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WO2024057013A1 - Modulateurs de nlrp3 - Google Patents

Modulateurs de nlrp3 Download PDF

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Publication number
WO2024057013A1
WO2024057013A1 PCT/GB2023/052363 GB2023052363W WO2024057013A1 WO 2024057013 A1 WO2024057013 A1 WO 2024057013A1 GB 2023052363 W GB2023052363 W GB 2023052363W WO 2024057013 A1 WO2024057013 A1 WO 2024057013A1
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Prior art keywords
compound
mmol
alkyl
disease
dimethyl
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English (en)
Inventor
Thorsten Nowak
Victor Sebastian PEREZ
Martin Lowe
Chido MPAMHANGA
Holly FOSTER
Marco Derudas
Giulia CHEMI
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Exscientia Ltd
Exscientia AI Ltd
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Exscientia Ltd
Exscientia AI Ltd
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Priority claimed from GBGB2213320.1A external-priority patent/GB202213320D0/en
Priority claimed from GBGB2306477.7A external-priority patent/GB202306477D0/en
Application filed by Exscientia Ltd, Exscientia AI Ltd filed Critical Exscientia Ltd
Publication of WO2024057013A1 publication Critical patent/WO2024057013A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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]
    • 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
    • A61P37/02—Immunomodulators

Definitions

  • the present disclosure relates to novel compounds capable of modulating NLRP3 activity. Such activity may be inhibited by the compounds described herein.
  • the present invention further describes the synthesis of the compounds and their uses as medicaments in diseases or disorders where modulation of NLRP3 may be beneficial.
  • NLR family pyrin domain containing 3 (NLRP3) (also known as NACHT, LRR and PYD domains- containing protein 3 [NALP3] and cryopyrin), is a protein that in humans is encoded by the NLRP3 gene.
  • NLRP3 is expressed predominantly in cells involved in innate immunity, such as macrophages and astrocytes and microglia in the CNS and is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome (Tao J.H., et al., (2013). "P2X7R: a potential key regulator of acute gouty arthritis", review. Seminars in Arthritis and Rheumatism. 43 (3), 376-80; Lu A., et al. (2015). "Structural mechanisms of inflammasome assembly", review. The FEBS Journal. 282 (3), 435-44).
  • the NLRP3 inflammasome detects products of damaged cells such as extracellular ATP and crystalline uric acid. Activated NLRP3 in turn triggers an immune response. Mutations in the NLRP3 gene are associated with a number of autoimmune and other diseases.
  • drugs are available that block IL-1 p, such as canakinumab® (anti-IL-1 ⁇ antibody), anakinra® (IL-1 receptor antagonist), and rilonacept® (decoy IL- 1 receptor).
  • canakinumab® anti-IL-1 ⁇ antibody
  • anakinra® IL-1 receptor antagonist
  • rilonacept® decoy IL- 1 receptor
  • Cryopyrin-associated periodic syndrome Cryopyrin-associated periodic syndrome (CAPS) and other diseases associated with IL-1 ⁇ (Dinarello C.A., et al. Treating inflammation by blocking interleukin-1 in humans; Semin Immunol. (2013) 25, 469-84).
  • IL-18 cytokines
  • IL-18 cytokines
  • IL-18 cytokines
  • IL-18 cytokines
  • IL-1 ⁇ production can be mediated by other inflammasomes or by inflammasome-independent pathways; so inhibitors aimed at IL-1 ⁇ may result in unintentional immunosuppressive effects. Therefore, pharmacological inhibitors which specifically target NLRP3 or the NLRP3 inflammasome only could be a better option for treatment of NLRP3-associated diseases.
  • NLRP3-related diseases or diseases associated with the NLRP3 inflammasome.
  • diseases are detailed in WO2022/063876, in the section entitled “Pharmacology” on pages 25-34, which is incorporated herein by reference, and the main categories are diseases associated with: inflammation, inflammatory disease, immune diseases, cancer, infections, central nervous system diseases, metabolic diseases, cardiovascular diseases, respiratory diseases, liver diseases, renal diseases, ocular diseases, skin diseases, lymphatic conditions, psychological disorders, graft versus host diseases, bone diseases, blood diseases, allodynia, any disease where an individual has been determined to carry a germline or somatic non-silent mutation in NLRP3.
  • NLRP3-related diseases or diseases associated with the NLRP3 inflammasome include: autoimmune disorder, inflammatory disease, cancer and/or oncologic disease (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis) and/or HIV infection and replication, inflammatory conditions such as rheumatoid arthritis, multiple sclerosis, psoriasis, asthma, atopic dermatitis, Crohn’s disease, autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type I / Type II diabetes and related complications (e.g.
  • autoimmune disorder e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis
  • HIV infection and replication e.g. HIV infection and replication
  • inflammatory conditions such as rheuma
  • neuroinflammation-related disorders e.g. brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease
  • atherosclerosis and cardiovascular risk e.g. cardiovascular risk reduction (CvRR), hypertension
  • hidradenitis suppurativa hidradenitis suppurativa
  • Ring A is a 6-membered heteroaryl ring containing 1-3 N atoms
  • R 1a is selected from the group consisting of: H, C1-C4 alkyl, C3-C6 cycloalkyi and C4-C6 heterocycioalkyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyi or C4-C6 heterocycioalkyl groups are optionally substituted with -OH or halogen;
  • R 1b is selected from the group consisting of: halogen, C1-C4 alkyl, -N(R 1a ) 2 and OR 13 ;
  • R 2 is C5-C10 monocyclic or bicyclic aryl or heteroaryl, optionally substituted with one or more substituents selected from R 2a ;
  • R 3 is selected from the group consisting of: H, C1-C2 alkyl, CN, or halogen;
  • E is N or C n is 2.
  • Xa and Xb are each independently selected from N and CR 3 ; or
  • R 3 is selected from the group consisting of: H, C1-C2 alkyl, CN, or halogen; and wherein is an aromatic bond (i.e. a bond in an aromatic system between two sp2 hybridised atoms).
  • a compound of structural Formula Illa or lllb wherein Ring A or Ring B, E, Xa, Xb, R 1 and R 2 are as defined for Formula I, Formula Ila and Formula lib (or sub-formulae thereof); wherein is an aromatic bond.
  • a compound of structural Formula V wherein E, Xa, Xb, R 1 and R 2 are as defined for Formula II and III (including subformulae).
  • C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl groups are optionally substituted with -OH or OR 1a , or halogen.
  • R 2 has the general Form wherein: denotes the attachment point to the bicyclic core;
  • W is a C5-C10 monocyclic aryl or heteroaryl; x is 1 , 2, 3 or 4 wherein R 2a is defined as in Formula I, wherein at least one R 2a is independently selected from the group consisting of: -OH, -[(CR 1a )2]nOH, wherein n is 1 to 3, OR 1a , -NHR 1a , -NHCOR 1a , - NHCON(R ia )2, -NHSO n R 1a -NHSO,iN(R 1a )2, wherein n is 1 or 2, C1-C3 alkyl optionally substituted by R s and/or R 7 , halogen and C1-C3 haloalkyl (e.g.
  • R 2 has the general Formula VII and at least one R 2a is OH or OMe.
  • R 2a is positioned ortho to the attachment point to Ring A.
  • R 2a is OH and positioned ortho to the attachment point to Ring A.
  • R 2 has the general formula Vila, Vllb, Vile or VI Id : denotes the attachment point to the bicyclic core;
  • R 2a and x are as for Formula VII.
  • R 2 is: wherein: denotes the attachment point to the bicyclic core.
  • R 1 is selected from the following:
  • R 1 b is as for Formula I; or wherein two R ic groups are attached to the same atom, the two R 1c groups combine to form an optionally substituted 3-7-membered ring, wherein the 3-7 membered ring may optionally contain 1-2 heteroatoms selected from N or O;
  • G is O or CH 2 ; m is 0, 1 , 2 or 3.
  • compounds of the present invention have a structure as defined in Table 1 (i.e. compounds 1-32, 33-36, 38-45, 52-55, 62, 69, 76-81 , 83-84, 87-92, 94-102, 104-107, 109, 111- 112, 114-117, 120, 122, 125-127, 130, 134-139, 141-158, 160-168, 170, 172-175, 177-178, 180-233).
  • Table 1 i.e. compounds 1-32, 33-36, 38-45, 52-55, 62, 69, 76-81 , 83-84, 87-92, 94-102, 104-107, 109, 111- 112, 114-117, 120, 122, 125-127, 130, 134-139, 141-158, 160-168, 170, 172-175, 177-178, 180-233).
  • compounds of the present invention have the structure of compound nos. 1-32, 33-34, 38-45, 62, 69, 76-77, 80-81 , 83-84, 87-92, 94-102, 104-107, 109, 1 11-112, 114-117, 120, 122, 125-127, 130, 134-139, 141-158, 160-168, 170, 172-175, 177-178, 180-233.
  • the invention provides a pharmaceutical composition comprising one or more compound of the first aspect of the invention or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form, or pharmaceutically active metabolite thereof, or combinations thereof, and one or more pharmaceutically acceptable carrier.
  • the invention provides the compound of the first aspect or the pharmaceutical composition of the second aspect for use in the treatment of a disorder or disease.
  • the disease or disorder is selected from the group consisting of: autoimmune disorder, inflammatory disease, cancer and/or oncologic disease (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis) and/or HIV infection and replication, inflammatory conditions such as rheumatoid arthritis, multiple sclerosis, psoriasis, asthma, atopic dermatitis, Crohn’s disease, autoinflammatory fever syndromes (e.g.
  • CAPS CAPS
  • sickle cell disease Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g. brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, and wound healing and scar formation; hepatic encephalopathy, chronic insomnia, stroke, migraine, atherosclerosis / coronary artery disease, glioma and CNS diseases.
  • CvRR cardiovascular risk reduction
  • CNS diseases or disorders that may be treated by the compounds of the present invention include, but are not limited to: Parkinson’s disease, Alzheimer’s disease, dementia, motor neuron disease, Huntington’s disease, cerebral malaria, brain injury from pneumococcal meningitis, intracranial aneurysms, traumatic brain injury, multiple sclerosis, and amyotrophic lateral sclerosis (see: W02002/063876: (1) page 32 lines 11 , and (2) page 25 line 34 to page 26 line 3, supported with literature references; which are each incorporated herein by reference); see also Song et al, Frontiers Cellular Neurosci.
  • Neurological disorders that involve the NLRP3 inflammasome with references therein which are each incorporated herein by reference: brain infection: S. pneumoniae meningitis, Japanese encephalitis, Influenza virus infection, HIV/AIDS,
  • Acute injury cerebral ischemia, traumatic brain injury, spinal cord injury, subarachnoid haemorrhage, intracerebral haemorrhage
  • Neurodegenerative diseases Alzheimer’s disease, Multiple sclerosis, Amyotprohic lateral sclerosis (with prion diseases as remains controversial)
  • CNS disorders are: Age-related cognitive function (Wang T, et al. Neurochem Int. 2022; 152: 105220); Epilepsy (Zhang H, et al. Neurochem Res. 2022; 47(3): 713- 722); Perioperative neurocognitive disorder (Chen K, et al. Adv Sci.; 2022 : e2104106); Autism (Zhao P, et al.. J Neuropathol Exp Neurol. 2022; ;81 (2): 127-134); Autoimmune encephalomyelitis (Li C, et al.
  • the compound is an inhibitor of NLRP3.
  • the use comprises administering the compound orally; topically; by inhalation; by intranasal administration; or systemically by intravenous, intraperitoneal, subcutaneous, or intramuscular injection.
  • the use comprises administering one or more compound according to the first or second aspects optionally in combination with one or more additional therapeutic agent.
  • the administering comprises administering the one or more compound according to any one of first or second embodiments simultaneously, sequentially or separately from the one or more additional therapeutic agent.
  • the use comprises administering to a subject an effective amount of the compound according to the first or second aspects, wherein the effective amount is between about 5 nM and about 10 pM in the blood, or component thereof, of the subject.
  • the invention provides a method of treatment of a disorder or disease where modulation of the NLRP3 inflammasome may be beneficial, wherein said method of treatment comprises administering to a patient in need thereof, one or more compounds of the first aspect of the invention or one or more pharmaceutical compositions of the second aspect of the invention.
  • the disorder or disease is selected from the group consisting of: autoimmune disorder, inflammatory disease, cancer and/or oncologic disease (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis) and/or HIV infection and replication, inflammatory conditions such as rheumatoid arthritis, multiple sclerosis, psoriasis, asthma, atopic dermatitis, Crohn’s disease, autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type I / Type II diabetes and related complications (e.g.
  • oncologic disease e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis
  • HIV infection and replication e.g. HIV infection and replication
  • inflammatory conditions such as rheumatoid arthritis, multiple s
  • neuroinflammation- reiated disorders e.g. brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease
  • atherosclerosis and cardiovascular risk e.g. cardiovascular risk reduction (CvRR), hypertension
  • hidradenitis suppurativa hidradenitis suppurativa
  • wound healing and scar formation e.g., hidradenitis suppurativa
  • the compound is an inhibitor of NLRP3 or an inhibitor of the NLRP3 inflammasome.
  • the various aspects, embodiments, examples and alternatives set out in the preceding paragraphs, in the claims and/or in the following description and drawings, and in particular the individual features thereof, may be taken independently or in any combination. That is, all embodiments and/or features of any embodiment can be combined in anyway and/or combination, unless such features are incompatible. More particularly, it is specifically intended that any embodiment of any aspect may form an embodiment of any other aspect, and all such combinations are encompassed within the scope of the invention.
  • the applicant reserves the right to change any originally filed claim or file any new claim, accordingly, including the right to amend any originally filed claim to depend on and/or incorporate any feature of any other claim although not originally claimed in that manner.
  • the chemical synthesis and biological testing of the compounds of the disclosure are also described.
  • the compounds, compositions, uses and methods have utility in research towards and/or the treatment of diseases or disorders in animals, such as humans.
  • Diseases or disorders which may benefit from NLRP3 modulation, or modulation of the NLRP3 inflammasome include, for example, autoimmune disorder, inflammatory disease, cancer and/or oncologic disease (e.g.
  • rheumatoid arthritis multiple sclerosis, psoriasis, asthma, atopic dermatitis, Crohn’s disease, autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g. brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, and wound healing and scar formation.
  • CAPS autoinflammatory fever syndromes
  • nephropathy, retinopathy e.g. nephropathy, retinopathy
  • hyperoxaluria gout
  • pseudogout chondrocalcinosis
  • chronic liver disease NASH
  • the compounds may also or alternatively be useful as lead molecules for the selection, screening and development of further derivatives that may have one or more improved beneficial drug property, as desired.
  • Such further selection and screening may be carried out using the proprietary computational evolutionary algorithm described e.g. in the Applicant’s earlier published patent application WO 2011/061548, which is hereby incorporated by reference in its entirety.
  • the disclosure also encompasses salts, solvates and functional derivatives of the compounds described herein. These compounds may be useful in the treatment of diseases or disorders which may benefit from NLRP3 modulation or modulation of the NLRP3 inflammasome, such as autoimmune disorder, inflammatory disease, cancer and/or oncoiogic disease (e.g.
  • coion cancer lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis) and/or HIV infection and replication, inflammatory conditions such as rheumatoid arthritis, multiple sclerosis, psoriasis, asthma, atopic dermatitis, Crohn’s disease, autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation- related disorders (e.g. brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, and wound healing and scar formation.
  • CAPS autoinflammatory fever syndromes
  • the terms 'molecule' or 'molecules are used interchangeably with the terms 'compound' or ‘compounds’, and sometimes the term 'chemical structure'.
  • the term 'drug' is typically used in the context of a pharmaceutical, pharmaceutical composition, medicament or the like, which has a known or predicted physiological or in vitro activity of medical significance; but such characteristics and qualities are not excluded in a molecule or compound of the disclosure.
  • the term 'drug' is therefore used interchangeably with the alternative terms and phrases 'therapeutic (agent)', 'pharmaceutical (agent)’, and 'active (agent)’.
  • Therapeutics according to the disclosure also encompass compositions and pharmaceutical formulations comprising the compounds of the disclosure.
  • Procirugs and solvates of the compounds of the disclosure are also encompassed within the scope of the disclosure.
  • the term 'prodrug' means a compound (e.g. a drug precursor) that is transformed in vivo to yield a compound of the disclosure or a pharmaceutically acceptable salt, solvate or ester of the compound.
  • the transformation may occur by various mechanisms (e.g. by metabolic or chemical processes), such as by hydrolysis of a hydrolysable bond, e.g. in blood (see Higuchi & Stella (1987), "Pro-drugs as Novel Delivery Systems", vol. 14 of the A.C.S. Symposium Series; (1987), "Bioreversible Carriers in Drug Design", Roche, ed., American Pharmaceutical Association and Pergamon Press).
  • the compositions and medicaments of the disclosure therefore may comprise prodrugs of the compounds of the disclosure.
  • the compounds of the disclosure are themselves prodrugs which may be metabolised in vivo to give the therapeutically effective compound.
  • the invention also includes various deuterated forms of the compounds of any of the Formulas disclosed herein, including Formulas I to V (inc. corresponding subgeneric formulas defined herein), respectively, or a pharmaceutically acceptable salt and/or a corresponding tautomer form thereof (including subgeneric formulas, as defined above) of the present invention.
  • Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom.
  • deuterated materials such as alkyl groups may be prepared by conventional techniques (see for example: methyl- d3 -amine available from Aldrich Chemical Co., Milwaukee, Wl, Cat. No.489, 689-2).
  • the subject invention also includes isotopically-labelled compounds which are identical to those recited in any of the Formulas disclosed herein, including Formulas I to V (inc. corresponding subgeneric formulas defined herein), respectively, or a pharmaceutically acceptable salt and/or a corresponding tautomer form thereof (including subgeneric formulas, as defined above) of the present invention but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine such as 3 H, 11 C, 14 C, 18 F, 123 I or 125 I.
  • Compounds of the present invention and pharmaceutically acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention.
  • Isotopically labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H or 14 C have been incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e. 3 H, and carbon-14, i.e. 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography).
  • the terms 'individual', 'subject', or 'patient' are used interchangeably to indicate an animal that may be suffering from a medical (pathological) condition and may be responsive to a molecule, pharmaceutical drug, medical treatment or therapeutic treatment regimen of the disclosure.
  • the animal is suitably a mammal, such as a human, cow, sheep, pig, dog, cat, bat, mouse or rat.
  • the subject may be a human.
  • alkyl refers to a monovalent, optionally substituted, saturated aliphatic hydrocarbon radical. Any number of carbon atoms may be present, but typically the number of carbon atoms in the alkyl group may be from 1 to about 20, from 1 to about 12, from 1 to about 6 or from 1 to about 4. Usefully, the number of carbon atoms is indicated, for example, a C1-12 alkyl (or C1-12 alkyl) refers to any alkyl group containing 1 to 12 carbon atoms in the chain.
  • An alkyl group may be a straight chain (i.e. linear), branched chain, or cyclic.
  • Lower alkyl refers to an alkyl of 1 to 6 carbon atoms in the chain, and may have from 1 to 4 carbon atoms, or 1 to 2 carbon atoms.
  • representative examples of lower alkyl radicals include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, amyl (C5H11), sec-butyl, tert-butyl, sec-amyl, tert-pentyl, 2-ethylbutyl, 2,3-dimethylbutyl, and the like.
  • Higher alkyl refers to alkyls of 7 carbons and above, including n-heptyl, n-octyl, n-nonyl, n-decyl, n-dodecyl, n- tetradecyl, n-hexadecyl, n-octadecyl, n-eicosyl, and the like, along with branched variations thereof.
  • a linear carbon chain of say 4 to 6 carbons would refer to the chain length not including any carbons residing on a branch, whereas in a branched chain it would refer to the total number.
  • Optional substituents for alkyl and other groups are described below.
  • substituted means that one or more hydrogen atoms (attached to a carbon or heteroatom) is replaced with a selection from the indicated group of substituents, provided that the designated atom's normal valency under the existing circumstances is not exceeded.
  • the group may be optionally substituted with particular substituents at positions that do not significantly interfere with the preparation of compounds falling within the scope of this invention and on the understanding that the substitution(s) does not significantly adversely affect the biological activity or structural stability of the compound. Combinations of substituents are permissible only if such combinations result in stable compounds.
  • stable compound or ‘stable structure’, it is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and/or formulation into an efficacious therapeutic agent.
  • optionally substituted it is meant that the group concerned is either unsubstituted, or at least one hydrogen atom is replaced with one of the specified substituent groups, radicals or moieties.
  • radical I group / moiety described herein that may be substituted (or optionally substituted) may be substituted with one or more (e.g. one, two, three, four or five) substituents, which are independently selected from the designated group of substituents.
  • substituents may be selected from the group: halogen (or ‘halo’, e.g.
  • substituents are on an aryl or other cyclic ring system
  • two adjacent atoms may be substituted with a methylenedioxy or ethylenedioxy group.
  • the substituents are selected from: halogen, hydroxy, amino, thiol, cyano, (C1- Ce)alkyl, (Ci-Ca)alkoxy, (Ci-Ce)alkenyl, (Ci-C5)alkynyl, aryl, aryl(Ci-Ce)alkyl, aryl(Ci-Ce)alkoxy, heteroaryl, (Ci-Ce)alkylthio, oxo, halo(Ci-Ce)alkyl, hydroxy(Ci-Ce)alkyl, nitro, phosphate, azido, (C1- Ce)alkoxycarbonyl, carboxy, (Ci-Cs)alkylcarboxy, (Ci-Cs)alkyla
  • the substituents are selected from one or more of: fluoro, chloro, bromo, hydroxy, (Ci-C6)alkyl, (Ci- C6)haloalkyl, (Ci-Celalkoxy, (C5-Cs)aryl, a 5- or 6-membered heteroaryl, (C4-C6)cycloalkyl, a 4- to 6- membered heterocycloalkyl, cyano, (Ci-Cs)alkylthio, amino, -NH(alkyl), -NH((Ci-Cs)cycloalkyl), -N((Ci- C6)alkyl)2, -OC(O)-(Ci-Co)alkyl, -OC(O)-(C5-Ce)aryl, -OC(0)-(Ci-Ce)cycloalkyl, carboxy and -C(O)O- (Ci-Ce)alkyl.
  • the substituents are selected from one or more of: fluoro, chloro, bromo, hydroxy, amino, (Ci-Ce)alkyl and (Ci-Co)alkoxy, wherein alkyl and alkoxy are optionally substituted by one or more chloro.
  • Particularly preferred substituents are: chloro, methyl, ethyl, methoxy and ethoxy
  • halo or ‘halogen’ refers to a monovalent halogen radical chosen from chloro, bromo, iodo, and fluoro.
  • a ‘halogenated’ compound is one substituted with one or more halo substituent.
  • Preferred halo groups are F, Cl and Br, and most preferred is F.
  • the term ‘independently’ in reference to the substitution of a parent moiety with one or more substituents, means that the parent moiety may be substituted with any of the listed substituents, either individually or in combination, and any number of chemically possible substituents may be used. In any of the embodiments, where a group is substituted, it may contain up to 5, up to 4, up to 3, or 1 and 2 substituents.
  • useful substituents include: phenyl or pyridine, independently substituted with one or more lower alkyl, lower alkoxy or halo substituents, such as: chlorophenyl, dichlorophenyl, trichlorophenyl, tolyl, xylyl, 2-chloro-3-methylphenyl, 2,3-dichloro- 4- methylphenyl, etc.
  • alkylene or ‘alkylenyl’ means a difunctional group obtained by removal of a hydrogen atom from an alkyl group as defined above.
  • alkylene include methylene, ethylene and propylene.
  • Lower alkylene means an alkylene having from 1 to 6 carbon atoms in the chain, and may be straight or branched. Alkylene groups are optionally substituted.
  • the number of carbon atoms in the alkenyl group may be indicated, such as from 2 to about 20.
  • a C2- 12 alkenyl or C2-12 alkenyl refers to an alkenyl group containing 2 to 12 carbon atoms in the structure.
  • Alkenyl groups may be straight (i.e. linear), branched chain, or cyclic.
  • Lower alkenyl refers to an alkenyl of 1 to 6 carbon atoms, and may have from 1 to 4 carbon atoms, or 1 to 2 carbon atoms.
  • Representative examples of lower alkenyl radicals include ethenyl, 1-propenyl, 1-butenyl, 1-pentenyl, 1-hexenyl, isopropenyl, isobutenyl, and the like.
  • Higher alkenyl refers to alkenyls of seven carbons and above, such as 1 -heptenyl, 1 -octenyl, 1-nonenyl, 1 -decenyl, 1 -dodecenyl, 1 -tetradecenyl, 1- hexadecenyl, 1 -octadecenyl, 1-eicosenyl, and the like, along with branched variations thereof.
  • Optional substituents include are described elsewhere.
  • the term ‘heteroalkenyl’ refers to an alkenyl comprising one or more heteroatoms. Suitably the heteroatoms are one or more N, O or S.
  • Alkenylene means a difunctional group obtained by removal of a hydrogen from an alkenyl group that is defined above.
  • Alkynyl and ‘lower alkynyl’ is defined similarly to the term ‘alkenyl’, except that it includes at least one carbon-carbon triple bond.
  • alkoxy refers to a monovalent radical of the formula RO-, where R is any alkyl, alkenyl or alkynyl as defined herein. Alkoxy groups may be optionally substituted by any of the optional substituents described herein. ‘Lower alkoxy’ has the formula RO-, where the R group is a lower alkyl, alkenyl or alkynyl.
  • alkoxy radicals include methoxy, ethoxy, n-propoxy, n-butoxy, n- pentyloxy, n-hexyloxy, isopropoxy, isobutoxy, isopentyloxy, amyloxy, sec-butoxy, tert-butoxy, tertpentyloxy, and the like.
  • Preferred alkoxy groups are methoxy and ethoxy.
  • aryl refers to a substituted or unsubstituted aromatic carbocyclic radical containing from 5 to about 15 carbon atoms; and preferably 5 or 6 carbon atoms.
  • An aryl group may have only one individual carbon ring, or may comprise one or more fused rings in which at least one ring is aromatic in nature.
  • a ‘phenyl’ is a radical formed by removal of a hydrogen atom from a benzene ring, and may be substituted or unsubstituted.
  • a ‘phenoxy’ group therefore, is a radical of the formula RO-, wherein R is a phenyl radical.
  • Benzyl is a radical of the formula R-CH2-, wherein R is phenyl
  • ‘benzyloxy’ is a radical of the formula RO-, wherein R is benzyl.
  • aryl radicals include, phenyl, naphthyl, benzyl, biphenyl, furanyl, pyridinyl, indanyl, anthraquinolyl, tetrahydronaphthyi, a benzoic acid radical, a furan-2-carboxylic acid radical, and the like.
  • heteroaryi is herein defined as a substituted or unsubstituted ‘aryl’ group in which one or more carbon atoms in the ring structure has been replaced with a heteroatom, such as nitrogen, oxygen or sulphur.
  • a heteroatom such as nitrogen, oxygen or sulphur.
  • the heteroaryl group contains one or two heteroatoms.
  • a preferred heteroatom is N.
  • heteroaryl groups include: furan, benzofuran, isobenzofuran, pyrrole, indole, isoindole, thiophene, benzothiophene, benzo[c]thiophene, imidazole, benzimidazole, purine, pyrazole, indazole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, pyridine, quinoline, isoquinoline, pyrazine, quinoxaline, acridine, pyrimidine, quinazoline, pyridazine and cinnoline.
  • heterocycle or ‘heterocyclic’ group or ‘heterocyclyl’ as used herein refer to a monovalent radical of from about 4- to about 15- ring atoms, and preferably 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10- ring members.
  • the heterocyclic group contains one, two or three heteroatoms, selected independently from nitrogen, oxygen and sulphur.
  • a preferred heteroatom is N.
  • a heterocyclic group may have only one individual ring or may comprise one or more fused rings in which at least one ring contains a heteroatom. It may be fully saturated or partially saturated and may be substituted or unsubstituted as in the case or aryl and heteroaryi groups.
  • unsaturated 5- membered heterocycles with only one heteroatom include 2- or 3-pyrrolyl, 2- or 3-furanyl, and 2- or 3- thiophenyl.
  • Corresponding partially saturated or fully saturated radicals include 3-pyrrolin-2-yl, 2- or 3- pyrrolindinyl, 2- or 3-tetrahydrofuranyl, and 2- or 3-tetrahydrothiophenyl.
  • Representative unsaturated 5-membered heterocyclic radicals having two heteroatoms include imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and the like. The corresponding fully saturated and partially saturated radicals are also included.
  • unsaturated 6-membered heterocycles with only one heteroatom include 2-, 3-, or 4-pyridinyl, 2H-pyranyl, and 4H-pryanyl.
  • Corresponding partially saturated or fully saturated radicals include 2-, 3-, or 4-piperidinyl, 2-, 3-, or 4-tetrahydropyranyl and the like.
  • Representative unsaturated 6-membered heterocyclic radicals having two heteroatoms include 3- or 4- pyridazinyl, 2-, 4-, or 5-pyrimidinyl, 2-pyrazinyl, morpholino, and the like.
  • the corresponding fully saturated and partially saturated radicals are also included, e.g. 2-piperazine.
  • the heterocyclic radical is bonded through an available carbon atom or heteroatom in the heterocyclic ring directly to the entity or through a linker such as an alkylene such as methylene or ethylene.
  • room temperature is intended to mean a temperature of from about 18 to 28°C, typically between about 18 and 25°C, and more typically between about 18 and 22°C. As used herein, the phrase ‘room temperature’ may be shortened to ‘rt’ or ‘RT’.
  • Ring A is a 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from N, O or S, suitably Ring A is a 6-membered heteroaryi ring containing 1-3 heteroatoms selected from N, O or S, suitably the 1-3 heteroatoms are N;
  • R 1a is selected from the group consisting of: H, C1-C4 alkyl, C3-C6 cycloalkyl and C4-C6 heterocycloalkyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl groups are optionally substituted with -OH or halogen;
  • R 1b is selected from the group consisting of: halogen, C1-C4 alkyl, -N(R 1a ) 2 and OR 1a ;
  • R 2 is C5-C10 monocyclic or bicyclic aryl or heteroaryl, optionally substituted with one or more substituents selected from R 2a ;
  • R 3 is selected from the group consisting of: H, C1-C2 alkyl, CN, or halogen.
  • E is N or C; n is 1 or 2, suitably n is 2.
  • Xa and Xb are each independently selected from N and CR 3 ,; or
  • R 3 is selected from the group consisting of: H, C1-C2 alkyl, CN, or halogen; and wherein is an aromatic bond (i,e. a bond in an aromatic system between two sp2 hybridised atoms).
  • a compound of structural Formula Illa or lllb wherein Ring A or Ring B, E, Xa, Xb, R 1 , R 2 , R3 and R4are as defined for Formula Ila and Formula wherein is an aromatic bond.
  • a compound of structural Formula IV, V and VI wherein Xa, Xb, R 1 , R 1a , R 2 , and R 3 are as defined for Formula II and III (including subformulae);
  • Y is CR 3 , NR 4 , O or S
  • R 4 is H or C1-C4 alkyl.
  • each of the above structures may optionally be substituted with 1 or 2 further substituents dependent on the number of ring atoms available with suitable valency, wherein the further substituents are independently selected from the group consisting of: OR 1a , N(R 1a )2, CN, halogen, C1-C4 alkyl, C4 amido, C1-C4 ester, C1-C4 alkoxy, C3-C6 cycloalkyl and C4-C6 heterocycloalkyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl groups are optionally substituted with -OH, C1-C2 alkyl, or halogen.
  • each of the above structures may optionally be substituted with 1 to 4 further substituents dependent on the number of ring atoms available with suitable valency, wherein the further substituents are independently selected from the group consisting of: OR 1a , N(R 1a )2, -SO 2 R1a , CN, halogen, C1-C4 alkyl, C1-C4 amido, C1-C4 ester, C1-C4 alkoxy, C3-C6 cycloalkyl and C4-C6 heterocycloalkyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycioalkyl groups are optionally substituted with -OH, C1-C2 alkyl, or halogen.
  • embodiments of Formula IV, V or VI have a structural formula as follows: wherein each of the above structures may optionally be substituted with 1 or 2 further substituents dependent on the number of ring atoms available with suitable valency, wherein the further substituents are independently selected from the group consisting of: OR 1a , N(R 1a )2, CN, halogen, C1-C4 alkyl, C4 amido, C1-C4 ester, C1-C4 alkoxy, C3-C6 cycloalkyl and C4-C6 heterocycloalkyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl groups are optionally substituted with -OH, C1-C2 alkyl, or halogen.
  • embodiments of Formula V have a structural formula as follows: wherein each of the above structures may optionally be substituted with 1 or 2 further substituents dependent on the number of ring atoms available with suitable valency, wherein the further substituents are independently selected from the group consisting of: OR 1a , N(R 1a )2, CN, halogen, C1-C4 alkyl, C4 amido, C1-C4 ester, C1-C4 alkoxy, C3-C6 cycloalkyl and C4-C6 heterocycloalkyl, wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl groups are optionally substituted with -OH, C1-C2 alkyl, or halogen.
  • Formula V is on one or more, suitably, one, of the carbon atoms adjacent (alpha to) the ring junction atom.
  • R 2 has the general Form wherein: denotes the attachment point to the bicyclic core;
  • W is a C5-C10 monocyclic aryl or heteroaryl; x is 1 , 2, 3 or 4 wherein R 2a is defined as in Formula I, and wherein at least one R 2a is independently selected from the group consisting of: -OH, -[(CR 1a )2]nOH, wherein n is 1 to 3, OR 1a , -NHR 1a , -NHCOR 1a , - NHCON(R 1a )2, -NHSO n R 1a -NHSO n N(R 1a )2, wherein n is 1 or 2, halogen (e.g.
  • R 2 has the general Formula VII and at least one R 2a is OH or Ome or Me.
  • R 2a is positioned ortho to the attachment point to Ring A.
  • R 2a is OH and positioned ortho to the attachment point to Ring A.
  • R 2 has the general formula Vila, Vllb, Vile or Vi Id : denotes the attachment point to the bicyclic core;
  • R 2a and x are as for Formula VII.
  • R 2a is selected from the group consisting of: Me, CF3, OMe, Cl and F.
  • R 2 is:
  • R 2 is: wherein: denotes the attachment point to the bicyclic core.
  • R 1 is selected from the following: wherein:
  • R 1c is selected from the group consisting of: halogen, -CN, -OR 1 ®, -N(R 1a )2, (CFfeJmOH, C6 cycloalkyl and C4-C6 heterocycloalkyl wherein the C1-C4 alkyl, C3-C6 cycloalkyl or C4-C6 heterocycloalkyl group can be further substituted with 1-3 substituents selected from R ib .
  • R ib is as for Formula I; or wherein two R 1c groups are attached to the same atom, the two R 1c groups combine to form an optionally substituted 3-7-membered ring, wherein the 3-7 membered ring may optionally contain 1-2 heteroatoms selected from N or O;
  • G is O or CH 2 ; m is 0, 1 , 2 or 3.
  • R 1 is selected from the following:
  • the compounds of the present invention have the structure as defined in
  • compounds of the present invention have the structure of compound nos. 1-32, 33-34, 38-45, 62, 69, 76-77, 80-81 , 83-84, 87-92, 94-102, 104-107, 109, 1 11-112, 114-117, 120, 122, 125-127, 130, 134-139, 141-158, 160-168, 170, 172-175, 177-178, 180-233.
  • Suitably compounds of the present invention have the structure of compound nos. 4, 193, 222, 209, 156, 220, 6, 164, 29, 155, 134, 221 , 227, 148, 22, 151 , 198, 155, and 189.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising one or more compound of the first aspect of the invention or a pharmaceutically acceptable salt, solvate, stereoisomer or mixture of stereoisomers, tautomer, isotopic form, or pharmaceutically active metabolite thereof, or combinations thereof, and one or more pharmaceutically acceptable carrier.
  • the invention provides the compound of the first aspect or the pharmaceutical composition of the second aspect for use in the treatment of a disorder or disease selected from inflammasome-related disease / disorders, immune diseases, inflammatory diseases, auto-immune diseases, or auto-inflammatory diseases, for example, autoinflammatory fever syndromes (e.g., cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver related disease / disorders (e.g. chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis related disorders (e.g.
  • a disorder or disease selected from inflammasome-related disease / disorders, immune diseases, inflammatory diseases, auto-immune diseases, or auto-inflammatory diseases, for example, autoinflammatory fever syndromes (e.g., cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE
  • gout gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy e.g. acute, chronic), kidney related diseases (e.g. hyperoxaluria, lupus nephritis, Type I i Type II diabetes and related complications (e.g. nephropathy, retinopathy), hypertensive nephropathy, hemodialysis related inflammation), neuroinflammation-related diseases (e.g, multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), cardiovascular / metabolic diseases/disorders (e.g.
  • CvRR cardiovascular risk reduction
  • PED peripheral artery disease
  • PED peripheral artery disease
  • inflammatory skin diseases e.g. hidradenitis suppurativa, acne
  • wound healing and scar formation e.g. asthma, sarcoidosis, age- related macular degeneration, and cancer related diseases / disorders (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis).
  • autoinflammatory fever syndromes e.g. CAPS
  • sickle cell disease e.g.
  • CvRR cardiovascular risk reduction
  • cancer e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis
  • CNS diseases and disorders as herein before defined.
  • the disorder or disease is selected from the group consisting of: rheumatoid arthritis, multiple sclerosis, psoriasis, atopic dermatitis, autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation- related disorders (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g.
  • CvRR cardiovascular risk reduction
  • hypertension hypertension
  • hidradenitis suppurativa wound healing and scar formation
  • cancer e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis
  • CNS diseases and disorders as herein before defined.
  • the compound is an inhibitor of NL.RP3.
  • the use comprises administering the compound orally; topically; by inhalation; by intranasal administration; or systemically by intravenous, intraperitoneal, subcutaneous, or intramuscular injection.
  • the use comprises administering one or more compound according to the first or second aspects optionally in combination with one or more additional therapeutic agent.
  • the administering comprises administering the one or more compound according to any one of first or second embodiments simultaneously, sequentially or separately from the one or more additional therapeutic agent.
  • the use comprises administering to a subject an effective amount of the compound according to the first or second aspects, wherein the effective amount is between about 5 nM and about 10 pM in the blood, or component thereof, of the subject.
  • the invention provides a method of treatment of a disorder or disease where modulation of the NLRP3 inflammasome may be beneficial wherein said method of treatment comprises administering to a patient in need thereof, one or more compounds of the first aspect of the invention or one or more pharmaceutical compositions of the second aspect of the invention.
  • the disorder or disease is selected from the group consisting of: inflammasome-related disease / disorders, immune diseases, inflammatory diseases, auto-immune diseases, or auto- inflammatory diseases, for example, autoinflammatory fever syndromes (e.g., cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver related disease / disorders (e.g. chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis related disorders (e.g.
  • autoinflammatory fever syndromes e.g., cryopyrin-associated periodic syndrome
  • SLE systemic lupus erythematosus
  • liver related disease / disorders e.g. chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease
  • inflammatory arthritis related disorders
  • gout gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy e.g. acute, chronic), kidney related diseases (e.g. hyperoxaluria, lupus nephritis, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), hypertensive nephropathy, hemodialysis related inflammation), neuroinflammation-related diseases (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), cardiovascular / metabolic diseases/disorders (e.g.
  • CvRR cardiovascular risk reduction
  • PED peripheral artery disease
  • PED peripheral artery disease
  • inflammatory skin diseases e.g. hidradenitis suppurativa, acne
  • wound healing and scar formation e.g. asthma, sarcoidosis, age- related macular degeneration, and cancer related diseases / disorders (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis).
  • autoinflammatory fever syndromes e.g. CAPS
  • sickle cell disease e.g.
  • CvRR cardiovascular risk reduction
  • cancer e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis
  • CNS diseases and disorders as herein before defined.
  • the compound is an inhibitor of NLRP3 or an inhibitor of the NLRP3 inflammasome.
  • NLRP3-induced IL-1 and IL-18 inflammatory responses have been associated with a number of different disorders (Menu et al, Clinical and Experimental Immunology, 2011 , 166, 1-15; Strowig et al, Nature, 2012, 481 , 278-286).
  • autoimmune diseases have been shown to involve NLRP3 including, in particular, multiple sclerosis, type-1 diabetes, psoriasis, rheumatoid arthritis (RA), Behcet's disease, Schnitzler syndrome, macrophage activation syndrome (Braddock et al. Nat. Rev. Drug Disc.2004, 3, 1-10; Inoue et al., Immunology, 2013, 139, 11-18, Coll et al, Nat. Med. 2015, 21 (3), 248-55; Scott et al, Clin. Exp. Rheumatol.
  • RA rheumatoid arthritis
  • NLRP3 has also been shown to play a role in a number of lung diseases including chronic obstructive pulmonary disorder (COPD), asthma (including steroid-resistant asthma), asbestosis, and silicosis (De Nardo et al, Am. J. Pathol., 2014, 184: 42-54; Kim et al. Am. J. Respir.
  • COPD chronic obstructive pulmonary disorder
  • asthma including steroid-resistant asthma
  • asbestosis and silicosis
  • NLRP3 has also been suggested to have a role in a number of central nervous system conditions, including Multiple Sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), dementia, Huntington’s disease, cerebral malaria, brain injury from pneumococcal meningitis (Walsh et al, Nature Reviews, 2014, 15, 84- 97; and Dempsey et al. Brain. Behav. Immun.2017, 61 , 306-16), intracranial aneurysms (Zhang et al. J. Stroke and Cerebrovascular Dis., 2015, 24, 5, 972-9), and traumatic brain injury (Ismael et al. J.
  • MS Multiple Sclerosis
  • PD Parkinson's disease
  • AD Alzheimer's disease
  • Huntington’s disease cerebral malaria
  • brain injury from pneumococcal meningitis Walsh et al, Nature Reviews, 2014, 15, 84- 97; and Dempsey et al. Brain. Behav
  • NRLP3 activity has also been shown to be involved in various metabolic diseases including type 2 diabetes (T2D) and its organ-specific complications, atherosclerosis, obesity, gout, pseudo-gout, metabolic syndrome (Wen et al, Nature Immunology, 2012, 13, 352-357; Duewell et al, Nature, 2010, 464, 1357-1361 ; Strowig et al, Nature, 2014, 481 , 278- 286), and non-alcoholic steatohepatitis (Mridha et al. J. Hepatol. 2017, 66(5), 1037-46).
  • a role for NLRP3 via IL-1 beta has also been suggested in atherosclerosis, myocardial infarction (van Hout et al. Eur. Heart J.2017, 38(1 1), 828-36), heart failure (Sano et al. J. Am. Coll. Cardiol. 2018, 71 (8), 875-66), aortic aneurysm and dissection (Wu et al. Arterioscler. Thromb. Vase. Biol., 2017,37(4), 694-706), and other cardiovascular events (Ridker et al., N. Engl. J. Med., 2017, 377(12), 11 19-31).
  • NLRP3 has been shown to be involved in other conditions including: ocular diseases such as both wet and dry age-related macular degeneration (Doyle et al. Nature Medicine, 2012, 18, 791-798; Tarallo et al. Cell 2012, 149(4), 847-59), diabetic retinopathy (Loukovaara et al. Acta Ophthalmol., 2017, 95(8), 803-8), non-infectious uveitis and optic nerve damage (Puyang et al. Sci.
  • ocular diseases such as both wet and dry age-related macular degeneration (Doyle et al. Nature Medicine, 2012, 18, 791-798; Tarallo et al. Cell 2012, 149(4), 847-59)
  • diabetic retinopathy Likovaara et al. Acta Ophthalmol., 2017, 95(8), 803-8
  • non-infectious uveitis and optic nerve damage Pieris et al. Sci.
  • liver diseases including non-alcoholic steatohepatitis (NASH) and acute alcoholic hepatitis (Henao-Meija et al, Nature, 2012, 482, 179-185); inflammatory reactions in the lung and skin (Primiano et al. J. Immunol.2016, 197(6), 2421-33) including contact hypersensitivity (such as bullous pemphigoid (Fang et al. J Dermatol Sci. 2016, 83(2), 116-23)), atopic dermatitis (Niebuhr et al. Allergy, 2014, 69(8), 1058- 67), Hidradenitis suppurativa (Alikhan et al. J. Am.
  • NLRP3 inflammasome has been found to be activated in response to oxidative stress. NLRP3 has also been shown to be involved in inflammatory hyperalgesia (Dolunay et al, Inflammation, 2017, 40, 366-86). Activation of the NLRP3 inflammasome has been shown to potentiate some pathogenic infections such as influenza and Leishmaniasis (Tate et al., Sci Rep., 2016, 10(6), 27912-20; Novias et al., PLOS Pathogens 2017, 13(2), e1006196).
  • NLRP3 has also been implicated in the pathogenesis of many cancers (Menu et al, Clinical and Experimental Immunology, 2011 , 166, 1-15). For example, several previous studies have suggested a role for IL-1 beta in cancer invasiveness, growth and metastasis, and inhibition of IL-1 beta with canakinumab has been shown to reduce the incidence of lung cancer and total cancer mortality in a randomised, double-blind, placebo-controlled trial (Ridker et al. Lancet., 2017, 390(10105), 1833-42). Inhibition of the NLRP3 inflammasome or IL-1 beta has also been shown to inhibit the proliferation and migration of lung cancer cells in vitro (Wang et al.
  • NLRP3 inflammasome has also been shown to mediate ch emo resista nee of tumor cells to 5-Fluorouracil (Feng et al. J. Exp. Clin. Cancer Res., 2017, 36(1), 81), and activation of NLRP3 inflammasome in peripheral nerve contributes to chemotherapy-induced neuropathic pain (Jia et al. Mol. Pain., 2017, 13, 1-11). NLRP3 has also been shown to be required for the efficient control of viruses, bacteria, and fungi.
  • NLRP3 The activation of NLRP3 leads to cell pyroptosis and this feature plays an important part in the manifestation of clinical disease (Yan-gang et al., Cell Death and Disease, 2017, 8(2), 2579; Alexander et al., Hepatology, 2014, 59(3), 898-910; Baldwin et al., J. Med. Chem., 2016, 59(5), 1691- 1710; Ozaki et al., J. Inflammation Research, 2015, 8, 15-27; Zhen et al., Neuroimmunology Neuroinflammation, 2014, 1 (2), 60-65; Mattia et al., J. Med.
  • the compounds of the present invention exhibit relevant pharmacological properties, e.g. NRLP3 inhibiting properties, e.g. as indicated by in vitro tests as provided in the next section, and are therefore indicated for therapy, prophylaxis (as appropriate) or for use as research chemicals, e.g. as tool compounds.
  • relevant pharmacological properties e.g. NRLP3 inhibiting properties, e.g. as indicated by in vitro tests as provided in the next section, and are therefore indicated for therapy, prophylaxis (as appropriate) or for use as research chemicals, e.g. as tool compounds.
  • the compounds of the invention may be useful in the treatment of an indication selected from: inflammasome-related disease / disorders, immune diseases, inflammatory diseases, auto-immune diseases, or auto-inflammatory diseases, for example, autoinflammatory fever syndromes (e.g., cryopyrin-associated periodic syndrome), sickle cell disease, systemic lupus erythematosus (SLE), liver related disease / disorders (e.g. chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), inflammatory arthritis related disorders (e.g.
  • autoinflammatory fever syndromes e.g., cryopyrin-associated periodic syndrome
  • SLE systemic lupus erythematosus
  • liver related disease / disorders e.g. chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease
  • gout gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy e.g. acute, chronic), kidney related diseases (e.g. hyperoxaluria, lupus nephritis, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), hypertensive nephropathy, hemodialysis related inflammation), neuroinflammation-related diseases (e.g. multiple sclerosis, brain infection, acute injury, neurodeg enerative diseases, Alzheimer’s disease), cardiovascular / metabolic diseases/disorders (e.g.
  • CvRR cardiovascular risk reduction
  • PED peripheral artery disease
  • PED peripheral artery disease
  • inflammatory skin diseases e.g. hidraden itis suppurativa, acne
  • wound healing and scar formation e.g. asthma, sarcoidosis, age-related macular degeneration, and cancer related diseases / disorders (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis).
  • autoinflammatory fever syndromes e.g. CAPS
  • sickle cell disease e.g.
  • CvRR cardiovascular risk reduction
  • cancer e.g. coion cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis
  • CNS diseases and disorders as herein before defined.
  • compounds of the invention may be useful in the treatment of a disease or disorder preferably selected from autoinflammatory fever syndromes (e.g. CAPS), sickle cell disease, Type I / Type II diabetes and related complications (e.g. nephropathy, retinopathy), hyperoxaluria, gout, pseudogout (chondrocalcinosis), chronic liver disease, NASH, neuroinflammation-related disorders (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease), atherosclerosis and cardiovascular risk (e.g. cardiovascular risk reduction (CvRR), hypertension), hidradenitis suppurativa, wound healing and scar formation, and cancer (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis); and CNS diseases and disorders as herein before defined.
  • autoinflammatory fever syndromes e.g. CAPS
  • CAPS autoinflammatory fever syndromes
  • compounds (or ‘active agents’) of the disclosure may beneficially provide a potent and selective (having a selectivity of greater than 5-fold, preferably greater than 20-fold by a suitable measure, such as plC50 in a suitable assay) NLRP3 or the NLRP3 inflammasome inhibition over other NLRP-isoforms, such as NLRP1 , 2 or 4, or other structurally similar receptors.
  • the active agents or compounds of the present invention may be provided as prodrugs of compounds of the disclosure.
  • active agent is typically used to refer to a compound according to the disclosure wh ich has inhibition activity against NLRP3 or the NLRP3 inflammasome; especially under physiological conditions.
  • the active agent may be difficult to administer or deliver to the physiological site of relevance, e.g. due to solubility, half-life or many other chemical or biological reasons. Therefore, it is known to use ‘prodrugs’ of the active agent in order to overcome physiochemical, biological or other barriers in drug efficiency and/or toxicity.
  • An active agent may be formed from a compound or prodrug of the disclosure by metabolism of the drug in vivo, and/or by chemical or enzymatic cleavage of the prodrug in vivo.
  • a prodrug may be a pharmacologically inactive compound that requires chemical or enzymatic transformation to become an effective, active agent inside the body in which it is intended to have its therapeutic effect.
  • the prodrug since a prodrug may, in some embodiments, have very close structural similarity to the active agent, in some such embodiments, the prodrug may also have activity against the NLRP3 target.
  • prodrugs of the disclosure may be active inhibitors of NLRP3.
  • prodrugs may be characterised by having lower inhibition activity against NLRP3 than the drug / active agent that is derived from the prodrug of the disclosure.
  • the prodrug can effectively ‘mask’ the form(s) of the active agent, and in such cases the prodrug may be completely (or essentially) completely inactive under physiological conditions.
  • the compounds, molecules or agents of the disclosure may be used to treat (e.g. cure, alleviate or prevent) one or more diseases, infections or disorders.
  • the compounds and molecules may be manufactured into medicaments or may be incorporated or formulated into pharmaceutical compositions.
  • the molecules, compounds and compositions of the disclosure may be administered by any convenient route, for example, methods of administration include intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intravaginal, transdermal, rectally, by inhalation, or topically to the skin.
  • Delivery systems are also known to include, for example, encapsulation in liposomes, microgels, microparticles, microcapsules, capsules, etc. Any other suitable delivery system known in the art is also envisioned in use.
  • Administration can be systemic or local. The mode of administration may be left to the discretion of the practitioner.
  • the dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic properties of the particular active agent; the chosen mode and route of administration; the age, health and weight of the recipient; the nature of the disease or disorder to be treated; the extent of the symptoms; any simultaneous or concurrent treatments; the frequency of treatment; and the effect desired.
  • a daily dosage of active agent of between about 0.001 and about 1 ,000 mg/kg of body weight can be expected.
  • the dosage may suitably be within the range of about 0.01 to about 100 mg/kg; between about 0.1 to about 25 mg/kg, or between about 0.5 and 10 mg/kg.
  • the required dosage of the active agent may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of e.g. two, three, or four times daily.
  • the therapeutic treatment regime according to the disclosure is devised for a single daily dose or for a divided daily dose of two doses.
  • Dosage forms of the pharmaceutical compositions of the disclosure suitable for administration may contain from about 1 mg to about 2,000 mg of the active ingredient per unit.
  • the daily dosage of compounds may be at least about 10 mg and at most about 1 ,500 mg per human dose; such as between about 25 and 1 ,250 mg or suitably between about 50 and 1 ,000 mg.
  • the daily dosage of compounds may be at most about 1000 mg.
  • the compound of the invention will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
  • the 'effective amount' or 'therapeutically effective amount' is meant to describe an amount of compound or a composition of the disclosure that is effective in curing, inhibiting, alleviating, reducing or preventing the adverse effects of the diseases or disorders to be treated, or the amount necessary to achieve a physiological or biochemically-detectable effect.
  • the compound or agent is able to produce the desired therapeutic, ameliorative, inhibitory or preventative effect in relation to disease or disorder.
  • an effective amount of the compound or composition of the disclosure may have the effect of inhibiting NLRP3.
  • Diseases or disorders which may benefit from NLRP3 inhibition include, for example, autoimmune disorders, inflammatory diseases, cancers and/or oncologic diseases, inflammatory conditions such as rheumatoid arthritis, multiple sclerosis, psoriasis, Sjogren's syndrome and systemic lupus erythematosus or vasculitic conditions, cancers of hematopoietic origin or solid tumors, including chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin lymphoma and other B cell lymphomas; and CNS diseases and disorders as herein before defined.
  • the effective amount or therapeutically effective amount of a compound / active agent of the disclosure may be at least about 50 nM or at least about 100 nM; typically at least about 200 nM or at least about 300 nM in the blood of the subject.
  • the effective amount or therapeutically effective amount may be at most about 5 pM, at most about 3 pM, suitably at most about 2 pM and typically at most about 1 pM in the blood of the subject.
  • the therapeutically effective amount may be at most about 500 nM, such as between about 100 nM and 500 nM.
  • the amount of therapeutic compound is measured in serum of the subject and the above concentrations may then apply to serum concentration of the compounds of the disclosure.
  • a compound of the disclosure When administered to a subject, a compound of the disclosure is suitably administered as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle.
  • a pharmaceutically acceptable carrier or vehicle One or more additional pharmaceutical acceptable carrier (such as diluents, adjuvants, excipients or vehicles) may be combined with the compound of the disclosure in a pharmaceutical composition.
  • additional pharmaceutical acceptable carrier such as diluents, adjuvants, excipients or vehicles
  • Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E. W. Martin. Pharmaceutical formulations and compositions of the disclosure are formulated to conform to regulatory standards and according to the chosen route of administration.
  • Acceptable pharmaceutical vehicles can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the pharmaceutical vehicles can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like.
  • auxiliary, stabilising, thickening, lubricating and colouring agents may be used.
  • the pharmaceutically acceptable vehicles are generally sterile. Water is a suitable vehicle when the compound is to be administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid vehicles, particularly for injectable solutions.
  • Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or buffering agents.
  • the medicaments and pharmaceutical compositions of the disclosure can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, powders, gels, capsules (for example, capsules containing liquids or powders), modified-release formulations (such as slow or sustained-release formulations), suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
  • suitable pharmaceutical vehicles are described in Remington's Pharmaceutical Sciences, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa., 19th ed., 1995, see for example pages 1447- 1676.
  • compositions or medicaments of the disclosure are formulated in accordance with routine procedures as a pharmaceutical composition adapted for oral administration (more suitably for humans).
  • Compositions for oral delivery may be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example.
  • the pharmaceutically acceptable vehicle is a capsule, tablet or pill.
  • Orally administered compositions may contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavouring agents such as peppermint, oil of Wintergreen, or cherry; colouring agents; and preserving agents, to provide a pharmaceutically palatable preparation.
  • sweetening agents such as fructose, aspartame or saccharin
  • flavouring agents such as peppermint, oil of Wintergreen, or cherry
  • colouring agents such as peppermint, oil of Wintergreen, or cherry
  • preserving agents to provide a pharmaceutically palatable preparation.
  • the compositions When the composition is in the form of a tablet or pill, the compositions may be coated to delay disintegration and absorption in the gastrointestinal tract, so as to provide a sustained release of active agent over an extended period of time.
  • Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compositions. In these dosage forms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which
  • dosage forms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations.
  • a time delay material such as glycerol monostearate or glycerol stearate may also be used.
  • Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Such vehicles are preferably of pharmaceutical grade.
  • the location of release may be the stomach, the small intestine (the duodenum, the jejunem, or the ileum), or the large intestine.
  • One skilled in the art is able to prepare formulations that will not dissolve in the stomach yet will release the material in the duodenum or elsewhere in the intestine.
  • the release will avoid the deleterious effects of the stomach environment, either by protection of the compound (or composition) or by release of the compound (or composition) beyond the stomach environment, such as in the intestine.
  • a coating impermeable to at least pH 5.0 would be essential.
  • examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and Shellac, which may be used as mixed films.
  • compositions and/or compounds of the disclosure may cause undesirable side-effects, such as intestinal inflammation which may lead to premature termination of a therapeutic treatment regime.
  • the therapeutic treatment regime is adapted to accommodate ‘treatment holidays’, e.g. one or more days of non-administration.
  • treatment regimens and therapeutic methods of the disclosure may comprise a repetitive process comprising administration of the therapeutic composition or compound for a number of consecutive days, followed by a treatment holiday of one or more consecutive days.
  • a treatment regime of the disclosure may comprise a repetitive cycle of administration of the therapeutic composition or compound for between 1 and 49 consecutive days, between 2 and 42 days, between 3 and 35 days, between 4 and 28 days, between 5 and 21 days, between 6 and 14 days, or between 7 and 10 days; followed by a treatment holiday of between 1 and 14 consecutive days, between 1 and 12 days, between 1 and 10 days, or between 1 and 7 days (e.g. 1 , 2, 3, 4, 5, 6 or 7 days).
  • surfactant might be added as a wetting agent.
  • Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate.
  • anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate.
  • Cationic detergents might be used and could include benzalkonium chloride or benzethomium chloride.
  • Nonionic detergents that could be included in the formulation as surfactants include: lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 20, 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants, when used, could be present in the formulation of the compound or derivative either alone or as a mixture in different ratios.
  • compositions for intravenous administration comprise sterile isotonic aqueous buffer.
  • the compositions may also include a solubilising agent.
  • Another suitable route of administration for the therapeutic compositions of the disclosure is via pulmonary or nasal delivery.
  • Additives may be included to enhance cellular uptake of the therapeutic agent of the disclosure, such as the fatty acids oleic acid, linoleic acid and linolenic acid.
  • the therapeutic agents of the disclosure may also be formulated into compositions for topical application to the skin of a subject.
  • the agents may be formulated separately or in a single dosage form, depending on the prescribed most suitable administration regime for each of the agents concerned.
  • the pharmaceutical compositions of the invention may be used in a treatment regime involving simultaneous, separate or sequential administration with the other one or more therapeutic agent.
  • the other therapeutic agent(s) may comprise a compound of the disclosure or a therapeutic agent known in the art).
  • the compounds and/or pharmaceutical compositions of the disclosure may be formulated and suitable for administration to the central nervous system (CNS) and/or for crossing the blood-brain barrier (BBB).
  • CNS central nervous system
  • BBB blood-brain barrier
  • Sample preparation Powders were solubilized in CDCb or DMSO-de transferred to a NMR tube for data acquisition.
  • Method B 0-60AB, Agiient instrument: Agiient 1260XG6125B SingieQuad; Column: Porosheil 120 EC C18 2.7pm 3.0*30mm; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0.00-3.00 min 0%-60%;B, 3.00-3.60 min 60% B; 3.60-3.61 min 60%-0% B; 3.61-4.00 min 0% B; flow 1 .0-1 .5 ml/min; temperature: 50 °C; DAD: 220 nm & 254 nm.
  • Instrument Agilent 1260 ⁇ G6125B SingleQuad; Column: XBridge C18 2.1*50mm, 5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0.00-0.70 min 0%-60%;B, 0.70- 1 .00 min 60% B; 1 .00-1 .01 min 60%-0% B; 1 .01-1 .10 min 0% B; flow 1 .5-2 ml/min; temperature: 40 °C; DAD: 220 nm & 254 nm.
  • Method H 0-60CD, Agilent Instrument: Agilent 1260XG6125B SingleQuad; Column: Waters XBridge C18 2.1 *50mm, 5um; eluent A: water * 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0.00-3.00 min 0%-60%;B, 3.00-3.60 min 60% B; 3.60-3.61 min 60%-0% B; 3.61-4.00 min 0% B; flow 0.8 ml/min; temperature: 40 °C; DAD: 220 nm & 254 nm.
  • Instrument Agilent 1260 ⁇ G6125B SingleQuad; Column: XBridge C18 2.1*50mm, 5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0.00-0.70 min 5%-95%;B, 0.70- 1.00 min 95% B; 1.00-1.01 min 95%-5% B; 1.01-1.10 min 5% B; flow 1.5-2 ml/min; temperature: 40 °C; DAD: 220 nm & 254 nm.
  • Instrument SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex® EVO C18 2.1x30mm 5um; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0.00-0.60 min 0%-60%;B, 0.60-0.78 min 60% B; 0.78-0.79 min 60%-0% B; 0.79-0.80 min 0% B; flow 2 ml/min; temperature: 50 °C; PDA: 220 nm & 254 nm.
  • Instrument SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex® EVO C182.1x30mm 5um; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0.00-0.60 min 30%-90%;B, 0.60-0.95 min 90%-100% B; 0.95-0.96 min 100%-30% B; 0.96- 1 .00 min 30% B; flow 1 .5-2 ml/min; temperature: 50 °C; PDA: 220 nm & 254 nm.
  • Method V 0-60CD, Shimadzu instrument: SHIMADZU LCMS-2020 SingleQuad; Column: XBridge C18 2.1 *30mm, 3.5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0.00-0.80 min 0%-60%;B, 0.80-0.94 min 60% B; 0.94-0.95 min 60%-0% B; 0.95-1.00 min 0% B; flow 1.5-2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.
  • Instrument SHIMADZU LCMS-2020 SingleQuad; Column: XBridge C18 2.1*50mm, 5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0.00-3.00 min 0%-60%;B, 3.00-3.70 min 60% B; 3.70-3.71 min 60%-0% B; 3.71-4.00 min 0% B; flow 0.6-1 .2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.
  • Instrument SHIMADZU LCMS-2020 SingleQuad; Column: XBridge C18 2.1 *30mm, 3.5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0.00-0.80 min 5%-95%;B, 0.80-0.94 min 95% B; 0.94-0.95 min 95%-5% B; 0.95-1.00 min 5% B; flow 1.5-2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.
  • Instrument SHIMADZU LCMS-2020 SingleQuad; Column: XBridge C18 2.1*50mm, 5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0.00-3.00 min 5%-95%;B, 3.00-3.70 min 95% B; 3.70-3.71 min 95%-5% B; 3.71-4.00 min 5% B; flow 0.6-1 .2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.
  • Instrument SHIMADZU LCMS-2020 SingleQuad; Column: XBridge C18 2.1*30mm, 3.5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0.00-0.60 min 30%-100%;B, 0.60-0.94 min 100% B; 0.94-0.95 min 100%-30% B; 0.95-1.00 min 30% B; flow 1 .5-2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.
  • Instrument SHIMADZU LCMS-2020 SingleQuad; Column: XBridge C18 2.1*50mm, 5um; eluent A: water + 0.025 vol % ammonium hydroxide, eluent B: acetonitrile; gradient: 0.00-2.50 min 30%-100%;B, 2.50-3.70 min 100% B; 3.70-3.71 min 100%-30% B; 3.71-4.00 min 30% B; flow 0.6-1.2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.
  • Method AB 0-60N, Shimadzu Instrument: SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex® EVO C18 2.1x30mm 5um; eluent A: water + 10mM ammonium bicarbonate, eluent B: acetonitrile; gradient: 0.00-0.80 min 0%-60%;B, 0.80-0.95 min 60% B; 0.95-0.96 min 60%-0% B; 0.96-1.00 min 0% B; flow 1.5-2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.
  • Instrument SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex® EVO C18 2.1x30mm 5um; eluent A: water + 10mM ammonium bicarbonate, eluent B: acetonitrile; gradient: 0.00-0.80 min 5%-95%;B, 0.80-0.95 min 95% B; 0.95-0.96 min 95%-5% B; 0.96-1.00 min 5% B; flow 1.5-2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.
  • Instrument SHIMADZU LCMS-2020 SingleQuad; Column: XBridge C18 2.1*30mm, 3.5um; eluent A: water* 10mM ammonium bicarbonate, eluent B: acetonitrile; gradient: 0.00-0.60 min 30%-90%;B, 0.60- 0.95 min 90%-100% B; 0.95-0.96 min 100%-30% B; 0.96-1.00 min 30% B; flow 1.5-2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.
  • Instrument SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex® EVO C18 2.1x30mm 5um; eluent A: water * 10mM ammonium bicarbonate, eluent B: acetonitrile; gradient: 0.00-0.60 min 30%-90%;B, 0.60-0.95 min 90%-100% B; 0.95-0.96 min 100%-30% B; 0.96-1.00 min 30% B; flow 1.5-2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.
  • Instrument SHIMADZU LCMS-2020 SingleQuad; Column: Kinetex® EVO C18 2.1x30mm 5um; eluent A: water + 10mM ammonium bicarbonate, eluent B: acetonitrile; gradient: 0.00-2.60 min 30%-90%;B, 2.60-3.85 min 90%-100% B; 3.85-3.86 min 100%-30% B; 3.86-4.00 min 30% B; flow 0.4-1 .2 ml/min; temperature: 40 °C; PDA: 220 nm & 254 nm.
  • Method AJ HPLC: Instrument: SHIMADZU LC-20AD SingleQuad; Column: Kinetex C18 LC Column 4.6X50mm,5um; eluent A: water + 0.0375 vol % trifluoroacetic acid, eluent B: acetonitrile + 0.01875 vol % trifluoroacetic acid; gradient: 0-2.40 min, 10-80% B, 2.40-3.70 min 80% B; 3.70-3.71 min 80-10% B; 3.71-4.00 min 10% B; flow 1.5 ml/min; temperature: 50 °C; PDA: 220 nm & 215 nm & 254 nm.
  • the reaction mixture was partitioned between sat. aq. sodium bicarbonate and 10% MeOH in DCM (10 mL of each). The layers were separated, and the aqueous was extracted with 10% MeOH in DCM (10 mL). The combined organics were washed with brine (3 x 10 mL), passed through a hydrophobic frit, and concentrated in vacuo to yield an orange gum.
  • reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (80 mL x 2). The combined organic layers were washed with brine (80 mL), dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate. Filtered and the filtrate was concentrated under reduced pressure to give a residue.
  • the crude was purified by reversed-phase column (column: C18, 40 g, mobile phase: [water(FA) - MeCN]; B%: 30% - 70%, 7 min) to give compound methyl 7-(2-hydroxy-4,6-dimethyl-phenyl)-2-(1-methyl-3-piperidyl)-1 ,8-naphthyridine-4- carboxylate (450 mg, 832 pmol, 71 % yield, 75% purity) as a yellow solid.
  • Compound 10 was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um); mobile phase: [CO 2 -MeCN/i-PrOH(0.1 % NH3-H2O)]; B%: 30%, isocratic elution mode) to give compound 11 (5.00 mg, 13.1 pmol, 20% yield, 99% purity) as a yellow solid and compound 12 (10.0 mg, 26.2 pmol, 40% yield, 99% purity) as a yellow solid.
  • SFC column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 um); mobile phase: [CO 2 -MeCN/i-PrOH(0.1 % NH3-H2O)]; B%: 30%, isocratic elution mode
  • Compound 13 was separated by SFC: (column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 um);mobile phase: [CO 2 -MeCN/i-PrOH(0.1 % NH3-H2O)]; B%: 55%-55%, 4.5 min is ocratic elution mode) to give compound 14 (7.31 mg, 19.6 pmol, 35% yield, 97% purity) as a yellow solid and compound 15 (9.70 mg, 25.7 pmol, 47% yield, 96% purity) as a yellow solid.
  • SFC column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 um);mobile phase: [CO 2 -MeCN/i-PrOH(0.1 % NH3-H2O)]; B%: 55%-55%, 4.5 min is ocratic elution mode
  • Compound 20 was separated by SFC: (column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 pm); mobile phase: [MeCN/IPA(0.1 %NH3H20)];B%:50%, isocratic elution mode) to give compound 21 (28.4 mg, 77.7 pmol, 28% yield, 99% purity) as a yellow solid and compound 22 (33.7 mg, 92.3 pmol, 33% yield, 99% purity) as a yellow solid.
  • SFC column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 pm); mobile phase: [MeCN/IPA(0.1 %NH3H20)];B%:50%, isocratic elution mode
  • Compound 25 was separated by SFC (column: DAICEL CHIRALPAK AY-H (250 mm x 30 mm, 10 pm); mobile phase: [dioxide carbon- acetonitrile/ ethanol (0.100% NHs’HzO)]; B%: 65%-65%, 7.8 min) to give compound 26 (54.8 mg, 148 pmol, 98% purity, 25% yield) as a yellow solid and compound 27 (49.0 mg, 128 pmol, 95% purity, 22% yield) as a yellow solid.
  • SFC column: DAICEL CHIRALPAK AY-H (250 mm x 30 mm, 10 pm); mobile phase: [dioxide carbon- acetonitrile/ ethanol (0.100% NHs’HzO)]; B%: 65%-65%, 7.8 min) to give compound 26 (54.8 mg, 148 pmol, 98% purity, 25% yield) as a yellow solid and compound 27 (49.0 mg, 128 pmol
  • the residue was purified by reversed phase (column: C18 40 g, mobile phase: [water (FA) - MeCN]; B%: 2Q%-70%, 7 min) to give the desired product.
  • the residue was separated by SFC (column: DAICEL CHIRALPAK AY-H (250 mm x 30 mm, 10 pm); mobile phase: [CO 2 -EtOH (0.1 % NH 3 *H 2 O)]; 35% B isocratic elution mode) to give compound 28 (12.3 mg, 30.0 pmol, 4% yield, 99% purity) and compound 29 (55.6 mg, 137 pmol, 17% yield, 99% purity) as a yellow solid.
  • N-[2-(2-methoxy-4,6-dimethyl-phenyl)-7-(3-piperidyl)-1 ,8-naphthyridin-4-yl]acetamide (64.1 mg, 159 pmol, 1 eq, HCI salt) in methanol (5 mL) were added potassium acetate (25.0 mg, 255 pmol, 1.61 eq), HCHO (9.81 mg, 327 pmol, 9.00 pL, 37% purity in water, 2.06 eq) and sodium cyanoboranuide (20.0 mg, 318 pmol, 2.01 eq) at 0 °C.
  • Compound 30 was separated by SFC (column: DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 um);mobile phase: [dioxide carbon-acetonitrile/ethanol (0.100% ammonium hydroxide)]; B%: 60%, isocratic elution mode) to give compound 31 (single enantiomer) (12.0 mg, 26.3 pmol, 22% yield, 99% purity, formate) as a yellow solid and compound 32 (single enantiomer) (15.6 mg, 34.2 pmol, 27% yield, 99% purity, formate) (15.58 mg, 38.52 pmol, 32% yield, 99% purity) as a yellow solid.
  • SFC column: DAICEL CHIRALPAK IC (250 mm x 30 mm, 10 um);mobile phase: [dioxide carbon-acetonitrile/ethanol (0.100% ammonium hydroxide)]; B%: 60%, isocratic el
  • the racemate was separated by SFC (column: DAICEL CHIRALPAK AY-H (250 mm x 30 mm, 10 um); mobile phase: [COs-MeCN/ MeOH (0.1 % NHs’HaO)]; B%: 40%, isocratic elution mode) to give Compound 34 (158 mg, 430 pmol, 36% yield, 99% purity) as a yellow solid.
  • the reaction mixture was partitioned between water and EtOAc (25 mL of each). The layers were separated, and the aqueous was extracted with EtOAc (2 x 25 mL). The combined organics were dried with Na2SO4, filtered, and concentrated in vacuo to yield a brown gum. The crude was purified by automated column chromatography (0 to 20% EtOAc in cyclohexane).
  • the vial was evacuated and back-filled with nitrogen three times, then 1 ,4-Dioxane (5 mL) was added, followed by 2 M potassium carbonate in water (1.08 mL, 2.16 mmol, 3 eq).
  • the reaction was heated to 90 °C, and left to stir for 1 hour.
  • the reaction mixture was partitioned between sat. aq. Sodium bicarbonate and 10% MeOH in DCM (20 mL of each). The layers were separated, and the aqueous was extracted with 10% MeOH in DCM (20 mL).
  • the combined organics were passed through a hydrophobic frit, and concentrated in vacuo to yield a brown gum.
  • the reaction was set up for SFC separation.
  • the residue was purified by SFC: (column: DAICEL CHIRALPAK IG (250mm x 30mm,10pm);mobile phase: [CO 2 -i-PrOH(0.1 %NH3 «H2O)];B%:50%, isocratic elution mode) to give Compound 38 (90.9 mg, 208 pmol, 49% yield, 97% purity) as a yellow solid.
  • the reaction was set up for SFC separation.
  • the residue was purified by SFC: (column: DAICEL CHIRALCEL OJ (250mm*30mm,10pm);mobile phase: [0.1 % NH 3 «H 2 O «MeOH];B%:10%, isocratic elution mode) to give 3,5-dimethyl-2-[7-[rel-(3S)-1-(3,3,3-trifluoropropyl)-3-piperidyl]-1 ,8-naphthyridin- 2-yl]phenol (15.4 mg, 33.2 pmol, 14% yield, 93% purity) as a yellow solid and 3,5-dimethyl-2-[7-[rel- (3S)-1-(3,3,3-trifluoropropyl)-3-piperidyl]-1 ,8-naphthyridin-2-yl]phenol (34.1 mg, 77.1 pmol, 33% yield, 97% purity) as a yellow solid.
  • the reaction was set up for SFC separation.
  • the residue was purified by SFC: (column: DAICEL CHIRALCEL OD (250mm x 50mm, 10 urn); mobile phase: [CO 2 -i-PrOH (0.1 % NHs’FW)]; B%: 35%, isocratic elution mode) to give 3-[7-(2-hydroxy-4,6-dimethyl-phenyl)-1 ,8-naphthyridin-2-yl]-1-methyl- piperidin-3-ol (15.0 mg, 40.8 pmol, 14% yield, 99% purity) as a white solid and 3-[7-(2-hydroxy-4,6- dimethyl-phenyl)-1 ,8-naphthyridin ⁇ 2-yi]-1 -methyl-piperidin-3-oi (15.0 mg, 40.4 pmol, 14% yield, 98% purity) as a white solid.
  • reaction mixture was quenched by saturated sodium bicarbonate aqueous solution (50 mL) at 0 °C, and then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue.

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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des composés, des compositions et des méthodes de traitement d'une maladie, de syndromes, d'états pathologiques et de troubles qui sont affectés par la modulation de NLRP3 et/ou de l'inflammasome NLRP3. De tels composés sont représentés par la formule (I), dans laquelle les variables sont définies dans la description.
PCT/GB2023/052363 2022-09-12 2023-09-12 Modulateurs de nlrp3 Ceased WO2024057013A1 (fr)

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GB2213320.1 2022-09-12
GBGB2213320.1A GB202213320D0 (en) 2022-09-12 2022-09-12 Nlrp3 modulators
GBGB2306477.7A GB202306477D0 (en) 2023-05-02 2023-05-02 Nlrp3 modulators
GB2306477.7 2023-05-02

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024169895A1 (fr) * 2023-02-14 2024-08-22 深圳众格生物科技有限公司 Composé pour inhiber nlrp3, procédé de préparation et utilisation
WO2025067343A1 (fr) * 2023-09-27 2025-04-03 纽欧申医药(上海)有限公司 Composé cyclique fusionné et son utilisation
WO2025153532A1 (fr) 2024-01-16 2025-07-24 NodThera Limited Polythérapies faisant intervenir des inhibiteurs de nlrp3 et des agonistes de glp-1
WO2025233837A1 (fr) 2024-05-07 2025-11-13 Takeda Pharmaceutical Company Limited Dérivés de 4h-pyrimido[1,2-a]pyrimidin-4-one destinés à être utilisés en tant qu'inhibiteurs de l'inflammasome nlrp3 pour le traitement d'un trouble neurodégénératif

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024169895A1 (fr) * 2023-02-14 2024-08-22 深圳众格生物科技有限公司 Composé pour inhiber nlrp3, procédé de préparation et utilisation
WO2025067343A1 (fr) * 2023-09-27 2025-04-03 纽欧申医药(上海)有限公司 Composé cyclique fusionné et son utilisation
WO2025153532A1 (fr) 2024-01-16 2025-07-24 NodThera Limited Polythérapies faisant intervenir des inhibiteurs de nlrp3 et des agonistes de glp-1
WO2025233837A1 (fr) 2024-05-07 2025-11-13 Takeda Pharmaceutical Company Limited Dérivés de 4h-pyrimido[1,2-a]pyrimidin-4-one destinés à être utilisés en tant qu'inhibiteurs de l'inflammasome nlrp3 pour le traitement d'un trouble neurodégénératif

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