GB2548542A

GB2548542A - Compounds

Info

Publication number: GB2548542A
Application number: GB1510493.8A
Authority: GB
Inventors: Bingham Matilda; Edward Armitage Simon; Pesnot Thomas
Original assignee: Redx Pharma Ltd
Current assignee: Redx Pharma Ltd
Priority date: 2015-06-16
Filing date: 2015-06-16
Publication date: 2017-09-27
Also published as: GB201510493D0

Abstract

Imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl compounds of formula (I) where A is a 6-membered heteroaryl group which may be optionally substituted as herein defined; Z is a substituent as herein defined; Y is a 5- or 6-membered carbocyclic or heterocyclic group which may be optionally substituted as herein defined; W is a bond or a substituent as herein defined; and R1 and R2 are each independently substituents as herein defined. The compounds of formula (I) are useful as indoleamine-2,3-dioxygenase (IDO) and/or tryptophan-2,3-dioxygenase (TDO) modulators (e.g. IDO and TDO inhibitors) and are preferably useful in treating indoleamine-2,3-dioxygenase (IDO) and/or tryptophan-2,3-dioxygenase (TDO) mediated diseases, such as IDO and/or TDO immunosuppression; treating conditions benefiting from inhibition of enzymatic activity of the IDO and/or TDO enzyme; enhancing the effectiveness of anti-cancer therapy; treating tumor specific immunosuppression associated with cancer; and treating immunosuppression associated with an infectious disease.

Description

[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 (TDO) modulators (e.g. IDO and/or TDO 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) and/or tryptophan 2,3-dioxygenase (TDO) mediated diseases, such as IDO and/or TDO mediated immunosuppression; treating a medical conditions that would benefit from the inhibition of enzymatic activity of the IDO and/or TDO 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 (ID01) and tryptophan dioxygenase (TDO) are heme-containing enzymes that catalyse the first and rate-limiting step in tryptophan metabolism (tryptophan to N-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.

[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 (TDO) modulators. For example, an aim of the present invention is to provide alternative or improved IDO and/or TDO 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):

wherein 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, C3-5 cycloalkyl, -ORA, -CN, -S02Me and C1-4 alkyl substituted with -ORA; Z is selected from: -(CRBRc)k-, -(CRBRc)kC(0)-, -(CRBRc)kC(NRA1)-, -(CRBRc)kC(N-ORA1)-, -(CRBRc)kC(ORA1)RB1-, and -(CRBRc)kC(NRA1RA2)RB1-; wherein k is selected from 1,2,3 and 4; Y is a 5 or 6 membered carbocyclic or heterocyclic group which is unsubstituted or substituted with 1,2 or 3 groups (where chemically possible) selected from: halo, C1-4 alkyl, C1-4 haloalkyl, C3-5 cycloalkyl, -ORA3, -CN, -S02Me and C1-4 alkyl substituted with -ORA3; W is selected from a bond, -NRA4-, -C(0)NRA4-, -NRA4C(0)-, -(CRB2Rc1)mNRA4C(0)-, - (CRB2Rc1)mC(0)NRA4-, -NRA4C(0)(CRB2Rc1)m-, -C(0)NRA4(CRB2Rc1)m- -NRA4C(0)NRA5-, -NRA4S02NRA5-, -SO2-, -S02NRA4-, -NRA4S02-, -(CRB2Rc1)mNRA4S(02)-, -(CRB2Rc1)mS(02)NRA4-, -NRA4S(02)(CRB2Rc1)m-, - S(02)NRA4(CRB2Rc1)m-, -NRA4C(0)0-, -0C(0)NRA4-, -NRA4C(0)0(CRB2Rc1)m-, -OC(O)-, -C(0)0, O and S; wherein m is 1 or 2; R1 is selected from substituted or unsubstituted: C1-10 alkyl, -N(Ci-io alkyl)RA6, and a 3 to 16 membered fully saturated, partially unsaturated or aromatic mono-, di- or tri-cyclic moiety, which optionally may include 1, 2, 3 or 4 heteroatoms (where chemically possible) selected from Ο, N and S, and when substituted R1 is 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, C3-6 heterocycloalkyl -ORA7, -NRA7RA8, -SRA7, -C(0)RA7, -0C(0)RA7, -C(0)0RA7, -NRA7C(0)RB3, -C(0)NRA7RA8, -NRA7S02RA8, -S02NRA7RA8, -S02RA7, =0, -N02, -CN, C1-4 alkyl substituted with -ORA7, C1-4 alkyl substituted with -NRA7RA8, C3-6 cycloalkyl substituted with -ORA7, phenyl substituted with 0, 1 or 2 RD, benzyl substituted with 0, 1 or 2 RD, and benzoyl substituted with 0, 1 or 2 RD; R2 is selected from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -ORA9 and C1-4 alkyl substituted with -ORA9; RA, RA1, RA2, RA3, RM, RA5, RAS, RA7, RA8, RA9 and RA1° are independently selected at each occurrence from: H, C1-4 alkyl and C1-4 haloalkyl; RB, RC, RB1, RB2, RC1 and RB3are each independently selected at each occurrence from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -CN, and -ORA1° or the RB and Rc groups on the same atom form, together with the carbon atom to which they are attached, cyclopropyl, oxirane or oxetane rings; RD is independently selected at each occurrence from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -CN, and -ORA8.

[0015] In a preferred embodiment, R2is H. Therefore, the compound of formula (I) may be a compound according to formula (la):

[0016] Optionally, ‘A’ is a 6 membered heteroaryl group, unsubstituted or substituted with 1 group (where chemically possible) selected from: halo, Ci^ alkyl, C1-4 haloalkyl and -CN.

[0017] In an embodiment, A is a ring selected from substituted or unsubstituted: pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. In an embodiment, A is a ring selected from substituted or unsubstituted: pyridyl, pyrimidinyl, and pyridazinyl. Most preferred is for A to be pyridyl.

[0018] In an embodiment A is a ring selected from substituted or unsubstituted: pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl (preferably pyridyl) and Z-(CRDRE)kC(0)- or-(CRDRE)kC(ORF)RC1-, preferably-CH2C(0)- and -CH2CH(OH)-.

[0019] In an embodiment A is not pyridyl. A may be a ring selected from substituted or unsubstituted: pyridazinyl, pyrimidinyl and pyrazinyl. In an embodiment, A is a ring selected from substituted or unsubstituted: pyrimidinyl and pyridazinyl.

[0020] In an embodiment, the compound of formula (I) is a compound according to formula (lla) to (lid) (optionally wherein R2 is H):

wherein n is selected from 0, 1,2 or 3, R3 is selected from: H, halo, C1-4 alkyl, C1-4 haloalkyl, C3-5 cycloalkyl, -ORA, -CN, -S02Me and C1-4 alkyl substituted with -ORA; optionally wherein RA is selected from: H, C1-4 alkyl and C1-4 haloalkyl.

[0021] Preferably the compound of the invention is a compound according to formula (lla) or (lid).

[0022] in an embodiment, A is unsubstituted. Thus, in an embodiment n may be 0.

[0023] In an embodiment A is substituted with 1,2 or 3 groups (where chemically possible) selected from: halo, C1-4 alkyl, -CN and C1-4 haloalkyl. Thus, in an embodiment R3 is selected from: halo, C1-4 alkyl, -CN and C1-4 haloalkyl and n may be 1,2 or 3.

[0024] In an embodiment, A is unsubstituted or 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, cyclopropyl, -S02Me, hydroxymethyl, hydroxyethyl and hydroxypropyl. Preferably, A is unsubstituted or substituted with 1 or 2 groups selected from: chloro, fluoro, methyl or trifluoromethyl.

[0025] In an embodiment, R3 is selected from: chloro, fluoro, methyl, ethyl, iso-propyl, tert-butyl, C1-2-haloalkyl (e.g. trifluromethyl, trifluoroethyl), -OH, -OMe, -OEt, -O-Ci-2-haloalkyl (e.g. trifluoromethoxy, trifluoroethoxy), -NH2, -NHMe, -ΝΜβ2, -NO2, -CN, cyclopropyl, -S02Me, hydroxyl methyl, hydroxyethyl and hydroxylpropyl. Preferably, R3 is absent (n=0) or R3 is selected from: chloro, fluoro, methyl or trifluoromethyl, optionally wherein n is 1.

[0026] In an embodiment, A is unsubstituted pyridyl, chloropyridyl, fluoropyridyl, methylpyridyl, ethylpyridyl, iso-propylpyridyl, tert-butylpyridyl, trifluoromethylpyridyl, methoxypyridyl, ethyoxypyridyl, aminopyridyl, /V-methyl-aminopyridyl, /V,/V-dimethyl-aminopyridyl, nitropyridyl, cyanopyridyl, unsubstituted pyrimidinyl, chloropyrimidinyl, fluoropyrimidinyl, methylpyrimidinyl, ethylpyrimidinyl, iso-propylpyrimidinyl, tert-butylpyrimidinyl, trifluoromethylpyrimidinyl, methoxypyrimidinyl, ethyoxypyrimidinyl, aminopyrimidinyl, N-methyl-aminopyrimidinyl, Ν,Ν-dimethyl-aminopyrimidinyl, nitropyrimidinyl, cyanopyrimidinyl, unsubstituted pyridazinyl, chloropyridazinyl, fluoropyridazinyl, methylpyridazinyl, ethylpyridazinyl, iso-propylpyridazinyl, tert-butylpyridazinyl, trifluoromethylpyridazinyl, methoxypyridazinyl, ethyoxypyridazinyl, aminopyridazinyl, /V-methyl-aminopyridazinyl, A/,A/-dimethyl-aminopyridazinyl, nitropyridazinyl, or cyanopyridazinyl.

[0027] In an embodiment, A is unsubstituted pyridyl, chloropyridyl, fluoropyridyl, methylpyridyl, ethylpyridyl, iso-propylpyridyl, tert-butylpyridyl, trifluoromethylpyridyl, methoxypyridyl, ethyoxypyridyl, aminopyridyl, /V-methyl-aminopyridyl, /V,/V-dimethyl-aminopyridyl, nitropyridyl or cyanopyridyl.

[0028] In an embodiment, A is unsubstituted pyrimidinyl, chloropyrimidinyl, fluoropyrimidinyl, methylpyrimidinyl, ethylpyrimidinyl, iso-propylpyrimidinyl, tert-butylpyrimidinyl, trifluoromethylpyrimidinyl, methoxypyrimidinyl, ethyoxypyrimidinyl, aminopyrimidinyl, N-methyl-aminopyrimidinyl, Ν,Ν-dimethyl-aminopyrimidinyl, nitropyrimidinyl or cyanopyrimidinyl.

[0029] In an embodiment, A is unsubstituted pyridazinyl, chloropyridazinyl, fluoropyridazinyl, methylpyridazinyl, ethylpyridazinyl, iso-propylpyridazinyl, tert-butylpyridazinyl, trifluoromethylpyridazinyl, methoxypyridazinyl, ethyoxypyridazinyl, aminopyridazinyl, /V-methyl-aminopyridazinyl, /V,/V-dimethyl-aminopyridazinyl, nitropyridazinyl or cyanopyridazinyl.

[0030] In an embodiment, A is pyridyl, methoxypyridyl, chloropyridyl, fluoropyridyl, trifluoromethylpyridyl, cyanopyridyl or methylpyridyl.

[0031] In an embodiment n is 0, 1 or 2, preferably, 0 or 1.

[0032] In an embodiment Y is a 5 or 6 membered carbocyclic or heterocyclic group which is unsubstituted or substituted with 1 group (where chemically possible) selected from: halo, C1-4 alkyl, C1-4 haloalkyl, C3-5 cycloalkyl, -ORA3, -CN, -SC>2Me and C1-4 alkyl substituted with -ORA3. Preferably Y is substituted with halo, optionally chloro.

[0033] In an embodiment Y is substituted or unsubstituted: C5-6 cycloalkyl, C5-6 heterocycloalkyl, C5-6 cycloalkenyl, C5-6 heterocycloalkenyl, C6 aryl orCs-6 heteroaryl.

[0034] Y may represent substituted or unsubstituted: cyclopentyl, cyclohexyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrolinyl, imidazolidinyl, imidazolinyl, succinimidyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, oxazolinyl, dioxolanyl, isoxazolidinyl, isoxazolinyl, thiazolidinyl, thiazolinyl, isothiazolidinyl, isothiazolinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dihydropyranyl, tetrahydropyranyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl.

[0035] Y may be substituted or unsubstituted: piperdinyl, phenyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, or pyrazolyl.

[0036] Where Y is substituted it may be substituted by 1,2 or 3 R4 groups, wherein R4 is independently selected from: halo, C1-4 alkyl, C1-4 haloalkyl, C3-5 cycloalkyl, -ORA3, -CN, -SC>2Me and C1-4 alkyl substituted with -ORA3. Preferably Y is substituted with halo, optionally chloro. Preferably Y is substituted by 1 R4 group and R4 is H or chloro.

[0037] Y may be substituted or unsubstituted: phenyl, pyridyl, piperidinyl or thiazolyl, optionally wherein Y is substituted with a halogen (preferably chloro).

[0038] Preferably Y is phenyl, chlorophenyl, pyridyl, piperidinyl or thiazolyl.

[0039] In an embodiment, the compound of formula (I) is a compound according to formula (Ilia) to (Hid):

wherein n is selected from 0, 1,2 or 3, and R4 is selected from: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA3, C3-5 cycloalkyl, -CN, -S02Me and C1-4 alkyl substituted with -ORA3.

[0040] Y has two substituents attached to it, Z and W. Y is a cyclic system. As such, the substitution pattern on Y can be defined following the ortho, meta and para nomenclature. In a preferred embodiment Z and W are substituted meta or para to one another on the ring of Y.

[0041] Preferably, when Y is a 6 membered ring Z and W are substituted para to one another and when Y is a 5 membered ring Z and W are substituted meta to one another. Therefore, for example, in an embodiment, the compound of formula (I) is a compound according to formula (IVa) to (IVp):

[0042] Preferably, the compound of the invention is a compound according to fomulae (IVa) to (IVd).

[0043] Z may be selected from: -(CRBRc)k-, -(CRBRc)kC(0)-, or -(CRBRc)kC(ORA1)RB1-, optionally wherein RB and Rc are independently selected from: H, methyl, -CF3, fluoro, chloro, -OMe, and -OCF3 or RB and Rc on the same atom form, together with the carbon atom to which they are attached, cyclopropyl, oxirane or oxetane rings.

[0044] Z may be selected from: -CH2-, -(CH2)2- or -C(Me)H-, -CH2C(0)-, -CH2C(NH)-, -CH2C(NMe)-, -CH2C(OH)H-, -CH2C(OH)Me-, -CH2C(OMe)H-, -0Η20(ΝΗ2)Η-, -CH2C(NHMe)H-, -CH2CHF-, -CH2CF2-, -CH2C(-CH2OCH2-)-, -C(Me)HC(0)-, -C(Me)HC(NH)-, -C(Me)HC(NMe)-, -C(Me)HC(OH)H-, -C(Me)HC(OH)Me-, -C(Me)HC(OMe)H-, -C(Me)HC(NH2)H-, -C(Me)HC(NHMe)H-, -C(Me)HCHF-, -C(Me)HCF2- and -C(Me)HC(-CH2OCH2-)-.

[0045] Preferably, Z is -CH2-, -(CH2)2-, -C(Me)H-, -CH2C(0)-, -CH2C(OH)H-, -CH2C(OH)Me-, -C(Me)HC(0)-, -C(Me)HC(OH)H- or-C(Me)HC(OH)Me-. In a particularly preferred embodiment Z is -CH2-, -CH2C(0)- or-CH2C(OH)H-.

[0046] In a particularly preferred embodiment Z is -CH2C(OH)H-.

[0047] W may be selected from a bond, -NRA4-, -C(0)NRA4-, -NRA4C(0)-, -(CRB2Rc1)mNRA4C(0)-, -(CRB2Rc1)mC(0)NRA4-, -NRA4C(0)NRA5-, -NRA4S02-, -NRA4C(0)0-, and -0C(0)NRA4-. Optionally, W is selected from a bond, -NH-, -C(0)NH-, -NHC(O)-, -CH2NHC(0)-, -CH2C(0)NH-, -NHC(0)NH-, -NHS02-, -NHC(0)0-, and -0C(0)NH-. Preferably, W is -NRA4C(Ο)NRA5-, optionally -NHC(0)NH-.

[0048] There are provided compounds of any formula disclosed herein wherein: Z is a -CH2- and W is a bond; Z is -CH2C(0)- and W is a bond; Z is -CH2C(OH)H- and W is a bond; Z is -CH2- and W is -NH-; Z is -CH2C(0)- and W is -NH-; Z is -CH2C(OH)H- and W is -NH-; Z is -CH2- and W is -NMe-; Z is -CH2C(0)- and W is -NMe-; Z is -CH2C(OH)H- and W is -NMe-; Z is -CH2- and W is -C(0)NH-; Z is -CH2C(0)- and W is -C(0)NH-; Z is -CH2C(OH)H- and W is -C(0)NH-; Z is -CH2- and W is -NH(CO)-; Z is -CH2C(0)- and W is -NH(CO)-; Z is -CH2C(OH)H- and W is -NH(CO)-; Z is -CH2- and W is -CH2NHC(0)-; Z is -CH2C(0)- and W is -CH2NHC(0)-; Z is -CH2C(OH)H- and W is -CH2NHC(0)-; Z is -CH2- and W is -CH2C(0)NH-; Z is -CH2C(0)- and W is -CH2C(0)NH-; Z is -CH2C(OH)H- and W is -CH2C(0)NH-; Z is -CH2- and W is -NHC(0)NH-; Z is -CH2C(0)- and W is -NHC(0)NH-; Z is -CH2C(OH)H- and W is -NHC(0)N H-; Z is -CH2- and W is -NHS02-; Z is -CH2C(0)- and W is -NHS02-; Z is -CH2C(OH)H- and W is -NHS02-; Z is -CH2- and W is -NHC(0)0-; Z is -CH2C(0)- and W is -NHC(0)0-; Z is -CH2C(OH)H- and W is -NHC(0)0-; or Z is -CH2- and W is -0C(0)NH-; Z is -CH2C(0)- and W is -0C(0)NH-; Z is -CH2C(OH)H- and W is -0C(0)NH-.

[0049] There are provided compounds of any formula disclosed herein wherein: Z is -CH2C(OH)H-and W is a bond; Z is -CH2C(OH)H- and W is -NH-; Z is -CH2C(OH)H- and W is -NMe; Z is -CH2C(OH)H-and W is -C(0)NH-; Z is -CH2C(OH)H- and W is -NH(CO)-; Z is -CH2C(OH)H- and W is -CH2NHC(0)-; Z is -CH2C(OH)H- and W is -CH2C(0)NH-; Z is -CH2C(OH)H- and W is -NHC(0)N H-; Z is -CH2C(OH)H-and W is -NHS02-; Z is -CH2C(OH)H- and W is -NHC(0)0-; or Z is -CH2C(OH)H- and W is -OC(0)NH-.

[0050] R1 may be selected from substituted or unsubstituted: C1-6 alkyl, -N(Ci-6 alkyl)RA6, and a 3 to 10 (optionally 3 to 9) membered fully saturated, partially unsaturated or aromatic mono- ordi-cyclic moiety, which optionally may include 1,2, 3 or 4 heteroatoms (where chemically possible) selected from Ο, N and S, and when substituted R1 is substituted as defined elsewhere herein.

[0051] In an embodiment, R1 is selected from substituted or unsubstituted: Ci-β alkyl, -N(Ci-e alkyl)RA6 and a 3 to 10 membered fully saturated, partially unsaturated or aromatic mono- ordi-cyclic moiety, which may optionally include 1,2 or 3 heteroatoms (where chemically possible) selected from Ο, N and S, and when substituted R1 is substituted as defined elsewhere herein.

[0052] In an embodiment, R1 is selected from substituted or unsubstituted: Ci-β alkyl, -N(Ci-e alkyl)RA6, C3-10 cycloalkyl, C5-10 heterocycloalkyl, C3-10 cycloalkylene, C5-10 heterocycloalkylene, Ce-10 aryl and C5-10 heteroaryl, and when substituted R1 is substituted as defined elsewhere herein.

[0053] In an embodiment, R1 is selected from substituted or unsubstituted: Ci-β alkyl, -N(Ci-4 alkyl)RA3, C3-6 cycloalkyl, C5-10 heterocycloalkyl, Ce aryl and C5-10 heteroaryl, and when substituted R1 is substituted as defined elsewhere herein.

[0054] C1-6 alkyl may represent methyl, ethyl, propyl, iso-propyl (1-methylethyl), butyl, iso-butyl (2-methylpropyl), tert-butyl (1,1-dimehtylethyl), sec-butyl (1-methylpropyl), pentyl, hexyl, and tert-hexyl (3,3-dimethylbutyl).

[0055] N(Ci-e alkyl)RA3 may represent NMeH, NMe2, N(CH2CH3)H, N(CH2CH2CH3)H, N(CH2CH2CH2CH3)H, N(CH2CH2CH2CH2CH3)H and N(CH2CH2CH2CH2CH2CH3)H.

[0056] C3-10 cycloalkyl may represent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0057] C510 heterocycloalkyl may represent oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, dioxolane, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, dioxane, or tetrahydropyran.

[0058] C3-10 cycloalkylene may represent cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl, cycloatadienyl, indanyl, indenyl and tetralinyl.

[0059] C5-10 heterocycloalkylene may represent pyroline, imidazoline, pyrazoline, oxazolidine, oxazoline, isoxazoline, thiazoline, isothiazoline, dihydropyridine, tetrahydropyridine, dihydropyran, indoline, isoindoline, chromene, chromane, isochromane, dihydroquinoline, tetrahydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, benzodioxolane or benzondioxane.

[0060] Ce-ίο aryl may represent phenyl or napthyl. Ce aryl may represent phenyl.

[0061] C5-10 heteroaryl may represent pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl and benzimidazolyl.

[0062] In an embodiment R1 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, dihydropyridine, tetrhydropyridine, 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.

[0063] In an embodiment R1 is selected from substituted or unsubstituted: methyl, ethyl, propyl, sec-butyl (1-methylpropyl), tert-hexyl (3,3-dimethylbutyl), ΝΜβ2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, azetidine, tetrahydrofuran, tetrahydrothiophene, imidazolidine, succinimide, piperidine, dihydropyran, tetra hydro pyridyl, morpholine, piperazine, tetrahydropyran, benzodioxolane, benzondioxane, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.

[0064] In a preferred embodiment R1 is selected from substituted or unsubstituted: ethyl, cyclopropyl, cyclohexyl, piperidine, tetrahydropyridine, dihydropyran, tetrahydropyran, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, and oxadiazolyl.

[0065] In an embodiment, the R1 moiety is substituted with 1,2 or 3 substituents selected from: halo, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, C3-6 heterocycloalkyl -ORA7, -NRA7RA8, -C(0)RA7, -0C(0)RA7, -C(0)0RA7, -NRA7C(0)RB3, -C(0)NRA7RA8, -S02RA7, =0, -CN and phenyl. .

[0066] In an embodiment, the R1 moiety is substituted with 1,2 or 3 substituents selected from halo (e.g. chloro orflouro), -CN, =0, -ORA3 (e.g. -OH, -OMe, -OEt or-OCF3), -NRA7RA8 (e.g. -NH2, -NHMe or -NMe2), -C(0)RA7 (e.g. -C(O)Me), -C(0)0RA7 (e.g. -C(0)0H, -C(0)0Me or-C(O)O'Bu), -C(0)NRA7RA8, (e.g. -C(0)NH2, -C(0)NHMe or-C(0)NMe2), -NRA7C(0)RB3 (e.g. -NHC(O)Me), -S02RA7 (e.g. -S02Me), C1-4 alkyl (e.g. methyl, ethyl, isopropyl ortert-butyl), C1-4 haloalkyl (e.g. difluoromethyl, trifluoromethyl or trifouroethyl), C3-6 heterocycloalkyl (e.g. morpholine), C3-6 cycloalkyl (e.g. cyclopropyl), C1-4 alkyl substituted with -ORA3 (e.g. -CH2OH or-CH20Me), C1-4 alkyl substituted with -NRA3RB3 (e.g. -CH2NH2), phenyl.

[0067] In an embodiment, the R1 moiety is substituted with 1 or 2 substituents selected from halo (e.g. chloro orflouro), -CN, -ORA7 (e.g. -OH, -OMe, -OEt or-OCF3), -NRA7RA8 (e.g. -NH2, -NHMe or-NMe2), -C(0)0RA7 (e.g. -C(0)OH, -C(0)0Me or-C(0)0‘Bu), C1-4 alkyl (e.g. methyl, ethyl, isopropyl ortert-butyl), orCi-4 alkyl substituted with -ORA7 (e.g. -CH2OH or-CH20Me). Preferably, 1 or 2 substituents selected from flouro, -CN, -OMe, -NH2, -C(0)0‘Bu, methyl, or-CH20Me.

[0068] In an embodiment, R2 is selected from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -ORA9 and C1-4 alkyl substituted with -ORA9. In an embodiment, R2 is selected from: H, chloro, fluoro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, trifluoroethyl, -OH, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl. In an embodiment, R2 is selected from: H, methyl and -OH. Preferably, R2 is H.

[0069] In an embodiment, R4 is independently selected at each occurrence from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -CN and -ORA3. In an embodiment, R4 is independently selected at each occurrence from: H, halo and C1-4 alkyl. In an embodiment, R4 is H orchloro. In an embodiment, R4 is chloro and p is 1.

[0070] In an embodiment, the compound of formula (I) is a compound according to formula (Va) to (Vc):

[0071] In an embodiment, the compound of formula (I) is a compound according to formula (Vd) to (Vf):

[0072] Optionally, RA, RA1RA2, RA3, RM, RA5, RA6, RA7, RA8, RA9 and RA1° are independently selected at each occurrence from: H, methyl, ethyl, trifluoromethyl, and trifluoroethyl.

[0073] Optionally, RB, Rc, RB1, RB2, RC1 and RB3 are each independently selected at each occurrence from: H, -ORA1°, halo, C1-4 alkyl, and C1-4 haloalkyl or the RB and Rc groups on the same atom form, together with the carbon atom to which they are attached, cyclopropyl, oxirane or oxetane rings. Preferably, RB and Rc are each independently selected at each occurrence from: H, fluoro, chloro, methyl, ethyl, trifluoromethyl, trifluoroethyl and cyclopropyl.

[0074] RD is independently selected at each occurrence from: H, fluoro, chloro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, trifluoromethyl, -CN, -OH and -OMe.

[0075] In an embodiment, the compound of formula (I) is a compound according to formula (VI) to formula (IX):

[0076] In an embodiment, the compound of formula (I) is a compound according to formula (Via) to formula (IXa):

[0077] In embodiments where the compound of formula (I) is a compound according to formula (VI) or (Via) R4 may preferentially be H or chloro.

[0078] The compound according to the invention may be selected from a preferred group consisting of:

[0079] The compound according to the invention may be selected from the particularly prefered compounds:

[0080] The above compounds have one or two chiral centres. All enantiomers and diastereomers of the above compounds are contemplated by the invention. Furthermore, the present invention encompasses all mixtures of enantiomers and diasteroeomers. The mixture may be or may not be a racemic mixture and the mixture may have the sme percentage of enantiomers or diasteromers or it may have different amounts of each enantiomer or diastereomer. Chiral centres are indicated on the compounds above with a * symbol. In one embodiment the compounds of the invention have the (Reconfiguration at a stereocentre or at the only stereocentre. In an alternative embodiment the compounds of the invention have the (S)-configuration at a stereocentre or the only 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.

[0081] In accordance with another aspect, the present invention provides a compound of the present invention for use as a medicament.

[0082] In accordance with another aspect, the present invention provides a pharmaceutical formulation comprising a compound of the present invention and a pharmaceutically acceptable excipient.

[0083] 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.

[0084] 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 (TDO). Usually conditions that are modulated by IDO and/or TDO are conditions that would be treated by the inhibition of IDO and/or TDO, 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 TDO.

[0085] IDO and/or TDO inhibition is relevant for the treatment of many different diseases associated with inhibition of IDO and/or TDO. In embodiments the condition treatable by the inhibition of IDO and/or TDO 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. 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 TDO may be selected from: immunosuppression melanoma, metastatic non-small cell lung cancer, nonsmall 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, glioblastoma, hepatocellular carcinoma, 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.

[0086] In particular the inhibition of TDO may be relevant for the treatment of glioblastoma and hepatocellular carcinoma.

[0087] 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.

[0088] 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, glioblastoma, hepatocellular carcinoma, 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.

[0089] In an aspect of the invention there is provided a method of treatment of a condition which is modulated by IDO and/or TDO, wherein the method comprises administering a therapeutic amount of a compound of the invention, to a patient in need thereof.

[0090] The method of treatment may be a method of treating a condition treatable by the inhibition of IDO and/or TDO. These conditions are described above in relation to conditions treatable by the inhibition of IDO and/or TDO.

[0091] 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, glioblastoma, hepatocellular carcinoma, 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.

[0092] 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 TDO. Usually conditions that are modulated by IDO and/or TDO are conditions that would be treated by the inhibition of IDO and/or TDO, 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 TDO. The condition may be any of the conditions mentioned above.

[0093] 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.

[0094] 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 TDO, wherein the system is exposed to a compound of the invention.

[0095] In accordance with another aspect, the present invention provides a compound of the present invention for use in treating IDO and/or TDO mediated immunosuppression.

[0096] In accordance with another aspect, the present invention provides a compound of the present invention for use in treating immunosuppression.

[0097] 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.

[0098] 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.

[0099] In accordance with another aspect, the present invention provides methods of modulating an activity of IDO and/or TDO comprising contacting an IDO and/or TDO containing system with a compound according to the present invention.

[00100] In accordance with another aspect, the present invention provides methods of treating IDO and/or TDO mediated immunosuppression in a subject in need thereof, comprising administering an effective amount of a compound according to the present invention.

[00101] In accordance with another aspect, the present invention provides methods of treating a medical condition that benefits from the inhibition of enzymatic activity of IDO and/or TDO comprising administering an effective amount of a compound according to the present invention.

[00102] 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.

[00103] 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.

[00104] 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.

[00105] 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, myelodysplastic syndrome, ovarian cancer, fallopian tube cancer, peritoneal tumor, glioblastoma, hepatocellular carcinoma and colorectal cancer.

DETAILED DESCRIPTION

[00106] 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.

[00107] 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.

[00108] The term “C1-6 alkyl” refers to a linear or branched hydrocarbon chain containing 1,2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, /so-propyl, /7-butyl, sec-butyl, ferf-butyl, n-pentyl and n-hexyl. Alkylene groups may likewise be linear or branched and may have two places of attachment to the remainder of the molecule. Furthermore, an alkylene group may, for example, correspond to one of those alkyl groups listed in this paragraph. The alkyl and alkylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C1-6 alkoxy.

[00109] The term “Ci-β alkoxy” refers to an alkyl group which is attached to a molecule via oxygen. This includes moieties where the alkyl part may be linear or branched and may contain 1,2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, /)-propyl, /so-propyl, /7-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Therefore, the alkoxy group may be methoxy, ethoxy, n-propoxy, /so-propoxy, n-butoxy, sec-butoxy, fe/f-butoxy, /)-pentoxy and /)-hexoxy. The alkyl part of the alkoxy group may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, Ci-β alkoxy.

[00110] 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-β 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.

[00111] 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.

[00112] 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.

[00113] The term “Ci-β 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-β heteroalkyl may be bonded to the rest of the molecule through a carbon ora heteroatom. For example, the “C1-6 heteroalkyl” may be C1-6 N-alkyl, C1-6 N,N-alkyl, or Ci-β O-alkyl.

[00114] 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.

[00115] 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.

[00116] 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.

[00117] 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. The one or more double bonds may be present at any positions within the ring tha tis chemically possible. For example, the “C3-8 cycloalkyl” may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.

[00118] The term “C3-8 heterocycloalkyl” refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least one heteroatom within the ring selected from N, O and S. For example there may be 1,2 or 3 heteroatoms, optionally 1 or 2. The “C3-8 heterocycloalkyl” may be bonded to the rest of the molecule through any carbon atom or heteroatom. The “C3-8 heterocycloalkyl” may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring. For example, the “C3-8 heterocycloalkyl” may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

[00119] The term “C3-8 heterocycloalkenyl” refers to an unsaturated hydrocarbon ring system, that is not aromatic, containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least one heteroatom within the ring selected from N, O and S. For example there may be 1,2 or 3 heteroatoms, optionally 1 or 2. The “C3-8 heterocycloalkenyl” may be bonded to the rest of the molecule through any carbon atom or heteroatom. The “C3-8 heterocycloalkenyl” may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring. For example, the “C3-8 heterocycloalkyl” may be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline.

[00120] 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.

[00121] 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.

[00122] 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 Ο, 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.

[00123] 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 -CFhphenyl and benzoyl refers to -C(0)phenyl.

[00124] 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.

[00125] The term “halogen” herein includes reference to F, Cl, Br and I. Halogen may be Cl. Halogen may be F.

[00126] Certain groups recited herein are defined, for example, as -C(0)NRA4-, -NRA4C(0)NRA5-, -NRA4C(0)0- and -OC(O)-. It wuld be immediately evident to one skilled in the art that “-C(O)-” represents a carbon-oxygen double bond. For example, -C(0)NRA4-, -NRA4C(0)NRA5-, -NRA4C(0)0- and -0C(0)- are respectively:

[00127] 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.

[00128] 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, C1-6 alkyl, C1-6 alkoxy, C1-6 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 orCi-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.

[00129] 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.

[00130] 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 “ *** ”.

[00131] “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.

[00132] “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.

[00133] 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, C1-6 alkyl, C3-8 cycloalkyl, phenyl, benzyl or phenethyl group, eg R is H orCi-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.

[00134] 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 ora 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.

[00135] 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.

[00136] 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.

[00137] 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).

[00138] 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.

[00139] 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.

[00140] 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.

[00141] 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).

[00142] Hereinafter all references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

[00143] 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.

[00144] 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.

[00145] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123l and 125l, nitrogen, such as 13N and 15N, oxygen, such as 1sO, 170 and 1sO, phosphorus, such as 32P, and sulphur, such as 35S.

[00146] 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. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[00147] 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.

[00148] 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.

[00149] 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.

[00150] 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.

[00151] 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, ortyrosine 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 [00152] 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.

[00153] 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-A/-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (Cl 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-1R kinase inhibitors, IGF receptor, kinase inhibitors; aurora kinase inhibitors and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors; and CCR2, CCR4 orCCR6 modulator; (v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™); thalidomide; lenalidomide; and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib; (vi) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2; (vii) immunotherapy approaches, including for example antibody therapy such as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®) and ofatumumab; interferons such as interferon a; interleukins such as IL-2 (aldesleukin); interleukin inhibitors for example IRAK4 inhibitors; cancer vaccines including prophylactic and treatment vaccines such as HPV vaccines, for example Gardasil, Cervarix, Oncophage and Sipuleucel-T (Provenge); gp100;dendritic cell-based vaccines (such as Ad.p53 DC); and toll-like receptor modulators for example TLR-7 or TLR-9 agonists; and (viii) cytotoxic agents for example fludaribine (fludara), cladribine, pentostatin (Nipent™); (ix) steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate, meprednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and their respective pharmaceutically acceptable derivatives. A combination of steroids may be used, for example a combination of two or more steroids mentioned in this paragraph; (x) targeted therapies, for example PI3Kd inhibitors, for example idelalisib and perifosine; PD-1, PD-L1, PD-L2 and CTL4-A modulators, antibodies and vaccines; other IDO inhibitors (such as indoximod); anti-PD-1 monoclonal antibodies (such as MK-3475 and nivolumab); anti-PDL1 monoclonal antibodies (such as MEDI-4736 and RG-7446); anti-PDL2 monoclonal antibodies; and anti-CTI_A-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(1H,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.

[00154] 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.

[00155] 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.

[00156] 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.

[00157] For the above-mentioned compounds of the invention the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, if the compound of the invention is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight (pg/kg) to 100 milligrams per kilogram body weight (mg/kg).

[00158] 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", Μ. E. Aulton, Churchill Livingstone, 1988.

[00159] 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.

[00160] 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.

[00161] 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.

[00162] 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.

[00163] For intravenous (parenteral) administration the compounds of the invention may be administered as a sterile aqueous or oily solution.

[00164] 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.

[00165] 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.

[00166] EXAMPLES AND SYNTHESES

[00167] General methods [00168] As used herein the following terms have the meanings given: “Boc” refers to tert-butyloxycarbonyl “BuLi” refers to n-butyllithium; “CBS” refers to Corey-Bakshi-Shibata reduction method; “CBz” refers to carboxybenzyl, “DCM” refers to dichloromethane; “DIPEA” refers to N,N-Diisopropylethylamine, “DMF” refers to /V,/V-dimethylformamide; “DiBAI” refers to diisobutylaluminium hydride, “EDC” refers to A/-(3-dimethylaminopropyl)-/V'-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)-W,A/-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; “SCF” refers to Super Critical Fluid Chromatography, “STAB” refers to sodium triacetoxyborohydride; “T3P” refers to propanephosphonic acid anhydride; “TBAF” refers to tetrabutylammonium fluoride, “TEA” refers to triethylamine, “TFA” refers to trifluoroacetic acid and “THF” refers to tetrahydrofuran.

[00169] 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 pL aliquot was injected onto a guard column (0.2 pm x 2 mm filters) and UPLC column (C18, 50 x 2.1 mm, < 2 pm) 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.

Table 1

[00170] NMR was also used to characterise final compounds. NMR spectra were obtained on a Bruker AVIII 400 Nanobay with 5 mm BBFO probe at room temperature unless otherwise stated. 1H NMRs are reported in ppm and referenced to either DMSO-de (2.50 ppm), CDCI3 (7.26 ppm) or CD3OD (3.31 ppm).

[00171] 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 below.

[00172] Table 2

[00173] 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.

[00174] Chemical Synthesis [00175] Procedure A: Preparation of protected and optionally substituted (imidazol-4-yl)heteroaryl carbaldehydes [00176] Protected and optionally substituted (imidazol-4-yl)heteroaryl carbaldehydes can be synthesised by analogy with the procedure described Scheme 1.

Scheme 1 [00177] 4-lodoimidazole can be protected on either Nitrogen atoms with a suitable protecting group (e.g. trityl, SEM). The resulting protected 4-iodoimidazoles can be converted into the corresponding boronic esters via metal-catalysed (e.g. Miyaura) borylation with diboron esters (e.g. bis(pinacolato)diboron, Bis(neopentyl glycolato)diboron). Alternatively, reaction of protected 4-iodoimidazoles with Grignard reagents such as isopropylmagnesium chloride followed by trimethyl borate and acid hydrolysis (e.g. HCI) can afford the corresponding protected imidazole boronic acids. Crosscoupling of protected imidazole boronic esters or acids with halogenoheteroaryl carbaldehydes (e.g. X = Cl, Br, I) can afford the corresponding protected and optionally substituted (imidazol-4-yl)heteroaryl carbaldehydes. Protected and optionally substituted (imidazol-4-yl)heteroaryl carbaldehydes can also be synthesized by direct cross-coupling of 4-iodoimidazoles with formylheteroaryl boronic acids or esters. Protection of the carbonyl moiety (e.g. dimethyl acetyl, 1,3-dioxolane, 1,3-dioxanes, 1,3-dithianes) may be required for the preparation of selected analogues. Where required, halogenoheteroaryl carbaldehydes can be prepared is two steps (e.g. Weinreb amide formation and reduction) the corresponding halogenoheteroaryl carboxylates.

[00178] Example A.1: Preparation of 3-(1-tritylimidazol-4-yl)pyridine-4-carbaldehyde

[00179] Stepl: 4-lodo-1 -trityl-imidazole

[00180] A/,A/-Diisopropylethylamine (67.4 mL, 387 mmol) was added slowly to a mixture of 4-iodoimidazole (50.0 g, 258 mmol) and trityl chloride (79.1 g, 284 mmol) in THF (500 mL). The resulting mixture was heated at 70 °C for 1 hour under nitrogen. The reaction was cooled to room temperature and diluted with water (300 mL) and DCM (500 mL). The combined organics were washed with brine (300 mL), dried over Na2S04, filtered and concentrated in vacuo to afford an off white solid characterised as 4-iodo-1 -trityl-imidazole (95.0 g, 218 mmol, 84% yield). 1H NMR (CDCI3, 400 MHz) δ: 7.37-7.32 (m, 9H), 7.32 (d, J 1.5 Hz, 1H), 7.15-7.09 (m, 6H), 6.91 (d, J 1.5 Hz, 1H). LCMS purity >95%, [Ph3C+]+ = 243 (only fragmentation product observed) 2.13 min (analytical short).

[00181] Step 2: (1-Tritylimidazol-4-yl)boronic acid

[00182] A 2 M isopropylmagnesium chloride solution in THF (160 mL, 320 mmol) was added dropwise to a solution of 4-iodo-1-trityl-imidazole (93.0 g, 213 mmol) in anhydrous THF (300 mL) at 0 °C under nitrogen. The resulting mixture was stirred at 0 °C for 10 minutes. Trimethyl borate (119 mL, 1.07 mol) was added drop 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 (100 mL, 100 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 (300 mL) and extracted with ethyl acetate (3 x 300 mL). The combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo to afford (1-tritylimidazol-4-yl)boronic acid (3.93 g, 11.1 mmol, 97% yield) as an off white solid which was taken through to the next synthetic step without further purification. LCMS purity 41%, [M+H]+ = 355, 1.29 min (analytical short).

[00183] Step 3: 3-(1-Tritylimidazol-4-yl)pyridine-4-carbaldehyde

[00184] Procedure A.1: Traditional heating [00185] To a degassed solution of 3-Bromo-4-pyridinecarboxaldehyde (25.0 g, 134 mmol), (1-tritylimidazol-4-yl)boronic acid (71.4 g, 202 mmol) and potassium carbonate (37.2 g, 269 mmol) in a 1,4-dioxane (400 mL) and water (160 mL) under nitrogen was added [1,1-

Bis(diphenylphosphino)ferrocene]Palladium(ll) chloride dichloromethane (5.52 g, 6.76 mmol). The resulting suspension was degassed with nitrogen (5 minutes) and heated to reflux at 110°C for 2 hours. The reaction was subsequently allowed to cool to room temperature and partitioned between ethyl acetate (1000 mL) and water (500 mL). The aqueous phase was re-extracted with ethyl acetate (500 mL). The combined organics were washed with brine (500 ml_), dried over sodium sulphate, filtered and concentrated in vacuo. Trituration from hot ethyl acetate (100 mL) afforded a pale brown solid characterised as 3-(1-tritylimidazol-4-yl)pyridine-4-carbaldehyde (32.0 g, 77.0 mmol, 57% yield).

[00186] Procedure A.2: Microwave heating [00187] 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, 0.11 mmol) were loaded in a 10-20 mL microwave vial. The vial was capped and the mixture degased with 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 with 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 NaHCC>3 (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 desired 3-(1 -tritylimidazol-4-yl)pyridine-4-carbaldehyde product was isolated via column chromatography with a 0-40% ethyl acetate in petroleum ether gradient.

[00188] 1H NMR (CDCb, 400 MHz) δ: 10.67 (d, J0.7 Hz, 1H), 8.91 (d, J0.7 Hz, 1H), 8.64 (dd, J5.0, 0.7 Hz, 1H), 7.68 (dd, J5.0, 0.7 Hz, 1H), 7.61 (d, J1.3 Hz, 1H), 7.41-7.36 (m, 9H), 7.22-7.18 (m, 7H). LCMS purity > 95%, [M+H]+ = 416, 1.93 min (analytical short).

[00189] Examples in Table 3 were prepared by analogy with Example A1.

Table 3

[00190] Example A.2: Preparation of 5-(1-tritylimidazol-4-yl)pyrimidine-4-carbaldehyde

[00191] Step 1:5 -Bromo-A/-methoxy-A/-methyl-pyrimidine-4-carboxamide

[00192] A mixture of 5-bromopyrimidine-4-carboxylic acid (3.57 g, 17.6 mmol) and A/,0-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 Na2SC>4, filtered and concentrated in vacuo. The crude material was purified with a 25-50% ethyl acetate in heptane eluent. Fractions containing the desired product were combined and concentrated in vacuo to afford a yellow oil characterised as 5-bromo-N-methoxy-A/-methyl-pyrimidine-4-carboxamide (863 mg, 3.50 mmol, 20% yield). 1H NMR (CDCI3, 400 MHz) δ: 9.14 (s, 1H), 8.90 (s, 1H), 3.61 (s, 3H), 3.41 (s, 3H). LCMS purity > 95%, [M+H]+ = 246/248, 1.07 min (analytical short).

[00193] Step 2: 5-Bromopyrimidine-4-carbaldehyde

[00194] Diisobutylaluminium hydride (1 M in toluene, 11.2 ml_, 11.2 mmol) was slowly added to a solution of 5-bromo-A/-methoxy-A/-methyl-pyrimidine-4-carboxamide (1.31 g, 5.34 mmol) in THF (20 ml_) at -10 °C under nitrogen. The reaction was stirred at -10°C for 1 hour, quenched with isopropanol (10 ml_) and water (20 ml_) and left to stand overnight at room temperature. The mixture was extracted with ethyl acetate (3 x 30 ml_). The combined organic fractions were dried over Na2SC>4, filtered and concentrated in vacuo. The resulting crude oil to yield was purified with a 10-50% (2.5% methanol in ethyl acetate) in heptane eluent. Fractions containing the desired product were combined and concentrated in vacuo to afford a yellow oil characterised as 5-bromopyrimidine-4-carbaldehyde (450 mg, 1.45 mmol, 60% purity, 27% yield). LCMS purity = 60%, [M+H]+ = 187/189, 0.50 min (analytical short).

[00195] Step 3: 5-(1-Tritylimidazol-4-yl)pyrimidine-4-carbaldehyde

[00196] 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 (111 mg, 0.140 mmol). The resulting solution was degassed under nitrogen and heated to reflux at 110°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 ethyl acetate (30 ml_). The combined filtrate was washed with water (3 x 20 mL). The aqueous layers were then extracted with ethyl acetate (2 x 30 ml_). The combined organics were dried over Na2SC>4, filtered and concentrated in vacuo. The crude was purified with a 10-75% ethyl acetate in heptane eluent. Fractions containing the desired product were combined and concentrated in vacuo to afford a yellow residue characterised as 5-(1-tritylimidazol-4-yl)pyrimidine-4-carbaldehyde (414 mg, 0.99 mmol, 41% yield). LCMS purity > 95%, [M+Na]+ = 439, 1.75 min (analytical short).

[00197] Procedure B: Preparation of substituted acetophenones [00198] 2,4 -disubstituted acetophenones can be synthesised by analogy with the procedure described Scheme 2.

Scheme 2 [00199] Example B.1: Preparation of 1-(4-amino-2-chloro-phenyl)ethanone

[00200] Step 1:1-(2-Chloro-4-nitro-phenyl)ethanone

[00201] To a suspension of magnesium(ll)chloride (3.11 g, 32.6 mmol) in toluene (45 ml_) was added triethylamine (15.5 ml_, 111 mmol) and dimethylmalonate (6.20 ml_, 54.3 mmol) under nitrogen. After stirring at room temperature for 1 hour, 2-Chloro-4-nitrobenzoyl chloride (10.2 g, 46.5 mmol) was added portion wise over 30 minutes. The resulting mixture was stirred at room temperature for 1 hour, and concentrated hydrochloric acid (15.0, ml_, 183 mmol) was added. The mixture was stirred for 10 minutes then diluted with ethyl acetate (50 ml_) and water (30 ml_). The layers were separated, and the aqueous layer was extracted with ethyl acetate (50 ml_). The combined organic layers were dried over Na2SC>4, filtered and concentrated in vacuo. The crude oil was dissolved in DMSO (40ml_) and water (1.7ml_), and heated to 100°C for 16 hours under nitrogen. The reaction was cooled to room temperature, diluted with water (100 ml_) and extracted with ethyl acetate (3 x 100 ml_). The combined organic fractions were washed saturated NaHCC>3 (aq, 150 ml_) and brine (150 ml_), dried over Na2SC>4, filtered and concentrated in vacuo to afford 1-(2-chloro-4-nitro-phenyl)ethanone as a brown oil (8.90 g, 37.7 mmol, 81% yield). No further purification done and material used crude. 1H NMR (CDCb, 400 MHz) δ: 8.30 (d, J 2.0 Hz, 1H), 8.18 (dd, J8.4, 2.0 Hz, 1H), 7.66 (d, J8.4 Hz, 1H), 2.68 (s, 3H). LCMS purity >95%, does not ionise, 1.55 min (analytical short).

[00202] Step 2:1-(4-Amino-2-chloro-phenyl)ethanone

[00203] To a solution of 1-(2-chloro-4-nitro-phenyl)ethanone (8.90 g, 37.7 mmol) in ethanol (240 ml_) was added iron (24.9 g, 446 mmol), ammonium chloride (24.0 g, 448 mmol) and water (60 ml_). The resulting mixture was then heated to reflux at 100°C under nitrogen for 2 hours. The reaction was cooled to room temperature, diluted with DCM (100 ml_) and filtered through a pad of celite. The celite was washed with DCM (200 ml_). The organic filtrate was washed with water (3 x 100 ml_) and the combined aqueous layers were extracted with DCM (100 ml_), dried over Na2SC>4, filtered and concentrated in vacuo to afford 1-(4-amino-2-chloro-phenyl)ethanone as a brown oil (6.78 g, 36.8 mmol, 97% yield). 1H NMR (CDCb, 400MHz) δ: 7.62 (d, J 8.5 Hz, 1H), 6.66 (d, J 2.3 Hz, 1H), 6.54 (dd, J 8.5, 2.3 Hz, 1H), 4.08 (br.s, 2H), 2.61 (s, 3H). LCMS purity >94%, [M+H]+ = 170/172, 1.21 min (analytical short).

[00204] Example B.2: Preparation of 4-acetyl-3-chloro-benzoic acid

[00205] Step 1: Methyl 4-acetyl-3-chloro-benzoate

[00206] Palladium (II) acetate (800 mg, 3.56 mmol) and Tri-o-tolylphosphine (1.97 g, 6.47 mmol) was added to a mixture of triethylamine (16.0 ml_, 115 mmol) in acetonitrile (100 ml_) under nitrogen. The resulting mixture was degassed with Nitrogen for 10 minutes. Methyl 3-chloro-4-iodo-benzoate (9.55 g, 32.2 mmol) and butyl vinyl ether (5.20 ml_, 40.2 mmol) were added and the reaction was heated at 85°C for 16 hours. The reaction was cooled to room temperature, 1 M HCI (50.0 ml, 50.0 mmol) was added and stirred for 1 hour. The mixture was extracted with ethyl acetate (3 x 100 ml_) and the combined organic fractions were washed with brine (150 ml_), dried over Na2S04, filtered and concentrated in vacuo. The crude was purified by column chromatography with 0-40% ethyl acetate in heptane eluent. Fractions containing the desired product were combined and concentrated in vacuo to afford methyl 4-acetyl-3-chloro-benzoate as a brown oil (2.42 g, 11.4 mmol, 35 % yield). 1H NMR (CDCb, 400MHz) δ: 8.07 (d, J 1.3 Hz, 1H), 7.96 (dd, J 8.0, 1.6 Hz, 1H), 7.56 (d, J 8.0 Hz, 1H), 3.94 (s, 3H), 2.65 (s, 3H). LCMS purity >95%, [M+H]+ = 213, 1.67 min (analytical short).

[00207] Step 2: 4-Acetyl-3-chloro-benzoic acid

[00208] A solution of sodium hydroxide (1.03 g, 25.8 mmol) in water (15ml_) was added to methyl 4-acetyl-3-chloro-benzoate (2.42 g, 11.4 mmol) in THF (30ml_). The resulting mixture was stirred at room temperature for 16 hours. The reaction was acidified to pH=1 with 1 M HCI (50 ml.) and extracted with ethyl acetate (3 x 50 ml_). The combined organic fractions were washed with brine (75 ml_), dried over Na2SC>4, filtered and concentrated in vacuo to afford 4-acetyl-3-chloro-benzoic acid (2.26 g,11.4 mmol, 100% yield) as a brown solid. 1H NMR (CDCI3, 400MHz) δ: 8.15 (d, J 1.4 Hz, 1H), 8.04 (dd, J 8.0, 1.6 Hz, 1H), 7.59 (d, J 8.0 Hz, 1H), 2.67 (s, 3H). LCMS purity >95%, [M-H]- =197, 1.37 min (analytical short).

[00209] Procedure C: Preparation of 1-aminoaryl-2-(imidazo-pyrrolo-heteroaryl)ethanol analogues [00210] 1-Aminoaryl-2-(imidazo-pyrrolo-heteroaryl)ethanol analogues can be synthesised from corresponding (imidazol-4-yl)heteroaryl carbaldehydes and substituted acetophenones by analogy with the procedure described in Scheme 3.

Scheme 3 [00211] (lmidazol-4-yl)heteroaryl carbaldehydes can be treated with protected (e.g. Boc, CBz) or nonprotected aminoarylmethyl ketones in basic conditions (e.g. NaOH, KOH) to afford the corresponding αβ-unsaturated ketones. Trityl deprotection and cyclisation of αβ-unsaturated ketone intermediates (e.g. using AcOH for trityl protecting groups) can afford 1-aminoaryl-2-(imidazo-pyrrolo-heteroaryl)ethanones. A variety of reducing agents (e.g. NaBH4, UBH4, CBS) can be used to reduce 1-aminoaryl-2-(imidazo-pyrrolo-heteroaryl)ethanones into the corresponding 1-aminoaryl-2-(imidazo-pyrrolo-heteroaryl)ethanols. When needed, deprotection of the amino functionality can be carried out with suitable reagents (e.g. H2 Pd/C, TFA).

[00212] Example C.1: Preparation of 1-(4-amino-2-chloro-phenyl)-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethanol

[00213] Step 1: (E)-1-(4-Amino-2-chloro-phenyl)-3-[3-(1-tritylimidazol-4-yl)-4-pyridyl]prop-2-en-1-one

[00214] 3-(1-Tritylimidazol-4-yl)pyridine-4-carbaldehyde (20 g, 48 mmol) and 1-(4-amino-2-chloro-phenyl)ethanone (8.2 g, 48 mmol) were dissolved in THF (150 ml.) and water (96 ml_). Sodium hydroxide (7.7 g, 0.19 mol) was added and the mixture was stirred at 50 °C overnight. The reaction was cooled to room temperature, concentrated into an oil and diluted with water (500 ml_). The pH was adjusted to 8 with dilute citric acid and the mixture was extracted in ethyl acetate. The organics were combined, washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo. The crude oil was triturated with ethyl acetate, the resulting solid was filtered and washed with ethyl acetate to give 17.3 g (63% yield) of the desired (E)-1-(4-amino-2-chloro-phenyl)-3-[3-(1-tritylimidazol-4-yl)-4-pyridyl]prop-2-en-1-one. 1H NMR (CDCIs, 400 MHz) δ: 8.95 (d, J0.6 Hz, 1H), 8.51 (dd, J 5.2, 0.4 Hz, 1H), 8.04 (d, J 15.8 Hz, 1H), 7.56 (d, J 1.4 Hz, 1H), 7.50 (d, J8.4 Hz, 1H), 7.44-7.47 (m, 1H), 7.32-7.40 (m, 11H), 7.26-7.29 (m, 1H), 7.18-7.21 (m, 6H), 7.04 (d, J1.4 Hz, 1H), 6.66 (d, J2.2 Hz, 1H), 6.53 (dd, J 8.4, 2.3 Hz, 1H). LCMS purity >95%, [M+H]+ = 567/569,1.81 min (analytical short).

[00215] Compounds drawn in Table 4 were prepared by analogy.

Table 4

[00216] Step 2: 1-(4-Amino-2-chloro-phenyl)-2-(5H-imidazo[2,3]pyrrolo[2,3-a]pyridin-5-yl)ethanone

[00217] (E)-1-(4-amino-2-chloro-phenyl)-3-[3-(1-tritylimidazol-4-yl)-4-pyridyl]prop-2-en-1-one (17.5 g, 30.9 mmol) was suspended in methanol (200 mL) and acetic acid (glacial) (617 mL) was added. The reaction was heated to reflux overnight. The mixture was allowed to cool to room temperature and concentrated in vacuo (neat followed with repeated azeotrope distillations with toluene). The crude was purified using a 0-10% methanol in DCM gradient. Fractions containing the desired product were combined and concentrated into an orange solid characterised as 1-(4-amino-2-chloro-phenyl)-2-(5H-imidazo[2,3]pyrrolo[2,3-a]pyridin-5-yl)ethanone (4.2 g, 42% yield). 1H NMR (DMSO-de, 400 MHz) δ: 8.88 (d, J0.9 Hz, 1H), 8.48 (d, J5.0 Hz, 1H), 7.75 (s, 1H), 7.71 (d, J8.7 Hz, 1H), 7.61-7.64 (m, 1H), 7.23 (s, 1H), 6.63 (d, J 2.2 Hz, 1H), 6.50 (dd, J 8.7, 2.2 Hz, 1H), 6.32 (s, 2H), 5.81 (dd, J 8.4, 4.3 Hz, 1H), 3.88 (dd, J 4.4, 18.1 Hz, 1H), 3.53 (dd, J 18.1,8.4 Hz, 1H). LCMS purity 97%, [M+H]+ = 325/327, 0.97 min (analytical short).

[00218] Compounds drawn in Table 5 were prepared by analogy.

Table ο

[00219] Step 3:1-(4-Amino-2-chloro-phenyl)-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethanol

[00220] Sodium borohydride (0.49 g, 13.1 mmol) was added to a solution of 1-(4-amino-2-chloro-phenyl)-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethanone (4.25 g, 13.1 mmol) in methanol (100 ml_) at 0 °C under nitrogen. After 1 hour, the methanol mixture was partitioned between brine and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the combined organics were washed with water. The organics were dried over sodium sulphate, filtered and concentrated under reduced pressure to produce 4.02 g, 94% yield of an orange foam characterised as 1-(4-amino-2-chloro-phenyl)-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethanol. 1H NMR (DMSO-de, 400 MHz) δ: 8.87-8.85 (m ,1H), 8.50 & 8.45 (2d, J 5.0 Hz, 1H), 8.00 & 7.80 (2s, 1H), 7.63-7.60 & 7.55-7.52 (2m ,1H), 7.34 & 7.30 (2d, J 8.2 Hz, 1H), 7.26-7.20 (2s, 1H), 6.58-6.49 (m, 2H), 5.68-5.49 (m, 2H), 5.30 (d, J4.8 Hz, 2H), 5.17-5.06 (m, 1H), 2.38-2.23, 2.14-2.07 & 1.79-1.71 (m, 2H). LCMS purity 95%, [M+H]+ = 327/329, 0.29 min (analytical short), 0.75 min (analytical long).

[00221] Compounds drawn in Table 6 were prepared by analogy.

Table 6 [00222] Procedure D: Preparation of urea-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanol analogues [00223] Urea-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanol analogues can be synthesised from the corresponding protected (imidazol-4-yl)heteroaryl carbaldehyde and methylketone precursors by analogy with the procedure described in Scheme 4.

[00224] Substituted ureas can be synthesised by condensation of aminoaryl methylketones with isocyanates or other anilines in presence of urea coupling agents (e.g. disuccinimidyl carbonate). Condensation of the resulting ureas with (imidazol-4-yl)heteroaryl carbaldehydes can generate the corresponding αβ-unsatured ureas. Imidazole deprotection in acidic conditions (e.g. acetic acid) can lead to closure into the corresponding urea substituted 1-(hetero)aryl-2-(imidazo-pyrrolo-heteroaryl)ethanone. Reduction of the latter with reducing agents (e.g. NaBhU) can produce the corresponding urea substituted 1-(hetero)aryl-2-(imidazo-pyrrolo-heteroaryl)ethanol analogues. Alternatively, 1-aminoaryl-2-(imidazo-pyrrolo-heteroaryl)ethanone or 1 -aminoaryl-2-(imidazo-pyrrolo-heteroaryl)ethanol prepared according to Scheme 3 can be derivatised into corresponding urea analogues using isocyanates or amines (aromatic or aliphatic) in presence of coupling agents (e.g. disuccinimidyl carbonate).

[00225] Example D.1: Preparation of 1-[3-chloro-4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]-3-(6-methoxy-3-pyridyl)urea

[00226] Step 1:1-(4-Acetyl-3-chloro-phenyl)-3-(6-methoxy-3-pyridyl)urea

[00227] To a solution of 1-(4-amino-2-chloro-phenyl)ethanone (500 mg, 2.95 mmol) in THF (12 ml_) was added disuccinimidyl carbonate (906 mg, 3.54 mmol). The reaction mixture was stirred at 30 °C for 30 minutes. 5-amino-2-methoxypyridine (439 mg, 3.54 mmol) and A/,/V-Diisopropylethylamine (0.67ml_, 3.8 mmol) was added and the reaction was heated to 60°c and stirred for 18 hours. The reaction was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (20 ml_) and NaHCC>3 solution (20 ml_). Phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 20 ml_) The combined organics were washed with saturated brine (50 ml_), dried over sodium sulphate, filtered and concentrated in vacuo. The product was isolated via column chromatography with a 0-100% ethyl acetate in DCM eluent. LCMS purity > 95%, [M+H]+ = 320.1, 1.48 min (analytical short).

[00228] Compounds drawn in Table 7 were prepared by analogy.

Table 7

[00229] Step 2: 1 -[3-Chloro-4-[(E)-3-[3-(1 -tritylimidazol-4-yl)-4-pyridyl]prop-2-enoyl]phenyl]-3-(6-methoxy-3-pyridyl)urea

[00230] To a solution of 1-(4-acetyl-3-chloro-phenyl)-3-(6-methoxy-3-pyridyl)urea (524 mg, 1.64 mmol) in THF (10 ml_) was added 3-(1-tritylimidazol-4-yl)pyridine-4-carbaldehyde (681 mg, 1.64 mmol) and 1 M sodium hydroxide (6.59 ml_, 6.59 mmol). The resulting mixture was heated to 55 °C for 2 hours. The reaction was cooled to ambient temperature and partitioned between NaHCC>3 (20 ml_) and DCM (20 ml_). The aqueous phase was extracted with DCM (2 x 20 ml_). The organics were combined, passed through a phase separator and concentrated in vacuo. Column chromatography of the crude with a 0-20% methanol in DCM eluent afforded 420 mg (36 %yield) of 1-[3-chloro-4-[(E)-3-[3-(1-tritylimidazol-4-yl)-4-pyridyl]prop-2-enoyl]phenyl]-3-(6-methoxy-3-pyridyl)urea. LCMS purity > 89%, [M+H]+ = 717.1, 1.88 min (analytical short).

[00231] Compounds drawn in Table 8 were prepared by analogy.

Table 8 [00232] Step 3: 1-[3-Chloro-4-[2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]phenyl]-3-(6-methoxy-3-pyridyl)urea

[00233] To a solution of 1-[3-chloro-4-[(E)-3-[3-(1-tritylimidazol-4-yl)-4-pyridyl]prop-2-enoyl]phenyl]-3-(6-methoxy-3-pyridyl)urea (420 mg, 0.590 mmol) in methanol (8 ml_) was added acetic acid (2 ml_). The reaction mixture was stirred at 80 °C for 2 hours. The solvent was removed in vacuo. Column chromatography of the crude material with a 0-20% methanol in DCM eluent afforded 138 mg (50% yield) of 1-[3-chloro-4-[2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]phenyl]-3-(6-methoxy-3-pyridyl)urea. LCMS purity 64%, [M+H]+ = 475.1,1.16 min (analytical short).

[00234] Compounds drawn in Table 9 were prepared by analogy.

Table 9

[00235] Step 4:1-[3-Chloro-4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]-3-(6-methoxy-3-pyridyl)urea

[00236] Sodium borohydride (66.0 mg, 1.74 mmol) was added to a solution of 1-[3-chloro-4-[2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]phenyl]-3-(6-methoxy-3-pyridyl)urea (138 mg, 0.290 mmol) in methanol (10 mL) at 0°C under nitrogen, the reaction was then allowed to warm to room temperature and stir for 30 minutes. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (20 mL) and NhU.HCI solution (20 mL). The aqueous phase was extracted with ethyl acetate (2 x 20 mL) and the combined organic phases were washed with brine (50 mL), dried over Na2SC>4 and concentrated in vacuo. Column chromatography of the crude material with a 0-20% methanol in DCM eluent afforded 61 mg (44% yield) of 1-[3-chloro-4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]-3-(6-methoxy-3-pyridyl)urea. 1H NMR (DMSO-de, 400MHz) δ: 8.91-8.92 (m, 1H), 8.88-8.87 (m, 1H), 8.66 (s, 1H), 8.53 (d, J5.06, 0.4H), 8.46 (d, J5.06, 0.6H), 8.20-8.19 (m, 1H), 8.06 (s, 0.6H), 7.89 (s, 0.4H), 7.83-7.79 (m, 1H), 7.63-7.67 (m, 1H), 7.61-7.61 (m, 1H), 7.57-7.55 (m, 1H), 7.37-7.31 (m, 1H), 7.28 (s, 0.6H), 7.22 (s, 0.4H), 6.79 (d, J 8.9, 1H), 5.91 (d, J 4.9, 0.6H), 5.71 (d, J 4.6, 0.4H), 5.66-5.59 (m, 1H), 5.26-5.13 (m, 1H), 3.82 (s, 3H), 2.42-1.81 (m, 2H). LCMS purity >90%, [M+H]+ = 477, 1.10 min (analytical short) , 2.43 min (analytical long).

[00237] Compounds in drawn Table 10 were prepared by analogy.

Table 10 [00238] Example D2: Preparation of 1-cyclohexyl-3-[4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]urea

[00239] Step 1:1-Cyclohexyl-3-[4-[2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]phenyl]urea

[00240] 1-(4-aminophenyl)-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethanone (100 mg, 0.340 mmol) was loaded in a microwave vial. The vial was capped and degased under nitrogen. DMF (2 mL) was added, followed by cyclohexyl isocyanate (0.33 mL, 2.6 mmol). The mixture was stirred at room temperature overnight. Water (10 mL) was added and the mixture was extracted with DCM (3x10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2S04, filtered and concentrated in vacuo. The crude was purified using column chromatography with a 1-20% methanol (0.1 N NH3) in ethyl acetate gradient to yield 1-cyclohexyl-3-[4-[2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]phenyl]urea (55 mg, 0.13 mmol, 38% yield) as an off-white powder. 1H NMR (CD3OD, 400 MHz) δ: 8.89 (s, 1H), 8.79 (s, 1H), 8.49 (d, J 4.8 Hz, 1H), 7.92 (d, J 8.8 Hz, 2H), 7.77 (s, 1H), 7.63 (d, J 5.6 Hz, 1H), 7.50 (d, J 8.8 Hz, 2H), 7.24 (s, 1H), 6.26 (d, J7.2 Hz, 1H), 5.84 (q, J4.4 Hz, 1H), 4.01-3.93 (m, 1H), 3.71-3.62 (m, 1H), 3.55-3.45 (m, 1H), 1.85-1.75 (m, 2H), 1.70-1.60 (m, 2H), 1.58-1.50 (m, 1H), 1.42-1.20 (m, 5H).

[00241] Compounds drawn in Table 11 were prepared by analogy.

Table 11

[00242] Step 2: 1-Cyclohexyl-3-[4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]urea

[00243] 1-cyclohexyl-3-[4-[2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]phenyl]urea (20 mg, 0.050 mmol) was dissolved in methanol (5 ml.) and sodium borohydride (2.7 mg, 0.070 mmol) was added. The mixture was stirred for 15 minutes at room temperature, concentrated in vacuo and purified with a 0-30% methanol (0.1% Nhh) in ethyl acetate gradient to yield 1-cyclohexyl-3-[4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]urea (17 mg, 0.040 mmol, 85% yield) as a colourless solid. 1H NMR (DMSO-de, 400 MHz) δ: 8.86 (s, 1H), 8.49 (d, J 5.2 Hz, 0.4H), 8.44 (d, J 5.2 Hz, 0.6H), 8.23 (s, 1H), 8.00 (s, 0.6H), 7.89 (s, 0.4H), 7.64 (d, J5.6 Hz, 0.4H), 7.57 (d, J4.8 Hz, 0.6H), 7.34-7.18 (m, 5H), 6.02 (d, J 8.0 Hz, 1H), 5.68 (d, J4.8 Hz, 0.6H), 5.56-5.42 (m, 1.4H), 4.90-4.76 (m, 1H), 3.48-3.35 (m, 1H), 2.45-2.15 (m, 1.4H), 1.87-1.72 (m, 2.6H), 1.68-1.60 (m, 2H), 1.57-1.48 (m, 1H), 1.34-1.10 (m, 5H). LCMS purity 96%, [M+H]+ = 418.0, 1.12 min (44%) and 1.14 min 55% (analytical short), 2.44 min 43% and 2.49 min 53% (analytical long).

[00244] Compounds drawn in Table 12 were prepared by analogy.

Table 12

[00245] Example D3: Preparation of 1-[3-chloro-4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]-3-(4-fluorophenyl)urea

[00246] To a solution of 1-(4-amino-2-chloro-phenyl)-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethanol (100 mg, 0.31 mmol) in DMF (5 ml_) was added 1-fluoro-4-isocyanato-benzene (209 uL, 1.84 mmol). The reaction mixture was stirred overnight at room temperature. Water (10 ml_) was added, and the aqueous mixture was extracted with DCM (3x10 ml_). The combined organic layers were washed with brine (20 ml.) and dried over a phase separator, before being concentrated in vacuo. The crude solid was passed through an SCX cartridge, eluted with 1N Nhb in methanol and concentrated in vacuo. The resulting solid was purified with a 5-20% methanol in DCM gradient to yield 1-[3-chloro-4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]-3-(4-fluorophenyl)urea (40 mg, 0.082 mmol, 27% yield1H NMR (DMSO-de, 400MHz): δ: 8.88-8.86 (m, 1H), 8.83 (br.s., 1H), 8.75 (br.s., 1H), 8.52 (d, J 5.0 Hz, 0.6H), 8.45 (d, J5.0 Hz, 0.4H), 8.05 (br.s., 0.5H), 7.88 (br.s., 0.5H), 7.66-7.59 (m, 2H), 7.57-7.54 (m, 1H), 7.48-7.42 (m, 2H), 7.36-7.29 (m, 1H), 7.27 (br.s., 0.4H), 7.21 (br.s., 0.6H), 7.14-7.09 (m, 2H), 5.91-5.88 (m, 0.4H), 5.72-5.69 (m, 0.6H), 5.65-5.57 (m, 1H), 5.26-5.11 (m, 1H), 2.50-1.80 (m, 2H). LCMS purity = 95%, [M+H]+ = 464,1.24 min (analytical short), 2.75/2.79 min (analytical long).

[00247] Compounds drawn in Table 13 were prepared by analogy.

Table 13 [00248] Procedure E: Preparation of amide-substituted 1-heterocyclyl-2-(imidazo-pyrrolo-heteroaryl)ethanol analogues [00249] Amide-substituted 1-heterocyclyl-2-(imidazo-pyrrolo-heteroaryl)ethanol analogues can be synthesised from the corresponding protected (imidazol-4-yl)heteroaryl carbaldehyde and methylketone precursors by analogy with the procedure described in Scheme 5.

Scheme 5 [00250] Heterocyclyl ureas can be synthesised by condensation of heterocyclylmethylketones with isocyanates or other anilines in presence of urea coupling agents (e.g. disuccinimidyl carbonate). Condensation of the resulting ureas with (imidazol-4-yl)heteroaryl carbaldehydes can generate the corresponding αβ-unsatured ureas. Imidazole deprotection in acidic conditions (e.g. acetic acid) can lead to closure into the corresponding amide substituted 1-heterocyclyl-2-(imidazo-pyrrolo-heteroaryl)ethanone. Reduction of the latter with reducing agents (e.g. NaBhU) can produce the corresponding amide substituted 1-heterocyclyl-2-(imidazo-pyrrolo-heteroaryl)ethanol analogues. Alternatively, 1 -heterocyclyl-2-(imidazo-pyrrolo-heteroaryl)ethanone or 1 -heterocyclyl-2-(imidazo-pyrrolo-heteroaryl)ethanol can be derivatised into corresponding urea analogues using isocyanates or amines (aromatic or aliphatic) in presence of coupling agents (e.g. disuccinimidyl carbonate).

[00251] Example E1: Preparation of 4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]-A/-phenyl-piperidine-1 -carboxamide

[00252] Step 1: 4-acetyl-A/-phenyl-piperidine-1-carboxamide

[00253] 1-piperidin-1-ium-4-ylethanone chloride (260 mg, 1.59 mmol) was dissolved in DCM (10ml_), triethylamine (0.27 ml_, 1.9 mmol) was added followed by phenyl isocyanate (0.21 ml_, 1.9 mmol). The reaction was stirred at RT for 1 h. The mixture was washed with HC11N, the organic layer was separated, washed with brine, dried over sodium sulphate and evaporated to dryness. The crude material was characterised as 4-acetyl-A/-phenyl-piperidine-1-carboxamide (417 mg, quantitative yield) and used in the next synthetic step without further purification. LCMS [M+H]+ = 247.1, 1.36 min (analytical short).

[00254] Step 2: /V-phenyl-4-[(E)-3-[3-(1 -tritylimidazol-4-yl)-4-pyridyl]prop-2-enoyl]piperidine-1 -carboxamide

[00255] To a solution of 3-(1-tritylimidazol-4-yl)pyridine-4-carbaldehyde (280 mg, 0.670 mmol) in THF (15 ml_), 4-acetyl-A/-phenyl-piperidine-1-carboxamide (0.43 ml_, 0.81 mmol) and sodium hydroxide (1.35 ml_, 2.70 mmol) 2 N were added. The mixture was heated to 55 °C and stirred overnight. The reaction mixture was seperated and the organic layer washed with sat. NaHCC>3 (10 ml_). The aqueous layers were combined and washed with DCM (20 ml_). The organic layers were combined and dried using Na2SC>4, filtered and concentrated to dryness by rotary evaporation to give /V-phenyl-4-[(E)-3-[3-(1-tritylimidazol-4-yl)-4-pyridyl]prop-2-enoyl]piperidine-1-carboxamide (445 mg, 0.691 mmol, quantitative yield) as a light brown solid which was used in the next synthetic step without further purification. LCMS [M+H]+ = 644.3, 1.95 min (analytical short).

[00256] Step 3: 4-[2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]-A/-phenyl-piperidine-1-carboxamide

[00257] A round bottom flask was charged with A/-phenyl-4-[(E)-3-[3-(1-tritylimidazol-4-yl)-4-pyridyl]prop-2-enoyl]piperidine-1-carboxamide (445 mg, 0.690 mmol) in methanol (18 ml_) and acetic acid (glacial) (1.19 ml_, 20.7 mmol) was added, before heating to 80 °C. The reaction mixture was stirred for 2 hours at this temperature. The reaction mixture was allowed to cool to room temperature and quenched with sat. NaHCCb (40 ml_). Solvents were removed under vacuo and the resulting aqueous layer was extracted with DCM (3 x 20 ml_). The organic layers were combined, dried using Na2SC>4, filtered and concentrated to dryness in vacuo to give 4-[2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]-A/-phenyl-piperidine-1-carboxamide (355 mg, quantitative yield) which was used in the next synthetic step without further purification. LCMS [M+H]+ = 402.2, 1.15 min (analytical short).

[00258] Step 4: 4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]-A/-phenyl-piperidine-1-carboxamide

[00259] 4-[2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]-/V-phenyl-piperidine-1-carboxamide (278 mg, 0.690 mmol) was dissolved in methanol (5 ml_) and sodium borohydride (26 mg, 0.69 mmol) was carefully added. The reaction was stired at ambient temperature for 1 h. sat aq NhUCI was added, the organic phase was extracted with DCM, dried over sodium sulphate and concentrated in vacuo. The residue was purified by normal phase chromatography (0-10% MeOH in DCM), affording 4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]-A/-phenyl-piperidine-1-carboxamide (53 mg, 0.13 mmol, 19% yield) as a beige solid. LCMS [M+H]+ = 404.2,1.13 min (analytical short), 2.30 (analytical long).

[00260] Procedure F: Preparation of/V-linked amide-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanol [00261] /V-linked amide-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanol analogues can be synthesised from the corresponding protected (imidazol-4-yl)heteroaryl carbaldehyde and methylketone precursors by analogy with the procedure described in Scheme 6.

Scheme 6 [00262] Substituted amides can be synthesised by condensation of aminoaryl methylketones with carboxylate derivatives using amide coupling agents (e.g. EDC, HBTU) or acid chlorides in presence of base (e.g. TEA, DIPEA). Condensation of the resulting amides with (imidazol-4-yl)heteroaryl carbaldehydes can generate the corresponding αβ-unsatured ketones. Imidazole deprotection in acidic conditions (e.g. acetic acid) can lead to ring closure into the corresponding amide-substituted 1-(hetero)aryl-2-(imidazo-pyrrolo-heteroaryl)ethanones. Reduction of the latter with reducing agents (e.g. NaBI-U) can produce the corresponding amide-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanols. Alternatively, the 1-aminoaryl-2-(imidazo-pyrrolo-heteroaryl)ethanone or 1-aminoaryl-2-(imidazo-pyrrolo-heteroaryl)ethanol intermediates prepared according to Scheme 2 can be derivatised into corresponding amides analogues using coupling reagents (e.g. EDC, HBTU). The NH functionality of the amide can optionally be alkylated (e.g. methyl, ethyl, isopropyl) at any suitable synthetic step in Scheme 6.

[00263] Example F1: Preparation of/V-[3-chloro-4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]-/V-methyl-2-phenyl-acetamide

[00264] Step 1: A/-(4-Acetyl-3-chloro-phenyl)-2-phenyl-acetamide

[00265] To a solution of 1-(4-amino-2-chloro-phenyl)ethanone (512 mg, 3.02 mmol) in THF (20 ml_) was added triethylamine (0.62 ml_, 4.5 mmol) and phenylacetyl chloride (0.52 ml_, 3.9 mmol).

The mixture was stirred under nitrogen overnight at room temperature. It was diluted with DCM (50 ml_) and washed with H2O (30 ml_), sat NH4CI (aq, 30 ml.) and brine (30 ml_). The organic layers were combined, dried over Na2S04, filtered and concentrated in vacuo. The product was isolated via column chromatography with a 10-25% ethyl acetate in heptane gradient to yield N-(4-acetyl-3-chloro-phenyl)-2-phenyl-acetamide (611 mg, 2.13 mmol, 71% yield). 1H NMR (CDCb, 400 MHz,) δ: 7.63 (d, J2.1 Hz, 1H), 7.59 (d, J8.5 Hz, 1H), 7.31-7.46 (m, 6H), 7.11 (br.s, 1H), 3.77 (s, 2H), 2.62 (s, 3H). LCMS purity = 91%, [M+H]+ = 288, 1.65 min (analytical short).

[00266] Compounds drawn in Table 14 were made by analogy.

[00267] Table 14 [00268] Step 2: A/-(4-Acetyl-3-chloro-phenyl)-/V-methyl-2-phenyl-acetamide

[00269] To a solution of A/-(4-acetyl-3-chloro-phenyl)-2-phenyl-acetamide (497 mg, 1.73 mmol) in anhydrous THF (25 ml.) at 0°C under nitrogen was added sodium hydride (60% dispersed in mineral oil) (107 mg, 2.67 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. It was subsequently chilled to 0°C and iodomethane (172 uL, 2.77 mmol) was added. The reaction was stirred under nitrogen overnight and allowed to warm to room temperature. The reaction was partitioned between ethyl acetate (50 ml.) and water (50 ml.) and the aqueous layer was extracted with ethyl acetate (2 x 50 ml_). The combined organics were dried over Na2SC>4, filtered and concentrated in vacuo. The product was isolated via column chromatography with a 10-25% ethyl acetate in heptane gradient to yield N-(4-acetyl-3-chloro-phenyl)-/V-methyl-2-phenyl-acetamide (217 mg, 0.72 mmol, 42% yield). 1H NMR (CDCIs, 400 MHz) δ: 7.59 (d, J8.2 Hz, 1H), 7.17-7.30 (m, 4H), 7.07-7.13 (m, 3H), 3.54 (br.s, 2H), 3.28 (s, 3H), 2.68 (s, 3H). LCMS purity 100%, [M+H]+ = 302, 1.69 min (analytical short).

[00270] Step 3: /V-[3-Chloro-4-[(E)-3-[3-(1-tritylimidazol-4-yl)-4-pyridyl]prop-2-enoyl]phenyl]-/V-methyl-2-phenyl-acetamide

[00271] To a suspension of A/-(4-acetyl-3-chloro-phenyl)-/V-methyl-2-phenyl-acetamide (273 mg, 0.910 mmol) and 3-(1-tritylimidazol-4-yl)pyridine-4-carbaldehyde (478 mg, 1.15 mmol) in THF (10 mL) was added a 2 M aqueous solution of sodium hydroxide (1.9 mL, 3.8 mmol). The reaction mixture was stirred under nitrogen at 80 °C for 2 hours. It was subsequently cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with H2O (3x15 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were then dried over Na2S04, filtered and concentrated in vacuo. The product was isolated via column chromatography with a 0-5% methanol in DCM gradient to yield N-[3-chloro-4-[(E)-3-[3-(1-tritylimidazol-4-yl)-4-pyridyl]prop-2-enoyl]phenyl]-/V-methyl-2-phenyl-acetamide (324 mg, 0.440 mmol, 49% yield). LCMS purity = 15%, [M+H]+ = 699, 2.08 min (analytical short).

[00272] Compounds drawn in Table 15 were made by analogy.

Table 15 [00273] Step 4: A/-[3-Chloro-4-[2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]phenyl]-A/-methyl-2-phenyl-acetamide

Acetic acid (glacial) (0.82 mL, 14 mmol) was added to a solution of /V-[3-chloro-4-[(E)-3-[3-(1-tritylimidazol-4-yl)-4-pyridyl]prop-2-enoyl]phenyl]-A/-methyl-2-phenyl-acetamide (324 mg, 0.46 mmol) in methanol (10 mL) under nitrogen. The resulting mixture was then heated to 80 °C for 2 hours. The reaction mixture was cooled room temperature and concentrated in vacuo. The product was isolated via column chromatography with a 1-5% methanol in DCM gradient to yield /V-[3-chloro-4-[2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]phenyl]-A/-methyl-2-phenyl-acetamide (87 mg, 0.19 mmol, 41% yield). 1H NMR (DMSO-de, 400 MHz) δ: 8.89 (d, J0.7 Hz, 1H), 8.50 (d, J5.1 Hz, 1H), 7.89 (d, J8.4 Hz, 1H), 7.82 (s, 1H), 7.63-7.65 (m, 1H), 7.59 (d, J2.0 Hz, 1H), 7.45 (dd, J8.3, 2.0 Hz, 1H), 7.29-7.17 (m, 4H), 7.13-7.09 (m, 2H), 5.86 (dd, J7.8, 4.4 Hz, 1H), 4.08 (dd, J 18.5, 4.2 Hz, 1H), 3.74 (dd, J 18.5, 8.0 1H), 3.59 (br.s, 2H), 3.24 (s, 3H). LCMS purity 54%, [M+H]+ = 457, 1.24 min (analytical short).

[00274] Compound drawn in Table 16 were made by analogy.

Table 16 [00275] Step 5: /V-[3-Chloro-4-[1 -hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]-/V-methyl-2-phenyl-acetamide

Sodium borohydride (39.7 mg, 1.05 mmol) was added to a solution of /V-[3-chloro-4-[2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]phenyl]-A/-methyl-2-phenyl-acetamide (87.4 mg, 0.190 mmol) in methanol (5 ml_) and this was stirred at room temperature under nitrogen for 1 hour. A saturated solution of NH4CI (10 ml_) was added to the reaction. The resulting mixture was partitioned and extracted with DCM (3 x 30 ml_). The combined organic fractions were passed through a phase separator and concentrated in vacuo. The product was isolated via column chromatography with a 0-10% methanol in DCM gradient to yield A/-[3-chloro-4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]-A/-methyl-2-phenyl-acetamide (24 mg, 0.050 mmol, 27% yield). 1H NMR (DMSO-d6, 400 MHz) δ: 8.88-8.86 (m, 1H), 8.52 (d, J 5.0 Hz, 0.3H), 8.44 (d, J 5.0 Hz, 0.7H), 8.08 (s, 0.7H), 7.92 (s, 0.3H), 7.77-7.55 (m, 2H), 7.42-7.33 (m, 2H), 7.28-7.16 (m, 4H), 7.04 (br.s, 2H), 6.04-6.02 (m, 0.7H), 5.83-5.81 (m, 0.3H), 5.68-5.61 (m, 1H), 5.30-5.24 (m, 0.7H), 5.18-5.13 (m, 0.3H), 3.42 (br.s, 2H), 3.16 (br.s, 3H), 2.46-2.35 (m, 0.7H), 2.31-2.23 (m, 0.3H), 2.00-1.88, (m, 1H). LCMS purity = 93%, [M+H]+ = 459, 1.18 min (analytical short), 2.59 min (analytical long).

[00276] Compounds drawn in Table 17 were made by analogy.

Table 17 [00277] Example F2: Preparation of/V-[3-chloro-4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]-3-cyano-benzamide

[00278] To a solution of 1-(4-amino-2-chloro-phenyl)-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethanol (100 mg, 0.310 mmol) and 3-cyanobenzoic acid (45 mg, 0.31 mmol) in DCM (7 mL) was added triethylamine (107 uL, 0.770 mmol) and propylphosphonic anhydride (273 uL, 0.460 mmol). The resulting mixture was left to stir under nitrogen for 1 hour. It was concentrated in vacuo and the product was isolated via column chromatography with a 0-20% methanol in DCM gradient to yield /V-[3-chloro-4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]-3-cyano-benzamide (26 mg, 0.057 mmol, 19% yield). 1H NMR (DMSO-de, 400MHz) δ: 10.56 (s, 1H), 8.88-8.87 (m, 1H), 8.52 (d, J5.0 Hz, 0.4H), 8.46 (d, J 5.0 Hz, 0.6H), 8.41-8.39 (m, 1H), 8.26-8.23 (m, 1H), 8.22-8.17 (m, 0.4H), 8.09-8.07 (m, 1.6H), 7.91-7.87 (m, 1.4H), 7.78-7.71 (m, 2.6H), 7.68-7.65 (m, 1H), 7.58-7.56 (m, 1H), 7.28 (s, 0.6H), 7.22 (s, 0.4H), 5.99 (d, J4.6 Hz, 0.6H), 5.79 (d, J4.6 Hz, 0.4H), 5.67-5.60 (m, 1H), 5.29-5.16 (m, 1H), 2.46-1.83 (m, 2H). LCMS purity > 90%, [M+H]+ = 456,1.17 min (analytical short), 2.55 min (analytical long).

[00279] Example F3: Preparation of N-[3-chloro-4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]-2,5-difluoro-benzamide

[00280] To a solution of 2,5-difluorobenzoyl chloride (20.7 uL, 0.170 mmol) and 1-(4-amino-2-chloro-phenyl)-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethanol (50 mg, 0.150 mmol) in DCM (5 ml.) was added triethylamine (32 uL, 0.23 mmol). This was left to stir for 2 hrs under nitrogen at ambient temperature. 2,5-Difluorobenzoyl chloride (9.4 uL, 0.080 mmol) was added and this was left to stir for 1 hour. The reaction was partitioned between NaHC03 and DCM and the organic layer was washed with brine, passed through a phase separator and concentrated in vacuo. The product was isolated via column chromatography with a 0-20% methanol in DCM gradient to yield /V-[3-chloro-4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]-2,5-difluoro-benzamide (10.2 mg,0.0218 mmol, 14% yield). 1H NMR (DMSO-de, 400MHz) δ: 10.65 (s, 1H), 8.89-8.88 (m, 1H), 8.53 (d, J5.1 Hz, 0.4H), 8.47 (d, J 5.1 Hz, 0.6H), 8.09 (s, 0.6H), 7.92 (s, 0.4H), 7.85-7.80 (m, 1H), 7.75-7.41 (m, 6H), 7.28 (s, 0.6H), 7.23 (s, 0.4H), 5.99 (d, J 4.8 Hz, 0.6H), 5.79 (d, J4.8 Hz, 0.4H), 5.67-5.60 (m, 1H), 5.29-5.16 (m, 1H), 2.42- 1.83 (m, 2H). LCMS purity > 90%, [M+H]+ = 467,1.23 min (analytical short), 2.77 min (analytical long).

[00281] Compounds drawn in Table 18 were prepared in analogy.

[00282] Table 18 [00283] Example F4: Preparation of /V-[4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]-2-phenyl-acetamide

[00284] Step 1: /V-[4-[2-(5H-lmidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]phenyl]-2-phenyl-acetamide

[00285] HATU (128 mg, 0.340 mmol) was added to a suspension of 1-(4-aminophenyl)-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethanone (101 mg, 0.290 mmol), A/,A/-diisopropylethylamine (101 uL, 0.580 mmol) and phenylacetic acid (47.8 mg, 0.350 mmol) in DCM (5 ml.) and DMF (5 mL). The resulting mixture was stirred overnight at ambient temperature under nitrogen. After 5 hours additional HATU (179 mg, 0.470 mmol) was added and this was left to stir at 50 °C overnight. The reaction was cooled to ambient temperature, diluted with DCM (25 mL) and washed with aqueous NH4CI (3x10 mL). The combined organics were passed through a phase separator and concentrated in vacuo. The product was isolated via column chromatography with a 1-10% methanol in DCM gradient to yield Λ/-[4-[2-(5Η-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]phenyl]-2-phenyl-acetamide (50 mg, 0.12 mmol, 42% yield). LCMS purity = 85%, [M+H]+ = 409, 1.19 min (analytical short).

[00286] The compound in Table 19 was made by analogy.

Table 19

[00287] Step 2: /V-[4-[1-Hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]-2-phenyl-acetamide

[00288] Sodium borohydride (28.1 mg, 0.740 mmol) was added to a solution of Λ/-[4-[2-(5Η-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]phenyl]-2-phenyl-acetamide (50.2 mg, 0.120 mmol) in methanol (5 mL) at 0 °C under nitrogen. The reaction was allowed to warm to room temperature overnight. Saturated aqueous NhUCI (10 mL) was added to the reaction which was extracted with DCM (3x15 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo. The product was isolated using semi-preparative LCMS (early method) followed by SCX-2 column eluting with 7N NH3. Fractions containing the desired product were concentrated in vacuo to yield N-[4-[1 -hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]-2-phenyl-acetamide (15 mg, 0.040 mmol, 29% yield). 1H NMR (DMSO-de, 400 MHz) δ: 10.15-10.12 (m, 1H), 8.87-8.86 (m, 1H), 8.51-8.44 (m, 1H), 8.06 (s, 0.6H), 7.95 (s, 0.4H), 7.67-7.52 (m, 3H), 7.34-7.21 (m, 9H), 5.59-5.45 (m, 1H), 4.93-4.83 (m, 1H), 3.62 (s, 2H), 2.50-1.81 (m, 2H). LCMS purity = 94% [M+H]+ = 411, 1.08 min (35%) and 1.09 min (59%) (analytical short), 2.35 min (40%) and 2.40 min (54%) (analytical long).

[00289] The compound drawn in Table 20 was made by analogy.

Table 20

[00290] Procedure G: Preparation of C-linked amide-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanol [00291] C-linked amide-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanol analogues can be prepared from the corresponding protected (imidazol-4-yl)heteroaryl carbaldehyde and methylketone precursors (prepared as in Procedure B) by analogy with the procedure described in Scheme 7.

Scheme 7 [00292] Acetaldehyde carboxylate derivatives (as described in Procedure B) can be converted into corresponding amides by coupling with amines (aliphatic or aromatic) using coupling agents (e.g. T3P, HATU). The resulting amidoarylmethyl ketones can be treated with (imidazol-4-yl)heteroaryl carbaldehydes under basic conditions (e.g. NaOH, KOH) to afford the corresponding amide-substituted αβ-unsaturated ketones. Trityl deprotection and cyclisation of amide-substituted αβ-unsaturated ketone intermediates (e.g. using AcOH) can afford the corresponding amide-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanones. A variety of reducing agents (e.g. NaBhU, LiBhU, CBS) can be used to reduce the amide-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanones into the corresponding amide-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanols.

[00293] Example G.1: Synthesis of 4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]-/V-phenyl-benzamide

[00294] Step 1: 4-Acetyl-/V-phenyl-benzamide

[00295] 4-Acetylbenzoic acid (766 mg, 4.67 mmol) and aniline (0.44 ml_, 4.7 mmol) were dissolved in anhydrous DCM (10 ml_). Triethylamine (1.62 ml_, 11.7 mmol) was added followed with propylphosphonic anhydride (4.4 ml_, 7.0 mmol) and the reaction was left to stir at room temperature for 10 minutes. The reaction was partitioned with NaHCC>3 (20 ml_) and DCM (15 ml_). The organic layer was washed with saturated NhUCI (25 ml_), dried over Na2SC>4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (0-100% ethyl acetate / heptane) to yield a colourless crystalline solid characterised as 4-acetyl-A/-phenyl-benzamide (370 mg, 1.54 mmol, 33% yield). LCMS purity > 70%, [M+H]+ = 240.1, 1.47 min (analytical short).

[00296] Compounds drawn in Table 21 were synthesised by analogy.

Table 21

[00297] Step 2: A/-phenyl-4-[3-[3-(1-tritylimidazol-4-yl)-4-pyridyl]prop-2-enoyl]benzamide

[00298] 4-Acetyl-A/-phenyl-benzamide (70 pL, 0.96 mmol) and 3-(1 -trityIimidazol-4-yI)pyridine-4-carbaldehyde (499 mg, 1.20 mmol) were dissolved in THF (20 ml_) and 1 M sodium hydroxide (4.81 ml_, 4.81 mmol). The mixture was stirred for 5 hours at 60 °C. Upon completion, the reaction mixture was allowed to cool to room temperature and partitioned with DCM (20 ml_). Both layers were separated and the aqueous layer was extracted with DCM (25 ml_). The organics were combined, dried over Na2SC>4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (40-100% ethyl acetate / heptane) to yield A/-phenyl-4-[3-[3-(1-tritylimidazol-4-yl)-4-pyridyl]prop-2-enoyl]benzamide (272 mg, 0.427 mmol, 44% yield) as a yellow powder. LCMS purity > 80%, [M+H]+ = 637.2, 1.96 min (analytical short).

[00299] Examples drawn in Table 22 were made by analogy.

Table 22 [00300] Step 3: 4-[2-(5H-lmidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]-/V-phenyl-benzamide

[00301] A/-phenyl-4-[3-[3-(1-tritylimidazol-4-yl)-4-pyridyl]prop-2-enoyl]benzamide (272 mg, 0.430 mmol) was dissolved in acetic acid (1 ml_) and methanol (5 ml_) and stirred at 80 °C for 3 hours. The mixture was allowed to cool to ambient temperature and concentrated in vacuo. The crude residue was purified by column chromatography (0-40% MeOH/DCM to afford 4-[2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]-A/-phenyl-benzamide (104 mg, 0.264 mmol, 62% yield) as an off white powder. 1H (DMSO-d6, 400MHz) 5:10.43 (s, 1H), 8.92 (s, 1H), 8.52 (d, J5.2 Hz, 1H), 8.17 (d, J7.2 Hz, 2H), 8.10 (d, J8.8 Hz, 2H), 7.85 (s, 1H), 7.78 (d, J8.4 Hz, 2H), 7.67 (d, J5.2 Hz, 1H), 7.37 (t, J8.2 Hz, 2H), 7.28 (s, 1H), 7.13 (t, J7.6 Hz, 1H), 5.90 (q, J3.9 Hz, 1H), 4.17 (dd, J19.2, 4.8 Hz, 1H), 3.87 (dd, J18.0, 8.0 Hz, 1H). LCMS purity > 90%, [M+H]+ = 395.1,1.17 min (analytical short), 2.58 min (analytical long).

[00302] Compounds drawn in Table 23 were made by analogy.

Table 23

[00303] Step 4: 4-[1-Hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]-N-phenyl-benzamide

[00304] /V-[4-[2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]phenyl]benzamide (45 mg, 0.11 mmol) was dissolved in methanol (5 mL) and sodium borohydride (10.8 mg, 0.290 mmol) was added. The mixture was left to stir at room temperature for 30 minutes. After this time the reaction was concentrated in vacuo. The residue was purified by column chromatography (2-30% MeOH/DCM) to afford 4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]-/V-phenyl-benzamide (39 mg, 0.098 mmol, 86% yield). 1H NMR (DMSO-de, 400MHz) δ: 10.20-10.18 (m, 1H), 8.88-8.86 (m, 1H), 8.52 (d, J4.8 Hz, 0.4H), 8.46 (d, J 4.8 Hz, 0.6H), 8.09 (s, 0.6H), 7.99 (s, 0.4H), 7.96-7.90 (m, 2H), 7.77 (d, J 7.6 Hz, 2H), 7.65 (d, J 5.2 Hz, 0.4H), 7.59 (d, J 5.2 Hz, 0.6H), 7.57-7.52 (m, 2H), 7.37-7.31 (m, 2H), 7.28 (s, 0.6H), 7.22 (s, 0.4H), 7.10 (t, J 7.2 Η, 1H), 6.00 (d, J5.2 Hz, 0.6H), 5.83 (d, J4.8 Hz, 0.4H), 5.61 (dd, J9.6, 3.6 Hz, 0.6H), 5.54 (t, J6.0 Hz, 0.4H), 5.20-4.88 (m, 1H), 2.45-2.22 (m, 1.4H), 2.00-1.82 (m, 0.6H). LCMS purity = 95%, [M+H]+ = 397.2, 1.00 (45%) and 1.02 (50%) min (analytical short).

[00305] Compounds drawn in Table 24 were made by analogy.

Table 24 [00306] Procedure H: Preparation of /V-linked sulphonamide-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanols [00307] /V-linked sulphonamide-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanol analogues can be prepared from the corresponding protected (imidazol-4-yl)heteroaryl carbaldehyde and methylketone precursors by analogy with the procedure described in Scheme 8.

Scheme 8 [00308] Aminoaryl methyl ketones can be converted into sulphonamides by treatment with sulphonyl chlorides in the presence of base (e.g. triethylamine, DIPEA). The resulting sulphonamide-arylmethyl ketones can be treated with (imidazol-4-yl)heteroaryl carbaldehydes under basic conditions (e.g. NaOH, KOH) to afford the corresponding sulphonamide-substituted αβ-unsaturated ketones. Trityl deprotection and cyclisation of the sulphonamide-substituted αβ-unsaturated ketone intermediates (e.g. using AcOH) can afford the corresponding /V-linked sulphonamide-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanones. A variety of reducing agents (e.g. NaBhU, LiBhU, CBS) can be used to reduce N-linked sulphonamide-subtituted substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanones into the corresponding /V-linked sulphonamide-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanols. Alternatively, sulphonyl chlorides can be reacted with 1-(4-amino-aryl)-2-(5H-imidazo[2,3]pyrrolo[2,3-a]pyridin-5-yl)ethanone and 1 -(4-amino-aryl)-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethanol synthesised according to Procedure C to afford /V-linked sulphonamide-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanones or/V-linked sulphonamide-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanols.

[00309] Example H.1: Synthesis of/V-[4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]benzenesulphonamide

[00310] Step 1: A/-(4-Acetylphenyl)benzenesulphonamide

[00311] To a solution of 4'-aminoacetophenone (1.0 g, 7.4 mmol) in ethanol (10 mL) and pyridine (10 ml_) was added benzenesulphonyl chloride (1.04 mL, 8.14 mmol) and the resulting mixture was stirred at 80 C overnight. The solvent was removed in vacuo. Water and DCM were added and the layers were separated. The aqueous layer was extracted with DCM and the combined organic layers were washed with brine, passed through a phase separator and concentrated in vacuo. The crude residue was purified by column chromatography (50-100% ethyl acetate / heptane) to afford A/-(4-acetylphenyl)benzenesulphonamide (890 mg, 3.23 mmol, 44% yield). LCMS purity > 85%, [M+H]+ = 276.1, 1.53 min (analytical short).

[00312] The compound drawn in Table 25 were synthesised by analogy.

Table 25 [00313] Step 2: A/-[4-[(E)-3-[3-(1-Tritylimidazol-4-yl)-4-pyridyl]prop-2-enoyl]phenyl]benzenesulphonamide

[00314] A solution of 3-(1-tritylimidazol-4-yl)pyridine-4-carbaldehyde (755 mg, 1.82 mmol) and A/-(4-acetylphenyl)benzenesulphonamide (500 mg, 1.82 mmol) in THF (10 ml_) and 1 M NaOH (7.26 ml_, 7.26 mmol) was stirred at 55 °C overnight. The reaction mixture was allowed to cool to ambient temperature and the mixture was partitioned with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, passed through a phase separator and the solvent removed in vacuo to afford N-[4-[(E)-3-[3-(1-tritylimidazol-4-yl)-4-pyridyl]prop-2-enoyl]phenyl]benzenesulphonamide (1.22 g, 1.82 mmol, quantitative yield), which was used directly in the next step without purification. LCMS purity > 60%, [M+H]+ = 673.2, 1.94 min (analytical short).

[00315] The compound drawn in Table 26 was synthesised by analogy.

Table 26

[00316] Step 3: /V-[4-[2-(5H-lmidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]phenyl]benzenesulphonamide

[00317] A solution of A/-[4-[(E)-3-[3-(1-tritylimidazol-4-yl)-4-pyridyl]prop-2- enoyl]phenyl]benzenesulphonamide (1.0 g, 1.5 mmol) in methanol (30 ml_) and acetic acid (10 mL) was heated at 80 °C for 2 hours. The reaction mixture was allowed to cool to room temperature and the solvents removed in vacuo. Saturated sodium bicarbonate solution and ethyl acetate were added and the layers separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, passed through a phase separator and the solvent removed in vacuo. The crude residue was purified by column chromatography (0-10% MeOH/DCM) to afford Λ/-[4-[2-(5Η-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]phenyl]benzenesulphonamide (366 mg, 0.850 mmol, 57% yield). LCMS purity > 95%, [M+H]+ = 431.1, 1.07 min (analytical short).

[00318] The compound in Table 27 was synthesised by analogy.

Table 27 [00319] Step 4: A/-[4-[1-Hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]benzenesulphonamide

[00320] To a solution of/V-[4-[2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]phenyl] benzenesulphonamide (366 mg, 0.850 mmol) in methanol (15 ml_) at 0°C under Nitrogen was added sodium borohydride (225 mg, 5.95 mmol) and the resulting mixture was stirred at ambient temperature overnight. Saturated ammonium chloride and DCM were added and the layers were separated. The aqueous layer was extracted with DCM, the combined organic layers passed through a phase separator and the solvent removed in vacuo. The crude residue was purified by column chromatography (0-20% MeOH/DCM) followed by reverse phase column chromatography (20-80% MeCN/water + 0.1% formic acid) to afford /V-[4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5- yl)ethyl]phenyl]benzenesulphonamide (100 mg, 0.231 mmol, 27% yield). 1H NMR (DMSO-d6, 400 MHz) δ: 10.25 (br.s, 1H), 8.85-8.84 (m, 1H), 8.47 (d, J5.1 Hz, 0.4H), 8.41 (d, J5.1 Hz, 0.6H), 7.98 (s, 0.6H), 7.88 (s, 0.4H), 7.77-7.72 (m, 2H), 7.63-7.48 (m, 4H), 7.27-7.17 (m, 3H), 7.05-6.98 (m, 2H), 6.52 (t, J 7.9 Hz, 0.6H), 5.74 (d, J4.8 Hz, 0.6H), 5.57 (d, J4.0 Hz, 0.4H), 5.55-5.35 (m, 1H), 4.89-4.74 (m, 1H), 2.44-2.21 (m, 1H), 2.08-2.17 (m, 0.4H), 1.82-1.73 (m, 0.6H). LCMS purity > 95%, [M+H]+ = 433.2, 2.28 and 2.32 min (analytical long).

[00321] The compound in Table 28 was synthesised by analogy.

Table 28 [00322] Procedure I: Preparation of /V-methylamide-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanols [00323] /V-methylamide-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanol analogues can be synthesised from the corresponding protected (imidazol-4-yl)heteroaryl carbaldehyde and haloarylmethylamine precursors by analogy with the procedure described in Scheme 9.

Scheme 9 [00324] Haloarylmethylamines can be coupled with carboxylic acids to form haloarylmethylamides in the presence of coupling agents (e.g. T3P, HATU). Haloarylmethylamides can be acetylated using conditions such as Palladium-mediated cross-coupling (e.g. butyl vinyl ether followed by hydrolysis with HCI). The resulting acetylarylmethylamides can be treated with (imidazol-4-yl)heteroaryl carbaldehydes under basic conditions (e.g. NaOH, KOH) to afford the corresponding /V-methylamide-substituted αβ-unsaturated ketones. Trityl deprotection and cyclisation of/V-methylamide-substituted αβ-unsaturated ketone intermediates (e.g. using AcOH) can afford the corresponding substituted /V-methylamide-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanones. A variety of reducing agents (e.g. NaBH4, L1BH4, CBS) can be used to reduce generate the corresponding A/-methylamide-substituted 1 -aryl-2-(imidazo-pyrrolo-heteroaryl)ethanols.

[00325] Example 1.1: Synthesis of/V-[[4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]methyl]benzamide

[00326] Step 1: /V-[(4-Bromophenyl)methyl]benzamide

[00327] To a solution of 4-bromobenzylamine hydrochloride (2.0 g, 9.0 mmol) in THF (50 ml_) was added A/,A/-diisopropylethylamine (4.7 ml_, 27 mmol) followed by benzoic acid (1.04 g, 8.54 mmol) and propylphosphonic anhydride (4.01 ml_, 13.5 mmol). The resulting mixture was heated at reflux over the weekend. The mixture was allowed to cool to ambient temperature and the solvent was removed in vacuo. Water and ethyl acetate were added and the layers separated. The organic layer was washed with 1 M HCI, passed through a phase separator and the solvent removed in vacuo to afford N-[(4-bromophenyl)methyl]benzamide (2.09 g, 7.20 mmol, 80% yield). LCMS purity > 85%, [M+H]+ = 290,1.69 min (analytical short).

[00328] Step 2: /V-[(4-Acetylphenyl)methyl]benzamide

[00329] A solution of/V-[(4-bromophenyl)methyl]benzamide (2.1 g, 7.2 mmol) tri-o-tolylphosphine (438 mg, 1.44 mmol) and triethylamine (3.01 mL, 21.6 mmol) in acetonitrile (50 ml_) was degassed and purged with Nitrogen. Palladium (II) acetate (162 mg, 0.720 mmol) and butyl vinyl ether (1.21 mL, 9.36 mmol) was added and the mixture which was degassed and purged with Nitrogen. The reaction mixture was heated to reflux and stirred overnight. It was subsequently cooled to ambient temperature and 1 M HCI (20 mL) was added and the mixture stirred for 1 hour. The mixture was extracted with ethyl acetate, passed through a phase separator and the solvent removed in vacuo. The crude residue was purified by column chromatography (0-100% ethyl acetate /heptane) to afford /V-[(4-acetylphenyl)methyl]benzamide (0.850 g, 3.36 mmol, 47% yield). LCMS purity > 95%, [M+H]+ = 254, 1.46 min (analytical short).

[00330] Step 3: /V-[[4-[(E)-3-[3-(1-Tritylimidazol-4-yl)-4-pyridyl]prop-2-enoyl]phenyl]methyl]benzamide

[00331] A solution of 3-(1-tritylimidazol-4-yl)pyridine-4-carbaldehyde (0.66 g, 1.6 mmol) and A/-[(4-acetylphenyl)methyl]benzamide (0.40 g, 1.6 mmol) in THF (15 ml_) and 1 M NaOH (6.32 ml_, 6.32 mmol) was stirred at 55 °C for 2 hours. The reaction mixture was allowed to cool to ambient temperature, water and ethyl acetate were added and the layers separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were passed through a phase separator and the solvent removed in vacuo to afford /V-[[4-[(E)-3-[3-(1-tritylimidazol-4-yl)-4-pyridyl]prop-2-enoyl]phenyl]methyl]benzamide (1.39 mg, 2.14 mmol, 135% crude yield). The crude was taken through to next step without further purification. LCMS purity > 40%, [M+H]+ = 651,1.95 min (analytical short).

[00332] Step 4: A/-[[4-[2-(5H-lmidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]phenyl]methyl]benzamide

[00333] A solution of A/-[[4-[(E)-3-[3-(1-tritylimidazol-4-yl)-4-pyridyl]prop-2- enoyl]phenyl]methyl]benzamide (1.00 g, 1.54 mmol) in methanol (10 ml_) and acetic acid (20 ml_) was heated at 80 °C for 2 hours. The solvents were removed in vacuo. Saturated sodium bicarbonate solution and ethyl acetate were added and the layers separated. The organic layer was passed through a phase separator and the solvent removed in vacuo. The crude residue was purified by column chromatography (0-20% MeOH/DCM) to afford /V-[[4-[2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]phenyl]methyl]benzamide (130 mg,0.318 mmol, 20.7% yield) . LCMS purity > 55%, [M+H]+ = 409, 1.10 min (analytical short).

[00334] Step 5: A/-[[4-[1-Hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]methyl]benzamide

[00335] To a solution of/V-[[4-[2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5- yl)acetyl]phenyl]methyl]benzamide (130 mg, 0.320 mmol) in methanol (5 mL) under nitrogen was added sodium borohydride (84.3 mg, 2.23 mmol) and the resulting mixture was stirred at ambient temperature for 3 hours. The solvent was removed in vacuo. Saturated ammonium chloride solution and DCM were added and the layers separated. The organic layer was passed through a phase separator and the solvent removed in vacuo to afford A/-[[4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]methyl]benzamide (70 mg,0.17 mmol, 54% yield). 1H NMR (DMSO-d6, 400MHz): 9.02 (t, J 7.2 Hz, 1H), 8.87-8.85 (m,1 H), 8.50 (d, J5.2 Hz, 0.4H), 8.44 (d, J5.2 Hz, 0.6H), 8.05 (s, 0.6H), 7.97 (s, 0.4H), 7.91-7.86 (m, 2H), 7.66 (d, J5.2 Hz, 0.4H), 7.57-7.43 (m, 3.6H), 7.39-7.34 (m, 2H), 7.31-7.26 (m, 2.6H), 7.22-7.20 (m, 0.4H), 5.80 (d, J5.0 Hz, 0.6H), 5.64 (d, J5.0 Hz, 0.4H), 5.58 (dd, J9.3, 3.6 Hz, 0.6H), 5.48 (t, J6.2 Hz, 0.4H), 4.99-4.85 (m, 1H), 4.48-4.43 (m, 2H), 2.46-2.35 (m, 1H), 2.23-2.14 (m, 0.4H), 1.89-1.80 (m, 0.6H). LCMS purity > 95%, [M+H]+ = 411, 1.02 and 1.03 min (analytical short), 2.21 and 2.26 min (analytical long).

[00336] Procedure J: Preparation of S-linked sulphonamide-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanol [00337] S-linked sulphonamide-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanol analogues can be synthesised from the corresponding protected (imidazol-4-yl)heteroaryl carbaldehyde and acetylarylsulphonyl chlorides precursors by analogy with the procedure described in Scheme 10.

Scheme 10 [00338] Acetylarylsulphonamide derivatives can be prepared by reaction of the corresponding acetylarylsulphonyl chlorides with amines in presence of pyridine. (lmidazol-4-yl)heteroaryl carbaldehydes can be treated with acetylarylsulphonamides in basic conditions (e.g. NaOH, KOH) to afford the corresponding S-linked sulphonamide-substituted αβ-unsaturated ketones. Trityl deprotection and cyclisation of S-linked sulphonamide-substituted αβ-unsaturated ketone intermediates (e.g. using AcOH) can afford S-linked sulphonamide-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanones which can be reduced to the corresponding S-linked sulphonamide-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanols with reducing agents (e.g. NaBH4, UAIH4, CBS).

[00339] Example J.1: Preparation of 4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]-/V-phenyl-benzenesulphonamide

[00340] Step 1: 4-Acetyl-/V-phenyl-benzenesulphonamide

[00341] 4-Acetylbenzenesulphonyl chloride (2.39 g, 10.96 mmol) in DCM (20 ml.) was slowly added to a solution of aniline (1.0 mL, 11 mmol) and pyridine (1.0 mL, 12 mmol) in DCM (100 ml.) at ambient temperature under nitrogen. After continuous stirring for 2 hours, the reaction then washed 1 M HCI (50 mL), saturated NaHCC>3 (50 mL) and brine (50 mL) to afford 4-acetyl-/V-phenyl-benzenesulphonamide (506 mg, 1.73 mmol, 16% yield). 1H NMR (CDCIs, 400 MHz) δ: 7.99 (d, J 8.7 Hz, 2H), 7.84 (d, J 8.7 Hz, 2H), 7.29-7.23 (m, 2H), 7.13-7.18 (m, 1H), 7.07-7.04 (m, 2H), 6.59 (br.s, 1H), 2.61 (s, 3H). LCMS purity > 95%, [M+H]+ = 276, 1.52 min (analytical short).

[00342] Step 2: A/-Phenyl-4-[(E)-3-[3-(1-tritylimidazol-4-yl)-4-pyridyl]prop-2-enoyljbenzenesulphonamide

[00343] To a suspension of 4-acetyl-/V-phenyl-benzenesulphonamide (506 mg, 1.73 mmol) and 3-(1-tritylimidazol-4-yl)pyridine-4-carbaldehyde (865 mg, 2.08 mmol) in THF (14 mL) was added 2 M aqueous solution of sodium hydroxide (3.4 mL, 6.8 mmol). The reaction was stirred at 80 °C under nitrogen for 2 hours, cooled to room temperature, diluted with ethyl acetate (25 mL) and washed with aq. sat NH4CI (20 mL) and water (2 x 25 mL). The aqueous layer was extracted with ethyl acetate (25 mL) and the combined organic layers were dried over Na2SC>4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography with a 1-8% methanol in DCM gradient, to afford the product as a yellow foam (756 mg, 1.06 mmol, 61.4%). 1H NMR (DMSO-de, 400 MHz) δ: 10.46 (br.s, 1H), 8.89 (d, J 0.5 Hz, 1H), 8.53 (d, J 5.2 Hz, 1H), 8.27 (d, J 15.7 Hz, 1H), 8.25 (d, J 8.7 Hz, 2H), 7.92-7.87 (m, 4H), 7.62 (d, J 1.3 Hz, 1H), 7.44-7.38 (m, 6H), 7.38-7.33 (m, 3H), 7.31 (d, J 1.3 Hz, 1H), 7.25-7.20 (m, 2H), 7.19-7.15 (m, 6H), 7.12-7.08 (m, 2H), 7.06-7.01 (m, 1H). LCMS purity 94%, [M+H]+ = 673, 1.95 min (analytical short).

[00344] Step 3: 4-[2-(5H-lmidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]-A/-phenyl-benzenesulphonamide

[00345] Acetic acid (1.82 mL, 31.8 mmol) was added to a suspension of /V-phenyl-4-[(E)-3-[3-(1 -tritylimidazol-4-yl)-4-pyridyl]prop-2-enoyl]benzenesulphonamide (756 mg, 1.06 mmol) in methanol (20 mL) under nitrogen. The resulting mixture was then heated to 80 °C under nitrogen for 30 minutes, upon which more acetic acid (5.0 mL, 87 mmol) was added. The reaction mixture was heated 80 °C for 2 hours, cooled to ambient temperature and concentrated in vacuo. The resulting orange residue was purified by column chromatography with a 1-5% methanol in dichloromethane gradient, to afford an off-white foam (357 mg, 0.770 mmol, 72.6%). 1H NMR (DMSO-de, 400 MHz) δ: 10.45 (br.s, 1H), 8.89 (d, J 0.9 Hz, 1H), 8.48 (d, J5.0 Hz, 1H), 8.16 (d, J8.6 Hz, 2H), 7.89 (d, J8.6 Hz, 2H), 7.77 (s, 1H), 7.61-7.58 (m, 1H), 7.26-7.20 (m, 3H), 7.10-7.07 (m2H), 7.06-7.01 (m, 1H), 5.82 (dd, J7.9, 4.1 Hz, 1H), 4.12 (dd, J 19.0, 4.2 Hz, 1H), 3.80 (dd, J 18.9, 8.0 Hz, 1H). LCMS purity 91%, [M+H]+ = 431, 1.10 min (analytical short).

[00346] Step 4: 4-[1-Hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]-A/-phenyl-benzenesulphonamide

[00347] Sodium borohydride (58.4 mg, 1.54 mmol) was added to a solution of 4-[2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)acetyl]-/V-phenyl-benzenesulphonamide (103 mg, 0.24 mmol) in methanol (20 mL) at ambient temperature under nitrogen. The reaction was stirred at room temperature for 1 hour. Aqueous sat NH4CI (50 mL) was added and the aqueous phase was extracted with DCM (3 x 50 mL). The combined organic phase was passed through a phase separator and evaporated in vacuo to afford the product as a yellow glassy solid (101 mg, 0.230 mmol, 95.6%). 1H NMR (DMSO-d6, 400 MHz) δ: 10.26 (br.s, 1H), 8.87-8.86 (m, 1H), 8.42 (d, J5.0 Hz, 0.4H), 8.49 (d, J5.0 Hz, 0.6H), 8.04 (s, 0.6H), 8.11 (s, 0.4H), 7.73-7.53 (m, 5H), 7.30-7.19 (m, 3H), 7.10-7.06 (m, 2H), 7.03-6.97 (m, 1H), 5.99 (d, J4.6, 0.6H), 5.83 (d, J4.6, 0.4H), 5.58 (dd, J9.7, 3.3 Hz, 0.6H), 5.52 (t, J6.3 Hz, 0.4H), 5.01-4.95 (m, 0.6H), 4.94-4.87 (m, 0.4H), 2.46-2.37 (m, 1H), 2.31-2.19 (m, 0.6H), 1.87-1.95 (m, 0.4H). LCMS purity > 95%, [M+H]+ = 433,1.16 and 1.17 min (analytical short), 2.47 and 2.50 min (analytical long).

[00348] Procedure K: Preparation of amine-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanols [00349] Amine-substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanol analogues can be synthesised by analogy with the procedure described in Scheme 11.

Scheme 11 [00350] Reactions of 1-aminoaryl-2-(imidazo-pyrrolo-heteroaryl)ethanol with aryl/heteroaryl halides in presence of palladium catalyst, ligand and a base can afford aryl substituted amine-subsituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanol analogues.

[00351] Example K.1: Preparation of 1-[2-Chloro-4-(2-pyridylamino)phenyl]-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethanol

[00352] To a microwave vial was added tris(dibenzylideneacetone)dipalladium (0) (7.0 mg, 0.010 mmol), cesium carbonate (99.7 mg, 0.310 mmol), 1-(4-amino-2-chloro-phenyl)-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethanol (50 mg, 0.15 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9 mg, 0.02 mmol). The vial was capped, purged with nitrogen for 10 minutes and 1,4-dioxane (2 ml_) was added followed by 2-bromopyridine (0.020 ml_, 0.17 mmol). The reaction mixture was heated to 100 °C overnight. The mixture was allowed to cool to ambient temperature and partitioned with a water/ethyl acetate mixture. The organic layer was dried over Na2SC>4, filtered and concentrated in vacuo. The residue was purified by column chromatography using a 0-35% methanol in ethyl acetate gradient. The product was loaded onto a methanol primed SCX cartridge, eluted with methanol then 1 M ammonia in methanol and concentrated in vacuo. The ammonia flush was then concentrated to afford the product as a yellow solid (7.5 mg, 0.020 mmol, 12%). 1H NMR (DMSO-de, 400 MHz) δ: 9.22 (s, 1H), 8.88 (s, 1H), 8.53 (d, J5.4 Hz, 0.4H), 8.46 (d, J5.4 Hz, 0.6H), 8.21-8.17 (m, 1H), 8.07 (s, 0.6H), 7.99 (d, J 2.0 Hz, 0.4H), 7.97 (d, J2.0 Hz, 0.6H), 7.87 (s, 0.4H), 7.62-7.49 (m, 4H), 7.28 (s, 0.6H), 7.22 (s, 0.4H), 6.83 (dd, J 8.6, 1.2 Hz, 1H), 6.80-6.76 (m, 1H), 5.86 (d, J 4.7, 0.6H), 5.68 (d, J 4.7 Hz, 0.4H), 5.66-5.61 (m, 0.6H), 5.61-5.57 (m, 0.4H), 5.28-5.21 (m, 0.6H), 5.21-5.13 (m, 0.4H), 2.46-2.14 (m, 2H). LCMS purity > 90%, [M+H]+ = 404.1,0.91 min (analytical short), 1.84 min (analytical long).

[00353] The compound in Table 29 was synthesised by analogy.

Table 29 [00354] Procedure L: Preparation of (het)aryl substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanol [00355] (Het)aryl substituted 1-aryl-2-(imidazo-pyrrolo-heteroaryl)ethanol analogues can be synthesised by analogy with the procedure described in Scheme 12.

Scheme 12 [00356] 1-Halogenoaryl-2-(imidazo-pyrrolo-heteroaryl)ethanols can be coupled to a (hetero)aryl boronic acid/ester using metal catalysis agents (e.g. Suzuki coupling conditions) to give the (Het)aryl substituted 1 -aryl-2-(imidazo-pyrrolo-heteroaryl)ethanol analogues.

[00357] Example L.1: Preparation of 1-[2-chloro-4-(3-pyridyl)phenyl]-2-(5H)imidazo[4,5]pyrrolo[1,2a]pyridin-5-yl)ethanol

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-pyridylboronic acid (20 mg, 0.16 mmol) was added 1,4-dioxane (2 ml_) and sodium carbonate (1.2 mmol) in water (0.61 ml_). The resulting mixture was degassed with Nitrogen for 5 mins. [1 ,T-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-(3-pyridyl)phenyl]-2- (5H)imidazo[4,5]pyrrolo[1,2a]pyridin-5-yl)ethanol (16 mg, 34% yield). 1H NMR (DMSO-de, 400 MHz) δ: 8.92 (d, J 1.7 Hz, 1H), 8.89-8.88 (m, 1H), 8.59 (dd, J 4.8, 1.4 Hz 1H), 8.54 (d, J 5.1 Hz, 0.4H), 8.46 (d, J 5.0 Hz, 0.6H), 8.13-8.10 (m, 1,6H), 7.97 (s, 0.4H), 7.86-7.75 (m, 3H), 7.68 (d, J 5.0 Hz, 0.4H), 7.58 (d, J 5.0Hz, 0.6H), 7.51-7.48 (m,1H), 7.29 (s, 0.6H), 7.23 (s, 0.4H), 6.06 (d, J4.9 Hz, 0.6H), 5.86 (d, J4.3 Hz, 0.4H), 5.71-5.63 (m, 1H), 5.36-5.29 (m, 0.6H), 5.25-5.19 (m, 0.4H), 2.44-2.37 (m, 1H), 2.30-2.22 (m, 0.4H), 1.97-1.88 (m, 0.6H). LCMS purity >95%, [M+H]+ = 389.2, 0.89 and 0.93 min (analytical short), 1.85 min (analytical long).

[00358] Compounds drawn in Table 30 were prepared by analogy.

iaoie au

[00359] Procedure M: Separation of stereoisomeric mixtures using SFC

[00360] Example M.1: Separation of the 4 stereoisomers of 1-[3-chloro-4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]-3-phenyl-urea into stereoisomers 1, 2, 3 and 4.

[00361] A stereoisomeric mixture of 1-[3-chloro-4-[1-hydroxy-2-(5H-imidazo[4,5]pyrrolo[1,2-a]pyridin-5-yl)ethyl]phenyl]-3-phenyl-urea (130 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 40% isopropanol (0.1 %NH3 H2O) / 60% CO2 mixture at 70 mL/min. After separation, the fractions were concentrated in vacuo at 40 °C to obtain a the four isolated isomers.

[00362] Stereoisomer 1: (28 mg, 22% yield, SFC: 3.50 min). 1H NMR (400 MHz, d6-DMSO) δ: 8.87 (s, 1H), 8.84 (s, 1H), 8.72 (s, 1H), 8.45 (d, J 4.8 Hz, 1H), 8.05 (s, 1H), 7.67-7.60 (m, 2H), 7.56 (d, J 4.8 Hz, 1H), 7.43 (d, J 7.6 Hz, 2H), 7.33 (dd, J 8.8 and 2.0 Hz, 1H), 7.32-7.25 (m, 3H), 6.98 (t, J 7.2 Hz, 1H), 5.90 (d, J 4.4 Hz, 1H), 5.63 (dd, J 10.0 and 2.8 Hz, 1H), 5.26-5.20 (m, 1H), 2.45-2.35 (m, 1H), 1.87-1.80 (m, 1H). LCMS purity 100%, [M+H]+ = 446.1, 1.21 min (analytical short), D.e. = 85%.

[00363] Stereoisomer 2: (26 mg, 20% yield, SFC: 4.43 min). 1H NMR (400 MHz, d6-DMSO) δ: 8.88 (s, 1H), 8.83 (s, 1H), 8.70 (s, 1H), 8.52 (d, J 5.2 Hz, 1H), 7.88 (s, 1H), 7.64-7.67 (m, 2H), 7.56 (d, J 9.2 Hz, 1H), 7.46-7.42 (m, 2H), 7.32-7.23 (m, 3H), 7.21 (s, 1H), 6.98 (t, J 8.0 Hz, 1H), 5.71 (d, J 4.0 Hz, 1H), 5.59 (t, J 6.8 Hz, 1H), 5.17-5.12 (m, 1H), 2.37-2.16 (m, 2H). LCMS [M+H]+ = 446.1, 1.22 min (analytical short). NMR D.e. > 90%.

[00364] Stereoisomer 3: (29 mg, 22% yield, SFC: 6.60 min). 1H NMR (400 MHz, d6-DMSO) δ: 8.87 (s, 1H), 8.83 (s, 1H), 8.71 (s, 1H), 8.45 (d, J 4.8 Hz, 1H), 8.06 (s, 1H), 7.67-7.60 (m, 2H), 7.56 (d, J 4.8 Hz, 1H), 7.44 (d, J 7.6 Hz, 2H), 7.33 (dd, J 8.8 and 2.0 Hz, 1H), 7.31-7.25 (m, 3H), 6.97 (t, J 7.2 Hz, 1H), 5.90 (d, J 4.4 Hz, 1H), 5.63 (dd, J 10.0 and 2.8 Hz, 1H), 5.26-5.20 (m, 1H), 2.45-2.35 (m, 1H), 1.87-1.80 (m, 1H). LCMS purity 100%, [M+H]+ = 446.1, 1.22 min (analytical short). D.e. > 90%.

[00365] Stereoisomer 4: (25 mg, 19% yield, SFC: 7.79 min). 1H NMR (400 MHz, d6-DMSO) δ: 8.88 (s, 1H), 8.83 (s, 1H), 8.72 (s, 1H), 8.52 (d, J 5.2 Hz, 1H), 7.92 (s, 1H), 7.67-7.64 (m, 2H), 7.56 (d, J 9.2 Hz, 1H), 7.46-7.42 (m, 2H), 7.32-7.25 (m, 3H), 7.23 (s, 1H), 6.97 (t, J 8.0 Hz, 1H), 5.71 (d, J 4.0 Hz, 1H), 5.59 (t, J 6.8 Hz, 1H), 5.17-5.12 (m, 1H), 2.37-2.32 (m, 2H). LCMS [M+H]+ = 446.1, 1.22 min (analytical short), D.e. = 55%.

[00366] Biology [00367] Biological example 1: Human Indoleamine 2,3-Dioxygenase (IDO) enzyme activity (biochemical) assay [00368] The IC50 values were determined by measuring the enzymatic activity of IDO upon treatment with each compound. The assay involves the conversion of tryptophan to /V-formylkynurenine (NFK) by recombinant human IDO enzyme (rhIDO) and the formation of an AMormylkynurenine-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.

[00369] Compounds at a concentration of 20 mM are serially diluted in 100% dimethyl sulfoxide (DMSO) nine times in 96-well plates for a total of 10 dilution points. Each dilution and a DMSO control are further diluted 1:25 in assay medium containing 50 mM potassium phosphate buffer (pH 6.5), 6.25 pM methylene blue, 6.25 mM ascorbic acid (freshly prepared, neutralised with an equimolar amount of NaOH), 62.5 pg/mL catalase (freshly prepared), 0.1 % Tween-20 and 0.01 % bovine serum albumin (BSA).

[00370] To each well of a 384-well CellCarrier plate (Perkin Elmer #6007550) 10 pL of the above described assay buffer containing rhIDO (R&D Systems 6030-AO, 15 nM final concentration) and 5 pL of diluted compounds (100 pM starting concentration, 0.5% DMSO) are added. Compounds are pre-incubated with the enzyme for 30 min at room temperature. The reaction is then started by addition of 5 pL of 4 X the desired tryptophan concentration diluted in assay medium, providing 35 pM final substrate concentration, and incubated for 90 min at room temperature. The reaction is stopped by addition of 5 pL 1 M piperidine to the 20 pL enzymatic reaction volume, providing 200 mM final concentration and the plates are covered with seals and incubated at 65 °C in an oven sand bath for 25 min. The plates are incubated for 1 h at room temperature and the fluorescence intensity at 535 nm in each well is read using an EnVision plate reader (Perkin Elmer equipped with a 400/25 nm excitation filter and a 535/25 nm emission filter).

[00371] In order to test autofluorescence of compounds, 15 pL of assay buffer is added to each well of a 384-well CellCarrier plate and 5 pL of diluted compounds (100 pM starting concentration, 0.5% DMSO final concentration) are added in duplicate. This plate is then incubated alongside the assay plate. 5 pL 1 M piperidine is added to each well, providing 200 mM final concentration and the plates are covered with seals and incubated at 65 °C in an oven sand bath for 25 min. The plates are incubated for 1 h at room temperature and the fluorescence intensity at 535 nm in each well is read using an EnVision plate reader (Perkin Elmer equipped with a 400/25 nm excitation filter and a 535/25 nm emission filter).

[00372] 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.

[00373] Biological example 2: Biological value IDO biochemical [00374] The results of the biochemical IDO assay for certain compounds of the invention are given in Table 31. The table shows the biochemical IDO inhibition activity of each compound based on the IC50 value of the compound as “++” and “+++”. The category “+” refers to compounds with an IC50 of > 10 μΜ. The category “++” refers to compounds with an IC50 of 1 to 10 μΜ. The category “+++” refers to compounds with an IC50 < 1 pM. All compounds are stereoisomeric mixtures unless otherwise stated.

Table 31 [00375] The following table, Table 32, provides values of the BTK binding efficacy of a selection of compounds of the invention.

Table 32

[00376] Biological example 3: Human Tryptophan 2,3-Dioxygenase (TD02) enzyme activity (biochemical) assay [00377] The IC50 values were determined by measuring the enzymatic activity of TD02 upon treatment with each compound. The assay involves the conversion of tryptophan to /V-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.

[00378] 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.

[00379] To each well of a 384-well CellCarrier plate (Perkin Elmer #6007550) 20 pL of the above described assay buffer containing rhTD02 (NTRC-TDO-10K, 50 nM final concentration) and 10 pL of diluted compounds (100 pM 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 pL of 4 X the desired tryptophan concentration diluted in assay medium, providing 200 pM 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 pL 1 M piperidine to the 40 pL enzymatic reaction volume, providing 111.1 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).

[00380] In order to test autofluorescence of compounds, 30 pL of assay buffer is added to each well of a 384-well CellCarrier plate and 10 pL of diluted compounds (100 pM starting concentration, 0.5% DMSO final concentration) are added in duplicate. This plate is then incubated alongside the assay plate. 5 pL 1 M piperidine is added to each well, providing 111.1 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).

[00381] 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.

[00382] Biological example 4: Biological value TD02 biochemical [00383] The results of the biochemical TD02 assay for certain compounds of the invention are given in

Table 33. The table shows the biochemical TD02 inhibition activity of each compound based on the IC50 value of the compound as “+”, “++” and “+++”. The category “+” refers to compounds with an IC50 of > 10 pM. The category “++” refers to compounds with an IC50 of 1 to 10 pM. The category “+++” refers to compounds with an IC50 < 1 pM. All compounds are stereoisomeric mixtures unless otherwise stated.

Table 33 [00384] 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.

[00385] 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.

[00386] 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

Claims

1. A compound of formula (I):

i wherein ‘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, C3-5 cycloalkyl, -ORA, -CN, -S02Me and C1-4 alkyl substituted with -ORA; Z is selected from: -(CRBRc)k-, -(CRBRc)kC(0)-, -(CRBRc)kC(NRA1)-, -(CRBRc)kC(N-ORA1)-, -(CRBRc)kC(ORA1)RB1-, and -(CRBRc)kC(NRA1RA2)RB1 -; wherein k is selected from 1,2, 3 and 4; Y is a 5 or 6 membered carbocyclic or heterocyclic group which is unsubstituted or substituted with 1,2 or 3 groups (where chemically possible) selected from: halo, C1-4 alkyl, C1-4 haloalkyl, C3-5 cycloalkyl, -ORA3, -CN, -S02Me and C1-4 alkyl substituted with -ORA3; W is selected from a bond, -NRA4-, -C(0)NRA4-, -NRA4C(0)-, -(CRB2Rc1)mNRA4C(0)-, - (CRB2Rc1)mC(0)NRA4-, -NRA4C(0)(CRB2Rc1)m-, -C(0)NRA4(CRB2Rc1)m- -NRA4C(0)NRA5-, -NRA4S02NRA5-, -S02-, -S02NRA4-, -NRA4S02-, -(CRB2Rc1)mNRA4S(02)-, -(CRB2Rc1)mS(02)NRA4-, -NRA4S(02)(CRB2Rc1)m-, - S(02)NRA4(CRB2Rc1)m-, -NRA4C(0)0-, -0C(0)NRA4-, -NRA4C(0)0(CRB2Rc1)m-, -OC(O)-, -C(0)0, O and S; wherein m is 1 or 2; R1 is selected from substituted or unsubstituted: C1-10 alkyl, -N(Cmo alkyl)RA6, and a 3 to 16 membered fully saturated, partially unsaturated or aromatic mono-, di- or tri-cyclic moiety, which optionally may include 1,2,3 or 4 heteroatoms (where chemically possible) selected from Ο, N and S, and when substituted R1 is 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, C3-6 heterocycloalkyl -ORA7, -NRA7RA8, -SRA7, -C(0)RA7, -OC(0)RA7, -C(0)0RA7, -NRA7C(0)RB3, -C(0)NRA7RA8, -NRA7S02RA8, -S02NRA7RA8, -S02RA7, =0, -NO2, -CN, C1-4 alkyl substituted with -ORA7, C1-4 alkyl substituted with -NRA7RA8, C3-6 cycloalkyl substituted with -ORA7, phenyl substituted with 0, 1 or 2 RD, benzyl substituted with 0, 1 or 2 RD, and benzoyl substituted with 0, 1 or 2 RD; R2 is selected from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -ORA9 and C1-4 alkyl substituted with -ORA9; RA, RA1, RA2, RA3, RA4, RA5, RA6, RA7, RA8, RA9 and RA1° are independently selected at each occurrence from: H, C1-4 alkyl and C1-4 haloalkyl; RB,RC, RB1, RB2, RC1 and RB3are each independently selected at each occurrence from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -CN, and -ORA1° or the RB and Rc groups on the same atom form, together with the carbon atom to which they are attached, cyclopropyl, oxirane or oxetane rings; RD is independently selected at each occurrence from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -CN, and -ORA8.
2. The compound of claim 1, wherein A is a ring selected from substituted or unsubstituted: pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
3. The compound of claim 1 or claim 2, wherein the compound of formula (I) is a compound according to formula (Ila) to (lid):

wherein n is selected from 0, 1,2 or 3, R3 is selected from: H, halo, C1-4 alkyl, C1-4 haloalkyl, C3-5 cycloalkyl, -ORA, -CN, -SC>2Me and C1-4 alkyl substituted with -ORA; optionally wherein RA is selected from: H, C1-4 alkyl and C1-4 haloalkyl.
4. The compound of claim 1 or claim 2, wherein A is pyridyl, methoxypyridyl, ch loro pyridyl, fluoropyridyl, trifluoromethylpyridyl, cyanopyridyl or methylpyridyl.
5. The compound of any preceding claim, wherein Y represents substituted or unsubstituted: cyclopentyl, cyclohexyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrolinyl, imidazolidinyl, imidazolinyl, succinimidyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, oxazolinyl, dioxolanyl, isoxazolidinyl, isoxazolinyl, thiazolidinyl, thiazolinyl, isothiazolidinyl, isothiazolinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dihydropyranyl, tetrahydropyranyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, orthiadiazolyl.
6. The compound of any of claims 1 to 4, wherein Y is phenyl, chlorophenyl, pyridyl, piperidinyl or thiazolyl.
7. The compound of any preceding claim wherein the compound of formula (I) is a compound according to formula (Ilia) to (Mid):

wherein n is selected from 0, 1,2 or 3, and R4 is selected from: halo, C1-4 alkyl, C1-4 haloalkyl, -ORA3, C3-5 cycloalkyl, -CN, -SCbMe and C1-4 alkyl substituted with -ORA3.
8. The compound of any preceding claim, wherein Z may be selected from: -(CRBRc)k-, -(CRBRc)kC(0)-, or -(CRBRc)kC(ORA1)RB1-, optionally wherein RB and Rc are independently selected from: H, methyl, -CF3, fluoro, chloro, -OMe, and -OCF3 or RB and Rc on the same atom form, together with the carbon atom to which they are attached, cyclopropyl, oxirane or oxetane rings.
9. The compound of claim 8, wherein Z is -CH2-, -CH2C(0)- or -CH2C(OH)H-.
10. The compound of any preceding claim, wherein W is selected from a bond, -NRA4-, -C(0)NRA4-, -NRA4C(0)-, -(CRB2Rc1)mNRA4C(0)-, -(CRB2Rc1)mC(0)NRA4-, -NRA4C(Ο)NRA5-, -NRA4S02-, -NRA4C(0)0-, and -0C(0)NRA4-.
11. The compound of any preceding claim, wherein R1 is selected from substituted or unsubstituted: C1-6 alkyl, -N(Ci-6 alkyl)RA6, C3-10 cycloalkyl, C5-10 heterocycloalkyl, C3-10 cycloalkylene, C5-10 heterocycloalkylene, Ce-io aryl and C5-10 heteroaryl.
12. The compound of any preceding claim, wherein R1 is selected from substituted or unsubstituted: methyl, ethyl, propyl, sec-butyl (1-methylpropyl), tert-hexyl (3,3-dimethylbutyl), NMe2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, azetidine, tetrahydrofuran, tetrahydrothiophene, imidazolidine, succinimide, piperidine, dihydropyran, tetrahydropyridyl, morpholine, piperazine, tetrahydropyran, benzodioxolane, benzondioxane, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, furanyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl.
13. The compound of any preceding claim, wherein R2 is H.
14. The compound of any preceding claim, wherein R3 is absent (n=0) or R3 is selected from: chloro, fluoro, methyl ortrifluoromethyl, optionally wherein n is 1
15. The compound of any preceding claim, wherein R4 is independently selected at each occurrence from: H, halo, C1-4 alkyl, C1-4 haloalkyl, -CN and -ORA3, optionally R4 is H or chloro
16. The compound of claim 1, wherein the compound of formula (I) is a compound selected from:
17. The compound of any preceding claim, wherein the compound is for use as a medicament.
18. A compound of any of claims 1 to 16 for use in the treatment of a condition which is modulated by indoleamine 2,3-dioxygenase (IDO) and/or tryptophan dioxygenase (TDO).
19. The compound of claim 17, wherein the condition modulated by IDO and/or TDO is a condition that is treatable by the inhibition of IDO and/or TDO.
20. The compound of claim 19, wherein the condition treatable by the inhibition of IDO and/or TDO 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.
21. A compound of any of claims 1 to 16, 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.
22. A compound of any of claims 1 to 16 for use in treating IDO and/or TDO mediated immunosuppression.
23. A compound of any of claims 1 to 16 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.
24. A method of inhibiting the degradation of tryptophan and preventing the production of N-formylkynurenine in a system comprising cells expressing IDO and/or TDO, wherein the system is exposed to a compound of any of claims 1 to 16.
25. 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 16 to a patient in need thereof.
26. A use of a compound of any of claims 1 to 16 in the manufacture of a medicament for the treatment of a condition which is modulated by IDO and/or TDO.
27. A pharmaceutical formulation comprising a compound of any of claims 1 to 16 and a pharmaceutically acceptable excipient.
28. The pharmaceutical formulation of claims 27, wherein the pharmaceutical formulation is a combination product comprising an additional pharmaceutically active agent