[go: up one dir, main page]

WO2009066060A2 - Composés 6-isopropyl-benzène-1,3-diols substitués en position 4 et leur utilisation - Google Patents

Composés 6-isopropyl-benzène-1,3-diols substitués en position 4 et leur utilisation Download PDF

Info

Publication number
WO2009066060A2
WO2009066060A2 PCT/GB2008/003871 GB2008003871W WO2009066060A2 WO 2009066060 A2 WO2009066060 A2 WO 2009066060A2 GB 2008003871 W GB2008003871 W GB 2008003871W WO 2009066060 A2 WO2009066060 A2 WO 2009066060A2
Authority
WO
WIPO (PCT)
Prior art keywords
independently
compound according
present
optionally substituted
diyl
Prior art date
Application number
PCT/GB2008/003871
Other languages
English (en)
Other versions
WO2009066060A3 (fr
Inventor
Jens Christian Norrild
Anne Lauritsen
Fredrik Björkling
Sreenivasa Murthy Vadlamudi
Original Assignee
Topotarget A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Topotarget A/S filed Critical Topotarget A/S
Publication of WO2009066060A2 publication Critical patent/WO2009066060A2/fr
Publication of WO2009066060A3 publication Critical patent/WO2009066060A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/74—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C07C311/13—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/28—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/12—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings
    • C07C39/15—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings with all hydroxy groups on non-condensed rings, e.g. phenylphenol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/24—Halogenated derivatives
    • C07C39/367—Halogenated derivatives polycyclic non-condensed, containing only six-membered aromatic rings as cyclic parts, e.g. halogenated poly-hydroxyphenylalkanes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C47/00—Compounds having —CHO groups
    • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
    • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/825—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups all hydroxy groups bound to the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
    • 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
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D263/36—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms

Definitions

  • the present invention pertains generally to the field of therapeutic compounds, and more specifically to certain 4-substituted-6-isopropyl-benzene-1 ,3-diol compounds (referred to herein as IBD compounds), which, inter alia, inhibit heat shock protein 90 (HSP90) function.
  • IBD compounds 4-substituted-6-isopropyl-benzene-1 ,3-diol compounds
  • HSP90 heat shock protein 90
  • the present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit HSP90 function, and in the treatment of diseases and conditions that are mediated by HSP90, that are ameliorated by the inhibition of HSP90 function, etc., including proliferative conditions such as cancer, etc.
  • Ranges are often expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent "about,” it will be understood that the particular value forms another embodiment.
  • HSP90s are ubiquitous chaperone proteins that are involved in folding, activation and assembly of a wide range of proteins, including key proteins involved in signal transduction, cell cycle control and transcriptional regulation. It has been reported that HSP90 is associated with important signaling proteins, such as steroid hormone receptors and protein kinases, including, e.g., Raf-1 , EGFR, v-Src family kinases, Cdk4, and ErbB-2 (Buchner 1999; Stepanova et al., 1996,; Dai. et al., 1996).
  • certain co-chaperones e.g., Hsp70, p60/Hop/Stil, Hip, Bag1 , HSP40/Hdj2/Hsjl, immunophilins, p23, and p50, may assist HSP90 in its function (Caplan, 1999).
  • Ansamycin antibiotics e.g., herbimycin A (HA), geldanamycin (GM), and 17- AAG are thought to exert anticancerous effects by tight binding of the N-terminus binding site of HSP90, thereby destabilizing substrates that normally interact with HSP90 (Stebbins et a/ 1997,).
  • This pocket is highly conserved and has weak homology to the ATP-binding site of DNA gyrase (Stebbins. et al. 1997; Grenert et al., 1997). Further, ATP and ADP have both been shown to bind this pocket with low affinity and to have weak ATPase activity (Prodromou eif al., 1997; Panaretou et al., 1998).
  • ansamycins and other HSP90 inhibitors alters HSP90 function and inhibits, for example, protein folding and activation.
  • ansamycins and other HSP90 inhibitors have been shown to prevent binding of protein substrates to HSP90 (Scheibel et al., 1999, Schulte et al. 1995; Whitesell, et al., 1994).
  • Ansamycins have also been demonstrated to inhibit the ATP- dependent release of chaperone-associated protein substrates (Schneider et al., 1996; Sepp-Lorenzino et al., 1995,). In either event, the substrates are degraded by a ubiquitin- dependent process in the proteasome (Schneider, et al., 1996; Sepp-Lorenzino, 1995, Whitesell, etal., 1994).
  • HSP90 substrate destabilization occurs in tumour and non-transformed cells alike and has been shown to be especially effective on a subset of signalling regulators, e.g., Raf (Schulte et al., 1997; Schulte et al. 1995), nuclear steroid receptors (Segnitz and Gehring.
  • EGF receptor EGFR
  • Her2/Neu Hartmann et al., 1997; Miller et a/., 1994; Mimnaugh et a/., 1996; Schnur et al., 1995
  • CDK4 mutant p53
  • the ansamycin-induced loss of these proteins leads to the selective disruption of certain regulatory pathways and results in growth arrest at specific phases of the cell cycle (Muise-Helmericks, et a/., 1998) and apoptosis, and/or differentiation of cells so treated (Vasilevskaya, et a/., 1999).
  • HSP90 inhibitors have also been implicated in a wide variety of other utilities, including use as anti-inflammatory agents, anti-infectious disease agents, agents for treating autoimmunity, agents for treating ischemia, and agents useful in promoting nerve regeneration ('Rosen et al., 2002; Defranco et a/., 1999; Gold, 2001 ).
  • fibrogenic disorders including but not limited to scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis, and pulmonary fibrosis may also be treatable with HSP90 inhibitors (Strehlow, 2002).
  • Ansamycins and other HSP90 inhibitors thus hold great promise for the treatment and/or prevention of many types of disorders.
  • their relative insolubility makes them difficult to formulate and administer, and they are not easily synthesized and currently must, at least in part, be generated through fermentation.
  • the dose limiting toxicity of ansamyins is hepatic.
  • IBD compounds 4-substituted-6-isopropyl-benzene-1 ,3-diol compounds
  • compositions e.g., a pharmaceutical composition
  • a pharmaceutical composition comprising an IBD compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising the step of admixing an IBD compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
  • Another aspect of the present invention pertains to a method of inhibiting heat shock protein 90 (HSP90) function in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of an IBD compound, as described herein (e.g., without a proviso regarding P-O01 through P-003).
  • HSP90 heat shock protein 90
  • Another aspect of the present invention pertains to a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting a cell with an effective amount of an IBD compound, as described herein (e.g., without a proviso regarding P-O01 through P-003).
  • Another aspect of the present invention pertains to a method of treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of an IBD compound, as described herein (e.g., without a proviso regarding P-001 through P-003), preferably in the form of a pharmaceutical composition.
  • a therapeutically-effective amount of an IBD compound as described herein (e.g., without a proviso regarding P-001 through P-003), preferably in the form of a pharmaceutical composition.
  • Another aspect of the present invention pertains to an IBD compound, as described herein (e.g., without a proviso regarding P-001 through P-003), for use in a method of treatment of the human or animal body by therapy.
  • Another aspect of the present invention pertains to an IBD compound, as described herein (e.g., without a proviso regarding P-001 through P-003), for the use in a method of treatment of the human or animal body by therapy wherein said compound is used in combination with other pharmaceutically active substances
  • Another aspect of the present invention pertains to use of an IBD compound, as described herein (e.g., without a proviso regarding P-001 through P-003), in the manufacture of a medicament for use in treatment.
  • the treatment is treatment of a disease or condition that is mediated by heat shock protein 90 (HSP90).
  • the treatment is treatment of a disease or condition that is ameliorated by the inhibition of heat shock protein 90 (HSP90) function.
  • HSP90 heat shock protein 90
  • the treatment is treatment of a disease or condition that is known to be treated by HSP90 inhibitors (e.g., 17-AAG, geldanamycin, etc.).
  • HSP90 inhibitors e.g., 17-AAG, geldanamycin, etc.
  • the treatment is treatment of a proliferative condition.
  • the treatment is treatment of cancer.
  • kits comprising (a) an IBD compound, as described herein (e.g., without a proviso regarding P-001 through P-003), preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the compound.
  • an IBD compound as described herein (e.g., without a proviso regarding P-001 through P-003), preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the compound.
  • Another aspect of the present invention pertains to an IBD compound obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to an IBD compound obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.
  • Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.
  • Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein.
  • One aspect of the present invention relates to certain 4-substituted-6-isopropyl- benzene-1 ,3-diol compounds (for convenience, collectively referred to herein as "IBD compounds”), which are structurally related to resorcinol.
  • IBD compounds 4-substituted-6-isopropyl- benzene-1 ,3-diol compounds
  • the compounds are selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • -X 1 - is independently a covalent single bond or -X 1L -;
  • -X 2 - is independently a covalent single bond or -X 2L -;
  • -A 1 - is independently -A 1A -;
  • -A 2 is independently -A 2A , -H, or -F;
  • each of -X 1L - and -X 2L - is independently:
  • each -R A is independently -R M , -R AB , or -R AC ; each -R ⁇ is independently saturated aliphatic C ⁇ alkyl; each -R AB is independently aliphatic C 2- 6alkenyl; each -R AC is independently saturated C 3 .
  • -A 1A - is independently -A 1AC - or -A 1AH -;
  • -A 1AG - is independently C 6- iocarboarylene;
  • -A 1AH - is independently C 5-12 heteroarylene; and each -A 1AC - and each -A 1AH - is independently unsubstituted or substituted with one or more substituents -Q 1 ;
  • -A 2A is independently -A 2AC or -A 2AH ;
  • -A 2AC is independently C 6- iocarboaryl;
  • -A 2AH is independently C 5- i 2 heteroaryl; and each -A 2AG and each -A 2AH is independently unsubstituted or substituted with one or more substituents -Q 2 ;
  • each -Q 1 and each -Q 2 is independently:
  • each -L 1A - is independently saturated aliphatic d. 5 alkylene; in each group -NR 1A2 R 1A3 , -R 1A2 and -R 1A3 , taken together with the nitrogen atom to which they are attached, form a A-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N, O, or S;
  • each -R 1A1 is independently:
  • each -R 1B1 is independently saturated aliphatic C 1-6 alkyl
  • each -R 1B2 is independently aliphatic C 2-6 alkenyl
  • each -R 1B3 is independently aliphatic C 2-6 alkynyl
  • each -R 1B4 is independently saturated C 3-6 cycloalkyl
  • each -R 1B5 is independently C 3 .
  • each -R 1D1 is independently saturated aliphatic C 1-4 alkyl, phenyl, or benzyl; each -L 1D - is independently saturated aliphatic Ci -5 alkylene; and in each group -NR 102 R 103 , -R 102 and -R 1D3 , taken together with the nitrogen atom to which they are attached, form a A-, 5-, 6-, or 7-membered non-aromatic ring having exactly 1 ring heteroatom or exactly 2 ring heteroatoms, wherein one of said exactly 2 ring heteroatoms is N, and the other of said exactly 2 ring heteroatoms is independently N, 0, or S;
  • two adjacent -Q 1 groups if present, may together form -0-CH 2 -O- or -0-CH 2 CH 2 -O-; and additionally, two adjacent -Q 2 groups, if present, may together form -0-CH 2 -O- or -0-CH 2 CH 2 -O-.
  • -X 1 - is a covalent single bond
  • -A 1 - is not: 1 ,2,4-triazine-6 ⁇ one, substituted 1,2,4-triazine 6-one, 1 ,2,4-triazine-6-thione, or substituted 1 ,2,4-triazine- ⁇ -thione (see, e.g., WO 2008/118391);
  • 2-amino-1 ,2,3,4-tetrahydropyrimidine or substituted 2-amino-1 ,2,3,4- tetrahydropyrimidine see, e.g., WO 2008/118391
  • pyrazol-diyl or substituted pyrazol-diyl see, e.g., WO 2007/021966
  • the compounds are optionally as defined herein, but with one or more optional provisos, as defined herein.
  • the compound is a compound as defined herein, with the proviso that the compound is not a compound selected from P-001 through P-003.
  • the compound is a compound as defined herein, with the proviso that the compound is not a compound selected from P-001 through P-003.
  • the compound is a compound as defined herein, with the proviso that the compound is not a compound selected from PP-001 through PP-003, and salts, hydrates, and solvates thereof.
  • the compounds are optionally as defined herein, but without any of the above provisos, that is, without a proviso regarding P-001 through P-003.
  • a reference to a particular group of compounds "without the proviso regarding P-001 through P-003" is intended to be a reference to the compounds as defined, but wherein the definition no longer includes the indicated proviso.
  • the definition no longer includes the indicated proviso.
  • -X 1 - is independently a covalent single bond or -X 1L - In one embodiment, -X 1 - is independently a covalent single bond. In one embodiment, -X 1 - is independently -X 1L -.
  • -X - is independently a covalent single bond or -X -
  • -X 2 - is independently a covalent single bond.
  • -X 2 - is independently -X 2L -.
  • -A 1 - is independently -A 1A -.
  • -A 2 is independently -A 2A , -H, or -F. In one embodiment, -A 2 is independently -A M or -H. In one embodiment, -A 2 is independently -A 2A . In one embodiment, -A 2 is independently -H or -F. In one embodiment, -A 2 is independently -H.
  • the group -X 1 -A 1 -X 2 -A 2 is independently:
  • the group -X 1 -A 1 -X 2 -A 2 is independently:
  • the group -X 1 -A 1 -X 2 -A 2 is independently -X 1L -A 1A -H or -X 1L -A 1A -F.
  • the group -X 1 -A 1 -X 2 -A 2 is independently -X 1L -A 1A -H.
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A 1A -X 2L -A 2A . In one embodiment, the group -X 1 -A 1 -X 2 -A 2 is independently -A ⁇ -A 2 *.
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A 1A -H or -A 1A -F.
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A 1A -H.
  • -X 1L - is independently:
  • -X 1L - is independently: -R L -,
  • -X 1L - is independently:
  • -X 2L - is independently:
  • -X 2L - is independently:
  • -X 2L - is independently:
  • -X 2L - is independently -R L -.
  • -X 2L - is independently -R L -O-.
  • each -R L - is independently:
  • each -R LA is independently saturated aliphatic Ci -6 alkylene
  • each -R LB is independently aliphatic C 2- 6alkenylene
  • each -R LC is independently saturated C 3 .
  • each -R L - is independently -R ⁇ -, -R LB -, or -R LC -. In one embodiment, each -R L -, if present, is independently -R LA -.
  • each -R L - is independently unsubstituted.
  • each -R LA if present, is independently saturated aliphatic
  • each -R LA if present, is independently saturated aliphatic
  • each -R LA if present, is independently saturated aliphatic C 1-2 alkylene.
  • each -R L - is independently -CH 2 - Or -CH 2 CH 2 -. In one embodiment, each -R L -, if present, is independently -CH 2 -.
  • each -R A if present, is independently -R M or -R AB . In one embodiment, each -R A , if present, is independently -R M . In one embodiment, each -R A , if present, is independently saturated aliphatic C 1-4 alkyl. In one embodiment, each -R A , if present, is independently -Me or -Et. In one embodiment, each -R A , if present, is independently -Me.
  • -A 1A - is independently -A 1AC - or -A 1AH -, wherein: -A 1AC - is independently C 6- i 0 carboarylene; -A 1AH - is independently C 5-12 heteroarylene; each -A 1AC - and -A 1AH - is independently unsubstituted or substituted with one or more substituents -Q 1 .
  • -A 1A - if present, is independently -A 1AC -.
  • -A 1AC - is independently phenylene or naphth-diyl, and is optionally substituted.
  • -A 1AC - is independently phenylene, and is optionally substituted.
  • -A 1AC - is independently phenyl-1 ,2-diyl, and is optionally substituted.
  • -A 1AC - is independently phenyl-1 ,3-diyl, and is optionally substituted.
  • -A 1AC - is independently phenyl-1 ,4-diyl, and is optionally substituted.
  • -A 1AC - is independently naphth-diyl, and is optionally substituted.
  • -A 1AC - is independently naphth-1 ,2-diyl, and is optionally substituted.
  • -A 1AC - is independently naphth-1 , 4-diyl, and is optionally substituted.
  • -A 1A - if present, is independently -A 1 ⁇ H -.
  • -A 1AH - is independently C 5-6 heteroarylene, and is optionally substituted. In one embodiment, -A 1AH -, if present, is independently C 7- i 0 heteroarylene, and is optionally substituted.
  • -A 1AH - is independently furan-diyl, thien-diyl, pyrrol-diyl, 1 ,2,3-triazol-diyl, tetrazol-diyl, oxazol-diyl, thiazol-diyl, isothiazol-diyl, pyridin-diyl, pyrimidin-diyl, pyrazin-diyl, or pyridazin-diyl, and is optionally substituted.
  • -A 1AH - is independently furan-diyl, thien-diyl, 1 ,2,3-triazol-diyl, oxazol-diyl, thiazol-diyl, or pyridin-diyl, and is optionally substituted.
  • -A 1AH - is independently triazol-diyl, and is optionally substituted.
  • -A 1AH - is independently 1 ,2,3-triazol-diyl, and is optionally substituted.
  • -A 1AH - is independently 1 ,2,3-triazol-1 ,4-diyl, and is optionally substituted.
  • -A 1AH - is independently 1 ,2,3-triazol-1 ,5-diyl, and is optionally substituted.
  • -A 1AH - is independently 1 ,2,3-triazol-1 ,4-diyl, and is optionally substituted, wherein -X 1 - is attached at the 1 -position of the 1 ,2,3-triazol-1 ,4-diyl.
  • -A 1AH - is independently 1 ,2,3-triazo]-1 ,4-diyl, and is optionally substituted, wherein -X 1 - is attached at the 4-position of the 1 ,2,3-triazol-1 ,4-diyl.
  • -A 1AH - is independently 1 ,2,3-triazol-i ,5-diyl, and is optionally substituted, wherein -X 1 - is attached at the 1-position of the 1 ,2,3-triazol-1 ,4-diyl.
  • -A 1AH - is independently 1 ,2,3-triazoM ,5-diyl, and is optionally substituted, wherein -X 1 - is attached at the 5-position of the 1 ,2,3-triazol-1 ,4-diyl.
  • -A 1AH - if present, is independently oxazol-diyl, and is optionally substituted. In one embodiment, -A 1AH -, if present, is independently oxazol-4,5-diyl, and is optionally substituted.
  • -A 1AH - is independently oxazol-2,4-diyl, and is optionally substituted.
  • -A 1AH - is independently oxazol-2,5-diyl, and is optionally substituted.
  • -A 1AH - is independently oxazol-4,5-diyl, and is optionally substituted, wherein -X 1 - is attached at the 4-position of the oxazol-4,5-diyl.
  • -A 1AH - is independently oxazol-4,5-diyl, and is optionally substituted, wherein -X 1 - is attached at the 5-position of the oxazo!-4,5-diyl.
  • -A 1AH - is independently furan-diyl, and is optionally substituted.
  • -A 1AH - is independently thien-diyl, and is optionally substituted.
  • -A 1AH - is independently pyridin-diyl, and is optionally substituted.
  • -A 1AH - is independently quinolin-diyl, and is optionally substituted.
  • -A 1AH - is independently isoquinolin-diyl, and is optionally substituted.
  • -A 2A if present, is independently -A 2AC or -A 2 ⁇ 1 wherein: -A 2AC is independently C 6- i 0 carboaryl; -A 2AH is independently C 5 . 12 heteroaryl; each -A 2AC and -A 2AH is independently unsubstituted or substituted with one or more substituents -Q 2 .
  • -A 2A if present, is independently -A 2AC . In one embodiment, -A 2AC , if present, is independently phenyl or naphthyl, and is optionally substituted.
  • -A 2AC if present, is independently phenyl, and is optionally substituted.
  • -A 2AG if present, is independently phenyl, and is optionally substituted at the para-position.
  • -A 2AC is independently naphthyl, and is optionally substituted.
  • -A 2AC is independently naphth-1-yl, and is optionally substituted.
  • -A 2AC is independently naphth-2-yl, and is optionally substituted.
  • -A 2A if present, is independently -A 2AH .
  • -A 2AH if present, is independently C 5 . 6 heteroaryl, and is optionally substituted.
  • -A 2AH is independently C 7-10 heteroaryl, and is optionally substituted.
  • -A 2AH is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and is optionally substituted.
  • -A 2AH if present, is independently pyridinyl, thiazolyl, or furanyl and is optionally substituted.
  • -A 2AH if present, is independently pyridinyl, and is optionally substituted.
  • -A 2AH if present, is independently pyridin-2-yl, and is optionally substituted.
  • -A 2AH if present, is independently pyridin-3-yl, and is optionally substituted. In one embodiment, -A 2AH , if present, is independently pyridin-4-yl, and is optionally substituted.
  • -A 2AH if present, is independently thiazolyl, and is optionally substituted.
  • -A 2AH if present, is independently thiazol-4-yl, and is optionally substituted.
  • -A 2AH if present, is independently furanyl, and is optionally substituted.
  • -A 2AH is independently furan-5-yl, and is optionally substituted.
  • -A 2AH is independently imidazolyl, and is optionally substituted.
  • -A 2AH is independently imidazol-1-yl, and is optionally substituted.
  • -A 2AH is independently quinolinyl, and is optionally substituted.
  • -A 2AH is independently quinolin-6-yl, and is optionally substituted.
  • -A 2AH is independently indolyl, and is optionally substituted.
  • -A 2AH is independently indol-5-yl, and is optionally substituted.
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A 2A ;
  • -A 2A is independently -A 2AC .
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A 2A ; and -A 2A is independently -A 2AH .
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A 1A -A 2A ; -A 1A - is independently -A 1AC -; and -A 2A is independently -A 2 ⁇ .
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A 1A -A 2A ; -A 1A - is independently -A 1AC -; and -A 2A is independently -A 2AH .
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A 1A -A 2A ; -A 1A - is independently -A 1AH -; and -A 2A is independently -A 2AG .
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A 1A -A 2A ; -A 1A - is independently -A 1AH -; and -A 2A is independently -A 2AH .
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A 1A -A 2A ;
  • -A 1A - is independently oxazol-4,5-diyl; and -A 2A is independently phenyl, and is optionally substituted.
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A 1A -A 2A ;
  • -A 1A - is independently oxazol-4,5-diyl; wherein -A 2A - is attached at the 5-position of the oxazol-4,5-diyl; and -A 2A is independently phenyl, and is optionally substituted.
  • the compounds are selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A 1A -A 2A ;
  • -A 1A - is independently oxazol-4,5-diyl
  • -A 2A is independently -A 2 ⁇ ;
  • -A 2AH is independently C 5 . 6 heteroaryl, and is optionally substituted.
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A 1A -A 2A ;
  • -A 1A - is independently oxazol-4,5-diyl; wherein -A 2A - is attached at the 5-position of the oxazol-4,5-diyl; -A 2A is independently -A 2AH ; and
  • -A 2AH is independently C 5-6 heteroaryl, and is optionally substituted.
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A ⁇ -A ⁇ ; -A 1A - is independently oxazol-2,5-diyl; and
  • -A 2A is independently phenyl, and is optionally substituted.
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A 1A -A 2A ; -A 1A - is independently oxazol-2,5-diyl; and
  • -A 2A is independently -A 2AH ; and -A 2AH is independently C 5-6 heteroaryl, and is optionally substituted.
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A 1A -A 2A ; -A 1A - is independently 1 ,2,3-triazol-1 ,4-diyl or 1 ,2,3-triazol-1 ,5-diyl; -A 2A is independently phenyl, and is optionally substituted. In one embodiment: the group -X 1 -A 1 -X 2 -A 2 is independently -A 1A -A 2A ;
  • -A 1A - is independently 1,2,3-triazol-1 ,4-diyl
  • -A 2A is independently phenyl, and is optionally substituted.
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A ⁇ -A ⁇ ;
  • -A 1A - is independently 1 ,2,3-triazol-1 ,5-diyl
  • -A 2A is independently phenyl, and is optionally substituted.
  • -A 1A - is independently phenyl, and is optionally substituted.
  • the group -X 1 -A 1 -X 2 -A 2 is independently -X 1L -A 1A -H or -X 1L -A 1A -F;
  • the group -X 1 -A 1 -X 2 -A 2 is independently -X 1L -A 1A -H;
  • the group -X 1 -A 1 -X 2 -A 2 is independently -X 1L -A 1A -H or -X 1L -A 1A -F;
  • the group -X 1 -A 1 -X 2 -A 2 is independently -X 1L -A 1A -H;
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A 1A -H; -A 1A - is independently phenyl and bears at least one substituent, -Q 1 , which is independently:
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A 1A -H;
  • -A 1A - is independently phenyl and bears at least one substituent, -Q 1 , which is independently:
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A ⁇ -X ⁇ -A 2 *; -A 1A - is independently 1 ,2,3-triazol-1 ,4-diyl or 1 ,2,3-triazoM ,5-diyl;
  • -X 2L - is independently -CH 2 -; and -A 2A is independently phenyl, and is optionally substituted.
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A ⁇ -X ⁇ -A ⁇ ;
  • -A 1A - is independently 1 ,2,3-triazol-1 ,4-diyl; -X 2L - is independently -CH 2 -; and -A 2A is independently phenyl, and is optionally substituted.
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A ⁇ -X ⁇ -A 2 *;
  • -A 1A - is independently 1,2,3-triazol-1 ,5-diyl
  • -X 2L - is independently -CH 2 -;
  • -A ZA is independently phenyl, and is optionally substituted.
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A ⁇ -X ⁇ -A 2 *; -A 1A - is independently oxazol-2,5-diyl;
  • -X 2L - is independently -CH 2 -; and -A 2A is independently phenyl, and is optionally substituted.
  • the group -X 1 -A 1 -X 2 -A 2 is independently -A 2A ;
  • -A 2A is independently phenyl, and is optionally substituted.
  • each -A 1AC - and -A 1AH - is independently unsubstituted or substituted with one or more substituents -Q 1 .
  • each -A 1AC - and -A 1AH -, if present, is independently unsubstituted.
  • each -A 1AC - and -A 1AH - is independently substituted with one or more substituents -Q 1 .
  • -A 1AG - if present, is independently unsubstituted.
  • -A 1AC - if present, is independently substituted with one or more substituents -Q 1 .
  • -A 1AH - if present, is independently unsubstituted. In one embodiment, -A 1AH -, if present, is independently substituted with one or more substituents -Q 1 .
  • each -Q 1 is independently:
  • each -Q 1 is independently: -F, -Cl, -Br, -I, -R 1A1 , -OH, -OR 1A1 ,
  • each -Q 1 is independently: -F, -Cl, -Br, -I, -R 1A1 , -OH, or -OR 1A1 .
  • each -Q 1 is independently:
  • each -Q 1 is independently selected from those substituents exemplified under the headings "Examples of Specific Embodiments” and “Additional Examples of Specific Embodiments”.
  • each -A 2AC - and -A 2AH - is independently unsubstituted or substituted with one or more substituents -Q 2 .
  • each -A 2AC - and -A 2AH -, if present, is independently unsubstituted.
  • each -A 2AC - and -A 2AH - is independently substituted with one or more substituents -Q 2 .
  • -A 2AC - if present, is independently unsubstituted. In one embodiment, -A 2AC -, if present, is independently substituted with one or more substituents -Q 2 .
  • -A 2AH - if present, is independently unsubstituted. In one embodiment, -A 2AH -, if present, is independently substituted with one or more substituents -Q 2 .
  • each -Q 2 is independently:
  • each -Q 2 is independently: -F, -Cl, -Br, -I, -R 1A1 , -OH, or -OR 1A1 .
  • each -Q 2 is independently:
  • each -Q 2 is independently selected from those substituents exemplified under the headings "Examples of Specific Embodiments” and “Additional Examples of Specific Embodiments”. Eleme ⁇ ts of -Q 1 and -Q 2
  • each -NR 1A2 R 1A3 is independently azetidino, pyrrolidino, imidazolidino, pyrazoiidino, piperidino, piperazino, morpholino, thiomorpholino, thiomorpholine-1 ,1 -dioxide, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from saturated aliphatic Ci -3 alkyl.
  • each -NR 1A2 R 1A3 is independently pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or thiomorpholine-1, 1 -dioxide, and is optionally substituted, for example, with one or more groups selected from saturated aliphatic Ci -3 alkyl.
  • each -R 1A1 is independently:
  • each -R 1A1 is independently:
  • each -R 1A1 is independently: -L 1B -R 1B6 , -L 18 -R 1B7 , or -L 1B -R 1B8 .
  • each -R 1A1 if present, is independently: -L 1B -R 1B6 or -L 1B -R 1B8 .
  • each -R 1A1 is independently:
  • each -R 1B6 is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl.or dioxanyl, and is optionally substituted.
  • each -R 186 is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl, and is optionally substituted.
  • each -R 1B7 if present, is independently phenyl, and is optionally substituted. In one embodiment, each -R 1B8 , if present, is independently C 5 . 6 heteroaryl, and is optionally substituted.
  • each -R 1B8 is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
  • each -L 1B - is independently -CH 2 -.
  • each -R 1C1 if present, is independently saturated aliphatic C 1-4 alkyl.
  • each -R 1C2 is independently:
  • each -R 1C2 is independently:
  • each -R 101 is independently saturated aliphatic C 1-4 alkyl.
  • each -NR 102 R 103 if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, thiomorpholino, thiomorpholine-1 ,1-dioxide, azepino, or diazepino, and is optionally substituted, for example, with one or more groups selected from saturated aliphatic C 1-3 alkyl.
  • each -NR 102 R 103 is independently pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or thiomorpholine-1 ,1 -dioxide, and is optionally substituted, for example, with one or more groups selected from saturated aliphatic Ci. 3 alkyl.
  • the IBD compound has a molecular weight of from 230 to 1200. In one embodiment, the bottom of the range is from 250, 275, 300, or 350. In one embodiment, the top of the range is 1100, 1000, 900, 800, 700, or 600. In one embodiment, the range is 250 to 600.
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
  • -X 2 - is c a covalent single bond
  • -A 2 is -H
  • One aspect of the present invention pertains to IBD compounds, as described herein, in substantially purified form and/or in a form substantially free from contaminants.
  • the substantially purified form is at least 50% by weight, e.g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight.
  • the substantially purified form refers to the compound in any stereoisomeric or enantiomeric form.
  • the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds.
  • the substantially purified form refers to one stereoisomer, e.g., optically pure stereoisomer, in one embodiment, the substantially purified form refers to a mixture of enantiomers.
  • the substantially purified form refers to a equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate).
  • the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer.
  • the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1% by weight.
  • the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer.
  • the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e.g., at least 99% optically pure.
  • 60% optically pure i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer
  • at least 70% optically pure e.g., at least 80% optically pure, e.g., at least 90% optically pure, e
  • Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; o, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; ⁇ - and ⁇ -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers” (or "isomeric forms").
  • isomers are structural (or constitutional) isomers (i.e., isomers which differ in the connections between atoms rather than merely by the position of atoms in space).
  • a reference to a methoxy group, -OCH 3 is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH 2 OH.
  • a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl.
  • Ci -7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
  • keto-, enol-, and enolate-forms as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.
  • keto enol enolate as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.
  • H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including 16 O and 18 O; and the like.
  • a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof.
  • Methods for the preparation e.g., asymmetric synthesis
  • separation e.g., fractional crystallisation and chromatographic means
  • isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al +3 .
  • Suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ).
  • suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and trometharnine, as well as amino acids, such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH 3 ) 4 + .
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
  • solvate is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
  • a reference to a particular compound also includes solvate and hydrate forms thereof.
  • chemically protected form is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like).
  • specified conditions e.g., pH, temperature, radiation, solvent, and the like.
  • well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions.
  • one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group).
  • the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
  • an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH 3 ); a benzyloxy amide (-NHCO-OCH 2 C 6 H 5 , -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH 3 ) 3 , -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC(CHs) 2 C 6 H 4 C 6 H 5 , -NH-Bpoc), as a 9- fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as
  • a carboxylic acid group may be protected as an ester for example, as: an C 1-7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a C-i -7 haloalkyl ester (e.g., a Ci -7 trihaloalkyl ester); a triC 1-7 alkylsiiyl-C 1-7 alkyl ester; or a C 5 . 2 oaryl-C 1-7 alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
  • an C 1-7 alkyl ester e.g., a methyl ester; a t-butyl ester
  • a C-i -7 haloalkyl ester e.g., a Ci -7 trihaloalkyl ester
  • prodrug refers to a compound which, when metabolised (e.g., in vivo), yields the desired active compound.
  • the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.
  • prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.).
  • the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
  • IBD compounds of the present invention are described herein. These and/or other well known methods may be modified and/or adapted in known ways in order to facilitate the synthesis of additional compounds within the scope of the present invention.
  • compositions e.g., a pharmaceutical composition
  • a pharmaceutical composition comprising an IBD compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • compositions e.g., a pharmaceutical composition
  • a pharmaceutical composition comprising admixing an IBD compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • HSP90 heat shock protein 90
  • One aspect of the present invention pertains to a method of inhibiting heat shock protein 90 (HSP90) function, in vitro or in vivo, comprising contacting an HSP90 with an effective amount of an IBD compound, as described herein (e.g., without a proviso regarding P-001 through P-003).
  • HSP90 heat shock protein 90
  • One aspect of the present invention pertains to a method of inhibiting heat shock protein 90 (HSP90) function in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of an IBD compound, as described herein (e.g., without a proviso regarding P-001 through P-003).
  • HSP90 heat shock protein 90
  • the method is performed in vitro. In one embodiment, the method is performed in vivo.
  • One of ordinary skill in the art is readily able to determine whether or not, and/or the degree to which, a candidate compound inhibits HSP90 function. Suitable assays for determining heat shock protein 90 (HSP90) function inhibition are described herein and/or are known in the art.
  • the IBD compounds described herein e.g., without a proviso regarding P-001 through P-003
  • regulate e.g., inhibit
  • cell cycle progression e.g., inhibit
  • promote e.g., promote apoptosis; or (d) a combination of one or more of these.
  • One aspect of the present invention pertains to a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting a cell with an effective amount of an IBD compound, as described herein (e.g., without a proviso regarding P-001 through P-003).
  • the method is a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), in vitro or in vivo, comprising contacting a cell with an effective amount of an IBD compound, as described herein (e.g., without a proviso regarding P-001 through P-003).
  • the method is performed in vitro. In one embodiment, the method is performed in vivo.
  • the IBD compound is provided in the form of a pharmaceutically acceptable composition.
  • Any type of cell may be treated, including but not limited to, lung, gastrointestinal
  • a candidate compound regulates (e.g., inhibits) cell proliferation, etc.
  • assays which may conveniently be used to assess the activity offered by a particular compound are described herein.
  • a sample of cells e.g., from a tumour
  • a compound brought into contact with said cells, and the effect of the compound on those cells observed.
  • effect the morphological status of the cells (e.g., alive or dead, etc.) may be determined.
  • this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a patient carrying cells of the same cellular type.
  • Another aspect of the present invention pertains to an IBD compound, as described herein (e.g., without a proviso regarding P-001 through P-003), for use in a method of treatment of the human or animal body by therapy.
  • Another aspect of the present invention pertains to use of an IBD compound, as described herein (e.g., without a proviso regarding P-001 through P-003), in the manufacture of a medicament for use in treatment.
  • the medicament comprises the IBD compound.
  • Another aspect of the present invention pertains to a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of an IBD compound, as described herein (e.g., without a proviso regarding P-001 through P-003), preferably in the form of a pharmaceutical composition.
  • a therapeutically effective amount of an IBD compound as described herein (e.g., without a proviso regarding P-001 through P-003), preferably in the form of a pharmaceutical composition.
  • the treatment is treatment of a disease or condition that is mediated by heat shock protein 90 (HSP90).
  • HSP90 heat shock protein 90
  • a disease or disorder that is mediated by HSP90 is, for example, a disease or disorder in which HSP90 and/or the action of HSP90 is important or necessary, e.g., for the onset, progresssion, expression, etc., of that disease or disorder.
  • the treatment is treatment of: a disease or condition that is ameliorated by the inhibition of heat shock protein 90 (HSP90) function.
  • HSP90 heat shock protein 90
  • the treatment is treatment of: a disease or condition that is known to be treated by HSP90 inhibitors (e.g., 17-AAG, geldanamycin, etc.)
  • HSP90 inhibitors e.g., 17-AAG, geldanamycin, etc.
  • the treatment is treatment of:
  • fibrogenic disorders such as: scleroderma, systemic sclerosis, polymyositis, systemic lupus erythematosus, liver cirrhosis, and keloids;
  • disorders involving angiogenesis such as: granuloma, retinal neovascularisation, choroidal neovascularisation, diabetic nephropathy, melorheostosis, asthma, inflammation, synovitis, abortifacients, wound healing, psoriasis, endometriosis, severe ovarian hyperstimulation syndrome, myelodysplasia syndrome, haemorrhagic telengectasia, atherosclerosis, restenosis, thrombosis,
  • viral infections such as:
  • HPV infection and influenza
  • parasitic infections such as: malaria, schistosomiasis, trypanosomiasis, toxoplasmosis, and leishmania;
  • the treatment is treatment of: a proliferative condition.
  • proliferative condition pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth.
  • the treatment is treatment of: a proliferative condition characterised by benign, pre-malignant, or malignant cellular proliferation, including but not limited to, neoplasms, hyperplasias, and tumours (e.g., histocytoma, glioma, astrocyoma, osteoma), cancers (see below), psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), pulmonary fibrosis, atherosclerosis, smooth muscle cell proliferation in the blood vessels, such as stenosis or restenosis following angioplasty.
  • a proliferative condition characterised by benign, pre-malignant, or malignant cellular proliferation, including but not limited to, neoplasms, hyperplasias, and tumours (e.g., histocytoma, glioma, astrocyoma, osteoma), cancers (see below), psoriasis, bone diseases, fibroprolife
  • the treatment is treatment of: cancer.
  • the treatment is treatment of: lung cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, stomach cancer, bowel cancer, colon cancer, rectal cancer, colorectal cancer, thyroid cancer, breast cancer, ovarian cancer, endometrial cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, renal cell carcinoma, bladder cancer, pancreatic cancer, brain cancer, glioma, sarcoma, osteosarcoma, bone cancer, nasopharyngeal cancer (e.g., head cancer, neck cancer), skin cancer, squamous cancer, Kaposi's sarcoma, melanoma, malignant melanoma, lymphoma, or leukemia.
  • lung cancer small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, stomach cancer, bowel cancer, colon cancer
  • rectal cancer colorectal cancer, thyroid cancer, breast cancer, ovarian cancer, endometrial cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, renal cell carcinoma, bladder
  • the treatment is treatment of: a carcinoma, for example a carcinoma of the bladder, breast, colon (e.g., colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, epidermal, liver, lung (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas), oesophagus, gall bladder, ovary, pancreas (e.g., exocrine pancreatic carcinoma), stomach, cervix, thyroid, prostate, skin (e.g., squamous cell carcinoma); a hematopoietic tumour of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non- Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; a hematopoietic tumour of lymph
  • the treatment is treatment of solid tumour cancer. In one embodiment, the treatment is treatment of liquid tumour cancer. In one embodiment, the treatment is treatment of hemotaological cancer.
  • the treatment is treatment of: skin cancer, melanoma, breast cancer, estrogen receptor-dependent and independent breast cancer, ovarian cancer, prostate cancer, androgen dependent and independent prostate cancer, renal cancer, colon and colorectal cancer, pancreatic cancer, bladder cancer, esophageal cancer, stomach cancer, genitourinary cancer, uterine cancer, astrocytomas, gliomas, basal cancer, squamous cell carcinoma, sarcoma, osteosarcoma, head and neck cancer, lung cancer, small cell lung carcinoma, non-small cell lung carcinoma, leukemia, lymphoma, and other blood cell cancers.
  • the treatment is treatment of: lung cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or glioma.
  • the anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of cell cycle progression, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis (programmed cell death).
  • the compounds of the present invention may be used in the treatment of the cancers described herein, independent of the mechanisms discussed herein.
  • treatment refers generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviatiation of symptoms of the condition, amelioration of the condition, and cure of the condition.
  • Treatment as a prophylactic measure i.e., prophylaxis
  • treatment is also included. For example, use with patients who have not yet developed the condition, but who are at risk of developing the condition, is encompassed by the term "treatment.”
  • treatment includes the prophylaxis of cancer, reducing the incidence of cancer, alleviating the symptoms of cancer, etc.
  • terapéuticaally-effective amount refers to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
  • treatment includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously.
  • the compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents, for example, cytotoxic agents, anticancer agents, etc.
  • treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g., drugs, antibodies (e.g., as in immunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiation therapy; photodynamic therapy; gene therapy; and controlled diets.
  • a compound as described herein may be beneficial to combine treatment with a compound as described herein with one or more other (e.g., 1 , 2, 3, 4) agents or therapies that regulates cell growth or survival or differentiation via a different mechanism, thus treating several characteristic features of cancer development.
  • one or more other agents or therapies that regulates cell growth or survival or differentiation via a different mechanism
  • One aspect of the present invention pertains to a compound as described herein, in combination with one or more additional therapeutic agents, as described below.
  • the agents may be administered simultaneously or sequentially, and may be administered in individually varying dose schedules and via different routes.
  • the agents can be administered at closely spaced intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1 , 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).
  • agents i.e., the compound described here, plus one or more other agents
  • the agents may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use.
  • the IBD compounds described herein may also be used as cell culture additives to inhibit heat shock protein 90 (HSP90) function, e.g., to inhibit cell proliferation, etc.
  • HSP90 heat shock protein 90
  • the IBD compounds described herein may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.
  • the IBD compounds described herein may also be used as a standard, for example, in an assay, in order to identify other compounds, other heat shock protein 90 (HSP90) function inhibitors, other anti-proliferative agents, other anti-cancer agents, etc.
  • HSP90 heat shock protein 90
  • the IBD compounds described herein may also be used as a herbicide.
  • kits comprising (a) an IBD compound as described herein, or a composition comprising an IBD compound as described herein, e.g., preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition.
  • the written instructions may also include a list of indications for which the active ingredient is a suitable treatment.
  • the IBD compound or pharmaceutical composition comprising the IBD compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular
  • the subject/patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey
  • a rodent e.g., a guinea pig, a
  • ape e.g., gorilla, chimpanzee, orangutang, gibbon
  • a human e.g., gorilla, chimpanzee, orangutang, gibbon
  • the subject/patient may be any of its forms of development, for example, a foetus.
  • the subject/patient is a human.
  • the IBD compound While it is possible for the IBD compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one IBD compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
  • the formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.
  • the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one IBD compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound.
  • pharmaceutically acceptable pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problenn or complication, commensurate with a reasonable benefit/risk ratio.
  • Each carrier, diluent, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 5th edition, 2005.
  • the formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.
  • carriers e.g., liquid carriers, finely divided solid carrier, etc.
  • the formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof.
  • Formulations may suitably be in the form of liquids, solutions (e.g., aqueous, nonaqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, losenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols.
  • solutions e.g., aqueous, nonaqueous
  • suspensions e.g., aqueous, non-aqueous
  • emulsions
  • Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like which is impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in the form of a depot or reservoir.
  • the compound may be dissolved in, suspended in, or admixed with one or more other pharmaceutically acceptable ingredients.
  • the compound may be presented in a liposome or other microparticulate which is designed to target the compound, for example, to blood components or one or more organs.
  • Formulations suitable for oral administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.
  • Formulations suitable for buccal administration include mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • Losenges typically comprise the compound in a flavored basis, usually sucrose and acacia or tragacanth.
  • Pastilles typically comprise the compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia.
  • Mouthwashes typically comprise the compound in a suitable liquid carrier.
  • Formulations suitable for sublingual administration include tablets, losenges, pastilles, capsules, and pills.
  • Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil- in-water, water-in-oil), mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • solutions e.g., aqueous, non-aqueous
  • suspensions e.g., aqueous, non-aqueous
  • emulsions e.g., oil- in-water, water-in-oil
  • mouthwashes e.g., gluges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.
  • solutions e.g., aqueous, non-aqueous
  • suspensions e.g., aqueous, non-aqueous
  • emulsions e.g., oil-in-water, water-in-oil
  • suppositories e.g., pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.
  • Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.
  • Tablets may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile.
  • Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach.
  • Ointments are typically prepared from the compound and a paraffinic or a water-miscible ointment base.
  • Creams are typically prepared from the compound and an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
  • Emulsions are typically prepared from the compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • an emulsifier also known as an emulgent
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax
  • the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.
  • suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for intranasal administration, where the carrier is a liquid include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the compound.
  • Formulations suitable for intranasal administration, where the carrier is a solid include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Formulations suitable for pulmonary administration include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
  • Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.
  • Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.
  • a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the compound, such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate).
  • sterile liquids e.g., solutions, suspensions
  • Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient.
  • excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like.
  • suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
  • the concentration of the compound in the liquid is from about 1 ng/ml to about 10 ⁇ g/ml, for example from about 10 ng/ml to about 1 ⁇ g/ml.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • appropriate dosages of the IBD compounds, and compositions comprising the IBD compounds can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular IBD compound, the route of administration, the time of administration, the rate of excretion of the IBD compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient.
  • the amount of IBD compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
  • Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.
  • a suitable dose of the IBD compound is in the range of about 10 ⁇ g to about 250 mg (more typically about 100 ⁇ g to about 25 mg) per kilogram body weight of the subject per day.
  • the compound is a salt, an ester, an amide, a prodrug, or the like
  • the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
  • 1 H NMR spectra were recorded at 25°C at 300 MHz on a Bruker Avance 300 system. Chemical shifts are reported in ppm.
  • the 1 H NMR spectra are referenced internally as follows: Spectra in CD 3 OD were referenced to CHD 2 OD: 3.33 ppm; CDCI 3 to CHCI 3 : 7.26 ppm, DMSO-Cf 6 to CHD 2 SOCD 3 : 2.50 ppm.
  • the protected triazole of the Formula I was dissolved in DCM (15 mL per mmol) under N 2 atmosphere and the solution cooled to -78°C. BBr 3 was added dropwise (1.2 eq. per OMe group). The mixture was stirred at -78°C for 15 minutes, and then at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was purified by column chromatography using appropriate mixtures of MeOH and DCM as eluent, to give the correspoinding triazole of the Formula II.
  • the dimethoxy compound of Formula III was dissolved in dry DCM under N 2 and cooled in ice. BBr 3 (1 M in DCM) was added (2 eq. / methoxy group). The red solution was allowed to warm to room temperature and left stirring overnight. The reaction mixture was quenched with ice and the product extracted into EtOAc. For basic compounds, the aqueous phase was adjusted to pH 8-9 before extraction. The organic phase was dried over MgSO 4 or Na 2 SO 4 (basic compounds), evaporated, and the resulting product of Formula IV was purified by flash chromatography on silica gel.
  • 2,4-Dihydroxy-acetophenone (15 g, 98.6 mmol) was dissolved in CH 3 CN (200 mL). Dry powdered K 2 CO 3 (40 g, 289 mmol) was added and the suspension stirred. Benzylbromide (26 mL, 218 mmol) was added drop-wise and the resulting mixture was heated to reflux for 5 h and left stirring at room temperature overnight. TLC (EtOAc-Hep 1 :1 ) showed complete reaction. The solvent was evaporated and the residue re- dissolved in CH 2 CI 2 -water. The phases were separated and the aqueous phase was extracted once with CH 2 CI 2 .
  • reaction mixture was poured into aqueous NaHCO 3 (saturated, 300 mL) and the phases separated. The aqueous phase was extracted once with CH 2 CI 2 and the combined organic phase was dried over MgSO 4 and evaporated to colorless (light tan) oil (9.1 g , still wet). Purified on Silicagel with EtOAc- Hep (1 :9). The yield of title compound was 6.5 g (97%) of a colorless oil which crystallizes.
  • Triisopropyl borate (2.66 ml_, 11.5 mmol) was dissolved in dry THF (20 ml_) in a new three-necked flask under N 2 and cooled to -78°C.
  • the cold THF solution of the lithiated reactant was slowly siphoned into the borate solution while stirring and keeping the temperature at -78 0 C.
  • the solution was allowed to warm to room temperature giving a colourless "milky" suspension. This was poured into ice/water, the pH was adjusted to 4 with HCI, and the product extracted with ether (3x). The combined organics were washed with brine and dried over MgSO 4 .
  • reaction mixture was quenched with 0 0 C NaHCO 3 -solution (to pH 8-9) and the product was extracted four times with PE: EtOAc (4:1). The combined organic phases was evaporated and the crude material was purified by preparative HPLC to yield 29 mg pure material. The product was used without further purification or analysis.
  • Step 1 Isolation of p-tolylsulfinic acid: Sodium p-tolylsulfinate (anhydrous) (3.21 g, 18.0 mmol) was suspended in water (25 mL). After stirring for 10 minutes, all was dissolved and £-butylmethylether (TBME) (25 mL) was added. Then, concentrated HCI (aq) (1.6 mL, 1 eq) was added dropwise. After stirring for 20 minutes, the organic phase was separated, diluted with toluene (25 mL), and evaporated in vacuo to remove 70-90% of the solvents.
  • TBME £-butylmethylether
  • step 2 The crude product from step 2 (1.27 g, 3.36 mmol) was suspended in dry THF (7 mL) at room temperature. To the white suspension was added POCI 3 (0.62 mL) and the resulting greenish suspension was stirred for 5 minutes, after which it was cooled to 0 0 C. Triethylamine (2.8 mL) was added slowly keeping the temperature below 5°C. The mixture was stirred at O 0 C for 45 minutes, after which EtOAc (5 mL) and water (5 mL) were added. The mixture was stirred for 5 minutes and the phases were separated.
  • Step 1 Isolation of p-tolylsulfinic acid: Sodium p-tolylsulfinate (anhydrous) (3.21 g, 18.0 mmol) was suspended in water (25 ml_). After stirring for 10 minutes, all was dissolved and f-butylmethylether (TBME) (25 ml_) was added. Then concentrated HCI (aq) (1.6 mL, 1 eq) was added dropwise. After stirring for 20 minutes, the organic phase was separated, diluted with toluene (25 mL), and evaporated in vacuo to remove 70-90% of the solvents.
  • TBME f-butylmethylether
  • 5-lsopropyl-2,4-dimethoxybenzaldehyde (1.50 g, 7.20 mmol) was dissolved in dry acetonitrile (3 mL) and dry toluene (3 mL). Molecular sieves (4A) were added. Formamide (0.72 mL, 2.5 eq) and TMSCI (1.00 mL, 1.1 eq) were added and the mixture was heated to 5O 0 C for 4 hours under a N 2 atmosphere. The resulting cloudy orange solution was evaporated to semi-dryness. Dry toluene was added and the solvent was re-evaporated.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne d'une manière générale le domaine des composés thérapeutiques, et elle porte plus spécifiquement sur certains composés 6-isopropyl-benzène-1,3-diols substitués en position 4 (appelés ici composés IBD), lesquels, entre autres, inhibent la fonction de la protéine de choc thermique 90 (HSP90). La présente invention porte également sur des compositions pharmaceutiques comprenant de tels composés, et sur l'utilisation de tels composés et de telles compositions, à la fois in vivo et in vitro, pour inhiber la fonction de HSP90, et dans le traitement de maladies et d'états pour lesquels le HSP90 sert d'intermédiaire, qui sont améliorés par inhibition de la fonction de HSP90, etc., comprenant des états prolifératifs tels que le cancer, etc.
PCT/GB2008/003871 2007-11-19 2008-11-18 Composés 6-isopropyl-benzène-1,3-diols substitués en position 4 et leur utilisation WO2009066060A2 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US98891507P 2007-11-19 2007-11-19
GBGB0722680.6A GB0722680D0 (en) 2007-11-19 2007-11-19 Therapeutic compounds and their use
GB0722680.6 2007-11-19
US60/988,915 2007-11-19
US5495308P 2008-05-21 2008-05-21
US61/054,953 2008-05-21

Publications (2)

Publication Number Publication Date
WO2009066060A2 true WO2009066060A2 (fr) 2009-05-28
WO2009066060A3 WO2009066060A3 (fr) 2009-12-23

Family

ID=38896559

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2008/003871 WO2009066060A2 (fr) 2007-11-19 2008-11-18 Composés 6-isopropyl-benzène-1,3-diols substitués en position 4 et leur utilisation

Country Status (2)

Country Link
GB (1) GB0722680D0 (fr)
WO (1) WO2009066060A2 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010015583A1 (fr) * 2008-08-08 2010-02-11 Neurosearch A/S Nouveaux dérivés du diphényl-1,2,3-triazole utiles en tant que modulateurs de récepteurs acétylcholines nicotiniques
WO2011027081A2 (fr) 2009-09-03 2011-03-10 Sanofi-Aventis Nouveaux derives de 5,6,7,8-tetrahydroindolizine inhibiteurs d'hsp90, compositions les contenant et utilisation
US7994185B2 (en) 2008-05-06 2011-08-09 Glaxo Smith Kline LLC Benzene sulfonamide thiazole and oxazole compounds
JP2012025686A (ja) * 2010-07-21 2012-02-09 National Agriculture & Food Research Organization 新規ビフェニル化合物
US20120046266A1 (en) * 2009-04-21 2012-02-23 Nerviano Medical Sciences S.R.L. Resorcinol derivatives as hsp90 inhibitors
WO2012087289A1 (fr) * 2010-12-21 2012-06-28 Colgate-Palmolive Company Biphénols halogénés en tant qu'agents antibactériens
US8778939B2 (en) 2009-09-29 2014-07-15 Glaxo Group Limited Compounds
US8835449B2 (en) 2011-11-11 2014-09-16 Pfizer Inc. 2-thiopyrimidinones
CN104059055A (zh) * 2013-12-10 2014-09-24 常州大学 1,2,3-三唑类化合物及其制备方法和用途
US9073875B2 (en) 2012-11-20 2015-07-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of indoleamine 2,3-dioxygenase
US9771332B2 (en) 2015-05-05 2017-09-26 Pfizer Inc. 2-thiopyrimidinones
JP2020512327A (ja) * 2017-03-20 2020-04-23 タイペイ メディカル ユニバーシティ 熱ショックタンパク質９０阻害剤
CN113651806A (zh) * 2021-06-09 2021-11-16 福建医科大学 一种4,5-二芳基噁唑类化合物的制备方法
CN114014849A (zh) * 2021-06-09 2022-02-08 福建医科大学 4,5-二芳基噁唑类化合物及其用途

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2393483T3 (es) * 2003-02-11 2012-12-21 Vernalis (R&D) Limited Compuestos de isoxazol como inhibidores de las proteínas de choque térmico
GB0315111D0 (en) * 2003-06-27 2003-07-30 Cancer Rec Tech Ltd Substituted 5-membered ring compounds and their use
WO2006055760A1 (fr) * 2004-11-18 2006-05-26 Synta Pharmaceuticals Corp. Composes triazole modulant l'activite de hsp90
DE102005022977A1 (de) * 2005-05-19 2006-12-07 Merck Patent Gmbh Phenylchinazolinderivate
EP1934185A1 (fr) * 2005-08-12 2008-06-25 Synta Pharmaceuticals Corporation Composes pyrazoles modulant l'activite de la proteine hsp90
WO2007021877A1 (fr) * 2005-08-18 2007-02-22 Synta Pharmaceuticals Corp. Dérivés d'imidazole modulant l'activité de hsp90

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8642759B2 (en) 2008-05-06 2014-02-04 Glaxosmithkline Llc Benzene sulfonamide thiazole and oxazole compounds
US7994185B2 (en) 2008-05-06 2011-08-09 Glaxo Smith Kline LLC Benzene sulfonamide thiazole and oxazole compounds
US9233956B2 (en) 2008-05-06 2016-01-12 Novartis Ag Benzene sulfonamide thiazole and oxazole compounds
WO2010015583A1 (fr) * 2008-08-08 2010-02-11 Neurosearch A/S Nouveaux dérivés du diphényl-1,2,3-triazole utiles en tant que modulateurs de récepteurs acétylcholines nicotiniques
US8993556B2 (en) * 2009-04-21 2015-03-31 Nerviano Medical Sciences S.R.L. Resorcinol derivatives as HSP90 inhibitors
US20120046266A1 (en) * 2009-04-21 2012-02-23 Nerviano Medical Sciences S.R.L. Resorcinol derivatives as hsp90 inhibitors
WO2011027081A2 (fr) 2009-09-03 2011-03-10 Sanofi-Aventis Nouveaux derives de 5,6,7,8-tetrahydroindolizine inhibiteurs d'hsp90, compositions les contenant et utilisation
US8778939B2 (en) 2009-09-29 2014-07-15 Glaxo Group Limited Compounds
JP2012025686A (ja) * 2010-07-21 2012-02-09 National Agriculture & Food Research Organization 新規ビフェニル化合物
RU2549543C2 (ru) * 2010-12-21 2015-04-27 Колгейт-Палмолив Компани Галогенированные бифенолы в качестве антибактериальных средств
CN103261138A (zh) * 2010-12-21 2013-08-21 高露洁-棕榄公司 作为抗菌剂的卤代联苯酚
US9334212B2 (en) 2010-12-21 2016-05-10 Colgate-Palmolive Company Compounds and compositions
WO2012087289A1 (fr) * 2010-12-21 2012-06-28 Colgate-Palmolive Company Biphénols halogénés en tant qu'agents antibactériens
US9873673B2 (en) 2011-11-11 2018-01-23 Pfizer Inc. 2-thiopyrimidinones
US8841314B2 (en) 2011-11-11 2014-09-23 Pfizer Inc. 2-Thiopyrimidinones
US8835449B2 (en) 2011-11-11 2014-09-16 Pfizer Inc. 2-thiopyrimidinones
US9399626B2 (en) 2011-11-11 2016-07-26 Pfizer Inc. 2-thiopyrimidinones
US9073875B2 (en) 2012-11-20 2015-07-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of indoleamine 2,3-dioxygenase
US9499497B2 (en) 2012-11-20 2016-11-22 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of indoleamine 2,3-dioxygenase
CN105440020A (zh) * 2013-12-10 2016-03-30 常州大学 具有抗肿瘤活性的1,2,3-三唑类化合物及其制备方法
CN104059055B (zh) * 2013-12-10 2016-08-31 常州大学 1,2,3-三唑类化合物及其制备方法和用途
CN104059055A (zh) * 2013-12-10 2014-09-24 常州大学 1,2,3-三唑类化合物及其制备方法和用途
CN105440020B (zh) * 2013-12-10 2018-12-18 常州大学 具有抗肿瘤活性的1,2,3-三唑类化合物及其制备方法
US9771332B2 (en) 2015-05-05 2017-09-26 Pfizer Inc. 2-thiopyrimidinones
JP2020512327A (ja) * 2017-03-20 2020-04-23 タイペイ メディカル ユニバーシティ 熱ショックタンパク質９０阻害剤
CN111164074A (zh) * 2017-03-20 2020-05-15 台北医学大学 热休克蛋白90抑制剂
EP3601226A4 (fr) * 2017-03-20 2021-03-03 Taipei Medical University Inhibiteurs de la protéine de choc thermique 90
JP7157462B2 (ja) 2017-03-20 2022-10-20 タイペイ メディカル ユニバーシティ 熱ショックタンパク質９０阻害剤
US11479528B2 (en) 2017-03-20 2022-10-25 Taipei Medical University Heat shock protein 90 inhibitors
CN111164074B (zh) * 2017-03-20 2024-02-02 台北医学大学 热休克蛋白90抑制剂
CN113651806A (zh) * 2021-06-09 2021-11-16 福建医科大学 一种4,5-二芳基噁唑类化合物的制备方法
CN114014849A (zh) * 2021-06-09 2022-02-08 福建医科大学 4,5-二芳基噁唑类化合物及其用途

Also Published As

Publication number Publication date
WO2009066060A3 (fr) 2009-12-23
GB0722680D0 (en) 2007-12-27

Similar Documents

Publication Publication Date Title
WO2009066060A2 (fr) Composés 6-isopropyl-benzène-1,3-diols substitués en position 4 et leur utilisation
JP6082409B2 (ja) ３−アリール−５−置換イソキノリン−１−オン化合物及びその治療的使用
US6664269B2 (en) Isoquinolinone derivatives
AU2001295789B2 (en) Phthalazinone derivatives
EP1417196B1 (fr) Inhibiteurs d'adn-pk
NZ542680A (en) Phthalazinone derivatives
WO2007029021A1 (fr) Tetrazoles 1,5-substitués en tant que composés thérapeutiques
JP6456392B2 (ja) ３−アリール−５−置換イソキノリン−１−オン化合物及びその治療的使用
WO2012117216A1 (fr) Composés amides d'acide n-(arylalkyl)-1h-indole-2-sulfonique et leur utilisation thérapeutique comme modulateurs allostériques des récepteurs cannabinoïdes
EP0757682A1 (fr) Derives de benzofurane utilises comme inhibiteurs de la resorption osseuse
EP2229393A2 (fr) Amides d'acides 4-oxo-3,4-dihydroimidazoý5,1-d¨ý1,2,3,5-tétrazine-8-carboxyliques substitués en position 3 et leur utilisation
EP3189037A1 (fr) Quinolones à titre d'inhibiteurs de protéines à bromodomaines de classe iv
EP2041110A1 (fr) Dérivés d'oxyhétéroarylamide 2 comme inhibiteurs d'activité parp
WO2006032869A1 (fr) Inhibiteurs d'adn-pk
JP3990061B2 (ja) プリン誘導体および糖尿病の予防・治療剤としてのアデノシンａ２受容体拮抗剤
EP2445915B1 (fr) Composés 3h-imidazo[5,1-d][1,2,3,5-tétrazin-4-one 3-substitués-8-substitués et leur utilisation
WO2008142376A1 (fr) Composés de l'acide bicyclosulfonylique et leur utilisation en tant qu'agents thérapeutiques
WO2009153566A1 (fr) Inhibiteurs de cyp26
EP2443113A1 (fr) Composés amido-isothiazole et leur utilisation comme inhibiteurs de la 11 -hsd1 dans le traitement du syndrome métabolique et des troubles apparentés
EP2888254B1 (fr) Composés hétérocycliques fusionnés et leurs utilisation
EP1416936B1 (fr) Thiopyrane-4-ones utilises comme inhibiteurs d'une proteine kinase dependante de l'adn
WO2014041349A1 (fr) Pyrimidines ou pyridazines tétrahydropyran-4-yléthylamino- ou tétrahydropyranyl-4-éthyloxy utiles comme inhibiteurs de l'isoprényl-cystéine-carboxy-méthyl-transférase
WO2010007389A1 (fr) Dérivés de 5-amidothiazole et leur utilisation comme inhibiteurs des checkpoint kinases
HK1172321B (en) 3-substituted-8-substituted-3h imidazo[5,1-d][1,2,3,5-tetrazin-4-one compounds and their use

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08851162

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08851162

Country of ref document: EP

Kind code of ref document: A2