WO2016051181A1 - 4h-imidazo[1,5-a]indole derivatives and their use as indoleamine 2,3-dioxygenase (ido) and/or tryptophan 2,3-dioxygenase (td02) modulators - Google Patents

4h-imidazo[1,5-a]indole derivatives and their use as indoleamine 2,3-dioxygenase (ido) and/or tryptophan 2,3-dioxygenase (td02) modulators Download PDF

Info

Publication number
WO2016051181A1
WO2016051181A1 PCT/GB2015/052868 GB2015052868W WO2016051181A1 WO 2016051181 A1 WO2016051181 A1 WO 2016051181A1 GB 2015052868 W GB2015052868 W GB 2015052868W WO 2016051181 A1 WO2016051181 A1 WO 2016051181A1
Authority
WO
WIPO (PCT)
Prior art keywords
bond
compound
substituted
alkyl
ido
Prior art date
Application number
PCT/GB2015/052868
Other languages
French (fr)
Inventor
Richard Armer
Matilda Bingham
Thomas Pesnot
Camille GIGNOUX
Original Assignee
Redx Pharma Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Redx Pharma Plc filed Critical Redx Pharma Plc
Publication of WO2016051181A1 publication Critical patent/WO2016051181A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • This invention relates to novel compounds and pharmaceutical compositions comprising the novel compounds. More specifically, the invention relates to compounds useful as indoleamine 2,3- dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TD02) modulators (e.g. ID01 , ID02 and/or TD02 inhibitors). This invention also relates to processes for preparing the compounds, uses of the compounds and methods of treatment employing the compounds.
  • IDO indoleamine 2,3- dioxygenase
  • TD02 tryptophan 2,3-dioxygenase
  • This invention also relates to processes for preparing the compounds, uses of the compounds and methods of treatment employing the compounds.
  • the compounds of the invention may therefore be used in treating indoleamine 2,3- dioxygenase (IDO) mediated diseases, such as IDO mediated immunosuppression; treating a medical conditions that would benefit from the inhibition of enzymatic activity of the IDO enzyme; enhancing the effectiveness of an anti-cancer treatment; treating tumour-specific IDO mediated diseases, such as IDO mediated immunosuppression; treating a medical conditions that would benefit from the inhibition of enzymatic activity of the IDO enzyme; enhancing the effectiveness of an anti-cancer treatment; treating tumour-specific
  • IDO Indoleamine 2,3 dioxygenase
  • TD02 tryptophan 2,3-dioxygenase
  • IDO is predominantly expressed in antigen presenting cells such as dendritic cells (DCs) and macrophages.
  • IDO expression in immune cells may be constitutive but is also up regulated during infection by proinflammatory mediators including type 1 and 2 interferons and TNF.
  • IDO IDO-induced DCs
  • Physiologically IDO plays an important role in the maintenance of immune self-tolerance and in the regulation of the immune response to infection.
  • Indoleamine 2,3-dioxygenase is an enzyme that is known in the art to have a role in immunosuppression, tumour resistance and/or rejection, chronic infections, HIV-infection, AIDS (including its manifestations such as cachexia, dementia and diarrhoea), autoimmune diseases or disorders (such as rheumatoid arthritis), and immunologic tolerance and prevention of foetal rejection in utero. Accordingly, therapeutic agents aimed at suppression of tryptophan degradation by inhibiting IDO activity are desirable.
  • ID01 In cancer, elevated tumour levels of ID01 have been linked to a decrease in both overall and progression free patient survival. Elevated expression of ID01 has been observed in many cancer types including lung, ovarian, colorectal, brain and thyroid cancers, melanoma, acute myeloid leukaemia and non-Hodgkin's lymphoma. Even in tumours where elevated ID01 expression is not seen in the cancer cells, ID01 upregulation in infiltrating immune cells in the tumour microenvironment and in local draining lymph nodes is thought to have a profound impact on tumour growth.
  • Inhibitors of IDO can be used to activate T cells and therefore enhance T cell activation when the T cells are suppressed by pregnancy, malignancy or a virus such as HIV. Inhibition of IDO may also be an important treatment strategy for patients with neurological or neuropsychiatric diseases or disorders such as depression.
  • WO2012142237 discloses various fused imidazole derivatives that are useful as IDO inhibitors.
  • An aim of the present invention is to provide alternative or improved indoleamine 2,3- dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TD02) modulators.
  • IDO indoleamine 2,3- dioxygenase
  • TD02 tryptophan 2,3-dioxygenase
  • an aim of the present invention is to provide alternative or improved IDO and/or TD02 inhibitors.
  • IDO indoleamine 2,3-dioxygenase
  • treating medical conditions that would benefit from the inhibition of enzymatic activity of the IDO enzyme enhancing the effectiveness of an anti-cancer treatment; treating tumour-specific immunosuppression associated with cancer; and/or treating
  • Another aim of certain embodiments of this invention is to provide compounds having a convenient pharmacokinetic profile and a suitable duration of action following dosing.
  • a further aim of certain embodiments of this invention is to provide compounds in which the metabolised fragment or fragments of the drug after absorption are GRAS (Generally Regarded As Safe).
  • the present invention provides a compound of formula (I):
  • 'A' is a 5 or 6 membered aryl or heteroaryl group, unsubstituted or substituted with 1 , 2 or 3 groups (where chemically possible) selected from: halo, C1-4 alkyl, C1-4 haloalkyl, -OR A , -NR A R B , -SR A , - C(0)R A , -OC(0)R c , -C(0)OR A , -NR A C(0)R c , -C(0)NR A R B , -NR A S0 2 R c , -S0 2 NR A R B , -NO2, -CN and C1-4 alkyl substituted with -OR A ;
  • X is a bond or -(CR A R B V;
  • Y is selected from: a bond, -(CR D R E ) m -, -0-, -NR F -, -S-, -C(O)-, -CCNR F )-, -C OR ⁇ R - C(NR F R G )R C -, -C(0)NR F -, -NR F C(0)-, -NR F C(0)NR G -, -NR F S0 2 NR G -, -SO2-, -S0 2 NR F -, -NR F S0 2 - , -OC(O)- and -C(0)0-;
  • Z is a bond or -(CR A2 R B2 ) k -;
  • n and k are each independently selected from 1 , 2, 3 and 4;
  • R 2 is selected from: H, halo, Ci- alkyl, C1-4 haloalkyl, -OR A4 and Ci- alkyl substituted with -OR A4 ;
  • R 3 and R 4 are each independently selected from: H, halo, Ci- 4 alkyl, Ci- 4 haloalkyl, C3-6 cycloalkyl, - OR A5 , -NR A5 R B4 , -CN, -SR A5 and Ci- alkyl substituted with— OR A5 ;
  • R A , R B , R c R A , R B , R A2 , R B2 , R A3 , R B3 , R A4 , R A5 , R B4 , R A6 and R B5 are at each occurrence independently selected from: H, Ci- 4 alkyl and Ci- 4 haloalkyl;
  • R F and R G are each independently selected from: H, Ci- 4 alkyl and Ci- 4 haloalkyl, C3-8 cycloalkyl, C3- 8 heterocycloalkyl, C3-8 cycloalkylene, C3-8 heterocycloalkylene, C6-10 aryl and C5-10 heteroaryl;
  • Z is not -(CR A2 R B2 )k- and Y is not -C(0)NR F -, -NR F C(0)- or -NR F C(0)NR F - when A is a pyridyl group;
  • Z is not -(CR A2 R B2 ) k -, Y is not -C(O)- or -NR F C(0)-, and R is not morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl when A is a pyridyl group.
  • Y is selected from: a bond, -0-, -NR F -, -S-, -C(O)-, -C(NR F )-, -C OR ⁇ R -C(NR F R G )R C -, -C(0)NR F -, -NR F C(0)-, -NR F C(0)NR G -, -NR F S0 2 NR G -, -S0 2 -, -S0 2 NR F -, - NR F S0 2 - , -OC(O)- and -C(0)0-; and
  • Z is a bond.
  • Y is selected from: a bond, -0-, -NR F -, -S-, -NR F C(0)-, - NR F C(0)NR G -, -NR F S0 2 NR G -, -SO2-, -S0 2 NR F -, -NR F S0 2 -, and -OC(O)-; and
  • Z is a bond or -(CR A2 R B2 ) k -.
  • n or k is 2, 3 or 4.
  • Y is a bond and X is a bond, i.e. optionally when Y is a bond, X cannot be -(CR A R B ) n -
  • A is a ring selected from substituted or unsubstituted: phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl and pyrrolyl.
  • A is a ring selected from substituted or unsubstituted: phenyl, pyridyl, pyrimidinyl, pyridazinyl and thiophenyl.
  • A is a ring selected from substituted or unsubstituted: phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl and pyrrolyl and Z is a bond.
  • A is a ring selected from substituted or unsubstituted: phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl and pyrrolyl and Y is selected from: a bond, -(CR D R E ) m -, - 0-, -NR F -, -S-, -C(NR F )-, -C(OR F )R c -, -C(NR F R G )R C -, -SO2-, -S0 2 NR F -, -NR F S0 2 - , -OC(O)-; and - C(0)0-.
  • A is not pyridyl.
  • A may be a ring selected from substituted or unsubstituted: phenyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl and pyrrolyl.
  • A is a ring selected from substituted or unsubstituted: phenyl, pyrimidinyl, pyridazinyl and thiophenyl.
  • the compound of formula (I) is a compound according to formula (lla) to (llj):
  • q is selected from 0, 1 , 2 or 3,
  • p is selected from 0, 1 or 2
  • R 5 is selected from: H, halo, Ci- alkyl, Ci- haloalkyl, -OR A , -NR A R B , -SR A , -C(0)R A , -OC(0)R c , - C(0)OR A , -NR A C(0)R c , -C(0)NR A R B , -NR A S0 2 R c , -S0 2 NR A R B , -N0 2 , -CN and Ci- 4 alkyl substituted with -OR A ; wherein R A , R B and R c are each independently selected from: H, Ci- 4 alkyl and Ci- 4 haloalkyl.
  • A is phenyl or pyridyl.
  • A is phenyl.
  • A is phenyl or pyridyl and Z is a bond.
  • A is phenyl or pyridyl and Y is selected from: a bond, -(CR D R E ) m -, -0-, -NR F -, -S-, -C(NR F )-, -C(OR F )R c -, -C(NR F R G )R C -, -SO2-, - S0 2 NR F -, -NR F S0 2 - , -OC(O)-; and -C(0)0-.
  • A is unsubstituted.
  • q and p may be 0.
  • A is substituted with 1 , 2 or 3 groups (where chemically possible) selected from: halo, Ci- alkyl, Ci- haloalkyl, -OR A , -NR A R B , -N0 2 , -CN and Ci- alkyl substituted with -OR A .
  • R 5 is selected from: halo, Ci- alkyl, Ci- haloalkyl, -OR A , -NR A R B , - N0 2 , -CN and Ci- 4 alkyl substituted with -OR A .
  • R A , R B and R c are as described above.
  • R A , R B and R c may each be independently selected from: H, methyl, ethyl, isopropyl, tert-butyl and trifluoromethyl.
  • A is substituted with 1 , 2 or 3 groups (where chemically possible) selected from: chloro, fluoro, methyl, ethyl, iso-propyl, tert-butyl, Ci- 2 -haloalkyl (e.g. trifluoromethyl, trifluoroethyl), -OH, -OMe, -OEt, -0-Ci- 2 -haloalkyl (e.g. trifluoromethoxy, trifluoroethoxy), -NH 2 , - NHMe, -NMe 2 , -N0 2 , -CN, hydroxyl methyl, hydroxyethyl and hydroxypropyl.
  • groups where chemically possible) selected from: chloro, fluoro, methyl, ethyl, iso-propyl, tert-butyl, Ci- 2 -haloalkyl (e.g. trifluoromethyl, trifluoroethyl), -OH
  • R 5 is selected from: chloro, fluoro, methyl, ethyl, iso-propyl, tert-butyl, Ci- 2 -haloalkyl (e.g. trifluoromethyl, trifluoroethyl), -OH, -OMe, -OEt, -O-Ci-2-haloalkyl (e.g. trifluoromethoxy, trifluoroethoxy), -NH2, -NHMe, - ⁇ 2, -NO2, -CN, hydroxyl methyl, hydroxyethyl and hydroxypropyl.
  • Ci- 2 -haloalkyl e.g. trifluoromethyl, trifluoroethyl
  • -OH e.g. trifluoromethyl, trifluoroethyl
  • -OH e.g. trifluoromethyl, trifluoroethyl
  • -OH e.g. trifluoromethyl, trifluoro
  • A is unsubstituted phenyl, methylphenyl, ethylphenyl, iso-propylphenyl, tert-butylphenyl, trifluoromethylphenyl, methoxyphenyl, ethyoxyphenyl, aminophenyl, N-methyl- aminophenyl, ⁇ , ⁇ -dimethyl-aminophenyl, nitrophenyl, cyanophenyl, unsubstituted pyridyl, methylpyridyl, ethylpyridyl, iso-propylpyridyl, tert-butylpyridyl, trifluoromethylpyridyl, methoxypyridyl, ethyoxypyridyl, aminopyridyl, N-methyl-aminopyridyl, ⁇ , ⁇ -dimethyl-aminopyridyl, nitropyri
  • aminothiophenyl N-methyl-aminothiophenyl, ⁇ , ⁇ -dimethyl-aminothiophenyl, nitrothiophenyl or cyanothiophenyl.
  • A is unsubstituted phenyl, methylphenyl, ethylphenyl, iso-propylphenyl, tert-butylphenyl, trifluoromethylphenyl, methoxyphenyl, ethyoxyphenyl, aminophenyl, N-methyl- aminophenyl, ⁇ , ⁇ -dimethyl-aminophenyl, nitrophenyl, cyanophenyl, unsubstituted pyridazinyl, methylpyridazinyl, ethylpyridazinyl, iso-propylpyridazinyl, tert-butylpyridazinyl,
  • trifluoromethylpyridazinyl methoxypyridazinyl, ethyoxypyridazinyl, aminopyridazinyl, N-methyl- aminopyridazinyl, ⁇ , ⁇ -dimethyl-aminopyridazinyl, nitropyridazinyl, cyanopyridazinyl, unsubstituted thiophenyl, methylthiophenyl, ethylthiophenyl, iso-propylthiophenyl, tert-butylthiophenyl, trifluoromethylthiophenyl, methoxythiophenyl, ethyoxythiophenyl, aminothiophenyl, N-methyl- aminothiophenyl, ⁇ , ⁇ -dimethyl-aminothiophenyl, nitrothiophenyl or cyanothiophenyl.
  • A is unsubstituted phenyl, methylphenyl, ethylphenyl, iso-propylphenyl, tert-butylphenyl, trifluoromethylphenyl, methoxyphenyl, ethyoxyphenyl, aminophenyl, N-methyl- aminophenyl, ⁇ , ⁇ -dimethyl-aminophenyl, nitrophenyl or cyanophenyl.
  • A is unsubstituted pyridyl, methylpyridyl, ethylpyridyl, iso-propylpyridyl, tert-butylpyridyl, trifluoromethylpyridyl, methoxypyridyl, ethyoxypyridyl, aminopyridyl, N-methyl- aminopyridyl, ⁇ , ⁇ -dimethyl-aminopyridyl, nitropyridyl or cyanopyridyl.
  • A is unsubstituted pyridazinyl, methylpyridazinyl, ethylpyridazinyl, iso- propylpyridazinyl, tert-butylpyridazinyl, trifluoromethylpyridazinyl, methoxypyridazinyl,
  • ethyoxypyridazinyl aminopyridazinyl, N-methyl-aminopyridazinyl, N,N-dimethyl-aminopyridazinyl, nitropyridazinyl or cyanopyridazinyl.
  • A is unsubstituted thiophenyl, methylthiophenyl, ethylthiophenyl, iso- propylthiophenyl, tert-butylthiophenyl, trifluoromethylthiophenyl, methoxythiophenyl,
  • ethyoxythiophenyl aminothiophenyl, N-methyl-aminothiophenyl, N,N-dimethyl-aminothiophenyl, nitrothiophenyl or cyanothiophenyl.
  • q is 0, 1 or 2, preferably, 0 or 1 .
  • p is 0 or 1 .
  • compounds of formula (I) with the proviso that X-Y-Z taken together is not methylene when R is substituted or unsubstituted: pyridyl and pyrimidine.
  • compounds of formula (I) with the proviso that X-Y-Z taken together is not alkylene when R is substituted or unsubstituted: pyridyl and pyrimidine.
  • Z may be a bond.
  • Z may be -(CR A2 R B2 ) k -.
  • X may be a bond.
  • X may be -(CR A R B ) n -.
  • Z is a bond and X is a bond.
  • Z is -(CR A2 R B2 )k- and X is a bond.
  • X is -(CR A R B ) n - and Z is a bond.
  • Z is -(CR A2 R B2 )k- and X is -(CR A R B ) n -.
  • Z is a bond.
  • Z is a bond
  • X is a bond
  • Y is selected from: -0-, -NR F -, -S-, -C(O)-, - C(NR F )-, -CCOR ⁇ R -C(NR F R G )R C -, -C(0)NR F -, -NR F C(0)-, -NR F C(0)NR G -, -NR F S0 2 NR G -, -SO2-, -S0 2 NR F -, -NR F S0 2 - , -OC(O)-, and -C(0)0-.
  • Z is -(CR A2 R B2 ) k -
  • X is a bond and Y is selected from: -0-, -NR F -, -S-, -C(O)-, -C(NR F )-, -C(OR F )R c -, -C(NR F R G )R C -, - C(0)NR F -, -NR F C(0)-, -NR F C(0)NR G -, -NR F S0 2 NR G -, -SO2-, -S0 2 NR F -, -NR F S0 2 -, -OC(O)-, and - C(0)0-.
  • X is -(CR A R B ) n -
  • Z is a bond and Y is selected from: - 0-, -NR F -, -S-, -C(O)-, -CCNR P )-, -CCOR ⁇ R -C(NR F R G )R C -, -C(0)NR F -, -NR F C(0)-, -NR F C(0)NR G - , -NR F S0 2 NR G -, -S0 2 -, -S0 2 NR F -, -NR F S0 2 - , -OC(O)-, and -C(0)0-.
  • Z is -(CR A2 R B2 )k-
  • X is -(CR A R B ) n -
  • Y is selected from: -0-, -NR F -, -S-, -C(O)-, -C(NR F )-, - C(OR F )R c -, -C(NR F R G )R C -, -C(0)NR F -, -NR F C(0)-, -NR F C(0)NR G -, -NR F S0 2 NR G -, -S0 2 -, -S0 2 NR F - , -NR F S0 2 - , -OC(O)-, and -C(0)0-.
  • n, m and k are 1 or 2.
  • R c , R F , R G , R A , R B , R A2 and R B2 are H or methyl.
  • n, m and k are 1 or 2 and R c , R F , R G , R A , R B , R A2 and R B2 are H or methyl.
  • Z is a bond
  • X is a bond
  • Y is selected from: -0-, -NR F -, -S-, -C(O)-, - CCNR P )-, -CCOR ⁇ R -C(NR F R G )R C -, -C(0)NR F -, -NR F C(0)-, -NR F C(0)NR G -, -NR F S0 2 NR G -, -S0 2 -, -S0 2 NR F -, -NR F S0 2 - , -OC(O)-, and -C(0)0-.
  • Z is -(CR A2 R B2 ) k -
  • X is a bond and Y is selected from: -0-, -NR F -, -S-, -NR F C(0)-, -NR F C(0)NR G -, -NR F S0 2 NR G -, -S0 2 -, -
  • X is -(CR A R B ) n -
  • Z is a bond and Y is selected from: -0-, -NR F -, -S-, -C(O)-, -CCNR p )-, -CCOR ⁇ R -C(NR F R G )R C -, -C(0)NR F -, -NR F C(0)-, -NR F C(0)NR G -, -NR F S0 2 NR G -, -S0 2 -, -S0 2 NR F -, -NR F S0 2 - , -OC(O)-, and -C(0)0-.
  • Z is -(CR A2 R B2 ) k -
  • X is -(CR A R B ) n -
  • Y is selected from: -0-, -NR F -, - S-, -NR F C(0)-, -NR F C(0)NR G -, -NR F S0 2 NR G -, -S0 2 -, -S0 2 NR F -, -NR F S0 2 - and -OC(O)-.
  • n, m and k are 1 or 2.
  • R c , R F , R G , R A , R B , R A2 and R B2 are H or methyl.
  • n, m and k are 1 or 2 and R c , R F , R G , R A , R B , R A2 and R B2 are H or methyl.
  • X may be a bond, -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-.
  • Z may be a bond, -CH 2 -, -(CH 2 ) 2 - or - C(Me)H-.
  • Y may be selected from: -0-, -NH-, -NMe-, -S-, -C(O)-, -C(NH)-, -C(NMe)-, -C(OH)H-, - C(NH 2 )H-, -C(0)NH-, -C(0)NMe-, -NHC(O)-, -NMeC(O)-, -NHC(0)NH-, -NHC(0)NMe-, - NMeC(0)NH-, -NMeC(0)NMe-, -NHSO2NH-, -NMeS0 2 NH-, -NHS0 2 NMe-, -NMeS0 2 NMe-, -SO2-, - SO2NH-, -S0 2 NMe-, -NHSO2- , -NMeS0 2 -, -OC(O)- and -C(0)0-.
  • Y may be selected from: -0-, -NH-, -NMe-, -S-, -NHC(O)-, -NMeC(O)-, -NHC(0)NH-, -NHC(0)NMe-, -NMeC(0)NH-, - NMeC(0)NMe-, -NHSO2NH-, -NMeS0 2 NH-, -NHS0 2 NMe-, -NMeS0 2 NMe-, -S0 2 -, -S0 2 NH-, - S0 2 NMe-, -NHS0 2 - , -NMeS0 2 -, and -OC(O)-.
  • Z may be a bond and Y may be selected from: -0-, -NH-, -NMe-, -S-, - C(O)-, -C(NH)-, -C(NMe)-, -C(OH)H-, -C(NH 2 )H-, -C(0)NH-, -C(0)NMe-, -NHC(O)-, -NMeC(O)-, - NHC(0)NH-, -NHC(0)NMe-, -NMeC(0)NH-, -NMeC(0)NMe-, -NHS0 2 NH-, -NMeS0 2 NH-, - NHS0 2 NMe-, -NMeS0 2 NMe-, -S0 2 -, -S0 2 NH-, -S0 2 NMe-, -NHS0 2 - , -NMeS0 2 -, -OC(O)- and
  • Z may be a bond, -CH 2 -, -(CH 2 ) 2 - or -C(Me)H- and Y may be selected from: - 0-, -NH-, -NMe-, -S-, -NHC(O)-, -NMeC(O)-, -NHC(0)NH-, -NHC(0)NMe-, -NMeC(0)NH-, - NMeC(0)NMe-, -NHS0 2 NH-, -NMeS0 2 NH-, -NHS0 2 NMe-, -NMeS0 2 NMe-, -S0 2 -, -S0 2 NH-, - S0 2 NMe-, -NHS0 2 - , -NMeS0 2 -, and -OC(O)-.
  • X is a bond, Y is -O- and Z is a bond;
  • X is a bond, Y is -O- and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -O- and Z is a bond;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -O- and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -NR F - and Z is a bond;
  • X is a bond, Y is -NR F - and Z is -CH 2 -, -(CH 2 ) 2 - or - C(Me)H-;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -NR F - and Z is a bond;
  • X is -CH 2 -, -(CH 2 ) 2 - or - C(Me)H-, Y is -NR F - and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -S- and Z is a bond;
  • X is a bond, Y is -S- and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -S- and Z is a bond;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -S- and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -C(O)- and Z is a bond; X is a bond, Y is -C(O)- and Z is -CH 2 -, -(CH 2 ) 2 - or -
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -C(O)- and Z is a bond;
  • X is -CH 2 -, -(CH 2 ) 2 - or - C(Me)H-, Y is -C(O)- and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -C(NR F )- and Z is a bond;
  • X is a bond, Y is -C(NR F )- and Z is -CH 2 -, -(CH 2 ) 2 - or - C(Me)H-;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -C(NR F )- and Z is a bond;
  • X is -CH 2 -, -(CH 2 ) 2 - or - C(Me)H-, Y is -C(NR F )- and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -C OR ⁇ H- and Z is a bond;
  • X is a bond, Y is -C(OR F )H- and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -C(OR F )H- and Z is a bond;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -C OR ⁇ H- and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -C(NR F R G )H- and Z is a bond; X is a bond, Y is -C(NR F R G )H- and Z is -CH 2 -, - (CH 2 ) 2 - or -C(Me)H-; X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -C(NR F R G )H- and Z is a bond; X is - CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -C(NR F R G )H- and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-; X is a bond, Y is -C(0)NR F - and Z is a bond; X is a bond, Y is -C(0)NR F
  • X is a bond, Y is -NR F C(0)- and Z is a bond;
  • X is a bond, Y is -NR F C(0)- and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -NR F C(0)- and Z is a bond;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -NR F C(0)- and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -NR F C(0)NR G - and Z is a bond; X is a bond, Y is -NR F C(0)NR G - and Z is -CH 2 -, - (CH 2 ) 2 - or -C(Me)H-; X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -NR F C(0)NR G - and Z is a bond; X is - CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -NR F C(0)NR G - and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -NR F S0 2 NR G - and Z is a bond; X is a bond, Y is -NR F S0 2 NR G - and Z is -CH 2 -, - (CH 2 ) 2 - or -C(Me)H-; X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -NR F S0 2 NR G - and Z is a bond; X is - CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -NR F S0 2 NR G - and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -S0 2 - and Z is a bond;
  • X is a bond, Y is -S0 2 - and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H- ;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -S0 2 - and Z is a bond;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -S0 2 - and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -S0 2 NR F - and Z is a bond; X is a bond, Y is -S0 2 NR F - and Z is -CH 2 -, -(CH 2 ) 2 - or - C(Me)H-; X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -S0 2 NR F - and Z is a bond; X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -S0 2 NR F - and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -NR F S0 2 - and Z is a bond; X is a bond, Y is -NR F S0 2 - and Z is -CH 2 -, -(CH 2 ) 2 - or - C(Me)H-; X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -NR F S0 2 - and Z is a bond; X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -NR F S0 2 - and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -OC(O)- and Z is a bond;
  • X is a bond, Y is -OC(O)- and Z is -CH 2 -, -(CH 2 ) 2 - or - C(Me)H-;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -OC(O)- and Z is a bond;
  • X is -CH 2 -, -(CH 2 ) 2 - or - C(Me)H-, Y is -OC(O)- and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -C(0)0- and Z is a bond;
  • X is a bond, Y is -C(0)0- and Z is -CH 2 -, -(CH 2 ) 2 - or - C(Me)H-;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -C(0)0- and Z is a bond; and
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -C(0)0- and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-.
  • X is a bond, Y is -O- and Z is a bond;
  • X is a bond, Y is -O- and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -O- and Z is a bond;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -O- and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -NR F - and Z is a bond;
  • X is a bond, Y is -NR F - and Z is -CH 2 -, -(CH 2 ) 2 - or - C(Me)H-;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -NR F - and Z is a bond;
  • X is -CH 2 -, -(CH 2 ) 2 - or - C(Me)H-, Y is -NR F - and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -S- and Z is a bond;
  • X is a bond, Y is -S- and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -S- and Z is a bond;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -S- and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -NR F C(0)- and Z is a bond;
  • X is a bond, Y is -NR F C(0)- and Z is a bond;
  • X is a bond, Y is -NR F
  • X is a bond, Y is -NR F C(0)NR G - and Z is a bond; X is a bond, Y is -NR F C(0)NR G - and Z is -CH 2 -, - (CH 2 ) 2 - or -C(Me)H-; X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -NR F C(0)NR G - and Z is a bond; X is - CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -NR F C(0)NR G - and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -NR F C(0)NR G - and Z is a bond; X is a bond, Y is -NR F S0 2 NR G - and Z is -CH 2 -, - (CH 2 ) 2 - or -C(Me)H-; X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -NR F S0 2 NR G - and Z is a bond; X is - CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -NR F S0 2 NR G - and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -S0 2 - and Z is a bond;
  • X is a bond, Y is -S0 2 - and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H- ;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -S0 2 - and Z is a bond;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -S0 2 - and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -S0 2 NR F - and Z is a bond; X is a bond, Y is -S0 2 NR F - and Z is -CH 2 -, -(CH 2 ) 2 - or - C(Me)H-; X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -S0 2 NR F - and Z is a bond; X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -S0 2 NR F - and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -NR F S0 2 - and Z is a bond; X is a bond, Y is -NR F S0 2 - and Z is -CH 2 -, -(CH 2 ) 2 - or - C(Me)H-; X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -NR F S0 2 - and Z is a bond; X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -NR F S0 2 - and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -OC(O)- and Z is a bond;
  • X is a bond, Y is -OC(O)- and Z is -CH 2 -, -(CH 2 ) 2 - or - C(Me)H-;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -OC(O)- and Z is a bond; and
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -OC(O)- and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-.
  • R F is H or Me
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -O- and Z is a bond;
  • X is a bond, Y is -O- and Z is a bond;
  • X is a bond
  • Y is -C OR ⁇ H- and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond, Y is -C(O)- and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond
  • Y is -NR F - and Z is a bond
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -NR F - and Z is a bond;
  • X is a bond
  • Y is -NR F C(0)- and Z is a bond
  • X is a bond
  • Y is -C(0)NR F - and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is a bond
  • Y is -S- and Z is a bond
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-
  • Y is -C(0)NR F - and Z is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-;
  • X is -CH 2 -, -(CH 2 ) 2 - or -C(Me)H-, Y is -NR F C(0)- and Z is a bond; X is a bond, Y is -NR F C(0)NR G - and Z is a bond; and
  • X is a bond
  • Y is -OC(O)- and Z is a bond.
  • X is a bond, Y is -O- and Z is a bond;
  • X is a bond
  • Y is -NR F - and Z is a bond
  • X is -CH2-, -(CH 2 ) 2 - or -C(Me)H-, Y is -NR F - and Z is a bond;
  • X is a bond
  • Y is -NR F C(0)- and Z is a bond
  • X is a bond
  • Y is -S- and Z is a bond
  • X is -CH2-, -(CH 2 ) 2 - or -C(Me)H-, Y is -NR F C(0)- and Z is a bond;
  • X is a bond
  • Y is -NR F C(0)NR G - and Z is a bond
  • X is a bond
  • Y is -OC(O)- and Z is a bond.
  • X is a bond, Y is -O- and Z is a bond;
  • X is a bond, Y is -C(OH)H- and Z is -CH 2 -;
  • X is a bond, Y is -C(OH)H- and Z is -C(Me)H-;
  • X is a bond, Y is -C(O)- and Z is -CH 2 -;
  • X is a bond, Y is -NH- and Z is a bond; X is a bond, Y is -NMe- and Z is a bond;
  • X is -CH 2 -, Y is -NH- and Z is a bond;
  • X is -CH 2 -, Y is -NMe- and Z is a bond;
  • X is a bond, Y is -NHC(O)- and Z is a bond; X is a bond, Y is -NMeC(O)- and Z is a bond; X is a bond, Y is -C(0)NH- and Z is -CH 2 -; X is a bond, Y is -C(0)NMe- and Z is -CH 2 -; X is a bond, Y is -S- and Z is a bond;
  • X is -CH 2 -, Y is -C(0)NH- and Z is -CH 2 -; X is -CH 2 -, Y is -C(0)NMe- and Z is -CH 2 -; X is -CH 2 -, Y is -NHC(O)- and Z is a bond; X is -CH 2 -, Y is -NMeC(O)- and Z is a bond;
  • X is a bond
  • Y is -NHC(0)NH- and Z is a bond
  • X is a bond
  • Y is -NMeC(0)NH- and Z is a bond
  • X is a bond
  • Y is -NHC(0)NMe- and Z is a bond
  • X is a bond
  • Y is -NMeC(0)NMe- and Z is a bond
  • X is -CH2-, Y is -O- and Z is a bond;
  • X is a bond, Y is -O- and Z is a bond;
  • X is a bond, Y is -NH- and Z is a bond; X is a bond, Y is -NMe- and Z is a bond;
  • X is -CH2 -, Y is -NH- and Z is a bond;
  • X is -CH2 -, Y is -NMe- and Z is a bond;
  • X is a bond, Y is -NHC(O)- and Z is a bond; X is a bond, Y is -NMeC(O)- and Z is a bond;
  • X is a bond
  • Y is -S- and Z is a bond
  • X is -CH2-, Y is -NHC(O)- and Z is a bond; X is -CH2-, Y is -NMeC(O)- and Z is a bond;
  • X is a bond
  • Y is -NHC(0)NH- and Z is a bond
  • X is a bond
  • Y is -NMeC(0)NH- and Z is a bond
  • X is a bond
  • Y is -NHC(0)NMe- and Z is a bond
  • X is a bond
  • Y is -NMeC(0)NMe- and Z is a bond
  • X is a bond
  • Y is -OC(O)- and Z is a bond.
  • X is -CH2-, Y is -O- and Z is a bond;
  • X is a bond, Y is -O- and Z is a bond;
  • X is a bond, Y is -C(OH)H- and Z is -CH2-;
  • X is a bond
  • Y is -C(OH)H- and Z is -C(Me)H-;
  • X is a bond
  • Y is -C(O)-
  • Z is -CH2 -.
  • X is -CH2-, Y is -O- and Z is a bond;
  • X is a bond
  • Y is -O- and Z is a bond
  • X is a bond
  • Y is -NH- and Z is a bond.
  • Y is -(CR D R E ) m -.
  • R A6 is H.
  • R B5 is H.
  • m is 1 or 2.
  • Y is -(CR D R E ) m - and m is 2.
  • the substituents R D and R E are each independently defined as above.
  • R D , R E and R D2 are H and R E2 is OH.
  • R D and R D2 are H, R E is methyl and R E2 is OH.
  • X is -(CR A R B ) n - and n is 1 or 2.
  • Y is -NR F -.
  • R F is selected from the group consisting of: H, Ci-4 alkyl and C1-4 haloalkyl.
  • R F is selected from the group consisting of: H, methyl and ethyl.
  • R is a 5 to 16 membered fully saturated, partially unsaturated or aromatic mono-, di- or tri-cyclic moiety, which may optionally include 1 , 2 or 3 heteroatoms (where chemically possible) selected from O, N and S, and is unsubstituted or substituted with 1 to 5 substituents (where chemically possible) selected from halo, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, -OR A3 , -NR A3 R B3 , -SR A3 , -C(0)R A3 , -OC(0)R A3 , -C(0)OR A3 , -NR A3 C(0)R B3 , -
  • C5-10 heterocycloalkyl will be understood to mean a 5 to 10 membered heterocycloalkyl ring containing 1 , 2 or 3 heteroatoms, as is consistent with the definition of R above.
  • C5-10 heteroaryl will be understood to mean a 5 to 10 membered heteroaryl ring containing 1 , 2 or 3 heteroatoms, as is consistent with the definition of R above. Accordingly, C5-10 heterocycloalkyl may be a 5 to 10 membered heterocycloalkyl ring and C5-10 heteroaryl may be a 5 to 10 membered heteroaryl ring both rings containing 1 , 2 or 3 heteroatoms.
  • C5-10 cycloalkyl may represent cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
  • cyclopropenyl cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl, cycloatadienyl, indanyl, indenyl and tetralinyl.
  • C5-10 heterocycloalkyl may represent oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, pyroline, imidazolidine, imidazoline, succinimide, pyrazolidine, pyrazoline, oxazolidine, oxazoline, dioxolane, isoxazolidine, isoxazoline, thiazolidine, thiazoline, isothiazolidine,
  • Ce-10 aryl may represent phenyl or napthyl.
  • C5-10 heteroaryl may represent pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl and benzimidazolyl.
  • R is a ring selected from unsubstituted or substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl, cycloatadienyl, indanyl, indenyl, tetralinyl, oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, pyroline, imidazolidine, imidazoline, succinimide, pyrazolidine, pyrazoline, oxazolidine, oxazolidine,
  • R is selected from substituted or unsubstituted: pyridyl, quinolinyl, pyrimidinyl, isoquinolinyl, cyclohexyl, piperidinyl, tetrahydroisoquinolinyl, phenyl, morpholinyl, piperazinyl, and oxadiazolyl.
  • R is a ring selected from substituted or unsubstituted: phenyl, napthyl, indanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl and benzimidazolyl.
  • R is a ring selected from substituted or unsubstituted: pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl and isoquinolinyl. In an embodiment, R is a ring selected from substituted or unsubstituted: pyridyl, pyrimidinyl, pyrazinyl, quinolinyl and isoquinolinyl.
  • R is selected from substituted or unsubstituted: cycloalkyl moieties, cycloalkenyl moieties and fused ring systems including an aromatic portion.
  • R is selected from substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • R is selected from substituted or unsubstituted: cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl and cyclooctadienyl.
  • R is selected from substituted or unsubstituted: heterocycloalkyl moieties, heterocycloalkenyl moieties and fused ring systems including a heteroaromatic portion.
  • R is selected from substituted or unsubstituted: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, pyroline, imidazolidine, imidazoline, succinimide, pyrazolidine, pyrazoline, oxazolidine, oxazoline, dioxolane, isoxazolidine, isoxazoline, thiazolidine, thiazoline, isothiazolidine, isothiazoline, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dihydropyran and tetrahydropyran.
  • R is selected from substituted or unsubstituted: oxirane, azir
  • R is selected from substituted or unsubstituted: phenyl, pyridyl, cyclohexyl, isoquinolinyl, quinolinyl, piperidinyl, morpholinyl, tetrahydroquinolinyl,
  • R is selected from substituted or unsubstituted: phenyl, pyridyl, cyclohexyl, isoquinolinyl, quinolinyl, piperidinyl, morpholinyl, tetrahydroquinolinyl,
  • R is selected from substituted or unsubstituted: phenyl, pyridyl and cyclohexyl,
  • halo e.g. chloro or fluoro
  • -OR A3 e.g. -OH, -OMe, -OEt or -OCF 3
  • -NR A3 R B3 e.g. -NH 2 , -NH
  • Ci- haloalkyl e.g. trifluoromethyl or trifluoroethyl
  • Ci- 4 alkyl substituted with -OR A3 e.g. -CH 2 OH
  • Ci- 4 alkyl substituted with -NR A3 R B3 e.g. -CH 2 NH 2
  • the R moiety is unsubstituted or substituted with a single substituent selected from CI, OMe, CN, Me, -CH 2 OH, -C(0)OH, and -C(0)OMe.
  • -Z-Y-X-R is -OCH 2 phenyl, -Ophenyl -OCH 2 pyridyl, -Opyridyl, -NHphenyl, -OCH 2 cyanophenyl, -Ocyanophenyl, -OCH 2 methylphenyl, -Omethylphenyl, -OCH 2 chlorophenyl, - Ochlorophenyl, -OCH 2 methoxyphenyl, -Omethoxyphenyl, -OCH 2 (hydroxymethyl)phenyl, - O(hydroxymethyl)phenyl, or
  • R 2 is selected from: H, halo, Ci- 4 alkyl, Ci- 4 haloalkyl, -OR A4 and Ci- 4 alkyl substituted with -OR A4 .
  • R 2 is selected from: H, chloro, fluoro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, trifluoroethyl, -OH, methoxy, ethoxy, hydroxy methyl, hydroxyethyl, hydroxypropyl.
  • R 2 is selected from: H and -OH.
  • R 2 may be H.
  • R 3 and R 4 are each independently selected from: H, halo, Ci- 4 alkyl, Ci- 4 haloalkyl, -CN and -OR A5 . In an embodiment, R 3 and R 4 are each independently selected from: H and Ci- alkyl. R 3 and R 4 may be H. [0070] In an embodiment m + n + k is 4 or less. Similarly, in an embodiment n + k is 4 or less. In an embodiment m, n and k are selected from 1 or 2. Preferably, m is 1 . Preferably, k is 1 .
  • the present invention also provides pharmaceutically acceptable salts of the compounds described herein.
  • the compound according to the invention may be selected from a preferred group consisting of:
  • the compound according to the invention may also be selected from a group consisting of:
  • the above compounds have a chiral centre. All enantiomers and diastereomers of the above compounds are contemplated by the invention. Chiral centres are indicated on the compounds above with a * symbol.
  • the compounds of the invention have the (R)-configuration at the stereocentre.
  • the compounds of the invention have the (S)-configuration at the stereocentre.
  • the present invention provides a compound of the present invention for use as a medicament.
  • the present invention provides a pharmaceutical formulation comprising a compound of the present invention and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition may be a combination product comprising an additional pharmaceutically active agent.
  • the additional pharmaceutically active agent may be an anti-tumor agent described below.
  • a compound of the present invention for use in the treatment of a condition which is modulated by indoleamine 2,3-dioxygenase (IDO) and/or tryptophan dioxygenase (TD02).
  • IDO indoleamine 2,3-dioxygenase
  • TD02 tryptophan dioxygenase
  • conditions that are modulated by IDO and/or TD02 are conditions that would be treated by the inhibition of IDO and/or TD02, using a compound of the present invention.
  • a compound of formula (I) may be for use in the treatment of a condition treatable by the inhibition of IDO and/or TD02.
  • IDO indoleamine 2,3-dioxygenase proteins
  • ID01 and ID02. there are two indoleamine 2,3-dioxygenase proteins
  • IDO may refer to ID01 and/or ID02, optionally to ID01 .
  • any condition which is modulated by IDO and/or TD02 may be a condition modulated by ID01 , ID02, and/or TD02.
  • IDOL the condition may be a condition modulated by ID01 and/or TD02.
  • IDO and/or TD02 inhibition is relevant for the treatment of many different diseases associated with inhibition of IDO and/or TD02.
  • the condition treatable by the inhibition of IDO and/or TD02 may be selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, neurodegenerative disorders, inflammation, autoimmune diseases and immunological diseases.
  • Specific cancers, sarcomas, melanomas, skin cancers, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammation and immunological diseases treatable by the inhibition of IDO and/or TD02 may be selected from: immunosuppression melanoma, metastatic non-small cell lung cancer, non-small cell lung cancer, metastatic melanoma, anxiety, depression, brain tumour, hormone refractory prostate cancer, prostate cancer, metastatic breast cancer, breast cancer, stage IV melanoma, solid tumor, metastatic pancreatic cancer, pancreatic cancer, myelodisplastic syndrome, ovarian cancer, fallopian tube cancer, peritoneal tumor, colorectal cancer, lung cancer, cervical cancer, testicular cancer, renal cancer, cancer of the head and neck, HIV-infection, AIDS (including its manifestations such as cachexia, dementia and diarrhoea), organ transplant rejection, dementia, Alzheimer's disease, Huntington's disease, age related cataracts, organ transplant
  • a compound of the invention may be for use in the treatment of a condition selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, neuro-degenerative disorders, inflammation and immunological diseases.
  • Specific cancers, sarcomas, melanomas, skin cancers, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammation, autoimmune diseases and immunological diseases that may be treated by the compound of the invention may be selected from: immunosuppression melanoma, metastatic non- small cell lung cancer, non-small cell lung cancer, metastatic melanoma, anxiety, depression, brain tumour, hormone refractory prostate cancer, prostate cancer, metastatic breast cancer, breast cancer, stage IV melanoma, solid tumor, metastatic pancreatic cancer, pancreatic cancer, myelodisplastic syndrome, ovarian cancer, fallopian tube cancer, peritoneal tumor, colorectal cancer, lung cancer, cervical cancer, testicular cancer, renal cancer, cancer of the head and neck, HIV-infection, AIDS (including its manifestations such as cachexia, dementia and diarrhoea), organ transplant rejection, dementia, Alzheimer's disease, Huntington's disease, age related cataracts, organ transplant
  • a method of treatment of a condition which is modulated by IDO and/or TD02 comprising administering a therapeutic amount of a compound of the invention, to a patient in need thereof.
  • the method of treatment may be a method of treating a condition treatable by the inhibition of IDO and/or TD02. These conditions are described above in relation to conditions treatable by the inhibition of IDO and/or TD02.
  • a method of treatment of a condition selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, neuro-degenerative disorders, inflammation and immunological diseases wherein the method comprises administering a therapeutic amount of a compound of the invention, to a patient in need thereof.
  • Specific cancers, sarcomas, melanomas, skin cancers, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammation, autoimmune diseases and immunological diseases that may be treated by the method of treatment may be selected from: immunosuppression melanoma, metastatic non- small cell lung cancer, non-small cell lung cancer, metastatic melanoma, anxiety, depression, brain tumour, hormone refractory prostate cancer, prostate cancer, metastatic breast cancer, breast cancer, stage IV melanoma, solid tumor, metastatic pancreatic cancer, pancreatic cancer, myelodisplastic syndrome, ovarian cancer, fallopian tube cancer, peritoneal tumor, colorectal cancer, lung cancer, cervical cancer, testicular cancer, renal cancer, cancer of the head and neck, HIV-infection, AIDS (including its manifestations such as cachexia, dementia and diarrhoea), organ transplant rejection, dementia, Alzheimer's disease, Huntington's disease, age related cataracts, organ transplant rejection
  • conditions that are modulated by IDO and/or TD02 are conditions that would be treated by the inhibition of IDO and/or TD02, using a compound of the present invention.
  • the condition may be any of the conditions mentioned above.
  • a compound for use in treating a condition treatable by the inhibition of the degradation of tryptophan and preventing the production of N-formylkynurenine is provided.
  • the present invention provides a compound of the present invention for use in treating IDO and/or TD02 mediated immunosuppression.
  • the present invention provides a compound of the present invention for use in treating immunosuppression.
  • the present invention provides a compound of the present invention for use in treating immunosuppression associated with cancer, in particular for use in treating tumour-specific immunosuppression associated with cancer.
  • the present invention provides a compound of the present invention for use in treating immunosuppression associated with an infectious disease, e.g., HIV-1 infection, influenza, hepatitis C virus, human papilloma virus, cytomegalovirus, Epstein-Barr virus, poliovirus, varicella zoster virus and coxsackie virus.
  • infectious disease e.g., HIV-1 infection, influenza, hepatitis C virus, human papilloma virus, cytomegalovirus, Epstein-Barr virus, poliovirus, varicella zoster virus and coxsackie virus.
  • the present invention provides methods of modulating an activity of IDO and/or TD02 comprising contacting an IDO and/or TD02 containing system with a compound according to the present invention.
  • the present invention provides methods of treating IDO and/or TD02 mediated immunosuppression in a subject in need thereof, comprising administering an effective amount of a compound according to the present invention.
  • the present invention provides methods of treating a medical condition that benefits from the inhibition of enzymatic activity of IDO and/or TD02 comprising administering an effective amount of a compound according to the present invention.
  • the present invention provides methods of enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound according to the present invention.
  • the present invention provides methods of treating tumour-specific immunosuppression associated with cancer comprising administering an effective amount of a compound according to the present invention.
  • the present invention provides methods of treating immunosuppression associated with an infectious disease, e.g., HIV-1 infection, comprising administering an effective amount of a compound according to the present invention.
  • an infectious disease e.g., HIV-1 infection
  • cancer may be selected from immunosuppression melanoma, metastatic non-small cell lung cancer, non-small cell lung cancer, metastatic melanoma, brain tumour, hormone refractory prostate cancer, prostate cancer, metastatic breast cancer, breast cancer, stage IV melanoma, melanoma, solid tumor, metastatic pancreatic cancer, pancreatic cancer, myelodysplasia syndrome, ovarian cancer, fallopian tube cancer, peritoneal tumor, and colorectal cancer.
  • halo refers to one of the halogens, group 17 of the periodic table.
  • the term refers to fluorine, chlorine, bromine and iodine.
  • the term refers to fluorine or chlorine.
  • Ci-e alkyl refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, / ' so-propyl, n-butyl, sec-butyl, fe/f-butyl, n- pentyl and n-hexyl.
  • Alkylene groups may likewise be linear or branched and may have two places of attachment to the remainder of the molecule.
  • an alkylene group may, for example, correspond to one of those alkyl groups listed in this paragraph.
  • the alkyl and alkylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, Ci-e alkoxy. [00106] The term "Ci-e alkoxy" refers to an alkyl group which is attached to a molecule via oxygen.
  • the alkyl part may be linear or branched and may contain 1 , 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, / ' so-propyl, n-butyl, sec-butyl, fe/f-butyl, n- pentyl and n-hexyl. Therefore, the alkoxy group may be methoxy, ethoxy, n-propoxy, / ' so-propoxy, n- butoxy, sec-butoxy, fe/f-butoxy, n-pentoxy and n-hexoxy.
  • the alkyl part of the alkoxy group may be unsubstituted or substituted by one or more substituents. Possible substituents are described below.
  • Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, Ci-e alkoxy.
  • halogen e.g. fluorine, chlorine, bromine and iodine
  • OH Ci-e alkoxy.
  • Ci-e alkoxy Ci-e alkoxy.
  • the term "Ci-e haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence, for example fluorine, chlorine, bromine and iodine.
  • the halogen atom may be present at any position on the hydrocarbon chain.
  • Ci-e haloalkyl may refer to chloromethyl, flouromethyl, trifluoromethyl, chloroethyl e.g. 1 - chloromethyl and 2-chloroethyl, trichloroethyl e.g. 1 ,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g. 1 -fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g. 1 ,2,2-trifluoroethyl and 2,2,2- trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl.
  • C2-6 alkenyl refers to a branched or linear hydrocarbon chain containing at least one double bond and having 2, 3, 4, 5 or 6 carbon atoms.
  • the double bond(s) may be present as the E or Z isomer.
  • the double bond may be at any possible position of the hydrocarbon chain.
  • the "C2-6 alkenyl” may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.
  • C2-6 alkynyl refers to a branched or linear hydrocarbon chain containing at least one triple bond and having 2, 3, 4, 5 or 6 carbon atoms.
  • the triple bond may be at any possible position of the hydrocarbon chain.
  • the "C2-6 alkynyl” may be ethynyl, propynyl, butynyl, pentynyl and hexynyl.
  • C1-6 heteroalkyl refers to a branched or linear hydrocarbon chain containing 1 , 2, 3, 4, 5, or 6 carbon atoms and at least one heteroatom selected from N, O and S positioned between any carbon in the chain or at an end of the chain.
  • the hydrocarbon chain may contain one or two heteroatoms.
  • the C1-6 heteroalkyl may be bonded to the rest of the molecule through a carbon or a heteroatom.
  • the "C1-6 heteroalkyl” may be C1-6 /V-alkyl, C1-6 ⁇ ,/V-alkyl, or C1-6 O-alkyl.
  • Carbocyclic refers to a saturated or unsaturated carbon containing ring system.
  • a “carbocyclic” system may be monocyclic or a fused polycyclic ring system, for example, bicyclic or tricyclic.
  • a “carbocyclic” moiety may contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system.
  • Carbocyclic encompasses cycloalkyl moieties, cycloalkenyl moieties, aryl ring systems and fused ring systems including an aromatic portion.
  • heterocyclic refers to a saturated or unsaturated ring system containing at least one heteroatom selected from N, O or S.
  • a “heterocyclic” system may contain 1 , 2, 3 or 4 heteroatoms, for example 1 or 2.
  • a “heterocyclic” system may be monocyclic or a fused polycyclic ring system, for example, bicyclic or tricyclic.
  • a “heterocyclic” moiety may contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system.
  • Heterocyclic encompasses heterocycloalkyl moieties, heterocycloalkenyl moieties and heteroaromatic moieties.
  • the heterocyclic group may be: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.
  • C3-8 cycloalkyl refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms.
  • the "C3-8 cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • C3-8 cycloalkenyl refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms that is not aromatic.
  • the ring may contain more than one double bond provided that the ring system is not aromatic.
  • the "C3-8 cycloalkyl” may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.
  • C3-8 heterocycloalkyl refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least one heteroatom within the ring selected from N, O and S. For example there may be 1 , 2 or 3 heteroatoms, optionally 1 or 2.
  • the "C3-8 heterocycloalkyl” may be bonded to the rest of the molecule through any carbon atom or heteroatom.
  • the "C3-8 heterocycloalkyl” may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring.
  • the "C3-8 heterocycloalkyl” may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.
  • C3-8 heterocycloalkenyl refers to an unsaturated hydrocarbon ring system, that is not aromatic, containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least one heteroatom within the ring selected from N, O and S. For example there may be 1 , 2 or 3 heteroatoms, optionally 1 or 2.
  • the "C3-8 heterocycloalkenyl” may be bonded to the rest of the molecule through any carbon atom or heteroatom.
  • the "C3-8 heterocycloalkenyl” may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring.
  • the "C3-8 heterocycloalkyl” may be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline.
  • aromatic when applied to a substituent as a whole means a single ring or polycyclic ring system with 4n + 2 electrons in a conjugated ⁇ system within the ring or ring system where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • aryl refers to an aromatic hydrocarbon ring system. The ring system has 4n +2 electrons in a conjugated ⁇ system within a ring where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • the "aryl” may be phenyl and naphthyl. The aryl system itself may be substituted with other groups.
  • heteroaryl refers to an aromatic hydrocarbon ring system with at least one heteroatom within a single ring or within a fused ring system, selected from O, N and S.
  • the ring or ring system has 4n +2 electrons in a conjugated ⁇ system where all atoms contributing to the conjugated ⁇ system are in the same plane.
  • the "heteroaryl” may be imidazole, thiene, furane, thianthrene, pyrrol, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.
  • alkaryl refers to an aryl group, as defined above, bonded to a C1-4 alkyl, where the Ci-4 alkyl group provides attachment to the remainder of the molecule.
  • alkheteroaryl refers to a heteroaryl group, as defined above, bonded to a Ci-4 alkyl, where the alkyl group provides attachment to the remainder of the molecule.
  • halogen herein includes reference to F, CI, Br and I.
  • Halogen may be CI.
  • Halogen may be F.
  • a bond terminating in a " " represents that the bond is connected to another atom that is not shown in the structure.
  • a bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be connected to any of the atoms in the ring structure where allowed by valency.
  • a moiety may be substituted at any point on the moiety where chemically possible and consistent with atomic valency requirements.
  • the moiety may be substituted by one or more substituents, e.g. 1 , 2, 3 or 4 substituents; optionally there are 1 or 2 substituents on a group. Where there are two or more substituents, the substituents may be the same or different.
  • the substituent(s) may be selected from: OH, NHR, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, C(0)H, acyl, acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, nitro, halo, Ci-e alkyl, Ci-e alkoxy, Ci-e haloalkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl or alkaryl.
  • R may be selected from H, C1-6 alkyl, C3-8 cycloalkyl, phenyl, benzyl or phenethyl group, e.g . R is H or C1-3 alkyl.
  • the adjacent substituents may form a C4-8 ring along with the atoms of the moiety on which the substituents are substituted, wherein the C4-8 ring is a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7, or 8 carbon atoms or a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7, or 8 carbon atoms and 1 , 2 or 3 heteroatoms.
  • ortho, meta and para substitution are well understood terms in the art.
  • "ortho" substitution is a substitution pattern where adjacent carbons possess a substituent, whether a simple group, for example the fluoro group in the example below, or other portions of the molecule, as indicated by the bond ending in " J*/"r ".
  • Metal substitution is a substitution pattern where two substituents are on carbons one carbon removed from each other, i.e with a single carbon atom between the substituted carbons. In other words there is a substituent on the second atom away from the atom with another substituent.
  • substituents are on the groups below are meta substituted.
  • acyl is meant an organic radical derived from, for example, an organic acid by the removal of the hydroxyl group, e.g. a radical having the formula R-C(O)-, where R may be selected from H, Ci-6 alkyl, C3-8 cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H or C1-3 alkyl.
  • R may be selected from H, Ci-6 alkyl, C3-8 cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H or C1-3 alkyl.
  • acyl is alkyl-carbonyl.
  • Examples of acyl groups include, but are not limited to, formyl, acetyl, propionyl and butyryl. A particular acyl group is acetyl.
  • the enantiomeric excess may be any of those disclosed above.
  • the compound is a single stereoisomer the compounds may still contain other diasteroisomers or enantiomers as impurities.
  • a single stereoisomer does not necessarily have an enantiomeric excess (e.e.) or diastereomeric excess (d.e.) of 100% but could have an e.e. or d.e. of about at least 85% [00131]
  • the invention contemplates pharmaceutically acceptable salts of the compounds of the invention. These may include the acid addition and base salts of the compounds. These may be acid addition and base salts of the compounds. In addition the invention contemplates solvates of the compounds.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 1 ,5- naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.
  • suitable salts see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when said solvent is water.
  • complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non- stoichiometric amounts.
  • the resulting complexes may be ionised, partially ionised, or non- ionised.
  • references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
  • the compounds of the invention include compounds of a number of formula as herein defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labelled compounds of the invention.
  • the present invention also includes all pharmaceutically acceptable isotopically-labelled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as C, 3 C and 4 C, chlorine, such as 36 CI, fluorine, such as 8 F, iodine, such as 23 l and 25 l, nitrogen, such as 3 N and 5 N, oxygen, such as 50, 7 0 and 8 0, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • Radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 4 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • the compounds of the present invention may exist as a mixture of enantiomers depending on the synthetic procedure used.
  • the enantiomers can be separated by conventional techniques known in the art.
  • the invention covers individual enantiomers as well as mixtures thereof.
  • any compatible protecting radical can be used.
  • methods of protection and deprotection such as those described by T.W.
  • the compounds of the present invention as well as intermediates for the preparation thereof can be purified according to various well-known methods, such as for example
  • One or more compounds of the invention may be combined with one or more
  • anti-viral agents for example anti-viral agents, chemotherapeutics, anti-cancer agents, immune enhancers, immunosuppressants, anti-tumour vaccines, anti-viral vaccines, cytokine therapy, or tyrosine kinase inhibitors, for the treatment of conditions modulated by the inhibition of IDO, for example cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammation and immunological diseases
  • the method of treatment or the compound for use in the treatment of cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammation and immunological diseases as defined hereinbefore may be applied as a sole therapy or be a combination therapy with an additional active agent.
  • the method of treatment or the compound for use in the treatment of cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, and central nervous system disorders may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti-tumor agents:
  • antiproliferative/antineoplastic drugs and combinations thereof such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard, bendamustin, melphalan, chlorambucil, chlormethine, busulphan, temozolamide, nitrosoureas, ifosamide, melphalan, pipobroman, triethylene-melamine, triethylenethiophoporamine, carmustine, lomustine, stroptozocin and dacarbazine); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludara
  • topoisomerase inhibitors for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan, mitoxantrone and camptothecin); bleomcin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (TaxolTM), nabpaclitaxel, docetaxel, mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide; (ii) cytostatic agents such as antiestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flu
  • anti-invasion agents for example dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function or antibodies to
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies, for example the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as gefitinib, erlotinib, 6-acrylamido-/V-(3-chloro-4- fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib) and antibodies to costimulatory molecules such as CTLA-4, 4-IBB and PD-I, or antibodies to cytokines (IL-IO, TGF-beta); inhibitors of the epidermal growth factor family (for example
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab
  • AvastinTM thalidomide
  • lenalidomide thalidomide
  • a VEGF receptor tyrosine kinase inhibitor such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib
  • immunotherapy approaches including for example antibody therapy such as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®) and ofatumumab; interferons such as interferon a; interleukins such as IL-2 (aldesleukin); interleukin inhibitors for example IRAK4 inhibitors; cancer vaccines including prophylactic and treatment vaccines such as HPV vaccines, for example Gardasil, Cervarix, Oncophage and Sipuleucel-T (Provenge); gp100;dendritic cell-based vaccines (such as Ad.p53 DC); and toll-like receptor modulators for example TLR-7 or TLR-9 agonists; and (viii) cytotoxic agents for example fludaribine (fludara), cladribine, pentostatin (NipentTM);
  • steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide,
  • (x) targeted therapies for example PI3Kd inhibitors, for example idelalisib and perifosine; PD-1 , PD-L1 , PD-L2 and CTL4-A modulators, antibodies and vaccines; other IDO inhibitors (such as indoximod); anti-PD-1 monoclonal antibodies (such as MK-3475 and nivolumab); anti-PDL1 monoclonal antibodies (such as MEDI-4736 and RG-7446); anti-PDL2 monoclonal antibodies; and anti-CTLA-4 antibodies (such as ipilimumab);
  • PI3Kd inhibitors for example idelalisib and perifosine
  • PD-1 , PD-L1 , PD-L2 and CTL4-A modulators antibodies and vaccines
  • other IDO inhibitors such as indoximod
  • anti-PD-1 monoclonal antibodies such as MK-3475 and nivolumab
  • anti-viral agents such as nucleotide reverse transcriptase inhibitors (for example, zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, adefovir diprovoxil, lobucavir, BCH-10652, emitricitabine, beta-L-FD4 (also called 3'-dicleoxy-5-fluoro-cytidine), (-)-beta-D-2,6-diamino-purine dioxolane, and lodenasine), non-nucleoside reverse transcriptase inhibitors (for example, nevirapine, delaviradine, efavirenz, PNU-142721 , AG-1549, MKC-442 (1 -ethoxy-methyl)-5-(1 - methylethyl)-6-(phenylmehtyl)-(2,4(1 H,3H)pyrimidineone), and (+
  • the method of treatment or the compound for use in the treatment of inflammation and immunological diseases may involve, in addition to the compound of the invention, additional active agents.
  • the additional active agents may be one or more active agents used to treat the condition being treated by the compound of the invention and additional active agent.
  • the additional active agents may include one or more of the following active agents:-
  • steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide,
  • TNF inhibitors for example etanercept; monoclonal antibodies (e.g. infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi)); fusion proteins (e.g. etanercept (Enbrel)); and 5- ⁇ 2 ⁇ agonists (e.g. 2,5-dimethoxy-4-iodoamphetamine, TCB-2, lysergic acid diethylamide (LSD), lysergic acid dimethylazetidide);
  • monoclonal antibodies e.g. infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi)
  • fusion proteins e.g. etanercept (Enbrel)
  • 5- ⁇ 2 ⁇ agonists e.g
  • anti-inflammatory drugs for example non-steroidal anti-inflammatory drugs
  • dihydrofolate reductase inhibitors/antifolates for example methotrexate, trimethoprim, brodimoprim, tetroxoprim, iclaprim, pemetrexed, ralitrexed and pralatrexate; and
  • immunosuppressants for example cyclosporins, tacrolimus, sirolimus pimecrolimus, angiotensin II inhibitors (e.g. Valsartan, Telmisartan, Losartan, Irbesatan, Azilsartan, Olmesartan, Candesartan, Eprosartan) and ACE inhibitors e.g. sulfhydryl-containing agents (e.g. Captopril, Zofenopril), dicarboxylate-containing agents (e.g.
  • Fosinopril casokinins, lactokinins and lactotripeptides.
  • Such combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within a therapeutically effective dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • Compounds of the invention may exist in a single crystal form or in a mixture of crystal forms or they may be amorphous.
  • compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, if the compound of the invention is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ( g/kg) to 100 milligrams per kilogram body weight (mg/kg).
  • a compound of the invention, or pharmaceutically acceptable salt thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutically acceptable adjuvant diluent or carrier.
  • the pharmaceutical composition which is used to administer the compounds of the invention will preferably comprise from 0.05 to 99 %w (per cent by weight) compounds of the invention, more preferably from 0.05 to 80 %w compounds of the invention, still more preferably from 0.10 to 70 %w compounds of the invention, and even more preferably from 0.10 to 50 %w compounds of the invention, all percentages by weight being based on total composition.
  • compositions may be administered topically (e.g. to the skin) in the form, e.g., of creams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.
  • parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.
  • the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets.
  • a carrier for example, lactose, saccharose, sorbitol, mannitol
  • a starch for example, potato starch, corn starch or amylopectin
  • a cellulose derivative for example, gelatine or polyvinylpyrrolidone
  • a lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and
  • the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
  • the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets.
  • liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol.
  • such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
  • the compounds of the invention may be administered as a sterile aqueous or oily solution.
  • the size of the dose for therapeutic purposes of compounds of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
  • Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient.
  • the standard duration of treatment with compounds of the invention is expected to vary between one and seven days for most clinical indications. It may be necessary to extend the duration of treatment beyond seven days in instances of recurrent infections or infections associated with tissues or implanted materials to which there is poor blood supply including bones/joints, respiratory tract, endocardium, and dental tissues.
  • the samples were eluted at a flow rate of 0.6 mL/min with a mobile phase system composed of A (0.1 % (v/v) Formic Acid in Water) and B (0.1 % (v/v) Formic Acid in Acetonitrile) according to the gradients outlined in Table 1 below. Retention times RT are reported in minutes.
  • NMR NMR was also used to characterise final compounds. NMR spectra were obtained on a Bruker AVMI 400 Nanobay with 5 mm BBFO probe at room temperature unless otherwise stated. 1 H NMRs are reported in ppm and referenced to either TMS (0.0 ppm), DMSO-d6 (2.50 ppm), CDC (7.26 ppm) or CDsOD (3.31 ppm).
  • Compound purification was performed by flash column chromatography on silica using SiliaSep Silica Pre-packed Solid-Load Cartridge with the eluting solvent described for the purification of each compound or by preparative LCMS.
  • LCMS purification was performed using a Waters 3100 Mass detector in positive and negative electrospray mode (m/z: 150-800) with a Waters 2489 UV/Vis detector.
  • Samples were eluted at a flow rate of 20 mL/min on a XBridgeTM prep C18 5 ⁇ OBD 19x100 mm column with a mobile phase system composed of A (0.1 % (v/v) Formic Acid in Water) and B (0.1 % (v/v) Formic Acid in Acetonitrile) according to the gradients outlined in Table 2 below.
  • Procedure A Preparation of imidazole-4,5-diester and related compounds.
  • tartaric acid in a first synthetic route can be di-nitrated in presence of nitric acid and a strong acid (e.g. sulphuric acid). Condensation of the di-nitrated intermediate with aldehydes and ammonia can be used to afford imidazole-4,5-dicarboxylic acids. These can be esterified into the corresponding imidazole-4,5-diesters (e.g. methyl esters, ethyl esters) upon activation of carboxylates into acid chlorides (using for example thionyl chloride or oxalyl chloride) and a source of alcohol (e.g.
  • a strong acid e.g. sulphuric acid
  • tartaric acid diester e.g. tartaric acid dimethyl ester, tartaric acid diethyl ester
  • aldehydes and a source of ammonia e.g. NH4OH
  • brominating agents such as but not limited to 1 ,3-Dibromo-5,5-dimethylhydantoin
  • Procedure B Preparation of trimethylsilylaryl trifluoromethanesulfonate and related compounds. Trimethylsilylaryl trifluoromethanesulfonate starting materials which are not commercially available can be synthesised by analogy with the procedure in Scheme 2.
  • O/f/70-bromohydroxyarenes can be silylated using reagents such as but not limited to HMDS. Treatment of the resulting silyl ethers with a strong base (e.g. n-BuLi, s-BuLi) followed by triflic anhydride can be used to afford the trimethylsilylaryl trifluoromethanesulfonate starting materials.
  • a strong base e.g. n-BuLi, s-BuLi
  • triflic anhydride e.g. n-BuLi, s-BuLi
  • o/f ?o-bromohydroxyarenes can be di-silylated using a strong base (e.g. n-BuLi, s- BuLi) and an excess of silylating agents (e.g. TMSCI, DMIPSCI).
  • Deprotection of the silyl ether functionalities can be achieved using a source of fluoride (e.g. TMAF, TBAF). Subsequent trifluoromethylsulphonylation can be achieved using triflic anhydride to afford trimethylsilylaryl trifluoromethanesulfonates.
  • a source of fluoride e.g. TMAF, TBAF
  • triflic anhydride to afford trimethylsilylaryl trifluoromethanesulfonates.
  • Procedure C Preparation of the imidazo[1 ,5-a]indole and related tricyclic core systems.
  • the imidazo[1 ,5-a]indol tricyclic core can be synthesised by analogy with the procedure described in Scheme 3.
  • lmidazole-4,5-diesters and trimethylsilylaryl trifluoromethanesulfonates can be condensed into a 4- oxoimidazo[1 ,5-a]indol-3-ester tricyclic systems in presence of a source of fluoride (e.g. TMAF, TBAF).
  • a source of fluoride e.g. TMAF, TBAF.
  • bases including NaOH, KOH can be used to hydrolyse the resulting 4- oxoimidazo[1 ,5-a]indole-3-esters into 4-oxoimidazo[1 ,5-a]indole-3-carboxylic acids.
  • Decarboxylation of these carboxylic acids into imidazo[1 ,5-a]indol-4-ones can be achieved using microwave irradiations at high temperature in solvents including but not limited to dichlorobenzene. Reduction of imidazo[1 ,5-a]indol-4-ones into corresponding alcohols (imidazo[1 ,5-a]indol-4-ols) can be achieved with reducing agents including but not limited to NaBhU.
  • Procedure D Preparation of methylene-linked imidazo[1 ,5-a]indole and related tricyclic compounds
  • lmidazo[1 ,5-a]indol-4-ones can be condensed with witting-type reagents (e.g. dimethoxyphosphoryl- ethanones) using a strong base (e.g. NaH) to afford a mixture of Z and E ⁇ , ⁇ -insaturated ketones.
  • witting-type reagents e.g. dimethoxyphosphoryl- ethanones
  • a strong base e.g. NaH
  • Knoevenagel condensation of lmidazo[1 ,5-a]indol-4-ones with malonic acid, malonic esters, or malonitrile can afford mixtures of Z and E ⁇ , ⁇ -insaturated carboxylic acids.
  • the latter can be reduced using reducing agents such as but not limited to zinc powder in acetic acid to afford the saturated 2-(4H-imidazo[1 ,5-a]indol-4-yl)acetic acid analogues.
  • Reduction of the latter carboxylic acids (or their esters) to the corresponding alcohols can be achieved using reducing agents such as but not limited to LiAlhU.
  • Re-oxidation of the alcohol moiety under mild oxidising conditions e.g.
  • 2-(4H-imidazo[1 ,5-a]indol-4-yl)acetic acids can be coupled with amines using amide coupling reaction conditions (e.g. EDC, HBTU) to afford the corresponding amides.
  • amides can be prepared from the corresponding acid chloride (prepared from reacting 2-(4H-imidazo[1 ,5- a]indol-4-yl)acetic acids with thionyl chloride or oxalyl chloride) and amines in presence of base (e.g. triethylamine, /V,/V-diisopropylethylamine, pyridine).
  • Ether analogues can be prepared from 2- (4H-imidazo[1 ,5-a]indol-4-yl)ethanols and chlorinated or brominated reagent in presence of base (e.g. NaH, KOtBu).
  • base e.g. NaH, KOtBu
  • Mitsunobu reaction conditions can be used to generate both ethers and thioethers by reacting 2-(4H-imidazo[1 ,5-a]indol-4-yl)ethanols with alcohol or thiol reagents.
  • 2-(4H-imidazo[1 ,5-a]indol-4-yl)acetaldehydes can be converted into 2-(4H-imidazo[1 ,5- a]indol-4-yl)ethanamines either by condensation with NH2OH followed by hydrogenation, reaction with NH3 under high temperatures in presence of hydride (e.g. STAB, NaCNBh ) or via a two-step reductive amination - deprotection process.
  • the intermediate amines may contain a protecting group (e.g. benzyl, 4-methoxybenzyl) that can be cleaved using hydrogenation, acidic hydrolysis or other deprotection conditions.
  • 2-(4H-lmidazo[1 ,5-a]indol-4-yl)ethanamines can be further derivatised into corresponding amides, sulphonamides or ureas by condensation with acid chlorides, isocyanates, or sulphonyl chlorides in presence of base (e.g. triethylamine, N,N- diisopropylethylamine, pyridine) or coupling agents (e.g. EDC, HBTU) if any is required.
  • base e.g. triethylamine, N,N- diisopropylethylamine, pyridine
  • coupling agents e.g. EDC, HBTU
  • Example D.1 Preparation of 1 -cyclohexyl-2-(4H-imidazo[1 ,5-a]indol-4-yl)ethanol
  • reaction was quenched with a saturated solution of aqueous ammonium chloride (20 ml_), the aqueous phase was extracted with ethyl acetate (3 x 20 ml_). The combined organic phases were washed with brine, dried over Na2S04, filtered and evaporated to dryness.
  • Procedure E Preparation of O-linked, /V-linked, S-linked and C-linked imidazo[1 ,5- a]indole and related tricyclic compounds from 4H-imidazo[1 ,5-a]indol-4-ols
  • O-linked, /V-linked, S-linked and C-linked imidazo[1 ,5-a]indole compounds and related tricyclic analogues can be synthesised via a variety of strategies as described in but not restricted to
  • R can represent R as defined herein or R can represent an amino protecting group or R F as defined herein.
  • imidazo[1 ,5-a]indol-4-ols can be deprotonated with a suitable base (e.g. but not restricted to NaH, tBuOH) and reacted with a halogenated (e.g. BnCI, BnBr), mesylated, tosylated, or triflated species to afford the corresponding ethers.
  • a suitable base e.g. but not restricted to NaH, tBuOH
  • a halogenated e.g. BnCI, BnBr
  • O-linked, /V-linked and S-linked compounds can be synthesised via an activation of the bridge alcohol of imidazo[1 ,5-a]indol-4-ols into a halide (e.g. Br, CI), a mesyl, a trityl or a triflate and its reaction with alcohols, amines or thiols.
  • a halide e.g. Br, CI
  • /V-linked amides, sulphonamides, and ureas can be obtained from the corresponding 4H- imidazo[1 ,5-a]indol-4-amines upon reaction with acid chlorides or sulphonyl chlorides in presence of a suitable base (e.g. but not restricted to triethylamine, ⁇ /,/V-diisopropylethylamine, pyridine) or upon reaction with isocyanates.
  • a suitable base e.g. but not restricted to triethylamine, ⁇ /,/V-diisopropylethylamine, pyridine
  • Example E.1 Preparation of O-linked imidazo[1 ,5-a]indole compounds using nucleophilic substitution or Mitsunobu conditions.
  • Method C1 b (Mitsunobu reaction): To a stirred suspension of 4H-imidazo[1 ,5-a]indol-4-ol (1 .0 eq.), triphenylphosphine (1 .5 eq.) and alcohol (1 .0 eq.) in THF (2 ml_) over molecular sieves at 0 °C was added DIAD (1 .5 eq.) dropwise. The mixture was left to stir for 1 h, before quenching with saturated aqueous NaHC03, warming to room temperature, extracting into DCM (2 x 10 ml_). Organic fractions were combined, dried over a phase separator and concentrated to dryness. The crude was loaded onto an SCX-2 cartridge, washed with MeOH, eluted with 7M NH3 in MeOH and
  • Procedure F Preparation of O-linked, /V-linked and S-linked imidazo[1 ,5-a]indole and related tricyclic compounds via Grignard addition to a carbaldehyde
  • O-linked, /V-linked and S-linked imidazo[1 ,5-a]indole compounds and related tricyclic analogues can be synthesised via strategies described in but not restricted to Scheme 7.
  • An alternative synthesis of O-linked, /V-linked, S-linked and C-linked imidazo[1 ,5-a]indole analogues can be initiated by the condensation of an halogenoaryl carbaldehyde with 4- iodoimidazoles (preferably protected on either of the Nitrogen atoms) in presence of a Grignard reagent (e.g. isopropylmagnesium chloride).
  • a Grignard reagent e.g. isopropylmagnesium chloride.
  • the alcohol functionality of the resulting 1 -imidazobenylalcohol analogues can be alkylated (e.g. using NaH and an alkylating agent) into corresponding ethers.
  • Displacement of the alcohol functionality with an amine or a thiol can lead to the corresponding amine on thioethers.
  • the amine reagent can optionally be substituted with R F .
  • Deprotection of the imidazole Nitrogen (e.g. acetic acid for a trityl protecting group) and subsequent Copper(l) iodide mediated ring closure can lead to O-linked, /V-linked, S-linked and C-linked imidazo[1 ,5-a]indole analogues.
  • Protecting groups can optionally be used at any stage during this procedure to facilitate chemical synthesis.
  • Example F.1 Preparation of 4-(4H-imidazo[1 ,5-a]indol-4-yloxymethyl)benzoic acid
  • Example F.2 Preparation of A/-phenyl-4H-imidazo[1 ,5-a]indol-4-amine
  • Example G.1 Separation of the 4 stereoisomers of 1 -cyclohexyl-2-(4H-imidazo[1 ,5-a]indol-4- yhethanol into stereoisomers A, B, C and D (Scheme 8):
  • Biological example 1 Human Indoleamine 2,3-Dioxygenase (IDOI) enzyme activity (biochemical) assay
  • the IC50 values were determined by measuring the enzymatic activity of ID01 upon treatment with each compound.
  • the assay involves the conversion of tryptophan to N- formylkynurenine (NFK) by recombinant human ID01 enzyme (rhIDOl) and the formation of an /V-formylkynurenine-derived fluorophore (NFKPIP) by reaction with piperidine.
  • the fluorescence intensity of the NFKPIP formed is directly related to the enzyme activity and can be measured at an excitation wavelength of 400 nm and an emission wavelength of 500 nm.
  • the reaction is stopped by addition of 5 ⁇ _ 1 M piperidine to the 20 ⁇ _ enzymatic reaction volume, providing 200 mM final concentration and the plates are covered with seals and incubated at 65 °C in an oven sand bath for 25 min. The plates are incubated for 1 h at room temperature and the fluorescence intensity at 535 nm in each well is read using an EnVision plate reader (Perkin Elmer equipped with a 400/25 nm excitation filter and a 535/25 nm emission filter).
  • the plates are incubated for 1 h at room temperature and the fluorescence intensity at 535 nm in each well is read using an EnVision plate reader (Perkin Elmer equipped with a 400/25 nm excitation filter and a 535/25 nm emission filter).
  • Biological example 2 Human Indoleamine 2,3-Dioxygenase (ID01) enzyme activity values
  • the results of the biochemical hlDOI assay for certain compounds of the invention are given in the table below.
  • the table shows the biochemical hlDOI inhibition activity of each compound based on the IC50 value of the compound as "+", "", "++” and "+++”.
  • the category “+” refers to compounds with an IC50 of > 100 ⁇ .
  • the category “++” refers to compounds with an IC50 of 1 to 100 ⁇ .
  • the category “+++” refers to compounds with an
  • Biological example 3 Human Tryptophan 2,3-Dioxygenase (TD02) enzyme activity (biochemical) assay
  • the IC50 values were determined by measuring the enzymatic activity of TD02 upon treatment with each compound.
  • the assay involves the conversion of tryptophan to N- formylkynurenine (NFK) by recombinant human TD02 enzyme (rhTD02) and the formation of an /V-formylkynurenine-derived fluorophore (NFKPIP) by reaction with piperidine.
  • NFKPIP N- formylkynurenine
  • rhTD02 recombinant human TD02 enzyme
  • NFKPIP /V-formylkynurenine-derived fluorophore
  • the reaction is stopped by addition of 5 ⁇ _ 1 M piperidine to the 40 ⁇ _ enzymatic reaction volume, providing 1 1 1 .1 mM final concentration and the plates are covered with seals and incubated at 65 °C in an oven sand bath for 25 min. The plates are incubated for 1 h at room temperature and the fluorescence intensity at 535 nm in each well is read using an EnVision plate reader (Perkin Elmer equipped with a 400/25 nm excitation filter and a 535/25 nm emission filter).
  • the plates are incubated for 1 h at room temperature and the fluorescence intensity at 535 nm in each well is read using an EnVision plate reader (Perkin Elmer equipped with a 400/25 nm excitation filter and a 535/25 nm emission filter).
  • the results of the biochemical TD02 assay for certain compounds of the invention are given in the Table below.
  • the table shows the biochemical TD02 inhibition activity of each compound based on the IC50 value of the compound as "+”, “", “++” and “+++”.
  • the category “+” refers to compounds with an IC50 of > 10 ⁇ .
  • the category “++” refers to compounds with an IC50 of 1 to 10 ⁇ .
  • the category “+++” refers to compounds with an IC50 ⁇ 1 ⁇ . All compounds are stereoisomeric mixtures unless otherwise stated.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Immunology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

This invention relates to novel compounds of formula (I) wherein wherein Ά' is a 5 or 6 membered aryl or heteroaryl group, unsubstituted or substituted with 1, 2 or 3 groups as defined in claim 1; X is a bond or -(CRA1R81)n- (wherein n is selected from 1, 2, 3 and 4); Y is selected from: a bond, -O-, -NRF, -S-, -C(O)-, -C(NRF)-, -C(ORF)Rc-, -C(NRFRG)RC-, -C(O)NRF-, -NRFC(O) -NRFC(O)NRG-, -NRFSO2NRG-, - SO2-, -SO2NRF-, -NRFSO2-, -OC(O)- and -C(O)O-; Z is a bond; R1 is H or a 3 to 16 membered fully saturated, partially unsaturated or aromatic mono-, di- or tri-cyc!ic moiety, which optionally may include 1, 2 or 3 heteroatoms selected from O, N and S, and which is unsubstituted or substituted with 1 to 5 substituents as defined in claim 1; R2 is selected from: H, halo, C1-4alkyl, C1-4haloalkyl, -ORA4 and C1-4alkyl substituted with -ORA4; and R3 and R4 are each independently selected from: H, halo, C1-4halkyl, C1-4haloalkyl, C3-6cycloalkyl, -ORA5, -NRA5RB4, -CN, -SRA5 and C1-4alkyl substituted with -ORA5; and pharmaceutical compositions comprising the novel compounds. More specifically, the invention relates to compounds useful as indoieamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxynase (TDO2) modulators (e.g. IDO1, IDO2 and/or TDO2 inhibitors).

Description

4H-IMIDAZO[1 ,5-A]INDOLE DERIVATIVES AND THEIR USE AS INDOLEAMINE 2,3-DIOXYGENASE (IDO) AND/OR TRYPTOPHAN 2,3-DIOXYGENASE (TD02) MODULATORS
[0001] This invention relates to novel compounds and pharmaceutical compositions comprising the novel compounds. More specifically, the invention relates to compounds useful as indoleamine 2,3- dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TD02) modulators (e.g. ID01 , ID02 and/or TD02 inhibitors). This invention also relates to processes for preparing the compounds, uses of the compounds and methods of treatment employing the compounds.
[0002] The compounds of the invention may therefore be used in treating indoleamine 2,3- dioxygenase (IDO) mediated diseases, such as IDO mediated immunosuppression; treating a medical conditions that would benefit from the inhibition of enzymatic activity of the IDO enzyme; enhancing the effectiveness of an anti-cancer treatment; treating tumour-specific
immunosuppression associated with cancer; and treating immunosuppression associated with an infectious disease.
BACKGROUND
[0003] Indoleamine 2,3 dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TD02) are heme- containing enzymes that catalyse the first and rate-limiting step in tryptophan metabolism
(tryptophan to /V-formylkynurenine). These enzymes play a role in diverse physiological processes including peripheral immune tolerance and innate host defence against infection and are attractive targets for novel therapeutics in cancer. There are two indoleamine 2,3-dioxygenase proteins, ID01 and ID02.
[0004] IDO is predominantly expressed in antigen presenting cells such as dendritic cells (DCs) and macrophages. IDO expression in immune cells may be constitutive but is also up regulated during infection by proinflammatory mediators including type 1 and 2 interferons and TNF.
Expression of IDO in DCs can also be controlled through direct cell-cell interactions with regulatory T cells. Physiologically IDO plays an important role in the maintenance of immune self-tolerance and in the regulation of the immune response to infection.
[0005] Indoleamine 2,3-dioxygenase (IDO) is an enzyme that is known in the art to have a role in immunosuppression, tumour resistance and/or rejection, chronic infections, HIV-infection, AIDS (including its manifestations such as cachexia, dementia and diarrhoea), autoimmune diseases or disorders (such as rheumatoid arthritis), and immunologic tolerance and prevention of foetal rejection in utero. Accordingly, therapeutic agents aimed at suppression of tryptophan degradation by inhibiting IDO activity are desirable.
[0006] In cancer, elevated tumour levels of ID01 have been linked to a decrease in both overall and progression free patient survival. Elevated expression of ID01 has been observed in many cancer types including lung, ovarian, colorectal, brain and thyroid cancers, melanoma, acute myeloid leukaemia and non-Hodgkin's lymphoma. Even in tumours where elevated ID01 expression is not seen in the cancer cells, ID01 upregulation in infiltrating immune cells in the tumour microenvironment and in local draining lymph nodes is thought to have a profound impact on tumour growth.
[0007] Inhibitors of IDO can be used to activate T cells and therefore enhance T cell activation when the T cells are suppressed by pregnancy, malignancy or a virus such as HIV. Inhibition of IDO may also be an important treatment strategy for patients with neurological or neuropsychiatric diseases or disorders such as depression.
[0008] WO2012142237 discloses various fused imidazole derivatives that are useful as IDO inhibitors.
[0009] An aim of the present invention is to provide alternative or improved indoleamine 2,3- dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TD02) modulators. For example, an aim of the present invention is to provide alternative or improved IDO and/or TD02 inhibitors.
[0010] Furthermore, it is an aim of certain embodiments of this invention to provide new compounds for use in: treating indoleamine 2,3-dioxygenase (IDO) mediated diseases, such as IDO mediated immunosuppression; treating medical conditions that would benefit from the inhibition of enzymatic activity of the IDO enzyme; enhancing the effectiveness of an anti-cancer treatment; treating tumour-specific immunosuppression associated with cancer; and/or treating
immunosuppression associated with an infectious disease.
[0011] In particular, it is an aim of certain embodiments of this invention to provide compounds which have comparable activity to existing treatments, ideally they should have better activity.
[0012] Another aim of certain embodiments of this invention is to provide compounds having a convenient pharmacokinetic profile and a suitable duration of action following dosing. A further aim of certain embodiments of this invention is to provide compounds in which the metabolised fragment or fragments of the drug after absorption are GRAS (Generally Regarded As Safe).
[0013] Certain embodiments of the present invention satisfy some or all of the above aims.
BRIEF SUMMARY OF THE DISCLOSURE
[0014] In accordance with one aspect, the present invention provides a compound of formula (I):
Figure imgf000004_0001
wherein
'A' is a 5 or 6 membered aryl or heteroaryl group, unsubstituted or substituted with 1 , 2 or 3 groups (where chemically possible) selected from: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA, -NRARB, -SRA, - C(0)RA, -OC(0)Rc, -C(0)ORA, -NRAC(0)Rc, -C(0)NRARB, -NRAS02Rc, -S02NRARB, -NO2, -CN and C1-4 alkyl substituted with -ORA;
X is a bond or -(CRA RBV;
Y is selected from: a bond, -(CRDRE)m-, -0-, -NRF-, -S-, -C(O)-, -CCNRF)-, -C OR^R - C(NRFRG)RC-, -C(0)NRF-, -NRFC(0)-, -NRFC(0)NRG-, -NRFS02NRG-, -SO2-, -S02NRF-, -NRFS02- , -OC(O)- and -C(0)0-;
Z is a bond or -(CRA2RB2)k-;
wherein m, n and k are each independently selected from 1 , 2, 3 and 4;
R is H or a 3 to 16 membered fully saturated, partially unsaturated or aromatic mono-, di- or tri-cyclic moiety, which optionally may include 1 , 2 or 3 heteroatoms (where chemically possible) selected from O, N and S, and which is unsubstituted or substituted with 1 to 5 substituents (where chemically possible) selected from halo, Ci- alkyl, Ci- haloalkyl, C3-6 cycloalkyl, -ORA3, -NRA3RB3, -SRA3, - C(0)RA3, -OC(0)RA3, -C(0)ORA3, -NRA3C(0)RB3, -C(0)NRA3RB3, -NRA3S02RB3, -S02NRA3RB3, - S02RA3, =0, -N02, -CN, C1-4 alkyl substituted with— ORA3, Ci- alkyl substituted with -NRA3RB3 and C3- 6 cycloalkyl substituted with -ORA3;
R2 is selected from: H, halo, Ci- alkyl, C1-4 haloalkyl, -ORA4 and Ci- alkyl substituted with -ORA4;
R3 and R4 are each independently selected from: H, halo, Ci-4 alkyl, Ci-4 haloalkyl, C3-6 cycloalkyl, - ORA5, -NRA5RB4, -CN, -SRA5 and Ci- alkyl substituted with— ORA5;
RA, RB, Rc RA , RB , RA2, RB2, RA3, RB3, RA4, RA5, RB4, RA6 and RB5 are at each occurrence independently selected from: H, Ci-4 alkyl and Ci-4 haloalkyl;
RD and RE are each independently selected from: H, =0, (i.e. RD and RE together form =0), =S (i.e. RD and RE together form =S), -ORA6, -SRA6, -NRA6RB5, halo, Ci- alkyl and Ci- haloalkyl, C3-s cycloalkyl, C3-8 heterocycloalkyl, C3-8 cycloalkylene, C3-8 heterocycloalkylene, C6-10 aryl and C5-10 heteroaryl; and
RF and RG are each independently selected from: H, Ci-4 alkyl and Ci-4 haloalkyl, C3-8 cycloalkyl, C3- 8 heterocycloalkyl, C3-8 cycloalkylene, C3-8 heterocycloalkylene, C6-10 aryl and C5-10 heteroaryl;
provided that:
(i) Z is not -(CRA2RB2)k- and Y is not -C(0)NRF-, -NRFC(0)- or -NRFC(0)NRF- when A is a pyridyl group; and
(ii) Z is not -(CRA2RB2)k-, Y is not -C(O)- or -NRFC(0)-, and R is not morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl when A is a pyridyl group.
[0015] In an embodiment Y is selected from: a bond, -0-, -NRF-, -S-, -C(O)-, -C(NRF)-, -C OR^R -C(NRFRG)RC-, -C(0)NRF-, -NRFC(0)-, -NRFC(0)NRG-, -NRFS02NRG-, -S02-, -S02NRF-, - NRFS02- , -OC(O)- and -C(0)0-; and
Z is a bond. [0016] In an alternative embodiment Y is selected from: a bond, -0-, -NRF-, -S-, -NRFC(0)-, - NRFC(0)NRG-, -NRFS02NRG-, -SO2-, -S02NRF-, -NRFS02-, and -OC(O)-; and
Z is a bond or -(CRA2RB2)k-.
[0017] In an embodiment, when Y is a bond, n or k is 2, 3 or 4. Optionally, Y is a bond and X is a bond, i.e. optionally when Y is a bond, X cannot be -(CRA RB )n-
[0018] In an embodiment, A is a ring selected from substituted or unsubstituted: phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl and pyrrolyl. In an embodiment, A is a ring selected from substituted or unsubstituted: phenyl, pyridyl, pyrimidinyl, pyridazinyl and thiophenyl.
[0019] In an embodiment A is a ring selected from substituted or unsubstituted: phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl and pyrrolyl and Z is a bond. In an alternative embodiment A is a ring selected from substituted or unsubstituted: phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl and pyrrolyl and Y is selected from: a bond, -(CRDRE)m-, - 0-, -NRF-, -S-, -C(NRF)-, -C(ORF)Rc-, -C(NRFRG)RC-, -SO2-, -S02NRF-, -NRFS02- , -OC(O)-; and - C(0)0-.
[0020] In an embodiment A is not pyridyl. A may be a ring selected from substituted or unsubstituted: phenyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl and pyrrolyl. In an embodiment, A is a ring selected from substituted or unsubstituted: phenyl, pyrimidinyl, pyridazinyl and thiophenyl.
[0021] In an embodiment, the compound of formula (I) is a compound according to formula (lla) to (llj):
Figure imgf000006_0001
Figure imgf000007_0001
(iig) (iih)
Figure imgf000007_0002
(iij)
wherein
q is selected from 0, 1 , 2 or 3,
p is selected from 0, 1 or 2, and
R5 is selected from: H, halo, Ci- alkyl, Ci- haloalkyl, -ORA, -NRARB, -SRA, -C(0)RA, -OC(0)Rc, - C(0)ORA, -NRAC(0)Rc, -C(0)NRARB, -NRAS02Rc, -S02NRARB, -N02, -CN and Ci-4 alkyl substituted with -ORA; wherein RA, RB and Rc are each independently selected from: H, Ci-4 alkyl and Ci-4 haloalkyl.
[0022] In an embodiment, A is phenyl or pyridyl. Optionally, A is phenyl. In an embodiment A is phenyl or pyridyl and Z is a bond. In an alternative embodiment A is phenyl or pyridyl and Y is selected from: a bond, -(CRDRE)m-, -0-, -NRF-, -S-, -C(NRF)-, -C(ORF)Rc-, -C(NRFRG)RC-, -SO2-, - S02NRF-, -NRFS02- , -OC(O)-; and -C(0)0-.
[0023] In an embodiment, A is unsubstituted. Thus, in an embodiment q and p may be 0.
[0024] In an embodiment A is substituted with 1 , 2 or 3 groups (where chemically possible) selected from: halo, Ci- alkyl, Ci- haloalkyl, -ORA, -NRARB, -N02, -CN and Ci- alkyl substituted with -ORA. In an embodiment R5 is selected from: halo, Ci- alkyl, Ci- haloalkyl, -ORA, -NRARB, - N02, -CN and Ci-4 alkyl substituted with -ORA. In an embodiment, RA, RB and Rc are as described above. Alternatively, RA, RB and Rc may each be independently selected from: H, methyl, ethyl, isopropyl, tert-butyl and trifluoromethyl.
[0025] In an embodiment, A is substituted with 1 , 2 or 3 groups (where chemically possible) selected from: chloro, fluoro, methyl, ethyl, iso-propyl, tert-butyl, Ci-2-haloalkyl (e.g. trifluoromethyl, trifluoroethyl), -OH, -OMe, -OEt, -0-Ci-2-haloalkyl (e.g. trifluoromethoxy, trifluoroethoxy), -NH2, - NHMe, -NMe2, -N02, -CN, hydroxyl methyl, hydroxyethyl and hydroxypropyl. In an embodiment, R5 is selected from: chloro, fluoro, methyl, ethyl, iso-propyl, tert-butyl, Ci-2-haloalkyl (e.g. trifluoromethyl, trifluoroethyl), -OH, -OMe, -OEt, -O-Ci-2-haloalkyl (e.g. trifluoromethoxy, trifluoroethoxy), -NH2, -NHMe, -ΝΜβ2, -NO2, -CN, hydroxyl methyl, hydroxyethyl and hydroxypropyl.
[0026] In an embodiment, A is unsubstituted phenyl, methylphenyl, ethylphenyl, iso-propylphenyl, tert-butylphenyl, trifluoromethylphenyl, methoxyphenyl, ethyoxyphenyl, aminophenyl, N-methyl- aminophenyl, Ν,Ν-dimethyl-aminophenyl, nitrophenyl, cyanophenyl, unsubstituted pyridyl, methylpyridyl, ethylpyridyl, iso-propylpyridyl, tert-butylpyridyl, trifluoromethylpyridyl, methoxypyridyl, ethyoxypyridyl, aminopyridyl, N-methyl-aminopyridyl, Ν,Ν-dimethyl-aminopyridyl, nitropyridyl, cyanopyridyl, unsubstituted pyridazinyl, methylpyridazinyl, ethylpyridazinyl, iso-propylpyridazinyl, tert-butylpyridazinyl, trifluoromethylpyridazinyl, methoxypyridazinyl, ethyoxypyridazinyl, aminopyridazinyl, N-methyl-aminopyridazinyl, Ν,Ν-dimethyl-aminopyridazinyl, nitropyridazinyl, cyanopyridazinyl, unsubstituted thiophenyl, methylthiophenyl, ethylthiophenyl, iso-propylthiophenyl, tert-butylthiophenyl, trifluoromethylthiophenyl, methoxythiophenyl, ethyoxythiophenyl,
aminothiophenyl, N-methyl-aminothiophenyl, Ν,Ν-dimethyl-aminothiophenyl, nitrothiophenyl or cyanothiophenyl.
[0027] In an embodiment, A is unsubstituted phenyl, methylphenyl, ethylphenyl, iso-propylphenyl, tert-butylphenyl, trifluoromethylphenyl, methoxyphenyl, ethyoxyphenyl, aminophenyl, N-methyl- aminophenyl, Ν,Ν-dimethyl-aminophenyl, nitrophenyl, cyanophenyl, unsubstituted pyridazinyl, methylpyridazinyl, ethylpyridazinyl, iso-propylpyridazinyl, tert-butylpyridazinyl,
trifluoromethylpyridazinyl, methoxypyridazinyl, ethyoxypyridazinyl, aminopyridazinyl, N-methyl- aminopyridazinyl, Ν,Ν-dimethyl-aminopyridazinyl, nitropyridazinyl, cyanopyridazinyl, unsubstituted thiophenyl, methylthiophenyl, ethylthiophenyl, iso-propylthiophenyl, tert-butylthiophenyl, trifluoromethylthiophenyl, methoxythiophenyl, ethyoxythiophenyl, aminothiophenyl, N-methyl- aminothiophenyl, Ν,Ν-dimethyl-aminothiophenyl, nitrothiophenyl or cyanothiophenyl.
[0028] In an embodiment, A is unsubstituted phenyl, methylphenyl, ethylphenyl, iso-propylphenyl, tert-butylphenyl, trifluoromethylphenyl, methoxyphenyl, ethyoxyphenyl, aminophenyl, N-methyl- aminophenyl, Ν,Ν-dimethyl-aminophenyl, nitrophenyl or cyanophenyl.
[0029] In an embodiment, A is unsubstituted pyridyl, methylpyridyl, ethylpyridyl, iso-propylpyridyl, tert-butylpyridyl, trifluoromethylpyridyl, methoxypyridyl, ethyoxypyridyl, aminopyridyl, N-methyl- aminopyridyl, Ν,Ν-dimethyl-aminopyridyl, nitropyridyl or cyanopyridyl.
[0030] In an embodiment, A is unsubstituted pyridazinyl, methylpyridazinyl, ethylpyridazinyl, iso- propylpyridazinyl, tert-butylpyridazinyl, trifluoromethylpyridazinyl, methoxypyridazinyl,
ethyoxypyridazinyl, aminopyridazinyl, N-methyl-aminopyridazinyl, N,N-dimethyl-aminopyridazinyl, nitropyridazinyl or cyanopyridazinyl.
[0031] In an embodiment, A is unsubstituted thiophenyl, methylthiophenyl, ethylthiophenyl, iso- propylthiophenyl, tert-butylthiophenyl, trifluoromethylthiophenyl, methoxythiophenyl,
ethyoxythiophenyl, aminothiophenyl, N-methyl-aminothiophenyl, N,N-dimethyl-aminothiophenyl, nitrothiophenyl or cyanothiophenyl.
[0032] In an embodiment q is 0, 1 or 2, preferably, 0 or 1 . In an embodiment p is 0 or 1 . [0033] There are provided compounds of formula (I) with the proviso that X-Y-Z taken together is not methylene when R is substituted or unsubstituted: pyridyl and pyrimidine. There are provided compounds of formula (I) with the proviso that X-Y-Z taken together is not alkylene when R is substituted or unsubstituted: pyridyl and pyrimidine. There are provided compounds of formula (I) with the proviso that X, Y and Z cannot all be a bond or -(CRDRE)m- or -(CRA RB )n-, or -(CRA2RB2)k- when R is substituted or unsubstituted: pyridyl and pyrimidine. There are provided compounds of formula (I) with the proviso that Y is not -(CRDRE)m-, when Z and X are a bond. There are provided compounds of formula (I) with the proviso that X, Y and Z cannot all be a bond or -(CRDRE)m- or - (CRA RB )n-, or -(CRA2RB2)k-.
[0034] Z may be a bond. Z may be -(CRA2RB2)k-. X may be a bond. X may be -(CRA RB )n-. In an embodiment Z is a bond and X is a bond. In an alternative embodiment Z is -(CRA2RB2)k- and X is a bond. In a further alternative embodiment X is -(CRA RB )n- and Z is a bond. In an alternative embodiment Z is -(CRA2RB2)k- and X is -(CRA RB )n-. In an embodiment, Z is a bond.
[0035] In an embodiment Z is a bond, X is a bond and Y is selected from: -0-, -NRF-, -S-, -C(O)-, - C(NRF)-, -CCOR^R -C(NRFRG)RC-, -C(0)NRF-, -NRFC(0)-, -NRFC(0)NRG-, -NRFS02NRG-, -SO2-, -S02NRF-, -NRFS02- , -OC(O)-, and -C(0)0-. In an alternative embodiment Z is -(CRA2RB2)k-, X is a bond and Y is selected from: -0-, -NRF-, -S-, -C(O)-, -C(NRF)-, -C(ORF)Rc-, -C(NRFRG)RC-, - C(0)NRF-, -NRFC(0)-, -NRFC(0)NRG-, -NRFS02NRG-, -SO2-, -S02NRF-, -NRFS02-, -OC(O)-, and - C(0)0-. In a further alternative embodiment X is -(CRA RB )n-, Z is a bond and Y is selected from: - 0-, -NRF-, -S-, -C(O)-, -CCNRP)-, -CCOR^R -C(NRFRG)RC-, -C(0)NRF-, -NRFC(0)-, -NRFC(0)NRG- , -NRFS02NRG-, -S02-, -S02NRF-, -NRFS02- , -OC(O)-, and -C(0)0-. In an alternative embodiment Z is -(CRA2RB2)k-, X is -(CRA RB )n- and Y is selected from: -0-, -NRF-, -S-, -C(O)-, -C(NRF)-, - C(ORF)Rc-, -C(NRFRG)RC-, -C(0)NRF-, -NRFC(0)-, -NRFC(0)NRG-, -NRFS02NRG-, -S02-, -S02NRF- , -NRFS02- , -OC(O)-, and -C(0)0-. Optionally, n, m and k are 1 or 2. Optionally, Rc, RF, RG, RA , RB , RA2 and RB2 are H or methyl. Optionally, n, m and k are 1 or 2 and Rc, RF, RG, RA , RB , RA2 and RB2 are H or methyl.
[0036] In an embodiment Z is a bond, X is a bond and Y is selected from: -0-, -NRF-, -S-, -C(O)-, - CCNRP)-, -CCOR^R -C(NRFRG)RC-, -C(0)NRF-, -NRFC(0)-, -NRFC(0)NRG-, -NRFS02NRG-, -S02-, -S02NRF-, -NRFS02- , -OC(O)-, and -C(0)0-. In an alternative embodiment Z is -(CRA2RB2)k-, X is a bond and Y is selected from: -0-, -NRF-, -S-, -NRFC(0)-, -NRFC(0)NRG-, -NRFS02NRG-, -S02-, -
S02NRF-, -NRFS02- and -OC(O)-. In a further alternative embodiment X is -(CRA RB )n-, Z is a bond and Y is selected from: -0-, -NRF-, -S-, -C(O)-, -CCNRp)-, -CCOR^R -C(NRFRG)RC-, -C(0)NRF-, - NRFC(0)-, -NRFC(0)NRG-, -NRFS02NRG-, -S02-, -S02NRF-, -NRFS02- , -OC(O)-, and -C(0)0-. In an alternative embodiment Z is -(CRA2RB2)k-, X is -(CRA RB )n- and Y is selected from: -0-, -NRF-, - S-, -NRFC(0)-, -NRFC(0)NRG-, -NRFS02NRG-, -S02-, -S02NRF-, -NRFS02- and -OC(O)-. Optionally, n, m and k are 1 or 2. Optionally, Rc, RF, RG, RA , RB , RA2 and RB2 are H or methyl. Optionally, n, m and k are 1 or 2 and Rc, RF, RG, RA , RB , RA2 and RB2 are H or methyl.
[0037] X may be a bond, -CH2-, -(CH2)2- or -C(Me)H-. Z may be a bond, -CH2-, -(CH2)2- or - C(Me)H-. Y may be selected from: -0-, -NH-, -NMe-, -S-, -C(O)-, -C(NH)-, -C(NMe)-, -C(OH)H-, - C(NH2)H-, -C(0)NH-, -C(0)NMe-, -NHC(O)-, -NMeC(O)-, -NHC(0)NH-, -NHC(0)NMe-, - NMeC(0)NH-, -NMeC(0)NMe-, -NHSO2NH-, -NMeS02NH-, -NHS02NMe-, -NMeS02NMe-, -SO2-, - SO2NH-, -S02NMe-, -NHSO2- , -NMeS02-, -OC(O)- and -C(0)0-. Alternatively, Y may be selected from: -0-, -NH-, -NMe-, -S-, -NHC(O)-, -NMeC(O)-, -NHC(0)NH-, -NHC(0)NMe-, -NMeC(0)NH-, - NMeC(0)NMe-, -NHSO2NH-, -NMeS02NH-, -NHS02NMe-, -NMeS02NMe-, -S02-, -S02NH-, - S02NMe-, -NHS02- , -NMeS02-, and -OC(O)-.
[0038] In an embodiment Z may be a bond and Y may be selected from: -0-, -NH-, -NMe-, -S-, - C(O)-, -C(NH)-, -C(NMe)-, -C(OH)H-, -C(NH2)H-, -C(0)NH-, -C(0)NMe-, -NHC(O)-, -NMeC(O)-, - NHC(0)NH-, -NHC(0)NMe-, -NMeC(0)NH-, -NMeC(0)NMe-, -NHS02NH-, -NMeS02NH-, - NHS02NMe-, -NMeS02NMe-, -S02-, -S02NH-, -S02NMe-, -NHS02- , -NMeS02-, -OC(O)- and - C(0)0-. Alternatively, Z may be a bond, -CH2-, -(CH2)2- or -C(Me)H- and Y may be selected from: - 0-, -NH-, -NMe-, -S-, -NHC(O)-, -NMeC(O)-, -NHC(0)NH-, -NHC(0)NMe-, -NMeC(0)NH-, - NMeC(0)NMe-, -NHS02NH-, -NMeS02NH-, -NHS02NMe-, -NMeS02NMe-, -S02-, -S02NH-, - S02NMe-, -NHS02- , -NMeS02-, and -OC(O)-.
[0039] There are provided compounds of formula (I) or formula (Ma) to (llj) wherein:
X is a bond, Y is -O- and Z is a bond; X is a bond, Y is -O- and Z is -CH2-, -(CH2)2- or -C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -O- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -O- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -NRF- and Z is a bond; X is a bond, Y is -NRF- and Z is -CH2-, -(CH2)2- or - C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -NRF- and Z is a bond; X is -CH2-, -(CH2)2- or - C(Me)H-, Y is -NRF- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -S- and Z is a bond; X is a bond, Y is -S- and Z is -CH2-, -(CH2)2- or -C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -S- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -S- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -C(O)- and Z is a bond; X is a bond, Y is -C(O)- and Z is -CH2-, -(CH2)2- or -
C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -C(O)- and Z is a bond; X is -CH2-, -(CH2)2- or - C(Me)H-, Y is -C(O)- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -C(NRF)- and Z is a bond; X is a bond, Y is -C(NRF)- and Z is -CH2-, -(CH2)2- or - C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -C(NRF)- and Z is a bond; X is -CH2-, -(CH2)2- or - C(Me)H-, Y is -C(NRF)- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -C OR^H- and Z is a bond; X is a bond, Y is -C(ORF)H- and Z is -CH2-, -(CH2)2- or -C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -C(ORF)H- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -C OR^H- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -C(NRFRG)H- and Z is a bond; X is a bond, Y is -C(NRFRG)H- and Z is -CH2-, - (CH2)2- or -C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -C(NRFRG)H- and Z is a bond; X is - CH2-, -(CH2)2- or -C(Me)H-, Y is -C(NRFRG)H- and Z is -CH2-, -(CH2)2- or -C(Me)H-; X is a bond, Y is -C(0)NRF- and Z is a bond; X is a bond, Y is -C(0)NRF- and Z is -CH2-, -(CH2)2- or -C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -C(0)NRF- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -C(0)NRF- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -NRFC(0)- and Z is a bond; X is a bond, Y is -NRFC(0)- and Z is -CH2-, -(CH2)2- or -C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -NRFC(0)- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -NRFC(0)- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -NRFC(0)NRG- and Z is a bond; X is a bond, Y is -NRFC(0)NRG- and Z is -CH2-, - (CH2)2- or -C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -NRFC(0)NRG- and Z is a bond; X is - CH2-, -(CH2)2- or -C(Me)H-, Y is -NRFC(0)NRG- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -NRFS02NRG- and Z is a bond; X is a bond, Y is -NRFS02NRG- and Z is -CH2-, - (CH2)2- or -C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -NRFS02NRG- and Z is a bond; X is - CH2-, -(CH2)2- or -C(Me)H-, Y is -NRFS02NRG- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -S02- and Z is a bond; X is a bond, Y is -S02- and Z is -CH2-, -(CH2)2- or -C(Me)H- ; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -S02- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -S02- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -S02NRF- and Z is a bond; X is a bond, Y is -S02NRF- and Z is -CH2-, -(CH2)2- or - C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -S02NRF- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -S02NRF- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -NRFS02- and Z is a bond; X is a bond, Y is -NRFS02- and Z is -CH2-, -(CH2)2- or - C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -NRFS02- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -NRFS02- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -OC(O)- and Z is a bond; X is a bond, Y is -OC(O)- and Z is -CH2-, -(CH2)2- or - C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -OC(O)- and Z is a bond; X is -CH2-, -(CH2)2- or - C(Me)H-, Y is -OC(O)- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -C(0)0- and Z is a bond; X is a bond, Y is -C(0)0- and Z is -CH2-, -(CH2)2- or - C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -C(0)0- and Z is a bond; and X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -C(0)0- and Z is -CH2-, -(CH2)2- or -C(Me)H-.
[0040] There are provided compounds of formula (I) or formula (Ma) to (llj) wherein:
X is a bond, Y is -O- and Z is a bond; X is a bond, Y is -O- and Z is -CH2-, -(CH2)2- or -C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -O- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -O- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -NRF- and Z is a bond; X is a bond, Y is -NRF- and Z is -CH2-, -(CH2)2- or - C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -NRF- and Z is a bond; X is -CH2-, -(CH2)2- or - C(Me)H-, Y is -NRF- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -S- and Z is a bond; X is a bond, Y is -S- and Z is -CH2-, -(CH2)2- or -C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -S- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -S- and Z is -CH2-, -(CH2)2- or -C(Me)H-; X is a bond, Y is -NRFC(0)- and Z is a bond; X is a bond, Y is -NRFC(0)- and Z is -CH2-, -(CH2)2- or -C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -NRFC(0)- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -NRFC(0)- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -NRFC(0)NRG- and Z is a bond; X is a bond, Y is -NRFC(0)NRG- and Z is -CH2-, - (CH2)2- or -C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -NRFC(0)NRG- and Z is a bond; X is - CH2-, -(CH2)2- or -C(Me)H-, Y is -NRFC(0)NRG- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -NRFC(0)NRG- and Z is a bond; X is a bond, Y is -NRFS02NRG- and Z is -CH2-, - (CH2)2- or -C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -NRFS02NRG- and Z is a bond; X is - CH2-, -(CH2)2- or -C(Me)H-, Y is -NRFS02NRG- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -S02- and Z is a bond; X is a bond, Y is -S02- and Z is -CH2-, -(CH2)2- or -C(Me)H- ; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -S02- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -S02- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -S02NRF- and Z is a bond; X is a bond, Y is -S02NRF- and Z is -CH2-, -(CH2)2- or - C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -S02NRF- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -S02NRF- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -NRFS02- and Z is a bond; X is a bond, Y is -NRFS02- and Z is -CH2-, -(CH2)2- or - C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -NRFS02- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -NRFS02- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -OC(O)- and Z is a bond; X is a bond, Y is -OC(O)- and Z is -CH2-, -(CH2)2- or - C(Me)H-; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -OC(O)- and Z is a bond; and X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -OC(O)- and Z is -CH2-, -(CH2)2- or -C(Me)H-.
[0041] Optionally RF is H or Me
[0042] There are provided compounds of formula (I) or formula (Ma) to (llj) wherein:
X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -O- and Z is a bond;
X is a bond, Y is -O- and Z is a bond;
X is a bond, Y is -C OR^H- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -C(O)- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -NRF- and Z is a bond;
X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -NRF- and Z is a bond;
X is a bond, Y is -NRFC(0)- and Z is a bond;
X is a bond, Y is -C(0)NRF- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is a bond, Y is -S- and Z is a bond;
X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -C(0)NRF- and Z is -CH2-, -(CH2)2- or -C(Me)H-;
X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -NRFC(0)- and Z is a bond; X is a bond, Y is -NRFC(0)NRG- and Z is a bond; and
X is a bond, Y is -OC(O)- and Z is a bond.
[0043] There are provided compounds of formula (I) or formula (Ma) to (llj) wherein: X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -O- and Z is a bond;
X is a bond, Y is -O- and Z is a bond;
X is a bond, Y is -NRF- and Z is a bond;
X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -NRF- and Z is a bond;
X is a bond, Y is -NRFC(0)- and Z is a bond;
X is a bond, Y is -S- and Z is a bond;
X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -NRFC(0)- and Z is a bond;
X is a bond, Y is -NRFC(0)NRG- and Z is a bond; and
X is a bond, Y is -OC(O)- and Z is a bond.
[0044] There are provided compounds of formula (I) or formula (Ma) to (llj) wherein: X is -CH2-, Y is -O- and Z is a bond;
X is a bond, Y is -O- and Z is a bond;
X is a bond, Y is -C(OH)H- and Z is -CH2-;
X is a bond, Y is -C(OH)H- and Z is -C(Me)H-;
X is a bond, Y is -C(O)- and Z is -CH2 -;
X is a bond, Y is -NH- and Z is a bond; X is a bond, Y is -NMe- and Z is a bond;
X is -CH2 -, Y is -NH- and Z is a bond; X is -CH2 -, Y is -NMe- and Z is a bond;
X is a bond, Y is -NHC(O)- and Z is a bond; X is a bond, Y is -NMeC(O)- and Z is a bond; X is a bond, Y is -C(0)NH- and Z is -CH2-; X is a bond, Y is -C(0)NMe- and Z is -CH2-; X is a bond, Y is -S- and Z is a bond;
X is -CH2-, Y is -C(0)NH- and Z is -CH2-; X is -CH2-, Y is -C(0)NMe- and Z is -CH2-; X is -CH2-, Y is -NHC(O)- and Z is a bond; X is -CH2-, Y is -NMeC(O)- and Z is a bond;
X is a bond, Y is -NHC(0)NH- and Z is a bond;
X is a bond, Y is -NMeC(0)NH- and Z is a bond;
X is a bond, Y is -NHC(0)NMe- and Z is a bond;
X is a bond, Y is -NMeC(0)NMe- and Z is a bond; and
X is a bond, Y is -OC(O)- and Z is a bond. [0045] There are provided compounds of formula (I) or formula (Ma) to (llj) wherein:
X is -CH2-, Y is -O- and Z is a bond;
X is a bond, Y is -O- and Z is a bond;
X is a bond, Y is -NH- and Z is a bond; X is a bond, Y is -NMe- and Z is a bond;
X is -CH2 -, Y is -NH- and Z is a bond; X is -CH2 -, Y is -NMe- and Z is a bond;
X is a bond, Y is -NHC(O)- and Z is a bond; X is a bond, Y is -NMeC(O)- and Z is a bond;
X is a bond, Y is -S- and Z is a bond;
X is -CH2-, Y is -NHC(O)- and Z is a bond; X is -CH2-, Y is -NMeC(O)- and Z is a bond;
X is a bond, Y is -NHC(0)NH- and Z is a bond;
X is a bond, Y is -NMeC(0)NH- and Z is a bond;
X is a bond, Y is -NHC(0)NMe- and Z is a bond;
X is a bond, Y is -NMeC(0)NMe- and Z is a bond; and
X is a bond, Y is -OC(O)- and Z is a bond.
[0046] Preferably, X is -CH2-, Y is -O- and Z is a bond;
X is a bond, Y is -O- and Z is a bond;
X is a bond, Y is -C(OH)H- and Z is -CH2-;
X is a bond, Y is -C(OH)H- and Z is -C(Me)H-; and
X is a bond, Y is -C(O)- and Z is -CH2 -.
[0047] Further preferably, X is -CH2-, Y is -O- and Z is a bond; and
X is a bond, Y is -O- and Z is a bond; and
X is a bond, Y is -NH- and Z is a bond.
[0048] In an embodiment, Y is -(CRDRE)m-. In an embodiment, RD and RE are each independently selected from: H, =0 (i.e. RD and RE together form =0), -ORA6, -SRA6, -NRA6RB5, halo, Ci-4 alkyl and C1-4 haloalkyl. In an embodiment, RD and RE are each independently selected from: H, =0 (i.e. RD and RE together form =0) and -ORA6 (e.g. -OH). In an embodiment, RA6 is H. In an embodiment, RB5 is H. In an embodiment, m is 1 or 2.
[0049] In an embodiment, Y is -(CRDRE)m- and m is 2. The substituents RD and RE are each independently defined as above. Thus, in this embodiment Y is -(CRD RE )(CRD2RE2)-, wherein RD , RE , RD2 and RE2 are each independently selected from: H, =0 (i.e. RD and RE together form =0), - ORA6, -SRA6, -NRA6RB5, halo, C1-4 alkyl and C1-4 haloalkyl, and preferably RD and RE are each independently selected from: H, =0 (i.e. RE and RF together form =0) and -ORA6 (e.g. -OH), and preferably RD , RE , RD2 and RE2 are each independently selected from: H, =0 (i.e. RD and RE together form =0) and— ORA6 (e.g. -OH). In an embodiment, RD , RE and RD2 are H and RE2 is OH. In an embodiment, RD and RD2 are H, RE is methyl and RE2 is OH. Optionally in the preceding embodiment X is -(CRA RB )n- and n is 1 or 2.
[0050] In an embodiment, Y is -NRF-. In an embodiment, RF is selected from the group consisting of: H, Ci-4 alkyl and C1-4 haloalkyl. In an embodiment, RF is selected from the group consisting of: H, methyl and ethyl.
[0051] In an embodiment, R is a 5 to 16 membered fully saturated, partially unsaturated or aromatic mono-, di- or tri-cyclic moiety, which may optionally include 1 , 2 or 3 heteroatoms (where chemically possible) selected from O, N and S, and is unsubstituted or substituted with 1 to 5 substituents (where chemically possible) selected from halo, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, -ORA3, -NRA3RB3, -SRA3, -C(0)RA3, -OC(0)RA3, -C(0)ORA3, -NRA3C(0)RB3, -
C(0)NRA3RB3, -NRA3S02RB3, -S02NRA3RB3, -S02RA3, =0, -NO2, -CN, C1-4 alkyl substituted with - ORA3 , C1-4 alkyl substituted with -NRA3RB3 and C3-6 cycloalkyl substituted with— ORA3.
[0052] In an embodiment, R is a 5 to 10 membered fully saturated, partially unsaturated or aromatic mono- or di-cyclic moiety, which optionally may include 1 , 2 or 3 heteroatoms (where chemically possible) selected from O, N and S, and which is unsubstituted or substituted with 1 to 5 substituents (where chemically possible) selected from halo, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, -ORA3, -NRA3RB3, -SRA3, -C(0)RA3, -OC(0)RA3, -C(0)ORA3, -NRA3C(0)RB3, - C(0)NRA3RB3, -NRA3S02RB3, -S02NRA3RB3, -S02RA3, =0, -NO2, -CN, C1-4 alkyl substituted with - ORA3 , C1-4 alkyl substituted with -NRA3RB3 and C3-6 cycloalkyl substituted with— ORA3.
[0053] In an embodiment, R is C5-10 cycloalkyl, C5-10 heterocycloalkyl, Ce-io aryl, C5-10 heteroaryl, which are unsubstituted or substituted with 1 to 5 substituents (where chemically possible) selected from halo, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, -ORA3, -NRA3RB3, -SRA3, -C(0)RA3, -OC(0)RA3, - C(0)ORA3, -NRA3C(0)RB3, -C(0)NRA3RB3, -NRA3S02RB3, -S02NRA3RB3, -S02RA3, -NO2, =0, -CN, Ci- 4 alkyl substituted with— ORA3 , C1-4 alkyl substituted with -NRA3RB3 and C3-S cycloalkyl substituted with— ORA3.
[0054] C5-10 heterocycloalkyl will be understood to mean a 5 to 10 membered heterocycloalkyl ring containing 1 , 2 or 3 heteroatoms, as is consistent with the definition of R above. C5-10 heteroaryl will be understood to mean a 5 to 10 membered heteroaryl ring containing 1 , 2 or 3 heteroatoms, as is consistent with the definition of R above. Accordingly, C5-10 heterocycloalkyl may be a 5 to 10 membered heterocycloalkyl ring and C5-10 heteroaryl may be a 5 to 10 membered heteroaryl ring both rings containing 1 , 2 or 3 heteroatoms.
[0055] C5-10 cycloalkyl may represent cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl, cycloatadienyl, indanyl, indenyl and tetralinyl.
[0056] C5-10 heterocycloalkyl may represent oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, pyroline, imidazolidine, imidazoline, succinimide, pyrazolidine, pyrazoline, oxazolidine, oxazoline, dioxolane, isoxazolidine, isoxazoline, thiazolidine, thiazoline, isothiazolidine,
isothiazoline, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dihydropyran, tetrahydropyran, indoline, isoindoline, chromene, chromane, isochromane, dihydroquinoline, tetrahydroquinoline, dihydroisoquinoline or tetrahydroisoquinoline.
[0057] Ce-10 aryl may represent phenyl or napthyl.
[0058] C5-10 heteroaryl may represent pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl and benzimidazolyl.
[0059] In an embodiment R is a ring selected from unsubstituted or substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl, cycloatadienyl, indanyl, indenyl, tetralinyl, oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, pyroline, imidazolidine, imidazoline, succinimide, pyrazolidine, pyrazoline, oxazolidine, oxazoline, dioxolane, isoxazolidine, isoxazoline, thiazolidine, thiazoline, isothiazolidine, isothiazoline, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dihydropyran, tetrahydropyran, indoline, isoindoline, chromene, chromane, isochromane, dihydroquinoline, tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, phenyl, napthyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl and benzimidazolyl.
[0060] In a preferred embodiment R is selected from substituted or unsubstituted: pyridyl, quinolinyl, pyrimidinyl, isoquinolinyl, cyclohexyl, piperidinyl, tetrahydroisoquinolinyl, phenyl, morpholinyl, piperazinyl, and oxadiazolyl.
[0061] In an embodiment, R is a ring selected from substituted or unsubstituted: phenyl, napthyl, indanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl and benzimidazolyl. In an embodiment, R is a ring selected from substituted or unsubstituted: pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl and isoquinolinyl. In an embodiment, R is a ring selected from substituted or unsubstituted: pyridyl, pyrimidinyl, pyrazinyl, quinolinyl and isoquinolinyl.
[0062] In an embodiment, R is selected from substituted or unsubstituted: cycloalkyl moieties, cycloalkenyl moieties and fused ring systems including an aromatic portion. In an embodiment, R is selected from substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. In an alternative embodiment, R is selected from substituted or unsubstituted: cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl and cyclooctadienyl.
[0063] In an embodiment, R is selected from substituted or unsubstituted: heterocycloalkyl moieties, heterocycloalkenyl moieties and fused ring systems including a heteroaromatic portion. In an embodiment, R is selected from substituted or unsubstituted: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, pyroline, imidazolidine, imidazoline, succinimide, pyrazolidine, pyrazoline, oxazolidine, oxazoline, dioxolane, isoxazolidine, isoxazoline, thiazolidine, thiazoline, isothiazolidine, isothiazoline, piperidine, morpholine, thiomorpholine, piperazine, dioxane, dihydropyran and tetrahydropyran. In an embodiment, R is selected from substituted or unsubstituted: tetrahydropyridine, dihydropyran, dihydrofuran and pyrroline.
[0064] In an embodiment R is selected from substituted or unsubstituted: phenyl, pyridyl, cyclohexyl, isoquinolinyl, quinolinyl, piperidinyl, morpholinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, piperazinyl, oxadiazolyl, tetrahydropyridine, dihydropyran, dihydrofuran and pyrroline. In an embodiment R is selected from substituted or unsubstituted: phenyl, pyridyl, cyclohexyl, isoquinolinyl, quinolinyl, piperidinyl, morpholinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, piperazinyl and oxadiazolyl. In an embodiment R is selected from substituted or unsubstituted: phenyl, pyridyl and cyclohexyl,
[0065] In an embodiment, the R moiety is substituted with a single substituent selected from halo, Ci-4 alkyl, Ci- haloalkyl, C3-6 cycloalkyl, -ORA3, -NRA3RB3, -SRA3, -C(0)RA3, -OC(0)RA3, -C(0)ORA3, - NRA3C(0)RB3, -C(0)NRA3RB3, -NRA3S02RB3, -S02NRA3RB3, -S02RA3, -N02, =0, -CN, Ci- alkyl substituted with— ORA3 , Ci- alkyl substituted with -NRA3RB3 and C3-S cycloalkyl substituted with - ORA3.
[0066] In an embodiment, the R moiety is substituted with a single substituent selected from halo (e.g. chloro or fluoro), =0, -ORA3 (e.g. -OH, -OMe, -OEt or -OCF3), -NRA3RB3 (e.g. -NH2, -NHMe or -NMe2), -C(0)ORA3 (e.g. -C(0)OH, -C(0)OMe or -C(O)OEt), -C(0)NRA3RB3, (e.g. -C(0)NH2, - C(0)NHMe or -C(0)NMe2) Ci-4 alkyl (e.g. methyl, ethyl , isopropyl or tert- butyl), Ci- haloalkyl (e.g. trifluoromethyl or trifluoroethyl) Ci-4 alkyl substituted with -ORA3 (e.g. -CH2OH) and Ci-4 alkyl substituted with -NRA3RB3 (e.g. -CH2NH2). Preferably, the R moiety is unsubstituted or substituted with a single substituent selected from CI, OMe, CN, Me, -CH2OH, -C(0)OH, and -C(0)OMe.
[0067] In an embodiment -Z-Y-X-R is -OCH2phenyl, -Ophenyl -OCH2pyridyl, -Opyridyl, -NHphenyl, -OCH2cyanophenyl, -Ocyanophenyl, -OCH2methylphenyl, -Omethylphenyl, -OCH2chlorophenyl, - Ochlorophenyl, -OCH2methoxyphenyl, -Omethoxyphenyl, -OCH2(hydroxymethyl)phenyl, - O(hydroxymethyl)phenyl, or
Figure imgf000017_0001
[0068] In an embodiment, R2 is selected from: H, halo, Ci-4 alkyl, Ci-4 haloalkyl, -ORA4 and Ci-4 alkyl substituted with -ORA4. In an embodiment, R2 is selected from: H, chloro, fluoro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, trifluoroethyl, -OH, methoxy, ethoxy, hydroxy methyl, hydroxyethyl, hydroxypropyl. In an embodiment, R2 is selected from: H and -OH. R2 may be H.
[0069] In an embodiment, R3 and R4 are each independently selected from: H, halo, Ci-4 alkyl, Ci-4 haloalkyl, -CN and -ORA5. In an embodiment, R3 and R4 are each independently selected from: H and Ci- alkyl. R3 and R4 may be H. [0070] In an embodiment m + n + k is 4 or less. Similarly, in an embodiment n + k is 4 or less. In an embodiment m, n and k are selected from 1 or 2. Preferably, m is 1 . Preferably, k is 1 .
[0071] The present invention also provides pharmaceutically acceptable salts of the compounds described herein. For example, there is provided pharmaceutically acceptable salts of the compounds of formula (I).
[0072] The compound according to the invention may be selected from a preferred group consisting of:
Figure imgf000018_0001
Figure imgf000018_0002
Figure imgf000018_0003

Figure imgf000019_0001
[0075] The compound according to the invention may also be selected from a group consisting of:
Figure imgf000020_0001

Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000022_0002
[0077] The above compounds have a chiral centre. All enantiomers and diastereomers of the above compounds are contemplated by the invention. Chiral centres are indicated on the compounds above with a * symbol. In one embodiment the compounds of the invention have the (R)-configuration at the stereocentre. In an alternative embodiment the compounds of the invention have the (S)-configuration at the stereocentre. In certain compounds there are two or more stereocentres. Where compounds have two stereocentres the stereocentres may have (R),(R) configuration, (S),(R) configuration, (R),(S) configuration or (S),(S) configuration. [0078] In accordance with another aspect, the present invention provides a compound of the present invention for use as a medicament.
[0079] In accordance with another aspect, the present invention provides a pharmaceutical formulation comprising a compound of the present invention and a pharmaceutically acceptable excipient.
[0080] In an embodiment the pharmaceutical composition may be a combination product comprising an additional pharmaceutically active agent. The additional pharmaceutically active agent may be an anti-tumor agent described below.
[0081] In accordance with another aspect, there is provided a compound of the present invention for use in the treatment of a condition which is modulated by indoleamine 2,3-dioxygenase (IDO) and/or tryptophan dioxygenase (TD02). Usually conditions that are modulated by IDO and/or TD02 are conditions that would be treated by the inhibition of IDO and/or TD02, using a compound of the present invention. A compound of formula (I) may be for use in the treatment of a condition treatable by the inhibition of IDO and/or TD02.
[0082] There are two indoleamine 2,3-dioxygenase proteins, ID01 and ID02. Where reference is made to IDO this encompasses both ID01 and ID02. Therefore, IDO may refer to ID01 and/or ID02, optionally to ID01 . Accordingly, any condition which is modulated by IDO and/or TD02 may be a condition modulated by ID01 , ID02, and/or TD02. Preferably, IDO is IDOL Therefore, the condition may be a condition modulated by ID01 and/or TD02.
[0083] IDO and/or TD02 inhibition is relevant for the treatment of many different diseases associated with inhibition of IDO and/or TD02. In embodiments the condition treatable by the inhibition of IDO and/or TD02 may be selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, neurodegenerative disorders, inflammation, autoimmune diseases and immunological diseases. Specific cancers, sarcomas, melanomas, skin cancers, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammation and immunological diseases treatable by the inhibition of IDO and/or TD02 may be selected from: immunosuppression melanoma, metastatic non-small cell lung cancer, non-small cell lung cancer, metastatic melanoma, anxiety, depression, brain tumour, hormone refractory prostate cancer, prostate cancer, metastatic breast cancer, breast cancer, stage IV melanoma, solid tumor, metastatic pancreatic cancer, pancreatic cancer, myelodisplastic syndrome, ovarian cancer, fallopian tube cancer, peritoneal tumor, colorectal cancer, lung cancer, cervical cancer, testicular cancer, renal cancer, cancer of the head and neck, HIV-infection, AIDS (including its manifestations such as cachexia, dementia and diarrhoea), organ transplant rejection, dementia, Alzheimer's disease, Huntington's disease, age related cataracts, organ transplant rejection, asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis, systemic lupus erythematosus and rheumatoid arthritis. [0084] The invention contemplates methods of treating the above mentioned conditions and contemplates compounds of the invention for use in a method of treatment of the above mentioned conditions.
[0085] In an aspect of the invention, a compound of the invention may be for use in the treatment of a condition selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, neuro-degenerative disorders, inflammation and immunological diseases. Specific cancers, sarcomas, melanomas, skin cancers, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammation, autoimmune diseases and immunological diseases that may be treated by the compound of the invention may be selected from: immunosuppression melanoma, metastatic non- small cell lung cancer, non-small cell lung cancer, metastatic melanoma, anxiety, depression, brain tumour, hormone refractory prostate cancer, prostate cancer, metastatic breast cancer, breast cancer, stage IV melanoma, solid tumor, metastatic pancreatic cancer, pancreatic cancer, myelodisplastic syndrome, ovarian cancer, fallopian tube cancer, peritoneal tumor, colorectal cancer, lung cancer, cervical cancer, testicular cancer, renal cancer, cancer of the head and neck, HIV-infection, AIDS (including its manifestations such as cachexia, dementia and diarrhoea), organ transplant rejection, dementia, Alzheimer's disease, Huntington's disease, age related cataracts, organ transplant rejection, asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis, systemic lupus erythematosus and rheumatoid arthritis.
[0086] In an aspect of the invention there is provided a method of treatment of a condition which is modulated by IDO and/or TD02, wherein the method comprises administering a therapeutic amount of a compound of the invention, to a patient in need thereof.
[0087] The method of treatment may be a method of treating a condition treatable by the inhibition of IDO and/or TD02. These conditions are described above in relation to conditions treatable by the inhibition of IDO and/or TD02.
[0088] In an aspect of the invention there is provided a method of treatment of a condition selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, neuro-degenerative disorders, inflammation and immunological diseases wherein the method comprises administering a therapeutic amount of a compound of the invention, to a patient in need thereof. Specific cancers, sarcomas, melanomas, skin cancers, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammation, autoimmune diseases and immunological diseases that may be treated by the method of treatment may be selected from: immunosuppression melanoma, metastatic non- small cell lung cancer, non-small cell lung cancer, metastatic melanoma, anxiety, depression, brain tumour, hormone refractory prostate cancer, prostate cancer, metastatic breast cancer, breast cancer, stage IV melanoma, solid tumor, metastatic pancreatic cancer, pancreatic cancer, myelodisplastic syndrome, ovarian cancer, fallopian tube cancer, peritoneal tumor, colorectal cancer, lung cancer, cervical cancer, testicular cancer, renal cancer, cancer of the head and neck, HIV-infection, AIDS (including its manifestations such as cachexia, dementia and diarrhoea), organ transplant rejection, dementia, Alzheimer's disease, Huntington's disease, age related cataracts, organ transplant rejection, asthma, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis, systemic lupus erythematosus and rheumatoid arthritis.
[0089] In an aspect of the invention there is provided a use of a compound of the invention in the manufacture of a medicament for the treatment of a condition which is modulated by IDO and/or TD02. Usually conditions that are modulated by IDO and/or TD02 are conditions that would be treated by the inhibition of IDO and/or TD02, using a compound of the present invention. In an embodiment there is provided a use of a compound of the invention in the manufacture of a medicament for the treatment of a condition treatable by the inhibition of IDO and/or TD02. The condition may be any of the conditions mentioned above.
[0090] In an aspect there is provided a compound for use in treating a condition treatable by the inhibition of the degradation of tryptophan and preventing the production of N-formylkynurenine.
[0091] In accordance with an aspect of the invention, there is provided a method of inhibiting the degradation of tryptophan and preventing the production of N-formylkynurenine in a system comprising cells expressing IDO and/or TD02, wherein the system is exposed to a compound of the invention.
[0092] In accordance with another aspect, the present invention provides a compound of the present invention for use in treating IDO and/or TD02 mediated immunosuppression.
[0093] In accordance with another aspect, the present invention provides a compound of the present invention for use in treating immunosuppression.
[0094] In accordance with another aspect, the present invention provides a compound of the present invention for use in treating immunosuppression associated with cancer, in particular for use in treating tumour-specific immunosuppression associated with cancer.
[0095] In accordance with another aspect, the present invention provides a compound of the present invention for use in treating immunosuppression associated with an infectious disease, e.g., HIV-1 infection, influenza, hepatitis C virus, human papilloma virus, cytomegalovirus, Epstein-Barr virus, poliovirus, varicella zoster virus and coxsackie virus.
[0096] In accordance with another aspect, the present invention provides methods of modulating an activity of IDO and/or TD02 comprising contacting an IDO and/or TD02 containing system with a compound according to the present invention.
[0097] In accordance with another aspect, the present invention provides methods of treating IDO and/or TD02 mediated immunosuppression in a subject in need thereof, comprising administering an effective amount of a compound according to the present invention.
[0098] In accordance with another aspect, the present invention provides methods of treating a medical condition that benefits from the inhibition of enzymatic activity of IDO and/or TD02 comprising administering an effective amount of a compound according to the present invention. [0099] In accordance with another aspect, the present invention provides methods of enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent and a compound according to the present invention.
[00100] In accordance with another aspect, the present invention provides methods of treating tumour-specific immunosuppression associated with cancer comprising administering an effective amount of a compound according to the present invention.
[00101] In accordance with another aspect, the present invention provides methods of treating immunosuppression associated with an infectious disease, e.g., HIV-1 infection, comprising administering an effective amount of a compound according to the present invention.
[00102] In an embodiment cancer may be selected from immunosuppression melanoma, metastatic non-small cell lung cancer, non-small cell lung cancer, metastatic melanoma, brain tumour, hormone refractory prostate cancer, prostate cancer, metastatic breast cancer, breast cancer, stage IV melanoma, melanoma, solid tumor, metastatic pancreatic cancer, pancreatic cancer, myelodysplasia syndrome, ovarian cancer, fallopian tube cancer, peritoneal tumor, and colorectal cancer.
DETAILED DESCRIPTION
[00103] Given below are definitions of terms used in this application. Any term not defined herein takes the normal meaning as the skilled person would understand the term.
[00104] The term "halo" refers to one of the halogens, group 17 of the periodic table. In particular the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.
[00105] The term "Ci-e alkyl" refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, /'so-propyl, n-butyl, sec-butyl, fe/f-butyl, n- pentyl and n-hexyl. Alkylene groups may likewise be linear or branched and may have two places of attachment to the remainder of the molecule. Furthermore, an alkylene group may, for example, correspond to one of those alkyl groups listed in this paragraph. The alkyl and alkylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, Ci-e alkoxy. [00106] The term "Ci-e alkoxy" refers to an alkyl group which is attached to a molecule via oxygen. This includes moieties where the alkyl part may be linear or branched and may contain 1 , 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, /'so-propyl, n-butyl, sec-butyl, fe/f-butyl, n- pentyl and n-hexyl. Therefore, the alkoxy group may be methoxy, ethoxy, n-propoxy, /'so-propoxy, n- butoxy, sec-butoxy, fe/f-butoxy, n-pentoxy and n-hexoxy. The alkyl part of the alkoxy group may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, Ci-e alkoxy. [00107] The term "Ci-e haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence, for example fluorine, chlorine, bromine and iodine. The halogen atom may be present at any position on the hydrocarbon chain. For example, Ci-e haloalkyl may refer to chloromethyl, flouromethyl, trifluoromethyl, chloroethyl e.g. 1 - chloromethyl and 2-chloroethyl, trichloroethyl e.g. 1 ,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g. 1 -fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g. 1 ,2,2-trifluoroethyl and 2,2,2- trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl.
[00108] The term "C2-6 alkenyl" refers to a branched or linear hydrocarbon chain containing at least one double bond and having 2, 3, 4, 5 or 6 carbon atoms. The double bond(s) may be present as the E or Z isomer. The double bond may be at any possible position of the hydrocarbon chain. For example, the "C2-6 alkenyl" may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.
[00109] The term "C2-6 alkynyl" refers to a branched or linear hydrocarbon chain containing at least one triple bond and having 2, 3, 4, 5 or 6 carbon atoms. The triple bond may be at any possible position of the hydrocarbon chain. For example, the "C2-6 alkynyl" may be ethynyl, propynyl, butynyl, pentynyl and hexynyl.
[00110] The term "C1-6 heteroalkyl" refers to a branched or linear hydrocarbon chain containing 1 , 2, 3, 4, 5, or 6 carbon atoms and at least one heteroatom selected from N, O and S positioned between any carbon in the chain or at an end of the chain. For example, the hydrocarbon chain may contain one or two heteroatoms. The C1-6 heteroalkyl may be bonded to the rest of the molecule through a carbon or a heteroatom. For example, the "C1-6 heteroalkyl" may be C1-6 /V-alkyl, C1-6 Λ ,/V-alkyl, or C1-6 O-alkyl.
[0011 1] The term "carbocyclic" refers to a saturated or unsaturated carbon containing ring system. A "carbocyclic" system may be monocyclic or a fused polycyclic ring system, for example, bicyclic or tricyclic. A "carbocyclic" moiety may contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. "Carbocyclic" encompasses cycloalkyl moieties, cycloalkenyl moieties, aryl ring systems and fused ring systems including an aromatic portion.
[00112] The term "heterocyclic" refers to a saturated or unsaturated ring system containing at least one heteroatom selected from N, O or S. A "heterocyclic" system may contain 1 , 2, 3 or 4 heteroatoms, for example 1 or 2. A "heterocyclic" system may be monocyclic or a fused polycyclic ring system, for example, bicyclic or tricyclic. A "heterocyclic" moiety may contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in a polycyclic system. "Heterocyclic" encompasses heterocycloalkyl moieties, heterocycloalkenyl moieties and heteroaromatic moieties. For example, the heterocyclic group may be: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.
[00113] The term "C3-8 cycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms. For example, the "C3-8 cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
[00114] The term "C3-8 cycloalkenyl" refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms that is not aromatic. The ring may contain more than one double bond provided that the ring system is not aromatic. For example, the "C3-8 cycloalkyl" may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.
[00115] The term "C3-8 heterocycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least one heteroatom within the ring selected from N, O and S. For example there may be 1 , 2 or 3 heteroatoms, optionally 1 or 2. The "C3-8 heterocycloalkyl" may be bonded to the rest of the molecule through any carbon atom or heteroatom. The "C3-8 heterocycloalkyl" may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring. For example, the "C3-8 heterocycloalkyl" may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran. [00116] The term "C3-8 heterocycloalkenyl" refers to an unsaturated hydrocarbon ring system, that is not aromatic, containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least one heteroatom within the ring selected from N, O and S. For example there may be 1 , 2 or 3 heteroatoms, optionally 1 or 2. The "C3-8 heterocycloalkenyl" may be bonded to the rest of the molecule through any carbon atom or heteroatom. The "C3-8 heterocycloalkenyl" may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring. For example, the "C3-8 heterocycloalkyl" may be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline.
[00117] The term "aromatic" when applied to a substituent as a whole means a single ring or polycyclic ring system with 4n + 2 electrons in a conjugated π system within the ring or ring system where all atoms contributing to the conjugated π system are in the same plane. [00118] The term "aryl" refers to an aromatic hydrocarbon ring system. The ring system has 4n +2 electrons in a conjugated π system within a ring where all atoms contributing to the conjugated π system are in the same plane. For example, the "aryl" may be phenyl and naphthyl. The aryl system itself may be substituted with other groups.
[00119] The term "heteroaryl" refers to an aromatic hydrocarbon ring system with at least one heteroatom within a single ring or within a fused ring system, selected from O, N and S. The ring or ring system has 4n +2 electrons in a conjugated π system where all atoms contributing to the conjugated π system are in the same plane. For example, the "heteroaryl" may be imidazole, thiene, furane, thianthrene, pyrrol, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.
[00120] The term "alkaryl" refers to an aryl group, as defined above, bonded to a C1-4 alkyl, where the Ci-4 alkyl group provides attachment to the remainder of the molecule.
[00121] The term "alkheteroaryl" refers to a heteroaryl group, as defined above, bonded to a Ci-4 alkyl, where the alkyl group provides attachment to the remainder of the molecule.
[00122] The term "halogen" herein includes reference to F, CI, Br and I. Halogen may be CI. Halogen may be F. [00123] A bond terminating in a " " represents that the bond is connected to another atom that is not shown in the structure. A bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be connected to any of the atoms in the ring structure where allowed by valency.
[00124] Where a moiety is substituted, it may be substituted at any point on the moiety where chemically possible and consistent with atomic valency requirements. The moiety may be substituted by one or more substituents, e.g. 1 , 2, 3 or 4 substituents; optionally there are 1 or 2 substituents on a group. Where there are two or more substituents, the substituents may be the same or different. The substituent(s) may be selected from: OH, NHR, amidino, guanidino, hydroxyguanidino, formamidino, isothioureido, ureido, mercapto, C(0)H, acyl, acyloxy, carboxy, sulfo, sulfamoyl, carbamoyl, cyano, azo, nitro, halo, Ci-e alkyl, Ci-e alkoxy, Ci-e haloalkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl or alkaryl. Where the group to be substituted is an alkyl group the substituent may be =0. R may be selected from H, C1-6 alkyl, C3-8 cycloalkyl, phenyl, benzyl or phenethyl group, e.g . R is H or C1-3 alkyl. Where the moiety is substituted with two or more substituents and two of the substituents are adjacent the adjacent substituents may form a C4-8 ring along with the atoms of the moiety on which the substituents are substituted, wherein the C4-8 ring is a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7, or 8 carbon atoms or a saturated or unsaturated hydrocarbon ring with 4, 5, 6, 7, or 8 carbon atoms and 1 , 2 or 3 heteroatoms.
[00125] Substituents are only present at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort which substitutions are chemically possible and which are not.
[00126] Ortho, meta and para substitution are well understood terms in the art. For the absence of doubt, "ortho" substitution is a substitution pattern where adjacent carbons possess a substituent, whether a simple group, for example the fluoro group in the example below, or other portions of the molecule, as indicated by the bond ending in " J*/"r ".
Figure imgf000030_0001
[00127] "Meta" substitution is a substitution pattern where two substituents are on carbons one carbon removed from each other, i.e with a single carbon atom between the substituted carbons. In other words there is a substituent on the second atom away from the atom with another substituent. For example the groups below are meta substituted.
Figure imgf000030_0002
[00128] "Para" substitution is a substitution pattern where two substituents are on carbons two carbons removed from each other, i.e with two carbon atoms between the substituted carbons. In other words there is a substituent on the third atom away from the atom with another substituent. For example the groups below are para substituted.
Figure imgf000030_0003
[00129] By "acyl" is meant an organic radical derived from, for example, an organic acid by the removal of the hydroxyl group, e.g. a radical having the formula R-C(O)-, where R may be selected from H, Ci-6 alkyl, C3-8 cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H or C1-3 alkyl. In one embodiment acyl is alkyl-carbonyl. Examples of acyl groups include, but are not limited to, formyl, acetyl, propionyl and butyryl. A particular acyl group is acetyl.
[00130] Throughout the description the disclosure of a compound also encompasses
pharmaceutically acceptable salts, solvates and stereoisomers thereof. Where a compound has a stereocentre, both (R) and (S) stereoisomers are contemplated by the invention, equally mixtures of stereoisomers or a racemic mixture are completed by the present application. Where a compound of the invention has two or more stereocentres any combination of (R) and (S) stereoisomers is contemplated. The combination of (R) and (S) stereoisomers may result in a diastereomeric mixture or a single diastereoisomer. The compounds of the invention may be present as a single stereoisomer or may be mixtures of stereoisomers, for example racemic mixtures and other enantiomeric mixtures, and diasteroemeric mixtures. Where the mixture is a mixture of enantiomers the enantiomeric excess may be any of those disclosed above. Where the compound is a single stereoisomer the compounds may still contain other diasteroisomers or enantiomers as impurities. Hence a single stereoisomer does not necessarily have an enantiomeric excess (e.e.) or diastereomeric excess (d.e.) of 100% but could have an e.e. or d.e. of about at least 85% [00131] The invention contemplates pharmaceutically acceptable salts of the compounds of the invention. These may include the acid addition and base salts of the compounds. These may be acid addition and base salts of the compounds. In addition the invention contemplates solvates of the compounds. These may be hydrates or other solvated forms of the compound. [00132] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 1 ,5- naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.
[00133] Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
[00134] Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods:
(i) by reacting the compound of the invention with the desired acid or base;
(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of the invention or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or
(iii) by converting one salt of the compound of the invention to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.
[00135] All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised. [00136] The compounds of the invention may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.
[00137] Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non- stoichiometric amounts. The resulting complexes may be ionised, partially ionised, or non- ionised. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).
[00138] Hereinafter all references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
[00139] The compounds of the invention include compounds of a number of formula as herein defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labelled compounds of the invention. [00140] The present invention also includes all pharmaceutically acceptable isotopically-labelled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
[00141] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as C, 3C and 4C, chlorine, such as 36CI, fluorine, such as 8F, iodine, such as 23l and 25l, nitrogen, such as 3N and 5N, oxygen, such as 50, 70 and 80, phosphorus, such as 32P, and sulphur, such as 35S.
[00142] Certain isotopically-labelled compounds, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 4C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
[00143] Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
[00144] Before purification, the compounds of the present invention may exist as a mixture of enantiomers depending on the synthetic procedure used. The enantiomers can be separated by conventional techniques known in the art. Thus the invention covers individual enantiomers as well as mixtures thereof.
[00145] For some of the steps of the process of preparation of the compounds of the invention, it may be necessary to protect potential reactive functions that are not wished to react, and to cleave said protecting groups in consequence. In such a case, any compatible protecting radical can be used. In particular methods of protection and deprotection such as those described by T.W.
GREENE (Protective Groups in Organic Synthesis, A. Wiley- Interscience Publication, 1981) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used. All of the above reactions and the preparations of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well-known to those skilled in the art with reference to literature precedents and the examples and preparations hereto.
[00146] Also, the compounds of the present invention as well as intermediates for the preparation thereof can be purified according to various well-known methods, such as for example
crystallization or chromatography.
[00147] One or more compounds of the invention may be combined with one or more
pharmaceutical agents, for example anti-viral agents, chemotherapeutics, anti-cancer agents, immune enhancers, immunosuppressants, anti-tumour vaccines, anti-viral vaccines, cytokine therapy, or tyrosine kinase inhibitors, for the treatment of conditions modulated by the inhibition of IDO, for example cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammation and immunological diseases
[00148] The method of treatment or the compound for use in the treatment of cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, inflammation and immunological diseases as defined hereinbefore may be applied as a sole therapy or be a combination therapy with an additional active agent.
[00149] The method of treatment or the compound for use in the treatment of cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, and central nervous system disorders may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumor agents:
(i) antiproliferative/antineoplastic drugs and combinations thereof, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard, bendamustin, melphalan, chlorambucil, chlormethine, busulphan, temozolamide, nitrosoureas, ifosamide, melphalan, pipobroman, triethylene-melamine, triethylenethiophoporamine, carmustine, lomustine, stroptozocin and dacarbazine); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine and hydroxyurea); antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); proteasome inhibitors, for example carfilzomib and bortezomib; interferon therapy; and
topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan, mitoxantrone and camptothecin); bleomcin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol™), nabpaclitaxel, docetaxel, mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide; (ii) cytostatic agents such as antiestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5a-reductase such as finasteride; and navelbene, CPT-II, anastrazole, letrazole, capecitabine, reloxifene,
cyclophosphamide, ifosamide, and droloxafine;
(iii) anti-invasion agents, for example dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function or antibodies to
Heparanase;
(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies, for example the anti-erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as gefitinib, erlotinib, 6-acrylamido-/V-(3-chloro-4- fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib) and antibodies to costimulatory molecules such as CTLA-4, 4-IBB and PD-I, or antibodies to cytokines (IL-IO, TGF-beta); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; modulators of protein regulators of cell apoptosis (for example Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib (AMN107); inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib , tipifarnib and lonafarnib), inhibitors of cell signalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1 R kinase inhibitors, IGF receptor, kinase inhibitors; aurora kinase inhibitors and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors; and CCR2, CCR4 or CCR6 modulator;
(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab
(Avastin™); thalidomide; lenalidomide; and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib;
(vi) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2;
(vii) immunotherapy approaches, including for example antibody therapy such as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®) and ofatumumab; interferons such as interferon a; interleukins such as IL-2 (aldesleukin); interleukin inhibitors for example IRAK4 inhibitors; cancer vaccines including prophylactic and treatment vaccines such as HPV vaccines, for example Gardasil, Cervarix, Oncophage and Sipuleucel-T (Provenge); gp100;dendritic cell-based vaccines (such as Ad.p53 DC); and toll-like receptor modulators for example TLR-7 or TLR-9 agonists; and (viii) cytotoxic agents for example fludaribine (fludara), cladribine, pentostatin (Nipent™);
(ix) steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate, meprednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and their respective pharmaceutically acceptable derivatives. A combination of steroids may be used, for example a combination of two or more steroids mentioned in this paragraph;
(x) targeted therapies, for example PI3Kd inhibitors, for example idelalisib and perifosine; PD-1 , PD-L1 , PD-L2 and CTL4-A modulators, antibodies and vaccines; other IDO inhibitors (such as indoximod); anti-PD-1 monoclonal antibodies (such as MK-3475 and nivolumab); anti-PDL1 monoclonal antibodies (such as MEDI-4736 and RG-7446); anti-PDL2 monoclonal antibodies; and anti-CTLA-4 antibodies (such as ipilimumab);
(xi) anti-viral agents such as nucleotide reverse transcriptase inhibitors (for example, zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, adefovir diprovoxil, lobucavir, BCH-10652, emitricitabine, beta-L-FD4 (also called 3'-dicleoxy-5-fluoro-cytidine), (-)-beta-D-2,6-diamino-purine dioxolane, and lodenasine), non-nucleoside reverse transcriptase inhibitors (for example, nevirapine, delaviradine, efavirenz, PNU-142721 , AG-1549, MKC-442 (1 -ethoxy-methyl)-5-(1 - methylethyl)-6-(phenylmehtyl)-(2,4(1 H,3H)pyrimidineone), and (+)-alanolide A and B) and protease inhibitors (for example, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lasinavir, DMP-450, BMS-2322623, ABT-378 and AG-1 549);
(xii) chimeric antigen receptors, anticancer vaccines and arginase inhibitors.
[00150] The method of treatment or the compound for use in the treatment of inflammation and immunological diseases may involve, in addition to the compound of the invention, additional active agents. The additional active agents may be one or more active agents used to treat the condition being treated by the compound of the invention and additional active agent. The additional active agents may include one or more of the following active agents:-
(i) steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate, meprednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and their respective pharmaceutically acceptable derivatives. A combination of steroids may be used, for example a combination of two or more steroids mentioned in this paragraph;
(ii) TNF inhibitors for example etanercept; monoclonal antibodies (e.g. infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi)); fusion proteins (e.g. etanercept (Enbrel)); and 5-ΗΪ2Α agonists (e.g. 2,5-dimethoxy-4-iodoamphetamine, TCB-2, lysergic acid diethylamide (LSD), lysergic acid dimethylazetidide);
(iii) anti-inflammatory drugs, for example non-steroidal anti-inflammatory drugs;
(iv) dihydrofolate reductase inhibitors/antifolates, for example methotrexate, trimethoprim, brodimoprim, tetroxoprim, iclaprim, pemetrexed, ralitrexed and pralatrexate; and
(v) immunosuppressants for example cyclosporins, tacrolimus, sirolimus pimecrolimus, angiotensin II inhibitors (e.g. Valsartan, Telmisartan, Losartan, Irbesatan, Azilsartan, Olmesartan, Candesartan, Eprosartan) and ACE inhibitors e.g. sulfhydryl-containing agents (e.g. Captopril, Zofenopril), dicarboxylate-containing agents (e.g. Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril, Benazepril, Imidapril, Zofenopril, Trandolapril), phosphate-containing agents (e.g.
Fosinopril), casokinins, lactokinins and lactotripeptides.
[00151] Such combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within a therapeutically effective dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
[00152] Compounds of the invention may exist in a single crystal form or in a mixture of crystal forms or they may be amorphous. Thus, compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose. [00153] For the above-mentioned compounds of the invention the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, if the compound of the invention is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ( g/kg) to 100 milligrams per kilogram body weight (mg/kg).
[00154] A compound of the invention, or pharmaceutically acceptable salt thereof, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example,
"Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.
[00155] Depending on the mode of administration of the compounds of the invention, the pharmaceutical composition which is used to administer the compounds of the invention will preferably comprise from 0.05 to 99 %w (per cent by weight) compounds of the invention, more preferably from 0.05 to 80 %w compounds of the invention, still more preferably from 0.10 to 70 %w compounds of the invention, and even more preferably from 0.10 to 50 %w compounds of the invention, all percentages by weight being based on total composition.
[00156] The pharmaceutical compositions may be administered topically (e.g. to the skin) in the form, e.g., of creams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.
[00157] For oral administration the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide.
Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.
[00158] For the preparation of soft gelatine capsules, the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.
[00159] For intravenous (parenteral) administration the compounds of the invention may be administered as a sterile aqueous or oily solution.
[00160] The size of the dose for therapeutic purposes of compounds of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.
[00161] Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient. The standard duration of treatment with compounds of the invention is expected to vary between one and seven days for most clinical indications. It may be necessary to extend the duration of treatment beyond seven days in instances of recurrent infections or infections associated with tissues or implanted materials to which there is poor blood supply including bones/joints, respiratory tract, endocardium, and dental tissues.
EXAMPLES AND SYNTHESIS
General methods
[00162] As used herein the following terms have the meanings given: "BuLi" refers to n- butyllithium; "DCM" refers to dichloromethane; "DEAD" refers to diethyl azodicarboxylate; "DIAD" refers to diisopropyl azodicarboxylate; "DMF" refers to A/,A/-dimethylformamide; "EDC" refers to N- (3-Dimethylaminopropyl)-/V'-ethylcarbodiimide; "HBTU" refers to (1 H-Benzotriazol-1 - yloxy)(dimethylamino)-/V,/V-dimethylmethaniminium hexafluorophosphate; "LCMS" refers to liquid chromatography/mass spectrometry; "min" refers to minutes; "rt" refers to retention time; "SCX" refers to strong cation exchange; "STAB" refers to sodium triacetoxyborohydride; "TBAF" refers to tetrabutylammonium fluoride, "TFA" refers to trifluoroacetic acid and "THF" refers to tetrahydrofuran; "TMAF" refers to tetramethylammonium fluoride.
[00163] Solvents, reagents and starting materials were purchased from commercial vendors and used as received unless otherwise described. All reactions were performed at room temperature unless otherwise stated. Compound identity and purity confirmations were performed by LCMS UV using a Waters Acquity SQ Detector 2 (ACQ-SQD2#LCA081). The diode array detector wavelength was 254 nM and the MS was in positive and negative electrospray mode (m/z: 150-800). A 2 L aliquot was injected onto a guard column (0.2 μηι χ 2 mm filters) and UPLC column (C18, 50 x 2.1 mm, < 2 μηι) in sequence maintained at 40 °C. The samples were eluted at a flow rate of 0.6 mL/min with a mobile phase system composed of A (0.1 % (v/v) Formic Acid in Water) and B (0.1 % (v/v) Formic Acid in Acetonitrile) according to the gradients outlined in Table 1 below. Retention times RT are reported in minutes.
Method 1 : "Short"
Figure imgf000039_0001
Table 1
[00164] NMR was also used to characterise final compounds. NMR spectra were obtained on a Bruker AVMI 400 Nanobay with 5 mm BBFO probe at room temperature unless otherwise stated. 1 H NMRs are reported in ppm and referenced to either TMS (0.0 ppm), DMSO-d6 (2.50 ppm), CDC (7.26 ppm) or CDsOD (3.31 ppm).
[00165] Compound purification was performed by flash column chromatography on silica using SiliaSep Silica Pre-packed Solid-Load Cartridge with the eluting solvent described for the purification of each compound or by preparative LCMS. LCMS purification was performed using a Waters 3100 Mass detector in positive and negative electrospray mode (m/z: 150-800) with a Waters 2489 UV/Vis detector. Samples were eluted at a flow rate of 20 mL/min on a XBridgeTM prep C18 5 μΜ OBD 19x100 mm column with a mobile phase system composed of A (0.1 % (v/v) Formic Acid in Water) and B (0.1 % (v/v) Formic Acid in Acetonitrile) according to the gradients outlined in Table 2 below.
Figure imgf000039_0002
1 .5 90 10
2 35 65
1 1 5 95
13.5 5 95
14.0 90 10
15.0 90 10
Table 2
[00166] Chemical names in this document were generated using mol2nam - Structure to Name Conversion by OpenEye Scientific Software. Starting materials were purchased from commercial sources or synthesised according to literature procedures.
Chemical Synthesis
[00167] Procedure A: Preparation of imidazole-4,5-diester and related compounds.
lmidazole-4,5-diester starting materials which are not commercially available can be synthesised by analogy with the procedure in Scheme 1 .
Figure imgf000040_0001
Scheme 1
In a first synthetic route tartaric acid can be di-nitrated in presence of nitric acid and a strong acid (e.g. sulphuric acid). Condensation of the di-nitrated intermediate with aldehydes and ammonia can be used to afford imidazole-4,5-dicarboxylic acids. These can be esterified into the corresponding imidazole-4,5-diesters (e.g. methyl esters, ethyl esters) upon activation of carboxylates into acid chlorides (using for example thionyl chloride or oxalyl chloride) and a source of alcohol (e.g.
methanol, ethanol). Alternatively, condensation of tartaric acid diester (e.g. tartaric acid dimethyl ester, tartaric acid diethyl ester) with aldehydes and a source of ammonia (e.g. NH4OH) in presence of brominating agents such as but not limited to 1 ,3-Dibromo-5,5-dimethylhydantoin can be used to afford imidazole-4,5-diesters.
[00168] Procedure B: Preparation of trimethylsilylaryl trifluoromethanesulfonate and related compounds. Trimethylsilylaryl trifluoromethanesulfonate starting materials which are not commercially available can be synthesised by analogy with the procedure in Scheme 2.
Figure imgf000041_0001
Scheme 2
O/f/70-bromohydroxyarenes can be silylated using reagents such as but not limited to HMDS. Treatment of the resulting silyl ethers with a strong base (e.g. n-BuLi, s-BuLi) followed by triflic anhydride can be used to afford the trimethylsilylaryl trifluoromethanesulfonate starting materials. Alternatively, o/f ?o-bromohydroxyarenes can be di-silylated using a strong base (e.g. n-BuLi, s- BuLi) and an excess of silylating agents (e.g. TMSCI, DMIPSCI). Deprotection of the silyl ether functionalities can be achieved using a source of fluoride (e.g. TMAF, TBAF). Subsequent trifluoromethylsulphonylation can be achieved using triflic anhydride to afford trimethylsilylaryl trifluoromethanesulfonates.
[00169] Procedure C: Preparation of the imidazo[1 ,5-a]indole and related tricyclic core systems. The imidazo[1 ,5-a]indol tricyclic core can be synthesised by analogy with the procedure described in Scheme 3.
Figure imgf000042_0001
Figure imgf000042_0002
Scheme 3
lmidazole-4,5-diesters and trimethylsilylaryl trifluoromethanesulfonates can be condensed into a 4- oxoimidazo[1 ,5-a]indol-3-ester tricyclic systems in presence of a source of fluoride (e.g. TMAF, TBAF). A variety of bases including NaOH, KOH can be used to hydrolyse the resulting 4- oxoimidazo[1 ,5-a]indole-3-esters into 4-oxoimidazo[1 ,5-a]indole-3-carboxylic acids. Decarboxylation of these carboxylic acids into imidazo[1 ,5-a]indol-4-ones can be achieved using microwave irradiations at high temperature in solvents including but not limited to dichlorobenzene. Reduction of imidazo[1 ,5-a]indol-4-ones into corresponding alcohols (imidazo[1 ,5-a]indol-4-ols) can be achieved with reducing agents including but not limited to NaBhU.
[00170] Example C.1 : Preparation of imidazo[1 ,5-a]indol-4-ol
[00171] Ethyl 4-oxoimidazo[1 ,5-a]indole-3-carboxylate
Figure imgf000042_0003
Diethyl 1 H-imidazole-4,5-dicarboxylate (1 .00 g, 4.71 mmol) and tetramethylammonium fluoride (1 .10 g, 1 1 .8 mmol) were added to a flask which was sealed and purged with nitrogen.
Anhydrous THF (52 ml) was added to the solid mixture followed by 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (1 .26 ml_, 5.18 mmol). The reaction was stirred at room temperature for 18 hours. It was subsequently concentred in vacuo and the resulting residue was partitioned with a mixture of DCM (100 ml) and water (100 ml). Organic and aqueous layers were separated and the aqueous layer was further extracted with DCM (100 ml). The combined organic layers were dried through a phase separator and concentrated in vacuo. Crude product was purified by flash column chromatography (80 g, eluted with a 12-100% ethyl acetate in petroleum ether eluent). Fractions containing desired product were concentrated to afford an orange solid characterised as ethyl 4- oxoimidazo[1 ,5-a]indole-3-carboxylate (953 mg, 3.93 mmol, 83% yield). Ή NMR (CDCI3, 400 MHz) δ: 7.91 (s, 1 H), 7.80 (dq, J 7.5, 0.6 Hz, 1 H), 7.62 (td, J 7.8, 1 .3 Hz, 1 H), 7.42-7.35 (m, 2H), 4.48 (q, J 7.2 Hz, 2H), 1 .47 (t, J 7.2 Hz, 3H). LCMS purity >95%, [M+H]+ = 243.0, 1 .32 min (analytical short).
[00172] 4-Oxoimidazo[1 ,5-a]indole-3-carboxylic acid
Figure imgf000043_0001
4-Oxoimidazo[1 ,5-a]indole-3-carboxylic acid (2.50 g, 10.3 mmol) was suspended in water (35 ml_) and methanol (35 ml_). Sodium hydroxide (1 .24 g, 31 .0 mmol) was added to the stirred solution, which was left to stir for 2 h at room temperature. The reaction mixture was acidified (pH ~ 1) with concentrated HCI and the resulting precipitate was filtered, washed with water and dried to afford 4-oxoimidazo[1 ,5-a]indole-3-carboxylic acid (1 .50 g, 7.00 mmol, 68% yield) as a beige solid. Ή NMR (DMSO-d6, 400 MHz) δ: 13.19 (s, 1 H), 8.55 (s, 1 H), 7.82-7.70 (m, 3H), 7.43-7.38 (m, 1 H). LCMS purity >95%, [M+H]+ = 215.0, 1 .01 min (analytical short).
[00173] lmidazo[1 ,5-a]indol-4-one
Figure imgf000043_0002
4-Oxoimidazo[1 ,5-a]indole-3-carboxylic acid (1 .50 g, 7.00 mmol) was suspended in 1 ,2- dichlorobenzene (54 mL). The resulting mixture was divided into 3 (25 mL) microwave vials which were degassed and heated in the microwave reactor at 250 °C for 1 hour. The combined reaction mixtures were loaded onto an SCX-2 cartridge (25 g), washed with methanol, eluted with ammonia in methanol (2 M) and concentrated in vacuo. The residue was purified by flash column
chromatography (100 g, eluted with a 20-100% ethyl acetate in petroleum ether eluent). Fractions containing the desired product were combined to afford imidazo[1 ,5-a]indol-4-one (718 mg, 4.22 mmol, 60% yield) as a light brown powder. Ή NMR (CDC , 400 MHz) δ: 8.26 (br s, 1 H), 7.76 (d, J 7.6 Hz, 1 H), 7.65-7.59 (m, 2H), 7.52-7.46 (m, 1 H), 7.37 (t, J 7.4 Hz, 1 H). LCMS purity >95%, [M+H]+ = 171 .2, 1 .08 min (analytical short), 2.09 min (analytical long).
[00174] lmidazo[1.5-a]indol-4-ol
Figure imgf000044_0001
To a stirred suspension of imidazo[1 ,5-a]indol-4-one (500 mg, 2.94 mmol) in anhydrous methanol (50 ml_) was added sodium borohydride (1 1 1 mg, 2.94 mmol) in one batch. The mixture was left to stir for 20 minutes at room temperature. To the reaction mixture was added water (30 ml_) and the organics were removed in vacuo. The resulting aqueous suspension was extracted with DCM (3 x 30 ml_), the combined organics were dried over a phase separator and concentrated to dryness to afford imidazo[1 ,5-a]indol-4-ol (427 mg, 2.48 mmol, 84% yield) as an orange powder. Ή NMR (DMSO-d6, 400 MHz) δ: 8.22 (s, 1 H), 7.64 (d, J 7.8 Hz, 1 H), 7.56 (d, J 7.6 Hz, 1 H), 7.43 (td, J 7.7, 0.9 Hz, 1 H), 7.25 (td, J 7.5, 1 .0 Hz, 1 H), 7.02 (d, J 0.8 Hz, 1 H), 6.05 (d, J 7.6 Hz, 1 H), 5.68 (d, J 7.2 Hz, 1 H). LCMS purity >95%, [M+H]+ = 172.9, 0.48 (analytical short), 0.41 min (analytical long).
[00175] Procedure D: Preparation of methylene-linked imidazo[1 ,5-a]indole and related tricyclic compounds
The preparation of methylene-linked imidazo[1 ,5-a]indole and related tricyclic compounds can be carried out by analogy with the synthetic routes described in Scheme 4 and Scheme 5.
Figure imgf000044_0002
Scheme 4
lmidazo[1 ,5-a]indol-4-ones can be condensed with witting-type reagents (e.g. dimethoxyphosphoryl- ethanones) using a strong base (e.g. NaH) to afford a mixture of Z and E α,β-insaturated ketones. These can be reduced in two steps using conditions including but not limited to zinc powder in acetic acid followed by NaBH4 to afford the corresponding substituted ethyl alcohols. Alternatively the Knoevenagel condensation of lmidazo[1 ,5-a]indol-4-ones with malonic acid, malonic esters, or malonitrile can afford mixtures of Z and E α,β-insaturated carboxylic acids. The latter can be reduced using reducing agents such as but not limited to zinc powder in acetic acid to afford the saturated 2-(4H-imidazo[1 ,5-a]indol-4-yl)acetic acid analogues. Reduction of the latter carboxylic acids (or their esters) to the corresponding alcohols can be achieved using reducing agents such as but not limited to LiAlhU. Re-oxidation of the alcohol moiety under mild oxidising conditions (e.g. Svern, Parikh-Doering, Dess-Martin) can lead to the corresponding acetaldehyde analogues. Final reaction of the aldehyde functionality with a Grignard reagent or a lithiated species can afford the desired substituted alcohols.
Figure imgf000045_0001
Scheme 5
2-(4H-imidazo[1 ,5-a]indol-4-yl)acetic acids can be coupled with amines using amide coupling reaction conditions (e.g. EDC, HBTU) to afford the corresponding amides. Alternatively amides can be prepared from the corresponding acid chloride (prepared from reacting 2-(4H-imidazo[1 ,5- a]indol-4-yl)acetic acids with thionyl chloride or oxalyl chloride) and amines in presence of base (e.g. triethylamine, /V,/V-diisopropylethylamine, pyridine). Ether analogues can be prepared from 2- (4H-imidazo[1 ,5-a]indol-4-yl)ethanols and chlorinated or brominated reagent in presence of base (e.g. NaH, KOtBu). Alternatively, Mitsunobu reaction conditions can be used to generate both ethers and thioethers by reacting 2-(4H-imidazo[1 ,5-a]indol-4-yl)ethanols with alcohol or thiol reagents. 2-(4H-imidazo[1 ,5-a]indol-4-yl)acetaldehydes can be converted into 2-(4H-imidazo[1 ,5- a]indol-4-yl)ethanamines either by condensation with NH2OH followed by hydrogenation, reaction with NH3 under high temperatures in presence of hydride (e.g. STAB, NaCNBh ) or via a two-step reductive amination - deprotection process. In the latter case, the intermediate amines may contain a protecting group (e.g. benzyl, 4-methoxybenzyl) that can be cleaved using hydrogenation, acidic hydrolysis or other deprotection conditions. 2-(4H-lmidazo[1 ,5-a]indol-4-yl)ethanamines can be further derivatised into corresponding amides, sulphonamides or ureas by condensation with acid chlorides, isocyanates, or sulphonyl chlorides in presence of base (e.g. triethylamine, N,N- diisopropylethylamine, pyridine) or coupling agents (e.g. EDC, HBTU) if any is required.
[00176] Example D.1 : Preparation of 1 -cyclohexyl-2-(4H-imidazo[1 ,5-a]indol-4-yl)ethanol
[00177] 1 -Cyclohexyl-2-dimethoxyphosphoryl-ethanone
Figure imgf000046_0001
To a stirring solution of dimethyl-methylphosphonate (2.74 mL, 25.3 mmol) in THF (20 mL) at -78 °C was added dropwise a 2.5 M solution of n-BuLi (10.1 mL, 25.3 mmol) under an atmosphere of nitrogen. The resulting mixture was stirred for 30 minutes. To this reaction mixture was added dropwise a solution of methyl cyclohexanoate (3.62 mL, 25.3 mmol) in THF (5 mL). After stirring for 30 minutes, the reaction mixture was allowed to warm to 0 °C and was stirred for 1 h. The solvent was removed under vacuum and the crude was diluted with saturated ammonium chloride solution (10 mL) and water (10 mL). The mixture was extracted with EtOAc (2 x 40 mL) and the combined organic extracts were washed with water (20 mL) followed by brine (20 mL) and dried over Na2S04. The solution was filtered and concentrated to yield 1 -cyclohexyl-2-dimethoxyphosphoryl-ethanone (5.12 g, 21 .9 mmol, 86% yield) as a pale yellow oil. Ή NMR (CDC , 400 MHz) δ: 3.76 (d, J 1 1 .4 Hz, 6H), 3.10 (d, J 22.3 Hz, 2H), 2.64-2.54 (m, 1 H), 1 .93-1 .56 (m, 5H), 1 .41 -1 .16 (m, 5H).
[00178] 1 -Cyclohexyl-2-imidazo[1 ,5-a]indol-4-ylidene-ethanone
Figure imgf000046_0002
A three-neck flask was charged with sodium hydride (60% dispersed in mineral oil, 123 mg, 3.08 mmol), sealed and flushed with N2. THF (5 mL) was added to the resulting white suspension which was stirred for 5 minutes and a solution of 1 -cyclohexyl-2-dimethoxyphosphoryl-ethanone (712 mg, 3.04 mmol) in anhydrous THF (10 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes. A solution of imidazo[1 ,5-a]indol-4-one (345 mg, 2.03 mmol) in anhydrous THF (22 mL) was added dropwise and the reaction mixture was heated at reflux for 24 hours. The reaction was quenched with a saturated solution of aqueous ammonium chloride (20 ml_), the aqueous phase was extracted with ethyl acetate (3 x 20 ml_). The combined organic phases were washed with brine, dried over Na2S04, filtered and evaporated to dryness. The residue was purified by flash column chromatography (80 g, eluted with a 25-100% ethyl acetate in petroleum ether eluent) to afford 1 -cyclohexyl-2-imidazo[1 ,5-a]indol-4-ylidene-ethanone (440 mg, 1 .58 mmol, 69% yield) as a brown oil (9/1 Z/E-isomer). Ή NMR (CD3OD, 400 MHz) δ: 8.35 (s, 1 H), 8.15 (s, 1 H), 8.0 (d, J 8.0 Hz, 1 H), 7.64 (d, J 7.8 Hz, 1 H), 7.54 (t, J 7.8 Hz, 1 H), 7.34 (t, J 7.7 Hz, 1 H), 7.19 (s, 1 H), 3.73-3.68 (m, 1 H), 2.77-2.69 (m, 1 H), 2.01 -1 .99 (m, 2H), 1 .91 -1 .82 (m, 2H), 1 .78- 1 .71 (m, 1 H), 1 .52-1 .32 (m, 4H). LCMS purity >95%, [M+H]+ = 279.2, 1 .58 and 1 .63 min (analytical short).
[00179] 1 -Cyclohexyl-2-(4H-imidazo[1 ,5-a]indol-4-yl)ethanone
Figure imgf000047_0001
To a solution of (2)-1 -cyclohexyl-2-imidazo[1 ,5-a]indol-4-ylidene-ethanone (330 mg, 1 .19 mmol) in acetic acid (35 ml_), was added zinc powder (165 mg, 2.52 mmol) in one portion. The reaction mixture was heated at reflux for 1 hour. The reaction mixture was subsequently evaporated to dryness, the residue was dissolved in DCM (30 ml_) and washed with water (30 ml_) followed by saturated aqueous NaHCC . After filtration through hydrophobic frit and evaporation of solvent, the residue was purified by flash column chromatography (50 g, eluted with a 20-100% ethyl acetate in petroleum ether eluent) to afford 1 -cyclohexyl-2-(4H-imidazo[1 ,5-a]indol-4-yl)ethanone (183 mg, 0.653 mmol, 55% yield) as a brown oil. Ή NMR (DMSO-d6, 400 MHz) δ: 8.25 (s, 1 H), 7.70 (d, J 8.3 Hz, 1 H), 7.53 (d, J 7.7 Hz, 1 H), 7.40 (t, J 8.0 Hz, 1 H), 7.24 (td, J 7.6, 1.1 Hz, 1 H), 6.69 (d, J 1.3 Hz, 1 H), 4.40 (dd, J 9.7, 5.0, Hz, 1 H), 3.35-3.28 (m, 1 H), 2.85 (dd, J 17.8, 9.2 Hz, 1 H), 2.45-2.38 (m, 1 H), 1 .83-1.59 (m, 5H), 1 .34-1 .13 (m, 5H). LCMS purity >95%, [M+H]+ = 281.2, 1.40 min (analytical short), final purity 3.00 min (analytical long).
[00180] 1-Cyclohexyl-2-(4H-imidazo[1,5-a]indol-4-yl)ethanol
Figure imgf000047_0002
1 -cyclohexyl-2-(4H-imidazo[1 ,5-a]indol-4-yl)ethanone (190 mg, 0.680 mmol) was dissolved in methanol (13 ml_) under N2 and cooled at 0°C. Sodium borohydride (77 mg, 2.0 mmol) was added carefully to the reaction mixture which was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness and 1 M HCI (10 mL) was added to the residue which was stirred at room temperature for 10 minutes. The product was extracted with DCM (3 x 20 mL) followed by ethyl acetate (3 x 20 mL). Organic layers were combined, dried using a phase separator and evaporated to dryness. The crude was purified by flash column chromatography (25 g, eluted with a 0-10% methanol in ethyl acetate eluent) to afford to pale orange film which was crystallised by co-evaporation with DCM (3 x 10 mL). 1 14 mg of 1 -cyclohexyl-2-(4H-imidazo[1 ,5-a]indol-4- yhethanol (60% yield) were isolated as a mixture of 4 diastereomers. H NMR (DMSO-d6, 400 MHz) δ 8.27-8.24 (m, 1 H), 7.71 -7.69 (m, 1 H), 7.59-7.53 (m, 1 H), 7.42-7.35 (m, 1 H), 7.27-7.22 (m, 1 H), 6.93-6.89 (m, 1 H), 4.80-4.65 (m, 1 H), 4.30-4.18 (m, 1 H), 3.65-3.54 (m, 1 H), 2.10-1 .60 (m, 7H), 1 .36-0.94 (m, 6H). LCMS purity 91 %, [M+H]+ = 283.4, 1 .35 min (analytical short), 2.93 min
(analytical long). 3:2 mixture of diastereomers.
[00181] Procedure E: Preparation of O-linked, /V-linked, S-linked and C-linked imidazo[1 ,5- a]indole and related tricyclic compounds from 4H-imidazo[1 ,5-a]indol-4-ols
O-linked, /V-linked, S-linked and C-linked imidazo[1 ,5-a]indole compounds and related tricyclic analogues can be synthesised via a variety of strategies as described in but not restricted to
Scheme 6. In Scheme 6 where there are two R groups, R can represent R as defined herein or R can represent an amino protecting group or RF as defined herein.
Figure imgf000048_0001
Scheme 6 In a first synthetic strategy imidazo[1 ,5-a]indol-4-ols can be deprotonated with a suitable base (e.g. but not restricted to NaH, tBuOH) and reacted with a halogenated (e.g. BnCI, BnBr), mesylated, tosylated, or triflated species to afford the corresponding ethers. Alternatively these ethers can be synthesised via standard Mitsunobu reaction conditions using reagents including but not restricted to DIAD and triphenylphosphine. O-linked, /V-linked and S-linked compounds can be synthesised via an activation of the bridge alcohol of imidazo[1 ,5-a]indol-4-ols into a halide (e.g. Br, CI), a mesyl, a trityl or a triflate and its reaction with alcohols, amines or thiols. The C-linked imidazo[1 ,5-a]indols can be synthesised from in a similar way by reaction with a lithiated species or Grignard reagents. /V-linked amides, sulphonamides, and ureas can be obtained from the corresponding 4H- imidazo[1 ,5-a]indol-4-amines upon reaction with acid chlorides or sulphonyl chlorides in presence of a suitable base (e.g. but not restricted to triethylamine, Λ/,/V-diisopropylethylamine, pyridine) or upon reaction with isocyanates.
[00182] Example E.1 : Preparation of O-linked imidazo[1 ,5-a]indole compounds using nucleophilic substitution or Mitsunobu conditions.
Figure imgf000049_0001
Method C1a (Nucleophilic substitution): 4H-imidazo[1 ,5-a]indol-4-ol (1 .0 eq.) and halide (1 .1 eq.) were dissolved in DMF (2 ml_) and stored under nitrogen. After stirring for 5 minutes, sodium hydride (1 .2 eq.) was added, and after stirring for another 3 h at room temperature, the mixture was cooled to 5 °C, quenched with saturated NhUCI (0.2 ml_) and concentrated under reduced pressure. The residue was dissolved in saturated NaHC03 (10 ml_) and extracted with 5% methanol in ethyl acetate (2 x 10 ml). The organic layers were combined, dried over Na2S04, filtered and
concentrated under reduced pressure. Crude material was purified by preparative chromatography according to method 1 , 2 or 3 or silica (SiliaSep with the reported elution system for each compound).
Method C1 b (Mitsunobu reaction): To a stirred suspension of 4H-imidazo[1 ,5-a]indol-4-ol (1 .0 eq.), triphenylphosphine (1 .5 eq.) and alcohol (1 .0 eq.) in THF (2 ml_) over molecular sieves at 0 °C was added DIAD (1 .5 eq.) dropwise. The mixture was left to stir for 1 h, before quenching with saturated aqueous NaHC03, warming to room temperature, extracting into DCM (2 x 10 ml_). Organic fractions were combined, dried over a phase separator and concentrated to dryness. The crude was loaded onto an SCX-2 cartridge, washed with MeOH, eluted with 7M NH3 in MeOH and
concentrated to dryness. Crude material was purified by preparative chromatography according to method 1 , 2 or 3 or silica (SiliaSep with the reported elution system for each compound).
Compound Name Yield (%) Synthesis method /
1H NMR and LCMS analytical data
purification method
4-(3-pyridylmethoxy)-4H-imidazo[1 ,5-
10% a]indole
1H NMR (CD3OD, 400 MHz) δ: 8.52-8.48 (m,
1 H), 8.47-8.42 (m, 1 H), 8.24 (s, 1 H), 7.83 (d,
J 7.6 Hz, 1 H), 7.68-7.60 (m, 2H), 7.49 (t, J C1 a / silica 7.4 Hz, 1 H), 7.42-7.36 (m, 1 H), 7.35-7.29 0-25% (m, 1 H), 7.20 (s, 1 H), 5.88 (s, 1 H), 4.70-4.63 methanol in
N (m, 2H). LCMS purity >90%, [M+H]+ = 264.1 , ethyl acetate
0.77 min (analytical short), 0.62 min
(analytical long)
4-phenoxy-4H-imidazo[1 ,5-a]indole 6%
Ή NMR (CD3OD, 400 MHz) δ: 8.24 (s, 1 H),
7.66 (t, J 6.8 Hz, 2H), 7.53 (t, J 7.6 Hz, 1 H),
7.41 -7.32 (m, 3H), 7.16-7.1 1 (m, 2H), 7.06
(t, J 7.3 Hz, 1 H), 6.98 (s, 1 H), 6.46 (s, 1 H). C1 b / 2 LCMS purity 100%, [M+H]+ = 249.1 , 1 .35
min (analytical short), 2.78 min (analytical
long)
4-(3-pyridyloxy)-4H-imidazo[1 ,5-a]indole 6%
Ή NMR (CD3OD, 400 MHz) δ: 8.38 (d, J 3.3
Hz, 1 H), 8.28-8.24 (m, 2H), 7.70-7.67 (m,
C1 b / silica 3H), 7.56 (td, J 7.7, 3.9 Hz, 1 H), 7.50-7.46
0-20% (m, 1 H), 7.37 (td, J 7.6, 0.9 Hz, 1 H), 7.04 (s,
methanol in 1 H), 6.58 (s, 1 H). LCMS purity 100%,
ethyl acetate [M+H]+ = 250, 0.92 min (analytical short),
1 .56 min (analytical long)
4-(2-pyridylmethoxy)-4H-imidazo[1 ,5-
17% a]indole
Ή NMR (CD3OD, 400 MHz) δ: 8.49-8.44 (m,
1 H), 8.22 (s, 1 H), 7.84 (td, J 8.0, 2.0 Hz,
C1 a / silica 1 H), 7.69-7.60 (m, 2H), 7.57-7.45 (m, 2H),
0-25% 7.38-7.30 (m, 2H), 7.17 (s, 1 H), 5.91 (s, 1 H),
methanol in
N 4.72-4.65 (m, 2H). LCMS purity >95%,
ethyl acetate [M+H]+ = 264.0, 0.90 min (analytical short),
1 .57 min (analytical long)
2-(4H-imidazo[1 ,5-a]indol-4-
8% yloxy)benzonitrile
H NMR (DMSO-d6, 400 MHz) δ: 8.40 (s,
1 H), 7.79-7.85 (m, 3H), 7.65-7.70 (m, 2H), C1 b / silica 7.57-7.61 (m, 1 H), 7.34-7.38 (m, 1 H), 7.21 - 0-10%
7.25 (m, 1 H), 7.06 (s, 1 H), 6.75 (S, 1 H). methanol in LCMS purity > 95%, [M+H]+ = 274, 1 .20 min DCM (analytical short), 2.64 min (analytical long)
3-(4H-imidazo[1 ,5-a]indol-4-
7% yloxy)benzonitrile
Figure imgf000051_0001
Figure imgf000052_0001
[00183] Procedure F: Preparation of O-linked, /V-linked and S-linked imidazo[1 ,5-a]indole and related tricyclic compounds via Grignard addition to a carbaldehyde
[00184] O-linked, /V-linked and S-linked imidazo[1 ,5-a]indole compounds and related tricyclic analogues can be synthesised via strategies described in but not restricted to Scheme 7.
[00185]
Figure imgf000053_0001
[00186] Scheme 7
[00187] An alternative synthesis of O-linked, /V-linked, S-linked and C-linked imidazo[1 ,5-a]indole analogues can be initiated by the condensation of an halogenoaryl carbaldehyde with 4- iodoimidazoles (preferably protected on either of the Nitrogen atoms) in presence of a Grignard reagent (e.g. isopropylmagnesium chloride). The alcohol functionality of the resulting 1 -imidazobenylalcohol analogues can be alkylated (e.g. using NaH and an alkylating agent) into corresponding ethers. Alternatively, Displacement of the alcohol functionality with an amine or a thiol (using conditions including Mitsunobu reaction or formation of a mesylate followed by displacement with nucleophile) can lead to the corresponding amine on thioethers. The amine reagent can optionally be substituted with RF. Deprotection of the imidazole Nitrogen (e.g. acetic acid for a trityl protecting group) and subsequent Copper(l) iodide mediated ring closure can lead to O-linked, /V-linked, S-linked and C-linked imidazo[1 ,5-a]indole analogues. Protecting groups can optionally be used at any stage during this procedure to facilitate chemical synthesis.
[00188] Example F.1 : Preparation of 4-(4H-imidazo[1 ,5-a]indol-4-yloxymethyl)benzoic acid
[00189] (2-Bromophenyl)-(1-tritylimidazol-4-yl)methanol
Figure imgf000053_0002
[00190] To a suspension of 1 -[cyclohexa-1 ,3,4,5-tetraen-1 -yl(diphenyl)methyl]-4-iodo-imidazole (12.4 g, 28.5 mmol) in THF (100 ml_) at 0 °C was slowly added ethylmagnesium bromide (1 1 .0 ml_, 31 .4 mmol). The resulting solution was left to stir for 30 minutes. 2- Bromobenzaldehyde (5.42 ml_, 34.3 mmol) was added drop wise and the reaction mixture was left to stir at 0°C. The reaction was quenched with water and partitioned using additional EtOAc. The organic layer was washed with brine, dried over Na2S04 and filtered. The solution was concentrated to dryness resulting in a colourless solid. Diethyl ether (50 mL) was charged to the vessel and stirred for 20 minutes. The solid was filtered and washed with diethyl ether (10 mL). The white solid was subsequently suspended and stirred in THF (40 mL) for 1 hour, before filtering and washing with THF (20 mL). The resulting solid was characterised as (2-bromophenyl)-(1 -tritylimidazol-4-yl)methanol (8.02 g,16.2 mmol, 56.7% yield). H NMR (CDCb, 400 MHz) δ: 7.77-7.72 (m, 1 H), 7.52-7.47 (m, 1 H), 7.43 (s, 1 H), 7.38-7.27 (m, 10H), 7.17-7.09 (m, 7H), 6.57 (s, 1 H), 6.1 1 (s, 1 H), 4.1 1 (s, 1 H). LCMS purity > 90%, [M+H]+ = 495 and 497, 1 .69 min (analytical short).
[00191] Methyl 4-[[(2-bromophenyl)-(1-tritylimidazol-4-yl)methoxy]methyl]benzoate
Figure imgf000054_0001
[00192] To a solution of (2-bromophenyl)-(1 -tritylimidazol-4-yl)methanol (300 mg, 0.610
mmol) and methyl-4-(bromomethyl)benzoate (146 mg, 0.640 mmol) in anhydrous THF (10mL) under nitrogen was added sodium hydride (60.6 mg, 1 .51 mmol). The reaction mixture was stirred for 1 hour. 1 M citric acid was added and the mixture was extracted with
EtOAc (x3). The combined organic layers were washed with water, brine, dried with Na2S04, filtered and concentrated under reduced pressure. The crude was purified with a 0-100% ethyl acetate in heptane gradient. Fraction containing the desired product were combined and concentrated under reduced pressure to yield a colourless solid
characterised as methyl 4-[[(2-bromophenyl)-(1 -tritylimidazol-4-yl)methoxy]methyl]benzoate
(195.7mg, 0.3041 mmol, 50.212% yield). H NMR (MeOD, 400 MHz) δ:7.98 (d, J 8.4 Hz, 2H), 7.71 (dd, J 8.0, 1 .8 Hz, 1 H), 7.57 (d, J 0.8 Hz, 1 H), 7.45-7.35 (m, 13H), 7.21 (t, J 7.6 Hz, 1 H), 7.06-7.02 (m, 6H), 6.63 (s, 1 H), 5.81 (s, 1 H), 4.65 (s, 2H), 3.92 (s, 3H). LCMS purity > 95%, [M+H]+ = 644, 2.15 min (analytical short).
[00193] Methyl 4-[[(2-bromophenyl)-(1H-imidazol-4-yl)methoxy]methyl]benzoate
Figure imgf000054_0002
[00194] To a solution of methyl 4-[[(2-bromophenyl)-(1 -tritylimidazol-4-yl)methoxy]methyl]benzoate (196 mg, 0.300 mmol) in methanol (18 mL) was added acetic acid (2mL). The mixture was heated to 80°C overnight, then cooled to room temperature. It was diluted with EtOAc (30 mL), and saturated aqueous NaHCC (40 mL) was added. The aqueous layer was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (40 mL), dried over Na2S04, filtered and concentrated in vacuo. This material was taken through a 5 g SCX cartridge (eluting with 1 N NH3) to yield a clear oil characterised as methyl 4-[[(2-bromophenyl)-(1 H-imidazol-4-yl)methoxy]methyl]benzoate
(103.3mg,0.2574mmol, 85% yield). H NMR (MeOD, 400 MHz) δ: 8.00 (d, J 8.4 Hz, 2H), 7.77 (dd, J 8.0, 1 .8 Hz, 1 H), 7.67 (d, J 0.8 Hz, 1 H), 7.59 (dd, J 8.0 and 1 .2 Hz, 1 H), 7.50 (d, J 8.4 Hz, 2H), 7.44 (t, J 7.6 Hz, 1 H), 7.25 (t, J 7.6 Hz, 1 H), 6.80 (s, 1 H), 5.94 (s, 1 H), 4.65 (s, 2H), 3.91 (s, 3H). LCMS purity > 90%, [M+H]+ = 402, 1 .28 min (analytical short).
[00195] Methyl 4-(4H-imidazo[ 1, 5-a]indol-4-yloxymethyl)benzoate
Figure imgf000055_0001
[00196] A microwave vial was charged with hexamethylenetriamine (18 mg, 0.13 mmol),
potassium carbonate (71 mg, 0.51 mmol) and Copper(l) iodide (25 mg, 0.13 mmol), and degassed with nitrogen. A solution of methyl 4-[[(2-bromophenyl)-(1 H-imidazol-4- yl)methoxy]methyl]benzoate (103 mg, 0.260 mmol) in DMF (4 mL) was added to the vessel and the solvent was degassed with nitrogen. The resulting solution was submitted to microwave irradiations at 130°C for 30 minutes. The reaction mixture was diluted with a saturated solution of NaHCC , and the aqueous layer was extracted with DCM (3 x). The combined organic layers were washed with brine and dried over a phase separator. The crude was purified by normal phase silica with a 0-5% methanol in DCM gradient, followed with reverse phase column chromatography with a 10-50% MeCN in H2O gradient.
Fractions containing the desired product were combined and concentrated under reduced pressure to yield an off white solid characterised as methyl 4-(4H-imidazo[1 ,5-a]indol-4- yloxymethyhbenzoate (36 mg,0.1 1 mmol, 44% yield). H NMR (MeOD, 400 MHz) δ: 8.30 (bs, 1 H), 8.01 (d, J 8.4 Hz, 2H), 7.67 (t, J 7.2 Hz, 2H), 7.48-7.54 (m, 3H), 7.33-7.38 (m, 1 H), 7.23 (bs, 1 H), 5.88 (s, 1 H), 4.71 (d, J 2.04, 2H), 3.92 (s, 3H). LCMS purity >99%, [M+H]+ = 321 , 1 .23 min (analytical short), 2.79 min (analytical long).
[00197] 4-(4H-lmidazo[1,5-a]indol-4-yloxymethyl)benzoic acid
Figure imgf000055_0002
[00198] A solution of sodium hydroxide (9.7 mg, 0.240 mmol) in water (1 mL) was added to a stirred solution of methyl 4-(4H-imidazo[1 ,5-a]indol-4-yloxymethyl)benzoate (26 mg, 0.080 mmol) in methanol (2 mL). The reaction mixture was left to stir at room temperature for 72 hours. 1 M HCI was added to the reaction mixture to bring it to a neutral pH. The aqueous mixture was extracted with n-butanol, and the combined organics were dried with Na2S04, filtered and concentrated to dryness to yield a beige powder characterised as 4-(4H- imidazo[1 ,5-a]indol-4-yloxymethyl)benzoic acid (9.1 mg, 0.030 mmol, 37% yield). H NMR (DMSO, 400 MHz) δ: 12.97 (bs, 1 H), 9.47 (bs, 1 H), 7.88-7.97 (m, 4H), 7.80 (d, J 7.5 Hz, 1 H), 7.63-7.68 (m, 1 H), 7.48-7.53 (m, 3H), 6.05 (bs, 1 H), 4.80 (q, J 17.8, 12.5 Hz,
2H). LCMS purity 100% [M+H]+ = 307, 1 .05 min (analytical short), 2.31 min (analytical long).
[00199] Example F.2: Preparation of A/-phenyl-4H-imidazo[1 ,5-a]indol-4-amine
Figure imgf000056_0001
[00200] 2-(Bromophenyl)-(1 -tritylimidazol-4-yl)methanol (400 mg, 0.810 mmol) (synthesised
according to example F.1) was dissolved in DCM (10 ml_). Molecular sieves were added followed by triethylamine (0.08 ml_, 0.6 mmol). Methanesulfonyl chloride (0.07 ml_, 0.9 mmol) was added and the mixture which was left to stir for 10 minutes. Aniline (0.18 ml_, 2.0 mmol) was subsequently added and the mixture was left to stir at room temperature for an hour. The reaction mixture was diluted with saturated NaHCC (15 ml) and DCM (15 ml_). Layers were separated and the aqueous layer was extracted with more DCM (15 ml_). Organics were combined, dried of Na2S04, filtered and concentrated under reduced pressure to give a colourless oil. This was purified on a 12 g normal phase column with a 10-100% ethyl acetate in heptane gradient. Fractions containing the desired product were combined and concentrated under reduced pressure to yield A/-[(2-bromophenyl)-(1 - tritylimidazol-4-yl)methyl]aniline (300 mg, 0.526 mmol, 65% yield). LCMS purity = 89%
[M+H]+ = 570 and 572, 2.1 1 min (analytical short).
[00201 ] N-[(2-bromophenyl)-(1H-imidazol-4-yl)methyl]aniline
Figure imgf000056_0002
[00202] /V-[(2-bromophenyl)-(1 -tritylimidazol-4-yl)methyl]aniline (300 mg, 0.530 mmol) was
dissolved in acetic acid (1 mL) and methanol (10 mL), and the resulting mixture was stirred at 80 °C under reflux for 18 hours. The mixture was concentrated under reduced pressure and purified on a 12 g normal phase column with a 0-20% methanol (0.1 % NH3) in ethyl acetate gradient. Fractions containing the desired product were combined and concentrated under reduced pressure to yield A/-[(2-bromophenyl)-(1 H-imidazol-4-yl)methyl]aniline (1 15 mg,0.350 mmol, 67% yield). LCMS purity > 95% [M+H]+ = 328, 330, 1 .28 min (analytical short). [00203] N-phenyl-4H-imidazo[ 1 ,5-a]indol-4-amine
Figure imgf000057_0001
[00204] A microwave vial was charged with potassium carbonate (73 mg, 0.53 mmol),
hexamethylenetetramine (20 mg, 0.14 mmol), copper(l) iodide (13 mg, 0.070 mmol), and N- [(2-bromophenyl)-(1 H-imidazol-4-yl)methyl]aniline (1 15 mg, 0.350 mmol). The vial was capped before degassing with nitrogen for 10 minutes. Anhydrous DMF (4 ml_) was added to the vial which was flushed with nitrogen and submitted to microwave irradiations at 130 °C for 30 minutes. The reaction mixture was subsequently partitioned between DCM (10 ml_) and sat. NaHC03 (10 ml_). The water layer was then extracted with 2 x DCM (10 ml_). The organic layers were combined, dried over Na2S04, filtered and concentrated under reduced pressure. The resulting solution was purified on a 12 g normal phase column with a 0%-30% methanol in ethyl acetate (0.02N NH3) gradient. Fractions containing the desired product were combined and concentrated under reduced pressure to give a grey black oily film. This was purified on a 12 g C18 column with a 5-50% acetonitrile in water eluent. Fractions containing the desired product were combined and taken through SCX to yield N- phenyl-4H-imidazo[1 ,5-a]indol-4-amine (30 mg, 0.12 mmol, 35% yield). H NMR (CDCI3, 400 MHz) δ: 9.21 (s, 1 H), 7.88 (d, J 8.0 Hz, 1 H), 7.65 (d, J 7.6 Hz, 1 H), 7.50 (t, J 7.6 Hz, 1 H), 7.25-7.39 (m, 2H), 7.1 1 (s, 1 H), 6.81 -6.93 (m, 3H), 5.87 (s, 1 H). LCMS purity 96% [M+H]+ = 248, 1 .16 min (analytical short).
[00205] According to this procedure was also prepared A/-benzyl-4H-imidazo[1 ,5-a]indol-4-amine.
H NMR (CD3OD, 400 MHz): 8.22 (s, 1 H), 7.70 (d, J 7.6 Hz, 1 H), 7.63 (d, J 7.6 Hz, 1 H), 7.46 (t, J 7.4 Hz, 1 H), 7.23-7.36 (m, 6H), 7.09 (s, 1 H), 5.15 (s, 1 H), 3.74 (s, 2H). LCMS purity 92%, [M+H]+ = 262.0, 0.92 min (analytical short), 1 .77 min (analytical long).
Procedure G: Separation of stereoisomeric mixtures using SCF chromatography
Example G.1 : Separation of the 4 stereoisomers of 1 -cyclohexyl-2-(4H-imidazo[1 ,5-a]indol-4- yhethanol into stereoisomers A, B, C and D (Scheme 8):
Figure imgf000058_0001
Scheme 8
[00206] 104 mg of the mixture of 4 stereoisomers of 1 -cyclohexyl-2-(4H-imidazo[1 ,5-a]indol-4- yhethanol was purified by Semi Critical Fluid (SFC) purification using a ChiralPak AD-H column with a 35% ethanol (0.05% diethylamine) in CO2 mobile phase at 70 mL/minutes.
Stereoisomer A, B, C and D were isolated in 19% yield (19.0 mg, rt = 3.1 min, 100% d.e.), 13% yield (13.0 mg, rt = 3.4 min, 97.7% d.e.), 22% yield (22.0 mg, rt = 4.1 min, 97.8% d.e.) and 1 1 % yield (1 1 .0 mg, rt = 5.3 min, 99.4% d.e.) respectively.
Stereoisomer A: H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1 H), 7.69 (d, J 8.0 Hz, 1 H), 7.58 (d, J 7.6 Hz, 1 H), 7.39 (t, J 7.6 Hz, 1 H), 7.23 (t, J 7.0 Hz, 1 H), 6.88 (s, 1 H), 4.64 (d, J 6.4 Hz, 1 H), 4.24-4.16 (m, 1 H), 3.62-3.58 (m, 1 H), 1 .85-1 .58 (m, 7H), 1 .38-1 .00 (m, 5H). LCMS purity 91 %, [M+H]+ = 283.3, 1 .41 min (analytical short).
Stereoisomer B: H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1 H), 7.69 (d, J 7.6 Hz, 1 H), 7.52 (d, J 7.6 Hz, 1 H), 7.39 (t, J 7.6 Hz, 1 H), 7.24 (t, J 7.0 Hz, 1 H), 6.92 (s, 1 H), 4.79 (d, J 6.0 Hz, 1 H), 4.28-4.24 (m, 1 H), 3.60-3.52 (m, 1 H), 2.10-2.02 (m, 1 H), 1 .83-1 .55 (m, 6H), 1 .35-0.98 (m, 6H). LCMS purity 91 %, [M+H]+ = 283.3, 1 .41 min (analytical short).
Stereoisomer C: H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1 H), 7.69 (d, J 7.6 Hz, 1 H), 7.58 (d, J 8.0 Hz, 1 H), 7.39 (t, J 7.6 Hz, 1 H), 7.24 (t, J 7.0 Hz, 1 H), 6.88 (s, 1 H), 4.65 (d, J 5.6 Hz, 1 H), 4.24-4.15 (m, 1 H), 3.62-3.58 (m, 1 H), 1 .83-1 .57 (m, 7H), 1 .35-1 .00 (m, 6H). LCMS purity 91 %, [M+H]+ = 283.3, 1 .41 min (analytical short).
Stereoisomer D: H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1 H), 7.69 (d, J 7.6 Hz, 1 H), 7.52 (d, J 7.6 Hz, 1 H), 7.39 (t, J 7.6 Hz, 1 H), 7.24 (t, J 7.0 Hz, 1 H), 6.92 (s, 1 H), 4.79 (d, J 6.0 Hz, 1 H), 4.28-4.24 (m, 1 H), 3.60-3.52 (m, 1 H), 2.10-2.02 (m, 1 H), 1 .83-1 .55 (m, 6H), 1 .35-0.98 (m, 6H). LCMS purity 91 %, [M+H]+ = 283.3, 1 .41 min (analytical short).
Biology
[00207] Biological example 1 : Human Indoleamine 2,3-Dioxygenase (IDOI) enzyme activity (biochemical) assay [00208] The IC50 values were determined by measuring the enzymatic activity of ID01 upon treatment with each compound. The assay involves the conversion of tryptophan to N- formylkynurenine (NFK) by recombinant human ID01 enzyme (rhIDOl) and the formation of an /V-formylkynurenine-derived fluorophore (NFKPIP) by reaction with piperidine. The fluorescence intensity of the NFKPIP formed is directly related to the enzyme activity and can be measured at an excitation wavelength of 400 nm and an emission wavelength of 500 nm.
[00209] Compounds at a concentration of 20 mM are serially diluted in 100% dimethyl sulfoxide (DMSO) nine times in 96-well plates for a total of 10 dilution points. Each dilution and a DMSO control are further diluted 1 :25 in assay medium containing 50 mM potassium phosphate buffer (pH 6.5), 6.25 μΜ methylene blue, 6.25 mM ascorbic acid (freshly prepared, neutralised with an equimolar amount of NaOH), 62.5 μg/mL catalase (freshly prepared), 0.1 % Tween-20 and 0.01 % bovine serum albumin (BSA).
[00210] To each well of a 384-well CellCarrier plate (Perkin Elmer #6007550) 10 μΙ_ of the above described assay buffer containing rhIDOl (R&D Systems 6030-AO, 15 nM final concentration) and 5 μΙ_ of diluted compounds (100 μΜ starting concentration, 0.5% DMSO) are added. Compounds are pre-incubated with the enzyme for 30 min at room temperature. The reaction is then started by addition of 5 μΙ_ of 4 X the desired tryptophan concentration diluted in assay medium, providing 35 μΜ final substrate concentration, and incubated for 90 min at room temperature. The reaction is stopped by addition of 5 μΙ_ 1 M piperidine to the 20 μΙ_ enzymatic reaction volume, providing 200 mM final concentration and the plates are covered with seals and incubated at 65 °C in an oven sand bath for 25 min. The plates are incubated for 1 h at room temperature and the fluorescence intensity at 535 nm in each well is read using an EnVision plate reader (Perkin Elmer equipped with a 400/25 nm excitation filter and a 535/25 nm emission filter).
[0021 1] In order to test autofluorescence of compounds, 15 μΙ_ of assay buffer is added to each well of a 384-well CellCarrier plate and 5 μΙ_ of diluted compounds (100 μΜ starting concentration, 0.5% DMSO final concentration) are added in duplicate. This plate is then incubated alongside the assay plate. 5 μΙ_ 1 M piperidine is added to each well, providing 200 mM final concentration and the plates are covered with seals and incubated at 65 °C in an oven sand bath for 25 min. The plates are incubated for 1 h at room temperature and the fluorescence intensity at 535 nm in each well is read using an EnVision plate reader (Perkin Elmer equipped with a 400/25 nm excitation filter and a 535/25 nm emission filter).
[00212] All data are analysed using the GraphPad Prism software package. Inhibition of rhIDOl enzymatic activity is assessed by determination of IC50 value, which is defined as the concentration of compound which decreased the fluorescent signal by 50%. Data are expressed as % inhibition using the DMSO control as 0% inhibition.
[00213] Biological example 2: Human Indoleamine 2,3-Dioxygenase (ID01) enzyme activity values [00214] The results of the biochemical hlDOI assay for certain compounds of the invention are given in the table below. The table shows the biochemical hlDOI inhibition activity of each compound based on the IC50 value of the compound as "+", "", "++" and "+++". The category "+" refers to compounds with an IC50 of > 100 μΜ. The category "++" refers to compounds with an IC50 of 1 to 100 μΜ. The category "+++" refers to compounds with an
Compound category
4-(4H-imidazo[1 ,5-a]indol-4-yloxymethyl)benzoic acid +
4-(2-methylphenoxy)-4H-imidazo[1 ,5-a]indole ++
N-phenyl-4H-imidazo[1 ,5-a]indol-4-amine ++
methyl 4-(4H-imidazo[1 ,5-a]indol-4-yloxymethyl)benzoate ++
4-(4-methylphenoxy)-4H-imidazo[1 ,5-a]indole ++
N-benzyl-4H-imidazo[1 ,5-a]indol-4-amine ++
4-(4-methoxyphenoxy)-4H-imidazo[1 ,5-a]indole +++
4-(2-methoxyphenoxy)-4H-imidazo[1 ,5-a]indole ++
4-(4-chlorophenoxy)-4H-imidazo[1 ,5-a]indole +++
[3-(4H-imidazo[1 ,5-a]indol-4-yloxy)phenyl]methanol ++
4-(2-chlorophenoxy)-4H-imidazo[1 ,5-a]indole ++
4-(3-chlorophenoxy)-4H-imidazo[1 ,5-a]indole ++
3-(4H-imidazo[1 ,5-a]indol-4-yloxy)benzonitrile +
2-(4H-imidazo[1 ,5-a]indol-4-yloxy)benzonitrile +
4-(3-pyridyloxy)-4H-imidazo[1 ,5-a]indole ++
4-phenoxy-4H-imidazo[1 ,5-a]indole ++
1 -cyclohexyl-2-[4H-imidazo[1 ,5-a]indol-4-yl]ethanol, Stereoisomer D +++
1 -cyclohexyl-2-[4H-imidazo[1 ,5-a]indol-4-yl]ethanol, Stereoisomer C +++
1 -cyclohexyl-2-[4H-imidazo[1 ,5-a]indol-4-yl]ethanol, Stereoisomer B ++
1 -cyclohexyl-2-[4H-imidazo[1 ,5-a]indol-4-yl]ethanol, Stereoisomer A ++
4-(3-pyridylmethoxy)-4H-imidazo[1 ,5-a]indole ++
4-(2-pyridylmethoxy)-4H-imidazo[1 ,5-a]indole +
1 -cyclohexyl-2-(4H-imidazo[1 ,5-a]indol-4-yl)ethanone ++
4H-imidazo[1 ,5-a]indol-4-ol + 3-(hydroxymethyl)-4H-imidazo[1 ,5-a]indol-4-ol +
imidazo[1 ,5-a]indol-4-one ++
[00215] The following table provides values of the hlDOI biochemical activity of a selection of compounds of the invention.
Figure imgf000061_0001
[00216] Biological example 3: Human Tryptophan 2,3-Dioxygenase (TD02) enzyme activity (biochemical) assay
[00217] The IC50 values were determined by measuring the enzymatic activity of TD02 upon treatment with each compound. The assay involves the conversion of tryptophan to N- formylkynurenine (NFK) by recombinant human TD02 enzyme (rhTD02) and the formation of an /V-formylkynurenine-derived fluorophore (NFKPIP) by reaction with piperidine. The fluorescence intensity of the NFKPIP formed is directly related to the enzyme activity and can be measured at an excitation wavelength of 400 nm and an emission wavelength of 500 nm.
[00218] Compounds at a concentration of 20 mM are serially diluted in 100% dimethyl sulfoxide (DMSO) nine times in 96-well plates for a total of 10 dilution points. Each dilution and a DMSO control are further diluted 1 :50 in iced assay buffer containing 100 mM potassium phosphate buffer (pH 7), 400 μΜ ascorbic acid (freshly prepared, neutralised with an equimolar amount of NaOH) and 0.2% Tween-20.
[00219] To each well of a 384-well CellCarrier plate (Perkin Elmer #6007550) 20 μΙ_ of the above described assay buffer containing rhTD02 (NTRC-TDO-10K, 50 nM final concentration) and 10 μΙ_ of diluted compounds (100 μΜ starting concentration, 0.5% DMSO) are added. Compounds are pre-incubated with the enzyme in the dark without a seal for 30 min at room temperature. The reaction is then started by addition of 5 μΙ_ of 4 X the desired tryptophan concentration diluted in assay medium, providing 200 μΜ final substrate concentration and incubated for 40 min in the dark without a seal at room temperature. The reaction is stopped by addition of 5 μΙ_ 1 M piperidine to the 40 μΙ_ enzymatic reaction volume, providing 1 1 1 .1 mM final concentration and the plates are covered with seals and incubated at 65 °C in an oven sand bath for 25 min. The plates are incubated for 1 h at room temperature and the fluorescence intensity at 535 nm in each well is read using an EnVision plate reader (Perkin Elmer equipped with a 400/25 nm excitation filter and a 535/25 nm emission filter).
[00220] In order to test autofluorescence of compounds, 30 μΙ_ of assay buffer is added to each well of a 384-well CellCarrier plate and 10 μΙ_ of diluted compounds (100 μΜ starting concentration, 0.5% DMSO final concentration) are added in duplicate. This plate is then incubated alongside the assay plate. 5 μΙ_ 1 M piperidine is added to each well, providing 1 1 1 .1 mM final concentration and the plates are covered with seals and incubated at 65 °C in an oven sand bath for 25 min. The plates are incubated for 1 h at room temperature and the fluorescence intensity at 535 nm in each well is read using an EnVision plate reader (Perkin Elmer equipped with a 400/25 nm excitation filter and a 535/25 nm emission filter).
[00221] All data are analysed using the GraphPad Prism software package. Inhibition of rhTD02 enzymatic activity is assessed by determination of IC50 value, which is defined as the concentration of compound which decreased the fluorescent signal by 50%. Data are expressed as % inhibition using the DMSO control as 0% inhibition.
[00222] Biological example 4: Human Tryptophan 2,3-Dioxygenase (hTD02) enzyme activity values
[00223] The results of the biochemical TD02 assay for certain compounds of the invention are given in the Table below. The table shows the biochemical TD02 inhibition activity of each compound based on the IC50 value of the compound as "+", "", "++" and "+++". The category "+" refers to compounds with an IC50 of > 10 μΜ. The category "++" refers to compounds with an IC50 of 1 to 10 μΜ. The category "+++" refers to compounds with an IC50 < 1 μΜ. All compounds are stereoisomeric mixtures unless otherwise stated.
Compound name IC50 category
4-(4H-imidazo[1 ,5-a]indol-4-yloxymethyl)benzoic acid +++
4-(2-methylphenoxy)-4H-imidazo[1 ,5-a]indole +++
N-phenyl-4H-imidazo[1 ,5-a]indol-4-amine +++
methyl 4-(4H-imidazo[1 ,5-a]indol-4-yloxymethyl)benzoate +++
4-(4-methylphenoxy)-4H-imidazo[1 ,5-a]indole +++
4-(2-methoxyphenoxy)-4H-imidazo[1 ,5-a]indole +++
4-(4-chlorophenoxy)-4H-imidazo[1 ,5-a]indole +++
4-(2-chlorophenoxy)-4H-imidazo[1 ,5-a]indole +++
2-(4H-imidazo[1 ,5-a]indol-4-yloxy)benzonitrile +++ 4-(3-pyridyloxy)-4H-imidazo[1 ,5-a]indole +++
4H-imidazo[1 ,5-a]indol-4-ol +
imidazo[1 ,5-a]indol-4-one +
[00224] The following table provides values of the hTD02 biochemical activity of a selection of compounds of the invention.
Figure imgf000063_0001
[00225] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of them mean "including but not limited to", and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.
[00226] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.
[00227] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

Claims

A compound of formula (I):
Figure imgf000064_0001
wherein
'A' is a 5 or 6 membered aryl or heteroaryl group, unsubstituted or substituted with 1 , 2 or 3 groups (where chemically possible) selected from: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA, -NRARB, -SRA, - C(0)RA, -OC(0)Rc, -C(0)ORA, -NRAC(0)Rc, -C(0)NRARB, -NRAS02Rc, -S02NRARB, -N02, -CN and Ci-4 alkyl substituted with -ORA;
X is a bond or -(CRA RB )n-;
Y is selected from: a bond, -0-, -NRF-, -S-, -C(O)-, -C(NRF)-, -C(ORF)Rc-, -C(NRFRG)RC-, -C(0)NRF- , -NRFC(0)-, -NRFC(0)NRG-, -NRFS02NRG-, -SO2-, -S02NRF-, -NRFS02- , -OC(O)- and -C(0)0-;
Z is a bond;
wherein n is selected from 1 , 2, 3 and 4;
R is H or a 3 to 16 membered fully saturated, partially unsaturated or aromatic mono-, di- or tri-cyclic moiety, which optionally may include 1 , 2 or 3 heteroatoms (where chemically possible) selected from O, N and S, and which is unsubstituted or substituted with 1 to 5 substituents (where chemically possible) selected from halo, Ci-4 alkyl, Ci-4 haloalkyl, C3-6 cycloalkyl, -ORA3, -NRA3RB3, -SRA3, - C(0)RA3, -OC(0)RA3, -C(0)ORA3, -NRA3C(0)RB3, -C(0)NRA3RB3, -NRA3S02RB3, -S02NRA3RB3, - S02RA3, =0, -NO2, -CN , C1-4 alkyl substituted with ORA3, C1-4 alkyl substituted with -NRA3RB3 and C3- 6 cycloalkyl substituted with ORA3;
R2 is selected from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -ORM and C1-4 alkyl substituted with -ORM;
R3 and R4 are each independently selected from: H, halo, C1-4 alkyl, C1 -4 haloalkyl, C3-6 cycloalkyl, - ORA5, -NRA5RB4, -CN , -SRA5 and C1-4 alkyl substituted with ORA5;
RA, RB, Rc RA , RB , RA3, RB3, RM, RA5 and RB4 are at each occurrence independently selected from: H, C1-4 alkyl and C1-4 haloalkyl; and
RF and RG are each independently selected from: H, C1-4 alkyl and C1-4 haloalkyl, C3-8 cycloalkyl, C3- 8 heterocycloalkyl, C3-8 cycloalkylene, C3-8 heterocycloalkylene, Ce-io aryl and C5-10 heteroaryl.
2. The compound of claim 1 , wherein the compound is a compound of formula (I) provided that X-Y-Z taken together is not methylene when R is substituted or unsubstituted: pyridyl and pyrimidine.
3. The compound of claim 1 or claim 2, wherein A is a ring selected from substituted or unsubstituted: phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl and pyrrolyl.
4. In an embodiment, the compound of formula (I) is a compound according to formula (lla) to
Figure imgf000065_0001
(lla) (lib) (lie)
Figure imgf000065_0002
(lid) (Me) (llf)
Figure imgf000065_0003
(llg) (llh)
Figure imgf000065_0004
(IN) (llj)
wherein
q is selected from 0, 1 , 2 or 3,
p is selected from 0, 1 or 2, and
R5 is selected from: H, halo, Ci-4 alkyl, Ci- haloalkyl, -ORA, -NRARB, -SRA, -C(0)RA, -OC(0)Rc, -
C(0)ORA, -NRAC(0)Rc, -C(0)NRARB, -NRAS02Rc, -S02NRARB, -N02, -CN and Ci-4 alkyl substituted with -ORA; wherein RA, RB and Rc are each independently selected from: H, C1-4 alkyl and C1-4 haloalkyl.
5. The compound of any preceding claim, wherein Z is a bond, X is a bond and -, Y is selected from: -0-, -NRF-, -S-, -C(O)-, -C(NRF)-, -C(ORF)Rc-, -C(NRFRG)RC-, -C(0)NRF-, -NRFC(0)-, - NRFC(0)NRG-, -NRFS02NRG-, -SO2-, -S02NRF-, -NRFS02- , -OC(O)-, and -C(0)0-.
6. The compound of any of claims 1 to 4, wherein X is -(CRA RB )n-, Z is a bond and -, Y is selected from: -0-, -NRF-, -S-, -C(O)-, -C NRF)-, -C(ORF)Rc-, -C(NRFRG)RC-, -C(0)NRF-, -NRFC(0)-, -NRFC(0)NRG-, -NRFS02NRG-, -SO2-, -S02NRF-, -NRFS02- , -OC(O)-, and -C(0)0-.
7. The compound of any of claims 1 to 4, wherein:
X is a bond, Y is -O- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -O- and Z is a bond;
X is a bond, Y is -NRF- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -NRF- and Z is a bond;
X is a bond, Y is -S- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -S- and Z is a bond;
X is a bond, Y is -C(O)- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -C(O)- and Z is a bond;
X is a bond, Y is -C(NRF)- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -C(NRF)- and Z is a bond;
X is a bond, Y is -CCOR^H- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -CCOR^H- and Z is a bond;
X is a bond, Y is -C(NRFRG)H- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -C(NRFRG)H- and Z is a bond;
X is a bond, Y is -C(0)NRF- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -C(0)NRF- and Z is a bond;
X is a bond, Y is -NRFC(0)- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -NRFC(0)- and Z is a bond;
X is a bond, Y is -NRFC(0)NRG- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is - NRFC(0)NRG- and Z is a bond;
X is a bond, Y is -NRFS02NRG- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is - NRFS02NRG- and Z is a bond;
X is a bond, Y is -S02- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -S02- and Z is a bond;
X is a bond, Y is -S02NRF- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -S02NRF- and Z is a bond;
X is a bond, Y is -NRFS02- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -NRFS02- and Z is a bond; X is a bond, Y is -OC(O)- and Z is a bond; X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -OC(O)- and Z is a bond;
X is a bond, Y is -C(0)0- and Z is a bond; and X is -CH2-, -(CH2)2- or -C(Me)H-, Y is -C(0)0- and Z is a bond.
8. The compound of any of claims 1 to 4, wherein: X is -CH2-, Y is -O- and Z is a bond; and X is a bond, Y is -O- and Z is a bond.
9. The compound of any preceding claim, wherein R is a 5 to 10 membered fully saturated, partially unsaturated or aromatic mono- or di-cyclic moiety, which optionally may include 1 , 2 or 3 heteroatoms (where chemically possible) selected from O, N and S, and which is unsubstituted or substituted with 1 to 5 substituents
10. The compound of any preceding claim, wherein R is selected from substituted or unsubstituted: phenyl, pyridyl, cyclohexyl, isoquinolinyl, quinolinyl, piperidinyl, morpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, piperazinyl, oxadiazolyl, tetrahydropyridine, dihydropyran, dihydrofuran and pyrroline.
11 . The compound of any preceding claim, wherein R2 is H.
12. The compound of any preceding claim, wherein R3 and R4 are each independently selected from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -CN and -ORA5.
13. The compound of claim 1 , wherein the compound of formula (I) is a compound selected from:
Figure imgf000067_0001
Figure imgf000067_0002
66
Figure imgf000068_0001
Figure imgf000068_0002
67
Figure imgf000069_0001
Figure imgf000070_0001
14. The compound of any preceding claim, wherein the compound of the present invention is for use as a medicament.
15. A compound of any of claims 1 to 13 for use in the treatment of a condition which is modulated by indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TD02).
16. The compound of claim 15, wherein the condition modulated by IDO and/or TD02 is a condition that is treatable by the inhibition of IDO and/or TD02.
17. The compound of claim 16, wherein the condition treatable by the inhibition of IDO and/or TD02 may be selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, neuro-degenerative disorders, inflammation, autoimmune diseases and immunological diseases.
18. A compound of any of claims 1 to 13, wherein the compound is for use in treating a condition treatable by the inhibition of the degradation of tryptophan and preventing the production of N- formylkynurenine.
19. A compound of any of claims 1 to 13 for use in treating IDO and/or TD02 mediated immunosuppression.
20. A compound of any of claims 1 to 13 for use in the treatment of a condition selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, neuro-degenerative disorders, inflammation and immunological diseases.
21 . A method of inhibiting the degradation of tryptophan and preventing the production of N- formylkynurenine in a system comprising cells expressing IDO and/or TD02, wherein the system is exposed to a compound of any of claims 1 to 13.
22. A method of treatment of a condition selected from: cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, central nervous system disorders, neuro-degenerative disorders, inflammation and immunological diseases, wherein the method comprises administering a therapeutic amount of a compound of any of claims 1 to 13 to a patient in need thereof.
23. A use of a compound of any of claims 1 to 13 in the manufacture of a medicament for the treatment of a condition which is modulated by IDO and/or TD02.
24. A pharmaceutical formulation comprising a compound of any of claims 1 to 13 and a pharmaceutically acceptable excipient.
25. The pharmaceutical formulation of claims 24, wherein the pharmaceutical formulation is a combination product comprising an additional pharmaceutically active agent
PCT/GB2015/052868 2014-10-01 2015-10-01 4h-imidazo[1,5-a]indole derivatives and their use as indoleamine 2,3-dioxygenase (ido) and/or tryptophan 2,3-dioxygenase (td02) modulators WO2016051181A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1417369.4 2014-10-01
GBGB1417369.4A GB201417369D0 (en) 2014-10-01 2014-10-01 Compounds

Publications (1)

Publication Number Publication Date
WO2016051181A1 true WO2016051181A1 (en) 2016-04-07

Family

ID=51901467

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2015/052868 WO2016051181A1 (en) 2014-10-01 2015-10-01 4h-imidazo[1,5-a]indole derivatives and their use as indoleamine 2,3-dioxygenase (ido) and/or tryptophan 2,3-dioxygenase (td02) modulators

Country Status (2)

Country Link
GB (1) GB201417369D0 (en)
WO (1) WO2016051181A1 (en)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016165613A1 (en) * 2015-04-12 2016-10-20 Hangzhou Innogate Pharma Co., Ltd. Heterocycles useful as ido and tdo inhibitors
WO2017134555A1 (en) 2016-02-02 2017-08-10 Emcure Pharmaceuticals Limited Derivatives of pyrroloimidazole or analogues thereof which are useful for the treatment of inter alia cancer
WO2018054365A1 (en) 2016-09-24 2018-03-29 Beigene, Ltd. NOVEL 5 or 8-SUBSTITUTED IMIDAZO [1, 5-a] PYRIDINES AS SELECTIVE INHIBITORS OF INDOLEAMINE AND/OR TRYPTOPHANE 2, 3-DIOXYGENASES
WO2018071873A2 (en) 2016-10-13 2018-04-19 Juno Therapeutics, Inc. Immunotherapy methods and compositions involving tryptophan metabolic pathway modulators
WO2018119440A1 (en) 2016-12-22 2018-06-28 Calithera Biosciences, Inc. Compositions and methods for inhibiting arginase activity
US11046682B2 (en) 2016-08-23 2021-06-29 Beijing Innocare Pharma Tech Co., Ltd. Fused heterocyclic derivatives, their preparation methods thereof and medical uses thereof
US11046649B2 (en) 2018-07-17 2021-06-29 Board Of Regents, The University Of Texas System Compounds useful as inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan dioxygenase
US11173145B2 (en) 2017-01-17 2021-11-16 Board Of Regents, The University Of Texas System Compounds useful as inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan dioxygenase
CN113797337A (en) * 2020-06-17 2021-12-17 中国医学科学院基础医学研究所 Application of small molecule inhibitor in preventing and treating respiratory viral pneumonia
CN113816965A (en) * 2021-11-23 2021-12-21 北京鑫开元医药科技有限公司 Compound with IDO (indomethacin diphosphate) inhibitory activity and preparation method thereof
EP4052705A1 (en) 2021-03-05 2022-09-07 Universität Basel Vizerektorat Forschung Compositions for the treatment of ebv associated diseases or conditions
WO2022184930A2 (en) 2021-03-05 2022-09-09 Universität Basel Compositions for the treatment of ebv associated diseases or conditions

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994024131A1 (en) * 1993-04-08 1994-10-27 The Du Pont Merck Pharmaceutical Company Novel polycyclic systems, and derivatives thereof, as neurotransmitter release enhancer useful in the treatment of cognitive disorders
WO2012142237A1 (en) * 2011-04-15 2012-10-18 Newlink Geneticks Corporation Fused imidazole derivatives useful as ido inhibitors
WO2014159248A1 (en) * 2013-03-14 2014-10-02 Newlink Genetics Corporation Tricyclic compounds as inhibitors of immunosuppression mediated by tryptophan metabolization

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994024131A1 (en) * 1993-04-08 1994-10-27 The Du Pont Merck Pharmaceutical Company Novel polycyclic systems, and derivatives thereof, as neurotransmitter release enhancer useful in the treatment of cognitive disorders
WO2012142237A1 (en) * 2011-04-15 2012-10-18 Newlink Geneticks Corporation Fused imidazole derivatives useful as ido inhibitors
WO2014159248A1 (en) * 2013-03-14 2014-10-02 Newlink Genetics Corporation Tricyclic compounds as inhibitors of immunosuppression mediated by tryptophan metabolization

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
C. CARITÉ ET AL: "Réactivé d'iminophosphoranes polyfonctionnalisés", TETRAHEDRON LETTERS, vol. 31, no. 48, 1990, GB, pages 7011 - 7014, XP055226924, ISSN: 0040-4039, DOI: 10.1016/S0040-4039(00)97229-0 *
DATABASE REGISTRY [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 16 November 1984 (1984-11-16), XP002750682, Database accession no. 51058-69-6 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016165613A1 (en) * 2015-04-12 2016-10-20 Hangzhou Innogate Pharma Co., Ltd. Heterocycles useful as ido and tdo inhibitors
US10358451B2 (en) 2015-04-12 2019-07-23 Hangzhou Innogate Pharma Co., Ltd. Heterocycles useful as IDO and TDO inhibitors
WO2017134555A1 (en) 2016-02-02 2017-08-10 Emcure Pharmaceuticals Limited Derivatives of pyrroloimidazole or analogues thereof which are useful for the treatment of inter alia cancer
US11046682B2 (en) 2016-08-23 2021-06-29 Beijing Innocare Pharma Tech Co., Ltd. Fused heterocyclic derivatives, their preparation methods thereof and medical uses thereof
WO2018054365A1 (en) 2016-09-24 2018-03-29 Beigene, Ltd. NOVEL 5 or 8-SUBSTITUTED IMIDAZO [1, 5-a] PYRIDINES AS SELECTIVE INHIBITORS OF INDOLEAMINE AND/OR TRYPTOPHANE 2, 3-DIOXYGENASES
WO2018071873A2 (en) 2016-10-13 2018-04-19 Juno Therapeutics, Inc. Immunotherapy methods and compositions involving tryptophan metabolic pathway modulators
US11896615B2 (en) 2016-10-13 2024-02-13 Juno Therapeutics, Inc. Immunotherapy methods and compositions involving tryptophan metabolic pathway modulators
EP4190335A1 (en) 2016-10-13 2023-06-07 Juno Therapeutics, Inc. Immunotherapy methods and compositions involving tryptophan metabolic pathway modulators
EP3842442A1 (en) 2016-12-22 2021-06-30 Calithera Biosciences, Inc. Compositions and methods for inhibiting arginase activity
WO2018119440A1 (en) 2016-12-22 2018-06-28 Calithera Biosciences, Inc. Compositions and methods for inhibiting arginase activity
US11173145B2 (en) 2017-01-17 2021-11-16 Board Of Regents, The University Of Texas System Compounds useful as inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan dioxygenase
US11046649B2 (en) 2018-07-17 2021-06-29 Board Of Regents, The University Of Texas System Compounds useful as inhibitors of indoleamine 2,3-dioxygenase and/or tryptophan dioxygenase
CN113797337A (en) * 2020-06-17 2021-12-17 中国医学科学院基础医学研究所 Application of small molecule inhibitor in preventing and treating respiratory viral pneumonia
CN113797337B (en) * 2020-06-17 2023-02-07 中国医学科学院基础医学研究所 Application of small-molecule inhibitor in preventing and treating respiratory viral pneumonia
EP4052705A1 (en) 2021-03-05 2022-09-07 Universität Basel Vizerektorat Forschung Compositions for the treatment of ebv associated diseases or conditions
WO2022184930A2 (en) 2021-03-05 2022-09-09 Universität Basel Compositions for the treatment of ebv associated diseases or conditions
CN113816965A (en) * 2021-11-23 2021-12-21 北京鑫开元医药科技有限公司 Compound with IDO (indomethacin diphosphate) inhibitory activity and preparation method thereof

Also Published As

Publication number Publication date
GB201417369D0 (en) 2014-11-12

Similar Documents

Publication Publication Date Title
WO2016051181A1 (en) 4h-imidazo[1,5-a]indole derivatives and their use as indoleamine 2,3-dioxygenase (ido) and/or tryptophan 2,3-dioxygenase (td02) modulators
US11459326B2 (en) N-pyridinyl acetamide derivatives as Wnt signalling pathway inhibitors
US10399989B2 (en) Pyrazolopyrimidine derivatives as BTK inhibitors for the treatment of cancer
US10538524B2 (en) Pyrazolopyrimidine derivatives useful as inhibitors of Bruton&#39;s tyrosine kinase
WO2016059412A1 (en) 6,7-heterocyclic fused 5h-pyrrolo[1,2-c]imidazole derivatives and their use as indoleamine 2,3-dioxygenase (ido) and/or tryptophan 2,3-dioxygenase (td02) modulators
USRE49361E1 (en) Fused bicyclic (hetero)aromatic compounds useful for the treatment of cancers
US20230339910A1 (en) Ras inhibitors and methods of using the same
WO2015140566A1 (en) Pyrazolo-pyrimidines as inhibitors of btk
GB2548542A (en) Compounds
EP3612544B1 (en) Azithromycin derivatives containing a phosphonium ion as anticancer agents
EP3612539A1 (en) Phosphonium-ion tethered tetracycline drugs for treatment of cancer
AU2022329187A1 (en) Phenyl- and pyridopyrazole derivatives as inhibitors of ddr1
AU2022383577A1 (en) Ddr1 and ddr2 inhibitors for the treatement of cancer and fibrotic diseases
WO2019234228A1 (en) Beta-amino-alpha-hydroxyalkylphenyl derivatives and their use for cancer treatment
BR112017006476B1 (en) COMPOUND DERIVED FROM N-PYRIDINYL ACETAMIDE, ITS USE, PHARMACEUTICAL FORMULATION AND PHARMACEUTICAL COMPOSITION

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15782011

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15782011

Country of ref document: EP

Kind code of ref document: A1