WO2008052352A1 - Substituted quinone indoleamine 2,3-dioxygenase (ido) inhibitors and syntheses and uses therefor - Google Patents

Substituted quinone indoleamine 2,3-dioxygenase (ido) inhibitors and syntheses and uses therefor Download PDF

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Publication number
WO2008052352A1
WO2008052352A1 PCT/CA2007/001976 CA2007001976W WO2008052352A1 WO 2008052352 A1 WO2008052352 A1 WO 2008052352A1 CA 2007001976 W CA2007001976 W CA 2007001976W WO 2008052352 A1 WO2008052352 A1 WO 2008052352A1
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carbon
aromatic
group
cyclic
branched
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PCT/CA2007/001976
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French (fr)
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Raymond Andersen
Michael Leblanc
Harry Brastianos
Eduardo Vottero
Michel Roberge
Grant Mauk
Gavin Carr
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The University Of British Columbia
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings

Definitions

  • This invention relates to substituted quinones that are inhibitors of indoleamine-2,3-dioxygenase (IDO). More specifically, this invention relates to the novel substituted quinones, and uses of substituted quinones or compositions thereof in the treatment of various diseases.
  • IDO indoleamine-2,3-dioxygenase
  • Indoleamine 2,3-dioxygenase (IDO; MW 48,000; EC 1.13.11.42) catalyzes the conversion of tryptophan into N-formylkynurenine in the first and rate limiting step in the catabolism of this essential amino acid (Shimizu et al. 1978. J. Biol. Chem 253:4700-4706).
  • the initial link between IDO and immune tolerance was established by Munn et al. when they showed that treatment of pregnant mice with the EDO inhibitor 1-methyltryptophan (1-MT) removed the toleragenic state protecting fetal tissue from the maternal immune system (Munn et al, 1998. Science 281:1191-1193).
  • Tryptophan is required for the normal immune response of killer T cells.
  • T cells In environments where tryptophan concentration has been depleted by IDO, T cells cannot be activated by antigens and they undergo Gl cell cycle arrest leading to apoptosis and immunosuppression (Munn et al, 1999. /. Exp Med 189: 1363-1372).
  • IDO contributes to this process by depleting local concentrations of tryptophan, much as it does in protecting fetal tissue. Consistent with this hypothesis is the observation that immune escape is an important part of solid tumor progression (Muller et al., 2005. Cancer Res. 65:8065-8068).
  • IDO is overexpressed in most tumors and it has been suggested that its role in immune escape by solid tumors parallels that postulated for fetal tissue (Muller, supra; Uyttenhove et al 2003. Nat. Med 9:1269-1274). Increased expression of IDO in tumor cells is correlated with poor prognosis for survival in patients with serious ovarian and colorectal cancers.
  • Some experimental studies looking at small molecule IDO inhibitors have focussed on the properties of IMT, which has a Ki of ⁇ 20 mM.
  • a library of marine natural product extracts has been screened against cloned human IDO in vitro (WO 2006/005185).
  • This invention is based, in part, on the discovery of novel compounds and compositions that are inhibitors of indoleamine-2,3-dioxygenase (IDO).
  • IDO indoleamine-2,3-dioxygenase
  • This invention is also based, in part on the discovery that the novel compounds and some known compounds are inhibitors of IDO and can be used for treatment or for preparation of medicaments for treatment of a condition characterized by pathology of IDO-mediated tryptophan metabolism and used in methods for treating a condition characterized by pathology of IDO-mediated tryptophan metabolism.
  • R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; or iii) a first carbon bonded to the carbon at position 6 and a second carbon bonded to the carbon at position 7; and R is selected from the group consisting of:
  • CO 2 R is selected from the group consisting of: CR , CR R , HCR , CH 2 , NH, NR , O and S;
  • R 12 is selected from the group consisting of: H and
  • R comprises one of: i) a carbon bonded to the carbon at position
  • R is selected from the group consisting of:
  • Z is H, R or OR;
  • R is selected from the group consisting of: H and a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic; R is selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO 2 , NH, or NR, and each carbon, O, S, SO, SO 2 , NH, or NR may be optionally substituted with one or more of:
  • R is H; n is 1 ; R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to tthhee ccaarrbboonn aatt ppoossiittiioonn 77 aanndd nnoo aattoomm ddirectly bonded to the carbon at position 6; and R is selected from the group consisting of:
  • Z is H, R or OR;
  • R .1 1 1 L comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; or iii) a first carbon bonded to the carbon at position 6 and a second carbon bonded to the carbon at position 7; and R is selected from the group consisting of:
  • CO 2 R is selected from the group consisting of: CR , CR R , HCR , CH 2 , NH, NR , O and S;
  • R 12 is selected from the group consisting of: H and
  • G and G are independently selected from the group consisting of: H, and
  • G and G are independently selected from the group consisting of H, Carbobenzyloxy (Cbz), teit-Butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC), Benzyl (Bn), and p-methoxyphenyl (PMP).
  • Z is H, R or OR; Z and Z are independently R; and each R in each of Z , Z and Z is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
  • R comprises i) a carbon bonded to the carbon at position 6 and is not directly bonded to the carbon at position 7.
  • composition comprising a compound or salt described herein, and a pharmaceutically acceptable carrier.
  • R is optionally selected from the group consisting of: H,
  • R , R , and R is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
  • X is selected from the group consisting of NH and NR wherein R is selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially- aromatic or non-aromatic.
  • condition results from accumulation of a product of tryptophan degradation.
  • condition is a neurodegenerative disorder.
  • condition is a mood disorder.
  • a use described herein for preparation of a medicament for said treatment or prophylaxis comprising administering to a patient in need thereof, an effective amount of a compound or composition described herein.
  • a method of treating, preventing, or reducing the likelihood of onset of a condition that is not cancer and is characterized by pathology of IDO-mediated tryptophan metabolism comprising administering to a patient in need thereof, an effective amount of a compound or salt of Formula A:
  • R is optionally selected from the group consisting of: H,
  • X is selected from the group consisting of NH and NR wherein R is selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
  • n is 1.
  • a method described herein wherein the condition results from suppression of T-cell mediated immunity results from suppression of T-cell mediated immunity.
  • condition results from accumulation of a product of tryptophan degradation.
  • condition is a neurodegenerative disorder.
  • x to y carbon group refers to a chemical entity that has a carbon skeleton or main carbon chain comprising a number from x to y (with all individual integers within the range included, including integers x and y) of carbon atoms.
  • the carbons of the carbon skeleton may be optionally replaced by a heteroatom or may be substituted with one more heteroatoms.
  • a "one to 15 carbon group” is a chemical entity that has either 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 carbon atoms and/or heteroatoms in its skeleton or main chain.
  • ethane and ethanol are both "two carbon groups"
  • butane and 2-methyl-butan-3-ol are both "four carbon groups”.
  • saturated when referring to a chemical entity means that the chemical entity does not have double or triple bonds.
  • unsaturated when referring to a chemical entity means that the chemical entity has bonds that have at least one double and/or triple bond.
  • Unsaturated chemical entities include “partially-unsaturated” and “partially-saturated” chemical entities, which means that the chemical entity has a mixture of single and non-single bonds. In other words an unsaturated chemical entity is a chemical entity that has at least one non-single bond.
  • cyclic when referring to a chemical entity means that at least a portion of the skeleton or main chain of the chemical entity is bonded in such a way so as to form a 'loop' or circle of atoms that are bonded together.
  • the atoms do not have to all be directly bonded to each other, but rather may be directly bonded to as few as two other atoms in the 'loop'.
  • Non-limiting examples of cyclic compounds include benzene, toluene, cyclopentane, bisphenol and 3-ethylcyclohexane.
  • linear when referring to a chemical entity means that the chemical entity does not contain any cyclic portions.
  • branched when referring to a chemical entity means that the chemical entity comprises a skeleton or main chain that splits off in more than one direction.
  • the portions of the skeleton or main chain that split off in more than one direction may be linear, cyclic or any combination thereof.
  • aromatic when referring to a chemical entity means that the chemical entity comprises conjugated double bonds. Often such compounds comprise 4n + 2 delocalized pi orbital electrons, where n is an integer.
  • Aromatic chemical entities include “partially-aromatic” chemical entities which means that a part of the chemical entity is aromatic, while another part of the chemical entity is not aromatic.
  • non-aromatic refers to a chemical entity that is not aromatic and not partially-aromatic.
  • An example of non-aromatic compounds are aliphatic compounds.
  • a point of attachment bond denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond.
  • Atoms may be referred to as having a position within a molecule.
  • atom positioning may be referred to by labeling an atom having a particular position with a number that is used as a positioning label. The following diagram provides numbering for use as positioning labels of some atoms appearing in a fused ring system that is common to all compounds of the present invention:
  • position 6 there is a carbon, or in other words the carbon at position 6.
  • an atom in a particular position will be annotated by using the letter describing the atom followed by a dash and a number, which is the positioning label.
  • C-6 denotes the carbon at position 6
  • C-7 denotes the carbon at position 7
  • X-I denotes X at position 1.
  • no other atoms are provided with the positioning labels 1, 2, 3, 4, 5, 6, 7, 8 or 9.
  • X may be NH, NR', O, or S.
  • Y may be NH, NR', O, or S.
  • R' may be a one to ten carbon, saturated, unsaturated, or cyclic alkyl group.
  • R 3 and R 4 may be linked to form a ring.
  • R 3 and R 5 may be linked to form a ring.
  • R 4 and R 5 may be linked to form a ring.
  • R 5 and R 6 may be linked to form a ring.
  • R. 6 and R 7 may be linked to form a ring.
  • R 7 and Rg may be linked to form a ring.
  • R 1 of the substituted quinones according to Formula 1, 2, 3, 4 or 5 is -CH 2 -CH 2 5 NH 2 , or -CH 2 -CH 2 NR 3 R 2 , or -CH 2 -CH(CO 2 R 4 )NR 2 R 3 .
  • R 2 of the substituted quinones according to Formula 1, 2, 3, 4 or 5 is H.
  • X of the substituted quinones according to Formula 1, 2, 3, 4 or 5 is N-Me or NR'.
  • Formulas 1, 2, 3, 4 and 5 may be considered together in the single Formula A:
  • X is selected from the group consisting of: NH, NR, O, and S;
  • R is bonded to one of: i) the carbon at position 6, ii) the carbon at position 7 or iii) both the carbon at position 6 and the carbon at position 7 and R is selected from the group consisting of: H,
  • Y is selected from the group consisting of: CR , CR R , HCR , CH 2 , NH, NR 9 , 0 and S;
  • R is optionally selected from the group consisting of: H,
  • each R in each of R , R , R , and R is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
  • at least one R is a group that blocks a Michael addition from nucleophiles to the indole quinone. This may be achieved by providing a steric effect, such as bulk or hindrance.
  • the blocked nucleophile may be a biological nucleophile or a be a nucleophile under biological conditions.
  • R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; or iii) a first carbon bonded to the carbon at position 6 and a second carbon bonded to the carbon at position 7.
  • X is NR 12 ;
  • R is selected from the group consisting of: H and a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic;
  • R 2 is H; n is 1;
  • R comprises one or: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; and
  • R is selected from the group consisting of:
  • Z 2 is H, R or OR
  • X is selected from the group consisting of NH and NR wherein R is selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
  • R is selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
  • X is NH.
  • R is H.
  • n 1
  • R is selected from the group consisting of:
  • Formula B may be used to describe these particular embodiments of Formula A where R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; or iii) a first carbon bonded to the carbon at position 6 and a second carbon bonded to the carbon at position 7.
  • n Ri l compri • ses one o cf: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; or iii) a first carbon bonded to the carbon at position 6 and a second carbon bonded to the carbon at position 7; and
  • R is selected from the group consisting of:
  • Y is selected from the group consisting of: CR , CR R , HCR , CH 2 , NH, NR 9 , O and S;
  • R is selected from the group consisting of: H and a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic;
  • G and G are independently selected from the group consisting of: a one to 12 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO 2 , NH, or NR, and each carbon, O, S, SO, SO 2 , NH, or
  • G , G , G , and G are independently selected from the group consisting of:
  • G is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
  • R is selected from the group consisting of:
  • each R in each of R , R , R , and R is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
  • R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; or iii) a first carbon bonded to the carbon at position 6 and a second carbon bonded to the carbon at position 7; and
  • R is a group that blocks a Michael addition from nucleophiles to the indole quinone. This may be achieved by providing a steric effect, such as bulk or hindrance.
  • the blocked nucleophile may be a biological nucleophile or a be a nucleophile under biological conditions.
  • R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; and
  • R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; and
  • R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; and
  • R is selected from the group consisting of:
  • Z is H, R or OR
  • G and G are independently selected from the group consisting of: H, and
  • Q is CH 2 , 0, NH, NR or S; k is O, 1, 2, 3, 4, 5, 6, or 7; and
  • G and G are independently selected from the group consisting of: H, and
  • G and G are independently selected from the group consisting of H, Carbobenzyloxy (Cbz), tert-Butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC), Benzyl (Bn), and p-methoxyphenyl (PMP).
  • R is H.
  • Q is O or CH 2 .
  • Q is O.
  • k is 1.
  • G may be as defined herein for any embodiment of Formula A and/or B;
  • R may be as defined herein for any embodiment of Formula A and/or B;
  • G may be as defined herein for any embodiment of Formula A, B and/or C;
  • R may be as defined herein for any embodiment of Formula A, B, and/or C;
  • Z is selected from the group consisting of H, R and OR and is bonded to the carbon of Z that is bonded to the carbon at position 6;
  • each R in each of Z and Z is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
  • R is not directly bonded to the carbon at position 7, and where present R , Z and/or Z +Z is selected from the group consisting of:
  • Z 2 is H, R or OR
  • G may be as defined herein for any embodiment of Formula A, B, C and/or
  • R may be as defined herein for any embodiment of Formula A, B, C and/or
  • Z is selected from the group consisting of H, R and OR;
  • G is H; where present, R . 11 i ⁇ s not directly bonded to the carbon at position 7, and where present R 11 , Z 1 , Z 3 +Z 2 and/or Z 4 +Z 5 +Z 5 +Z 6 +Z 7 +Z 2 is:
  • T is H, R or OR
  • Z and Z are independently R;
  • each R in each of Z , Z and Z is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
  • R may be as defined herein for any embodiment of Formula E;
  • Z and Z are independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
  • a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
  • R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; or iii) a first carbon bonded to the carbon at position 6 and a second carbon bonded to the carbon at position 7; and
  • R is selected from the group consisting of:
  • Y is selected from the group consisting of: CR , CR R , HCR , CH 2 , NH,
  • R is selected from the group consisting of: H and a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic;
  • G and G are independently selected from the group consisting of: H, and
  • Q is CH 2 , O, NH, NR or S; k is O, 1, 2, 3, 4, 5, 6, or 7;
  • R , R , R , R , R , R , R , R 8 , R 9 , R 10 , R 11 , R 12 , G 8 , G 9 , G 10 , G 11 , G 12 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z9, X, Y, Z, and n, wherein present, may be as defined herein for any one of Formulas A, B, C, D, E and or F.
  • F and/or G may be a prodrug.
  • a prodrug is a compound that may be administered in a less active, or inactive form, and metabolized in the subject's body into an active, or more active, compound.
  • the substituted quinones according to Formula A, B, C, D, E, F and/or G may further include a counterion.
  • counterions include sulfate, phosphate, chloride, bromide, iodide, acetate, succinate and other counterions known to a person of skill in the art.
  • the compounds described herein are provided in the form of pharmaceutically-acceptable salts and/or pharmaceutically-acceptable compositions.
  • Many compounds of this invention or for use in this invention are generally water soluble and may be formed as salts.
  • pharmaceutical compositions in accordance with this invention may comprise a salt of such a compound, preferably a physiologically acceptable salt, which are known in the art.
  • Pharmaceutical preparations will typically comprise one or more carriers acceptable for the mode of administration of the preparation, be it by injection, inhalation, topical administration, lavage, or other modes suitable for the selected treatment. Suitable carriers are those known in the art for use in such modes of administration.
  • Suitable pharmaceutical compositions may be formulated by means known in the art and their mode of administration and dose determined by the skilled practitioner.
  • a compound may be dissolved in sterile water or saline or a pharmaceutically acceptable vehicle used for administration of non- water soluble compounds such as those used for vitamin K.
  • the compound may be administered in a tablet, capsule or dissolved in liquid form.
  • the tablet or capsule may be enteric coated, or in a formulation for sustained release.
  • Many suitable formulations are known, including, polymeric or protein microparticles encapsulating a compound to be released, ointments, gels, hydrogels, or solutions which can be used topically or locally to administer a compound.
  • a sustained release patch or implant may be employed to provide release over a prolonged period of time.
  • Many techniques known to skilled practitioners are described in Remington: the Science & Practice of Pharmacy by Alfonso Gennaro, 20 th ed., Williams & Wilkins, (2000).
  • Formulations for parenteral administration may, for example, contain excipients, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes.
  • Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds.
  • parenteral delivery systems for modulatory compounds include ethylene- vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.
  • Munn et al. (US Patents 6,451,840 and 6,482,416) describe administering to a subject an effective amount of a pharmaceutical composition comprising an inhibitor of IDO, and uses thereof.
  • Ophthalmic compositions such as sterile aqueous solutions may be prepared using techniques known in the art by the skilled practitioner.
  • Pigiet et al. (US Patent 4,771,036) describe a method and an ophthalmic composition for the prevention and reversal of cataracts.
  • Itoh et al. (US Patent 6,500,813) describe ophthalmic compositions, including eye drops, used for preventing deterioration of the optical transparency.
  • Babizhayev et al. Drugs RaD, 3, 87-103 describe a human trial of eye drops containing drugs in a phosphate-buffered saline for the treatment of cataracts.
  • Ophthalmic compositions may be packaged in a suitable container or eye dropper adopted for the delivery of drops to the eye.
  • chemotherapeutics or other therapeutic modalities, particularly for the treatment of a cancer.
  • Other therapeutic modalities include, but are not limited to, chemotherapeutics, radiation therapy, antiviral agents, antibacterial agents, antifungal agents, antimicrobial agents, signal transduction inhibitors, cytokines, vaccines, hormone therapy, surgical resection, immunostimulatory therapy, anti-tumor vaccines, antibody based therapies, whole body irradiation, bone marrow transplantation and peripheral blood stem cell transplantation.
  • An IDO inhibitor may be administered before, after or during the other therapeutic modality.
  • chemotherapeutic refers to a chemical compound or composition that may be used to treat a disease in a patient. There are many chemotherapeutics and of particular interest are cancer chemotherapeutics.
  • cancer chemotherapeutics including, alkylating and oxidizing agents, antimetabolites, antibiotics, mitotic inhibitors, chromatin function inhibitors, hormone and hormone inhibitors, antibodies, immunomodulators, angiogenesis inhibitors, rescue/protective agents, and others.
  • the alkylating and oxidizing agent class of cancer chemotherapeutics includes seven subclasses: nitrogen mustards, ethylenimines, alkyl sulfonates, nitrosureas, triazenes and platinum coordinating complexes.
  • nitrogen mustards include mechlorethamine (MustargenTM), cyclophosphamide (CytoxanTM and NeosarTM), ifosfamide (IfexTM), phenylalanine mustard, melphalen (AlkeranTM), chlorambucol (LeukeranTM), uracil mustard and estramustine (EmcytTM).
  • An example of an ethylanimine is thiotepa (ThioplexTM).
  • alkyl sulfonate is busulfan (MyerlanTM).
  • Examples of nitrosureas are lomustine (CeeNUTM), carmustine (BiCNUTM and BCNUTM) and streptozocin (ZanosarTM).
  • Examples of triazines are dicarbazine (DTIC-DomeTM) and temozolamide (TemodarTM).
  • Examples of platinum coordination complexes are cis-platinum, cisplatin (PlatinolTM and Platinol AQTM) and carboplatin (ParaplatinTM).
  • Other examples of alkylating and oxidizing agents include altretamine (HexalenTM) and arsenic (TrisenoxTM).
  • chemotherapeutics are generally cell cycle non-specific (although a greater effect in the Gl, S phase of the cell cycle is often observed) and work through the alkylation of DNA (through carbonium ion intermediates). They may encourage covalent cross-linking of DNA, RNA and proteins, cause single-stranded DNA breaks or provide abnormal DNA base pairing. Through these mechanisms these chemotherapeutics tend to interrupt cell replication.
  • platinum coordinating complex agents generally cause cross-linking of DNA strands and have an affinity for alkylation at guanine bases (at the N7 position) and adenine (at the N7 position). This may cause interstrand and intrastrand cross-linking.
  • the drugs themselves may also bind to protein SH groups.
  • the antimetabolite class of cancer chemotherapeutics includes: folic acid analogs, pyrimidine analogs and purine analogs.
  • folic acids include: methotrexate (AmethopterinTM, FolexTM, MexateTM, RheumatrexTM).
  • pyrimidine analogs include 5-fluoruracil (AdrucilTM, EfudexTM, FluoroplexTM), floxuridine, 5-fluorodeoxyuridine (FUDRTM), capecitabine (XelodaTM), flurdarabine (FludaraTM), cytosine arabinoside (CytaribineTM, CyrosarTM, ARA-CTM).
  • purine analog examples include: 6-mercaptopurine (Purinethol), 6-thioguanine (ThioguanineTM), gemcitabine (GemzarTM), cladribine (LeustatinTM), deoxycoformycin and pentostatin (NipentTM).
  • chemotherapeutics are generally S phase specific and are often structurally related to normal cellular components. They often work through interference with nucleotide syntheses and compete with cellular nucleotides in DNA and RNA synthesis.
  • the antibiotic class of cancer chemotherapeutics includes: doxorubicin (AdriamycinTM, RubexTM, DoxilTM, DaunoxomeTM-liposomal preparation), daunorubicin (DaunomycinTM, CerubidineTM), idarubicin (IdamycinTM), valrubicin (ValstarTM), epirubicin, mitoxantrone (NovantroneTM), dactinomycin (Actinomycin DTM, CosmegenTM), mithramycin, plicamycin (MithracinTM), mitomycin C (MutamycinTM), bleomycin (BlenoxaneTM), procarbazine (MatulaneTM).
  • doxorubicin AdriamycinTM, RubexTM, DoxilTM, DaunoxomeTM-liposomal preparation
  • daunorubicin DaunomycinTM, CerubidineTM
  • idarubicin IdamycinTM
  • chemotherapeutics in this class are also generally cell cycle non-specific (exceptions include bleomyacin and procarbozine).
  • This class of chemotherapeutics generally intercalates into double-stranded DNA and disrupts the DNA by binding to the DNA helix. These chemotherapeutics also inhibit DNA synthesis by inhibiting nucleotide incorporation or inhibiting DNA dependent RNA synthesis. Some of these chemotherapeutics also inhibit DNA coiling and in some cases achieve this by inhibiting topoisomerase II which leads to strand breaks.
  • doxorubicin intercalates in DNA, binding to the sugar phosphate backbone of the DNA. Doxorubicin also binds to cell membranes blocking the phosphatidyl-inositol activation. Doxorubicin can also inhibit topoisomerase II.
  • the mitotic inhibitor class of cancer chemotherapeutics includes: taxanes or diterepenes and vinca alkaloids.
  • taxanes include paclitaxel (TaxolTM) and docetaxel (TaxotereTM).
  • vinca alkaloids include vinblastine sulfate (VelbanTM, VelsarTM, VLBTM), vincristine sulfate (OncovinTM, Vincasa PFSTM, VincrexTM) and, vinorelbine sulfate (NavelbineTM).
  • This class of chemotherapeutics are cell cycle specific and generally disrupt the cell cycle during the M phase.
  • This class of cancer chemotherapeutic disrupts the mitotic spindle thereby inhibiting chromosomal segregation and blocking mitosis.
  • the taxanes groups of mitotic inhibitors which include paclitaxel and docetaxel, are derived from the bark of the Pacific Yew tree. They prevent microtubular depolymerization thereby inhibiting a reorganization of the microtubular network. Microtubular stabilization also promotes the formation of abnormal bundles of microtubules.
  • the chromatin function inhibitor class of cancer chemotherapeutics includes: camptothecins and epipodophyllotoxins. Examples of camptothecins include topotecan (CamptosarTM) and irinotecan (HycamtinTM).
  • epipodophyllotoxins examples include etoposide (VP- 16TM, VePesidTM and ToposarTM) and teniposide (VM-26TM and VumonTM). These chemotherapeutics are generally cell cycle specific and may bind to either topoisomerase I or topoisomerase II. In the case where they bind to topoisomerase I, this prevents re-ligation of breaks in the DNA. In the case where they bind with topoisomerase II, this prevents transcription replication of the DNA thereby killing the cell.
  • etoposide VP- 16TM, VePesidTM and ToposarTM
  • VM-26TM and VumonTM teniposide
  • the hormone and hormone inhibitor class of cancer chemotherapeutics includes: estrogens, antiestrogens, aromatase inhibitors, progestins, GnRH agonists, androgens, antiandrogens and inhibitors of syntheses.
  • estrogens include diethylstilbesterol (StilbesterolTM and StilphostrolTM), estradiol, estrogen, esterified estrogens (EstratabTM and MenestTM) and estramustine (EmcytTM).
  • anti-estrogens include tamoxifin (NolvadexTM) and toremifene (FarestonTM).
  • aromatase inhibitors include anastrozole (ArimidexTM) and letrozol (FemaraTM).
  • progestins include 17-OH-progesterone, medroxyprogesterone, and megastrol acetate (MegaceTM).
  • GnRH agonists include gosereline (ZoladexTM) and leuprolide (LeupronTM).
  • androgens include testosterone, methyltestosterone and fluoxmesterone (Android-FTM, HalotestinTM).
  • antiandrogens include flutamide (EulexinTM), bicalutamide (CasodexTM) and nilutamide (NilandronTM).
  • inhibitors of synthesis include aminoglutethimide (CytadrenTM) and ketoconozole (NizoralTM). These chemotherapeutics bind to a variety of hormones, generally estrogens and androgens or block receptors to these hormones. Cell growth and development is impaired by these chemotherapeutics by interfering with a cell's ability to bind a particular hormone, either by blocking the receptor or by binding to the hormone itself.
  • the antibodies class of cancer chemotherapeutics includes: rituximab (RituxanTM), trastuzumab (HerceptinTM), gemtuzumab ozogamicin (MylotargTM), tositumomab (BexxarTM) and bevacizumab.
  • These chemotherapeutics may be antibodies that are targeted to a particular protein on the cell surface of a cancer cell. These antibodies may provide a motif for generating an immune response to the antibody and hence the cancer cell or possibly induce apoptosis. Other mechanisms of action of this class of chemotherapeutic include inhibiting stimulation from growth factors by binding to receptors on cancer cells.
  • the immunomodulators class of cancer chemotherapeutics includes: denileukin diftitox (OntakTM), levamisole (ErgamisolTM), bacillus Calmette-Gueran, BCG (TheraCysTM, TICE BCGTM), interferon alpha-2a, interferon alpha-2b (Roferon-ATM, Intron ATM) and interleukin-2 and aldesleukin (ProLeukinTM).
  • These chemotherapeutics provide an interaction with or a stimulation of the host immune system so that the host immune system attacks the cancer cells.
  • Interleukin-2 modulation, stimulation of cytotoxic T cells, macrophages, as well as B cells are common mechanisms of action for this class of cancer chemotherapeutics .
  • the angiogenesis class of cancer chemotherapeutics includes: thalidomide (ThalomidTM), angiostatin and endostatin. These chemotherapeutics generally inhibit tumour vascularization thereby preventing growth of tumors by reducing blood supply to the tumours.
  • the rescue/protective agents class of cancer chemotherapeutics includes: dexrazoxane (ZinecardTM), amifostine (EthyolTM), G-CSF (NeupogenTM), GM-CSF (LeukineTM), erythopoetin (EpogenTM, ProcritTM), oprelvekin and IL-Il (NeumegaTM). These chemotherapeutics work through a variety of different mechanisms of action. These mechanisms of action include protecting DNA, binding to cisplatin metabolites protecting the kidneys or cardioprotective mechanisms. Other chemotherapeutics in this class will stimulate granulocyte, macrophage, erythroid progenitor and megakaryocyte proliferation and differentiation. Other cancer chemotherapeutics include imatinib mesylate, STI-571 (GleevecTM),
  • chemotherapeutics may inhibit the Bcr-Abl tyrosine kinase, for example imatinib mesylate.
  • Prendergast et al (WO 2004/093871) describe methods for the treatment of cancer, malignancy and chronic viral infection using IDO inhibitors alone and IDO inhibitors in combination with other chemotherapeutics.
  • Munn et al. (US Patent Application publication number 2004/0234623) describe the use of inhibitors of indoleamine-2,3-dioxygenase in combination with other therapeutic modalities.
  • an EDO inhibitor, a chemotherapeutic, or both may be independently by systemic, parenteral, intravenous, subcutaneous, transdermal, transmucosal, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intranasal, aerosol, topical, surgical, oral or parenteral administration. Dosage and duration of treatment will be determined by the practitioner in accordance with standard protocols and information concerning the activity and toxicity of the chosen compound.
  • Compounds or pharmaceutical compositions in accordance with this invention or for use in this invention may be administered by means of a medical device or appliance such as an implant, graft, prosthesis, stent, etc.
  • implants may be devised which are intended to contain and release such compounds or compositions.
  • An example would be an implant made of a polymeric material adapted to release the compound over a period of time.
  • An "effective amount" of a pharmaceutical composition according to the invention includes a therapeutically effective amount or a prophylactically effective amount.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as improved IDO inhibition, reduced tumour growth or tumour regression.
  • a therapeutically effective amount of a compound may vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects.
  • a “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as reduced tumour growth or no tumor growth. Typically, a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effective amount may be less than a therapeutically effective amount.
  • dosage values may vary with the severity of the condition to be alleviated.
  • specific dosage regimens may be adjusted over time according to the individual need and the professional judgement of the person administering or supervising the administration of the compositions.
  • Dosage ranges set forth herein are exemplary only and do not limit the dosage ranges that may be selected by medical practitioners.
  • the amount of active compound(s) in the composition may vary according to factors such as the disease state, age, sex, and weight of the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
  • parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • compounds of the invention should be used without causing substantial toxicity.
  • Toxicity of the compounds of the invention can be determined using standard techniques, for example, by testing in cell cultures or experimental animals and determining the therapeutic index, i.e., the ratio between the LD50 (the dose lethal to 50% of the population) and the LDlOO (the dose lethal to 100% of the population). In some circumstances however, such as in severe disease conditions, it may be necessary to administer substantial excesses of the compositions.
  • a "subject” may be a human, non-human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc.
  • the subject may be suspected of having or at risk for having an EDO-mediated disease. Diagnostic methods for various IDO mediated diseases and disorders and the clinical delineation of IDO mediated disease and disorder diagnoses are known to those of ordinary skill in the art.
  • compounds and compositions described herein may be used in the treatment of diseases characterized by the pathology of the IDO-mediated tryptophan metabolic pathway.
  • diseases include but are not limited to cancer, diseases of the eye, cataracts, autoimmune diseases, and mood disorders.
  • IDO inhibitors may be useful as drugs for treating diseases characterized by a pathology involving the IDO-mediated tryptophan metabolic pathway.
  • a subject having a disease characterized by a pathology involving the IDO-mediated tryptophan metabolic pathway may be administered a compound or composition described herein.
  • IDO plays a role in several diseases, including Clamydia psittaci infection and Streptococcus pyogenes infection, systemic lupus erythematosus, rheumatoid arthritis, Alzheimer's disease, Huntington's disease, Parkinson's disease, lyme neuroborreliosis, late lyme encephalopathy, Tourette's syndrome, systemic sclerosis, multiple sclerosis, coronary heart disease, T-cell mediated immune diseases, chronic infections (viral, bacterial, fungal and microbial), depression, neurological disorders, cancer tumors, and cataracts. Inhibitors of IDO may be used to treat these diseases.
  • IDO inhibitors may be used to treat include, but are not limited to, human immunodeficiency virus (HIV), AIDS-related cancers, adrenocorticocancer, basal cell carcinoma, bladder cancer, bowel cancer, brain and CNS tumors, breast cancers, B-cell lymphoma, carcinoid tumors, cervical cancer, childhood cancers, chondrosarcoma, choriocarcinoma, chronic myeloid leukemia, rectal cancers, endocrine cancers, endometrial cancer, esophageal cancer, Ewing's sarcoma, eye cancer, gastric cancer or carcinoma, gastrointestinal cancers, genitourinary cancers, glioma, gynecological cancers, head and neck cancers, hepatocellular cancer, Hodgkins disease, hypopharynx cancer, islet cell cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer, lung cancer (including small-cell
  • cancer refers to a proliferative or neoplastic disorder caused or characterized by the proliferation of cells which have lost susceptibility to normal growth control.
  • the term cancer includes tumors and any other proliferative disorders. Cancers of the same tissue type usually originate in the same tissue, and may be divided into different subtypes based on their biological characteristics. Four general categories of cancers are carcinoma (epithelial tissue derived), sarcoma (connective tissue or mesodermal derived), leukemia (blood-forming tissue derived) and lymphoma (lymph tissue derived). Over 200 different types of cancers are known, and every organ and tissue of the body may be affected.
  • organs and tissues that may be affected by various cancers include pancreas, breast, thyroid, ovary, uterus, testis, prostate, thyroid, pituitary gland, adrenal gland, kidney, stomach, esophagus or rectum, head and neck, bone, nervous system, skin, blood, nasopharyngeal tissue, lung, urinary tract, cervix, vagina, exocrine glands and endocrine glands.
  • a cancer may be multicentric or of unknown primary site (CUPS).
  • IDO inhibitors may also be used to treat an autoimmune disease.
  • An autoimmune disease is a disease resulting from the failure of an organism to recognize its constituent parts as 'self, which results in an acquired immune response against its own tissues and/or cells.
  • autoimmune diseases may include Crohn's disease, type I diabetes, celdisease, systemic lupus erythematosus, Sjogren's syndrome, rheuma arthritis, acute disseminated encephalomyelitis, Addison's disease, aplastic anemia, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, multiple sclerosis, opsoclonus myoclonus syndrome, optic neuritis, pemphigus, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, Wegener's granulomatosis, and alopecia.
  • IDO inhibitors may also be used to treat mood disorders.
  • Mood disorders include depression, anxiety, and bipolar disorder.
  • Neopetrosia exigua (140 g wet wt) was collected by hand using SCUBA in Milne Bay in Papua New Guinea (10° 32.02' S, 150° 39.07' E).
  • N. exigua is a red/brown smooth encrusting sheet sponge (specimen size ⁇ 2mm x 10 cm) found growing on the underside of overhang at 15 m. depth.
  • a voucher sample has been deposited at the Zootechnisch Museum, University of Amsterdam, Mauritskade 61, 1092 AD Amsterdam (ref No. ZMAPOR19113). Freshly collected sponge specimens were frozen on site and stored frozen until workup.
  • the frozen sponge was thawed and extracted exhaustively with MeOH (4 x IL).
  • MeOH 4 x IL
  • the combined MeOH extracts were reduced in vacuo to give a brown solid (5.6 g) that was dissolved in 400 mL of H 2 O and sequentially extracted with EtOAc (3 x 200 mL) and n-butanol (3 x 200 mL).
  • EtOAc 3 x 200 mL
  • n-butanol 3 x 200 mL
  • the IDO inhibitory n-butanol fraction (1.2 g) was subjected to SephadexTM LH-20 size exclusion chromatography eluting with 100% methanol.
  • the IDO inhibitory fractions were combined and further fractionated on a reversed-phase Sep PakTM (gradient elution: H 2 O to MeOH) which yielded 300 mg of active material.
  • the bioactive material was subjected to gradient reversed-phase HPLC (Inertsil C 18, 9.4 X 250 mm, H 2 O to CH 3 CN containing 0.1% TFA, monitored by UV detection at 254 nm) giving 98 mg of an IDO inhibitory fraction.
  • This material was further purified by isocratic reversed phase HPLC (Inertsil C 18 , 9.4 X 250 mm, 9 H 2 0: 1 CH 3 CN: 0.1% TFA) to give pure exiguamine A (20 mg) and exiguamine B (4.5 mg). Pure exiguamine A was suspended in 1 N HCl and the solution was evaporated in vacuo. Repeating this process four times generated the HCl salt, which gave deep red crystals from MeOH.
  • the structures of Exiguamine A and Exigamine B are:
  • Exaguamine A and Exaguamine B Exiguamine A was isolated as deep-red optically-inactive crystals that gave a [M]+ ion at mlz 492.1882 in the HRESIMS consistent with an elemental composition of C 25 H 26 N 5 O 6 (calcd 492.1883).
  • the 13 C NMR spectrum showed 25 well-resolved resonances in agreement with the HRMS analysis, and the HMQC/ DEPT data indicated that 22 of the 26 hydrogen atoms were attached to carbon (C x 15; CH x 2, CH 2 x 4, CH 3 x 4).
  • Fragments of exiguamine A could be assembled from 2D NMR data.
  • a complex multiplet at ⁇ 2.99 (H 2 -25: HMQC to 38.3) showed COSY correlations to a second multiplet at 2.92 (H 2 -24: HMQC to ⁇ 23.3) and to a broad singlet at 7.82 (NH 3 -26).
  • the H 2 -24 resonance and the NH-26 resonance showed HMQC correlations to a nitrogen resonance at ⁇ -349 (N-26) in agreement with the presence of an ethylamine moiety.
  • the methine at ⁇ 7.30 (H-2) showed a COSY correlation to an exchangeable resonance at ⁇ 13.10 (NH- 1) and a HMQC correlation to the nitrogen resonance at ⁇ -218 (N-I), which demonstrated that C-2 was bonded to an NH.
  • a pair of carbon resonances at ⁇ 173.4 (C-5 or C-8) and 179.7 (C-5 or C-8) were assigned to quinone carbonyls.
  • a NOESY correlation was observed between ⁇ 7.52 (H-13) and 3.51 (Me-28). All of the above data were consistent with the fragment II.
  • a methyl resonance at ⁇ 3.07 (Me-30: HMQC to ⁇ 25.2) showed HMBC correlations to carbon resonances at ⁇ 154.5 (C-21) and 168.6 (C-23) and a HMQC correlation to a nitrogen resonance at ⁇ -248 (N-22), while a second methyl resonance at ⁇ 2.44 (Me- 29: HMQC to ⁇ 26.0) showed HMBC correlations to carbon resonances at ⁇ 154.5 (C-21) and 85.4 (C- 19) and a HMQC correlation to a nitrogen resonance at ⁇ -275 (N-20). These data were assigned to fragment III.
  • TLC Thin-layer chromatography
  • NMR spectra were recorded on a Bruker AV600 spectrometer fitted with an inverse triple resonance ( H, C, N) cryoprobe. NMR solvents were purchased from Cambridge Isotope laboratories and were referenced to solvent peaks ⁇ H 2.49 ppm and ⁇ C 39.5 ppm for OMSO-d6. Low resolution ESI mass spectra were taken on a Bruker Esquire LC mass spectrometer. High resolution ESI mass spectra was taken on a Macromass LCT mass spectrometer. Optical rotations were recorder with a JASCO J-1010 polarimeter equipped with a halogen lamp (589 nm) and a 10 mm micro cell.
  • Examples 2 - 7 Synthesis of six Compounds for Testing Synthesis of A tryptamine quinone fragment followed an elegant sequential oxidative strategy based on the preparation of indole quinone intermediates used in the synthesis of lymphostin by Tatsuta et al. (Tatsuta, K et al. Tehrahedron Lett. 2004, 45, 2847-2850). Tryptamine (4) was first protected as its Cbz derivative (5) and then oxidized to the ketone (6) in good yield with DDQ (Scheme 1). Selective hydroxylation of (6) at C-4 to give phenol (7) was carried out by reaction with T1(OCOCF 3 ) 3 followed by treatment with
  • tryptamine quinone derivatives (9), (11), (13), (16), and (17) were tested for their ability to inhibit IDO in a pure enzyme assay and in the cell-based yeast assay (See Examples 13 and 14).
  • Carboxybenzyl-protected tryptamine quinone (9) was prepared using a modified literature protocol (Tatsuta, K.; Imamura, K.; Itoh, S.; Kasai, S. Tetrahedron Lett. 2004, 45, 2847-2850) according to scheme 1.
  • Tryptamine (4) (1.99 g, 12.42 mmol) was dissolved in chloroform (20 mL) under nitrogen, and cooled to O 0 C.
  • diisopropylethylamine 4.4 mL, 25.26 mmol
  • benzyl chloroformate 2.0 mL, 14.0 mmol
  • the solution was allowed to warm to room temperature and stirred for 1 h. Water (20 mL) was added, and the organic layer was separated, concentrated in vacuo, and purified by silica gel flash chromatography (10% EtOAc/Hexanes to 100% EtOAc) to give
  • Methyl l-methyl-S-propyl-S-hydantoincarboxylate (14a) was synthesized using a modification of a literature protocol (Li, J.P. J. Org. Chem. 1975, 40, 3414-3417).
  • a yeast growth restoration assay provides for expression of human IDO in yeast cells to restrict their growth by depleting the intracellular tryptophan pool. Growth is restored by IDO inhibition. Yeast growth was determined by optical density at 600nm. A yeast growth restoration curve for caulerpin is shown in Vottero et al. 2006. Biotechnology J. 1:282-288. A description of the yeast assay is also provided in Vottero et al.
  • the yeast growth restoration assay was used as a stringent filter to provide information about IDO inhibitors already identified as IDO inhibitors in the enzyme assay of Example 13 (or otherwise identified as IDO inhibitors). In particular, preliminary information regarding a compounds ability to cross cell membranes, preliminary information related to potential toxicity and preliminary in vivo information. Table 2 shows the results of the compounds tested. TABLE 2
  • yeast cells are known to have cell membranes that pose special difficulties for molecules to cross and here again this result is to be used as a guide for selecting suitable compounds for a particular use.
  • Compounds described as toxic and inactive in Table 2 may be useful embodiments for particular uses, such as cancer treatment and in non-yeast cells.

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Abstract

The present invention relates to substituted mdoloqumone compounds of the general formula (A) and (B) and pharmaceutical compositions thereof that are inhibitors of mdoleamme-2,3-dioxygenase (IDO) More specifically, the invention relates to said compounds and compositions that are useful for treatment or prophylaxis of a condition characterised by pathology of IDO-mediated tryptophan metabolism such as cancer, suppression of T-cell mediated immunity, accumulation of a product of tryptophan degradation, neurodegenrative disorder, mood disorder and cataract or yellowing of the eye.

Description

SUBSTITUTED QUINONE INDOLEAMINE 2,3-DIOXYGENASE (IDO) INHIBITORS AND SYNTHESES AND USES THEREFOR
Technical Field This invention relates to substituted quinones that are inhibitors of indoleamine-2,3-dioxygenase (IDO). More specifically, this invention relates to the novel substituted quinones, and uses of substituted quinones or compositions thereof in the treatment of various diseases.
Background
Indoleamine 2,3-dioxygenase (IDO; MW 48,000; EC 1.13.11.42) catalyzes the conversion of tryptophan into N-formylkynurenine in the first and rate limiting step in the catabolism of this essential amino acid (Shimizu et al. 1978. J. Biol. Chem 253:4700-4706). The initial link between IDO and immune tolerance was established by Munn et al. when they showed that treatment of pregnant mice with the EDO inhibitor 1-methyltryptophan (1-MT) removed the toleragenic state protecting fetal tissue from the maternal immune system (Munn et al, 1998. Science 281:1191-1193).
Tryptophan is required for the normal immune response of killer T cells. In environments where tryptophan concentration has been depleted by IDO, T cells cannot be activated by antigens and they undergo Gl cell cycle arrest leading to apoptosis and immunosuppression (Munn et al, 1999. /. Exp Med 189: 1363-1372). One of the hallmarks of solid tumor cancers is immune evasion and it has been proposed that IDO contributes to this process by depleting local concentrations of tryptophan, much as it does in protecting fetal tissue. Consistent with this hypothesis is the observation that immune escape is an important part of solid tumor progression (Muller et al., 2005. Cancer Res. 65:8065-8068). IDO is overexpressed in most tumors and it has been suggested that its role in immune escape by solid tumors parallels that postulated for fetal tissue (Muller, supra; Uyttenhove et al 2003. Nat. Med 9:1269-1274). Increased expression of IDO in tumor cells is correlated with poor prognosis for survival in patients with serious ovarian and colorectal cancers. Some experimental studies looking at small molecule IDO inhibitors have focussed on the properties of IMT, which has a Ki of ~ 20 mM. A library of marine natural product extracts has been screened against cloned human IDO in vitro (WO 2006/005185). One of the compounds discovered using the in vitro screen was the hydroid metabolite annulin C, which has a Ki of ~ 140 nM, making it much more potent than IMT (Pereira, A. et al. J. Nat. Prod. 2006, 69, 1496-1499). Other known IDO inhibitors are tryptophan analogs that are active only at concentrations of ~ 10 μM or greater (Muller et al. 2005. Expert Opin. Ther. Targets 9:831-349). Muller et al. found that the IDO inhibitor IMT used in combination with a cytotoxic agent such as paclitaxel led to regression of tumors in mouse models that showed no response to the cytotoxin administered alone (Muller et al. 2005. Nat. Med 11:3212-319). A similarly positive in vivo response has been obtained by using siRNA to silence the IDO gene in B16F10 tumor-bearing mice (Zheng, X. et al. Immunol. 2006, 177, 5639-5646).
Summary
This invention is based, in part, on the discovery of novel compounds and compositions that are inhibitors of indoleamine-2,3-dioxygenase (IDO). This invention is also based, in part on the discovery that the novel compounds and some known compounds are inhibitors of IDO and can be used for treatment or for preparation of medicaments for treatment of a condition characterized by pathology of IDO-mediated tryptophan metabolism and used in methods for treating a condition characterized by pathology of IDO-mediated tryptophan metabolism.
In one aspect of the present invention, there is provided a compound of Formula B or a pharmaceutically acceptable salt thereof:
Figure imgf000003_0001
Formula B wherein R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; or iii) a first carbon bonded to the carbon at position 6 and a second carbon bonded to the carbon at position 7; and R is selected from the group consisting of:
Figure imgf000004_0001
, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon not bonded to the carbon at position 6 or the carbon at position 7 is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and
Q O 10 O Q
CO2R; Y is selected from the group consisting of: CR , CR R , HCR , CH2, NH, NR , O and S; R3, R4, R5, R6, R7, R8, R9 and R10 are each independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R; R12 is selected from the group consisting of: H and a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic; G and G are independently selected from the group consisting of: a one to 12 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; G3, G4, G5, and G6 are independently selected from the group consisting of: H, R, OH, OR, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; each R in each of R3, R4, R5, R6, R7, R8, R9, R10, R1 \ G , G , G , G , G , and G is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
In another aspect of the present invention there is provided a compound or salt described herein wherein R is selected from the group consisting of:
Figure imgf000005_0001
, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon that is not bonded to the carbon at position 6 or the carbon at position 7 is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R; R , R , R , and R are each independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in each of R , R , R , and R is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic. In another aspect of the present invention there is provided a compound or salt described herein wherein R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; and R is selected from the group consisting of: a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon not bonded to the carbon at position 6 is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in R is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic. In another aspect of the present invention there is provided a compound or salt described herein wherein R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; and R is selected from the group consisting of: a three to eight carbon partially- aromatic or non-aromatic ring or fused ring system, where each carbon not bonded to the carbon at position 6 is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; the carbon in R11 bonded to the carbon at position 6 or position 7 is further substituted with H, R or OR; and each R in R is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
In another aspect of the present invention there is provided a compound or salt described herein wherein R comprises one of: i) a carbon bonded to the carbon at position
6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the ccaarrbboonn aatt ppoossiittiioonn 77 aanndd nnoo aattoomm ddiirreecctly bonded to the carbon at position 6; and R is selected from the group consisting of:
Figure imgf000006_0001
wherein Z is H, R or OR; Z , Z , Z , and Z are independently selected from the group consisting of: CH2, O, S, NH, and are optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; at least one of Z4, Z5, Z6, and Z7 is N optionally substituted with OH, OR, R, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in each of Z2, Z4, Z5, Z6, and Z7 is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
In another aspect of the present invention there is provided a compound of Formula A or a pharmaceutically acceptable salt thereof:
Figure imgf000007_0001
Formula A
12 12 wherein X is NR ; R is selected from the group consisting of: H and a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic; R is selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR may be optionally substituted with one or more of:
OH, OR, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2
2 . 11 and CO2R; R is H; n is 1 ; R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to tthhee ccaarrbboonn aatt ppoossiittiioonn 77 aanndd nnoo aattoomm ddirectly bonded to the carbon at position 6; and R is selected from the group consisting of:
Figure imgf000007_0002
wherein Z is H, R or OR; Z , Z , Z , and Z are independently selected from the group consisting of: CH2, O, S, NH, and are optionally substituted with OH, OR, R, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; at least one of Z4, Z5, Z6, and Z7 is N optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in each of Z2, Z4, Z5, Z6, and Z7 is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
In another aspect of the present invention there is provided a compound or salt described herein wherein R is selected from the group consisting of:
Figure imgf000008_0001
wherein G and G are independently selected from the group consisting of: a one to 12 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; G3, G4, G5, and G6 are independently selected from the group consisting of: H, R, OH, OR, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in each of G1, G2, G3, G4, G5, and G6 is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
In another aspect of the present invention there is provided a compound or salt
1 2 described herein wherein G and G are independently selected from the group consisting of: H, and
Figure imgf000009_0001
wherein Q is CH2, O, NH, NR or S; k is 0, 1, 2, 3, 4, 5, 6, or 7; G7 is an three to eight carbon cyclic, branched-cyclic group that is optionally aromatic, partially-aromatic or non-aromatic, where each carbon is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in G7 is selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
In another aspect of the present invention there is provided a compound of Formula G or a pharmaceutically acceptable salt thereof:
Figure imgf000009_0002
Formula G wherein R .111 L comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; or iii) a first carbon bonded to the carbon at position 6 and a second carbon bonded to the carbon at position 7; and R is selected from the group consisting of:
Figure imgf000009_0003
and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon not bonded to the carbon at position 6 or the carbon at position 7 is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and
Q Q in Q Q
CO2R; Y is selected from the group consisting of: CR , CR R , HCR , CH2, NH, NR , O and S; R3, R4, R5, R6, R7, R8, R9 and R10 are each independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R; R12 is selected from the group consisting of: H and a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or
1 2 non-aromatic; G and G are independently selected from the group consisting of: H, and
wherein Q is CH2, O, NH, NR or S; k is 0, 1, 2, 3, 4, 5, 6, or 7; G3, G4, G5, and G6 are independently selected from the group consisting of: H, R, OH, OR, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; G7 is a three to fourteen carbon cyclic, branched-cyclic group that is optionally aromatic, partially-aromatic or non-aromatic, where each carbon is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; G3, G4, G5, and G6 are independently selected from the group consisting of: H, R, OH, OR, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; each R in each of R3, R4, R5, R6, R7, R8, R9, R10, R1 \ G1, G2, G3, G4, G5, G6 and G7 is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic. In another aspect of the present invention there is provided a compound or salt described herein wherein G and G are independently selected from the group consisting of: H, and
Figure imgf000011_0001
wherein Q is CH2, O, NH, NR or S; k is 0, 1, 2, 3, 4, 5, 6, or 7; G8, G9, G10, G11 and G12 are independently selected from the group consisting of: H, R, OH, OR, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in each of G8, G9, G , G and G is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non- aromatic.
In another aspect of the present invention there is provided a compound or salt described herein wherein Q is O or CH2.
In another aspect of the present invention there is provided a compound or salt described herein wherein Q is O. In another aspect of the present invention there is provided a compound or salt described herein wherein k is 1. hi another aspect of the present invention there is provided a compound or salt
1 2 described herein wherein G and G are independently selected from the group consisting of H, Carbobenzyloxy (Cbz), teit-Butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC), Benzyl (Bn), and p-methoxyphenyl (PMP).
In another aspect of the present invention there is provided a compound or salt described herein wherein G is H.
In another aspect of the present invention there is provided a compound or salt described herein wherein R is selected from the group consisting of:
Figure imgf000012_0001
2 8 9 2 8 wherein Z is H, R or OR; Z and Z are independently R; and each R in each of Z , Z and Z is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
In another aspect of the present invention there is provided a compound or salt described herein wherein R comprises i) a carbon bonded to the carbon at position 6 and is not directly bonded to the carbon at position 7.
In another aspect of the present invention there is provided a compound or salt described herein wherein R12 is H.
In another aspect of the present invention there is provided a compound having the structure:
Figure imgf000012_0002
or a salt thereof.
In another aspect of the present invention there is provided a compound having the structure:
Figure imgf000013_0001
or a salt thereof.
In another aspect of the present invention there is provided a compound having the structure:
Figure imgf000013_0002
or a salt thereof.
In another aspect of the present invention there is provided a compound having the structure:
Figure imgf000013_0003
or a salt thereof. In another aspect of the present invention there is provided a compound having the structure:
Figure imgf000014_0001
or a salt thereof.
In another aspect of the present invention there is provided a compound having the structure:
Figure imgf000014_0002
or a salt thereof.
In another aspect of the present invention there is provided a compound having the structure:
Figure imgf000014_0003
or a salt thereof.
In another aspect of the present invention there is provided a compound having the structure: or a salt thereof.
In another aspect of the present invention there is provided a compound having the structure:
Figure imgf000015_0002
or a salt thereof.
In another aspect of the present invention there is provided a compound having the structure:
Figure imgf000015_0003
or a salt thereof.
In another aspect of the present invention there is provided a composition comprising a compound or salt described herein, and a pharmaceutically acceptable carrier. In another aspect of the present invention there is provided a compound or composition described herein for use in the treatment or prophylaxis of a condition characterized by pathology of IDO-mediated tryptophan metabolism.
In another aspect of the present invention there is provided the use of a compound or composition described herein for treatment or prophylaxis of a condition characterized by pathology of IDO-mediated tryptophan metabolism.
In another aspect of the present invention there is provided the use of a compound or composition described herein for preparation of a medicament for treatment or prophylaxis of a condition characterized by pathology of IDO-mediated tryptophan metabolism. In another aspect of the present invention there is provided the use of a compound or salt of Formula A:
Figure imgf000016_0001
Formula A
1 2 wherein X is selected from the group consisting of: NH, NR, O, and S; R and R are independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR may be optionally substituted with one or more of: OH, OR, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R; n is 1 or 2; R1 ' is optionally bonded to the carbon at position 6, the carbon at position 7 or bonded to both the carbon at position 6 and the carbon at position 7 and is selected from the group consisting of: H,
Figure imgf000016_0002
, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R; Y is selected from the group consisting of: CR9, CR9R10, HCR9, CH2, NH, NR9, 0 and S; and R3, R4, R5, R6, R7, R8, R9 and R10 are each independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R; and each R in each of X, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, for treatment or prophylaxis of a condition that is not cancer and is characterized by pathology of EDO-mediated tryptophan metabolism.
In another aspect of the present invention there is provided a use described herein wherein, R is optionally selected from the group consisting of: H,
Figure imgf000017_0001
, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R; R3, R5, R8, and R9 are each independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in each
3 5 8 9 of R , R , R , and R is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
In another aspect of the present invention there is provided a use described herein wherein X is selected from the group consisting of NH and NR wherein R is selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially- aromatic or non-aromatic.
In another aspect of the present invention there is provided a use described herein wherein X is NH.
In another aspect of the present invention there is provided a use described herein wherein n is 1.
In another aspect of the present invention there is provided a use described herein wherein the condition results from suppression of T-cell mediated immunity.
In another aspect of the present invention there is provided a use described herein wherein the condition results from accumulation of a product of tryptophan degradation. In another aspect of the present invention there is provided a use described herein wherein the condition is a neurodegenerative disorder.
In another aspect of the present invention there is provided a use described herein wherein the condition is a mood disorder.
In another aspect of the present invention there is provided a use described herein wherein the condition is a cataract or yellowing of the eye.
In another aspect of the present invention there is provided a use described herein wherein the condition results from a chronic infection by a virus or microorganism.
In another aspect of the present invention there is provided a use described herein for preparation of a medicament for said treatment or prophylaxis. In another aspect of the present invention there is provided a method of treating, preventing, or reducing the likelihood of onset of a condition characterized by pathology of IDO-mediated tryptophan metabolism comprising administering to a patient in need thereof, an effective amount of a compound or composition described herein.
In another aspect of the present invention, there is provided a method described herein wherein said condition is cancer and the compound or composition is administered before, during or after administration of a chemotherapeutic agent or radiation therapy.
In another aspect of the present invention, there is provided a method of treating, preventing, or reducing the likelihood of onset of a condition that is not cancer and is characterized by pathology of IDO-mediated tryptophan metabolism comprising administering to a patient in need thereof, an effective amount of a compound or salt of Formula A:
Figure imgf000019_0001
Formula A wherein X is selected from the group consisting of: NH, NR, O, and S; R and R are independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R; n is 1 or 2; R is optionally bonded to the carbon at position 6, the carbon at position 7 or bonded to both the carbon at position 6 and the carbon at position 7 and is selected from the group consisting of: H,
Figure imgf000019_0002
a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R; Y is selected from the group consisting of: CR9, CR9R10, HCR9, CH2, NH, NR9, O and S; and R3, R4, R5, R6, R7, R8, R9 and R10 are each independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non- aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R; and each R in each of X, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
In another aspect of the present invention, there is provided a method described herein wherein, R is optionally selected from the group consisting of: H,
Figure imgf000020_0001
, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R; R3, R5, R8, and R9 are each independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in each of R , R , R , and R is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic. hi another aspect of the present invention, there is provided a method described herein wherein X is selected from the group consisting of NH and NR wherein R is selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
In another aspect of the present invention, there is provided a method described herein wherein X is NH.
In another aspect of the present invention, there is provided a method described herein wherein n is 1. In another aspect of the present invention, there is provided a method described herein wherein the condition results from suppression of T-cell mediated immunity.
In another aspect of the present invention, there is provided a method described herein wherein the condition results from accumulation of a product of tryptophan degradation. hi another aspect of the present invention, there is provided a method described herein wherein the condition is a neurodegenerative disorder.
In another aspect of the present invention, there is provided a method described herein wherein the condition is a mood disorder.
In another aspect of the present invention, there is provided a method described herein wherein the condition is a cataract or yellowing of the eye.
In another aspect of the present invention, there is provided a method described herein wherein the condition results from a chronic infection by a virus or microorganism.
Detailed Description As used herein, the phrase "x to y carbon group" refers to a chemical entity that has a carbon skeleton or main carbon chain comprising a number from x to y (with all individual integers within the range included, including integers x and y) of carbon atoms. The carbons of the carbon skeleton may be optionally replaced by a heteroatom or may be substituted with one more heteroatoms. For example a "one to 15 carbon group" is a chemical entity that has either 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 carbon atoms and/or heteroatoms in its skeleton or main chain. For example, ethane and ethanol are both "two carbon groups", while butane and 2-methyl-butan-3-ol are both "four carbon groups".
As used herein, the term "saturated" when referring to a chemical entity means that the chemical entity does not have double or triple bonds.
As used herein, the term "unsaturated" when referring to a chemical entity means that the chemical entity has bonds that have at least one double and/or triple bond. Unsaturated chemical entities include "partially-unsaturated" and "partially-saturated" chemical entities, which means that the chemical entity has a mixture of single and non-single bonds. In other words an unsaturated chemical entity is a chemical entity that has at least one non-single bond.
As used herein, the term "cyclic" when referring to a chemical entity means that at least a portion of the skeleton or main chain of the chemical entity is bonded in such a way so as to form a 'loop' or circle of atoms that are bonded together. The atoms do not have to all be directly bonded to each other, but rather may be directly bonded to as few as two other atoms in the 'loop'. Non-limiting examples of cyclic compounds include benzene, toluene, cyclopentane, bisphenol and 3-ethylcyclohexane. As used herein, the term "linear" when referring to a chemical entity means that the chemical entity does not contain any cyclic portions.
As used herein, the term "branched" when referring to a chemical entity means that the chemical entity comprises a skeleton or main chain that splits off in more than one direction. The portions of the skeleton or main chain that split off in more than one direction may be linear, cyclic or any combination thereof.
As used herein, the term "aromatic" when referring to a chemical entity means that the chemical entity comprises conjugated double bonds. Often such compounds comprise 4n + 2 delocalized pi orbital electrons, where n is an integer. Aromatic chemical entities include "partially-aromatic" chemical entities which means that a part of the chemical entity is aromatic, while another part of the chemical entity is not aromatic.
As used herein, the term "non-aromatic" refers to a chemical entity that is not aromatic and not partially-aromatic. An example of non-aromatic compounds are aliphatic compounds. As used herein, the symbol "
Figure imgf000023_0001
" (hereinafter may be referred to as "a point of attachment bond") denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond. For
example, "
Figure imgf000023_0002
" indicates that the chemical entity "XY" is bonded to another chemical entity via the point of attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entity may be specified by providing a positioning label. For
example "
Figure imgf000023_0003
" indicates that the chemical entity "XY" is attached to the carbon at position 6 of the non-depicted chemical entity via the a point of attachment bond. Atoms may be referred to as having a position within a molecule. As used herein, atom positioning may be referred to by labeling an atom having a particular position with a number that is used as a positioning label. The following diagram provides numbering for use as positioning labels of some atoms appearing in a fused ring system that is common to all compounds of the present invention:
Figure imgf000023_0004
For example, in position 6, there is a carbon, or in other words the carbon at position 6. Sometimes an atom in a particular position will be annotated by using the letter describing the atom followed by a dash and a number, which is the positioning label. For example "C-6" denotes the carbon at position 6, "C-7" denotes the carbon at position 7 and "X-I" denotes X at position 1. As used herein, no other atoms are provided with the positioning labels 1, 2, 3, 4, 5, 6, 7, 8 or 9.
In some embodiments of the present invention, there is provided compounds having a general formula of at least one of Formulas 1, 2, 3, 4 and/or 5:
Figure imgf000024_0001
Formula 1 Formula 2
Figure imgf000024_0002
Formula 3 Formula 4 and
Figure imgf000024_0003
Formula 5
For each of Formula 1, 2, 3, 4 or 5, X may be NH, NR', O, or S.
For each of Formula 2 or 3, Y may be NH, NR', O, or S.
Ri may be H, or a one to 15 carbon saturated, unsaturated, or cyclic alkyl group, where C may be replaced by O, S, SO, SO2, NH, or NR', and may be optionally substituted with OH, OR', F, Cl, Br, I, =O, SH, SR', NH2, NHR', NR'2, OSO3H, OPO3H3, CO2H, CO2R', and the like.
R2 may be H, or a one to 15 carbon saturated, unsaturated, or cyclic alkyl group, where C may be replaced by O, S, SO, SO2, NH, or NR', and may be optionally substituted with OH, OR', F, Cl, Br, I, =0, SH, SR', NH2, NHR', NR'2, OSO3H, OPO3H3, CO2H, CO2R', and the like. R3 may be H, or a one to 15 carbon saturated, unsaturated, or cyclic alkyl group, where C may be replaced by O, S, SO, SO2, NH, or NR', and may be optionally substituted with OH, OR', F, Cl, Br, I, =0, SH, SR', NH2, NHR', NR'2, OSO3H, OPO3H3, CO2H, CO2R', and the like. R4 may be H, or a one to 15 carbon saturated, unsaturated, or cyclic alkyl group, where C may be replaced by O, S, SO, SO2, NH, or NR', and may be optionally substituted with OH, OR', F, Cl, Br, I, =O, SH, SR', NH2, NHR', NR'2, OSO3H, OPO3H3, CO2H, CO2R', and the like.
R5 may be H, or a one to 15 carbon saturated, unsaturated, or cyclic alkyl group, where C may be replaced by O, S, SO, SO2, NH, or NR', and may be optionally substituted with OH, OR', F, Cl, Br, I, =0, SH, SR', NH2, NHR', NR'2, OSO3H, OPO3H3, CO2H, CO2R', and the like.
R^ may be H, or a one to 15 carbon saturated, unsaturated, or cyclic alkyl group, where C may be replaced by O, S, SO, SO2, NH, or NR', and may be optionally substituted with OH, OR', F, Cl, Br, I, =0, SH, SR', NH2, NHR', NR'2, OSO3H, OPO3H3, CO2H, CO2R', and the like.
R7 may be H, or a one to 15 carbon saturated, unsaturated, or cyclic alkyl group, where C may be replaced by O, S, SO, SO2, NH, or NR', and may be optionally substituted with OH, OR', F, Cl, Br, I, =0, SH, SR', NH2, NHR', NR'2, OSO3H, OPO3H3, CO2H, CO2R', and the like.
Rg may be H, or a one to 15 carbon saturated, unsaturated, or cyclic alkyl group, where C may be replaced by O, S, SO, SO2, NH, or NR', and may be optionally substituted with OH, OR', F, Cl, Br, I, =O, SH, SR', NH2, NHR', NR'2, OSO3H, OPO3H3, CO2H, CO2R', and the like. R' may be a one to ten carbon, saturated, unsaturated, or cyclic alkyl group.
R3 and R4 may be linked to form a ring.
R3 and R5 may be linked to form a ring.
R4 and R5 may be linked to form a ring. R5 and R6 may be linked to form a ring.
R.6 and R7 may be linked to form a ring.
R7 and Rg may be linked to form a ring.
In some embodiments, R1 of the substituted quinones according to Formula 1, 2, 3, 4 or 5 is -CH2-CH2 5NH2, or -CH2-CH2NR3R2, or -CH2-CH(CO2R4)NR2R3.
In some embodiments, R2 of the substituted quinones according to Formula 1, 2, 3, 4 or 5 is H.
In some embodiments, X of the substituted quinones according to Formula 1, 2, 3, 4 or 5 is N-Me or NR'. In some embodiments of the present invention, Formulas 1, 2, 3, 4 and 5 may be considered together in the single Formula A:
Figure imgf000026_0001
Formula A wherein
X is selected from the group consisting of: NH, NR, O, and S;
1 2 R and R are independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR may be optionally substituted with one or more of: OH, OR, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R; n is 1 or 2;
R is bonded to one of: i) the carbon at position 6, ii) the carbon at position 7 or iii) both the carbon at position 6 and the carbon at position 7 and R is selected from the group consisting of: H,
Figure imgf000027_0001
, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R;
Q Q I f) Q
Y is selected from the group consisting of: CR , CR R , HCR , CH2, NH, NR9, 0 and S; and
R , R , R , R , R , R , R and R are each independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R; and each R in each of X, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
In some embodiments of Formula A described herein, R is optionally selected from the group consisting of: H,
Figure imgf000027_0002
, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R;
3 5 8 9
R , R , R , and R are each independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and
3 5 8 9 each R in each of R , R , R , and R is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic. In some embodiments of Formula A described herein at least one R is a group that blocks a Michael addition from nucleophiles to the indole quinone. This may be achieved by providing a steric effect, such as bulk or hindrance. The blocked nucleophile may be a biological nucleophile or a be a nucleophile under biological conditions.
In some embodiments of Formula A described herein, R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; or iii) a first carbon bonded to the carbon at position 6 and a second carbon bonded to the carbon at position 7. In some embodiments of Formula A, X is NR12;
R is selected from the group consisting of: H and a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic; R is selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR may be optionally substituted with one or more of: OH, OR, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R;
R2 is H; n is 1;
„ 11 . r
R comprises one or: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; and
R is selected from the group consisting of:
Figure imgf000029_0001
wherein
Z2 is H, R or OR;
Z , Z , Z , and Z are independently selected from the group consisting of: CH2, O, S, NH, and are optionally substituted with OH, OR, R, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; at least one of Z , Z , Z , and Z is N optionally substituted with OH, OR, R, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in each of Z , Z , Z , Z , and Z is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic. In some embodiments of Formula A described herein, X is selected from the group consisting of NH and NR wherein R is selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic. In some embodiments of Formula A described herein, X is NH.
In some embodiments of Formula A R is H.
In some embodiments of Formula A described herein, n is 1.
In particular embodiments of Formula A described herein, R is selected from the group consisting of:
Figure imgf000030_0001
wherein
1 2
G and G are independently selected from the group consisting of: a one to 12 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R;
G , G , G , and G are independently selected from the group consisting of: H, R, OH, OR, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in each of G , G , G , G , G , and G is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic. Formula B may be used to describe these particular embodiments of Formula A where R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; or iii) a first carbon bonded to the carbon at position 6 and a second carbon bonded to the carbon at position 7.
Figure imgf000031_0001
Formula B wherein n Ri l compri •ses one o cf: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; or iii) a first carbon bonded to the carbon at position 6 and a second carbon bonded to the carbon at position 7; and
R is selected from the group consisting of:
Figure imgf000031_0002
, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon not bonded to the carbon at position 6 or the carbon at position 7 is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R;
9 9 10 9
Y is selected from the group consisting of: CR , CR R , HCR , CH2, NH, NR9, O and S; R3, R4, R5, R6, R7, R8, R9 and R10 are each independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R;
R is selected from the group consisting of: H and a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic;
1 2
G and G are independently selected from the group consisting of: a one to 12 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or
NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2,
OSO3H, OPO3H3, CO2H, and CO2R; G , G , G , and G are independently selected from the group consisting of:
H, R, OH, OR, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and
CO2R; each R in each of R3, R4, R5, R6, R7, R8, R9, R10, R1 \ G1, G2, G3, G4, G5, and
G is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
In some embodiments of Formula A and/or B described herein, R is selected from the group consisting of:
Figure imgf000033_0001
, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon that is not bonded to the carbon at position 6 or the carbon at position 7 is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R;
R , R , R , and R are each independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and
3 5 8 9 each R in each of R , R , R , and R is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic. hi some embodiments of Formula A and/or B described herein R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; or iii) a first carbon bonded to the carbon at position 6 and a second carbon bonded to the carbon at position 7; and
R is a group that blocks a Michael addition from nucleophiles to the indole quinone. This may be achieved by providing a steric effect, such as bulk or hindrance. The blocked nucleophile may be a biological nucleophile or a be a nucleophile under biological conditions.
In some embodiments of Formula A and/or B described herein, R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; and
R is selected from the group consisting of: a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon not bonded to the carbon at position 6 is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in R is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic. In some embodiments of Formula A and/or B described herein, R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; and
R is selected from the group consisting of: a three to eight carbon partially-aromatic or non-aromatic ring or fused ring system, where each carbon not bonded to the carbon at position 6 is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; the carbon in R bonded to the carbon at position 6 or position 7 is further substituted with H, R or OR; and each R in R is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic. In some embodiments of Formula A and/or B described herein, R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; and
R is selected from the group consisting of:
Figure imgf000035_0001
wherein
Z is H, R or OR;
Z , Z , Z , and Z are independently selected from the group consisting of: CH2, O, S, NH, and are optionally substituted with OH, OR, R, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; at least one of Z4, Z5, Z6, and Z7 is N optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in each of Z , Z , Z , Z , and Z is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
1 2
In some embodiments of Formula A and/or B described herein, G and G are independently selected from the group consisting of: H, and
Figure imgf000035_0002
wherein
Q is CH2, 0, NH, NR or S; k is O, 1, 2, 3, 4, 5, 6, or 7; and
G is a three to eight carbon cyclic, branched-cyclic group that is optionally aromatic, partially-aromatic or non-aromatic, where each carbon is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in G is selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
In some embodiments of Formula A and/or Formula B described herein, G and G are independently selected from the group consisting of: H, and
Figure imgf000036_0001
wherein
Q is CH2, O, NH, NR or S; k is O, 1, 2, 3, 4, 5, 6, or 7; G , G , G , G and G are independently selected from the group consisting of: H, R, OH, OR, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in each of G , G , G , G and G is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
1 2
In some embodiments of Formula A and/or B described herein, G and G are independently selected from the group consisting of H, Carbobenzyloxy (Cbz), tert-Butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC), Benzyl (Bn), and p-methoxyphenyl (PMP).
12 hi some embodiments of Formula A and/or B described herein R is H. In some embodiments of Formula A and/or B described herein Q is O or CH2. In some embodiments of Formula A and/or B described herein Q is O.
In some embodiments of Formula A and/or B described herein k is 1. In some particular embodiments of Formula A and/or B described herein G is H; R is not directly bonded to the carbon at position 7, R comprises a carbon bonded to the carbon at position 6 and R is selected from the group consisting of: a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon not bonded to the carbon at position 6 is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in R is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic. These particular embodiments of Formula A and/or B may be described as Formula C:
Figure imgf000037_0001
Formula C wherein
G may be as defined herein for any embodiment of Formula A and/or B;
.12
R may be as defined herein for any embodiment of Formula A and/or B; and
Z comprises a carbon bonded to the carbon at position 6 and Z is selected from the group consisting of: a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon not bonded to the carbon at position 6 is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in Z is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
2
In some particular embodiments of Formula A, B and/or C described herein G is H; where present, R is not directly bonded to the carbon at position 7, and where present R and/or Z comprises a carbon bonded to the carbon at position 6 and where present R and/or Z is selected from the group consisting of: a three to eight carbon partially-aromatic or non-aromatic ring or fused ring system, where each carbon not bonded to the carbon at position 6 is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; where present the carbon in R and/or Z bonded to the carbon at position 6 may be further substituted with H, R or OR; and where present each R in R and Z is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
These particular embodiments are also embodiments of Formula A, B and/or C and may be described as Formula D:
Figure imgf000038_0001
Formula D wherein
G may be as defined herein for any embodiment of Formula A, B and/or C;
R may be as defined herein for any embodiment of Formula A, B, and/or C;
Z comprises a carbon bonded to the carbon at position 6 and Z is a three to eight carbon partially-aromatic or non-aromatic ring or fused ring system, where each carbon not bonded to the carbon at position 6 is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and
Z is selected from the group consisting of H, R and OR and is bonded to the carbon of Z that is bonded to the carbon at position 6;
2 3 each R in each of Z and Z is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
In some particular embodiments of Formula A, B, C and/or D described herein G is H; where present, R is not directly bonded to the carbon at position 7, and where present R , Z and/or Z +Z is selected from the group consisting of:
Figure imgf000039_0001
wherein Z2 is H, R or OR;
Z , Z , Z , and Z are independently selected from the group consisting of: CH2, O, S, NH, and are optionally substituted with OH, OR, R, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; at least one of Z , Z , Z , and Z is N optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in each of Z , Z , Z , Z , and Z is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic. These particular embodiments are also embodiments of Formula A, B, C and/or D and may be described as Formula E:
Figure imgf000040_0001
Formula E wherein
G may be as defined herein for any embodiment of Formula A, B, C and/or
D;
.12
R may be as defined herein for any embodiment of Formula A, B, C and/or
D; τ2 .
Z is selected from the group consisting of H, R and OR;
Z , Z , Z , and Z are independently selected from the group consisting of: CH2, O, S and NH, where each CH2, O, S, NH is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; at least one of Z4, Z5, Z6, and Z7 is N optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in each of Z , Z , Z , Z , and Z is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
In some particular embodiments of Formula A, B, C, D, and/or E described herein G is H; where present, R . 11 i ■s not directly bonded to the carbon at position 7, and where present R11, Z1, Z3+Z2 and/or Z4+Z5+Z5+Z6+Z7+Z2 is:
Figure imgf000041_0001
wherein
T is H, R or OR;
Z and Z are independently R; and
2 8 9 each R in each of Z , Z and Z is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic. These particular embodiments are also embodiments of Formula A, B, C, D and/or E and may be described as Formula F:
Figure imgf000041_0002
Formula F wherein
G may be as defined herein for any embodiment of Formula E;
R may be as defined herein for any embodiment of Formula E;
2
Z may be as defined herein for any embodiment of Formula E;
8 9
Z and Z are independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic. In some aspects of the present invention, there is provided compounds having the general formula, Formula G:
Figure imgf000042_0001
Formula G wherein R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; or iii) a first carbon bonded to the carbon at position 6 and a second carbon bonded to the carbon at position 7; and
R is selected from the group consisting of:
Figure imgf000042_0002
, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially- aromatic or non- aromatic, where each carbon not bonded to the carbon at position 6 or the carbon at position 7 is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R; Q Q 10 Q
Y is selected from the group consisting of: CR , CR R , HCR , CH2, NH,
NR9, O and S;
R3, R4, R5, R6, R7, R8, R9 and R10 are each independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R;
R is selected from the group consisting of: H and a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic;
1 2
G and G are independently selected from the group consisting of: H, and
Figure imgf000043_0001
wherein Q is CH2, O, NH, NR or S; k is O, 1, 2, 3, 4, 5, 6, or 7;
G , G , G , and G are independently selected from the group consisting of: H, R, OH, OR, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; G is a three to fourteen carbon cyclic, branched-cyclic group that is optionally aromatic, partially-aromatic or non-aromatic, where each carbon is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R;
G , G , G , and G are independently selected from the group consisting of: H, R, OH, OR, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; each R in each of R3, R4, R5, R6, R7, R8, R9, R10, R1 \ G1, G2, G3, G4, G5, G6 and G is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic. In these embodiments, R , R , R , R , R , R , R8, R9, R10, R11, R12, G8, G9, G10, G11, G12, Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, X, Y, Z, and n, wherein present, may be as defined herein for any one of Formulas A, B, C, D, E and or F. In some embodiments, the substituted quinones according to Formula A, B, C, D, E,
F and/or G may be a prodrug. A prodrug is a compound that may be administered in a less active, or inactive form, and metabolized in the subject's body into an active, or more active, compound.
In some embodiments, the substituted quinones according to Formula A, B, C, D, E, F and/or G may further include a counterion. Examples of counterions include sulfate, phosphate, chloride, bromide, iodide, acetate, succinate and other counterions known to a person of skill in the art. Depending on the charge of the embodiment of Formula A, B, C, D, E, F and/or G there may be more than one counterion and there will be sufficient counterions to provide an overall neutral charge when the charge of the counterion(s) and the embodiment of Formula A, B, C, D, E, F and/or G are taken together.
Detailed methods of isolating and/or making compounds of the present invention are provided in detail in the Examples below. A person of skill in the art will appreciate that minor variations to the synthetic routes set out in the examples may be used to prepare compounds of the invention that are different compounds then those compounds specifically set out in the Examples. In addition, the following general synthetic schemes are provided as a guide to a person of skill in the art. In the following general schemes protecting groups on the indole NH and the side chain NH are generally recommended unless nucleophiles that are less basic than those NH' s are used.
Figure imgf000045_0001
1. T1(OCOCF3)3/TFA
2. CuSθ4-5H2θ/DMF
Figure imgf000045_0002
General Scheme I
Figure imgf000046_0001
General Scheme II HCBz
Figure imgf000047_0001
Figure imgf000047_0002
General Scheme III HCBz
Figure imgf000047_0003
General Scheme IV
The following are references that describe reactions from which Schemes I, II, III, and/or IV above have been derived, are similar to or contain similar chemical steps. As such the chemistry described in the following references may provide additional guidance to a person of skill in the art when synthesizing compounds of the present invention. Tapia et al, 2006, Synth. Commun. 36: 771-776; Tapia et al, 2001, Tetrahedron Lett. 42: 887-889; Kraus et al, 2005, Eur. J. Org. Chem. 2005:3040-3044; Swartz et al., 2005, Org. Lett. 7:3163-3166; Tapia et al., 2003, Bioorganic and Medicinal Chemistry, 11:3407-3412; Leegntil, et al, 2003, Tetrahedron Lett., 44:2473-2475; and Bouaziz et al, 2002, Eur. J. Org. Chem. 1834-1838.
In some embodiments, the compounds described herein are provided in the form of pharmaceutically-acceptable salts and/or pharmaceutically-acceptable compositions. Many compounds of this invention or for use in this invention are generally water soluble and may be formed as salts. In such cases, pharmaceutical compositions in accordance with this invention may comprise a salt of such a compound, preferably a physiologically acceptable salt, which are known in the art. Pharmaceutical preparations will typically comprise one or more carriers acceptable for the mode of administration of the preparation, be it by injection, inhalation, topical administration, lavage, or other modes suitable for the selected treatment. Suitable carriers are those known in the art for use in such modes of administration.
Suitable pharmaceutical compositions may be formulated by means known in the art and their mode of administration and dose determined by the skilled practitioner. For parenteral administration, a compound may be dissolved in sterile water or saline or a pharmaceutically acceptable vehicle used for administration of non- water soluble compounds such as those used for vitamin K. For enteral administration, the compound may be administered in a tablet, capsule or dissolved in liquid form. The tablet or capsule may be enteric coated, or in a formulation for sustained release. Many suitable formulations are known, including, polymeric or protein microparticles encapsulating a compound to be released, ointments, gels, hydrogels, or solutions which can be used topically or locally to administer a compound. A sustained release patch or implant may be employed to provide release over a prolonged period of time. Many techniques known to skilled practitioners are described in Remington: the Science & Practice of Pharmacy by Alfonso Gennaro, 20th ed., Williams & Wilkins, (2000). Formulations for parenteral administration may, for example, contain excipients, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes. Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds. Other potentially useful parenteral delivery systems for modulatory compounds include ethylene- vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel. Munn et al. (US Patents 6,451,840 and 6,482,416) describe administering to a subject an effective amount of a pharmaceutical composition comprising an inhibitor of IDO, and uses thereof.
Ophthalmic compositions such as sterile aqueous solutions may be prepared using techniques known in the art by the skilled practitioner. Pigiet et al. (US Patent 4,771,036) describe a method and an ophthalmic composition for the prevention and reversal of cataracts. Itoh et al. (US Patent 6,500,813) describe ophthalmic compositions, including eye drops, used for preventing deterioration of the optical transparency. Babizhayev et al. Drugs RaD, 3, 87-103 describe a human trial of eye drops containing drugs in a phosphate-buffered saline for the treatment of cataracts. Ophthalmic compositions may be packaged in a suitable container or eye dropper adopted for the delivery of drops to the eye. Compounds described herein may be used in combination with chemotherapeutics or other therapeutic modalities, particularly for the treatment of a cancer. Other therapeutic modalities include, but are not limited to, chemotherapeutics, radiation therapy, antiviral agents, antibacterial agents, antifungal agents, antimicrobial agents, signal transduction inhibitors, cytokines, vaccines, hormone therapy, surgical resection, immunostimulatory therapy, anti-tumor vaccines, antibody based therapies, whole body irradiation, bone marrow transplantation and peripheral blood stem cell transplantation. An IDO inhibitor may be administered before, after or during the other therapeutic modality.
As used herein, a "chemotherapeutic" refers to a chemical compound or composition that may be used to treat a disease in a patient. There are many chemotherapeutics and of particular interest are cancer chemotherapeutics.
There are many groups of cancer chemotherapeutics including, alkylating and oxidizing agents, antimetabolites, antibiotics, mitotic inhibitors, chromatin function inhibitors, hormone and hormone inhibitors, antibodies, immunomodulators, angiogenesis inhibitors, rescue/protective agents, and others.
The alkylating and oxidizing agent class of cancer chemotherapeutics includes seven subclasses: nitrogen mustards, ethylenimines, alkyl sulfonates, nitrosureas, triazenes and platinum coordinating complexes. Examples of nitrogen mustards include mechlorethamine (Mustargen™), cyclophosphamide (Cytoxan™ and Neosar™), ifosfamide (Ifex™), phenylalanine mustard, melphalen (Alkeran™), chlorambucol (Leukeran™), uracil mustard and estramustine (Emcyt™). An example of an ethylanimine is thiotepa (Thioplex™). An example of an alkyl sulfonate is busulfan (Myerlan™). Examples of nitrosureas are lomustine (CeeNU™), carmustine (BiCNU™ and BCNU™) and streptozocin (Zanosar™). Examples of triazines are dicarbazine (DTIC-Dome™) and temozolamide (Temodar™). Examples of platinum coordination complexes are cis-platinum, cisplatin (Platinol™ and Platinol AQ™) and carboplatin (Paraplatin™). Other examples of alkylating and oxidizing agents include altretamine (Hexalen™) and arsenic (Trisenox™). This class of chemotherapeutics are generally cell cycle non-specific (although a greater effect in the Gl, S phase of the cell cycle is often observed) and work through the alkylation of DNA (through carbonium ion intermediates). They may encourage covalent cross-linking of DNA, RNA and proteins, cause single-stranded DNA breaks or provide abnormal DNA base pairing. Through these mechanisms these chemotherapeutics tend to interrupt cell replication. In particular, platinum coordinating complex agents generally cause cross-linking of DNA strands and have an affinity for alkylation at guanine bases (at the N7 position) and adenine (at the N7 position). This may cause interstrand and intrastrand cross-linking. The drugs themselves may also bind to protein SH groups.
The antimetabolite class of cancer chemotherapeutics includes: folic acid analogs, pyrimidine analogs and purine analogs. Examples of folic acids include: methotrexate (Amethopterin™, Folex™, Mexate™, Rheumatrex™). Examples of pyrimidine analogs include 5-fluoruracil (Adrucil™, Efudex™, Fluoroplex™), floxuridine, 5-fluorodeoxyuridine (FUDR™), capecitabine (Xeloda™), flurdarabine (Fludara™), cytosine arabinoside (Cytaribine™, Cyrosar™, ARA-C™). Examples of purine analog include: 6-mercaptopurine (Purinethol), 6-thioguanine (Thioguanine™), gemcitabine (Gemzar™), cladribine (Leustatin™), deoxycoformycin and pentostatin (Nipent™). These chemotherapeutics are generally S phase specific and are often structurally related to normal cellular components. They often work through interference with nucleotide syntheses and compete with cellular nucleotides in DNA and RNA synthesis.
The antibiotic class of cancer chemotherapeutics includes: doxorubicin (Adriamycin™, Rubex™, Doxil™, Daunoxome™-liposomal preparation), daunorubicin (Daunomycin™, Cerubidine™), idarubicin (Idamycin™), valrubicin (Valstar™), epirubicin, mitoxantrone (Novantrone™), dactinomycin (Actinomycin D™, Cosmegen™), mithramycin, plicamycin (Mithracin™), mitomycin C (Mutamycin™), bleomycin (Blenoxane™), procarbazine (Matulane™). chemotherapeutics in this class are also generally cell cycle non-specific (exceptions include bleomyacin and procarbozine). This class of chemotherapeutics generally intercalates into double-stranded DNA and disrupts the DNA by binding to the DNA helix. These chemotherapeutics also inhibit DNA synthesis by inhibiting nucleotide incorporation or inhibiting DNA dependent RNA synthesis. Some of these chemotherapeutics also inhibit DNA coiling and in some cases achieve this by inhibiting topoisomerase II which leads to strand breaks. In particular, doxorubicin intercalates in DNA, binding to the sugar phosphate backbone of the DNA. Doxorubicin also binds to cell membranes blocking the phosphatidyl-inositol activation. Doxorubicin can also inhibit topoisomerase II.
The mitotic inhibitor class of cancer chemotherapeutics includes: taxanes or diterepenes and vinca alkaloids. Examples of taxanes include paclitaxel (Taxol™) and docetaxel (Taxotere™). Examples of vinca alkaloids include vinblastine sulfate (Velban™, Velsar™, VLB™), vincristine sulfate (Oncovin™, Vincasa PFS™, Vincrex™) and, vinorelbine sulfate (Navelbine™). This class of chemotherapeutics are cell cycle specific and generally disrupt the cell cycle during the M phase. This class of cancer chemotherapeutic disrupts the mitotic spindle thereby inhibiting chromosomal segregation and blocking mitosis. The taxanes groups of mitotic inhibitors, which include paclitaxel and docetaxel, are derived from the bark of the Pacific Yew tree. They prevent microtubular depolymerization thereby inhibiting a reorganization of the microtubular network. Microtubular stabilization also promotes the formation of abnormal bundles of microtubules. The chromatin function inhibitor class of cancer chemotherapeutics includes: camptothecins and epipodophyllotoxins. Examples of camptothecins include topotecan (Camptosar™) and irinotecan (Hycamtin™). Examples of epipodophyllotoxins include etoposide (VP- 16™, VePesid™ and Toposar™) and teniposide (VM-26™ and Vumon™). These chemotherapeutics are generally cell cycle specific and may bind to either topoisomerase I or topoisomerase II. In the case where they bind to topoisomerase I, this prevents re-ligation of breaks in the DNA. In the case where they bind with topoisomerase II, this prevents transcription replication of the DNA thereby killing the cell.
The hormone and hormone inhibitor class of cancer chemotherapeutics includes: estrogens, antiestrogens, aromatase inhibitors, progestins, GnRH agonists, androgens, antiandrogens and inhibitors of syntheses. Examples of estrogens include diethylstilbesterol (Stilbesterol™ and Stilphostrol™), estradiol, estrogen, esterified estrogens (Estratab™ and Menest™) and estramustine (Emcyt™). Examples of anti-estrogens include tamoxifin (Nolvadex™) and toremifene (Fareston™). Examples of aromatase inhibitors include anastrozole (Arimidex™) and letrozol (Femara™). Examples of progestins include 17-OH-progesterone, medroxyprogesterone, and megastrol acetate (Megace™). Examples of GnRH agonists include gosereline (Zoladex™) and leuprolide (Leupron™). Examples of androgens include testosterone, methyltestosterone and fluoxmesterone (Android-F™, Halotestin™). Examples of antiandrogens include flutamide (Eulexin™), bicalutamide (Casodex™) and nilutamide (Nilandron™). Examples of inhibitors of synthesis include aminoglutethimide (Cytadren™) and ketoconozole (Nizoral™). These chemotherapeutics bind to a variety of hormones, generally estrogens and androgens or block receptors to these hormones. Cell growth and development is impaired by these chemotherapeutics by interfering with a cell's ability to bind a particular hormone, either by blocking the receptor or by binding to the hormone itself.
The antibodies class of cancer chemotherapeutics includes: rituximab (Rituxan™), trastuzumab (Herceptin™), gemtuzumab ozogamicin (Mylotarg™), tositumomab (Bexxar™) and bevacizumab. These chemotherapeutics may be antibodies that are targeted to a particular protein on the cell surface of a cancer cell. These antibodies may provide a motif for generating an immune response to the antibody and hence the cancer cell or possibly induce apoptosis. Other mechanisms of action of this class of chemotherapeutic include inhibiting stimulation from growth factors by binding to receptors on cancer cells. The immunomodulators class of cancer chemotherapeutics includes: denileukin diftitox (Ontak™), levamisole (Ergamisol™), bacillus Calmette-Gueran, BCG (TheraCys™, TICE BCG™), interferon alpha-2a, interferon alpha-2b (Roferon-A™, Intron A™) and interleukin-2 and aldesleukin (ProLeukin™). These chemotherapeutics provide an interaction with or a stimulation of the host immune system so that the host immune system attacks the cancer cells. Interleukin-2 modulation, stimulation of cytotoxic T cells, macrophages, as well as B cells are common mechanisms of action for this class of cancer chemotherapeutics .
The angiogenesis class of cancer chemotherapeutics includes: thalidomide (Thalomid™), angiostatin and endostatin. These chemotherapeutics generally inhibit tumour vascularization thereby preventing growth of tumors by reducing blood supply to the tumours.
The rescue/protective agents class of cancer chemotherapeutics includes: dexrazoxane (Zinecard™), amifostine (Ethyol™), G-CSF (Neupogen™), GM-CSF (Leukine™), erythopoetin (Epogen™, Procrit™), oprelvekin and IL-Il (Neumega™). These chemotherapeutics work through a variety of different mechanisms of action. These mechanisms of action include protecting DNA, binding to cisplatin metabolites protecting the kidneys or cardioprotective mechanisms. Other chemotherapeutics in this class will stimulate granulocyte, macrophage, erythroid progenitor and megakaryocyte proliferation and differentiation. Other cancer chemotherapeutics include imatinib mesylate, STI-571 (Gleevec™),
1-aspariginase (Elspar™, Kidrolase™), pegaspasgase (Oncaspar™), hydroxyurea (Hydrea™, Doxia™), leucovorin (Wellcovorin™), mitotane (Lysodren™), porfimer (Photofrin™) and tretinoin (Veasnoid™). Some chemotherapeutics may inhibit the Bcr-Abl tyrosine kinase, for example imatinib mesylate.
Prendergast et al (WO 2004/093871) describe methods for the treatment of cancer, malignancy and chronic viral infection using IDO inhibitors alone and IDO inhibitors in combination with other chemotherapeutics. Munn et al. (US Patent Application publication number 2004/0234623) describe the use of inhibitors of indoleamine-2,3-dioxygenase in combination with other therapeutic modalities.
Administration of an EDO inhibitor, a chemotherapeutic, or both may be independently by systemic, parenteral, intravenous, subcutaneous, transdermal, transmucosal, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intranasal, aerosol, topical, surgical, oral or parenteral administration. Dosage and duration of treatment will be determined by the practitioner in accordance with standard protocols and information concerning the activity and toxicity of the chosen compound. Compounds or pharmaceutical compositions in accordance with this invention or for use in this invention may be administered by means of a medical device or appliance such as an implant, graft, prosthesis, stent, etc. Also, implants may be devised which are intended to contain and release such compounds or compositions. An example would be an implant made of a polymeric material adapted to release the compound over a period of time. An "effective amount" of a pharmaceutical composition according to the invention includes a therapeutically effective amount or a prophylactically effective amount. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as improved IDO inhibition, reduced tumour growth or tumour regression. A therapeutically effective amount of a compound may vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result, such as reduced tumour growth or no tumor growth. Typically, a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effective amount may be less than a therapeutically effective amount.
It is to be noted that dosage values may vary with the severity of the condition to be alleviated. For any particular subject, specific dosage regimens may be adjusted over time according to the individual need and the professional judgement of the person administering or supervising the administration of the compositions. Dosage ranges set forth herein are exemplary only and do not limit the dosage ranges that may be selected by medical practitioners. The amount of active compound(s) in the composition may vary according to factors such as the disease state, age, sex, and weight of the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It may be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. In general, compounds of the invention should be used without causing substantial toxicity. Toxicity of the compounds of the invention can be determined using standard techniques, for example, by testing in cell cultures or experimental animals and determining the therapeutic index, i.e., the ratio between the LD50 (the dose lethal to 50% of the population) and the LDlOO (the dose lethal to 100% of the population). In some circumstances however, such as in severe disease conditions, it may be necessary to administer substantial excesses of the compositions.
As used herein, a "subject" may be a human, non-human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc. The subject may be suspected of having or at risk for having an EDO-mediated disease. Diagnostic methods for various IDO mediated diseases and disorders and the clinical delineation of IDO mediated disease and disorder diagnoses are known to those of ordinary skill in the art.
In some embodiments, compounds and compositions described herein may be used in the treatment of diseases characterized by the pathology of the IDO-mediated tryptophan metabolic pathway. Such diseases include but are not limited to cancer, diseases of the eye, cataracts, autoimmune diseases, and mood disorders. IDO inhibitors may be useful as drugs for treating diseases characterized by a pathology involving the IDO-mediated tryptophan metabolic pathway. A subject having a disease characterized by a pathology involving the IDO-mediated tryptophan metabolic pathway may be administered a compound or composition described herein.
IDO plays a role in several diseases, including Clamydia psittaci infection and Streptococcus pyogenes infection, systemic lupus erythematosus, rheumatoid arthritis, Alzheimer's disease, Huntington's disease, Parkinson's disease, lyme neuroborreliosis, late lyme encephalopathy, Tourette's syndrome, systemic sclerosis, multiple sclerosis, coronary heart disease, T-cell mediated immune diseases, chronic infections (viral, bacterial, fungal and microbial), depression, neurological disorders, cancer tumors, and cataracts. Inhibitors of IDO may be used to treat these diseases. Other diseases that IDO inhibitors may be used to treat include, but are not limited to, human immunodeficiency virus (HIV), AIDS-related cancers, adrenocorticocancer, basal cell carcinoma, bladder cancer, bowel cancer, brain and CNS tumors, breast cancers, B-cell lymphoma, carcinoid tumors, cervical cancer, childhood cancers, chondrosarcoma, choriocarcinoma, chronic myeloid leukemia, rectal cancers, endocrine cancers, endometrial cancer, esophageal cancer, Ewing's sarcoma, eye cancer, gastric cancer or carcinoma, gastrointestinal cancers, genitourinary cancers, glioma, gynecological cancers, head and neck cancers, hepatocellular cancer, Hodgkins disease, hypopharynx cancer, islet cell cancer, Kaposi's sarcoma, kidney cancer, laryngeal cancer, liver cancer, lung cancer (including small-cell lung carcinoma and non-small-cell carcinoma), lymphoma, male breast cancer, melanoma, mesothelioma, multiple myeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkins lymphoma, non-melanoma skin cancer, osteosarcoma, ovarian cancer, pancreas cancer, pituitary cancer, prostate cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, skin cancer, squamous cell carcinoma, stomach cancer, testicular cancer or seminoma, thymus cancer, thyroid cancer, transitional cell cancer, trophoblastic cancer, uterine cancer, vaginal cancer, Waldenstrom's macroglobulinemia, and WiIm' s tumor, colorectum, cervix, endometrium, ovary, testis, mesothelial lining, white blood cell (including lymphoma and leukemia) esophagus, muscle, connective tissue, adrenal gland, bone, glioblastoma, and cutaneous basocellular carcinoma. IDO inhibitors may be used to treat such diseases.
A "cancer" refers to a proliferative or neoplastic disorder caused or characterized by the proliferation of cells which have lost susceptibility to normal growth control. The term cancer, as used in the present application, includes tumors and any other proliferative disorders. Cancers of the same tissue type usually originate in the same tissue, and may be divided into different subtypes based on their biological characteristics. Four general categories of cancers are carcinoma (epithelial tissue derived), sarcoma (connective tissue or mesodermal derived), leukemia (blood-forming tissue derived) and lymphoma (lymph tissue derived). Over 200 different types of cancers are known, and every organ and tissue of the body may be affected. Specific examples of cancers that do not limit the definition of cancer may include melanoma, leukemia, astrocytoma, glioblastoma, retinoblastoma, lymphoma, glioma, Hodgkins' lymphoma and chronic lymphocyte leukemia. Examples of organs and tissues that may be affected by various cancers include pancreas, breast, thyroid, ovary, uterus, testis, prostate, thyroid, pituitary gland, adrenal gland, kidney, stomach, esophagus or rectum, head and neck, bone, nervous system, skin, blood, nasopharyngeal tissue, lung, urinary tract, cervix, vagina, exocrine glands and endocrine glands. Alternatively, a cancer may be multicentric or of unknown primary site (CUPS).
IDO inhibitors may also be used to treat an autoimmune disease. An autoimmune disease is a disease resulting from the failure of an organism to recognize its constituent parts as 'self, which results in an acquired immune response against its own tissues and/or cells. Examples of autoimmune diseases may include Crohn's disease, type I diabetes, celdisease, systemic lupus erythematosus, Sjogren's syndrome, rheuma arthritis, acute disseminated encephalomyelitis, Addison's disease, aplastic anemia, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, multiple sclerosis, opsoclonus myoclonus syndrome, optic neuritis, pemphigus, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, Wegener's granulomatosis, and alopecia.
IDO inhibitors may also be used to treat mood disorders. Mood disorders include depression, anxiety, and bipolar disorder.
Various alternative embodiments and examples of the invention are described herein. These embodiments and examples are illustrative and should not be construed as limiting the scope of the invention.
Examples
Example 1 - Isolation of IDO Inhibitors
A MeOH extract of the sponge Neopetrosia exigua collected in Papua New Guinea showed potent activity in an in vitro IDO inhibitory activity assay (see Example 3).
Bioassay guided fractionation revealed that the alkaloid exiguamine A was the major IDO inhibitory component of the crude extract. Details of the isolation, structure elucidation, and biological activity of exiguamine A are described below. Neopetrosia exigua (140 g wet wt) was collected by hand using SCUBA in Milne Bay in Papua New Guinea (10° 32.02' S, 150° 39.07' E). N. exigua is a red/brown smooth encrusting sheet sponge (specimen size ~ 2mm x 10 cm) found growing on the underside of overhang at 15 m. depth. A voucher sample has been deposited at the Zoologisch Museum, University of Amsterdam, Mauritskade 61, 1092 AD Amsterdam (ref No. ZMAPOR19113). Freshly collected sponge specimens were frozen on site and stored frozen until workup.
The frozen sponge was thawed and extracted exhaustively with MeOH (4 x IL). The combined MeOH extracts were reduced in vacuo to give a brown solid (5.6 g) that was dissolved in 400 mL of H2O and sequentially extracted with EtOAc (3 x 200 mL) and n-butanol (3 x 200 mL). The IDO inhibitory n-butanol fraction (1.2 g) was subjected to Sephadex™ LH-20 size exclusion chromatography eluting with 100% methanol. The IDO inhibitory fractions were combined and further fractionated on a reversed-phase Sep Pak™ (gradient elution: H2O to MeOH) which yielded 300 mg of active material. The bioactive material was subjected to gradient reversed-phase HPLC (Inertsil C 18, 9.4 X 250 mm, H2O to CH3CN containing 0.1% TFA, monitored by UV detection at 254 nm) giving 98 mg of an IDO inhibitory fraction. This material was further purified by isocratic reversed phase HPLC (Inertsil C18, 9.4 X 250 mm, 9 H20: 1 CH3CN: 0.1% TFA) to give pure exiguamine A (20 mg) and exiguamine B (4.5 mg). Pure exiguamine A was suspended in 1 N HCl and the solution was evaporated in vacuo. Repeating this process four times generated the HCl salt, which gave deep red crystals from MeOH. The structures of Exiguamine A and Exigamine B are:
Figure imgf000057_0001
Exaguamine A and Exaguamine B Exiguamine A was isolated as deep-red optically-inactive crystals that gave a [M]+ ion at mlz 492.1882 in the HRESIMS consistent with an elemental composition of C25H26N5O6 (calcd 492.1883). The 13C NMR spectrum showed 25 well-resolved resonances in agreement with the HRMS analysis, and the HMQC/ DEPT data indicated that 22 of the 26 hydrogen atoms were attached to carbon (C x 15; CH x 2, CH2 x 4, CH3 x 4). A LRESIMS measurement made in MeOH gave a [M]+ ion at mlz 492.2, and the same experiment using CD3OD gave a [M]+ ion at mlz 496.2, confirming that the four remaining hydrogen atoms were exchangeable. H, N gs-HMQC correlations identified five distinct nitrogen resonances (δ -349, N-26; -310, N-15; -275, N-20; -248, N-22; -218, N-I), also in agreement with the HRMS data.
Fragments of exiguamine A could be assembled from 2D NMR data. A complex multiplet at δ 2.99 (H2-25: HMQC to 38.3) showed COSY correlations to a second multiplet at 2.92 (H2-24: HMQC to δ 23.3) and to a broad singlet at 7.82 (NH3-26). The H2-24 resonance and the NH-26 resonance showed HMQC correlations to a nitrogen resonance at δ -349 (N-26) in agreement with the presence of an ethylamine moiety. A methine at δ 7.30 (d, J = 2.2 Hz, H-2) showed a HMBC correlation to the C-24 resonance at δ 23.3, and H2-24 (δ 2.92) showed HMBC correlations to carbon resonances at δ 120.7 (C-3), 121.3 (C-4), and 126.5 (C-2) indicating that the ethylamine moiety was attached to a trisubstituted double bond. The methine at δ 7.30 (H-2) showed a COSY correlation to an exchangeable resonance at δ 13.10 (NH- 1) and a HMQC correlation to the nitrogen resonance at δ -218 (N-I), which demonstrated that C-2 was bonded to an NH. A pair of carbon resonances at δ 173.4 (C-5 or C-8) and 179.7 (C-5 or C-8) were assigned to quinone carbonyls. Weak HMBC correlations observed between H-2 (δ 7.30) and both of the quinone carbonyl resonances, assigned to W coupling, and between NH-I (δ 13.10) and carbon resonances at δ 179.7 (C-5 or C-8), 173.4 (C-5 or C-8), 120.7 (C-3), 126.5 (C-2), and 131.6 (C-9), were consistent with fragment I.
An isolated H spin system composed of two sets of adjacent methylene protons (δ 3.22, H-17; 3.73, H-17'; HMQC to δ 28.5: 3.84, H-16; 4.17, H-16'; HMQC to 67.4) was identified from the COSY, HMQC, and HMBC data. A pair of methyl resonances at δ 3.43 (Me-27: HMQC to δ 54.3, HMBC to 53.2) and 3.51 (Me- 28: HMQC to δ 53.2, HMBC to 54.3) each showed HMBC correlations to the carbon correlated to the other methyl resonance in the HMQC spectrum, indicating that the methyls were geminal, and their carbon chemical shifts suggested they were attached to nitrogen. The Me-27 and Me-28 resonances (δ 3.43 and 3.51) both showed HMBC correlations to the C-16 resonance at δ 67.4 and both the H-16 and H-16' resonances (δ 3.84 and 4.17) showed HMBC correlations to Me-27 (δ 54.3) demonstrating that C-16 was attached to the same nitrogen (N-15). H-16' (δ 4.17), H-17' (3.73), Me-27 (3.43), and Me-28 (3.51) all showed HMBC correlations to a nonprotonated carbon resonance at δ 142 (C-14), and H-16', H-17', and H-17 (3.22) all showed HMBC correlations to a nonprotonated carbon resonance at δ 122.8 (C-18), which together demonstrated that N-15 and C- 17 were linked via a tetrasubstituted double bond to form an N,N-dimethyldihydropyrrole. Strong HMBC correlations were observed from a singlet methine at δ 7.52 (H- 13:
HMQC to 108.7) to carbon resonances at δ 122.8 (C-18), 142 (C-14 and C-12), and 146.5 (C-I l), and a weak correlation was observed to 114.7 (C-10). Additional HMBC correlations were observed between an exchangeable proton (OH- 12; δ 10.42) and carbon resonances at δ 108.7 (C- 13), 142 (C-12), and 146.5 (C-I l). The H-13 (δ 7.52), Me-27 (3.43), Me-28 (3.51), and H-17 (3.22) resonances all showed HMQC correlations to a nitrogen resonance at δ -310 (N-15). A NOESY correlation was observed between δ 7.52 (H-13) and 3.51 (Me-28). All of the above data were consistent with the fragment II.
A methyl resonance at δ 3.07 (Me-30: HMQC to δ 25.2) showed HMBC correlations to carbon resonances at δ 154.5 (C-21) and 168.6 (C-23) and a HMQC correlation to a nitrogen resonance at δ -248 (N-22), while a second methyl resonance at δ 2.44 (Me- 29: HMQC to δ 26.0) showed HMBC correlations to carbon resonances at δ 154.5 (C-21) and 85.4 (C- 19) and a HMQC correlation to a nitrogen resonance at δ -275 (N-20). These data were assigned to fragment III.
Although fragments I- III accounted for all of the atoms in exiguamine A, there was insufficient information in the NMR data to assign a constitution to the entire molecule. Therefore, exiguamine A was subjected to single-crystal X-ray diffraction analysis, which confirmed the presence of fragments I- III and revealed their connectivity. Exiguamine A crystallized in space group ClIc. The mirror symmetry relationship produced by the c-glide plane in this space group requires that both enantiomers must be present in the unit cell in equal amounts. This means exiguamine A occurs as a natural racemate in agreement with its lack of optical activity.
All solvents used for extraction and chromatography were HPLC grade. When used for HPLC, solvents were filtered through a 0.45 μm filter (Osmonics, Inc). Ten gram reversed-phase C- 18 Si gel Sep-paks and 2 gram normal-phase Si gel Sep-paks were purchased from Waters, Inc. HPLC separations were carried out on a Waters 2487 dual channel detector/system controller (Waters Series 515 pump; chart recorder, 0.25cm/min), or a Waters 600 controller and Waters 486 Tunable Absorbance Detector. A 5μm Inertsil column from Chromatography Sciences (Montreal, PQ) was used for reversed phase HPLC and separations were carried out at 2.0 mL/min, monitoring at 220 run. Thin-layer chromatography (TLC) plates were Whatman MKC 18F (reversed Phase) and Kieselgel 60F254 (normal phase). TLC spots were visualized using either a spray solution of Anis-aldehyde (1% p-anisaldehyde, 2% H2SO4, 20% acetic acid, and 77% ethanol) or under ultraviolet light (254 nm).
NMR spectra were recorded on a Bruker AV600 spectrometer fitted with an inverse triple resonance ( H, C, N) cryoprobe. NMR solvents were purchased from Cambridge Isotope laboratories and were referenced to solvent peaks δH 2.49 ppm and δC 39.5 ppm for OMSO-d6. Low resolution ESI mass spectra were taken on a Bruker Esquire LC mass spectrometer. High resolution ESI mass spectra was taken on a Macromass LCT mass spectrometer. Optical rotations were recorder with a JASCO J-1010 polarimeter equipped with a halogen lamp (589 nm) and a 10 mm micro cell.
Examples 2 - 7: Synthesis of six Compounds for Testing Synthesis of A tryptamine quinone fragment followed an elegant sequential oxidative strategy based on the preparation of indole quinone intermediates used in the synthesis of lymphostin by Tatsuta et al. (Tatsuta, K et al. Tehrahedron Lett. 2004, 45, 2847-2850). Tryptamine (4) was first protected as its Cbz derivative (5) and then oxidized to the ketone (6) in good yield with DDQ (Scheme 1). Selective hydroxylation of (6) at C-4 to give phenol (7) was carried out by reaction with T1(OCOCF3)3 followed by treatment with
CuSO45H2O. Ketone (7) was deoxygenated with NaBH3CN to give to give (8), which was oxidized with Fremy's salt [NO(SO3K)2] to give Cbz protected tryptamine quinone (9) in good yield. Scheme 1
Figure imgf000061_0001
CBzCI R = H (4)
I— RR == Cbz (5) BF3 Et2O NaBH4 THF HCbz
Figure imgf000061_0002
Reaction of quinone (9) with the alkyl amine (10) gave the Michael addition product
(11) in quantitative yield, confirming that nucleophiles would add to (9) at C-5. The ready addition of primary amines at C-5 of (9) explained our observation that deprotection of (9) by hydrogenolysis failed to give any isolatable products. Presumably the deprotected tryptamine quinone polymerizes by intermolecular nucleophilic attack of the primary C-2' amine at C-5.
The first attempt to add a hydantoin substituent at C-5 in (9) involved treatment of the commercially available N,N-dimethylhydantoin with base in DMF followed by addition to quinone (9) in DMF. This reaction failed to give any addition product, presumably because the hydantoin carbanion was being quenched by proton transfer from either one or both of the indole or Cbz protected amine NHs. In order to circumvent this problem, we were guided by a literature report that the readily deprotonated 2-phenyl-l,3-indanedione
(12) adds to electrochemically generated 2,3-dimethylparaquinone in the presence of sodium acetate (Davarani, S.S.H.; et al. J. Org. Chem. 2006, 71, 2139-2142). We found that (12) similarly reacted smoothly with the protected tryptamine quinone (9) to give the C-5 Michael adduct (13) in excellent yield (Scheme 2). Scheme 2 Cbz no reaction HCbz
Figure imgf000062_0002
Figure imgf000062_0001
The ability of (12) to act as an effective carbanion nucleophile in a Michael addition to (9), suggested that an analogous hydantoin of the general structure (14) might serve as a synthon for adding the desired hydantoin substituent to C-5 of tryptamine quinone derivative (9). Hydantoin (14a) was prepared in good yield from 2-(N-methylamino)dimethylmalonate and n-propylisocyanate using a modification of a literature procedure (Scheme 3). Reaction of hydantoin (14a) and quinone (9) gave the Michael adduct (15) in nearly quantitative yield. Deprotection of (15) with BBr3 removed the Cbz group and the methyl ester resulting in spontaneous decarboxylation to give the desired C-5 substituted tryptamine quinone (16). Compound (16) was stable to normal organic chemistry manipulations indicating that the hydantoin substituent at C-5 was sufficient to block further Michael additions at C-6 and cyclic, branched-cyclic iminoquinone formation. Deprotection of (15) using hydrogenolysis conditions gave the analog (17), which still retained the methyl ester. Scheme 3
Figure imgf000063_0001
-N*. C.
*O
Figure imgf000063_0002
The tryptamine quinone derivatives (9), (11), (13), (16), and (17) were tested for their ability to inhibit IDO in a pure enzyme assay and in the cell-based yeast assay (See Examples 13 and 14).
Details: Synthesis of 9:
Carboxybenzyl-protected tryptamine quinone (9) was prepared using a modified literature protocol (Tatsuta, K.; Imamura, K.; Itoh, S.; Kasai, S. Tetrahedron Lett. 2004, 45, 2847-2850) according to scheme 1. Tryptamine (4) (1.99 g, 12.42 mmol) was dissolved in chloroform (20 mL) under nitrogen, and cooled to O0C. To this solution was added diisopropylethylamine (4.4 mL, 25.26 mmol) followed by benzyl chloroformate (2.0 mL, 14.0 mmol). The solution was allowed to warm to room temperature and stirred for 1 h. Water (20 mL) was added, and the organic layer was separated, concentrated in vacuo, and purified by silica gel flash chromatography (10% EtOAc/Hexanes to 100% EtOAc) to give
(5) (3.71 g, quant.) (5) (1.96 g, 6.67 mmol) was dissolved in a mixture of THF (10 mL) and water (2 mL). To this solution was added a solution of DDQ (3.35 g, 14.67 mmol) in THF (8 mL). The reaction was stirred for 1 h at room temperature, and dried in vacuo. Methanol (20 mL) was added, the solution was filtered, and the precipitate collected to give crude (6). Crude
(6) was dissolved in a minimum volume of DMSO, methanol was added, and the solution was allowed to stand overnight to give crystals of pure (6) (1.41 g, 69%).
(6) (1.41 g, 4.58 mmol), under nitrogen, was dissolved in TFA (10 mL), and a solution of thallium (III) trifluoroacetate (2.60 g, 4.79 mmol) in TFA (10 mL) was added. The solution was stirred for 1 h at room temperature and dried in vacuo. Traces of TFA were removed by repeatedly adding 1,2-dichloroethane and drying in vacuo. The solid was dissolved in DMF (20 mL) and copper sulfate pentahydrate (5.50 g, 22.04 mmol) was added. The solution was heated to 14O0C for 10 minutes and dried in vacuo. The solid was suspended in DCM and purified by silica gel flash chromatography (DCM to 10% EtOAc/DCM) to give 615.7 mg of crude (7) (42 %).
Crude (7) (120 mg, 0.37 mmol) was dissolved in THF (10 mL), and to this solution was added boron trifluoride diethyl etherate (0.5 mL, 5.44 mmol) and excess sodium borohydride (150 mg, 3.75 mmol). The reaction mixture was stirred for 1 h at room temperature, and quenched by the addition of saturated ammonium chloride (10 mL). This solution was then extracted with DCM (3 x 10 mL). The organic layer was concentrated in vacuo, and purified by silica gel flash chromatography (DCM to 10% EtOAc/DCM) to give (8) (39.3 mg, 34 %).
(8) (39.3 mg, 0.13 mmol) was dissolved in acetone (2 mL), and a solution of potassium nitrosodisulfonate (112 mg, 0.42 mmol) in water (3 mL) and phosphate buffer (pH = 7.2, 1 mL) was added. The reaction mixture was allowed to stir overnight at room temperature, and was extracted with dichloromethane (3 x 5 mL). The organic layer was concentrated in vacuo, and purified by silica gel flash chromatography (DCM to 10% EtOAc/DCM) to give (9) (22.5 mg, 55%).
1H NMR (400 MHz, Acetone) δ 7.30-7.35 (5H, m, H-15, H-16, H-17, H-18, H-19), 7.12 (IH, br. s, H-2), 6.56 (2H, d, J = 2.6 Hz, H-6, H-7), 5.04 (2H, s, H-13), 3.43 (2H, q, J = 6.8 Hz, H-Il), 2.95 (2H, t, J = 6.9 Hz, H-IO); 13C NMR (100 MHz, Acetone) δ 185.0 (C, C-5), 177.8 (C, C-8), 157.2 (C, C-12), 139.1 (CH, H-6), 138.0 (C, C- 14), 136.9 (CH, C-7), 132.0 (C, C-9), 128.0-130.0 (CH, C-15, C-16, C-17, C-18, C-19), 125.5 (CH, C-2), 124.1 (C, C-4), 114.9 (C, C-3), 66.4 (CH2, C-13), 41.8 (CH2, C-Il), 26.8 (CH2, C-IO); HRESMS(+) m/z 347.1007 (calc'd for C18H16N2O4Na 347.1008).
Synthesis of 11:
To a solution of (9) (5.0 mg, 0.015 mmol) in dichloromethane (2 mL) was added excess dodecylamine (100 mg, 0.54 mmol) in DCM (2 mL), and the solution was stirred for 5 h at room temperature. The mixture was purified by silica gel flash chromatography (DCM to 50% EtOAc/Hexanes) to give (11) (6.0 mg, 77%).
1H NMR (400 MHz, DCM) δ 7.30-7.35 (5H, m, H-27, H-28, H-29, H-30, H-31), 6.69 (IH, s, H-2), 6.09 (IH, s, H-7), 5.04 (2H, s, H-25), 3.43 (2H, t, J = 6.5 Hz, H-23), 3.12 (2H, q, J = 6.8 Hz, H-10), 2.90 (2H, t, J = 6.5 Hz, H-22), 1.66 (2H, m, H-11), 1.25-1.30 (18H, br. s, H-12, H-13, H-14, H-15, H-16, H-17, H-18, H-19, H-20), 0.88 (3H, t, J = 6.8 Hz, H-21); 13C NMR (100 MHz, DCM) δ 179.0 (C, C-5), 177.5 (C, C-8), 156.0 (C, C-25), 150.4 (C, C-6), 137.0 (C, C-26), 135.5 (C, C-9), 128.0-129.0 (CH, C-27, C-28, C-29, C-30, C-31), 123.5 (C, C-4), 121.4 (C, C-3), 119.1 (CH, C-2), 95.4 (CH, C-7), 66.6 (CH2, C-25), 43.4 (CH2, C-10), 41.6 (CH2, C-23), 32.3 (CH2, C-I l), 27.0-30.0 (CH2, C-12, C-13, C-14, C-15, C-16, C-17, C-18, C-19), 26.4 (CH2, C-22), 23.1 (CH2, C-20), 14.2 (CH3, C-21); HRESIMS(+) m/z 530.2980 (calc'd for C30H41N3O4Na 530.2995).
Synthesis of 13:
To a solution of (9) (5.9 mg, 0.018 mmol) in MeOH (3 mL) was added a solution of 2-phenyl-l,3-indandione (15.0 mg, 0.068 mmol) in MeOH (2 mL), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was dried in vacuo, dissolved in dichloromethane, and purified by silica gel flash chromatography (DCM to 50% EtOAc/Hexanes) to give (13) (7.6 mg, 77%).
1H NMR (400 MHz, DCM) δ 9.57 (IH, br. s, H-I), 7.99 (2H, m, H-13, H-16), 7.86 (2H, m, H-14, H-15), 7.35-7.50 (5H, m, H-20, H-21, H-22, H-23, H-24), 7.30-7.35 (5H, m, H-30, H-31, H-32, H-33, H-34), 6.79 (IH, br. s, H-2), 5.97 (IH, s, H-7), 5.02 (2H, s, H-28), 3.29 (2H, t, J = 6.4 Hz, H-26), 2.78 (2H, t, / = 6.5 Hz, H-25); 13C NMR (100 MHz, DCM) δ 197.6 (C, C-Il, C-18), 183.5 (C, C-5), 176.6 (C, C-8), 156.8 (C, C-27), 152.1 (C, C-6), 141.7 (C, C-12, C-17), 139.4 (CH, C-7), 137.7 (C, C-29), 136.2 (CH, C-14, C-15), 132.6 (C, C-9), 128.0-130.0 (C-19, C-20, C-21, C-22, C-23, C-24, C-30, C-31, C-32, C-33, C-34),
124.8 (CH, C-2), 124.6 (CH, C-12, C-16), 122.4 (C, C-3), 67.1 (CH2, C-28), 66.9 (C, C-IO), 41.4 (CH2, C-26), 26.4 (CH2, C-25); HRESMS(+) m/z 567.1534 (calc'd forC33H24N2O6Na 567.1532).
Synthesis of 14a:
Methyl l-methyl-S-propyl-S-hydantoincarboxylate (14a) was synthesized using a modification of a literature protocol (Li, J.P. J. Org. Chem. 1975, 40, 3414-3417).
Synthesis of 15:
To a solution of (9) (6.4 mg, 0.020 mmol) in MeOH (3 niL) was added excess (14a) (23 mg, 0.107 mmol) in MeOH, and the solution was stirred overnight at room temperature. The reaction mixture was dried in vacuo, dissolved in dichloromethane, and purified by silica gel flash chromatography (DCM to 60% EtOAc/Hexanes) to give (15) (7.1 mg, 67%).
1H NMR (600 MHz, DCM) δ 9.73 (IH, br. s, H-I), 7.30-7.35 (5H, m, H-19, H-20, H-21, H-22, H-23), 6.93 (IH, s, H-2), 6.49 (IH, s, H-7), 5.03 (2H, s, H-17), 3.81 (3H, s, H-27), 3.52 (2H, t, J = 7.2 Hz, H-24), 3.42 (2H, m, H- 15), 2.94 (2H, m, H- 14), 2.89 (3H, s, H-28), 1.62 (2H, m, H-25), 0.92 (3H, t, / = 7.6 Hz, H-26); 13C NMR (125 MHz, DCM) δ 181.8 (C, C-5), 175.7 (C, C-8), 167.2 (C, C-12), 165.4 (C, C-13), 156.6 (C, C-16), 156.2 (C, C-Il), 141.8 (C, C-6), 137.1 (C, C-18), 137.0 (CH, C-7), 131.3 (C, C-9), 128.0-129.0 (CH, C-19, C-20, C-21, C-22, C-23), 125.4 (CH, C-2), 124.8 (C, C-3), 123.0 (C, C-4), 71.0 (C, C-10), 66.7 (CH2, C-17), 54.0 (CH3, C-27), 41.8 (CH2, C-24), 41.3 (CH2, C-15), 27.6 (CH3, C-28), 26.2 (CH2, C-14), 21.5 (CH2, C-25), 11.2 (CH3, C-26); HRESMS(+) m/z 559.1810 (calc'd for C27H28N4O8Na 559.1805).
Synthesis of 16:
A solution of (15) (8.0 mg, 0.015 mmol) in dichloromethane (3 mL), under nitrogen, was cooled to O0C, and to this solution was added a solution of boron tribromide in dichloromethane (0.2 mL, 1.0 M). The reaction mixture was allowed to warm to room temperature, and stirred for 4 h. The reaction mixture was extracted with water (3 x 5 mL), and the aqueous layer was purified on a Waters 2 g reversed-phase Sep Pak (water to 10% MeOH/water) to give (16) (2.7 mg, 53%). 1H NMR (600 MHz, MeOD) δ 7.10 (IH, s, H-2), 6.76 (IH, s, H-7), 4.90 (IH, s, H-IO), 3.50 (2H, m, H-15), 3.18 (2H, t, / = 6.9 Hz, H-14), 3.04 (2H, t, /= 7.5 Hz, H-13), 2.85 (3H, s, H-18), 1.69 (2H, m, H-16), 0.97 (3H, t, J = 7.5 Hz, H-17); 13C NMR (125 MHz, MeOD) δ 183.4 (C, C-5), 1771. (C, C-8), 172.9 (C, C-I l), 158.7 (C, C-12), 142.0 (C, C-6), 139.8 (CH, C-7), 133.4 (C, C-9), 126.9 (CH, C-2), 123.8 (C, C-4), 121.7 (C, C-3), 63.4 (CH, C-IO), 42.0 (CH2, C-15), 40.5 (CH2, C-14), 28.2 (CH3, C-18), 24.9 (CH2, C-13), 22.3 (CH2, C-16), 11.6 (CH3, C-17); HRESIMS(+) m/z 345.1569 (calc'd for CnH21N4O4 345.1563).
Synthesis of 17: To a vial containing (15) (1.5 mg, 0.003 mmol) was added excess platinum (IV) oxide, and methanol (3 mL). The reaction mixture was flushed with nitrogen, followed by hydrogen, and a balloon containing hydrogen was added via syringe. The reaction mixture was stirred for 15 minutes at room temperature. The mixture was then filtered, concentrated in vacuo, and purified on a Waters 2g reversed-phase Sep Pak (H2O to 50% MeOH/H2O) to give 0.5 mg of (17) (44 %).
1H NMR (600 MHz, MeOD) δ 7.10 (IH, s, H-2), 6.64 (IH, s, H-7), 3.84 (3H, s, H-19), 3.53 (2H, t, J = 6.9 Hz, H-16), 3.08 (2H, t, J = 6.9 Hz, H-15), 2.99 (2H, m, H-14), 2.91 (3H, s, H-20), 1.69 (2H, q, J = 7.3 Hz, H-17), 0.93 (3H, t, J = 7.5 Hz, H-18); 13C NMR (125 MHz, MeOD) δ 182.8 (C, C-5), 169.1 (C, C-12), 166.0 (C, C-13), 157.3 (C, C-Il), 139.0 (CH, C-7), 132.6 (C, C-6), 131.7 (C, C-9), 127.0 (CH, C-2), 123.2 (C, C-4), 122.4 (C, C-3), 72.4 (C, C-10), 54.1 (CH3, C-19), 42.1 (CH2, C-16), 40.5 (CH2, C-15), 26.0 (CH2, C-14), 21.7 (CH2, C-17), 11.3 (CH3, C-18); HRESIMS(+) m/z (calc'd for C19H22N4O6 ).
Example 8 - Synthesis of 23:
Figure imgf000067_0001
(23) was prepared using a modified literature protocol (Tatsuta, K.; Imamura, K.; Itoh, S.; Kasai, S. Tetrahedron Lett. 2004, 45, 2847-2850). Tryptamine (4) (250 mg, 1.56 mmol) was dissolved in dichloromethane (10 mL) under nitrogen, and to this solution was added diisopropylethylamine (0.6 mL, 3.2 mmol) followed by hydrocinnamoyl chloride (0.25 mL, 1.70 mmol). The solution was stirred at room temperature for 1 h. Water (10 mL) was added, and the organic layer was separated, concentrated in vacuo, and purified by silica gel flash chromatography (DCM to 20% EtOAc/DCM) to give (18) (351.4 mg, 77%):
Figure imgf000068_0001
(18) (351.4 mg, 1.20 mmol) was dissolved in a mixture of THF (10 mL) and water (2 mL). To this solution was added a solution of DDQ (545 mg, 2.4 mmol) in THF (8 mL). The reaction was stirred for 1 h at room temperature, and dried in vacuo. Methanol (10 mL) was added, the solution was filtered, and the precipitate collected to give (19) (299.2 mg, 81%):
Figure imgf000068_0002
(19) (299.2 mg, 0.98 mmol), under nitrogen, was dissolved in TFA (8 mL), and a solution of thallium (III) trifluoroacetate (568 mg, 1.08 mmol) in TFA (6 mL) was added. The solution was stirred for 1 h at room temperature and dried in vacuo. Traces of TFA were removed by repeatedly adding 1,2-dichloroethane and drying in vacuo. The solid was dissolved in DMF (10 mL) and copper sulfate pentahydrate (1.25 g, 5.0 mmol) was added. The solution was heated to 13O0C for 10 minutes and dried in vacuo. Water (10 mL) was added, and the solution was extracted with DCM (3 x 10 mL). The organic layer was dried in vacuo, and purified by silica gel flash chromatography (DCM to 10% EtOAc/DCM) to give 256.5 mg of (20) (84 %):
Figure imgf000069_0001
(20) (256.5 mg, 0.80 mmol) was dissolved in THF (12 mL), and to this solution was added boron trifluoride diethyl etherate (0.8 mL, 8.70 mmol) and excess sodium cyanoborohydride (250 mg, 4.0 mmol). The reaction mixture was stirred for 1 h at room temperature, and quenched by the addition of saturated ammonium chloride (10 mL). This solution was then extracted with DCM (3 x 10 mL). The organic layer was concentrated in vacuo, and purified by silica gel flash chromatography (DCM to 10% EtOAc/DCM) to give crude (21) (328.4 mg):
Figure imgf000069_0002
Crude (21) (164.2 mg) was dissolved in acetone (6 mL), and a solution of potassium nitrosodisulfonate (430 mg, 1.6 mmol) in water (9 mL) and phosphate buffer (pH = 7.2, 3 mL) was added. The reaction mixture was stirred at room temperature for 1 h, and extracted with dichloromethane (3 x 5 mL). The organic layer was concentrated in vacuo, and purified by silica gel flash chromatography (DCM to 50% EtOAc/DCM) to give (22) (24.4 mg, 20% over two steps):
Figure imgf000070_0001
(22) (24.4 mg, 0.076 mmol) was dissolved in MeOH (2 mL) and to this solution was added a solution of (14a) (26.4 mg, 0.12 mmol) in MeOH (3 mL). The solution was stirred overnight at room temperature, dried in vacuo, and purified by silica gel flash chromatography (DCM to 50% EtOAc/DCM) to give (23) (19.5 mg, 48%). A portion of this was purified by reversed-phase HPLC (60% MeOH/H2O) to give 1.6 mg of pure (23).
1H NMR (600 MHz, Acetone) δ 7.20-7.30 (5H, m, H-20, H-21, H-22, H-23, H-24), 7.09 (IH, s, H-2), 6.60 (IH, s, H-7), 3.83 (3H, s, H-28), 3.47 (2H, t, J = 7.1 Hz, H-25), 3.41 (2H, q, J = 6.6 Hz, H-15), 2.92 (3H, s, H-29), 2.87 (2H, m, H-18), 2.85 (2H, m, H-14), 2.40 (2H, t, J= 7.6 Hz, H-17), 1.67 (2H, m, H-26), 0.91 (3H, t, / = 7.5 Hz, H-27); 13C NMR (125 MHz, Acetone) δ 182.3 (C, C-5), 176.3 (C, C-8), 172.1 (C, C-16), 167.8 (C, C-12), 166.1 (C, C-13), 156.7 (C, C-Il), 142.7 (C, C-6), 142.2 (C, C-19), 138.2 (CH, C-7), 131.9 (C, C-9), 128.0-129.0 (CH, C-20, C-21, C-22, C-23, C-24), 126.6 (CH, C-2), 125.4 (C, C-3), 124.2 (C, C-4), 71.8 (C, C-10), 54.1 (CH3, C-28), 41.9 (CH2, C-25), 39.6 (CH2, C-15), 38.6 (CH2, C- 17), 32.4 (CH2, C- 18), 27.6 (CH3, C-29), 26.6 (CH2, C- 14), 21.9 (CH2, C-26), 11.4 (CH3, C-27); HRESIMS(+) m/z 557.2021 (calc'd for C28H30N4O7Na 557.2012).
Example 9 - Synthesis of 24:
Figure imgf000070_0002
To a solution of 4-hydroxyindole (46.4 mg, 0.35 mmol) in MeOH (6 mL) was added a solution of potassium nitrosodisulfonate (187 mg, 0.70 mmol) in water (9 mL) and phosphate buffer (pH = 7.2, 3 mL). After stirring for 6 h at room temperature, the solution was extracted with dichloromethane (3 x 10 mL), dried in vacuo, and purified by silica gel flash chromatography (Hexanes to 10% EtOAc/DCM) to give (24) (12.0 mg, 23%).
Example 10 - Synthesis of 25:
Figure imgf000071_0001
(24) (2.7 mg, 0.018 mmol) was dissolved in MeOH (2 mL), and to this solution was added a solution of (14a) (5.3 mg) in MeOH (3 mL). The reaction mixture was allowed to stir overnight at room temperature. The mixture was then dried in vacuo, and purified by silica gel flash chromatography (10% EtOAc/Hexanes to 40% EtOAc/Hexanes) to give 4.2 mg (64%) of (25).
1U NMR (600 MHz, Acetone) δ 7.35 (IH, d, J = 2.5 Hz, H-2), 6.66 (IH, s, H-7), 6.62 (IH, d, J = 2.8 Hz, H-3), 3.84 (3H, s, H-17), 3.51 (2H, dt, J = 7.1, 1.8 Hz, H-14), 2.92 (3H, s, H-18), 1.68 (2H, dq, J = 7.2, 1.8 Hz, H-15), 0.92 (3H, t, / = 7.4 Hz); 13C NMR (125 MHz, Acetone) δ 181.3 (C, C-5), 175.4 (C, C-8), 167.6 (C, C-I l), 165.9 (C, C-13), 156.7 (C, C-12), 141.8 (C, C-6), 72.0 (C, C-10), 54.1 (CH3, C-17), 41.7 (CH2, C-14), 27.5 (CH3, C-18), 21.8 (CH2, C-15), 11.4 (CH3, C-16); HRESIMS(+) mJz 382.1014 (calc'd for C17H17N3O6Na 382.1015).
Example 11 - Synthesis of 26:
Figure imgf000072_0001
To a solution of (9) (5.0 mg, 0.015 mmol) in dichloromethane (3 mL), under nitrogen, was added a solution of 1,3-diphenyl-isobenzofuran (20.0 mg, 0.074 mmol) in dichloromethane (2 mL). The reaction mixture was stirred overnight at room temperature, cooled to -780C, and a solution of boron tribromide in dichloromethane (0.2 mL, 1.0 M) was added. The reaction mixture was allowed to warm to room temperature, and then refluxed for 3 h. Additional dichloromethane (5 mL) was added, and the solution was extracted with water (4 x 5 mL), and the aqueous layer was purified on a Waters 2 g reversed-phase Sep Pak (water to 75% MeOH/water) to give (26) ( 1.5 mg, 22%).
1H NMR (600 MHz, MeOD) δ 7.20-7.75 (14H, m, H-9, H-10, H-I l, H-12, H-19, H-20, H-21, H-22, H-23, H-25, H-26, H-27, H-28, H-29), 7.06 (IH, s, H-2), 3.08 (2H, t, J = 7.3 Hz, H-31), 2.97 (2H, t, J = 7.2 Hz); 13C NMR (125 MHz, MeOD) δ 184.2 (C, C-5),
177.1 (C, C-16), 127.0-146.0 (C-6, C-7, C-8, C-9, C-10, C-I l, C-12, C-13, C-14, C-15, C-18, C-19, C-20, C-21, C-22, C-23, C-24, C-25, C-26, C-27, C-28, C-29), 135.9 (C, C-17),
127.2 (CH, C-2), 126.1 (C, C-4), 121.0 (C, C-3), 41.2 (CH2, C-31), 25.0 (CH2, C-30); HRESIMS(+) m/z 443.1774 (calc'd for C30H23N2O2 443.1760).
Example 12 - Synthesis of 27:
Figure imgf000073_0001
(13) (2.5 mg, 0.0046 mmol) was dissolved in dichloromethane, cooled to O0C, and to this solution was added a solution of boron tribromide in dichloromethane (0.1 mL, 1.0 M). The reaction mixture was allowed to warm to room temperature, and stirred for 3 h. The solution was extracted with water (3 x 5 mL), and the aqueous layer was dried in vacuo and purified by reversed-phase HPLC (MeOH to MeOH + 0.1% AcOH) to give (27) (1.0 mg, 53%).
1H NMR (600 MHz, MeOD) 6 8.02 (2H, dd, J = 5.7, 2.9 Hz, H-13, H-16), 7.94 (2H, dd, J = 5.5, 3.0 Hz, H-14, H-15), 7.44 (5H, m, H-20, H-21, H-22, H-23, H-24), 7.06 (IH, s, H-2), 5.85 (IH, s, H-7), 3.03 (2H, t, J= 7.3 Hz, H-26), 2.91 (2H, t, J= 7.5 Hz, H-25); 13C NMR (125 MHz, MeOD) δ 198.5 (C, C-Il, C-18), 184.3 (C, C-5), 177.2 (C, C-8), 152.2 (C, C-6), 142.5 (C, C-12, C-17), 139.9 (CH, C-7), 137.10 (CH, C-14, C-15), 133.4 (C, C-9), 129.6-130.7 (C-19, C-20, C-21, C-22, C-23, C-24), 126.9 (CH, C-2), 125.0 (CH, C-13, C- 16), 124.3 (C, C-4), 122.1 (C, C-3), 67.4 (C, C-10), 40.5 (CH2, C-26), 24.9 (CH2, C-25); HRESIMS(+) mJz 411.1348 (calc'd for C25Hi9N2O4411.1345).
Example 13 - In Vitro Recombinant IDO Enzyme Activity Assays.
The effect of extracts, purified compounds and synthesized compounds on IDO activity was determined with the use of recombinant human IDO expressed in E. coli
(Vottero et al. 2006. Biotechnology J. 1:282-288) and purified (Sugimoto et al. 2006. Proc. Natl Acad. ScL USA, 103: 2611-2616). Protein concentration was determined from the intensity of absorbance at the Soret maximum (-413 run). Inhibitory constants (Ki values) were determined with a continuous spectrophotometric activity assay (Sono et al. 1989. Biochemistry, 28, 5392- 329) performed in sodium phosphate buffer (100 mM, pH 6.5, 25 0C) with [IDO] of 100 nM and [L-Trp] of 4.375-70 μM, [ascorbic acid] = 10 mM, [methylene blue] = 1.25 μM, [catalase] = 2.5 μg/mL. Table 1 shows the results of the compounds tested.
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Example 14 - In Vivo IDO Activity - Yeast Growth Restoration Assay
A yeast growth restoration assay provides for expression of human IDO in yeast cells to restrict their growth by depleting the intracellular tryptophan pool. Growth is restored by IDO inhibition. Yeast growth was determined by optical density at 600nm. A yeast growth restoration curve for caulerpin is shown in Vottero et al. 2006. Biotechnology J. 1:282-288. A description of the yeast assay is also provided in Vottero et al.
The yeast growth restoration assay was used as a stringent filter to provide information about IDO inhibitors already identified as IDO inhibitors in the enzyme assay of Example 13 (or otherwise identified as IDO inhibitors). In particular, preliminary information regarding a compounds ability to cross cell membranes, preliminary information related to potential toxicity and preliminary in vivo information. Table 2 shows the results of the compounds tested. TABLE 2
Compound Result
Not Active
Not Active
Not Active
Not Active
Figure imgf000078_0001
TABLE 2
Compound Result
Not Active (Toxic)
Weakly active at about 50μg/mL
Not Active
Not Active
Figure imgf000079_0001
Figure imgf000080_0001
Compounds described as "toxic" in Table 2 are inactive at concentrations below which they showed cytotoxicity in the yeast assay. This measure of toxicity maybe useful as a guide for selecting suitable compound for a particular use, but does not indicate that the compound is not useful for in vivo purposes. Many compounds that are used to treat cancer are toxic and indeed meant to be toxic. In some embodiments of the present invention, the toxicity of the compounds may provide for benefits for use of the compounds, for example in the treatment of cancers. Non- toxic compounds are also useful in the treatment of cancers. A result of no activity in the yeast assay may not be significant with respect to IDO inhibitory activity. In particular, yeast cells are known to have cell membranes that pose special difficulties for molecules to cross and here again this result is to be used as a guide for selecting suitable compounds for a particular use. Compounds described as toxic and inactive in Table 2 may be useful embodiments for particular uses, such as cancer treatment and in non-yeast cells.
Although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art. Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way. Numeric ranges are inclusive of the numbers defining the range. The word "comprising" is used herein as an open-ended term, substantially equivalent to the phrase "including, but not limited to", and the word
"comprises" has a corresponding meaning. As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a thing" includes more than one such thing. Citation of references herein is not an admission that such references are prior art to the present invention. Any priority document(s) and all publications, including but not limited to patents and patent applications, cited in this specification are incorporated herein by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein and as though fully set forth herein. The invention includes all embodiments and variations substantially as hereinbefore described and with reference to the examples and drawings.

Claims

What is claimed is:
1. A compound of Formula B or a pharmaceutically acceptable salt thereof:
Figure imgf000082_0001
Formula B wherein
R .11 comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; or iii) a first carbon bonded to the carbon at position 6 and a second carbon bonded to the carbon at position 7; and
R is selected from the group consisting of:
Figure imgf000082_0002
, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon not bonded to the carbon at position 6 or the carbon at position 7 is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R; O O 10 Q
Y is selected from the group consisting of: CR , CR R , HCR , CH2, NH, NR9, O and S;
R , R , R , R , R , R , R and R are each independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R;
12
R is selected from the group consisting of: H and a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic;
G and G are independently selected from the group consisting of: a one to 12 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R;
G , G , G , and G are independently selected from the group consisting of: H, R, OH, OR, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; each R in each of R3, R4, R5, R6, R7, R8, R9, R10, R11, G1, G2, G3, G4, G5, and G is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
2. The compound or salt of claim 1 wherein R is selected from the group consisting of:
Figure imgf000084_0001
, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon that is not bonded to the carbon at position 6 or the carbon at position 7 is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R;
R , R , R , and R are each independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially- aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and
3 5 8 9 each R in each of R , R , R , and R is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
3. The compound or salt of claim 1 or 2 wherein
„ 11 . -.
R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; and
R is selected from the group consisting of: a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon not bonded to the carbon at position 6 is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in R is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
4. The compound or salt of any one of claims 1 to 3 wherein
R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; and
R is selected from the group consisting of: a three to eight carbon partially- aromatic or non- aromatic ring or fused ring system, where each carbon not bonded to the carbon at position 6 is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; the carbon in R bonded to the carbon at position 6 or position 7 is further substituted with H, R or OR; and each R in R is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
5. The compound of any one of claims 1 to 4 wherein n Ri l compri ■ses one o cf: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; and
R is selected from the group consisting of: *Λ 6
Z*. V vpTiC- 6t )
wherein
T is H, R or OR;
Z , Z , Z , and Z are independently selected from the group consisting of: CH2, O, S, NH, and are optionally substituted with OH, OR, R, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; at least one of Z , Z , Z , and Z is N optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in each of Z , Z , Z , Z , and Z is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
6. A compound of Formula A or a pharmaceutically acceptable salt thereof:
Figure imgf000086_0001
Formula A wherein
X is NR12;
12
R is selected from the group consisting of: H and a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic; R is selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR may be optionally substituted with one or more of: OH, OR, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R;
R2 is H; n is 1;
„ 11 . r
R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; and
R is selected from the group consisting of:
Figure imgf000087_0001
wherein
Z is H, R or OR;
Z , Z , Z , and Z are independently selected from the group consisting of: CH2, O, S, NH, and are optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; at least one of Z4, Z5, Z6, and Z7 is N optionally substituted with OH, OR, R, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in each of Z , Z , Z , Z , and Z is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
7. The compound or salt of claim 6 wherein R is selected from the group consisting of:
Figure imgf000088_0001
wherein
G and G are independently selected from the group consisting of: a one to 12 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; G , G , G , and G are independently selected from the group consisting of:
H, R, OH, OR, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in each of G , G , G , G , G , and G is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
8. The compound or salt of any one of claim 1 to 5 and 7 wherein G and G are independently selected from the group consisting of: H, and
O
wherein T<
Q is CH2, O, NH, NR or S; k is 0, 1, 2, 3, 4, 5, 6, or 7;
G is an three to eight carbon cyclic, branched-cyclic group that is optionally aromatic, partially-aromatic or non-aromatic, where each carbon is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in G is selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
9. A compound of Formula G or a pharmaceutically acceptable salt thereof:
Figure imgf000089_0001
Formula G wherein
R comprises one of: i) a carbon bonded to the carbon at position 6 and no atom directly bonded to the carbon at position 7; or ii) a carbon bonded to the carbon at position 7 and no atom directly bonded to the carbon at position 6; or iii) a first carbon bonded to the carbon at position 6 and a second carbon bonded to the carbon at position 7; and
R is selected from the group consisting of:
Figure imgf000089_0002
and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon not bonded to the carbon at position 6 or the carbon at position 7 is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R;
Q Q 10 Q
Y is selected from the group consisting of: CR , CR R , HCR , CH2, NH, NR9, O and S;
R , R , R , R , R , R , R and R are each independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R;
12 R is selected from the group consisting of: H and a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic;
G and G are independently selected from the group consisting of: H, and
Figure imgf000090_0001
wherein
Q is CH2, O, NH, NR or S; k is O, 1, 2, 3, 4, 5, 6, or 7;
G , G , G , and G are independently selected from the group consisting of: H, R, OH, OR, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; G is a three to fourteen carbon cyclic, branched-cyclic group that is optionally aromatic, partially-aromatic or non-aromatic, where each carbon is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; G , G , G , and G are independently selected from the group consisting of: H, R, OH, OR, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; each R in each of R3, R4, R5, R6, R7, R8, R9, R10, R1 ', G1, G2, G3, G4, G5, G6 and G is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
1 2
10. The compound or salt of any one of claim 1 to 5, and 7 to 9 wherein G and G are independently selected from the group consisting of: H, and
Figure imgf000091_0001
wherein
Q is CH2, O, NH, NR or S; k is O, 1, 2, 3, 4, 5, 6, or 7; G , G , G , G and G are independently selected from the group consisting of: H, R, OH, OR, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and each R in each of G , G , G , G and G is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
11. The compound or salt of any one of claims 8 to 10 wherein Q is O or CH2.
12. The compound or salt of any one of claims 8 to 11 wherein Q is O.
13. The compound or salt of any one of claims 8 to 12 wherein k is 1. 1 2
14. The compound or salt of any one of claim 1 to 5 and 7 wherein G and G are independently selected from the group consisting of H, Carbobenzyloxy (Cbz), tert-Butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC), Benzyl (Bn), and p-methoxyphenyl (PMP).
2
15. The compound or salt of any one of claim 1 to 5 and 7 tol4 wherein G is H.
16. The compound or salt of any one of claims 1 to 15 wherein R is selected from the group consisting of:
Figure imgf000092_0001
wherein
Z2 is H, R or OR;
8 9
Z and Z are independently R; and
2 8 9 each R in each of Z , Z and Z is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
17. The compound of any one of one of claims 1 to 16 wherein R comprises i) a carbon bonded to the carbon at position 6 and is not directly bonded to the carbon at position 7.
18. The compound or salt of any one of claims 1 to 17 wherein R12 is H.
19. A compound having the structure:
Figure imgf000093_0001
or a salt thereof.
20. A compound having the structure:
Figure imgf000093_0002
or a salt thereof.
21. A compound having the structure:
Figure imgf000093_0003
or a salt thereof.
22. A compound having the structure:
Figure imgf000094_0001
or a salt thereof.
23. A compound having the structure:
Figure imgf000094_0002
or a salt thereof.
24. A compound having the structure:
Figure imgf000094_0003
or a salt thereof.
25. A compound having the structure:
Figure imgf000095_0001
or a salt thereof.
26. A compound having the structure:
Figure imgf000095_0002
or a salt thereof.
27. A compound having the structure:
Figure imgf000095_0003
or a salt thereof.
28. A compound having the structure:
Figure imgf000096_0001
or a salt thereof.
29. A composition comprising a compound or salt of any one of claims 1 to 28, and a pharmaceutically acceptable carrier.
30. The compound of any one of claims 1 to 28 or the composition of claim 29 for use in the treatment or prophylaxis of a condition characterized by pathology of IDO-mediated tryptophan metabolism.
31. Use of a compound of any one of claims 1 to 28 or a composition of claim 29 for treatment or prophylaxis of a condition characterized by pathology of IDO-mediated tryptophan metabolism.
32. Use of a compound of any one of claims 1 to 28 or a composition of claim 29 for preparation of a medicament for treatment or prophylaxis of a condition characterized by pathology of IDO-mediated tryptophan metabolism.
33. Use of a compound or salt of Formula A:
Figure imgf000097_0001
Formula A wherein
X is selected from the group consisting of: NH, NR, O, and S;
1 2
R and R are independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR may be optionally substituted with one or more of: OH, OR, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R; n is 1 or 2;
R is optionally bonded to the carbon at position 6, the carbon at position 7 or bonded to both the carbon at position 6 and the carbon at position 7 and is selected from the group consisting of: H,
Figure imgf000097_0002
, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R; Y is selected from the group consisting of: CR9, CR9R10, HCR9, CH2, NH, NR9, 0 and S; and R , R , R , R , R , R , R and R are each independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R; and each R in each of X, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially- aromatic or non-aromatic, for treatment or prophylaxis of a condition that is not cancer and is characterized by pathology of IDO-mediated tryptophan metabolism.
34. The use of claim 33 wherein, R is optionally selected from the group consisting of: H,
, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R;
3 5 8 9
R , R , R , and R are each independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and
3 5 8 9 each R in each of R , R , R , and R is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
35. The use of claim 33 or 34 wherein X is selected from the group consisting of NH and NR wherein R is selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
36. The use of any one of claims 33 to 35 wherein X is NH.
37. The use of any one of claims 33 to 36 wherein n is 1.
38. The use of any one of claims 33 to 37 wherein the condition results from suppression of T-cell mediated immunity.
39. The use of any one of claims 33 to 37 wherein the condition results from accumulation of a product of tryptophan degradation.
40. The use of any one of claims 33 to 37 wherein the condition is a neurodegenerative disorder.
41. The use of any one of claims 33 to 37 wherein the condition is a mood disorder.
42. The use of any one of claims 33 to 37 wherein the condition is a cataract or yellowing of the eye.
43. The use of any one of claims 33 to 37 wherein the condition results from a chronic infection by a virus or microorganism.
44. The use of any one of claims 33 to 37 for preparation of a medicament for said treatment or prophylaxis.
45. A method of treating, preventing, or reducing the likelihood of onset of a condition characterized by pathology of IDO-mediated tryptophan metabolism comprising administering to a patient in need thereof, an effective amount of the compound of any one of claims 1 to 28 or the composition of claim 29.
46. The method of claim 45, wherein said condition is cancer and the compound or composition is administered before, during or after administration of a chemotherapeutic agent or radiation therapy.
47. A method of treating, preventing, or reducing the likelihood of onset of a condition that is not cancer and is characterized by pathology of IDO-mediated tryptophan metabolism comprising administering to a patient in need thereof, an effective amount of a compound or salt of Formula A:
Figure imgf000100_0001
Formula A wherein X is selected from the group consisting of: NH, NR, O, and S;
1 2
R and R are independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R; n is 1 or 2; R is optionally bonded to the carbon at position 6, the carbon at position 7 or bonded to both the carbon at position 6 and the carbon at position 7 and is selected from the group consisting of: H,
Figure imgf000101_0001
a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R; q Q I O Q Y is selected from the group consisting of: CR , CR R , HCR , CH2, NH,
NR9, 0 and S; and
R , R , R , R , R , R , R and R are each independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH,
SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R; and each R in each of X, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11 is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
48. The method of claim 47 wherein, R is optionally selected from the group consisting of: H,
Figure imgf000102_0001
, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon is optionally substituted with one or more of: OH, OR, R, F, Cl, Br, I, =0, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, CON(R)2 and CO2R;
R , R , R , and R are each independently selected from the group consisting of: H, and a one to 15 carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic, where each carbon is optionally replaced by O, S, SO, SO2, NH, or NR, and each carbon, O, S, SO, SO2, NH, or NR is optionally substituted with OH, OR, R, F, Cl, Br, I, =O, SH, SR, NH2, NHR, N(R)2, OSO3H, OPO3H3, CO2H, and CO2R; and
3 5 8 9 each R in each of R , R , R , and R is independently selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non- aromatic.
49. The method of claim 47 or 48 wherein X is selected from the group consisting of NH and NR wherein R is selected from the group consisting of: a one to ten carbon group that is optionally saturated, unsaturated, linear, branched-linear, cyclic, branched-cyclic, aromatic, partially-aromatic or non-aromatic.
50. The method of any one of claims 47 to 49 wherein X is NH.
51. The method of any one of claims 47 to 50 wherein n is 1.
52. The method of any one of claims 47 to 51 wherein the condition results from suppression of T-cell mediated immunity.
53. The method of any one of claims 47 to 51 wherein the condition results from accumulation of a product of tryptophan degradation.
54. The method of any one of claims 47 to 51 wherein the condition is a neurodegenerative disorder.
55. The method of any one of claims 47 to 51 wherein the condition is a mood disorder.
56. The method of any one of claims 47 to 51 wherein the condition is a cataract or yellowing of the eye.
57. The method of any one of claims 47 to 51 wherein the condition results from a chronic infection by a virus or microorganism.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011045341A1 (en) * 2009-10-13 2011-04-21 Ludwig Institute For Cancer Research Ltd Ido inhibitors and therapeutic uses thereof
WO2018071873A2 (en) 2016-10-13 2018-04-19 Juno Therapeutics, Inc. Immunotherapy methods and compositions involving tryptophan metabolic pathway modulators
CN110734423A (en) * 2018-07-18 2020-01-31 复旦大学 indoloquinones indoleamine-2,3-dioxygenase inhibitor and medicinal application thereof
US10906914B2 (en) 2015-01-08 2021-02-02 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Furoquinolinediones as inhibitors of TDP2

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BRASTIANOS H.C. ET AL.: "Exiguamine A, an Indoleamine-2,3-dioxygenase (IDO) Inhibitor Isolated from the Marine Sponge Neopetrosia exigua", J. AM. CHEM. SOC., vol. 128, no. 50, 2006, pages 16046 - 16047 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011045341A1 (en) * 2009-10-13 2011-04-21 Ludwig Institute For Cancer Research Ltd Ido inhibitors and therapeutic uses thereof
US10906914B2 (en) 2015-01-08 2021-02-02 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Furoquinolinediones as inhibitors of TDP2
WO2018071873A2 (en) 2016-10-13 2018-04-19 Juno Therapeutics, Inc. Immunotherapy methods and compositions involving tryptophan metabolic pathway modulators
EP4190335A1 (en) 2016-10-13 2023-06-07 Juno Therapeutics, Inc. Immunotherapy methods and compositions involving tryptophan metabolic pathway modulators
US11896615B2 (en) 2016-10-13 2024-02-13 Juno Therapeutics, Inc. Immunotherapy methods and compositions involving tryptophan metabolic pathway modulators
CN110734423A (en) * 2018-07-18 2020-01-31 复旦大学 indoloquinones indoleamine-2,3-dioxygenase inhibitor and medicinal application thereof
CN110734423B (en) * 2018-07-18 2022-07-08 复旦大学 Indoloquinone indoleamine-2,3-dioxygenase inhibitor and medicinal application thereof

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