2-methylene-4-oxo-butanoic acid derivatives for the treatment of inflammation

2:

• The compound according to claim 1 which is a compound of formula (Ia):
• wherein:
• RA is selected from the group consisting of C6-10 cycloalkyl optionally fused to phenyl, CH2(phenyl) and CH2(pyridyl);
• wherein when RA is C6-10 cycloalkyl optionally fused to phenyl, the cycloalkyl ring is optionally substituted on an available carbon atom by one or more RA2, wherein RA2 is selected from the group consisting of methyl, halo and trifluoromethyl, and/or two RA2 are attached to the same carbon atom and join to form a C3-6 cycloalkyl or a 4-6 membered heterocyclic ring;
• and the fused phenyl ring is optionally substituted on an available carbon atom by one or more substituents selected from the group consisting of C1-4 haloalkyl and halo;
• wherein when RA is CH2(phenyl) or CH2(pyridyl):
• the CH2 group is optionally substituted by one or two RA3 wherein RA3 is selected from the group consisting of C1-4 alkyl, C3-5 cycloalkyl, C1-4 haloalkyl and C1-2 hydroxyalkyl, or two RA3 groups are attached to the CH2 carbon atom and join to form a C3-6 cycloalkyl or a 4- or 5-membered heterocyclic ring;
• and
• the phenyl or pyridyl group is optionally substituted by one or more RA4, wherein RA4 is selected from the group consisting of C1-4 haloalkyl, halo, or SC1-4 haloalkyl;
• RB is selected from the group consisting of H;
• C2-3 alkyl substituted with OH or N(RB2)(RB3);
• and
• wherein:
• when RB is C2-3 alkyl substituted with N(RB2)(RB3), RB2 is selected from H and methyl and RB3 is selected from methyl and SO2(C1-2 alkyl) or RB2 and RB3, together with the nitrogen atom to which they are attached, combine to form a 4- to 6-membered heterocyclic ring optionally containing a further heteroatom selected from O and N;
• wherein, when RB is
• RB4 is H or methyl;
• E is N, O or SO2;
• wherein when E is N, RE is selected from the group consisting of R9B, C(O)R9B and SO2R9B;
• wherein R9B is C1-4 alkyl;
• and when E is O or SO2, RE is absent;
• nE and mE are independently 1 or 2;
• RC and RD are each independently H, C1-2 alkyl, hydroxy, methoxy or fluoro;
• each of RF and RG is independently H or methyl, provided that at least one of RF and RG is H;
• and
• wherein when the CH2 of the CH2(substituted phenyl) or CH2(substituted pyridyl) of RA is substituted by one RA3 the stereochemistry of the carbon to which RA3 is attached is as follows:
• wherein the dashed lines indicate attachment to the remainder of the compound of formula (I);
• and wherein when RA4 is Cl, the CH2 group is unsubstituted or is substituted by one RA3;
• and
• wherein, when RB is H, RA is not unsubstituted cyclohexyl;
• or a pharmaceutically acceptable salt and/or solvate thereof.

11:

• The compound or a pharmaceutically acceptable salt and/or solvate thereof according to claim 1 wherein:
• the phenyl or pyridyl group is substituted by one RA4, which is in the para-position with respect to the linkage to the remainder of the molecule;
• or
• the phenyl or pyridyl group is substituted by two RA4, wherein the first RA4 is in the para-position with respect to the linkage to the remainder of the molecule and the second RA4 is in the meta position with respect to the linkage to the remainder of the molecule, wherein each RA4 is independently selected from CHF2, CF3CF2, CF3, fluoro, chloro, bromo and SF5.

14:

• The compound or a pharmaceutically acceptable salt and/or solvate thereof according to claim 13, wherein RB is H or C2-3 alkyl substituted with OH or N(RB2)(RB3),
• wherein:
• RB2 is H and RB3 is SO2(C1-2 alkyl);
• or
• RB2 is H or methyl, and RB3 is methyl;
• or
• RB2 and RB3 together with the nitrogen atom to which they are attached combine to form a morpholine ring.

23:

• The compound or a pharmaceutically acceptable salt and/or solvate thereof according to claim 1, wherein:
• RF is H and RG is H;
• or
• each of RF and RG is independently H or methyl, provided that at least one of RF and RG is H;
• or
• RF is phenyl or C1-4 alkyl optionally substituted with phenyl, ORK or N(RK)(RL) and RG is H;
• or
• RF is H and RG is phenyl or C1-4 alkyl optionally substituted with phenyl, ORK or N(RK)(RL).

24:

• The compound or a pharmaceutically acceptable salt and/or solvate thereof according to claim 23 wherein:
• the compound is a compound of formula (Ic):
• wherein RF is phenyl or C1-4 alkyl optionally substituted with phenyl, ORK or N(RK)(RL) and RA, RC, RD and RZ are as defined in claim 1;
• or
• the compound is a compound of formula (Id):
• wherein RF is phenyl or C1-4 alkyl optionally substituted with phenyl, ORK or N(RK)(RL) and RA, RC, RD and RB are as defined for formula (I).

25:

• The compound according to claim 1 selected from:
• 1-(methylsulfonyl)piperidin-4-yl 4-((4-chlorobenzyl)amino)-2-methylene-4-oxobutanoate;
• 1-(methylsulfonyl)piperidin-4-yl 4-(cyclooctylamino)-2-methylene-4-oxobutanoate;
• (S)-2-methylene-4-oxo-4-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)butanoic acid;
• 2-methylene-4-oxo-4-((2-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)butanoic acid;
• 2-methylene-4-oxo-4-((1-(4-(trifluoromethyl)phenyl)cyclobutyl)amino)butanoic acid;
• 2-methylene-4-oxo-4-((4-(trifluoromethyl)benzyl)amino)butanoic acid;
• 2-methylene-4-oxo-4-((2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)amino)butanoic acid;
• (S)-2-methylene-4-oxo-4-((1-(4-(trifluoromethyl)phenyl)propyl)amino)butanoic acid;
• 1-(methylsulfonyl)piperidin-4-yl 2-methylene-4-oxo-4-((1-(4-(trifluoromethyl)phenyl)cyclobutyl) amino)butanoate;
• 4-((cyclopropyl(4-(trifluoromethyl)phenyl)methyl)amino)-2-methylene-4-oxobutanoic acid;
• 2-methylene-4-oxo-4-((1-(4-(trifluoromethyl)phenyl)cyclopropyl)amino)butanoic acid;
• (R)-4-((2-hydroxy-1-(4-(trifluoromethyl)phenyl)ethyl)amino)-2-methylene-4-oxobutanoic acid;
• 2-methylene-4-oxo-4-((3-(4-(trifluoromethyl)phenyl)oxetan-3-yl)amino)butanoic acid;
• 2-methylene-4-oxo-4-((1-(4-(trifluoromethyl)phenyl)cyclopentyl)amino)butanoic acid;
• (S)-4-((1-(4-chlorophenyl)ethyl)amino)-2-methylene-4-oxobutanoic acid;
• (S)-4-((1-(4-bromophenyl)ethyl)amino)-2-methylene-4-oxobutanoic acid;
• (S)-4-((1-(4-bromophenyl)ethyl)amino)-2-methylene-4-oxobutanoic acid;
• (S)-4-((1-(4-(difluoromethyl)phenyl)ethyl)amino)-2-methylene-4-oxobutanoic acid;
• (S)-4-((1-(3-fluoro-4-(trifluoromethyl)phenyl)ethyl)amino)-2-methylene-4-oxobutanoic acid;
• (S)-2-methylene-4-oxo-4-((1-(4-(perfluoroethyl)phenyl)ethyl)amino)butanoic acid;
• (R)-2-methylene-4-oxo-4-((2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)amino)butanoic acid;
• 1-(methylsulfonyl)piperidin-4-yl (S)-2-methylene-4-oxo-4-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)butanoate;
• 4-((cyclopropyl(4-(trifluoromethyl)phenyl)methyl)amino)-2-methylene-4-oxobutanoic acid;
• 1-methylpiperidin-4-yl (S)-2-methylene-4-oxo-4-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)butanoate;
• 2-(methylsulfonamido)ethyl (S)-2-methylene-4-oxo-4-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)butanoate;
• 2-(dimethylamino)ethyl (S)-2-methylene-4-oxo-4-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)butanoate;
• 1,1-dioxidothietan-3-yl (S)-2-methylene-4-oxo-4-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)butanoate;
• 3-methyloxetan-3-yl (S)-2-methylene-4-oxo-4-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)butanoate;
• 2-morpholinoethyl 2-(diethoxyphosphoryl)-4-oxo-4-(((S)-1-(4-(trifluoromethyl)phenyl)ethyl)amino)butanoate;
• (S)-2-methylene-4-oxo-4-((1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)amino)butanoic acid;
• 1-(methylsulfonyl)piperidin-4-yl (S)-2-methylene-4-oxo-4-((1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)amino)butanoate;
• 1-methylpiperidin-4-yl (S)-2-methylene-4-oxo-4-((1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)amino)butanoate;
• 1,1-dioxidothietan-3-yl (S)-2-methylene-4-oxo-4-((1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)amino)butanoate;
• 2-hydroxyethyl (S)-2-methylene-4-oxo-4-((1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)amino)butanoate;
• 1-acetylpiperidin-4-yl (S)-2-methylene-4-oxo-4-((1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)amino)butanoate;
• 1-acetylazetidin-3-yl (S)-2-methylene-4-oxo-4-((1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)amino)butanoate;
• 1-(methylsulfonyl)azetidin-3-yl (S)-2-methylene-4-oxo-4-((1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)amino)butanoate;
• (S)-2-methylene-4-oxo-4-((1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)amino)butanoic acid;
• 2-methylene-4-oxo-4-((1-(5-(trifluoromethyl)pyridin-2-yl)cyclobutyl)amino)butanoic acid;
• 2-methylene-4-oxo-4-((5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)amino)butanoic acid;
• (S,Z)-2-(2-oxo-2-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)ethyl)but-2-enoic acid;
• and
• (S,E)-2-(2-oxo-2-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)ethyl)but-2-enoic acid;
• (S,E)-2-(2-oxo-2-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)ethyl)pent-2-enoic acid;
• (S,E)-4-methyl-2-(2-oxo-2-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)ethyl)pent-2-enoic acid;
• (S,E)-5-methyl-2-(2-oxo-2-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)ethyl)hex-2-enoic acid;
• (S,E)-2-(2-oxo-2-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)ethyl)-5-phenylpent-2-enoic acid;
• (S,E)-2-benzylidene-4-oxo-4-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)butanoic acid;
• (S,Z)-2-benzylidene-4-oxo-4-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)butanoic acid;
• (S,E)-4-(dimethylamino)-2-(2-oxo-2-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)ethyl)but-2-enoic acid;
• (S)-3,3-dimethyl-2-methylene-4-oxo-4-((1-(4-(trifluoromethyl)phenyl)ethyl)amino)butanoic acid;
• 3-methyl-2-methylene-4-oxo-4-((2-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)butanoic acid;
• 3-methyl-2-methylene-4-oxo-4-((2-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)butanoic acid ISOMER 1;
• 3-methyl-2-methylene-4-oxo-4-((2-(4-(trifluoromethyl)phenyl)propan-2-yl)amino)butanoic acid ISOMER 2;
• 3-methyl-2-methylene-4-oxo-4-(((S)-1-(4-(trifluoromethyl)phenyl)ethyl)amino)butanoic acid ISOMER 1;
• 3-methyl-2-methylene-4-oxo-4-(((S)-1-(4-(trifluoromethyl)phenyl)ethyl)amino)butanoic acid;
• (S)-2-methylene-4-oxo-4-((1-(4-(pentafluoro-λ6-sulfaneyl)phenyl)ethyl)amino)butanoic acid ISOMER 2;
• (S)-3-(1H-tetrazol-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)but-3-enamide;
• or a pharmaceutically acceptable salt and/or solvate of any one thereof.

29:

• The method according to claim 28 wherein the inflammatory disease or disease associated with an undesirable immune response is a disease selected from the group consisting of:
• psoriasis (including chronic plaque, erythrodermic, pustular, guttate, inverse and nail variants), asthma, chronic obstructive pulmonary disease (COPD, including chronic bronchitis and emphysema), heart failure (including left ventricular failure), myocardial infarction, angina pectoris, other atherosclerosis and/or atherothrombosis-related disorders (including peripheral vascular disease and ischaemic stroke), a mitochondrial and neurodegenerative disease (such as Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, retinitis pigmentosa or mitochondrial encephalomyopathy), autoimmune paraneoplastic retinopathy, transplantation rejection (including antibody-mediated and T cell-mediated forms), multiple sclerosis, transverse myelitis, ischaemia-reperfusion injury (e.g. during elective surgery such as cardiopulmonary bypass for coronary artery bypass grafting or other cardiac surgery, following percutaneous coronary intervention, following treatment of acute ST-elevation myocardial infarction or ischaemic stroke, organ transplantation, or acute compartment syndrome), AGE-induced genome damage, an inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis), primary sclerosing cholangitis (PSC), PSC-autoimmune hepatitis overlap syndrome, non-alcoholic fatty liver disease (non-alcoholic steatohepatitis), rheumatica, granuloma annulare, cutaneous lupus erythematosus (CLE), systemic lupus erythematosus (SLE), lupus nephritis, drug-induced lupus, autoimmune myocarditis or myopericarditis, Dressler's syndrome, giant cell myocarditis, post-pericardiotomy syndrome, drug-induced hypersensitivity syndromes (including hypersensitivity myocarditis), eczema, sarcoidosis, erythema nodosum, acute disseminated encephalomyelitis (ADEM), neuromyelitis optica spectrum disorders, MOG (myelin oligodendrocyte glycoprotein) antibody-associated disorders (including MOG-EM), optic neuritis, CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids), diffuse myelinoclastic sclerosis, Addison's disease, alopecia areata, ankylosing spondylitis, other spondyloarthritides (including peripheral spondyloarthritis, that is associated with psoriasis, inflammatory bowel disease, reactive arthritis or juvenile onset forms), antiphospholipid antibody syndrome, autoimmune hemolytic anaemia, autoimmune hepatitis, autoimmune inner ear disease, pemphigoid (including bullous pemphigoid, mucous membrane pemphigoid, cicatricial pemphigoid, herpes gestationis or pemphigoid gestationis, ocular cicatricial pemphigoid), linear IgA disease, Behçet's disease, celiac disease, Chagas disease, dermatomyositis, diabetes mellitus type I, endometriosis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome and its subtypes (including acute inflammatory demyelinating polyneuropathy, AIDP, acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), pharyngeal-cervical-brachial variant, Miller-Fisher variant and Bickerstaff s brainstem encephalitis), progressive inflammatory neuropathy, Hashimoto's disease, hidradenitis suppurativa, inclusion body myositis, necrotising myopathy, Kawasaki disease, IgA nephropathy, Henoch-Schonlein purpura, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura (TTP), Evans' syndrome, interstitial cystitis, mixed connective tissue disease, undifferentiated connective tissue disease, morphea, myasthenia gravis (including MuSK antibody positive and seronegative variants), narcolepsy, neuromyotonia, pemphigus vulgaris, pernicious anaemia, psoriatic arthritis, polymyositis, primary biliary cholangitis (also known as primary biliary cirrhosis), rheumatoid arthritis, palindromic rheumatism, schizophrenia, autoimmune (meningo-)encephalitis syndromes, scleroderma, Sjogren's syndrome, stiff person syndrome, polymylagia rheumatica, giant cell arteritis (temporal arteritis), Takayasu arteritis, polyarteritis nodosa, Kawasaki disease, granulomatosis with polyangitis (GPA;
• formerly known as Wegener's granulomatosis), eosinophilic granulomatosis with polyangiitis (EGPA;
• formerly known as Churg-Strauss syndrome), microscopic polyarteritis/polyangiitis, hypocomplementaemic urticarial vasculitis, hypersensitivity vasculitis, cryoglobulinemia, thromboangiitis obliterans (Buerger's disease), vasculitis, leukocytoclastic vasculitis, vitiligo, acute disseminated encephalomyelitis, adrenoleukodystrophy, Alexander's disease, Alper's disease, balo concentric sclerosis or Marburg disease, cryptogenic organising pneumonia (formerly known as bronchiolitis obliterans organizing pneumonia), Canavan disease, central nervous system vasculitic syndrome, Charcot-Marie-Tooth disease, childhood ataxia with central nervous system hypomyelination, chronic inflammatory demyelinating polyneuropathy (CIDP), diabetic retinopathy, globoid cell leukodystrophy (Krabbe disease), graft-versus-host disease (GVHD) (including acute and chronic forms, as well as intestinal GVHD), hepatitis C (HCV) infection or complication, herpes simplex viral infection or complication, human immunodeficiency virus (HIV) infection or complication, lichen planus, monomelic amyotrophy, cystic fibrosis, pulmonary arterial hypertension (PAH, including idiopathic PAH), lung sarcoidosis, idiopathic pulmonary fibrosis, paediatric asthma, atopic dermatitis, allergic dermatitis, contact dermatitis, allergic rhinitis, rhinitis, sinusitis, conjunctivitis, allergic conjunctivitis, keratoconjunctivitis sicca, dry eye, xerophthalmia, glaucoma, macular oedema, diabetic macular oedema, central retinal vein occlusion (CRVO), macular degeneration (including dry and/or wet age related macular degeneration, AMD), post-operative cataract inflammation, uveitis (including posterior, anterior, intermediate and pan uveitis), iridocyclitis, scleritis, corneal graft and limbal cell transplant rejection, gluten sensitive enteropathy (coeliac disease), dermatitis herpetiformis, eosinophilic esophagitis, achalasia, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, aortitis and periaortitis, autoimmune retinopathy, autoimmune urticaria, (idiopathic) Castleman's disease, Cogan's syndrome, IgG4-related disease, retroperitoneal fibrosis, juvenile idiopathic arthritis including systemic juvenile idiopathic arthritis (Still's disease), adult-onset Still's disease, ligneous conjunctivitis, Mooren's ulcer, pityriasis lichenoides et varioliformis acuta (PLEVA, also known as Mucha-Habermann disease), multifocal motor neuropathy (MMN), paediatric acute-onset neuropsychiatric syndrome (PANS) (including paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)), paraneoplastic syndromes (including paraneoplastic cerebellar degeneration, Lambert-Eaton myaesthenic syndrome, limbic encephalitis, brainstem encephalitis, opsoclonus myoclonus ataxia syndrome, anti-NMDA receptor encephalitis, thymoma-associated multiorgan autoimmunity), perivenous encephalomyelitis, reflex sympathetic dystrophy, relapsing polychondritis, sperm & testicular autoimmunity, Susac's syndrome, Tolosa-Hunt syndrome, Vogt-Koyanagi-Harada Disease, anti-synthetase syndrome, autoimmune enteropathy, immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX), microscopic colitis, autoimmune lymphoproliferative syndrome (ALPS), autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APEX), gout, pseudogout, amyloid (including AA or secondary amyloidosis), eosinophilic fasciitis (Shulman syndrome) progesterone hypersensitivity (including progesterone dermatitis), amilial Mediterranean fever (FMF), tumour necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS), hyperimmunoglobulinaemia D with periodic fever syndrome (HIDS), PAPA (pyogenic arthritis, pyoderma gangrenosum, severe cystic acne) syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), deficiency of the interleukin-36-receptor antagonist (DITRA), cryopyrin-associated periodic syndromes (CAPS) (including familial cold autoinflammatory syndrome [FCAS], Muckle-Wells syndrome, neonatal onset multisystem inflammatory disease [NOMID]), NLRP12-associated autoinflammatory disorders (NLRP12AD), periodic fever aphthous stomatitis (PFAPA), chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), Majeed syndrome, Blau syndrome (also known as juvenile systemic granulomatosis), macrophage activation syndrome, chronic recurrent multifocal osteomyelitis (CRMO), familial cold autoinflammatory syndrome, mutant adenosine deaminase 2 and monogenic interferonopathies (including Aicardi-Goutières syndrome, retinal vasculopathy with cerebral leukodystrophy, spondyloenchondrodysplasia, STING [stimulator of interferon genes]-associated vasculopathy with onset in infancy, proteasome associated autoinflammatory syndromes, familial chilblain lupus, dyschromatosis symmetrica hereditaria), Schnitzler syndrome;
• familial cylindromatosis, congenital B cell lymphocytosis, OTULIN-related autoinflammatory syndrome, type 2 diabetes mellitus, insulin resistance and the metabolic syndrome (including obesity-associated inflammation), atherosclerotic disorders (e.g. myocardial infarction, angina, ischaemic heart failure, ischaemic nephropathy, ischaemic stroke, peripheral vascular disease, aortic aneurysm), renal inflammatory disorders (e.g. diabetic nephropathy, membranous nephropathy, minimal change disease, crescentic glomerulonephritis, acute kidney injury, renal transplantation).

30:

• The compound or a pharmaceutically acceptable salt and/or solvate thereof according to claim 1 for use in combination with a further therapeutic agent, such as a corticosteroid (glucocorticoid), retinoid (e.g. acitretin, isotretinoin, tazarotene), anthralin, vitamin D analogue (e.g. cacitriol, calcipotriol), calcineurin inhibitors (e.g. tacrolimus, pimecrolimus), phototherapy or photochemotherapy (e.g. psoralen ultraviolet irradiation, PUVA) or other form of ultraviolet light irradiation therapy, ciclosporine, a thiopurine (e.g. azathioprine, 6-mercaptopurine), methotrexate, an anti-TNFα agents (e.g. infliximab, etanercept, adalimumab, certolizumab, golimumab or a biosimilar), phosphodiesterase-4 (PDE4) inhibition (e.g. apremilast, crisaborole), anti-IL-17 agent (e.g. brodalumab, ixekizumab, secukinumab), anti-IL12/IL-23 agent (e.g. ustekinumab, briakinumab), anti-IL-23 agent (e.g. guselkumab, tildrakizumab), JAK (Janus Kinase) inhibitor (e.g. tofacitinib, ruxolitinib, baricitinib, filgotinib, upadacitinib), plasma exchange, intravenous immune globulin (IVIG), cyclophosphamide, anti-CD20 B cell depleting agent (e.g. rituximab, ocrelizumab, ofatumumab, obinutuzumab), anthracycline analogue (e.g. mitoxantrone), cladribine, sphingosine 1-phosphate receptor modulator or sphingosine analogue (e.g. fingolimod, siponimod, ozanimod, etrasimod), interferon beta preparation (including interferon beta 1b/1a), glatiramer, anti-CD3 therapy (e.g. OKT3), anti-CD52 targeting agent (e.g. alemtuzumab), leflunomide, teriflunomide, gold compound, laquinimod, potassium channel blocker (e.g. dalfampridine/4-aminopyridine), mycophenolic acid, mycophenolate mofetil, purine analogue (e.g. pentostatin), mTOR (mechanistic target of rapamycin) pathway inhibitor (e.g. sirolimus, everolimus), anti-thymocyte globulin (ATG), IL-2 receptor (CD25) inhibitor (e.g. basiliximab, daclizumab), anti-IL-6 receptor or anti-IL-6 agent (e.g. tocilizumab, siltuximab), Bruton's tyrosine kinase (BTK) inhibitor (e.g. ibrutinib), tyrosine kinase inhibitor (e.g. imatinib), ursodeoxycholic acid, hydroxychloroquine, chloroquine, B cell activating factor (BAFF, also known as BLyS, B lymphocyte stimulator) inhibitor (e.g. belimumab, blisibimod), other B cell targeted therapy including a fusion protein targeting both APRIL (A PRoliferation-Inducing Ligand) and BLyS (e.g. atacicept), PI3K inhibitor including pan-inhibitor or one targeting the p110δ and/or p110γ containing isoforms (e.g. idelalisib, copanlisib, duvelisib), an interferon α receptor inhibitor (e.g. anifrolumab, sifalimumab), T cell co-stimulation blocker (e.g. abatacept, belatacept), thalidomide and its derivatives (e.g. lenalidomide), dapsone, clofazimine, a leukotriene antagonist (e.g. montelukast), theophylline, anti-IgE therapy (e.g. omalizumab), an anti-IL-5 agent (e.g. mepolizumab, reslizumab), a long-acting muscarinic agent (e.g. tiotropium, aclidinium, umeclidinium), a PDE4 inhibitor (e.g. roflumilast), riluzole, a free radical scavenger (e.g. edaravone), a proteasome inhibitor (e.g. bortezomib), a complement cascade inhibitor including one directed against C5 (e.g. eculizumab), immunoadsor, antithymocyte globulin, 5-aminosalicylates and their derivatives (e.g. sulfasalazine, balsalazide, mesalamine), an anti-integrin agent including one targeting α4β1 and/or α4β7 integrins (e.g. natalizumab, vedolizumab), an anti-CD11-α agent (e.g. efalizumab), a non-steroidal anti-inflammatory drug (NSAID) including a salicylate (e.g. aspirin), a propionic acid (e.g. ibuprofen, naproxen), an acetic acid (e.g. indomethacin, diclofenac, etodolac), an oxicam (e.g. meloxicam) a fenamate (e.g. mefenamic acid), a selective or relatively selective COX-2 inhibitor (e.g. celecoxib, etroxicoxib, valdecoxib and etodolac, meloxicam, nabumetone), colchicine, an IL-4 receptor inhibitor (e.g. dupilumab), topical/contact immunotherapy (e.g. diphenylcyclopropenone, squaric acid dibutyl ester), anti-IL-1 receptor therapy (e.g. anakinra), IL-1β inhibitor (e.g. canakinumab), IL-1 neutralising therapy (e.g. rilonacept), chlorambucil, a specific antibiotic with immunomodulatory properties and/or ability to modulate NRF2 (e.g. tetracyclines including minocycline, clindamycin, macrolide antibiotics), anti-androgenic therapy (e.g. cyproterone, spironolactone, finasteride), pentoxifylline, ursodeoxycholic acid, obeticholic acid, fibrate, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, a VEGF (vascular endothelial growth factor) inhibitor (e.g. bevacizumab, ranibizumab, pegaptanib, aflibercept), pirfenidone or mizoribine.

31:

• A process for the preparation of a compound according to claim 1 or a salt and/or solvate thereof comprising:
• A. for a compound in which RZ is C(O)ORB:
• reacting a compound of formula (II):
• or a salt thereof;
• with amine RA—NH2 (V), or a salt thereof;
• wherein RB is:
• or
• B. for a compound in which RZ is C(O)ORB:
• deprotecting a compound of formula (VII):
• or a salt thereof,
• wherein P is a carboxylic acid protecting group;
• or
• C. for a compound in which RZ is C(O)ORB:
• reacting a compound of formula (VIIIa) or (VIIIb):
• or a salt thereof;
• with aqueous C(RF)(RG)═O in the presence of a base;
• or
• D. for a compound in which RZ is C(O)ORB, where RB is H and RA is CH2(substituted phenyl) or CH2(substituted pyridyl), wherein the CH2 group is optionally substituted with one RA3 and the phenyl or pyridyl group is substituted with one or more RA4:
• reacting a compound of formula (Va):
• wherein RA is CH2(substituted phenyl) or CH2(substituted phenyl), wherein the CH2 group is optionally substituted with one or two RA3 and the phenyl or pyridyl group is substituted with one or more RA4;
• with an itaconic anhydride derivative of formula (XX):
• wherein RC, RD, RF and RG are defined in claim 1;
• or
• E. for a compound in which RF and RG are both H and RZ is C(O)ORB:
• reacting a compound of formula (XXV):
• with triphenylphosphine, palladium acetate and carbon monoxide, followed by a base such as triethylamine and a carboxylic acid such as acetic acid to give a compound of formula (I) in which RB is H;
• and optionally
• reacting a compound of formula (I) in which RZ is C(O)OH with a compound of formula (VI):
• where in RB is not H;
• to give a compound of formula (I) in which RZ is C(O)ORB, where in RB is as defined in claim 1 except that it is not H;
• or
• F. for a compound in which RZ is tetrazol-5-yl:
• reacting a compound of formula (XXXI):
• or a salt thereof;
• with trimethylsilyl azide (TMSN3) in the presence of a catalyst. Suitable catalysts include dibutyl tin oxide.

A compound of formula (II):

• wherein
• RC and RD are each independently H, C1-2 alkyl, hydroxy, methoxy or fluoro;
• each of RF and RG is independently selected from H, phenyl and C1-4 alkyl optionally substituted with phenyl, ORK or N(RK)(RL), wherein each of RK and RL is independently selected from H, methyl and ethyl, provided that at least one of RF and RG is H;
• RB is:
• RB4 is H or methyl;
• E is N, O or SO2;
• wherein when E is N, RE is selected from the group consisting of R9B, C(O)R9B and SO2R9B wherein R9B is C1-4 alkyl;
• and when E is O or SO2, RE is absent;
• nE and mE are independently 1 or 2;
• or
• a compound of formula (VII):
• wherein RA is selected from the group consisting of C6-10 cycloalkyl optionally fused to phenyl, CH2(phenyl) and CH2(pyridyl);
• wherein when RA is C6-10 cycloalkyl optionally fused to phenyl, the cycloalkyl ring s optionally substituted on an available carbon atom by one or more RA2, wherein each RA2 is independently selected from the group consisting of methyl, halo and trifluoromethyl, and/or two RA2 are attached to the same carbon atom and join to form a C3-6 cycloalkyl or a 4-6 membered heterocyclic ring;
• and the fused phenyl ring is optionally substituted on an available carbon atom by one or more substituents selected from the group consisting of C1-4 haloalkyl and halo;
• wherein when RA is CH2(phenyl) or CH2(pyridyl):
• the CH2 group is optionally substituted by one or two RA3 wherein each RA3 is independently selected from the group consisting of C1-4 alkyl, C3-5 cycloalkyl, C1-4 haloalkyl and C1-2 hydroxyalkyl, or two RA3 groups are attached to the CH2 carbon atom and join to form a C3-6 cycloalkyl or a 4- or 5-membered heterocyclic ring;
• and
• the phenyl or pyridyl group is optionally substituted by one or more RA4, wherein each RA4 is independently selected from the group consisting of C1-4 haloalkyl, halo, SF5 or SC1-4 haloalkyl;
• RC and RD are each independently H, C1-2 alkyl, hydroxy, methoxy or fluoro;
• each of RF and RG is independently selected from H, phenyl and C1-4 alkyl optionally substituted with phenyl, ORK or N(RK)(RL), wherein each of RK and RL is independently selected from H, methyl and ethyl, provided that at least one of RF and RG is H;
• and
• wherein when the CH2 of the CH2(substituted phenyl) or CH2(substituted pyridyl) of RA is substituted by one RA3 the stereochemistry of the carbon to which RA3 is attached is as follows:
• wherein the dashed lines indicate attachment to the remainder of the compound of formula (I):
• and wherein when RA4 is Cl, the CH2 group is unsubstituted or is substituted by one RA3;
• and wherein P is a carboxylic acid protecting group;
• or
• a compound of formula (VIIIa) or (VIIIb):
• wherein RA is selected from the group consisting of C6-10 cycloalkyl optionally fused to phenyl, CH2(phenyl) and CH2(pyridyl):
• wherein when RA is C6-10 cycloalkyl optionally fused to phenyl, the cycloalkyl ring s optionally substituted on an available carbon atom by one or more RA2, wherein each RA2 is independently selected from the group consisting of methyl, halo and trifluoromethyl, and/or two RA2 are attached to the same carbon atom and join to form a C3-6 cycloalkyl or a 4-6 membered heterocyclic ring;
• and the fused phenyl ring is optionally substituted on an available carbon atom by one or more substituents selected from the group consisting of C1-4 haloalkyl and halo;
• wherein when RA is CH2(phenyl) or CH2(pyridyl);
• the CH2 group is optionally substituted by one or two RA3 wherein each RA3 is independently selected from the group consisting of C1-4 alkyl, C3-5 cycloalkyl, C1-4 haloalkyl and C1-2 hydroxyalkyl, or two RA3 groups are attached to the CH2 carbon atom and join to form a C3-6 cycloalkyl or a 4- or 5-membered heterocyclic ring;
• and
• the phenyl or pyridyl group is optionally substituted by one or more RA4, wherein each RA4 is independently selected from the group consisting of C1-4 haloalkyl, halo, SF5 or SC1-4 haloalkyl;
• RC and RD are each independently H, C1-2 alkyl, hydroxy, methoxy or fluoro;
• wherein when the CH2 of the CH2(substituted phenyl) or CH2(substituted pyridyl) of RA is substituted by one RA3 the stereochemistry of the carbon to which RA3 is attached is as follows:
• wherein the dashed lines indicate attachment to the remainder of the compound of formula (I);
• and wherein when RA4 is Cl, the CH2 group is unsubstituted or is substituted by one RA3;
• or
• a compound of formula (XXXI):
• wherein RA is selected from the group consisting of C6-10 cycloalkyl optionally fused to phenyl, CH2(phenyl) and CH2(pyridyl);
• wherein when RA is C6-10 cycloalkyl optionally fused to phenyl, the cycloalkyl ring s optionally substituted on an available carbon atom by one or more RA2, wherein each RA2 is independently selected from the group consisting of methyl, halo and trifluoromethyl, and/or two RA2 are attached to the same carbon atom and join to form a C3-6 cycloalkyl or a 4-6 membered heterocyclic ring;
• and the fused phenyl ring is optionally substituted on an available carbon atom by one or more substituents selected from the group consisting of C1-4 haloalkyl and halo;
• wherein when RA is CH2(phenyl) or CH2(pyridyl):
• the CH2 group is optionally substituted by one or two RA3 wherein each RA3 is independently selected from the group consisting of C1-4 alkyl, C3-5 cycloalkyl, C1-4 haloalkyl and C1-2 hydroxyalkyl, or two RA3 groups are attached to the CH2 carbon atom and join to form a C3-6 cycloalkyl or a 4- or 5-membered heterocyclic ring;
• and
• the phenyl or pyridyl group is optionally substituted by one or more RA4, wherein each RA4 is independently selected from the group consisting of C1-4 haloalkyl, halo, SF5 or SC1-4 haloalkyl;
• RC and RD are each independently H, C1-2 alkyl, hydroxy, methoxy or fluoro;
• each of RF and RG is independently selected from H, phenyl and C1-4 alkyl optionally substituted with phenyl, ORK or N(RK)(RL), wherein each of RK and RL is independently selected from H, methyl and ethyl, provided that at least one of RF and RG is H;
• and wherein when the CH2 of the CH2(substituted phenyl) or CH2(substituted pyridyl) of RA is substituted by one RA3 the stereochemistry of the carbon to which RA3 is attached is as follows:
• wherein the dashed lines indicate attachment to the remainder of the compound of formula (I);
• and wherein when RA4 is Cl, the CH2 group is unsubstituted or is substituted by one RA3;
• or
• a compound of formula (XXV):
• wherein RA is selected from the group consisting of C6-10 cycloalkyl optionally fused to phenyl, CH2(phenyl) and CH2(pyridyl);
• wherein when RA is C6-10 cycloalkyl optionally fused to phenyl, the cycloalkyl ring s optionally substituted on an available carbon atom by one or more RA2, wherein each RA2 is independently selected from the group consisting of methyl, halo and trifluoromethyl, and/or two RA2 are attached to the same carbon atom and join to form a C3-6 cycloalkyl or a 4-6 membered heterocyclic ring;
• and the fused phenyl ring is optionally substituted on an available carbon atom by one or more substituents selected from the group consisting of C1-4 haloalkyl and halo;
• wherein when RA is CH2(phenyl) or CH2(pyridyl):
• the CH2 group is optionally substituted by one or two RA3 wherein each RA3 is independently selected from the group consisting of C1-4 alkyl, C3-5 cycloalkyl, C1-4 haloalkyl and C1-2 hydroxyalkyl, or two RA3 groups are attached to the CH2 carbon atom and join to form a C3-6 cycloalkyl or a 4- or 5-membered heterocyclic ring;
• and
• the phenyl or pyridyl group is optionally substituted by one or more RA4, wherein each RA4 is independently selected from the group consisting of C1-4 haloalkyl, halo, SF5 or SC1-4 haloalkyl:
• RC and RD are each independently H, C1-2 alkyl, hydroxy, methoxy or fluoro;
• wherein when the CH2 of the CH2(substituted phenyl) or CH2(substituted pyridyl) of RA is substituted by one RA3 the stereochemistry of the carbon to which RA3 is attached is as follows:
• wherein the dashed lines indicate attachment to the remainder of the compound of formula (I);
• and wherein when RA4 is Cl, the CH2 group is unsubstituted or is substituted by one RA3;
• or
• a salt and/or solvate of any of the above.