WO2009066060A2 - 4-substituted-6-isopropyl-benzene-1,3-diol compounds and their use - Google Patents

4-substituted-6-isopropyl-benzene-1,3-diol compounds and their use Download PDF

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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
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independently
compound according
present
optionally substituted
diyl
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WO2009066060A3 (en
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Jens Christian Norrild
Anne Lauritsen
Fredrik Björkling
Sreenivasa Murthy Vadlamudi
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Topotarget A/S
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    • 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
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    • 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
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    • 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
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    • 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
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    • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
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    • 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
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    • 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
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    • 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
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    • C07C39/24—Halogenated derivatives
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    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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
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    • 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.

Abstract

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. 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.

Description

4-SUBSTITUTED-6-ISOPROPYL-BENZENE-1.3-DIOL COMPOUNDS AND THEIR USE
RELATED APPLICATIONS
This application is related to: United States patent application number 61/054,953 filed 21 May 2008; United States patent application number 60/988,915 filed 19 November 2007; and United Kingdom patent application number 0722680.6 filed 19 November 2007; the contents of each of which are incorporated herein by reference in their entirety.
TECHNICAL FIELD
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. 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.
BACKGROUND
A number of patents and publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
Throughout this specification, including the claims which follow, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and
"comprising," will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.
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.
This disclosure includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Heat Shock Protein 90 (HSP90)
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). Furthermore, 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). In vitro and in vivo studies have demonstrated that occupancy of this N- terminal pocket by ansamycins and other HSP90 inhibitors alters HSP90 function and inhibits, for example, protein folding and activation. At high concentrations, 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. 1997; Smith, et al., 1995), v-src (Whitesell et al., 1994) and certain transmembrane tyrosine kinases (Sepp-Lorenzino et a/., 1995) such as EGF receptor (EGFR) and Her2/Neu (Hartmann et al., 1997; Miller et a/., 1994; Mimnaugh et a/., 1996; Schnur et al., 1995), CDK4, and mutant p53 (Erlichman et al. 2001). 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).
In addition to anti-cancer and antitumourigenic activity, 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 ). In addition, 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. However, 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. Further, the dose limiting toxicity of ansamyins is hepatic.
SUMMARY OF THE INVENTION
One aspect of the invention pertains to certain 4-substituted-6-isopropyl-benzene-1 ,3-diol compounds (referred to herein as "IBD compounds"), as described herein.
Another aspect of the invention pertains to a composition (e.g., a pharmaceutical composition) comprising an IBD compound, as described herein, and a pharmaceutically acceptable carrier or diluent.
Another aspect of the invention pertains to method of preparing a composition (e.g., a pharmaceutical 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).
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.
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. In one embodiment, the treatment is treatment of a disease or condition that is mediated by heat shock protein 90 (HSP90).
In one embodiment, the treatment is treatment of a disease or condition that is ameliorated by the inhibition of heat shock protein 90 (HSP90) function.
In one embodiment, the treatment is treatment of a disease or condition that is known to be treated by HSP90 inhibitors (e.g., 17-AAG, geldanamycin, etc.).
In one embodiment, the treatment is treatment of a proliferative condition.
In one embodiment, the treatment is treatment of cancer.
Another aspect of the present invention pertains to a kit 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.
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.
As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspect of the invention. DETAILED DESCRIPTION OF THE INVENTION
Compounds
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.
Figure imgf000007_0001
4~substituted-6-isopropyl-benzene-1 ,3-diol resorcinol
In one embodiment, the compounds are selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000007_0002
wherein:
-X1- is independently a covalent single bond or -X1L-; -X2- is independently a covalent single bond or -X2L-;
-A1- is independently -A1A-; -A2 is independently -A2A, -H, or -F;
except that if: -X2- is -X2L-, then: -A2 is -A2A;
each of -X1L- and -X2L- is independently:
-RL-,
-C(=O)-, -RL-C(=O)-, -C(=O)-RL-,
-RL-C(=O)-RL-, -O-RL-C(=O)-,
-C(=O)-RL-O-,
-C(=O)-RL-S-,
-O-RL-C(=O)-RL-O,"
-NH-S(=O)2-, -NRA-S(=O)2-,
-RL-NH-S(=O)2-, -RL-NRA-S(=O)2-,
-NH-S(=O)2-RL-, -NRA-S(=O)2-RL-,
-RL-NH-S(=O)2-RL-, -RL-NRA-S(=O)2-RL-,
-S(=O)2-NH-, -S(=O)2-NRA-,
-RL-S(=O)2-NH-, -RL-S(=O)2-NRA-,
-C(=O)-NH-RL-, -C(=O)-NRA-RL-,
-RL-S(=O)2-NH-RL-, -RL-S(=O)2-NRA-RL-,
-O-,
-RL-O-,
-O-RL-,
-RL-O-RL-,
-NH-C(=O)-, -NRA-C(=O)-,
-RL-NH-C(=O)-, -RL-NRA-C(=O)-,
-NH-C(=O)-RL-, -NRA-C(=O)-RL-,
-RL-NH-C(=O)-RL-, -RL-NRA-C(=O)-RL-,
-C(=O)-NH-, -C(=O)-NRA-,
-RL-C(=O)-NH-, -RL-C(=O)-NRA-,
-C(=O)-NH-RL-, -C(=O)-NRA-RL-,
-RL-C(=O)-NH-RL-, -RL-C(=O)-NRA-RL-,
-NH-C(=O)-NH-, -NRA-C(=O)-NH-,
-NH-C(=O)-NRA-, -NRA-C(=O)-NRA-,
-RL-NH-C(=O)-NH-, -RL-NRA-C(=O)-NH-, -RL-NH-C(=O)-NRA-, -RL-NRA-C(=O)-NRA-,
-NH-C(=O)-NH-RL-, -NRA-C(=O)-NH-RL-, -NH-C(=O)-NRA-RL-, -NRA-C(=O)-NRA-RL-,
-RL-NH-C(=O)-NH-RL-, -RL-NRA-C(=O)-NH-RL-,
-RL-NH-C(=O)-NRA-RL-, -RL-NRA-C(=O)-NRA-RL-, -NH-, -NRA-, -RL-NH-, -RL-NRA-, -NH-RL-, -NRA-RL-, -RL-NH-RL-, -RL-NRA-RL-,
-C(=O)-O- -RL-C(=O)-O-, -C(=O)-O-RL-, -RL-C(=O)-O-RL-,
-O-C(=O)-, -RL-O-C(=O)-, -O-C(=O)-RL-, -RL-O-C(=O)-RL-,
-S(=O)-, -RL-S(=O)-, -S(=O)-RL-, -RL-S(=O)-RL-,
-S(=O)2-, -RL~S(=O)2-,
Figure imgf000009_0001
-RL-S(=O)2-RL-;
except that -X1L- is not:
-C(=O)-NH-, -C(=O)-NRA-, -C(=O)-NH-RL-, or -C(=O)-NRA-RL-; (see, e.g., WO 2006/109075)
wherein:
each -RA is independently -RM, -RAB, or -RAC; each -Rω is independently saturated aliphatic C^alkyl; each -RAB is independently aliphatic C2-6alkenyl; each -RAC is independently saturated C3.δcycloalkyl; and each -RM, -RΛB, and -RAC is independently unsubstituted or substituted with one or more substituents selected from -F, -Cl, -Br, -I, -OH, -OR, -NH2, -NHR, -NR2, -NHC(=O)R, -NRC(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NH2, -C(=O)NHR, and -C(=O)NR2, wherein each R is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl; each -RL- is independently -RL\ -RLB-, -RLG-, -R^-R10-, -R^-R^-, or -R^-R^-R^-; each -RLA is independently saturated aliphatic C1-6alkylene; each -RLB is independently aliphatic C2.6alkenylene; each -RLC is independently saturated C3-6cycloalkylene; and each -RLA, -RLB, and -RLC is independently unsubstituted or substituted with one or more substituents selected from -F, -Cl, -Br, -I, -OH, -OR, -NH2, -NHR, -NR2, -NHC(=O)R, -NRC(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NH2l -C(=O)NHR, and -C(=O)NR2, wherein each R is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl;
and wherein:
-A1A- is independently -A1AC- or -A1AH-; -A1AG- is independently C6-iocarboarylene; -A1AH- is independently C5-12heteroarylene; and each -A1AC- and each -A1AH- is independently unsubstituted or substituted with one or more substituents -Q1;
-A2A is independently -A2AC or -A2AH; -A2AC is independently C6-iocarboaryl; -A2AH is independently C5-i2heteroaryl; and each -A2AG and each -A2AH is independently unsubstituted or substituted with one or more substituents -Q2;
wherein:
each -Q1 and each -Q2 is independently:
-F, -Cl, -Br, -I,
-R1A1, -CF3, -OCF3,
-OH, -L1A-OH, -O-L1A-OH,
-OR1A1, -L1A-OR1A1, -O-L1A-OR1A1,
-SH, -SR1A1,
-CN, -NO2,
-NH2, -NHR1A1, -NR1A1 2, -NR1A2R1A3,
-L1A-NH2, -L1A-NHR1A1, -L1A-NR1A1 2, -L1A-NR1A2R1A3,
-O-L1A-NH2, -O-L1A-NHR1A1, -O-L1A-NR1A1 2, -O-L1A-NR1A2R1A3,
-NH-L1A-NH2, -NH-L1A-NHR1A1, -NH-L1A-NR1A1 2, -NH-L1A-NR1A2R1A3, -NR1A1-L1A-NH2, -NR1A1-L1A-NHR1A1, -NR1A1-L1A-NR1A1 2, -NR1A1-L1A-NR1A2R1A3,
-C(=O)OH, -C(=O)OR1A1, -OC(=O)R1A1, -C(=O)NH2, -C(=O)NHR1A1, -C(=O)NR1A1 2, -C(=O)NR1A2R1A3,
-NHC(=O)R1A1, -NR1A1C(=O)R1A1,
-C(=O)NHOR1A1, -C(=O)NR1A1OR1A1,
-NHC(=O)R1A1, -NR1A1C(=O)R1A1, -NHC(=O)OR1A1, -NR1A1C(=O)OR1A1,
-OC(=O)NH2, -OC(=O)NHR1A1, -OC(=O)NR1A1 2, -OC(=O)NR1A2R1A3,
-C(=O)R1A1,
-NHC(=O)NH2, -NHC(=O)NHR1A1,
-NHC(=O)NR1A1 2, -NHC(=O)NR1A2R1A3, -NR1A1C(=O)NH2, -NR1A1C(=O)NHR1A1,
-NR1A1C(=O)NR1A1 2, -NR1A1C(=O)NR1A2R1A3,
-NHS(=O)2R1A1 , -NR1A1S(=O)2R1A1,
-S(=O)2NH2l -S(=O)2NHR1A1, -S(=O)2NR1A1 2, -S(=O)2NR1A2R1A3,
-S(=O)R1A1, -S(=O)2R1A1, -OS(=O)2R1A1, or -S(=O)2OR1A1;
wherein:
each -L1A- is independently saturated aliphatic d.5alkylene; in each group -NR1A2R1A3, -R1A2 and -R1A3, 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 -R1A1 is independently:
R1B1 D1B2 D1B3 D1B4 D1B5 D1B6 D1B7 D1B8 , -K , -K , -K , -K , -K , -K , -K ,
-L1B-R1B4, -L1B-R1B5, -L1B-R1B6, -L1B-R1B7, or -L1B-R1B8; wherein: each -R1B1 is independently saturated aliphatic C1-6alkyl; each -R1B2 is independently aliphatic C2-6alkenyl; each -R1B3 is independently aliphatic C2-6alkynyl; each -R1B4 is independently saturated C3-6cycloalkyl; each -R1B5 is independently C3.6cycloalkenyl; each -R1B6 is independently non-aromatic C3-7heterocyclyl; each -R1B7 is independently C6.i0carboaryl; each -R1BS is independently C5-10heteroaryl; each -L1B- is independently saturated aliphatic C1-3alkylene; and wherein: each -R1B4, -R1B5, -R1B6, -R1B7, and -R1B8 is optionally substituted, for example, with one or more substituents -R1C1 and/or one or more substituents -R1C2, and each -R1B1, -R182, -R1B3, and -L1B- is optionally substituted, for example, with one or more substituents -R1C2, wherein: each -R1C1 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl; each -R1C2 is independently:
-F, -Cl, -Br, -I1 -CF3, -OCF3,
-OH, -L1D-OH, -O-L1D-OH, -OR101, -L1D-OR1D1, -O-L1D-OR1D1, -SH1 -SR101,
-CN, -NO2,
-NH2, -NHR1D\ -NR1D1 2, -NR102R103, -L1D-NH2, -L1D-NHR101, -L1D-NR1D1 2, or -L1D-NR1O2R103, -O-L1D-NH2, -O-L1D-NHR1D1, -O-L1D-NR1D1 2, -O-L10-NR1D2R1D3,
-NH-L1D-NH2, -NH-L1D-NHR1D1, -NH-L1D-NR1D1 2, -NH-L1D-NR1D2R103, -NR1D1-L1D-NH2, -NR1D1-L1D-NHR1D1,
-NR1D1-L10-NR1 D1 2, -NR1D1-L1O-NR1D2R1D3, ' -C(=O)OH,
-C(=O)OR1D1, -OC(=O)R1D1, -C(=O)R101,
-C(=O)NH2, -C(=O)NHR1D1, -C(=O)NR1D1 2, -C(=O)NR1D2R103, -NHC(=O)R1D1, -NR1D1C(=O)R1D\
-S(=O)2NH2, -S(=O)2NHR1A1, -S(=O)2NR1A1 2, -S(=O)2NR1A2R1A3, or -S(=O)2R1A1; wherein: each -R1D1 is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl; each -L1D- is independently saturated aliphatic Ci-5alkylene; and in each group -NR102R103, -R102 and -R1D3, 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;
and additionally, two adjacent -Q1 groups, if present, may together form -0-CH2-O- or -0-CH2CH2-O-; and additionally, two adjacent -Q2 groups, if present, may together form -0-CH2-O- or -0-CH2CH2-O-.
except that:
if -X1- is a covalent single bond, then -A1- 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-β-thione (see, e.g., WO 2008/118391);
2-OXO-1 ,2,3,4-tetrahydropyrimidine or substituted 2-oxo-1 , 2,3,4- tetrahydropyrimidine (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);
1 ,3-dihydro-imidazol-2-one-diyl or substituted 1 ,3-dihydro-imidazol-2-one-diyl (see, e.g., WO 2007/021877);
1 ,3-dihydro-imidazol-2-thione-diyl or substituted 1 ,3-dihydro-imidazol-2-thione-diyl (see, e.g., WO 2007/021877);
1 ,2,4-triazol-diyl or substituted 1 ,2,4-triazol-diyl (see, e.g., WO 2006/095783);
2,4-dihydro-[1,2,4]triazol-3-one-diyl or substituted 2,4-dihydro- [1 ,2,4]triazol-3-one-diyl (see, e.g., WO 2006/055760);
2,4-dihydro-[1 ,2,4]triazol-3-thione-diyl or substituted 2,4-dihydro- [1 ,2,4]triazol-3-thione-diyl (see, e.g., WO 2006/055760); or isoxazol-diyl or substituted isoxazol-diyl (see, e.g., WO 2004/072051).
Optional Provisos
In one or more aspects of the present invention (e.g., compounds, compositions, compounds for use in therapy, use of compounds in the manufacture of a medicament, methods, methods of treatment, etc.), the compounds are optionally as defined herein, but with one or more optional provisos, as defined herein.
In one embodiment, 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.
Figure imgf000013_0001
Figure imgf000014_0001
In one embodiment, 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.
In one embodiment, 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.
In one or more aspects of the present invention (e.g., compounds for use in therapy, use of compounds in the manufacture of a medicament, methods, methods of treatment, etc.), 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.
For example, a reference to a particular group of compounds "without the proviso regarding P-001 through P-003" (e.g., for use in therapy) is intended to be a reference to the compounds as defined, but wherein the definition no longer includes the indicated proviso. In such cases, it is as if the indicated proviso has been deleted from the definition of compounds, and the definition has been expanded to encompass those compounds which otherwise would have been excluded by the indicated proviso.
The Group -X1-
In one embodiment, -X1- is independently a covalent single bond or -X1L- In one embodiment, -X1- is independently a covalent single bond. In one embodiment, -X1- is independently -X1L-.
The Group -X2-
In one embodiment, -X - is independently a covalent single bond or -X - In one embodiment, -X2- is independently a covalent single bond. In one embodiment, -X2- is independently -X2L-.
The Group -A1-
In one embodiment, -A1- is independently -A1A-.
The Group -A2
In one embodiment, -A2 is independently -A2A, -H, or -F. In one embodiment, -A2 is independently -AM or -H. In one embodiment, -A2 is independently -A2A. In one embodiment, -A2 is independently -H or -F. In one embodiment, -A2 is independently -H.
Combinations of the Group -X1-. -A1-. -X2-, and -A2
In one embodiment, the group -X1-A1-X2-A2 is independently:
-X1L-A1A-X2L-A2A, -χiL_A 1A-A2A,
.χii-_A1A-H,
Figure imgf000015_0001
-A1A-X2L-A2A, -A1A-A2A, -A1A-H, or
-A1A-F.
In one embodiment, the group -X1-A1-X2-A2 is independently:
-X1L-A1A-H,
Figure imgf000015_0002
-A1A-X2L-A2A,
-A1A-A2A,
-A1A-H, or -A1A-F.
In one embodiment, the group -X1-A1-X2-A2 is independently -X1L-A1A-H or -X1L-A1A-F.
In one embodiment, the group -X1-A1-X2-A2 is independently -X1L-A1A-H.
In one embodiment, the group -X1-A1-X2-A2 is independently -A1A-X2L-A2A. In one embodiment, the group -X1-A1-X2-A2 is independently -A^-A2*.
In one embodiment, the group -X1-A1-X2-A2 is independently -A1A-H or -A1A-F.
In one embodiment, the group -X1-A1-X2-A2 is independently -A1A-H.
The Group -X1L-
In one embodiment, -X1L-, if present, is independently:
-RL-,
-C(=O)-, -RU-C(=O)-,
-C(=O)-RL-, -RL-C(=O)-RL-,
-O-RL-C(=O)-, -C(=O)-RL-O-,
-C(=O)-RL-S-, or -O-RL-C(=O)-RL-O,
In one embodiment, -X1L-, if present, is independently: -RL-,
-C(=O)-,
-C(=O)-RL-,
-C(=O)-RL-O-, or
-C(=O)-RL-S-.
In one embodiment, -X1L-, if present, is independently:
-C(=O)-,
-C(=O)-RL-,
-C(=0)-RL-O, or -C(=O)-RL-S-.
In one embodiment, -X1L-, if present, is independently -C(=O)-.
In one embodiment, -X1L-, if present, is independently -C(=O)-RL-.
In one embodiment, -X1L-, if present, is independently -C(=O)-RL-O-. In one embodiment, -X1L-, if present, is independently -RL-.
The Group -X2L-
In one embodiment, -X2L-, if present, is independently:
-RL-,
-NH-S(=O)2-, -NRA-S(=O)2-,
-RL-NH-S(=O)2-, -RL-NRA-S(=O)2-, -NH-S(=O)2-RL-, -NRA-S(=O)2-RL-, -RL-NH-S(=O)2-RL-, -RL-NRA-S(=O)2-RL-,
-S(=O)2-NH-, -S(=O)2-NRA-,
-RL-S(=O)2-NH-, -RL-S(=O)2-NRA-, -C(=O)-NH-RL-, -C(=O)-NRA-RL-, -RL-S(=O)2-NH-RL-, -RL-S(=O)2-NRA-RL-,
-O1
-RL-O-, -O-RL-S -RL-O-RL-,
-NH-C(=O)-, -NRA-C(=O)-,
-RL-NH-C(=O)-, -RL-NRA-C(=O)-, -NH-C(=O)-RL-, -NRA-C(=O)-RL-, -RL-NH-C(=O)-RL-, -RL-NRA-C(=O)-RL-,
-C(=O)-NH-, -C(=O)-NRA-,
-RL-C(=O)-NH-, -RL-C(=O)-NRA-, -C(=O)-NH-RL-, -C(=O)-NRA-RL-, -RL-C(=O)-NH-RL-, or -RL-C(=O)-NRA-RL-.
In one embodiment, -X2L-, if present, is independently:
-RL-,
-NH-S(=O)2-, -NRA-S(=O)2-, -RL-NH-S(=O)2-, -RL-NRA-S(=O)2-,
-NH-S(=O)2-RL-, -NRA-S(=O)2-RL-, -RL-NH-S(=O)2-RL-, -RL-NRA-S(=O)2-RL-,
-O-, -RL-O-, -O-RL-,
-RL-O-RL-,
-C(=O)-NH-, -C(=O)-NRA-, -RL-C(=O)-NH-, -RL-C(=O)-NRA-, -C(=O)-NH-RL-, -C(=O)-NRA-RL-,
-RL-C(=O)-NH-RL-, or -RL-C(=O)-NRA-RL-.
In one embodiment, -X2L-, if present, is independently:
-RL-,
-NH-S(=O)2-, -NRA-S(=O)2-,
-NH-S(=O)2-RL-, -NRA-S(=O)2-RL-,
-RL-O-,
-C(=O)-NH-, -C(=O)-NRA-, -C(=O)-NH-RL-, or -C(=O)-NRA-RL-.
In one embodiment, -X2L-, if present, is independently -RL-.
In one embodiment, -X2L-, if present, is independently -NH-S(=O)2-, -NRA-S(=O)2-, NH-S(=O)2-RL- or -NRA-S(=O)2-RL-.
In one embodiment, -X2L-, if present, is independently -NH-S(=O)2- or -NRA-S(=O)2-.
In one embodiment, -X2L-, if present, is independently -NH-S(=O)2-RL- or -NRA-S(=O)2-RL-.
In one embodiment, -X2L-, if present, is independently -RL-O-.
In one embodiment, -X2L-, if present, is independently -C(=O)-NH- or -C(=O)-NRA-.
In one embodiment, -X2L-, if present, is independently -C(=O)-NH-RL- or -C(=O)-NRA-RL-.
The Group -RL-
In one embodiment, each -RL-, if present, is independently:
-RLA-, -Rl-EL1 .RLC-1
Figure imgf000018_0001
or .R^LC.^ wherein: each -RLA is independently saturated aliphatic Ci-6alkylene; each -RLB is independently aliphatic C2-6alkenylene; each -RLC is independently saturated C3.6cycloalkylene; and each -RLA, -RLB, and -RLC is independently unsubstituted or substituted with one or more substituents selected from -F, -Cl, -Br, -I1 -OH, -OR, -NH2, -NHR, -NR2, -NHC(=O)R, -NRC(=O)R,
Figure imgf000019_0001
-OC(=O)R, -C(=O)NH2, -C(=O)NHR, and -C(=O)NR2, wherein each R is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl.
In one embodiment, each -RL-, if present, is independently -R^-, -RLB-, or -RLC-. In one embodiment, each -RL-, if present, is independently -RLA-.
In one embodiment, each -RL-, if present, is independently unsubstituted.
In one embodiment, each -RLA, if present, is independently saturated aliphatic
C-,.4alkylene.
In one embodiment, each -RLA, if present, is independently saturated aliphatic
Ci.3alkylene.
In one embodiment, each -RLA, if present, is independently saturated aliphatic C1-2alkylene.
In one embodiment, each -RL-, if present, is independently -CH2- Or -CH2CH2-. In one embodiment, each -RL-, if present, is independently -CH2-.
The Group -RA
In one embodiment, each -RA, if present, is independently: -R^ -R^ or -R*0, wherein: each -RM is independently saturated aliphatic C1-6alkyl; each -RAB is independently aliphatic C2-6alkenyl; each -RAC is independently saturated C3-6cycloalkyl; and each -RM, -RAB, and -RAC is independently unsubstituted or substituted with one or more substituents selected from -F, -Cl, -Br, -I1 -OH, -OR, -NH2, -NHR, -NR2, -NHC(=O)R, -NRC(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NH2, -C(=O)NHR, and -C(=O)NR2, wherein each R is independently saturated aliphatic d^alkyl, phenyl, or benzyl.
In one embodiment, each -RA, if present, is independently -RM or -RAB. In one embodiment, each -RA, if present, is independently -RM. In one embodiment, each -RA, if present, is independently saturated aliphatic C1-4alkyl. In one embodiment, each -RA, if present, is independently -Me or -Et. In one embodiment, each -RA, if present, is independently -Me.
The Group -A1A-
In one embodiment, -A1A-, if present, is independently -A1AC- or -A1AH-, wherein: -A1AC- is independently C6-i0carboarylene; -A1AH- is independently C5-12heteroarylene; each -A1AC- and -A1AH- is independently unsubstituted or substituted with one or more substituents -Q1.
In one embodiment, -A1A-, if present, is independently -A1AC-.
In one embodiment, -A1AC-, if present, is independently phenylene or naphth-diyl, and is optionally substituted.
In one embodiment, -A1AC-, if present, is independently phenylene, and is optionally substituted.
In one embodiment, -A1AC-, if present, is independently phenyl-1 ,2-diyl, and is optionally substituted.
In one embodiment, -A1AC-, if present, is independently phenyl-1 ,3-diyl, and is optionally substituted.
In one embodiment, -A1AC-, if present, is independently phenyl-1 ,4-diyl, and is optionally substituted.
In one embodiment, -A1AC-, if present, is independently naphth-diyl, and is optionally substituted.
In one embodiment, -A1AC-, if present, is independently naphth-1 ,2-diyl, and is optionally substituted.
In one embodiment, -A1AC-, if present, is independently naphth-1 , 4-diyl, and is optionally substituted.
In one embodiment, -A1A-, if present, is independently -A1ΛH-.
In one embodiment, -A1AH-, if present, is independently C5-6heteroarylene, and is optionally substituted. In one embodiment, -A1AH-, if present, is independently C7-i0heteroarylene, and is optionally substituted.
In one embodiment, -A1AH-, if present, 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.
In one embodiment, -A1AH-, if present, is independently furan-diyl, thien-diyl, 1 ,2,3-triazol-diyl, oxazol-diyl, thiazol-diyl, or pyridin-diyl, and is optionally substituted.
In one embodiment, -A1AH-, if present, is independently triazol-diyl, and is optionally substituted.
In one embodiment, -A1AH-, if present, is independently 1 ,2,3-triazol-diyl, and is optionally substituted.
In one embodiment, -A1AH-, if present, is independently 1 ,2,3-triazol-1 ,4-diyl, and is optionally substituted.
In one embodiment, -A1AH-, if present, is independently 1 ,2,3-triazol-1 ,5-diyl, and is optionally substituted.
In one embodiment, -A1AH-, if present, is independently 1 ,2,3-triazol-1 ,4-diyl, and is optionally substituted, wherein -X1- is attached at the 1 -position of the 1 ,2,3-triazol-1 ,4-diyl.
In one embodiment, -A1AH-, if present, is independently 1 ,2,3-triazo]-1 ,4-diyl, and is optionally substituted, wherein -X1- is attached at the 4-position of the 1 ,2,3-triazol-1 ,4-diyl.
In one embodiment, -A1AH-, if present, is independently 1 ,2,3-triazol-i ,5-diyl, and is optionally substituted, wherein -X1- is attached at the 1-position of the 1 ,2,3-triazol-1 ,4-diyl.
In one embodiment, -A1AH-, if present, is independently 1 ,2,3-triazoM ,5-diyl, and is optionally substituted, wherein -X1- is attached at the 5-position of the 1 ,2,3-triazol-1 ,4-diyl.
In one embodiment, -A1AH-, if present, is independently oxazol-diyl, and is optionally substituted. In one embodiment, -A1AH-, if present, is independently oxazol-4,5-diyl, and is optionally substituted.
In one embodiment, -A1AH-, if present, is independently oxazol-2,4-diyl, and is optionally substituted.
In one embodiment, -A1AH-, if present, is independently oxazol-2,5-diyl, and is optionally substituted.
In one embodiment, -A1AH-, if present, is independently oxazol-4,5-diyl, and is optionally substituted, wherein -X1- is attached at the 4-position of the oxazol-4,5-diyl.
In one embodiment, -A1AH-, if present, is independently oxazol-4,5-diyl, and is optionally substituted, wherein -X1- is attached at the 5-position of the oxazo!-4,5-diyl.
In one embodiment, -A1AH-, if present, is independently furan-diyl, and is optionally substituted.
In one embodiment, -A1AH-, if present, is independently thien-diyl, and is optionally substituted.
In one embodiment, -A1AH-, if present, is independently pyridin-diyl, and is optionally substituted.
In one embodiment, -A1AH-, if present, is independently quinolin-diyl, and is optionally substituted.
In one embodiment, -A1AH-, if present, is independently isoquinolin-diyl, and is optionally substituted.
The Group -A2A
In one embodiment, -A2A, if present, is independently -A2AC or -A2^1 wherein: -A2AC is independently C6-i0carboaryl; -A2AH is independently C5.12heteroaryl; each -A2AC and -A2AH is independently unsubstituted or substituted with one or more substituents -Q2.
In one embodiment, -A2A, if present, is independently -A2AC. In one embodiment, -A2AC, if present, is independently phenyl or naphthyl, and is optionally substituted.
In one embodiment, -A2AC, if present, is independently phenyl, and is optionally substituted.
In one embodiment, -A2AG, if present, is independently phenyl, and is optionally substituted at the para-position.
In one embodiment, -A2AC, if present, is independently naphthyl, and is optionally substituted.
In one embodiment, -A2AC, if present, is independently naphth-1-yl, and is optionally substituted.
In one embodiment, -A2AC, if present, is independently naphth-2-yl, and is optionally substituted.
In one embodiment, -A2A, if present, is independently -A2AH.
In one embodiment, -A2AH, if present, is independently C5.6heteroaryl, and is optionally substituted.
In one embodiment, -A2AH, if present, is independently C7-10heteroaryl, and is optionally substituted.
In one embodiment, -A2AH, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and is optionally substituted.
In one embodiment, -A2AH, if present, is independently pyridinyl, thiazolyl, or furanyl and is optionally substituted.
In one embodiment, -A2AH, if present, is independently pyridinyl, and is optionally substituted.
In one embodiment, -A2AH, if present, is independently pyridin-2-yl, and is optionally substituted.
In one embodiment, -A2AH, if present, is independently pyridin-3-yl, and is optionally substituted. In one embodiment, -A2AH, if present, is independently pyridin-4-yl, and is optionally substituted.
In one embodiment, -A2AH, if present, is independently thiazolyl, and is optionally substituted.
In one embodiment, -A2AH, if present, is independently thiazol-4-yl, and is optionally substituted.
In one embodiment, -A2AH, if present, is independently furanyl, and is optionally substituted.
In one embodiment, -A2AH, if present, is independently furan-5-yl, and is optionally substituted.
In one embodiment, -A2AH, if present, is independently imidazolyl, and is optionally substituted.
In one embodiment, -A2AH, if present, is independently imidazol-1-yl, and is optionally substituted.
In one embodiment, -A2AH, if present, is independently quinolinyl, and is optionally substituted.
In one embodiment, -A2AH, if present, is independently quinolin-6-yl, and is optionally substituted.
In one embodiment, -A2AH, if present, is independently indolyl, and is optionally substituted.
In one embodiment, -A2AH, if present, is independently indol-5-yl, and is optionally substituted.
Some Preferred Combinations: Aryl-Resorcinols
In one embodiment: the group -X1-A1-X2-A2 is independently -A2A; and
-A2A is independently -A2AC. In one embodiment: the group -X1-A1-X2-A2 is independently -A2A; and -A2A is independently -A2AH.
Some Preferred Combinations: Aryl-Aryl-Resorcinols
In one embodiment: the group -X1-A1-X2-A2 is independently -A1A-A2A; -A1A- is independently -A1AC-; and -A2A is independently -A2^.
In one embodiment: the group -X1-A1-X2-A2 is independently -A1A-A2A; -A1A- is independently -A1AC-; and -A2A is independently -A2AH.
In one embodiment: the group -X1-A1-X2-A2 is independently -A1A-A2A; -A1A- is independently -A1AH-; and -A2A is independently -A2AG.
In one embodiment: the group -X1-A1-X2-A2 is independently -A1A-A2A; -A1A- is independently -A1AH-; and -A2A is independently -A2AH.
Some Preferred Combinations: Phenyl-Oxazolyl-Resorcinols
In one embodiment: the group -X1-A1-X2-A2 is independently -A1A-A2A;
-A1A- is independently oxazol-4,5-diyl; and -A2A is independently phenyl, and is optionally substituted.
In one embodiment: the group -X1-A1-X2-A2 is independently -A1A-A2A;
-A1A- is independently oxazol-4,5-diyl; wherein -A2A- is attached at the 5-position of the oxazol-4,5-diyl; and -A2A is independently phenyl, and is optionally substituted. In one embodiment, the compounds are selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000026_0001
In one embodiment: the group -X1-A1-X2-A2 is independently -A1A-A2A;
-A1A- is independently oxazol-4,5-diyl; and
-A2A is independently -A2^; and
-A2AH is independently C5.6heteroaryl, and is optionally substituted.
In one embodiment: the group -X1-A1-X2-A2 is independently -A1A-A2A;
-A1A- is independently oxazol-4,5-diyl; wherein -A2A- is attached at the 5-position of the oxazol-4,5-diyl; -A2A is independently -A2AH; and
-A2AH is independently C5-6heteroaryl, and is optionally substituted.
In one embodiment: the group -X1-A1-X2-A2 is independently -A^-A^; -A1A- is independently oxazol-2,5-diyl; and
-A2A is independently phenyl, and is optionally substituted.
In one embodiment: the group -X1-A1-X2-A2 is independently -A1A-A2A; -A1A- is independently oxazol-2,5-diyl; and
-A2A is independently -A2AH; and -A2AH is independently C5-6heteroaryl, and is optionally substituted.
Some Preferred Combinations: Phenyl-Triazolyl-Resorcinols
In one embodiment: the group -X1-A1-X2-A2 is independently -A1A-A2A; -A1A- is independently 1 ,2,3-triazol-1 ,4-diyl or 1 ,2,3-triazol-1 ,5-diyl; -A2A is independently phenyl, and is optionally substituted. In one embodiment: the group -X1-A1-X2-A2 is independently -A1A-A2A;
-A1A- is independently 1,2,3-triazol-1 ,4-diyl; and
-A2A is independently phenyl, and is optionally substituted.
In one embodiment: the group -X1-A1-X2-A2 is independently -A^-A^;
-A1A- is independently 1 ,2,3-triazol-1 ,5-diyl; and
-A2A is independently phenyl, and is optionally substituted.
Some Preferred Combinations: Keto-resorcinols
In one embodiment: the group -X1-A1-X2-A2 is independently -X1L-A1A-H or -X1L-A1A-F; -X1L- is independently -C(=O)-, -C(=O)-CH2-, -C(=O)-CH2-O-, or -C(=O)-CH2-S-; and
-A1A- is independently phenyl, and is optionally substituted.
In one embodiment: the group -X1-A1-X2-A2 is independently -X1L-A1A-H or -X1L-A1A-F;
-X1L- is independently -C(=O)-CH2-; and -A1A- is independently phenyl, and is optionally substituted.
In one embodiment: the group -X1-A1-X2-A2 is independently -X1L-A1A-H;
-X1L- is independently -C(=O)-CH2-; and -A1A- is independently phenyl, and is optionally substituted.
In one embodiment: the group -X1-A1-X2-A2 is independently -X1L-A1A-H or -X1L-A1A-F;
-X1L- is independently -C(=O)-; and -A1A- is independently phenyl, and is optionally substituted.
In one embodiment: the group -X1-A1-X2-A2 is independently -X1L-A1A-H;
-X1L- is independently -C(=O)-; and -A1A- is independently phenyl, and is optionally substituted. Some Preferred Combinations: Sulfonamide-Phenyl-Resorcinols
In one embodiment: the group -X1-A1-X2-A2 is independently -A1A-H; -A1A- is independently phenyl and bears at least one substituent, -Q1, which is independently:
-NHS(=O)2R1A1, -NR1A1S(=O)2R1A1,
-S(=O)2NH2, -S(=O)2NHR1A1, -S(=O)2NR1A1 2, or -S(=O)2NR1A2R1A3.
In one embodiment: the group -X1-A1-X2-A2 is independently -A1A-H;
-A1A- is independently phenyl and bears at least one substituent, -Q1, which is independently:
-NHS(=O)2R1A1 or -NR1A1S(=O)2R1A1.
Some Preferred Combinations: Benzyl-Triazolyl-Resorcinols
In one embodiment: the group -X1-A1-X2-A2 is independently -A^-X^-A2*; -A1A- is independently 1 ,2,3-triazol-1 ,4-diyl or 1 ,2,3-triazoM ,5-diyl;
-X2L- is independently -CH2-; and -A2A is independently phenyl, and is optionally substituted.
In one embodiment: the group -X1-A1-X2-A2 is independently -A^-X^-A^;
-A1A- is independently 1 ,2,3-triazol-1 ,4-diyl; -X2L- is independently -CH2-; and -A2A is independently phenyl, and is optionally substituted.
In one embodiment: the group -X1-A1-X2-A2 is independently -A^-X^-A2*;
-A1A- is independently 1,2,3-triazol-1 ,5-diyl;
-X2L- is independently -CH2-; and
-AZA is independently phenyl, and is optionally substituted. Some Preferred Combinations: Benzyl-Qxazolyl-Resorcinols
In one embodiment: the group -X1-A1-X2-A2 is independently -A^-X^-A2*; -A1A- is independently oxazol-2,5-diyl;
-X2L- is independently -CH2-; and -A2A is independently phenyl, and is optionally substituted.
Some Preferred Combinations: Phenyl-Resorcinols
In one embodiment: the group -X1-A1-X2-A2 is independently -A2A; and
-A2A is independently phenyl, and is optionally substituted.
The Optional Substituents -Q1
In one embodiment, each -A1AC- and -A1AH-, if present, is independently unsubstituted or substituted with one or more substituents -Q1.
In one embodiment, each -A1AC- and -A1AH-, if present, is independently unsubstituted.
In one embodiment, each -A1AC- and -A1AH-, if present, is independently substituted with one or more substituents -Q1.
In one embodiment, -A1AG-, if present, is independently unsubstituted.
In one embodiment, -A1AC-, if present, is independently substituted with one or more substituents -Q1.
In one embodiment, -A1AH-, if present, is independently unsubstituted. In one embodiment, -A1AH-, if present, is independently substituted with one or more substituents -Q1.
In one embodiment, each -Q1, if present, is independently:
-F, -Cl, -Br, -I,
-R1A1,
-CF3, -OCF3,
-OH, -L1A-OH, -O-L1A-OH,
-OR1A\ -L1A-OR1A1, -O-L1A-OR1A1, -NO2,
-NH2, -NHR1A1, -NR1A1 2, -NR1A2R1A3, -C(=O)OH, -C(=O)OR1A1,
-C(=O)NH2, -C(=O)NHR1A1, -C(=O)NR1A1 2, -C(=O)NR1A2R1A3, -NHC(=O)R1A1, -NR1A1C(=O)R1A1, ■ -NHS(=O)2R1A1, -NR1A1S(=O)2R1A1, -S(=O)2NH2l -S(=O)2NHR1A1, -S(=O)2NR1A1 2, or -S(=O)2NR1A2R1A3; and additionally, two adjacent -Q1 groups, if present, may together form -0-CH2-O- or -0-CH2CH2-O-.
In one embodiment, each -Q1, if present, is independently: -F, -Cl, -Br, -I, -R1A1, -OH, -OR1A1,
-NHS(=O)2R1A1, -NR1A1S(=O)2R1A1, -S(=O)2NH2, -S(=O)2NHR1A1, -S(=O)2NR1A1 2, or -S(=O)2NR1A2R1A3.
In one embodiment, each -Q1, if present, is independently: -F, -Cl, -Br, -I, -R1A1, -OH, or -OR1A1.
In one embodiment, each -Q1, if present, is independently:
-R1A1.
In one embodiment, at least one -Q1 is present, and is independently: -NHS(=O)2R1A1, -NR1A1S(=O)2R1A1, -S(=O)2NH2, -S(=O)2NHR1A1, -S(=O)2NR1A1 2, or -S(=O)2NR1A2R1A3.
In one embodiment, at least one -Q1 is present, and is independently: -NHS(=O)2R1A1 or -NR1A1S(=O)2R1A1.
In one embodiment, each -Q1, if present, is independently selected from those substituents exemplified under the headings "Examples of Specific Embodiments" and "Additional Examples of Specific Embodiments".
The Optional Substituents -Q2
In one embodiment, each -A2AC- and -A2AH-, if present, is independently unsubstituted or substituted with one or more substituents -Q2.
In one embodiment, each -A2AC- and -A2AH-, if present, is independently unsubstituted.
In one embodiment, each -A2AC- and -A2AH-, if present, is independently substituted with one or more substituents -Q2.
In one embodiment, -A2AC-, if present, is independently unsubstituted. In one embodiment, -A2AC-, if present, is independently substituted with one or more substituents -Q2.
In one embodiment, -A2AH-, if present, is independently unsubstituted. In one embodiment, -A2AH-, if present, is independently substituted with one or more substituents -Q2.
In one embodiment, each -Q2, if present, is independently:
-F1 -Cl1 -Br1 -I,
-R1A1,
-CF3, -OCF3,
-OH, -L1A-OH, -O-L1A-OH,
-OR1A1, -L1A-OR1A1, -O-L1A-OR1A1, -NO2,
-NH2, -NHR1A\ -NR1A1 2, -NR1A2R1A3,
-C(=O)OH, -C(=O)OR1A1,
-C(=O)NH2, -C(=O)NHR1A1, -C(=O)NR1A1 2, -C(=O)NR1A2R1A3,
-NHC(=O)R1A1, -NR1A1C(=O)R1A1, -NHS(=O)2R1A1, -NR1A1S(=O)2R1A1,
-S(=O)2NH2, -S(=O)2NHR1A1, -S(=O)2NR1A1 2, or -S(=O)2NR1A2R1A3; and additionally, two adjacent -Q1 groups, if present, may together form -0-CH2-O- or -0-CH2CH2-O-.
In one embodiment, each -Q2, if present, is independently: -F, -Cl1 -Br, -I1 -R1A1, -OH, -0R1A1, -NHS(=O)2R1A1, -NR1A1S(=O)2R1A1, -S(=O)2NH2, -S(=O)2NHR1A\ -S(=O)2NR1A1 2, or -S(=O)2NR1A2R1A3.
In one embodiment, each -Q2, if present, is independently: -F, -Cl, -Br, -I, -R1A1, -OH, or -OR1A1.
In one embodiment, each -Q2, if present, is independently:
-R1A1.
In one embodiment, each -Q2, if present, is independently selected from those substituents exemplified under the headings "Examples of Specific Embodiments" and "Additional Examples of Specific Embodiments". Elemeπts of -Q1 and -Q2
In one embodiment, each -NR1A2R1A3, if present, 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-3alkyl.
In one embodiment, each -NR1A2R1A3, if present, 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-3alkyl.
In one embodiment, each -R1A1, if present, is independently:
_p1B1 _D1B4 _p1B6 _p1B7 _p1B8 -L1B-R1B4, -L1B-R1B6, -L1B-R1B7, or -L1B-R1B8.
In one embodiment, each -R1A1, if present, is independently:
_p1B1 _p1B4 _p1B7
-L1B-R1B4, or -L1B-R1B7.
In one embodiment, each -R1A1, if present, is independently: -L1B-R1B6, -L18-R1B7, or -L1B-R1B8.
In one embodiment, each -R1A1, if present, is independently: -L1B-R1B6 or -L1B-R1B8.
In one embodiment, each -R1A1, if present, is independently:
-R1B1.
In one embodiment, each -R1B6, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl.or dioxanyl, and is optionally substituted.
In one embodiment, each -R186, if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl, and is optionally substituted.
In one embodiment, each -R1B7, if present, is independently phenyl, and is optionally substituted. In one embodiment, each -R1B8, if present, is independently C5.6heteroaryl, and is optionally substituted.
In one embodiment, each -R1B8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
In one embodiment, each -L1B-, if present, is independently -CH2-.
In one embodiment, each -R1C1, if present, is independently saturated aliphatic C1-4alkyl.
In one embodiment, each -R1C2, if present, is independently:
-F, -Cl, -Br, -I1
-CF3, -OCF3, -OH,
-OR1D1,
-SH, -SR1D\
-CN,
-NO2, -NH2, -NHR1D1, -NR1D1 2, -NR1D2R1D3,
-C(=O)OH, -C(=O)OR1D\ -OC(=O)R1D1,
-C(=O)R1D1,
-C(=O)NH2, -C(=O)NHR1D1, -C(=O)NR1D1 2, -C(=O)NR1D2R1D3,
-NHC(=O)R1D1, -NR1D1C(=O)R1D1, -S(=O)2NH2, -S(=O)2NHR1A1, -S(=O)2NR1A1 2, -S(=O)2NR1A2R1A3, or
-S(=O)2R1 A1.
In one embodiment, each -R1C2, if present, is independently:
-F, -Cl, -Br, -I1 -CF3, -OCF3,
-OH,
-0R1D1,
-NH2, -NHR1D1, -NR1D1 2, -NR102R103,
-C(=O)OH, -C(=O)OR101, -OC(=O)R1D1, -C(=O)R1D1,
-C(=O)NH2, -C(=O)NHR1D1, -C(=O)NR1D1 2, -C(=O)NR1D2R103,
-NHC(=O)R1D1, -NR1D1C(=O)R1D1,
-SC=O)2NH2, -S(=O)2NHR1A1, -S(=O)2NR1A1 2, or -S(=O)2NR1A2R1A3.
In one embodiment, each -R101, if present, is independently saturated aliphatic C1-4alkyl. In one embodiment, each -NR102R103, 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 C1-3alkyl.
In one embodiment, each -NR102R103, if present, 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.3alkyl.
Combinations
Each and every compatible combination of the embodiments described above is explicitly disclosed herein, as if each and every combination was individually and explicitly recited.
Molecular Weight
In one embodiment, 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.
Examples of Specific Embodiments
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000041_0001
Figure imgf000042_0001
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000055_0001
Additional Examples of Specific Embodiments
Oxazole-Resorcinols
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000056_0001
Figure imgf000057_0001
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000058_0001
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000058_0002
Figure imgf000059_0001
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000059_0002
Figure imgf000060_0001
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000060_0002
Triazole-Resorcinols
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000061_0001
Figure imgf000062_0001
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000063_0001
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000064_0001
Figure imgf000065_0001
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000066_0001
Keto-Resorcinols
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000067_0001
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000068_0001
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000068_0002
Figure imgf000069_0001
Figure imgf000070_0001
Phenyl-Resorcinols
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000073_0002
Figure imgf000074_0001
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000074_0002
Heteroaryl-Resorcinols
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000075_0001
Naphthyl-Resorcinols
In one embodiment, the compounds are selected from compounds of the following formulae and pharmaceutically acceptable salts, hydrates, and solvates thereof:
TABLE 17
Compounds where -X1- is a covalent single bond, -A1- is naphth-diyl,
-X2- is c a covalent single bond, and -A 2 is -H
R
HO
Compound R Compound R
17-1
Substantiallv Purified Forms
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.
In one embodiment, 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.
Unless specified, the substantially purified form refers to the compound in any stereoisomeric or enantiomeric form. For example, in one embodiment, the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds. In one embodiment, 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. In one embodiment, the substantially purified form refers to a equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer.
In one embodiment, 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.
Unless specified, 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.
In one embodiment, 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.
Isomers
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; α- and β-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").
Note that, except as discussed below for tautomeric forms, specifically excluded from the term "isomers," as used herein, 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). For example, a reference to a methoxy group, -OCH3, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., Ci-7alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
The above exclusion does not pertain to tautomeric forms, for example, 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
Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H (D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; O may be in any isotopic form, including 16O and 18O; and the like.
Unless otherwise specified, 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) and separation (e.g., fractional crystallisation and chromatographic means) of such 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. Salts
It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. ScL Vol. 66, pp. 1-19.
For example, if the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO"), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth cations such as Ca2+ and Mg2+, and other cations such as Al+3. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4 +) and substituted ammonium ions (e.g., NH3R+, NH2R2 +, NHR3 +, NR4 +). Examples of some 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(CH3)4 +.
If the compound is cationic, or has a functional group which may be cationic (e.g., -NH2 may be -NH3 +), then a salt may be formed with a suitable anion. Examples of 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.
Examples of 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. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
Unless otherwise specified, a reference to a particular compound also includes salt forms thereof. Solvates and Hydrates
It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the compound. The term "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.
Unless otherwise specified, a reference to a particular compound also includes solvate and hydrate forms thereof.
Chemically Protected Forms
It may be convenient or desirable to prepare, purify, and/or handle the compound in a chemically protected form. The term "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). In practice, well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions. In a chemically protected form, 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). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).
A wide variety of such "protecting," "blocking," or "masking" methods are widely used and well known in organic synthesis. For example, a compound which has two nonequivalent reactive functional groups, both of which would be reactive under specified conditions, may be derivatized to render one of the functional groups "protected," and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group may be "deprotected" to return it to its original functionality.
For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(=O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH3l -OAc). For example, an aldehyde or ketone group may be protected as an acetal (R-CH(OR)2) or ketal (R2C(OR)2), respectively, in which the carbonyl group (>C=O) is converted to a diether (>C(OR)2), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
For example, 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-CH3); a benzyloxy amide (-NHCO-OCH2C6H5, -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH3)3, -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC(CHs)2C6H4C6H5, -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 an allyloxy amide (-NH-Alloc), as a 2(-phenylsulfonyl)ethyloxy amide (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>N-O*).
For example, a carboxylic acid group may be protected as an ester for example, as: an C1-7alkyl ester (e.g., a methyl ester; a t-butyl ester); a C-i-7haloalkyl ester (e.g., a Ci-7trihaloalkyl ester); a triC1-7alkylsiiyl-C1-7alkyl ester; or a C5.2oaryl-C1-7alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
For example, a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH2NHC(=O)CH3).
Prodrugs
it may be convenient or desirable to prepare, purify, and/or handle the compound in the form of a prodrug. The term "prodrug," as used herein, pertains to a compound which, when metabolised (e.g., in vivo), yields the desired active compound. Typically, the prodrug is inactive, or less active than the desired active compound, but may provide advantageous handling, administration, or metabolic properties.
For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=O)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid groups (-C(=0)0H) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.
Also, some 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.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
Chemical Synthesis
Several methods for the chemical synthesis of 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
One aspect of the present invention pertains to a composition (e.g., a pharmaceutical composition) comprising an IBD compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
Another aspect of the present invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising admixing an IBD compound, as described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.
Uses
The compounds described herein (e.g., without a proviso regarding P-001 through P-003) are useful, for example, in the treatment of diseases and conditions that are ameliorated by the inhibition of heat shock protein 90 (HSP90) function, such as, for example, proliferative conditions, cancer, etc.
Use in Methods of Inhibiting Heat Shock Protein 90 (HSP90) Function
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).
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).
In one embodiment, 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.
Use in Methods of Inhibiting Cell Proliferation, Etc.
The IBD compounds described herein (e.g., without a proviso regarding P-001 through P-003), e.g., (a) regulate (e.g., inhibit) cell proliferation; (b) inhibit cell cycle progression; (c) 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).
In one embodiment, 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).
In one embodiment, the method is performed in vitro. In one embodiment, the method is performed in vivo.
In one embodiment, 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
(including, e.g., bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.
One of ordinary skill in the art is readily able to determine whether or not a candidate compound regulates (e.g., inhibits) cell proliferation, etc. For example, assays which may conveniently be used to assess the activity offered by a particular compound are described herein.
For example, a sample of cells (e.g., from a tumour) may be grown in vitro and a compound brought into contact with said cells, and the effect of the compound on those cells observed. As an example of "effect," the morphological status of the cells (e.g., alive or dead, etc.) may be determined. Where the compound is found to exert an influence on the cells, 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.
Use in Methods of 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 use in a method of treatment of the human or animal body by therapy.
Use in the Manufacture of Medicaments
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.
In one embodiment, the medicament comprises the IBD compound.
Methods of Treatment
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.
Conditions Treated - Conditions Mediated by Heat Shock Protein 90 (HSP90)
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of a disease or condition that is mediated by heat shock protein 90 (HSP90).
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.
Conditions Treated - Conditions Ameliorated by the Inhibition of Heat Shock Protein 90 (HSP90) Function
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: a disease or condition that is ameliorated by the inhibition of heat shock protein 90 (HSP90) function. Conditions Treated - Conditions Known to be Treated by Heat Shock Protein 90 (ΗSP9CH Inhibitors
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: a disease or condition that is known to be treated by HSP90 inhibitors (e.g., 17-AAG, geldanamycin, etc.)
Conditions Treated
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of:
neurological damage caused by stroke or cardiac arrest;
fibrogenic disorders, such as: scleroderma, systemic sclerosis, polymyositis, systemic lupus erythematosus, liver cirrhosis, and keloids;
interstitial nephritis;
pulmonary fibrosis;
rheumatoid arthritis;
osteoarthritis;
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,
Crohn's disease, inflammatory bowel disease, ulcerative colitis, and macular degeneration;
viral infections, such as:
HPV infection, and influenza;
parasitic infections, such as: malaria, schistosomiasis, trypanosomiasis, toxoplasmosis, and leishmania;
fungal infection;
diseases involving a translocated toxin, such as: Diphtheria, and
Botulism; and
bacterial infection.
Conditions Treated - Proliferative Conditions and Cancer
In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: a proliferative condition. The term "proliferative condition," as used herein, pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth.
In one embodiment, 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.
In one embodiment, the treatment is treatment of: cancer.
In one embodiment, 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.
In one embodiment, 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 tumor of myeloid lineage, for example acute and chronic myelogenous leukemias, myeiodysplastic syndrome, or promyelocytic leukemia; a tumour of mesenchymal origin, for example fibrosarcoma or habdomyosarcoma; a tumor of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xenoderoma pigmentoum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma.
In one embodiment, 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.
In one embodiment, 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.
In one embodiment, 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
The term "treatment," as used herein in the context of treating a condition, pertains 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) 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."
For example, treatment includes the prophylaxis of cancer, reducing the incidence of cancer, alleviating the symptoms of cancer, etc.
The term "therapeutically-effective amount," as used herein, pertains 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.
Combination Therapies
The term "treatment" includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously. For example, 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. Examples of 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.
For example, it 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 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 particular combination would be at the discretion of the physician who would select dosages using his common general knowledge and dosing regimens known to a skilled practitioner.
The agents (i.e., the compound described herein, plus one or more other agents) may be administered simultaneously or sequentially, and may be administered in individually varying dose schedules and via different routes. For example, when administered sequentially, 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).
The agents (i.e., the compound described here, plus one or more other 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. Other Uses
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.
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.
The IBD compounds described herein may also be used as a herbicide.
Kits
One aspect of the invention pertains to a kit 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.
Routes of Administration
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, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.
The Subject/Patient
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
(e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human.
Furthermore, the subject/patient may be any of its forms of development, for example, a foetus.
In one preferred embodiment, the subject/patient is a human.
Formulations
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.
Thus, 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.
The term "pharmaceutically acceptable," as used herein, 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.
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.
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 (e.g., by ingestion) 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.
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.
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 p-hydroxybenzoate, sorbic acid); flavours, flavour enhancing agents, and sweeteners. 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. If desired, 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. Preferably, 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. Together, the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax, and 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. The choice of 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. Thus 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 (e.g., by inhalation or insufflation therapy) 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.
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.
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 (e.g., by injection), 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). 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. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
Typically, the concentration of the compound in the liquid is from about 1 ng/ml to about 10 μg/ml, for example from about 10 ng/ml to about 1 μg/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.
Dosage
It will be appreciated by one of skill in the art that 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.
In general, a suitable dose of the IBD compound is in the range of about 10 μg to about 250 mg (more typically about 100 μg to about 25 mg) per kilogram body weight of the subject per day. Where 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. EXAMPLES
The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.
Genera/
1H NMR spectra were recorded at 25°C at 300 MHz on a Bruker Avance 300 system. Chemical shifts are reported in ppm. The 1H NMR spectra are referenced internally as follows: Spectra in CD3OD were referenced to CHD2OD: 3.33 ppm; CDCI3 to CHCI3: 7.26 ppm, DMSO-Cf6 to CHD2SOCD3: 2.50 ppm.
Column chromatograpy was unless otherwise stated performed using flash silicagel (0.040 - 0.063 mm).
Evaporations were performed in vacuo on a rotary evaporator at 40-50 0C.
LC-MS data were obtained on an Agilent 1200/Bruker Esquire 3000+ system.
Materials
All chemicals used were of reagent grade, and all solvents were of HPLC grade.
General Procedure 1
Click reaction between 1-ethynyl-5-isopropyl-2,4-dimethoxybenzene and azides to form triazoles of the Formula I, for example, as illustrated in the following scheme.
Scheme 1
Figure imgf000096_0001
1-Ethynyl-5-isopropyl-2,4-dimethoxybenzene was dissolved in DMF (7 mL pr mmol) and the arylazide or benzylazide was added (1.05 eq.) together with sodium ascorbate (25 mol%) and CuSO45H2O (a few crystals). The mixture was reacted in a microwave oven for 15 minutes at 900C. The mixture was poured over ice-water, extracted with EtOAc (3 times), and the organic phase was dried (MgSO4), filtered, and the solvents were evaporated. The residue was purified by column chromatography using 20:80 EtOAc/heptane yielding the corresponding triazole of the Formula I.
General Procedure 2
De-methylation of compounds of the Formula I to yield compounds of the Formula il, for example, as illustrated in the following scheme.
Scheme 2
Figure imgf000097_0001
The protected triazole of the Formula I was dissolved in DCM (15 mL per mmol) under N2 atmosphere and the solution cooled to -78°C. BBr3 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.
General Procedure 3
Suzuki-type coupling of 1-bromo-5-isopropyl-2,4-dimethoxybenzene with boronic acids to yield compounds of Formula III, for example, as illustrated in the following scheme.
Scheme 3
Figure imgf000097_0002
DME (2.7 mL), K2CO3 (0.7 mL, 2 M, aq) and tetrabutylammonium bromide (TBAB, 0.05 eq.) were mixed in a microwave oven vial and N2 was passed through the solution for a couple of minutes. Pd(PPh3)4 (19.2 μmol) was added followed by 1-bromo-5- isopropyl-2,4-dimethoxybenzene (0.19 mmol) and the appropriate boronic acid (0.38 mmol). The vial was sealed and reacted at 60-1200C until completion of the coupling (40 minutes to 1.5 hours). The reaction mixture was added to EtOAc and water, and the organic phase was separated, washed with brine, and dried over Na2SO4. The resulting crude product of Formula III was purified by flash chromatography.
General Procedure 4
Demethylation of compounds of Formula III to yield compounds of Formula IV, for example, as illustrated in the following scheme.
Scheme 4
Figure imgf000098_0001
The dimethoxy compound of Formula III was dissolved in dry DCM under N2 and cooled in ice. BBr3 (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 MgSO4 or Na2SO4 (basic compounds), evaporated, and the resulting product of Formula IV was purified by flash chromatography on silica gel.
General Procedure 5
Van Leusen-type oxazole synthesis to yield compounds of Formula V, as illustrated in the following scheme.
Scheme 5
Figure imgf000098_0002
Aldehyde (2.5 mmol) and TosMIC (p-toluensulfonylmethylisocyanide) (2.5 mmol) was suspended in dry MeOH (8 ml_). K2CO3 (oven dried and powdered) (2.5 mmol) was added and the mixture was heated at reflux for 3 hours or until TLC confirmed complete reaction. The reaction mixture was cooled and the solvent was removed in vacuo. The residue was poured into ice-water and extracted with EtOAc (3 times). The organic phase was washed with dilute HC! (aq) (0.1 M), water and brine and dried over MgSO4. The MgSO4 was filtered off and evaporation of the solvent yielded oxazoles of Formula V adequately pure for further reaction (in most cases > 95 % pure). ("Inversed" Procedure 5 means the corresponding reaction between a TosMIC analogue of protected resorcinol with an aromatic aldehyde).
General Procedure 6
Formation of sulfonamides of Formula VII from 5'-isopropyl-2',4'-dimethoxybiphenyl-2- amine, as illustrated in the following scheme.
Scheme 6
Figure imgf000099_0001
5'-lsopropyl-2',4'-dimethoxybiphenyl-2-amine (27 mg, 0.1 mmol) was dissolved in dry pyridine (5 ml_) under a nitrogen atmosphere. The solution was cooled to 00C and the appropriate sulfonyl chloride (1.2 eq.) dissolved in dry CH2CI2 (1.5 mL) was slowly added. After addition, the reaction mixture was allowed to stand at room temperature over night. The completion of the reaction was checked with ninhydrin (if positive, another 0.3 eq. of sulfonyl chloride was added and allowed to react for 3 hours). The solvent was evaporated in vacuo, and then HCI (aq, 0.1 M, 20 mL) was added. The product was extracted into petrolether/ ethylacetate (2:1) (3 x 10 mL). The combined organic phase was washed with water and brine and dried over Na2SO4. The solvent was evaporated and the residue was re-dissolved in MeOH (2 mL) and filtered through an lsolute PE-AX SPE column to remove any unreacted reagent. The sulfonamides thus obtained were adequately pure for use in subsequent reactions.
General Procedure 7
Formation of carbonyl compounds of the Formula VIII by Friedel Craft reaction using 1-isopropyl-2,4-dimethoxybenzene, as illustrated in the following scheme. Scheme 7
Figure imgf000100_0001
To a solution of 1-isopropyl-2,4-dimethoxybenzene (144 mg, 0.80 mmol) in dry DCM (5 ml_) was added acid chloride (1.0 mmol). The reaction mixture was cooled to 00C and TiCI4 (0.87 mmol) was added dropwise and the reaction stirred at 00C for 30 minutes and then at room temperature for 1 hour. H2O (10 mL) was added and the aqueous layer was extracted with DCM (3 x 5 mL). The organic phase was washed with H2O (10 mL), brine (10 mL), 10% K2CO3 solution, dried (MgSO4), filtered, and the solvent was evaporated. The crude product was dissolved in a small volume of EtOAc, passed through a short pad of SiO2 (rinsing with EtOAc), and the collected organic phase was evaporated to dryness. The product of Formula VIII was purified by column chromatography.
General Procedure 8
Demethylation of compounds of the Formula VIII to yield compounds of the Formula IX, as illustrated in the following scheme.
Scheme 8
Figure imgf000100_0002
To a stirred solution of a compound of the Formula VIII (0.537 mmol) in dry DCM (10 mL) at 00C was added BBr3 (1 M in DCM, 3.2 mL, 3.2 mmol). The mixture was stirred at reflux for 2 days. The reaction mixture was evaporated and the residue dissolved in diethylether and washed with water, dried over MgSO4, filtered, and the solvent evaporated. The residue was purified by column chromatography to give the corresponding compound of Formula IX. For some compounds, reflux might not be necessary and performing the reaction at room temperature may be sufficient. General Procedure 9
1-Ethynyl-5-isopropyl-2,4-dimethoxybenzene was prepared from 2,4- dimethoxyacetophenone, as shown in the following scheme.
Scheme 9
Figure imgf000101_0001
General Procedure 10
Debenzylation of compounds of Formula X to yield compounds of Formula IV, for example, as illustrated in the following scheme.
Figure imgf000101_0002
To a stirred solution of a compound of the Formula X in EtOH or EtOAc solution is added a catalytic amount of Pd/C (5%) pre-wetted with the solvent. Hydrogen gas is added from balloon until the reaction is complete. In some cases the reaction mixture needs heeting to 400C. After the end of reaction, the Pd/C is filtered off through celite and the solvents removed in vacuo. The residue is purified by flash chromatography or crystallisation. Synthesis 1 2,4-Dimethoxy-1-(prop-1-en-2-yl)benzene (Compound 1)
Figure imgf000102_0001
To a cooled (O0C) suspension of methyltriphenylphosphoniumbromide (2.08 g, 5.82 mmol) in dry THF (25 ml_) was dropwise added BuLi (1.02 M, 5.7 ml_, 5.82 mmol) and the mixture stirred at 00C for 30 minutes. A solution of 2,4-dimethoxyacetophenone (1.05 g, 5.83 mmol) in dry THF (10 mL) was added dropwise and the mixture was stirred at rt for 4 h. The reaction was quenched with H2O (30 mL) and the aqueous layer was extracted with diethylether (3 x 50 mL), the organic phase was washed with H2O (2 x 50 mL), brine (50 mL), dried (MgSO4), filtered and the solvents evaporated. The resulting residue was purified by flash chromatography using petrol ether/EtOAc (10:1) as eluent. The title compound was isolated as a colorless oil (0.43 g, 41%). An extra purification by column chromatography or treatment with activated charcoal could be necessary for a successful reduction (next step). 1H-NMR (CDCI3): δ 7.03 (m, 1H), 6.39 (m, 2H), 5.05 (m, 2H), 3.74 (s, 6H), 2.02 (s, 3H).
Synthesis 2
1-lsopropyl-2,4-dimethoxybenzene (Compound 2)
Figure imgf000102_0002
A solution of single chromatographed 2,4-dimethoxy-1-(prop-1-en-2-yl)benzene (8.90 g, 50 mmol) in EtOH (200 mL) was treated twice with 1 g activated charcoal with intermediate titrations through celite. The resulting filtered solution was deoxygenated by passing N2 through the solution and 5% Pd/C (500 mg) was added. Hydrogen was added from balloon. Reduction proceeded at room temperature. When HPLC showed complete reaction, the reaction mixture was filtered through a short pad of celite and the solvent was evaporated. The title compound was isolated as a colourless oil which was pure by 1H-NMR and HPLC and could be used without further purification in subsequent steps. The yield was 8.34 g (92%). 1H-NMR (CDCI3): δ 7.10 (d, 1 H), 6.45 (m, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 3.22 (sep, 1H), 1.18 (d, 6H). Synthesis 3
1-Bromo-5-isopropyl-2,4-dimethoxybenzene (Compound 3)
Figure imgf000103_0001
A solution of 1-isopropyl-2,4-dimethoxybenzene (3.00, 16.6 mmol) in chloroform (70 ml_) was added a solution of tetrabutylammonium tribromide (8.83 g, 18.3 mmol) in chloroform (30 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with a 5% solution of Na2S2O3 and stirred at room temperature for 30 minutes. The organic phase was isolated and washed with 1 M HCI (aq), brine, dried (Na2SO4), and solvents evaporated. The residue was purified by column chromatography using 20:80 EtOAc/heptane. The title compound was isolated as a white solid (3.25 g, 75%). 1H-NMR (DMSO-c/6): δ 7.26 (s, 1 H), 6.71 (s, 1 H)1 3.85 (s, 3H), 3.84 (s, 3H), 3.13 (sep, 1H), 1.12 (d, 6H).
Synthesis 4 1-lodo-5-isopropyl-2,4-dimethoxybenzene (Compound 4)
Figure imgf000103_0002
A solution of 1-bromo-5-isopropyl-2,4-dimethoxybenzene (0.396 g, 1.53 mmol) in dry diethylether (3 mL) was cooled to -78°C. t-Bul\ (1 mL, 1.7 M) was added dropwise and the mixture stirred at -78°C for 45 minutes. A solution of I2 (0.391 g, 1.54 mmol) in ether (3 mL) was added in one portion and the temperature maintained at -780C for 1 hour, and then heated to room temperature. The reaction mixture was washed with a solution of 25% NaS2O3 to remove excess iodine. The organic phase was isolated, dried (MgSO4), and evaporated. The residue was purified by column chromatography using 10% EtOAc in heptane as eluent. The title compound (0.249 g, 53%) was isolated as a white solid. NMR (DMSO-CZ6): δ 7.41 (s, 1 H), 6.64 (s, 1 H), 3.76 (s, 3H), 3.72 (s, 3H), 3.10 (m, 1H), 1.11 (d, 6H). Synthesis 5
((5-lsopropyl-2,4-dimethoxyphenyl)ethynyl)trimethylsilane (Compound 5)
Figure imgf000104_0001
A suspension of 1-iodo-5-isopropyl-2,4-dimethoxybenzene (344 mg, 1.12 mmol) in freshly distilled Et3N in a screwcap vial was added Pd(PPh3)2CI2 (48 mg), CuI (68 mg, 0.36 mmol), and trimethylsilyiacetylene (0.8 ml, 5.66 mmol). The mixture was stirred at reflux overnight. The vial was then cooled to room temperature and the reaction mixture diluted with diethylether, and the organic phase was washed with a saturated solution of NH4CI and then with a saturated solution of NaHCO3. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using 5% EtOAc in petrol ether as eluent. The title compound (219 mg, 70%) was isolated as a solid. NMR (DMSO-c/e): δ 7.09 (s, 1 H), 6.61 (s, 1 H), 3.85 (s, 3H), 3.83 (s, 3H), 3.11 (m, 1 H), 1.11 (d, 6H), 0.198 (s, 9H).
Synthesis 6
1-Ethynyl-5-isopropyl-2,4-dimethoxybenzene (Compound 6)
Figure imgf000104_0002
A solution of ((5-isopropyl-2,4-dimethoxyphenyl)ethynyl)trimethylsilane (0.219 mg, 0.79 mmol) in MeOH (4 mL) and CHCI3 (2 mL) was added a solution of NaOH (2 M, 0.8 mL). The mixture was stirred at room temperature for 2 hours and the mixture was evaporated to remove organic solvents. The resulting residue was re-dissolved in EtOAC and washed with a saturated solution of NaHCO3. The organic phase was dried (MgSO4) and evaporated. The residue was purified by column chromatography using 8% EtOAc in heptane as eluent. The title compound (125 mg, 78%) was obtained as a yellow solid. NMR (DMSO-Cy6): δ 7.13 (s, 1 H), 6.62 (s, 1H), 4.02 (s, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.11 (m, 1 H), 1.1 1 (d, 6H). Synthesis 7 4-(5-lsopropyl-2,4-dimethoxyphenyl)-1 -phenyl-1 H- 1 ,2,3-triazole (Compound 7)
Obtained using General Procedure 1. Starting materials: Azidobenzene and 1 -ethynyl-5- isopropy!-2,4-dimethoxybenzene. 1H-NMR (DMSO-Cf6): δ 8.82 (s, 1H), 7.99 (m, 3H), 7.63 (m, 2H), 7.51 (m, 2H), 3.98 (s, 3H), 3.90 (s, 3H), 3.24 (sep, 1 H), 1.21 (d, 6H).
Synthesis 8
4-(5-lsopropyl-2,4-dimethoxyphenyl)-1 -(2-methoxyphenyl)-1 H- 1 ,2,3-triazole
(Compound 8)
Figure imgf000105_0002
Obtained using General Procedure 1. Starting materials: 2-Methoxyazidobenzene and 1- ethynyl-5-isopropyl-2,4-dimethoxybenzene. 1H-NMR (DMSO-c/6): δ 8.49 (s, 1 H), 7.99 (s, 1 H), 7.65 (m, 1 H), 7.56 (m, 1 H), 7.34 (d, 1 H), 7.17 (m, 1H), 6.74 (s, 1 H)1 3.94 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H), 3.24 (sep, 1H), 1.21 (d, 6H).
Synthesis 9
4-(5-lsopropyl-2,4-dimethoxyphenyl)-1 -(3-methoxyphenyl)-1 H-1 ,2,3-triazole
(Compound 9)
Figure imgf000105_0003
Obtained using General Procedure 1. Starting materials: 3-Methoxyazidobenzene and 1-ethynyl-5-isopropyl-2,4-dimethoxybenzene. 1H-NMR (DMSO-Cf6): δ 8.83 (s, 1H), 7.98 (s, 1 H), 7.55 (m, 3H), 7.08 (m, 1 H), 6.75 (s, 1 H), 3.98 (s, 3H), 3.90 (s, 3H), 3.88 (s, 3H), 3.23 (sep, 1H), 1.21 (d, 6H).
Synthesis 10
4-(5-lsopropyl-2,4-dimethoxyphenyl)-1 -(3,4-dimethoxyphenyl)-1 H- 1 ,2,3-triazole
(Compound 10)
Figure imgf000106_0001
Obtained using General Procedure 1. Starting materials: 3,4-Dimethoxyazidobenzene and 1-ethynyl-5-isopropyl-2,4-dimethoxybenzene. 1H-NMR (DMSO-Of6): δ 8.73 (s, 1 H), 7.97 (s, 1H), 7.48 (m, 2H), 7.15 (d, 1H), 6.75 (s, 1H), 3.95 (s, 3H), 3.89 (s, 3H), 3.84 (s, 3H), 3.13 (sep, 1 H), 1.21 (d, 6H).
Synthesis 11
4-(5-lsopropyl-2,4-dimethoxyphenyl)-1 -(4-n-butyl-phenyl)-1 H- 1 ,2,3-triazole
(Compound 11 )
Figure imgf000106_0002
Obtained using General Procedure 1. Starting materials: 4-(/?-Butyl)azidobenzene and 1-ethynyl-5-isopropyl-2,4-dimethoxybenzene. 1H-NMR (DMSO-d6): δ 8.76 (s, 1 H), 7.99 (s, 1 H), 7.88 (s, 1 H), 7.85 (s, 1 H), 7.44 (s, 1 H), 7.41 (s, 1 H), 6.75 (s, 1H), 3.98 (s, 3H), 3.90 (s, 3H), 3.23 (sep, 1 H), 2.68 (t, 2H), 1.61 (m, 2H), 1.34 (m, 2H), 1.21 (d, 6H), 0.93 (t, 3H). Synthesis 12 1 -Benzyl-4-(5-isopropy!-2,4-dimethoxyphenyl)-1 H- 1 ,2,3-triazole (Compound 12)
Figure imgf000107_0001
Obtained using General Procedure 1. Starting materials: Benzylazide and 1-ethynyl-5- isopropyl-2,4-dimethoxybenzene. 1H-NMR (DMSO-c/6): δ 8.32 (s, 1H), 7.94 (s, 1H)1 7.34 (m, 5H), 6.70 (s, 1 H), 5.65 (s, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.21 (sep, 1H), 1.18 (d, 6H).
Synthesis 13
1 -(2-Chloro-4-fluorobenzyl)-4-(5-isopropyl-2,4-dimethoxyphenyl)-1 W- 1 ,2,3-triazole
(Compound 13)
Figure imgf000107_0002
Obtained using General Procedure 1. Starting materials: 2-Chloro-4-fluorobenzylazide and 1-ethynyl-5-isopropyl-2,4-dimethoxybenzene. 1H-NMR (DMSO-de): δ 8.31 (s, 1H), 7.94 (s,1H), 7.58-7.53 (m, 1 H), 7.29-7.26 (m, 2H), 6.71 (s, 1 H), 5.74 (s, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.21 (sep, 1H), 1.18 (d, 6H).
Synthesis 14
1-(3,4-Difluorobenzyl)-4-(5-isopropyl-2,4-dimethoxyphenyl)-1/-/-1 ,2,3-triazole
(Compound 14)
Figure imgf000108_0001
Obtained using General Procedure 1. Starting materials: 3,4-Difluorobenzylazide and 1- ethynyl-5-isopropyl-2,4-dimethoxybenzene. 1H-NMR (DMSO-Cf6): δ 8.36 (s, 1 H), 7.93 (s, 1 H), 7.50-7.41 (m, 2H), 7.21-7.14 (m, 1 H), 6.71 (s, 1H), 5.65 (s, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 3.21 (sep, 1 H), 1.18 (d, 6H).
Synthesis 15
4-(5-lsopropyl-2,4-dimethoxyphenyl)-1 -(naphthalen-2-ylmethyl)-1 H-λ ,2,3-triazole
(Compound 15)
Figure imgf000108_0002
Obtained using General Procedure 1. Starting materials: 2-Azidomethylnaphthaiene and 1-ethynyl-5-isopropyl-2,4-dimethoxybenzene. 1H-NMR (DMSO-CZ6): δ 8.37 (s, 1 H), 7.96- 7.84 (m, 4H), 7.55-7.44 (m, 2H), 6.70 (s, 1 H), 5.82 (s, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.21 (sep, 1 H), 1.18 (d, 6H). Svnthesis 16
1-(4-Fluorobenzyl)-4-(5-isopropyl-2,4-dimethoxyphenyl)-1H-1 ,2,3-triazole (Compound 16)
Figure imgf000109_0001
Obtained using General Procedure 1. Starting materials: 4-Fluorobenzylazide and 1- ethynyl-5-isopropyl-2,4-dimethoxybenzene. 1H-NMR (DMSO-Cf6): δ 8.33 (s, 1 H), 7.93 (s, 1 H), 7.42-7.37 (m, 2H), 7.25-7.19 (m, 2H), 6.7 (s, 1 H), 5.64 (s, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 3.20 (sep, 1 H), 3.18 (d, 6H).
Synthesis 17 1 -(4-Chlorobenzyl)-4-(5-isopropyl-2,4-dimethoxyphenyl)-1 H- 1 ,2,3-triazole (Compound 17)
Figure imgf000109_0002
Obtained using General Procedure 1. Starting materials: 4-Chlorobenzylazide and 1- ethynyl-5-isopropyl-2,4-dimethoxybenzene. 1H-NMR (DMSO-Cf6): δ 8.34 (s, 1 H), 7.94 (s, 1 H), 7.47-7.44 (m, 2H), 7.36-7.33 (m, 2H), 6.71 (s, 1 H), 5.66 (s, 2H)1 3.92 (s, 3H), 3.87 (s, 3H), 3.21 (sep, 1 H), 3.18 (d, 6H). Synthesis 18 1-(4-Methylbenzyl)-4-(5-isopropyl-2,4-dimethoxyphenyl)-1/-/-1 ,2,3-triazole (Compound 18)
Figure imgf000110_0001
Obtained using General Procedure 1. Starting materials: 4-Methylbenzylazide and 1- ethynyl-5-isopropyl-2,4-dimethoxybenzene. 1H-NMR (DMSO-c/6): δ 8.27 (s, 1H), 7.93 (s, 1 H), 7.24-7.17 (m, 4H), 6.7 (s, 1 H), 5.59 (s, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.20 (sep, 1 H), 2.28 (s, 3H), 1.18 (d, 6H).
Synthesis 19
1 -(3,4-Dichlorobenzyl)-4-(5-isopropy!-2,4-dimethoxyphenyl)-1 HA ,2,3-triazole
(Compound 19)
Figure imgf000110_0002
Obtained using General Procedure 1. Starting materials: 3,4-Dichlorobenzylazide and 1- ethynyl-5-isopropyl-2,4-dimethoxybenzene. 1H-NMR (DMSO-c/6): δ 8.39 (s, 1 H), 7.94 (s, 1 H), 7.67-7.63 (m, 2H), 7.28 (dd, 1H), 6.71 (s, 1 H), 5.68 (s, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 3.21 (sep, 1 H), 1.18 (d, 6H). Svnthesis 20
1 -(4-lsopropylbenzyl)-4-(5-isopropyl-2,4-dimethoxyphenyl)-1 H- 1 ,2,3-triazole
(Compound 20)
Figure imgf000111_0001
Obtained using General Procedure 1. Starting materials: 4-lsopropylbenzylazide and 1- ethynyl-5-isopropyl-2,4-dimethoxybenzene. 1H-NMR (DMSO-Cf6): δ 8.30 (s, 1H), 7.93 (s, 1 H), 7.25 (m, 4H), 6.70 (s, 1 H), 5.59 (s, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.25 (sep, 1 H), 2.87 (sep, 1 H), 1.20-1.17 (m, 12H).
Synthesis 21 1-(3-Chlorobenzyl)-4-(5-isopropyl-2,4-dimethoxyphenyl)-1/-/-1 ,2,3-triazole (Compound 21)
Figure imgf000111_0002
Obtained using General Procedure 1. Starting materials: 3-Chlorobenzylazide and 1- ethynyl-5-isopropyl-2,4-dimethoxybenzene. 1H-NMR (DMSO-Gf6): δ 8.37 (s, 1 H), 7.94 (s, 1 H), 7.42-7.39 (m, 3H), 7.29-7.25 (m, 1 H), 6.71 (s, 1 H), 5.67 (s, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 3.21 (sep, 1 H), 1.18 (d, 6H). Synthesis 22 1 -(2-Fluorobenzyl)-4-(5-isopropyl-2,4-dimethoxyphenyl)-1 H- 1 ,2,3-triazole (Compound 22)
Figure imgf000112_0001
Obtained using General Procedure 1. Starting materials: 2-Fluorobenzylazide and 1- ethynyl-5-isopropyl~2,4-dimethoxybenzene. 1H-NMR (DMSO-Of6): δ 8.29 (s, 1 H), 7.93 (s, 1 H), 7.42 (m, 1H), 7.35-7.15 (m, 3H), 6.70 (s, 1H), 5.71 (s, 2H), 3.91 (s, 3H), 3.86 (s, 3H), 3.20 (sep, 1 H), 1.17 (d, 6H).
Synthesis 23 1 -(2-Chlorobenzyl)-4-(5-isopropyl-2,4-dimethoxyphenyl)-7H-1 ,2,3-triazole (Compound 23)
Figure imgf000112_0002
Obtained using General Procedure 1. Starting materials: 2-Chlorobenzylazide and 1- ethynyl-5-isopropyl-2,4-dimethoxybenzene. 1H-NMR (DMSO-Cf6): δ 8.31 (s, 1 H), 7.95 (s, 1 H), 7.53 (m, 1 H), 7.44-7.31 (m, 2H), 7.12 (m, 1 H), 6.71 (s, 1 H), 5.75 (s, 2H), 3.90 (s, 3H), 3.86 (s, 3H), 3.21 (sep, 1 H), 1.17 (d, 6H).
Synthesis 24 4-(5-lsopropyl-2,4-dimethoxyphenyl)-1-(2-methylbenzyl)-1/-/-1 ,2,3-triazole (Compound 24)
Figure imgf000112_0003
Obtained using General Procedure 1. Starting materials: 2-Methylbenzylazide and 1- ethynyl-5-isopropyl-2,4-dimethoxybenzene. 1H-NMR (DMSO-CZ6): δ 8.21 (s, 1H), 7.95 (s, 1 H), 7.27-7.14 (m, 3H), 7.00 (m, 1 H), 6.70 (s, 1H), 5.66 (s, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 3.21 (sep, 1 H), 1.17 (d, 6H).
Synthesis 25 1-Benzyl-5-(5-isopropyl-2,4-dimethoxyphenyl)-1/-M ,2,3-triazole (Compound 25)
Figure imgf000113_0001
1-Ethynyl-5-isopropyl-2,4-dimethoxybenzene (Compound 6, 40 mg, 194 mmol) and benzylazide (33 mg, 250 mmol) was dissolved in THF (1 mL) in a microwave vial. Freshly prepared Cp*RuCI(PPh3)2 (catalytic amount from small spatule tip) was added and the vial was sealed. The reaction mixture was heated for 15 min at 1200C. The solvent was evaporated in vacuo and the residue was purified by flash chromatography (7% EtOAc in PE) to give the title compound. Yield 36 mg (55%). 1H-NMR (CDCI3): δ 7.63 (s, 1 H), 7.18 (d, 2H), 6.93 (d, 2H), 6.76 (s, 1H), 6.46 (s, 1 H), 5.36 (s, 2H), 3.89 (s, 3H), 3.67 (s, 3H), 3.20 (sep, 1 H), 1.08 (d, 6H).
Synthesis 26
1 -(4-Chlorobenzyl)-5-(5-isopropyl-2,4-dimethoxyphenyl)-1 H- 1 ,2,3-triazole (Compound 26)
Figure imgf000113_0002
Made analogous to 1~Benzyl-5-(5-isopropyl-2,4-dimethoxyphenyl)-1H-1,2,3-triazole. Starting materials: 1-Ethynyl-5-isopropyl-2,4-dimethoxybenzene and 1-(azidomethyl)-4- chlorobenzene. 1H-NMR (CDCI3): δ 7.64 (s, 1 H), 7.25-7.17 (m, 3H), 7.05-6.96 (m, 2H), 6.77 (s, 1 H), 6.47 (s, 1 H), 5.36 (s, 2H), 3.89 (s, 3H), 3.68 (s, 3H), 3.18 (sep, 1 H), 1.05 (d, 6H). Svnthesis 27 1 -(5-lsopropyl-2,4-dimethoxyphenyl)-2-phenylethanone (Compound 27)
Figure imgf000114_0001
Obtained using General Procedure 7. Starting materials: 2-Phenylacetyl chloride and 1- isopropyl-2,4-dimethoxybenzene. 1H-NMR (CDCI3): δ 7.73 (s, 1 H), 7.26 (m, 5H), 6.40 (s, 1 H), 4.28 (s, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.18 (sep, 1 H), 1.17 (d, 6H).
Synthesis 28 (5-lsopropyl-2,4-dimethoxyphenyl)(4-methoxyphenyl)methanone (Compound 28)
Figure imgf000114_0002
Obtained using General Procedure 7. Starting materials: 4-Methoxybenzoyl chloride and 1-isopropyl-2,4-dimethoxybenzene. 1H-NMR (CDCI3): δ 7.65 (d, 2H), 7.11 (s, 1 H), 7.02 (d, 2H), 6.72 (s, 1 H), 3.92 (s, 3H), 3.84 (s, 3H), 3.69 (s, 3H), 3.19 (sep, 1 H), 1.14 (d, 6H).
Synthesis 29 (5-lsopropyl-2,4-dimethoxyphenyl)(4-chlorophenyl)methanone (Compound 29)
Figure imgf000114_0003
Obtained using General Procedure 7. Starting materials: 4-Chlorobenzoyl chloride and 1- isopropyl-2,4-dimethoxybenzene. 1H-NMR (CDCI3): δ 7.68-7.63 (m, 2H), 7.57-7.52 (m, 2H), 7.22 (S, 1 H), 6.73 (s, 1 H), 3.93 (s, 3H), 3.67 (s, 3H), 3.18 (sep, 1H), 1.15 (d, 6H). Synthesis 30
(5-lsopropyl-2,4-dimethoxyphenyl)(2,6-dichlorophenyl)methanone (Compound 30)
Figure imgf000115_0001
Obtained using General Procedure 7. Starting materials: 2, 6-Dichlorobenzoyl chloride and 1-isopropyl-2,4-dimethoxybenzene. 1H-NMR (CDCI3): δ 7.72 (s, 1H), 7.52-7.40 (m, 3H), 6.64 (s, 1 H), 3.94 (s, 3H), 3.56 (s, 3H), 3.15 (sep, 1 H), 1.16 (d, 6H).
Synthesis 31
(4-(Dimethylamino)phenyl)(2-hydroxy-5-isopropyl-4-methoxyphenyl)methanone
(Compound 31)
Figure imgf000115_0002
Obtained using General Procedure 7. Starting materials: 4-(Dimethylamino)benzoyl chloride and 1-isopropyl-2,4-dimethoxybenzene. 1H-NMR (DMSO-Cf5): δ 12.12 (s, 1H), 7.63-7.56 (m, 2H), 7.37 (s, 1 H), 6.82-6.75 (m, 2H), 6.56 (s, 1 H), 3.86 (s, 3H), 3.12 (sep, 1 H), 3.04 (s, 6H), 1.10 (s, 6H). The position (2 vs. 4) of the single methoxy group was not verified.
Synthesis 32 (5-lsopropyl-2,4-dimethoxyphenyl)(3-methoxypheny!)methanone (Compound 32)
Figure imgf000115_0003
Obtained using General Procedure 7. Starting materials: 3-Methoxybenzoyl chloride and 1-isopropyl-2,4-dimethoxybenzene. 1H-NMR (CDCI3): δ 7.43-7.34 (m, 1 H), 7.21-7.15 (m, 4H), 6.72 (s, 1 H), 3.92 (s, 3H), 3.78 (s, 3H), 3.67 (s, 3H), 3.18 (sep, 1 H), 1.13 (d, 6H). Synthesis 33
1-(2,4-Bis(benzyloxy)phenyl)ethanone (Compound 33)
Figure imgf000116_0001
2,4-Dihydroxy-acetophenone (15 g, 98.6 mmol) was dissolved in CH3CN (200 mL). Dry powdered K2CO3 (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 CH2CI2 -water. The phases were separated and the aqueous phase was extracted once with CH2CI2. The combined organic phase was washed with brine and dried over MgSO4. The organic phase was evaporated to yield a yellowish oil which crystallized upon standing. Heptane was added for complete crystallization and the white crystals were filtered off and washed thoroughly with heptane. Yield after drying was 29.4 g (90%) of 1-(2,4-bis(benzy!oxy)-phenyl)ethanone. 1H-NMR (CDCI3): δ 7.88-7.82 (m, 1H), 7.49-7.30 (m, 11 H), 6.67-6.59 m, 2H), 5.11 (s, 2H), 5.09 (s, 2H), 2.56 (s, 3H).
Synthesis 34 2-(2,4-Bis(benzyloxy)phenyl)propan-2-ol (Compound 34)
Figure imgf000116_0002
1-(2,4-Bis(benzyloxy)-phenyl)ethanone (15.0 g, 45 mmol) was dissolved under N2 in dry THF (250 mL, HPLC grade dried through Alumina Super I). The solution was cooled to O0C and MeMgBr (3 M, 30 mL, 90 mmol) was added drop-wise keeping T < 5 0C. After end addition the solution was left to heat to RT and stirred for 2 h. TLC showed complete reaction (EtOAc-Hep 1 :3). The reaction mixture was poured onto ice/water and extracted into ether. The combined organic phase was washed with water and brine and dried over MgSO4. Evaporation of solvents gave a white solid (16.0 g) which could be re-crystallized from approx. 50 mL of boiling MeOH. After cooling in the freezer the solid was isolated and washed with small portions of ice-cold MeOH. After drying in vacuum the yield of the title compound was 12.3 g (78%). 1H-NMR (CDCI3): δ 7.48-7.30 (m, 10H), 7.24 (masked, 1 H), 6.67 (d, 1 H), 6.55 (dd, 1H), 5.11 (s, 2H), 5.04 (s, 2H), 4.02 (s, 1 H), 1.60 (s, 6H). Svnthesis 35
4-lsopropyl-1 ,3-dibenzyloxybenzene (Compound 35)
Figure imgf000117_0001
2-(2,4-Bis(benzyloxy)phenyl)propan-2-ol (7.00 g, 20.1 mmol) was dissolved in dry CH2CI2 (140 mL) under N2 and cooled to -78 0C. Et3SiH (4.2 ml_, 26.1 mmol) was added followed by TFA (3.1 mL, 40.2 mmol; added drop-wise over 5-10 min). An orange color appeared and temporarily a precipitate which re-dissolved with more TFA. The mixture was left to slowly heat up to room temperature. The mixture was left stirring overnight. TLC (EtOAc- Hep 2:8) showed complete conversion. The reaction mixture was poured into aqueous NaHCO3 (saturated, 300 mL) and the phases separated. The aqueous phase was extracted once with CH2CI2 and the combined organic phase was dried over MgSO4 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. 1H-NMR (CDCI3): δ 7.54-7.29 (m, 10H), 1.14 (d, 1 H), 6.66-6.54 (m, 2H), 5,06 (s, 2H), 5.04 (s, 2H), 3.35 (sep, 1 H), 1.23 (d, 6H).
Synthesis 36 2,4-Bis(benzyloxy)-5-isopropylbenzaldehyde (Compound 36)
Figure imgf000117_0002
DMF (20 mL) was placed in a 100 mL 3-necked flask equipped with a reflux condenser and CaCI2 drying tube. After cooling in ice, POCI3 (1.05 mL, 11 mmol) was added dropwise. After stirring at 00C for 10 minutes, 4-lsopropyl-1 ,3-dibenzyloxybenzene (2.50 g, 7.5 mmol) was added dropwise. The resulting solution was heated to 1000C for 2 hours giving a brown solution. TLC indicated complete reaction and the reaction mixture was poured onto 20 mL crushed ice. The pH was adjusted to 6 with 10% NaOAc and the suspension was placed in the fridge over night to crystallize. The precipitate was filtered off and washed with water and dried. 1H NMR confirmed that the product was the desired product. The crude product was further purified (to remove small amounts of Compound 2) by flash chromatography (silica gel, EtOAc-Hep (30:70) to (80:20). The yield of colourless oil, which crystallized on standing, was 2.94 g (85%). 1H-NMR (CDCI3): δ 10.39 (s, 1 H), 7.75 (s, 1H), 7.44-7.31 (m, 10H), 6.51 (s, 1 H), 5.12 (s, 2H), 5.10 (s, 2H), 3.28 (sep, 1 H), 1.22 (s, 6H). Synthesis 37 2,4-Dimethoxy-5-isopropylphenylboronic acid (Compound 37)
Figure imgf000118_0001
1-Bromo-5-isopropyl-2,4-dimethoxybenzene (1.00 g, 3.84 mmol) was dissolved in dry THF (20 ml_) in a three-necked flask and kept under a N2 atmosphere. The solution was cooled to -78°C and BuLi (2.4 M (titrated before use) in hexanes) was added (1.95 ml_, 1.2 eq). The initial orange colour faded quickly to a colourless clear solution. The mixture was stirred for 1 hour at -78°C. Triisopropyl borate (2.66 ml_, 11.5 mmol) was dissolved in dry THF (20 ml_) in a new three-necked flask under N2 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 -780C. After addition, 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 MgSO4. The filtered ether solution was evaporated to dryness and the residue recrystallized from EtOH-water to yield pure title compound. 1H-NMR (DMSO-Gf6): δ 7.44 (s, 1H), 7.42 (s, 2H), 6.57 (s, 1 H), 3.85 (s, 1 H), 3.84 (s, 3H), 3.13 (sep, 1 H), 1.12 (d, 6H).
Synthesis 38 3-(5-lsopropyl-2,4-dimethoxyphenyl)pyridine (Compound 38)
Figure imgf000118_0002
Obtained using General Procedure 3. Starting materials: Pyridine-3-boronic acid and 1- bromo-5-isopropyl-2,4-dimethoxybenzene. 1H-NMR (CDCI3): δ 8.75 (dd, 1 H), 8.51 (dd, 1 H), 7.83 (dq, 1 H), 7.30 (ddd, 1H), 7.14 (s, 1H), 6.55 (s, 1 H), 3.90 (s, 3H), 3.82 (s, 3H), 3.29 (sep, 1 H) , 1.22 (d, 6H). Svnthesis 39 Λ/-(5'-lsopropyl-21,4'-dimethoxybiphenyl-2-yl)methanesulfonamide (Compound 39)
Figure imgf000119_0001
Obtained using General Procedure 3. Starting materials: 2-Methylsulfonylamino- phenylboronic acid and 1-bromo-5-isopropyl-2,4-dimethoxybenzene. 1H-NMR (CDCI3): δ 7.62 (d, 1 H), 7.38 (m, 1 H), 7.31 (m, 1 H), 7.28 (d, 1 H), 7.01 (s, 1 H), 6.84 (bs, 1H), 6.56 (s, 1H), 3.92 (s, 3H), 3.83 (s, 3H), 3.28 (sep, 1H), 2.54 (s, 3H), 1.25-1.10 (m, 6H).
Synthesis 40 1 -(5'-lsopropyl-2',4'-dimethoxybiphenyl-2-ylsulfonyl)pyrrolidine (Compound 40)
Figure imgf000119_0002
Obtained using General Procedure 3. Starting materials: Λ/-Pyrrolidinyl-2-boron- benzensulfonamide and 1-bromo-5-isopropyl-2,4-dimethoxybenzene. An impure product was obtained, which may have contained bis(2,2'-pyrrolidinylsulfonamid)biphenyl from homo-coupling of boronic acid. The product was used without further purification in subsequent reactions. 1H-NMR (CDCI3): δ 8.19 (dd, 1 H), 7.60-7.50 (dt, 1 H1 masked), 7.40 (dt, 1H), 7.28 (dd, 1H), 7.09 (s, 1 H), 6.48 (s, 1H), 3.88 (s, 3H), 3.73 (s, 3H), 3.31- 3.21 (m, 1H, masked), 2.96 (m, 2H), 2.76 (m, 2H), 1.76 (m, 2H, masked), 1.65 (m, 2H, masked), 1.20 (d, 3H), 1.17 (d, 3H). Spectrum contains unknown (possible) pyrrolidinyl- phenylsulfonamide component.
Synthesis 41 5'-lsopropyl-2',4'-dimethoxybiphenyl-2-amine (Compound 41)
Figure imgf000119_0003
Obtained using General Procedure 3. Starting materials: 2-Aminophenylboronic acid and 1-bromo-5-isopropyl-2,4-dimethoxybenzene. 1H-NMR (CDCI3): δ 7.20-7.08 (m, 2H), 7.07 (s, 1 H), 6.87-6.73 (m, 2H), 6.54 (s, 1 H), 3.89 (s, 3H), 3.80 (s, 3H), 3.71 (bs, 2H), 3.27 (sep, 1 H), 1.19 (d, 6H). MS: [M+1]+1 = 272.1.
Synthesis 42
A/-(5'-lsopropyl-2',4'-dimethoxybiphenyl-2-yl)-4-methylbenzene-sulfonamide
(Compound 42)
Figure imgf000120_0001
Obtained using General Procedure 6. Starting materials: 4-Methylphenylsulfonyl chloride and 5'-isopropyl-2',4'-dimethoxybiphenyl-2-amine. TLC-pure material was obtained. Product was used without further purification or analysis.
Synthesis 43
4-Fluoro-Λ/-(5'-isopropyl-2',4'-dimethoxybiphenyl-2-yl)benzenesulfonamide
(Compound 43)
Figure imgf000120_0002
Obtained using General Procedure 6. Starting materials: 4-Fluorobenzenesulfonyl chloride and δ'-isopropyl^'^'-dimethoxybiphenyl^-amine. TLC-pure material was obtained. Product was used without further purification or analysis.
Synthesis 44
Λf-(5'-lsopropyl-2',4'-dimethoxybiphenyl-2-yl)-1-phenylnnethane-sulfonamicle
(Compound 44)
Figure imgf000121_0001
Obtained using General Procedure 6. Starting materials: Phenylmethanesulfonyl chloride and 5'-isopropyl-2',41-dimethoxybiphenyl-2-amine. TLC-pure material was obtained. Product was used without further purification or analysis.
Synthesis 45
1-(4-Chlorophenyl)-N-(5'-isopropyl-2',4'-dimethoxybiphenyl-2-yl)methane-sulfonamide
(Compound 45)
Figure imgf000121_0002
Obtained using General Procedure 6. Starting materials: (4-Chlorophenyl)methane- sulfonyl chloride and 5'-isopropyl-2',4'-dimethoxybiphenyl-2-amine. TLC-pure material was obtained. The product was used without further purification or analysis.
Synthesis 46 A/-(5'-lsopropyl-2',4'-dimethoxybiphenyl-2-yl)naphthalene-2-sulfonamide (Compound 46)
Figure imgf000121_0003
Obtained using General Procedure 6. Starting materials: Naphthalene-2-sulfonyl chloride and 5'-isopropyl-2',4'-dimethoxybiphenyl-2-amine. TLC-pure material was obtained. Product was used without further purification or analysis. Synthesis 47 A/-(5'-lsopropyl-2',4'-dimethoxybiphenyl-2-yl)ethanesulfonamide (Compound 47)
Figure imgf000122_0001
Obtained using General Procedure 6. Starting materials: Ethanesulfonyl chloride and 5'- isopropyl-2',4'-dimethoxybiphenyl-2-amine. TLC-pure material was obtained. Product was used without further purification or analysis.
Synthesis 48 Λ/-(5'-lsopropyl-2',4'-dimethoxybiphenyl-2-yl)propane-1 -sulfonamide (Compound 48)
Figure imgf000122_0002
Obtained using General Procedure 6. Starting materials: Propanesulfonyl chloride and 51- isopropyl-2',4'-dimethoxybiphenyl-2-amine. TLC-pure material was obtained. Product was used without further purification or analysis.
Synthesis 49 A/-(5'-lsopropyl-2',4'-dimethoxybiphenyl-2-yl)cyclopropane-sulfonamide (Compound 49)
Figure imgf000122_0003
Obtained using General Procedure 6. Starting materials: Cyclopropanesulfonyl chloride and 5'-isopropyl-2',4'-dimethoxybiphenyl-2-amine. TLC-pure material was obtained. Product was used without further purification or analysis. Synthesis 50
3-(5-lsopropyl-2,4-dimethoxyphenyl)thiophene (Compound 50)
Figure imgf000123_0001
Obtained using General Procedure 3. Starting materials: Thiophene-3-boronic acid and 1-bromo-5-isopropyl-2,4-dimethoxybenzene. 1H-NMR (CDCI3): δ 7.49 (dd, J=1.1/3.8 Hz, 1 H), 7.41 (dd, J=1.1/4.9 Hz, 1 H), 7.32 (dd, J=3.8/4.9 Hz, 1H), 7.29 (s, 1H), 6.53 (s, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.27 (sep, 1 H), 1.22 (d, 6H).
Synthesis 51 5-(5-lsopropyl-2,4-dimethoxyphenyl)benzo[d][1 ,3]dioxole (Compound 51 )
Figure imgf000123_0002
Obtained using General Procedure 3. Starting materials: 3,4-(Methylenedioxy)- phenylboronic acid and 1-bromo-5-isopropyl-2,4-dimethoxybenzene. 1H-NMR (CDCI3): δ 7.10 (s, 1 H), 7.03 (d, 1 H), 6.95 (dd, 1 H), 6.85 (d, 1H), 6.52 (s, 1 H), 5.97 (s, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 3.27 (sep, 1 H), 1.21 (d, 6H).
Synthesis 52 5'-lsopropyl-2',4'-dimethoxybiphenyl-2-carboxamide (Compound 52)
Figure imgf000123_0003
Obtained using "inversed" General Procedure 3. Starting materials: 2,4-Dimethoxy-5- isopropylphenylboronic acid (100 mg, 0.45 mmol) and 2-bromopyridine. No NMR data recorded. LC-MS confirmed 70% pure (product contains some Ph3PO + unknown). MS+: 258.1 (M+1 ), 537.0 (2M+Na). Synthesis 53 5-lsopropyl-2,4-dimethoxy-2'-phenoxybiphenyl (Compound 53)
Figure imgf000124_0001
Obtained using General Procedure 3. Starting materials: 1 -Bromo-5-isopropyl-2,4- dimethoxybenzene and 2 phenoxyphenylboronic acid. TLC-pure material was obtained. The product was used without further purification or analysis.
Synthesis 54 /V^δ'-lsopropyl^'^'-dimethoxybiphenyl^-yOacetamide (Compound 54)
Figure imgf000124_0002
Prepared using a method analogous to General Procedure 6, replacing the sulfonyl chloride with acetyl chloride. Starting materials: 5'-lsopropyl-2',4'-dimethoxybiphenyl-2- amine and acetyl chloride. TLC-pure material was obtained. The product was used without further purification or analysis.
Synthesis 55
4'-Fluoro-5-isopropyl-2,4-dimethoxybiphenyl (Compound 55)
Figure imgf000124_0003
Obtained using General Procedure 3. Starting materials: 1-Bromo-5-isopropyl-2,4- dimethoxybenzene and 4-fluorophenylboronic acid. TLC-pure material was obtained. The product was used without further purification or analysis. Synthes'is 56
4'-Chloro-5-isopropyl-2,4-dimethoxybiphenyl (Compound 56)
Figure imgf000125_0001
Obtained using General Procedure 3. Starting materials: 1-Bromo-5-isopropyl-2,4- dimethoxybenzene and 4-chlorophenylboronic acid. TLC-pure material was obtained. The product was used without further purification or analysis.
Synthesis 57
4'-FIuoro-5-isopropyl-2,4-dimethoxy-3'-methylbiphenyl (Compound 57)
Figure imgf000125_0002
Obtained using General Procedure 3. Starting materials: 1 -Bromo-5-isopropyl-2,4- dimethoxybenzene and 4-fluoro-3-methylphenylboronic acid. TLC-pure material was obtained. The product was used without further purification or analysis.
Synthesis 58
3',4'-Difluoro-5-isopropyl-2,4-dimethoxybiphenyl (Compound 58)
Figure imgf000125_0003
Obtained using General Procedure 3. Starting materials: 1-Bromo-5-isopropyl-2,4- dimethoxybenzene and 3,4-difluorophenylboronic acid. TLC-pure material was obtained. The product was used without further purification or analysis. Synthesis 59 4'-Fluoro-5-isopropyl-2,4-dimethoxy-2'-methylbiphenyl (Compound 59)
Figure imgf000126_0001
Obtained using General Procedure 3. Starting materials: 1-Bromo-5-isopropyl-2,4- dimethoxybenzene and 4-fluoro-2-methylphenylboronic acid. TLC-pure material was obtained. The product was used without further purification or analysis.
Synthesis 60 5-lsopropyl-2,4-dimethoxy-3'-(3-methoxybenzyloxy)biphenyl (Compound 60)
Figure imgf000126_0002
Obtained using General Procedure 3. Starting materials: 1-Bromo-5-isopropyl-2,4- dimethoxybenzene and 3-(3-methoxybenzyloxy)phenylboronic acid. TLC-pure material was obtained. The product was used without further purification or analysis.
Synthesis 61 3'-Fluoro-5-isopropyl-2,4,4'-trimethoxybiphenyl (Compound 61)
Figure imgf000126_0003
Obtained using General Procedure 3. Starting materials: 1-Bromo-5-isopropyl-2,4- dimethoxybenzene and 3-fluoro-4-methoxyphenylboronic acid. TLC-pure material was obtained. The product was used without further purification or analysis. Svnthesis 62
4-Butoxy-2,3,5,6-tetrafluoro-51-isopropyl-21,4'-dimethoxybiphenyl (Compound 62)
Figure imgf000127_0001
Obtained using General Procedure 3. Starting materials: 1-Bromo-5-isopropyl-2,4- dimethoxybenzene and 4-butyloxy-2,3,5,6-tetrafluorophenylboronic acid. TLC-pure material was obtained. The product was used without further purification or analysis.
Synthesis 63 4'-Fluoro-2'-isopropoxy-5-isopropyI-2,4-dimethoxybiphenyl (Compound 63)
Figure imgf000127_0002
Obtained using General Procedure 3. Starting materials: 1 -Bromo-5-isopropyl-2,4- dimethoxybenzene and 4-fluoro-2-isopropoxyphenylboronic acid. TLC-pure material was obtained. The product was used without further purification or analysis.
Synthesis 64
4-Fluoro-5'-isopropyl-2',4'-dimethoxybiphenyl-3-carboxylic acid (Compound 64)
Figure imgf000127_0003
Obtained using General Procedure 3. Starting materials: 1-Bromo~5-isopropyl-2,4- dimethoxybenzene and 5-borono-2-fluorobenzoic acid. TLC-pure material was obtained. The product was used without further purification or analysis. Svnthesis 65
4-Fluoro-Λ/,5'-diisopropyl-21,4'-dimethoxybiphenyl-3-carboxamide (Compound 65)
Figure imgf000128_0001
Obtained using General Procedure 3. Starting materials: 1-Bromo-5-isopropyl-2,4- dimethoxybenzene and 4-fluoro-3-(isopropylcarbamoyl)phenylboronic acid. TLC-pure material was obtained. The product was used without further purification or analysis.
Synthesis 66
(4-Fluoro-5'-isopropyl-2',4'-dimethoxybiphenyl-3-yl)(morpholino)methanone
(Compound 66)
Figure imgf000128_0002
Obtained using General Procedure 3. Starting materials: 1-Bromo-5-isopropyl-2,4- dimethoxybenzene and 4-fluoro-3-(morpholine-4-carbonyl)phenylboronic acid. TLC-pure material was obtained. The product was used without further purification or analysis.
Synthesis 67 4-Fluoro-5'-isopropyl-2',4'-dimethoxy-Λ/-phenylbiphenyl-3-carboxamide (Compound 67)
Figure imgf000128_0003
Obtained using General Procedure 3. Starting materials: 1-Bromo-5-isopropyl-2,4- dimethoxybenzene and 4-fIuoro-3-(phenylcarbamoyl)phenylboronic acid. TLC-pure material was obtained. The product was used without further purification or analysis. Svnthesis 68
5'-!sopropyl-2',4'-dimethoxybiphenyl-3-amine (Compound 68)
Figure imgf000129_0001
Obtained using General Procedure 3. Starting materials: 1-Bromo-5-isopropyl-2,4- dimethoxybenzene and 3-aminophenylboronic acid hydrochloride. TLC-pure material was obtained. The product was used without further purification or analysis.
Synthesis 69 Λ/-(5'-lsopropyl-2\4'-dimethoxybiphenyl-3-yl)methanesulfonamide (Compound 69)
Figure imgf000129_0002
Obtained using General Procedure 6. Starting materials: Methanesulfonyl chloride and 5'- isopropyl-2',4'-dimethoxybiphenyl-3-amine. TLC-pure material was obtained. The product was used without further purification or analysis.
Synthesis 70
Λ/-(5'-lsopropyl-2',4'-dimethoxybiphenyl-3-yl)-1-phenylmethanesulfonamide
(Compound 70)
Figure imgf000129_0003
Obtained using General Procedure 6. Starting materials: Phenylmethanesulfonyl chloride and 5'-isopropyl-2',4'-dimethoxybiphenyl-3-amine. TLC-pure material was obtained. The product was used without further purification or analysis. Svnthesis 71
^-(S'-lsopropyl^'^'-dimethoxybiphenyl-S-yO^-methylbenzenesulfonamicie (Compound
71)
Figure imgf000130_0001
Obtained using General Procedure 6. Starting materials: 4-Methylphenylsulfonyl chloride and 5'-isopropyl-2',4'-dimethoxybiphenyl-3-amine. TLC-pure material was obtained. The product was used without further purification or analysis.
Synthesis 72
1-(4-Chlorophenyl)-Λ/-(5'-isopropyl-2',4I-dimethoxybiphenyl-3-yl)methanesulfonamide
(Compound 72)
Figure imgf000130_0002
Obtained using General Procedure 6. Starting materials: (4-Chlorophenyl)methane- sulfonyl chloride and 5'-isopropyl-2',4'-dimethoxybiphenyl-3-amine. TLC-pure material was obtained. The product was used without further purification or analysis.
Synthesis 73
4-Fluoro-5'-isopropyl-2',4'-dimethoxybiphenyl-2-amine (Compound 73)
Figure imgf000130_0003
Obtained using General Procedure 3. Starting materials: 1-Bromo-5-isopropyl-2,4- dimethoxybenzene and 2-amino-4-fluorophenylboronic acid. TLC-pure material was obtained. The product was used without further purification or analysis. Synthesis 74
Λ/-(4-Fluoro-5I-isopropyl-2',41-dimethoxybiphenyl-2-yl)-4-methylbenzenesulfonamide
(Compound 74)
Figure imgf000131_0001
Obtained using General Procedure 6. Starting materials: 4-Methylphenylsulfonyl chloride and 4-fluoro-5'-isopropyl-2',4t-dimethoxybiphenyl-2-amine. TLC-pure material was obtained. The product was used without further purification or analysis.
Synthesis 75
1-(4-Chlorophenyl)-Λ/-(4-fluoro-5'-isopropyl-2',4'-dimethoxybiphenyl-2- yl)methanesulfonamide (Compound 75)
Figure imgf000131_0002
Obtained using General Procedure 6. Starting materials: 4-Chlorophenylmethanesulfonyl chloride and 4-fluoro-5'-isopropyl-2',4'-dimethoxybiphenyl-2-amine. TLC-pure material was obtained. The product was used without further purification or analysis.
Synthesis 76
2-(4-(Dimethylamino)phenyl)-/V-(5I-isopropyl-2',4'-dimethoxybiphenyl-3-yl)acetamide
(Compound 76)
Figure imgf000131_0003
4-Dimethylaminophenylacetic acid (24.6 mg, 0.14 mmol) was dissolved in dry DMF (5 mL). TBTU (48 mg, 0,19 mmol) and DIPEA (65 μl_, 3 eq) was added and the mixture was stirred for 20 minutes. Then 5'-lsopropyl-2',4'-dimethoxybiphenyl-3-amine (0.25 M in THF, 0.50 mL, 0.125 mmol) was added and the mixture left stirring over night. The solvents were evaporated in vacuo and the ccrude product was purified on preperative HPLC to yield 26.8 mg pure material (HPLC). The product was used without further purification or analysis.
Synthesis 77
Λ/-(4-((1 H- 1 ,2,4-Triazol-1 -yOmethyObenzyO-S'-isopropyl-Z^'-dimethoxybiphenyl-S-amine
(Compound 77)
Figure imgf000132_0001
4-((1/-/-1 ,2,4-Triazol-1-yl)methyl)benzaldehyde (27.3 mg, 0.134 mmol) and δ'-lsopropyl- 2',4'-dimethoxybiphenyl-3-amine (0.25 M in THF, 0.50 mL, 0.125 mmol) was dissolved in 2 mL THF:HOAc (3:1 ). Na2SO4 (50 mg) was added and the mixture was stirred for 1 h. NaBH(OAc)3 (80.1 mg, 3 eq) was added and the mixture was stirred over night. The reaction mixture was quenched with 0 0C NaHCO3-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.
Synthesis 78
5-lsopropyl-2,4-dimethoxybenzaldehyde (Compound 78)
Figure imgf000132_0002
DMF (15 mL) was placed in a 100 mL 3-necked flask equipped with a reflux condenser and CaCI2 drying tube. After cooling in ice, POCI3 (2.3 mL, 25 mmol) was added dropwise. After stirring at O0C for 10 minutes, Compound 2 (3.00 g, 16.6 mmol) was added dropwise. The resulting green solution was heated to 1000C for 2 hours. TLC indicated complete reaction and the reaction mixture was poured onto 200 mL crushed ice. The pH was adjusted to 6 with 10% NaOAc and the suspension was placed in the fridge over night to crystallize. The precipitate was filtered off and washed with water and dried. 1H NMR confirmed that the product was the desired product. The crude product was further purified (to remove small amounts of Compound 2) by flash chromatography (silica gel, EtOAc-Hep (30:70) to (80:20). The yield of colourless oil, which crystallized on standing, was 2.94 g (85%). 1H-NMR (CDCI3): δ 10.31 (s, 1H), 7.70 (s, 1H), 6.40 (s, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.20 (sep, 1 H), 1.19 (d, 6H).
Synthesis 79 5-(5-lsopropyl-2,4-dimethoxyphenyl)oxazole (Compound 79)
Figure imgf000133_0001
Obtained using General Procedure 5. Starting material: 5-lsopropyl-2,4- dimethoxybenzaldehyde. 1H-NMR (CDCI3): δ 7.87 (s, 1 H), 7.58 (s, 1 H), 7.41 (s, 1 H), 7.51 (s, 1 H), 3.95 (s, 3H), 3.88 (s, 3H), 3.28 (hep, 1 H), 1.23 (d, 6H).
Synthesis 80 1 -Ethyl-5-(isocyano(tosyl)methyl)-2,4-dirnethoxybenzene (Compound 80)
Figure imgf000133_0002
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. Heptane (7 mL) was added to the resulting slurry, and the precipitate was isolated on a glass filter, washed with heptane, and dried in vacuo. The resulting crude p-tolylsulfinic acid was used fresh in the next step without further purification.
Step 2:
Figure imgf000133_0003
Toluene (dry, 3 ml_) and acetonitrile (dry, 3 mL), both dried over 4 A molecular sieve, was placed in a three-necked round bottomed flask. 5-Ethyl-2,4-dimethoxybenzaldehyde (1.25 g, 6.44 mmol) was added followed by molecular sieves (4A, 0.5 g). Formamide (0.64 mL, 16.1 mmol) and TMSCI (0.90 mL, 7.1 mmol) were added and the mixture stirred a 50°C under a nitrogen atmosphere for 4 hours. Precipitation of yellow-green product was observed. Then, freshly prepared p-tolylsulfinic acid (1.51 g, 9.65 mmol) from step 1 was added and stirring at 5O0C was continued for another 4 hours. To the cooled and almost clear reaction mixture was added TBME (5 mL), and after stirring for 5 minutes, all was poured into ice-water. A precipitate was observed in the upper layer. After stirring at O0C for 1 hour, the precipitate was filtered off and washed with TBDE and dried in vacuo. Weight of crude product: 1.28 g (52 %).
Step 3:
Figure imgf000134_0001
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 POCI3 (0.62 mL) and the resulting greenish suspension was stirred for 5 minutes, after which it was cooled to 00C. Triethylamine (2.8 mL) was added slowly keeping the temperature below 5°C. The mixture was stirred at O0C 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. The organic phase was washed with water twice, once with saturated NaHCθ3, and with brine, and then dried over MgSO4, filtered, and evaporated to yield 1.2 g of orange-brown oil. 1-Propanol (5 mL) was added and the resulting suspension was evaporated to half volume and cooled in ice for 45 minutes, after which the resulting solid was isolated by filtration and washed with cold 1-propanol. After drying in vacuo, the yield was 521 mg (43%) of a light tan solid. LC-MS and 1H NMR showed the desired Compound 47 as >95% pure. 1H NMR (CD3OD) δ 7.60 (d, 2H), 7.42 (d, 2H), 6.96 (s, 1 H), 6.51 (s, 1H), 6.41 (s, 1H), 3.88 (s, 3H), 3.68 (s, 3H), 2.53 (q, 2H), 2.48 (s, 3H), 1.11 (t, 3H). MS+: 382.0 (M+Na), 740.7 (2M+Na), MS-: 358.2 (M-H). Synthesis 81 1 -(lsocyano(tosyl)methyi)-5-isopropyl-2,4-dimethoxybenzene (Compound 81 )
Figure imgf000135_0001
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. Heptane (7 mL) was added to the resulting slurry and the precipitate was isolated on a glass filter, washed with heptane, and dried in vacuo. The resulting crude p-tolylsulfinic acid was used fresh in the next step without further purification.
Step 2:
Figure imgf000135_0002
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 5O0C for 4 hours under a N2 atmosphere. The resulting cloudy orange solution was evaporated to semi-dryness. Dry toluene was added and the solvent was re-evaporated. To the residual oil was added acetonitrile (1 mL) and toluene (1 mL) followed by p-tolylsulfinic acid (freshly prepared in step 1) (1.69 g, 2.5 eq). The solution was stirred at 500C for 5 hours and then at room temperature overnight. To the resulting yellow suspension was added TBME (2 mL). After stirring for 5 minutes, water (10 mL) was added after which the precipitate dissolved. The mixture was stirred at 00C for 1 hour. The organic phase was isolated and evaporated in vacuo at 35°C to give a viscous oil (2.4 g). HPLC and LC-MS show mixture of products (possibly due to degradation on the column). The above raw product (2.4 g) was suspended in dry THF (7 ml) in a two-necked flask equipped with thermometer. POCI3 (1.13 mL, 2 eq) was added and the solution cooled on acetone/ice bath to O0C. Triethylamine (5.1 mL, 6 eq.) was added slowly, keeping the temperature below 5°C. The mixture was stirred at O0C for 45 minutes. To the solution was added EtOAc (5 mL) and H2O (5 mL) and the mixture was stirred for 10 minutes. The organic phase was separated and washed twice with water, twice with saturated NaHCO3, once with brine, and dried over Na2SO4. Evaporation yielded (2.2 g) of a viscous oil. LC-MS showed that it was the desired product; [M-H]"1 = 372.2 and [M+Na]+1 = 396.0. From the UV-trace, the content of the desired compound was estimated to be about 30-40% in mixture with 2 major unidentified by-products. The title product was used as obtained for further reactions. An analytical sample was further purified on silica gel (EtOAc-PE (7:3) ) to give the following NMR data: 1H-NMR (CD3OD): δ 7.58 (d, 2H), 7.42 (d, 2H), 6.95 (s, 1H), 6.52 (s, 1H), 6.42 (s, 1H), 3.89 (s, 3H), 3.71 (s, 3H), 3.19 (sep, 1 H), 2.48 (S1 3H), 1.1 1 (d, 6H).
Synthesis 82 5-(4-Ethylphenyl)-4-(5-isopropyl-2,4-dimethoxyphenyl)oxazole (Compound 82)
Figure imgf000136_0001
Prepared using an "inversed" General Procedure 5. Starting materials: Crude 1-(isocyano(tosyl)methyl)-5-isopropyl-2,4-dimethoxybenzene and 4-ethylbenzaldehyde. The compound was obtained as approximately 70% pure as judged from LC-MS. MS: [M+H]+1 = 352.20. The product was used in subsequent reactions without further purification.
Synthesis 83
5-(4-Fluorophenyl)-4-(5-isopropyl-2,4-dimethoxyphenyl)oxazoIe (Compound 83)
Figure imgf000136_0002
Prepared using an "inversed" General Procedure 5. Starting materials: 1 -(isocyano(tosyl)methyl)-5-isopropyl-2,4-dimethoxybenzene and 4-fluoro-benzaldehyde. The compound was obtained as approximately 50% pure as judged from LC-MS. MS: [M+H]+1 = 342.10. The product was used in subsequent reactions without further purification.
Synthesis 84 4-(5-lsopropyl-2,4-dimethoxyphenyl)-5-(naphthalen-2-yl)oxazole (Compound 84)
Figure imgf000137_0001
Prepared using an "inversed" General Procedure 5. Starting materials: Crude 1 -(isocyano(tosyl)methyl)-5-isopropyl-2,4-dimethoxybenzene and 2-naphthaldehyde. 1H-NMR (CD3OD): δ 8.35 (s, 1 H)1 8.02 (s, 1 H), 7.88-7.75 (m, 3H), 7.57-7.44 (m, 3H), 7.29 (s, 1 H), 6.71 (s, 1 H), 3.96 (s, 3H), 3.61 (s, 3H), 3.31 (sep, 1H, masked), 1.20 (d, 6H). LC-MS. -90% pure. MS: [M+H]+1 = 374.1.
Synthesis 85 1 -(Isocyano(phenyl)methylsulfonyl)-4-methylbenzene (Compound 85)
Figure imgf000137_0002
Synthesized analogous to 1-(isocyano(tosyi)methyl)-5-isopropyl-2,4-dimethoxybenzene using benzaldehyde as starting material. 1H-NMR (CD3OD): δ 7.67-7.62 (m, 2H), 7.54- 7.34 (m, 7H), 2.49 (s, 3H). MS: [M+H]+1 = 294.0.
Synthesis 86
5-(5-lsopropyl-2,4-dimethoxyphenyl)-4-phenyloxazole (Compound 86)
Figure imgf000137_0003
Prepared using General Procedure 5. Starting materials: 1-(lsocyano(phenyl)- methylsulfonyl)-4-methylbenzene and 5-isopropyl-2,4-dimethoxybenzaldehyde. Crude product -80 % pure. Used as is for subsequent step. 1H-NMR (DMSO-c/6): δ 8.44 (s,
1 H), 7.53-7.47 (m, 2H), 7.36-7.20 (m, 3H), 7.14 (s, 1 H), 6.75 (s, 1 H), 3.91 (s, 3H), 3.67 (s, 3H), 3.18 (sep, 1 H), 1.09 (d, 6H). Synthesis 87 1-Fluoro-4-(isocyano(tosyl)methyl)benzene (Compound 87)
Figure imgf000138_0001
Synthesized analogous to 1-(isocyano(tosyl)methyl)-5-isopropyl-2,4-dimethoxybenzene using 4-fluorobenzaldehyde as starting material. 1H-NMR (CD3OD): δ 7.68 (d, 2H), 7.47 (d, 2H), 7.46-7.38 (m, 2H), 7.24-7.14 (m, 2H), 2.50 (s, 3H). MS: [M+Na]+1 = 312.1.
Synthesis 88 4-(4-Fluorophenyl)-5-(5-isopropyl-2,4-dimethoxyphenyl)oxazole (Compound 88)
Figure imgf000138_0002
Prepared using General Procedure 5. Starting materials: 1-Fluoro-4- (isocyano(tosyl)methyl)benzene and 5-isopropy!-2,4-dimethoxybenzaldehyde. Crude product -75 % pure. Used as is for subsequent step. 1H-NMR (DMSOd6): δ 8.44 (s, 1 H), 7.50 (m, 2H), 7.22-7.12 (m, 3H), 6.74 (s, 1 H), 3.91 (s, 3H)1 3.66 (s, 3H), 3.18 (sep, 1 H), 1.10 (d, 6H). MS: [M+H]+1 = 342.2.
Synthesis 89 1-Ethyl-4-(isocyano(tosyl)methyl)benzene (Compound 89)
Figure imgf000138_0003
Synthesized analogous to 1-(isocyano(tosyl)methyl)-5-isopropyl-2,4-dimethoxybenzene using 4-ethylbenzaldehyde as starting material. 1H-NMR (CD3OD): δ 7.64 (d, 2H), 7.44 (d, 2H), 7.27 (bs, 4H), 2.70 (q, 2H), 2.50 (s, 3H), 1.26 (t, 3H). MS: [M+Na]+1 = 322.2. Svnthesis 90 4-(4-Ethylphenyl)-5-(5-isopropyl-2,4-dimethoxyphenyl)oxazo!e (Compound 90)
Figure imgf000139_0001
Prepared using General Procedure 5. Starting materials: 1-Ethyl-4- (isocyano(tosyl)methyl)benzene and 5-isopropyl-2,4-dimethoxybenzaldehyde. Impure. Used as is for subsequent step. 1H-NMR (DMSO-Cf6): δ 8.41 (s, 1 H)1 7.41 (m, 2H), 7.17- 7.1 1 (m, 2H), 7.12 (s, 1 H), 6.74 (s, 1 H), 3.91 (s, 3H), 3.67 (s, 3H), 3.17 (sep, 1H), 2.57 (q, 2H), 1.15 (t, 3H) 1.08 (d, 6H). MS: [M+H]+1 = 352.1.
Synthesis 91 4-(lsocyano(tosyl)methyl)-6-isopropyl-1 ,3-dibenzyloxybenzene (Compound 91)
Figure imgf000139_0002
Synthesized analogous to 1-(isocyano(tosyl)methyl)-5-isopropyl-2,4-dimethoxybenzene using (2,4-bis(benzyloxy)-5-isopropyl-benzaldehyde) as starting material. The product was isolated as a white solid in 18 % overall yield (2 steps). 1H-NMR (CD3OD): δ 7.55- 7.49 (m, 2H), 7.46-7.30 (m, 12H), 7.00 (s, 1 H), 6.66 (s, 1 H), 6.40 (s, <1 H, deut. exchange), 5.12 (s, 2H), 5.05 (d, 1H), 4.9 (masked d, 1H), 3.26 (sep, 1 H), 2.46 (s, 3H), 1.14 (dd, 6H). 1H-NMR (DMSO-Cy6): δ 7.59-7.29 (m, 14H), 6.89 (s, 1 H), 6.84 (s, 1H), 6.68 (1H), 5.18 (s, 2H), 5.13 (d, 1 H), 5.99 (d, 1 H), 3.14 (sep, 1H), 2.41 (s, 3H), 1.04 (dd, 6H). MS: [M+Na]+1 = 548.1.
Synthesis 92 4-(2,4-Bis(benzyloxy)-5-isopropylphenyl)-5-phenyloxazole (Compound 92)
Figure imgf000139_0003
Prepared using an "inversed" General Procedure 5. Starting materials: 4- (lsocyano(tosy[)methyl)-6-isopropyl-1 ,3-dibenzyloxybenzene and benzaldehyde. 1H-NMR (CD3OD): δ 8.29 (s, 1 H), 7.52-7.13 (arom 14H), 6.96 (m, 2H), 6.81 (s, 1 H), 5.16 (s, 2H), 4.9 (masked, 2H), 3.36 (sep, masked, 1H), 1.23 (d, 6H).
Synthesis 93 4-(2,4-Bis(benzyloxy)-5-isopropylphenyl)-5-(2-ethylphenyl)oxazole (Compound 93)
Figure imgf000140_0001
Prepared using an "inversed" General Procedure 5. Starting materials: 4- (lsocyano(tosyl)methy!)-6-isopropyl-1 ,3-dibenzyloxybenzene and 2-ethylbenzaldehyde. -70 % pure. Used as is for subsequent steps. 1H-NMR (CD3OD): δ 8.34 (s, 1H), 7.51- 7.0 (m, arom. H), 6.59 (s, 1 H), 5.23 (d, 2H), 5.02 (s, 2H), 3.27 (sep, 1H), 2.49 (q, 2H), 1.14 (d, 6H), 1.00 (t, 3H). MS: [M+H]+1 = 504.3.
Synthesis 94 4-(2,4-Bis(benzyloxy)-5-isopropylphenyl)-5-(4-methoxyphenyl)oxazoIe (Compound 94)
Figure imgf000140_0002
Prepared using an "inversed" General Procedure 5. Starting materials: A- (lsocyano(tosyl)methyl)-6-isopropyl-1 ,3-dibenzyloxybenzene and 4-methoxy- benzaldehyde. -85% pure. Used as is for subsequent reaction. 1H-NMR (CD3OD): δ 8.24 (s, 1H), 7.51-7.34 (m, 8H), 7.27 (s, 1 H), 7.22-7.17 (m, 3H)1 7.02-6.96 (m, 2H), 6.91- 6.86 (m, 2H), 6.81 (s, 1 H), 5.25 (d, 1 H), 5.16 (s, 2H), 4.9 (masked d, 1 H), 3.81 (s, 3H), 3.26 (sep, 1 H), 2.46 (s, 3H), 1.22 (d, 6H). MS: [M+H]+1 = 506.3.
Synthesis 95
4-(2,4-Bis(benzyloxy)-5-isopropylphenyl)-5-(3,4-dimethoxyphenyl)oxazole (Compound 95)
Figure imgf000140_0003
Prepared using an "inversed" General Procedure 5. Starting materials: A- (lsocyano(tosyl)methyl)-6-isopropyl-1 ,3-dibenzyloxybenzene and 3,4- dimethoxybenzaldehyde. 1H-NMR (CD3OD): δ 8.25 (s, 1H), 7.49-6.80 (arom, 16H), 5.18 (s, 2H), 4.9 (masked, 2H), 3.85 (s, 3H), 3.48 (s, 3H), 3.26 (sep, 1 H), 1.23 (d, 6H). MS: [M+H]+1 = 536.3.
Synthesis 96
5-(Benzo[d][1 ,3]dioxol-5-yl)-4-(2,4-bis(benzyloxy)-5-isopropylphenyl)oxazole
(Compound 96)
Figure imgf000141_0001
Prepared using an "inversed" General Procedure 5. Starting materials: 4- (lsocyano(tosy!)methyl)-6-isopropyl-1 ,3-dibenzyloxybenzene and piperonal. 1H-NMR (CD3OD): δ 8.23 (s, 1 H), 7.55-6.74 (arom, 16H), 5.96 (s, 2H), 5.17 (s, 2H), 4.9 (masked, 2H), 3.85 (s, 3H), 3.48 (s, 3H), 3.26 (sep, 1 H), 1.23 (d, 6H). MS: [M+H]+1 = 520.3.
Synthesis 97 2-(4-(2,4-Bis(benzyloxy)-5-isopropylphenyl)oxazol-5-yl)benzonitrile (Compound 97)
Figure imgf000141_0002
Prepared using an "inversed" General Procedure 5. Starting materials: 4- (lsocyano(tosyl)methyl)-6-isopropyl-1 ,3-dibenzyloxybenzene and 2-formylbenzonitrile. 1H-NMR (DMSO-de): δ 8.64 (s, 1H), 7.74 (dd, 1H), 7.58 (dt, 1H), 7.50-7.20 (arom, 12H), 6.90-6.84 (m, 3H), 5.16 (s, 2H), 4.77 (s, 2H), 3.24 (sep, 1 H), 1.16 (d, 6H). MS: [M+H]+1 = 501.3; [M+Na]+1 = 523.3. Synthesis 98 4-(4-(4_(2,4-Bis(benzyloxy)-5-isopropylphenyl)oxazol-5-yl)ben2yl)morpholine
(Compound 98)
Figure imgf000142_0001
Prepared using an "inversed" General Procedure 5. Starting materials: 4- (lsocyano(tosyl)methyl)-6-isopropyl-1 ,3-dibenzyloxybenzene and 4- (morpholinomethyl)benzaldehyde. 1H-NMR (CD3OD): δ 8.35 (s, 1 H), 7.60-6.93 (arom, 16H), 6.85 (s, 1H), 5.19 (s, 2H), 4.9 (masked, 2H), 4.0 (br, 2H), 3.77 (br, 4H), 3.26 (masked sep, 1 H), 2.88 (br, 4H), 1.24 (d, 6H). MS: [M+H]+1 = 575.4.
Synthesis 99
5-(4-((1 H-lmidazol-1-yl)methyl)phenyl)-4-(2,4-bis(benzyloxy)-5-isopropylphenyl)oxazole
(Compound 99)
Figure imgf000142_0002
Prepared using an "inversed" General Procedure 5. Starting materials: 4-
(lsocyano(tosyl)methyl)-6-isopropyl-1 ,3-dibenzyloxybenzene and 4-((1H-imidazol-1- yl)methyl)benzaldehyde. 1H-NMR (DMSO-c/6): δ 8.44 (s, 1H), 7.72 (s, 1H), 7.54-6.81 (arom, 18H), 5.20(s, 2H), 5.19 (s, 2H), 4.92 (s, 2H), 3.24 (sep, 1H), 1.15 (d, 6H).
Synthesis 100
5-(4-((1 /-/-1 , 2,4-TriazoM -yl)methyl)phenyl)-4-(2,4-bis(benzyloxy)-5- isopropylphenyl)oxazole (Compound 100)
Figure imgf000142_0003
Prepared using an "inversed" General Procedure 5. Starting materials: 4- (lsocyano(tosyl)methyl)-6-isopropyl-1 ,3-dibenzyloxybenzene and 4-((1/7-1 ,2,4-triazol-1- yl)methyl)benzaldehyde. 1H-NMR (DMSO-c/6): δ 8.64 (s, 1H), 8.45 (s, 1H), 7.98 (s, 1H), 7.53-7.06 (arom, 13H), 6.95 (s, 1 H), 6.83 (m, 2H), 5.42 (s, 2H), 5.20 (s, 2H), 4.91 (s, 2H), 3.26 (sep, 1H), 1.15 (s, 6H). MS: [M+H]+1 = 557.3.
Synthesis 101
4-(2,4-Bis(benzyloxy)-5-isopropylphenyl)-5-(4-(piperidin-1-ylmethyl)phenyl)oxazole
(Compound 101)
Figure imgf000143_0001
Prepared using an "inversed" General Procedure 5. Starting materials: 4- (!socyano(tosyl)methy!)-6-isopropyl-1 ,3-dibenzyloxybenzene and 4-(piperidin-1- ylmethyl)benzaldehyde. 1H-NMR (CD3OD): δ 8.30 (s, 1 H), 7.53-7.11 (arom, 13), 6.95 (m, 2H), 6.82 (s, 1 H), 5.18 (s, 2H), 4.9 (masked, 2H), 3.51 (s, 2H), 2.41 (br, 4H), 1.57 (br, 4H), 1.44 (br, 2H), 1.23 (d, 6H). MS: [M+H]+1 = 573.4.
Synthesis 102
4-(2,4-bis(benzyloxy)-5-isopropylphenyl)-5-(4-((4-methylpiperazin-1- yl)methyl)phenyl)oxazole (Compound 102)
Figure imgf000143_0002
Prepared using an "inversed" General Procedure 5. Starting materials: A- (lsocyano(tosyl)methyl)-6-isopropyl-1 ,3-dibenzyloxybenzene and 4-((4-/V- methy!piperazin-1-yl)methyl)benzaldehyde. 90% pure LC-MS. MS: [M+H]+1 = 588.4.
Synthesis 103
4-(2,4-Bis(benzyloxy)-5-isopropylphenyI)-5-(4-((4-methyl-1 ,4-diazepan-1- yl)methyl)phenyi)oxazole (Compound 103)
Figure imgf000143_0003
Prepared using an "inversed" General Procedure 5. Starting materials: A- (lsocyano(tosyl)methyl)-6-isopropyl-1 ,3-dibenzyloxybenzene and 4-((4-Λ/-methyl-1 ,4- diazepan-1-yl)methyl)benzaldehyde. 1H-NMR (CD3OD): δ 8.30 (s, 1H), 7.54-6.91 (arom, 15H), 6.84 (s, 1 H), 5.18 (s, 2H), 4.93 (masked s, 2H), 3.71 (s, 2H), 3.26 (sep, 1H), 3.22 (m, 2H), 3.06 (2H, m), 2.8 (m, 2H), 2.75 (m, 2H), 2.75 (s, 3H), 1.95 (m, 2H), 1.24 (d, 6H). MS: [M+H]+1 = 602.4.
Synthesis 104
4-(2,4-Bis(benzyloxy)-5-isopropylphenyl)-5-(4-(pyrrolidin-1-ylmethyl)phenyl)oxazole (Compound 104)
Figure imgf000144_0001
Prepared using an "inversed" General Procedure 5. Starting materials: A- (lsocyano(tosyl)methyl)-6-isopropyl-1 ,3-dibenzyloxybenzene and 4-(pyrrolidin-1- ylmethyl)benzaldehyde. 1H-NMR (CD3OD): δ 8.30 (s, 1 H), 7.53-7.25 (arom, 10H), 7.18 (m, 3H), 6.96 (m, 2H), 6.82 (s, 1 H), 5.18 (s, 2H), 4.9 (masked s, 2H), 3.66 (s, 2H), 3.26 (masked sep, 1 H), 2.53 (br, 4H), 1.80 (br, 4H), 1.24 (d, 6H). MS: [M+H]+1 = 594.4.
Synthesis 105
4-(4-(2,4-Bis(benzyloxy)-5-isopropylphenyl)oxazol-5-yl)-N-(2-morpholinoethyl)aniline (Compound 105)
Figure imgf000144_0002
Prepared using an "inversed" General Procedure 5. Starting materials: A- (lsocyano(tosyl)methyl)-6-isopropyl-1 ,3-dibenzyloxybenzene and 4-(2- morpholinoethylamino)benzaldehyde. Yield was -25 % (LC-MS). Crude product contained approximately 50% 4-(2-morpholinoethylamino)benzaldehyde. Product confirmed from LC-MS : MS: [M+H]+1 = 604.4. 1H-NMR (CD3OD): δ 8.28 (s, 1 H), 5.19 (s, 2H), 4.98 (s, 2H), 1.14 (d, 6H). Other signals were unconfirmed. The product was used in subsequent reaction without further purification. Svnthesis 106
5-(3-((1/-/-lmidazol-1-yl)methyl)phenyl)-4-(2,4-bis(ben2yloxy)-5-isopropylphenyl)oxazole
(Compound 106)
Figure imgf000145_0001
Prepared using an "inversed" General Procedure 5. Starting materials: A-
(lsocyano(tosyl)methyl)-6-isopropyl-1 ,3-dibenzyloxybenzene and 3-((1H-imidazol-1- yl)methyl)benzaldehyde. 1H-NMR (DMSO-d6): δ 8.46 (s, 1 H), 7.66 (s, 1 H), 7.56-6.78 (arom, 18H), 5.25 (s, 2H), 5.16 (s, 2H), 4.85 (s, 2H), 3.26 (masked sep, 1 H), 1.16 (d, 6H). MS: [M+H]+1 = 556.4.
Synthesis 107
5-(3-((1H-1 ,2,4-Triazol-1-yl)methyl)phenyl)-4-(2,4-bis(benzyloxy)-5-isopropylphenyl)- oxazole (Compound 107)
Figure imgf000145_0002
Prepared using an "inversed" General Procedure 5. Starting materials: A-
(lsocyano(tosy!)methyl)-6-isopropyl-1 ,3-dibenzyloxybenzene and 3-((1H-1 ,2,4-triazol-1- yl)methyl)benzaldehyde. 1H-NMR (DMSO-c/6): δ 8.58 (s, 1 H), 8.45 (s, 1H), 7.95 (s, 1H), 7.57- 7.08 (arom, 13H), 6.91 (s, 1 H), 6.82 (d, 2H), 5.40 (s, 2H), 5.25 (s, 2H), 4.86 (s, 2H), 3.26 (masked sep, 1 H), 1.16 (d, 6H). MS: [M+H]+1 = 557.4.
Synthesis 108
4-(2,4-Bis(benzyloxy)-5-isopropylphenyl)-5-(3-((4-methylpiperazin-1-yl)methyl)phenyl)- oxazole (Compound 108)
Figure imgf000145_0003
Prepared using an "inversed" General Procedure 5. Starting materials: A- (lsocyano(tosyl)methyl)-6-isopropyl-1 ,3-dibenzyloxybenzene and 3-((4-/V- methylpiperazin-1-y|)methyl)benzaldehyde. 1H-NMR (DMSO-c/6): δ 8.46 (s, 1 H), 7.54- 7.11 (arom, 13H), 6.96 (s, 1H), 6.90 (d, 2H), 5.21 (s, 2H), 4.96 (s, 2H). Remaining signals were not assigned due to broadening and overlap with DMSO and H2O signals. LC-MS indicated pure compound. MS: [M+H]+1 = 588.5.
Synthesis 109
4-(2,4-bis(benzyloxy)-5-isopropylphenyl)-5-(3-(pyrrolidin-1-ylmethyl)phenyl)oxazole
(Compound 109)
Figure imgf000146_0001
Prepared using an "inversed" General Procedure 5. Starting materials: 4- (lsocyano(tosyl)methyl)-6-isopropyl-1 ,3-dibenzyloxybenzene and 3-(pyrrolidin-1 - ylmethyl)benzaldehyde. 1H-NMR (DMSO-Cf6): δ 8.45 (s, 1H), 7.53-7.11 (arom, 13H), 6.98-6.88 (arom, m, 3H), 5.20 (s, 2H), 4.96 (s, 2H), 3.51 (br.s, 2H), 3.26 (masked sep, 1 H), 2.34 (br, 4H), 1.62 (br, 4H). 1.15 (d, 6H). MS: [M+H]+1 = 559.5.
Synthesis 110
4-(2,4-Bis(benzyloxy)-5-isopropylphenyl)-5-(3-(pyridin-3-yl)phenyl)oxazole
(Compound 110)
Figure imgf000146_0002
Prepared using an "inversed" General Procedure 5. Starting materials: 4- (!socyano(tosyl)methyl)-6-isopropyl-1 ,3-dibenzyloxybenzene and 3-(pyridin-3- yl)benzaldehyde. LC-MS shows pure compound. No NMR spectrum was recorded. MS: [M+H]+1 = 553.4.
Synthesis 111 Methyl 4-(2,4-bis(benzyloxy)-5-isopropylphenyl)oxazole-5-carboxylate (Compound 111)
Figure imgf000146_0003
4-(lsocyano(tosyl)methyl)-6-isopropyl-1,3-dibenzyloxybenzene (600 mg, 1.14 mmol) was suspended in dry MeOH (20 mL). To the suspension was added ethylglyoxylate solution (50% in toluene) folowed by dry K2CO3. The mixture was heated to reflux under N2 for 3 days. LC-MS showed a mixture of products. Solvents were evaporate and the residue partitioned between water and EtOAc. The aqueous phase was extracted twice with
EtOAc and the combined organic phases were washed with 0.1 M HCI (aq), water, brine, and dried over MgSO4. The EtOAc was evaporated and the residue purified by flash chromatography to give 370 mg of methyl 4-(2,4-bis(benzyloxy)-5- isopropylphenyl)oxazole-5-carboxylate. 1H-NMR (DMSO-c/6): δ 8.62 (s, 1H), 7.55-7.23 (arom, 11 H), 6.95 (s, 1 H), 5.21 (s, 2H)1 5.10 (s, 1H), 3.61 (s, 3H), 3.26 (masked sep, 1H), 1.16 (ds, 6H). MS: [M+H]+1 = 458.3.
Synthesis 112 4-(5-lsopropyl-2,4-dimethoxyphenyl)oxazole-5~carboxylic acid (Compound 112)
Figure imgf000147_0001
Methyl 4-(5-isopropyl-2,4-dimethoxyphenyl)oxazole-5-carboxylate (370 mg, 0.81 mmol) was suspended in MeOH (5 mL) and KOH (5 mL, 1 M) was added. The mixture was refluxed for 6 h. MeOH was removed in vacuo and the aqueous solution was acidified (pH = 1) with HCI (2 M) and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4 and evaporated to dryness. The crude product was purified by ion-exchange chromatography using a lsolute (PE-AX) column eluting bi-products first with CH3CN and the acid with a mixture of CH3CN and 1 M HCI (aq). Evaporation of the eluate gave the free acid (160 mg) as more than 90 % pure (HPLC) which was adequate for use in subsequent steps. 1H-NMR (DMSO-c/6): δ 8.57 (s, 1 H), 7.54-7.29 (arom, 10H), 7.20 (S, 1H), 6.92 (s, 1 H), 5.19 (s, 2H), 5.09 (s, 2H), 3.26 (masked sep, 1H), 1.16 (d, 6H). MS: [M+H]+1 = 444.2.
Synthesis 113 Λ/-Benzyl-4-(5-isopropyl-2,4-dimethoxyphenyl)oxazole-5-carboxamide (Compound 113)
Figure imgf000147_0002
4-(5-lsopropyl-2,4-dimethoxyphenyl)oxazole-5-carboxylic acid (made analogous to the benzylated analogue) (19.3 mg, 66.3 μmol) was dissolved in dry DMF (4 mL). TBTU (18.58 mg, 72.9 μmol) and DIPEA (28.4 μL, 166 μmol) was added and the mixture was stirred for 15 min at RT. Benzylamine (8.7 μL, 80 μmol) was added and stirring was continued for 3 h. TLC showed complete reaction. The solvent was evaporated in vacuo and the residue was purified by flash chromatography (EtOAOHeptane (1 :1 )). The yield of Λ/-Benzyl-4-(5-isopropyl-2,4-dimethoxyphenyl)oxazole-5-carboxamide was 11.5 mg. 1H-NMR (DMSO-c/6): δ 8.49 (s, 1 H), 7.34-7.17 (arom, 6H), 6.63 (s, 1H)1 4.37 (d, 2H), 3.86 (s, 3H), 3.61 (s, 3H), 3.26 (masked sep, 1 H), 1.13 (d, 6H). MS: [M+H]+1 = 381.2.
Synthesis 114
Λ/-((1W-indol-5-yl)methyl)-4-(2,4-bis(benzyloxy)-5-isopropylphenyl)oxazole-5-carboxamide
(Compound 114)
Figure imgf000148_0001
4-(5-lsopropyl-2,4-dimethoxyphenyl)oxazole-5-carboxylic acid (40 mg, 90 //mol) was dissolved in dry DMF (4 mL). TBTU (25.3 mg, 99 μmol) and DIPEA (38.6 //I, 225 μmol) were added and the resulting mixture was stirred for 15 min at RT. Then (1H-indol-5- yl)methanamine (13.2 mg, 90 μmol) was added and the mixture was stirred overnight. The solvent was evaporated in vacuo and the residue was purified by flash chromatography (3% MeOH in CDCI3). The yield Λ/-((1H-indoI-5-yl)methyl)-4-(2,4- bis(benzyloxy)-5-isopropylphenyl)oxazole-5-carboxamide was 21.5 mg. 1H-NMR (CD3OD): δ 11.00 (bs, 1 H), 8.69 (t, 1 H), 8.50 (s, 1 H), 7.52-7.18 (arom, 14 H), 7.00 (d, 1 H), 6.87 (s, 1H), 6.33 (bs, 1H), 5.16 (s, 2H), 5.04 (s, 2H), 4.38 (d, 2H), 3.26 (masked sep, 1H), 1.15 (d, 6H). MS: [M+H]+1 = 572.2.
Svnthesis 115
4-(2,4-bis(benzyloxy)-5-isopropylphenyl)-Λ/-(4-(Λ/,Λ/-dimethylamino)benzyl)oxazole-5- carboxamide (Compound 115)
Figure imgf000149_0001
4-(5-lsopropyl-2,4-dimethoxyphenyl)oxazole-5-carboxylic acid (40 mg, 90 μmol) was dissolved in dry DMF (4 m!_). TBTU (25.3 mg, 99 μmol) and DIPEA (38.6 //I, 225 μmol) were added and the resulting mixture was stirred for 15 min at RT. Then 4-(N1N- dimethylamino)benzylamine bis-hydrochloride (20.1 mg, 90 μmol) was added and the mixture was stirred overnight. The solvent was evaporated in vacuo and the residue was purified by flash chromatography (3% MeOH in CDCI3). The yield of 4-(2,4- bis(benzyloxy)-5-isopropylphenyl)-/V-(4-(/V,/V-dimethylamino)benzyl)oxazole-5- carboxamide was 26.6 mg. 1H-NMR (DMSO-c/6): δ 8.51 (s, 1 H), 7.50-7.26 (arom, 10H), 7.20 (s, 1 H), 7.06 (d, 2H), 6.86 (s, 1 H), 6.60 (d, 2H), 5.16 (s, 2H), 5.03 (s, 2H), 4.20 (d, 2H), 3.22 (sep, 1H), 2.81 (s, 6H), 1.15 (d, 6H). MS: [M+H]+1 = 576.3.
Synthesis 116
/V-(4-(4-(2,4-Bis(benzyloxy)-5-isopropylphenyl)oxazσl-5-yl)phenyl)-Λ/-(2- morpholinoethyl)acetamide (Compound 116)
Figure imgf000149_0002
Prepared using an "inversed" General Procedure 5. Starting materials: 4-
(lsocyano(tosyl)methyl)-6-isopropyl-1 ,3-dibenzyloxybenzene and /V-(4-formylphenyl)-Λ/- (2-morpholinoethyl)acetamide. 1H-NMR (DMSO-d6): δ 8.55 (s, 1 H), 7.84 (d, 2H), 7.50- 7.26 (arom, 12H), 7.21 (s, 1 H), 6.87 (s, 1 H), 5.16 (s, 2H), 5.04 (s, 2H), 4.37 (d, 2H), 3.22 (sep, 1 H), 2.5 (masked s, 3H)1 1.14 (d, 6H). MS: [M+H]+1 = 575.2. Synthesis 117
4-(2-(4-(4-(2,4-Bis(benzyloxy)-5-isopropylphenyl)oxazol-5-yl)phenoxy)ethyl)morpholine
(Compound 117)
Figure imgf000150_0001
Prepared using an "inversed" General Procedure 5. Starting materials: 4- (!socyano(tosyl)methyl)-6-isopropyl-1 ,3-dibenzyloxybenzene and 4-(2- morpholinoethoxy)benzaldehyde. No NMR of the free amine was obtained. LC-MS indicated pure compound. MS: [M+H]+1 = 605.4.
Synthesis 118 4-lsopropyl-6-(1 -phenyl-1 H- 1 ,2,3-triazol-4-yl)benzene-1 ,3-diol (Compound DD-001 )
Figure imgf000150_0002
Prepared using General Procedure 2. Starting material: 4-(5-lsopropyl-2,4- dimethoxyphenyl)-1 -phenyl-1 H-1 ,2,3-triazole. 1H-NMR (DMSO-c/6): δ 9.91 (br s, 1H), 9.43 (br s, 1 H), 8.79 (s, 1 H), 7.96 (m, 2H), 7.77 (s, 1 H), 7.62 (m, 2H)1 7.50 (m, 1 H), 6.50 (s, 1 H), 3.16 (sep, 1 H), 1.20 (d, 6H).
Synthesis 119
4-(1-(2-Hydroxyphenyl)-1 H-1 , 2,3-triazol-4-yl)-6-isopropylbenzene-1 ,3-diol
(Compound DD-002)
Figure imgf000150_0003
Prepared using General Procedure 2. Starting material: 4-(5-lsopropyl-2,4- dimethoxyphenyl)-1-(2-methoxyphenyl)-1H-1 ,2,3-triazole. 1H-NMR (DMSO-Qf6): δ 10.51 (bs, 1H), 9.84 (s, 1 H), 9.36 (s, 1 H), 8.60 (s, 1 H), 7.79 (s, 1H), 7.64 (d, 1 H), 7.34 (m, 1H), 7.12 (d, 1 H), 7.00 (m, 1 H), 6.48 (s, 1 H), 3.15 (sep, 1 H), 1.19 (d, 6H).
Synthesis 120
4-(1 -(3-Hydroxyphenyl)-1 H-1 ,2,3-triazol-4-yl)-6-isopropylbenzene-1 ,3-diol
(Compound DD-003)
Figure imgf000151_0001
Prepared using General Procedure 2. Starting material: 4-(5-lsopropyl-2,4- dimethoxyphenyl)-1-(3-methoxyphenyl)-1 H-1 ,2,3-triazole. 1H-NMR (DMSO-Cf6): δ 10.02 (s, 1 H), 9.91 (s, 1 H), 9.43 (s, 1 H), 8.72 (s, 1 H), 7.76 (s, 1 H), 7.35 (m, 3H), 6.88 (m, 1H), 6.49 (s, 1 H), 3.15 (sep, 1 H), 1.19 (d, 6H).
Synthesis 121
4-(1 -(3,4-Dihydroxyphenyl)-1 H-1 ,2,3-triazol-4-yl)-6-isopropylbenzene-1 ,3-diol
(Compound DD-004)
Figure imgf000151_0002
Prepared using General Procedure 2. Starting material: 4-(5-lsopropyl-2,4- dimethoxyphenyl)-1-(3,4-dimethoxyphenyl)-1H-1 ,2,3-triazole. 1H-NMR (DMSO-c/6): δ 9.92 (br s), 9.41 (br s), 8.60 (s, 1H), 7.73 (s, 1H), 7.29 (d, 1H), 7.15 (d, 1H), 6.89 (d, 1H), 6.48 (s, 1H), 3.14 (sep, 1H), 1.19 (d, 6H). Synthesis 122
4-(1 -(4-n-Butylphenyl)-1 H-1 ,2,3-triazol-4-yl)-6-isopropy!benzene-1 ,3-diol
(Compound DD-005)
Figure imgf000152_0001
Prepared using General Procedure 2. Starting material: 4-(5-lsopropyl-2,4- dimethoxyphenyl)-1-(4-/>butyl-phenyl)-1/-/-1 ,2,3-triazole. 1H-NMR (DMSO-d6): δ 9.91 (s, 1 H), 9.43 (s, 1 H), 8.75 (s, 1 H), 7.85 (s, 1 H), 7.83 (s, 1 H), 7.76 (s, 1 H), 7.44 (s, 1 H)1 7.41 (s, 1 H), 6.50 (S, 1H), 3.15 (sep, 1 H), 2.67 (t, 2H), 1.61 (m, 2H), 1.34 (m, 2H), 1.19 (d, 6H), 0.92 (t, 3H).
Synthesis 123 4-(1-Benzyl-1/-/-1 ,2,3-triazol-4-yl)-6-isopropylbenzene-1 ,3-diol (Compound DD-006)
Figure imgf000152_0002
Prepared using General Procedure 2. Starting material: 1-Benzyl-4-(5-isopropyl-2,4- dimethoxyphenyl)-1W-1 ,2,3-triazole. 1H-NMR (DMSO-Cy6): δ 9.82 (bs, 1H), 9.34 (bs, 1 H), 8.29 (s, 1 H), 7.70 (s, 1 H), 7.34 (m, 5H), 6.43 (s, 1 H), 5.64 (s, 1 H), 5.64 (s, 2H), 3.12 (sep, 1 H), 1.16 (d, 6H).
Svnthesis 124
4-(1-(2-Chloro-4-fluorobenzyl)-1/-/-1,2,3-triazol-4-yl)-6-isopropy!benzene-1 ,3-diol
(Compound DD-007)
Figure imgf000153_0001
Prepared using General Procedure 2. Starting material: 1-(2-Chloro-4-fluorobenzyl)-4-(5- isopropyl-2,4-dimethoxyphenyl)-1W-1 ,2,3-triazole. 1H-NMR (DMSOd6): δ 9.77 (br s, 1H), 9.32 (br s, 1 H), 8.22 (s, 1H), 7.67 (s, 1 H), 7.51 (dd, 1H), 7.31-7.19 (m, 2H), 6.39 (s, 1 H), 5.68 (s, 2H), 3.08 (sep, 1 H), 1.12 (d, 6H).
Synthesis 125
4-(1-(2,4-Difluorobenzyl)-1/-/-1 ,2,3-triazol-4-yl)-6-isopropylbenzene-1 ,3-diol
(Compound DD-008)
Figure imgf000153_0002
Prepared using General Procedure 2. Starting material: 1-(3,4-Difluorobenzyl)-4-(5- isopropyl-2,4-dimethoxyphenyl)-1tf-1 ,2,3-triazole. 1H-NMR (DMSOd6): 6 9.81 (s, 1H), 9.34 (s, 1 H), 8.33 (s, 1 H), 7.70 (s, 1 H), 7.52-7.41 (m, 2H), 7.21-7.17 (m, 1H), 6.44 (s, 1H), 5.64 (s, 1 H), 3.12 (sep, 1H), 1.16 (d, 6H). Svnthesis 126
4-lsopropyl-6-(1-(naphthalen-2-ylmethyl)-1/-/-1 ,2,3-triazol-4-yl)benzene -1 ,3-diol
(Compound DD-009)
Figure imgf000154_0001
Prepared using General Procedure 2. Starting material: 4-(5-lsopropyl-2,4- dimethoxyphenyl)-1-(naphthalen-2~ylmethyl)-1H-1 ,2,3-triazole. 1H-NMR (DMSO-Cf6): δ 9.82 (s, 1H), 9.33 (s, 1 H), 8.34 (s, 1 H), 7.95-7.85 (m, 4H), 7.71 (s, 1H), 7.57-7.52 (m, 2H), 7.45 (dd, 1 H), 6.43 (s, 1H), 5.82 (s, 2H), 3.12 (sep, 1H), 1.16 (d, 6H).
Synthesis 127
4-(1-(4-Fluorobenzyl)-1H-1 ,2,3-triazol-4-yl)-6-isopropylbenzene-1 ,3-diol
(Compound DD-010)
Figure imgf000154_0002
Prepared using General Procedure 2. Starting material: 1-(4-Fluorobenzyl)-4-(5- isopropyl-2,4-dimethoxyphenyl)-1H-1 ,2,3-triazole. 1H-NMR (DMSO-Cf6): δ 9.82 (s, 1H), 9.34 (s, 1 H), 8.30 (s, 1 H), 7.70 (s, 1 H), 7.42-7.38 (m, 2H), 7.24-7.19 (m, 2H), 6.43 (s, 1 H), 5.63 (s, 2H), 3.12 (sep, 1H), 1.16 (d, 6H). Svnthesis 128
4-(1 -(4-Chlorobenzyl)-1 H- 1 ,2,3-triazol-4-yl)-6-isopropylbenzene-1 ,3-diol
(Compound DD-011 )
Figure imgf000155_0001
Prepared using General Procedure 2. Starting material: 1 -(4-Chlorobenzyl)-4-(5- isopropyl-2,4-dimethoxyphenyl)-1H-1 ,2,3-triazole. 1H-NMR (DMSO-dβ): δ 9.82 (s, 1H), 9.34 (s, 1 H), 8.31 (s, 1 H), 7.70 (s, 1 H), 7.48-7.43 (m, 2H), 7.36-7.32 (m, 2H), 6.44 (s, 1H), 5.65 (s, 2H), 3.12 (sep, 1 H), 1.16 (d, 6H).
Synthesis 129
4-(1-(4-Methylbenzyl)-1H-1 ,2,3-triazol-4-yl)-6-isopropylbenzene-1 ,3-diol
(Compound DD-012)
Figure imgf000155_0002
Prepared using General Procedure 2. Starting material: 1-(4-Methylbenzyl)-4-(5- isopropyl-2,4-dimethoxyphenyl)-1W-1 ,2,3-triazole. 1H-NMR (DMSO-Cf6): δ 9.82 (s, 1H), 9.33 (s, 1 H), 8.25 (s, 1 H), 7.69 (s, 1H), 7.24-7.17 (m, 4H), 6.43 (s, 1H), 5.58 (s, 2H), 3.12 (sep, 1 H), 2.29 (s, 3H), 1.16 (d, 6H). Svnthesis 130
4-(1 -(3,4-Dichlorobenzy!)-1 H- 1 ,2,3-triazol-4-yl)-6-isopropylbenzene-1 ,3-diol
(Compound DD-013)
Figure imgf000156_0001
Prepared using General Procedure 2. Starting material: 1-(3,4-Dichlorobenzyl)-4-(5- isopropyl-2,4-dimethoxyphenyl)~1/-/-1 ,2,3-triazole. 1H-NMR (DMSO-cfe): δ 9.82 (s, 1H), 9.35 (s, 1 H), 8.35 (s, 1 H), 7.71-7.63 (m, 3H)1 7.31-7.27 (m, 1 H), 6.44 (s, 1H), 5.67 (s, 2H), 3.12 (sep, 1 H), 1.16 (d, 6H).
Synthesis 131
4-(1 -(4-isopropylbenzyl)-1 H- 1 ,2,3-triazol-4-yl)-6-isopropylbenzene-1 ,3-diol
(Compound DD-014)
Figure imgf000156_0002
Prepared using General Procedure 2. Starting material: 1-(4-isopropylbenzyl)-4-(5- isopropyl-2,4-dimethoxyphenyl)-1 H-1 ,2,3-triazole. 1H-NMR (DMSO-Cf6): δ 9.83 (s, 1H), 9.34 (S, 1 H), 8.28 (s, 1 H), 7.69 (s, 1 H), 7.25 (s, 4H), 6.43 (s, 1 H), 5.59 (s, 2H), 3.12 (sep, 1H), 2.87 (sep, 1 H), 1.18 (d, 6H), 1.15 (d, 6H). Synthesis 132
4-(1 -(3-Chlorobenzyl)-1 H-1 ,2,3-triazol-4-yl)-6-isopropylbenzene-1 ,3-diol
(Compound DD-015)
Figure imgf000157_0001
Prepared using General Procedure 2. Starting material: 1-(3-Chlorobenzyl)-4-(5- isopropyl-2,4-dimethoxyphenyl)-1H-1 ,2,3-triazole. 1H-NMR (DMSO-Cf6): δ 9.82 (s, 1H), 9.34 (s, 1 H)1 8.34 (s, 1 H), 7.71 (s, 1 H), 7.42-7.39 (m, 3H), 7.30-7.25 (m, 1H), 6.44 (s, 1H), 5.67 (s, 2H), 3.12 (sep, 1 H), 1.16 (d, 6H).
Synthesis 133
4-(1 -(2-Fluorobenzyl)-1 H-1 ,2,3-triazol-4-yl)-6-isopropylbenzene-1 ,3-diol
(Compound D-016)
Figure imgf000157_0002
Prepared using General Procedure 2. Starting material: 1-(2-Fluorobenzyl)-4-(5- isopropyl-2,4-dimethoxyphenyl)-1H-1 ,2,3-triazole. 1H-NMR (DMSO-c/6): δ 9.81 (s, 1 H), 9.33 (s, 1 H), 8.26 (s, 1 H), 7.70 (s, 1 H), 7.49-7.18 (arom, 4H), 6.43 (s, 1 H), 5.70 (s, 2H), 3.11 (sep, 1 H), 1.15 (d, 6H). MS: [M+H]+1 = 328.3.
Synthesis 134
4-(1 -(2-Chlorobenzyl)-1 H- 1 ,2,3-triazol-4-yl)-6-isopropylbenzene-1 ,3-diol
(Compound DD-017)
Figure imgf000158_0001
Prepared using General Procedure 2. Starting material: 1-(2-Chlorobenzyl)-4-(5- isopropyl-2,4-dimethoxyphenyl)-1H-1 ,2,3-triazole. 1H-NMR (DMSO-Cf6): δ 9.81 (s, 1H)1 9.34 (s, 1 H), 8.27 (s, 1 H), 7.71 (s, 1 H), 7.53 (m, 1 H), 7.42-7.31 (m, 2H), 7.18 (s, 1H), 6.43 (s, 1 H), 5.74 (s, 2H), 3.12 (sep, 1 H), 1.16 (d, 6H). MS: [M+H]+1 = 344.2.
Synthesis 135
4-lsopropyl-6-(1 -(2-methylbenzyl)-1 H- 1 ,2,3-triazol-4-yl)benzene-1 ,3-diol
(Compound DD-018)
Figure imgf000158_0002
Prepared using General Procedure 2. Starting material: 1-(2-Methylbenzyl)-4-(5- isopropyl-2,4-dimethoxyphenyl)-1H-1 ,2,3-triazole. 1H-NMR (DMSO-Cf6): 5 9.81 (s, 1H). 9.33 (s, 1 H), 8.18 (s, 1 H), 7.70 (s, 1 H), 7.28-7.14 (m, 3H), 7.06 (d, 1H), 6.42 (s, 1H), 5.65 (s, 2H), 3.12 (sep, 1 H), 2.32 (s, 3H), 1.15 (d, 6H). MS: [M+H]+1 = 324.1.
Synthesis 136 4-(1-Benzyl-1 H-1 ,2,3-triazol-5-yl)-6-isopropylbenzene-1 ,3-diol (Compound DD-019)
Figure imgf000158_0003
Prepared using General Procedure 2. Starting material: 1 -Benzyl-5-(5-isopropyl-2,4- dimethoxyphenyl)-1H-1 ,2,3-triazole. 1H-NMR (CDCI3): δ 7.66 (s, 1H), 7.14 (m, 3H), 6.94 (m, 2H), 6.73 (s, 1 H), 6.57 (s, 1 H), 6.5-5.5 (br., 2H) 5.38 (br. s, 2H), 3.09 (sep, 1H)1 0.99 (d, 6H). MS: [M+H]+1 = 310.1.
Synthesis 137
4-(1 -(4-Chlorobenzyl)-1 H- 1 ,2,3-triazol-5-yl)-6-isopropylbenzene-1 ,3-diol
(Compound DD-020)
Figure imgf000159_0001
Prepared using General Procedure 2. Starting material: 1-(4-Chlorobenzyl)-5-(5- isopropyl-2,4-dimethoxyphenyl)-1H-1 ,2,3-triazole. 1H-NMR (CDCI3): δ 7.66 (s, 1H), 7.15 (d, 2H), 6.92 (d, 2H), 6.61 (s, 1H), 6.60 (s, 1 H), 7.5-6.5 (br., 2H) 5.38 (br. s, 2H), 3.09 (sep, 1 H), 1.07 (d, 6H). MS: [M+H]+1 = 344.2.
Synthesis 138 1 -(2,4-Dihydroxy-5-isopropylphenyl)-2-phenylethanone (Compound BB-001 )
Figure imgf000159_0002
Prepared using General Procedure 8. Starting material: 1-(5-lsopropyl-2,4- dimethoxyphenyl)-2-phenylethanone. 1H-NMR (DMSO-d6): δ 12.34 (s, 1H), 10.64 (s, 1 H), 7.72 (s, 1H), 7.29 (m, 5H), 6.30 (s, 1H), 4.32 (s, 2H), 3.09 (sep, 1 H), 1.16 (d, 6H). Svnthesis 139
(2,4-Dihydroxy-5-isopropylphenyl)(4-hydroxyphenyl)methanone (Compound BB-002)
Figure imgf000160_0001
Prepared using General Procedure 8. Starting material: (5-lsopropyl-2,4- dimethoxyphenyl)(4-methoxyphenyl)methanone. 1H-NMR (CDCI3): δ 12.31 (s, 1H), 7.55- 7.51 (m, 2H), 7.35 (s, 1 H), 6.86-6.82 (m, 2H), 6.30 (s, 1 H), 5.39 (s, 1H), 5.20 (s, 1 H), 3.02 (sep, 1 H), 1.08 (d, 6H).
Synthesis 140
(2,4-Dihydroxy-5-isopropylphenyl)(4-chlorophenyl)methanone (Compound BB-003)
Figure imgf000160_0002
Prepared using General Procedure 8. Starting material: (5-lsopropyl-2,4- dimethoxyphenyl)(4-chlorophenyl)methanone. 1H-NMR (DMSO-Cf6): δ 11.77 (s, 1H), 10.77 (br s, 1H), 7.68-7.59 (m, 4H), 7.22 (s, 1H), 6.42 (s, 1H), 3.06 (sep, 1H), 1.08 (d, 6H).
Synthesis 141
(2,4-Dihydroxy-5-isopropylphenyl)(2,6-dichlorophenyl)methanone (Compound BB-004)
Figure imgf000160_0003
Prepared using General Procedure 8. Starting material: (5-lsopropyl-2,4- dimethoxyphenyl)(2,6-dichlorophenyl)methanone. 1H-NMR (DMSO-Cf6): δ 11.45 (br s, 1 H), 11.00 (br s, 1 H), 7.64-7.51 (m, 3H), 6.97 (br s, 1H), 6.40 (s, 1 H), 3.01 (sep, 1H), 1.02 (d, 6H).
Synthesis 142
(2,4-Dihydroxy-5-isopropylphenyl)(4-(dimethylamino)phenyl)methanone
(Compound BB-005)
Figure imgf000161_0001
Prepared using General Procedure 8. Starting material: (4-(Dimethylamino)phenyl)(2- hydroxy-5-isopropyl-4-methoxyphenyl)methanone. 1H-NMR (DMSO-Cf6): δ 12.15 (s, 1H), 10.47 (s, 1 H), 7.57 (d, 2H), 7.35 (s, 1 H), 6.78 (d, 2H), 6.38 (s, 1 H), 3.09 (masked sep, 1 H), 3.03 (s, 6H), 1.10 (d, 6H). MS: [M+H]+1 = 300.1.
Synthesis 143 (2,4-Dihydroxy-5-isopropylphenyl)(3-hydroxyphenyl)methanone (Compound BB-006)
Figure imgf000161_0002
Prepared using General Procedure 8. Starting material: (5-lsopropyl-2,4- dimethoxyphenyl)(3-methoxyphenyl)methanone. 1H-NMR (DMSO-c/e): δ 12.10 (s, 1H), 10.75 (s, 1 H), 9.82 (s, 1 H), 7.38- 7.27 (m, 2H), 7.07-6.94 (m, 3H), 6.40 (s, 1 H), 3.05 (sep, 1H), 1.07 (d, 6H). MS: [M+H]+1 = 273.1.
Synthesis 144 (2,4-Dihydroxy-5-isopropylphenyl)(3,4-dimethoxyphenyl)methanone (Compound BB-007)
Figure imgf000161_0003
4-lsopropyl-1 ,3-dibenzyloxybenzene (216 mg, 0.65 mmol) was dissolved in dry CH2CI2 (5 mL) and cooled to 0 0C. 4-Methoxybenzoy! chloride (167 mg, 0.83 mmol) was added followed by TiCI4 (78 μl_, 1.1 eq) and the resulting mixture was stirred for 1 h at 0 0C. Additional TiCI4 added (143 μL, 2 eq) and the mixture was stirred for another 2 h. The reaction mixture was quenched by addition of H2O and the phases were separated. The organic phase was washed with sat. NaHCO3 and dried over MgSO4. TLC (5% MeOH in CH2CI2) showed one major spot. Purification by flash chromatography yielded 7.7 mg of pure (2,4-Dihydroxy-5-isopropylphenyl)(3,4-dimethoxyphenyl)methanone. 1H NMR (DMSO-CZ6): δ 12.04 (s, 1H), 10.66 (s, 1H), 7.35 (s, 1H), 7.29-7.22 (m, 2H), 7.11 (d, 3JN- H=8.3 Hz, 1 H), 6.41 (s, 1 H), 3.86 (s, 3H), 3.80 (s, 3H), 3.10 (sep, 1 H), 1.09 (d, 6H). MS: [M+H]+1 = 317.2.
Synthesis 145 (2,4-Dihydroxy-5-isopropyiphenyl)(4-methoxyphenyl)methanone (Compound BB-008)
Figure imgf000162_0001
Synthesized analogous to (2,4-Dihydroxy-5-isopropylphenyl)(3,4- dimethoxyphenyi)methanone using 4-isopropyl-1 ,3-dibenzyloxybenzene and 3,4- dimethoxybenzoyl chloride as reactants. 1H NMR (DMSO-d6): δ 12.00 (s, 1H), 10.8-10.4 (br., 1 H), 7.64 (d, 2H), 7.29 (s, 1 H), 7.08 (d, 2H), 6.39 (s, 1 H), 3.86 (s, 3H), 3.07 (sep, 1H), 1.09 (d, 6H). MS: [M+H]+1 = 287.2.
Synthesis 146
4-lsopropyl-6-(pyridin-3-yl)benzene-1 ,3-diol (Compound EE-001)
Figure imgf000162_0002
Prepared using General Procedure 4. Starting material: 3-(5-isopropyl-2,4- dimethoxyphenyl)pyridine. 1H-NMR (DMSO-dβ): δ 9.53 (s, 1 H), 9.48 (s, 1H), 8.79 (bs, 1 H), 8.49 (bs, 1H), 8.11 (d, 1 H), 7.55 (bt, 1 H), 7.05 (s, 1 H), 6.51 (s, 1H), 3.11 (sep, 1H), 1.16 (d, 6H). Synthesis 147 Λ/-(21,41-Dihydroxy-5'-isopropy!biphenyl-2-yl)methanesulfonamide (Compound CC-002)
Figure imgf000163_0001
Prepared using General Procedure 4. Starting material: A/-(5'-isopropyl-2',4'- dimethoxybiphenyl-2-yl)methanesulfonamide. 1H-NMR (DMSO-Cf6): δ 10.00 (bs, 1H), 9.45 (s, 1 H), 8.31 (s, 1 H), 7.87 (bs, 1 H), 7.40-7.25 (m, 4H), 6.83 (s, 1 H), 6.53 (s, 1H), 3.12 (sep, 1 H), 2.52 (s, 3H), 1.12 (d, 6H).
Synthesis 148 5-lsopropyl-2'-(pyrrolidin-1 -ylsulfonyl)biphenyl-2,4-diol (Compound CC-003)
Figure imgf000163_0002
Prepared using General Procedure 4. Starting material: 1-(5'-lsopropyl-2',4'- dimethoxybiphenyl-2-ylsulfonyl)pyrrolidine. Obtained as 85-90% pure. Contains 10-15% mono-methoxy analog. 1H-NMR (CDCI3): δ 8.16 (dd, 1 H), 7.61 (dt, 1H)1 7.51 (dt, 1H), 7.30 (dd, 1 H), 6.85 (s, 1 H), 6.51 (s, 1 H), 4.95-4.65 (bs, 2H), 3.17 (sep, 1 H), 3.00-2.95 (m, 2H), 2.85-2.75 (m, 2H), 1.75-1.65 (m, 4H), 1.24 (d, 3H), 1.20 (d, 3H).
Synthesis 149
A/-(2',4'-Dihydroxy-5'-isopropylbiphenyl-2-yl)-4-methylbenzene-sulfonamide
(Compound CC-004)
Figure imgf000163_0003
Prepared using General Procedure 4. Starting material: Λ/-(5'-isopropyl-2',4'- dimethoxybiphenyl-2-yl)-4-methylbenzene-sulfonamide. 1H-NMR (DMSO-c/6): δ 10.16 (bs, 1 H)1 9.40 (bs, 1 H), 8.39 (s, 1 H), 7.35 (dd, 1 H), 7.27 (dt, 1H), 7.19 (dt, 1H, masked), 7.18 (d, 2H), 7.10 (dd, 1H, masked), 7.08 (d, 2H), 6.50 (s, 1 H), 6.38 (s, 1H), 3.02 (sep, 1 H), 2.26 (s, 3H), 1.07 (d, 6H).
Synthesis 150
Λ/-(2',4I-Dihydroxy-5'-isopropylbiphenyi-2-yl)-4-f!uorobenzene-sulfonamide
(Compound CC-005)
Figure imgf000164_0001
Prepared using General Procedure 4. Starting material: 4-Fluoro-Λ/-(5'~isopropyl-2',4l- dimethoxybiphenyl-2-yl)benzenesulfonamide. 1H-NMR (DMSO-c/6): δ 10.27 (bs, 1 H), 9.41 (bs, 1 H)1 8.55 (s, 1 H), 7.40-7.20 (m, 5H), 7.15-7.00 (m, 3H), 6.47 (s, 1H), 6.33 (s, 1H)1 3.00 (sep, 1 H), 1.06 (d, 6H).
Synthesis 151
Λ/-(2',4'-Dihydroxy-5'-isopropylbipheny!-2-yl)-1-phenylmethane-sulfonamide
(Compound CC-006)
Figure imgf000164_0002
Prepared using General Procedure 4. Starting material: ΛHS'-lsopropyl^'^1- dimethoxybiphenyl-2-yl)-1-phenylmethane-sulfonamide. 1H-NMR (DMSO-Cf6): δ 9.95 (bs, 1H), 9.45 (bs, 1H), 7.92 (s, 1H), 7.40 (d, 1H), 7.35-7.20 (m, 6H), 7.09 (d, 2H), 6.94 (s, 1 H), 6.52 (s, 1 H), 3.13 (sep, 1 H), 1.13 (d, 6H).
Synthesis 152
1-(4-Chlorophenyl)-N-(2I,4l-dihydroxy-5'-isopropylbiphenyl-2-yl)-methanesulfonamide
(Compound CC-007)
Figure imgf000164_0003
Prepared using General Procedure 4. Starting material: 1-(4-Chlorophenyl)-N-(5'- isopropyl-2',4'-dimethoxybiprienyi-2-yl)methane-sulfonamide. 1H-NMR (DMSO-c/6): δ 9.94 (bs, 1 H), 9.48 (bs, 1 H), 7.95 (s, 1 H), 7.45 (d, 1 H), 7.35-7.22 (m, 6H), 7.08 (d, 2H), 6.94 (s, 1 H), 6.50 (s, 1 H), 3.13 (sep, 1 H), 1.13 (d, 6H).
Synthesis 153
A/-(2f,4'-Dihydroxy-5'-isopropylbiphenyl-2-yl)naphthalene-2-sulfonamide
(Compound CC-008)
Figure imgf000165_0001
Prepared using General Procedure 4. Starting material: Λ/^S'-lsopropyl^1^1- dimethoxybiphenyl-2-yl)naphthalene-2-sulfonamide. 1H-NMR (DMSO-Qf6): δ 10.27 (bs, 1 H), 9.41 (bs, 1 H), 8.65 (s, 1 H), 8.0 (d, 1 H, J = 1.5 Hz), 7.90 (d, 2H), 7.74 (d, 1 H), 7.63 (dt, 1H), 7.57 (dt, 1H), 7.40 (dd, 1 H), 7.28 (dt, 1H), 7.25-7.15 (m, 2H), 7.06 (dd, 1H), 6.52 (s, 1 H), 6.17 (s, 1H), 2.78 (sep, 1 H), 0.78 (d, 6H).
Synthesis 154 /V-(2\4'-Dihydroxy-5'-isopropylbiphenyl-2-y!)ethanesulfonamide (Compound CC-009)
Figure imgf000165_0002
Prepared using General Procedure 4. Starting material: /V-(5'-lsopropyl-2',4'- dimethoxybiphenyl-2-yl)ethanesulfonamide. 1H-NMR (DMSO-Qf6): δ 10.07 (s, 1 H), 9.46 (bs, 1H), 7.82 (s, 1H), 7.43-7.22 (m, 4H), 6.89 (s, 1H), 6.53 (s, 1H), 3.13 (sep, 1H), 2.65 (q, 2H), 1.13 (d, 6H)1 0.73 (t, 3H). Svnthesis 155 A/-(2',4'-Dihydroxy-5'-isopropylbiphenyl-2-yl)propane-1 -sulfonamide (Compound CC-010)
Figure imgf000166_0001
Prepared using General Procedure 4. Starting material: A/-(5'-lsopropyl-2',4'- dimethoxybiphenyl-2-yl)propane-1-sulfonamide. 1H-NMR (DMSO-Cf6): δ 10.13 (s, 1 H), 9.47 (bs, 1H), 7.92 (s, 1H), 7.42-7.23 (m, 4H), 6.90 (s, 1 H), 6.54 (s, 1 H), 3.12 (sep, 1H), 2,56 (bt, 2H), 1.22 (m, 2H), 1.14 (d, 6H), 0.66 (t, 3H).
Synthesis 156
Λ/-(2',4'-Dihydroxy-51-isopropylbiphenyl-2-yl)cyclopropanesulfonamide
(Compound CC-001 )
Figure imgf000166_0002
Prepared using General Procedure 4. Starting material: Λ/-(5'-lsopropyl-2',4'- dimethoxybiphenyl-2-yl)cyclopropane-sulfonamide. 1H-NMR (DMSO-c/6): δ 10.17 (s, 1H), 9.46 (bs, 1 H), 7.93 (s, 1H), 7.41-7.25 (m, 4H), 6.91 (s, 1H), 6.54 (s, 1H), 3.12 (sep, 1H), 1.94 (m, 1 H)1 1.11 (d, 6H), 0.55 (m, 4H).
Synthesis 157
4-lsopropyl-6-(thiophen-3-yl)benzene-1 ,3-diol (Compound EE-002)
Figure imgf000166_0003
Prepared using General Procedure 4. Starting material: 3-(5-lsopropyl-2,4- dimethoxyphenyl)thiophene. 1H-NMR (DMSO-c/6): δ 9.32 (s, 1 H), 9.19 (s, 1H), 7.60 (dd, 1 H), 7.46 (m, 2H), 7.15 (s, 1 H), 6.44 (s, 1 H), 3.10 (sep, 1 H), 1.15 (d, 2H). Synthesis 158
5-lsopropylbiphenyl-2,3',4,4'-tetraol (Compound CC-011)
Figure imgf000167_0001
Prepared using General Procedure 4. Starting material: 5-(5-lsopropyl-2,4- dimethoxyphenyl)benzo[d][1 ,3]dioxole. LC-MS of product indicates 85% pure. 1H-NMR (DMSO-CZ6): δ 9.05 (bs, 1 H), 8.88 (bs, 1 H), 9.20-8.20 (vbs, 2H), 6.91 (s, 1H), 6.85 (s, 1H), 6.77-6.50 (m, 2H), 6.39 (s, 1H), 3.10 (sep, 1H), 1.13 (d, 6H).
Synthesis 159 4-lsopropyl-6-(pyridin-2-yI)benzene-1 ,3-diol (Compound EE-003)
Figure imgf000167_0002
Prepared using General Procedure 4. Starting material: 5'-lsopropyl-2',4'- dimethoxybiphenyl-2-carboxamide. 1H-NMR (CDCI3): δ 14.50 (bs, 1H), 8.44 (m, 1H), 7.87-7.74 (m, 2H), 7.59 (s, 1 H), 7.15 (m, 1 H), 6.43 (s, 1 H), 5.3 (bs, 1 H), 3.19 (sep, 1 H), 1.29 (d, 6H).
Synthesis 160 5-lsopropyl-2'-phenoxybiphenyl-2,4-diol (Compound CC-012)
Figure imgf000167_0003
Prepared using General Procedure 4. Starting material: 5-lsopropyl-2,4-dimethoxy-2'- phenoxybiphenyl. 1H-NMR (DMSO-Cf6): δ 9.10 (s, 1 H), 8.93 (s, 1H), 7.36 (dd, 1 H), 7.33- 7.20 (m, 3H), 7.15 (dt, 1H), 7.04-6.82 (m, 4H), 6.80 (s, 1H), 6.36 (s, 1H), 3.01 (sep, 1 H), 0.97 (d, 6H). Svnthesis 161 A/-(2',4'-Dihydroxy-5'-isopropylbiphenyl-2-yl)acetamicle (Compound CC-013)
Figure imgf000168_0001
Prepared using General Procedure 4. Starting material: Λ/-(5'-lsopropyl-2',4'- dimethoxybiphenyl-2-yl)acetamide. 1H-NMR (DMSO-d6): δ 9.47 (bs, 1H), 9.29 (bs, 1 H), 8.66 (bs, 1 H), 7.63 (d, 1 H), 7.30-7.08 (m, 3H), 7.80 (s, 1 H), 6.49 (s, 1 H), 3.11 (sep, 1H), 1.91 (s, 3H), 1.12 (d, 6H).
Synthesis 162
4'-Fluoro-5-isopropylbiphenyl-2,4-diol (Compound CC-014)
Figure imgf000168_0002
Prepared using General Procedure 4. Starting material: 4'-Fluoro-5-isopropyl-2,4- dimethoxybiphenyl. 1H-NMR (DMSO-c/6): δ 9.23 (s, 1 H), 9.16 (s, 1H), 7.54-7.43 (m, 2H), 7.20-7.09 (m, 2H), 6.92 (s, 1 H), 6.45 (s, 1 H) ,3.10 (sep, 1 H), 1.13 (d, 6H).
Synthesis 163
4'-Chloro-5-isopropylbiphenyl-2,4-diol (Compound CC-015)
Figure imgf000168_0003
Prepared using General Procedure 4. Starting material: 4'-Chloro-5-isopropyl-2,4- dimethoxybiphenyl. 1H-NMR (CDCI3): δ 7.50-7.35 (arom, 4H), 7.01 (s, 1H), 6.41 (s, 1 H), 5.1 (br, 2H), 3.14 (sep, 1H), 1.25 (d, 6H). MS: [M-H]"1 = 261.1. Svnthesis 164 4'-Fluoro-5-isopropyl-3'-methylbiphenyl-2,4-diol (Compound CC-016)
Figure imgf000169_0001
Prepared using General Procedure 4. Starting material: 4'-Fluoro-5-isopropyl-2,4- dimethoxy-3'-methylbiphenyl. 1H-NMR (CDCI3): δ 7.30-7.03 (arom, 3H), 6.98 (s, 1H), 6.42 (s, 1H), 5.36 (br, 2H), 3.14 (sep, 1 H), 2.33 (d, 3H), 1.25 (d, 6H).
Synthesis 165
3',4'-Difluoro-5-isopropylbiphenyl-2,4-diol (Compound CC-017)
Figure imgf000169_0002
Prepared using General Procedure 4. Starting material: 3',4'-Difluoro-5-isopropyl-2,4- dimethoxybiphenyl. 1H-NMR (CDCI3): δ 7.36-7.12 (arom, 3H), 7.00 (s, 1H), 6.40 (s, 1H), 4.53 (br, 2H), 3.14 (sep, 1 H), 1.25 (d, 6H). MS: [M-H]"1 = 263.0.
Synthesis 166 4'-Fluoro-5-isopropyl-2'-methylbiphenyl-2,4-diol (Compound CC-018)
Figure imgf000169_0003
Prepared using General Procedure 4. Starting material: 4'-Fluoro-5-isopropyl-2,4- dimethoxy-2'-methylbiphenyl. 1H-NMR (CDCI3): δ 7.19 (dd, 1 H)1 7.07-6.91 (m, 2H), 6.86 (s, 1 H), 6.43 (s, 1 H), 5.67 (br, 2H), 3.14 (sep, 1 H), 2.16 (s, 3H), 1.25 (d, 6H). Svnthesis 167 5-lsopropylbiphenyl-2,3',4-triol (Compound CC-019)
Figure imgf000170_0001
Prepared using General Procedure 4. Starting material: 5-lsopropyl-2,4-dimethoxy-3'-(3- methoxybenzyloxy)biphenyl. 1H-NMR (DMSO-d6): δ 9.5-8.6 (br, 2H), 7.11 (t, 1H), 7.00- 6.83 (arom, 3H), 6.60 (d, 1 H), 6.42 (s, 1 H), 3.10 (sep, 1 H), 1.13 (d, 6H). MS: [M-H]"1 = 243.0.
Synthesis 168
S'-Fluoro-δ-isopropylbiphenyl^^'-triol (Compound CC-020)
Figure imgf000170_0002
Prepared using General Procedure 4. Starting material: 3'-Fluoro-5-isopropyl-2,4,4'- trimethoxybiphenyl. 1H-NMR (DMSO-c/6): δ 9.64 (br, 1H), 9.17 (br. 1H), 9.11 (br, 1H), 7.25 (dd, 1 H), 7.09 (dd, 1H), 6.91 (m, 2H), 6.41 (s, 1 H), 3.09 (sep, 1 H), 1.14 (d, 6H). MS: [M+H]+1 = 263.1.
Synthesis 169 2',3',51,6'-Tetrafluoro-5-isopropylbiphenyl-2,4,4'-triol (Compound CC-021 )
Figure imgf000170_0003
Prepared using General Procedure 4. Starting material: 4-Butoxy-2,3,5,6-tetrafluoro-51- isopropyl-2',4'-dimethoxybiphenyl. 1H-NMR (DMSO-CZ6): δ 9.72 (s, 1H), 9.38 (s, 1H), 7.05 (s, 1 H), 6.54 (br, s, OH), 6.48 (s, 1 H), 3.04 (sep, 1H), 1.09 (d, 6H). MS: [M-H]"1 = 315.0. Svπthesis 170
4'-Fluoro-5-isopropylbiphenyl-2,2\4-trio! (Compound CC-022)
Figure imgf000171_0001
Prepared using General Procedure 4. Starting material: 4'-Fluoro-2'-isopropoxy-5- isopropyl-2,4-dimethoxybiphenyl. 1H-NMR (CDCI3): δ 7.19 (t, 1 H), 6.99 (s, 1 H), 6.82-6.68 (m, 2H), 6.47 (s, 1H), 6.43 (br. s, 1H), 6.05 (br. s, 1H), 3.15 (sep, 1H), 1.24 (d, 6H). MS: [M+H]+1 = 263.1.
Synthesis 171 4-Fluoro-2',4'-dihydroxy-5'-isopropylbiphenyl-3-carboxylic acid (Compound CC-023)
Figure imgf000171_0002
Prepared using General Procedure 4. Starting material: 4-Fluoro-5'-isopropyl-2',4I- dimethoxybiphenyl-3-carboxylic acid. 1H-NMR (DMSO-Cf6): δ 13.2 (br, 1H), 9.32 (s, 1H), 9.29 (S, 1 H), 7.95 (dd, 1 H), 7.70 (ddd, 1 H), 7.26 (dd, 1 H), 6.95 (s, 1 H), 6.46 (s, 1H), 3.11 (sep, 1H), 1.14 (d, 6H). MS: [M+H]+1 = 291.1.
Synthesis 172
4-Fluoro-2',4'-dihydroxy-/V,51-diisopropylbiphenyl-3-carboxamide (Compound CC-024)
Figure imgf000171_0003
Prepared using General Procedure 4. Starting material: 4-Fluoro-Λ/,5'-diisopropyl-2',4I- dimethoxybiphenyl-3-carboxamide. 1H-NMR (CDCI3): δ 8.34 (dd, NH), 7.55 (ddd, 1H), 7.17 (dd, 1 H), 7.2 (br, 1 H), 6.99 (s, 1 H), 6.75 (dd, 1 H), 6.67 (s, 1H), 6.3 (br. 1H), 4.35 (sep, 1 H), 3.20 (sep, 1 H), 1.26 (d, 6H), 1.24 (d, 6H). MS: [M+H]+1 = 332.2. Synthesis 173
(4-Fluoro-2',4'-dihydroxy-51-isopropylbiphenyl-3-yl)(morphormo)methanone
(Compound CC-025)
Figure imgf000172_0001
Prepared using General Procedure 4. Starting material: (4-Fluoro-5'-isopropyi-2',4'- dimethoxybiphenyl-3-yl)(morpholino)methanone. 1H-NMR (CDCI3): δ 7.66 (dd, 1H), 7.57 (dd, 1 H), 7.11 (t, 1 H), 6.95 (s, 1 H), 6.25 (s, 1 H), 3.82 (m, 2H), 3.77 (m, 2H), 3.65 (br, 2H), 3.41 (br, 2H), 3.15 (sep, 1 H), 1.19 (d, 6H). MS: [M+H]+1 = 360.2.
Synthesis 174
4-Fluoro-2',4'-dihydroxy-5'-isopropyl-N-phenylbiphenyl-3-carboxamide
(Compound CC-026)
Figure imgf000172_0002
Prepared using General Procedure 4. Starting material: 4-Fluoro-5'-isopropyl-2',4'- dimethoxy-A/-phenylbiphenyl-3-carboxamide. 1H-NMR (DMSO-c/6): δ 10.40 (s, 1H), 9.31 (br, 2H), 7.80-7.60 (arom, 4H), 7.42-7.05 (arom, 4H), 7.00 (s, 1 H), 6.48 (s, 1H), 3.10 (sep, 1H), 1.15 (d, 6H). MS: [M+H]+1 = 366.2.
Synthesis 175
3'-Amino-5-isopropylbiphenyl-2,4-diol (Compound CC-027)
Figure imgf000172_0003
Prepared using General Procedure 4. Starting material: 5'-lsopropyl-2\4'- dimethoxybiphenyl-3-amine. 1H-NMR (DMSO-d6): δ 9.03 (br, 2H), 6.96 (t, 1H), 6.87 (s, 1 H), 6.68 (s, 1H), 6.61 (d, 1 H), 6.41 (masked d, 1H), 6.40 (s, 1H), 4.92 (br, 2H), 3.10 (sep, 1 H), 1.13 (d, 6H). MS: [M+H]+1 = 244.1.
Synthesis 176 Λ/-(2',4'-Dihvdroxy-5'-isopropylbiphenyl-3-yl)methaπesulfonamide (Compound CC-028)
Figure imgf000173_0001
Prepared using General Procedure 4. Starting material: Λ/-(5'-lsopropyl-2'.4'- dimethoxybiphenyl-3-vOmethanesulfonamide. 1H-NMR (DMSO-Cf6): δ 9.63 (s, NH), 9,24 (br, 2H), 7.38 (s, 1 H), 7.27 (t, 1 H), 7.21 (d, 1 H), 7.05 (d, 1 H), 6.92 (s, 1 H), 6.42 (s, 1 H), 3.10 (sep, 1 H), 2.98 (s, 3H), 1.14 (d, 6H). MS: [M+Na]+1 = 344.0.
Synthesis 177
A/-(2',4'-Dihydroxy-5'-isopropylbiphenyl-3-yl)-1-phenylmethanesulfonamide
(Compound CC-029)
Figure imgf000173_0002
Prepared using General Procedure 4. Starting material: /V-(5'-lsopropyl-2',4'- dimethoxybiphenyl-3-yl)-1-phenylmethanesulfonamide. 1H-NMR (DMSOd6): δ 9.77 (s, NH), 9,29 (s, 1 H), 9.22 (s, 1 H) ), 7.46-7.04 (arom, 9H), 6.95 (s, 1 H), 6.48 (s, 1H), 4.46 (s, 2H), 3.10 (sep, 1 H), 1.14 (d, 6H). MS: [M+Na]+1 = 420.1.
Synthesis 178
Λ/-(2',4'-Dihydroxy-5'-isopropylbiphenyl-3-yl)-4-methylbenzenesulfonamide- methylbenzenesulfonamide (Compound CC-030)
Figure imgf000173_0003
Prepared using General Procedure 4. Starting material: Λ/-(5'-lsopropyl-2',4'- dimethoxybiphenyl-3-yl)-4-methylbenzenesulfonamide. 1H-NMR (DMSO-Qf6): δ 9.36 (br, 3H), 7.67 (d, 2H), 7.28 (d, 2H), 7.25-6.80 (arom, 4H), 6.70 (s, 1H), 6.43 (s, 1H), 4.46 (s, 2H), 3.10 (sep, 1 H), 1.14 (d, 6H). MS: [M+Na]+1 = 420.1.
Synthesis 179
1-(4-Chlorophenyl)-Λ/-(2',4'-dihydroxy-5'-isopropylbiphenyl-3-yl)methanesulfonamide
(Compound CC-031)
Figure imgf000174_0001
Prepared using General Procedure 4. Starting material: 1-(4-Chlorophenyl)-Λ/-(4-fluoro- 5'-isopropyl-2',4'-dimethoxybiphenyl-2-yl)methanesulfonamide. 1H-NMR (DMSO-Cf6): δ 9.75 (s, NH), 9.27 (s, 1 H), 9.21 (s, 1H), 7.48-7.04 (arom, 8H), 6.94 (s, 1 H), 6.46 (s, 1H), 4.46 (s, 2H), 3.10 (sep, 1H), 1.14 (d, 6H). MS: [M+Na]+1 = 354.0.
Synthesis 180
Λ/-(4-fIuoro-2',4'-dihydroxy-5'-isopropylbiphenyl-2-yl)-4-methylbenzenesulfonamide
(Compound CC-032)
Figure imgf000174_0002
Prepared using General Procedure 4. Starting material: Λ/-(4-Fluoro-5'-isopropyl-2',4'- dimethoxybiphenyl-2-y!)-4-methylbenzenesulfonamide. 1H-NMR (DMSO-c/6): δ 10.13 (br, 1 H), 9.45 (br, 1 H), 8.54 (s, 1 H), 7.39-6.95 (arom, 7H), 6.49 (s, 1H), 6.39 (s, 1 H), 3.10 (sep, 1 H), 2.28 (s, 3H),1.14 (d, 6H). MS: [M+Na]+1 = 438.0. Svnthesis 181
1-(4-Chlorophenyl)-/V-(4-fluoro-2l,4'-dihydroxy-5'-isopropylbiphenyl-2- yl)methanesulfonamide (Compound CC-033)
Figure imgf000175_0001
Prepared using General Procedure 4. Starting material: 1-(4-Chlorophenyl)-Λ/-(4-fluoro- 5'-isopropyl-2',4'-dimethoxybiphenyl-2-yl)methanesulfonamide. 1H-NMR (DMSO-Cf6): δ 9.85 (s, 1 H), 9.45 (s, 1 H), 8.03 (s, 1 H), 7.37-6.98 (arom, 7H), 6.88 (s, 1 H), 6.50 (s, 1H). 3.10 (sep, 1 H), 1.14 (d, 6H). MS: [M-H]"1 = 448.1.
Synthesis 182
/V-(2',4'-Dihydroxy-5'-isopropylbiphenyl-3-yl)-2-(4-(dimethylamino)phenyl)acetamide
(Compound CC-034)
Figure imgf000175_0002
Prepared using General Procedure 4. Starting material: 2-(4-(Dimethylamino)phenyl)-Λ/- (5'-isopropyl-2',4'-dimethoxybiphenyl-3-yI)acetamide. 1H-NMR (DMSO-Of6): δ 10.00 (s, 1 H), 9.2 (br, 2H), 7.61 (s, 1 H), 7.54 (d, 1 H), 7.28-7.10 (arom, 4H), 6.90 (s, 1 H), 6.68 (d, 2H), 6.43 (s, 1 H), 3.48 (s, 2H), 3.10 (sep, 1 H), 2.85 (s, 6H),1.14 (d, 6H). MS: [M+H]+1 = 405.3.
Synthesis 183
3'-(4-((1 HA ,2,4-Triazol-1 -yl)methyl)benzylamino)-5-isopropylbiphenyl-2,4-diol
(Compound CC-035)
Figure imgf000175_0003
Prepared using General Procedure 4. Starting material: /V-(4-((1/-/-1 ,2,4-Triazol-1- yl)methyl)benzyl)-5'-isopropyi-2',4'-dimethoxybiphenyl-3-amine. 1H-NMR (DMSO-cfe): δ 9.12 (s, 1H), 8.92 (s, 1 H), 8.63 (s, 1 H), 7.96 (s, 1H), 7.36-7.27 (arom, 3H), 7.11 (m, 1H), 6.98 (t, 1 H), 6.81 (s, 1 H), 6.67 (m, 2H), 6.39 (s, 1H). 6.38 (masked m, 1H)1 6.15 (m, 1H), 5.39 (s, 2H), 4,24 (d, 2H), 3.08 (sβp, 1 H), 1.10 (d, 6H). MS: [M+H]+1 = 415.3.
Synthesis 184 4-lsopropyl-6-(oxazol-5-yl)benzene-1 ,3-diol (Compound AA-004)
Figure imgf000176_0001
Prepared using General Procedure 4. Starting materials: 5-(5-lsopropyl-2,4- dimethoxyphenyl)oxazole. Obtained as 90-95 % pure. 1H-NMR (DMSO-c/6): δ 9.96 (s, 1 H), 9.54 (s, 1 H), 8.25 (s, 1 H), 7.31 (s, 1 H), 7.27 (s, 1 H), 6.49 (s, 1 H), 3.11 (sep, 1 H), 1.15 (d, 6H). MS+: 220.0 (M+1 ). MS-: 218.0 (M-H).
Synthesis 185 4-(5-(4-Ethylphenyl)oxazol-4-yl)-6-isopropylbenzene-1 ,3-diol (Compound AA-001 )
Figure imgf000176_0002
Prepared using General Procedure 4. Starting material: 5-(4-Ethylphenyl)-4-(5-isopropyl- 2,4-dimethoxyphenyl)oxazole. 1H-NMR (DMSO-c/6): δ 9.39 (bs, 1H), 9.24 (bs, 1H), 8.41 (S1 1H), 7.39 (d, 2H), 7.20 (d, 2H), 6.99 (s, 1 H), 6.42 (s, 1 H), 3.09 (sep, 1H), 2.59 (q, 2H), 1.16 (t, 3H), 1.08 (d, 6H).
Synthesis 186 4-(5-(4-Fluorophenyl)oxazol-4-yl)-6-isopropylbenzene-1 ,3-diol (Compound AA-002)
Figure imgf000176_0003
Prepared using General Procedure 4. Starting material: 5-(4-Fluorophenyl)-4-(5- isopropy)-2,4-dimethoxyphenyl)oxazole. 1H-NMR (DMSO-Of6): δ 9.42 (bs, 1H), 9.26 (bs, 1 H), 8.43 (s, 1 H), 7.49 (m, 2H), 7.23 (m, 2H), 7.01 (s, 1 H), 6.45 (s, 1H), 3.10 (sep, 1H), 1.09 (d, 6H).
Synthesis 187 4-lsopropyl-6-(5-(naphthalen-2-yl)oxazol-4-yl)benzene-1 ,3-diol (Compound AA-003)
Figure imgf000177_0001
Prepared using General Procedure 4. Starting material: 4-(5-lsopropyl~2,4- dimethoxyphenyl)-5-(naphthalen-2-yl)oxazole. 1H-NMR (DMSO-c/6): δ 9.45 (s, 1 H), 9.28 (bs, 1H), 8.51 (s, 1H), 8.08 (s, 1H), 7.91-7.82 (m, 3H), 7.57-7 Al (m, 3H), 7.09 (s, 1H), 6.45 (s, 1 H), 3.11 (sep, 1 H), 1.09 (d, 6H).
Synthesis 188 4-lsopropyl-6-(4-phenyloxazol-5-yl)benzene-1 ,3-diol (Compound AA-005)
Figure imgf000177_0002
Prepared using General Procedure 4. Starting material: 5-(5-lsopropyl-2,4- dimethoxyphenylH-phenyloxazole. 1H-NMR (DMSOd6): δ 9.64 (br, 1H), 9.50 (br, 1H), 8.38 (S1 1H), 7.57 (m, 2H), 7.35-7.18 (m, 3H), 6.95 (s, 1 H), 6.49 (s, 1H), 3.09 (sep, 1H), 1.07 (d, 6H). MS: [M+H]+1 = 296.1.
Synthesis 189 4-(4-(4-Fluorophenyl)oxazol-5-yl)-6-isopropylbenzene-1 ,3-diol (Compound AA-006)
Figure imgf000177_0003
Prepared using General Procedure 4. Starting material: 4-(4-Fluorophenyl)-5-(5- isopropy!-2,4-dimethoxyphenyl)oxazole. 1H-NMR (DMSO-αfβ): δ 9.66 (br, 1H), 9.50 (br, 1 H), 8.38 (s, 1 H), 7.57 (m, 2H), 7.16 (m, 2H), 6.96 (s, 1 H), 6.49 (s, 1 H), 3.09 (sep, 1 H), 1.08 (d, 6H). MS: [M+H]+1 = 314.1. Svnthesis 190 4-(4-(4-Ethylphenyl)oxazol-5-yl)-6-isopropylbenzene-1 ,3-diol (Compound AA-007
Figure imgf000178_0001
Prepared using General Procedure 4. Starting material: 4-(4-Ethylphenyl)-5-(5-isopropyl- 2,4-dimethoxyphenyl)oxazole. 1H-NMR (DMSO-Qf6): δ 9.62 (br, 1H), 9.44 (br, 1H), 8.35 (s, 1 H), 7.48 (d, 2H), 7.14 (d, 2H), 6.95 (s, 1 H), 6.48 (s, 1 H), 3.09 (sep, 1H), 2.56 (masked q, 2H), 1.15 (t, 3H), 1.07 (d, 6H). MS: [M+H]+1 = 322.2.
Synthesis 191 4-lsopropyl-6-(5-phenyloxazol-4-yl)benzene-1 ,3-diol (Compound AA-008)
Figure imgf000178_0002
Prepared using General Procedure 10. Starting material: 4-(2,4-Bis(benzyloxy)-5- isopropylphenyl)-5-phenyloxazole. 1H-NMR (DMSO-c/6): δ 9.42 (s, 1H), 9.26 (s, 1 H), 8.44 (s, 1 H), 7.53-7.22 (arom, 5H), 7.00 (s, 1 H), 6.43 (s, 1 H), 3.09 (sep, 1 H), 1.08 (d, 6H). MS: [M+H]+1 = 296.2.
Synthesis 192 4-(5-(2-Ethylphenyl)oxazol-4-yl)-6-isopropylbenzene-1 ,3-diol (Compound AA-009)
Figure imgf000178_0003
Prepared using General Procedure 10. Starting material: 4-(2,4-Bis(benzyloxy)-5- isopropylphenyl)-5-(2-ethylphenyl)oxazole. 1H-NMR (DMSO-c/6): δ 10.12 (s, 1H), 9.42 (s, 1 H), 8.66 (s, 1 H), 7.53-7.28 (arom, 4H), 6.70 (s, 1H), 6.30 (s, 1H), 2.92 (sep, 1 H), 2.45 (masket q, 2H), 0.99 (t, 3H), 0.80 (d, 6H). MS: [M+H]+1 = 324.2. Svπthesis 193 4-lsopropyl-6-(5-(4-methoxyphenyl)oxazol-4-yl)benzene-1 ,3-dio! (Compound AA-010)
Figure imgf000179_0001
Prepared using General Procedure 10. Starting material: 4-(2,4-Bis(benzyloxy)-5- isopropylphenyl)-5-(4-methoxyphenyl)oxazole. 1H-NMR (DMSO-Cf6): δ 9.39 (s, 1H), 9.25 (s, 1 H), 8.38 (s, 1 H), 7.40 (d, 2H), 6.98 (s, 1 H), 6.95 (d, 2H), 6.41 (s, 1H), 3.75 (s, 3H), 3.09 (sep, 1 H), 1.08 (d, 6H). MS: [M+H]+1 = 326.2.
Synthesis 194 4-(5-(3,4-dimethoxyphenyl)oxazol-4-yl)-6-isopropylbenzene-1 ,3-diol (Compound AA-011 )
Figure imgf000179_0002
Prepared using General Procedure 10. Starting material: 4-(3,4-Dimethoxyphenyl)-5-(5- isopropyl~2,4-dimethoxyphenyl)oxazole. 1H-NMR (DMSO-Cf6): δ 9.39 (s, 1H), 9.27 (s, 1H), 8.38 (s, 1 H), 7.09-6.93 (arom, 4H), 6.43 (s, 1 H), 3.75 (s, 3H), 3.60 (s, 3H), 3.09 (sep, 1H), 1.08 (d, 6H). MS: [M+H]+1 = 356.2.
Synthesis 195
4-(5-(Benzo[d][1 ,3]dioxol-5-yl)oxazol-4-yl)-6-isopropylbenzene-1 ,3-diol
(Compound AA-012)
Figure imgf000179_0003
Prepared using General Procedure 10. Starting material: 5-(Benzo[d][1 ,3]dioxol-5-yl)-4- (2,4-bis(benzyloxy)-5-isopropylphenyl)oxazole. 1H-NMR (DMSO-Cf6): δ 9.41 (s, 1H), 9.27 (s, 1 H), 8.38 (s, 1 H), 7.04-6.90 (arom, 4H), 6.42 (s, 1 H), 6.02 (s, 2H), 3.09 (sep, 1H), 1.09 (d, 6H). MS: [M+H]+1 = 340.2. Svnthesis 196 2-(4-(2,4-Dihydroxy-5-isopropylphenyl)oxazol-5-yl)benzonitrile (Compound AA-013)
Figure imgf000180_0001
Prepared using General Procedure 10. Starting material: 2-(4-(2,4-Bis(benzyloxy)-5- isopropylpheny!)oxazol-5-yl)benzonitrile. 1H-NMR (DMSO-d6): δ 9.44 (s, 1H), 9.34 (s, 1 H), 8.63 (s, 1 H), 7.93 (dd, 1 H), 7.70 (dt, 1 H), 7.56 (dt, 1 H), 7.45 (dd, 1H), 7.10 (s, 1H), 6.33 (s, 1 H), 3.06 (sep, 1 H), 1.06 (d, 6H). MS: [M+H]+1 = 321.2.
Synthesis 197
4-isopropyl-6-(5-(4-(morpholinomethyl)phenyl)oxazol-4-yl)benzene-1 ,3-diol
(Compound AA-014)
Figure imgf000180_0002
Prepared using General Procedure 10. Starting material: 4-(4-(4-(2,4-Bis(benzyloxy)-5- isopropylphenyl)oxazol-5-yl)benzyl)morpholine. 1H-NMR (DMSO-Cf5): δ 9.49 (s, 1 H), 9.27 (S1 1 H), 8.49 (S, 1 H), 7.55 (d, 2H), 7.48 (d, 2H), 7.00 (s, 1 H), 6.45 (s, 1 H), 4.33 (br, 2H), 3.96 (br, 2H), 3.6 (masked, 2H), 3.24 (br, 2H), 3.10 (br. masked, 2H), 3.09 (sep, 1H), 1.07 (d, 6H). MS: [M+H]+1 = 395.2.
Synthesis 198
4-(5-(4-((1W-lmidazol-1-yl)methyl)phenyl)oxazol-4-yl)-6-isopropylbenzene-1 ,3-diol
(Compound AA-015)
Figure imgf000180_0003
Prepared using General Procedure 10. Starting material: 5-(4-((1W-lmidazol-1- yl)methyl)phenyl)-4-(2,4-bis(benzyloxy)-5-isopropylphenyl)oxazo!e. 1H-NMR (DMSO-c/6): δ 9.42 (s, 1 H), 9.24 (s, 1 H), 8.43 (s, 1 H), 7.73 (s, 1 H), 7.44 (d, 2H), 7.25 (d, 2H), 7.17 (s, 1 H), 6.99 (s, 1H), 6.90 (s, 1 H), 6.41 (s, 1 H), 5.18 (s, 2H), 3.09 (br. masked, 2H), 3.09 (sep, 1 H), 1.08 (d, 6H). MS: [M+H]+1 = 376.2.
Synthesis 199 4-(5-(4-((1 H- 1 ,2,4-Triazol-1 -yl)methyl)phenyl)oxazol-4-yl)-6-isopropylbenzene-1 ,3-diol
(Compound AA-016)
Figure imgf000181_0001
Prepared using General Procedure 10. Starting material: 5-(4-((1/-/-1 ,2,4-Triazol-1- yl)methyl)phenyl)-4-(2,4-bis(benzyloxy)-5-isopropylphenyl)oxazole. 1H-NMR (DMSO-d6): δ 9.42 (s, 1 H), 9.25 (s, 1 H), 8.65 (s, 1 H), 8.43 (s, 1 H), 7.98 (s, 1H), 7.44 (d, 2H), 7.26 (d, 2H), 7.00 (s, 1 H), 6.41 (s, 1 H), 5.40 (s, 2H), 3.09 (br. masked, 2H), 3.09 (sep, 1H), 1.08 (d, 6H). MS: [M+H]+1 = 377.2.
Synthesis 200 4-lsopropyl-6-(5-(4-(piperidin-1 -ylmethyl)phenyl)oxazol-4-yl)benzene-1 ,3-diol
(Compound AA-017)
Figure imgf000181_0002
Prepared using General Procedure 10. Starting material: 4-(2,4-Bis(benzyloxy)-5- isopropylphenyl)-5-(4-(piperidin-1-ylmethyl)phenyl)oxazole. 1H-NMR (DMSO-c/6): δ 9.42 (s, 1 H), 9.29 (s, 1H), 8.43 (s, 1 H), 7.42 (d, 2H), 7.29 (d, 2H), 6.99 (s, 1 H), 6.42 (s, 1H), 3.40 (br, 2H), 3.09 (sep, 1H), 2.31 (br, 4H), 1.49 (br, 4H), 1.37 (br, 2H), 1.07 (d, 6H). MS: [M+H]+1 = 393.3.
Synthesis 201
4-lsopropyl-6-(5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)oxazol-4-yl)benzene-1 ,3-diol
(Compound AA-018)
Figure imgf000182_0001
Prepared using General Procedure 10. Starting material: 4-(2,4-bis(benzyloxy)-5- isopropylphenyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)oxazole. 1H-NMR (DMSO- Cf6): δ 9.43 (s, 1 H), 9.24 (s, 1 H), 8.43 (s, 1 H), 7.43 (s, 2H), 7.28 (d, 2H), 6.98 (s, 1 H), 6.42 (S1 1 H)1 3.43 (s, 2H), 3.09 (sep, 1 H), 2.33 (br, 8H), 2.14 (s, 3H), 1.08 (d, 6H). MS: [M+H]+1 = 408.3.
Synthesis 202
4-lsopropyi-6-(5-(4-((4-methyl-1 ,4-diazepan-1-yl)methyl)phenyl)oxazol-4-yl)benzene-1 I3- diol (Compound AA-019)
Figure imgf000182_0002
Prepared using General Procedure 10. Starting material: 4-(2,4-Bis(benzyloxy)-5- isopropylphenyl)-5-(4-((4-methyl-1 ,4-diazepan-1 -yl)methyl)phenyl)oxazole. 1H-NMR (DMSO-Cy6): δ 9.43 (s, 1H), 9.30 (s, 1 H), 8.43 (s, 1 H), 7.43 (s, 2H), 7.30 (d, 2H), 6.98 (s, 1 H), 6.42 (s, 1 H), 3.58 (s, 2H), 3.09 (sep, 1 H), 2.65-2.54 (m, 4H), 2.5 (masked, 4H), 2.26 (s, 3H), 1.70 (m, 1H), 1.08 (d, 6H). MS: [M+H]+1 = 422.3.
Synthesis 203
4-lsopropyl-6-(5-(4-(pyrrolidin-1-ylmethyl)phenyl)oxazol-4-yl)benzene-1 ,3-diol
(Compound AA-020)
Figure imgf000182_0003
Prepared using General Procedure 10. Starting material: 4-(2,4-Bis(benzyloxy)-5- isopropylphenyl)-5-(4~(pyrrolidin-1-ylmethyl)phenyl)oxazoie. 1H-NMR (DMSO-Cf6): δ 9.44 (s, 1 H), 9.29 (s, 1 H), 8.44 (s, 1 H), 7.44 (s, 2H)1 7.33 (d, 2H), 7.00 (s, 1H), 6.44 (s, 1H), 3.67 (br, 2H), 3.09 (sep, 1 H), 1.72 (br, 4H), 1.08 (d, 6H). MS: [M+H]+1 = 379.3.
Synthesis 204
4-lsopropyl-6-(5-(4-(2-morpholinoethylamino)phenyl)oxazol-4-yl)benzene-1 ,3-diol
(Compound AA-021 )
Figure imgf000183_0001
Prepared using General Procedure 10. Starting material: 4-(4-(2,4-Bis(benzyloxy)-5- isopropylphenyl)oxazol-5-yl)-N-(2-morpholinoethyl)aniline. 1H-NMR (DMSO-Ct6): δ 9.36 (s, 1 H), 9.31 (s, 1 H), 8.31 (s, 1 H), 7.22 (s, 2H), 6.98 (s, 1H), 6.57 (d, 2H), 6.39 (s, 1H), 5.77 (br, NH), 3.58 (m, 4H), 3.15 (m, 2H), 3.08 (sep, 1 H), 2.52-2.35 (masked br, 6H), 1.06 (d, 6H). MS: [M+H]+1 = 424.3.
Synthesis 205
4-(5-(3-((1H-lmidazol-1-yl)methyl)phenyl)oxazol-4-yl)-6-isopropylbenzene-1 ,3-diol
(Compound AA-022)
Figure imgf000183_0002
Prepared using General Procedure 10. Starting material: 5-(3-((1H-lmidazol-1- yl)methyl)phenyl)-4-(2,4-bis(benzyloxy)-5-isopropylphenyl)oxazole. 1H-NMR (DMSO-Qf6): δ 9.42 (s, 1 H), 9.23 (s, 1 H), 8.44 (s, 1 H), 7.78 (s, 1 H), 7.45 (s, 1H), 7.32 (m, 2H), 7.17 (m, 2H), 6.99 (s, 1 H), 6.42 (s, 1H), 5.19 (s, 2H), 3.10 (sep, 1H), 1.09 (d, 6H). MS: [M+H]+1 = 376.2.
Svnthesis 206
4-(5-(3-((1 H-1 ,2,4-Triazol-1 -yl)methyi)phenyl)oxazol-4-yl)-6-isopropylbenzene-1 ,3-diol
(Compound AA-023)
Figure imgf000184_0001
Prepared using General Procedure 10. Starting material: 5-(3-((1H-1 ,2,4-Triazol-1- yl)methyl)phenyl)-4-(2,4-bis(benzyloxy)-5-isopropylphenyl)-oxazole. 1H-NMR (DMSO-Cf6): δ 9.42 (s, 1 H), 9.22 (s, 1 H), 8.63 (s, 1 H), 8.44 (s, 1 H), 7.96 (s, 1 H), 7.47 (s, 1 H), 7.32 (m, 2H), 7.19 (m, 1 H), 6.99 (s, 1 H), 6.42 (s, 1 H), 5.42 (s, 2H), 3.10 (sep, 1H), 1.08 (d, 6H). MS: [M+H]+1 = 377.2.
Synthesis 207
4-lsopropyl-6-(5-(3-((4-methylpiperazin-1-yl)methyl)phenyl)oxazol-4-yl)benzene-1 ,3-diol
(Compound AA-024)
Figure imgf000184_0002
Prepared using General Procedure 10. Starting material: 4-(2,4-Bis(benzyloxy)-5- isopropylphenyl)-5-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-oxa2ole. 1H-NMR (DMSO- Cf6): δ 9.39 (s, 1 H), 9.20 (s, 1 H), 8.42 (s, 1 H), 7.48-7.13 (arom, 4H), 6.98 (s, 1 H), 6.41 (s, 1 H), 3.39 (s, 2H), 3.09 (sep, 1 H), 2.27 (br, 8H), 2.13 (s, 3H), 1.08 (d, 6H). MS: [M+H]+1 = 408.3.
Synthesis 208
4-lsopropyl-6-(5-(3-(pyrrolidin-1-ylmethyl)phenyl)oxazol-4-yl)benzene-1 ,3-diol
(Compound AA-025)
Figure imgf000184_0003
Prepared using General Procedure 10. Starting material: 4-(2,4-bis(benzyloxy)-5- isopropylphenyl)-5-(3-(pyrrolidin-1-ylmethyl)phenyl)oxazole. 1H-NMR (DMSO-Cf6): δ 9.39 (s, 1 H), 9.22 (s, 1 H), 8.43 (s, 1 H), 7.45 (s, 1 H), 7.36-7.18 (arom, 3H), 6.98 (s, 1 H), 6.42 (S, 1 H), 3.52 (s, 2H), 3.09 (sep, 1 H), 2.37 (br, 4H), 1.66 (br., 4H)1 1.08 (d, 6H). MS: [M+H]+1 = 379.3.
Synthesis 209 4-lsopropy!-6-(5-(3-(pyridin-3-yl)phenyl)oxazol-4-yl)benzene-1 ,3-diol (Compound AA-026)
Figure imgf000185_0001
Prepared using General Procedure 10. Starting material: 4-(2,4-Bis(benzyloxy)-5- isopropylphenyl)-5-(3-(pyridin-3-yl)phenyl)oxazole. 1H-NMR (DMSO-d6): δ 9.46 (s, 1H), 9.36 (s, 1 H), 8.76 (d, 1 H), 8.57 (dd, 1 H), 8.49 (s, 1 H), 7.96 (m, 1 H), 7.73 (m, 1H), 7.66 (dt, 1 H), 7.59-7.51 (m, 2H), 7.46 (dd, 1 H), 7.05 (s, 1 H), 6.47 (s, 1 H), 3.09 (sep, 1 H), 1.07 (d, 6H). MS: [M+H]+1 = 373.2.
Synthesis 210 4-(2,4-Dihydroxy-5-isopropylphenyl)oxazole-5-carboxylic acid (Compound AA-027)
Figure imgf000185_0002
Prepared using General Procedure 10. Starting material: 4-(5-lsopropyl-2,4- dimethoxyphenyl)oxazole-5-carboxylic acid. 1H-NMR (DMSO-c/6): δ 10.0 (vbr. OH+COOH), 9.52 (s, 1H), 8.57 (s, 1 H), 7.44 (s, 1H), 6.36 (s, 1H), 3.09 (sep, 1H), 1.12 (d, 6H). MS: [M+H]+1 = 264.0.
Synthesis 211
Λ/-Benzyl-4-(2,4-dihydroxy-5-isopropylphenyl)oxazole-5-carboxamide
(Compound AA-028)
Figure imgf000185_0003
Prepared using General Procedure 4. Starting material: Λ/-Benzyl-4-(5-isopropyl-2,4- dimethoxyphenyl)oxazole-5-carboxamide. 1H-NMR (DMSO-c/6): δ 10.12 (bs, 1 H), 9.59 (bs, 1 H), 9.22 (bt, NH), 8.65 (s, 1H), 7.58 (s, 1H), 7.35-7.18 (arom, 5H), 6.37 (s, 1H), 4.45 (d, 2H)1 3.10 (sep, 1 H), 1.13 (d, 6H). MS: [M+H]+1 = 353.1.
Synthesis 212
/V-((1 H-lndol-5-yl)methyl)-4-(2,4-dihydroxy-5-isopropylphenyl)oxazole-5-carboxamide
(Compound AA-029)
Figure imgf000186_0001
Prepared using General Procedure 10. Starting material: Λ/-((1H-indol-5-yl)methyl)-4- (2,4-bis(benzyloxy)-5-isopropylphenyl)oxazole-5-carboxamide. 1H-NMR (DMSO-Cf6)'- δ 11.02 (bs, 1 H), 10.23 (s, 1 H), 9.59 (s, 1 H), 9.21 (bs, 1 H), 8.63 (s, 1 H), 7.56 (s, 1H), 7.45 (s, 1 H), 7.31 (m, 2H), 7.05 (d, 1 H), 6.38 (s, 1 H), 6.38 (masked m, 1H), 4.51 (d, 2H), 3.10 (sep, 1 H), 1.13 (d, 6H). MS: [M+H]+1 = 392.2.
Synthesis 213
4-(2,4-Dihydroxy-5-isopropylphenyl)-Λ/-(4-(/V,Λ/-dimethylamino)benzyl)oxazole-5- carboxamide (Compound AA-030)
Figure imgf000186_0002
Prepared using General Procedure 10. Starting material: 4-(2,4-bis(benzyloxy)-5- isopropyIphenyl)-/V-(4-(/V,/V-dimethylamino)benzyl)oxazole-5-carboxamide. 1H-NMR (DMSO-Cf6): δ 10.2 (s, 1H), 9.59 (s, 1 H), 9.13 (bs, 1 H), 8.63 (s, 1H), 7.54 (s, 1H), 7.13 (d, 2H), 6.65 (s, 2H), 6.38 (s, 1 H), 4.32 (d, 2H), 3.10 (sep, 1 H), 2.84 (s, 6H), 1.13 (d, 6H). MS: [M+H]+1 = 396.1. Synthesis 214
Rac-4-(2,4-Dihydroxy-5-isopropylphenyl)-N-(4-(1-hydroxyethyl)benzyl)oxazole-5- carboxamide (Compound AA-031)
Figure imgf000187_0001
Prepared using Genera! Procedure 10. Starting material: Λ/-(4-Acetylbenzyl)-4-(2,4- bis(benzyloxy)-5-isopropylphenyl)oxazole-5-carboxamide. 1H-NMR (DMSO-Cf6): δ 10.14 (s, OH), 9.60 (s, OH), 9.22 (t, NH), 8.64 (s, 1 H), 7.57 (s, 1 H), 7.25 (m, 4H), 6.38 (s, 1H), 5.08 (d, OH), 4.67 (m, 1 H), 4.42 (d, 2H), 3.10 (sep, 1 H), 1.28 (d, 3H), 1.13 (d, 6H). MS: [M+Na]+1 = 419.2.
Synthesis 215
/V-(4-(4-(2,4-Dihydroxy-5-isopropylphenyl)oxazol-5-yl)phenyl)-N-(2- morpholinoethyl)acetamide (Compound AA-032)
Figure imgf000187_0002
Prepared using General Procedure 10. Starting material: Λ/-(4-(4-(2,4-Bis(benzyloxy)-5- isopropylphenyl)oxazol-5-yl)phenyl)-Λ/-(2-morpholinoethyl)acetamide. 1H-NMR (DMSO- Cf6): δ 9.46 (s, 1 H), 9.32 (s, 1 H), 8.47 (s, 1 H), 7.53 (d, 2H), 7.34 (m, 3H), 6.99 (s, 1H), 6.45 (S, 1 H), 3.72 (t, 2H), 3.49 (m, 4H), 3.10 (sep, 1H), 2.37-2.23 (m, 6H), 1.74 (bs, 3H), 1.08 (s, 6H). MS: [M+H]+1 = 466.3.
Svnthesis 216
4-lsopropyl-6-(5-(4-(2-morpholinoethoxy)phenyl)oxazol-4-yl)benzene-1,3-diol
(Compound AA-033)
Figure imgf000188_0001
Prepared using General Procedure 10. Starting material: 4-(2-(4-(4-(2,4-Bis(benzyloxy)- 5-isopropylpheny!)oxazol-5-yl)phenoxy)ethyl)morpholine. 1H-NMR (DMSO-Cf6): δ 9.39 (bs, 1 H), 9.25 (bs, 1 H), 8.38 (s, 1 H), 7.39 (d, 2H), 6.98 (s, 1 H), 6.95 (d, 2H), 6.41 (s, 1 H) 4.08 (t, 2H), 3.56 (m, 4H), 3.09 (sep, 1 H), 2.67 (m, 2H), 2.45 (masked m, 4H), 1.08 (d, 6H). MS: [M+H]+1 = 425.3.
Biological Methods
Primary Assay : ATPase Activity
Briefly, this assay relies on the enzymatic hydrolysis of ATP to ADP + Pi (inorganic phosphate) by the yeast homologue of Hsp90, Hsp82. The level of Pi is detected by malachite green reagent. Measurement of Pi formation in the presence and absence of of a test compound provides an indication of that compounds ability to inhibit Hsp82 activity.
Hsp82 was recombinant^ expressed as a GST-tagged protein from E. CoIi. Hsp82 was incubated for 3 hours in assay buffer (50 mM HEPES-KOH, pH 7.5, 150 mM KAc, 8 mM MgAc, 0.25 mg/ml BSA) with 500 mM ATP in the presence of test compound. The extent of Pi formation was determined by addition of 100 μL malachite green solution (0.2% (w/v), ammonium molybdate, 0.7 M HCI, 0.03% (w/v) malachite green, 0.05% (v/v) Triton X-100) followed by 10 μL 37% (w/v) sodium citrate.
Expression/purification of GST-Hsp82
Rossetta pLysS (Novagen Inc) transformed with pGEX6P-Hsp82, were grown in Lennox Broth (supplemented with 100 μ/mL Ampicillin, 30 μg/mL Chloramphenical) at 37°C with agitation. At 0.70D6oo. the cultures were cooled to 300C and induced with 0.5 μM IPTG for 3 hours. The cultures were harvested by centrifugation (Sorvall GS3 rotor, ΘOOOrpm, 10 minutes). Each 1 L pellet was re-suspended in 20 mL ice cold phosphate-buffered saline (PBS) + 1% Tween + 1x complete protease inhibitors (Roche), 200 mM KCI,
10 mM DTT and incubated on ice for 5 minutes. The cell suspensions were sonicated at maximum power 4 x 10 second bursts on ice. Triton was added to a final concentration of 1% (v/v) and the lysates centrifuged (Sorvall SS34 rotor, 20,000 rpm, 20 minutes, 40C). The supematants were recovered and added to 2 mL of 50% v/v GST-Sepharose-4B beads in PBS + 1% Tween (PBST) and incubated on a rotating wheel at 4°C for 1 hour. The GST-beads were washed twice in 25 mL of PBST. Protein was eluted 3 times in 1 mL of 50 mM Tris, pH 8, 10 mM reduced glutathione. Each elution was performed for 5 minutes at 4°C on a rotating wheel.
Assay method
GST-Hsp82 was incubated with 500 mM ATP along with appropriate dilutions of candidate compounds (5 μL) in a total volume of 50 μL of assay buffer in clear 96 well plates (nunc polysorp). The reaction was carried out at 370C for 3 hours, after which 100 μL of malachite green solution (prepared 30 minutes earlier) was added followed by 10 //L of 37% (w/v) sodium citrate. The colour reaction was allowed to develop for 10 minutes and then measured on a scanning multi-well spectrophotometer at 690 nm.
Percent activity (% activity) for each test compound was calculated as:
% activity = { (Sc - B) / (S0 - B) } x 100
wherein Sc denotes signal measured in the presence of enzyme and the compound being tested, S° denotes signal measured in the presence of enzyme but in the absence of the compound being tested, and B denotes the background signal measured in the absence of both enzyme and compound being tested. The IC50 corresponds to the concentration which achieves 50% activity.
Secondary Assays
Compounds with Hsp90 inhibition activity, as determined using the primary assay, were subsequently evaluated using one or more secondary cell-based assays.
Secondary Assay: Her-2 Degradation Assay
Compounds which inhibit intracellular Hsp90 will result in the degradation of Hsp90 client proteins. HER2 is a well characterized client protein of Hsp90 and has been reliably shown to be degraded in response to Hsp90 inhibitors. This assay measures the quantity of extracellular HER2 present on MCF7 breast carcinoma cells by fluorescence.
MCF7 breast carcinoma cells (ATCC) were grown in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum (FBS), 100 units/mL penicillin and 0.1 mg/mL streptomycin plated in 6-well plates (400,000 cells/well/2mL). 24 hours later (cells were 65-70% confluent), test compounds were added at appropriate concentrations and the radicicol control at 1 μM and incubated overnight for 16 hours. The wells were washed with 1 mL of PBS, and 500 μL trypsin was added to each well. After trypsinization was complete, 1 mL of Media was added to each well. The cells were transferred to 1.5 mL eppendorf tubes and centrifuged at 6000 rpm (Eppendorf benchtop centrifuge) for 5 minutes. The supernatant was drawn off and discarded, and the cell pellet was washed twice in PBA buffer (PBS + 0.2% w/v BSA and 0.2% w/v sodium azide). The cells were then re-suspended in 100 μL PBA + PE conjugated anti-Her-2/neu antibody (Becton Dickinson, #340552, 1/20, final concentration 0.25 μg/mL) at 4°C on a rotating wheel for 1 hour. The cells were washed twice with 1 mL of PBA buffer, resuspended in 500 μL of FACS flow buffer (BD Biosciences), and transferred to FACSCAN tubes. Samples were analyzed using a FACScan flow cytometer (Becton Dickinson, San Jose, CA) configured to emit 488 nm-light to excite the phycoerythrin fluorochrome. 30,000 events were collected per sample. A fluorescence histogram was generated and the Geometric mean (GE) of each sample was determined using Cellquest software. Cells were always incubated with DMSO as untreated controls, since the compounds were re-suspended in DMSO and 1 μM radicicol as the positive control.
Compound activity was expressed as the leftwards fold shift in the GE relative to the untreated control:
activity = Sc/ S°
wherein Sc denotes GE measured in the presence of enzyme and the compound being tested, S0 denotes signal measured in the untreated control.
Secondary Assay: HCT116 WST-1 Assay
The following cell line was used: HCT116 - Human colorectal cancer cell line (ATCC CCL-247). Cells were cultured, exposed to candidate compounds, and incubated for a time, and the number of viable cells was then assessed using the Cell Proliferation Reagent WST-1 from Boehringer Mannheim (Cat. No. 1 644 807), described below.
Cells were plated in 96-well plates at 3-10 x 103 cells/well in 100 μl_ of culture medium. The following day, different concentrations of candidate compounds were added and the cells incubated at 370C for 48 hours. Subsequently, 10 μL/well of WST-1 reagent was added and the cells re-incubated for 1 hour. After the incubation time, absorbance was measured.
WST-1 is a tetrazolium salt which is cleaved to formazan dye by cellular enzymes. An expansion in the number of viable cells results in an increase in the overall activity of mitochondrial dehydrogenases in the sample. This augmentation in the enzyme activity leads to an increase in the amount of formazan dye formed, which directly correlates to the number of metabolically active cells in the culture. The formazan dye produced is quantified by a scanning multi-well spectrophotometer by measuring the absorbance of the dye solution at 450 nm wavelength (reference wavelength: 690 nm).
Percent activity (% activity) in reducing the number of viable cells was calculated for each test compound as:
% activity = { (Sc - B) / (S° - B) } x 100
wherein Sc denotes signal measured in the presence of the compound being tested, S0 denotes signal measured in the absence of the compound being tested, and B denotes the background signal measured in blank wells containing medium only. The IC50 corresponds to the concentration which achieves 50% activity. IC50 values were calculated using the software package Prism 4.0 (GraphPad Software Inc., San Diego, CA).
Biological Data
The following compounds were tested in the "ATPase Activity" assay described above: AA-001 , AA-002, AA-003, AA-004, BB-001 , BB-002, CC-003, CC-012, CC-014, DD-004, DD-009.
The following compounds have a "% inhibition at 100 μM" of at least 5%: AA-001, AA-002, AA-003, BB-001 , BB-002, CC-003, CC-012, CC-014, DD-004, DD-009.
The following compounds have a "% inhibition at 100 μM" of at least 10%: AA-002, AA-003, BB-001 , CC-003, CC-012, CC-014, DD-004, DD-009.
One compound, compound AA-002, has a "% inhibition at 100 μM" of 16.2%. One compound, compound BB-002, has a "% inhibition at 100 μM" of 7.5%. One compound, compound CC-014, has a "% inhibition at 100 μM" of 30.2%. One compound, compound DD-009, has a "% inhibition at 100 μM" of 16.4%.
The following compounds were tested in the Ηer-2 Degradation Assay" assay described above: AA-002, AA-004, AA-009, AA-015, AA-017, BB-002, BB-003, CC-002, CC-011, CC-012, CC-013, CC-014, DD-006, DD-008, EE-001.
The following compounds have a fold-shift of GE, at 1 μM, of at least 5: AA-015, AA-017.
The following compounds have a fold-shift of GE, at 10 μM, of at least 1.3: AA-002, AA-009, BB-002, BB-003, CC-012, CC-013, CC-014. DD-008.
The following compounds have a fold-shift of GE, at 10 μM, of at least 2: AA-002, BB-002, CC-013, CC-014.
The following compounds have a fold-shift of GE, at 50 μM, of at least 1.5: AA-004, CC-002, CC-011 , DD-006, EE-001. The following compounds have a fold-shift of GE, at 50 μM, of at least 2: AA-004, CC-002, DD-006.
The ability of several compounds to inhibit heat shock protein 90 (HSP90) activity was determined using the "HCT116 WST- 1 Assay" described above.
The following compounds were tested: AA-O01 , AA-005, AA-006, AA-007, AA-008, AA-009, AA-013, AA-015, AA-016, AA-017, AA-018, AA-019, AA-020, AA-021, AA-022, AA-023, AA-024, AA-029, AA-030, AA-031 , AA-032, AA-033, BB-002, BB-005, BB-007, BB-008, CC-002, CC-012, CC-013, CC-014, DD-015, DD-019, DD-020.
All of those compounds have an IC50 of less than 50 μM.
The following compounds have an IC50 of 10 μM or more, and less than 50 μM: AA-001 , AA-009, AA-022, AA-029, AA-030, AA-031 , CC-002, CC-013, DD-015, DD-019, DD-020.
The following compounds have an IC50 of less than 10 μM: BB-002, CC-012, CC-014.
The following compounds have an IC50of 1 μM or more, and of less than 10 μM: AA-005, AA-006, AA-007, AA-008, AA-013, AA-018, AA-019, AA-021 , AA-023, AA-024, AA-033, BB-002, BB-007, BB-008, CC-012, CC-014.
The following compounds have an IC50 of less than 1 μM: AA-015, AA-016, AA-017, AA-020, AA-032, BB-005.
One compound, compound AA-001 , has an IC50 value of 24.0 μM. One compound, compound AA-005, has an IC50 value of 1.6 μM
One compound, compound BB-002, has an IC50 value of 5.3 μM.
One compound, compound BB-007, has an IC50 value of 3.8 μM.
One compound, compound CC-012, has an 1C50 value of 3.5 μM.
One compound, compound CC-014, has an IC50 value of 5.9 μM. One compound, compound DD-015, has an IC50 value of 46.1 μM. The foregoing has described the principles, preferred embodiments, and modes of operation of the present invention. However, the invention should not be construed as limited to the particular embodiments discussed. Instead, the above-described embodiments should be regarded as illustrative rather than restrictive, and it should be appreciated that variations may be made in those embodiments by workers skilled in the art without departing from the scope of the present invention.
REFERENCES
A number of patents and publications are cited above in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
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Claims

CLAlMS
1. A compound selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000197_0001
wherein:
-X1- is independently a covalent single bond or -X1L-; -X2- is independently a covalent single bond or -X2L-;
-A1- is independently -A1A-;
-A2 is independently -A2A, -H, or -F; except that if: -X2- is -X2L-, then: -A2 is -A2A;
each of -X1L- and -X2L- is independently:
-RL-,
-C(=O)-, -RL-C(=O)-,
-C(=O)-RL-, -RL-C(=O)-RL-,
-O-RL-C(=O)-, -C(=O)-RL-O-,
-C(=O)-RL-S-, -O-RL-C(=O)-RL-O,
-NH-S(=O)2-, -NRA-S(=O)2-, -RL-NH-S(=O)2-, -RL-NRA-S(=O)2-,
-NH-S(=O)2-RL-, -NRA-S(=O)2-RL-, -RL-NH-S(=O)2-RL-, -RL-NRA-S(=O)2-RL-,
-S(=O)2-NH-, -S(=O)2-NRA-, -RL-S(=O)2-NH-, -RL-S(=O)2-NRA-,
-C(=O)-NH-RL-, -C(=O)-NRA-RL-, -RL-S(=O)2-NH-RL-, -RL-S(=O)2-NRA-RL-, -O-, -RL-O-, -O-RL-, -RL-O-RL-,
-NH-C(=O)-, -NRA-C(=O)-, -RL-NH-C(=O)-, -RL-NRA-C(=O)-, -NH-C(=O)-RL-, -NRA-C(=O)-RL-, -RL-NH-C(=O)-RL-, -RL-NRA-C(=O)-RL-,
-C(=O)-NH-, -C(=O)-NRA-, -RL-C(=O)-NH-, -RL-C(=O)-NRA-, -C(=O)-NH-RL-, -C(=O)-NRA-RL-, -RL-C(=O)-NH-RL-, -RL-C(=O)-NRA-RL-,
-NH-C(=O)-NH-, -NRA-C(=O)-NH-, -NH-C(=O)-NRA-, -NRA-C(=O)-NRA-,
-RL-NH-C(=O)-NH-, -RL-NRA-C(=O)-NH-,
-RL-NH-C(=O)-NRA-, -RL-NRA-C(=O)-NRA-,
-NH-C(=O)-NH-RL-, -NRA-C(=O)-NH-RL-, -NH-C(=O)-NRA-RL-, -NRA-C(=O)-NRA-RL-,
-RL-NH-C(=O)-NH-RL-, -RL-NRA-C(=O)-NH-RL-, -RL-NH-C(=O)-NRA-RL-, -RL-NRA-C(=O)-NRA-RL-,
-NH-, -NR\ -RL-NH-, -RL-NRA-,
-NH-R1-, -NRA-RL-, -RL-NH-RL-, -RL-NRA-RL-,
-C(=O)-O- -RL-C(=O)-O-,
-C(=O)-O-RL-, -RL-C(=O)-O-RL-,
-O-C(=O)-, -RL-O-C(=O)-,
-O-C(=O)-RL-, -RL-O-C(=O)-RL-,
-S(=O)-, -RL-S(=O)-, -S(=O)-RL-,
-RL-S(=O)-RL-,
-S(=O)2-, -RL-S(=O)2-, -S(=O) 2-RL-, or
-RL-S(=O)2-RL-;
except that -X1L- is not:
-C(=O)-NH-, -C(=O)-NRA-, -C(=O)-NH-RL-, or -C(=O)-NRA-RL-;
wherein:
each -RA is independently -RM, -RAB, or -RAC; each -RM is independently saturated aliphatic C1-6alkyl; each -RAB is independently aliphatic C2-6alkenyl; each -RAC is independently saturated C3-6cycloalkyl; and each -RM, -RAB, and -RAC is independently unsubstituted or substituted with one or more substituents selected from -F1 -Cl, -Br, -I, -OH, -OR, -NH2, -NHR, -NR2,
-NHC(=O)R, -NRC(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NH2) -C(=O)NHR, and -C(=O)NR2, wherein each R is independently saturated aliphatic C^alkyl, phenyl, or benzyl;
each -RL- is independently -Ru-, -RLB-, -RLC-, -RLA-RLC-, -R^-R^-, or
each -RLA is independently saturated aliphatic Ci-βalkylene; each -RLB is independently aliphatic C2_6alkenylene; each -RLC is independently saturated C3-6cycloalkylene; and each -RLA, -RLB, and -RLC is independently unsubstituted or substituted with one or more substituents selected from -F, -Cl, -Br, -I, -OH, -OR, -NH2, -NHR, -NR2, -NHC(=O)R, -NRC(=O)R, -C(=O)OR, -OC(=O)R, -C(=O)NH2, -C(=O)NHR, and
-C(=O)NR2, wherein each R is independently saturated aliphatic C1-4alkyl, phenyl, or benzyl;
and wherein:
-A1A- is independently -A1AC- or -A1AH-; -A1AC- is independently C6.10carboarylene; -A1AH- is independently C5-12heteroarylene; and each -A1AG- and each -A1AH- is independently unsubstituted or substituted with one or more substituents -Q1;
-A2A is independently -A2^ or -A2AH; -A2AC is independently C6-iocarboaryl; -A2AH is independently C5-12heteroaryl; and each -A2AC and each -A2AH is independently unsubstituted or substituted with one or more substituents -Q2;
wherein:
each -Q1 and each -Q2 is independently:
-F, -Cl, -Br, -I,
-R1A1,
-CF3, -OCF3,
-OH, -L1A-OH, -O-L1A-OH, -OR1A1, -L1A-OR1A1, -O-L1A-OR1A1,
-SH, -SR1A1,
-CN,
-NO2,
-NH2, -NHR1A1, -NR1A1 2, -NR1A2R1A3, -L1A-NH2, -L1A-NHR1A1 , -L1A-NR1A1 2, -L1 A-NR1 A2R1A3,
-O-L1A-NH2, -O-L1A-NHR1A1, -O-L1A-NR1A1 2, -O-L1A-NR1A2R1A3,
-NH-L1A-NH2, -NH-L1A-NHR1A1, -NH-L1A-NR1A1 2, -NH-L1A-NR1A2R1A3,
-NR1A1-L1A-NH2, -NR1A1-L1A-NHR1A1, -NR1A1-L1A-NR1A1 2, -NR1A1-L1A-NR1A2R1A3,
-C(=O)OH, -C(=O)OR1A1, -OC(=O)R1A1, -C(O)NH2, -C(=O)NHR1A1, -C(=O)NR1A1 2, -C(=O)NR1A2R1A3,
-NHC(=O)R1A1, -NR1A1C(=O)R1A1,
-C(=O)NHOR1A\ -C(=O)NR1A1OR1A1,
-NHC(=O)R1A1 , -NR1A1C(=O)R1A1 ,
-NHC(=O)OR1A1, -NR1A1C(=O)OR1A1, -OC(=O)NH2, -OC(=O)NHR1A1, -OC(=O)NR1A1 2, -OC(=O)NR1A2R1A3,
-C(=O)R1A1,
-NHC(=O)NH2, -NHC(=O)NHR1A1,
-NHC(=O)NR1A1 2, -NHC(=O)NR1A2R1A3,
-NR1A1C(=O)NH2, -NR1A1C(=O)NHR1A1, -NR1A1C(=O)NR1A1 2, -NR1A1C(=O)NR1A2R1A3,
-NHS(=O)2R1A1, -NR1A1S(=O)2R1A1, -S(=O)2NH2, -S(=O)2NHR1A1, -S(=O)2NR1A1 2, -S(=O)2NR1A2R1A3, -S(=O)R1A1, -S(=O)2R1A1, -OS(=O)2R1A1, or -S(=O)2OR1A1;
wherein:
each -L1A- is independently saturated aliphatic C^alkylene; in each group -NR1A2R1A3, -R1A2 and -R1A3, taken together with the nitrogen atom to which they are attached, form a 4-, 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 -R1A1 is independently:
-RiEi1 _p1B2 _p1B3 _p1β4 -P1 B5 -R1 B6 -R1 B7 -R1B8 -L1B-R1B4, -L1B-R1B5, -L1B-R1B6, -L1B-R1B7, or -L1B-R1B8; wherein: each -R1B1 is independently saturated aliphatic C1-6alkyl; each -R1B2 is independently aliphatic C2-6alkenyl; each -R183 is independently aliphatic C2.6alkynyl; each -RtB4 is independently saturated C3.6cycloalkyl; each -R1B5 is independently C3-6cycloalkenyl; each -R1B6 is independently non-aromatic C3-7heterocyclyl; each -R1B7 is independently C6-iocarboaryl; each -R1B8 is independently C5-ioheteroaryl; each -L1B- is independently saturated aliphatic C1-3alkylene; and wherein: each -R1B4, -R1B5, -R1B6, -R1B7, and -R1B8 is optionally substituted, for example, with one or more substituents -R1C1 and/or one or more substituents -R1C2, and each -R1B1, -R1B2, -R1B3, and -L1B- is optionally substituted, for example, with one or more substituents -R1C2, wherein: each -R1C1 is independently saturated aliphatic d^alkyl, phenyl, or benzyl; each -R1C2 is independently:
-F, -Cl, -Br, -I, -CF3, -OCF3,
-OH, -L1D-OH, -O-L1D-OH, -OR1D1, -L1D-OR1D1, -O-L1D-OR1D1, -SH, -SR1D1, -CN, -NO2,
-NH2, -NHR1D1, -NR1D12, -NR102R103, -L1D-NH2, -L1D-NHR1D1, -L1D-NR1D1 2l or -L1D-NR1D2R1D3,
-O-L1D-NH2, -O-L1D-NHR1D1, -O-L1D-NR1D1 2| -O-L1D-NR1D2R1D3,
-NH-L1D-NH2, -NH-L1D-NHR1D1, -NH-L1D-NR1D1 2, -NH-L1D-NR1D2R1D3,
-NR1D1-L1D-NH2, -NR1D1-L1D-NHR1D1, -NR1D1-L1D-NR1D1 2, -NR1D1-L1D-NR1D2R1D3,
-C(=O)OH, -C(=O)OR1D1, -OC(=O)R101,
-C(=O)R1D1,
-C(=O)NH2, -C(=O)NHR1D1, -C(=O)NR1D1 2, -C(=O)NR1D2R1D3,
-NHC(=O)R1D1, -NR1D1C(=O)R1D1, -S(=O)2NH2, -S(=O)2NHR1A1 , -S(=O)2NR1A1 2, -S(=O)2NR1A2R1A3, or
-S(=O)2R1A1; wherein: each -R1D1 is independently saturated aliphatic C^alkyl, phenyl, or benzyl; each -L1D- is independently saturated aliphatic C1-5alkylene; and in each group -NR102R103, -R102 and -R103, taken together with the nitrogen atom to which they are attached, form a 4-, 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;
and additionally, two adjacent -Q1 groups, if present, may together form -0-CH2-O- or -0-CH2CH2-O-; and additionally, two adjacent -Q2 groups, if present, may together form -0-CH2-O- or -0-CH2CH2-O-.
except that:
if -X1- is a covalent single bond, then -A1- 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-6~thione;
2-0X0-1 ,2,3,4-tetrahydropyrimidine or substituted 2-oxo-1, 2,3,4- tetrahydropyrimidine;
2-amino-1 ,2,3,4-tetrahydropyrimidine or substituted 2-amino-1 ,2,3,4- tetrahydropyrimidine; pyrazol-diyl or substituted pyrazol-diyl;
1 ,3-dihydro-imidazol-2-one-diyl or substituted 1 ,3-dihydro-imidazol-2-one-diyl;
1 ,3-dihydro-imidazol-2-thione-diyl or substituted 1 ,3-dihydro-imidazol-2-thione-diyl;
1 ,2,4-triazol-diyl or substituted 1 ,2,4-triazol-diyl;
2,4-dihydro-[1 ,2,4]triazol-3-one-diyl or substituted 2,4-dihydro- [1 ,2,4]triazol-3-one-diyl; 2l4-dihydro-[1 ,2,4]triazol-3-thione-diyl or substituted 2,4-dihydro- [1 ,2,4]triazol-3-thione-diyl; or isoxazol-diyl or substituted isoxazol-diyl;
and with the proviso that the compound is not a compound selected from the following compounds, and salts, hydrates, and solvates thereof: (P-001) 4-(2,4-Dihydroxy-5-isopropyl-phenyl)-6-isopropyl-3-methyl- [1 ,2]benzoquinone;
(P-002) (2,4-Dihydroxy-5-isopropyl-phenyl)-phenyl-methanone; and (P-003) 4-[1 -(3-Bromo-phenyl)-ethyl]-6-isopropyl-benzene-1 ,3-diol.
2. A compound according to claim 1 , wherein -X1- is independently a covalent single bond.
3. A compound according to claim 1 , wherein -X1- is independently -X1L-.
4. A compound according to any one of claims 1 to 3, wherein -X2- is independently a covalent single bond.
5. A compound according to any one of claims 1 to 3, wherein -X2- is independently -X2L-.
6. A compound according to any one of claims 1 to 5, wherein -A2 is independently -A2A or -H.
7. A compound according to any one of claims 1 to 5, wherein -A2 is independently -A2A.
8. A compound according to any one of claims 1 to 5, wherein -A2 is independently -H or -F.
9. A compound according to any one of claims 1 to 5, wherein -A2 is independently -H.
10. A compound according to claim 1 , wherein the group -X1-A1-X2-A2 is independently:
_X1L-A1A-X2L-A2A, 5 _χiL_A1A-A2A,
_χ1L-A 1A-H, -X1L-A1A-F, -A1A-X2L-A2A, -A1A-A2A, 0 -A1A-H, or
-A1A-F.
1 1. A compound according to claim 1 , wherein the group -X1-A1-X2-A2 is independently: 5 -X1L-A1A-H,
_X 1L-A1A-F,
_A1A_χ2L_A2A
-A1A-A2A, -A1A-H, or 0 -A1A-F.
12. A compound according to claim 1 , wherein the group -X1-A1-X2-A2 is independently -X1L-A1A-H or -X1L-A1A-F. 5
13. A compound according to claim 1 , wherein the group -X1-A1-X2-A2 is independently -X1L-A1A-H.
14. A compound according to claim 1 , wherein the group -X1-A1-X2-A2 is independently -A1A-X2L-A2A. 0
15. A compound according to claim 1 , wherein the group -X1-A1-X2-A2 is independently -A1A-A2A.
16. A compound according to claim 1 , wherein the group -X1-A1-X2-A2 is5 independently -A1A-H or -A1A-F.
17. A compound according to claim 1 , wherein the group -X1-A1-X2-A2 is independently -A1A-H. Q * * *
18. A compound according to any one of claims 1 to 17, wherein -X1L-, if present, is independently:
-RL-, -C(=O)-,
5 -RL-C(=O)-,
-C(=O)-RL-, -RL-C(=O)-RL-, -O-RL-C(=O)-, -C(=O)-RL-O-, 0 -C(=O)-RL-S-, or
-O-RL-C(=O)-RL-O,
19. A compound according to any one of claims 1 to 17, wherein -X1L-, if present, is independently: 5 -RL-,
-C(=O)-,
-C(=O)-RL-,
-C(=O)-RL-S-, or
-C(=O)-RL-O-. 0
20. A compound according to any one of claims 1 to 17, wherein -X1L-, if present, is independently:
-C(=O)-, -C(=O)-RL-, 5 -C(=O)-RL-S-, or
-C(=O)-RL-O-.
21. A compound according to any one of claims 1 to 17, wherein -X1L-, if present, is independently -C(=O)-. 0
22. A compound according to any one of claims 1 to 17, wherein -X1L-, if present, is independently -C(=O)-RL-.
23. A compound according to any one of claims 1 to 17, wherein -X1L-, if present,5 is independently -C(=O)-RL-O-.
24. A compound according to any one of claims 1 to 17, wherein -X1L-, if present, is independently -RL-. Q * * *
25. A compound according to any one of claims 1 to 24, wherein -X2L-, if present, is independently:
-RL-,
-NH-S(=O)2-, -NRA-S(=O)2-,
-RL-NH-S(=O)2-, -RL-NRA-S(=O)2-,
-NH-S(=O)2-RL-, -NRA-S(=O)2-RL-,
-RL-NH-S(=O)2-RL-, -RL-NRA-S(=O)2-RU-,
-SC=O)2-NH-, -S(=O)2-NRA-,
-RL-S(=O)2-NH-, -RL-S(=O)2-NRA-,
-C(=O)-NH-RL-, -C(=O)-NRA-RL-,
-RL-S(=O)2-NH-RL-, -RL-S(=O)2-NRA-RL-,
-O-,
-RL-O-,
-O-RL-,
-RL-O-RL-,
-NH-C(=O)-, -NRA-C(=O)-,
-RL-NH-C(=O)-, -RL-NRA-C(=O)-,
-NH-C(=O)-RL-, -NRA-C(=O)-RL-,
-RL-NH-C(=O)-RL-, -RL-NRA-C(=O)-RL-,
-C(=O)-NH-, -C(=O)-NRA-,
-RL-C(=O)-NH-, -RL-C(=O)-NRA-,
-C(=O)-NH-RL-, -C(=O)-NRA-RL-,
-RL-C(=O)-NH-RL-, or -RL-C(=O)-NRA-RL-.
26. A compound according to any one of claims 1 to 24, wherein -X2L-, if present, is independently:
-RL-,
-NH-S(=O)2-, -NRA-S(=O)2-,
-RL-NH-S(=O)2-, -RL-NRA-S(=O)2~,
-NH-S(=O)2-RL-, -NRA-S(=O)2-RL-,
-RL-NH-S(=O)2-RL-, -RU-NRA-S(=O)2-RL-,
-O-, -RL-O-, -O-RL-, -RL-O-RL-,
-C(=O)-NH-, -C(=O)-NRA-,
-RL-C(=O)-NH-, -RL-C(=O)-NRA-, -C(=O)-NH-RL-, -C(=O)-NRA-RL-, -RL-C(=O)-NH-RL-, or -RL-C(=O)-NRA-RL-.
27. A compound according to any one of claims 1 to 24, wherein -X2L-, if present, is independently:
-RL-,
-NH-S(=O)2-, -NRA-S(=O)2-, -NH-S(=O)2-RL-, -NRA-S(=O)2-RL-, -RL-O-,
-C(=O)-NH-, -C(=O)-NRA-, -C(=O)-NH-RL-, or -C(=O)-NRA-RL-.
28. A compound according to any one of claims 1 to 24, wherein -X2L-, if present, is independently -RL-.
29. A compound according to any one of claims 1 to 24, wherein -X2L-, if present, is independently -NH-S(=O)2-, -NRA-S(=O)2-, NH-S(=O)2-RL- or -NRA-S(=O)2-RL-.
30. A compound according to any one of claims 1 to 24, wherein -X2L-, if present, is independently -NH-S(=O)2- or -NRA-S(=O)2-.
31. A compound according to any one of claims 1 to 24, wherein -X2L-, if present, is independently -NH-S(=O)2-RL- or -NRA-S(=O)2-RL-.
32. A compound according to any one of claims 1 to 24, wherein -X2L-, if present, is independently -RL-O-.
33. A compound according to any one of claims 1 to 24, wherein -X2L-, if present, is independently -C(=O)-NH- or -C(=O)-NRA-.
34. A compound according to any one of claims 1 to 24, wherein -X2L-, if present, is independently -C(=O)-NH-RL- or -C(=O)-NRA-RL-.
* * *
35. A compound according to any one of claims 1 to 34, wherein each -RL-, if present, is independently -RLA-, -RLB-, or -RLC-.
36. A compound according to any one of claims 1 to 34, wherein each -RL-, if present, is independently -RUA-.
37. A compound according to any one of claims 1 to 39, wherein each -RL-, if present, is independently unsubstituted.
38. A compound according to any one of claims 1 to 36, wherein each -R1A if present, is independently saturated aliphatic Ci.4alkylene.
39. A compound according to any one of claims 1 to 36, wherein each -R1A if present, is independently saturated aliphatic Ci-3alkylene.
40. A compound according to any one of claims 1 to 36, wherein each -R1A if present, is independently saturated aliphatic Ci.2alkylene.
41. A compound according to any one of claims 1 to 34, wherein each -RL-, if present, is independently -CH2- or -CH2CH2-.
42. A compound according to any one of claims 1 to 34, wherein each -RL-, if present, is independently -CH2-.
* * *
43. A compound according to any one of claims 1 to 42, wherein each -RΛ, if present, is independently -RM or -RAB.
44. A compound according to any one of claims 1 to 42, wherein each -RA, if present, is independently -RM.
45. A compound according to any one of claims 1 to 42 wherein each -RA, if present, is independently saturated aliphatic C^alkyl.
46. A compound according to any one of claims 1 to 42, wherein each -RA, if present, is independently -Me or -Et.
47. A compound according to any one of claims 1 to 42, wherein each -RA, if present, is independently -Me.
48. A compound according to any one of claims 1 to 47, wherein -A1A-, if present, is independently -A1AC-.
49. A compound according to any one of claims 1 to 48, wherein -A1AG-, if present, is independently phenyfene or naphth-diyl, and is optionally substituted.
50. A compound according to any one of claims 1 to 48, wherein -A1AC-, if present, is independently phenylene, and is optionally substituted.
51. A compound according to any one of claims 1 to 48, wherein -A1AC-, if present, is independently phenyl-1 ,2-diyl, and is optionally substituted.
52. A compound according to any one of claims 1 to 48, wherein -A1AC-, if present, is independently phenyl-1 ,3-diyl, and is optionally substituted.
53. A compound according to any one of claims 1 to 48, wherein -A1AC-, if present, is independently phenyl-1 , 4-diyl, and is optionally substituted.
54. A compound according to any one of claims 1 to 48, wherein -A1AC-, if present, is independently naphth-diyl, and is optionally substituted.
55. A compound according to any one of claims 1 to 48, wherein -A1AC-, if present, is independently naphth-1 ,2-diyl, and is optionally substituted.
56. A compound according to any one of claims 1 to 48, wherein -A1AC-, if present, is independently naphth-1 ,4-diyi, and is optionally substituted.
* * *
57. A compound according to any one of claims 1 to 47, wherein -A1A-, if present, is independently -A1AH-.
58. A compound according to any one of claims 1 to 47 and 57, wherein -A1AH-, if present, is independently C5.6heteroarylene, and is optionally substituted.
59. A compound according to any one of claims 1 to 47 and 57, wherein -A1AH-, if present, is independently C7-10heteroarylene, and is optionally substituted.
60. A compound according to any one of claims 1 to 47 and 57, wherein -A1AH-, if present, is independently furan-diyl, thien-diyl, pyrrol-diyl, 1 ,2,3-triazol-diyl, tetrazol-diyl, oxazol-diyl, thiazol-diyl, isothiazoi-diyl, pyridin-diyl, pyrimidin-diyl, pyrazin-diyl, or pyridazin-diyl, and is optionally substituted.
61. A compound according to any one of claims 1 to 47 and 57, -A1AH-, if present, is independently furan-diyl, thien-diyl, 1 ,2,3-triazol-diyl, oxazol-diyl, thiazol-diyl, or pyridin-diyl, and is optionally substituted.
62. A compound according to any one of claims 1 to 47 and 57, -A1AH-, if present, is independently triazol-diyl, and is optionally substituted.
63. A compound according to any one of claims 1 to 47 and 57, -A1AH-, if present, is independently 1 ,2,3-triazol-diyl, and is optionally substituted.
64. A compound according to any one of claims 1 to 47 and 57, -A1AH-, if present, is independently 1 ,2,3-triazol-1 ,4-diyl, and is optionally substituted.
65. A compound according to any one of claims 1 to 47 and 57, -A1AH-, if present, is independently 1 ,2,3-triazol-1 ,5-diyl, and is optionally substituted.
66. A compound according to any one of claims 1 to 47 and 57, -A1AH-, if present, is independently 1 ,2,3-triazol-1 ,4-diyl, and is optionally substituted, wherein -X1- is attached at the 1 -position of the 1 ,2,3-triazol-1 ,4-diyl.
67. A compound according to any one of claims 1 to 47 and 57, -A1AH-, if present, is independently 1 ,2,3-triazol-1 ,4-diyl, and is optionally substituted, wherein -X1- is attached at the 4-position of the 1 ,2,3-triazoM ,4-diyl.
68. A compound according to any one of claims 1 to 47 and 57, -A1AH-, if present, is independently 1 ,2,3-triazol-1 ,5-diyl, and is optionally substituted, wherein -X1- is attached at the 1 -position of the 1 ,2, 3-triazol-1 ,4-diyl.
69. A compound according to any one of claims 1 to 47 and 57, -A1AH-, if present, is independently 1 ,2,3-triazoM ,5-diyl, and is optionally substituted, wherein -X1- is attached at the 5-position of the 1 ,2,3-triazoM ,4-diyl.
70. A compound according to any one of claims 1 to 47 and 57, -A1AH-, if present, is independently oxazol-diyl, and is optionally substituted.
71. A compound according to any one of claims 1 to 47 and 57, -A1AH-, if present, is independently oxazol-4,5-diyl, and is optionally substituted.
72. A compound according to any one of claims 1 to 47 and 57, -A1AH-, if present, is independently oxazol-2,4-diyl, and is optionally substituted.
73. A compound according to any one of claims 1 to 47 and 57, -A1AH-, if present, is independently oxazol-2,5-diyl, and is optionally substituted.
74. A compound according to any one of claims 1 to 47 and 57, -A1AH-, if present, is independently oxazol-4,5-diyl, and is optionally substituted, wherein -X1- is attached at the 4-position of the oxazol-4,5-diyl.
75. A compound according to any one of claims 1 to 47 and 57, -A1AH-, if present, is independently oxazol-4,5-diyl, and is optionally substituted, wherein -X1- is attached at the 5-position of the oxazol-4,5-diyl.
76. A compound according to any one of claims 1 to 47 and 57, -A1AH-, if present, is independently furan-diyl, and is optionally substituted.
77. A compound according to any one of claims 1 to 47 and 57, -A1AH-, if present, is independently thien-diyl, and is optionally substituted.
78. A compound according to any one of claims 1 to 47 and 57, -A1AH-, if present, is independently pyridin-diyl, and is optionally substituted.
79. A compound according to any one of claims 1 to 47 and 57, -A1AH-, if present, is independently quinolin-diyl, and is optionally substituted.
80. A compound according to any one of claims 1 to 47 and 57, -A1AH-, if present, is independently isoquinolin-diyl, and is optionally substituted.
81. A compound according to any one of claims 1 to 80, wherein -A2A, if present, is independently -A2AC.
82. A compound according to any one of claims 1 to 81 , -A2AC, if present, is independently phenyl or naphthyl, and is optionally substituted.
83. A compound according to any one of claims 1 to 81 , -A2AG, if present, is independently phenyl, and is optionally substituted.
84. A compound according to any one of claims 1 to 81 , -A2^1 if present, is independently phenyl, and is optionally substituted at the para-position.
85. A compound according to any one of claims 1 to 81 , -A2AC, if present, is independently naphthyl, and is optionally substituted.
86. A compound according to any one of claims 1 to 81 , -A2AC, if present, is independently naphth-1-yl, and is optionally substituted.
87. A compound according to any one of claims 1 to 81 , -A2AC, if present, is independently naphth-2-yl, and is optionally substituted.
88. A compound according to any one of claims 1 to 80, wherein -A2A, if present, is independently -A2AH.
89. A compound according to any one of claims 1 to 80 and 88, wherein -A2AH, if present, is independently C5.6 heteroaryl, and is optionally substituted.
90. A compound according to any one of claims 1 to 80 and 88, wherein -A2AH, if present, is independently C7--I0 heteroary I, and is optionally substituted.
91. A compound according to any one of claims 1 to 80 and 88, wherein -A2AH, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, and is optionally substituted.
92. A compound according to any one of claims 1 to 80 and 88, wherein -A2AH, if present, is independently pyridinyl, thiazolyl, or furanyl, and is optionally substituted.
93. A compound according to any one of claims 1 to 80 and 88, wherein -A2AH, if present, is independently pyridinyl, and is optionally substituted.
94. A compound according to any one of claims 1 to 80 and 88, wherein -A2AH, if present, is independently pyridin-2-yl, and is optionally substituted.
95. A compound according to any one of claims 1 to 80 and 88, wherein -A2AH, if present, is independently pyridin-3-yl, and is optionally substituted.
96. A compound according to any one of claims 1 to 80 and 88, wherein -A2AH, if present, is independently pyridin-4-yl, and is optionally substituted.
97. A compound according to any one of claims 1 to 80 and 88, wherein -A2AH, if present, is independently thiazolyl, and is optionally substituted.
98. A compound according to any one of claims 1 to 80 and 88, wherein -A2AH, if present, is independently thiazol-4-yl, and is optionally substituted.
99. A compound according to any one of claims 1 to 80 and 88, wherein -A2AH, if present, is independently furanyl, and is optionally substituted.
100. A compound according to any one of claims 1 to 80 and 88, wherein -A2AH, if present, is independently furan-5-yl, and is optionally substituted.
101. A compound according to any one of claims 1 to 80 and 88, wherein -A2AH, if present, is independently imidazolyl, and is optionally substituted.
102. A compound according to any one of claims 1 to 80 and 88, wherein -A2'*'1"1, if present, is independently imidazol-1-yl, and is optionally substituted.
103. A compound according to any one of claims 1 to 80 and 88, wherein -A2AH, if present, is independently quinolinyl, and is optionally substituted.
104. A compound according to any one of claims 1 to 80 and 88, wherein -A2AH, if present, is independently quinolin-6-yl, and is optionally substituted.
105. A compound according to any one of claims 1 to 80 and 88, wherein -A2AH, if present, is independently indolyl, and is optionally substituted.
106. A compound according to any one of claims 1 to 80 and 88, wherein -A2AH, if present, is independently indol-5-yl, and is optionally substituted.
107. A compound according to claim 1, wherein: the group -X1-A1-X2-A2 is independently -A^-A2*; -A1A- is independently oxazol-4,5-diyl; and -A2A is independently phenyl, and is optionally substituted.
108. A compound according to claim 1 , wherein: the group -X1-A1-X2-A2 is independently -A1A-A2A; -A1A- is independently oxazol-4,5-diyl; wherein -A2A- is attached at the 5-position of the oxazol-4,5-diyl; and -A2A is independently phenyl, and is optionally substituted.
109. A compound according to claim 1 , selected from compounds of the following formula, and pharmaceutically acceptable salts, hydrates, and solvates thereof:
Figure imgf000214_0001
110. A compound according to claim 1, wherein: the group -X1-A1-X2-A2 is independently -A1A-A2A; -A1A- is independently oxazol-4,5-diyl; and -A2A is independently -A2AH; and ~A2AH is independently C5.6heteroaryl, and is optionally substituted.
111. A compound according to claim 1 , wherein: the group -X1-A1-X2-A2 is independently -A1A-A2A; -A1A- is independently oxazol-4,5-diyl; and wherein -A2A- is attached at the 5-position of the oxazol-4,5-diyl; and
-A2A is independently -A2AH; and -A2AH is independently C5.6heteroaryl, and is optionally substituted.
1 12. A compound according to claim 1 , wherein: the group -X1-A1-X2-A2 is independently -A1A-A2A;
-A1A- is independently oxazol-2,5-diyl; and -A2A is independently phenyl, and is optionally substituted.
113. A compound according to claim 1 , wherein: the group -X1-A1-X2-A2 is independently -A1A-A2A; -A1A- is independently oxazol-2,5-diyl; and -A2A is independently -A2AH; and -A2AH is independently Cs^heteroaryl, and is optionally substituted.
114. A compound according to claim 1 , wherein: the group -X1-A1-X2-A2 is independently -A^-A2*; -A1A- is independently 1 ,2,3-triazol-1 ,4-diyl or 1 ,2,3-triazol-1 ,5-diyl; -A2A is independently phenyl, and is optionally substituted.
115. A compound according to claim 1 , wherein: the group -X1-A1-X2-A2 is independently -A1A-A2*; -A1A- is independently 1 ,2,3-triazol-i ,4-diyl; and -A2A is independently phenyl, and is optionally substituted.
1 16. A compound according to claim 1 , wherein: the group -X1-A1-X2-A2 is independently -A1A-A2A; -A1A- is independently 1 ,2,3-triazol-1 ,5-diyl; and -A2A is independently phenyl, and is optionally substituted.
1 17. A compound according to claim 1 , wherein: the group -X1-A1-X2-A2 is independently -X1L-A1A-H or -X1L-A1A-F; -X1L- is independently -C(=O)-, -C(=O)-CH2-, -C(=O)-CH2-O-, or -C(=O)-RL-S-, or; and
-A1A- is independently phenyl, and is optionally substituted.
1 18. A compound according to claim 1 , wherein: the group -X1-A1-X2-A2 is independently -X1L-A1A-H or -X1U-A1A-F; -X1L- is independently -C(O)-CH2-; and
-A1A- is independently phenyl, and is optionally substituted.
1 19. A compound according to claim 1 , wherein: the group -X1-A1-X2-A2 is independently -X1L-A1A-H; -X1L- is independently -C(O)-CH2-; and
-A1A- is independently phenyl, and is optionally substituted.
120. A compound according to claim 1 , wherein: the group -X1-A1-X2-A2 is independently -X1L-A1A-H or -X1L-A1A-F; -X1L- is independently -C(O)-; and
-A1A- is independently phenyl, and is optionally substituted.
121. A compound according to claim 1 , wherein: the group -X1-A1-X2-A2 is independently -X1L-A1A-H; -X1L- is independently -C(=O)-; and -A1A- is independently phenyl, and is optionally substituted.
122. A compound according to claim 1 , wherein: the group -X1-A1-X2-A2 is independently -A1A-H;
.-A1A- is independently phenyl and bears at least one substituent, -Q1, which is independently:
-NHS(=O)2R1A1, -NR1A1S(=O)2R1A1,
-S(O)2NH2, -S(=O)2NHR1A1, -S(=O)2NR1A1 2l or -S(=O)2NR1A2R1A3.
123. A compound according to claim 1 , wherein: the group -X1~A1-X2-A2 is independently -A1A-H;
-A1A- is independently phenyl and bears at least one substituent, -Q1, which is independently:
-NHS(=O)2R1A1 or -NR1A1S(=O)2R1A1.
124. A compound according to claim 1 , wherein: the group -X1-A1-X2-A2 is independently -A1A-X2L-A2A;
-A1A- is independently 1 ,2,3-triazol-i ,4-diyl or 1 ,2,3-triazol-1 ,5-diyl;
-X2L- is independently -CH2-; and
-A2A is independently phenyl, and is optionally substituted.
125. A compound according to claim 1 , wherein: the group -X1-A1-X2-A2 is independently -A1A-X2L-A2A; -A1A- is independently 1 , 2, 3-triazol-1 ,4-diyl; -X2L- is independently -CH2-; and -A2A is independently phenyl, and is optionally substituted.
126. A compound according to claim 1 , wherein: the group -X1-A1-X2-A2 is independently -A1A-X2L-A2A; -A1A- is independently 1,2,3-triazol-1 ,5-diyl; -X2L- is independently -CH2-; and
-A2A is independently phenyl, and is optionally substituted.
127. A compound according to claim 1 , wherein: the group -X1-A1-X2-A2 is independently -A1A-X2L-A2A; -A1A- is independently oxazol-2,5-diyl; -X2L- is independently -CH2-; and -A2A is independently phenyl, and is optionally substituted.
128. A compound according to claim 1 , wherein: the group -X1-A1-X2-A2 is independently -A2A;
-A2A is independently phenyl, and is optionally substituted.
129. A compound according to any one of claims 1 to 128, wherein each -Q1, if present, is independently: -F1 -Cl1 -Br1 -I,
-R1A1,
-CF3, -OCF3,
-OH, -L1A-OH, -O-L1A-OH,
-OR1A1, -L1A-OR1A1, -O-L1A-OR1A1, -NO2,
-NH2, -NHR1A1, -NR1A1 2, -NR1A2R1A3,
-C(=O)OH, -C(=O)OR1A1,
-C(=O)NH2, -C(=O)NHR1A1, -C(=O)NR1A1 2, -C(=O)NR1A2R1A3,
-NHC(=O)R1A1, -NR1A1C(=O)R1A1, -NHS(=O)2R1A1, -NR1A1S(=O)2R1A\
-S(=O)2NH2, -S(=O)2NHR1A1, -S(=O)2NR1A1 2, or -S(=O)2NR1A2R1A3; and additionally, two adjacent -Q1 groups, if present, may together form
-0-CH2-O- or -0-CH2CH2-O-.
130. A compound according to any one of claims 1 to 128, wherein each -Q1, if present, is independently:
-F, -Cl, -Br, -I, -R1A1, -OH, -OR1A1,
-NHS(=O)2R1A1, -NR1A1S(=O)2R1A\
-S(=O)2NH2, -S(=O)2NHR1A1, -S(=O)2NR1A1 2, or -S(=O)2NR1A2R1A3.
131. A compound according to any one of claims 1 to 128, wherein each -Q1, if present, is independently: -F, -Cl, -Br, -I, -R1A1, -OH, or -OR1A1.
132. A compound according to any one of claims 1 to 128, wherein each -Q1, if present, is independently: -R1A1.
133. A compound according to any one of claims 1 to 128, wherein at least one -Q1 is present, and is independently:
-NHS(=O)2R1A\ -NR1A1S(=O)2R1A1,
-S(=O)2NH2) -S(=O)2NHR1A\ -S(=O)2NR1A1 2, or -S(=O)2NR1A2R1A3.
134. A compound according to any one of claims 1 to 128, wherein at least one -Q1 is present, and is independently: -NHS(=O)2R1A1 or -NR1A1S(=O)2R1A1.
135. A compound according to any one of claims 1 to 128, wherein each -Q2, if present, is independently:
-F, -Cl, -Br, -I,
-R1A1, -CF31 -OCF3,
-OH, -L1A-OH, -O-L1A-OH,
-OR1A1, -L1A-OR1A1, -O-L1A-OR1A1,
-NO2,
-NH2, -NHR1A1, -NR1A1 2, -NR1A2R1A3, -C(=O)OH, -C(=O)OR1A1,
-C(=O)NH2, -C(=O)NHR1A1, -C(=O)NR1A1 2, -C(=O)NR1A2R1A3,
-NHC(=O)R1A1, -NR1A1C(=O)R1A1,
-NHS(=O)2R1A1, -NR1A1S(=O)2R1A1,
-S(=O)2NH2, -S(=O)2NHR1A1, -S(=O)2NR1A1 2, or -S(=O)2NR1A2R1A3; and additionally, two adjacent -Q1 groups, if present, may together form
-0-CH2-O- or -0-CH2CH2-O-.
136. A compound according to any one of claims 1 to 128, wherein each -Q2, if present, is independently: -F, -Cl, -Br, -I, -R1A1, -OH, -OR1A1,
-NHS(=O)2R1A\ -NR1A1S(=O)2R1A1, -S(O)2NH2, -S(=O)2NHR1A1, -S(=O)2NR1A1 2, or -S(=O)2NR1A2R1A3.
137. A compound according to any one of claims 1 to 128, wherein each -Q2, if present, is independently: -F, -Cl, -Br, -I, -R1A1, -OH, or -OR1A1.
138. A compound according to any one of claims 1 to 128, wherein each -Q2, if present, is independently: -R1A1.
* * *
139. A compound according to any one of claims 1 to 138, wherein each -NR1A2R1A3, if present, is independently azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperazino, morpholino, thiomorpholino, thiomorpholine-1,1 -dioxide, azepino, or diazepino, and is optionally substituted with one or more groups selected from saturated aliphatic Ci.3alkyl.
140. A compound according to any one of claims 1 to 138, wherein each -NR1A2R1A3, if present, is independently pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or thiomorpholine-1 ,1-dioxide, and is optionally substituted with one or more groups selected from saturated aliphatic C1-3alkyl.
141. A compound according to any one of claims 1 to 140, wherein each -R1A1, if present, is independently:
_p1B1 _p1B4 _p1B6 _Q1 B7 _D1B8 -L1B-R1B4, -L1B-R1B6, -L1B-R1B7, or -L1B-R1B8.
142. A compound according to any one of claims 1 to 140, wherein each -R1A1, if present, is independently:
Figure imgf000219_0001
-L1B-R1B4, or -L1B-R1B7.
143. A compound according to any one of claims 1 to 140, wherein each -R1A1, if present, is independently -L1B-R1B6, -L1B-R1B7, or -L1B-R1B8.
144. A compound according to any one of claims 1 to 140, wherein each -R1A1, if present, is independently -L1B-R1B6 or -L1B-R1B8.
145. A compound according to any one of claims 1 to 140, wherein each -R1A1, if present, is independently - R1B1.
146. A compound according to any one of claims 1 to 145, wherein each -R1B6, if present, is independently azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, azepinyl, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl, and is optionally substituted.
147. A compound according to any one of claims 1 to 145, wherein each -R1BΘ, if present, is independently pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, or dioxanyl, and is optionally substituted.
148. A compound according to any one of claims 1 to 147, wherein each -R1B7, if present, is independently phenyl, and is optionally substituted.
149. A compound according to any one of claims 1 to 148, wherein each -R1B8, if present, is independently C5.6heteroaryl, and is optionally substituted.
150. A compound according to any one of claims 1 to 148, wherein each -R1B8, if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyi, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, or pyridazinyl, and is optionally substituted.
151. A compound according to any one of claims 1 to 150, wherein each -L1B-, if present, is independently -CH2-.
152. A compound according to any one of claims 1 to 151 , wherein each -R1C1, if present, is independently saturated aliphatic C^alkyl.
153. A compound according to any one of claims 1 to 152, wherein each -R1C2, if present, is independently:
-F, -Cl, -Br, -I,
-CF3, -OCF3, -OH,
-OR1D1,
-SH, -SR101,
-CN,
-NO2, -NH2, -NHR1D1, -NR1D1 2, -NR102R103,
-C(=O)OH, -C(=O)OR1D1, -OC(=O)R1D\
-C(=O)R1D1,
-C(=O)NH2, -C(=O)NHR1D1, -C(=O)NR1D1 2, -C(=O)NR1D2R103,
-NHC(=O)R1D1, -NR1D1C(=O)R1D1, -S(O)2NH2, -S(=O)2NHR1A1, -S(=O)2NR1A1 2, -S(=O)2NR1A2R1A3, or
-S(=O)2R1A1.
154. A compound according to any one of claims 1 to 152, wherein each -R1C2, if present, is independently: -F, -Cl, -Br, -I,
-CF3, -OCF3,
-OH,
-OR101,
-NH2, -NHR1D1, -NR1D1 2, -NR102R103, -C(=O)OH, -C(=O)OR101, -OC(=O)R1D1,
-C(=O)R1D1, -C(O)NH2, -C(=O)NHR1D1, -C(=0)NR1D1 2, -C(=O)NR1D2R1D3,
-NHC(=O)R1D1, -NR1D1C(=O)R1D1,
-S(=O)2NH2, -S(=O)2NHR1A\ -S(=O)2NR1A1 2, or -S(=O)2NR1A2R1A3.
155. A compound according to any one of claims 1 to 154, wherein each -R1D\ if present, is independently saturated aliphatic Ci-4alkyl.
156. A compound according to any one of claims 1 to 155, wherein each -NR102R103, if present, is independently azetidino, pyrrolidino, imidazoiidino, pyrazolidino, piperidino, piperazino, morpholino, thiomorpholino, thiomorpholine-1 ,1-dioxide, azepino, or diazepino, and is optionally substituted with one or more groups selected from saturated aliphatic C^alkyl.
157. A compound according to any one of claims 1 to 155, wherein each -NR102R103, if present, is independently pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or thiomorpholine-1 ,1 -dioxide, and is optionally substituted with one or more groups selected from saturated aliphatic C^alkyl.
158. A compound selected from the following compounds, and pharmaceutically acceptable salts, hydrates, and solvates thereof: Compound Nos. AA-001 through AA-004.
159. A compound selected from the following compounds, and pharmaceutically acceptable salts, hydrates, and solvates thereof: Compound Nos. BB-001 through BB-004.
160. A compound selected from the following compounds, and pharmaceutically acceptable salts, hydrates, and solvates thereof: Compound Nos. CC-001 through CC-014.
161. A compound selected from the following compounds, and pharmaceutically acceptable salts, hydrates, and solvates thereof: Compound Nos. DD-001 through DD-015.
162. A compound selected from the following compounds, and pharmaceutically acceptable salts, hydrates, and solvates thereof: Compound Nos. EE-001 through EE-004.
163. A pharmaceutical composition comprising a compound according to any one of claims 1 to 162, and a pharmaceutically acceptable carrier or diluent.
164. A method of preparing a pharmaceutical composition comprising the step of admixing a compound according to any one of claims 1 to 162, and a pharmaceutically acceptable carrier or diluent.
165. A compound according to any one of claims 1 to 162, without the proviso regarding P-O01 through P-003, for use in a method of treatment of the human or animal body by therapy.
166. A compound according to any one of claims 1 to 162, without the proviso regarding P-001 through P-003, for use in a method of treatment of a disease or condition that is mediated by heat shock protein 90 (HSP90).
167. A compound according to any one of claims 1 to 162, without the proviso regarding P-001 through P-003, for use in a method of treatment of a disease or condition that is ameliorated by the inhibition of heat shock protein 90 (HSP90) function.
168. A compound according to any one of claims 1 to 162, without the proviso regarding P-001 through P-003, for use in a method of treatment of a disease or condition that is known to be treated by heat shock protein 90 (HSP90) inhibitors.
169. A compound according to any one of claims 1 to 162, without the proviso regarding P-001 through P-003, for use in a method of treatment of a proliferative condition.
170. A compound according to any one of claims 1 to 162, without the proviso regarding P-001 through P-003, for use in a method of treatment of cancer.
* * *
171. Use of a compound according to any one of claims 1 to 162, without the proviso regarding P-001 through P-003, in the manufacture of a medicament for the treatment of a disease or condition that is mediated by heat shock protein 90 (HSP90).
172. Use of a compound according to any one of claims 1 to 162, without the proviso regarding P-001 through P-003, in the manufacture of a medicament for the treatment of a disease or condition that is ameliorated by the inhibition of heat shock protein 90 (HSP90) function.
173. Use of a compound according to any one of claims 1 to 162, without the proviso regarding P-001 through P-003, in the manufacture of a medicament for the treatment of a disease or condition that is known to be treated by heat shock protein 90 (HSP90) inhibitors.
174. Use of a compound according to any one of claims 1 to 162, without the proviso regarding P-001 through P-003, in the manufacture of a medicament for the treatment of a proliferative condition.
175. Use of a compound according to any one of claims 1 to 162, without the proviso regarding P-001 through P-003, in the manufacture of a medicament for the treatment of cancer.
176. A method of treatment of a disease or condition that is mediated by heat shock protein 90 (HSP90) comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to any one of claims 1 to 162, without the proviso regarding P-001 through P-003.
177. A method of treatment of a disease or condition that is ameliorated by the inhibition of heat shock protein 90 (HSP90) function comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to any one of claims 1 to 162, without the proviso regarding P-001 through P-003.
178. A method of treatment of a disease or condition that is known to be treated by heat shock protein 90 (HSP90) inhibitors comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to any one of claims 1 to 162, without the proviso regarding P-001 through P-003.
179. A method of treatment of a proliferative condition comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to any one of claims 1 to 162, without the proviso regarding P-001 through P-003.
180. A method of treatment of cancer comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to any one of claims 1 to 162, without the proviso regarding P-001 through P-003.
181. A method of inhibiting heat shock protein 90 (HSP90) function, in vitro or in vivo, comprising contacting a HSP90 with an effective amount of a compound according to any one of claims 1 to 162, without the proviso regarding P-001 through P-003.
182. 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 a compound according to any one of claims 1 to 162, without the proviso regarding P-001 through P-003.
183. A method of inhibiting cell proliferation, inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting the cell with an effective amount of a compound according to any one of claims 1 to 162, without the proviso regarding P-001 through P-003.
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