WO2016059412A1 - 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 - Google Patents

Abstract

This invention relates to novel compounds of formula (I) wherein 'A' is a 5 or 6 membered heteroaryl group, unsubstituted or substituted with 1, 2 or 3 groups as defined in claim 1; X is a bond or -(CR^A1R^B1)n-; Y is selected from: a bond, -(CR^DR^E)m-, -O-, -NR^F, -S-, -C(O)-, -C(NR^F) -, -C(OR^F)R^c-, -C(NR^FR^G)R^C-, -C(O)NR^F, -NR^FC(O)-, -NR^FC(O)NR^G-, - NR^FSO₂NR^G-, -SO₂-, -SO₂NR^F-, -NR^FSO₂-, -OC(O)- and -C(O)O-; Z is a bond or -(CR^A2R^B2)k-; wherein m, n and k are each independently selected from 1, 2, 3 and 4; R¹ 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 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, C_1-4alkyl, C_1-4 haloalkyl, -OR^A4 and C_1-4alkyl substituted with -OR^A4; and R³ and R⁴ are each independently selected from: H, halo, C_1-4alkyl, C_1-4haloalkyl, C_3-6cycloalkyl, -OR^A4, -NR^A5R^B4, -CN, -SR^AS and C_1-4alkyl substituted with -OR^A5; 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. IDOl, and ID02 and/or TD02 inhibitors).

Description

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

[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 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] ID01 is predominantly expressed in antigen presenting cells such as dendritic cells (DCs) and macrophages. ID01 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 ID01 in DCs can also be controlled through direct cell-cell interactions with regulatory T cells. Physiologically ID01 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):

(I)

wherein

'A' is a 5 or 6 membered heteroaryl group, unsubstituted or substituted with 1 , 2 or 3 groups (where chemically possible) selected from: halo, Ci-₄ alkyl, Ci-₄ haloalkyl, -OR^A, -NR^AR^B, -SR^A, -C(0)R^A, - OC(0)R^c, -C(0)OR^A, -NR^AC(0)R^c, -C(0)NR^AR^B, -NR^AS0₂R^c, -S0₂NR^AR^B, -NO2, -CN and C1-4 alkyl substituted with -OR^A;

X is a bond or -(CR^A R^BV;

Y is selected from: a bond, -(CR^DR^E)_m-, -0-, -NR^F-, -S-, -C(O)-, -CCNR^F)-, -C OR^R - C(NR^FR^G)R^C-, -C(0)NR^F-, -NR^FC(0)-, -NR^FC(0)NR^G-, -NR^FS0₂NR^G-, -SO2-, -S0₂NR^F-, -NR^FS0₂- , -OC(O)- and -C(0)0-;

Z is a bond or -(CR^A2R^B2)_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) independently selected at each occurrence from: halo, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, -OR^A3, -NR^A3R^B3, -SR^A3, -C(0)R^A3, -OC(0)R^A3, -C(0)OR^A3, -NR^A3C(0)R^B3, -C(0)NR^A3R^B3, -NR^A3S0₂R^B3, -S0₂NR^A3R^B3, -S0₂R^A3, =0, -NO2, -CN, C1-4 alkyl substituted with— OR^A3, C1-4 alkyl substituted with -NR^A3R^B3, C₃-_e cycloalkyl substituted with— OR^A3, phenyl substituted with 0, 1 or 2 R^H, benzyl substituted with 0, 1 or 2 R^H, and benzoyl substituted with 0, 1 or 2 R^H;

R² is selected from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -OR^M and C1-4 alkyl substituted with -OR^M;

R³ and R⁴ are each independently selected from: H, halo, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, - OR^A5, -NR^A5R^B4, -CN, -SR^A5 and C1-4 alkyl substituted with— OR^A5;

R^A, R^B, R^c RA1 , RB1 , RA2_{7 RB2 I R}A3₇

RAT _{A ND} RB5 _are independently selected at each occurrence from: H, C1-4 alkyl and C1-4 haloalkyl;

R^D and R^E are each independently selected at each occurrence from: H, =0, (i.e. R^D and R^E together form =0), =S (i.e. R^D and R^E together form =S), -OR^A6, -SR^A6, -NR^A6R^B5, halo, C1-4 alkyl, C1-4 haloalkyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C3-8 cycloalkenyl, C3-8 heterocycloalkenyl, Ce-io aryl and C5-10 heteroaryl;

R^F and R^G are each independently selected from: H, C1-4 alkyl and C1-4 haloalkyl, C3-8 cycloalkyl, C3- 8 heterocycloalkyl, C3-8 cycloalkenyl, C3-8 heterocycloalkenyl, Ce-io aryl and C5-10 heteroaryl; and

R^H is independently selected at each occurrence from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -CN, and -OR^A7.

[0015] The present invention contemplates pharmaceutically acceptable salts of any compound disclosed herein. For example, the invention provides compounds of formula (I) and

pharmaceutically acceptable salts thereof.

[0016] Optionally, 'A' is a 5 membered 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^AR^B, - SR^A, -C(0)R^A, -OC(0)R^c, -C(0)OR^A, -NR^AC(0)R^c, -C(0)NR^AR^B, -NR^AS0₂R^c, -S0₂NR^AR^B, -NO2, - CN and C1-4 alkyl substituted with -OR^A. [0017] Optionally, 'A' is a 6 membered 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^AR^B, - SR^A, -C(0)R^A, -OC(0)R^c, -C(0)OR^A, -NR^AC(0)R^c, -C(0)NR^AR^B, -NR^AS0₂R^c, -S0₂NR^AR^B, -N0₂, - CN and Ci-₄ alkyl substituted with -OR^A.

[0018] In an embodiment, A is a ring selected from substituted or unsubstituted: pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl. In an embodiment, A is a ring selected from substituted or unsubstituted: pyridyl, pyrimidinyl, pyridazinyl and thiophenyl.

[0019] In an embodiment, A is a ring selected from substituted or unsubstituted: pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, preferably selected from substituted or unsubstituted: pyridyl, pyrimidinyl and pyridazinyl.

[0020] In an embodiment, A is a ring selected from substituted or unsubstituted: thiophenyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl, preferably substituted or

unsubstituted thiophenyl.

[0021] In an embodiment A is a ring selected from substituted or unsubstituted: 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: pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl and pyrrolyl and Y is selected from: a bond, -(CR^DR^E)_m-, -0-, -NR^F-, -S-, - C(NR^F)-, -CCOR^R -C(NR^FR^G)R^C-, -SO2-, -S0₂NR^F-, -NR^FS0₂- , -OC(O)-; and -C(0)0-.

[0022] In an embodiment A is a ring selected from substituted or unsubstituted: pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl and pyrrolyl and X is a bond. In an alternative embodiment A is a ring selected from substituted or unsubstituted: pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl and pyrrolyl, X is a bond, and Y is selected from: a bond, -(CR^DR^E)_m-, -0-, -NR^F-, -S-, -C(NR^F)-, -C(OR^F)R^c-, -C(NR^FR^G)R^C-, -S0₂-, -S0₂NR^F-, -NR^FS0₂- , -OC(O)-; and -C(0)0-.

[0023] In an embodiment A is not pyridyl. A may be a ring selected from substituted or unsubstituted: pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl. In an embodiment, A is a ring selected from substituted or unsubstituted: pyrimidinyl, pyridazinyl and thiophenyl.

[0024] In an embodiment, the compound of formula (I) is a compound according to formula (lla) to (llj):

(lid) (lie) (I If)

(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- alkyl, Ci- haloalkyl, -OR^A, -NR^AR^B, -SR^A, -C(0)R^A, -OC(0)R^c, - C(0)OR^A, -NR^AC(0)R^c, -C(0)NR^AR^B, -NR^AS0₂R^c, -S0₂NR^AR^B, -N0₂, -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.

[0025] Additionally, the compound of formula (I) may be a compound according to formula (Ilk):

(Ilk) wherein

p is selected from 0, 1 or 2, and

R⁵ is selected from: H, halo, Ci- alkyl, Ci- haloalkyl, -OR^A, -NR^AR^B, -SR^A, -C(0)R^A, -OC(0)R^c, - C(0)OR^A, -NR^AC(0)R^c, -C(0)NR^AR^B, -NR^AS0₂R^c, -S0₂NR^AR^B, -N0₂, -CN and Ci- 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.

[0026] In an embodiment, A is substituted pyridyl (optionally halo substituted pyridyl), pyridyl or pyrimidinyl. Optionally, A is pyridyl or substituted pyridyl (optionally halo substituted pyridyl). In an embodiment A is substituted pyridyl (optionally halo substituted pyridyl), pyridyl or pyrimidinyl and Z is a bond. In an embodiment A is substituted pyridyl (optionally halo substituted pyridyl), pyridyl or pyrimidinyl and X is a bond. In an embodiment A is substituted pyridyl (optionally halo substituted pyridyl), pyridyl or pyrimidinyl and Y is selected from: a bond, -(CR^DR^E)_m-, -0-, -NR^F-, -S-, -C(NR^F)-, -C(OR^F)R^c-, -C(NR^FR^G)R^C-, -SO2-, -S0₂NR^F-, -NR^FS0₂- , -OC(O)-; and -C(0)0-. In an embodiment A is substituted pyridyl (optionally halo substituted pyridyl), pyridyl or pyrimidinyl, X is a bond and Y is selected from: a bond, -(CR^DR^E)_m-, -0-, -NR^F-, -S-, -C(NR^F)-, -C(OR^F)R^c-, -C(NR^FR^G)R^C-, -S0₂-, - S0₂NR^F-, -NR^FS0₂- , -OC(O)-; and -C(0)0-.

[0027] In an embodiment, A is pyridyl or pyrimidinyl. Optionally, A is pyridyl. In an embodiment A is pyridyl or pyrimidinyl and Z is a bond. In an embodiment A is pyridyl or pyrimidinyl and X is a bond. In an embodiment A is pyridyl or pyrimidinyl and Y is selected from: a bond, -(CR^DR^E)_m-, -0-, -NR^F-, -S-, -C(NR^F)-, -C OR^R -C(NR^FR^G)R^C-, -S0₂-, -S0₂NR^F-, -NR^FS0₂- , -OC(O)-; and - C(0)0-. In an embodiment A is pyridyl or pyrimidinyl, X is a bond and Y is selected from: a bond, - (CR^DR^E)m-, -0-, -NR^F-, -S-, -C(NR^F)-, -C OR^R -C(NR^FR^G)R^C-, -S0₂-, -S0₂NR^F-, -NR^FS0₂- , - OC(O)-; and -C(0)0-.

[0028] In an embodiment, A is substituted pyridyl (optionally halo substituted pyridyl), pyridyl or pyrimidinyl and Z is -(CR^A2R^B2)k-. Optionally, X is a bond. In an embodiment, A is pyridyl or pyrimidinyl. Optionally, A is pyridyl. In an embodiment A is pyridyl or pyrimidinyl and Z is - (CR^A2R^B2)k-. Optionally, X is a bond.

[0029] In an embodiment A is substituted pyridyl (optionally halo substituted pyridyl), pyridyl or pyrimidinyl, Z is -(CR^A2R^B2)_k- and Y is -C OR^R -C(0)NR^F-, or -C(O)-. Optionally, X is a bond. In an embodiment A is pyridyl or pyrimidinyl, Z is -(CR^A2R^B2)_k- and Y is -C(OR^F)R^c-, -C(0)NR^F-, or - C(O)-. Optionally, X is a bond. [0030] In an embodiment A is substituted pyridyl (optionally halo substituted pyridyl), pyridyl or pyrimidinyl, Z is -(CR^A2R^B2)_k- and Y is -C OR^R⁰- or -C(O)-. Optionally, X is a bond. In an embodiment A is pyridyl or pyrimidinyl, Z is -(CR^A2R^B2)k- and Y is -C(OR^F)R^c- or -C(O)-. Optionally, X is a bond.

[0031] In an embodiment, A is unsubstituted. Thus, in an embodiment q and p may be 0.

[0032] In an embodiment A is substituted with 1 , 2 or 3 groups (where chemically possible) selected from: halo, Ci-₄ alkyl, Ci-₄ haloalkyl, -OR^A, -NR^AR^B, -NO2, -CN and Ci-₄ alkyl substituted with -OR^A. In an embodiment R⁵ is selected from: halo, Ci-₄ alkyl, Ci- haloalkyl, -OR^A, -NR^AR^B, - NO2, -CN and Ci-₄ alkyl substituted with -OR^A. In an embodiment, R^A, R^B and R^c are as described above. Alternatively, R^A, R^B and R^c may each be independently selected from: H, methyl, ethyl, isopropyl, tert-butyl and trifluoromethyl.

[0033] 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. trifluromethyl, trifluoroethyl), -OH, -OMe, -OEt, -O-Ci-2-haloalkyl (e.g. trifluoromethoxy, trifluoroethoxy), -NH2, - NHMe, -ΝΜβ2, -NO2, -CN, hydroxyl methyl, hydroxyethyl and hydroxylpropyl. In an embodiment, R⁵ is selected from: chloro, fluoro, methyl, ethyl, iso-propyl, tert-butyl, Ci-2-haloalkyl (e.g. trifluromethyl, trifluoroethyl), -OH, -OMe, -OEt, -O-Ci-2-haloalkyl (e.g. trifluoromethoxy, trifluoroethoxy), -NH2, - NHMe, -ΝΜβ2, -NO2, -CN, hydroxyl methyl, hydroxyethyl and hydroxylpropyl.

[0034] A may be substituted with 1 , 2 or 3 groups (where chemically possible) selected from: chloro, fluoro, and -OMe. R⁵ may be selected from: chloro, fluoro, and -OMe.

[0035] In an embodiment, A is unsubstituted pyridyl, chloropyridyl, fluoropyridyl, methylpyridyl, ethylpyridyl, iso-propylpyridyl, tert-butylpyridyl, trifluoromethylpyridyl, methoxypyridyl,

ethyoxypyridyl, aminopyridyl, /V-methyl-aminopyridyl, Λ/,/V-dimethyl-aminopyridyl, nitropyridyl, cyanopyridyl, unsubstituted pyrimidinyl, chloropyrimidinyl, fluoropyrimidinyl, methylpyrimidinyl, ethylpyrimidinyl, iso-propylpyrimidinyl, tert-butylpyrimidinyl, trifluoromethylpyrimidinyl,

methoxypyrimidinyl, ethyoxypyrimidinyl, aminopyrimidinyl, /V-methyl-aminopyrimidinyl, N,N- dimethyl-aminopyrimidinyl, nitropyrimidinyl, cyanopyrimidinyl, unsubstituted pyridazinyl, chloropyridazinyl, fluoropyridazinyl, methylpyridazinyl, ethylpyridazinyl, iso-propylpyridazinyl, tert- butylpyridazinyl, trifluoromethylpyridazinyl, methoxypyridazinyl, ethyoxypyridazinyl,

aminopyridazinyl, /V-methyl-aminopyridazinyl, /V,/V-dimethyl-aminopyridazinyl, nitropyridazinyl, cyanopyridazinyl, unsubstituted thiophenyl, chlorothiopenyl, fluorothiophenyl, methylthiophenyl, ethylthiophenyl, iso-propylthiophenyl, tert-butylthiophenyl, trifluoromethylthiophenyl,

methoxythiophenyl, ethyoxythiophenyl, aminothiophenyl, /V-methyl-aminothiophenyl, Λ/,/V-dimethyl- aminothiophenyl, nitrothiophenyl or cyanothiophenyl.

[0036] In an embodiment, A is unsubstituted pyridyl, chloropyridyl, fluoropyridyl, methylpyridyl, ethylpyridyl, iso-propylpyridyl, tert-butylpyridyl, trifluoromethylpyridyl, methoxypyridyl,

ethyoxypyridyl, aminopyridyl, /V-methyl-aminopyridyl, Λ/,/V-dimethyl-aminopyridyl, nitropyridyl or cyanopyridyl. [0037] In an embodiment, A is unsubstituted pyrimidinyl, chloropyrimidinyl, fluoropyrimidinyl, methylpyrimidinyl, ethylpyrimidinyl, iso-propylpyrimidinyl, tert-butylpyrimidinyl,

trifluoromethylpyrimidinyl, methoxypyrimidinyl, ethyoxypyrimidinyl, aminopyrimidinyl, N-methyl- aminopyrimidinyl, A/,A/-dimethyl-aminopyrimidinyl, nitropyrimidinyl or cyanopyrimidinyl.

[0038] In an embodiment, A is unsubstituted pyridazinyl, chloropyridazinyl, fluoropyridazinyl, methylpyridazinyl, ethylpyridazinyl, iso-propylpyridazinyl, tert-butylpyridazinyl,

trifluoromethylpyridazinyl, methoxypyridazinyl, ethyoxypyridazinyl, aminopyridazinyl, /V-methyl- aminopyridazinyl, A/,A/-dimethyl-aminopyridazinyl, nitropyridazinyl or cyanopyridazinyl.

[0039] In an embodiment, A is unsubstituted thiophenyl, chlorothiopenyl, fluorothiophenyl, methylthiophenyl, ethylthiophenyl, iso-propylthiophenyl, tert-butylthiophenyl,

trifluoromethylthiophenyl, methoxythiophenyl, ethyoxythiophenyl, aminothiophenyl, /V-methyl- aminothiophenyl, A/,A/-dimethyl-aminothiophenyl, nitrothiophenyl or cyanothiophenyl.

[0040] In an embodiment, A is pyridyl, pyrimidinyl, methoxypyridyl, fluoropyridyl or chloropyridyl. In an embodiment, A is pyridyl, pyrimidinyl, methoxypyridyl, or chloropyridyl.

[0041] In an embodiment q is 0, 1 or 2, preferably, 0 or 1 . In an embodiment p is 0 or 1 .

[0042] 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 -(CR^DR^E)_m- or -(CR^A R^B )_n-, or -(CR^A2R^B2)_k- when R is substituted or unsubstituted: pyridyl and pyrimidine. There are provided compounds of formula (I) with the proviso that Y is not -(CR^DR^E)_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 -(CR^DR^E)_m- or - (CR^A R^B )n-, or -(CR^A2R^B2)_k-.

[0043] Z may be a bond. Z may be -(CR^A2R^B2)_k-. X may be a bond. X may be -(CR^A R^B )_n-. In an embodiment Z is a bond and X is a bond. In an alternative embodiment Z is -(CR^A2R^B2)k- and X is a bond. In a further alternative embodiment X is -(CR^A R^B )_n- and Z is a bond. In an alternative embodiment Z is -(CR^A2R^B2)_k- and X is -(CR^A R^B )_n-. In an embodiment, Z is a bond.

[0044] In an embodiment Z is a bond, X is a bond and -, Y is selected from: -0-, -NR^F-, -S-, -C(O)-, -C(NR^F)-, -CCOR^R -C(NR^FR^G)R^C-, -C(0)NR^F-, -NR^FC(0)-, -NR^FC(0)NR^G-, -NR^FS0₂NR^G-, -S0₂- , -S0₂NR^F-, -NR^FS0₂- , -OC(O)-, and -C(0)0-. In an alternative embodiment Z is -(CR^A2R^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^FR^G)R^C-, - C(0)NR^F-, -NR^FC(0)-, -NR^FC(0)NR^G-, -NR^FS0₂NR^G-, -S0₂-, -S0₂NR^F-, -NR^FS0₂- , -OC(O)-, and - C(0)0-. In a further alternative embodiment X is -(CR^A R^B )_n-, Z is a bond and -, Y is selected from: -0-, -NR^F-, -S-, -C(O)-, -C(NR^F)-, -C(OR^F)R^c-, -C(NR^FR^G)R^C-, -C(0)NR^F-, -NR^FC(0)-, -

NR^FC(0)NR^G-, -NR^FS0₂NR^G-, -S0₂-, -S0₂NR^F-, -NR^FS0₂- , -OC(O)-, and -C(0)0-. In an alternative embodiment Z is -(CR^A2R^B2)_k-, X is -(CR^A R^B )_n- and -, Y is selected from: -0-, -NR^F-, -S-, -C(O)-, - CCNR^P)-, -CCOR^R -C(NR^FR^G)R^C-, -C(0)NR^F-, -NR^FC(0)-, -NR^FC(0)NR^G-, -NR^FS0₂NR^G-, -S0₂-, -S0₂NR^F-, -NR^FS0₂- , -OC(O)-, and -C(0)0-. Optionally, n, m and o are 1 or 2. Optionally, R^D, R^E, _RAi _RBi _RA2 _{a nd R}B2 _{are H or me}thyl. Optionally, n, m and o are 1 or 2 and R^D, R^E, R^A , R^B , R^A2 and R^B2 are H or methyl.

[0045] 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-, -NHS0₂NH-, -NMeS0₂NH-, -NHS0₂NMe-, -NMeS0₂NMe-, -S0₂-, - S0₂NH-, -S0₂NMe-, -NHS0₂- , -NMeS0₂-, -OC(O)- and -C(0)0-.

[0046] 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 -NR^F- and Z is a bond; X is a bond, Y is -NR^F- and Z is -CH₂-, -(CH₂)₂- or - C(Me)H-; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -NR^F- and Z is a bond; X is -CH₂-, -(CH₂)₂- or - C(Me)H-, Y is -NR^F- 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(NR^F)- and Z is a bond; X is a bond, Y is -C(NR^F)- and Z is -CH₂-, -(CH₂)₂- or - C(Me)H-; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -C(NR^F)- and Z is a bond; X is -CH₂-, -(CH₂)₂- or - C(Me)H-, Y is -C(NR^F)- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-;

X is a bond, Y is -CCOR^H- and Z is a bond; X is a bond, Y is -C(OR^F)H- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -C(OR^F)H- and Z is a bond; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -CCOR^H- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-;

X is a bond, Y is -C(NR^FR^G)H- and Z is a bond; X is a bond, Y is -C(NR^FR^G)H- and Z is -CH₂-, - (CH₂)₂- or -C(Me)H-; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -C(NR^FR^G)H- and Z is a bond; X is - CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -C(NR^FR^G)H- and Z is -CH₂-, -(CH₂)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- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -C(0)NR^F- and Z is a bond; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -C(0)NR^F- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-;

X is a bond, Y is -NR^FC(0)- and Z is a bond; X is a bond, Y is -NR^FC(0)- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -NR^FC(0)- and Z is a bond; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -NR^FC(0)- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-; X is a bond, Y is -NR^FC(0)NR^G- and Z is a bond; X is a bond, Y is -NR^FC(0)NR^G- and Z is -CH2-, - (CH₂)₂- or -C(Me)H-; X is -CH2-, -(CH₂)₂- or -C(Me)H-, Y is -NR^FC(0)NR^G- and Z is a bond; X is - CH2-, -(CH₂)₂- or -C(Me)H-, Y is -NR^FC(0)NR^G- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-;

X is a bond, Y is -NR^FS0₂NR^G- and Z is a bond; X is a bond, Y is -NR^FS0₂NR^G- and Z is -CH₂-, - (CH₂)₂- or -C(Me)H-; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -NR^FS0₂NR^G- and Z is a bond; X is - CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -NR^FS0₂NR^G- 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 -S0₂NR^F- and Z is a bond; X is a bond, Y is -S0₂NR^F- and Z is -CH₂-, -(CH₂)₂- or - C(Me)H-; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -S0₂NR^F- and Z is a bond; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -S0₂NR^F- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-;

X is a bond, Y is -NR^FS0₂- and Z is a bond; X is a bond, Y is -NR^FS0₂- and Z is -CH₂-, -(CH₂)₂- or - C(Me)H-; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -NR^FS0₂- and Z is a bond; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -NR^FS0₂- 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-.

[0047] Optionally, X is a bond, Y is -C(OR^F)H- and Z is a bond; X is a bond, Y is -C(OR^F)H- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, 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 -CH₂-, -(CH₂)₂- or -C(Me)H-;

[0048] Optionally R^F is H or Me

[0049] There are provided compounds of formula (I) or formula (Ma) to (llj) wherein:

X is a bond, Y is a bond 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 -O- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-;

X is a bond, Y is -O- and Z is a bond;

X is a bond, Y is -CCOR^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 -NR^F- and Z is a bond;

X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -NR^F- and Z is a bond; X is a bond, Y is -NR^FC(0)- and Z is a bond;

X is a bond, Y is -C(0)NR^F- and Z is -CH2-, -(CH₂)₂- or -C(Me)H-;

X is a -CH2-, -(CH₂)₂- or -C(Me)H-, Y is -C(0)NR^F- 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)NR^F- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -NR^FC(0)- and Z is a bond;

X is a bond, Y is -NR^FC(0)NR^G- and Z is a bond; or

X is a bond, Y is -OC(O)- and Z is a bond.

[0050] Preferably, X is a bond, Y is -C(0)NR^F- 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 -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -C(0)NR^F- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-;

X is a -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -CCOR^H- and Z is bond;

X is a -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -CCOR^H- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-;

X is a bond, Y is -CCOR^H- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-; or

X is a bond, Y is -O- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-.

[0051] There are provided compounds of formula (I) or formula (Ma) to (llj) wherein:

X is a bond, Y is a bond and Z is a bond;

X is -CH₂-, Y is -⁽ D- and Z is a bond;

X is a bond, Y is -O- and Z is a bond;

X is a bond, Y is -O- and Z is -(CH₂)₂-;

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 -NH- and Z is -(CH₂)₂-;

X is a bond, Y is -NMe- and Z is -(CH₂)₂-;

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(O)- and Z is -CH2-;

X is a bond, Y is -NMeC(O)- and Z is -CH2-;

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 -CH2-; or

X is a bond, Y is -OC(O)- and Z is a bond.

[0052] Preferably, X is a bond, Y is -C(0)NH- and Z is -CH2-;

X is a bond, Y is -C(O)- and Z is -CH2 -;

X is -CH2-, Y is -C(0)NH- and Z is -CH2-;

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-; or

X is a bond, Y is -O- and Z is -(CH₂)2-.

[0053] Optionally, X is -CH2-, -(CH₂)₂- or -C(Me)H-, Y is -CCOR^H- and Z is bond; X is a -CH2-, - (CH₂)₂- or -C(Me)H-, Y is -C(OR^F)H- and Z is -CH2-, -(CH₂)₂- or -C(Me)H-; or X is a bond, Y is - C(OR^F)H- and Z is -CH2-, -(CH₂)₂- or -C(Me)H-.

[0054] Preferably, X is a bond, Y is -C(OH)H- and Z is -CH2-; or X is a bond, Y is -C(OH)H- and Z is -C(Me)H-.

[0055] In an embodiment, when Y is a bond, n or k is 2, 3 or 4.

[0056] In an embodiment, Y is -(CR^DR^E)_m-. In an embodiment, R^D and R^E are each independently selected from: H, =0 (i.e. R^D and R^E together form =0), -OR^A6, -SR^A6, -NR^A6R^B5, halo, Ci-₄ alkyl and C1-4 haloalkyl. In an embodiment, R^D and R^E are each independently selected from: H, =0 (i.e. R^D and R^E together form =0) and -OR^A6 (e.g. -OH). In an embodiment, R^A6 is H. In an embodiment, R^B5 is H. In an embodiment, m is 1 or 2.

[0057] In an embodiment, Y is -(CR^DR^E)_m- and m is 2. The substituents R^D and R^E are each independently defined as above. Thus, in this embodiment Y is -(CR^D R^E )(CR^D2R^E2)-, wherein R^D , R^E , R^D2 and R^E2 are each independently selected from: H, =0 (i.e. R^D and R^E together form =0), - OR^A6, -SR^A6, -NR^A6R^B5, halo, Ci-₄ alkyl and Ci-₄ haloalkyl, and preferably R^D and R^E are each independently selected from: H, =0 (i.e. R^E and R^F together form =0) and -OR^A6 (e.g. -OH), and preferably R^D , R^E , R^D2 and R^E2 are each independently selected from: H, =0 (i.e. R^D and R^E together form =0) and— OR^A6 (e.g. -OH). In an embodiment, R^D , R^E and R^D2 are H and R^E2 is OH. In an embodiment, R^D and R^D2 are H, R^E is methyl and R^E2 is OH. Optionally in the preceding embodiment X is -(CR^A R^B )_n- and n is 1 or 2.

[0058] In an embodiment, Y is -NR^F-. In an embodiment, R^F is selected from the group consisting of: H, Ci-4 alkyl and C1-4 haloalkyl. In an embodiment, R^F is selected from the group consisting of: H, methyl and ethyl.

[0059] 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, -OR^A3, -NR^A3R^B3, -SR^A3, -C(0)R^A3, -OC(0)R^A3, -C(0)OR^A3, -NR^A3C(0)R^B3, - C(0)NR^A3R^B3, -NR^A3S0₂R^B3, -S0₂NR^A3R^B3, -S0₂R^A3, =0, -NO2, -CN, C1-4 alkyl substituted with - OR^A3, C1-4 alkyl substituted with -NR^A3R^B3 and C3-6 cycloalkyl substituted with— OR^A3, phenyl substituted with 0, 1 or 2 R^H, benzyl substituted with 0, 1 or 2 R^H, and benzoyl substituted with 0, 1 or 2 R^H.

[0060] In an embodiment, R is a 5 to 10 membered fully saturated, partially unsaturated or aromatic mono- or di-cyclic moiety, which may optionally 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, -OR^A3, -NR^A3R^B3, -SR^A3, -C(0)R^A3, -OC(0)R^A3, -C(0)OR^A3, -NR^A3C(0)R^B3, - C(0)NR^A3R^B3, -NR^A3S0₂R^B3, -S0₂NR^A3R^B3, -S0₂R^A3, =0, -N0₂, -CN, C1-4 alkyl substituted with - OR^A3, C1-4 alkyl substituted with -NR^A3R^B3 and C3-6 cycloalkyl substituted with— OR^A3, phenyl substituted with 0, 1 or 2 R^H, benzyl substituted with 0, 1 or 2 R^H, and benzoyl substituted with 0, 1 or 2 R^H

[0061] In an embodiment, R is C5-10 cycloalkyl, 5 to 10 membered heterocycloalkyl, C6-10 aryl, 5 to 10 membered 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, -OR^A3, -NR^A3R^B3, - SR^A3, -C(0)R^A3, -OC(0)R^A3, -C(0)OR^A3, -NR^A3C(0)R^B3, -C(0)NR^A3R^B3, -NR^A3S0₂R^B3, - S0₂NR^A3R^B3, -S0₂R^A3, =0, -N0₂, -CN, C1-4 alkyl substituted with— OR^A3, C1-4 alkyl substituted with - NRA3RB3 _anc| c₃.₆ cycloalkyl substituted with— OR^A3, phenyl substituted with 0, 1 or 2 R^H, benzyl substituted with 0, 1 or 2 R^H, and benzoyl substituted with 0, 1 or 2 R^H. [0062] In an embodiment, R is C5-10 cycloalkyl, C5-10 cycloalkenyl, 5 to 10 membered

heterocycloalkyl, 5 to 10 membered heterocycloalkenyl, Ce-io aryl, 5 to 10 membered 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, -OR^A3, -NR^A3R^B3, -SR^A3, -C(0)R^A3, -OC(0)R^A3, - C(0)OR^A3, -NR^A3C(0)R^B3, -C(0)NR^A3R^B3, -NR^A3S0₂R^B3, -S0₂NR^A3R^B3, -S0₂R^A3, =0, -NO2, -CN, Ci- 4 alkyl substituted with -OR^A3, C1-4 alkyl substituted with -NR^A3R^B3 and C3-6 cycloalkyl substituted with -OR^A3, phenyl substituted with 0, 1 or 2 R^H, benzyl substituted with 0, 1 or 2 R^H, and benzoyl substituted with 0, 1 or 2 R^H.

[0063] C5-10 cycloalkyl may represent cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. C5-10 cycloalkyl may represent cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl, cycloatadienyl, indanyl, indenyl and tetralinyl.

[0064] The 5 to 10 membered heterocycloalkyl may represent tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, dioxolane, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, dioxane, or tetrahydropyran.. The 5 to 10 membered heterocycloalkenyl may represent pyroline, imidazoline, pyrazoline, oxazoline, isoxazoline, thiazoline, isothiazoline, dihydropyran, indoline, isoindoline, chromene, chromane, isochromane, dihydroquinoline, tetrahydroquinoline, dihydroisoquinoline or

tetrahydroisoquinoline.

[0065] Ce-io aryl may represent phenyl or napthyl.

[0066] The 5 to 10 membered 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.

[0067] 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.

[0068] In a preferred embodiment R is selected from substituted or unsubstituted: pyridyl, quinolinyl, pyrimidinyl, isoquinolinyl, cyclohexyl, piperidinyl, tetrahydropyranyl, azetidyl,

tetrahydroisoquinolinyl, phenyl, morpholinyl, piperazinyl, and oxadiazolyl. [0069] 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.

[0070] 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.

[0071] 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: tetrahydropyndine, dihydropyran, dihydrofuran and pyrroline.

[0072] In an embodiment R is selected from substituted or unsubstituted: phenyl, pyridyl, cyclohexyl, isoquinolinyl, quinolinyl, piperidinyl, morpholinyl, tetrahydroquinolinyl,

tetrahydroisoquinolinyl, piperazinyl, oxadiazolyl, tetrahydropyndine, 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, isoquinolinyl and cyclohexyl.

[0073] In an embodiment R is selected from substituted or unsubstituted: tetrahydropyranyl, phenyl, pyridyl, cyclohexyl, isoquinolinyl, quinolinyl, piperidinyl, morpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, piperazinyl, oxadiazolyl, tetrahydropyndine, dihydropyran, dihydrofuran and pyrroline. In an embodiment R is selected from substituted or unsubstituted: tetrahydropyran phenyl, pyridyl, cyclohexyl, isoquinolinyl, quinolinyl, piperidinyl, morpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, piperazinyl and oxadiazolyl. In an embodiment R is selected from substituted or unsubstituted: phenyl, pyridyl, tetrahydropyranyl, isoquinolinyl and cyclohexyl.

[0074] In an embodiment, the R moiety is substituted with 1 , 2 or 3 substituents selected from: halo, Ci-4 alkyl, Ci-₄ haloalkyl, -OR^A3, -NR^A3R^B3, Ci-₄ alkyl substituted with OR^A3, Ci-₄ alkyl substituted with -NR^A3R^B3, phenyl substituted with 0, 1 or 2 R^H, benzyl substituted with 0, 1 or 2 R^H, and benzoyl substituted with 0, 1 or 2 R^H, optionally wherein R^H is fluoro, chloro or methyl. [0075] In an embodiment, the R moiety is substituted with a single substituent selected from halo (e.g. chloro, flouro, bromo or iodo), -OR^A3 (e.g. -OH, -OMe, -OEt or -OCF₃), -NR^A3R^B3 (e.g. -NH₂, - NHMe or -NMe2), C1-4 alkyl (e.g. methyl, ethyl , isopropyl or tert-butyl), C1-4 haloalkyl (e.g.

trifluoromethyl or trifouroethyl), Ci-₄ alkyl substituted with— OR^A3 (e.g. -CH2OH) , C1-4 alkyl substituted with -NR^A3R^B3 (e.g. -CH2NH2), benzyl substituted with 0, 1 or 2 R^H (preferably 0 or 1 R^H), and benzoyl substituted with 0, 1 or 2 R^H (preferably 0 or 1 R^H), optionally wherein R^H is fluoro, chloro or methyl.

[0076] In an embodiment, the R moiety is substituted with a single substituent selected from: halo, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, -OR^A3, -NR^A3R^B3, -SR^A3, -C(0)R^A3, -OC(0)R^A3, -C(0)OR^A3, - NR^A3C(0)R^B3, -C(0)NR^A3R^B3, -NR^A3S0₂R^B3, -S0₂NR^A3R^B3, -S0₂R^A3, =0, -NO2, -CN, C1-4 alkyl substituted with— OR^A3, C1-4 alkyl substituted with -NR^A3R^B3, C3-6 cycloalkyl substituted with— OR^A3, phenyl substituted with 0, 1 or 2 R^H, benzyl substituted with 0, 1 or 2 R^H, and benzoyl substituted with 0, 1 or 2 R^H.

[0077] In an embodiment, the R moiety is substituted with a single substituent selected from halo (e.g. chloro or flouro), =0, -OR^A3 (e.g. -OH, -OMe, -OEt or -OCF3), -NR^A3R^B3 (e.g. -NH₂, -NHMe or -NMe₂), -C(0)OR^A3 (e.g. -C(0)OH, -C(0)OMe or -C(O)OEt), -C(0)NR^A3R^B3, (e.g. -C(0)NH₂, - C(0)NHMe or -C(0)NMe₂) C1-4 alkyl (e.g. methyl, ethyl , isopropyl or tert-butyl), C1-4 haloalkyl (e.g. trifluoromethyl or trifouroethyl), C1-4 alkyl substituted with— OR^A3 (e.g. -CH2OH) , C1-4 alkyl substituted with -NR^A3R^B3 (e.g. -CH2NH2), benzyl substituted with 0, 1 or 2 R^H (preferably 0 or 1 R^H), and benzoyl substituted with 0, 1 or 2 R^H (preferably 0 or 1 R^H),

[0078] In an embodiment, R² is selected from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -OR^A4 and C1-4 alkyl substituted with -OR^A4. 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, methyl and -OH.

[0079] In an embodiment, R³ and R⁴ are each independently selected from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -CN and -OR^A5. In an embodiment, R³ and R⁴ are each independently selected from: H and C1-4 alkyl. In an embodiment, one of R³ or R⁴ is H and the other is C1-4 alkyl.

[0080] 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 .

[0081] Optionally, 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, R^A7 and R^B5 are independently selected at each occurrence from: H, methyl, ethyl, trifluoromethyl, and trifluoroethyl.

[0082] Optionally, R^D and R^E are each independently selected at each occurrence from: H, -OR^A6, -NR^A6R^B5, halo, C1-4 alkyl, C1-4 haloalkyl, and C₃-₈ cycloalkyl. Optionally, R^D and R^E are each independently selected at each occurrence from: H, OH, fluoro, chloro, methyl, ethyl,

trifluoromethyl, trifluoroethyl and cyclopropyl. Preferably, R^D and R^E are each independently selected at each occurrence from: H, fluoro, chloro, methyl, ethyl, trifluoromethyl, trifluoroethyl and cyclopropyl. [0083] Optionally, R^F and R^G are each independently selected from: H, C1-4 alkyl and C1-4 haloalkyi, and C3-8 cycloalkyl. Preferably, R^F and R^G are each independently selected from: H, methyl, ethyl, trifluoromethyl, trifluoroethyl and cyclopropyl.

[0084] R^H is independently selected at each occurrence from: H, fluoro, chloro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, trifluoromethyl, -CN, -OH and -OMe.

[0085] The compound according to the invention may be selected from a preferred group consisting of:



[0087] 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 (/^-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.

[0088] In accordance with another aspect, the present invention provides a compound of the present invention for use as a medicament.

[0089] In accordance with another aspect, the present invention provides a pharmaceutical formulation comprising a compound of the present invention and a pharmaceutically acceptable excipient.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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 erythematosusor and rheumatoid arthritis.

[0094] 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.

[0095] 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 erythematosusor and rheumatoid arthritis. [0096] 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.

[0097] 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.

[0098] 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 erythematosusor and rheumatoid arthritis.

[0099] 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.

[00100] 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 /V-formylkynurenine.

[00101] In accordance with an aspect of the invention, there is provided a method of inhibiting the degradation of tryptophan and preventing the production of /V-formylkynurenine in a system comprising cells expressing IDO and/or TD02, wherein the system is exposed to a compound of the invention.

[00102] 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. [00103] In accordance with another aspect, the present invention provides a compound of the present invention for use in treating immunosuppression.

[00104] 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.

[00105] 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.

[00106] 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.

[00107] 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.

[00108] 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.

[00109] 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.

[00110] 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.

[0011 1] 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.

[00112] 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

[00113] 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. [00114] 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.

[00115] The term "Ci-e alkyi" 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/ -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 alkyi groups listed in this paragraph. The alkyi and alkylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyi group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, Ci-e alkoxy.

[00116] The term "Ci-e alkoxy" refers to an alkyi group which is attached to a molecule via oxygen. This includes moieties where the alkyi 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/ -butoxy, n-pentoxy and n-hexoxy. The alkyi part of the alkoxy group may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyi group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, Ci-e alkoxy. [00117] 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.

[00118] 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.

[00119] 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.

[00120] 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 Ci-e heteroalkyl may be bonded to the rest of the molecule through a carbon or a heteroatom. For example, the "Ci-e heteroalkyl" may be Ci-e /V-alkyl,

C1-6 Λ ,/V-alkyl, or Ci-e O-alkyl. [00121] 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.

[00122] 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.

[00123] 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.

[00124] 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.

[00125] The term "heterocycloalkyl" refers to a saturated hydrocarbon ring system containing 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 "heterocycloalkyl" may be bonded to the rest of the molecule through any carbon atom or heteroatom. The "heterocycloalkyl" may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring. For example, the "heterocycloalkyl" may be a "C3-8 heterocycloalkyl". The term "C3-8 heterocycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 atoms and at least one heteroatom within the ring selected from N, O and S. The "heterocycloalkyl" may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

[00126] The term "heterocycloalkenyl" refers to an unsaturated hydrocarbon ring system, that is not aromatic, containing 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

"heterocycloalkenyl" may be bonded to the rest of the molecule through any carbon atom or heteroatom. The "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

"heterocycloalkenyl" may be a "C3-8 heterocycloalkenyl" The term "C3-8 heterocycloalkenyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 atoms and at least one heteroatom within the ring selected from N, O and S. The "heterocycloalkenyl" may be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline.

[00127] 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.

[00128] 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. [00129] 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.

[00130] The term "alkaryl" refers to an aryl group, as defined above, bonded to a C1-4 alkyl, where the C1-4 alkyl group provides attachment to the remainder of the molecule. Benzyl refers to -Chbphenyl and benzoyl refers to -C(0)phenyl.

[00131] The term "alkheteroaryl" refers to a heteroaryl group, as defined above, bonded to a C1-4 alkyl, where the alkyl group provides attachment to the remainder of the molecule.

[00132] The term "halogen" herein includes reference to F, CI, Br and I. Halogen may be CI. Halogen may be F.

[00133] 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.

[00134] 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.

[00135] 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.

[00136] 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 " -^r ~^<" ".

[00137] "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.

[00138] "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.

[00139] 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.

[00140] 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%, at least 60% or less. For example, the e.e. or d.e. may be 90% or more, 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, or 10% or more.

[00141] 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. [00142] 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. [00143] 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).

[00144] 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. [00145] 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.

[00146] 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.

[00147] 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).

[00148] Hereinafter all references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof. [00149] 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.

[00150] 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.

[00151] 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.

[00152] 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.

[00153] 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.

[00154] 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.

[00155] 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.

[00156] 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.

[00157] 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 [00158] 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.

[00159] 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, reloxafme,

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-PD-L1 monoclonal antibodies (such as MEDI-4736 and RG-7446); anti-PD-L2 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.

[00160] 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.

[00161] 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.

[00162] 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.

[00163] 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).

[00164] 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.

[00165] 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.

[00166] 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.

[00167] 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.

[00168] 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.

[00169] For intravenous (parenteral) administration the compounds of the invention may be administered as a sterile aqueous or oily solution.

[00170] 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.

[00171] 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 SYNTHESES

[00172] General methods

[00173] As used herein the following terms have the meanings given: "BuLi" refers to n- butyllithium; "CBS" refers to Corey-Bakshi-Shibata; "DCM" refers to dichloromethane; "DiBAL" refers to diisobutylaluminium hydride, "DMAP" refers to 4-dimethylaminopyridine; "DMF" refers to A/,A/-dimethylformamide; "EDC" refers to A/-(3-dimethylaminopropyl)-A/'-ethylcarbodiimide; "HATU" refers to (1 -[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid

hexafluorophosphate), "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; "SEM" refers to 2-(trimethylsilyl)ethoxymethyl; "SFC" refers to Super Critical Fluid Chromatography, "STAB" refers to sodium triacetoxyborohydride; "TBAF" refers to

tetrabutylammonium fluoride, "TFA" refers to trifluoroacetic acid and "THF" refers to tetrahydrofuran.

[00174] 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 are reported in minutes.

Method 1 : "Short"

Time (min) %A %B

0 95 5

1 .1 95 5

6.1 5 95

7 5 95

7.5 95 5

8 95 5

Method 2: "Long"

Time (min) %A %B

0 95 5

0.3 95 5

2 5 95

Table 1

[00175] NMR was also used to characterise final compounds. NMR spectra were obtained on a Bruker AVIII 400 Nanobay with 5 mm BBFO probe or a Bruker ASCEND 400 MHz spectrometer at room temperature unless otherwise stated. H NMRs are reported in ppm and referenced to either TMS (0.0 ppm), DMSO-d6 (2.50 ppm), CDCb (7.26 ppm) or CD₃OD (3.31 ppm).

[00176] Compound purification was performed by flash column chromatography on silica using SiliaSep Silica Pre-packed Solid-Load Cartridge with the eluting solvent being described for the purification of each compound. Alternatively, 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.

Method 1 : "Early"

Time (min) %A %B

0 90 10

1 .5 90 10

1 1 .7 55 45

12.0 5 95

13.7 5 95

14.0 90 10

15.0 90 10

Method 2: "Middle"

Time (min) %A %B

0 90 10

1 .5 90 10

2 70 30

1 1 20 80

1 1 .5 5 95

13.5 5 95

14 90 10

15 90 10

Method 3: "Late"

Time (min) %A %B

0 90 10

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

[00177] 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.

[00178] Chemical Synthesis

[00179] Procedure A: preparation of halogenopyridine carbaldehydes

[00180] Commercially unavailable halogenopyridine carbaldehydes can be synthesised by analogy with the procedure described in Scheme 1 and Scheme 2.

on

Scheme 1

Scheme 2

[00181] Commercially available 2-bromo,3-amino,5-halogenopyridines can be protected (e.g. Boc protection using B0C2O anhydride) an undergo cross-coupling into the corresponding 2-vinyl,3- amino,5-halogenopyridines using Stille or other coupling conditions. Subsequent deprotection (e.g. under acidic conditions for Boc protecting group) and bromination can be used to afford the corresponding 2-vinyl,3-bromo,5-halogenopyridines. Ozonolysis of the vinyl moiety using ozone under reducing conditions (e.g. dimethylsulfide) can be used to afford 3-bromo,5-halogeno-pyridine- 2-carbaldehydes as described in Scheme 1. Alternatively, favourably substituted halogenopyridine

(e.g. 3-bromo,5-fluoropyridine in Scheme 2) can be carbonylated using conditions such as LDA followed by DMF to yield the desired halogenopyridine carbaldehydes.

[00182] Example A.1 : Preparation of 3-bromo-5-chloropyridine-2-carbaldehyde

[00183] fe/f-butyl-A/-(2-bromo-5-chloropyridin-3-yl)-A/-[(fe/f-butoxy)carbonyl]carbamate

[00184] Triethylamine (36.6 g, 360 mmol) was added to a solution of 2-bromo-5-chloropyridin-3- amine (25.0 g, 120 mmol) in DCM (200 mL) and the mixture was stirred at ambient temperature for 10 minutes. DMAP (0.7 g, 6 mmol) was added followed by portion-wise addition of (Βο Ο (65.8 g, 300 mmol). The resulting mixture was stirred at ambient temperature for 14 hours. The reaction was diluted with DCM (300 mL). Ice was/water added and the resulting mixture was stirred for 30 minutes. Layers were separated and the aqueous layer was extracted with DCM (100 mL). The combined organics were washed with saturated Na2C03 (200 mL), brine (400 mL), dried over

Na2S04 and concentrated to give a colourless solid (52 g, 41 % yield) characterised as fe/ -butyl-/V- (2-bromo-5-chloropyridin-3-yl)-/V-[(fe/ -butoxy)carbonyl]carbamate which was used in the next step without further purification. H NMR (CDCb, 400 MHz) δ: 8.30 (s, 1 H), 7.54 (s, 1 H), 1 .43 (s, 18H).

[00185] fe/f-butyl-/V-[(fe/f-butoxy)carbonyl]-/V-(5-chloro-2-ethenylpyridin-3-yl)carbamate

[00186] Tributyl(vinyl)tin (42.1 g, 130 mmol) was added to fe/ -butyl-/V-(2-bromo-5-chloropyridin-3- yl)-/V-[(fe/ -butoxy)carbonyl]carbamate (52 g, 120 mmol) in toluene (400 mL). The reaction mixture was degassed with Nitrogen and Tetrakis(triphenylphosphine)palladium(0) (2.08 g, 18 mmol) was added. The reaction mixture was further degassed and heated to reflux for 18 hours. To the reaction was added a saturated solution of KF (200 mL), and this was stirred for 2 hours. The reaction mixture was filtered and the cake washed with toluene (2 x 100 mL). The combined filtrates were partitioned and the aqueous layer extracted with toluene (2 x 200 mL). The combined toluene layers were washed with water (300 mL), brine (500 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give 46.0 g (quantitative yield) of an oil characterised as fe/ -butyl-/V-[(fe/ -butoxy)carbonyl]-/V-(5-chloro-2-ethenylpyridin-3-yl)carbamate.

[00187] 5-chloro-2-ethenylpyridin-3-amine

[00188] fe/f-butyl-/V-[(fe/f-butoxy)carbonyl]-/V-(5-chloro-2-ethenylpyridin-3-yl)carbamate (7.1 g, 20 mmol) was dissolved in DCM (10 mL). Trifluoroacetic acid (20 mL) was added and the mixture was stirred at ambient temperature for 4 hours. It was subsequently poured into ice and stirred for 20 minutes. pH was adjusted to 8.0 with Na2C03. The aqueous layer was extracted with DCM (3 x 100 mL). The combined organics were dried over Na2S04, filtered, concentrated under reduced pressure and purified with a 10/1 Petroleum ether in ethyl acetate mixture to give 2.9 g (92% yield) of a light yellow solid characterised as 5-chloro-2- ethenylpyridin-3-amine. H NMR (CDCb, 400 MHz) δ: 7.98 (s, 1 H), 6.97 (s, 1 H), 6.77 (dd, J 16.8 and 10.8 Hz, 1 H), 6.18 (d, J 17.2 Hz, 1 H), 5.52 (d, J 1 1 .2 Hz, 1 H), 3.83 (br.s, 2H).

[00189] 3-bromo-5-chloro-2-ethenylpyridine

[00190] 5-chloro-2-ethenylpyridin-3-amine (4.6 g, 30 mmol) was dissolved in acetonitrile (70 mL) and cooled to -30 °C. BF3.0Et2 (6.0 mL, 60 mmol) was added and the mixture was stirred for 10 minutes. t-BuONO (6.0 mL, 60 mmol) was added. The mixture was stirred at -20 °C for 1 hour. A suspension of CuBr (6.5 g, 45 mmol) in acetonitrile (30 mL) was added dropwise. The reaction mixture was stirred for another 45 minutes. To the mixture was added ice/water (200 g) and this was extracted with ethyl acetate (3 x 100 mL). The combined organics were washed with water followed with brine and concentrated under reduced pressure. The crude was purified using a 1/100 ethyl acetate in heptane eluent to afford 3-bromo-5-chloro-2-ethenylpyridine (3.3 g, 50% yield). H NMR (CDCb, 400 MHz) δ: 8.46 (d, J 2.0 Hz, 1 H), 7.86 (d, J 2.0 Hz, 1 H), 7.18 (dd, J 16.8 and 10.4 Hz, 1 H), 6.44 (dd, J 16.8 and 1 .2 Hz, 1 H), 5.58 (d, J 10.4 and 1 .6 Hz, 1 H).

[00191] 3-bromo-5-chloropyridine-2-carbaldehyde

[00192] 3-bromo-5-chloro-2-ethenylpyridine (3.3 g, 1 .5 mmol) was dissolved in DCM (200 mL) and chilled to -60 °C. Ozone was bubbled in the mixture for 2 hours. Dimethylsulfide (7 mL, 160 mmol) was added to the mixture which was stirred for 1 hour allowing to warm back to room temperature. Solvent was removed under reduced pressure and the residue purified using a 1/20 (ethyl acetate / petroleum ether) eluent system to yield a colourless solid (1 .2 g, 36% yield) characterised as 3-bromo-5-chloropyridine-2-carbaldehyde. H NMR (CDCb, 400 MHz) 6: 10.17 (s, 1 H), 8.69 (d, J 1 .6 Hz, 1 H), 8.06 (d, J 2.0 Hz, 1 H).

[00193] Procedure described in Example A.1 was also used to produce 3-bromo-5-fluoropyridine- 2-carbaldehyde in (600 mg, 5% overall yield over 5 steps). H NMR (CDCb, 400 MHz) δ: 10.16 (s, 1 H), 8.61 (d, J 24 Hz, 1 H), 7.79 (dd, J 7.6 and 2.0 Hz, 1 H).

[00194] Example A.2: Preparation of 3-bromo-5-fluoro-pyridine-4-carbaldehyde

[00195] n-BuLi (5.5 mL, 14 mmol) was added to a stirred solution of /V,/V-diisopropylamine (1 .5 g, 15 mmol) in THF (50 mL) slowly at -78 °C. The temperature was allowed to reach -50 °C and stirred at this temperature for 30 minutes. The solution was cooled to -78 °C and to it was added a solution of 3-Bromo-5-fluoropyridine (2.0 g, 1 .1 mmol) in THF (15 mL). The resulting mixture was stirred at this temperature for 45 minutes. A solution of ethyl formate (8.4 g, 1 13 mmol) in THF (15 mL) was added over 15 minutes and the resulting mixture was stirred at this temperature for 1 .5 hours. A saturated solution of NH4CI was added and the resulting mixture was partitioned with ethyl acetate. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by silica gel to afford a bright yellow solid characterised as 3-bromo-5-fluoro- pyridine-4-carbaldehyde (1 .4 g, 60% yield). H NMR (CDC , 400 MHz) δ: 10.32 (s, 1 H), 8.71 (s, 1 H), 8.567 (s, 1 H).

[00196] Procedure B: Preparation of protected and optionally substituted (imidazol-4-yl)heteroaryl carbaldehydes

[00197] Protected and optionally substituted (imidazol-4-yl)heteroaryl carbaldehydes can be synthesised by analogy with the procedure described Scheme 3.

Scheme 3

[00198] Commercially available 4-iodoimidazole derivatives can be protected on either Nitrogen atoms with a suitable protecting group (e.g. trityl, SEM, S02NMe2). The resulting protected 4- iodoimidazoles can be converted into the corresponding boronic esters via metal-catalysed (e.g. Miyaura) borylation with boronic esters (e.g. bis(pinacolato)diboron). Alternatively, reaction of protected 4-iodoimidazoles with isopropylmagnesium chloride (or other organometallic reagents) followed by trimethyl borate and acid hydrolysis (e.g. HCI) can afford the corresponding boronic acids. Cross-coupling of protected imidazole boronic esters or acids with halogenoheteroaryl carbaldehydes (e.g. CHO(Het)Ar-l, CHO(Het)Ar-Br, CHO(Het)Ar-CI) can afford the corresponding protected and optionally substituted (imidazol-4-yl)heteroaryl carbaldehydes. Halogenoheteroaryl carbaldehydes can optionally be prepared from the corresponding halogenoheteroaryl carboxylates, via Weinreb amide activation followed by reduction into the corresponding aldehyde with a suitable reducing agent (e.g. DiBAL). Alternatively protected and optionally substituted (imidazol-4- yhheteroaryl carbaldehydes can be synthesised by direct cross-coupling of optionally protected 4- iodoimidazoles with formylheteroaryl boronic acids or esters. Protection of the carbonyl moiety may be required for the preparation of selected analogues. Protections may include but are not limited to dimethyl acetyl, 1 ,3-dioxolane, 1 ,3-dioxanes, 1 ,3-dithianes.

[00199] Example B.1 : Preparation of 3-(1 -tritylimidazol-4-yl)pyridine-4-carbaldehyde

[00200] 4-iodo-1 -trityl-imidazole

[00201] Triethylamine (36.0 ml_, 258 mmol) was added to a mixture of 4-iodoimidazole (24.8 g, 128 mmol) and trityl chloride (39.2 g, 141 mmol) in THF (275 ml_), the resulting mixture was heated at 70 °C for 3 hours under nitrogen. The reaction was cooled to 45 °C and filtered to remove the suspended white solid (Et3N.HCI). The filtrate was concentrated in vacuo, dissolved in DCM (500 ml_) and washed with 5 wt% aq. sodium thiosulfate solution (300 ml_). The aqueous layer was extracted with DCM (150 ml_). The combined organics were dried over Na2S04, filtered and concentrated in vacuo to afford an off white solid. Hot filtration was carried out with methanol (500 ml) at 90°C to afford a white solid characterised as 4-iodo-1 -trityl-imidazole (45.2 g, 104 mmol, 81 % yield). H NMR (CDCb, 400 MHz) δ: 7.36-7.44 (m, 9H), 7.28-7.32 (m, 1 H), 7.10-7.15 (m, 6H), 6.94 (s, 1 H). LCMS purity >95%, [M+H]⁺ = 437.0, 4.47 min (analytical long).

[00202] (1 -Tritylimidazol-4-yl)boronic acid

HCk JDH [00203] A 2 M isopropylmagnesium chloride solution in THF (8.60 ml_, 17.2 mmol) was added dropwise to a solution of 4-iodo-1 -trityl-imidazole (5.00 g, 1 1 .5 mmol) in anhydrous THF (55 ml_) at 0 °C under nitrogen. The resulting mixture was stirred at 0 °C for 10 minutes. Trimethyl borate (6.39 ml_, 57.3 mmol) was added portion wise and the reaction mixture was left to stir for 10 minutes at 0 °C. It was allowed to warm to room temperature and stirred for another 10 minutes. 1 M aqueous hydrochloric acid (30 ml_, 30.0 mmol) was added to the reaction mixture which was stirred for 10 minutes. The reaction was quenched by slowly pouring into a saturated solution of aqueous sodium hydrogen carbonate (100 ml_) and extracted with ethyl acetate (3 x 50 ml_). The combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo to afford the product (1 -tritylimidazol-4-yl)boronic acid (3.93 g, 1 1 .1 mmol, 97% yield) as an off white solid which was taken through to the next synthetic step without further purification. LCMS purity >90%, 1 .42 min (analytical short).

[00204] 3-(1 -tritylimidazol-4-yl)pyridine-4-carbaldehyde

[00205] Procedure B.1 - Traditional heating

[00206] To a degassed solution of 3-Bromo-4-pyridinecarboxaldehyde (2.8 g, 15.1 mmol), (1 - tritylimidazol-4-yl)boronic acid (8.00 g, 22.6 mmol) and potassium carbonate (4.25 g, 30.7 mmol) in a 2:1 mixture of 1 ,4-dioxane and water (75 ml_) under nitrogen was added [1 ,1 - Bis(diphenylphosphino)ferrocene]Palladium(ll) chloride dichloromethane complex (619 mg, 0.76 mmol). The resulting suspension was degassed with nitrogen (5 minutes) and heated to reflux at 1 10°C for 2 hours. The reaction was subsequently allowed to cool to room temperature, filtered through a pad of celite and washed with ethyl acetate (150 ml_). The combined filtrate was washed with water (3 x 100 ml_). The aqueous layers were extracted with ethyl acetate (2 x 150 ml_). The combined organics were dried over sodium sulphate filtered and concentrated in vacuo. The product was isolated via column chromatography with a 0-100% ethyl acetate in petroleum ether gradient.

[00207] Procedure B.2 - microwave heating

[00208] 3-Bromo-4-pyridinecarboxaldehyde (200 mg, 1 .07 mmol), (1 -tritylimidazol-4-yl)boronic acid (500 mg, 1 .41 mmol), potassium carbonate (297 mg, 215 mmol) and [1 ,1 - Bis(diphenylphosphino)ferrocene]Palladium(ll) chloride dichloromethane complex (88 mg, 0.1 1 mmol) were loaded in a microwave vial. The vial was capped and the mixture degased under nitrogen. A 2:1 mixture of 1 ,4-dioxane and water (9 ml_) - preliminarily degased under nitrogen - was added to the solid mixture and the resulting suspension was degased under nitrogen for another 5 minutes. The mixture was submitted to microwave irradiations at 120°C for 1 hour. The reaction was allowed to cool to room temperature, diluted with ethyl acetate (50 mL) and washed with a saturated solution of NaHC03 (50 mL). The aqueous solution was extracted with ethyl acetate (50 mL) and the organic layers were combined, dried over sodium sulphate filtered and concentrated in vacuo. The product was isolated via column chromatography with a 0-40% ethyl acetate in petroleum ether gradient. H NMR (CDC , 400 MHz) δ: 10.70 (s, 1 H), 8.94 (d, J 0.8 Hz, 1 H), 8.66 (dd, J 5.1 , 0.6 Hz, 1 H), 7.68 (dd, J 5.1 , 0.7 Hz, 1 H), 7.62 (d, J 1 .3 Hz, 1 H), 7.36-7.40 (m, 9H), 7.18-7.22 (m, 6H), 6.85 (d, J 1 .2 Hz, 1 H). LCMS purity >95%, [M+H]⁺ = 416, 1 .88 min (analytical short).

[00209] The following intermediates (in Table 3) were prepared by analogy with Procedure B and/or Example B1.

Name Yield (%)

Compound Procedure /

LCMS analytical data

purification method

CI 2-chloro-5-(1 -tritylimidazol-4-yl)pyridine-4-

48

carbaldehyde procedure 2 / 0-30%

LCMS purity >95%, [M+Na]⁺ = 472, 2.16 min ethyl acetate in

(analytical short). heptane

Trt'

2-(1 -tritylimidazol-4-yl)pyridine-3- 54

carbaldehyde

LCMS purity >90%, [M+H]⁺ = 416, 2.03 min procedure 2 / 0-50%

(analytical short). ethyl acetate in

petroleum ether

Trt^/

3-chloro-5-(1 -tritylimidazol-4-yl)pyridine-4- 87

carbaldehyde

LCMS purity >80%, [M+Na]⁺ = 472, 2.04 min procedure 2 / 5-35%

(analytical short). ethyl acetate in

petroleum ether

Trt^/

3-(1 -tritylimidazol-4-yl)pyridine-2- 36

carbaldehyde

LCMS purity >90%, [M+Na]⁺ = 438.2, 1 .77 procedure 2 / 20- min (analytical short). 100% ethyl acetate in heptane

Trt'

3-fluoro-5-(1 -tritylimidazol-4-yl)pyridine-4- 24

carbaldehyde H NMR (CDCI3, 400 MHz) δ: 10.44 (s, 1 H), Silica gel, Petroleum 8.74 (s, 1 H), 8.46 (s, 1 H), 7.60-7.18 (m, ether/ ethyl acetate

17H). (5/1)

Trt'

5-chloro-3-(1 -tritylimidazol-4-yl)pyridine-2- 45

carbaldehyde

H NMR (CDCI3, 400 MHz) δ: 10.26 (s, 1 H), Silica gel, Petroleum 8.59 (d, J 2.0 Hz, 1 H), 8.35 (d, J 2.0 Hz, 1 H), ether/ ethyl acetate 7.61 (d, J 1 .2 Hz, 1 H), 7.57 (d, J 0.8 Hz, 1 H), (7/1)

7.39-7.18 (m, 15H).

Trt'

5-Fluoro-3-(1 -tritylimidazol-4-yl)pyridine-2- 60

carbaldehyde

H NMR (CDCI3, 400 MHz) δ: 10.24 (s, 1 H), Silica gel, Petroleum 8.50 (d, J 2.4 Hz, 1 H), 8.10 (d, J 10.0 Hz, ether/ ethyl acetate 1 H), 7.68 (d, J 1 .2 Hz, 1 H), 7.57 (s, 1 H), (7/1)

7.39-7.18 (m, 15H).

Trt'

Table 3

[00210] Example B.2: Preparation of 5-(1 -tritylimidazol-4-yl)pyrimidine-4-carbaldehyde

[0021 1] 5-bromo-/V-methoxy-/V-methyl-pyrimidine-4-carboxamide

[00212] A mixture of 5-bromopyrimidine-4-carboxylic acid (3.57 g, 17.6 mmol) and Λ/,Ο- dimethylhydroxylamine hydrochloride (2.58 g, 26.4 mmol) in DCM (70 mL) and N,N- Diisopropylethylamine (15 mL, 86 mmol) was stirred at room temperature under nitrogen. The mixture was chilled to 0 °C and HATU (8.08 g, 21 .3 mmol) was added to the reaction which was stirred at 0 °C under nitrogen for 1 hour. The reaction was diluted with DCM (70 mL) and washed with brine (2 x 100 mL). The combined organics were dried over Na2S04, filtered and concentrated in vacuo to afford a black crude oil. This was purified with a 25-50% EtOAc in heptane eluent. Fractions containing the desired product were combined and concentrated in vacuo to afford a yellow oil (863 mg, 3.5 mmol, 20% yield). H NMR (CDCI3, 400 MHz) δ: 9.14 (s, 1 H), 8.90 (s, 1 H), 3.61 (s, 3H), 3.41 (s, 3H). LCMS purity >95%, [M+H]+ = 245.8, 247.8, 1 .07 min (analytical short).

[00213] 5-bromopyrimidine-4-carbaldehyde

[00214] Diisobutylaluminium hydride (1 M in toluene, 1 1 .2 mL, 1 1 .2 mmol) was slowly added to a solution of 5-bromo-/V-methoxy-/V-methyl-pyrimidine-4-carboxamide (1 .31 g, 5.34 mmol) in THF (20 mL) a -10 °C under nitrogen. The reaction was stirred at -10°C for 1 hour. The reaction was quenched with isopropanol (10 mL) and water (20 mL) and left to stand overnight at room temperature. The mixture was extracted with EtOAc (3 x 30 mL). The combined organic fractions were dried over Na2S04, filtered and concentrated in vacuo to yield an oil which was purified with a 10-50% (2.5% methanol in EtOAc) in heptane eluting solvent. Fractions containing the desired product were combined and concentrated in vacuo to afford a yellow oil (450 mg, 1 .45 mmol, 60% purity, 27% yield. LCMS purity <60%, [M+H]⁺ = 187, 189, 0.50 min (analytical short).

[00215] 5-(1 -tritylimidazol-4-yl)pyrimidine-4-carbaldehyde

[00216] To a degassed solution of 5-bromopyrimidine-4-carbaldehyde (450 mg, 2.41 mmol), (1 - tritylimidazol-4-yl)boronic acid (859 mg, 2.42 mmol) and potassium carbonate (671 mg, 4.85 mmol) in 1 ,4-dioxane (10 mL) and water (5 mL) under nitrogen was added [1 ,1 - Bis(diphenylphosphino)ferrocene]Palladium(ll) chloride dichloromethane complex (1 1 1 mg, 0.140 mmol). The resulting solution was degassed under nitrogen and heated to reflux at 1 10°C for 2 hours. The reaction was allowed to cool to room temperature and left standing overnight. It was subsequently filtered through a pad of celite and washed with EtOAc (30 mL). The combined filtrate was washed with water (3 x 20 mL). The aqueous layers were then extracted with EtOAc (2 x 30 mL). The combined organics were dried over Na2S04, filtered and concentrated in vacuo to afford a brown foam. The crude was purified with a 10-75% EtOAc in heptane eluent. Fractions containing the desired product were combined and concentrated in vacuo to afford a yellow residue (414 mg, 0.99 mmol, 41 % yield). LCMS purity >95%, [M+Na]⁺ = 439.3, 1 .75 min (analytical short).

[00217] Procedure C: Preparation of 1 -substituted-2-(imidazo-pyrrolo-heteroaryl)ethanol and 1 - substituted-2-(imidazo-pyrrolo-heteroaryl)ethanamine analogues

[00218] 1 -Substituted-2-(imidazo-pyrrolo-heteroaryl)ethanol and 1 -substituted-2-(imidazo-pyrrolo- heteroaryhethanamine analogues can be synthesised from (imidazol-4-yl)heteroaryl carbaldehydes by analogy with the procedure described in Scheme 4.

Condensation

and cyclisation

Scheme 4

[00219] (lmidazol-4-yl)heteroaryl carbaldehydes can be treated with substituted methyl ketones in basic conditions (e.g. NaOH, KOH) to afford the corresponding αβ-unsaturated ketones.

Alternatively αβ-unsaturated ketones can be generated by condensation with Wittig reagents (e.g. triethyl phosphonoacetate) in basic conditions (e.g. NaH). Deprotection and cyclisation of ap- unsaturated ketone intermediates (e.g. using AcOH for trityl protecting groups) can afford 1 - substituted-2-(imidazo-pyrrolo-heteroaryl)ethanones. In another route, (lmidazol-4-yl)heteroaryl carbaldehydes can be protected (e.g. dimethyl acetyl, 1 ,3-dioxolane, 1 ,3-dioxanes, 1 ,3-dithianes for the carbonyl functionality). Protection can simultaneously lead to deprotection of the imidazole ring. This protection strategy can allow for the modifications of substitution patterns on the A ring.

Deprotection of the acetal moieties into the corresponding carbaldehydes can be carried out in acidic conditions. Subsequent condensation of the carbaldehydes can afford the newly modified 1 - substituted-2-(imidazo-pyrrolo-heteroaryl)ethanones. A variety of reducing agents (e.g. NaBhU,

LJBH4, CBS) can be used to reduce 1 -substituted-2-(imidazo-pyrrolo-heteroaryl)ethanones into the corresponding 1 -substituted-2-(imidazo-pyrrolo-heteroaryl)ethanols. Alternatively, reductive amination of 1 -substituted-2-(imidazo-pyrrolo-heteroaryl)ethanones with primary or secondary amines can afford the corresponding substituted (imidazo-pyrrolo-heteroaryl)ethanamines. At any stage during this procedure a protecting group may be used when required and subsequently removed to afford the desired unprotected 1 -substituted-2-(imidazo-pyrrolo-heteroaryl)ethanols.

[00220] Example C.1 : Preparation of 1 -cyclohexyl-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5- yhethanol

[00221] (E)-1 -cyclohexyl-3-[3-(1 -tritylimidazol-4-yl)-4-pyridyl]prop-2-en-1 -one

[00222] To a solution of 3-(1 -tritylimidazol-4-yl)pyridine-4-carbaldehyde (6.66 g, 16.0 mmol) and 1 - acetylcyclohexane (2.65 mL, 19.3 mmol) in THF (100 mL) was added sodium hydroxide (3.21 g, 80.3 mmol) in water (50 mL). The reaction was heated at 50 °C under nitrogen overnight. It was subsequently allowed to cool to room temperature, diluted with EtOAc (150 mL) and washed with water (3 x 50 mL). The combined aqueous layers were then extracted with EtOAc (3 x 50 mL). The combined organics were dried over Na2S04, filtered and concentrated in vacuo to afford a light brown solid. The crude was purified with a 20-100% EtOAc in heptane eluting solvent. This afforded (E)-1 -cyclohexyl-3-[3-(1 -tritylimidazol-4-yl)-4-pyridyl]prop-2-en-1 -one as yellow gum (1 .41 g, 2.70 mmol, 17% yield). H NMR (CDCI₃, 400 MHz) δ: 8.91 (s, 1 H), 8.49 (d, J 5.2 Hz, 1 H), 8.09 (d, J 16.1 Hz, 1 H), 7.57 (d, J 1 .3 Hz, 1 H), 7.35-7.41 (m, 10H), 7.18-7.21 (m, 6H), 7.02 (d, J 1 .3 Hz, 1 H), 6.76 (d, J 16.1 Hz, 1 H), 2.56-2.64 (m, 1 H), 1 .75-1 .89 (m, 3H), 1 .64-1 .71 (m, 1 H), 1 .19-1 .42 (m, 6H). LCMS purity 100%, [M+H]⁺ = 524.5, 2.18 min (analytical short).

[00223] 1 -cyclohexyl-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanone

[00224] Acetic acid (Glacial) (3.7 mL, 65 mmol) was added to a solution of (E)-1 -cyclohexyl-3-[3- (1 -tritylimidazol-4-yl)-4-pyridyl]prop-2-en-1 -one (1 .15 g, 2.20 mmol) in methanol (15 mL) under nitrogen. The resulting mixture was heated at 90°C overnight. The reaction was cooled to room temperature diluted with EtOAc (150 mL) and an aqueous solution of saturated sodium bicarbonate (80 mL) was added until the pH was basic (pH ~ 8). The organic layer was washed with water (50 mL) and dried over Na2S04, filtered and concentrated in vacuo to afford a brown gum. The crude was purified with a 0-10% methanol in DCM to afford 1 -cyclohexyl-2-(5H-imidazo[4,5]pyrrolo[1 ,2- a]pyridin-5-yl)ethanone as a yellow solid (208 mg, 0.740 mmol, 33%). H NMR (CD3OD, 400 MHz) δ: 8.84 (d, J 0.9 Hz, 1 H), 8.47 (d, J 5.0 Hz, 1 H), 7.79 (s, 1 H), 7.58 (s, 1 H), 7.28 (s, 1 H), 5.75 (dd, J 3.9, 9.3 Hz, 1 H), 3.48 (dd, J 3.9, 18.4 Hz, 1 H), 3.12 (dd, J 9.3, 18.4 Hz, 1 H) 2.47-2.53 (m, 1 H), 1 .75- 1.97 (m, 4H), 1.67-1.72 (m, 1H), 1.16-1.48 (m, 5H). LCMS purity 100%, [M+H]⁺ (analytical short).

[00225] 1-cyclohexyl-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanol

[00226] Sodium borohydride (79.1 mg, 2.09 mmol) was added to a solution of 1-cyclohexyl-2-(5H- imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanone (289 mg, 1.03 mmol) in methanol (16 mL) at 0 °C under nitrogen. After 45 minutes, water (30 mL) was added to quench the reaction and it was extracted with ethyl acetate (2 χ 60 mL). The combined organics were dried over sodium sulphate, filtered and concentrated in vacuo to afford a yellow gum. The crude was purified with a 1-10% methanol in DCM to afford 1-cyclohexyl-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanol as a yellow foam (290 mg, 1.02 mmol, 99%). H NMR (DMSO-d6, 400 MHz) δ: 8.88 (s, 1 H), 8.46-8.48 (m, 1H), 7.95-8.00 (m, 1H), 7.58-7.61 (m, 1H), 7.20-7.23 (m, 1H), 5.45-5.52 (m, 1H), 4.79-5.00 (m, 1H), 3.50-3.64 (m, 1H), 2.07-2.23 (m, 1H), 1.52-1.94 (m, 5H), 0.95-1.30 (m, 7H). LCMS purity 100%, [M+H]⁺ = 284.1, 1.12 min (analytical short), 2.44 min (analytical long).

[00227] The following intermediates (in Table 4) were prepared by analogy with Procedure C and/or Exam le C1.

purity > 95%, [M+H]⁺ = 279, 0.49 min

(analytical short), 0.54 min (analytical

long).

2-(5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-

63 5-yl)-1 -tetrahydropyran-4-yl-ethanol

H NMR (CD3OD, 400MHz) δ: 8.38-8.42

(m, 1 H), 7.99-8.10 (m, 1 H), 7.96 (s, 1 H),

7.35-7.45 (m, 1 H), 7.26-7.31 (m, 1 H),

0-30%

5.44-5.50 (m, 0.6H), 5.32-5.38 (m,

methanol in 0.4H), 3.65-4.02 (m, 3H), 3.32-3.38 (m,

ethyl acetate

N 2H), 2.32-2.42 (m, 1 H), 1 .38-2.10 (m,

(0.1 % NH3) 6H). LCMS purity > 95%, [M+H]⁺ = 286,

0.86 and 0.88 min (analytical short),

1 .66 and 1 .80 min (analytical long).

2-(5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-

65 5-yl)-1 -(6-methoxy-3-pyridyl)ethanol

H NMR (CD3OD, 400MHz) δ: 8.34-8.44

(m, 1 H), 8.05-8.1 1 (m, 1 H), 7.96-8.01

(m, 2H), 7.68-7.71 (m, 1 H), 7.33-7.41

(m, 1 H), 7.23-7.32 (m, 1 H), 6.70-6.74 0-30% (m, 1 H), 5.40-5.50 (m, 1 H), 4.90-5.02 methanol in (m, 1 H), 3.86-3.88 (m, 3H), 2.55-2.80 ethyl acetate

(m, 1 H), 2.18-2.52 (m, 1 H). LCMS purity (0.1 % NH3) > 95%, [M+H]⁺ = 309, 0.92 (analytical

short), 1 .92 and 1 .94 min (analytical

long).

2-(5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-

64 5-yl)-1 -(o-tolyl)ethanol

H NMR (CD3OD, 400 MHz): 8.35-8.45

(m, 1 H), 7.93-8.15 (m, 2H), 7.49-7.57

(m, 1 H), 7.35-7.42 (m, 1 H), 7.32 (s,

0.55H), 7.26 (s, 0.45H), 7.15-7.22 (m,

1 H), 7.05-7.14 (m, 2H), 5.45-5.57 (m, 0-30% 1 .45H), 5.24-5.28 (m, 0.55H), 2.62-2.70 methanol in (m, 0.55H), 2.44-2.51 (m, 0.45H), 2.29- ethyl acetate

2.39 (m, 0.45H), 2.20-2.28 (m, 3H), (0.1 % NH3) 1 .99-2.08 (m, 0.55H). LCMS purity >

95%, [M+H]⁺ = 292.1 , 1 .10 min

(analytical short), 2.43 min (analytical

long).

2-(5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-

52 5-yl)-1 -(2-methoxyphenyl)ethanol

H NMR (DMSO-d6, 400 MHz): 8.35- 8.42 (m, 1 H), 8.04 (s, 0.4H), 7.97-8.02

(m, 1 H), 7.81 (m, 0.6H), 7.48-7.58 (m,

1 H), 7.20-7.40 (m, 3H), 6.88-7.01 (m, 0-30% 2H), 5.24-5.45 (m, 3H), 3.75 (s, 1 .8H), methanol in 3.67 (s, 1 .2H), 2.38-2.45 (m, 1 H), 1 .75- ethyl acetate

2.1 1 (m, 1 H). LCMS purity > 95%, (0.1 % NH3) [M+H]⁺ = 308.0, 1 .01 and 1 .04 min

(analytical short), 2.21 and 2.30 min

(analytical long). 2-(5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-

71 5-yl)-1 -(p-tolyl)ethanol

H NMR (DMSO-d6, 400 MHz): 8.35- 8.42 (m, 1 H), 7.96-8.05 (m, 2H), 7.35- 7.41 (m, 1 H), 7.23-7.32 (m, 3H), 7.09-

0-30% 7.15 (m, 2H), 5.55-5.76 (m, 1 H), 5.25- methanol in

5.37 (m, 1 H), 4.96-5.12 (m, 1 H), 2.15- ethyl acetate

N 2.38 (m, 4H), 1 .82-1 .92 (m, 1 H). LCMS

(0.1 % NH3) purity > 95%, [M+H]⁺ = 292.1 , 1 .09 and

1 .1 1 min (analytical short), 2.41 and

2.46 min (analytical long).

1 -(2-chlorophenyl)-2-(5H- imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5- 43 - yl)ethanol

CI H NMR (DMSO-d6, 400 MHz): 8.35- 8.42 (m, 1 H), 7.90-8.15 (m, 2H), 7.62- 7.73 (m, 1 H), 7.20-7.43 (m, 5H), 5.70-

0-30% 6.20 (m, 1 H), 5.33-5.55 (m, 2H), 2.1 - methanol in 2.45 (m, 1 H), 1 .78-1 .88 (m, 1 H). LCMS

N ethyl acetate purity > 95%, [M+H]⁺ = 312.1 , 1 .1 1 min

(analytical short), 2.45 min (analytical

long).

2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-

22 5-yl)-1 -(3-methoxyphenyl)ethanol H NMR (DMSO-d6, 400 MHz); 8.86 (m,

1 H), 8.50 (d, J 5.0 Hz, 0.4H), 8.44 (d, J

5.0 Hz, 0.6H), 8.03 (s, 0.6H), 7.91 (s,

0.4H), 7.66 (d, J 5.1 Hz, 0.4H), 7.56 (d,

J 5.0 Hz, 0.6H), 7.26-7.20 (m, 2H), 6.97- 6.95 (m, 2H), 6.82-6.78 (m, 1 H), 5.82 (d, 0-30%

HO J 4.6 Hz, 0.6H), 5.66 (d, J 5.2 Hz, 0.4H), methanol in

N 5.58 (dd, J 3.2 and 9.6 Hz, 0.6H), 5.49 ethyl acetate

(m, 0.4H), 4.95-4.85 (m, 1 H), 3.73 (m,

3H), 2.20-1 .85 (2H, m). LCMS purity >

90%, [M+H]⁺ = 308, 0.93 and 0.96 min

(analytical short), 1 .94 and 2.03 min

(analytical long).

1 -(4-chlorophenyl)-2-(5H- imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5- 56 yl)ethanol

H NMR (DMSO-d6, 400 MHz); 8.87 (m,

0.5H), 8.86 (m, 0.5H), 8.56 (d, J 5.0 Hz,

0.5H), 8.44 (d, J 5.0 Hz, 0.5H), 8.06 (s,

0.5H), 7.96 (s, 0.5H), 7.66 (m, 0.5H), Reverse 7.57 (m, 0.5H), 7.43-7.32 (m, 4H), 7.26 phase (s, 0.5H), 7.20 (s, 0.5H), 5.91 (d, J 4.0 chromatogra Hz, 0.5H), 5.74 (d, J 4.0 Hz, 0.5H), 5.58 phy (5-95%

N (m, 0.5H), 5.50 (m, 0.5H), 4.96 (m, MeCN:H20+

0.5H), 4.88 (m, 0.5H), 2.37-2.21 (m, 0.1 % formic 1 .5H), 1 .90 (m, 0.5H). LCMS purity > acid) 90%, [M+H]⁺ = 312.1 , 1 .05 and 1 .08 min

(analytical short), 2.29 and 2.37 min

(analytical long).

H NMR (DMSO-d6, 400 MHz) δ: 8.85 &

8.86 (2d, J 0.8 Hz, 1 H), 8.44 & 8.49 (2d,

J 5.0 Hz, 1 H), 7.96 and 8.05 (2s, 1 H),

7.55-7.70 (m, 3H), 7.19-7.27 (m, 3H), 1 -10% 5.71 -5.90 (2m, 1 H), 5.47-5.59 (2m, 1 H), methanol in 4.82-4.95 (2m, 1 H), 1 .84-2.45 (2m, 2H). DCM

HO LCMS purity 92%, [M+H]⁺ = 404, 1 .15

N and 1 .18 min (analytical short), 2.51 and

2.58 min (analytical long).

1 -(4-bromo-2-chloro-phenyl)-2-(5H- imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5- 40 yl)ethanol

H NMR (DMSO-d6, 400 MHz) δ: 8.86- 8.88 (m, 1 H), 8.45 and 8.51 (2d, J 5.0

Hz, 1 H), 7.93 and 8.07 (2s, 1 H), 7.52- 7.68 (m, 4H), 7.21 and 7.27 (2s, 1 H),

0-10% 5.83-6.07 (m, 1 H), 5.59-5.66 (m, 1 H),

methanol in 5.08-5.25 (m, 1 H), 1 .83-1 .91 , 2.17-2.24

N ethyl acetate

& 2.29-2.41 (3m, 2H). LCMS purity

94%, [M+H]⁺ = 390/392/394, 1 .25 min

(analytical short), 2.70 and 2.73 min

(analytical long).

1 -cyclohexyl-2-(6-fluoro-5H- imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5- 59 yl)ethanol

H NMR (DMSO-d6, 400 MHz) δ: 8.75

(d, J 2.2 Hz, 0.59 H), 8.71 (d, J 2.2 Hz,

0.33 H), 8.46 (d, J 1 .0 Hz, 0.62 H), 8.41

(d, J 1 .1 Hz, 0.34 H), 8.02 (s, 0.35 H),

7.98 (s, 0.61 H), 7.30 (s, 0.60 H), 7.26

(s, 0.33 H), 5.79-5.72 (m, 1 H), 5.01 (d, J

6.2 Hz, 0.65 H), 4.41 (d, J 5.6 Hz, 0.39 0-6% H), 3.58-3.50 (m, 0.75 H), 3.15-3.09 (m, methanol in

N 0.45H), 2.39-2.31 (m, 0.37 H), 2.28-2.20 DCM

(m, 0.69H), 2.07-1 .99 (m, 0.39 H), 1 .83-

1 .76 (m, 0.66H), 1 .74-1 .51 (m, 5H),

1 .32-0.85 (m, 6H). LCMS purity >95%,

[M+H]⁺ = 302, 1 .24 min (analytical

short), 2.68 and 2.70 min (analytical

long).

2-(8-chloro-5H-imidazo[4,5]pyrrolo[1 ,2-

54 b]pyridin-5-yl)-1 -cyclohexyl-ethanol

H NMR (DMSO-d6, 400 MHz) δ: 8.43

(d, J 2.2 Hz, 0.31 H), 8.41 (d, J 2.2 Hz,

0.67H), 8.21 (d, J 2.3 Hz, 0.30), 8.18 (d,

J 2.3 Hz, 0.70 H), 8.06 (s, 0.75H), 8.01

(s, 0.32H), 7.32 (s, 0.33H), 7.29 (s,

0.71 H), 5.42-5.38 (m, 0.31 H), 5.37-5.33 0-5% (m, 0.69H), 4.98 (d, J 6.2 Hz, 0.31 H), methanol in

N 4.68 (d, J 5.8 Hz, 0.69H), 3.77-3.59 (m, DCM

1 H), 2.28-2.20 (m, 0.36H), 2.17-2.10 (m,

0.69H), 2.01 -1 .92 (m, 0.70H), 1 .84-1 .76

(m, 0.33H), 1 .76-1 .55 (m, 5H), 1 .30-0.93

(m, 6H). LCMS purity >95%, [M+H]⁺ =

318/320, 1 .42 and 1 .44 min (analytical short), 3.04 and 3.10 min (analytical

long).

1 -cyclohexyl-2-(8-fluoro-5H- imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5- 77

yl)ethanol

H NMR (DMSO-d6, 400 MHz) δ: 8.39- 8.35 (m, 1 H), 8.06 (s, 0.73H), 8.03-7.97

(m, 1 .26H), 7.31 (s, 0.28H), 7.29 (s,

0.72H), 5.38 (dd, J 10.3, 2.9 Hz, 0.25H),

5.32 (t, J 6.0 Hz, 0.74H), 3.82-3.75 (m,

0.73H), 3.66-3.59 (m, 0.26H), 2.29-2.21 0-10%

(m, 0.28H), 2.1 1 (ddd, J 14.1 , 6.6, 2.6 methanol in

N Hz, 0.73H), 1 .95 (ddd, J 14.1 , 10.2, 5.6 DCM

Hz, 0.72H), 1 .83-1 .53 (m, 5.19H), 1 .35- 0.85 (m, 6H). LCMS purity >95%,

[M+H]⁺ = 302, 1 .34 and 1 .36 min

(analytical short), 2.89 and 2.95 min

(analytical long).

Table 4

[00228] Example C.2: 1 -cyclohexyl-2-(7-methoxy-5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5-yl)ethanol

[00229] 2-chloro-4-(1 ,3-dioxolan-2-yl)-5-(1 H-imidazole-4-yl)pyridine

[00230] A suspension of ethylene glycol (7.5 mL, 134 mmol), p-toluenesulfonic acid monohydrate (498 mg, 2.62 mmol) and 2-chloro-5-(1 -tritylimidazol-4-yl)pyridine-4-carbaldehyde (1 .07 g, 2.38 mmol) was stirred at 70 °C for 1 hour. The reaction mixture was diluted in EtOAc (100 mL) and washed with a saturated solution of sodium bicarbonate solution (50 mL), water (3 x 50 mL) and brine (50 mL). The aqueous fractions were combined and extracted with EtOAc (2 x 100 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo to give a pale yellow solid. This was purified by flash column chromatography with a 0-10% MeOH in DCM eluent to give 2-chloro-4-(1 ,3-dioxolan-2-yl)-5-(1 H-imidazol-4-yl)pyridine (240 mg, 0.954 mmol, 40% yield) as a pale yellow solid. H NMR: (400 MHz, CDCI₃) 10.7 (br s, 0.5H), 9.6 (br s, 0.5H), 8.86 (s, 0.5H), 8.58 (s, 0.5H), 7.82 (s, 1 H), 7.65 (m, 1 H), 7.56 (s, 0.5H), 7.41 (s, 0.5H), 6.14 (s, 0.5H), 5.82 (s, 0.5H), 4.1 1 -4.21 (m, 4H). LCMS purity 96%, [M+H]⁺ = 252.0, 0.97 min (analytical short).

[00231] 4-(1 ,3-dioxolan-2-yl)-5-(1 H-imidazol-4-yl)-2-methoxy-pyridine

[00232] A solution of 2-chloro-4-(1 ,3-dioxolan-2-yl)-5-(1 H-imidazol-4-yl)pyridine (210 mg, 0.830 mmol) and sodium methoxide in methanol (12 mL, 210 mmol) was submitted to microwave irradiations at 120 °C in for 3 hours The reaction mixture was diluted in EtOAc (75 mL) and washed with water (2 x 30 mL). The aqueous was extracted with EtOAc (3 x 30 mL), and the combined organics were dried over sodium sulphate, filtered and concentrated in vacuo to give 4-(1 ,3- dioxolan-2-yl)-5-(1 H-imidazol-4-yl)-2-methoxy-pyridine (136 mg, 0.550 mmol, 66% yield) as a light yellow solid. H NMR: (400 MHz, CD₃OD) 8.39 (s, 1 H), 7.80 (s, 1 H), 7.39 (s, 1 H), 7.07 (s, 1 H), 5.86 (s, 1 H), 4.17-4.03 (m, 4H), 3.96 (s, 3H). LCMS purity 96%, [M+H]⁺ = 248.1 , 0.96 min (analytical short).

[00233] 5-(1 H-imidazol-4-yl)-2-methoxy-pyridine-4-carbaldehyde

[00234] A solution of 4-(1 ,3-dioxolan-2-yl)-5-(1 H-imidazol-4-yl)-2-methoxy-pyridine (135 mg, 0.550 mmol) in hydrogen chloride (2.0 mL, 12 mmol) was stirred at 50 °C for 24 hours. To the reaction mixture was added a saturated solution of sodium bicarbonate solution (100 mL), and the organic phase was extracted with EtOAc (4 x 50 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo to give a yellow foam. This material was taken through to the next stage without further purification. LCMS purity >90% [M+H]⁺ = 204.0, 0.45 min (analytical short).

[00235] (E)-1 -cyclohexyl-3-[5-(1 H-imidazol-4-yl)-2-methoxy-4-pyridyl]prop-2-en-1 -one

[00236] sodium hydroxide (124.01 mg, 3.1 mmol) was dissolved in water (1 .5ml_) and added slowly to a stirring solution of 5-(1 H-imidazol-4-yl)-2-methoxy-pyridine-4-carbaldehyde (90 mg, 0.44 mmol) and 1 -acetylcyclohexane (0.07 mL, 0.53 mmol) in THF (3 mL). The resulting orange solution was heated at 70 °C for 2 hours. The reaction mixture was allowed to cool to room temperature, diluted in EtOAc (50 mL) and washed with water (20 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL) and the organics combined, dried over sodium sulphate, filtered and concentrated in vacuo to give a brown oil. This was purified by flash column chromatography with a 0-10% methanol in DCM eluent. Fractions containing the desired product were combined and concentrated under reduced pressure to afford (E)-1 -cyclohexyl-3-[5-(1 H-imidazol-4-yl)-2-methoxy-4-pyridyl]prop- 2-en-1 -one (20 mg, 0.06 mmol, 14% yield). LCMS purity 90% [M+H₃0]⁺ = 312.3, 1 .38 min

(analytical short).

[00237] 1 -cyclohexyl-2-(7-methoxy-5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5-yl)ethanone

[00238] A solution of (E)-1 -cyclohexyl-3-[5-(1 H-imidazol-4-yl)-2-methoxy-4-pyridyl]prop-2-en-1 -one (20 mg, 0.060 mmol) in methanol (1 mL) and acetic acid (0.250 mL) was stirred at 90 °C for 1 .5 hours. The reaction was allowed to cool to room temperature and a saturated solution of sodium carbonate solution was added (10 mL). The resulting aqueous solution was extracted with EtOAc (3 x 15 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo to give a yellow film characterised as 1 -cyclohexyl-2-(7-methoxy-5H-imidazo[4,5]pyrrolo[1 ,2- b]pyridin-5-yl)ethanone (20 mg, 0.06 mmol, quantitative yield). H NMR: (400 MHz, CD₃OD) 8.38 (s, 1 H), 7.70 (s, 1 H), 7.12 (s, 1 H), 6.94 (s, 1 H), 5.67-5.68 (m, 1 H), 3.96 (s, 3H). 3.42-3.48 (m, 1 H), 3.08-3.16 (m, 1 H), 2.40-2.50 (m, 1 H), 1 .26-1 .90 (m, 10H). LCMS purity = 85% [M+H]⁺ = 312.3, 1 .38 min (analytical short).

[00239] 1 -cyclohexyl-2-(7-methoxy-5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5-yl)ethanol.

[00240] Sodium borohydride (4.86 mg, 0.130 mmol) was added to a stirring solution of 1 - cyclohexyl-2-(7-methoxy-5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5-yl)ethanone (20 mg, 0.060 mmol) in methanol (1 ml_) at room temperature for 45 minutes. Water (10 ml_) was added to the reaction mixture, and this was extracted with EtOAc (4 x 15 ml_). The combined organics were dried over sodium sulphate, filtered and concentrated in vacuo to give an off white solid. This was purified by flash column chromatography (0-7.5% methanol in EtOAc) to give a white solid characterised as 1 - cyclohexyl-2-(7-methoxy-5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5-yl)ethanol (16.5 mg, 0.0527 mmol, 82% yield). H NMR: (CD₃OD, 400 MHz) δ: 8.39 (s, 1 H), 7.92-7.96 (m, 1 H), 7.13-7.16 (m, 1 H), 6.96- 7.00 (m, 1 H), 5.46-5.55 (m, 1 H), 3.97 (s, 3H), 3.57-3.68 (m, 1 H), 2.08-2.28 (m, 2H), 0.87-1 .96 (m, 1 1 H). LCMS purity 100%, [M+H]+ = 314, 1 .39 min (short analytical), 2.93 and 2.96 min (long analytical).

Procedure D: Preparation of optionally substituted imidazo-pyrrolo-heteroaryl esters, ethers, amines and amides

[00241] Imidazo-pyrrolo-heteroaryl esters, ethers, amines and amides can be synthesised from the corresponding protected (imidazol-4-yl)heteroaryl carbaldehyde precursors by analogy with the procedure described in Scheme 5.

Scheme 5

[00242] Protected (imidazol-4-yl)heteroaryl carbaldehydes can be condensed with nitriles or esters (e.g. malonitrile, dimethyl malonate) in basic conditions (e.g. NaH) to generate αβ-unsatured nitriles or esters. Alternatively αβ-unsatured nitriles or esters can be generated via Wittig reaction conditions using reagents including but not limited to triethyl phosphonoacetate. Imidazole deprotection in acidic conditions (e.g. acetic acid) can lead to closure into the corresponding imidazo-pyrrolo-heteroaryl acetonitriles and imidazo-pyrrolo-heteroaryl acetates. Hydrolysis of these analogues can afford the corresponding imidazo-pyrrolo-heteroaryl ethanoic acids. These can then be converted to carboxylic azides and subjected to Curtius rearrangement conditions to give the corresponding imidazo-pyrrolo-heteroaryl methylamine analogues. The latter amines can be functionalised via reductive amination with aldehydes or ketones under standard conditions (e.g. STAB, NaCNBh ). The imidazo-pyrrolo-heteroaryl ethanoic acid intermediates can also be coupled to primary or secondary amines using coupling reaction conditions including but not limited to HBTU and EDC to afford the corresponding amides. Reduction of the amide functionality under reducing conditions (e.g. borane) can lead to the corresponding imidazo-pyrrolo-heteroaryl ethanamine analogues. Imidazo-pyrrolo-heteroaryl acetate intermediates can also be reduced (with for example DiBAL, UAIH4) to their corresponding imidazo-pyrrolo-heteroaryl acetaldehydes or imidazo-pyrrolo- heteroaryl ethanols. Reductive amination of the imidazo-pyrrolo-heteroaryl acetaldehyde analogues with primary or secondary amines can lead to secondary or tertiary imidazo-pyrrolo-heteroaryl ethanamines. Alternatively, alkylation of imidazo-pyrrolo-heteroaryl ethanols can be carried out in basic conditions to produce the corresponding imidazo-pyrrolo-heteroaryl ethyl ether analogues. Whenever needed, protecting groups may be used to afford the desired compounds.

[00243] Procedure E: Preparation of aryl and heteroaryl substituted imidazo-pyrrolo-heteroaryl analogues

[00244] Aryl-linked imidazo-pyrrolo-heteroaryl analogues can be synthesised from the corresponding protected (imidazol-4-yl)heteroaryl carbaldehyde precursors, halogenoheteroaryl carbaldehyde or halgoenoheteroaryl carboxylates by analogy with the procedure described in Scheme 6.

Scheme 6

[00245] Protected (imidazol-4-yl)heteroaryl carbaldehydes can be reacted with Ar-Li (prepared with Ar-X and BuLi), or Grignard reagents (e.g. Ar-MgCI, Ar-MgBr) to generate the corresponding secondary alcohols. Deprotection of the imidazole moiety (e.g. using acetic acid for trityl protecting group), followed by cyclisation under basic conditions or with activating agents (e.g. thionyl chloride) can afford the aryl or heteroaryl-linked imidazo-pyrrolo-heteroaryl analogues. Alternatively substituted halogenoheteroaryl methanol intermediates can be generated from the corresponding carbaldehydes by reaction with (Het)Ar-Li (prepared with (Het)Ar-X and (Het)BuLi), or Grignard reagents (e.g. (Het)Ar-MgCI, (Het)Ar-MgBr). Halogenoheteroaryl methanol intermediates can be reacted with optionally substituted imidazoles (upon activation of the alcohol using thionyl chloride, mesyl chloride, tosyl chloride or triflic anhydride, or under mitsunobu conditions) and cyclised using Heck coupling reaction conditions to afford aryl or heteroaryl-linked imidazo-pyrrolo-heteroaryl analogues. Whenever needed, protecting groups may be used to afford the desired compounds.

[00246] Example E.1 : Preparation 5-(8-isoquinolyl)-5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridine

[00247] 8-isoquinolyl-[3-(1 -tritylimidazol-4-yl)-2-pyridyl]methanol

[00248] 8-Bromoisoquinoline (131 mg, 0.630 mmol) was loaded in a 3-neck flask along with molecular sieves and dissolved in anhydrous THF (5 ml_). The resulting solution was stirred at -78 °C for 10 minutes. To this solution was added n-butyllithium solution (217 uL, 0.540 mmol) and the resulting mixture was sitrred at -78 °C for 5 min. To this was added an anhydrous solution of 3-(1 - tritylimidazol-4-yl)pyridine-2-carbaldehyde (150 mg, 0.360 mmol) in THF (5 ml_). The resulting mixture was allowed to reach room temperature and stirred at this temperature for 1 hour. The reaction was subsequently quenched by addition of sat. NaHCC (15 ml_) and extracted with ethyl acetate (2 x 15 ml_). The organics were combined, dried over Na2S04, filtered and concentrated under reduced pressure to yield a bright yellow crude. This was purified with a 20-100% ethyl acetate in heptane eluent. Fractions containing the desired product were combined and concentrated under reduced pressure to yield 8-isoquinolyl-[3-(1 -tritylimidazol-4-yl)-2- pyridyl]methanol (75 mg, 0.138 mmol, 38% yield) as a bright yellow film. H NMR (CDCI₃, 400MHz) δ: 9.44 (s, 1 H), 8.49 (dd, J 4.8, 1 .7 Hz, 1 H), 8.47 (d, J 5.7 Hz, 1 H), 7.98 (dd, J 7.8, 1 .7 Hz, 1 H), 7.67 (d, J 8.2 Hz, 1 H), 7.59 (dd, J 5.8, 0.8 Hz, 1 H), 7.47-7.51 (m, 1 H), 7.45 (d, J 1 .3 Hz, 1 H), 7.22-7.31 (m, 12H), 6.93-6.96 (m, 6H), 6.84 (bs, 1 H), 6.67 (d, J 1 .4 Hz, 1 H). LCMS purity 100%, [M+H]⁺ = 545.2, 1 .71 min (analytical short).

[00249] [3-(1 H-imidazol-4-yl)-2-pyridyl]-(8-isoquinolyl)methanol

[00250] 8-isoquinolyl-[3-(1 -tritylimidazol-4-yl)-2-pyridyl]methanol (75 mg, 0.140 mmol) was dissolved in acetic acid (2.5 mL) and methanol (5 mL) and the mixture was heated to 80 °C for 3 hours. Solvents were removed and the residue was taken through SCX-2 and eluted with 1 M NH3 in methanol. Fractions containing the desired product were combined and concentrated under reduced pressure to yield [3-(1 H-imidazol-4-yl)-2-pyridyl]-(8-isoquinolyl)methanol (40 mg, 0.13 mmol, 96% yield). H NMR (CDCI3, 400 MHz) δ: 9.23 (s, 1 H), 8.43 (d, J 5.2 Hz, 2H), 7.93 (d, J 7.6 Hz, 1 H), 7.60-7.73 (m, 6H), 7.29 (dd, J 7.8, 4.8 Hz, 1 H), 6.86 (s, 1 H). LCMS [M+H]⁺ = 303.1 , 0.42 min (analytical short).

[00251] 5-(8-isoquinolyl)-5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridine

[00252] [3-(1 H-imidazol-4-yl)-2-pyridyl]-(8-isoquinolyl)methanol (34 mg, 0.1 1 mmol) was dissolved in THF (5 mL) and thionyl chloride (16 uL, 0.22 mmol) was added. The reaction was left to stir at room temperature for 30 minutes. A saturated aqueous solution of NaHCC (15 mL) was added and the aqueous layer was extracted with ethyl acetate (3 x 15 mL), the organic layers were combined, dried over Na2S04, filtered and concentrated under reduced pressure to yield a colourless oil. This was purified with a 0-15% methanol in ethyl acetate eluent. Fractions containing the desired product were combined and concentrated under reduced pressure to yield 5-(8-isoquinolyl)-5H- imidazo[4,5]pyrrolo[1 ,2-b]pyridine (7.2 mg, 0.025 mmol, 22% yield). H NMR (CD3OD, 400MHz) δ: 10.1 1 (bs, 1 H), 8.53 (bs, 1 H), 8.28 (dd, J 5.0, 1 .4 Hz, 1 H), 8.17 (bs, 1 H), 7.43-8.00 (m, 7H), 6.84 (bs, 1 H). LCMS purity 100%, [M+H]⁺ = 285.1 , 0.83 min (analytical short).

[00253] Procedure F: Separation of stereoisomeric mixtures using SFC

[00254] Example F.1 : Separation of the 4 stereoisomers of 1 -cyclohexyl-2-(5H- imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanol into stereoisomers 1 , 2, 3 and 4.

[00255] First separation stage

[00256] A stereoisomeric mixture of 1 -cyclohexyl-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5- yhethanol (220.4 mg) was purified by SFC on a MG Π Pre SFC equipped with a ChiralPak AD-H, 250x30mml column equilibrated at 38 C. Compounds were eluted with a 30% CO2 and ethanol (0.1 %NH3.H2O) at 70 mL/min eluent. After separation, the fractions were concentrated in vacuo at 40 °C to get a mixture of stereoisomer! and stereoisomer 3, a mixture of stereoisomer 2 and stereoisomer 4.

[00257] Second separation stage

[00258] Both stereoisomeric mixtures (1 and 3, and 2 and 4) were purified by SFC on a MG Π Pre SFC equipped with a ChiralCel OD-H, 250x30mml column equilibrated at 38 °C. Compounds were eluted with a 30% CO2 and ethanol (0.1 %ΝΗ₃.Η2θ) at 60 mL/min eluent. After separation, the fractions were concentrated in vacuo at 40 °C to afford stereoisomer 1 , 2, 3 and 4. Analytical characterisation and enantiomeric excesses were recorded as follows:

[00259] Stereoisomer 1 (48.7 mg, 22% yield). H NMR (DMSO-d6, 400 MHz) δ: 8.86 (d, J 0.8 Hz, 1 H), 8.47 (d, J 4.8 Hz, 1 H), 7.96 (s, 1 H), 7.59 (d, J 5.2 Hz, 1 H), 7.23 (s, 1 H), 5.50 (dd, J 3.6, 10.4 Hz, 1 H), 5.00 (d, J 6 Hz, 1 H), 3.65-3.57 (m, 1 H), 2.22-2.16 (m, 1 H), 1 .85-1 .50 (6H, m), 1 .35-0.90 (6H, m). LCMS purity >95%, [M+H]⁺ = 284, 2.38 min (analytical long). SFC, 4.334 min, >95% d.e..

[00260] Stereoisomer 2 (43.9 mg, 20% yield). H NMR (DMSO-d6, 400 MHz) δ: 8.86 (d, J 0.8 Hz, 1 H), 8.47 (d, J 4.8 Hz, 1 H), 7.96 (s, 1 H), 7.59 (d, J 5.2 Hz, 1 H), 7.23 (s, 1 H), 5.50 (dd, J 3.6, 10.4 Hz, 1 H), 5.00 (d, J 6 Hz, 1 H), 3.65-3.57 (m, 1 H), 2.22-2.16 (m, 1 H), 1 .85-1 .50 (6H, m), 1 .35-0.90 (6H, m). LCMS purity >95%, [M+H]⁺ = 284, 2.38 min (analytical long). SFC, 4.334 min, >95% d.e..

[00261] Stereoisomer 3 (9.3 mg, 4% yield). H NMR (DMSO-d6, 400 MHz) δ: 8.86 (s, 1 H), 8.47 (d, J 4.8 Hz, 1 H), 8.00 (s, 1 H), 7.60 (d, J 5.2 Hz, 1 H), 7.21 (s, 1 H), 5.50-5.45 (m, 1 H), 4.80 (d, J 5.6 Hz, 1 H), 3.56-3.48 (m, 1 H), 2.22-0.90 (13H, m). LCMS purity >95%, [M+H]⁺ = 284, 2.34 min (analytical long). SFC, 4.913 min 61 % d.e. Contaminating enantiomer is stereoisomer 2.

[00262] Stereoisomer 4 (9.8 mg, 4% yield). LCMS purity >95%, [M+H]⁺ = 284, 2.35 min (analytical long). SFC, 5.228 min 13% d.e. Contaminating enantiomer is stereoisomer 1 .

[00263] Procedure G: Preparation of phenyl substituted 1 -aryl-2-(imidazo-pyrrolo- heteroaryl)ethanol

[00264] Phenyl substituted 1 -aryl-2-(imidazo-pyrrolo-heteroaryl)ethanol analogues can be synthesised by analogy with the procedure described in Scheme 7.

Scheme 7

[00265] 1 -Halogenoaryl-2-(imidazo-pyrrolo-heteroaryl)ethanols can be coupled to a phenyl boronic acid/ester using metal catalysis agents (e.g. Suzuki coupling conditions) to give the phenyl substituted 1 -aryl-2-(imidazo-pyrrolo-heteroaryl)ethanol analogues. [00266] Example G.1

[00267] 1 -(2-Chloro-4-phenyl-phenyl)-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanol

[00268] To a vial containing a solution of 1 -(4-bromo-2-chloro-phenyl)-2-(5H- imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanol (48 mg, 0.12 mmol) and 3-phenylboronic acid (19 mg, 0.16 mmol) was added 1 ,4-dioxane (2 ml_) and sodium carbonate (130 mg, 1 .2 mmol) in water (0.61 ml_). The resulting mixture was degassed with Nitrogen for 5 mins. [1 ,1 '- Bis(diphenylphosphino)ferrocene]Palladium(ll) chloride dichloromethane complex (10 mg, 0.010 mmol) was added and the vial capped. The solution was heated to 100 °C and stirred overnight. The mixture was allowed to cool to ambient temperature, filtered over a celite pad and concentrated in vacuo. The product was purified via column chromatography (eluting with 0-10% gradient of MeOH in DCM) to afford 1 -(2-chloro-4-phenyl-phenyl)-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5- yhethanol (18.5 mg, 39% yield). 1 H NMR (DMSO-d6, 400 MHz) δ: 8.89 (m, 1 H), 8.54 (d, J 4.9, 0.4H), 8.46 (d, J 4.9 Hz, 0.6H), 8.10 (s, 0.6H), 7.95 (s, 0.4H), 7.82 (d, J 8.0 Hz, 0.6H), 7.76-7.64 (m, 5H), 7.58 (d, J 4.4 Hz, 0.4H,), 7.47 (t, J 7.2 Hz, 2H), 7.41 (d, J 7.2 Hz, 1 H), 7.29 (s, 0.6 H), 7.23 (s, 0.4H), 6.03 (d, J 4.2 ,0.6H), 5.83 (d, J 4.2 Hz, 0.4H), 5.70-5.64 (m, 1 H), 5.34-5.29 (m, 0.6H), 5.25- 5.19 (m, 0.4H), 2.47-2.35 (m, 1 H), 2.37-2.21 (m, 0.4H), 1 .95-1 .89 (m, 0.6H). LCMS purity > 90%, [M+H]⁺ = 388.2, 3.12 and 3.14 min (analytical long).

[00269] Example G.2

[00270] 1 -[2-Chloro-4-(4-fluorophenyl)phenyl]-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanol

[00271] 1 -[2-Chloro-4-(4-fluorophenyl)phenyl]-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanol can be synthesised by analogy to the procedure outlined in Example G.1. H NMR (DMSO-d6, 400 MHz) δ: 8.88 (m, 1 H), 8.53 (d, J 4.8 Hz, 0.4H), 8.46 (d, J 5.0 Hz, 0.6H), 8.39 (s, 1 H), 8.10 (s, 0.6H), 7.95 (s, 0.4H), 7.81 (d, J 7.7 Hz, 0.6H), 7.76-7.64 (m, 5H), 7.58 (d, J 5.0 Hz, 0.6H), 7.32-7.28 (m, 2.6H), 7.22 (s, 0.4H), 6.07 (br.s, 0.4H), 5.88 (br.s, 0.6H), 5.70-5.63 (m, 1 H), 5.31 (dd, J 10.1 , 2.6 Hz, 0.6 H), 5.22 (dd, J 10.1 , 2.6 Hz, 0.4H), 2.43-2.36 (m, 1 H), 2.28-2.22 (m, 1 H), 2.04-1 .88 (m, 1 H). LCMS purity > 90%, [M+H]⁺ = 406.1 , 1 .37 min (analytical short), 3.16 and 3.18 min (analytical long). [00272] Biology

[00273] Biological example 1 : Human Indoleamine 2,3-Dioxygenase (ID01) enzyme activity (biochemical) assay

[00274] 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 (rhlDOI) and the formation of an N- 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.

[00275] Compounds at a concentration of 100 mM are serially diluted in 100% dimethyl sulfoxide (DMSO) six times in 96-well plates for a total of 7 dilution points. Each dilution and a DMSO control are further diluted 1 :125 in assay medium containing 50 mM potassium phosphate buffer (pH 6.5), 10 μΜ methylene blue, 10 mM ascorbic acid (freshly prepared, neutralised with an equimolar amount of NaOH), 100 μg/mL catalase (freshly prepared) and 0.01 % (v/v) bovine serum albumin (BSA).

[00276] Each well in a 96-well Hard-Shell® Low-Profile Thin-Wall Skirted PCR Plates (Bio-Rad #HSP-9645) contains 40 μΙ_ of enzymatic reaction volume per sample, including 10 μΙ_ of assay medium, 15 μΙ_ of purified rhIDO (R&D Systems 6030-AO) diluted in 50 mM potassium phosphate buffer (pH 6.5) containing 0.01 % Tween20 (v/v) and 0.01 % BSA (v/v), providing 15 nM final concentration and 5 μΙ_ compound DMSO dilution at 8 X the desired concentration, providing 100 μΜ at the final maximum concentration. Compounds are pre-incubated with the enzyme for 30 min at room temperature. The reaction is then started by addition of 10 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 10 μΙ_ 1 M piperidine to the 40 μΙ_ enzymatic reaction volume, providing 200 mM final concentration and the plates are covered with seals and incubated in a water bath set to 65 °C for 20 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).

[00277] All data are analysed using the GraphPad Prism software package. Inhibition of rhIDO 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 and the best fit value of the bottom of the reference compound concentration-response curve as 100% inhibition.

[00278] Biological example 2: Human Indoleamine 2,3-Dioxygenase (ID01) enzyme activity values

[00279] The results of the biochemical hlDOI assay for certain compounds of the invention are given in Table 5. 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 IC50 < 1 μΜ. All compounds are stereoisomeric mixtures unless otherwise stated.

Compound

category

1 -cyclohexyl-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanone ++

1 -cyclohexyl-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanol +++

2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)-1 -phenyl-ethanol ++

2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)-1 -phenyl-ethanone ++

1 -cyclohexyl-2-(5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5-yl)ethanol +++

1 -cyclohexyl-2-(5H-imidazo[2,3]pyrrolo[2,3-b]pyridin-5-yl)ethanol ++

2-(6-chloro-5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5-yl)-1 -cyclohexyl-ethanol ++

2-(7-chloro-5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5-yl)-1 -cyclohexyl-ethanol ++

5-(8-isoquinolyl)-5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridine +

1 -cyclohexyl-2-(7-methoxy-5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5-yl)ethanol ++

1 -cyclohexyl-2-(5H-imidazo[4,5]pyrrolo[1 ,2-b]pyrimidin-5-yl)ethanol +

1 -cyclohexyl-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanol, stereoisomer +++ 1

1 -cyclohexyl-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanol, stereoisomer ++ 2

1 -cyclohexyl-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanol, stereoisomer +

3

1 -cyclohexyl-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanol, stereoisomer +

4

1 -cyclohexyl-2-(8-fluoro-5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5-yl)ethanol

++

2-(8-chloro-5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5-yl)-1 -cyclohexyl-ethanol

++

1 -cyclohexyl-2-(6-fluoro-5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5-yl)ethanol

+++

1 -(4-bromo-2-chloro-phenyl)-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-

++ yl)ethanol

2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)-1 -(4-iodophenyl)ethanol

++

1 -(4-amino-2-chloro-phenyl)-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-

++ yl)ethanol

1 -(2-chloro-6-fluoro-phenyl)-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-

++ yl)ethanol

2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)-1 -[2-

++ (trifluoromethyl)phenyl]ethanol 1 -(2-bromophenyl)-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanol

++

1 -(2-chlorophenyl)-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanol

++

2-[1 -hydroxy-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethyl]phenol

++

1 -[4-fluoro-2-(trifluoromethyl)phenyl]-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-

++ yl)ethanol

1 -(2-fluorophenyl)-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanol

++

1 -(3-chlorophenyl)-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanol

++

1 -(4-aminophenyl)-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanol

++

2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)-1 -tetrahydropyran-4-yl-ethanol

++

1 -(4-chlorophenyl)-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanol

++

2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)-1 -(3-methoxyphenyl)ethanol

++

2-(5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5-yl)-1 -(p-tolyl)ethanol

++

2-(5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5-yl)-1 -(2-methoxyphenyl)ethanol

+

2-(5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5-yl)-1 -(o-tolyl)ethanol

++

1 -(2-chlorophenyl)-2-(5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5-yl)ethanol

++

2-(5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5-yl)-1 -(6-methoxy-3-pyridyl)ethanol

+

2-(5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5-yl)-1 -tetrahydropyran-4-yl-ethanol

++

2-(5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5-yl)-1 -(2-pyridyl)ethanol

++

1 -(2-Chloro-4-phenyl-phenyl)-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-

+++ yl)ethanol

1 -[2-Chloro-4-(4-fluorophenyl)phenyl]-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-

+++

5-yl)ethanol

Table 5

[00280] The following table provides values of the hlDOI biochemical activity of a selection of compounds of the invention. All compounds are stereoisomeric mixtures unless otherwise stated. hlDOI

Compound

activity

1 -cyclohexyl-2-(5H-imidazo[4,5]pyrrolo[1 ,2-a]pyridin-5-yl)ethanol 622 nM

1 -cyclohexyl-2-(5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5-yl)ethanol 468 nM

1 -cyclohexyl-2-(6-fluoro-5H-imidazo[4,5]pyrrolo[1 ,2-b]pyridin-5-yl)ethanol 999 nM [00281] Biological example 3: Human Tryptophan 2,3-Dioxygenase (hTD02) enzyme activity (biochemical) assay

[00282] The IC50 values were determined by measuring the enzymatic activity of hTD02 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 N- 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.

[00283] 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.

[00284] 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).

[00285] 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).

[00286] 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. [00287] Biological example 4: Human Tryptophan 2,3-Dioxygenase (hTD02) enzyme activity values

[00288] The following table provides values of the hTD02 biochemical activity of a selection of compounds of the invention. All compounds are stereoisomeric mixtures unless otherwise stated

[00289] 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.

[00290] 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.

[00291] 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):

(I)

wherein

'A' is a 5 or 6 membered heteroaryl group, unsubstituted or substituted with 1 , 2 or 3 groups (where chemically possible) selected from: halo, Ci- alkyl, Ci- haloalkyl, -OR^A, -NR^AR^B, -SR^A, -C(0)R^A, - OC(0)R^c, -C(0)OR^A, -NR^AC(0)R^c, -C(0)NR^AR^B, -NR^AS0₂R^c, -S0₂NR^AR^B, -N0₂, -CN and Ci-₄ alkyl substituted with -OR^A;

X is a bond or -(CR^A R^B )_n-;

Y is selected from: a bond, -(CR^DR^E)_m-, -0-, -NR^F-, -S-, -C(O)-, -C(NR^F)-, -C OR^R -

C(NR^FR^G)R^C-, -C(0)NR^F-, -NR^FC(0)-, -NR^FC(0)NR^G-, -NR^FS0₂NR^G-, -S0₂-, -S0₂NR^F-, -NR^FS0₂- , -OC(O)- and -C(0)0-;

Z is a bond or -(CR^A2R^B2)_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) independently selected at each occurrence from halo, Ci-₄ alkyl, Ci-₄ haloalkyl, C3-6 cycloalkyl, -OR^A3, -NR^A3R^B3, -SR^A3, -C(0)R^A3, -OC(0)R^A3, -C(0)OR^A3, -NR^A3C(0)R^B3, -C(0)NR^A3R^B3, -NR^A3S0₂R^B3, -S0₂NR^A3R^B3, -S0₂R^A3, =0, -N0₂, -CN, Ci- alkyl substituted with— OR^A3, Ci- alkyl substituted with -NR^A3R^B3 and C3-6 cycloalkyl substituted with -OR^A3, phenyl substituted with 0, 1 or 2 R^H, benzyl substituted with 0, 1 or 2 R^H, and benzoyl substituted with 0, 1 or 2 R^H;

R² is selected from: H, halo, Ci- alkyl, Ci- haloalkyl, -OR^M and Ci- alkyl substituted with -OR^M;

R³ and R⁴ are each independently selected from: H, halo, Ci-₄ alkyl, Ci-₄ haloalkyl, C3-6 cycloalkyl, - OR^A5, -NR^A5R^B4, -CN, -SR^A5 and Ci- alkyl substituted with— OR^A5;

R^A, R^B, R^c RA1 , RB1 , RA2_{7 RB2 I R}A3₇

RAT _AND RB5 _are independently selected at each occurrence from: H, Ci-₄ alkyl and Ci-₄ haloalkyl;

R^D and R^E are each independently selected at each occurrence from: H, =0, (i.e. R^D and R^E together form =0), =S (i.e. R^D and R^E together form =S), -OR^A6, -SR^A6, -NR^A6R^B5, halo, Ci- alkyl and Ci-₄ haloalkyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C3-8 cycloalkenyl, C3-8 heterocycloalkenyl, C6-10 aryl and C5-10 heteroaryl; R^F and R^G are each independently selected from: H, C1-4 alkyl and C1-4 haloalkyl, C3-8 cycloalkyl, C3- 8 heterocycloalkyl, C3-8 cycloalkenyl, C3-8 heterocycloalkenyl, Ce-io aryl and C5-10 heteroaryl; and

R^H is independently selected at each occurrence from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -CN, and -OR^A7.

2. The compound of claim 1 , wherein A is a ring selected from substituted or unsubstituted: pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl.

3. The compound of claim 1 or claim 2, wherein the compound of formula (I) is a compound according to formula (Ma) to (llj):

(llj) (Ilk) 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, -OR^A, -NR^AR^B, -SR^A, -C(0)R^A, -OC(0)R^c, - C(0)OR^A, -NR^AC(0)R^c, -C(0)NR^AR^B, -NR^AS0₂R^c, -S0₂NR^AR^B, -N0₂, -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.

4. The compound of any preceding claim, wherein Z is a bond, 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^FR^G)R^C-, -C(0)NR^F-, -NR^FC(0)-, - NR^FC(0)NR^G-, -NR^FS0₂NR^G-, -S0₂-, -S0₂NR^F-, -NR^FS0₂- , -OC(O)-, and -C(0)0-.

5. The compound of any of claims 1 to 3, wherein Z is -(CR^A2R^B2)k-, X is a bond and -, Y is selected from: -0-, -NR^F-, -S-, -C(O)-, -CCNR^p)-, -C(OR^F)R^C-, -C(NR^FR^G)R^C-, -C(0)NR^F-, -NR^FC(0)-, -NR^FC(0)NR^G-, -NR^FS0₂NR^G-, -S0₂-, -S0₂NR^F-, -NR^FS0₂- , -OC(O)-, and -C(0)0-.

6. The compound of any of claims 1 to 3, wherein X is -(CR^A R^B )_n-, Z is a bond and -, Y is selected from: -0-, -NR^F-, -S-, -C(O)-, -CCNR^p)-, -C(OR^F)R^C-, -C(NR^FR^G)R^C-, -C(0)NR^F-, -NR^FC(0)-, -NR^FC(0)NR^G-, -NR^FS0₂NR^G-, -S0₂-, -S0₂NR^F-, -NR^FS0₂- , -OC(O)-, and -C(0)0-.

7. The compound of any of claims 1 to 3, wherein Z is -(CR^A2R^B2)_k-, X is -(CR^A R^B )_n- and -, Y is selected from: -0-, -NR^F-, -S-, -C(O)-, -CCNR^p)-, -C(OR^F)R^C-, -C(NR^FR^G)R^C-, -C(0)NR^F-, -NR^FC(0)-, -NR^FC(0)NR^G-, -NR^FS0₂NR^G-, -S0₂-, -S0₂NR^F-, -NR^FS0₂- , -OC(O)-, and -C(0)0-.

8. The compound of any of claims 1 to 3, 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 -NR^F- and Z is a bond; X is a bond, Y is -NR^F- and Z is -CH₂-, -(CH₂)₂- or - C(Me)H-; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -NR^F- and Z is a bond; X is -CH₂-, -(CH₂)₂- or - C(Me)H-, Y is -NR^F- 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(NR^F)- and Z is a bond; X is a bond, Y is -C(NR^F)- and Z is -CH₂-, -(CH₂)₂- or - C(Me)H-; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -C(NR^F)- and Z is a bond; X is -CH₂-, -(CH₂)₂- or - C(Me)H-, Y is -C(NR^F)- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-;

X is a bond, Y is -CCOR^H- and Z is a bond; X is a bond, Y is -C(OR^F)H- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -C(OR^F)H- and Z is a bond; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -CCOR^H- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-; X is a bond, Y is -C(NR^FR^G)H- and Z is a bond; X is a bond, Y is -C(NR^FR^G)H- and Z is -CH2-, - (CH₂)₂- or -C(Me)H-; X is -CH2-, -(CH₂)₂- or -C(Me)H-, Y is -C(NR^FR^G)H- and Z is a bond; X is - CH2-, -(CH₂)₂- or -C(Me)H-, Y is -C(NR^FR^G)H- and Z is -CH₂-, -(CH₂)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- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -C(0)NR^F- and Z is a bond; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -C(0)NR^F- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-;

X is a bond, Y is -NR^FC(0)- and Z is a bond; X is a bond, Y is -NR^FC(0)- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -NR^FC(0)- and Z is a bond; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -NR^FC(0)- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-;

X is a bond, Y is -NR^FC(0)NR^G- and Z is a bond; X is a bond, Y is -NR^FC(0)NR^G- and Z is -CH₂-, - (CH₂)₂- or -C(Me)H-; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -NR^FC(0)NR^G- and Z is a bond; X is - CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -NR^FC(0)NR^G- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-;

X is a bond, Y is -NR^FS0₂NR^G- and Z is a bond; X is a bond, Y is -NR^FS0₂NR^G- and Z is -CH₂-, - (CH₂)₂- or -C(Me)H-; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -NR^FS0₂NR^G- and Z is a bond; X is - CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -NR^FS0₂NR^G- 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 -S0₂NR^F- and Z is a bond; X is a bond, Y is -S0₂NR^F- and Z is -CH₂-, -(CH₂)₂- or - C(Me)H-; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -S0₂NR^F- and Z is a bond; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -S0₂NR^F- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-;

X is a bond, Y is -NR^FS0₂- and Z is a bond; X is a bond, Y is -NR^FS0₂- and Z is -CH₂-, -(CH₂)₂- or - C(Me)H-; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -NR^FS0₂- and Z is a bond; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -NR^FS0₂- 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-.

9. The compound of claim 8, wherein X is a bond, Y is -C(OR^F)H- and Z is a bond; X is a bond, Y is -CCOR^H- and Z is -CH₂-, -(CH₂)₂- or -C(Me)H-; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is - C(OR^F)H- and Z is a bond; X is -CH₂-, -(CH₂)₂- or -C(Me)H-, Y is -CCOR^H- and Z is -CH₂-, - (CH₂)₂- or -C(Me)H-.

10. The compound of any of claims 1 to 4, wherein: X is a bond, Y is -C(0)NH- and Z is -CH₂-; X is a bond, Y is -C(O)- and Z is -CH₂ -; X is -CH2-, Y is -C(0)NH- and Z is -CH2-;

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-; or

X is a bond, Y is -O- and Z is -(CH₂)2-.

11 . 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 may optionally include 1 , 2 or 3 heteroatoms selected from O, N and S, and which is unsubstituted or substituted with 1 to 5 substituents.

12. The compound of any preceding claim, wherein R is selected from substituted or unsubstituted: pyridyl, quinolinyl, pyrimidinyl, isoquinolinyl, cyclohexyl, piperidinyl, tetrahydropyranyl, azetidyl, tetrahydroisoquinolinyl, phenyl, morpholinyl, piperazinyl, and oxadiazolyl.

13. The compound of any preceding claim, wherein R² is selected from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -OR^M and C1-4 alkyl substituted with -OR^M.

14. 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 -OR^A5.

15. The compound of claim 1 , wherein the compound of formula (I) is a compound selected from:

77

16. The compound of any preceding claim, wherein the compound is for use as a medicament.

17. A compound of any of claims 1 to 15 for use in the treatment of a condition which is modulated by indoleamine 2,3-dioxygenase (IDO) and/or tryptophan dioxygenase (TD02).

18. The compound of claim 17, wherein the condition modulated by IDO and/or TD02 is a condition that is treatable by the inhibition of IDO and/or TD02.

19. The compound of claim 18, 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.

20. A compound of any of claims 1 to 15, 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.

21 . A compound of any of claims 1 to 15 for use in treating IDO and/or TD02 mediated immunosuppression.

22. A compound of any of claims 1 to 15 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.

23. 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 15.

24. 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 15 to a patient in need thereof.

25. A use of a compound of any of claims 1 to 15 in the manufacture of a medicament for the treatment of a condition which is modulated by IDO and/or TD02.

26. A pharmaceutical formulation comprising a compound of any of claims 1 to 15 and a pharmaceutically acceptable excipient.

27. The pharmaceutical formulation of claims 26, wherein the pharmaceutical formulation is a combination product comprising an additional pharmaceutically active agent