25, or 100 nM (in DMSO) for 16 hours The cells are then collected and rinsed in ice-cold PBS and stored in liquid nitrogen until further analysis lmmunoblot
PBMC are prepared in Western lysis buffer (10 mrnol/L HEPES, 42 mmol/L KCI1 5 mmol/L MgCI2, 0 1 mmol/L EDTA, 0 1 mmol/L EGTA1 1 mmol/L DTT, 1% Triton X-100, freshly supplemented with 1x protease inhibitor cocktail from Pierce, Rockford, IL) Lysate protein concentrations are quantified by bicinchoninic acid assay (Pierce) and normalized Equal amounts of protein are loaded onto 10 % NuPAGE Bis-Tris Gels (Invitrogen) and subsequently transferred onto polyvinylidene difluoride membranes The membranes are blocked in 5% milk in TBST Primary antibody of glucocorticod receptor from Santa Cruz Biotechnology, lnc is added and incubated at room temperature for 1 hour with shaking The blots are washed extensively in TBST before secondary antibodies are added for overnight incubation at 40C with gentle shaking The blots are again washed extensively and developed with SuperSignal West Femto substrate (Pierce) The immunoblot analysis is performed to measure the level of total GRs by Quantity One software from Bio-Rad
Example I: Suppression of Glucocorticoid Receptor Levels in Human PBMCs and Renal Cells, as well as in Several Human Cancer Cell Lines
Cell Preparation
Normal human renal proximal tubule epithelial cells and tumor cell lines of MV-4-11 , Kasumι-1 , and HeIa are obtained from Cambrex Byproducts and American Type Culture Collection, respectively Cells are cultured wιth10% fetal bovine serum/DMEM The whole blood samples from healthy human volunteers are collected and the PBMCs are isolated immediately as described in Example I Isolated human PBMCs are cultured in 10%fetal bovine serum/DMEM
Treatment
Human PBMCs, kasumι-1, Mv-4-11 , HeIa, and human renal proximal tubule epithelial cells are treated with DMSO (control), compounds of the invention, 17-DMAG at concentrations of 0, 5, 25, or 100 nM (in DMSO) for 16 hours The cells are then collected and rinsed in ice- cold PBS and stored in liquid nitrogen until further analysis
Immunoblot
PBMC, renal and tumor cell pellets are prepared in Western lysis buffer (10 mmol/L HEPES, 42 mmol/L KCI, 5 mmol/L MgCI2, 0 1 mmol/L EDTA, 0.1 mmol/L EGTA, 1 mmol/L DTT, 1% Tπton X-100, freshly supplemented with 1x protease inhibitor cocktail from Pierce, Rockford, IL) Lysate protein concentrations are quantified by bicinchoninic acid assay (Pierce) and normalized Equal amounts of protein are loaded onto 10 % NuPAGE Bis-Tris Gels (Invitrogen) and subsequently transferred onto polyvinylidene difluoride membranes The membranes are blocked in 5% milk in TBST Primary antibody of glucocorticod receptor from Santa Cruz Biotechnology, lnc is added and incubated at room temperature for 1 hour with shaking The blots are washed extensively in TBST before secondary antibodies are added for overnight incubation at 4°C with gentle shaking The blots are again washed extensively and developed with SuperSignalWest Femto substrate (Pierce) Compounds of the invention are expected to suppress the expression of glucocorticoid receptors in cancer cells as well as in normal PBMCs and renal cells
Example J: Suppression of Glucocorticoid Receptor Levels In vivo
Male adult Sprague-Dawley (SD) rats, five per group, are randomly assigned into five testing groups which receive treatments as shown in Table 10
Table 10
Figure imgf000249_0001
The test compounds are administered daily intravenously via tail vein for four days All rats are sacrificed at the study day 5 About 1-2 mL of blood samples are collected per animal The blood samples are then pulled together as a group for PBMC isolation PBMCs are isolated and an immunoblot using an antibody that recognizes the glucocorticoid receptor is prepared, as described in Examples I and J
Example K Inhibition of Topoisomerase Il
The ability of compounds of the invention to inhibit the activity of topoisomerase Il is examined with a kDNA decatenation assay (TopoGEN, lnc Port Orange, FL) Substrate kDNA is mixed with compounds (10, 100, or 500 μM) and incubated at 37 0C for 30 mm The reaction is stop by adding 1/5 volume of stop buffer. 20 μl of the reaction is loaded on 1% agarose gel. Image of decatenation of kDNA by compounds is taken by Kodak Image Station 440.
All publications, patent applications, patents, and other documents cited herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

CLAIMS What is claimed is:
1. A compound represented by the following structural formula:
Figure imgf000251_0001
(I) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, wherein:
R1 , R2, and R3 are each, independently, -OH1 -SH, -NHR7, -OR26, -SR26, -O(CH2)mOH, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH,
-S(CH2)mNR7H, -OC(O)NR10Rii, -SC(O)NR10Rn, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NRiORi1, -SCH2C(O)NR10Rii, -NR7CH2C(O)NR1ORiI 1 -OS(O)PR7, -SS(O)PR7, -S(O)POR7> -NR7S(O)PR7,
-OS(0)pNR10Rii, -SS(O)PNRiORi1, -NR7S(0)pNRioRii, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRioRii, -SC(S)NR10Rii, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NRB)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NR10R11, -NR7C(NR8)NRi0R11, -OP(O)(OR7)2, or
-SP(O)(OR7)2;
R5 is an optionally substituted alkyl; an optionally substituted heteroaryl or an optionally substituted aryl;
R5 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR7, -SR7, -NR10R1I, -OC(O)NRi0R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7,
-SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10Ri1, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R1I, -OS(O)PR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)PNR10R1I, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NR8)NR10R11, -C(O)R7, -C(O)OR7, -C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -S(0)p0R7, -S(O)PNR10R11, or -S(O)PR7;
R7 and R8, for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is independently, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3 or 4.
The compound of Claim 1 , wherein R5 is represented by the following formula:
Figure imgf000252_0001
wherein:
R33 is a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;
R34 is H, a lower alkyl, or a lower alkylcarbonyl; and Ring B and Ring C are optionally substituted with one or more substituents.
3. The compound of Claim 1, wherein R5 is selected from the group consisting of:
Figure imgf000253_0001
wherein:
X11, for each occurrence, is independently CH, CR9, N, N(O), or N+(R17), provided that at least two X1I groups are independently selected from CH and CR9;
X12, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least one X12 group is independently selected from CH and CR9;
X13, for each occurrence, is independently O, S, S(O)p, NR7, or NRi7;
R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a hydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Ri1, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)pOR7, -NR8S(O)pR7, or -S(O)pNR10Rii, -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(OR7)2, -S(O)pOR7, -OP(O)(OR7)2, or -SP(O)(OR7)2; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
R17, for each occurrence, is independently an alkyl or an aralkyl.
The compound of Claim 3, wherein Rs is represented by the following formula:
Figure imgf000253_0002
wherein:
X-15, for each occurrence, is independently CH2, CHR7, or NR7.
5. The compound of Claim 1, wherein R5 is represented by the following formula:
Figure imgf000254_0001
wherein:
Z is a substituent; and n is O, 1, 2, 3, 4, or 5. 6. The compound of Claim 5, wherein n is 1.
7. The compound of Claim 6, wherein Z is an optionally substituted alkyl, an optionally substituted alkoxy, an amino, an alkyl amino, or a dialkyl amino.
8. The compound of Claim 1, wherein R6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl.
9. The compound of Claim 1, wherein R8 is -L-Rx, wherein
L is an optionally substituted 1 to 6 atom linker, wherein each linker atom is independently selected from the group consisting of C, O, S or N; and
Rx is an optionally substituted heteroaryl or an optionally substituted aryl.
10. The compound of Claim 9, wherein Rx is an optionally substituted phenyl, an optionally substituted iπdolyl, an optionally substituted benzoimidazolyl, an optionally substituted indazolyl, an optionally substituted 3H-indazolyl, an optionally substituted indolizinyl, an optionally substituted quinolinyl, an optionally substituted isoquinolinyl, an optionally substituted benzoxazolyl, an optionally substituted benzo[1 ,3]dioxolyl, an optionally substituted benzofuryl, an optionally substituted benzothiazolyl, an optionally substituted benzo[d]isoxazolyl, an optionally substituted benzo[d]isothiazolyl, an optionally substituted thiazolo[4,5-c]pyridinyl, an optionally substituted thiazolo[5,4-c]pyridinyl, an optionally substituted thiazolo[4,5- . b]pyridinyl, an optionally substituted thiazolo[5,4-b]pyridinyl, an optionally substituted oxazolo[4,5-c]pyridinyl, an optionally substituted oxazolo[5,4-c]pyridinyl, an optionally substituted oxazolo[4,5-b]pyridinyl, an optionally substituted oxazolo[5,4-b]pyridinyl,an optionally substituted imidazopyridinyl, an optionally substituted benzothiadiazolyl, benzoxadiazolyl, an optionally substituted beπzotriazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted
' 5 azaindolyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted imidazo[4,5-a]pyridinyl, an optionally substituted imidazo[1 i2-a]pyridinyl, an optionally substituted 3/-/-imidazo[4,5-b]pyridinyl, an optionally substituted 1H-imidazo[4,5-b]pyridinyl, an optionally substituted 1H- imidazo[4,5-c]pyridiny!, an optionally substituted 3/-/-imidazo[4,5-c]pyridinyl, an 0 optionally substituted pyridopyrdazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyridopyrimidinyl, an optionally substituted pyrrolo[2,3]pyrimidyl, an optionally substituted pyrazolo[3,4]pyrimidyl an optionally substituted cyclopentaimidazolyl, an optionally substituted cyclopentatriazolyl, an optionally substituted pyrrolopyrazolyl, an optionally substituted pyrroloimidazolyl,
15 an optionally substituted pyrrolotriazolyl, or an optionally substituted benzo(b)thienyl.
11. The compound of Claim 10, wherein Rx is an optionally substituted phenyl.
0 12. The compound of Claim 9, wherein L is a C1 -C4 alkylene.
13. The compound of Claim 1 , wherein R1, R2, and R3 are each, independently, -OH, - SH1 Or -NHR7.
5 14. The compound of Claim 13, wherein R2 and R3 are each -OH.
15. The compound of any one of Claims 2 through 7, wherein
R6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl; and 0 Ri, R2, and R3 are each, independently, -OH or -SH.
16. The compound of Claim 1 , wherein the compound is represented by the following structure:
Figure imgf000256_0001
(H)
wherein:
X41 is O, S, or NR42;
X42 is CR44 or N;
Y40 is N or CR43;
Y41 is N or CR45;
Y42, for each occurrence, is independently N, C or CR46;
R40 is OH, SH, or NHR7;
R41 is -H, -OH, -SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryi, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)NRioRii, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(O)R7, -SC(O)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NR10R11, -OC(S)NR10R11, -OC(NR8)NR10Rii, -SC(O)NR10R11, -SC(NR8)NR,0Rii, -SC(S)NR10R11, -OC(NR6)R7, -SC(NR8)R7, -C(O)NR10R11, -NR8C(O)R71 -NR7C(S)R71 -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(O)OR7, -NR7C(NR8)OR7, -NR7C(O)NR10R11, -NR7C(S)NR10R11, -NR7C(NR8)NR10R11, -SR7, -S(O)PR7, -OS(O)PR7, -OS(O)POR7, -OS(O)PNR10R11, -S(O)pOR7, -NR8S(O)PR7, -NR7S(O)PNR10R11, -NR7S(O)POR7, -S(O)PNR10R11, -SS(O)PR7, -SS(O)POR7, -SS(O)PNR10R11, -OP(O)(ORy)2, or -SP(O)(OR7)2;
R42 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryi, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, -C(O)R7, -(CH2)mC(O)OR7, -C(O)OR7, -OC(O)R7, -C(O)NRi0R11, -S(O)pR7, -S(O)pOR7, or -S(O)pNR10Rn;
R43 and R44 are, independently, -H, -OH, an optionally substituted alky), an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR6C(O)R7, -SR7, -S(O)PR7,
-OS(O)pR7, -S(O)pOR7, -NR8S(O)pR7, -S(O)pNR10Rn, or R43 and R44 taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl; R45 Is -H1 -OH1 -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH,
-O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(O)NR10R11, -SC(O)NRi0R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11,
-NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)PNR10R1I, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NRB)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7,
-OC(NR8)NR10R11, -SC(NR8)NR10R111 Or -NR7C(NR8)NR10R11; and
R48, for each occurrence, is independently, selected from the group consisting of H, an optionally substituted alky!, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)pR7, or -S(O)PNR10R11.
17. The compound of Claim 16, wherein X41 is NR42 and X42 is CR44.
18. The compound of Claim 16, wherein X41 is NR42 and X42 is N.
19. The compound of Claim 16, wherein R41 is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
20. The compound of Claim 16, wherein R41 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
21. The compound of Claim 16, wherein X41 is NR42, and R42 is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, -C(O)N(R27)2, and -C(O)OH, wherein each R27 is independently -H or a lower alkyl.
22. The compound of Claim 16, wherein X41 is NR42, and R42 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, -C(O)OH1 -(CH2)mC(O)OH, -CH2OCH3, -CH2CH2OCH3, and -C(O)N(CHs)2.
23. The compound of Claim 16, wherein R43 and R44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
24. The compound of Claim 16, wherein X42 is CR44; Y40 is CR43; and R43 and R44 together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring.
25. The compound of Claim 24, wherein R43 and R44 together with the carbon atoms to which they are attached form a CS-CB cycloalkenyl or a C5-C8 aryl.
26. The compound of Claim 24, wherein R45 or CR45 is selected from the group consisting of -H, -OH, -SH, -NH2, a lower alkoxy, a lower alkyl amino, and a lower dialkyl amino.
27. The compound of Claim 26, wherein R45 is selected from the group consisting of -H, -OH, methoxy and ethoxy.
28. The compound of Claim 24, wherein X41 is O.
29. The compound of Claim 16, wherein R4o is -OH or -SH.
30. The compound of Claim 16, wherein the compound is represented by the following structural formula:
Figure imgf000259_0001
(III) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R39 is -OH or -SH.
31. The compound of Claim 30, wherein X42 is CR44, and R43 and R44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
32. The compound of Claim 30, wherein X42 is CR44, and R43 and R44, taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring.
33. The compound of Claim 32, wherein R43 and R44, taken together with the carbon atoms to which they are attached, form a Cs-C8 cycloalkenyl or a C5-C8 aryl.
34. The compound of Claim 30, wherein X42 is CR44.
35. The compound of Claim 30, wherein X42 is N.
36. The compound of Claim 30, wherein the compound is represented by the following structural formula:
Figure imgf000260_0001
(IV) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: X45 is CR64 or N;
R39 is -OH or -SH;
R56 is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl;
R52 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, -(CHa)2OCH3, -CH2C(O)OH, and -C(O)N(CH3)2;
R53 and R54 are each, independently, -H, methyl, ethyl, or isopropyl; or R53 and R54 taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring; and
R55 is selected from the group consisting of -H, -OH, -OCH3, and - OCH2CH3.
37. The compound of Claim 1 , wherein the compound is selected from the group consisting of
2-Ethyl-6-[5-mercapto-4-(1-methyl-1 H-indol-5-yl)-4H-[1 ,2,4]triazol-3-yl]-pyridine-3,5-diol;
2-[5-Hydroxy-4-(1-methyl-1 H-indol-5-yl)-4H-[1 ,2,4]triazol-3-yl]-6-isopropyl-pyridine-3,5- diol;
2-[4-(4-Dimethylamino-phenyl)-5-hydroxy-4H-[1 ,2,4]triazol-3-yl]-6-isopropyl-pyridine-3,5- diol;
2-lsopropyl-6-[5-mercapto-4-(2-methoxy-indan-5-yl)-4H-[1,2,4]triazol-3-yl]-pyridine-3,5- diol;
2-[5-Mercapto-4-(4-methoxymethyl-phenyl)-4H-[1 ,2,4]triazol-3-y|]-6-phenethyl-pyridine-
3,5-diol;
2-[4-(4-Dimethylaminomethyl-phenyl)-5-hydroxy-4H-[1 ,2,4]triazol-3-yl]- 6-pheπethyl-pyridiπe-3,5-diol;
2-Ethyl-6-[5-hydroxy-4-(4-methoxy-benzyl)-4H-[1 ,2>4]triazol-3-yl]-pyridine-3,5-diol;
2-Cydopropyl-6-[4-(4-dimethylamino-benzyl)-5-hydroxy-4H-[1 ,2,4]triazol-3-yl]-pyridine-
3,5-diol;
2-[5-Hydroxy-4-(1-methyl-2,3-dihydro-1 H-indol-5-yl)-4H-[1 ,2,4]triazol-3-yl]-6-isopropyl- pyridine-3,5-diol;
2-{5-Hydroxy-4-[2-(2-methoxy-ethyl)-2,3-dihydro-1 H-isoindol-5-yl]-4H-[1 ,2,4)triazol-3-yl}-
6-isopropyl-pyridine-3,5-diol; or
2-{5-Hydroxy-4-[2-(2-hydroxy-ethoxy)-indan-5-yl]-4H-[1 ,2,4]triazol-3-yl}-6-isopropyl- pyridine-3,5-diol;
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof.
38. A compound represented by the following structural formula:
Figure imgf000261_0001
(V) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or aprodrug thereof, wherein:
R', is , -NHR7, -NHC(O)NR10R11, -NHC(O)R7, -NHC(O)OR7, -NHCH2C(O)R7, -NHCH2C(O)OR7, -NHCH2C(O)NR10R11, -NHS(O)PR7, -NHS(O)pNR10Rn, -NHS(O)POR7, -NHC(S)R7, -NHC(S)OR7, -NHC(S)NR10Rn, -NHC(NR8)R7, -NHC(NR8)OR7, Or -NHC(NR8)NR10Rn;
R2 is -OH, -SH, -NR7H, -OR26, -SR26, -O(CH2)mOH, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(O)NR10R11, -SC(O)NR10Rn, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R1I, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)pR7, -S(O)POR7, -NR7S(O)pR7, -OS(O)PNR10R11, -SS(O)PNRi0R11, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R'3 is -OH, -SH, or -NHR7; R's is an optionally substituted heteroaryl or an optionally substituted aryl;
R7 and R8, for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyciyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyciyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyciyl or an optionally substituted heteroaryl; R26 is a lower alkyl;
Z is a substituent; p, for each occurrence, is independently, 1 or 2; m, for each occurrence, is independently, 1 , 2, 3 or 4; t is O, 1 , 2, or 3; and with the proviso that the compound is not
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-amino-[1,2,4] triazole,
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-methoxy-phenyl)-5-amino-[1,2,4] triazole, 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-amino-[1 ,2,4] triazole,
3-(2,4-Dihydroxy-phenyl)-4-phenyl-5-(sulfamoylamino)- [1 ,2,4] triazole,
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-1 -yl)-5-ureido-[1 ,2,4] triazole, 3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(2,3-difluorophenyl)-5-ureido-[1,2,4] triazole,
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-ureido-[1 ,2,4] triazole,
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(quinolin-5-yi)-5-ureido-[1 ,2,4] triazole, 3-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-(3-methyl-quinolin-5-yl)-5- carboxyamino-[1 ,2,4] triazole,
S-^^-Dihydroxy-phenylM-O-methyl^-chloro-indoM-yO-S-carbamoyloxy- [1 ,2,4] triazole,
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-[3,5-di-(trifluoromethyl)-phenyl]-5- carbamoyloxy-[1 ,2,4] triazole,
3-(2,4-Dihydroxy-5-methoxy-pheny!)-4-(3-trifluoromethyl-phenyl)-5- (sulfamoylamino)- [1 ,2,4] triazole,
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-1-yl)-5- (sulfamoylamino)- [1,2,4] triazole,
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(1-isopropyl-benzoimidazol-4-yl)-5- (sulfamoylamiπo)- [1,2,4] triazole, or
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(3-isopropylphenyl)-5- (thiocarboxyamino)- [1 ,2,4] triazole.
39. The compound of Claim 38, wherein R'5 is represented by the following formula:
Figure imgf000263_0001
wherein:
R33 is a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;
R34 is H, a lower alkyl, or a lower alkylcarbonyl; and
Ring B and Ring C are optionally substituted with one or more substituents.
40. The compound of Claim 38, wherein R'5 is selected from the group consisting of:
Figure imgf000263_0002
wherein: Xi1, for each occurrence, is independently CH, CR9, N, N(O)1 or N+(R17), provided that at least one X11 is N, N(O), or N+(R17) and at least two Xn groups are independently selected from CH and CR9;
X12, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least one X12 group is independently selected from CH and CR9;
X13, for each occurrence, is independently O, S, S(O)p, NR7, or NR17; R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a hydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)pOR7, -NR8S(O)pR7, or -S(O)PNR10R11, -S(O)POR7, -OP(0)(OR7)2, or
-SP(O)(OR7)2, -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(OR7)2; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
R17, for each occurrence, is independently an alkyl or an aralkyl.
41. The compound of Claim 38, wherein R', is -NHR7.
42. The compound of Claim 38 wherein R2 is -OH, -SH, or -NHR7.
43. The compound of Claim 38, wherein R'3 is -OH or -SH.
44. The compound of Claim 38, wherein Z, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)NR,oRii, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR6)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(O)R7,
-SC(O)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NR10R11, -OC(S)NR10R11, -OC(NR8)NR10R111 -SC(O)NR10R11, -SC(NR8)NR10R11, -SC(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -C(O)NR10R11, -NR8C(O)R7, -NR7C(S)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(O)OR7, -NR7C(NR8)OR7, -NR7C(O)NR10R11, -NR7C(S)NR10R11, -NR7C(NR8)NR10R1I, -SR7, -S(O)PR7, -OS(O)pR7l -OS(O)pOR7, -OS(O)PNR10R111 -S(0)p0R7, -NR6S(O)PR7, -NR7S(O)PNR10R11, -NR7S(O)POR7, -S(O)PNR10R11, -SS(0)pR7, -SS(O)POR7, -SS(O)PNR10R11, -OP(O)(OR7)2l or -SP(O)(ORy)2.
45. The compound of Claim 44, wherein t is 1.
46. The compound of Claim 38, wherein t is O.
47. The compound of Claim 38, wherein the compound is represented by the following structure:
Figure imgf000265_0001
(Vl) wherein R6 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR7, -SR7, -NR10R111 -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)pR7, -NR7S(O)pR7, -OS(O)PNR1ORi1, -SS(O)pNR10Rn, -NR7S(O)PNR10R11, -OS(O)pOR7l -SS(O)pOR7, -NR7S(O)pOR7l -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NR8)NR10R11, -C(O)R7, -C(O)OR7, -C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NRe)NR10R11, -C(NR8)SR7, -S(O)pOR7, -S(O)PNR10R11, or -S(O)PR7.
48. The compound of Claim 47, wherein R's is represented by the following formula:
Figure imgf000266_0001
wherein: R33 is a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;
R34 is H, a lower alkyl, or a lower alkylcarbonyl; and
Ring B and Ring C are optionally substituted with one or more substituents.
49. The compound of Claim 47, wherein R'5 is selected from the group consisting of
Figure imgf000266_0002
wherein:
X11, for each occurrence, is independently CH, CR9, N, N(O), or N+(Ri7), provided that at least one X11 is N, N(O), or N+(R17) and at least two X11 groups are independently selected from CH and CR9;
X12, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least one X12 group is independently selected from CH and CR9;
X13, for each occurrence, is independently O, S, S(O)p, NR7, or NR17;
R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a hydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Ri1, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)pOR7l -NRBS(O)pR7, or -S(O)pNR10Rn, -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(OR7)2, -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(OR7)2; or two Rg groups taken together with the carbon atoms to which they are attached form a fused ring; and
R17, for each occurrence, is independently an alkyl or an aralkyl.
50. The compound of Claim 47, wherein R6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1- C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl. 51. The compound of Claim 47, wherein R'i is -NHR7.
52. The compound of Claim 47, wherein R2 is -OH, -SH, or -NHR7.
53. The compound of Claim 47, wherein R'3 is -OH or -SH.
54. The compound of Claim 48 or 49, wherein
R1 ! is -NHR7; R2 Is -OH, -SH, Or -NHR7; R'3 is -OH or -SH; and
R6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl.
55. The compound of Claim 38, wherein the compound is represented by the following structure:
Figure imgf000267_0001
wherein:
X41 is O, S, or NR42; X42 is CR44 or N; Y40 is N or CR43; Y41 is N or CR45;
Y42, for each occurrence, is independently N, C or CR46; R'4O is NHR7;
R41 is -H, -OH, -SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, -NR10R1I, -OR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7,
-C(S)NR10R11, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10Ri1, -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(O)R7, -SC(O)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NR10R11, -OC(S)NR10R11, -OC(NR8)NR10R11, -SC(O)NR10Ri1, -SC(NR8)NR10R11, -SC(S)NR10R11, -OC(NR6)R7, -SC(NR8)R7, -C(O)NR10R11, -NR8C(O)R7, -NR7C(S)R7, -NR7C(S)OR7,
-NR7C(NR8)R7, -NR7C(O)OR7, -NR7C(NR8)OR7, -NR7C(O)NR10R11, -NR7C(S)NR10R11, -NR7C(NR8)NR10Ri1, -SR7, -S(O)PR7, -OS(O)PR7, -OS(O)POR7, -OS(O)PNR10R11, -S(O)pOR7, -NRflS(O)pR7, -NR7S(O)PNR10R11, -NR7S(O)POR7, -S(O)PNR10R11, -SS(O)PR7, -SS(O)pOR7, -SS(O)PNR10R11, -OP(O)(ORy)2, or -SP(O)(OR7)2;
R42 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, -C(O)R7, -(CH2)mC(O)OR7, -C(O)OR7, -OC(O)R7, -C(O)NR10Ri i, -S(O)pR7, -S(O)pOR7, or -S(O)PNR10R11;
R43 and R44 are, independently, -H, -OH1 an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)pR7, -S(O)POR7, -NR8S(O)PR7, -S(O)PNR10R11, or R43 and R44 taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl; R45 is -H, -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -0(CH2)m0H, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(O)NR10R1I, -SC(O)NR10R11, -NR7C(O)NR10R1I, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7,
-NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)PNR1OR111 -SS(O)PNR10R11, -NR7S(O)PNR10R11, -0S(0)p0R7, -SS(0)p0R7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7,
-NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10Ri1, or -NR7C(NR8)NR10R11; and
R46, for each occurrence, is independently, selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)pOR7l
-NR8S(O)pR7, or -S(O)PNR10R11.
56. The compound of Claim 55, wherein X41 is NR42 and X42 is CR44.
57. The compound of Claim 55, wherein X41 is NR42 and X42 is N.
58. The compound of Claim 55, wherein R41 is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
59. The compound of Claim 55, wherein R41 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
60. The compound of Claim 55, wherein X41 is NR42, and R42 is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, -C(O)N(R27J2, and -C(O)OH, wherein each R27 is independently -H or a lower alkyl.
61. The compound of Claim 55, wherein X41 is NR42, and R42 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, -C(O)OH, -(CH2)mC(0)0H, -CH2OCH3, -CH2CH2OCH3, and -C(O)N(CH3)2.
62. The compound of Claim 55, wherein R43 and R44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
63. The compound of Claim 55, wherein X42 is CR44; Y40 is CR43; and R43 and R44 together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring.
64. The compound of Claim 63, wherein R43 and R44 together with the carbon atoms to which they are attached form a C5-C8 cycloalkenyl or a C5-C8 aryl.
65. The compound of Claim 63, wherein R45 or CR45 is selected from the group consisting of -H, -OH, -SH, -NH2, a lower alkoxy, a lower alkyl amino, and a lower dialkyl amino.
66. The compound of Claim 65, wherein R45 is selected from the group consisting of -H, -OH, methoxy and ethoxy.
67. The compound of Claim 63, wherein X41 is O.
68. The compound of Claim 55, wherein the compound is represented by the following structural formula:
Figure imgf000271_0001
(VIII) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
69. The compound of Claim 68, wherein X42 is CR44, and R43 and R44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
70. The compound of Claim 68, wherein X42 is CR44, and R43 and R44, taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring.
71. The compound of Claim 70, wherein R« and R44, taken together with the carbon atoms to which they are attached, form a C5-C8 cycloalkenyl or a C5-C8 aryl.
72. The compound of Claim 68, wherein X42 is CR44.
73. The compound of Claim 68, wherein X42 is N.
74. The compound of Claim 68, wherein the compound is represented by the following structural formula:
Figure imgf000272_0001
(IX) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:
X45 is CR54 or N;
R56 is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl;
R52 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, -(CHz)2OCH3, -CH2C(O)OH, and -C(O)N(CH3)2;
R53 and R54 are each, independently, -H, methyl, ethyl, or isopropyl; or
R53 and R54 taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring; and
R55 is selected from the group consisting of -H, -OH, -OCH3, and OCH2CH3.
75. The compound of Claim 55, wherein the compound is represented by the following structural formula:
Figure imgf000273_0001
(X) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R6O is -H, an optionally substituted alkyl, or an optionally substituted aryl.
76. The compound of Claim 75, wherein R41 is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
77. The compound of Claim 76, wherein R41 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
78. The compound of Claim 77, wherein R42 is -H or an optionally substituted lower alkyl.
79. The compound of Claim 38, wherein the compound is selected from the group consisting of
4-lsopropyl-6-[4-(1 -methyl-1 H-indol-5-yl)-5-phenylamino-4H-[1 ,2,4]triazol-3-yl]-benzene-
1 ,3-diol;
4-lsopropyl-6-[4-(1 -methyl-1 H-indol-5-yl)-5-methylamino-4H-[1 ,2,4]triazol-3-yl]-benzene-
1 ,3-diol;
4-lsopropyl-6-[4-(1 -methyl-1 H-indol-5-yl)-5-benzylamino-4H-[1 ,2,4]triazol-3-yl]-benzene-
1 ,3-diol;
4-(5-amino-4-(1-methyl-1H-indol-5-yl)-4H-1,2,4-triazol-3-yl)-6-isopropylbenzene-1 ,3-diol;
4-isopropyl-6-(4-(1 -methyl-1 H-indol-5-yl)-5-(qUinolin-6-ylamino)-4H-1, 2,4-triazol-3- yl)benzene-1 ,3-diol;
4-(5-(3-aminophenylamino)-4-(1-methyl-1H-iπdol-5-yl)-4H-1,2,4-triazol-3-yl)-6- ιsopropylbenzene-1 ,3-dιol,
4-ιsopropyl-6-(4-(1-methyl-1 H-ιndol-5-yl)-5-(3-(tπfluoromethyl)phenylamιno)-4H-1 ,2,4- trιazol-3-yl)benzeπe-1 ,3-dιol,
4-ιsopropyl-6-(5-(3-methoxyphenylamιno)-4-(1-methyl-1H-ιndol-5-yl)-4H-1 ,2,4-tπazol-3- yl)benzene-1 ,3-dιol,
N-(5-(2,4-dιhydroxy-5-ιsopropylphenyl)-4-(1-methyl-1H-ιπdol-5-yl)-4H-1,2,4-tπazol-3- yl)benzamιde,
N-(5-(2,4-dιhydroxy-5-ιsopropylphenyl)-4-(1-methyl-1 H-ιndol-5-yl)-4H-1 ,2,4-tπazol-3-yl)- 5-methylιsoxazole-3-carboxamιde,
N-(5-(2,4-dιhydroxy-5-ιsopropylphenyl)-4-(1-methyl-1 H-indol-5-yl)-4H-1 ,2,4-tnazol-3- y!)acetamιde,
N-(5-(2,4-dιhydroxy-5-ιsopropylphenyl)-4-(1 -methyl-1 H-ιndol-5-yl)-4H-1 ,2,4-trιazoi-3- yl)butyramιde,
N-(5-(2,4-dιhydroxy-5-ιsopropylphenyl)-4-(1-methyl-1 H-ιndol-5-yl)-4H-1 ,2,4-tπazol-3-yl)- 2-methoxyaceta m ide,
N-(5-(2,4-dιhydroxy-5-ιsopropylphenyl)-4-(1 -methyl-1 H-ιndol-5-yl)-4H-1 , 2, 4-tπazol-3- yl)ιsobutyramιde,
N-(5-(2,4-dιhydroxy-5-ιsopropylphenyl)-4-(1-methyl-1 H-ιndol-5-yl)-4H-1,2,4-tπazol-3- yl)furan-2-carboxamιde,
N-(5-(2,4-dιhydroxy-5-ιsopropylphenyl)-4-(1-methyl-1 H-ιndol-5-yl)-4H-1 ,2,4-tπazol-3-yl)- 2-phenylacetamιde,
N-(5-(2,4-dιhydroxy-5-ιsopropylphenyl)-4-(1 -methyl-1 H-ιndol-5-yl)-4H-1 ,2,4-tπazol-3-yl)- 3,4-dιfluorobenzamιde,
N-(5-(2,4-dιhydroxy-5-ιsopropylphenyl)-4-(1-methyl-1 H-ιndol-5-yl)-4H-1,2,4-tπazol-3-yl)- 2,2,2-trιfluoroacetamιde,
2-(4-chlorophenoxy)-N-(5-(2,4-dιhydroxy-5-ιsopropylphenyl)-4-(1 -methyl-1 H-ιndol-5-yl)- 4H-1 ,2,4-trιazol-3-yl)acetamιde, or
N-(5-(2,4-dιhydroxy-5-ιsopropylphenyl)-4-(1-methyl-1 H-ιndol-5-yl)-4H-1 ,2,4-tπazol-3- yl)cyclopentanecarboxamιde,
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof
80 A compound represented by the following structural formula
Figure imgf000275_0001
(Xl) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, wherein:
X is -O- or -S-;
R'5 is an optionally substituted heteroaryl or an optionally substituted aryl;
R'6 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR7, -SR7, -NR10Rn, -OC(O)NR10R11, -SC(O)NR10Rn, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R1 I, -OS(O)PR7, -SS(O)pR7, -NR7S(O)pR7, -OS(O)PNR10R11, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NRe)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NR8)NR10R11, -C(O)R7, -C(O)OR7, -C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -S(O)POR7, -S(O)pNR10Rn, or -S(O)PR7;
R7 and R8, for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted hεteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R'i7ι Riβ. and R19 are each, independently, -H, -C(O)R22, or (alk)O(alk); provided that at least one of R'17| R18, or Rig is not -H;
Ra2, for each occurrence is independently optionally substituted alkyl, optionally substituted aryl, -O(alk), amino, alkyl amino, or dialkyl amino; alk is a lower alkyl; p, for each occurrence, is independently 1 or 2; with the proviso that the compound is not
3-(2-Hydroxy-4-methoxymethyoxy-phenyl)-4-(naphthalen-1-yl)-5-rnercapto- [1 ,2,4] triazole;
3-[2-Hydroxy-4-(2-hydroxy-ethoxy)-phenyl]-4-(naphthalen-1-yl)-5-mercapto- [1 ,2,4] triazole; a-^^-DKdimethyl-carbamoyloxyJ-phenylH^naphthalen-i-yO-δ-Cdimethyl- carbamoylsulfanyl)- [1 ,2,4] triazole; 3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-1 -yl)-5-
(dimethylcarbamoylsulfanyl)- [1 ,2,4] triazole;
3-(2,4-Diethoxycarbonyloxy-phenyl)-4-(naphthalen-1-yl)-5- (ethoxycarbonylsulfanyl)- [1 ,2,4] triazole;
3-(2,4-Di-isobutyry!oxy-phenyl)-4-(naphthaleπ-1-yl)-5-(isobutyrylsulfanyI)- [1 ,2,4] triazole;
3-[2,4-Di-(dimethyl-carbamoyloxy)-phenyl]-4-(quinolin-5-yl)-5-(dimethyl- carbamoylsulfanyl)- [1 ,2,4] triazole;
3-(2,4-Diacetoxy-phenyl)-4-(naphthalen-1-yl)-5-(acetylsulfanyl)- [1,2,4] triazole; 3-(2,4-Diacetoxy-phenyl)-4-(naphthalen-1-yl)-5-mercapto-[1 ,2,4] triazole;
3-(2,4-Diethylcarbamoyloxy-phenyl)-4-(naphthalen-1-yl)-5- (ethylcarbamoylsulfanyl)- [1 ,2,4] triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-trifluoromethyl-phenyl)-5- carbamoyloxy-[1 ,2,4] triazole; 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-methyl-indol-4-yl)-5-carbamoyloxy-
[1 ,2,4] triazole;
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(8-methoxy-quinolin-5-yl)-5- carbamoyloxy-[1 ,2,4] triazole; 3-(2-Hydroxy-4-et.hoxycarbonyoxy-5-methoxy-phenyl)-4-(1-isopropyl- benzoimidazol-4-yl)-5-hydroxy-[1 ,2,4] triazole;
3-(2-Hydroxy-4-ethoxycarbonyoxy-5-ethyl-phenyl)-4-(naphthalin-2-yl)-5- hydroxy-[1 ,2,4] triazole; 3-[2-Hydroxy-4-(dimethyl-carbamoyoxy)-5-ethyl-phenyl]-4-(naphthalin-2-yl)-
5-hydroxy-[1,2,4] triazole;
3-[2-Hydroxy-4-(dimethyl-carbamoyoxy)-5-chloro-phenyl]-4-(quinolin-5-yl)-5- mercapto-[1,2,4] triazole;
3-[2-Hydroxy-4-(dimethyl-carbamoyoxy)-5-ethyl-phenyl]-4-(2,3-difluoro- phenyl)-5-mercapto-[1,2,4] triazole; or
3-[2-Hydroxy-4-isobutyryloxy-5-ethyl-phenyl]-4-(1-methyl-beπzo-imidazol-4- yl)-5-hydroxy-[1 ,2,4] triazole.
81. The compound of Claim 80, wherein R'5 is represented by the following formula:
Figure imgf000277_0001
wherein:
. Rg, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7,
-OC(O)R7, -C(0)NRioRii, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)pR7, or -S(O)pNR10Rii, -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(OR7)2; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and q is zero or an integer from 1 to 7.
82, The compound of Claim 80, wherein R'5 is represented by the following formula:
Figure imgf000278_0001
whereiπ;
R33 is a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;
R34 is H, a lower alkyl, or a lower alkylcarbonyl; and
Ring B and Ring C are optionally substituted with one or more substituents.
The compound of Claim 80, wherein R's is selected from the group consisting of:
Figure imgf000278_0002
wherein:
X11, for each occurrence, is independently CH, CR9, N, N(O), or N+(Ru), provided that at least one X11 is N, N(O), or N+(R17) and at least two X11 groups are independently selected from CH and CRg;
Xi2, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least one X12 group is independently selected from CH and CR9;
Xi3, for each occurrence, is independently O, S, S(O)p, NR7, or NR17;
R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a hydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, -NR10Ri1, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R1I, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)pOR7, -NR8S(O)pR7, or -S(O)pNR10Rn, -S(O)POR7, -OP(O)(ORy)2, or -SP(O)(ORy)2, -S(O)pOR7, -OP(O)(ORy)2, or -SP(O)(OR7)2; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
R^, for each occurrence, is independently an alkyl or an aralkyl.
84, The compound of Claim 80, wherein R'6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1- C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl.
85. The compound of Claim 80, wherein R'8 is -H.
86. The compound of Claim 80, wherein the compound is represented by the following formula:
Figure imgf000279_0001
(XII)
87. The compound of Claim 86, wherein R'β is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1- C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl.
88. The compound of Claim 86, wherein R'6 is -H.
89. The compound of Claim 86, wherein the compound is represented by the following formula:
Figure imgf000279_0002
(XIII)
90. The compound of Claim 89, wherein R'6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1- C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl.
91. The compound of Claim 89, wherein R"6 is -H.
92. The compound of Claim 86 or 89, wherein R19 is -H.
93. The compound of Claim 80, wherein the compound is selected from the group consisting of
4-ethyl-6-(5-mercapto-4-(naphthalen-1-yl)-4H-1 ,2,4-triazol-3-yl)-1 ,3-phenylene bis(2,2- dimethylpropanoate);
4-ethyl-6-(5-mercapto-4-(naphthalen-1-yl)-4H-1,2,4-triazol-3-yl)-1 ,3-phenylene dibenzoate;
2-(5-mercapto-4-(naphthalen-1-yl)-4H-1,2,4-triazol-3-yl)-5-(2-methoxyethoxy)phenol;
4-(5-(ethylcarbamoylthio)-4-(naphthalen-1-yl)-4H-1 ,2,4-triazol-3-yl)-1,3-phenylene bis(dimethylcarbamate); or
5-hydroxy-2-isopropyl-4-(5-(3-methoxypropanoyloxy)-4-(1-methyl-1 H-indol-5-yl)-4H-
1 ,2,4-triazol-3-yl)phenyl 3-methoxypropanoate;
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof.
94. A compound represented by the following structural formula:
Figure imgf000280_0001
(XIV) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, wherein: X' is -0-0- or -S-S-;
R'2 and R'3 are, independently, -OH, -SH, or -NHR7; R'5 is an optionally substituted heteroaryl or an optionally substituted aryl; R'a is -H1 an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR7, -SR7, -NR1ORi11 -OC(O)NR1OR11, -SC(O)NR10Ri1, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7,
-NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CHZC(O)NR10R11, -OS(O)PR7, -SS(O)pR7, -NR7S(O)pR7, -OS(0)pNRioRii, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -0S(O)pOR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10Ri1,
-NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0R11, -SC(NR8)NR10Ri1, -NR7C(NR8)NR10R11, -C(O)R7, -C(O)OR7, -C(O)NR10Rn1 -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NRB)NRI0R11, -C(NR8)SR7, -S(0)POR7, -S(O)PNR10R11, or -S(O)PR7;
R7 and R8, for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; p, for each occurrence, is independently 1 or 2.
95. The compound of Claim 94, wherein R'5 is an optionally substituted phenyl.
96. The compound of Claim 94, wherein R'2 and R'3 are each -OH.
97. The compound of Claim 94, wherein X' is -S-S-.
98. The compound of Claim 94, wherein R'6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1- C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl.
99. The compound of Claim 94, wherein the compound is 6,6'-(5(5'-disulfanediylbis(4- (4-(dimethylamino)phenyl)-4H-1,2,4-triazole-5,3-diyl))bis(4-isopropylbenzene-1,3- diol) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof.
100. A compound represented by the following structural formula:
Figure imgf000282_0001
(XV) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, wherein:
R70, R'2, and R'3 are, independently, -OH, -SH, Or -NHR7;
R'5 is an optionally substituted heteroaryl or an optionally substituted aryl;
R'6 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR7, -SR7, -NR1ORiI1 -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R1I, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)pR7, -NR7S(O)pR7, -OS(O)PNR10R11, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -OS(O)pOR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR10Rn, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR6)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10RI1, -SC(NR8)NR10R11, -NR7C(NR8)NR10R11, -C(O)R7, -C(O)OR7, -C(O)NR10R11, -C(O)SR7, -C(S)R7,
-C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10Ri1, -C(NR8)SR7, -S(0)p0R7, -S(O)PNR10R11, or -S(0)pR7;
R7 and R8, for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R20 is C(O)R/,
Ry is an optionally substituted alkyl; p, for each occurrence, is independently 1 or 2.
101. The compound of Claim 100, wherein R'6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1- C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl.
102. The compound of Claim 100, wherein the compound is selected from the group consisting of
2-amino-1-(5-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1,2,4-triazol-4-yl)-1H- indol-1-yl)ethanone;
1 -(5-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1 ,2,4-triaEol-4-yl)-1 H-indol-1 - yl)ethanone; tert-butyl 3-(5-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1 ,2,4-triazol-4-yl)-1 H- indol-1 -yl)-3-oxopropylcarbamate; or 1-(5-(3-(2,4-dihydroxy-5-isopropylphenyl)-5-hydroxy-4H-1 ,2,4-triazol-4-yI)-1 H-indol-1-y!)-
3-methoxypropan-1-one;
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof.
103. A compound represented by the following structural formula:
Figure imgf000284_0001
(XVI) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, wherein:
X is -O- or -S-;
XI is O or S;
R'5 is an optionally substituted heteroaryl or an optionally substituted aryl;
R'6 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR7, -SR7, -NR10Rn, -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -OS(O)pR7, -SS(O)pR7, -NR7S(O)PR7, -OS(O)PNR10R11, -SS(O)PNRi0R11, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1 I, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR0)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR6)NR10R11, -NR7C(NR8)NR10R11, -C(O)R7, -C(O)OR7, -C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -S(O)pOR7, -S(O)pNR10Rii, or -S(O)PR7;
R7 and RB, for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
Rio and R11, for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R71 and R72 are each, independently, -H, -C(O)R22, or (alk)O(alk);
R22, for each occurrence is independently optionally substituted alkyl, optionally substituted aryl, -O(alk), amino, alkyl amino, or dialkyl amino;
R23 is -C(O)R22 or -alk-O-C(O)R22; alk is a lower alkyl; p, for each occurrence, is independently 1 or 2.
104. The compound of Claim 103, wherein the compound is represented by the following structural formula:
Figure imgf000285_0001
(XVIl) wherein:
R24 and R25 are each, independently -OH or -SH.
105. The compound of Claim 104, wherein R'5 is represented by the following formula:
Figure imgf000286_0001
wherein
R33 is a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl,
R34 is H, a lower alkyl, or a lower alkylcarbonyl, and
Ring B and Ring C are optionally substituted with one or more substituents
The compound of Claim 104, wherein R'5 is selected from the group consisting of
Figure imgf000286_0002
wherein
X11, for each occurrence, is independently CH, CR9, N1 N(O), or N+(Ri7), provided that at least one X11 is N, N(O), or N+(Ri7) and at least two Xn groups are independently selected from CH and CR9,
X12, for each occurrence, is independently CH, CR9, N, N(O), N+(Rn), provided that at least one Xi2 group is independently selected from CH and CR9,
X13, for each occurrence, is independently O, S, S(O)p, NR7, or NRi7,
R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a hydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)pR7, -S(O)pOR7, -NR8S(O)pR7, or -S(O)PNR10R11, -S(O)POR7, -OP(O)(ORy)2, or -SP(O)(OR7)2, -S(O)pOR7, -OP(O)(ORT)21 or -SP(O)(OR7J2, or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
R17, for each occurrence, is independently an alkyl or an aralkyl.
107. The compound of Claim 104, wherein R'6 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1- C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl.
108. The compound of Claim 104, wherein the compound is represented by the following structure:
Figure imgf000287_0001
(XVIII)
wherein:
X41 is O, S, or NR42;
X42 is CR44 or N;
Y40 is N or CR43;
Y41 is N or CR45;
Y42, for each occurrence, is independently N, C or CR46;
R4i is -H1 -OH, -SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)NR10R11, -C(NRB)OR7, -C(NR8)R7, -C(NRB)NR10R11, -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(O)R7, -SC(O)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NR10R11, -OC(S)NR10R11, -OC(NR8)NR10R11, -SC(O)NR10R11, -SC(NR8)NR10R11, -SC(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -C(O)NR10R11, -NR8C(O)R7, -NR7C(S)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(O)OR7, -NR7C(NR8)OR7, -NR7C(O)NR10Ru, -NR7C(S)NR10R11, -NR7C(NR8)NR10R11, -SR7, -S(0)pR7, -OS(0)PR7, -0S(0)p0R7, -OS(0)pNRioRii, -S(0)p0R7, -NR8S(O)PR7, -NR7S(O)PNR10R11, -NR7S(O)POR7, -S(O)PNR10R11, -SS(O)PR7, -SS(O)pOR7, -SS(O)PNR10R11, -OP(O)(OR7)Z, or -SP(O)(OR7)2;
R42 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, -C(O)R7, -(CH2)mC(O)OR7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -S(O)PR7, -S(O)pOR7, or -S(O)11NR10R11;
R43 and R44 are, independently, -H1 -OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)pR7, -S(O)pOR7, -NR8S(O)PR71 -S(O)PNR10R11, or R43 and R44 taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl;
R45 is -H, -OH, -SH1 -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -0(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H,
-OC(O)NR10R1I, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)PNR10R11,
-SS(O)PNR10R11, -NR7S(O)PNR10R1I, -OS(O)POR7, -SS(O)pOR7l -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rii, -SC(S)NRi0R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NRB)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NRB)NR10R11, or -NR7C(NR8)NR10Ri1; and
R46, for each occurrence, is independently, selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)pR7, or -S(O)PNR10R11.
109. The compound of Claim 108, wherein X41 is NR42 and X42 is CR44.
110. The compound of Claim 108, wherein X41 is NR42 and X42 is N.
111. The compound of Claim 108, wherein R41 is selected from the group consisting of - H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
112. The compound of Claim 108, wherein R41 is selected from the group consisting of - H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
113. The compound of Claim 108, wherein X41 is NR42, and R42 is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, -C(O)N(R27J2, and -C(O)OH, wherein each R27 is independently -H or a lower alkyl.
114. The compound of Claim 108, wherein X41 is NR42, and R42 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec- butyl, ferf-butyl, n-pentyl, n-hexyl, -C(O)OH, -(CH2)mC(O)OH, -CH2OCH3, -CH2CH2OCH3, and -C(O)N(CH3)2.
115. The compound of Claim 108, wherein R43 and R44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
116. The compound of Claim 108, wherein X42 is CR44; Y40 is CR43; and R43 and R44 together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring.
117. The compound of Claim 116, wherein R43 and R44 together with the carbon atoms to which they are attached form a C5-C8 cycloalkenyl or a C5-C8 aryl.
118. The compound of Claim 116, wherein R45 or CR45 is selected from the group consisting of -H, -OH, -SH, -NH2, a lower alkoxy, a lower alkyl amino, and a lower dialkyl amino.
119. The compound of Claim 118, wherein R45 is selected from the group consisting of -H1 -OH, methoxy and ethoxy.
120. The compound of Claim 116, wherein X41 is O.
121. The compound of Claim 108, wherein R40 is -OH or -SH.
122. The compound of Claim 108, wherein the compound is represented by the following structural formula:
Figure imgf000290_0001
(XIX) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
123. The compound of Claim 122, wherein X42 is CR44, and R43 and R44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
124. The compound of Claim 122, wherein X42 is CR44, and R43 and R44, taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring.
125. The compound of Claim 124, wherein R43 and R44, taken together with the carbon atoms to which they are attached, form a C5-C8 cycloalkenyl or a C5-C8 aryl.
126. The compound of Claim 122, wherein X42 is CR44.
127. The compound of Claim 122, wherein X42 is N.
128. The compound of Claim 122, wherein the compound is represented by the following structural formula:
Figure imgf000291_0001
(XX) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:
X45 is CR54 or N;
R56 is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl;
R52 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, -(CH2)2OCH3, -CH2C(O)OH, and -C(O)N(CH3)2;
R53 and R54 are each, independently, -H, methyl, ethyl, or isopropyl; or
R53 and R54 taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring; and
R55 is selected from the group consisting of -H, -OH, -OCH3, and OCH2CH3.
129. The compound of Claim 123, wherein the compound is selected from the group consisting of
3-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-1-propionyl-1 H-1 ,2,4- triazol-5(4H)-one; (3-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-5-oxo-4,5-dihydro-1H- I.Σ.'Mriazol-i-yOmethyl pivalate;
(3-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-5-oxo-4,5-dihydro-1H- 1 ,2,4-triazol-1-yl)methyl 2-amino-3-methylbutanoate;
(3-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-5-oxo-4,5-dihydro-1H- 1 ,2,4-triazol-1-yl)methyl 2-amino-3-phenylpropanoate;
(3-(2,4-dihydroxy-5-isopropylphenyl)-4-(1-methyl-1H-indol-5-yl)-5-oxo-4,5-dihydro-1 H- 1,2,4-triazol-1-yl)methyl 2,2-bis(tert-butoxycarbonylamino)-3-methylbutanoate;
4-(1-(2-aminoacetyl)-4-(1-methyl-1H-indol-5-yl)-5-oxo-4,5-dihydro-1H-1 ,2,4-triazol-3-yl)- 6-isopropyl-1 ,3-phenylene bis(2-aminoacetate) trihydrochloride;
4-(1-(2-aminopropanoyl)-4-(1-methyl-1H-indol-5-yl)-5-oxo-4,5-dihydro-1H-1 ,2,4-triazol-3- yl)-6-isopropyl-1 ,3-phenylene bis(2-aminopropanoate) trihydrochloride; or
4-(1-(2-amino-3-phenylpropanoyl)-4-(1-methyl-1 H-indol-5-yl)-5-oxo-4,5-dihydro-1H-1 ,2,4- triazol-3-yl)-6-isopropyl-1 ,3-phenylene bis(2-amino-3-phenylpropanoate) trihydrochloride;
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof.
130. A compound represented by structural formula (XXI):
Figure imgf000292_0001
(XXI)
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein: ring A is optionally further substituted with one or two independently selected substituents in addition to R3; ring E is aromatic or non-aromatic;
Xi6 is -O-, -NR7-, or -S-; Y is -(CR33R'38)κ-, -C(O)-, -C(S)-, -C(NR8)-, -CR7=, -O-, -NR7-, -N=, or -S-
Z1 is -(CR38R'39)k-, =CRr, -O-, -S-, -NR7-, =N-, or -CRUo=CRV, R100 and R3 are each, independently, -OH, -SH, -NR7H, -OR'26, -SR'26l -0(CH2)JDH, -0(CHz)1T1SH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7 -SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7,
-NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -0S(0)pR7, -SS(0)pR7, -S(0)p0R7, -NR7S(O)PR7, -OS(O)PNR10R11, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(0)p0R7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7,
-SC(NR8)R7, -NR7C(NR6)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R111 -SC(NR8)NR10R11, -NR7C(NR8)NR10R11, -OP(O)(ORy)2, or -SP(O)(OR7J2,
R'5 is an optionally substituted aryi or an optionally substituted heteroaryl, R7 and R8, for each occurrence, are, independently, -H1 an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl,
R10 and R11, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl, or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl,
R'26, for each occurrence is, independently, a C1-C6 alkyl R3B and R'39, for each occurrence, are independently H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)NR10R11, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(O)R7, -SC(O)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NR10R11, -OC(S)NR10R11, -OC(NRB)NR10Rii, -SC(O)NR10RU, -SC(NRB)NR10Rn, -SC(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -C(O)NR10R11, -NR8C(O)R7, -NR7C(S)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(O)OR7, -NR7C(NR8)OR7, -NR7C(O)NR10R11, -NR7C(S)NR10R11, -NR7C(NR8)NR10R11, -SR7, -S(0)pR7l -0S(0)pR7, -0S(0)p0R7, -OS(O)PNR10R11, -S(0)p0R7, -NR8S(O)PR7, -NR7S(O)PNR10R11, -NR7S(O)pOR7,
-S(O)PNR10R11, -SS(0)pR7, -SS(0)p0R7, -SS(O)PNR10R11, -OP(O)(0R7)2, or -SP(O)(OR7)2; or R38 and R'3g together with the carbon or carbon atoms to which they are attached form a three to eight membered cycloalkyl or a three to eight membered cycloalkenyl; R'40 and R'41l for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rr 40 and R'41, together with the carbon atoms to which they are attached form a three to eight membered cycloalkenyl; p, for each occurrence, is, independently, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3, or 4; and k is 1 or 2; provided that when R'5 is p-chlorophenyl, rings A and E together are not benzofuranyl.
131. The compound of Claim 130, wherein R'5 is represented by the following formula:
Figure imgf000294_0001
wherein: Rg, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)pOR7r -NR8S(O)pR7, or -S(O)PNR10R11, -S(O)POR7, -OP(0)(OR7)2, or -SP(O)(OR7)2; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and q is zero or an integer from 1 to 7.
132. The compound of Claim 131 , wherein R'5 is represented by one of the following formulas:
Figure imgf000295_0001
wherein: q is zero or an integer from 1 to 5; and u is zero or an integer from 1 to 5.
133. The compound of Claim 130, wherein R'5 is represented by the following structural formula:
Figure imgf000295_0002
wherein:
R33 is H, a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;
R34 is H, a lower alkyl, or a lower alkylcarbonyl; and
Ring B and Ring C are optionally substituted with one or more independently selected substituents.
134. The compound of Claim 130, wherein R's is selected from the group consisting of:
Figure imgf000296_0001
Figure imgf000297_0001
wherein:
X6, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least three X6 groups are independently selected from CH and CR9;
X7, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least three X7 groups are independently selected from CH and CRg;
Xs, for each occurrence, is independently CH2, CHR9, C(R9)Z, O, S, S(O)p, NR7, or NR17;
X9, for each occurrence, is independently N or CH;
Xio, for each occurrence, is independently CH, CRg, N, N(O), N+(R17), provided that at least one X10 is selected from CH and CR9;
R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10Rii, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)pR7, or -S(O)PNR10R11, -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(OR7)2, -S(O)15OR7, -OP(O)(OR7)2, or -SP(O)(OR7)2; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
R17, for each occurrence, is independently -H, an alkyl, an aralkyl, -C(O)R7, -C(O)OR7, or -C(O)NR10R11.
135. The compound of Claim 130, wherein R'5 is selected from the group consisting of:
Figure imgf000298_0001
wherein:
X11, for each occurrence, is independently CH1 CR9, N, N(O), or N+(R17), provided that at least one X11 is N, N(O), or N+(R17) and at least two X11 groups are independently selected from CH and CR9;
X12, for each occurrence, is independently CH1 CR9, N, N(O), N+(R17), provided that at least one X12 group is independently selected from CH and CR9;
X13, for each occurrence, is independently O, S, S(O)P, NR7, or NR17; R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a hydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)pOR7, -NR8S(O)pR7, or -S(O)PNR10R11, -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(OR7)2, -S(O)pOR7, -OP(O)(OR7)2, or -SP(O)(OR7)2; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
R17, for each occurrence, is independently an alkyl or an aralkyl.
136. The compound of Claim 130, wherein R'5 is a phenyl which is optionally substituted with from one to five substituents independently selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl,
-C(O)NR'28R'29, -C(S)NR'2βR'29l
Figure imgf000298_0002
-NR'3oC(0)R'31, -NR'3oC(S)R'3i, -NR'30C(NR'32)R'31, halo, -OR'30, cyano, nitro, haloalkoxy, -C(O)R'30, -C(S)R'3O, -C(NR'32)R'30l -NR'28R'29, -C(O)OR1 S0, -C(S)OR'30, -C(NR^2)OR1 J0, -OC(O)R'30l -OC(S)R'30l -OC(NR^2)R1 S0, -NR MC(O)NR1MR1Z9, -NR1 S0C(S)NR1 Z8R1 M, -NR13oC(NR'32)NR'28R'29, -OC(O)NR1 28R'29l -OC(S)NR'28R'29, -OC(NR1^NR1 JeR1 M, -NR1S0C(O)OR1S1, -NR1S0C(S)OR1Si, -NR1S0C(NR1 S2)OR1S1, -S(O)11R1 S01 -OS(O)pR'30, , -NR1S0S(O)PR1SO, -S(O)pNR'28R'29, -OS(O)pNR'28R'28l or -NR'soS^pNR'^R^, wherein: R'28 and R'29, for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R'28 and R^e taken together with the nitrogen to which they are attached is optionally substituted heterocyclyl or optionally substituted heteroaryl;
R1 S0 and R^1 for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and
R'32| for each occurrence is, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, -C(O)R1S0, -C(O)NR'28R'29, -S(0)pR'3o, or -S(O)pNR'28R'29; p, for each occurrence, is independently, 1 or 2; and h is O, 1 or 2.
137. The compounds of Claim 136, wherein R'5 is a phenyl which is substituted with from one to five substituents independently selected from the group consisting of an alkyl, an alkoxy, a haloalkyl, an amino, an alkylamino, a dialkylamino, a cycloalkoxy, a halo, carboxy, -C(O)R35, -OC(O)R1M, -C(O)OR1M, -NR35C(O)R'26, -C(O)NR35R36, -
NR35C(O)NR36R37, -NR35C(NR8)NR36R37, -S(O)2R1M, -S(O)2NR35R36, - NR35S(O)2R'26, an alkoxyalkyl, a dialkylamino, an alkoxyalkoxy, an alkylaminoalkyl, a dialkylaminoalkyl, an alkylaminoalkoxy, a dialkylaminoalkoxy, an alkoxyalkylaminoalkoxy, an alkoxydialkylaminoalkoxy, heterocyclyl, an alkyl substituted with a heterocyclyl, an alkoxy substituted with a heterocyclyl, or a heteroaralkyl, wherein the heterocycle and the heteroaryl are optionally substituted with a lower alkyl; and wherein R35, R36, and R37, for each occurrence, are each independently, H or an alkyl.
138. The compound of Claim 130, wherein R'5 is represented by the following formula:
Figure imgf000300_0001
wherein:
X8, for each occurrence, is independently CH2, CHR9, C(Rg)2, O, S, S(O)P, NR71 Or NR17;
R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Ri1, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(0)p0R7, -NR8S(O)pR7, or -S(O)PNR10R11, -S(O)POR7, -OP(O)(OR7)2, or -SP(0)(OR7)2, -S(O)pOR7, -OP(O)(OR7)2, or -SP(0)(OR7)2; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring;
R17, for each occurrence, is independently -H, an alkyl, an aralkyl, -C(O)R7, -C(O)OR7, or -C(O)NR10R11; p, for each occurrence, is independently, 1 or 2; and k is 0, 1 or 2.
139. The compound of Claim 130, wherein the compound is represented by structural formula (XXII):
Figure imgf000301_0001
(XXII) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof.
140. The compound of Claim 139, wherein Xi6 is NR35 and R35 is H or a lower alkyl.
141. The compound of Claim 140, wherein one of R'4O or R'41 is H and the other is a lower alkyl, a lower alkoxy, or a three to six membered cycloalkyl.
142. The compound of Claim 141 , wherein R'4O and R'4i are H.
143. The compound of Claim 130, wherein the compound is represented by structural formula (XXlII):
Figure imgf000301_0002
(XXIIl) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein:
X16 is -O-, -NR35-, or -S-;
Z' is -O-, -S-, -NR35- or CR35R36; and R35 and R36, for each occurrence, are independently, H or a lower alkyl.
144. The compound of Claim 143, wherein X16 is -NH- and Z' is -NR35-.
145. The compound of Claim 143, wherein X16 and Z' are -O-.
146. The compound of Claim 143, wherein Z' is CR35R36.
147. The compound of Claim 146, wherein X16 is NH.
148. The compound of Claim 130, wherein the compound is represented by structural formula (XXIV):
Figure imgf000302_0001
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein the dashed line is a single or a double bond.
149. The compound of Claim 148, wherein R'40 is H and R1^1 is a lower alkyl, a lower alkoxy, or a 3 to 6 membered cycloalkyl.
150. The compound of Claim 148, wherein R'41 is H and R'4O is a lower alkyl, a lower alkoxy, or a 3 to 6 membered cycloalkyl.
151. The compound of Claim 148, wherein R'40 and R'41 are H.
152. The compound of Claim 148, wherein the dashed line is a double bond.
153. The compound of Claim 152, wherein R1^0 and R'41 together with the carbon to which they are attached form a five or six membered cycloalkenyl.
154. The compound of Claim 130, wherein the compound is represented by structural formula (XXV):
Figure imgf000303_0001
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein:
X16 is -NH-, -O-, or -S-;
Z' is -NR35-, -O-, -S- or -CR35R3S-;
R35 and R38, for each occurrence, are independently, H or a lower alkyl.
155. The compound of Claim 154, wherein:
R38 and R'39 are each, independently, H or a lower alkyl; X16 is -NH-; and Z iS -NR35- Or -O-.
156. The compound of Claim 154, wherein:
R38 and R'39 are each, independently, H or a lower alkyl; X16 is -O-; and Z' is -NR35- or -O-.
157. The compound of Claim 130, wherein the compound is represented by structural formula (XXVI):
Figure imgf000304_0001
(XXVI) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein:
X16 Is -O-, -NH-, or -S-.
158. The compound of Claim 157, wherein R7 is H or a lower alkyl.
159. The compound of Claim 158, wherein X16 is -NH-.
160. The compound of Claim 130, wherein the compound is represented by structural formula (XXVII):
Figure imgf000304_0002
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, wherein:
X16 Js -O-, -NH-, or -S-.
161. The compound of Claim 157, wherein R7 is H or a lower alkyl.
162. The compound of Claim 158, wherein X16 Js -NH-.
163. The compound of Claim 139, 143, 148, 154, 157| or 158, wherein Ri and R3 are each independently -OH, -SH, -NHR7, -OC(O)NR10Rn, -SC(O)NR10R11, -OC(O)R7, -SC(O)R7, -OC(O)OR7, -SC(O)OR7, -OS(O)PR7, -S(O)POR7, -SS(O)PR7, -OS(O)POR7, -SS(O)POR7, -OC(S)R7, -SC(S)R7, -OC(S)OR7, -SC(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -OP(O)(OR7)2 or -SP(O)(OR7)2.
164. The compound of Claim 163, wherein: R1 is -OH or -SH; and R3 Js -OH.
165. The compound of Claim 163 or 164, wherein R'5 is represented by the following structural formula:
Figure imgf000305_0001
wherein:
R33 is H, a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;
R34 is H, a lower alkyl, or a lower alkylcarbonyl; and
Ring B and Ring C are optionally substituted with one or more independently selected substituents.
166. The compound of Claim 163 or 164, wherein R'5 is a phenyl which is optionally substituted with from one to five substituents independently selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted heteroalkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, -C(O)NR'28R'28| -C(S)NR'2βR'29, -C(NR1 S2)NR1^R1 Z9, -NR1 S0C(O)R1 S1, -NR1 S0C(S)R1 S1, -NR1 S0C(NR^2)R1 S1, halo, -OR'30, cyano, nitro, haloalkoxy, -C(O)R1S0, -C(S)R1S0, -C(NR1S2)R1S0, -NR1Z8RW, -C(O)OR1S0. -C(S)OR1S0,
-C(NR1S2)OR1S0, -OC(0)R(so, -OC(S)R1S0, -OC(NR1S2)R1S0, -NR1SoC(O)NR1J8R1S9, -NR13oC(S)NR128R'29, -NR1SoC(NR1S2)NR1Z8R^9, -OC(O)NR1J8R1Z9, -OC(S)NR1Z6R1Z3, -OC(NR1Sz)NR1S8R1Z9, -NR'30C(O)OR'31, -NR'3oC(S)OR'31, -NR1SoC(NR1S2)OR1Si, -S(O)11R1 S0, -OS(O)PR1S0, , -NR1SoS(O)PR1 S0, -StOJpNR'zsRW -OS(O)PNR1 Z8R1 Z9, or -NR1SoS(O)PNR1 Z8R1 Z9, wherein R1 Z8 and R'29, for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R1 Z8 and R'2g taken together with the nitrogen to which they are attached is optionally substituted heterocyclyl or optionally substituted heteroaryl;
R'3O and R'31 for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and
R'32, for each occurrence is, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, -C(O)R'30, -C(O)NR1 Z8R1 Z9, -S(0)pR'3o, Or -S(O)PNR1 J8RW, p, for each occurrence, is independently, 1 or 2; and h is O, 1 or 2.
167. The compound of Claim 130, selected from the group consisting of:
3-[3-methyl-6-hydroxy-1H-indol-5-yl]- 4-(6-methoxy-naphthalen-1-yl)-5-hydroxy-
4H-[1 ,2,4]triazole;
3-[6-hydroxy-1H-indol-5-yl]- 4-(1-ethyl-1H-indol-4-yl)-5-mercapto-4H-
[1 ,2,4]triazole;
3-(2-oxo-1 ,3-dihydro-3-methyl-6-hydroxy-benzoimidazol-5-yl)-4-(2,3- dihydrobenzo[1 ,4]dioxin-5-yl)-5-mercapto-4/-/-[1 ,2,4]triazole;
3-(6-hydroxy-2,2-dimethyl-benzo[1,3]dioxol-5-yl)-4-(4-methyl-phenyl)-5-hydroxy- 4H-[1 ,2,4]triazo!e;
3-(2-oxo-6-hydroxy-benzo[1,3]dioxol-5-yl)-4-(4-methoxy-phenyl)-5-mercapto- 4H-[1 ,2,4]triazole;
3-(2-oxo-6-hydroxy-1 >3-dihydro-indol-5-yl)-4-(3,5-dimethyl-phenyl)-5-hydroxy- 4H-[1,2,4]triazole;
3-(6-hydroxy-1H-benzoimidazol-5-yl)-4-(acenaphthen-5-yl)-5-mercapto-4H- [1 ,2,4]triazole;
3-(6-hydroxy-1H-indazol-5-ylH-(2,3-dichloro-phenyl)-5-hydroxy-4H- [1,2,4]triazole;
3-(2-oxo-7-hydroxy-1H-quinolin-6-yl)-4-(quiπolin-5-yl)-5-mercapto-4/-/- [1 ,2,4]triazole;
3-[2,3-dimethyl-6-hydroxy-1H-indol-5-yl]- 4-(2,3-dimethyl-1H-indol-4-yl)-5- mercapto-4/-/-[1 ,2,4]triazole;
3-(2-methyl-6-hydroxy-1/-/-benzoimidazol-5-yl)-4-(4-carboxy-naphthalen-1-yl)-5- mercapto-4H-[1 ,2,4]triazole;
3-(3-isopropyl-6-hydroxy-1H-indazol-5-yl)-4-(4-dimethylcarbamoyl-naphthalen- 1-yl)-5-hydroxy-4H-[1 ,2,4]triazole;
3-(2-oxo-4-methyl-7-hydroxy-1H-quinolin-6-yl)-4-(2,3-dimethyl-4-methoxy- phenyl)-5-mercapto-4/-/-[1 ,2,4]triazole;
3-(2-oxo-3-ethyl-6-hydroxy-1 ,3-dihydro-indol-5-yl)-4-(1-isopropyl-iH-indol-4-yl)- 5-hydroxy-4/-/-[1 ,2,4]triazole;
3-(2-oxo-3,3-dimethyl-6-hydroxy-1 ,3-dihydro-indol-5-yl)-4-[1-(2-methoxy-ethyl)- 1 H-indol-4-yl]-5-mercapto-4H-[1 ,2,4]triazole;
3-(2-oxo-6-hydroxy-benzo[1 ,3]dioxol-5-yl)-4-(1-isopropyl-1H-indol-4-yl)-5- mercapto-4H-[1 ,2,4]triazole;
3-(6-hydroxy-2,2-diethyl-benzo[1,3]dioxol-5-yl)-4-(1-dimethylcarbamoyl-1H- indot-4-yl)-5-mercapto-4H-[1 ,2,4]triazole;
3-(2-oxo-1,3-dihydro-3-isopropyl-6-hydroxy-benzoimidazol-5-yl)-4-(1 ,2,3- trimethyl-1 H-indol-5-yl)-5-hydroxy-4H-[1 ,2,4]triazole;
S-li-dimethylcarbamoyl-e-dimethylcarbamoyoxy-IH-indol-δ-yll^^i-ethyl-I H- indol-4-yl)-5-dimethylcarbamoylsulfanyl-4H-[1,2,4]triazole;
3-(6-ethoxycarbonyloxy-1H-benzoimidazol-5-yl)-4-(πaphthalene-5-yl)-5- ethoxycarbonyloxy-4H-[1 ,2,4]triazole;
3-(3-cyclopropyl-6-acetoxy-1/-/-indazol-5-yl)-4-(naphthalen-1-yl)-5-acetoxy-4H- [1,2,4]triazole;
3-(2-oxo-3,3-dimethyl-6-hydroxy-1 ,3-dihydro-indol-5-yl)-4-(naphthalen-1-yl)-5- (2-hydroxy-ethylsulfanyl-4/-/-[1 ,2,4]tπazole,
3-(2-oxo-3-methyl-7-hydroxy-1H-quιnolιn-6-yl)-4-(benzothιazol-4-yl)-5-hydroxy- 4H-[1 ,2,4]trιazole,
3-(2-oxo-6-hydroxy-benzo[1 ,3]dιoxol-5-yl)-4-[2-(1H-tetrazol-5-yl)-pheπyl]-5- hydroxy-4/-/-[1 ,2,4]tπazole,
3-(6-hydroxy-2,2-dimethyl-benzo[1 ,3]dioxol-5-yl)-4-(9H-purin-6-yl)-5-hydroxy- 4H-[1 ,2,4]trιazole,
3-(2-oxo-1 ,3-dιhydro-6-hydroxy-benzoιmιdazol-5-yl)-4-phenyl-5-sulfamoylamιno- 4H-[1 ,2,4]tπazole,
3-l3-methyl-6-hydroxy-1H-ιndol-5-yl]- 4-(1-ιsopropyl-1 H-ιndol-4-yl)-5-ureιdo-4H- [1 ,2,4]tπazole,
3-[3-methoxy-6-hydroxy-1 H-ιndol-5-yl]- 4-(naphthalen-1 -yl)-5-carbamoyloxy-4/-/- [1 ,2,4]trιazole,
3-(6-hydroxy-1H-benzoιmιdazol-5-yl)-4-(8-methoxy-quιnolιn-5-yl)-5- carbamoyloxy-4H-[1 ,2,4]trιazole,
3-(3-ιsopropyl-6-hydroxy-1/-/-ιndazol-5-yl)-4-(1-methyl-2-chloro-1H-ιndol-4-yl)-5- carboxyamιno-4H-[1 ,2,4]tπazole,
3-(2-oxo-3-propyl-6-hydroxy-1,3-dιhydro-ιndol-5-yl)-4-(3-tπfluoromethyl-phenyl)- 5-sulfamoylamιno-4H-[1,2,4]trιazole,
3-(2-oxo-7-hydroxy-1H-quιnolιn-6-yl)-4-(1-ιsopropyl-1H-benzoιmιdazol-4-yl)-5- sulfamoylamιno-4H-[1 ,2,4]trιazole,
3-(2-oxo-6-hydroxy-benzo[1,3]dιoxol-5-yl)-4-(1-ιsopropyl-1H-benzoιmιdazol-4- yl)-5-sulfamoyloxy-4H-[1 ,2,4]tπazole,
3-(6-hydroxy-benzo[1 ,3]dιoxol-5-yl)-4-(1-ιsopropyl-1H-benzoimιdazol-4-yl)-5- hydroxy-4/-/-[1 ,2,4]trιazole,
3-(2-oxo-3-methyl-6-hydroxy-1,3-dιhydro-ιndol-5-yl)-4-(1-ιsopropyl-7-methoxy- 1 H-ιndol-4-y l)-5-mercapto-4H-[1 ,2,4]trιazole,
3-[2,3-dιmethyl-6-hydroxy-1 /-/-ιndol-5-yl]- 4-(1 -ethyl-2-methyl-1 H-benzoimidazol- 5-yl)-5-mercapto-4H-[1 ,2,4]trιazole,
3-(2-tπfluoromethyl-6-hydroxy-1H-benzoιmιdazol-5-yl)-4-(1-cyclopropylmethyl- 1/-/-ιndol-4-y!)-5-mercapto-4H-[1 ,2,4]trιazole,
S^Θ-hydroxy-IH-indazol-δ-yO^I-methyl-S-ethyl-IH-indol-δ-yO-δ-mercapto^H- [1,2,4]trιazole,
3-[6-hydroxy-1H-ιπdol-5-yl]- 4-(1-methyl-1H-ιndol-5-yl)-5-hydroxy-4H- [1 ,2,4]trιazole,
3-{2-oxo-1,3-dιhydro-3-ιsopropyl-6-hydroxy-benzoιmιdazol-5-yl)-4-(2-methyl-7- methoxy-benzofuran-4-yl)-5-mercapto-4/-/-[1,2,4]trιazole,
3-(2-oxo-6-hydroxy-benzo[1,3]dιoxol-5-yl)-4-(2-methyl-benzooxazol-5-yl)-5- mercapto-4H-[1 ,2,4]triazole;
3-(6-hydroxy-2,2-dimethyl-benzo[1,3]dioxol-5-yl)-4-(1 ,3-climethyl-iH-inciol-5-y|)- 5-hydroxy-4H-[1 ,2,4]tria2ole;
3-(2-oxo-1,3-dihydro-3-methyl-6-hydroxy-benzoimidazol-5-yl)-4-(2-methyl-7- methoxy-benzofuran-4-yl)-5-mercapto-4H-[1,2,4]triazole;
3-[3-methyl-6-hydroxy-1 W-indol-5-yl]- 4-(1-methyl-1 H-indazol-5-yl)-5-mercapto- 4/7-[1 ,2,4]triazole;
3-(6-hydroxy-benzo[1 ,3]dioxol-5-yl)-4-( benzo[1,3]dioxol-5-yl)-5-mercapto-4H- [1 ,2,4]triazole;
3-[2,3-dimethyl-6-hydroxy-1H-indol-5-yl]- 4-(4-propyl-3,4-dihydro-2H- benzo[1 ,4]oxazin-6-yl)-5-mercapto-4H-[1 ,2,4]triazole; or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof.
A compound represented by structural formula (XXVIII):
Figure imgf000309_0001
(XXVIII) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, wherein: ring F is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents In addition to R3; ring G is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to -T1-V1-T2- V2;
R100 IS -OH, -SH, -NR7H, -OR'26l -SR'26, -NHR'26, -O(CH2)mOH, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H,
-OC(O)NR10R11, -SC(O)NR10R1I, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10Rii, -SCH2C(O)NR10R11, -NR7CH2C(O)NR1ORU, -OS(O)PR7, -SS(O)pR7l -S(O)POR7, -NR7S(O)PR7, -OS(O)pNR10Rii, -SS(O)PNR10RI1, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR6)R7, -NR7C(NR8)R7, -0C(NRB)0R7, -SC(NR8)OR7, -NR7C(NR8)OR7,
-OC(NRB)NR10R11, -SC(NR8)NR10R11, -NR7C(NRB)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R103 IS -OH, -SH, -NR7H, -OR'26l -SR'26l -NHR'26, -0(CH2)m0H, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10Ri1, -OC(O)R7, -SC(O)R7,
-NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10RH, -OS(O)PR7, -SS(O)PR7, -S(0)p0R7, -NR7S(O)PR7, -OS(O)PNR10R111 -SS(O)PNR10R11, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7,
-NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR71 -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NR8)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -S(O)NHR8, -S(O)2NHR8, -OP(O)(OR7)2 or
-SP(O)(OR7)2;
R7 and R8, for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl;
R10 and R11, for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R'26 is a C1-C6 alkyl; T1 is absent or a C1-C4 alkylene;
T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -NRaRb, -NR8S(O)2 R**, -S(0)NRaRb, -S(O)2NR8R" or -C(0)NRaRb; or T2 is absent or a C1-C4 alkylene, V1 is -O-, -S-, -N(R*)- or -C(O)N(R-)- and V2 is -S(O)NRBRb, -S(O)2NR8R" or -C(O)NR3R6; or
T2 is a C2-C4 alkylene, V1 is -0-, -S, -N(R-)-, -C(O)O-, C(O)N(R-)- and V2 is -N R8R", or -NRaS(O)2R**; each R- is independently -H or C1-C3 alkyl; each R** is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl;
Ra and Rb, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or heteroaryl, or an optionally substituted aralkyl; or Ra and Rb, taken together with the nitrogen to which they are attached, form an optionally substituted heteroaryl or heterocyclyl; p, for each occurrence, is independently, O, 1 or 2; and m, for each occurrence, is independently, 1 , 2, 3 or 4; wherein when T1, T2 and V1 are absent and V2 is -NRaRb then ring G is not phenyl, and when T1, T2 and V1 are absent and V2 is -C(0)NRaRb then ring G is not naphthyl or indolyl.
169. The compound of Claim 168, wherein the compound is represented by structural formula (XXXIII):
Figure imgf000311_0001
(XXXIII) wherein:
R73, and R74, for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR10R11, -OR7, -SR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)NR10R11, -C(NRB)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -0C(NRa)0R7, -SC(O)R7, -SC(O)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NR10R11, -OC(S)NR10R11, -OC(NR8)NR10R11, -SC(O)NR10R11, -SC(NR8)NR10R11, -SC(S)NR10R11, -OC(NR8)R7,
-SC(NR8)R7, -C(O)NR10R11, -NR7C(O)R7, -NR7C(S)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -NR7C(NR8)OR7, -NR7C(O)NR10R11, -NR7C(S)NR10R1 11 -NR7C(NR8)NR10R111 -SR71 -S(0)pR7, -0S(0)pR7, -0S(0)p0R7,
-OS(O)PNR10R11, -S(0)p0R7l -NR8S(O)PR7, -NR7S(O)PNR10R11, -NR7S(O)pOR7, -S(O)PNR10R11, -SS(0)pR7, -SS(0)p0R7, -SS(O)PNR10R11, -OP(0)(OR7)2, or -SP(O)(OR7)2;
R'25 for each occurence is independently a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, -OH, -SH, -NHR7, -(CH2)bOH, -(CH2)bSH, -(CH2)bNR7H, -OCH3,
-SCH3, -NHCH3, -OCH2CH2OH, -OCH2CH2SH, -OCH2CH2NR7H, -SCH2CH2OH, -SCH2CH2SH, -SCH2CH2NR7H, -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11,
-NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)PNR10R11, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7,
-OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NRB)NR1OR11, -C(O)R7, -C(O)OR7, -C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NRg)NR10R11, -C(NR8)SR7, -S(O)POR7, -S(O)PNR10R11, or -S(O)PR7; b is 1, 2, 3, or 4 e and f for each occurrence, is independently an integer from O to 4; and x is O or 1 , provided that e+x is less than or equal to 4.
The compound of Claim 169, wherein: R'25 is -OH, -SH, -NHR7, -(CH2)bOH, -(CH2)bSH, -(CH2)bNR7H, -OCH3,
-SCH3, -NHCH3, -OCH2CH2OH, -OCH2CH2SH, -OCH2CH2NR7H, -SCH2CH2OH, -SCH2CH2SH, -SCH2CH2NR7H, -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10Ri i, -SCH2C(O)NR10Rn, -NR7CH2C(O)NR10Rii, -OS(O)PR7, -SS(0)pR7, -NR7S(O)PR7, -OS(O)PNR10R11, -SS(0)pNRioRii, -NR7S(O)PNR10R1I, -0S(0)p0R7, -SS(0)p0R7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7,
-NR7C(NR8)R7, -OC(NRB)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NRB)NR10R11, -C(O)R7, -C(O)OR7, -C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -S(O)POR7, -S(O)PNR10R11 Or -S(O)PR7.
171. The compound of Claim 170, wherein the compound is represented by structural formula (XXXIV):
Figure imgf000313_0001
(XXXIV)
172. The compound of Claim 171 , wherein R100, R103 and R'25 for each occurrence is independently -OH, -SH, -NHR7, -OC(O)NR10R11, -SC(O)NR10R11, -OC(O)R7, -SC(O)R7, -OC(O)OR7, -SC(O)OR7, -OS(O)PR7, -S(O)POR7, -SS(O)PR7, -OS(O)POR7, -SS(O)POR7, -OC(S)R7, -SC(S)R7, -OC(S)OR7, -SC(S)OR7, -OC(S)NR10R11,
-SC(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -OP(0)(OR7)2 or -SP(O)(OR7)2.
173. The compound of Claim 172, wherein R74 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR7, -SR7, -NR10Rn, -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7,
-SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)PNR10R11, -SS(O)pNR10Rn, -NR7S(O)pNR10Rii, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rii, -SC(S)NR10RH, -NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRB)NR10Rii, -SC(NR8)NR10Rii, -NR7C(NR8)NR10R11, -C(O)R7, -C(O)OR7,
-C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -S(0)p0R7, -S(O)PNR10R11 or -S(O)PR7; and f is O or 1.
174. The compound of Claim 173, wherein R73 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR7, -SR7, -NR10Ru,
-OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)PNR10R11,
-SS(O)PNR10R11, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NRe)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NR8)NR10R11, -C(O)R7, -C(O)OR7,
-C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -S(O)POR7, -S(O)PNR10R11 or -S(O)PR7.
175. The compound of Claim 174, wherein Ring G is a six membered nitrogen containing heteroaryl substituted with T1-V1-T2-V2 and optionally further substituted with one or more R30 group.
176. The compound of Claim 175, wherein R73 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1- C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 atkylsulfanyl or a C3-C6 cycloalkyl.
177. The compound of Claim 176, wherein the compound is represented by structural formula (XXXV): C
Figure imgf000315_0001
(XXXV)
178 The compound of Claim 177, wherein R100 and R103 are each, independently, -OH, -SH or -NHR7
179 The compound of Claim 178, wherein
Ra and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, -COOH, C2-6 acetal, C2-6 ketal, ammo, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino and a cycloalkyl, or Ra and Rb taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl,
Ti is absent or a C1-C2 alkylene, and
T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -NRaRb or
-S(O)2NR3R", or
T2 is absent or a C1-C4 alkylene, V1 is -0-, -S- or -N(R )-, and V2 is
-S(O)2NRV, or anb
T2 is a C2-C4 alkylene, V1 is -0-, -S- or -N(R )-, and V2 is -NR R
180 The compound of Claim 179, wherein the compound is represented by structural formula (XXXVI)
c
Figure imgf000315_0002
(XXXVI)
181. The compound of Claim 180, wherein R74 is a -OH, -SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl.
182. The compound of Claim 181 , wherein R1Oo, R103 and R'25 for each occurrence, is independently -SH or -OH1 and R6 is cyclopropyl or isopropyl.
183. The compound of Claim 182, wherein the compound is represented by structural formula (XXXVII):
or1
Figure imgf000316_0001
(XXXVII)
184. The compound of Claim 183, wherein R74 is a methyl, ethyl, propyl, isopropyl, methoxy or ethoxy.
185. The compound of Claim 184, wherein:
R" and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -COOH, C2-6 acetal, C2-6 ketal, amino, C1-C6 alkoxy, alkylamino and dialkylamino; or Ra and Rb taken together with the nitrogen to which they are attached are:
Figure imgf000316_0002
R'35 is -H, a C1-C4 alkyl or a C1-C4 acyl;
T1 is absent; and
T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -NRaRb.
186. The compound of Claim 174, wherein Ring G is phenyl substituted with T1-V1-T2-V2 and optionally further substituted with one or more R74 group.
187. The compound of Claim 186, wherein R73 is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1- C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkylsulfanyl or a C3-C6 cycloalkyl.
188. The compound of Claim 187, wherein the compound is represented by structural formula (XXXVIII):
1
Figure imgf000317_0001
(XXXVIII)
189. The compound of Claim 188, wherein R1Oo and R103 are each, independently, -OH, -SH or -NHR7.
190. The compound of Claim 189, wherein:
Ra and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino and a cycloalkyl; or Ra and Rb taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl;
R** is independently, -H, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, amino, a C1-C6 alkoxy, alkylamino and dialkylamino;
Ti is absent or a C1-C2 alkylene; and
T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -S(O)2NRaRb, or -NR8S(O)2 R**; or
T2 is absent or a C1-C4 alkylene, V1 is -O-, -S- or -N(R*)-, and V2 is -S(O)2NR8R"; or
T2 is a C2-C4 alkylene, V1 is -O-, -S- or -N(R')-, and V2 is -NRaRb or -NR8S(O)2 R**
191. The compound of Claim 190, wherein R74 is a -OH, -SH, halogen, cyano, a C1-C6 alky), C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl.
192. The compound of Claim 191 , wherein R1Oo, R103 and R'25 for each occurrence, is independently -SH or -OH, and R6 is cyclopropyl or isopropyl.
193. The compound of Claim 192, wherein the compound is represented by a structural formula selected from:
or 1
Figure imgf000318_0001
(XXXIX) or
Figure imgf000318_0002
(XL)
194. The compound of Claim 193, wherein R74 is a methyl, ethyl, propyl, isopropyl, methoxy or ethoxy.
195. The compound of Claim 194, wherein:
Ra and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH1 -COOH, amino, C1-C6 alkoxy, alkylamino and dialkylamino; or Ra and Rb taken together with the nitrogen to which they are attached are: 35
Figure imgf000319_0001
R'35 is -H, a C1-C4 alkyl or a C1-C4 acyl;
R** is independently, -H, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, amino, a C1-C6 alkoxy, alkylamino and dialkylamino;
T1 is absent; and
T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -S(O)2NRaRb, or -NR3S(O)2 R**.
196. A compound represented by a structural formula selected from:
Figure imgf000319_0002
(XXIX) or (XXX) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof, wherein: ring G is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or more substituents in addition to -T1-V1-T2- V2;
X14 is O, S or NR7;
R100 is -OH, -SH, -NR7H, -OR'26l -SR1 J26, -NHR'26, -O(CH2)mOH, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R11, -SCH2C(O)NR10Ru, -NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)pNR10Ru, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R1I, -SC(S)NR10RiI, -NR7C(S)NR10RH1 -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NR6)NR10R11, -S(0)p0R7, -OP(O)(OR7)2 or -SP(O)(OR7)2;
R103 is -OH, -SH, -NR7H, -OR'26, -SR'a, -NHR'2B, -0(CH2)m0H, -0(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(O)NR10R11, -SC(O)NR10R11, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R71 -OCH2C(O)OR7, -SCH2C(O)OR7,
-NR7CH2C(O)OR7, -OCH2C(O)NR10Ri1, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)PNR10R11, -SS(O)PNR10R11, -NR7S(O)PNR10R11, -0S(0)p0R7, -SS(0)p0R7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7,
-NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NR10R11, -NR7C(NRB)NR10R11, -C(O)OH, -C(O)NHR8, -C(O)SH, -S(O)OH, -S(O)2OH, -S(O)NHR8, -S(O)2NHR8, -S(0)p0R7, -OP(0)(OR7)2 or -SP(O)(OR7)2; R7 and R8, for each occurrence, is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl or an optionally substituted heteraralkyl;
R10 and R11, for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and R11, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R'22, for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl, a haloalkyl, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -S(O)pR7, -S(O)p0R7 or -S(O)pNR10Rn; and
R'23 and R'24, for each occurrence, is independently -H, an optionally substituted alky, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R1 I, -NR8C(O)R7, -SR7, -S(O)pR7, -OS(O)pR7, -S(O)pOR7l -NR8S(O)PR7 or -S(OpNR10R11;
R'2e is a C1-C6 alkyl;
Ra and Rb, for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or heteroaryl, an optionally substituted aralkyl; or Ra and Rb, taken together with the nitrogen to which they are attached, form an optionally substituted heteroaryl or heterocyclyl;
T1 is absent or a C1-C4 alkylene;
T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -NRaRb, -NR8S(O)2 R", -S(O)NR8R", -S(O)2NRBRb or -C(O)NRaRb; or
T2 is absent or a C1-C4 alkylene, V1 is -0-, -S-, -N(R*)- or -C(O)N(R-)- and V2 is -S(O)NRaRb, -S(O)2NRaRb or -C(O)NRaRb; or
T2 is a C2-C4 alkylene, V1 is -0-, -S1 -N(R>, -C(O)O-, C(O)N(R")- and V2 is -NRBRb, or -NR8S(O)2R**; each R* is independently -H or C1 -C3 alkyl; each R** is independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; p, for each occurrence, is independently, O, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3 or 4.
197. The compound of Claim 196, wherein Ring G is a six membered nitrogen containing heteroaryl substituted with T1-V1-T2-V2 and optionally further substituted with one or more RM group.
198. The compound of Claim 197, wherein R10o is -OH, -SH, or -NHR7.
199. The compound of Claim 198, wherein ring G is pyridyl substituted with T1-V1-T2-V2 and optionally further substituted with one or more R74 group.
200. The compound of Claim 199, wherein R'2_ is -H, an alkyl, an aralkyl, -C(O)R7, -C(O)OR7 or -C(O)NR10Rn.
201. The compound of Claim 200, wherein:
Ra and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH1 -CN, -SH1 -COOH, C2-6 acetal, C2-6 ketal, amino, a C1-
C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino and a cycloalkyl; or Ra and Rb taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromattc, nitrogen-containing heterocyclyl;
Ti is absent or a C1-C2 alkylene; and T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -NRaRb or
-S(O)2NRaRb; or
T2 is absent or a C1-C4 alkylene, V1 is -O-, -S- or -N(R*)-, and V2 is -S(O)2NRaRb; or
T2 is a C2-C4 alkylene, V1 is -O-, -S- or -N(R*)-, and V2 is -NRaRb.
202. The compound of Claim 201 , wherein the Ring G is represented by the following structural formula:
cπ
Figure imgf000322_0001
203. The compound of Claim 202, wherein R74 for each occurrence is independently -OH, -SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl.
204. The compound of Claim 203, wherein the ring G is represented by the following structural formula:
Figure imgf000323_0001
205. The compound of Claim 204, wherein X14 is O,
206. The compound of Claim 205, wherein:
Ra and Rb are each independently a hydrogen, a C1 -C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -COOH, C2-6 acetal, C2-6 ketal, amino, C1-C6 alkoxy, alkylamino and dialkylamino; or Ra and Rb taken together with the nitrogen to which they are attached are:
Figure imgf000323_0002
R'35 is -H, a C1-C4 alkyl or a C1-C4 acyl; T1 is absent; and
T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -NRaRb.
207. The compound of Claim 196, wherein Ring G is phenyl substituted with T1-V1-T2-V2 and optionally further substituted with one or more R74 group.
208. The compound of Claim 207, wherein R1Oo is -OH, -SH, or -NHR7.
209. The compound of Claim 208, wherein R'22 is -H, an alkyl, an aralkyl, -C(O)R7, -C(O)OR7 or -C(O)NR10Rn.
210. The compound of Claim 209, wherein: Ra and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino and a cycloalkyl; or Ra and Rb taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl;
R** is independently, -H, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, -CN, -SH, amino, a C1-C6 alkoxy, alkylamino and dialkylamino;
T1 is absent or a C1-C2 alkylene; and
T2 is absent or a C1-C4 alkylene, \Λ is absent and V2 is -S(O)2NRDRb, or -NR8S(O)2 R**; or
T2 is absent or a C1-C4 alkylene, V1 is -0-, -S- or -N(R*)-, and V2 is -S(O)2NRV; or
T2 is a C2-C4 alkylene, V-, is -0-, -S- or -N(R*)-, and V2 is -NR8S(O)2 R**.
211. The compound of Claim 210, wherein wherein ring G is represented by a structural formula selected from:
Figure imgf000324_0001
212. The compound of Claim 211 , wherein R74 for each occurrence is independently -OH, -SH, halogen, cyano, a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkyl sulfanyl.
213. The compound of Claim 212, wherein X14 is O.
214. The compound of Claim 213, wherein: Ra and Rb are each independently a hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by one or more groups selected from the group consisting of -OH, -COOH, amino, C1-C6 alkoxy, alkylamino and dialkylamino; or Ra and Rb taken together with the nitrogen to which they are attached are:
Figure imgf000325_0001
R'35 is -H, a C1-C4 alkyl or a C1-C4 acyl;
R** is independently, -H, a C1-C6 straight or branched alkyl optionally substituted by one or more groups selected from the group consisting of -OH, amino, a C1-C6 alkoxy, alkylamino and dialkylamino;
T1 is absent; and
T2 is absent or a C1-C4 alkylene, V1 is absent and V2 is -S(O)2NRaRb, or -NR8S(O)2 R**.
215. A method of inhibiting Hsp90 in a cell, comprising administering to the cell an effective amount of a compound of any one of Claims 1 through 214.
216. A method of treating or preventing proliferative disorder in a mammal, comprising administering to the mammal an effective amount of a compound of any one of
Claims 1 through 214.
217. A method of treating cancer in a mammal, comprising administering to the mammal an effective amount of a compound of any one of Claims 1 through 214.
218. A method of inducing degradation of a c-kit protein, comprising administering to the mammal an effective amount of a compound of any one of Claims 1 through 214.
219. A method of treating a c-kit associated cancer in a mammal, comprising administering to the mammal an effective amount of a compound of any one of
Claims 1 through 214.
220. A method of inducing degradation of a Bcr-Abl protein, comprising administering to the mammal an effective amount of a compound of any one of Claims 1 through 214.
221. A method of treating a Bcr-Abl associated cancer in a mammal, comprising administering to the mammal an effective amount of a compound of any one of Claims 1 through 214.
222. A method of inducing degradation of a FLT3 protein, comprising administering to the mammal an effective amount of a compound of any one of Claims 1 through 214.
223. A method of treating a FLT3 associated cancer in a mammal, comprising administering to the mammal an effective amount of a compound of any one of
Claims 1 through 214.
224. A method of inducing degradation of an EGFR protein, comprising administering to the mammal an effective amount of a compound of any one of Claims 1 through 214.
225. A method of treating an EGFR associated cancer in a mammal, comprising administering to the mammal an effective amount of a compound of any one of Claims 1 through 214.
226. A method of treating or inhibiting angiogenesis in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Claims 1 through 214.
227. A method of blocking, occluding, or otherwise disrupting blood flow in neovasculature, comprising contacting the neovasculature with an effective amount of a compound of any one of Claims 1 through 214.
228. The method of Claim 227, wherein the neovasculature is in a subject and blood flow in the neovasculature is blocked, occluded, or otherwise disrupted in the subject by administering to the subject an effective amount of the compound.
229. The method of Claim 228, wherein the subject is human.
230. A method of treating a non-Hodgkin's lymphoma, comprising administering to the mammal an effective amount of a compound of any one of Claims 1 to 214, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
231. The method of Claim 230, wherein the non-Hodgkin's lymphoma is a B-cell non- Hodgkin's lymphoma.
232. The method of Claim 231 , wherein the B-cell non-Hodgkin's lymphoma is selected from the group consisting of Burkitt's lymphoma, follicular lymphoma, diffuse large
B-cell lymphoma, nodal marginal zone B-cell lymphoma, plasma cell neoplasms, small lymphocytic lymphoma/chroπic lymphocytic leukemia, mantle cell lymphoma, and lymphoplamacytic lymphoma/Waldenstrom macroglobulinemia.
233. The method of Claim 230, wherein the non-Hodgkin's lymphoma is a T-cell non- Hodgkin's lymphoma,
234. The method of Claim 233, wherein the T-cell non-Hodgkin's lymphoma is selected from the group consisting of anaplastic large-cell lymphoma, precursor-T-cell lymphoblastic leukemia/lymphoma, unspecified peripheral T-cell lymphoma, and angioimmunoblastic T-cell lymphoma.
235. A method of treating or preventing an infection in a subject, comprising administering to the subject an effective amount of a compound of any one of Claims 1 to 214, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
236. A method of treating or preventing a fungal infection in a subject, comprising administering to the subject an effective amount of a compound of any one of Claims 1 to 214, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
237. A method of treating or preventing a bacterial infection in a subject, comprising administering to the subject an effective amount of a compound of any one of Claims 1 to 214, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
238. A method of treating or preventing a viral infection in a subject, comprising administering to the subject an effective amount of a compound of any one of
Claims 1 to 214, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
239. A method of treating or preventing a parasitic infection in a subject, comprising administering to the subject an effective amount of a compound of any one of Claims 1 to 214, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
240. The method of any one of Claims 235 to 239, wherein the compound is administered with an additional therapeutic agent.
241. A method of inhibiting topoisomerase Il in a subject, comprising administering to the subject an effective amount of a compound of any one of Claims 1 to 214, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
242. A method of modulating the activity of glucocorticoid receptors in a cell, comprising administering to the cell an effective amount of any one of Claims 1 to 214, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
243. A method of treating or preventing an inflammatory disorder in a subject, comprising administering to the subject an effective amount of a compound of any one of Claims 1 to 214, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
244. A method of treating or preventing an immune disorder in a subject, comprising administering to the subject an effective amount of a compound of any one of Claims 1 to 214, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
245. A method of suppressing the immune system in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of Claims 1 to 214, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
246. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of any one of Claims 1 through 214.
247. The pharmaceutical composition of Claim 246, further comprising one or more additional therapeutic agents.
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