Fused pentacyclic imidazole derivatives

Abstract

Herein is provided a compound of Formula (III) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

Description

[0001] FUSED PENTACYCLIC IMIDAZOLE DERIVATIVES

[0002] FIELD

[0003] Herein is provided a compound of Formula (III) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof:

[0004] Formula (III)

[0005] BACKGROUND

[0006] The compound of Formula (II) is a pharmacologically active substituted fused pentacyclic benzimidazole derivative which shows pharmacological activity on TNFo signalling.

[0007] Formula (II)

[0008] The compound of Formula (II) has the chemical name (7R,14R)-11 -[2-(1 - aminocyclobutyl)pyrimidin-5-yl]-1 -(difluoromethoxy)-6-methyl-6,7-dihydro-7,14- methanobenzimidazo[1 ,2-b][2,5]benzodiazocin-5(14H)-one and is described in WO 2018 / 197503.

[0009] There is a need to provide active derivatives of the compound of Formula (II) for example which may present suitable pharmaceutical properties for their use as medicaments.

[0010] Further there is a need to provide active derivatives of the compound of Formula (II) which may have alternative or improved pharmacokinetic properties. Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, typically through specialized enzymatic systems. The primary purpose of drug metabolism is to convert chemical compounds into more readily excretable products.

[0011] During the metabolism of the compound of Formula (II) various metabolites are produced that may have unique pharmacological properties. Understanding and utilizing these metabolites may enhance therapeutic outcomes and provide alternative treatment strategies.

[0012] Herein are described novel compounds which are isolated or synthesized metabolites, or derivates thereof, of the compound of Formula (II).

[0013] SUMMARY

[0014] In a first aspect, herein is provided a compound of Formula (III) or an A / -oxi de thereof, or a pharmaceutically acceptable salt thereof:

[0015] Formula (III) wherein:

[0016] R1is selected from the group consisting of: a 1 -hydroxy-n- butyl group; a 1 ,2-dihydroxy-n-butyl group; or a cyclobutyl group optionally substituted with one or more substituents each independently selected from the group consisting of: -NH?, -NHOH, -OH, =0, -N=0 and -NO?;

[0017] R2is selected from the group consisting of H, Me, CH?OH and CH?R3; provided that the compound is not (7R,14R)-11-[2-(1 -aminocyclobutyl)pyrimidin-5-yl]-1 - (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1 ,2- b][2,5]benzodiazocin-5(14H)-one or a pharmaceutically acceptable salt thereof.

[0018] In a second aspect, herein is provided a compound of Formula (I) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof:

[0019] Formula (I) wherein:

[0020] R1is a 1 -hydroxy-n-butyl group; or a cyclobutyl group optionally substituted with one or more substituents each independently selected from the group consisting of: -NH?, -NHOH, -OH, =0, -N=0 and -N02;

[0021] R2is selected from the group consisting of H, Me, CH?OH and CH?R3; and provided that the compound is not (7R,14R)-11-[2-(1 -aminocyclobutyl)pyrimidin-5-yl]-1 - (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1 ,2- b][2,5]benzodiazocin-5(14H)-one or a pharmaceutically acceptable salt thereof.

[0022] In a third aspect, herein is provided a pharmaceutical composition comprising a compound of Formula (III) or an A / -oxi de thereof, or a pharmaceutically acceptable salt thereof, according to the first aspect, and a pharmaceutically acceptable carrier. In a fourth aspect, herein is provided a pharmaceutical composition comprising a compound of Formula (I) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof, according to the second aspect, and a pharmaceutically acceptable carrier.

[0023] In a fifth aspect, herein is provided a compound of Formula (III) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof according to the first aspect, or a composition according to the third aspect, for use in therapy.

[0024] In an sixth aspect, herein is provided a compound of Formula (I) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof according to the second aspect, or a composition according to the fourth aspect, for use in therapy.

[0025] DETAILED DESCRIPTION

[0026] In a first aspect, herein is provided a compound of Formula (III) or an A / -oxi de thereof, or a pharmaceutically acceptable salt thereof:

[0027] Formula (III) wherein:

[0028] R1is selected from the group consisting of: a 1 -hydroxy-n- butyl group; a 1 ,2-dihydroxy-n-butyl group; or a cyclobutyl group optionally substituted with one or more substituents each independently selected from the group consisting of: -NH?, -NHOH, -OH, =0, -N=0 and -NO?;

[0029] R2is selected from the group consisting of H, Me, CH2OH and CH2R3;

[0030] R4is H or OH; provided that the compound is not (7R,14R)-11 -[2-(1 -aminocyclobutyl)pyrimidin-5-yl]-1 - (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1 ,2- b][2,5]benzodiazocin-5(14H)-one or a pharmaceutically acceptable salt thereof.

[0031] In one embodiment of the first aspect, herein is provided a compound of Formula (III) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof:

[0032] Formula (III) wherein:

[0033] R1is selected from the group consisting of: a 1 -hydroxy-n- butyl group; a 1 ,2-dihydroxy-n-butyl group; or a cyclobutyl group optionally substituted with one or more substituents each independently selected from the group consisting of: -NH?, -NHOH, -OH, =0, -N=0 and -NO?;

[0034] R2is selected from the group consisting of H, Me, CH?OH and CH?R3;

[0035] R4is H or OH; and when R2is methyl and R4is H, then R1is different from a 1 -aminocyclobutyl group.

[0036] In one embodiment of the first aspect: when R1is a 1 -hydroxy-n-butyl group; a 1 ,2-dihydroxy-n-butyl group; or a cyclobutyl group substituted with one or more substituents each independently selected from the group consisting of: -NHOH, -OH, =0, -N=0 and -NO?; then R2is selected from the group consisting of H, Me, CH?OH and CH?R3; or when R1is a 1 -hydroxy-n-butyl group; a 1 ,2-dihydroxy-n-butyl group; or a cyclobutyl group substituted with one or more substituents each independently selected from the group consisting of: -NH?, -NHOH, -OH, =0, -N=0 and -NO?; then R2is selected from the group consisting of H, CH?OH and CH?R3.

[0037] In one embodiment of the first aspect, R1is a 1 -hydroxy-n-butyl group or a 1 ,2-dihydroxy- n-butyl group. Typically, R1is a 1 -hydroxy-n-butyl group.

[0038] In one embodiment of the first aspect,

[0039] R1is a 1 -hydroxy-n-butyl group; 1 ,2-dihydroxy-n-butyl group; or a cyclobutyl group optionally substituted with one or more substituents each independently selected from the group consisting of: -NH?, -NHOH, -OH, =0, -N=0 and -NO?; and R2is selected from the group consisting of H, CH?OH and CH?R3.

[0040] In one embodiment of the first aspect,

[0041] R1is a 1 -hydroxy-n-butyl group; 1 ,2-dihydroxy-n-butyl group; or a cyclobutyl group selected from the group consisting of:

[0042] In one embodiment of the first aspect, when R1is a 1 -hydroxy-n-butyl group; a 1 ,2- dihydroxy-n-butyl group; or a cyclobutyl group substituted with one or more substituents each independently selected from the group consisting of: -NH?, -NHOH, -OH, =0, -N=0 and -NO?; then R2is selected from the group consisting of H, CH?OH and CH?R3.

[0043] In one embodiment of the first aspect, R4is H.

[0044] In one embodiment of the first aspect, R4is OH. In one embodiment of the first aspect, herein is provided a compound of Formula (I lib) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof: wherein:

[0045] R2is selected from the group consisting of H, Me, CH2OH and CH2R3; R6is H or OH. Typically, R6is H.

[0046] In one embodiment of the first aspect, herein is provided a compound of Formula (I He) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof:

[0047] Formula (lllc) wherein:

[0048] R2is selected from the group consisting of H, Me, CH2OH and CH2R3;

[0049] R5is one or more optional substituents each independently selected from the group consisting of: -NH?, -NHOH, -OH, =0, -N=0 and -NO?; and n is 0 or a positive integer; provided that the compound is not (7R,14R)-11-[2-(1 -aminocyclobutyl)pyrimidin-5-yl]-1 - (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1 ,2- b][2,5]benzodiazocin-5(14H)-one or a pharmaceutically acceptable salt thereof.

[0050] Typically, n is 0, 1, 2, 3 or 4. More typically, n is 0, 1 or 2. More typically, n is 1 .

[0051] In one embodiment of the first aspect, herein is provided a compound of Formula (Illa) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof:

[0052] Formula (Illa) wherein:

[0053] R1is selected from the group consisting of: a 1 -hydroxy-n- butyl group; a 1 ,2-dihydroxy-n-butyl group; or a cyclobutyl group optionally substituted with one or more substituents each independently selected from the group consisting of: -NH?, -NHOH, -OH, =0, -N=0 and -NO?;

[0054] R2is selected from the group consisting of H, Me, CH?OH and CH?R3; and provided that the compound is not (7R,14R)-11 -[2-(1 -aminocyclobutyl)pyrimidin-5-yl]-1 - (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1 ,2- b][2,5]benzodiazocin-5(14H)-one or a pharmaceutically acceptable salt thereof.

[0055] In one embodiment of the first aspect, herein is provided a compound of Formula (Hid) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof: wherein:

[0056] R2is selected from the group consisting of H, Me, CH2OH and CH2R3;

[0057] R6is H or OH. Typically, R6is H.

[0058] In one embodiment of the first aspect, herein is provided a compound of Formula (Hie) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof:

[0059] Formula (Hie) wherein:

[0060] R2is selected from the group consisting of H, Me, CH2OH and CH2R3;

[0061] R5is one or more optional substituents each independently selected from the group consisting of: -NH?, -NHOH, -OH, =0, -N=0 and -NO?; and n is 0 or a positive integer; provided that the compound is not (7R,14R)-11-[2-(1 -aminocyclobutyl)pyrimidin-5-yl]-1 - (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1 ,2- b][2,5]benzodiazocin-5(14H)-one or a pharmaceutically acceptable salt thereof.

[0062] Typically, n is 0, 1, 2, 3 or 4. More typically, n is 0, 1 or 2. More typically, n is 1 .

[0063] In one embodiment of the first aspect, the compound of Formula (III) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof, is a compound of Formula (I) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof according to the second aspect. In the compound of Formula (I), the R4of the compound of Formula (III) is H and therefore not typically drawn.

[0064] In a second aspect, herein is provided a compound of Formula (I) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof:

[0065] Formula (I) wherein:

[0066] R1is a 1 -hydroxy-n-butyl group; or a cyclobutyl group optionally substituted with one or more substituents each independently selected from the group consisting of: -NH?, -NHOH, -OH, =0, -N=0 and -NO?;

[0067] R2is selected from the group consisting of H, Me, CH?OH and CH?R3; and provided that the compound is not (7R,14R)-11-[2-(1 -aminocyclobutyl)pyrimidin-5-yl]-1 - (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1 ,2- b][2,5]benzodiazocin-5(14H)-one or a pharmaceutically acceptable salt thereof.

[0068] In one embodiment of the first or second aspect, herein is provided a compound of Formula (I) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof:

[0069] Formula (I) wherein:

[0070] R1is a 1 -hydroxy-n-butyl group; or a cyclobutyl group optionally substituted with one or more substituents each independently selected from the group consisting of: -NH?, -NHOH, -OH, =0, -N=0 and -N02;

[0071] R2is selected from the group consisting of H, Me, CH?OH and CH?R3; and and when R2represents a methyl group, then R1is different from a 1 -amino-cyclobutyl group.

[0072] In one embodiment of the first or second aspect, herein is provided a compound of Formula (I) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof:

[0073] Formula (I) wherein:

[0074] R1is a 1 -hydroxy-n-butyl group; or a cyclobutyl group substituted with one or more substituents each independently selected from the group consisting of: -NHOH, -OH, =0, -N=0 and -NO?; and R2is selected from the group consisting of H, Me, CH?OH and CH?R3; or

[0075] R1is a 1 -hydroxy-n-butyl group; or a cyclobutyl group substituted with one or more substituents each independently selected from the group consisting of: -NH?, -NHOH, - OH, =0, -N=0 and -NO?; and R2is selected from the group consisting of H, CH?OH and CH?R3; wherein R3is:

[0076] In one embodiment of the first or second aspect, herein is provided a compound of Formula (la) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof:

[0077] Formula (la) wherein:

[0078] R2is selected from the group consisting of H, Me, CH?OH and CH?R3; and

[0079] In one embodiment of the first or second aspect, herein is provided a compound of Formula (lb) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof: wherein:

[0080] R2is selected from the group consisting of H, Me, CH2OH and CH2R3;

[0081] R5is one or more optional substituents each independently selected from the group consisting of: -NH2, -NHOH, -OH, =0, -N=0 and -NO2; and n is 0 or a positive integer; provided that the compound is not (7R,14R)-11 -[2-(1 -aminocyclobutyl)pyrimidin-5-yl]-1 - (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1 ,2- b][2,5]benzodiazocin-5(14H)-one or a pharmaceutically acceptable salt thereof.

[0082] Typically, n is 0, 1 , 2, 3 or 4. More typically, n is 0, 1 or 2. More typically, n is 1 .

[0083] In one embodiment of the first or second aspect, R1is a 1 -hydroxy-n-butyl group; or a cyclobutyl group substituted with one or more substituents each independently selected from the group consisting of: -NHOH, -OH, =0, -N=0 and -NO2; and R2is selected from the group consisting of H, Me, CH2OH and CH2R3. In one embodiment of the first or second aspect,

[0084] R1is a 1 -hydroxy-n-butyl group; or a cyclobutyl group optionally substituted with one or more substituents each independently selected from the group consisting of: -NH?, -NHOH, -OH, =0, -N=0 and -NO?; and

[0085] R2is selected from the group consisting of H, CH2OH and CH2R3.

[0086] In one embodiment of the first or second aspect,

[0087] R1is a 1 -hydroxy-n-butyl group; or a cyclobutyl group selected from the group consisting

[0088] In one embodiment of the first aspect or second aspect,

[0089] R1is a 1 -hydroxy-n-butyl group, or a cyclobutyl group substituted with -NHOH;

[0090] Q<N- and R2is Me. Typically, R1is a 1 -hydroxy-n-butyl group or HOH• and R2is Me

[0091] In one embodiment of the first aspect, the compound of Formula (III) is in the form of an A / -oxide. Typically, the A / -oxide is pyrimidine A / -oxide.

[0092] In one embodiment of the second aspect, the compound of Formula (I) is in the form of an A / -oxide. Typically, the A / -oxide is pyrimidine A / -oxide.

[0093] In one embodiment of the first or second aspect, when R1is a cyclobutyl group, this group is substituted with one or more substituents each independently selected from -NH?, - NHOH, -OH, =0, -N=O and -NO?. Typically, when R1is a cyclobutyl group, this group is substituted with one or more substituents each independently selected from -NH?, -NHOH, and -OH. Typically, when R1is a cyclobutyl group, this group is substituted with one or two substituents each independently selected from -NH?, -NHOH and -OH. Typically, when R1is a cyclobutyl group, this group is substituted with one substituent selected from -NH? and - NHOH. In one embodiment of the first or second aspect, when R1is a cyclobutyl group it is substituted with at least one substituent. Typically, when R1is a cyclobutyl group it is substituted with at least two substituents.

[0094] In one embodiment of the first aspect or second aspect, R1is a cyclobutyl group substituted with one, two, three or four substituents. Typically, R1is a cyclobutyl group substituted with one, two or three substituents. More typically, R1is a cyclobutyl group substituted with one or two substituents. More typically, R1is a cyclobutyl group substituted with one substituent. More typically, R1is a cyclobutyl group substituted with two substituents.

[0095] In one embodiment of the first or second aspect, R1is selected from the group consisting of:

[0096] Typically, R1is selected from the group consisting of:

[0097] More typically, R1is selected from the group consisting of:

[0098] In one embodiment of the first or second aspect, R1is cyclobutyl optionally substituted with one or more substituents each independently selected from the group consisting of: - NH?, -NHOH, -OH, =0, -N=0 and -NO?. Typically, when R1is cyclobutyl, the cyclobutyl is selected from the group consisting of: typically, when R1is cyclobutyl, the cyclobutyl is selected from the group consisting of: typically, when R1is cyclobutyl, the cyclobutyl is selected from the group consisting of:

[0099] In another embodiment of the first or second aspect, R1is a 1 -hydroxy-n-butyl group. The

[0100] 1 -hydroxy- n- butyl group has the structure: OH

[0101] In one embodiment of the first or second aspect, R2is selected from the group consisting of H, Me and CH2OH. Typically, R2is Me or H. More typically, R2is H. More typically, R2is Me.

[0102] In one embodiment of the first or second aspect, R2is selected from the group consisting of H, CH2OH and CH2R3. Typically, R2is CH2OH or CH2R3. Typically, R2is CH2OH.

[0103] In one embodiment of the first or second aspect, R2is CH2R3.

[0104] In the context of the present specification

[0105] Glucuronidation is a reaction in drug metabolism which involves the conjugation of glucuronic acid to a drug molecule, typically at a hydroxyl. In the living organisms the reaction is catalysed by UDP-glucuronosyltransferases (UGTs). The resulting glucuronides are usually more water-soluble and are excreted via urine or bile. The compound glucuronic acid (also known chemically as B-D-glucopyranuronic acid).

[0106] In one embodiment of the first or second aspect, the compound is selected from the group consisting of:

[0107]

[0108] 5 In one embodiment of the first or second aspect, the compound is selected from the group consisting of:

[0109]

[0110] In one embodiment of the first or second aspect, the compound is selected from the group consisting of: In one embodiment of the first or second aspect, the compound is selected from the group consisting of:

[0111] In one embodiment of the first or second aspect, the compound is selected from the group consisting of:

[0112] In one embodiment of the first or second aspect, the compound is selected from the group consisting of: In one embodiment of the first or second aspect, the compound is selected from the group consisting of:

[0113] Herein is also provided an isolated or synthesized compound which is selected from a compound of Formula (III) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof according to the first aspect.

[0114] Herein is also provided an isolated or synthesized compound which is selected from a compound of Formula (I) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof according to the second aspect.

[0115] Herein is provided an isolated or synthesized compound selected from any of the compounds described herein, or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof.

[0116] “Isolated" as used herein means that the compound has been separated from the in vivo environment in which it was formed via metabolic pathways. For example, when a compound has been formed through the metabolic pathway of a human, the compound is "isolated" when it is no longer contained within the organs or systems of the human body but has been eliminated, excreted ex vivo and / or otherwise removed from the body. for example, via withdrawal of blood samples containing the compound. Accordingly, an isolated compound as described herein may contain at least 90%, at least 92%, at least 95% or at least 99% by weight of said compound.

[0117] In a third aspect, herein is provided a pharmaceutical composition comprising a compound of Formula (III) or an A / -oxi de thereof, or a pharmaceutically acceptable salt thereof according to the first aspect and a pharmaceutically acceptable carrier.

[0118] In a fourth aspect, herein is provided a pharmaceutical composition comprising a compound of Formula (I) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof according to the second aspect, and a pharmaceutically acceptable carrier.

[0119] Herein is also provided a pharmaceutical composition comprising an isolated or synthesized compound of Formula (III) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof according to the first aspect, and a pharmaceutically acceptable carrier.

[0120] Herein is also provided a pharmaceutical composition comprising an isolated or synthesized compound of Formula (I) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof according to the second aspect, and a pharmaceutically acceptable carrier.

[0121] Pharmaceutical compositions according to the third or fourth aspect may take a form suitable for oral, buccal, sublingual, subcutaneous, intramuscular, intravenous, parenteral, nasal, topical, transdermal, local, intra-tracheal, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.

[0122] For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients. The term "pharmaceutically acceptable excipient" as used herein refers to a compound suitable for use in contact with humans, and having a toxicity, irritation, or allergic response commensurate with a reasonable benefit / risk ratio, and effective for their intended use. The said excipients are selected, in accordance with the pharmaceutical form and method of administration desired, from customary excipients, which are known to a person skilled in the art. The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.

[0123] In a fifth aspect, herein is provided a compound of Formula (III) an A / -oxide thereof, or a pharmaceutically acceptable salt thereof according to the first aspect, or a pharmaceutical composition according to the third aspect, for use in therapy. Typically, the therapy is the treatment and / or prevention of disorders for which the administration of a modulator of TNFa function is indicated. More typically, the therapy is the treatment and / or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder.

[0124] In a sixth aspect, herein is provided a compound of Formula (I) an A / -oxide thereof, or a pharmaceutically acceptable salt thereof according to the second aspect, or a pharmaceutical composition according to the fourth aspect, for use in therapy. Typically, the therapy is the treatment and / or prevention of disorders for which the administration of a modulator of TNFa function is indicated. More typically, the therapy is the treatment and / or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder.

[0125] Herein is also provided the use of a compound of Formula (III) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof according to the first aspect, for the manufacture of a medicament for the treatment and / or prevention of disorders for which the administration of a modulator of TNFa function is indicated.

[0126] Herein is also provided the use of a compound of Formula (I) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof according to the second aspect, for the manufacture of a medicament for the treatment and / or prevention of disorders for which the administration of a modulator of TNFa function is indicated.

[0127] Herein is also provided the use of a compound of Formula (III) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof according to the first aspect, for the manufacture of a medicament for the treatment and / or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder.

[0128] Herein is also provided the use of a compound of Formula (I) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof according to the second aspect, for the manufacture of a medicament for the treatment and / or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder.

[0129] Herein is also provided a method for the treatment and / or prevention of disorders for which the administration of a modulator of TNFo function is indicated which comprises administering to a patient in need of such treatment a therapeutically effective amount a compound of Formula (III) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof according to the first aspect or a composition according to the third aspect.

[0130] Herein is also provided a method for the treatment and / or prevention of disorders for which the administration of a modulator of TNFo function is indicated which comprises administering to a patient in need of such treatment a therapeutically effective amount a compound of Formula (I) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof, according to the second aspect or a composition according to the fourth aspect.

[0131] Herein is also provided a method for the treatment and / or prevention of an inflammatory or autoimmune disorder, a neurological or neuro-degenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula (III) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof, according to the first aspect or a composition according to the third aspect.

[0132] Herein is also provided a method for the treatment and / or prevention of an inflammatory or autoimmune disorder, a neurological or neuro-degenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula (I) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof, according to the second aspect or a composition according to the fourth aspect.

[0133] As used herein, the term “therapeutically effective amount” means the amount of the compound of formula (III) or formula (I), that, when administered to a patient for treating and / or preventing a disease, is sufficient to effect such treatment and / or prevention for the disease. The “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient.

[0134] Inflammatory and autoimmune disorders include systemic autoimmune disorders, autoimmune endocrine disorders and organ-specific autoimmune disorders. Systemic autoimmune disorders include systemic lupus erythematosus (SLE), psoriasis, psoriatic arthropathy, vasculitis, inflammatory myopathy (including polymyositis, dermatomyositis and inclusion body myositis), scleroderma, multiple sclerosis, systemic sclerosis, ankylosing spondylitis, rheumatoid arthritis, non-specific inflammatory arthritis, juvenile inflammatory arthritis, juvenile idiopathic arthritis (including oligoarticular and polyarticular forms thereof), anaemia of chronic disease (ACD), Still’s disease (juvenile and / or adult onset), Behcet’s disease and Sjogren’s syndrome. Autoimmune endocrine disorders include thyroiditis. Organ-specific autoimmune disorders include Addison’s disease, haemolytic or pernicious anaemia, acute kidney injury (AKI; including cisplatin- induced AKI), diabetic nephropathy (DN), obstructive uropathy (including cisplatin-induced obstructive uropathy), glomerulonephritis (including Goodpasture’s syndrome, immune complex-mediated glomerulonephritis and antineutrophil cytoplasmic antibodies (ANCA)- associated glomerulonephritis), lupus nephritis (LN), minimal change disease, Graves’ disease, idiopathic thrombocytopenic purpura, inflammatory bowel disease (including Crohn’s disease, ulcerative colitis, indeterminate colitis and pouchitis), pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliary cirrhosis, autoimmune pneumonitis, autoimmune carditis, myasthenia gravis, spontaneous infertility, osteoporosis, osteopenia, erosive bone disease, chondritis, cartilage degeneration and / or destruction, fibrosing disorders (including various forms of hepatic and pulmonary fibrosis), asthma, rhinitis, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome, sepsis, fever, muscular dystrophy (including Duchenne muscular dystrophy), organ transplant rejection (including kidney allograft rejection), scleritis (including giant cell arteritis scleritis), Takayasu arteritis, hidradenitis suppurativa, pyoderma gangrenosum, sarcoidosis, polymyalgia rheumatic and axial spondyloarthritis.

[0135] Neurological and neurodegenerative disorders include Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ischaemia, stroke, amyotrophic lateral sclerosis, spinal cord injury, head trauma, seizures and epilepsy.

[0136] Cardiovascular disorders include thrombosis, cardiac hypertrophy, hypertension, irregular contractility of the heart (e.g. during heart failure), and sexual disorders (including erectile dysfunction and female sexual dysfunction). Modulators of TNFo function may also be of use in the treatment and / or prevention of myocardial infarction.

[0137] Metabolic disorders include diabetes (including insulin-dependent diabetes mellitus and juvenile diabetes), dyslipidemia and metabolic syndrome.

[0138] Ocular disorders include retinopathy (including diabetic retinopathy, proliferative retinopathy, non -proliferative retinopathy and retinopathy of prematurity), macular oedema (including diabetic macular oedema), age-related macular degeneration (ARMD), vascularisation (including corneal vascularisation and neovascularisation), retinal vein occlusion, and various forms of uveitis (including iritis) and keratitis.

[0139] Oncological disorders, which may be acute or chronic, include proliferative disorders, especially cancer, and cancer-associated complications (including skeletal complications, cachexia and anaemia). Particular categories of cancer include haematological malignancy (including leukaemia and lymphoma) and non-haematological malignancy (including solid tumour cancer, sarcoma, meningioma, glioblastoma multiforme, neuroblastoma, melanoma, gastric carcinoma and renal cell carcinoma). Chronic leukaemia may be myeloid or lymphoid. Varieties of leukaemia include lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), chronic lymphocytic / lymphoid leukaemia (CLL), hairy-cell leukaemia, acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML), myelodysplastic syndrome, chronic neutrophilic leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, mantle cell leukaemia, multiple myeloma, acute megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia and erythroleukaemia. Varieties of lymphoma include malignant lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, lymphoblastic T cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, MALT1 lymphoma and marginal zone lymphoma. Varieties of non-haematological malignancy include cancer of the prostate, lung, breast, rectum, colon, lymph node, bladder, kidney, pancreas, liver, ovary, uterus, cervix, brain, skin, bone, stomach and muscle. Modulators of TNFo function may also be used to increase the safety of the potent anticancer effect of TNF.

[0140] If desired, a compound of Formula (III) may be co-administered with another pharmaceutically active agent, e.g. an anti-inflammatory molecule.

[0141] If desired, a compound of Formula (I) may be co-administered with another pharmaceutically active agent, e.g. an anti-inflammatory molecule.

[0142] For use in medicine, the salts of the compounds of Formula (III) will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of Formula (III) or of their pharmaceutically acceptable salts.

[0143] For use in medicine, the salts of the compounds of Formula (I) will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of Formula (I) or of their pharmaceutically acceptable salts.

[0144] As used herein, the term “pharmaceutically acceptable salt” refers to salts that are, within the scope of sound medical judgment, suitable for administration to a subject without undue toxicity, irritation, allergic response or other undesired effect, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. In some embodiments, the pharmaceutically acceptable salts are the hydrochloride salt or the trifluoroacetic acid salt.

[0145] As used herein, the term “subject” refers to a human or animal. In some embodiments, the subject is human (e.g. a “patient”). In some embodiments, the subject is an animal.

[0146] Where the compounds of Formula (III) and (I) have one or more asymmetric centres, they may accordingly exist as enantiomers. Where the compounds of Formula (III) or (I) possess two or more asymmetric centres, they may additionally exist as diastereomers. The compounds are to be understood to extend to the use of all such enantiomers and diastereomers, and to mixtures thereof in any proportion, including racemates. Formula (III) or (I) and the formulae depicted herein are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise. For the avoidance of doubt, insofar as is practicable any embodiment of a given aspect of the processes herein described may occur in combination with any other embodiment of the same aspect. In addition, insofar as is practicable it is to be understood that any preferred, typical or optional embodiment of any aspect of the processes herein described should also be considered as a preferred, typical or optional embodiment of any other aspect.

[0147] EXAMPLES

[0148] Analytical Methods: LCMS Method:

[0149] 1H NMR method:1H NMR was performed on a Bruker NMR spectrometer at 400 MHz

[0150] HPLC Method Parameters (Example 1 ):

[0151] HPLC Method Parameters (Example 2):

[0152] Preparation Examples:

[0153] Example 1 :

[0154] Preparation of (7R,14R)-1-(difluoromethoxy)-11-(2-(1- (hydroxyamino)cyclobutyl)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (designated hereafter as metabolite M8) and the trifluoroacetic acid salt thereof

[0155] Step 1 : Preparation of 2-((1 -(5-((7R,14R)-1 -(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1 ,2-a][1 ,4]diazocin-11 -yl)pyrimidin-2- yl ) eye lobuty I ) a mi no ) aceto ni tri le

[0156] To a solution of the compound of Formula (II) (8.00 g, 15.9 mmol, 1 .00 eq) in acetonitrile (MeCN) (40.0 mL) was added Na?CO3 (3.37 g, 31.8 mmol, 2.00 eq) and 2-chloroacetonitrile (1 .80 g, 23.9 mmol, 1.51 mL, 1 .50 eq) at 25 °C. The mixture was stirred at 60 °C for 24 (hours) hrs. HPLC indicated the starting material was consumed completely and one new peak formed. The reaction was filtered, and the filtrate was concentrated in vacuum.

[0157] The crude product was triturated with methyl tert-butyl ether (MTBE) (20.0 mL) at 25 °C for 30 mins to give the title compound (8.00 g, 14.8 mmol, 92.8% yield) as a yellow solid.

[0158] LCMS: RT = 0.377 min, 90.5% purity, [M+H]+= 542.2.1H NMR: 400 MHz DMSO § 9.08 (s, 2H), 8.27 (t, J = 4.8 Hz, 1 H), 7.77-7.79 (m, 2H), 7.61 -7.64 (m, 2H), 7.49 (d, J = 5.2 Hz, 2H), 6.31 (d, J = 7.2 Hz, 1 H), 5.25 (d, J = 7.2 Hz, 1 H), 3.43-3.56 (m, 4H), 3.36 (s, 3H), 2.84 (d, J = 13.6 Hz, 1 H), 2.54-2.61 (m, 2H), 2.18-2.26 (m, 3H), 1.98-2.07 (m, 1 H), 1.75-1.81 (m, 1 H)

[0159] Step 2: Preparation of 1 -cyano-N-(1 -(5-((7R,14R)-1 -(difluoromethoxy)-6-methyl-5-oxo- 5,6,7,14-tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1 ,2-a][1 ,4]diazocin-11 - yl)pyrimidin-2-yl)cyclobutyl)methanimine oxide

[0160] To a solution of meta-chloroperoxybenzoic acid (m-CPBA) (7.97 g, 36.9 mmol, 80.0% purity, 2.50 eq) in dichloromethane (DCM) (160 mL) was added MgSO4(3.56 g, 29.5 mmol, 2.00 eq) at 25 °C, after 30 mins, the mixture was filtered, the filter cake was washed with DCM (40.0 mL), the filtrate was added to a solution of the title compound from step 1 (8.00 g, 14.8 mmol, 1.00 eq) in DCM (80.0 mL) dropwise at 0 °C under N? for 2 hrs. The reaction mixture was stirred at 25 °C for 2 hrs. HPLC indicated the starting compound was consumed completely and one new peak formed. The mixture was added Na2S?O3 (300 mL) at 0 °C, the aqueous phase was extracted with DCM (300 mL, 100 mL). The combined organic phase was washed with Na2S?O3 (200 mL, 100 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. TLC (Petroleum ether / Ethyl acetate = 0 / 1 ) showed Rf = 0.40 is desired spot. The residue was purified by column chromatography (S1O2, Petroleum ether / Ethyl acetate = 100 / 1 to 0 / 1 ) to give the title compound (6.00 g, 9.29 mmol, 62.8% yield, 86.0% purity) as a yellow solid.

[0161] LCMS: RT = 0. 431 min, 86.0% purity, [M+H]+= 556.2.1H NMR: 400 MHz DMSO § 9.17 (s, 2H), 8.27 (t, J = 4.8 Hz, 1 H), 7.87-7.88 (m, 1 H), 7.78-7.81 (m, 2H), 7.64-7.68 (m, 2H), 7.49 (d, J = 5.2 Hz, 2H), 6.31 (d, J = 7.2 Hz, 1 H), 5.26 (d, J = 7.2 Hz, 1 H), 3.50-3.57 (m, 1 H), 3.36 (s, 3H), 2.83-2.99 (m, 5H), 1.86-1.94 (m, 2H).

[0162] Step 3: (7R,14R)-1 - (difluoromethoxy) -11 - (2- (1 -(hydroxyamino)cyclobutyl)pyrimidin-5-yl)-6- methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1 ,2-a][1 ,4]diazocin-5(14H)- one

[0163] To a solution of the title compound from step 2 (6.00 g, 10.8 mmol, 1 .00 eq) in MeOH (120 mL) was added NH?OH HCl (3.75 g, 54.0 mmol, 5.00 eq) at 25 °C. The mixture was stirred at 60 °C for 12 hrs. HPLC indicated the starting compound was consumed completely and one new peak formed. The reaction mixture was concentrated in vacuum. A mixture of the title compound (3.50 g, 6.31 mmol, 1.00 eq, HCl) in MeOH (5.00 mL) was poured into NaHCOs (sat. aq. 100 mL), filtered, and the filter cake was washed with H?O (20.0 m L), the filter cake was collected to give the title compound example 1 (2.50 g, 4.82 mmol, 44.6% yield) which was obtained as a yellow solid.

[0164] LCMS: RT = 0.334 min. HPLC: RT (starting material) = 3.440 min, RT (title compound) =2.632 min.

[0165] Salt formation step 4: (7R,14R)-1 -(difluoromethoxy)-11 -(2-(1 - (hydroxyamino)cyclobutyl)pyrimidin-5-yl)-6-methyl-6,7-dihydro-7,14- methanobenzo[f]benzo[4,5]imidazo[1 ,2-a][1 ,4]diazocin-5(14H)-one trifluoroacetic acid salt

[0166] A mixture of the title compound from step 3 (2.50 g, 4.82 mmol, 1 .00 eq) in MeOH (15.0 mL) was degassed and purged with N? for 3 times, before adding TFA (2.50 ml), and then the mixture was stirred at 25 °C for 12 hrs under N? atmosphere. HPLC indicated the starting compound was consumed completely and one new peak formed. The reaction mixture was purified directly without work-up. The crude product was purified by prep- HPLC (column: Phenomenex luna C18 (250*70mm,15 um); mobile phase: [H?O (0.1%TFA) - ACN]; gradient:! 5% - 45% B over 20.0 min) to give the title compound example 1 TFA salt (1 .05 g, 1 .35 mmol, 28.0% yield) as a white solid.

[0167] HPLC: RT = 5.544 min, 99.1% purity. MS: [M+H]+= 519.4.1H NMR: 400 MHz DMSO 11.8- 12.1 (m, 1 H), 11.0-11.1 (m, 2H), 9.22 (s, 2H), 8.27 (d, J = 2.4 Hz, 1 H), 7.80-7.83 (m, 2H), 7.67-7.71 (m, 2H), 7.49-7.51 (m, 2H), 6.32 (d, J = 7.2 Hz, 1 H), 5.27 (d, J = 7.2 Hz, 1 H), 3.53-3.55 (m, 1 H), 3.37 (s, 3H), 2.85 (d, J = 14 Hz, 1 H), 2.66-2.71 (m, 4H), 2.08-2.11 (m, 2H).

[0168] Example 2:

[0169] Preparation of (7R, 14R)-1-(difluoromethoxy)-11-(2-(1-hydroxybutyl)pyrimidin-5-yl)-6- methyl-6,7-dihydro-7, 14-methanobenzo[f]benzo[4,5]imidazo[1 ,2-a][1 ,4]diazocin- 5(14H)-one (designated hereafter as metabolite M17) and the corresponding (R) and (S) diastereomers

[0170] Step 1 : Preparation of 1 -(5-bromopyrimidin-2-yl)butan-1 -ol

[0171] -60 to 25 C, 13.6 hrs

[0172] To a solution of 5-bromo-2-iodopyrimidine (50.0 g, 176 mmol, 1.00 eq) in toluene (Tol). (300 mL) was added dropwise n-BuLi (2.50 M, 84.3 mL, 1 .20 eq) at - 60 °C during 6 minutes. After stirring at - 60 °C for 1 hr, a solution of butyraldehyde (13.9 g, 193 mmol, 17.0 mL, 1 .10 eq) in Tol. (50.0 mL) was added at -60 °C during 10 minutes. The reaction mixture was stirred at -60 °C for 20 minutes and then at 25 °C for 12 hrs. LC-MS showed the starting compound was consumed completely and one main peak with desired m / z. The reaction mixture was poured with sat. aq. NH4CI (2.00 L) and stirred for 10 mins. The aqueous phase was extracted with ethyl acetate (500 mL x 2). The combined organic phase was washed with brine (250 mL), dried over Na?SO4 and concentrated in vacuum. The title compound (50.0 g, crude) was obtained as a yellow oil. TLC (Petroleum ether / Ethyl acetate = 3 / 1 ) showed the Rf of the title compound is 0.6. The crude compound was purified by column chromatography (S1O2, Petroleum ether / Ethyl acetate = 100 / 1 to 0 / 1 ) to give the title compound (9.80 g, 24.8% yield, 91.2% purify) as a white solid.

[0173] LCMS: RT = 1.243 min, [M+H]+= 231.2.1H NMR: (400 MHz, DMSO-J6) d 8.97 (s, 2H), 5.27 (d, J = 6.0 Hz, 1 H), 4.61 (q, J = 6.0 Hz, J = 13.2 Hz, 1H), 1.70-1.74 (m, 2H), 1.28-1.33 (m, 2H), 0.86 (t, J = 2.0 Hz, 3H).

[0174] Step 2: Preparation of 5-bromo-2-(1 -((tert-butyldimethylsilyl)oxy)butyl)pyrimidine

[0175] 25 C, 12 hrs

[0176] To a mixture of the title compound from step 1 (9.80 g, 42.4 mmol, 1 .00 eq) and imidazole (5.77 g, 84.8 mmol, 2.00 eq) in DCM (45.0 mL) was added tri methylsilyl chloride (TBSCI) (12.8 g, 84.8 mmol, 10.4 mL, 2.00 eq) in one portion at 25 °C under N?. The reaction mixture was stirred at 25 °C for 12 hrs. LC-MS showed the starting compound was consumed completely and one main peak with desired m / z. The reaction mixture was filtered and the filtrate was concentrated in vacuum. The filter cake was discarded. The title compound (15.0 g, crude) was obtained as a light yellow oil.

[0177] LC-MS: RT = 2.749 min.1H NMR: (400 MHz, DMSO-J6) d 9.03 (s, 2H), 4.92 (q, J = 6.0 Hz, J = 8.0 Hz, 1H), 1.76-1.80 (m, 2H), 1.29-1.31 (m, 2H), 0.88-0.93 (m, 12H), 0.02 (s, 6H).

[0178] Step 3: Preparation of (2-(1 -((tert-butyldimethylsilyl)oxy)butyl)pyrimidin-5-yl)boronic acid B2Pin2(1.12 eq)

[0179] N? was bubbled into the reaction at 25 °C for 20 minutes. To a solution of the title compound from step 2 (15.0 g, 43.43 mmol, 1.00 eq), Bis(pinacolato)diboron (BzPim) (12.4 g, 48.7 mmol, 1.12 eq), potassium acetate (AcOK) (8.53 g, 86.9 mmol, 2.00 eq) and H2O (7.82 mg, 434 pmol, 7.82 pL, 0.01 eq) in dioxane (200 mL) was added chloro(2- dicyclohexylphosphino-2',4',6'-triisopropyl-1 ,1'-biphenyl)[2-(2'-amino-1 ,T- biphenyl)]palladium(ll) (Xphos PdG2)(888 mg, 1.13 mmol, 0.026 eq). The mixture was stirred at 90 °C for 12 hrs. LC-MS showed the starting compound was consumed completely and one main peak with desired m / z. The reaction mixture (100 % yield) was used directly into the next step.

[0180] LC-MS: RT = 0.600 min.

[0181] Step 4: (7R, 14R) -11 (2 (1 -((tert-butyldimethylsilyl)oxy)butyl)pyrimidin-5-yl)-1 - (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2- a][1 ,4]diazocin-5(14H)-one

[0182] N? was bubbled into the reaction at 25 °C for 20 minutes. To a solution of the title compound from step 3 (17.0 g, 43.3 mmol, 1.00 eq), compound (7R, 14R)-11 -chloro-1 - (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methano-benzimidazo[1 ,2- b][2,5]benzodiazocin-5(14H)-one (WO 2018 / 197503 intermediate 3) (8.44 g, 21.7 mmol, 0.50 eq), K3PO4 (46.0 g, 217 mmol, 5.00 eq) in dioxane (340 mL) and H2O (127 mL) was added Xphos PdG? (341 mg, 433 pmol, 0.01 eq). The mixture was stirred at 90 °C for 1 hr. LC-MS showed the starting compound was consumed completely and one main peak with desired m / z. The reaction mixture was poured with water (1 .00 L) and stirred for 10 mins. The aqueous phase was extracted with ethyl acetate (250 mL x 2). The combined organic phase was washed with brine (50.0 mL), dried over Na?SO4 and concentrated in vacuum. The title compound (20.0 g, crude) was obtained as a black solid.

[0183] LC-MS: RT = 2.552 min.

[0184] Step 5: Preparation of (7R,14R)-1 -(difluoromethoxy)-11 -(2-(1 -hydroxybutyl)pyrimidin-5-yl)- 6-methyl-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1 ,2-a][1 ,4]diazocin-5(14H)- one

[0185] To a solution of the title compound of step 4 (20.0 g, 32.3 mmol, 1 .00 eq) in tetra hydrofuran (THF) (40.0 mL) was added tetra-n-butylammonium fluoride (TBAF) (1.00 M, 48.4 mL, 1.50 eq) at 25 °C. The mixture was stirred at 25 °C for 12 hrs. LC-MS showed the starting compound was consumed completely and one main peak with desired m / z. The reaction mixture was poured with water (200 mL) and stirred for 10 mins. The aqueous phase was extracted with ethyl acetate (150 mL x 2). The combined organic phase was washed with brine (50.0 mL), dried over Na?SO4 and concentrated in vacuum. The title compound (15.0 g, crude) was obtained as a black oil. TLC (Petroleum ether / Ethyl acetate = 0 / 1 ) showed the Rf of the title compound is 0.3. The crude compound (15.0 g) was purified by column chromatography (SiO?, Petroleum ether / Ethyl acetate = 100 / 1 to 0 / 1 ) to give the title compound example 2 (5.00 g, 9.89 mmol, 30.6% yield) as an off-white solid.

[0186] LCMS: RT = 1.554 min, [M+H]+= 506.3.1H NMR: (400 MHz, CDCl3) d 8.86 (s, 2H), 8.43 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.34-7.40 (m, 2H), 7.26 (d, J = 8.4 Hz, 1H), 6.79 (t, J = 72.8 Hz, 1 H), 6.24(d, J = 7.2 Hz, 1H), 4.93 (d, J = 7.2 Hz, 2H), 4.83 (q, J = 4.0 Hz, J = 8.0 Hz, 1 H), 3.46 (s, 2H), 3.39-3.44 (m, 1H), 2.84 (d, J = 13.6 Hz, 1H), 1.96- 1 .97 (m, 1 H), 1.69-1 .72 (m, 2H), 1 .40-1.48(m, 2H), 0.91 (t, J = 7.6 Hz, 3H).

[0187] Resolution step 6: (7R,14R)-1 - (difluoromethoxy) -11 -(2-((R)-1 -hydroxybutyl)pyrimidin-5-yl)-6-methyl-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1 ,2-a][1 ,4]diazocin-5(14H)-one; and

[0188] (7R,14R)-1 - (difluoromethoxy) -11 - (2- ((S) -1 -hydroxybutyl)pyrimidin-5-yl)-6-methyl-6,7- dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1 ,2-a][1 ,4]diazocin-5(14H)-one

[0189] The product from step 5 was purified twice by supercritical fluid chromatography (SFC) (column: DAICEL CHIRALPAK IG (250 mm x 50 mm, 10 um); mobile phase: [COz-MeOH]; B%: 45%, isocratic elution mode).

[0190] The (R)-diastereomer compound example 2 (1.02 g, 2.02 mmol, 20.40% yield) was obtained as an off-white solid.

[0191] LCMS: RT = 0.232 min, [M+H]+= 506.20. HPLC: RT = 5.399 min, 99.7% purity. SFC: RT = 3.485 min, 99.8% ee.1H NMR: (400 MHz, CDCl3) (58.93 (s, 2H), 8.50 (d, J = 7.6 Hz, 1 H),

[0192] 7.84 (d, J = 8.4 Hz, 1 H), 7.71 (s, 1 H), 7.41 -7.47 (m, 2H), 7.32 (d, J = 8.0 Hz, 1 H), 6.86 (t, J = 72.8 Hz, 1 H), 6.31 (d, J = 8.0 Hz, 1 H), 4.99 (d, J = 7.2 Hz, 1 H), 4.88-4.91 (m, 1 H), 4.03 (d, J = 6.0 Hz, 1 H), 3.49-3.53 (m, 4H), 2.91 (d, J = 13.6 Hz, 1 H), 1.80-2.01 (m, 1 H), 1.76- 1.79 (m, 3H), 1.51 -1.55 (m, 2H), 0.99 (t, J = 7.2 Hz, 3H).

[0193] The (S) -diastereomer compound example 2 (880 mg, 1 .74 mmol, 17.60% yield) was obtained as an off-white solid. The compound was purified by column chromatography (SiO?, Petroleum ether / Ethyl acetate = 100 / 1 to 0 / 1 ) to give the compound (810 mg, 1.60 mmol, 92.1% yield) which was obtained as an off-white solid.

[0194] LCMS: RT = 0.236 min, [M+H]+= 506.20. HPLC: RT = 5.399 min, 99.7% purity. SFC: RT = 3.722 min, 99.6% ee.1H NMR: (400 MHz, CDCl3) <58.93 (s, 2H), 8.50 (d, J = 8.0 Hz, 1 H),

[0195] 7.85 (d, J = 8.4 Hz, 1 H), 7.71 (s, 1 H), 7.44-7.47 (m, 2H), 7.33-7.44 (m, 1 H), 6.86 (t, J = 72.8 Hz, 1 H), 6.31 (d, J = 8.0 Hz, 1 H), 5.00 (d, J = 7.2 Hz, 1 H), 4.90-4.91 (m, 1 H), 4.03 (s, 1 H), 3.48-3.53 (m, 4H), 2.91 (d, J = 13.6 Hz, 1 H), 1.78-2.05 (m, 1 H), 1.74-1.77 (m, 3H), 1.55-1.57 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H).

[0196] Example 3: Preparation of (7R,14R)-11-(2-(1-aminocyclobutyl)pyrimidin-5-yl)-1-(difluoromethoxy)- 6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one (designated hereafter as metabolite M5), hydrochloride salt

[0197] Step 1 : Preparation of tert- butyl (1 -(5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)pyrimidin-2-yl)cyclobutyl)carbamate

[0198] To a solution of tert-butyl (1 -(5-bromopyrimidin-2-yl)cyclobutyl)carbamate (18.0 g, 54.8 mmol, 1.00 eq) and bis(pinacolato)diboron (15.6 g, 61.4 mmol, 1.12 eq) in dioxane (180 mL) was added potassium acetate (AcOK) (9.96 g, 101 mmol, 1.85 eq), then XPHOS-PD-G? (431 mg, 548 mol, 0.01 eq) was added under N?, the mixture was stirred at 80 °C for 8 hrs. LCMS indicated the starting material was consumed completely. The mixture was used into the next step without further purification.

[0199] LCMS: Rt= 1 .096 min, [M+H]+= 294.4

[0200] Step 2: Preparation tert-butyl (1 -(5-((7R,14R)-1 -(difluoromethoxy)-5-oxo-5,6,7,14- tetrahydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1 ,2-a][1 ,4]diazocin-11 -yl)pyrimidin-2- yl)cyclobutyl)carbamate ,

[0201] To a solution of the title compound from step 1 (20.6 g, 54.8 mmol, 1 .00 eq) was added (7R, 14R) - 11 -chloro-1 -(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1 ,2- b][2,5]benzodiazocin-5(14H)-one (WO 2016 / 050975, Example 11 ) (15.4 g, 41.1 mmol, 0.75 eq) in dioxane (180 mL) a solution of K3PO4 (22.1 g, 104 mmol, 1.90 eq) in H?O (98.0 mL). The suspension was degassed and purged with N? for 3 times, XPHOS-PD-G? (431 mg, 548 pmol, 0.01 eq). The mixture was stirred at 80 °C for 5 hrs. LCMS indicated the starting material was consumed completely. The suspension was filtered, and the filter cake washed with EtOAc (200 mL x 2). The filtrate was extracted with EtOAC 300 mL. The combined organic layers were washed with brine 300 mL, dried over Na?SO4, filtered and concentrated under reduced pressure to give a residue. To a solution of the title compound in dioxane (6 V) was added heptane (200 mL) at 40 °C. The mixture was stirred at 20 ° C for 2 hrs. The suspension was filtered and the filter cake concentrate under vacuum. The title compound (18.0 g, 30.5 mmol, 55.6% yield) was obtained as a white solid.

[0202] LCMS: Rt= 1.584 min, [M+H]+= 589.4.1H NMR: (400 MHz, DMSO-J6) d 9.16 (d, J = 7.2 Hz, 1 H), 9.03 (s, 2H), 8.22-8.24 (m, 1 H), 7.73-7.77 (m, 3H), 7.60-7.69 (m, 2H), 7.50-7.51 (m, 2H), 6.37 (d, J = 7.2 Hz, 1 H), 4.90 (t, J = 6.8 Hz, 1 H), 3.49-3.51 (m, 1 H), 2.76 (d, J = 13.2 Hz, 1 H), 2.58-2.74 (m, 2H), 2.32-2.45 (m, 2H), 1.91 -2.13 (m, 2H), 1.01 -1.37 (m, 9H).

[0203] Step 3: Preparation of (7R,14R)-11 -(2-(1 -aminocyclobutyl)pyrimidin-5-yl)-1 - (difluoromethoxy)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1 ,2- a][1 ,4]diazocin-5(14H)-one hydrochloride To a solution of the title compound from step 2 (18.0 g, 30.5 mmol, 1 .00 eq) in isopropanol (IPA) (180 mL) was added HCl in isopropanol (HCl / IPA) (5 M, 30.5 mL, 5.00 eq). The mixture was stirred at 40 °C for 12 hrs. TLC (PE / EtOAc = 0 / 1 , starting material: Rf = 0.43, title compound, Rf = 0.15) indicated the starting material was consumed completely. The mixture was filtered and the filter cake washed with IPA (20.0 mL). The filter cake was concentrated under vacuum. The title compound example 3 HCl salt (14.0 g, 26.5 mmol, 86.7% yield, 99.5% purity, HCl) was obtained as an off-white solid.

[0204] LCMS: RT = 1.708 min, M+H+= 489.2.1H NMR: (400 MHz, MeOD) 6 9.20 (s, 2H), 8.38 (d, J = 4 Hz 2H), 8.13 (s, 1 H), 8.01 (s, 2H), 7.58-7.59 (m, 2H), 7.39 (t, J = 63.2 Hz, 1 H), 6.85 (d, J = 7.2 Hz, 1 H), 3.71 -3.78 (m, 1 H), 3.08 (d, J = 14 Hz, 1 H), 2.88-2.91 (m, 2H), 2.63-2.66 (m, 2H), 2.33-2.40 (m, 2H).

[0205] Example 4: Metabolites in vitro activity

[0206] Inhibition of TNFa-induced NF-KB activation

[0207] Stimulation of HEK-293 cells by TNFo leads to activation of the NF-KB pathway. The reporter cell line used to determine TNFo activity was purchased from InvivoGen. HEK- Blue™ CD40L is a stable HEK-293 transfected cell line expressing SEAP (secreted embryonic alkaline phosphatase) under the control of the IFNB minimal promoter fused to five NF-KB binding sites. Secretion of SEAP by these cells is stimulated in a dose-dependent manner by TNFo, with an EC50 of 0.5 ng / mL for human TNFo. Compounds were diluted from 10 mM DMSO stocks (final assay concentration 0.3% DMSO) to generate a 10-point 3-fold serial dilution curve (e.g. 30,000 nM to 2 nM final concentration). Diluted compound was preincubated with TNFo for 60 minutes prior to addition to a 384-well microtiter plate and incubated for 18 h. The final TNFo concentration in the assay plate was 0.5 ng / mL. SEAP activity was determined in the supernatant using a colorimetric substrate, e.g. QUANTI- Blue™ or HEK-Blue™ Detection media (InvivoGen). Percentage inhibitions for compound dilutions were calculated between a DMSO control and maximum inhibition (by excess control compound) and an IC50 value calculated using Genedata screener software (4 parameter logistic model).

[0208] Table 1 shows the results in this in vitro activity assay for metabolites M8, M17 (its two diastereoisomers) and M5.

[0209] Table 1

[0210] Results in Table 1 show that all the compounds exemplified herein are active in this in vitro activity assay, with IC50 values below 0.1 micromolar.

[0211] Example 5: Metabolites Caco2 permeability

[0212] Cell Culture and Preparation

[0213] Caco-2 TC7 cells, derived from a human colon adenocarcinoma, were used to model intestinal epithelial permeability. Cells were seeded at a density of 6.3 x 104cells / cm2(1 .2 x 105cells / mL) on 0.4 pm polycarbonate Transwell® inserts (Corning #3391 ) in 96-well plates (“ABR” assay code), or 1 pm PET Transwell® inserts in 24-well plates (“ABD” assay code) (Falcon #351181 ) and cultured for 21-25 days. Culture medium was replaced every two days until cell monolayers reached full differentiation. Cells were used for up to 60 passages from cryopreserved vials.

[0214] Permeability Assay

[0215] The permeability assay evaluated compound transport across the cell monolayer in the apical-to-basolateral (A-B) direction. On the day of the assay, monolayers were preequilibrated by washing twice with assay buffer. The apical compartment received 100 pL of test compound solution (20 pM in HBSS-HEPES buffer, pH 6.5 or 7.4, supplemented with 0.5% BSA and 0.186 mM sodium taurocholate). The basolateral compartment contained 260 pL of corresponding buffer (pH 7.4, with 0.0%, 0.5% or 5% BSA).

[0216] Detection of Compounds

[0217] After incubation, apical and basolateral samples were collected and processed with a 2x volume of stop solution (98% acetonitrile, 2% methanol, containing as internal standard 10 nM irbesartan). Samples were vortexed, centrifuged at 1 ,300 x g for 20 minutes, and the supernatant was analyzed using HPLC-MS / MS.

[0218] Cell Monolayer Integrity Monolayer integrity was assessed post-assay using Lucifer Yellow (192 pM in HBSS buffer, pH 7.4). Fluorescence was measured (Synergy H4 plate reader; excitation: 428 nm, emission: 540 nm). Monolayers with apparent permeability (Papp) of Lucifer Yellow < 0.5 x 10“6cm / s were considered intact.

[0219] Calculation of Permeability

[0220] The apparent permeability coefficient (P_app) was calculated using the formula:

[0221] Papp = where Q is the compound concentration in the receiver compartment (nM), C is the initial donor concentration (pM), A is the surface area of the insert and t is the incubation time (minutes).

[0222] Table 2 shows the results in this permeability assay for metabolites M8, M17 (its two diastereoisomers) and M5.

[0223] Results in Table 2 show that metabolites M8 and M17 have high intestinal cell permeability, hence a favorable profile for oral bioavailability.

[0224] Example 6: Pharmacokinetics

[0225] Study outline

[0226] Pharmacokinetics parameters for the compounds of examples 1 , 2 and 3 (metabolites M8, M17 and M5) were assessed in a phase 1 study, wherein the compound of Formula (II) was administered orally with a single dose of 200 mg to healthy adult participants. Metabolites concentrations were determined by LC-MS / MS (Liquid Chromatography with tandem Mass Spectrometry) in human plasma samples from the study.

[0227] The compound of Formula (II) was administered as an oral solution formulation, supplied in a single-use glass bottle containing 200 mg of the compound of Formula (II) with microtracer [14C]-Formula (II). Each bottle contained a single dose of 200 mg of [14C]- Formula (II) at a concentration of 200 mg per 50 mL (4.0 mg / mL) and a radioactive dose of 37 kBq (1 pCi). The pH of the oral solution was between 2.0 to 4.0. The solution contained the following excipients: water for injection and citric acid monohydrate.

[0228] A single dose of such an oral solution formulation was taken by the participants in the morning under fasted condition, following an overnight fasting of at least 10 hours. Participants were institutionalized until 12 (minimum) to 19 (maximum) days, with a follow-up period up to 3 weeks after Day 19.

[0229] Seven (7) healthy male participants were enrolled. Pre- and post-dose plasma samples were collected after oral administration of the compound of Formula (II) to determine the plasma-concentration time profiles of the metabolites of interest, and pharmacokinetic parameters were derived using non-compartmental analysis.

[0230] Plasma samples preparation and LC-MS / MS method for compound of formula (II) and for metabolites M5 and M17

[0231] A LC-MS / MS detection following protein precipitation was developed and validated for the quantitation of the compound of Formula (II) and its metabolites M5 and M17 in human plasma, using compound of Formula (Ila) (raw formula C2613CH2iD3F2N6O2, stable label for compound of Formula (II)) as the internal standard. See below its developed formula:

[0232] The compound of Formula (II), M5, M17 and the internal standard of Formula (Ila) were extracted from 25 pL aliquots of human plasma by precipitation of plasma proteins with acetonitrile. Chromatographic separation was achieved using an Kinetex, PS C18 column Phenomenex (50x2.1 mm, 2.6pm) at 40°C with a mobile phase of A: water:formic acid (100:0.2), B: acetonitrile:formic acid (100:0.2). Optimal chromatographic separation was achieved by elution gradient: TO.00 min 15% of B, T2.20 min 24% of B, T5.00 min 49% of B, T5.20 min 98% of B, T6.00 min 98% of B, T6.10 min 15% of B and kept constant for 0.40 min at a flow rate of 0.3 mL / min. The retention time of the compound of formula (II), M5 and M17 were approximately 1.47 min, 1.08 min and 3.76 min, respectively, with a 6.50- minute total run time. Of note, under the present chromatographic conditions the (R) and (S) diastereomers coelute, allowing the joint quantification of the mixture of the two diastereoisomers in the plasma sample. A Sciex API 65000 (ESI+) mass spectrometer was used. Parent ions at m / z 503.2, m / z 489.2, m / z 506.2, and m / z 507.2 and their corresponding product ions at m / z 486.1 , m / z 472.2, m / z 475.1 and m / z 490.3 were monitored the compound of Formula (II), M5, M17 and the internal standard, respectively. Calibration curves for the compound of Formula (II) and the compound M5 over the range of 2.00 to 1000 ng / mL, and for M17 over the range of 0.500 to 250 ng / mL, were fitted to a linear model using weighting of 1 / Concentration. The method was validated according to linearity, accuracy, precision, dilution, specificity and selectivity, carryover, stability and in matrix effect testing.

[0233] Plasma samples preparation and LC-MS / MS method for metabolite M8

[0234] For the metabolite M8, plasma samples were pretreated with diluted phosphoric acid to stabilize the compound, allowing a robust method qualification.

[0235] A LC-MS / MS detection following protein precipitation was developed and qualified for the quantitation of M8 (TFA salt) in treated human plasma with orthophosphoric acid (Human plasma, EDTA: [water: orthophosphoric acid (>85%) (80:20)] (2:1 )), using verapamil hydrochloride as the internal standard. The compound M8 and the internal standard were extracted from 60.0 pL of treated plasma (equivalent to 40.0 pL native / untreated plasma) by precipitation on wet ice of plasma proteins with acetonitrile, after addition of 25 pL ascorbic acid (284 mM) as antioxidant. Chromatographic separation was achieved using a Kinetex, BiPhenyl column Phenomenex (50x2.1 mm, 2.6pm) at 30° C with a mobile phase of A: water:formic acid (100:0.2), B: methanokformic acid (100:0.2). Optimal chromatographic separation was achieved in an elution gradient: TO.00 min 40% of B, TO.20 min 40% of B, T3.60 min 98% of B, T5.00 min 98% of B, T5.10 min 60% of B, and kept constant for 0.40 min at a flow rate of 0.3 mL / min. The retention time of M8 and of the internal standard were approximately 1 .96 min and 1 .68 min, respectively, with a 5.50- minute total run time. A Sciex API 65000 (ESI+) mass spectrometer was used. Parent ions at m / z 519.2 and m / z 455.3 and their corresponding product ions at m / z 486.1 and m / z 165.1 were monitored for M8 and the internal standard, respectively. Calibration curves for M8 over the range of 0.25 to 200 ng / mL were fitted to a linear model using weighting of 1 / Concentration. The method was qualified according to linearity, accuracy, precision, dilution, specificity and selectivity, carryover, stability and in matrix effect testing. Table 3 shows the results of this pharmacokinetics study in terms of maximum plasma concentration observed (Cmax), half-life (tv?) and plasma area under the curve (AUC) for metabolites M8, M17 and M5. Values in table 3 represent the arithmetic mean ± standard deviation (geometric mean). “R met AUC, MW” designates the molecular weight adjusted metabolite / parent AUC ratio, presented as mean + / - SD (geometric mean).

[0236] Table 3

[0237] Table 3 shows that M8 and M17 present higher exposure levels compared to M5, following administration with compound of Formula (II).

[0238] Aspects:

[0239] The following represent aspects of the inventions:

[0240] 1 . A compound of Formula (I) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof:

[0241] Formula (I) wherein: R1is a 1 -hydroxy-n-butyl group; or a cyclobutyl group optionally substituted with one or more substituents each independently selected from the group consisting of: -NH?, -NHOH, -OH, =0, -N=0 and -NO?;

[0242] R2is selected from the group consisting of H, Me, CH2OH and CH2R3; and provided that the compound is not (7R,14R)-11-[2-(1 -aminocyclobutyl)pyrimidin-5-yl]-1 - (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1 ,2- b][2,5]benzodiazocin-5(14H)-one or a pharmaceutically acceptable salt thereof.

[0243] 2. The compound according to aspect 1 , wherein the cyclobutyl group of R1is substituted with one or more substituents each independently selected from the group consisting of -NH?, -NHOH, and -OH.

[0244] 3. The compound according to any preceding aspect, wherein the cyclobutyl group of R1is substituted with one or two substituents.

[0245] 4. The compound according to any preceding aspect, wherein R1is cyclobutyl optionally substituted with one or more substituents each independently selected from the group consisting of: -NH?, -NHOH, -OH, =0, -N=0 and -NO?.

[0246] 5. The compound according to aspect 4, wherein R1is selected from the group consisting of:

[0247] 6. The compound according to aspect 1 , wherein R1is 1 -hydroxy-n-butyl.

[0248] 7. The compound according to any preceding aspect, wherein R2is Me or H.

[0249] 8. The compound according to any aspect 7, wherein R2is Me. The compound according to aspect 1 , selected from the group consisting of: A pharmaceutical composition comprising a compound of Formula (I) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof, as described in any one of aspects 1 -9, and a pharmaceutically acceptable carrier. A compound of Formula (I) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof, as described in any one of aspects 1 -9, or a composition as described in aspect 10, for use in therapy. A compound of Formula (I) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof, as described in any one of aspects 1 -9, or a composition as described in aspect 10, for use in the treatment and / or prevention of disorders for which the administration of a modulator of TNFo function is indicated. A compound of Formula (I) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof, as described in any one of aspects 1 -9, or a composition as described in aspect 10, for use in the treatment and / or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder.

Claims

CLAIMS1 .A compound of Formula (III) or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof:Formula (III) wherein:R1is selected from the group consisting of: a 1 -hydroxy-n- butyl group; a 1 ,2-dihydroxy-n-butyl group; or a cyclobutyl group optionally substituted with one or more substituents each independently selected from the group consisting of: -NH?, -NHOH, -OH, =0, -N=0 and -NO?;R2is selected from the group consisting of H, Me, CH?OH and CH?R3;R4is H or OH; provided that the compound is not (7R,14R)-11-[2-(1 -aminocyclobutyl)pyrimidin-5-yl]-1 - (difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1 ,2- b][2,5]benzodiazocin-5(14H)-one or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R1is selected from a 1 -hydroxy-n-butyl group and a 1 ,2-dihydroxy-n-butyl group.

3. The compound of claim 1 or claim 2, wherein the compound is a compound of Formula (Illa):Formula (Illa).

4. The compound of any preceding claim, wherein the compound is a compound of Formula (I):Formula (I).

5. The compound according to any preceding claim, wherein the cyclobutyl group of R1is substituted with one or more substituents each independently selected from the group consisting of -NH?, -NHOH, and -OH.

6. The compound according to one of claims 1 -4, wherein R1is cyclobutyl optionally substituted with one or more substituents each independently selected from the group consisting of: -NH?, -NHOH, -OH, =0, -N=0 and -NO?.

7. The compound according to claim 6, wherein R1is selected from the group consisting of:

8. The compound according to any preceding claim, wherein the cyclobutyl group of R1is substituted with one or two substituents.

9. The compound according to any one of claims 1 -4, wherein R1is 1 -hydroxy-n-butyl.

10. The compound according to any preceding claim, wherein R2is Me or H.11 . The compound according to claim 10, wherein R2is Me.

12. The compound according to claim 1 , selected from the group consisting of:

13. The compound according to claim 1 , wherein the compound is:

14. The compound according to claim 1 , wherein the compound is:

15. A pharmaceutical composition comprising a compound or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 -14, and a pharmaceutically acceptable carrier.

16. A compound or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 -14, or a pharmaceutical composition as claimed in claim 15, for use in therapy.

17. A compound or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 -14, or a pharmaceutical composition as claimed in claim 15, for use in the treatment and / or prevention of disorders for which the administration of a modulator of TNFa function is indicated.

18. A compound or an A / -oxide thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 -14, or a pharmaceutical composition as claimed in claim 15, for use in the treatment and / or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder.

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