WO2006055760A1 - Triazole compounds that modulate hsp90 activity - Google Patents

Triazole compounds that modulate hsp90 activity Download PDF

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Publication number
WO2006055760A1
WO2006055760A1 PCT/US2005/041779 US2005041779W WO2006055760A1 WO 2006055760 A1 WO2006055760 A1 WO 2006055760A1 US 2005041779 W US2005041779 W US 2005041779W WO 2006055760 A1 WO2006055760 A1 WO 2006055760A1
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Prior art keywords
optionally substituted
triazole
mercapto
phenyl
dihydroxy
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PCT/US2005/041779
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French (fr)
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WO2006055760A9 (en
Inventor
Weiwen Ying
David James
Shijie Zhang
Teresa Przewloka
Junghyun Chae
Dinesh U. Chimmanamada
Chi-Wan Lee
Elena Kostik
Howard P. Ng
Kevin Foley
Zhenjian Du
James Barsoum
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Synta Pharmaceuticals Corp.
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=35966006&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2006055760(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to CA2586612A priority Critical patent/CA2586612C/en
Priority to SI200531647T priority patent/SI1817295T1/en
Priority to MX2007005940A priority patent/MX2007005940A/en
Priority to AU2005306484A priority patent/AU2005306484C1/en
Priority to KR1020137030848A priority patent/KR20140006070A/en
Priority to PL05851788T priority patent/PL1817295T3/en
Priority to RS20130040A priority patent/RS52642B/en
Priority to MEP-2013-16A priority patent/ME01498B/en
Priority to BRPI0518315A priority patent/BRPI0518315B8/en
Application filed by Synta Pharmaceuticals Corp. filed Critical Synta Pharmaceuticals Corp.
Priority to CN2005800418702A priority patent/CN101072759B/en
Priority to NZ555158A priority patent/NZ555158A/en
Priority to KR1020077013728A priority patent/KR101374553B1/en
Priority to EP05851788A priority patent/EP1817295B1/en
Priority to JP2007543263A priority patent/JP4954083B2/en
Priority to DK05851788.9T priority patent/DK1817295T3/en
Priority to ES05851788T priority patent/ES2399241T3/en
Publication of WO2006055760A1 publication Critical patent/WO2006055760A1/en
Publication of WO2006055760A9 publication Critical patent/WO2006055760A9/en
Priority to IL183108A priority patent/IL183108A/en
Priority to HK08100772.6A priority patent/HK1107700A1/en
Priority to HRP20130095TT priority patent/HRP20130095T1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine

Definitions

  • chemotherapeutic agents act on a specific molecular target thought to be involved in the development of the malignant phenotype.
  • a complex network of signaling pathways regulate cell proliferation, and the majority of malignant cancers are facilitated by multiple genetic abnormalities in these pathway. Therefore, it is unlikely that a therapeutic agent that acts on one molecular target will be fully effective in curing a patient who has cancer.
  • HSPs Heat shock proteins
  • HSPs are a class of chaperone proteins that are up- regulated in response to elevated temperature and other environmental stresses, such as ultraviolet light, nutrient deprivation, and oxygen deprivation. HSPs act as chaperones to other cellular proteins (called client proteins) and facilitate their proper folding and repair, and aid in the refolding of misfolded client proteins.
  • client proteins cellular proteins
  • the Hsp90 family is one of the most abundant HSP families, accounting for about 1- 2% of proteins in a cell that is not under stress and increasing to about 4-6% in a cell under stress. Inhibition of Hsp90 results in degradation of its client proteins via the ubiquitin proteasome pathway.
  • Hsp90 Unlike other chaperone proteins, the client proteins of Hsp90 are mostly protein kinases or transcription factors involved in signal transduction, and a number of its client proteins have been shown to be involved in the progression of cancer. Examples of Hsp90 client proteins that have been implicated in the progression of cancer are described below.
  • Her-2 is a transmembrane tyrosine kinase cell surface growth factor receptor that is expressed in normal epithelial cells.
  • Her2 has an extracellular domain that interacts with extracellular growth factors and an internal tyrosine kinase portion that transmits the external growth signal to the nucleus of the cell.
  • Her2 is overexpressed in a significant proportion of malignancies, such as breast cancer, ovarian cancer, prostate cancer, and gastric cancers, and is typically associated with a poor prognosis.
  • c-Kit is a membrane receptor protein tyrosine kinase which binds Stem Cell Factor (SCF) to its extraellular domain.
  • SCF Stem Cell Factor
  • c-Kit is involved in the development of melanocytes, mast, germ and hematopoietic cells, and there is evidence that it plays a role in several types of cancer including leukemias, mast cell tumors, small cell lung cancer, testicular cancer, cancers of the gastointesinal tract and cancers of the central nervous system.
  • c-Met is a receptor tyrosine kinase that is encoded by the Met protooncogene and transduces the biological effects of hepatocyte growth factor (HGF), which is also referred to as scatter factor (SF).
  • HGF hepatocyte growth factor
  • SF scatter factor
  • c- Met and HGF are expressed in numerous tissues, although their expression is normally confined predominantly to cells of epithelial and mesenchymal origin, respectively.
  • c-Met and HGF are required for normal mammalian development and have been shown to be important in cell migration, cell proliferation and survival, morphogenic differentiation, and organization of 3-dimensional tubular structures (e.g., renal tubular cells, gland formation, etc.).
  • the c-Met receptor has been shown to be expressed in a number of human cancers.
  • c-Met and its ligand, HGF have also been shown to be co-expressed at elevated levels in a variety of human cancers (particularly sarcomas).
  • c-Met signaling is most commonly regulated by tumor-stroma (tumor-host) interactions.
  • c-Met gene amplification, mutation, and rearrangement have been observed in a subset of human cancers. Families with germine mutations that activate c-Met kinase are prone to multiple kidney tumors as well as tumors in other tissues.
  • Numerous studies have correlated the expression of c-Met and/or HGF/SF with the state of disease progression of different types of cancer (including lung, colon, breast, prostate, liver, pancreas, brain, kidney, ovaries, stomach, skin, and bone cancers).
  • the overexpression of c-Met or HGF have been shown to correlate with poor prognosis and disease outcome in a number of major human cancers including lung, liver, gastric, and breast.
  • Akt kinase is a serine/threonine kinase which is a downstream effector molecule of phosphoinositide 3-kinase and is involved in protecting the cell from apoptosis. Akt kinase is thought to be involved in the progression of cancer because it stimulates cell proliferation and suppresses apoptosis.
  • Cdk4/cyclin D complexes are involved in phosphorylation of retinoblastoma protein which is an essential step in progression of a cell through the Gl phase of the cell cycle. Disruption of Hsp90 activity has been shown to decrease the half life of newly synthesized Cdk4.
  • Raf-1 is a MAP 3-kinase (MAP3K) which when activated can phosphorylate and acitivate the serine/threonine specific protein kinases ERKl and ERK2.
  • MAP3K MAP 3-kinase
  • Activated ERKs play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration.
  • the transforming protein of Rous sarcoma virus, v-src is a prototype of an oncogene family that induces cellular transformation (i.e., tumorogenesis) by non- regulated kinase activity.
  • Hsp90 has been shown to complex with v-scr and inhibit its degradation.
  • the BCR-ABL fusion protein associated with chronic myelogenous leukemia and in a subset of patients with acute lymphoblastic leukemia. The fusion protein is a consequence of exchange of genetic material from the long arms of chromosomes 9 and 22 and results in unregulated tyrosine kinase activity.
  • BCR- ABL exists as a complex with Hsp90 and is rapidly degraded when the action of Hsp90 is inhibited.
  • Hsp90 is required to maintain steroid hormone receptors in a conformation capable of binding hormone with high affinity. Inhibition of the action of Hsp90 therefore is expected to be useful in treating hormone-associated malignancies such as breast cancer.
  • p53 is a tumor suppressor protein that causes cell cycle arrest and apoptosis. Mutation of the p53 gene is found in about half of all human cancers making it one of the most common genetic alterations found in cancerous cells. In addition, p53 mutation is associated with a poor prognosis. Wild-type p53 has been shown to interact with Hsp90, but mutated p53 forms a more stable association than wild-type p53 as a result of its misfolded conformations.
  • Hsp90 A stronger interaction with Hsp90 protects the mutated protein form normal proteolytic degradation and prolongs its half-life.
  • inhibition of the stabilizing effect of Hsp90 causes mutant p53 to be degraded and restores the normal transcriptional activity of wild-type p53.
  • Hif-lcc is a hypoxia-inducible transcription factor that is up-regulated under low oxygen conditions.
  • Hif-l ⁇ associates with Von Hippel-Lindau (VHL) tumor suppressor protein and is degraded.
  • VHL Von Hippel-Lindau
  • Low oxygen conditions inhibits this association and allows Hif-l ⁇ to accumulate and complex with Hif-l ⁇ to form an active transcription complex that associates with hypoxia- response elements to activate the transcription of vascular endothelial growth factor (VEGF).
  • VHL Von Hippel-Lindau
  • VEGF vascular endothelial growth factor
  • Increased Hif-l ⁇ is associated with increased metastasis and a poor prognosis.
  • Hsp90 has been shown by mutational analysis to be necessary for the survival of normal eukaryotic cells. However, Hsp90 is over expressed in many tumor types indicating that it may play a significant role in the survival of cancer cells and that cancer cells may be more sensitive to inhibition of Hsp90 than normal cells. For example, cancer cells typically have a large number of mutated and overexpressed oncoproteins that are dependent on Hsp90 for folding. In addition, because the environment of a tumor is typically hostile due to hypoxia, nutrient deprivation, acidosis, etc., tumor cells may be especially dependent on Hsp90 for survival.
  • Hsp90 a family of natural products that inhibit Hsp90, has shown evidence of therapeutic activity in clinical trials.
  • benzoquinone ansamycins suffer from a number of limitations. For example, they have low oral bioavailability, and their limited solubility makes them difficult to formula. In addition, they are metabolized by polymorphic cytochrome P450 CYP3A4 and are a substrate for P- glycoprotein export pump involved in the development of multidrug resistance. Therefore, a need exist for new therapeutics that improve the prognosis of cancer patients and that reduces or overcomes the limitations of currently used anti-cancer agents.
  • the present invention provides novel compounds which inhibit the activity of Hsp90 and are useful in the treatment of proliferative disorders, such as cancer.
  • the present invention also provides new uses for previously disclosed compounds.
  • the present invention provides compounds having the 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 ;
  • Ri is -OH, -SH, -NR 7 H, -OR 26 , -SR 26 , -NHR 26 , -O(CH 2 ) m OH, -O(CH 2 ) m SH, -O(CH 2 ) m NR 7 H, -S(CH 2 ) m OH, -S(CH 2 ) m SH, -S(CH 2 ) m NR 7 H, -OC(O)NR 10 R 1 I, -SC(O)NRi 0 R n , -NR 7 C(O)NR 10 Ri 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 3 is -OH, -SH, -NR 7 H, -OR 26 , -SR 26 , -NHR 26 , -0(CH 2 ) m 0H, -O(CH 2 ) m SH, -O(CH 2 ) m NR 7 H, -S(CH 2 ) m OH, -S(CH 2 ) m SH, -S(CH 2 ) m NR 7 H, -OC(O)NR 10 Ri,, -SC(O)NRi 0 Ri i, -NR 7 C(O)NRi 0 Ri 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
  • Rs is an optionally substituted heteroaryl or an optionally substituted 8 to 14 membered aryl
  • R 7 and R 8 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,o and Rn 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 26 is a lower alkyl; p, for each occurrence, is, independently, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
  • ring A of the the compounds of formula (I) is not a substituted [l,2,3]triazole, and/or compounds represented by formula (I) do not include 3-(2,4-dihydroxy-phenyl)-4-(7-naphthalen-l-yl)-5-mercapto-triazole.
  • the present invention also provides compounds having the formula (II):
  • ring A, Ri, 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, -NRi 0 Rn, -OR 20 , -C(O)R 7 ,
  • 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.
  • compounds represented by formula (II) do not include 3-(2,4-dihydroxy-phenyl)-4-(7-naphthalen-l-yl)-5-mercapto-triazole, 3-(2,4- dihydroxyphenyl)-4-(2,5-dimethoxyphenyl)-5-mercapto-triazole, 3-(l-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 (III):
  • Ri 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, -NR 10 Rn, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 ,
  • compounds represented by formula (III) do not include compounds in which Ri 8 is not cyclohexyl.
  • the invention also provides compounds represented by formula (IV) or formula (V):
  • Ri and R3 are defined as for formula (I);
  • Xi 4 is O, 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 -H or is 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, a haloalkyl, -C
  • R 2 3 and R 24 are independently -H or are 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, -NR 10 Rn, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 R 11 , -NR 8 C(O)R 7 , -SR 7 , -S(O) P R 7 , -
  • the present invention also provides compounds 1 ⁇ presented by formula (VI):
  • X 42 is CR 44 or N; 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 ;
  • R 4I 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,
  • R 42 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, -C(O)R 7 , -(CH 2 ) m C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 R 11 , -S(O) P R 7 , -S(O) P OR 7 , or -S(0) p NR lo R u ;
  • R 43 and R 44 are, independently, -H, -OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 Rn, -NR 8 C(O)R 7 , -SR 7 , -S(O) P R 7 , -OS(O) P R 7 , -
  • R 45 is -H, -OH, -SH, -NR 7 H, -OR 26 , -SR 26 , -NHR 26 , -0(CH 2 ) m 0H, -O(CH 2 ) m SH, -O(CH 2 ) m NR 7 H, -S(CH 2 ) m OH, -S(CH 2 ) m SH, -S(CH 2 ) m NR 7 H, -OC(0)NRioRii, -SC(O)NRi 0 R 1 I , -NR 7 C(O)NR 10 R 11 , -OC(O)R 7 , -SC(O)R 7 , -NR 7 C(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -NR 7 C(O)OR 7 , -OCH 2 C(O)R 7 , -SCH 2 C(O)R 7 , -NR 7
  • the present invention also provides compounds represented by formula
  • X 42 , R 41 , R 42 , R43, and R 45 are defined as above.
  • the present invention also provides compounds having the formula (VIII):
  • X 4 S is CR5 4 or N
  • Z 1 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 OCH 3 , -CH 2 C(O)OH, and - C(O)N(CHa) 2
  • R 53 and R 54 are each, independently, -H, methyl, ethyl, or isopropyl; or R 53 and R 54 taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring;
  • R 55 is selected from the group consisting of -H, -OH, -OCH 3 , and - OCH 2 CH 3 ;
  • R 56 is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl.
  • the present invention also provides compounds having the formula (IX):
  • Y 43 is NR 42 , C(R 4 O) 2 , C(R 46 ) 2 -C(R 4 6) 2) C(O), C(S), C(R 46 J 2 C(O), or C(R ⁇ ) 2 C(S);
  • R 4I is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
  • R 41 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
  • R 42 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-b ⁇ tyl, n-pentyl, n-hexyl, -C(O)OH, -(CH 2 ) m C(O)OH, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , and -C(O)N(CHs) 2 .
  • Y 41 is CR 4 5.
  • R 45 is H, a lower alkoxy, or -OH.
  • Y 42 is CH.
  • Y 43 is CH 2 .
  • Y 43 is NR 42 , wherein R 42 is H or a lower alkyl.
  • one OfX 44 is NR 42 and the other is CH 2 or C(Re) 2 .
  • one OfX 44 is NR 42 and the other is CH 2 .
  • Z is -OH.
  • Z is -SH.
  • the compound is selected from the group consisting of:
  • Compounds of formula (EX) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer.
  • compounds of formula (IX) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
  • the present invention also provides compounds having the formula (X):
  • X 41 , Y 41 , Y 42 , Z, R 7 , R 8 , Rio, Rn, R 41 , R 4 6 and p are defined as above.
  • Hsp90 is necessary for the survival of ' normal eukaryotic cells.
  • Hsp90 is over expressed in many tumor types indicating that it may play a significant role in the survival of cancer cells and that cancer cells may be more sensitive to inhibition of Hsp90 than normal cells.
  • the compounds shown in Table 1 or compounds of any formula herein, or tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof, are useful treating proliferative disorders such as cancer.
  • chemotherapeutic agents initially cause tumor regression, most agents that are currently used to treat cancer target only one pathway to tumor progression. Therefore, in many instances, after treatment with one or more chemotherapeutic agents, a tumor develops multidrug resistance and no longer responses positively to treatment.
  • One of the advantages of inhibiting Hsp90 activity is that several of its client proteins, which are mostly protein kinases or transcription factors involved in signal transduction, have been shown to be involved in the progression of cancer. Thus, inhibition of Hsp90 provides a method of short circuiting several pathways for tumor progression simultaneously.
  • treatment of tumors with an Hsp90 inhibitor of the invention is more likely to result in regression or elimination of the tumor, and less likely to result in the development of more aggressive multidrug resistant tumors than other currently available therapeis.
  • Figure 1 is a graph showing the ATPase activity of Hsp90 when untreated, when treated with 40 mM of Geldanamycin, a known Hsp90 inhibitor as a positive control, and when treated with 40 ⁇ M or 4 ⁇ M of Compound 108 of the invention;
  • Figure 2 is gel showing the amount of Her2, an Hsp90 client protein, in cells that are untreated, in cells that have been treated with 0.5 ⁇ M, 2 ⁇ M, or 5 ⁇ M of 17AAG, a known Hsp90 inhibitor, and in cells that have been treated with 0.5 ⁇ M, 2 ⁇ M, or 5 ⁇ M of Compound 108 or Compound 49;
  • Figure 3 is a graph showing an FACSCalibur flow cytometer analysis of the c-kit positive population of HEL92.1.7 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 17AAG, an Hsp90 inhibitor that is currently in phase II clinical trials.
  • Figure 4 is a graph showing an FACSCalibur flow cytometer analysis of the c-kit positive population of Kasumi-1 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 17AAG, an Hsp90 inhibitor that is currently in phase II clinical trials.
  • Figure 5 is a Western blot analysis of the c-kit from Kasumi-1 cells treated with Hsp90 inhibitors of the invention or 17AAG (as a positive control).
  • Figure 6 is a Western blot analysis of the c-met from NCI-Hl 193 cells treated with Hsp90 inhibitors of the invention or 17AAG (as a positive control).
  • Figure 7 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-17-demethoxygeldanarnycin (17- AAG);
  • FIG 8 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 3).
  • Tumor bearing animals 8 mice/group
  • IP intraperitoneal
  • 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 9 displays the results of a nude mouse xenograft study to determine the effect of Compound 188 on the in vivo growth rate of RERF-LC- AI IVP human lung tumor cells.
  • Tumor bearing animals (8 mice/group) were i.p. injected 5 times per week for a total of 15 doses (hatched bar) and the average tumor volumes for each group (error bars represent SEM) were determined every 3-4 days.
  • Tumor bearing animals (8 mice/group) were i.p. injected 5 times per week for a total of 15 doses (hatched bar) and the cumulative average percent changes in body weights for each group relative to the start of dosing were determined every 2-3 days.
  • Treatment with a dose of 200 mg/kg body weight of Compound 188 was not overtly toxic, as indicated by the minimal effects on the animal body weights in the test article-treated versus vehicle-treated groups.
  • the present invention provides compounds and uses of said compounds.
  • 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.
  • the present invention encompasses the use of compounds of the invention to slow or stop the growth of cancerous cells or to reduce or eliminate cancerous cells in a mammal.
  • the compounds of the invention can be used in combination with other chemotherapeutic agents and may help to prevent or reduce the development of multidrug resistant cancerous cells in a mammal.
  • the compounds of the invention may allow a reduced efficacious amount of a second chemotherapeutic agent given to a mammal, because compounds of the invention should inhibit the development of multidrug resistant cancerous cells.
  • alkyl means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms.
  • Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n- heptyl, n-octyl, n-nonyl and n-decyl; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4- methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-d
  • (Ci-C 6 )alkyl means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms.
  • Representative (Ci-Ce)alkyl groups are those shown above having from 1 to 6 carbon atoms.
  • Alkyl groups included in compounds of this invention may be optionally substituted with one or more substituents.
  • alkenyl means a saturated straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and having at least one carbon-carbon double bond.
  • Representative straight chain and branched (C 2 -C]o)alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3 -methyl- 1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2- octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, 3- decenyl and the like.
  • alkynyl means a saturated straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and having at 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-l-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
  • 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.
  • 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
  • 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 independently selected from -F, -Cl, -Br, and -I.
  • halomethyl means a methyl in which one to three hydrogen radical(s) have been replaced by a halo group.
  • Representative haloalkyl groups include trifluoromethyl, bromomethyl, 1,2-dichloroethyl, 4-iodobutyl, 2-fluoropentyl, and the like.
  • an "alkoxy” is an alkyl group which is attached to another moiety via an oxygen linker.
  • an “haloalkoxy” is an haloalkyl group which is attached to another moiety via an oxygen linker.
  • an "aromatic ring” or “aryl” means a hydrocarbon monocyclic or polycyclic radical in which at least one ring is aromatic.
  • suitable aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl.
  • Aryl groups may be optionally substituted with one or more substituents.
  • the aryl group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, referred to herein as "(C 6 )aryl.”
  • aralkyl means an aryl group that is attached to another group by a (Ci-C 6 )alkylene group.
  • Representative aralkyl groups include benzyl, 2-phenyl-ethyl, na ⁇ hth-3-yl-methyl and the like.
  • Aralkyl groups may be optionally substituted with one or more substituents.
  • alkylene refers to an alkyl group that has two points of attachment.
  • (Ci-C 6 )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.
  • 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.
  • 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, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • heteroatom may be substituted with a protecting group known to those of ordinary skill in the art, for example, the hydrogen on a nitrogen may be substituted with a tert-butoxycarbonyl group.
  • the heterocyclyl may be optionally substituted with one or more substituents. Only stable isomers of such substituted heterocyclic groups are contemplated in this definition.
  • the term "heteroaromatic”, “heteroaryl” or like terms means a monocyclic or polycyclic heteroaromatic ring comprising carbon atom ring members and one or more heteroatom ring members.
  • Each heteroatom is independently selected from nitrogen, which can be oxidized (e.g., N(O)) or quaternized; oxygen; and sulfur, including sulfoxide and sulfone.
  • Representative heteroaryl groups include pyridyl, 1-oxo-pyridyl, furanyl, benzo[l,3]dioxolyl, benzo[l,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,
  • 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.
  • (C5)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.
  • (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 (Ce)heteroaryls include pyridyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl and the like.
  • heteroarylkyl means a heteroaryl group that is attached to another group by a (Cj-C 6 )alkylene.
  • Representative heteroaralkyls include 2-(pyridin-4-yl)-propyl, 2-(thien-3-yl)-ethyl, imidazol-4-yl-methyl and the like.
  • Heteroaralkyl groups may be optionally substituted with one or more substituents.
  • halogen or "halo" means -F, -CI, -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.
  • 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 28 R 2 9, -C(S)NR 28 R 29 , -C(NR 32 )NR 28 R 29 , -NR 30 C(O)R 3 I, -NR 30 C(S)R 3 ], -NR 30 C(NR 32 )
  • R 30 and R 31 for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and
  • R 32 for each occurrence is, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, -C(O)R 30 , -C(O)NR 28 R 29 , -S(O)pR 30 , or -S(O) P NR 28 R 29 ; p, for each occurrence, is independently, 1 or 2; and h is 0, 1 or 2.
  • heterocyclyl, heteroaryl, or heteroaralkyl group When a heterocyclyl, heteroaryl, or heteroaralkyl group contains a nitrogen atom, it may be substituted or unsubstituted. When a nitrogen atom in the aromatic ring of a heteroaryl group has a substituent the nitrogen may be a quaternary nitrogen.
  • the terms “subject”, “patient” and “mammal” are used interchangeably.
  • the terms “subject” and “patient” refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), preferably a mammal including a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee and a human), and more preferably a human.
  • a non-primate e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse
  • a primate e.g., a monkey, chimpanzee and a human
  • the subject is a non-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.
  • a farm animal e.g., a horse, cow, pig or sheep
  • a pet e.g., a dog, cat, guinea pig or rabbit.
  • the subject is a human.
  • lower refers to a group having up to four atoms.
  • a “lower alkyl” refers to an alkyl radical having from 1 to 4 carbon atoms
  • “lower alkoxy” refers to "-O-(Ci-C 4 )alkyl
  • a “lower alkenyl” or “lower alkynyl” refers to an alkenyl or alkynyl radical having from 2 to 4 carbon atoms, respectively.
  • the compounds of the invention containing reactive functional groups 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.
  • suitable protecting groups for hydroxyl groups include benzyl, methoxymethyl, allyl, trimethylsilyl, tert-butyldimethylsilyl, acetate, and the like.
  • suitable amine protecting groups include benzyloxycarbonyl, tert-butoxycarbonyl, tert-butyl, benzyl and fluorenylmethyloxy- carbonyl (Fmoc).
  • thiol protecting groups examples 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.
  • the term "compound(s) of this invention” and similar terms refers to a compound of formula (I), (II), (EI), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph or prodrug thereof, and also include protected derivatives thereof.
  • the compounds of the invention may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers.
  • 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).
  • one enantiomer, diastereomer or geometric isomer will possess superior activity or an improved toxicity or kinetic profile compared to other isomers. In those cases, such enantiomers, diastereomers and geometric isomers of compounds of this invention are preferred.
  • polymorph means solid crystalline forms of a compound of the present invention or complex thereof. Different polymorphs of the same compound can exhibit different physical, chemical and/or spectroscopic properties. Different physical properties include, but are not limited to stability (e.g., to heat or light), compressibility and density (important in formulation and product manufacturing), and dissolution rates (which can affect bioavailability).
  • Differences in stability can result from changes in chemical reactivity ⁇ e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical characteristics ⁇ e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both ⁇ e.g., tablets of one polymorph are more susceptible to breakdown at high humidity).
  • Different physical properties of polymorphs can affect their processing. For example, one polymorph might be more likely to form solvates or might be more difficult to filter or wash free of impurities than another due to, for example, the shape or size distribution of particles of it.
  • hydrate means a compound of the present invention or a salt thereof, that further includes a stoichiometric or non- stoichiometric amount of water bound by non-covalent intermolecular forces.
  • clathrate means a compound of the present invention or a salt thereof in the form of a crystal lattice that contains spaces ⁇ e.g., channels) that have a guest molecule (e.g., a solvent or water) trapped within.
  • prodrug means a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions ⁇ in vitro or in vivo) to provide a compound of this invention. Prodrugs may become active upon such reaction under biological conditions, or they may have activity in their unreacted forms.
  • prodrugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1 that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • prodrugs include derivatives of compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1 that comprise -NO, -NO 2 , -ONO, or -ONO 2 moieties.
  • Prodrugs can typically be prepared using well-known methods, such as those described by 1 BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5 th ed).
  • biohydrolyzable amide means an amide, ester, carbamate, carbonate, ureide, or phosphate analogue, respectively, that either: 1) does not destroy the biological activity of the compound and confers upon that compound advantageous properties in vivo, such as improved water solubility, improved circulating half-life in the blood (e.g., because of reduced metabolism of the prodrug), improved uptake, improved duration of action, or improved onset of action; or 2) is itself biologically inactive but is converted in vivo to a biologically active compound.
  • biohydrolyzable amides include, but are not limited to, lower alkyl amides, ⁇ -amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.
  • biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters.
  • biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines, and polyether amines.
  • Hsp90 includes each member of the family of heat shock proteins having a mass of about 90-kiloDaltons.
  • the highly conserved Hsp90 family includes cytosolic Hsp90 ⁇ and Hsp90 ⁇ isoforms, as well as GRP94, which is found in the endoplasmic reticulum, and HSP75/TRAP1, which is found in the mitochondrial matrix.
  • c-kit or "c-kit kinase” refers to a membrane receptor protein tyrosine kinase which is preferably activated upon binding Stem Cell Factor (SCF) to its extracellular domain (Yarden et al., 1987; Qiu et al., 1988).
  • SCF Stem Cell Factor
  • the full length amino acid sequence of a c-kit kinase preferably is as set forth in Yarden, et al.,
  • c-kit kinase Mutant versions of c-kit kinase are encompassed by the term "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.
  • a "proliferative disorder” or a “hyperproliferative disorder,” and other equivalent terms, means a disease or medical condition involving pathological growth of cells.
  • Proliferative disorders include cancer, smooth muscle cell proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, retinopathy, e.g., diabetic retinopathy or other retinopathies, cardiac hyperplasia, reproductive system associated disorders such as benign prostatic hyperplasia and ovarian cysts, pulmonary fibrosis, endometriosis, fibromatosis, harmatomas, lymphangiomatosis, sarcoidosis, desmoid tumors,
  • Smooth muscle cell proliferation includes hyperproliferation of cells in the vasculature, for example, intimal smooth muscle cell hyperplasia, restenosis and vascular occlusion, particularly stenosis following biologically- or mechanically- mediated vascular injury, e.g., vascular injury associated with angioplasty.
  • intimal smooth muscle cell hyperplasia can include hyperplasia in smooth muscle other than the vasculature, e.g., bile duct blockage, bronchial airways of the lung in patients with asthma, in the kidneys of patients with renal interstitial fibrosis, and the like.
  • Non-cancerous proliferative disorders also include hyperproliferation of cells in the skin such as psoriasis and its varied clinical forms, Reiter's syndrome, pityriasis rubra pilaris, and hyperproliferative variants of disorders of keratinization (e.g., actinic keratosis, senile keratosis), scleroderma, and the like.
  • the proliferative disorder is cancer.
  • Cancers that can be treated or prevented by the methods of the present invention include, but are not limited to human sarcomas and carcinomas, e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medu
  • leukemias include acute and/or chronic leukemias, e.g., lymphocytic leukemia (e.g., as exemplified by the p388 (murine) cell line), large granular lymphocytic leukemia, and lymphoblastic leukemia; T-cell leukemias, e.g., T-cell leukemia (e.g., as exemplified by the CEM, Jurkat, and HSB-2 (acute), YAC- 1 (murine) cell lines), T-lymphocytic leukemia, and T-lymphoblastic leukemia; B cell leukemia (e.g., as exemplified by the SB (acute) cell line) , and B-lymphocytic leukemia; mixed cell leukemias, e.g., B and T cell leukemia and B and T lymphocytic leukemia; myeloid leukemias, e.g., granuloc
  • 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-l(acute) cell line); and lymphoma (e.g., as exemplified by the U937 cell line).
  • T-leukemia e.g., as exemplified by Jurkat and CEM cell lines
  • B-leukemia e.g., as exemplified by the SB cell line
  • promyelocytes e.g., as exemplified by the HL-60 cell line
  • 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 treating the subject with the cancer.
  • many tumors will initially respond to treatment with an anti-cancer drug by decreasing in size or even going into remission, only to develop resistance to the drug.
  • Drug resistant tumors are characterized by a resumption of their growth and/or reappearance after having seemingly gone into remission, despite the administration of increased dosages of the anti-cancer drug.
  • Cancers that have developed resistance to two or more anti-cancer drugs are said to be "multi-drug resistant". For example, it is common for cancers to become resistant to three or more anti-cancer agents, often five or more anti-cancer agents and at times ten or more anti-cancer agents.
  • c-kit associated cancer refers to a cancer which has aberrant expression and/or activation of c-kit.
  • c-Kit associated cancers include leukemias, mast cell tumors, small cell lung cancer, testicular cancer, some cancers of the gastrointestinal tract and some central nervous system.
  • c-kit has been implicated in playing a role in carcinogenesis of the female genital tract (Inoue, et al., 1994, Cancer Res., 54(l l):3049-3053), sarcomas of neuroectodermal origin (Ricotti, et al, 1998, Blood, 97:2397-2405), and Schwann cell neoplasia associated with neurofibromatosis (Ryan, et al., 1994, J. Neuro. Res., 37:415-432).
  • 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), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1.
  • 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,/?- toluenesulfonate, and pamoate (i.e., l,r-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
  • pamoate i.e., l,r
  • pharmaceutically acceptable salt also refers to a salt prepared from a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1 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-hydroxy
  • pharmaceutically acceptable salt also refers to a salt prepared from a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1 having a basic functional group, such as an amine functional group, and a pharmaceutically acceptable inorganic or organic acid.
  • Suitable acids include, but are not limited to, hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), nitric acid, hydrogen bisulfide, phosphoric acid, lactic acid, salicylic acid, tartaric acid, bitartratic acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, andp- toluenesulfonic acid.
  • solvate is a solvate formed from the association of one or more pharmaceutically acceptable solvent molecules to one of the compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1.
  • solvate includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).
  • a pharmaceutically acceptable carrier may contain inert ingredients which do not unduly inhibit the biological activity of the compounds.
  • the pharmaceutically acceptable carriers should be biocompatible, i.e., non-toxic, non ⁇ inflammatory, non-immunogenic and devoid of other undesired reactions upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed, such as those described in Remington's Pharmaceutical Sciences, ibid.
  • Suitable pharmaceutical carriers for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing about 0.9% mg/ml benzyl alcohol), phosphate-buffered saline, Hank's solution, Ringer's-lactate and the like.
  • the term "effective amount” refers to an amount of a compound of this invention which is sufficient to reduce or ameliorate the severity, duration, progression, or onset of a 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.
  • an "effective amount" of the second agent will depend on the type of drug used.
  • Suitable dosages are known for approved agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the invention being used. In cases where no amount is expressly noted, an effective amount should be assumed.
  • the invention provides a method of preventing, treating, managing, or ameliorating a proliferative disorder or one or more symptoms thereof, said methods comprising administering to a subject in need thereof a dose of at least 150 ⁇ g/kg, preferably at least 250 ⁇ g/kg, at least 500 ⁇ g/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at least 200 mg/kg or more of one or more compounds of the invention once every day, preferably, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 10 days, once every two weeks, once every three weeks, or once a month.
  • dosages of a chemotherapeutic agents other than compounds of the invention which have been or are currently being used to prevent, treat, manage, or ameliorate a proliferative disorder, or one or more symptoms thereof, can be used in the combination therapies of the invention.
  • the recommended dosages of agents currently used for the prevention, treatment, management, or amelioration of a proliferative disorder, or one or more symptoms thereof can obtained from any reference in the art including, but not limited to, Hardman et 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.
  • 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).
  • 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.
  • 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.
  • the terms “treat”, “treatment” and “treating” refer to the reduction or stabilization of tumor size or cancerous cell count.
  • a compound of the invention is administered as a preventative measure to a patient, preferably a human, having a genetic predisposition to any of the disorders described herein.
  • a therapeutic agent refers to any agent(s) which can be used in the treatment, management, or amelioration of a proliferative disorder or one or more symptoms thereof.
  • the term “therapeutic agent” refers to a compound of the invention.
  • the term “therapeutic agent” refers does not refer to a compound of the invention.
  • a therapeutic agent is an agent which is known to be useful for, or has been or is currently being used for the treatment, management, prevention, or amelioration a proliferative disorder or one or more symptoms thereof.
  • the term "synergistic” refers to a combination of a compound of the invention and another therapy (e.g., a prophylactic or therapeutic agent), which is more effective than the additive effects of the therapies.
  • a synergistic effect of a combination of therapies permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a subject with a proliferative disorder.
  • a therapy e.g., a prophylactic or therapeutic agent
  • a synergistic effect can result in improved efficacy of agents in the prevention, management or treatment of a proliferative disorder.
  • a synergistic effect of a combination of therapies may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone.
  • side effects encompasses unwanted and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Side effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a therapy (e.g., prophylactic or therapeutic agent) might be harmful or uncomfortable or risky. Side effects include, but are not limited to fever, chills, lethargy, gastrointestinal toxicities (including gastric and intestinal ulcerations and erosions), nausea, vomiting, neurotoxicities, nephrotoxicities, renal toxicities
  • 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.
  • 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
  • a prophylactic or therapeutic agent such as a compound of the invention
  • can be administered prior to e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before
  • concomitantly with, or subsequent to e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after
  • the administration of a second therapy e.g., a second therapy
  • a prophylactic or therapeutic agent such as an anti-cancer agent
  • a proliferative disorder such as cancer
  • 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 “protocol” includes dosing schedules and dosing regimens.
  • the protocols herein are methods of use and include prophylactic and therapeutic protocols.
  • a subject is administered one or more therapies (e.g., one or more prophylactic or therapeutic agents) to "manage” a disease so as to prevent the progression or worsening of the disease.
  • therapies e.g., one or more prophylactic or therapeutic agents
  • composition that "substantially" comprises a compound means that the composition contains more than about 80% by weight, more preferably more than about 90% by weight, even more preferably more than about
  • a reaction that is "substantially complete” means that the reaction contains more than about 80% by weight of the desired product, more preferably more than about 90% by weight of the desired product, even more preferably more than about 95% by weight of the desired product, and most preferably more than about 97% by weight of the desired product.
  • a racemic mixture means about 50% of one enantiomer and about 50% of is corresponding enantiomer relative to a chiral center in the molecule.
  • the invention encompasses all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures of the compounds of the invention.
  • Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or diastereomers by well known methods, such as chiral- phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
  • the compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
  • a patient e.g., to a non-human animal for veterinary use or for improvement of livestock, or to a human for clinical use
  • the compounds of the invention are administered in isolated form or as the isolated form in a pharmaceutical composition.
  • isolated means that the compounds of the invention are separated from other components of either (a) a natural source, such as a plant or cell, preferably bacterial culture, or (b) a synthetic organic chemical reaction mixture.
  • the compounds of the invention are purified via conventional techniques.
  • purified means that when isolated, the isolate contains at least 95%, preferably at least 98%, of a compound of the invention by weight of the isolate either as a mixture of stereoisomers or as a diastereomeric or enantiomeric pure isolate.
  • composition that is "substantially free" of a compound means that the composition contains less than about 20% by weight, more preferably less than about 10% by weight, even more preferably less than about 5% by weight, and most preferably less than about 3% by weight of the compound.
  • the present invention emcompasses compounds having Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), and those set forth in Table 1 and tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof.
  • the invention provides compounds of formula (I) as set forth below:
  • 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 (I) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
  • R 5 is an optionally substituted naphthyl.
  • R 5 is represented by the following formula:
  • R9 for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRioRn, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NRi 0 R 11 , -NR 8 C(O)R 7 , -SR 7 , -S(
  • R 5 is represented by one of the following formulas:
  • R9 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.
  • R5 is selected from the group consisting of:
  • 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 + (Ri 7 ), provided that at least three X 7 groups are independently selected from CH and CR 9 ;
  • X 8 for each occurrence, is independently CH 2 , CHR 9 , CR 9 R 9 , O, S, S(O)p, NR 7 , or NR n ;
  • X 9 for each occurrence, is independently N or CH;
  • X 10 for each occurrence, is independently CH, CR 9 , N, N(O), N + (R n ), provided that at least one X] 0 is selected from CH and CR9;
  • Ri 7 for each occurrence, is independently -H, an alkyl, an aralkyl, -C(O)R 7 , -C(O)OR 7 , or -C(0)NRioRii; wherein R 7 , R 9 , Rio, Rn and p are defined as above.
  • R 5 is an optionally substituted indolyl, an optionally substituted benzoimidazolyl, an optionally substituted indazolyl, an optionally substituted 3H-indazolyl, an optionally substituted indolizinyl, an optionally substituted quinolinyl, an optionally substituted 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- c]pyridinyl, an optionally substituted thiazolo[5,4-c]pyridinyl, an optionally substituted thiazolo[4,5-b]pyridinyl,
  • R 5 is an optionally substituted indolyl.
  • R5 is an indolyl represented by the following structural formula:
  • R33 is a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;
  • R34 is ⁇ , a lower alkyl, or a lower alkylcarbonyl
  • Ring B and Ring C are optionally substituted with one or more substituents.
  • R5 is selected from the group consisting of: wherein:
  • Xn for each occurrence, is independently CH, CR 9 , N, N(O), or N + (Rn), provided that at least one Xi 1 is N, N(O), or N + (Rn) and at least two Xn groups are independently selected from CH and CR 9 ;
  • Xi 2 for each occurrence, is independently CH, CR 9 , N, N(O), N + (Ri 7 ), provided that at least one X 12 group is independently selected from CH and CR 9 ;
  • Xi 3 for each occurrence, is independently O, S, S(O)p, NR 7 , Or NRi 7 ; wherein R 7 , R 9 and Rn are defined as above.
  • the compound 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 the following structural formula:
  • R 6 for each occurrence, is independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NR 10 Rn, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -C(S)R 7 , -C(O)SR 7 , -C(S)SR 7 , -C(S)OR 7 , -C(S)NR 10 Rn, -C(NR 8 )OR 7
  • R 25 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 heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NRi 0 R n , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -C(S)R 7 , -C(O)SR 7 , -C(S)SR 7 , -C(S)OR 7 , -C(S)NR 10
  • k is 1, 2, 3, or 4; and r is zero or an integer from 1 to 3, wherein R 7 , R 8 , Rio, Rn, and p are defined as above.
  • Ri, R 3 and R 25 are each independently -OH, -SH, -NHR 7 , -OC(O)NRi 0 R 11, -SC(O)NRi 0 Ri i, -OC(O)R 7 , -SC(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7 , -OS(O) P R 7 , -S(O) P OR 7 , -SS(O)pR 7 , -OS(O) 13 OR 7 , -SS(O) P OR 7 , -OC(S)R 7, -SC(S)R 7, -OC(S)OR 7, -SC(S)OR 7, -OC(S)NRioRii , -SC(S)NRi 0 R 11, -OC(NR 8 )R 7, -SC(NR 8 )R 7, -OC(NR 8 )OR 7, -SC(NR 8 )OR 7, -SC(NR 8 )OR 7,
  • Ri and R 3 are each, independently, -OH, -SH, or -NHR 7 .
  • R 6 can be 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 , -NRi 0 Ri 1 , -OC(O)NRi 0 Rii, -SC(O)NR 10 R 11 , -NR 7 C(O)NRi 0 Rn, -OC(O)R 7 , -SC(O)R 7 , -NR 7 C(O)R 7 , -OC(O)OR 7 , -SC(O)OR 7
  • Ri is -SH or -OH; R 3 and R 25 are -OH; R 6 is a lower alkyl, C3-C6 cycloalkyl, lower alkoxy, a lower alkyl sulfanyl, or -NRi 0 Rn; and R9, 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.
  • Ri and R 3 are each, independently, -OH, -SH, or -NHR 7 .
  • R 6 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR 7 , -SR 7 , -NR 1O Rn,
  • R 1 is -SH or -OH; R 3 and R 25 are -OH; R 12 is a lower alkyl, lower alkoxy, a lower alkyl sulfanyl, or -NR 10 R 11 ; 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.
  • the compound is represented by one of the following structural formulas:
  • X 3 and X 4 are each, independently, N, N(O), N + (R 17 ), CH or CR 6 ;
  • the compound is selected from the group consisting of:
  • the invention provides compounds of formula (II) as set forth below:
  • 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 ⁇ , -O-R 20 , -C(O)R 7 , -C(O)OR 20 , -OC(O)R 7 , -C(O)NRi 0 Ri I , -NR 8 C(O)R 7 , -SR 7 , -S(O)
  • 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, 1 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.
  • the compounds represented by formula (II) do not include 3-(2,4-dihydroxy-phenyl)-4-(7-naphthalen-l-yl)-5-mercapto-triazole, 3-(2,4- dihydroxyphenyl)-4-(2,5-dimethoxyphenyl)-5-mercapto-triazole, 3-(l-phenyl-5- amino-pyrazol-4-yl)-4-(2,4-dichloropheny)-5 -mercapto-triazole, and 3 -(2-hydroxy- phenyl)4-(2,4-dimethylphenyl)-5-mercapto-triazole.
  • , R 2 , R 3 , R ⁇ , and n are defined as above.
  • Ri, R 2 , R 3 , R 6 , R 2 5 and r are defined as above.
  • Ri and R 3 are each, independently, -OH, -SH, or -NHR 7 .
  • Ri, R 2 , R 3 , R 6 and R 25 are defined as above.
  • Ri is -SH or -OH;
  • R 3 and R 25 are -OH;
  • Ri 2 is a lower alkyl, lower alkoxy, a lower alkyl sulfanyl, or -NRi 0 Ri ⁇ and Rg, 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.
  • the compound is represented by one of the following structural formulas:
  • R 1 , R 2 , R3, R 6 , X 3 , X 4 , X5 and n are defined as above.
  • the compound is selected from the group consisting of:
  • the invention provides compounds of formula (III) as set forth below:
  • Ri 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, -NRi 0 Ri 1, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 R 11 , -NR 8 C(O)R 7 , -SR 7 , -S(O)pR 7 , -OS(O) P R 7 ,
  • Compounds of formula (III) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (III) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
  • Ri 8 is not cyclohexyl.
  • Ri 8 is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl.
  • Ri 8 is a substituted alkyl.
  • Ri, R 3 , R 6 , Ri 8 , and n are defined as above.
  • Ri, R 3 , R 6 , Ri 8 , R25 and r are defined as above.
  • Ri and R 3 are each, independently, -OH, -SH, or -NHR 7 .
  • Ri is -SH or -OH
  • R 3 and R 25 are -OH
  • Ri 2 is a lower alkyl, lower alkoxy, a lower alkyl sulfanyl, or -NRi 0 Ri i-
  • Ri, R 3 , R 6 , Ri 8 , X3, X 4 , X5, and n are defined as above.
  • R 1 , R 3 , Rj 8 , and R 25 are defined as above.
  • the invention provides compounds of formula (IV) or (V) as set forth below:
  • R 1 and R 3 are as defined above; and X 14 is O, 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 is independently an -H or is 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, a haloalkyl, -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 Rn, -NR 8 C(O)R 7 , -S(O) 15 R 7 , -S(O) P OR 7 , or -S(0)pNRioRn; and
  • R 23 and R 24 are independently -H or are 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, -NRi 0 Rn, -OR 7 , -C(O)R 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NRi 0 Ri 1 , -NR 8 C(O)R 7 , -SR 7 , -S(O)pR 7
  • R 2 i is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl or an optionally substituted heteroaryl.
  • Rj is -OH, -SH, or -NHR 7 .
  • R 22 is -H, an alkyl, an aralkyl, -C(O)R 7 , -C(O)OR 7 , or -C(O)NRi 0 Rn.
  • X H is O.
  • 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.
  • the invention provides compounds represented by formula (VI):
  • Y 42j for each occurrence, is independently N, C or CR 46 ;
  • Z is OH, SH, Or NHR 7 ;
  • R 41 is -H, -OH, -SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, -NRi 0 R 11 , -OR 7 , -C(O)R 7 , -C(O)OR 7 , -C(S)R 7 , -C(O)SR 7 , -C(S)SR 7 , -C(S)OR 7 ,
  • R 42 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, -C(O)R 7 , -(CH 2 ) m C(O)OR 7 , -C(O)OR 7 , -OC(O)R 7 , -C(O)NR 10 Rn, -S(O) P R 7 , -S(O) P OR 7 , or -S(O) P NR 10 R n ; R 43 and R 44 are, independently, -H, -
  • R 45 is -H, -OH, -SH, -NR 7 H, -OR 26 , -SR 26 , -NHR 26 , -O(CH 2 ) m OH, -O(CH 2 ) m SH, -O(CH 2 ) m NR 7 H, -S(CH 2 ) m OH, -S(CH 2 ) m SH, -S(CH 2 ) m NR 7 H, -OC(O)NR 10 Ri 1 , -SC(O)NRi 0 Rn, -NR 7 C(O)NRi 0 Ri 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
  • R 7 , R 8 , Rio, Rn, R 2 6, P, and m are defined as above.
  • X 41 is NR 42 and X 42 is CR 44 .
  • X 4I is NR 42 and X 42 is N.
  • R 41 is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy. In another embodiment, in formula (VI), R 41 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
  • X 41 is NR 42 , and R 42 is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, -C(O)N(R 27 ) 2 , and -C(O)OH, wherein R 27 is -H or a lower alkyl.
  • X 41 is NR 42
  • R 42 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n- butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, -C(O)OH, -(CH 2 ) m C(0)0H, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , and -C(O)N(CH 3 ) 2 .
  • Y 40 is CR 43 .
  • Y 40 is CR 43 and R 43 is H or a lower alkyl.
  • R 43 and R 44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
  • X 42 is CR 44 ;
  • Y is CR 43 ; and
  • R 44 together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring.
  • R 43 and R 44 together with the carbon atoms to which they are attached form a Cs-C 8 cycloalkenyl or a C 5 -C 8 aryl.
  • R 45 is selected from the group consisting of -H, -OH, -SH, -NH 2 , a lower alkoxy, a lower alkyl amino, and a lower dialkyl amino.
  • R 45 is selected from the group consisting of -H, -OH, methoxy and ethoxy.
  • X 4I is O.
  • the compound is selected from the group consisting of:
  • Z is -OH.
  • the compound is selected from the group consisting of:
  • Z is -SH.
  • the compound is selected from the group consisting of:
  • Compounds of formula (VI) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (VI) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
  • the invention provides compounds represented by formula (VII):
  • X 42 , R 41 , R 42 , R 4 3, and R 45 are defined as above.
  • Zi is -OH.
  • Zi is -SH.
  • R 41 is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
  • R 41 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
  • R 42 is selected from the group consisting of lower alkyl, lower cycloalkyl, -C(O)N(R 27 ) 2 , or -C(O)OH, wherein R 27 is -H or a lower alkyl.
  • R 42 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, -C(O)OH, -(CH 2 ) m C(O)OH, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , and -C(O)N(CH 3 ) 2 .
  • R 43 is H or a lower alkyl.
  • X 42 is CR 44
  • R 43 and R 44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
  • X 42 is CR 44 , and R 43 and R 44 , taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring.
  • R 43 and R 44 taken together with the carbon atoms to which they are attached, form a Cs-C 8 cycloalkenyl or a C 5 -C 8 aryl.
  • R 45 is selected from the group consisting of -H, -OH, -SH, -NH 2 , a lower alkoxy, a lower alkyl amino, and a lower dialkyl amino.
  • R 45 is selected from the group consisting of -H, -OH, methoxy, and ethoxy.
  • X 43 is CR 44 .
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of
  • the invention provides compounds represented by formula (VIII):
  • 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 OCH 3 , -CH 2 C(O)OH, and - C(O)N(CH 3 ) 2 ;
  • R53 and R 54 are each, independently, -H, methyl, ethyl, or isopropyl; or R 53 and R 54 taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring;
  • R 55 is selected from the group consisting of -H, -OH, -OCH 3 , and - OCH 2 CH 3 ; and R56 is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl.
  • Zi is -OH.
  • Zi is -SH.
  • R 53 is H or a lower alkyl.
  • X 45 is CR 54 .
  • R 54 is H or a lower alkyl.
  • X 45 is N.
  • 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 (VIII) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (VIII) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
  • the invention provides compounds represented by formula
  • X 44 for each occurrence, is independently, O, NR 42 or C(R 4 O) 2 ; Y 43 is NR 42 or C(R, 6 ) 2 ;
  • Y 4 i, Y 42 , Z, R 41 , R 42 , and R 46 are defined as above.
  • R 41 is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy. In another embodiment, in formula (IX), R 41 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
  • R 42 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, terf-butyl, n-pentyl, n-hexyl, -C(O)OH, -(CH 2 ) m C(O)OH, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , and -C(O)N(CH 3 ) 2 .
  • Y 4 i is CR 4 5.
  • R 4 S is H, a lower alkoxy, or -OH.
  • Y 42 is CH.
  • Y 43 is CH 2 .
  • Y 43 is NR 42 , wherein R 42 is H or a lower alkyl.
  • one OfX 44 is NR 42 and the other is CH 2 or C(Rs) 2 .
  • one of X 44 is NR 42 and the other is CH 2
  • Z is -OH.
  • Z is -SH.
  • Compounds of formula (IX) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (IX) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
  • the invention provides compounds represented by formula
  • R 4 is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
  • R 41 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
  • X 41 is NR 42 .
  • R 42 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, ter/-butyl, n-pentyl, n-hexyl, -C(O)OH, -(CH 2 ) m C(O)OH, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , and -C(O)N(CH 3 ) 2 . More preferably, R 42 is H or a lower alkyl.
  • X 4I is O. In another embodiment, in formula (X), X 4I is S.
  • Y 4 ] is CR 4 5.
  • R 4 5 is H, a lower alkoxy, or -OH.
  • Y 42 is CH.
  • R 46 is H or a lower alkyl.
  • the compound is 3-(2,4-dihydroxy-5-isopropyl-phenyl)- 4-(2-methyl-indazol-6-yl)-5-mercapto-[l,2,4]triazole.
  • Compounds of formula (X) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (X) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
  • Exemplary compounds of the invention are depicted in Table 1 below, including tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof .
  • Preferred 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 1 :
  • X 14 O, S, orNR 7
  • prodrugs i.e. compounds which can be metabolized or hydro lyzed in vivo to a compound of the present invention are encompassed by the present description.
  • prodrugs i.e. compounds which can be metabolized or hydro lyzed in vivo to a compound of the present invention are encompassed by the present description.
  • the following embodiments of a compound of the present invention can be produced in vivo in the following reaction:
  • R 2 oo is R 2 , R5 or Rj 8 .
  • hydrolyzable protecting groups can be employed with the compounds of the present invention to obtain prodrugs encompassed by the present description.
  • Intermediate (C) can be cyclized to form a triazole core (D) by heating it in an aqueous solution which includes about 2 molar equivalents of NaOH (see Scheme I below).
  • Starting materials useful for preparing compounds of the invention and intermediates therefore, are commercially available or can be prepared from commercially available materials using known synthetic methods and reagents.
  • a hydrazide can be prepared by reacting an ester (such as 2,4- dihydroxybenzoic acid methyl ester) or acid chloride with hydrazine.
  • Isocyanates and isothiocyanates (Xi 4 is O or S, respectively) can be formed in a number of ways from compounds that have a primary amine group.
  • a primary amine can be reacted with phosgene or thiophosgene to form an isocyanate or an isothiocyanate, respectively.
  • a cyanate or thiocyanate ion can be reacted with an alkyl halide to form an alkyl isocyanate or an alkyl isothiocyanate.
  • a isothiocyanate can be prepared by reacting a diazonium salt with a thiocyanate ion.
  • Carbodiimides (Xi 4 is NR 7 ) can be prepared by dehydration of ureas using a dehydration agent such as tosyl chloride in pyridine, POCI 3 , PCI5, P 2 ⁇ 5 -pyridine, and Ph 3 PBr 2 -Et 3 N.
  • a dehydration agent such as tosyl chloride in pyridine, POCI 3 , PCI5, P 2 ⁇ 5 -pyridine, and Ph 3 PBr 2 -Et 3 N.
  • Other methods of preparing isocyanates, thioisocyanates, and carbodiimides can be found in March, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, the entire teachings of which are incorporated by reference.
  • Reactive functional groups can be protected during one or more reaction step, then deprotected to restore the original functionality.
  • suitable protecting groups for hydroxyl groups include benzyl, methoxymethyl, allyl, trimethylsilyl, tert-butyldimethylsilyl, acetate, and the like.
  • suitable amine protecting groups include benzyloxycarbonyl, tert-butoxycarbonyl, tert-butyl, benzyl and fluorenylmethyloxy-carbonyl (Fmoc).
  • suitable thiol protecting groups include benzyl, tert-butyl, acetyl, 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.
  • Compound (iii) is then combined with a hydrazide compound (iv) in a solvent and heated to about 5O 0 C to about 100 0 C for about 0.5 to 5 hrs to form compound (v).
  • compound (iii) and compound (iv) can be present in about equal molar ratio or a slight excess of compound (iii), such as about 1.01 to about 1.1 molar eq. of compound (iii) compare to compound (iv).
  • Compound (v) can then be cyclized to form a triazole compound of the invention (vi) by suspending it in aqueous solution containing about 2 molar eq.
  • the NaOH solution containing compound (v) is degassed before heating by bubbling an inert gas, such as nitrogen or argon, through it.
  • ring A of the compounds of the invention is a 2,4- dihydroxyphenyl group.
  • 4-methyl-piperizine-l -carbamoyl group is used to protect the 4-hydroxy group (see Scheme III).
  • a compound of the invention such as compound (E) is treated with about one molar equivalents of 4-methyl-piperizine-l -carbonyl chloride (F) in the presence of a base to form compound (G) in which the 4-hydroxy group is protected.
  • the metcapto group can be protected first by reacting compound (E) with about one molar equivalent of acyl chloride in the presence of a base to form intermediate (H).
  • Intermediate (H) can them be reacted with about one molar equivalent of 4-m ethyl- piperizine-1-carbonyl chloride (F) in the presence of a base, then the acetyl group can be removed by treatment with a mild acid to form compound (G).
  • Another prodrug of compounds of the invention can be formed by addition of a phosphate group to the 4-hydroxy group (Scheme IV).
  • a compound of the invention such as compound (E)
  • compound (J) is treated with about one molar equivalent of diisopropyl phosphoramidous acid di-t-butyl ester in the presence of tetrazole to yield compound (J).
  • the phosphorous group is then oxidized with m-CPBA to form a phosphoric acid di-t-butyl ester group of compound K.
  • the t-butyl groups are then hydrolyzed with trifluoroacetic acid (TFA) to yield a phosphoric acid group or compound L.
  • TFA trifluoroacetic acid
  • 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.
  • 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.
  • the invention provides a method of inhibiting the activity of Hsp90 in a cell, comprising administering to the cell an effective amount of a compound represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or any embodiment thereof, or a compound shown in Table 1.
  • the compound is administered to a cell in a subject, preferably a mammal, and more preferably a human.
  • the invention provides a method of treating or preventing a proliferation disorder in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or any embodiment thereof, or a compound shown in Table 1.
  • the compound is administered to a human to treat or prevent a proliferative disorder.
  • the proliferation disorder is cancer.
  • the compound is administered with one or more additional therapeutic agents.
  • the additional therapeutic agent is an anticancer agent.
  • the invention provides a method for treating cancer in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),or any embodiment thereof, or a compound shown in Table 1.
  • the compound is administered to a human to treat or prevent cancer.
  • the compound is administered with one or more additional therapeutic agents.
  • the one or more additional therapeutic agents are anticancer agents.
  • the invention provides a method for treating a c-kit associated cancer in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or any embodiment thereof, or a compound shown in Table 1.
  • the compound is administered to a human to treat or prevent the c-kit associated cancer.
  • the compound is administered with one or more additional therapeutic agents.
  • the one or more additional therapeutic agents are anticancer agents.
  • 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, seesperling, et al., 1997, Haemat., 82:617-621; Escribano, et al., 1998, Leuk. Lymph., 30:459-466).
  • c-kit is expressed in the majority of AML cells, its expression does not appear to be prognostic of disease progression (Sperling, et al, 1997, Haemat. £2:617-621). However, SCF protected AML cells from apoptosis induced by chemotherapeutic agents (Hassan, et al., 1996, Acta. Hem., 95:251-262). 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.
  • CML chronic myelogenous leukemia
  • 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, 279:511-580).
  • c-kit expressed in GISTs from several different patients was observed to have mutations in the intracellular juxtamembrane domain leading to constitutive activation (Hirota, et al., 1998, Science 279:577-580). Therefore, degradation of c-kit caused by the inhibition of Hsp90 by the compounds of the invention will be an efficacious means for the treatment of these cancers.
  • Male germ cell tumors have been histologically categorized into seminomas, which retain germ cell characteristics, and nonseminomas which can display characteristics of embryonal differentiation. Both seminomas and nonseminomas are thought to initiate from a preinvasive stage designated carcinoma in situ (CIS) (Murty, 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
  • c-kit is expressed by the majority of carcinomas in situ and seminomas, but c-kit is expressed in only a minority of nonseminomas (Strohmeyer, et al, 1991, Cane. Res., 57:181 1-1816; Rajpert-de Meyts, et al, 1994, Int. J. Androl, 77:85-92; Izquierdo, et al, 1995, J. Pathol, 777:253-258; Strohmeyer, et al, 1995, J. Urol, 755:511-515; Bokenmeyer, et al, 1996, J. Came. Res., Clin.
  • 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., 50: 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, et al, 1992, Cane. Res., 52:3498-3502; Tada, et al, 1994, J. Neuro., 50:1063-1073; Stanulla, et al, 1995, Act. Neuropath., 59:158-165).
  • the invention also provides methods of preventing, treating, managing, or ameliorating a proliferative disorder, such as cancer, or one or more symptoms thereof, said methods comprising administering to a subject in need thereof one or more compounds of the invention and one or more other therapies ⁇ e.g., one or more prophylactic or therapeutic agents that are currently being used, have been used, are known to be useful or in development for use in the prevention, treatment or amelioration of a proliferative disorder, such as cancer, or one or more symptoms associated with said proliferative disorder).
  • the prophylactic or therapeutic agents of the combination therapies of the invention can be administered sequentially or concurrently.
  • the combination therapies of the invention comprise one or more compounds and at least one other therapy (e.g., another prophylactic or therapeutic agent) which has the same mechanism of action as said compounds.
  • the combination therapies of the invention comprise one or more compounds of the invention and at least one other therapy (e.g., another prophylactic or therapeutic agent) which has a different mechanism of action than said compounds.
  • the combination therapies of the present invention improve the prophylactic or therapeutic effect of one or more compounds of the invention by functioning together with the compounds to have an additive or synergistic effect.
  • the combination therapies of the present invention reduce the side effects associated with the therapies (e.g., prophylactic or therapeutic agents).
  • the combination therapies of the present invention reduce the effective dosage of one or more of the therapies.
  • the prophylactic or therapeutic agents of the combination therapies can be administered to a subject, preferably a human subject, in the same pharmaceutical composition.
  • the prophylactic or therapeutic agents of the combination therapies can be administered concurrently to a subject in separate pharmaceutical compositions.
  • the prophylactic or therapeutic agents may be administered to a subject by the same or different routes of administration.
  • a pharmaceutical composition comprising one or more compounds of the invention is administered to a subject, preferably a human, to prevent, treat, manage, or ameliorate a proliferative disorder, such as cancer, or one or more symptom thereof.
  • a proliferative disorder such as cancer
  • pharmaceutical compositions of the invention may also comprise one or more other agents (e.g., prophylactic or therapeutic agents which are currently being used, have been used, or are known to be useful in the prevention, treatment or amelioration of a proliferative disorder or a symptom thereof).
  • the invention provides methods for preventing, managing, treating or ameliorating a proliferative disorder, such as cancer, or one or more symptoms thereof in a subject refractory (either completely or partially) to existing agent therapies for such a proliferative disorder, said methods comprising administering to said subject a dose of an effective amount of one or more compounds of the invention and a dose of an effective amount of one or more therapies (e.g., one or more prophylactic or therapeutic agents useful for the prevention, treatment, management, or amelioration of a proliferative disorder or a symptom thereof).
  • a proliferative disorder such as cancer
  • a subject refractory either completely or partially
  • therapies e.g., one or more prophylactic or therapeutic agents useful for the prevention, treatment, management, or amelioration of a proliferative disorder or a symptom thereof.
  • the invention also provides methods for preventing, treating, managing, or ameliorating a proliferative disorder or a symptom thereof by administering one or more compounds of the invention in combination with any other therapy(ies) to patients who have proven refractory to other therapies but are no longer on these therapies.
  • the compounds of the invention and/or other therapies can be administered to a subject by any route known to one of skill in the art. Examples of routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), intranasal, transdermal (topical), transmucosal, and rectal administration.
  • the compounds of the invention can be particularly effective at treating subjects whose cancer has become multi-drug resistant.
  • 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 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.
  • Anticancer agents that can be co-administered with the compounds of the invention include TaxolTM, 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.
  • TaxolTM also referred to as "paclitaxel”
  • TaxotereTM 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 stabilization or inhibition of microtubules.
  • anti-cancer agents that can be employed in combination with the compounds of the invention include Avastin, Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; 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; carbop
  • anti-cancer drugs that can be employed in combination with the compounds of the invention include: 20-epi-l,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- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara
  • 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.
  • 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 sulfonates ⁇ e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), or triazenes (decarbazine, etc.).
  • 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).
  • folic acid analog e.g., methotrexate
  • 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).
  • vinca alkaloids e.g., vinblastin, vincristine
  • epipodophyllotoxins e.g., etoposide
  • antibiotics e.g., daunorubicin, doxorubicin, bleomycin
  • enzymes e.g., L-asparaginase
  • biological response modifiers e.g., interferon alpha
  • alkylating agents examples 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.).
  • nitrogen mustards e.g., mechloroethamine, cyclophosphamide, chlorambucil, melphalan, etc.
  • ethylenimine and methylmelamines e.g., hexamethlymelamine, thiotepa
  • alkyl sulfonates e.g.
  • 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).
  • folic acid analog e.g., methotrexate
  • 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).
  • 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-asparagina
  • 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).
  • adrenocorticosteroids e.g., prednisone
  • progestins e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate
  • 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
  • anti-cancer agents which act by arresting cells in the G2-M phases due to stabilization or inhibition of microtubules and which can be used in combination with the compounds of the invention include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R- 55104), Dolastatin 10 (also known as DLS-IO 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), Cemadot
  • a composition comprises one or more compounds of the invention, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or prodrug thereof.
  • 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.
  • 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.
  • 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.
  • a composition of the invention is a pharmaceutical composition or a single unit dosage form.
  • Pharmaceutical compositions and dosage forms of the invention comprise one or more active ingredients in relative amounts and formulated in such a way that a given pharmaceutical composition or dosage form can be used to treat or prevent proliferative disorders, such as cancer.
  • Preferred pharmaceutical compositions and dosage forms comprise a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1, 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.
  • 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.
  • 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.
  • 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.
  • mucosal e.g., nasal, sublingual, vaginal, buccal, or rectal
  • parenteral e.g., subcutaneous, intravenous, bolus injection, intramuscular, or intraarterial
  • transdermal administration to a patient.
  • 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.
  • suspensions e.g., aqueous
  • composition, shape, and type of dosage forms of the invention will typically vary depending on their use.
  • a dosage form suitable for mucosal administration may contain a smaller amount of active ingredient(s) than an oral dosage form used to treat the same indication.
  • This aspect of the invention will be readily apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences (1990) 18th ed., Mack Publishing, Easton PA.
  • Typical pharmaceutical compositions and dosage forms comprise one or more excipients.
  • Suitable excipients are well known to those skilled in the art of pharmacy, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art including, but not limited to, the way in which the dosage form will be administered to a patient.
  • 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.
  • 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
  • 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)ZNF (XVI).
  • USP U.S. Pharmocopia
  • XXI U.S. Pharmocopia
  • lactose-free compositions comprise active ingredients, a binderZfiller, 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.
  • Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.
  • Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are preferably anhydrous if substantial contact with moisture andZor humidity during manufacturing, packaging, andZor storage is expected.
  • An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained.
  • 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.
  • compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose.
  • compounds which are referred to herein as "stabilizer” include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
  • 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).
  • 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.
  • 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.
  • excipients suitable for use in solid oral dosage forms include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.
  • Such dosage forms can be prepared by any of the methods of pharmacy.
  • 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.
  • 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.
  • 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- 103 J and Starch 1500 LM.
  • fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the binder or filler in pharmaceutical compositions of the invention is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
  • Disintegrants are used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms of the invention.
  • the amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, preferably from about 1 to about 5 weight percent of disintegrant.
  • Disintegrants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
  • Lubricants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
  • Additional lubricants include, for example, a syloid silica gel
  • AEROSIL 200 manufactured by W.R. Grace Co. of Baltimore, MD
  • a coagulated aerosol of synthetic silica marketed by Degussa Co. of Piano, TX
  • CAB-O-SIL a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA
  • lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
  • Active ingredients of the invention can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference.
  • Such dosage forms can be used to provide slow or control led-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.
  • controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.
  • 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.
  • 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.
  • the drug In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body.
  • Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.
  • a particular extended release formulation of this invention comprises a therapeutically or prophylactically effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, or prodrug thereof, in spheroids which further comprise microcrystalline cellulose and, optionally, hydroxypropylmethyl- cellulose coated with a mixture of ethyl cellulose and hydroxypropylmethylcellulose.
  • Such extended release formulations can be prepared according to U.S. Patent No. 6,274,171, the entirely of which is incorporated herein by reference.
  • a specific controlled-release formulation of this invention comprises from about 6% to about 40% a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, or prodrug thereof, by weight, about 50% to about 94% microcrystalline cellulose, NF, by weight, and optionally from about 0.25% to about 1% by weight of hydroxypropyl-methylcellulose, USP, wherein the spheroids are coated with a film coating composition comprised of ethyl cellulose and hydroxypropylmethylcellulose.
  • 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
  • non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • Transdermal, topical, and mucosal dosage forms of the invention include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences (1980 & 1990) 16th and 18th eds., Mack Publishing, Easton PA and Introduction to Pharmaceutical Dosage Forms (1985) 4th ed., Lea & Febiger, Philadelphia. Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels. Further, transdermal dosage forms include "reservoir type" or "matrix type” patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients.
  • Suitable excipients e.g., carriers and diluents
  • 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.
  • 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.
  • 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.
  • the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery.
  • Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery.
  • 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.
  • the amount of the compound or composition of the invention which will be effective in the prevention, treatment, management, or amelioration of a proliferative disorders, such as cancer, or one or more symptoms thereof, will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered.
  • the frequency and dosage will also vary according to factors specific for each patient depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the patient.
  • Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • Suitable regiments can be selected by one skilled in the art by considering such factors and by following, for example, dosages reported in the literature and recommended in the Physician 's Desk Reference (57th ed., 2003).
  • Exemplary doses of a small molecule include milligram or microgram amounts of the small molecule per kilogram of subject or sample weight (e.g., about 1 microgram per kilogram to about 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram).
  • the recommended daily dose range of a compound of the invention for the conditions described herein lie within the range of from about 0.01 mg to about 1000 mg per day, given as a single once-a-day dose preferably as divided doses throughout a day.
  • the daily dose is administered twice daily in equally divided doses.
  • a daily dose range should be from about 5 mg to about 500 mg per day, more specifically, between about 10 mg and about 200 mg per day.
  • the therapy should be initiated at a lower dose, perhaps about 1 mg to about 25 mg, and increased if necessary up to about 200 mg to about 1000 mg per day as either a single dose or divided doses, depending on the patient's global response.
  • dosage amounts and dose frequency schedules are also encompassed by the above described dosage amounts and dose frequency schedules.
  • 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.
  • 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 ⁇ g/kg, preferably 250 ⁇ g/kg, 500 ⁇ g/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, or 200 mg/kg or more of a patient's body weight.
  • the dosage of the composition of the invention or a compound of the invention administered to prevent, treat, manage, or ameliorate a proliferative disorders, such as cancer, or one or more symptoms thereof in a patient is a unit dose of 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 12 mg, 0.1 mg to 10 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 to 8 mg, 0.25 mg to 7m g, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.
  • 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.
  • dosages lower than those which have been or are currently being used to prevent, treat, manage, or ameliorate a proliferative disorders, or one or more symptoms thereof, are used in the combination therapies of the invention.
  • the recommended dosages of agents currently used for the prevention, treatment, management, or amelioration of a proliferative disorders, such as cancer, or one or more symptoms thereof can obtained from any reference in the art including, but not limited to, Hardman 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.
  • the therapies are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours part.
  • two or more therapies e.
  • 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.
  • a first therapy e.g., a first prophylactic or therapeutic agents
  • a second therapy e.g., a second prophylactic or therapeutic agents
  • a third therapy e.g., a third prophylactic or therapeutic agents
  • administration of the same compound of the invention may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
  • administration of the same prophylactic or therapeutic agent may be repeated and the administration may be separated by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.
  • 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 ⁇ g/kg, preferably at least 250 ⁇ g/kg, at least 500 ⁇ g/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at least 200 mg/kg or more of one or more compounds of the invention once every day, preferably, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 10 days, once every two weeks, once every three weeks, or once a month.
  • 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 vitro or in vivo assays).
  • 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 110 0 C for 2 hours. The solution was allowed to cool to room temperature then acidified with cone. 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%).
  • 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 11O 0 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 8O 0 C for 30 minutes. The reaction mixture was extracted with ethyl acetate and water to remove excess hydrazine. The organic layer was dried over MgSO 4 , and filtered to remove drying agent.
  • Lawesson's reagent (1.51 g, 3.74 mmol, 0.6 equiv.) in 50 mL toluene at 11O 0 C for three hours.
  • Toluene was removed on rotary evaporator and vacuum pump, and the residue was treated with
  • Carbodiimidazole (CDI)(3.02 g, 18.7 mmol, 3.00 equiv.) was added to the solution, and the solution was refluxed (65 0 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-(l,3-dimethyl-indol-5-yl)-5-hydroxy-[l,2,4] triazole as light brown solid (2.20 g, 5.42 mmol, 87%).
  • 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 HCl 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.
  • Example 7 Compound 5 ESMS calcd for C 19 H 15 N 3 O 2 S: 365.08; Found: 266.0 (M+H) + .
  • Example 27 Compound 27 ESMS calcd for Ci 8 Hi 9 N 3 O 2 S: 341.12; Found: 342.0 (M+H) + .
  • Example 28 Compound 28 ESMS calcd for C 6 H 15 N 3 O 2 S: 313.09; Found: 314.0 (M+H) + .
  • Example 31 Compound 31 ESMS calcd for Ci 4 H 10 FN 3 O 2 S: 303.05; Found: 304.0 (M+H) + .
  • Example 36 Compound 36 ESMS calcd for C20H15N3O2S: 361.1; Found: 362.0 (M+l) + .
  • Example 39 Compound 39 1 H NMR (DMSO-de) ⁇ 9.74 (s, IH), 9.63 (s, IH), 8.14 (m, IH), 7.52-7.48
  • Example 44 Compound 45 ESMS calcd for Ci 9 Hj 5 N 3 O 2 S: 349.09; Found: 350.0 (M+l) + .
  • Example 48 Compound 49 1 H NMR (DMSOd 6 ) ⁇ 9.49 (s, IH), 9.40 (s, IH), 7.94-7.99 (m, 2H), 7.38-
  • Example 52 Compound 53 1 H NMR (CDCl 3 ) ⁇ 12.0 (br s, IH), 9.87 (br s, IH), 9.83 (br s, IH), 7.97 (d, J
  • Example 55 Compound 61 1 H NMR (DMSO-U 6 ) ⁇ 9.66(s, IH), 9.60(s, IH), 7.29-7.27(m, IH), 7.12-7- 10(m, 2H), 7.03-7.00(m, IH), 6.19-6.17(m, 2H), 1.18(s, 18H);
  • Example 59 Compound 67 ESMS calcd for C 2 ]H 19 N 3 O 3 S: 393.11; Found: 394.0 (M+l) + .
  • Example 64 Compound 72 1 H NMR (DMSO-d 6 ) ⁇ 10.3 (br s, IH), 7.95-8.19 (m, 2H), 7.48-7.72 (m,
  • Example 69 Compound 77 ESMS calcd for C 2 iHi 9 N 3 O 3 S: 393.11; Found: 394.0 (M+H) + .
  • Example 84 Compound 93 ESMS calcd for C] 6 H 15 N 3 O 4 S: 345.08; Found: 346.0 (M+H) + .
  • Example 90 Compound 101 ESMS calcd for Ci 9 H n N 5 O 3 S: 395.11; Found: 396.0 (M+H) + .
  • Example 94 Compound 106 ESMS calcd for C 20 Hi 7 N 4 O 2 S: 377.1; Found: 378.0(M+H) + .
  • Example 98 Compound 122 1 H-NMR (CDCl 3 ) ⁇ 7.98(m, 2H), 7.60-7.55(m, 3H), 7.51-7.45(m, IH), 7.36-
  • Example 102 Compound 128 ESMS calcd for CnHi 3 N 3 O 2 S: 251.07; Found: 252.0 (M+H) + .
  • Example 106 Compound 177 1 H NMR (DMSO-de) ⁇ 9.34(s, IH), 9.22 (s, IH), 8.01-7.96 (m, 2H), 7.58-
  • Example 109 Compound 180 ESMS calcd for Ci 9 Hi 5 N 3 O 2 S: 349.09; Found: 350.0 (M+H) + .
  • Example 112 Compound 183
  • Example 118 Compound 192 ESMS calcd. for C 20 H 22 N 5 O 2 S: 395.1; Found: 396.0 (M + I) + .
  • Example 123 Compound 197 ESMS calcd. for C 22 H 24 N 4 O 2 S: 408.16; Found: 409.2 (M+l) + .
  • Example 124 Compound 198 ESMS calcd. for C 23 H 26 N 4 O 2 S: 422.18; Found: 423.3 (M+l) + .
  • Example 127 Compound 201 ESMS calcd. for C 23 H 24 N 4 O 3 S: 436.16; Found: 437.3 (M+l) + .
  • Example 132 Compound 207 ESMS calcd. for C 20 H 21 N 4 O 2 S: 380.1; Found: 381.1 (M + I) + .
  • Example 136 Compound 211 ESMS calcd. for C 2 iH 22 N 4 O 3 S: 410.14; Found: 411.1 (M+l) + .
  • Example 143 Compound 218 ESMS calcd. for C 21 H 23 N 4 O 2 S: 394.1; Found: 395.1 (M + I) + .
  • Example 146 Compound 221 ESMS calcd. for C 20 H 21 N 4 O 2 S: 379.1; Found: 381.1 (M + I) + .
  • Example 155 Compound 231 ESMS calcd. for Ci 9 Hi 9 N 5 O 2 S: 381.13; Found: 382.1 (M+l) + .
  • Example 160 Compound 239 ESMS clcd for Ci 9 H 2i N 4 O 2 S: 368.1; Found: 369.1 (M + H) + .
  • Hsp90 protein was obtained from Stressgen (Cat#SPP-770). Assay buffer: 100 mM Tris-HCl, Ph7.4, 20 mM KCl, 6 mM MgCl 2 . Malachite green (0.0812% w/v) (M9636) and polyviny alcohol USP (2.32% w/v) (Pl 097) were obtained from Sigma. A Malachite Green Assay (see Methods MoI Med, 2003, 85: 149 for method details) was used for examination of ATPase activity of Hsp90 protein.
  • Hsp90 protein in assay buffer 100 mM Tris-HCl, Ph7.4, 20 mM KCl, 6 mM MgCl 2
  • ATP alone negative control
  • KCl KCl
  • Compound 108 Compound 108
  • Malachite green reagent was added to the reaction.
  • the mixtures were incubated at 37 0 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.
  • BT-474 cells were treated with 0.5 ⁇ M, 2 ⁇ M, or 5 ⁇ M of 17AAG (a positive control) or 0.5 ⁇ M, 2 ⁇ M, or 5 ⁇ M of Compound 108 or Compound 49 overnight in DMEM medium.
  • each cytoplasmic sample was prepared from IxIO 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, 2Ox Peroxide (#7003, Cell Signaling) was used for visualization.
  • Compound 49 which is even more active than Compound 108 causes complete degradation of Her2 when cells are treated with 2 ⁇ M and 5 ⁇ M and causes partial degradated when cells are treated with 0.5 ⁇ M 17AAG is a known Hsp90 inhibitor and is used as a positive control.
  • HEL92.1.7 and Kasumi-1 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 (3X10 5 per well) were treated with 17AAG (0.5 ⁇ M), 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.
  • 17-AAG which is a potent Hsp90 inhibitor and is in phase 2 clinical trials, could not induce c-kit degradation at 0.5 ⁇ M in two leukemia cell lines, HEL92.1.7 (see Fig. 3) and Kasumi-1 (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.
  • 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.
  • Example 170 Compound 49 Displays Anti-tumor Activity Against the Human
  • the human tumor cell line MDA-MB-435S (ATCC #HTB-129; G. Ellison, et al., MoI. 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 (FB S), 1 % 10OX L- glutamine, 1% IOOX Penicillin-Streptomycin, 1% IOOX sodium pyruvate and 1% IOOX MEM non-essential amino acids.
  • FBS was obtained from Sigma-Aldrich Corp. (St.
  • 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 IX Trypsin-EDTA (Invitrogen) and incubating at 37 0 C until the cells detached from the surface of the flask.
  • PBS room temperature phosphate buffered saline
  • IX Trypsin-EDTA Invitrogen
  • 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.
  • mice Six to eight week old, female Crl:CD-l- «wBR (nude) 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 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/ml in PBS.
  • the corpus adiposum is a fat body located in the ventral abdominal vicera in the right quadrant of the abdomen at the juncture of the os coxae (pelvic bone) and the os femoris (femur). Tumors were then permitted to develop in vivo until they reached approximately 150 mm 3 in volume, which typically required 2-3 weeks following implantation.
  • DMSO dimethyl sulfoxide
  • Cremophore RH40 polyoxyl 40 hydrogenated castor oil; BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany
  • D5W 5% dextrose in water
  • This solution was stored at room temperature for up to 3 months prior to use.
  • DMSO stock solutions were diluted 1:10 with 20% Cremophore RH40.
  • the final formulation for dosing contained 10% DMSO, 18% Cremophore RH40, 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.
  • IP intraperitoneal
  • Example 171 Compound 188 Displays Anti-tumor Activity against Human Tumor Cells in a nude Mouse Xenograft Model
  • the human squamous non-small cell lung cancer cell line RERF-LC-AI (RCB0444; S. Kyoizumi, et al., Cancer. Res. 45:3274-3281, 1985), was obtained from the Riken Cell Bank (Tsukuba, Ibaraki, Japan).
  • 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), 1% IOOX L- glutamine, 1% IOOX penicillin-streptomycin, 1% IOOX sodium pyruvate and 1% IOOX MEM non-essential amino acids.
  • FBS was obtained from American Type Culture Collection (Manassas, Virginia, USA) and all other reagents were obtained from Invitrogen Corp. (Carlsbad, California, 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.
  • 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 IX trypsin-EDTA (Invitrogen) and incubating at 37 0 C until the cells detached from the surface of the flask.
  • IX trypsin-EDTA Invitrogen
  • 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 0 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.
  • mice Seven to eight week old, female Crl:CD-l- «wBR (nude) 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 between 8 and 12 weeks of age at implantation.
  • RERF-LC-AITM 1 In vivo passaged RERF-LC-AI tumor cells (RERF-LC-AITM 1 ”) were isolated to improve the rate of tumor implantation relative to the parental cell line in nude mice. RERF-LC-AI tumors were permitted to develop in vivo until they reached approximately 250 mm 3 in volume, which required approximately 3 weeks following implantation. Mice were euthanized via CO 2 asphyxiation and their exteriors sterilized with 70% ethanol in a laminar flow hood. Using sterile technique, tumors were excised and diced in 50 ml PBS using a scalpel blade.
  • a single cell suspension was prepared using a 55 ml Wheaton Safe-Grind tissue grinder (catalog #62400-358; VWR International, West Chester, Pennsylvania, USA) by plunging the pestle up and down 4-5 times without twisting.
  • the suspension was strained through a 70 ⁇ M nylon cell strainer and then centrifuged to pellet the cells.
  • the resulting pellet was resuspended in 0.1 M NH 4 Cl to lyse contaminating red blood cells and then immediately centrifuged to pellet the cells.
  • the cell pellet was resuspended in growth media and seeded into 175 cm 2 flasks containing 50 ml of growth media at 1-3 tumors/flask or approximately 10 x 10(6) cells/flask.
  • RERF-LC -AITM 1* cells were then implanted as above and tumors were permitted to develop in vivo until the majority reached an average of 100-200 mm 3 in tumor volume, which typically required 2-3 weeks following implantation. Animals with oblong or very small or large tumors were discarded, and only animals carrying tumors that displayed consistent growth rates were selected for studies. Animals were randomized into treatment groups so that the average tumor volumes of each group were similar at the start of dosing.
  • the HSP90 inhibitor ⁇ -allylamino-lT-demethoxygeldanamycin (17- AAG) was employed as a positive control (Albany Molecular Research, Albany, New York, USA).
  • Stock solutions of test articles 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 weekly, stored at -2O 0 C and diluted fresh each day for dosing.
  • DMSO dimethyl sulfoxide
  • Cremophore RH40 polyoxyl 40 hydrogenated castor oil
  • D5W 5% dextrose in water
  • Abbott Laboratories North Chicago, Illinois, USA
  • D5W 5% dextrose in water
  • Cremophore RH40 50-60 0 C
  • 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.
  • DMSO stock solutions were diluted 1: 10 with 20% Cremophore RH40.
  • the final formulation for dosing contained 10% DMSO, 18% Cremophore RH40, 3.6% dextrose, 68.4% water and the appropriate amount of test article.

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Abstract

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

Description

TRIAZOLE COMPOUNDS THAT MODULATE HSP90 ACTIVITY
RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No. 60/628,979, filed November 18, 2004; U.S. Provisional Application No. 60/709,358, filed August 18, 2005, and U.S. Provisional Application No. 60/725,044, filed October 6, 2005. The entire teachings of the above applications are incorporated herein by reference.
BACKGROUND OF THE INVENTION
Although tremendous advances have been made in elucidating the genomic abnormalities that cause malignant cancer cells, currently available chemotherapy remains unsatisfactory, and the prognosis for the majority of patients diagnosed with cancer remains dismal. Most chemotherapeutic agents act on a specific molecular target thought to be involved in the development of the malignant phenotype. However, a complex network of signaling pathways regulate cell proliferation, and the majority of malignant cancers are facilitated by multiple genetic abnormalities in these pathway. Therefore, it is unlikely that a therapeutic agent that acts on one molecular target will be fully effective in curing a patient who has cancer.
Heat shock proteins (HSPs) are a class of chaperone proteins that are up- regulated in response to elevated temperature and other environmental stresses, such as ultraviolet light, nutrient deprivation, and oxygen deprivation. HSPs act as chaperones to other cellular proteins (called client proteins) and facilitate their proper folding and repair, and aid in the refolding of misfolded client proteins. There are several known families of HSPs, each having its own set of client proteins. The Hsp90 family is one of the most abundant HSP families, accounting for about 1- 2% of proteins in a cell that is not under stress and increasing to about 4-6% in a cell under stress. Inhibition of Hsp90 results in degradation of its client proteins via the ubiquitin proteasome pathway. Unlike other chaperone proteins, the client proteins of Hsp90 are mostly protein kinases or transcription factors involved in signal transduction, and a number of its client proteins have been shown to be involved in the progression of cancer. Examples of Hsp90 client proteins that have been implicated in the progression of cancer are described below.
Her-2 is a transmembrane tyrosine kinase cell surface growth factor receptor that is expressed in normal epithelial cells. Her2 has an extracellular domain that interacts with extracellular growth factors and an internal tyrosine kinase portion that transmits the external growth signal to the nucleus of the cell. Her2 is overexpressed in a significant proportion of malignancies, such as breast cancer, ovarian cancer, prostate cancer, and gastric cancers, and is typically associated with a poor prognosis. c-Kit is a membrane receptor protein tyrosine kinase which binds Stem Cell Factor (SCF) to its extraellular domain. c-Kit is involved in the development of melanocytes, mast, germ and hematopoietic cells, and there is evidence that it plays a role in several types of cancer including leukemias, mast cell tumors, small cell lung cancer, testicular cancer, cancers of the gastointesinal tract and cancers of the central nervous system. c-Met is a receptor tyrosine kinase that is encoded by the Met protooncogene and transduces the biological effects of hepatocyte growth factor (HGF), which is also referred to as scatter factor (SF). Jiang et al., Crit. Rev. Oncol. Hemtol. 29: 209- 248 (1999), the entire teachings of which are incorporated herein by reference, c- Met and HGF are expressed in numerous tissues, although their expression is normally confined predominantly to cells of epithelial and mesenchymal origin, respectively. c-Met and HGF are required for normal mammalian development and have been shown to be important in cell migration, cell proliferation and survival, morphogenic differentiation, and organization of 3-dimensional tubular structures (e.g., renal tubular cells, gland formation, etc.). The c-Met receptor has been shown to be expressed in a number of human cancers. c-Met and its ligand, HGF, have also been shown to be co-expressed at elevated levels in a variety of human cancers (particularly sarcomas). However, because the receptor and ligand are usually expressed by different cell types, c-Met signaling is most commonly regulated by tumor-stroma (tumor-host) interactions. Furthermore, c-Met gene amplification, mutation, and rearrangement have been observed in a subset of human cancers. Families with germine mutations that activate c-Met kinase are prone to multiple kidney tumors as well as tumors in other tissues. Numerous studies have correlated the expression of c-Met and/or HGF/SF with the state of disease progression of different types of cancer (including lung, colon, breast, prostate, liver, pancreas, brain, kidney, ovaries, stomach, skin, and bone cancers). Furthermore, the overexpression of c-Met or HGF have been shown to correlate with poor prognosis and disease outcome in a number of major human cancers including lung, liver, gastric, and breast.
Akt kinase is a serine/threonine kinase which is a downstream effector molecule of phosphoinositide 3-kinase and is involved in protecting the cell from apoptosis. Akt kinase is thought to be involved in the progression of cancer because it stimulates cell proliferation and suppresses apoptosis.
Cdk4/cyclin D complexes are involved in phosphorylation of retinoblastoma protein which is an essential step in progression of a cell through the Gl phase of the cell cycle. Disruption of Hsp90 activity has been shown to decrease the half life of newly synthesized Cdk4.
Raf-1 is a MAP 3-kinase (MAP3K) which when activated can phosphorylate and acitivate the serine/threonine specific protein kinases ERKl and ERK2. Activated ERKs play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration.
The transforming protein of Rous sarcoma virus, v-src, is a prototype of an oncogene family that induces cellular transformation (i.e., tumorogenesis) by non- regulated kinase activity. Hsp90 has been shown to complex with v-scr and inhibit its degradation. The BCR-ABL fusion protein associated with chronic myelogenous leukemia and in a subset of patients with acute lymphoblastic leukemia. The fusion protein is a consequence of exchange of genetic material from the long arms of chromosomes 9 and 22 and results in unregulated tyrosine kinase activity. BCR- ABL exists as a complex with Hsp90 and is rapidly degraded when the action of Hsp90 is inhibited.
Hsp90 is required to maintain steroid hormone receptors in a conformation capable of binding hormone with high affinity. Inhibition of the action of Hsp90 therefore is expected to be useful in treating hormone-associated malignancies such as breast cancer. p53 is a tumor suppressor protein that causes cell cycle arrest and apoptosis. Mutation of the p53 gene is found in about half of all human cancers making it one of the most common genetic alterations found in cancerous cells. In addition, p53 mutation is associated with a poor prognosis. Wild-type p53 has been shown to interact with Hsp90, but mutated p53 forms a more stable association than wild-type p53 as a result of its misfolded conformations. A stronger interaction with Hsp90 protects the mutated protein form normal proteolytic degradation and prolongs its half-life. In a cell that is heterozygous for mutated and wild-type p53, inhibition of the stabilizing effect of Hsp90 causes mutant p53 to be degraded and restores the normal transcriptional activity of wild-type p53.
Hif-lcc is a hypoxia-inducible transcription factor that is up-regulated under low oxygen conditions. Under normal oxygen conditions Hif-lα associates with Von Hippel-Lindau (VHL) tumor suppressor protein and is degraded. Low oxygen conditions inhibits this association and allows Hif-lα to accumulate and complex with Hif-lβ to form an active transcription complex that associates with hypoxia- response elements to activate the transcription of vascular endothelial growth factor (VEGF). Increased Hif-lα is associated with increased metastasis and a poor prognosis.
Hsp90 has been shown by mutational analysis to be necessary for the survival of normal eukaryotic cells. However, Hsp90 is over expressed in many tumor types indicating that it may play a significant role in the survival of cancer cells and that cancer cells may be more sensitive to inhibition of Hsp90 than normal cells. For example, cancer cells typically have a large number of mutated and overexpressed oncoproteins that are dependent on Hsp90 for folding. In addition, because the environment of a tumor is typically hostile due to hypoxia, nutrient deprivation, acidosis, etc., tumor cells may be especially dependent on Hsp90 for survival. Moreover, inhibition of Hsp90 causes simultaneous inhibition of a number of oncoproteins, as well as hormone receptors and transcription factors making it an attractive target for an anti-cancer agent. In fact, benzoquinone ansamycins, a family of natural products that inhibit Hsp90, has shown evidence of therapeutic activity in clinical trials.
Although promising, benzoquinone ansamycins, and their derivatives, suffer from a number of limitations. For example, they have low oral bioavailability, and their limited solubility makes them difficult to formula. In addition, they are metabolized by polymorphic cytochrome P450 CYP3A4 and are a substrate for P- glycoprotein export pump involved in the development of multidrug resistance. Therefore, a need exist for new therapeutics that improve the prognosis of cancer patients and that reduces or overcomes the limitations of currently used anti-cancer agents.
SUMMARY OF THE INVENTION
The present invention provides novel compounds which inhibit the activity of Hsp90 and are useful in the treatment of proliferative disorders, such as cancer. The present invention also provides new uses for previously disclosed compounds.
The present invention provides compounds having the formula (I):
Figure imgf000006_0001
(I) 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 R3;
Ri is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(O)NR10R1I, -SC(O)NRi0Rn, -NR7C(O)NR10Ri1, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(0)NRioRu, -SCH2C(O)NRi0Ri1, -NR7CH2C(0)NRioRi i, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7, -OS(O)PNRI0RI I5 -SS(O)PNR1ORI I, -NR7S(O)PNR,0RI I, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRi0RiI, -SC(S)NRi0Ri i, -NR7C(S)NRi0Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0Ri,, -SC(NRg)NRi0RiI, -NR7C(NR8)NRi0RiI, -OP(O)(OR7^, or -SP(O)(OR7)2;
R3 is -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -0(CH2)m0H, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(O)NR10Ri,, -SC(O)NRi0Ri i, -NR7C(O)NRi0Ri1, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R1I, -SCH2C(O)NR10Rn, -NR7CH2C(O)NRiORi1, -OS(O)PR7, -SS(O)PR7, -S(O)POR7, -NR7S(O)PR7,
-OS(O)pNRi0Rn, -SS(O)pNR10Rii, -NR7S(O)PNRi0Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRi0Ri,, -SC(S)NRi0Ri i, -NR7C(S)NRi0Ri1, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0R,,, -SC(NR8)NR10R,,, -NR7C(NR8)NRi0R,,, -OP(O)(OR7J2, or -SP(O)(OR7)2;
Rs is an optionally substituted heteroaryl or an optionally substituted 8 to 14 membered aryl;
R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; R,o and Rn, 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 Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26 is a lower alkyl; p, for each occurrence, is, independently, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
In one embodiment, ring A of the the compounds of formula (I) is not a substituted [l,2,3]triazole, and/or compounds represented by formula (I) do not include 3-(2,4-dihydroxy-phenyl)-4-(7-naphthalen-l-yl)-5-mercapto-triazole.
The present invention also provides compounds having the formula (II):
Figure imgf000008_0001
(II) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. In formula (II), ring A, Ri, and R3 are defined as for formula (I); and 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, -NRi0Rn, -OR20, -C(O)R7,
-C(O)OR20, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)pR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)PR7, or -S(0)pNRloRn, 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, -NRi0Rn, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)pR7, -OS(O)PR7, -S(O)pOR7, -NR8S(O)pR7, or -S(0)pNRloRn; 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-l-yl)-5-mercapto-triazole, 3-(2,4- dihydroxyphenyl)-4-(2,5-dimethoxyphenyl)-5-mercapto-triazole, 3-(l-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 (III):
Figure imgf000009_0001
(III) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. In formula (III), ring A, Ri, and R3 are defined as for formula (I); and Ri8 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, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)pR7, -S(O)POR7, -NR8S(O)PR7, or -S(O)pNR10Rπ, -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(OR7)2;
In one embodiment, compounds represented by formula (III) do not include compounds in which Ri8 is not cyclohexyl.
The invention also provides compounds represented by formula (IV) or formula (V):
Figure imgf000010_0001
(IV) (V)
and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. In formulas (IV) and (V), Ri and R3 are defined as for formula (I); and
Xi4 is O, S, or NR7;
R21 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; R22, for each occurrence, is independently -H or is 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, a haloalkyl, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NRi0Rn, -NR8C(O)R7, -S(O)PR7, -S(O)POR7, or -S(0)pNRioRπ; and
R23 and R24, for each occurrence, are independently -H or are 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, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)PR7, or -S(O)pNR10Rπ.
The present invention also provides compounds 1 ^presented by formula (VI):
Figure imgf000011_0001
(VI) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein: X41 is O, S, or NR42;
X42 is CR44 or N;
Figure imgf000012_0001
Y41 is N or CR45;
Y42, for each occurrence, is independently N, C or CR46; Z is OH, SH, or NHR7; R4I is -H, -OH, -SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted 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,
-NRioRn, -OR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)NR10Rn, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10Rn, -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(O)R7, -SC(O)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NR10R11, -OC(S)NR10R1,, -OC(NR8)NR10R11, -SC(O)NR10R11, -SC(NR8)NR10R11, -SC(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -C(O)NR10R11, -NR8C(O)R7, -NR7C(S)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(O)OR7, -NR7C(NR8)OR7, -NR7C(O)NR10R11, -NR7C(S)NR10R11, -NR7C(NR8)NR10RH, -SR7, -S(O)PR7, -OS(O)PR7, -OS(O)POR7, -OS(O)PNRi0R1U -S(O)POR7, -NR8S(O)PR7, -NR7S(O)PNR10R1 !, -NR7S(O)POR7, -S(0)pNRloRn, -SS(O)pR7, -SS(O)POR7, -SS(O)pNR10R,i, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R42 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, -C(O)R7, -(CH2)mC(O)OR7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -S(O)PR7, -S(O)POR7, or -S(0)pNRloRu;
R43 and R44 are, independently, -H, -OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)pOR7, -NR8S(O)pR7, -S(O)PNR10R1 u or R43 and R44 taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl;
R45 is -H, -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -0(CH2)m0H, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(0)NRioRii, -SC(O)NRi0R1 I, -NR7C(O)NR10R11, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(0)NRioRi i, -SCH2C(O)NRI0RH, -NR7CH2C(O)NR1ORH, -OS(O)PR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)PNR10R1 u -SS(0)pNRioRi,, -NR7S(O)PNR10R11, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Ri i, -SC(S)NR10Ri 1, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR1ORiI, -SC(NR8)NRi0Rn, or -NR7C(NR8)NRi0R1I; R46, for each occurrence, is independently selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)PR7, or -S(O)PNRi0R1 ,; R7, R8, R10, Rn, R26, p, and m are defined as above.
The present invention also provides compounds represented by formula
(VII):
Figure imgf000014_0001
(VII) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs, wherein: Zi is -OH or -SH; and
X42, R41, R42, R43, and R45 are defined as above.
The present invention also provides compounds having the formula (VIII):
Figure imgf000014_0002
(VIII) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein: X4S is CR54 or N; Z1 is -OH or -SH; R52 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, -(CH2)2OCH3, -CH2C(O)OH, and - C(O)N(CHa)2; R53 and R54 are each, independently, -H, methyl, ethyl, or isopropyl; or R53 and R54 taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring;
R55 is selected from the group consisting of -H, -OH, -OCH3, and - OCH2CH3; and
R56 is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl.
The present invention also provides compounds having the formula (IX):
Figure imgf000015_0001
(IX) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein, X44, for each occurrence, is independently, O, S, NR42 or C(R4O)2;
Y43 is NR42, C(R4O)2, C(R46)2-C(R46)2) C(O), C(S), C(R46J2C(O), or C(R^)2C(S);
Y41, Y42, Z, R41, R42, and R46 are defined as above. In one embodiment, in formula (IX), R4I is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
In another embodiment, in formula (IX), R41 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy. In another embodiment, in formula (IX), R42 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-bυtyl, n-pentyl, n-hexyl, -C(O)OH, -(CH2)mC(O)OH, -CH2OCH3, -CH2CH2OCH3, and -C(O)N(CHs)2.
In another embodiment, in formula (IX), Y41 is CR45. Preferably, R45 is H, a lower alkoxy, or -OH. In another embodiment, in formula (IX), Y42 is CH.
In another embodiment, in formula (IX), Y43 is CH2.
In another embodiment, in formula (IX), Y43 is NR42, wherein R42 is H or a lower alkyl.
In another embodiment, in formula (IX), one OfX44 is NR42 and the other is CH2 or C(Re)2. Preferably, one OfX44 is NR42 and the other is CH2.
In another embodiment, in formula (VI), Z is -OH.
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-(l,3-benzodiaxol-5-yl)-5-mercapto-[l,2,4] triazole;
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(indan-5-yl)-5-mercapto-[l,2,4] triazole;
4-Ethyl-6-[5-mercapto-4-(l-methyl-2,3-dihydro-lH-indol-5-yl)-4H-[l,2,4]triazol-3- yl]-benzene-l,3-diol;
5-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-mercapto-4H-l,2,4-triazol-4-yl)indolin-2- one;
5-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-mercapto-4H-l,2,4-triazol-4-yl)-lH- benzo[d]imidazol-2(3H)-one;
5-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-mercapto-4H-l,2,4-triazol-4-yl)-l- methylindolin-2-one;
4-isopropyl-6-(5-mercapto-4-(4-propyl-3,4-dihydro-2H-benzo[b][l,4]oxazin-6-yl)- 4H-l,2,4-triazol-3-yl)benzene-l,3-diol;
6-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-mercapto-4H-l,2,4-triazol-4-yl)-2H- benzo[b] [1 ,4]oxazin-3(4H)-one;
6-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-mercapto-4H-l,2,4-triazol-4-yl)-3- methylbenzo[d]thiazol-2(3H)-one;
6-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-mercapto-4H-l,2,4-triazol-4- yl)benzo[d]thiazol-2(3H)-one; and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof.
Compounds of formula (EX) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (IX) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
The present invention also provides compounds having the formula (X):
Figure imgf000017_0001
(X) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein:
X41, Y41, Y42, Z, R7, R8, Rio, Rn, R41 , R46 and p are defined as above.
The compounds shown in Table 1 or compounds of any formula herein, or tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof, inhibit the activity of Hsp90 and, thereby facilitates the degradation of Hsp90 client proteins. Hsp90 is necessary for the survival of ' normal eukaryotic cells. However, Hsp90 is over expressed in many tumor types indicating that it may play a significant role in the survival of cancer cells and that cancer cells may be more sensitive to inhibition of Hsp90 than normal cells. Thus, the compounds shown in Table 1 or compounds of any formula herein, or tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof, are useful treating proliferative disorders such as cancer.
Although chemotherapeutic agents initially cause tumor regression, most agents that are currently used to treat cancer target only one pathway to tumor progression. Therefore, in many instances, after treatment with one or more chemotherapeutic agents, a tumor develops multidrug resistance and no longer responses positively to treatment. One of the advantages of inhibiting Hsp90 activity is that several of its client proteins, which are mostly protein kinases or transcription factors involved in signal transduction, have been shown to be involved in the progression of cancer. Thus, inhibition of Hsp90 provides a method of short circuiting several pathways for tumor progression simultaneously. Therefore, treatment of tumors with an Hsp90 inhibitor of the invention either alone, or in combination with other chemotherapeutic agents, is more likely to result in regression or elimination of the tumor, and less likely to result in the development of more aggressive multidrug resistant tumors than other currently available therapeis.
BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention.
Figure 1 is a graph showing the ATPase activity of Hsp90 when untreated, when treated with 40 mM of Geldanamycin, a known Hsp90 inhibitor as a positive control, and when treated with 40μM or 4μM of Compound 108 of the invention;
Figure 2 is gel showing the amount of Her2, an Hsp90 client protein, in cells that are untreated, in cells that have been treated with 0.5μM, 2μM, or 5μM of 17AAG, a known Hsp90 inhibitor, and in cells that have been treated with 0.5 μM, 2μM, or 5μM of Compound 108 or Compound 49;
Figure 3 is a graph showing an FACSCalibur flow cytometer analysis of the c-kit positive population of HEL92.1.7 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 17AAG, an Hsp90 inhibitor that is currently in phase II clinical trials. Figure 4 is a graph showing an FACSCalibur flow cytometer analysis of the c-kit positive population of Kasumi-1 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 17AAG, an Hsp90 inhibitor that is currently in phase II clinical trials.
Figure 5 is a Western blot analysis of the c-kit from Kasumi-1 cells treated with Hsp90 inhibitors of the invention or 17AAG (as a positive control).
Figure 6 is a Western blot analysis of the c-met from NCI-Hl 193 cells treated with Hsp90 inhibitors of the invention or 17AAG (as a positive control). Figure 7 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-17-demethoxygeldanarnycin (17- AAG);
Figure 8 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 3). 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 9 displays the results of a nude mouse xenograft study to determine the effect of Compound 188 on the in vivo growth rate of RERF-LC- AIIVP human lung tumor cells. Tumor bearing animals (8 mice/group) were i.p. injected 5 times per week for a total of 15 doses (hatched bar) and the average tumor volumes for each group (error bars represent SEM) were determined every 3-4 days. Treatment with a dose of 200 mg/kg body weight of Compound 188 inhibited tumor growth, as did a dose of 75 mg/kg body weight of 17- AAG (both compounds were dosed at approximately their maximum tolerated doses in nude mice); and Figure 10 demonstrates that treatment with Compound 188 does not cause overt toxicity in a nude mouse xenograft model using RERF-LC -AIIVP human lung tumor cells (data derived from the same study presented in Figure 5). Tumor bearing animals (8 mice/group) were i.p. injected 5 times per week for a total of 15 doses (hatched bar) and the cumulative average percent changes in body weights for each group relative to the start of dosing were determined every 2-3 days.
Treatment with a dose of 200 mg/kg body weight of Compound 188 was not overtly toxic, as indicated by the minimal effects on the animal body weights in the test article-treated versus vehicle-treated groups.
DETAILED DESCRIPTION OF THE INVENTION A description of preferred embodiments of the invention follows.
The present invention provides compounds and uses of said compounds. 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. In particular, the present invention encompasses the use of compounds of the invention to slow or stop the growth of cancerous cells or to reduce or eliminate cancerous cells in a mammal.
In certain embodiments, the compounds of the invention can be used in combination with other chemotherapeutic agents and may help to prevent or reduce the development of multidrug resistant cancerous cells in a mammal. In this embodiment, the compounds of the invention may allow a reduced efficacious amount of a second chemotherapeutic agent given to a mammal, because compounds of the invention should inhibit the development of multidrug resistant cancerous cells.
A. Terminology
Unless otherwise specified, the below terms used herein are defined as follows: As used herein, the term "alkyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms. Representative saturated straight chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n- heptyl, n-octyl, n-nonyl and n-decyl; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4- 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-C6)alkyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 1 to 6 carbon atoms. Representative (Ci-Ce)alkyl groups are those shown above having from 1 to 6 carbon atoms. Alkyl groups included in compounds of this invention may be optionally substituted with one or more substituents.
As used herein, the term "alkenyl" means a saturated straight chain or branched non-cyclic hydrocarbon having from 2 to 10 carbon atoms and having at least one carbon-carbon double bond. Representative straight chain and branched (C2-C]o)alkenyls include vinyl, allyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3 -methyl- 1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2- octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, 3- decenyl and the like. 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-l-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 independently selected from -F, -Cl, -Br, and -I. The term "halomethyl" means a methyl in which one to three hydrogen radical(s) have been replaced by a halo group. Representative haloalkyl groups include trifluoromethyl, bromomethyl, 1,2-dichloroethyl, 4-iodobutyl, 2-fluoropentyl, and the like.
As used herein, an "alkoxy" is an alkyl group which is attached to another moiety via an oxygen linker. As used herein, an "haloalkoxy" is an haloalkyl group which is attached to another moiety via an oxygen linker.
As used herein, the term an "aromatic ring" or "aryl" means a hydrocarbon monocyclic or polycyclic radical in which at least one ring is aromatic. Examples of suitable aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Aryl groups may be optionally substituted with one or more substituents. In one embodiment, the aryl group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, referred to herein as "(C6)aryl."
As used herein, the term "aralkyl" means an aryl group that is attached to another group by a (Ci-C6)alkylene group. Representative aralkyl groups include benzyl, 2-phenyl-ethyl, naρhth-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 "(Ci-C6)alkylene" refers to an alkylene group that has from one to six carbon atoms. Straight chain (C1-C6)alkylene groups are preferred. Non-limiting examples of alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), and the like. Alkylene groups may be optionally substituted with one or more substituents.
As used herein, the term "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, 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, 1-oxo-pyridyl, furanyl, benzo[l,3]dioxolyl, benzo[l,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[l,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 "(C5)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 "(C6)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 (Ce)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 (Cj-C6)alkylene. Representative heteroaralkyls include 2-(pyridin-4-yl)-propyl, 2-(thien-3-yl)-ethyl, imidazol-4-yl-methyl and the like. Heteroaralkyl groups may be optionally substituted with one or more substituents.
As used herein, the term "halogen" or "halo" means -F, -CI, -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)NR28R29, -C(S)NR28R29, -C(NR32)NR28R29, -NR30C(O)R3I, -NR30C(S)R3], -NR30C(NR32)R31, halo, -OR30, cyano, nitro, haloalkoxy, -C(O)R30, -C(S)R30, -C(NR32)R30, -NR28R29, -C(O)OR30, -C(S)OR30, -C(NR32)OR30, -OC(O)R30, -OC(S)R30, -OC(NR32)R30, -NR30C(O)NR28R29, -NR30C(S)NR28R29, -NR30C(NR32)NR28R29, -OC(O)NR28R29, -OC(S)NR28R29, -OC(NR32)NR28R29, -NR30C(O)OR3I, -NR30C(S)OR3I, -NR30C(NR32)OR31, -S(O)hR30, -OS(O)pR30, , -NR30S(O)pR30, -S(O)PNR28R29, -OS(O)PNR28R29, or -NR30S(O)pNR28R29, wherein R28 and R29, 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 R28 and R29 taken together with the nitrogen to which they are attached is optionally substituted heterocyclyl or optionally substituted heteroaryl;
R30 and R31 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
R32, for each occurrence is, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, -C(O)R30, -C(O)NR28R29, -S(O)pR30, or -S(O)PNR28R29; p, for each occurrence, is independently, 1 or 2; and h is 0, 1 or 2.
In addition, alkyl, cycloalkyl, alkylene, a heterocyclyl, and any saturated portion of a alkenyl, cycloalkenyl, alkynyl, aralkyl, and heteroaralkyl groups, may also be substituted with =0, =S, =N-R32.
When a heterocyclyl, heteroaryl, or heteroaralkyl group contains a nitrogen atom, it may be substituted or unsubstituted. When a nitrogen atom in the aromatic ring of a 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 1 to 4 carbon atoms, "lower alkoxy" refers to "-O-(Ci-C4)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), (II), (EI), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph or prodrug thereof, and also include protected derivatives thereof. The compounds of the invention may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or 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.
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), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1 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), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1 that comprise -NO, -NO2, -ONO, or -ONO2 moieties. Prodrugs can typically be prepared using well-known methods, such as those described by 1 BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed). As used herein and unless otherwise indicated, the terms "biohydrolyzable amide", "biohydrolyzable ester", "biohydrolyzable carbamate", "biohydrolyzable carbonate", "biohydrolyzable ureide" and "biohydrolyzable phosphate analogue" mean an amide, ester, carbamate, carbonate, ureide, or phosphate analogue, respectively, that either: 1) does not destroy the biological activity of the compound and confers upon that compound advantageous properties in vivo, such as improved water solubility, improved circulating half-life in the blood (e.g., because of reduced metabolism of the prodrug), improved uptake, improved duration of action, or improved onset of action; or 2) is itself biologically inactive but is converted in vivo to a biologically active compound. Examples of biohydrolyzable amides include, but are not limited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and choline esters. Examples of biohydrolyzable carbamates include, but are not limited to, lower alkylamines, substituted ethylenediamines, aminoacids, 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 Hsp90α and Hsp90β isoforms, as well as GRP94, which is found in the endoplasmic reticulum, and HSP75/TRAP1, which is found in the mitochondrial matrix.
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, EMBO J., 77:3341-3351; and Qiu, et al., \9U, EMB0 J., 7:1003-1011, which are incorporated by reference herein in their entirety, including any drawings. Mutant versions of c-kit kinase are encompassed by the term "c-kit 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, 772:165-170), 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, a "proliferative disorder" or a "hyperproliferative disorder," and other equivalent terms, means a disease or medical condition involving pathological growth of cells. Proliferative disorders include cancer, smooth muscle cell proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, retinopathy, e.g., diabetic retinopathy or other retinopathies, cardiac hyperplasia, reproductive system associated disorders such as benign prostatic hyperplasia and ovarian cysts, pulmonary fibrosis, endometriosis, fibromatosis, harmatomas, lymphangiomatosis, sarcoidosis, desmoid tumors,
Smooth muscle cell proliferation includes hyperproliferation of cells in the vasculature, for example, intimal smooth muscle cell hyperplasia, restenosis and vascular occlusion, particularly stenosis following biologically- or mechanically- mediated vascular injury, e.g., vascular injury associated with angioplasty.
Moreover, intimal smooth muscle cell hyperplasia can include hyperplasia in smooth muscle other than the vasculature, e.g., bile duct blockage, bronchial airways of the lung in patients with asthma, in the kidneys of patients with renal interstitial fibrosis, and the like. Non-cancerous proliferative disorders also include hyperproliferation of cells in the skin such as psoriasis and its varied clinical forms, Reiter's syndrome, pityriasis rubra pilaris, and hyperproliferative variants of disorders of keratinization (e.g., actinic keratosis, senile keratosis), scleroderma, and the like.
In a preferred embodiment, the proliferative disorder is cancer. Cancers that can be treated or prevented by the methods of the present invention include, but are not limited to human sarcomas and carcinomas, e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma; leukemias, e.g., acute lymphocytic leukemia and acute myelocytic leukemia (myeloblastic, promyelocyte, myelomonocytic, monocytic and erythroleukemia); chronic leukemia (chronic myelocytic (granulocytic) leukemia and chronic lymphocytic leukemia); and polycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenstrobm's macroglobulinemia, and heavy chain disease. Other examples of leukemias include acute and/or chronic leukemias, e.g., lymphocytic leukemia (e.g., as exemplified by the p388 (murine) cell line), large granular lymphocytic leukemia, and lymphoblastic leukemia; T-cell leukemias, e.g., T-cell leukemia (e.g., as exemplified by the CEM, Jurkat, and HSB-2 (acute), YAC- 1 (murine) cell lines), T-lymphocytic leukemia, and T-lymphoblastic leukemia; B cell leukemia (e.g., as exemplified by the SB (acute) cell line) , and B-lymphocytic leukemia; mixed cell leukemias, e.g., B and T cell leukemia and B and T lymphocytic leukemia; myeloid leukemias, e.g., granulocytic leukemia, myelocytic leukemia (e.g., as exemplified by the HL-60 (promyelocyte) cell line), and myelogenous leukemia (e.g., as exemplified by the K562(chronic)cell line); neutrophilic leukemia; eosinophilic leukemia; monocytic leukemia (e.g., as exemplified by the THP-I (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-l(acute) cell line); and lymphoma (e.g., as exemplified by the U937 cell line).
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 treating the subject with the cancer. For example, many tumors will initially respond to treatment with an anti-cancer drug by decreasing in size or even going into remission, only to develop resistance to the drug. Drug resistant tumors are characterized by a resumption of their growth and/or reappearance after having seemingly gone into remission, despite the administration of increased dosages of the anti-cancer drug. Cancers that have developed resistance to two or more anti-cancer drugs are said to be "multi-drug resistant". For example, it is common for cancers to become resistant to three or more anti-cancer agents, often five or more anti-cancer agents and at times ten or more anti-cancer agents.
As used herein, the term "c-kit associated cancer" refers to a cancer which has aberrant expression and/or activation of c-kit. c-Kit associated cancers include leukemias, mast cell tumors, small cell lung cancer, testicular cancer, some cancers of the gastrointestinal tract and some central nervous system. In addition, c-kit has been implicated in playing a role in carcinogenesis of the female genital tract (Inoue, et al., 1994, Cancer Res., 54(l l):3049-3053), sarcomas of neuroectodermal origin (Ricotti, et al, 1998, Blood, 97:2397-2405), and Schwann cell neoplasia associated with neurofibromatosis (Ryan, et al., 1994, J. Neuro. Res., 37:415-432).
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), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1. 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,/?- toluenesulfonate, and pamoate (i.e., l,r-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term "pharmaceutically acceptable salt" also refers to a salt prepared from a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1 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), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1 having a basic functional group, such as an amine functional group, and a pharmaceutically acceptable inorganic or organic acid.. Suitable acids include, but are not limited to, hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), nitric acid, hydrogen bisulfide, phosphoric acid, lactic acid, salicylic acid, tartaric acid, bitartratic acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucaronic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, andp- toluenesulfonic acid.
As used herein, the term "pharmaceutically acceptable solvate," is a solvate formed from the association of one or more pharmaceutically acceptable solvent molecules to one of the compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1. The term solvate includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).
A pharmaceutically acceptable carrier may contain inert ingredients which do not unduly inhibit the biological activity of the compounds. The pharmaceutically acceptable carriers should be biocompatible, i.e., non-toxic, non¬ inflammatory, non-immunogenic and devoid of other undesired reactions upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed, such as those described in Remington's Pharmaceutical Sciences, ibid. Suitable pharmaceutical carriers for parenteral administration include, for example, sterile water, physiological saline, bacteriostatic saline (saline containing about 0.9% mg/ml benzyl alcohol), phosphate-buffered saline, Hank's solution, Ringer's-lactate and the like. Methods for encapsulating compositions (such as in a coating of hard gelatin or cyclodextran) are known in the art (Baker, et ah, "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 comprising administering to a subject in need thereof a dose of at least 150 μg/kg, preferably at least 250 μg/kg, at least 500 μg/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at least 200 mg/kg or more of one or more compounds of the invention once every day, preferably, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 10 days, once every two weeks, once every three weeks, or once a month. The dosages of a chemotherapeutic agents other than compounds of the invention, which have been or are currently being used to prevent, treat, manage, or ameliorate a proliferative disorder, or one or more symptoms thereof, can be used in the combination therapies of the invention. Preferably, dosages lower than those which have been or are currently being used to prevent, treat, manage, or ameliorate a proliferative disorder, or one or more symptoms thereof, are used in the combination therapies of the invention. The recommended dosages of agents currently used for the prevention, treatment, management, or amelioration of a proliferative disorder, or one or more symptoms thereof, can obtained from any reference in the art including, but not limited to, Hardman et al, eds., 1996, Goodman & Gilman's The Pharmacological Basis Of Basis Of Therapeutics 9th Ed, Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57th Ed., 2003, Medical Economics Co., Inc., Montvale, NJ, which are incorporated herein by reference in its entirety.
As used herein, the terms "treat", "treatment" and "treating" refer to the reduction or amelioration of the progression, severity and/or duration of a 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.
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 ulcerations and erosions), nausea, vomiting, neurotoxicities, nephrotoxicities, renal toxicities
(including such conditions as papillary necrosis and chronic interstitial nephritis), hepatic toxicities (including elevated serum liver enzyme levels), myelotoxicities (including leukopenia, myelosuppression, thrombocytopenia and anemia), dry mouth, metallic taste, prolongation of gestation, weakness, somnolence, pain (including muscle pain, bone pain and headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms, akathisia, cardiovascular disturbances and sexual dysfunction.
As used herein, the term "in combination" refers to the use of more than one therapies (e.g., one or more prophylactic and/or therapeutic agents). The use of the term "in combination" does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with a proliferative disorder. A first therapy (e.g., a prophylactic or therapeutic agent such as a compound of the invention) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy
(e.g., a 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.
As used herein, a composition that "substantially" comprises a compound means that the composition contains more than about 80% by weight, more preferably more than about 90% by weight, even more preferably more than about
95% by weight, and most preferably more than about 97% by weight of the compound.
As used herein, a reaction that is "substantially complete" means that the reaction contains more than about 80% by weight of the desired product, more preferably more than about 90% by weight of the desired product, even more preferably more than about 95% by weight of the desired product, and most preferably more than about 97% by weight of the desired product.
As used herein, a racemic mixture means about 50% of one enantiomer and about 50% of is corresponding enantiomer relative to a chiral center in the molecule. The invention encompasses all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures of the compounds of the invention. Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or diastereomers by well known methods, such as chiral- phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well known asymmetric synthetic methods.
The compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity. When administered to a patient, e.g., to a non-human animal for veterinary use or for improvement of livestock, or to a human for clinical use, the compounds of the invention are administered in isolated form or as the isolated form in a pharmaceutical composition. As used herein, "isolated" means that the compounds of the invention are separated from other components of either (a) a natural source, such as a plant or cell, preferably bacterial culture, or (b) a synthetic organic chemical reaction mixture. Preferably, the compounds of the invention are purified via conventional techniques. As used herein, "purified" means that when isolated, the isolate contains at least 95%, preferably at least 98%, of a compound of the invention by weight of the isolate either as a mixture of stereoisomers or as a diastereomeric or enantiomeric pure isolate.
As used herein, a composition that is "substantially free" of a compound means that the composition contains less than about 20% by weight, more preferably less than about 10% by weight, even more preferably less than about 5% by weight, and most preferably less than about 3% by weight of the compound.
Only those choices and combinations of substituents that result in a stable structure are contemplated. Such choices and combinations will be apparent to 'those of ordinary skill in the art and may be determined without undue experimentation. The invention can be understood more fully by reference to the following detailed description and illustrative examples, which are intended to exemplify non- limiting embodiments of the invention. B. The Compounds of the Invention
The present invention emcompasses compounds having Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), and those set forth in Table 1 and tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs and prodrugs thereof. In one aspect, the invention provides compounds of formula (I) as set forth below:
Figure imgf000040_0001
(I) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein ring A, Ri, R3 and R5 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 (I) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
In one embodiment, in the compounds of formula (I), R5 is an optionally substituted naphthyl.
In another embodiment, in the compounds of formula (I), R5 is represented by the following formula:
Figure imgf000040_0002
wherein:
R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted 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, -NRioRn, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NRi0R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)PR7, or -S(0)pNR,oRn, -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(OR7)2; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and m is zero or an integer from 1 to 7, wherein R7, R8, Ri0, Rn, and p are defined as above.
In another embodiment, in the compounds represented by formula (I), R5 is represented by one of the following formulas:
Figure imgf000041_0001
wherein R9 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.
In another embodiment, in the compounds represented by formula (I), R5 is selected from the group consisting of:
Figure imgf000041_0002
Figure imgf000042_0001
Figure imgf000043_0001
wherein:
X6, for each occurrence, is independently CH, CR9, N, N(O), N+(Ri7), provided that at least three X6 groups are independently selected from CH and CR9; X7, for each occurrence, is independently CH, CR9, N, N(O), N+(Ri7), provided that at least three X7 groups are independently selected from CH and CR9;
X8, for each occurrence, is independently CH2, CHR9, CR9R9, O, S, S(O)p, NR7, or NRn;
X9, for each occurrence, is independently N or CH; X10, for each occurrence, is independently CH, CR9, N, N(O), N+(Rn), provided that at least one X] 0 is selected from CH and CR9;
Ri7, for each occurrence, is independently -H, an alkyl, an aralkyl, -C(O)R7, -C(O)OR7, or -C(0)NRioRii; wherein R7, R9, Rio, Rn and p are defined as above.
In another embodiment, in the compounds represented by formula (I), R5 is an optionally substituted indolyl, an optionally substituted benzoimidazolyl, an optionally substituted indazolyl, an optionally substituted 3H-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- c]pyridinyl, an optionally substituted thiazolo[5,4-c]pyridinyl, an optionally substituted thiazolo[4,5-b]pyridinyl, an optionally substituted thiazolo[5,4- b]pyridinyl, an optionally substituted oxazolo[4,5-c]pyridinyl, an optionally substituted oxazolo[5,4-c]pyridinyl, an optionally substituted oxazolo[4,5- b]pyridinyl, an optionally substituted oxazolo[5,4-b]pyridinyl,an optionally substituted imidazopyridinyl, an optionally substituted benzothiadiazolyl, benzoxadiazolyl, an optionally substituted benzotriazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted 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 IH- imidazo[4,5-b]pyridinyl, an optionally substituted lH-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 (I), R5 is an optionally substituted indolyl. Preferably, R5 is an indolyl represented by the following structural formula:
Figure imgf000044_0001
wherein:
R33 is a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;
R34 is Η, a lower alkyl, or a lower alkylcarbonyl; and
Ring B and Ring C are optionally substituted with one or more substituents.
In another embodiment, in the compounds represented by formula (I), R5 is selected from the group consisting of:
Figure imgf000045_0001
wherein:
Xn, for each occurrence, is independently CH, CR9, N, N(O), or N+(Rn), provided that at least one Xi 1 is N, N(O), or N+(Rn) and at least two Xn groups are independently selected from CH and CR9;
Xi2, for each occurrence, is independently CH, CR9, N, N(O), N+(Ri7), provided that at least one X12 group is independently selected from CH and CR9;
Xi3, for each occurrence, is independently O, S, S(O)p, NR7, Or NRi7; wherein R7, R9 and Rn 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 the following structural formula:
Figure imgf000045_0002
wherein Ri, R3, and R5 are defined as above; and
R6, 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, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)NR10Rn, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NRi0Rn, -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(O)R7, -SC(O)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NR10Rn, -OC(S)NR10Rn, -OC(NR8)NR10R11, -SC(O)NR10Rn, -SC(NR8)NRi0Rn, -SC(S)NR10Rn, -OC(NR8)R75 -SC(NR8)R7, -C(O)NRi0Ri i, -NR8C(O)R75 -NR7C(S)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(O)OR7, -NR7C(NR8)OR7, -NR7C(O)NRi0RiI5 -NR7C(S)NRiORI b -NR7C(NR8)NRiORI b -SR7, -S(0)pR7, -0S(0)pR7, -OS(O)POR7, -OS(0)pNR,oRn, -S(0)pOR7, -NR8S(O)pR7, -NR7S(0)pNR,oRn, -NR7S(O)POR7, -S(0)pNR,oR, i5 -SS(0)pR7, -SS(0)p0R7, -SS(O)pNRi0R,b -OP(O)(OR7)2, or -SP(O)(OR7)2; and n is zero of an integer from 1 to 4, wherein R7, R8, Ri0, Rn, 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 the following structural formula:
Figure imgf000046_0001
wherein Ri, R3, Rs, and R6 are defined as above; and R25 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 heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NRi0Rn, -OR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)NR10Rn, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10R11, -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(O)R7, -SC(O)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NR10Rn, -OC(S)NRi0Rn, -OC(NR8)NRi0Ri 1, -SC(O)NRi0Rn, -SC(NR8)NRi0Rn, -SC(S)NR10RI I, -OC(NR8)R7, -SC(NR8)R7, -C(O)NR10R1 1, -NR8C(O)R7, -NR7C(S)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(O)OR7, -NR7C(NR8)OR7, -NR7C(O)NRi0Ri i, -NR7C(S)NR10R1I, -NR7C(NR8)NRi0R1 1, -SR7, -S(O)PR7, -OS(O)pR7, -OS(O)POR7, -OS(O)pNR10Rn, -S(O)POR7, -NR8S(O)pR7, -NR7S(O)pNR10Rn, -NR7S(O)POR7, -S(O)pNRi0Rn, -SS(O)PR7, -SS(O)13OR7, -SS(O)pNR,0R, !, -OP(O)(OR7)2, or -SP(O)(OR7)2; k is 1, 2, 3, or 4; and r is zero or an integer from 1 to 3, wherein R7, R8, Rio, Rn, and p are defined as above.
In another embodiment of the compound represented by the above formula, Ri, R3 and R25 are each independently -OH, -SH, -NHR7, -OC(O)NRi0R11, -SC(O)NRi0Ri i, -OC(O)R7, -SC(O)R7, -OC(O)OR7, -SC(O)OR7, -OS(O)PR7, -S(O)POR7, -SS(O)pR7, -OS(O)13OR7, -SS(O)POR7, -OC(S)R7, -SC(S)R7, -OC(S)OR7, -SC(S)OR7, -OC(S)NRioRii, -SC(S)NRi0R11, -OC(NR8)R7, -SC(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -OP(O)(OR7)2 or -SP(O)(OR7)2. In another embodiment of the compound represented by the above formula,
Ri and R3 are each, independently, -OH, -SH, or -NHR7. In this case, R6 can be an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR7, -SR7, -NRi0Ri 1, -OC(O)NRi0Rii, -SC(O)NR10R11, -NR7C(O)NRi0Rn, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(0)NRioRi 1, -SCH2C(O)NRi0Rn, -NR7CH2C(O)NRi0RiI, -OS(O)pR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)PNRI0R1 U -SS(O)PNR1ORI I, -NR7S(0)pNRloRn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)pOR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRI0RI 1, -SC(S)NRI0R1 I, -NR7C(S)NRI0R115 -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0R11, -SC(NR8)NR10Rn,
-NR7C(NR8)NRI0RH, -C(O)R7, -C(O)OR7, -C(O)NR,0R,,, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NRi0Ri1, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10Rn, -C(NR8)SR7, -S(O)POR7, -S(O)pNR10Rii, or -S(O)PR7.
In another embodiment of the above compound, Ri is -SH or -OH; R3 and R25 are -OH; R6 is a lower alkyl, C3-C6 cycloalkyl, lower alkoxy, a lower alkyl sulfanyl, or -NRi0Rn; and R9, 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 (I), or any of the embodiments of formula (I) in which particular groups are disclosed, Ri and R3 are each, independently, -OH, -SH, or -NHR7.
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 the following structural formula:
Figure imgf000048_0001
wherein Ri, R3, R5, and R25 are defined as above; and
R6 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR7, -SR7, -NR1ORn,
-OC(O)NR10Rii, -SC(O)NRi0Rn, -NR7C(O)NRi0Rn, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NRi0RiI, -SCH2C(O)NRi0Rn, -NR7CH2C(O)NR10RI I, -OS(O)PR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)pNR10Rn, -SS(0)pNR,oRn, -NR7S(O)pNRi0Rn, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRI0RI i, -SC(S)NR,0Rπ, -NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NRg)NRi0R1I, -SC(NR8)NRI0RH, -NR7C(NR8)NR10Rn, -C(O)R7, -C(O)OR7, -C(O)NRi0Rn, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10Rn, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NRi0R11, -C(NR8)SR7, -S(O)POR7, -S(0)pNRloRπ, or -S(O)PR7, wherein R7, R8, R)O, Ru, and p are defined as above. In a prefered embodiment, R1 is -SH or -OH; R3 and R25 are -OH; R12 is a lower alkyl, lower alkoxy, a lower alkyl sulfanyl, or -NR10R11; and R9, 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 (I), 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:
Figure imgf000049_0001
wherein Ri, R3, R5, R6 and n are as defined above; and
X3 and X4 are each, independently, N, N(O), N+(R17), CH or CR6; and
X5 is O, S, NRn, CH=CH, CH=CR6, CR6=CH, CR6=CR6, CH=N, CR6=N,
CH=N(O), CR6=N(O), N=CH, N=CR6, N(O)=CH, N(O)=CR6, N+(Rn)=CH,
N+(Rn)=CR6, CH=N+(Rn), CR6=N+(Ri7), or N=N; wherein Rn is 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 selected from the group consisting of:
Figure imgf000050_0001
Figure imgf000050_0002
Figure imgf000050_0003
Figure imgf000050_0004
Figure imgf000051_0001
wherein Ri, R3, R5, and R25 are defined as above.
In another aspect, the invention provides compounds of formula (II) as set forth below:
Figure imgf000051_0002
(H) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein ring A, Ri and R3 are defined as above; and
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, -NRioRπ, -O-R20, -C(O)R7, -C(O)OR20, -OC(O)R7, -C(O)NRi0RiI, -NR8C(O)R7, -SR7, -S(O)pR7, -OS(O)PR7, -S(O)pOR7, -NR8S(O)PR7, or -S(O)pNRi0Rn, 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, -NRioRπ, -OR7, -C(O)R7,
-C(O)OR7, -OC(O)R7, -C(O)NRi0Ri i, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)pOR7, -NR8S(O)PR7, or -S(O)pNR,0Rπ; 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; p, for each occurrence, is, independently, 1 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-l-yl)-5-mercapto-triazole, 3-(2,4- dihydroxyphenyl)-4-(2,5-dimethoxyphenyl)-5-mercapto-triazole, 3-(l-phenyl-5- amino-pyrazol-4-yl)-4-(2,4-dichloropheny)-5 -mercapto-triazole, and 3 -(2-hydroxy- phenyl)4-(2,4-dimethylphenyl)-5-mercapto-triazole.
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 the following structural formula:
Figure imgf000052_0001
wherein R|, R2, R3, Rδ, 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 the following structural formula:
Figure imgf000053_0001
wherein Ri, R2, R3, R6, R25 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, Ri and R3 are each, independently, -OH, -SH, or -NHR7.
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 the following structural formula:
Figure imgf000053_0002
wherein Ri, R2, R3, R6 and R25 are defined as above. In a preferred embodiment, Ri is -SH or -OH; R3 and R25 are -OH; Ri2 is a lower alkyl, lower alkoxy, a lower alkyl sulfanyl, or -NRi0Ri ύ and Rg, 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:
Figure imgf000054_0001
wherein R1, R2, R3, R6, X3, X4, X5 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:
Figure imgf000054_0002
Figure imgf000054_0003
Figure imgf000054_0004
;
Figure imgf000055_0001
Figure imgf000055_0002
; wherein Ri, R2, R3, and R25 are defined as above.
In another aspect, the invention provides compounds of formula (III) as set forth below:
Figure imgf000055_0003
(III) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs. In formula (III), ring A, Ri, and R3 are defined as above; and
Ri8 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, -NRi0Ri 1, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)pR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)pR7, or -S(O)pNR10Rn, wherein R7, R8, R10, Rn, and p are defined as above.
Compounds of formula (III) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (III) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
In one embodiment, in formula (III) Ri8 is not cyclohexyl.
In another embodiment, in formula (III) Ri8 is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl.
In another embodiment, in formula (III) Ri8 is a substituted alkyl.
In another embodiment, in compounds represented by formula (III), or any of the embodiments of formula (III) in which particular groups are disclosed, the compound is represented by the following structural formula:
Figure imgf000056_0001
wherein Ri, R3, R6, Ri8, and n are defined as above.
In another embodiment, in compounds represented by formula (III), or any of the embodiments of formula (III) in which particular groups are disclosed, the compound is represented by the following structural formula:
Figure imgf000056_0002
wherein Ri, R3, R6, Ri 8, R25 and r are defined as above.
In another embodiment, in compounds represented by formula (III), or any of the embodiments of formula (III) in which particular groups are disclosed, Ri and R3 are each, independently, -OH, -SH, or -NHR7.
In another embodiment, in compounds represented by formula (III), or any of the embodiments of formula (III) in which particular groups are disclosed, the compound is represented by the following structural formula:
Figure imgf000057_0001
wherein Ri, R3, R6, R18, and R25 are defined as above. In a preferred embodiment, Ri is -SH or -OH; R3 and R25 are -OH; and Ri2 is a lower alkyl, lower alkoxy, a lower alkyl sulfanyl, or -NRi0Ri i-
In another embodiment, in compounds represented by formula (III), or any of the embodiments of formula (III) in which particular groups are disclosed, the compound is represented by one of the following structural formulas:
Figure imgf000057_0002
wherein Ri, R3, R6, Ri8, X3, X4, X5, and n are defined as above.
In another embodiment, in compounds represented by formula (III), or any of the embodiments of formula (III) in which particular groups are disclosed, the compound is selected from the group consisting of:
Figure imgf000058_0001
Figure imgf000058_0002
Figure imgf000058_0003
Figure imgf000058_0004
Figure imgf000059_0001
wherein R1, R3, Rj8, and R25 are defined as above.
In another aspect, the invention provides compounds of formula (IV) or (V) as set forth below:
Figure imgf000059_0002
(IV) (V)
and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. In formulas (IV) and (V), R1 and R3 are as defined above; and X14 is O, S, or NR7;
R21 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;
R22, for each occurrence, is independently an -H or is 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, a haloalkyl, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -S(O)15R7, -S(O)POR7, or -S(0)pNRioRn; and
R23 and R24, for each occurrence, are independently -H or are 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, -NRi0Rn, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NRi0Ri1, -NR8C(O)R7, -SR7, -S(O)pR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)pR7, or -S(O)pNRi0Ru; wherein R7, R8, Ri0, Rn and p are defined as above.
In one embodiment, in formulas (IV) and (V), R2i 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), Rj is -OH, -SH, or -NHR7.
In another embodiment, in the formulas (IV) and (V), R22 is -H, an alkyl, an aralkyl, -C(O)R7, -C(O)OR7, or -C(O)NRi0Rn. In another embodiment, in the formulas (IV) and (V), XH is O.
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 aspect, the invention provides compounds represented by formula (VI):
Figure imgf000061_0001
(VI) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein: X4I is O, S, Or NR42;
X42 is CR44 or N; Y40 is N or CR43; Y41 is N or CR45;
Y42j for each occurrence, is independently N, C or CR46; Z is OH, SH, Or NHR7;
R41 is -H, -OH, -SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, -NRi0R11, -OR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)NR10Rn, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NRi0Rπ, -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(O)R7, -SC(O)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NRi 0Rn, -OC(S)NRi0R1I,
-OC(NR8)NRi0RiI, -SC(O)NRi0R, 1, -SC(NR8)NRI0RU, -SC(S)NRI0RH, -OC(NR8)R75 -SC(NR8)R7, -C(O)NR10R1 1, -NR8C(O)R75 -NR7C(S)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(O)OR7, -NR7C(NR8)OR7, -NR7C(0)NRioRu, -NR7C(S)NRioRii, -NR7C(NR8)NRIORI I, -SR7, -S(O)PR7, -OS(O)pR7, -OS(O)pOR7, -OS(O)pNRi0Rn, -S(O)POR7, -NR8S(O)PR7, -NR7S(O)pNR10Rn, -NR7S(O)POR7, -S(O)pNR10Rπ, -SS(O)pR7, -SS(O)POR7, -SS(O)pNR10Rπ, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R42 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, -C(O)R7, -(CH2)mC(O)OR7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -S(O)PR7, -S(O)POR7, or -S(O)PNR10Rn; R43 and R44 are, independently, -H, -OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)pR7, -S(O)pOR7, -NR8S(O)PR75 -S(O)PNR10R11, or R43 and R44 taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl;
R45 is -H, -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(O)NR10Ri 1, -SC(O)NRi0Rn, -NR7C(O)NRi0Ri 1, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R75 -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NRiORi 1, -SCH2C(O)NRi0Ri 1, -NR7CH2C(O)NR10Rii, -OS(O)PR7, -SS(O)PR7, -NR7S(O)PR7, -OS(O)pNR10Rii, -SS(O)PNR10R11, -NR7S(O)PNR10R1 ,, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10R11, -SC(S)NRi0R11, -NR7C(S)NRi0R1 I, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10Rii, -SC(NR8)NR10Ri 1, or -NR7C(NR8)NRi0Ri,; R46, for each occurrence, is independently selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi0R11, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)pOR7, -NR8S(O)pR7, or -S(O)PNR10R11 ;
R7, R8, Rio, Rn, R26, P, and m are defined as above. In one embodiment, in formula (VI), X41 is NR42 and X42 is CR44.
In another embodiment, in formula (VI), X4I is NR42 and X42 is N.
In another embodiment, in formula (VI), R41 is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy. In another embodiment, in formula (VI), R41 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
In another embodiment, in formula (VI), X41 is NR42, and R42 is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, -C(O)N(R27)2, and -C(O)OH, wherein R27 is -H or a lower alkyl.
In another embodiment, in formula (VI), X41 is NR42, and R42 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n- butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, -C(O)OH, -(CH2)mC(0)0H, -CH2OCH3, -CH2CH2OCH3, and -C(O)N(CH3)2. In one embodiment, Y40 is CR43. Preferably, Y40 is CR43 and R43 is H or a lower alkyl.
In another embodiment, in formula (VI), 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 (VI), X42 is CR44; Y is CR43; and R43 and
R44 together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring. In one aspect of this embodiment, R43 and R44 together with the carbon atoms to which they are attached form a Cs-C8 cycloalkenyl or a C5-C8 aryl.
In another embodiment, in formula (VI), R45 is selected from the group consisting of -H, -OH, -SH, -NH2, a lower alkoxy, a lower alkyl amino, and a lower dialkyl amino.
In another embodiment, in formula (VI), R45 is selected from the group consisting of -H, -OH, methoxy and ethoxy.
In another embodiment, in formula (VI), X4I is O.
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-[l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(benzofuran-5-yl)-5-mercapto- [l,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-l,3-benzoxaz-5-yl)-5- mercapto-[l,2,4]triazole, and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof.
In another embodiment, in formula (VI), Z is -OH. In another embodiment, the compound is selected from the group consisting of:
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l,3-dimethyl-indol-5-yl)-5-hydroxy- [l,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l,3-dimethyl-indol-5-yl)-5- hydroxy-[l,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l-methyl-indol-5-yl)-5-hydroxy- [l,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l-isopropyl-indol-4-yl)-5-hydroxy- [l,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-dmydroxy-5-isopropyl-phenyl)-4-(l-methyl-indazol-5-yl)-5- mercapto-[l ,2,4]triazole, 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l-methyl-indazol-6-yl)-5- mercapto-[l,2,4]triazole, and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof.
Compounds of formula (VI) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (VI) 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 (VII):
(VII) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein:
Figure imgf000065_0002
X42, R41, R42, R43, and R45 are defined as above. In one embodiment, in formula (VII), Zi is -OH. In another embodiment, in formula (VII), Zi is -SH. In another embodiment, in formula (VII), R41 is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
In another embodiment, in formula (VII), R41 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
In another embodiment, in formula (VII), R42 is selected from the group consisting of lower alkyl, lower cycloalkyl, -C(O)N(R27)2, or -C(O)OH, wherein R27 is -H or a lower alkyl. In another embodiment, in formula (VII), R42 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, -C(O)OH, -(CH2)mC(O)OH, -CH2OCH3, -CH2CH2OCH3, and -C(O)N(CH3)2.
In another embodiment, R43 is H or a lower alkyl. In another embodiment, in formula (VII), X42 is CR44, and R43 and R44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
In another embodiment, in formula (VII), X42 is CR44, and R43 and R44, taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring. Preferably, in this embodiment, R43 and R44, taken together with the carbon atoms to which they are attached, form a Cs-C8 cycloalkenyl or a C5-C8 aryl.
In another embodiment, in formula (VII), R45 is selected from the group consisting of -H, -OH, -SH, -NH2, a lower alkoxy, a lower alkyl amino, and a lower dialkyl amino.
In another embodiment, in formula (VII), R45 is selected from the group consisting of -H, -OH, methoxy, and ethoxy.
In another embodiment, in formula (VII), X43 is CR44.
In another embodiment, the compound is selected from the group consisting of:
3-(2,4-dihydroxyphenyl)-4-(l-ethyl-indol-4-yl)-5-mercapto-[l,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-yl)-5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(l-methoxyethyl-indol-4-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-indol-4-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(l-dimethylcarbamoyl-indol-4-yl)-5-mercapto- [l,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-propyl-indol-4-yl)-5-mercapto-
[l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l,2,3-trimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-acetyl-2,3-dimethyl-indol-5-yl)-5- mercapto-[ 1 ,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-7-methoxy-indol-4-yl)-5- mercapto-[l,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-propyl-2,3-dimethyl-indol-5-yl)-5- mercapto-[ 1 ,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-tetrahydrocarbozol-7-yl)-5- mercapto-[l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-cyclononan[a]indol-5-yl)-5- mercapto-[l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-n-butyl-indol-4-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-n-pentyl-indol-4-yl)-5-mercapto- [l,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-n-hexyl-indol-4-yl)-5-mercapto-
[l,2,4]triazole, 3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(l-(l-methylcyclopropyl)-indol- 4-yl)-5-mercapto-[ 1 ,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(l-isopropyl-7-methoxy-indol-4- yl)-5-mercapto-[l ,2,4]triazole, 3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(l,2,3-trimethyl-indol-5-yl)-5- mercapto-[ 1 ,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-7-methoxy-indol-4-yl)-5- mercapto-[l,2,4]triazole disodium salt,
3-(2,4-dihydroxy-5-ter/-butyl-phenyl)-4-(l-isopropyl-7-methoxy-indol-4-yl)- 5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(l-propyl-7-methoxy-indol-4-yl)- 5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-methyl-3-ethyl-indol-5-yl)-5- mercapto-[l,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l,3-dimethyl-indol-5-yl)-5-mercapto-
[l,2,4]triazole, 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l-isopropyl-7-methoxy-indol-4-yl)-
5-mercapto-[l,2,4]triazole,
3 -(2,4-dihydroxy-5 -ethyl-phenyl)-4-( 1 -methyl-3 -isopropy l-indol-5 -y l)-5 - mercapto-[l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-ethyl-carbozol-7-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-7-hydroxy-indol-4-yl)-5- mercapto-[ 1 ,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-7-ethoxy-indol-4-yl)-5- mercapto-[ 1 ,2,4]triazole,
S^^-dihydroxy-S-ethyl-pheny^^-Cl^-dimethyl-indol-S-yO-S-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l,3-dimethyl-indol-5-yl)-5- mercapto-[l,2,4]triazole, 3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(l,3-dimethyl-indol-5-yl)-5- mercapto-[l ,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(l-methyl-indol-5-yl)-5- mercapto-[ 1 ,2,4]triazole, 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(lH-indol-5-yl)-5-mercapto-
[l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l,2-dimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l-ethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l-propyl-indol-5-yl)-5-mercapto- [l,2,4]triazole, and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. In another embodiment, in formula (VII), X42 is N.
In another embodiment, the compound is selected from the group consisting of
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-ethyl-benzimidazol-4-yl)-5-mercapto- [l,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-ethyl-benzimidazol -4-yl)-5- mercapto-[l,2,4]triazole HCL salt,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-3-ethyl-benzimidazol-5-yl)-5- mercapto-[l,2,4]triazole,
3 -(2,4-dihydroxy-5 -ethyl-phenyl)-4-( 1 -ethyl-2-methyl-benzimidazol-5 -yl)-5- mercapto-[l,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l-methyl-2-trifluoromethyl- benzimidazol-5-yl)-5-mercapto-[l,2,4]triazole, and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof. Compounds of formula (VII) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (VII) 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 (VIII):
Figure imgf000070_0001
(VIII) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein: X45 is CR54 or N;
Zi is -OH or -SH;
R52 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, -(CH2)2OCH3, -CH2C(O)OH, and - C(O)N(CH3)2; R53 and R54 are each, independently, -H, methyl, ethyl, or isopropyl; or R53 and R54 taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring;
R55 is selected from the group consisting of -H, -OH, -OCH3, and - OCH2CH3; and R56 is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl.
In one embodiment, in formula (VIII), Zi is -OH.
In another embodiment, in formula (VIII), Zi is -SH.
In another embodiment, in formula (VIII), R53 is H or a lower alkyl. In another embodiment, in formula (VIII), X45 is CR54. Preferably, R54 is H or a lower alkyl.
In another embodiment, X45 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 (VIII) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (VIII) 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
(IX):
Figure imgf000071_0001
(IX) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein,
X44, for each occurrence, is independently, O, NR42 or C(R4O)2; Y43 is NR42 or C(R,6)2;
Y4i, Y42, Z, R41, R42, and R46 are defined as above.
In one embodiment, in formula (IX), R41 is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy. In another embodiment, in formula (IX), R41 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
In another embodiment, in formula (IX), R42 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, terf-butyl, n-pentyl, n-hexyl, -C(O)OH, -(CH2)mC(O)OH, -CH2OCH3, -CH2CH2OCH3, and -C(O)N(CH3)2.
In another embodiment, in formula (IX), Y4i is CR45. Preferably, R4S is H, a lower alkoxy, or -OH. In another embodiment, in formula (IX), Y42 is CH.
In another embodiment, in formula (IX), Y43 is CH2.
In another embodiment, in formula (IX), Y43 is NR42, wherein R42 is H or a lower alkyl.
In another embodiment, in formula (IX), one OfX44 is NR42 and the other is CH2 or C(Rs)2. Preferably, one of X44 is NR42 and the other is CH2
In another embodiment, in formula (VI), Z is -OH.
In another embodiment, Z is -SH.
Compounds of formula (IX) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (IX) 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
(X):
Figure imgf000073_0001
(X) and tautomers, pharmaceutically acceptable salts, solvates, clathrates, and prodrugs thereof, wherein: X41, Y41, Y42, Z, R7, R8, Rio, Rn, R41, R46, and p are defined as above.
In one embodiment, in formula (X), R4] is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
In another embodiment, in formula (X), R41 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
In another embodiment, in formula (X), X41 is NR42. Preferably, R42 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, ter/-butyl, n-pentyl, n-hexyl, -C(O)OH, -(CH2)mC(O)OH, -CH2OCH3, -CH2CH2OCH3, and -C(O)N(CH3)2. More preferably, R42 is H or a lower alkyl.
In another embodiment, in formula (X), X4I is O. In another embodiment, in formula (X), X4I is S.
In another embodiment, in formula (X), Y4] is CR45. Preferably, R45 is H, a lower alkoxy, or -OH. In another embodiment, in formula (X), Y42 is CH.
In another embodiment, in formula (X), R46 is H or a lower alkyl. In one embodiment, the compound is 3-(2,4-dihydroxy-5-isopropyl-phenyl)- 4-(2-methyl-indazol-6-yl)-5-mercapto-[l,2,4]triazole.
Compounds of formula (X) inhibit the activity of Hsp90 and are particularly useful for treating or preventing proliferative disorders, such as cancer. In addition, compounds of formula (X) are particularly useful in treating cancer when given in combination with other anti-cancer agent.
i) Exemplary Compounds of the Invention Exemplary compounds of the invention are depicted in Table 1 below, including tautomers, pharmaceutically acceptable salts, solvates, clathrates, hydrates, polymorphs or prodrugs thereof .
Table 1
Figure imgf000074_0001
■
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
-
-
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
■
Figure imgf000090_0001
-
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
-
-
Figure imgf000094_0001
-
Figure imgf000095_0001
-
Figure imgf000096_0001
-
-
-
-
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
-
Figure imgf000104_0001
Figure imgf000105_0001
-
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
-
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Preferred 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 1 :
Figure imgf000115_0002
Tautomer
^200 ~ R-2> ^5» or ^18
X14 = O, S, orNR7
Similarly, prodrugs, i.e. compounds which can be metabolized or hydro lyzed in vivo to a compound of the present invention are encompassed by the present description. For example, the following embodiments of a compound of the present invention can be produced in vivo in the following reaction:
Figure imgf000116_0001
where R2oo is R2, R5 or Rj8.
One skilled in the art will understand that other hydrolyzable protecting groups can be employed with the compounds of the present invention to obtain prodrugs encompassed by the present description.
Without wishing to be bound by any theory, it is believed that the compounds of the invention preferentially bind to Hsp90 in the tautomeric form shown above, and thereby inhibit the activity of Hsp90. C. Methods for Making Compounds of the Invention Compounds of the invention can be obtained via standard, well-known synthetic methodology, see e.g., March, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992. In particular, compounds of the invention can be obtained by heating a hydrazide (A) with an isocyanate (XH = O), isothiocyanate, (Xi4 = S) or carbodiimide (Xi4 = NR7) (B) in an alcohol to form intermediate (C). Intermediate (C) can be cyclized to form a triazole core (D) by heating it in an aqueous solution which includes about 2 molar equivalents of NaOH (see Scheme I below). Starting materials useful for preparing compounds of the invention and intermediates therefore, are commercially available or can be prepared from commercially available materials using known synthetic methods and reagents. For example, a hydrazide can be prepared by reacting an ester (such as 2,4- dihydroxybenzoic acid methyl ester) or acid chloride with hydrazine. Isocyanates and isothiocyanates (Xi4 is O or S, respectively) can be formed in a number of ways from compounds that have a primary amine group. For example, a primary amine can be reacted with phosgene or thiophosgene to form an isocyanate or an isothiocyanate, respectively. Alternatively, a cyanate or thiocyanate ion can be reacted with an alkyl halide to form an alkyl isocyanate or an alkyl isothiocyanate. In addition, a isothiocyanate can be prepared by reacting a diazonium salt with a thiocyanate ion. Carbodiimides (Xi4 is NR7) can be prepared by dehydration of ureas using a dehydration agent such as tosyl chloride in pyridine, POCI3, PCI5, P2θ5-pyridine, and Ph3PBr2-Et3N. Other methods of preparing isocyanates, thioisocyanates, and carbodiimides can be found in March, J. Advanced Organic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992, the entire teachings of which are incorporated by reference.
Compounds represented by formulas (IV) and (V) can be made in an analoguous fashion as compounds depicted in Scheme I.
Reactive functional groups can be protected during one or more reaction step, then deprotected to restore the original functionality. Examples of suitable protecting groups for hydroxyl groups include benzyl, methoxymethyl, allyl, trimethylsilyl, tert-butyldimethylsilyl, acetate, and the like. Examples of suitable amine protecting groups include benzyloxycarbonyl, tert-butoxycarbonyl, tert-butyl, benzyl and fluorenylmethyloxy-carbonyl (Fmoc). Examples of suitable thiol protecting groups include benzyl, tert-butyl, acetyl, methoxymethyl and the like. Other suitable protecting groups are well known to those of ordinary skill in the art and include those found in T. W. Greene, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.
Scheme I: Synthesis of triazole compounds of the invention
Figure imgf000118_0001
(A) (C)
2 eq. NaOH or R18 NR7
Figure imgf000118_0002
(D)
An alternative method of preparing the compounds of the invention is shown in Scheme II. In this method, an aryl, heteroaryl, cycloalkyl, or alkyl amine compound (i) is stirred at about room temperature with a thiocarbonyl (ii) which has two leaving groups, Li and L2, such as imidazole- 1-yl groups, to form compound (iii). Typically, the thiocarbonyl compound is present in a slight molar excess of about 1.05 eq. to about 1.3 eq. compared with compound (i). Compound (iii) is then combined with a hydrazide compound (iv) in a solvent and heated to about 5O0C to about 1000C for about 0.5 to 5 hrs to form compound (v). Typically, compound (iii) and compound (iv) can be present in about equal molar ratio or a slight excess of compound (iii), such as about 1.01 to about 1.1 molar eq. of compound (iii) compare to compound (iv). Compound (v) can then be cyclized to form a triazole compound of the invention (vi) by suspending it in aqueous solution containing about 2 molar eq. of NaOH and heating the solution to about 750C to about HO0C for about 0.5 hr to about 2 hrs. Typically, the NaOH solution containing compound (v) is degassed before heating by bubbling an inert gas, such as nitrogen or argon, through it.
Scheme II: Alternative synthesis of triazole compounds of the invention
Figure imgf000119_0001
In one embodiment, ring A of the compounds of the invention is a 2,4- dihydroxyphenyl group. In this embodiment, it is sometimes desirable to prepare a prodrug by protecting the 4-hydroxy group with a moiety that can be hydrolyzed in vivo. Protection of the 4-hydroxy group is expected to improve the circulating half- life of compound compounds of the invention. In addition, it is desirable that a group added to the 4-hydroxy group increase the water solubility of the compounds of the invention. In one embodiment, 4-methyl-piperizine-l -carbamoyl group is used to protect the 4-hydroxy group (see Scheme III). In this embodiment, a compound of the invention, such as compound (E), is treated with about one molar equivalents of 4-methyl-piperizine-l -carbonyl chloride (F) in the presence of a base to form compound (G) in which the 4-hydroxy group is protected. Alternatively, the metcapto group can be protected first by reacting compound (E) with about one molar equivalent of acyl chloride in the presence of a base to form intermediate (H). Intermediate (H) can them be reacted with about one molar equivalent of 4-m ethyl- piperizine-1-carbonyl chloride (F) in the presence of a base, then the acetyl group can be removed by treatment with a mild acid to form compound (G).
Scheme III: Preparation of prodrugs in which the 4-hydroxy group of compounds of the invention is protected with 4-methyl-piperizine-l-carbamoyl.
Figure imgf000120_0001
Another prodrug of compounds of the the invention can be formed by addition of a phosphate group to the 4-hydroxy group (Scheme IV). In this embodiment, a compound of the invention, such as compound (E), is treated with about one molar equivalent of diisopropyl phosphoramidous acid di-t-butyl ester in the presence of tetrazole to yield compound (J). The phosphorous group is then oxidized with m-CPBA to form a phosphoric acid di-t-butyl ester group of compound K. The t-butyl groups are then hydrolyzed with trifluoroacetic acid (TFA) to yield a phosphoric acid group or compound L.
Scheme IV: Preparation of prodrugs in which the 4-hydroxy group of compounds of the invention is protected with a phosphate group. 1. (t-BuO)2PNi-Pr2, tetrazole
Figure imgf000121_0001
Figure imgf000121_0002
Figure imgf000121_0003
D. Uses of Compounds of the Invention 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 one aspect, the invention provides a method of inhibiting the activity of Hsp90 in a cell, comprising administering to the cell an effective amount of a compound represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or any embodiment thereof, or a compound shown in Table 1. In one embodiment, the compound is administered to a cell in a subject, preferably a mammal, and more preferably a human.
In another aspect, the invention provides a method of treating or preventing a proliferation disorder in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or any embodiment thereof, or a compound shown in Table 1. In one embodiment, the compound is administered to a human to treat or prevent a proliferative disorder. In another embodiment, the proliferation disorder is cancer. In another embodiment, the compound is administered with one or more additional therapeutic agents. In a preferred embodiment, the additional therapeutic agent is an anticancer agent. In another aspect, the invention provides a method for treating cancer in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X),or any embodiment thereof, or a compound shown in Table 1. In one embodiment, the compound is administered to a human to treat or prevent cancer. In another embodiment, the compound is administered with one or more additional therapeutic agents. In a preferred embodiment, the one or more additional therapeutic agents are anticancer agents.
In another aspect, the invention provides a method for treating a c-kit associated cancer in a mammal, comprising administering to the mammal an effective amount of a compound represented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or any embodiment thereof, or a compound shown in Table 1. In one embodiment, the compound is administered to a human to treat or prevent the c-kit associated cancer. In another embodiment, the compound is administered with one or more additional therapeutic agents. In a preferred embodiment, the one or more additional therapeutic agents are anticancer agents.
1. c-Kit Associated Cancers
SCF binding to the c-kit protects hematopoietic stem and progenitor cells from apoptosis (Lee, et al., 1997, J. Immunol., 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, et al, 1997, Haemat. £2:617-621). However, SCF protected AML cells from apoptosis induced by chemotherapeutic agents (Hassan, et al., 1996, Acta. Hem., 95:251-262). 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, §5:319-327) 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, et al., 1998, Leuk, 72:136-138), which appears to primarily result from inhibition of apoptotic death (Jones, 1997, Curr. Opin. One, 9:3-7). The product of the Philadelphia chromosome, p210.sup.BCR- ABL, has been reported to mediate inhibition of apoptosis (Bedi, et al., 1995, Blood, 56:1148-1158). Since p210.sup.BCR-ABL and the c-kit RTK both inhibit apoptosis and p62.sup.dok has been suggested as a substrate (Carpino, et al., 1997, Cell, 55:197-204), it is possible that clonal expansion mediated by these kinases occurs through a common signaling pathway. However, c-kit has also been reported to interact directly with p210.sup.BCR-ABL (Hallek, et al., 1996, Brit. JHaem., 94:5-16), which suggests that c-kit may have a more causative role in CML pathology. Therefore, degradation of c-kit caused by the inhibition of Hsp90 by the compounds of the invention will prove useful in the treatment of CML. Normal colorectal mucosa does not express c-kit (Bellone, 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, 74:295-302; Lahm, et al, 1995, Cell Growth & Differ., 6:1111-1118; Bellone, et al, 1997, J. Cell Physiol, 772:1-11). 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, (5:1111-1118; Bellone, et al, 1997, /. Cell Physiol, 772:1-11). SCF/c-kit autocrine loops have been observed in gastric carcinoma cell lines
(Turner, et al, 1992, Blood, 50:374-381; 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, 279:511-580). The c-kit expressed in GISTs from several different patients was observed to have mutations in the intracellular juxtamembrane domain leading to constitutive activation (Hirota, et al., 1998, Science 279:577-580). Therefore, degradation of c-kit caused by the inhibition of Hsp90 by the compounds of the invention will be an efficacious means for the treatment of these cancers. Male germ cell tumors have been histologically categorized into seminomas, which retain germ cell characteristics, and nonseminomas which can display characteristics of embryonal differentiation. Both seminomas and nonseminomas are thought to initiate from a preinvasive stage designated carcinoma in situ (CIS) (Murty, 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, 755:337-344). 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, 752:2151-2154). These tumors express both c-kit and SCF, and an autocrine loop may contribute to the tumorigenesis (Kondoh, et al, 1995, Oncogene, 70:341-347) associated with cellular loss of functional p53 and the retinoblastoma gene product by association with E6 and E7 (Dyson, et al, 1989, Science, 243:934-937; Werness, et al, 1990, Science, 248:16-19; Scheffher, et al, 1990, Cell, (53:1129-1136). Defective signaling mutants of SCF (Kondoh, et al, 1995, Oncogene, 70:341-347) or c-kit (Li, et al, 1996, Cane. Res., 5(5:4343-4346) inhibited formation of testicular tumors in mice expressing HPVl 6 E6 and E7. Since c-kit kinase activation is pivotal to tumorigenesis in these animals, the compounds of the invention which inhibit Hsp90 and thereby cause the degradation of c-kit will be useful for preventing or treating testicular tumors associated with human papilloma virus.
Expression of c-kit on germ cell tumors shows that the receptor is expressed by the majority of carcinomas in situ and seminomas, but c-kit is expressed in only a minority of nonseminomas (Strohmeyer, et al, 1991, Cane. Res., 57:181 1-1816; Rajpert-de Meyts, et al, 1994, Int. J. Androl, 77:85-92; Izquierdo, et al, 1995, J. Pathol, 777:253-258; Strohmeyer, et al, 1995, J. Urol, 755:511-515; Bokenmeyer, et al, 1996, J. Came. Res., Clin. Oncol, 722:301-306; Sandlow, et al, 1996, J. Androl, 77:403-408). Therefore, degradation of c-kit caused by the inhibition of Hsp90 by the compounds of the invention will be an efficacious means for the treatment of these cancers.
SCF and c-kit are expressed throughout the central nervous system of developing rodents, and the pattern of expression suggests a role in growth, migration and differentiation of neuroectodermal cells. Expression of SCF and c-kit have also been reported in the adult brain (Hamel, et al., 1997, J. Neuro-Onc, 35:327-333). Expression of c-kit has also been observed in normal human brain tissue (Tada, et al. 1994, J. Neuro., 50: 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, et al, 1992, Cane. Res., 52:3498-3502; Tada, et al, 1994, J. Neuro., 50:1063-1073; Stanulla, et al, 1995, Act. Neuropath., 59:158-165).
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. Cane, 52:197-201), (Tada, et al 1994, J. Neuro., 50:1063-1073), while others report it is not expressed (Kristt, et al, 1993, Neuro., 35:106-115). 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 neuroblastomas, while SCF was found in 18% of tumors (Beck, et al., 1995, Blood, 55:3132-3138). 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, 84:3465-3412). Therefore, degradation of c-kit caused by the inhibition of Hsp90 by the compounds of the invention will be an efficacious means for treating some cancers of the central nervous system.
2. Combination Therapies and Treatment of Refractory Cancers
The invention also provides methods of preventing, treating, managing, or ameliorating a proliferative disorder, such as cancer, or one or more symptoms thereof, said methods comprising administering to a subject in need thereof one or more compounds of the invention and one or more other therapies {e.g., one or more prophylactic or therapeutic agents that are currently being used, have been used, are known to be useful or in development for use in the prevention, treatment or amelioration of a proliferative disorder, such as cancer, or one or more symptoms associated with said proliferative disorder). The prophylactic or therapeutic agents of the combination therapies of the invention can be administered sequentially or concurrently. In a specific embodiment, the combination therapies of the invention comprise one or more compounds and at least one other therapy (e.g., another prophylactic or therapeutic agent) which has the same mechanism of action as said compounds. In another specific embodiment, the combination therapies of the invention comprise one or more compounds of the invention and at least one other therapy (e.g., another prophylactic or therapeutic agent) which has a different mechanism of action than said compounds. In certain embodiments, the combination therapies of the present invention improve the prophylactic or therapeutic effect of one or more compounds of the invention by functioning together with the compounds to have an additive or synergistic effect. In certain embodiments, the combination therapies of the present invention reduce the side effects associated with the therapies (e.g., prophylactic or therapeutic agents). In certain embodiments, the combination therapies of the present invention reduce the effective dosage of one or more of the therapies.
The prophylactic or therapeutic agents of the combination therapies can be administered to a subject, preferably a human subject, in the same pharmaceutical composition. In alternative embodiments, the prophylactic or therapeutic agents of the combination therapies can be administered concurrently to a subject in separate pharmaceutical compositions. The prophylactic or therapeutic agents may be administered to a subject by the same or different routes of administration.
In a specific embodiment, a pharmaceutical composition comprising one or more compounds of the invention is administered to a subject, preferably a human, to prevent, treat, manage, or ameliorate a proliferative disorder, such as cancer, or one or more symptom thereof. In accordance with the invention, pharmaceutical compositions of the invention may also comprise one or more other agents (e.g., prophylactic or therapeutic agents which are currently being used, have been used, or are known to be useful in the prevention, treatment or amelioration of a proliferative disorder or a symptom thereof).
The invention provides methods for preventing, managing, treating or ameliorating a proliferative disorder, such as cancer, or one or more symptoms thereof in a subject refractory (either completely or partially) to existing agent therapies for such a proliferative disorder, said methods comprising administering to said subject a dose of an effective amount of one or more compounds of the invention and a dose of an effective amount of one or more therapies (e.g., one or more prophylactic or therapeutic agents useful for the prevention, treatment, management, or amelioration of a proliferative disorder or a symptom thereof). The invention also provides methods for preventing, treating, managing, or ameliorating a proliferative disorder or a symptom thereof by administering one or more compounds of the invention in combination with any other therapy(ies) to patients who have proven refractory to other therapies but are no longer on these therapies. The compounds of the invention and/or other therapies can be administered to a subject by any route known to one of skill in the art. Examples of routes of administration include, but are not limited to, parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), intranasal, transdermal (topical), transmucosal, and rectal administration.
3. Agents Useful In Combination With the Compounds of the Invention Without wishing to be bound by theory, it is believed that the compounds of the invention can be particularly effective at treating subjects whose cancer has become multi-drug resistant. Although chemotherapeutic agents initially cause tumor regression, most agents that are currently used to treat cancer target only one pathway to tumor progression. Therefore, in many instances, after treatment with one or more chemotherapeutic agents, a tumor develops multidrug resistance and no longer 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.
Anticancer agents that can be co-administered with the compounds of the invention include Taxol™, also referred to as "paclitaxel", is a well-known anti¬ cancer drug which acts by enhancing and stabilizing microtubule formation, and analogs of Taxol™, such as Taxotere™. Compounds that have the basic taxane skeleton as a common structure feature, have also been shown to have the ability to arrest cells in the G2-M phases due to stabilization or inhibition of microtubules.
Other anti-cancer agents that can be employed in combination with the compounds of the invention include Avastin, Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; 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-nl ; interferon alfa-n3; interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; 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; porfϊmer 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-l,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- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; 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; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-poφhyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin
A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin
8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin 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- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, A-; 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 metalloproteinase 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; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; 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; porfϊromycin; 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; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl; 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 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). Examples of anti-cancer agents which act by arresting cells in the G2-M phases due to stabilization or inhibition of microtubules and which can be used in combination with the compounds of the invention include without limitation the following marketed drugs and drugs in development: Erbulozole (also known as R- 55104), Dolastatin 10 (also known as DLS-IO 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-112378 (Aventis), Vincristine sulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM- 97 (Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HC1), AC-7700 (Ajinomoto, also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, 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), HlO (Kansas State University), Hl 6 (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 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- 115781 (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-318315 (Abbott), HTI-286 (also known as SPA- 110, trifluoroacetate salt) ( Wyeth), D-82317 (Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphate sodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411 (Sanofi). E. Compositions and Methods for Administering Therapies
The present invention provides compositions for the treatment, prophylaxis, and amelioration of proliferative disorders, such as cancer. In a specific embodiment, a composition comprises one or more compounds of the invention, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or prodrug thereof. In another embodiment, a composition of the invention comprises one or more prophylactic or therapeutic agents other than a compound of the invention, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, prodrug thereof. In another embodiment, a composition of the invention comprises one or more compounds of the invention, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or prodrug thereof, and one or more other prophylactic or therapeutic agents. In another embodiment, the composition comprises a compound of the invention, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
In a preferred embodiment, a composition of the invention is a pharmaceutical composition or a single unit dosage form. Pharmaceutical compositions and dosage forms of the invention comprise one or more active ingredients in relative amounts and formulated in such a way that a given pharmaceutical composition or dosage form can be used to treat or prevent proliferative disorders, such as cancer. Preferred pharmaceutical compositions and dosage forms comprise a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1, 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 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)ZNF (XVI). In general, lactose-free compositions comprise active ingredients, a binderZfiller, 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 andZor humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations.
Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are preferably anhydrous if substantial contact with moisture andZor humidity during manufacturing, packaging, andZor storage is expected. An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are preferably packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
The invention further encompasses pharmaceutical compositions and dosage forms that comprise one or more compounds that reduce the rate by which an active ingredient will decompose. Such compounds, which are referred to herein as "stabilizer" include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.
1) Oral Dosage Forms
Pharmaceutical compositions of the invention that are suitable for oral administration can be presented as discrete dosage forms, such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of active ingredients, and may be prepared by methods of pharmacy well known to those skilled in the art. See generally, Remington's Pharmaceutical Sciences (1990) 18th ed., Mack Publishing, Easton PA. Typical oral dosage forms of the invention are prepared by combining the active ingredient(s) in an admixture with at least one excipient according to conventional pharmaceutical compounding techniques. Excipients can take a wide variety of forms depending on the form of preparation desired for administration. For example, excipients suitable for use in oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for use in solid oral dosage forms (e.g., powders, tablets, capsules, and caplets) include, but are not limited to, starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid excipients are employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such dosage forms can be prepared by any of the methods of pharmacy. In general, pharmaceutical compositions and dosage forms are prepared by uniformly and intimately admixing the active ingredients with liquid carriers, finely divided solid carriers, or both, and then shaping the product into the desired presentation if necessary.
For example, a tablet can be prepared by compression or molding. Compressed tablets can be prepared by compressing in a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with an excipient. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
Examples of excipients that can be used in oral dosage forms of the invention include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.
Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. One specific binder is a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or low moisture excipients or additives include AVICEL-PH- 103 J and Starch 1500 LM.
Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof. The binder or filler in pharmaceutical compositions of the invention is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
Disintegrants are used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms of the invention. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, preferably from about 1 to about 5 weight percent of disintegrant.
Disintegrants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
Lubricants that can be used in pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a syloid silica gel
(AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, TX), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If used at all, lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
2) Controlled Release Dosage Forms Active ingredients of the invention can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or control led-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release.
All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled- release formulations include extended activity of the drug, reduced dosage frequency, and increased patient compliance.
Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds. A particular extended release formulation of this invention comprises a therapeutically or prophylactically effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, or prodrug thereof, in spheroids which further comprise microcrystalline cellulose and, optionally, hydroxypropylmethyl- cellulose coated with a mixture of ethyl cellulose and hydroxypropylmethylcellulose. Such extended release formulations can be prepared according to U.S. Patent No. 6,274,171, the entirely of which is incorporated herein by reference. A specific controlled-release formulation of this invention comprises from about 6% to about 40% a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, clathrate, or prodrug thereof, by weight, about 50% to about 94% microcrystalline cellulose, NF, by weight, and optionally from about 0.25% to about 1% by weight of hydroxypropyl-methylcellulose, USP, wherein the spheroids are coated with a film coating composition comprised of ethyl cellulose and hydroxypropylmethylcellulose.
3) Parenteral Dosage Forms
Parenteral dosage forms can be administered to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions.
Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and
Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl 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.
4) Transdermal, Topical, and Mucosal Dosage Forms
Transdermal, topical, and mucosal dosage forms of the invention include, but are not limited to, ophthalmic solutions, sprays, aerosols, creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences (1980 & 1990) 16th and 18th eds., Mack Publishing, Easton PA and Introduction to Pharmaceutical Dosage Forms (1985) 4th ed., Lea & Febiger, Philadelphia. Dosage forms suitable for treating mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels. Further, transdermal dosage forms include "reservoir type" or "matrix type" patches, which can be applied to the skin and worn for a specific period of time to permit the penetration of a desired amount of active ingredients.
Suitable excipients (e.g., carriers and diluents) and other materials that can be used to provide transdermal, topical, and mucosal dosage forms encompassed by this invention are well known to those skilled in the pharmaceutical arts, and depend on the particular tissue to which a given pharmaceutical composition or dosage form will be applied. With that fact in mind, typical excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butane- 1,3- diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form lotions, tinctures, creams, emulsions, gels or ointments, which are non-toxic and pharmaceutically acceptable. Moisturizers or humectants can also be added to pharmaceutical compositions and dosage forms if desired. Examples of such additional ingredients are well known in the art. See, e.g., Remington's Pharmaceutical Sciences (1980 & 1990) 16th and 18th eds., Mack Publishing, Easton PA. Depending on the specific tissue to be treated, additional components may be used prior to, in conjunction with, or subsequent to treatment with active ingredients of the invention. For example, penetration enhancers can be used to assist in delivering the active ingredients to the tissue. Suitable penetration enhancers include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).
The pH of a pharmaceutical composition or dosage form, or of the tissue to which the pharmaceutical composition or dosage form is applied, may also be adjusted to improve delivery of one or more active ingredients. Similarly, the polarity of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery. Compounds such as stearates can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients so as to improve delivery. In this regard, stearates can serve as a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a delivery-enhancing or penetration-enhancing agent. Different salts, hydrates or solvates of the active ingredients can be used to further adjust the properties of the resulting composition.
5) Dosage & Frequency of Administration
The amount of the compound or composition of the invention which will be effective in the prevention, treatment, management, or amelioration of a proliferative disorders, such as cancer, or one or more symptoms thereof, will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The frequency and dosage will also vary according to factors specific for each patient depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body, weight, response, and the past medical history of the patient. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. Suitable regiments can be selected by one skilled in the art by considering such factors and by following, for example, dosages reported in the literature and recommended in the Physician 's Desk Reference (57th ed., 2003). Exemplary doses of a small molecule include milligram or microgram amounts of the small molecule per kilogram of subject or sample weight (e.g., about 1 microgram per kilogram to about 500 milligrams per kilogram, about 100 micrograms per kilogram to about 5 milligrams per kilogram, or about 1 microgram per kilogram to about 50 micrograms per kilogram). In general, the recommended daily dose range of a compound of the invention for the conditions described herein lie within the range of from about 0.01 mg to about 1000 mg per day, given as a single once-a-day dose preferably as divided doses throughout a day. In one embodiment, the daily dose is administered twice daily in equally divided doses. Specifically, a daily dose range should be from about 5 mg to about 500 mg per day, more specifically, between about 10 mg and about 200 mg per day. In managing the patient, the therapy should be initiated at a lower dose, perhaps about 1 mg to about 25 mg, and increased if necessary up to about 200 mg to about 1000 mg per day as either a single dose or divided doses, depending on the patient's global response. It may be necessary to use dosages of the active ingredient outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response.
Different therapeutically effective amounts may be applicable for different proliferative disorders, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat or ameliorate such proliferative disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the compounds of the invention are also encompassed by the above described dosage amounts and dose frequency schedules. Further, when a patient is administered multiple dosages of a compound of the invention, not all of the dosages need be the same. For example, the dosage administered to the patient may be increased to improve the prophylactic or therapeutic effect of the compound or it may be decreased to reduce one or more side effects that a particular patient is experiencing.
In a specific embodiment, the dosage of the composition of the invention or a compound of the invention administered to prevent, treat, manage, or ameliorate a proliferative disorders, such as cancer, or one or more symptoms thereof in a patient is 150 μg/kg, preferably 250 μg/kg, 500 μg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, or 200 mg/kg or more of a patient's body weight. In another embodiment, the dosage of the composition of the invention or a compound of the invention administered to prevent, treat, manage, or ameliorate a proliferative disorders, such as cancer, or one or more symptoms thereof in a patient is a unit dose of 0.1 mg to 20 mg, 0.1 mg to 15 mg, 0.1 mg to 12 mg, 0.1 mg to 10 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mg to 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg, 0.25 to 10 mg, 0.25 to 8 mg, 0.25 mg to 7m g, 0.25 mg to 5 mg, 0.5 mg to 2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mg to 8 mg, 1 mg to 7 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.
The dosages of prophylactic or therapeutic agents other than compounds of the invention, which have been or are currently being used to prevent, treat, manage, or proliferative disorders, such as cancer, or one or more symptoms thereof can be used in the combination therapies of the invention. Preferably, dosages lower than those which have been or are currently being used to prevent, treat, manage, or ameliorate a proliferative disorders, or one or more symptoms thereof, are used in the combination therapies of the invention. The recommended dosages of agents currently used for the prevention, treatment, management, or amelioration of a proliferative disorders, such as cancer, or one or more symptoms thereof, can obtained from any reference in the art including, but not limited to, Hardman et al, eds., 1996, Goodman & Gilman's The Pharmacological Basis Of Basis Of Therapeutics 9th Ed, Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57th Ed., 2003, Medical Economics Co., Inc., Montvale, NJ, which are incorporated herein by reference in its entirety.
In certain embodiments, when the compounds of the invention are administered in combination with another therapy, the therapies (e.g., prophylactic or therapeutic agents) are administered less than 5 minutes apart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours apart, at about 3 hours to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5 hours to about 6 hours apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8 hours apart, at about 8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at about 10 hours to about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours part. In one embodiment, two or more therapies (e.g., prophylactic or therapeutic agents) are administered within the same patent visit.
In certain embodiments, one or more compounds of the invention and one or more other the therapies {e.g., prophylactic or therapeutic agents) are cyclically administered. Cycling therapy involves the administration of a first therapy (e.g., a first prophylactic or therapeutic agents) for a period of time, followed by the administration of a second therapy (e.g., a second prophylactic or therapeutic agents) for a period of time, followed by the administration of a third therapy (e.g., a third prophylactic or therapeutic agents) for a period of time and so forth, and repeating this sequential administration, i.e., the cycle in order to reduce the development of resistance to one of the agents, to avoid or reduce the side effects of one of the agents, and/or to improve the efficacy of the treatment.
In certain embodiments, administration of the same compound of the invention may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In other embodiments, administration of the same prophylactic or therapeutic agent may be repeated and the administration may be separated by at least at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months. In a specific embodiment, the invention provides a method of preventing, treating, managing, or ameliorating a proliferative disorders, such as cancer, or one or more symptoms thereof, said methods comprising administering to a subject in need thereof a dose of at least 150 μg/kg, preferably at least 250 μg/kg, at least 500 μg/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at least 200 mg/kg or more of one or more compounds of the invention once every day, preferably, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every 8 days, once every 10 days, once every two weeks, once every three weeks, or once a month.
F. Other Embodiments
The compounds of the invention may be used as research tools (for example, to evaluate the mechanism of action of new drug agents, to isolate new drug discovery targets using affinity chromatography, as antigens in an ELISA or ELISA- like assay, or as standards in in vitro or in vivo assays). These and other uses and embodiments of the compounds and compositions of this invention will be apparent to those of ordinary skill in the art.
The invention is further defined by reference to the following examples describing in detail the preparation of compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the purpose and interest of this invention. The following examples are set forth to assist in understanding the invention and should not be construed as specifically limiting the invention described and claimed herein. Such variations of the invention, including the substitution of all equivalents now known or later developed, which would be within the purview of those skilled in the art, and changes in formulation or minor changes in experimental design, are to be considered to fall within the scope of the invention incorporated herein.
EXAMPLES Reagents and solvents used below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). 1H-NMR and 13C- NMR spectra were recorded on a Varian 300MHz NMR spectrometer. Significant peaks are tabulated in the order: δ (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
Figure imgf000150_0001
2 eq NaOH
Figure imgf000150_0002
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 1100C for 2 hours. The solution was allowed to cool to room temperature then acidified with cone. 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%).
1H NMR (DMSOd6) δ 9.43-9.53 (bs, 2H),8.11-8.16 (m, IH), 7.47-7.55 (m, 2H), 7.38 (d, J=8.1 Hz, IH), 7.31-7.36 (m, IH), 6.98 (d, J=8.1 Hz, IH), 6.71 (s, IH), 6.17 (s, IH), 3.98 (s, 3H), 2.17 (q, J=7.5 Hz, 2H), 0.73 (t, J=7.5 Hz, 3H); ESMS calculated for (C2IHi9N3O3S) 393.11; Found 394.1(M+1)+.
Example 2: Synthesis of Compound 124
3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole (505 mg, 1.5 mmol), which is commercially available from Scientific Exchange, Inc., Center Ossipee, NH 03814, and Et3N (0.84ml, 6.0 mmol) in 15ml CH2Cl2 were treated dropwise with ethyl isocyanate (360mg, 5.0 mmol) at O0C. The mixture was then warmed to room temperature and stirred for 3h. The reaction mixture was diluted with CH2Cl2, washed with H2O and saturated brine, dried with Na2SO4, and concentrated in vacuo. The residue was chromatographed (Hexane/ EtOAc 3: 1) to give Compound 124 as a white solid (480 mg, 58%).
1H-NMR (CDCl3) δ 10.13 (s, IH), 7.96 (d, J=9.0 Hz, 2H), 7.61-7.57 (m, 3H), 7.49-7.36(m, 2H), 7.01(s, IH), 6.88 (d, J=8.4Hz, IH), 6.70 (d, J=8.4Hz, IH), 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=15.0 Hz, J=7.2Hz, 6H);
ESMS calculated for C27H28N6O5S: 548.18; Found: 549.1 (M+l)+.
Example 3: Synthesis of Compound 188
Figure imgf000152_0001
NaOH/MeOH
Figure imgf000152_0002
1-Benzenesulfonyl- 7-methoxy-lH-indole (Q)
To a solution of 7-methoxyindole (1 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.
1-Benzenesulfonyl- 7-nιethoxy-4-nitro-lH-indole (R)
To a solution of l-benzenesulfonyl-7-methoxy-lH-indole (Q) (leq) in dichloromethane cooled in an ice bath was added SiO2-HNO3 (2 wt eq) in small portions. The reaction was stirred for 1 hr at room temperature. Activated carbon (2 wt eq) was added then the entire mixture was stirred for 1 hr. The mixture was then filtered and evaporated to dryness. Separation of the isomers was achieved by column chromatography.
7-Methoxy-4-nitro-lH-indole (S)
To a solution of l-benzenesulfonyl-7-methoxy-4-nitro-lH-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-lH-indole (T) To a solution of 7-methoxy-4-nitro-lH-indole (S) (1 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. 2-Iodopropane (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-lH-indol-4-ylamine (U) A solution of l-isopropyl-7-methoxy-4-nitro-lH-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 1 hr. The reaction was then filtered through Celite and evaporated to dryness to produce the desired product.
l-Isopropyl-4-isothiocyanato- 7-methoxy-lH-indole (V) To a solution of l-isopropyl-7-methoxy-lH-indol-4-ylamine (U) (leq) in dichloromethane was added l,l'-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.
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-7-methoxy-indol-4-yl)-5- mercapto-[l,2,4] triazole (Compound 188)
5-Ethyl-2,4-dihydroxy-benzoic acid hydrazide (W) (leq) and l-isopropyl-4- isothiocyanato-7-methoxy-lH-indole (V) (1.01 eq) were heated in ethanol (0.02 M based on isothiocyante) at 8O0C 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 11O0C for 1 hr under a nitrogen atmosphere then allowed to cool to room temperature.
Neutralisation with cone. HCl 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%)
1H-NMR (DMSO-de) δ (ppm), 9.52 (s, IH), 9.42 (s, IH), 7.40 (d, J=3.3Hz,
IH), 6.82 (d, J=8.4Hz, IH), 6.61 (s, IH), 6.20 (s, IH), 6.05 (d, j=3.3 Hz, IH), 5.30 (qn, J=6.6Hz, IH), 3.89 (s, 3H), 2.14 (q, J=7.5Hz, 2H), 1.41-1.47 (m, 6H), 0.68 (t, J=7.5Hz, 3H); ESMS CALCULATED. FOR C22H24N4O3S: 424.16; FOUND: 425.1 (M+l)+.
Example 4: Synthesis of Compound 223
Figure imgf000155_0001
Compound 223
2,4-Dimethoxy-5-isopropylbenzoic acid (2.24 g, 10.0 mmol, 1.00 equiv.) in 50 mL CH2Cl2 at room temperature was treated with (COCl)2 (1.40 g, 11.0 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 CH2Cl2, and treated with l,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 O0C 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%).
1H NMR (CDCl3) δ (ppm) 9.78 (br s, IH), 8.21 (s, IH), 8.09 (d, J= 2.1 Hz, IH), 7.31 (dd, J= 8.7 Hz, 2.1 Hz, IH), 7.22 (d, J= 8.7 Hz, IH), 6.82 (s, IH), 6.50 (s, IH), 4.09 (s, 3H), 3.92 (s, 3H), 3.73 (s, 3H), 3.26 (hept, J= 6.9 Hz, IH), 2.32 (s, 3H), 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 11O0C 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 8O0C for 30 minutes. The reaction mixture was extracted with ethyl acetate and water to remove excess hydrazine. The organic layer was dried over MgSO4, 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 (650C) 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-(l,3-dimethyl-indol-5-yl)-5-hydroxy-[l,2,4] triazole as light brown solid (2.20 g, 5.42 mmol, 87%).
1H NMR (CDCl3), δ (ppm) 9.63 (br s, IH), 7.34 (d, J= 2.1 Hz, IH), 7.20 (s, IH), 7.18 (d, J= 8.4 Hz, IH), 7.00 (dd, J= 8.4 Hz, 2.1 Hz, IH), 6.80 (s, IH), 6.19 (s, IH), 3.76 (s, 3H), 3.69 (s, 3H), 3.40 (s, 3H), 3.15 (hept, J= 6.9 Hz, IH), 2.20 (s, 3H), 1.10 (d, J= 6.9 Hz, 6H).
3-(2,4-methoxy-5-isopropyl-phenyl)-4-(l,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.), NaI (0.812 g, 5.42 mmol, 1.0 equiv.) and 0.5 mL water at 2050C under nitrogen protection for 1 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 HCl to PH around 5, and extracted with 3 x 100 mL EtOAc. The combined EtOAc layer was diluted with 50 mL THF, dried over MgSO4, 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-(l,3-dimethyl-indol-5- yl)-5-hydroxy-[l,2,4] triazole (Compound 223) was obtained as an off-white solid (1.75g, 4.63mmol, 85%). 1H NMR (CD3OD), δ (ppm) 7.46 (d, J= 1.8 Hz, IH), 7.41 (d, J= 8.4 Hz, IH), 7.04 (dd, J= 8.4 Hz, 1.8 Hz, IH), 7.02 (s, IH), 6.53 (s, IH), 6.26 (s, IH), 3.74 (s, 3H), 2.88 (sept, J= 6.9 Hz, IH), 2.24 (s, 3H), 0.62 (d, J= 6.9 Hz, 6H);
ESMS calculated, for C2iH23N4O3: 378.1; Found: 379.1 (M + I)+.
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 1 through 4.
Example 5: Compound 1
ESMS calcd for Ci8Hi3N3OS: 319.1; Found: 320.0 (M+l)+.
Example 6: Compound 2
ESMS calcd for C2]H19N3O4S: 409.11; Found: 410.0 (M+H)+.
Example 7: Compound 5 ESMS calcd for C19H15N3O2S: 365.08; Found: 266.0 (M+H)+.
Example 8: Compound 6
ESMS calcd for C20H17N3O2S: 379.10; Found: 380.0 (M+H)+.
Example 9; Compound 7
ESMS calcd for C21H19N3O2S: 393.11; Found: 394.0 (M+H)+.
Example 10: Compound 8
ESMS calcd for C21Hi9N3O3S: 393.11; Found: 394.0(M+H)+.
Example 11: Compound 9
ESMS calcd for C21H19N3O2S: 393.11; Found: 394.0 (M+H)+. NOT FURNISHED UPON FILING
ESMS calcd for C15Hi3N3O3S: 315.07; Found: 316.0 (M+H)+.
Example 21: Compound 22
ESMS calcd for C15Hi3N3O3S: 315.07; Found: 316.0 (M+H)+.
Example 22: Compound 23
ESMS calcd for Ci4H10FN3O2S: 303.05; Found: 304.0 (M+H)+.
Example 23: Compound 23 1H NMR (DMSO-d6) δ 9.69 (s, IH), 9.65 (s, IH), 7.16 (d, J=7.2Hz, IH),
7.05 (t, J=7.2Hz, IH), 6.93 (d, J=8.1Hz, 2H), 6.11-6.16 (m, 2H), 2.21 (s, 3H), 1.89 (s, 3H);
ESMS Calcd C16Hi5N3O2S: 313.09, Found 314.1(M+1)+.
Example 24: Compound 24
ESMS calcd for Ci6Hi5N3O2S: 313.09; Found: 314.0 (M+H)+.
Example 25: Compound 25
1H NMR (DMSO-d6) δ 10.44 (m, IH), 8.00-7.95 (m, 2H), 7.55-7.37 (m, 5H), 6.61 (d, J= 7.8 and 1.8 Hz, IH), 6.51 (t, J= 8.6 Hz, IH), 6.41(d, J= 10.8 Hz, IH); ESMS calcd for Ci8H12FN3OS: 337.07; Found: 338.0 (M+l)+.
Example 26: Compound 26
1H NMR (DMSO-d6) δ 9.57 (s, IH), 7.99 (d, J= 8.4 Hz, IH), 7.96 (d, J= 6.9 Hz, IH), 7.55-7.37 (m, 5H), 6.61 (d, J= 8.1 Hz, IH), 5.83 (d, J= 2.1 Hz, IH), 5.73(dd, J= 8.1 and 1.8 Hz, IH), 5.24 (s, 2H);
ESMS calcd for Ci8Hi4N4OS: 334.09; Found: 335.0 (M+l)+.
Example 27: Compound 27 ESMS calcd for Ci8Hi9N3O2S: 341.12; Found: 342.0 (M+H)+.
Example 28: Compound 28 ESMS calcd for C6H15N3O2S: 313.09; Found: 314.0 (M+H)+.
Example 29: Compound 29
ESMS calcd for C16Hi5N3O2S: 313.09; Found: 314.0 (M+H)+.
Example 30: Compound 30
ESMS calcd for C16H15N3O2S: 313.09; Found: 314.0 (M+H)+.
Example 31: Compound 31 ESMS calcd for Ci4H10FN3O2S: 303.05; Found: 304.0 (M+H)+.
Example 32: Compound 32
ESMS calcd for Ci5Hi3N3O2S: 331.04; Found: 332.0 (M+H)+.
Example 33: Compound 33
ESMS calcd for Ci8Hi3N3O2S: 335.07; Found: 336.0 (M+H)+.
Example 34: Compound 34
ESMS calcd for Ci6Hi5N3O2S: 313.09; Found: 314.0 (M+H)+.
Example 35: Compound 35
ESMS calcd for Ci5Hi2FN3O2S: 317.06; Found: 317.0 (M+H)+.
Example 36: Compound 36 ESMS calcd for C20H15N3O2S: 361.1; Found: 362.0 (M+l)+.
Example 37: Compound 37
1H NMR (DMSO-d6) δ 10.03 (s, IH), 8.00-7.96 (m, 2H), 7.55-7.37 (m, 5H), 7.00 (d, J= 8.1 Hz, IH), 6.20 (m, 2H), 3.57 (s, 3H); ESMS calcd for Ci9Hi5N3O2S: 349.09; Found: 350.0 (M+l)+. Example 38; Compound 38
ESMS calcd for Ci4H9Cl2N3O2S: 352.98; Found: 353.9 (M+H)+.
Example 39: Compound 39 1H NMR (DMSO-de) δ 9.74 (s, IH), 9.63 (s, IH), 8.14 (m, IH), 7.52-7.48
(m, 2H), 7.37 (d, J= 8.4 Hz, IH), 7.32 (m, IH), 6.96 (d, = 8.1 Hz, IH), 6.90 (d, = 8.4 Hz, IH), 6.08 (d, = 1.9 Hz, IH), 6.01 (d, = 8.4 Hz, IH), 3.98 (s, 3H); ESMS calcd for C19H15N3O3S: 365.08; Found: 366.0 (M+l)+.
Example 40: Compound 40
ESMS calcd for C25Hj6N3O2S: 409.09; Found: 410.0 (M+l)+.
Example 41: Compound 42
1H NMR (DMSO-de) δ 9.75(s, IH), 9.67(s, IH), 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, IH), 1.64-1.60(m, 4H); ESMS calcd for Ci8 H17N3O2S: 339.10; Found: 340.0 (M+l)+.
Example 42: Compound 43
ESMS calcd for C22Hi5N3O2S: 385.09; Found: 386.0 (M+l)+.
Example 43: Compound 44
ESMS calcd for C20Hi5N3O2S: 361.09; Found: 362.0 (M+l)+.
Example 44: Compound 45 ESMS calcd for Ci9Hj5N3O2S: 349.09; Found: 350.0 (M+l)+.
Example 45: Compound 46
ESMS calcd for Cj9H21N3O3S: 371.13; Found: 372.0 (M+l)+.
Example 46: Compound 47
ESMS calcd for C22H27N3O3S: 413.18; Found: 414.1 (M+l)+. Example 47: Compound 48
ESMS calcd for Ci8Hi2ClN3O2S: 369.03; Found: 370.0 (M+H)+.
Example 48: Compound 49 1H NMR (DMSOd6) δ 9.49 (s, IH), 9.40 (s, IH), 7.94-7.99 (m, 2H), 7.38-
7.56 (m, 5H), 6.70 (s, IH), 6.13 (s, IH), 2.12 (q, J=7.2 Hz, 2H), 0.71 (t, J=7.2Hz, 3H);
ESMS Calcd for C20HnN3O2S: 363.10, Found 364.1(M+1)+.
Example 49: Compound 50
ESMS calcd for C20H]5N3O5S: 409.07; Found: 410.0 (M+H)+.
Example 50: Compound 51
ESMS calcd for Ci8H]4N4O2S: 350.08; Found: 351.0 (M+H)+.
Example 51: Compound 52
ESMS calcd for C]7H]2N4OS: 320.07; Found: 320.9 (M+H)+.
Example 52: Compound 53 1H NMR (CDCl3) δ 12.0 (br s, IH), 9.87 (br s, IH), 9.83 (br s, IH), 7.97 (d, J
= 8.1 Hz, 2H), 7.41-7.56 (m, 5H), 7.13 (d, J= 1.5 Hz, IH), 7.07 (d, J= 8.7 Hz, IH), 6.71 (dd, J= 1.8 Hz, 8.1 Hz, IH), 1.93 (s, 3H);
ESMS calcd for C20H]7N4O2S: 376.1; Found: 377.0(M+l)+.
Example 53: Compound 56
ESMS calcd for C16H]5N3O4S: 345.08; Found: 346.0 (M+l)+.
Example 54: Compound 57
ESMS calcd for Ci8H16N4O2S: 352.10; Found: 353.0 (M+l)+.
Example 55: Compound 61 1H NMR (DMSO-U6) δ 9.66(s, IH), 9.60(s, IH), 7.29-7.27(m, IH), 7.12-7- 10(m, 2H), 7.03-7.00(m, IH), 6.19-6.17(m, 2H), 1.18(s, 18H);
ESMS calcd for C22H27N3O2S: 397.18; Found: 398.1 (M+l)+.
Example 56: Compound 64
ESMS calcd for C21H]5N3O3S: 389.08; Found: 390.0 (M+H)+.
Example 57: Compound 65
ESMS calcd for C19H13N3O4S: 379.06; Found: 380.0 (M+l)+.
Example 58: Compound 66
ESMS calcd for C2]Hi8N4O3S: 406.11; Found: 407.0 (M+l)+.
Example 59: Compound 67 ESMS calcd for C2]H19N3O3S: 393.11; Found: 394.0 (M+l)+.
Example 60: Compound 68
ESMS calcd for C21H]9N3O3S: 393.11; Found: 394.0 (M+l)+.
Example 61: Compound 69
ESMS calcd for C21H19N3O3S: 393.11; Found: 394.0 (M+l)+.
Example 62: Compound 70
ESMS calcd for C17H12N4O2S: 336.07; Found: 337.0 (M+H)+.
Example 63: Compound 71
ESMS calcd for C21H19N3O3S: 393.11; Found: 394.0 (M+l)+.
Example 64: Compound 72 1H NMR (DMSO-d6) δ 10.3 (br s, IH), 7.95-8.19 (m, 2H), 7.48-7.72 (m,
5H), 7.17 (d, J= 8.4 Hz, IH), 6.44 (d, J= 8.4 Hz, IH), 5.95 (d, J= 2.1 Hz, IH), 5.73 (dd, J= 2.1 Hz, 8.4 Hz, IH), 5.47 (br s, IH), 3.62 (s, 3H); ESMS calcd for C19HnN4O2S2: 412.1; Found: 413.0(M+l)+.
Example 65: Compound 73
1H NMR (DMSOd6) δ 9.37 (s, IH), 8.94 (s, IH), 7.94-7.98 (m, 2H), 7.43- 7.60 (m, 5H), 5.97 (s, IH), 1.85 (s, 3H), 1.81 (s, 3H);
ESMS calcd for C20H18N3O2S: 363.1; Found: 364.0(M+l)+.
Example 66: Compound 74
ESMS calcd for C21H)9N3O4S: 409.11; Found: 410.0 (M+H)+.
Example 67: Compound 75
1H NMR (DMSO-d6) δ 9.46 (s, IH), 9.45 (s, IH), 7.95-8.00 (m, 2H), 7.38- 7.56 (m, 5H), 6.65 (s, IH), 6.15 (s, IH), 2.07-2.14 (m, 2H), 081-1.18 (m, HH);
ESMS calcd for C24H26N3O2S: 419.1; Found: 420.1(M+l)+.
Example 68: Compound 76
ESMS calcd for C21Hi9N3O3S: 393.11; Found: 394.0 (M+H)+.
Example 69: Compound 77 ESMS calcd for C2iHi9N3O3S: 393.11; Found: 394.0 (M+H)+.
Example 70: Compound 78
1H NMR (DMSOKI6) δ 9.71 (s, IH), 9.35 (s, IH), 7.98-8.04 (m, 2H), 7.50- 7.62 (m, 5H), 6.58 (s, IH), 2.15 (q, J= 7.5 Hz, 2H), 0.58 (t, J= 7.5 Hz, 3H); ESMS calcd for C20Hi7ClN3O2S: 397.0; Found: 398.0(M+l)+.
Example 71: Compound 79
ESMS calcd for Ci9H2iN3O3S: 371.13; Found: 372.0 (M+H)+.
Example 72: Compound 80
ESMS calcd for C2iH19N3O2S: 393.11; Found: 394.0 (M+H)+. Example 73; Compound 81
ESMS calcd for C20Hi7N3O2S: 379.10; Found: 380.0 (M+H)+.
Example 74; Compound 82 ESMS calcd for C2IHj9N3O2S: 393.11; Found: 394.0 (M+H)+.
Example 75: Compound 83
ESMS calcd for C20Hi7N3O3S: 379.10; Found: 380.0 (M+H)+.
Example 76; Compound 84
ESMS calcd for C20HnN3O3S: 379.10; Found: 380.0 (M+H)+.
Example 77; Compound 85
ESMS calcd for Ci9H15N3O2S: 365.08; Found: 266.0 (M+H)+.
Example 78: Compound 86
1H NMR (DMSO-d6) δ 9.68 (s, IH), 9.58 (s, IH), 8.2 (dd, J= 7.0 and 2.4 Hz, IH), 7.50 (m, 2H), 7.40 (tr, J= 8.1 Hz, IH), 7.32 (m, IH), 6.97 (d, J= 7.5 Hz, IH), 6.95 (m, IH), 6.89 (d, = 8.4 Hz, IH), 6.08 (d, = 2.1 Hz, IH), 6.0 (dd, = 7.4 and 2.1 Hz, IH), 3.96 (s, 3H);
ESMS calcd for Ci9Hi5N3O3S: 365.08; Found: 366.0 (M+l)+.
Example 79: Compound 87
1H NMR (MeOH-d4) δ 8.25 (m, IH), 7.96 (s, IH), 7.46-7.44 (m, 2H), 7.26 (d, J= 8.4 Hz, IH), 6.83 (d, J= 8.1 Hz, IH), 6.70 (d, J= 8.7 Hz, IH), 6.17 (d, J= 2.1 Hz, IH), 5.98 (dd, J= 8.4 and 2.4 Hz, IH);
ESMS calcd for Ci8Hi3N3O3S: 351.07; Found: 352.0 (M+l)+.
Example 80: Compound 88 1H-NMR (DMSO-de) δ 9.69 (s, IH), 9.59 (s, IH), 7.54 (d, J=8.1Hz, IH),
7.46 (d, J=3Hz, IH), 7.14 (t, J=7.8 Hz, IH), 6.97 (d, J=7.2 Hz, IH), 6.89 (d, J=8.7Hz, IH), 6.12-6.13 (m, 2H), 6.02 (dd, J7=2.4 Hz, J2=SA Hz, IH), 4.74 (qn, J=6.6Hz, IH)5 1.40-1.46 (m, 6H);
ESMS calcd for Ci9H18N4O2S: 366.12; Found: 367.1 (M+l)+.
Example 81; Compound 89
ESMS calcd for C22H2]N3O2S: 391.14; Found: 392.0 (M+H)+.
Example 82: Compound 90
1H NMR (DMSO-d6) δ 9.47 (s, IH), 9.43 (s, IH), 7.94-8.00 (m, 2H), 7.39- 7.57 (m, 5H), 6.68 (s, IH), 6.15 (s, IH), 2.05-2.15 (m, 2H), 1.05-1.17 (m, 2H), 0.50 (t, J= 7.5 Hz, 3H); ESMS calcd for C2iH20N3O2S: 377.1; Found: 378.0(M+l)+.
Example 83: Compound 91
1H NMR (DMSO-d6) δ 9.15 (s, IH), 8.50 (s, IH), 8.00 -8.07 (m, 2H), 7.47- 7.63 (m, 5H), 6.27 (s, IH), 2.06 (q, J= 7.5 Hz, 2H), 1.93 (s, 3H), 0.45 (t, J= 7.5 Hz, 3H);
ESMS calcd for C2]H20N3O2S: 377.1; Found: 378.0(M+l)+.
Example 84: Compound 93 ESMS calcd for C]6H15N3O4S: 345.08; Found: 346.0 (M+H)+.
Example 85: Compound 95
ESMS calcd for C]6H]2N4O2S: 324.07; Found: 325.0 (M+H)+.
Example 86: Compound 96
ESMS calcd for C19H18N4O3S: 382.11; Found: 383.0 (M+H)+.
Example 87: Compound 98
ESMS calcd for C17Hi2N4O2S: 336.07; Found: 337.0 (M+H)+.
Example 88: Compound 99
ESMS calcd for Ci9H13N3O4S: 379.06; Found: 379.9 (M+H)+. Example 89; Compound 100
1H-NMR (DMSO-d6) δ 9.52 (s, IH), 9.42 (s, IH), 7.56 (d, J=8.7Hz, IH), 7.49 (d, J=3.3Hz, IH), 7.14 (t, J=7.5 Hz, IH), 6.95 (d, J=8.4Hz, IH), 6.61 (s, IH), 6.21 (s, IH), 6.14 (dd, J=3.3Hz, IH), 4.76 (qn, J=6.6Hz, IH), 2.14 (q, J=7.5Hz, 2H), 1.41-1.47 (m, 6H), 0.66 (t, J=7.5Hz, 3H);
ESMS calcd for C2]H22N4O2S: 394.15; Found: 395.1 (M+l)+.
Example 90: Compound 101 ESMS calcd for Ci9HnN5O3S: 395.11; Found: 396.0 (M+H)+.
Example 91: Compound 102
ESMS calcd. for Ci9H20N5O2S: 381.1; Found: 382.0 (M + I)+.
Example 92: Compound 103
1H NMR (DMSO-d6) δ 9.48 (s, IH), 9.38 (s, IH), 7.29(d, J= 8.4 Hz, IH), 7.25(d, J= 1.8 Hz, IH), 6.85-6.89 (m, 2H), 6.18 (s, IH), 3.61 (s, 3H), 2.30 (s, 3H), 2.29 (q, J= 7.5 Hz, 2H), 2.09 (s, 3H), 0.94 (t, J= 7.5 Hz, 3H);
ESMS calcd for C21H23N4O2S: 394.1; Found: 395.0(M+l)+.
Example 93: Compound 104
ESMS calcd for Ci9Hi5N3O3S: 365.08; Found: 366.0 (M+H)+.
Example 94: Compound 106 ESMS calcd for C20Hi7N4O2S: 377.1; Found: 378.0(M+H)+.
Example 95: Compound 107
ESMS calcd for C18Hi3ClN3O2S: 369.0; Found: 370.0(M+H)+.
Example 96: Compound 116
1H NMR (DMSO-de) δ 7.98-7.56 (m, 2H), 7.55-7.30 (m, 6H), 6.43 (dd, J = 8.1 and 1.8 Hz, IH), 6.29 (m, IH), 3.65 (s, 3H), 3.16 (s, 3H); ESMS calcd for C20HnN3O2S: 363.10; Found: 364.0 (M+l)+.
Example 97: Compound 117
1H-NMR (CDCl3) δ 7.83(d, J=8.1 Hz, 2H), 7.48-7.34(m, 4H), 7.28-7.20(m, IH), 6.99 (d, J=I.8Hz, IH), 6.80(d, J=8.7Hz, IH), 6.62-6.58(m, IH), 2.94(s, 3H), 2.89(s, 3H), 2.84(s, 3H), 2.81(s, 3H), 2.75-2.69(m, 6H);
ESMS calcd for C27H28N6O5S: 548.18; Found: 549.2 (M+l)+.
Example 98: Compound 122 1H-NMR (CDCl3) δ 7.98(m, 2H), 7.60-7.55(m, 3H), 7.51-7.45(m, IH), 7.36-
7.33(m, IH), 6.98-6.97(m, IH), 6.86(d, J=9.9Hz, IH), 6.70-6.67(m, IH), 2.86(s, 3H), 2.26(s, 3H), 2.21(s, 3H);
ESMS calcd for C24Hi9N3O5S: 461.10; Found: 462.0 (M+l)+.
Example 99: Compound 125
ESMS calcd for C20H17N3O3S: 379.10; Found: 380.0 (M+H)+.
Example 100: Compound 126
ESMS calcd for Ci0Hi 1N3O2S: 237.06; Found: 238.0 (M+H)+.
Example 101: Compound 127
ESMS calcd for CnH13N3O2S: 251.07; Found: 252.0 (M+H)+.
Example 102: Compound 128 ESMS calcd for CnHi3N3O2S: 251.07; Found: 252.0 (M+H)+.
Example 103: Compound 129
ESMS calcd for CHHHN3O2S: 249.06; Found: 250.0 (M+H)+.
Example 104: Compound 130
ESMS calcd for Ci2Hi5N3O2S: 265.09; Found: 266.0 (M+H)+. Example 105: Compound 131
ESMS calcd for C20Hi5N3O4S: 393.08; Found: 394.1 (M+H)+.
Example 106: Compound 177 1H NMR (DMSO-de) δ 9.34(s, IH), 9.22 (s, IH), 8.01-7.96 (m, 2H), 7.58-
7.44 (m, 5H), 6.56 (s, IH), 6.14 (s, IH), 3.29 (s, 3H);
ESMS calcd for Ci9Hi5N3O3S: 365.08; Found: 366.0(M+l)+.
Example 107: Compound 178 1H NMR (DMSO-d6) δ 10.29 (s, IH), 9.49 (s, IH), 9.42 (s, IH), 8.16 (t, J=
5.1 Hz, IH), 7.45-7.43 (m, 2H), 7.26 (t, J= 8.0 Hz, IH), 6.84 (d, J= 7.8 Hz, IH), 6.75 (d, J= 8.7 Hz, IH), 6.66 (s, IH), 6.14 (s, IH), 2.12 (q, J= 7.5 Hz, 2H), 0.70 (t, J= 7.2 Hz, 3H);
ESMS calcd for C20Hi7N3O3S: 379.10; Found: 379.9 (M+l)+.
Example 108: Compound 179
ESMS calcd for Ci9Hi5N3O2S: 349.09; Found: 350.0 (M+l)+.
Example 109: Compound 180 ESMS calcd for Ci9Hi5N3O2S: 349.09; Found: 350.0 (M+H)+.
Example 110: Compound 181
ESMS calcd for C20H15N3O2S: 361.09; Found: 362.0 (M+H)+.
Example 111: Compound 182
ESMS calcd for Ci6Hi5 N3O3S: 329.08; Found: 330.0 (M+H)+.
Example 112: Compound 183
ESMS calcd for C20Hi7N3O2S: 363.10; Found: 364.0 (M+H)+.
Example 113: Compound 184
ESMS calcd for C18HnN3O3S: 350.38; Found: 351.9(M+H)+. Example 114; Compound 185
ESMS calcd. for C20H21N4O2S: 380.1; Found: 381.0 (M + I)+.
Example 115: Compound 187
ESMS calcd. for Ci9H20N5O2S: 381.1; Found: 382.0 (M + I)+.
Example 116: Compound 190
ESMS CALCD. FOR C2IH22N4O2S: 394.15; FOUND: 395.0 (M+l)+.
Example 117: Compound 191
ESMS calcd. for C22H23N4O4S: 438.1; Found: 439.0 (M + I)+.
Example 118: Compound 192 ESMS calcd. for C20H22N5O2S: 395.1; Found: 396.0 (M + I)+.
Example 119: Compound 193
ESMS calcd. for C20H22N5O2S: 395.1; Found: 396.0 (M + I)+.
Example 120: Compound 194
ESMS calcd. for C23H27N4O2S: 422.1; Found: 423.0 (M + I)+.
Example 121: Compound 195
ESMS calcd. for C23H25N4O2S: 420.1; Found: 421.0 (M + I)+.
Example 122: Compound 196
ESMS calcd. for C25H29N4O2S: 448.1; Found: 449.3 (M + I)+.
Example 123: Compound 197 ESMS calcd. for C22H24N4O2S: 408.16; Found: 409.2 (M+l)+.
Example 124: Compound 198 ESMS calcd. for C23H26N4O2S: 422.18; Found: 423.3 (M+l)+.
Example 125: Compound 199
ESMS calcd. for C24H28N4O2S: 436.19; Found: 437.3 (M+l)+.
Example 126: Compound 200
ESMS calcd. for C22H22N4O2S: .406.15; Found: 407.2 (M+l)+.
Example 127: Compound 201 ESMS calcd. for C23H24N4O3S: 436.16; Found: 437.3 (M+l)+.
Example 128: Compound 202
ESMS calcd. for C22H23N4O2S: 406.1; Found: 407.0 (M + H)+.
Example 129: Compound 204
ESMS calcd. for C24H28N4O3S: .452.19; Found: 453.2 (M+l)+.
Example 130: Compound 205
ESMS calcd. for C23H24N4O3S: 436.16; Found: 437.1 (M+l)+.
Example 131: Compound 206
ESMS calcd. for C2]H23N4O2S: 394.1; Found: 395.1 (M + I)+.
Example 132: Compound 207 ESMS calcd. for C20H21N4O2S: 380.1; Found: 381.1 (M + I)+.
Example 133: Compound 208
ESMS calcd. for C23H26N4O3S: 438.17; Found: 439.1 (M+l)+.
Example 134: Compound 209
ESMS calcd. for C22H24N4O2S: 408.1; Found: 409.1 (M + I)+. Example 135: Compound 210
ESMS calcd. for C24H23N4O2S: 430.1; Found: 431.1 (M + I)+.
Example 136: Compound 211 ESMS calcd. for C2iH22N4O3S: 410.14; Found: 411.1 (M+l)+.
Example 137: Compound 212
ESMS calcd. for C23H26N4O3S: 438.17; Found: 439.1 (M+l)+.
Example 138: Compound 213
ESMS calcd. for C20H21N4O2S : 380.1 ; Found: 381.1 (M + I)+.
Example 139: Compound 214
ESMS calcd. for C19Hj9N4O2S: 366.1; Found: 367.1 (M + I)+.
Example 140: Compound 215
ESMS calcd. for C20Hi9N3O4S: 397.1; Found: 398.1 (MB-I)+.
Example 141: Compound 216 1H NMR (DMSO-d6): δ (ppm) 9.56 (s, IH), 9.40 (s, IH), 8.03 (d, J= 2.4 Hz,
IH), 7.58 (d, J= 8.4 Hz, IH), 7.54 (d, J= 2.1 Hz, IH), 7.11 (dd, J = 8.4, 2.1 Hz, IH), 6.97 (d, J = 2.4 Hz, IH), 6.89 (s, IH), 6.17 (s, IH), 2.23 (q, J= 7.2 Hz, 2H), 0.93 (t, J= 7.2 Hz, 3H);
ESMS calcd. for Ci8H15N3O3S: 353.08; Found: 354.0 (M+l)+.
Example 142: Compound 217
1H NMR (DMSO-d6): δ (ppm) 9.59 (s, IH), 9.43 (s, IH), 7.67 (d, J= 8.7 Hz, IH), 7.54 (d, J= 2.1 Hz, IH), 7.20 (dd, J= 8.4, 2.1 Hz, IH), 6.96 (s, IH), 6.18 (s, IH), 2.60 (s, 3H), 2.34 (q, J= 7.2 Hz, 2H), 0.98 (t, J= 7.2 Hz, 3H); ESMS calcd. for Ci8Hi6N4O3S: 368.09; Found: 369.0 (M+l)+.
Example 143: Compound 218 ESMS calcd. for C21H23N4O2S: 394.1; Found: 395.1 (M + I)+.
Example 144; Compound 219
ESMS calcd. for C2iH2iN4O2S: 392.1; Found: 393.1 (M + I)+.
Example 145: Compound 220
ESMS calcd. for C20H2iN4O3: 364.1; Found: 365.1 (M + I)+.
Example 146: Compound 221 ESMS calcd. for C20H21N4O2S: 379.1; Found: 381.1 (M + I)+.
Example 147: Compound 222
ESMS calcd. for C21H23N4O2S: 394.1; Found: 395.1(M + I)+.
Example 148: Compound 224
ESMS calcd. for Q9H2IN4O2S: 368.1; Found: 369.1 (M + I)+.
Example 149: Compound 225
ESMS calcd. for Ci9Hi9N4O2S: 366.1; Found: 367.1(M + I)+.
Example 150: Compound 226
ESMS calcd. for C20H2iN4O3: 364.1; Found: 365.1 (M + I)+.
Example 151; Compound 227 ESMS calcd. for C21H22N4O2S: 394.15; Found: 395.1 (M+l)+.
Example 152: Compound 228
ESMS calcd. for C22H24N4O2S: 408.16; Found: 409.1 (M+l)+.
Example 153: Compound 229
ESMS calcd. for C20Hi8 F3N5O2S: 449.11; Found: 450.1 (M+l)+. Example 154: Compound 230
ESMS calcd. for C19Hi9N5O2S: 381.13; Found: 382.1 (M+l)+.
Example 155: Compound 231 ESMS calcd. for Ci9Hi9N5O2S: 381.13; Found: 382.1 (M+l)+.
Example 156: Compound 232
ESMS calcd. for C22H24N4O3S: 392.18; Found: 393.1 (M+l)+.
Example 157: Compound 233
ESMS calcd. for C18H17N3O4S: 371.09; Found: 372.1 (M+l)+.
Example 158: Compound 234
ESMS calcd. for C20H21N3O2S: 367.14; Found: 368.1 (M+l)+.
Example 159: Compound 235
ESMS calcd. for C19Hi9N5O2S: 381.13; Found: 382.1 (M+l)+.
Example 160: Compound 239 ESMS clcd for Ci9H2iN4O2S: 368.1; Found: 369.1 (M + H)+.
Example 161: Compound 240
ESMS clcd for Ci8Hi6N4O3S: 368.09.10; Found: 369.1 (M+H)+.
Example 162: Compound 241
ESMS clcd for CnH15N5O3S: 369.09; Found: 370.1 (M+H)+.
Example 163: Compound 242
ESMS clcd for Ci9Hi8N4O3S: 382.11; Found: 383.1 (M+H)+.
Example 164: Compound 243
ESMS clcd for C22H26N4O3S: 426.17; Found: 427.1 (M+H)+. Example 165: Compound 244
ESMS clcd for Ci8Hi6N4O4S: 384.09; Found: 385.1 (M+H)+
Example 166: Compound 245
ESMS clcd for Ci8Hi6N4O3S2: 400.07; Found: 401.1 (M+H)+
Example 167: Compound 245
ESMS clcd for C17Hj4N4O3S2: 386.05; Found: 387.0 (M+H)+.
Example 168: Inhibition of Hsp90
Hsp90 protein was obtained from Stressgen (Cat#SPP-770). Assay buffer: 100 mM Tris-HCl, Ph7.4, 20 mM KCl, 6 mM MgCl2. Malachite green (0.0812% w/v) (M9636) and polyviny alcohol USP (2.32% w/v) (Pl 097) were obtained from Sigma. A Malachite Green Assay (see Methods MoI 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-HCl, Ph7.4, 20 mM KCl, 6 mM MgCl2) was mixed with ATP alone (negative control) or in the presence of Geldanamycin (a positive control) or Compound 108 in a 96-well plate. Malachite green reagent was added to the reaction. The mixtures were incubated at 370C 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 μM of geldanamycin, a natural product known to inhibit Hsp90 activity, the ATPase activity of Hsp90 was only slightly higher than background. 40 μM Compound 108 showed an even greater inhibition of ATPase activity of Hsp90 than geldanamycin, and even at 4μM Compound 108 showed significant inhibition of ATPase activity of Hsp90 protein.
Example 169: Degradation of Hsp90 Client Proteins via Inhibition of Hsp90 Activity
A. Cells and Cell Culture Human high-Her2 breast carcinoma BT474 (HTB-20), SK-BR-3 (HTB-30) and MCF-7 breast carcinoma (HTB-22) from American Type Culture Collection, VA, USA were grown in Dulbecco's modified Eagle's medium with 4 mM L- glutamine and antibiotics (lOOIU/ml penicillin and 100 ug/ml streptomycine;GibcoBRL). To obtain exponential cell growth, cells were trypsinized, counted and seeded at a cell density of 0.5xl06 cells /ml regularly, every 3 days. All experiments were performed on day 1 after cell passage.
B. Degradation of Her2 in Cells after Treatment with a Compound of the Invention
BT-474 cells were treated with 0.5μM, 2μM, or 5μM of 17AAG (a positive control) or 0.5μM, 2μM, or 5μM of Compound 108 or Compound 49 overnight in DMEM medium. After treatment, each cytoplasmic sample was prepared from IxIO6 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, 2Ox Peroxide (#7003, Cell Signaling) was used for visualization. As can be seen from Figure 2, Her2, an Hsp90 client protein, is almost completely degraded when cells are treated with 5μM of Compound 108 and partially degradated when cells are treated with 2μM and 0.5μM of Compound 108. Compound 49 which is even more active than Compound 108 causes complete degradation of Her2 when cells are treated with 2μM and 5μM and causes partial degradated when cells are treated with 0.5μM 17AAG is a known Hsp90 inhibitor and is used as a positive control. 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 lxPBS/l%FBS, and then stained with anti-Her2- FITC (#340553, BD) for 30 min at 4°C. 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 IC50 range for Hsp90 inhibition by compounds of the invention are Used below in Table 2.
Table 2: IC50 range of compounds of the invention for inhibition of Hsp90
Figure imgf000177_0001
D. Apoptosis analysis
After treatment with the compounds of the invention, cells were washed once with lxPBS/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 (3X105 per well) were treated with 17AAG (0.5 μM), 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# K0105-4) in 100 ml IX PBS at 40C for 1 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 μM 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 μM in two leukemia cell lines, HEL92.1.7 (see Fig. 3) and Kasumi-1 (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-1 cells (myelogenous leukemia), 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.
F. Degradation of c-Met in Cells after Treatment with a Compound of the Invention We examined the ability of the Hsp90 inhibitors of the invention to induce the degradation of c-Met, an Hsp90 client protein that is expressed at high levels in several types of non-small cell lung cancer. NCI-H 1993 (ATCC, cat# CRL-5909) were seeded in 6-well plates at 5 X 105 cells/well. The cells were treated with 17AAG (100 nM or 400 nM) or Compound 221 (100 nM or 400 nM), and cell lysis was prepared 24 h after treatment. Equal amount of proteins were used for Western blot analysis. The compounds of the invention potently induced degradation of c- Met in this cell line due to inhibition of Hsp90 (see Fig. 6).
Example 170: 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., MoI. 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 (FB S), 1 % 10OX L- glutamine, 1% IOOX Penicillin-Streptomycin, 1% IOOX 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, USA). Approximately 4-5 x 10(6) cells that had been cryopreserved in liquid nitrogen were rapidly thawed at 370C and transferred to a 175 cm2 tissue culture flask containing 50 ml of growth media and then incubated at 370C in a 5% CO2 incubator. The growth media 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 IX Trypsin-EDTA (Invitrogen) and incubating at 370C 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 cm2 flasks containing 50 ml of growth media and incubated at 370C in a 5% CO2 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-l-«wBR (nude) 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 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/ml 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 the juncture of the os coxae (pelvic bone) and the os femoris (femur). Tumors were then permitted to develop in vivo until they reached approximately 150 mm3 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 -2O0C and diluted fresh each day for dosing. A solution of 20% Cremophore RH40 (polyoxyl 40 hydrogenated castor oil; BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany) in 80% D5W (5% dextrose in water; Abbott Laboratories, North Chicago, Illinois, USA) was also prepared by first heating 100% Cremophore RH40 at 50-600C until liquefied and clear, diluting 1:5 with 100% D5W, reheating again until clear and then mixing well. This solution 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 RH40, 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 7, treatment with 300 mg/kg body weight of Compound 49 decreased the growth rate of MDA-MB -435 S 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 8).
Example 171; Compound 188 Displays Anti-tumor Activity Against Human Tumor Cells in a nude Mouse Xenograft Model
The human squamous non-small cell lung cancer cell line, RERF-LC-AI (RCB0444; S. Kyoizumi, et al., Cancer. Res. 45:3274-3281, 1985), was obtained from the Riken Cell Bank (Tsukuba, Ibaraki, Japan). 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), 1% IOOX L- glutamine, 1% IOOX penicillin-streptomycin, 1% IOOX sodium pyruvate and 1% IOOX MEM non-essential amino acids. FBS was obtained from American Type Culture Collection (Manassas, Virginia, USA) and all other reagents were obtained from Invitrogen Corp. (Carlsbad, California, 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 cm2 tissue culture flask containing 50 ml of growth media and then incubated at 370C in a 5% CO2 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 IX trypsin-EDTA (Invitrogen) and incubating at 370C 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 cm2 flasks containing 50 ml of growth media and incubated at 370C in a 5% CO2 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-l-«wBR (nude) 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 between 8 and 12 weeks of age at implantation. To implant RERF-LC-AI tumor cells into nude mice, the cells were trypsinized as above, washed in PBS and resuspended at a concentration of 50 x 10(6) cells/ml in 50% non-supplemented RPMI Media 1640 and 50% Matrigel Basement Membrane Matrix (#354234; BD Biosciences; Bedford, Massachusetts, USA). Using a 27 gauge needle and 1 cc syringe, 0.1 ml of the cell suspension was injected subcutaneously into the flank of each nude mouse. 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).
In vivo passaged RERF-LC-AI tumor cells (RERF-LC-AI™1") were isolated to improve the rate of tumor implantation relative to the parental cell line in nude mice. RERF-LC-AI tumors were permitted to develop in vivo until they reached approximately 250 mm3 in volume, which required approximately 3 weeks following implantation. Mice were euthanized via CO2 asphyxiation and their exteriors sterilized with 70% ethanol in a laminar flow hood. Using sterile technique, tumors were excised and diced in 50 ml PBS using a scalpel blade. A single cell suspension was prepared using a 55 ml Wheaton Safe-Grind tissue grinder (catalog #62400-358; VWR International, West Chester, Pennsylvania, USA) by plunging the pestle up and down 4-5 times without twisting. The suspension was strained through a 70 μM nylon cell strainer and then centrifuged to pellet the cells. The resulting pellet was resuspended in 0.1 M NH4Cl to lyse contaminating red blood cells and then immediately centrifuged to pellet the cells. The cell pellet was resuspended in growth media and seeded into 175 cm2 flasks containing 50 ml of growth media at 1-3 tumors/flask or approximately 10 x 10(6) cells/flask. After overnight incubation at 370C in a 5% CO2 incubator, non¬ adherent cells were removed by rinsing two times with PBS and then the cultures were fed with fresh growth media. When the flasks reached 90% confluence, the above passaging process was repeated until sufficient cells had been obtained for implantation into mice.
RERF-LC -AI™1* cells were then implanted as above and tumors were permitted to develop in vivo until the majority reached an average of 100-200 mm3 in tumor volume, which typically required 2-3 weeks following implantation. Animals with oblong or very small or large tumors were discarded, and only animals carrying tumors that displayed consistent growth rates were selected for studies. Animals were randomized into treatment groups so that the average tumor volumes of each group were similar at the start of dosing.
The HSP90 inhibitor, π-allylamino-lT-demethoxygeldanamycin (17- AAG), was employed as a positive control (Albany Molecular Research, Albany, New York, USA). Stock solutions of test articles 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 weekly, stored at -2O0C and diluted fresh each day for dosing. A solution of 20% Cremophore RH40 (polyoxyl 40 hydrogenated castor oil; BASF Corp.,
Aktiengesellschaft, Ludwigshafen, Germany) in 80% D5W (5% dextrose in water; Abbott Laboratories, North Chicago, Illinois, USA) was also prepared by first heating 100% Cremophore RH40 at 50-600C until liquefied and clear, diluting 1:5 with 100% D5W, reheating again until clear and then mixing well. This solution 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 RH40, 3.6% dextrose, 68.4% water and the appropriate amount of test article. Animals were intraperitoneally (i.p.) injected with this solution at 10 ml per kg body weight on a schedule of 5 days per week (Monday, Tuesday, Wednesday, Thursday and Friday, with no dosing on Saturday and Sunday) for a total of 15 doses. As shown in Figure 9, treatment with 200 mg/kg body weight of Compound
188 decreased the growth rate of RERF-LC-AIIVP human lung tumor cells in nude mice, as did a dose of 75 mg/kg body weight of 17-AAG (an unrelated HSP90 inhibitor). This effect was not associated with overt toxicity, as shown by the minimal effect on body weights depicted in Figure 10.
All publications, patent applications, patents, and other documents cited herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

CLAIMS What is claimed is:
1. A compound represented by the following structural formula:
Figure imgf000185_0001
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug 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 R3;
R1 and R3 are, independently, -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)raNR7H, -OC(O)NR, 0Rπ, -SC(O)NR10Rπ, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7,
-NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10R1I, -SCH2C(O)NR10R11, -NR7CH2C(O)NR10R11, -OS(O)PR7, -SS(O)pR7, -S(O)pOR7, -NR7S(O)15R7, -OS(O)PNR10R11, -SS(0)pNR,oRπ, -NR7S(O)pNRi0Rn, -OS(O)POR7, -SS(O)pOR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7,
-SC(S)OR7, -NR7C(S)OR7, -OC(S)NR10Rn, -SC(S)NR1ORU, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NRi0R11, -NR7C(NR8)NR10R11, -OP(O)(OR7)2, or -SP(O)(OR7)2;
R5 is an optionally substituted heteroaryl or an optionally substituted 8 to 14 membered aryl; R7 and R8, for each occurrence, are, independently, -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;
R10 and Rn, for each occurrence, are independently -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R10 and Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; R26 is a Cl-C6 alkyl; p, for each occurrence, is, independently, 0, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4; provided that ring A is not a substituted [l,2,3]triazole; and provided that the compound is not 3-(2,4-dihydroxy-phenyl)-4-(7- naphthalen- 1 -yl)-5-mercapto-triazole.
2. The compound of Claim 1, wherein R5 is represented by the following formula:
Figure imgf000186_0001
wherein:
R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted 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, -NRioRn, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)pR7, -OS(O)PR7, -S(O)pOR7, -NR8S(O)PR7, or -S(O)pNR10Rii, -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(OR7)2; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and m is zero or an integer from 1 to 7.
3. The compound of Claim 2, wherein R$ is represented by one of the following formulas:
Figure imgf000187_0001
wherein: q is zero or an integer from 1 to 7; and u is zero or an integer from 1 to 8.
The compound of Claim 1, wherein R5 is represented by the following structural formula:
Figure imgf000188_0001
wherein:
R33 is a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lower haloalkoxy, and lower alkyl sulfanyl;
R34 is H, a lower alkyl, or a lower alkylcarbonyl; and
Ring B and Ring C are optionally substituted with one or more substituents.
5. The compound of Claim 1, wherein R5 is selected from the group consisting of:
Figure imgf000188_0002
Figure imgf000189_0001
X6, for each occurrence, is independently CH, CR9, N, N(O), N+(R17), provided that at least three X6 groups are independently selected from CH and CR9;
X7, for each occurrence, is independently CH, CR9, N, N(O), N+(Rn), provided that at least three X7 groups are independently selected from CH and CR9;
X8, for each occurrence, is independently CH2, CHR9, C(R9)2, S,
Figure imgf000190_0001
X9, for each occurrence, is independently N or CH; X10, for each occurrence, is independently CH, CR9, N, N(O),
N+(Ri7), provided that at least one Xio is selected from CH and CR9;
R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRioRn, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NRi0RiI, -NR8C(O)R7, -SR7, -S(OJpR7,
-OS(O)PR7, -S(O)POR7, -NR8S(O)pR7, or -S(O)pNR10Rπ, -S(O)POR7, -OP(O)(OR7)Z, or -SP(O)(OR7)2, -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(OR7)2; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
Ri7, for each occurrence, is independently -H, an alkyl, an aralkyl, -C(O)R7, -C(O)OR7, or -C(O)NRi0Ri 1.
6. The compound of Claim 5, wherein R5 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[d]isothiazolyl, an optionally substituted thiazolo[4,5-c]pyridinyl, an optionally substituted thiazolo[5,4-c]pyridinyl, an optionally substituted thiazolo[4,5-b]pyridinyl, an optionally substituted thiazolo[5,4-b]pyridinyl, an optionally substituted oxazolo[4,5-c]pyridinyl, an optionally substituted oxazolo[5,4-c]pyridinyl, an optionally substituted oxazolo[4,5-b]pyridinyl, an optionally substituted oxazolo[5,4-b]pyridinyl,an optionally substituted imidazopyridinyl, an optionally substituted benzothiadiazolyl, benzoxadiazolyl, an optionally substituted benzotriazolyl, an optionally substituted tetrahydroindolyl, an optionally substituted 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 IH- imidazo[4,5-b]pyridinyl, an optionally substituted lH-imidazo[4,5- cjpyridinyl, 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.
7. The compound of Claim 1, wherein Rs is selected from the group consisting of:
Figure imgf000192_0001
wherein:
Xn, for each occurrence, is independently CH, CRg, N, N(O), or N+(R17), provided that at least one Xn is N, N(O), or N+(Rn) and at least two Xn groups are independently selected from CH and CR9;
Xi2, for each occurrence, is independently CH, CR9, N, N(O), N+(Rn), provided that at least one Xj2 group is independently selected from CH and CR9;
Xi3, for each occurrence, is independently O, S, S(O)p, NR7, or NRi7; R9, for each occurrence, is independently a substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a hydroxyalkyl, alkoxyalkyl, haloalkyl, a heteroalkyl, -NRi0Rn, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)pR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)pR7, or -S(O)pNR10Rii, -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(OR7)2, -S(O)POR7, -OP(O)(OR7)2, or
-SP(O)(OR7)2; or two R9 groups taken together with the carbon atoms to which they are attached form a fused ring; and
Ri7, for each occurrence, is independently an alkyl or an aralkyl.
8. The compound of Claim 1, wherein the compound is represented by the following structural formula:
Figure imgf000193_0001
wherein:
R6, 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, -NRi0Ri i, -OR7, -C(O)R7,
-C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)NRi0RiI, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10Rn, -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(O)R7, -SC(O)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NRi0Ri i, -OC(S)NRi0RiI, -OC(NR8)NRi0Rn, -SC(O)NR]0Ri i, -SC(NR8)NRi0Ri,,
-SC(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -C(O)NRi0RiI, -NR8C(O)R7, -NR7C(S)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(O)OR7, -NR7C(NR8)OR7, -NR7C(O)NRi0Rn, -NR7C(S)NRi0R11, -NR7C(NR8)NR10R11, -SR7, -S(O)PR7, -OS(O)PR7, -OS(O)POR7, -OS(0)pNRloRn, -S(O)pOR7, -NR8S(O)PR75 -NR7S(O)PNR10R11,
-NR7S(O)pOR7, -S(O)pNRi0Rπ, -SS(O)PR7, -SS(O)POR7, -SS(O)PNR1OR11, -OP(O)(OR7)2, or -SP(O)(OR7)2; and n is zero of an integer from 1 to 4.
The compound of Claim 8, wherein R5 is moiety R2, and wherein 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, -NRi oRn, -0-R20, -C(O)R7,
-C(O)OR20, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)PR7, -S(0)pNRloRπ, -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(OR7)2;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, -NRi0Rn, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)pR7, -S(O)POR7, -NR8S(O)pR7, -S(O)pNR10Rn, -OP(O)(OR7)2, or -SP(O)(OR7)2, -S(O)POR7.
10. A compound of Claim 1, wherein R5 is a moiety Ri8, and further wherein
Ri8 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, -NRi0Ri 1, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NRi0Rn, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)pOR7, -NR8S(O)PR7, or -S(O)pNRi0Rn,
-S(O)POR7, -OP(O)(OR7)2, or -SP(O)(OR7)2; and m, for each occurrence, is independently, 1, 2, 3, or 4; provided that Ri8 is not cyclohexyl.
11. The compound of Claim 10, wherein Ri8 is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl.
12. The compound of Claim 10, wherein Ri8 is a substituted alkyl.
13. The compound of Claim 8, wherein the compound is represented by the following structural formula:
Figure imgf000195_0001
wherein:
R25 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 heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy, -NRi0Rn, -OR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR75 -C(S)SR7, -C(S)OR75 -C(S)NR1ORI U -C(NR8)OR7^C(NR8)R7,
-C(NR8)NRioRii, -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(O)R7, -SC(O)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NR10Rii, -OC(S)NR10Ri i, -OC(NR8)NR10RI i, -SC(O)NRi0Rn, -SC(NR8)NRioRi i, -SC(S)NRi0Ri ,, -OC(NR8)R7, -SC(NR8)R7, -C(O)NRi0Ri1, -NR8C(O)R7, -NR7C(S)R7, -NR7C(S)OR7,
-NR7C(NR8)R7, -NR7C(O)OR7, -NR7C(NR8)OR7, -NR7C(O)NR]0R11, -NR7C(S)NRI0RI I5 -NR7C(NR8)NR10R1 15 -SR7, -S(O)PR7, -OS(O)PR7, -OS(O)pOR7, -OS(O)PNRi0RI h -S(O)POR7, -NR8S(O)PR7, -NR7S(0)pNRioRn, -NR7S(O)15OR7, -S(O)pNRi0Rn, -SS(O)pR7, -SS(O)POR7, -SS(0)pNRioRπ, -OP(O)(OR7)2) or -SP(O)(OR7)2; k is 1, 2, 3, or 4; and r is zero or an integer from 1 to 3.
14. The compound of Claim 13 wherein R1, R3 and R25 are each independently -OH, -SH, -NHR7, -OC(O)NRI0RI 1, -SC(O)NR, 0Rn, -OC(O)R7, -SC(O)R7, -OC(O)OR7, -SC(O)OR7, -OS(O)PR7> -S(O)POR7, -SS(O)PR7, -OS(0)POR7, -SS(O)pOR7, -OC(S)R7, -SC(S)R7, -OC(S)OR7, -SC(S)OR7, -OC(S)NR10R11,
-SC(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -OP(O)(OR7)2 or -SP(O)(OR7)2.
15. The compound of Claim 3, wherein R1 and R3 are each, independently, -OH, -SH, or -NHR7.
16. The compound of Claim 15, wherein the compound is represented by the following structural formula:
Figure imgf000196_0001
wherein R6 is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, -OR7, -SR7, -NRIORU5 -OC(O)NRI0R1 I, -SC(O)NRI0RH,
-NR7C(O)NR10Rii, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(0)NR,oRii, -SCH2C(O)NR10Ri i, -NR7CH2C(O)NR10Ri i, -0S(0)pR7, -SS(O)PR7, -NR7S(O)pR7, -OS(O)pNR10Rii, -SS(O)pNR10Rπ, -NR7S(O)PNR10Rn, -0S(0)p0R7, -SS(0)p0R7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7,
-OC(S)NR10R11, -SC(S)NR10R11, -NR7C(S)NR10R11, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NRi0R11, -NR7C(NR8)NR10Rii, -C(O)R7, -C(O)OR7, -C(O)NR10R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10R11, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7,
-C(NR8)NR10R11, -C(NR8)SR7, -S(O)POR7, -S(O)pNR10Rπ, or -S(O)PR7.
17. The compound of Claim 16, wherein:
Ri is -SH or -OH; R3 and R25 are -OH;
R6 is a lower alkyl, C3-C6 cycloalkyl, lower alkoxy, a lower alkyl sulfanyl, or -NR10Rn; and
Rg, 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.
18. The compound of Claim 14, wherein the compound is represented by the following structural formula:
Figure imgf000197_0001
19. The compound of Claim 18, wherein RO is a C 1 -C6 alkyl, a C 1 -C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl.
20. The compound of Claim 19, wherein Ri and R3 are each, independently, -OH, -SH, or -NHR7-
21. The compound of Claim 20, wherein:
R1 is -SH or -OH; R3 and R25 are -OH;
R6 is a lower alkyl, C3-C6 cycloalkyl, lower alkoxy, a lower alkyl sulfanyl, or -NRi oRn.
22. The compound of Claim 1, wherein the compound is represented by one of the following structural formulas:
Figure imgf000198_0001
wherein:
X3 and X4 are each, independently, N, N(O), N+(Rn), CH or CR6;
X5 is O, S, NRi7, CH=CH, CH=CR6, CR6=CH, CR6=CR6, CH=N, CR6=N, CH=N(O), CR6=N(O), N=CH, N=CR6, N(O)=CH, N(O)=CR6,
N+(Rn)=CH, N+(Rn)=CR6, CH=N+(R17), CR6=N+(R17), or N=N;
R6, 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, -NR10Rn, -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10Rn, -NR8C(O)R7, -SR7, -S(OJpR7, -OS(OJpR7, -S(O)POR7, -NR8S(O)pR7, or -S(O)pNR10Rπ, -S(O)POR7, -OP(O)(OR7)2, or -SP(O)(OR7)2;
Ri7, for each occurrence, is independently an alkyl or an aralkyl; and n is zero or an integer from 1 to 4.
23. The compound of Claim 22, wherein the compound is selected from the group consisting of:
Figure imgf000199_0001
Figure imgf000200_0001
wherein:
R25 is a halo, a haloalkyl, a haloalkoxy, a heteroalkyl, -OH, -SH, -NHR7, -(CH2)kOH, -(CH2)kSH, -(CH2)kNR7H, -OCH3, -SCH3, -NHCH3, -OCH2CH2OH, -OCH2CH2SH, -OCH2CH2NR7H, -SCH2CH2OH, -SCH2CH2SH, -SCH2CH2NR7H, -OC(O)NR10Ri i, -SC(O)NRi0Rn, -NR7C(O)NR10RH, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7, -OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NR10RH, -SCH2C(O)NR10R11, -NR7CH2C(O)NRi0R11, -OS(O)PR7, -SS(O)pR7, -NR7S(O)PR7, -OS(O)PNR10RI 15 -SS(O)PNR1ORI I, -NR7S(0)pNRloRii, -OS(O)POR7, -SS(O)POR7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7, -OC(S)NRI0RI i, -SC(S)NR10Rn, -NR7C(S)NR10Rn, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NR10R11, -SC(NR8)NRi0Rn, -NR7C(NR8)NR10Rn, -C(O)R7, -C(O)OR7, -C(O)NRi0R11, -C(O)SR7, -C(S)R7, -C(S)OR7, -C(S)NR10Rn, -C(S)SR7, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NR10Rn, -C(NR8)SR7, -S(O)POR7, -S(O)pNR10Rn, or -S(O)PR7, -S(O)pOR7, -OP(O)(OR7)2, or -SP(O)(OR7)2; and k is 1, 2, 3, or 4.
24. The compound of Claim 1, selected form the group consisting of
3-(2-Hydroxyphenyl)-4-(naphthalen- 1 -yl)-5-mercapto-triazole; 3-(2,4-Dihydroxyphenyl)-4-[4-(2-methoxyethoxy)-naphthalen- 1 -yl]-5-mercapto- triazole;
3-(2,4-Dihydroxyphenyl)-4-(2-methyl-4-bromophenyl)-5-mercapto-triazole;
3-(3,4-Dihydroxyphenyl)-4-(6-methoxy-naphthalen-l-yl)-5-mercapto-triazole;
3-(3,4-Dihydroxyphenyl)-4-(6-ethoxy-naphthalen-l-yl)-5-mercapto-triazole; 3-(3,4-Dihydroxyphenyl)-4-(6-propoxy-naphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(5-methoxy-naphthalen-l-yl)-5-mercapto- triazole;
3-(3,4-Dihydroxyphenyl)-4-(6-isopropoxy-naphthalen-l-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxyphenyl)-4-(2,6-diethylphenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(2-methy-6-ethylphenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(2,6-diisopropylphenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(l-ethyl-indol-4-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-5-mercapto- triazole;
3-(2,4-Dihydroxyphenyl)-4-(3-methylphenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(4-methylphenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(2-chlorophenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(3-chlorophenyl)-5-mercapto-triazole; 3-(2,4-Dihydroxyphenyl)-4-(4-chlorophenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(2-methoxyphenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(3-methoxyphenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(3-fluorophenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(2-ethylphenyl)-5-mercapto-triazole; 3-(2-Hydroxy-4-fluorophenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(2-Hydroxy-4-aminophenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(2-methyl-4-butyl-phenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(2,4-dimethyl-phenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(2,6-dimethyl-phenyl)-5-mercapto-triazole; 3-(2,4-Dihydroxyphenyl)-4-(2,6-dimethyl-phenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(4-fluorophenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(2-methylsulfanylphenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(naphthalene-2-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(2,3-dimethylphenyl)-5-mercapto-triazole; 3-(2,4-Dihydroxyphenyl)-4-(2-methyl-4-fluorophenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(acenaphthalen-5-yl)-5-mercapto-triazole;
3-(2-Hydroxy-4-methoxy-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxyphenyl)-4-(2,3-dichlorophenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(5-methoxynaphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(pyren- 1 -yl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(quinolin-5-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxyphenyl)-4-(l,2,3,4-tetrahydronaphthalen-5-yl)-5-mercapto- triazole;
3-(2,4-Dihydroxyphenyl)-4-(anthracen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(biphenyl-2-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-6-methyl-phenyl)-4-(naphthalene-l-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxyphenyl)-4-(4-pentyloxyphenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(4-octyloxyphenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(4-chloronaphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(7-carboxymethoxy-naphthalen-l-yl)-5- mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(2-methyl-quinolin-4-yl)-5-mercapto-triazole;
3-(3-Hydroxypyridin-4-yl)-4-(naphthalen-l-yl)-5-mercapto-triazole; .
3-(2-Hydroxy-4-acetylamino-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-phenyl)-4-(l,2,3,4-tetrahydronaphthalen-l-yl)-5-mercapto- triazole;
3-(2,4-Dihydroxy-phenyl)-4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-5-mercapto- triazole;
3-(2,4-Dihydroxy-phenyl)-4-(3,5-dimethoxyphenyl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-phenyl)-4-(2,3 -dimethyl- 1 H-indol-4-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxy-3-propyl-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(4,6-Dihydroxy-l-ethyl-pyridin-3-yl)-4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(4,6-Dihydroxy-l-methyl-pyridin-3-yl)-4-(naphthalen-l-yl)-5-mercapto- triazole;
3 -(2,4-Dihydroxy-pheny l)-4-(3 , 5 -di-tert-buty lphenyl)-5 -mercapto-triazole ; 3-(2,6-Dihydroxy5-fluoro-pyridin-3-yl) 4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-5-methyl-phenyl)-4-(naphthalene-l-yl)-5-mercapto-triazole;
3-[2,4-Dihydroxy-phenyl]-4-(3-benzoylphenyl)-5-mercapto-triazole; 3-(2,4-Dihydroxy-phenyl)-4-(4-carboxy-naphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-phenyl)-4-[4-(N,N-dimethylcarbamoyl)-naphthalen-l-yl]-5- mercapto-triazole;
3-(2,4-Dihydroxy-phenyl)-4-(4-propoxy-naphthalen-l-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxy-phenyl)-4-(4-isopropoxy-naphthalen-l-yl)-5-mercapto- triazole;
3-(2,4-Dihydroxy-phenyl)-4-(5-isopropoxy-naphthalen-l-yl)-5-mercapto- triazole;
3-(2,4-Dihydroxy-phenyl)-4-(isoquinolin-5-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxy-phenyl)-4-(5-propoxy-naphthalen- 1 -yl)-5-mercapto-triazole;
3-(2-Hydroxy-4-methanesulfonamino-phenyl)-4-(naphthalen-l-yl)-5-mercapto- triazole;
3-(2,4-Dihydroxy-3,6-dimethyl-phenyl)-4-(naphthalen-l-yl)-5-mercapto- triazole; 3-(2,4-Dihydroxy-phenyl)-4-[7-(2-methoxyethoxy)-naphthalen-l -yl]-5- mercapto-triazole;
3-(2,4-Dihydroxy-5-hexyl-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(4-methoxy-naphthalen-l-yl)-5-mercapto- triazole; 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(6-methoxy-naphthalin-l-yl)-5-mercapto- triazole;
3-(2,4-Dihydroxy-3-chloro-5-ethyl-phenyl)-4-(naphthalen-l-yl)-5-mercapto- triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethy-4-methoxy-phenyl)-5- mercapto-triazole;
3-(2,4-Dihydroxy-phenyl)-4-(7-isopropoxy-naphthalen-l-yl)-5-mercapto- triazole;
3-(2,4-Dihydroxy-phenyl)-4-(7-ethoxy-naphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-phenyl)-4-(7-propoxy-naphthalen-l-yl)-5-mercapto-triazole; 3-(2-Hydroxy-4-methoxymethyoxy-phenyl)-4-(naphthalen- 1 -yl)-5-mercapto- triazole; 3-[2-Hydroxy-4-(2-hydroxy-ethoxy)-phenyl]-4-(naphthalen-l-yl)-5-mercapto- triazole;
3-(2,4-Dihydroxyphenyl)-4-(7-methoxy-naphthalen-l-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxyphenyl)-4-(5-methoxy-naphthalen-l-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxyphenyl)-4-(4-hydroxy-naphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxyphenyl)-4-(l-isopropyl-indol-4-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxy-5-tert-butyl-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxy-5-propyl-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxy-3-methyl-5-ethyl-phenyl)-4-(naphthalen-l-yl)-5-mercapto- triazole;
3-(2,4-Dihydroxy-5-isobutyl-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxy-phenyl)-4-(2,3-dimethoxy-phenyl)-5-mercapto-triazole; 3-(2,4-Dihydroxy-phenyl)-4-(2-methoxy-3-chloro-phenyl)-5-mercapto-triazole; 3-(2,4-Dihydroxy-phenyl)-4-(indol-4-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxy-phenyl)-4-[l-(2-methoxyethoxy)-indol-4-yl]-5-mercapto- triazole;
3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-l-yl)-5-hydroxy-triazole; 3-(l-Oxo-3-hydroxy-pyridin-4-yl)-4-(naphthalen-l-yl)-5-mercapto-triazole; 3-(2,5-Dihydroxy-4-carboxy)-4-(naphthalen-l-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-indol-4-yl)-5-mercapto- triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-[l-(dimethyl-carbamoyl)-indol-4-yl]-5- mercapto-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(l-ethyl-benzoimidazol-4-yl)-5-mercapto- triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(l,2,3-trimethyl-indol-5-yl)-5-mercapto- triazole;
3-(2,5-Dihydroxy-4-hydroxymethyl-phenyl)-4-(naphthalen-l-yl)-5-mercapto- triazole; 3-(2-Hydroxy-4-amino-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(2-Hydroxy-4-acetylamino-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxy-3-chloro-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole; 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-methox-phenyl)-5-hydroxy-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(naphthalen-l-yl)-5-hydroxy-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-indol-3-yl)-5-hydroxy-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-indol-4-yl)-5-amino-triazole; 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-methoxy-phenyl)-5-amino-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(naphthalen-l-yl)-5-amino-triazole;
3-(2-Hydroxy-5-ethyloxy-phenyl)-4-(naphthalen-l-yl)-5-hydroxy-triazole;
3-(2-Hydroxy-5-isopropyl-phenyl)-4-(naphthalen-l-yl)-5-hydroxy-triazole;
3-(2-Dihydroxy-phenyl)-4-(7-fluoro-naphthalen-l-yl)-5-hydroxy-triazole; 3-(2,4-Dihydroxy-phenyl)-4-(2,3-difluorophenyl)-5-hydroxy-triazole;
3-(2,4-Dihydroxy-phenyl)-4-[2-(lH-tetrazol-5-yl)-phenyl]-5-hydroxy-triazole;
3-(2,4-Dihydroxy-phenyl)-4-(benzothiazol-4-yl)-5-hydroxy-triazole;
3-(2,4-Dihydroxy-phenyl)-4-(9H-purin-6-yl)-5-hydroxy-triazole;
3-(2,4-Dihydroxy-phenyl)-4- {4-[2-(moropholin- 1 -yl)-ethoxy] -phenyl} -5- hydroxy-triazole;
3-(2,4-Dihydroxy-phenyl)-4-cyclopentyl-5-hydroxy-triazole;
3-(2,4-Dihydroxy-phenyl)-4-phenyl-5-(sulfamoylamino)-triazole;
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-l-yl)-5-ureido-triazole;
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(2,3-difluorophenyl)-5-ureido-triazole; 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-indol-4-yl)-5-ureido-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(quinolin-5-yl)-5-ureido-triazole;
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-l-yl)-5-carbamoyloxy- triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-trifluoromethyl-phenyl)-5- carbamoyloxy-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(l-methyl-indol-4-yl)-5-carbamoyloxy- triazole;
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(8-methoxy-quinolin-5-yl)-5- carbamoyloxy-triazole; 3-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-(3-methyl-quinolin-5-yl)-5- carboxyamino-triazole; 3-(2,4-Dihydroxy-phenyl)-4-(l-methyl-2-chloro-indol-4-yl)-5-carbamoyloxy- triazole;
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-[3,5-di-(trifluoromethyl)-phenyl]-5- carbamoyloxy-triazole; 3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(3-trifluoromethyl-phenyl)-5-
(sulfamoylamino)-triazole;
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-l-yl)-5-(sulfamoylamino)- triazole;
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(l-isopropyl-benzoimidazol-4-yl)-5- (sulfamoylamino)-triazole;
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(3-isopropylphenyl)-5- (thiocarboxyamino)-triazole;
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(3-isopropyloxy-phenyl)-5- (sulfamoyloxy)-triazole; 3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-l-yl)-5-(sulfamoyloxy)- triazole;
3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(5-hydroxy-naphthalen-l-yl)-5-mercapto- triazole; 3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-l-ylmethyl)-5-mercapto-triazole;
3-(2-Hydroxy-4-methoxyphenyl)-4-(naphthalen-l-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-phenyl)-4-(biphenyl-3-yl)-5-mercapto-triazole;
3-(2,4-Dihydroxy-phenyl)-4-(2-methyl-5-hydroxymethyl-phenyl)-5-mercapto- triazole; 3 -(2,4-Dihydroxy-phenyl)-4-( 1 -dimethylcarbamoyl-indol-4-yl)-5 -mercapto- triazole;
3 -(2,4, 5 -Trihydroxy-phenyl)-4-(naphthalene- 1 -y l)-5 -mercapto-tr iazole ;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl-indol-5-yl)-5-mercapto- triazole; 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-t-butyl-4-methoxy-phenyl)-5-mercapto- triazole; 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(l-ethyl-lH-benzoimidazol-4-yl)-5- mercapto-triazole, HCl salt;
3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-7-methoxy-indol-4-yl)-5- mercapto-triazole; and 3-(2,4-Dihydroxy-5-cyclopropyl-phenyl)-4-(naphthalene-l-yl)-5-mercapto- triazole or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or a prodrug thereof.
25. A compound represented by the following structural formula:
Figure imgf000207_0001
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:
X41 is O, S, or NR42; X42 Js CR44 Or N;
Y4O is N or CR43;
Y41 is N or CR45;
Y42j for each occurrence, is independently N, C or CR46;
Z is OH, SH, or NHR7; R4I is -H, -OH, -SH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy, -NR10R11, -OR7, -C(O)R7, -C(O)OR7, -C(S)R7, -C(O)SR7, -C(S)SR7, -C(S)OR7, -C(S)NR10Rn, -C(NR8)OR7, -C(NR8)R7, -C(NR8)NRIORH, -C(NR8)SR7, -OC(O)R7, -OC(O)OR7, -OC(S)OR7, -OC(NR8)OR7, -SC(O)R7, -SC(O)OR7, -SC(NR8)OR7, -OC(S)R7, -SC(S)R7, -SC(S)OR7, -OC(O)NR10R1 ,, -OC(S)NRi0Ri1, -OC(NR8)NR10RH, -SC(O)NRi0Ri i, -SC(NR8)NRi0R1 I, -SC(S)NR10R1 1,
-OC(NR8)R7, -SC(NR8)R7, -C(O)NR10R11, -NR8C(O)R7, -NR7C(S)R7, -NR7C(S)OR7, -NR7C(NR8)R7, -NR7C(O)OR7, -NR7C(NR8)OR7, -NR7C(O)NRi0R11, -NR7C(S)NR10Rn, -NR7C(NR8)NR10Rn, -SR7, -S(0)pR7, -0S(0)pR7, -OS(O)pOR7, -OS(0)pNRloRn, -S(O)pOR7, -NR8S(O)pR7, -NR7S(0)pNRloRii, -NR7S(O)pOR7, -S(O)PNR10R11,
-SS(0)pR7, -SS(0)p0R7, -SS(O)pNR10Rn, -OP(O)(OR7)2, or -SP(O)(OR7)2; R42 is -H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, -C(O)R7, -(CH2)mC(O)OR7, -C(O)OR75 -OC(O)R7, -C(O)NRi0R11, -S(O)pR7, -S(O)POR7, or -S(O)pNR10Rn; R43 and R44 are, independently, -H, -OH, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R11, -NR8C(O)R7, -SR7, -S(O)PR7, -OS(O)PR7, -S(O)POR7, -NR8S(O)PR7, -S(O)PNR10R115 or R43 and R44 taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heterocyclyl, or an optionally substituted heteroaryl; R45 is -H, -OH, -SH, -NR7H, -OR26, -SR26, -NHR26, -O(CH2)mOH, -O(CH2)mSH, -O(CH2)mNR7H, -S(CH2)mOH, -S(CH2)mSH, -S(CH2)mNR7H, -OC(O)NRI0RI l, -SC(O)NRi0Rn, -NR7C(O)NRi0Ri1, -OC(O)R7, -SC(O)R7, -NR7C(O)R7, -OC(O)OR7, -SC(O)OR7, -NR7C(O)OR7, -OCH2C(O)R7, -SCH2C(O)R7, -NR7CH2C(O)R7,
-OCH2C(O)OR7, -SCH2C(O)OR7, -NR7CH2C(O)OR7, -OCH2C(O)NRi0R11, -SCH2C(O)NRi0Ri1, -NR7CH2C(O)NR10R11, -0S(0)pR7, -SS(O)pR7, -NR7S(O)pR7, -OS(O)PNR10RI 15 -SS(O)PNRIORI 1, -NR7S(0)pNRioRn, -OS(O)pOR7, -SS(0)p0R7, -NR7S(O)POR7, -OC(S)R7, -SC(S)R7, -NR7C(S)R7, -OC(S)OR7, -SC(S)OR7, -NR7C(S)OR7,
-OC(S)NRi0Ri1, -SC(S)NRi0Ri i, -NR7C(S)NR10RH, -OC(NR8)R7, -SC(NR8)R7, -NR7C(NR8)R7, -OC(NR8)OR7, -SC(NR8)OR7, -NR7C(NR8)OR7, -OC(NR8)NRi0RiI, -SC(NR8)NRi0Rn5 Or -NR7C(NR8)NRi0Rn; R46, for each occurrence, is independently, selected from the group consisting of H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, -NRi0Rn5 -OR7, -C(O)R7, -C(O)OR7, -OC(O)R7, -C(O)NR10R1 1, -NR8C(O)R7, -SR7, -S(OJpR7, -OS(OJpR7, -S(O)POR7, -NR8S(O)PR7, or -S(0)pNRjoRn; R7 and R8, for each occurrence, are, independently, -H5 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 Rn, 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 Rn, taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl;
R26, for each occurrence is, is independently, a lower alkyl; p, for each occurrence, is, independently, 1 or 2; and m, for each occurrence, is independently, 1, 2, 3, or 4.
26. The compound of claim 25, wherein X41 is NR42 and X42 is CR44.
27. The compound of claim 25, wherein X41 is NR42 and X42 is N.
28. The compound of claim 25, wherein R4I is selected from the group consisting of -H, lower alkyl, lower alkoxy, lower cycloalkyl, and lower cycloalkoxy.
29. The compound of claim 25, wherein R4I is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
30. The compound of claim 25, wherein X4] is NR42, and R42 is selected from the group consisting of -H, a lower alkyl, a lower cycloalkyl, -C(O)N(R27)2, and -C(O)OH, wherein each R27 is independently -H or a lower alkyl.
31. The compound of claim 25, wherein X4] is NR42, and R42 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n- butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, -C(O)OH, -(CH2)mC(O)OH, -CH2OCH3, -CH2CH2OCH3, and -C(O)N(CH3)2. 32. The compound of claim 25, wherein R43 and R44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
33. The compound of claim 25, wherein X42 is CR44; Y40 is CR43; and R43 and R44 together with the carbon atoms to which they are attached form a cycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring.
34. The compound of claim 33, wherein R43 and R44 together with the carbon atoms to which they are attached form a Cs-C8 cycloalkenyl or a C5-C8 aryl.
35. The compound of claim 33, wherein R45 or CR45 is selected from the group consisting of -H, -OH, -SH, -NH2, a lower alkoxy, a lower alkyl amino, and a lower dialkyl amino.
36. The compound of Claim 35, wherein R45 is selected from the group consisting of -H, -OH, methoxy and ethoxy.
37. The compound of claim 33, wherein X41 is O.
38. The compound of claim 37, wherein said 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-
[l,2,4]triazole, and
3 -(2,4-dihydroxy-5 -ethyl-phenyl)-4-(2-methy 1- 1 , 3 -benzoxaz-5 -y l)-5 - mercapto-[ 1 ,2,4]triazole.
39. The compound of claim 25, wherein Z is -OH or -SH.
40. A compound of Claim 25 represented by the following structural formula:
Figure imgf000212_0001
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Zi is -OH or -SH.
41. The compound of claim 40, wherein X42 is CR44, and R43 and R44 are, independently, selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.
42. The compound of claim 40, wherein X42 is CR44, and R43 and R44, taken together with the carbon atoms to which they are attached, form a cycloalkenyl, aryl, heterocyclyl, or heteroaryl ring.
43. The compound of claim 42, wherein R43 and R44, taken together with the carbon atoms to which they are attached, form a C5-C8 cycloalkenyl or a C5-
C8 aryl.
44. The compound of claim 40, wherein X42 is CR44.
45. The compound of claim 40, wherein X42 is N.
46. A compound of Claims 40 represented by the following structural formula:
Figure imgf000213_0001
or a tautomer, pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: X45 is CR54 or N; Zl is -OH or -SH;
R.56 is selected from the group consisting of -H, methyl, ethyl, isopropyl, and cyclopropyl; R52 is selected from the group consisting of -H, methyl, ethyl, n-propyl, isopropyl, n- butyl, n-pentyl, n-hexyl, -(CH2)2OCH3, -CH2C(O)OH, and -C(O)N(CH3)2; R53 and R54 are each, independently, -H, methyl, ethyl, or isopropyl; or R53 and R54 taken together with the carbon atoms to which they are attached form a phenyl, cyclohexenyl, or cyclooctenyl ring; and R55 is selected from the group consisting of -H, -OH, -OCH3, and -OCH2CH3.
47. The compound of claim 25, wherein said compound is selected from the group consisting of:
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l,3-dimethyl-indol-5-yl)-5- hydroxy-[l ,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l,3-dimethyl-indol-5-yl)-5- hydroxy-[l ,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l-methyl-indol-5-yl)-5- hydroxy-[l,2,4]triazole, and
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l-isopropyl-indol-4-yl)-5- hydroxy-[l ,2,4]triazole. 48. The compound of claim 25, wherein said compound is selected from the group consisting of:
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l-methyl-indazol-5-yl)-5- mercapto-[l,2,4]triazole and 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l-methyl-indazol-6-yl)-5- mercapto-[l ,2,4]triazole.
49. The compound of claim 25, wherein said compound is selected from the group consisting of: 3-(2,4-dihydroxyphenyl)-4-(l-ethyl-indol-4-yl)-5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(l-isopropyl-indol-4-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(indol-4-yl)-5-mercapto-[l,2,4]triazole, 3-(2,4-dihydroxyphenyl)-4-(l-methoxyethyl-indol-4-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-indol-4-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxyphenyl)-4-(l-dimethylcarbamoyl-indol-4-yl)-5-mercapto- [l,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-propyl-indol-4-yl)-5-mercapto-
[l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l,2,3-trimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-acetyl-2,3-dimethyl-indol-5-yl)-5- mercapto-[l ,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-7-methoxy-indol-4-yl)-5- mercapto-[ 1 ,2,4]triazole, S-Ca^-dihydroxy-S-ethyl-phenyO^-Cl-propyl^^-dimethyl-indol-S-yO-S- mercapto-[l ,2,4]triazole, 3-(2,4-dihydroxy-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-[ 1 ,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-n-butyl-indol-4-yl)-5-mercapto-
[l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-n-pentyl-indol-4-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-n-hexyl-indol-4-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(l-(l-methylcyclopropyl)-indol- 4-yl)-5-mercapto-[ 1 ,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(l-isopropyl-7-methoxy-indol-4- yl)-5-mercapto-[ 1 ,2,4]triazole, 3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(l,2,3-trimethyl-indol-5-yl)-5- mercapto-[ 1 ,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-7-methoxy-indol-4-yl)-5- mercapto-[l,2,4]triazole disodium salt,
3-(2,4-dihydroxy-5-ter/-butyl-phenyl)-4-(l-isopropyl-7-methoxy-indol-4-yl)- 5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(l-propyl-7-methoxy-indol-4-yl)- 5-mercapto-[l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-methyl-3-ethyl-indol-5-yl)-5- mercapto-[l ,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l,3-dimethyl-indol-5-yl)-5-mercapto-
[l,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l-isopropyl-7-methoxy-indol-4-yl)- 5 -mercapto-[ 1 ,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-methyl-3-isopropyl-indol-5-yl)-5- mercapto-[l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-ethyl-carbozol-7-yl)-5-mercapto- [l,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-7-hydroxy-indol-4-yl)-5- mercapto-[ 1 ,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-isopropyl-7-ethoxy-indol-4-yl)-5- mercapto-[ 1 ,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l,2-dimethyl-indol-5-yl)-5-mercapto-
[l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l,3-dimethyl-indol-5-yl)-5- mercapto-[l,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(l,3-dimethyl-indol-5-yl)-5- mercapto-[l,2,4]triazole,
3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(l-methyl-indol-5-yl)-5- mercapto-[ 1 ,2,4]triazole, 3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(lH-indol-5-yl)-5-mercapto-
[l,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l,2-dimethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole,
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l-ethyl-indol-5-yl)-5-mercapto- [l,2,4]triazole, and
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l-propyl-indol-5-yl)-5-mercapto- [l,2,4]triazole.
50. The compound of claim 25, wherein said compound is selected from the group consisting of
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-ethyl-benzimidazol-4-yl)-5- mercapto-[ 1 ,2,4]triazole,
3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-ethyl-benzimidazol -4-yl)-5- mercapto-[l,2,4]triazole HCL salt, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-3-ethyl-benzimidazol-
5-yl)-5-mercapto-[l,2,4]triazole, 3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(l-ethyl-2-methyl-benzimidazol- 5-yl)-5-mercapto-[l,2,4]triazole, and
3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(l-methyl-2-trifluoromethyl- benzimidazol-5-yl)-5-mercapto-[l,2,4]triazole.
51. The compound of claim 25, wherein said compound is 3-(2,4-dihydroxy-5- isopropyl-phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto-[l,2,4]triazole.
52. A method for inhibiting Hsp90 in a cell, comprising administering to the cell an effective amount of any of the compounds of Claims 1 -51 or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
53. A method for treating or preventing a proliferation disorder in a mammal, comprising administering to the cell an effective amount of any of the compounds of Claims 1-51 or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
54. A method for treating cancer in a mammal, comprising administering to the mammal an effective amount of any of the compounds of Claims 1-51 or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
55. A method of inducing degradation of a c-kit protein, comprising administering to the mammal an effective amount of any of the compounds of Claims 1-51 or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
56. A method of treating a c-kit associated cancer in a mammal, comprising administering to the mammal an effective amount of any of the compounds of Claims 1-51 or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof. 57. A method of inducing degradation of a c-met protein, comprising administering to the mammal an effective amount of any of the compounds of Claims 1-51 or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
58. A method of treating a c-met associated cancer in a mammal, comprising administering to the mammal an effective amount of any of the compounds of Claims 1-51 or a tautomer, pharmaceutically acceptable salt, solvate, clathrate or a prodrug thereof.
59. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and one or more compounds of Claims 1-51.
PCT/US2005/041779 2004-11-18 2005-11-17 Triazole compounds that modulate hsp90 activity WO2006055760A1 (en)

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Cited By (72)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006087077A2 (en) * 2005-02-17 2006-08-24 Merck Patent Gmbh Hsp90-inhibiting triazole derivatives
EP1704856A1 (en) * 2003-12-26 2006-09-27 Kyowa Hakko Kogyo Co., Ltd. Hsp90 family protein inhibitor
WO2007021877A1 (en) * 2005-08-18 2007-02-22 Synta Pharmaceuticals Corp. Imidazole compounds that modulate hsp90 activity
WO2007139955A2 (en) * 2006-05-25 2007-12-06 Synta Pharmaceuticals Corp. Triazole compounds that modulate hsp90 activity
WO2007139952A2 (en) * 2006-05-25 2007-12-06 Synta Pharmaceuticals Corp. Method for the preparation of triazole compounds with hsp90 modulating activity
WO2007139960A2 (en) * 2006-05-25 2007-12-06 Synta Pharmaceuticals Corp. Compounds that modulate hsp90 activity and methods for identifying same
WO2007140002A2 (en) * 2006-05-25 2007-12-06 Synta Pharmaceuticals Corp. Method for treating non-hodgkin's lymphoma
WO2007139951A2 (en) * 2006-05-25 2007-12-06 Synta Pharmaceuticals Corp. Method for treating proliferative disorders associated with protooncogene products
WO2008021364A2 (en) * 2006-08-17 2008-02-21 Synta Pharmaceuticals Corp. Triazole compounds that modulate hsp90 activity
WO2007139967A3 (en) * 2006-05-25 2008-02-28 Synta Pharmaceuticals Corp Triazole compounds that modulate hsp90 activity
WO2008041610A1 (en) 2006-10-03 2008-04-10 Nippon Kayaku Kabushiki Kaisha Compound of resorcinol derivative with polymer
WO2008044034A1 (en) * 2006-10-12 2008-04-17 Astex Therapeutics Limited Hydrobenzamide derivatives as inhibitors of hsp90
WO2008051416A2 (en) * 2006-10-19 2008-05-02 Synta Pharmaceuticals Corp. Compounds that inhibit the activity of hsp90 for treating infections
WO2008049994A1 (en) 2006-10-24 2008-05-02 Sanofi-Aventis New fluorene derivatives, compositions containing the same and use thereof as inhibitors of the protein chaperone hsp 90
WO2008057246A2 (en) * 2006-10-26 2008-05-15 Synta Pharmaceuticals Corp. Method for treating inflammatory disorders
WO2008103353A1 (en) * 2007-02-20 2008-08-28 Synta Pharmaceuticals Corp. Triazole compounds that modulate hsp90 activity
WO2008112199A1 (en) * 2007-03-12 2008-09-18 Synta Pharmaceuticals Corp. Method for inhibiting topoisomerase ii
WO2008097640A3 (en) * 2007-02-08 2008-10-02 Synta Pharmaceuticals Corp Triazole compounds that are useful in the treatment of proliferative disorders, such as cancer
WO2008153730A2 (en) * 2007-05-25 2008-12-18 Synta Pharmaceuticals Corp. Method for treating proliferative disorders associated with mutations in c-met
WO2009066060A2 (en) * 2007-11-19 2009-05-28 Topotarget A/S 4-substituted-6-isopropyl-benzene-1,3-diol compounds and their use
WO2009049305A3 (en) * 2007-10-12 2009-07-02 Arqule Inc 5- (2-hydroxyphenyl) tetrazoles as hsp90 inhibitors against cancer
FR2928645A1 (en) * 2008-03-14 2009-09-18 Sanofi Aventis Sa NOVEL CARBAZOLE DERIVATIVES INHIBITORS OF HSP90, COMPOSITIONS CONTAINING SAME AND USE THEREOF
JP2009538322A (en) * 2006-05-25 2009-11-05 シンタ ファーマシューティカルズ コーポレーション Triazole compounds that modulate Hsp90 activity
WO2010017479A1 (en) * 2008-08-08 2010-02-11 Synta Pharmaceuticals Corp. Triazole compounds that modulate hsp90 activity
US7662813B2 (en) 2005-08-18 2010-02-16 Synta Pharmaceuticals Corp. Triazole compounds that modulate HSP90 activity
WO2010017545A3 (en) * 2008-08-08 2010-04-01 Synta Pharamceuticals Corp. Triazole compounds that modulate hsp90 activity
US7700625B2 (en) 2005-04-13 2010-04-20 Astex Therapeutics Ltd. Hydroxybenzamide derivatives and their use as inhibitors of Hsp90
US7754725B2 (en) 2006-03-01 2010-07-13 Astex Therapeutics Ltd. Dihydroxyphenyl isoindolymethanones
JP2010536753A (en) * 2007-08-13 2010-12-02 シンタ ファーマシューティカルズ コーポレーション Triazole compounds that modulate HSP90 activity
WO2011004132A1 (en) 2009-07-10 2011-01-13 Sanofi-Aventis Novel hsp90-inhibiting indole derivatives, compositions containing said derivatives, and use thereof
WO2011027081A2 (en) 2009-09-03 2011-03-10 Sanofi-Aventis Novel derivatives of 5,6,7,8-tetrahydroindolizine inhibiting hsp90, compositions containing same, and use thereof
JP2011511008A (en) * 2008-02-04 2011-04-07 マーキュリー セラピューティクス，インコーポレイテッド AMPK regulator
US8188222B2 (en) 2006-11-08 2012-05-29 Nippon Kayaku Kabushiki Kaisha High molecular weight derivative of nucleic acid antimetabolite
WO2012084602A1 (en) 2010-12-20 2012-06-28 Sigma-Tau Research Switzerland S.A. Aryl triazole compounds with antitumoural activity
WO2012096919A1 (en) * 2011-01-11 2012-07-19 Synta Pharmaceuticals Corp. Combination therapy of hsp90 inhibitory compounds with proteasome inhibitors
WO2012078757A3 (en) * 2010-12-08 2012-08-02 Synta Pharmaceuticals Corp. Combination for breast cancer therapy with hsp90 inhibitory compounds
WO2012116061A1 (en) * 2011-02-23 2012-08-30 Synta Pharmaceuticals Corp. Combination therapy of hsp90 inhibitory compounds with radiotherapy
WO2012162584A1 (en) * 2011-05-26 2012-11-29 Synta Pharmaceuticals Corp. Combination therapy of hsp90 inhibitory compounds with chk inhibitors
WO2012162372A1 (en) * 2011-05-24 2012-11-29 Synta Pharmaceuticals Corp. Combination therapy of hsp90 inhibitory compounds with mtor/p13k inhibitors
WO2012162293A1 (en) * 2011-05-23 2012-11-29 Synta Pharmaceuticals Corp. Combination therapy of hsp90 inhibitory compounds with mek inhibitors
US8323669B2 (en) 2006-03-28 2012-12-04 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of taxane
US8334364B2 (en) 2006-11-06 2012-12-18 Nipon Kayaku Kabushiki Kaisha High-molecular weight derivative of nucleic acid antimetabolite
WO2012141796A3 (en) * 2011-02-24 2012-12-27 Synta Pharmaceuticals Corp. Prostate cancer therapy with hsp90 inhibitory compounds
US20130156755A1 (en) * 2010-04-19 2013-06-20 Synta Pharmaceuticals Corp. Cancer therapy using a combination of a hsp90 inhibitory compounds and a vegf inhibitor
WO2013148857A1 (en) * 2012-03-28 2013-10-03 Synta Pharmaceuticals Corp. Triazole derivatives as hsp90 inhibitors
US8703878B2 (en) 2007-09-28 2014-04-22 Nippon Kayaku Kabushiki Kaisha High-molecular weight conjugate of steroids
WO2014063080A1 (en) * 2012-10-19 2014-04-24 Synta Pharmaceuticals Corp. Treating polycystic kidney disease with hsp90 inhibitory compounds
US8808749B2 (en) 2009-05-15 2014-08-19 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of bioactive substance having hydroxy group
AU2012200157B2 (en) * 2006-05-25 2014-08-21 Synta Pharmaceuticals Corp. Method for treating proliferative disorders associated with protooncogene products
US8901308B2 (en) 2004-11-18 2014-12-02 Synta Pharmaceuticals Corp. Triazole compounds that modulate Hsp90 activity
US8920788B2 (en) 2008-03-18 2014-12-30 Nippon Kayaku Kabushiki Kaisha High-molecular weight conjugate of physiologically active substances
US8940332B2 (en) 2006-05-18 2015-01-27 Nippon Kayaku Kabushiki Kaisha High-molecular weight conjugate of podophyllotoxins
US9018323B2 (en) 2010-11-17 2015-04-28 Nippon Kayaku Kabushiki Kaisha Polymer derivative of cytidine metabolic antagonist
US9149540B2 (en) 2008-05-08 2015-10-06 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of folic acid or folic acid derivative
WO2015167211A1 (en) * 2014-04-30 2015-11-05 경북대학교 산학협력단 3-aryl-1,2,4-triazole derivative and use thereof
KR20150125596A (en) * 2014-04-30 2015-11-09 경북대학교 산학협력단 3-Aryl-1,2,4-triazole derivatives and use thereof
US9346923B2 (en) 2011-09-11 2016-05-24 Nippon Kayaku Kabushiki Kaisha Method for manufacturing block copolymer
US9573936B2 (en) 2015-05-20 2017-02-21 Amgen Inc. Triazole agonists of the APJ receptor
US9598365B2 (en) 2012-05-22 2017-03-21 Trustees Of Dartmouth College Method for synthesizing cycloalkanyl[b]indoles, cycloalkanyl[b]benzofurans, cycloalkanyl[b]benzothiophenes, compounds and methods of use
US9730912B2 (en) 2006-10-12 2017-08-15 Astex Therapeutics Limited Pharmaceutical compounds
US20180009794A1 (en) * 2015-01-22 2018-01-11 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Resorcinol Derivative As HSP90 Inhibitor
US9988369B2 (en) 2016-05-03 2018-06-05 Amgen Inc. Heterocyclic triazole compounds as agonists of the APJ receptor
US10689367B2 (en) 2016-11-16 2020-06-23 Amgen Inc. Triazole pyridyl compounds as agonists of the APJ receptor
US10736883B2 (en) 2016-11-16 2020-08-11 Amgen Inc. Triazole furan compounds as agonists of the APJ receptor
WO2020205948A1 (en) * 2019-04-03 2020-10-08 Tarveda Therapeutics, Inc. Hsp90-binding conjugates and formulations thereof
US10906890B2 (en) 2016-11-16 2021-02-02 Amgen Inc. Triazole phenyl compounds as agonists of the APJ receptor
US11020395B2 (en) 2016-11-16 2021-06-01 Amgen Inc. Cycloalkyl substituted triazole compounds as agonists of the APJ receptor
US11046680B1 (en) 2016-11-16 2021-06-29 Amgen Inc. Heteroaryl-substituted triazoles as APJ receptor agonists
US11149040B2 (en) 2017-11-03 2021-10-19 Amgen Inc. Fused triazole agonists of the APJ receptor
US11168093B2 (en) 2018-12-21 2021-11-09 Celgene Corporation Thienopyridine inhibitors of RIPK2
US11191762B2 (en) 2016-11-16 2021-12-07 Amgen Inc. Alkyl substituted triazole compounds as agonists of the APJ Receptor
US11807624B2 (en) 2018-05-01 2023-11-07 Amgen Inc. Substituted pyrimidinones as agonists of the APJ receptor

Families Citing this family (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2598899A1 (en) * 2005-03-09 2006-09-14 Nippon Kayaku Kabushiki Kaisha Novel hsp90 inhibitor
US8399464B2 (en) * 2005-03-09 2013-03-19 Nippon Kayaku Kabushiki Kaisha HSP90 inhibitor
CA2618377A1 (en) 2005-08-12 2007-02-22 Synta Pharmaceuticals Corp. Pyrazole compounds that modulate hsp90 activity
US20070250391A1 (en) * 2006-04-05 2007-10-25 Prade Hendrik D Merchandising system and method for food and non-food items for a meal kit
EP2073807A1 (en) 2006-10-12 2009-07-01 Astex Therapeutics Limited Pharmaceutical combinations
JP5528806B2 (en) 2006-10-12 2014-06-25 アステックス、セラピューティックス、リミテッド Compound drug
DE102007002715A1 (en) * 2007-01-18 2008-07-24 Merck Patent Gmbh triazole
KR100947696B1 (en) * 2007-11-23 2010-03-16 재단법인서울대학교산학협력재단 Hsp90 ihbibitors containing 1,2,4-triazole derivatives and anti-cancer drugs using them
WO2009139916A1 (en) * 2008-05-16 2009-11-19 Synta Pharmaceuticals Corp. Tricyclic triazole compounds that modulate hsp90 activity
US8450500B2 (en) 2008-06-04 2013-05-28 Synta Pharmaceuticals Corp. Pyrrole compounds that modulate HSP90 activity
WO2009158026A1 (en) 2008-06-27 2009-12-30 Synta Pharmaceuticals Corp. Hydrazonamide compounds that modulate hsp90 activity
NZ622713A (en) 2009-10-19 2015-07-31 Synta Pharmaceuticals Corp Combination cancer therapy with hsp90 inhibitory compounds
US9205086B2 (en) * 2010-04-19 2015-12-08 Synta Pharmaceuticals Corp. Cancer therapy using a combination of a Hsp90 inhibitory compounds and a EGFR inhibitor
WO2011146803A1 (en) 2010-05-20 2011-11-24 Synta Pharmaceuticals Corp. Method of treating lung adenocarcinoma with hsp90 inhibitory compounds
US20130172333A1 (en) 2010-05-20 2013-07-04 Synta Pharmaceuticals Corp. Formulation and dosing of hsp90 inhibitory compounds
US20130171105A1 (en) 2010-05-24 2013-07-04 Synta Pharmaceuticals Corp. Cancer therapy using a combination of a hsp90 inhibitory compound and a topoisomerase ii inhibitor
WO2012026433A1 (en) * 2010-08-23 2012-03-01 第一三共株式会社 Free crystal of tricyclic pyrazolopyrimidine derivative
EP2616063A1 (en) 2010-09-13 2013-07-24 Synta Pharmaceuticals Corp. Hsp90 inhibitors for treating non-small cell lung cancers in wild-type egfr and/or kras patients
CA2817564A1 (en) 2010-11-18 2012-05-24 Ronald K. Blackman Preselection of subjects for therapeutic treatment based on hypoxic status
WO2012068487A1 (en) 2010-11-18 2012-05-24 Synta Pharmaceuticals Corp. Preselection of subjects for therapeutic treatment with oxygen sensitive agents based on hypoxic status
WO2012116247A1 (en) 2011-02-25 2012-08-30 Synta Pharmaceuticals Corp. Hsp90 inhibitory compounds in treating jak/stat signaling-mediated cancers
US8906885B2 (en) 2011-07-07 2014-12-09 Synta Pharmaceuticals Corp. Treating cancer with HSP90 inhibitory compounds
WO2013028505A1 (en) * 2011-08-19 2013-02-28 Synta Pharmaceuticals Corp. Combination cancer therapy of hsp90 inhibitor with antimetabolite
WO2013067162A1 (en) 2011-11-02 2013-05-10 Synta Pharmaceuticals Corp. Cancer therapy using a combination of hsp90 inhibitors with topoisomerase i inhibitors
CA2853806C (en) 2011-11-02 2020-07-14 Synta Pharmaceuticals Corp. Combination therapy of hsp90 inhibitors with platinum-containing agents
AU2012339679A1 (en) 2011-11-14 2014-06-12 Synta Pharmaceuticals Corp. Combination therapy of Hsp90 inhibitors with BRAF inhibitors
US20140079636A1 (en) 2012-04-16 2014-03-20 Dinesh U. Chimmanamada Targeted therapeutics
JP2015516439A (en) 2012-05-10 2015-06-11 シンタ ファーマシューティカルズ コーポレーション Treating cancer with Hsp90-inhibiting compounds
WO2015038649A1 (en) 2013-09-10 2015-03-19 Synta Pharmaceuticals Corp. Targeted therapeutics
WO2015066053A2 (en) * 2013-10-28 2015-05-07 Synta Pharmaceuticals Corp. Targeted therapeutics
MA39481A (en) 2014-03-03 2015-09-11 Synta Pharmaceuticals Corp TARGETED THERAPIES
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LT3179991T (en) 2014-08-11 2021-11-10 Acerta Pharma B.V. Therapeutic combinations of a btk inhibitor and a bcl-2 inhibitor
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US10626096B2 (en) 2015-11-24 2020-04-21 Sanford Burnham Prebys Medical Discovery Institute Azole derivatives as apelin receptor agonist
US11154538B2 (en) 2016-02-29 2021-10-26 Synta Pharmaceuticals Corporation Combination therapy for treatment of ovarian cancer
CN109666022B (en) * 2017-10-17 2021-06-15 中国科学院上海药物研究所 Triazole derivative and preparation method and application thereof
EP3653611A1 (en) * 2018-11-15 2020-05-20 Centre National De La Recherche Scientifique Inhibitors of metallo-beta-lactamases

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5489598A (en) * 1994-06-08 1996-02-06 Warner-Lambert Company Cytoprotection utilizing aryltriazol-3-thiones
WO2003055860A1 (en) * 2001-12-21 2003-07-10 Vernalis (Cambridge) Limited 3,4-diarylpyrazoles and their use in the therapy of cancer
WO2005000300A1 (en) * 2003-06-27 2005-01-06 Vernalis (Cambridge) Limited Substituted 5-membered ring compounds and their use
WO2005097758A1 (en) * 2004-03-26 2005-10-20 Amphora Discovery Corporation Certain triazole-based compounds, compositions, and uses thereof

Family Cites Families (129)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB928919A (en) * 1960-08-16 1963-06-19 Bellon Labor Sa Roger Triazole derivatives and a process for their preparation
US3536809A (en) 1969-02-17 1970-10-27 Alza Corp Medication method
US3598123A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3845770A (en) 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3916899A (en) 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US4008719A (en) 1976-02-02 1977-02-22 Alza Corporation Osmotic system having laminar arrangement for programming delivery of active agent
US4178253A (en) * 1977-04-05 1979-12-11 Ciba-Geigy Corporation Corrosion inhibited lubricant compositions
US4269846A (en) * 1979-10-29 1981-05-26 Usv Pharmaceutical Corporation Heterocyclic compounds useful as anti-allergy agents
JPS5770820A (en) 1980-10-20 1982-05-01 Haruo Ogura Immunoregulating agent
JPS5910574A (en) 1982-07-07 1984-01-20 Fujisawa Pharmaceut Co Ltd Triazole derivative and its preparation
FR2546887B1 (en) 1983-05-30 1985-08-30 Paris 7 Universite PROCESS FOR THE PREPARATION OF 2,4-DIHYDRO-TRIAZOL-1,2,4 THIONES-3 DISUBSTITUTED IN POSITIONS 4 AND 5 AND NOVEL COMPOUNDS THAT CAN BE PREPARED BY THIS PROCESS
IE58110B1 (en) 1984-10-30 1993-07-14 Elan Corp Plc Controlled release powder and process for its preparation
US4740568A (en) * 1985-04-09 1988-04-26 Minnesota Mining And Manufacturing Company Triazolinethione-containing polymer
US4624995A (en) * 1985-04-09 1986-11-25 Minnesota Mining And Manufacturing Company Triazolinethione-containing polymer
US5436252A (en) * 1986-12-19 1995-07-25 Merrell Dow Pharmaceuticals Inc. 5-aryl-3H-1,2,4-triazol-3-ones and their use in the treatment of neurodegenerative disorders
US5006650A (en) * 1987-02-11 1991-04-09 The Upjohn Company Novel N-1 substituted beta-lactams as antibiotics
DE3729070A1 (en) * 1987-09-01 1989-03-09 Bayer Ag SUBSTITUTED TRIAZOLINONES
US5241074A (en) * 1988-05-09 1993-08-31 Bayer Aktiengesellschaft Sulphonylaminocarbonyltriazolinones
US5073543A (en) 1988-07-21 1991-12-17 G. D. Searle & Co. Controlled release formulations of trophic factors in ganglioside-lipsome vehicle
IT1229203B (en) 1989-03-22 1991-07-25 Bioresearch Spa USE OF 5 METHYLTHETRAHYDROPHOLIC ACID, 5 FORMYLTHETRAHYDROPHOLIC ACID AND THEIR PHARMACEUTICALLY ACCEPTABLE SALTS FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS IN THE FORM OF CONTROLLED RELEASE ACTIVE IN THE THERAPY OF MENTAL AND ORGANIC DISORDERS.
US5120548A (en) 1989-11-07 1992-06-09 Merck & Co., Inc. Swelling modulated polymeric drug delivery device
US5733566A (en) 1990-05-15 1998-03-31 Alkermes Controlled Therapeutics Inc. Ii Controlled release of antiparasitic agents in animals
US5219722A (en) * 1990-09-21 1993-06-15 Konica Corporation Silver halide color photographic light-sensitive material
CZ283018B6 (en) * 1991-02-01 1997-12-17 Merck Sharp And Dohme Limited Imidazole, triazole and tetrazole derivatives, process of their preparation, their use and pharmaceuticals based thereon
US5580578A (en) 1992-01-27 1996-12-03 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
EP0630374B1 (en) * 1992-03-13 2001-09-05 MERCK SHARP & DOHME LTD. Imidazole, triazole and tetrazole derivatives
TW218017B (en) * 1992-04-28 1993-12-21 Takeda Pharm Industry Co Ltd
DE4222771A1 (en) * 1992-07-10 1994-01-13 Bayer Ag Heterocyclyltriazolinones
DE4234801A1 (en) * 1992-10-15 1994-04-21 Bayer Ag Sulfonylaminocarbonyltriazolinone
US5591767A (en) 1993-01-25 1997-01-07 Pharmetrix Corporation Liquid reservoir transdermal patch for the administration of ketorolac
DE4303376A1 (en) * 1993-02-05 1994-08-11 Bayer Ag Substituted triazolinones
DE4303676A1 (en) * 1993-02-09 1994-08-11 Bayer Ag 1-aryltriazolin (thi) one
DE4411913A1 (en) * 1994-04-07 1995-10-12 Bayer Ag Substituted sulfonylaminocarbonyltriazolinones
US5538988A (en) * 1994-04-26 1996-07-23 Martinez; Gregory R. Benzocycloalkylazolethione derivatives
IT1270594B (en) 1994-07-07 1997-05-07 Recordati Chem Pharm CONTROLLED RELEASE PHARMACEUTICAL COMPOSITION OF LIQUID SUSPENSION MOGUISTEIN
JP3372365B2 (en) * 1994-08-19 2003-02-04 富士写真フイルム株式会社 Silver halide photographic material and image forming method using the same
DE19502579A1 (en) * 1995-01-27 1996-08-01 Bayer Ag Sulfonylamino (thio) carbonyl-triazolin (thi) one
US6080772A (en) 1995-06-07 2000-06-27 Sugen, Inc. Thiazole compounds and methods of modulating signal transduction
DE19521162A1 (en) * 1995-06-09 1996-12-12 Bayer Ag N-aryl-1,2,4-triazolin-5-one
DE19525162A1 (en) * 1995-07-11 1997-01-16 Bayer Ag Sulfonylamino (thio) carbonyl compounds
JP4108747B2 (en) 1995-07-13 2008-06-25 アボット ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト Piperazine derivatives as therapeutic agents
DE19540737A1 (en) * 1995-11-02 1997-05-07 Bayer Ag Substituted sulfonylamino (thio) carbonyl compounds
DE19609059A1 (en) * 1996-03-08 1997-09-11 Bayer Ag Substituted arylsulfonylamino (thio) carbonyl-triazolin (thi) one
US6274171B1 (en) 1996-03-25 2001-08-14 American Home Products Corporation Extended release formulation of venlafaxine hydrochloride
ZA974703B (en) * 1996-05-30 1997-12-30 Bayer Ag Substituted sulfonylamino(thio)carbonyl compounds.
TW467902B (en) 1996-07-31 2001-12-11 Bristol Myers Squibb Co Diphenyl heterocycles as potassium channel modulators
DE19632945A1 (en) * 1996-08-16 1998-02-19 Bayer Ag Substituted sulfonylamino (thio) carbonyl compounds
CA2269617A1 (en) * 1996-11-12 1998-05-22 Chris H. Senanayake 2r,4s,r,s- and 2s,4r,r,s-hydroxyitraconazole- and hydroxysaperconazole derivatives
US5968921A (en) * 1997-10-24 1999-10-19 Orgegon Health Sciences University Compositions and methods for promoting nerve regeneration
JP3788676B2 (en) * 1997-11-11 2006-06-21 富士写真フイルム株式会社 Organic electroluminescent device material and organic electroluminescent device using the same
US6583090B1 (en) * 1998-03-09 2003-06-24 Basf Aktiengesellschaft Hetaryl-substituted benzyl phenyl ethers, method for the production thereof, and their use for combating harmful fungi and animal pests
US6185567B1 (en) * 1998-05-29 2001-02-06 The Trustees Of The University Of Pennsylvania Authenticated access to internet based research and data services
IT1302034B1 (en) * 1998-08-31 2000-07-20 Enirisorse Spa SUPER-ACID SOLID CATALYSTS FOR THE ISOMERIZATION OF HYDROCARBONS AND SOL-GEL PROCESS FOR THEIR OBTAINING
JP2000100570A (en) 1998-09-25 2000-04-07 Toray Ind Inc Luminescent device
JP2000284412A (en) 1999-03-30 2000-10-13 Fuji Photo Film Co Ltd Heat developable photographic material
US6492406B1 (en) * 1999-05-21 2002-12-10 Astrazeneca Ab Pharmaceutically active compounds
US20040110684A1 (en) * 1999-08-02 2004-06-10 Universite Catholique De Louvain Novel pharmaceutical compositions for modulating angiogenesis
WO2001072779A1 (en) * 2000-03-24 2001-10-04 Duke University Characterization of grp94-ligand interactions and purification, screening, and therapeutic methods relating thereto
CA2409819C (en) 2000-05-19 2009-09-15 Yamanouchi Pharmaceutical Co., Ltd. Triazole derivatives
US20030216385A1 (en) * 2000-05-19 2003-11-20 Takahiko Tobe Triazole derivatives
WO2002002123A1 (en) * 2000-06-29 2002-01-10 Trustees Of Boston University Use of geldanamycin and related compounds for prophylaxis or treatment of fibrogenic disorders
US6946456B2 (en) * 2000-07-28 2005-09-20 Sloan-Kettering Institute For Cancer Research Methods for treating cell proliferative disorders and viral infections
EP2308515A1 (en) 2000-11-02 2011-04-13 Sloan-Kettering Institute For Cancer Research Methods for enhancing the efficacy of cytotoxic agents through the use of HSP90 inhibitors
WO2002066447A1 (en) 2001-02-21 2002-08-29 Ono Pharmaceutical Co., Ltd. 4h-1,2,4-triazole-3(2h)-thione deratives as sphingomyelinase inhibitors
WO2002069900A2 (en) 2001-03-01 2002-09-12 Conforma Therapeutics Corp. Methods for treating genetically-defined proliferative disorders with hsp90 inhibitors
WO2002094259A1 (en) * 2001-05-03 2002-11-28 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Compounds that inhibit hsp90 and stimulate hsp70 and hsp40, useful in the prevention or treatment of diseases associated with protein aggregation and amyloid formation
JP2004529188A (en) * 2001-05-23 2004-09-24 スローン − ケッタリング インスティチュート フォー キャンサー リサーチ Treatment of cancer associated with elevation
JP4102124B2 (en) 2001-08-01 2008-06-18 富士フイルム株式会社 Silver halide emulsion and silver halide photographic light-sensitive material
WO2003013430A2 (en) 2001-08-06 2003-02-20 Kosan Biosciences, Inc. Benzoquinone ansamycins
US20050154039A1 (en) 2001-11-28 2005-07-14 Marie-Odile Glacera Contour 5-Sulphanyl-4h-1,2,4-triazole derivatives and their use as medicine
WO2003050295A2 (en) 2001-12-12 2003-06-19 Conforma Therapeutics Corporation Assays and implements for determining and modulating hsp90 binding activity
US7045520B2 (en) 2002-02-07 2006-05-16 The Curators Of The University Of Missouri Opioid receptor active compounds
GB0207362D0 (en) 2002-03-28 2002-05-08 Univ Liverpool Chemotherapy
GB0208516D0 (en) 2002-04-15 2002-05-22 Univ Liverpool Chemotherapy
GB0228417D0 (en) 2002-12-05 2003-01-08 Cancer Rec Tech Ltd Pyrazole compounds
GB0229618D0 (en) 2002-12-19 2003-01-22 Cancer Rec Tech Ltd Pyrazole compounds
JP4921162B2 (en) 2003-02-11 2012-04-25 ヴァーナリス（ケンブリッジ）リミテッド Isoxazole compounds as inhibitors of heat shock proteins
EP1457499A1 (en) 2003-03-12 2004-09-15 Tufts University School Of Medicine Inhibitors of extracellular Hsp90
JP2006514994A (en) 2003-03-13 2006-05-18 コンフォーマ・セラピューティクス・コーポレイション Pharmaceutical formulations with long and medium chain triglycerides
CZ300336B6 (en) 2003-03-17 2009-04-22 Seco Tools Ab Indexable cutting insert for a milling tool
BR0301799A (en) 2003-04-09 2005-03-22 Elzo Ferreira Use of the extraction process of extract, sap, tincture, mass and products derived therefrom, originating from the xaxim - dicksonia sellowiana - presl - hooker 1844 plant belonging to the dicksoniaceae family for use in the following areas and sectors: human chemistry, industrial, pharmacological, human and animal biology, medicinal, phytomedicinal, herbal medicine, allopath, food, nutritional, vitamin, dermatological, cosmetic and veterinary
JP2006522745A (en) * 2003-04-11 2006-10-05 ノボ　ノルディスク　アクティーゼルスカブ Pharmaceutical use of substituted 1,2,4-triazoles
JP2006522750A (en) 2003-04-11 2006-10-05 ノボ　ノルディスク　アクティーゼルスカブ Combination therapy using 11β-hydroxysteroid dehydrogenase type 1 inhibitors and antihypertensive agents to treat metabolic syndrome and related diseases and disorders
WO2004089415A2 (en) * 2003-04-11 2004-10-21 Novo Nordisk A/S COMBINATIONS OF AN 11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 INHIBITOR AND A GLUCOCORTICOID RECEPTOR AGONIST
SE0301232D0 (en) 2003-04-25 2003-04-25 Astrazeneca Ab Novel use
GB0309637D0 (en) 2003-04-28 2003-06-04 Cancer Rec Tech Ltd Pyrazole compounds
US20050020556A1 (en) * 2003-05-30 2005-01-27 Kosan Biosciences, Inc. Method for treating diseases using HSP90-inhibiting agents in combination with platinum coordination complexes
US20050026893A1 (en) * 2003-05-30 2005-02-03 Kosan Biosciences, Inc. Method for treating diseases using HSP90-inhibiting agents in combination with immunosuppressants
US20050020534A1 (en) * 2003-05-30 2005-01-27 Kosan Biosciences, Inc. Method for treating diseases using HSP90-inhibiting agents in combination with antimetabolites
US20050054625A1 (en) * 2003-05-30 2005-03-10 Kosan Biosciences, Inc. Method for treating diseases using HSP90-inhibiting agents in combination with nuclear export inhibitors
US7691838B2 (en) * 2003-05-30 2010-04-06 Kosan Biosciences Incorporated Method for treating diseases using HSP90-inhibiting agents in combination with antimitotics
US20050054589A1 (en) * 2003-05-30 2005-03-10 Kosan Biosciences, Inc. Method for treating diseases using HSP90-inhibiting agents in combination with antibiotics
US20050020557A1 (en) * 2003-05-30 2005-01-27 Kosan Biosciences, Inc. Method for treating diseases using HSP90-inhibiting agents in combination with enzyme inhibitors
ATE389651T1 (en) 2003-08-15 2008-04-15 Vertex Pharma PYRROLE COMPOSITIONS SUITABLE AS INHIBITORS OF C-MET
JP2005084612A (en) 2003-09-11 2005-03-31 Fuji Photo Film Co Ltd Silver halide emulsion, silver halide photosensitive material and heat developable photosensitive material
EP1673355A1 (en) * 2003-09-22 2006-06-28 Pfizer Limited Substituted triazole derivatives as oxytocin antagonists
MXPA06003163A (en) 2003-09-23 2006-06-05 Novartis Ag Combination of a vegf receptor inhibitor with a chemotherapeutic agent.
WO2005040345A2 (en) 2003-09-24 2005-05-06 Vertex Pharmceuticals Incorporated 4-azole substituted imidazole compositions useful as inhibitors or c-met receptor tyrosine kinase
US20050085531A1 (en) 2003-10-03 2005-04-21 Hodge Carl N. Thiophene-based compounds exhibiting ATP-utilizing enzyme inhibitory activity, and compositions, and uses thereof
EP1677786A1 (en) 2003-10-18 2006-07-12 Bayer HealthCare AG 5-substituted 2-(phenylmethyl)thio-4-phenyl-4h-1,2,4-triazole derivatives and related compounds as gaba-agonists for the treatment of urinary incontinence and related diseases
WO2005041879A2 (en) 2003-10-28 2005-05-12 Pharmacia Corporation COMBINATIONS COMPRISING AN Hsp90 INHIBITOR AND A PHOPHODIESTERASE INHIBITOR FOR TREATING OR PREVENTING NEOPLASIA
WO2005044194A2 (en) 2003-10-28 2005-05-19 Pharmacia Corporation TREATMENT OR PREVENTION OF NEOPLASIA BY USE OF AN Hsp90 INHIBITOR
WO2005087750A1 (en) * 2004-03-08 2005-09-22 Wyeth Ion channel modulators
DE102004039280A1 (en) 2004-08-13 2006-02-23 Merck Patent Gmbh 1,5-diphenyl-pyrazoles
DE102004049078A1 (en) 2004-10-08 2006-04-13 Merck Patent Gmbh phenylpyrazoles
KR101374553B1 (en) 2004-11-18 2014-03-17 신타 파마슈티칼스 코프. Triazole compounds that modulate hsp90 activity
DE102005007304A1 (en) 2005-02-17 2006-08-24 Merck Patent Gmbh triazole derivatives
CA2598899A1 (en) 2005-03-09 2006-09-14 Nippon Kayaku Kabushiki Kaisha Novel hsp90 inhibitor
JP2008137894A (en) 2005-03-22 2008-06-19 Nippon Kayaku Co Ltd New acetylene derivative
US7473784B2 (en) 2005-08-01 2009-01-06 Bristol-Myers Squibb Company Benzothiazole and azabenzothiazole compounds useful as kinase inhibitors
CA2618377A1 (en) * 2005-08-12 2007-02-22 Synta Pharmaceuticals Corp. Pyrazole compounds that modulate hsp90 activity
JP5118039B2 (en) * 2005-08-18 2013-01-16 シンタ ファーマシューティカルズ コーポレーション Triazole compounds that modulate HSP90 activity
CA2618724A1 (en) * 2005-08-18 2007-02-22 Synta Pharmaceuticals Corp. Imidazole compounds that modulate hsp90 activity
AU2007267847B2 (en) * 2006-05-25 2012-04-12 Synta Pharmaceuticals Corp. Triazole compounds that modulate Hsp90 activity
TW200800260A (en) * 2006-05-25 2008-01-01 Synta Pharmaceuticals Corp Method for treating proliferative disorders associated with protooncogene products
CA2653327A1 (en) * 2006-05-25 2007-12-06 Synta Pharmaceuticals Corp. Compounds that modulate hsp90 activity and methods for identifying same
EP2035396B1 (en) * 2006-05-25 2014-05-14 Synta Pharmaceuticals Corp. Triazole compounds that modulate hsp90 activity
EP2038262B1 (en) * 2006-05-25 2014-11-12 Synta Pharmaceuticals Corp. Triazole compounds that modulate hsp90 activity
US8063083B2 (en) * 2006-05-25 2011-11-22 Synta Pharmaceuticals Corp. Method for treating non-Hodgkin's lymphoma
US8188075B2 (en) * 2006-08-17 2012-05-29 Synta Pharmaceuticals Corp. Triazole compounds that modulate HSP90 activity
US20110046125A1 (en) 2006-10-19 2011-02-24 Synta Pharmaceuticals Corp. Method for treating infections
US20100280032A1 (en) 2006-10-26 2010-11-04 Synta Pharmaceuticals Corp. Method for treating inflammatory disorders
BRPI0807219A2 (en) 2007-02-08 2015-05-26 Synta Pharmaceuticals Corp Thiazole Compounds that modulate hsp90 activity
TW200904417A (en) 2007-02-20 2009-02-01 Synta Pharmaceuticals Corp Triazole compounds that modulate Hsp90 activity
US8993608B2 (en) 2007-03-12 2015-03-31 Synta Pharmaceuticals Corp. Method for inhibiting topoisomerase II
AU2008232354B9 (en) 2007-03-27 2012-07-26 Synta Pharmaceuticals Corp. Triazinone and diazinone derivatives useful as Hsp90 inhibitors
WO2008153730A2 (en) 2007-05-25 2008-12-18 Synta Pharmaceuticals Corp. Method for treating proliferative disorders associated with mutations in c-met
WO2009023211A1 (en) 2007-08-13 2009-02-19 Synta Pharmaceuticals Corp. Triazole compounds that modulate hsp90 activity
US8548104B2 (en) * 2010-11-23 2013-10-01 Siano Mobile Silicon Ltd. Receiver with configurable clock frequencies

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5489598A (en) * 1994-06-08 1996-02-06 Warner-Lambert Company Cytoprotection utilizing aryltriazol-3-thiones
WO2003055860A1 (en) * 2001-12-21 2003-07-10 Vernalis (Cambridge) Limited 3,4-diarylpyrazoles and their use in the therapy of cancer
WO2005000300A1 (en) * 2003-06-27 2005-01-06 Vernalis (Cambridge) Limited Substituted 5-membered ring compounds and their use
WO2005097758A1 (en) * 2004-03-26 2005-10-20 Amphora Discovery Corporation Certain triazole-based compounds, compositions, and uses thereof

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
B. W. DYMOCK ET AL.: "Inhibitors of HSP90 and other chaperones for the treatment of cancer", EXPERT OPIN. THER. PATENTS, vol. 14, no. 6, June 2004 (2004-06-01), pages 837 - 847, XP002372377 *
DATABASE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002372385, Database accession no. 625992 (BRN) *
DATABASE BEILSTEIN [online] Beilstein Institut zur Förderung der Chemischen Wissenschaften, Frankfurt am Main, DE; XP002372386, Database accession no. 574001 (BRN) *
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002372384, retrieved from STN Database accession no. 1989:8130 *
DOLESCHALL, ACTA CHIM. ACAD. SCI. HUNG., vol. 90, 1976, pages 419 - 422 *
GAWANDE ET AL.: "Synthesis of some thiosemicarbazides and related compounds", ACTA CIENCIA INDICA, CHEMISTRY, vol. 13, no. 2, 1987, pages 109 - 111 *
L. LABANAUSKAS ET AL.: "Synthesis of 5-(2-,3- and 4-methoxyphenyl)-4H-1,2,4-triazole-3-thiol derivatives exhibiting anti-inflammatory activity", IL FARMACO, vol. 59, April 2004 (2004-04-01), pages 255 - 259, XP002372378 *
M. TANDON ET AL., INDIAN JOURNAL OF CHEMISTRY, SECTION B: ORGANIC CHEMISTRY INCLUDING MEDICINAL CHEMISTRY, vol. 20b, no. 11, 1981, pages 1017 - 1018, XP009063370 *
ROSTOM S A F ET AL: "Polysubstituted pyrazoles, part 5. Synthesis of new 1-(4-chlorophenyl)-4-hydroxy-1H-pyrazole-3-carboxylic acid hydrazide analogs and some derived ring systems. A novel class of potential antitumor and anti-HCV agents", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 38, no. 11-12, November 2003 (2003-11-01), pages 959 - 974, XP004475841, ISSN: 0223-5234 *
SHAH ET AL., INDIAN J. CHEM., vol. 5, 1967, pages 391 - 392 *

Cited By (153)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1704856A1 (en) * 2003-12-26 2006-09-27 Kyowa Hakko Kogyo Co., Ltd. Hsp90 family protein inhibitor
EP1704856A4 (en) * 2003-12-26 2009-08-19 Kyowa Hakko Kirin Co Ltd Hsp90 family protein inhibitor
US9090569B2 (en) 2004-11-18 2015-07-28 Synta Pharmaceuticals Corp. Triazone compounds that modulate HSP90 activity
US8901308B2 (en) 2004-11-18 2014-12-02 Synta Pharmaceuticals Corp. Triazole compounds that modulate Hsp90 activity
WO2006087077A3 (en) * 2005-02-17 2006-11-02 Merck Patent Gmbh Hsp90-inhibiting triazole derivatives
JP2008530149A (en) * 2005-02-17 2008-08-07 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング Triazole derivative
US8618285B2 (en) 2005-02-17 2013-12-31 Merck Patent Gmbh Triazole derivatives
WO2006087077A2 (en) * 2005-02-17 2006-08-24 Merck Patent Gmbh Hsp90-inhibiting triazole derivatives
US7700625B2 (en) 2005-04-13 2010-04-20 Astex Therapeutics Ltd. Hydroxybenzamide derivatives and their use as inhibitors of Hsp90
US8101648B2 (en) 2005-04-13 2012-01-24 Astex Therapeutics, Ltd. Hydroxybenzamide derivatives and their use as inhibitors of HSP90
US9914719B2 (en) 2005-04-13 2018-03-13 Astex Therapeutics Ltd. Hydroxybenzamide derivatives and their use as inhibitors of HSP90
US9156794B2 (en) 2005-08-18 2015-10-13 Synta Pharmaceuticals Corp. Imidazole compounds that modulate HSP90 activity
US8629285B2 (en) 2005-08-18 2014-01-14 Synta Pharmaceuticals Corp. Imidazole compounds that modulate HSP90 activity
US7662813B2 (en) 2005-08-18 2010-02-16 Synta Pharmaceuticals Corp. Triazole compounds that modulate HSP90 activity
AU2006338265B2 (en) * 2005-08-18 2011-04-14 Synta Pharmaceuticals Corp. Triazole compounds that modulate HSP90 activity
WO2007021877A1 (en) * 2005-08-18 2007-02-22 Synta Pharmaceuticals Corp. Imidazole compounds that modulate hsp90 activity
US7754725B2 (en) 2006-03-01 2010-07-13 Astex Therapeutics Ltd. Dihydroxyphenyl isoindolymethanones
US8106057B2 (en) 2006-03-01 2012-01-31 Astex Therapeutics, Ltd. Dihydroxyphenyl isoindolylmethanones
US8323669B2 (en) 2006-03-28 2012-12-04 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of taxane
US8940332B2 (en) 2006-05-18 2015-01-27 Nippon Kayaku Kabushiki Kaisha High-molecular weight conjugate of podophyllotoxins
US8034834B2 (en) 2006-05-25 2011-10-11 Synta Pharmaceuticals Corp. Method for treating proliferative disorders with HSP90 inhibitors
US8053456B2 (en) 2006-05-25 2011-11-08 Synta Pharmaceuticals Corp. Triazole compounds that modulate Hsp90 activity
US8318790B2 (en) 2006-05-25 2012-11-27 Synta Pharmaceuticals Corp. Triazole compounds that modulate HSP90 activity
AU2012200157B2 (en) * 2006-05-25 2014-08-21 Synta Pharmaceuticals Corp. Method for treating proliferative disorders associated with protooncogene products
US9006277B2 (en) 2006-05-25 2015-04-14 Synta Pharmaceuticals Corp. Triazole compounds that modulate HSP90 activity
US8835464B2 (en) 2006-05-25 2014-09-16 Synta Pharmaceuticals Corp. Triazole compounds that modulate HSP90 activity
WO2007139951A3 (en) * 2006-05-25 2008-12-24 Synta Pharmaceuticals Corp Method for treating proliferative disorders associated with protooncogene products
WO2007140002A3 (en) * 2006-05-25 2008-12-24 Synta Pharmaceuticals Corp Method for treating non-hodgkin's lymphoma
WO2007139955A2 (en) * 2006-05-25 2007-12-06 Synta Pharmaceuticals Corp. Triazole compounds that modulate hsp90 activity
US8415377B2 (en) 2006-05-25 2013-04-09 Synta Pharmaceuticals Corp. Triazole compounds that modulate HSP90 activity
US9101614B2 (en) 2006-05-25 2015-08-11 Synta Pharmaceuticals Corp. Method for treating non-Hodgkin's lymphoma
US20120122869A1 (en) * 2006-05-25 2012-05-17 Synta Pharmaceuticals Corp. Trizaole compounds that modulate hsp90 activity
WO2007139952A2 (en) * 2006-05-25 2007-12-06 Synta Pharmaceuticals Corp. Method for the preparation of triazole compounds with hsp90 modulating activity
WO2007139960A2 (en) * 2006-05-25 2007-12-06 Synta Pharmaceuticals Corp. Compounds that modulate hsp90 activity and methods for identifying same
WO2007140002A2 (en) * 2006-05-25 2007-12-06 Synta Pharmaceuticals Corp. Method for treating non-hodgkin's lymphoma
JP2009538322A (en) * 2006-05-25 2009-11-05 シンタ ファーマシューティカルズ コーポレーション Triazole compounds that modulate Hsp90 activity
US8063083B2 (en) 2006-05-25 2011-11-22 Synta Pharmaceuticals Corp. Method for treating non-Hodgkin's lymphoma
WO2007139955A3 (en) * 2006-05-25 2008-08-21 Synta Pharmaceuticals Corp Triazole compounds that modulate hsp90 activity
WO2007139951A2 (en) * 2006-05-25 2007-12-06 Synta Pharmaceuticals Corp. Method for treating proliferative disorders associated with protooncogene products
US8969396B2 (en) 2006-05-25 2015-03-03 Synta Pharmaceuticals Corp. Method for treating a B-raf associated cancer with an Hsp90 inhibitor
US8927548B2 (en) 2006-05-25 2015-01-06 Synta Pharmaceuticals Corp. Triazole compounds that modulate HSP90 activity
US9206162B2 (en) 2006-05-25 2015-12-08 Synta Pharmaceuticals Corp. Triazole compounds that modulate Hsp90 activity
WO2007139967A3 (en) * 2006-05-25 2008-02-28 Synta Pharmaceuticals Corp Triazole compounds that modulate hsp90 activity
WO2007139960A3 (en) * 2006-05-25 2008-03-20 Synta Pharmaceuticals Corp Compounds that modulate hsp90 activity and methods for identifying same
WO2007139952A3 (en) * 2006-05-25 2008-03-13 Synta Pharmaceuticals Corp Method for the preparation of triazole compounds with hsp90 modulating activity
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US8188075B2 (en) 2006-08-17 2012-05-29 Synta Pharmaceuticals Corp. Triazole compounds that modulate HSP90 activity
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US20160279164A1 (en) * 2006-10-03 2016-09-29 Nippon Kayaku Kabushiki Kaisha High-Molecular Weight Conjugate Of Resorcinol Derivatives
WO2008041610A1 (en) 2006-10-03 2008-04-10 Nippon Kayaku Kabushiki Kaisha Compound of resorcinol derivative with polymer
US20150011715A1 (en) * 2006-10-03 2015-01-08 Nippon Kayaku Kabushiki Kaisha High-Molecular Weight Conjugate Of Resorcinol Derivatives
US9730912B2 (en) 2006-10-12 2017-08-15 Astex Therapeutics Limited Pharmaceutical compounds
KR101571568B1 (en) 2006-10-12 2015-11-24 아스텍스 테라퓨틱스 리미티드 90 hydrobenzamide derivatives as inhibitors of hsp90
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WO2008044034A1 (en) * 2006-10-12 2008-04-17 Astex Therapeutics Limited Hydrobenzamide derivatives as inhibitors of hsp90
WO2008051416A2 (en) * 2006-10-19 2008-05-02 Synta Pharmaceuticals Corp. Compounds that inhibit the activity of hsp90 for treating infections
WO2008051416A3 (en) * 2006-10-19 2008-10-30 Synta Pharmaceuticals Corp Compounds that inhibit the activity of hsp90 for treating infections
US8163750B2 (en) 2006-10-24 2012-04-24 Sanofi-Aventis Fluorene derivatives, compositions containing the same and use thereof as inhibitors of the protein chaperone HSP 90
WO2008049994A1 (en) 2006-10-24 2008-05-02 Sanofi-Aventis New fluorene derivatives, compositions containing the same and use thereof as inhibitors of the protein chaperone hsp 90
WO2008057246A2 (en) * 2006-10-26 2008-05-15 Synta Pharmaceuticals Corp. Method for treating inflammatory disorders
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US8334364B2 (en) 2006-11-06 2012-12-18 Nipon Kayaku Kabushiki Kaisha High-molecular weight derivative of nucleic acid antimetabolite
US8188222B2 (en) 2006-11-08 2012-05-29 Nippon Kayaku Kabushiki Kaisha High molecular weight derivative of nucleic acid antimetabolite
JP2010518085A (en) * 2007-02-08 2010-05-27 シンタ ファーマシューティカルズ コーポレーション Triazole compounds useful for the treatment of proliferative disorders such as cancer
WO2008097640A3 (en) * 2007-02-08 2008-10-02 Synta Pharmaceuticals Corp Triazole compounds that are useful in the treatment of proliferative disorders, such as cancer
AU2008214279B2 (en) * 2007-02-08 2012-08-16 Synta Pharmaceuticals Corp. Triazole compounds that are useful in the treatment of proliferative disorders, such as cancer
US8748424B2 (en) 2007-02-08 2014-06-10 Synta Pharmaceuticals Corp. Triazole compounds that modulate Hsp90 activity
KR101567608B1 (en) 2007-02-08 2015-11-09 신타 파마슈티칼스 코프. Triazole compounds that are useful in the treatment of proliferative disorders such as cancer
US8299107B2 (en) 2007-02-08 2012-10-30 Synta Pharmaceuticals Corporation Triazole compounds that modulate HSP90 activity
TWI417093B (en) * 2007-02-08 2013-12-01 Synta Pharmaceuticals Corp Triazole compounds that modulate hsp90 activity
WO2008103353A1 (en) * 2007-02-20 2008-08-28 Synta Pharmaceuticals Corp. Triazole compounds that modulate hsp90 activity
US8993608B2 (en) * 2007-03-12 2015-03-31 Synta Pharmaceuticals Corp. Method for inhibiting topoisomerase II
WO2008112199A1 (en) * 2007-03-12 2008-09-18 Synta Pharmaceuticals Corp. Method for inhibiting topoisomerase ii
US20100249185A1 (en) * 2007-03-12 2010-09-30 Synta Pharmaceuticals Corp. Method for inhibiting topoisomerase ii
US8648104B2 (en) 2007-05-25 2014-02-11 Synta Pharmaceuticals Corp. Method for treating proliferative disorders associated with mutations in c-Met
WO2008153730A2 (en) * 2007-05-25 2008-12-18 Synta Pharmaceuticals Corp. Method for treating proliferative disorders associated with mutations in c-met
WO2008153730A3 (en) * 2007-05-25 2009-05-07 Synta Pharmaceuticals Corp Method for treating proliferative disorders associated with mutations in c-met
JP2010536753A (en) * 2007-08-13 2010-12-02 シンタ ファーマシューティカルズ コーポレーション Triazole compounds that modulate HSP90 activity
USRE46190E1 (en) 2007-09-28 2016-11-01 Nippon Kayaku Kabushiki Kaisha High-molecular weight conjugate of steroids
US8703878B2 (en) 2007-09-28 2014-04-22 Nippon Kayaku Kabushiki Kaisha High-molecular weight conjugate of steroids
WO2009049305A3 (en) * 2007-10-12 2009-07-02 Arqule Inc 5- (2-hydroxyphenyl) tetrazoles as hsp90 inhibitors against cancer
US7932279B2 (en) 2007-10-12 2011-04-26 Arqule, Inc. Substituted tetrazole compounds and uses thereof
JP4792128B2 (en) * 2007-10-12 2011-10-12 アークル インコーポレイテッド 5- (2-hydroxyphenyl) tetrazole as HSP90 inhibitor against cancer
WO2009066060A3 (en) * 2007-11-19 2009-12-23 Topotarget A/S 4-substituted-6-isopropyl-benzene-1,3-diol compounds and their use
WO2009066060A2 (en) * 2007-11-19 2009-05-28 Topotarget A/S 4-substituted-6-isopropyl-benzene-1,3-diol compounds and their use
JP2014028828A (en) * 2008-02-04 2014-02-13 Mercury Therapeutics Inc Ampk modulators
JP2011511008A (en) * 2008-02-04 2011-04-07 マーキュリー セラピューティクス，インコーポレイテッド AMPK regulator
US8980895B2 (en) 2008-02-04 2015-03-17 Mercury Therapeutics, Inc. AMPK modulators
FR2928645A1 (en) * 2008-03-14 2009-09-18 Sanofi Aventis Sa NOVEL CARBAZOLE DERIVATIVES INHIBITORS OF HSP90, COMPOSITIONS CONTAINING SAME AND USE THEREOF
WO2009122034A2 (en) * 2008-03-14 2009-10-08 Sanofi-Aventis Novel hsp90 inhibitory carbazole derivatives, compositions containing same, and use thereof
US8309721B2 (en) 2008-03-14 2012-11-13 Sanofi HSP90 inhibitory carbazole derivatives, compositions containing same and use thereof
WO2009122034A3 (en) * 2008-03-14 2009-12-03 Sanofi-Aventis Novel dhsp90 inhibitory carbazole derivatives, compositions containing same, and use thereof
US8920788B2 (en) 2008-03-18 2014-12-30 Nippon Kayaku Kabushiki Kaisha High-molecular weight conjugate of physiologically active substances
US9149540B2 (en) 2008-05-08 2015-10-06 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of folic acid or folic acid derivative
US9539243B2 (en) 2008-08-08 2017-01-10 Synta Pharmaceuticals Corp. Triazole compounds that modulate HSP90 activity
WO2010017479A1 (en) * 2008-08-08 2010-02-11 Synta Pharmaceuticals Corp. Triazole compounds that modulate hsp90 activity
US8937094B2 (en) 2008-08-08 2015-01-20 Synta Pharmaceuticals Corp. Triazole compounds that modulate HSP90 activity
WO2010017545A3 (en) * 2008-08-08 2010-04-01 Synta Pharamceuticals Corp. Triazole compounds that modulate hsp90 activity
US8486932B2 (en) 2008-08-08 2013-07-16 Synta Pharmaceuticals Corp. Triazole compounds that modulate Hsp90 activity
US8106083B2 (en) 2008-08-08 2012-01-31 Synta Pharmaceuticals Corp. Triazole compounds that modulate HSP90 activity
US9126953B2 (en) 2008-08-08 2015-09-08 Synta Pharmaceuticals Corp. Triazole compounds that modulate HSP90 activity
US8808749B2 (en) 2009-05-15 2014-08-19 Nippon Kayaku Kabushiki Kaisha Polymer conjugate of bioactive substance having hydroxy group
WO2011004132A1 (en) 2009-07-10 2011-01-13 Sanofi-Aventis Novel hsp90-inhibiting indole derivatives, compositions containing said derivatives, and use thereof
WO2011027081A2 (en) 2009-09-03 2011-03-10 Sanofi-Aventis Novel derivatives of 5,6,7,8-tetrahydroindolizine inhibiting hsp90, compositions containing same, and use thereof
US20130156755A1 (en) * 2010-04-19 2013-06-20 Synta Pharmaceuticals Corp. Cancer therapy using a combination of a hsp90 inhibitory compounds and a vegf inhibitor
US9018323B2 (en) 2010-11-17 2015-04-28 Nippon Kayaku Kabushiki Kaisha Polymer derivative of cytidine metabolic antagonist
WO2012078757A3 (en) * 2010-12-08 2012-08-02 Synta Pharmaceuticals Corp. Combination for breast cancer therapy with hsp90 inhibitory compounds
US20140005145A1 (en) * 2010-12-08 2014-01-02 Synta Pharmaceuticals Corp. Combination breast cancer therapy with hsp90 inhibitory compounds
WO2012084602A1 (en) 2010-12-20 2012-06-28 Sigma-Tau Research Switzerland S.A. Aryl triazole compounds with antitumoural activity
WO2012096919A1 (en) * 2011-01-11 2012-07-19 Synta Pharmaceuticals Corp. Combination therapy of hsp90 inhibitory compounds with proteasome inhibitors
US20130331357A1 (en) * 2011-01-11 2013-12-12 Synta Pharmaceuticals Corp. Combination therapy of hsp90 inhibitory compounds with proteasome inhibitors
WO2012116061A1 (en) * 2011-02-23 2012-08-30 Synta Pharmaceuticals Corp. Combination therapy of hsp90 inhibitory compounds with radiotherapy
WO2012141796A3 (en) * 2011-02-24 2012-12-27 Synta Pharmaceuticals Corp. Prostate cancer therapy with hsp90 inhibitory compounds
WO2012162293A1 (en) * 2011-05-23 2012-11-29 Synta Pharmaceuticals Corp. Combination therapy of hsp90 inhibitory compounds with mek inhibitors
WO2012162372A1 (en) * 2011-05-24 2012-11-29 Synta Pharmaceuticals Corp. Combination therapy of hsp90 inhibitory compounds with mtor/p13k inhibitors
WO2012162584A1 (en) * 2011-05-26 2012-11-29 Synta Pharmaceuticals Corp. Combination therapy of hsp90 inhibitory compounds with chk inhibitors
US9346923B2 (en) 2011-09-11 2016-05-24 Nippon Kayaku Kabushiki Kaisha Method for manufacturing block copolymer
WO2013148857A1 (en) * 2012-03-28 2013-10-03 Synta Pharmaceuticals Corp. Triazole derivatives as hsp90 inhibitors
US9598365B2 (en) 2012-05-22 2017-03-21 Trustees Of Dartmouth College Method for synthesizing cycloalkanyl[b]indoles, cycloalkanyl[b]benzofurans, cycloalkanyl[b]benzothiophenes, compounds and methods of use
WO2014063080A1 (en) * 2012-10-19 2014-04-24 Synta Pharmaceuticals Corp. Treating polycystic kidney disease with hsp90 inhibitory compounds
KR101711732B1 (en) * 2014-04-30 2017-03-02 경북대학교 산학협력단 3-Aryl-1,2,4-triazole derivatives and use thereof
KR20150125596A (en) * 2014-04-30 2015-11-09 경북대학교 산학협력단 3-Aryl-1,2,4-triazole derivatives and use thereof
WO2015167211A1 (en) * 2014-04-30 2015-11-05 경북대학교 산학협력단 3-aryl-1,2,4-triazole derivative and use thereof
US20180009794A1 (en) * 2015-01-22 2018-01-11 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Resorcinol Derivative As HSP90 Inhibitor
US10035792B2 (en) * 2015-01-22 2018-07-31 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Resorcinol derivative as HSP90 inhibitor
US9868721B2 (en) 2015-05-20 2018-01-16 Amgen Inc. Triazole agonists of the APJ receptor
US10344016B2 (en) 2015-05-20 2019-07-09 Amgen Inc. Bromotriazole intermediates
US9751864B2 (en) 2015-05-20 2017-09-05 Amgen Inc. Methods for preparing triazole agonists of the APJ receptor
US9745286B2 (en) 2015-05-20 2017-08-29 Amgen Inc. Triazole agonists of the APJ receptor
US9656997B2 (en) 2015-05-20 2017-05-23 Amgen Inc. Triazole agonists of the APJ receptor
US9845310B2 (en) 2015-05-20 2017-12-19 Amgen Inc. Intermediates for preparing triazole agonists of the APJ receptor
US9656998B2 (en) 2015-05-20 2017-05-23 Amgen Inc. Intermediates for preparing triazole agonists of the APJ receptor
US10058550B2 (en) 2015-05-20 2018-08-28 Amgen Inc. Methods of treating heart failure
US9573936B2 (en) 2015-05-20 2017-02-21 Amgen Inc. Triazole agonists of the APJ receptor
US10221162B2 (en) 2015-05-20 2019-03-05 Amgen Inc. Triazole agonists of the APJ receptor
US10150760B2 (en) 2016-05-03 2018-12-11 Amgen Inc. Compounds for use in preparing heterocyclic triazole agonists of the APJ receptor
US9988369B2 (en) 2016-05-03 2018-06-05 Amgen Inc. Heterocyclic triazole compounds as agonists of the APJ receptor
US11020395B2 (en) 2016-11-16 2021-06-01 Amgen Inc. Cycloalkyl substituted triazole compounds as agonists of the APJ receptor
US10736883B2 (en) 2016-11-16 2020-08-11 Amgen Inc. Triazole furan compounds as agonists of the APJ receptor
US10906890B2 (en) 2016-11-16 2021-02-02 Amgen Inc. Triazole phenyl compounds as agonists of the APJ receptor
US10689367B2 (en) 2016-11-16 2020-06-23 Amgen Inc. Triazole pyridyl compounds as agonists of the APJ receptor
US11046680B1 (en) 2016-11-16 2021-06-29 Amgen Inc. Heteroaryl-substituted triazoles as APJ receptor agonists
US11191762B2 (en) 2016-11-16 2021-12-07 Amgen Inc. Alkyl substituted triazole compounds as agonists of the APJ Receptor
US11149040B2 (en) 2017-11-03 2021-10-19 Amgen Inc. Fused triazole agonists of the APJ receptor
US11807624B2 (en) 2018-05-01 2023-11-07 Amgen Inc. Substituted pyrimidinones as agonists of the APJ receptor
US11168093B2 (en) 2018-12-21 2021-11-09 Celgene Corporation Thienopyridine inhibitors of RIPK2
WO2020205948A1 (en) * 2019-04-03 2020-10-08 Tarveda Therapeutics, Inc. Hsp90-binding conjugates and formulations thereof
EP3946320A4 (en) * 2019-04-03 2022-12-28 Tva (Abc), Llc Hsp90-binding conjugates and formulations thereof

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