WO2024089421A1 - Tetrazole derivatives - Google Patents

Tetrazole derivatives Download PDF

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Publication number
WO2024089421A1
WO2024089421A1 PCT/GB2023/052791 GB2023052791W WO2024089421A1 WO 2024089421 A1 WO2024089421 A1 WO 2024089421A1 GB 2023052791 W GB2023052791 W GB 2023052791W WO 2024089421 A1 WO2024089421 A1 WO 2024089421A1
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Prior art keywords
compound
solvate
pharmaceutically acceptable
disease
acceptable salt
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PCT/GB2023/052791
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French (fr)
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Thomas Michael WAUGH
Alessandro Mazzacani
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Sitryx Therapeutics Limited
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Publication of WO2024089421A1 publication Critical patent/WO2024089421A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/23—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and carboxyl groups, other than cyano groups, bound to the same unsaturated acyclic carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/52—Esters of acyclic unsaturated carboxylic acids having the esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/593—Dicarboxylic acid esters having only one carbon-to-carbon double bond
    • C07C69/60—Maleic acid esters; Fumaric acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • the present invention relates to compounds and their use in treating or preventing inflammatory diseases or diseases associated with an undesirable immune response, and to related compositions, methods and intermediate compounds.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • SLE systemic lupus erythematosus
  • psoriasis Crohn’s disease
  • ulcerative colitis uveitis
  • COPD chronic obstructive pulmonary disease
  • Non-steroidal anti-inflammatory drugs are the most widespread medicines employed for treating inflammatory disorders, but these agents do not prevent the progression of the inflammation and only treat the accompanying symptoms.
  • Glucocorticoids are powerful anti-inflammatory agents, making them emergency treatments for acute inflammatory flares, but given longer term these medicines give rise to a plethora of unwanted side-effects and may also be subject to resistance (Straub R. H. and Cutolo M., 2016). Thus, considerable unmet medical need still exists for the treatment of inflammatory disorders and extensive efforts to discover new medicines to alleviate the burden of these diseases is ongoing (Hanke T. et al., 2016).
  • DMF Dimethyl fumarate
  • CAC citric acid cycle
  • This compound’s efficacy has been attributed to a multiplicity of different phenomena involving covalent modification of proteins and the conversion of “prodrug” DMF to MMF.
  • the following pathways have been highlighted as being of relevance to DMF’s anti-inflammatory effects: 1) activation of the anti-oxidant, anti-inflammatory, nuclear factor (erythroid-derived 2)- like 2 (NRF2) pathway as a consequence of reaction of the electrophilic a, - unsaturated ester moiety with nucleophilic cysteine residues on kelch-like ECH-associated protein 1 (KEAP1) (Brennan M. S.
  • membrane permeable diester DMF tends to exhibit much more profound biological effects in cells compared to its monoester counterpart MMF.
  • MMF membrane permeable diester DMF
  • the CAC intermediate aconitate is decarboxylated by the protein product of immune-responsive gene 1 (IRG1), one of the most highly upregulated genes in macrophages under proinflammatory conditions, subsequently named aconitate decarboxylase 1, to produce itaconic acid (Michelucci A. et al., 2013).
  • IRG1 immune-responsive gene 1
  • This unsaturated diacid is an inhibitor of the bacterial enzyme isocitrate lyase and, as such, it exerts anti-bacterial activity.
  • itaconic acid is an a,p-unsaturated carboxylic acid. As such, it is a Michael acceptor which induces a global electrophilic stress response.
  • the itaconic acid diester dimethyl itaconate (DMI) like DMF, produces an anti-inflammatory response, reducing the expression levels of pro-inflammatory cytokines I L-1 p, IL-6, IL-12 and IL-18 in lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (WO2017/142855A1, incorporated herein by reference).
  • DMI ameliorates IL-17-mediated pathologies, highlighting the therapeutic potential of this regulatory pathway (W02019/036509A1 , incorporated herein by reference). Further highlighting its pharmacologic potential, DMI has recently been reported to 1) demonstrate a protective effect on cerebral ischemia/reperfusion injury, thereby offering potential for the treatment of ischemic stroke (Zhang D. et al., 2019); 2) provide protection from the cardiotoxic effects of doxorubicin (Shan Q. et al., 2019); and 3) protect against lippolysacchride-induced mastitis in mice by activating MAPKs and NRFrf2 while inhibiting NF-KB signaling pathways (Zhao C.
  • DMI ulcerative colitis and canceration thereof
  • CN110731955, Sun Yat-sen University Cancer Center Sun Yat-sen University Cancer Center
  • NRF2/HO-1 signalling pathway a signalling pathway for DMI.
  • DMI is not metabolised to itaconic acid intracellularly (ElAzzouny M. et al., 2017).
  • Other a, - unsaturated esters exhibit IL-1 [3-lowering effects in macrophages by inhibiting the NLRP3 inflammasome (Cocco M.
  • W02020/222011 , W02020/222010, WO2021/130492, WO2022/029438, WO2022/038365, W02022/090723, W02022/090714, W02022/090724, WO2022/229617, WO2022/269251 and WO2023/017269 all disclose certain itaconate derivatives.
  • WO2022/029438 discloses compounds of formula (I): wherein R B can be CHztetrazolyl, ring A can be a 5-membered heteroaryl ring, R A2 can be absent and R A1 is other than H.
  • the present invention provides a compound of formula (I): wherein:
  • K is bond or C(R 1 )(R 2 );
  • R 1 and R 2 are independently selected from the group consisting of H, Ci-4 alkyl and C1-4 haloalkyl, or R 1 and R 2 join to form a C3.5 cycloalkyl ring or a 4- to 6-membered heterocyclic ring, wherein the C3.5 cycloalkyl ring or 4- to 6-membered heterocyclic ring is optionally substituted by halo, cyano, C1.2 alkyl, C1.2 alkoxy, C1.2 haloalkyl or C1.2 haloalkoxy;
  • A is C5-7 cycloalkyl, phenyl or 5-6-membered heteroaryl wherein A is optionally substituted by one or more R 3 wherein R 3 is selected from the group consisting of halo, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1.4 haloalkoxy, hydroxy, cyano, SFs, SC1.4 alkyl, SC1.4 haloalkyl, (CH2)o-3Cs-7 cycloalkyl, 5-7-membered heterocyclyl, O-phenyl and O-heteroaryl wherein said C3-7 cycloalkyl, said 5-7-membered heterocyclyl, said O-phenyl and said O-heteroaryl are optionally substituted by one or more groups selected from halo, C1.4 alkyl, C1.4 haloalkyl, O(Ci-4 alkyl) and C1.4 hydroxyalkyl; wherein two alkyl groups which are attached to the same carbon
  • R c and R D are each independently H, C1-2 alkyl, hydroxy, fluoro or Ci_ 2 alkoxy; or R c and R D may join to form a C3-5 cycloalkyl ring; or a pharmaceutically acceptable salt and/or solvate thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for use as a medicament.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for use in treating or preventing an inflammatory disease or a disease associated with an undesirable immune response.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof in the manufacture of a medicament for treating or preventing an inflammatory disease or a disease associated with an immune response.
  • the present invention provides a method of treating or preventing an inflammatory disease or a disease associated with an undesirable immune response, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof.
  • Embodiments and preferences set out herein with respect to the compound of formula (I) apply equally to the pharmaceutical composition, compound or pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use and method aspects of the invention, as well as intermediates used in the synthesis of the compounds of formula (I).
  • Embodiments and preferences for one variable in the compound of formula (I) may be combined with embodiments and preferences for other variables in the compound of formula (I)
  • alkyl such as “C1.4 alkyl or “C1.2 alkyl” refers to a straight or branched fully saturated hydrocarbon group having the specified number of carbon atoms.
  • the term encompasses methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
  • alkyl also encompasses “alkylene” which is a bifunctional straight or branched fully saturated hydrocarbon group having a specified number of carbon atoms.
  • Example “alkylene” groups include methylene, ethylene, n-propylene and n-butylene.
  • alkoxy refers to an alkyl group, such as “C1.4 alkyl” as defined above, singularly bonded via an oxygen atom.
  • alkoxy groups include OCH 3 .
  • haloalkyl such as “C1.3 haloalkyl” or “C1.2 haloalkyl” as used herein refers to a straight or a branched fully saturated hydrocarbon chain containing the specified number of carbon atoms and at least one halogen atom, such as fluoro or chloro, especially fluoro.
  • An example of haloalkyl is CF 3 .
  • Further examples of haloalkyl are CHF 2 and CH2CF3.
  • haloalkoxy refers to a haloalkyl group, such as “C1.3 haloalkyl” or “C1.2 haloalkyl”, as defined above, singularly bonded via an oxygen atom.
  • haloalkoxy groups include OCF3, OCHF2 and OCH2CF3.
  • hydroxy refers to an -OH group.
  • hydroxyalkyl such as “C1.4 hydroxyalkyl”, refers to an alkyl or alkylene chain having one to four carbon atoms, wherein one of the carbon atoms is substituted by an -OH group. Examples include -CH 2 C(H)OH, -C(H)OHCH 3 and -C(H)OH.
  • halo refers to fluoro, chloro, bromo or iodo. Particular examples of halo are fluoro and chloro, especially fluoro.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon group having the specified number of carbon atoms.
  • the term encompasses cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl as well as bridged systems such as bicyclo[1 .1 .1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl and adamantyl.
  • Particularly preferred groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • heterocyclic ring or “heterocyclyl”, such as “4- to 6-membered heterocyclic ring” or “5- 7-membered heterocyclyl” refers to a non-aromatic cyclic group having the specified number of ring atoms and wherein at least one of the ring atoms is a heteroatom selected from N, O, S and B.
  • heterocyclic ring is interchangeable with “heterocyclyl”.
  • the term encompasses oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.
  • Heterocyclic groups can typically be substituted by one or more (e.g. one or two) oxo groups.
  • thietanyl is substituted by one or two oxo groups.
  • heteroaryl such as “5- or 6-membered heteroaryl” refers to a cyclic group with aromatic character containing the indicated number of atoms (e.g. 5 or 6) wherein at least one of the atoms in the cyclic group is a heteroatom independently selected from N, O and S.
  • the term encompasses pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyradizinyl and pyrazinyl.
  • R c is as defined herein.
  • X is H.
  • X is CH 3 .
  • the 5-membered heteroaryl ring selected from the group consisting of imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1 ,2,4-triazole, 1,2,4-oxadiazole, 1 ,2,5-oxadiazole, 1 ,3,4-oxadiazole, 1 ,2,4-thiadiazole, 1 ,2,5-thiadiazole, 1 ,3,4-thiadiazole and tetrazole.
  • L represents pyrazole
  • substituent K can be bound to a carbon or nitrogen atom of the pyrazole moiety.
  • L represents 1 ,2,4-oxadiazole, it is intended to represent and/or , in formula (I).
  • L represents an oxadiazole, in particular 1 ,2,4-oxadiazole.
  • L represents 1 ,2,4-oxadiazole.
  • K is bond.
  • K is C(R 1 )(R 2 ) wherein R 1 and R 2 are defined below.
  • K is C(R 1 )(R 2 ).
  • K is C(R 1 )(R 2 ).
  • L is 5-membered heteroaryl
  • K is bond.
  • R 1 is H.
  • R 1 is C1-4 alkyl such as methyl.
  • R 1 is C1-4 haloalkyl such as CF3.
  • R 2 is H. In other suitable compounds of formula (I), R 2 is C1-4 alkyl such as methyl. In other suitable compounds of formula (I), R 2 is C1-4 haloalkyl such as CF3.
  • R 1 is methyl and R 2 is H.
  • R 1 and R 2 are different, suitably R 1 and R 2 have the following stereochemical configuration:
  • R 1 and R 2 join to form a C3-5 cycloalkyl ring such as a C4 cycloalkyl ring:
  • R 1 and R 2 join to form a 4- to 6-membered heterocyclic ring such as a 4-membered heterocyclic ring e.g. oxetanyl:
  • the C3-5 cycloalkyl ring is unsubstituted. In other suitable compounds of formula (I), the C3-5 cycloalkyl ring is substituted by halo, cyano, C1.2 alkyl, C1.2 alkoxy, C1.2 haloalkyl or C1.2 haloalkoxy. In some suitable compounds of formula (I), the 4- to 6-membered heterocyclic ring is unsubstituted. In other suitable compounds of formula (I), the 4- to 6-membered heterocyclic ring is substituted by halo, cyano, C1.2 alkyl, C1.2 alkoxy, C1.2 haloalkyl or C1-2 haloalkoxy.
  • the substituent is halo. In other suitable compounds of formula (I), the substituent is cyano. In other suitable compounds of formula (I), the substituent is C1-2 alkyl such as methyl. In other suitable compounds of formula (I), the substituent is C1.2 alkoxy such as OCH3. In other suitable compounds of formula (I), the substituent is C1.2 haloalkyl such as CF 3 . In other suitable compounds of formula (I), the substituent is C1.2 haloalkoxy such as OCF3.
  • A is C5-7 cycloalkyl. In other suitable compounds of formula (I), A is phenyl. In other suitable compounds of formula (I), A is 5-6-membered heteroaryl.
  • A is phenyl or 6-membered heteroaryl.
  • A is phenyl or pyridyl.
  • A is unsubstituted. In other suitable compounds of formula (I), A is substituted by one or more (such as one, two or three, e.g. one) R 3 wherein R 3 is defined herein.
  • R 3 is halo. In other suitable compounds of formula (I), R 3 is C1-4 alkyl. In other suitable compounds of formula (I), R 3 is C1-4 alkoxy such as butoxy. In other suitable compounds of formula (I), R 3 is C1-4 haloalkyl such as CF 3 . In other suitable compounds of formula (I), R 3 is C1.4 haloalkoxy. In other suitable compounds of formula (I), R 3 is hydroxy. In other suitable compounds of formula (I), R 3 is cyano. In other suitable compounds of formula (I), R 3 is SF 5 . In other suitable compounds of formula (I), R 3 is SC1.4 alkyl. In other suitable compounds of formula (I), R 3 is SC1.4 haloalkyl.
  • R 3 is (CH 2 )O-3C 3 -7 cycloalkyl. In other suitable compounds of formula (I), R 3 is 5-7-membered heterocyclyl. In other suitable compounds of formula (I), R 3 is O-phenyl. In other suitable compounds of formula (I), R 3 is O-heteroaryl such as 0-5- or 6-membered heteroaryl.
  • R 3 is CF3.
  • said C3.7 cycloalkyl, said 5-7-membered heterocyclyl, said O-phenyl and said O-heteroaryl of R 3 are not substituted.
  • said C3.7 cycloalkyl, said 5-7-membered heterocyclyl, said O-phenyl and said O- heteroaryl of R 3 are substituted by one or more groups selected from halo, C1.4 alkyl, C1.4 haloalkyl , O(Ci-4 alkyl) and C1.4 hydroxyalkyl.
  • two alkyl groups of R 3 which are attached to the same carbon atom are optionally joined to form a C3-7 cycloalkyl ring.
  • R c is H, C1-2 alkyl, hydroxy, fluoro or Ci-2 alkoxy such as H.
  • R D is H, C1-2 alkyl, hydroxy, fluoro or C1-2 alkoxy such as H.
  • R c and R D join to form a C3-5 cycloalkyl ring.
  • R c is H and R D are H.
  • K is bond and A is optionally substituted phenyl or optionally substituted 5-6-membered heteroaryl;
  • K is C(R 1 )(R 2 ) wherein R 1 and R 2 are defined elsewhere herein, and A is C5-7 cycloalkyl;
  • K is C(R 1 )(R 2 ) wherein R 1 and R 2 are defined elsewhere herein, and A is C5-7 cycloalkyl or 5-6-membered heteroaryl wherein the 6-membered heteroaryl is other than pyridyl;
  • K is CH 2 and A is C5-7 cycloalkyl
  • K is CH 2 and A is C5-7 cycloalkyl or 5-6-membered heteroaryl wherein the 6-membered heteroaryl is other than pyridyl; and/or
  • R 3 is C 2 -4 alkyl, C1-4 alkoxy, C 2 -4 haloalkyl, C1.4 haloalkoxy, hydroxy, cyano, SF 5 , SC1.4 alkyl, SC1.4 haloalkyl, (CH 2 )o-3C3-7 cycloalkyl, 5-7-membered heterocyclyl, O-phenyl and O-heteroaryl wherein said C3-7 cycloalkyl, said 5-7-membered heterocyclyl, said O-phenyl and said O-heteroaryl are optionally substituted by one or more groups selected from halo, C1.4 alkyl, C1.4 haloalkyl, O(Ci-4 alkyl) and C1.4 hydroxyalkyl.
  • the compound of formula (I) is other than a compound of formula (IA): wherein:
  • R A is selected from the group consisting of Ce-7 cycloalkyl, CH 2 (phenyl) and CH 2 (pyridyl); wherein when R A is Cs-7 cycloalkyl, the cycloalkyl ring is optionally substituted on an available carbon atom by one or more R A2 , wherein each R A2 is independently selected from the group consisting of methyl, halo and trifluoromethyl, and/or two R A2 are attached to the same carbon atom and join to form a C3-6 cycloalkyl; wherein when R A is CH 2 (phenyl) or CH 2 (pyridyl): the CH 2 group is optionally substituted by one or two R A3 wherein each R A3 is independently selected from the group consisting of C1.4 alkyl or C1.4 haloalkyl, or two R A3 groups are attached to the CH 2 carbon atom and join to form a C3-5 cycloalkyl or a 4- or 5- membered heterocyclic ring; and
  • R c and R D are each independently H, C1.2 alkyl, hydroxy, methoxy or fluoro; wherein when the CH 2 of the ( ⁇ (substituted phenyl) or ( ⁇ (substituted pyridyl) of R A is substituted by one R A3 the stereochemistry of the carbon to which R A3 is attached is as follows: wherein the dashed lines indicate attachment to the remainder of the compound of formula (I); and wherein when R A4 is Cl, the CH 2 group is unsubstituted or is substituted by one R A3 ; or a pharmaceutically acceptable salt and/or solvate thereof.
  • the compound of formula (I) is other than Example 1.
  • Compounds of formula (II) can be made by reacting acids of formula (IV) with amines of formula (III) under standard coupling conditions such as DCC and DMAP in DCM.
  • Step 1 Nitriles of formula (X) may be converted to compounds of formula (IX) using aqueous hydroxylamine.
  • Step 2 Compounds of formula (IX) may be converted to phosphonates of formula (VIII) wherein R z is Ci-4 alkyl such as Et and L is a 1,2,4-oxadiazole ring by reaction with corresponding carboxylic acid (XIII) under standard coupling conditions such as T3P and TEA in EtOAc.
  • Step 3 Phosphonates of formula (VIII) may be converted to compounds of formula (Vila) using paraformaldehyde under basic conditions such as TEA in THF.
  • Step 4 Protecting group PG (such as C1.4 alkyl e.g. tBu or Me) in compounds of formula (Vila) may be removed using conditions known to the skilled person, to give compounds of formula (Via); if PG is tBu then conditions such as TFA in DCM may be used.
  • Step 5 Carboxylic acids (Via) may be converted to amides (Va) by activation of the acid by an activating agent e.g. oxalyl chloride, followed by addition of a source of NH 3 e.g. ammonium hydroxide.
  • an activating agent e.g. oxalyl chloride
  • Step 6 Amides (Va) may be converted to nitriles (Ila) using known methods, for example TFAA in pyridine.
  • Step 1 Alcohols of formula (XI) may be coupled to carboxylic acids (XII) using standard coupling conditions such as DCC and DMAP in DCM to give esters of formula (Vllb).
  • Step 2 Compounds of formula (Vllb) may be converted to compounds of formula (Vlb) by removal of protecting group PG (such as C1.4 alkyl e.g. tBu or Me) using conditions known to the skilled person such as LiOH in THF.
  • protecting group PG such as C1.4 alkyl e.g. tBu or Me
  • Step 3 Carboxylic acids (Vlb) may be converted to amides (Vb) by activation of the acid by an activating agent e.g. oxalyl chloride, followed by addition of a source of NH 3 e.g. aqueous NH 3 .
  • an activating agent e.g. oxalyl chloride
  • Step 4 Amides (Vb) may be converted to nitriles (lib) using known methods, for example TFAA in pyridine.
  • Nitriles of formula (II) may be converted to the compounds of formula (I) by reacting the nitrile portion of (II) with an azide source (such as TMSN 3 or NaN 3 ) to produce tetrazoles of formula (I).
  • an azide source such as TMSN 3 or NaN 3
  • a compound of formula (II) wherein are as defined for the compound of formula (I); or a salt and/or solvate thereof.
  • a compound of formula (V) wherein are as defined for the compound of formula (I); or a salt and/or solvate thereof.
  • a compound of formula (VI) wherein are as defined for the compound of formula (I); or a salt and/or solvate thereof.
  • PG is a protecting group such as C1.4 alkyl e.g. tBu or Me; or a salt and/or solvate thereof.
  • salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art.
  • Pharmaceutically acceptable salts include acid addition salts, suitably salts of compounds of the invention comprising a basic group such as an amino group, formed with inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid.
  • salts formed with organic acids e.g., succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid and 1 ,5-naphthalenedisulfonic acid.
  • organic acids e.g., succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid and 1 ,5-naphthalenedisulfonic acid.
  • Other salts e.g., oxalates or formates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention, as are basic addition salts such as sodium, potassium, calcium, aluminium, zinc, magnesium
  • Pharmaceutically acceptable salts may also be formed with organic bases such as basic amines, e.g., with ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine or lysine.
  • organic bases such as basic amines, e.g., with ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine or lysine.
  • a compound of formula (I) in the form of a pharmaceutically acceptable salt.
  • a compound of formula (I) in the form of a free acid.
  • the compound contains a basic group as well as the free acid it may be Zwitterionic.
  • the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is the compound of formula (I).
  • the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is a salt of the compound of formula (I).
  • the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is a pharmaceutically acceptable salt of the compound of formula (I).
  • the pharmaceutically acceptable salt is a basic addition salt such as a carboxylate salt formed with a group 1 metal (e.g., a sodium or potassium salt), a group 2 metal (e.g., a magnesium or calcium salt) or an ammonium salt of a basic amine (e.g., an NH 4 + salt), such as a sodium salt.
  • a group 1 metal e.g., a sodium or potassium salt
  • a group 2 metal e.g., a magnesium or calcium salt
  • an ammonium salt of a basic amine e.g., an NH 4 + salt
  • the compounds of formula (I) may be prepared in crystalline or non-crystalline form and, if crystalline, may optionally be solvated, e.g., as the hydrate.
  • This invention includes within its scope stoichiometric solvates (e.g., hydrates) as well as compounds containing variable amounts of solvent (e.g., water).
  • solvent e.g., water
  • the compound of formula (I) is not a solvate.
  • the invention extends to a pharmaceutically acceptable derivative thereof, such as a pharmaceutically acceptable prodrug of compounds of formula (I).
  • Typical prodrugs of compounds of formula (I) which comprise a carboxylic acid include ester (e.g. CI-B alkyl e.g. Ci- 4 alkyl ester) derivatives thereof.
  • ester e.g. CI-B alkyl e.g. Ci- 4 alkyl ester
  • the compound of formula (I) is provided as a pharmaceutically acceptable prodrug.
  • the compound of formula (I) is not provided as a pharmaceutically acceptable prodrug.
  • the present invention encompasses all isomers of compounds of formula (I) including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures).
  • the invention extends to all tautomeric forms of the compounds of formula (I).
  • the present invention includes within its scope all possible diastereoisomers, including mixtures thereof.
  • the different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
  • the present invention also includes all isotopic forms of the compounds provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exists as a mixture of mass numbers.
  • unnatural variant isotopic form also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form").
  • the term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring.
  • Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.
  • An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium ( 2 H or D), carbon-11 ( 11 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-15 ( 15 N), oxygen-15 ( 15 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), phosphorus-32 ( 32 P), sulphur-35 ( 35 S), chlorine-36 ( 36 CI), chlorine-37 ( 37 CI), fluorine-18 ( 18 F) iodine-123 ( 123 l), iodine-125 ( 125 l) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.
  • isotopes such as deuterium ( 2 H or D), carbon-11 ( 11 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-15 ( 15 N), oxygen-15 ( 15 O), oxygen-17 ( 17 O
  • Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon- 14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Unnatural variant isotopic forms which incorporate deuterium i.e. 2 H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, and would be useful in positron emission topography (PET) studies for examining substrate receptor occupancy.
  • PET positron emission topography
  • the compounds of formula (I) are provided in a natural isotopic form.
  • the compounds of formula (I) are provided in an unnatural variant isotopic form.
  • the unnatural variant isotopic form is a form in which deuterium (i.e. 2 H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of formula (I).
  • the atoms of the compounds of formula (I) are in an isotopic form which is not radioactive.
  • one or more atoms of the compounds of formula (I) are in an isotopic form which is radioactive.
  • radioactive isotopes are stable isotopes.
  • the unnatural variant isotopic form is a pharmaceutically acceptable form.
  • a compound of formula (I) is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of formula (I) is provided whereby two or more atoms exist in an unnatural variant isotopic form.
  • Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms.
  • unnatural isotopic variant forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the Examples.
  • the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the purer forms used in the pharmaceutical compositions.
  • Compounds of formula (I) are of use in therapy, particularly for treating or preventing an inflammatory disease or a disease associated with an undesirable immune response.
  • example compounds of formula (I) reduced cytokine release more effectively than 4-octyl itaconate, 2-(2-chlorobenzyl)acrylic acid and monomethyl fumarate in IL- 1P and/or IL-6, as demonstrated by lower IC50 values.
  • Example 3 exhibited improved cytokinelowering potencies compared to Reference Example 1 in IL-113.
  • Example 4 exhibited improved cytokine-lowering potencies compared to Reference Example 2 in IL-6.
  • Cytokines are important mediators of inflammation and immune-mediated disease as evidenced by the therapeutic benefit delivered by antibodies targeting them.
  • certain example compounds of formula (I) showed improved activity in this assay compared to 2-(2- chlorobenzyl)acrylic acid, as demonstrated by their lower EC50 and/or higher E m ax values for NRF2 activation.
  • the compounds may be expected to have utility in the treatment of diseases wherein such activity may be beneficial (such as multiple sclerosis, psoriasis and chronic obstructive pulmonary disease: Cuadrado et al., Nat. Rev. Drug Discov. 2019, 18, 295-317).
  • certain example compounds of formula (I) showed improved metabolic stabilities compared to 4-octyl itaconate in both human and mouse species. Certain compounds showed improved metabolic stabilities compared to Reference Example compounds.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein, for use as a medicament.
  • composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein.
  • present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein, for use as a medicament.
  • the present invention provides a compound of formula (I) ora pharmaceutically acceptable salt and/or solvate thereof as defined herein, for use in treating or preventing an inflammatory disease or a disease associated with an undesirable immune response.
  • the present invention provides a pharmaceutical composition as defined herein, for use in treating or preventing an inflammatory disease or a disease associated with an undesirable immune response.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein, in the manufacture of a medicament for treating or preventing an inflammatory disease or a disease associated with an undesirable immune response.
  • the present invention provides the use of a pharmaceutical composition as defined herein, in the manufacture of a medicament for treating or preventing an inflammatory disease or a disease associated with an undesirable immune response.
  • the present invention provides a method of treating or preventing an inflammatory disease or a disease associated with an undesirable immune response, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein.
  • the present invention provides a method of treating or preventing an inflammatory disease or a disease associated with an undesirable immune response, which comprises administering a pharmaceutical composition as defined herein.
  • the compound is administered to a subject in need thereof, wherein the subject is suitably a human subject.
  • a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein for use in treating an inflammatory disease or disease associated with an undesirable immune response.
  • the use of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein in the manufacture of a medicament for treating an inflammatory disease or a disease associated with an undesirable immune response.
  • a method of treating an inflammatory disease or a disease associated with an undesirable immune response which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein.
  • a pharmaceutical composition as defined herein for use in treating an inflammatory disease or disease associated with an undesirable immune response.
  • a method of treating an inflammatory disease or a disease associated with an undesirable immune response which comprises administering a pharmaceutical composition as defined herein.
  • a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein for use in preventing an inflammatory disease or a disease associated with an undesirable immune response.
  • a method of preventing an inflammatory disease or a disease associated with an undesirable immune response which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein.
  • a pharmaceutical composition as defined herein for use in preventing an inflammatory disease or a disease associated with an undesirable immune response.
  • the use of a pharmaceutical composition as defined herein in the manufacture of a medicament for preventing an inflammatory disease or a disease associated with an undesirable immune response.
  • a method of preventing an inflammatory disease or a disease associated with an undesirable immune response which comprises administering a pharmaceutical composition as defined herein.
  • a method of treating or preventing an inflammatory disease which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein, or a pharmaceutical composition as defined herein for use in treating or preventing a disease associated with an undesirable immune response.
  • a method of treating or preventing a disease associated with an undesirable immune response comprises administering a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
  • An undesirable immune response will typically be an immune response which gives rise to a pathology i.e. is a pathological immune response or reaction.
  • the inflammatory disease or disease associated with an undesirable immune response is an auto-immune disease.
  • the inflammatory disease or disease associated with an undesirable immune response is, or is associated with, 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
  • PSC primary sclerosing cholangitis
  • PSC-autoimmune hepatitis overlap syndrome nonalcoholic 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, Dressier’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
  • myocardial infarction e.g. diabetic nephropathy, membranous nephropathy, minimal change disease, crescentic glomerulonephritis, acute kidney injury, renal transplantation.
  • renal inflammatory disorders e.g. diabetic nephropathy, membranous nephropathy, minimal change disease, crescentic glomerulonephritis, acute kidney injury, renal transplantation.
  • the inflammatory disease or disease associated with an undesirable immune response is, or is associated with, a disease selected from the following autoinflammatory diseases: familial 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, and 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, and 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
  • the inflammatory disease or disease associated with an undesirable immune response is, or is associated with, a disease selected from the following diseases mediated by excess NF-KB or gain of function in the NF-KB signalling pathway or in which there is a major contribution to the abnormal pathogenesis therefrom (including non-canonical NF-KB signalling): 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), asthma, COPD, type 1 diabetes mellitus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), and SLE.
  • renal inflammatory disorders e.g. diabetic nephropathy, membranous nephropathy, minimal change disease, crescentic glomerulonephritis, acute kidney injury, renal transplantation
  • asthma COPD
  • type 1 diabetes mellitus rheumatoid arthritis
  • multiple sclerosis multiple sclerosis
  • inflammatory bowel disease including ulcerative colitis and Crohn’s disease
  • the disease is selected from the group consisting of spondyloarthrpathies, polymyalgia rheumatica and erosive osteoarthritis of the hands.
  • the disease is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, psoriasis, Crohn’s disease, ulcerative colitis, uveitis, cryopyrin-associated periodic syndromes, Muckle-Wells syndrome, juvenile idiopathic arthritis, chronic obstructive pulmonary disease and asthma.
  • the literature provides support for targeting IL-1beta, IL-6 and/or NRF2 and treating at least rheumatoid arthritis (Giacomelli et al. 2016); psoriatic arthritis (Al-Hwas et al., 2022); systemic lupus erythematosus (Sung et al. 2020); multiple sclerosis (Mendiola et al. 2018); psoriasis (Tsuji et al. 2020); Crohn’s disease (Piotrowska et al. 2021); ulcerative colitis (Liso et al. 2022); juvenile idiopathic arthritis (Toplak et al.
  • celiac disease Naasserinejad et al., 2019
  • dermatomyositis Authier et al. 1997
  • hidradenitis suppurativa Witte-Handel et al. 2019
  • Sjogren's syndrome Bardsen et al. 2019
  • giant cell arteritis temporary arteritis
  • systemic juvenile idiopathic arthritis Still’s disease
  • Toplak et al. 2018 familial Mediterranean fever (F F) (Migita et al. 2015); tumour necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS) (Dandekar et al.
  • hyperimmunoglobulinaemia D with periodic fever syndrome HI DS
  • cryopyrin-associated periodic syndromes CAS
  • Aicardi-Goutieres syndrome Takanohashi et al. 2013
  • spondyloenchondrodysplasia Lidahl et al. 2022.
  • the disease is selected from the group consisting of rheumatoid arthritis; psoriatic arthritis; systemic lupus erythematosus; multiple sclerosis; psoriasis; Crohn’s disease; ulcerative colitis; juvenile idiopathic arthritis; uveitis; spondyloarthropathies; ankylosing spondylitis; temporal arteritis; polymyalgia rheumatica; erosive osteoarthritis of the hands; Lupus nephritis; Parkinson's disease; inflammatory bowel disease; celiac disease; dermatomyositis; hidradenitis suppurativa; Sjogren's syndrome; giant cell arteritis (temporal arteritis); systemic juvenile idiopathic arthritis (Still’s disease); familial Mediterranean fever (FMF); tumour necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS); hyperimmun
  • the disease is multiple sclerosis. In one embodiment, the disease is psoriasis. In one embodiment, the disease is asthma. In one embodiment, the disease is chronic obstructive pulmonary disease. In one embodiment, the disease is systemic lupus erythematosus. In one embodiment, the disease is rheumatoid arthritis. In one embodiment, the disease is psoriatic arthritis. In one embodiment, the disease is Parkinson’s disease. In one embodiment, the disease is Crohn’s disease. In one embodiment, the disease is ulcerative colitis. In one embodiment, the disease is juvenile idiopathic arthritis. In one embodiment, the disease is uveitis. In one embodiment, the disease is spondyloarthropathies.
  • the disease is ankylosing spondylitis. In one embodiment, the disease is temporal arteritis. In one embodiment, the disease is polymyalgia rheumatica. In one embodiment, the disease is erosive osteoarthritis of the hands. In one embodiment, the disease is Lupus nephritis. In one embodiment, the disease is inflammatory bowel disease. In one embodiment, the disease is celiac disease. In one embodiment, the disease is dermatomyositis. In one embodiment, the disease is hidradenitis suppurativa. Administration
  • the compound of formula (I) is usually administered as a pharmaceutical composition.
  • a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable diluents or carriers.
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein.
  • the compound of formula (I) may be administered by any convenient method, e.g. by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical compositions adapted accordingly.
  • the compound of formula (I) may be administered topically to the target organ e.g. topically to the eye, lung, nose or skin.
  • a pharmaceutical composition comprising a compound of formula (I) optionally in combination with one or more topically acceptable diluents or carriers.
  • a compound of formula (I) which is active when given orally can be formulated as a liquid or solid, e.g. as a syrup, suspension, emulsion, tablet, capsule or lozenge.
  • a liquid formulation will generally consist of a suspension or solution of the compound of formula (I) in a suitable liquid carrier(s).
  • a suitable liquid carrier e.g. polyethylene glycol or an oil.
  • the formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures, e.g. pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatine capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), e.g. aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatine capsule.
  • suitable pharmaceutical carrier(s) e.g. aqueous gums, celluloses, silicates or oils
  • Typical parenteral compositions consist of a solution or suspension of the compound of formula (I) in a sterile aqueous carrier or parenterally acceptable oil, e.g. polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous carrier or parenterally acceptable oil e.g. polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the compound of formula (I) in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container which can take the form of a cartridge or refill for use with an atomising device.
  • the sealed container may be a disposable dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve.
  • the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas e.g. air, or an organic propellant such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). Aerosol dosage forms can also take the form of pump-atomisers.
  • a propellant can be a compressed gas e.g. air, or an organic propellant such as a chlorofluorocarbon (
  • Aerosol formulations typically comprise the active ingredient suspended or dissolved in a suitable aerosol propellant, such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC).
  • a suitable aerosol propellant such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC).
  • Topical administration to the lung may also be achieved by use of a non-pressurised formulation such as an aqueous solution or suspension.
  • a non-pressurised formulation such as an aqueous solution or suspension.
  • a nebuliser e.g. one that can be hand-held and portable or for home or hospital use (i.e. non-portable).
  • the formulation may comprise excipients such as water, buffers, tonicity adjusting agents, pH adjusting agents, surfactants and co-solvents.
  • Topical administration to the lung may also be achieved by use of a dry-powder formulation.
  • the formulation will typically contain a topically acceptable diluent such as lactose, glucose or mannitol (preferably lactose).
  • the compound of the invention may also be administered rectally, for example in the form of suppositories or enemas, which include aqueous or oily solutions as well as suspensions and emulsions and foams.
  • suppositories can be prepared by mixing the active ingredient with a conventional suppository base such as cocoa butter or other glycerides.
  • the drug is mixed with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • the total amount of the compound of the present invention will be about 0.0001 to less than 4.0% (w/w).
  • compositions administered according to the present invention will be formulated as solutions, suspensions, emulsions and other dosage forms.
  • compositions administered according to the present invention may also include various other ingredients, including, but not limited to, tonicity agents, buffers, surfactants, stabilizing polymer, preservatives, co-solvents and viscosity building agents.
  • Suitable pharmaceutical compositions of the present invention include a compound of the invention formulated with a tonicity agent and a buffer.
  • the pharmaceutical compositions of the present invention may further optionally include a surfactant and/or a palliative agent and/or a stabilizing polymer.
  • tonicity agents may be employed to adjust the tonicity of the composition, preferably to that of natural tears for ophthalmic compositions.
  • sodium chloride, potassium chloride, magnesium chloride, calcium chloride, simple sugars such as dextrose, fructose, galactose, and/or simply polyols such as the sugar alcohols mannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, and hydrogenated starch hydrolysates may be added to the composition to approximate physiological tonicity.
  • Such an amount of tonicity agent will vary, depending on the particular agent to be added.
  • compositions will have a tonicity agent in an amount sufficient to cause the final composition to have an ophthalmically acceptable osmolality (generally about 150-450 mOsm, preferably 250-350 mOsm and most preferably at approximately 290 mOsm).
  • ophthalmically acceptable osmolality generally about 150-450 mOsm, preferably 250-350 mOsm and most preferably at approximately 290 mOsm.
  • the tonicity agents of the invention will be present in the range of 2 to 4% w/w.
  • Preferred tonicity agents of the invention include the simple sugars or the sugar alcohols, such as D-mannitol.
  • An appropriate buffer system e.g. sodium phosphate, sodium acetate, sodium citrate, sodium borate or boric acid
  • the particular concentration will vary, depending on the agent employed.
  • the buffer will be chosen to maintain a target pH within the range of pH 5 to 8, and more preferably to a target pH of pH 5 to 7.
  • Surfactants may optionally be employed to deliver higher concentrations of compound of the present invention.
  • the surfactants function to solubilise the compound and stabilise colloid dispersion, such as micellar solution, microemulsion, emulsion and suspension.
  • examples of surfactants which may optionally be used include polysorbate, poloxamer, polyosyl 40 stearate, polyoxyl castor oil, tyloxapol, Triton, and sorbitan monolaurate.
  • Preferred surfactants to be employed in the invention have a hydrophile/lipophile/balance "HLB" in the range of 12.4 to 13.2 and are acceptable for ophthalmic use, such as TritonX114 and tyloxapol.
  • Additional agents that may be added to the ophthalmic compositions of compounds of the present invention are demulcents which function as a stabilising polymer.
  • the stabilizing polymer should be an ionic/charged example with precedence for topical ocular use, more specifically, a polymer that carries negative charge on its surface that can exhibit a zeta-potential of (-)10-50 mV for physical stability and capable of making a dispersion in water (i.e. water soluble).
  • a preferred stabilising polymer of the invention would be polyelectrolyte, or polyelectrolytes if more than one, from the family of cross-linked polyacrylates, such as carbomers and Pemulen(R), specifically Carbomer 974p (polyacrylic acid), at 0.1 -0.5% w/w.
  • viscosity enhancing agents include, but are not limited to: polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextrans, various polymers of the cellulose family; vinyl polymers; and acrylic acid polymers.
  • Topical ophthalmic products are typically packaged in multidose form. Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben, phenylethyl alcohol, edentate disodium, sorbic acid, polyquaternium-1 , or other agents known to those skilled in the art. Such preservatives are typically employed at a level of from 0.001 to 1.0% w/v. Unit dose compositions of the present invention will be sterile, but typically unpreserved. Such compositions, therefore, generally will not contain preservatives.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles where the compound of formula (I) is formulated with a carrier such as sugar and acacia, tragacanth, or gelatine and glycerine.
  • a carrier such as sugar and acacia, tragacanth, or gelatine and glycerine.
  • compositions suitable for transdermal administration include ointments, gels and patches.
  • the composition may contain from 0.1% to 100% by weight, for example from 10 to 60% by weight, of the compound of formula (I), depending on the method of administration.
  • the composition may contain from 0% to 99% by weight, for example 40% to 90% by weight, of the carrier, depending on the method of administration.
  • the composition may contain from 0.05mg to 1000mg, for example from 1.0 mg to 500 mg, such as from 1.0 mg to 50 mg, e.g. about 10 mg of the compound of formula (I), depending on the method of administration.
  • the composition may contain from 50 mg to 1000 mg, for example from 100mg to 400mg of the carrier, depending on the method of administration.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 500mg, such as from 1.0 mg to 50 mg, e.g. about 10 mg and such unit doses may be administered more than once a day, for example two or three times a day. Such therapy may extend for a number of weeks or months.
  • the compound of formula (I) is used in combination with a further therapeutic agent or agents.
  • the compounds may be administered either sequentially or simultaneously by any convenient route. Alternatively, the compounds may be administered separately.
  • Therapeutic agents which may be used in combination with the present invention include: corticosteroids (glucocorticoids), retinoids (e.g. acitretin, isotretinoin, tazarotene), anthralin, vitamin D analogues (e.g. stirtriol, 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, thiopurines (e.g. azathioprine, 6- mercaptopurine), methotrexate, anti-TNFa agents (e.g.
  • infliximab etanercept, adalimumab, certolizumab, golimumab and biosimilars
  • PDE4 inhibition e.g. apremilast, crisaborole
  • anti-IL-17 agents e.g. brodalumab, ixekizumab, secukinumab
  • anti-IL12/IL-23 agents e.g. ustekinumab, briakinumab
  • anti-IL-23 agents e.g. guselkumab, tildrakizumab
  • JAK Janus Kinase
  • tofacitinib ruxolitinib, baricitinib, filgotinib, upadacitinib), plasma exchange, intravenous immune globulin (MG), cyclophosphamide, anti- CD20 B cell depleting agents (e.g. rituximab, ocrelizumab, ofatumumab, obinutuzumab), anthracycline analogues (e.g. mitoxantrone), cladribine, sphingosine 1 -phosphate receptor modulators or sphingosine analogues (e.g.
  • interferon beta preparations including interferon beta 1 b/1 a
  • glatiramer anti-CD3 therapy (e.g. OKT3), anti-CD52 targeting agents (e.g. alemtuzumab), leflunomide, teriflunomide, gold compounds, laquinimod, potassium channel blockers (e.g. dalfampridine/4-aminopyridine), mycophenolic acid, mycophenolate mofetil, purine analogues (e.g. pentostatin), mTOR (mechanistic target of rapamycin) pathway inhibitors (e.g.
  • sirolimus, everolimus anti-thymocyte globulin (ATG), IL-2 receptor (CD25) inhibitors (e.g. basiliximab, daclizumab), anti-IL-6 receptor or anti-IL-6 agents (e.g. tocilizumab, siltuximab), Bruton’s tyrosine kinase (BTK) inhibitors (e.g. ibrutinib), tyrosine kinase inhibitors (e.g. imatinib), ursodeoxycholic acid, hydroxychloroquine, chloroquine, B cell activating factor (BAFF, also known as BLyS, B lymphocyte stimulator) inhibitors (e.g.
  • BK tyrosine kinase
  • BAFF also known as BLyS, B lymphocyte stimulator
  • belimumab, blisibimod other B cell targeted therapy including fusion proteins targeting both APRIL (A PRoliferation-lnducing Ligand) and BLyS (e.g. atacicept), PI3K inhibitors including pan-inhibitors or those targeting the p110b and/or p110y containing isoforms (e.g. idelalisib, copanlisib, duvelisib), interferon a receptor inhibitors (e.g. anifrolumab, sifalimumab), T cell co-stimulation blockers (e.g. abatacept, belatacept), thalidomide and its derivatives (e.g.
  • APRIL A PRoliferation-lnducing Ligand
  • BLyS e.g. atacicept
  • PI3K inhibitors including pan-inhibitors or those targeting the p110b and/or p110y containing isoforms (e.g. idelali
  • lenalidomide lenalidomide
  • dapsone clofazimine
  • leukotriene antagonists e.g. montelukast
  • theophylline anti-lgE therapy (e.g. omalizumab), anti-IL-5 agents (e.g. mepolizumab, reslizumab), long-acting muscarinic agents (e.g. tiotropium, aclidinium, umeclidinium), PDE4 inhibitors (e.g. roflumilast), riluzole, free radical scavengers (e.g. edaravone), proteasome inhibitors (e.g.
  • bortezomib complement cascade inhibitors including those directed against C5 (e.g. eculizumab), immunoadsor, antithymocyte globulin, 5-aminosalicylates and their derivatives (e.g. sulfasalazine, balsalazide, mesalamine), anti-integrin agents including those targeting a4[31 and/or a4[37 integrins (e.g. natalizumab, vedolizumab), anti-CD11-a agents (e.g. efalizumab), non-steroidal anti-inflammatory drugs (NSAIDs) including the salicylates (e.g. aspirin), propionic acids (e.g.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • ibuprofen e.g. ibuprofen, naproxen
  • acetic acids e.g. indomethacin, diclofenac, etodolac
  • oxicams e.g. meloxicam
  • fenamates e.g. mefenamic acid
  • selective or relatively selective COX-2 inhibitors e.g. celecoxib, etroxicoxib, valdecoxib and etodolac, meloxicam, nabumetone
  • colchicine e.g. dupilumab
  • topical/contact immunotherapy e.g. diphenylcyclopropenone, squaric acid dibutyl ester
  • anti-IL-1 receptor therapy e.g.
  • IL- ip inhibitor e.g. canakinumab
  • IL-1 neutralising therapy e.g. rilonacept
  • chlorambucil specific antibiotics 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, cystic fibrosis transmembrane conductance regulator (CFTR) modulators, VEGF (vascular endothelial growth factor) inhibitors (e.g. bevacizumab, ranibizumab, pegaptanib, aflibercept), pirfenidone, or mizoribine.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • VEGF vascular endothelial growth factor
  • bevacizumab ranibizumab
  • pegaptanib pegaptanib
  • aflibercept pirfenidone
  • mizoribine mizoribine
  • Compounds of formula (I) may display, or may be expected to have, one or more of the following desirable properties:
  • cytokines e.g., IL-1 p and/or IL-6
  • TLC Thin layer chromatography
  • the crude acyl chloride was re-dissolved in DCM (10 mL) and added to a solution of NH 4 OH (244 mg, 8.33 mmol, 25 wt% aqueous solution) in DCM (10 mL) and the reaction mixture was stirred at room temperature for 1 h. After such time the mixture was quenched with water (10 mL) and the layers separated. The aqueous layer was further extracted with DCM (3x10 mL). The combined organics were washed with brine (20 mL), dried over Na 2 SO4 and filtered. The filtrate was concentrated at 35 °C under reduced pressure.
  • Paraformaldehyde (37 mg, 1.2 mmol) was added to a mixture of tert-butyl 3-(3-(4-butoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (0.70 g, 1.2 mmol, 86 % purity) and potassium carbonate (0.17 g, 1.2 mmol) in THF (20 mL). The mixture was heated to 65 °C and stirred for 2 h.
  • the crude acyl chloride was re-dissolved in DCM (10 mL) and added to a solution of ammonium hydroxide (1.07 mL, 7.54 mmol, 28% wt aqueous solution) in DCM (10 mL) dropwise at RT and further stirred at RT for 18 h.
  • the reaction was quenched with water (30 mL) and the layers separated.
  • the aqueous layer was further extracted with DCM (2x20 mL).
  • Titanium(IV) ethoxide (8.9 ml_, 43 mmol) was added to a mixture of 5- (trifluoromethyl)picolinaldehyde (5.0 g, 28.6 mmol) and (S)-2-methylpropane-2-sulfinamide (5.19 g, 42.8 mmol) in THF (100 ml_). The mixture was heated to 75 °C and stirred for 3 days. The mixture was cooled to RT and diluted with water (50 mL) and stirred rapidly for 10 min. The mixture was then filtered through celite, eluting with EtOAc (200 mL). The filtrate was concentrated and the residue was dissolved in DCM (10 mL), dried (MgSC ) and concentrated.
  • the crude acyl chloride was dissolved in DCM (2 mL) and added to a solution of NH4OH (174 mg, 4.98 mmol, 25 wt% aqueous solution) in DCM (2 mL), and the reaction mixture was stirred at RT for 2 h. The mixture was quenched with water (10 mL), the layers separated and the aqueous layer was further extracted with DCM (3x5 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered.
  • the filtrate was concentrated at 35 °C under reduced pressure, and the residue was purified by prep- HPLC (Column: Waters X-bridge Prep C18 OBD 10pm 19*250mm; Flow Rate: 20 mL/min; solvent system: MeCN/(0.2% formic acid/water) gradient: MeCN: 65% ⁇ 95%; collection wavelength: 214 nm).
  • the fractions were concentrated at 30 °C under reduced pressure to remove MeCN, and the residue was lyophilized to give 1-(4-(trifluoromethyl)phenyl)cyclobutyl (E)-3-cyanoacrylate (80.6 mg, 0.27 mmol) as a white solid.
  • At-column dilution pump gives 2 mL min-1 Methanol over the entire method, which is included in the following MeCN percentages.
  • Gradient information 0.0-0.5 min, 40% MeCN; 0.5-10.5 min, ramped from 40% MeCN to 70% MeCN; 10.5-10.6 min, ramped from 70% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN.
  • the clean fractions were evaporated in a Genevac to give 5-(2-(1H-tetrazol-5-yl)allyl)-3-(4-butoxyphenyl)-1 ,2,4- oxadiazole (30.9 mg, 0.1 mmol) as a light brown solid.
  • At-column dilution pump gives 2 mL min-1 Methanol over the entire method, which is included in the following MeCN percentages.
  • the clean fractions were evaporated in a Genevac to give (E)-5-(2-(1 H-tetrazol-5-yl)prop- 1-en-1-yl)-3-(4-butoxyphenyl)-1 ,2,4-oxadiazole (41.9 mg, 0.13 mmol) as a pale brown solid.
  • the reaction mixture was allowed to warm to RT then heated to 60 °C and stirred for 18 h. Once cooled, the mixture was carefully quenched with water (20 mL) and extracted with EtOAc (80 mL). The organic layer was washed with brine (4x15 mL), dried (Na2SO4), filtered and concentrated. The crude product was purified by chromatography on silica gel (0-60% MTBE/isohexane followed by 0-10% MeOH/DCM).
  • Aqueous formaldehyde (37% wt, 17 pL, 0.23 mmol) was added to a suspension of 3-(5- (trifluoromethyl)pyridin-2-yl)oxetan-3-yl 2-(diethoxyphosphoryl)-3-(1 H-tetrazol-5-yl)propanoate (0.08 g, 0.15 mmol, 95 % purity) and K2CO3 (32 mg, 0.23 mmol) in THF (2 mL).
  • the mixture was stirred at RT for 18 h.
  • the mixture was cooled to RT, carefully quenched with water (10 mL) and extracted with DCM (2x10 mL).
  • the combined organic phases were dried (MgSO4), filtered and concentrated.
  • the cytokine inhibition profiles of compounds of formula (I) were determined in a differentiated THP-1 cell assay. All assays were performed in RPMI-1640 growth medium (Gibco), supplemented with 10% fetal bovine serum (FBS; Gibco), 1 % penicillin-streptomycin and 1% sodium pyruvate unless specified otherwise.
  • the IL-1 p and IL-6 cytokine inhibition assays were run in a background of differentiated THP-1 cells as described below. All reagents described were from Sigma-Aldrich unless specified otherwise. Compounds were prepared as 10mM DMSO stocks.
  • THP-1 cells were expanded as a suspension up to 80% confluence in appropriate growth medium. Cells were harvested, suspended, and treated with an appropriate concentration of phorbol 12- myristate 13-acetate (PMA) over a 72hr period (37°C/5% CO2).
  • PMA phorbol 12- myristate 13-acetate
  • THP-1 cell incubation Following 72hrs of THP-1 cell incubation, cellular medium was removed and replaced with fresh growth media containing 1% of FBS. Working concentrations of compounds were prepared separately in 10% FBS treated growth medium and pre-incubated with the cells for 30 minutes (37°C/5% CO2). Following the 30 minute compound pre-incubation, THP-1s were treated with an appropriate concentration of LPS and the THP-1 s were subsequently incubated for a 24hr period (37°C/5% CO2). An appropriate final concentration of Nigericin was then dispensed into the THP- 1 plates and incubated for 1 hour (37°C/5% CO2) before THP-1 supernatants were harvested and collected in separate polypropylene 96-well holding plates.
  • IL-1 p and IL-6 commercial kits were prepared and run according to the manufacturer’s instructions. Subsequently, fluorescence signal detection in a microplate reader was measured (EnVision® Multilabel Reader, Perkin Elmer). Percentage inhibition was calculated per cytokine by normalising the sample data to the high and low controls used within each plate (+/- LPS respectively). Percentage inhibition was then plotted against compound concentration and the 50% inhibitory concentration (IC50) was determined from the resultant concentration-response curve.
  • IC50 50% inhibitory concentration
  • NRF2 neurotrophic factor erythroid 2-related factor 2
  • PathHunter NRF2 translocation kit DiscoverX
  • the NRF2 translocation assay was run using an engineered recombinant cell line, utilising enzyme fragment complementation to determine activation of the Keap1-NRF2 protein complex and subsequent translocation of NRF2 into the nucleus. Enzyme activity was quantified using a chemiluminescent substrate consumed following the formation of a functional enzyme upon PK-tagged NRF2 translocation into the nucleus.
  • the assay was run under either +/- GSH (glutathione) conditions to determine the attenuating activities of GSH against target compounds.
  • U2OS PathHunter express cells were thawed from frozen prior to plating. Following plating, U2OS cells were incubated for 24hrs (37°C/5%CO2) in commercial kit provided cell medium.
  • the U2OS plates were incubated for a further 6 hours (37°C/5%CO2) before detection reagent from the PathHunter NRF2 commercial kit was prepared and added to test plates according to the manufacturer’s instructions. Subsequently, the luminescence signal detection in a microplate reader was measured (PHERAstar®, BMG Labtech). Percentage activation was calculated by normalising the sample data to the high and low controls used within each plate (+/- DMF). Percentage activation/response was then plotted against compound concentration and the 50% activation concentration (EC50) was determined from the plotted concentration-response curve.
  • EC50 50% activation concentration
  • cryo-preserved hepatocytes (viability > 70%) were used to determine the metabolic stability of a compound via calculation of intrinsic clearance (Clint; a measure of the removal of a compound from the liver in the absence of blood flow and cell binding). Clearance data are particularly important for in vitro work as they can be used in combination with in vivo data to predict the half-life and oral bioavailability of a drug.
  • the metabolic stability in hepatocytes assay involved a time-dependent reaction using both positive and negative controls.
  • the cells must be pre-incubated at 37 °C then spiked with test compound (and positive control); samples taken at pre-determined time intervals were analysed to monitor the change in concentration of the initial drug compound over 60 minutes.
  • a buffer incubation reaction (with no hepatocytes present) acted as a negative control and two cocktail solutions, containing compounds with known high and low clearance values (verapamil/7- hydroxycoumarin and propranolol/diltiazem), acted as positive controls. 1.
  • the assay was run with a cell concentration of 0.5 x 10 6 cells/mL in Leibovitz buffer.
  • the assay was initiated by adding compounds, 3.3pL of 1mM in 10% DM SO-90% Buffer; final DMSO concentration is 0.1%.
  • Sample volume was 40pL and added to 160pL of crash solvent (acetonitrile with internal standard) and stored on ice.
  • the crash plates were centrifuged at 3500rpm for 20mins at 4 °C. 11. 80 L of clear supernatant was removed and mixed with 80 L of deionised water before being analysed by LC-MS/MS.
  • Example 3 is expected to be more stable (lower intrinsic clearance (Clint) and longer half-life (T1/2) values) compared with RE1.
  • Example 4 is expected to be more stable (lower intrinsic clearance (Cl int) and/or longer half-life (T1/2) values in at least human or mouse species) compared with RE2.

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Abstract

The invention relates to compounds of formula (I) and related aspects.

Description

TETRAZOLE DERIVATIVES
Field of the invention
The present invention relates to compounds and their use in treating or preventing inflammatory diseases or diseases associated with an undesirable immune response, and to related compositions, methods and intermediate compounds.
Background of the invention
Chronic inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), multiple sclerosis, psoriasis, Crohn’s disease, ulcerative colitis, uveitis and chronic obstructive pulmonary disease (COPD) represent a significant burden to society because of lifelong debilitating illness, increased mortality and high costs for therapy and care (Straub R.H. and Schradin C., 2016). Non-steroidal anti-inflammatory drugs (NSAIDs) are the most widespread medicines employed for treating inflammatory disorders, but these agents do not prevent the progression of the inflammation and only treat the accompanying symptoms. Glucocorticoids are powerful anti-inflammatory agents, making them emergency treatments for acute inflammatory flares, but given longer term these medicines give rise to a plethora of unwanted side-effects and may also be subject to resistance (Straub R. H. and Cutolo M., 2016). Thus, considerable unmet medical need still exists for the treatment of inflammatory disorders and extensive efforts to discover new medicines to alleviate the burden of these diseases is ongoing (Hanke T. et al., 2016).
Dimethyl fumarate (DMF), a diester of the citric acid cycle (CAC) intermediate fumaric acid, is utilised as an oral therapy for treating psoriasis (Bruck J. et a!., 2018) and multiple sclerosis (Mills E. A. et al., 2018). Importantly, following oral administration, none of this agent is detected in plasma (Dibbert S. et al., 2013), the only drug-related compounds observed being the hydrolysis product monomethyl fumarate (MMF) and glutathione (GSH) conjugates of both the parent (DMF) and metabolite (MMF). DMF’s mechanism of action is complex and controversial. This compound’s efficacy has been attributed to a multiplicity of different phenomena involving covalent modification of proteins and the conversion of “prodrug” DMF to MMF. In particular, the following pathways have been highlighted as being of relevance to DMF’s anti-inflammatory effects: 1) activation of the anti-oxidant, anti-inflammatory, nuclear factor (erythroid-derived 2)- like 2 (NRF2) pathway as a consequence of reaction of the electrophilic a, - unsaturated ester moiety with nucleophilic cysteine residues on kelch-like ECH-associated protein 1 (KEAP1) (Brennan M. S. et al., 2015); 2) induction of activating transcription factor 3 (ATF3), leading to suppression of pro-inflammatory cytokines interleukin (IL)-6 and IL-8 (Muller S. et al., 2017); 3) inactivation of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) through succination of its catalytic cysteine residue with a Michael accepting unsaturated ester (Kornberg M. D. et al., 2018; Angiari S. and O’Neill L. A., 2018); 4) inhibition of nuclear factor- kappaB (NF-KB)-driven cytokine production (Gillard G. O. et al., 2015); 5) preventing the association of PKC0 with the costimulatory receptor CD28 to reduce the production of IL-2 and block T-cell activation (Blewett M. M. etal., 2016); 6) reaction of the electrophilic a,f>-unsaturated ester with the nucleophilic thiol group of anti-oxidant GSH, impacting cellular responses to oxidative stress (Lehmann J. C. U. etal., 2007); 7) agonism of the hydroxycarboxylic acid receptor 2 (HCA2) by the MMF generated in vivo through DMF hydrolysis (von Glehn F. et al., 2018); 8) allosteric covalent inhibition of the p90 ribosomal S6 kinases (Andersen J. L. et al., 2018); 9) inhibition of the expression and function of hypoxia-inducible factor-1a (HIF-1a) and its target genes, such as IL-8 (Zhao G. et al., 2014); and 10) inhibition of Toll-like receptor (TLR)-induced M1 and K63 ubiquitin chain formation (McGuire V. A. et al., 2016). In general, with the exception of HCA2 agonism (Tang H. etal., 2008), membrane permeable diester DMF tends to exhibit much more profound biological effects in cells compared to its monoester counterpart MMF. However, the lack of systemic exposure of DMF in vivo has led some researchers to assert that MMF is, in fact, the principal active component following oral DMF administration (Mrowietz U. et al., 2018). As such, it is evident that some of the profound biology exerted by DMF in cells is lost because of hydrolysis in vivo to MMF.
Recently, it has been discovered that, during inflammatory macrophage activation, the CAC becomes anaplerotic and is diverted such that the unsaturated diacid itaconic acid, “itaconate”, is generated (Murphy M. P. and O’Neill L. A. J., 2018; O’Neill L. A. J. and Artyomov M. N., 2019; Yu X.-H. et al., 2019). Instead of being hydrated to isocitrate by aconitate hydratase, the CAC intermediate aconitate is decarboxylated by the protein product of immune-responsive gene 1 (IRG1), one of the most highly upregulated genes in macrophages under proinflammatory conditions, subsequently named aconitate decarboxylase 1, to produce itaconic acid (Michelucci A. et al., 2013). This unsaturated diacid is an inhibitor of the bacterial enzyme isocitrate lyase and, as such, it exerts anti-bacterial activity. In addition, itaconic acid has been shown to inhibit the CAC enzyme succinate dehydrogenase (SDH) (Ackermann et al., 1949), leading accordingly to succinate accumulation (Cordes T. et al., 2016). By inhibiting SDH, an enzyme critical for the inflammatory response (E. L. Mills et al., 2016), itaconate ameliorates inflammation in vitro and in vivo during macrophage activation and ischemia-reperfusion injury (Lampropoulou V. et al., 2016).
Like fumaric acid, itaconic acid is an a,p-unsaturated carboxylic acid. As such, it is a Michael acceptor which induces a global electrophilic stress response. In this regard, the itaconic acid diester dimethyl itaconate (DMI), like DMF, produces an anti-inflammatory response, reducing the expression levels of pro-inflammatory cytokines I L-1 p, IL-6, IL-12 and IL-18 in lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (WO2017/142855A1, incorporated herein by reference). This response appears to be mediated, in part, by NRF2 activation, via alkylation of KEAP1 cysteine residues by the electrophilic a, [3- unsaturated ester moiety (Mills E. L. et al., 2018), which enhances the expression of downstream genes with anti-oxidant and antiinflammatory capacities. Nevertheless, not all of the pronounced immunoregulatory effects engendered by DMI can be attributed to NRF2 activation. In particular, the modulation of IKB by DMI is independent of NRF2 and is mediated via upregulation of ATF3, a global negative regulator of immune activation that downregulates various cytokines, such as IL-6 (Bambouskova M. et al., 2018). Moreover, by inhibiting IKB protein production, DMI ameliorates IL-17-mediated pathologies, highlighting the therapeutic potential of this regulatory pathway (W02019/036509A1 , incorporated herein by reference). Further highlighting its pharmacologic potential, DMI has recently been reported to 1) demonstrate a protective effect on cerebral ischemia/reperfusion injury, thereby offering potential for the treatment of ischemic stroke (Zhang D. et al., 2019); 2) provide protection from the cardiotoxic effects of doxorubicin (Shan Q. et al., 2019); and 3) protect against lippolysacchride-induced mastitis in mice by activating MAPKs and NRFrf2 while inhibiting NF-KB signaling pathways (Zhao C. et al., 2019). Furthermore, DMI is said to have utility in preventing and treating ulcerative colitis and canceration thereof (CN110731955, Sun Yat-sen University Cancer Center); and has been reported to protect against fungal keratitis by activating the NRF2/HO-1 signalling pathway (Gu L. et al., 2020). Nevertheless, it should be noted that DMI is not metabolised to itaconic acid intracellularly (ElAzzouny M. et al., 2017). Other a, - unsaturated esters exhibit IL-1 [3-lowering effects in macrophages by inhibiting the NLRP3 inflammasome (Cocco M. etal., 2017 and 2014), and have been demonstrated to inhibit the TLR4 pathway, leading ultimately to suppression of LPS-induced stimulation of NF-KB, tumour necrosis factor (TNF)-a, IL-1 (3 and nitric oxide release (Zhang S. et al., 2012).
Other itaconic acid derivatives have been demonstrated to elicit anti-inflammatory effects (Bagavant G. etal., 1994). A notable example is 4-octyl itaconic acid (4OI), an itaconate derivative with improved cellular uptake. Since the a,[3-unsaturated carboxylic acid is not esterified in 4OI, this electrophile exhibits low reactivity with biological thiols (Schmidt T. J. et al., 2007), much like the situation encountered with itaconic acid itself. As a result of its low reactivity/electrophilicity, the NRF2-activating effects of 4OI are not attenuated by GSH, in contrast to the findings with the much more reactive DMI. In this latter case, the a,[3-unsaturated carboxylic acid is esterified and, as a consequence, the IL-6-lowering and NRF2-activating effects of DMI are reversed by the thiols N-acetylcysteine and GSH, respectively. Through the reaction with KEAP1 and the resulting NRF2 activation, as well as GAPDH inhibition (Liao S.-T. et al., 2019), 4OI has been demonstrated to produce a wide range of interesting biological effects, including: 1) protection of neuronal cells from hydrogen peroxide (Liu H. et al., 2018); 2) inhibition of proinflammatory cytokine production in peripheral blood mononuclear cells of SLE patients (Tang C. et al., 2018); and 3) protection of human umbilical vein endothelial cells from high glucose (Tang C. et al., 2019); 4) inhibition of osteoclastogenesis by suppressing the E3 ubiquitin ligase Hrd1 and activating NRF2 signaling (Sun X. et al., 2019); 5) induction of repression of STING by NRF2 and type I IFN production in cells from patients with STING-dependent interferonopathies (Olagnier D. et al., 2018); 6) protection against renal fibrosis via inhibiting the TGF-beta/Smad pathway, autophagy and reducing generation of reactive oxygen species (Tian F. et al., 2020); 7) reduction of brain viral burden in mice intracranially injected with Zika virus (Daniels B. P. et al. 2019); and 8) protection against liver ischemia-reperfusion injury (Yi F. et al. 2020). Furthermore, itaconate has been reported to modulate tricarboxylic acid and redox metabolism to mitigate reperfusion injury (Cordes T. et al., 2020). In addition, raised plasma itaconate levels demonstrate a clear correlation with reduction in rheumatoid arthritis disease activity scores following commencement of therapy with conventional disease modifying anti-rheumatic drug (cDMARD) therapy (Daly R. et al. 2019).
Artyomov et al. (WO2017/142855; WO2019/036509) disclose the use of itaconate, malonate or a derivative thereof as an immunomodulatory agent.
W02020/222011 , W02020/222010, WO2021/130492, WO2022/029438, WO2022/038365, W02022/090723, W02022/090714, W02022/090724, WO2022/229617, WO2022/269251 and WO2023/017269 (Sitryx Therapeutics Limited) all disclose certain itaconate derivatives.
In particular, WO2022/029438 discloses compounds of formula (I):
Figure imgf000005_0001
wherein RB can be CHztetrazolyl, ring A can be a 5-membered heteroaryl ring, RA2 can be absent and RA1 is other than H.
In spite of the above findings, there remains a need to identify and develop new itaconate derivatives possessing enhanced properties compared to known or currently marketed antiinflammatory agents. The inventors have now developed compounds which are more effective at reducing cytokine release in cells and/or in activating NRF2-driven effects compared with 4-octyl itaconate, 2-(2-chlorobenzyl)acrylic acid, monomethyl fumarate and/or other known itaconate derivatives, with reduced metabolic clearance in human hepatocytes, which translates to improved exposure in vivo, whilst retaining efficacy in inflammation models.
Summary of the invention
In a first aspect, the present invention provides a compound of formula (I):
Figure imgf000006_0001
wherein:
Figure imgf000006_0002
L is selected from the group consisting of NHC(=O), OC(=O) and 5-membered heteroaryl;
K is bond or C(R1)(R2);
R1 and R2 are independently selected from the group consisting of H, Ci-4 alkyl and C1-4 haloalkyl, or R1 and R2 join to form a C3.5 cycloalkyl ring or a 4- to 6-membered heterocyclic ring, wherein the C3.5 cycloalkyl ring or 4- to 6-membered heterocyclic ring is optionally substituted by halo, cyano, C1.2 alkyl, C1.2 alkoxy, C1.2 haloalkyl or C1.2 haloalkoxy;
A is C5-7 cycloalkyl, phenyl or 5-6-membered heteroaryl wherein A is optionally substituted by one or more R3wherein R3 is selected from the group consisting of halo, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1.4 haloalkoxy, hydroxy, cyano, SFs, SC1.4 alkyl, SC1.4 haloalkyl, (CH2)o-3Cs-7 cycloalkyl, 5-7-membered heterocyclyl, O-phenyl and O-heteroaryl wherein said C3-7 cycloalkyl, said 5-7-membered heterocyclyl, said O-phenyl and said O-heteroaryl are optionally substituted by one or more groups selected from halo, C1.4 alkyl, C1.4 haloalkyl, O(Ci-4 alkyl) and C1.4 hydroxyalkyl; wherein two alkyl groups which are attached to the same carbon atom are optionally joined to form a C3-7 cycloalkyl ring; and
Rc and RD are each independently H, C1-2 alkyl, hydroxy, fluoro or Ci_2 alkoxy; or Rc and RD may join to form a C3-5 cycloalkyl ring; or a pharmaceutically acceptable salt and/or solvate thereof.
The present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof.
The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for use as a medicament.
The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof for use in treating or preventing an inflammatory disease or a disease associated with an undesirable immune response.
The present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof in the manufacture of a medicament for treating or preventing an inflammatory disease or a disease associated with an immune response.
The present invention provides a method of treating or preventing an inflammatory disease or a disease associated with an undesirable immune response, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof.
Also provided are intermediate compounds of use in the preparation of compounds of formula (I).
Detailed description of the invention
Compounds of formula (I)
Embodiments and preferences set out herein with respect to the compound of formula (I) apply equally to the pharmaceutical composition, compound or pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use and method aspects of the invention, as well as intermediates used in the synthesis of the compounds of formula (I).
Embodiments and preferences for one variable in the compound of formula (I) (e.g. A) may be combined with embodiments and preferences for other variables in the compound of formula (I)
Figure imgf000008_0001
The term “alkyl”, such as “C1.4 alkyl or “C1.2 alkyl” refers to a straight or branched fully saturated hydrocarbon group having the specified number of carbon atoms. The term encompasses methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The term “alkyl” also encompasses “alkylene” which is a bifunctional straight or branched fully saturated hydrocarbon group having a specified number of carbon atoms. Example “alkylene” groups include methylene, ethylene, n-propylene and n-butylene.
The term “alkoxy” refers to an alkyl group, such as “C1.4 alkyl” as defined above, singularly bonded via an oxygen atom. Examples of alkoxy groups include OCH3.
The term “haloalkyl”, such as “C1.3 haloalkyl” or “C1.2 haloalkyl” as used herein refers to a straight or a branched fully saturated hydrocarbon chain containing the specified number of carbon atoms and at least one halogen atom, such as fluoro or chloro, especially fluoro. An example of haloalkyl is CF3. Further examples of haloalkyl are CHF2 and CH2CF3.
The term “haloalkoxy” refers to a haloalkyl group, such as “C1.3 haloalkyl” or “C1.2 haloalkyl”, as defined above, singularly bonded via an oxygen atom. Examples of haloalkoxy groups include OCF3, OCHF2 and OCH2CF3.
The term “hydroxy” (which may also be referred to as “hydroxyl”) refers to an -OH group.
The term “hydroxyalkyl”, such as “C1.4 hydroxyalkyl”, refers to an alkyl or alkylene chain having one to four carbon atoms, wherein one of the carbon atoms is substituted by an -OH group. Examples include -CH2C(H)OH, -C(H)OHCH3 and -C(H)OH.
The term “halo” refers to fluoro, chloro, bromo or iodo. Particular examples of halo are fluoro and chloro, especially fluoro.
The term “cycloalkyl”, such as “C3-5 cycloalkyl”, “C5-7 cycloalkyl” or “C3-7 cycloalkyl”, refers to a fully saturated cyclic hydrocarbon group having the specified number of carbon atoms. The term encompasses cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl as well as bridged systems such as bicyclo[1 .1 .1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl and adamantyl. Particularly preferred groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term “heterocyclic ring” or “heterocyclyl”, such as “4- to 6-membered heterocyclic ring” or “5- 7-membered heterocyclyl” refers to a non-aromatic cyclic group having the specified number of ring atoms and wherein at least one of the ring atoms is a heteroatom selected from N, O, S and B. The term “heterocyclic ring” is interchangeable with “heterocyclyl”. The term encompasses oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl. Heterocyclic groups can typically be substituted by one or more (e.g. one or two) oxo groups. Suitably, thietanyl is substituted by one or two oxo groups.
The term “heteroaryl” such as “5- or 6-membered heteroaryl” refers to a cyclic group with aromatic character containing the indicated number of atoms (e.g. 5 or 6) wherein at least one of the atoms in the cyclic group is a heteroatom independently selected from N, O and S. The term encompasses pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyradizinyl and pyrazinyl.
In some suitable compounds of formula (I):
Figure imgf000009_0001
wherein Rc and RD are as defined herein.
In other suitable compounds of formula (I):
Figure imgf000009_0002
wherein Rc is as defined herein. In one embodiment, X is H. Alternatively, X is CH3.
In other suitable compounds of formula (I):
Figure imgf000009_0003
In some suitable compounds of formula (I), L is NHC(=O). In other suitable compounds of formula (I), L is OC(=O). In further suitable compounds of formula (I), L is 5-membered heteroaryl.
Suitably, the 5-membered heteroaryl ring selected from the group consisting of imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1 ,2,4-triazole, 1,2,4-oxadiazole, 1 ,2,5-oxadiazole, 1 ,3,4-oxadiazole, 1 ,2,4-thiadiazole, 1 ,2,5-thiadiazole, 1 ,3,4-thiadiazole and tetrazole.
When L represents imidazole, it is intended to represent
Figure imgf000010_0001
, jn formula (I). For the avoidance of doubt, substituent K can be bound to a carbon or nitrogen atom of the imidazole moiety.
When L represents pyrazole, it is intended to represent
Figure imgf000010_0002
, in formula (I). For the avoidance of doubt, substituent K can be bound to a carbon or nitrogen atom of the pyrazole moiety.
Figure imgf000010_0003
When L represents 1 ,2,3-triazole, it is intended to represent
Figure imgf000010_0004
, in formula (I). For the avoidance of doubt, substituent K can be bound to a carbon or nitrogen atom of the 1 ,2,3- triazole moiety. When L represents 1 ,2,4-triazole, it is intended to represent
Figure imgf000011_0001
and/or
Figure imgf000011_0002
, in formula (I). For the avoidance of doubt, substituent K can be bound to a carbon or nitrogen atom of the 1 ,2,4-triazole moiety.
When L represents 1 ,2,4-oxadiazole, it is intended to represent
Figure imgf000011_0003
and/or
Figure imgf000011_0004
, in formula (I).
When L represents 1,2,5-oxadiazole, it is intended to represent
Figure imgf000011_0005
When L represents 1,3,4-oxadiazole, it is intended to represent
Figure imgf000011_0006
When L represents 1 ,2,4-thiadiazole, it is intended to represent
Figure imgf000011_0007
and/or
Figure imgf000011_0008
in formula (I).
When L represents 1,2,5-thiadiazole, it is intended to represent
Figure imgf000011_0009
When L represents 1,3,4-thiadiazole, it is intended to represent
Figure imgf000012_0001
formula (I).
When L represents tetrazole, it is intended to represent
Figure imgf000012_0002
In one embodiment, L represents an oxadiazole, in particular 1 ,2,4-oxadiazole.
Suitably, the 1 ,2,4-oxadiazole
Figure imgf000012_0003
In any one of the above embodiments or other suitable compounds disclosed herein, - or indicates the connection point to the remainder of the compound of formula (I).
In some suitable compounds of formula (I), L represents 1 ,2,4-oxadiazole.
In the representations above, where a substituent is not indicated as being bound to a carbon atom or nitrogen atom and is instead shown as intersecting a double or single bond of a heteroaryl compound, this indicates that the point of attachment is undefined, and may be any attachment point which is chemically feasible. Furthermore, each of the above mentioned heteroaryl groups is shown as a single tautomer. The skilled person recognises that although a single tautomer is shown, the compound may exist as a mixture of tautomeric forms. Thus, the invention extends to all tautomeric forms of the compounds of formula (I).
In some suitable compounds of formula (I), K is bond. In other suitable compounds of formula (I), K is C(R1)(R2) wherein R1 and R2 are defined below.
Suitably, when L is NHC(=O) or OC(=O), K is C(R1)(R2). Alternatively, when L is 5-membered heteroaryl, K is bond. In some suitable compounds of formula (I), R1 is H. In other suitable compounds of formula (I), R1 is C1-4 alkyl such as methyl. In other suitable compounds of formula (I), R1 is C1-4 haloalkyl such as CF3.
In some suitable compounds of formula (I), R2 is H. In other suitable compounds of formula (I), R2 is C1-4 alkyl such as methyl. In other suitable compounds of formula (I), R2 is C1-4 haloalkyl such as CF3.
Suitably, R1 is methyl and R2 is H.
When R1 and R2 are different, suitably R1 and R2 have the following stereochemical configuration:
Figure imgf000013_0001
In other suitable compounds of formula (I), R1 and R2 join to form a C3-5 cycloalkyl ring such as a C4 cycloalkyl ring:
Figure imgf000013_0002
In other suitable compounds of formula (I), R1 and R2 join to form a 4- to 6-membered heterocyclic ring such as a 4-membered heterocyclic ring e.g. oxetanyl:
Figure imgf000013_0003
In some suitable compounds of formula (I), the C3-5 cycloalkyl ring is unsubstituted. In other suitable compounds of formula (I), the C3-5 cycloalkyl ring is substituted by halo, cyano, C1.2 alkyl, C1.2 alkoxy, C1.2 haloalkyl or C1.2 haloalkoxy. In some suitable compounds of formula (I), the 4- to 6-membered heterocyclic ring is unsubstituted. In other suitable compounds of formula (I), the 4- to 6-membered heterocyclic ring is substituted by halo, cyano, C1.2 alkyl, C1.2 alkoxy, C1.2 haloalkyl or C1-2 haloalkoxy.
In some suitable compounds of formula (I), the substituent is halo. In other suitable compounds of formula (I), the substituent is cyano. In other suitable compounds of formula (I), the substituent is C1-2 alkyl such as methyl. In other suitable compounds of formula (I), the substituent is C1.2 alkoxy such as OCH3. In other suitable compounds of formula (I), the substituent is C1.2 haloalkyl such as CF3. In other suitable compounds of formula (I), the substituent is C1.2 haloalkoxy such as OCF3.
In some suitable compounds of formula (I), A is C5-7 cycloalkyl. In other suitable compounds of formula (I), A is phenyl. In other suitable compounds of formula (I), A is 5-6-membered heteroaryl.
Suitably, A is phenyl or 6-membered heteroaryl.
Most suitably, A is phenyl or pyridyl.
In some suitable compounds of formula (I), A is other than tetrazolyl, such as when L is OC(=O).
In some suitable compounds of formula (I), A is C5-7 cycloalkyl, phenyl or 6-membered heteroaryl, such as when L is OC(=O).
In some suitable compounds of formula (I), A is unsubstituted. In other suitable compounds of formula (I), A is substituted by one or more (such as one, two or three, e.g. one) R3 wherein R3 is defined herein.
In some suitable compounds of formula (I), R3 is halo. In other suitable compounds of formula (I), R3 is C1-4 alkyl. In other suitable compounds of formula (I), R3 is C1-4 alkoxy such as butoxy. In other suitable compounds of formula (I), R3 is C1-4 haloalkyl such as CF3. In other suitable compounds of formula (I), R3 is C1.4 haloalkoxy. In other suitable compounds of formula (I), R3 is hydroxy. In other suitable compounds of formula (I), R3 is cyano. In other suitable compounds of formula (I), R3 is SF5. In other suitable compounds of formula (I), R3 is SC1.4 alkyl. In other suitable compounds of formula (I), R3 is SC1.4 haloalkyl. In other suitable compounds of formula (I), R3 is (CH2)O-3C3-7 cycloalkyl. In other suitable compounds of formula (I), R3 is 5-7-membered heterocyclyl. In other suitable compounds of formula (I), R3 is O-phenyl. In other suitable compounds of formula (I), R3 is O-heteroaryl such as 0-5- or 6-membered heteroaryl.
Suitably, R3 is CF3.
In some suitable compounds of formula (I), said C3.7 cycloalkyl, said 5-7-membered heterocyclyl, said O-phenyl and said O-heteroaryl of R3 are not substituted. In other suitable compounds of formula (I), said C3.7 cycloalkyl, said 5-7-membered heterocyclyl, said O-phenyl and said O- heteroaryl of R3 are substituted by one or more groups selected from halo, C1.4 alkyl, C1.4 haloalkyl , O(Ci-4 alkyl) and C1.4 hydroxyalkyl.
In some suitable compounds of formula (I), two alkyl groups of R3 which are attached to the same carbon atom are optionally joined to form a C3-7 cycloalkyl ring.
In some suitable compounds of formula (I), Rc is H, C1-2 alkyl, hydroxy, fluoro or Ci-2 alkoxy such as H. In some suitable compounds of formula (I), RD is H, C1-2 alkyl, hydroxy, fluoro or C1-2 alkoxy such as H.
In some suitable compounds of formula (I), Rc and RD join to form a C3-5 cycloalkyl ring.
Suitably, Rc is H and RD are H.
In some suitable compounds of formula (I), L is OC(=O) or 5-membered heteroaryl and
Figure imgf000015_0001
In some suitable compounds of formula (I), L is NHC(=O), and
Figure imgf000015_0002
Figure imgf000016_0001
In some suitable compounds of formula (I), L is NHC(=O) and:
K is bond and A is optionally substituted phenyl or optionally substituted 5-6-membered heteroaryl;
K is C(R1)(R2) wherein R1 and R2 are defined elsewhere herein, and A is C5-7 cycloalkyl;
K is C(R1)(R2) wherein R1 and R2 are defined elsewhere herein, and A is C5-7 cycloalkyl or 5-6-membered heteroaryl wherein the 6-membered heteroaryl is other than pyridyl;
K is CH2 and A is C5-7 cycloalkyl;
K is CH2 and A is C5-7 cycloalkyl or 5-6-membered heteroaryl wherein the 6-membered heteroaryl is other than pyridyl; and/or
R3 is C2-4 alkyl, C1-4 alkoxy, C2-4 haloalkyl, C1.4 haloalkoxy, hydroxy, cyano, SF5, SC1.4 alkyl, SC1.4 haloalkyl, (CH2)o-3C3-7 cycloalkyl, 5-7-membered heterocyclyl, O-phenyl and O-heteroaryl wherein said C3-7 cycloalkyl, said 5-7-membered heterocyclyl, said O-phenyl and said O-heteroaryl are optionally substituted by one or more groups selected from halo, C1.4 alkyl, C1.4 haloalkyl, O(Ci-4 alkyl) and C1.4 hydroxyalkyl.
In some suitable compounds of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, the compound of formula (I) is other than a compound of formula (IA):
Figure imgf000016_0002
wherein:
Figure imgf000016_0003
RA is selected from the group consisting of Ce-7 cycloalkyl, CH2(phenyl) and CH2(pyridyl); wherein when RA is Cs-7 cycloalkyl, the cycloalkyl ring is 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; 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 or C1.4 haloalkyl, or two RA3 groups are attached to the CH2 carbon atom and join to form a C3-5 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 (^(substituted phenyl) or (^(substituted pyridyl) of RA is substituted by one RA3 the stereochemistry of the carbon to which RA3 is attached is as follows:
Figure imgf000017_0001
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 pharmaceutically acceptable salt and/or solvate thereof.
Suitably, the compound of formula (I) is other than Example 1.
In one embodiment there is provided a compound of formula (I), which is selected from the list consisting of:
(S)-3-(1 H-tetrazol-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)but-3-enamide;
(S,E)-3-(1 H-tetrazol-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)but-2-enamide;
5-(2-(1 H-tetrazol-5-yl)allyl)-3-(4-butoxyphenyl)-1 ,2,4-oxadiazole;
(E)-5-(2-(1 H-tetrazol-5-yl)prop-1-en-1-yl)-3-(4-butoxyphenyl)-1 ,2,4-oxadiazole;
3-(5-(trifluoromethyl)pyridin-2-yl)oxetan-3-yl 2-((1 H-tetrazol-5-yl)methyl)acrylate; and ammonium (E)-5-(3-oxo-3-(1-(4-(trifluoromethyl)phenyl)cyclobutoxy)prop-1-en-1-yl)tetrazol-1- ide; and pharmaceutically acceptable salts and/or solvates of any one thereof.
Compounds of formula (I) may be synthesised as shown in the schemes below and as shown in the Examples section. For each scheme, variables are as defined above unless otherwise stated. Scheme 1 : Synthesis of compounds of formula (II) when L is -NH-C(=O)-
Figure imgf000018_0001
Compounds of formula (II) can be made by reacting acids of formula (IV) with amines of formula (III) under standard coupling conditions such as DCC and DMAP in DCM.
Scheme 2: Synthesis of compounds of formula (II) when L is 5-membered heteroaryl such as oxadiazole
Figure imgf000018_0002
This route is particularly suitable for compounds wherein K = bond. Step 1 : Nitriles of formula (X) may be converted to compounds of formula (IX) using aqueous hydroxylamine.
Step 2: Compounds of formula (IX) may be converted to phosphonates of formula (VIII) wherein Rz is Ci-4 alkyl such as Et and L is a 1,2,4-oxadiazole ring by reaction with corresponding carboxylic acid (XIII) under standard coupling conditions such as T3P and TEA in EtOAc. Step 3: Phosphonates of formula (VIII) may be converted to compounds of formula (Vila) using paraformaldehyde under basic conditions such as TEA in THF.
Step 4: Protecting group PG (such as C1.4 alkyl e.g. tBu or Me) in compounds of formula (Vila) may be removed using conditions known to the skilled person, to give compounds of formula (Via); if PG is tBu then conditions such as TFA in DCM may be used. Step 5: Carboxylic acids (Via) may be converted to amides (Va) by activation of the acid by an activating agent e.g. oxalyl chloride, followed by addition of a source of NH3 e.g. ammonium hydroxide.
Step 6: Amides (Va) may be converted to nitriles (Ila) using known methods, for example TFAA in pyridine.
Scheme 3: Synthesis of compounds of formula (II) when L is -Q-C(=O)-
Figure imgf000019_0001
This route is particularly suitable for compounds wherein K = C(R1)(R2).
Step 1 : Alcohols of formula (XI) may be coupled to carboxylic acids (XII) using standard coupling conditions such as DCC and DMAP in DCM to give esters of formula (Vllb).
Step 2: Compounds of formula (Vllb) may be converted to compounds of formula (Vlb) by removal of protecting group PG (such as C1.4 alkyl e.g. tBu or Me) using conditions known to the skilled person such as LiOH in THF.
Step 3: Carboxylic acids (Vlb) may be converted to amides (Vb) by activation of the acid by an activating agent e.g. oxalyl chloride, followed by addition of a source of NH3 e.g. aqueous NH3.
Step 4: Amides (Vb) may be converted to nitriles (lib) using known methods, for example TFAA in pyridine.
Scheme 4: of formula (I) from of formula
Figure imgf000019_0002
Nitriles of formula (II) may be converted to the compounds of formula (I) by reacting the nitrile portion of (II) with an azide source (such as TMSN3 or NaN3) to produce tetrazoles of formula (I).
There is provided a compound of formula (II):
Figure imgf000020_0001
wherein
Figure imgf000020_0002
are as defined for the compound of formula (I); or a salt and/or solvate thereof. There is also provided a compound of formula (V):
Figure imgf000020_0003
wherein
Figure imgf000020_0004
are as defined for the compound of formula (I); or a salt and/or solvate thereof. There is also provided a compound of formula (VI):
Figure imgf000020_0005
wherein
Figure imgf000020_0006
are as defined for the compound of formula (I); or a salt and/or solvate thereof. There is also provided a compound of formula (VII):
Figure imgf000020_0007
wherein
Figure imgf000021_0001
are as defined for the compound of formula (I), and PG is a protecting group such as C1.4 alkyl e.g. tBu or Me; or a salt and/or solvate thereof.
It will be appreciated that for use in therapy the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include acid addition salts, suitably salts of compounds of the invention comprising a basic group such as an amino group, formed with inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid. Also included are salts formed with organic acids, e.g., succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid and 1 ,5-naphthalenedisulfonic acid. Other salts, e.g., oxalates or formates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention, as are basic addition salts such as sodium, potassium, calcium, aluminium, zinc, magnesium and other metal salts.
Pharmaceutically acceptable salts may also be formed with organic bases such as basic amines, e.g., with ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine or lysine. Thus, in one embodiment there is provided a compound of formula (I) in the form of a pharmaceutically acceptable salt. Alternatively, there is provided a compound of formula (I) in the form of a free acid. When the compound contains a basic group as well as the free acid it may be Zwitterionic.
Suitably, the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is the compound of formula (I).
Suitably, the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is a salt of the compound of formula (I).
Suitably, the compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof is a pharmaceutically acceptable salt of the compound of formula (I).
Suitably, where the compound of formula (I) is in the form of a salt, the pharmaceutically acceptable salt is a basic addition salt such as a carboxylate salt formed with a group 1 metal (e.g., a sodium or potassium salt), a group 2 metal (e.g., a magnesium or calcium salt) or an ammonium salt of a basic amine (e.g., an NH4 + salt), such as a sodium salt.
The compounds of formula (I) may be prepared in crystalline or non-crystalline form and, if crystalline, may optionally be solvated, e.g., as the hydrate. This invention includes within its scope stoichiometric solvates (e.g., hydrates) as well as compounds containing variable amounts of solvent (e.g., water). Suitably, the compound of formula (I) is not a solvate.
The invention extends to a pharmaceutically acceptable derivative thereof, such as a pharmaceutically acceptable prodrug of compounds of formula (I). Typical prodrugs of compounds of formula (I) which comprise a carboxylic acid include ester (e.g. CI-B alkyl e.g. Ci-4 alkyl ester) derivatives thereof. Thus, in one embodiment, the compound of formula (I) is provided as a pharmaceutically acceptable prodrug. In another embodiment, the compound of formula (I) is not provided as a pharmaceutically acceptable prodrug.
It is to be understood that the present invention encompasses all isomers of compounds of formula (I) including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). In particular, the invention extends to all tautomeric forms of the compounds of formula (I). Where additional chiral centres are present in compounds of formula (I), the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
The present invention also includes all isotopic forms of the compounds provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exists as a mixture of mass numbers. The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form"). The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.
An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (2H or D), carbon-11 (11C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (15O), oxygen-17 (17O), oxygen-18 (18O), phosphorus-32 (32P), sulphur-35 (35S), chlorine-36 (36CI), chlorine-37 (37CI), fluorine-18 (18F) iodine-123 (123l), iodine-125 (125l) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.
Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon- 14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium i.e. 2H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as 11C, 18F, 15O and 13N, and would be useful in positron emission topography (PET) studies for examining substrate receptor occupancy.
In one embodiment, the compounds of formula (I) are provided in a natural isotopic form. In one embodiment, the compounds of formula (I) are provided in an unnatural variant isotopic form. In a specific embodiment, the unnatural variant isotopic form is a form in which deuterium (i.e. 2H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of formula (I). In one embodiment, the atoms of the compounds of formula (I) are in an isotopic form which is not radioactive. In one embodiment, one or more atoms of the compounds of formula (I) are in an isotopic form which is radioactive. Suitably radioactive isotopes are stable isotopes. Suitably the unnatural variant isotopic form is a pharmaceutically acceptable form.
In one embodiment, a compound of formula (I) is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of formula (I) is provided whereby two or more atoms exist in an unnatural variant isotopic form.
Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the Examples. Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the purer forms used in the pharmaceutical compositions.
Therapeutic indications
Compounds of formula (I) are of use in therapy, particularly for treating or preventing an inflammatory disease or a disease associated with an undesirable immune response. As shown in Biological Example 1 below, example compounds of formula (I) reduced cytokine release more effectively than 4-octyl itaconate, 2-(2-chlorobenzyl)acrylic acid and monomethyl fumarate in IL- 1P and/or IL-6, as demonstrated by lower IC50 values. Example 3 exhibited improved cytokinelowering potencies compared to Reference Example 1 in IL-113. Example 4 exhibited improved cytokine-lowering potencies compared to Reference Example 2 in IL-6. Cytokines are important mediators of inflammation and immune-mediated disease as evidenced by the therapeutic benefit delivered by antibodies targeting them. As shown in Biological Example 2 below, certain example compounds of formula (I) showed improved activity in this assay compared to 2-(2- chlorobenzyl)acrylic acid, as demonstrated by their lower EC50 and/or higher Emax values for NRF2 activation. Thus, the compounds may be expected to have utility in the treatment of diseases wherein such activity may be beneficial (such as multiple sclerosis, psoriasis and chronic obstructive pulmonary disease: Cuadrado et al., Nat. Rev. Drug Discov. 2019, 18, 295-317). As shown in Biological Example 3 below, certain example compounds of formula (I) showed improved metabolic stabilities compared to 4-octyl itaconate in both human and mouse species. Certain compounds showed improved metabolic stabilities compared to Reference Example compounds.
Thus, in a further aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein, for use as a medicament.
Also provided is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein. Thus, in a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein, for use as a medicament.
In a further aspect, the present invention provides a compound of formula (I) ora pharmaceutically acceptable salt and/or solvate thereof as defined herein, for use in treating or preventing an inflammatory disease or a disease associated with an undesirable immune response.
In a further aspect, the present invention provides a pharmaceutical composition as defined herein, for use in treating or preventing an inflammatory disease or a disease associated with an undesirable immune response.
In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein, in the manufacture of a medicament for treating or preventing an inflammatory disease or a disease associated with an undesirable immune response.
In a further aspect, the present invention provides the use of a pharmaceutical composition as defined herein, in the manufacture of a medicament for treating or preventing an inflammatory disease or a disease associated with an undesirable immune response.
In a further aspect, the present invention provides a method of treating or preventing an inflammatory disease or a disease associated with an undesirable immune response, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein.
In a further aspect, the present invention provides a method of treating or preventing an inflammatory disease or a disease associated with an undesirable immune response, which comprises administering a pharmaceutical composition as defined herein.
For all aspects of the invention, suitably the compound is administered to a subject in need thereof, wherein the subject is suitably a human subject.
In one embodiment is provided a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein, for use in treating an inflammatory disease or disease associated with an undesirable immune response. In one embodiment of the invention is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein, in the manufacture of a medicament for treating an inflammatory disease or a disease associated with an undesirable immune response. In one embodiment of the invention is provided a method of treating an inflammatory disease or a disease associated with an undesirable immune response, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein.
In one embodiment is provided a pharmaceutical composition as defined herein, for use in treating an inflammatory disease or disease associated with an undesirable immune response. In one embodiment of the invention is provided the use of a pharmaceutical composition as defined herein, in the manufacture of a medicament for treating an inflammatory disease or a disease associated with an undesirable immune response. In one embodiment of the invention is provided a method of treating an inflammatory disease or a disease associated with an undesirable immune response, which comprises administering a pharmaceutical composition as defined herein.
In one embodiment is provided a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein, for use in preventing an inflammatory disease or a disease associated with an undesirable immune response. In one embodiment of the invention is provided the use of a compound of formula (I) ora pharmaceutically acceptable salt and/or solvate thereof as defined herein, in the manufacture of a medicament for preventing an inflammatory disease or a disease associated with an undesirable immune response. In one embodiment of the invention is provided a method of preventing an inflammatory disease or a disease associated with an undesirable immune response, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein.
In one embodiment is provided a pharmaceutical composition as defined herein, for use in preventing an inflammatory disease or a disease associated with an undesirable immune response. In one embodiment of the invention is provided the use of a pharmaceutical composition as defined herein, in the manufacture of a medicament for preventing an inflammatory disease or a disease associated with an undesirable immune response. In one embodiment of the invention is provided a method of preventing an inflammatory disease or a disease associated with an undesirable immune response, which comprises administering a pharmaceutical composition as defined herein.
In one embodiment is provided a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein, or a pharmaceutical composition as defined herein, for use in treating or preventing an inflammatory disease. In one embodiment of the invention is provided the use of a compound of formula (I) ora pharmaceutically acceptable salt and/or solvate thereof as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for treating or preventing an inflammatory disease. In one embodiment of the invention is provided a method of treating or preventing an inflammatory disease, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
In one embodiment is provided a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein, or a pharmaceutical composition as defined herein, for use in treating or preventing a disease associated with an undesirable immune response. In one embodiment of the invention is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein, or a pharmaceutical composition as defined herein, in the manufacture of a medicament for treating or preventing a disease associated with an undesirable immune response. In one embodiment of the invention is provided a method of treating or preventing a disease associated with an undesirable immune response, which comprises administering a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein, or a pharmaceutical composition as defined herein.
An undesirable immune response will typically be an immune response which gives rise to a pathology i.e. is a pathological immune response or reaction.
In one embodiment, the inflammatory disease or disease associated with an undesirable immune response is an auto-immune disease.
In one embodiment, the inflammatory disease or disease associated with an undesirable immune response is, or is associated with, 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, nonalcoholic 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, Dressier’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, CLI PPERS (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, Behget'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 (Cl DP), 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, lgG4- 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), familial Mediterranean fever (FMF), tumour necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS), hyperimmunoglobulinaemia D with periodic fever syndrome (HI DS), 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-Goutieres 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), and renal inflammatory disorders (e.g. diabetic nephropathy, membranous nephropathy, minimal change disease, crescentic glomerulonephritis, acute kidney injury, renal transplantation).
In one embodiment, the inflammatory disease or disease associated with an undesirable immune response is, or is associated with, a disease selected from the following autoinflammatory diseases: familial 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, and 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, and 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-Goutieres 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) and Schnitzler syndrome.
In one embodiment, the inflammatory disease or disease associated with an undesirable immune response is, or is associated with, a disease selected from the following diseases mediated by excess NF-KB or gain of function in the NF-KB signalling pathway or in which there is a major contribution to the abnormal pathogenesis therefrom (including non-canonical NF-KB signalling): 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), asthma, COPD, type 1 diabetes mellitus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease (including ulcerative colitis and Crohn’s disease), and SLE.
In another embodiment, the disease is selected from the group consisting of spondyloarthrpathies, polymyalgia rheumatica and erosive osteoarthritis of the hands.
In one embodiment, the disease is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, psoriasis, Crohn’s disease, ulcerative colitis, uveitis, cryopyrin-associated periodic syndromes, Muckle-Wells syndrome, juvenile idiopathic arthritis, chronic obstructive pulmonary disease and asthma.
The link between certain diseases listed herein and targeting IL-1 beta, IL-6 or NRF2 is known from the literature as described below inter alia. Thus, compounds of formula (I) (which compounds target IL-1 beta, IL-6 and/or NRF2 as shown in the Biological Example section) are expected to have utility in the treatment of such diseases.
In particular, the literature provides support for targeting IL-1beta, IL-6 and/or NRF2 and treating at least rheumatoid arthritis (Giacomelli et al. 2016); psoriatic arthritis (Al-Hwas et al., 2022); systemic lupus erythematosus (Sung et al. 2020); multiple sclerosis (Mendiola et al. 2018); psoriasis (Tsuji et al. 2020); Crohn’s disease (Piotrowska et al. 2021); ulcerative colitis (Liso et al. 2022); juvenile idiopathic arthritis (Toplak et al. 2018); uveitis (Fabiani et al. 2017); spondyloarthropathies (Keller et al. 2003); ankylosing spondylitis (Ferrandiz et al. 2018); polymyalgia rheumatica (Weyand et al. 1994); erosive osteoarthritis of the hands (Fioravanti et al. 2019); Lupus nephritis (Italiani et al. 2018); Parkinson's disease (Karpenko et al. 2018); inflammatory bowel disease (Friedrich et al. 2021); celiac disease (Nasserinejad et al., 2019); dermatomyositis (Authier et al. 1997); hidradenitis suppurativa (Witte-Handel et al. 2019); Sjogren's syndrome (Bardsen et al. 2019); giant cell arteritis (temporal arteritis) (Ly et al. 2014); systemic juvenile idiopathic arthritis (Still’s disease) (Toplak et al. 2018); familial Mediterranean fever (F F) (Migita et al. 2015); tumour necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS) (Dandekar et al. 2015); hyperimmunoglobulinaemia D with periodic fever syndrome (HI DS) (Kaneko et al. 2019); cryopyrin-associated periodic syndromes (CAPS) (Dhimolea 2011); Aicardi-Goutieres syndrome (Takanohashi et al. 2013); and spondyloenchondrodysplasia (Lindahl et al. 2022).
Thus in one embodiment, the disease is selected from the group consisting of rheumatoid arthritis; psoriatic arthritis; systemic lupus erythematosus; multiple sclerosis; psoriasis; Crohn’s disease; ulcerative colitis; juvenile idiopathic arthritis; uveitis; spondyloarthropathies; ankylosing spondylitis; temporal arteritis; polymyalgia rheumatica; erosive osteoarthritis of the hands; Lupus nephritis; Parkinson's disease; inflammatory bowel disease; celiac disease; dermatomyositis; hidradenitis suppurativa; Sjogren's syndrome; giant cell arteritis (temporal arteritis); systemic juvenile idiopathic arthritis (Still’s disease); familial Mediterranean fever (FMF); tumour necrosis factor (TNF) receptor-associated periodic fever syndrome (TRAPS); hyperimmunoglobulinaemia D with periodic fever syndrome (HI DS); cryopyrin-associated periodic syndromes (CAPS); Aicardi-Goutieres syndrome; and spondyloenchondrodysplasia.
In one embodiment, the disease is multiple sclerosis. In one embodiment, the disease is psoriasis. In one embodiment, the disease is asthma. In one embodiment, the disease is chronic obstructive pulmonary disease. In one embodiment, the disease is systemic lupus erythematosus. In one embodiment, the disease is rheumatoid arthritis. In one embodiment, the disease is psoriatic arthritis. In one embodiment, the disease is Parkinson’s disease. In one embodiment, the disease is Crohn’s disease. In one embodiment, the disease is ulcerative colitis. In one embodiment, the disease is juvenile idiopathic arthritis. In one embodiment, the disease is uveitis. In one embodiment, the disease is spondyloarthropathies. In one embodiment, the disease is ankylosing spondylitis. In one embodiment, the disease is temporal arteritis. In one embodiment, the disease is polymyalgia rheumatica. In one embodiment, the disease is erosive osteoarthritis of the hands. In one embodiment, the disease is Lupus nephritis. In one embodiment, the disease is inflammatory bowel disease. In one embodiment, the disease is celiac disease. In one embodiment, the disease is dermatomyositis. In one embodiment, the disease is hidradenitis suppurativa. Administration
The compound of formula (I) is usually administered as a pharmaceutical composition. Thus, in one embodiment, is provided a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable diluents or carriers. Also provided is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and/or solvate thereof as defined herein.
The compound of formula (I) may be administered by any convenient method, e.g. by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical compositions adapted accordingly.
The compound of formula (I) may be administered topically to the target organ e.g. topically to the eye, lung, nose or skin. Hence the invention provides a pharmaceutical composition comprising a compound of formula (I) optionally in combination with one or more topically acceptable diluents or carriers.
A compound of formula (I) which is active when given orally can be formulated as a liquid or solid, e.g. as a syrup, suspension, emulsion, tablet, capsule or lozenge.
A liquid formulation will generally consist of a suspension or solution of the compound of formula (I) in a suitable liquid carrier(s). Suitably the carrier is non-aqueous e.g. polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.
A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose.
A composition in the form of a capsule can be prepared using routine encapsulation procedures, e.g. pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatine capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), e.g. aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatine capsule.
Typical parenteral compositions consist of a solution or suspension of the compound of formula (I) in a sterile aqueous carrier or parenterally acceptable oil, e.g. polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the compound of formula (I) in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container which can take the form of a cartridge or refill for use with an atomising device. Alternatively, the sealed container may be a disposable dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas e.g. air, or an organic propellant such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). Aerosol dosage forms can also take the form of pump-atomisers.
Topical administration to the lung may be achieved by use of an aerosol formulation. Aerosol formulations typically comprise the active ingredient suspended or dissolved in a suitable aerosol propellant, such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC).
Topical administration to the lung may also be achieved by use of a non-pressurised formulation such as an aqueous solution or suspension. These may be administered by means of a nebuliser e.g. one that can be hand-held and portable or for home or hospital use (i.e. non-portable). The formulation may comprise excipients such as water, buffers, tonicity adjusting agents, pH adjusting agents, surfactants and co-solvents.
Topical administration to the lung may also be achieved by use of a dry-powder formulation. The formulation will typically contain a topically acceptable diluent such as lactose, glucose or mannitol (preferably lactose).
The compound of the invention may also be administered rectally, for example in the form of suppositories or enemas, which include aqueous or oily solutions as well as suspensions and emulsions and foams. Such compositions are prepared following standard procedures, well known by those skilled in the art. For example, suppositories can be prepared by mixing the active ingredient with a conventional suppository base such as cocoa butter or other glycerides. In this case, the drug is mixed with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. Generally, for compositions intended to be administered topically to the eye in the form of eye drops or eye ointments, the total amount of the compound of the present invention will be about 0.0001 to less than 4.0% (w/w).
Preferably, for topical ocular administration, the compositions administered according to the present invention will be formulated as solutions, suspensions, emulsions and other dosage forms.
The compositions administered according to the present invention may also include various other ingredients, including, but not limited to, tonicity agents, buffers, surfactants, stabilizing polymer, preservatives, co-solvents and viscosity building agents. Suitable pharmaceutical compositions of the present invention include a compound of the invention formulated with a tonicity agent and a buffer. The pharmaceutical compositions of the present invention may further optionally include a surfactant and/or a palliative agent and/or a stabilizing polymer.
Various tonicity agents may be employed to adjust the tonicity of the composition, preferably to that of natural tears for ophthalmic compositions. For example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, simple sugars such as dextrose, fructose, galactose, and/or simply polyols such as the sugar alcohols mannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, and hydrogenated starch hydrolysates may be added to the composition to approximate physiological tonicity. Such an amount of tonicity agent will vary, depending on the particular agent to be added. In general, however, the compositions will have a tonicity agent in an amount sufficient to cause the final composition to have an ophthalmically acceptable osmolality (generally about 150-450 mOsm, preferably 250-350 mOsm and most preferably at approximately 290 mOsm). In general, the tonicity agents of the invention will be present in the range of 2 to 4% w/w. Preferred tonicity agents of the invention include the simple sugars or the sugar alcohols, such as D-mannitol.
An appropriate buffer system (e.g. sodium phosphate, sodium acetate, sodium citrate, sodium borate or boric acid) may be added to the compositions to prevent pH drift under storage conditions. The particular concentration will vary, depending on the agent employed. Preferably however, the buffer will be chosen to maintain a target pH within the range of pH 5 to 8, and more preferably to a target pH of pH 5 to 7.
Surfactants may optionally be employed to deliver higher concentrations of compound of the present invention. The surfactants function to solubilise the compound and stabilise colloid dispersion, such as micellar solution, microemulsion, emulsion and suspension. Examples of surfactants which may optionally be used include polysorbate, poloxamer, polyosyl 40 stearate, polyoxyl castor oil, tyloxapol, Triton, and sorbitan monolaurate. Preferred surfactants to be employed in the invention have a hydrophile/lipophile/balance "HLB" in the range of 12.4 to 13.2 and are acceptable for ophthalmic use, such as TritonX114 and tyloxapol.
Additional agents that may be added to the ophthalmic compositions of compounds of the present invention are demulcents which function as a stabilising polymer. The stabilizing polymer should be an ionic/charged example with precedence for topical ocular use, more specifically, a polymer that carries negative charge on its surface that can exhibit a zeta-potential of (-)10-50 mV for physical stability and capable of making a dispersion in water (i.e. water soluble). A preferred stabilising polymer of the invention would be polyelectrolyte, or polyelectrolytes if more than one, from the family of cross-linked polyacrylates, such as carbomers and Pemulen(R), specifically Carbomer 974p (polyacrylic acid), at 0.1 -0.5% w/w.
Other compounds may also be added to the ophthalmic compositions of the compound of the present invention to increase the viscosity of the carrier. Examples of viscosity enhancing agents include, but are not limited to: polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextrans, various polymers of the cellulose family; vinyl polymers; and acrylic acid polymers.
Topical ophthalmic products are typically packaged in multidose form. Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben, phenylethyl alcohol, edentate disodium, sorbic acid, polyquaternium-1 , or other agents known to those skilled in the art. Such preservatives are typically employed at a level of from 0.001 to 1.0% w/v. Unit dose compositions of the present invention will be sterile, but typically unpreserved. Such compositions, therefore, generally will not contain preservatives.
Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles where the compound of formula (I) is formulated with a carrier such as sugar and acacia, tragacanth, or gelatine and glycerine.
Compositions suitable for transdermal administration include ointments, gels and patches.
The composition may contain from 0.1% to 100% by weight, for example from 10 to 60% by weight, of the compound of formula (I), depending on the method of administration. The composition may contain from 0% to 99% by weight, for example 40% to 90% by weight, of the carrier, depending on the method of administration. The composition may contain from 0.05mg to 1000mg, for example from 1.0 mg to 500 mg, such as from 1.0 mg to 50 mg, e.g. about 10 mg of the compound of formula (I), depending on the method of administration. The composition may contain from 50 mg to 1000 mg, for example from 100mg to 400mg of the carrier, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 500mg, such as from 1.0 mg to 50 mg, e.g. about 10 mg and such unit doses may be administered more than once a day, for example two or three times a day. Such therapy may extend for a number of weeks or months.
In one embodiment of the invention, the compound of formula (I) is used in combination with a further therapeutic agent or agents. When the compound of formula (I) is used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route. Alternatively, the compounds may be administered separately.
Therapeutic agents which may be used in combination with the present invention include: corticosteroids (glucocorticoids), retinoids (e.g. acitretin, isotretinoin, tazarotene), anthralin, vitamin D analogues (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, thiopurines (e.g. azathioprine, 6- mercaptopurine), methotrexate, anti-TNFa agents (e.g. infliximab, etanercept, adalimumab, certolizumab, golimumab and biosimilars), phosphodiesterase-4 (PDE4) inhibition (e.g. apremilast, crisaborole), anti-IL-17 agents (e.g. brodalumab, ixekizumab, secukinumab), anti- IL12/IL-23 agents (e.g. ustekinumab, briakinumab), anti-IL-23 agents (e.g. guselkumab, tildrakizumab), JAK (Janus Kinase) inhibitors (e.g. tofacitinib, ruxolitinib, baricitinib, filgotinib, upadacitinib), plasma exchange, intravenous immune globulin (MG), cyclophosphamide, anti- CD20 B cell depleting agents (e.g. rituximab, ocrelizumab, ofatumumab, obinutuzumab), anthracycline analogues (e.g. mitoxantrone), cladribine, sphingosine 1 -phosphate receptor modulators or sphingosine analogues (e.g. fingolimod, siponimod, ozanimod, etrasimod), interferon beta preparations (including interferon beta 1 b/1 a), glatiramer, anti-CD3 therapy (e.g. OKT3), anti-CD52 targeting agents (e.g. alemtuzumab), leflunomide, teriflunomide, gold compounds, laquinimod, potassium channel blockers (e.g. dalfampridine/4-aminopyridine), mycophenolic acid, mycophenolate mofetil, purine analogues (e.g. pentostatin), mTOR (mechanistic target of rapamycin) pathway inhibitors (e.g. sirolimus, everolimus), anti-thymocyte globulin (ATG), IL-2 receptor (CD25) inhibitors (e.g. basiliximab, daclizumab), anti-IL-6 receptor or anti-IL-6 agents (e.g. tocilizumab, siltuximab), Bruton’s tyrosine kinase (BTK) inhibitors (e.g. ibrutinib), tyrosine kinase inhibitors (e.g. imatinib), ursodeoxycholic acid, hydroxychloroquine, chloroquine, B cell activating factor (BAFF, also known as BLyS, B lymphocyte stimulator) inhibitors (e.g. belimumab, blisibimod), other B cell targeted therapy including fusion proteins targeting both APRIL (A PRoliferation-lnducing Ligand) and BLyS (e.g. atacicept), PI3K inhibitors including pan-inhibitors or those targeting the p110b and/or p110y containing isoforms (e.g. idelalisib, copanlisib, duvelisib), interferon a receptor inhibitors (e.g. anifrolumab, sifalimumab), T cell co-stimulation blockers (e.g. abatacept, belatacept), thalidomide and its derivatives (e.g. lenalidomide), dapsone, clofazimine, leukotriene antagonists (e.g. montelukast), theophylline, anti-lgE therapy (e.g. omalizumab), anti-IL-5 agents (e.g. mepolizumab, reslizumab), long-acting muscarinic agents (e.g. tiotropium, aclidinium, umeclidinium), PDE4 inhibitors (e.g. roflumilast), riluzole, free radical scavengers (e.g. edaravone), proteasome inhibitors (e.g. bortezomib), complement cascade inhibitors including those directed against C5 (e.g. eculizumab), immunoadsor, antithymocyte globulin, 5-aminosalicylates and their derivatives (e.g. sulfasalazine, balsalazide, mesalamine), anti-integrin agents including those targeting a4[31 and/or a4[37 integrins (e.g. natalizumab, vedolizumab), anti-CD11-a agents (e.g. efalizumab), non-steroidal anti-inflammatory drugs (NSAIDs) including the salicylates (e.g. aspirin), propionic acids (e.g. ibuprofen, naproxen), acetic acids (e.g. indomethacin, diclofenac, etodolac), oxicams (e.g. meloxicam) and fenamates (e.g. mefenamic acid), selective or relatively selective COX-2 inhibitors (e.g. celecoxib, etroxicoxib, valdecoxib and etodolac, meloxicam, nabumetone), colchicine, IL-4 receptor inhibitors (e.g. dupilumab), topical/contact immunotherapy (e.g. diphenylcyclopropenone, squaric acid dibutyl ester), anti-IL-1 receptor therapy (e.g. anakinra), IL- ip inhibitor (e.g. canakinumab), IL-1 neutralising therapy (e.g. rilonacept), chlorambucil, specific antibiotics 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, cystic fibrosis transmembrane conductance regulator (CFTR) modulators, VEGF (vascular endothelial growth factor) inhibitors (e.g. bevacizumab, ranibizumab, pegaptanib, aflibercept), pirfenidone, or mizoribine.
Compounds of formula (I) may display, or may be expected to have, one or more of the following desirable properties:
• low IC50 values for inhibiting release of cytokines, e.g., IL-1 p and/or IL-6, from cells;
• low EC50 and/or high Emax values for activating the NRF2 pathway;
• high EC50 and/or low Emax values for activating the N F2 pathway;
• enhanced efficacy through improved hydrolytic stability;
• reduced dose and dosing frequency through improved pharmacokinetics; • improved oral systemic bioavailability;
• reduced plasma clearance following intravenous dosing;
• improved metabolic stability, e.g., as demonstrated by improved stability hepatocytes;
• augmented cell permeability;
• enhanced aqueous solubility;
• good tolerability, for example, by limiting the flushing and/or gastrointestinal side effects provoked by oral DMF (Hunt T. et al., 2015; WO2014/152494A1, incorporated herein by reference), possibly by reducing or eliminating HCA2 activity;
• low toxicity at the relevant therapeutic dose;
• distinct anti-inflammatory profiles resulting from varied electrophilicities, leading to differential targeting of the cysteine proteome (van der Reest J. et al., 2018) and, therefore, modified effects on gene activation;
• insensitivity of biological effects to added glutathione; and/or
• avoiding the oncometabolite fumaric acid (Kulkarni R. A. et al., 2019).
Abbreviations
°C degrees centigrade
Ac acetyl app apparent aq. aqueous br broad singlet
BBFO broadband fluorine observe
BEH ethylene bridged hybrid ca. circa cone. concentrated
CSH charged surface hybrid d doublet
DAD diode array detector
DCC N,N’-dicyclohexylcarbodiimide
DCM dichloromethane
DMA N,N-dimethylacetamide
DIPEA N,N-diisopropylethylamine
DMAP 4-dimethylaminopyridine
DMF dimethyl fumarate
DMSO dimethyl sulfoxide
DMSO-d6 deuterated dimethyl sulfoxide DIPEA N,N-diisopropylethylamine
EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
Et ethyl
EtOAc ethyl acetate
EtOH ethanol
ES+ electrospray
FBS fetal bovine serum g gram(s)
GSH glutathione h hour(s)
HATU 1-[bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
HPLC high-perfomance liquid chromatography
IL interleukin
I PA isopropyl alcohol
IV intravenous
LDA lithium diisopropylamide
LCMS liquid chromatography-mass spectrometry m multiplet
M molar concentration / molar mass m/z mass to charge ratio
MeOH methanol
MHz (mega)hertz min(s) minute(s) mL millilitres mmol millimole
MS mass spectrometry
MTBE methyl tertiary-butyl ether n-BuLi n-butyl lithium
NMM 4-methylmorpholine
NMR nuclear magnetic resonance
NMP N-methyl-2-pyrrolidone p quintet
PBS phosphate buffered saline
PDA photodiode array
P B para-methoxybenzyl q quartet rpm revolutions per minute
RT room temperature s singlet sat. saturated t triplet
T3P propylphosphonic anhydride
TBTU 2-(1 H-benzotriazole-1-yl)-1 ,1 ,3,3-tetramethylaminium tetrafluoroborate
TMSN3 trimethylsilyl azide
Tf trifluoromethanesulfonyl, i.e., CF3SO2-
TFA trifluoroacetic acid
TFAA trifluoroacetic anhydride
THF tetrahydrofuran pL microlitre pM micromolar
UPLC ultra performance liquid chromatography wt weight
EXAMPLES
Analytical Equipment
Thin layer chromatography (TLC) was performed on silica gel plates (GF254, glass, silica gel size: 400~600 mesh). Spots were visualized by UV light (214 and 254 nm) or color reagents (iodine, KMnC aq.).
Bruker 400 MHz Avance III spectrometer fitted with a BBFO 5 mm probe, or a Bruker 500 MHz Avance III HD spectrometer equipped with a Bruker 5 mm SmartProbeTM. 1H chemical shifts are reported in 6 values in ppm with the deuterated solvent as the internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constant (Hz), integration. STX-P3373PCT Application as filed
Figure imgf000042_0001
STX-P3373PCT Application as filed
Figure imgf000043_0001
Commercial Materials
All starting materials are commercially available unless otherwise stated.
Synthesis of Intermediates
Intermediate 1: 3-cyanobut-3-enoic acid
(COCI)2,NH3 (aq) N,N-dimethylformamide, DCM
Figure imgf000044_0001
TFAA, TEA, DCM LiOH, THF/H2O
Step 2 Step 3
Figure imgf000044_0002
Figure imgf000044_0003
Step 1
To a solution of 4-methoxy-2-methylene-4-oxobutanoic acid (1.00 g, 6.94 mmol) and N,N- dimethylformamide (0.1 ml_, cat.) in DCM (20 mL) was added oxalyl chloride (1.06 g, 8.33 mmol) in portions at 0 °C. The reaction mixture was stirred at room temperature for 2 h. Then the mixture was concentrated at 35 °C under reduced pressure to give the crude acyl chloride. The crude acyl chloride was re-dissolved in DCM (10 mL) and added to a solution of NH4OH (244 mg, 8.33 mmol, 25 wt% aqueous solution) in DCM (10 mL) and the reaction mixture was stirred at room temperature for 1 h. After such time the mixture was quenched with water (10 mL) and the layers separated. The aqueous layer was further extracted with DCM (3x10 mL). The combined organics were washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was concentrated at 35 °C under reduced pressure. The crude product was purified by chromatography on silica gel (0-12% MeOH/DCM) to give methyl 3-carbamoylbut-3-enoate (680 mg, 68% yield) as a white solid. LCMS: (System 2, Method C) m/z 144.2 [M+H]+ (ES+).
Step 2
To a solution of methyl 3-carbamoylbut-3-enoate (680 mg, 4.19 mmol) and triethylamine (1.27 g, 12.57 mmol) in DCM (10 mL) was added TFAA (1.76 g, 8.38 mmol) at 0 °C. The reaction was warmed to RT and stirred for 1 h then quenched with water (3 mL). The layers were separated, and the aqueous layer was further extracted with DCM (2x3 mL). The combined organics were washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated 20 °C under reduced pressure, and the crude product was purified by chromatography on silica gel (0- 6% MTBE/ petroleum ether) to give methyl 3-cyanobut-3-enoate (300 mg, 57% yield) as a colourless oil, which is volatile. 1H NMR (400 MHz, CDCI3) 6: 6.07 (s, 1 H), 5.91 (s, 1 H), 3.77 (s, 3H), 3.29 (s, 2H).
Step 3
To a solution of methyl 3-cyanobut-3-enoate (300 mg, 2.40 mmol) in THF (2 mL) was added aqueous LiOH (2M, 1.8 mL, 3.60 mmol), and the reaction mixture was stirred at RT for 1 h. The reaction mixture was then acidified with aqueous HCI (0.5 M) until pH ~ 3, and extracted with EtOAc (3x5 mL). The combined organics were washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated 20 °C under reduced pressure to give 3-cyanobut-3-enoic acid (200 mg, 75% yield) as a colourless oil, which is volatile. 1H NMR (400 MHz, CDCh) 5: 6.10 (s, 1H), 5.94 (s, 1 H), 3.34 (s, 2H).
Intermediate 2: (S,E)-3-cyano-N-(1 -(4-(trifluoromethyl)phenyl)ethyl)but-2-enarnide
(COCI)2, N,N-dimethylformamide,
Figure imgf000045_0001
Step 1
To a solution of 4-methoxy-2-methylene-4-oxobutanoic acid (1.40 g, 9.71 mmol) and N,N- dimethylformamide (0.1 mL, cat.) in DCM (20 mL) was added oxalyl chloride (1.85 g, 14.56 mmol) in portions at 0 °C The reaction mixture was stirred at RT for 16 h. Then the mixture was concentrated at 35 °C under reduced pressure to give the crude acyl chloride. The crude acyl chloride was re-dissolved in DCM (20 mL) and to this solution was added NH4OH (990 mg, 14.56 mmol, 25 wt% aqueous solution) at 0 °C. The reaction mixture was stirred at RT for 1 h. After such time the mixture was concentrated at 35 °C under reduced pressure and the crude product was purified by chromatography on silica gel (0-12% MeOH/DCM) to give methyl (E)-4-amino-3- methyl-4-oxobut-2-enoate (1.00 g, 72% yield) as a pale solid. LCMS: (System 2, Method C) m/z
144.4 [M+H] (ES+). Step 2
To a solution of methyl (E)-4-amino-3-methyl-4-oxobut-2-enoate (1.00 g, 6.99 mmol) and triethylamine (1.42 g, 13.98 mmol) in DCM (10 mL) was added TFAA (2.20 g, 10.48 mmol) at 0 °C. The reaction was warmed to RT and stirred for 1 h then quenched with water (5 mL). The mixture was extracted with diethyl ether (2x10 mL) and the combined organic layers were washed with brine (20 mL), dried over Na2SC>4 and filtered. The filtrate was concentrated at 15 °C under reduced pressure, and the crude product was purified by chromatography on silica gel (0-3% MTBE/ petroleum ether) to give methyl (E)-3-cyanobut-2-enoate (300 mg, 34%) as a colourless oil, which is volatile. LCMS: (System 2, Method C) m/z 126.3 [M+H]+ (ES+).
Step 3
To a solution of methyl (E)-3-cyanobut-2-enoate (300 mg, 2.40 mmol) in THF (6 mL) was added aqueous LiOH (2M, 2.4 mL, 4.80 mmol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was then acidified with aqueous HCI (2M) until pH ~ 5, and the mixture was extracted with MTBE (3x5 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SC>4 and filtered. The filtrate was concentrated at 20 °C under reduced pressure to give (E)-3-cyanobut-2-enoic acid (150 mg, 56% yield) as a colourless oil, which is volatile.
Step 4
A mixture of (E)-3-cyanobut-2-enoic acid (150 mg, 1.35 mmol) (S)-1-(4- (trifluoromethyl)phenyl)ethan-1-amine (204 mg, 1.08 mmol), DCC (417 mg, 3.02 mmol) and □MAP (16 mg, 0.13 mmol) in DCM (5 mL) was stirred at RT for 3 h. The mixture was filtered, and the filtrate was concentrated at 35 °C under reduced pressure. The crude product was purified by chromatography on silica gel (10-30% MTBE/petroleum ether) to give (S,E)-3-cyano-N-(1-(4- (trifluoromethyl)phenyl)ethyl)but-2-enamide (150 mg, 40% yield) as a white solid. LCMS: (System 2, Method C) m/z 283.2 [M+H]+ (ES+)
Intermediate 3: 4-(tert-butoxy)-3-(diethoxyphosphoryl)-4-oxobutanoic acid
Figure imgf000046_0001
Sodium hydride (60 wt% dispersion in mineral oil, 9.0 g, 225 mmol) was added portionwise to a solution of tert-butyl 2-(diethoxyphosphoryl)acetate (50 mL, 213 mmol) in THF (500 mL) at 0 °C. The mixture was stirred for 15 min before ethyl bromoacetate (23 mL, 210 mmol) was added dropwise. The mixture was stirred for 1 h then quenched with sat. aq. NH4CI (100 mL) and extracted with EtOAc (3x100 mL). The combined organic phases were washed with brine (300 mL), dried (MgSO4) and concentrated to afford 1 -(tert-butyl) 4-ethyl 2- (diethoxyphosphoryl)succinate (77.1 g, 182 mmol, 80% purity) as a colourless oil. LCMS (System 3, Method D) m/z 361.2 [M+Na]+ (ES+). 1H NMR (400 MHz, DMSO-d6) 6 4.13 - 4.01 (m, 6H), 3.28 (ddd, J = 23.8, 11.3, 3.9 Hz, 1H), 2.78 (ddd, J = 17.2, 11.3, 8.2 Hz, 1H), 2.64 (ddd, J = 17.1 ,
8.5, 4.0 Hz, 1 H), 1.40 (s, 9H), 1.28 - 1.21 (m, 6H), 1.18 (t, J = 7.1 Hz, 3H).
Step 2
An aqueous solution of sodium hydroxide (1 M, 250 mL, 250 mmol) was added to a solution of 1- (tert-butyl) 4-ethyl 2-(diethoxyphosphoryl)succinate (77.1 g, 182 mmol, 80% purity) in THF (250 mL). The mixture was stirred at RT for 16 h. The mixture was partially concentrated to ca. 250 mL, then extracted with EtOAc (3x100 mL). The aqueous phase was acidified to pH 1 with cone. HCI and extracted with EtOAc (3x100 mL). The combined organic phases were washed with brine (250 mL), dried (MgSO4) and concentrated. The residue was triturated with hexane (300 mL) and the resulting solid collected by filtration to afford 4-(tert-butoxy)-3-(diethoxyphosphoryl)-4- oxobutanoic acid (53.0 g, 0.15 mol, 90% purity) as a white solid. LCMS (System 3, Method D) m/z 333.2 [M+Na]+ (ES+). 1H NMR (400 MHz, DMSO-d6) 5 12.44 (s, 1 H), 4.11 - 3.99 (m, 4H), 3.22 (ddd, J = 23.7, 11.5, 3.7 Hz, 1H), 2.73 (ddd, J = 17.3, 11.5, 7.6 Hz, 1H), 2.56 (ddd, J = 17.3,
8.6, 3.7 Hz, 1 H), 1.40 (s, 9H), 1.25 (dt, J = 8.3, 7.0 Hz, 6H). 31P NMR (162 MHz, DMSO-d6) 0 21.88.
Intermediate 4: 2-((3-(4-butoxyphenyl)-1 ,2,4-oxadiazol-5-yl)methyl)acrylonitrile
Figure imgf000047_0001
Step 1
A solution of aqueous hydroxylamine (50% wt, 27.0 ml_, 441 mmol) was added to a solution of 4- butoxybenzonitrile (2.73 g, 15.6 mmol) in EtOH (25 mL). The mixture was stirred at 45 °C for 16 h. The mixture was concentrated, and the residue was co-evaporated with toluene (5x20 mL). The residue was triturated with MTBE/isohexane (ca. 1 :10, 50 mL) and the resulting solid was isolated by filtration to afford 4-butoxy-N-hydroxybenzimidamide (3.07 g, 14 mmol) as a white solid. LCMS (System 3, Method D) m/z 209.3 [M+H]+ (ES+). 1H NMR (400 MHz, DMSO-d6) 5 9.43 (s, 1 H), 7.62 - 7.54 (m, 2H), 6.94 - 6.86 (m, 2H), 5.70 (s, 2H), 3.98 (t, J = 6.5 Hz, 2H), 1.74 - 1.63 (m, 2H), 1.49 - 1.36 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H).
Step 2
T3P (50 wt% in EtOAc, 12.3 mL, 20.6 mmol) was added dropwise to a mixture of 4-butoxy-N- hydroxybenzimidamide (2.0 g, 8.26 mmol, 86 % purity), 4-(tert-butoxy)-3-(diethoxyphosphoryl)-4- oxobutanoic acid (Intermediate 3, 2.56 g, 8.26 mmol) and triethylamine (3.45 mL, 24.8 mmol) in EtOAc (15 mL). The mixture was stirred at RT for 10 min, then heated to 80 °C and stirred for 18 h. The mixture was cooled to RT and poured into water (100 mL). The phases were separated and the aqueous phase was extracted with EtOAc (3x50 mL). The combined organic phases were washed with aqueous HOI (1M, 100 mL), aqueous NaOH (2M, 100 mL), brine (100 mL), dried (MgSO4) and concentrated. The crude product was purified by chromatography on silica gel (0- 100% MTBE/isohexane) to afford tert-butyl 3-(3-(4-butoxyphenyl)-1 ,2,4-oxadiazol-5-yl)-2- (diethoxyphosphoryl)propanoate (2.81 g, 5.2 mmol, 90% purity) as a pale green oil. LCMS (System 3, Method D) m/z 483.4 [M+H]+ (ES+). 1H NMR (400 MHz, DMSO-d6) 6 7.94 - 7.84 (m, 2H), 7.14 - 7.05 (m, 2H), 4.16 - 3.99 (m, 6H), 3.65 (ddd, J = 23.3, 10.8, 4.6 Hz, 1 H), 3.43 (ddd, J = 16.8, 10.8, 9.6 Hz, 1 H), 3.36 - 3.27 (m, 1 H), 1.76 - 1.66 (m, 2H), 1.51 - 1.40 (m, 2H), 1.37 (s, 9H), 1.26 (q, J = 6.8 Hz, 6H), 0.94 (t, J = 7.4 Hz, 3H). 31P NMR (162 MHz, DMSO-d6) 520.28. Step 3
Paraformaldehyde (37 mg, 1.2 mmol) was added to a mixture of tert-butyl 3-(3-(4-butoxyphenyl)- 1 ,2,4-oxadiazol-5-yl)-2-(diethoxyphosphoryl)propanoate (0.70 g, 1.2 mmol, 86 % purity) and potassium carbonate (0.17 g, 1.2 mmol) in THF (20 mL). The mixture was heated to 65 °C and stirred for 2 h. The suspension was cooled to RT, adsorbed onto silica gel and purified by chromatography on silica gel (0-100% EtOAc/isohexane) to afford tert-butyl 2-((3-(4- butoxyphenyl)-1 ,2,4-oxadiazol-5-yl)methyl)acrylate (200 mg, 0.53 mmol) as a yellow oil. LCMS (System 3, Method D) m/z 303.1 [M-'Bu+H]+ (ES+). 1H NMR (400 MHz, DMSO) 5 7.93 - 7.87 (m, 2H), 7.12 - 7.06 (m, 2H), 6.28 (d, J = 1.2 Hz, 1 H), 5.96 (q, J = 1.3 Hz, 1 H), 4.05 (t, J = 6.5 Hz, 2H), 4.01 (s, 2H), 1.77 - 1.68 (m, 2H), 1.51 - 1.40 (m, 2H), 1.34 (s, 9H), 0.95 (t, J = 7.4 Hz, 3H). Step 4
To an ice-cooled solution of tert-butyl 2-((3-(4-butoxyphenyl)-1,2,4-oxadiazol-5-yl)methyl)acrylate (200 mg, 0.53 mmol) in DCM (10.0 mL) was added TFA (430 pL, 5.58 mmol). Stirring was continued at RT for 20 h. The solvent was removed under reduced pressure and the excess TFA was co-evaporated with toluene (2x10 ml_). The crude product was purified by chromatography on silica gel (0-100% EtOAc/isohexane) to afford 2-((3-(4-butoxyphenyl)-1 ,2,4-oxadiazol-5- yl)methyl)acrylic acid (95 mg, 0.31 mmol) as a white solid. LCMS (System 3, Method D) m/z 303.1 [M+H]+ (ES+ ). 1H NMR (400 MHz, DMSO-d6) 5 12.90 (s, 1 H), 7.96 - 7.84 (m, 2H), 7.12 - 7.04 (m, 2H), 6.31 (d, J = 1.3 Hz, 1 H), 5.97 (s, 1 H), 4.05 (t, J = 6.5 Hz, 2H), 4.00 (s, 2H), 1.78 - 1.68 (m, 2H), 1.51 - 1.40 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H).
Step 5
To a solution of 2-((3-(4-butoxyphenyl)-1 ,2,4-oxadiazol-5-yl)methyl)acrylic acid (1.9 g, 6.28 mmol) and /V,/V-dimethylformamide (48.7 pL, 628 pmol, cat.) in DCM (20 mL) was added oxalyl chloride (660 pL, 7.54 mmol) dropwise at 0 °C over 10 min. The reaction was then warmed to RT and stirred for 2 h. After such time the reaction mixture was concentrated under reduced pressure to give the crude acyl chloride. The crude acyl chloride was re-dissolved in DCM (10 mL) and added to a solution of ammonium hydroxide (1.07 mL, 7.54 mmol, 28% wt aqueous solution) in DCM (10 mL) dropwise at RT and further stirred at RT for 18 h. The reaction was quenched with water (30 mL) and the layers separated. The aqueous layer was further extracted with DCM (2x20 mL). The combined organic layers were washed with brine (40 mL), dried (MgSO4), filtered and the solvent removed under reduced pressure to give 2-((3-(4-butoxyphenyl)-1 ,2,4-oxadiazol-5- yl)methyl)acrylamide (1.56 g, 5.1 mmol) as a white solid. LCMS (System 3, Method D) m/z 302.3 [M+H]+ (ES+). 1H NMR (400 MHz, DMSO) 6 7.93 - 7.85 (m, 2H), 7.75 (s, 1 H), 7.16 (s, 1 H), 7.11 - 7.04 (m, 2H), 6.06 (s, 1 H), 5.75 - 5.69 (m, 1H), 4.04 (t, J = 6.5 Hz, 2H), 3.94 (s, 2H), 1.77 - 1.67 (m, 2H), 1.51 - 1.39 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H).
Step 6
To an ice cold, stirred solution of 2-((3-(4-butoxyphenyl)-1 ,2,4-oxadiazol-5-yl)methyl)acrylamide (1.57 g, 5.21 mmol) and pyridine (1.26 mL, 15.5 mmol) in THE (25.9 mL) was added TFAA (876 pL, 6.30 mmol) dropwise over 10 min. The reaction was stirred at 0 °C for 1 h then allowed to warm to RT and stirred for a further 20 min. The reaction was poured into water (50 mL) and extracted with EtOAc (3x20 mL). The combined organic layers were washed with aqueous HCI (1 M, 2x20 mL), sat. aqueous NaHCCh (20 mL), brine (20 mL), dried (MgSO4), filtered and the solvent removed under reduced pressure. The crude product was purified by chromatography on silica gel (0-50% EtOAc/isohexane) to afford 2-((3-(4-butoxyphenyl)-1 ,2,4-oxadiazol-5- yl)methyl)acrylonitrile (1.27 g, 3.7 mmol, 83% purity) as a light pink solid. LCMS (System 3, Method D) m/z 284.4 [M+H]+ (ES+). 1H NMR (400 MHz, DMSO-d6) 5 7.95 - 7.90 (m, 2H), 7.14 - 7.06 (m, 2H), 6.36 (s, 1 H), 6.33 (t, J = 1.3 Hz, 1 H), 4.22 (t, J = 1.1 Hz, 2H), 4.05 (t, J = 6.5 Hz, 2H), 1.77 - 1.66 (m, 2H), 1.50 - 1.38 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). Intermediate 5: (S)-3-cyano-N-(1 -(5-(trifluoromethyl)pyridin-2-yl)ethyl)but-3-enamide
Figure imgf000050_0001
Step 1
Titanium(IV) ethoxide (8.9 ml_, 43 mmol) was added to a mixture of 5- (trifluoromethyl)picolinaldehyde (5.0 g, 28.6 mmol) and (S)-2-methylpropane-2-sulfinamide (5.19 g, 42.8 mmol) in THF (100 ml_). The mixture was heated to 75 °C and stirred for 3 days. The mixture was cooled to RT and diluted with water (50 mL) and stirred rapidly for 10 min. The mixture was then filtered through celite, eluting with EtOAc (200 mL). The filtrate was concentrated and the residue was dissolved in DCM (10 mL), dried (MgSC ) and concentrated. The crude product was purified by chromatography on silica gel (0-30% MTBE/isohexane) to afford (S,E)-2-methyl- N-((5-(trifluoromethyl)pyridin-2-yl)methylene)propane-2-sulfinamide (4.73 g, 14 mmol, 85% purity) as a white solid. 1H NMR (400 MHz, DMSO-d6) 6 9.19 - 9.16 (m, 1 H), 8.56 (s, 1 H), 8.44 - 8.39 (m, 1H), 8.31 - 8.22 (m, 1 H), 1.22 (s, 9H).
Step 2
Methylmagnesium chloride (3 M in THF, 4.0 mL, 12 mmol) was added dropwise to a solution of (S,E)-2-methyl-N-((5-(trifluoromethyl)pyridin-2-yl)methylene)propane-2-sulfinamide (2.0 g, 6.11 mmol, 85% purity) in THF (25 mL) at -78 °C. The mixture was stirred for 3 h, then quenched with sat. aqueous NH4CI (10 mL). The mixture was separated and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (100 mL), dried (MgSO4) and concentrated. The crude product was purified by chromatography on silica gel (0- 100% EtOAc/isohexane) to afford (S)-2-methyl-N-((S)-1-(5-(trifluoromethyl)pyridin-2- yl)ethyl)propane-2-sulfinamide (1.68 g, 5.7 mmol) as a pale yellow solid. LCMS (System 3, Method D) m/z 295.1 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) 58.97 - 8.83 (m, 1 H), 8.28 - 8.17 (m, 1H), 7.79 (d, J = 8.3 Hz, 1 H), 5.90 (d, J = 8.1 Hz, 1 H), 4.63 - 4.42 (m, 1 H), 1.45 (d, J = 6.9 Hz, 3H), 1.13 (s, 9H). Step 3
A mixture of (S)-2-methyl-N-((S)-1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)propane-2-sulfinamide (1.68 g, 5.7 mmol) and HCI (4 M in 1 ,4-dioxane, 6 ml_, 24 mmol) in MeOH (15 mL) was stirred for 18 h at RT. The mixture was concentrated and the residue triturated with MTBE (30 mL). The resulting solid was isolated by filtration to afford (S)-1-(5-(trifluoromethyl)pyridin-2-yl)ethan-1- amine dihydrochloride (1.44 g, 5.4 mmol) as a pale yellow solid. LCMS (System 3, Method D) m/z 191.2 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) 5 9.04 - 9.01 (m, 1 H), 8.68 (br. s, 3H), 8.34 (ddd, J = 8.3, 2.4, 0.8 Hz, 1H), 8.11 (br. s, 1 H), 7.82 (d, J = 8.3 Hz, 1 H), 4.73 - 4.54 (m, 1H), 1.53 (d, J = 6.8 Hz, 3H).
Step 4
TBTU (146 mg, 456 pmol) was added to a mixture of (S)-1-(5-(trifluoromethyl)pyridin-2-yl)ethan- 1-amine dihydrochloride (100 mg, 0.38 mmol), 3-cyanobut-3-enoic acid (Intermediate 1, 55.4 mg, 0.4 mmol, 80% purity) and DIPEA (331 pL, 1.90 mmol) in /V,/V-dimethylformamide (2 mL). The mixture was stirred at RT for 2 h. The reaction was quenched with water (15 mL) and extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine (3x10 mL), dried (MgSC ), filtered and the solvent removed under reduced pressure. The crude product was dissolved in 1.1 mLwith DMSO, filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters X-Select CSH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40 mL min-1 eluting with a 0.1% Formic acid in water-MeCN gradient over 17.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At- column dilution pump gives 2 mL min-1 Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 20% MeCN; 0.5-15.5 min, ramped from 20% MeCN to 50% MeCN; 15.5-15.6 min, ramped from 50% MeCN to 100% MeCN; 15.6-17.5 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac to give (S)-3-cyano-N-(1-(5-(trifluoromethyl)pyridin-2-yl)ethyl)but-3-enamide (46 mg, 0.16 mmol) as a white solid. LCMS (System 3, Method D) m/z 284.3 [M+H]+ (ES+). 1H NMR (400 MHz, DMSO- d6) 5 8.93 - 8.87 (m, 1H), 8.72 (d, J = 7.3 Hz, 1 H), 8.18 (dd, J = 8.5, 2.6 Hz, 1 H), 7.58 (d, J = 8.4 Hz, 1 H), 6.10 (d, J = 2.3 Hz, 1 H), 6.02 - 5.96 (m, 1H), 5.07 - 4.97 (m, 1 H), 3.26 (s, 2H), 1.44 - 1.36 (m, 3H). 19F NMR (376 MHz, DMSO-d6) 6 -60.69.
Intermediate 6: (S)-3-cyano-N-(1 -(6-(trifluoromethyl)pyridin-3-yl)ethyl)but-3-enamide
Figure imgf000051_0001
Prepared by an analogous method to Intermediate 5 starting from 6- (trifluoromethyl)nicotinaldehyde (4.22 g, 24.1 mmol) and (R)-2-methylpropane-2-sulfinamide (4.38 g, 36.1 mmol) to give (S)-3-cyano-N-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)but-3-enamide (49.4 mg, 0.17 mmol) as a white solid. LCMS (System 3, Method D) m/z 284.5 [M+H]+ (ES+). 1H NMR (400 MHz, DMSO-d6) 5 8.78 - 8.69 (m, 2H), 7.99 (dd, J = 8.1 , 2.2 Hz, 1 H), 7.88 (dd, J = 8.1 , 0.8 Hz, 1 H), 6.11 (s, 1 H), 6.00 (d, J = 1.3 Hz, 1 H), 5.08 - 4.98 (m, 1 H), 3.25 (s, 2H), 1.42 (d, J = 7.0 Hz, 3H). 19F NMR (376 MHz, DMSO-d6) 5 -66.22
Intermediate 7: (S)-3-cyano-N-(1-(4-(trifluoromethyl)phenyl)ethyl)but-3-enamide
Figure imgf000052_0001
A mixture of 3-cyanobut-3-enoic acid (Intermediate 1, 450 mg, 4.05 mmol), (S)-1-(4- (trifluoromethyl)phenyl)ethan-1-amine (613 mg, 3.24 mmol), DCC (1.25 g, 6.07 mmol) and DMAP (49 mg, 0.40 mmol) in DCM (10 mL) was stirred at RT for 3 h. The mixture was filtered, the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (10-30% MTBE/petroleum ether) to give (S)-3-cyano-/V-(1-(4- (trifluoromethyl)phenyl)ethyl)but-3-enamide (750 mg, 2.65 mmol) as a white solid. 1H NMR (400 MHz, DMSO-da) 5: 7.61 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 6.07 (s, 1 H), 5.94 (s, 1 H), 5.92 (d, J = 8.0 Hz, 1H), 5.18-5.15 (m, 1H), 3.16 (s, 2H), 1.54 (d, J = 6.8 Hz, 3H).
Intermediate 8: 1-(4-(trifluoromethyl)phenyl)cyclobutan-1-ol
Figure imgf000052_0002
To a solution of 1-bromo-4-(trifluoromethyl)benzene (45.0 g, 165.4 mmol) in THF (550 mL) was added a solution of n-BuLi in hexanes (2.5 M, 66.2 mL, 165.4 mmol) at -78 °C; and the mixture was stirred at -78 °C for 1 h. Cyclobutanone (11.58 g, 165.4 mmol) was added, and the mixture was stirred at -78 °C for 2 h. The reaction mixture was quenched with sat. aqueous NH4CI (500 mL), the layers were separated and the aqueous layer was further extracted with MTBE (2x600 mL). The combined organic layers were washed by brine, dried over Na2SC>4, filtered and concentrated at 30 °C under reduced pressure. The crude product was purified by chromatography on silica gel (0-14% MTBE/petroleum ether) to give 1-(4- (trifluoromethyl)phenyl)cyclobutanol (27.0 g, 124.8 mmol) as a light-yellow oil. 1H NMR (400 MHz, CDCI3) 6: 7.64 (d, J = 8.8 Hz, 4H), 2.60-2.53 (m, 2H), 2.45-2.37 (m, 2H), 2.13-2.04 (m, 2H), 1.79- 1.72 (m, 1 H). Intermediate 9: 1-(4-(trifluoromethyl)phenyl)cyclobutyl (E)-3-cyanoacrylate
Figure imgf000053_0001
Step 1
A mixture of 1-(4-(trifluoromethyl)phenyl)cyclobutan-1-ol (Intermediate 8, 18.0 g, 83.3 mmol), (E)- 4-methoxy-4-oxobut-2-enoic acid (10.8 g, 83.3 mmol), DCC (25.7 g, 124.9 mmol) and DMAP (1.02 g, 8.33 mmol) in DCM (300 ml_) was stirred at RT for 2 h. The mixture was filtered, and the filtrate was concentrated at 35 °C under reduced pressure, and the crude product was purified by chromatography on silica gel (0-18% MTBE/petroleum ether) to give methyl (1-(4- (trifluoromethyl)phenyl)cyclobutyl) fumarate (22.0 g, 80% yield) as a light-yellow oil. LCMS (System 2, Method C) m/z 350.9 [M+Na]+ (ES+).
Step 2
To a solution of methyl (1-(4-(trifluoromethyl)phenyl)cyclobutyl) fumarate (22.0 g, 67.1 mmol) in THF (335 mL) was added aqueous LiOH (2M, 33.53 mL, 67.1 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C~5 °C for 30 min. The reaction mixture was acidified with aqueous HCI (0.5 M) until pH ~ 5. The mixture was extracted with MTBE (2x400 mL). The combined organics were concentrated at 30 °C under reduced pressure. The residue was diluted with MTBE (200 mL) and aqueous K2CO3 (2M) was added until pH ~ 8. Additional water (200 mL) was added and the mixture was filtered through a pad of Celite. The layers were separated and the aqueous layer was further extracted with MTBE (2x100 mL). The aqueous layer was acidified with aqueous HCI (2M) until pH ~ 5, and extracted with MTBE (2x200 mL). The combined organics were washed with brine, dried over Na2SC>4, filtered and concentrated at 30 °C under reduced pressure. The crude product was purified by chromatography on silica gel (0-25% MTBE/n-hexane) to give (E)- 4-oxo-4-(1-(4-(trifluoromethyl)phenyl)cyclobutoxy)but-2-enoic acid (10.8 g, 34.3 mmol) as white solid. 1 H NMR (400 MHz, DMSO-d6) 5: 13.24 (br, 1 H), 7.72 (q, J = 10.4 Hz, 4H), 6.69 (d, J = 2.0 Hz, 2H), 2.64 (t, J = 7.2 Hz, 4H), 2.04-1.95 (m, 1 H), 1.83-1.74 (m, 1 H).
Step 3
To the solution of (E)-4-oxo-4-(1-(4-(trifluoromethyl)phenyl)cyclobutoxy)but-2-enoic acid (520 mg, 1.32 mmol, 80% purity) and oxalyl chloride (422 mg, 3.32 mmol) in DCM (6 mL) was added N,N- dimethylformamide (1 drop, cat.), and the reaction mixture was stirred at RT for 30 min. Then the mixture was concentrated at 35 °C under reduced pressure to give crude acyl chloride. The crude acyl chloride was dissolved in DCM (2 mL) and added to a solution of NH4OH (174 mg, 4.98 mmol, 25 wt% aqueous solution) in DCM (2 mL), and the reaction mixture was stirred at RT for 2 h. The mixture was quenched with water (10 mL), the layers separated and the aqueous layer was further extracted with DCM (3x5 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated at 35 °C under reduced pressure, and the crude product was purified by chromatography on silica gel (20-40% MTBE/petroleum ether) to to give (E)-1-(4-(trifluoromethyl)phenyl)cyclobutyl 4-amino-4-oxobut-2-enoate (230 mg, 0.73 mmol) as a white solid. LCMS: (System 2, Method C) m/z 336.1 [M+Na]+ (ES+).
Step 4
To a solution of (E)-1-(4-(trifluoromethyl)phenyl)cyclobutyl 4-amino-4-oxobut-2-enoate (200 mg, 0.64 mmol) and triethylamine (258 mg, 2.56 mmol) in DCM (3 mL) was added TFAA (269 mg, 1.28 mmol) at 0 °C. The reaction was warmed to RT and stirred for 1 h. The mixture was quenched with water (3 mL) and the layers were separated. The aqueous layer was extracted with DCM (2x3 mL). The combined organics were washed with brine, dried over Na2SC>4 and filtered. The filtrate was concentrated at 35 °C under reduced pressure, and the residue was purified by prep- HPLC (Column: Waters X-bridge Prep C18 OBD 10pm 19*250mm; Flow Rate: 20 mL/min; solvent system: MeCN/(0.2% formic acid/water) gradient: MeCN: 65%~95%; collection wavelength: 214 nm). The fractions were concentrated at 30 °C under reduced pressure to remove MeCN, and the residue was lyophilized to give 1-(4-(trifluoromethyl)phenyl)cyclobutyl (E)-3-cyanoacrylate (80.6 mg, 0.27 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6) 5: 7.72 (dd, J = 23.6, 8.4 Hz, 4H), 7.06 (d, J = 16.4 Hz, 1 H), 6.76 (d, J = 16.4 Hz, 1 H), 2.64 (d, J = 8.4 Hz, 4H), 2.02-1.96 (m, 1 H), 1.80-1.73 (m, 1 H).
Intermediate 10: 5-(chloromethyl)-1-trityl-1H-tetrazole
Figure imgf000054_0001
Step 1
At 0 °C, (chloromethanetriyl)tribenzene (5.65 g, 20.2 mmol) was added to a solution of 5-
(chloromethyl)-I H-tetrazole (2.0 g, 16.9 mmol), triethylamine (3.53 mL, 25.3 mmol) and DMAP (103 mg, 0.84 mmol) in DCM (50.0 mL). The reaction mixture was stirred at RT for 23 h. Sat. aq. NH CI (100 mL) and DCM (100 mL) were added. The layers were separated and the aqueous layer was further extracted with DCM (3x50 mL). The combined organic layers were filtered through a phase separator and concentrated. The crude product was purified by chromatography on silica gel (0-100% MTBE/isohexane) to afford 5-(chloromethyl)-1-trityl-1 H-tetrazole (4.62 g, 12 mmol, 95 % purity) as a white solid. LCMS (System 4, Method F) m/z 383.0 [M+Na]+ (ES+). 1H NMR (400 MHz, DMSO) 5 7.44 - 7.36 (m, 9H), 7.05 - 6.98 (m, 6H), 5.07 (s, 2H).
Intermediate 11 : 2-trityl-2H-tetrazole-5-carbaldehyde
Figure imgf000055_0001
Step 1
A mixture of ethyl 1 H-tetrazole-5-carboxylate (4.6 g, 32.4 mmol), triphenylmethyl chloride (9.0 g,
32.4 mmol) and K2CO3 (4.5 g, 32.4 mmol) in N,N-dimethylformamide (50 mL) was stirred at RT for 18 h. The reaction mixture was diluted with sat aq. NH4CI (150 mL) and extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SC>4, filtered and the filtrate concentrated at 40 °C. The residual solid was purified by trituration in a mixed solvent system of petroleum ether (30 mL) and ethyl acetate (3 ml) to give ethyl 2-trityl-2H- tetrazole-5-carboxylate (6.4 g, 16.6 mmol) as a white solid. LCMS (System 2, Method C). m/z
407.4 [M+Na]+ (ES+).
Step 2
To a solution of 2-trityl-2H-tetrazole-5-carboxylate (2.1 g, 5.8 mmol) in THF (50 mL) was added lithium aluminum hydride (416 mg, 10.94 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was quenched by adding IS^SC ’IOhhO (2.1 g) in portions. Then the mixture was filtered and the filtrate was concentrated at 35 °C under reduced pressure to give (2-trityl-2H-tetrazol-5-yl)methanol (1.4 g ,4.08 mmol) as a white solid. LCMS (System 2, Method C). m/z 365.4 [M+Na]+ (ES+).
Step 3
To a solution of (2-trityl-2H-tetrazol-5-yl)methanol (1.4 g, 4.08 mmol) in DCM (1 mL) was added Dess-Martin periodinane (2.6 g, 6.1 mmol ) at 0 °C, and the reaction mixture was stirred at RT for 30 min. The reaction mixture was quenched by adding a sat. aq. solution of Na2S2C>3 (20 mL) followed by a sat. aq. solution of NaHCCh (20 mL). The mixture was extracted with DCM (2x50 mL). The combined organic layers were dried over Na2SC>4, filtered and the filtrate concentrated at 30 °C. The crude product was purified by chromatography on silica gel (0-5% EtOAc/petroleum ether) to give 2-trityl-2H-tetrazole-5-carbaldehyde (720 mg, 2.11 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6) 6 10.15 (s, 1H), 7.44-7.41 (m, 9H), 7.08-7.05 (m, 6H). Synthesis of Examples
Example 1 : (S)-3-(1 H-tetrazol-5-yl)-N-(1 -(4-(trifluoromethyl)phenyl)ethyl)but-3-enamide
Figure imgf000056_0001
Step 1
A mixture of (S)-3-cyano-A/-(1-(4-(trifluoromethyl)phenyl)ethyl)but-3-enamide (Intermediate 7, 200 mg, 0.71 mmol), azidotrimethylsilane (164 mg, 1.42 mmol) and dibutyltin oxide (18 mg, 0.07 mmol) in 1 ,4-dioxane (4 ml_) was stirred at 90 °C for 2 h under a nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated at 40 °C under reduced pressure. The residue was purified by prep-HPLC (Column: Waters SUNFIRE Prep C18 OBD 10pm 19x250mm; Flow Rate: 20 mL/min; solvent system: MeCN/(0.05% formic acid/water) gradient: 65-95% MeCN; collection wavelength: 214 nm). The fractions were concentrated under reduced pressure to remove MeCN, and the residue was lyophilized to give (S)-3-(1H-tetrazol-5-yl)-/V-(1- (4-(trifluoromethyl)phenyl)ethyl)but-3-enamide (174 mg, 0.53 mmol) as a white solid. LCMS (System 2, Method B) m/z 326.2 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) 5: 16.52 (br, 1H), 8.67 (d, J = 7.6 Hz, 1 H), 7.65 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 6.06 (s, 1 H), 5.63 (s, 1 H), 4.95-4.88 (m, 1H), 3.55-3.46 (m, 2H), 1.37 (d, J = 7.2 Hz, 1 H).
Example 2: (S, E)-3-( 1 H-tetrazol-5-yl)-N-(1 -(4-(trifluoromethyl)phenyl)ethyl)but-2-enamide
TMSN B S O t l
Figure imgf000056_0002
Step 1
A mixture of (S,E)-3-cyano-N-(1-(4-(trifluoromethyl)phenyl)ethyl)but-2-enamide (Intermediate 2, 150 mg, 0.53 mmol), azidotrimethylsilane (122 mg, 1 .06 mmol) and dibutyltin oxide (125 mg, 0.06 mmol) in toluene (3 mL) was stirred at 95 °C for 16 h under a nitrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated at 40 °C under reduced pressure. The residue was purified by prep-HPLC (Column: Waters SUNFIRE Prep C18 OBD 10pm 19*250mm; Flow Rate: 20 mL/min; solvent system: MeCN/(0.05% formic acid/water) gradient: MeCN: 65%~95%; collection wavelength: 214 nm). The fractions were concentrated at 35 °C under reduced pressure to remove MeCN, and the residue was lyophilized to give (S,E)-3-(1 H-tetrazol- 5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)but-2-enamide (10.6 mg, 0.03 mmol) as a white solid. LCMS (System 2, Method B) m/z 326.2 [M+H]+ (ES+). 1H NMR (400 MHz, DMSO-d6) 6: 8.96 (d, J = 7.6 Hz, 1 H), 7.70 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 1.6 Hz, 1 H), 5.08- 5.02 (m, 1H), 2.50 (s, 3H), 1.40 (d, J = 7.6 Hz, 3H). One exchangeable proton not observed.
Example 3: 5-(2-(1 H-tetrazol-5-yl)allyl)-3-(4-butoxyphenyl)-1,2,4-oxadiazole
TMSN Bu SnO dioxane
Figure imgf000057_0001
To a solution of 2-((3-(4-butoxyphenyl)-1 ,2,4-oxadiazol-5-yl)methyl)acrylonitrile (Intermediate 4, 0.1 g, 0.35 mmol) in 1,4-dioxane (1 mL) was added dibutyltin oxide (17.6 mg, 0.07 mmol) and azidotrimethylsilane (93.7 pL, 0.71 mmol). The reaction was heated to 100 °C for 2 h. After such time the reaction was cooled to RT and diluted with EtOAc (5 mL) and water (5 mL). The layers were separated and the aqueous layer further extracted with EtOAc (2x5 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and the solvent removed under reduced pressure. The crude material was dissolved in 2.1 mL of DMSO, filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters X-Select CSH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40 mL min-1 eluting with a 0.1% Formic acid in water-MeCN gradient over 12.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1 Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 40% MeCN; 0.5-10.5 min, ramped from 40% MeCN to 70% MeCN; 10.5-10.6 min, ramped from 70% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac to give 5-(2-(1H-tetrazol-5-yl)allyl)-3-(4-butoxyphenyl)-1 ,2,4- oxadiazole (30.9 mg, 0.1 mmol) as a light brown solid. LCMS (System 3, Method D) m/z 327.4 [M+H]+ (ES+). 1H NMR (400 MHz, DMSO) 6 7.88 - 7.83 (m, 2H), 7.10 - 7.04 (m, 2H), 6.30 (s, 1 H), 5.92 (d, J = 1.3 Hz, 1 H), 4.37 (s, 2H), 4.03 (t, J = 6.5 Hz, 2H), 1.76 - 1.66 (m, 2H), 1.49 - 1.38 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). One exchangeable proton not observed.
Example 4: (E)-5-(2-(1 H-tetrazol-5-yl)prop-1 -en-1 -yl)-3-(4-butoxyphenyl)-1 ,2,4-oxadiazole
Figure imgf000057_0002
Step 1
To a suspension of 2-((3-(4-butoxyphenyl)-1 ,2,4-oxadiazol-5-yl)methyl)acrylonitrile (0.1 g, 0.35 mmol) and tnethylamme hydrochloride (243 mg, 1.76 mmol) in toluene (1.7 mL) was added sodium azide (115 mg, 1.76 mmol) all at once and the reaction was heated to 90 °C for 1 h. After such time the reaction was quenched with water (10 mL) and then extracted with EtOAc (3x10 ml_). The combined organic layers were washed with brine (20 mL), dried over MgSCU, filtered and the solvent removed under reduced pressure. The crude product was dissolved in 1.5 mL of DMSO, filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters X-Select CSH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40 mL min-1 eluting with a 0.1 % Formic acid in water-MeCN gradient over 12.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilution pump gives 2 mL min-1 Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 50% MeCN; 0.5-10.5 min, ramped from 50% MeCN to 80% MeCN; 10.5-10.6 min, ramped from 80% MeCN to 100% MeCN; 10.6-12.5 min, held at 100% MeCN. The clean fractions were evaporated in a Genevac to give (E)-5-(2-(1 H-tetrazol-5-yl)prop- 1-en-1-yl)-3-(4-butoxyphenyl)-1 ,2,4-oxadiazole (41.9 mg, 0.13 mmol) as a pale brown solid. LCMS (System 3, Method D) m/z 327.4 [M+H]+ (ES+). 1H NMR (400 MHz, DMSO-d6) 5 8.02 - 7.97 (m, 2H), 7.52 (q, J = 1.4 Hz, 1 H), 7.16 - 7.10 (m, 2H), 4.07 (t, J = 6.5 Hz, 2H), 2.80 (d, J = 1.5 Hz, 3H), 1.79 - 1.68 (m, 2H), 1.53 - 1.40 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). One exchangeable proton not observed.
Example 5: 3-(5-(trifluoromethyl)pyridin-2-yl)oxetan-3-yl 2-((1H-tetrazol-5- yl)methyl)acrylate o o
Figure imgf000058_0001
Step 1
To a stirred solution of 2-bromo-5-(trifluoromethyl)pyridine (4.94 g, 21.9 mmol) in DCM (50 mL) was added dropwise n-BuLi in hexane (2.5 M, 8.83 mL, 22.1 mmol) at -78 °C. The mixture was stirred at -78 °C for 30 min. then oxetan-3-one (1.33 mL, 20.8 mmol) was added dropwise at -78 °C. The resulting mixture was allowed to warm to -20 °C over 2 h then quenched with a few drops of MeOH and sat. aq. NH4CI (50 mL). The mixture was stirred at RT for 10 min. then the layers were separated. The aqueous layer was extracted with DCM (3x20 mL) and the combined organic layers were filtered through a phase separator and concentrated. The crude product was purified by chromatography on silica gel (0-70% MTBE/isohexanes) to afford 3-(5-(trifluoromethyl)pyridin- 2-yl)oxetan-3-ol (3.24 g, 14 mmol, 95 % purity) as a brown solid. LCMS (System 4, Method F) m/z 220.0 [M+H]+ (ES)+. 1H NMR (400 MHz, DMSO-d6) 5 9.07 - 9.02 (m, 1 H), 8.23 (dd, J = 8.3, 2.4 Hz, 1 H), 7.81 (d, J = 8.3 Hz, 1 H), 6.80 (s, 1 H), 4.91 (d, J = 6.2 Hz, 2H), 4.69 (d, J = 6.2 Hz, 2H).
Step 2
EDC (665 mg, 3.47 mmol) was added to a mixture of 2-(diethoxyphosphoryl)acetic acid (523 pL,
3.25 mmol), 3-(5-(trifluoromethyl)pyridin-2-yl)oxetan-3-ol (500 mg, 2.17 mmol, 95 % purity) and DMAP (265 mg, 2.17 mmol) in DCM (2.5 mL) at 0 °C. The mixture was allowed to warm to RT and stirred for 18 h. The mixture was diluted with aqueous HCI (1M, 15 mL). The phases were separated and the aqueous phase was extracted with DCM (3x15 mL). The combined organic phases were washed with brine (20 mL), filtered through a phase separator and concentrated. The crude product was purified by chromatography on silica gel (0-3% MeOH/DCM) to afford 3- (5-(trifluoromethyl)pyridin-2-yl)oxetan-3-yl 2-(diethoxyphosphoryl)acetate (495 mg, 1.2 mmol, 95% purity) as a brown oil. LCMS (System 4, Method F) m/z 398.2 [M+H]+ (ES+). 1H NMR (400 MHz, DMSO-d6) 5 9.12 - 9.06 (m, 1H), 8.29 (dd, J = 8.6, 2.4 Hz, 1 H), 7.78 (d, J = 8.4 Hz, 1H), 5.03 (d, J = 7.8 Hz, 2H), 4.85 (d, J = 7.5 Hz, 2H), 4.22 - 3.99 (m, 4H), 3.37 (d, J = 21.4 Hz, 2H),
1.25 (t, J = 7.0 Hz, 6H).
Step 3
Sodium hydride (60 wt% dispersion in mineral oil, 49.7 mg, 1.24 mmol) was added portionwise to a solution of 3-(5-(trifluoromethyl)pyridin-2-yl)oxetan-3-yl 2-(diethoxyphosphoryl)acetate (495 mg, 1.18 mmol, 95 % purity) in THF (4.0 mL) at 0°C. The mixture was stirred for 15 min before a solution of 5-(chloromethyl)- 1 -trityl- 1 H-tetrazole (Intermediate 10, 463 mg, 1.22 mmol, 95 % purity) in THF (2.0 mL) and DMF (4.0 mL) was added dropwise. The reaction mixture was allowed to warm to RT then heated to 60 °C and stirred for 18 h. Once cooled, the mixture was carefully quenched with water (20 mL) and extracted with EtOAc (80 mL). The organic layer was washed with brine (4x15 mL), dried (Na2SO4), filtered and concentrated. The crude product was purified by chromatography on silica gel (0-60% MTBE/isohexane followed by 0-10% MeOH/DCM). The crude material was then re-purified by chromatography on silica gel (0-100% TBME/isohexane) to afford 3-(5-(trifluoromethyl)pyridin-2-yl)oxetan-3-yl 2-(diethoxyphosphoryl)-3-(1-trityl-1 H- tetrazol-5-yl)propanoate (270 mg, 0.32 mmol, 85% purity) as a colourless oil. LCMS (System 4, Method F) m/z 744.2 [M+Na]+ (ES+). 1H NMR (400 MHz, DMSO) 5 9.03 - 8.97 (m, 1 H), 8.02 (dd, J = 8.5, 2.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1 H), 7.44 - 7.28 (m, 9H), 7.05 - 6.95 (m, 6H), 4.91 (d, J = 7.4 Hz, 2H), 4.71 (d, J = 7.5 Hz, 1 H), 4.62 (d, J = 7.4 Hz, 1 H), 4.19 - 4.07 (m, 4H), 3.98 (ddd, J = 23.4, 10.8, 4.4 Hz, 1H), 3.57 - 3.44 (m, 1 H), 3.42 - 3.33 (m, 1 H), 1.23 (td, J = 7.0, 5.3 Hz, 6H). Step 4
At 0 °C, TFA (245 pL, 3.18 mmol) was added to a solution of 3-(5-(trifluoromethyl)pyridin-2- yl)oxetan-3-yl 2-(diethoxyphosphoryl)-3-(1-trityl-1 H-tetrazol-5-yl)propanoate (270 mg, 0.32 mmol, 85 % purity) in DCM (3.0 mL). The reaction mixture was stirred at 0 °C for 2 h then quenched with water (5 mL) and sat. aqueous NaHCOa (20 mL) until pH~8. DCM (10 mL) was added, the layers were separated and the aqueous layer was extracted with DCM (2x10 mL). The organic layer was discarded, and the aqueous layer was acidified with aqueous HCI (1M) until pH~3. The mixture was extracted with DCM/MeOH (90:10) (3x10 mL). The combined DCM/MeOH layers was filtered through a phase separator then concentrated to afford 3-(5-(trifluoromethyl)pyridin-2- yl)oxetan-3-yl 2-(diethoxyphosphoryl)-3-(1 H-tetrazol-5-yl)propanoate (78 mg, 0.15 mmol, 95% purity) as a colourless oil. LCMS (System 4, Method F) m/z 480.0 [M+H]+ (ES+). 1H NMR (400 MHz, DMSO-d6) 5 9.02 (dd, J = 2.1 , 1.1 Hz, 1 H), 8.15 (dd, J = 8.6, 2.4 Hz, 1 H), 7.70 (d, J = 8.4 Hz, 1H), 4.99 (dd, J = 11.9, 7.4 Hz, 2H), 4.82 (dd, J = 7.4, 2.1 Hz, 2H), 4.22 - 4.10 (m, 4H), 3.99 (ddd, J = 23.1 , 11 .1 , 4.2 Hz, 1 H), 3.48 - 3.35 (m, 2H), 1.26 (q, J = 6.9 Hz, 6H). One exchangeable proton not observed.
Step 5
Aqueous formaldehyde (37% wt, 17 pL, 0.23 mmol) was added to a suspension of 3-(5- (trifluoromethyl)pyridin-2-yl)oxetan-3-yl 2-(diethoxyphosphoryl)-3-(1 H-tetrazol-5-yl)propanoate (0.08 g, 0.15 mmol, 95 % purity) and K2CO3 (32 mg, 0.23 mmol) in THF (2 mL). The mixture was stirred at RT for 18 h. The mixture was cooled to RT, carefully quenched with water (10 mL) and extracted with DCM (2x10 mL). The combined organic phases were dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography on RP Flash C18 (5-100% (0.1 % Formic acid in MeCN) I (0.1% Formic Acid in Water)) to afford 3-(5-(trifluoromethyl)pyridin-2- yl)oxetan-3-yl 2-((1 H-tetrazol-5-yl) methylacrylate (0.03 g, 0.08 mmol, 95% purity) as colourless gum. LCMS (System 4, Method F) m/z 356.0 [M+H]+ (ES+). 1H NMR (400 MHz, DMSO-d6) 6 16.19 (s, 1 H), 9.10 - 8.98 (m, 1 H), 8.30 - 8.18 (m, 1 H), 7.60 (d, J = 8.4 Hz, 1 H), 6.53 (s, 1H), 6.09 - 6.02 (m, 1H), 5.04 - 4.94 (m, 2H), 4.86 (d, J = 7.6 Hz, 2H), 4.00 (s, 2H). Example 6: ammonium (E)-5-(3-oxo-3-(1-(4-(trifluoromethyl)phenyl)cyclobutoxy)prop-1- en-1 -yl)tetrazol-1 -ide
Figure imgf000061_0001
Step 1
A mixture of 1-(4-(trifluoromethyl)phenyl)cyclobutan-1-ol (Intermediate 8, 400 mg, 1.85 mmol), 2- bromoacetic acid (258 mg, 1.85 mmol), DCC (458 mg, 2.22 mmol) and DMAP (22 mg, 0.18 mmol) in DCM (5 mL) was stirred at RT for 18 h. The mixture was filtered, and the filtrate was concentrated at 35 °C under reduced pressure, and the crude product was purified by chromatography on silica gel (0-6% MTBE/petroleum ether) to give 1-(4- (trifluoromethyl)phenyl)cyclobutyl 2-bromoacetate (600 mg, 1.78 mmol) as a light-yellow oil. 1H NMR (400 MHz, CDCI3) 5: 7.62 (m, 4H), 3.75 (s, 2H), 2.73-2.61 (m, 4H), 2.08-2.00 (m, 1 H), 1.81- 1.73 (m, 1 H).
Step 2
A mixture of 1-(4-(trifluoromethyl)phenyl)cyclobutyl 2-bromoacetate (600 mg, 1.78 mmol) and triethyl phosphite (296 mg, 1.78 mmol) in toluene (4 mL) was stirred at 130 °C for 16 h. Once cooled to RT the solvent was concentrated at 50 °C under reduced pressure, and the crude product was purified by chromatography on silica gel (0-80% MTBE/petroleum ether) to give 1- (4-(trifluoromethyl)phenyl)cyclobutyl 2-(diethoxyphosphoryl)acetate (600 mg, 1.58 mmol) as a colorless oil. LCMS (System 2, Method C) m/z 416.9 [M+Na]+ (ES+).
Step 3
To a solution of 1-(4-(trifluoromethyl)phenyl)cyclobutyl 2-(diethoxyphosphoryl)acetate (500 mg,
1.27 mmol) in DMF (3 mL) was added sodium hydride (60 wt% dispersion in mineral oil, 56 mg, 1.40 mmol) at 0 °C. The mixture was stirred at RT for 30 min. then the solution of 5-methyl-4H- 1 ,2,4-triazole-3-carbaldehyde (Intermediate 11 , 141 mg, 1.27 mmol) in N,N-dimethylformamide (2 mL) was added. The resulting mixture was stirred at RT for 2 h. The mixture was quenched with sat. aq. NH4CI (5 mL), and then extracted with MTBE (3x6 mL). The combined organic layers were washed by brine, dried over Na2SO4, filtered and concentrated at 30 °C under reduced pressure. The crude residue was purified prep-HPLC (Column: Waters X-bridge Prep C18 OBD lOpm 19*250mm; Flow Rate: 20 mL/min; solvent system: MeCN/(10mmol/L NH4HCO3/water) gradient: MeCN: 35%~55%; collection wavelength: 214 nm). The fractions were concentrated at 30 °C under reduced pressure to remove MeCN, and the residue was lyophilized to give (E)-5- (3-oxo-3-(1-(4-(trifluoromethyl)phenyl)cyclobutoxy)prop-1-en-1-yl)tetrazol-1-ide ammonium salt (3.8 mg, 0.01 mmol) as a light-yellow solid. LCMS: (System 2, Method B) m/z 339.1 [M+H]+ (ES+). 1H NMR (400 MHz, DMSO-d6) 5: 7.73 (dd, J = 15.6, 6.8 Hz, 4H), 7.60 (d, J = 16.4 Hz, 1H), 7.09 (t, J = 50.0 Hz, 3H), 6.62 (d, J = 15.6 Hz, 1 H), 2.67-2.63 (m, 4H), 2.02-1.99 (m, 1 H), 1.83-1.78 (m, 1H). One exchangeable proton not observed.
Biological Example 1 - TH P-1 AlphaLISA IL-16 and IL-6 Cytokine Assay
Measuring inhibitory effects on IL- IB cytokine and IL-6 output from TH P-1 s
The cytokine inhibition profiles of compounds of formula (I) were determined in a differentiated THP-1 cell assay. All assays were performed in RPMI-1640 growth medium (Gibco), supplemented with 10% fetal bovine serum (FBS; Gibco), 1 % penicillin-streptomycin and 1% sodium pyruvate unless specified otherwise. The IL-1 p and IL-6 cytokine inhibition assays were run in a background of differentiated THP-1 cells as described below. All reagents described were from Sigma-Aldrich unless specified otherwise. Compounds were prepared as 10mM DMSO stocks.
Assay Procedure
THP-1 cells were expanded as a suspension up to 80% confluence in appropriate growth medium. Cells were harvested, suspended, and treated with an appropriate concentration of phorbol 12- myristate 13-acetate (PMA) over a 72hr period (37°C/5% CO2).
Following 72hrs of THP-1 cell incubation, cellular medium was removed and replaced with fresh growth media containing 1% of FBS. Working concentrations of compounds were prepared separately in 10% FBS treated growth medium and pre-incubated with the cells for 30 minutes (37°C/5% CO2). Following the 30 minute compound pre-incubation, THP-1s were treated with an appropriate concentration of LPS and the THP-1 s were subsequently incubated for a 24hr period (37°C/5% CO2). An appropriate final concentration of Nigericin was then dispensed into the THP- 1 plates and incubated for 1 hour (37°C/5% CO2) before THP-1 supernatants were harvested and collected in separate polypropylene 96-well holding plates.
Reagents from each of the IL-1 p and IL-6 commercial kits (Perkin Elmer) were prepared and run according to the manufacturer’s instructions. Subsequently, fluorescence signal detection in a microplate reader was measured (EnVision® Multilabel Reader, Perkin Elmer). Percentage inhibition was calculated per cytokine by normalising the sample data to the high and low controls used within each plate (+/- LPS respectively). Percentage inhibition was then plotted against compound concentration and the 50% inhibitory concentration (IC50) was determined from the resultant concentration-response curve.
Reference Examples
Figure imgf000063_0002
Compounds of formula (I) were tested in this assay and the results of those compounds tested are shown in Table 1 below. 4-Octyl itaconate, 2-(2-chlorobenzyl)acrylic acid, monomethyl fumarate, RE1 and RE2 were included as comparator compounds.
Table 1 - THP-1 cell IL-16 and IL-6 ICso values (pM)
Figure imgf000063_0001
§NT means not tested in this assay
Compounds of formula (I) that were tested in this assay exhibited improved cytokine-lowering potencies compared to 4-octyl itaconate, 2-(2-chlorobenzyl)acrylic acid and monomethyl fumarate in IL-1 p and/or IL-6. Example 3 exhibited improved cytokine-lowering potencies compared to Reference Example 1 in I L-1 p. Biological Example 2 - NRF2 +/- GSH activation assay
Measuring compound activation effects on the anti-inflammatory transcription factor NRF2 in DiscoverX PathHunter NRF2 translocation kit
Potency and efficacy of compounds of formula (I) against the target of interest to activate NRF2 (nuclear factor erythroid 2-related factor 2) were determined using the PathHunter NRF2 translocation kit (DiscoverX). The NRF2 translocation assay was run using an engineered recombinant cell line, utilising enzyme fragment complementation to determine activation of the Keap1-NRF2 protein complex and subsequent translocation of NRF2 into the nucleus. Enzyme activity was quantified using a chemiluminescent substrate consumed following the formation of a functional enzyme upon PK-tagged NRF2 translocation into the nucleus.
The assay was run under either +/- GSH (glutathione) conditions to determine the attenuating activities of GSH against target compounds.
Additionally, a defined concentration of dimethyl fumarate was used as the ‘High’ control to normalise test compound activation responses to.
Assay Procedure
U2OS PathHunter express cells were thawed from frozen prior to plating. Following plating, U2OS cells were incubated for 24hrs (37°C/5%CO2) in commercial kit provided cell medium.
Following 24hrs of U2OS incubation, cells were directly treated with an appropriate final concentration of compound, for -GSH conditions, or for +GSH conditions, an intermediate plate containing 6x working concentrations of compound stocks was prepared in a 6mM working concentration of GSH solution (solubilised in sterile PBS). Following a 30 minute compound-GSH pre-incubation (37°C/5%CO2) for +GSH treatment, plated U2OS cells were incubated with an appropriate final concentration of compound and GSH.
Following compound (+/-GSH) treatment, the U2OS plates were incubated for a further 6 hours (37°C/5%CO2) before detection reagent from the PathHunter NRF2 commercial kit was prepared and added to test plates according to the manufacturer’s instructions. Subsequently, the luminescence signal detection in a microplate reader was measured (PHERAstar®, BMG Labtech). Percentage activation was calculated by normalising the sample data to the high and low controls used within each plate (+/- DMF). Percentage activation/response was then plotted against compound concentration and the 50% activation concentration (EC50) was determined from the plotted concentration-response curve.
A number of compounds of formula (I) were tested in this assay, and the results are shown in Table 2 below. 2-(2-chlorobenzyl)acrylic acid was included as a comparator compound.
Table 2 - NRF2 activation
Figure imgf000065_0001
Compounds of formula (I) tested in this assay showed improved activity in this assay (such as under -GSH conditions) compared to 2-(2-chlorobenzyl)acrylic acid, as demonstrated by their lower EC50 and/or higher Emax values for NRF2 activation.
Biological Example 3 - Hepatocyte stability assay
Defrosted cryo-preserved hepatocytes (viability > 70%) were used to determine the metabolic stability of a compound via calculation of intrinsic clearance (Clint; a measure of the removal of a compound from the liver in the absence of blood flow and cell binding). Clearance data are particularly important for in vitro work as they can be used in combination with in vivo data to predict the half-life and oral bioavailability of a drug.
The metabolic stability in hepatocytes assay involved a time-dependent reaction using both positive and negative controls. The cells must be pre-incubated at 37 °C then spiked with test compound (and positive control); samples taken at pre-determined time intervals were analysed to monitor the change in concentration of the initial drug compound over 60 minutes. A buffer incubation reaction (with no hepatocytes present) acted as a negative control and two cocktail solutions, containing compounds with known high and low clearance values (verapamil/7- hydroxycoumarin and propranolol/diltiazem), acted as positive controls. 1. The assay was run with a cell concentration of 0.5 x 106 cells/mL in Leibovitz buffer.
2. All compounds and controls were run in duplicate.
3. Compound concentration was 10pM.
4. All compounds and controls were incubated with both cells and buffer to show turnover is due to hepatic metabolism.
5. All wells on the incubation plate had 326.7pL of either cells or buffer added.
6. Prior to assay, cell and buffer-only incubation plates were preincubated for 10 mins at 37 °C.
7. The assay was initiated by adding compounds, 3.3pL of 1mM in 10% DM SO-90% Buffer; final DMSO concentration is 0.1%.
8. Samples were taken at regular timepoints (0, 5, 10, 20, 40, 60 min) until 60 mins.
9. Sample volume was 40pL and added to 160pL of crash solvent (acetonitrile with internal standard) and stored on ice.
10. At the end of the assay, the crash plates were centrifuged at 3500rpm for 20mins at 4 °C. 11. 80 L of clear supernatant was removed and mixed with 80 L of deionised water before being analysed by LC-MS/MS.
Raw LC-MS/MS data were exported to, and analysed in, Microsoft Excel for determination of intrinsic clearance. The percentage remaining of a compound was monitored using the peak area of the initial concentration as 100%. Intrinsic clearance and half-life values were calculated using a graph of the natural log of percentage remaining versus the time of reaction in minutes. Halflife (min) and intrinsic clearance (Clint in L min-1 10'5 cells) values were calculated using the gradient of the graph (the elimination rate constant, k) and Equations 1 and 2.
{Equation 1}
{Equation 2}
Figure imgf000066_0001
A number of compounds of formula (I) were tested in this assay, and the results are shown in Table 3 below. 4-Octyl itaconate, RE1 and RE2 were included as comparator compounds. Table 3 - Hepatocyte stability
Figure imgf000067_0001
The results indicate that the compounds of the invention, at least those of Table 3, are expected to have acceptable or improved metabolic stabilities, as shown by their intrinsic clearance (Cl int) and half-life (T1/2) values, in this assay. All compounds in Table 3 were more stable, i.e., they exhibited lower intrinsic clearance (Clint) and/or longer half-life (T1/2) values compared to 4-octyl itaconate in both human and mouse species.
Example 3 is expected to be more stable (lower intrinsic clearance (Clint) and longer half-life (T1/2) values) compared with RE1. Example 4 is expected to be more stable (lower intrinsic clearance (Cl int) and/or longer half-life (T1/2) values in at least human or mouse species) compared with RE2.
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Miscellaneous
All references referred to in this application, including patent and patent applications, are incorporated herein by reference to the fullest extent possible.
Throughout the specification and the claims which follow, unless the context requires otherwise, the word ‘comprise’, and variations such as ‘comprises’ and ‘comprising’, will be understood to imply the inclusion of a stated integer, step, group of integers or group of steps but not to the exclusion of any other integer, step, group of integers or group of steps.
The application, of which this description and claims form part, may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims.

Claims

1. A compound of formula (I):
Figure imgf000071_0001
wherein:
Figure imgf000071_0002
L is selected from the group consisting of NHC(=O), OC(=O) and 5-membered heteroaryl;
K is bond or C(R1)(R2);
R1 and R2 are independently selected from the group consisting of H, C1-4 alkyl and C1-4 haloalkyl, or R1 and R2 join to form a C3-5 cycloalkyl ring or a 4- to 6-membered heterocyclic ring, wherein the C3-5 cycloalkyl ring or 4- to 6-membered heterocyclic ring is optionally substituted by halo, cyano, C1.2 alkyl, C1.2 alkoxy, C1.2 haloalkyl or C1.2 haloalkoxy;
A is C5-7 cycloalkyl, phenyl or 5-6-membered heteroaryl wherein A is optionally substituted by one or more R3wherein R3 is selected from the group consisting of halo, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1.4 haloalkoxy, hydroxy, cyano, SF5, SC1.4 alkyl, SC1.4 haloalkyl, (CH2)o-3C3-7 cycloalkyl, 5-7-membered heterocyclyl, O-phenyl and O-heteroaryl wherein said C3-7 cycloalkyl, said 5-7-membered heterocyclyl, said O-phenyl and said O-heteroaryl are optionally substituted by one or more groups selected from halo, C1.4 alkyl, C1.4 haloalkyl, O(Ci-4 alkyl) and C1.4 hydroxyalkyl; wherein two alkyl groups which are attached to the same carbon atom are optionally joined to form a C3-7 cycloalkyl ring; and
Rc and RD are each independently H, C1-2 alkyl, hydroxy, fluoro or Ci_2 alkoxy; or Rc and RD may join to form a C3-5 cycloalkyl ring; or a pharmaceutically acceptable salt and/or solvate thereof.
2. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to claim 1 which is a compound of formula (I).
3. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to claim 1 which is a pharmaceutically acceptable salt of the compound of formula (I).
4. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 3 wherein:
Figure imgf000072_0001
and Rc and RD are as defined in claim 1.
5. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 3 wherein:
Figure imgf000072_0002
and Rc is as defined in claim 1.
6. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 3 wherein:
Figure imgf000072_0003
7. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 6 wherein L is NHC(=O).
8. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 6 wherein L is OC(=O).
9. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 6 wherein L is 5-membered heteroaryl.
10. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to claim 9 wherein L is 1,2,4-oxadiazole.
11. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 10 wherein K is bond.
12. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 10 wherein K is C(R1)(R2) and R1 and R2 are as defined in claim 1.
13. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 12 wherein R1 is H.
14. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 12 wherein R1 is C1-4 alkyl e.g. methyl.
15. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 12 wherein R1 is C1-4 haloalkyl.
16. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 15 wherein R2 is H.
17. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 12 wherein R1 and R2 join to form a C3-5 cycloalkyl ring wherein the C3-5 cycloalkyl ring is optionally substituted by halo, cyano, C1.2 alkyl, C1.2 alkoxy, C1.2 haloalkyl or Ci- 2 haloalkoxy e.g. a C4 cycloalkyl ring.
18. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 12 wherein R1 and R2 join to form a 4- to 6-membered heterocyclic ring wherein the 4- to 6-membered heterocyclic ring is optionally substituted by halo, cyano, C1-2 alkyl, C1-2 alkoxy, C1.2 haloalkyl or C1.2 haloalkoxy, e.g. a 4-membered heterocyclic ring.
19. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 18 wherein A is C5-7 cycloalkyl wherein A is optionally substituted by one or more R3.
20. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 18 wherein A is phenyl wherein A is optionally substituted by one or more R3.
21. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 18 wherein A is 5-6-membered heteroaryl e.g. pyridyl wherein A is optionally substituted by one or more R3.
22. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 19 to 21 wherein A is substituted by one or more R3.
23. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 22 wherein R3 is Ci^ alkoxy such as butoxy or C1-4 haloalkyl such as CF3.
24. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 19 to 21 wherein A is unsubstituted.
25. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 24 wherein Rc is H.
26. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 25 wherein RD is H.
27. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 5 wherein X is H.
28. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 5 wherein X is CH3.
29. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 28 wherein L is OC(=O) or 5-membered heteroaryl and
Figure imgf000074_0001
Figure imgf000075_0001
wherein Rc, RD and X are defined in claim 1.
30. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 28 wherein L is NHC(=O), and
Figure imgf000075_0002
wherein Rc and X are defined in claim 1.
31. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 28 wherein L is NHC(=O) and:
K is bond and A is optionally substituted phenyl or optionally substituted 5-6-membered heteroaryl;
K is C(R1)(R2) wherein R1 and R2 are defined in claim 1, and A is C5.7 cycloalkyl;
K is C(R1)(R2) wherein R1 and R2 are defined in claim 1, and A is C5-7 cycloalkyl or 5-6- membered heteroaryl wherein the 6-membered heteroaryl is other than pyridyl;
K is CH2 and A is C5-7 cycloalkyl;
K is CH2 and A is C5-7 cycloalkyl or 5-6-membered heteroaryl wherein the 6-membered heteroaryl is other than pyridyl; and/or
R3 is C2-4 alkyl, C1-4 alkoxy, C2-4 haloalkyl, C1.4 haloalkoxy, hydroxy, cyano, SF5, SC1.4 alkyl, SC1.4 haloalkyl, (CH2)o-3C3-7 cycloalkyl, 5-7-membered heterocyclyl, O-phenyl and O-heteroaryl wherein said C3-7 cycloalkyl, said 5-7-membered heterocyclyl, said O-phenyl and said O-heteroaryl are optionally substituted by one or more groups selected from halo, C1.4 alkyl, C1.4 haloalkyl, O(Ci-4 alkyl) and C1.4 hydroxyalkyl.
32. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 28, the compound of formula (I) is other than a compound of formula (IA):
Figure imgf000076_0001
wherein:
Figure imgf000076_0002
RA is selected from the group consisting of Ce-7 cycloalkyl, CH2(phenyl) and CH2(pyridyl); wherein when RA is Ce-7 cycloalkyl, the cycloalkyl ring is 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; 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 or C1.4 haloalkyl, or two RA3 groups are attached to the CH2 carbon atom and join to form a C3-5 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, Ci-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:
Figure imgf000076_0003
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 pharmaceutically acceptable salt and/or solvate thereof.
33. The compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 28 wherein the compound of formula (I) is other than Example 1.
34. A compound according to claim 1 which is selected from the list consisting of:
(S)-3-(1 H-tetrazol-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)but-3-enamide;
(S,E)-3-(1 H-tetrazol-5-yl)-N-(1-(4-(trifluoromethyl)phenyl)ethyl)but-2-enamide;
5-(2-(1 H-tetrazol-5-yl)allyl)-3-(4-butoxyphenyl)-1 ,2,4-oxadiazole;
(E)-5-(2-(1 H-tetrazol-5-yl)prop-1-en-1-yl)-3-(4-butoxyphenyl)-1 ,2,4-oxadiazole;
3-(5-(trifluoromethyl)pyridin-2-yl)oxetan-3-yl 2-((1 H-tetrazol-5-yl)methyl)acrylate; and ammonium (E)-5-(3-oxo-3-(1-(4-(trifluoromethyl)phenyl)cyclobutoxy)prop-1-en-1-yl)tetrazol-1- ide; and pharmaceutically acceptable salts and/or solvates of any one thereof.
35. A pharmaceutical composition comprising a compound according to any one of claims 1 to 34 or a pharmaceutically acceptable salt and/or solvate thereof.
36. A compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 34 or a pharmaceutical composition according to claim 35 for use as a medicament.
37. A compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 34 or a pharmaceutical composition according to claim 35 for use in treating or preventing an inflammatory disease or a disease associated with an undesirable immune response.
38. Use of a compound ora pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 34 or a pharmaceutical composition according to claim 35 in the manufacture of a medicament for treating or preventing an inflammatory disease or a disease associated with an undesirable immune response.
39. A method of treating or preventing an inflammatory disease or a disease associated with an undesirable immune response, which comprises administering a compound or a pharmaceutically acceptable salt and/or solvate thereof according to any one of claims 1 to 34 or a pharmaceutical composition according to claim 35.
40. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to any one of claims 1 to 39, for treating an inflammatory disease or a disease associated with an undesirable immune response.
41. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to any one of claims 1 to 39, for preventing an inflammatory disease or a disease associated with an undesirable immune response.
42. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to any one of claims 1 to 39, for treating or preventing an inflammatory disease.
43. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to any one of claims 1 to 39, for treating or preventing a disease associated with an undesirable immune response.
44. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to any one of claims 1 to 43, wherein the inflammatory disease or disease associated with an undesirable immune response is, or is associated with, 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, Dressier’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, Behget'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, Al DP, acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), pharyngeal-cervical-brachial variant, Miller-Fisher variant and Bickerstaffs 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 (Cl DP), 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, lgG4- 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 (HI DS), 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-Goutieres 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), spondyloarthrapathies, polymyalgia rheumatica and erosive osteoarthritis of the hands.
45. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 44, wherein the inflammatory disease or disease associated with an undesirable immune response is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, psoriasis, Crohn’s disease, ulcerative colitis, uveitis, cryopyrin-associated periodic syndromes, Muckle-Wells syndrome, juvenile idiopathic arthritis, chronic obstructive pulmonary disease and asthma.
46. The compound or pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 44, wherein the inflammatory disease or disease associated with an undesirable immune response is selected from the group consisting of rheumatoid arthritis; psoriatic arthritis; systemic lupus erythematosus; multiple sclerosis; psoriasis; Crohn’s disease; ulcerative colitis; juvenile idiopathic arthritis; uveitis; spondyloarthrapathies; ankylosing spondylitis; temporal arteritis; polymyalgia rheumatica; erosive osteoarthritis of the hands; Lupus nephritis; Parkinson's disease; inflammatory bowel disease; celiac disease; dermatomyositis; hidradenitis suppurativa; Sjogren's syndrome; giant cell arteritis (temporal arteritis); systemic juvenile idiopathic arthritis (Still’s disease); familial Mediterranean fever (FMF); tumour necrosis factor (TN F) receptor-associated periodic fever syndrome (TRAPS); hyperimmunoglobulinaemia Dwith periodic fever syndrome (HI DS); cryopyrin-associated periodic syndromes (CAPS); Aicardi-Goutieres syndrome; and spondyloenchondrodysplasia.
47. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is multiple sclerosis.
48. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is psoriasis.
49. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is asthma.
50. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is chronic obstructive pulmonary disease.
51. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is systemic lupus erythematosus.
52. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is rheumatoid arthritis.
53. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is psoriatic arthritis.
54. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is Parkinson’s disease.
55. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is Crohn’s disease.
56. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is ulcerative colitis.
57. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is juvenile idiopathic arthritis.
58. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is uveitis.
59. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is spondyloarthrpathies.
60. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is ankylosing spondylitis.
61. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is temporal arteritis.
62. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is polymyalgia rheumatica.
63. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is erosive osteoarthritis of the hands.
64. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is Lupus nephritis.
65. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is inflammatory bowel disease.
66. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is celiac disease.
67. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is dermatomyositis.
68. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to claim 45, wherein the inflammatory disease or disease associated with an undesirable immune response is hidradenitis suppurativa.
69. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or a pharmaceutically acceptable salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to any one of claims 1 to 68, wherein the compound is for administration to a human subject.
70. The compound or a pharmaceutically acceptable salt and/or solvate thereof, pharmaceutical composition, compound or salt and/or solvate thereof for use, pharmaceutical composition for use, use or method according to any one of claims 1 to 69, 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-TNFa 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 1 b/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-lnducing Ligand) and BLyS (e.g. atacicept), PI3K inhibitor including pan-inhibitor or one targeting the p1105 and/or p110y containing isoforms (e.g. idelalisib, copanlisib, duvelisib), an interferon a 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-lgE 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 05 (e.g. eculizumab), immunoadsor, antithymocyte globulin, 5-aminosalicylates and their derivatives (e.g. sulfasalazine, balsalazide, mesalamine), an anti-integrin agent including one targeting a4|31 and/or a4[37 integrins (e.g. natalizumab, vedolizumab), an anti-CD11-a 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- 1P 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.
71. A process for the preparation of the compound of formula (I) or a salt such as a pharmaceutically acceptable salt, and/or solvate thereof, which comprises converting a compound of formula (II):
Figure imgf000087_0001
or salt thereof; to a compound of formula (I), for example by reacting the compound of formula (II) with an azide
(N3‘) source; wherein
Figure imgf000087_0002
are defined in any one of claims 1 to 34.
72. A compound of formula (II):
Figure imgf000087_0003
or salt thereof; wherein L, K and A are defined in any one of claims 1 to 34.
73. A compound of formula (V):
Figure imgf000087_0004
or salt thereof; wherein L, K and A are defined in any one of claims 1 to 34.
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