WO2013083991A1 - Nouveaux composés et leur utilisation en thérapie - Google Patents

Nouveaux composés et leur utilisation en thérapie Download PDF

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WO2013083991A1
WO2013083991A1 PCT/GB2012/053041 GB2012053041W WO2013083991A1 WO 2013083991 A1 WO2013083991 A1 WO 2013083991A1 GB 2012053041 W GB2012053041 W GB 2012053041W WO 2013083991 A1 WO2013083991 A1 WO 2013083991A1
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alkyl
alkylene
heterocycle
optionally
groups
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Robin LEATHERBARROW
Edward TATE
Zhiyong Yu
Mark Rackham
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Imperial Innovations Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to compounds for formula (I), (IIA), (IIB), (IIC), (IID), (HE), (IIF), (III) and (IV), which are N-myristoyl transferase inhibitors, and to uses of such compounds as medicaments, in particular in the treatment of a disease or disorder in which inhibition of N-myristoyl transferase provides a therapeutic or prophylactic effect.
  • diseases include microbial infections, including viral and fungal infections, and hyperproliferative disorders, neurological diseases/disorders, ischemia, osteoporosis and diabetes.
  • Certain compounds of the invention find particular use in the treatment of protozoan infections, for example malaria, leishmaniasis and sleeping sickness.
  • N-myristoyltransferase is a monomelic enzyme, which is ubiquitous in eukaryotes. ⁇ catalyses an irreversible co-translational transfer of myristic acid (a saturated 14-carbon fatty acid) from myristoyl-Coenzyme A (myr-CoA) to a protein substrate containing an N-terminal glycine with formation of an amide bond (Farazi, T. A., Waksman, G., Gordon, J. I., J. Biol. Chem., 2001. 276(43): p. 39501-39504). N-myristoylation by ⁇ follows an ordered Bi-Bi mechanism.
  • Myr-CoA binds to ⁇ in the first ⁇ binding pocket prior to the binding of a protein substrate (Rudnick, D. A., McWherter C. A., Rocque, W. J., et al, J. Biol. Chem., 1991. 266(15): p. 9732-9739).
  • the bound myr-CoA facilitates the opening of a second binding pocket where the protein substrate binds.
  • ⁇ plays a key role in protein trafficking, mediation of protein-protein interactions, stabilization of protein structures and signal transduction in living systems. Inhibition of the ⁇ enzyme has the potential to disrupt multi-protein pathways, which is an attractive characteristic to reduce the risk of the development of resistance in, for example, treatment or prophylaxis of microbial infections and hyperproliferative disorders.
  • NMT fungal and mammalian enzymes from various sources have been well characterized, see for example the following references: Saccharomyces cerevisiae (Duronio, R. J., Towler, D. A., Heuckeroth, R. O., et al., Science, 1989. 243(4892): p. 796-800), Candida albicans (Wiegand, R. C, Carr, C, Minnerly, J.C., et al, J. Biol. Chem., 1992. 267(12): p. 8591-8598) and Cryptococcus neoformans (Lodge, J. K., Johnson, R. L., Weinberg, R.
  • NMT has also been characterised in protozoan parasites. See for example the following references: Plasmodium falciparum (Pf) (Gunaratne, R. S., Sajid, M., Ling, I. T., et al., Biochem. J., 2000. 348: p. 459-463), Plasmodium vivax (Pv), Leishmania major (Lm) (Price, H. P., Menon, M. R.,
  • ⁇ inhibitors As described above, there are two binding pockets in ⁇ . One is the myr-CoA binding pocket and the other is the peptide binding pocket. Most ⁇ inhibitors reported to date target the peptide binding pocket. Most ⁇ inhibitors developed to date have been targeted to fungal NMTs.
  • WO00/37464 discloses certain benzofuran compounds which inhibit NMT and show antifungal activity.
  • Sheng et al. Sheng et al, Eur. J. Med. Chem., 2010. 45(9): p. 3531-3540
  • WO2010/026365 Universality of Dundee
  • US2004/0014764 discloses cyclohexyl- or methyl- octahydro-pyrolo[l,2-a]pyrazine groups which inhibit human NMT for the treatment of hyperproliferative disorders and viral infections.
  • RO-09- 4609 are only weak inhibitors of protozoan NMTs (specifically Plasmodium falciparum and Leishmania donovani NMTs).
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder in which inhibition of N- myristoyltransferase provides a therapeutic or prophylactic effect
  • A is either an 8- to 10-membered bicyclic aromatic carbocycle or heterocycle, or a 5- to 6-membered monocyclic aromatic carbocycle or heterocycle;
  • X and Q are either attached to adjacent ring atoms or are attached to ring atoms which are separated by one intervening ring atom, and where A is an 8- to 10-membered aromatic carbocycle or heterocycle, X and Q are attached to the same ring;
  • X is -0-, -S-, -NH-, -CH 2 0-, -CH 2 S-, -CH 2 NH-, -0-Ci_ 6 alkylene,
  • X is -0-Ci_ 6 alkylene, -0-C 2 _ 6 alkenylene, -0-C 2 _ 6 alkynylene, -0-C 3 _ 7 cycloalkylene,
  • -S-Ci_ 6 alkylene -S-C 2 _ 6 alkenylene, -S-C 2 _ 6 alkynylene, -S-C 3 _ 7 cycloalkylene, -NH-Ci_ 6 alkylene, -NH- C 2 _ 6 alkenylene, -NH-C 2 _ 6 alkynylene, -NH-C 3 _ 7 cycloalkylene, Ci_ 6 alkylene, C 2 _ 6 alkenylene or
  • alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups independently selected from F and CI; and V is NR 2 R 3 ;
  • each R 1 is independently selected from Ci_ 6 alkyl, 3- to 10-membered carbocycle, 3- to 10-membered heterocycle, 3- to 10-membered carbocycle-Ci_ 2 alkyl-, 3- to 10-membered heterocycle-Ci_ 2 alkyl, C(0)-0-C(R') 2 -0-C(0)R', C(0)-0-C(R') 2 -0-P(0)(OR') 2 , C(0)-R' or C(0)-0-R' wherein said alkyl, carbocycle or heterocycle may optionally be substituted with 1 or 2 R A groups;
  • R 2 is hydrogen, Ci_ 6 alkyl, 3- to 10-membered carbocycle, 3- to 10-membered heterocycle, 3- to 10- membered carbocycle-Ci_ 2 alkyl-, or 3- to 10-membered heterocycle-Ci_ 2 alkyl, wherein said alkyl, carbocycle or heterocycle may optionally be substituted with 1 or 2 R A groups;
  • R 3 is hydrogen, Ci_ 6 alkyl, a 3- to 10-membered carbocycle, 3- to 10-membered heterocycle, 3- to 10- membered carbocycle-Ci_ 2 alkyl-, 3- to 10-membered heterocycle-Ci_ 2 alkyl,
  • p is an integer of from 0 to 3;
  • each R 4 is independently selected from R B groups and cyano
  • Q is - Q 1 - Q 2 -, wherein:
  • Q 2 is bond, Ci_ 4 alkylene, C 2 _ 4 alkenylene or C 2 _ 4 alkynylene, wherein said Ci_ 4 alkylene, C 2 - 4 alkenylene or C 2 - 4 alkynylene may optionally be substituted with one or two substituents selected from R A groups and B, and wherein up to two methylene groups of said
  • Ci_ 4 alkylene, C 2 - 4 alkenylene or C 2 - 4 alkynylene may each independently be replaced by -0-,
  • B is C 2 _ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, 5- to 10-membered carbocycle or 5- to 10-membered heterocycle comprising up to three heteroatoms, wherein said Ci_ 6 alkyl, C 2 _ 6 alkenyl or C 2 _ 6 alkynyl may optionally be substituted with 1 or 2 R A groups, and wherein said carbocycle or heterocycle may optionally be substituted with from 1 to 3 substituents each independently selected from R B , -0-Ci_ 6 alkyl-CN, -S(O) 0 - 2 C 1 _ 6 alkyl, -S(O) 0 - 2 C 1 _ 6 alkyl-CN, -C(0)-C 1 _ 6 alkyl-CN, C(0)NH-C 1 _ 6 alkyl-CN and phenyl;
  • each R A is independently selected from OR c , N(R D ) 2 and halogen;
  • each R B is independently selected from Ci_ 4 alkyl, C 2 _ 4 alkenyl, C 2 _ 4 alkynyl, trihaloCi_ 4 alkyl,
  • each R c is independently selected from hydrogen, Ci_ 4 alkyl, C 2 _ 4 alkenyl; C 2 _ 4 alkynyl, trihaloCi_ 4 alkyl and -C(0)Ci_ 4 alkyl;
  • each R D is independently selected from hydrogen, Ci_ 4 alkyl, C 2 _ 4 alkenyl; C 2 _ 4 alkynyl, trihaloCi_ 4 alkyl,
  • each R' is independently selected from hydrogen and Ci_ 6 alkyl.
  • the invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof
  • A is an 8- to 10-membered bicyclic aromatic heterocycle or carbocycle
  • X and Q are attached to the same ring, and are either attached to adjacent ring atoms or are attached to ring atoms which are separated by one intervening ring atom;
  • X is -0-, -S-, -NH-, -CH 2 0-, -CH 2 S-, -CH 2 NH-, -0-Ci_ 6 alkylene,
  • X is -0-Ci_ 6 alkylene, -0-C 2 - 6 alkenylene, -0-C 2 - 6 alkynylene, -0-C 3 _ 7 cycloalkylene,
  • -S-Ci_ 6 alkylene -S-C 2 _ 6 alkenylene, -S-C 2 _ 6 alkynylene, -S-C 3 _ 7 cycloalkylene, -NH-Ci_ 6 alkylene, -NH- C 2 _ 6 alkenylene, -NH-C 2 _ 6 alkynylene, -NH-C 3 _ 7 cycloalkylene, Ci_ 6 alkylene, C 2 _ 6 alkenylene or
  • alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups independently selected from F and CI; and V is NR 2 R 3 ;
  • each R 1 is independently selected from Ci_ 6 alkyl, 3- to 10-membered carbocycle, 3- to 10-membered heterocycle, 3- to 10-membered carbocycle-Ci_ 2 alkyl-, 3- to 10-membered heterocycle-Ci_ 2 alkyl, C(0)-0-C(R') 2 -0-C(0)R', C(0)-0-C(R') 2 -0-P(0)(OR') 2 , C(0)-R' or C(0)-0-R'; wherein said alkyl, carbocycle or heterocycle may optionally be substituted with 1 or 2 R A groups;
  • R 2 is hydrogen, Ci_ 6 alkyl, 3- to 10-membered carbocycle, 3- to 10-membered heterocycle, 3- to 10- membered carbocycle-Ci_ 2 alkyl-, or 3- to 10-membered heterocycle-Ci_ 2 alkyl, wherein said alkyl, carbocycle or heterocycle may optionally be substituted with 1 or 2 R A groups;
  • R 3 is hydrogen, Ci_ 6 alkyl, a 3- to 10-membered carbocycle, 3- to 10-membered heterocycle, 3- to 10- membered carbocycle-Ci_ 2 alkyl-, 3- to 10-membered heterocycle-Ci_ 2 alkyl, C(0)-0-C(R') 2 -0-C(0)R', C(0)-0-C(R') 2 -0-P(0)(OR') 2 , C(0)-R' or C(0)-0-R', wherein said alkyl, carbocycle or heterocycle may optionally be substituted with 1 or 2 R A groups;
  • p is an integer of from 0 to 3;
  • each R 4 is independently selected from R B groups and cyano
  • Q is - Q 1 - Q 2 -, wherein:
  • Q 2 is Ci_ 4 alkylene, bond, C 2 _ 4 alkenylene or C 2 _ 4 alkynylene, wherein said Ci_ 4 alkylene,
  • C 2 _ alkenylene or C 2 _ alkynylene may optionally be substituted with one or two substituents selected from R A groups and B, and wherein up to two methylene groups of said
  • Ci_ alkylene, C 2 _ alkenylene or C 2 _ alkynylene may each independently be replaced by -0-,
  • B is a 5 - to 10-membered carbocycle or 5- to 10-membered heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from 1 to 3 substituents each independently selected from R B , -0-Ci_ 6 alkyl-CN, -S(O) 0 - 2 Ci_ 6 alkyl, -S(O) 0 - 2 Ci_ 6 alkyl-CN, -C(0)-Ci_ 6 alkyl-CN, C(0)NH-Ci_ 6 alkyl-CN and phenyl, or B is C 2 _ 6 alkyl, C 2 _ 6 alkenyl or C 2 _ 6 alkynyl, wherein said C 2 _ 6 alkyl, C 2 _ 6 alkenyl or C 2 _ 6 alkynyl may optionally be substituted with 1 or 2 R A groups;
  • each R A is independently selected from OR c , N(R D ) 2 and halogen;
  • each R B is independently selected from Ci_ 4 alkyl, C 2 _ 4 alkenyl, C 2 _ 4 alkynyl, trihaloCi_ 4 alkyl,
  • each R c is independently selected from hydrogen, Ci_ alkyl, C 2 _ alkenyl; C 2 _ alkynyl, trihaloCi_ alkyl and -C(0)Ci_ alkyl;
  • each R D is independently selected from hydrogen, Ci_ alkyl, C 2 _ alkenyl; C 2 _ alkynyl, trihaloCi_ alkyl,
  • each R' is independently selected from hydrogen and Ci_ 6 alkyl
  • the invention also provides a compound of formula (I), or a pharmaceutically acceptable salt thereof
  • A is a 5- to 6-membered monocyclic aromatic carbocycle or heterocycle
  • X and Q are either attached to adjacent ring atoms or are attached to ring atoms which are separated by one intervening ring atom;
  • X is -0-, -S-, -NH-, -CH 2 0-, -CH 2 S-, -CH 2 NH-, -0-Ci_ 6 alkylene,
  • X is -0-Ci_ 6 alkylene, -0-C 2 _ 6 alkenylene, -0-C 2 _ 6 alkynylene, -0-C 3 _ 7 cycloalkylene,
  • -S-Ci_ 6 alkylene -S-C 2 _ 6 alkenylene, -S-C 2 _ 6 alkynylene, -S-C 3 _ 7 cycloalkylene, -NH-Ci_ 6 alkylene, -NH- C 2 _ 6 alkenylene, -NH-C 2 _ 6 alkynylene, -NH-C 3 _ 7 cycloalkylene, Ci_ 6 alkylene, C 2 _ 6 alkenylene or
  • alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups independently selected from F and CI; and V is NR 2 R 3 ;
  • each R 1 is independently selected from Ci_ 6 alkyl, 3- to 10-membered carbocycle, 3- to 10-membered heterocycle, 3- to 10-membered carbocycle-Ci_ 2 alkyl-, 3- to 10-membered heterocycle-Ci_ 2 alkyl,
  • R 2 is hydrogen, Ci_ 6 alkyl, 3- to 10-membered carbocycle, 3- to 10-membered heterocycle, 3- to 10- membered carbocycle-Ci_ 2 alkyl-, or 3- to 10-membered heterocycle-Ci_ 2 alkyl, wherein said alkyl, carbocycle or heterocycle may optionally be substituted with 1 or 2 R A groups;
  • R 3 is hydrogen, Ci_ 6 alkyl, a 3- to 10-membered carbocycle, 3- to 10-membered heterocycle, 3- to 10- membered carbocycle-Ci_ 2 alkyl-, 3- to 10-membered heterocycle-Ci_ 2 alkyl, C(0)-0-C(R') 2 -0-C(0)R', C(0)-0-C(R') 2 -0-P(0)(OR') 2 , C(0)-R' or C(0)-0-R'; wherein said alkyl, carbocycle or heterocycle may optionally be substituted with 1 or 2 R A groups;
  • p is an integer of from 0 to 3;
  • each R 4 is independently selected from R B groups and cyano;
  • Q is - Q 1 - Q 2 -, wherein:
  • Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle or -C(0)-N(R D )-C(NH)-, -NH-N(R D )- C(O)-, -C(0)-NH-C(0)-, -CH 2 -C(0)0-, -CH 2 -0-C(0)-, wherein said carbocycle or heterocycle may optionally be substituted with one or two substituents independently selected from R B groups and Q 2 - B;
  • Q 2 is bond, Ci_ 4 alkylene, C 2 - 4 alkenylene or C 2 - 4 alkynylene, wherein said Ci_ 4 alkylene,
  • C 2 _ 4 alkenylene or C 2 _ 4 alkynylene may optionally be substituted with one or two substituents selected from R A groups and B, and wherein up to two methylene groups of said
  • Ci_ 4 alkylene, C 2 _ alkenylene or C 2 _ alkynylene may each independently be replaced by -0-,
  • B is C 2 _ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, 5- to 10-membered carbocycle or 5- to 10-membered heterocycle comprising up to three heteroatoms, wherein said Ci_ 6 alkyl, C 2 _ 6 alkenyl or C 2 _ 6 alkynyl may optionally be substituted with 1 or 2 R A groups, and wherein said carbocycle or heterocycle may optionally be substituted with from 1 to 3 substituents each independently selected from R B , -0-Ci_ 6 alkyl-CN, -S(O) 0 - 2 C 1 _ 6 alkyl, -S(O) 0 - 2 C 1 _ 6 alkyl-CN, -C(0)-C 1 _ 6 alkyl-CN, C(0)NH-C 1 _ 6 alkyl-CN and phenyl;
  • each R A is independently selected from OR c , N(R D ) 2 and halogen;
  • each R B is independently selected from Ci_ alkyl, C 2 _ alkenyl, C 2 _ alkynyl, trihaloCi_ alkyl,
  • each R c is independently selected from hydrogen, Ci_ alkyl, C 2 _ alkenyl; C 2 _ alkynyl, trihaloCi_ alkyl and -C(0)Ci_ alkyl;
  • each R D is independently selected from hydrogen, Ci_ alkyl, C 2 _ alkenyl; C 2 _ alkynyl, trihaloCi_ alkyl,
  • each R' is independently selected from hydrogen and Ci_ 6 alkyl
  • NMT inhibitors have surprisingly been found to be NMT inhibitors, and accordingly have use in the treatment or prophylaxis of diseases or disorders in which inhibition of N- myristoyltransferase provides a therapeutic or prophylactic effect.
  • the invention also provides a compound of formula ( ⁇ ), (IIB), (IIC), (IID),(IIE) or (IIF), or a pharmaceutically acceptable salt thereof:
  • V is a 3-7-membered nitrogen-containing heterocycle, wherein said heterocycle may optionally be substituted with one R 1 group which is Ci_ 2 alkyl, C(0)-0-C(R') 2 -0-C(0)R', C(0)-0-C(R') 2 -0-P(0)(OR') 2 , C(0)-R' or C(0)-0-R';
  • X is -0-C 2 _ 4 alkylene, -0-C 2 _ 4 alkenylene, -0-C 2 _ 4 alkynylene, -0-C 3 _ 6 cycloalkylene,
  • alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups selected from F and CI; and V is NR 2 R 3 ;
  • R 2 is hydrogen or d_ 2 alkyl
  • R 3 is hydrogen, methyl, C(0)-0-C(R') 2 -0-C(0)R', C(0)-0-C(R') 2 -0-P(0)(OR') 2 C(0)-R' or C(0)-0-
  • p is an integer of from 0 to 3;
  • each R 4 is independently selected from R B groups and cyano
  • R 5 is hydrogen or Ci_ 4 alkyl
  • Q is - Q 1 - Q 2 -, wherein:
  • Q 1 is -C(0)0-,-C(0)N(R D )-, -OC(O)-, -N(R D )C(0)-, -C(O)-, -0-, -CH 2 -0-, -CH 2 -C(0)0-, -CH 2 -0- C(O)-, -N(R D )-,
  • Q 2 is bond, Ci_ 4 alkylene, C 2 _ 4 alkenylene or C 2 _ 4 alkynylene, wherein said Ci_ alkylene,
  • C 2 _ alkenylene or C 2 _ alkynylene may optionally be substituted with one or two substituents selected from R A groups and B, and wherein up to two methylene groups of said
  • Ci_ alkylene, C 2 _ alkenylene or C 2 _ alkynylene may each independently be replaced by -0-,
  • B is C 2 _ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, 5- to 10-membered carbocycle or 5- to 10-membered heterocycle comprising up to three heteroatoms, wherein said Ci_ 6 alkyl, C 2 _ 6 alkenyl or C 2 _ 6 alkynyl may optionally be substituted with 1 or 2 R A groups, and wherein said carbocycle or heterocycle may optionally be substituted with from 1 to 3 substituents each independently selected from R B , -0-Ci_ 6 alkyl-CN, -S(O) 0 - 2 C 1 _ 6 alkyl, -S(O) 0 - 2 C 1 _ 6 alkyl-CN, -C(0)-C 1 _ 6 alkyl-CN, C(0)NH-C 1 _ 6 alkyl-CN and phenyl;
  • each R A is independently selected from OR c , N(R D ) 2 and halogen;
  • each R B is independently selected from Ci_ alkyl, C 2 _ alkenyl, C 2 _ alkynyl, trihaloCi_ alkyl,
  • each R c is independently selected from hydrogen, Ci_ alkyl, C 2 _ alkenyl; C 2 _ alkynyl, trihaloCi_ alkyl and -C(0)Ci_ alkyl;
  • each R D is independently selected from hydrogen, Ci_ alkyl, C 2 _ alkenyl; C 2 _ alkynyl, trihaloCi_ alkyl, OH, -C(0)Ci_ alkyl, -C(0)CF 3 and cyano; and each R' is independently selected from hydrogen and Ci_ 6 alkyl.
  • the invention also provides a compound of formula (III), or a pharmaceutically acceptable solvate or salt thereof:
  • X is -0-, -S-, CH 2 , -0-CH 2 - or -S-CH 2 -;
  • V is a 3- to 7- membered nitrogen-containing heterocycle which may be optionally substituted with one R 1 group which is Ci -2 alkyl, C(0)-0-C(R') 2 -0-C(0)R', C(0)-0-C(R') 2 -0-P(0)(OR') 2 ,C(0)-R' or C(0)-0-R';
  • p is an integer of from 0 to 3;
  • R 4 is R B groups or cyano
  • R 5 is hydrogen or Ci_ 4 alkyl
  • Q is - Q 1 - Q 2 -, wherein:
  • Q 1 is -C(0)0-,-C(0)N(R D )-, -OC(O)-, -N(R D )C(0)-, -C(O)-, -0-, -CH 2 -0-, -CH 2 -C(0)0-, -CH 2 -0- C(O)-, -N(R D )-,
  • R D group may optionally form, together with the R 5 group, the nitrogen atom of the
  • Q 2 is bond, Ci_ 4 alkylene, C 2 _ 4 alkenylene or C 2 _ 4 alkynylene, wherein said Ci_ alkylene,
  • C 2 _ alkenylene or C 2 _ alkynylene may optionally be substituted with one or two substituents selected from R A groups and B, and wherein up to two methylene groups of said
  • Ci_ alkylene, C 2 _ alkenylene or C 2 _ alkynylene may each independently be replaced by -0-,
  • B is C 2 _ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, 5- to 10-membered carbocycle or 5- to 10-membered heterocycle comprising up to three heteroatoms, wherein said Ci_ 6 alkyl, C 2 _ 6 alkenyl or C 2 _ 6 alkynyl may optionally be substituted with 1 or 2 R A groups, and wherein said carbocycle or heterocycle may optionally be substituted with from 1 to 3 substituents each independently selected from R B , -0-Ci_ 6 alkyl-CN, -S(O) 0 - 2 C 1 _ 6 alkyl, -S(O) 0 - 2 C 1 _ 6 alkyl-CN, -C(0)-C 1 _ 6 alkyl-CN, C(0)NH-C 1 _ 6 alkyl-CN and phenyl;
  • each R A is independently selected from OR c , N(R D ) 2 and halogen;
  • each R B is independently selected from Ci_ 4 alkyl, C 2 - 4 alkenyl, C 2 _ 4 alkynyl, trihaloCi_ 4 alkyl,
  • each R c is independently selected from hydrogen, Ci_ 4 alkyl, C 2 _ 4 alkenyl; C 2 _ 4 alkynyl, trihaloCi_ alkyl and -C(0)Ci_ alkyl;
  • each R D is independently selected from hydrogen, Ci_ alkyl, C 2 _ alkenyl; C 2 _ alkynyl, trihaloCi_ alkyl, OH, -C(0)Ci_ alkyl, -C(0)CF 3 and cyano; and
  • each R' is independently selected from hydrogen and Ci_ 6 alkyl;with the proviso that the compound of formula (III) is not 3-methyl-4-(piperidin-4-yloxy)-benzofuran-2-carboxylic acid ethyl ester or 3- methyl-4-(piperidin-3-ylmethoxy)-benzofuran-2-carboxylic acid ethyl ester.
  • the invention also provides 3-methyl-4-(piperidin-4-yloxy)-benzofuran-2-carboxylic acid ethyl ester or 3-methyl-4-(piperidin-3-ylmethoxy)-benzofuran-2-carboxylic acid ethyl ester, or a
  • the invention also provides a compound of formula (IV), or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of a disease or disorder in which inhibition of N-myristoyltransferase provides a therapeutic or prophylactic effect, and which is a protozoan infection
  • X is -0-C 2 _ alkylene, -0-C 2 _ alkenylene, -0-C 2 _ alkynylene, -0-C 3 _ 6 cycloalkylene,
  • R 2 is hydrogen or Ci_ 2 alkyl
  • R 3 is hydrogen, methyl, C(0)-0-C(R') 2 -0-C(0)R', C(0)-0-C(R') 2 -0-P(0)(OR') 2 , C(0)-R' or C(0)-0-
  • p is an integer of from 0 to 3;
  • each R 4 is independently selected from R B groups and cyano
  • R 5 is hydrogen or Ci_ 4 alkyl
  • Q is - Q 1 - Q 2 -, wherein:
  • Q 1 is -C(0)0-,-C(0)N(R D )-, -OC(O)-, -N(R D )C(0)-, -C(O)-, -0-, -CH 2 -0-, -CH 2 -C(0)0-, -CH 2 -0- C(O)-, -N(R D )-,
  • Q 2 is bond, Ci_ 4 alkylene, C 2 _ 4 alkenylene or C 2 _ 4 alkynylene, wherein said Ci_ alkylene,
  • C 2 _ alkenylene or C 2 _ alkynylene may optionally be substituted with one or two substituents selected from R A groups and B, and wherein up to two methylene groups of said
  • Ci_ alkylene, C 2 _ alkenylene or C 2 _ alkynylene may each independently be replaced by -0-,
  • B is C 2 _ 6 alkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, 5- to 10-membered carbocycle or 5- to 10-membered heterocycle comprising up to three heteroatoms, wherein said Ci_ 6 alkyl, C 2 _ 6 alkenyl or C 2 _ 6 alkynyl may optionally be substituted with 1 or 2 R A groups, and wherein said carbocycle or heterocycle may optionally be substituted with from 1 to 3 substituents each independently selected from R B , -0-Ci_ 6 alkyl-CN, -S(O) 0 - 2 C 1 _ 6 alkyl, -S(O) 0 - 2 C 1 _ 6 alkyl-CN, -C(0)-C 1 _ 6 alkyl-CN, C(0)NH-C 1 _ 6 alkyl-CN and phenyl;
  • each R A is independently selected from OR c , N(R D ) 2 and halogen;
  • each R B is independently selected from Ci_ alkyl, C 2 _ alkenyl, C 2 _ alkynyl, trihaloCi_ alkyl,
  • each R c is independently selected from hydrogen, Ci_ alkyl, C 2 _ alkenyl; C 2 _ alkynyl, trihaloCi_ alkyl and -C(0)Ci_ alkyl;
  • each R D is independently selected from hydrogen, Ci_ alkyl, C 2 _ alkenyl; C 2 _ alkynyl, trihaloCi_ alkyl,
  • each R' is independently selected from hydrogen and Ci_ 6 alkyl.
  • a compound of the invention for use as a medicament.
  • the compounds of the invention are useful in the treatment or prophylaxis of a disease or disorder in which inhibition of N- myristoyltransferase provides a therapeutic or prophylactic effect.
  • X is -0-, -S-, -CH 2 -, -0-CH 2 - or -S-CH 2 -; and V is a 3-7-membered nitrogen-containing heterocycle, wherein said heterocycle may optionally be substituted with one R 1 group which is Ci_ 2 alkyl, C(0)-0-C(R') 2 -0-C(0)R' or C(0)-0-C(R') 2 -0-P(0)(OR') 2 ;
  • X is -0-C 2 _ 4 alkylene, -0-C 2 _ 4 alkenylene, -0-C 2 _ 4 alkynylene, -0-C 3 _ 6 cycloalkylene, -S-C 2 _ 4 alkylene, -S-C 2 _ alkenylene, -S-C 2 _ alkynylene, -S-C 3 _ 6 cycloalkylene,
  • R 3 is hydrogen, methyl, C(0)-0-C(R') 2 -0-C(0)R' or C(0)-0-C(R') 2 -0-P(0)(OR') 2 , (i.e. certain compounds of formula (I), and compounds of formula (IIA), (IIB), (IIC), (IID), (HE), (IIF), (III), (IV), 3-methyl-4-(piperidin-4-yloxy)-benzofuran-2-carboxylic acid ethyl ester, and 3-methyl-4-(piperidin- 3-ylmethoxy)-benzofuran-2-carboxylic acid ethyl ester) have surprisingly been found to be inhibitors of protozoan NMT, and are accordingly useful in the treatment or prophylaxis of a disease or disorder which is a protozoan infection.
  • composition comprising a compound of the invention together with a pharmaceutically acceptable carrier.
  • the present invention provides compounds that are NMT inhibitors.
  • NMT inhibitor as used herein is intended to cover any moiety which binds to NMT and inhibits its activity.
  • the inhibitors may act as competitive inhibitors, or partial competitive inhibitors.
  • the inhibitor may bind to NMT at the myr-CoA binding pocket or at the peptide binding pocket (or inhibit NMT through another mechanism).
  • Compounds of the present invention preferably bind and inhibit NMT through the peptide binding pocket.
  • alkyi means both straight and branched chain saturated hydrocarbon groups.
  • alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, pentyl and hexyl groups.
  • unbranched alkyl groups there are preferred methyl, ethyl, n-propyl, iso-propyl, n-butyl groups.
  • branched alkyl groups there may be mentioned t-butyl, i-butyl, 1-ethylpropyl and 1-ethylbutyl groups.
  • alkylene means both straight and branched chain divalent hydrocarbon radical.
  • alkyl groups include methyene, ethyene, n-propylene, iso-propylene, n-butylen, t-butylen, i-butylen, sec-butylene, pentylen and hexylene groups.
  • unbranched alkyl groups there are preferred methylene, ethylene, n-propylene, iso-propylene, n-butylene groups.
  • branched alkyl groups there may be mentioned t-butylene, i-butylene, 1-ethylpropylene and 1 - ethylbutylene groups
  • alkenyl means both straight and branched chain unsaturated hydrocarbon groups with at least one carbon carbon double bond.
  • alkenyl groups include ethenyl, propenyl, butenyl, pentenyl and hexenyl.
  • Preferred alkenyl groups include ethenyl, 1-propenyl, 2- propenyl and but-2-enyl.
  • alkenylene refers to a straight or branched chain divalent hydrocarbon radical with at least one carbon carbon double bond.
  • alkenylenes groups include ethenylene, 1-propenylene, 2-propenylene and but-2-enylene.
  • alkynyi means both straight and branched chain unsaturated hydrocarbon groups with at least one carbon carbon triple bond.
  • alkynyi groups include ethynyl, propynyl, butynyl, pentynyl and hexynyl.
  • Preferred alkynyi groups include ethynyl, 1-propynyl and 2-propynyl.
  • alkynylene means both straight and branched chain divalent hydrocarbon radical with at least one carbon carbon triple bond.
  • alkynylene groups include ethynylene, l-propynylene, 2-propynylene, hutynyiene, pentynylene and hexynylene.
  • Carbocycle is intended to mean any 3- to 13-membered carbon ring system, which may be saturated, partially unsaturated, or aromatic.
  • the carbon ring system may be monocyclic or contain more than one ring (e.g. the ring system may be bicyclic).
  • monocyclic saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyeloheptyl, cyclooctyl.
  • bicyclic saturated carbocycles examples include bicyclooctane, bicyclononane, bicyclodecane (decalin) and bicyclooctane.
  • a further example of a saturated carbocycle is adamantane.
  • monocyclic non- saturated carbocycles include cyclobutene, cyclopentene, cyclopentadiene, cyclohexene.
  • aromatic carbocycles include phenyl and naphthyl.
  • Further examples of carbocycles include tetrahydronaphthyl (tetralin) and indane .
  • the term "eycloalkyl" means a saturated group in a ring system.
  • a cycloalkyl group can be monocyclic or bicyclic.
  • a bicyclic group may, for example, be fused or bridged.
  • Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl and cyclopentyl.
  • Other examples of monocyclic cycloalkyl groups are cyclohexyl, cycioheptyl and cyclooctyl.
  • Examples of bicyclic cycloalkyl groups include bicycle [2. 2. 1
  • the cycloalkyl group is monocyclic.
  • cycloalkylene means a 3 - to 7-membered non-aromatic alicyclic divalent hydrocarbon radical
  • examples of cycloalkyl ene include cyclopropyl ene, cyc!obutyl ene and cyclopentylene.
  • Other examples of monocyclic cycloalkyl groups are cyclohexyl ene and
  • cycloheptylene Preferably, the cycloalkylene group is monocyclic.
  • halogen or halo means fluorine, chlorine, bromine or iodine. Fluorine, chlorine and bromine are particularly preferred.
  • haloalkyl means an alky 1 group having a halogen substituent, the terms “alkyl” and “halogen” being understood to have the meanings outlined above.
  • dihaloalky l means an alkyl group having two halogen substituents and the term “trihaloalkyl” means an alkyl group having three halogen substituents.
  • haloalkyl groups include fluoromethyl, chloromethyl, bromomethyl, fluoromethyl, fluoropropyl and fluorobutyl groups; examples of dihaloalkyl groups include difluoromethyl and difluoroethvl groups: examples of tnihaloalkyl groups include tri fluoromethyl and trifluoroethyl groups.
  • heterocyclyl means an aromatic or a non-aromatic cyclic group of carbon atoms wherein from one to three of the carbon atoms is/are replaced by one or more heteroatoms independently selected from nitrogen, oxygen or sulfur.
  • a heterocyclyl (or heterocycle) group may, for example, be monocyclic or bicyclic. In a bicyclic heterocyclyl (or heterocycle) group there may be one or more heteroatoms in each ring, or only in one of the rings.
  • a heteroatom may be S, O or N, and is preferably O or .
  • Heterocyclyl groups containing a suitable nitrogen atom include the corresponding N-oxides.
  • monocyclic non-aromatic heterocyclyl examples include aziridinyl, azetidinyl, pyrrolidinvl. imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl,
  • bicyclic heterocyclyl groups in which one of the rings is non-aromatic include dihydrobenzofuranvl, indanvl. indolinyl, isoindolinyl, tetrahydroisoquinoiinvl, tetraliydroquinolvl and benzoazepanyl.
  • monocyclic aromatic heterocyclyl (or heterocycle) groups include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, tetrazolyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pvrazolvl and pyrimidinyl .
  • bicyclic aromatic heterocyclyl groups include quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, qiiinolin l. benzofuranyl, indolyl, benzothiazolyl, oxazoiyl[4,5-b]pyridiyl, pyridopyrimidinyl.
  • the compounds of the invention may contain chiral (asymmetric) centers or the molecule as a whole may be chiral.
  • the individual stereoisomers (enaiitiomers and diastereoisomers) and mixtures of these are within the scope of the present invention.
  • X and Q are attached to adjacent ring atoms of the A group.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • A is an 8- to 10-membered bicyclic aromatic carbocycle (e.g. napthalenyl) or, preferably, a heterocycle (e.g. quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, benzoxazolyl, benzothiazolyl, pyridopyridyl, pyrrolopyridyl, furanopyridyl, thienopyridyl).
  • a heterocycle e.g. quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, benzoxazolyl, benzothiazolyl, pyridopyridyl, pyrrolopyridyl, furanopyridyl, thienopyridyl).
  • the heterocyclic ring typically comprises from one to three heteroatoms each independently selected from nitrogen, oxygen and sulfur.
  • the compound of formula (I) has the formula (IA) or (IB)
  • p is 0 or 1; still more preferably the compound of formula (I) has the formula (IF) or (IEE), p is 0 or 1, and R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen and OCi_ 2 alkyl; yet more preferably the compound of formula (I) has the formula (IF), p is 0 or 1, and R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen and OCi_ 2 alkyl; most preferably the compound of formula (I) has the formula (IFa), (IFb) or (IFc):
  • R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen or OCi_ 2 alkyl.
  • A is an 8- to 10-membered bicyclic aromatic carbocycle (e.g. napthalenyl) or, preferably, a heterocycle (e.g. quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, indolyl, benzoxazolyl, benzothiazolyl, pyridopyridyl, pyrrolopyridyl, furanopyridyl, thienopyridyl) are particularly active against NMT of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv), and in particular Plasmodium falciparum (Pf).
  • Pf Plasmodium falciparum
  • Pv Plasmodium vivax
  • Pf Plasmodium falciparum
  • A is a 5- to 6-membered monocyclic aromatic carbocycle (e.g. phenyl) or heterocycle (e.g. pyridyl, pyrrolyl, thiophenyl, furanyl).
  • A is a 5- to 6-membered monocyclic heterocycle
  • the heterocyclic ring typically comprises one or two heteroatoms each independently selected from nitrogen, oxygen and sulfur.
  • G is -C(R E )- or -N-;
  • p is 0 or 1
  • each R E is independently selected from hydrogen, Ci_ 4 alkyl, C 2 - 4 alkenyl, C 2 - 4 alkynyl, trihaloCi_ 4 alkyl, OR c , -C(0)Ci_ 4 alkyl, -C(0)CF 3 , -C(0)N(R D ) 2 and C 3 _ 6 cycloalkyl. More preferably, the compound of formula (I) h
  • the compound of formula (I) has the formula (IJ) or (IK), p is 0 or 1, and R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen and OCi_ 2 alkyl; yet more preferably the compound of formula (I) has the formula (IK), p is 0 or 1, and R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen and OCi_ 2 alkyl.
  • A is a 5- to 6- membered monocyclic aromatic carbocycle or heterocycle
  • the compound of formula (I) has the formula (IM), (IN), (10), (IP) or (IQ):
  • each R 4 is independently selected from the group consisting of Ci_ 2 alkyl, trihalomethyl, halogen and OCi_ 2 alkyl; more preferably the compound has the formula (IM), (IN), (10), (IP) or (IQ), and where present each R 4 is independently selected from the group consisting of halogen or methoxy.
  • the compound of formula (I) has the formula (IPP)
  • R 4 is halogen
  • A is a 5 - to 6-membered, and especially 6-membered, monocyclic aromatic carbocycle (e.g. phenyl) or heterocycle (e.g. pyridyl, pyrrolyl, thiophenyl, furanyl) are particularly active against NMT of Plasmodium falciparum (Pf), Plasmodium vivax (Pv), and Leishmania donovani (Ld), and in particular Plasmodium falciparum (Pf) and Leishmania donovani (Ld).
  • Pf Plasmodium falciparum
  • Pv Plasmodium vivax
  • Ld Leishmania donovani
  • Pf Plasmodium falciparum
  • Pv Plasmodium vivax
  • Ld Leishmania donovani
  • Pf Plasmodium falciparum
  • Ld Leishmania donovani
  • A is a 5 - to 6-membered, and especially 6-membered, monocyclic aromatic carbocycle (e.g. phenyl) or heterocycle (e.g. pyridyl, pyrrolyl, thiophenyl, furanyl) substituted with one or more methoxy groups are at least are particularly active against NMT of Plasmodium falciparum (Pf).
  • monocyclic aromatic carbocycle e.g. phenyl
  • heterocycle e.g. pyridyl, pyrrolyl, thiophenyl, furanyl
  • X and Q are attached to adjacent ring atoms. In another embodiment, X and Q are attached to ring atoms which are separated by one intervening ring atom.
  • X is -0-, -S-, -NH-, -CH 2 0-, -CH 2 S-, -CH 2 NH-, - 0-Ci_ 6 alkylene, -0-C 2 _ 6 alkenylene, -0-C 2 _ 6 alkynylene, -0-C 3 - 7 cycloalkylene,-S-Ci_ 6 alkylene, -S-C 2 _ 6 alkenylene, -S-C 2 _ 6 alkynylene, -S-C 3 _ 7 cycloalkylene, -NH-Ci_ 6 alkylene, -NH-C 2 - 6 alkenylene, -NH-C 2 - 6 alkynylene, -NH-C 3 _ 7 cycloalkylene, Ci_ 6 alkylene,
  • X is -0-, -S-, CH 2 , -0-CH 2 - or -S-CH 2 -; more preferably X is -0-, -S- or -0-CH 2 -, most preferably X is -0-.
  • V is a 3- to 7-membered nitrogen-containing heterocycle which may be optionally substituted with one R 1 group; more preferably V is pyrrolidinyl or piperidyl; still more preferably V is piperidyl, yet more preferably V is 3 -piperidyl or 4-piperidyl; most preferably V is 4- piperidyl.
  • R 1 where present is preferably Ci_ 6 alkyl, phenyl-Ci_ 2 alkyl, 5- or 6-membered heterocycle- d_ 2 alkyl, C(0)-0-C(R') 2 -0-C(0)R', C(0)-0-C(R') 2 -0-P(0)(OR') 2 , C(0)-R' or C(0)-0-R'; wherein said phenyl or heterocycle may optionally be substituted with one or two R A groups.
  • R 1 is phenyl-Ci_ 2 alkyl or 5- or 6-membered heterocycle-Ci_ 2 alkyl, wherein said phenyl or heterocycle may optionally be substituted with one or two R A groups.
  • R 1 is preferably absent or is d_ 3 alkyl, C(0)-0-C(R') 2 -0-C(0)R', C(0)-0-C(R') 2 -0-P(0)(OR'), C(0)-R' or C(0)-0-R'; more preferably R 1 is absent or is d_ 2 alkyl, C(0)-0-C(R') 2 -0-C(0)R', C(0)-0-C(R') 2 - 0-P(0)(OR'), C(0)-R' or C(0)-0-R'; more preferably Ri is absent or is Ci_ 2 alkyl. In one preferred embodiment Ri is absent. In another preferred embodiment Ri is methyl.
  • X is -0-, -S-, CH 2 , -0-CH 2 - or -S-CH 2 -; and V is a 3- to 7- membered nitrogen- containing heterocycle which may be optionally substituted with one R 1 group which is Ci_ 2 alkyl. More preferably X is -0-, -S- or -0-CH 2 -; and V is piperidyl. Most preferably, X is -0-; and V is 4- piperidyl. In certain preferred embodiments, X is -0-, -S-, CH 2 , -0-CH 2 - or -S-CH 2 -; and V is a 3- to 7- membered nitrogen-containing heterocycle.
  • X is -O- and V is a 4-7 membered nitrogen-containing heterocycle. In certain preferred embodiments, X is -O- and V is a 4-7 membered non-aromatic nitrogen-containing heterocycle. In certain preferred embodiments, X is -O- and V is a pyrrolidine or piperidine ring. In certain referred embodiments, X is -O- and V is 4-
  • piperidyl or pyrrolidinyl e.g. X-V may be or
  • X is -0-Ci_ 6 alkylene, -0-C 2 _ 6 alkenylene, -0-C 2 _ 6 alkynylene, -0-C 3 _ vcycloalkylene, -S-Ci_ 6 alkylene, -S-C 2 _ 6 alkenylene, -S-C 2 _ 6 alkynylene, -S-C 3 _ 7 cycloalkylene,
  • R 6 is hydrogen, Ci_ 6 alkyl, 3- to 10-membered carbocycle, 3- to 10-membered heterocycle, 3- to 10-membered carbocycle-Ci_ 2 alkyl-, or 3- to 10-membered heterocycle-Ci_ 2 alkyl, wherein said alkyl, carbocycle or heterocycle may optionally be substituted with 1 or 2 R A groups; and R 3 is hydrogen, Ci_ 6 alkyl, a 3- to 10-membered carbocycle, 3- to 10-membered heterocycle,
  • X is -0-C 2 _ 4 alkylene, -0-C 2 _ 4 alkenylene, -O- C 2 _ 4 alkynylene, -0-C 3 _ 6 cycloalkylene, -S-C 2 _ 4 alkylene, -S-C 2 _ alkenylene,
  • alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups selected from F and CI; more preferably X is -0-C 2 _ alkylene or -S-C 2 _ alkynylene; still more preferably X is X is -0-C 3 alkylene.
  • R 2 is hydrogen, Ci_ 6 alkyl, phenyl-Ci_ 2 alkyl or 5- or 6-membered heterocycle-Ci_ 2 alkyl, wherein said phenyl or heterocycle may optionally be substituted with one or two R A groups.
  • R 2 is phenyl-Ci_ 2 alkyl or 5- or 6-membered heterocycle-Ci_ 2 alkyl, wherein said phenyl or heterocycle may optionally be substituted with one or two R A groups.
  • R 2 is preferably hydrog en or Ci_ 2 alkyl.
  • R 2 is hydrogen.
  • R 2 is methyl.
  • R 3 is hydrogen, d_ 2 alkyl, C(0)-0-C(R') 2 -0-C(0)R', C(0)-0-C(R') 2 -0-P(0)(OR') 2 , C(0)-R' or C(0)-0-R'; more preferably R 3 is hydrogen or methyl. In one preferred embodiment R 3 is hydrogen. In another preferred embodiment R 3 is methyl. In certain preferred embodiments, X is -0-C 2 _ alkylene, -0-C 2 _ alkenylene, -0-C 2 _ alkynylene, -0-C 3 _ 6 cycloalkylene, -S-C 2 _ alkylene, -S-C 2 _ alkenylene,
  • X is -0-C 3 _ 7 cycloalkylene and V is NR 2 R 3 , wherein R 2 and R 3 are each independently selected from the group consisting of hydrogen and Ci_ 6 alkyl.
  • X is -0-C c cloalkylene and V is NR 2 R 3 (e.g. X-V may be
  • R 1 or R 3 is C(0)-0-C(R') 2 -0-C(0)R', C(0)-0-C(R') 2 -0- P(0)(OR') 2 , C(0)-R' or C(0)-0-R' act as prodrug compounds.
  • the C(0)-0-C(R') 2 -0- C(0)R', C(0)-0-C(R') 2 -0-P(0)(OR') 2 , C(0)-R' or C(0)-0-R' group is cleaved from the nitrogen atom in the V group leaving an NH group behind to exert its therapeutic effect.
  • p is an integer of from 0 to 2; more preferably p is 0 or 1 ; most preferably p is 0.
  • R 4 is d_ 4 alkyl, trihaloC 1 _ 4 alkyl, -C(0)C 1 _ 4 alkyl, -C(0)CF 3 , -C(0)N(R D ) 2 , -CH 2 OR c , halogen, OR c , N(R D ) 2 and SR C ; more preferably R 4 is halogen, Ci_ 4 alkyl or -OCi_ 3 alkyl; still more preferably R 4 is Ci_ 4 alkyl or -OCi_ 3 alkyl.
  • R G is selected from hydrogen, Ci_ 4 alkyl, trihaloCi_ 4 alkyl, halogen and -OCi_ 3 alkyl.
  • Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carboc cle or heterocycle may optionally be substituted with one group; more preferably Q is
  • R G is selected from hydrogen, Ci_ 4 alkyl, trihaloCi_ 4 alkyl, halogen and -OCi_ 3 alkyl; most
  • Q 1 is preferably a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionall be substituted with one group; more preferably Q is
  • R G is selected from hydrogen, Ci_ 4 alkyl, trihaloCi_ 4 alkyl, halogen and -OCi_ 3 alkyl; most
  • Q 1 is Q 2 is preferably bond or Ci_ 4 alkylene, wherein said Ci_ 4 alkylene may be optionally substituted with one R A groups, and wherein one methylene group of said Ci_ 4 alkylene may optionally be replaced by - 0-, -S- or N(R D ); more preferably Q 2 is bond, -CH 2 -, -CH 2 -CH 2 - -CH 2 -CH 2 -CH 2> -0-CH 2 -,
  • B is preferably C 2 _ 4 alkyl, C 5 _i 0 cycloalkyl or a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said C 5 _i 0 cycloalkyl may optionally be substituted with one or two Ci_ alkyl groups, and said carbocycle or heterocycle may be optionally substituted with from one to three groups each independently selected from Ci_ alkyl, trihaloCi_ alkyl, -OH, -OCi_ 3 alkyl,-N(R D ) 2 , -C(0)d_ 3 alkyl, -C(0)CF 3 ,-C(0)N(R D ) 2 , -CH 2 OR c , halogen, -SH and -SC ⁇ alkyl; more preferably B is a 5- to 10-membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may be optionally substituted with from one to three groups each
  • B is a 5-10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen; more preferably B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen; still more preferably B is phenyl or a 5-6 membered aromatic heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.
  • Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R B group, R B where present is selected from the group consisting of Ci_ alkyl, 0-Ci_ alkyl, halogen, NH 2 and hydroxy, Q 2 is bond or Ci_ alkylene, wherein said Ci_ alkylene may optionally be substituted with one R A group, and R A where present is selected from the group consisting of halogen, OH and OCi_ 3 alkyl. More preferably, Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle and Q 2 is bond or Ci_
  • Q 2 is -CH 2 - or -CH 2 -CH 2 -.
  • each R A is independently selected from OH, OCi_ 3 alkyl, -NH 2 , -NH(Ci_ 3 alkyl), -N(Ci_ 3 alkyl) 2 , NHC(0)Ci_ 4 alkyl and halogen.
  • Q is -C(0)0-CH 2 -CH 2 -, oxadiazolyl-CH 2 -, oxadiazolyl-CH 2 -CH 2 -; and B is phenyl optionally substituted by one to three groups each independently selected from Ci_ alkyl, 0-Ci_ 3 alkyl, halogen, trihaloCi_ alkyl.
  • Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R B group, R B where present is selected from the group consisting of Ci_ alkyl, 0-Ci_ alkyl, halogen, NH 2 and hydroxy, Q 2 is bond or Ci_ alkylene, wherein said Ci_ alkylene may optionally be substituted with one group, R A where present is selected from the group consisting of halogen, OH and OCi_ 3 alkyl, and B is a 5- 10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.
  • Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle
  • Q 2 is bond or Ci_ alkylene
  • B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.
  • Q 1 is , Q 2 is -CH 2 - or -CH 2 - CH 2 - and B is phenyl or a 5-6 membered aromatic heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ 4 alkyl, OCi_ 4 alkyl and halogen.
  • each R B is independently selected from Ci_ 4 alkyl, trihaloCi_ 4 alkyl, -C(0)Ci_ alkyl, - C(0)CF 3 , -C(0)N(R D ) 2 , -CH 2 OR c , halogen, OR c , N(R D ) 2 and SR C .
  • each R c is independently selected from hydrogen, Ci_ alkyl and trihaloCi_ alkyl.
  • each R D is independently selected from hydrogen, Ci_ alkyl and trihaloCi_ alkyl.
  • each R' is independently selected from hydrogen and Ci_ 3 alkyl.
  • Q 2 is bond or Ci_ alkylene, wherein said Ci_ alkylene may optionally be substituted with one R A group, and wherein one methylene group of said Ci_ alkylene may optionally be replaced by -
  • X is -0-, -S-, CH 2 , -0-CH 2 - or -S-CH 2 -
  • V is a 3- to 7- membered nitrogen-containing heterocycle which may be optionally substituted with one R 1 group which is Ci_ 2 alkyl; or X is -0-C 2 _ alkylene, -0-C 2 _ alkenylene, -0-C 2 _ alkynylene, -O- C 3 _ 6 cycloalkylene, -S-C 2 _ alkylene, -S-C 2 _ alkenylene, -S-C 2 _ alkynylene, -S-C 3 _ 6 cycloalkylene, -NH- C 2 _ alkylene, -NH-C 2 _ alkenylene, -NH-C 2 _ alkynylene, -NH-C 3 _ 6 cycloalkylene, C 2 _ alkylene, C 2 _ alkylene, C
  • Q 1 is -C(0)0- and Q 2 is bond
  • B is C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, 5- to 10-membered carbocycle or 5- to 10-membered heterocycle comprising up to three heteroatoms
  • said C 2 _ 6 alkenyl or C 2 _ 6 alkynyl may optionally be substituted with 1 or 2 R A groups
  • said carbocycle or heterocycle may optionally be substituted with from 1 to 3 substituents each independently selected from R B , -0-Ci_ 6 alkyl-CN, -S(O) 0 - 2 Ci_ 6 alkyl, -S(O) 0 - 2 Ci_ 6 alkyl-CN, -C(0)-Ci_ 6 alkyl-CN, C(0)NH-Ci_ 6 alkyl-CN and phenyl.
  • B is 5- to 10-membered carbocycle or 5- to 10-membered heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from 1 to 3 substituents each independently selected from R B , -O-C ⁇ alkyl-CN, -S(O) 0 - 2 C 1 _ 6 alkyl, -S(O) 0 - 2 C 1 _ 6 alkyl-CN, -C C -C ⁇ alkyl-CN, C(0)NH-d_ 6 alkyl-CN and phenyl.
  • A is an 8- to 10-membered bicyclic aromatic carbocycle or heterocycle (e.g. in a compound of formula (IA) or (IB)), preferably B is C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, 5- to 10-membered carbocycle or 5- to 10-membered heterocycle comprising up to three heteroatoms, wherein said C 2 _ 6 alkenyl or C 2 _ 6 alkynyl may optionally be substituted with 1 or 2 R A groups, and wherein said carbocycle or heterocycle may optionally be substituted with from 1 to 3 substituents each independently selected from R B , -0-Ci_ 6 alkyl-CN, -S(O) 0 - 2 C 1 _ 6 alkyl, -S(O) 0 - 2 C 1 _ 6 alkyl-CN, -C(0)-C 1 _ 6 alkyl-CN, C(0)NH-C 1 _ 6 alkyl-CN and phenyl;
  • A is an 8- to 10-membered bicyclic aromatic carbocycle or heterocycle (e.g. in a compound of formula (IA) or (IB)), preferably Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R B group; R B where present is selected from the group consisting of Ci_ alkyl, 0-Ci_ alkyl, halogen, NH 2 and hydroxy; Q 2 is bond or Ci_ 4 alkylene, wherein said Ci_ 4 alkylene may optionally be substituted with one R A group; R A where present is selected from the group consisting of halogen, OH and OCi_ 3 alkyl; and B is a 5- 10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ 4 alkyl, OCi_ 4 alkyl and halogen.
  • Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle
  • Q 2 is bond or Ci_ alkylene
  • B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.
  • Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle
  • Q 2 is bond or Ci_ alkylene
  • B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.
  • Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle
  • Q 2 is bond or Ci_ alkylene
  • B is a 5-10 membered aromatic carbocycle or heterocycle comprising
  • Q is -CH 2 - or -CH 2 -
  • B is phenyl or a 5-6 membered aromatic heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.
  • the compound of formula I has the formula (IE), (IF) or (IEE), wherein p is 0 or 1, and R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen or OCi_ 2 alkyl;
  • X is -0-;
  • V is 4- piperidyl;
  • Q is -C(0)0-CH 2 -CH 2 -, oxadiazolyl-CH 2 - or oxadiazolyl-CH 2 -CH 2 -;
  • B is phenyl optionally substituted by one to three groups each independently selected from Ci_ alkyl, 0-Ci_ 3 alkyl, halogen and trihaloCi_ alkyl.
  • A is not naphthalene. In certain embodiments of the compound of formula (I) in which A is an 8- to 10-membered bicyclic aromatic heterocycle or carbocycle, Q 1 is not pyrimidine. In certain embodiments of the compound of formula (I) in which A is an 8- to 10- membered bicyclic aromatic heterocycle or carbocycle, A is not indole. In certain embodiments of the compound of formula (I) in which A is an 8- to 10-membered bicyclic aromatic heterocycle or carbocycle and V is a 3- to 7-membered nitrogen-containing heterocycle, V is not aromatic.
  • R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen and OCi_ 2 alkyl;
  • X is -0-, -S-, CH 2 , -0-CH 2 - or -S-CH 2 -; and V is a 3- to 7- membered nitrogen-containing heterocycle,
  • X is -0-C 3 _ 7 cycloalkylene; and V is NR 2 R 3 ; R 2 and R 3 are each independently selected from the group consisting of hydrogen and Ci_ 6 alkyl; Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R B group; R B where present is selected from the group consisting of Ci_ 4 alkyl, 0-Ci_ 4 alkyl, halogen, NH 2 and hydroxy; Q 2 is bond or Ci_ 4 alkylene, wherein said Ci_ 4 alkylene may optionally be substituted with one R A group; R A where present is selected from the group consisting of halogen, OH and OCi_ 3 alkyl; and B is a 5-10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ al
  • the compound of formula (I) has the formula (IFa), (IFb) or (IFc); R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen or OCi_ 2 alkyl; X is -0-, -S-, CH 2 , -0-CH 2 - or -S-CH 2 -; V is a 3- to 7- membered nitrogen-containing heterocycle; Q 1 is a 5- to 6- membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R B group; R B where present is selected from the group consisting of Ci_ alkyl, 0-Ci_ alkyl, halogen, NH 2 and hydroxy; Q 2 is bond or Ci_ alkylene, wherein said Ci_ alkylene may optionally be substituted with one R A group; R A where present is selected from the group consisting of halogen, OH and OCi_ 3 alkyl; and B is a 5-10 member
  • the compound of formula (I) has the formula (IFa), (IFb) or (IFc); R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen or OCi_ 2 alkyl; X is -0-; V is a 4-7 membered non-aromatic nitrogen-containing heterocycle; Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle; Q 2 is bond or Ci_ alkylene; and B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.
  • R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen or OCi_ 2 alkyl
  • X is -0-
  • V is a 4-7 membered non-aromatic nitrogen-containing heterocycle
  • Q 1 is a 5- to 6-membered aromatic carb
  • the compound of formula (I) has the formula (IFa), (IFb) or (IFc); R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen or OCi_ 2 alkyl; X is -0-; V is a piperidine or a pyrrolidine ring (e.g. X-V may be ); Q 1 is
  • B is phenyl or a 5-6 membered aromatic heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ 4 alkyl, OCi_ 4 alkyl and halogen.
  • the compound of formula (I) has the formula (IFa), (IFb) or (IFc); R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen or OCi_ 2 alkyl; X is -0-C 3 _ vcycloalkylene; V is NR 2 R 3 ; R 2 and R 3 are each independently selected from the group consisting of hydrogen and Ci_ 6 alkyl; Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R B group; R B where present is selected from the group consisting of Ci_ 4 alkyl, 0-Ci_ 4 alkyl, halogen, NH 2 and hydroxy; Q 2 is bond or Ci_ 4 alkylene, wherein said Ci_ 4 alkylene may optionally be substituted with one R A group; R A where present is selected from the group consisting of halogen, OH and OCi_ 3 alkyl; and B is
  • the compound of formula (I) has the formula (IFa), (IFb) or (IFc); R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen or OCi_ 2 alkyl; X is -O- C cycloalkylene; V is NR 2 R 3 ; R 2 and R 3 are each independently selected from the group consisting of hydrogen and Ci_ 2 alkyl; Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle; Q 2 is bond or Ci_ alkylene; and B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.
  • R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen or OCi_ 2 alkyl
  • X is -O- C cycloalkylene
  • V is NR 2
  • the compound of formula (I) has the formula (IFa), (IFb) or (IFc); R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen or OCi_ 2 alkyl; X is
  • V is NR 2 R 3 (e.g. X-V may be
  • Q 2 is -CH 2 - or -CH 2 -CH 2 -; and B is phenyl or a 5-6 membered aromatic heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ 4 alkyl, OCi_ 4 alkyl and halogen.
  • the invention provides a compound of formula (IF)
  • R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen or OCi_ 2 alkyl;
  • X is -0-, -S-, CH 2 , -0-CH 2 - or -S- CH 2 -;
  • V is a 3- to 7- membered nitrogen-containing heterocycle (e.g. piperidine or pyrrolidine) which is substituted with 1 or 2 fluorine atoms;
  • Q is Q : -Q 2 ;
  • Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R group
  • Ci_ 4 alkyl 0-Ci_ 4 alkyl, halogen, NH 2 and hydroxy
  • Q 2 is bond or Ci_ 4 alkylene, wherein said Ci_ 4 alkylene may optionally be substituted with one group (e.g. Q 2 may be -CH 2 - or -CH 2 -CH 2 -);
  • R A where present is selected from the group consisting of halogen, OH and OCi_ 3 alkyl;
  • B is a 5-10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.
  • A is a 5- to 6-membered monocyclic aromatic carbocycle or heterocycle, preferably Q 1 is a 5- or 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R B group;
  • Q 2 is bond or Ci_ alkylene, wherein said Ci_ alkylene may be optionally substituted with one R A groups, and wherein one methylene group of said Ci_ alkylene may optionally be replaced by -0-, -S- or N(R D ); and
  • B is C 2 _ alkyl, C 5 _i 0 cycloalkyl or 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said C 5 _ l ocycloalkyl may optionally be substituted with one or two Ci_ alkyl groups, and said carbocycle or heterocycle may be optionally substituted with from one to three groups each independently selected from -C(0)CF 3 ,-C(0)N(R D )
  • X is -0-, -S-, CH 2 , -0-CH 2 - or -S- CH 2 -
  • V is a 3- to 7- membered nitrogen-containing heterocycle which may be optionally substituted with one R 1 group which is Ci_ 2 alkyl; or X is -0-C 2 _ alkylene, -0-C 2 _ alkenylene, -O- C 2 _ alkynylene, -0-C 3 _ 6 cycloalkylene, -S-C 2 _ alkylene, -S-C 2 _ alkenylene, -S-C 2 _ alkynylene, -S-C 3 _ 6 cycloalkylene, -NH-C 2 _ alkylene, -NH-C 2 _ alkenylene, -NH-C 2 _ alkynylene, -NH-C 3 _ 6 cycloalkylene, C 2 _ alkylene, C 2 _ alkylene, C
  • X is -0-, -S-, CH 2 , -0-CH 2 - or -S-CH 2 -; and V is a 3- to 7- membered nitrogen-containing heterocycle.
  • X is -O- and V is a 4-7 membered nitrogen-containing heterocycle.
  • X is -O- and V is a 4-7 membered non-aromatic heterocycle.
  • X is -O- and V is a pyrrolidine or piperidine ring (e.g. X-V may be
  • A is a phenyl ring
  • X is -0-, -S-, -NH-, -CH 2 0-, -CH 2 S-, -CH 2 NH-, -0-Ci_ 6 alkylene, -0-C 2 _ 6 alkenylene, -0-C 2 _ 6 alkynylene, -0-C 3 - 7 cycloalkylene,-S-Ci_ 6 alkylene, -S-C 2 _ 6 alkenylene, -S-C 2 _ 6 alkynylene, -S-C 3 _ 7 cycloalkylene, -NH-Ci_ 6 alkylene,
  • A is a phenyl ring
  • X is -0-, -S-, CH 2 , -0-CH 2 - or -S-CH 2 -; and V is a 3- to 7- membered nitrogen-containing heterocycle.
  • X is -O- and V is a 4-7 membered nitrogen-containing heterocycle. In certain preferred embodiments, X is -O- and V is a 4-7 membered non-aromatic nitrogen- containin heterocycle. In certain preferred embodiments, X is -O- and V is pyrrolidine or piperidine
  • X is -0-, -NH-, -CH 2 0-, -CH 2 S-, -CH 2 NH-, -0-Ci_ 6 alkylene, -0-C 2 _ 6 alkenylene,
  • X is -0-Ci_ 6 alkylene, -0-C 2 _ 6 alkenylene, -0-C 2 _ 6 alkynylene, -0-C 3 _ 7 cycloalkylene, -S-Ci_ 6 alkylene, -S-C 2 - 6 alkenylene, -S-C 2 - 6 alkynylene, -S-C 3 _ 7 cycloalkylene, -NH-Ci_ 6 alkylene, -NH- C 2 _ 6 alkenylene, -NH-C 2 - 6 alkynylene, -NH-C 3 _ 7 cycloalkylene, Ci_ 6 alkylene, C 2 _ 6 alkenylene or
  • alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups independently selected from F and CI; and V is NR 2 R 3 .
  • the compound of formula I has the formula (IJ) or (IK), wherein p is 0 or 1, and R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen and OCi_ 2 alkyl; X is -0-; V is 4- piperidyl; Q is -C(0)0-CH 2 -CH 2 -, oxadiazolyl-CH 2 -, oxadiazolyl-CH 2 -CH 2 -; and B is phenyl optionally substituted by one to three groups each independently selected from Ci_ 4 alkyl, 0-Ci_ 3 alkyl, halogen, trihaloCi_ 4 alkyl.
  • the compound of formula (I) has the formula (IM), (IN), (10), (IP) or (IQ); where present each R 4 is independently selected from the group consisting of Ci_ 2 alkyl, trihalomethyl, halogen and OCi_ 2 alkyl; X is -0-, -S-, CH 2 , -0-CH 2 - or -S-CH 2 -; V is a 3- to 7- membered nitrogen-containing heterocycle; Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R B group; R B where present is selected from the group consisting of Ci_ 4 alkyl, 0-Ci_ 4 alkyl, halogen, NH 2 and hydroxy; Q 2 is bond or Ci_ alkylene, wherein said Ci_ alkylene may optionally be substituted with one R A group; R A where present is selected from the group consisting of halogen, OH and OCi_
  • the compound of formula (I) has the formula (IM), (IN), (10), (IP) or (IQ); where present each R 4 is independently selected from the group consisting of Ci_ 2 alkyl, trihalomethyl, halogen and OCi_ 2 alkyl; X is -0-; V is a 4-7 membered non-aromatic nitrogen-containing heterocycle; Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle; Q 2 is bond or Ci_ alkylene; and B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.
  • the compound of formula (I) has the formula ((IM), (IN), (10), (IP) or (IQ); where present each R 4 is independently selected from the group consisting of halogen and methoxy;
  • X is -0-;
  • V is a pyrrolidine or piperidine ring (e.g. X-V may be ;
  • Q is -CH 2 - or -CH 2 -CH 2 -; and
  • B is phenyl or a 5-
  • 6 membered aromatic heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ 4 alkyl, OCi_ 4 alkyl and halogen.
  • each R 4 is independently selected from the group consisting of Ci_ 2 alkyl, trihalomethyl, halogen and OCi_ 2 alkyl;
  • X is -0-, -S-, CH 2 , -0-CH 2 - or -S-CH 2 -;
  • V is a 3- to 7- membered nitrogen- containing heterocycle (e.g. piperidine or pyrrolidine) which is substituted with 1 or 2 fluorine atoms;
  • Q is Q : -Q 2 ;
  • Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R B group (e.g. Q 1 may
  • R where present is selected from the group consisting of Ci_ 4 alkyl, 0-Ci_ 4 alkyl, halogen, NH 2 and hydroxy;
  • Q 2 is bond or wherein said Ci_ 4 alkylene may optionally be substituted with one R A group (e.g. Q 2 may be -CH 2 - or -CH 2 -CH 2 -);
  • R A where present is selected from the group consisting of halogen, OH and OCi_ 3 alkyl; and B is a 5-10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ 4 alkyl, OCi_ 4 alkyl and halogen.
  • R c , R D and R' are the same as for the compound of formula (I) above.
  • the compound has the formula ( II A). (IIB), (IIC), (IID) or (HE).
  • X is -0-, -S-, -CH 2 -, -0-CH 2 - or -S-CH 2 -; and V is a 3-7-membered nitrogen- containing heterocycle, wherein said heterocycle may optionally be substituted with one R 1 group which is d_ 2 alkyl, C(0)-0-C(R') 2 -0-C(0)R' or C(0)-0-C(R') 2 -0-P(0)(OR') 2 .
  • X is -0-, -S- or -0-CH 2 -, most preferably X is -0-.
  • V is pyrrolidinyl or piperidyl; still more preferably V is piperidyl, yet more preferably V is 3-piperidyl or 4-piperidyl; most preferably V is 4-piperidyl.
  • R 1 is preferably absent or is Ci_ 2 alkyl. In one preferred embodiment Ri is absent. In another preferred embodiment Ri is methyl.
  • X is -0-, -S-, CH 2 , -0-CH 2 - or -S-CH 2 -; and V is a 3- to 7- membered nitrogen- containing heterocycle which may be optionally substituted with one R 1 group which is Ci_ 2 alkyl. More preferably, X is -0-, -S- or -0-CH 2 -; and V is piperidyl.
  • X is -0-, -S-, CH 2 , -0-CH 2 - or -S-CH 2 -; and V is a 3- to 7- membered nitrogen-containing heterocycle.
  • X is -O- and V is a 4-7 membered nitrogen-containing heterocycle.
  • X is -O- and V is a 4-7 membered non-aromatic nitrogen-containing heterocycle.
  • X is -O-
  • V is a pyrrolidine or piperidine ring (e.g. X-V may be or
  • X is -0-C 2 _ 4 alkylene, -0-C 2 _ alkenylene, -0-C 2 _ alkynylene, -0-C 3 _
  • X is -0-C 2 _ 4 alkylene or -S-C 2 _ 4 alkynylene; still more preferably X is -0-C 3 alkylene.
  • R 2 is hydrogen. In another preferred embodiment R 2 is methyl.
  • R 3 is hydrogen or methyl. In one preferred embodiment R 3 is hydrogen. In another preferred embodiment R 3 is methyl.
  • X is -0-C 2 _ 4 alkylene, -O- C 2 _ 4 alkenylene, -0-C 2 _ 4 alkynylene, -0-C 3 _ 6 cycloalkylene, -S-C 2 _ 4 alkylene, -S-C 2 _ 4 alkenylene, -S-C 2 _ 4 alkynylene, -S-C 3 _ 6 cycloalkylene, -NH-C 2 _ 4 alkylene, -NH-C 2 _ 4 alkenylene,
  • X is -0-C 3 _ 7 cycloalkylene and V is NR 2 R 3 , wherein R 2 and R 3 are each independently selected from the group consisting of hydrogen and Ci_ 6 alkyl.
  • X is -0-C 4 c cloalkylene and V is NR 2 R 3 (e.g. X-V may be
  • R 5 is preferably Ci_ 3 alkyl, more preferably methyl.
  • R G is selected from hydrogen, Ci_ 4 alkyl, trihaloCi_ 4 alkyl, halogen and -OCi_ 3 alkyl.
  • Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carboc cle or heterocycle may optionally be substituted with one group; more preferably Q is
  • R G is selected from hydrogen, Ci_ 4 alkyl, trihaloCi_ 4 alkyl, halogen and -OCi_ 3 alkyl; most
  • Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one group
  • R B where present is selected from the group consisting of Ci_ 4 alkyl, 0-Ci_ 4 alkyl, halogen, NH 2 and hydroxy
  • Q 2 is bond or Ci_ alkylene, wherein said Ci_ alkylene may optionally be substituted with one R A group, R A where present is selected from the group consisting of halogen, OH and OCi_ 3 alkyl
  • B is a 5-10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.
  • Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle
  • Q 2 is bond or Ci_ alkylene
  • B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and
  • Q 1 is , or
  • Q 2 is -CH 2 - or -CH 2 -CH 2 - and B is phenyl or a 5-6 membered aromatic heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.
  • X is -0-, -S-, CH 2 , -0-CH 2 - or -S-CH 2 -; and V is a 3- to 7- membered nitrogen-containing heterocycle which may be optionally substituted with one R 1 group which is Ci_ 2 alkyl; or X is -0-C 2 _ 4 alkylene, -0-C 2 _ 4 alkenylene, -0-C 2 _ 4 alkynylene, -0-C 3 _ 6 cycloalkylene, -S-C 2 _ 4 alkylene, -S-C 2 _ alkenylene, -S-C 2 _ alkynylene, -S-C 3 _ 6 cycloalkylene, -NH-C 2 _ alkylene, -NH-C 2 _ alkenylene, -NH- C 2 _ alkyn
  • B is C 2 _ alkyl, C 5 _i 0 cycloalkyl or 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said C 5 _i 0 cycloalkyl may optionally be substituted with one or two Ci_ alkyl groups, and said carbocycle or heterocycle may be optionally substituted with from one to three groups each independently selected from Ci_ alkyl, trihaloCi_ alkyl, -OH, -OCi_ 3 alkyl,-N(R D ) 2 , - C(0)d_ 3 alkyl, -C(0)CF 3 ,-C(0)N(R D ) 2 , -CH 2 OR c , halogen, -SH and -SC ⁇ alkyl.
  • p is 0 or 1
  • R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen and OCi_ 2 alkyl;
  • X is -0-;
  • V is 4-piperidyl;
  • Q is -C(0)0-CH 2 -CH 2 -, oxadiazolyl-CH 2 -, oxadiazolyl-CH 2 -CH 2 -;
  • B is phenyl optionally substituted by one to three groups each independently selected from Ci_ alkyl, 0-Ci_ 3 alkyl, halogen, trihaloCi_ alkyl.
  • the compound has the formula (IIF); p is 0; X is -0-, - S-, CH 2 , -0-CH 2 - or -S-CH 2 -; V is a 3- to 7- membered nitrogen-containing heterocycle; R 5 is Ci_ 3 alkyl; Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R B group; R B where present is selected from the group consisting of Ci_ alkyl, 0-Ci_ alkyl, halogen, NH 2 and hydroxy; Q 2 is bond or Ci_ alkylene, wherein said Ci_ alkylene may optionally be substituted with one R A group; R A where present is selected from the group consisting of halogen, OH and OCi_ 3 alkyl; and B is a 5-10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optional
  • the compound has the formula (IIF); p is 0; X is -0-; V is a 4-7 membered non-aromatic nitrogen-containing heterocycle; R 5 is methyl; Q 1 is a 5- to 6- membered aromatic carbocycle or heterocycle; Q 2 is bond or Ci_ 4 alkylene; and B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ 4 alkyl, OCi_ 4 alkyl and halogen.
  • the com ound has the formula (IIF); p is 0; X is -0-; V
  • X-V is a pyrrolidine or piperidine ring (e.g. X-V may be
  • B is phenyl or a 5-6 membered aromatic heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ 4 alkyl, OCi_ alkyl and halogen.
  • the invention provides a compound of formula ( ⁇ ), (IIB), (IIC), (IID), (HE) or (IIF)
  • IID HE
  • IIF a pharmaceutically acceptable salt thereof, wherein: p is 0 or 1; R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen or OCi_ 2 alkyl, X is -0-, -S-, CH 2 , -O- CH 2 - or -S-CH 2 -; V is a 3- to 7- membered nitrogen-containing heterocycle (e.g.
  • the compound has the formula (IIF); p is 0; R 5 is Ci_ 3 alkyl.
  • the compound of formula (III) has the formula (Ilia), (Illb)
  • R 4 is Ci_ 2 alkyl, trihalomethyl, halogen or OCi_ 2 alkyl; and R 5 is Ci_ 3 alkyl. More preferably, the compound of formula (III) has the formula (Ilia), (Illb) or (IIIc); R 4 where present is halogen; and R 5 is methyl.
  • X is -0-, -S- or -0-CH 2 -, most preferably X is -0-.
  • V is pyrrolidinyl or piperidyl; still more preferably V is piperidyl, yet more preferably V is 3-piperidyl or 4-piperidyl; most preferably V is 4-piperidyl.
  • R 1 is preferably absent or is Ci_ 2 alkyl.
  • Ri is absent.
  • Ri is methyl.
  • X is -0-, -S- or -O-CH 2 -; and V is piperidyl.
  • X is -0-, -S- or -0-CH 2 -; and V is 3-piperidyl or 4- piperidyl.
  • X is -0-, -S-, CH 2 , -0-CH 2 - or -S-CH 2 -; and V is a 3- to 7- membered nitrogen-containing heterocycle.
  • X is -O- and V is a 4-7 membered nitrogen-containing heterocycle.
  • X is -O- and V is a 4-7 membered non-aromatic nitrogen-containing heterocycle.
  • X is
  • V is a pyrrolidine or piperidine ring (e.g. X-V may be
  • X is -0-, -S- or -0-CH 2 -;
  • B is C 2 _ alkyl, C 5 _i 0 cycloalkyl or 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said C 5 _i 0 cycloalkyl may optionally be substituted with one or two Ci_ alkyl groups, and said carbocycle or heterocycle may be optionally substituted with from one to three groups each independently selected from Ci_ alkyl, trihaloCi_ alkyl, -OH, -OCi_ 3 alkyl,-N(R D ) 2 , - C C Cwalkyl, -C(0)CF 3 ,-C(0)N(R D ) 2 , -CH 2 OR c , halogen, -SH and -SC ⁇ alkyl.
  • Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R B group, R B where present is selected from the group consisting of Ci_ alkyl, 0-Ci_ alkyl, halogen, NH 2 and hydroxy, Q 2 is bond or Ci_ alkylene, wherein said Ci_ alkylene may optionally be substituted with one R A group, R A where present is selected from the group consisting of halogen, OH and OCi_ 3 alkyl, and B is a 5- 10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ 4 alkyl, OCi_ 4 alkyl and halogen.
  • Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle
  • Q 2 is bond or Ci_ 4 alkylene
  • B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ 4 alkyl, OCi_ alkyl and halogen.
  • Q 1 is
  • CH 2 - and B is phenyl or a 5-6 membered aromatic heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.
  • Ci_ 4 alkylene wherein said Ci_ 4 alkylene may optionally be substituted with one R A group, and wherein one methylene group of said Ci_ alkylene may optionally be replaced by -0-, -S- or N(R D ).
  • p is 0 or 1, and R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen and OCi_ 2 alkyl;
  • X is -0-;
  • V is 4-piperidyl;
  • Q is -C(0)0-CH 2 -CH 2 -, oxadiazolyl-CH 2 -, oxadiazolyl-CH 2 -CH 2 -;
  • B is phenyl optionally substituted by one to three groups each independently selected from Ci_ alkyl, 0-Ci_ 3 alkyl, halogen, trihaloCi_ alkyl.
  • the compound has the formula (Ilia), (Illb) or (IIIc); where present R 4 is Ci_ 2 alkyl, trihalomethyl, halogen or OCi_ 2 alkyl; R 5 is Ci_ 3 alkyl; X is -0-, -S-, CH 2 , -0-CH 2 - or -S-CH 2 -; V is a 3- to 7- membered nitrogen-containing heterocycle; R 5 is Ci_ 3 alkyl; Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally be substituted with one R B group; R B where present is selected from the group consisting of Ci_ alkyl, 0-Ci_ alkyl, halogen, NH 2 and hydroxy; Q 2 is bond or Ci_ alkylene, wherein said Ci_ alkylene may optionally be substituted with one R A group; R A where present is selected from the group consisting of halogen, OH
  • the compound has the formula (Ilia), (Illb) or (IIIc); R 4 where present is halogen; R 5 is methyl; X is -0-; V is a 4-7 membered non-aromatic nitrogen- containing heterocycle; R 5 is methyl; Q 1 is a 5- to 6-membered aromatic carbocycle or heterocycle; Q 2 is bond or Ci_ 4 alkylene; and B is a 5-10 membered aromatic carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ 4 alkyl, OCi_ 4 alkyl and halogen.
  • the compound has the formula (Ilia), (Illb) or (IIIc); R 4 where resent is halogen; R 5 is methyl; X is -0-; V is a pyrrolidine or piperidine ring (e.g. X-V may
  • B is phenyl or a 5-6 membered aromatic heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ 4 alkyl, OCi_ alkyl and halogen.
  • the invention provides a compound of formula (Ilia), (Illb) or (IIIc)
  • R 4 is Ci_ 2 alkyl, trihalomethyl, halogen or OCi_ 2 alkyl
  • R 5 is Ci_ 3 alkyl
  • X is -0-, -S-, CH 2 , -0-CH 2 - or -S-CH 2 -
  • V is a 3- to 7- membered nitrogen-containing heterocycle (e.g. piperidine or pyrrolidine) which is substituted with 1 or 2 fluorines
  • R 5 is Ci_ 3 alkyl
  • Q is Q : -Q 2
  • Q 1 is a 5- to 6- membered aromatic carbocycle or heterocycle, wherein said carbocycle or heterocycle may optionally
  • R B group e.g. Q 1 may be or
  • R where present is selected from the group consisting of Ci_ 4 alkyl, O-C 1- 4 alkyl, halogen, NH 2 and hydroxy;
  • Q 2 is bond or Ci_ 4 alkylene, wherein said Ci_ 4 alkylene may optionally be substituted with one group (e.g.
  • Q 2 may be -CH 2 - or -CH 2 -CH 2 -); R A where present is selected from the group consisting of halogen, OH and OCi_ 3 alkyl; and B is a 5-10 membered carbocycle or heterocycle comprising up to three heteroatoms, wherein said carbocycle or heterocycle may optionally be substituted with from one to three groups each independently selected from Ci_ alkyl, OCi_ alkyl and halogen.
  • the compounds of the invention have activity as N-myristoyl transferase inhibitors.
  • Compounds of the invention which are defined as having activity as N-myristoyl transferase inhibitors have an IC 50 of less than or equal to ⁇ , preferably less than or equal to 20 ⁇ , and more preferably less than or equal to 5 ⁇ .
  • the compounds of the invention may be competitive inhibitors or partial competitive inhibitors of the NMT enzyme.
  • the compounds of the invention may thus be used in the treatment of diseases or disorders associated with NMT activity or may be used in the treatment of a diseases or disorders by targeting NMT activity (for example in microbial infections, hyperproliferative diseases of disorders). Accordingly, there is provided a compound of the invention for use as a medicament.
  • the invention also provides a method for the treatment or prophylaxis of a disease or disorder in a subject in which inhibition of N -i ⁇ ri sto I trail s fc rase provides a therapeutic or prophylactic effect, which comprises administering to the mammal a therapeutically effective amount of a compound according to the invention.
  • the invention also provides the use of a compound according to the invention, for the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder in which inhibition of N- myristoyltransferase provides a therapeutic or prophylactic effect.
  • Clinical conditions i.e. diseases/disorders
  • diseases/disorders include, but are not limited to, microbial infections including fungi and viruses, hypcrprolifcrativc disorders, neurological diseases/disorders, ischemia, osteoporosis and diabetes.
  • the compounds of the invention find particular application in the treatment or prophylaxis of the following: microbial infections including fungi and viruses (for example HIV), hyperproliferative disorders (for example cancers such as human colorectal cancer, gallbladder carcinoma and brain tumors) and diabetes.
  • microbial infections including fungi and viruses (for example HIV), hyperproliferative disorders (for example cancers such as human colorectal cancer, gallbladder carcinoma and brain tumors) and diabetes.
  • Compounds of the invention which are selective for a particular NMT enzyme may be particularly useful. For example, use of selective compound may result in reduced side effects compared with use of a less selective compound.
  • Preferably compounds of the invention are selective over Human NMTl and/or Human NMT2.
  • Compounds of the invention which are considered selective have a ratio of IC 50 values of greater than 10, preferably greater than 100, more preferably greater than 1000, and most preferably greater than 10,000.
  • X is -0-, -S-, -CH 2 -, -0-CH 2 - or -S-CH 2 -; and V is a 3-7-membered nitrogen-containing heterocycle, wherein said heterocycle may optionally be substituted with one R 1 group which is Ci_ 2 alkyl, C(0)-0-C(R') 2 -0-C(0)R' or C(0)-0-C(R') 2 -0-P(0)(OR') 2 ;
  • X is -0-C 2 _ 4 alkylene, -0-C 2 _ 4 alkenylene, -0-C 2 _ 4 alkynylene, -0-C 3 _ 6 cycloalkylene, -S-C 2 _ 4 alkylene, -S-C 2 _ alkenylene, -S-C 2 _ alkynylene, -S-C 3 _ 6 cycloalkylene,
  • R 3 is hydrogen, methyl, C(0)-0-C(R') 2 -0-C(0)R' or C(0)-0-C(R') 2 -0-P(0)(OR') 2
  • those compounds of the invention include compounds of formula (I) having X,V, R 1 , R 2 and/or R 3 groups as indicated above, as well as compounds of formula (IIA), (IIB), (IIC), (IID), (HE), (IIF) and (III). Accordingly, those compounds find use in the treatment or prophylaxis of a disease or disorder in which inhibition of N-myristoyltransferase provides a therapeutic or prophylactic effect, and which is a protozoan infection.
  • compounds of formula (IV) have surprisingly been found to be inhibitors of parasitic/protozoan NMT, and accordingly those compounds also find use in the treatment or prophylaxis of a disease or disorder in which inhibition of N-myristoyltransferase provides a therapeutic or prophylactic effect, and which is a protozoan infection.
  • the preferences for p, R 4 , Q 1 , Q : . B, R ⁇ R B , R c , R D . and R' in the compounds of formula (IV) are the same as for the compounds of formula ( I I A). (IIB), (IIC), (IID), ( H E) or (IIF) above
  • X is preferably -0-C 2 - 4 alkylene or -S-C 2 - 4 alkynylene; still more preferably X is X is -0-C 3 alkylene.
  • R 2 is hydrogen.
  • R 2 is methyl.
  • R 3 is hydrogen or methyl.
  • R 3 is hydrogen.
  • R 3 is methyl.
  • X is -0-C 2 - 4 alkylene, -0-C 2 _ 4 alkenylene, -0-C 2 _ 4 alkynylene, -0-C 3 _ 6 cycloalkylene, -S-C 2 _ 4 alkylene, -S-C 2 _ 4 alkenylene, -S- C 2 _ 4 alkynylene, -S-C 3 _ 6 cycloalkylene, -NH-C 2 _ 4 alkylene, -NH-C 2 _ 4 alkenylene, -NH-C 2 _ 4 alkynylene, - NH-C 3 _ 6 cycloalkylene, C 2 _ 4 alkylene, C 2 _ 4 alkenylene or C 2 _ 4 alkynylene, wherein said alkylene, alkenylene or alkynylene groups or part-groups may optionally be substituted with one or two groups selected from F and
  • R 5 is d_ 4 alkyl
  • Q 2 is bond or Ci_ 4 alkylene, wherein said Ci_ 4 alkylene may optionally be substituted with one R A group, and wherein one methylene group of said Ci_ 4 alkylene may optionally be replaced by -0-, -S- or N(R D ); and B is C 2 _ 4 alkyl, C 5
  • Preferred compounds of the invention having activity as inhibitors of parasitic/protozoan NMT include those in which X is -0-, -S- or -0-CH 2 -; more preferably X is -O-.; and in which V is pyrrolidinyl or piperidyl; still more preferably V is piperidyl, yet more preferably V is 3-piperidyl or 4-piperidyl; most preferably V is 4-piperidyl.
  • Ri is absent or is Ci_ 2 alkyl. In one preferred embodiment Ri is absent. In another preferred embodiment Ri is methyl.
  • X is -0-, -S- or -0-CH 2 -; and V is piperidyl.
  • X is -0-, -S- or -0-CH 2 -; and V is 4-piperidyl or 3-piperidyl.
  • Additional preferred compounds of the invention having activity as inhibitors of parasitic/protozoan NMT are those in which X is -0-C 2 _ 4 alkylene or -S-C 2 _ 4 alkynylene; N is R 2 R 3 ; R 2 is hydrogen or methyl; and R 3 is preferably hydrogen or methyl. More preferably, X is -0-C 3 alkylene; R 2 is hydrogen or methyl; and R 3 is hydrogen.
  • the compound has the formula (IEE), (IEF), (IJ), (IK), (IF) or, (III), wherein p is 0 or 1, and R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen and OCi_ 2 alkyl;
  • X is -O- or -S-;
  • V is 4-piperidyl or 4-dimethylpiperidyl;
  • B is ethyl, naphthyl, 4- methylenedioxyphenyl or phenyl, wherein said phenyl may optionally be substituted by one to three groups each independently selected from Ci_ 4 alkyl, 0-Ci_ 3 alkyl,
  • the compound has the formula (IJ), (IF) or, (III), wherein p is 0 or 1, and R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen and OCi_ 2 alkyl;
  • X is -0-;
  • V is 4-piperidyl;
  • Q is - C(0)0-CH 2 -CH 2 -, -C(0)0-CH 2 -, oxadiazolyl-CH 2 - or oxadiazolyl-CH 2 -CH 2 -;
  • B is phenyl optionally substituted by one to three groups each independently selected from d_ 3 alkyl, 0-Ci_ 3 alkyl, halogen, trihaloCi_ 4 alkyl.
  • the compound has the formula (IF), (IE), (IEE), (IEF), (IJ), (IK) or, (III), wherein p is 0 or 1, and R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen and OCi_ 2 alkyl;
  • X is -O- or -S-;
  • V is 4-piperidyl or 4-methylpiperidyl;
  • Q is -C(0)0-CH 2 -CH 2 -, -C(0)0-CH 2 -, -C(0)0-CH 2 - CH 2 -CH 2 -, C(0)0-CH 2 -CH 2 -0-, -C(0)N-CH 2 -CH 2 -, -C(0)N-CH 2 -, -C(0)N-CH 2 -CH 2 -, C(0)N- CH 2 -CH 2 -0-, oxadiazolyl-CH 2 -, oxadiazolyl-CH 2 -CH 2 -; and B is
  • the compound has the formula (IF) or (IJ), wherein p is 0 or 1, and R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen and OCi_ 2 alkyl; X is -0-; V is 4-piperidyl; Q is -C(0)0-CH 2 -CH 2 -, -C(0)0- CH 2 -, oxadiazolyl-CH 2 - or oxadiazolyl-CH 2 -CH 2 -; and B is phenyl optionally substituted by one to three groups each independently selected from 0-Ci_ 3 alkyl, halogen, trihaloCi_ alkyl.
  • Pv Plasmodium vivax
  • the compound has the formula (IJ), (IK), (IL), (IE), (IF) or, (III), wherein p is 0 or 1, and R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen and OCi_ 2 alkyl;
  • X is -0-, -S- or - OCH 2 -;
  • V is 4-piperidyl or 3- azetidyl;
  • Q is -C(0)0-CH 2 -CH 2 -, -C(0)0-CH 2 -, -C(0)0-CH 2 -CH 2 - CH 2 -, -CH 2 -0-CH 2 , -CH 2 -0-C(0)-, CH 2 -C(0)0-, -C(0)N-CH 2 -, oxadiazolyl-CH 2 -, oxadiazolyl-CH 2 -CH 2 -; and
  • B is ethyl, naphthyl or phenyl, where
  • the compound has the formula (IJ), (IK), (IF) or, (III), wherein p is 0 or 1, and R 4 where present is Ci_ 2 alkyl, trihalomethyl, halogen and OCi_ 2 alkyl;
  • X is -0-;
  • V is 4-piperidyl;
  • Q is -C(0)0-CH 2 -CH 2 -, -C(0)0-CH 2 -, oxadiazolyl-CH 2 - or oxadiazolyl-CH 2 - CH 2 -;
  • B is phenyl optionally substituted by one to three groups each independently selected from Ci_ 4 alkyl, 0-Ci_ 3 alkyl, halogen, trihaloCi_ 4 alkyl.
  • These embodiments may have particular activity as inhibitors of Leishmania donovani (Ld) N-myristoyl transferase.
  • those compounds find use as a medicament, particularly in the treatment or prophylaxis of a disease or disorder in which inhibition of N-myristoyltransferase provides a therapeutic or prophylactic effect, and in particular those diseases or disorders which are a protozoan infection.
  • the invention also provides a method for the treatment or prophylaxis of a disease or disorder in a subject in which inhibition of N-myristoyltransferase provides a therapeutic or prophylactic effect, and which is a protozoan infection, which comprises administering to the mammal a therapeutically effective amount of a compound according to the invention.
  • the invention also provides the use of a compound according to the invention, for the manufacture of a medicament for the treatment or prophylaxis of a disease or disorder in which inhibition of N- myristoyltransferase provides a therapeutic or prophylactic effect, and which is a protozoan infection.
  • the disease or disorder is a protozoan infection caused by a species of Plasmodium, Leishmania or Trypanosoma (for example Plasmodium falciparum, Plasmodium, vivax, Leishmania donovani, Trypanosoma brucei).
  • a species of Plasmodium, Leishmania or Trypanosoma for example Plasmodium falciparum, Plasmodium, vivax, Leishmania donovani, Trypanosoma brucei.
  • N-myristoyltransferase Diseases or disorders in which inhibition of N-myristoyltransferase provides a therapeutic or prophylactic effect include malaria, leishmaniasis and sleeping sickness (also known as human African trypanosomiasis).
  • the compounds may form esters, amides, carbamates and/or salts.
  • Salts of compounds of the invention which are suitable for use in medicine are those wherein a counter-ion is pharmaceutically acceptable.
  • salts having non-pharmaceutically acceptable counter-ions are within the scope of the present invention, for example, for use as intermediates in the preparation of the compounds of the invention and their pharmaceutically acceptable salts, and physiologically functional derivatives.
  • physiologically functional derivative is meant a chemical derivative of a compound of the invention having the same physiological function as the free compound of the invention, for example, by being convertible in the body thereto.
  • Esters, amides and carbamates are examples of physiologically functional derivatives.
  • Suitable salts according to the invention include those formed with organic or inorganic acids or bases.
  • suitable salts formed with acids according to the invention include those formed with mineral acids, strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, such as saturated or unsaturated dicarboxylic acids, such as hydroxycarboxylic acids, such as amino acids, or with organic sulfonic acids, such as (C 1 -C 4 )-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted, for example by halogen.
  • Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric, acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic, perchloric, fumaric, maleic, glycolic, lactic, salicylic, oxaloacetic, methanesulfonic, ethane sulfonic, p-toluenesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic, malic, phthalic, aspartic, and glutamic acids, lysine and arginine.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutical acceptable acid addition salts.
  • Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts, for example those of potassium and sodium, alkaline earth metal salts, for example those of calcium and magnesium, and salts with organic bases, for example dicyclohexylamine, N-methyl-D-glucomine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl-propylamine, or a mono-, di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. Corresponding internal salts may furthermore be formed.
  • Compounds of the invention may have an appropriate group converted to an ester, an amide or a carbamate.
  • typical ester and amide groups formed from an acid group in the compound of the formula I include -C(0)OC 1 _ 6 alkyl, -C(0)N(C 1 _ 6 alkyl) 2 , -S(0) 2 OC 1 _ 6 alkyl, or ) 2
  • typical ester and amide and carbamate groups formed from a hydroxyl or amine group in the compound of the formula I include -OC(0)Ci_ 6 alkyl, -NHC(0)Ci_ 6 alkyl, -NHC(0)OCi_ 6 alkyl - OS(0) 2 C 1 _ 6 alkyl, and -NHS(0) 2 C 1 _ 6 alkyl.
  • Solvates of compounds of the invention which are suitable for use in medicine are those wherein the associated solvent is pharmaceutically acceptable.
  • a hydrate is an example of a pharmaceutically acceptable solvate.
  • solvates having non-pharmaceutically acceptable associated solvents may find use as intermediates in the preparation of the compounds of the invention and their pharmaceutically acceptable esters, amides, carbamates and/or salts thereof.
  • a compound which, upon administration to the recipient, is capable of being converted into a compound of the invention as described above, or an active metabolite or residue thereof, is known as a "prodrug".
  • a prodrug may, for example, be converted within the body, e. g. by hydrolysis in the blood, into its active form that has medical effects.
  • Pharmaceutical acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series (1976); "Design of Prodrugs” ed. H. Bundgaard, Elsevier, 1985; and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, which are incorporated herein by reference.
  • the amount of active ingredient which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, including the type, species, age, weight, sex, and medical condition of the subject and the renal and hepatic function of the subject, and the particular disorder or disease being treated, as well as its severity.
  • An ordinarily skilled phy sician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Oral dosages of the present invention when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 mg per kg of body weight per day (mg/kg/day) to 10 mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day, for adult humans.
  • the compositions are preferably provided in the fonn of tablets or other forms of presentation provided in discrete units containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from about 1 mg to about 100 mg of active ingredient. Intravenously, the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion .
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • the invention provides a pharmaceutical formulation or composition comprising a compound according to the invention, and a pharmaceutically acceptable diluent, excipient or carrier (collectively referred to herein as "carrier" materials).
  • carrier a pharmaceutically acceptable diluent, excipient or carrier
  • Pharmaceutical compositions of the invention may take the form of a pharmaceutical formulation as described below.
  • the pharmaceutical formulations according to the invention include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous [bolus or infusion], and intraarticular), inhalation (including fine particle dusts or mists which may be generated by means of various types of metered dose pressurized aerosols), nebulizers or insufflators, rectal, intraperitoneal and topical (including dermal, buccal, sublingual, and intraocular) administration, although the most suitable route may depend upon, for example, the condition and disorder of the recipient.
  • parenteral including subcutaneous, intradermal, intramuscular, intravenous [bolus or infusion], and intraarticular
  • inhalation including fine particle dusts or mists which may be generated by means of various types of metered dose pressurized aerosols
  • nebulizers or insufflators rectal, intraperitoneal and topical (including dermal, buccal, sublingual, and intraocular) administration, although the most suitable route may depend upon,
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the ait of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid earners or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, pills or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a nonaqueous liquid, for example as elixirs, tinctures, suspensions or syrups; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or moulding, optionally with one or more accessory- ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • the present compounds can, for example, be administered in a form suitable for immediate release or extended release.
  • Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.
  • the present compounds can also be administered liposomal! ⁇ '.
  • compositions for oral administration include suspensions which can contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which can contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the ait.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate,
  • compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG).
  • Such formulations can also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g. Carbopol 934).
  • HPC hydroxy propyl cellulose
  • HPMC hydroxy propyl methyl cellulose
  • SCMC sodium carboxy methyl cellulose
  • maleic anhydride copolymer e.g., Gantrez
  • agents to control release such as polyacrylic copolymer (e.g. Carbopol 934).
  • Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chlor
  • the compounds of the present invention can also be administered in the form of liposome deliver ⁇ ' systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, 1,2-dipalmitoylphosphatidylcholine, phosphatidyl ethanol amine (cephaline) , or phosphatidylcholine (lecithin).
  • Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-injection, immediately prior to use.
  • compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.
  • suitable non-toxic, parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.
  • compositions for nasal, aerosol or inhalation administration include solutions in saline, which can contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
  • Formulations for rectal administration may be presented as a suppositor with the usual carriers such as cocoa butter, synthetic glyceride esters or polyethylene glycol. Such carriers are typically solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug.
  • Formulations for topical administration in the mouth for example buccal! ⁇ or sublingual! ⁇ .
  • lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in a basis such as gelatin and glycerine or sucrose and acacia.
  • Exemplaiy compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).
  • Preferred unit dosage formulations are those containing an effective dose, as hereinbefore recited, or an appropriate fraction thereof, of the active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • a compound of the invention may be used as the sole active ingredient in a medicament, it is also possible for the compound to be used in combination with one or more further active agents. Accordingly there is provided a compound of the invention, together with a further active ingredient for simulataneous, sequential or separate administration.
  • Such further active agents may be further compounds according to the invention, or they may be different therapeutic agents, for example agents useful for treatment of malaria, leishmaniasis, sleeping sickness, anti-fungal agents, anti-viral agents (including anti-HIV agents), chemotherapeutic agents, antidepressants, anxiolytic, anti-psychotic, osteoporosis, ischemia and/or diabetes,or other pharmaceutically active material.
  • the compounds of the invention may be effectively administered in combination with an effective amount of an anti-protozoan/anti -parasitic agent.
  • an anti-protozoan/anti -parasitic agent may be used in combination with a compound of the invention.
  • the compounds of the present invention can be used in combination with other agents useful for the treatment or prophylaxis of a disease or disorder in which inhibition of N-myristoyl transferase provides a therapeutic or prophylactic effect.
  • the individual components of such combinations can be adm inistered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • the present invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
  • the compounds of formula (I) When combined with a second of further therapeutic agent, the compounds of formula (I) may be employed in a weight ratio to the additional agent within the range from about 10: 1 to about 1 : 10.
  • the compounds of the invention as described above also find use, optionally in labelled form, as a diagnostic agent for the diagnosis of a disease or disorder in which inhibition of NMT provides a therapeutic or prophylactic effect.
  • a diagnostic agent for the diagnosis of a disease or disorder in which inhibition of NMT provides a therapeutic or prophylactic effect.
  • such a compound may be radioactively labelled.
  • the invention provides a method of discovering a inhibitor of NMT which comprises use of a compound of the invention or a compound of the invention in labelled form, as a reference compound.
  • a method of discovering a inhibitor of NMT which comprises use of a compound of the invention or a compound of the invention in labelled form, as a reference compound.
  • such a method may involve a competitive binding experiment in which binding of a compound of the invention to the NMT enzyme is reduced by the presence of a further compound which has NMT-binding characteristics, for example stronger NMT-binding characteristics than the compound of the invention in question.
  • Compounds of the invention include, but are not limited to, the compounds specifically named in the Examples herein.
  • hydroxybenzotriazole (HOBt, 1.3 eq.) and the mixture stirred for 30 min. After that, the mixture was treated with N,N-Diisopropylethylamine (DIPEA, 2.0 eq.) and alcohol (1.1 eq.). The resulting mixture was further stirred at room temperature for another 12 hours. After that, the solution was evaporated to dryness in vacuo. The residue was re-dissolved in ethyl acetate (20 mL mmol -1 ) and washed with 5% NaHC0 3 , water and brine (each 20 mL mmol -1 ). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. The product was isolated by flash column
  • Carboxylic acid (1 eq.), 1-hydroxybenzotriazole (1 eq.) and 3-(ethyliminomethylene amino)-N,N- dimethyl-propan-1 -amine (EDC, 1 eq.) were taken up in DMF (25 mL mmol -1 ) and stirred at room temperature for 30 min.
  • EDC 3-(ethyliminomethylene amino)-N,N- dimethyl-propan-1 -amine
  • Carboxylic acid (1 eq.), 1-hydroxybenzotriazole (1 eq.) and 3-(ethyliminomethylene amino)-N,N- dimethyl-propan-1 -amine (EDC, 1 eq.) were taken up in anhydrous acetonitrile (20 mL mmol -1 ) and stirred at room temperature for 30 min, followed by the addition of amidoxime (1 eq.) and DIPEA (2.0 eq.). The resulting mixture was further stirred at room temperature for 12 hours. After that, the solution was evaporated to dryness in vacuo.
  • the Boc-protected product was taken up in a solution of trifluoroacetic acid (TFA, 5%) in DCM (30 mL mmol -1 ). After stirring at room temperature for 2 hours all volatiles were removed by exposure to a stream of nitrogen gas. The crude product was purified by LC-MS or HPLC.
  • the trityl-protected product was taken up in a solution of trifluoroacetic acid (TFA, 0.1%) and water (0.2%) in DCM (10 mL mmol -1 ). After stirring at room temperature for 2 hours all volatiles were removed by exposure to a stream of nitrogen gas. The crude product was purified by semi-preparative HPLC, with no formic acid in the mobile phases.
  • reaction mixture 7.19 mmol and 4-dimethylaminopyridine (88 mg, 0.72 mmol) and reaction mixture stirred for 18 h at room temperature. Reaction mixture filtered through celite and washed with ethyl acetate (5 ⁇
  • Lithium aluminium hydride (53 mg, 1.4 mmol) was added gradually to an ice-cooled solution of Intermediate 17 (185 mg, 0.65 mmol) in anhydrous tetrahydrofuran (1.5 mL) over 5 min. Reaction mixture stirred at 0°C for 10 min, warmed to room temperature over 10 min then stirred at room temperature for 2 h. Reaction mixture was then diluted with saturated ammonium chloride (1.2 mL) and resulting slurry was filtered through a plug of celite which was washed with ethyl acetate (6 ⁇ 5 mL).
  • Methyl thiosalicylate (168 mg, 1.00 mmol) was dissolved in DMSO (1 mL) and 50% NaOH (aq) (0.5 mL).
  • l-Boc-4-bromopiperidine (264 mg, 1.00 mmol) was added and the mixture stirred at room temperature for 90 min after which time TLC analysis (ethyl acetate) revealed partial consumption of starting material (R/0.89) and a major product (R/0.41).
  • the reaction mixture was diluted with ethyl acetate (30 mL) and the organic phase washed with 2 x 30 mL HC1 solution (2 M) then with brine (30 mL).
  • Examples 6 to 14 were prepared in analogous fashion to Example 5.
  • Example 6 Naphthalen-l-ylmethyl 3-methyl-4-(piperidin-4-yloxy)-l-benzo-furan-2- carboxylate
  • Example 18 was prepared in analogous fashion to Example
  • Example 18 ⁇ [3-Methyl-4-(piperidin-4-yloxy)-l-benzofuran-2-yl] methyl ⁇ -(naphthalen-l- ylmethyl)amine
  • Example 79 3-(3-Chlorobenzyl)-5-(3-(piperidin-4-yloxy)phenyl)-l,2,4-oxadiazole Prepared according to the methods for amidoxime formation, 1,2,4-oxadiazole formation (Method A) and Boc deprotection. The product was obtained as an off-white amorphous solid (40.0 mg, yield: 27%).
  • Examples 90 to 105 were prepared in analogous fashion to Example 89.
  • Example 104 4-( ⁇ 2-[3-(2-Phenylet aphthalen-l-yl ⁇ oxy)piperidine
  • Example 105 4-[(2- ⁇ 3-[(3-Methoxyphenyl)methyl]-l,2,4-oxadiazol-5-yl ⁇ naphthalen-l- yl)oxy] piperidine
  • Example 107 was prepared in analogous fashion to Example 106.
  • Examples 109 to 111 were prepared in analogous fashion to Example 108.
  • Example 111 4-( ⁇ 3-[3-(2-phenylethyl -l,2,4-oxadiazol-5-yl]naphthalen-l-yl ⁇ oxy)piperidine

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés qui inhibent la N-myristoyltransférase, sont sélectifs par rapport à la N-myristoyltransférase protozoaire et sont par conséquent adaptés pour traiter des infections microbiennes, y compris les infections virales et fongiques, et des infections protozoaires telles que le paludisme, la leishmaniose et la maladie du sommeil.
PCT/GB2012/053041 2011-12-06 2012-12-06 Nouveaux composés et leur utilisation en thérapie WO2013083991A1 (fr)

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105315188A (zh) * 2014-06-03 2016-02-10 上海药明康德新药开发有限公司 一种2-(1-(叔丁氧羰基)氮杂环丁基-3-)环丙基甲酸的制备方法
US9296701B2 (en) 2012-04-24 2016-03-29 Vertex Pharmaceuticals Incorporated DNA-PK inhibitors
US9340557B2 (en) 2013-03-12 2016-05-17 Vertex Pharmaceuticals Incorporated Substituted quinoxaline DNA-PK inhibitors
WO2017001812A1 (fr) * 2015-06-29 2017-01-05 Imperial Innovations Limited Composés et leur utilisation en tant qu'inhibiteurs de la n-myristoyl transférase
US10039761B2 (en) 2013-10-17 2018-08-07 Vertex Pharmaceuticals Incorporated Co-crystals and pharmaceutical compositions comprising the same
WO2020128473A1 (fr) 2018-12-19 2020-06-25 Imperial College Innovations Limited Nouveaux composés et leur utilisation en thérapie
WO2020128475A1 (fr) 2018-12-19 2020-06-25 Imperial College Innovations Limited Traitements du cancer
WO2021008512A1 (fr) * 2019-07-18 2021-01-21 石药集团中奇制药技术（石家庄）有限公司 Composé inhibiteur de nmt et son utilisation
US11110108B2 (en) 2016-09-27 2021-09-07 Vertex Pharmaceuticals Incorporated Method for treating cancer using a combination of DNA-damaging agents and DNA-PK inhibitors
US11168093B2 (en) 2018-12-21 2021-11-09 Celgene Corporation Thienopyridine inhibitors of RIPK2
WO2022058745A2 (fr) 2020-09-18 2022-03-24 Imperial College Innovations Limited Nouveaux composés et leur utilisation en thérapie
WO2022090746A1 (fr) 2020-11-02 2022-05-05 Imperial College Innovations Limited Inhibiteur de la nmt pour le traitement de maladies ou de troubles associés à la sénescence
US11534441B2 (en) 2020-01-15 2022-12-27 Blueprint Medicines Corporation MAP4K1 inhibitors
US11690847B2 (en) 2016-11-30 2023-07-04 Case Western Reserve University Combinations of 15-PGDH inhibitors with corticosteroids and/or TNF inhibitors and uses thereof
US11718589B2 (en) 2017-02-06 2023-08-08 Case Western Reserve University Compositions and methods of modulating short-chain dehydrogenase
WO2024052684A1 (fr) 2022-09-09 2024-03-14 MyricX Pharma Limited Conjugué anticorps-médicament comprenant un inhibiteur de nmt et son utilisation

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000037464A2 (fr) 1998-12-18 2000-06-29 Basilea Pharmaceutica Ag Nouveaux composes bicycliques
US20040014764A1 (en) 2002-03-29 2004-01-22 Smith Charles D. N-myristoyltransferase inhibitor compositions and methods of use
WO2005111018A1 (fr) * 2004-05-18 2005-11-24 Sanofi-Aventis Deutschland Gmbh Derives de pyridazinone, procedes de production de ces derives et leur utilisation comme pharmaceutiques
WO2010026365A1 (fr) 2008-09-02 2010-03-11 University Of Dundee Inhibiteurs de n-myristoyl-transférase

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000037464A2 (fr) 1998-12-18 2000-06-29 Basilea Pharmaceutica Ag Nouveaux composes bicycliques
US20040014764A1 (en) 2002-03-29 2004-01-22 Smith Charles D. N-myristoyltransferase inhibitor compositions and methods of use
WO2005111018A1 (fr) * 2004-05-18 2005-11-24 Sanofi-Aventis Deutschland Gmbh Derives de pyridazinone, procedes de production de ces derives et leur utilisation comme pharmaceutiques
WO2010026365A1 (fr) 2008-09-02 2010-03-11 University Of Dundee Inhibiteurs de n-myristoyl-transférase

Non-Patent Citations (28)

* Cited by examiner, † Cited by third party
Title
BOWYER ET AL., BIOCHEM. J., vol. 408, 2007, pages 173 - 180
BRANNINGAN, J. A.; SMITH, B. A.; YU, Z. ET AL., J. MOL. BIOL, vol. 396, 2010, pages 985 - 999
CHUNQUAN SHENG ET AL: "Homology modeling and molecular dynamics simulation of N-myristoyltransferase from protozoan parasites: active site characterization and insights into rational inhibitor design", JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, KLUWER ACADEMIC PUBLISHERS, DO, vol. 23, no. 6, 16 April 2009 (2009-04-16), pages 375 - 389, XP019678501, ISSN: 1573-4951 *
DURONIO, R. J.; TOWLER, D. A.; HEUCKEROTH, R. O. ET AL., SCIENCE, vol. 243, no. 4892, 1989, pages 796 - 800
EDWARD B. ROCHE: "Bioreversible Carriers in Drug Design", 1987, AMERICAN PHARMACEUTICAL ASSOCIATION AND PERGAMON PRESS
FARAZI, T. A.; WAKSMAN, G.; GORDON, J. I., J. BIOL. CHEM., vol. 276, no. 43, 2001, pages 39501 - 39504
GIANG, D.K.; CRAVATT, B. F., J. BIOL. CHEM., vol. 273, 1998, pages 6595 - 6598
GONCALVES, V. ET AL., ANALYTICAL BIOCHEMISTRY, vol. 421, 2012, pages 342 - 344
GONCALVES, V. ET AL., J. MED. CHEM, vol. 55, 2012, pages 3578
GUNARATNE, R. S.; SAJID, M.; LING, I. T. ET AL., BIOCHEM. J., vol. 348, 2000, pages 459 - 463
H. BUNDGAARD,: "Design of Prodrugs", 1985, ELSEVIER
JOHNSON, D. R.; BHATNAGAR, R. S.; GORDON, J. I. ET AL., ANNU. REV. BIOCHEM., vol. 63, 1994, pages 869 - 914
JOULE, J. A.; MILLS, K., HETEROCYCLIC CHEMISTRY, 2000
LODGE, J. K.; JOHNSON, R. L.; WEINBERG, R. A. ET AL., J. BIOL. CHEM., vol. 269, no. 4, 1994, pages 2996 - 3009
MASUBUCHI ET AL., BIOORG. & MED. CHEM. LETT., vol. 11, 2001, pages 1833 - 1837
MCILHINNEY, R. A. J.; MCGLONE, K., EXP. CELL RES., vol. 223, 1996, pages 348 - 356
PAUL W. BOWYER ET AL: "Molecules incorporating a benzothiazole core scaffold inhibit the N-myristoyltransferase of Plasmodium falciparum", BIOCHEMICAL JOURNAL, vol. 408, no. 2, 1 December 2007 (2007-12-01), pages 173, XP055052904, ISSN: 0264-6021, DOI: 10.1042/BJ20070692 *
PRICE, H. P.; MENON, M. R.; PANETHYMITAKI, C. ET AL., J. BIOL. CHEM., vol. 278, no. 9, 2003, pages 7206 - 7214
R. LIU: "Water-Insoluble Drug Formulation, 2nd ed.", CRC PRESS, pages: 553
RUDNICK, D. A.; MCWHERTER C. A.; ROCQUE, W. J. ET AL., J. BIOL. CHEM., vol. 266, no. 15, 1991, pages 9732 - 973 9
RUSSELL M G N ET AL: "N-Arylsulfonylindole derivatives as serotonin 5 - HT6 receptor ligands", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 44, no. 23, 8 November 2001 (2001-11-08), pages 3881 - 3895, XP002234833, ISSN: 0022-2623, DOI: 10.1021/JM010943M *
S. BYM ET AL., PHARMACEUTICAL RESEARCH, vol. 12, no. 7, 1995, pages 954 - 954
SHENG ET AL., EUR. J. MED. CHEM., vol. 45, no. 9, 2010, pages 3531 - 3540
T. HIGUCHI; V. STELLA: "Prodrugs as Novel Delivery Systems", vol. 14, 1976, A. C. S. SYMPOSIUM SERIES
W. MEISEL ET AL: "275. Attempts to find new antimalarials. Part IX. 8-?-Amino-butylamino-6-ethoxyquinoline", JOURNAL OF THE CHEMICAL SOCIETY (RESUMED), 1 January 1934 (1934-01-01), pages 1267, XP055052780, ISSN: 0368-1769, DOI: 10.1039/jr9340001267 *
WIEGAND, R. C; CARR, C.; MINNERLY, J.C. ET AL., J. BIOL. CHEM., vol. 267, no. 12, 1992, pages 8591 - 8598
YU, Z. ET AL., J. MED. CHEM., vol. 55, 2012, pages 8879 - 8890
ZHIYONG YU ET AL: "Design and Synthesis of Inhibitors of Plasmodium falciparumN -Myristoyltransferase, A Promising Target for Antimalarial Drug Discovery", JOURNAL OF MEDICINAL CHEMISTRY, vol. 55, no. 20, 25 October 2012 (2012-10-25), pages 8879 - 8890, XP055052898, ISSN: 0022-2623, DOI: 10.1021/jm301160h *

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