WO2019234228A1 - Beta-amino-alpha-hydroxyalkylphenyl derivatives and their use for cancer treatment - Google Patents

Beta-amino-alpha-hydroxyalkylphenyl derivatives and their use for cancer treatment Download PDF

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Publication number
WO2019234228A1
WO2019234228A1 PCT/EP2019/064970 EP2019064970W WO2019234228A1 WO 2019234228 A1 WO2019234228 A1 WO 2019234228A1 EP 2019064970 W EP2019064970 W EP 2019064970W WO 2019234228 A1 WO2019234228 A1 WO 2019234228A1
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alkyl
compound
independently
occurrence
phenyl
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PCT/EP2019/064970
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French (fr)
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Brett Stevenson
Andrew Ratcliffe
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Rising Tide Foundation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5407—Acyclic saturated phosphonium compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to compounds that disrupt cell function, such as the disruption of cell metabolism in particular cancer cell metabolism, that are useful as cancer therapies.
  • the compounds comprise (3-amino-ohydroxyalkyl)phenyl derivatives having a phosphonium cation tethered to the (3-amino-ohydroxyalkyl)phenyl amine.
  • Certain chemicals are based on the (3-amino-ohydroxyalkyl)phenyl portion of chloramphenicol
  • the invention also relates to methods of using said compounds and to pharmaceutical formulations comprising said compounds.
  • Cancer is the fourth greatest cause of mortality in the developed world. In 2016 it was predicted that more than 1.6 million new cases of cancer would be diagnosed in the U.S. alone, and that cancer would be responsible for nearly 600,000 U.S. deaths.
  • Cancer is characterized by the unregulated proliferation of cells, which disrupt the function of tissues.
  • the proliferation of cells can be caused by an abnormal increase in cell production or a disruption in the cell death pathway.
  • disruptors of cell function can impact the proliferation of cells and in particular cancer cells by reducing or inhibiting cell proliferation.
  • the modulation of cancer cell metabolism can lead to the reduction or inhibition of cell proliferation.
  • compounds of the invention may reduce, disrupt, or inhibit the growth or proliferation of a cancer cell or it may induce the death of a cancer cell.
  • cancer cell metabolism, and reducing cell proliferation is a potential target for disrupting cancer growth and ultimately a therapeutic pathway for cancer treatment.
  • the certain embodiments of the invention contemplate compounds that modulate cancer cell metabolism and/or reduce cell proliferation. Reduction in cell proliferation could be achieved either by increasing cell death or by reducing the rate of cell growth.
  • The“prevention” of cancer may be taken as including the prevention of the formation of tumours, including primary tumours, metastatic tumours, or tumours associated with cancer onset, resistance or relapse.
  • the prevention of cancer may also be taken as encompassing the prevention of the progression of cancer.
  • prevention of development of cancer may be demonstrated by preventing an increase in the“stage” of a tumour (using an appropriate cancer staging method) that has been treated using the compounds of the invention.
  • the prevention of increase in cancer stage may be compared to progression of an untreated tumour, or compared to the extent of progression that would be expected by a clinician in the event that the tumour was not treated.
  • The“treatment” of cancer may be taken as including any improvement of pathology, symptoms or prognosis that is achieved in respect of cancer in a subject receiving compounds of the invention. Treatment may be indicated by a partial improvement of such indications, or by a total improvement (e.g. the absence of cancer following medical use of the compounds of the invention).
  • antibiotics may be useful in cancer treatment.
  • the mechanisms by which these agents, which include the antibiotics azithromycin and doxycycline, exert a therapeutic effect have been open to markedly different explanations.
  • Some authors have suggested that these agents inhibit matrix metalloproteinases (MMPs) and thereby achieve an anti- inflammatory effect, while others suggest that they impair the cells’ response to DNA damage, thereby increasing the effectiveness of chemotherapy or radiotherapy on bulk tumour cells.
  • MMPs matrix metalloproteinases
  • Still other articles have indicated that the antibiotics target mitochondrial function.
  • a therapeutically effective amount of a compound of the invention may be an amount of such a compound sufficient to treat a variety of cancers, including the modulation of cancer cells or other dysfunctional cells (such as tumour initiating cells, stem-like cancer cells, cancer stem cells, or a population of cells with stem cell-like features that exist in tumors and that give rise to the bulk of tumor cells with more differentiated phenotypes).
  • cancer cells include hybrid and giant cells. It will be appreciated that the therapeutically effective amount of the compound of the invention may be provided in a single incidence of administration, or cumulatively through multiple incidences of administration.
  • -L 1 - is independently absent or is selected from -C(O)-, -C(0)0-, -S(0) 2 -, -C(0)NR 6 , and - S(0) 2 NR 6 -;
  • -L 2 - and -L 4 - are each independently at each occurrence -Ci-C4-alkylene-, each alkylene group being unsubstituted or substituted with from 1 to 6 independently selected R 9 groups; provided that any -l_ 2 - or -L 4 - group that is attached at each end to an atom selected from oxygen, nitrogen, sulphur or phosphorous is -C 2 -C4-alkylene-; n is an integer selected from 0, 1 , 2, 3, 4 and 5;
  • L 1 , L 2 , L 3 , L 4 and n are selected such that length of the linker formed by those groups is from 3 to 20 atoms;
  • R 1a , R 1b and R 1c are each independently selected from phenyl, biphenyl, naphthyl, 5-, 6-,
  • R 2 and R 6 are each independently at each occurrence selected from H and Ci-C 6 -alkyl;
  • R 3 is independently selected from H, halo, OR 12 and NR 13 R 14 ;
  • R 4 is independently at each occurrence selected from: H, and C(0)Ci-C 6 -alkyl
  • R 5 and R 10 are each independently at each occurrence selected from: Ci-C 6 -alkyl, C2-C6- alkynyl, C2-C6-alkenyl, Ci-C 6 -haloalkyl, C3-C6-cycloalkyl, 4- to 8-membered
  • heterocycloalkyl 5-, 6-, 9- or 10- membered heteroaryl, phenyl, OR 12 , SR 13 , NR 13 R 14 , C(0)OR 13 , C(0)NR 13 R 13 , halo, cyano, nitro, C(0)R 13 , S(0) 2 0R 13 , S(0)R 13 , S(0) 2 R 13 , S(0) 2 NR 13 R 13 , 0C(0)NR 13 R 13 and NR 13 C(0)0R 13 ;
  • R 7 and R 14 are each independently at each occurrence selected from: H, Ci-C 6 -alkyl, C(0)Ci-Ce-alkyl and S(0) 2 -Ci-Ce-alkyl;
  • R 8 is independently at each occurrence selected from H, Ci-C 4 -alkyl and halo;
  • R 9 is independently at each occurrence selected from: Ci-C 6 -alkyl, C2-C6-alkynyl, C2-C6- alkenyl, Ci-C 6 -haloalkyl, OR 12 , SR 13 , NR 13 R 14 , C(0)OR 13 , C(0)NR 13 R 13 , halo, cyano, nitro, C(0)R 13 , S(0) 2 0R 13 , S(0) 2 R 13 , S(0) R 13 , S(0) 2 NR 13 R 13 , 0C(0)NR 13 R 13 and
  • R 11 is independently at each occurrence selected from: oxo, Ci-C 6 -alkyl, C2-C6-alkynyl, C2- C 6 -alkenyl, Ci-C 6 -haloalkyl, C3-C6-cycloalkyl, 4- to 8-membered heterocycloalkyl, 5-, 6-, 9- or 10- membered heteroaryl, phenyl, OR 12 , SR 13 , NR 13 R 14 , C(0)OR 13 , C(0)NR 13 R 13 , halo, cyano, nitro, C(0)R 13 , S(0) 2 0R 13 , S(0)R 13 ⁇ S(0) 2 R 13 , S(0) 2 NR 13 R 13 , 0C(0)NR 13 R 13 and NR 13 C(0)0R 13 ;
  • R 12 is independently at each occurrence selected from: H, Ci-C 6 -alkyl and Ci-C 6 -haloalkyl
  • R 13 is independently at each occurrence selected from: H and Ci-C 6 -alkyl
  • m is an integer selected from 0, 1 , 2, 3, 4 and 5;
  • heterocycloalkyl, heteroaryl or phenyl groups is optionally substituted where chemically allowable by from 1 to 4 groups independently selected from oxo, Ci-C 6 -alkyl, C2-C6- alkynyl, C2-Ce-alkenyl, Ci-Ce-haloalkyl, OR a , NR a R b , SR a , C(0)0R a , C(0)NR a R a , halo, cyano, nitro, C(0)R a , S(0) 2 0R a , S(0) 2 R a , S(0)R a and S(0) 2 NR a R a ; wherein R a is independently at each occurrence selected from: H and Ci-C 6 -alkyl; and R b is
  • H independently at each occurrence selected from: H, Ci-C 6 -alkyl, C(0)Ci-C 6 -alkyl and S(0) 2 -Ci-C 6 -alkyl.
  • each -L 3 -L 4 - unit is selected independently of the other each -L 3 -L 4 - unit or -L 3 -L 4 - units.
  • each -L 3 -L 4 - unit may be the same or they may be different.
  • the atom length of the linkers formed by L 1 , L 2 , L 3 and L 4 is the number of atoms in a straight chain from the phosphorous atom of the phosphonium to the nitrogen atom that is also attached to R 2 .
  • the length does not include any substituents or branching that might be present on the chain.
  • the ion of formula (I) is an ion of formula (II):
  • R 1a , R 1b , R 1c , R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , L 3 , L 4 , n and m are as described above for formula (I).
  • the ion of formula (I) is an ion of formula (III):
  • R 1a , R 1b , R 1c , R 3 , R 5 , L 1 , L 2 , L 3 , L 4 , n and m are as described above for formula (I).
  • the ion of formula (I) is an ion of formula (IV):
  • R 1a , R 1b , R 1c , R 3 , L 1 , L 2 , L 3 , L 4 and n are as described above for formula (I).
  • the ion of formula (I) is an ion of formula (V):
  • R 1a , R 1b , R 1c , R 3 , L 1 , L 2 , L 3 , L 4 and n are as described above for formula (I).
  • R 1a , R 1b and R 1c are each independently selected from phenyl, biphenyl, 5- or 6- membered heteroaryl and C 3 to Cs-cycloalkyl, wherein said phenyl, biphenyl and 5- or 6- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R 10 groups, and wherein said C3 to Cs-cycloalkyl is optionally substituted with from 1 to 5 independently selected R 11 groups; provided that R 1a , R 1b and R 1c are not each unsubstituted phenyl.
  • R 1a , R 1b and R 1c are each independently selected from phenyl, biphenyl, pyridyl and cyclohexyl, wherein said phenyl, biphenyl and pyridyl is optionally substituted with from 1 to 5 independently selected R 10 groups, and wherein said cyclohexyl group is optionally substituted with from 1 to 5 independently selected R 11 groups; provided that R 1a , R 1b and R 1c are not each unsubstituted phenyl.
  • R 1a , R 1b and R 1c are each independently selected from phenyl, biphenyl, pyridyl and cyclohexyl, wherein said phenyl, biphenyl and pyridyl is optionally substituted with 1 to 3 independently selected R 10 groups, and wherein said cyclohexyl group is optionally substituted with 1 to 3 independently selected R 11 groups; provided that R 1a , R 1b and R 1c are not each unsubstituted phenyl.
  • R 1a , R 1b and R 1c are each independently selected from phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl; wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R 10 groups, provided that R 1a , R 1b and R 1c are not each
  • R 1a , R 1b and R 1c are each independently selected from phenyl, optionally substituted with from 1 to 5 independently selected R 10 groups, provided that R 1a , R 1b and R 1c are not each unsubstituted phenyl.
  • R 1a , R 1b and R 1c are each independently selected from phenyl; wherein said phenyl is optionally substituted with from 1 , 2 or 3 independently selected R 10 groups, provided that R 1a , R 1b and R 1c are not each unsubstituted phenyl.
  • R 1a , R 1b and R 1c are each independently selected from phenyl; wherein said phenyl is optionally substituted with from 1 , 2 or 3 R 10 groups; provided that R 1a , R 1b and R 1c are not each unsubstituted phenyl.
  • R 1a , R 1b and R 1c are each independently selected from C 3 to Cs cycloalkyl, C-i-Cs-alkyl and 4 to 8 membered heterocycloalkyl; wherein said C 3 to Cs cycloalkyl, C-i-Cs-alkyl and 4 to 8 membered heterocycloalkyl is optionally substituted with from 1 to 5 independently selected R 11 groups.
  • R 1a , R 1b and R 1c may be different or they may be the same.
  • R 11 is independently at each occurrence selected from C1-C6- alkyl, halo, OR 12 , NR 13 R 14 and S(0) 2 0R 13 .
  • R 11 is independently at each occurrence selected from OCH 3 , OCH 2 (CH 3 ) 2 , N(CH 3 ) 2 , S0 2 OH, F and Cl.
  • R 1a , R 1b and R 1c are each independently selected from phenyl, biphenyl and pyridyl wherein said phenyl, biphenyl and pyridyl is optionally substituted with 1 to 3 independently selected R 10 groups, wherein R 10 is independently at each occurrence selected from Ci-C 6 -alkyl, halo, OR 12 , NR 13 R 14 and S(0) 2 0R 10 .
  • R 1a , R 1b and R 1c are each independently selected from phenyl, biphenyl and pyridyl wherein said phenyl, biphenyl and pyridyl is optionally substituted with 1 to 3 independently selected R 10 groups, wherein R 10 is independently at each occurrence selected from OCH3, OCH2(CH3)2, N(CH3)2, SO2OH, F and Cl.
  • R 1a is C 3 to Cs-cycloalkyl
  • R 1b is C 3 to Cs-cycloalkyl
  • R 1c is C 3 to Cs-cycloalkyl
  • R 1a and R 1b are each unsubstituted phenyl and R 1c is independently selected from: substituted phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, C 3 to Cs-cycloalkyl, Ci-Cs-alkyl and 4- to 8-membered
  • R 1a and R 1b are each unsubstituted phenyl and R 1c is substituted phenyl.
  • R 1a and R 1b are each unsubstituted phenyl and R 1c is pyridyl.
  • R 1a and R 1b are each C3 to Cs-cycloalkyl and R 1c is
  • phenyl independently selected from: phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, C-i-Cs-alkyl and 4- to 8-membered heterocycloalkyl.
  • R 1a and R 1b are each cyclohexyl and R 1c is substituted biphenyl.
  • R 1a , R 1b and R 1c are each phenyl. In embodiments, R 1a , R 1b and R 1c are each phenyl. In embodiments, R 1a , R 1b and R 1c are each phenyl. In embodiments, R 1a , R 1b and R 1c are each phenyl. In embodiments, R 1a , R 1b and R 1c are each phenyl. In embodiments, R 1a , R 1b and
  • R 1c are each unsubstituted phenyl.
  • R 1a , R 1b and R 1c are each substituted phenyl. It may be that R 1a , R 1b and R 1c are each fluorophenyl, e.g. para- fluorophenyl. It may be that R 1a , R 1b and R 1c are each chlorophenyl, e.g. para- chlorophenyl. It may be that R 1a , R 1b and R 1c are each methoxyphenyl, e.g. para- methoxyphenyl.
  • R 1a , R 1b and R 1c are each C 3 to Cs-cycloalkyl. In embodiments, R 1a , R 1b and R 1c are each cyclohexyl.
  • R 1a , R 1b and R 1c are each benzyl.
  • at least one of R 1a , R 1b and R 1c is 5-, 6-, 9- or 10- membered heteroaryl or 4- to 8-membered heterocycloalkyl. It may be that a single one of R 1a , R 1b and R 1c is 5-, 6-, 9- or 10- membered heteroaryl or 4- to 8-membered heterocycloalkyl.
  • At least one of R 1a , R 1b and R 1c is 5-, 6-, 9- or 10- membered heteroaryl or 4- to 8-membered heterocycloalkyl, wherein said heteroaryl or heterocycloalkyl group comprises at least one nitrogen atom in the ring. It may be that a single one of R 1a , R 1b and R 1c is 5-, 6-, 9- or 10- membered heteroaryl or 4- to 8-membered heterocycloalkyl, wherein said heteroaryl or heterocycloalkyl group comprises at least one nitrogen atom in the ring.
  • At least one of R 1a , R 1b and R 1c is 5- or 6- membered heteroaryl group, wherein said heteroaryl group comprises at least one nitrogen atom in the ring. It may be that a single one of R 1a , R 1b and R 1c is 5- or 6- membered heteroaryl group, wherein said heteroaryl group comprises at least one nitrogen atom in the ring. In these embodiments, it may be that any of R 1a , R 1b and R 1c that are not heteroaryl or
  • heterocyclolkyl are phenyl, e.g. unsubstituted phenyl.
  • R 1a , R 1b and R 1c are Ci-C 6 -alkyl (e.g. methyl). It may be that a single one of R 1a , R 1b and R 1c is Ci-C 6 -alkyl (e.g. methyl). It may be that two or more of R 1a , R 1b and R 1c is Ci-C 6 -alkyl (e.g. methyl). It may be that each of R 1a , R 1b and R 1c is Ci-C 6 -alkyl (e.g. methyl). In these embodiments, it may be that any of R 1a , R 1b and R 1c that are not Ci-C 6 -alkyl are phenyl, e.g. unsubstituted phenyl.
  • R 1a and R 1b are connected to each other via a bond or a group selected from -0-, -S(0) 2 -, NR 6 , and Ci-C3-alkylene. It may be that R 1a and R 1b are connected to each other via a bond or a Ci-C3-alkylene group. It may be that R 1a and R 1b are connected to each other via a bond. It may be that R 1a and R 1b are each phenyl and are connected to each other via a bond or a group selected from -0-, NR 6 , and C1-C3- alkylene.
  • R 1a and R 1b are each phenyl and are connected to each other via a bond or a Ci-C3-alkylene group. It may be that R 1a and R 1b are each phenyl and are connected to each other via a bond.
  • R 1a and R 1b are not connected to each other via a bond or a group selected from -0-, -S(0) 2 -, NR 6 , and Ci-C3-alkylene.
  • R 1a , R 1b and R 1c are unsubstituted or substituted phenyl.
  • - + PR 1a R 1b R 1c is selected from PPhi3
  • R 2 may be Ci-C4-alkyl, e.g. methyl. Preferably, however, R 2 is H.
  • R 3 may be H.
  • R 3 may be selected from F and OR 12 .
  • R 3 may be selected from F and OH.
  • R 3 may be F.
  • R 3 may be OR 12 , e.g. OH.
  • R 4 may be C(0)Ci-C 4 -aikyl, e.g. C(0)Me. Preferably, however, R 4 is H.
  • R 5 may be independently at each occurrence selected from: Ci-C 6 -alkyl, C2-C6- alkynyl, C2-C6-alkenyl, Ci-C 6 -haloalkyl, OR 12 , S(0) 2 Ci-C 4 -alkyl, halo, cyano and nitro.
  • R 5 may be independently at each occurrence selected from: Ci-C 6 -alkyl, Ci-C 6 -haloalkyl, S(0) 2 Ci-C 4 -alkyl, halo, cyano and nitro.
  • R 5 may be selected from S(0) 2 Ci-C 4 -alkyl and nitro.
  • R 5 may be selected from nitro.
  • m may be an integer from 0 to 2.
  • m may be an integer from 0 to 1.
  • m may be an integer from 1 to 3.
  • m may be 0.
  • m may be 1. Where m is not 0, it may be that one of the R 5 groups is situated para to the point of connection of the rest of the molecule. It may be that m is 1 and the R 5 group is situated para to the point of connection of the rest of the molecule.
  • m is 1 and the R 5 group is situated para to the point of connection of the rest of the molecule and is selected from: Ci-C 6 -alkyl, Ci-C 6 -haloalkyl, S(0) 2 Ci-C 4 - alkyl, halo, cyano and nitro. It may be that m is 1 and the R 5 group is situated para to the point of connection of the rest of the molecule and is selected from S(0) 2 Ci-C 4 -alkyl and nitro. It may be that m is 1 and the R 5 group is situated para to the point of connection of the rest of the molecule and is nitro. This is the substitution on the corresponding phenyl group of chloramphenicol.
  • R 2 and R 4 are each H. It may be that R 2 and R 4 are each H and R 3 is selected from F and OH. It may be that R 2 and R 4 are each H, R 3 is selected from F and OH, m is 1 and the R 5 group is situated para to the point of connection of the rest of the molecule and is nitro. It may be that R 2 and R 4 are each H, R 3 is OH, m is 1 and the R 5 group is situated para to the point of connection of the rest of the molecule and is nitro. It may be that R 2 and R 4 are each H, m is 1 and the R 5 group is situated para to the point of connection of the rest of the molecule and is nitro. These embodiments apply particularly to compounds of formula (II).
  • R 6 is at any particular occurrence H. In embodiments, R 6 is at each occurrence H.
  • R 7 is at any particular occurrence H. In embodiments, R 7 is at each occurrence H.
  • R 10 may be independently at each occurrence selected from: Ci-C 6 -alkyl, C2-C6- alkynyl, C2-C6-alkenyl, Ci-C 6 -haloalkyl, OR 12 , halo, cyano and nitro.
  • R 11 may be independently at each occurrence selected from: oxo, halo, C1-C6- alkyl. R 11 may be independently at each occurrence Ci-C 6 -alkyl. [0061] In embodiments, R 12 is at any particular occurrence H. In embodiments, R 7 is at each occurrence H.
  • R 12 is at any particular occurrence Ci-C 4 -alkyl, e.g. methyl. In embodiments, R 12 is at each occurrence Ci-C 4 -alkyl, e.g. methyl.
  • R 13 is at any particular occurrence H.
  • R 7 is at each occurrence H.
  • R 13 is at any particular occurrence Ci-C 4 -alkyl, e.g. methyl. In embodiments, R 13 is at each occurrence Ci-C 4 -alkyl, e.g. methyl. [0065] In embodiments, R 14 is at any particular occurrence selected from H and Ci-C 4 - alkyl, e.g. methyl. In embodiments, R 14 is at each occurrence selected from H and Ci-C 4 - alkyl, e.g. methyl.
  • R 14 is at any particular occurrence H.
  • R 8 is at each occurrence H.
  • R 14 is at any particular occurrence Ci-C 4 -alkyl, e.g. methyl.
  • R 8 is at each occurrence Ci-C 4 -alkyl, e.g. methyl.
  • L 1 is selected from -C(O)- and -S(0) 2 -. In embodiments, L 1 is absent. In embodiments, L 1 is -C(O)-.
  • L 3 is at each occurrence absent.
  • the group -L 2 - (L 3 -L 4 ) n - may form an alkylene linker group.
  • L 1 is selected from -C(O)- and -S(0) 2 - and L 3 is at each occurrence absent. In embodiments, L 1 is -C(O)- and L 3 is at each occurrence absent.
  • L 3 is at each occurrence -O- and -L 4 - is at each occurrence -C2-C 4 -alkylene-.
  • the group -(L 3 -L 4 ) n - may form a ether or polyether linker group.
  • -L 4 - may at each occurrence represent -CH2CH2- or -CH2CH2CH2-.
  • the group -(L 3 -L 4 ) n - may form an ethylene glycol, polyethyleneglycol, propyleneglycol or polypropylene glycol linker group.
  • L 3 is at each occurrence selected from -NR 6 C(0)- and - C(0)NR 6 .
  • the group— (L 3 -L 4 ) n - may form a peptide linker group.
  • -L 4 - is at each occurrence -Ci-alkylene-.
  • L 3 is at each occurrence -O- and -L 4 - is at each occurrence -C2-C 4 -alkylene-.
  • the group -(L 3 -L 4 ) n - may form a ether or polyether linker group.
  • -L 4 - may at each occurrence represent -CH2CH2- or -ChhCI-hCI-h-.
  • the group -(L 3 -L 4 ) n - may form a, ethylene glycol, polyethyleneglycol, propyleneglcyol or polypropylene glycol linker group.
  • L 1 , L 2 , L 3 , L 4 and n are selected such that length of the linker formed by those groups is from 7 to 17 atoms. In embodiments, L 1 , L 2 , L 3 , L 4 and n are selected such that length of the linker formed by those groups is from 9 to 17 atoms, e.g. 10-17 atoms. [0075] In embodiments the group -L 1 -L 2 -(L 3 -L 4 ) n -P + R 1a R 1b R 1c is: wherein L 5 is a C2-Ci9-alkylene group optionally substituted with from 0 to 10 R 9 groups.
  • L 5 may be a C 6 -Ci 6 -alkylene group optionally substituted with from 0 to 10 R 9 groups.
  • L 5 may be a Cg-Ci 6 -alkylene group optionally substituted with from 0 to 10 R 9 groups.
  • L 5 may be unsubstituted.
  • n is an integer selected from 0 or 1.
  • the ion of formula (I) is an ion selected from:
  • the cation of formula (I) will be associated with an anionic counter ion.
  • the cation of formula (I) will be associated with a pharmaceutically acceptable anionic counterion.
  • the first aspect of the invention also, therefore, provides a compound comprising the ion of formula (I) and a pharmaceutically acceptable anion.
  • the anion may have a single negative charge.
  • the anion may be selected from: halo (e.g.
  • each anion listed in the preceding sentence possesses a single negative charge.
  • the anion may have multiple negative charges, e.g. P0 4 3 or C0 3 2 .
  • the anion may be derived from a di- or tri-acid, e.g.
  • carboxylate anions may each be accompanied by a pharmaceutically acceptable metal cation or by another cation of formula (I).
  • the anions associated with the cations of the invention can be quite labile. It may be therefore that the cation of the invention is present associated with two or more different anions. Ion exchange processes can be used to control the identity of the anion associated with the cation of the invention.
  • the anion is Cl, Br, I, PF 6 , CF 3 C(0)0, or HC(0)0.ln an aspect of the invention, the compounds of the invention are for medical use.
  • the compounds of the first aspect of the invention are for use in the treatment of cancer.
  • the compounds may be effective in treating cancer stem cells.
  • the compounds may also be for use in reducing cell proliferation of abnormal cells, such as cancer cells.
  • the compounds of the first aspect of the invention are for use in the treatment of solid tumours and other cancers, e.g. cancers classed as not being solid cancers.
  • cancers that can be treated by the compounds of the invention are: leukaemia, lymphoma, sarcoma, or carcinoma.
  • a method for the treatment of cancer comprising the administration of a therapeutically effective amount of a compound of the first aspect of the invention.
  • the method may be effective in treating cancer stem cells.
  • the method may also be for use in reducing cell proliferation of abnormal cells, such as cancer cells.
  • the method is for the treatment of solid tumours and other cancers, e.g. cancers classed as not being solid cancers.
  • cancers that can be treated by the methods of the invention are: leukaemia, lymphoma, sarcoma, or carcinoma.
  • The“treatment” of cancer may be taken to include prevention. Treatment also encompasses including any improvement of pathology, symptoms or prognosis that is achieved in respect of cancer in a subject receiving compounds of the invention.
  • Treatment may be indicated by a partial improvement of such indications, or by a total improvement (e.g. the absence of cancer following medical use of the compounds of the invention).
  • The“prevention” of cancer may be taken as including the prevention of the formation of new tumours, including new primary tumours or new metastatic tumours.
  • the prevention of cancer may also be taken as encompassing the prevention of the progression of cancer.
  • prevention of development of cancer may be demonstrated by preventing an increase in the“stage” of a tumour (using an appropriate cancer staging method) that has been treated using the compounds of the invention.
  • the prevention of increase in cancer stage may be compared to progression of an untreated tumour, or compared to the extent of progression that would be expected by a clinician in the event that the tumour was not treated.
  • the compounds of the first aspect of the invention may be for use in increasing cancer cell death or for decreasing cell proliferation by another mechanism, such as inhibiting cell replication.
  • the compounds may be used for this purpose in vitro or in vivo.
  • the compounds of the invention may be for use in the modulation of cancer cells or other dysfunctional cells (such as tumour initiating cells, stem-like cancer cells, cancer stem cells, or a population of cells with stem cell-like features that exist in tumors and that give rise to the bulk of tumor cells with more differentiated phenotypes). Accordingly, there is provided a method of modulating cancer cells or other dysfunctional cells in vivo or in vitro by exposing the cancer cells or other dysfunctional cells to a compound of the first aspect of the invention. The compound may be exposed to the cancer cells or other dysfunctional cells in an effective amount, for example a therapeutically effective amount such as in the case of a method of treatment or an in vivo method.
  • cancer cells or other dysfunctional cells such as tumour initiating cells, stem-like cancer cells, cancer stem cells, or a population of cells with stem cell-like features that exist in tumors and that give rise to the bulk of tumor cells with more differentiated phenotypes.
  • composition comprising a compound of the invention and one or more pharmaceutically acceptable excipients.
  • pharmaceutical composition may be a combination product comprising one or more different pharmaceutically active agents.
  • the one or more additional pharmaceutically active agents may be an anti-cancer agent described below.
  • the one or more pharmaceutically active agents may independently be selected from a different therapeutic class, e.g. antibiotic, anti-viral, anti-emetic, pain management, etc.
  • halo refers to an atom selected from fluorine, chlorine, bromine and iodine.
  • Halo or“halogen” may refer to an atom selected from Cl and F.
  • Halo or“halogen” may refer to fluorine.
  • alkyl refers to a linear or branched hydrocarbon chain.
  • C-i-Cs alkyl refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
  • C 1 -C 6 alkyl refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • the term“C 1 -C 6 alkyl” for example refers to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.
  • the “alkyl” group may be substituted or unsubstituted by one or more substituents.
  • alkyl group may be halo (for example fluorine, chlorine, bromine and iodine), OH and C 1 -C 6 alkoxy.
  • alkylene groups may be linear or branched and may have two places of attachment to the remainder of the molecule.
  • alkylene refers to a divalent group which is a linear or branched hydrocarbon chain. With the“alkylene” group being divalent, the group must form two bonds to other groups.
  • C-i-Cs-alkylene may refer to -CH 2 -, -CH 2 CH 2 -, - CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, - CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2- or substituted
  • alkylene group may be unsubstituted or substituted by one or more substituents.
  • cycloalkyl refers to a saturated hydrocarbon ring system.
  • C 3 - Ce cycloalkyl refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms.
  • the ring system may be a single ring or a bi-cyclic or tri-cyclic ring system. Where the ring system is bicyclic one of the rings may be an aromatic ring, for example as in indane.
  • the term“cycloalkyl” may refer to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and indane.
  • the cycloalkyl group may be substituted with one or more substituents.
  • haloalkyl refers to a linear or branched hydrocarbon chain which is substituted with at least one halogen atom which are independently selected at each occurrence from fluorine, chlorine, bromine and iodine.
  • C1-C6 haloalkyl refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5 or 6 carbon atoms. The halogen atom may be at substituted at any position on the
  • C1-C6 haloalkyl may refer to, for example, fluoromethyl, trifluoromethyl, chloromethyl, fluoroethyl, trifluoroethyl, chloroethyl, trichloroethyl (such as 1 ,2,2-trichloroethyl and 2,2,2-trichloroethyl), fluoropropyl and chloropropyl.
  • the haloalkyl group may be substituted with one or more substituents.
  • alkenyl refers to a linear or branched hydrocarbon chain containing at least one carbon-carbon double bond and having at least two carbon atoms.
  • C2-C6 alkenyl refers to a linear or branched hydrocarbon chain containing at least one carbon-carbon double bond and having 2, 3, 4, 5 or 6 carbon atoms.
  • the double bond or double bonds may be E or Z isomers.
  • the double bond may be present at any possible position of the hydrocarbon chain.
  • C2-C 6 alkenyl may refer to, for example, ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.
  • the alkenyl group may be substituted or unsubstituted by one or more substituents.
  • cycloalkenyl refers to an unsaturated hydrocarbon ring system.
  • C 3 -C 8 cycloalkenyl refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms.
  • the ring may contain more than one double bond.
  • cycloalkenyl may refer to, for example cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloocatadienyl.
  • the cycloalkenyl group may be substituted with one or more substituents.
  • alkynyl refers to a linear or branched hydrocarbon chain contain at least one carbon-carbon triple bond and having at least two carbon atoms.
  • C2- C 6 alkynyl refers to a linear or branched hydrocarbon chain containing at least one carbon-carbon triple bond and having 2, 3, 4, 5 or 6 carbon atoms.
  • the triple bond or triple bonds may be present at any possible position of the hydrocarbon chain.
  • C2-C 6 alkynyl may refer to, for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl.
  • the alkynyl group may be unsubstituted or substituted by one or more substituents.
  • the term“heteroalkyl” refers to a linear or branched hydrocarbon chain containing at least one heteroatom selected from N, O and S which is positioned between any possible carbon atom in the chain or at the end of the chain.
  • the term“C1-C6 heteroalkyl” refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5, or 6 carbon atoms and at least one heteroatom selected from N, O and S which is positioned between any possible carbon atom in the chain or at the end of the chain.
  • the heteroalkyl may be attached to another group by the heteroatom or the carbon atom.
  • the term“C-i- C6 heteroalkyl” may refer to, for example, -CH2NHCH3, -NHCH2CH3 and -CH2CH2NH2.
  • the heteroalkyl group may be unsubstituted or substituted by one or more substituents.
  • heterocycloalkyl refers to a saturated hydrocarbon ring system containing at least one heteroatom within the ring system selected from N, O and S.
  • the term“4- to 8- membered heterocycloalkyl” refers to a saturated hydrocarbon ring with 4, 5, 6, 7, 8, 9 or 10 atoms selected from carbon, N, O and S, at least one being a heteroatom.
  • The“heterocycloalkyl” group may also be denoted as a“3 to 10 membered
  • heterocycloalkyl which is also a ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 atoms, at least one being a heteroatom.
  • the ring system may be a single ring or a bi-cyclic or tri cyclic ring system.
  • Bicyclic systems may be spiro-fused, i.e. where the rings are linked to each other through a single carbon atom; vicinally fused, i.e. where the rings are linked to each other through two adjacent carbon or nitrogen atoms; or they may be share a bridgehead, i.e. the rings are linked to each other two non-adjacent carbon or nitrogen atoms.
  • one of the rings may be an aromatic ring, for example as in chromane.
  • The“heterocycloalkyl” may be bonded to the rest of the molecule through any carbon atom or heteroatom.
  • The“heterocycloalkyl” may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring.
  • the“heterocycloalkyl” may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine,
  • heterocycloalkenyl refers to an unsaturated hydrocarbon ring system containing at least one heteroatom selected from N, O or S.
  • C 3 -C 8 refers to an unsaturated hydrocarbon ring system containing at least one heteroatom selected from N, O or S.
  • heterocycloalkenyl refers to an unsaturated hydrocarbon ring system containing 3, 4, 5,
  • the ring system may be a single ring or a bi-cyclic or tri-cyclic ring system.
  • one of the rings may be an aromatic ring, for example as in indoline and dihydrobenzofuran.
  • the heterocycloalkenyl may be attached to another group by any carbon or heteroatom.
  • the term heterocycloalkenyl may refer to, for example tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline, dihydrobenzofuran, dihydrobenzothiophene and indoline.
  • the heterocycloalkenyl group may be substituted with one or more substituents.
  • aryl refers to an aromatic hydrocarbon ring system which satisfies Huckel’s rule for aromaticity or that contains a ring system which satisfies Huckel’s rule for aromaticity.
  • an aryl group may be a single ring or a bi-cyclic or tri-cyclic ring system.
  • the term“aryl” may refer to, for example, phenyl, naphthyl, indane, tetralin and anthracene.
  • the aryl group may be unsubstituted or substituted with one or more substituents. Any aryl group may be a phenyl ring.
  • heteroaryl refers to an aromatic hydrocarbon ring system with at least one heteroatom selected from N, O or S which satisfies Huckel’s rule for aromaticity or a ring system that contains a heteroatom and an aromatic hydrocarbon ring.
  • the heteroaryl may be a single ring system or a fused ring system.
  • the term“5-, 6-, 9- or 10- membered heteroaryl” refers to an aromatic ring system within 5, 6, 9, or 10 members selected from carbon, N, O or S either in a single ring or a bicyclic ring system.
  • heteroaryl may refer to, for example, imidazole, thiazole, oxazole, isothiazole, isoxazole, triazole, tetraazole, thiophene, furan, thianthrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine, indole, isoindole, quinolone, and isoquinoline.
  • alkoxy refers to an alkyl group which is linked to another group by oxygen.
  • the alkyl group may be linear or branched.
  • C1-C6 alkoxy refers to an alkyl group containing 1 , 2, 3, 4, 5 or 6 carbon atoms which is linked to another group by oxygen.
  • the alkyl group may be, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl.
  • C1-C6 alkoxy may refer to, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n- pentoxy and n-hexoxy.
  • the alkyl group may be substituted or unsubstituted by one or more substituents.
  • a bond terminating in a“ - rJ ⁇ r ” means that the bond is connected to another group that is not shown.
  • a bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be connected to any of the atoms in the ring structure where allowed by valency.
  • a group may be substituted at any point on the group where chemically possible and consistent with valency requirements.
  • the group may be substituted by one or more substituents.
  • the group may be substituted with 1 , 2, 3 or 4 substituents. Where there are two or more substituents, the substituents may be the same or different.
  • Substituent(s) may be, for example, halo, CN, nitro, oxo, C1-C6- alkyl, C2-C6-alkynyl, C2-C6-alkenyl, Ci-C 6 -haloalkyl, OR a , NR a R b , SR a , C(0)0R a ,
  • R a is independently at each occurrence selected from: H and Ci-C 6 -alkyl
  • R b is independently at each occurrence selected from: H, Ci-C 6 -alkyl, C(0)Ci-C 6 -alkyl and S(0) 2 -Ci-C 6 -alkyl.
  • a cyclic substituent may be substituted on a group so as to form a spiro-cycle.
  • Meta substitution is a substitution pattern where two substituents are on carbons one carbon removed from each other, i.e with a single carbon atom between the substituted carbons. In other words there is a substituent on the second atom away from the atom with another substituent.
  • substituents are on carbons one carbon removed from each other, i.e with a single carbon atom between the substituted carbons.
  • substituents are on the second atom away from the atom with another substituent.
  • the groups below are meta substituted.
  • “Parent” substitution is a substitution pattern where two substituents are on carbons two carbons removed from each other, i.e with two carbon atoms between the substituted carbons. In other words there is a substituent on the third atom away from the atom with another substituent.
  • the groups below are para substituted.
  • the cation of formula (I) will be associated with a pharmaceutically acceptable anionic counter ion for administration to a subject. Nevertheless, where either the cation of formula (I) or the anionic counter ion comprise either basic or acidic groups, those groups may themselves be protonated or deprotonated and associated with an appropriate counter ion.
  • Suitable acid addition salts are formed from acids which form non-toxic salts, for example, acetate, aspartate, benzoate, besylate, bicarbonate/carbonate,
  • Suitable base salts are formed from bases which form non-toxic salts, for example including the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • suitable salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
  • the salt may be an acid addition salt.
  • the salts may be formate or hydrochloride.
  • the reactions above are typically carried out in solution and the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
  • the compounds may exist in both unsolvated and solvated forms.
  • 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • 'hydrate' is employed when said solvent is water.
  • Complexes are contemplated, such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • Complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non- stoichiometric amounts are also contemplated.
  • the resulting complexes may be ionised, partially ionised, or non- ionised. A review of such complexes is found in J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).
  • radionuclides that may be incorporated include 2 H (also written as“D” for deuterium), 3 H (also written as“T” for tritium), 11 C, 13 C, 14 C, 15 0, 17 0, 18 0, 18 F and the like.
  • the radionuclide that is used will depend on the specific application of that radio-labelled derivative. For example, for in vitro competition assays, 3 H or 14 C are often useful. For radio-imaging applications, 11 C or 18 F are often useful.
  • the radionuclide is 3 H.
  • the radionuclide is 14 C.
  • the radionuclide is 11 C.
  • the radionuclide is 18 F.
  • references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
  • the compounds include a number of formulae as herein defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labelled compounds of the invention.
  • the compounds Before purification, the compounds may exist as a mixture of enantiomers depending on the synthetic procedure used.
  • the enantiomers can be separated by conventional techniques known in the art. Thus the compounds cover individual enantiomers as well as mixtures thereof.
  • any compatible protecting radical can be used.
  • methods of protection and deprotection such as those described by T.W. Greene (Protective Groups in Organic Synthesis, A. Wiley- Interscience Publication, 1981 ) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used.
  • the compounds as well as intermediates for the preparation thereof can be purified according to various well-known methods, such as for example crystallization or chromatography.
  • the method of treatment or the compound for use in the treatment of solid tumours, leukaemia, lymphoma, sarcoma, or carcinoma as defined hereinbefore may be applied as a sole therapy or be a combination therapy with an additional active agent.
  • the method of treatment or the compound for use in the treatment of solid tumours, leuekaemia, lymphoma, sarcoma, or carcinoma may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti-cancer agents:
  • antiproliferative/antineoplastic drugs and combinations thereof such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, bendamustin, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, and hydroxyurea); antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine
  • cytostatic agents such as antiestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride;
  • antiestrogens for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene
  • antiandrogens for example bical
  • anti-invasion agents for example dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase;
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies, for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as gefitinib, erlotinib and 6-acrylamido-/V-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)- quinazolin-4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib);
  • growth factor antibodies and growth factor receptor antibodies for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetux
  • inhibitors of the hepatocyte growth factor family include modulators of protein regulators of cell apoptosis (for example Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib (AMN107); inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib , tipifarnib and lonafarnib), inhibitors of cell signalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1 R kinase inhibitors, IGF receptor, kinase inhibitors; aurora kinase inhibitors and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM); thalidomide; lenalidomide; and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib;
  • immunotherapy approaches including checkpoint inhibitors of targets such as PD-1 , PD-L1 and CTCLA-4, for example antibody therapy such as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®), pembrolizumab and ofatumumab; interferons such as interferon a; interleukins such as IL-2 (aldesleukin); interleukin inhibitors for example IRAK4 inhibitors; cancer vaccines including prophylactic and treatment vaccines such as HPV vaccines, for example Gardasil, Cervarix, Oncophage and Sipuleucel-T (Provenge); and toll-like receptor modulators for example TLR-7 or TLR-9 agonists; and
  • cytotoxic agents for example fludaribine (fludara), cladribine, pentostatin
  • steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide,
  • hydrocortisone valerate icomethasone, icomethasone enbutate, meprednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and their respective pharmaceutically acceptable derivatives.
  • a combination of steroids may be used, for example a
  • (x) targeted therapies for example PI3Kd inhibitors, for example idelalisib and perifosine.
  • Such combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products may be administered so that the combination is provided in a therapeutically effective amount, for example the compounds of this invention may be administered within a therapeutically effective dosage range described herein and the other pharmaceutically-active agent may be administered in an amount of less than or within its approved dosage range.
  • a pharmaceutical product comprising a compound of the first aspect of the invention, or a pharmaceutically acceptable salt thereof as defined herein and an additional active agent.
  • the additional active agent may be a cancer therapy as defined hereinbefore for the combination treatment of cancer.
  • a method of treating cancer comprising administering a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with an additional anti-cancer agent, as defined hereinbefore, to a patient in need thereof.
  • a compound of the invention for use simultaneously, sequentially or separately with an additional anti-cancer agent as defined herein, in the treatment of cancer.
  • the compound of the invention in combination with an anti-cancer agent, such as those hereinbefore described.
  • the compound of the invention may be used simultaneously, sequentially or separately with the additional anti-cancer agent.
  • the use may be in a single combination product comprising the compound of the invention and the anti-cancer agent.
  • the additional anti-cancer agent may be a further compound of the first aspect of the invention.
  • a method of providing a combination product comprising providing a compound of the invention simultaneously, sequentially or separately with an anti-cancer agent, as defined hereinbefore.
  • the method may comprise combining the compound of the invention and the anti-cancer agent in a single dosage form.
  • the method may comprise providing the anti-cancer agent as separate dosage forms.
  • Compounds of the invention may exist in a single crystal form or in a mixture of crystal forms or they may be amorphous.
  • compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying.
  • Microwave or radio frequency drying may be used for this purpose.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
  • the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight (pg/kg) to 100 milligrams per kilogram body weight (mg/kg).
  • a compound of the invention, or pharmaceutically acceptable salt thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutically acceptable adjuvant diluent or carrier.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
  • the pharmaceutical composition which is used to administer the compounds of the invention will preferably comprise from 0.05 to 99 %w (percent by weight) compounds of the invention, more preferably from 0.05 to 80 %w compounds of the invention, still more preferably from 0.10 to 70 %w compounds of the invention, and even more preferably from 0.10 to 50 %w compounds of the invention, all percentages by weight being based on total composition.
  • compositions may be administered topically (e.g. to the skin) in the form, e.g., of creams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.
  • parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.
  • the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets.
  • a carrier for example, lactose, saccharose, sorbitol, mannitol
  • a starch for example, potato starch, corn starch or amylopectin
  • a cellulose derivative for example, gelatine or polyvinylpyrrolidone
  • a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and
  • the cores may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets.
  • liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • the compounds of the invention may be administered as a sterile aqueous or oily solution.
  • the size of the dose for therapeutic purposes of compounds of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
  • Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient.
  • Certain ions of the invention can be synthesised according to or analogously to methods described in the General Schemes below and/by other techniques known to those of ordinary skill in the art. Certain ions of the invention can be synthesised according to or analogously to the methods described in the Examples.
  • Reaction of amine (1 ) with phosphonium acid (2) can furnish phosphonium amide (3).
  • the reaction can be performed using standard peptide coupling agents, such as N,N’- diisopropylcarbodiimide (DCC) in an organic solvent, such as DCM at a temperature from 0 to 30 °C or 1-ethyl-3-(3’-dimethyl)amino)carbodiimide HCI, in the presence of a base, such as NaHCC>3 or E ⁇ bN in an organic solvent, such as DCM or DMF at a temperature from 0 to 30 °C.
  • DCC diisopropylcarbodiimide
  • HCI 1-ethyl-3-(3’-dimethyl)amino)carbodiimide HCI
  • a base such as NaHCC>3 or E ⁇ bN
  • an organic solvent such as DCM or DMF at a temperature from 0 to 30 °C.
  • Phosphonium acid (2) can be
  • Phosphonium amide (3) can also be accessed by an alternative sequence of reactions involving amide formation between amine (1 ) and acid (4) using standard peptide coupling agents, followed by displacement of the resultant product halide with phosphine (5), which can be accomplished by heating in an organic solvent, such as MeCN at a temperature from 50 to 80 °C.
  • Reaction of amine (1 ) with halo sulphonic acid (6) can furnish halo sulphonamide (7).
  • the reaction can be performed using SOCI2 in an organic solvent, such as DMF or DCM at a temperature from 20 to 60 °C.
  • Reaction of halo sulphonamide (7) with phosphine (5) can deliver phosphonium sulphonamide (8).
  • the reaction can be accomplished by heating in an organic solvent, such as MeCN at a temperature from 50 to 80 °C.
  • Certain ions of formula (I) (where R 3 is independently selected form H, halo and OR 12 ) can be made by Scheme C
  • the reaction can be performed in a mixed organic solvent comprising of EtOH and DCM, at a temperature from 25 to 40 °C.
  • Reaction of halo urea (10) with phosphine (5) can deliver phosphonium urea (11 ).
  • the reaction can be accomplished by heating in an organic solvent, such as MeCN at a temperature from 50 to 80 °C.
  • reaction can be accomplished with diphenylphosphoryl azide ((Ph0) 2 P(0)N 3 ) in the presence of a base, such as E ⁇ bN in an organic solvent, such as toluene at a temperature from 50 to 100 °C.
  • a base such as E ⁇ bN
  • organic solvent such as toluene
  • the reaction can be performed in the presence of a base, such as E ⁇ bN in an organic solvent, such as toluene at a temperature from 25 to 70 °C.
  • Reaction of halo sulphonyl urea (13) with phosphine (5) can deliver phosphonium sulphonyl urea (14).
  • the reaction can be accomplished by heating in an organic solvent, such as MeCN at a temperature from 50 to 80 °C.
  • a base such as E ⁇ bN
  • organic solvent such as DCM
  • the reaction can be performed in the presence of an inorganic base, such as Na2CC>3 in an organic solvent, such as DCM at a temperature from 0 to 10 °C.
  • Reaction of halo carbamate (17) with phosphine (5) can deliver phosphonium carbamate (18).
  • the reaction can be accomplished by heating in an organic solvent, such as MeCN at a temperature from 50 to 80 °C.
  • the reaction can be accomplished with triphosgene in the presence of a base, such as pyridine in an organic solvent, such as DCM or THF at a temperature from -10 to 30 °C.
  • Alcohol (20) (synthesised from Schemes A - E) can be converted to bromide (21 ).
  • the reaction can be accomplished with NBS and PPfi 3 in the presence of pyridine in an organic solvent, such as THF at a temperature from 0 to 30 °C.
  • the bromide (21 ) can be transformed to azide (22).
  • the reaction can be performed with sodium azide in an organic solvent, such as DMF at a temperature from 20 to 70 °C.
  • Reduction of azide (22) can deliver primary amine (23).
  • the reaction can be accomplished by standard hydrogenation, techniques, such as Pd/C catalyst systems in organic solvents, such as EtOAc.
  • primary amine (23) can be accessed by reduction of azide (22) with PPfi 3 followed by H2O in an organic solvent, such as THF at a temperature from 10 to 30 °C.
  • Bromide (21 ) (synthesised from Scheme F) can be converted to secondary amine (24).
  • organic solvent such as DMF
  • Optional is the addition of CsOH.hhO and 4A molecular sieves.
  • Bromide (21 ) (synthesised from Scheme F) can be converted to tertiary amine (25).
  • an inorganic base such as K 2 CO 3
  • organic solvent such as dioxane
  • the reaction can be accomplished in the presence of a base, such as E ⁇ bN or pyridine in an organic solvent, such as DCM or EtOAc at a temperature from -5 to 30 °C.
  • the reaction can be accomplished in the presence of a base, such as E ⁇ bN or pyridine in an organic solvent, such as DCM or EtOAc at a temperature from -5 to 30 °C.
  • DCC diisopropylcarbodiimide
  • DCM dichloromethane
  • DMF dimethylformamide
  • DMSO dimethyl sulfoxide
  • MTBE methyl-t-butylether
  • N-bromosuccinimide N-bromosuccinimide
  • THF tetrahydrofuran
  • Example 11 (11- ⁇ [(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl ⁇ undecyl)( 1 -methyl-1 H-pyrazol-4-yl)diphenylphosphonium chloride 4-(diphenylphosphoryl)- 1 -methyl- 1 H-pyrazole
  • Example 11 step (b) Prepared following Example 11 step (b) but using 1 1 -bromoundecanoic acid.
  • Silica column chromatography was performed using the eluting system 0-10% MeOH in DCM.
  • (10-carboxydecyl)(1 -methyl-1 H-pyrazol-4-yl)diphenylphosphonium bromide was isolated as a colourless oil, which was used in the next step.
  • Example 11 step (c) The title compound was prepared as a white solid following the procedure described in Example 11 step (c) but using 10-carboxydecyl)(1 -methyl-1 H-pyrazol-4- yl)diphenylphosphonium bromide (prepared as described in Example 13 step (a)).
  • Silica column chromatography was performed using the eluting system 0-20% 7M NH3 in MeOH in DCM.
  • Example 11 step (b) Prepared following Example 11 step (b) but using 10-bromodecanoic acid.
  • Silica column chromatography was performed using the elution system 0-10% MeOH in DCM.
  • (9- carboxynonyl)(1 -methyl-1 H-pyrazol-4-yl)diphenylphosphonium bromide was isolated as a light brown oil, which was used in the next step.
  • Example 11 step (c) The title compound was prepared as a white solid following the procedure described in Example 11 step (c) but using (9-carboxynonyl)(1 -methyl-1 H-pyrazol-4- yl)diphenylphosphonium bromide (prepared as described in Example 14 step (a)).
  • Silica column chromatography was performed using the eluting system 0-20% 7M NH3 in MeOH in DCM.
  • Example 11 step (b) Prepared following Example 11 step (b) but using 9-bromononanoic acid.
  • Silica column chromatography was performed using the eluting system 0-10% MeOH in DCM.
  • (8- carboxyoctyl)(1 -methyl-1 H-pyrazol-4-yl)diphenylphosphonium bromide was isolated as a colourless oil, which was used in the next step.
  • Example 11 step (c) The title compound was prepared as a white solid following the procedure described in Example 11 step (c) but using (8-carboxyoctyl)(1 -methyl-1 H-pyrazol-4- yl)diphenylphosphonium bromide (prepared as described in Example 15 step (a)).
  • Silica column chromatography was performed using the eluting system 0-20% 7M NH 3 in MeOH in DCM.
  • Example 11 step (b) Prepared following Example 11 step (b) but using 8-bromooctanoic acid.
  • Silica column chromatography was performed using the eluting system 0-10% MeOH in DCM.
  • (7- carboxyheptyl)(1 -methyl-1 H-pyrazol-4-yl)diphenylphosphonium bromide was isolated as a colourless oil, which was used in the next step.
  • Example 11 step (c) The title compound was prepared as a white solid following the procedure described in Example 11 step (c) but using (7-carboxyheptyl)(1 -methyl-1 H-pyrazol-4- yl)diphenylphosphonium bromide (prepared as described in Example 16 step (a)).
  • Silica column chromatography was performed using the eluting system 0-20% 7M NH 3 in MeOH in DCM.
  • Example 6 step (a) Prepared following Example 6 step (a) but using 16-bromohexadecanoic acid.
  • Silica column chromatography was performed using the eluting system 0-10% 7M NH 3 in MeOH in DCM.
  • 16-bromo-N-[(1 R,2R)-1 ,3-dihydroxy-1 -(4-nitrophenyl)propan-2- yl]hexadecanamide was isolated as a white solid, which was used in the next step.
  • Example 20 (11- ⁇ [(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl ⁇ undecyl)tris(3,5-dimethylphenyl)phosphonium chloride
  • Example 6 step (a) Prepared following Example 6 step (a) but using 8-bromooctanoic acid.
  • Silica column purification was performed using the eluting system 0-10% 7M NH 3 in MeOH in DCM.
  • 8- bromo-N-[(1 R,2R)-1 ,3-dihydroxy-1-(4-nitrophenyl)propan-2-yl]octanamide was isolated as a colourless oil, which was used in the next step.
  • Example 22 (7- ⁇ [(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl ⁇ heptyl)tris(3,5-dimethylphenyl)phosphonium chloride
  • Example 21 but using tris(3,5-dimethylphenyl)phosphine in step (b).
  • the confluence value is a surrogate for cell proliferation and growth.
  • the value is expressed as a percent confluence, which represents the fraction of culture dish-surface that is occupied by cells. As the number of cells in the dish increases over time due to proliferation, so will their coverage of that surface increase. Expansion of the cell population on the cell culture-dish surface and confluence have mostly a linear relationship until the cells on the plate surface begin to reach saturation or maximum density.
  • Confluence is determined based on image analysis.
  • Image based software can identify objects in the image field based on changes to pixel density in a grey scale image. The software can then assign a mask to those pixels within the object. Objects can be ‘gated’ out based on size and shape.
  • images of cells are first masked as objects. The surface area of the image that is masked is measured and compared to the total surface area of the culture dish surface to obtain a percent confluence.
  • MDA-231 cancer cells were obtained from ATCC. Cells were cultured in Dulbecco’s
  • DMEM Modified Eagle Medium
  • FBS Fetal Bovine Serum
  • NEAA Non Essential Amino Acid
  • DMSO Modified Eagle Medium
  • FBS Fetal Bovine Serum
  • NEAA Non Essential Amino Acid
  • DMSO Modified Eagle Medium
  • FBS Fetal Bovine Serum
  • NEAA Non Essential Amino Acid
  • DMSO concentrations were ⁇ 0.1 %. Images were acquired with an IncuCyte Live Cell Imaging microscopy (Essen Bioscience) at every 3 h under cell culture conditions with 10X objective over 4-5 d. Cell confluence was calculated from one field of view per well using the IncuCyte in-built algorithm. Relative confluence values were obtained by normalising each value to the time zero value in each sample.

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Abstract

This invention relates to compounds that disrupt cell function, such as the disruption of cell metabolism in particular cancer cell metabolism, that are useful as cancer therapies. The compounds comprise (β-amino-α-hydroxyalkyl)phenyl derivatives having a phosphonium cation tethered to the (β-amino-α-hydroxyalkyl)phenyl amine.

Description

BETA-AMINO-ALPHA-HYDROXYALKYLPHENYL DERIVATIVES
AND THEIR USE FOR CANCER TREATMENT
[0001] This invention relates to compounds that disrupt cell function, such as the disruption of cell metabolism in particular cancer cell metabolism, that are useful as cancer therapies. The compounds comprise (3-amino-ohydroxyalkyl)phenyl derivatives having a phosphonium cation tethered to the (3-amino-ohydroxyalkyl)phenyl amine. Certain chemicals are based on the (3-amino-ohydroxyalkyl)phenyl portion of chloramphenicol The invention also relates to methods of using said compounds and to pharmaceutical formulations comprising said compounds.
BACKGROUND
[0002] Cancer is the fourth greatest cause of mortality in the developed world. In 2016 it was predicted that more than 1.6 million new cases of cancer would be diagnosed in the U.S. alone, and that cancer would be responsible for nearly 600,000 U.S. deaths.
[0003] Cancer is characterized by the unregulated proliferation of cells, which disrupt the function of tissues. The proliferation of cells can be caused by an abnormal increase in cell production or a disruption in the cell death pathway. In any event, disruptors of cell function can impact the proliferation of cells and in particular cancer cells by reducing or inhibiting cell proliferation. For example, the modulation of cancer cell metabolism can lead to the reduction or inhibition of cell proliferation. Equally, compounds of the invention may reduce, disrupt, or inhibit the growth or proliferation of a cancer cell or it may induce the death of a cancer cell. As such, cancer cell metabolism, and reducing cell proliferation, is a potential target for disrupting cancer growth and ultimately a therapeutic pathway for cancer treatment. Accordingly, the certain embodiments of the invention contemplate compounds that modulate cancer cell metabolism and/or reduce cell proliferation. Reduction in cell proliferation could be achieved either by increasing cell death or by reducing the rate of cell growth.
[0004] It has been observed that certain compounds having antibiotic activity have a beneficial effect when administered to patients with cancer. The inventors have found that compounds having a phosphonium ion linked to (3-amino-ohydroxyalkyl)phenyl amines are able to modulate cancer cell metabolism in cancer cell lines and, accordingly, prevent and/or treat cancer.
[0005] The“prevention” of cancer may be taken as including the prevention of the formation of tumours, including primary tumours, metastatic tumours, or tumours associated with cancer onset, resistance or relapse. The prevention of cancer may also be taken as encompassing the prevention of the progression of cancer. In this context, prevention of development of cancer may be demonstrated by preventing an increase in the“stage” of a tumour (using an appropriate cancer staging method) that has been treated using the compounds of the invention. The prevention of increase in cancer stage may be compared to progression of an untreated tumour, or compared to the extent of progression that would be expected by a clinician in the event that the tumour was not treated.
[0006] The“treatment” of cancer may be taken as including any improvement of pathology, symptoms or prognosis that is achieved in respect of cancer in a subject receiving compounds of the invention. Treatment may be indicated by a partial improvement of such indications, or by a total improvement (e.g. the absence of cancer following medical use of the compounds of the invention).
[0007] Accordingly, the prevention and/or treatment as defined above are intended aims of certain embodiments of the invention. The above definitions of treatment or prevention of cancer apply equally to the specific forms of cancer that are also contemplated.
[0008] Recent developments in cancer therapy have suggested that certain antibiotic compounds may be useful in cancer treatment. The mechanisms by which these agents, which include the antibiotics azithromycin and doxycycline, exert a therapeutic effect have been open to markedly different explanations. Some authors have suggested that these agents inhibit matrix metalloproteinases (MMPs) and thereby achieve an anti- inflammatory effect, while others suggest that they impair the cells’ response to DNA damage, thereby increasing the effectiveness of chemotherapy or radiotherapy on bulk tumour cells. Still other articles have indicated that the antibiotics target mitochondrial function.
[0009] However, there have also been reports that antibiotic use can increase risk of colorectal cancer. A recent study identified that increasing duration of antibiotic use was significantly associated with an increased risk of colorectal adenoma (Cao Y, Wu K,
Mehta R, et al,“Long-term use of antibiotics and risk of colorectal adenoma”, Gut, 2017,
0, page 1-7).
[0010] Surprisingly, the inventors have found that compounds having a phosphonium ion linked to (3-amino-ohydroxyalkyl)phenyl have increased activity against certain cancer cell lines compared to related (3-amino-ohydroxyalkyl)phenyl compounds that do not have the phosphonium ion. This is demonstrated by the reduced cancer cell proliferation observed in a cell confluence assay. [0011] Also provided is a method of preventing and/or treating cancer in a subject needing such prevention and/or treatment, the method comprising administering a therapeutically effective amount of a compound of the invention to the subject. A therapeutically effective amount of a compound of the invention may be an amount of such a compound sufficient to treat a variety of cancers, including the modulation of cancer cells or other dysfunctional cells (such as tumour initiating cells, stem-like cancer cells, cancer stem cells, or a population of cells with stem cell-like features that exist in tumors and that give rise to the bulk of tumor cells with more differentiated phenotypes). References to cancer cells include hybrid and giant cells. It will be appreciated that the therapeutically effective amount of the compound of the invention may be provided in a single incidence of administration, or cumulatively through multiple incidences of administration.
[0012] The same considerations regarding the types of cancers to be treated, and benefits provided by treatment, described with respect to the medical uses of the compounds of the invention also apply to the methods of treatment of the invention.
BRIEF SUMMARY OF THE DISCLOSURE
[0013] In a first aspect of the invention there is provided a compound comprising an ion of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000004_0001
-L1- is independently absent or is selected from -C(O)-, -C(0)0-, -S(0)2-, -C(0)NR6, and - S(0)2NR6-;
-L3- is independently at each occurrence either absent or selected from: -0-, -S-, -NR7-,- C(O)-, -OC(O)-, -0(0)0-, -S(0)2-, -S(O)-, -NR6C(0)-, -C(0)NR6, -NR6S(0)2-, -S(0)2NR6-, - 0C(0)NR6-,-NR6C(0)0-, NR6C(0)NR6, -CR8=CR8- and -CºC-;
-L2- and -L4- are each independently at each occurrence -Ci-C4-alkylene-, each alkylene group being unsubstituted or substituted with from 1 to 6 independently selected R9 groups; provided that any -l_2- or -L4- group that is attached at each end to an atom selected from oxygen, nitrogen, sulphur or phosphorous is -C2-C4-alkylene-; n is an integer selected from 0, 1 , 2, 3, 4 and 5;
wherein L1, L2, L3, L4 and n are selected such that length of the linker formed by those groups is from 3 to 20 atoms;
R1a, R1b and R1c are each independently selected from phenyl, biphenyl, naphthyl, 5-, 6-,
9- or 10- membered heteroaryl, C3 to Cs-cycloalkyl, Ci-Cs-alkyl and 4- to 8-membered heterocycloalkyl; wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R10 groups; and wherein said C3 to Cs-cycloalkyl, C-i-Cs-alkyl and 4- to 8-membered heterocycloalkyl is optionally substituted with from 1 to 5 independently selected R11 groups; wherein R1a and R1b are optionally connected to each other via a bond or a group selected from -0-, - S(0)2-, NR6, and Ci-C3-alkylene;
R2 and R6 are each independently at each occurrence selected from H and Ci-C6-alkyl;
R3 is independently selected from H, halo, OR12 and NR13R14;
R4 is independently at each occurrence selected from: H, and C(0)Ci-C6-alkyl;
R5 and R10 are each independently at each occurrence selected from: Ci-C6-alkyl, C2-C6- alkynyl, C2-C6-alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 4- to 8-membered
heterocycloalkyl, 5-, 6-, 9- or 10- membered heteroaryl, phenyl, OR12, SR13, NR13R14, C(0)OR13, C(0)NR13R13, halo, cyano, nitro, C(0)R13, S(0)20R13, S(0)R13, S(0)2R13, S(0)2NR13R13, 0C(0)NR13R13 and NR13C(0)0R13;
R7 and R14 are each independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci-Ce-alkyl and S(0)2-Ci-Ce-alkyl;
R8 is independently at each occurrence selected from H, Ci-C4-alkyl and halo;
R9 is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C2-C6- alkenyl, Ci-C6-haloalkyl, OR12, SR13, NR13R14, C(0)OR13, C(0)NR13R13, halo, cyano, nitro, C(0)R13, S(0)20R13, S(0)2R13, S(0) R13, S(0)2NR13R13, 0C(0)NR13R13 and
NR13C(0)0R13;
R11 is independently at each occurrence selected from: oxo, Ci-C6-alkyl, C2-C6-alkynyl, C2- C6-alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 4- to 8-membered heterocycloalkyl, 5-, 6-, 9- or 10- membered heteroaryl, phenyl, OR12, SR13, NR13R14, C(0)OR13, C(0)NR13R13, halo, cyano, nitro, C(0)R13, S(0)20R13, S(0)R13· S(0)2R13, S(0)2NR13R13, 0C(0)NR13R13 and NR13C(0)0R13;
R12 is independently at each occurrence selected from: H, Ci-C6-alkyl and Ci-C6-haloalkyl; R13 is independently at each occurrence selected from: H and Ci-C6-alkyl; and m is an integer selected from 0, 1 , 2, 3, 4 and 5;
and wherein any of the abovementioned alkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, heteroaryl or phenyl groups is optionally substituted where chemically allowable by from 1 to 4 groups independently selected from oxo, Ci-C6-alkyl, C2-C6- alkynyl, C2-Ce-alkenyl, Ci-Ce-haloalkyl, ORa, NRaRb, SRa, C(0)0Ra, C(0)NRaRa, halo, cyano, nitro, C(0)Ra, S(0)20Ra, S(0)2Ra, S(0)Ra and S(0)2NRaRa; wherein Ra is independently at each occurrence selected from: H and Ci-C6-alkyl; and Rb is
independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci-C6-alkyl and S(0)2-Ci-C6-alkyl.
[0014] For the absence of doubt, where n is greater than 1 , each -L3-L4- unit is selected independently of the other each -L3-L4- unit or -L3-L4- units. Thus, each -L3-L4- unit may be the same or they may be different.
[0015] For the absence of doubt the atom length of the linkers formed by L1, L2, L3 and L4 is the number of atoms in a straight chain from the phosphorous atom of the phosphonium to the nitrogen atom that is also attached to R2. The length does not include any substituents or branching that might be present on the chain.
[0016] For the absence of doubt where a bivalent group (e.g. L1, L2, L3, L4, or a combination thereof) is represented in text, the left hand portion of the linker group is attached, either directly or indirectly, to the nitrogen atom that is also attached to R2 and the right hand portion of the linker group is attached, either directly or indirectly, to the phosphorous atom of the phosphonium.
[0017] In embodiments, the ion of formula (I) is an ion of formula (II):
Figure imgf000006_0001
wherein R1a, R1b, R1c, R2, R3, R4, R5, L1, L2, L3, L4, n and m are as described above for formula (I).
[0018] In embodiments, the ion of formula (I) is an ion of formula (III):
Figure imgf000007_0001
wherein R1a, R1b, R1c, R3, R5, L1, L2, L3, L4, n and m are as described above for formula (I).
[0019] In embodiments, the ion of formula (I) is an ion of formula (IV):
Figure imgf000007_0002
wherein R1a, R1b, R1c, R3, L1, L2, L3, L4 and n are as described above for formula (I).
[0020] In embodiments, the ion of formula (I) is an ion of formula (V):
Figure imgf000007_0003
wherein R1a, R1b, R1c, R3, L1, L2, L3, L4 and n are as described above for formula (I).
[0021] The following statements apply to compounds of any of formulae (I) to (V).
These statements are independent and interchangeable. In other words, any of the features described in any one of the following statements may (where chemically allowable) be combined with the features described in one or more other statements below. In particular, where a compound is exemplified or illustrated in this specification, any two or more of the statements below which describe a feature of that compound, expressed at any level of generality, may be combined so as to represent subject matter which is contemplated as forming part of the disclosure of this invention in this
specification.
[0022] In embodiments, R1a, R1b and R1c are each independently selected from phenyl, biphenyl, 5- or 6- membered heteroaryl and C3 to Cs-cycloalkyl, wherein said phenyl, biphenyl and 5- or 6- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R10 groups, and wherein said C3 to Cs-cycloalkyl is optionally substituted with from 1 to 5 independently selected R11 groups; provided that R1a, R1b and R1c are not each unsubstituted phenyl. [0023] In embodiments, R1a, R1b and R1c are each independently selected from phenyl, biphenyl, pyridyl and cyclohexyl, wherein said phenyl, biphenyl and pyridyl is optionally substituted with from 1 to 5 independently selected R10 groups, and wherein said cyclohexyl group is optionally substituted with from 1 to 5 independently selected R11 groups; provided that R1a, R1b and R1c are not each unsubstituted phenyl.
[0024] In embodiments, R1a, R1b and R1c are each independently selected from phenyl, biphenyl, pyridyl and cyclohexyl, wherein said phenyl, biphenyl and pyridyl is optionally substituted with 1 to 3 independently selected R10 groups, and wherein said cyclohexyl group is optionally substituted with 1 to 3 independently selected R11 groups; provided that R1a, R1b and R1c are not each unsubstituted phenyl.
[0025] In embodiments, R1a, R1b and R1c are each independently selected from phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl; wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R10 groups, provided that R1a, R1b and R1c are not each
unsubstituted phenyl.
[0026] In embodiments, R1a, R1b and R1c are each independently selected from phenyl, optionally substituted with from 1 to 5 independently selected R10 groups, provided that R1a, R1b and R1c are not each unsubstituted phenyl.
[0027] In embodiments, R1a, R1b and R1c are each independently selected from phenyl; wherein said phenyl is optionally substituted with from 1 , 2 or 3 independently selected R10 groups, provided that R1a, R1b and R1c are not each unsubstituted phenyl.
[0028] In embodiments, R1a, R1b and R1c are each independently selected from phenyl; wherein said phenyl is optionally substituted with from 1 , 2 or 3 R10 groups; provided that R1a, R1b and R1c are not each unsubstituted phenyl.
[0029] In embodiments, R1a, R1b and R1c are each independently selected from C3 to Cs cycloalkyl, C-i-Cs-alkyl and 4 to 8 membered heterocycloalkyl; wherein said C3 to Cs cycloalkyl, C-i-Cs-alkyl and 4 to 8 membered heterocycloalkyl is optionally substituted with from 1 to 5 independently selected R11 groups.
[0030] R1a, R1b and R1c may be different or they may be the same.
[0031] In embodiments, R11 is independently at each occurrence selected from C1-C6- alkyl, halo, OR12, NR13R14 and S(0)20R13.
[0032] In embodiments, R11 is independently at each occurrence selected from OCH3, OCH2(CH3)2, N(CH3)2, S02OH, F and Cl. [0033] In embodiments, R1a, R1b and R1c are each independently selected from phenyl, biphenyl and pyridyl wherein said phenyl, biphenyl and pyridyl is optionally substituted with 1 to 3 independently selected R10 groups, wherein R10 is independently at each occurrence selected from Ci-C6-alkyl, halo, OR12, NR13R14 and S(0)20R10.
[0034] In embodiments, R1a, R1b and R1c are each independently selected from phenyl, biphenyl and pyridyl wherein said phenyl, biphenyl and pyridyl is optionally substituted with 1 to 3 independently selected R10 groups, wherein R10 is independently at each occurrence selected from OCH3, OCH2(CH3)2, N(CH3)2, SO2OH, F and Cl.
[0035] In embodiments, R1a is C3 to Cs-cycloalkyl, R1b is C3 to Cs-cycloalkyl and R1c is C3 to Cs-cycloalkyl.
[0036] In embodiments, R1a and R1b are each unsubstituted phenyl and R1c is independently selected from: substituted phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, C3 to Cs-cycloalkyl, Ci-Cs-alkyl and 4- to 8-membered
heterocycloalkyl.
[0037] In embodiments, R1a and R1b are each unsubstituted phenyl and R1c is substituted phenyl.
[0038] In embodiments, R1a and R1b are each unsubstituted phenyl and R1c is pyridyl.
[0039] In embodiments, R1a and R1b are each C3 to Cs-cycloalkyl and R1c is
independently selected from: phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, C-i-Cs-alkyl and 4- to 8-membered heterocycloalkyl.
[0040] In embodiments, R1a and R1b are each cyclohexyl and R1c is substituted biphenyl.
[0041] In embodiments, R1a, R1b and R1c are each phenyl. In embodiments, R1a, R1b and
R1c are each unsubstituted phenyl. In embodiments, R1a, R1b and R1c are each substituted phenyl. It may be that R1a, R1b and R1c are each fluorophenyl, e.g. para- fluorophenyl. It may be that R1a, R1b and R1c are each chlorophenyl, e.g. para- chlorophenyl. It may be that R1a, R1b and R1c are each methoxyphenyl, e.g. para- methoxyphenyl.
[0042] In embodiments, R1a, R1b and R1c are each C3 to Cs-cycloalkyl. In embodiments, R1a, R1b and R1c are each cyclohexyl.
[0043] In embodiments, R1a, R1b and R1c are each benzyl. [0044] In embodiments, at least one of R1a, R1b and R1c is 5-, 6-, 9- or 10- membered heteroaryl or 4- to 8-membered heterocycloalkyl. It may be that a single one of R1a, R1b and R1c is 5-, 6-, 9- or 10- membered heteroaryl or 4- to 8-membered heterocycloalkyl. In embodiments, at least one of R1a, R1b and R1c is 5-, 6-, 9- or 10- membered heteroaryl or 4- to 8-membered heterocycloalkyl, wherein said heteroaryl or heterocycloalkyl group comprises at least one nitrogen atom in the ring. It may be that a single one of R1a, R1b and R1c is 5-, 6-, 9- or 10- membered heteroaryl or 4- to 8-membered heterocycloalkyl, wherein said heteroaryl or heterocycloalkyl group comprises at least one nitrogen atom in the ring. In embodiments, at least one of R1a, R1b and R1c is 5- or 6- membered heteroaryl group, wherein said heteroaryl group comprises at least one nitrogen atom in the ring. It may be that a single one of R1a, R1b and R1c is 5- or 6- membered heteroaryl group, wherein said heteroaryl group comprises at least one nitrogen atom in the ring. In these embodiments, it may be that any of R1a, R1b and R1c that are not heteroaryl or
heterocyclolkyl are phenyl, e.g. unsubstituted phenyl.
[0045] In embodiments, at least one of R1a, R1b and R1c is Ci-C6-alkyl (e.g. methyl). It may be that a single one of R1a, R1b and R1c is Ci-C6-alkyl (e.g. methyl). It may be that two or more of R1a, R1b and R1c is Ci-C6-alkyl (e.g. methyl). It may be that each of R1a, R1b and R1c is Ci-C6-alkyl (e.g. methyl). In these embodiments, it may be that any of R1a, R1b and R1c that are not Ci-C6-alkyl are phenyl, e.g. unsubstituted phenyl.
[0046] It may be that R1a and R1b are connected to each other via a bond or a group selected from -0-, -S(0)2-, NR6, and Ci-C3-alkylene. It may be that R1a and R1b are connected to each other via a bond or a Ci-C3-alkylene group. It may be that R1a and R1b are connected to each other via a bond. It may be that R1a and R1b are each phenyl and are connected to each other via a bond or a group selected from -0-, NR6, and C1-C3- alkylene. It may be that R1a and R1b are each phenyl and are connected to each other via a bond or a Ci-C3-alkylene group. It may be that R1a and R1b are each phenyl and are connected to each other via a bond.
[0047] It may be that R1a and R1b are not connected to each other via a bond or a group selected from -0-, -S(0)2-, NR6, and Ci-C3-alkylene.
[0048] It may be that at least two of R1a, R1b and R1c are unsubstituted or substituted phenyl. [0049] In embodiments, -+PR1aR1bR1c is selected from PPhi3
Figure imgf000011_0001
Figure imgf000011_0002
PCT/EP2019/064970
Figure imgf000012_0001
Figure imgf000013_0001
[0050] R2 may be Ci-C4-alkyl, e.g. methyl. Preferably, however, R2 is H.
[0051] R3 may be H. R3 may be selected from F and OR12. R3 may be selected from F and OH. R3 may be F. R3 may be OR12, e.g. OH.
[0052] R4 may be C(0)Ci-C4-aikyl, e.g. C(0)Me. Preferably, however, R4 is H.
[0053] R5 may be independently at each occurrence selected from: Ci-C6-alkyl, C2-C6- alkynyl, C2-C6-alkenyl, Ci-C6-haloalkyl, OR12, S(0)2Ci-C4-alkyl, halo, cyano and nitro. R5 may be independently at each occurrence selected from: Ci-C6-alkyl, Ci-C6-haloalkyl, S(0)2Ci-C4-alkyl, halo, cyano and nitro. R5 may be selected from S(0)2Ci-C4-alkyl and nitro. R5 may be selected from nitro.
[0054] m may be an integer from 0 to 2. m may be an integer from 0 to 1. m may be an integer from 1 to 3. m may be 0. m may be 1. Where m is not 0, it may be that one of the R5 groups is situated para to the point of connection of the rest of the molecule. It may be that m is 1 and the R5 group is situated para to the point of connection of the rest of the molecule.
[0055] It may be that m is 1 and the R5 group is situated para to the point of connection of the rest of the molecule and is selected from: Ci-C6-alkyl, Ci-C6-haloalkyl, S(0)2Ci-C4- alkyl, halo, cyano and nitro. It may be that m is 1 and the R5 group is situated para to the point of connection of the rest of the molecule and is selected from S(0)2Ci-C4-alkyl and nitro. It may be that m is 1 and the R5 group is situated para to the point of connection of the rest of the molecule and is nitro. This is the substitution on the corresponding phenyl group of chloramphenicol.
[0056] It may be that R2 and R4 are each H. It may be that R2 and R4 are each H and R3 is selected from F and OH. It may be that R2 and R4 are each H, R3 is selected from F and OH, m is 1 and the R5 group is situated para to the point of connection of the rest of the molecule and is nitro. It may be that R2 and R4 are each H, R3 is OH, m is 1 and the R5 group is situated para to the point of connection of the rest of the molecule and is nitro. It may be that R2 and R4 are each H, m is 1 and the R5 group is situated para to the point of connection of the rest of the molecule and is nitro. These embodiments apply particularly to compounds of formula (II).
[0057] In embodiments, R6 is at any particular occurrence H. In embodiments, R6 is at each occurrence H.
[0058] In embodiments, R7 is at any particular occurrence H. In embodiments, R7 is at each occurrence H.
[0059] R10 may be independently at each occurrence selected from: Ci-C6-alkyl, C2-C6- alkynyl, C2-C6-alkenyl, Ci-C6-haloalkyl, OR12, halo, cyano and nitro.
[0060] R11 may be independently at each occurrence selected from: oxo, halo, C1-C6- alkyl. R11 may be independently at each occurrence Ci-C6-alkyl. [0061] In embodiments, R12 is at any particular occurrence H. In embodiments, R7 is at each occurrence H.
[0062] In embodiments, R12 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R12 is at each occurrence Ci-C4-alkyl, e.g. methyl.
[0063] In embodiments, R13 is at any particular occurrence H. In embodiments, R7 is at each occurrence H.
[0064] In embodiments, R13 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R13 is at each occurrence Ci-C4-alkyl, e.g. methyl. [0065] In embodiments, R14 is at any particular occurrence selected from H and Ci-C4- alkyl, e.g. methyl. In embodiments, R14 is at each occurrence selected from H and Ci-C4- alkyl, e.g. methyl.
[0066] In embodiments, R14 is at any particular occurrence H. In embodiments, R8 is at each occurrence H.
[0067] In embodiments, R14 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R8 is at each occurrence Ci-C4-alkyl, e.g. methyl.
[0068] In embodiments, L1 is selected from -C(O)- and -S(0)2-. In embodiments, L1 is absent. In embodiments, L1 is -C(O)-.
[0069] In certain embodiments, L3 is at each occurrence absent. Thus, the group -L2- (L3-L4)n- may form an alkylene linker group.
[0070] In embodiments, L1 is selected from -C(O)- and -S(0)2- and L3 is at each occurrence absent. In embodiments, L1 is -C(O)- and L3 is at each occurrence absent.
[0071] In certain embodiments, L3 is at each occurrence -O- and -L4- is at each occurrence -C2-C4-alkylene-. Thus, the group -(L3-L4)n- may form a ether or polyether linker group. -L4- may at each occurrence represent -CH2CH2- or -CH2CH2CH2-. Thus, the group -(L3-L4)n- may form an ethylene glycol, polyethyleneglycol, propyleneglycol or polypropylene glycol linker group.
[0072] In certain embodiments, L3 is at each occurrence selected from -NR6C(0)- and - C(0)NR6. Thus, the group— (L3-L4)n- may form a peptide linker group. In these embodiments, it may be that -L4- is at each occurrence -Ci-alkylene-.
[0073] In certain embodiments, L3 is at each occurrence -O- and -L4- is at each occurrence -C2-C4-alkylene-. Thus, the group -(L3-L4)n- may form a ether or polyether linker group. -L4- may at each occurrence represent -CH2CH2- or -ChhCI-hCI-h-. Thus, the group -(L3-L4)n- may form a, ethylene glycol, polyethyleneglycol, propyleneglcyol or polypropylene glycol linker group.
[0074] In embodiments, L1, L2, L3, L4 and n are selected such that length of the linker formed by those groups is from 7 to 17 atoms. In embodiments, L1, L2, L3, L4 and n are selected such that length of the linker formed by those groups is from 9 to 17 atoms, e.g. 10-17 atoms. [0075] In embodiments the group -L1-L2-(L3-L4)n-P+R1aR1bR1c is:
Figure imgf000016_0001
wherein L5 is a C2-Ci9-alkylene group optionally substituted with from 0 to 10 R9 groups. L5 may be a C6-Ci6-alkylene group optionally substituted with from 0 to 10 R9 groups. L5 may be a Cg-Ci6-alkylene group optionally substituted with from 0 to 10 R9 groups. L5 may be unsubstituted.
[0076] In embodiments, n is an integer selected from 0 or 1.
[0077] In an embodiment of the invention the ion of formula (I) is an ion selected from:
Figure imgf000016_0002
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
20
Figure imgf000021_0001
Figure imgf000022_0001
[0078] In an embodiment of the invention the ion of formula (I) is not
Figure imgf000022_0002
[0079] The cation of formula (I) will be associated with an anionic counter ion. For administration to a subject, the cation of formula (I) will be associated with a pharmaceutically acceptable anionic counterion. The first aspect of the invention also, therefore, provides a compound comprising the ion of formula (I) and a pharmaceutically acceptable anion. The anion may have a single negative charge. For example the anion may be selected from: halo (e.g. Cl, Br and I), BF4, PF6, CF3C(0)0, HC(0)0, HCO3, (CF3S02)2N, (C2F5)3PF3, HSO4, Ci-Ci5-alkylS04, CH3C(0)0, CF3S03, Tosyl-O, C(CN)3, N(CN)2 or the carboxylate anion of a proteinogenic amino acid. For the avoidance of doubt each anion listed in the preceding sentence possesses a single negative charge. The anion may have multiple negative charges, e.g. P04 3 or C03 2 . The anion may be derived from a di- or tri-acid, e.g. glutamic acid, succinic acid, malic acid, citric acid, tartaric acid. It may be a mono-carboxylate of said di- or tri-acid. The remaining carboxylic acid groups may be in the form of protonated carboxylic acids, Ci-Ci2- alkylesters, or they may likewise be carboxylate anions. Said carboxylate anions may each be accompanied by a pharmaceutically acceptable metal cation or by another cation of formula (I).
[0080] The anions associated with the cations of the invention can be quite labile. It may be therefore that the cation of the invention is present associated with two or more different anions. Ion exchange processes can be used to control the identity of the anion associated with the cation of the invention.
[0081] In embodiments the anion is Cl, Br, I, PF6, CF3C(0)0, or HC(0)0.ln an aspect of the invention, the compounds of the invention are for medical use.
[0082] In an aspect the compounds of the first aspect of the invention are for use in the treatment of cancer. The compounds may be effective in treating cancer stem cells. The compounds may also be for use in reducing cell proliferation of abnormal cells, such as cancer cells.
[0083] In an embodiment the compounds of the first aspect of the invention are for use in the treatment of solid tumours and other cancers, e.g. cancers classed as not being solid cancers. Amongst cancers that can be treated by the compounds of the invention are: leukaemia, lymphoma, sarcoma, or carcinoma.
[0084] In a further aspect of the invention there is provided a method for the treatment of cancer, wherein the method comprises the administration of a therapeutically effective amount of a compound of the first aspect of the invention. The method may be effective in treating cancer stem cells. The method may also be for use in reducing cell proliferation of abnormal cells, such as cancer cells. [0085] In an embodiment the method is for the treatment of solid tumours and other cancers, e.g. cancers classed as not being solid cancers. Amongst cancers that can be treated by the methods of the invention are: leukaemia, lymphoma, sarcoma, or carcinoma.
[0086] The“treatment” of cancer may be taken to include prevention. Treatment also encompasses including any improvement of pathology, symptoms or prognosis that is achieved in respect of cancer in a subject receiving compounds of the invention.
Treatment may be indicated by a partial improvement of such indications, or by a total improvement (e.g. the absence of cancer following medical use of the compounds of the invention).
[0087] The“prevention” of cancer may be taken as including the prevention of the formation of new tumours, including new primary tumours or new metastatic tumours. The prevention of cancer may also be taken as encompassing the prevention of the progression of cancer. In this context, prevention of development of cancer may be demonstrated by preventing an increase in the“stage” of a tumour (using an appropriate cancer staging method) that has been treated using the compounds of the invention. The prevention of increase in cancer stage may be compared to progression of an untreated tumour, or compared to the extent of progression that would be expected by a clinician in the event that the tumour was not treated.
[0088] The compounds of the first aspect of the invention may be for use in increasing cancer cell death or for decreasing cell proliferation by another mechanism, such as inhibiting cell replication. The compounds may be used for this purpose in vitro or in vivo.
[0089] The compounds of the invention may be for use in the modulation of cancer cells or other dysfunctional cells (such as tumour initiating cells, stem-like cancer cells, cancer stem cells, or a population of cells with stem cell-like features that exist in tumors and that give rise to the bulk of tumor cells with more differentiated phenotypes). Accordingly, there is provided a method of modulating cancer cells or other dysfunctional cells in vivo or in vitro by exposing the cancer cells or other dysfunctional cells to a compound of the first aspect of the invention. The compound may be exposed to the cancer cells or other dysfunctional cells in an effective amount, for example a therapeutically effective amount such as in the case of a method of treatment or an in vivo method.
[0090] In another aspect of the invention there is provided a pharmaceutical composition, wherein the composition comprises a compound of the invention and one or more pharmaceutically acceptable excipients. [0091] In an embodiment the pharmaceutical composition may be a combination product comprising one or more different pharmaceutically active agents. The one or more additional pharmaceutically active agents may be an anti-cancer agent described below. The one or more pharmaceutically active agents may independently be selected from a different therapeutic class, e.g. antibiotic, anti-viral, anti-emetic, pain management, etc.
DETAILED DESCRIPTION
[0092] Given below are definitions of terms used in this application. Any term not defined herein takes the normal meaning as the skilled person would understand the term.
[0093] The term“halo” or“halogen” refers to an atom selected from fluorine, chlorine, bromine and iodine.“Halo” or“halogen” may refer to an atom selected from Cl and F. “Halo” or“halogen” may refer to fluorine.
[0094] The term“alkyl” refers to a linear or branched hydrocarbon chain. The term“C-i-Cs alkyl” refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5, 6, 7 or 8 carbon atoms. The term“C1-C6 alkyl” refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5 or 6 carbon atoms. The term“C1-C6 alkyl” for example refers to methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. The “alkyl” group may be substituted or unsubstituted by one or more substituents.
Substituents for the alkyl group may be halo (for example fluorine, chlorine, bromine and iodine), OH and C1-C6 alkoxy. In addition, alkylene groups may be linear or branched and may have two places of attachment to the remainder of the molecule.
[0095] The term“alkylene” refers to a divalent group which is a linear or branched hydrocarbon chain. With the“alkylene” group being divalent, the group must form two bonds to other groups. The term“C-i-Cs-alkylene” may refer to -CH2-, -CH2CH2-, - CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2-, - CH2CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2CH2CH2- or substituted
equivalents thereof. The alkylene group may be unsubstituted or substituted by one or more substituents.
[0096] The term cycloalkyl refers to a saturated hydrocarbon ring system. The term C3- Ce cycloalkyl” refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms. The ring system may be a single ring or a bi-cyclic or tri-cyclic ring system. Where the ring system is bicyclic one of the rings may be an aromatic ring, for example as in indane. The term“cycloalkyl” may refer to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and indane. The cycloalkyl group may be substituted with one or more substituents.
[0097] The term“haloalkyl” refers to a linear or branched hydrocarbon chain which is substituted with at least one halogen atom which are independently selected at each occurrence from fluorine, chlorine, bromine and iodine. For example, the term“C1-C6 haloalkyl” refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5 or 6 carbon atoms. The halogen atom may be at substituted at any position on the
hydrocarbon chain. The term“C1-C6 haloalkyl” may refer to, for example, fluoromethyl, trifluoromethyl, chloromethyl, fluoroethyl, trifluoroethyl, chloroethyl, trichloroethyl (such as 1 ,2,2-trichloroethyl and 2,2,2-trichloroethyl), fluoropropyl and chloropropyl. The haloalkyl group may be substituted with one or more substituents.
[0098] The term“alkenyl” refers to a linear or branched hydrocarbon chain containing at least one carbon-carbon double bond and having at least two carbon atoms. The term “C2-C6 alkenyl” refers to a linear or branched hydrocarbon chain containing at least one carbon-carbon double bond and having 2, 3, 4, 5 or 6 carbon atoms. The double bond or double bonds may be E or Z isomers. The double bond may be present at any possible position of the hydrocarbon chain. The term“C2-C6 alkenyl” may refer to, for example, ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl. The alkenyl group may be substituted or unsubstituted by one or more substituents.
[0099] The term“cycloalkenyl” refers to an unsaturated hydrocarbon ring system. The term“C3-C8 cycloalkenyl” refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms. The ring may contain more than one double bond. The term cycloalkenyl may refer to, for example cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloocatadienyl. The cycloalkenyl group may be substituted with one or more substituents.
[00100] The term“alkynyl” refers to a linear or branched hydrocarbon chain contain at least one carbon-carbon triple bond and having at least two carbon atoms. The term“C2- C6 alkynyl” refers to a linear or branched hydrocarbon chain containing at least one carbon-carbon triple bond and having 2, 3, 4, 5 or 6 carbon atoms. The triple bond or triple bonds may be present at any possible position of the hydrocarbon chain. The term “C2-C6 alkynyl” may refer to, for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl. The alkynyl group may be unsubstituted or substituted by one or more substituents. [00101] The term“heteroalkyl” refers to a linear or branched hydrocarbon chain containing at least one heteroatom selected from N, O and S which is positioned between any possible carbon atom in the chain or at the end of the chain. The term“C1-C6 heteroalkyl” refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5, or 6 carbon atoms and at least one heteroatom selected from N, O and S which is positioned between any possible carbon atom in the chain or at the end of the chain. The heteroalkyl may be attached to another group by the heteroatom or the carbon atom. The term“C-i- C6 heteroalkyl” may refer to, for example, -CH2NHCH3, -NHCH2CH3 and -CH2CH2NH2.
The heteroalkyl group may be unsubstituted or substituted by one or more substituents.
[00102] The term“heterocycloalkyl” refers to a saturated hydrocarbon ring system containing at least one heteroatom within the ring system selected from N, O and S. The term“4- to 8- membered heterocycloalkyl” refers to a saturated hydrocarbon ring with 4, 5, 6, 7, 8, 9 or 10 atoms selected from carbon, N, O and S, at least one being a heteroatom. The“heterocycloalkyl” group may also be denoted as a“3 to 10 membered
heterocycloalkyl” which is also a ring system containing 3, 4, 5, 6, 7, 8, 9 or 10 atoms, at least one being a heteroatom. The ring system may be a single ring or a bi-cyclic or tri cyclic ring system. Bicyclic systems may be spiro-fused, i.e. where the rings are linked to each other through a single carbon atom; vicinally fused, i.e. where the rings are linked to each other through two adjacent carbon or nitrogen atoms; or they may be share a bridgehead, i.e. the rings are linked to each other two non-adjacent carbon or nitrogen atoms. Where the ring system is bicyclic one of the rings may be an aromatic ring, for example as in chromane. The“heterocycloalkyl” may be bonded to the rest of the molecule through any carbon atom or heteroatom. The“heterocycloalkyl” may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring. For example, the“heterocycloalkyl” may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine,
thiomorpholine, piperazine, tetrahydropyran, and chromane.
[00103] The term“heterocycloalkenyl” refers to an unsaturated hydrocarbon ring system containing at least one heteroatom selected from N, O or S. The term“C3-C8
heterocycloalkenyl” refers to an unsaturated hydrocarbon ring system containing 3, 4, 5,
6, 7 or 8 carbon atoms and at least one heteroatom selected from N, O or S. There may be more than one double bond present. The double bond will typically be between two carbon atoms but may be between a carbon atom and a nitrogen atom. There may also be more than 1 heteroatom present. For example, there may be 1 , 2 or 3 heteroatoms present. The ring system may be a single ring or a bi-cyclic or tri-cyclic ring system.
Where the ring system is bicyclic one of the rings may be an aromatic ring, for example as in indoline and dihydrobenzofuran. The heterocycloalkenyl may be attached to another group by any carbon or heteroatom. The term heterocycloalkenyl may refer to, for example tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline, dihydrobenzofuran, dihydrobenzothiophene and indoline. The heterocycloalkenyl group may be substituted with one or more substituents.
[00104] The term“aryl” refers to an aromatic hydrocarbon ring system which satisfies Huckel’s rule for aromaticity or that contains a ring system which satisfies Huckel’s rule for aromaticity. As such an aryl group may be a single ring or a bi-cyclic or tri-cyclic ring system. The term“aryl” may refer to, for example, phenyl, naphthyl, indane, tetralin and anthracene. The aryl group may be unsubstituted or substituted with one or more substituents. Any aryl group may be a phenyl ring.
[00105] The term“heteroaryl” refers to an aromatic hydrocarbon ring system with at least one heteroatom selected from N, O or S which satisfies Huckel’s rule for aromaticity or a ring system that contains a heteroatom and an aromatic hydrocarbon ring. The heteroaryl may be a single ring system or a fused ring system. The term“5-, 6-, 9- or 10- membered heteroaryl” refers to an aromatic ring system within 5, 6, 9, or 10 members selected from carbon, N, O or S either in a single ring or a bicyclic ring system. The term heteroaryl may refer to, for example, imidazole, thiazole, oxazole, isothiazole, isoxazole, triazole, tetraazole, thiophene, furan, thianthrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine, indole, isoindole, quinolone, and isoquinoline.
[00106] The term“alkoxy” refers to an alkyl group which is linked to another group by oxygen. The alkyl group may be linear or branched. The term“C1-C6 alkoxy” refers to an alkyl group containing 1 , 2, 3, 4, 5 or 6 carbon atoms which is linked to another group by oxygen. The alkyl group may be, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. The term“C1-C6 alkoxy” may refer to, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n- pentoxy and n-hexoxy. The alkyl group may be substituted or unsubstituted by one or more substituents.
[00107] A bond terminating in a“ -rJ~r” means that the bond is connected to another group that is not shown. A bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be connected to any of the atoms in the ring structure where allowed by valency. [00108] Where a group is substituted, it may be substituted at any point on the group where chemically possible and consistent with valency requirements. The group may be substituted by one or more substituents. For example, the group may be substituted with 1 , 2, 3 or 4 substituents. Where there are two or more substituents, the substituents may be the same or different. Substituent(s) may be, for example, halo, CN, nitro, oxo, C1-C6- alkyl, C2-C6-alkynyl, C2-C6-alkenyl, Ci-C6-haloalkyl, ORa, NRaRb, SRa, C(0)0Ra,
C(0)NRaRa, halo, cyano, nitro, C(0)Ra, S(0)20Ra, S(0)2Ra and S(0)2NRaRa; wherein Ra is independently at each occurrence selected from: H and Ci-C6-alkyl; and Rb is independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci-C6-alkyl and S(0)2-Ci-C6-alkyl.
[00109] If chemically possible to do so, a cyclic substituent may be substituted on a group so as to form a spiro-cycle.
[00110] Substituents are only present at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort which substitutions are chemically possible and which are not.
[00111] Ortho, meta and para substitution are well understood terms in the art. For the absence of doubt,“ortho” substitution is a substitution pattern where adjacent carbons possess a substituent, whether a simple group, for example the fluoro group in the example below, or other portions of the molecule, as indicated by the bond ending in“
Figure imgf000029_0001
[00112]‘ Meta” substitution is a substitution pattern where two substituents are on carbons one carbon removed from each other, i.e with a single carbon atom between the substituted carbons. In other words there is a substituent on the second atom away from the atom with another substituent. For example the groups below are meta substituted.
Figure imgf000029_0002
[00113]“ Para” substitution is a substitution pattern where two substituents are on carbons two carbons removed from each other, i.e with two carbon atoms between the substituted carbons. In other words there is a substituent on the third atom away from the atom with another substituent. For example the groups below are para substituted.
Figure imgf000030_0001
[00114] The cation of formula (I) will be associated with a pharmaceutically acceptable anionic counter ion for administration to a subject. Nevertheless, where either the cation of formula (I) or the anionic counter ion comprise either basic or acidic groups, those groups may themselves be protonated or deprotonated and associated with an appropriate counter ion.
[00115] Suitable acid addition salts are formed from acids which form non-toxic salts, for example, acetate, aspartate, benzoate, besylate, bicarbonate/carbonate,
bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate,
hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 1 ,5- naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and triflu oroacetate salts.
[00116] Suitable base salts are formed from bases which form non-toxic salts, for example including the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. A review of suitable salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
[00117] The salt may be an acid addition salt.
[00118] The salts may be formate or hydrochloride.
[00119] Pharmaceutically acceptable salts of ions of formula (I) may be prepared by one or more of the following methods:
(i) reacting the ion of formula (I) with the desired acid or base;
(ii) removing an acid- or base-labile protecting group from a suitable precursor of the ion of formula (I) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) converting one salt of the ion of formula (I) to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.
[00120] The reactions above are typically carried out in solution and the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
[00121] The compounds may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.
[00122] Complexes are contemplated, such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non- stoichiometric amounts are also contemplated. The resulting complexes may be ionised, partially ionised, or non- ionised. A review of such complexes is found in J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).
[00123] Compounds, ions and salts described in this specification may be isotopically-labelled (or“radio-labelled”). Accordingly, one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of radionuclides that may be incorporated include 2H (also written as“D” for deuterium), 3H (also written as“T” for tritium), 11C, 13C, 14C, 150, 170, 180, 18F and the like. The radionuclide that is used will depend on the specific application of that radio-labelled derivative. For example, for in vitro competition assays, 3H or 14C are often useful. For radio-imaging applications, 11C or 18F are often useful. In some embodiments, the radionuclide is 3H. In some embodiments, the radionuclide is 14C. In some embodiments, the radionuclide is 11C. And in some embodiments, the radionuclide is 18F.
[00124] Hereinafter all references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
[00125] The compounds include a number of formulae as herein defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labelled compounds of the invention.
[00126] Before purification, the compounds may exist as a mixture of enantiomers depending on the synthetic procedure used. The enantiomers can be separated by conventional techniques known in the art. Thus the compounds cover individual enantiomers as well as mixtures thereof.
[00127] For some of the steps of the process of preparation of the compounds of formula (I), it may be necessary to protect potential reactive functions that are not wished to react, and to cleave said protecting groups in consequence. In such a case, any compatible protecting radical can be used. In particular methods of protection and deprotection such as those described by T.W. Greene (Protective Groups in Organic Synthesis, A. Wiley- Interscience Publication, 1981 ) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used. All of the above reactions and the preparations of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well-known to those skilled in the art with reference to literature precedents and the examples and preparations hereto.
[00128] Also, the compounds as well as intermediates for the preparation thereof can be purified according to various well-known methods, such as for example crystallization or chromatography.
[00129] The method of treatment or the compound for use in the treatment of solid tumours, leukaemia, lymphoma, sarcoma, or carcinoma as defined hereinbefore may be applied as a sole therapy or be a combination therapy with an additional active agent.
[00130] The method of treatment or the compound for use in the treatment of solid tumours, leuekaemia, lymphoma, sarcoma, or carcinoma may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-cancer agents:
(i) antiproliferative/antineoplastic drugs and combinations thereof, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, bendamustin, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, and hydroxyurea); antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); proteasome inhibitors, for example carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan, mitoxantrone and camptothecin);
(ii) cytostatic agents such as antiestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride;
(iii) anti-invasion agents, for example dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase;
(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies, for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as gefitinib, erlotinib and 6-acrylamido-/V-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)- quinazolin-4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib);
inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; modulators of protein regulators of cell apoptosis (for example Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib (AMN107); inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib , tipifarnib and lonafarnib), inhibitors of cell signalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1 R kinase inhibitors, IGF receptor, kinase inhibitors; aurora kinase inhibitors and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;
(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™); thalidomide; lenalidomide; and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib;
(vi) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2;
(vii) immunotherapy approaches, including checkpoint inhibitors of targets such as PD-1 , PD-L1 and CTCLA-4, for example antibody therapy such as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®), pembrolizumab and ofatumumab; interferons such as interferon a; interleukins such as IL-2 (aldesleukin); interleukin inhibitors for example IRAK4 inhibitors; cancer vaccines including prophylactic and treatment vaccines such as HPV vaccines, for example Gardasil, Cervarix, Oncophage and Sipuleucel-T (Provenge); and toll-like receptor modulators for example TLR-7 or TLR-9 agonists; and
(viii) cytotoxic agents for example fludaribine (fludara), cladribine, pentostatin
(Nipent™);
(ix) steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate,
hydrocortisone valerate, icomethasone, icomethasone enbutate, meprednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and their respective pharmaceutically acceptable derivatives. A combination of steroids may be used, for example a
combination of two or more steroids mentioned in this paragraph;
(x) targeted therapies, for example PI3Kd inhibitors, for example idelalisib and perifosine. [00131] Such combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products may be administered so that the combination is provided in a therapeutically effective amount, for example the compounds of this invention may be administered within a therapeutically effective dosage range described herein and the other pharmaceutically-active agent may be administered in an amount of less than or within its approved dosage range.
[00132] According to a further aspect of the invention there is provided a pharmaceutical product comprising a compound of the first aspect of the invention, or a pharmaceutically acceptable salt thereof as defined herein and an additional active agent. The additional active agent may be a cancer therapy as defined hereinbefore for the combination treatment of cancer.
[00133] According to a further aspect of the invention there is provided a method of treating cancer comprising administering a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with an additional anti-cancer agent, as defined hereinbefore, to a patient in need thereof.
[00134] According to a further aspect of the invention there is provided a compound of the invention, or a pharmaceutically acceptable salt thereof for use simultaneously, sequentially or separately with an additional anti-cancer agent as defined herein, in the treatment of cancer.
[00135] According to another aspect of the invention there is provided a use of the compound of the invention in combination with an anti-cancer agent, such as those hereinbefore described. The compound of the invention may be used simultaneously, sequentially or separately with the additional anti-cancer agent. The use may be in a single combination product comprising the compound of the invention and the anti-cancer agent. The additional anti-cancer agent may be a further compound of the first aspect of the invention.
[00136] According to a further aspect there is provided a method of providing a combination product, wherein the method comprises providing a compound of the invention simultaneously, sequentially or separately with an anti-cancer agent, as defined hereinbefore. The method may comprise combining the compound of the invention and the anti-cancer agent in a single dosage form. Alternatively the method may comprise providing the anti-cancer agent as separate dosage forms. [00137] Compounds of the invention may exist in a single crystal form or in a mixture of crystal forms or they may be amorphous. Thus, compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying.
Microwave or radio frequency drying may be used for this purpose.
[00138] For the above-mentioned compounds of the invention the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, if the compound of the invention is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight (pg/kg) to 100 milligrams per kilogram body weight (mg/kg).
[00139] A compound of the invention, or pharmaceutically acceptable salt thereof, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
[00140] Depending on the mode of administration of the compounds of the invention, the pharmaceutical composition which is used to administer the compounds of the invention will preferably comprise from 0.05 to 99 %w (percent by weight) compounds of the invention, more preferably from 0.05 to 80 %w compounds of the invention, still more preferably from 0.10 to 70 %w compounds of the invention, and even more preferably from 0.10 to 50 %w compounds of the invention, all percentages by weight being based on total composition.
[00141] The pharmaceutical compositions may be administered topically (e.g. to the skin) in the form, e.g., of creams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol. [00142] For oral administration the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
[00143] For the preparation of soft gelatine capsules, the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
[00144] For intravenous (parenteral) administration the compounds of the invention may be administered as a sterile aqueous or oily solution.
[00145] The size of the dose for therapeutic purposes of compounds of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
[00146] Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient.
[00147] Throughout the description and claims of this specification, the words“comprise” and“contain” and variations of them mean“including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.
[00148] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments.
The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.
[00149] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.
Methods for Synthesizing Compounds
[00150] Certain ions of the invention can be synthesised according to or analogously to methods described in the General Schemes below and/by other techniques known to those of ordinary skill in the art. Certain ions of the invention can be synthesised according to or analogously to the methods described in the Examples.
[00151] Certain ions of formula (I) (where R3 is independently selected form H, halo and OR12) can be made by Scheme A
Figure imgf000039_0001
Scheme A
[00152] Reaction of amine (1 ) with phosphonium acid (2) can furnish phosphonium amide (3). The reaction can be performed using standard peptide coupling agents, such as N,N’- diisopropylcarbodiimide (DCC) in an organic solvent, such as DCM at a temperature from 0 to 30 °C or 1-ethyl-3-(3’-dimethyl)amino)carbodiimide HCI, in the presence of a base, such as NaHCC>3 or EίbN in an organic solvent, such as DCM or DMF at a temperature from 0 to 30 °C. Optional is the addition of 1-hydroxybenzotriazole or 1-hydroxy-7- azabenzotriazole. [00153] Phosphonium acid (2) can be prepared from reaction of halo acid (4) (where X =
Cl or Br) with phosphine (5). The reaction can be accomplished by heating in an organic solvent, such as MeCN at a temperature from 50 to 80 °C. Phosphonium amide (3) can also be accessed by an alternative sequence of reactions involving amide formation between amine (1 ) and acid (4) using standard peptide coupling agents, followed by displacement of the resultant product halide with phosphine (5), which can be accomplished by heating in an organic solvent, such as MeCN at a temperature from 50 to 80 °C.
[00154] Certain ions of formula (I) (where R3 is independently selected form H, halo and OR12) can be made by Scheme B
Figure imgf000040_0001
Scheme B
[00155] Reaction of amine (1 ) with halo sulphonic acid (6) (where X = Cl or Br) can furnish halo sulphonamide (7). The reaction can be performed using SOCI2 in an organic solvent, such as DMF or DCM at a temperature from 20 to 60 °C. Reaction of halo sulphonamide (7) with phosphine (5) can deliver phosphonium sulphonamide (8). The reaction can be accomplished by heating in an organic solvent, such as MeCN at a temperature from 50 to 80 °C. [00156] Certain ions of formula (I) (where R3 is independently selected form H, halo and OR12) can be made by Scheme C
Figure imgf000041_0001
Scheme C [00157] Reaction of amine (1 ) with halo isocyanate (9) (where X = Cl or Br) can furnish halo urea (10). The reaction can be performed in a mixed organic solvent comprising of EtOH and DCM, at a temperature from 25 to 40 °C. Reaction of halo urea (10) with phosphine (5) can deliver phosphonium urea (11 ). The reaction can be accomplished by heating in an organic solvent, such as MeCN at a temperature from 50 to 80 °C. Halo isocyanate (9) can be prepared from halo acid (4) (where X = Cl or Br). The reaction can be accomplished with diphenylphosphoryl azide ((Ph0)2P(0)N3) in the presence of a base, such as EίbN in an organic solvent, such as toluene at a temperature from 50 to 100 °C. [00158] Certain ions of formula (I) (where R3 is independently selected form H, halo and
OR12) can be made by Scheme D
Figure imgf000042_0001
Scheme D [00159] Reaction of amine (1 ) with halo chlorosulphonylamine (12) (where X = Cl or Br) can furnish halo sulphonyl urea (13). The reaction can be performed in the presence of a base, such as EίbN in an organic solvent, such as toluene at a temperature from 25 to 70 °C. Reaction of halo sulphonyl urea (13) with phosphine (5) can deliver phosphonium sulphonyl urea (14). The reaction can be accomplished by heating in an organic solvent, such as MeCN at a temperature from 50 to 80 °C. Halo chlorosulphonylamine (12) can be prepared from halo amine (15) (where X = Cl or Br). The reaction can be accomplished with SO2CI2 in the presence of a base, such as EίbN in an organic solvent, such as DCM at a temperature from -10 to 10 °C. [00160] Certain ions of formula (I) (where R3 is independently selected form H, halo and
OR12) can be made by Scheme E
Figure imgf000044_0001
Scheme E
[00161] Reaction of amine (1 ) with halo chlorocarbonate (16) (where X = Cl or Br) can furnish halo carbamate (17). The reaction can be performed in the presence of an inorganic base, such as Na2CC>3 in an organic solvent, such as DCM at a temperature from 0 to 10 °C. Reaction of halo carbamate (17) with phosphine (5) can deliver phosphonium carbamate (18). The reaction can be accomplished by heating in an organic solvent, such as MeCN at a temperature from 50 to 80 °C. Halo chlorocarbonate (16) can be prepared from halo alcohol (19) (where X = Cl or Br). The reaction can be accomplished with triphosgene in the presence of a base, such as pyridine in an organic solvent, such as DCM or THF at a temperature from -10 to 30 °C.
[00162] Certain ions of formula (I) (where R3 is Nhh) can be made by Scheme F
Figure imgf000045_0001
Scheme F
[00163] Alcohol (20) (synthesised from Schemes A - E) can be converted to bromide (21 ). The reaction can be accomplished with NBS and PPfi3 in the presence of pyridine in an organic solvent, such as THF at a temperature from 0 to 30 °C. The bromide (21 ) can be transformed to azide (22). The reaction can be performed with sodium azide in an organic solvent, such as DMF at a temperature from 20 to 70 °C. Reduction of azide (22) can deliver primary amine (23). The reaction can be accomplished by standard hydrogenation, techniques, such as Pd/C catalyst systems in organic solvents, such as EtOAc. Alternatively, primary amine (23) can be accessed by reduction of azide (22) with PPfi3 followed by H2O in an organic solvent, such as THF at a temperature from 10 to 30 °C.
[00164] Certain ions of formula (I) (where R3 is NHR13 and R13 = Ci-C6-alkyl) can be made by Scheme G
Figure imgf000046_0001
Scheme G
[00165] Bromide (21 ) (synthesised from Scheme F) can be converted to secondary amine (24). The reaction can be accomplished with amine NH2R13 (where R13 = C1-C6- alkyl) in an organic solvent, such as DMF at a temperature from 20 to 50 °C. Optional is the addition of CsOH.hhO and 4A molecular sieves.
[00166] Certain ions of formula (I) (where R3 is NR13R14 and R13 = Ci-C6-alkyl, R14 = C1- C6-alkyl) can be made by Scheme H
Figure imgf000047_0001
Scheme H
[00167] Bromide (21 ) (synthesised from Scheme F) can be converted to tertiary amine (25). The reaction can be accomplished with amine NHR13R14 (where R13 = Ci-C6-alkyl, R14 = Ci-C6-alkyl) in the presence of an inorganic base, such as K2CO3 in an organic solvent, such as dioxane at a temperature from 20 to 50 °C.
[00168] Certain ions of formula (I) (where R13 = H, R14 = COCi-C6-alkyl) can be made by
Scheme I
Figure imgf000048_0001
Scheme I
[00169] Amine (23) (synthesised from Scheme F) can be acylated with acid chloride (27) (where R15 = Ci-C6-alkyl) to give amide (26). The reaction can be accomplished in the presence of a base, such as EίbN or pyridine in an organic solvent, such as DCM or EtOAc at a temperature from -5 to 30 °C.
[00170] Certain ions of formula (I) (where R13 = H, R14 = SC>2Ci-C6-alkyl) can be made by
Scheme J
Figure imgf000049_0001
Scheme J
[00171] Amine (23) (synthesised from Scheme F) can be sulphonated with sulphonyl chloride (29) (where R15 = Ci-C6-alkyl) to sulphonamide (28). The reaction can be accomplished in the presence of a base, such as EίbN or pyridine in an organic solvent, such as DCM or EtOAc at a temperature from -5 to 30 °C.
Experimental
Analytical methods [00172] NMR spectra were obtained on a 400 MHz Bruker AV III (Method A) or 500 MHz
Bruker Avance III HD (Method B)
[00173] UPLC/MS was carried out using a Waters SQ mass detector and Methods A to C or a Walters Acquity QDa mass detector and Method D
[00174] Method A [00175] Column: Waters Acquity UPLC BEH C18, 1.7 pm, 2.1 x 30 mm; Gradient Eluent:
5-95% MeCN/H20 containing 10 mM (NH4)2C03; Time: 0-15 min [00176] Method B
[00177] Column: Waters Acquity UPLC BEH C18, 1.7 pm, 2.1 x 30 mm; Gradient Eluent: 5-95% MeCN/hhO containing 10 mM (NhU^COs; Time: 0-3 min
[00178] Method C [00179] Column: Waters Acquity UPLC CSH C18, 1.7 pm, 2.1 x 30 mm; Gradient Eluent:
5-95% MeCN/hhO containing 0.1 % HCOOH; Time: 0-15 min
[00180] Method D
[00181] Column: Waters Acquity UPLC CSH C18, 1.7 pm, 2.1 x 30 mm; Gradient Eluent: 5-95% MeCN/H20 containing 0.1 % HCOOH; Time: 0-3 min
[00182] The following abbreviations have been used throughout the specification in the examples and the description: N,N’-diisopropylcarbodiimide (DCC). dichloromethane (DCM), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl-t-butylether (MTBE), N-bromosuccinimide (NBS) andtetrahydrofuran (THF). .
Example 1 - (11-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}undecyl)triphenylphosphonium chloride
Figure imgf000050_0001
[00183] To a solution of (11-carboxyundecyl)triphenylphosphonium bromide (prepared as described in WO2011/146589) (490 mg, 0.91 mmol), (1 R,2R)-2-amino-1-(4-nitrophenyl)- 1 ,3-diol (160 mg, 0.75 mmol) and 1 H-[1 ,2,3]triazolo[4,5-b]pyridine-1-ol hydrate (35 mg, 0,23 mmol) in DCM (10 mL) was added N,N’-diisopropylcarbodiimide (DCC) (130 mί,
0.83 mmol). The resulting reaction mixture was stirred at room temperature. After 16 h the reaction was diluted with further DCM (10 mL) and washed with aqueous saturated NaHCOs (10 mL). The separated aqueous layer was extracted with DCM (2 x 10 mL) and the combined organics dried over Na2S04 and concentrated under reduced pressure. The resulting residue was purified by silica column chromatography eluting with 0-10% 7M NH3 in MeOH in DCM to give a white solid, which was taken up in MeOH (10 ml.) and filtered through an Amberlite IRA-400(CI) ion exchange resin. The collected MeOH was recycled through the column 3 x, followed by a fresh volume of MeOH. The combined MeOH washings were concentrated under reduced pressure to give the title compound (220 mg, 41 % yield) as a white solid.
[00184] 1 H NMR (Method A) (DMSO-de): d (delta) ppm 8.16-8.09 (m, 2H), 7.95-7.87 (m, 3H), 7.85-7.72 (m, 12H), 7.62-7.55 (m, 2H), 7.50 (d, J = 9.2 Hz, 1 H), 5.86 (d, J = 5.3 Hz,
1 H), 5.05 (dd, J = 5.3, 2.4 Hz, 1 H), 4.87 (dd, J = 6.5, 4.8 Hz, 1 H), 4.08-3.96 (m, 1 H), 3.64- 3.50 (m, 3H), 2.07-1 .85 (m, 2H), 1 .62-1 .38 (m, 4H), 1 .33-1.00 (m, 13H), 0.98-0.74 (m, 2H); 31 P NMR (162 MHz, DMSO-de) d (delta) ppm +24.07 (s); LC-MS (Method A) 655
[M]+; RT 6.16 min
Example 2 - (10-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}decyl)triphenylphosphonium chloride
Figure imgf000051_0001
[00185] The title compound was prepared as a white solid following the procedure described in Example 1 but using (l O-carboxydecyl)triphenylphosphonium bromide. Silica column chromatography was performed using the eluting system 0-20% 7M NH3 in MeOH in DCM.
[00186] 1 H NMR (Method B) (DMSO-de): d (delta) ppm 8.15-8.1 1 (m, 2H), 7.93-7.86 (m, 3H), 7.83-7.74 (m, 12H), 7.60-7.55 (m, 2H), 7.45 (d, J = 9.3 Hz, 1 H), 5.83 (d, J = 5.1 Hz,
1 H), 5.49 (d, J = 7.9 Hz, 1 H), 5.04 (dd, J = 5.4, 2.4 Hz, 1 H), 4.84 (dd, J = 6.5, 4.7 Hz, 1 H), 4.08-3.96 (m, 1 H), 3.59-3.47 (m, 3H), 2.03-1 .84 (m, 2H), 1 .57-1 .47 (m, 2H), 1 .46-1 .38 (m, 2H), 1 .29-1 .15 (m, 4H), 1 .15-1 .01 (m, 6H), 0.98-0.77 (m, 2H); 31 P NMR (202 MHz, DMSO-de) d (delta) ppm +24.05 (s); LC-MS (Method C) 641 [M]+; RT 4.56 min Example 3 - (9-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}nonyl)triphenylphosphonium chloride
Figure imgf000052_0001
[00187] The title compound was prepared as a white solid following the procedure described in Example 1 but using (9-carboxynonyl)triphenylphosphonium bromide. Silica column purification was performed using the eluting system 0-20% 7M NH3 in MeOH in DCM.
[00188] 1 H NMR (Method B) (DMSO-de): d (delta) ppm 8.13-8.09 (m, 2H), 7.92-7.87 (m, 3H), 7.84-7.73 (m, 12H), 7.57 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 9.3 Hz, 1 H), 5.83 (d, J = 5.2 Hz, 1 H), 5.03 (dd, J = 5.5, 2.4 Hz, 1 H), 4.85 (dd, J = 6.4, 4.7 Hz, 1 H), 4.06-3.96 (m, 1 H), 3.60-3.47 (m, 3H), 3.31 -3.27 (m, 1 H), 2.03-1 .85 (m, 2H), 1 .58-1 .46 (m, 2H), 1.41 (p, J = 7.3 Hz, 2H), 1 .29-1 .10 (m, 4H), 1 .08-0.96 (m, 4H), 0.94-0.76 (m, 2H); 31 P NMR (202 MHz, DMSO-de) d (delta) ppm +24.07 (s); LC-MS (Method C) 627 [M]+; RT 4.23 min
Example 4 - (8-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}octyl)triphenylphosphonium chloride
Figure imgf000052_0002
[00189] The title compound was prepared as a white solid following the procedure described in Example 1 but using (8-carboxyoctyl)triphenylphosphonium bromide. Silica column chromatography was performed using the eluting system 0-20% 7M NH3 in MeOH in DCM. [00190] 31 P NMR (202 MHz, DMSO-de) d (delta) ppm +24.03 (s); LC-MS (Method C) 613 [M]+; RT 3.98 min
Example 5 (7-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyi)propan-2- yl]carbamoyl}heptyl) triphenylphosphonium bromide
Figure imgf000053_0001
[00191] The title compound was prepared as an opaque gum following the procedure described in Example 1 but using (8-carboxyheptyl)triphenylphosphonium bromide and avoiding application of an ion exchange resin. Silica column chromatography was performed using the eluting system 0-7% 7M NH3 in MeOH in DCM. [00192] LC-MS (Method B) 599 [M]+; RT 1.13 min
Example 6 (11-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}undecyl)diphenyl(pyridine-2-yl)phosphonium chloride
12-bromo-N-[( 1 R, 2R)- 1, 3-dihydroxy- 1 -(4-nitrophenyl)propan-2-yl]dodecanamide
Figure imgf000053_0002
[00193] To a cold (0-5 °C) solution of 12-bromododecanoic acid (1 g, 3.58 mmol) in THF was added dropwise 1-chloro-N,N-2-trimethyl-1-propenylamine (Ghosez’s reagent) (498 mί, 3.76 mmol). The resulting reaction mixture was warmed to room temperature. After stirring for a further 40 min the solution was added dropwise to a solution of (1 R,2R)-2- amino-1-(4-nitrophenyl)propane-1 ,3-diol (760 mg, 3.58 mmol) in THF (10 mL) and 50% w/w aqueous NaOAc (5 g in 10 mL) at room temperature. The resulting reaction mixture was stirred for a further 2.5 h, the layers separated and the aqueous extracted with EtOAc (2 x 20 ml_). The combined organics were dried over Na2S04 and concentrated under reduced pressure. The crude product was purified by silica column chromatography eluting with 0-10% 7M NH3 in MeOH in DCM to give 12-bromo-N-[(1 R,2R)-1 ,3-dihydroxy- 1 -(4-nitrophenyl)propan-2-yl)]dodecanamide (1 .5 g, 84% yield) as a colourless gum, which was used in the next step.
[00194] LC-MS (Method A) 473/475 [M+H]+; RT 1 .64 min
(11 -{[ (1R,2R)-1, 3-dihydroxy- 1 -(4-nitrophenyl)propan-2- yl]carbamoyl}undecyl)diphenyl(pyridine-2-yl)phosphonium chloride
Figure imgf000054_0001
[00195] To a degassed solution of 12-bromo-N-[(1 R,2R)-1 ,3-dihydroxy-1 -(4- nitrophenyl)propan-2-yl)]dodecanamide (prepared as described in Example 6 step (a)) (100 mg, 0.21 mmol) and Nal (7.9 mg) in MeCN (5 mL) was added 2- (diphenylphosphino)pyridine (58 mg, 0.22 mmol). The resulting reaction mixture was refluxed for 16 h. On cooling the reaction mixture was concentrated under reduced pressure and the resulting crude product purified by silica column chromatography eluting with 0-10% 7M NH3 in MeOH in DCM. The resulting white solid was taken up in MeOH (5 mL) and filtered through an Amberlite IRA-400(CI) ion exchange resin. The collected MeOH was recycled through the column 3 x, followed by a fresh volume of MeOH. The combined MeOH washings were concentrated under reduced pressure to give the title compound (10 mg, 7% yield) as a white solid.
[00196] 1 H NMR (Method B) (DMSO-d6): d (delta) ppm 9.00 (d, J = 4.1 Hz, 1 H), 8.24- 8.15 (m, 1 H), 8.13 (d, J = 8.3 Hz, 3H), 8.01 -7.94 (m, 1 H), 7.93-7.81 (m, 6H), 7.80-7.72 (m, 4H), 7.58 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 9.1 Hz, 1 H), 5.82 (d, J = 5.2 Hz, 1 H), 5.03 (dd, J = 5.5, 2.4 Hz, 1 H), 5.13-4.97 (m,1 H), 4.84 (t, J = 5.5 Hz, 2H), 4.07-3.95 (m, 1 H), 3.66-3.47 (m, 2H), 2.47-2.38 (m, 1 H), 2.06-1.81 (m, 2H), 1 .66-1 .52 (m, 2H), 1 .47-1 .37 (m, 2H), 1 .30- 1 .18 (m, 4H), 1 .17-1 .08 (m, 4H), 1 .08-0.97 (m, 4H), 0.95-0.78 (m, 2H); 31 P NMR (202 MHz, DMSO-de) d (delta) ppm +20.31 (s); LC-MS (Method A) 656 [M]+; RT 6.12 min
Example 7 - (11-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}undecyl)diphenyl(propan-2-yl)phosphonium chloride
Figure imgf000055_0001
[00197] The title compound was prepared as a white solid following the procedure described in Example 6 but using isopropyldiphenylphosphine in step (b).
[00198] 1 H NMR (Method B) (DMSO-d6): d (delta) ppm 8.12 (d, J = 8.1 Hz, 2H), 7.94- 7.81 (m, 6H), 7.77 (td, J = 7.7, 3.2 Hz, 4H), 7.58 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 9.2 Hz, 1 H), 5.84 (d, J = 5.2 Hz, 1 H), 5.04 (dd, J = 5.5, 2.3 Hz, 1 H), 4.86 (dt, J = 6.4, 4.8 Hz, 1 H),
4.07-3.97 (m, 1 H), 3.68-3.59 (m, 1 H), 3.58-3.51 (m, 1 H), 3.31 -3.24 (m, 1 H), 3.09-3.01 (m, 2H), 2.01 -1 .85 (m, 2H), 1 .39-1 .21 (m, 5H), 1 .20-1 .14 (m, 6H), 1 .14-1 .06 (m, 7H), 1 .06- 0.97 (m, 4H), 0.97-0.76 (m, 2H); 31 P NMR (202 MHz, DMSO-de) d (delta) ppm +34.70 (s); LC-MS (Method A) 621 [M]+; RT 6.02 min Example 8 - tert-Butyl (11-{[(1R,2R)-1,3-dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}undecyl)diphenylphosphonium chloride
Figure imgf000055_0002
[00199] The title compound was prepared as a white solid following the procedure described in Example 6 but using tert-butyldiphenylphosphine in step (b). [00200] 1 H NMR (Method B) (DMSO-d6): d (delta) ppm 8.13 (d, J = 8.6 Hz, 2H), 7.98-
7.87 (m, 6H), 7.78 (td, J = 7.8, 3.2 Hz, 4H), 7.59 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 9.3 Hz, 1 H), 5.83 (d, J = 5.1 Hz, 1 H), 5.04 (m, 1 H), 4.85 (t, J = 1 .8 Hz, 1 H), 4.08-3.97 (m, 1 H), 3.60-3.51 (m, 1 H), 3.18-3.09 (m, 2H), 2.04-1 .84 (m, 2H), 1 .50-1.30 (m, 10H), 1 .30-1.22 (m, 3H), 1 .22-1 .14 (m, 3H), 1 .14-1.07 (m, 4H), 1 .07-0.99 (m, 4H), 0.99-0.74 (m, 2H); 31 P NMR (202 MHz, DMSO-de) d (delta) ppm +37.47 (s); LC-MS (Method A) 635 [M]+; RT 6.32 min
Example 9 (11-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}undecyl)(methyl)diphenylphosphonium chloride
(11 -carboxyundecyl)(methyl)diphenylphosphonium bromide
Figure imgf000056_0001
[00201] A suspension of 12-bromododecanoic acid (1 .33 g, 4.76 mmol) in MeCN (20 mL) was warmed to 40 °C until a clear solution was obtained. The resulting solution was degassed with bubbling N2 for 30 min and treated with methyldiphenylphosphine (0.93 mL, 4.99 mmol). The resulting solution was heated at 90 °C under N2for 16 h. On cooling to room temperature the solution was added to MTBE (100 mL) and (1 1 - carboxyundecyl)(methyl)diphenylphosphonium bromide (2.1 g) collected as a colourless gum, which was used in the next step without further purification.
[00202] LC-MS (Method D) 399.4 [M]+; RT 1 .08 min
(11 -{[ (1R,2R)-1, 3-dihydroxy- 1 -(4-nitrophenyl)propan-2
yl]carbamoyl}undecyl)(methyl)diphenylphosphonium chloride
Figure imgf000056_0002
[00203] The title compound was prepared as a colourless gum following the procedure described in Example 1 , but using (1 1 -carboxyundecyl)(methyl)diphenylphosphonium bromide (prepared as described in Example 9 step (a)). Silica column chromatography was performed using the eluting system 0-20% 7M NH3 in MeOH in DCM.
[00204] 1 H NMR (Method B) (DMSO-de): d (delta) ppm 8.16-8.1 1 (m, 2H), 7.95-7.89 (m, 4H), 7.82 (td, J = 7.4, 1.6 Hz, 2H), 7.72 (td, J = 7.7, 3.2 Hz, 4H), 7.62-7.56 (m, 2H), 7.49 (d, J = 9.2 Hz, 1 H), 5.85 (d, J = 5.2 Hz, 1 H), 5.05 (dd, J = 5.4, 2.4 Hz, 1 H), 4.87 (dd, J = 6.4, 4.8 Hz, 1 H), 4.08-3.97 (m, 1 H), 3.61 -3.50 (m, 1 H), 3.32-3.26 (m. 1 H), 3.10-2.99 (m. 2H), 2.67 (d, J = 14.2 Hz, 3H), 2.02-1 .84 (m, 2H), 1 .51 -1 .35 (m, 4H), 1 .30-1.21 (m, 4H), 1 .21 -1 .10 (m, 4H), 1 .10-1.02 (m, 4H), 0.99-0.79 (m, 2H); 31 P NMR (202 MHz, DMSO-de) d (delta) ppm +24.27 (s); LC-MS (Method A) 593 [M]+; RT 5.52 min
Example 10 (11-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}undecyl)dimethylphenylphosphonium chloride
(11 -carboxyundecyl)dimethylphenylphosphonium bromide
Figure imgf000057_0001
[00205] Prepared following the procedure in Example 9 step (a) using
dimethylphenylphosphine. (1 1 -carboxyundecyl)dimethylphenylphosphonium bromide was collected as a white solid and used in the next step without any purification.
[00206] LC-MS (Method D) 337.4 [M]+; 0.96 min
(11 -{[ (1R,2R)-1, 3-dihydroxy- 1 -(4-nitrophenyl)propan-2- yl]carbamoyl}undecyl)dimethylphenylphosphonium chloride
Figure imgf000058_0001
[00207] The title compound was prepared as a colourless gum following the procedure described in Example 1 , but using (1 1 -carboxyundecyl)dimethylphenylphosphonium bromide (prepared as described in Example 10 step (a)). Silica column chromatography was performed using the eluting system 0-20% 7M NH3 in MeOH in DCM.
[00208] 1 H NMR (Method B) (DMSO-de): d (delta) ppm 8.17-8.12 (m, 2H), 8.00-7.92 (m, 4H), 7.82-7.77 (m, 1 H), 7.71 (td, J = 7.7, 3.2 Hz, 2H), 7.61 -7.57 (m, 2H), 7.46 (d, J = 9.2 Hz, 1 H), 5.83 (d, J = 5.1 Hz, 1 H), 5.04 (dd, J = 4.9, 2.3 Hz, 1 H), 4.85 (dd, J = 6.4, 4.7 Hz,
1 H), 4.07-3.97 (m, 1 H), 3.59-3.51 (m, 1 H), 3.35-3.33 (m, 1 H), 2.56-2.52 (m, 2H), 2.21 (d, J = 14.6 Hz, 6H), 2.03-1 .87 (m, 2H), 1 .48-1 .37 (m, 2H), 1 .37-1 .28 (m, 2H), 1 .28-1 .10 (m,
8H), 1.09-1 .02 (m, 4H), 0.96-0.79 (m, 2H); 31 P NMR (202 MHz, DMSO-de) d (delta) ppm +26.09 (s); LC-MS (Method A) 531 [M]+; RT 4.71 min
Example 11 (11-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}undecyl)( 1 -methyl-1 H-pyrazol-4-yl)diphenylphosphonium chloride 4-(diphenylphosphoryl)- 1 -methyl- 1 H-pyrazole
Figure imgf000058_0002
[00209] Butyllithium (2.5 M in hexanes) (2.73 ml_, 6.83 mmol) was added dropwise to a solution of 4-bromo-1 -methyl-1 H-pyrazole (0.64 mL, 6.21 mmol) in toluene (10 mL) at -78 °C. The resulting reaction mixture was allowed to warm to 0 °C. After stirring for 15 min chlorodiphenylphosphine (1 .27 mL, 6.83 mmol) was added dropwise and the reaction mixture allowed to warm to room temperature. After stirring for 1 h the reaction mixture was diluted with EtOAc (10 mL) and washed with H2O (10 mL) followed by brine (10 ml_). The resulting organics were dried over MgS04 and solvent removed under vacuo. The resulting residue was purified by silica column chromatography eluting with 0-50% TBME in isohexane to give 4-(diphenylphosphonyl)-1 -methyl-1 H-pyrazole (780 mg, 47% yield) as a colourless oil, which was used in the next step without any further purification.
[00210] LC-MS (Method D) 267 [M+H]+; RT 1.56 min
(11 -carboxyundecyl) ( 1 -methyl- 1 H-pyrazol-4-yl)diphenylphosphonium bromide
Figure imgf000059_0001
[00211] A suspension of 12-bromododecanoic acid (440 mg, 1.58 mmol) in MeCN (3.5 mL) was warmed to 40 °C until a clear solution was obtained. The resulting solution was degassed with bubbling N2 for 30 min and treated with 4-(diphenylphosphoryl)-1-methyl- 1 H-pyrazole (460 mg, 1.74 mmol) (prepared as described in Example 11 step (a)). The resulting solution was heated at 80 °C under N2for 48 h. On cooling to room temperature, the solvent was removed under reduced pressure and the resulting residue purified by silica column chromatography eluting with 0-10% MeOH in DCM to give (1 1 - carboxyundecyl)(1 -methyl-1 H-pyrazol-4-yl)diphenylphosphonium bromide (600 mg, 61 % yield) as a colourless sticky oil, which was used in the next step without further purification.
[00212] LC-MS (Method D) 465 [M]+; 1.1 1 min (11-{[(1R,2R)-1, 3-dihydroxy- 1 -(4-nitrophenyl)propan-2-yl]carbamoyl}undecyl)( 1 -methyl-
1 H-pyrazol-4-yl)diphenylphosphonium chloride
Figure imgf000060_0001
[00213] The title compound was prepared as a colourless gum following the procedure described in Example 1 , but using (1 1 -carboxyundecyl)(1 -methyl-1 H-pyrazol-4- yl)diphenylphosphonium bromide (prepared as described in Example 11 step (b)). Silica column chromatography was performed using the eluting system 0-20% 7M NH3 in MeOH in DCM.
[00214] 1 H NMR (Method B) (DMSO-d6): d (delta) ppm 8.48 (s, 1 H), 8.15-8.1 1 (m, 2H), 8.05 (s, 1 H), 7.86 (td, J = 7.3, 1.7 Hz, 2H), 7.84-7.77 (m, 4H), 7.74 (td, J = 7.7, 3.5 Hz,
4H), 7.60-7.56 (m, 2H), 7.46 (d, J = 9.2 Hz, 1 H), 5.83 (d, J = 5.1 Hz, 1 H), 5.04 (dd, J = 5.9, 2.3 Hz, 1 H), 4.85 (dd, J = 6.4, 4.7 Hz, 1 H), 4.05-4.00 (m, 1 H), 3.99 (s, 3H), 3.58-3.51 (m,
1 H), 3.40-3.33 (m, 2H), 2.03-1 .86 (m, 2H), 1 .55-1 .45 (m, 2H), 1 .45-1 .37 (m, 2H), 1 .31 - 1 .09 (m, 9H), 1 .09-0.99 (m, 4H), 0.95-0.78 (m, 2H); 31 P NMR (202 MHz, DMSO-de) d (delta) ppm +13.47 (s); LC-MS (Method C) 659 [M]+; RT 4.40 min
Example 12 - 5-(11-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}undecyl)-5-phenyl-5H-benzo[b]phosphindol-5-ium chloride
Figure imgf000060_0002
[00215] The title compound was prepared as a pale brown gum following the procedure described in Example 6 but using 5-phenyl-5H-benzo[b]phosphindole in step (b).
[00216] LC-MS (Method A) 653 [M]+; RT 6.34 min Example 13 (10-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}decyl)(1 -methyl-1 H-pyrazol-4-yl)diphenylphosphonium chloride
( 10-carboxydecyl) ( 1 -methyl- 1 H-pyrazol-4-yl)diphenylphosphonium bromide
Figure imgf000061_0001
Prepared following Example 11 step (b) but using 1 1 -bromoundecanoic acid. Silica column chromatography was performed using the eluting system 0-10% MeOH in DCM. (10-carboxydecyl)(1 -methyl-1 H-pyrazol-4-yl)diphenylphosphonium bromide was isolated as a colourless oil, which was used in the next step.
LC-MS (Method D) 451 [M]+; RT 1 .02 min
( 10-{[ (1R,2R)-1, 3-dihydroxy- 1 -(4-nitrophenyl)propan-2-yl]carbamoyl}decyl)( 1 -methyl- 1 H- pyrazol-4-yl)diphenylphosphonium chloride
Figure imgf000061_0002
The title compound was prepared as a white solid following the procedure described in Example 11 step (c) but using 10-carboxydecyl)(1 -methyl-1 H-pyrazol-4- yl)diphenylphosphonium bromide (prepared as described in Example 13 step (a)). Silica column chromatography was performed using the eluting system 0-20% 7M NH3 in MeOH in DCM.
LC-MS (Method C) 645 [M]+; RT 4.04 min Example 14 - (9-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}nonyl)( 1 -methyl-1 H-pyrazol-4-yl)diphenylphosphonium chloride
( 9-carboxynonyl)( 1 -methyl- 1 H-pyrazol-4-yl)diphenylphosphonium bromide
Figure imgf000062_0001
Prepared following Example 11 step (b) but using 10-bromodecanoic acid. Silica column chromatography was performed using the elution system 0-10% MeOH in DCM. (9- carboxynonyl)(1 -methyl-1 H-pyrazol-4-yl)diphenylphosphonium bromide was isolated as a light brown oil, which was used in the next step.
LC-MS (Method D) 437 [M]+; RT 0.98 min
( 9-{[ (1R,2R)-1, 3-dihydroxy- 1 -(4-nitrophenyl)propan-2-yl]carbamoyl}nonyl)( 1 -methyl- 1 H- pyrazol-4-yl)diphenylphosphonium chloride
Figure imgf000062_0002
The title compound was prepared as a white solid following the procedure described in Example 11 step (c) but using (9-carboxynonyl)(1 -methyl-1 H-pyrazol-4- yl)diphenylphosphonium bromide (prepared as described in Example 14 step (a)). Silica column chromatography was performed using the eluting system 0-20% 7M NH3 in MeOH in DCM.
LC-MS (Method C) 631 [M]+; RT 3.66 min Example 15 (8-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}octyl)(1 -methyl-1 H-pyrazol-4-yl)diphenylphosphonium chloride
( 8-carboxyoctyl)( 1 -methyl- 1 H-pyrazol-4-yl)diphenylphosphonium bromide
Figure imgf000063_0001
Prepared following Example 11 step (b) but using 9-bromononanoic acid. Silica column chromatography was performed using the eluting system 0-10% MeOH in DCM. (8- carboxyoctyl)(1 -methyl-1 H-pyrazol-4-yl)diphenylphosphonium bromide was isolated as a colourless oil, which was used in the next step.
LC-MS (Method C) 423 [M]+; RT 0.91 min
( 8-{[ (1R,2R)-1, 3-dihydroxy- 1 -(4-nitrophenyl)propan-2-yl]carbamoyl}octyl)( 1 -methyl- 1 H- pyrazol-4-yl)diphenylphosphonium chloride
Figure imgf000063_0002
The title compound was prepared as a white solid following the procedure described in Example 11 step (c) but using (8-carboxyoctyl)(1 -methyl-1 H-pyrazol-4- yl)diphenylphosphonium bromide (prepared as described in Example 15 step (a)). Silica column chromatography was performed using the eluting system 0-20% 7M NH3 in MeOH in DCM.
LC-MS (Method C) 617 [M]+; RT 3.38 min Example 16 (7-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}heptyl)(1 -methyl-1 H-pyrazol-4-yl)diphenylphosphonium chloride
(7-carboxyheptyl)( 1 -methyl- 1 H-pyrazol-4-yl)diphenylphosphonium bromide
Figure imgf000064_0001
Prepared following Example 11 step (b) but using 8-bromooctanoic acid. Silica column chromatography was performed using the eluting system 0-10% MeOH in DCM. (7- carboxyheptyl)(1 -methyl-1 H-pyrazol-4-yl)diphenylphosphonium bromide was isolated as a colourless oil, which was used in the next step.
LC-MS (Method D) 409 [M]+; RT 0.83 min
(7-{[(1R,2R)-1, 3-dihydroxy- 1 -(4-nitrophenyl)propan-2-yl]carbamoyl}heptyl) ( 1 -methyl- 1 H- pyrazol-4-yl)diphenylphosphonium chloride
Figure imgf000064_0002
The title compound was prepared as a white solid following the procedure described in Example 11 step (c) but using (7-carboxyheptyl)(1 -methyl-1 H-pyrazol-4- yl)diphenylphosphonium bromide (prepared as described in Example 16 step (a)). Silica column chromatography was performed using the eluting system 0-20% 7M NH3 in MeOH in DCM. LC-MS (Method C) 603 [M]+; RT 3.07 min
Example 17 - (15-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}pentadecyl)triphenylphosphonium bromide
16-bromo-N-[( 1 R, 2R)- 1, 3-dihydroxy- 1 -(4-nitrophenyl)propan-2-yl]hexadecanamide
Figure imgf000065_0001
Prepared following Example 6 step (a) but using 16-bromohexadecanoic acid. Silica column chromatography was performed using the eluting system 0-10% 7M NH3 in MeOH in DCM. 16-bromo-N-[(1 R,2R)-1 ,3-dihydroxy-1 -(4-nitrophenyl)propan-2- yl]hexadecanamide was isolated as a white solid, which was used in the next step.
LC-MS (Method B) 473/475 [M+H]+; RT 1.63 min
(15-{[(1 R,2R)-1 ,3-dihydroxy-1 -(4-nitrophenyl)propan-2- yl]carbamoyl}pentadecyl)triphenylphosphonium bromide
Figure imgf000065_0002
To a degassed solution of 16-bromo-N-[(1 R,2R)-1 ,3-dihydroxy-1-(4-nitrophenyl)propan-2- yl]hexadecanamide (prepared as described in Example 17 step (a)) (150 mg, 0.28 mmol) in MeCN (10 mL) was added triphenylphosphine (1 14 mg, 0.44 mmol). The resulting reaction mixture was refluxed for 16 h. On cooling the reaction mixture was concentrated under reduced pressure and the resulting crude product purified by silica column chromatography eluting with 0-10% 7M NH3 in MeOH in DCM to give the title compound (30 mg, 13% yield) as colourless glass. LC-MS (Method A) 71 1 [M]+; RT 8.16 min
Example 18 - di-tert-Butyl (11-{[(1R,2R)-1,3-dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}undecyl)phenylphosphonium chloride
Figure imgf000066_0001
The title compound was prepared as a tan coloured solid following the procedure of Example 6 but using di-tert-butyl(phenyl)phosphine in step (b).
LC-MS (Method A) 615 [M]+; RT 3.00 min; 31 P NMR (202 MHz, DMSO-de) d (delta) ppm +43.87 (s) Example 19 - (11-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}undecyl)(2-methoxyethyl)diphenylphosphonium chloride
Figure imgf000066_0002
The title compound was prepared as a white solid following the procedure of Example 6 but using (2-methoxyethyl)diphenylphosphine in step (b).
LC-MS (Method A) 638 [M]+; RT 6.03 min; 31 P NMR (202 MHz, DMSO-de) d (delta) ppm +27.04 (s)
Example 20 - (11-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}undecyl)tris(3,5-dimethylphenyl)phosphonium chloride
Figure imgf000067_0002
The title compound was prepared as a white solid following the procedure of Example 6 but using tris(3,5-dimethylphenyl)phosphine in step (b).
LC-MS (Method A) 740 [M]+; RT 8.81 min Example 21 - (7-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}heptyl)(2-methoxyethyl)diphenylphosphonium chloride
Figure imgf000067_0001
Prepared following Example 6 step (a) but using 8-bromooctanoic acid. Silica column purification was performed using the eluting system 0-10% 7M NH3 in MeOH in DCM. 8- bromo-N-[(1 R,2R)-1 ,3-dihydroxy-1-(4-nitrophenyl)propan-2-yl]octanamide was isolated as a colourless oil, which was used in the next step.
LC-MS (Method B) 417/419 [M+H]+; RT 1.26 min
(7-{[ (1R, 2R)- 1, 3-dihydroxy- 1-(4-nitrophenyl)propan-2-yl]carbamoyl}heptyl) ( 2- methoxyethyl)diphenylphosphonium chloride
Figure imgf000068_0001
To a degassed solution of 8-bromo-N-[(1 R,2R)-1 ,3-dihydroxy-1 -(4-nitrophenyl)propan-2- yl]octanamide (prepared as described in Example 21 step (a)) (100 mg, 0.24 mmol) and Nal (36 mg) in MeCN (5 mL) was added (2-methoxyethyl)diphenylphosphine (61 mg, 0.25 mmol). The resulting reaction mixture was refluxed for 16 h. On cooling the reaction mixture was concentrated under reduced pressure and the resulting crude product purified by silica column chromatography eluting with 0-10% 7M NH3 in MeOH in DCM. The resulting white solid was taken up in MeOH (20 mL) and filtered through an Amberlite IRA- 400(CI) ion exchange resin. The collected MeOH was recycled through the column 3 x, followed by a fresh volume of MeOH. The combined MeOH washings were concentrated under reduced pressure to give the title compound (25 mg, 16% yield) as a white solid.
LC-MS (Method A) 581 [M]+; RT 4.38 min; 31 P NMR (202 MHz, DMSO-de) d (delta) ppm +26.97 (s)
Example 22 - (7-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}heptyl)tris(3,5-dimethylphenyl)phosphonium chloride
Figure imgf000068_0002
The title compound was prepared as a tan coloured solid following the procedure of
Example 21 , but using tris(3,5-dimethylphenyl)phosphine in step (b).
LC-MS (Method A) 683 [M]+; RT 7.72 min Example 23 - {[1.1’-Biphenyl]-(7-{[(1R,2R)-1,3-dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}heptyl)diphenylphosphonium chloride
Figure imgf000069_0001
The title compound was prepared as a white solid following the procedure of Example 21 but using [1 T-biphenyl]-2-yldiphenylphosphine in step (b).
LC-MS (Method A) 675 [M]+; RT 6.17 min
Example 24 - Tribenzyl (7-{[(1R,2R)-1,3-dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}heptyl)phosphonium chloride
Figure imgf000069_0002
The title compound was prepared as a white solid following the procedure of Example 21 but using tribenzylphosphine in step (b).
LC-MS (Method A) 641 [M]+; RT 5.87 min; 31 P NMR (202 MHz, DMSO-de) d (delta) ppm +27.69 (s) Example 25 - (7-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}heptyl)tris(3-methylphenyl)phosphonium chloride
Figure imgf000070_0001
The title compound was prepared as a white solid following the procedure of Example 21 but using tris(3-methylphenyl)phosphine in step (b).
LC-MS (Method A) 641 [M]+; RT 6.41 min
Example 26 - Tricyclohexyl (7-{[(1R,2R)-1,3-dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}heptyl)phosphonium chloride
Figure imgf000070_0002
he title compound was prepared as a white solid following the procedure of Example 21 , but using tricyclohexanephosphine in step (b).
LC-MS (Method A) 617 [M]+; RT 6.53 min; 31 P NMR (202 MHz, DMSO-de) d (delta) ppm +32.46 (s)
Example 27 - (7-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}heptyl)(methyl)diphenylphosphonium chloride
Figure imgf000071_0001
The title compound was prepared as a white solid following the procedure of Example 21 but using methyldiphenylphosphine in step (b). Silica column chromatography was performed using the eluting system 0-20% 7M NH3 in MeOH in DCM. LC-MS (Method A) 537 [M]+; RT 3.92 min
Example 28 (11-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl]carbamoyl}undecyl)(1 -methyl-1 H-1, 2, 3-triazol-4-yl)diphenylphosphonium chloride
4-(diphenylphosphoryl)- 1 -methyl- 1 H- 1, 2, 3-triazole
Figure imgf000071_0002
Butyllithium (2.5 M in hexanes) (1.84 mL, 4.59 mmol) was added dropwise to a solution of 4-bromo-1 -methyl-1 H-1 ,2,3-triazole (0.68 g, 4.17 mmol) in toluene (20 mL) at -78 °C. The resulting reaction mixture was allowed to warm to 0 °C. After stirring for 15 min chlorodiphenylphosphine (0.85 mL, 4.59 mmol) was added dropwise and the reaction mixture allowed to warm to room temperature. After stirring for 1 h the reaction mixture was diluted with EtOAc (10 mL) and washed with H2O (2 x 10 mL) followed by brine (10 mL). The resulting organics were dried over MgS04 and solvent removed under vacuo. The resulting residue was purified by silica column chromatography eluting with 0-40% EtOAc in hexanes to give 4-(diphenylphosphoryl)-1 -methyl-1 H-1 ,2,3-triazole (280 mg,
19% yield) as a colourless oil, which solidified on standing and was used in the next step without any further purification.
LC-MS (Method B) 268 [M+H]+; RT 1.44 min (11 -carboxyundecyl)( 1 -methyl- 1H-1,2, 3-triazol-4-yl)diphenylphosphonium bromide
A solution of 12-bromododecanoic acid (209 mg, 0.75 mmol) and 4-(diphenylphosphoryl)- 1 -methyl-1 H-1 ,2, 3-triazole (prepared as described in Example 28 step (a)) (280 mg, 0.79 mmol) in MeCN (10 ml.) was degassed with bubbling N2. After 30 min the resulting solution was heated at 80 °C under N2for 48 h. On cooling to room temperature, the solvent was removed under reduced pressure and the resulting residue purified by silica column chromatography eluting with 0-10% 7M NH3 in MeOH in DCM to give (11- carboxyundecyl)(1 -methyl-1 H-1 ,2, 3-triazol-4-yl)diphenylphosphonium bromide (250 mg, 68% yield) as a colourless sticky oil, which was used in the next step without further purification
LC-MS (Method B) 466 [M]+; RT 1.06 min
(11 -{[(1 R,2R)-1 , 3-dihydroxy- 1 -(4-nitrophenyl)propan-2-yl]carbamoyl}undecyl)( 1 -methyl- 1H-1,2, 3-triazol-4-yl)diphenylphosphonium chloride
Figure imgf000072_0002
The title compound was prepared as a colourless glass following the procedure described in Example 1 but using (11-carboxyundecyl)(1 -methyl-1 H-1 , 2, 3-triazol-4- yl)diphenylphosphonium bromide (prepared as described in Example 28 step (b)). Silica column chromatography was performed using the eluting system 0-20% 7M NH3 in MeOH in DCM. LC-MS (Method A) 660 [M]+; RT 5.66 min; 31 P NMR (202 MHz, DMSO-de) d (delta) ppm +12.94 (s)
Example 29 (11-{[(1R,2R)-1,3-Dihydroxy-1-(4-nitrophenyl)propan-2- yl](methyl)carbamoyl}undecyl)triphenylphosphonium chloride
Figure imgf000073_0001
The title compound was prepared as a colourless glass following the procedure described in Example 1 but using (1 R,2R)-2-(methylamino)-1 -(4-nitrophenyl)propane-1 ,3-diol.
LC-MS (Method A) 669 [M]+; RT 1 .64 min
Inhibition of proliferation assay
[00217] Cell confluence
[00218] The confluence value is a surrogate for cell proliferation and growth. The value is expressed as a percent confluence, which represents the fraction of culture dish-surface that is occupied by cells. As the number of cells in the dish increases over time due to proliferation, so will their coverage of that surface increase. Expansion of the cell population on the cell culture-dish surface and confluence have mostly a linear relationship until the cells on the plate surface begin to reach saturation or maximum density.
[00219] Confluence is determined based on image analysis. Image based software can identify objects in the image field based on changes to pixel density in a grey scale image. The software can then assign a mask to those pixels within the object. Objects can be ‘gated’ out based on size and shape. To determine cell confluence, images of cells are first masked as objects. The surface area of the image that is masked is measured and compared to the total surface area of the culture dish surface to obtain a percent confluence.
MDA-231 cancer cells were obtained from ATCC. Cells were cultured in Dulbecco’s
Modified Eagle Medium (DMEM) supplemented with 10% Fetal Bovine Serum (FBS), 2 mM Glutamax, 1 mM Non Essential Amino Acid (NEAA) solution and 1 mM sodium pyruvate. Compounds were dissolved in DMSO at 10 mM and diluted in cellular medium and tested at 10 mM (micromolar). Final DMSO concentrations were <0.1 %. Images were acquired with an IncuCyte Live Cell Imaging microscopy (Essen Bioscience) at every 3 h under cell culture conditions with 10X objective over 4-5 d. Cell confluence was calculated from one field of view per well using the IncuCyte in-built algorithm. Relative confluence values were obtained by normalising each value to the time zero value in each sample.
Figure imgf000074_0001
Figure imgf000075_0001

Claims

1 . A compound comprising an ion of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000076_0001
-L1- is independently absent or is selected from -C(O)-, -C(0)0-, -S(0)2-, -C(0)NR6, and - S(0)2NR6-;
-L3- is independently at each occurrence either absent or selected from: -0-, -S-, -NR7-,- C(O)-, -OC(O)-, -0(0)0-, -S(0)2-, -S(0)-, -NR6C(0)-, -C(0)NR6, -NR6S(0)2-, -S(0)2NR6-, - 0C(0)NR6-,-NR6C(0)0-, NR6C(0)NR6, -CR8=CR8- and -CºC-;
-L2- and -L4- are each independently at each occurrence -Ci-C4-alkylene-, each alkylene group being unsubstituted or substituted with from 1 to 6 independently selected R9 groups; provided that any -l_2- or -L4- group that is attached at each end to an atom selected from oxygen, nitrogen, sulphur or phosphorous is -C2-C4-alkylene-;
n is an integer selected from 0, 1 , 2, 3, 4 and 5;
wherein L1, L2, L3, L4 and n are selected such that length of the linker formed by those groups is from 3 to 20 atoms;
R1a, R1b and R1c are each independently selected from phenyl, biphenyl, naphthyl, 5-, 6-,
9- or 10- membered heteroaryl, C3 to Cs-cycloalkyl, Ci-Cs-alkyl and 4- to 8-membered heterocycloalkyl; wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R10 groups; and wherein said C3 to Cs-cycloalkyl, C-i-Cs-alkyl and 4- to 8-membered heterocycloalkyl is optionally substituted with from 1 to 5 independently selected R11 groups; wherein R1a and R1b are optionally connected to each other via a bond or a group selected from -0-, - S(0)2-, NR6, and Ci-C3-alkylene;
R2 and R6 are each independently at each occurrence selected from H and Ci-C6-alkyl;
R3 is independently selected from H, halo, OR12 and NR13R14;
R4 is independently at each occurrence selected from: H, and C(0)Ci-C6-alkyl; R5 and R10 are each independently at each occurrence selected from: Ci-C6-alkyl, C2-C6- alkynyl, C2-C6-alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 4- to 8-membered
heterocycloalkyl, 5-, 6-, 9- or 10- membered heteroaryl, phenyl, OR12, SR13, NR13R14, C(0)0R13, C(0)NR13R13, halo, cyano, nitro, C(0)R13, S(0)20R13, S(0)R13, S(0)2R13, S(0)2NR13R13, 0C(0)NR13R13 and NR13C(0)0R13;
R7 and R14 are each independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci-Ce-alkyl and S(0)2-Ci-C6-alkyl;
R8 is independently at each occurrence selected from H, Ci-C4-alkyl and halo;
R9 is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C2-C6- alkenyl, CrCe-haloalkyl, OR12, SR13, NR13R14, C(0)0R13, C(0)NR13R13, halo, cyano, nitro, C(0)R13, S(0)20R13, S(0)2R13, S(0) R13, S(0)2NR13R13, 0C(0)NR13R13 and
NR13C(0)0R13;
R11 is independently at each occurrence selected from: oxo, Ci-C6-alkyl, C2-C6-alkynyl, C2- C6-alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 4- to 8-membered heterocycloalkyl, 5-, 6-, 9- or 10- membered heteroaryl, phenyl, OR12, SR13, NR13R14, C(0)0R13, C(0)NR13R13, halo, cyano, nitro, C(0)R13, S(0)20R13, S(0)R13· S(0)2R13, S(0)2NR13R13, 0C(0)NR13R13 and NR13C(0)0R13;
R12 is independently at each occurrence selected from: H, Ci-C6-alkyl and Ci-C6-haloalkyl; R13 is independently at each occurrence selected from: H and Ci-C6-alkyl; and
m is an integer selected from 0, 1 ,
2, 3, 4 and 5;
and wherein any of the abovementioned alkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, heteroaryl or phenyl groups is optionally substituted where chemically allowable by from 1 to 4 groups independently selected from oxo, Ci-C6-alkyl, C2-C6- alkynyl, C2-Ce-alkenyl, CrCe-haloalkyl, ORa, NRaRb, SRa, C(0)0Ra, C(0)NRaRa, halo, cyano, nitro, C(0)Ra, S(0)20Ra, S(0)2Ra, S(0)Ra and S(0)2NRaRa; wherein Ra is independently at each occurrence selected from: H and Ci-C6-alkyl; and Rb is
independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci-C6-alkyl and S(0)2-Ci-C6-alkyl.
A compound of claim 1 , wherein the ion is an ion of formula (II)
Figure imgf000077_0001
3. A compound of claim 1 or claim 2, wherein R2 is H.
4. A compound of any one of claims 1 to 3, wherein R4 is H.
5. A compound of any one of claims 1 to 4, wherein R3 is selected from F and OH.
6. A compound of any one of claims 1 to 5, wherein m is 1 and the R5 group is
situated para to the point of connection of the rest of the molecule and is selected from S(0)2Ci-C4-alkyl and nitro.
7. A compound of any one of claims 1 to 6, wherein L1 is -C(O)-.
8. A compound of any one of claims 1 to 7, wherein L1, L2, L3, L4, and n are selected such that length of the linker formed by those groups is from 7 to 17 atoms.
9. A compound of any one of claims 1 to 8, wherein L3 is at each occurrence absent.
10. A compound of claim 7, wherein the group -L1-L2-(L3-L4)n-P+R1aR1bR1c is:
Figure imgf000078_0001
wherein L5 is a C2-C2o-alkylene group optionally substituted with from 0 to 10 R9 groups.
1 1. A compound of claim 10, wherein L5 is unsubstituted.
12. A compound of any one of claims 1 to 11 , wherein R1a, R1b and R1c are each
independently phenyl.
13. A compound of claim 12, wherein R1a, R1b and R1c are each unsubstituted phenyl.
14. A compound of any one of claims 1 to 11 , wherein R1a and R1b are each
unsubstituted phenyl and R1c is independently selected from: substituted phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, C3 to Cs-cycloalkyl, C1- Ce-alkyl and 4- to 8-membered heterocycloalkyl.
15. A compound of any one of claims 1 to 11 , wherein at least one of R1a, R1b and R1c is Ci-C6-alkyl.
16. A compound of claim 15, wherein any of R1a, R1b and R1c that are not Ci-C6-alkyl are phenyl.
17. A compound of claim 1 , wherein the ion of formula (I) is an ion selected from: 
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
81
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
18. The compound of claims 1 to 17 for use as a medicament.
19. The compound of claims 1 to 17 for use in the treatment of cancer.
20. A method for the treatment of cancer, wherein the method comprises the
administration of a therapeutically effective amount of a compound of any one of claims 1 to 17.
21. A pharmaceutical composition comprising the compound of claims 1 to 17 and one or more pharmaceutically acceptable excipients.
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