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WO2018193111A1 - Azithromycin derivatives containing a phosphonium ion as anticancer agents - Google Patents

Azithromycin derivatives containing a phosphonium ion as anticancer agents Download PDF

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Publication number
WO2018193111A1
WO2018193111A1 PCT/EP2018/060226 EP2018060226W WO2018193111A1 WO 2018193111 A1 WO2018193111 A1 WO 2018193111A1 EP 2018060226 W EP2018060226 W EP 2018060226W WO 2018193111 A1 WO2018193111 A1 WO 2018193111A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
compound
independently
occurrence
phenyl
Prior art date
Application number
PCT/EP2018/060226
Other languages
French (fr)
Inventor
Tim SPAREY
Andrew Ratcliffe
Brett Stevenson
Franz LAGASSE
Edward COCHRANE
Gilbert Lassalle
Original Assignee
Novintum Biotechnology Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB1706316.5A external-priority patent/GB201706316D0/en
Priority claimed from GBGB1721758.9A external-priority patent/GB201721758D0/en
Application filed by Novintum Biotechnology Gmbh filed Critical Novintum Biotechnology Gmbh
Publication of WO2018193111A1 publication Critical patent/WO2018193111A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • 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 azithromycin derivatives having a
  • 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 doxycydine, exert a therapeutic effect have been open to markedly different explanations.
  • MMPs matrix metalloproteinases
  • Some authors have suggested that these agents inhibit matrix metalloproteinases (MMPs) and thereby achieve an antiinflammatory 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
  • 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.
  • Z 1 is R 2c ;
  • -L 1 - is independently absent or is selected from -C(O)-, -C(0)0-, -S(0)2-, -S(O)-, - C(0)NR 5 , and -S(0) 2 NR 5 -;
  • -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 8 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 -C 4 -alkylene-;
  • -L 5 - is independently selected from: -0-, -S-, -NR 6 -, -0C(0)-, -NR 5 C(0)-, NR 5 S(0) 2 -, - OC(0)NR 5 -, -NR 5 C(0)0- and NR 5 C(0)NR 5 ;
  • n is an integer selected from 0, 1 , 2, 3 and 5;
  • L 1 , L 2 , L 3 , L 4 , L 5 and n are selected such that length of the linker formed by those groups is from 3 to 16 atoms;
  • R 1a , R 1b and R 1c are each independently selected from phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, C3 to Cs-cycloalkyI, Ci-Cs-alkyI and 4- to 8-membered heterocycloalkyi; wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R 1d groups; and wherein said C3 to Cs-cycloalkyI, Ci-Cs-alkyI and 4- to 8-membered heterocycloalkyi is optionally substituted with from 1 to 5 independently selected R 1e groups; provided that R 1a , R 1b and R 1c are not each unsubstituted phenyl; wherein R 1a and R 1b are optionally connected to each other via a bond or a group selected from -0-, NR 6a , and C
  • R 2a , R 2b and R 2c are each independently selected from H and Ci-C6-alkyl;
  • R 3a is independently selected from: H , d-Ce-alkyl or C(0)-Ci-Ce-alkyl;
  • R 3b and R 3c are each independently selected from: H and C(0)-Ci-C6-alkyl
  • R 4a and R 4b are each independently selected from: H , Ci-Ce-alkyl or C(0)-Ci-Ce-alkyl; or R 4a and R 4b together from C(O);
  • R 5 and R 6a are each independently at each occurrence selected from H and Ci-C6-alkyl;
  • R 6 and R 11 are independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci- Ce-alkyl and S(0) 2 -Ci-C 6 -alkyl;
  • R 7 is independently at each occurrence selected from H , Ci-C 4 -alkyl and halo;
  • R 8 is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C2-C6- alkenyl, Ci-C 6 -haloalkyl, OR 9 , SR 10 , NR 10 R 11 , C(0)OR 1 °, C(O)NR 10 R 10 , halo, cyano, nitro, C(0)R 10 , S(0) 2 OR 10 , S(0) 2 R 10 S(0)R, OC(O)NR 10 R 10 , NR 10 C(O)OR 10 and S(O) 2 NR 10 R 10 ;
  • R 9 is independently at each occurrence selected from: H, Ci-C6-alkyl and Ci-C6-haloalkyl
  • R 10 is independently at each occurrence selected from: H and Ci-C6-alkyl
  • R 1d is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C2-C6- alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyi, 5-, 6-, 9- or 10- membered heteroaryl, phenyl, OR 9 , SR 10 , NR 10 R 11 , C(0)OR 1 °, C(O)NR 10 R 10 , halo, cyano, nitro, C(0)R 10 , S(0) 2 OR 1 °, S(0)R i S(0) 2 R 1 °, S(O) 2 NR 10 R 10 , OC(O)NR 10 R 10 and NR 10 C(O)OR 10 ;
  • R 1e is independently at each occurrence selected from: oxo, Ci-C6-alkyl, C2-C6-alkynyl, C2- C6-alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyi, 5-, 6-, 9- or 10- membered heteroaryl, phenyl, OR 9 , SR 10 , NR 10 R 11 , C(0)OR 1 °, C(O)NR 10 R 10 , halo, cyano, nitro, C(0)R 10 , S(0) 2 OR 1 °, S(0)R i S(0) 2 R 1 °, S(O) 2 NR 10 R 10 , OC(O)NR 10 R 10 and NR 10 C(O)OR 10 ;
  • heterocycloalkyi, 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, C 2 -C 6 -alkenyl, Ci-C 6 -haloalkyl, OR a , NR a R b , SR a , C(0)OR a , C(0)NR a R a , halo, cyano, nitro, C(0)R a , S(0) 2 OR 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-C6-alkyl; and R b is
  • H independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci-C6-alkyl and S(0) 2 -Ci-C 6 -alkyl.
  • a compound comprising an ion of formula (I) or a pharmaceutically acceptable salt thereof:
  • -L 1 - is independently absent or is selected from -C(O)-, -C(0)0-, -S(0)2-, -S(O)-, - C(0)NR 5 , and -S(0) 2 NR 5 -;
  • -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 6 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 -C 4 -alkylene-;
  • -L 5 - is independently selected from: -0-, -S-, -NR 6 -, -OC(O)-, -NR 5 C(0)-, NR 5 S(0) 2 -, - OC(0)NR 5 -, -NR 5 C(0)0- and NR 5 C(0)NR 5 ;
  • n is an integer selected from 0, 1 , 2, 3 and 5;
  • L 1 , L 2 , L 3 , L 4 , L 5 and n are selected such that length of the linker formed by those groups is from 3 to 16 atoms;
  • R 1 a , R 1 b and R 1 c are each independently selected from phenyl, biphenyl, naphthyl, 5-, 6-,
  • R 2a , R 2b and R 2c are each independently selected from H and Ci-C6-alkyl;
  • R 3a is independently selected from: H, Ci-C6-alkyl or C(0)-Ci-C6-alkyl;
  • R 3b and R 3c are each independently selected from: H and C(0)-Ci-C6-alkyl
  • R 4a and R 4b are each independently selected from: H, Ci-C6-alkyl or C(0)-Ci-C6-alkyl; or R 4a and R 4b together from C(O);
  • R 5 is independently at each occurrence selected from H and Ci-C6-alkyl
  • R 6 and R 1 1 are independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci- Ce-alkyl and S(0) 2 -Ci-C 6 -alkyl;
  • R 7 is independently at each occurrence selected from H, Ci-C4-alkyl and halo;
  • R 8 is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C2-C6- alkenyl, Ci-C 6 -haloalkyl, OR 9 , SR 10 , N R 10 R 1 1 , C(0)OR 1 °, C(O)N R 10 R 10 , halo, cyano, nitro, C(0)R 10 , S(0) 2 OR 10 , S(0) 2 R 10 S(0)R, OC(O)N R 10 R 10 , N R 10 C(O)OR 10 and S(O) 2 N R 10 R 10 ;
  • R 9 is independently at each occurrence selected from: H, Ci-C6-alkyl and Ci-C6-haloalkyl;
  • R 10 is independently at each occurrence selected from: H and Ci-C6-alkyl
  • R 1 1 is independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci-C6-alkyl and S(0) 2 -Ci-C 6 -alkyl;
  • R 1 d is independently at each occurrence selected from: Ci-C6-alkyl, C 2 -C6-alkynyl, C 2 -C6- alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyi, 5-, 6-, 9- or
  • R 1 e is independently at each occurrence selected from: oxo, Ci-C6-alkyl, C 2 -C6-alkynyl, C 2 - C6-alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyi, 5-, 6-, 9- or 10- membered heteroaryl, phenyl, OR 9 , SR 10 , N R 10 R 1 1 , C(0)OR 1 °, C(O)N R 10 R 10 , halo, cyano, nitro, C(0)R 10 , S(0) 2 OR 10 , S(0)R i S(0) 2 R 10 , S(O) 2 NR 10 R 10 , OC(O)NR 10 R 10 and NR 10 C(O)OR 10 ;
  • heterocycloalkyi, 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, C 2 -C 6 -alkenyl, Ci-C 6 -haloalkyl, OR a , NR a R b , SR a , C(0)OR a , C(0)NR a R a , halo, cyano, nitro, C(0)R a , S(0) 2 OR 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-C6-alkyl; and R b is
  • H independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci-C6-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 L 4 and L 5 is the number of atoms in a straight chain from the phosphorous atom of the phosphonium to the oxygen or nitrogen atom via which the linker is attached to the azithromycin portion of the molecules.
  • 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):
  • the ion of formula (I) is an ion of formula (III):
  • the ion of formula (I) is an ion of formula (IV):
  • the ion of formula (I) is an ion of formula (V):
  • Ci5-alkylene group optionally substituted with from 0 to 10 R 8 groups.
  • R 1a , R 1b and R 1c 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 R 1d groups, and wherein said C3 to Cs-cycloalkyl is optionally substituted with from 1 to 5 independently selected R 1e 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 1d groups, and wherein said cyclohexyl group is optionally substituted with from 1 to 5 independently selected R 1e 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 1d groups, and wherein said cyclohexyl group is optionally substituted with 1 to 3 independently selected R 1e 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 1d 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 1d 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 1d 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 1d 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 C3 to Cs cycloalkyl, d-Cs-alkyl and 4- to 8- membered heterocycloalkyl; wherein said C3 to Cs cycloalkyl, d-Cs-alkyl and 4- to 8- membered heterocycloalkyl is optionally substituted with from 1 to 5 independently selected R 1e groups.
  • R 1a , R 1b and R 1c are each independently selected from C3 to Cs cycloalkyi, d-Cs-alkyl and 5- to 8- membered heterocycloalkyi; wherein said C3 to Cs cycloalkyi, Ci-Cs-alkyl and 5- to 8- membered heterocycloalkyi is optionally substituted with from 1 to 5 independently selected R 1e groups.
  • R 1a , R 1b and R 1c are different or the same.
  • R 1e is independently at each occurrence selected from Ci-dr alkyl, halo, OR 9 , NR 10 R 11 and S(0) 2 OR 1 °.
  • R 1e is independently at each occurrence selected from OCH3, OCH 2 (CH 3 ) 2 , N(CH 3 ) 2 , S0 2 OH, F and CI.
  • 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 1d groups, wherein R 1d is independently at each occurrence selected from Ci-C 6 -alkyl, halo, OR 9 , NR 10 R 11 and S(0) 2 OR 10 .
  • 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 1d groups, wherein R 1d is independently at each occurrence selected from OCH 3 , OCH 2 (CH 3 ) 2 , N(CH 3 ) 2 , S0 2 OH, F and CI.
  • 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 independently selected from: substituted phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, C 3 to Cs-cycloalkyl, Ci-Cs-alkyl and 5- 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
  • R 1a and R 1b are each C3 to Cs-cycloalkyl and R 1c is
  • R 1a and R 1b are each cyclohexyl and R 1c is substituted biphenyl.
  • 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 1a , R 1b and R 1c are each C 3 to Cs-cycloalkyl.
  • R 1a , R 1b and R 1c are each cyclohexyl.
  • R 1a 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 heterocycloalkyi. 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 heterocycloalkyi.
  • At least one of R 1a , R 1b and R 1c is 5-, 6-, 9- or 10- membered heteroaryl or 4- to 8-membered heterocycloalkyi, wherein said heteroaryl or heterocycloalkyi 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 heterocycloalkyi, wherein said heteroaryl or heterocycloalkyi 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.
  • At least one of R 1a , R 1b and R 1c is 5-, 6-, 9- or 10- membered heteroaryl or 5- to 8-membered heterocycloalkyi. It may be that a single one of R 1a , R 1b and R 1c is 5-, 6-, 9- or 10- membered heteroaryl or 5- to 8-membered heterocycloalkyi. In embodiments, at least one of R 1a , R 1b and R 1c is 5-, 6-, 9- or 10- membered heteroaryl or 5- to 8-membered heterocycloalkyi, wherein said heteroaryl or heterocycloalkyi group comprises at least one nitrogen atom in the ring.
  • R 1a , R 1b and R 1c is 5-, 6-, 9- or 10- membered heteroaryl or 5- to 8-membered heterocycloalkyi, wherein said heteroaryl or heterocycloalkyi 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.
  • 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.
  • 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-C6-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-C6-alkyl (e.g. methyl). In these embodiments, it may be that any of R 1a , R 1b and R 1c that are not Ci-C6-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-, NR 6a , 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 6a , 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. [0052] It may be that R 1a and R 1b are not connected to each other via a bond or a group selected from -0-, NR 6a , and Ci-C3-alkylene.
  • - + PR 1a R 1b R 1c is selected from
  • R 2a is Ci-C 6 alkyl.
  • R 2c is Ci-C 6 alkyl.
  • R 2a is Ci-C 6 alkyl and R 2c is Ci-C 6 alkyl.
  • R 2b is C1-C6 alkyl.
  • R 2a is Ci-C 6 alkyl
  • R 2 is Ci-C 6 alkyl
  • R 2c is Ci-C 6 alkyl
  • R 2a is methyl
  • R 2c is methyl
  • R 2a is methyl and R 2c is methyl.
  • R 2b is methyl
  • R 2a is methyl
  • R 2b is methyl
  • R 2c is methyl
  • R 2a and R 2b are each independently selected from is H and methyl.
  • R 3a is H.
  • R 3b is H.
  • R 3b is C(0)CH 3 .
  • R 3a is H and R 3 is H.
  • R 3a is H and R 3b is C(0)CH 3 .
  • R 3c is selected from H and C(0)CH 3 .
  • R 3c is H.
  • R 3c is C(0)CH 3 .
  • R 4a is H.
  • R 4b is H.
  • R 4a is H and R 4 is H.
  • R 4a and R 4b together form C(O).
  • R 4a and R 4b together form C(O) and R 3b is C(0)CH 3 .
  • R 4a and R 4 together form C(O) and R 3b is H.
  • R 4a and R' are each H and R 3b is H.
  • R 5 is at any particular occurrence H. In embodiments, R 5 is at each occurrence H.
  • R 5 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R 5 is at each occurrence Ci-C4-alkyl, e.g. methyl.
  • R 6 is at any particular occurrence H. In embodiments, R 6 is at each occurrence H.
  • R 6 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R 6 is at each occurrence Ci-C4-alkyl, e.g. methyl.
  • R 7 is at any particular occurrence H. In embodiments, R 7 is at each occurrence H.
  • L 2 and L 4 are unsubstituted.
  • R 8 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R 8 is at each occurrence Ci-C4-alkyl, e.g. methyl. [0085] In embodiments, R 9 is at any particular occurrence H. In embodiments, R 9 is at each occurrence H.
  • R 9 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R 9 is at each occurrence Ci-C4-alkyl, e.g. methyl.
  • R 10 is at any particular occurrence H. In embodiments, R 10 is at each occurrence H.
  • R 10 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R 10 is at each occurrence Ci-C4-alkyl, e.g. methyl.
  • R 11 is at any particular occurrence H. In embodiments, R 11 is at each occurrence H. [0090] In embodiments, R 11 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R 11 is at each occurrence Ci-C4-alkyl, e.g. methyl.
  • R 4a is H
  • R 4b is H
  • R 2a is Ci-C 6 alkyl
  • R 2b is Ci-C 6 alkyl
  • R 2c is C1-C6 alkyl.
  • R 4a is H
  • R 4b is H
  • R 2a is Ci-C 6 alkyl
  • R 2b is Ci-C 6 alkyl
  • R 2c is Ci-C 6 alkyl
  • R 3c is H.
  • R 4a and R 4b together form C(O), R 2a is Ci-C 6 alkyl, R 2b is Ci-C 6 alkyl and R 2c (when present) is C1-C6 alkyl.
  • R 4a is H
  • R 4b is H
  • R 2a is Ci-C 6 alkyl
  • R 2b is Ci-C 6 alkyl
  • R 2c when present is Ci-C 6 alkyl
  • R 3a is H and R 3b is H or C(0)CH 3 .
  • R 4a and R 4b together form C(O), R 2a is Ci-C 6 alkyl, R 2b is Ci-C 6 alkyl, R 2c (when present) is Ci-C 6 alkyl, R 3a is H and R 3b is H or C(0)CH 3 .
  • R 4a and R 4b together form C(O), R 2a is Ci-C 6 alkyl, R 2b is Ci-C 6 alkyl, R 2c (when present) is Ci-C 6 alkyl, R 3a is H, R 3b is H or C(0)CH 3 and R 3c is H.
  • R 4a is H
  • R 4b is H
  • R 2a is methyl
  • R 2b is methyl
  • R 2c is methyl
  • R 4a and R 4b together form C(O), R 2a is methyl, R 2b is methyl and R 2c (when present) is methyl.
  • R 4a is H
  • R 4b is H
  • R 2a is methyl
  • R 2b is methyl and R 2c (when present) is methyl
  • R 3a is H and R 3b is H or C(0)CH 3 .
  • R 4a and R 4b together form C(O), R 2a is methyl, R 2b is methyl and R 2c (when present) is methyl, R 3a is H and R 3b is H or C(0)CH 3 .
  • R 4a and R 4b together form C(O), R 2a is methyl, R 2b is methyl and R 2c (when present) is methyl, R 3a is H, R 3b is H or C(0)CH 3 and R 3c is H.
  • R 4a is H
  • R 4b is H
  • R 2a is Ci-C 6 alkyl
  • R 2b is Ci-C 6 alkyl
  • R 2c is C1-C6 alkyl.
  • R 4a and R 4b together form C(O), R 2a is Ci-C 6 alkyl, R 2b is Ci-C 6 alkyl, R 2c (when present) is Ci-C 6 alkyl.
  • R 4a is H
  • R 4b is H
  • R 2a is Ci-C 6 alkyl
  • R 2b is Ci-C 6 alkyl
  • R 2c is Ci-C 6 alkyl
  • R 3a is H
  • R 3b is H or C(0)CH 3 .
  • R 4a and R 4b together form C(O), R 2a is Ci-C 6 alkyl, R 2b is Ci-C 6 alkyl, R 2c (when present) is Ci-C 6 alkyl, R 3a is H, R 3b is H or C(0)CH 3 .
  • R 4a is H
  • R 4b is H
  • R 2a is methyl
  • R 2b is methyl
  • R 2c when present is methyl
  • R 3a is H
  • R 3b is H or C(0)CH 3 .
  • R 4a is H
  • R 4b is H
  • R 2a is methyl
  • R 2b is methyl
  • R 2c when present is methyl
  • R 3a is H
  • R 3b is H.
  • R 4a and R 4b together form C(O), R 2a is methyl, R 2b is methyl and R 2c is methyl, R 3a is H, R 3b is H or C(0)CH 3 .
  • R 4a and R 4b together form C(O), R 2a is methyl, R 2b is methyl and R 2c is methyl, R 3a is H, R 3b is H. [00110] In embodiments R 3a , R 3b and R 3c are each H.
  • L 1 is selected from -C(O)- and -S(0) 2 -.
  • L 1 is -C(O)-.
  • L 1 is absent.
  • L 3 is at each occurrence absent.
  • the group -L 2 - (L 3 -L 4 ) n - may form an alkylene linker group.
  • L 3 is at each occurrence -O- and -L 4 - is at each occurrence -C2-C4-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 -NR 5 C(0)-, -C(0)NR 5 .
  • the group— (L 3 -L 4 ) n - may form a peptide linker group.
  • -L 4 - is at each occurrence -Ci-alkylene-.
  • L 1 , L 2 , L 3 , L 4 and n are selected such that length of the linker formed by those groups is from 8 to 14 atoms.
  • L 7 is a C2-Ci3-alkylene group optionally substituted with from 0 to 10 R 8 groups.
  • L 7 may be a Cs-Cn-alkylene group optionally substituted with from 0 to 10 R 8 groups.
  • L 7 may be unsubstituted.
  • -L 5 -L 2 -(L 3 -L 4 ) n - represents -OC(0)N H(CH 2 )io-, - OC(0)N H(CH 2 ) 8 -, -OC(0)N H(CH 2 ) 6 -, -OC(0)N H (CH 2 )n-, -OC(0)N H (CH 2 ) 9 -, - OC(0)NH(CH 2 ) 7 -, or -OC(0)NH(CH 2 ) 5 -.
  • -L 5 -L 2 -(L 3 -L 4 ) n - represents -OC(0)N H(CH 2 )i
  • L 5 is selected from -O-C(O)- and -OC(0)NR 5 -.
  • L 5 is-OC(0)NR 5 -, e.g. OC(0)NH-.
  • L 3 is at each occurrence absent.
  • the group -L 2 - (L 3 -L 4 ) n - may form an alkylene linker group.
  • L 3 is at each occurrence -O- and -L 4 - is at each occurrence -C2-C4-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 a, ethylene glycol, polyethyleneglycol, propyleneglcyol or polypropylene glycol linker group.
  • L 3 is at each occurrence -NR 5 C(0)-, -C(0)NR 5 .
  • the group— (L 3 -L 4 ) n - may form a peptide linker group.
  • it may be that -L 4 - is at each occurrence -Ci-alkylene-.
  • L 5 , L 2 , L 3 , L 4 and n are selected such that length of the linker formed by those groups is from 8 to 14 atoms.
  • Z 1 is: and Z 2 is OR 3c ; wherein L 6 is a C2-Cis-alkylene group optionally substituted with from 0 to 10 R 8 groups. L 6 may be a C7-Ci3-alkylene group optionally substituted with from 0 to 10 R 8 groups. L 6 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
  • 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. CI, Br and I), BF 4 , PF 6 , CF 3 C(0)0, HC(0)0, HC0 3 , (CF 3 S0 2 ) 2 N, (C2F 5 ) 3 PF 3!
  • 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. 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, C1-C12- 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).
  • 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 CI, 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.
  • 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
  • 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 wherein the composition comprises a compound of the invention and one or more pharmaceutically acceptable excipients.
  • 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.
  • a compound comprising an ion of formula (I) or a pharmaceutically acceptable salt thereof:
  • -L 1 - is independently absent or is selected from -C(O)-, -C(0)0-, -S(0)2-, -S(O)-, - C(0)NR 5 , and -S(0) 2 NR 5 -;
  • -L 5 - is independently selected from: -0-, -S-, -N R 6 -, -OC(O)-, -N R 5 C(0)-, N R 5 S(0) 2 -, - OC(0)N R 5 -, -N R 5 C(0)0- and N R 5 C(0)N R 5 ;
  • n is an integer selected from 0, 1 , 2, 3 and 5;
  • L 1 , L 2 , L 3 , L 4 , L 5 and n are selected such that length of the linker formed by those groups is from 3 to 16 atoms;
  • R 1 a , R 1 b and R 1 c are each independently selected from phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, C3 to Cs-cycloalkyl, Ci-Cs-alkyl and 5- to 8- membered heterocycloalkyi; wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R 1 d groups; and wherein said C3 to Cs-cycloalkyl, Ci-Cs-alkyl and 5- to 8-membered heterocycloalkyi is optionally substituted with from 1 to 5 independently selected R 1 e groups; provided that R 1 a , R 1 b and R 1 c are not each unsubstituted phenyl;
  • R 2a , R 2b and R 2c are each independently selected from H and Ci-C6-alkyl;
  • R 3a is independently selected from: H, Ci-Ce-alkyI or C(0)-Ci-Ce-alkyl;
  • R 3b and R 3c are each independently selected from: H and C(0)-Ci-C6-alkyl
  • R 4a and R 4b are each independently selected from: H, Ci-Ce-alkyI or C(0)-Ci-Ce-alkyl; or R 4a and R 4b together from C(O);
  • R 5 is independently at each occurrence selected from H and Ci-C6-alkyl
  • R 6 and R 1 1 are independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci-C 6 -alkyl and S(0) 2 -Ci-C 6 -alkyl;
  • R 7 is independently at each occurrence selected from H, Ci-C 4 -alkyl and halo;
  • R 8 is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C2- Ce-alkenyl, Ci-C 6 -haloalkyl, OR 9 , SR 10 , N R 10 R 1 1 , C(0)OR 1 °, C(O)N R 10 R 10 , halo, cyano, nitro, C(0)R 10 , S(0) 2 OR 1 °, S(0) 2 R 1 ° S(0)R, OC(O)N R 10 R 10 , N R 10 C(O)OR 10 and S(O) 2 N R 10 R 10 ;
  • R 9 is independently at each occurrence selected from: H, Ci-C6-alkyl and C1-C6- haloalkyl;
  • R 10 is independently at each occurrence selected from: H and Ci-C6-alkyl;
  • R 11 is independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci-C6-alkyl and S(0) 2 -Ci-C 6 -alkyl;
  • R 1d is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C 2 - C6-alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyi, 5-, 6-
  • R 1e is independently at each occurrence selected from: oxo, Ci-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyi, 5-
  • heterocycloalkyi, heteroaryl or phenyl groups is optionally substituted where chemically allowable by from 1 to 4 groups independently selected from oxo, Ci-Ce- alkyI, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, Ci-C 6 -haloalkyl, OR a , NR a R b , SR a , C(0)OR a , C(0)NR a R a , halo, cyano, nitro, C(0)R a , S(0) 2 OR 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-C6-alkyl; and R b is independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci-C6-alkyl and S(0) 2 -Ci-C 6 -alkyl.
  • R 1a , R 1b and R 1c are each C3 to Cs-cycloalkyl. 16. A compound of any one of clauses 1 to 13, wherein R 1a , R 1b and R 1c are each benzyl.
  • R 1c is independently selected from: substituted phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, C3 to Cs-cycloalkyl, Ci-Cs-alkyl and 5- to 8-membered heterocycloalkyi. 18. A compound of any one of clauses 1 to 13, wherein R 1a and R 1b are each C3 to Cs- cycloalkyl and R 1c is independently selected from: phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, Ci-Cs-alkyl and 5- to 8-membered heterocycloalkyi. 19. A compound of any one of clauses 1 to 13, wherein at least one of R 1a , R 1 b and R 1c is d-Ce-alkyl.
  • a pharmaceutical composition comprising the compound of clauses 1 to 20 and one or more pharmaceutically acceptable excipients.
  • halo refers to an atom selected from fluorine, chlorine, bromine and iodine.
  • Halo or “halogen” may refer to an atom selected from CI and F.
  • Halo or “halogen” may refer to fluorine.
  • alkyl refers to a linear or branched hydrocarbon chain.
  • the term "Ci- 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.
  • alkyl group may be halo (for example fluorine, chlorine, bromine and iodine), OH and C1-C6 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 -CH2-, -CH2CH2-, - CH2CH2CH2-, -CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2-, - CH2CH2CH2CH2CH2CH2-, -CH2CH2CH2CH2CH2CH2- or substituted equivalents thereof.
  • the alkylene group may be unsubstituted or substituted by one or more substituents.
  • cycloalkyl refers to a saturated hydrocarbon ring system.
  • C3-C8 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.
  • 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-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.
  • cycloalkenyl refers to an unsaturated hydrocarbon ring system.
  • 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.
  • 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- 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.
  • 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.
  • heteroalkyi 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.
  • C1-C6 heteroalkyi 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 heteroalkyi may be attached to another group by the heteroatom or the carbon atom.
  • Ci- C 6 heteroalkyi may refer to, for example, -CH2NHCH3, -NHCH2CH3 and -CH2CH2NH2.
  • the heteroalkyi group may be unsubstituted or substituted by one or more substituents.
  • heterocycloalkyi refers to a saturated hydrocarbon ring system containing at least one heteroatom within the ring system selected from N, O and S.
  • heterocycloalkyi refers to a saturated hydrocarbon ring with 5, 6, 7, 8, 9 or 10 atoms selected from carbon, N, O and S, at least one being a heteroatom.
  • the "heterocycloalkyi” group may also be denoted as a "3 to 10 membered
  • heterocycloalkyi 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 tricyclic 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 "heterocycloalkyi” may be bonded to the rest of the molecule through any carbon atom or heteroatom.
  • the “heterocycloalkyi” 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 "heterocycloalkyi” 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.
  • heterocycloalkenyl 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, 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.
  • 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 " " 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, C 2 -C 6 -alkynyl, C 2 -C 6 -alkenyl, Ci-C 6 -haloalkyl, OR a , NR a R b , SR a , C(0)OR a ,
  • a cyclic substituent may be substituted on a group so as to form a spiro-cycle.
  • Metal 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 there is a substituent on the second atom away from the atom with another substituent.
  • the groups below are meta substituted.
  • Para 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 exam le 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.
  • Pharmaceutically acceptable salts of ions of formula (I) may be prepared by one or more of the following methods:
  • 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.
  • anti-cancer agents such as 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
  • 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 (CI 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 cetuxim
  • 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.
  • 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.
  • 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.
  • 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 ( g/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.
  • 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.
  • the singular encompasses the plural unless the context otherwise requires.
  • the indefinite article the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.
  • 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.
  • Compound (1 ) and compound (29) may be prepared by the procedure described in European Journal of Medicinal Chemistry 40, 201 1 , 5196.
  • Compound (9) and compound (24) may be prepared by the procedure described in WO2004/101590.
  • the reaction can be performed in the presence of a non- nucleophilic base, such as DBU, in an organic solvent, such as DMF, at room
  • the reaction can be performed by heating in an organic solvent, such as MeCN, at a temperature from 50 to 80 °C.
  • Reaction of the phosphonium isoindoline-1 ,3-dione (6) with hydrazine hydrate in an alcoholic solvent, such as EtOH, at a temperature from 50 to 75 °C can furnish phosphonium amine (2).
  • Reaction of amine (9) with phosphonium acid (1 1 )(L 8 is a C2-Ci4-alkylene group optionally substituted with from 0 to 10 R 8 groups) can furnish phosphonium amide (12).
  • the reaction can be performed using standard peptide coupling agents, such as 1 ,3- dicyclohexylcarboiimide (DCC), in a chlorinated solvent, such as DCM at room temperature. Addition of DMAP is optional.
  • 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) can be made by Scheme F.
  • Cyclic carbonate protection of amine (9) to give (13) can be accomplished by reaction with ethylene carbonate in the presence of a base, such as K2CO3, in an organic solvent, such as toluene, at a temperature of 70 to 100 °C. Cyclic carbonate amine (13) can be transformed to phosphonium amide (14). The reaction can be performed using phosphonium acid (1 1 ) and standard peptide coupling agents, such as 1 ,3- dicyclohexylcarboiimide (DCC), in DMS, at room temperature. Addition of DMAP is optional.
  • a base such as K2CO3
  • organic solvent such as toluene
  • the reaction can be performed using SOC in an organic solvent, such as DMF or DCM, at a temperature from 20 to 60 °C.
  • Reaction of phosphine (5) with halo sulphonamide (16) can deliver phosphonium sulphonamide (17).
  • the reaction can be accomplished by heating in an organic solvent, such as MeCN at a temperature from 50 to 80 °C.
  • phosphonium carbamate (19) The reaction can be accomplished in the presence of a base, such as pyridine, in an organic solvent, such as DCM, at a temperature from 0 °C to room temperature.
  • a base such as pyridine
  • organic solvent such as DCM
  • Phosphonium alcohol (21 ) through treatment with triphosgene in the presence of a base, such as DIEA, in an organic solvent, such as THF, at a temperature from -5 to 5 °C.
  • the reaction can be accomplished by heating in an organic solvent, such as MeCN, at a temperature from 50 to 80 °C
  • Reaction of alcohol (29) with phosphonium acid (30) can furnish phosphonium ester (31 ).
  • the reaction can be performed using standard coupling agents for ester formation, such as N-(3-dimethylaminopropyl)-N-ethylcarbodiimide.HCI (EDAC.HCI) in the presence of DMAP, in an organic solvent, such as DCM, at room temperature.
  • standard coupling agents for ester formation such as N-(3-dimethylaminopropyl)-N-ethylcarbodiimide.HCI (EDAC.HCI) in the presence of DMAP, in an organic solvent, such as DCM, at room temperature.
  • cyclic carbonate (32) can be effected by heating in an alcoholic solvent, such as MeOH, at a temperature from 25 to 50 °C.
  • Deprotection of the cyclic carbonate in (32) to give phosphonium ester (33) can be performed in the presence of a base, such as K2CO3, in an alcoholic solvent, such as MeOH, at a temperature from 25 to 80 °C.
  • Amide bond formation between amine (34) and phosphonium carboxylic acid (36) can deliver phosphonium amide (35).
  • the reaction can be effected by standard peptide coupling reagents, such as HATU or TATU or 1 ,3-dicyclohexylcarboiimide (DCC) in the presence of HOAT, in the presence of a base, such as ⁇ , ⁇ -diisopropylethylamine (DIEA), in an organic solvent, such as DCM, at a temperature of 25 to 40 °C
  • standard peptide coupling reagents such as HATU or TATU or 1 ,3-dicyclohexylcarboiimide (DCC) in the presence of HOAT, in the presence of a base, such as ⁇ , ⁇ -diisopropylethylamine (DIEA), in an organic solvent, such as DCM, at a temperature of 25 to 40 °C
  • UPLC/MS was carried out using a Waters Acquity QDa mass detector and Methods A, I, J or Waters SQ mass detector and Methods B, C, D, E, F, H or Agilent 6120 MSD and Method G
  • dichloromethane (DCM), tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 4-dimethylaminopyridine (DMAP), N,N,diisopropylethylamine (DIEA), trifluoroacetic acid (TFA), 1 ,8-diazabicyclo[5.4.0]undec- 7-ene (DBU), 1 -hydroxy-7-azabenzotriazole (HOAT), 0-(7-azabenzotriazole-1 - yl)N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), (1-
  • Example 2 (2S,3S,4R,6R)-6- ⁇ [(2R,3S,4R,5R,8R,10R,11 R,12S,13S,14R)-11 - ⁇ [(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy ⁇ -2-ethyl-3,4,10- trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1 -oxa-6-azacyclopentadecan-13- yl]oxy ⁇ -4-methoxy-2,4-dimethyloxan-3-yl N- ⁇ 8-[tris(4- methoxyphenyl)phosphoniumyl]octyl ⁇ carbamate bromide
  • Example 1 step (c) Prepared following the procedure of Example 1 step (c) using (9- aminononyl)(methyl)diphenylphosphonium bromide (prepared as described in Example 4 step (b)). Purification by 0-3% MeOH/0.7 M NH 3 in DCM. Title compound isolated as a white foam.
  • Example 1 step (b) Prepared following the procedure in Example 1 step (b) using [9-(1 ,3-dioxo-2,3-dihydro- IH-isoindol-2-yl)nonyl]dimethylphenylphosphonium bromide (prepared as described in Example 7 step (a)). Purification by 0-100% EtOAc in DCM followed by 0-40% MeOH in DCM.
  • Example 1 step (c) Prepared following the procedure of Example 1 step (c) using (9- aminononyl)dimethylphenylphosphonium bromide (prepared as described in Example 7 step (b)). Purification by 0-10% MeOH/0.7 M NH 3 in DCM. Title compound isolated as a white foam.
  • Cell confluence 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
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS Fetal Bovine Serum
  • NEAA Non Essential Amino Acid
  • DMSO Dulbecco's 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.
  • the compounds of the invention are considerably more effective at limiting cancer cell proliferation than azithromycin.

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Abstract

This invention relates to compounds that are useful as cancer therapies. The compounds comprise azithromycin derivatives having a phosphonium cation tethered to the azithromycin macrocycle. The invention also relates to methods of using said compounds and to pharmaceutical formulations comprising said compounds. The compounds comprise an ion of formula (I) wherein either Z1 is formula (A) and Z2 is OR3c;or Z2 is formula (B) and Z1 is R2c;

Description

COMPOUNDS
[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 azithromycin derivatives having a
phosphonium cation tethered to the azithromycin macrocycle. 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 inked to azithromycin 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 doxycydine, 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 antiinflammatory 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 azithromycin have increased activity against certain cancer cell lines compared to the corresponding azithromycin itself. 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 imgf000005_0001
wherein either Z1 is
Figure imgf000005_0002
or Z2 is
Figure imgf000005_0003
and Z1 is R2c; -L1- is independently absent or is selected from -C(O)-, -C(0)0-, -S(0)2-, -S(O)-, - C(0)NR5, and -S(0)2NR5-;
-L3- is independently at each occurrence either absent or selected from: -0-, -S-, -NR6-, - C(0)-, -OC(O)-, -C(0)0-, -S(0)2-, -S(0)-, -NR5C(0)-, -C(0)NR5, -NR5S(0)2-, -S(0)2NR5-, - OC(0)NR5-, -NR5C(0)0-, NR5C(0)NR5, -CR7=CR7- and -C≡C-;
-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 R8 groups; provided that any -L2- or -L4- group that is attached at each end to an atom selected from oxygen, nitrogen, sulphur or phosphorous is -C2-C4-alkylene-;
-L5- is independently selected from: -0-, -S-, -NR6-, -0C(0)-, -NR5C(0)-, NR5S(0)2-, - OC(0)NR5-, -NR5C(0)0- and NR5C(0)NR5;
n is an integer selected from 0, 1 , 2, 3 and 5;
wherein L1 , L2, L3, L4, L5 and n are selected such that length of the linker formed by those groups is from 3 to 16 atoms;
R1a, R1b and R1c are each independently selected from phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, C3 to Cs-cycloalkyI, Ci-Cs-alkyI and 4- to 8-membered heterocycloalkyi; wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R1d groups; and wherein said C3 to Cs-cycloalkyI, Ci-Cs-alkyI and 4- to 8-membered heterocycloalkyi is optionally substituted with from 1 to 5 independently selected R1e groups; provided that R1a, R1b and R1c are not each unsubstituted phenyl; wherein R1a and R1b are optionally connected to each other via a bond or a group selected from -0-, NR6a, and C1-C3- alkylene;
R2a, R2b and R2c are each independently selected from H and Ci-C6-alkyl;
R3a is independently selected from: H , d-Ce-alkyl or C(0)-Ci-Ce-alkyl;
R3b and R3c are each independently selected from: H and C(0)-Ci-C6-alkyl;
R4a and R4b are each independently selected from: H , Ci-Ce-alkyl or C(0)-Ci-Ce-alkyl; or R4a and R4b together from C(O);
R5 and R6a are each independently at each occurrence selected from H and Ci-C6-alkyl; R6 and R11 are independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci- Ce-alkyl and S(0)2-Ci-C6-alkyl;
R7 is independently at each occurrence selected from H , Ci-C4-alkyl and halo; R8 is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C2-C6- alkenyl, Ci-C6-haloalkyl, OR9, SR10, NR10R11, C(0)OR1°, C(O)NR10R10, halo, cyano, nitro, C(0)R10, S(0)2OR10, S(0)2R10 S(0)R, OC(O)NR10R10, NR10C(O)OR10 and S(O)2NR10R10;
R9 is independently at each occurrence selected from: H, Ci-C6-alkyl and Ci-C6-haloalkyl; R10 is independently at each occurrence selected from: H and Ci-C6-alkyl;
R1d is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C2-C6- alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyi, 5-, 6-, 9- or 10- membered heteroaryl, phenyl, OR9, SR10, NR10R11, C(0)OR1°, C(O)NR10R10, halo, cyano, nitro, C(0)R10, S(0)2OR1°, S(0)Ri S(0)2R1°, S(O)2NR10R10, OC(O)NR10R10 and NR10C(O)OR10;
R1e is independently at each occurrence selected from: oxo, Ci-C6-alkyl, C2-C6-alkynyl, C2- C6-alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyi, 5-, 6-, 9- or 10- membered heteroaryl, phenyl, OR9, SR10, NR10R11, C(0)OR1°, C(O)NR10R10, halo, cyano, nitro, C(0)R10, S(0)2OR1°, S(0)Ri S(0)2R1°, S(O)2NR10R10, OC(O)NR10R10 and NR10C(O)OR10;
and wherein any of the abovementioned alkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyi, 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-C6-alkenyl, Ci-C6-haloalkyl, ORa, NRaRb, SRa, C(0)ORa, C(0)NRaRa, halo, cyano, nitro, C(0)Ra, S(0)2ORa, 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] A compound comprising an ion of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000008_0001
wherein either Z1 is
Figure imgf000008_0002
or Z2 is
Figure imgf000008_0003
-L1- is independently absent or is selected from -C(O)-, -C(0)0-, -S(0)2-, -S(O)-, - C(0)NR5, and -S(0)2NR5-;
-L3- is independently at each occurrence either absent or selected from: -0-, -S-, -NR6-, - C(O)-, -OC(O)-, -C(0)0-, -S(0)2-, -S(O)-, -NR5C(0)-, -C(0)NR5, -NR5S(0)2-, -S(0)2NR5-, - OC(0)NR5-, -NR5C(0)0-, -NR5C(0)NR5, -CR7=CR7- and -C≡C-;
-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 R6 groups; provided that any -L2- or -L4- group that is attached at each end to an atom selected from oxygen, nitrogen, sulphur or phosphorous is -C2-C4-alkylene-;
-L5- is independently selected from: -0-, -S-, -NR6-, -OC(O)-, -NR5C(0)-, NR5S(0)2-, - OC(0)NR5-, -NR5C(0)0- and NR5C(0)NR5;
n is an integer selected from 0, 1 , 2, 3 and 5;
wherein L1 , L2, L3, L4, L5 and n are selected such that length of the linker formed by those groups is from 3 to 16 atoms; R1 a, R1 b and R1 c are each independently selected from phenyl, biphenyl, naphthyl, 5-, 6-,
9- or 10- membered heteroaryl, C3 to Cs-cycloalkyl, Ci-Cs-alkyl and 5- to 8-membered heterocycloalkyi; wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R1 d groups; and wherein said C3 to Cs-cycloalkyl, Ci-Ce-alkyI and 5- to 8-membered heterocycloalkyi is optionally substituted with from 1 to 5 independently selected R1 e groups; provided that R1 a, R1 b and R1 c are not each unsubstituted phenyl;
R2a, R2b and R2c are each independently selected from H and Ci-C6-alkyl;
R3a is independently selected from: H, Ci-C6-alkyl or C(0)-Ci-C6-alkyl;
R3b and R3c are each independently selected from: H and C(0)-Ci-C6-alkyl;
R4a and R4b are each independently selected from: H, Ci-C6-alkyl or C(0)-Ci-C6-alkyl; or R4a and R4b together from C(O);
R5 is independently at each occurrence selected from H and Ci-C6-alkyl;
R6 and R1 1 are independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci- Ce-alkyl and S(0)2-Ci-C6-alkyl;
R7 is independently at each occurrence selected from H, Ci-C4-alkyl and halo;
R8 is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C2-C6- alkenyl, Ci-C6-haloalkyl, OR9, SR10, N R10R1 1 , C(0)OR1°, C(O)N R10R10, halo, cyano, nitro, C(0)R10, S(0)2OR10, S(0)2R10 S(0)R, OC(O)N R10R10, N R10C(O)OR10 and S(O)2N R10R10; R9 is independently at each occurrence selected from: H, Ci-C6-alkyl and Ci-C6-haloalkyl;
R10 is independently at each occurrence selected from: H and Ci-C6-alkyl;
R1 1 is independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci-C6-alkyl and S(0)2-Ci-C6-alkyl;
R1 d is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C2-C6- alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyi, 5-, 6-, 9- or
10- membered heteroaryl, phenyl, OR9, SR10, N R10R1 1 , C(0)OR1°, C(O)N R10R10, halo, cyano, nitro, C(0)R10, S(0)2OR10, S(0)Ri S(0)2R10, S(O)2N R10R10, OC(O)N R10R10 and N R10C(O)OR10;
R1 e is independently at each occurrence selected from: oxo, Ci-C6-alkyl, C2-C6-alkynyl, C2- C6-alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyi, 5-, 6-, 9- or 10- membered heteroaryl, phenyl, OR9, SR10, N R10R1 1 , C(0)OR1°, C(O)N R10R10, halo, cyano, nitro, C(0)R10, S(0)2OR10, S(0)Ri S(0)2R10, S(O)2NR10R10, OC(O)NR10R10 and NR10C(O)OR10;
and wherein any of the abovementioned alkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyi, 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-C6-alkenyl, Ci-C6-haloalkyl, ORa, NRaRb, SRa, C(0)ORa, C(0)NRaRa, halo, cyano, nitro, C(0)Ra, S(0)2ORa, 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.
[0015] 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.
[0016] For the absence of doubt the atom length of the linkers formed by L1, L2, L3 L4 and L5 is the number of atoms in a straight chain from the phosphorous atom of the phosphonium to the oxygen or nitrogen atom via which the linker is attached to the azithromycin portion of the molecules. The length does not include any substituents or branching that might be present on the chain.
[0017] For the absence of doubt where a bivalent group (e.g. L1, L2, L3, L4, L5 or a combination thereof) is represented in text, the left hand portion of the linker group is attached, either directly or indirectly, to the carbon or nitrogen atom via which the linker is attached to the azithromycin portion of the ions and the right hand portion of the linker group is attached, either directly or indirectly, to the phosphorous atom of the
phosphonium.
[0018] In embodiments the ion of formula (I) is an ion of formula (II):
Figure imgf000011_0001
[0019] In embodiments, the ion of formula (I) is an ion of formula (III):
Figure imgf000011_0002
[0020] In embodiments, the ion of formula (I) is an ion of formula (IV):
Figure imgf000012_0001
. Typically, L7 is a C2-C13- alkylene group optionally substituted with from 0 to 10 R8 groups. [0021] In embodiments, the ion of formula (I) is an ion of formula (V):
Figure imgf000012_0002
Ci5-alkylene group optionally substituted with from 0 to 10 R8 groups.
[0022] 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. [0023] 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 R1d groups, and wherein said C3 to Cs-cycloalkyl is optionally substituted with from 1 to 5 independently selected R1e 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 from 1 to 5 independently selected R1d groups, and wherein said cyclohexyl group is optionally substituted with from 1 to 5 independently selected R1e 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, pyridyl and cyclohexyl, wherein said phenyl, biphenyl and pyridyl is optionally substituted with 1 to 3 independently selected R1d groups, and wherein said cyclohexyl group is optionally substituted with 1 to 3 independently selected R1e 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, 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 R1d 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, optionally substituted with from 1 to 5 independently selected R1d 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 independently selected R1d groups, provided that R1a, R1b and R1c are not each unsubstituted phenyl.
[0029] In embodiments, R1a, R1b and R1c are each independently selected from phenyl; wherein said phenyl is optionally substituted with from 1 , 2 or 3 R1d groups; provided that R1a, R1b and R1c are not each unsubstituted phenyl.
[0030] In embodiments, R1a, R1b and R1c are each independently selected from C3 to Cs cycloalkyl, d-Cs-alkyl and 4- to 8- membered heterocycloalkyl; wherein said C3 to Cs cycloalkyl, d-Cs-alkyl and 4- to 8- membered heterocycloalkyl is optionally substituted with from 1 to 5 independently selected R1e groups. [0031] In embodiments, R1a, R1b and R1c are each independently selected from C3 to Cs cycloalkyi, d-Cs-alkyl and 5- to 8- membered heterocycloalkyi; wherein said C3 to Cs cycloalkyi, Ci-Cs-alkyl and 5- to 8- membered heterocycloalkyi is optionally substituted with from 1 to 5 independently selected R1e groups.
[0032] In embodiments R1a, R1b and R1c are different or the same.
[0033] In embodiments, R1e is independently at each occurrence selected from Ci-dr alkyl, halo, OR9, NR10R11 and S(0)2OR1°.
[0034] In embodiments, R1e is independently at each occurrence selected from OCH3, OCH2(CH3)2, N(CH3)2, S02OH, F and CI.
[0035] 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 R1d groups, wherein R1d is independently at each occurrence selected from Ci-C6-alkyl, halo, OR9, NR10R11 and S(0)2OR10.
[0036] 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 R1d groups, wherein R1d is independently at each occurrence selected from OCH3, OCH2(CH3)2, N(CH3)2, S02OH, F and CI.
[0037] In embodiments, R1a is C3 to Cs-cycloalkyl, R1b is C3 to Cs-cycloalkyl and R1c is C3 to Cs-cycloalkyl. [0038] 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
heterocycloalkyi.
[0039] 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 5- to 8-membered
heterocycloalkyi.
[0040] In embodiments, R1a and R1b are each unsubstituted phenyl and R1c is substituted phenyl.
[0041] In embodiments, R1a and R1b are each unsubstituted phenyl and R1c is pyridyl. [0042] 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, d-Cs-alkyl and 4- to 8-membered heterocycloalkyi.
[0043] 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, d-Cs-alkyl and 5- to 8-membered heterocycloalkyi.
[0044] In embodiments, R1a and R1b are each cyclohexyl and R1c is substituted biphenyl.
[0045] 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.
[0046] In embodiments, R1a R1a, R1b and R1c are each C3 to Cs-cycloalkyl. In
embodiments, R1a, R1b and R1c are each cyclohexyl.
[0047] In embodiments, R1a R1a, R1b and R1c are each benzyl. [0048] In embodiments, at least one of R1a, R1b and R1c is 5-, 6-, 9- or 10- membered heteroaryl or 4- to 8-membered heterocycloalkyi. 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 heterocycloalkyi. In embodiments, at least one of R1a, R1b and R1c is 5-, 6-, 9- or 10- membered heteroaryl or 4- to 8-membered heterocycloalkyi, wherein said heteroaryl or heterocycloalkyi 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 heterocycloalkyi, wherein said heteroaryl or heterocycloalkyi 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.
[0049] In embodiments, at least one of R1a, R1b and R1c is 5-, 6-, 9- or 10- membered heteroaryl or 5- to 8-membered heterocycloalkyi. It may be that a single one of R1a, R1b and R1c is 5-, 6-, 9- or 10- membered heteroaryl or 5- to 8-membered heterocycloalkyi. In embodiments, at least one of R1a, R1b and R1c is 5-, 6-, 9- or 10- membered heteroaryl or 5- to 8-membered heterocycloalkyi, wherein said heteroaryl or heterocycloalkyi 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 5- to 8-membered heterocycloalkyi, wherein said heteroaryl or heterocycloalkyi 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.
[0050] 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.
[0051] It may be that R1a and R1b are connected to each other via a bond or a group selected from -0-, NR6a, 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-, NR6a, 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. [0052] It may be that R1a and R1b are not connected to each other via a bond or a group selected from -0-, NR6a, and Ci-C3-alkylene.
[0053] In embodiments, -+PR1aR1bR1c is selected from
Figure imgf000017_0001
Figure imgf000018_0001
[0054] In embodiments, R2a is Ci-C6 alkyl.
[0055] In embodiments, R2c is Ci-C6 alkyl.
[0056] In embodiments, R2a is Ci-C6 alkyl and R2c is Ci-C6 alkyl. [0057] n embodiments, R2b is C1-C6 alkyl.
[0058] n embodiments, R2a is Ci-C6 alkyl, R2 is Ci-C6 alkyl and R2c is Ci-C6 alkyl.
[0059] n embodiments, R2a is methyl.
[0060] n embodiments, R2c is methyl.
[0061] n embodiments, R2a is methyl and R2c is methyl.
[0062] n embodiments, R2b is methyl.
[0063] n embodiments, R2a is methyl, R2b is methyl and R2c is methyl.
[0064] n embodiments R2a and R2b are each independently selected from is H and methyl.
[0065] n embodiments, R3a is H.
[0066] n embodiments, R3b is H.
[0067] n embodiments, R3b is C(0)CH3.
[0068] n embodiments, R3a is H and R3 is H.
[0069] n embodiments, R3a is H and R3b is C(0)CH3.
[0070] n embodiments, R3c is selected from H and C(0)CH3.
[0071] n embodiments, R3c is H.
[0072] n embodiments, R3c is C(0)CH3.
[0073] n embodiments, R4a is H.
[0074] n embodiments, R4b is H.
[0075] n embodiments, R4a is H and R4 is H.
[0076] n embodiments, R4a and R4b together form C(O).
[0077] n embodiments, R4a and R4b together form C(O) and R3b is C(0)CH3. In embodiments, R4a and R4 together form C(O) and R3b is H. In embodiments, R4a and R' are each H and R3b is H.
[0078] In embodiments, R5 is at any particular occurrence H. In embodiments, R5 is at each occurrence H.
[0079] In embodiments, R5 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R5 is at each occurrence Ci-C4-alkyl, e.g. methyl. [0080] In embodiments, R6 is at any particular occurrence H. In embodiments, R6 is at each occurrence H.
[0081] In embodiments, R6 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R6 is at each occurrence Ci-C4-alkyl, e.g. methyl. [0082] In embodiments, R7 is at any particular occurrence H. In embodiments, R7 is at each occurrence H.
[0083] In embodiments, L2 and L4 are unsubstituted.
[0084] In embodiments, R8 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R8 is at each occurrence Ci-C4-alkyl, e.g. methyl. [0085] In embodiments, R9 is at any particular occurrence H. In embodiments, R9 is at each occurrence H.
[0086] In embodiments, R9 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R9 is at each occurrence Ci-C4-alkyl, e.g. methyl.
[0087] In embodiments, R10 is at any particular occurrence H. In embodiments, R10 is at each occurrence H.
[0088] In embodiments, R10 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R10 is at each occurrence Ci-C4-alkyl, e.g. methyl.
[0089] In embodiments, R11 is at any particular occurrence H. In embodiments, R11 is at each occurrence H. [0090] In embodiments, R11 is at any particular occurrence Ci-C4-alkyl, e.g. methyl. In embodiments, R11 is at each occurrence Ci-C4-alkyl, e.g. methyl.
[0091] In embodiments, R4a is H, R4b is H, R2a is Ci-C6 alkyl, R2b is Ci-C6 alkyl and R2c (when present) is C1-C6 alkyl.
[0092] In embodiments, R4a is H, R4b is H, R2a is Ci-C6 alkyl, R2b is Ci-C6 alkyl, R2c (when present) is Ci-C6 alkyl and R3c is H.
[0093] In embodiments, R4a and R4b together form C(O), R2a is Ci-C6 alkyl, R2b is Ci-C6 alkyl and R2c (when present) is C1-C6 alkyl. [0094] In embodiments, R4a is H, R4b is H, R2a is Ci-C6 alkyl, R2b is Ci-C6 alkyl, R2c (when present) is Ci-C6 alkyl, R3a is H and R3b is H or C(0)CH3.
[0095] In embodiments, R4a and R4b together form C(O), R2a is Ci-C6 alkyl, R2b is Ci-C6 alkyl, R2c (when present) is Ci-C6 alkyl, R3a is H and R3b is H or C(0)CH3.
[0096] In embodiments, R4a and R4b together form C(O), R2a is Ci-C6 alkyl, R2b is Ci-C6 alkyl, R2c (when present) is Ci-C6 alkyl, R3a is H, R3b is H or C(0)CH3 and R3c is H.
[0097] In embodiments, R4a is H, R4b is H, R2a is methyl, R2b is methyl and R2c (when present) is methyl.
[0098] In embodiments, R4a and R4b together form C(O), R2a is methyl, R2b is methyl and R2c (when present) is methyl.
[0099] In embodiments, R4a is H, R4b is H, R2a is methyl, R2b is methyl and R2c (when present) is methyl, R3a is H and R3b is H or C(0)CH3.
[00100] In embodiments, R4a and R4b together form C(O), R2a is methyl, R2b is methyl and R2c (when present) is methyl, R3a is H and R3b is H or C(0)CH3.
[00101] In embodiments, R4a and R4b together form C(O), R2a is methyl, R2b is methyl and R2c (when present) is methyl, R3a is H, R3b is H or C(0)CH3 and R3c is H.
[00102] In embodiments, R4a is H, R4b is H, R2a is Ci-C6 alkyl, R2b is Ci-C6 alkyl, R2c (when present) is C1-C6 alkyl.
[00103] In embodiments, R4a and R4b together form C(O), R2a is Ci-C6 alkyl, R2b is Ci-C6 alkyl, R2c (when present) is Ci-C6 alkyl.
[00104] In embodiments, R4a is H, R4b is H, R2a is Ci-C6 alkyl, R2b is Ci-C6 alkyl, R2c (when present) is Ci-C6 alkyl, R3a is H, R3b is H or C(0)CH3.
[00105] In embodiments, R4a and R4b together form C(O), R2a is Ci-C6 alkyl, R2b is Ci-C6 alkyl, R2c (when present) is Ci-C6 alkyl, R3a is H, R3b is H or C(0)CH3.
[00106] In embodiments, R4a is H, R4b is H, R2a is methyl, R2b is methyl and R2c (when present) is methyl, R3a is H, R3b is H or C(0)CH3.
[00107] In embodiments, R4a is H, R4b is H, R2a is methyl, R2b is methyl and R2c (when present) is methyl, R3a is H, R3b is H.
[00108] In embodiments, R4a and R4b together form C(O), R2a is methyl, R2b is methyl and R2c is methyl, R3a is H, R3b is H or C(0)CH3.
[00109] In embodiments, R4a and R4b together form C(O), R2a is methyl, R2b is methyl and R2c is methyl, R3a is H, R3b is H. [00110] In embodiments R3a, R3b and R3c are each H.
[00111] In embodiments, L1 is selected from -C(O)- and -S(0)2-.
[00112] In embodiments, L1 is -C(O)-.
[00113] In embodiments, L1 is absent. [00114] In certain embodiments, L3 is at each occurrence absent. Thus, the group -L2- (L3-L4)n- may form an alkylene linker group.
[00115] 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.
[00116] In certain embodiments, L3 is at each occurrence -NR5C(0)-, -C(0)NR5. 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-. [00117] In embodiments, L1, L2, L3, L4 and n are selected such that length of the linker formed by those groups is from 8 to 14 atoms.
[00118] In embodiments Z2 is:
Figure imgf000022_0001
and Z1 is R2c; wherein L7 is a C2-Ci3-alkylene group optionally substituted with from 0 to 10 R8 groups. L7 may be a Cs-Cn-alkylene group optionally substituted with from 0 to 10 R8 groups. L7 may be unsubstituted.
[00119] In specific embodiments, -L5-L2-(L3-L4)n- represents -OC(0)N H(CH2)io-, - OC(0)N H(CH2)8-, -OC(0)N H(CH2)6-, -OC(0)N H (CH2)n-, -OC(0)N H (CH2)9-, - OC(0)NH(CH2)7-, or -OC(0)NH(CH2)5-.
[00120] In specific embodiments, -L5-L2-(L3-L4)n- represents -OC(0)N H(CH2)i
OC(0)NH(CH2)8-, or -OC(0)NH(CH2)6-. [00121] In embodiments, L5 is selected from -O-C(O)- and -OC(0)NR5-. In
embodiments, L5 is-OC(0)NR5-, e.g. OC(0)NH-.
[00122] In certain embodiments, L3 is at each occurrence absent. Thus, the group -L2- (L3-L4)n- may form an alkylene linker group. [00123] 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 a, ethylene glycol, polyethyleneglycol, propyleneglcyol or polypropylene glycol linker group. [00124] In certain embodiments, L3 is at each occurrence -NR5C(0)-, -C(0)NR5. 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-.
[00125] In embodiments, L5, L2, L3, L4 and n are selected such that length of the linker formed by those groups is from 8 to 14 atoms.
[00126] In embodiments Z1 is:
Figure imgf000023_0001
and Z2 is OR3c; wherein L6 is a C2-Cis-alkylene group optionally substituted with from 0 to 10 R8 groups. L6 may be a C7-Ci3-alkylene group optionally substituted with from 0 to 10 R8 groups. L6 may be unsubstituted.
[00127] In embodiments n is an integer selected from 0 or 1 .
[00128] In an embodiment of the invention the ion of formula (I) is an ion selected from:
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000026_0002
Figure imgf000026_0003
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
[00130] 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. CI, Br and I), BF4, PF6, CF3C(0)0, HC(0)0, HC03, (CF3S02)2N, (C2F5)3PF3! HS04, 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, C1-C12- 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).
[00131] 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.
[00132] In embodiments the anion is CI, 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.
[00133] 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.
[00134] 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.
[00135] 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.
[00136] 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.
[00137] 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).
[00138] 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.
[00139] 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.
[00140] 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.
[00141] 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.
[00142] 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.
[00143] The present invention also encompasses the subject matter of the following numbered clauses:
1 . A compound comprising an ion of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000039_0001
wherein either Z1 is
Figure imgf000039_0002
or Z2 is
Figure imgf000039_0003
-L1- is independently absent or is selected from -C(O)-, -C(0)0-, -S(0)2-, -S(O)-, - C(0)NR5, and -S(0)2NR5-;
-L3- is independently at each occurrence either absent or selected from: -0-, -S-, - NR6-, -C(O)-, -OC(O)-, -C(0)0-, -S(0)2-, -S(O)-, -NR5C(0)-, -C(0)NR5, -NR5S(0)2-, - S(0)2NR5-, -OC(0)NR5-, -NR5C(0)0-, -NR5C(0)NR5, -CR7=CR7- and -C≡C-; -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 R6 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-;
-L5- is independently selected from: -0-, -S-, -N R6-, -OC(O)-, -N R5C(0)-, N R5S(0)2-, - OC(0)N R5-, -N R5C(0)0- and N R5C(0)N R5;
n is an integer selected from 0, 1 , 2, 3 and 5;
wherein L1, L2, L3, L4, L5 and n are selected such that length of the linker formed by those groups is from 3 to 16 atoms;
R1 a, R1 b and R1 c are each independently selected from phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl, C3 to Cs-cycloalkyl, Ci-Cs-alkyl and 5- to 8- membered heterocycloalkyi; wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R1 d groups; and wherein said C3 to Cs-cycloalkyl, Ci-Cs-alkyl and 5- to 8-membered heterocycloalkyi is optionally substituted with from 1 to 5 independently selected R1 e groups; provided that R1 a, R1 b and R1 c are not each unsubstituted phenyl;
R2a, R2b and R2c are each independently selected from H and Ci-C6-alkyl;
R3a is independently selected from: H, Ci-Ce-alkyI or C(0)-Ci-Ce-alkyl;
R3b and R3c are each independently selected from: H and C(0)-Ci-C6-alkyl;
R4a and R4b are each independently selected from: H, Ci-Ce-alkyI or C(0)-Ci-Ce-alkyl; or R4a and R4b together from C(O);
R5 is independently at each occurrence selected from H and Ci-C6-alkyl;
R6 and R1 1 are independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci-C6-alkyl and S(0)2-Ci-C6-alkyl;
R7 is independently at each occurrence selected from H, Ci-C4-alkyl and halo;
R8 is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C2- Ce-alkenyl, Ci-C6-haloalkyl, OR9, SR10, N R10R1 1 , C(0)OR1°, C(O)N R10R10, halo, cyano, nitro, C(0)R10, S(0)2OR1°, S(0)2R1° S(0)R, OC(O)N R10R10, N R10C(O)OR10 and S(O)2N R10R10;
R9 is independently at each occurrence selected from: H, Ci-C6-alkyl and C1-C6- haloalkyl; R10 is independently at each occurrence selected from: H and Ci-C6-alkyl;
R11 is independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci-C6-alkyl and S(0)2-Ci-C6-alkyl;
R1d is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C2- C6-alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyi, 5-, 6-
, 9- or 10- membered heteroaryl, phenyl, OR9, SR10, NR10R11 , C(0)OR1°,
C(O)NR10R10, halo, cyano, nitro, C(0)R10, S(0)2OR1°, S(0)Ri S(0)2R1°,
S(O)2NR10R10, OC(O)NR10R10 and N R10C(O)OR10;
R1e is independently at each occurrence selected from: oxo, Ci-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyi, 5-
, 6-, 9- or 10- membered heteroaryl, phenyl, OR9, SR10, NR10R11 , C(0)OR1°,
C(O)NR10R10, halo, cyano, nitro, C(0)R10, S(0)2OR1°, S(0)R10' S(0)2R1°,
S(O)2NR10R10, OC(O)NR10R10 and N R10C(O)OR10;
and wherein any of the abovementioned alkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyi, heteroaryl or phenyl groups is optionally substituted where chemically allowable by from 1 to 4 groups independently selected from oxo, Ci-Ce- alkyI, C2-C6-alkynyl, C2-C6-alkenyl, Ci-C6-haloalkyl, ORa, NRaRb, SRa, C(0)ORa, C(0)NRaRa, halo, cyano, nitro, C(0)Ra, S(0)2ORa, 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. . The compound of clause 1 , wherein Z1 is
Figure imgf000041_0001
and Z2 is OR3c, preferably wherein R3c is H. . The compound of clause 2, wherein L1 is -C(O)-. . The compound of clause 2, wherein L1 is absent. . The compound of clause 1 , wherein Z2 is
Figure imgf000041_0002
and Z1 is R2c, preferably wherein R2c is methyl. 6. The compound of clause 5, wherein L5 is -OC(O)-.
7. The compound of any one of clauses 1 to 6, wherein L3 is at each occurrence absent.
8. The compound of any one of clauses 1 to 7, wherein L1, L2, L3, L4, L5 and n are selected such that length of the linker formed by those groups is from 8 to 14 atoms. 9. The compound of any one of clauses 1 to 8, wherein R2a is C1-C6 alkyl, preferably methyl.
10. The compound of any one of clauses 1 to 9, wherein R2b is C1-C6 alkyl, preferably methyl.
1 1. The compound of any one of clauses 1 to 10, wherein R3a is H and R3b is H or C(0)CH3.
12. The compound of any one of clauses 1 to 1 1 , wherein R4a and R4b are each H.
13. The compound of any one of clauses 1 to 1 1 , wherein R4a and R4b together form C(O).
14. A compound of any one of clauses 1 to 13, wherein R1a, R1b and R1c are each substituted phenyl.
15. A compound of any one of clauses 1 to 13, wherein R1a, R1b and R1c are each C3 to Cs-cycloalkyl. 16. A compound of any one of clauses 1 to 13, wherein R1a, R1b and R1c are each benzyl.
17. A compound of any one of clauses 1 to 13, 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, Ci-Cs-alkyl and 5- to 8-membered heterocycloalkyi. 18. A compound of any one of clauses 1 to 13, wherein 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, Ci-Cs-alkyl and 5- to 8-membered heterocycloalkyi. 19. A compound of any one of clauses 1 to 13, wherein at least one of R1a, R1 b and R1c is d-Ce-alkyl.
20. A compound of clause 19, wherein any of R1a, R1 b and R1c that are not Ci-C6-alkyl are phenyl. 21 . The compound of clauses 1 to 20 for use as a medicament.
22. The compound of clauses 1 to 20 for use in the treatment of cancer.
23. 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 clauses 1 to 20. 24. A pharmaceutical composition comprising the compound of clauses 1 to 20 and one or more pharmaceutically acceptable excipients.
DETAILED DESCRIPTION
[00144] 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.
[00145] 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 CI and F. "Halo" or "halogen" may refer to fluorine.
[00146] The term "alkyl" refers to a linear or branched hydrocarbon chain. The term "Ci- 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.
[00147] 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.
[00148] The term "cycloalkyl" refers to a saturated hydrocarbon ring system. The term "C3-C8 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.
[00149] 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.
[00150] 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.
[00151] 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. [00152] 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.
[00153] The term "heteroalkyi" 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 heteroalkyi" 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 heteroalkyi may be attached to another group by the heteroatom or the carbon atom. The term "Ci- C6 heteroalkyi" may refer to, for example, -CH2NHCH3, -NHCH2CH3 and -CH2CH2NH2. The heteroalkyi group may be unsubstituted or substituted by one or more substituents.
[00154] The term "heterocycloalkyi" refers to a saturated hydrocarbon ring system containing at least one heteroatom within the ring system selected from N, O and S. The term "5- to 8- membered heterocycloalkyi" refers to a saturated hydrocarbon ring with 5, 6, 7, 8, 9 or 10 atoms selected from carbon, N, O and S, at least one being a heteroatom. The "heterocycloalkyi" group may also be denoted as a "3 to 10 membered
heterocycloalkyi" 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 tricyclic 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 "heterocycloalkyi" may be bonded to the rest of the molecule through any carbon atom or heteroatom. The "heterocycloalkyi" 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 "heterocycloalkyi" may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine,
thiomorpholine, piperazine, tetrahydropyran, and chromane. [00155] 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.
[00156] 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.
[00157] 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.
[00158] 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.
[00159] A bond terminating in a " " 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.
[00160] 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)ORa,
C(0)NRaRa, halo, cyano, nitro, C(0)Ra, S(0)2ORa, 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.
[00161] If chemically possible to do so, a cyclic substituent may be substituted on a group so as to form a spiro-cycle.
[00162] 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.
[00163] 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
the bond ending in "
Figure imgf000047_0001
[00164] "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 imgf000048_0001
[00165] "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 exam le the groups below are para substituted.
Figure imgf000048_0002
[00166] 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.
[00167] 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 trifluoroacetate salts.
[00168] 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).
[00169] The salt may be an acid addition salt.
[00170] The salts may be formate or hydrochloride. [00171] 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.
[00172] 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.
[00173] 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.
[00174] 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).
[00175] 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.
[00176] Hereinafter all references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
[00177] 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.
[00178] 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.
[00179] 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.
[00180] 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.
[00181] 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.
[00182] 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 (CI 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.
[00183] 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.
[00184] 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.
[00185] 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.
[00186] 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.
[00187] 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. [00188] 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.
[00189] 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.
[00190] 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 ( g/kg) to 100 milligrams per kilogram body weight (mg/kg).
[00191] 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.
[00192] 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.
[00193] 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.
[00194] 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.
[00195] 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.
[00196] For intravenous (parenteral) administration the compounds of the invention may be administered as a sterile aqueous or oily solution.
[00197] 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.
[00198] 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. [00199] 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.
[00200] 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.
[00201] 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
[00202] 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.
[00203] Compound (1 ) and compound (29) may be prepared by the procedure described in European Journal of Medicinal Chemistry 40, 201 1 , 5196. Compound (9) and compound (24) may be prepared by the procedure described in WO2004/101590.
[00204] Certain ions of formula (I) can be made by Scheme A.
Figure imgf000057_0001
Scheme A
[00205] Reaction of imidazolecarboxylate (1 ) with phosphonium amine (2) (L7 is a C2-C13- alkylene group optionally substituted with from 0 to 10 R8 groups) can furnish
phosphonium carbamate (3). The reaction can be performed in the presence of a non- nucleophilic base, such as DBU, in an organic solvent, such as DMF, at room
temperature.
[00206] Phosphonium amine (2) can be furnished by Scheme B.
Figure imgf000058_0001
Scheme B
[00207] Reaction of halo isoindoline-1 ,3-dione (4) (where X = CI or Br) with phosphine (5) can deliver phosphonium isoindoline-1 ,3-dione (6). The reaction can be performed by heating in an organic solvent, such as MeCN, at a temperature from 50 to 80 °C. Reaction of the phosphonium isoindoline-1 ,3-dione (6) with hydrazine hydrate in an alcoholic solvent, such as EtOH, at a temperature from 50 to 75 °C can furnish phosphonium amine (2).
[00208] Certain ions of formula (I) can be made by Scheme C.
Figure imgf000059_0001
Scheme C
[00209] Deprotection of the cyclic carbonate and acetate in (3) (prepared as described in Scheme A) to give (7) can be accomplished by base, such as K2CO3, in a H20/MeOH mixed solvent, at a temperature of 25 to 50 °C.
[00210] Certain ions of formula (I) can be made by Scheme D.
Figure imgf000060_0001
Scheme D
[00211] Selective removal of the acetate in (3) (prepared as described in Scheme A) to give cyclic carbonate (8) can be accomplished by heating in an alcoholic solvent, such as MeOH, at a temperature from 50 to 65 °C.
[00212] Certain ions of formula (I) can be made by Scheme E.
Figure imgf000061_0001
(12)
Scheme E
[00213] Reaction of amine (9) with phosphonium acid (1 1 )(L8 is a C2-Ci4-alkylene group optionally substituted with from 0 to 10 R8 groups) can furnish phosphonium amide (12). The reaction can be performed using standard peptide coupling agents, such as 1 ,3- dicyclohexylcarboiimide (DCC), in a chlorinated solvent, such as DCM at room temperature. Addition of DMAP is optional. Phosphonium acid (1 1 ) can be prepared from reaction of halide (10) (X = CI or Br) with phosphine PR1aR1bR1c (5). The reaction can be accomplished by heating in an organic solvent, such as MeCN at a temperature from 50 to 80 °C. [00214] Certain ions of formula (I) can be made by Scheme F.
Figure imgf000062_0001
(19)
Scheme F
[00215] Cyclic carbonate protection of amine (9) to give (13) can be accomplished by reaction with ethylene carbonate in the presence of a base, such as K2CO3, in an organic solvent, such as toluene, at a temperature of 70 to 100 °C. Cyclic carbonate amine (13) can be transformed to phosphonium amide (14). The reaction can be performed using phosphonium acid (1 1 ) and standard peptide coupling agents, such as 1 ,3- dicyclohexylcarboiimide (DCC), in DMS, at room temperature. Addition of DMAP is optional.
Figure imgf000063_0001
Scheme G [00217] Reaction of amine (9) with halo sulphonic acid (15) (where X = CI or Br; and where (L9 is a C2-Ci4-alkylene group optionally substituted with from 0 to 10 R8 groups)) can furnish halo sulphonamide (16). The reaction can be performed using SOC in an organic solvent, such as DMF or DCM, at a temperature from 20 to 60 °C. Reaction of phosphine (5) with halo sulphonamide (16) can deliver phosphonium sulphonamide (17). The reaction can be accomplished by heating in an organic solvent, such as MeCN at a temperature from 50 to 80 °C.
[00218] Replacement of amine (9) in Scheme G with cyclic carbonate amine (13) can provide phosphonium sulphonamide (18), a subset of ions of formula (I).
Figure imgf000064_0001
[00219] Certain ions of formula (I) can be made by Scheme H.
Figure imgf000065_0001
(19)
Scheme H
[00220] Reaction of amine (9) with phosphonium chlorocarbonate (22) (L10 is a C2-C13- alkylene group optionally substituted with from 0 to 10 R8 groups) can furnish
phosphonium carbamate (19). The reaction can be accomplished in the presence of a base, such as pyridine, in an organic solvent, such as DCM, at a temperature from 0 °C to room temperature. Phosphonium chloroacetate (22) can be synthesised from
phosphonium alcohol (21 ) through treatment with triphosgene in the presence of a base, such as DIEA, in an organic solvent, such as THF, at a temperature from -5 to 5 °C. Phosphonium alcohol (21 ) can be synthesised from halo alcohol (20) (where X = CI or Br) and phosphine PR1aR1bR1c (5). The reaction can be accomplished by heating in an organic solvent, such as MeCN, at a temperature from 50 to 80 °C
[00221] Replacement of amine (9) in Scheme H with cyclic carbonate amine (13) can provide phosphonium carbamate (23), a subset of ions of formula (I).
Figure imgf000066_0001
[00222] Replacement of amine (9) in Scheme E, F, G and H with isomer amine (24) can provide phosphonium ions (25), (26), (27) and (28), which represent a subset of ions of formula (I).
Figure imgf000067_0001
[00223] Certain ions of formula (I) can be made by Scheme I.
Figure imgf000068_0001
Scheme I
[00224] Reaction of alcohol (29) with phosphonium acid (30) (L11 is a C2-Ci4-alkylene group optionally substituted with from 0 to 10 R8 groups) can furnish phosphonium ester (31 ). The reaction can be performed using standard coupling agents for ester formation, such as N-(3-dimethylaminopropyl)-N-ethylcarbodiimide.HCI (EDAC.HCI) in the presence of DMAP, in an organic solvent, such as DCM, at room temperature.
[00225] Certain ions of formula (I) can be made by Scheme J.
Figure imgf000069_0001
Scheme J
[00226] Selective removal of the acetate in (31 ) to give cyclic carbonate (32) can be effected by heating in an alcoholic solvent, such as MeOH, at a temperature from 25 to 50 °C. Deprotection of the cyclic carbonate in (32) to give phosphonium ester (33) can be performed in the presence of a base, such as K2CO3, in an alcoholic solvent, such as MeOH, at a temperature from 25 to 80 °C. Scheme K
Certain ions of formula (V) can be made by Scheme K
Figure imgf000070_0001
(35) Scheme K
Amide bond formation between amine (34) and phosphonium carboxylic acid (36) can deliver phosphonium amide (35). The reaction can be effected by standard peptide coupling reagents, such as HATU or TATU or 1 ,3-dicyclohexylcarboiimide (DCC) in the presence of HOAT, in the presence of a base, such as Ν,Ν-diisopropylethylamine (DIEA), in an organic solvent, such as DCM, at a temperature of 25 to 40 °C
Experimental
[00227] Analytical methods
[00228] NMR spectra were obtained on a 400 MHz Bruker AV III
[00229] UPLC/MS was carried out using a Waters Acquity QDa mass detector and Methods A, I, J or Waters SQ mass detector and Methods B, C, D, E, F, H or Agilent 6120 MSD and Method G
[00230] Method A
[00231] Column: Waters Acquity UPLC CSH C18, 1 .7 μηΐ, 2.1 x 30 mm; Gradient Eluent: 5-95% MeCN/H20 containing 0.1 % HCOOH; Time: 0-10 min
[00232] Method B
[00233] Column: Waters Acquity UPLC CSH C18, 1 .7 μηη, 2.1 x 50 mm; Gradient Eluent: 2-98% MeCN/H20 containing 0.02% HCOOH; Time: 0-4.5 min
[00234] Method C
[00235] Column: Waters Acquity UPLC CSH C18, 1 .7 μιτι, 2.1 x 50 mm; Gradient Eluent: 2-98% MeCN containing 0.035% TFA H20 containing 0.05% TFA; Time: 0-4.5 min
[00236] Method D
[00237] Column: Waters Acquity UPLC CSH C18, 1 .7 μιτι, 2.1 x 100 mm; Gradient
Eluent: 2-98% MeCN containing 0.035% TFA H20 containing 0.05% TFA; Time: 0-15 min
[00238] Method E
[00239] Column: Waters Acquity UPLC BEH C18, 1 .7 μιη, 2.1 x 30 mm; Gradient Eluent: 5-95% MeCN/H20 containing 10 mM (NH4)2C03; Time: 0-3 min
[00240] Method F
[00241] Column: Waters Acquity UPLC CSH C18, 1 .7 μίπ, 2.1 x 50 mm; Gradient Eluent: 2-100% MeCN containing 0.035% TFA/H20 containing 0.05% TFA; Time: 0-3 min
[00242] Method G
[00243] Column: Waters Acquity UPLC CSH C18, 2.5 μηη, 4.6 x 30 mm; Gradient Eluent: 5-95% MeCN/H20 containing 0.1 % HCOOH; Time: 0-3 min [00244] Method H
[00245] Column: Waters Acquity UPLC BEH C18, 1.7 μηι, 2.1 x 30 mm; Gradient Eluent: 5-95% MeCN/h O containing 10 mM (NH4)2C03; Time: 0-15 min
[00246] Method I [00247] Column: Waters Acquity UPLC BEH C18, 1.7 m, 2.1 x 30 mm; Gradient Eluent: 5-95% MeCN/H20 containing 10 mM (NH4)2C03; Time: 0-3 min
[00248] Method J
[00249] Column Waters Acquity UPLC CSH C18, 1.7 m, 2.1 x 30 mm; Gradient Eluent: 5-95% MeCN/H20 containing 0.1 % HCOOH; Time: 0-3 min [00250] Preparative HPLC was carried out using a ZQ Mass Spectrometer and Method A or Gilson PLC2020 and Method B,C
[00251] Method A
[00252] Waters X-Select Prep-C18, 5 μηΐ, 19 x 50 mm eluting with MeCN/H2O/0.1 % HCOOH
[00253] Method B
[00254] Gemini NX-C18, 10 pm, 30 x 250 mm eluting with a mixture of MeCN/0.035% TFA and H2O/0.05% TFA
[00255] Method C
[00256] Gemini NX-C18, 10 μηη, 50 x 300 mm eluting with a mixture of MeCN/H2O/0.1 % TFA
[00257] The following abbreviations have been used throughout the specification in the examples and the description: dichloromethane (DCM), tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 4-dimethylaminopyridine (DMAP), N,N,diisopropylethylamine (DIEA), trifluoroacetic acid (TFA), 1 ,8-diazabicyclo[5.4.0]undec- 7-ene (DBU), 1 -hydroxy-7-azabenzotriazole (HOAT), 0-(7-azabenzotriazole-1 - yl)N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU), (1-
[Bis(dimethylamino)methyiene]-1 H-1 ,2,3-iriazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU). [00258] Example 1 - (2S,3R,4S,6R)-2-{[(3aR,4R,7 ,8S,9S,10R,11 R,13R,16R,16aR)-4- ethyl-11 -hydroxy-8-{[(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[({8-[tris(4- methoxyphenyl)phosphoniumyl]octyl}carbamoyl)oxy]oxan-2-yl]oxy}- 3a,7,9,11 ,13,15,16-heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 - oxa-6-azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-methyloxan-3-yl acetate bromide
[00259] Γ8-Μ ,3-dioxo-2,3-dihvdro-1 H-isoindol-2-yl)octylltris(4- methoxyphenvQphosphonium bromide
Figure imgf000073_0001
A mixture of 2-(8-bromodecyl)isoindoline-1 ,3-dione (0.91 g, 2.70 mmol) and tris(4- methoxyphenyl)phosphine (1 g, 2.84 mmol) in MeCN (10 mL) was heated at 70 °C overnight. On cooling the solvent was removed in vacuo and the resulting residue purified by column chromatography eluting with 10% MeOH in DCM to give [8-(1 ,3-dioxo-2,3- dihydro-1 H-isoindol-2-yl)octyl]tris(4-methoxyphenyl)phosphonium bromide (1 .56 g, 82%) as a white foam.
1 H NMR (Method A) (DMSO-d6): δ (delta) ppm 7.88-7.81 (4H, m), 7.65 (6H, m), 7.28 (6H, m), 3.88 (9H, s), 3.54 (2H, t), 3.31 (2H, m), 1 .61 -1.36 (6H, m), 1 .23 (6H, m); 31 P NMR (162 MHz, DMSO-d6): δ ppm +21.7 ppm; LC-MS (Method G) 610 [M]+; RT 2.13 min
[00260] (8-aminooctyl)tris(4-methoxyphenyl)phosphonium bromide
Figure imgf000074_0001
To a solution of [8-(1 ,3-dioxo-2,3-dihydro-1 H-isoindol-2-yl)octyl]tris(4- methoxyphenyl)phosphonium bromide (1 .56 g, 2.26 mmol) in EtOH (20 mL) was added anhydrous hydrazine in THF (1 M, 5.65 mL). The resulting reaction mixture was refluxed for 18 h. On cooling the solvent was removed under vacuo and the resulting residue purified by column chromatography eluting with 0-100% EtOAc in DCM followed by 0-10% MeOH in DCM to give (8-aminooctyl)tris(4-methoxyphenylphosphonium bromide (0.65 g, 48%) as a white foam.
1 H NMR (Method A) (DMSO-d6): δ (delta) ppm 7.70-7.63 (6H, m), 7.62 (2H, broad s), 7.29 (6H, m), 3.89 (9H, s), 3.36 (2H, m), 2.78-2.70 (2H, t), 1 .59-1 .35 (6H, m), 1 .20 (6H, m); 31 P NMR (162 MHz, DMSO-d6): δ ppm +21.7 ppm; LC-MS (Method G) 480 [M]+; RT 1 .28 min
[00261 ] (2S,3R,4S,6R)-2-{r(3aR,4R,7R,8S,9S,10R,1 1 R,13R,16R,16aR)-4-ethyl-1 1 - hvdroxy-8-{r(2R.4R.5S,6S)-4-methoxy-4.6-dimethyl-5-r({8-rtris(4- methoxyphenyl)phosphoniumylloctyl)carbamoyl)oxyloxan-2-ylloxy)-3a,7,9,1 1 ,13,15.16- heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3ldioxolo[4,5-cl1 -oxa-6-azacvclopentadecan- 10-vHoxy)-4-(dimethylamino)-6-methyloxan-3-yl acetate bromide
Figure imgf000075_0001
A solution of (2S!3S!4R!6R)-6-{[(3aR!4R!7R!8S!9S!10R,1 1 R,13R,16R,16aR)-10- {[(2S!3R,4S,6R)-3-(acetyloxy)-4-(dimethylamino)-6-methyloxan-2-yl]oxy}-4-ethyl-1 1 - hydroxy-3a,7,9,1 1.I S.I S.ie-heptamethyl^.e-dioxo-tetradecahydro^H-tl .Sldioxolo^.S- c]1 -oxa-6-azacyclopentadecan-8-yl]oxy}-4-methoxy-2,4-dimethyloxan-3-yl 1 H imidazole-1 - carboxylate (prepared as described in European Journal of Medicinal Chemistry 40, 201 1 , 5196) (0.75 g, 0.83 mmol) and (8-aminooctyl)tris(4-methoxyphenylphosphonium bromide (prepared as described in step (b)) (0.65 g, 1 .16 mmol) in DCM (7 mL) was treated with DBU (0.25 mL, 1.66 mmol) and DMAP (2 mg). After stirring at room temperature for 15 h the reaction mixture was quenched with aqueous saturated NaHCC>3 (7 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were dried over Na2S04 and solvent removed under vacuo. The resulting crude residue was purified by column
chromatography eluting with 0-10% MeOH/0.7 M NH3 in DCM to give (2S,3R,4S,6R)-2- {[(3aR,4R,7R,8S,9S,10R,1 1 R,13R,16R,16aR)-4-ethyl-1 1 -hydroxy-8-{[(2R,4R,5S,6S)-4- methoxy-4,6-dimethyl-5-[({8-[tris(4- methoxyphenyl)phosphoniumyl]octyl}carbamoyl)oxy]oxan-2-yl]oxy}-3a,7,9,1 1 ,13,15,16- heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 -oxa-6-azacyclopentadecan- 10-yl]oxy}-4-(dimethylamino)-6-methyloxan-3-yl acetate bromide Example 1 (0.84 g, 71 %) as a white foam.
1 H NMR (Method A) (DMSO-d6): δ (delta) ppm 7.67 (dd, 6H), 7.29 (dd, 6H), 6.95 (t, J = 5.8 Hz, 1 H), 6.77 (s, 1 H), 4.90 (d, J = 4.9 Hz, 1 H), 4.79 (dd, J = 9.4, 3.2 Hz, 1 H), 4.60- 4.50 (m, 2H), 4.39 (d, J = 9.8 Hz, 1 H), 4.29-4.15 (m, 3H), 4.04 (hept, J = 1 .6, 0.8 Hz, 1 H), 3.89 (s, 9H), 3.69-3.57 (m, 1 H), 3.42 (d, J = 6.9 Hz, 1 H), 3.40-3.31 (m, 2H), 3.25 (s, 3H), 3.18-2.99 (m, 1 H), 2.98-2.83 (m, 1 H), 2.82-2.74 (m, 1 H), 2.68-2.58 (m, 1 H), 2.37-2.28 (m, 2H), 2.27-2.20 (m, 1 H), 2.18 (s, 6H), 2.08 (s, 3H), 1 .95 (s, 3H), 1 .92-1 .86 (m, 1 H), 1 .86- 1 .78 (m, 2H), 1.78-1 .64 (m, 2H), 1 .63-1 .53 (m, 1 H), 1 .50-1.40 (m, 6H), 1 .38-1 .30 (m, 4H), 1 .28-1.07 (m, 17H), 1 .06-0.92 (m, 9H), 0.84 (t, J = 7.4 Hz, 9H); 31 P NMR (162 MHz, DMSO-d6) δ +21 .68 (s); LC-MS (Method E) 1323 [M]+; RT 2.24 min
[00262] Example 2 - (2S,3S,4R,6R)-6-{[(2R,3S,4R,5R,8R,10R,11 R,12S,13S,14R)-11 - {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-2-ethyl-3,4,10- trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1 -oxa-6-azacyclopentadecan-13- yl]oxy}-4-methoxy-2,4-dimethyloxan-3-yl N-{8-[tris(4- methoxyphenyl)phosphoniumyl]octyl}carbamate bromide
Figure imgf000076_0001
To a solution of (2S,3R,4S,6R)-2-{[(3aR,4R,7R,8S,9S,10R,1 1 R,13R,16R,16aR)-4-ethyl- 1 1 -hydroxy-8-{[(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[({8-[tris(4- methoxyphenyl)phosphoniumyl]octyl}carbamoyl)oxy]oxan-2-yl]oxy}-3a,7,9,1 1 ,13,15,16- heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 -oxa-6-azacyclopentadecan- 10-yl]oxy}-4-(dimethylamino)-6-methyloxan-3-yl acetate bromide (prepared as described in Example 1 ) (0.28 g, 0.20 mmol) in H20 (1.2 mL) and MeOH (2.5 mL) was added K2C03 (0.28 g, 2.03 mmol). After stirring at 45 °C for 16 h the reaction was allowed to cool to room temperature and solvent was removed under vacuo. The residue was treated with DCM (2 mL) and the resulting suspension filtered through a millipore filter. The resulting filtrate was concentrated under vacuo to give (2S,3S,4R,6R)-6-
{[(2R,3S,4R,5R,8R,10R,1 1 R,12S,13S,14R)-1 1 -{[(2S,3R,4S,6R)-4-(dimethylamino)-3- hydroxy-6-methyloxan-2-yl]oxy}-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl- 15-OXO-1 -oxa-6-azacyclopentadecan-13-yl]oxy}-4-methoxy-2,4-dimethyloxan-3-yl N-{8- [tris(4-methoxyphenyl)phosphoniumyl]octyl}carbamate bromide (0.23 g, 80%) as a white foam.
LC-MS (Method E) 1255.06 [M]+; RT 2.07 min
[00263] Example 3 - (2S,3S,4R,6R)-6-{[(3aR,4R,7 ,8S,9S,10R,11 R,13R,16R,16aR)-10- {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-4-ethyl-11 - hydroxy -3a,7,9,11 ,13, 15,16-heptamethyl-2, 6-dioxo-tetradecahydro-2H- [1 ,3]dioxolo[4,5-c]1 -oxa-6-azacyclopentadecan-8-yl]oxy}-4-methoxy-2,4- dimethyloxan-3-yl N-{8-[tris(4-methoxyphenyl)phosphoniumyl]octyl}carbamate bromide
Figure imgf000077_0001
A solution of (2S!3R!4S!6R)-2-{[(3aR!4R!7R!8S!9S!10R,1 1 R,13R,16R,16aR)-4-ethyl-1 1 - hydroxy-8-{[(2R!4R!5S!6S)-4-methoxy-4,6-dimethyl-5-[({8-[tris(4- methoxyphenyl)phosphoniumyl]octyl}carbamoyl)oxy]oxan-2-yl]oxy}-3a,7,9,1 1 ,13,15,16- heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 -oxa-6-azacyclopentadecan- 10-yl]oxy}-4-(dimethylamino)-6-methyloxan-3-yl acetate bromide (prepared as described in Example 1 ) (0.3 g, 0.21 mmol) in MeOH (3 mL) was heated at 64 °C for 3 h. After cooling to room temperature the solvent was removed under vacuo to give
(2S,3S,4R,6R)-6-{[(3aR,4R,7R,8S,9S,10R,1 1 R,13R,16R,16aR)-10-{[(2S,3R,4S,6R)-4- (dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy]-4-ethyl-1 1 -hydroxy-3a,7,9,1 1 ,13,15,16- heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 -oxa-6-azacyclopentadecan- 8-yl]oxy}-4-methoxy-2,4-dimethyloxan-3-yl N-{8-[tris(4- methoxyphenyl)phosphoniumyl]octyl}carbamate bromide (0.28 g, 85%) as a white foam. LC-MS (Method E) 1281 .97 [M]+; RT 2.10 min Example 4 - (2S,3R,4S,6R)-2-{[(3aR,4R,7 ,8S,9S,10R,11 R,13R,16R,16aR)-4-ethyl-11 - hydroxy-8-{[(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-({[9- (methyldiphenylphosphoniumyl)nonyl]carbamoyl}oxy)oxan-2-yl]oxy}- 3a,7,9,11 ,13,15,16-heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 - oxa-6-azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-methyloxan-3-yl acetate bromide
[9-(1 ,3-dioxo-2,3-dihvdro-IH-isoindol-2-yl)nonvn(me bromide
Figure imgf000078_0001
Prepared following the procedure in Example 1 step (a) using methyldiphenylphosphine. Purification by 0-10% MeOH in DCM.
LC-MS (Method J) 472 [M]+; RT 1.49 min
(9-aminononyl)(methyl)diphenylphosphonium bromide
Figure imgf000078_0002
Prepared following the procedure in Example 1 step (b) using [9-(1 ,3-dioxo-2,3-dihydro- IH-isoindol-2-yl)nonyl](methyl)diphenylphosphonium bromide (prepared as described in Example 4 step (a)). Purification by 0-100% EtOAc in DCM.
LC-MS (Method I) 342 [M]+; RT 0.88 min
(2S,3R,4S,6R)-2-{r(3aR,4R,7R,8S,9S,10R,1 1 R,13R,16R,16aR)-4-ethyl-1 1 -hvdroxy-8- {r(2R.4R.5S,6S)-4-methoxy-4.6-dimethyl-5- r9- (methyldiphenylphosphoniumyl)nonyllcarbamoyl)oxy)oxan-2-ylloxy)-3a,7,9,1 1 ,13,15,16- heptamethyl-2,6-dioxo-tetradecahvdro-2H-[1 ,3ldioxolo[4,5-cl1 -oxa-6-azacyclopentadecan- 10-ylloxy)-4-(dimethylamino)-6-methyloxan-3-yl acetate bromide
Figure imgf000079_0001
Prepared following the procedure of Example 1 step (c) using (9- aminononyl)(methyl)diphenylphosphonium bromide (prepared as described in Example 4 step (b)). Purification by 0-3% MeOH/0.7 M NH3 in DCM. Title compound isolated as a white foam.
LC-MS (Method H) 1085 [M]+; RT 9.28 min
Example 5 - (2S,3S,4R,6R)-6-{[(2R,3S,4R,5R,8R,10R,11 R,12S,13S,14R)-11 - {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-2-ethyl-3,4,10- trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1 -oxa-6-azacyclopentadecan-13- yl]oxy}-4-methoxy-2,4-dimethyloxan-3-yl N-[9- (methyldiphenylphosphoniumyl)nonyl]carbamate bromide
Figure imgf000079_0002
Prepared following the procedure in Example 2 using (2S,3R,4S,6R)-2- { aR^RJR^S^S OR I R SR eR eaRH-ethyl-H -hydroxy-S-i R^R^S^SH- methoxy-4,6-dimethyl-5-({[9-(methyldiphenylphosphoniumyl)nonyl]carbamoyl}oxy)oxan-2- yl]oxy^3aJ,9,1 1 ,13,15,16-heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 - oxa-6-azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-methyloxan-3-yl acetate bromide (prepared as described in Example 4). Purification by 0-10% MeOH/0.7 M NH3 in DCM. Title compound isolated as a white foam.
LC-MS (Method H) 1 1 17 [M]+; RT 8.06 min
Example 6 - (2S,3S,4R,6R)-6-{[(3aR,4R,7 ,8S,9S,10R,11 R,13R,16R,16aR)-10- {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-4-ethyl-11 - hydroxy-3a^,9 1 S S G-heptamethyl^.G^ioxo-tetradecahydro^H- II .Sldioxolo^S^ll -oxa-G-azacyclopentadecan-e-ylloxy^-methoxy^,^^
dimethyloxan-3-yl N-[9-(methyldiphenylphosphoniumyl)nonyl]carbamate bromide
Figure imgf000080_0001
Prepared following the procedure in Example 3 using (2S,3R,4S,6R)-2- { aR^RJR^S^S OR I R SR eR eaRH-ethyl-H -hydroxy-S-i R^R^S^SH- methoxy-4,6-dimethyl-5-({[9-(methyldiphenylphosphoniumyl)nonyl]carbamoyl}oxy)oxan-2- yl]oxy}-3a!7!9!1 1 !13!15!16-heptamethyl-2!6-dioxo-tetradecahydro-2H-[1 !3]dioxolo[4,5-c]1 - oxa-6-azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-methyloxan-3-yl acetate bromide (prepared as described in Example 4). Title compound isolated as a white solid.
LC-MS (Method H) 1 143 [M]+; RT 8.76 min
Example 7 - (2S,3R,4S,6R)-2-{[(3aR,4R,7R,8S,9S,10R,11 R,13R,16R,16aR)-8- {[(2R,4R,5S,6S)-5-[({9-[dimethyl(phenyl)phosphoniumyl]nonyl}carbamoyl)oxy]-4- methoxy-4,6-dimethyloxan-2-yl]oxy}-4-ethyl-11 -hydroxy-3a,7,9,11 ,13,15,16- heptamethyl-2,6-dioxo-tetradecahydro-2H-[1 ,3]dioxolo[4,5-c]1 -oxa-6- azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6-methyloxan-3-yl acetate bromide [9-(1 ,3-dioxo-2,3-dihvdro-IH-isoindol-2-yl)nonylldimethylphenylphosphon bromide
Figure imgf000081_0001
Prepared following the procedure in Example 1 step (a) using dimethylphenylphosphine. Purification by 0-20% MeOH in DCM.
LC-MS (Method J) 410 [M]+; RT 1.09 min
(9-aminononyl)dimethylphenylphosphonium bromide
Figure imgf000081_0002
Prepared following the procedure in Example 1 step (b) using [9-(1 ,3-dioxo-2,3-dihydro- IH-isoindol-2-yl)nonyl]dimethylphenylphosphonium bromide (prepared as described in Example 7 step (a)). Purification by 0-100% EtOAc in DCM followed by 0-40% MeOH in DCM.
LC-MS (Method I) 280 [M]+; RT 0.61 min
(2S,3R,4S,6R)-2-{r(3aR,4R,7R,8S,9S,10R,1 1 R,13R,16R,16aR)-8-{r(2R,4R,5S,6S)-5-r({9- [dimethyl(phenyl)phosphoniumyllnonyl)carbamoyl)oxyl-4-methoxy-4,6-dimethyloxan-2- ylloxy)-4-ethyl-1 1 -hvdroxy-3a.7.9.1 1.13.15.16-heptamethyl-2.6-dioxo-tetradecahvdro-2H- [1 ,3ldioxolo[4,5-cl1 -oxa-6-azacvclopentadecan-10-vHoxy)-4-(dimethylamino)-6- methyloxan-3-yl acetate bromide
Figure imgf000082_0001
Prepared following the procedure of Example 1 step (c) using (9- aminononyl)dimethylphenylphosphonium bromide (prepared as described in Example 7 step (b)). Purification by 0-10% MeOH/0.7 M NH3 in DCM. Title compound isolated as a white foam.
LC-MS (Method H) 1 123 [M]+; RT 8.59 min
Example 8 - (2S,3S,4R,6R)-6-{[(2R,3S,4R,5R,8R,10R,11 R,12S,13S,14R)-11 - {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-2-ethyl-3,4,10- trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo-1 -oxa-6-azacyclopentadecan-13- yl]oxy}-4-methoxy-2,4-dimethyloxan-3-yl N-{9-
[dimethyl(phenyl)phosphoniumyl]nonyl}carbamate bromide
Figure imgf000082_0002
Prepared following the procedure in Example 2 using (2S,3R,4S,6R)-2-
Figure imgf000083_0001
[dimethyl(phenyl)phosphoniumyl]nonyl}carbamo
yl]oxy}-4-ethyl-1 1 -hydroxy-3a,7,9,1 1 ,13,15,16-heptamethyl-2,6-dioxo-tetradecahydro-2H- [1 ,3]dioxolo[4,5-c]1 -oxa-6-azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6- methyloxan-3-yl acetate bromide (prepared as described in Example 7). Purification by 0- 10% MeOH/0.7 M NH3 in DCM. Title compound isolated as a white foam.
LC-MS (Method H) 1055 [M]+; RT 7.50 min
Example 9 - (2S,3S,4R,6R)-6-{[(3aR,4R,7R,8S,9S,10R,11 R,13R,16R,16aR)-10- {[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-4-ethyl-11 - hydroxy-3a,7,9,11 ,13,15,16-heptamethyl-2,6-dioxo-tetradecahydro-2H- [1 ,3]dioxolo[4,5-c]1 -oxa-6-azacyclopentadecan-8-yl]oxy}-4-methoxy-2,4- dimethyloxan-3-yl N-{9-[dimethyl(phenyl)phosphoniumyl]nonyl}carbamate bromide
Figure imgf000083_0002
Prepared following the procedure in Example 3 using (2S,3R,4S,6R)-2- { aR^RJR^S^S OR I R SR eR eaR^S-i R^R^S^S)^-^- [dimethyl(phenyl)phosphoniumyl]nonyl}carbamoyl)oxy]-4-methoxy-4,6-dimethyloxan-2- y oxyH-ethyl-H -hydroxy-SaJ^ US S e-heptamethyl^^-dioxo-tetradecahydro^H- [1 ,3]dioxolo[4,5-c]1 -oxa-6-azacyclopentadecan-10-yl]oxy}-4-(dimethylamino)-6- methyloxan-3-yl acetate bromide (prepared as described in Example 7). Purification by 0- 10% MeOH/0.7 M NH3 in DCM. Title compound isolated as a white solid.
LC-MS (Method H) 1081 [M]+; RT 7.79 min
Inhibition of proliferation assay
[00264] Cell confluence [00265] 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.
[00266] 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.
[00267] 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 μΜ (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.
Concentration μΜ
Example % Confluence
(micromolar)
Azithromycin 100 17
Azithromycin 10 99.1
1 10 4.7
2 10 6.9
3 10 9
4 10 8.3
5 10 1 15
6 10 7.4
7 10 92.2
8 10 123 As is readily apparent, the compounds of the invention are considerably more effective at limiting cancer cell proliferation than azithromycin.

Claims

1 . A compound comprising an ion of formula (I) or a pharmaceutically acceptable salt thereof:
Figure imgf000086_0001
wherein either Z1 is
Figure imgf000086_0002
or Z2 is
Figure imgf000086_0003
-L1- is independently absent or is selected from -C(O)-, -C(0)0-, -S(0)2-, -S(O)-, - C(0)NR5, and -S(0)2NR5-;
-L3- is independently at each occurrence either absent or selected from: -0-, -S-, - NR6-, -C(O)-, -OC(O)-, -C(0)0-, -S(0)2-, -S(0)-, -NR5C(0)-, -C(0)NR5, -NR5S(0)2-, - S(0)2NR5-, -OC(0)NR5-, -NR5C(0)0-, -NR5C(0)NR5, -CR7=CR7- and -C≡C-;
-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 R8 groups; provided that any -L2- or -L4- group that is attached at each end to an atom selected from oxygen, nitrogen, sulphur or phosphorous is -C2-C4- alkylene-; -L5- is independently selected from: -0-, -S-, -N R6-, -0C(0)-, -N R5C(0)-, N R5S(0)2-, - OC(0)N R5-, -N R5C(0)0- and N R5C(0)N R5;
n is an integer selected from 0, 1 ,
2, 3 and 5;
wherein L1, L2, L3, L4, L5 and n are selected such that length of the linker formed by those groups is from 3 to 16 atoms;
R1 a, R1 b and R1 c 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 heterocycloalkyi; wherein said phenyl, biphenyl, naphthyl, 5-, 6-, 9- or 10- membered heteroaryl is optionally substituted with from 1 to 5 independently selected R1 d groups; and wherein said C3 to Cs-cycloalkyl, Ci-Cs-alkyl and 4- to 8-membered heterocycloalkyi is optionally substituted with from 1 to 5 independently selected R1 e groups; provided that R1 a, R1 b and R1 c are not each unsubstituted phenyl; wherein R1 a and R1 b are optionally connected to each other via a bond or a group selected from - 0-, N R6a, and Ci-C3-alkylene;
R2a, R2b and R2c are each independently selected from H and Ci-C6-alkyl;
R3a is independently selected from: H, Ci-Ce-alkyI or C(0)-Ci-Ce-alkyl;
R3b and R3c are each independently selected from: H and C(0)-Ci-C6-alkyl;
R4a and R4b are each independently selected from: H, Ci-Ce-alkyI or C(0)-Ci-Ce-alkyl; or R4a and R4b together from C(O);
R5 and R6a are each independently at each occurrence selected from H and Ci-Ce- alkyI;
R6 and R1 1 are independently at each occurrence selected from: H, Ci-C6-alkyl, C(0)Ci-C6-alkyl and S(0)2-Ci-C6-alkyl;
R7 is independently at each occurrence selected from H, Ci-C4-alkyl and halo;
R8 is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C2- Ce-alkenyl, Ci-C6-haloalkyl, OR9, SR10, N R10R1 1 , C(0)OR1°, C(O)N R10R10, halo, cyano, nitro, C(0)R10, S(0)2OR1°, S(0)2R1° S(0)R, OC(O)N R10R10, N R10C(O)OR10 and S(O)2N R10R10;
R9 is independently at each occurrence selected from: H, Ci-C6-alkyl and C1-C6- haloalkyl;
R10 is independently at each occurrence selected from: H and Ci-C6-alkyl; R1d is independently at each occurrence selected from: Ci-C6-alkyl, C2-C6-alkynyl, C2- C6-alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyi, 5-, 6- , 9- or 10- membered heteroaryl, phenyl, OR9, SR10, NR10R11 , C(0)OR1°,
C(O)NR10R10, halo, cyano, nitro, C(0)R10, S(0)2OR1°, S(0)Ri S(0)2R1°,
S(O)2NR10R10, OC(O)NR10R10 and N R10C(O)OR10;
R1e is independently at each occurrence selected from: oxo, Ci-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, 5- to 8-membered heterocycloalkyi, 5- , 6-, 9- or 10- membered heteroaryl, phenyl, OR9, SR10, NR10R11 , C(0)OR1°,
C(O)NR10R10, halo, cyano, nitro, C(0)R10, S(0)2OR1°, S(0)Ri S(0)2R1°,
S(O)2NR10R10, OC(O)NR10R10 and N R10C(O)OR10;
and wherein any of the abovementioned alkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyi, heteroaryl or phenyl groups is optionally substituted where chemically allowable by from 1 to 4 groups independently selected from oxo, Ci-Ce- alkyI, C2-C6-alkynyl, C2-C6-alkenyl, Ci-C6-haloalkyl, ORa, NRaRb, SRa, C(0)ORa, C(0)NRaRa, halo, cyano, nitro, C(0)Ra, S(0)2ORa, 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.
, wherein Z1 is
Figure imgf000088_0001
and Z2 is OR3c, preferably wherein R3c is H.
3. The compound of claim 2, wherein L1 is -C(O)-.
4. The compound of claim 2, wherein L1 is absent.
5. The compound of claim 1 , wherein Z2 is
Figure imgf000088_0002
and Z1 is R2c, preferably wherein R2c is methyl.
6. The compound of claim 5, wherein L5 is -OC(O)-.
7. The compound of any one of claims 1 to 6, wherein L3 is at each occurrence absent.
8. The compound of any one of claims 1 to 7, wherein L1, L2, L3, L4, L5 and n are selected such that length of the linker formed by those groups is from 8 to 14 atoms.
9. The compound of any one of claims 1 to 8, wherein R2a is C1-C6 alkyl, preferably methyl.
10. The compound of any one of claims 1 to 9, wherein R2b is C1-C6 alkyl, preferably methyl.
1 1 . The compound of any one of claims 1 to 10, wherein R3a is H and R3b is H.
12. The compound of any one of claims 1 to 1 1 , wherein R4a and R4b are each H.
13. The compound of any one of claims 1 to 1 1 , wherein R4a and R4b together form C(O).
14. A compound of any one of claims 1 to 13, wherein R1a, R1b and R1c are each substituted phenyl.
15. A compound of any one of claims 1 to 13, wherein R1a, R1b and R1c are each C3 to Cs-cycloalkyl.
16. A compound of any one of claims 1 to 13, wherein R1a, R1b and R1c are each benzyl.
17. A compound of any one of claims 1 to 13, 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, Ci-Cs-alkyI and 4- to 8-membered heterocycloalkyi.
18. A compound of any one of claims 1 to 13, wherein 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, Ci-Cs-alkyI and 4- to 8-membered heterocycloalkyi.
19. A compound of any one of claims 1 to 13, wherein at least one of R1a, R1b and R1c is d-Ce-alkyl.
20. A compound of claim 19, wherein any of R1a, R1b and R1c that are not Ci-C6-alkyl are phenyl.
21 . A compound of claim 1 , wherein the ion of formula (I) is an ion selected from:
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
The compound of claims 1 to 21 for use as a medicament.
The compound of claims 1 to 21 for use in the treatment of cancer.
24. 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 21 .
25. A pharmaceutical composition comprising the compound of claims 1 to 21 and one or more pharmaceutically acceptable excipients.
PCT/EP2018/060226 2017-04-20 2018-04-20 Azithromycin derivatives containing a phosphonium ion as anticancer agents WO2018193111A1 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0941998A2 (en) * 1998-03-03 1999-09-15 Pfizer Products Inc. 3,6-ketal and enol ether macrolide antibiotics

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0941998A2 (en) * 1998-03-03 1999-09-15 Pfizer Products Inc. 3,6-ketal and enol ether macrolide antibiotics

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BARBARA BACHOWSKA ET AL: "High Cytotoxic Activity of Phosphonium Salts and Their Complementary Selectivity towards HeLa and K562 Cancer Cells: Identification of Tri- n -butyl- n -hexadecylphosphonium bromide as a Highly Potent Anti-HeLa Phosphonium Salt", CHEMISTRY OPEN, vol. 1, no. 1, 1 February 2012 (2012-02-01), pages 33 - 38, XP055248822, ISSN: 2191-1363, DOI: 10.1002/open.201100003 *

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