AU2012200157B2 - Method for treating proliferative disorders associated with protooncogene products - Google Patents

Method for treating proliferative disorders associated with protooncogene products Download PDF

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AU2012200157B2
AU2012200157B2 AU2012200157A AU2012200157A AU2012200157B2 AU 2012200157 B2 AU2012200157 B2 AU 2012200157B2 AU 2012200157 A AU2012200157 A AU 2012200157A AU 2012200157 A AU2012200157 A AU 2012200157A AU 2012200157 B2 AU2012200157 B2 AU 2012200157B2
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cancer
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Zhenjian Du
Kevin Foley
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Synta Phamaceuticals Corp
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Abstract

C\NRPonbIhDCOREC\4075614_ .DOC-1/1012012 The present invention relates to methods of inhibiting the activity of Hsp90 in a subject in need thereof and methods for treating Bcr-Abl, FLT-3, EGFR, c-Kit, B-raf, and NPM-ALK associated cancers, in a subject in need thereof.

Description

Australian Patents Act 1990 - Regulation 3.2A ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title "Method for treating proliferative disorders associated with protooncogene products" The following statement is a full description of this invention, including the best method of performing it known to us: C \NRPortbN\)CC\REC\4075350_1.DOC- 10/1/12 CUNRPortbDCOREC4075614_ .DOC-111012012 METHOD FOR TREATItNG PROLIFERATIVE DISORDERS ASSOCIATED WITH PROTOONCOGENE PRODUCTS RELATED APPLICATIONS This application is a divisional of Australian Patent Application No. 2007267843, the entire content of which is incorporated herein by reference. This application relates to U.S. Provisional Application No. 60/808,296, filed on May 25, 2006; U.S. Provisional Application No. 60/808,249, filed on May 25, 2006; U.S. Provisional Application No. 60/808,361, filed on May 25, 2006; and U.S. Provisional Application No. 60/808,363, filed on May 25, 2006. The entire teachings of the above applications are incorporated herein by reference. FIELD OF THE INVENTION The invention relates to a method of inhibiting the activity of Hsp90 in a subject in need thereof and methods for treating proliferative disorders associated with aberrant expression or regulation of c-kit, Flt3, EGFR, or B-raf or associated with the expression of tyrosine kinase fusion proteins BCR-ABL or NPM-ALK. 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. 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 C-\NRPonb\DCCREC\(075614_1 DOC-1/10/2012 -2 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. Protein kinases (PKs) play a role in signal transduction pathways regulating a number of cellular functions, such as cell growth, differentiation, and cell death. PKs are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. 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. The members of the type Ill group of receptor tyrosine kinases include platelet-derived growth factor (PDGF) receptors (PDGF receptors alpha and beta), colony-stimulating factor (CSF-1) receptor (CSF-l R, c Fms), Fms-like tyrosine kinase (FLT3), and stem cell factor receptor (c-kit). FLT3 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). 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 ITD 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), 11:3449- C \NRPortbl\DCC\REC\4075614_1 DOC-1/102012 3457). 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 1 1 band q23 (I 1 q23) and occur in approximately 80% of infant hematological malignancies and 10% of adult acute leukemias. Although certain I 1q23 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). Therefore, it is believed that FLT3 signally is involved in the development and maintenance of MLL (see Armstrong, et al., Cancer Cell (2003), 3:173-183). 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), 11:3449-3457). FLT3 has been shown to be a client protein of Hsp90, and 17AAG, a benzoquinone ansamycin antibiotic that inhibits the activity of Hsp90, has been shown to disrupt 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 17AAG (Yao, et al., Clinical Cancer Research (2003), 9:4483-4493). 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 (such as GIST) and central nervous system. In addition, c-Kit has been implicated in carcinogenesis of the female genital tract sarcomas of neuroectodermal origin and in Schwann cell C-\NRPonbl\DCC\REO4075614_1 DOC-111012012 -4 neoplasia associated with neurofibromatosis. (Yang et al., J Clin Invest. (2003), 112:1851-1861; Viskochil, JClin Invest. (2003), 112:1791-1793). c-Kit has been shown to be a client protein of Hsp90, and Hsp90 inhibitor 17AAG, a benzoquinon ansamycin, has been shown to induce apoptosis in Kasumi-l cells, an acute myeloid leukemia cell line that harbors a mutation in c-kit. In addition, benzoquinone ansamycins have shown evidence of therapeutic activity in clinical trials for a number of cancers. Epidermal Growth Factor Receptor (EGFR) is a member of the type I 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 a (TGFa), 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 P13 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, el al., Crit. Rev. Oncol. Hematol. (1995);19:183-232). 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), 19:221-8; Veale, et al., Br. J. Cancer (1993); 68:162-5). 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 C:\NRPornbl\DCC\REC4075614_I DOC-1/10/2012 -5 down-regulated after 15 minutes, where as mutant EGFR was internalized more slowly and continued to be activated for up to three hours (Lynch, et al., The New England Journal of Medicine (2006), 350:2129-2139). 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 TGFc and has constitutive, ligand-independent tyrosine kinase activity. Hsp90 co-purifies with EGFRvIlI indicating that Hsp90 complexes with EGFRvIll. Moreover, Hsp90 inhibitor geldanamycin, a benzoquinone ansamycin antibiotic, was able to decrease the expression of EGFRvIII indicating that interaction with Hsp90 is essential to maintain high expression levels of EGFRvIII (Lavictoire, et al., Journal of Biological Chemistry (2003), 278(7):5292-5299). The Raf family of proto-oncogenes (A-raf, B-raf and C-raf) was first identified when C-raf 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 non-Hodgkins lymphoma and has been reported in glioma, saroma, breast cancer, cholangiocarcinoma, and liver cancer. Most mutations in B-raf that C:\NRPonbDCC\RECW)75614_ .DOC-/101211 -6 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, et al., 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 TI 799A. 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 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): 10686-1069 1). BCR-ABL is an oncoprotein 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 C:\NRPorbl\DCC\REC4M075614_1 DOC-1/10/2012 -7 proteins, p 2 30 Bcr-Abl, p210 Bcr-Abl, and p190 Bcr-Abl which have unregulated tyrosine kinase activity. The p210 Bcr-Ab fusion protein is most often associated with CML, while the p190 Bcr Abi 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-Abl-positive leukemias. For example, agents such as As 2
O
3 which lower Bcr-Abl expression have been shown to be highly effective against Bcr-AbI leukemias. In addition, inhibition of Bcr-AbI tyrosine kinase activity by Imatinib (also known as ST1571 and Gleevec) 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 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 that cause it to be resistence to Imatinib. (See Nimmanapalli, et al., Cancer Research (2001), 61:1799-1804; and Gorre, et al., Blood (2002), 100:3041-3044). 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. NPM-ALK is another fusion protein that has been associated with the genesis and progression of certain types of cancers such as anaplastic large-cell lymphoma (ALCL). ALCL is a type of non-Hodgkin's lymphoma characterized by the expression of CD30/Ki-I 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/Ki-l 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 an oncogenetic fusion protein NPM-ALK which has 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 C \NRPorbl\DCC\REC4075614_1 DOC-1/10/2012 -8 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, et al., Exp. Hematology (2006), 34(12):1670-1679; Bonvini, et al., Cancer Research (2002), 62:1559-1566). 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, including FLT3, EGFR, c-Kit, and B-raf associated cancers and cancers that express Bcr-Abl or NPM-ALK fusion protein. The present invention also provides pharmaceutical compositions for treating FLT3, EGFR, c-Kit, and B-raf associated cancers and cancers that express Bcr-Abl or NPM-ALK fusion protein. In one embodiment, the present invention provides compounds having the formula (1): R5 A N R R3 (1) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. In formula (I), ring A 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 3
;
C:\NRPonb\DCCREC'4075614I1 DOC-1/10/2012 -9
R
, is -OH, -SH, -NR 7 H, -OR 26 , -SR 2 6 , -NHR 26 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -OC(O)NRioR 1 , -SC(O)NRioR,
-NR
7 C(O)NRioR 1 , -OC(O)R 7 , -SC(O)R 7 , -NR 7
C(O)R
7 , -OC(O)OR 7 , -SC(O)OR 7 , -NRC(O)OR,, -OCH 2
C(O)R
7 , -SCH 2 C(O)R7, -NR 7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRioR 11 , -SCH 2 C(O)NRoR,
-NR
7
CH
2 C(O)NRioR 1 , -OS(O),R 7 , -SS(O),R 7 , -S(O),OR 7 , -NR 7
S(O),R
7 , -OS(O)pNRioR, -SS(O),NRioR 11 , -NR 7 S(O),NRioR 1 , -OS(O)pOR 7 , -SS(O),OR 7 , -NR 7 S(O)pOR 7 , -OC(S)R 7 ,
-SC(S)R
7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR 1 , -SC(S)NRioR 11 , -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 ,
-SC(NR
8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR)NRioR 1 , -SC(NR 8 )NRioR 1 , -NR 7 C(NR)NRioR, OP(O)(OR7) 2 , or -SP(O)(OR 7
)
2 ;
R
3 is -OH, -SH, -NR 7 H, -OR 2 6 , -SR 2 6 , -NHR 26 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -OC(O)NRioR 1 , -SC(O)NRioR 1 ,
-NR
7 C(O)NRioR, 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 , -SCH 2
C(O)R
7 , -NR 7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRioR 1 , -SCH 2 C(O)NRioR 1 1 , -N R 7
CH
2 C(O)N R 0 oR, -OS(O),R 7 , -SS(O),R 7 , -S(O),OR 7 , -N R 7
S(O),R
7 , -OS(O),NR 0 oR, SS(O),N RoR, 1 , -NR 7
S(O),NR
0 oR 1 , -OS(O),OR 7 , -SS(O),OR 7 , -NR 7 S(O)pOR 7 , -NR 7
S(O),R
7 , OS(O),NRjoR 1 , -SS(O),NRjoR 11 , -NR 7 S(O),NRioR 11 , -OS(O),OR 7 , -SS(O),OR 7 , NR 7
S(O),OR
7 , -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR 1 , -SC(S)NRoR 1 , -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR8)OR 7 , -SC(NR 8
)OR
7 , -NR 7 C(NR8)OR 7 , -OC(NR)NRioR 1 , -SC(NR 8 )NRioR 11 , N R 7 C(N R 8 )NRoR, -C(O)OH, -C(O)N H R 8 , -C(O)SH, -S(O)OH, -S(O) 2 0H, -S(O)N H R 8 ,
-S(O)
2
NHR
8
,-OP(O)(OR
7
)
2 , or -SP(O)(OR) 2 ;
R
5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14 membered aryl;
R
7 and R 8 , 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 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 C\NRPorbl\DCCRE\U)7M,14_ DOC 1110/2012 -10 optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or RIO and R, 1 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R
2 6 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4. In one embodiment, ring A of the the compounds of formula (I) is not a substituted [1,2,3]triazole, and/or compounds represented by formula (I) do not include 3-(2,4-dihydroxy phenyl)-4-(7-naphthalen- I -yi)-5-mercapto-triazole. The present invention also provides compounds having the formula (11): R2 A N R1 N-N
R
3 (11) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. In formula (II), ring A, R 1 , and R 3 are defined as for formula (I); and
R
2 is a substituted phenyl, wherein the phenyl group is substituted with: i) one substituent selected from nitro, cyano, a haloalkoxy, 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, hydroxylalkyl, alkoxyalkyl, guanadino, -NRIOR 1 , -O-R 20 , -C(O)R 7 , -C(O)OR 20 , -OC(O)R 7 , C(O)NRioRI 1 , -NR 8
C(O)R
7 , -SR7, -S(O),R 7 , -OS(O)pR 7 , -S(O)pOR 7 , NR 8 S(O)pR 7 , or -S(O),NRioR 1 , or ii) two to five substituents 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 CNNRPorb1\DCC\REC\4(756141 DOC-1/102012 - 11 substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, -F, -Br, -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRIOR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , OC(O)R 7 , -C(O)NRioR 1 , -NR 8 C(O)R7, -SR 7 , -S(O),R 7 , -OS(O),R 7 ,
-S(O),OR
7 , -NR 8
S(O),R
7 , or -S(O),NRioR 1 ; and R20, 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, or an optionally substituted heteraralkyl. In one embodiment, compounds represented by formula (II) do not include 3-(2,4 dihydroxy-phenyl)-4-(7-naphthalen- I -yl)-5-mercapto-triazole, 3-(2,4-dihydroxyphenyl)-4-(2,5 dimethoxyphenyl)-5-mercapto-triazole, 3-( I-phenyl-5-amino-pyrazol-4-yl)-4-(2,4-dichloropheny) 5-mercapto-triazole, or 3-(2-hydroxy-phenyl)4-(2,4-dimethylphenyl)-5-mercapto-triazole. The present invention also provides compounds having the formula (Ill): RIB A N R1 N-N
R
3 (IlI) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. In formula (Ill), ring A, R 1 , and R 3 are defined as for formula (1); and
R
18 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRIOR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NRIOR 1 ,
-NR
8
C(O)R
7 , -SR 7 , -S(O)pR 7 , -OS(O)pR 7 , -S(O), 0
R
7 , -NR 8 S(O)pR 7 , or -S(O),NRioRII; In one embodiment, compounds represented by formula (Ill) do not include compounds in which R 18 is not cyclohexyl.
C-\NRPorthlDCOREC417614_ I DOC-1/10/20 12 - 12 The invention also provides compounds represented by formula (IV) or formula (V): R22 R23 R244 X4N R21 R24 X14 X14R2 RR1 NN R*3 R1N R Z2N-N R22
N-
R3 R (IV) (V) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. In formulas (IV) and (V), R, and R 3 are defined as for formula (1); and
X
14 is 0, S, or NR 7 ;
R
21 is 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
22 , for each occurrence, is independently a substituent 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, or an optionally substituted heteraralkyl, a haloalkyl, -C(O)R 7 ,
-C(O)OR
7 , -OC(O)R 7 , -C(O)NRoR 1 , -NR 8
C(O)R
7 , -S(O)pR 7 , -S(O)p0R 7 , or -S(O)pNRIoR 1 ; and
R
23 and R 2 4 , for each occurrence, are independently a substituent 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, or an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRIORII, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NRioR 1 , -NR 8
C(O)R
7 , -SR 7 , -S(O)pR 7 , -OS(O),R 7 , -S(O),OR 7 , -NR 8
S(O),R
7 , or -S(O),NRioR 1
.
C \NRPonb\DCC\REC\4075614_ LDOC-1/10/2012 - 13 In one embodiment, the present invention is an Hsp90 inhibitor represented by structural formula (VI): R5 A ZR HN-N R3 (VI) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In formula (V I): ring A 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 3 ; Ri is -OH, -SH, -NR 7 H, -0R 26 , -SR 2 6 , -NHR 26 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -OC(O)NRioR 11 , -SC(O)NRioR,
-NR
7
C(O)NR
1 oR 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
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRioR 11 , -SCH 2 C(O)NRioR 1 ,
-NR
7
CH
2 C(O)NRioR 11 , -OS(O),R 7 , -SS(O),R 7 , -S(O),OR 7 , -NIR 7 S(O)pR , -OS(O),NRioR 1 , -SS(O),NRioR, 1 , -NR 1 S(O),NRioR 1 , -OS(O),OR 7 , -SS(O),OR 7 , -NR 7 S(O)pOR7, -OC(S)R 7 ,
-SC(S)R
7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR 1 , -SC(S)NRioR 11 , -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 ,
-SC(NR
8
)OR
7 , -NR 7 C(NRs)OR 7 , -OC(NRs)NRioR 1 , -SC(NR 8 )NRioR 1 , -NR 7
C(NR
8 )NRioR 1 , OP(O)(OR 7
)
2 , or -SP(O)(OR 7
)
2 ;
R
3 is -OH, -SH, -NR 7 H, -0R 26 , -SR 26 , -NHR 2 6 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -OC(O)NRioR 1 , -SC(O)NRioR 1 ,
-NR
7 C(O)NRioR 1 , -OC(O)R 7 , -SC(O)R 7 , -NR7C(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
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRIORII, -SCH 2 C(O)NRioR,
-NR
7 CH2C(O)NR oR, -OS(O)pR 7 , -SS(O),R7, -S(O)pOR 7 , -NR 7 S(O)pR,, -OS(O),NRioR, -SS(O),NRioR 11 , -NR 7 S(O)pNR oR 11 , -OS(O),OR 7 , -SS(O),OR 7 , -NR 7 S(O)pOR 7 , -OC(S)R 7 ,
-SC(S)R
7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR 1 , -SC(S)NRioR 11 , -NR 7 C(S)NRIORII, -OC(NRs)R 7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8 )R7, -OC(NR 8
)OR
7 ,
-SC(NR
8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR)NRioR 1 , -SC(NR 8 )NRIORII, -NR 7 C(NR)NRIORII, - C:\NRPonbl\DCC\REC4O75614_1.DOC-1/10/2I)12 - 14 C(O)OH, -C(O)NHR 8 , -C(O)SH, -S(O)OH, -S(O) 2 0H, -S(O)NHR 8 , -S(O) 2
NHR
8 , OP(O)(OR 7
)
2 , or -SP(O)(OR 7
)
2 ;
R
5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R
7 and R 8 , 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 RI 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; or Rio and R 1 , 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; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4. In another embodiment of the present invention, the Hsp90 inhibitor is represented by structural formula (V II): R2' ? HN-N R3 (VII). In formual (VII), R 2 ' is an optionally substituted phenyl group. Preferably, R 2 ' is substituted with one or more group represented by R 30 , wherein R 30 , 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 heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NRIOR 1 , -OR 7 , -C(O)R 7
,
C :NRPonbl\DCCREC\4075614_1 DOC. 1/10/2012 - 15
-C(O)OR
7 , -C(S)R 7 , -C(O)SR 7 , -C(S)SR 7 , -C(S)OR 7 , -C(S)NR 0 oR I, -C(NR 8
)OR
7 , -C(NR 8
)R
7 ,
-C(NR
8
)NR
0 oR I, -C(NR 8
)SR
7 , -OC(O)R 7 , -OC(O)OR 7 , -OC(S)OR 7 , -OC(NR 8
)OR
7 , -SC(O)R 7 ,
-SC(O)OR
7 , -SC(NR 8
)OR
7 , -OC(S)R 7 , -SC(S)R 7 , -SC(S)OR 7 , -OC(O)N R 1 oR, -OC(S)NRioR 1 , -OC(NRs)NR 0 oR 1 , -SC(O)NR, 0 oR 1 , -SC(N R 8 )N R 1 oR 1 , -SC(S)N RoR, 1 , -OC(NR 8
)R
7 , -SC(NR8)R 7 , -C(O)N R 1 ioR 1 , -NR 8
C(O)R
7 , -N R 7
C(S)R
7 , -NR 7
C(S)OR
7 , -NR 7
C(NR
8
)R
7 , -NR 7
C(O)OR
7 ,
-NR
7
C(NR
8
)OR
7 , -NR 7
C(O)NR
0 oR, -NR 7 C(S)NRioR, -N R 7 C(N R 8
)NR
1 oR 1 , -SR7, -S(O),R7, -OS(O),R7, -OS(O)pOR7, -OS(O)pNRioR 1 , -S(O)pOR7, -N R 8 S(O)pR7, -N R7S(O)pNR 0 oR 1 , -N R7S(O)pOR7, -S(O)pNRoR 1 , -SS(O)pR7, -SS(O)pOR7, -SS(O)pNR oR 1 , -OP(O)(OR7) 2 , or -SP(O)(OR7) 2 . The remainder of the variables in structural formula (VII) have values defined above with reference to structural formula (VI). In another embodiment of the present invention, the Hsp90 inhibitor is represented by structural formula (VIll): R18 A R HN-N R3 (V IIf). In formula (VIII), R 18 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRIORII, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NRioR 1 , -NR 8 C(O)R7, -SR7, -S(O)pR7, -OS(O)pR7, -S(O),OR7, -NRsS(O),R7, or -S(O)pNRIoR 1 . The remainder of the variables in structural formula (VIll) have values defined above with reference to structural formula (VI).
C:\NRPortbt\DCC\REC\4075614_I DOC-1110f2012 - 16 In one embodiment, the present invention is an Hsp90 inhibitor represented by structural formula (IX):
R
5 A R1 N R3 (IX) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In formula (IX): ring A 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 3 ; R, is -OH, -SH, -NR 7 H, -OR 26 , -SR 26 , -NHR 2 6 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -OC(O)NRIORII, -SC(O)NRIORII,
-NR
7 C(O)NRioR 1 , -OC(O)R 7 , -SC(O)R 7 , -NR7C(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
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRioR 11 , -SCH 2 C(O)NRioR,
-NR
7
CH
2 C(O)NRjoRjj, -OS(O)pR 7 , -SS(O),R 7 , -S(O)pOR 7 , -NR 7
S(O),R
7 , -OS(O),NRioR, 1 1 -SS(O)pNRioR 1 , -NR 7 S(O),NRioR 1 , -OS(O),OR 7 , -SS(O)pOR7, -NR 7
S(O),OR
7 , -OC(S)R 7 ,
-SC(S)R
7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR, -SC(S)NRIORII, -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 , -SC(NRs)OR 7 , -NR 7
C(NR
8
)OR
7 , -OC(NR 8 )NRioR 11 , -SC(NR 8 )NRioR 1 , -NR 7 C(NR)NRioR, OP(O)(OR) 2 , or -SP(O)(OR 7
)
2 ;
R
3 is -OH, -SH, -NR 7 H, -OR 2 6 , -SR 26 , -NHR 2 6 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -OC(O)NRioR 11 , -SC(O)NRjoR 1 ,
-NR
7 C(O)NRioR 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 , -SCH 2
C(O)R
7 , -NR 7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRioR 1 , -SCH 2 C(O)NRioR,
-NR
7
CH
2 C(O)NRjoR 1 , -OS(O),R 7 , -SS(O)pR 7 , -S(O)pOR 7 , -NR 7 S(O)pR 7 , -OS(O),NRioR 1 , -SS(O)pNRioR , -NR 7 S(O)pNRioR 11 , -OS(O),OR 7 , -SS(O),OR 7 , -NR 7
S(O),OR
7 , -OC(S)R 7 ,
-SC(S)R
7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR7C(S)OR 7 , -OC(S)NRioR 1 , -SC(S)NRioR 11 , -NR 7 C(S)NRioR 11 , -OC(NR 8
)R
7 , -SC(NRs)R 7 , -NR 7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 ,
-SC(NR
8
)OR
7 , -NR 7 C(N R 8
)OR
7 , -OC(NR 8 )NRioR 1 , -SC(NR 8 )NRioR 1 , -NR 7
C(NR
8 )NRioR, - C\NRPorb\DCC\REC\4075614.1 DOC-1/10/2012 - 17 C(O)OH, -C(O)NHR 8 , -C(O)SH, -S(O)OH, -S(0) 2 0H, -S(O)NHR 8 , -S(O) 2
NHR
8 , OP(O)(OR) 2 , or -SP(O)(OR) 2 ;
R
5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14-membered aryl;
R
7 and R 8 , 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
10 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; or Rio and R, 1 , 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, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4. In another embodiment of the present invention, the Hsp90 inhibitor is represented by structural formula (X): R2' AR1 N R3 (X). In formual (X), R 2 ' is an optionally substituted phenyl group. Preferably, R2' is substituted with one or more group represented by R 30 , wherein R 30 , for each occurrence, are 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 heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NRIOR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -C(S)R 7
,
C:\NRPortb\DCC\REC407564_1DOC.1/10/2012 - 18
-C(O)SR
7 , -C(S)SR 7 , -C(S)OR 7 , -C(S)N R 1 oR 1 , -C(N R 8
)OR
7 , -C(N R 8
)R
7 , -C(NR 8 )NRioR 1 , -C(NR8)SR 7 , -OC(O)R 7 , -OC(O)OR 7 , -OC(S)OR 7 , -OC(NR 8
)OR
7 , -SC(O)R 7 , -SC(O)OR 7 , -SC(N R 8
)OR
7 , -OC(S)R 7 , -SC(S)R 7 , -SC(S)OR 7 , -OC(O)N R 1 oR I, -OC(S)NRioR, 1 , -OC(NR)NRioR 1 , -SC(O)NRioR 1, -SC(NR)NRioR 1 , -SC(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -C(O)N RoR 1 , -N R 8
C(O)R
7 , -NR 7
C(S)R
7 , -NR 7
C(S)OR
7 , -NR 7 C(N R 8
)R
7 , -N R 7
C(O)OR
7 , -N R 7 C(N R 8
)OR
7 , -NR 7 C(O)N R oR 1 , -N R 7 C(S)N R 1 oR 1 , -NR 7 C(N R 8 )NRoR 1 , -SR 7 , -S(O),R 7 ,
-OS(O),R
7 , -OS(O)pOR 7 , -OS(O),N RoR, 1 , -S(O)pOR 7 , -N R 8
S(O),R
7 , -N R 7 S(O)pN RioR 1 , -N R7S(O)pOR 7 , -S(O),NR oR 1 , -SS(O),R 7 , -SS(O),OR 7 , -SS(O),NR oR 1 , -OP(O)(OR) 2 , or
-SP(O)(OR
7
)
2 . The remainder of the variables in structural formula (X) have values defined above with reference to structural formula (IX). In another embodiment of the present invention, the Hsp90 inhibitor is represented by structural formula (XI):
R
1 8 A R1 N
R
3 (X1). In formula (XI), R1 8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRIOR 11 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NRIORII, -NR 8
C(O)R
7 , -SR 7 , -S(O),R 7 , -OS(O)pR 7 , -S(O),OR 7 , -NR 8
S(O),R
7 , or -S(O),NRioR 1 . The remainder of the variables in structural formula (XI) have values defined above with reference to structural formula (IX). In another embodiment, the present invention is a method of inhibiting Hsp90 in a mammal in need of such treatment. The method comprises administering to the mammal an effective amount of an Hsp90 inhibitor disclosed herein.
C \NRPor1blDCC\REC\)756I14_1 DOC-1/10/2012 - 19 In another embodiment, the present invention is a method of inhibiting Hsp90 in a cell. The method comprises administering to the cell an effective amount of an Hsp90 inhibitor disclosed herein. In another embodiment, the present invention is a method of treating a proliferative disorder in a mammal comprising administering an effective amount of an Hsp90 inhibitor disclosed herein. In another embodiment, the present invention is a method of treating cancer in a mammal. The method comprises administering to the mammal an effective amount of an Hsp90 inhibitor disclosed herein. In another embodiment, the present invention is a method of inducing degradation of a FLT3 kinase in a subject. The method comprises administering to the subject an effective amount of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In another embodiment, the present invention is a method of treating a FLT3 associated cancer in a subject. The method comprises administering to the subject an effective amount of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In another embodiment, the present invention is a method of treating a FLT3 associated cancer in a subject, wherein FLT3 has developed a resistance to a tyrosine kinase inhibitor, such as Sunitinib (also called SUI 1248). The method comprises administering to the subject an effective amount of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In another embodiment of the present invention is directed to a pharmaceutical composition comprising a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, and a pharmaceutically acceptable carrier. The pharmaceutical compositions can be used in therapy, e.g., to inhibit Hsp90 activity in a mammal in need of such inhibition, to treat a mammal with a proliferative disorder, or to treat a mammal with cancer, including a FLT3 associated cancer or a FLT3 associated cancer, wherein FLT3 has developed a resistance to a tyrosine kinase inhibitor, such as Sunitinib. In another embodiment of the present invention is the use of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof for the C \NRPortbl\DCC\RECM475614_1 DOC-1/10/2012 - 20 manufacture of a medicament for inhibiting Hsp90 in a mammal in need of such inhibition or for treating a mammal with cancer, including a FLT3 associated cancer or a FLT3 associated cancer, wherein FLT3 has developed a resistance to a tyrosine kinase inhibitor, such as Sunitinib. In another embodiment, the present invention is a method of inducing degradation of a c-kit kinase in a subject. The method comprises administering to the subject an effective amount of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In another embodiment, the present invention is a method of treating a c-kit associated cancer in a subject. The method comprises administering to the subject an effective amount of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In another embodiment, the present invention is a method of treating a c-kit associated cancer in a subject, wherein c-kit has developed a resistance to inhibition by a tyrosine kinase inhibitor, such as Gleevec. The method comprises administering to the subject an effective amount of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In another embodiment of the present invention is directed to a pharmaceutical composition comprising a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, and a pharmaceutically acceptable carrier. The pharmaceutical compositions can be used in therapy, e.g., to inhibit Hsp90 activity in a mammal in need of such inhibition, to treat a mammal with a proliferative disorder, or to treat a mammal with cancer, including a c-kit associated cancer or a c-kit associated cancer, wherein c-kit has developed a resistance to inhibition by a tyrosine kinase inhibitor, such as Gleevec. In another embodiment of the present invention is the use of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof for the manufacture of a medicament for inhibiting Hsp90 in a mammal in need of such inhibition or for treating a mammal with cancer, including a c-kit associated cancer or a c-kit associated cancer, wherein c-kit has developed a resistance to inhibition by a tyrosine kinase inhibitor, such as Gleevec.
CANRPortbl\DCC\REC\4,5614_I DOC-1/10/2012 -21 In another embodiment, the present invention is a method of inducing degradation of EGFR in a subject. The method comprises administering to the subject an effective amount of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In another embodiment, the present invention is a method of treating an EGFR associated cancer in a subject. The method comprises administering to the subject an effective amount of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In another embodiment, the present invention is a method of treating an EGFR associated cancer in a subject, wherein the EGFR has developed a resistance to inhibition with a tyrosine kinase inhibitor, such as Gefitinib. The method comprises administering to the subject an effective amount of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In another embodiment of the present invention is directed to a pharmaceutical composition comprising a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, and a pharmaceutically acceptable carrier. The pharmaceutical compositions can be used in therapy, e.g., to inhibit Hsp90 activity in a mammal in need of such inhibition, to treat a mammal with a proliferative disorder, or to treat a mammal with cancer, including an EGFR associated cancer or an EGFR associated cancer, wherein the EGFR has developed a resistance to inhibition with a tyrosine kinase inhibitor, such as Gefitinib. In another embodiment of the present invention is the use of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof for the manufacture of a medicament for inhibiting Hsp90 in a mammal in need of such inhibition or for treating a mammal with cancer, including an EGFR associated cancer or an EGFR associated cancer, wherein the EGFR has developed a resistance to inhibition with a tyrosine kinase inhibitor, such as Gefitinib. In another embodiment, the present invention is a method of inducing degradation of B-raf in a subject. The method comprises administering to the subject an effective amount of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof.
C \NRPorbl\DCCREC4075614_IDOC./1012012 - 22 In another embodiment, the present invention is a method of treating a B-raf associated cancer in a subject. The method comprises administering to the subject an effective amount of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In another embodiment, the present invention is a method of treating a B-raf associated cancer in a subject, wherein B-raf has developed a resistance to inhibition with a kinase inhibitor, such as Sorafenib. The method comprises administering to the subject an effective amount of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In another embodiment of the present invention is directed to a pharmaceutical composition comprising a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, and a pharmaceutically acceptable carrier. The pharmaceutical compositions can be used in therapy, e.g., to inhibit Hsp90 activity in a mammal in need of such inhibition, to treat a mammal with a proliferative disorder, or to treat a mammal with cancer, including a B-raf associated cancer or a B-raf associated cancer, wherein B-raf has developed a resistance to inhibition with a kinase inhibitor, such as Sorafenib. In another embodiment of the present invention is the use of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof for the manufacture of a medicament for inhibiting Hsp90 in a mammal in need of such inhibition or for treating a mammal with cancer, including a B-raf associated cancer or a B-raf associated cancer, wherein B-raf has developed a resistance to inhibition with a tyrosine kinase inhibitor, such as Sorafenib. In another embodiment, the present invention is a method of inducing degradation of a Bcr AbI protein in a subject. The method comprises administering to the subject an effective amount of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In another embodiment, the present invention is a method of treating a cancer that expresses a Bcr-Abl fusion protein in a subject. The method comprises administering to the subject an effective amount of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof.
C:\NRPotbl\DCCOREC\4075614_ .DOC-111201I2 -23 In another embodiment, the present invention is a method of treating a cancer that expresses a Bcr-Abl fusion protein in a subject, wherein the Bcr-AbI fusion protein has developed a resistance to inhibition with a tyrosine kinase inhibitor that inhibits Bcr-Abl, such as Gleevec. The method comprises administering to the subject an effective amount of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In another embodiment of the present invention is directed to a pharmaceutical composition comprising a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, and a pharmaceutically acceptable carrier. The pharmaceutical compositions can be used in therapy, e.g., to inhibit Hsp90 activity in a mammal in need of such inhibition, to treat a mammal with a proliferative disorder, or to treat a mammal with cancer, including a cancer that expresses Bcr-Abl fusion protein or a cancer that expresses Bcr-AbI fusion protein that has become resistant to inhibition with a tyrosine kinase inhibitor that inhibits Bcr-Abl, such as Gleevec. In another embodiment of the present invention is the use of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof for the manufacture of a medicament for inhibiting Hsp90 in a mammal in need of such inhibition or for treating a mammal with cancer, including a cancer that expresses Bcr-AbI fusion protein or a cancer that expresses Bcr-Abl fusion protein that has become resistant to inhibition with a tyrosine kinase inhibitor that inhibits Bcr-Abl, such as Gleevec. In another embodiment, the present invention is a method of inducing degradation of an NPM-ALK fusion protein in a subject. The method comprises administering to the subject an effective amount of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In another embodiment, the present invention is a method of treating a cancer that expresses an NPM-ALK fusion protein in a subject. The method comprises administering to the subject an effective amount of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In another embodiment, the present invention is a method of treating a cancer that expresses an NPM-ALK fusion protein in a subject, wherein the NPM-ALK fusion protein has developed a resistance to inhibition with a tyrosine kinase inhibitor. The method comprises administering to the C:\NRPonbtDCMREC4075614_l.DOC-1/10/2012 - 24 subject an effective amount of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof. In another embodiment of the present invention is directed to a pharmaceutical composition comprising a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof, and a pharmaceutically acceptable carrier. The pharmaceutical compositions can be used in therapy, e.g., to inhibit Hsp90 activity in a mammal in need of such inhibition, to treat a mammal with a proliferative disorder, or to treat a mammal with cancer, including a cancer that expresses an NPM-ALK fusion protein or a cancer that expresses an NPM-ALK fusion protein that has become resistant to inhibition with a tyrosine kinase inhibitor. In another embodiment of the present invention is the use of a compound of the invention, or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof for the manufacture of a medicament for inhibiting Hsp90 in a mammal in need of such inhibition or for treating a mammal with cancer, including a cancer that expresses an NPM-ALK fusion protein or a cancer that expresses an NPM-ALK fusion protein that has become resistant to inhibition with a tyrosine kinase inhibitor. The compounds shown in Tables 5, 6, and 7, 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 cause the degradation of Hsp90 client proteins, such as Bcr-Abl, FLT3, EGFR, c-Kit, B-raf, and NPM-ALK. 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 5, 6, or 7, 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, in particular cancers associated with abberant activity of FLT3, EGFR, c Kit, or B-raf, or cancers which express oncoproteins such as Bcr-Abl or NPM-ALK. 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 C\.NRPonbIDCOCREC407%14_I DOC-1/10/2012 -25 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. Moreover, treatment of cancers with kinase inhibitors, such as Gleevec, has been shown to be initially highly successful but ultimately fails in most cases because the inhibited kinase develops one or more mutation that makes it resistant to the kinase inhibitor. Therefore, treatment of cancers 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 cancer, and less likely to result in the development of more aggressive multidrug resistant cancers than other currently available therapies. In one aspect the present invention provides a method of treating an FLT3, c-kit, B-raf, Bcr-AbI fusion protein, or NPM-ALK fusion protein associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (1): R5 A N-N
R
3 (I) or a tautomer, or a pharmaceutically acceptable salt thereof, wherein ring A 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 3 ; R, is -OH, -SH, -NR 7 H, -0R 26 , -SR2 6 , -NHR 26 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -OC(O)NRoR 11 , -SC(O)NRioR,
-NR
7 C(O)NRioR 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 , -SCH 2
C(O)R
7 , -NR 7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRioR 11 , -SCH 2
C(O)NR
0 oR 1 , NR 7
CH
2 C(O)NRioR 1 , -OS(O)pR 7 , -SS(O),R 7 , -S(O),OR 7 , -NR 7 S(O)pR 7 , -OS(O),NR 1 oR 11 , -SS(O),NRioR 11 , -NR 7 S(O),NRioRa, -OS(O),OR 7 , -SS(O)pOR 7 , -NR 7 S(O)pOR 7 , -OC(S)R 7 ,
-SC(S)R
7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR 1 , -SC(S)NRioR 11 , -NR 7 C(S)NRioR 11 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR 8
)OR
7
,
C-NRPotbI\DCC\REC\4075614I_ DOC./10/20 12 - 26 -SC(NR 8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NRg)NRioR 1 , -SC(NR)NRioR 1 , -NR 7 C(NR)NRIoR 1 , OP(O)(OR7) 2 , or -SP(O)(OR) 2 ;
R
3 is -0H, -SH, -NR 7 H, -OR 26 , -SR 2 6 , -NHR 2 6 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -OC(O)NRIoR 1 , -SC(O)NRioR 1 ,
-NR
7 C(O)NRioR 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 , -SCH 2
C(O)R
7 , -NR 7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(0)NRioR 11 , -SCH 2 C(O)NRIoR 1 , NR 7
CH
2 C(O)NRioR 1 , -OS(O),R 7 , -SS(O),R 7 , -S(O),OR 7 , -NR 7
S(O),R
7 , -OS(O)pNRIoR 1 , SS(O),N RIoR I, -N R 1 S(O)pNRioR 1 , -OS(O)pOR 7 , -SS(O)pOR 7 , -N R 7
S(O),OR
7 , -N R 7
S(O),R
7 , OS(O),NRIoR, -SS(O),NRIoR 1 , -NR 7 S(O),NRIORII, -OS(O),OR 7 , -SS(O),OR 7 , NR 7 S(O),OR7, -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRIoR 1 , -SC(S)NRIoR 1 , -NR 7 C(S)NRioR,
-OC(NR
8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 , -SC(NRs)OR 7 ,
-NR
7
C(NR
8
)OR
7 , -OC(NR 8 )NRioR 1 , -SC(NR 8 )NRioR 11 , -NR 7
C(NR
8 )NRioR 11 , -C(O)OH, C(O)NHR 8 , -C(O)SH, -S(O)OH, -S(O) 2 0H, -S(O)NHR 8 ,
-S(O)
2
NHR
8 , -OP(O)(OR 7
)
2 , or -SP(O)(OR 7
)
2 ;
R
5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14 membered aryl;
R
7 and R 8 , 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 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; or RIO and RI , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R
2 6 is a lower alkyl; p, for each occurrence, is, independently, 0, I or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
CANRPonbl\DCkREC%40756| l DOC-1110f2012 -27 In one aspect the present invention provides a method of treating an FLT3, c-kit, B-raf, Bcr-Abl fusion protein, or NPM-ALK fusion protein associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (II): R2 A R, N--N
R
3 (II) or a tautomer, or a pharmaceutically acceptable salt thereof, wherein: ring A 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 3 ; R, is -OH, -SH, -NR 7 H, -OR 26 , -SR 26 , -NHR 2 6 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR7H, -OC(O)NRioR 1 , -SC(O)NRioR I,
-NR
7 C(O)NRioR 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 , -SCH 2
C(O)R
7 , -NR 7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRioR 1 , -SCH 2 C(O)NRIORII, NR 7
CH
2
C(O)NR
1 oR 11 , -OS(O),R 7 , -SS(O),R 7 , -S(O),OR 7 , -NR 7
S(O),R
7 , -OS(O),NRioR 11 ,
-SS(O),NR
1 oR 1 , -NR 7 S(O),NRioR, 1 , -OS(O),OR 7 , -SS(O),OR 7 , -NR 1
S(O),OR
7 , -OC(S)R 7 ,
-SC(S)R
7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioRo, -SC(S)NRioR 1 , -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NRs)OR 7 ,
-SC(NR
8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR)NRioR 1 , -SC(NR)NRioR 1 , -NR 7
C(NR
8 )NRioRI, OP(O)(OR7) 2 , or -SP(O)(OR 7
)
2 ;
R
3 is -OH, -SH, -NR 7 H, -OR 2 6 , -SR 26 , -NHR 26 , -O(CH 2 )mOH, -O(CH 2 ),mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -OC(O)NRioR 1 , -SC(O)NRioR 1 ,
-NR
7 C(O)NRioR 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 , -OCH2C(O)R 7 , -SCH 2 C(O)R7, -NR 7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -N R 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRioR 1 , -SCH 2 C(O)NRoR 1 , NR 7
CH
2
C(O)NR
0 oR 1 , -OS(O),R 7 , -SS(O),R 7 , -S(O),OR 7 , -NR 7
S(O),R
7 , -OS(O),NR 1 oR 11 , SS(O),N RIORII, -N R 7 S(O),N R oR 1 , -OS(O),OR 7 , -SS(O)pOR 7 , -N R 7
S(O),OR
7 , -N R 7
S(O),R
7 , OS(O),NR 1 oR 11 , -SS(O),NRoR 11 , -NR 7 S(O),NR oR 1 , -OS(O),OR 7 , -SS(O),OR7, NR 7
S(O),OR
7 , -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR 1 , -SC(S)NRioR 1 , -NR 7 C(S)NRioR 11 , -OC(NR 8 )R7, -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7
,
C:\NRPortbl\DCC\REC\407-61I DOC- I1120I12 - 28 -OC(NR 8
)OR
7 , -SC(NR 8
)OR
7 , -NR 7 C(NRs)OR 7 , -OC(NR 8 )NRioR 1 , -SC(NR 8 )NRioR 1 , NR 7
C(NR
8 )NRioR 1 , -C(O)OH, -C(O)NHR 8 , -C(O)SH, -S(O)OH, -S(0)20H, -S(O)NHR 8 , -S(0) 2 N HR 8
,-OP(O)(OR
7
)
2 , or -SP(O)(OR) 2 ;
R
2 is a substituted phenyl, wherein the phenyl group is substituted with: i) one substituent selected from nitro, cyano, a haloalkoxy, 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, hydroxylalkyl, alkoxyalkyl, guanadino, -NRioR 1 , -0-R 20 , -C(O)R 7 , -C(O)OR 20 , -OC(O)R 7 , C(O)NRioR 1 , -NRC(O)R 7 , -SR 7 , -S(O),R 7 , -OS(O),R 7 , -S(O),OR 7 , NR 8
S(O),R
7 , or -S(O)pNRIOR 1 , or ii) two to five substituents 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, -F, -Br, -1, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRIOR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , OC(O)R 7 , -C(O)NRIORII, -NR 8
C(O)R
7 , -SR 7 , -S(O),R 7 , -OS(O)pR 7 ,
-S(O),OR
7 , -NR 8
S(O),R
7 , or -S(O),NRIoR I; and
R
7 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 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; or RIO and R, 1 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; C \NtRPonb1\DCC\REC\4075614_1 DOC-1/1/2M 12 - 29 R 2 0 , 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, or an optionally substituted heteraralkyl; R26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4. In one aspect the present invention provides a method of treating an FLT3, c-kit, B-raf, Bcr-Abl fusion protein, or NPM-ALK fusion protein associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by formula (Ill):
R
1 8 A R1 N-N R3 (Ill) or a tautomer, or a pharmaceutically acceptable salt thereof, wherein: ring A 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 3 ; R, is -OH, -SH, -NR 7 H, -OR 26 , -SR 26 , -NHR 26 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mN R 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -OC(O)NRioR 11 , -SC(O)NRIOR 1 ,
-NR
7 C(O)NRioR 11 , -OC(O)R 7 , -SC(O)R7, -NR 7
C(O)R
7 , -OC(O)OR7, -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
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRoR 11 , -SCH 2 C(O)NRIORII, NR 7
CH
2
C(O)NRIOR
1 , -OS(O)pR 7 , -SS(O),R 7 , -S(O)pOR 7 , -NR 7
S(O),R
7 , -OS(O),NRIORII, -SS(O)pNRioR 11 , -NR 7 S(O)pNRioR, 1 , -OS(O)pOR 7 , -SS(O),OR 7 , -NR 7 S(O)pOR 7 , -OC(S)R 7 ,
-SC(S)R
7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)N R 1 oR 11 , -SC(S)NRoR 1 , -NR 7 C(S)NR oR , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NRs)OR 7 ,
-SC(NR
8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR)NRioR 1 , -SC(NR)NRioR 1 , -NR 7 C(NR)NRioR 1 , OP(O)(OR7) 2 , or -SP(O)(OR) 2 ;
R
3 is -OH, -SH, -NR 7 H, -OR 26 , -SR 2 6 , -NHR 26 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -OC(O)NRioR 1 , -SC(O)NRioR, C :NRPonbl\DCC\REC\4075614_1 DOC. 1(1/2012 -30 -NR7C(O)NRioR 1 , -OC(O)R 7 , -SC(O)R 7 , -NR 7
C(O)R
7 , -OC(O)OR 7 , -SC(O)OR 7 , -NR7C(O)OR 7 , -OCH 2
C(O)R
7 , -SCH 2
C(O)R
7 , -NR 7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRioR 1 , -SCH 2 C(O)NRioR 11 , NR 7
CH
2 C(O)NRoRI, -OS(O),R 7 , -SS(O),R 7 , -S(O)pOR 7 , -NR 7
S(O),R
7 , -OS(O),NRioR 1 , SS(O),N R 1 ioR, -N R 7 S(O)pN R,oR, -OS(O)pOR 7 , -SS(O),OR 7 , -NR 7
S(O),OR
7 , -N R 7
S(O),R
7 , OS(0),NRjoR 1 , -SS(O),NRjoR , -NR 7 S(O),NRioR 11 , -OS(O)pOR 7 , -SS(O),OR 7 , NR 7
S(O),OR
7 , -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR 1 , -SC(S)NRioR 11 , -NR 7 C(S)NRioR, 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 ,
-OC(NR
8
)OR
7 , -SC(NR8)OR 7 , -NR 7
C(NR
8
)OR
7 , -OC(NR 8 )NRoR 1 , -SC(NR 8 )NRioR 11 , NR 7 C(NR)NRioR 1 , -C(O)OH, -C(O)NHR 8 , -C(O)SH, -S(O)OH, -S(O) 2 0H, -S(O)NHR 8 ,
-S(O)
2 N H R 8
,-OP(O)(OR
7
)
2 , or -SP(O)(OR) 2 ;
R
7 and R 8 , 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 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; or RIO and R, 1 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R
1 8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRIORoI, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NRioRa,
-NR
8
C(O)R
7 , -SR 7 , -S(O)pR 7 ,
-OS(O),R
7 , -S(O)OR 7 , -NR 8
S(O),R
7 , or -S(O),NRIoRII;
R
26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
C \NRPonbl\DCCREC\4l75614_1 DOC-1/10/2012 -31 In one aspect the present invention provides a method of treating an FLT3, c-kit, B-raf, Bcr-Abl fusion protein, or NPM-ALK fusion protein associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by the following formula:
R
55 N RR52 HO / R 53 N / Z 1 OH N-N or a tautomer or pharmaceutically acceptable salt thereof, wherein:
X
45 is CRs 4 ; Zi is -OH or -SH;
R
52 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, -(CH 2
)
2 0CH 3 , -CH 2 C(O)OH, and -C(O)N(CH 3
)
2 ;
R
5 3 is -H, methyl, ethyl, or isopropyl;
R
54 is -H or a lower alkyl;
R
55 is selected from the group consisting of -H, -OH, -OCH 3 , and -OCH 2
CH
3 ; and
R
56 is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl.
Ic1 Ire ' er cwNRI'r1Nb DCV1C 1,5,I?!'_ Ldoc-: 1'21114 - 32 In one aspect the present invention provides a method of inducing degradation of F113. c kit. 13-raf. Bcr-AbI fusion protein, or NPM-ALK fitsion protein in a subject inl need thereof, comprising administering to the subject an effective amount of a compound represented by the following fom-iulIa:
R
55 /R52 N
R
5 3 HO X53 N N / Z , OH N-N or a lantomer and/or pharmaceutically acceptable salt thereof, wherein: Xl 5 is CR.
1 : /n is -OI or -SI 1;
R
5 - is selected from the group consisting of -1I, methyl, ethyl n-propyl, isopropy l, n-butylt n-pcntyl, n-hcxyl, -(CH2OC-Hs -CI-H2C(O)OHf, and -C(O)N(CI 1)2;
R
53 is -HI, methyl, ethyl. or isopropyl; R5, is -11 or a lower alkyl; R" is selected from the group consisting of -H. -OH, --OCH [-, and --OCI ,CI: I, and Rs is selected from the group consisting of -AI, methyl, ethyl, isopropyl. and cyclopropyl. In one aspect the present invention prove ides a method of treating a BRA F associated cancer or in a subject, comprising administering to the subject an effective amount of 3-(2,4 dihydroxy-5-isopropyl-phenyl)-4-(I -methyl-indol-5-yI)-5-hydroxy-I I,2,41triazole or a lautomer or plhamiiIaceuticaly )'acceptable salt thereof wherein the 13-raf associated cancer is a cancer having a 13-raf with an activating Mutation in the kinase domain. In one aspect the present invention provides a method of inducing degradation of BRA F in a subject in need thereof, comprising administering to the subject an effective amount of a compound represented by the following formula: ;hIC. '.[IIG~ ciNRi0 .DrCI] C R -Ifi1 I dI -1 100I -32A
R
55 /R52 N R56 R5 3 HO N OH N-N or a tautomer and/or phariaceutically acceptable salt thereof, wherein:
XQ
5 is CR.,; Zn is -0H or --SIH; Ru is selected from -H, methyl ethyl n-propyl, isopropyl, nbutyl, n-pentyl. n-hexyl. (CL),OC1, -CHl1C(0)0H, and -C(O)N(CH);; R5; is -Hl, methyl, ethyl, or isopropyl: R. is -11 or a lower alkyl; R" is selected from -H, -01, --OClH 3 , and --- OCIH 2 Cl3; and
R
5 is selected from -H, methyl ethyl, isopropyl, and cyclopropyl, and wherein the 13-raf associated cancer is a cancer having a 1-iaf with an activating mutation in the kinase donaiii. In one aspect the present invention provides use of 3-(2A-dihydroxy-5-isopropy-lpenyl ) 4-} 1 -imethl-indo l-5-yI)5-hydroxy-|I 2. 4triazole in the manuFacture of a nedicanen t for treating a 13RA F associated cancer wherein the B-ra associated cancer is a cancer having a B-a U ith an activating animation in the kinase domain. In one aspect the present invention provWs use of a compound represented by the following formula: R5 5 /R52 N HO NZ, H
N-N
- 3213 or a tautomer or pharmaceutical ly acceptable salt thereofl wherein: X1 5 is CR.I; %i is - Ol or -Sl: R5' is selected from -1, mii ethyl, ethyl. n-propyl, isopropyl, n-bulty, n-pentyl. nl-hexyl, (Cl ) OC! I. -CI C(O)OH, and -C(O)N(C 1-)2; RZ53 is -1H, methyl, ethyl, or isopropyl; Ru is -1 or a lower al kyl; R, is selected From -11, -011, - OC -, and --OC12CH; and R% is selected from -1-, methyl. ethyl. isopropyl, and cyclopropyl. in the manufacture of a medicament for inducing degradation of BRAF, and wherein the 13-i-af associated cancer is a cancer having a B-raf with an activating mi station in the kinase domain. In oiie aspect the present invention provides use of a compond represented by formula (1): R5 A R N N R3 (I) or a tautomer, or a pharmaceutically acceptable salt thereof, wherein ring A is an aryl or a heteroaryl, wherein the aryl or the heteroaryl are optionally further substituted with one or m1ore substitLients in addition to R; Ri is -01 . -SF1. -NR- 1. -O -SR, -NHR -O(CH2.O . -O(C m 11L, >i I ()(CH J.),N R 1, -S(C I.),,,Ol 1. -S(Cl 1,)mSi 1. -S(Cl 1,NRy -OC(O)NR mjzn, -SC(O)N R ,mR ,, C:\NRPorbl\DCCOREC\4075614_1 DOC-1/102012 - 33 -NR7C(O)NRioR 1 , -OC(O)R 7 , -SC(O)R 7 , -NR7C(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
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRIoR 1 , -SCH 2 C(O)NRioR 1 , NR 7
CH
2
C(O)NR
1 oR 11 , -OS(O),R7, -SS(O),R 7 , -S(O),OR 7 , -NR 7
S(O),R
7 , -OS(O),NRioR 1 , -SS(O),NRioR 1 , -NR 7 S(O),NRioR 1 , -OS(O),OR 7 , -SS(O),OR 7 , -NR7S(O),OR 7 , -OC(S)R 7 , -SC(S)R7, -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRIoR 1 , -SC(S)NRioR 1 , -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8 )R7, -NR 7
C(NR
8
)R
7 , -OC(NRs)OR 7 , -SC(NRs)OR 7 , -NR 7
C(NR
8 )OR7, -OC(NRg)NRioR 1 , -SC(NR)NRioR 1 , -NR 7
C(NR
8 )NRioR, 1 , OP(O)(OR7) 2 , or -SP(O)(OR) 2 ;
R
3 is -0H, -SH, -NR 7 H, -OR 26 , -SR 26 , -NHR 2 6 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -0C(O)NRIoR 11 , -SC(O)NRIoR 1 ,
-NR
7 C(O)NRioR 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
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRIoR 11 , -SCH 2 C(O)NRioR 1 , NR 7
CH
2 C(O)NRioR 1 , -OS(O),R 7 , -SS(O),R 7 , -S(O),OR 7 , -NR 7
S(O),R
7 , -OS(0),NRIoR 1 , SS(0),NRIoR I, -N R 7 S(O)pNR, 0 oR I, -OS(O)pOR 7 , -SS(O)pOR 7 , -NR 7
S(O),OR
7 , -N R 7 S(O)pR 7 , OS(O),NRIoR 1 , -SS(O),NRioR 11 , -NR 7
S(O),NRIORI
1 , -OS(O)pOR 7 , -SS(O),OR 7 , NR 7
S(O),OR
7 , -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioRII, -SC(S)NRIoR 1 , -NR 7 C(S)NRIORII,
-OC(NR
8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 , -SC(NR 8
)OR
7 ,
-NR
7
C(NR
8
)OR
7 , -OC(NR)NRIORII, -SC(NR)NRIORII, -NR 7 C(NR)NRioR, -C(O)OH, C(O)NHR 8 , -C(O)SH, -S(O)OH, -S(O) 2 0H, -S(O)NHR 8 ,
-S(O)
2 N H R8, -OP(O)(OR 7
)
2 , or -SP(O)(OR) 2 ;
R
5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14 membered aryl;
R
7 and R 8 , 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 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 C:\NRPonbl\DCC\REC\4075614_J.DOC-If10/2012 -34 an optionally substituted heteraralkyl; or R 1 0 -and RI, 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; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4, in the manufacture of a medicament for treating an FLT3, c-kit, B-raf, Bcr-Abl fusion protein, or NPM-ALK fusion protein associated cancer. In one aspect the present invention provides use of a compound represented by formula (II): R2 A NR1 q?--- -- N
R
3 (II) or a tautomer, or a pharmaceutically acceptable salt thereof, wherein: ring A 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 3 ; R, is -OH, -SH, -NR 7 H, -OR 2 6 , -SR 26 , -NHR 2 6 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -OC(O)NRoR 1 , -SC(O)NRioR 1 ,
-NR
7 C(O)NRioR 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 , -SCH 2
C(O)R
7 , -NR 7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRIORII, -SCH 2 C(O)NRIORII, NR 7
CH
2 C(O)NRioR 11 , -OS(O),R 7 , -SS(O),R 7 , -S(O),OR 7 , -NR 7
S(O),R
7 , -OS(O),NRioR 1 , -SS(O),NRIORII, -NR 7 S(O)pNRioR 11 , -OS(O),OR 7 , -SS(O),OR 7 , -NR 7
S(O),OR
7 , -OC(S)R 7 ,
-SC(S)R
7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR 1 , -SC(S)NRioR 11 , -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 ,
-SC(NR
8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR 8 )NRioR 11 , -SC(NR 8 )NRioR 1 , -NR 7
C(NR
8 )NRioR 1 , OP(O)(OR7) 2 , or -SP(O)(OR) 2 ;
R
3 is -OH, -SH, -NR 7 H, -OR 2 6 , -SR 2 6 , -NHR 26 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mN R 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -OC(O)NRioR 11 , -SC(O)NRioR 1 ,
-NR
7 C(O)NRioRI, -OC(O)R 7 , -SC(O)R 7 , -NR 7
C(O)R
7 , -OC(O)OR 7 , -SC(O)OR 7
,
C \NRPonbl\DCCREC\4756I4_I DOC-1/If/2012 - 35 -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
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7 CH2C(O)OR 7 , -OCH 2 C(O)NRioR 11 , -SCH 2 C(O)NRioR 1 , NR 7
CH
2 C(O)NR oR 1 , -OS(O),R 7 , -SS(O)pR 7 , -S(O)pOR 7 , -NR 7
S(O),R
7 , -OS(O),NRioR I, SS(O),NR 1 oR I, -N R 7
S(O),NR
0 oR I, -OS(O),OR 7 , -SS(O),OR 7 , -NR 7
S(O),OR
7 , -N R 7
S(O),R
7 , OS(O),NRjoR, -SS(O),NRjoR 11 , -NR 7 S(O),NRioR 1 , -OS(O),OR 7 , -SS(O),OR 7 , NR 7
S(O),OR
7 , -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR 11 , -SC(S)NRioR, -NR 7 C(S)NRioR, -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 ,
-OC(NR
8
)OR
7 , -SC(NR 8
)OR
7 , -NR 7 C(NRs)OR 7 , -OC(NR)NRioR 1 , -SC(NR 8 )NRioR, 1 , NR 7
C(NR
8 )NRioR 1 , -C(O)OH, -C(O)NHR 8 , -C(O)SH, -S(O)OH, -S(O) 2 0H, -S(O)NHR 8 ,
-S(O)
2 N HR 8
,-OP(O)(OR
7
)
2 , or -SP(O)(OR) 2 ; R2 is a substituted phenyl, wherein the phenyl group is substituted with: i) one substituent selected from nitro, cyano, a haloalkoxy, 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, hydroxylalkyl, alkoxyalkyl, guanadino, -NRIORII, -O-R20, -C(O)R 7 , -C(O)OR 20 , -OC(O)R 7 , C(O)NRIORII, -NR 8
C(O)R
7 , -SR 7 , -S(O)pR 7 , -OS(O),R 7 , -S(O)pOR 7 , NRgS(O)pR 7 , or -S(O),NRIOR 1 , or ii) two to five substituents 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, -F, -Br, -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRIOR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , OC(O)R 7 , -C(O)NRioR 1 , -NR 8
C(O)R
7 , -SR 7 , -S(O)pR 7 , -OS(O),R 7 ,
-S(O),OR
7 , -NR 8
S(O),R
7 , or -S(O),NRIOR 1 ; and
R
7 and R 8 , 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; C:WRPonb\DCCREC4075614_I DOC-10/2012 - 36 RIO 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; or RIO and R, 1 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R
20 , 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, or an optionally substituted heteraralkyl;
R
26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, I, 2, 3, or 4, in the manufacture of a medicament for treating an FLT3, c-kit, B-raf, Bcr-Abl fusion protein, or NPM-ALK fusion protein associated cancer. In one aspect the present invention provides use of a compound represented by formula (Ill): R18 A R1 N--N
R
3 (III) or a tautomer, or a pharmaceutically acceptable salt thereof, wherein: ring A 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 3 ; RI is -OH, -SH, -NR 7 H, -OR 26 , -SR 26 , -NHR 2 6 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -0C(0)NRIoR 1 , -SC(O)NRoR,
-NR
7 C(O)NRioR, 1 , -OC(O)R 7 , -SC(O)R 7 , -NR 7 C(O)R7, -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
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRIORI, -SCH 2 C(O)NRIORII, - C RPorblDCC\REC\4075614_1 DOC-1/10/2012 -37
NR
7
CH
2
C(O)NR
1 oR 11 , -OS(O)pR 7 , -SS(O),R 7 , -S(O),OR 7 , -NR 7
S(O),R
7 , -OS(O),NRIoR 1 , -SS(O)pNR 1 oR 1 1 , -NR 7 S(O),NRioR 11 , -OS(O)pOR 7 , -SS(O)pOR 7 , -NR 7 S(O)pOR 7 , -OC(S)R 7 , -SC(S)R,, -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRIoR 1 , -SC(S)NRioR 11 , -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8 )R7, -NR 7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 ,
-SC(NR
8
)OR
7 , -NR 7 C(NRs)OR 7 , -OC(NR)NRioR 1 , -SC(NR 8
)NR
1 oR 1 , -NR7C(NR 8 )NRioR 1 , OP(O)(OR7) 2 , or -SP(O)(OR) 2 ;
R
3 is -OH, -SH, -NR 7 H, -OR 26 , -SR 26 , -NHR 2 6 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2
).NR
7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -OC(O)NRIoR 1 , -SC(O)NRIoR 1 ,
-NR
7 C(O)NRioR 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 , -SCH 2
C(O)R
7 , -NR 7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRIoR 1 , -SCH 2
C(O)NRIOR
11 , NR7CH 2 C(O)NRioR, -OS(O)pR 7 , -SS(O),R 7 , -S(O)pOR 7 , -NR 7
S(O),R
7 , -OS(O)pNRIoR I, SS(O),NRIoR I, -N R 7 S(O),N R 1 oR I, -OS(O),OR 7 , -SS(O),OR 7 , -NR 7 S(O)pOR 7 , -NR 7 S(O)pR 7 , OS(O)pNRIoR 1 , -SS(O)pNRioR, -NR 7 S(O)pNRioR 1 , -OS(O),OR 7 , -SS(O),OR 7 , NR 7
S(O),OR
7 , -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR 1 , -SC(S)NRioR 1 , -NR 7 C(S)NRioRII, -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 ,
-OC(NR
8
)OR
7 , -SC(NR 8
)OR
7 , -NR 7 C(NRs)OR 7 , -OC(NR)NRioR 1 , -SC(NR)NRioR 1 , NR 7 C(NR)NRioR 1 , -C(O)OH, -C(O)NHR 8 , -C(O)SH, -S(O)OH, -S(O) 2 0H, -S(O)NHR 8 ,
-S(O)
2
NHR
8
,-OP(O)(OR
7
)
2 , or -SP(O)(OR 7
)
2 ;
R
7 and R 8 , 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 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; or RIO and R, 1 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R
1 8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally C:\NRPonb\DCC\REC\4076%4_ DOC-1/10f2012 - 38 substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRIOR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R7, -C(O)NRioR,
-NR
8
C(O)R
7 , -SR 7 , -S(0),R 7 ,
-OS(O),R
7 , -S(O),OR 7 , -NR 8 S(O)pR 7 , or -S(0),NRIoRII; R2 6 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4, in the manufacture of a medicament for treating an FLT3, c-kit, B-raf, Bcr-Abl fusion protein, or NPM-ALK fusion protein associated cancer. In one aspect the present invention provides use of of a compound represented by the following formula: R55
/R
52 N RR53 HO X45 N / \ Z1 OH N-N or a tautomer or pharmaceutically acceptable salt thereof, wherein:
X
4 5 is CRs 4 ; Z, is -OH or -SH;
R
52 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, -(CH 2
)
2 0CH 3 , -CH 2 C(O)OH, and -C(O)N(CH 3
)
2 ;
R
53 is -H, methyl, ethyl, or isopropyl;
R
54 is -H or a lower alkyl;
R
5 5 is selected from the group consisting of -H, -OH, -OCH 3 , and -OCH 2
CH
3 ; and
R
56 is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl, in the manufacture of a medicament for treating an FLT3, c-kit, B-raf, Bcr-AbI fusion protein, or NPM ALK fusion protein associated cancer.
C:\RPorb\DCC\RE 4495749_1 DOC-7126/2012 - 39 In one aspect the present invention provides use of a compound represented by the following formula: R55 / R52 N HO R53 X45 N Z OH N-N or a tautomer and/or pharmaceutically acceptable salt thereof, wherein:
X
45 is CR 54 ; Z, is -OH or -SH;
R
52 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, -(CH 2
)
2 0C-1 3 , -CI1 2 C(O)O-l, and -C(O)N(CH 3
)
2 ; R53 is -I-, methyl, ethyl, or isopropyl;
R
5 4 is -H or a lower alkyl;
R
55 is selected from the group consisting of -- , -01-, -OCHI 3 , and -OCI-H 2 C-1 3 ; and RZ56 is selected from the group consisting of -I, methyl, ethyl, isopropyl, and cyclopropyl, in the manufacture of a medicament for inducing degradation of FLT3, c-kit, B-raf, Ber-Abl fusion protein, or NPM-ALK fusion protein. In one aspect the present invention provides a method of treating a B-raf associated cancer or an NPIM-ALK fusion protein associated cancer in a subject, comprising administering to the subject an effective amount of a compound represented by the following formula:
R
55 /R52 N R56 5 HO X45 N OH N-N or a tautomer or pharmaceutically acceptable salt thereof, wherein:
X
45 is CR 54
;
C -\ N R P o n h l C C \R EC 4 4 9 5 7 4 9 . L ,DO C -7 /2 6f /2 112 -39A Z, is -01- or -SI-;
R
52 is selected from -- 1, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pCntyl, n-hexyl, (CH-1 2
)
2 0C1H1 3 , -CI- 2 C(O)OH, and -C(0)N(CI-H 3
)
2 ;
R
53 is -H, methyl, ethyl, or isopropyl;
R
54 is -H or a lower alkyl;
R
55 is selected from --1, -OH, -OCI- 3 , and -OCH 2 C1 3 ; and
I
56 is selected from -H, methyl, ethyl, isopropyl, and cyclopropyl. In one aspect the present invention provides a method of inducing degradation of B-raf or a NPM-A LK fusion protein in a subject in need thereof, comprising administering to the subject an effective amount of a compound represented by the following formula: R55 /R52 N
R
56 HO/
R
53 HO X45 N Z1 OH N-N or a tautomer and/or pharmaceutically acceptable salt thereof, wherein:
X
45 is CR 54 ; Zi is -01-I or -SH;
R
52 is selected from -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, (ClH 2
)
2 0CH,, -CH 2 C(O)OI-, and -C(O)N(CI-1 3
)
2 ;
R
53 is --I, methyl, ethyl, or isopropyl;
R
54 is -1-1 or a lower alkyl;
R
55 is selected from -- I, -01H, -OCI-H, and -OCH-I2C-I3; and
I
56 is selected from -H, methyl, ethyl, isopropyl, and cyclopropyl. In one aspect the present invention provides use of a compound represented by the following formula: C \NRPortbIDC(REC\4495749_1 DOC-7/2W12012 - 39B R55 R52 N R56 5 HO R53 N Z OH N-N or a tautomer or pharmaceutically acceptable salt thereof, wherein:
X
4 5 is CRs 4 ; ZI is -01- or -S-I;
R
52 is selected from -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, (CIH 2
)
2 0CH 3 , -CI- 2 C(O)OH, and -C(O)N(CI-1 3
)
2 ;
R
53 is -H4, methyl, ethyl, or isopropyl;
R
54 is -I-I or a lower alkyl;
R
55 is selected from -I-I, -OH, -OCH 3 , and -OCI-H 2
CI-
3 ; and R56 is selected from -H, methyl, ethyl, isopropyl, and cyclopropyl, in the manufacture of a medicament for treating a B-raf associated cancer or an NPM-ALK fusion protein associated cancer. In one aspect the present invention provides use of a compound represented by the following formula:
R
5 5 R52 N
R
56 HO / R 53 X-- X45 N OH N-N or a tautomer or pharmaceutically acceptable salt thereof, wherein:
X
4 5 is CRS 4 ; Z, is -01H or-SI-I;
R
52 is selected from -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, (C-1 2
)
2 OCH3, -CH 2 C(O)O-1, and -C(O)N(CI-H 3
)
2
;
C:NRPorlb\DCC\RECV49574_I DOC-7f26(2012 - 39C
R
5 3 is -1-, methyl, ethyl, or isopropyl;
R
54 is -- 1 or a lower alkyl; R55 is selected from -H, -01, -OC-1 3 , and -OCI-1 2 C-1 3 ; and
R
5 (, is selected from -- 1, methyl, ethyl, isopropyl, and cyclopropyl, in the manufacture of a medicament for inducing degradation of 13-raf or a NPM-ALK fusion protein. BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a graph showing the ATPase activity of -isp90 when untreated, when treated with 40 mM of Geldanamycin, a known I-sp90 inhibitor as a positive control, and when treated with 40pM or 4pM of Compound 108 of the invention. Figure 2 is gel showing the amount of H-er2, an -Isp90 client protein, in cells that are untreated, in cells that have been treated with 0.5pM, 2pM, or 5pM of 17AAG, a known Hsp90 inhibitor, and in cells that have been treated with 0.5pM, 2pM, or 5pM of Compound 108 or Compound 49. Figure 3 is a graph showing an FACSCalibur flow cytormeter analysis of the c-kit positive population of H-EL92.1.7 cells treated with -Isp90 inhibitors of the invention or I 7AAG (as a positive control). The results indicate that the Hsp9O inhibitors of the invention induce c-kit C:\NRPortb1DCC\REC\4075614 I DOC-/ 012 - 40 degradation at a lower concentration than 17AAG, an Hsp90 inhibitor that is currently in phase I clinical trials. Figure 4 is a graph showing an FACSCalibur flow cytometer analysis of the c-kit positive population of Kasumi- I cells treated with Hsp90 inhibitors of the invention or 17AAG (as a positive control). The results indicate that the Hsp90 inhibitors of the invention induce c-kit degradation at a lower concentration than 1 7AAG, an Hsp90 inhibitor that is currently in phase 11 clinical trials. Figure 5 is a Western blot analysis of c-kit from Kasumi-I cells which carry c-Kit tyrosine kinase receptor which has an activating N822K mutation were either untreated (negative control, lane I) or treated with 100 nM and 400 nM of Compound 221 of the invention or I 7AAG (as a positive control). Figure 6 is a Western blot analysis of EGFR of NCI-H 1975 non-small cell lung cancer cell line which harbors both the T790M and the L858R mutations in EGFR. The cells were either untreated (negative control, lane I) or treated with 1.0 pM, 0.5 pM and 0.1 pM of Compound 226 of the invention or 17AAG (as a positive control). Figure 7 is a Western blot ananlysis of B-raf from A375 melanoma cells which carry B-raf tyrosine kinase that has the V600E activating mutation. The cells were either untreated (negative control, lane 1) or treated with 0.5 M, 0.1 jaM or 0.01 pM of Compound 226 of the invention or 17AAG (as a positive control). Figure 8 is a Western blot ananlysis of phosphorylated Bcr-Abl from KU812 chronic myeloid leukemia cells. The cells were either untreated (negative control, lane 1) or treated with 1.0 pM or 0.1 jaM of Compound 226, 17AAG (positive control), or 17DMAG (positive control). Figure 9 is a Western blot ananlysis of phosphorylated and total NPM-ALK from Karpas 299 cells. The cells were either untreated (negative control, lane I) or treated with 0.5 pM, 0.1 pM or 0.05 pM of Compound 226 or 17AAG (positive control). Figure 10 is a graph of showing cell survival of MV-4-1 I cells, which carry an internal tandem duplication (ITD) mutation in FIt3, which is the most common molecular defect associated with AML, after treatment with Compound 226, 208, 205 or 188 of the invention or after treatment with 17AAG or DMAG. Figure I I is a graph of showing cell survival of Kasumi-1 cells, which harbor the N822K mutation in c-kit, after treatment with Compound 226, 208 or 188 of the invention or 17AAG, DMAG or Gleevec. Figure 12 is a graph of showing cell survival of mouse mastacytoma cell line P815 which carry an activated form of c-Kit that expresses an activating mutation D814Y which is equivalent C:\NRPonbI\DCC\RECuW75614_I DOC-1/10/2012 - 41 to the D816Y mutation in human c-Kit (D816Y) and confers resistance to Gleevec, after treatment with Compound 226, 17AAG, 17DMAG or Gleevec. Figure 13 is a graph of showing cell survival of NCI-H 1975 human lung cancer cell line, which harbors both the T790M and the L858R mutations in EGFR after treatment with Compound 226, 17AAG, or DMAG. Figure 14 is a graph of showing cell survival of human melanoma cell line, A375, which contains the V600E mutation in B-raf that confers constitutive tyrosine kinase activity, after treatment with Compound 226, 17AAG, or DMAG. Figure 15 is a graph showing cell survival of human chronic myelogenous leukemia (CML) cell line, K-562 which express Bcr-Abl fusion protein, after treatment with Compound 226 of the invention, 17AAG, DMAG, Radicicol, Vernalis 60-0164, Conforma 60-0 170, or Gleevec. Figure 16 is a graph of showing cell survival of Human Karpas-299 cell line which expresses NPM-ALK fusion protein, after treatment with Compound 226, 17AAG, or DMAG. Figure 17 displays the results of a nude mouse xenograft study to determine the effect of Compound 49 on the in vivo growth rate of the human tumor cell line MDA-MB-435S. Tumor bearing animals (8 mice/group) were intraperitoneal (IP) injected 5 times per week for 3 weeks (hatched bar) and the average tumor volumes for each group (+/- SEM) were determined every 3-5 days. Treatment with a dose of 300 mg/kg body weight of Compound 49 decreased the growth rate of MDA-MB-435S cells in nude mice to a greater extent than did a dose of 100 mg/kg body weight of the Hsp90 inhibitor 17-allylamino-I 7-demethoxygeldanamycin (I 7-AAG). Figure 18 demonstrates that treatment with Compound 49 did not cause toxicity in a nude mouse xenograft model using the human tumor cell line MDA-MB-435S (tumor growth data from the same study is presented in Figure 16). Tumor bearing animals (8 mice/group) were intraperitoneal (IP) injected 5 times per week for 3 weeks (hatched bar) and the average percent changes in body weights for each group relative to the start of dosing were determined every 1-3 days (error bars not shown for clarity; mean coefficient of variation = 18%). Treatment with a dose of 300 mg/kg body weight of Compound 49 was not toxic, as indicated by its lack of an effect on the body weights in animals treated with Compound 49 versus vehicle treated animals. Figure 19 shows the results of a nude mouse xenograft study to determine the effects of Compound #226 on the in vivo growth rate of the human FLT3-ITD expressing acute myelogenous leukemia tumor cell line Mv 4-I 1. Tumor bearing animals (8 mice/group) were i.v. injected 1 time per week for a total of 3 doses (arrowheads) and the median tumor volumes for each group (error bars represent SEM) were determined every 2-4 days. Treatment with doses of 50 and 125 mg/kg body weight of Compound #226 substantially inhibited tumor growth, with %T/C values of -63.8 C:NRPotb\DCC\RECW4756NJI DOC-1110/2012 - 42 and -93.0 observed on day 41, respectively. In the 125 mg/kg treatment group, 2 of 8 animals had no apparent tumors by day 41. Overt toxicity was not observed, with the highest dose group treated with 125 mg/kg Compound #226-treated group having an average bodyweight loss relative to the start of the study of -1.4% (+/- 1.6 SEM) on day 41. Figure 20 shows the results of a SCID mouse xenograft study to determine the effects of Compound #226 on the in vivo growth rate of the human c-Kit (N822K)-expressing tumor cell line Kasumi-l. Tumor bearing animals (8 mice/group) were i.v. injected 5 times per week for a total of 14 doses (arrowheads) and the median tumor volumes for each group (error bars represent SEM) were determined every 3-4 days. Treatment with a dose of 25 mg/kg body weight of Compound #226 substantially inhibited tumor growth, with a %T/C value of -15.3 observed on day 50. Treatment with a single dose of 25 mg/kg body weight of Compound #226 on day 30 was sufficient to cause tumor regression, with a %T/C value of -4.I observed on day 33. Overt toxicity was not observed, with the Compound #226-treated group having an average bodyweight gain relative to the start of the study of +0.7% (+/- 2.0 SEM) on day 50. Figure 21 shows the results of a SCID mouse xenograft study to determine the effects of Compound #226 on the in vivo growth rate of the human Bcr-Abl-positive chronic myelogenous leukemia tumor cell line K-562. Tumor bearing animals (8 mice/group) were i.v. injected 5 times per week for a total of 6 doses (arrowheads) and the median tumor volumes for each group (error bars represent SEM) were determined every 2-4 days. Treatment with a dose of 35 mg/kg body weight of Compound #226 substantially inhibited tumor growth, with a %T/C value of 25 observed on day 17. Excessive toxicity was not observed, with the Compound #226-treated group having an average bodyweight loss relative to the start of the study of - 12.4% (+/- 1.4 SEM) on day 17. Figure 22 shows the results of a nude mouse xenograft study to determine the effects of Compound #226 on the in vivo growth rate of the human B-raf(V600E)-expressing malignant melanoma tumor cell line A-375. Tumor bearing animals (8 mice/group) were i.v. injected 3 time per week for a total of 8 doses (arrowheads) and the average tumor volumes for each group (error bars represent SEM) were determined every 3-4 days. Treatment with a dose of 50 mg/kg body weight of Compound #226 substantially inhibited tumor growth, with a %T/C value of 17 observed on day 63 (indicated on right). Overt toxicity was not observed, with the 50 mg/kg Compound #226-treated group having an average bodyweight gain relative to the start of the study of 2.7% (+/- 1.1 SEM) on day 60.
C:\NRPotbnDCC\REC\407%564_1 DOC-110/2012 -43 DETAILED DESCRIPTION OF THE INVENTION The present invention encompasses the use of the compounds of the invention to inhibit Hsp90 activity and for the treatment of a proliferative disorder, such as cancer, including FLT3, EGFR, c-Kit, and B-raf associated cancers, and cancers that express Bcr-Able or NPM-ALK fusion proteins. In particular, the present invention encompasses the use of compounds of the invention to slow or stop the growth of cancerous cells, to reduce or eliminate cancerous cells in a mammal, and/or to reduce or prevent metastasis of the cancer. 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. 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 I 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-methylhexyl, 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 ethylpentyl, 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 "(CI-C 6 )alkyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from I to 6 carbon atoms. Representative (C-C)alkyl groups are those shown above C:NRPortbl\DCCREC\4075614_L DOC- 1/10/2012 - 44 having from I 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 (C 2 -Cio)alkenyls include vinyl, allyl, I-butenyl, 2 butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-I-butenyl, 2-methyl-2-butenyl, 2,3 dimethyl-2-butenyl, 1 -hexenyl, 2-hexenyl, 3-hexenyl, I -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. Alkenyl 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 lease one carbon-carbon triple bond. Representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2 butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-I-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-pentalenyl, 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 and alkyl group in which one or more (including all) the hydrogen radicals are replaced by a halo group, wherein each halo group is C:WRPanb\DCC\REC\475614_ I DOC-1/10/2012 - 45 independently selected from -F, -CI, -Br, and -1. 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 "(C 6 )aryl." As used herein, the term "aralkyl" means an aryl group that is attached to another group by a (CI-C)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 "(C,-C)alkylene" refers to an alkylene group that has from one to six carbon atoms. Straight chain (C 1
-C
6 )alkylene groups are preferred. Non-limiting examples of alkylene 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. As used herein, the term "heterocyclyl" 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 on 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, thiomorpholinyl, pyrrolidinonyl, C RPrtbhlDC REC%4075614_ I DOC-1/10/2012 - 46 pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 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, I -oxo-pyridyl, furanyl, benzo[ I,3]dioxolyl, benzo[I,4]dioxinyl, 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, pyrazolo[3,4]pyrimidinyl, imidazo[1,2-a]pyridyl, 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 to another group 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 "(C 5 )heteroaryl" 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 (Cs)heteroaryls include furanyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyrazinyl, triazolyl, thiadiazolyl, and the like. As used herein, the term "(C 6 )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 )heteroaryls 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 (C-C 6 )alkylene. Representative heteroaralkyls include 2-(pyridin-4-yl)-propyl, C:WRPorbI\DCC\REC4075614_l .DOC-1/10/2012 - 47 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 "halogen" or "halo" means -F, -Cl, -Br or -I. Suitable substituents for an alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups include any substituent which will form a stable 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, a haloalkyl, -C(O)NR 2 8
R
2 9 , C(S)NR 2 8
R
2 9 , -C(NR 3 2
)NR
2 8
R
2 9 , -NR 3 oC(O)R 31 , -NR 3 0
C(S)R
3 1 , -NR 30
C(NR
3 2
)R
31 , halo, -OR 30 , cyano, nitro, haloalkoxy, -C(O)R 30 , -C(S)R 30 , -C(NR 32
)R
30 , -NR 2 8
R
29 , -C(O)OR 30 , -C(S)OR 30 , C(N R 3 2
)OR
30 , -OC(O)R 30 , -OC(S)R 30 , -OC(N R 32
)R
3 0 , -N R 30 C(O)N R 28
R
29 , -N R 30 C(S)N R 2 8
R
29 , -N R 30 C(N R 32 )N R 28
R
29 , -OC(O)N R 28
R
29 , -OC(S)N R 2 8
R
29 , -OC(N R 32 )N R 28
R
29 , -N R 30
C(O)OR
3 1 , -N R 30
C(S)OR
3 1 , -N R 3 oC(N R 32
)OR
3 i, -S(O)h R 30 , -OS(O),R 30 , , -N R 3 0S(O),R3 0 , -S(O),N R 28
R
29 ,
-OS(O),NR
28
R
29 , or -NR 3 0S(O),NR 2 8
R
2 9 , wherein R 2 s 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 2 8 and
R
29 taken together with the nitrogen to which they are attached is optionally substituted heterocyclyl or optionally substituted heteroaryl.
R
3 0 and R 3 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)R 30 , -C(O)NR 2 8
R
29 , -S(O),R 30 , or -S(O),NR 28
R
2 9; and h is 0, 1 or 2.
C:\NRPortbl\DCC\REC\40764_I DOC-1/1012012 -48 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-R 32 . 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 heteroaryl 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-human 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 I to 4 carbon atoms, "lower alkoxy" refers to
"-O-(CI-C
4 )alkyl and a "lower alkenyl" or "lower alkynyl" refers to an alkenyl or alkynyl radical having from 2 to 4 carbon atoms, respectively. 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, 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. As used herein, the term "compound(s) of this invention" and similar terms refers to a compound of formula (I) through (LXXII) and Tables 5, 6, and 7, or a pharmaceutically acceptable C:\NRWPonb\DCC\RECW75614_ I DOC-/I1/2012 -49 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 diastereomers. 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 stereochemically 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.
C:NRPortbl\DCOREC4)75614_L DOC-I/10/2012 - 50 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) through (LXXII) and Tables 5, 6, and 7 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) through (LXXII), and Tables 5, 6, and 7, that comprise -NO, -NO 2 , -ONO, or -ON0 2 moieties. Prodrugs can typically be prepared using well-known methods, such as those described by I BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5 th 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: I) 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, a-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, hydroxyalkylamines, 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 Hsp90cc and Hsp90p isoforms, as well as GRP94, which is found in the endoplasmic reticulum, and HSP75/TRAP1, which is found in the mitochondrial matrix. FLT3 kinase is a tyrosine kinase receptor involved in the regulation and stimulation of cellular proliferation (see Gilliland et al., Blood (2002), 100:1532-42, the entire teachings of which are incorporated herein by reference). The FLT3 kinase has five immunoglobulin-like domains in its extracellular region as well as an insert region of 75-100 amino acids in the middle of its C:\NRPortblOCC\REC4075614_ .DOC-1/10/2012 - 51 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 Stat5, Ras, phosphatidylinositol-3-kinase (P13K), PLCy, Erk2, Akt, MAPK, SHC, SHP2, and SHIP (see Rosnet et al., Acia Haematol. (1996), 95:218; Hayakawa et al., Oncogene (2000), 19:624; Mizuki et al., Blood (2000), 96:3907; and Gilliand et al., Curr. Opin. Hematol. (2002), 9: 274-81). 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, el al., Blood (1993), 82:1110-19; Small Ie al., Proc. Nail. Acad Sci. US.A. (1994), 91:459-63; and Rosnet el al., Leukemia (1996), 10:238 48). 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 et al., Blood (2000), 95:3489-97). Numerous hematologic malignancies express FLT3 kinase, the most prominent of which is AML (see Yokota e al., Leukemia (1997), 11:1605-09). Other FLT3 expressing malignancies include B-precursor cell acute lymphoblastic leukemias, myelodysplastic leukemias, T-cell acute lymphoblastic leukemias, and chronic myelogenous leukemias (see Rasko et al., Leukemia (1995), 9:2058-66). 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" or "FLT3 kinase" refers to both wild type FLT3 kinase and mutant FLT3 kinases, such as FLT3 kinases that have activating mutations. As used herein, the term "FLT3 associated cancer" refers to a cancer that has inappropriate or abnormal FLT3 activity. Inappropriate or abnormal FLT3 activity includes, but is not limited to, enhanced FLT3 activity resulting from increased or de novo expression of FLT3 in cells, increase expression of FLT3 ligand, 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 C:\NRPonbl\DCC\RECWI)756 I.DOC-1/10/2012 -52 determined using flow cytometric analysis, immunohistochemical analysis, and in situ hybridization techniques. 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, et al., 1987, EMBOJ., 11:3341-3351; and Qiu, et al., 1988, EMBO J., 7:1003-101 1, 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 (Ma, et al., 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, 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, et al., 1994, Cancer Res., 54(11):3049-3053), sarcomas of neuroectodermal origin (Ricotti, et al., 1998, Blood, 91:2397-2405), and Schwann cell neoplasia associated with neurofibromatosis (Ryan, et al., 1994, J Neuro. Res., 37:415-432). The term "epidermal growth factor receptor" or "EGFR," as used herein, refers to any epidermal growth factor receptor (EGFR) protein, peptide, or polypeptide having EGFR or EGFR family (e.g., HER 1, 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., HER 1, HER2, HER3, and/or HER4), mutant EGFR genes, splice variants of EGFR genes, and EGFR gene polymorphisms. As used herein, the term "EGFR associated cancer" refers to a cancer which has aberrant expression and/or activation of EGFR. EGFR associated cancers include 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.
C:\NRPort1bDCC\REC\4075614_1 DOC-IfI012 -53 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. 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, et al., Journal of Clinical Oncology (2005), 23(27):6771-6790). The term "B-raf," as used herein refers to all such splicing variants of B-raf and mutated forms of B-raf, including mutated forms of B-raf which confer constitutive or elevated tyrosine kinase activity. The term "B-raf associated cancers," as used herein, refers to 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, "Bcr-Abl" refers to a fusion protein which results from the translocation of gene sequences from c-ABL protein tyrosine kinase on chromosome 9 into BCR sequences on C\NRPrtbl\DCC\REC\4075614_1 DOC-1110/2012 - 54 chromosome 22 producing the Philiadelphia chromosome. A schematic representation of human Bcr, Abl, 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 tyrosine kinase (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 Ber-AbI is characteristic of ALL. Expression of Bcr-AbI fusion protein is associated with several human cancers and is particularly associated with hematological cancers, including chronic myelogenous leukemia (CML), acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), granulocytic hyperplasia, myelomonocytic leukemia, lymphomas and erythroid leukemia. 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, et al., Oncogene (2001), 20:5623-5637. Cancers which express NPM-ALK fusion protein include ALCL and diffuse large B-cell lymphomas. As used herein, the terms "benzoquinone ansamycin" refers to a compound comprising a benzoquinone nucleus connected at two non-adjacent positions by a macrocyclic lactam. Specific examples of naturally-occurring benzoquinone ansamycins include but are not limited to geldanamycin, herbimycin, macbecin, mycotrienes, and ansamitocin. The term "geldanamycin analog" refers to a type of benzoquinone ansamycin that can be derived from geldanamycin by chemical manipulation or by manipulation of the geldanamycin biosynthetic gene cluster, such as 17-allylamino- 1 7-desmethoxygeldanamycin (1 7AAG) or 17-(2-dimethylaminoethy- l)amino- 17 desmethoxygeldanamycin (I 7DMAG or DMAG). 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, C:WPortb\DCOREC4075614_.DOC-1/1012012 - 55 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 C:\NRPornbl\DCC\REC4071614_1 DOC-1/10/2012 -56 by the CEM, Jurkat, and HSB-2 (acute), YAC-l(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-l(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-I(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 a FLT3 associated cancer. In one embodiment, the disclosed method is believed to be particularly effective in treating subject with a c-kit associated cancer. In one embodiment, the disclosed method is believed to be particularly effective in treating subject with an EGFR associated cancer. In one embodiment, the disclosed method is believed to be particularly effective in treating subject with a B-raf associated cancer. In one embodiment, the disclosed method is believed to be particularly effective in treating a subject with a cancer that expresses Bcr-AbI fusion protein. In one embodiment, the disclosed method is believed to be particularly effective in treating a subject with a cancer that expresses NPM-ALK fusion protein. 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 anti-cancer drug becomes resistant to the anti-cancer drug when the anti-cancer drug is no longer effective in C:\NRPonbl\DCORE04075614I1 DOC-1/1W12012 - 57 treating the subject with the cancer. For example, many tumors will initially respond to treatment with an anti-cancer drug, such as a tyrosine kinase inhibitor, 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 "pharmaceutically acceptable salt," is a salt formed from, for example, an acid and a basic group of one of the compounds of formula (I) through (LXXII) and Tables 5, 6, and 7. 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, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term "pharmaceutically acceptable salt" also refers to a salt prepared from a compound of formula (I) through (LXXII) and Tables 5, 6, and 7 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)-amines, such as N,N dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like. The term "pharmaceutically acceptable salt" also refers to a salt prepared from a compound of formula (I) through (LXXII) and Tables 5, 6, and 7 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 (HCI), 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, C:\NRPortblDCC\RECW075614_1 DOC-1/1012012 - 58 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 (1) through (LXXII) and Tables 5, 6, and 7. The term solvate includes hydrates (e.g., hem ihydrate, 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/mI 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, et aL., "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 proliferative disorder, prevent the advancement of a proliferative disorder, cause the regression of a proliferative, prevent the recurrence, development, onset or progression of a symptom associated with 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 general 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 C:NRPorb\DCC\RECW756t14_I DOC.10/2012 -59 comprising administering to a subject in need thereof a dose of at least 150 pg/kg, preferably at least 250 pg/kg, at least 500 gg/kg, at least I 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 al., 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. As used herein, the terms "treat", "treatment" and "treating" refer to the reduction or amelioration of the progression, severity and/or duration of a proliferative disorder, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of 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 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 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.
C.\NRPonbl\DCC\REC\4075614_1.DOC-1/10/2012 - 60 As used herein, the terms "prevent", "prevention" and "preventing" refer to the reduction in the risk of acquiring or developing a given proliferative disorder, or the reduction or inhibition of the recurrence or 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 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 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 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 proliferative disorder. In addition, a synergistic effect can result in improved efficacy of agents in the prevention, management or treatment of 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 C:\NRPortbl\DCMRECO075614_1 DOC-1/10/2012 -61 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, I hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, I 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, I hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, I 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 prophylactic 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.
C:\NRPonbPDCC\RECW075614 IDOC-1/10/12012 - 62 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 CNRPonbl\DCC\REC\4075614_L DOC- I10/2012 - 63 as a mixture of stereoisomers or as a diastereomeric or enantiomeric pure isolate. An "isolated agent" can be a synthetic or naturally occurring molecule having a molecular weight of about 1000 daltons or less, or a natural product having a molecular weight of greater than 1000 daltons. For example, an isolated agent can be an antibody, or fragment thereof, or an antibiotic. 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 encompasses compounds having formula (I) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7, and tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof. In one aspect, the invention provides compounds of formula (1) as set forth below: R5 AR, N--N
R
3 (I) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein ring A, R 1 , R 3 and R 5 are defined as above. Compounds of formula (I) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (1) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
CNRPonbl\DCCREC4075614_1 DOC-1/Il/2012 - 64 In one embodiment, in the compounds of formula (I), R 5 is an optionally substituted naphthyl. In another embodiment, in the compounds of formula (I), R 5 is represented by the following formula:
(R
9 )m wherein:
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, -NRioR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 ,
-OC(O)R
7 , -C(O)NRioR 1 , -NR 8
C(O)R
7 , -SR 7 , -S(O),R 7 , -OS(O),R 7 , -S(O),OR 7 , -NR 8
S(O),R
7 , or -S(O),NRioR 1 ; or two R 9 groups taken together with the carbon atoms to which they are attached form a fused ring; and m is zero or an integer from 1 to 7, wherein R 7 , R 8 , R o, RaI, and p are defined as above. In another embodiment, in the compounds represented by formula (1), R 5 is represented by one of the following formulas: (R9)q (R9)u wherein R 9 is defined as above; q is zero or an integer from 1 to 7; and u is zero or an integer from 1 to 8.
C :NRPonbI\DCREVO75614_1 DOC-1110/2012 - 65 In another embodiment, in the compounds represented by formula (I), R 5 is selected from the group consisting of: 6 XX X6 X6 X6X6 X7 X X X 7 x X7 (6 X8 xX7 XX7 X7
X
8
X
7 X x X 7 N7 X 7 , X 7 N X7~N~ .- -7 7 X X7 XX 7
X
7 - XX N N 7 X8X 7
X
7 x C NRPonbl\DCC\REC\407564_l .DOC-1/10/2012 -66 X7 X X7 X 10 X10 X10 X 10 xe X7 X10 \ X10 -X10 X7 N _ /
X
7 10 X10 X10 X10 and X10 X10 wherein:
X
6 , for each occurrence, is independently CH, CR 9 , N, N(O), N'(Ry), 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'(RI 7 ), provided that at least three X 7 groups are independently selected from CH and CR 9 ; X8, for each occurrence, is independently CH 2 , CHR 9 , CR 9
R
9 , 0, 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-(Ry), provided that at least one X 10 is selected from CH and CR9;
R
1 7 , for each occurrence, is independently -H, an alkyl, an aralkyl, -C(O)R 7 , -C(O)OR 7 , or -C(0)NRIOR 1 ; wherein R 7 , R 9 , RIO, R, 1 and p are defined as above. In another embodiment, in the compounds represented by formula (I), Rs 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[l,3]dioxolyl, an optionally substituted benzofuryl, an optionally substituted benzothiazolyl, an optionally substituted benzo[d]isoxazolyl, an optionally substituted benzo[dlisothiazolyl, 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 C:\NRPorbI\DCC\RE0475614_ I DOC-111012012 - 67 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 3H-imidazo[4,5-b]pyridinyl, an optionally substituted I H-imidazo[4,5 bipyridinyl, an optionally substituted IH-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 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 (1), R 5 is an optionally substituted indolyl. Preferably, R 5 is an indolyl represented by the following structural formula: R33R3 N B C wherein:
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 substituents. In another embodiment, in the compounds represented by formula (I), R 5 is selected from the group consisting of: X-- X1 1" OX13 1 11 X 12 X 12 X l ' and X13 X11 'X 11 - X12 X12 a wherein: C\NRPorbI\DCC\REC4075614_ DOC-I/10/2012 -68
X
11 , for each occurrence, is independently CH, CR 9 , N, N(O), or N'(RI 7 ), provided that at least one X I is N, N(O), or N*(R 17 ) and at least two XII groups are independently selected from CH and CR 9 ;
X
1 2 , for each occurrence, is independently CH, CR 9 , N, N(O), N*(R 17 ), provided that at least one X 1 2 group is independently selected from CH and CR 9 ;
X
13 , for each occurrence, is independently 0, S, S(O)p, NR 7 , or NR 1 7 ; wherein R 7 , R 9 and
R
1 - are defined as above. In another embodiment, in compounds represented by formula (I), or any of the embodiments of formula (I) in which particular groups are disclosed, the compound is represented by formula (XII): R5 (R)n R1 N-N
R
3 (XII) wherein R 1 , R 3 , and R 5 are defined as above; and
R
6 , 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 haloalkyl, a heteroalkyl, -NRIOR 11 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NRioR 1 ,
-NR
8
C(O)R
7 , -SR 7 , -S(O),R 7 , -OS(O),R 7 , -S(O),OR 7 , -NR 8
S(O),R
7 , or -S(O)pNRIoR 1 ; and n is zero of an integer from I to 4, wherein R 7 , R 8 , Rio, R, 1 , and p are defined as above. In another embodiment, in compounds represented by formula (I), or any of the embodiments of formula (I) in which particular groups are disclosed, the compound is represented by structural formula (XIII): C:\NJRPonbhkDCC\REC\475614_.DOC-1/10/2012 - 69 (R 6 )r R25 R N R1 N-N R3 (XIII) wherein R 1 , R 3 , R 5 , and R, are defined as above; and
R
25 is a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, -OH, -SH, -NHR 7 , -(CH2)kOH, (CH 2 )kSH, -(CH 2 )kNR 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)NRioR 1 , -SC(O)NRjoR 1 , -NR 7 C(O)NRioR 1 , -OC(O)R 7 , -SC(O)R 7 , -NR 7
C(O)R
7 , -OC(0)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
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRIORII, -SCH 2 C(O)NRioR, -NR7CH 2 C(O)NRioR,, -OS(O),R 7 , -SS(O),R 7 , -NR 7
S(O),R
7 , -OS(O),NRoR 11 , -SS(O),NRoR 1 ,
-NR
7 S(O),NRioR 1 , -OS(O)pOR,, -SS(O),OR 7 , -NR 7
S(O),OR
7 , -OC(S)R 7 , -SC(S)R 7 ,
-NR
7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR7C(S)OR 7 , -OC(S)NIRioR 11 , -SC(S)NRioR 11 ,
-NR
7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 , -SC(NR 8
)OR
7 , NR 7
C(NR
8
)OR
7 , -OC(NR 8 )NRioR, -SC(NR 8 )NRIORII, -NR 7 C(NR)NRioR 1 , -C(O)R 7 ,
-C(O)OR
7 , -C(O)NRioR, -C(O)SR 7 , -C(S)R 7 , -C(S)OR 7 , -C(S)NRIOR 1 , -C(S)SR 7 , C(NR 8
)OR
7 , -C(NR 8
)R
7 , -C(NR 8 )NRioR 11 , -C(NR 8
)SR
7 , -S(O),OR 7 , -S(O),NRioR 1 , or -S(O),R7; k is 1, 2, 3, or 4; and r is zero or an integer from I to 3, wherein R 7 , R 8 , R 1 0 , R, 1 , and p are defined as above. In another embodiment, in compounds represented by formula (I), or any of the embodiments of formula (I) in which particular groups are disclosed, R, and R 3 are each, independently, -OH, -SH, or -NHR 7 . In another embodiment, in compounds represented by formula (1), or any of the embodiments of formula (I) in which particular groups are disclosed, the compound is represented by structural formula (XIV): C:\NRPortbl\DCC\REC\4175614_1 DOC.I/10/2012 - 70 R12 R5 R25 N" R1 N-N R3 (XIV) wherein R 1 , R 3 , R 5 , and R 2 5 are defined as above; and
R
12 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 , -SR7, -NRIORII, -OC(O)NRioR 1 , -SC(O)NRioR 1 , -NR7C(O)NRioR 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 , -SCH 2
C(O)R
7 , -NR 7
CH
2 C(O)R7,
-OCH
2
C(O)OR
7 , -SCH 2
C(O)OR
7 , -NR7CH 2
C(O)OR
7 ,
-OCH
2
C(O)NR
0 oR 1 , -SCH 2 C(O)NRioR, 1 , -NR 7
CH
2
C(O)NR
1 oR 1 , -OS(O)pR 7 ,
-SS(O),R
7
,-NR
7
S(O),R
7 , -OS(O),NRIOR 1 , -SS(O),NRioR, 1 , -NR 7 S(O),NRioR 1 , -OS(O),OR 7 , SS(O),OR 7 , -NR 7 S(O),OR7, -OC(S)R 7 , -SC(S)R 7 , -NR7C(S)R 7 , -OC(S)OR 7 , -SC(S)OR 7 ,
-NR
7
C(S)OR
7 , -OC(S)NRioR 1 , -SC(S)NRioR 1 , -NR 7 C(S)NRioR 1 , -OC(NR 8 )R7, -SC(NR 8
)R
7 ,
-NR
7
C(NR
8
)R
7 , -OC(NR 8 )OR7, -SC(NR 8 )OR7, -NR7C(NR 8
)OR
7 , -OC(NR 8 )NRioR 1 ,
-SC(NR
8 )NRioR 1 , -NR 7
C(NR
8 )NRIORII, -C(O)R 7 , -C(O)OR 7 , -C(O)NRIORII, -C(O)SR 7 ,
-C(S)R
7 , -C(S)OR7, -C(S)NRioR 1 , -C(S)SR 7 , -C(NR 8
)OR
7 , -C(NR 8
)R
7 , -C(NR 8 )NRioR,
-C(NR
8
)SR
7 , -S(O),OR 7 , -S(O),NRioR 1 , or -S(O),R 7 , wherein R 7 , R 8 , Rio, R, 1 , and p are defined as above. In a prefered embodiment, R, is -SH or -OH; R 3 and R 2 5 are -OH; R 1 2 is a lower alkyl, lower alkoxy, a lower alkyl sulfanyl, or -NRIOR 1 ; and R 9 , for each occurrence, is independently selected from the group consisting of -OH, -SH, halo, a lower haloalkyl, cyano, a lower alkyl, a lower alkoxy, and a lower alkyl sulfanyl. In another embodiment, in compounds represented by formula (1), or any of the embodiments of formula (I) in which particular groups are disclosed, the compound is represented by one of the following structural formulas: C:\NRPorbl\DCCREC\4075614 1 DOC-I/10/2012 - 71 (R6)n R5 (R6)n R5
X
4 -- X5 X -X4 N N X3 R1X3 R1 N-N N--N R3
R
3 (XV) (XVI) wherein R 1 , R 3 , R 5 , R6 and n are as defined above; and
X
3 and X 4 are each, independently, N, N(O), N'(RI 7 ), CH or CR,; and
X
5 is 0, S, NR 17 , CH=CH, CH=C&(, CR6=CH, CR 6
=CR
6 , CH=N, C&(=N, CH=N(O), CR6=N(O), N=CH, N=CR6, N(O)=CH, N(O)=CR6, N*(R1 7 )=CH, N-(R 17
)=CR
6 , C H=N(R 17 ), CR6=N(Ri), or N=N; wherein R17 is defined as above. In another embodiment, in compounds represented by formula (1), or any of the embodiments of formula (I) in which particular groups are disclosed, the compound is selected from the group consisting of: R5 R5 N N I N-N N-N R3
R
3 (XVIla) (XVIIb) O N Rd R25 N N R1 NR1 N--N N-N R3 R3; (XV1le) (XV Ild) C:\4RPonbL\DCC\REC\4075614_1 DOC-1110/2012 - 72 R5 R 5 R1 Y '- II R1 R //r YN-N N-N R3 'R3; (XVIIe) (XVIIf)
R
25
R
25 R5
R
5 O S NN R1 NR1 N--N N-N
R
3 '
R
3 (XVIIg) (XVIIh) 0 5 NN yl--R1 N R1 N-N and N
R
3 (XVIIi) (XVIIj) wherein R 1 , R 3 , R 5 , and R 25 are defined as above. In another aspect, the invention provides compounds of formula (II) as set forth below: R2 A R1 N-N
R
3 (II) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein ring A, R, and R 3 are defined as above; and CANRPorthDCREC%407S614_ DOC-1110f2012 - 73 R 2 is a substituted phenyl, wherein the phenyl group is substituted with: i) one substituent selected from nitro, cyano, a haloalkoxy, 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, hydroxylalkyl, alkoxyalkyl, guanadino, -NRIOR 1 , -O-R 20 , -C(O)R 7 , -C(O)OR 20 , -OC(O)R 7 , -C(O)NRioR 1 , -NR 8
C(O)R
7 , -SR 7 , -S(O),R 7 , -OS(O),R 7 , -S(O),OR 7 ,
-NR
8
S(O),R
7 , or -S(O),NRIOR 1 , or ii) two to five substituents 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, -F, -Br, -I, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRIOR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 ,
-OC(O)R
7 , -C(O)NRioR, 1 , -NR 8
C(O)R
7 , -SR 7 , -S(O),R 7 , -OS(0),R 7 , -S(O),OR 7 ,
-NR
8
S(O),R
7 , or -S(O),NRIoRII;
R
20 , 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, or an optionally substituted heteraralkyl; p, for each occurrence, is, independently, 0, I or 2. Compounds of formula (II) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (II) are particularly useful in treating cancer when given in combination with other anti-cancer agent. In one embodiment, the compounds represented by formula (II) do not include 3-(2,4 dihydroxy-phenyl)-4-(7-naphthalen- I -yl)-5-mercapto-triazole, 3-(2,4-dihydroxyphenyl)-4-(2,5 dimethoxyphenyl)-5-mercapto-triazole, 3-(I-phenyl-5-amino-pyrazol-4-yl)-4-(2,4-d ichloropheny) 5-mercapto-triazole, and 3-(2-hydroxy-phenyl)4-(2,4-d imethylphenyl)-5-mercapto-triazole.
C:NRPorbl\DCCREC\U075614_ .DOC-1/10/2012 - 74 In another embodiment, in compounds represented by formula (II), or any of the embodiments of formula (II) in which particular groups are disclosed, the compound is represented by structural formula (XVIII): R2 (R6)n NR1 N-N
R
3 (XVIII) wherein R 1 , R 2 , R 3 , R6, and n are defined as above. In another embodiment, in compounds represented by formula (II), or any of the embodiments of formula (II) in which particular groups are disclosed, the compound is represented by structural formula (XIX):
(R
6 )r R25 R N R1 N- N R3 (XIX) wherein R 1 , R 2 , R 3 , R, R 2 5 and r are defined as above. In another embodiment, in compounds represented by formula (II), or any of the embodiments of formula (II) in which particular groups are disclosed, R, and R 3 are each, independently, -OH, -SH, or -NHR 7 . In another embodiment, in compounds represented by formula (II), or any of the embodiments of formula (11) in which particular groups are disclosed, the compound is represented by structural formula (XX): C:NRPortbl\DCC\REC407564_1.DOC1/1/2012 - 75 R12 R2 R251 NN R1 N-N R3 (XX) wherein R 1 , R 2 , R 3 , R 12 and R 2 5 are defined as above. In a preferred embodiment, R, is -SH or -OH; R 3 and R 2 5 are -OH; R 1 2 is a lower alkyl, lower alkoxy, a lower alkyl sulfanyl, or -NRioR 1 ; and R 9 , for each occurrence, is independently selected from the group consisting of -OH, -SH, halo, a lower haloalkyl, cyano, a lower alkyl, a lower alkoxy, and a lower alkyl sulfanyl. In another embodiment, in compounds represented by formula (II), or any of the embodiments of formula (II) in which particular groups are disclosed, the compound is represented by one of the following structural formulas: (R6)n(R 6 )n
X
4 -- x 5
X
5 R2 X3 R1 N R1 N-N il N-N
R
3
R
3 (XXI) (XXII) wherein R 1 , R 2 , R 3 , R 6 , X 3 , X 4 , X 5 and n are defined as above. In another embodiment, in compounds represented by formula (II), or any of the embodiments of formula (II) in which particular groups are disclosed, the compound is selected from the group consisting of: R2 R2 N
-
R1 R1 /r/ N-N N-N
R
3
R
3 (XXIIla) (XXIIIb) C,\SoblfCC\REC\4O75614_ I D)OC-1110/2012 - 76 I L (XXIIIe) (XXII1f) 0 2 R2 2 R /r /7
R
3
R
3 (XXIIli) (XXII Ij) wenR25 R25 3 n R 5 aedfne saoe C NRPortbl\DCC\REC\475614_I DOC- 1/10/2012 - 77 In another aspect, the invention provides compounds of formula (Ill) as set forth below:
R
1 8 AN R1 N-N
R
3 (Ill) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs. In formula (Ill), ring A, R 1 , and R 3 are defined as above; and R1 8 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRIORII, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NRioR,
-NR
8
C(O)R
7 , -SR 7 , -S(O),R 7 , -OS(O),R 7 , -S(O),OR7, -NR 8
S(O),R
7 , or -S(O),NRIOR, wherein
R
7 , R 8 , Rio, R, 1 , and p are defined as above. Compounds of formula (111) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (Ill) are particularly useful in treating cancer when given in combination with other anti-cancer agent. In one embodiment, in formula (Ill) R 1 8 is not cyclohexyl. In another embodiment, in formula (111) R 18 is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl. In another embodiment, in formula (Ill) R 1 8 is a substituted alkyl.
C:\NRPortbl\DCCRECW475614_1 DOC-l/10/2012 - 78 In another embodiment, in compounds represented by formula (111), or any of the embodiments of formula (III) in which particular groups are disclosed, the compound is represented by structural formula (XXIV): R18
(R
6 )r R1 N-N R3 (XXIV) wherein R 1 , R 3 , R 6 , R 1 8 , and n are defined as above. In another embodiment, in compounds represented by formula (111), or any of the embodiments of formula (III) in which particular groups are disclosed, the compound is represented by structural formula (XXV): (X)r
R
2 5 a d s N R1 N-NI R3 (XXV) wherein R11, R3, R6, R18, R25 and r are defined as above. In another embodiment, in compounds represented by formula (111), or any of the embodiments of formula (Il1) in which particular groups are disclosed, R, and R 3 are each, independently, -OH, -SH, or -NHR 7
.
C:\NRPortblDCC\REC4075614_ DOC-1/10/2012 - 79 In another embodiment, in compounds represented by formula (Ill), or any of the embodiments of formula (111) in which particular groups are disclosed, the compound is represented by structural formula (XXVI): R12 R18 R25I N R1 N-N R3 (XXVI) wherein R 1 , R 3 , R 12 , R 1 8 , and R 25 are defined as above. In a preferred embodiment, Rf is -SH or -OH; R 3 and R 2 5 are -OH; and R 1 2 is a lower alkyl, lower alkoxy, a lower alkyl sulfanyl, or -NRioR o. In another embodiment, in compounds represented by formula (III), or any of the embodiments of formula (Ill) in which particular groups are disclosed, the compound is represented by one of the following structural formulas: (R6)n R8(R) R)8
X
4 _ -x 5 X - X5- -X4 X3R1X N R 1 X3K \_/ R
R
3
R
3 (XXVII) (XXVIII) wherein R 1 , R 3 , R,, R 18 , X 3 , X 4 , X 5 , and n are defined as above. In another embodiment, in compounds represented by formula (111), or any of the embodiments of formula (Il1) in which particular groups are disclosed, the compound is selected from the group consisting of: R18 R1 NN NR1 C N R1 N-N N-N R3
R
3 (XXIXa) (XXIXb) CANRfonblDCC\RECA4075614-1 DOC-1I/10/2012 - 80 0''~ R18R2R8 NN
R
3 R (XX IXc) (XXIXd) 0 R 18 R1 / R, R, N__
N
R
3 R 3 (XXIXe) (XXIXf)
R
25 R 25 0R 18 Rls
R
3 R (XXIXg) (XXIXh) N 18
N
1
R
3 N (XXIXI) (XX IXj) wherein RI, R 3 , R 18 , and R 25 are defined as above.
C:\NRPonbfDCC\REC\47614I. DOC- 101/2012 - 81 In another aspect, the invention provides compounds of formula (IV) or (V) as set forth below: R22 R23 R24 N
R
2 1
R
2 4 X14 R2 N R R23 R N N/ R1 R3 N- N R22 R3 N--N R3 R 3 (IV) (V) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. In formulas (IV) and (V), R, and R 3 are as defined above; and X1 4 is 0, S, or NR 7 ;
R
21 is 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
22 , for each occurrence, is independently a substituent 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, or an optionally substituted heteraralkyl, a haloalkyl, -C(O)R 7 , -C(O)OR,, -OC(O)R 7 , -C(O)NRIoR 1 , -NR 8
C(O)R
7 , -S(O),R 7 , -S(O),OR 7 , or -S(O),NRIoR 1 ; and
R
23 and R 24 , for each occurrence, are independently a substituent 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, or an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRIOR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NRIoR 1 ,
-NR
8
C(O)R
7 , -SR 7 , -S(O),R 7 , -OS(O),R 7 , -S(O),OR 7 , -NR 8
S(O),R
7 , or -S(O),NRioRI1; wherein R 7 , R 8 , RIO, RI and p are defined as above.
C.\NRPotbl\DCC\REC\4)75614_1 DOC-1/10/21112 -82 In one embodiment, in formulas (IV) and (V), R 2 1 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. In another embodiment, in the formulas (IV) and (V), R, is -OH, -SH, or -NHR 7 . In another embodiment, in the formulas (IV) and (V), R 22 is an alkyl, an aralkyl, -C(O)R 7 ,
-C(O)OR
7 , or -C(O)NRIORII. In another embodiment, in the formulas (IV) and (V), X] 4 is 0. Compounds of formula (IV) or (V) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (IV) or (V) are particularly useful in treating cancer when given in combination with other anti-cancer agent. In another embodiment, the invention provides compounds represented by formula (XXX): 41 X 41 1 Y HO4 N / Z OH N-N (XXX) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein:
X
4 1 is 0, S, orNR42;
X
42 is CR 44 or N;
Y
40 is N or CR 4 3 ;
Y
41 is N or CR 45 ;
Y
42 , for each occurrence, is independently N, C or CR 46 ; Z is OH, SH, or NHR 7 ; 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, C:\NRPonbI\DCCREC4075614_1 DOC-1/10/2012 - 83 -NRoR, -OR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)NRioR 1 ,
-C(NR
8
)OR
7 , -C(NR 8 )R7, -C(NR8)N RioR 11 , -C(N R 8 )SR7, -OC(O)R 7 , -OC(O)OR 7 , -OC(S)OR 7 ,
-OC(NR
8 )OR7, -SC(O)R 7 , -SC(O)OR7, -SC(NR 8
)OR
7 , -OC(S)R7, -SC(S)R 7 , -SC(S)OR 7 ,
-OC(O)NR
0 oR 1 , -OC(S)NR 0 oR 1, -OC(NR 8 )NRoR, 1 , -SC(O)NR 0 oR 1 , -SC(NR)NRioR 1 , -SC(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -C(O)NRoR, 1 , -N R 8 C(O)R7, -N R7C(S)R 7 , -N R7C(S)OR7, -NR7C(NR)R 7 , -N R7C(O)OR7, -NR7C(N R 8 )OR7, -NR7C(O)NRioR, -NR7C(S)NRioR 1 , -NR 7 C(N R 8 )NRoR, 1 , -SR7, -S(O)pR 7 , -OS(O)pR 7 , -OS(O),OR 7 , -OS(O),N R 1 ioR 1 , -S(O)pOR 7 , -N R 8
S(O),R
7 , -NR 7 S(O),NRioR 1 , -NR 7
S(O),OR
7 , -S(O)pNR 0 oR 1 ,
-SS(O),R
7 , -SS(O),OR7, -SS(O)pN R 1 oR 1 , -OP(O)(OR7) 2 , or -SP(O)(OR) 2 ;
R
4 2 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, -(CH 2 )mC(O)OR 7 , -C(O)OR7, -OC(O)R7, -C(O)NRioR 1 , -S(O)pR7, -S(O)pOR 7 , or -S(O)pNRIoRII;
R
4 3 and R 4 4 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)NRioRII, -NR 8
C(O)R
7 , -SR 7 , -S(O),R 7 , -OS(O),R7,
-S(O),OR
7 , -NRsS(O)pR7, -S(O)pNRioR 1 , or R43 and R4 4 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, -NR 7 H, -OR 26 , -SR 26 , -NHR 26 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -OC(O)NRoR 1 , -SC(O)NRoR 1 , -NR 7 C(O)NRioR 1 , -OC(O)R7, -SC(O)R 7 ,
-NR
7 C(O)R7, -OC(O)OR 7 , -SC(O)OR7, -NR7C(O)OR7, -OCH 2
C(O)R
7 , -SCH 2 C(O)R7, -NR7CH 2 C(O)R7, -OCH 2 C(O)OR7, -SCH 2 C(O)OR7, -NR 7
CH
2 C(0)OR7 ,
-OCH
2 C(O)NRioR 11 , -SCH 2 C(O)NRioR 11 , -NR7CH 2 C(O)NRioR 1 , -OS(O)pR7, -SS(O),R 7 , -NRS(O)pR7, -OS(O),NRjoR 1 , -SS(O)pNRjoR 11 , -NR 7 S(O),NRioR 11 , -OS(O)pOR 7 , -SS(O)pOR 7 , -NR 7 S(O)pOR 7 , -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR 7 ,
-SC(S)OR
7 , -NR7C(S)OR7, -OC(S)NRioR 1 , -SC(S)NRIORII, -NR7C(S)NRIORII, CN RPonbhDCOREC04075614_ .DOC-l/2012 - 84 -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 , -SC(NR 8
)OR
7 ,
-NR
7
C(NR
8 )OR7, -OC(NR 8 )NRioR 1 , -SC(NR)NRoR, or -NR 7 C(NR)NRIOR ;
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, -NRIOR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NRioR 1 ,
-NR
8
C(O)R
7 , -SR7, -S(O),R7, -OS(O),R7, -S(O),OR7, -NR 8 S(O),R7, or -S(O)pNRIoRII; R7, R 8 , Rio, R 1 1, R 2 6 , p, and m are defined as above. In one embodiment, in formula (XXX), X 4 ] is NR 4 2 and X 42 is CR 44 . In another embodiment, in formula (XXX), X 41 is NR 4 2 and X 42 is N. In another embodiment, in formula (XXX), R41 is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy. In another embodiment, in formula (XXX), R41 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. In another embodiment, in formula (XXX), 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(R27) 2 , and -C(O)OH, wherein R 2 7 , for each occurrence, is independently is -H or a lower alkyl. In another embodiment, in formula (XXX), X 41 is NR 42 , and 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 )mC(O)OH, -CH2OCH 3 , -CH2CH 2 0CH 3 , and -C(O)N(CH 3
)
2 . In one embodiment, Y 40 is CR 4 3 . Preferably, Y 40 is CR 4 3 and R 4 3 is H or a lower alkyl. In another embodiment, in formula (XXX), 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 formula (XXX), X 42 is CR 44 ; Y is CR4 3 ; and R43 and R4 4 together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring. In one aspect of this embodiment, R43 and R4 4 together with the carbon atoms to which they are attached form a Cs-C 8 cycloalkenyl or a Cs-Cs aryl. In another embodiment, in formula (XXX), R45 is selected from the group consisting of -H, -OH, -SH, -NH 2 , a lower alkoxy, a lower alkyl amino, and a lower dialkyl amino. In another embodiment, in formula (XXX), R45 is selected from the group consisting of -H, -OH, methoxy and ethoxy.
C:\NRPornb\DCC\REC\W 5614_.DOC-1/10/2012 -85 In another embodiment, in formula (XXX), X 41 is 0. In another embodiment, the compound is selected from the group consisting of: 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-7-methoxy-benzofuran-4-yl)-5-mercapto [1,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(benzofuran-5-yl)-5-mercapto-[1,2,4]triazole, 3-(2,4-d ihydroxy-5 -ethyl-phenyl)-4-(2-methyl- 1,3-benzoxaz-5 -yl)-5-mercapto [I ,2,4]triazole, and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. In another embodiment, in formula (XXX), Z is -OH. In another embodiment, the compound is selected from the group consisting of: 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[ I,2,4]triazole, 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy [I ,2,4]triazole, 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(I -methyl-indol-5-yi)-5-hydroxy-[ I,2,4]triazole, 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(I -isopropyl-indol-4-yl)-5-hydroxy [1,2,4]triazole, and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. In another embodiment, Z is -SH. In another embodiment, the compound is selected from the group consisting of: 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1 -methyl-indazol-5-yl)-5-mercapto [1,2,4]triazole, 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(I -methyl-indazol-6-yl)-5-mercapto [I,2,4]triazole, and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. Compounds of formula (XXX) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (XXX) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
CANRPornblDCC\REC\4Ol5614_ I DOC-1110/2012 -86 In another aspect, the invention provides compounds represented by formula (XXXI): R5 1 N / R43 N \4Z1 HOH OH N-N (XXXI) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein: Z, is -OH or -SH;
X
42 , R41, R 42 , R43, and R45 are defined as above. In one embodiment, in formula (XXXI), Z, is -OH. In another embodiment, in formula (XXXI), Z, is -SH. In another embodiment, in formula (XXXI), R 4 1 is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy. In another embodiment, in formula (XXXI), R4 1 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. In another embodiment, in formula (XXXI), R 42 is selected from the group consisting of lower alkyl, lower cycloalkyl, -C(O)N(R 2 7
)
2 , or -C(O)OH, wherein R27, for each occurrence, is independently is -H or a lower alkyl. In another embodiment, in formula (XXXI), 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 )mC(O)OH, -CH 2 0CH 3 , -CH 2
CH
2
OCH
3 , and -C(O)N(CH 3
)
2 . In another embodiment, R43 is H or a lower alkyl. In another embodiment, in formula (XXXI), X 42 is CR 44 , and R43 and R 44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. In another embodiment, in formula (XXXI), X 42 is CR 44 , and R43 and R44, taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or C\NRPortbl\DCC\RECO075614_ DOC- I[0/2012 -87 heteroaryl ring. Preferably, in this embodiment, R43 and R 4 4 , 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. In another embodiment, in formula (XXXI), R 4 5 is selected from the group consisting of -H, -OH, -SH, -NH 2 , a lower alkoxy, a lower alkyl amino, and a lower dialkyl amino. In another embodiment, in formula (XXXI), R4 5 is selected from the group consisting of -H, -OH, methoxy, and ethoxy. In another embodiment, in formula (XXXI), X 43 is CR 44 . In another embodiment, the compound is selected from the group consisting of: 3-(2,4-dihydroxyphenyl)-4-(l -ethyl-indol-4-yl)-5-mercapto-[ I,2,4]triazole, 3-(2,4-dihydroxyphenyl)-4-(1 -isopropyl-indol-4-yl)-5-mercapto-[ l,2,4]triazole, 3-(2,4-dihydroxyphenyl)-4-(indol-4-yI)-5-mercapto-[ 1,2,4]triazole, 3-(2,4-dihydroxyphenyl)-4-(1 -methoxyethyl-indol-4-yl)-5-mercapto-[ I,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(I -isopropyl-indol-4-yl)-5-mercapto-[ l,2,4]triazole, 3-(2,4-dihydroxyphenyl)-4-(1 -dimethylcarbamoyl-indol-4-yl)-5-mercapto-[ I,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1 -propyl-indol-4-yl)-5-mercapto-[ I,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2,3-trimethyl-indol-5-yl)-5-mercapto [I,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl-indol-5-yl)-5-mercapto-[ I,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(I -acetyl-2,3-dimethyl-indol-5-yl)-5-mercapto [I,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(I -isopropyl-7-methoxy-indol-4-y)-5-mercapto [1,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(I -propyl-2,3-dimethyl-indol-5-yl)-5-mercapto [1,2,4]triazole, 3-(2,4-d ihydroxy-5 -ethyl-phenyl)-4-(N-methyl-tetrahydrocarbozol-7-yl)-5-mercapto [1,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-cyclononan[a]indol-5-yl)-5-mercapto [I,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(I -n-butyl-indol-4-yi)-5-mercapto-[ I,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(I -n-pentyl-indol-4-yl)-5-mercapto-[ 1,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1 -n-hexyl-indol-4-yl)-5-mercapto-[ I,2,4]triazole, 3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1 -(1 -methylcyclopropyl)-indol-4-yl)-5 mercapto-[ 1,2,4]triazole, C ANRPontbIU)MCN~F4fi7.%14_ DO>C-1110f2012 - 88 3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-( 1 -isopropyl-7-methoxy-indol-4-yI)-5 mercapto-[ 1 ,2,4]triazole, 3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-( 1,2,3 -trimethyl-indol-5-yI)-5-mercapto [1,2,4]triazole, 3 -(2,4-d ihydroxy-5 -ethyl -phenyl)-4-( I -isopropyl-7-methoxy-i ndol-4-yI )-5 -mercapto [1 ,2,4]triazole disodium salt, 3 -(2,4-d ihydroxy-5 -tert-butyl-phenyl)-4-( 1 -isopropyl-7-methoxy-indol-4-yI)-5 -mercapto 1 ,2,4]triazole, 3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-( 1 -propyl-7-methoxy-indol-4-yI)-5-mercapto [ 1,2,4]triazole, 3-(2,4-d ihydroxy-5-ethyl-phenyl)-4-( I -methyl-3-ethyl-indol-5-yl)-5-mercapto [ 1,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1I,3-dimethyl-indol-5-yI)-S-mercapto-[ I ,2,4]triazole, 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-( I -isopropyl-7-methoxy-indol-4-yI)-S-mercapto [ 1,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-( I -methyl-3-isopropyl-indoi-5-yI)-5-mercapto [ 1,2,4]triazole, 3 -(2,4-d i hyd roxy-5 -ethylI-phenyl )-4-(N -ethyl -carbozolI-7-y l)-5 -m ercapto- [ I ,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-( I -isopropyl-7-hydroxy-indol-4-yI)-5-mercapto [ 1,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-( I -isopropyl-7-ethoxy-indol-4-yl)-5-mercapto [I ,2,4]triazole, 3-(2,4-d ihydroxy-5-ethyl-phenyl)-4-(1I,2-dimethyl-indol-5-yl)-5-mercapto-[ I ,2,4]triazole, 3-(2,4-d ihydroxy-5-ethyl-phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto-[ I ,2,4]triazole, 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1I,3-dimethyl-indol-5-yI)-S-mercapto [I ,2,4]triazole, 3-(2,4-d ihydroxy-5-cyclopropyl-phenyl)-4-( 1,3-dimethyl-indol-5-yI)-5-mercapto [I ,2,4]triazole, 3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-( I -methyl-indol-5-yi)-5-mercapto [I ,2,4]triazole, 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-( I H-indol-5-yi)-5-mercapto-[ I ,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1I,2-dimethyl-indol-5-yI)-5-mercapto-[ I ,2,4]triazole, 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-( I -ethyl-indol.5-yi)-5-mercapto-[ I ,2,4]triazole, CANRPortblDCC\REC\4075614ILDOC-1/10/2012 - 89 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(I -propyl-indol-5-yl)-5-mercapto-[ I,2,4]triazole, and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. In another embodiment, in formula (XXXI), X 42 is N. In another embodiment, the compound is selected from the group consisting of 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(] -ethyl-benzimidazol-4-yl)-5-mercapto [I,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(I-ethyl-benzimidazol -4-yl)-5-mercapto [ I,2,4]triazole HCL salt, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-3-ethyl-benzimidazol-5-yl)-5-mercapto [I,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(I -ethyl-2-methyl-benzimidazol-5-yl)-5-mercapto [ l,2,4]triazole, 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1 -methyl-2-trifluoromethyl-benzimidazol-5-yl) 5-mercapto-[ ,2,4]triazole, and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. Compounds of formula (XXXI) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (XXX I) are particularly useful in treating cancer when given in combination with other anti-cancer agent. In another aspect, the invention provides compounds represented by formula (XXXII): R55
/R
52 N RR53 HO / X_ )X45 N \ /Z1 OH N-N (XXXII) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein: C:\NRPortbl\DCC\REC\4075614_ DOC.1/10/2012 - 90 X 4 5 is CR 5 4 or N; Zi is -OH or -SH;
R
5 2 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, -(CH 2
)
2 0CH 3 , -CH 2 C(O)OH, and -C(O)N(CH 3
)
2 ;
R
5 3 and R 54 are each, independently, -H, methyl, ethyl, or isopropyl; or R 5 3 and R 5 4 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 -OCH 2
CH
3 ; and
R
56 is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl. In one embodiment, in formula (XXXII), Z, is -OH. In another embodiment, in formula (XXXII), Zi is -SH. In another embodiment, in formula (XXXII), R 53 is H or a lower alkyl. In another embodiment, in formula (XXXII), X 4 5 is CR 54 . Preferably, R 54 is H or a lower alkyl. In another embodiment, X 4 5 is N. In another embodiment, the compound is 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(N methyl-indol-5-yl)-5-mercapto-[l,2,4]triazole. Compounds of formula (XXXII) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (XXXII) are particularly useful in treating cancer when given in combination with other anti-cancer agent. In another aspect, the invention provides compounds represented by formula (XXXIll): '2 \ HO Y44 Y42 N N Z OH N-N (XXXIII) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein,
X
44 , for each occurrence, is independently, 0, NR 42 or C(R46)2; C.\NRPortbl\DCC\RECW0756 4_ .DOC-1/1012012 - 91 Y 43 is NR 42 or C(R46)2;
Y
4 1 , Y 42 , Z, R41, R 42 , and R 46 are defined as above. In one embodiment, in formula (XXXIII), R 41 is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy. In another embodiment, in formula (XXXIII), Ra1 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. In another embodiment, in formula (XXXIII), 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, -(CH 2 )mC(O)OH, -CH 2 0CH 3 , -CH 2
CH
2 0CH 3 , and -C(O)N(CH 3
)
2 . In another embodiment, in formula (XXXIII), Y 41 is CR 45 . Preferably, R4s is H, a lower alkoxy, or -OH. In another embodiment, in formula (XXXIII), Y 42 is CH. In another embodiment, in formula (XXXIII), Y 43 is CH 2 . In another embodiment, in formula (XXXIII), Y 43 is NR 42 , wherein R 42 is H or a lower alkyl. In another embodiment, in formula (XXXIII), one of X 44 is NR 42 and the other is CH 2 or
C(R
6
)
2 . Preferably, one of X 44 is NR 42 and the other is CH 2 . In another embodiment, in formula (XXXIII), Z is -OH. In another embodiment, Z is -SH. Compounds of formula (XXXIII) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (XXXIII) are particularly useful in treating cancer when given in combination with other anti-cancer agent. In another aspect, the invention provides compounds represented by formula (XXXIV): FR46 41 HO N Y42N N / Z OH N-N
(XXXIV)
C:WRPortbl\DCC\REC4075614_I DOC-1/1/2012 - 92 and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein:
X
4 1 , Y 4 1 , Y 42 , Z, R 7 , R 8 , Rio, R 11 , R41, R 4 6 , and p are defined as above. In one embodiment, in formula (XXXIV), R 4 1 is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy. In another embodiment, in formula (XXXIV), R41 is selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. In another embodiment, in formula (XXXIV), X 4 1 is NR 42 . Preferably, 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 )mC(O)OH, -CH 2
OCH
3 , -CH 2
CH
2 0CH 3 , and
-C(O)N(CH
3
)
2 . More preferably, R 42 is H or a lower alkyl. In another embodiment, in formula (XXXIV), X 41 is 0. In another embodiment, in formula (XXXIV), X 4 ] is S. In another embodiment, in formula (XXXIV), Y 4 1 is CR45. Preferably, R45 is H, a lower alkoxy, or -OH. In another embodiment, in formula (XXXIV), Y 42 is CH. In another embodiment, in formula (XXXIV), Ra is H or a lower alkyl. In one embodiment, the compound is 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(2-methyl indazol-6-yi)-5-mercapto-[ I,2,4]triazole. Compounds of formula (XXXIV) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (XXXIV) are particularly useful in treating cancer when given in combination with other anti-cancer agent. In one embodiment the present invention provides compounds having formula (I) as described above or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
C.%NRPonb1\flCM~ECN4073i64_1 DOC. 1110/2012 - 93 In another embodiment, the compounds of the present invention can be represented by structural formula (XXXV): NRaRb (R3o)y
(R
7 1)X
N
(XXXV) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof. In formula (XXXV), R, is -OH, -SH, -NR 7 H, -OR 26 , -SR 26 , -NHR 26 , -O(CHA 2 )mOH, 0O(CH 2 )mSH, 0O(CH 2 ),N R 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(GH 2 ),N R 7 H, -OC(O)NRIORII,
SC(O)NR
0
R
11 , -NR 7
C(O)NR
0
R
11 , -OC(O)R 7 , -SC(O)R 7 , -NR 7
C(O)R
7 , -OC(O)0R 7 , SC(O)0R 7 , -N R 7 C(O)0R 7 , -OCH 2
C(O)R
7 , -SCH 2
G(O)R
7 , -N R 7
CH
2
C(O)R
7 , -OCH 2 C(O)0R 7 ,
-SCH
2 C(O)0R 7 , -N R 7 CI-bC(O)0R 7 , -OCH 2
C(O)NR
0
R
11 , -SCH 2 C(O)N RoR,,
-NR
7
CH
2 C(O)N R 10
R
11 , -OS(O)pR 7 , -SS(O)pR 7 , -S(O)pOR 7 , -N R 7 S(O)pR 7 , -OS(O)pNR 10 R,, -SS(O)pNRoR 11 , -N RS(O)pN R 10
R,
1 , -OS(O)pOR 7 , -SS(O),OR 7 , -N R 7 S(O)pOR 7 , -OC(S)R 7 ,
-SC(S)R
7 , -NR 7
C(S)R
7 , -OC(S)0R 7 , -SC(S)0R 7 , -NR 7 C(S)0R 7 , -OC(S)NR 0
R
1 ,, -SC(S)N R 10
R
1 1 , -N R 7 C(S)N R 10
R
11 , -OC(N R 8
)R
7 , -SC(N R 8
)R
7 , -N R 7 C(N R8)R 7 , -OC(NR 8 )0R 7 , -SC(N R 8 )0R 7 , -N R 7 C(N R 8 )0R 7 , -OC(N R 8
)NR
10
R
11 , -SC(NR 8
)NR
0
R
11 , -N R 7
C(NR
8
)NR
0
R
11 , OP(O)(0R 7
)
2 , or -SP(O)(0R 7
)
2 . Preferably, R, is -OH, -SH, -NHR 7 , -OC(O)NR 0
R
1 I SC(O)NR 0 R, 1 , -OC(O)R 7 , -SC(O)R7, -OC(O)0R 7 , -SC(O)0R 7 , -OS(O)pR 7 , -S(O)pOR 7 , -SS(O)pR 7 , -OS(O)pOR 7 , -SS(O)pOR 7 , -OC(S)R 7 , -SC(S)R 7 , -OC(S)0R 7 , -SC(S)0R 7 , -OC(S)NR 0 R,,
-SC(S)NR
0
R
11 I, -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -OC(NR 8 )0R 7 , -SC(NR 8 )0R 7 , -OP(O)(OR7) 2 or -SP(O)(0R 7
)
2 . More preferably, R, is -OH, -SH, or -NHR?. Even more preferably, R 1 , is -SH or -OH;
R
3 iS 0OH, -SH, -NR 7 H, -NHR 26 , 0O(CH 2 )mOH, 0O(CH 2 )mSH, 0O(CH 2 )mNR 7 H, S(CH 2 ), OH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, 0OC(O)NRI 0 RII, -SC(O)NRI 0 RII, NR 7
C(O)NR
0
R
11 , -OC(O)R 7 , -SC(O)R 7 , -NR 7
C(O)R
7 , -OC(O)0R 7 , -SC(O)0R 7
,
NR
7 C(O)0R 7 , -OCH 2 C(O)R7, -SCH 2
C(O)R
7 , -NR 7
CH
2
C(O)R
7 , -OCH 2 C(O)0R 7
,
SCH
2 C(O)0R 7 , -NR 7
CH
2 C(O)0R 7 , -OCH 2
C(O)NR
0
R
1 , -SCH 2
C(O)NR
0
R,
1 , N R 7
CH
2 C(O)N R 10
R,
1 , -OS(O)pR7, -SS(O)pR,-S(O)pOR7, -N R 7 S(O)pR 7 , -OS(O)pN R 10
R,
1
,
C-\NRPonbI\DCCRECM07564_I DOC-1/10/2012 - 94 -SS(O),NRoR, -NR7S(O),NRioR 1 , -OS(O),OR 7 , -SS(O)pOR 7 , -NR 7 S(O)pOR 7 , -OC(S)R 7 , -SC(S)R7, -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR, -SC(S)NRioR 11 , -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR)OR 7 ,
-SC(NR
8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR 8 )NRioR 1 , -SC(NR)NRioR 1 , -NR 7 C(NR)NRioRa, -C(O)OH, -C(O)NHR 8 , -C(O)SH, -S(O)OH, -S(O) 2 0H, -S(O)NHR 8 , -S(O) 2
NHR
8 ,
-OP(O)(OR)
2 , or -SP(O)(OR 7
)
2 . In another embodiment, -OR 26 and -SR 26 , are additional values for R 3 . Preferably, R 3 is -OH, -SH, -NHR 7 , -OC(O)NRIOR a,-SC(O)NRIOR n,-OC(O)R 7 , -SC(O)R 7 ,
-OC(O)OR
7 , -SC(O)OR 7 , -OS(O),R 7 , -S(O),OR 7 , -SS(O),R7, -OS(O),OR 7 , -SS(O),OR7, -OC(S)R 7 ,
-SC(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -OC(S)NRioR 1 , -SC(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(N R 8
)R
7 ,
-OC(NR
8
)OR
7 , -SC(NR 8
)OR
7 , -OP(O)(OR 7
)
2 or -SP(O)(OR 7
)
2 . More preferably, R 3 is -OH, -SH, or -NHR 7 . Even more preferably, R 3 is -SH or -OH;
R
70 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 heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NRioR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -C(S)R 7 , -C(O)SR 7 , -C(S)SR 7 , -C(S)OR7, -C(S)NR 0 oR 1 , -C(NR8)OR 7 , -C(NR 8 )R7, -C(N R 8 )N R oR, -C(N R 8
)SR
7 , -OC(O)R 7 , -OC(O)OR 7 , -OC(S)OR 7 , -OC(NR8)OR 7 , -SC(O)R 7 , -SC(O)OR 7 ,
-SC(NR
8
)OR
7 , -OC(S)R 7 , -SC(S)R 7 , -SC(S)OR 7 , -OC(O)NRioR 1 , -OC(S)NRioR 1 , OC(NR 8
)NR
0 oR 1 , -SC(O)NRIOR 1 , -SC(NR)NRIOR 1 , -SC(S)NRIOR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -C(O)N R oR 1 , -N R 8
C(O)R
7 , -N R 7
C(S)R
7 , -NR 7
C(S)OR
7 , -NR 7 C(N R 8
)R
7 , -NR 7
C(O)OR
7 ,
-NR
7
C(NR
8
)OR
7 , -NR 7
C(O)NRIOR
1 , -NR 7 C(S)NRoR, -NR 7
C(NR
8 )NR,oR,, -SR 7 , -S(O),R 7 ,
-OS(O),R
7 , -OS(O),OR 7 , -OS(O),NRoR 1 , -S(O),OR 7 , -N R 8
S(O),R
7 , -NR 7 S(O),N RioR 11 , -N R 7
S(O),OR
7 , -S(O),NRIORII, -SS(O),R 7 ,
-SS(O),OR
7 , -SS(O),NRIOR, 1, -OP(O)(OR 7
)
2 , or -SP(O)(OR 7
)
2 . Preferably, R7 0 for each occurrence, is independently 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 , -NRoR 1 , -OC(O)NRjoRjj, -SC(O)NRioR 1 , -NR 7 C(O)NRIORII, -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
7 , -OCH 2
C(O)OR
7 , -SCH 2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRioR,
-SCH
2 C(O)NRioR 11 , -NR 7
CH
2 C(O)NRioR 11 , -OS(O),R 7 , -SS(O),R 7 , -NR 7
S(O),R
7
,
C :NRPornblDCC\REU(075614_ .DOC-1/10/2012 - 95 -OS(O)pNRIoR 1 , -SS(O),NRIoR 1 , -NR 7 S(O)pNRioR 1 , -OS(O)pOR 7 , -SS(O),OR 7 ,
-NR
7
S(O),OR
7 , -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , OC(S)NRIoR 11 , -SC(S)NRIoR 11 , -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8 )R7, -NR 7
C(NR
8
)R
7 , -OC(NR8)OR 7 , -SC(NRs)OR 7 , -NR 7
C(NR
8
)OR
7 , -OC(NR 8 )NRioR 1 , -SC(NR)NRioR,
-NR
7 C(NR)NRioR 1 , -C(O)R 7 , -C(O)OR 7 , -C(O)NRIoR 11 , -C(O)SR 7 , -C(S)R 7 , -C(S)OR 7 , -C(S)NRioR 1 , -C(S)SR 7 , -C(NR 8
)OR
7 , -C(NR 8
)R
7 , -C(NR 8 )NRIoR] 1 , -C(NR 8
)SR
7 , -S(O)pOR 7 , -S(O)pNRIORo, or -S(O)pR 7 . More preferably, Ry for each occurrence, is independently a CI-C6 alkyl, a Cl-C6 haloalkyl, a CI-C6 alkoxy, a Cl-C6 haloalkoxy, a CI-C6 alkyl sulfanyl or a C3-C6 cycloalkyl. Even more preferably, R70 for each occurrence, is independently cyclopropyl or isopropyl;
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. Preferably, R 7 and R 8 , for each occurrence, is independently -H, CI-C3 alkyl, C I-C6 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. More preferably, R 7 and R 8 , for each occurrence, is independently -H or CI -C3 alkyl. RIO and R, 1 , 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. Preferably, RIO and R 1 , for each occurrence, is independently -H, CI-C3 alkyl, CI-C6 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. More preferably, RIO and R, 1 , for each occurrence, is independently -H or CI-C3 alkyl. Alternatively, RIO and R, 1 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl. Preferably Rio and R, 1 , taken together with the nitrogen to which they are attached, form an optionally substituted imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, iosoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrazinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, pyranzinyl, thiomorpholinyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl. More preferably Rio and R 1 , taken together with C :NRPotbl\CC\RECW75614_LDOC-1/10/2012 - 96 the nitrogen to which they are attached, form an optionally substituted pyrrolidinyl, piperidinyl, piperazinyl, tetrahydroisoquinolinyl, morpholinyl or pyrazolyl.
R
71 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 heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NRIORII, -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)NRIORII,
-C(NR
8
)OR
7 , -C(NR 8
)R
7 , -C(NR)NR 0 oR 1 , -C(NR 8
)SR
7 , -OC(O)R 7 , -OC(O)OR 7 , -OC(S)OR 7 , -OC(NRs)OR 7 , -SC(O)R 7 , -SC(O)OR 7 , -SC(NR 8
)OR
7 , -OC(S)R 7 , -SC(S)R 7 , -SC(S)OR 7 , -OC(O)NRioR 1 , -OC(S)NRioR 1 , -OC(NR)NRIOR 1 , -SC(O)NRioR 1 , -SC(NR 8 )NRioR 1 , -SC(S)NR 1 oR 11 , -OC(N R 8
)R
7 , -SC(NR 8
)R
7 , -C(O)NR 0 oR, -NR 8
C(O)R
7 , -NR 7
C(S)R
7 , -N R 7
C(S)OR
7 , -N R 7
C(NR
8
)R
7 , -NR 7
C(O)OR
7 , -NR 7
C(NR
8
)OR
7 , -N R 7 C(O)NRioR 1 , -N R 7
C(S)NR
0 oR I, -NR 7
C(NR
8 )N R 1 oR 1 , -SR 7 , -S(O),R 7 , -OS(O),R 7 , -OS(O),OR 7 ,
-OS(O),NR
0 oR 1 , -S(O),OR 7 , -NR 8
S(O),R
7 , -N R 7 S(O)pN R 1 oR 11 , -NR 7
S(O),OR
7 , -S(O)pNRioR 1 ,
-SS(O),R
7 ,
-SS(O),OR
7 , -SS(O),NRioR 1 , -OP(O)(OR 7
)
2 , or -SP(O)(OR 7
)
2 . Preferably R 71 for each occurrence, is independently -OH, -SH, -NHR 7 , -(CH 2 )kOH, -(CH 2 )kSH, -(CH 2 )kNR 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)NRioR 1 , -SC(O)NRioR 1 , -NR 7
C(O)NR
0 oR,
-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
7 , -OCH 2
C(O)OR
7 , -SCH 2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 ,
-OCH
2 C(O)NRioRII, -SCH 2 C(O)NRioR 11 , -NR 7
CH
2 C(O)NRioR 1 , -OS(O),R 7 , -SS(O),R 7 ,
-NR
7
S(O),R
7 , -OS(O),NRoR, 1 , -SS(O),NRjoR 11 , -NR 7 S(O),NRioR 1 , -OS(O),OR 7 , -SS(O),OR 7 ,
-NR
7
S(O),OR
7 , -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , OC(S)NRioR 1 , -SC(S)NRioR 11 , -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 ,
-OC(NR
8
)OR
7 , -SC(NRs)OR 7 , -NR 7
C(NR
8
)OR
7 , -OC(NR 8 )NRioR 1 1 , -SC(NR 8 )NRioR 1 ,
-NR
7
C(NR
8 )NRioR 11 , -C(O)R 7 , -C(O)OR 7 , -C(O)NRioR 11 , -C(O)SR 7 , -C(S)R 7 , -C(S)OR 7 , -C(S)NRioR 11 , -C(S)SR 7 , -C(NRs)OR 7 , -C(NR 8
)R
7 , -C(NR 8 )NR oR , -C(NR 8
)SR
7 , -S(O)pOR 7 ,
-S(O),NRIOR
1 , or -S(O),R 7 . More preferably, R 7 1 for each occurrence, is independently -OH, -SH, -NHR 7 , -OC(O)NRioR 1 , -SC(O)NR 0 oR 1 , -OC(O)R 7 , -SC(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 ,
-OS(O)PR
7 , -S(O)pOR 7 , -SS(O),R 7 , -OS(O)pOR 7 , -SS(O),OR 7 , -OC(S)R 7 , -SC(S)R 7 , -OC(S)OR 7 ,
-SC(S)OR
7 , -OC(S)NR 0 oR 1 , -SC(S)NR 0 oR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -OC(NR 8
)OR
7
,
C:\RPonb\DCC\REC40756i4_I DOC-1110/2012 - 97 -SC(NR 8 )OR7, -OP(O)(OR) 2 or -SP(O)(OR 7
)
2 . Even more preferably, R 71 for each occurrence, is independently -SH or -OH;
R
26 is a C I-C6 alkyl;
R
30 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 heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NRoR 1 , -OR7, -C(O)R 7 , -C(0)OR 7 , -C(S)R 7 , -C(O)SR 7 , -C(S)SR 7 , -C(S)OR 7 , -C(S)NR 0 oR 1 ,
-C(NR
8
)OR
7 , -C(N R 8
)R
7 , -C(NR 8 )NR oR I, -C(NR 8 )SR7, -OC(O)R 7 , -OC(O)OR 7 , -OC(S)OR 7 ,
-OC(NR
8
)OR
7 , -SC(O)R 7 , -SC(0)OR 7 , -SC(NR 8
)OR
7 , -OC(S)R 7 , -SC(S)R 7 , -SC(S)OR 7 , -OC(O)NRioR 1 , -OC(S)NRioR 1 , -OC(NR 8 )NRioR o, -SC(O)NRioR 1 , -SC(NR)NRioR, -SC(S)N RIoRll, -OC(NR 8
)R
7 , -SC(N R 8
)R
7 , -C(O)NR IORI, -NR 8
C(O)R
7 , -NR 7
C(S)R
7 ,
-NR
7
C(S)OR
7 , -N R 7 C(N R 8
)R
7 , -NR 7
C(O)OR
7 , -NR 7 C(N R 8
)OR
7 , -NR 7 C(O)NRioR 1 , -N R 7 C(S)NRIOR 1 , -N R 7
C(NR
8 )N RioR 1, -SR 7 , -S(O),R 7 , -OS(O),R 7 , -OS(O),OR 7 , -OS(O)pN RioR 1 , -S(O),OR 7 , -NR 8
S(O),R
7 , -N R 7 S(O)pN RioR 1 , -N R 7 S(O)pOR 7 , -S(O),N RioR 11 , SS(O),R 7 , -SS(O),OR 7 , -SS(O),NR oR 1 , -OP(O)(OR) 2 , or -SP(O)(OR 7
)
2 . Preferably R 3 0 for each occurrence, is independently 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 , -NRioR, -OC(O)NRioR 1 , -SC(O)NRioR 1 , -NR 7 C(O)NRioR 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 , -SCH 2
C(O)R
7 ,
-NR
7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 , -SCH 2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRioR 1 , SCH 2 C(O)NRoR 1 , -NR 7
CH
2 C(O)NRioR 1 , -OS(O),R,, -SS(O),R 7 , -NR 7
S(O),R
7 , OS(O),NRioR 1 , -SS(O),NR 0 oR, -NR 7 S(O),NRioR 11 , -OS(O),OR 7 , -SS(O),OR 7 , NR 7 S(O)pOR 7 , -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , OC(S)NRioR 11 , -SC(S)NRIORII, -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 ,
-OC(NR
8
)OR
7 , -SC(NR 8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR 8 )NRioRII, -SC(NR 8 )NRioR,
-NR
7
C(NR
8 )NRioR 11 , -C(O)R 7 , -C(O)OR 7 , -C(O)NRioR , -C(O)SR 7 , -C(S)R 7 , -C(S)OR 7 , -C(S)NRioR 11 , -C(S)SR 7 , -C(NR8)OR 7 , -C(NR 8
)R
7 , -C(NR 8 )NRioR 1 , -C(NR 8
)SR
7 , -S(O)pOR 7 , -S(O),NRIOR 1 , or -S(O)pR 7 . More preferably, R 30 for each occurrence, is independently a hydrogen, -OH, -SH, halogen, cyano, a Cl-C6 alkyl, Cl-C6 haloalkyl, CI -C6 alkoxy, Cl -C6 C:NRPortbl\DCC\REC4075614 1 DOC-1/10/2012 - 98 haloalkoxy or Cl -C6 alkyl sulfanyl. Even more preferably, R 30 for each occurrence, is independently a hydrogen, methyl, ethyl, propyl, isopropyl, methoxy or ethoxy;
R
35 is -H, a Cl -C4 alkyl or a Cl-C4 acyl; 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. Preferably, Ra and Rb for each occurrence, is independently a hydrogen, a Cl -C6 straight or branched alkyl, optionally substituted by -OH, -CN, -SH, amino, a CI-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl. More preferably, Ra and Rb for each occurrence, is independently a hydrogen, methyl, ethyl, propyl, isopropyl; Alternatively, Ra and Rb, taken together with the nitrogen to which they are attached, form an optionally substituted heteroaryl or heterocyclyl. Preferably, R' and Rb taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen containing heterocyclyl. More preferably, Ra and Rb taken together with the nitrogen to which they are attached, are: -N No -N N-R 35 N\-/0 -N \ /S k is 1, 2, 3 or 4;. p, for each occurrence, is independently, 0, 1 or 2; m, for each occurrence, is independently, 1, 2, 3 or 4; z and y for each occurance, is independently an integer from 0 to 4. Preferably z and y for each occurance, is independently 0, 1, or 2. More preferably z and y for each occurance, is independently 0 or 1; and x is 0 or 1, provided that z+x is less than or equal to 4. In a first preferred embodiment, the values for the variables in formula (IV) are as described in the following paragraphs;
R
7 o, R 71 and R 30 , 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 C-\NRPorbl\DCC\REC\4075614_1 DOC-1/110/2012 - 99 optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NRIOR 1 , -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
0 oR 1 , -C(NR 8
)OR
7 , -C(N R 8
)R
7 , -C(NR 8 )NRioR 1 , -C(NR 8
)SR
7 , -OC(O)R7, -OC(O)OR 7 ,
-OC(S)OR
7 , -OC(NR 8
)OR
7 , -SC(O)R7, -SC(O)OR 7 , -SC(NR 8
)OR
7 , -OC(S)R 7 , -SC(S)R 7 ,
-SC(S)OR
7 , -OC(O)NR 0 oR 1 , -OC(S)NR 0 oR 1 , -OC(NR 8
)NR
1 oR 1 , -SC(O)NRioR 1 ,
-SC(NR)NR
0 oR, -SC(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(N R 8
)R
7 , -C(O)N R 1 oRf, -N R 8
C(O)R
7 ,
-NR
7
C(S)R
7 , -NR 7
C(S)OR
7 , -N R 7 C(N R 8
)R
7 , -N R 7
C(O)OR
7 , -NR 7
C(NR
8
)OR
7 , -N R 7 C(O)NRioR 1 ,
-NR
7 C(S)NRioR, -NR 7
C(NR)NR
0 oR, -SR 7 , -S(O),R 7 , -OS(O),R 7 , -OS(O),OR 7 , OS(O),N R 1 oR 11 , -S(O),OR 7 , -N R 8
S(O),R
7 , -NR 7 S(O),NR oR , -N R 7
S(O),OR
7 , -S(O),NR oR n,
-SS(O),R
7 , -SS(O),OR 7 , -SS(O),NRIoR 1 , -OP(O)(OR) 2 , or -SP(O)(OR 7
)
2 . Preferably, R7o and R 30 are as just described and R 7 1 is -OH, -SH, -NHR 7 , -(CH 2 )kOH, -(CH 2 )kSH, -(CH 2 )kNR7H, 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)NRioR 1 , -SC(O)NRioR 1 , -NR 7 C(O)NRioR 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 ,
-SCH
2
C(O)R
7 , -NR 7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 , -SCH 2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , OCH 2 C(O)NRioR 1 , -SCH 2 C(O)NRoR 1 , -NR 7
CH
2 C(O)NRioR 11 , -OS(O),R 7 , -SS(O),R 7 , NR 7
S(O),R
7 , -OS(O)NR 1 oR 11 , -SS(O),NRoR 11 , -NR 7 S(O),NRioR 1 , -OS(O),OR 7 , -SS(O),OR 7 ,
-NR
7
S(O),OR
7 , -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , OC(S)NRioR 1 , -SC(S)NRioR 1 , -NR 7 C(S)NRoR 11 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 ,
-OC(NR
8
)OR
7 , -SC(NR 8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR)NRioRII, -SC(NR 8 )NRioR 1 ,
-NR
7
C(NR
8 )NRioR 11 , -C(O)R 7 , -C(O)OR 7 , -C(O)NRioR 1 , -C(O)SR 7 , -C(S)R 7 , -C(S)OR7, -C(S)NRioR 1 , -C(S)SR 7 , -C(NR8)OR 7 , -C(NR 8
)R
7 , -C(NR 8 )NRioR 1 , -C(NR 8
)SR
7 , -S(O),OR 7 ,
-S(O),NRIOR
1 , or -S(O),R7; k is 1, 2, 3, or 4; z and y for each occurance, is independently an integer from 0 to 4; x is 0 or 1, provided that n+x less than or equal to 4; and the values and preferred values for the remainder of the variables in formula (IV) are as described immediately above.
C :NRPortbl\DCC\REC\4075614_I DOC-/10/f2012 - 100 In a second preferred embodiment, the present invention provides compounds represented by structural formula (XXXVI): NR"Rb (R3R)0 I, 1 (R71) (R70).N R, \/ N--N R, (XXXVI) The values and preferred values for the variables in formula (XXXVI) are as described above for formula (XXXV). Alternatively, the values and preferred values for the variables in formula (XXXVI) are as described in the first preferred embodiment for formula (XXXV) immediately above. In a third preferred embodiment, the present invention provides compounds represented by structural formula (XXXVII): NR'R b
R
70 (R3D) or 1
R
7 1
R
1 N-N R3 (XXXVII) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof. The values and preferred vaulues for the variables in formula (XXXVII) are as described above for formula (XXXV). Preferably, the values and preferred values for the variables in formula (XXXVII) are as described for formula (XXXVI). More preferably, the values for the variables in formula (XXXVII) are described in the following paragraphs:
R
3 0 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 , -NRioR, -OC(O)NRioR 1 , -SC(O)NRioR 1 , -NR 7 C(O)NRioR, -OC(O)R 7 , -SC(O)R7, -NR 7
C(O)R
7
,
C \NRPortbI\DCCREC4075614_1 DOC-1/10/2012 - 101 -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
7 ,
-OCH
2
C(O)OR
7 , -SCH 2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 ,
-OCH
2 C(O)NRioR, -SCH 2 C(O)NRoR 1 , -NR 7
CH
2 C(O)NRioR 1 , -OS(O),R 7 , -SS(O)pR 7
,-NR
7 S(O)pR 7 , -OS(O),NRoR 1 , -SS(O),NRioR 1 , -NR 7 S(O),NRioR 1 , -OS(O)pOR 7 , SS(O),OR 7 , -NR 7 S(O),OR7, -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 ,
-NR
7
C(S)OR
7 , -OC(S)NRioR 1 , -SC(S)NRioR 1 , -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 ,
-NR
7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 , -SC(NR 8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR 8 )NRioR, 1 ,
-SC(NR
8 )NRioR 1 , -NR 7 C(NR)NRioR 1 , -C(O)R 7 , -C(O)OR 7 , -C(O)NRfoR 1 , -C(O)SR 7 ,
-C(S)R
7 , -C(S)OR 7 , -C(S)NRioR 1 , -C(S)SR 7 , -C(NR 8
)OR
7 , -C(NR 8
)R
7 , -C(NR 8 )NRioR,
-C(NR
8
)SR
7 , -S(O)pOR 7 , -S(O),NRioR 1 , or -S(O),R 7 ; and the values and preferred values for the remainder of the variables are as described above for formula (XXXV). Preferably, the values and preferred values for the remainder of the variables in formula (XXXVII) are as described for formula (XXXVI). More preferably for formula (XXXVII), R 7 0 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 , -NRIOR, -OC(O)NRIORII, -SC(O)NRIORII, -NR 7 C(O)NRioR ,
-OC(O)R
7 , -SC(O)R 7 , -NR 7
C(O)R
7 , -OC(O)OR,, -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
7 , -OCH 2
C(O)OR
7 , -SCH 2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 ,
-OCH
2 C(O)NRioR 1 , -SCH 2 C(O)NRioR 11 , -NR 7
CH
2 C(O)NRioR 1 , -OS(O),R 7 , -SS(O)pR 7 ,
-NR
7
S(O),R
7 , -OS(O)pNRIoR 1 , -SS(O),NRjoR 1 , -NR 7 S(O)pNRioR 11 , -OS(O),OR 7 , -SS(O)pOR 7 ,
-NR
7 S(O)pOR 7 , -OC(S)R 7 , -SC(S)R7, -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioRI, -SC(S)NRioR 1 , -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 ,
-OC(NR
8
)OR
7 , -SC(NR 8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR)NRioR 1 , -SC(NR 8 )NRioR,
-NR
7
C(NR
8 )NRioR 1 , -C(O)R 7 , -C(O)OR 7 , -C(O)NRioR 11 , -C(O)SR 7 , -C(S)R 7 , -C(S)OR 7 , -C(S)NRioR 11 , -C(S)SR 7 , -C(NRs)OR 7 , -C(NR 8
)R
7 , -C(NR 8 )NRioR 11 , -C(NR 8
)SR
7 , -S(O)pOR 7 ,
-S(O),NRIOR
1 , or -S(O),R 7 ; the values for R 3 0 are as described in the preceding paragraph; and the values and preferred values for the remainder of the variables are as described above for formula (XXXV). Preferably, the values and preferred values for the variables in formula (XXXVII) are as described for formula (XXXVI).
C:\NRPonbl\DCC\REC'4075614_ 1DOC.-1/10/2012 -102 In a fourth preferred embodiment, the present invention provides compounds represented by a structural formula selected from formulas (XXXVIII) and (XXXIX) (R30)0 or 1 ab rNRaR (R30) 0 or 1 R71 __/ N R 7 1 / R1 N N-N \ R3 R 3 N-N (XXXVIII) (XXXIX) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof. The values and preferred values for formulas (XXXVIII) and (XXXIX) are as described above for formula (XXXV). Preferably, the values and preferred values for formulas (XXXVIII) and (XXXIX) are as described above for formula (XXXVII). More preferably, the values for the variables in formulas (XXXVIII) and (XXXIX) are described in the following paragraphs:
R
1 , R 3 or R7 1 are each independently -OH, -SH, -NHR 7 , -OC(O)NRIOR, -SC(O)NRIORI 1 , OC(O)R 7 , -SC(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -OS(O),R7, -S(O),OR 7 , -SS(O),R 7 , -OS(O),OR 7 , -SS(O)pOR 7 , -OC(S)R 7 , -SC(S)R 7 , -OC(S)OR 7 , -SC(S)OR 7 , -OC(S)N R ioR 1 -SC(S)N R ioR 1 -OC(N R 8
)R
7 , -SC(N R 8
)R
7 , -OC(N R 8
)OR
7 , -SC(NR 8 )OR7, -OP(O)(OR) 2 or -SP(O)(OR 7
)
2 . Preferably, Ri and R 3 are each, independently, -OH, -SH, or -N HR 7 and R 71 is as just described; and the values and preferred values for the remainder of the variables are as described above for formula (XXXV) or formula (XXXVII). In a first more preferred embodiment for formulas (XXXVIII) and (XXXIX), R 1 , R 3 and
R
7 1 are as described in the immediately preceeding two paragraphs: and Ra and Rb are each independently a hydrogen, a CI-C6 straight or branched alkyl, optionally substituted by -OH, -CN, -SH, amino, a Cl-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or 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; and the values and preferred values for the remainder of the variables are as described above for formula (XXXV) formula (XXXV II). In a second more preferred embodiment for formulas (XXXVIII) and (XXXIX), R 70 is a CI-C6 alkyl, a CI-C6 haloalkyl, a Cl-C6 alkoxy, a CI-C6 haloalkoxy, a Cl-C6 alkyl sulfanyl or a CANRPonbl\DCCREC\4075614_ DOC- 111012012 - 103 C3-C6 cycloalkyl; and the values and preferred values for the remainder of the variables are as described above for first more preferred embodiment for formulas (XXXVIII) and (XXXIX). In a third more preferred embodiment for formulas (XXXVIII) and (XXXIX): R, and R 3 are each, independently, -OH, -SH, or -NHR 7 ;
R
70 is a CI -C6 alkyl, a CI -C6 haloalkyl, a C l -C6 alkoxy, a C I -C6 haloalkoxy, a CI -C6 alkyl sulfanyl or a C3-C6 cycloalkyl;
R
7 1 is -OH, -SH, -NHR 7 , -OC(O)NRioR, 1 -SC(O)NRioR 1 , -OC(O)R 7 , -SC(O)R 7 , OC(O)OR 7 , -SC(O)OR 7 , -OS(O),R 7
-S(O),OR
7 , -SS(O),R 7 , -OS(O),OR 7
-SS(O),OR
7 , -OC(S)R 7 ,
-SC(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -OC(S)N RoR, 1 , -SC(S)NR IOR 1 , -OC(N R 8
)R
7 , -SC(NR 8
)R
7 , -OC(NRs)OR 7 , -SC(NR 8
)OR
7 , -OP(O)(OR) 2 or -SP(O)(OR) 2 ;
R
30 is -OH, -SH, halogen, cyano, a C I-C6 alkyl, CI -C6 haloalkyl, CI -C6 alkoxy, CI -C6 haloalkoxy or CI-C6 alkyl sulfanyl. Preferably, R 30 is methyl, ethyl, propyl, isopropyl, methoxy or ethoxy; R" and Rb are each independently a hydrogen, a CI -C6 straight or branched alkyl, optionally substituted by -OH, -CN, -SH, amino, a Cl-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or 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; and the values and preferred values for the remainder of the variables are as described above for formula (XXXVII). In a fourth more preferred embodiment for formulas (XXXVIII) and (XXXIX):
R
1 , R 3 and R 71 for each occurance, is independently -SH or -OH;
R
70 is cyclopropyl or isopropyl.; and the remainder of the variables are as desribed for the third more preferred embodiment for formulas (XXXVIII) and (XXXIX). More preferably R 30 is methyl,ethyl, propyl, isopropyl, methoxy or ethoxy. Even more preferably, R 30 is methyl, ethyl, propyl, isopropyl, methoxy or ethoxy and Ra and Rb are each independently a hydrogen, methyl, ethyl, propyl, isopropyl, or taken together with the nitrogen to which they are attached, are: -- N ) -N -N N-R35 -N 0 -- N S wherein R 35 is -H, a CI -C4 alkyl or a CI -C4 acyl; and C:\NRPortbiDCC\REC44)75614_ LDOC-1/10/2012 - 104 the values and preferred values for the remainder of the variables are as described above for formula (XXXVII). In another preferred embodiment, the present invention is a compound represented by formula (XXXV), (XXXVI), (XXXVII), (XXXVIII) or (XXXIX), wherein R 1 , R 3 and R7, are --SH or -OH and R 6 is cyclopropyl or isopropyl and the remainder of the variables are as described for Formula (XXXV), (XXXVI), (XXXVII), (XXXVIII) or (XXXIX), respectively. In another embodiment, the present invention provides compounds represented by a structural formula selected from formulas (XL) and (XLI): NRaRb NRaRb B B X4'----X5'.5-~-~4
X
3 N R1 N R1 N--NN- N
R
3 (XL) (XLI) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof. In formulas (XL) and (XLI), ring B is further optionally substituted with one or more substituents in addition to -NRaRb. Preferably ring B is substituted with (R 3 0 )y where y is 0, 1, 2, 3 or 4, preferably y is 0 or 1; R, is -OH, -SH, -NR 7 H, -OR 26 , -SR 26 , -NHR 2 6 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -OC(O)NRioR 1 , -SC(O)NRioR, 1 ,
-NR
7 C(O)NRioR, -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
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRIORII, -SCH 2 C(O)NRIORII,
-NR
7
CH
2 C(O)NRioR 11 , -OS(O),R 7 , -SS(O),R 7 , -S(O),OR 7 , -NR 7
S(O),R
7 , -OS(O),NRIOR 1 , -SS(O),NRioR 11 , -NR 7 S(O),NRioR 11 , -OS(O),OR 7 , -SS(O),OR 7 , -NR 7
S(O),OR
7 , -OC(S)R 7 ,
-SC(S)R
7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR, -SC(S)NRioR 11 , -NR 7 C(S)NRIORII, -OC(NR 8
)R
7 , -SC(NRs)R7, -NR 7
C(NR
8
)R
7 , -OC(NR8)OR 7 ,
-SC(NR
8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR 8 )NRioR 11 , -SC(NR 8
)NRIOR
1 , or -NR 7
C(NR
8 )NRIORII,
-OP(O)(OR)
2 or -SP(O)(OR) 2 . Preferably, R, is -OH, -SH, -HNR 7 , -OC(O)NRIOR, 1 SC(O)NRioR I, -OC(O)R 7 , -SC(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -OS(O),R 7 , -S(O),OR7, -SS(O),R 7
,
C:NRPorbl\DCC\REC4075614_l DOC-1/1/12012 - 105
-OS(O),OR
7 , -SS(O),OR 7 , -OC(S)R 7 , -SC(S)R 7 , -OC(S)OR 7 , -SC(S)OR 7 , -OC(S)NR 0 oR, -SC(S)N R 1 oR I, -OC(NR 8
)R
7 , -SC(N R 8
)R
7 , -OC(NR 8
)OR
7 , -SC(N R 8
)OR
7 ,
-OP(O)(OR)
2 or -SP(O)(OR 7
)
2 . More preferably, R, is -OH, -SH, or -NHR 7 . Even more preferably, R, is -SH or -OH;
R
3 is -OH, -SH, -NR 7 H, -OR 26 , -SR 2 6 , -NHR 26 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 ).NR7H, -OC(O)NRioR 1 , -SC(O)NRioRa,
-NR
7 C(O)NRioR 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 , -SCH 2
C(O)R
7 , -NR 7
CH
2 C(O)R7, -OCH 2 C(O)OR7,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRIORII, -SCH 2 C(O)NRioR 1 ,
-NR
7
CH
2 C(O)NRIORII, -OS(O)pR 7 , -SS(O),R 7 , -S(O),OR 7 , -NR 7
S(O),R
7 , -OS(O),NRioRI 1 , -SS(O),NRioRa 1 , -NR 7 S(O),NRoR 1 , -OS(O),OR 7 , -SS(O),OR 7 , -NR 7 S(O),OR7, -OC(S)R 7 ,
-SC(S)R
7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NR 1 oR 1 , -SC(S)NRioR, 1 , -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 ,
-SC(NR
8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR)NRioR 1 , -SC(NR 8 )NRioR, 1 , -NR 7
C(NR
8
)NRIOR
1 , C(O)OH, -C(O)NHR 8 , -C(O)SH, -S(O)OH, -S(O) 2 0H, -S(O)NHR 8 , -S(O) 2
NHR
8 , OP(O)(OR 7
)
2 , or -SP(O)(OR 7
)
2 . Preferably, R 3 is -OH, -SH, -HNR 7 , -OC(O)NRIOR 1 , SC(O)N R ioR 11 , -OC(O)R 7 , -SC(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -OS(O),R 7 , -S(O),OR 7 , -SS(O)pR 7 ,
-OS(O),OR
7 , -SS(O),OR 7 , -OC(S)R 7 , -SC(S)R 7 , -OC(S)OR 7 , -SC(S)OR 7 , -OC(S)NR 0 oR 1 , -SC(S)N RioR I, -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -OC(NR 8
)OR
7 , -SC(NR 8
)OR
7 ,
-OP(O)(OR
7
)
2 or -SP(O)(OR 7
)
2 . More preferably, R 3 is -OH, -SH, or -NHR 7 . Even more preferably, R 3 is -SH or -OH;
R
70 , 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 heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -N R 1 oR 1 , -OR 7 , -C(O)R 7 , -C(O)OR7, -C(S)R 7 , -C(O)SR 7 , -C(S)SR 7 , -C(S)OR 7 , -C(S)NRioR 1 , -C(NRs)OR 7 , -C(NR 8
)R
7 , -C(NR 8 )NR,oR I, -C(NR 8
)SR
7 , -OC(O)R 7 , -OC(O)OR 7 , -OC(S)OR 7 ,
-OC(NR
8
)OR
7 , -SC(O)R 7 , -SC(O)OR 7 , -SC(NR 8
)OR
7 , -OC(S)R 7 , -SC(S)R 7 , -SC(S)OR 7 ,
-OC(O)NR
0 oR, -OC(S)NR 0 oR, -OC(NR 8
)NR
0 oR, -SC(O)NR 0 oR, -SC(NR 8
)NR
1 oR 1 , -SC(S)N RioR 1 , -OC(N R 8
)R
7 , -SC(NR 8
)R
7 , -C(O)NR oR , -NR 8
C(O)R
7 , -NR 7
C(S)R
7 , -N R 7
C(S)OR
7 , -N R 7
C(NR
8 )R7, -N R 7
C(O)OR
7 , -N R 7 C(N R 8
)OR
7 , -N R 7 C(O)N R 1 oR 11 ,
-NR
7 C(S)N R,oR, -NR 7 C(N R 8 )N RioRl, -SR 7 , -S(O),R 7 , -OS(O)pR 7 , -OS(O),OR 7 , -OS(O)pNRjoR 1 , -S(O),OR 7 , -N R 8
S(O),R
7 , -N R 7 S(O),N R 1 oR 1 , -N R 7 S(O)pOR 7 , -S(O),N RoRl, - C:NRPonbl\DCC\RECU075614_1.DOC-1/10/2012 - 106
SS(O),R
7 , -SS(O)pOR 7 or -SS(O),NRIoRII. Preferably, R 70 is for each occurrence, is independently an optionally substituted CI-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 )kOH,
-(CH
2 )kSH, -(CH 2 )kNR 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 CH2SH, -SCH 2
CH
2
NR
7 H, -OC(O)NRioRj 1 , -SC(O)NRioR 1 , -NR 7 C(O)NRIORII, -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
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 ,
-OCH
2 C(O)NRIORII, -SCH 2 C(O)NRIORII, -NR 7
CH
2
C(O)NRIOR
1 , -OS(O),R 7 , -SS(O),R 7 ,
-NR
7
S(O),R
7 , -OS(O),NRoR,, -SS(O),NRjoRjj, -NR 7 S(O),NRioR 1 , -OS(O),OR 7 , -SS(O),OR 7 ,
-NR
7
S(O),OR
7 , -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR7, -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR 1 , -SC(S)NRioR 1 , -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR8)OR 7 , -SC(NR 8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR)NRioR 1 , -SC(NR 8 )NRioR 1 ,
-NR
7
C(NR
8 )NRioR 1 , -C(O)R7, -C(O)OR 7 , -C(O)NRioR 11 , -C(O)SR 7 , -C(S)R 7 , -C(S)OR 7 , -C(S)NRioR 11 , -C(S)SR 7 , -C(NR 8
)OR
7 , -C(NR 8
)R
7 , -C(NR 8 )NRioR 11 , -C(NR 8
)SR
7 , -S(O),OR 7 , -S(O),NRoR 1 , -S(O),R 7 , -OP(O)(OR 7
)
2 or -SP(O)(OR7) 2 . More preferably, R7o, 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)NRIOR 1 ,
-SC(O)NR
0 oR I, -OC(O)R 7 , -SC(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -OS(O)pR 7 , -S(O),OR 7 , -SS(O)pR 7 ,
-OS(O),OR
7 , -SS(O),OR 7 , -OC(S)R 7 , -SC(S)R 7 , -OC(S)OR 7 , -SC(S)OR 7 , -OC(S)NRioR 1 ,
-SC(S)NRIOR
1 , -OC(N R 8
)R
7 , -SC(NR 8
)R
7 , -OC(NR 8
)OR
7 , -SC(NR 8
)OR
7 , -OP(O)(OR) 2 or
-SP(O)(OR
7
)
2 . Even more preferably, R 70 is for each occurrence, is independently a CI-C6 alkyl, a Cl -C6 haloalkyl, a Cl -C6 alkoxy, a Cl -C6 haloalkoxy, a Cl -C6 alkyl sulfanyl or a C3-C6 cycloalkyl. Still more preferably, R7 0 for each occurrence, is independently a cyclopropyl or isopropyl;
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. Preferably, R 7 and R 8 , for each occurrence, is independently -H, CI-C3 alkyl, Cl-C6 cycloalkyl, an optionally substituted aryl or an optionally C :NRPonbl\DCC\REC\U075614_1,DOC.-/I1/20l2 - 107 substituted heteroaryl. More preferably, R 7 and R 8 , for each occurrence, is independently -H or CI-C3 alkyl; RIO and R, 1 , 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. Preferably, RIO and R 11 , for each occurrence, is independently -H, Cl-C3 alkyl, C1-C6 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. More preferably, RIO and R, 1 , for each occurrence, is independently -H or CI-C3 alkyl; alternatively, RIO and R, 1 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl. Preferably RIO and R, 1 , taken together with the nitrogen to which they are attached, form an optionally substituted imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, iosoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrazinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, pyranzinyl, thiomorpholinyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl. More preferably RIO and R, 1 , taken together with the nitrogen to which they are attached, form an optionally substituted pyrrolidinyl, piperidinyl, piperazinyl, tetrahydroisoquinolinyl, morpholinyl or pyrazolyl;
R
17 , for each occurrence, is independently an alkyl or an aralkyl. Preferably R 17 for each occurance is independently a CI-C6 alkyl;
R
26 is a CI-C6 alkyl;
R
3 0 , 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 heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -H, -NRioR 1 , -OR 7 , -C(O)R7, -C(O)OR 7 , -C(S)R 7 , -C(O)SR 7 , -C(S)SR 7 , -C(S)OR 7 , -C(S)NR 0 oR 1 ,
-C(NR
8
)OR
7 , -C(NR 8
)R
7 , -C(NR 8 )NRIOR I, -C(NRs)SR 7 , -OC(O)R 7 , -OC(O)OR 7 , -OC(S)OR 7 , -OC(N R 8
)OR
7 , -SC(O)R 7 , -SC(O)OR 7 , -SC(N R 8
)OR
7 , -OC(S)R 7 , -SC(S)R7, -SC(S)OR7, -OC(O)NRIoR 1 , -OC(S)N RIoRj 1 , OC(NR 8
)NR
1 oR I, -SC(O)NR 0 oR I, -SC(NR 8 )N R IoR 11 , -SC(S)N R oR 11 , -OC(NRs)R 7 , -SC(NRs)R 7 ,
-C(O)NR
0 oR, -NR 8
C(O)R
7 , -NR 7
C(S)R
7 , -NR 7
C(S)OR
7 , -NR 7
C(NR
8
)R
7 , -NR 7 C(O)0R 7 ,
-NR
7
C(NR
8
)OR
7 , -NR 7 C(O)NRioR 1 , -NR 7
C(S)NR
0 oR 1 , -NR 7
C(NR
8
)NR
0 oR I, -SR 7 , -S(O)pR 7
,
C:WRPonbl\DCC\REC\4075614_ .DOC-1/10/2012 - 108
-OS(O),R
7 , -OS(O),OR 7 , -OS(O),N R 1 oR 1 , -S(O),OR 7 , -N R 8
S(O),R
7 , -N R 7 S(O),NRioR 1 ,
-NR
7
S(O),OR
7 , -S(O)pNRioR, , -SS(O)pR 7 ,
-SS(O),OR
7 , or -SS(O),NRIOR 1 . Preferably R 30 for each occurrence, is independently 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 , -NRioR 1 , OC(O)NRioR 1 , -SC(O)NRioR 11 , -NR 7 C(O)NRioR 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 , -SCH 2
C(O)R
7 , -NR 7
CH
2
C(O)R
7 ,
-OCH
2
C(O)OR
7 , -SCH 2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRioR 1 , -SCH 2 C(O)NRjoR 1 ,
-NR
7
CH
2 C(O)NRioR 1 , -OS(O),R 7 , -SS(O),R 7 , -NR7S(O),R 7 , -OS(O),NRoR 1 , -SS(O),NRioR 1 ,
-NR
7 S(O),NRioR 11 , -OS(O)pOR 7 , -SS(O),OR 7 , -NR7S(O)pOR 7 , -OC(S)R 7 , -SC(S)R 7 ,
-NR
7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR 11 , -SC(S)NRioR 1 , NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NRs)OR 7 , -SC(NR 8
)OR
7 ,
-NR
7 C(NRs)OR 7 , -OC(NR 8 )NRioR 1 , -SC(NR 8 )NRioR 1 , -NR 7 C(NR)NRIORII, -C(O)R 7 ,
-C(O)OR
7 , -C(O)NRioR 1 , -C(O)SR 7 , -C(S)R 7 , -C(S)OR 7 , -C(S)NRIOR 1 , -C(S)SR 7 ,
-C(NR
8
)OR
7 , -C(NR 8
)R
7 , -C(NR 8 )NRioR 1 , -C(NR 8
)SR
7 , -S(O),OR 7 , -S(O),NRioR 1 or -S(O)pR 7 . More preferably, R 30 for each occurrence, is independently a hydrogen, -OH, -SH, halogen, cyano, a Cl -C6 alkyl, Cl -C6 haloalkyl, Cl -C6 alkoxy, Cl -C6 haloalkoxy or Cl -C6 alkyl sulfanyl. Even more preferably, R30 for each occurrence, is independently a hydrogen, methyl, ethyl, propyl, isopropyl, methoxy or ethoxy; 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. Preferably, Ra and Rb for each occurrence, is independently a hydrogen, a CI-C6 straight or branched alkyl, optionally substituted by -OH, -CN, -SH, amino, a CI-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl. More preferably, Ra and Rb for each occurrence, is independently a hydrogen, methyl, ethyl, propyl, isopropyl; C:\NRPonblDCC\REC\4756 14_ DOC-1/10/2t I 2 - 109 Alternatively, Ra and Rb, taken together with the nitrogen to which they are attached, form an optionally substituted heteroaryl or heterocyclyl. Preferably, R" and Rb taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen containing heterocyclyl. More preferably, Ra and Rb taken together with the nitrogen to which they are attached, are: -N N -N N-R 35 -N \/0 N\O
X
3 ' and X 4 ' are each, independently, N, N(O), N'(R 17 ), CH or CR 7 o;
X
5 ' is 0, S, NR 17 , CH 2 , CH(R 70 ), C(R 70
)
2 , CH=CH, CH=CR 7 0, CR 7 0 =CH, CR 7 0
=CR
70 , CH=N, CR 70 =N, CH=N(O), CR 70 =N(O), N=CH, N=CR 70 , N(O)=CH, N(O)=CR 70 , N+(R 17 )=CH,
N'(R
17 )=CR7 0 , CH=N+(R 1 7 ), CR 70
=N*(RI
7 ), or N=N, provided that at least one X 3 ', X 4 ' or X 5 ' is a heteroatom; k is 1, 2, 3, or 4; p, for each occurrence, is independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4. In a fifth preferred embodiment, the present invention provides a compound represented by a structural formula selected from formulas (XLII) and (XLIII): NRaRb NRaRb (R30)s (3) (RR3o)s-.<
X
4 , X 5 '
X
5
'-)(
4 ' II ~ NN X3 R1 X3 N R1 R3 N-N N-NIr 3 R3 (XLII) (XLIII) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof. Preferably the values and preferred values for formulas (XLII) and (XLIII) are as described above for formulas (XL) and (XLI), and more preferably: C:\NRPorbl\DCC\REC\A075614_.DOC./101212 -110
R
70 is for each occurrence, is independently an optionally substituted Cl -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 )kOH, -(CH 2 )kSH, -(CH 2 )kNR7H, -OCH 3 , -SCH 3 ,
-NHCH
3 , -OCH 2 CH20H, -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)NRioR 11 , -SC(O)NRioR 1 , -NR 7 C(O)NRioR 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 , -SCH 2
C(O)R
7 ,
-NR
7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 , -SCH 2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRioRo,
-SCH
2 C(O)NRioR 1 , -NR 7
CH
2 C(O)NRioR 1 , -OS(O),R 7 , -SS(O),R 7 , -NR 1
S(O),R
7 , -OS(O),NRoR 1 , -SS(O),NRjoR 1 , -NR 7
S(O),NR
1 oR 1 , -OS(O),OR 7 , -SS(O),OR 7 , -NR7S(O),OR 7 , -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , OC(S)NRIOR 1 , -SC(S)NRIORII, -NR 7 C(S)NRIORII, -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 ,
-OC(NR
8
)OR
7 , -SC(NR 8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR 8
)NRIOR
1 , -SC(NR)NRIORII,
-NR
7
C(NR
8 )NRIORII, -C(O)R 7 , -C(O)OR 7 , -C(O)NRioR 1 , -C(O)SR 7 , -C(S)R 7 , -C(S)OR 7 , -C(S)NRIORII, -C(S)SR 7 , -C(NR 8
)OR
7 , -C(NR 8
)R
7 , -C(NR)NRIORII, -C(NR 8
)SR
7 , -S(O),OR 7 , -S(O)pN RioR 1, -S(O),R 7 , -OP(O)(OR) 2 or -SP(O)(OR 7
)
2 ;
R
30 , 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, -NRoR 1 , -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 0 oR 1 ,
-C(NR
8
)OR
7 , -C(NR 8
)R
7 , -C(NR 8
)NR
0 oR I, -C(NR 8
)SR
7 , -OC(O)R 7 , -OC(O)OR 7 , -OC(S)OR 7 ,
-OC(NR
8
)OR
7 , -SC(O)R 7 , -SC(O)OR 7 , -SC(N R 8
)OR
7 , -OC(S)R 7 , -SC(S)R 7 , -SC(S)OR 7 , -OC(O)NRIOR I, -OC(S)N R oR I, OC(NR 8
)NR
1 ioR 1 , -SC(O)NRioR 1 , -SC(NR)NR 0 oR 1 , -SC(S)NR 0 oR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -C(O)N R 1 oR 1 , -N R 8
C(O)R
7 , -N R 7
C(S)R
7 , -N R 7
C(S)OR
7 , -NR 7
C(NR
8
)R
7 , -NR 7
C(O)OR
7 , -NR7C(NR 8
)OR
7 , -NR 7 C(O)NRioR 1 , -NR 7 C(S)NRioR 1, -NR 7
C(NR
8
)NR,
0 oR 1 , -SR7, -S(O),R 7 ,
-OS(O),R
7 , -OS(O),OR 7 , -OS(O),N R 1 oR 1 , -S(O),OR 7 , -NR 8
S(O),R
7 , -N R 7 S(O),NRioR 1 , -N R 7
S(O),OR
7 , -S(O),N RIORI 1 , -SS(O),R 7 ,
-SS(O),OR
7 or -SS(O),NR IoR 1 ; s is 0, 1, 2, 3 or 4; k is 1, 2, 3, or 4; and CANRPorl\hDCC\REC'407564_ DOC-1/1012012 - 111 the values and preferred values for the remainder of the variables are as described above for formulas (XL) and (XLI). In a sixth preferred embodiment, the present invention provides a compound represented by a structural formula selected from formulas (XLIV) and (XLV): NRaRb NRaRb (R30)0 or 1 (R30)o or 1
X
4
-X
5 ' YX 5
'-X
4 ' // N N3R1 X3K NR R N-N N-N 3 R3 (XLIV) (XLV). or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof. The values and preferred values for formulas (XLIV) and (XLV) are as described above for formulas (XL) and (XLI). Preferably the values and preferred values for formulas (XLIV) and (XLV) are as described for formulas (XLII) and (XLIII). More preferably, the values for formulas (XLIV) and (XLV) are described in the following paragraphs:
R
3 0 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 , -NRIOR 1 , -OC(O)NRioR, 1 , -SC(O)NRioR 11 , -NR 7 C(O)NRioR 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
7 ,
-OCH
2
C(O)OR
7 , -SCH 2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 ,
-OCH
2 C(O)NRioR 1 , -SCH 2 C(O)NRioR 1 , -NR 7
CH
2 C(O)NRioR 11 , -OS(O)pR 7 ,
-SS(O),R
7
,-NR
7
S(O),R
7 , -OS(O)pNRjoR 1 , -SS(O)pNRjoR , -NR 7 S(O)pNRioR 1 , -OS(O),OR 7 , SS(O)pOR 7 , -NR 7 S(O)pOR 7 , -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 ,
-NR
7
C(S)OR
7 , -OC(S)NRIORII, -SC(S)NRIORII, -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 ,
-NR
7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 , -SC(NR 8
)OR
7 , -NR 7 C(NRs)OR 7 , -OC(NR 8 )NRoR 11 ,
-SC(NR
8 )NRioR 11 , -NR 7
C(NR
8 )NRIORII, -C(O)R 7 , -C(O)OR 7 , -C(O)NRioR 11 , -C(O)SR 7 ,
-C(S)R
7 , -C(S)OR 7 , -C(S)NRioR 1 , -C(S)SR 7 , -C(NR 8
)OR
7 , -C(NR 8
)R
7 , -C(NR 8 )NRjoR,
-C(NR
8
)SR
7 , -S(O)pOR 7 , -S(O),NRoR, or -S(O)pR 7 ; and C \NRPorblODCC\REC4075614_1.DOC-I/10J/2012 - 112 the values and preferred values for the remainder of the variables are as described above for formulas (XLIV) and (XLV) are as described above for formulas (XL) and (XLI). Preferably the values and preferred values for the remainder of the variables in formulas (XLIV) and (XLV) are as described for formulas (XLII) and (XLIII). In a seventh more preferred embodiment, the present invention provides a compound represented by a structural formula selected from formulas (XLVI) - (XLIX): NRaRb NRaR' (R30)0 or 1 (R 30
)
0 or I x 4 -x 5 x 5 -x 4 // N / N X3 R 1 X3 RI X7/r / N--N 1N--N
R
3 R 3 (XLVI); (XLVII);
(R
30
)
0 or 1
(R
30
)
0 or I NRaR' -NR'R' x 4 -x 5 xs-x 4 // N N X3 R1 X3 R1 N--N N-N 3 R 3 (XLVIII) (XLIX). or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof. The values and preferred values for formulas (XLVI) - (XLIX) are as described above for formulas (XL) and (XLI). Preferably the values and preferred values for formulas (XLVI) - (XLIX) are as described above for formulas (XLIV) and (XLV). More preferably, the values for formulas (XLVI)-(XLIX) are provided below in the following paragraphs: R, and R 3 are each independently -OH, -SH, -HNR 7 , -OC(O)NRIOR 1 , -SC(O)NR 0 oR 1 , OC(O)R , -SC(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -OS(O),R 7 , -S(O),OR 7 , -SS(O),R7, -OS(O),OR 7
,
C:\NRPonbI\DCC\RECMA075614_ .DOC-1/1012012 -113 -SS(O)pOR 7 , -OC(S)R 7 , -SC(S)R 7 , -OC(S)OR 7 , -SC(S)OR 7 , -OC(S)NRioR 1 , -SC(S)NRjoR 1 , -OC(N R8)R 7 , -SC(NR 8
)R
7 , -OC(N R 8
)OR
7 , -SC(N R 8
)OR
7 ,
-OP(O)(OR
7
)
2 or -SP(O)(OR) 2 ; and
R
70 , 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)NRIOR,
1 -SC(O)NRoR 1 , -OC(O)R 7 . -SC(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -OS(O),R 7 ,
-S(O),OR
7 , -SS(O),R 7 , -OS(O)pOR 7 , -SS(O)pOR 7 , -OC(S)R 7 , -SC(S)R 7 , -OC(S)OR 7 , -SC(S)OR 7 ,
-OC(S)NR
0 oR, -SC(S)N R 1 oR, -OC(N R 8
)R
7 , -SC(N R 8
)R
7 , -OC(NR 8
)OR
7 . -SC(NR 8
)OR
7 ,
-OP(O)(OR)
2 or -SP(O)(OR 7
)
2 ; and the values and preferred values for the remainder of the variables are as described for formulas (XLIV) and (XLV). Still more preferably for formulas (XLVI) - (XLIX), RI R 3 and R 70 are as described in the immediately preceeding paragraphs; and Ra and Rb are each independently a hydrogen, a CI -C6 straight or branched alkyl, optionally substituted by -OH, -CN, -SH, amino, a CI-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or 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; and the values and preferred values for the remainder of the variables are as described for formulas (XLIV) and (XLV). Still more preferably for formulas (XLVI) - (XLIX), RI R 3 , R 6 , Raand Rb are as described in the immediately preceeding paragraphs; and
R
70 is a CI-C6 alkyl, a CI-C6 haloalkyl, a CI-C6 alkoxy, a CI-C6 haloalkoxy, a CI-C6 alkyl sulfanyl or a C3-C6 cycloalkyl; and the values and preferred values for the remainder of the variables are as described above for formulas (XL) and (XLI). More preferably, the values and preferred values for the remainder of the variables are as described above for forumulas (XLIV) and (XLV).
C:\NRPorbhDCOREC\4075614_I DOC- /10/2012 - 114 In an eighth preferred embodiment, the present invention provides a compound represented by a structural formula selected from formulas (La)-(Lp): NR'Rb NRaRb (R30)0 . 1 (Ra)o or 1 N N NN R1 N R, N-N N-N (La) R 3 NROR , (Lb) R 3 NR'Rb (R3o)0 I, (R30)o ,1 N R N;N 3 RN (Lc) (Ld) NRORb NR8Rb (R30) 0 or1 (R3)o 1 N N R70R17R Ra N-N R N-N (Le) (Lf) NR'Rb NR'Rb (R30)o,, I(R30) 0 1 0 S K R R N--N N-N ( ) ' R 3 (Lg) (Lh) C:NRPorbl\DCCRECU075614_. DOC-I1/10/2012 - 115 (R3).1r(R1 NR*R b NNRaRR N NN R1 N R1 N-N q N-N
R
3 R, (Li) (R ) 0 o 1 (Lj) (Ro)o r 1 NR Rb NR"Rb | | N
R
7 0 / O/ NNy N-N N--N R( R 3 (Lk) (R30)0ow,1 (Rao)o or 1 NR"Rb NRaRb
R
70 R70 O S / / N N R1 R, R N--N R N--N
R
3 R 3 (Lm) (Ln) (ao ,(Rooor 1 NR"Rb NRaRb 'N4 o 7 0 S N -- fN *r R1N'N R, N--N R N--N (Lo) and 3 (Lp) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof. The values and preferred values for formulas (La) through (Lp) are as described above for formulas (XL) and (XLI). Preferably the values and preferred values for formulas (La) - (Lp) are as described for formulas (XLVI)-(XLIX). More preferably, R, and R 3 are each, independently, -OH, C:\NRPortbl\DCCMRECWO75614_1 DOC.1/lO2012 - 116 -SH, or -NHR 7 . Even more preferable, R, and R 3 are each, independently, -OH, -SH, or -NHR 7 ; and R 30 is -OH, -SH, halogen, cyano, a CI -C6 alkyl, CI -C6 haloalkyl, C I-C6 alkoxy, C I -C6 haloalkoxy or CI-C6 alkyl sulfanyl (preferably methyl, ethyl, propyl, isopropyl, methoxy or ethoxy). Even more preferably, R, and R 3 for each occurance, is independently -SH or -OH; R 70 is cyclopropyl or isopropyl; and R 30 is -OH, -SH, halogen, cyano, a CI-C6 alkyl, C I-C6 haloalkyl, CI -C6 alkoxy, CI -C6 haloalkoxy or CI-C6 alkyl sulfanyl (preferably methyl, ethyl, propyl, isopropyl, methoxy or ethoxy). Even more preferably yet, R 1 , R 3 , R7 0 and R 30 are as just described and Ra and Rb are each independently a hydrogen, methyl, ethyl, propyl, isopropyl, or taken together with the nitrogen to which they are attached, are: N -N -N N-R 35 -N S -N 0
R
35 is -H, a CI -C4 alkyl or a CI-C4 acyl; and the values and preferred values for the remainder of the variables are as defined for formulas (XLVI)-(XLIX). In another embodiment the compounds of the present invention are represented by a structural formula selected from formulas (LIa) and (LIb): NRaRb NRaRb R22R B R23B R24 B B N 24 14X14R2 _ N
R
23 R N N R R33 R3 and (LIa) (Lib) or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof. In formulas (LIa) and (LIb), ring B is further optionally substituted with one or more substituents in addition to -NRaR . Preferably ring B is further substituted with (R 3 0 ), where s is 0, 1, 2, 3 or 4, preferably s is 0 or I; C~kNPPor1bi~DCCGRECi.4U756j,4-I DOC.111012012 - 117 R, is -OH, -SH, -NR 7 H, -OR 26 , -SR 26 , -NHR 26 , 0O(CH 2 )mOH, 0O(CH 2 )mSH, O(CH 2 )mN R 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mN R 7 H, 0OC(O)N R 10
R
11 , -SC(O)N R 10
R
1 , -N R 7 C(O)N R 1 0
R
1 , -OC(O)R 7 , -SC(O)R 7 , -NR 7
C(O)R
7 , -OC(O)0R 7 , -SC(O)0R 7 , -N R 7
C(O)OR
7 , -OC H 2
C(O)R
7 , -SCH 2
C(O)R
7 , -N R 7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 ,
-SCH
2 C(O)0R 7 , -N R 7
CI-
2
C(O)OR
7 , -OCH 2 C(O)N R 10
R
1 1 , -SCH- 2
C(O)NR
0
R
1 ,,
-NR
7
CH
2 C(O)N R 10
R
11 , -0S(O)pR 7 , -SS(0)pR 7 , -S(O)pOR 7 , -NR7S(O)pR 7 , -OS(O)pNR 10 R, -SS(O)pN R 10
R
11 , -N R 7 S(0)pNR 0
R
11 , -OS(O)pOR 7 , -SS(O)pOR 7 , -N R 7 S(O)pOR 7 , -OC(S)R 7 , -SC(S)R7, -N R 7
C(S)R
7 , -OC(S)0R 7 , -SC(S)0R 7 , -NR 7 C(S)0R 7 , -OC(S)N R 10 R, -SC(S)N R 10
R
11 , -N R 7 C(S)N R 10 R,I, -OC(N R 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR 8 )0R 7 ,
-SC(NR
8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR 8
)NR
0
R
11 , -SC(NR 8
)NR
0
R
11 , -NR 7
C(NR
8
)NR
0
R
11 , OP(O)(OR 7
)
2 or -SP(O)(0R 7
)
2 . Preferably, R, is -OH, -SH, -HNR 7 , -OC(O)NR 0 R 1 , SC(O)N R 1 o R 1 , -OC(O)R 7 , -SC(O)R 7 , -OC(O)0R 7 , -SC(O)OR 7 , -OS(O)pR 7 , -S(O)pOR 7 , -SS(O)pR 7 , -OS(O)pOR 7 , -SS(O)pOR 7 , -OC(S)R 7 , -SC(S)R 7 , -OC(S)0R 7 , -SC(S)0R 7 , -OC(S)NR 0 R, 1 , -SC(S)N R 10
R
11 I -OC(N R 8 )R, -SC(NR 8
)R
7 , -OC(NR 8 )0R 7 , -SC(N R 8 )0R 7 , -OP(O)(0R 7
)
2 or -SP(O)(0R 7
)
2 . More preferably, III is -OH, -SH, or -NHR 7 . Even more preferably, R, is -SH or -OH;
R
3 iS 0OH, -SH, -NR 7 H, -OR 26 , -SR 26 , -NHR 26 , 0O(CH 2 )mOH, 0O(CH 2 )mSH, O(CH 2 )mN R 7 H, -S(CH 2 ),,OH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, 0OC(O)N R 10
R
11 , -SC(O)NR,oR,,
-NR
7
C(O)NRI
0 RII, -OC(O)R 7 , -SC(O)R 7 , -NR 7
C(O)R
7 , -OC(O)0R 7 , -SC(O)0R 7 , -N R 7 C(O)0R 7 , -OCH 2
C(O)R
7 , -SCH 2 C(O)R7, -N R 7 C H 2
C(O)R
7 , -OCH 2 C(O)0R 7 ,
-SCH
2 C(O)0R 7 , -N R 7
CH
2 C(O)0R 7 , -OCH 2
C(O)NRI
0 RII, -SCH 2 C(O)N R 10
R
1 ,, -N R 7
CH
2 C(O)N R 10
R
11 , -OS(O)pR 7 , -SS(O)pR 7 , -S(O)pOR 7 , -NR7S(O)pR 7 , -OS(O)pNR 10 R,, -SS(O)pN R 10
R
11 , -N R7S(O)pNR 0
R
11 , -OS(O)pOR 7 , -SS(O)pOR 7 , -N R 7 S(O)pOR 7 , -OC(S)R 7 ,
-SC(S)R
7 , -NR 7
C(S)R
7 , -OC(S)0R 7 , -SC(S)0R 7 , -NR 7 C(S)0R 7 , -OC(S)N R 1 0
R
1 ,,
-SC(S)NR
0
R
11 , -N R 7 C(S)N R 0
R
11 , -OC(N R 8
)R
7 , -SC(N R 8
)R
7 , -N R 7 C(N R 8
)R
7 , -OC(N R 8 )0R 7 , -SC(N R 8 )0R 7 , -N R 7
C(NR
8 )0R 7 , -OC(N R 8
)NR
10
R
11 , -SC(NR 8
)NR
0
R
11 , -N R 7 C(N R 8 )N R 10
R
1 ,, -C(O)OH, -C(O)NHR 8 , -C(O)SH, -S(O)OH, -S(O) 2 0H, -S(O)NHR 8 , -S(O) 2
NHR
8 , -OP(O)(0R 7
)
2 , or -SP(O)(0R 7
)
2 . Preferably, R 3 is -OH, -SH, -HNR 7 , -OC(O)NR 0 R 1 ,
-SC(O)NR
0
R
11 I, -OC(O)R 7 , -SC(O)R 7 , -OC(O)0R, 7 -SC(O)0R 7 . -OS(O)pR 7 , -S(O)pOR 7 , -SS(O)pR 7 , -OS(O)pOR 7 , -SS(O)pOR 7 , -OC(S)R 7 , -SC(S)R 7 , -OC(S)0R 7 , -SC(S)0R 7 , -OC(S)NR 0
R
1 , SC(S)NR 0 R, 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -OC(NR 8 )0R 7 , -SC(NR 8 )0R 7 , -OP(O)(0R 7
)
2 or -SP(O)(0R 7
)
2 . More preferably, R 3 is -OH, -SH, or -NHR 7 . Even more preferably, R 3 is -SH or
-OH;
C \NRPonb\DCC\RECU075614_1 DOC-1110/2012 - 118 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. Preferably, R 7 and R 8 , for each occurrence, is independently -H, C I -C3 alkyl, Cl-C6 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. More preferably, R 7 and R 8 , for each occurrence, is independently -H or C I -C3 alkyl; RIO and R, 1 , 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. Preferably, RIO and RII, for each occurrence, is independently -H, C l -C3 alkyl, C I-C6 cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. More preferably, RIO and R, 1 , for each occurrence, is independently -H or Cl-C3 alkyl; Alternatively, RIO and R,, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl. Preferably RIO and R 11 , taken together with the nitrogen to which they are attached, form an optionally substituted imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, iosoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrazinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, pyranzinyl, thiomorpholinyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl. More preferably RIO and R 1 , taken together with the nitrogen to which they are attached, form an optionally substituted pyrrolidinyl, piperidinyl, piperazinyl, tetrahydroisoquinolinyl, morpholinyl or pyrazolyl;
R
22 , 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, a haloalkyl, -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NRjoR 1 ,
-NR
8
C(O)R
7 , -S(O)pR 7 , -S(O)pOR 7 , or -S(O),NRIoR 1 . Preferably, R 22 is -H, an alkyl, an aralkyl,
-C(O)R
7 , -C(O)OR 7 , or -C(O)NRIOR 1 ;
R
2 1 and R 24 , for each occurrence, is independently -H, an optionally substituted alky, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted C:\NRPrbIlCC\REC\475S614_1 DOC-1/10/2012 -119 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, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRioR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NRioR 1 , -NR 8
C(O)R
7 , -SR 7 , -S(O),R 7 ,
-OS(O),R
7 , -S(O),OR 7 , -NR 8
S(O),R
7 , or -S(O)pNRIoR 1 . Preferably, R 23 and R 24 for each occurance is independently -H; R26 is a CI-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. Preferably, R' and Rb for each occurrence, is independently a hydrogen, a C I-C6 straight or branched alkyl, optionally substituted by -OH, -CN, -SH, amino, a CI-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl. More preferably, Ra and R b for each occurrence, is independently a hydrogen, methyl, ethyl, propyl or isopropyl; Alternatively, Ra and Rb, taken together with the nitrogen to which they are attached, form an optionally substituted heteroaryl or heterocyclyl. Preferably, Ra and Rb taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen containing heterocyclyl. More preferably, R' and R b taken together with the nitrogen to which they are attached, are: -N -N
N-R
35 -N 0 -N S
X
1 4 is 0, S, or NR 7 . Preferably, X 14 is 0; p, for each occurrence, is independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4. Preferably for the compound represented by formulas (LIa) and (LIb), R, is -OH, -SH, or
-NHR
7 ; and R 2 2 is -H, an alkyl, an aralkyl, -C(O)R 7 , -C(O)OR 7 , or -C(O)NRIOR 1 . More preferably, R, is -OH, -SH, or -NHR 7 ; R22 is -H, an alkyl, an aralkyl, -C(O)R 7 , -C(O)OR 7 , or -C(O)NRIOR 1 ; and X 1 4 is O. The values and preferred values for the remainder of the variables are as described above.
C.\NRPortblOCC\REC\4075614_1 DOC.1/10/2012 - 120 In one embodiment, a compound of the present invention is represented by the structural formulas (VI)-(VIII): R5 R2' A R, A R HN- N
HN-
R3 (VI) R3 (VII). R18 A ZR HN-N R3 (ViII). In formulas (VI-Vill): ring A is an aryl or a heteroaryl, optionally further substituted with one or more substituents in addition to R 3 . Preferably, Ring A is represented one of the following tructural formulas:
(R
70 )z R 70
(R
71 )x R71R7
(R
7 0)z or
R
3 R3 R3 where z is 0, 1, 2, 3 or 4; x is 0 or 1; and z + x is less than or equal to 4. R, is -OH, -SH, -NR 7 H, -OR 2 6 , -SR 26 , -NHR 26 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -OC(O)NRioR 1 , -SC(O)NRjoR,
-NR
7 C(O)NRioR 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 , -SCH 2
C(O)R
7 , -NR 7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRioR 1 ,
-SCH
2 C(O)NRioR 1 , -NR 7
CH
2 C(O)NRioR 1 , -OS(O),R 7 , -SS(O),R 7 , -S(O),OR 7 ,
-NR
7
S(O),R
7 , -OS(O),NRjoR 1 , -SS(O),NRjoR 11 , -NR 7 S(O),NRioR 11 , -OS(O),OR 7 ,
-SS(O),OR
7 , -NR 7
S(O),OR
7 , -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR 7 ,
-SC(S)OR
7 , -NR 7
C(S)OR
7 , -OC(S)NRoR 1 , -SC(S)NRoR, -NR7C(S)NRioR, C \NRPonbl\DCC\REC\4075614_I.DOC-1/10/2012 - 121 -OC(NRs)R 7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NRs)OR 7 , -SC(NRs)OR 7 ,
-NR
7
C(NR
8
)OR
7 , -OC(NR)NRioR 1 , -SC(NR 8 )NRioR, -NR 7 C(NR)NRioR,
-OP(O)(OR
7
)
2 , or -SP(O)(OR 7
)
2 . Preferably, R, is -OH, -SH, -NHR 7 , -OC(O)NRioRI SC(O)NRoR 1 , -OC(O)R 7 , -SC(O)R7, -OC(O)OR 7 , -SC(O)OR 7 , -OS(O),R 7 , -S(O),OR 7 , -SS(O),R 7 ,
-OS(O),OR
7 , -SS(O)pOR 7 , -OC(S)R 7 , -SC(S)R 7 , -OC(S)OR, -SC(S)OR 7 , -OC(S)NRioR 1 , -SC(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -OC(NR 8
)OR
7 , -SC(NR 8
)OR
7 , -OP(O)(OR 7
)
2 or
-SP(O)(OR
7
)
2 . More preferably, R, is -OH, -SH, or -NHR 7 . Even more preferably, RI, is -SH or -OH;
R
2 ' is an optionally substituted phenyl group. Preferably, R 2 ' is substituted with one or more group represented by R 30 , wherein R 30 , for each occurrence, are 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 heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NRIOR 1 , -OR 7 , -C(O)R 7 , -C(O)ORy, -C(S)R 7 ,
-C(O)SR
7 , -C(S)SR 7 , -C(S)OR 7 , -C(S)NR 0 oR, -C(N R 8
)OR
7 , -C(NR 8
)R
7 , -C(N R 8 )NRoR 1 , -C(N R 8
)SR
7 , -OC(O)R 7 , -OC(O)OR 7 , -OC(S)OR 7 , -OC(N Rs)OR 7 , -SC(O)R 7 , -SC(O)OR 7 , -SC(N R 8
)OR
7 , -OC(S)R 7 , -SC(S)R 7 , -SC(S)OR 7 , -OC(O)N RioR 1 , -OC(S)NR 1 ioR 1 ,
-OC(NR
8
)NR
0 oR 1 , -SC(O)NRioR 1 , -SC(NR 8 )NRioR 1 , -SC(S)NR 0 oR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -C(O)N R 1 oR 1 , -N R 8
C(O)R
7 , -NR 7
C(S)R
7 , -N R 7
C(S)OR
7 , -NR 7
C(NR
8
)R
7 , -N R7C(O)OR 7 ,
-NR
7 C(N R 8
)OR
7 , -NR 7 C(O)N R 1 oR , -NR 7 C(S)N R 1 oR 1 , -N R 7
C(NR
8
)NR,
0 oR, -S R 7 , -S(O),R 7 , -OS(O),R7, -OS(O)pOR 7 , -OS(O),NR 0 oR, -S(O),OR 7 , -NR 8
S(O),R
7 , -NR 7
S(O),NR
0 oR 1 ,
-NR
7
S(O),OR
7 , -S(O)pN R oR 1 , -SS(O),R 7 , -SS(O),OR 7 , -SS(O),N R 1 oR 1 , -OP(O)(OR 7
)
2 , or
-SP(O)(OR
7
)
2 . More preferably, R2' is an optionally substituted indolyl group or a phenyl group substituted with NRIORaI and optionally with at least one other substitutent represented by R 30 ;
R
3 is -OH, -SH, -NR 7 H, -NHR 2 6 , -O(CH 2 )mOH, -O(CH 2 )mSH, -O(CH 2 )mNR 7 H, S(CH 2 )m 1 OH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -OC(O)NRioR 11 , -SC(O)NRioR 11 , NR 7
C(O)NR
1 oR 1 , -OC(O)R 7 , -SC(O)R,, -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,, -NR 7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 , SCH 2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRioR 11 , -SCH 2 C(O)NRioR 11 , NR 7
CH
2 C(O)NRioR 1 , -OS(O),R 7 , -SS(O),R 7 , -S(O)pOR 7 , -NR 7
S(O),R
7 , -OS(O),NRioR 1 , -SS(O),NRIoRII, -NR 7 S(O),NRioR 1 , -OS(O),OR, -SS(O),OR 7 , -NR 7
S(O),OR
7 , -OC(S)R,
-SC(S)R
7 , -NR 7 C(S)R7, -OC(S)OR,, -SC(S)OR,, -NR 7 C(S)OR7, -OC(S)NR oR, -SC(S)NRioR,,, -NR 7 C(S)NRioR,,, -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8 )R,, -OC(NR 8
)OR
7
,
C:NRPonbl\DCC\REC\4075614 L DOC.1/10l/2012 - 122 -SC(NR 8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR)NRioR 1 , -SC(NR)NRioR 1 , -NR 7 C(NR)NRioR, -C(O)OH, -C(O)NHR 8 , -C(O)SH, -S(O)OH, -S(O) 2 0H, -S(O)NHR 8 , -S(O) 2 NHRs,
-OP(O)(OR
7
)
2 , or -SP(O)(OR 7
)
2 . In another embodiment, -OR 26 and -SR 26 , are additional values for R 3 . Preferably, R 3 is -OH, -SH, -NHR 7 , -OC(O)NRiR, -SC(O)NRIOR n,-OC(O)R 7 , -SC(O)R 7 ,
-OC(O)OR
7 , -SC(O)OR 7 , -OS(O),R 7 , -S(O),OR 7 , -SS(O),R 7 , -OS(O),OR 7 . -SS(O),OR 7 , -OC(S)R 7 ,
-SC(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -OC(S)NRoR, 1 -SC(S)NRo 0 R 1, -OC(N R 8
)R
7 , -SC(NR 8
)R
7 ,
-OC(NR
8 )OR7, -SC(NR 8
)OR
7 , -OP(O)(OR) 2 or -SP(O)(OR 7
)
2 . More preferably, R 3 is -OH, -SH, or -NHR 7 . Even more preferably, R 3 is -SH or -OH;
R
5 is an optionally substituted heteroaryl; an optionally substituted 6 to 14-membered aryl.
R
70 , for each occurrenc, 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 heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, -NRIOR 1 , -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)NRIOR, 1 , -C(NR 8
)OR
7 , -C(NR 8
)R
7 , -C(NR 8 )NRIOR 1 , -C(N R 8
)SR
7 , -OC(O)R 7 , -OC(O)OR 7 ,
-OC(S)OR
7 , -OC(NR 8
)OR
7 , -SC(O)R 7 , -SC(O)OR 7 , -SC(NR 8
)OR
7 , -OC(S)R 7 , -SC(S)R7,
-SC(S)OR
7 , -OC(O)NR 0 oR, -OC(S)NR 0 oR, -OC(NR 8 )NRIORII, -SC(O)NRoR 1 ,
-SC(NR)NRIOR
1 , -SC(S)NRIOR, -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -C(O)NRIOR 1 , -NR 8
C(O)R
7 ,
-NR
7
C(S)R
7 , -N R 7
C(S)OR
7 , -N R7C(N R 8 )R7, -N R 7
C(O)OR
7 , -NR 7 C(N R 8
)OR
7 , -N R 7 C(O)NRioR 1 ,
-NR
7 C(S)NR oR, -NR 7
C(NR
8 )NRoR 1 , -SR7, -S(O),R7, -OS(O),R7, -OS(O),OR7, -OS(O),N RIORII, -S(O),OR 7 , -N R 8 S(O),R7, -N R7S(O),NRIoRII, -N R.,S(O),OR7, -S(O),NR oR 1 , -SS(O)pR7, -SS(O),OR7, -SS(O),NRioR 1 , -OP(O)(OR7) 2 , or -SP(O)(OR 7
)
2 . Preferably, R7 0 is selected from the group consisting of -H, CI-C6 alkyl, CI-C6 alkoxy, CI-C6 cycloalkyl, and CI-C6 cycloalkoxy, more preferably from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
R
71 , 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 heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR IORI, -OR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)N R IORI,
-C(NR
8 )OR7, -C(NR 8 )R7, -C(NR 8
)NR
0 oR I, -C(NR 8 )SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, C:\NRPortb\DCC\REC\4075614_ DOC-I/10/2012 - 123 -OC(NR 8
)OR
7 , -SC(O)R 7 , -SC(O)OR7, -SC(NR 8
)OR
7 , -OC(S)R 7 , -SC(S)R 7 , -SC(S)OR 7 , -OC(O)NRIoR 1 , -OC(S)NRioR 1 , -OC(NR)NR 0 oR, -SC(O)NR 0 oR, -SC(NR)NRioR 1 , -SC(S)NRIoR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -C(O)NRioR, -NR 8
C(O)R
7 , -N R 7
C(S)R
7 , -N R 7
C(S)OR
7 , -NR 7 C(N R 8
)R
7 , -NR 7
C(O)OR
7 , -NR 7 C(N R 8
)OR
7 , -NR 7
C(O)NR
0 oR, -N R 7
C(S)NR
0 oR 1 , -NR 7
C(NR
8 )N RioR I, -SR 7 , -S(O),R 7 , -OS(O),R 7 , -OS(O)pOR 7 , -OS(O),NRioR I, -S(O),OR 7 , -N R 8
S(O),R
7 , -NR 7 S(O)pN RioR I, -NR 7
S(O),OR
7 , -S(O),N RoR 1 1 ,
-SS(O),R
7 , -SS(O),OR7, -SS(O),NR 10
R
1 , -OP(O)(0R 7
)
2 , or -SP(O)(OR 7
)
2 .
R
7 and R 8 , 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 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; or RIO and R, 1 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R
18 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRoR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NRioR 1 ,
-NR
8
C(O)R
7 , -SR 7 , -S(O),R,, -OS(O),R 7 , -S(O),OR 7 , -NR 8
S(O),R
7 , or -S(O),NRioR 1 ;
R
26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
CxINRornbIDCC'R'4OI16I4I.OOC. IIOlOI 12 - 124
R
5 in structural formula (VI) is preferably represented by the following structural formula:
(R
9 )m wherein:
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, -NRIOR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 ,
-OC(O)R
7 , -C(O)NRioR 1 , -NR 8
C(O)R
7 , -SR 7 , -S(O),R 7 , -OS(O),R,, -S(O),OR 7 , -NR 8
S(O),R
7 , or -S(O),NRIoR 1 ; or two R 9 groups taken together with the carbon atoms to which they are attached form a fused ring; and m is zero or an integer from I to 7. More preferably, substituent R 5 in structural formula (VI) is represented by one of the following structural formulas: (Rg)u wherein:
R
9 is as defined as above, q is zero or an integer from I to 7 and u is zero or an integer from I to 8.
C:\NRPonbl\DCC\REC\W7564_I DOC./10/2012 - 125 In another alternative, R 5 in structural formula (VI) is represented by the following structural formula: R33 R34 N B C wherein:
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 substituents. In another alternative, R 5 in structural formula (VI) is selected from a group listed in Table I. Table I # R.,# R, 1 X X 2 X7 X RX 5 XeXe X7 7 X X-X II 2
X
6 ,, ~X 6
X
7 ,_ .N /
X
7 x N 3 Xe 6 X 64x 7 X Xe) X,
X
7 X7 X, X6
X
7
X
C- \RPonbIKDCCRECUO0756I-t I DOC-1/II)/2012 - 126 X ,8 X7- X7'"X xX7 9 x 7 10 7 X
X
7 X
X
7 II12 X4, X xe X
X
7 X 7 11N X7X X7X
X
7 X 13 14 16X7 X x 7 x 15 X -11X7 X 16X10-.;.----XI C:\NRPortbl\DCC\REC4075614_ I DOC-1/10/2012 - 127 19 X1o
X
10 X1
X
10
-
N XIo In the structural formulas of Table 1:
X
6 , for each occurrence, is independently CH, CR 9 , N, N(O), N'(R] 7 ), 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'(RIy), provided that at least three X 7 groups are independently selected from CH and CR 9 ; X8, for each occurrence, is independently CH 2 , CHR 9 , CR 9
R
9 , 0, S, S(O),, NR7, or NR 17 ;
X
9 , for each occurrence, is independently N or CH;
X
1 0 , for each occurrence, is independently CH, CR 9 , N, N(O), N'(R] 7 ), provided that at least one X 10 is selected from CH and CR 9 ;
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, -NRIOR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 ,
-OC(O)R
7 , -C(O)NRioR 1 , -NR 8
C(O)R
7 , -SR 7 , -S(O),R 7 , -OS(O),R 7 , -S(O),OR 7 , -NR 8
S(O),R
7 , or -S(O),NRioRII; or two R 9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
R
17 , for each occurrence, is independently -H, an alkyl, an aralkyl, -C(O)R7, -C(O)OR 7 , or -C(O)NRIORII. Preferred R 5 groups from Table I are selected from the group consisting of 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 C:RPorbIDCCRECM071% 4 1 DOC-1/10/2012 - 128 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 azaindolyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted imidazo(4,5-a]pyridinyl, an optionally substituted imidazo[l,2-a]pyridinyl, an optionally substituted 3H-imidazo[4,5-b]pyridinyl, an optionally substituted I H-imidazo[4,5 b]pyridinyl, an optionally substituted I 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 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 alternative, R 5 in structural formula (VI) is selected from the group consisting of: x 1 1 X11 \ //X
X
12 and wherein:
X
1 1, for each occurrence, is independently CH, CR 9 , N, N(O), or N'(R 17 ), provided that at least one X 1 1 is N, N(O), or N*(R 17 ) and at least two X 1 1 groups are independently selected from CH and CR 9 ;
X
1 2 , for each occurrence, is independently CH, CR 9 , N, N(O), N'(R 17 ), provided that at least one X 1 2 group is independently selected from CH and CR 9 ;
X
13 , for each occurrence, is independently 0, S, S(O)p, NR 7 , or NR 1 y;
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 C WRPorbl\DCC\REC\4075614_ .DOC-1/10/2012 - 129 optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a hydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, -NRIOR 11 , -OR 7 , -C(O)R 7 , -C(O)OR 7 ,
-OC(O)R
7 , -C(O)NRioR 1 ,
-NR
8
C(O)R
7 , -SR 7 , -S(O),R 7 , -OS(O),R 7 , -S(O),OR 7 , -NR 8
S(O),R
7 , or -S(O),NRIoR 11 ; or two
R
9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
R
17 , for each occurrence, is independently an alkyl or an aralkyl. The remainder of the variables have values defined above with reference to structural formula (1). In a preferred embodiment, the compound of the invention is represented by structural formula (LII): R 1v01 X101 70 Yo02\ HO y1 Y102 is102 X R1 OH HN--N In structural formula (LII):
X
1 01 is 0, S, or NRIo2 andX 2 is CR1o4 orN. Preferably, XR 1 o is NRo2and X102 is CR-S4. Alternatively, X1o1 is NR1o2 and X1O2 is N; Y, for each occurrence, is independently N or CRios; Ylo, is N or CR1oS; Y102 is N, C or CRio6; R, is -OH-, -SH, or NH R7. Preferably, R, is -OH or -SH;
R
70 is 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, cycloalkoxy, a haloalkoxy, -NRIOR 1 , -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)NRIOR I, -C(NR 8
)OR
7 , -C(NRs)R 7 , -C(NR 8 )NR, oR I, -C(NR 8
)SR
7 , -OC(O)R 7 , -OC(O)OR 7 , -OC(S)OR7, -OC(NR 8
)OR
7 ,
-SC(O)R
7 , -SC(O)OR 7 , -SC(NR 8
)OR
7 , -OC(S)R7, -SC(S)R 7 , -SC(S)OR 7 , -OC(O)NR 0 oRj , -OC(S)NRjoR 1 , -OC(NR 8 )NRIOR I, -SC(O)NRioR I, -SC(NRs)NRIORI 1 , -SC(S)NR 0 oR 1 ,
-OC(NR
8
)R
7 , -SC(N R 8
)R
7 , -C(O)N RI oRI, -NR 8 C(O)R7, -N R 7
C(S)R
7 , -NR 7 C(S)OR7, -N R 7 C(N R 8
)R
7 , -NR 7
C(O)OR
7 , -NR 7 C(N R 8
)OR
7 , -N R 7
C(O)NRIOR
1 , -N R 7 C(S)N RIOR I, - C \NRPortbIDCC\REC4075S614_ .DOC-1/10/2012 - 130 N R7C(NRs)NR ioR , ,-SR7, -S(O),R7, -OS(0),R7, -OS(O),OR7, -OS(O),NRioR a, -S(O),0R7, -N R 8 S(O),R7, -NR7S(O),N RioR 1 , -NR7S(O),OR7, -S(O),NRioR , -SS(O)R7, -SS(O),OR7, -SS(O),NRioR 1 , -OP(O)(ORy) 2 , or -SP(O)(OR7) 2 . Preferably, R7 0 is selected from the group consisting of -H, C I-C6 alkyl, CI -C6 alkoxy, C I -C6 cycloalkyl, and CI-C6 cycloalkoxy, more preferably from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy;
R
10 2 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, -(CH 2 )mC(O)OR 7 , -C(O)OR7, -OC(O)R7, -C(O)NRioR I, -S(O),R7, -S(O),OR7, or -S(O),NRIoRII; preferably, R 10 2 is selected from the group consisting of -H, a C I-C6 alkyl, a Cl -C6 cycloalkyl, -C(O)N(R 27
)
2 , and -C(O)OH, wherein
R
2 7 , for each occurrence, is independently is -H or a lower alkyl;
R
10 3 and Rio4 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(0)R7, -C(O)OR7, -OC(O)R7, -C(O)NRioRI, -NR8C(O)R7, -SR7, -S(O),R7, -OS(O),R7, -S(O),OR7, -NR 8 S(O),R7, -S(O),NRioR 1 , or R 10 3 and R1 0 4 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; preferably, RI 0 and Ri04 are independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy; Rjo 5 is -H, -OH, -SH, -NR7H, -OR2 6 , -SR 2 6 , -NHR2 6 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -0C(O)NRjoR 1 , -SC(O)NRioR, -NR7C(O)NRioR 1 , -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH 2 C(O)R7, -NR7CH2C(O)R7, -OCH 2 C(O)OR7, -SCH2C(O)OR7, -NR7CH 2 C(O)OR7, -OCH 2 C(O)NRjoR 1 1 , -SCH 2 C(O)NRioR, -NR7CH 2
C(O)NR
1 oR 11 , -OS(O),R7, -SS(O),R7, -NR7S(O),R7, -OS(O),NRoR 1 , -SS(O),NRjoR 1 , -NR7S(O),NRoR 1 , -OS(O),OR7, -SS(O),OR7, -NR7S(O),OR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRioR 1 , -SC(S)NRioR 1 , -NR7C(S)NRioR 1 , -OC(NR 8 )R7, -SC(NR 8 )R7, -NR7C(NR 8 )R7, -OC(NR 8 )OR7, -SC(NR 8 )OR7, - C:NRPortb1\DCCNREC\4075614_I DOC-111012012 - 131 NR 7
C(NR
8
)OR
7 , -OC(NR 8 )NRioR 1 , -SC(NR)NRIOR, or -NR 7 C(NR8)NRIoR,; preferably, R 105 is selected from the group consisting of -H, -OH, -SH, -NH 2 , a CI -C6 alkoxy, a C I-C6 alkyl amino, and a CI-C6 dialkyl amino, more preferably from the group consisting of -H, -OH, methoxy and ethoxy; and
R
106 , 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, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRioRI, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NRioR 1 , -NR 8
C(O)R
7 , -SR 7 , -S(O),R 7 ,
-OS(O),R
7 , -S(O),OR 7 , -NR 8
S(O),R
7 , or -S(O),NRIORII. The remainder of the variables of the compounds of structural formula (LII) has values defined above with reference to structural formula (VI). In one preferred set of values for the variables of the Hsp90 inhibitor represented by formula (LII), Xio 1 is NR 10 2 , R 102 is selected from the group consisting of -H, a CI-C6 alkyl, a CI C6 cycloalkyl, -C(O)N(R 27
)
2 , and -C(O)OH, each R 27 , for each occurrence, is independently is -H or a lower alkyl, and the values for the remainder of the variables are as described above for formula (LII). In a second preferred set of values for the variables of the Hsp90 inhibitor represented by formula (LII), X 101 is NR 10 2 , R 102 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 )mC(O)OH, -CH 2 0CH 3 , -CH 2
CH
2 0CH 3 , and -C(O)N(CH 3
)
2 and the values for the remainder of the variables are as described above for formula (LII). In third preferred set of values for the variables of the Hsp90 inhibitor represented by formula (LII), X 10 2 is CR 104 ; Y is CR 103 ; and R 103 and R 104 together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring. Preferably, R 103 and
R
104 together with the carbon atoms to which they are attached form a Cs-C 8 cycloalkenyl or a C 5 Cs aryl and the values for the remainder of the variables are as described above for formula (LII). In fourth preferred set of values for the variables of the Hsp90 inhibitor represented by formula (LII), R, is -OH or -SH and the values for the remainder of the variables are as described above for formula (LII).
C:\NRPorblDCC\REC)75614_I DOC-1/10/20l2 - 132 In another preferred embodiment, the Hsp90 inhibitor of the invention is represented by structural formula (Lill):
R
70 R10R HO /Ro 2 N R1 03 X103 HO HN, R1 HN N (LIll), where X 1 03 is CRI 04 or N and the remainder of the variables is defined above with reference with structural formulas (LII). In another preferred embodiment, the Hsp90 inhibitor of the invention is represented by a structural formula selected from formulas (LIVa)-(LIVi): (Ry1)x R5 (R71)x RY (Ryo)z R1 (Ryo)z 'R1 HN--N HN--N R3 (LIVa) R3 (LIVb) (R70)z (R71)x R1Ld R71 r% (Ryo)z R1 R1 HN-N HN-N R3 (LIVc) R3 (LIVd) C:\NRPorbl\DCC\REC0075614 I DOC-1/10/2012 - 133 (R 70 )z (R 7 0)z R2' R18 R71 R71 R1 R1 H N-N HN-N R3 (LIVe) R3 (LIVf) Ry0 Ry0 R71 R5R71 R2' R1 R1 HN-N HN--N R3 (LIVg) R3 (LIVh) Ry0 Ry1, HN-N R3 (LIVi) The values for the variables in structural formulas (LIVa)-(LIVi) are as described in structural formulas (VI), (VII), and (V Ill). In one preferred set of values for the variables of the Hsp90 inhibitor represented by structural formulas (LIVa)-(LIV i):
R
5 is as described for structural formula (VI), (VII), and (VIII) or a structural formula from Table 1;
R
7 o and R 71 , for each occurrence, are 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 heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NRIOR 1 , -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)NRioR I, -C(N R 8
)OR
7 , -C(N R 8
)R
7 , -C(NR 8
)NR
0 oR I, -C(NR 8
)SR
7 , -OC(O)R 7 , -OC(O)OR 7 , -OC(S)OR7, -OC(NR 8
)OR
7 , -SC(O)R,, -SC(O)OR 7 , -SC(NR 8
)OR
7 , -OC(S)R, -SC(S)R 7 ,
-SC(S)OR
7 , -OC(O)NRioR 1 , -OC(S)NRIOR 1 , -OC(NR 8
)NR
0 oR 1 , -SC(O)NRioR 1 , -SC(N R 8 )N R oR 1 , -SC(S)NR 0 oR, -OC(NR 8
)R
7 , -SC(N R 8
)R
7 , -C(O)N R oR 1 , -N R 8
C(O)R
7
,
C:\NRPonb\DCC\RECW4O75614_ I DOC-1/10/201 2 - 134 -N R 7
C(S)R
7 , -N R 7
C(S)OR
7 , -N R 7
C(NR
8
)R
7 , -N R 7
C(O)OR
7 , -N R 7 C(N R 8
)OR
7 , -NR 7 C(O)N RoR 11 ,
-NR
7 C(S)N RioR 11 , -NR 7 C(NR)NRioR, -SR 7 , -S(O),R 7 , -OS(O)pR 7 , -OS(O),OR 7 , -OS(O),NR oR, 1 , -S(O),OR 7 , -N RgS(O),R 7 , -NR 7 S(O),NR oR 1 , -NR 7 S(O)pOR 7 , -S(O),N R 1 oR 1 ,
-SS(O),R
7 ,
-SS(O),OR
7 , -SS(O)pNRioR 1 , -OP(O)(OR 7
)
2 , or -SP(O)(OR 7
)
2 ; z in structural formula (LIVa)-(LIVc) is zero or an integer from I to 4; z in structural formula (LlVd)-(LIVf) is zero or an integer from I to 3; x is 0 or 1; z + x in structural formula (LIVa)-(LIVc) is less than or equal to 4; and the remainder of the variables in formulas (LIVa)-(LIVi) have values defined above with reference to structural formula (VI), (VII) and (VIII). A second preferred set of values for the variables of the Hsp90 inhibitor represented by structural formula (LIVa)-(LIVc) is provided in the following paragraphs:
R
7 1 is a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, -OH, -SH, -NHR 7 , -(CH 2 )kOH, (CH 2 )kSH, -(CH 2 )kNR 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)NRioR, -SC(O)NRioR 11 , -NR 7 C(O)NRioR 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
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7 CH2C(O)OR 7 , -OCH 2 C(O)NRoR 1 , -SCH 2 C(O)NRoR,
-NR
7
CH
2 C(O)NRioR 11 , -OS(O),R 7 , -SS(O),R 7 , -NR 7 S(O)pR7, -OS(O)pNRIoR 1 , -SS(O)pNRIoR 1 ,
-NR
7 S(O)pNRioRII, -OS(O)pOR 7 , -SS(O),OR 7 , -NR 7
S(O),OR
7 , -OC(S)R 7 , -SC(S)R 7 ,
-NR
7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR 11 , -SC(S)NRioR 1 ,
-NR
7 C(S)NRioR 11 , -OC(NR 8
)R
7 , -SC(NR 8 )R7, -NR 7
C(NR
8
)R
7 , -OC(NRs)OR , -SC(NR 8
)OR
7 , NR 7
C(NR
8
)OR
7 , -OC(NR 8 )NRoR 1 , -SC(NR 8 )NRioR 1 1 , -NR 7
C(NR
8 )NRioR 1 , -C(O)R 7 ,
-C(O)OR
7 , -C(O)NRioR 1 , -C(O)SR 7 , -C(S)R 7 , -C(S)OR 7 , -C(S)NRioR 1 , -C(S)SR 7 , C(NR 8
)OR
7 , -C(NR 8
)R
7 , -C(NR 8 )NRioR 1 , -C(NR 8
)SR
7 , -S(O),OR 7 , -S(O),NRioR 1 , or -S(O)pR 7 ; and k is 1, 2, 3, or 4; and R 1 , R 3 , R 70 and the remainder of the variables are as described in the first preferred set of values for the variables in structural formulas (LIVa)-(LIVc). Preferably, R, and R 3 are each, independently, -OH, -SH, or -NHR 7 . A third preferred set of values for the variables of the Hsp90 inhibitor represented by formula (LIVa)-(LIVc) is provided in the following paragraphs: R, and R 3 are each, independently, -OH, -SH, or -NHR 7 ;
R
70 is an optionally substituted alkyl or cycloalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, C:\NRPonbl\DCC\REC4075614_1 DOC-/10/2012 - 135 alkoxy, haloalkoxy, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR 7 , -SR 7 , -NRIOR 11 , -OC(O)NRIORII, -SC(O)NRioRI 1 , -NR 7
C(O)NRIOR,
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 ,
-SCH
2
C(O)R
7 , -NR 7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 , -SCH 2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 ,
-OCH
2 C(O)NRioR 1 , -SCH 2 C(O)NRioR 1 , -NR 7
CH
2 C(O)NRjoRj 1 , -OS(O),R 7 , -SS(O),R 7 ,
-NR
7
S(O),R
7 , -OS(O),NRjoR 1 , -SS(O),NRjoR 11 , -NR 7 S(O),NRioR 1 , -OS(O),OR 7 , -SS(O),OR 7 ,
-NR
7
S(O),OR
7 , -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , OC(S)NRioR 11 , -SC(S)NRioR 1 , -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 ,
-OC(NR
8
)OR
7 , -SC(NR8)OR 7 , -NR7C(NR 8
)OR
7 , -OC(NR 8 )NRioR 1 , -SC(NR 8 )NRioR 1 ,
-NR
7
C(NR
8 )NRioR 1 , -C(O)R 7 , -C(O)OR 7 , -C(O)NRioRII, -C(O)SR 7 , -C(S)R 7 , -C(S)OR 7 , -C(S)NRioR , -C(S)SR 7 , -C(NR 8
)OR
7 , -C(NR 8
)R
7 , -C(NR 8 )NRIORII, -C(NR 8
)SR
7 , -S(O),OR 7 , -S(O),NRIoR,, or -S(O),R 7 and R, and R 3 and the remainder of the variables are as described in the second preferred set of values for the variables in structural formulas (LIVa)-(LIVc). In a fourth preferred set of values for the variables of Structural Formulas (LIVa)-(LIVc): R, is -SH or -OH;
R
3 and R 7 1 are -OH;
R
70 is a CI-C6 alkyl, a C3-C6 cycloalkyl, a CI-C6 alkoxy, a CI-C6 haloalkoxy, a CI -C6 alkyl sulfanyl, or -NRIOR,; and The remainder of the variables are as defined in Structural Formula (VI)-(VI11). In another preferred embodiment, the Hsp90 inhibitor is represented by a structural formula selected from formulas (LVa)-(LVf): R5 R5 XY4'--X5' XY5'-X4' X3' R1 X3' R1 HN-N HN-Nr 3 (LVa); R3 (LVb). R2' R2' X4'-Xs' X '---X4' X3' R1 X3' R1 Y HN--N H N---N R3 (LVc) R3 (LVd) CMNRPDnb4WDCC1REC\44)75614_ I DOC-1/10/201 2 - 136 R18 R18 )4-X5' x1Y'-'-m (' X30 R1 X3' R1 Y HN-N H N -- N 3 (LVe) R3 (LVf) In formulas (LVa) and (LVb):
R
5 is as described for structural formula (VI) or a structural formula from Table 1;
X
3 ' and X 4 ' are each, independently, N, N(O), N'(R 1 7 ), CH or CR 7 0;
X
5 ' is 0, S, NR 1 7 , CH 2 , CH(R 70 ), C(R 70
)
2 , CH=CH, CH=CR 7 0 , CR 70 =CH, CR 70
=CR
70 , CH=N, CR 70 =N, CH=N(O), CR 70 =N(O), N=CH, N=CR 70 , N(O)=CH, N(O)=CR 7 o, N+(R 17 )=CH,
N'(R
1 7
)=CR
70 , CH=N*(R 7 ), CR 70
=N*(R
1 A), or N=N, provided that at least one X 3 ', X 4 ' or X 5 ' is a heteroatom;
R
70 , 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 heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NRoR, -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)NRIORII,
-C(NR
8
)OR
7 , -C(N R 8
)R
7 , -C(NRg)N RioR 11 , -C(N R 8 )S R 7 , -OC(O)R 7 , -OC(O)OR7, -OC(S)OR7,
-OC(NR
8
)OR
7 , -SC(O)R 7 , -SC(O)OR 7 , -SC(NR 8
)OR
7 , -OC(S)R 7 , -SC(S)R 7 , -SC(S)OR 7 , -OC(O)NRioR, -OC(S)NR 0 oR, -OC(NR 8 )NRioR 1 , -SC(O)NR 0 oR, -SC(NR)NRioR 1 , -SC(S)N R 1 oR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -C(O)NR IOR 1 , -N R 8
C(O)R
7 , -NR 7
C(S)R
7 , -N R 7
C(S)OR
7 , -NR7C(N R 8
)R
7 , -N R 7
C(O)OR
7 , -N R 7 C(N R 8
)OR
7 , -NR 7 C(O)N RIOR 1 ,
-NR
7
C(S)NR
0 oR 1 , -N R 7
C(NR
8 )N RioR 1 , -SR7, -S(O),R 7 , -OS(O),R 7 , -OS(O),OR 7 , -OS(O),NRIORII, -S(O),OR 7 , -NR 8
S(O),R
7 , -N R 7 S(O),N R 1 ioR 1 , -NR 7
S(O),OR
7 , -S(O),NR 1 oR,
-SS(O),R
7 ,
-SS(O),OR
7 , -SS(O),NRIOR 1 , -OP(O)(OR) 2 , or -SP(O)(OR 7
)
2 ;
R
17 , for each occurrence, is independently an alkyl or an aralkyl; and n is zero or an integer from I to 4; and the remainder of the variables has values defined above with reference to structural formulas (VI), (VII), and (Vill). Preferably, Hsp90 inhibitor of structural formulas (LVa)-(LVf) are selected from Table 2a c.
C \NRPortbl\DCCRE04075614_1 DOC-I/Ior2012 - 137 Table 2a Number Compound Number Compound 0 R1 R1 HN-N R HN-N R5 R5 N7 R HN--N 7 R HN-N 2.R3 HN N7. R3HN R 7 0 0 R 1 R, HN-N
HN
R 5 R5 R1 R 3. R 3 8. R 3 0/ 7 R, R, NH-N NN 5.R 3 10. R 3 C\NRPortb\DCC\REC%4O756 IA I DOC-1/112f012 -138 Table 2b Number Compound Number Compound R3 ~6. R R, R, 2: 3R38. R 3 R70 IR'12.
R
7 0 sR HN-N HN-N 4. R39. R R2R 2 ' 0 S NH-N
H
5. 310. R 3 C:WNRPorhlOCC\REC\75614_I DOC. 1fl/l 012 - 139 Table 2c Number Compound Number Compound
R
18 R
HN
. R 3 6. R3 RIB R 70 N~~ RRiRy -- r R, N R1 HN -N HN 2. R 3 7. R3 0 RIB S R18 H-N HN-N 3. 3 . R3 R70 R70 ORie Ra HN-N HN-N 4. R3 9. R3 OR18 R18 NH-N YHN N 5. R3 ;10. R3 The values for the variables for the formulas in Tables 2a-c are as defined for structural formulas (LVa)-(LVf). Preferably, R70 is a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, -OH, -SH,
-NHR
7 , -(CH 2 )kOH, -(CH 2 )kSH, -(CH 2 )kNR 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)NRioR 1 1 , -SC(O)NRioR 1 , -NR 7 C(O)NRioR 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 , -SCH 2
C(O)R
7 , -NR 7
CH
2
C(O)R
7 ,
-OCH
2
C(O)OR
7 , -SCH 2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7
,
CANRPorlbf\DCC\RECW4D75614_1 DOC-1/10/2012 -140
-OCH
2 C(O)NRioRo, -SCH 2 C(0)NRjoR 1 , -NR 7
CH
2 C(O)NRioR 1 , -OS(O),R 7 , -SS(O),R 7 ,
-NR
7
S(O),R
7 , -0S(0),NRjoR,, -SS(O),NRjoR 11 , -NR 7 S(O),NRioR 11 , -OS(O),OR 7 , -SS(O),OR 7 ,
-NR
7
S(O),OR
7 , -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR 11 , -SC(S)NRioR 1 , -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NRs)OR 7 , -SC(NR 8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR)NRioRn, -SC(NR 8 )NRioR 1 , NR 7
C(NR
8 )NRioR 11 , -C(O)R 7 , -C(O)OR 7 , -C(O)NRioR 1 , -C(O)SR 7 , -C(S)R 7 , -C(S)OR 7 , -C(S)NRioR 11 , -C(S)SR 7 , -C(NR 8
)OR
7 , -C(NR 8
)R
7 , -C(NR 8 )NRioR 1 , -C(NR 8
)SR
7 , -S(O),OR 7 , -S(O),NRIORn, or -S(O),R 7 ; and k is 1, 2, 3, or 4. In another preferred embodiment, the Hsp90 inhibitor of the present invention is represented by structural formula (LVI):
NR
10
R
11
R
70 - (R30)0 or 1
R
7 1 ' R1 HN-N
R
3 (LVI).
R
7 o and R 71 , for each occurrence, are 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 heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NRoR 1 , -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
1 oR I, -C(NR 8
)OR
7 , -C(N R 8
)R
7 , -C(NR 8 )N R 1 oR I, -C(NR 8 )S R 7 , -OC(O)R 7 , -OC(O)OR 7 ,
-OC(S)OR
7 , -OC(NR 8
)OR
7 , -SC(O)R 7 , -SC(O)OR 7 , -SC(NR 8
)OR
7 , -OC(S)R 7 , -SC(S)R 7 ,
-SC(S)OR
7 , -OC(O)NRoR 1, -OC(S)NR 0 oR 1 , -OC(NR)NR 0 oR 1 , -SC(O)NRoRj ,
-SC(NR
8 )NRIOR 1 , -SC(S)NR 0 oR 1 , -OC(NR 8 )R7, -SC(NRs)R 7 , -C(O)NR 0 oR 1 , -NR 8
C(O)R
7 ,
-NR
7
C(S)R
7 , -N R7C(S)OR 7 , -N R 7 C(NR8)R 7 , -N R 7
C(O)OR
7 , -NR 7 C(N R 8
)OR
7 , -NR 7
C(O)NR
1 ioR 11 ,
-NR
7 C(S)NRioRn, -NR 7 C(N R 8
)NRIOR
1 , -SR 7 , -S(O),R 7 , -OS(O),R 7 , -OS(O),0R 7 , -OS(O),N RjoR , -S(O),OR 7 , -N R 8
S(O),R
7 , -N R 7 S(O),N R 1 oR 1 , -N R 7
S(O),OR
7 , -S(O),N RoR 11 , -SS(O)pR 7 , -SS(O)pOR 7 , -SS(O),NRioR 1 , -OP(O)(OR) 2 , or -SP(O)(OR) 2 . Preferably, R 70 is selected from an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted C NRPortbl\DCC\REC'0756I1DOC-/110/2o12 - 141 heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR 7 , -SR 7 , -NRIOR 1 , OC(O)NRioR 1 , -SC(0)NRIoR 11 , -NR 7 C(O)NRioR 1 , -OC(O)R 7 , -SC(O)R 7 , -NR 7
C(O)R
7 , -OC(0)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
7 ,
-OCH
2
C(O)OR
7 , -SCH 2 C(0)OR 7 , -NR 7
CH
2 C(0)OR 7 , -OCH 2 C(0)NRIoR 11 , -SCH 2 C(O)NRioRa,
-NR
7
CH
2 C(O)NRioR 11 , -OS(O),R 7 , -SS(O),R 7 , -NR 7
S(O),R
7 , -OS(O),NRIoR , -SS(0),NRioR 1 ,
-NR
7 S(O),NRioR 1 , -OS(O),OR 7 , -SS(O),OR 7 , -NR7S(O),OR 7 , -OC(S)R 7 , -SC(S)R7,
-NR
7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRIORII, -SC(S)NRioR,
-NR
7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 , -SC(NR 8
)OR
7 , NR 7 C(NR8)OR 7 , -OC(NR)NRioR 1 , -SC(NR)NRioR 1 , -NR 7 C(NR)NRioR 1 , -C(O)R 7 ,
-C(O)OR
7 , -C(O)NRIORII, -C(O)SR 7 , -C(S)R 7 , -C(S)OR 7 , -C(S)NRioR 1 , -C(S)SR 7 , C(NR 8
)OR
7 , -C(NR 8
)R
7 , -C(NR 8 )NRoR 1 , -C(NR 8
)SR
7 , -S(O),OR 7 , -S(O),NRioR 1 , or
-S(O),R
7 and R7 1 is as just described. The values for the remainder of the variables are as described for structural formulas (VI), (VII), and (VIII). In another preferred embodiment, the Hsp90 inhibitors is represented by structural formula (LVIIa) or (LVIlIb): (R30)0 or 1 NR 10
R
11 NR10R11 (R30)0 or 1 Ry0 Ry0
R
7 1 /
R
7 1 / 7R 1 R
R
3 HN-N (LVIIa); R3 HN-N (LVIIb). The variables in formulas (LVIIa) and (LVIIb) are defined above with reference to formula (LVI). A first preferred set of values for the variables of structural formula (LVIIa) and (LVIIb) is provided in the following paragraph: RI, R 3 or R 7 1 are each independently selected from -OH, -SH, -NHR 7 , -OC(O)NRoR 1 , SC(O)NRIOR I, -OC(O)R 7 , -SC(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -OS(O),R 7 , -S(O),OR 7 , -SS(O)pR 7 ,
-OS(O),OR
7 , -SS(O),OR 7 , -OC(S)R 7 , -SC(S)R 7 , -OC(S)OR 7 , -SC(S)OR 7 , -OC(S)NRioR 1 ,
-SC(S)NR
0 oR 1 , -OC(NR 8
)R
7 , -SC(NRs)R 7 , -OC(NR 8
)OR
7 , -SC(NR 8
)OR
7 , -OP(O)(OR) 2 or
-SP(O)(OR
7
)
2 , and p, R 70 , R 7 , R, Rio, R, 1 and R 30 are as described for structural formula (LVI). Preferably, when R 1 , R 3 and R 7 1 have these values, RIO and R, 1 are preferably each independently a hydrogen, a CI-C6 straight or branched alkyl, optionally substituted by -OH, -CN, -SH, amino, a Cl -C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or RIO and R 1 taken together with the nitrogen to which they are attached form a substituted or unsubstituted C:NRPorbl\DCC\REC 75614_ LDOC-1/10/2012 - 142 nonaromatic, nitrogen-containing heterocyclyl; and p, R7 0 , R7, and R3 0 are as described for structural formula (LVI). More preferably, when RI, R3, Rio, Ro, and R7 1 have these values, Ry 0 is preferably a CI-C6 alkyl, a CI -C6 haloalkyl, a CI-C6 alkoxy, a CI-C6 haloalkoxy, a C I -C6 alkyl sulfanyl or a C3-C6 cycloalkyl; and p, R7, R 8 and R3 0 are as described for structural formula (LVI). A second preferred set of values for the variables of structural formula (LVIIa) and (LVib) is provided in the following paragraph: R, and R3 are each independently -OH or -SH; R7 0 is preferably a CI-C6 alkyl, a CI-C6 haloalkyl, a CJ -C6 alkoxy, a C I -C6 haloalkoxy, a CI-C6 alkyl sulfanyl or a C3-C6 cycloalkyl; Rio and R, are preferably each independently a hydrogen, a Cl -C6 straight or branched alkyl, optionally substituted by -OH, -CN, -SH, amino, a Cl-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or RIO and R, 1 taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl; R7, 1 is -OH, -SH, -NIHR7, -OC(O)NRIoR 1 , -SC(0)NRIoR 1, -OC(O)R7, -SC(O)R7, -OC(O)OR7, -SC(O)OR7, -OS(O),R7, -S(O),OR7, -SS(O),R7, -OS(O),0 R7, -SS(O),OR7, -OC(S)R7, -SC(S)R7, -OC(S)OR7, -SC(S)OR7, -OC(S)NRIoR 1 , -SC(S)NRIoR 1
-OC(NR
8 )R7, -SC(NR 8 )R7,
-OC(NR
8 )OR7, -SC(NR 8 )OR7, -OP(O)(OR7) 2 or -SP(O)(OR7) 2 ; and p, R 7
R
8 and R3 0 are as described for structural formula (LVI). Preferably, R3 0 is a -OH, -SH, halogen, cyano, a C I -C6 alkyl, CI-C6 haloalkyl, Cl-C6 alkoxy, CI-C6 haloalkoxy or CI-C6 alkyl sulfanyl and the remainder of the variables are as just described. A third preferred set of values for the variables of structural formula (LVIla) and (LVIIb) is provided in the following paragraph: C:\NRPortb1\DCC\REC\4075614_ DOC.I/102012 - 143 RI, R 3 and R 71 are independently -SH or -OH; R 70 is cyclopropyl or isopropyl; RIO and R, 1 are each independently a hydrogen, a Cl -C6 straight or branched alkyl, optionally substituted by -OH, -CN, -SH, amino, a C I-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or RIO and R, 1 taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl; and R 30 is -OH, -SH, halogen, cyano, a CI-C6 alkyl, CI -C6 haloalkyl, CI -C6 alkoxy, CI-C6 haloalkoxy or CI-C6 alkyl sulfanyl. Preferably, R 30 is a methyl, ethyl, propyl, isopropyl, methoxy or ethoxy. More preferably, R 1 , R 3 ,
R
7 o, R 71 and R 3 o are as just described and and RIO and R, 1 are each independently a hydrogen, methyl, ethyl, propyl, isopropyl, or taken together with the nitrogen to which they are attached, are: -N Q -N N N-R35 -N O -N S wherein R 35 is -H, a C I-C4 alkyl or a Cl -C4 acyl. In another preferred embodiment, the Hsp90 inhibitor is represented by structural formulas (LVIIIa) or (LVIIIb):
NRI
0
R
1 1 NR 0
R
11 (Rao)or - - (R Co)oor1 X3' RX3R HN-N HN-N
R
3 (LVIIIa); R 3 (LVIllIb); The values for the variables in structural formulas (LVIlila) and (LVIIIb) are as described for structural formulas (LVc) and (LVd). Preferably, R 3 0 is 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, alkoxy, haloalkoxy, -NRIOR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -C(S)R7, -C(O)SR 7 , -C(S)SR 7 , -C(S)OR 7 , -C(S)N R IoR 1 , -C(N R 8
)OR
7 , -C(N Rg)R7, -C(NR 8 )N RioR 1 , -C(NR 8
)SR
7 , -OC(O)R 7 , -OC(O)OR 7 ,
-OC(S)OR
7 , -OC(NR 8
)OR
7 , -SC(O)R 7 , -SC(O)OR 7 , -SC(NR 8
)OR
7 , -OC(S)R 7 , -SC(S)R,, - C NRPrbliDCC\REC)7156N_ I DOC-1/10/2012 - 144
SC(S)OR
7 , -OC(O)NR 0 oR 1 , -OC(S)NR, 0 oR 1 , -OC(NR 8 )NRioR 1 , -SC(O)NR 0 oR 1 , SC(NR)NR 0 oR 1 , -SC(S)N RioR 1 , -OC(NR 8
)R
7 , -SC(NR8)R 7 , -C(O)NRioR 1 , -NR 8
C(O)R
7 , NR 7 C(S)R7, -N R 7
C(S)OR
7 , -N R 7 C(N R 8
)R
7 , -N R 7
C(O)OR
7 , -NR 7
C(NR
8
)OR
7 , -N R 7 C(O)NRioR 1 ,
-NR
7 C(S)N R 1 oR 1 , -NR 7
C(NR
8 )N R 1 oR, -SR 7 , -S(O),R 7 , -OS(O),R 7 , -OS(O)pOR 7 , -OS(O),NRioR 1 , -S(O),OR 7 , -N RsS(O)pR 7 , -NR 7 S(O),N RioR 1 , -N R 7
S(O),OR
7 , -S(O),N R 1 oR 1 , -SS(O)pR 7 , -SS(O),OR 7 , -SS(O)pNRioR I, -OP(O)(OR) 2 , or -SP(O)(OR 7
)
2 . More preferably, R 30 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 , -NRIOR 1 , -OC(O)NRioR 1 , -SC(O)NRioR 1 , -NR 7 C(O)NRioR 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
7 , OCH 2
C(O)OR
7 , -SCH 2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRIORII, -SCH 2
C(O)NRIORI
1 ,
-NR
7
CH
2 C(O)NRioR 11 , -OS(O),R 7 , -SS(O)pR 7 , -NR7S(O),R 7 , -OS(O),NRoR n, -SS(O),NRoR 1 ,
-NR
7 S(O),NRioR, 1 , -OS(O),OR 7 , -SS(O),OR7, -NR 7
S(O),OR
7 , -OC(S)R 7 , -SC(S)R 7 ,
-NR
7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NR 1 oR 1 , -SC(S)NRioR 1 ,
-NR
7 C(S)NRioRI, -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR 8 )OR7, -SC(NR 8
)OR
7 , NR7C(NR 8
)OR
7 , -OC(NR)NRioR 1 , -SC(NR)NRioR 1 , -NR 7 C(NRg)NRjoR 1 , -C(O)R 7 ,
-C(O)OR
7 , -C(O)NRioR 11 , -C(O)SR 7 , -C(S)R 7 , -C(S)OR 7 , -C(S)NRioR 11 , -C(S)SR 7 , C(NR 8
)OR
7 , -C(NR 8
)R
7 , -C(NR 8 )NRioR 11 , -C(NR 8
)SR
7 , -S(O),OR 7 , -S(O),NRioR 11 , or -S(O)pR 7 . In another preferred embodiment, the Hsp90 inhibitor is represented by a structural formula selected from formulas (LIXa)-(LlXd):
NR
10
R
11
NR
10
R
11 (R 30)o o (R 30
)
0 or 1 x 4 -x 5 x 5 -x 4 X3 R1 X R HN-N HN--N
R
3 (LIXa); R 3 (LIXb); C:\NRPorbM)COREC4075614_L DOC-1/10/2012 - 145 (R 30 ) or 1 (R30)or 1 N R oR j N R10Rii
X
4 -Xs x - x 4 x 3 R1 X3 R H N -- N H N -- N
R
3 (LIXc); 3(LIXa) The values of the variables in structural formulas (LIXa)-(LIXd) are defined above with reference to structural formulas (LV II1a) and (LV I I Ib). A first preferred set of values for the variables in structural formulas (LIXa)-(LIXd) are as described in the following paragraphs: R, and R 3 are each independently -OH or -SH, -HNR 7 , -OC(O)NRIOR, -SC(O)NRIORII, OC(O)R 7 , -SC(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -OS(O),R 7 , -S(O)pOR 7 , -SS(O)pR 7 , -OS(O)pOR 7 , -SS(O)pOR 7 , -OC(S)R 7 , -SC(S)R 7 , -OC(S)OR 7 , -SC(S)OR 7 , -OC(S)NRIoR 1 , -SC(S)NR 0 oR 1 , -OC(N R 8
)R
7 , -SC(NR 8 )R7, -OC(NR8)OR, -SC(N R 8
)OR
7 ,
-OP(O)(OR
7
)
2 or -SP(O)(OR) 2 ;
R
70 , 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)NRIOR I, -SC(O)NRIOR I, -OC(O)R 7 , -SC(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -OS(O),R 7 , -S(O)pOR 7 , -SS(O)pR 7 , -OS(O),OR 7 , -SS(O),OR 7 , -OC(S)R 7 , -SC(S)R 7 , -OC(S)OR 7 , -SC(S)OR, -OC(S)NRoR, -SC(S)N RoR, -OC(NRg)R 7 , -SC(NR 8
)R
7 , -OC(NR 8
)OR
7 , -SC(N R 8
)OR
7 ,
-OP(O)(OR
7
)
2 or -SP(O)(OR 7
)
2 . Preferably, R 70 is a CI-C6 alkyl, a C I -C6 haloalkyl, a CI -C6 alkoxy, a CI-C6 haloalkoxy, a CI-C6 alkyl sulfanyl or a C3-C6 cycloalkyl; and Rio and R, 1 and the remainder of the variables in structural formulas (LIXa)-(LIXd) are as described for structural formulas (LVIa) and (LVIllIb). Preferably, RIO and R 11 are each independently a hydrogen, a CI -C6 straight or branched alkyl, optionally substituted by -OH, -CN, -SH, amino, a Cl -C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or Rio and R 1 taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl.
C:NRPortblOCCREC4075614_1 DOC-/10/2012 - 146 In another preferred embodiment, the Hsp90 inhibitor is represented by a structural formula selected from formulas (LXa)-(LXp):
NR
10
R
1 1
NR
10
R
11 (R30)oor1 (R 30
)
0 or 1 N H NR-- , N -- R HN-N R HN-N (LXa) (LXb)
NR
1 0
R
11
NR
1 0
R
11 (R30)0 or 1 (R 30
)
0 or 1 O _ N R70 R1 R1 / N HN--N HN-N R3 R3; (LXc) (LXd)
NR
1 0
R
11
NR
1 0
R
11 (Raolo or 1 (R 3 0
)
0 or 1 R( R70 O S R1 R1 R3 HN--N R3 HN-N (LXe) (LXf) C\NRPonlbI\DCC'ECl40756 I4 I DOC-I11012012 - 147
NR
1 0
R
11
NR
10
R
1 1 (R00or 1 (R00or1i 0 / HN-N HN-N R3 K (LXi) (LXj) (R 30
)
0 or 1 (R 30
)
0 or
NR
10
R
11 NR 0 R 1 (LXki) (LXI) C \NRPonbl\DCCREC\4075614_-IDOC-1/11/2012 - 148 (R 3 0
)
0 or 1
(R
30
)
0 or 1
NR
1
R
11
NR
1 R, R70 Ry0 o s R1 R1 R3 HN--N R3 HN-N (LXm) (LXn) (R 3o)n oa1 (Repo)O or 1 NRjoRjj NRiORij R1 R1 H N---N H N--N R 3 RK3 (LXo) (LX p) The values of the variables in structural formulas (LXa)-(LXp) are defined above with reference to structural formulas (XmXa)-(XLaXd). A first preferred set of values for the variables in structural formulas (LX) are as described in the following paragraphs: R, and R3 are each independently -OH or -SH, or -HNR7; R70, is a ClI-C6 alkyl, a C I -C6 haloalkyl, a C I -C6 alkoxy, a C I -C6 haloalkoxy, a C I -C6 alkyl sulfanyl or a C3-C6 cycloalkyl; Rio and R, 1 and the remainder of the variables in structural formulas (LXa)-(LXp) are as described for structural formnulas (LVIlla) and (LVIIlb). Preferably, Rio and RI, are each independently a hydrogen, a CI-C6 straight or branched alkyl, optionally substituted by -OH, -CN, -SH, amino, a CI-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or Rio and
R,
1 taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl; and C:\NRPortbDCC\REC\47564_LDOC-I/10/I212 -149
R
30 and the remainder of the variables in structural formulas (LXa)-(LXp) are as described for structural formulas (LIXa)-(LIXd). Preferably, R3 0 is -OH, -SH, halogen, cyano, a CI -C6 alkyl, Cl -C6 haloalkyl, C I -C6 alkoxy, C I -C6 haloalkoxy or Cl -C6 alkyl sulfanyl. A second preferred set of values for the variables in structural formulas (LXa)-(LXp) are as described in the following paragraphs: R, and R 3 are independently -SH or -OH;
R
7 o is cyclopropyl or isopropyl; RIO and R, 1 are each independently a hydrogen, a CI-C6 straight or branched alkyl, optionally substituted by -OH, -CN, -SH, amino, a CI-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or RIO and R 1 taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl;
R
30 is -OH, -SH, halogen, cyano, a Cl-C6 alkyl, Cl-C6 haloalkyl, Cl-C6 alkoxy, Cl-C6 haloalkoxy or CI -C6 alkyl sulfanyl. Preferably, R 30 is a methyl, ethyl, propyl, isopropyl, methoxy or ethoxy; and the remainder of the variables are as described for formulas (LVIIIa) and (LVIIlb). More preferably, RIO and R, are each independently a hydrogen, methyl, ethyl, propyl, isopropyl, or taken together with the nitrogen to which they are attached, are: -N -N -N N-R 35 -N S -N 0 wherein R 35 is -H, a C I-C4 alkyl or a Cl -C4 acyl. In another embodiment, the Hsp90 inhibitor of the present invention is represented by structural formulas (LXIa) or (LXlb): R22 R23 R24 R24 R2 X14 NR1X14_ R21 R23 HN-N R2HN--N R (LXIa); R3 (LXIb). In formulas (LX Ia) and (LXIb):
X
14 is 0, S, or NR7. Preferably, X1 4 is 0; C:\NRPortblOCC\REC\40756 14_DOC-/10/2012 - 150 R, is -OH, -SH, -NR 7 H, -OR 26 , -SR 26 , -NHR 26 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -0C(O)NRioR I, -SC(O)NRioRa,
-NR
7 C(O)NRioR 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 , -SCH 2
C(O)R
7 , -NR 7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRjoR 1 , -SCH 2 C(O)NRioR 1 ,
-NR
7
CH
2 C(O)NRioR 11 , -OS(O)pR 7 , -SS(O),R 7 , -S(O),OR 7 , -NR 7
S(O),R
7 , -OS(0),NRIoR 1 , -SS(O),NRioR I, -NR 7 S(O)pNRioR 1 , -OS(O),OR 7 , -SS(O),OR 7 , -NR 7
S(O),OR
7 , -OC(S)R 7 ,
-SC(S)R
7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR, -SC(S)NRioR 1 , -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR8)OR 7 ,
-SC(NR
8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR)NRioR 1 , -SC(NR 8 )NRioRa, -NR 7
C(NR
8 )NRioR, OP(O)(OR 7
)
2 , or -SP(O)(OR 7
)
2 . Preferably, RI is -OH, -SH, or -NHR 7 ;
R
3 is -0H, -SH, -NR 7 H, -OR 26 , -SR 26 , -NHR 2 6 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR7H, -0C(O)NRjoR 1 , -SC(O)NR oR, 1 ,
-NR
7 C(O)NRioR 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 , -SCH 2
C(O)R
7 , -NR 7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRjoR 1 , -SCH 2 C(O)NRioRa,
-NR
7
CH
2 C(O)NRioR 11 , -OS(O),R 7 , -SS(O),R 7 , -S(O)pOR 7 , -NR 7
S(O),R
7 , -OS(O),NRioR 1 , -SS(O),NRioR 1 , -NR 7 S(O),NRioR 1 , -OS(O)pOR 7 , -SS(O),OR 7 , -NR 7 S(O)pOR 7 , -OC(S)R 7 ,
-SC(S)R
7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRoR, -SC(S)NRioR 11 , -NR 7 C(S)NRioR 1 , -OC(NR 8 )R?, -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NRs)OR 7 ,
-SC(NR
8
)OR
7 , -NR7C(NRs)OR 7 , -OC(NR 8 )NRioR 11 , -SC(NR)NRioR 1 , -NR 7
C(NR
8 )NRioRa, -C(O)OH, -C(O)NHR 8 , -C(O)SH, -S(O)OH, -S(O) 2 0H, -S(O)NHR 8 , -S(O) 2
NHR
8 ,
-OP(O)(OR)
2 , or -SP(O)(OR 7
)
2 ;
R
7 and R 8 , 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 RI , 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 RIO and R, 1 , taken together with the nitrogen to which C:\NRPortbDCC\RE4075614_ I DOC-1/1012012 -151 they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R
2 1 is 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, R21 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. Alternatively, R 21 is
NR
1
R
11 (R30)0 or I
(R
30
)
0 or 1 NR 1
R
11 or wherein Rio and R 1 is defined as above; and
R
30 is 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, alkoxy, haloalkoxy, -NRIOR 1 , -OR 7 , -C(O)R 7 ,
-C(O)OR
7 , -C(S)R7, -C(O)SR 7 , -C(S)SR 7 , -C(S)OR 7 , -C(S)NRoR, 1 , -C(NR 8
)OR
7 , -C(NR 8
)R
7 ,
-C(NR)NR
0 oR I, -C(NR 8
)SR
7 , -OC(O)R 7 , -OC(O)OR 7 , -OC(S)OR 7 , -OC(NR 8
)OR
7 , -SC(O)R 7 ,
-SC(O)OR
7 , -SC(N R 8
)OR
7 , -OC(S)R 7 , -SC(S)R 7 , -SC(S)OR 7 , -OC(O)NRioR 1 , -OC(S)NRioR 1 ,
-OC(NR
8 )NRioR 1 , -SC(O)NR 0 oR 1 , -SC(NR)NR 0 oR 1 , -SC(S)NR 0 oR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -C(O)N R 1 oR 1 , -N R 8
C(O)R
7 , -N R 7
C(S)R
7 , -NR 7
C(S)OR
7 , -N R 7
C(NR
8
)R
7 , -NR 7
C(O)OR
7 ,
-NR
7
C(NR
8
)OR
7 , -NR 7
C(O)NR
1 oR , -NR 7
C(S)NR
0 oR, -NR 7
C(NR)NR
0 oR, -SR 7 , -S(O),R 7 , -OS(O)pR 7 , -OS(O)pOR 7 , -OS(O)pNR 1 oR 1 , -S(O),OR 7 , -N R 8 S(O)pR 7 , -NR 7 S(O),NRioR 1 , -N R 7
S(O),OR
7 , -S(O)pN R 1 oR 1 , -SS(O)pR 7 , -SS(O),OR 7 , -SS(O),N R 1 oR 1 , -OP(O)(OR) 2 , or
-SP(O)(OR
7
)
2 ; z and q are independently an integer from 0 to 4; and x is 0 or 1, provided that z+x less than or equal to 4.
R
22 , for each occurrence, is independently a substituent selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted C:\NRPortbl\DCCREC\40I75614_l.DOC-1110/20 12 - 152 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)NRioR 1 , -NR 8
C(O)R
7 , -S(O),R 7 , -S(O),OR 7 , or -S(O),NRIoR 1 . Preferably, R 22 is an alkyl, an aralkyl, -C(O)R 7 , -C(O)OR 7 , or -C(O)NRIORu; and
R
2 3 and R 2 4 , for each occurrence, are independently a substituent 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, or an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRIOR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NRioR 1 , -NR 8
C(O)R
7 , -SR 7 , -S(O)pR 7 , -OS(O),R 7 , -S(O),OR 7 , -NR 8
S(O),R
7 , or -S(O),NRjoRi1;
R
26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4. In one embodiment, a compound of the present invention is represented by a structural formula selected from formulas (IX), (X) and (XI):
R
5 R A R, A N R1 N N R3 (IX)
R
3 (X).
R
18 A R1 N
R
3 (Xl). In formulas (IX)-(XI): C:\NRPorbl\DCC\REC4015614 1 DOC.IIIOflOI2 - 153 ring A is an aryl or a heteroaryl, optionally further substituted with one or more substituents in addition to R 3 . Preferably, Ring A is represented one of the following tructural formulas:
R
70 (Ry1)x (R70)z R71 R 7 1 (Ryo)z
R
3 R 3 or R3 wherein z is 0, 1, 2, 3 or 4; x is 0 or I; and z + x is less than or equal to 4. R, is -OH, -SH, -NR 7 H, -OR 26 , -SR 26 , -NHR 26 , -O(CH 2 ).OH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -OC(O)NR oR 11 , -SC(O)NRioR 1 ,
-NR
7 C(O)NRioR 11 , -OC(O)R 7 , -SC(O)R 7 , -NR 7
C(O)R
7 , -OC(O)OR,, -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
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRioR 1 , -SCH 2 C(O)NRioR,
-NR
7
CH
2 C(O)NRioR 1 , -OS(O),R 7 , -SS(O),R 7 , -S(O),OR 7 , -NR 7
S(O),R
7 , -OS(O),NRioR, -SS(O),NRioR 1 , -NR 7 S(O)pNRioR 11 , -OS(O)pOR 7 , -SS(O),OR 7 , -NR 7
S(O),OR
7 , -OC(S)R 7 ,
-SC(S)R
7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR, -SC(S)NRioR 11 , -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 ,
-SC(NR
8
)OR
7 , -NR7C(NR 8
)OR
7 , -OC(NR 8 )NRIORII, -SC(NR 8 )NRioR 1 , -NR 7
C(NR
8 )NRioR 1 , OP(O)(OR) 2 , or -SP(O)(OR 7
)
2 . Preferably, R, is -OH, -SH, -NHR 7 , -OC(O)NRioR I, SC(O)NR 0 oR 1 , -OC(O)R 7 , -SC(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -OS(O),R 7 , -S(O)pOR 7 , -SS(O),R7,
-OS(O),OR
7 , -SS(O)pOR 7 , -OC(S)R7, -SC(S)R 7 , -OC(S)OR, -SC(S)OR, -OC(S)NR 0 oR,
-SC(S)NR
0 oR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -OC(NR 8
)OR
7 , -SC(NR 8
)OR
7 , -OP(O)(OR) 2 or
-SP(O)(OR
7
)
2 . More preferably, R, is -OH, -SH, or -NHR 7 . Even more preferably, Ri, is -SH or -OH;
R
2 ' is an optionally substituted phenyl group. Preferably, R 2 ' is substituted with one or more group represented by R 30 , wherein R 30 , for each occurrence, are 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 heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NRIORII, -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)N RIOR I, -C(N R 8
)OR
7 , -C(NR 8
)R
7 , -C(N Rs)NR ioR 1
,
C:\NRPortbhDCC\REC\4075614_ LDOC- 1/11/2012 -154 -C(N Rs)SR 7 , -OC(O)R 7 , -OC(O)OR 7 , -OC(S)OR 7 , -OC(NR8)OR 7 , -SC(O)R 7 , -SC(O)OR 7 ,
-SC(NR
8
)OR
7 , -OC(S)R 7 , -SC(S)R 7 , -SC(S)OR 7 , -OC(O)NR 0 oR 1 , -OC(S)N R 1 oR 1 ,
-OC(NR
8
)NR
0 oR, -SC(O)NRioR 1 , -SC(NR)NRioR 1 , -SC(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 ,
-C(O)NR
1 oR , -N R 8
C(O)R
7 , -N R 7
C(S)R
7 , -NR 7
C(S)OR
7 , -N R7C(NR 8
)R
7 , -NR 7
C(O)OR
7 ,
-NR
7
C(NR
8
)OR
7 , -NR 7 C(O)N R,oR, -NR 7 C(S)NRioR, -NR 7 C(N R 8 )N RIOR 1 , -SR 7 , -S(O)pR7,
-OS(O)PR
7 , -OS(O),OR 7 , -OS(O),NRioR I, -S(O)pOR 7 , -NR 8
S(O),R
7 , -NR 7 S(O)N R oR 1 ,
-NR
7
S(O),OR
7 , -S(O),NRoRI, -SS(O),R 7 , -SS(O),OR 7 , -SS(O)pNR 0 oR 1 , -OP(O)(OR) 2 , or
-SP(O)(OR
7
)
2 . More preferably, R 2 ' is an optionally substituted indolyl group or a phenyl group substituted with NRIOR 1 , and optionally with at least one other substitutent represented by R 30 ;
R
3 is -OH, -SH, -NR 7 H, -NHR 26 , -O(CH 2 )mOH, -O(CH 2 )mSH, -O(CH 2 )mNR 7 H, S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -OC(O)NRioR 1 , -SC(O)NRioR j, NR 7 C(O)NRioR 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
7 , -OCH 2
C(O)OR
7 , SCH 2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRoR 1 , -SCH 2 C(O)NRioR 1 , NR 7
CH
2 C(O)NRioR 11 , -OS(O),R 7 , -SS(O)pR 7 , -S(O)pOR 7 , -NR 7 S(O)pR 7 , -OS(O)pNRjoR 1 , -SS(O),NRioR 1 , -NR 7 S(O),NRoR 1 , -OS(O),OR 7 , -SS(O),OR 7 , -NR 7
S(O),OR
7 , -OC(S)R 7 ,
-SC(S)R
7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR, -SC(S)NRioR 11 , -NR 7 C(S)NRioR 11 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 ,
-SC(NR
8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR 8 )NRioR 11 , -SC(NR)NRioR 1 , -NR7C(NR 8 )NRioR, -C(O)OH, -C(O)NHR, -C(O)SH, -S(O)OH, -S(O) 2 0H, -S(O)NHR 8 , -S(O) 2
NHR
8 ,
-OP(O)(OR)
2 , or -SP(O)(OR 7
)
2 . In another embodiment, -OR 2 6 and -SR 26 , are additional values for R 3 . Preferably, R 3 is -OH, -SH, -NHR 7 , -OC(O)NRIOR, 1 -SC(O)NRIOR 1 , -OC(O)R 7 , -SC(O)R 7 ,
-OC(O)OR
7 , -SC(O)OR 7 , -OS(O)pR 7 , -S(O),OR 7 , -SS(O)pR7, -OS(O)pOR 7 , -SS(O),OR 7 , -OC(S)R 7 ,
-SC(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -OC(S)NRioR 1 , -SC(S)N RioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 ,
-OC(NR
8
)OR
7 , -SC(NR 8
)OR
7 , -OP(O)(OR 7
)
2 or -SP(O)(OR 7
)
2 . More preferably, R 3 is -OH, -SH, or -NHR 7 . Even more preferably, R 3 is -SH or -OH.
R
5 is an optionally substituted heteroaryl; an optionally substituted 6 to 14-membered aryl.
R
70 , for each occurrenc, 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 heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, -NRIORII, -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)N R 1oR 1 , -C(N Rs)OR 7 , -C(N R 8
)R
7 , -C(N R 8 )NRoR 1 , -C(NRs)SR 7 , -OC(O)R 7 , -OC(O)OR 7
,
C:WRPorblIDCMRC41l7%I l I.DOC-1/lf/2012 - 155 -OC(S)OR 7 , -OC(NR 8
)OR
7 , -SC(O)R 7 , -SC(O)OR 7 , -SC(NR 8
)OR
7 , -OC(S)R 7 , -SC(S)R 7 ,
-SC(S)OR
7 , -OC(O)NRIoR I, -OC(S)NRIoR 1 , -OC(NR)NRioR I, -SC(O)NR 0 oR 1 , -SC(NR)NRioR 1 , -SC(S)N RioR 11 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -C(O)N R 1 oR 1 , -N R 8
C(O)R
7 ,
-NR
7
C(S)R
7 , -NR 7
C(S)OR
7 , -N R 7
C(NR
8
)R
7 , -NR 7
C(O)OR
7 , -NR 7 C(N R 8
)OR
7 , -N R 7 C(O)NRioR 1 ,
-NR
7 C(S)NRioR 1 , -NR 7
C(NR
8 )N R 1 oR, , -SR 7 , -S(O),R 7 , -OS(O),R 7 , -OS(O),OR 7 , -OS(O)pNRIoR 1 , -S(O),OR 7 , -NR 8
S(O),R
7 , -N R 7 S(O),N R 1 oR 1 , -N R 7 S(0),0R 7 , -S(O)pNRioR 1 ,
-SS(O),R
7 ,
-SS(O),OR
7 , -SS(O),NRIoR 1 , -OP(O)(OR 7
)
2 , or -SP(O)(OR 7
)
2 . Preferably, R 70 is selected from the group consisting of -H, Cl -C6 alkyl, CI -C6 alkoxy, C I-C6 cycloalkyl, and C l -C6 cycloalkoxy, more preferably from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
R
71 , 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 heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NRIoR 1 , -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)NRioRII,
-C(NR
8
)OR
7 , -C(NRs)R 7 , -C(NR)NRioR 1 , -C(NR 8
)SR
7 , -OC(O)R 7 , -OC(O)OR 7 , -OC(S)OR 7 ,
-OC(NR
8
)OR
7 , -SC(O)R 7 , -SC(O)OR 7 , -SC(NR 8
)OR
7 , -OC(S)R 7 , -SC(S)R 7 , -SC(S)OR 7 , -OC(O)NRIoR 1 , -OC(S)NRIoR 1 , -OC(NR 8
)NR
0 oR 1 , -SC(0)NRIoR, -SC(NR 8 )NRoR 1 , -SC(S)NRIoR I, -OC(N R 8
)R
7 , -SC(NR 8
)R
7 , -C(O)N R 1 oR 1 , -NR 8
C(O)R
7 , -N R 7
C(S)R
7 , -NR7C(S)OR 7 , -N R 7 C(N R 8
)R
7 , -NR 7
C(O)OR
7 , -NR 7
C(NR
8
)OR
7 , -NR 7 C(O)N RoR 11 , -N R 7 C(S)N RioR 11 , -N R 7 C(N R 8 )NRoR I, -SR 7 , -S(O),R 7 , -OS(O),R 7 , -OS(O)pOR 7 ,
-OS(O),NR
1 IoR 1 , -S(O),OR 7 , -N R 8
S(O),R
7 , -NR 7 S(O),N R 1 oR I, -NR 7
S(O),OR
7 , -S(O),N RoR 11 ,
-SS(O),R
7 ,
-SS(O),OR
7 , -SS(O)pNRioR I, -OP(O)(OR 7
)
2 , or -SP(O)(OR 7
)
2 .
R
7 and R 8 , 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 R, , 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 C WRPortbIlDCC\REC\4)75614_ .DOC-11111/2012 - 156 optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or Rio and R1, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R
18 is an optionally substituted cycloalkyl, and optionally substituted cycloalkenyl, or a substituted alkyl, wherein the alkyl group is substituted with one or more substituents independently selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, -NRIOR 1 , -OR 7 , -C(O)R7, -C(O)OR 7 , -OC(O)R 7 , -C(O)NRioR 1 ,
-NR
8
C(O)R
7 , -SR 7 , -S(O)pR 7 , -OS(O),R 7 , -S(O),OR7, -NRsS(O),R 7 , or -S(O),NRioRII;
R
2 6 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
R
5 in structural formula (IX) is preferably represented by the following structural formula: (R9)m wherein: C.\NRPortbl\DCC\REC\4075614_LDOC.I/10/2012 - 157
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, -NRioR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 ,
-OC(O)R
7 , -C(O)NRioR 1 , -NR 8
C(O)R
7 , -SR 7 , -S(O),R 7 , -OS(O),R 7 , -S(O),OR 7 , -NR 8
S(O),R
7 , or -S(O)pNRIOR 1 ; or two R 9 groups taken together with the carbon atoms to which they are attached form a fused ring, and m is zero or an integer from I to 7. More preferably, substituent R 5 is represented by one of the following structural formulas: (Rg)q (Rq). or wherein:
R
9 is as defined as above; q is zero or an integer from I to 7; and u is zero or an integer from I to 8. The remainder of the variables have values defined above with reference to structural formula (IX). In another alternative, R 5 in structural formula (IX) is represented by the following structural formula:
R
3 3 N B C wherein:
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 C:\NRPortb\DCC\REC\407%4_ IDOC.1/10/2012 - 158 optionally substituted with one or more substituents. The remainder of the variables have values defined above with reference to structural formula (IX). In another alternative, R 5 in structural formula (IX) is selected from a group listed in Table 3. Table 3 Number Substituent R 5 Number Substituent Rj XX IIX N Xe X -e ,X
/
)( --- X7 0
XX
7 10 X XX X 7 X7 X7 X7 N 32 -12 K
X
7 N X X7 X7 X1 X 7 N 'X X7 N ,/ 4 .13 - X7X 7 5 X7 14 C:NRPonbI\DCCREC\4075614_ DOC-1/10/2012 -159 X7 XX X7 X XX7 Xe X7 X7 X7 N X77
X
7 X6 6 X7 X101X X7 X 7 X1 X7 X 8 7 X7N7 X X 7 X 7 7 X716 XX10 X1 97 18 10 61 X1 X7 7 X1 X : X1 77 X6 x1o X7 X7 11 \ 10/ 8 170 180 x 10
X
10
-
X 19 In the structural formulas of Table 3:
X
6 , for each occurrence, is independently CH, CR 9 , N, N(O), N(RI 7 ), 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*(Ry), provided that at least three X, groups are independently selected from CH and CR 9 ;
X
8 , for each occurrence, is independently CH 2 , CHR 9 , CR 9
R
9 , 0, S, S(O)p, NR 7 , or NRj 7 ;
X
9 , for each occurrence, is independently N or CH;
X
1 0 , for each occurrence, is independently CH, CR 9 , N, N(O), N'(R, 7 ), provided that at least one X 10 is selected from CH and CR 9
;
C -NRPoblkDCCkRECN4I75614_I DOC-I/IO/20 12 - 160
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, -NRioR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 ,
-OC(O)R
7 , -C(O)NRioR 1 , -NR 8
C(O)R
7 , -SR 7 , -S(O),R 7 , -OS(O),R 7 , -S(O),OR 7 , -NR 8
S(O),R
7 , or -S(O),NRioR,1; or two R 9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
R
17 , for each occurrence, is independently -H, an alkyl, an aralkyl, -C(O)R 7 , -C(O)OR7, or -C(O)NRIORII. Preferred R 5 groups from Table 3 are selected from the group consisting of 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[l,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-clpyridinyl, 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 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 3H-imidazo[4,5-b]pyridinyl, an optionally substituted I H-imidazo[4,5 b]pyridinyl, an optionally substituted I 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 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.
C:WRPortbM)CCREC\4075614IDOC-1/1o/2012 - 161 In another alternative, R 5 in structural formula (IX) is selected from the group consisting of: X i X X 13 X, X12 X 12 X13 x 11 \ / x
X
1 2 and wherein:
X,
1 , for each occurrence, is independently CH, CR 9 , N, N(O), or N'(RA), provided that at least one X, 1 is N, N(O), or N+(R 17 ) and at least two X, groups are independently selected from CH and CR 9 ;
X
12 , for each occurrence, is independently CH, CR 9 , N, N(O), N'(R 7 ), provided that at least one X 12 group is independently selected from CH and CR 9 ;
X
13 , for each occurrence, is independently 0, 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, -NRIOR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 ,
-OC(O)R
7 , -C(O)NRIORII, -NR 8
C(O)R
7 , -SR 7 , -S(O),R 7 , -OS(O),R7, -S(O),OR 7 , -NR 8
S(O),R
7 , or -S(O),NRioR 1 ; or two R 9 groups taken together with the carbon atoms to which they are attached form a fused ring; and R 17 , for each occurrence, is independently an alkyl or an aralkyl. The remainder of the variables have values defined above with reference to structural formula (IX).
C:\NRorbl\DCC\REC%4075%614_1 DOC-1/10/20112 - 162 In a preferred embodiment, the compound of the invention is represented by structural formula (LX II): R70 1 -X101 Y02\ HO 12 0
X
10 2 N R1 OH N (LX II). In structural formula (LXII):
X
1 01 is 0, S, or NR 1 02 and X 1 02 is CR 1 04 or N. Preferably, X 101 is NRi 02 and X] 02 is CR 1 04 . Alternatively, X 1 01 is NR 102 and X 1 02 is N; Y, for each occurrence, is independently N or CR 103 ; Y jo, is Nor CRio 5 ;
Y
102 is N, C or CR 106 ; R, is OH, SH, or NHR 7 . Preferably, R, is -OH or -SH;
R
70 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, -NRoR,I, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -C(S)R 7 , -C(O)SR7, -C(S)SR 7 , -C(S)OR 7 , -C(S)N R 1 oR 11 ,
-C(NR
8
)OR
7 , -C(NR)R 7 , -C(NR 8 )NRioR I, -C(NR 8
)SR
7 , -OC(O)R 7 , -OC(O)OR 7 , -OC(S)OR 7 ,
-OC(NR
8
)OR
7 , -SC(O)R 7 , -SC(O)OR 7 , -SC(NRs)OR 7 , -OC(S)R 7 , -SC(S)R 7 , -SC(S)OR 7 , -OC(O)NRioR I, -OC(S)NR 0 oR, -OC(NR)NRioR I, -SC(O)NR 0 oR I, -SC(NR)NR 0 oR 1 ,
-SC(S)NR
0 oR I, -OC(N R 8
)R
7 , -SC(N R 8
)R
7 , -C(O)N R oR,, -N R 8
C(O)R
7 , -N R 7
C(S)R
7 ,
-NR
7
C(S)OR
7 , -N R 7 C(N R 8
)R
7 , -NR 7
C(O)OR
7 , -NR 7
C(NR
8
)OR
7 , -N R 7
C(O)NR
0 oR 1 , -N R 7 C(S)N R oR 11 , -NR 7
C(NR
8 )N R oR 1 , -SR 7 , -S(O)pR 7 , -OS(O),R 7 , -OS(O),OR 7 , -OS(O),N RIOR I, -S(O)pOR 7 , -N RsS(O)pR 7 , -N R 7 S(O)pNR oR I, -N R 7
S(O),OR
7 , -S(O)pNR oR 1 ,
-SS(O),R
7 , -SS(O),OR 7 , -SS(O),NRioR 1 , -OP(O)(OR) 2 , or -SP(O)(OR) 2 . Preferably, R7 0 is selected from the group consisting of -H, Cl -C6 alkyl, C I -C6 alkoxy, Cl -C6 cycloalkyl, and CI C6 cycloalkoxy, more preferably from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy; C NRPonbIMlCCREC4075614_1 DOC-1/10/O12 - 163 R 10 2 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, -(CH 2 )mC(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NRioR 1 , -S(O),R 7 , -S(O),OR 7 , or -S(O),NRIoRII; preferably, R 10 2 is selected from the group consisting of -H, a CI -C6 alkyl, a CI-C6 cycloalkyl, -C(O)N(R 27
)
2 , and -C(O)OH, wherein
R
27 , for each occurrence, is independently is -H or a lower alkyl;
R
1 03 and R 1 04 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)NRioR 1 , -NR 8
C(O)R
7 , -SR 7 , -S(O),R 7 , -OS(O),R 7 ,
-S(O),OR
7 , -NR 8
S(O),R
7 , -S(O),NRIoR 1 , or R 1 0 3 and R 1 0 4 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; preferably, R 1 03 and
R
104 are independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy;
R
105 is -H, -OH, -SH, -NR 7 H, -OR 26 , -SR 26 , -NHR 26 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -OC(O)NRIORII, -SC(O)NRioR,
-NR
7 C(O)NRioR 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
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR7CH 2
C(O)OR
7 , -OCH 2 C(O)NRioR 1 , -SCH 2 C(O)NRioR 11 ,
-NR
7
CH
2 C(O)NRioR 1 , -OS(O)pR 7 , -SS(O),R 7 , -NR 7
S(O),R
7 , -OS(O),NRioRa 1 , -SS(O)pNRioR 1 ,
-NR
7 S(O),NRioR 11 , -OS(O)pOR 7 , -SS(O),OR 7 , -NR 7
S(O),OR
7 , -OC(S)R 7 , -SC(S)R 7 ,
-NR
7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR 1 , -SC(S)NRioRII,
-NR
7 C(S)NRIORII, -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 , -SC(NR 8
)OR
7 , NR 7
C(NR
8
)OR
7 , -OC(NR)NRIORII, -SC(NR)NRIOR 1 , or -NR 7 C(NR)NRioR ; preferably, R 1 05 is selected from the group consisting of -H, -OH, -SH, -NH 2 , a CI-C6 alkoxy, a CI-C6 alkyl amino, and a CI-C6 dialkyl amino, more preferably from the group consisting of -H, -OH, methoxy and ethoxy; and
R
106 , for each occurrence, is independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted C:NRPortbDCCREC\4075614I .DOC-1/10/2012 - 164 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, -NRioR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NRioR 1 , -NR 8
C(O)R
7 , -SR 7 , -S(O),R 7 ,
-OS(O),R
7 , -S(O),OR 7 , -NR 8
S(O),R
7 , or -S(O),NRIoRII. The remainder of the variables of the compounds of structural formula (LXII) has values defined above with reference to structural formula (IX). In one preferred set of values for the variables of the Hsp90 inhibitor represented by formula (LXII), Xio, is NR 102 , R 10 2 is selected from the group consisting of -H, a CI-C6 alkyl, a C l -C6 cycloalkyl, -C(O)N(R 2 7
)
2 , and -C(O)OH, wherein R 27 , for each occurrence, is independently is -H or a lower alkyl and the values for the remainder of the variables are as described above for formula (LXII). In a second preferred set of values for the variables of the Hsp90 inhibitor represented by formula (LXII), X 1 0 1 is NR 1 02 , R 1 02 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 )mC(O)OH, -CH 2 0CH 3 , -CH 2
CH
2 0CH 3 , and -C(O)N(CH 3
)
2 and the values for the remainder of the variables are as described above for formula (LXII). In third preferred set of values for the variables of the Hsp90 inhibitor represented by formula (LXII), Xi 02 is CRio 4 ; Y is CR 10 3 ; and R 1 03 and R 104 together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring. Preferably,
R
103 and R 10 4 together with the carbon atoms to which they are attached form a CS-C 8 cycloalkenyl or a C 5
-C
8 aryl and the values for the remainder of the variables are as described above for formula (LXII). In fourth preferred set of values for the variables of the Hsp90 inhibitor represented by formula (LXII), R, is -OH or -SH and the values for the remainder of the variables are as described above for formula (LXII).
C:\NRPonb]\DCC\REC\4075614_ DOC-1/10/2012 - 165 In another preferred embodiment, the Hsp90 inhibitor of the invention is represented by structural formula (LXIll): R70 R1 05 HO /Ro 2 / /R,0 N / -R103
X
103 N HO N (LXIII), where X 103 is CRI 04 or N and the remainder of the variables is defined above with reference with structural formulas (LX II). In another preferred embodiment, the Hsp90 inhibitor of the invention is represented by structural formula selected from (LXIVa)-(LXIVi): (R71)x 7R
(R
7 1) R N (Ryo)z N" R1 (Ryo)z N R1 N N
R
3 (LXIVa) R 3 (LXIVb)
(R
7 o)z (R71)x R1 RS (R70)z R1 R1 N N R3 (LXIVc) R3 (LXIlVd) (7olz (R70 z R71 R71 R1 R (Rio)i R N N R3 (LXIVe) R3 (LXIVf) C NRPortblDCC\REC\4075614_ DOC./10/2,112 - 166 R70 R 70 R1 RR 7 1 12 N N R1 R1 N N
R
3 (LXIVg) R 3 (LXIVh) Ry0
R
18 R71 N N R3 (LXIVi) The values for the variables in structural formulas (LXIVa)-(LXIVi) are as described in structural formula (IX), (X), and (XI). In one preferred set of values for the variables of the Hsp90 inhibitor represented by structural formulas (Vla-c)-(Vllla-c): Rs is as described for structural formula (IX), (LXII), (LXIII) or a structural formula from Table 1; Ryo and R 71 , for each occurrence, are 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 heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NRoR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -C(S)R 7 , -C(O)SR7, -C(S)SR 7 , -C(S)OR 7 , -C(S)NR IOR I, -C(N R 8
)OR
7 , -C(N R 8
)R
7 , -C(NR 8 )N RIORI, -C(N R 8
)SR
7 , -OC(O)R 7 , -OC(O)OR 7 ,
-OC(S)OR
7 , -OC(NR 8
)OR
7 , -SC(O)R 7 , -SC(O)OR 7 , -SC(NR 8
)OR
7 , -OC(S)R 7 , -SC(S)R 7 ,
-SC(S)OR
7 , -OC(O)NR 0 oR 1 , -OC(S)NR 0 oR 1 , -OC(NR 8
)NR
0 oR 1 , -SC(O)NRioR 1 ,
-SC(NR
8
)NRIOR
1 , -SC(S)NR 0 oR, -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -C(O)NR 0 oR, -NR 8
C(O)R
7 ,
-NR
7 C(S)R,, -NR 7 C(S)OR7, -NR 7
C(NR
8
)R
7 , -NR 7
C(O)OR
7 , -NR 7
C(NR
8
)OR
7 , -NR 7 C(O)NRIOR, 1 , -N R 7 C(S)N R IOR 1 , -N R 7
C(NR
8 )N RIORn, -SR 7 , -S(O),R 7 , -OS(O),R 7 , -OS(O),OR 7 , -OS(O),N R 10 R , -S(O),OR 7 , -N R 8
S(O),R
7 , -N R 7 S(O),NR oR 1 , -NR 7
S(O),OR
7 , -S(O),N RoR 11 ,
-SS(O),R
7 , -SS(O)pOR 7 , -SS(O)pNR 0 oR 1 , -OP(O)(OR) 2 , or -SP(O)(OR 7
)
2
;
C.\NRPortblDCC\REC\4075614 IDOC-1/10l2012 - 167 z in structural formula (Vla-c) is zero or an integer from I to 4; z in structural formula (Vlla-c) is zero or an integer from I to 3; x is 0 or 1; z + x in structural formula (LXIVa)-(LXIVc) is less than or equal to 4; and the remainder of the variables in formulas (LXIVa)-(LXIVi) have values defined above with reference to structural formula (IX), (X), and (XI). A second preferred set of values for the variables of the Hsp90 inhibitor represented by structural formula (LXIVa)-(LXIVi) is provided in the following paragraphs:
R
7 1 is a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, -OH, -SH, -NHR 7 , -(CH 2 )kOH, (CH 2 )kSH, -(CH 2 )kNR 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)NRIORII, -SC(O)NRioR 1 , -NR 7 C(O)NRioR 1 , -OC(O)R 7 , -SC(O)R 7 , -NR 7
C(O)R
7 , -OC(O)OR7,
-SC(O)OR
7 , -NR 7
C(O)OR
7 , -OCH2C(O)R 7 , -SCH 2
C(O)R
7 , -NR 7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRioR 1 , -SCH 2 C(O)NRioR 1 ,
-NR
7
CH
2 C(O)NRioR 1 , -OS(O),R 7 , -SS(O),R 7 , -NR 7
S(O),R
7 , -OS(O),NRoR 1 , -SS(O),NRioR,
-NR
7 S(O)pNRioR 1 , -OS(O),OR 7 , -SS(O),OR 7 , -NR 7
S(O),OR
7 , -OC(S)R 7 , -SC(S)R 7 ,
-NR
7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR 11 , -SC(S)NRioR,
-NR
7 C(S)NRioR, 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 , -SC(NR 8
)OR
7 , NR 7
C(NR
8
)OR
7 , -OC(NR)NRioR 1 , -SC(NR 8 )NRioR 11 , -NR 7
C(NR
8 )NRioR 11 , -C(O)R 7 ,
-C(O)OR
7 , -C(O)NRioR 11 , -C(O)SR 7 , -C(S)R 7 , -C(S)OR 7 , -C(S)NRoR 1 , -C(S)SR 7 ,
-C(NR
8
)OR
7 , -C(NR 8
)R
7 , -C(NR)NRioR 1 , -C(NRg)SR 7 , -S(O),OR 7 , -S(O),NRIoR 11 , or
-S(O),R
7 ; and k is 1, 2, 3, or 4; and RI, R 3 , R7 0 and the remainder of the variables are as described in the first preferred set of values for the variables in structural formulas (LXIVa)-(LXIVi). Preferably, R, and R 3 are each, independently, -OH, -SH, or -NHR 7 . A third preferred set of values for the variables of the Hsp90 inhibitor represented by formula (LXIVa)-(LXIVi) is provided in the following paragraphs: R, and R 3 are each, independently, -OH, -SH, or -NHR 7 ;
R
70 is an optionally substituted alkyl or cycloalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, alkoxy, haloalkoxy, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR 7 , -SR 7 , -NRoR , -OC(O)NRjoR 1 , -SC(O)NRIORII, -NR 7
C(O)NRIOR
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 ,
-SCH
2
C(O)R
7 , -NR7CH 2
C(O)R
7 , -OCH 2
C(O)OR
7 , -SCH 2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7
,
C\NRPotbl\DCC\EC\0756 14_1 DOC-/10112012 - 168 -OCH 2 C(O)NRioR 11 , -SCH 2 C(O)NRioR 1 , -NR 7
CH
2 C(O)NRioR, 1 1
-OS(O),R
7 , -SS(O),R 7 ,
-NR
7
S(O),R
7 , -OS(O),NRioR 1 , -SS(O),NRioR 1 , -NR 7 S(O),NRioR 1 , -OS(O),OR 7 , -SS(O),OR 7 , -NR7S(O),OR 7 , -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR , -SC(S)NRioR 1 , -NR 7 C(S)NRioR 11 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 ,
-OC(NR
8
)OR
7 , -SC(NR 8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR)NRioR 1 , -SC(NR)NRioR,
-NR
7
C(NR
8 )NRioR 1 , -C(O)R 7 , -C(O)OR 7 , -C(O)NRioR 1 1 , -C(O)SR 7 , -C(S)R 7 , -C(S)OR 7 , -C(S)NRioR 1 , -C(S)SR 7 , -C(NR 8
)OR
7 , -C(NR 8 )R7, -C(NR 8 )NRioR 1 , -C(NR 8
)SR
7 , -S(O),OR 7 , -S(O),NRIOR, or -S(O),R 7 and Ri and R3 and the remainder of the variables are as described in the second preferred set of values for the variables in structural formulas (LXIVa)-(LXIVi). In a fourth preferred set of values for the variables of Structural Formulas (LXIVa) (LXIVi): R, is -SH or -OH;
R
3 and R 2 5 are -OH;
R
70 is a CI-C6 alkyl, a C3-C6 cycloalkyl, a CI-C6 alkoxy, a CI-C6 haloalkoxy, a CI-C6 alkyl sulfanyl, or -NRIORI; and The remainder of the variables are as defined in Structural Formula (IX), (X), and (XI). In another preferred embodiment, the Hsp90 inhibitor is represented by a structural formula selected from (LXVa)-LXVf): R5__R5 X'- X5' R5X5'-'.R
X
3 LR1 X3 R1 N N 3 (LXVa) R 3 (LXVb) R2' R )'- X5' X5' X 1 X3R1 X3' R1 /r> N N R3 (LXVc) R3 (LXVd) C:\NRPorb1l\OCC\REC\4075614_ DOC-1/10l2012 - 169
R
18 R 18
X
4 '- X5' X5'- X 4 ' X3' ' R1 X3' R1 N N
R
3 (LXVe) R 3 (LXVf) In formulas (LXVa) and (LXVb):
R
5 is as described for structural formula (IX), (LXII), or (LXIII), or a structural formula from Table 1;
X
3 ' and X 4 ' are each, independently, N, N(O), N'(Riy), CH or CR 7 o;
X
5 ' is 0, S, NR 17 , CH 2 , CH(R 7 0 ), C(R 70
)
2 , CH=CH, CH=CR 7 0 , CR 7 0 =CH, CR 70
=CR
70 , CH=N, CR 70 =N, CH=N(O), CR 70 =N(O), N=CH, N=CR 70 , N(O)=CH, N(O)=CR 7 0 , N*(R] 7 )=CH,
N*(R
17
)=CR
7 0 , CH=N'(R] 7 ), CR 60
=N'(R
17 ), or N=N, provided that at least one X 3 ', X 4 ' or X 5 ' is a heteroatom;
R
70 , 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 heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NRioR 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 0 oR 1 ,
-C(NR
8
)OR
7 , -C(NR 8
)R
7 , -C(NR 8 )NRioR 1 , -C(NR8)SR7, -OC(O)R 7 , -OC(O)OR, -OC(S)OR 7 ,
-OC(NR
8
)OR
7 , -SC(O)R 7 , -SC(O)OR 7 , -SC(NR 8
)OR
7 , -OC(S)R 7 , -SC(S)R 7 , -SC(S)OR 7 ,
-OC(O)NR
0 oR 1 , -OC(S)NRoR 1 , -OC(NR 8
)NR
0 oR 1 , -SC(O)NR oR 1 , -SC(NR)NRioR 1 , -SC(S)N RIOR I, -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -C(O)NR 0 oR, -NR 8
C(O)R
7 , -NR 7
C(S)R
7 , -N R 7
C(S)OR
7 , -N R 7
C(NR
8
)R
7 , -N R 7
C(O)OR
7 , -N R 7
C(NR
8
)OR
7 , -NR 7 C(O)N RIORII,
-NR
7 C(S)NRIORII, -N R 7 C(N R 8 )NR oR 1 , -SR 7 , -S(O),R 7 , -OS(O),R 7 , -OS(O),OR 7 ,
-OS(O),NR
0 oR, -S(O)pOR 7 , -NR 8
S(O),R
7 , -NR 7 S(O),NRIOR I, -NR 7 S(O)pOR 7 , -S(O)pNR oR 1 , -SS(O)pR 7 ,
-SS(O),OR
7 , -SS(O),NR oR 1 , -OP(O)(OR 7
)
2 , or -SP(O)(OR 7
)
2 ;
R
17 , for each occurrence, is independently an alkyl or an aralkyl; and n is zero or an integer from I to 4; and the remainder of the variables has values defined above with reference to structural formulas (IX), (X), and (XI). Preferably, Hsp90 inhibitor of structural formulas (LXVa)-LXVf) are selected from Table C.U4RPa.bIlDCMC'"OJ756IJ I DOC-1/10/20I12 - 170 4a-c. Table 4a Number Compound Number Compound N NR I 36.
R
3 /Rs
R
5 /r // 2. R 3 7.R
R
70 0s 0 0 5 N R 3. R 3 8. R
R
70
R
7 0 s NN 4. R,9. R R5 R5 R 3
.I
CA PNPo, blCC\REC\407 564_I1DOC-/ 102012 -171 Table 4b Number Compound Number Compound
R
2 R 2 ' 0 1. R. R,
NR
70 N RN6.R N RR2' R2' N N NJ N N 4. 9, .R R2'
R
2 . 0 0 5. R, 1. R 3 C:\RPonbI\DCC\REC%4075614_1 DOC-1/10/2012 - 172 Table 4c Number Compound Number Compound
R
1 8 R18 N R1 R1 N N R 6. R3 R18 O NR18 R70 N R/
R
1 N N 2. R3 7. R3
R
18
R
1 8 Ri R N N 3. R3 . R 3 Ryo Ryo O Rje R18 N R1 R, N N 4. R3 9. R3 OR18 R18 R1 R1 N N 5. R3 ;10. R3 The values for the variables for the formulas in Tables 4a-c are as defined for structural formulas (LXVa)-(LXVf). Preferably, R 7 0 is a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, -OH, -SH,
-NHR
7 , -(CH 2 )kOH, -(CH 2 )kSH, -(CH 2 )kNR7H, -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)NRioR 1 , -SC(O)NRioR 11 , -NR 7 C(O)NRIORII, -OC(O)R,, -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)R7, -NR 7
CH
2
C(O)R
7 ,
-OCH
2
C(O)OR
7 , -SCH 2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7
,
C:\NRPobqDCC\REC\4075614_ .DOC-1/10/2012 - 173 -OCH 2 C(0)NRjoR 11 , -SCH 2 C(O)NRioR 11 , -NR 7
CH
2 C(O)NRioR 1 , -OS(O),R 7 , -SS(O),R 7 ,
-NR
7
S(O),R
7 , -OS(O),NRioR 1 , -SS(O)pNRioR 1 , -NR 7 S(O),NRjoR 1 , -OS(O),OR 7 , -SS(O),OR 7 ,
-NR
7 S(O)pOR 7 , -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRjoR 1 , -SC(S)NRioR 1 , -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 ,
-OC(NR
8
)OR
7 , -SC(NR 8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR 8 )NRioR 11 , -SC(NRs)NRioR 1 ,
-NR
7 C(NR)NRioR 1 , -C(O)R 7 , -C(O)OR 7 , -C(O)NRioR 1 , -C(O)SR 7 , -C(S)R 7 , -C(S)OR 7 , -C(S)NRioR 11 , -C(S)SR 7 , -C(NRs)OR 7 , -C(NR 8
)R
7 , -C(NR 8 )NRioR 1 , -C(NR 8
)SR
7 , -S(O),OR 7 , -S(O),NRIOR, or -S(O),R 7 ; and k is 1, 2, 3, or 4. In another preferred embodiment, the Hsp90 inhibitor of the present invention is represented by structural formula (LXVI):
NR
1 0
R
11 R70 -(R3o) 0 or 1
R
7 1 \ N , N R3 (LXVI)
R
7 0 and R 7 1, for each occurrence, are 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 heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NRIORII, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -C(S)R 7 , -C(O)SR7, -C(S)SR 7 , -C(S)OR 7 , -C(S)NR oR 1 1 , -C(N Rs)OR 7 , -C(N R 8
)R
7 , -C(NR 8 )NRoR I, -C(NR 8
)SR
7 , -OC(O)R 7 , -OC(O)OR 7 ,
-OC(S)OR
7 , -OC(NR 8
)OR
7 , -SC(O)R 7 , -SC(O)OR 7 , -SC(N R)OR 7 , -OC(S)R 7 , -SC(S)R,
-SC(S)OR
7 , -OC(O)NRIOR 1 , -OC(S)NR 0 oR 1 , -OC(NR)NRIORII, -SC(O)NR 0
R
1 ,
-SC(NR
8
)NR
0 oR I, -SC(S)NRIOR I, -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -C(O)NRIOR 1 , -NR 8 C(O)R7,
-NR
7
C(S)R
7 , -NR 7
C(S)OR
7 , -NR 7
C(NR
8
)R
7 , -N R 7
C(O)OR
7 , -NR 7 C(N R 8
)OR
7 , -N R 7 C(0)NRi 0 Rjj,
-NR
7 C(S)NRIOR I, -N R 7 C(N R 8 )N RIOR 1 1 , -SR 7 , -S(O),R 7 , -OS(O),R7, -OS(O),OR 7 , -OS(O),NRjoR I, -S(O),OR 7 , -N R 8
S(O),R
7 , -NR 7 S(O),N R IoR 1 1 , -N R 7
S(O),OR
7 , -S(O),N RjoR ,
-SS(O),R
7 ,
-SS(O),OR
7 , -SS(O),NRioR 1 , -OP(O)(OR) 2 , or -SP(O)(OR 7
)
2 . Preferably, R 70 is selected from an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted C:\NRPortbl\DCORE04075614_. IDOC-1/10/2012 -174 heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR 7 , -SR 7 , -NRIORI 1 , -OC(O)NRIoR 1 , -SC(O)NRIORII, -NR 7 C(O)NRioR 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 , -SCH 2
C(O)R
7 , -NR 7
CH
2
C(O)R
7 ,
-OCH
2
C(O)OR
7 , -SCH 2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 ,
-OCH
2 C(O)NRioRI, -SCH 2 C(O)NRioR 1 , -NR 7
CH
2 C(O)NRioR 1 , -OS(O),R 7 ,
-SS(O),R
7
,-NR
7
S(O),R
7 , -OS(O),NRioR 1 , -SS(0),NRioR 11 , -NR 7 S(O),NRoR 1 , -OS(O),OR 7 , SS(O),OR 7 , -NR 7
S(O),OR
7 , -OC(S)R 7 , -SC(S)R 7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 ,
-NR
7
C(S)OR
7 , -OC(S)NRIoR 1 , -SC(S)NRioR 1 , -NR 7 C(S)NRioR 11 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 ,
-NR
7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 , -SC(NR 8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR 8 )NRioR,
-SC(NR
8 )NRioR 11 , -NR 7 C(NR)NRioR 1 , -C(O)R 7 , -C(O)OR 7 , -C(O)NRioR 1 , -C(O)SR 7 , -C(S)R7, -C(S)OR 7 , -C(S)NRIORII, -C(S)SR 7 , -C(NR 8
)OR
7 , -C(NR 8
)R
7 , -C(NR 8 )NRioR,
-C(NR
8
)SR
7 , -S(O),OR 7 , -S(O),NRioRa, or -S(O),R 7 and R 71 is as just described. The values for the remainder of the variables are as described for structural formulas (IX), (X), and (XI). In another preferred embodiment, the Hsp90 inhibitors are represented by structural formula (LXVIla) or (LXVIIb): (R30)O or 1 NR 10
R
11 NR10R11 (R3o)o or 1
R
70 R70
R
7 1 N
R
7 1 /
R
3 (LXVIIa); R3 (LXVIIb). The variables in formulas (LXVIIa) and (LXVIlb) are defined above with reference to formula (LXVI). A first preferred set of values for the variables of structural formula (LXVIIa) and (LXVIb) is provided in the following paragraph: RI, R 3 or R 7 1 are each independently selected from -OH, -SH, -NHR 7 , -OC(O)NRIOR, SC(O)NRIoR I, -OC(O)R 7 , -SC(O)R,, -OC(O)OR 7 , -SC(O)OR 7 , -OS(O),R 7 , -S(O),OR 7 , -SS(O),R 7 ,
-OS(O),OR
7 , -SS(O),OR -OC(S)R 7 , -SC(S)R 7 , -OC(S)OR, -SC(S)OR, -OC(S)NRIoR 1 , -SC(S)N R IoR 1 , -OC(N R 8 )R, -SC(NR 8
)R
7 , -OC(NR 8
)OR
7 , -SC(N R 8
)OR
7 , -OP(O)(OR 7
)
2 or
-SP(O)(OR)
2 , and p, R7o, R 7 , R 8 , Rio, R 1 and R 30 are as described for structural formula (LXVI). Preferably, when RI, R 3 and R 7 1 have these values, RIO and R, are preferably each independently a hydrogen, a C I -C6 straight or branched alkyl, optionally substituted by -OH, -CN, -SH, amino, a CI-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or Rioand R, taken C:\NRPorblOCC\REC\407564_1 DOC-1/10/2012 - 175 together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl; and p, Ry0, R 7 , and R 30 are as described for structural formula (LXVI). More preferably, when RI, R 3 , Rio, R 1 , and R7 1 have these values, R 70 is preferably a Cl -C6 alkyl, a C l -C6 haloalkyl, a Cl -C6 alkoxy, a Cl -C6 haloalkoxy, a Cl -C6 alkyl sulfanyl or a C3-C6 cycloalkyl; and p, R 7 , R 8 and R 3 0 are as described for structural formula (LXVI). A second preferred set of values for the variables of structural formula (LXVIla) and (LXVIIb) is provided in the following paragraph: R, and R 3 are each independently -OH, -SH; R 70 is preferably a Cl-C6 alkyl, a C1-C6 haloalkyl, a Cl -C6 alkoxy, a Cl -C6 haloalkoxy, a C l -C6 alkyl sulfanyl or a C3-C6 cycloalkyl; Rio and R, 1 are preferably each independently a hydrogen, a Cl -C6 straight or branched alkyl, optionally substituted by -OH, -CN, -SH, amino, a Cl -C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or RIO and R, 1 taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl; R 71 is -OH, -SH, -NHR 7 , -OC(0)NRIoR 1 , -SC(O)NRIoR I, -OC(O)R 7 , -SC(O)R 7 , -OC(O)OR 7 ,
-SC(O)OR
7 , -OS(O),R7, -S(O),OR 7 , -SS(O)pR 7 , -OS(O),OR 7 , -SS(O),OR 7 , -OC(S)R 7 , -SC(S)R 7 ,
-OC(S)OR
7 , -SC(S)OR 7 , -OC(S)NRIoR 1 , -SC(S)NRoR 1 , -OC(N R 8 )R,, -SC(N R 8
)R
7 ,
-OC(NR
8
)OR
7 , -SC(NR 8
)OR
7 , -OP(O)(OR 7
)
2 or -SP(O)(OR 7
)
2 ; and p, R 7
R
8 and R 30 are as described for structural formula (LXVI). Preferably, R 30 is -OH, -SH, halogen, cyano, a CI -C6 alkyl, CI -C6 haloalkyl, CI-C6 alkoxy, Cl -C6 haloalkoxy or CI -C6 alkyl sulfanyl and the remainder of the variables are as just described. A third preferred set of values for the variables of structural formula (LXVIIa) and (LXVIlb) is provided in the following paragraph: C:\NRPorb0lCC\REC40756I4 1DOC-111012012 - 176 R 1 , R 3 and R7 1 are independently -SH or -OH; R 70 is cyclopropyl or isopropyl; Rio and R 1 are each independently a hydrogen, a Cl -C6 straight or branched alkyl, optionally substituted by -OH, -CN, -SH, amino, a Ci -C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or RIO and R, 1 taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl; and R 30 is -OH, -SH, halogen, cyano, a Cl -C6 alkyl, CI -C6 haloalkyl, Cl -C6 alkoxy, Cl -C6 haloalkoxy or Cl -C6 alkyl sulfanyl. Preferably, R 30 is a methyl, ethyl, propyl, isopropyl, methoxy or ethoxy. More preferably, R 1 , R 3 ,
R
7 0 , R 71 and R 3 0 are as just described and and RIO and RI are each independently a hydrogen, methyl, ethyl, propyl, isopropyl, or taken together with the nitrogen to which they are attached, are: -N N -N N-R 3 5 -N 0 -N S wherein R 35 is -H, a C I -C4 alkyl or a C I-C4 acyl. In another preferred embodiment, the Hsp90 inhibitor is represented by structural formulas (LXVIIIa) or (LXVIIIb): NRIoR, NR,oRl /1/ N RN X R X3 R, N N
R
3 (LXVilla); R3 (LXVIIIb); The values for the variables in structural formulas (LXVlla) and (LXVIIIb) are as described for structural formulas (LXVc) and (LXVd). Preferably, R 30 is 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, alkoxy, haloalkoxy, -NRoR I, -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 1 oR 11 , -C(N Rs)OR 7 , -C(N R 8
)R
7 , -C(N R 8 )N RioR I, -C(N R 8
)SR
7 , -OC(O)R 7 , -OC(O)OR 7 ,
-OC(S)OR
7 , -OC(NR 8
)OR
7 , -SC(O)R 7 , -SC(O)OR 7 , -SC(NR 8
)OR
7 , -OC(S)R 7 , -SC(S)R 7
,
C:\NRPonb1\DCC\REC\4075614 _L DOC-I/1If2012 -177 -SC(S)OR 7 , -OC(O)NRioR 1 , -OC(S)NR 0 oR, -OC(NR)NRioR I, -SC(O)NRioR 1 , -SC(N R 8
)NR
0 oR I, -SC(S)NR 0 oR, -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -C(O)N R 1 oR 1 , -NR 8
C(O)R
7 , -N R 7
C(S)R
7 , -N R 7
C(S)OR
7 , -N R7C(NRs)R 7 , -N R 7
C(O)OR
7 , -NR 7
C(NR
8
)OR
7 , -N R 7 C(O)N R 1 oR 1 , -N R 7 C(S)NRioR, -NR 7 C(N R 8 )N R 1 oR I, -SR 7 , -S(O),R 7 , -OS(O),R 7 , -OS(O),OR 7 , OS(O),NR oR 1 , -S(O),OR 7 , -N R 8
S(O),R
7 , -NR 7 S(O),NRioR 1 , -N R 7
S(O),OR
7 , -S(O),N RioR 11 , -SS(O)pR 7 , -SS(O),OR 7 , -SS(O),NRioR 1 , -OP(O)(OR 7
)
2 , or -SP(O)(OR 7
)
2 . More preferably, R 30 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 , -NRIOR 1 , OC(O)NRioR 1 , -SC(O)NRioR 11 , -NR 7 C(O)NRioR, 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 , -SCH 2
C(O)R
7 , -NR 7
CH
2
C(O)R
7 ,
-OCH
2 C(O)OR7, -SCH 2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2
C(O)NRIORI
1 , -SCH 2
C(O)NRIOR
1 , -NR7CH2C(O)NRioRI, -OS(O),R7, -SS(O),R7, -NR7S(O)pR7, -OS(O),NRIORIJ, -SS(O),NRioR,
-NR
7 S(O),NRjoRjj, -OS(O),OR 7 , -SS(O)pOR 7 , -NR 7
S(O),OR
7 , -OC(S)R 7 , -SC(S)R7,
-NR
7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR 1 , -SC(S)NRioRII,
-NR
7 C(S)NRIORII, -OC(NRs)R 7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 , -SC(NR 8
)OR
7 , NR 7
C(NR
8 )OR7, -OC(NR)NRioR 1 , -SC(NR)NRIORII, -NR 7 C(NR)NRioR 1 , -C(O)R 7 ,
-C(O)OR
7 , -C(O)NRioR 1 , -C(O)SR 7 , -C(S)R 7 , -C(S)OR 7 , -C(S)NRoR 1 , -C(S)SR 7 , C(NR 8
)OR
7 , -C(NR 8
)R
7 , -C(NR 8 )NRioR 1 , -C(NR 8
)SR
7 , -S(O)pOR 7 , -S(O)pNRioR 1 , or
-S(O),R
7 . In another preferred embodiment, the Hsp90 inhibitor is represented by a structural formula selected from formulas (LXIXa)-(LXIXd):
NR
10
R
11
NR
1 0
R
11 (R30)o or 1 (R30)o or 1 4-X5 x5-X4 N N X3 R1 X3 R1 N N
R
3 (LXIXa) R 3 (LXIXb) C:WRPonb\DCCREC\40756 I .DOC.1/10/2012 - 178 (R30)o or 1 (R30)o or 1
NR
1 0 Rj 1 NR 1 oR 1 i N N
X
3 R1 X3 R1 N N
R
3 (LXIXc) R 3 (LXIXd) The values of the variables in structural formulas (LXIXa)-(LXIXd) are defined above with reference to structural formulas (LXVIIIa) and (LXVIIIb). A first preferred set of values for the variables in structural formulas (LXIXa)-(LXIXd) are as described in the following paragraphs: R, and R 3 are each independently -OH, -SH, -HNR 7 , -OC(O)NRioR, 1 -SC(O)NRioR, OC(O)R 7 , -SC(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -OS(O),R 7 , -S(O),OR 7 , -SS(O),R 7 , -OS(O),OR 7 , -SS(O)pOR 7 , -OC(S)R 7 , -SC(S)R 7 , -OC(S)OR 7 , -SC(S)OR 7 , -OC(S)NRioR 1 , -SC(S)NRIOR 1 ,
-OC(NR
8
)R
7 , -SC(N R 8
)R
7 , -OC(NR8)OR, -SC(N R 8
)OR
7 , -OP(O)(OR) 2 or -SP(O)(OR 7
)
2 ;
R
70 , 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)NRoR 1 , -SC(O)NRIOR 1 , -OC(O)R 7 , -SC(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -OS(O),R 7 ,
-S(O),OR
7 , -SS(O),R 7 , -OS(O),OR 7 , -SS(O),OR 7 , -OC(S)R 7 , -SC(S)R 7 , -OC(S)OR 7 , -SC(S)OR 7 ,
-OC(S)NR
0 oR 1 , -SC(S)NR oR 1 , -OC(NR 8
)R
7 -SC(N R 8
)R
7 , -OC(N R 8
)OR
7 , -SC(N R 8
)OR
7 ,
-OP(O)(OR
7
)
2 or -SP(O)(OR 7
)
2 . Preferably, R 70 is a C I-C6 alkyl, a CI -C6 haloalkyl, a CI-C6 alkoxy, a Cl -C6 haloalkoxy, a CI -C6 alkyl sulfanyl or a C3-C6 cycloalkyl; and Rio and R, and the remainder of the variables in structural formulas (LXIXa)-(LXIXd) are as described for structural formulas (LXVIlla) and (LXVIllb). Preferably, Rio and R 1 1 are each independently a hydrogen, a C I -C6 straight or branched alkyl, optionally substituted by -OH, -CN, -SH, amino, a Cl -C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or Rio and R, taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl.
C:\NRPorblDCC\REC\4075614_ .DOC./1/2012 - 179 In another preferred embodiment, the Hsp90 inhibitor is represented by a structural formula selected form formulas (LXXa)-(LXXp):
NR
1 0
R
11
NR
10
R
11 (R30)oor 1 (R 30
)
0 0r1 R1 N R1 N q' N R3 R3 (LXXa) (LXXb)
NR
1 0
R
11
NR
1 0
R
11 (R30)0 or 1
(R
3 0
)
0 or 1 0 ,R 70 / N N NN R3
R
3 (LXXc) (LXXd)
NR
10
R
1
NR
10
R
11 (R30)0 or 1 (R30)0 or 1
R
70 R70 0 S N R N R, R3N R3 N (LXXe) (LXXf) C NPPonbI\CCMEC4(J756I4-IDOC-I/I1l0121 - 180 NR 10
R
11
NR
10
R
11 0 s N RN R /K N N
R
3 R (LXXg) (LXXh)
(R
30
)
0 or 1 (R 30
)
0 or I
NR
10 Ri 1
NR
1 0 Rj, NN~ N Nq
R
3 R 3 (LXXi) (LXXj)
(R
30
)
0 or 1 (R 30
)
0 or 1
NR
10
R
11
NR
10
R
11 NR 70 / N N
R
3 R 3 (LXXk) (LXXI) C WRPonbl\DCC\REC\4075614_I.DOC.10/(12012 - 181 (R 30
)
0 or 1 (R 30
)
0 or 1 NRjc)R11
NR
1 0
R
11 R7o R70 0 S N N N N
R
3 R 3 (LXXm) (LXXn)
(R
30
)
0 or 1
(R
30
)
0 or 1 NRlR 11
NR
10
R
11 0 S N N \/r N N
R
3
R
3 (LXXo) (LXXp) The values of the variables in structural formulas (LXXa)-(LXXp) are defined above with reference to structural formulas (LXIXa)-(LXIXd). A first preferred set of values for the variables in structural formulas (XIVa-p) are as described in the following paragraphs: R, and R 3 are each independently -OH, -SH, -HNR 7 ; R7 0 , is a Cl -C6 alkyl, a Cl -C6 haloalkyl, a Cl -C6 alkoxy, a C I-C6 haloalkoxy, a C I-C6 alkyl sulfanyl or a C3-C6 cycloalkyl; Rio and R, 1 and the remainder of the variables in structural formulas (LXXa)-(LXXp) are as described for structural formulas (LXVIlla) and (LXVIllb). Preferably, Rio and R I are each independently a hydrogen, a CI-C6 straight or branched alkyl, optionally substituted by -OH, -CN, -SH, amino, a CI-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or Rio and R, taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl; and C:\NRPonbiDCC\REC\4075,14_ DOC-1/10/2012 - 182 R 30 and the remainder of the variables in structural formulas (LXXa)-(LXXp) are as described for structural formulas (LXIXa)-(LXIXd). Preferably, R 3 0 is -OH, -SH, halogen, cyano, a C I -C6 alkyl, CI -C6 haloalkyl, CI-C6 alkoxy, C I -C6 haloalkoxy or Cl-C6 alkyl sulfanyl. A second preferred set of values for the variables in structural formulas (LXXa)-(LXXp) are as described in the following paragraphs: R, and R 3 are independently -SH or -OH;
R
70 is cyclopropyl or isopropyl; Rio and R, are each independently a hydrogen, a CI-C6 straight or branched alkyl, optionally substituted by -OH, -CN, -SH, amino, a Cl-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or RIO and R 1 taken together with the nitrogen to which they are attached form a substituted or unsubstituted nonaromatic, nitrogen-containing heterocyclyl;
R
30 is -OH, -SH, halogen, cyano, a CI-C6 alkyl, Cl-C6 haloalkyl, C1-C6 alkoxy, CI-C6 haloalkoxy or Cl -C6 alkyl sulfanyl. Preferably, R 30 is a methyl, ethyl, propyl, isopropyl, methoxy or ethoxy; and the remainder of the variables are as described for formulas (LXVIIla) and (LXVIllb). More preferably, Rio and R 11 are each independently a hydrogen, methyl, ethyl, propyl, isopropyl, or taken together with the nitrogen to which they are attached, are: N-N - N N-R35 -N S -N O wherein R 35 is -H, a C I -C4 alkyl or a CI-C4 acyl. In another embodiment, the Hsp90 inhibitor of the present invention is represented by structural formulas (LXXI) and (LXX II): R22
R
23 R24 R24 R2 N R21 N NN
R
23 R R2 N R3 (LXXI);
R
3 (LXXII). In formulas (LXXI) and (LXXII):
X
14 is 0, S, or NR7. Preferably, X 14 is 0; C:NtRPornb1\DCCREC\4075614_ .DOC-1/10/12012 - 183 RI is -OH, -SH, -NR 7 H, -OR26, -SR 26 , -NHR 2 6 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 )mSH, -S(CH 2 )mNR 7 H, -0C(0)NRIoR 1 , -SC(O)NRioR,
-NR
7 C(O)NRioR 1 , -OC(O)R 7 , -SC(O)R 7 , -NR 7
C(O)R
7 , -OC(O)OR 7 , -SC(O)OR 7 ,
-NR
1
C(O)OR
7 , -OCH 2
C(O)R
7 , -SCH 2
C(O)R
7 , -NR 7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRoR , -SCH 2 C(O)NRIORII,
-NR
7
CH
2 C(O)NRioR 1 , -OS(O),R 7 , -SS(O),R 7 , -S(O),OR 7 , -NR 7
S(O),R
7 , -OS(O),NR 1 oR 1 , -SS(O),NRioR 1 1 , -NR 7 S(O)pNRioR 1 , -OS(O),OR 7 , -SS(O)pOR 7 , -NR 7 S(O)pOR 7 , -OC(S)R 7 ,
-SC(S)R
7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioRa, -SC(S)NRioR 1 , -NR 7 C(S)NRioR 1 , -OC(NR 8 )R7, -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 ,
-SC(NR
8
)OR
7 , -NR7C(NR8)OR7, -OC(NR 8 )NRioR 1 , -SC(NR)NRioR, -NR 7
C(NR
8 )NRioR, OP(O)(OR 7
)
2 , or -SP(O)(OR 7
)
2 . Preferably, R, is -OH, -SH, or -NHR 7 ; R3 is -0H, -SH, -NR 7 H, -0R26, -SR 26 , -NHR 2 6 , -O(CH 2 )mOH, -O(CH 2 )mSH, O(CH 2 )mNR 7 H, -S(CH 2 )mOH, -S(CH 2 ),mSH, -S(CH 2 )mNR 7 H, -0C(O)NRIoR 11 , -SC(O)NRioR,
-NR
7 C(O)NRioR 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)OR7, -OCH 2
C(O)R
7 , -SCH 2
C(O)R
7 , -NR 7
CH
2
C(O)R
7 , -OCH 2
C(O)OR
7 ,
-SCH
2
C(O)OR
7 , -NR 7
CH
2
C(O)OR
7 , -OCH 2 C(O)NRIoR 1 , -SCH 2 C(O)NRioR 1 ,
-NR
7
CH
2 C(O)NRioR 1 , -OS(O),R 7 , -SS(O),R 7 , -S(O)pOR 7 , -NR 7
S(O),R
7 , -OS(O),NRIORI 1 , -SS(O),NRioR 11 , -NR 7 S(O)pNRioR 1 , -OS(O)pOR 7 , -SS(O)pOR 7 , -NR 7
S(O),OR
7 , -OC(S)R 7 ,
-SC(S)R
7 , -NR 7
C(S)R
7 , -OC(S)OR 7 , -SC(S)OR 7 , -NR 7
C(S)OR
7 , -OC(S)NRioR,
-SC(S)NR
1 oR 11 , -NR 7 C(S)NRioR 1 , -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -NR 7
C(NR
8
)R
7 , -OC(NR 8
)OR
7 ,
-SC(NR
8
)OR
7 , -NR 7
C(NR
8
)OR
7 , -OC(NR 8 )NRIORII, -SC(NR 8 )NRioR 11 , -NR 7
C(NR
8 )NRoR, -C(O)OH, -C(O)NHR 8 , -C(O)SH, -S(O)OH, -S(O) 2 0H, -S(O)NHR 8 , -S(O) 2
NHR
8 ,
-OP(O)(OR)
2 , or -SP(O)(OR) 2 ;
R
7 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 R, , 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 RIO and R, 1 , taken together with the nitrogen to which C:\NRPonb\DCREC\4075614-I DOC.1/10/2012 -184 they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R
21 is 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,
R
21 is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl. Alternatively, R 21 is
NR
1 R 11
(R
3 o)o or I
(R
30 )or NR 10
R
1 or wherein RIO 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 or heteroaryl, an optionally substituted aralkyl; or RIO and RI , taken together with the nitrogen to which they are attached, form an optionally substituted heteroaryl or heterocyclyl; and
R
30 is 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, alkoxy, haloalkoxy, -NRIORn 1 , -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)N R 1 oR 11 , -C(N R)OR 7 , -C(NR 8
)R
7 ,
-C(NR
8 )N RioR I, -C(NR 8
)SR
7 , -OC(O)R 7 , -OC(O)OR 7 , -OC(S)OR 7 , -OC(NR8)OR 7 , -SC(O)R 7 ,
-SC(O)OR
7 , -SC(NR 8
)OR
7 , -OC(S)R 7 , -SC(S)R 7 , -SC(S)OR 7 , -OC(O)NR oR 1 , -OC(S)N RioR 11 ,
-OC(NR
8
)NR
0 oR 1 , -SC(O)NRIOR 1 , -SC(NR)NRIOR I, -SC(S)NRIORII, -OC(NR 8
)R
7 , -SC(NR 8
)R
7 , -C(O)N R 1 ioR 1 , -NR 8
C(O)R
7 , -N R 7
C(S)R
7 , -N R 7
C(S)OR
7 , -N R 7
C(NR
8
)R
7 , -NR 7
C(O)OR
7 , -N R 7 C(N R 8
)OR
7 , -N R 7 C(O)N R 1 oR 1 , -NR 7
C(S)NR
1 ioR 1 , -N R 7 C(N R 8 )N R 1 oR, -S R 7 , -S(O)pR 7 , -OS(O)pR 7 , -OS(O)pOR 7 , -OS(O),N RIoR 1 , -S(O),OR 7 , -N R 8 S(O)pR 7 , -N R 7 S(O),N R oR 1
,
C:\NRPotbIlDCC\REO4075614 I DOC- lMOM/ 12 - 185 -N R 7
S(O),OR
7 , -S(O),N R 1 oR 1 , -SS(O),R 7 , -SS(O),OR 7 , -SS(O),NRoRI , -OP(O)(OR) 2 , or
-SP(O)(OR
7
)
2 ; z and q are independently an integer from 0 to 4; and x is 0 or 1, provided that z+x less than or equal to 4.
R
2 2 , for each occurrence, is independently -H or 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
0 oR 1 , -NR 8
C(O)R
7 , -S(O),R 7 , -S(O)pOR 7 , or -S(O),NRIOR 1 . Preferably, R 22 is -H, an alkyl, an aralkyl, -C(O)R 7 , -C(O)OR 7 , or -C(O)NRIOR,; and
R
23 and R 2 4 , for each occurrence, are independently -H, 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, or an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRIOR 1 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NRioR 1 , -NR 8
C(O)R
7 , -SR 7 , -S(O),R 7 , -OS(O),R, -S(O),OR 7 , -NR 8
S(O),R
7 , or -S(O)pNRioR, ;
R
26 is a lower alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4. i) Exemplary Compounds of the Invention Exemplary triazole compounds of the invention are depicted in Table 5 below, including tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof.
C.V4RPon1bIlDCM~EC\40756 [II DOC.1/1012012 - 186 Table 5 No. Structure Tautomeric Structure Name N N Hydroxyphenyl)-4 N s (naphthalen- I -yI)-5 Ir mercapto-triazole OH N NN OH 3-(2,4 2 Dihydroxyphenyl)-4 HO /2 NO- HO Nmethoxyethoxy) N sm N s naphthalen- I -yI]-5 \ / mercapto-triazole OH NN OH N-NH Br Br 3-(2,4 3~ Dihydroxyphenyl )-4 HO_ // HO--/ CF (2-methyl-4 s N "I bromophenyl)-5 \ / - mercapto-triazole OH N OH N N Br Br 4 3-(2,4 HO-/ HO Dihydroxyphenyl)-4 N N (4-bromophenyl)-5 /r mercapto-triazole OH N N OH 3-(3,4 5 /O HO N Dihydroxyphenyl)-4 N/ N> s (6-methoxy \_/ naphthalen- I-yl)-5 C NNOH N-NH mercapto-triazole CAR~ob\CCkREC'"4U75tI4_ DOC.1/10/f2012 - 187 No. Structure Tautomeric Structure Name 3-(3,4 6 /0_ a c Dihydroxyphenyl)-4 N SH (6-ethoxy \ /naphthalen- I-yI)-5 0. OM mercapto-triazole 3-(3,4 7 00//Dihydroxyphenyl)-4 / (6-propoxy HU H-NHnaphthalen-I -yl)-5 0- OHmercapto-triazole 3-(2,4-Dihydroxy-5 8: ethyl-phenyl)-4-(5 8 HO HOmethoxy-naphthalen N SH N s I -yI)-5-mercapto \ / -. trazole - N p I 3-(3,4 9 /.0 S Dihydroxyphenyl)-4 N (6-isopropoxy OH 0. mercapto-triazole 10 HO HO3-(2,4 10 O H N Dihydroxypheriyl)-4 N SN ~'~ s (2,6-diethyiphenyl) \ /\ 5-mercapto-triazole OH N OH NN 1 3-(2,4 HO /HO Dihydroxyphenyl)-4 N HN s (2-methy-6 \ / -.- ' ethylphenyl)-5 OH NN H N-NH mercapto-triazole C:\NRPonbI\DCC\REC\4O75614_ .DOC-1/10/2012 - 188 No. Structure Tautomeric Structure Name 3-(2,4 12 Dihydroxyphenyl)-4 13N N 26 O r diisopropylphenyl) -N SH N s5-mercapto-triazole OH OH 3-(2,4 13 0Dihydroxyphenyl)-4 HO N HO / N (I -ethyl-_indo-4-yI) )s 5-mercapto-triazole N-NHN-Ne OH OH 0 3-(2,4 14 HO 0HO / - Dihydroxyphenyl)-4 (2,3-dihydro N s N benzo[1,4]dioxin-5 /\ / yI)-5-mercapto N O N-N__ triazole 15 O H 3-(2,4 15 HO /HO Dihydroxyphenyl)-4 N s N (3-methylphenyl)-5 N/ mercapto-triazole OH OH N-NH HO /HO Dihydroxyphenyl)-4 N /\N (4-methylphenyl)-5 \ / mercapto-triazole OH N N
OH
C XNRPonbI\DCCMEC'4n7%64 I DOC-1/10/2012 - 189 No. Structure Tautomeric Structure Name 1'7 HOCHO 3-(2,4 HO ' ~/ \ Dihydroxyphenyl)-4 N s P- N NH (2-chlorophenyl)-5 \ / S mercapto-triazole OH OH 18 O H 3-(2,4 18 H / H / ~Dihydroxyphenyl)-4 N s N (3-chlorophenyl)-5 \ /r mercapto-triazole OH N OH N N CI Cl 19 3-(2,4 19 HO ,- HO //Dihydroxyphenyl)-4 N N (4-chlorophenyl)-5 /r mercapto-triazole OH OH 2 HO_01,HO 0, 3-(2,4 N /\ Dihydroxyphenyl)-4 / HN (2-methoxyphenyl) Ir 5-mercapto-triazole OH N OH N N C" 21 3-(2,4 21 - HO Dihydroxyphenyl)-4 HO N (3-methoxyphenyl) SF S 5-mercapto-triazole OH N OH N N C \NRPontbIWCC'\RE(\I75614IJ DOC-111012012 - 190 No. Structure Tautomeric Structure Name
~CH
3 0 >-C 3 22 X Dihydroxyphenyl)-4 NO HO N (4-methoxyphenyl) N r s N 5-mercapto-triazole OH N N OH F 23 HO HO '~ 3-(2,4 H O/\ /Dihydroxyphenyl)-4 N sN (3-fluorophenyl)-5 \ /r mercapto-triazole OH N OH N N 24 HO_ HO3-(2,4 24 H / H Dihydroxyphenyl)-4 N SH N (2-ethylphenyl)-5 \\ / mercapto-triazole OH N OH N N 25 F F 3-(2-Hydroxy-4 /1 P\ fluorophenyl)-4 mercapto-triazole OH N NOH N N 26 H2N - ~ H 2 N /-11 3-(2-Hydroxy-4 N s N (naphthalen- I-yI)-5 \ / mercapto-triazole OH -OH N N C:NRPortbl\DCC\REC407514I DOC-1110/2012 - 191 No. Structure Tautomeric Structure Name 3-(2,4 27 Dihydroxyphenyl)-4 HO HO (2-methyl-4-butyl N__N SH N phenyl)-5-mercapto \ /s triazole OH OH 3-(2,4 28 Dihydroxyphenyl)-4 HO HO (2,4-dimethyl N sN phenyl)-5-mercapto N-- triaZole OH N-NH OH 3-(2,4 29 HO HO Dihydroxyphenyl)-4 N N (2,6-dimethyl N sN phenyl)-5-mercapto \ / triazole OH N-N OH N-NH 3-(2,4 30 HO HO Dihydroxyphenyl)-4 N / N (2,6-dimethyl s phenyl)-5-mercapto OH N-N OH N-NH triazole FF 31 3-(2,4 HO HO Dihydroxyphenyl)-4 N N (4-fluorophenyl)-5 S N mercapto-triazole OH N-NH
OH
C NRP*,Onb CCRECM04 _1 DOC- 1/10/2012 -192 No. Structure Tautomeric Structure Name 3-(2,4 32 HO / " HO s Dihydroxyphenyl)-4 N /\ (2 N SH N "'r s methylsulfanyipheny \ / I)-5 -mercapto OH N OH N-H triazole 33 3-(2,4 X ~Diydroxyphenyl)z4 HO / HO nptaee2y) N N 5-mercapto-triazole OH N N OH 1 - 3-(2,4 34 HO--/ HO Dihydroxyphenyl)-4 N sN (2,3 S dimethylphenyl)-S / mercapto-triazole OH N OH N N F F 3-(2,4 35 .. ~ Dihydroxyphenyl)-4 HO- HO /2mthl N N fluorophenyl)-5 \ /r-. mercapto-triazole OH N-NH OH 3-(2,4 36 z ~Dihydroxyphenyl)-4 HO H aeahhln5 N HON (ac5-encapthe- \ /
-
triazole OH N N
OH
C \NRPortbIWfCCWRC'407%14-I DOC-1/1012012 - 193 No. Structure Tautomeric Structure Name -~ ~. 3-(2-Hydroxy-4 37 0- 0/ 0 methoxy-phenyl)-4 N sN (naphthalen- I-yI)-5 r / r mercapto-triazole OH N OH N N C 38 HO_ HO- ;( Dihydroxyphenyl)-4 38/N -, N (2,3 / dichlorophenyl)-5 ____ mercapto-triazole OH N OH N N 0 0~ A- ~ 3-(2,4 39 Dihydroxyphenyl)-4 HO / NO HO ,/- methoxynaphthalen s NN I -yi)-5-mercapto \ r / triazole OH 40 3-(2,4 40 HOx-~- Dihydroxyphenyl)-4 N -1; -- NN NH(pyren- I-yi)-5 N N CH N-N N N 41 HO HO 3-(2,4 HO / ~ HO / ~Diliydroxyphenyl )-4 N sN (quinolin-5-yI)-5 \ / - mercapto-triazole OH N OH N N C \NRP.nblCCIREC4U136I4-I DO.C- 11111121 - 194 No. Structure Tautomeric Structure Name 1 3-(2,4 42 HO HO Dihydroxyphenyl)-4 HO HO 1 (1,2,3,4 N s N tetrahydronaphthalen \ / -5-yI)-5-mercapto OH N OH -H triazole 43 H HO 3-(2,4 HO/\ HO/\Di hydroxyphenyl)-4 ~ ~_/ SM ~ \(anthracen- I-yI)-5 N-NMN mercapto-triazole 44 X \ 3-(2,4 N4 NDH Dihydroxyphenyl)-4 O -OH N-NH mercapto-triazole 45 HHO3-(2,4-Dihydroxy-6 HO N H HO /\ ~methyl-phenyl)-4 N SH 'r s (naphthalene-1I-yl) \ /-l 5-mercapto-triazole OH N OH N N 46 I3-(2,4 -~ - ~ Dihydroxyphenyl)-4 HO HO y N (4-pentyloxyphenyl) s N 5-mercapto-triazole
OH
C MPoblDCC~tEC',4O756IJ I DOC- It1012012 - 195 No. Structure Tautomeric Structure Name 47 3-(2,4 /O HO Dihydroxyphenyl)-4 N N (4-octyloxyphenyl) ~. \/ -. 5-mercapto-triazole OH N-N NN OOH Cl CI 3-(2,4 48 .- : Dihydroxyphenyl)-4 NO HO ,/ N (4-chloronaphthalen N s N I -yi)-5-mercapto. OH N-NH OH 49 HO HO 3-(2,4-Dihydroxy-5 pk HO kH ethyl-phenyl)-4 N sN (naphthalen- I-yi)-5 \ r / mercapto-triazole OH NNOH N-NH I - l 3-(2,4-Dihydroxy-5 50 //o ethyl-phenyl)-4-(7 0 No carboxymethoxy N-N, naphthalen- I-yi)-5 N N 3-(2,4 51 HO / HO /7Dihydroxyphenyl)-4 NN (2-methyl-quinolin \ /r SH N 4-yl)-5-mercapto OH NN OH N-NH triazole C:\NRPorb\DCC\REC4075614 I DOC-1/10l/2012 - 196 No. Structure Tautomeric Structure Name 3-(3 52 Hydroxypyridin-4 N N SH N yl)-4-(naphthalen-1 S yI)-5-mercapto ___ triazole N- N-NH OH OH 0*I3-(2-Hydroxy-4 53 HN HN acetylamino N N s phenyl)-4 \ sH s (naphthalen-I-yi)-5 OH NN H N-NH mercapto-triazole 3-(2,4-Dihydroxy 54 HO HO / phenyl)-4-(1,2,3,4 N SH N tetrahydronaphthalen SH g- -1-yl)-5-mercapto OH N-N OH N-NH triazole 0 0 3-(2,4-Dihydroxy 55 0 phenyl)-4-(2,3 N~ /\ dhyd ro N SN S benzo[I,4]dioxin-5 N /\ NH yl)-5-mercapto OH OH N-NH triazole 56 3-(2,4-Dihydroxy HO HO phenyl)-4-(3,5 N N dimethoxyphenyl)-5 N N mercapto-triazole OH N-NH
OH
CX1NRPonbflDCC\REC%4(075%614- DOC- 1/101201 2 - 197 No. Structure Tautomeric Structure Name ~ / / 3-(2,4-Dihydroxy H57 H phenyl)-4-(2,3 / dimethyl-]H-indol S4-yi)-5-mercapto OH NNOH N-Htriazole 58 ' HO 'N3-(2,4-Dihydroxy-3 N8 propyl-phenyl)-4 N SH s (naphthalen- I -yi)-5 \h " O mercapto-triazole N~ N -(1I-ethyl-4 59 N hydroxy-6-oxo- 1,6 59 0 0dihydro-pyridin-3 SH N r s yI)-4-(naphthalen-I \ / yI)-5-mercapto OH N OH NH triazolIe 5 -l I / 60 ~ N3-(4-hydroxy-6-oxo 60 0-zN 0 Npyridin-3-yi)-4 N SH N s (naphthalen- I-yi)-5 \ / mercapto-triazole 61 I 3-(2,4-Dihydroxy 61 HO HOphenyl)-4-(3,5-di N SH s tert-butylphenyl)-5 mercapto-triazole OH OH "N 3-(2,6-Dihydroxy5 62 HO HOfluoro-pyridin-3-yi) N N S N N s 4-(naphthalen- Il-yl) N_ N 5-mercapto-triazole OH OH NN C \NR.PonbIlflCCREC 407.6I4-1,DC.I(0122 - 198 No. Structure Tautomeric Structure Name 3-(2,4-Dihydroxy-5 63 HO HOmethyl-phenyl)-4 N SH N "r (naphthalene- I-yI) \ 5-mercapto-triazole OH O 64 3-[2,4-Dihydroxy HO HOphenyl]-4-(3 N N benzoylphenyl)-5 \ / -mercapto-triazole OH NN OH N-MI i - 3-(2,4-Dihydroxy 65 I phenyl)-4-(4 HO HOcarboxy-naphthalen N SH N s I -yi)-5-mercapto \ 7 triazole NN-N OH OH NN 3-(2,4-Dihydroxy 66 I phenyl)-4-[4-(N,N diehlarbamoyl) HOHO naphthalen- Il-yi]-5 HoY SH N mercapto-triazole OH OH NN -~ 3-(2,4-Dihydroxy 67 phenyl)-4-(4 HO-/ HO-N propoxy-naphthalen N S N s I -yi)-5-mercapto SH S triazole OH N OH NN C \NRPonbIUflCCREO44'7f4l ]DOC-[/IW20 12 -199 No. Structure Tautomeric Structure Name 3-(2,4-Dihydroxy 68 phenyl)-4-(4 isopropoxy HN_ ,O naphthalen- I-yI)-5 N/r SHN mercapto-triazole OH N OH N N / 3-(2,4-Dihydroxy 69 phenyl)-4-(5 'N 'Nisopropoxy NO- HO Nnaphthalen- I-yI)-5 N r SH s mercapto-triazole OH N OH N N 70 HO 'Nl~ HO 'N3-(2,4-Dihydroxy N SH /\ Nphenyl)-4 \ (i soq u inoIi n- 5-yI1)-5 OK SH OHmercapto-triazole 3-(2,4-Dihydroxy 71 ''Nphenyl)-4-(5 NO HO_ propoxy-naphthalen si SH N1 -yI)-S-mercapto \ /'-. triazole OH OH N N N N 3-(2-Hydroxy-4 72 H ~ H ,, methanesulfonamino \\6N \ C N s -phenyl)-4 \ / (naphthalen- I-yI)-5 OH N-NH mercapto-triazole C NR~onbI\DCMC'IEO4 1N4_ DOC-I1/I10201I2 - 200 No. Structure Tautomeric Structure Name 'N 3-(2,4-Dihydroxy 73 HO /HO /3,6-dimethyl N SN N s phenyl)-4 \ / -.. (naphthalen- I-yI)-5 OH N-NOH N-H mercapto-triazole ~ ~ 3-(2,4-Dihydroxy 74 oN phenyl)-4-[7-(2 methoxyethoxy) naphthalen-1I -yI]-5 mercapto-triazole 0NH 3-(2,4-Dihydroxy-5 75 HO0 hexyl-phenyl)-4 H 6H mercapto-triazole 3-(2,4-Dihydroxy-5 76 NNethyl -phenyl1)-4-(4 HOH methoxy-naphthalen SN I -yl)-5-mercapto SH N s triazole OH O I 3-(2,4-Dihydroxy-5 77 HO ,-/ON ethyl-phenyl)-4-(6 N N methoxy-naphthalin OH NNOH N-NH triazole ~I 3-(2,4-Dihydroxy-3 7 HOHO chloro-5-ethyl N SHN s phenyl)-4 OH NI OH N-NH mercapto-triazole C ANRPonblODCOEC'4O7S6I4- DOC.11101201 2 -201 No. Structure Tautomeric Structure Name 3-(2,4-Dihydroxy-5 HN- HO- / dimethy-4-methoxy s phenyl)-5-mercapto triazole OH N N OH ~ I ~ 3-(2,4-Dihydroxy 80 NIsopropoxy / NNflnaphthalen- I-yI)-5 0. OHmercapto-triazole g a-, ,- -2,-iydoy 81 O /9 a . phenyl)-4-(7-ethoxy \__/ ---. naphthalen- I-yI)-5 0. OH NNf mercapto-triazole 3-(2,4-Dihydroxy 82 / ,* Npropoxy-naphthalen ___ I -yi)-5-mercapto N triazole 83I 3-(2-Hydroxy-4 83 0 7 /methoxymethyoxy N \ _S N/h ny) N-N \/ (naphthalen- I-yi)-5 O. Ofi -N mercapto-triazole / I 3-[2-H-ydroxy-4-(2 84 0 0 hydroxy-ethoxy) NO HNO s phenyl]-4 N-N\ r (naphthalen- I-yI)-5 H N NN-NH mercapto-triazole I 3-(2,4 85 H -1HO 0 Dihydroxyphenyl)-4 85/ N N (7-methoxy -- naphthalen- I-yl)-5 N H N-NH mercapto-triazole C:\NRPortbl\DCC\REC0475614_ I DOC-/10/21012 - 202 No. Structure Tautomeric Structure Name 3-(2,4 86 Dihydroxyphenyl)-4 HO HO (5-methoxy N N naphthalen- I-yl)-5 SH N\ mercapto-triazole OH OH OH OH 3-(2,4 87 "Dihydroxyphenyl)-4 HO HO (4-hydroxy N N s naphthalen- I-yl)-5 \ / mercapto-triazole OH N-N OH N-NH N N N 3-(2,4 88 Dihydroxyphenyl)-4 HON/ HO (I -isopropyl-indol-4 N SH N yl)-5-mercapto \ / triazole OH NN OH N-NH 3-(2,4-Dihydroxy-5 89 HO HO tert-butyl-phenyl)-4 N N s (naphthalen-I-yl)-5 mercapto-triazole OH OH 3-(2,4-Dihydroxy-5 90 HO HO propyl-phenyl)-4 N N s (naphthalen-I -yl)-5 \ /\ mercapto-triazole OH
OH
C \Nr~ornbIlDCCREC\4075614- IDOC.X-IIfl/21 - 203 No. Structure Tautomeric Structure Name 3-(2,4-Dihydroxy-3 91 HO /H / methyl-5-ethyl N SHN s phenyl)-4 \ /(naphthalen- I-yI)-5 N N-NH mercapto-triazole OH OH 3-(2,4-Dihydroxy-5 92 HO /HO isobutyl-phenyl)-4 N _SH N s (naphthalen- I -yi)-5 \ / mercapto-triazole OH OH N o- 0 93 HO 0 HO' 3-(2,4-Dihydroxy N3 NO/ZH phenyl)-4-(2,3 N SH N s dimethoxy-phenyl) \ / ____ 5-mercapto-triazole OH N OH N N C I I 3-(2,4-Dihydroxy 94 HO N ) I HO p phenyl)-4-(2 N s N methoxy-3-chloro phenyl)-5-mercapto \ /___ triazole OH OH N N H N 3-(2,4-Dihydroxy N5HOO/HO phenyl)-4-(indol-4 SH s yI)-5-mercapto \ / triazole OH NNOH N N C 'RPonblOCC\REC075614_1 DOC.1/I10/2012 - 204 No. Structure Tautomeric Structure Name N N 3-(2,4-Dihydroxy 96 phenyl)-4-[ 1 -(2 methoxyethoxy) HO HO N indol-4-yi]-5 N SH N mercapto-triazole N-N OH OH 3-(2,4-Dihydroxy 97 HO / - HO / phenyl)-4 N OH N O (naphthalen-1-yl)-5 hydroxy-triazole OH OH 3-(I-Oxo-3-hydroxy 98 N O N pyridin-4-yI)-4 N SH N S (naphthalen-I-yl)-5 N-N N---H mercapto-triazole OH OH Ho O HO 0 3-(2,5-Dihydroxy-4 99 carboxy)-4 N H N s (naphthalen- I-yl)- 5 N-N mercapto-triazole OH OH N N 3-(2,4-Dihydroxy-5 100 ethyl-phenyl)-4-(1 HO HO isopropyl-indol-4 SH N yl)-5-mercapto \ triazole OH N-N OH N-NH CUWRPcrnbI\DCCREC'4O756I4- DONC.1/1/2012 - 205 No. Structure Tautomeric Structure Name 0 N0 N N \ 3-(2,4-Dihydroxy-5 ethyl-phenyl)-4-[ I 101 ~. // (dimethyl N0 HO / carbamoyl)-indol-4 N s yI]-5-mercapto OH N/ H NN triazole NN-N N I ) 3-(2,4-Dihydroxy-5 10 HO, N H ethyl-phenyl)-4-(1 102 H HOethyl-benzoimidazol N / SH N s 4-yI)-5-mercapto ____'I triazole OH OH N ~N 3-(2,4-Dihydroxy-5 103 ethyl-phenyl)-4 HO /HO (1 ,2,3-trimethyl N SHN indol-5-yI)-5 \ H /s mercapto-triazole OH N OH N N H OHO HO 3-(2,5-Dihydroxy-4 1 O04 hydroxymethyl 10 SH N s phenyl)-4 \ / ___ (naphthalen- I-yi)-5 O H NNOH N-H mercapto-triazole 105 HN H2N3-(2-Hydroxy-4 105 2N N I2NN amino-phenyl)-4 SHs (naphthalen-1I -yI)-5 \ / mercapto-triazole OH
OH
C\NRPonbl\DCORE04075614_1 DOC.1/1012012 - 206 No. Structure Tautomeric Structure Name 3-(2-Hydroxy-4 106 HN N HN acetylamino N N s phenyl)-4 SH/ S (naphthalen-I-yl)-5 OH NOH N-NH mercapto-triazole 3-(2,4-Dihydroxy-3 107 HO HO chloro-phenyl)-4 N N s (naphthalen- I -yl)-5 c N-N N H mercapto-triaZoe OH OH 3-(2,4-Dihydroxy 108 HO HO phenyl)-4 N SH N s (naphthalen-1-yI)-5 N--N N--NH mercapto-triazole OH OH 3-(2,4-Dihydroxy 109 11 7HO phenyl)-4-(2-methyl N s N phenyl)-5-mercapto N / triazole OH OH N-NH OO 0 110 / HO 3-(2,4-Dihydroxy 110 HO HO 7 phenyl)-4-(2,5 N s N s dimethoxy-phenyl) N SH N -NH 5-e yi OH OH HO / HO 3-(2,4-Dihydroxy N N phenyl)-4-phenyl-5 S Smercapto-triazole OH N-N OH N-NH C :NRPorbiDCC\REC,4i756I4_1.DOC-1/10/2012 - 207 No. Structure Tautomeric Structure Name 0o 3-(2-Hydroxy 112 / phenyl)-4-(2 N SH N s methoxy-phenyl)-5 \ / mercapto-triazole N-N N-NH OH OH 113 phenyl)-4-(4-methyl \ phenyl)-5-mercapto N sN triazole N-N OH N-NH OH Br Br 3-(2-Hydroxy 114 phenyl)-4-(4-bromo phenyl)-5-mercapto N N triazole OH N-NH OH 3-(2,4-Dihydroxy 115 HO phenyl)-4 N (naphthalen- l-yl)-5 s" (methyl sulfanyl) N-N triazole
OH
C V4RPoniblflCC'RE"04756 14-1DOC1110/2012 - 208 No. Structure Tautomeric Structure Name /; / 3-(2,4-Dimethoxy 116 /0 N H /~ phenyl)-4 (naphthalen- I -yI)-5 /-N mercapto-triazole 0 0 7 /4-i(dmthl carbamoyloxy) 117 0 phenyl]-4 0 (dimethyl carbamoylsulIfanyl) triazole / 3-(2,4-Dihydroxy 118 HO /phenyl)-4 N /(naphthalen- I-yi)-5 _/ N(dimethylcarbamoyis OH 0 ulfanyl)-triazole N - 3-(2,4 (0~~ O /\Diethoxycarbonylox 0- (naphthalen- I -yI)-5 o (ethoxycarbonylsu Ifa (0 nyl)-triazole N ~- 3-(2,4-Di 07\ isobutyryloxy 120 _/phenyl)-4 0 ~(naphthalen- I -yI)-5 (isobutytylsulfanyl) triazole N ~ 3-[2,4-Di-(dimethyl 0/ carbamoyloxy) 121 0 phenyl]-4-(quinolin 0 5-yI)-5-(dimethyl carbamoylsulfanyl). 7 triazole C \NRPonhbllCC\RECU075614_1 DOC- I1I41/2012 - 209 No. Structure Tautomeric Structure Name 3-24-iceoy 122 p o ,phenyl)-4 0 (naphthalen-1I -yI)-5 0 0 (acetylsulfanyl) triazole D/7\ N3-(2,4-D lacetoxy 12 phenyl)-4 12 N_/0__ (naphthalen-I-yI)-5 0 0 mercapto-triazole _"C/y\ " Diethylcarbamoylox 124 0 \__ N' y-phenyl)-4 0 0 (naphthalen- I -yi)-5 (ethylcarbamoylsulfa ( nyl)-triazole -~ 'N3-(2,4-Dihydroxy 'N - phenyl)-4 125 "0/ \(naphthalen- I -yI)-5 S (2 OH -Nhydroxyethylsu Ifanyl )-triazole N26HO s N 3-(2,4-Dihydroxy I~ ' u-.. -'- I p h e n y l) -4 -e th y l- 5 mercapto-tizl OH O 127 HlO / N HO /N 3-(2,4-Dihydroxy s phenyl)-4-propyl-5 \ " mercapto-triazole OH NNOH N N C \NRPOnb\DCC "0C4756J I![ C-11f10/2012 -210 No. Structure Tautomeric Structure Name 128 N HO N 3-(2,4-Dihydroxy \ / --... phenyl)-4-isopropyl N-N N-NH 5-mercapto-triazole OH OH 129 HO 7HO 73-(2,4-Dihydroxy N sN phenyl)-4-butyl-5 \ /r mercapto-triazole OH N NOH N-NH HO / j HO,~ 3-(2,4-Dihydroxy 130 N sN pheny1)-4 \ / cyclopropyl-5 OH N NOH N-NH mercapto-triazole 3-(2,4-Dihydroxy 131 /0- 0 phenyl)-4 N ~(naphthalen- I -yi)-S ___ (carboxyethysulfanyl OH N )-triazole F F 0 3-(2,6-Dimethoxy-5 132 /70 /N SH N s luoro-pyridin-3-yl) NN "-r 4-(naphthalen- I-yl) /0N /0N 5 -mercapto-triazole H- Methanesu Ifonyloxy N / N N~~-~ methanesulfonylami 0- NN no-phenyl)-4 0 "/0 ~(n aph thalIe n -I -yI1)-5 mercapto-triazole CANP.Po~b1\DCCRFCU071-1 DOC- I/1W012 -211 No. Structure Tautomeric Structure Name 3-(2-Methoxy 134 phenyl)-4-(4 NN methoxy-phenyl)-5 s mercapto-triazole 01 N-NH 135 3-(3-Hydroxy 135 naphtha len-2-yi )-4 N s N phenyl-5-mercapto r /\ triazole OH N OH N N
CH
3
C
3 3-(2-Methoxy 136 phenyl)-4-(4-methyl N N phenyl)-5-mercapto Sr triazole 00 0 3-(2,4-Dihydroxy-5 17 HO H N O ethyl-phenyl)-4-(3 HO N 0 methox-phenyl)-5 13 / ___ hydroxy-triazole OH NNOH
NN
C ANR"nblCCR.EO4075614- I OC.IIW!/2012 -212 No. Structure Tautomeric Structure Name HO HO3-(2,4-Dihydroxy-5 138 O/\ OH O Nethyl-phenyl)-4 OH 0 (naphthalen- I -yi)-5 13 /1 ____ hydroxy-triazole NN N 3-(2,4-Dihydroxy-5 ~ / / ethyl-phenyl)-4-( I 139 HON HO Nisopropyl-indol-3 OHf N yI)-5-hydroxy \ / -triazole OH N OH NN NN / / 3-(2,4-Dihydroxy-5 140 HO HOethyl-phenyl)-4-(1 140 H / NHO 7isopropyl-indol-4 NH2 NHNH yl)-5-amino-triazole OH OH 0 0 3-(2,4-Dihydroxy-5 HO /HO /ethyl-phenyl)-4-(3 11N NH2 NH methoxy-phenyl)-5 1 4 OH N OH a m in o -tria zo le N-N N' 'N'3-(2,4-Dihydroxy-5 12 HO 7HO ethyl-phenyl)-4 N _NH N NH(naphthalen- I-yI)-5 \ / "r amino-triazole OH
OH
C:\NRPorbl\ICC\RECU075614_ LDOC. 1/10/2012 -213 No. Structure Tautomeric Structure Name O O 3-(2-Hydroxy-5 143 /\ ethyloxy-phenyl)-4 143N OH I N O (naphthalen-1-yl)-5 \ / hydroxy-triazole OH N-N OH N--NH 3-(2-Hydroxy-5 144 N isopropyl-phenyl)-4 OH N O (naphthalen-1 -yl)-5 \ / hydroxy-triazole OH N N OH N-NH 3-(2-Dihydroxy 145 ON N phenyl)-4-(7-fluoro 145 N OH 0 naphthalen- I-yl)-5 N--NH hydroxy-triazole OH NNOH NN F HO 3-(2,4-Dihydroxy 146 HO \ N HO phenyl)-4-(2,3 N O N difluorophenyl)-5 N-/ hydroxy-triazole OH OH N-NH H H 3-(2,4-Dihydroxy HO_ N- HO N--pey)4[-lH 147 N N tetrazol-5-yl) r __phenyl]-5-hydroxy N- OH N-NH triazole S\ HO N HO N 3-(2,4-Dihydroxy phenyl)-4 148 HON OH HO o (benzothiazol-4-yi) H / 5-hydroxy-triazole OH N-N OH N-NH CANRPonbIKDC0REC'407561H I OC.I/101201 2 -214 No. Structure Tautomeric Structure Name rN H rN H N N. N N 3-(2,4-Dihydroxy 19 HO /N HO N phenyl)-4-(9H-purin 14 N OH N o 6-yI)-5-hydroxy \ r / triazole OH OH 0 0 NN 3-(2,4-Dihydroxy 150 .- (moropholin- I-yI) HO-,/ HO ethoxy]-phenyll}-5 N 0 hydroxy-triazole OH N-N OOH HO / HO 73-(2,4-Dihydroxy 151 N 0N "r phenyl)-4 "I cyclopentyl-5 \ I___ hydroxy-triazole OH OH 3-(2,4-Dihydroxy 152 HO_, N K 0 phenyl)-4-phenyl-5 "I \ *(sulfamoylamino) OH / triazole IN 3-(2,4-Dihydroxy-5 153 HO 7 \ N methoxy-phenyl)-4 ) -Y N (naphthalene- I -yI) N N 5-ureido-triazole OH 0 F 3-(2,4-Dihydroxy-5 /0 \ methoxy-phenyl)-4 154 N- N (2,3-difluorophenyl) .- \/.rN 5-ureido-triazole OH 0 C \NRPoflbIDCC~kE'4I)7% 14_ 1DOC.I111012012 -215 No. Structure Tautomeric Structure Name 3-(2,4-Dihydroxy-5 155 HO ethyl-phenyl)-4-( I N isopropyl-indol-4 ~. ~ / >W yi)-5-ureido-triazole OH 0 - 3-(2,4-Dihydroxy-5 156 \ ethyl-phenyl)-4 ''/1 ureido-triazole 0/ 3-(2,4-Dihydroxy-5 /O-1 methoxy-phenyl )-4 157 N (naphthalene- Il-yi) . -0_ \Ni 5-carbamoyloxy OH 0 triazole 3-(2,4-Dihydroxy-5 ethyl-phenyl)-4-(3 158 trifluoromethyl 158 N -0phenyl)-5 N-N carbamoyloxy 0 triazole 3-(2,4-Dihydroxy-5 ethyl-phenyl)-4-( 1 159 HO methyl-indol-4-yi) 0 ) - 5-carbamoyloxy N N triazole ~ N~ -(2,4-Dihydroxy-5 0" methoxy-phenyl)-4 160 HO (8-methoxy N 0quinolin-5-yi)-5 ) \ / TN, carbamoyloxy OH 0 triazole C 14RMonbtODCCREC\,40756I4-1.DOC-IIII)12012 -216 No. Structure Tautomeric Structure Name "~ ~"3-(2,4-Dihydroxy-5 - isopropyl-phenyl)-4 16/O (3-methyl-quinol in 16 51y)-5 ~ ~ /r carboxyamino OH 0 triazole N 3 -(2,4-Dihydroxy phenyl)-4-(l -methyl 162 H \ 2-chloro-indol-4-yi) Ir -05-carbamoyloxy N-N triazole 0/F3C CF3 3-(2,4-Dihydroxy-5 o~' methoxy-phenyl)-4 HO [3,5-di 163 N (trifluoromethyl ) phenyl]-5 OH carbamoyloxy ____________________________ triazole V I 3-(2,4-Dihydroxy-5 I methoxy-phenyl)-4 164 /HO N (3-trifluoromethyl N-__ (sulfamoylamino) OM 0 tria z o le "N "~3-(2,4-Dihydroxy-5 HO methoxy-phenyl )-4 165 N "\ N (naphthalene- Il-yI) ~ \_/ \ 5-(sulfamoylamino) OH 0 triazole N 3-(2,4-Dihydroxy-5 me/h1x-phenyl)-4 166 /O N (1 -isopropyl N benzoimidazol-4-yl) \ ) 5-(sulfamoylamino) N-N triazole C ANR~onblDCCREC'4I)7%4I DOC-I1/If21 -217 No. Structure Tautomeric Structure Name 'N.. 3-(2,4-Dihydroxy-5 methoxy-phenyl)-4 167 HO /(3-isopropyiphenyl) N H 5 - \ ) \.< (thiocarboxyamino) OH striazole o 3-(2,4-Dihydroxy-5 0"' methoxy-phenyl)-4 168 Ho-" (3-isopropyloxy N phenyl)-5 ) __/ \ WN (sulfamoyloxy) OH N Ntriazole 3-(2,4-Dihydroxy-5 HO methoxy-phenyl)-4 169 / \ N (naphthalene- I -yI) '~ __/ \ c 5-(sulfamoyloxy) 0 triazole N 3-(2,4-Dihydroxy-5 mehx-phenyl)-4 170 N (I-isopropyl 170 -~N bnzoim idazol-4-yI ) ) / 0\ ~N 5-(sulfamoyloxy) N N 0triazole 0/N / " N> 3-(2-H-ydroxy-4 > ethoxycarbonyoxy 171 0N 0 N 5-methoxy-phenyl) 171/ 0 / 4-(1 -isopropyl \- / o \ benzoimidazol-4-yi) C 5-hydroxy-triazole 3-(2-Hydroxy-4 0 ethoxycarbonyoxy OHl 0~~ 5-ethyl-phenyl)-4 O- \ , \ (naphthal in-2-yI)-5 ~"otlhydroxy-triazole C VMRPombIflCCEC'W0764_1DOC- 1/F'2012 -218 No. Structure Tautomeric Structure Name 3-[2-Hydroxy-4 -A (dimethyl 173- 0 \ _/ / carbamoyoxy)-5 1 73 0 / N _ N _ H / N - N O ethy l-pheny l]-4 \__ -\ (naphthalin-2-yi)-5 C OHN -N hydroxy-triazole C1 C13-[2-Hydroxy-4 (dimethyl 174- O~' / \ NO _Y carbamoyoxy)-5 SH4 N> chloro-phenyl]-4 \N /- /N' ~ ' (quinolin-5-yI)-5 OH O mercapto-triazole N F 'N 3-[2-Hydroxy-4 F -X (dimethyl 15 0 /_ N 0 / carbamoyoxy)-5 zt-- \/ -- -- ethyl-phenyl]-4-(2,3 /N N- N N difluoro-phenyl)-5 OH O NH mercapto-triazole N \N N\ 3-[2-H-ydroxy-4 N N isobutyryloxy-5 176 o 0 N / ethyl-phenyl]-4-(l N 0M N r methyl-benzo \ / ~ _ imidazol-4-yI)-5 N-11N O -H hydroxy-triazole 0 1 3-(2,4-Dihydroxy-5 177 HO -" HO P O ~ methoxy-phenyl)-4 A\ N sN (naphthalen- I-yi)-5 \ >/-SH \mercapto-triazole OH N-N OH N-NH__ ______ OH OH HO HO 3-(2,4-Dihydroxy-5 178 / ethyl-phenyl)-4-(5 hydroxy-naphthalen N N I-i--ecpo HO I/>-SH HO I _ =sti-yI-5-ercpo
H
C\NRPonbI\DCC\REC%4075614_ DOC-IIO/2012 -219 No. Structure Tautomeric Structure Name HO HO 3-(2,4-Dihydroxy 179 -phenyl)-4 (naphthalen-I N N ylmethyl)-5 HO N i>SH HO N S mercapto-triazole N 'ZZ H N ' 3-(2-Hydroxy-4 180 /0 N /0 N methoxyphenyl)-4 _SH S (naphthalen-I-yl)-5 OH N-N OH N-NH mercapto-triazole 3-(2,4-Dihydroxy 181 HO HO phenyl)-4-(biphenyl N H /N 3-yl)-5-mercapto \SH " triazole OH OH N-NH OH OH 3-(2,4-Dihydroxy 182 HO HO phenyl)-4-(2-methyl CH 5-hydroxymethyl N (CH N phenyl)-5-mercapto ? / SH s triazole OH N /N OH N NH 0 / N N 3-(2,4-Dihydroxy 183 phenyl)-4-(I HO HO dimethylcarbamoyl NrSH N indol-4-yi)-5 mercapto-triazole N-N OH N-NH HO OH - HO O 3-(2,4,5-Trihydroxy N N (naphthalene-I-yI) '' 5-mercapto-triazole OH N-N OH N-NH C:\NRPortbIDCC\REC44)75614_ I DOC- 1/10/2012 - 220 No. Structure Tautomeric Structure Name HN HN 3-(2,4-Dihydroxy-5 185 ethyl-phenyl)-4-(2,3 HO HO / 5 N dimethyl-indol-5-yl) N SH N -:S 5-mercapto-triazole OH N-N OH N-NH 3-(2,4-Dihydroxy-5 186 HO HO ethyl-phenyl)-4-(3-t butyl-4-methoxy N N phenyl)-5-mercapto /HSN / s triazole OH NN OH N NH N N 3-(2,4-Dihydroxy-5 I /> ,~ ethyl-phenyl)-4-(l 187 H N HC N HC ethyl- l H HO ON/H O N benzoimidazol-4-yl) S 5-mercapto-triazole, OH N-N OH N-NH HCI salt 0 O N N 3-(2,4-Dihydroxy-5 188 ( / ethyl-phenyl)-4-(I HO /\ HO / isopropyl-7 N SHN S methoxy-indol-4-yl)
-
N 5-mercapto-triazole OH N-N OH N-NH 3-(2,4-Dihydroxy-5 189 HO / HO / cyclopropyl-phenyl) N SH N, 4-(naphthalene-l yl)-5-mercapto OH N-N OH NNH triazole C \NRPonbIOfCCREC0J75614_I DOC-U/102 -221 No. Structure Tautomeric Structure Name ~ N ~W 3-(2,4-dihydroxy-5 190 I - /I~ / ethyl-phenyl)-4-(1 HO / HO /propyl-indol-4-yi)-5 N N<S S mercapto-[ 1,2,4] O H N-N OH N-NH tizl
H
2 C-\ 2C\N 3-(2,4-dihydroxy-5 19/ O ethyl -phenyl1)-4-(] 191 HO 1H acetyl-2,3-dimethyl NN indol-5-yi)-5 SH== mercapto-[ 1,2,4] OH lK /-S OH NLN triazole -N H N,/, N 3-(2,4-diliydroxy-5 12 HO,,/ HO ethyl -phenyl1)-4-(2 192 methyl-3-ethyl I" N N benzimidazol-5-yI) OH >! SH OH I N 5-mercapto-[ 1,2,41 OH N H - trazole Ni 3 -(2,4-dihydroxy-5 13N HO r- ethyl-phenyl)-4-( 1 HOH ethyl-2-methyl O r Z ,benzimidazol-5-yi) N I =~ 5-mercapto-[ 1,2,41 OH /N SH OH N >= = triazole -N
H
C :NRPonbl\DCC\REC4075614_I.DOC-[/10/2012 - 222 No. Structure Tautomeric Structure Name N N 3-(2,4-dihydroxy-5 194 K ethyl-phenyl)-4-(1 HO HO propyl-2,3-dimethyl - indol-5-yi)-5 N N mercapto-[1,2,4] OH SHOHtriazole OH /N SH OH ILN OH H N N 3-(2,4-dihydroxy-5 195 HO HO ethyl-phenyl)-4-(N HO ' methyl N N tetrahydrocarbozol H /SH H N S 7-yI)-5-mercapto N H [1,2,4] triazole N N 3-(2,4-dihydroxy-5 196 HO HO ethyl-phenyl)-4-(N methyl ' N N cyclononan[a]indol H SH OH LN 5-yl)-5-mercapto N H [1,2,4] triazole N N 3-(2,4-dihydroxy-5 197 I ethyl-phenyl)-4-(i-n HO HO / butyl-indol-4-yl)-5 N SH N 7S mercapto-[ 1,2,4] OH N-N OH N-NH triazole N N 3-(2,4-dihydroxy-5 198 ethyl-phenyl)-4-(I -n HO /Hpentyl-indol-4-yl)-5 N SH Nz \ mercapto-[1,2,4] O - Ntriazole OH -NOH
N-NH
C:NRPonb\DCC\REC\40756|J _ .DOC-1/1012112 -223 No. Structure Tautomeric Structure Name r NN3-(2,4-dihydroxy-5 199 N N ethyl-phenyl)-4-( 1-n HO / HO / hexyl-indol-4-yi)-5 NrSH N S mercapto-[1,2,4] / triazole OH N-N OH N-NH N-4 3-(2,4-dihydroxy-5 N N cyclopropyl-phenyl) 200 4(-l HO / HO H 0 N methylcyclopropyl) N SH N S indol-4-yi)-5 H N-N H N-NH mercapto-[ 1,2,4] triazole O 0 N N 3-(2,4-dihydroxy-5 201 cyclopropyl-phenyl) HO HO 4-(l-isopropyl-7 N S N methoxy-indol-4-yi) \ \ 5-mercapto-[1,2,4] OH N-N OH N-NH triazole N N 3-(2,4-dihydroxy-5 202 HO HO cyclopropyl-phenyl) 2 4-(1,2,3-trimethyl N N indol-5-yl)-5 O SH >==S mercapto-[ 1,2,4] OH OH LN triazole -N H 3-(2,4-dihydroxy-5 ethyl-phenyl)-4-(I 203 ( / isopropyl-7 NaO / \ N methoxy-indol-4-yl) \ S 5-mercapto-[ 1,2,4] OH N-N triazole disodium salt C NR~ortblDCC\EC',4U756IJ_ D OC.II-1121 - 224 No. Structure Tautomeric Structure Name 0 N, 0 ~ N N 3-(2,4-dihydroxy-5 204 1 . 1 l, ert-butyl-phenyl)-4 H O/\ HO / ((I -isopropyl-7 N N s methoxy-indol-4-yi) rSH 5-mercapto-[I1,2,4] OH N-N OH N-NH triazole
N
0 0 r SN ",N 3-(2,4-dihydroxy-5 ~. / I / cyclopropyl-phenyl) 205 HO / HO ,-4-(]1 -propyl-7 N N methoxy-indol-4-yi) OH N-N OH N-NH triazole N N 206 HOHO / \3-(2,4-dihydroxy..5 methyl-3-ethyl -' N -~ N indol-5-yI)-5 OH~ SH OH s mercapto-[ 1,2,4] "N H triazole \N \N /H\ 3-(2,4-dihydroxy-5 207 HOc zz / HO N', ethyl-phenyl)-4-(1,3 1 15- N dimethyl-indol-5-yl) X N 5-mercapto-[ 1,2,4] OH /N SH OH LN>= triazole N H
N
0 0 -~N N 3-(2,4-dihydroxy-5 208 ,./I,./ isopropyl-phenyl)-4 H O /\ HO 1/ (1 -isopropyl-7 Nr H- N f s methoxy-indol-4-yi) OH N-N OH N-NH triazole C. NRPonM\DCM~EC%407SI4- 1, DOC.I1110121112 - 225 No. Structure Tautomeric Structure Name \N \N / \ 3-(2,4-dihydroxy-5 209 HO HO ethyl-phenyl)-4-( 1 methyl-3-isopropyl -s N -~ N indol-5-yI)-5 OH ~,/>-SH OH LN>=smercapto-[ 1,2,4] NH triazole -\N \ N 210" HO HO " 3-(2,4-dihydroxy-5 210 HOethyl-phenyl)-4-(N K- N Nethyl-carbozoi-7-yi) N >==s 5-mercapto-[ 1,2,4] OH L 6 -S OHN N triazole N H OH OH -- ~NN N 3-(2,4-dihydroxy-5 211 ././ ethyl-phenyl)-4-(I HO /H 0 0 isopropyl-7 N >SHN s hydroxy-indol-4-yi) r-SH - -- S 5-mercapto-[ 1,2,4] OH N-N OH N-NH triazole 3-(2,4-dihydroxy-5 212 N -~ N ethyl-phenyl)-4-( 1 x/ ( 0'/ isopropyl-7-ethoxy HO / N- HO / N indol-4-yl)-5 rSH S mercapto-[ 1,2,4] OH N-N OH N-NH tizl N N 213 HO/ s"" HO / 3-(2,4-dihydroxy-5 213 HO ethyl-phenyl)-4-(1I,2 -~ -~ N dimethyl-indol-5-yi) I 5-mercapto-[ 1,2,4] 1/ SH OH Ntriazole OIH /-O N
H
C,%NRPonb~lOCCREC'UI75 M14 1 DOC- li10/2012 - 226 No. Structure Tautomeric Structure Name N- N 214 HOethyl-phenyl)-4-(N N methyl-indol-5-yI) NN 5-mercapto-[I1,2,4] OH S OH rL > S triazole HH HO0 3-(2,4-dihydroxy-5 215 HO HO . ~ .~~ ethyl-phenyl)-4-(2 INzo methyl-7-methoxy N N )=s benzofuran-4-yI)-5 OH NI/2-SH OH N-. N mercapto-[I1,2,41 N H triazole 216 O HOethyl-phenyl)-4 (benzofuran-5-yI)-5 - N /-S N / SH mercapto-[ 1,2,4] OH >SHOH N- triazole TN 3-(2,4-dihydroxy-5 217 HO HON ethyl-phenyl)-4-(2 HO, O r methyl-1,3 - N benzoxaz-5 -yi)-5 I S N mercapto-[ 1,2,4] O N-N OH -SH triazole N N / ~ HO /3-(2,4-dihydroxy-5 218 HO -. isopropyl-phenyl)-4 -s -~ N (1,3-dimethyl-indol SHN>= 5-yI)-5-mercapto OIH -H OH N N [1,2,4] triazole
H
C kNRPonblDCCRECi4B)756 II IOOC-1112012 - 227 No. Structure Tautomeric Structure Name \N \N / \ 3-(2,4-dihydroxy-5 219 O HOcyclopropyl-phenyl) 219 O ~ / "" HO4-(1,3-dimethyl N - N indol-5-yI)-5 LI >==s mercapto-[ 1,2,4] OH /N-N OH "N triazole -N H N N HO' 3-(2,4-dihydroxy-5 220 HO HO ~ethyl-phenyl)-4-( 1,3 I~ N4 N dimethyl-indol-5-yi) OH I = 5-hydroxy-[I1,2,41 OH />-O OH LN triazole -N H N- N / \ 3-(2,4-dihydroxy-5 221 HO /HO isopropyl-phenyl)-4 N (N-methyl-indol-5 N N== yl)-5-mercapto OH -SH OH N[1,2,4] triazole H \N \N / ~' HO / 3-(2,4-dihydroxy-5 222 HO isopropyl-phenyl)-4 1. N (1 ,2-dimethyl-indol -~ N 5 -yi)-5-mercapto OH r'LN OH >== [1,2,4] triazole
H
C:\NRPonbl\DCC\REC\4075614_ .DOC-1/1012012 - 228 No. Structure Tautomeric Structure Name N N HO 3-(2,4-dihydroxy-5 223 HO HO isopropyl-phenyl)-4 (1,3-dimethyl-indol N N5-yi)-5-hydroxy OH N OH OH >=N[1,2,4] triazole -N HN N N N HO" 3-(2,4-dihydroxy-5 224 HO HO cyclopropyl-phenyl) 11 N 4-(I-methyl-indol-5 N N yl)-5-mercapto OH N SH OH >S [1,2,4] triazole OH /-H OH N N H HN- HN HO HO 3-(2,4-dihydroxy-5 225 isopropyl-phenyl)-4 N N (I H-indol-5-yi)-5 SH >=S mercapto-[1,2,4] OH / OH LN triazole N H N N 3-(2,4-dihydroxy-5 226 HO HO isopropyl-phenyl)-4 (I -methyl-indol-5 N N yl)-5-hydroxy OH N OH OH 1N [,2,4] triazole
H
C VNRPonbl\DCCREC41)7.%14- I OC-1/11fl21 - 229 No. Structure Tautomeric Structure Name 27 HO - " HO (I -ethyl-indol-S-yI) 5-mercapto-[ 1,2,4] N \ -S H N -SH triazole OH N- H OH N-N N N 3-(2,4-dihydroxy-5 228 isopropyl-phenyl)-4 HO HO/ (I -propyl-indol-5 HO HOyI)-5-mercapto - N .- N [1,2,4] triazole OH N-N OH N-N CF CF 3 N--( 3-(2,4-dihydroxy-5 29 HO /\ N HO/ N isopropyl-phenyl)-4 229 (1 -methyl-2 K N K Ntrifluoromethyl HO SHH benzimidazol-5-yi) Hu N_ N5-mercapto-[1,2,4] H triazole N- N- 230 /H\ 3-(2,4-dihydroxy-5 230 isopropyl-phenyl)-4 I K. (1 -methyl-indazol-5 NN yI)-5-mercapto HO / SH O s [1,2,4] triazole N SH HO NH HO ~ N H/ \N~ HO N HO3-(2,4-dihydroxy-5 231 Kisopropyl-phenyl)-4 KN N (I1-methyl-indazol-6 SH HOyi)-5-mercapto H/>HO N N >=s 1,2,4] triazole N
H
C kNRPonbIXDCCxREC'4)75614 I DOC. 1/1020)12 -230 No. Structure Tautomeric Structure Name / 3-(2,4-dihydroxy-5 232 - /isopropyl-phenyl)-4 HO / HO Z (1 -isopropyl-indol-4 N OHN~f: yI)-5-hydroxy OH N-N OH N-NH [,,]tizl / \ 3-(2,4-dihydroxy-5 233 HO N . HO N.isopropyl-phenyl)-4 N N (1 ,3-benzodiaxol-5 / -SH S y)-5-mercapto OH N-N OH N-NH I24tizl HO HO/ 3-(2,4-dihydroxy-5 234 HO O isopropyl-phenyl)-4 NN (indan-5-yi)-5 I 1 -. triazole OH N-N OH N-erato[,24 /N /N 235 N HO 3-(2,4-dihydroxy-5 235 isopropyl-phenyl)-4 N (2-methyl-indazol-6 N H HO \ yi)-5-mercapto HO N >= [1,2,4] tizl N H 00-, HO / \ NH HO /\ NH 3-(2,4-dihydroxy-5 236 ethyl-phenyl)-4-(3 H LN SHO N =Sbenzo[1,4]oxazin-6 N H [1,2,4] triazole C-NRPorbl\DCC\REO4C75614_I DOC-1/10/2.12 -231 No. Structure Tautomeric Structure Name 00 HNHN 3-(2,4-dihydroxy-5 237 H NH H NH ethyl-phenyl)-4-(2 oxo-1,3-dihydro N benzoimidazol-5-yl) NZ S5-mercapto-[ 1,2,4] HO N N N triazole N H H /3-(2,4-dihydroxy-5 238 HON H / N isopropyl-phenyl)-4 (2H N N benzo[1,4]oxazin-6 HO I SH HO yl)-5-mercapto N WN [1,2,4] triazole H
N
4-Ethyl-6-[5 / / mercapto-4-(l HO HO ,- methyl-2,3-dihydro 239 II H-indol-5-yl)-4H N N [1,2,4]triazol-3-yl] OH N OH IN S benzene- 1,3-diol H 0 O HN HN 5-(3-(5-ethyl-2,4 dihydroxyphenyl)-5 240 HO mercapto-4H- 1,2,4 N S HO triazol-4-yl)indolin SN- s 2-one OHOH N-NH HN4 HN4 NH NH 5-(3-(5-ethyl-2,4 dihydroxyphenyl)-5 241 1 mercapto-4H- 1,2,4 HO / N HO triazol-4-yl)-I H SH N S g benzo[d]imidazol N-NN-NH 2(3H)-one
OOH
C \NRPonbM\CC\RECU756 14_1 DOC-l/l(1f2012 - 232 No. Structure Tautomeric Structure Name NN 5-(3-(5-ethyl-2,4 242 dihydroxyphenyl)-5 HO mercapto-4H-1 ,2,4 HO 7N HO 7triazol-4-yi)-I \/ >SH N S methylindolin-2-one OHN-N O H N-NH 0 0 4-isopropyl-6-(5 NN_, mercapto-4-(4 11 propyl-3 ,4-d ihydro 243 HO /HO /2H \ ,S N s benzo[b][1,4]oxazin \f 6-yI)-4H-1,2,4 O -NH N-NH triazol-3-yI)benzene I ,3-diol O~riO0y0 \NH NH 6-(3 -(5 -ethyl -2,4 HO HO dihydroxyphenyl)-5 244 1mercapto-4H- 1,2,4 - N - N triazol-4-yI)-2H />- S >=SH benzo[b][I1,4]oxazin OH N- N OH N-NH 3(4H)-one 6-(3 -(5 -ethyl -2,4 245 s\. S dihydroxyphenyl)-5 HO .. HO" mercapto-4H-I,2,4 o r triazol-4-yI)-3 - N - N methylbenzo[d]thiaz I ,)-SH N - H o-(H OH N-N OH N-NH o-(H-n HN--e HN_ / 6-(3 -(5 -ethyl -2,4 S S dihydroxyphenyl)-5 246 HO" MH mercapto-4H-I,2,4 triazol-4 - N />S N )r-SH yI)benzo[d]thiazol OHN H N- H 2(3 H)-one ClN fb0CW'0%4 I DOC.1110t212 -233 No. Structure Tautomeric Structure Name 247 \ 04(-3 r (diethylamino)-4 NO N\ _ N -N methoxyphenyl)-5 / NH N mercapto-41-- 1,2,4 HO WN>N ' N > s triazol-3-yi)-6 H ethylbenzene- 1,3 diol 248\0\ -4(-N HO~ /? H \ isopropyl-N NO N O -N propylam ino)-4 HO /N MH N methoxyphenyl)-5 No N >N H N = mercapto-4H-1,2,4 H triazol-3-yi)-6 ethylbenzene- 1,3 diol 249\b\ -4(-N / / isopropyl-N HO/\ N HO/ N SH methylamino)-4 N N methoxyphenyl)-5 No NL/S HO N, = ecpt-H124 H -N N mrat-H124 H triazol-3-yI)-6 ethylbenzene- 1,3 diol 250 \04-(4-(3-(N-ethyl-N NO /\ N~HO /\ N methylamino)-4 NO - NO methoxyphenyl)-5 K N K' N mercapto-4H- 1,2,4 HO / _SH HO N, - s triazol-3-yI)-6 H ethylbenzene- 1 ,3 diol C VNRPof1bIhfCC\RErCO75I4_ I DOC- 1/ 1012012 -234 No. Structure Tautomeric Structure Name 251 \0\ -(-3 / / (dimethylamino)-4 HON\ HO N methoxyphenyl)-5 "N N "'~N mercapto-4H- 1,2,4 HO N S HO NI >triazol-3-yI)-6 H ethylbenzene- 1,3 diol 252 // 4-(4-(3 HO / N HO / N\ (dimethylamino)phe "N N 's Nnyl)-5-mercapto-4H N N H ethylbenzene- I ,3 diol 253 \0\O4-(4-(3 -(N -ethyl -N N isopropylamino)-4 HO / N HO / \ N methoxyphenyl)-5 N ' N mercapto-4H- I ,2,4 I/ SH H -~>Z HO N~.. N> O triazol-3-yI)-6 H ethyl benzene- 1,3 diol 254 4-ethyl-6-(5 HO /\ N HO /\ N mercapto-4-(3 N "N N(pyrrolidin-l HO / SH NyI)phenyl)-4H-I,2,4 H triazol-3-yi)benzene I ,3-diol 255 \\04-ethyl-6-(5 HO~ / \ N O \ N mercapto-4-(4 HO N- _H methoxy-3 N N morpholinophenyl) HO N 4H-1NN HH ~,2,4-triazol-3 N H yI)benzene-1I,3-diol C \NRPonbIflCMCW0'475614_ IDOC- I/ 0/20 12 - 235 No. Structure Tautomeric Structure Name 256\0\ -4(-N HO/ N HO/\ isopropyl-N r propylamino)-4 N N methoxyphenyl)-5 HO N.../.N S HO N =s mercapto-4H-1,2,4 H triazol-3-yI)-6 isopropyl benzene I ,3-d jot 257 \\04-(4-(3-(N-methyl HO N-propylamino)-4 HO/ N /\ N HO HOmethoxyphenyl)-5 N KN mercapto-4H-I1,2,4 Ho / SH HO >=s 3-l)6 HO~ N N triazol-3y)6 H ~isopropyl benzene 1,3 -d jot 258 \04-(4-(3-(N-methyl HO N~HC/ \ N-ethylamino)-4 - 1 methoxy-phenyl)-5 I N N -s mercapto-4H-I1,2,4 1/ SH HO N HO W- />- NH triazol-3-yi)-6 isopropylIbenzene 1,3-d jot 259 AN WN4(-4 HO HO \o (dimethylam ino)-3 HO 0 -O\ / 0 -0 methoxyphenyl)-5 K N K' N mercapto-4H- 1,2,4 / - SH HOSN HO W_.. N > O N triazol-3-yi)-6 H ethylibenzene- I ,3 diol C:NRPortbl\DCC\REC\407%14_ .DOC-110120I2 -236 No. Structure Tautomeric Structure Name 260 0H N O -- I HO N SH HO N N H 261 HO NH2 HO NH 2 4-(4-(3 HONH H N am inophenyl)-5 N KN mercapto-4H-1,2,4 HO / SH HO N triazol-3-yi)-6 NN N-- N H ethylbenzene-1,3 diol 262 HO _7 HO/ N N HO SH HO -=S N N H 263 o 4-(4-(3-(N-isopentyl / \ H N N-methylamino)-4 N- methoxyphenyl)-5 SH HO s mercapto-4H-1,2,4 triazol-3-yl)-6 isopropylbenzene 1,3-diol 264 0 NH HO /\ NH HO N C O N HO / SN HO N N H CANRPonbllCCRCl07%1I!I DOC 110120 12 - 237 No. Structure Tautomeric Structure Name 265 \ 04(-3(-2 H HO\ N (dimethylamino)ethy -0 I)-N-methylamino) / SH 4-methoxyphenyl)-5 N mercapto-4H- 1,2,4 triazol-3-yI)-6 isopropylbenzene I ,3-diol 266 \04(4(-(-2 H / \ H /\ N methoxyethyl)-N I I 3 methylamino)-4 N N N -4/ SH HO >=smethoxyphenyl)-5 N mercapto-4H- I ,2,4 triazol-3-yI)-6 isopropyl benzene 1,3-diol 267 \ -4(-N H / \ ' / \(cyclopropylmethyl) -N N-methylamino)-4 H / N s methoxyphenyl)-5 N H mercapto-4H- 1,2,4 triazol-3-yi)-6 isopropyl benzene 1,3-diol 268 "a4-(4-(3-(N-butyl-N / H /\ N methylamino)-4 I - I ~methoxyphenyl)-5 HO SNH ~ > mercapto-4H-1,2,4 N triazol-3-yi)-6 isopropyl benzene I ,3-diol CvINRPon1blDCC'REC40756I4_ i DOC.w/1012 - 238 No. Structure Tautomeric Structure Name 269 0\04-(4-(3-(N-isobutyl HO /\ N HO /\ N N-methylamino)-4 0 methoxyphenyl)-5 N N> smercapto-4H- 1,2,4 HO N -/ SH HO) N NN H triazol-3-yI)-6 isopropylbenzene I ,3-diol 270 \\14-(4-(3-(N-(2-(I H H /\ N /\ N imidazol- I-yi)ethyl) I N \ N-methylamino)-4 HO I SH HI)methoxyphenyl)- H mercapto-4H- 1,2,4 triazol-3-yI)-6 i sopropyl benzene 1,3-diol 271 4-(4-(3-(N-methyl 0/ HO /\ N HO /\ N N-propylamino)-4 HO N O- m ethoxyphenyl)-5 N N> smercapto-4H-1,2,4 HO / SH HO N Ho N Ntriazol-3-yi)-6 N H isopropylbenzene 1,3-diol 272 \ S4(-3 HO i\ H/ \ N (dimethylamino)-4 HO - H - (methylthio)phenyl) "N N 'N~ N 5-mercapto-4H H./ SH /-HO tiz-3y)6 HO N N- N 1 ,2,4-tizl3y)6 H isopropylbenzene I ,3-diol C kNPPornbl\flCCU0475614 I DOC111012112 - 239 No. Structure Tautomeric Structure Name 273 HON H 4-(4-(3-([IH-pyrrol HO0 1 -yI)phenyl)-5 N N N hydroxy-4H-I1,2,4 HO N L/> OH N 1N>= triazol-3-yi)-6 H ethylbenzene- 1,3 diol 274 N/ = 4-(4-(3 -(1I H HO N HO "' N I;) ;" imidazol-1 "N N N yI)phenyl)-5 HO / 1 > SH HO N LN > mercapto-4H-1,2,4 N H triazol-3-yl)-6 isopropyl benzene I ,3-diol 27500 H / N HO / \ N IN N HO N HO >-N N H 276N HO H N 'KN HO N . > SH HO N == 277 N N 4(-4 HO / N HO / (d imethylamino)phe nyl)-5-mercapto-4H >1 I ,2,4-triazol-3-yi)-6 H / SH H ethylbenzene-I1,3 N N Ndiol C INR~onbrDfCC\REC\4075624-I DOC- 111012012 - 240 No. Structure Tautomeric Structure Name 278 j 4(- N N (diethylamino)pheny HO ~~, \I)-5-mercapto-4H HO HO ,2,4-triazol-3-yi)-6 N ethylbenzene- 1,3 HO ~ / SH s = diol 279 0,4-ethyl-6-(5 No mercapto-4-(4 morphol inophenyl) HO / \ HO / 4H-1,2,4-triazol-3 ""' NK ' NyI)benzene-I1,3-diol HO N /NHH N N H 28I / - 4-(4-(4-( I H N N imidazol-I / \ / \yI)phenyl)-5 HO HO mercapto-4H- 1,2,4 K' NK' Ntriazol-3-yl)-6 HO 1/ SH HO ethylbenzene-I,3 N diol 281 04-(4-(2,5 -diethoxy-4 N0 No morpholinophenyl) HO HO\ 5-mercapto-4H I ,2,4-triazol-3-yI)-6 0- N 0-\ ethylbenzene-l1,3 I,~~ SHHs...) diol *HO N/ r>S ONI
N
C\NRPonbI\DCC\REC075614_.DOC-1/10O202 -241 No. Structure Tautomeric Structure Name 282 '=~D- 4-(4-(3-(l H-pyrrol N N I -yl)phenyl)-5 HO / mercapto-4H-1,2,4 N SH S N S triazol-3-yi)-6 OH N-N OH N-NH ethylbenzene-l,3 diol 283 N/ N 4-(4-(4-(1 H-pyrazol N N I-yl)phenyl)-5 mercapto-4H- I,2,4 HO Htriazol-3-yi)-6 N HSH N N s ethylbenzene-1,3 OH N-N OH N-NH diol 284 NH 2
NH
2 4-(4-(4-(amino)-3 H \ OH H OH hydroxyphenyl)-5 HO HO mercapto-4H-1,2,4 N SH N triazol-3-yi)-6 OH N-N OH N-NH ethylbenzene-1,3 diol 285 NH NH 4-(4~(4 \ OH \ OH (methylamino)-3 OH OH hydroxyphenyl)-5 N / N mercapto-4H- 1,2,4 OH /Ng--SH OH/N S triazol-3-yl)-6 OH N-S OH N-NH ethylbenzene- 1,3 diol C:\NRPOrtbI\DCCREO45C14_ IDOC-1/10/2012 - 242 No. Structure Tautomeric Structure Name 286 N' ' 4~(4~(4~ (dimethylamino)-3 HO H methylphenyl)-5 mercapto-4H- 1,2,4 N -A N N >O=N triazol-3-yl)-6 OH N N ethylbenzene- 1,3 diol Exemplary pyrazole compounds of the invention are depicted in Table 6 below, including tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof. Table 6 No. Structure Name HO 0 4-[3-(N,N-diethylamino)-4-methoxy 287 N phenyl]-3-(5-ethyl-2,4-dihydroxy-phenyl) 5-mercapto-2H-pyrazole HO ~ HN N SH H 0 ~ /4-[3-(isopropyl-propyl-amino)-4-methoxy 288 N phenyl]-3-(5-ethyl-2,4-dihydroxy-phenyl) HO 5-mercapto-2H-pyrazole HNII N SH HO 0 4-[3-(isopropyl-methyl-amino)-4-methoxy 289 \ / N phenyl]-3-(5-ethyl-2,4-dihydroxy-phenyl) HO - 5-mercapto-2H-pyrazole HN N SH HO 0 -- /---- 4-[3-(ethyl-methyl-amino)-4-methoxy 290 \ / N phenyl]-3-(5-ethyl-2,4-dihydroxy-phenyl) HO -5-mercapto-2H-pyrazole HN" N
SH
C \NRoNWIDCCREC\4I75614 I DOC-1/ 10120)12 - 243 No. Structure Name HO0 -/ \ /4-[3-(N,N-methylamino)-4-methoxy 291 \ /N\ phenyl ]-3 -(5 -ethyl -2,4-d ihydroxy-phenyl) HO 5-mercapto-2H-pyrazole HN~ N SH HO -/ \ /4-[3-(N,N-methylamino)-phenyl]-3-(5 292 \ /N ethyl1-2,4-d ihyd roxy-phenyl)-S -mercapto 2H-pyrazole HO HN N SH HO N -/ \4-[4-(N,N-methylamino)-3-methoxy 293 0 phenyl] -3 -(5 -ethyl -2,4-d ihydroxy-phenyl) HO 5-mercapto-2H-pyrazole HN~ N SH HO 0 -/ ,r-4-[3-(isopropyl-ethyl-amino)-4-methoxy 294 \ /N phenyl] -3 -(5 -ethyl -2,4-d ihydroxy-phenyl) 5-mercapto-2H-pyrazole HO0 HN N 7 SH HO -/ ~ ~4-[3-(pyrrol idin- 1 -yI)-pheriyl]-3-(5-ethyl 295 No/ 2,4-dihydroxy-phenyl)-5-mercapto-2H HO pyrazole HN N 7 SH H 0 - / \4-[3-(isopropyl-propyl-amino)-4-methoxy 296 N /\ phenyl ]-3 -(5 -i sopropyl1-2,4-d ihydroxy HO -phenyl)-5-mercapto-2H-pyrazole HO HO 0 4-[3-(methyl-propyl-amino)-4-methoxy 297 \ /N phenyl]-3-(5-isopropyl-2,4-dihydroxy Ho phenyl)-5-mercapto-2H-pyrazole HO N
S
C \NRPonbO\DCC\REC%40756 14 [ iDC mon12 - 244 No. Structure Name HO 0 - \ I4- [3 -(ethyl -methylI-am ino)-4-methoxy 298 \ /N phenyl ]-3 -(5- isopropy 1-2,4-d ihydroxy HO -phenyl)-5-mercapto-2H-pyrazole HN 1N SM H299 4-[3-(morpholino-I-yi)-4-methoxy-phenyl] ~' N"~b3-(5-ethyl-2,4-dihydroxy-phenyl)-5 299 O mercapto-2H-pyrazole HO -/ \ I4-[3-(ethyl-methyl-amino)-4-methoxy 300 \ /N phenyl]-3-(5-isopropyl-2,4-dihydroxy Ho phenyl)-5-hydroxy-2H-pyrazole HN N 7 OH HO -/ \ ,,r-4-[3-(N,N-diethyl-amino)-4-methoxy 31N phenyl]-3-(5-ethyl-2,4-dihydroxy-phenyl) 5-hydroxy-2H-pyrazole 4-[3-(pyrrol idin-1I-yI)-4-methoxy-phenyl]-3 32NoJ (5-ethyl-2,4-dihydroxy-phenyl)-5-hydroxy 2H-pyrazole H 0 -/ \ /4-[3-(ethyl-methyl-amino)-4-methoxy 303 N phenyl]-3-(5-cyclopropyl-2,4-d ihydroxy HO /phenyl)-5-hydroxy-2H-pyrazole HNN 7 O HO 0 / \ / 4- [3 -(ethyl -methylI-am ino)-4-methoxy 34N phenyl]-3-(5-cyclopropyl-2,4-dihydroxy HO phenyl)-5-mercapto-2H-pyrazole HN, S
"IN
C \NRNOnbMCCRE0,4076IJ_1 DOC.1/10/2fl12 - 245 No. Structure Name HO0 N Phosphoric acid mono f4-[3 -(ethyl -methylI 305 /amino)-4-methoxy-phenyl]-3-(5-isopropyl HO -2,4-d ihydroxy-phenyl)-2H-pyrazol-5-yI} HNN ester HO 0 \P= I H / \ HO 0 \ - N\ Phosphoric acid 14- [3 -(ethyl -methyl 306 HO -am ino)-4-methoxy-phenyl]-3 -(5-isopropyl HNy 0 2,4-dihydroxy-phenyl)-21I-pyrazol-5-yl} N HO P~oester ethyl ester 00 ___ - /4-[3-(N,N-methylamino)-4-methoxy 307 N /phenyl]-3-(5-isopropyl-2-hydroxy-4 307 / dimethy lam inocarbamoy loxy-pheny l)-5 HO -mercapto-2H-pyrazole HN SH 0 - 0 4-[3-(pyrrol idin- I -yI)-4-methoxy-phenyl]-3 308 ~ \ No (5-isopropyl-2-hydroxy-4 d imethy lam inocarbamoylIoxy-phenyl)-5 H -mercapto-2H-pyrazole HN., N SH HO - 4-[3-(N,N-methylamino)-4-methoxy / /9 N phenyl]-3-(5-isopropyl-2,4-dihydroxy 309 phenyl)-5-(2-hydroxy-ethylsulfanyl)-2H HO -OH pyrazole HN S HO 310 ~ /N 4-( I -isopropyl- I H-indol-4-yI)-3-(2,4 HO HO d ihydroxy-phenyl)-5 -mercapto-2H-pyrazole H Nz "N SH H 311 /NH 4-( I H-indol-4-yI)-3-(2,4-dihydroxy HO -phenyl)-5-mercapto-211-pyrazole HN \ N
SH
C:\NRPonlbIflCC\REC,4075614_ IDOC-I1110/2012 - 246 No. Structure Name HO0 - f \ f 4-[ -(2-methoxy-ethyl)- IH-indol-4-yI-3 312 \ /N (2,4-d ihydroxy-phenyl)-5-mercapto-2H HO _ .pyrazole HNN H HO -/ \4-( I -isopropyl- I H-i ndol-4-yI)-3 -(5 -ethyl 313 \ /N 2,4-dihydroxy-phenyl)-5-mercapto-2H HO pyrazole HN N SH NN 314 \ / -(2,4-d ihydroxy-phenyl )-5 -mercapto-2H HO - pyrazole IkHNI 7 SH HO 315/ N 4-(1I -propyl- I H-indol-4-yI)-3-(5-ethyl-2,4 15 \ /dihydroxy-phenyl)-5-mercapto-2H-pyrazole HO HNX 7 SH HO 31 N 4-( I -ethyl- I H- indol -4-yl)-3 -(5 -ethyli-2,4 16 \ N' ~d ihydroxy-phenyl)-5-mercapto-2H-pyrazole HO HN~ 11 SH HON -/ \ I4-(I,2,3-trimethyl- IH-indol-4-yI)-3-(5 317 \ /ethyl -2,4-d i hyd roxy-pheny l)-5 -mercapto HO -2H-pyrazole HN N SH HO H HO N -/ \ I4-(2,3-dimethyl- IH-indol-4-yI)-3-(5-ethyl 318 \ /2,4-d ihydroxy-phenyl)-5 -mercapto-2H pyrazole
HO
HN" N
SH
C \,'4RPoibIDCGREC4O07614I DOC.I/I(1f2012 - 247 No. Structure Name HO 319 4-( I -ethyl- I H-benzoimidazol-4-yl)-3-(5 319 /N ~ ethyl-2,4-di hydroxy-phenyl)-5 -mercapto 2H-pyrazole HON HNN S HOC HO 320 / / \ /4-(I -carboxy-2,3-dimethyl- IH-indol-5-yl) 320 3-(5-ethyl-2,4-dihydroxy-phenyl)-5 HO mnercapto-2H-pyrazole HN~ N SH HO\ 4-( I -ethyl-2-methyl- I H-benzoimidazol-6 321 N yl)-3-(5-ethyl-2,4-dihydroxy-phenyl)-5 HO mercapto-2H-pyrazole HN~ N SH HO - 4-(]I -isopropy-7-methoxy- I H-indol-4-yl)-3 322 \ /N (5-ethyl-2,4-dihydroxy-phenyl)-5-mercapto HO 2H-pyrazole HN N SH HO N 4-( 1 -propy-2,3-dimethyl- I H-indol-5-yl)-3 323 - / \ I(5 -ethyl -2,4-d ihydroxy-phenyl)-5 -mercapto \ / 2H-pyrazole HO HN~ N, SH HO -/ \4-( 1-ethyl- I H-indol-4-yl)-3-(5-isopropyl 324 \ /N' 2,4-dihydroxy-phenyl)-5-hydroxy-2H HO pyrazole HN N OH 32/5 4-(] I-ethyl- I H-indol-4-yI)-3-(5-cyclopropyl 325 \ N' 2,4-dihydroxy-phenyl)-5 -hydroxy-2H __ pyrazole HO HNI,
OH
C \NRPornbIOCCAfEC\4O75614_1 fOC.II111012 - 248 No. Structure Name HON 326 \ / / ~4-(1,2,3-trimethyl- IH-indol-5-yi)-3-(5 326ethyl-2,4-d ihydroxy-phenyl )-5 -am ino-2H HO pyrazole HN~ N NH, HO0 / \ 4-( I -isopropyl-7-methoxy- I H-indol-4-yI)-3 327 \ /N (5 -ethyl -2,4-d ihydroxy-phenyl)-5 -am ino HO 2H-pyrazole HN~ N NH, HO,0 32 / N 4-( I -isopropyl-7-methoxy- I H-indol-4-yI)-3 328 / N(5-isopropyl-2,4-dihydroxy-phenyl)-5 HO hydroxy-2H-pyrazole HNN I N OH HO N -/~ I4-(1,3-dimethyl- IH-indol-5-yi)-3-(5 329 \ /isopropyl-2,4-dihydroxy-phenyl)-5 HO -hydroxy-2H-pyrazole HN~ N OH HO N -/ \ I4-(l -methyl-1IH-indol-5-yI)-3-(5-isopropyl 330 \ /2,4-d ihydroxy-phenyl)-5-hydroxy-2H pyrazole H0 HNII N OH HON -/ \ I4-(l -methyl- IH-indol-5-yI)-3-(5-isopropyl 331 \ /2,4-dihydroxy-phenyl)-5-mercapto-2H HO - pyrazole HN N SH HO N -/ \ I4-(l -methyl- IH-indol-5-yl)-3-(5-isopropyl 332 \ /2,4-d ihydroxy-phenyl )-5-am ino-2H pyrazole
HO
HN 11 N NH, C:\NRPonl\DCC0RE\40756 14 1,I DOC- ItI1,/201 2 - 249 No. Structure Name HO 0 -/ \4-(7-methoxy-benzofuran-4-yi)-3 -(5 333 0 isopropyl-2,4-dihydroxy-phenyl)-5 hydroxy-2H-pyrazole HO HN N 7 OH HO /0 4-(5-methoxy-naphthalene- I-yI)-3-(5 334 \ /isopropyl-2,4-d ihydroxy-phenyl)-5 mercapto-2H-pyrazole
HO
HN~ N SH HO 33 / 0 4-(benzo[ I ,4]dioxin-5-yI)-3-(5-ethyl-2,4 \ / dihydroxy-phenyl)-5-mercapto-2H-pyrazole 1O0 HN, I- SH HO /36 4-(acenaphthen-5-yl)-3-(5-isopropyl-2,4 336 \ /dihydroxy-phenyl)-5-hydroxy-2H-pyrazole HO HNII N OH HO 33 N NH 4-(9H-purin-6-yI)-3-(5-isopropyl-2,4 337 / - NHdihydroxy-phenyl)-5-hydroxy-2H-pyrazole HO N HN~ "I OH HO 338 \ 4-(benzothiazol-4-yI)-3-(5-isopropyl-2,4 dihydroxy-phenyl)-S-mercapto-2H-pyrazole Fl N H N7 SH HO -/ \4-(7-fluoro-naphthylen- I-yi)-3-(5 339 \ /cyclopropyl-2,4-dihydroxy-phenyl)-5 mercapto-2H-pyrazole HO 0 H"N SH F C ANRPonbKDfCCREC4075614I .DOC -/102012 - 250 No. Structure Name HO N 340 4-(qu inol in-4-yl)-3 -(5-isopropyl-2,4 340 \ /dihydroxy-phenyl)-5-mercapto-2H-pyrazole HO HN~ N SH HO N -/ \4-(I -methyl- IH-indol-5-yl)-3-(5-isopropyl 341 2,4-d ihydroxy-phenyl)-5-carbamoyloxy HO -2H-pyrazole HN 0 ________ H HO N -/ ~'4-(] -methyl- IH-indol-5-yI)-3-(5 342 /cyclopropyl-2,4-d ihydroxy-phenyl)-5 HO -carboxyam ino-2H-pyrazole HN N N HO -/ ""'4-(l -methyl- I H-indol-5-yl)-3-(5-methoxy 343 HO2,4-dihydroxy-phenyl)-5-aminosulfam ido HO 2H-pyrazole HN 7 N NH N 0 00 34 - / 4-(4-methoxy-naphthalene- I-yi)-3-(5 344 \ /isopropyl-2-hydroxy-4-ethoxycarbonyloxy HO phenyl)-5-mercapto-2H-pyrazole HNN I SH FNH - /\4-(naphthalene- I-yl)-3-(5-isopropyl-2,4 345 0 " / _ ethylcarbamoyloxy-phenyl)-5 -mercapto -- OHN\N S 2H-pyrazole C:NRPotbI\DCC\'RE4075614_ I DOC-1/10/20l2 -251 No. Structure Name NWH - / 'N 4-(1 -methyl-I H-indol-4-yl)-3-(5-isopropyl 346 _ 2,4-ethylcarbamoyloxy-phenyl)-5 HNNN dimethylcarbamoylsulfanyl-2H-pyrazole r NH N 0 0 / _ N 4-(1,2-dimethyl- I H-indol-4-yi)-3-(5 347 Q isopropyl-2,4-ethyloxycarbonyloxy - _ Hphenyl)-5-ethoxycarbamoylsulfanyl-2H o HN S pyrazole 34 HO 4-(naphthalen- 1 -yl)-3-(5-ethyl-2,4 dihydroxy-phenyl)-5-hydroxy-2H-pyrazole OH OH N-NH HO F 349 4-(2-methyl-4-fluorophenyl)-3-(5-ethyl-2,4 dihydroxy-phenyl)-5-mercapto-2H-pyrazole HO HN N SH HN HO 0 350\4-(3,5-dimethoxyphenyl)-3-(5-ethyl-2,4 350 /dihydroxy-phenyl)-5-amino-2H-pyrazole HO 0 HNN
NH
2 HO 4-[2-(1 H-tetrazol-5 -yl)-phenyl]-3 -(5-ethyl 351 \ H 2,4-dihydroxy-phenyl)-5-hydroxy-2H N pyrazole HO -- N HN OH Exemplary imidazolyl compounds of the invention are depicted in Table 7 below, including tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof.
C:MRPonbIOfCC\REC\4O756I4I1 DOC-1110/2012 - 252 Table 7 No. Structure Name \0 HO / \ N 1-(3-diethylamino-4-methoxy-phenyl)-2 352 mercapto-5 -(2,4-d ihydroxy-5 -ethyl -phenylI) N 1 H-imidazole HO I /IS / N 1 -[3 -(propyl-isopropylam ino)-4-methoxy 353 phenyl]-2-mercapto-5-(2,4-dihydroxy-5 N ethyl-phenyl)-IH-imidazole HO 0* / SH H /\ N 1-[3-(methyl-isopropylamino)-4-methoxy 354 Kphenyl]-2-mercapto-5-(2,4-dihydroxy-5 HO I >.....SHethyl-phenyl)- 1H-imidazole HO N 1 -[3 -(methylI-ethyl am ino)-4-methoxy 355 / phenyl]-2-mercapto-5-(2,4-dihydroxy-5 K N ethyl -phenyl)- IH-i midazol e HO I/_SH N HO / - \ N]-(3Adi methy lam ino-4-methoxy-pheny1)-2 356 mercapto-5-(2,4-d ihydroxy-5-ethyl-phenyl ) K N I H-imidazole HO /> SH HO / \ \ 1-(3Adi methy lam ino-phenylI)-2-mercapto-5 357 /(2,4-d ihydroxy-5-ethyl-phenyl)- I H K N imidlazole HO / SH C \,NRPonbW\CC\REC'4O756I4_ DOC.1110f01 2 -253 No. Structure Name H / \ O\ -(3 -methoxy-4-d imethy lam ino-phenyl)-2 358 -~mercapto-S-(2,4-dihydroxy-5-ethyl-phenyl) I I H-imidazole N *HO I/ SH N 0 HO / \ 1I-[3 -(ethyl -isopropy lam ino)-4-methoxy 360 phenyl]-2-mercapto-5-(2,4-dihydroxy-5 "" Nethyl-phenyl)- IH-imidazole HO / SH HO ~~ N -(3-pyrrol idin- I -yi-phenyl)-2-mercapto-5 361 I(2,4-d ihydroxy-5 -ethyl -phenyl)- I H N imidazole HO I/ S N 06 f HO /\ N I-[3-(propyl-isopropylamino)-4-methoxy 362 -~phenyl]-2-mercapto-5-(2,4-dihydroxy-5 N isopropyl-phenyl)- IH-imidazole HO / SH N \0 HO /\ N I-[3-(methyl-propylamino)-4-methoxy 363 -~phenyl]-2-mercapto-5-(2,4-dihydroxy-5 N isopropyl-phenyl)- I H-imidazole HO / -SH N \0 HO /\ N 1-[3 -(methylI-ethyl am ino)-4-methoxy 364 -~phenyl]-2-mercapto-5-(2,4-dihydroxy-5 N isopropyl-phenyl)- I H-im idazole NO / S N HO / NI-[3-(morpholino- 1 -yI)-4-methoxy-phenyl] 365 2-mereapto-5 -(2,4-d ihydroxy-5 -ethyl N k ~ N phenyl)-IH-imidazole HO / _SH C NRPonb\DCCREC,4075614_1 DOC-1/102112 -254 No. Structure Name 0 HO /\ N I-[3-(methyl-ethylamino)-4-methoxy 366 - .. '1phenyl]-2-hydroxy-5-(2,4-d ihydroxy-5 N. N isopropyl-phenyl)- I H-imidazole HO >_/OH \0 HO / \ N I -(3 -d iethy lam ino-4- methoxy-phenyl)-2 367 hyd roxy-5 -(2,4-d i hydroxy-5 -ethyl -phenylI) N- 0 H-imidazole IkON HO I/-O N \ HO / -\No~~I I-[3-(pyrrol idin- I -yi)-4-methoxy-phenyll-2 368 hydroxy-5 -(2,4-dihydroxy-5-ethyl-phenyl) II H-imidazole KN HO /-OH N \0 HO /\ N l-[3-(methyl-ethylamino)-4-methoxy 369 -phenyl]-2-hydroxy-5-(2,4-dihydroxy-5 N. N cyclopropyl-phenyl)- I H-imidazole HO /-OH I N \0 HO /\ N 1-[3-(methyl-ethylamino)-4-methoxy 370 -~pheriyl]-2-mercapto-5-(2,4-dihydroxy-5 N. N cyclopropyl-phenyl)- I H-imidazole HO / SH N HO I- ]-[3-(methyl-ethylamino)-4-methoxy 371 / ~zk phenyl]-2-phosphonooxy-5 -(2,4-dihydroxy N. N 5-isopropyl-phenyl)-lIH-imidazole HO / NZ--) _________N HOP___________________ C \NRI'onb\DCCREC\4075614_I DOC-1/10120 12 -255 No. Structure Name HO N ]-[3 -(methyl-ethylam ino)-4-methoxy 372 phenyl]-2-(ethoxy-hydroxy 372phosphoryloxy)-5 -(2,4-d i hyd roxy-5 HO I \-O isopropyl-phenyl)- IH-imidazole N HO-/ 0) \0 N1-(3 -d imethy lam ino-4-methoxy-phenyl)-2 37/ mercapto-5-(2-hydroxy-4 / dimethylcarbamoyloxy-5-isopropyl K N phenyl)-IH-imidazole HO / SH 0 / 1KJ -[3-(pyrrolidin- I-yi)-4-methoxy-phenyl]-2 374 mercapto-5-(2-hydroxy-4-isobutyryloxy-5 Kz N isopropyl-phenyl)- IH-imidazole *HO I "/ SH /1-(3 -d i methy lam i no-4-methoxy-phenyl )-2 HO _N(2-hydroxy-ethylsulfanyl)-5-(2,4 37 OH dihydroxy-5-isopropyl-phenyl)- I H K N imidazole HO / S HO UN1 -(I1-ethyl- I H-indol-4-yI)-2-mercapto-5 376 K N (2,4-dihydroxy-phenyl)- IH-imidazole HO >_/SH HO I-(I -isopropyl- 1 H-indol-4-yI)-2-mercapto 37K 5-(2,4-dihydroxy-phenyl)- IH-imidazole HO I/ SH N HO / NH 37 7 I-(] H-indol-4-yI)-2-mercapto-5-(2,4 378 N dihydroxy-phenyl)- IH-imidazole HO I/ SH _______ ___________________________C___ C '.NRPornblDCC'R\ 756 I! [ DOC. If/I0/2012 - 256 No. Structure Name 1 -[ 1 -(2-methoxy-ethyl)- I H-indol-4-yI]-2 39 HO N mercapto-5 -(2,4-d ihydroxy-phenyl)- I H / 7 imidazole N HO / SH HO I ~ -(I -isopropyl- IH-indol-4-yi)-2-mercapto 380 /75-(2,4-dihydroxy-5-ethyl-phenyl)-lI H "N N imidazole HO / SH -NN HO /;\ Nf I -(I -dimethylcarbamoyl- I H-indol-4-yI)-2 381 -~mercapto-5 -(2,4-dihydroxy-phenyl)- I H N imidazole N HO P N I -(I -propyl- I H-indol-4-yl)-2-mercapto-5 382 7(2,4-dihydroxy-5-ethyl-phenyl)- I H I imidazole N HO / NI -(I -ethyl- I H-indol-4-yl)-2-mercapto-5 383 /7(2,4-d ihydroxy-5 -ethyl -pheny I)- IH 'N N imidazole HO / SH N HO I -(I ,2,3-trimethyl- I H-indol-5-yl)-2 384 mercapto-5 -(2,4-d ihydroxy-5 -ethyl -phenyl) NI H-imidazole HO / SN C NRPortbhDCOREC4075614_ LDOC- I/11)12012 - 257 No. Structure Name HN HO I -(2,3-dimethyl- 1 H-indol-5-y!)-2-mercapto 385 5-(2,4-dihydroxy-5-ethyl-phenyl)- I H K N im idazole HO /-SH HO -~I -(I -ethyl- IH-benzoimidazol-4-yi)-2 386 N mercapto-5 -(2,4-d ihydroxy-5 -ethyl-phenyl) N IH-imidlazole HO I/ SH N H I -(I -carboxy-2,3-dimethyl- 1 H-indol-5-yI) 387 2-mercapto-5-(2,4-d ihydroxy-5 -ethyl K N phenyl)-IH-imidazole I / N__ HO /\ N., I -(I -ethyl-2-methyl- IH-benzoimidazol-6 388 -yI)-2-mercapto-5 -(2,4-d ihydroxy-5 -ethyl K N phenyl)-IH-imidazole HO / SH N \0 HO I -(I -isopropyl-7-methoxy- I H-indol-4-yI)-2 389 -~mercapto-5 -(2,4-d ihydroxy-5-ethyl-phenyl) K N HI H-imidazole HO I/ SH N N I -(1 -propyl-2,3-dimethyl- I H-indol-5-yl)-2 390 HO /\mercapto-5-(2,4-dihydroxy-5-ethyl-phenyl) I H-imidazole K' N HO I/ -SH C RPorb\DCREO4075614_LDOC.I11/2012 - 258 No. Structure Name HO N I -(I-ethyl-I H-indol-4-yl)-2-hydroxy-5-(2,4 391 dihydroxy-5-isopropyl-phenyl)-IH N imidazole HO OH N HO NI -(I-ethyl-I H-indol-4-yl)-2-hydroxy-5-(2,4 392 dihydroxy-5-cyclopropyl-phenyl)-I H N imidazole HO I/ OH N N HO I -(1,2,3-trimethyl- I H-indol-5-yl)-2-amino 393 5-(2,4-dihydroxy-5-ethyl-phenyl)- I H N imidazole HO / NH, N HO N I -(I -isopropyl-7-methoxy- I H-indol-4-yl)-2 394 -' amino-5-(2,4-dihydroxy-5-ethyl-phenyl) N IH-imidazole HO / NH2 N 0 HO N I -(I -isopropyl-7-methoxy- I H-indol-4-yl)-2 395 hydroxy-5-(2,4-dihydroxy-5-isopropyl N phenyl)-IH-imidazole HO /OH N N HO 1-(1,3-dimethyl- I H-indol-5-yl)-2-hydroxy 396 5-(2,4-dihydroxy-5-isopropyl-phenyl)- I H N imidazole HO / OH N N HO I -(1-methyl-I H-indol-5-yl)-2-hydroxy-5 397 (2,4-dihydroxy-5-isopropyl-phenyl)- I H N imidazole N HO
>_/OH
CMNPonbtOfCCkECW)75614_1 DOC-1/10f2012 -259 No. Structure Name N HO I -(1 -methyl- I K-indol-5-yi)-2-mercapto-5 398 -~(2,4-dihydroxy-5-isopropyl-phenyl)- I11 "N N imidazole HO / _SN N N HO I -(9-methyl-6,7,8,9-tetrahydro-5 H 399 -~carbazol-3 -yI)-2-mercapto-5-(2,4 N d ihyd roxy-5 -ethyl -phenylI)- 1 H-imidazole HO I/ SN N N HO 1 -(I1-methyl- I H-indol-5-yI)-2-amino-5-(2,4 400 - dihydroxy-5-isopropyl-phenyl)- I H "N N imidazole HO / NH 2 N \0 HO 0 \ I-(7-methoxy-benzofuran-4-yI)-2-hydroxy 401 5-(2,4-dihydroxy-5-isopropyl-phenyl)- I H N imidazole N \0 HO / 1I-(5-methoxy-naphthylen- I -yI)-2-mercapto 402 Ok5-(2,4-dihydroxy-5-isopropyl-phenyl)- I H N imidazole HO >SH HO / -\- 1 -(2,3-dihydro-benzo[ I ,4]dioxin-5-yl)-2 403 / -O mercapto-5-(2,4-d ihydroxy-5 -ethyl-phenyl) 0 IH-imidazole HO I/ SH N HO / ~1-(3-acenaphthylen-5-yl)-2-hydroxy-5-(2,4 404 /dihydroxy-5-isopropyl-phenyl)- I H "N N imidazole HO / C N1RPob\DCCREC4O)75%6t4-1DOC.III0/2012 - 260 No. Structure Name HO N HI-(9H-purin-6-yI)-2-hydroxy-5-(2,4 405 N7 dihydroxy-5-isopropyl-phenyl)- I H "N N imidazole HO /_OH HO / \ S I -(benzoth iazol-4-yi)-2-mercapto-5-(2,4 406 N N dihydroxy-5-isopropyl-phenyl)- IH HO / SH HO / ] -(7-fluaro-naphthylen- I-yI)-2-mercapto-5 407 f(2,4-dihydroxy-5 -cyc lopropyl-phenyl)- I H K N F imidazole HO /_SH HO N\ HOI -(quinol in-4-yl)-2-mercapto-5-(2,4 408 dihydroxy-5-isopropyl-phenyl)- IH "N N imidazole HO / >SH N HO 1 -(I -methyl-indol-5-yI)-2-carbamoyloxy-5 409 /(2,4-dihydroxy-5-isopropyl-phenyl)- I H N imidazole HO /- 0r N HO 1 -(I -methyl-indol-5-yl)-2-carboxyamino-5 410 f(2,4-dihydroxy-5-cycolpropyl-phenyl)- I H 'NN N imidazole HO />-NH H \ O N HO I -(1 -methyl- I H-indol-5-yl)-2 411 / I \~ am inosulfam ido-5-(5-methoxy-2,4 HO" N NHdihydroxy-phenyl)- I H-imidazole HO / NH
N,
CANRPorbM~CC\REC%407 %14_ 1 DOC.I1/112012 - 261 No. Structure Name \0 0~ 0 I -(4-methoxy-naphthylen- I -yI)-2-mercapto 412 )-5-(2-hydroxy-4-ethoxycarbonyloxy-5 0Nl" isopropyl-phenyl)- IH-imidazole O Ik / SH HO /> NN I -(naphthylen-1I-yi)-2-mercapto-5-[2,4-di 413 /N S (ethoxycarbamoyloxy)-5 -isopropyl-phenyl] QY0 1 H-imidazole -N I -(I-methyl- IH-indol-4-yI)-2 414 N dimethylcarbamoylsulfanyl-5-[2,4-di 0N /- (ethoxycarbamoyloxy)-5 -isopropyl-phenyl] y~ ~ kN H-imidazole / 71-(I,2-dimethyl- IH-indol-4-yi)-2 415 roNethoxycarbonylsulfanyl-5-[2,4-di // S(ethoxycarbonyloxy)-5 -isopropyl-phenyl] :yN -OIH-imidazole 416 HOI -(naphthylen- I -yi)-2-hydroxy-5-(2,4 N dihydroxy-5-ethyl-phenyl)- I H-imidazole 47 HO / ] -(2,5-dimethoxyphenyl)-2-amino-5-(2,4 1 0~-- dihydroxy-5-ethyl-phenyl)- IH-im idazole HO /-NH, CkNRPornbI\DCC\RECW(75614_I DOC-1/10/2012 - 262 No. Structure Name F H 1-(2-methyl-4-fluoro-phenyl)-2-mercapto-5 418 (2,4-dihydroxy-5-ethyl-phenyl)- I H N imidazole HO SH HO H-[2-(l H-tetrazol-5-yl)-phenyl]-2-hydroxy 419 N 5-(2,4-dihydroxy-5-ethyl-phenyl)-IH N N-N imidazole HO OH Preferred triazole compounds of the invention are those compounds that can form a tautomeric structure as shown below and as exemplified by the tautomeric structures shown in Table 5: R27
R
2 7 A N
X
14 H A N X14 N- N N -NH
R
3 R3 Tautomer R27 = R 2 , R 5 , or R 18 X4= 0, S, or NR 7 Also preferred are compounds which can be metabolized or hydrolyzed in vivo to a compound which can form the tautomeric structure shown above. For example, the following embodiments of a compound of formula (I) can be produced in vivo in the following reaction:
R
5
R
5 A O H A N OH N- N HO OH N- N R3 R 3 C:NRPotbl\DCCREC\4)75614_ DOC-1/1012012 - 263 RS R 5 A N A QH Q Q=O0, S-/ N- N H 2 N N--N
R
3 R3
R
5 R A, L H ANH A N O N NH2 N-N HO N- N
R
3
R
3 R5 HO R 5 OH OH A N X A XH N-N X= 0, S or NH N-N
R
3
R
3 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. It is understood that the pyrazole compounds of the present invention, including compounds of formulas (VI) through (VIII) and Table 6 can be purified, isolated, obtained and used in a form of a pharmaceutically acceptable salt, a solvate, a clathrate, a tautomer or a prodrug.
C:\NRPonb\DCC\REC4075614_1 DOC-1/102012 - 264 For example, a compound of formula (VI) can undergo the following tautomerization: R5 R5 A yoH A yo HN-N HN-NH R3 R3 R5 N-NH R3 where X 0 is 0, S, or NR 7 . It is understood that where a structural formula is depicted, all possible tautomeric forms of the compound are encompassed within that formula. 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 formula (VI) can be produced in vivo in the following reaction: R5
R
5 A 0 H 2 0 A OH HN-N HO OH HN-N R3
R
3
R
5
R
5 A Q H20 A QH HN-N H 2 N Q=,S HN-N R3 R 3
R
5
R
5 H A N
H
2 0 A
NH
2 HN-N HO HN-N
R
3
R
C NRPorb1\DCCMRECW075614_I DOC-1/10/2012 - 265 R HO A X OHOH H 2 0 A XH Z / OH X= 0, S or NH/ R HN-N R N R 3 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. It is understood that the compounds of the present invention, including compounds of formulas (IX) through (XI) and Tables 7 can be purified, isolated, obtained and used in a form of a pharmaceutically acceptable salt, a solvate, a clathrate, a tautomer or a prodrug. For example, a compound of formula (IX) can undergo the following tautomerization: R5 R5 A
X
0 H A N NH
R
3
R
3 R5 A N
X
0 H N
R
3 where X 0 is 0, S, or NR 7 . It is understood that where a structural formula is depicted, all possible tautomeric forms of the compound are encompassed within that formula.
C:\NRPonbI\DCC\REC\4075614_l DOC-1/10/2112 - 266 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 formula (IX) can be produced in vivo in the following reaction:
R
5
R
5 A 0 A N H2O A N OH N HO OH N
R
3 R3 R5 R5 AN
H
2 0 A N QH N H2N N
R
3
R
3
R
5 R N H AN 1H 2 0 A N NH 2 N HO \ N
R
3 R3
R
5 HOOH FZ OH H0X A 0 H 2 A N X R3 \ r/ 0 OH X=0, Sor NH (R 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. C. Methods for Making Compounds of the Invention Methods of making the compounds of the invention are disclosed in U.S. Patent Application Serial No. 11/282,119, filed on November 17, 2005; and in U.S. Provisional Patent Application Serial No. 60/709,310, filed August 18, 2005; U.S. Provisional Patent Application Serial No. 60/724,105, filed October 6, 2005; U.S. Provisional Patent Application Serial No.
C :WRPonbl\DCC\REC\4075614_LDOC-1/10l2012 - 267 60/709,358, filed August 18, 2005; U.S. Provisional Patent Application Serial No. 60/725,044, filed October 6, 2005; U.S. Provisional Patent Application Serial No. 60/707,836, filed August 12, 2005; U.S. Provisional Patent Application Serial No. 60/709,228, file August 18, 2005; the entire teachings of each of these patent applications is incorporated herein by reference. Additional methods of preparing the compounds of the invention can be found in the following U.S. provisional applications: 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; U.S. Provisional patent Application Serial No. 60/902,031, filed on February 16, 2007; and Attorney Docket No. 3211.1042-002, entitled "Synthesis of Triazole Compounds that Modulate HSP90 Activity," filed on May 25, 2007, the entire teachings of each of these applications are incorporated herein by reference. D. Uses of Compounds of the Invention I) Treatment of FLT3 Associated Cancers The present invention is directed to therapies which involve administering one or more compounds of the invention, or 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 FLT3 has been implicated as contributing to neoplastic pathology by administering one or more compounds of the invention. In another embodiment the invention is directed to a method of treating a FLT3 associated cancer in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent has an IC 5 0 for cell survival of less than about 20 nM, even more preferably less than about 10 nM, even more preferably less than about 5 nM in MV-4 11, a FLT3-positive cell line. In one embodiment, the agent is a molecule having a molecular weight of about 1000 Daltons or less. In another embodiment, the agent is an antibiotic or derivative thereof. In another embodiment the invention is directed to a method of treating a FLT3 associated cancer in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent is at least about 5 times, preferably 6 times, more preferably 7 times, still more preferably 8 times more affective at killing MV-4-l cells than C:\NRPonbl\DCC\REC\4075614_ .DOC-11/012 -268 geldanamycin analogs. In one embodiment, the agent is a molecule having a molecular weight of about 1000 Daltons or less. In another embodiment, the agent is an antibiotic or derivative thereof. In another embodiment, the present invention is directed to a method of inducing degradation of a FLT3 kinase in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent has an IC 5 0 for cell survival of less than about 20 nM, even more preferably less than about 10 nM, even more preferably less than about 5 nM in MV-4-1 1, a FLT3-positive cell line. In one embodiment, the agent is a molecule having a molecular weight of about 1000 Daltons or less. In another embodiment, the agent is an antibiotic or derivative thereof. In another embodiment, the present invention is directed to a method of inducing degradation of a FLT3 kinase in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent is at least about 5 times, preferably 6 times, more preferably 7 times, still more preferably 8 times more affective at killing MV-4-l cells than geldanamycin analogs. In one embodiment, the agent is a molecule having a molecular weight of about 1000 Daltons or less. In another embodiment, the agent is an antibiotic or derivative thereof. In another embodiment, the present invention is directed to a method of inducing degradation of a FLT3 kinase in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7. In one embodiment, the compound is administered to a cell in a subject, preferably a mammal, and more preferably a human. 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 one embodiment, the present invention is directed to a method of treating a FLT3 associated cancer in a subject. The method comprises adiministering to the subject an effective amount of a compound represented by formula (I) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7. In one embodiment, the compound is administered to a cell in a subject, preferably a mammal, and more preferably a human. 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 one embodiment, the present invention is directed to a method of treating a FLT3 associated cancer in a subject, wherein FLT3 has developed a resistance to treatment with a tyrosine kinase inhibitor. The method comprises adiministering to the subject an effective amount of a compound represented by formula (I) through (LXXII), or any embodiment thereof, or a C:\NRPortbl\DCC\REC407%14_l DOC-1/10/2012 - 269 compound shown in Table 5, 6, or 7. In one embodiment, the compound is administered to a cell in a subject, preferably a mammal, and more preferably a human. 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. 2) FLT3 Associated Cancers FLT3 associated cancers are cancers in which inappropriate expression or activity of FLT3 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). 3) Treatment of c-Kit Associated Cancers The present invention is directed to therapies which involve administering one or more compounds of the invention, or 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 contributing to neoplastic pathology by administering one or more compounds of the invention. In another embodiment the invention is directed to a method of treating a c-kit associated cancer in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent has an IC 5 0 for cell survival of less than about 50 nM, preferably less than about 40 nM, or more preferably less than about 30 nM, even more preferably less than about 10 nM, even more preferably less than about 5 nM in the AML cell line Kasumi- I. In one embodiment, the agent is a molecule having a molecular weight of about 1000 Daltons or less. In another embodiment, the agent is an antibiotic or derivative thereof. In this embodiment, the compounds disclosed in U.S. Patent Application Serial No. 11/282,119, filed on November 17, 2005, are not included. In another embodiment the invention is directed to a method of treating a c-kit associated cancer in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent is at least about 5 times, preferably 10 times, more C NRPonbl\DCCREC4075614_1 DOC-1/10/2012 - 270 preferably 15 times, still more preferably 20 times more affective at killing AML cell line Kasumi I than geldanamycin analogs. In one embodiment, the agent is a molecule having a molecular weight of about 1000 Daltons or less. In another embodiment, the agent is an antibiotic or derivative thereof. In this embodiment, the compounds disclosed in U.S. Patent Application Serial No. 11/282,119, filed on November 17, 2005, are not included. In another embodiment, the present invention is directed to a method of inducing degradation of a c-kit kinase in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent has an ICso for cell survival of less than about 50 nM, preferably less than about 40 nM, or more preferably less than about 30 nM, even more preferably less than about 10 nM, even more preferably less than about 5 nM in the AML cell line Kasumi-l. In one embodiment, the agent is a molecule having a molecular weight of about 1000 Daltons or less. In another embodiment, the agent is an antibiotic or derivative thereof. In this embodiment, the compounds disclosed in U.S. Patent Application Serial No. 11/282,119, filed on November 17, 2005, are not included. In another embodiment, the present invention is directed to a method of inducing degradation of a c-kit kinase in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent is at least about 5 times, preferably 10 times, more preferably 15 times, still more preferably 20 times more affective at killing AML cell line Kasumi-l than geldanamycin analogs. In one embodiment, the agent is a molecule having a molecular weight of about 1000 Daltons or less. In another embodiment, the agent is an antibiotic or derivative thereof. In this embodiment, the compounds disclosed in U.S. Patent Application Serial No. 11/282,119, filed on November 17, 2005, are not included. In another embodiment, the present invention is directed to a method of inducing degradation of a c-kit kinase in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7. In one embodiment, the compound is administered to a cell in a subject, preferably a mammal, and more preferably a human. 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 one embodiment, the present invention is directed to a method of treating c-kit associated cancers in a subject. The method comprises adiministering to the subject an effective amount of a compound represented by formula (1) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7. In one embodiment, the compound is administered to a cell in a subject, preferably a mammal, and more preferably a human. In another embodiment, the C NRPortbDCC\REC4075614 I.DOC./10/2012 -271 compound is administered with one or more additional therapeutic agents. In a preferred embodiment, the additional therapeutic agent is an anticancer agent. In one embodiment, the present invention is directed to a method of treating c-kit associated cancers in a subject, wherein c-kit has developed a resistance to a tyrosine kinase inhibitor such as Gleevec. The method comprises adiministering to the subject an effective amount of a compound represented by formula (I) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7. In one embodiment, the compound is administered to a cell in a subject, preferably a mammal, and more preferably a human. 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. 4) c-Kit Associated Cancers SCF binding to the c-kit protects hematopoietic stem and progenitor cells from apoptosis (Lee, et al., 1997, J. Immunol., 159:3211-3219), 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, Haemat., 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, el al, 1997, Haemat. 82:617-621). However, SCF protected AML cells from apoptosis induced by chemotherapeutic agents (Hassan, et al., 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 al., 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, el al., 1998, Leuk., 12:136-138), which appears to primarily result from inhibition of apoptotic death (Jones, 1997, Curr. Opin. Onc., 9:3-7). The product of the Philadelphia chromosome, p210 BCR-ABL, has been reported to mediate inhibition of apoptosis (Bedi, et al., 1995, Blood, 86:1148-1158). Since p210 BCR-ABL and the c-kit RTK both inhibit apoptosis and p 6 2 dok has been suggested as a substrate (Carpino, et al., 1997, Cell, 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 p2lOBCR-ABL (Hallek, el al., 1996, Brit. J Haem., 94:5-16), which suggests that c-kit may have a more causative role in C:\NRPotbl\DCC\RECW75614_ LDOC-1/10/2012 -272 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, et al., 1997, J. Cell Physiol., 172:1-11). However, c-kit is frequently expressed in colorectal carcinoma (Bellone, et al., 1997, J. Cell Physiol., 172: 1-11), and autocrine loops of SCF and c-kit have been observed in several colon carcinoma cell lines (Toyota, et al., 1993, Turn. Biol., 14:295-302; Lahm, et al., 1995, Cell Growth & Differ., 6: I 1-1-118; Bellone, et al., 1997, J. Cell Physiol., 172:1- 11). Furthermore, disruption of the autocrine loop by the use of neutralizing antibodies (Lahm, et al., 1995, Cell Growth & Differ., 6:1111-1118) and downregulation of c-kit and/or SCF significantly inhibits cell proliferation (Lahm, et al., 1995, Cell Growth & Differl., 6:1111-1118; Bellone, et al., 1997, J. Cell Physiol., 172: 1-11 ). SCF/c-kit autocrine loops have been observed in gastric carcinoma cell lines (Turner, et al., 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, et al., 1998, Science, 279:577-580). The c-kit expressed in GISTs from several different patients was observed to have mutations in the intracellularjuxtamembrane 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, et 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., 153:337-344). 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, et al., 1997, J. Endocrinol., 153:337-344). Testicular tumors develop from Leydig cells with high frequency in transgenic mice expressing human papilloma virus 16 (HPV 16) E6 and E7 oncogenes (Kondoh, et al., 1991, J. Virol., 65:3335-3339; Kondoh, et al., 1994, J. Urol., 152:2151-2154). These tumors express both c-kit and SCF, and an autocrine loop may contribute to the tumorigenesis (Kondoh, et al., 1995, Oncogene, 10:341-347) associated with cellular loss of C:WRPrb1DCC\REC\4075614_I DOC-1/10/2012 - 273 functional p53 and the retinoblastoma gene product by association with E6 and E7 (Dyson, el al., 1989, Science, 243:934-937; Werness, et al., 1990, Science, 248:76-79; Scheffner, et al., 1990, Cell, 63:1129-1136). Defective signaling mutants of SCF (Kondoh, et al., 1995, Oncogene, 10:341 347) or c-kit (Li, et al., 1996, Canc. 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, Canc. Res., 51:1811-1816; Rajpert-de Meyts, et al., 1994, Int. J. Androl., 17:85-92; lzquierdo, et al., 1995, J. Pathol., 177:253-258; Strohmeyer, el al., 1995, J. Urol., 153:51 1-515; Bokenmeyer, el al., 1996, J. Cance. Res., Clin. Oncol., 122:301-306; Sandlow, et al., 1996, J Androl., 17:403-408). 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. Neuro., 80:1063-1073). Glioblastoma and astrocytoma, which define the majority of intracranial tumors, arise from neoplastic transformation of astrocytes (Levin, et al., 1997, Principles & Practice of Oncology, 2022-2082). Expression of c kit has been observed in glioblastoma cell lines and tissues (Berdel, ei al., 1992, Canc. 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, et al., 1992, Int. J Canc., 52:197-20 1), (Tada, el al. 1994, J. Neuro., 80:1063-1073), while others report it is not expressed (Kristt, et al., 1993, Neuro., 33:106-115). In the former case, high levels of c-kit expression in high grade tumors were observed (Kristt, et al., 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 C:\NRPorbl\DCC\REC4175614_1 DOC-1/10/20M2 -274 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, et 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. 5) Treatment of EGFR Associated Cancers The present invention is directed to therapies which involve administering one or more compounds of the invention, or 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 EGFR has been implicated as contributing to neoplastic pathology by administering one or more compounds of the invention. In another embodiment the invention is directed to a method of treating an EGFR associated cancer in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent has an IC 50 for cell survival of less than about 50 nM, preferably less than about 40 nM, or more preferably less than about 30 nM, even more preferably less than about 10 nM, even more preferably less than about 5 nM in NCI-H 1975 human lung cancer cell line (obtainable from American Type Culture Collection) which harbors both the T790M and the L858R mutations in EGFR. In one embodiment, the agent is a molecule having a molecular weight of about 1000 Daltons or less. In another embodiment, the agent is an antibiotic or derivative thereof. In another embodiment the invention is directed to a method of treating an EGFR associated cancer in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent is at least about 5 times, preferably 6 times, more preferably 8 times, still more preferably 10 times more affective at killing NCI-H 1975 human lung cancer cell line than geldanamycin analogs. In one embodiment, the agent is a molecule having a molecular weight of about 1000 Daltons or less. In another embodiment, the agent is an antibiotic or derivative thereof.
C:\NRPonbl\DCC\REC\4075614_ DOC-A/10/2012 - 275 In another embodiment, the present invention is directed to a method of inducing degradation of EGFR in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent has an IC 50 for cell survival of less than about 50 nM, preferably less than about 40 nM, or more preferably less than about 30 nM, even more preferably less than about 10 nM, even more preferably less than about 5 nM in NCl-H 1975 human lung cancer cell line. In one embodiment, the agent is a molecule having a molecular weight of about 1000 Daltons or less. In another embodiment, the agent is an antibiotic or derivative thereof. In another embodiment, the present invention is directed to a method of inducing degradation of EGFR in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent is at least about 5 times, preferably 6 times, more preferably 8 times, still more preferably 10 times more affective at killing NCI-H 1975 human lung cancer cell line than geldanamycin analogs. In one embodiment, the agent is a molecule having a molecular weight of about 1000 Daltons or less. In another embodiment, the agent is an antibiotic or derivative thereof. In another embodiment, the present invention is directed to a method of inducing degradation of EGFR in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (1) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7. In one embodiment, the compound is administered to a cell in a subject, preferably a mammal, and more preferably a human. 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 embodiment, the present invention is directed to a method of treating EGFR associated cancers in a subject. The method comprises adiministering to a subject an effective amount of a compound represented by formula (1) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7. In one embodiment, the compound is administered to a cell in a subject, preferably a mammal, and more preferably a human. 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 embodiment, the present invention is directed to a method of treating EGFR associated cancers in a subject, wherein EGFR has developed a resistance to treatment with a tyrosine kinase inhibitor, such as Tarceva (so called erlotinib), Tykerb (also called lapatinib), and gefitinib (also called irressa). The method comprises adiministering to a subject an effective amount of a compound represented by formula (I) through (LXXII), or any embodiment thereof, or C:\NRPonbl\DCC\REC4075614_ I.DOC. 1/10/2012 -276 a compound shown in Table 5, 6, or 7. In one embodiment, the compound is administered to a cell in a subject, preferably a mammal, and more preferably a human. 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. 6) 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 EGFRvIII 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 C NRPootbDCC\REC\4075614_ .DOC-1/10/2012 -277 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 EGFR, 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. 7) Treatment of B-raf Associated Cancers The present invention is directed to therapies which involve administering one or more compounds of the invention, or compositions comprising said compounds to a subject, preferably a human subject, to inhibit the activity of B-raf 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 B-raf has been implicated as contributing to neoplastic pathology by administering one or more compounds of the invention. In another embodiment, the present invention is directed to a method of inducing degradation of B-raf in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7. In one embodiment, the compound is administered to a cell in a subject, preferably a mammal, and more preferably a human. 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 embodiment, the present invention is directed to a method of treating B-raf associated cancers in a subject. The method comprises adiministering to a subject an effective amount of a compound represented by formula (I) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7. In one embodiment, the compound is administered to a cell in a subject, preferably a mammal, and more preferably a human. 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.
C \NRPonbl\DCC\REC\407%14_l DOC-/10/2012 - 278 In another embodiment, the present invention is directed to a method of treating B-raf associated cancers in a subject, wherein B-raf has developed a resistance to treatment with a kinase inhibitor, such as BAY 43-9006 (so called Sorafenib). The method comprises adiministering to a subject an effective amount of a compound represented by formula (I) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7. In one embodiment, the compound is administered to a cell in a subject, preferably a mammal, and more preferably a human. 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. 8) B-Raf Associated Cancers B-raf associated cancers are cancers in which inappropriate B-raf activity, overexpression of B-raf or mutation of B-raf which causes constitutive tyrosine kinase activity) has been implicated as a contributing factor. In one embodiment, B-raf associated cancers that have increased B-raf activity, often have 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. 9) Treatment of Cancers which Express Bcr-AbI Fusion Protein The present invention is directed to therapies which involve administering one or more compounds of the invention, or 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 (including Bcr-Abl associated cancers), or one or more symptoms thereof. In another embodiment the invention is directed to a method of treating a cancer that expresses a Bcr-AbI fusion protein in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent has an IC 50 for cell C:\NRPortblDCCREC\4075614_1 .DOC-1/10i/2012 - 279 survival of less than about 15 nM, preferably less than about 10 nM, or more preferably less than about 5 nM in CML cell line KU812. In one embodiment, the agent is a molecule having a molecular weight of about 1000 Daltons or less. In another embodiment, the agent is an antibiotic or derivative thereof. In another embodiment the invention is directed to a method of treating a cancer that expresses a Bcr-Abl fusion protein in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent is at least about 5 times, preferably 6 times, more preferably 7 times, and still more preferably 8 time more affective at killing CML cell line KU812 than geldanamycin analogs. In one embodiment, the agent is a molecule having a molecular weight of about 1000 Daltons or less. In another embodiment, the agent is an antibiotic or derivative thereof. In another embodiment, the present invention is directed to a method of inducing degradation of a Bcr-Abl protein in a subject, comprising administering to the mammal an effective amount of an isolated agent that inhibits Hsp90, wherein the agent has an IC 5 0 for cell survival of less than about 15 nM, preferably less than about 10 nM, or more preferably less than about 5 nM in CML cell line KU812. In one embodiment, the agent is a molecule having a molecular weight of about 1000 Daltons or less. In another embodiment, the agent is an antibiotic or derivative thereof. In another embodiment, the present invention is directed to a method of inducing degradation of a Bcr-Abl protein in a subject, comprising administering to the mammal an effective amount of an isolated agent that inhibits Hsp90, wherein the agent is at least about 5 times, preferably 6 times, more preferably 7 times, and still more preferably 8 time more affective at killing CML cell line KU812 than geldanamycin analogs. In one embodiment, the agent is a molecule having a molecular weight of about 1000 Daltons or less. In another embodiment, the agent is an antibiotic or derivative thereof. In another embodiment, the present invention is directed to a method of inducing degradation of a Bcr-AbI protein in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7. In one embodiment, the compound is administered to a cell in a subject, preferably a mammal, and more preferably a human. 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 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 C :NRPonbi\DCC\REC4)75614_DOC-lO/2012 - 280 adiministering to a patient an effective amount of a compound represented by formula (1) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7. In one embodiment, the compound is administered to a cell in a subject, preferably a mammal, and more preferably a human. 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 one embodiment, the present invention is directed to treating cancers in which expression of Bcr-AbI has been implicated as a contributing factor, wherein Bcr-Abl has developed a resistance to inhibition with a tyrosine kinase inhibitor such as Gleevec. The method comprises adiministering to a patient an effective amount of a compound represented by formula (1) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7. In one embodiment, the compound is administered to a cell in a subject, preferably a mammal, and more preferably a human. 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. 10) Cancers which Express Bcr-Abl Fusion Protein 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, el al., Science (1990), 247:824-830; and Honda, Blood(1998), 9/: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 Bcr-Abl 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, Fla. 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-AbI 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 C:NRPortbl\DCCRE04075614_1.DOC.1/10/2012 -281 herein by reference). The Bcr-Abl oncoprotein p210 Bcr-AbI is associated with both CML and ALL, whereas the smaller oncoprotein, p 1 85 Bcr-Abl, is associated with ALL patients, although some CML patients also express p185 Bcr-Abl. 11) Treatment of Cancers which Express NPM-ALK Fusion Protein The present invention is directed to therapies which involve administering one or more compounds of the invention, or 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 (including cancers which express NPM-ALK fusion protein), or one or more symptoms thereof. In another embodiment the invention is directed to a method of treating a cancer that expresses a NPM-ALK fusion protein in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent has an IC 50 for cell survival of less than about 10 nM in ALCL cell line Karpas-299. In one embodiment, the agent is a molecule having a molecular weight of about 1000 Daltons or less. In another embodiment, the agent is an antibiotic or derivative thereof. In another embodiment the invention is directed to a method of treating a cancer that expresses a NPM-ALK fusion protein in a subject, comprising administering to the subject an effective amount of an isolated agent that inhibits Hsp90, wherein the agent is at least about 5 times, preferably 6 times more affective at killing ALCL cell line Karpas-299 than geldanamycin analogs. In one embodiment, the agent is a molecule having a molecular weight of about 1000 Daltons or less. In another embodiment, the agent is an antibiotic or derivative thereof. In another embodiment, the present invention is directed to a method of inducing degradation of a NPM-ALK fusion protein in a subject, comprising administering to the mammal an effective amount of an isolated agent that inhibits Hsp90, wherein the agent has an IC 50 for cell survival of less than about 10 nM in ALCL cell line Karpas-299. In one embodiment, the agent is a molecule having a molecular weight of about 1000 Daltons or less. In another embodiment, the agent is an antibiotic or derivative thereof. In another embodiment, the present invention is directed to a method of inducing degradation of a NPM-ALK fusion protein in a subject, comprising administering to the mammal an effective amount of an isolated agent that inhibits Hsp90, wherein the agent is at least about 5 times, preferably 6 times more affective at killing ALCL cell line Karpas-299 than geldanamycin analogs. In one embodiment, the agent is a molecule having a molecular weight of about 1000 Daltons or less. In another embodiment, the agent is an antibiotic or derivative thereof.
C-NRPonbl\DCC\REC\4(75614_I DOC-1/10/2012 -282 In another embodiment, the present invention is directed to a method of inducing degradation of a NPM-ALK fusion protein in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7. In one embodiment, the compound is administered to a cell in a subject, preferably a mammal, and more preferably a human. 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 one embodiment, the present invention is directed to treating cancers in which expression of NPM-ALK fusion protein has been implicated as a contributing factor. The method comprises adiministering to a patient an effective amount of a compound represented by formula (I) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7. In one embodiment, the compound is administered to a cell in a subject, preferably a mammal, and more preferably a human. 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 one embodiment, the present invention is directed to treating cancers in which expression of NPM-ALK fusion protein has been implicated as a contributing factor, wherein Bcr Abi has developed a resistance to inhibition with a tyrosine kinase inhibitor such as Gleevec. The method comprises adiministering to a patient an effective amount of a compound represented by formula (I) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7. In one embodiment, the compound is administered to a cell in a subject, preferably a mammal, and more preferably a human. 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. 12) Cancers which Express NPM-ALK Fusion Protein Cancers which express NPM-ALK fusion protein include ALCL and diffuse large B-cell lymphomas. 2) 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, C\NRPortbhDCC\REC\4075614_ I DOC-1/1012012 - 283 after treatment with one or more chemotherapeutic agents, a tumor develops multidrug resistance and no longer response 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. The compounds of the invention are useful for treating patients with FLT3 associated cancers, such as hematological cancers, that have become resistant to tyrosine kinase inhibitors, such as Imatinib. Compounds of the invention act by inhibiting the activity of Hsp90 which disrupt FLT3/Hsp9O complexes and causes degradation of FLT3 kinases. Therefore, compounds of the invention are effective in treating FLT3 associated cancers that have become resistant to tyrosine kinase inhibitors since they act through a different mechanism. Compounds of the invention can be administered alone or with a tyrosine kinase inhibitor in patients who have a FLT3 associated cancer that is not resistant to tyrosine kinase inhibitors or to patients whose cancer has become resistant to tyrosine kinase inhibitors. The compounds of the invention are useful for treating patients with c-kit associated cancers, such as gastrointestinal stromal tumors, that have become resistant to Imatinib, a chemotherapeutic agent that acts by inhibiting tyrosine kinase activity of c-kit. Compounds of the invention act by inhibiting the activity of Hsp90 which disrupt c-kit/Hsp90 complexes and causes degradation of c-kit. Therefore, compounds of the invention are effective in treating Imatinib resistant c-kit associated cancers 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 c kit associated cancer that is not resistant to Imatinib or to patients whose cancer has become resistant to Imatinib. The compounds of the invention are useful for treating patients with EGFR associated cancers, such as patients with glioblastomas or non-small cell lung cancer, that have become resistant to tyrosine kinase inhibitors, such as Gefitinib or Tarceva, tyrosine kinase inhibitors that inhibit the activity of EGFR. Compounds of the invention act by inhibiting the activity of Hsp90 which disrupt EGFR/Hsp90 complexes and causes degradation of EGFR, including EGFR that has a mutation that makes it constitutively active. Therefore, compounds of the invention are effective C \NRPorbl\DCCREC075614_I DOC-1/10120|2 - 284 in treating Gefitinib or Tarceva resistant EGFR associated cancers since they act through a different mechanism. Compounds of the invention can be administered alone or with a tyrosine kinase inhibitor in patients who have an EGFR associated cancer that is not resistant to tyrosine kinase inhibitors or to patients whose cancer has become resistant to tyrosine kinase inhibitors. The compounds of the invention are useful for treating patients with B-raf associated cancers, such as patients with 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, that have become resistant to kinase inhibitors, such as Sorafenib, a kinase inhibitor that inhibits the activity of B-raf. Compounds of the invention act by inhibiting the activity of Hsp90 which disrupt B-raf/Hsp90 complexes and causes degradation of B-raf, including B-raf that has a mutation that makes it constitutively active. Therefore, compounds of the invention are effective in treating Sorafenib resistant B-raf associated cancers since they act through a different mechanism. Compounds of the invention can be administered alone or with a tyrosine kinase inhibitor in patients who have a B-raf associated cancer that is not resistant to kinase inhibitors or to patients whose cancer has become resistant to kinase inhibitors. In addition, the compounds of the invention are useful for treating patients with cancer that expresses a Bcr-AbI fusion protein, such as 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, et al., Cancer Research (2001), 61:1799-1804; and Gorre, et al., 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/Hsp9O 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.
C:NRPonb1\DCC\REC4075614_L DOC-1/10/2012 - 285 In addition, the compounds of the invention are useful for treating patients with cancer that expresses a NPM-ALK fusion protein, such as hematological cancers, that have become resistant to one or more tyrosine kinase inhibitors. Compounds of the invention act by inhibiting the activity of Hsp90 which disrupt NPM-ALK/Hsp90 complexes. When NPM-ALK is not complex to Hsp90 it is rapidly degraded. Therefore, compounds of the invention are effective in treating tyrosine kinase inhibitor resistant lymphomas such as ALCL since they act through a different mechanism than tyrosine kinase inhibitors. Compounds of the invention can be administered alone or with a tyrosine kinase inhibitor in patients who have an NPM-ALK associated cancer that is not resistant to a tyrosine kinase inhibitor or to patients whose cancer has become resistant to a tyrosine kinase inhibitor. Other anticancer agents that can be co-administered with the compounds of the invention include TaxoTM, also referred to as "paclitaxel", is a well-known anti-cancer drug which acts by enhancing and stabilizing microtubule formation, and analogs of TaxolTM, such as TaxotereTM. 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 stabilized microtubules. Other anti-cancer agents that can be employed in combination with the compounds of the invention include Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cladribine; 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; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n I ; interferon alfa-n3; interferon beta-] a; interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; C:NRPorbl\DCCREC\4756141 DOC-1/10/2012 - 286 leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic 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; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; 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-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-I; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; C:\NRPonbICC\REC4075614_ DOC-I/10/2012 -287 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 B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9- dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-I receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metal loproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; 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 B; mycobacterial cell wall extract; myriaporone; 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-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palm itoylrhizoxin; pamidronic acid; panaxytriol; C:\NRPonbI0OCC\REC4075614_ .DOC. 1/10/2012 -288 panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum triamine 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; purpurins; pyrazoloacridine; pyridoxylated 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; RI1 retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone BI; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; 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-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. Preferred anti-cancer drugs are 5-fluorouracil 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., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl C:\NRPonblDCC\REC\4075614_ DOC-1110/201 2 - 289 sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), or triazenes (decarbazine, etc.). 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, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.). 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).
C:\NRPornb\DCCRECW)75614_ .DOC.11/2012 - 290 Other examples of anti-cancer agents which act by arresting cells in the G2-M phases due to stabilized microtubules include without limitation the following marketed drugs and drugs in development: Examples of anti-cancer agents which act by arresting cells in the G2-M phases due to stabilized 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 LU-103793 and NSC-D-669356), Epothilones (such as Epothilone A, Epothilone B, 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-1 12378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885 B), GS-1 64 (Takeda), GS-1 98 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU-22365 1), 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 A, Canadensol, Centaureidin (also known as NSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-I (Parker Hughes Institute, also known as DDE-261 and WHI-261), HIO (Kansas State University), H16 (Kansas State University), Oncocidin Al (also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-I (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 C:NRPorbl\fDCCREC\4075614_ DOC-1/11/2012 -291 State University), Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine (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-l 15781 (Aventis), Eleutherobins (such as Desmethyleleutherobin, Desaetyleleutherobin, Isoeleutherobin 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 (Aventis), 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-3 183 15 (Abbott), HTI-286 (also known as SPA- 110, trifluoroacetate salt) (Wyeth), D-823 17 (Zentaris), D-823 18 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-25041 I (Sanofi). 2) 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, including Bcr-Abl, FLT3, EGFR, c-Kit, B-raf, and NPM-ALK associated cancers. Preferred pharmaceutical compositions and dosage forms comprise a compound of formula (I) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7, C:NRPonbl\DCC\REC'4(7564_LDOC-1/1lO/2012 - 292 or a pharmaceutically acceptable prodrug, salt, solvate, clathrate, hydrate, or prodrug thereof, optionally in combination with one or more additional active agents. 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 non-aqueous 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 C \NRPrtbl\DCC\REC\475614_ .DOC-1/10/2012 - 293 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 C :NRPortblDCC\RE04075614_1 DOC-1/102012 - 294 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. i) Oral Dosa2e 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 C NRPortbl\DCC\REM4075614 IDOC-1/10/2012 - 295 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.
C \NRPonbl\DCCOREC475614_I.DOC.I/101/2012 - 296 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 I 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 Plano, 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 I weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated. ii) 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 C:NRPortbl\DCCREC\75614_I DOC-1/10/2012 - 297 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 (1) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7, 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 C:\NRPortbl\DCC\RECN40.75614_ I DOC-1/10/2012 -298 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) through (LXXII), or any embodiment thereof, or a compound shown in Table 5, 6, or 7, 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 hydroxypropylmethylcel lulose. iii) 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 myristate, 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. iv) 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, C:\NRPorb1\DCC\REC4O75614 DOC-1/10/2012 - 299 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 C:VWRPortbDCCREC'075614_1 DOC-1/10/2012 - 300 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. v) 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 (5 7th 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 I 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 0.0 1 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. In another embodiment, the compounds of the invention are administered one to three times a week. Specifically, a 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 I 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 C :NRPorblDCCECM0756141 DOC-l10/2012 -301 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 pg/kg, preferably 250 ig/kg, 500 pg/kg, I 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, I mg to 20 mg, I mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 8 mg, 1 mg to 7 mg, I mg to 5 mg, or I 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, C-\NRPonbl\DCC\REC\4)75614_I DOC-1/10120 12 - 302 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 et al., eds., 1996, Goodman & Gilman's The Pharmacological Basis Of Basis Of Therapeutics 9 1h Ed, Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57 'h 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, I hour apart, at about I hour apart, at about I 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 I 1 hours apart, at about I I 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 I day, 2 days, 3 days, 5 days, 10 C \NRPortbi\DCC\RECM115614_.DOC-II10OI2 - 303 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 I 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 gg/kg, preferably at least 250 Rg/kg, at least 500 gg/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. D. 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 ELISA-like assay, or as standards in in vilro 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.
C WRPonblDC RC04756%14_ .DOC. 1/10/2012 -304 1. EXAMPLES Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). 'H-NMR and I 3 C-NMR spectra were recorded on a Varian 300MHz NMR spectrometer. Significant peaks are tabulated in the order: 8 (ppm): chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s, broad singlet), coupling constant(s) in Hertz (Hz) and number of protons. Example 1: Synthesis of Compound 76 H NHNH 2 NA/ Et0H HNH H 0 -HOe OH NSHO OH NCS 5 (M) (N) (P) 2 eq NaOH 0~~ HOO N/ N SH OH N-N Compound 76 The hydrazide (M) (1.45 g, 7.39 mmol) and the isothiocyanate (N) (1.59 g, 7.39 mmol) were dissolved in ethanol (20 ml) with heating. When the starting materials were dissolved the solution was allowed to cool to room temperature and a precipitate formed. This precipitate was filtered then washed with ether to provide the intermediate (P) as a white solid (2.85 g, 97%). The intermediate (VII) (1.89 g, 4.77 mmol) was heated in a solution of sodium hydroxide (0.38 g, 9.54 mmol) in water (20 mL) at II 0C for 2 hours. The solution was allowed to cool to room temperature then acidified with conc. HCL. The resulting precipitate was filtered then washed with water (100 mL) and dried. The crude product was recrystallized from ethanol to produce compound 76 as a white solid (1.4 g, 75%). H NMR (DMSO-d 6 ) 8 9.43-9.53 (bs, 2H),8.I 1-8.16 (m, I H), 7.47-7.55 (m, 2H), 7.38 (d, J=8.1 Hz, I H), 7.31-7.36 (m, I H), 6.98 (d, J=8.1 Hz, I H), 6.71 (s, I H), 6.17 (s, I H), 3.98 (s, 3H), 2.17 (q, J=7.5 Hz, 2H), 0.73 (t, J=7.5 Hz, 3 H); C \NRPonbl\DCC\REC475614_l .DOC-1/1012012 -305 ESMS calculated for (C 2 1 HjqN 3 0 3 S) 393.11; Found 394.1(M+1)*. Example 2: Synthesis of Compound 124 3-(2,4-Dihydroxy-phenyl)-4-(naphthalen- I -yl)-5-mercapto-triazole (505 mg, 1.5 mmol), which is commercially available from Scientific Exchange, Inc., Center Ossipee, NH 03814, and Et 3 N (0.84ml, 6.0 mmol) in 15ml CH 2
CI
2 were treated dropwise with ethyl isocyanate (360mg, 5.0 mmol) at 0 0 C. The mixture was then warmed to room temperature and stirred for 3h. The reaction mixture was diluted with CH 2 Cl 2 , washed with H 2 0 and saturated brine, dried with Na 2
SO
4 , and concentrated in vacuo. The residue was chromatographed (Hexane/ EtOAc 3:1) to give Compound 124 as a white solid (480 mg, 58%). H-NMR (CDCI 3 ) 8 10.13 (s, 1 H), 7.96 (d, J=9.0 Hz, 21-), 7.61-7.57 (m, 3H), 7.49-7.36(m, 2H), 7.01(s, I H), 6.88 (d, J=8.4Hz, Il H), 6.70 (d, J=8.4Hz, I H), 4.98-4.96(m, 2H), 3.56(q, J=7.2 Hz, J=12.6 Hz, 2H), 3.28-3.10(m, 4H), 1.33(t, J=7.2 Hz, 3H), 1.13 (q, J=1 5.0 Hz, J=7.2Hz, 6H); ESMS calculated for C 27
H
2 8
N
6 OSS: 548.18; Found: 549.1 (M+1)*.
C :NRPortb\DCCREC4075614 1.DOC-1/10/2012 -306 Example 3: Synthesis of Compound 188 O NaH O S SO2Ph PhSO 2 CI N SiO 2
-HNO
3 2
NO
2 NaOH/MeOH O O O H N H 2 /PdC NaH
NH
2
NO
2
NO
2 (U) S (T) (S) ~ m Im --0 0 0~H H HO & OH 0'N-S NCS /S OH N-N 0 (188) N' NH2 H HO OH (W) I-Benzenesulfonyl-7-methoxy-IH-indole (Q) To a solution of 7-methoxyindole (I eq) in DMF cooled in an ice bath was added NaH (60% dispersion in oil, 1.2 eq). The reaction was stirred for 1 hr at room temperature then recooled in an ice bath. Benzenesulfonyl chloride (1 .1 eq) was added then the reaction was stirred for 2 hrs at room temperature. Water/ethyl acetate were added and the ethyl acetate layer was washed repeatedly (3x) with water. The ethyl acetate layer was concentrated and evaporated to dryness. J-Benzenesulfonyl-7-methoxy-4-nitro-I H-indole (R) To a solution of l-benzenesulfonyl-7-methoxy-I H-indole (Q) (leq) in dichloromethane cooled in an ice bath was added SiO 2
-HNO
3 (2 wt eq) in small portions. The reaction was stirred C:\NRPonbIDCC\REC\4075614_ DOC-1/10/2012 -307 for I hr at room temperature. Activated carbon (2 wt eq) was added then the entire mixture was stirred for I hr. The mixture was then filtered and evaporated to dryness. Separation of the isomers was achieved by column chromatography. 7-Methoxy-4-nitro-JH-indole (S) To a solution of l-benzenesulfonyl-7-methoxy-4-nitro-I H-indole (R) (leq) in methanol was added a solution of sodium hydoxide (5 eq) in water. The solution was heated to reflux for 3 hrs. Methanol was removed under reduced pressure then water and ethyl acetate were added. The ethyl acetate layer separated and washed repeatedly (3x) with water. The ethyl acetate layer was concentrated and evaporated to dryness to produce the desired product. 1-Isopropyl-7-methoxy-4-nitro-JH-indole (T) To a solution of 7-methoxy-4-nitro-I H-indole (S) (I eq) in DMF cooled in an ice bath was added NaH (60% dispersion in oil, 1.2 eq). The reaction was stirred for I hr at room temperature then recooled in an ice bath. 2-lodopropane (1 .1 eq) was added then the reaction was stirred for 2 hrs at room temperature. Water and ethyl acetate were added. The ethyl acetate layer was separated and washed repeatedly (3x) with water. The ethyl acetate layer was concentrated then evaporated to dryness. Further purification by column chromatography produced the pure desired product. 1-Isopropyl- 7-methoxy-IH-indol-4-ylamine (U) A solution of I-isopropyl-7-methoxy-4-nitro-I H-indole (T) (leq) and palladium 10% on activated carbon (0.1 wt eq) in methanol/ethyl acetate (1:1) was shaken on a Parr hydrogenation apparatus under hydrogen for I hr. The reaction was then filtered through Celite and evaporated to dryness to produce the desired product. J-Isopropyl-4-isothiocyanato-7-methoxy-JH-indole (V) To a solution of I-isopropyl-7-methoxy-I H-indol-4-ylamine (U) (Ieq) in dichloromethane was added 1,1 '-thiocarbonyldiimidazole (1.2 eq). The reaction was stirred for 2 hrs at room temperature then evaporated to dryness. Further purification by column chromatography produced the pure desired product.
C \NRPonbl\DCC\REC\407564_LDOC.1/10/2012 -308 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(I-isopropyl- 7-methoxy-indol-4-yI)-5-mercapto-[1,2,4 triazole (Compound 188) 5-Ethyl-2,4-dihydroxy-benzoic acid hydrazide (W) (Ieq) and I-isopropyl-4 isothiocyanato-7-methoxy-l H-indole (V) (1.0 1 eq) were heated in ethanol (0.02 M based on isothiocyante) at 80C for 1 hr. The solution was allowed to cool to room temperature overnight. The resulting precipitate was filtered, washed with ether, dried and used without further purification (yield 80%). The precipitate was suspended in aqueous NaOH solution (2 eq NaOH) and nitrogen was bubbled through this suspension for 10 min. The reaction was then heated to I 10 C for I hr under a nitrogen atmosphere then allowed to cool to room temperature. Neutralisation with conc. HCI produced a white precipiate which was filtered and washed with water. Repeated recrystallisation from EtOH/water produced the desired product (purity >95%, yield 50-70%) H-NMR (DMSO-d 6 ) 8 (ppm), 9.52 (s, I H), 9.42 (s, I H), 7.40 (d, J=3.3Hz, I H), 6.82 (d, J=8.4Hz, I H), 6.61 (s, I H), 6.20 (s, 1 H), 6.05 (d, J=3.3 Hz, I H), 5.30 (qn, J=6.6Hz, I H), 3.89 (s, 31H), 2.14 (q, J=7.5 Hz, 2H), 1.41-1.47 (m, 6H), 0.68 (t, J=7.5Hz, 3H); 2. ESMS calculated. for C 22
H
2 4
N
4 0sS: 424.16; Found: 425.1 (M+1)+.
C aRortbl\Dcc\RFc\4075614_l.DOc-1/10/2012 - 309 Example 4: Synthesis of Compound 223 10 Lawesson's OI/ 1. (COCI) 2 , cat. DMF, CH 2
CI
2 H reagent OH N 2. H 2 N toluene, O O , Et 3 N O O N 110"C, 3 SN hours H NH 2 NH2 | H CDI N N EtOAc, I Dioxane, 80 0 C, 30 minutes reflux, O S N O NH 2 N 2 hours N N N 1-0 HCI HO N Nal, 205 C, I hour N O > N OH OH OH Compound 223 2,4-Dimethoxy-5-isopropylbenzoic acid (2.24 g, 10.0 mmol, 1.00 equiv.) in 50 mL CH 2 C1 2 at room temperature was treated with (COCl) 2 (1.40 g, 1 1.0 mmol, 1 .10 equiv.) and catalytic amount of DMF (0.1 mL) for 1 hour. Solvent and excess (COCl) 2 were removed in vacuo. The residue was dissolved in 100 mL CH 2 Cl 2 , and treated with 1,3-dimethyl-5-aminoindole (1.60 g, 10.0 mmol, 1.00 equiv.) and triethylamine (1.55 g, 15.0 mmol, 1.50 equiv.) at 0 0 C for one hour. Aqueous workup and removal of solvent gave a light brown solid which was washed with ether to yield off-white solid (2.28g, 6.22 mmol, 62%). 'H NMR (CDCl 3 ) 8 (ppm) 9.78 (br s, I H), 8.21 (s, I H), 8.09 (d, J= 2.1 Hz, 1 H), 7.31 (dd, J= 8.7 Hz, 2.1 Hz, I H), 7.22 (d, J= 8.7 Hz, I H), 6.82 (s, I H), 6.50 (s, I H), 4.09 (s, 3 H), 3.92 (s, 3 H), 3.73 (s, 3 H), 3.26 (hept, J= 6.9 Hz, I H), 2.32 (s, 3 H), 1.24 (d, J= 6.9 Hz, 6H). The off-white solid obtained above was treated with Lawesson's reagent (1.51 g, 3.74 mmol, 0.6 equiv.) in 50 mL toluene at I I0 C for three hours. Toluene was removed on rotary evaporator and vacuum pump, and the residue was treated with hydrazine (anhydrous, 3.0 g, 94 mmol, 15.0 equiv.) in 20 mL dioxane at 80"C for 30 minutes. The reaction mixture was extracted with ethyl acetate and water to remove excess hydrazine. The organic layer was dried over C:\NRPonbDCC\RE4075614_ DOC-1110/2012 -310 MgSO 4 , and filtered to remove drying agent. Carbodiimidazole (CDI)(3.02 g, 18.7 mmol, 3.00 equiv.) was added to the solution, and the solution was refluxed (65*C) for 2 hours. Solvent was removed, and the residue was treated with 20 mL THF and 10 mL NaOH (2M) to destroy excess CDI. Extraction with ethyl acetate (EtOAc) and water, followed by chromatography purification gave the desired product 3-(2,4-methoxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5 hydroxy-[1,2,4] triazole as light brown solid (2.20 g, 5.42 mmol, 87%). 'H NMR (CDC 3 ), 8 (ppm) 9.63 (br s, I H), 7.34 (d, J = 2.1 Hz, I H), 7.20 (s, I H), 7.18 (d, J = 8.4 Hz, I H), 7.00 (dd, J= 8.4 Hz, 2.1 Hz, I H), 6.80 (s, I H), 6.19 (s, 1 H), 3.76 (s, 3H), 3.69 (s, 3H), 3.40 (s, 3H), 3.15 (hept, J= 6.9 Hz, IL H), 2.20 (s, 3H), 1.10 (d, .= 6.9 Hz, 6H). 3-(2,4-methoxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4] triazole obtained above was treated with pyridine hydrochloride (12.53 g, 108.3 mmol, 20.0 equiv.), Nal (0.812 g, 5.42 mmol, 1.0 equiv.) and 0.5 mL water at 205'C under nitrogen protection for I hour. The reaction mixture was treated with 200 mL water. The solid was collected by filtration, washed with 3 x 20 mL water, and dissolved in 50 mL 2M NaOH solution. The aqueous solution was extracted with 100 mL EtOAc, and the EtOAc layer was extracted with 2 x 20 mL 0.5M NaOH. EtOAc layer was discarded. The aqueous layer were combined, neutralized with HCI to PH around 5, and extracted with 3 x 100 mL EtOAc. The combined EtOAc layer was diluted with 50 mL THF, dried over MgSO 4 , and filtered through silica gel plug. Most of solvents were removed to form a slurry with around 2 mL of solvent left. Solid was collected by filtration, washed with 2 mL EtOAc, and dried. The desired product 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-dimethyl indol-5-yl)-5-hydroxy-[1,2,4] triazole (Compound 223) was obtained as an off-white solid (1.75g, 4.63mmol, 85%). 'H NMR (CD30D), S (ppm) 7.46 (d, J= 1.8 Hz, IH), 7.41 (d,J= 8.4 Hz, I H), 7.04 (dd,J = 8.4 Hz, 1.8 Hz, I H), 7.02 (s, I H), 6.53 (s, I H), 6.26 (s, I H), 3.74 (s, 3H), 2.88 (sept, J= 6.9 Hz, I H), 2.24 (s, 3 H), 0.62 (d, J= 6.9 Hz, 6H); ESMS calculated. for C 21
H
23
N
4 0 3 378.1; Found: 379.1 (M + 1)*. The following compounds were prepared as described above in the section entitled "Methods of Making the Compounds of the Invention" and as exemplified in Examples I through 4.
C :NRPotbl\DCC\REC\4(75614_l.DOC-1/10/2012 -311 Example 5: Compound 1 ESMS calcd for C 18
H
13
N
3 OS: 319.1; Found: 320.0 (M+1)*. Example 6: Compound 2 ESMS calcd for C 21 1 9
N
3 0 4 S: 409.11; Found: 410.0 (M+H)*. Example 7: Compound 5 ESMS calcd for Cl 9 Hl 5
N
3 0 2 S: 365.08; Found: 266.0 (M+H)*. Example 8: Compound 6 ESMS called for C 20 Hl 7
N
3 0 2 S: 379.10; Found: 380.0 (M+H)*. Example 9: Compound 7 ESMS calcd for C 2 1
H
19
N
3 0 2 S: 393.11; Found: 394.0(M+H)*. Example 10: Compound 8 ESMS called for C 2 1
H
1 9
N
3 0 3 S: 393.11; Found: 394.0(M+H)*. Example 11: Compound 9 ESMS calcd for C 2 1
H
1 9
N
3 0 2 S: 393.11; Found: 394.0(M+H)*. Example 12: Compound 13 'H-NMR (DMSO-d 6 ) 8 9.65 (s, I H), 9.57 (s, I H), 7.50 (d, J=8.I Hz, 1 H), 7.35 (d, J=3.3Hz, I H), 7.14 (t, J=7.8 Hz, I H), 6.96 (d, J=7.5 Hz, I H), 6.88 (d, J=8.1 Hz, I H), 6.09-6.11 (m, 2H), 6.01 (dd, J;=2.1 Hz, J 2 =8.1 Hz, I H), 4.13-4.22 (m, 2H), 1.36 (t, J=7.2Hz, 3H); ESMS calcd for C 18 Hl 6
N
4 0 2 S: 352.10; Found: 353.1 (M+1)". Example 13: Compound 14 'H NMR (DMSO-d 6 ) 5 9.72(s, 1 H), 9.67(s, I H), 7.04-7.01 (m, I H), 6.83-6.78(m, 2H), 6.66-6.63(m, I H), 6.20-6.19(m, 2H), 4.22(s, 4H); ESMS calcd for C 16
H
13 N30 4 S: 343.06; Found: 344.0 (M+1)1.
C'NRPonbl\DCCOREC4075614_ .DOC-1/10/2012 -312 Example 14: Compound 15 ESMS calcd for Cl 5
H
13
N
3 0 2 S: 299.07; Found: 300.0 (M+H)*. Example 15: Compound 16 ESMS calcd for C 15
H]
3
N
3 0 2 S: 299.07; Found: 300.0 (M+H)~. Example 16: Compound 17 ESMS calcd for Ci 4
HIOCIN
3 0 2 S: 319.02; Found: 320.0 (M+H)*. Example 17: Compound 18 ESMS calcd for C 1 4 HIOClN 3 0 2 S: 319.02; Found: 320.0 (M+H)*. Example 18: Compound 19 ESMS calcd for C 1 4 HIOClN 3 0 2 S: 319.02; Found: 320.1 (M+H)*. Example 19: Compound 20 ESMS called for C 15
H
13
N
3 0 3 S: 315.07; Found: 316.0 (M+H)*. Example 20: Compound 21 ESMS calcd for Cl 5
H
13
N
3 0 3 S: 315.07; Found: 316.0 (M+H)*. Example 21: Compound 22 ESMS calcd for Ci 5
H
13
N
3 0 3 S: 315.07; Found: 316.0 (M+H)*. Example 22: Compound 23 ESMS calcd for Cl 4 HoFN 3 0 2 S: 303.05; Found: 304.0 (M+H)*. Example 23: Compound 23 H NMR (DMSO-d 6 ) 8 9.69 (s, 1 H), 9.65 (s, I H), 7.16 (d, J=7.2Hz, 1 H), 7.05 (t, J=7.2Hz, 1 H), 6.93 (d, J=8.1 Hz, 2H), 6.11-6.16 (m, 2H), 2.21 (s, 3H), 1.89 (s, 3H); ESMS Calcd C 16 Hl 5
N
3 0 2 S: 313.09, Found 314.1 (M+1)*. Example 24: Compound 24 ESMS calcd for CIH 15
N
3 0 2 S: 313.09; Found: 314.0 (M+H)*.
C:\NRPortbl\DCCREC4075614 LDOC.1/10/2012 - 313 Example 25: Compound 25 'H NMR (DMSO-d 6 )8 10.44 (m, I H), 8.00-7.95 (m, 2H), 7.55-7.37 (m, 5H), 6.61 (d, J= 7.8 and 1.8 Hz, I H), 6.51 (t, J= 8.6 Hz, I H), 6.41(d, J= 10.8 Hz, I H); ESMS calcd for CisH, 2
FN
3 OS: 337.07; Found: 338.0 (M+1)*. Example 26: Compound 26 'H NMR (DMSO-d 6 ) 8 9.57 (s, I H), 7.99 (d, J= 8.4 Hz, I H), 7.96 (d, J= 6.9 Hz, Il H), 7.55-7.37 (m, 5H), 6.61 (d, J= 8.1 Hz, I H), 5.83 (d, J= 2.1 Hz, I H), 5.73(dd, J= 8.1 and 1.8 Hz, I H), 5.24 (s, 2H); ESMS calcd for CIH, 4
N
4 OS: 334.09; Found: 335.0 (M+1)*. Example 27: Compound 27 ESMS calcd for C, 8 Hj 9
N
3 0 2 S: 341.12; Found: 342.0 (M+H)*. Example 28: Compound 28 ESMS calcd for C 6 H, 5
N
3 0 2 S: 313.09; Found: 314.0 (M+H)*. Example 29: Compound 29 ESMS called for C1 6 HIsN 3 0 2 S: 313.09; Found: 314.0 (M+H)*. Example 30: Compound 30 ESMS calcd for Cl 6 Hj 5
N
3 0 2 S: 313.09; Found: 314.0 (M+H)*. Example 31: Compound 31 ESMS calcd for C, 4 HoFN 3 0 2 S: 303.05; Found: 304.0 (M+H)'. Example 32: Compound 32 ESMS calcd for C 5 Hl 3
N
3 0 2 S: 331.04; Found: 332.0 (M+H)*. Example 33: Compound 33 ESMS calcd for C 1 8 Hl 3
N
3 0 2 S: 335.07; Found: 336.0 (M+H)*.
C:\NRPorbl\DCCREC4075614_ I DOC-1/ 1/2012 -314 Example 34: Compound 34 ESMS calcd for Cl 6
H
1 sN 3 0 2 S: 313.09; Found: 314.0 (M+H)*. Example 35: Compound 35 ESMS calcd for C 15
H
12
FN
3 0 2 S: 317.06; Found: 317.0 (M+H)*. Example 36: Compound 36 ESMS calcd for C20H I 5N302S: 361.1; Found: 362.0 (M+1)*. Example 37: Compound 37 H NMR (DMSO-d 6 ) 8 10.03 (s, I H), 8.00-7.96 (m, 2H), 7.55-7.37 (m, 5H), 7.00 (d, J= 8.1 Hz, I H), 6.20 (m, 2H), 3.57 (s, 3H); ESMS calcd for Cl 9 HisN 3 0 2 S: 349.09; Found: 350.0 (M+l)~. Example 38: Compound 38 ESMS calcd for C 14
H
9 Cl 2
N
3 0 2 S: 352.98; Found: 353.9 (M+H)*. Example 39: Compound 39 'H NM R (DMSO-d 6 ) 6 9.74 (s, I H), 9.63 (s, I H), 8.14 (m, 1 H), 7.52-7.48 (m, 2H), 7.37 (d, J = 8.4 Hz, I H), 7.32 (m, 1 H), 6.96 (d, = 8.1 Hz, I H), 6.90 (d, = 8.4 Hz, I H), 6.08 (d, = 1.9 Hz, I H), 6.01 (d, = 8.4 Hz, 1 H), 3.98 (s, 3H); ESMS calcd for Cl 9
H
15
N
3 0 3 S: 365.08; Found: 366.0 (M+l)*. Example 40: Compound 40 ESMS calcd for C 2 5
H
16
N
3 0 2 S: 409.09; Found: 410.0 (M+1)*. Example 41: Compound 42 'H NMR (DMSO-d 6 ) 6 9.75(s, I H), 9.67(s, I H), 7.08(s, 2H), 6.96-6.94(m, 2H), 6.18 6.13(m, 2H), 2.72-2.50(m, 3H), 2.35-2.28(m, I H), 1.64-1.60(m, 4H); ESMS called for C 18
H
17
N
3 0 2 S: 339.10; Found: 340.0 (M+1)*. Example 42: Compound 43 ESMS calcd for C 2 2
H
15
N
3 0 2 S: 385.09; Found: 386.0 (M+1)*.
CNRPorbIlOCOREC4)75%614 I DOC-I/1 1/2012 -315 Example 43: Compound 44 ESMS calcd for C 2 0 Hl 5
N
3 0 2 S: 361.09; Found: 362.0 (M+1)*. Example 44: Compound 45 ESMS called for Cl 9
H
15
N
3 0 2 S: 349.09; Found: 350.0 (M+I)'. Example 45: Compound 46 ESMS calcd for C 19
H
21
N
3 0 3 S: 371.13; Found: 372.0 (M+])*. Example 46: Compound 47 ESMS calcd forC 2 2
H
2 7
N
3 0 3 S: 413.18; Found: 414.1 (M+1)". Example 47: Compound 48 ESMS calcd for Ci 8
H
12
CIN
3 0 2 S: 369.03; Found: 370.0 (M+H)*. Example 48: Compound 49 H NMR (DMSO-d 6 ) 8 9.49 (s, I H), 9.40 (s, I H), 7.94-7.99 (m, 2H), 7.38-7.56 (m, 5H), 6.70 (s, I H), 6.13 (s, I H), 2.12 (q, J=7.2 Hz, 2H), 0.71 (t, J=7.2Hz, 3H); ESMS Calcd for C 20
H
17
N
3 0 2 S: 363.10, Found 364.1(M+1)*. Example 49: Compound 50 ESMS calcd for C 20 H 15
N
3 0 5 S: 409.07; Found: 410.0 (M+H)*. Example 50: Compound 51 ESMS calcd for C1 8
H
14
N
4 0 2 S: 350.08; Found: 351.0 (M+H)'. Example 51: Compound 52 ESMS calcd for C 17
H
12
N
4 OS: 320.07; Found: 320.9 (M+H)*. Example 52: Compound 53 H NMR (CDCl 3 ) 8 12.0 (br s, I H), 9.87 (br s, 1 H), 9.83 (br s, I H), 7.97 (d, J= 8.1 Hz, 2H), 7.41-7.56 (m, 5H), 7.13 (d, J= 1.5 Hz, 1 H), 7.07 (d, J= 8.7 Hz, I H), 6.71 (dd, J= 1.8 Hz, 8.1 Hz, I H), 1.93 (s, 3 H); ESMS calcd for C 20
H
1
,N
4 0 2 S: 376.1; Found: 377.0(M+1)*.
C:\NRPonbnDCC\REC\4O75614_I.DOC.1/10f2012 -316 Example 53: Compound 56 ESMS calcd for C 1 6 Hl 5
N
3 0 4 S: 345.08; Found: 346.0 (M+ 1)'. Example 54: Compound 57 ESMS calcd for C 1 8 Hl 6
N
4 0 2 S: 352.10; Found: 353.0 (M+1)*. Example 55: Compound 61 H NMR (DMSO-d 6 ) 8 9.66(s, I H), 9.60(s, I H), 7.29-7.27(m, I H), 7.12-7-10(m, 2H), 7.03-7.00(m, I H), 6.19-6.17(m, 2H), 1 .18(s, 18H); ESMS caled for C 22
H
27
N
3 0 2 S: 397.18; Found: 398.1 (M+1)*. Example 56: Compound 64 ESMS calcd for C2 1
H
15
N
3 0 3 S: 389.08; Found: 390.0 (M+H)*. Example 57: Compound 65 ESMS called for C 9 Hl 3
N
3 0 4 S: 379.06; Found: 380.0 (M+1)*. Example 58: Compound 66 ESMS calcd for C 2 1
H
18
N
4 0 3 S: 406.11; Found: 407.0 (M+1)*. Example 59: Compound 67 ESMS calcd for C 21 l1 9
N
3 0 3 S: 393.11; Found: 394.0 (M+1)*. Example 60: Compound 68 ESMS called for C 21 Hl 9
N
3 0 3 S: 393.11; Found: 394.0 (M+1)*. Example 61: Compound 69 ESMS calcd for C 21 HlgN 3 0 3 S: 393.1 1; Found: 394.0 (M+1)*. Example 62: Compound 70 ESMS calcd for C 17
H
1 2
N
4 0 2 S: 336.07; Found: 337.0 (M+H)*.
C:\NRPorbl\DCC\REC4075614_1 DOC-1/1012012 -317 Example 63: Compound 71 ESMS called for C 21
H
19
N
3 0 3 S: 393.11; Found: 394.0 (M+1)*. Example 64: Compound 72 'H NMR (DMSO-d 6 ) 5 10.3 (br s, I H), 7.95-8.19 (m, 2H), 7.48-7.72 (m, 5H), 7.17 (d, J= 8.4 Hz, I H), 6.44 (d, J= 8.4 Hz, I H), 5.95 (d, J= 2.1 Hz, I H), 5.73 (dd, J= 2.1 Hz, 8.4 Hz, I H), 5.47 (br s, I H), 3.62 (s, 3 H); ESMS called for C1 9
HI
7
N
4 0 2
S
2 : 412.1; Found: 413.0(M+1)*. Example 65: Compound 73 'H NMR (DMSO-d 6 ) 8 9.37 (s, I H), 8.94 (s, I H), 7.94-7.98 (m, 2H), 7.43-7.60 (m, 5H), 5.97 (s, I H), 1.85 (s, 3 H), 1.81 (s, 3 H); ESMS calcd for C 20 Hj 8
N
3 0 2 S: 363.1; Found: 364.0(M+1)-. Example 66: Compound 74 ESMS calcd for C 21
H
1 9
N
3 0 4 S: 409.11; Found: 410.0 (M+H)'. Example 67: Compound 75 'H NMR (DMSO-d 6 ) 8 9.46 (s, I H), 9.45 (s, I H), 7.95-8.00 (m, 2H), 7.38-7.56 (m, 5H), 6.65 (s, I H), 6.15 (s, I H), 2.07-2.14 (m, 2H), 081-1.18 (m, Il H); ESMS calcd for C 24
H
26
N
3 0 2 S: 419.1; Found: 420.1 (M+ 1)'. Example 68: Compound 76 ESMS calcd for C 2 lH1 9
N
3 0 3 S: 393.11; Found: 394.0 (M+H)*. Example 69: Compound 77 ESMS called for C 21
H,
9
N
3 0 3 S: 393.11; Found: 394.0 (M+H)*. Example 70: Compound 78 'H NMR (DMSO-d 6 ) 5 9.71 (s, 1 H), 9.35 (s, I H), 7.98-8.04 (m, 2H), 7.50-7.62 (m, 5H), 6.58 (s, I H), 2.15 (q, J= 7.5 Hz, 2H), 0.58 (t, J= 7.5 Hz, 3H); ESMS calcd for C 20 Hl 7
CIN
3 0 2 S: 397.0; Found: 398.0(M+1)*.
C:\NRPonbl\DCCREC\4075614_ .DOC-1/10/2012 -318 Example 71: Compound 79 ESMS calcd for C, 9
H
2 1 N303S: 371.13; Found: 372.0 (M+H)*. Example 72: Compound 80 ESMS calcd for C 21
H
1 9
N
3 0 2 S: 393.1 1; Found: 394.0 (M+H)~. Example 73: Compound 81 ESMS calcd for C 2 0 H1 7
N
3 0 2 S: 379.10; Found: 380.0 (M+H)*. Example 74: Compound 82 ESMS calcd for C 21
H,
9
N
3 0 2 S: 393.1 1; Found: 394.0 (M+H)*. Example 75: Compound 83 ESMS calcd for C 2 0 Hl 7
N
3 0 3 S: 379.10; Found: 380.0 (M+H)*. Example 76: Compound 84 ESMS called for C 20 Hl 7
N
3 0 3 S: 379.10; Found: 380.0 (M+H)*. Example 77: Compound 85 ESMS calcd for Cl 9
HI
5
N
3 0 2 S: 365.08; Found: 266.0 (M+H)*. Example 78: Compound 86 'H NMR (DMSO-d 6 ) 6 9.68 (s, I H), 9.58 (s, I H), 8.2 (dd, J = 7.0 and 2.4 Hz, I H), 7.50 (m, 2H), 7.40 (tr,.J= 8.1 Hz, I H), 7.32 (m, I H), 6.97 (d, J= 7.5 Hz, I H), 6.95 (m, I H), 6.89 (d, = 8.4 Hz, I H), 6.08 (d, = 2.1 Hz, I H), 6.0 (dd, = 7.4 and 2.1 Hz, I H), 3.96 (s, 3H); ESMS calcd for CjqH, 5
N
3 03S: 365.08; Found: 366.0 (M+1)'. Example 79: Compound 87 'H NMR (MeOH-d 4 ) 68.25 (m, I H), 7.96 (s, I H), 7.46-7.44 (m, 2H), 7.26 (d, J= 8.4 Hz, 1 H), 6.83 (d, J= 8.1 Hz, I H), 6.70 (d, J= 8.7 Hz, 1 H), 6.17 (d, J= 2.1 Hz, 1 H), 5.98 (dd,.J= 8.4 and 2.4 Hz, I H); ESMS calcd for CisH, 3
N
3 0 3 S: 351.07; Found: 352.0 (M+1)*.
CANRPonbl\DCC\REC\4075614.1 DOC./10/2012 -319 Example 80: Compound 88 'H-NMR (DMSO-d 6 ) 5 9.69 (s, 1H), 9.59 (s, 1H), 7.54 (d, J=8.1Hz, 1H), 7.46 (d, J=3Hz, I H), 7.14 (t, J=7.8 Hz, I H), 6.97 (d, J=7.2 Hz, I H), 6.89 (d, J=8.7Hz, 1 H), 6.12-6.13 (m, 2H), 6.02 (dd, J;=2.4 Hz, 12=8.4 Hz, 1 H), 4.74 (qn, J=6.6Hz, 1 H), 1.40-1.46 (m, 6H); ESMS calcd for Cl 9 Hl 8
N
4 0 2 S: 366.12; Found: 367.1 (M+1)*. Example 81: Compound 89 ESMS called for C 22
H
2 1
N
3 0 2 S: 391.14; Found: 392.0 (M+H)f. Example 82: Compound 90 'H NMR (DMSO-d 6 ) 6 9.47 (s, I H), 9.43 (s, I H), 7.94-8.00 (m, 2H), 7.39-7.57 (m, 5H), 6.68 (s, I H), 6.15 (s, I H), 2.05-2.15 (m, 2H), 1.05-1.17 (m, 2H), 0.50 (t, J= 7.5 Hz, 3H); ESMS calcd for C 2 , H 20
N
3 0 2 S: 377.1; Found: 378.0(M+l)*. Example 83: Compound 91 'H NMR (DMSO-d 6 ) 6 9.15 (s, I H), 8.50 (s, I H), 8.00 -8.07 (m, 2H), 7.47-7.63 (m, 5H), 6.27 (s, I H), 2.06 (q, J= 7.5 Hz, 2H), 1.93 (s, 3 H), 0.45 (t, J= 7.5 Hz, 3H); ESMS calcd for C 2 1
H
2 0
N
3 0 2 S: 377.1; Found: 378.0(M+])*. Example 84: Compound 93 ESMS calcd for C1 6 Hl 5
N
3 0 4 S: 345.08; Found: 346.0 (M+H)*. Example 85: Compound 95 ESMS calcd for Ci 6
H,
2
N
4 0 2 S: 324.07; Found: 325.0 (M+H)". Example 86: Compound 96 ESMS calcd for Cl9H, 8
N
4 0 3 S: 382.11; Found: 383.0 (M+H)*. Example 87: Compound 98 ESMS calcd for C 7 Hl 2
N
4 0 2 S: 336.07; Found: 337.0 (M+H)f. Example 88: Compound 99 ESMS calcd for C, 9 H1 3
N
3 0 4 S: 379.06; Found: 379.9 (M+H) 4
.
C:\NRPonbhDCC\REC\4075614_ 1 DOC- I/10f/2012 - 320 Example 89: Compound 100 'H-NMR (DMSO-d 6 ) 8 9.52 (s, I H), 9.42 (s, I H), 7.56 (d, J=8.7Hz, 1 H), 7.49 (d, J=3.3Hz, 1 H), 7.14 (t, J=7.5 Hz, I H), 6.95 (d, J=8.4Hz, 1 H), 6.61 (s, I H), 6.21 (s, I H), 6.14 (dd, J=3.3 Hz, I H), 4.76 (qn, J=6.6Hz, I H), 2.14 (q, J=7.5Hz, 2H), 1.41-1.47 (m, 6H), 0.66 (t, J=7.5 Hz, 3 H); ESMS calcd for C 21
H
22
N
4 0 2 S: 394.15; Found: 395.1 (M+1)*. Example 90: Compound 101 ESMS calcd for CjqHl7N 5 0 3 S: 395.11; Found: 396.0 (M+H)*. Example 91: Compound 102 ESMS calcd. for CjqH 2 0
N
5
O
2 S: 381.1; Found: 382.0 (M + 1)*. ExampDle 92: Compound 103 H NMR (DMSO-d 6 ) 3 9.48 (s, I H), 9.38 (s, I H), 7.29(d, J= 8.4 Hz, I H), 7.25(d, J= 1.8 Hz, 1 H), 6.85-6.89 (m, 2H), 6.18 (s, I H), 3.61 (s, 3H), 2.30 (s, 3H), 2.29 (q, J= 7.5 Hz, 2H), 2.09 (s, 3 H), 0.94 (t, J= 7.5 Hz, 3 H); ESMS calcd for C 2 1
H
23
N
4 0 2 S: 394.1; Found: 395.0(M+ 1)+. Example 93: Compound 104 ESMS calcd for C 1 gH 15
N
3 0 3 S: 365.08; Found: 366.0 (M+H)*. Example 94: Compound 106 ESMS calcd for C 20 Hl 7
N
4 0 2 S: 377.1; Found: 378.0(M+H)". Example 95: Compound 107 ESMS calcd for C 18 Hl 3
CIN
3 0 2 S: 369.0; Found: 370.0(M+H)*. Example 96: Compound 116 H NMR (DMSO-d 6 ) 3 7.98-7.56 (m, 2H), 7.55-7.30 (m, 6H), 6.43 (dd, J= 8.1 and 1.8 Hz, 1 H), 6.29 (m, I H), 3.65 (s, 3 H), 3.16 (s, 3 H); ESMS calcd for C 20 Hl 7 N30 2 S: 363.10; Found: 364.0 (M+I)*.
C \NRPotbI\DCC\RECU4)75614. DOC./10/2012 -321 Example 97: Compound 117 'H-NMR (CDC 3 ) 6 7.83(d, J=8.1 Hz, 2H), 7.48-7.34(m, 4H), 7.28-7.20(m, 1 H), 6.99 (d, J=1 .8Hz, I H), 6.80(d, J=8.7Hz, I H), 6.62-6.58(m, I H), 2.94(s, 3H), 2.89(s, 3H), 2.84(s, 3H), 2.8 1(s, 3 H), 2.75-2.69(m, 6H); ESMS calcd for C 2 7
H
2 8
N
6 0 5 S: 548.18; Found: 549.2 (M+ I)*. Example 98: Compound 122 'H-NMR (CDCl 3 ) 6 7.98(m, 2H), 7.60-7.55(m, 3H), 7.5 1-7.45(m, I H), 7.36-7.33(m, I H), 6.98-6.97(m, I H), 6.86(d, J=9.9Hz, I H), 6.70-6.67(m, I H), 2.86(s, 3 H), 2.26(s, 3 H), 2.21(s, 3 H); ESMS calcd for C 2 4
H
19
N
3 0 5 S: 461.10; Found: 462.0 (M+1)*. Example 99: Compound 125 ESMS calcd for C 2 0 Hl 7
N
3 0 3 S: 379.10; Found: 380.0 (M+H)*. Example 100: Compound 126 ESMS calcd for CIOH IN 3 02S: 237.06; Found: 238.0 (M+H)*. Example 101: Compound 127 ESMS calcd for C 1
H
1 3
N
3 0 2 S: 251.07; Found: 252.0 (M+H)*. Example 102: Compound 128 ESMS calcd for CI H 13
N
3 0 2 S: 251.07; Found: 252.0 (M+H)*. Example 103: Compound 129 ESMS calcd for CIIHIIN 3 0 2 S: 249.06; Found: 250.0 (M+H)*. Example 104: Compound 130 ESMS calcd for Cl 2 Hj 5
N
3 0 2 S: 265.09; Found: 266.0 (M+H)*. Example 105: Compound 131 ESMS calcd for C 20 Hj 5
N
3 0 4 S: 393.08; Found: 394.1 (M+H)*.
C\NRPorb\DCC\REC4075614_ I DOC-1/10/2012 - 322 Example 106: Compound 177 'H NM R (DMSO-d 6 ) 8 9.34(s, 1 H), 9.22 (s, I H), 8.01-7.96 (m, 2H), 7.58-7.44 (m, 5H), 6.56 (s, I H), 6.14 (s, I H), 3.29 (s, 3 H); ESMS calcd for C 1 9
H
1 5
N
3 0 3 S: 365.08; Found: 366.0(M+1)*. Example 107: Compound 178 'H NMR (DMSO-d 6 ) 5 10.29 (s, I H), 9.49 (s, I H), 9.42 (s, 1 H), 8.16 (t,J= 5.1 Hz, 1 H), 7.45-7.43 (m, 2H), 7.26 (t, J= 8.0 Hz, I H), 6.84 (d, J= 7.8 Hz, 1 H), 6.75 (d, J= 8.7 Hz, 1 H), 6.66 (s, I H), 6.14 (s, I H), 2.12 (q,J= 7.5 Hz, 2H), 0.70 (t,J= 7.2 Hz, 3H); ESMS called for C 20 Hl 7
N
3 0 3 S: 379.10; Found: 379.9 (M+1)*. Example 108: Compound 179 ESMS called for Ci 9 Hi 5
N
3 0 2 S: 349.09; Found: 350.0 (M+1)*. Example 109: Compound 180 ESMS calcd for Cl 9 Hl 5
N
3 0 2 S: 349.09; Found: 350.0 (M+H)*. Example 110: Compound 181 ESMS called for C20H 1 5N302S: 361.09; Found: 362.0 (M+H)'. Example 111: Compound 182 ESMS calcd for C 16
H
15
N
3 0 3 S: 329.08; Found: 330.0 (M+H)*. Example 112: Compound 183 ESMS calcd for C 20 Hl 7
N
3 0 2 S: 363. 10; Found: 364.0 (M+H)*. Example 113: Compound 184 ESMS calcd for C 18
H
1 3
N
3 0 3 S: 350.38; Found: 351.9(M+H)*. Example 114: Compound 185 ESMS calcd. for C 20
H
2 1
N
4 0 2 S: 380.1; Found: 381.0 (M + 1)*. 3. Example 115: Compound 187 ESMS calcd. for Cl 9
H
2 0 NS0 2 S: 381.1; Found: 382.0 (M + 1)'.
C:\NRPorbl\DCCREC\4075614_ I DOC-1/10/2012 - 323 Example 116: Compound 190 4. ESMS calcd. for C2,H2 2
N
4 02S: 394.15; Found: 395.0 (M+1)+. Example 117: Compound 191 ESMS calcd. for C 22
H
23
N
4 0 4 S: 438.1; Found: 439.0 (M + 1)*. Example 118: Compound 192 ESMS calcd. for C 20
H
22
N
5 0 2 S: 395.1; Found: 396.0 (M + )*. Example 119: Compound 193 ESMS calcd. for C 2 0
H
22
N
5 0 2 S: 395.1; Found: 396.0 (M + 1)+. Example 120: Compound 194 ESMS called. for C 23
H
27
N
4 0 2 S: 422.1; Found: 423.0 (M + 1)*. Example 121: Compound 195 ESMS caled. for C 23
H
25
N
4 0 2 S: 420.1; Found: 421.0 (M + 1)*. Example 122: Compound 196 ESMS called. for C 25
H
29
N
4 0 2 S: 448.1; Found: 449.3 (M + 1)*. Example 123: Compound 197 ESMS calcd. for C 2 2
H
2 4
N
4 0 2 S: 408.16; Found: 409.2 (M+1)*. Example 124: Compound 198 ESMS called. for C 2 3
H
2 6
N
4 0 2 S: 422.18; Found: 423.3 (M+1)*. Example 125: Compound 199 ESMS calcd. for C 24 H2 8
N
4 0 2 S: 436.19; Found: 437.3 (M+1)*. Example 126: Compound 200 ESMS calcd. for C 22
H
22
N
4 0 2 S: .406.15; Found: 407.2 (M+])*.
C:\NRPortbl\DCC\REC\4075614_I DOC-1/10/212 -324 Example 127: Compound 201 ESMS calcd. for C 2 3
H
24
N
4 0 3 S: 436.16; Found: 437.3 (M+I)*. Example 128: Compound 202 ESMS called. for C 22
H
23
N
4 0 2 S: 406.1; Found: 407.0 (M + H)-. Example 129: Compound 204 ESMS calcd. for C 24 H2 8
N
4 0 3 S: .452.19; Found: 453.2 (M+])+. Example 130: Compound 205 ESMS calcd. for C 2 3
H
2 4
N
4 0 3 S: 436.16; Found: 437.1 (M+I). Example 131: Compound 206 ESMS caled. for C 21
H
2 3
N
4 0 2 S: 394.1; Found: 395.1 (M + 1)*. Example 132: Compound 207 ESMS calcd. for C 20
H
21
N
4 0 2 S: 380.1; Found: 381.1 (M + 1)*. Example 133: Compound 208 ESMS calcd. for C 2 3
H
2 6
N
4 0 3 S: 438.17; Found: 439.1 (M+I)*. Example 134: Compound 209 ESMS calcd. for C 22
H
24
N
4 0 2 S: 408.1; Found: 409.1 (M + 1)*. Example 135: Compound 210 ESMS calcd. for C 24
H
23
N
4 0 2 S: 430.1; Found: 43 11 (M + 1)*. Example 136: Compound 211 ESMS calcd. for C 2 iH22N 4 0 3 S: 410.14; Found: 411.1 (M+1)*. Example 137: Compound 212 ESMS calcd. for C 2 3H 26
N
4 0 3 S: 438.17; Found: 439.1 (M+])*.
C WRPortb\DCC\REC\407561_1 DOC-1/10/21)[2 - 325 Example 138: Compound 213 ESMS calcd. for C 20
H
21
N
4 0 2 S :380.1; Found: 381.1 (M + 1)'. Example 139: Compound 214 ESMS calcd. for C 9 H 9
N
4 0 2 S: 366.1; Found: 367.1 (M + l)*. Example 140: Compound 215 ESMS calcd. for C 20
H
1 9
N
3 0 4 S: 397.1; Found: 398.1 (M+1)*. Example 141: Compound 216 'H NMR (DMSO-d 6 ): 5 (ppm) 9.56 (s, I H), 9.40 (s, 1 H), 8.03 (d, J= 2.4 Hz, I H), 7.58 (d, J= 8.4 Hz, I H), 7.54 (d, J= 2.1 Hz, I H), 7.11 (dd, J = 8.4, 2.1 Hz, I H), 6.97 (d, J= 2.4 Hz, l H), 6.89 (s, 1 H), 6.17 (s, I H), 2.23 (q, J= 7.2 Hz, 2H), 0.93 (t, J= 7.2 Hz, 3H); ESMS calcd. for C 1 8 Hl 5
N
3 0 3 S: 353.08; Found: 354.0 (M+1)*. Example 142: Compound 217 'H NMR (DMSO-d 6 ): S (ppm) 9.59 (s, I H), 9.43 (s, I H), 7.67 (d, J = 8.7 Hz, I H), 7.54 (d, J= 2.1 Hz, I H), 7.20 (dd, J= 8.4, 2.1 Hz, 1 H), 6.96 (s, I H), 6.18 (s, I H), 2.60 (s, 3 H), 2.34 (q, J 7.2 Hz, 2H), 0.98 (t, J= 7.2 Hz, 3H); ESMS calcd. for CgH 6
N
4 0 3 S: 368.09; Found: 369.0 (M+1)*. Example 143: Compound 218 ESMS calcd. for C 21
H
2 3
N
4 0 2 S: 394.1; Found: 395.1 (M + 1)'. Example 144: Compound 219 ESMS calcd. for C 21
H
21
N
4 0 2 S: 392.1; Found: 393.1 (M + 1)'. Example 145: Compound 220 ESMS calcd. for C 20
H
21
N
4 0 3 : 364.1; Found: 365.1 (M + 1)'. Example 146: Compound 221 ESMS calcd. for C 20
H
2 jN 4 0 2 S: 379.1; Found: 381.1 (M + 1)*.
C:\NRPorbl\DCC\REC4075614_ 1DOC-1/10/2012 -326 Example 147: Compound 222 ESMS calcd. for C 21
H
2 3
N
4 0 2 S: 394.1; Found: 395.l(M + 1)*. Example 148: Compound 224 ESMS calcd. for C 19
H
21
N
4 0 2 S: 368.1; Found: 369.1 (M + ). Example 149: Compound 225 ESMS calcd. for CjqH 19
N
4 0 2 S: 366.1; Found: 367.l(M + 1)*. Example 150: Compound 226 ESMS called. forC 2 0
H
2 1
N
4 0 3 : 364.1; Found: 365.1 (M + I)-. Example 151: Compound 227 ESMS calcd. for C 21
H
2 2
N
4 0 2 S: 394.15; Found: 395.1 (M+l)*. Example 152: Compound 228 ESMS calcd. for C 2 2
H
24
N
4 0 2 S: 408.16; Found: 409.1 (M+1)'. Example 153: Compound 229 ESMS calcd. forC 2 0 HisF 3
N
5
O
2 S: 449.11; Found: 450.1 (M+1)+. Example 154: Compound 230 ESMS calcd. for C 9
H
1 9
N
5
O
2 S: 381.13; Found: 382.1 (M+])'. Example 155: Compound 231 ESMS calcd. for CjqHjqN 5 0 2 S: 381.13; Found: 382.1 (M+1). Example 156: Compound 232 ESMS calcd. for C 2 2H 24
N
4 0 3 S: 392.18; Found: 393.1 (M+I)*. Example 157: Compound 233 ESMS calcd. for Cl8H 17N304S: 371.09; Found: 372.1 (M+1)+.
C\NRPonb2\DCC\REC\4073614_1 DOC-1/10/2012 -327 Example 158: Compound 234 ESMS calcd. for C20H21 N302S: 367.14; Found: 368.1 (M+1)+. Example 159: Compound 235 ESMS calcd. for C 1 gH 19
N
5 0 2 S: 381.13; Found: 382.1 (M+1)*. Example 160: Compound 239 ESMS clcd for Cl 9
H
2 1
N
4 0 2 S: 368.1; Found: 369.1 (M + H)'. Example 161: Compound 240 ESMS clcd forC 18
H
1 6
N
4 0 3 S: 368.09.10; Found: 369.1 (M+H). Example 162: Compound 241 ESMS clcd for Cl7H 15
N
5 0 3 S: 369.09; Found: 370.1 (M+H)*. Example 163: Compound 242 ESMS clcd for C 19 Hl 8
N
4 0 3 S: 382.11; Found: 383.1 (M+H)*. Example 164: Compound 243 ESMS clcd for C 2 2
H
26
N
4 0 3 S: 426.17; Found: 427.1 (M+H)*. Example 165: Compound 244 ESMS clcd for Cl 8
H
1 6
N
4 0 4 S: 384.09; Found: 385.1 (M+H)* Example 166: Compound 245 ESMS clcd for C 18 Hl 6
N
4 0 3
S
2 : 400.07; Found: 401.1 (M+H)* Example 167: Compound 245 ESMS clcd for C 17
H
14
N
4 0 3
S
2 : 386.05; Found: 387.0 (M+H)*.
C:\NRPorb\DC C\REC4075614 DOC-1/1/2012 - 328 Example 168: 4-{5-Hydroxy-4-[4-methoxy-3-(methylpropylamino)phenyl]-4H-[ 1,2,4]triazol-3 yl}-6-isopropyl-benzene- 1,3-diol O N H 00I NrOH OH N-N Scheme I 0 BnCI00 S K2CO3 iOH OH 1 (COCI) 2 HO OH BnO O~n BnO OBn O (1) (2) N
NH
2 0 O O 1. Lawesson's N N . N N 2. NH 2
NH
2 B H 2 Pd e H Na 3* CDIH2P BnO OBn HN ON OH OBn N-N OH N-N (3) (4) To a solution of 2,4-dihydroxy-5-isopropylbenzoic acid methyl ester (1.63 g, 7.75 mmol) in dimethylformamide (DMF) (100 mL) was added potassium carbonate (3.21 g, 23 mmol) then benzyl chloride (1.95 ml, 17 mmol). The suspension was heated to 80'C for 16 hrs under a nitrogen atmosphere. Ethyl acetate (100 ml) and water (100 ml) were added, and then the ethyl acetate layer was washed with water (3x50 mL), and then dried over magnesium sulfate, filtered and evaporated to dryness to produce the desired compound as brown oil (2.9 g, 97%). 2,4-Bis-benzyloxy-5-isopropylbenzoic acid methyl ester (3.23 g, 8.27 mmol) and LiOH (1.0 g, 24.8 mmol) were heated in a mixture of tetrahydrofuranyl (THF)/methanol/water (100 mL, 3:1:1) for 16 hrs. Ethyl acetate (100 mL) and water (100 ml) were added, then the ethyl acetate layer was washed with water (3x50 mL), dried over magnesium sulfate, filtered and evaporated to dryness to produce the desired compound as a yellow solid (2.6 g, 83%). 2,4-Bis-benzyloxy-5-isopropylbenzoic acid (1.25 g, 3.32 mmol) was dissolved in dichloromethane (50 mL) and cooled in an ice bath. Oxalyl chloride (0.32 mL, 3.65 mmol) was added followed by the dropwise addition of DMF (0.1 mL). The reaction was stirred at room C:\NRPortbKlDCC\REC\407564_I DOC-1/10/2012 -329 temperature for 1 hr then evaporated to dryness under reduced pressure to produce a brown solid. This solid was dissolved in THF (50 mL) and cooled in an ice bath. A solution of 4-Methoxy-N 3 methyl-N 3 -propyl-benzene-1,3-diamine (0.71 g, 3.65 mmol) in THF (20 mL) was added dropwisely followed by the triethylamine (1.6 mL) and the reaction was stirred at room temperature for 16 hrs. Ethyl acetate (50 mL) and water (100 mL) were added. The ethyl acetate layer was washed with water (3x50 mL), dried over magnesium sulfate, filtered and evaporated to dryness to produce the crude product as a brown solid. Purification by silicagel chromatography (elution with 25 % ethyl acetate/hexane) provided the desired compound as a white solid (1.8 g, 93%). 2,4-Bis-benzyloxy-5-isopropyl-N-[4-methoxy-3-(methylpropylamino)phenyl]benzamide (700 mg, 1.27 mmol) and Lawesson's reagent (0.3 1 g, 0.76 mmol) were dissolved in toluene (20 mL) and heated to II 0C for 3 hrs then evaporated to dryness under reduced pressure to produce a yellow oil. This crude product was dissolved in dioxane (10 mL), anhydrous hydrazine (0.6 mL) was added and the reaction was heated to 80*C for 30 min. After cooling, ethyl acetate (50 mL) and water (50 mL) were added. The ethyl acetate layer was washed with water (3x50 mL), dried over magnesium sulfate, filtered and evaporated to dryness to produce the crude product as a brown solid. This solid was dissolved in ethyl acetate (50 mL), CDI (0.66 g, 4.08 mmol) was added then the reaction was heated to reflux for 3 hrs. Removal of the solvent under reduced pressure followed by purification by silicagel chromatography (elution with 50 % ethyl acetate/hexane) provided the desired compound as a white solid (250 mg, 33% over 3 steps). 5-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-4-[4-methoxy-3-(methylpropylamino)phenyl] 4H-[ 1,2,4]triazol-3-ol (240 mg, 0.4 mmol) was dissolved in methanol (10 mL) then 10% palladium on charcoal (200 mg) was added and the reaction was stirred under an atmosphere of hydrogen for I6hrs. Filtration was carried out through a silca gel plug and removal of the solvent under reduced pressure produced the desired compound as a white solid (150 mg, 94%). 'H NMR (300 MHz, DMSO-d 6 ), 3 (ppm): 11.8 (s, I H), 9.55 (s, I H), 9.39 (s, I H), 6.88 (d, J = 8.7 Hz, I H), 6.77-6.79 (m, 2H), 6.5 (s, I H), 6.24 (s, I H), 3.73 (s, 3H), 2.97 (qn, J= 6.9 Hz, I H), 2.79 (t, J= 7.5 Hz, 2H), 2.48 (s, 31H), 1.30 (m, 2H), 0.97 (d, J= 6.9 Hz, 6H), 0.73 (t, J= 7.5 Hz, 3 H). ESMS clcd for C 2 2
H
28
N
4 0 4 : 412.21; Found: 413.2 (M+H)*.
C \NRPortbI\DCC\REC\40756I4_I DOC-1/10/2012 - 330 Example 169: 4-Isopropyl-6-{5-mercapto-4-[4-methoxy-3-(methyl-propyl-amino)-phenyl]-4 H [1,2,4]triazol-3-yi} -benzene- 1,3-diol 0 HO \N N H O SH HO N-N 'N Scheme 2
N
0 2 0
NH
2 C1 Et 3 N, DMC (> N CH 3 1, NaH, THF N
NO
2 NO 2 NO 2 2 3 01 0 1 0 01 N O BH3~ Me 2 S, THF N H 2 / Pd N N N
NO
2
NO
2
NH
2 NCS 3 4 5 6 HON HO y 0 OqH/\N HONHNH2 + N H N N HO - N N~a NI OH O NCS OH O H H H N 7 6 8 HO N.-N 2-methoxy-5-nitroaniline (1) (10.1 g, 60.0 mmol) in 250 mL dichloromethane at 0O- 5OC was treated with triethylamine (10.0 g, 100.0 mmol) and propionyl chloride (6.7g, 6.3 mL, 72.0 mmol) for I hour and 0.5 h at room temperature (RT). Normal aqueous workup and removal of solvent gave a light yellow solid which was washed with hexane/EtOAc (9:1) to yield solid N-(2 Methoxy-5-nitro-phenyl)-propionamide (2) (13.2 g, 98%). To a stirred solution of 11.2 g (50.0 mmol) of (2) in 150 mL of anhydrous THIF at 0C under the nitrogen, was added 3.Og (75mmol) of NaH (60% in oil). The suspension was stirred for 0.5h at 0*C and I OmL (1 50mmol) of iodomethane was added at 0 0 C. After the mixture warmed to room temperature and stirred for 3h, the reaction was quenched by ice brine and extracted with EtOAc (200mL). The organic phase was washed with brine, dried (Na 2
SO
4 ), filtered, evaporated in C \NRPorbl\DCC\REC\4075614_1 DOC-l/10/2012 -331 vacuo and the solid was washed with hexane/EtOAc (9:1) to give pure product N-(2-Methoxy-5 nitro-phenyl)-N-methyl-propionamide (3) as a light yellow solid (11.3 g, 95% yield). N-(2-Methoxy-5-nitro-phenyl)-N-methyl-propionamide (3) (10.Og 42mmol ) and borane methyl sulfide complex (21 mL of 2.OM solution in tetrahydrofurane) in 50 mL THF were heated unter reflux for 30 min, cooled and quenched by ice- water (slowly). Extraction with EtOAc and the organic layer washed with brine dried (Na2SO 4 ), filtered and evaporated in vacuo to give (9.1g, 96% ) (2-Methoxy-5-nitro-phenyl)-methyl-propyl-amine (4) as a yellow oil. A solution of 9.0 g (40.1mmol mmol) of (2-Methoxy-5-nitro-phenyl)-methyl-propyl amine (4) in 200 mL of MeOH/EtOAc (1:1) containing 5% w/w of Pd-C (10%) was subjected to hydrogenation (I 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 7.7 g (92%) of crude amine 4-Methoxy-N3-methyl-N3-propyl-benzene-1,3-diamine (5) of an oil. To a stirred solution of 6.8 g (35.0 mmol) of (5) in 150 mL of CH 2 Cl 2 at RT was added 6.4g (35mmol) of 1,1 '-thiocarbonyldiimidazole. The mixture was stirred at room temperature for 15 minutes and then evaporated under reduced pressure and the residue was passed through a short pad of silica gel, eluting with a gradient of hexane/EtOAc, which gave (5-isothiocyanato-2 methoxy-phenyl)-methyl-propyl-amine (6) (7.85g, 95%) as a colorless oil. To a stirred solution of 4.5g (19.Ommol) of the isothiocyanate (6) in 60mL of ethanol was added 4.0 g (19.Ommol) of the hydrazide (7) portion wise. The resultant mixture was then heated at 70 'C for I 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 (2 X 50 mL) and vacuum dried to 7.6 g (90%) of(8) as white solid. To a solution of 1.36 g (34mmol) of NaOH in 80 mL of water was added 7.5g (16.8mmol) of the intermediate (8) portion-wise. After the dissolution of the solid (1 -2 min), the flask was flushed with nitrogen and heated to 110 *C for 3h. The reaction mixture was cooled, an additional 100 mL of water was added and the whole mixture was acidified with conc. HCI to pH 7. The white precipitate thus obtained was filtered, washed with water (3 X 75 mL) and dried. The crude product was then re-dissolved in a mixture of 200 mL of ethyl acetate, dried over anhydrous Na2SO 4 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 in 3:1 hexane/ethyl acetate to give 6.83 g (95%) of 4-isopropyl-6-{5-mercapto-4-[4-methoxy-3-(methyl-propyl amino)-phenyl]-4H-[l,2,4]triazol-3-yl}-benzene-1,3-diol as white solid.
C .NRPorbl\DCC'REC\4175614_1.DOC-1/10/2012 -332 'H NMR (300 MHz, DMSO-d 6 ), (ppm): 9.58 (s, I H); 9.39 (s, I H); 6.92- 6.83 (m, 3H); 6.56(d, J=1.8 Hz, IH); 6.23 (s, I H); 3.74 (s, 3H); 3.0-2.93(m, I H); 2.8 1(t,J=6.9 Hz, 2H); 2.48(s, 3H); 1.31-1.24 (m, 2H); 0.96 (d, J= 6.9 Hz, 6H); 0.72 (t, J=7.2 Hz, 3H); ESMS clcd for C 22
H
2 8
N
4 03S: 428.19; Found: 429.2 (M+H)*. Example 170:4-(4-{3-[(2-Dimethylamino-ethyl)-methyl-amino]-4-methoxy-phenyl}-5-mercapto 4H-[ 1,2,4]triazol-3-yl)-6-isopropyl-benzene- 1,3-diol OMe N N HO N rSH OH N-N Scheme 3, H O O ,N N 0 Br N N / 1) H 2 , Pd/C N N Cs 2
CO
3 , X-phos, Pd (OAc) 2 2) thiocarbodiimidazole
NO
2 toluene, 100 *C NO 2 NCS (1) (2) (3) OMe HO NN 1) OHCONHNH2 H / 2) NaOH \N SH OH N-N (4) An oven-dried flask was charged with cesium carbonate (2.28 g, 7 mmol, 1.4 eq), Pd(OAc) 2 (79 mg, 0.35 mmol, 0.07 eq), and X-phos (238 mg, 0.5 mmol, 0.1 eq) under nitrogen. 2 bromo-1 -methoxy-4-nitrobenzene (I.16g, 5 mmol, I eq), N', N 2 , N 2 -trimethylethane-1,2-diamine (613 mg, 6 mmol, 1.2 eq) and toluene (20 mL, 0.25 M) were added, and the mixture was heated to 100 0 C with stirring overnight. The reaction mixture was cooled to room temperature and concentrated. The crude product was then purified by flash chromatography on silica gel to give N'-(2-nethoxy-5-nitrophenyl)-N4, N2, N2-trimethylethane-1,2-diamine(2) (340 mg, 1.34 mmol, 27%).
C:\NRPortbIDCC\REC\4I75614_ LDOC-11012012 - 333 A solution of 340 mg of N'-(2-methoxy-5-nitrophenyl)-N', N 2 , N 2 -trimethylethane-1,2 diamine (2) in 20 mL of ethanol containing 5% w/w of Pd-C (10%) was subjected to hydrogenation (1 atm, balloon) for 1.5 h. The contents of the flask were passed through a short pad of celite and washed with MeOH. The filtrate was evaporated under reduced pressure and crude amine obtained was carried over to the next reaction without further purification. Thiocarbodiimidazole (260 mg, 1.46 mmol) was added to the crude amine in dichloromethane (10 mL) at room temperature. The reaction mixture was stirred at room temperature for I h, and concentrated. The crude product was then purified by flash chromatography on silica gel to give N'-(5-isothiocyanato-2 meIhoxypheny)-)-N', N 2 , N 2 -trimethyleihane-1,2-diamine (3) (110 mg, 0.42 mmol, 3 1%). To a stirred solution of 1 10 mg (0.54 mmol) of the isothiocyanate (3) in 5mL of ethanol was added 105 mg (0.54 mmol) of 2,4-dihydroxy-5-isopropyl-benzoic acid hydrazide portion wise. The resultant mixture was then heated at 80 'C for 1 h, and 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 (2 X 20 mL) and vacuum dried to crude product as white solid. This solid was added to a solution of 44 mg (1.08 mmol) of NaOH in 5 mL of water portion wise. After the dissolution of the solid (1-2 min), the flask was flushed with nitrogen and heated to I 10 *C for 1.5 h. The reaction mixture was cooled, an additional 20 mL of water was added and the whole mixture was acidified with conc. HCI to pH 7. The white precipitate thus obtained was filtered, washed with water (3 X 20 mL) and dried. The crude product was then re-dissolved in a mixture of 20 mL of ethyl acetate, dried over anhydrous Na 2
SO
4 and passed through a short pad of silica gel with an additional 15 mL of ethyl acetate as eluent. The filtrates were concentrated and crude product was re-precipitated in 3:1 hexane/ethyl acetate to give 97 mg of 4-(4-(3-((2 (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)-5-mercapto-4H-1,2,4-triazol-3-yI)-6 isopropylbenzene-I,3-diol (4) as white solid. 'H-NMR300 MHz, DMSO-d 6 ) 8 (ppm): 9.80 (s, I H), 9.62 (br s, I H), 6.85 (m. 3H), 6.63 (m, I H), 6.41 (s, I H), 3.78 (s, 3H), 3.06 (m, 2H), 2.97 (q, J= 6.9 Hz, I H), 2.55 (s, 3H), 2.47 (m, 2H), 2.24 (s, 6H), 0.99 (s, 3H), 0.97 (s, 3H). ESMS clcd for C 23
H
3
IN
5 0 3 S: 457.21; Found: 458.2 (M+H)*.
C:\RPonbIDCC\REC4O75614_ I.DOC-1/10/2012 - 334 Example 171: 4-Isopropyl-6-(5-mercapto-4-{4-methoxy-3-[(2-methoxy ethyl)methylamino]phenyl}-4H-[l,2,4]triazol-3-yI)-benzene-I,3-diol N HO / N SH OH N-N 'H NMR (300 MHz, DMSO-d 6 ) 5 (ppm): 9.57 (s, I H), 9.39 (s, l H), 6.83-6.90 (m, 3H), 6.59 (d, J= 2.1 Hz, IH), 6.23 (s, IH), 3.74 (s, 3H), 3.39 (t, J=6Hz, 2H), 3.14 (s, 3H), 3.07 (t, J=6Hz, 2H), 2.96 (qn, J=6.9 Hz, I H), 2.54 (s, 3H), 0.97 (d,J= 6.9 Hz, 6H). ESMS clcd for C 22
H
28
N
4 0 4 S: 444.18; Found: 445.2 (M+H)*. Example 172: 4-{4-[3-(Cyclopropylmethylmethylamino)-4-methoxy-phenyl]-5-mercapto-4H [I,2,4]triazol-3-yl}-6-isopropylbenzene-1,3-dioI 0 N HO /| N, SH OH N-N 'H NMR (300 MHz, DMSO-d 6 ) 3 (ppm): 9.56 (s, I H), 9.39 (s, I H), 6.85-6.90 (m, 3H), 6.58 (d, 1= 2.1 Hz, I H), 6.23 (s, I H), 3.76 (s, 3H), 2.96 (qn, J= 6.9 Hz, I H), 2.76 (d, J= 6.3 Hz, 2H), 2.57 (s, 3H), 0.99 (d, J= 6.9 Hz, 6H), 0.58-0.64 (m, I H), 0.32-0.34 (m, 2H), -0.03-0.01 (m, 2H). ESMS clcd for C 23
H
28
N
4 0 3 S: 440.19; Found: 441.1 (M+H)~.
C \NRPortblDCOREC4075614_I DOC-1110i2012 - 335 Example 173: N-{4-[3-(5-Ethyl-2,4-dihydroxy-phenyl)-5-mercapto-[l,2,4]triazol-4-yl]-phenyl} N-methyl-acetamide, NO 0 HO N N HO N/ SH ESMS clcd for C 1 9
H
2 0
N
4 0 3 S: 384.13; Found: 385.1 (M+H)*. Example 174: N-Ethyl-N-{5-[3-(5-ethyl-2,4-dihydroxy-phenyl)-5-mercapto-[l,2,4]triazol-4-yl]-2 methoxy-phenyl}-acetamide, 0 N HO N 0 , SH HO N N ESMS clcd for C 21
H
24
N
4 0 4 S: 428.15; Found: 429.2 (M+H)*. Example 175: 4-[4-(3-Diethylamino-4-methoxy-phenyl)-5-mercapto-4H-[1,2,4]triazol-3-yI]-6 ethyl-benzene- I,3-diol 0 N HO ON / N N ESMS clcd for C 2 1
H
26
N
4 0 3 S: 414.17; Found: 415.2 (M+H)*.
CANRPonbflDCCRECWO7S6IJI DOC-1110/2012 - 336 Example 176: 4-[4-(4-Dimethylamino-phenyl)-5-mercapto-4H-[1I,2,4]triazol-3-yl]-6-ethyl benzene- I ,3-diol HO K N SH HO N/ N ESMS clcd for C 18
H
2 0
N
4 0 2 S: 356.13; Found: 357.2 (M+H)'. Example 177: 4-[4-(4-Diethylamino-phenyl)-5-mercapto-4H-[1I,2,4] triazol1-3 -y I]-6-ethyl -benzene I ,3-diol HO K N HO N../ S ESMS clcd for C 2 oH- 24
N
4 0 2 S: 384.16; Found: 385.2 (M+-)'. Example 178: 4-Ethyl-6-[5-mercapto-4-(4-morphol in-4-yI-phenyl)-4H-[ 1,2,4]triazol-3-yI] benzene- 1,3-diol 0 No HO K' N , - SH N-_ ESMS clcd for C 20
H
22
N
4 0 3 S: 398.14; Found: 399.2 (M+H)'.
C V4"PonbI'flCC\REO.W)756l4- DOC.1/ 102012 - 337 Example 179: 4-Ethyl-6-[4-(4-imidazol- I -yI-phenyl)-5 -mercapto-4H--[ I ,2,4Jtriazol-3 -yi] -benzene I ,3-diol N-i HO K N HO N.../ SH ESMS clcd for CjqH 17
N
5 0 2 S: 379.11; Found: 380.2 (M+H)+. Example 180: 4-[4-(2,5-Diethoxy-4-morphol in-4-yl-phenyl)-5-mercapto-4H-[ I,2,4]triazol-3-yl]-6 ethyl-benzene- I ,3-diol C0 N) 0 HO KH'N/> S N ESMS clcd for C 24
H
30
N
4 0 5 S: 486.19; Found: 487.3 (M+H)*.
C NRPonI\DCCEC%4O)7.%14-1 DOC.I/10/2012 - 338 Example 181: 4-Ethyl-6- {4-[3-(isopropyl-propyl-amino)-4-methoxy-phenyl]-5-mercapto-4H [I,2,4]triazol-3-yi } -benzene- I ,3-diol HON N HO SN ESMS clcd for C 2 3H 3 0
N
4 0 3 S: 442.20; Found: 443.3 (M4H)'. Example 182: 4-[4-(4-Dimethylamino-3-methoxy-phenyl)-5-mercapto-4H-[1I,2,4]triazol-3-yI]-6 ethyl-benzene- I ,3-diol HO0 K' N HO N-/ ESMS clcd for Cl 9
H
22
N
4 0 3 S: 386.14; Found: 387.2 (M+H)+. Example 183: 4-Ethyl-6-[5-mercapto-4-(3-pyrrolidin-1I-yI-phenyl)-4H-[1I,2,4]triazol-3-yI] benzene- I ,3-diol HO N/\ HO ~/ SH N ESMS clcd for C 20
H
22
N
4 0 2 S: 382.15; Found: 383.2 (M+H) .
CA~NRPoflbIIfCC\REC\O7 %14- 1 DOC. t/10/201 2 -339 Example 184: 4-[4-(3-Dimethylamino-phenyl)-5-mercapto-4H-[ 1,2,4]triazol-3-yI]-6-ethyl benzene- 1 ,3-diol HO K N HO N />-SH ESMS clcd for C18H 2
ON
4
O
2 S: 356.13; Found: 357.2 (M+H)'. Example 185: 4- Ethyl -6- (4- [3 -(i sopropylI-methylI-am ino)-4-methoxy-phenyl]-5 -mercapto-4H [I,2,4]triazol-3-yi} -benzene- I ,3-dil HO N HO, N /> SH ESMS clcd for C 21
H
26
N
4 0 3 S: 414.17; Found: 415.2 (M+H)'. Example 186: 4-[4-(3-Dimethylamino-4-methoxy-phenyl)-5-mercapto-4-1I,2,4]triazol-3-yl]-6 ethyl-benzene-1 ,3-diol HO K' N HO N. / SH N ESMS clcd for C 19 1- 2
N
4 03S: 386.14; Found: 387.2 (M+H) 4
.
C:NfRPortblOCC\REC\Jf75614_ 1 DOC-/110/2012 -340 Example 187: 4-Ethyl-6-{4-[3-(ethyl-methyl-amino)-4-methoxy-phenyl]-5-mercapto-4H [1,2,4]triazol-3-yi} -benzene- 1,3-diol HON N HO N SH N ESMS clcd for C 20
H
24
N
4 0 3 S: 400.16; Found: 401.2 (M+H)*. Example 188: 4-Isopropyl-6-{4-[3-(isopropyl-propyl-amino)-4-methoxy-phenyl]-5-mercapto-4H [1,2,4]triazol-3-yi} -benzene- 1,3-diol N HO N HO N / SH 0 N_ ESMS clcd for C 24
H
3 2
N
4 0 3 S: 456.22; Found: 457.3 (M+H)*. Example 189: 4-Ethyl-6- {4-[3-(ethyl-isopropyl-amino)-4-methoxy-phenyl]-5-mercapto-4H [1,2,4]triazol-3-yl}-benzene-1,3-diol I\N HO N HO / SH N N N ESMS clcd for C 22
H
28
N
4 0 3 S: 428.19; Found: 429.3 (M+H) t
.
C:NRPnblDCC\REC\4)75614_ .DOC-/10/2012 - 341 Eample 190: 4-Ethyl-6-[5-mercapto-4-(4-methoxy-3-morpholin-4-yl-phenyl)-4H-[1,2,4]triazol-3 yl]-benzene- 1,3-diol O HOO HO N\, N HO SH ESMS clcd for C 2 jH 24
N
4 0 4 S: 428.15; Found: 429.2 (M+H)*. Example 191: 4-Isopropyl-6-{5-mercapto-4-[4-methoxy-3-(methyl-propyl-amino)-phenyl]-4H [I,2,4]triazol-3-yl}-benzene- 1,3-diol HO HO N N HO N SH H NMR (300 MHz, DMSO-d 6 ) 8 (ppm): 9.58 (s, I H); 9.39 (s, I H); 6.92- 6.83 (m, 3H); 6.56(d, J=I.8 Hz, I H); 6.23 (s, I H); 3.74 (s, 3H); 3.0-2.93(m, 1 H); 2.8 (t,.1=6.9 Hz, 2H); 2.48(s, 3H); 1.31-1.24 (m, 2H); 0.96 (d, J= 6.9 Hz, 6H); 0.72 (t, J=7.2 Hz, 3H); ESMS clcd for C22H 2 sN 4 0 3 S: 428.19; Found: 429.2 (M+H)".
C.\NRPorlbl\DCGREO4075614_ .DOC-1/10/2012 - 342 Example 192: 4-{4-[3-(Ethyl-methyl-amino)-4-methoxy-phenyl]-5-mercapto-4H-[ l,2,4]triazol-3 yl}-6-isopropyl-benzene- 1,3-diol HO N HO N 'H NMR (300 MHz, DMSO-d 6 ) 8 (ppm): 9.58 (s, I H); 9.40 (s, I H); 6.92-6.85 (m, 3 H); 6.58 (d, J=1.8Hz, I H); 6.24 (s, I H); 3.76 (s, 3H); 3.02-2.90 (m, 3H); 2.49(s, 3H) 0.99 (d, J= 6.9 Hz, 6H); 0.86 (t, J=7.2 Hz, 3H). ESMS cled for C 21
H
2 6
N
4 0 3 S: 414.17; Found: 415.1 (M+H)*. Example 193: 4-Isopropyl-6-(5-mercapto-4-{4-methoxy-3-[methyl-(3-methyl-butyl)-amino] phenyl}-4H-[I,2,4]triazol-3-yI)-benzene-1,3-diol O N HO N HO Ncdo C2HS : ESMS clcd for G 24
H
32
N
4 0 3 S: 456.22; Found: 457.2 (M+H)+.
C RPoribl\DCC\REC\4075614_ .DOC.1/10/2012 - 343 Example 194: 4-Isopropyl-6-{5-mercapto-4-[4-methoxy-3-(methyl-propyl-amino)-phenyl]-4H [I,2,4]triazol-3-yl} -benzene- 1,3-diol; compound with hydrogen chloride HCI \N HON N HO N/> SH NN ESMS clcd for C 22
H
2 9 C1N 4 0 3 S: 464.16; Found: 429.3 (M+H)'. Example 195: 4-{4-[3-(Butyl-methyl-amino)-4-methoxy-phenyl]-5-mercapto-4H-[ I,2,4]triazol-3 yl}-6-isopropyl-benzene- 1,3-diol HO N N HO N / SH N ESMS clcd for C 2 3
H
30
N
4 0 3 S: 442.20; Found: 443.3 (M+H)*. Example 196: 4-{4-[3-(Isobutyl-methyl-amino)-4-methoxy-phenyl]-5-mercapto-4H-[1,2,4]triazol 3-yl }-6-isopropyl-benzene- 1,3-diol HON HO N ESMS clcd for C 23
H
30
N
4 0 3 S: 442.20; Found: 443.1 (M+H)*.
C \NRPonblCCIRE407 5614 1.DOCII1110121 - 344 Example 197: 4-(4- {3-[(2-Imidazol- I-yI-ethyl)-methyl-amino]-4-methoxy-phenyl }-5-mercapto 4H-[1I,2,4]triazol-3-yI)-6-isopropyl-benzene-1I,3-diol HO/ N SHN N-N OH ESMS clcd for C 24
H-
28
N
6 0 3 S: 480.19; Found: 481.1 (M±H)'. Example 198: 4-(4-(3-( IH-pyrrol-1I-yl)phenyl)-5-mercapto-4H-1I,2,4-triazol-3-yl)-6-ethylbenzene I ,3-diol HO/\ OH N-N ESMS clcd forCG 20 Hl 8
N
4 0 2 S: 378.12; Found: 379.1 (M+H)'. Example 199: 4-(4-(4-(lI H-pyrazol- I -yl)phenyl)-5-mercapto-4H- I ,2,4-triazol-3-yI )-6 ethylbenzene- 1 ,3-diol N OH
N-N
C:NRPor.br\DCC\REC475614_1 0oC.io202 - 345 ESMS cled for C 19
H
1 7
N
5 0 2 S: 379.1 1; Found: 380.1 (M+H)*. Example 200: 4-(4-(3 -(d imethylam ino)-4-(methylth io)phenyl)-5-mercapto-4H- 1,2,4-triazol-3 -yl) 6-isopropylbenzene- 1,3-diol S N N HO / N N,/ SH OH N-N ESMS cled forC 20
H
2 4
N
4 0 2
S
2 : 416.13; Found: 417.1 (M+H)*. Example 201: 4-isopropyl-6-(5-mercapto-4-(4-methoxy-3-(propylamino)phenyl)-4 H-,2,4-triazol 3-yl)benzene- I,3-diol OMe H N, HO / N N SH OH N-N ESMS cled for C 21
H
26
N
4 0 3 S: 414.17; Found: 415.1 (M+H)*. Example 202: 4-[4-(4-Amino-3-hydroxy-phenyl)-5-mercapto-4H-[l,2,4]triazol-3-yl]-6-ethyl benzene- 1,3-diol
NH
2 OH HO " /5 N O I - SH OH
N'N
C\NRPo1bl\DCC\REC\4075614_1 DOC.1/10/2012 - 346 ESMS clcd for CiH 16
N
4 0 3 S: 344.09; Found: 345.1 (M+H)*. Example 203: 4-ethyl-6-(4-(3-hydroxy-4-(methylamino)phenyl)-5-mercapto-4H-1,2,4-triazol-3 yl)benzene-1,3-diol NH OH OH /~ N , g-SH OH N-N ESMS clcd for C 1 7 Hl 8
N
4 0 3 S: 358.11; Found: 359.1 (M+H)* Example 204: 4-(4-(3-ami nophenyl)-5-mercapto-4H- ,2,4-triazol-3-yl)-6-ethylbenzene- 1,3 -diol HO
NH
2 HO / N ,>SH OH N-N ESMS clcd for Ci 6 Hl 6
N
4 0 2 S: 328.10; Found: 329.1 (M+H)*. Example 205: 4-[4-(4-Dimethylamino-3-methyl-phenyl)-5-mercapto-4H-[I,2,4]triazol-3-yI]-6 ethyl-benzene- 1,3-diol HO N OH SH O N ESMS clcd for CiqH 23
N
4 0 2 S: 371.1; Found: 371.1 (M + H)*.
C :NRPortbl\DCC\REC\4075614_1.DOC-1/102012 - 347 Example 206: 4-[4-(3-Imidazol- I -yl-phenyl)-5-mercapto-4H-[ l,2,4]triazol-3-yl]-6-isopropyl benzene-1,3-diol HO N OH ~NSH ESMS cled. for C 20
H
20
N
5 0 2 S: 394.1; Found: 394.1 (M + H)*. Example 207: 4-[4-(3-Imidazol- I -yl-phenyl)-5-mercapto-4H-[ I,2,4]triazol-3-yl]-6-isopropyl benzene- 1,3-diol 0 HO N N 1/SH OH S 2-{3-[3-(2,4-Dihydroxy-5-isopropyl-phenyl)-5-mercapto-[ I,2,4]triazol-4-yl]-phenyl} -5-methyl 2,4-d ihydro-pyrazol-3 -one 'H NMR (300 MHz, DMSO-d 6 ) 8 (ppm): 9.63 (br s, 1 H); 7.70-7.80 (m, 2H); 7.37-7.43 (m, I H); 6.99-7.02 (m, I H); 6.91 (s, I H); 6.25 (s, 1 H); 5.35 (s, I H); 3.70 (s, 2H); 2.96 (hept, J= 6.9 Hz, I H); 2.09 (s, 3 H); 0.99 (d, J= 6.9 Hz, 6H); ESMS clcd. for C 21
H
2 2
N
5 0 3 S: 424.1; Found: 424.1 (M + H)+. Example 208: Inhibition of Hsp90 Hsp90 protein was obtained from Stressgen (Cat#SPP-770). Assay buffer: 100 mM Tris HCI, Ph7.4, 20 mM KCI, 6 mM MgCl 2 . Malachite green (0.0812% w/v) (M9636) and polyviny alcohol USP (2.32% w/v) (PI 097) were obtained from Sigma. A Malachite Green Assay (see Methods Mol Med, 2003, 85:149 for method details) was 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 MgCI 2 ) was mixed with ATP alone (negative control) or in the presence of Geldanamycin (a C:NRPorb1\DCC\REC4075614_ DOC-1/10/2012 - 348 positive control) or Compound 108 in a 96-well plate. Malachite green reagent was added to the reaction. The mixtures were incubated at 37'C for 4 hours and sodium citrate buffer (34% w/v sodium citrate) was added to the reaction. The plate was read by an ELISA reader with an absorbance at 620 nm. As can be seen in Figure 1, 40 ptM of geldanamycin, a natural product known to inhibit Hsp90 activity, the ATPase activity of Hsp90 was only slightly higher than background. 40 laM Compound 108 showed an even greater inhibition of ATPase activity of Hsp90 than geldanamycin, and even at 4pM Compound 108 showed significant inhibition of ATPase activity of Hsp90 protein. Example 209: Degradation of 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 (1001U/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 I after cell passage. B. Degradation of Her2 in Cells after Treatment with a Compound of the Invention I. Method I BT-474 cells were treated with 0.5gM, 2pM, or 5pM of 17AAG (a positive control) or 0.5pjiM, 2pM, or 5pM of Compound 108 or Compound 49 overnight in DMEM medium. After treatment, each cytoplasmic sample was prepared from 1x10 6 cells by incubation of cell lysis buffer (#9803, cell Signaling Technology) on ice for 10 minutes. The resulting supernatant used as the cytosol fractions were 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 was 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) were used as secondary Ab (#7074, #7076, Cell Signaling) and LumiGLO reagent, 20x Peroxide (#7003, Cell Signaling) was used for visualization.
C:NRPortbI'DC\REC\4O75614_ DOC-1/10/2012 - 349 As can be seen from Figure 2, Her2, an Hsp90 client protein, is almost completely degraded when cells are treated with 5ltM of Compound 108 and partially degradated when cells are treated with 2 M and 0.5pM of Compound 108. Compound 49 which is even more active than Compound 108 causes complete degradation of Her2 when cells are treated with 2gM and 5pM and causes partial degradated when cells are treated with 0.5pM 17AAG is a known Hsp90 inhibitor and is used as a positive control. 2. Method 2 MV-4-1 I cells (20,000 cells/well) are cultured in 96-well plates and maintained at 37 0 C for several hours. The cells are treated with a compound of the invention or 1 7AAG (a positive control) at various concentrations and incubated at 37'C for 72 hours. Cell survival is measured with Cell Counting Kit-8 (Dojindo Laboratories, Cat. # CK04). Table 8: IC 50 range of compounds of the invention for inhibition of Her2 degradation
IC
50 Range Compound Number <3 8, 13,39,49,63,76,77,79,87,88,95,96, 100, 103, 177, 178,185, 188, 189,247,248,249,250,251,252,259 3pgM to I OlM 2, 5, 6, 7, 9, 14, 27, 28, 34, 36, 38, 42, 48, 64, 70, 93, 97, 108, 122, 183, 184 1OpM to I00pM 21, 22, 30, 51, 59, 60, 61, 62, 94, 98, 99, 102, 104, 123, 181, 182, 186, 187, 348 C. 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 were washed twice with IxPBS/I%FBS, and then stained with anti-Her2- FITC (#340553, BD) for 30 min at 4C. Cells were then washed three times in FACS buffer before the fixation in 0.5 ml 1% paraformadehydrede. Data was 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 were recorded from each sample. Data were analysed by using CellQuest software (BD Biosciences). The IC 5 o range for Hsp90 inhibition by compounds of the invention are lised below in Table 2.
C:\NRPortbl\DCC\REC\44)75614_ DOC./1122 -350 D. Apoptosis analysis After treatment with the compounds of the invention, cells were washed once with 1 xPBS/l%FBS, and then stained in binding buffer with FITC-conjugated Annexin V and Propidium iodide (PI) (all obtained from BD Biosciences) for 30 min at 4'C. Flow cytometric analysis was performed with FACSCalibur (BD Biosciences) and a total 10,000 events were recorded from each sample. Data were analyzed by using CellQuest software (BD Biosciences). The relative fluorescence was 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, were used for testing c-kit degradation induced by Hsp90 inhibitors of the invention. The cells (3X 105 per well) were treated with 17AAG (0.5 IM), Compound 188 or Compound 221 for about 18 h (see Figs. 3 and 4 for concentrations). The cells were collected and centrifuged (SORVALL RT 6000D) at 1200 rpm for 5 min. The supernatants were discarded, and the cells were washed one time with IX PBS. After centrifugation the cells were stained with FITC conjugated c-kit antibody (MBL International, Cat# KO 105-4) in 100 ml IX PBS at 4"C for I h. The samples were read and analysized with FACSCalibur flow cytometer (Becton Dicknson). c-Kit, a tyrosine kinase receptor and one of the Hsp90 client proteins, was selected and used in a FACS-based degradation assay. The results of the assay showed that Compound 188 and Compound 221, induced c-kit degradation at 0.5 and 0.05 ptM in a dose-dependent manner. Surprisingly, 17-AAG, which is a potent Hsp90 inhibitor and is in phase 2 clinical trials, could not induce c-kit degradation at 0.5 jiM in two leukemia cell lines, HEL92.1.7 (see Fig. 3) and Kasumi I (see Fig. 4). Since the compounds of the invention cause c-kit degradation more efficiently than other Hsp90 inhibitors, the compounds of the invention are expected to be more 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 were confirmed with Western blot analysis (see Fig. 5). In Kasumi-I cells (myelogenous leukemia, carrying a form of the c-Kit tyrosine kinase receptor which has the activating N822K mutation), Compound 221 (100 nM and 400 nM) induced the degradation of c-Kit. In contrast, 17-AAG had no effect of c-Kit protein levels.
C \NRPoTbl\DCC\REC\4075614_.DOC-1/10/2o 12 -351 F. Degradation of EGFR in Cells after Treatment with a Compound of the Invention Non-small cell lung cancer cell line, NCI-H 1975 (2 x 106 cells), which harbors both the T790M and the L858R mutations in EGFR and is resistant to erlotinib, was obtained from American Type Culture Collection and was treated with either Compound 226 (1.0 pIM, 0.5 PM and 0.1 pM) or 17-AAG (1.0 gM, 0.5 pM and 0.1 pM). After 18 hours, the cells were lysed with I x lysis buffer and a western blot was perform, and phosphorylated and total EGFR was detected with anti-EGFR antibodies. As can be seen from Figure 6, Compound 226 induced degradation phosphorylated and total EGFR more potently than 17AAG. G. Degradation of B-Raf in Cells after Treatment with a Compound of the Invention Melanoma cell line, A375 (2 x 106 cells), which contains the V600E mutation in the B-raf protein that confers constitutive tyrosine kinase activity, was treated with either Compound 226 (0.5 pM, 0.1 pM and 0.0 1 pM) or 17-AAG (0.5 gM, 0.1 pM and 0.01 pM). After 18 hours, the cells were lysed with I x lysis buffer and a western blot was perform, and B-raf was detected with anti-B-raf antibody. As can be seen from Figure 7, Compound 226 induced degradation of V600E mutant B-raf at 0.5 mM and 0.1 mM, whereas 17AAG did not induce significant degradation at these concentrations. H. Degradation of Bcr-Abl in Cells after Treatment with a Compound of the Invention KU812 chronic myeloid leukemia cells (ATCC) (2 x 106 cells), which harbor the Philidelphia chromosome that produces Bcr-Abl tyrosine kinase, were treated (0.1 pM and 1.0 pM) with either Compound 226, 17-AAG or 17-DMAG. After 18 hours, the cells were lysed with 1 x lysis buffer, and a western blot was perform using anti-BCR-ABL antibody to detect phosphorylated Bcr-Abl. As can be seen from Figure 8, treatment of KU812 cells with 1.0 PM Compound 226 and 0.1 jM induced complete degradation of phosphorylated Bcr-Abl. In contrast, treatment with 1.0 gM 17-DMAG induced complete degradation of phosphorylated Bcr-Abl at 1.0 iM but only produced partial degradation at 0.1 pM, and 17AAG only partially degraded phosphorylated Bcr-Abl at 1.0 pM but did not degrade the protein at 0.1 gM.
C \NRPortblDCC\RECU075614_ .DOC-11111l2012 - 352 I. Degradation of NPM-ALK in Karpas-299 Cells after Treatment with a Compound of the Invention Anaplastic large-cell lymphoma cells, Karpas-299 cells (the German resource center for biological material) (2 x 106 cells), which harbor the fusion protein NPM-ALK, were treated (0.05 pM, 0.1 AM and 0.5 pM) with either Compound 226 or 17-AAG. After 18 hours and the cells were lysed with I x lysis buffer and a western blot was perform using an anti-ALK antibody to detect and phosphorylated NPM-ALK and total NPM-ALK. As shown in Figure 9, treatment of cells with Compound 226 produced total degradation of phosphorylated NPM-ALK at 0.5 pM and partial degradation of phosphorylated and total NPM-ALK 0.05 AM and 0.1 pM. In contrast, 17AAG produced partial degradation of phosphorylated and total NPM-ALK at 0.5 AM and had no effect at 0.05 pM and 0.1 pM. Example 210: Cell Survival after Treatment with Hsp90 Inhibitors A. Evaluation of IC 50 for Cell Survival in MV-4-1 I Cells Treated with Compounds of the Invention Human acute myelogenous leukemia (AML) cell line, MV 4-l1 (ATCC #CRL-9591), was obtained from the American Type Culture Collection (ATCC; Manassas, Virginia, USA). Growth of this tumor cell line is dependent upon the expression of an activated form of the FLT3 tyrosine kinase receptor carrying an internal tandem duplication (ITD) mutation, which is the most common molecular defect associated with AML (K.W. Yee et al., Blood 100:2941-2949, 2002). MV 4-1 1 cells (20,000 cells/well) were cultured in 96-well plates and maintained at 37"C for several hours. The cells were incubated at 37"C for 72 hours with various concentrations of compounds of the invention, 17AAG, or DMAG. 17AAG and DMAG are Hsp90 inhibitors that are currently in clinical trials and are used here as positive controls for Hsp90 inhibition. Cell survival was measured with Cell Counting Kit-8 (Dojindo Laboratories, Cat # CK04). As can be seen from Figure 10, certain compounds of the invention had a lower IC 50 for cell survival than 17AAG and DMAG. The IC 5 0 values are shown in the table below: Compound ICso (JiM) 17AAG 0.035 DMAG 0.033 C NRPortblDCCREC\4075614- DOC-1/10/2012 - 353 Compound 226 <0.004 Compound 208 0.020 Compound 205 0.049 Compound 188 0.025 B. Evaluation of IC 5 0 for Cell Survival in Kasumi- I Cells Treated with Compounds of the Invention Human acute myelogenous leukemia cell line, Kasumi-l, carries an activated form of the c-Kit tyrosine kinase receptor which has the N822K mutation (A. Beghini, et al., Exp. Hematol. 33:682-688, 2005, the entire teachings of which are incorporated herein by reference). Kasumi-l cells (20,000 cells/well) were cultured in 96-well plates and maintained at 37"C for several hours. The cells were incubated at 37"C for 72 hours with various concentrations of compounds of the invention, 17AAG, DMAG, or Gleevec. 17AAG and DMAG are Hsp90 inhibitors that are currently in clinical trials and are used here as positive controls for Hsp90 inhibition. Gleevec (also known as imatinib) is a tyrosine kinase inhibitor that is currently used to treat GIST and CML. Cell survival was measured with Cell Counting Kit-8 (Dojindo Laboratories, Cat # CK04). As can be seen from Figure 11, compounds of the invention had a lower IC50 for cell survival than 17AAG, DMAG or Gleevec. The IC 50 values are shown in the table below: Compound ICso (pM) 17AAG 0.685 DMAG 0.101 Gleevec 0.281 Compound 226 0.004 Compound 208 0.049 Compound 188 0.072 C. Evaluation of IC 5 0 for Cell Survival in Mouse Mastacytoma Cell Line P815 Treated with Hsp90 inhibitors Mouse mastacytoma cell line P815 was obtained from the American Type Culture Collection (ATCC; Manassas, Virginia, USA). P815 cells carry an activated form of c-Kit which expresses an activating mutation D81 4Y, which is equivalent to the D816Y mutation in human c- C:WRPortbl\DCCa1REC\475614_ DOC.1110/2012 - 354 Kit (D816Y) and confers resistance to Gleevec. P815 cells (20,000 cells/well) were cultured in 96 well plates and maintained at 37*C for several hours. The cells were incubated at 37*C for 72 hours with various concentrations of compound 226 of the invention, 17AAG, 17DMAG and Gleevec. I 7AAG and 17DMAG are Hsp90 inhibitors that are currently in clinical trials and are used here as positive controls for Hsp90 inhibition. Gleevec (also known as imatinib) is a tyrosine kinase inhibitor that is currently used to treat of c-kit associated cancers such as GIST and CML. Cell survival was measured with Cell Counting Kit-8 (Dojindo Laboratories, Cat # CK04). As can be seen from Figure 12, compound 226 of the invention had a lower IC 5 0 for cell survival than 17AAG, 17DMAG or Gleevec. D. Evaluation of IC 5 0 for Cell Survival in NCI-H 1975 Cells Treated with Compounds of the Invention Human lung cancer cell line NCI-H 1975 which harbors both the T790M and the L858R mutations in EGFR was obtained from American Type Culture Collection. NCI-H 1975 (10,000 cells/well) were cultured in 96-well plates and maintained at 37*C for several hours. The cells were incubated at 37'C for 72 hours with various concentrations of compound 226 of the invention, 17AAG or DMAG. 17AAG and DMAG are Hsp90 inhibitors that are currently in clinical trials and are used here as positive controls for Hsp90 inhibition. Cell survival was measured with Cell Counting Kit-8 (Dojindo Laboratories, Cat # CK04). As can be seen from Figure 13, and the table below certain compounds of the invention had a lower IC 50 for cell survival than 17AAG or DMAG. The IC 5 0 values are shown in the table below: Compound
IC
5 0 (pM) I 7AAG 0.446 DMAG 0.171 Compound 226 0.016 E. Evaluation of IC 50 for Cell Survival in NCI-H 1975 Cells Treated with Compounds of the Invention Human melanoma cell line, A375 (2 x 106 cells), which contains the V600E mutation in the B-raf protein that confers constitutive tyrosine kinase activity, was obtained from American Type Culture Collection. A375 cells (20,000 cells/well) were cultured in 96-well plates and maintained at 37'C for several hours. The cells were incubated at 37 0 C for 72 hours with various C NRPonb\DCC\REC'4075614_l.DOC-1/1012012 - 355 concentrations of compound 226, 17AAG or 17DMAG. 17AAG and 17DMAG are Hsp90 inhibitors that are currently in clinical trials and are used here as positive controls for Hsp90 inhibition. Cell survival was measured with Cell Counting Kit-8 (Dojindo Laboratories, Cat # CK04). As can be seen from Figure 14, and the table below certain compound 226 of the invention had a lower IC 5 0 for cell survival than 17AAG and approximately the same IC50 as 17DMAG. The IC 5 0 values are shown in the table below: Compound
IC
0 o (pM) 1 7AAG 0.07 17DMAG 0.004 Compound 226 0.004 F. Evaluation of IC 0 for Cell Survival in K562 Cells Treated with Hsp90 inhibitors Human chronic myelogenous leukemia (CML) cell line, K562 (ATCC #CCL-243), was obtained from the American Type Culture Collection (ATCC; Manassas, Virginia, USA). Growth of this tumor cell line is dependent upon the expression of the Bcr-Abl fusion protein (C. Gambacarti-Passerini et al., Blood Cells Mol. Dis. 23:380-394, 1997). K562 cells (20,000 cells/well) were cultured in 96-well plates and maintained at 37*C for several hours. The cells were incubated at 37'C for 72 hours with various concentrations of compound 226 of the invention, 17AAG, DMAG, Radicical, Vernalis 60-0164, Conforma 60-0170, or Gleevec. I7AAG, DMAG, and Radicical are Hsp90 inhibitors that are currently in clinical trials and are used here as positive controls for Hsp90 inhibition. Vernalis 60-0164 and Conforma 60-0 170 are Hsp90 inhibitors that are currently under development. Gleevec (also known as imatinib) is a tyrosine kinase inhibitor that is currently used to treat GIST and CML. Cell survival was measured with Cell Counting Kit 8 (Dojindo Laboratories, Cat # CK04). As can be seen from Figure 15, compound 226 of the invention had a lower IC 5 0 for cell survival than 17AAG, DMAG, Radicical, Vernalis 60-0164, Conforma 60-0170, or Gleevec. The IC 5 0 values are shown in the table below: Compound ICo (9M) 17AAG 0.122 DMAG 0.113 Radicical 0.33 1 C:\NRPortbIlDCC\REC\4075614_ .DOC-1/1012012 - 356 Vemalis 60-0164 0.581 Conforma 60-0170 0.404 Gleevec 0.295 Compound 226 0.014 G. Evaluation of IC 5 for Cell Survival in Human Karpas-299 cells Treated with Hsp90 inhibitors Human Karpas-299 cell line was obtained from the German Resource Center for Biological Material. Growth of this tumor cell line is dependent upon the expression of the NPM ALK fusion protein. Karpas-299 cells (20,000 cells/well) were cultured in 96-well plates and maintained at 37'C for several hours. The cells were incubated at 37'C for 72 hours with various concentrations of compound 226 of the invention, 17AAG, and 17DMAG. 17AAG and 17DMAG are Hsp90 inhibitors that are currently in clinical trials and are used here as positive controls for Hsp90 inhibition. Cell survival was measured with Cell Counting Kit-8 (Dojindo Laboratories, Cat # CK04). As can be seen from Figure 16, compound 226 of the invention had a lower IC 50 for cell survival than 17AAG and 17DMAG. The IC 5 o values are shown in the table below: Compound
IC
50 (p±M) 17AAG 0.506 17DMAG 0.062 Compound 226 0.01 Example 211: Compound 49 Displays 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., Mol. Pathol. 55:294-299, 2002), was obtained from the American Type Culture Collection (Manassus, Virginia, USA). The cell line was cultured in growth media prepared from 50% Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI Media 1640, 10% fetal bovine serum (FBS), I% IOOX L-glutamine, 1% IOOX Penicillin-Streptomycin, 1% 1OOX sodium pyruvate and 1% IOOX MEM non-essential amino acids. FBS was obtained from Sigma-Aldrich Corp. (St. Louis, Missouri, USA), and all other reagents were obtained from Invitrogen Corp. (Carlsbad, California, C:NRPonb1\DCCREC\4075614_ .DOC-1110/2012 -357 USA). Approximately 4-5 x 10(6) cells that had been cryopreserved in liquid nitrogen were rapidly thawed at 37*C and transferred to a 175 cm 2 tissue culture flask containing 50 ml of growth media and then incubated at 37 0 C in a 5% CO 2 incubator. The growth media was 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 was washed with 10 ml of room temperature phosphate buffered saline (PBS) and the cells were disassociated by adding 5 ml l X Trypsin-EDTA (Invitrogen) and incubating at 37 0 C until the cells detached from the surface of the flask. To inactivate the trypsin, 5 ml of growth media was added and then the contents of the flask were centrifuged to pellet the cells. The supernatant was aspirated and the cell pellet was resuspended in 10 ml of growth media and the cell number determined using a hemocytometer. Approximately 1-3 x 10(6) cells per flask were seeded into 175 cm 2 flasks containing 50 ml of growth media and incubated at 37*C in a 5% CO 2 incubator. When the flasks reached 90% confluence, the above passaging process was repeated until sufficient cells had been obtained for implantation into mice. Six to eight week old, female Crl:CD-1-nuBR (nude) mice were obtained from Charles River Laboratories (Wilmington, Massachusetts, USA). Animals were housed 4-5/cage in micro isolators, with a 12hr/l2hr light/dark cycle, acclimated for at least I week prior to use and fed normal laboratory chow ad libitum. Studies were conducted on animals between 7 and 12 weeks of age at implantation. To implant tumor cells into nude mice, the cells were trypsinized as above, washed in PBS and resusupended at a concentration of 50 x 10(6) cells/mI in PBS. Using a 27 gauge needle and 1 cc syringe, 0.1 ml of the cell suspension was 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 thejuncture of the os coxae (pelvic bone) and the os femoris (femur). Tumors were then permitted to develop in vivo until they reached approximately 150 mm 3 in volume, which typically required 2-3 weeks following implantation. Tumor volumes (V) were 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 were randomized into treatment groups so that the average tumor volumes of each group were similar at the start of dosing. Sock solutions of test compounds were prepared by dissolving the appropriate amounts of each compound in dimethyl sulfoxide (DMSO) by sonication in an ultrasonic water bath. Stock solutions were prepared at the start of the study, stored at -20 0 C and diluted fresh each day for dosing. A solution of 20% Cremophore RIH40 (polyoxyl 40 hydrogenated castor oil; BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany) in 80% D5W (5% dextrose in water; Abbott Laboratories, North Chicago, Illinois, USA) was also prepared by first heating 100% Cremophore RH40 at 50-60C until liquefied and clear, diluting 1:5 with 100% D5W, reheating again until C :\RPortbhDCC\REC\4075614_1 DOC-1/10/2012 - 358 clear and then mixing well. This solution was stored at room temperature for up to 3 months prior to use. To prepare formulations for daily dosing, DMSO stock solutions were diluted 1:10 with 20% Cremophore RH40. The final formulation for dosing contained 10% DMSO, 18% Cremophore RIH40, 3.6% dextrose and 68.4% water and the appropriate amount of test article. Animals were 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. As shown in Figure 17, treatment with 300 mg/kg body weight of Compound 49 decreased the growth rate of MDA-MB-435S cells in nude mice to a greater extent than did a dose of 100 mg/kg body weight of the Hsp90 inhibitor 17-AAG. This effect was not associated with significant toxicity, as shown by the lack of an effect on body weights (Figure 18). Example 212: Compound #226 Displays Anti-tumor Activity Against Human Tumor Cells Expressing the FLT3 Tyrosine Kinase Receptor in a Mouse Xenograft Model The human acute myelogenous leukemia (AML) cell line, Mv 4-11 (ATCC #CRL-9591), was obtained from the American Type Culture Collection (ATCC; Manassas, Virginia, USA). Growth of this tumor cell line is dependent upon the expression of an activated form of the FLT3 tyrosine kinase receptor carrying an internal tandem duplication (ITD) mutation, which is the most common molecular defect associated with AM L (K.W. Yee et al., Blood 100:2941-2949, 2002). The cells were cultured in growth media prepared with Iscove's Modified Dulbecco's Media, 10% fetal bovine serum (FBS), 1% IOOX Penicillin-Streptomycin, 1% 100X sodium pyruvate and 1% 1OX MEM non-essential amino acids. FBS was obtained from ATCC and all other reagents were obtained from Invitrogen Corp. (Carlsbad, California, USA). Cells that had been cryopreserved in liquid nitrogen were rapidly thawed at 37 0 C and transferred to a tissue culture flask containing growth media and then incubated at 37"C in a 5% CO 2 incubator. To expand the cell line, cultures were passaged 1:2 to a density of 5 x 10(6) cells/ml every three days by adding an equal volume of fresh growth media. When the flasks reached a density of approximately 10 x 10(6) cells/ml, the above passaging process was repeated until sufficient cells had been obtained for implantation into mice. Seven to eight week old, female Crl:CD-l-nuBR (nude) mice were obtained from Charles River Laboratories (Wilmington, Massachusetts, USA). Animals were housed 4-5/cage in micro isolators, with a 12hr/l 2hr light/dark cycle, acclimated for at least I week prior to use and fed normal laboratory chow ad libitum. Studies were conducted on animals between 8 and 10 weeks of age at implantation. To implant Mv 4-1 I tumor cells into nude mice, cell cultures were C \NRPortbl\DCC\RECW)75614_1.DOC.1/10/20 12 -359 centrifuged to pellet the cells, the supernatant was aspirated, the cell pellet was resuspended in 10 ml of growth media and the cell number determined using a hemocytometer. The cells were then washed in PBS and resusupended at a concentration of 5 x 10(7) cells/mI in 50% non supplemented Iscove's Modified Dulbecco's Media and 50% Matrigel Basement Membrane Matrix (#354234; BD Biosciences; Bedford, Massachusetts, USA). Using a 27 gauge needle and I cc syringe, 0.1 ml of the cell suspension was injected subcutaneously into the shaved flanks of SCID mice. Tumors were then permitted to develop in vivo until the majority reached 100-200 mm' in tumor volume, which typically required 1-2 weeks following implantation. Animals with oblong, very small or large tumors were discarded, and only animals carrying tumors that displayed consistent growth rates were selected for studies. Tumor volumes (V) were 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 were randomized into treatment groups so that the median tumor volumes of each group were similar at the start of dosing. %T/C values, as a measure of efficacy, were determined as follows: (i) If AT>0: %T/C=(AT/ACx 100 (ii) If AT < 0: %T/C = (AT/To) x 100 (iii) AT = Change in median tumor volume between start of dosing and the end of study. (iv) AC = Change in median tumor volume between start of dosing and the end of study. (v) To = Median tumor volume at start of dosing. To formulate Compound #226 in DRD, stock solutions of the test article were prepared by dissolving the appropriate amounts of the compound in dimethyl sulfoxide (DMSO) by sonication in an ultrasonic water bath. Stock solutions were prepared weekly, stored at -20*C and diluted fresh each day for dosing. 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) was also prepared by first heating 100% Cremophore RH40 at 50-60"C until liquefied and clear, diluting 1:5 with 100% D5W, reheating again until clear and then mixing well. This solution was stored at room temperature for up to 3 months prior to use. To prepare DRD formulations for daily dosing, DMSO stock solutions were diluted 1:10 with 20% Cremophore RH40. The final DRD formulation for dosing contained 10% CANRPonblIDCCREC\0)75614_I DOC-1110/2012 -360 DMSO, 18% Cremophore RH40, 3.6% dextrose, 68.4% water and the appropriate amount of test article. Animals were intravenously (i.v.) injected with this formulation at 10 ml per kg body weight on one day each week for a total of 3 doses. As shown in Figure 19, treatment 1 time per week with a dose of 50 or 125 mg/kg body weight of Compound #226 substantially decreased the growth rate of Mv 4-1 1 cells in nude mice, with a %T/C values of -63.8 and -93.0, respectively. Remarkably, in the 125 mg/kg treatment group, 2 of 8 animals had no apparent tumors by the end of the study. This effect was not associated with excessive toxicity, as the highest dose group treated with 125 mg/kg Compound #226 had an average bodyweight loss of -1.4% (+/- 1.6 SEM) over the course of the study. Example 213: Compound #226 Displays Anti-tumor Activity Against Human Tumor Cells Expressing the c-Kit Tyrosine Kinase Receptor in a Mouse Xenograft Model The human acute myelogenous leukemia cell line, Kasumi-l (ATCC #CRL-2724), was obtained from the American Type Culture Collection (ATCC; Manassas, Virginia, USA). Growth of this tumor cell line is dependent upon the expression of an activated form of the c-Kit tyrosine kinase receptor carrying a N822K mutation (A. Beghini, et al., Exp. Hematol. 33:682-688, 2005). The cells were cultured in growth media prepared with RPMI Media 1640 (high glucose), 20% fetal bovine serum (FBS), 1% IOOX Penicillin-Streptomycin, 1% IOOX sodium pyruvate and 1% IOOX MEM non-essential amino acids. FBS was obtained from ATCC and all other reagents were obtained from Invitrogen Corp. (Carlsbad, California, USA). Cells that had been cryopreserved in liquid nitrogen were rapidly thawed at 37 0 C and transferred to a tissue culture flask containing growth media and then incubated at 37'C in a 5% CO 2 incubator. To expand the cell line, cultures were passaged 1:2 to a density of 5 x 10(6) cells/ml every three days by adding an equal volume of fresh growth media. When the flasks reached a density of approximately 10 x 10(6) cells/ml, the above passaging process was repeated until sufficient cells had been obtained for implantation into mice. Seven to eight week old, female CB I 7/1cr-Prkdc"cd/Crl (SCID) mice were obtained from Charles River Laboratories (Wilmington, Massachusetts, USA). Animals were housed 4-5/cage in micro-isolators, with a 12hr/12hr light/dark cycle, acclimated for at least I week prior to use and fed normal laboratory chow ad libitum. Studies were conducted on animals that were between 8 and 12 weeks of age at the time of tumor cell implantation. To implant Kasumi-l tumor cells into SCID mice, cell cultures were centrifuged to pellet the cells, the supernatant was aspirated and the cell pellet was resuspended in 10 ml of growth media and the cell number determined using a C:NRPornb\DCC\REC\407614_I.DOC-1/10/2012 - 361 hemocytometer, washed in PBS and resusupended at a concentration of 5-10 x 10(7) cells/mI 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 I cc syringe, 0.1 ml of the cell suspension was injected subcutaneously into the shaved flanks of SCID mice. Tumors were then permitted to develop in vivo until the majority reached 100-200 mm' in tumor volume, which typically required 4-5 weeks following implantation. Animals with oblong, very small or large tumors were discarded, and only animals carrying tumors that displayed consistent growth rates were selected for studies. Tumor volumes (V) were 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 were randomized into treatment groups so that the median tumor volumes of each group were similar at the start of dosing. %T/C values, as a measure of efficacy, were determined as follows: (vi) If AT > 0: %T/C = (AT/AC) x 100 (vii) If AT < 0: %T/C = (AT/To) x 100 (viii) AT = Change in median tumor volume between start of dosing and the end of study. (ix) AC = Change in median tumor volume between start of dosing and the end of study. (x) To = Median tumor volume at start of dosing. To formulate Compound #226 in DRD, stock solutions of the test article were prepared by dissolving the appropriate amounts of the compound in dimethyl sulfoxide (DMSO) by sonication in an ultrasonic water bath. Stock solutions were prepared weekly, stored at -20*C and diluted fresh each day for dosing. 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) was also prepared by first heating 100% Cremophore RH40 at 50-60'C until liquefied and clear, diluting 1:5 with 100% D5W, reheating again until clear and then mixing well. This solution was stored at room temperature for up to 3 months prior to use. To prepare DRD formulations for daily dosing, DMSO stock solutions were diluted 1:10 with 20% Cremophore RH40. The final DRD formulation for dosing contained 10% DMSO, 18% Cremophore RH40, 3.6% dextrose, 68.4% water and the appropriate amount of test article. Animals were intravenously (i.v.) injected with this formulation at 10 ml per kg body CANRPorbl\DCC\REC\4075614_1 DOC- 1110/2012 - 362 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 14 doses. As shown in Figure 20, treatment 5 times per week with a dose of 25 mg/kg body weight of Compound #226 substantially decreased the growth rate of Kasumi-1 cells in SCID mice, with a %T/C value of -15.3. Remarkably, treatment with a single dose of 25 mg/kg body weight of Compound #226 was sufficient to cause tumor regression, with a %T/C value of -4.1 observed 3 days after the first dose. This effect was not associated with overt toxicity, with the Compound #226-treated group having an average bodyweight gain +0.7% (+/- 2.0 SEM) over the course of the study. Example 214: Compound #226 Displays Anti-tumor Activity Against Human Chronic Myelogenous Leukemia Tumor Cells in a Mouse Xenograft Model The human chronic myelogenous leukemia (CML) cell line, K-562 (ATCC #CCL-243), was obtained from the American Type Culture Collection (ATCC; Manassas, Virginia, USA). Growth of this tumor cell line is dependent upon the expression of the Bcr-Abl fusion protein (C. Gambacarti-Passerini et al., Blood Cells Mol. Dis. 23:380-394, 1997). The cells were cultured in growth media prepared with Iscove's Modified Dulbecco's Media, 10% fetal bovine serum (FBS), 1% IOOX Penicillin-Streptomycin, 1% lOOX sodium pyruvate and 1% IOOX MEM non-essential amino acids. FBS was obtained from ATCC and all other reagents were obtained from Invitrogen Corp. (Carlsbad, California, USA). Cells that had been cryopreserved in liquid nitrogen were rapidly thawed at 37'C and transferred to a tissue culture flask containing growth media and then incubated at 37*C in a 5% CO 2 incubator. To expand the cell line, cultures were passaged 1:2 to a density of 5 x 10(6) cells/ml every three days by adding an equal volume of fresh growth media. When the flasks reached a density of approximately 10 x 10(6) cells/ml, the above passaging process was repeated until sufficient cells had been obtained for implantation into mice. Seven to eight week old, female CB I 7/1cr-Prkd"I/Crl (SCID) mice were obtained from Charles River Laboratories (Wilmington, Massachusetts, USA). Animals were 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 were conducted on animals that were between 8 and 12 weeks of age at the time of tumor cell implantation. To implant K-562 tumor cells into SCID mice, cell cultures were centrifuged to pellet the cells, the supernatant was aspirated, the cell pellet was resuspended in 10 ml of growth media and the cell number determined using a hemocytometer. The cells were then washed in PBS and resusupended at a concentration of 5-10 x 10(7) cells/ml in 50% non-supplemented Iscove's Modified Dulbecco's Media and 50% C:\NRPonbI\DCC\REC\407564_1 DOC-1/10/2012 - 363 Matrigel Basement Membrane Matrix (#354234; BD Biosciences; Bedford, Massachusetts, USA). Using a 27 gauge needle and I cc syringe, 0.1 ml of the cell suspension was injected subcutaneously into the shaved flanks of SCID mice. Tumors were then permitted to develop in vivo until the majority reached 100-200 mm' in tumor volume, which typically required 1-2 weeks following implantation. Animals with oblong, very small or large tumors were discarded, and only animals carrying tumors that displayed consistent growth rates were selected for studies. Tumor volumes (V) were 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 were randomized into treatment groups so that the median tumor volumes of each group were similar at the start of dosing. %T/C values, as a measure of efficacy, were determined as follows: (xi) If AT > 0: %T/C = (AT/AC) x 100 (xii) If AT < 0: %T/C = (AT/To) x 100 (xiii) AT = Change in median tumor volume between start of dosing and the end of study. (xiv) AC = Change in median tumor volume between start of dosing and the end of study. (xv) To = Median tumor volume at start of dosing. To formulate Compound #226 in DRD, stock solutions of the test article were prepared by dissolving the appropriate amounts of the compound in dimethyl sulfoxide (DMSO) by sonication in an ultrasonic water bath. Stock solutions were prepared weekly, stored at -20'C and diluted fresh each day for dosing. 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) was also prepared by first heating 100% Cremophore RH40 at 50-60'C until liquefied and clear, diluting 1:5 with 100% D5W, reheating again until clear and then mixing well. This solution was stored at room temperature for up to 3 months prior to use. To prepare DRD formulations for daily dosing, DMSO stock solutions were diluted 1:10 with 20% Cremophore RH40. The final DRD formulation for dosing contained 10% DMSO, 18% Cremophore R H40, 3.6% dextrose, 68.4% water and the appropriate amount of test article. Animals were intravenously (i.v.) injected with this formulation 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 6 doses.
C:\NRPonbICC\REC\4075614_ DOC-1110/2012 - 364 As shown in Figure 21, treatment 5 times per week with a dose of 35 mg/kg body weight of Compound #226 substantially decreased the growth rate of K-562 cells in SCID mice, with a %T/C value of 24.7. This effect was not associated with excessive toxicity, as the Compound #226-treated group had an average bodyweight loss of -12.4% (+/- 1.4 SEM) over the course of the study. Example 215: Compound #226 Displays Anti-tumor Activity Against Human Tumor Cells Expressing Activated B-RAF in a Mouse Xenograft Model The human malignant melanoma cell line, A-375 (ATCC #CRL-1619), was obtained from the American Type Culture Collection (ATCC; Manassas, Virginia, USA). Growth of this tumor cell line is dependent upon the expression of an activated form of the B-RAF serine/threonine kinase carrying a V600E mutation (K.P. Hoeflich el al., Cancer Res. 66:999 1006, 2006; D.J. Panka et al., Cancer Res. 66:1611-1619, 2006). This is the most frequent genetic abnormality observed in melanoma (N. Dhomen and R. Marais, Curr. Opin. Genet. Dev. 17:3 1-39, 2007). The cells were cultured in growth media prepared with Dulbecco's Modified Eagle Medium (high glucose), 10% fetal bovine serum (FBS), 1% 1OOX Penicillin-Streptomycin, 1% IOOX sodium pyruvate and 1% IOOX MEM non-essential amino acids. FBS was obtained from ATCC and all other reagents were obtained from Invitrogen Corp. (Carlsbad, California, USA). Cells that had been cryopreserved in liquid nitrogen were rapidly thawed at 37 0 C and transferred to a tissue culture flask containing growth media and then incubated at 37 0 C in a 5%
CO
2 incubator. To expand the cell line, growth media was replaced every 2-3 days until the flask became 90% confluent, typically in 4-8 days. Cultures were passaged by washing with 10 mL of room temperature phosphate buffered saline (PBS) and then disassociating cells by adding 5 mL I X trypsin-EDTA and incubating at 37*C until the cells detached from the surface of the flask. To inactivate the trypsin, 5 mL of growth media was added and then the contents of the flask were centrifuged to pellet the cells. The supernatant was aspirated and the cell pellet was resuspended in 10 mL of growth media and the cell number determined using a hemocytometer. Approximately 3-4 x 10(6) cells per flask were seeded into 175 cm 2 flasks containing 50 mL of growth media and incubated at 37*C in a 5% CO 2 incubator. When the flasks reached 90% confluence, the above passaging process was repeated until sufficient cells had been obtained for implantation into mice. Seven to eight week old, female Crl:CD-I-Foxn 1"" (nude) mice were obtained from Charles River Laboratories (Wilmington, Massachusetts, USA). Animals were housed 4-5/cage in C NRPonb1\DCC\REC\47M(514_1 DOC- 1/10/12 - 365 micro-isolators, with a 12hr/12hr light/dark cycle, acclimated for at least I week prior to use and fed normal laboratory chow ad libitum. Animals were between 12 and 13 weeks of age at implantation. To implant A-375 tumor cells into nude mice, cell cultures were trypsinized as above, washed in PBS and resusupended at a concentration of -5-10 x 10(7) cells/mL in 50% non supplemented Dulbecco's Modified Eagle Medium (high glucose) and 50% Matrigel Basement Membrane Matrix (#354234; BD Biosciences; Bedford, Massachusetts, USA). Using a 27 gauge needle and I cc syringe, 0.1 mL of the cell suspension was injected subcutaneously into the flanks of nude mice. Tumors were then permitted to develop in vivo until the majority reached 90-160 mm 3 in tumor volume, which required -5-6 weeks following implantation. Animals with oblong, very small or large tumors were discarded and only animals carrying tumors that displayed consistent growth rates were selected for studies. Tumor volumes (V) were 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 were randomized into treatment groups so that the average tumor volumes of each group were similar at the start of dosing. %T/C values, as a measure of efficacy, were determined as follows: (xvi) If AT > 0: %T/C = (AT/AC) x 100 (xvii) If AT < 0: %T/C =(AT/To) x 100 (xviii) AT = Change in average tumor volume between start of dosing and the end of study. (xix) AC = Change in average tumor volume between start of dosing and the end of study. (xx) To = Average tumor volume at start of dosing. To formulate Compound #226 in DRD, stock solutions of the test article were prepared by dissolving the appropriate amounts of the compound in dimethyl sulfoxide (DMSO) by sonication in an ultrasonic water bath. Stock solutions were prepared weekly, stored at -20'C and diluted fresh each day for dosing. 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) was also prepared by first heating 100% Cremophore RH40 at 50-60*C until liquefied and clear, diluting 1:5 with 100% D5W, reheating again until clear and then mixing well. This solution can be stored at room temperature for up to 3 months prior to use. To prepare DRD formulations for daily dosing, DMSO stock solutions were C kNRPonbl\DCC\REC\4075614_1 DOC-11102012 - 366 diluted 1:10 with 20% Cremophore RH40. The final DRD formulation for dosing contained 10% DMSO, 18% Cremophore RH40, 3.6% dextrose, 68.4% water and the appropriate amount of test article. Animals were intravenously (i.v.) injected with this formulation at 10 mL per kg body weight on three days each week (Monday, Wednesday, Friday) for a total of 8 doses. As shown in Figure 22, treatment 3 times per week with a dose of 50 mg/kg body weight of Compound #226 substantially decreased the growth rate of A-375 cells in nude mice, with a %T/C value of 17. This effect was not associated with excessive toxicity, as the dose group treated with 50 mg/kg Compound #226 had an average body weight gain of 2.7% (+/- 1.1 SEM) over the course of the study. 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. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims (11)

  1. 2. A method ofI inducing degradation of BRAF in a subject ill need IICICof. comllpris iniig administering to the subject all effctive amon t Of a compound represented by th1e followiing formula: R55 R 52 N R 56 HO N OH N- N or a tautoiler and/or pharmaceutically acceptable salt thereof, wherein: X.; is CR 5 4 : Z, is --011 or -SI I; R 57 is selected fom -11. methyl. ethyl, l-propyl isoplropylI, l-bltyL in-Ipentyl. nl-hexyL. (Cl 2C I 1. -Cl lC(O)O H, and -C(O)N(Cl 11)2: Ri 3 is -11L methyl, ethyl, or isopropyl: Rs, is -i1 or a lower alkyl: R5 is selected rnom -11. -011. OCI-. and - OCI C";, and Rs(, is selected from -II, methyl. ethyl. isopropyl. and cyclopropyl. and wherein the B-iaf associated cancer is a cancer having a B-raf with al acti vailg mlt'Ltatioll in the kinase domain.
  2. 3. Use of 3-(2,4-dilydroxy-5-isopropyl-phenyl)-4-(I-methyl-indol-5-yl)-5-hdroxy I I.214ltriazole in the mailliufactunre of a medicaimfeilt foi treating a BRAF associated cancer !-r: nl me NRIIr-ILD( CRht M~ C dt-, 1,1?1! 1 ,, I 1 - 368 whercin the 3-raf associated cancer is a cancer having a B-raf with an activating mutation in the kinase domain.
  3. 4. Use of a compound represented by the following form ula: R55 R5 2 N R56 HO /> -P 5 3 HOX45 N Z OH N- N or a tautomer or pharmaceutically acceptable salt thereof, wherein: X 1 is CR 1 : / is - OHl or -SI l: Ri2 is selected from -H1, methyl, ethyl, n-propyl, isopropyl, n-iiutyI, n-pentyll. n-hexyl, (Cl 1) 2 0C1 h, -CHI2C(O)OH, and -C(O)N(C H3)2; R 53 is -Hl, methyl, ethyl, or isopropyl; R is -1l or a lower alkyl; R, is selected from -1 I, -Oil, OCI 13, and OCIHCI l; and Rj, is selected from -11, methyl. ethyl, isopropyl, and cyclopropyl. in the muanuflacture of a medicament for inducing degradation of BRA F, and wherein the Bi-raf associated cancer is a cancer having a 13-raf with an activating mutation in the kinase domain.
  4. 5. The method of claim 2 or use of claim 4, wherein Zi is --011.
  5. 6. The method ofelaim 2 or use ofclaim 4. wherein Z, is -- SI 1.
  6. 7. The method or use of any one of claims 2 and 4 to 6, wherein R, is IH.
  7. 8. The method or ise of any one of claims 2 and 4 to 7, wherein R 5 is 1H. N ',iI I) C tO ( t - r5 21 i1 - 369 9. The method or use of any one of' claims 2 and 4 to 8, wherein R-, is F I or -OC [13. l. The method or cli m 2 or use of claim 4, wherein the compound is selected from: 3-(2,4-d ihydroxyphenyl )-4-( I -ethyl-indol-4-yI)-5-mercaplto-{ I,2,4]triazole, 3-(2,4-dihydroxyphenyl)-4-(1-isopropyi-indol-4-yl)-5-iercapto-[I,2,4]triazole, 2,4-c ihydroxyphonyl)-4-(i ndol-4-yl)-5-mercapto-[I ,2,4]triazole, 3-(2,4-dihydroxyphenyl)-4-( I -methoxyctlhyl-indol-4-yl)-5-mercapto-I L2,4| triazole, 3-(2,.4-d ilydroxy-5-ethyl-phenyl)-4-(1 -isopropyi-indol-4-yl)-5-mercapto- 1.2.4 ]iriazole, 3-(2,4-dihydroxyphenyl)-4 -(I-dinthylcarbamoyl-indol-4-yl)-Smr icapto- 1.2,4 triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-( I -propyi-indol-4-yl)-5-mercapto-I 1.2.4|triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2,3-triiethyl-indol-5-yl)-5-mercapto SI,2,4]triazole, 3 -(24-dihydroxy-5-ethyl-plheny)-4-(2,3-dimethyindol-5-yl)-5-mercapto I,2,4 Itriazole, 3-(2,4-d ihydroxy-5-ethyl-phenyl)-4-(lI -acetyl-2.3-dimethyl-indol-5-yl)-5-mercapto 1,.21 triazole. 3.-(2.4 -dihydlroxy-5 -ethylpheny'I)-4-( I-isopropyI- 7-miethoxy-indol-4-yl)-5-miercapto [1.2.-1 jiriazole. 1.24 Itriazole, 3-(2.4-dihydroxy-5-ethyi-phenyl)-4-( I -propyl-2.3 -dimethylindol-5-yl )-5-iercapto 11,2,4]triazole, 3-(2,4 -d ihydroxy-5 -ethyl-phcnyl)-4-(N-ietlhyl-tetrahydrocarbozo7 l--yl)-5-mercapto 1.2,4 jtriazole, 3-(2,4-diih yd roxy-5-etiy I-ph en>l'])-4-(N-m ethyl-y ononana! jindo1-5 -y)-5-m ercapto |.2.4 Jtriazole, 3-(2.4-dihydroxy-5-et hyl-phenyl)-4-( I -n-butyl I- indo I-4-Iyl)-5-mercapto il.2.4 Itriazolc, 3-(2,4-d ihydroxy-5-ethyl -phenyl )-4 -( I -n-pentyl-indol-4l-yl )-5-me rcapto-| L 2,4! Jtriazole. 3-(2,4-clihydroxy-5-ethiyl-plhenyl)-4-(1I-n-hexyl-i ndol-4-yl )-5 -mercapto-! 1L2.4 jriazole. 3 -(2,4-dihydroxy-5-cyc lopropyl-phenyl)-4-( I -( 1-methyley clopropyl)-i ndol--i)-5 mercapto-1 I,2,4]triazole, 3-(2,4-dihydroxy-5-cyclopropyl-plienyl)-4-( I -isopropyl-7-methoxy-indo]-4-yl)-5 mercapto-[ l,2,4]triazole. 3 -(2,-dihydroxy-5-cc!lopropyI-phenyl)-4-(I.2.3-trimethyl-indol-5-yI)-5- iercapto I .2,4] triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-( I -isopropy 1-7-nethoxy-indol-4-N y)-5-mercapto 1,2.41triazolc disodium salt, I d-Ir:I0,.I.II - 370 3-(2,4-dihyldroxy-5-/ert-butyl-pcnyI)-4-(I -isopropyt7-ietlioxy-indol-l-yl)- 5 -ticeiapto 11,2.4 triazole, 3-(2,1 -d ihydroxy-5-cy clopropyl-phenyl)-4-( I -propyl-7-tnhoxy-indol-4-yI)-5-mrc a pto I I,2.4 jtriazolc. 3-(2.4-dihydroxy-5-cthyl-phcnyl)-4-( I -melyl-3-ethyl-indo-5-yl)-5-mercaplto 1 .2.4 ]triazolc, 3-(2,4-dihydroxy-5-ethyl-phcnyl)-4-(1,3-dimeitliyl-indol-5-yl)-5-mcrcapto-f 1,2.4]triazole, 3-(24-dihydroxy-5-isopropylphcnyl)- 4 -(1 -isopropyl-7-methoxy-indol-4-y)-5-mrcapto I ,2,4]jriazole, 3-(2.1-dihydroxy-5-ehylphenyI)-4-( I -mOhyl-3-isopropy-indoI5-yl )-5-mercapto 11 .2,4 ]riazoc, 3-(2.4-dihydroxy-5-ethyl-phenyl)-4-(N-ethyl-carbozol-7-yi)-5-mercapto-I
  8. 12.4 |Iriazole. 3-(2,-cdihydroxy-5-t hyl-phiy )-4-( - isopropy-7-hydroxy-indol -4yI )-5 -mercapto I,2,4 ]triazColc, 3-(24-dihydlroxy-5-ethyl-phenyl)- 4 -( -isopropyL7-cthoxy-ildoI-4-yl)-5-mcrcapto I I,2,4] riazolc, 3-(2,4- ihydroxy-5-ethyphenyl)-4-( I 2-diietliy-indol-5-yl)-5-mercapo-[ L,2,4|triazole. 3-(2,4-d ihydroxy-5-ethyl-phncyl)-4-(N-methyl-indol-5-yl)- 5 -meC1aptoI 1,2,M triazoe, 3-(2,4-d iydroxy-5-isopropyl-phenyl)- 4 -( 1,3-dimethy-indol-5-yl)-5-mercapto 1 .2.4 ltriazole, 3-(2,4-dihydroxy-5-cyclopropyl-pheny1)-4-(1,3-d imchy I-indol-5-yI)-5-mcrcapto 11.2,4 |triazole, 3-(2,1 -dihydroxy-5-cyclopropyl-phenyl)-4-(1 -nethyl-i ndol-5-yl)-5-mcrcapto [1 ,2,4ltriazolc, 3-(2,4-dihydroxy-5-isopropyl-phCnyl)-4-(1 H-indol-5-yl)-5-icrcapto-[ 1,2.4 Itriazole, 3-(2.4-] ihydroxy-5-ethyl-pheoyl)-4-(1,2-d imethyl-indol-5-yi )-5-mercapto-[I .2.4 Itriazole, 3-(2.4-dihydroxy-5-isopropyl-phenylI)--(1-ethyl-indol-5-yI)-5-mcrcapto- L24| triazole. and 3-(2A-dihydroxy-5-isopropyI-pheny l)-4-(I -prop) indol-5-yI)-5-nrcapto-( L2,4jriazole, or a tautomer or a pharmaceutical acceptable salt thereof. : RVrH- DC V kRE-L 2 1 1 d -il WIlI -371 11. The method of claim 2 or Ise of claim 4, where in the compound is selected from the group consisting of: 3-(2.4-di hydroxy-5-ethyl-pheny l)-4-(1-isopropy l-7-methoxy-iindol-4-yil)-5 -merccapto triazole. 3-(2.4-dihydroxy-5-cyclopropyl-phenyl)-4-( I -propyl-7-methoxy-indol-4-yi)-5-mercapto [ L2.1 triazole. 3-( 2 ,4-dihydroxy-5-isopropyl-phenyl)-4-( I isopropy'l-7-imethoxy-indol-4-yl)-5-mercapio [ 2..4 triazole, and 3-(2.4-dihydroxy-5-isopropyl-phenyl)-4-(I -methyl-indol-5-yl)-5-liydroxy-I I,2,4Jtriazole. or a tautomer or a pharmaceutically acceptable salt thereof. 12. The method of claim 2 or use of claim 4, wherein the compound is 3-(2.4-dihydroxy-5 ethyl-phenyi)-4-( 1 -sopropy-7-methoxy-indol-4-yI)-5-mercapto-triazole, or a tautomer or a pharmaceutical) acceptable salt thereof.
  9. 13. The method of claim 2 or use of claim 4. where in the compound is 3-(2.4-dihydroxy-5 cyclopropyl-phenyl )-4-( I -pi-opyl-7-iiethoxy-indol-4-yI )-5-mercapto-I I.2.4jtriazoic, or a Ia utomer or a pharmaceutically' acceptable salt thereof. Ni. The im1ethod of claim 2 or use of claim 4, wherein ihe compound is 3-(2.4-dihydioxy-5 isopropyl-pheny I)-4--( I -isopropyl-7-i ethoxy-indol-4-yl)-5 -mercapto-[ I .2.4 jtriazole, or a tautomer or a pharmaceutically acceptable salt thereof.
  10. 15. The method of claim 2 or use of claim 4, wherein the compound is 3-(2,4-dihyd roxy-5 isopiopi-phenyl)-4-(1 i-methyl-indol-5-yi)-5 -hydroxy-I 1,2,4triazole, or a tautomer or a harm acutically acceptable salt thereof.
  11. 16. ]'he method of claim ) or use of Claim 3. wherein the cancer is selected From melanoma, non-Hodgkin lymphoma, colon cancer, papillary thyroid carcinoma. acute myeloid leukemia, and non-small cell lung carcinoma. - 372 |7. The method of claim I or use of claim 3, wherein the cancer is lymphoma or non-small cell lung cancer. I 8. Method according to claim I or claim 2 or use according to clain 3 or claim 4 substantially as hereinbefore described with re ference to any one of the EIxamples.
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