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WO2025133307A1 - Heterocyclic modulators of the nlrp3 inflammasome pathway - Google Patents

Heterocyclic modulators of the nlrp3 inflammasome pathway Download PDF

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Publication number
WO2025133307A1
WO2025133307A1 PCT/EP2024/088193 EP2024088193W WO2025133307A1 WO 2025133307 A1 WO2025133307 A1 WO 2025133307A1 EP 2024088193 W EP2024088193 W EP 2024088193W WO 2025133307 A1 WO2025133307 A1 WO 2025133307A1
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disease
syndrome
disorder
compound
abnormality
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French (fr)
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Jérôme Molette
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AC Immune SA
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AC Immune SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to novel compounds that are useful for the treatment, alleviation or prevention of a disease, disorder or abnormality which is responsive to the modulation, in particular inhibition of the activation, of a component of the NLRP3 inflammasome pathway.
  • the component of the inflammasome pathway is NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome.
  • NLR NOD-like receptor
  • NLRP3 inflammasome pathway is NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome.
  • the compounds of the present invention have the capability to modulate, e.g., inhibit the activation of, the NLRP3 inflammasome pathway.
  • the compounds of the present invention have the capability to modulate, in particular decrease, IL-1 beta and/or IL-18 levels.
  • the present invention relates to novel compounds for the treatment, alleviation or prevention of a disease, disorder or abnormality which is responsive to the inhibition of the activation of the NLRP3 inflammasome pathway.
  • the present invention relates to novel compounds for the treatment, alleviation or prevention of a disease, disorder or abnormality which is responsive to the modulation of IL-1 beta and/or IL-18 levels.
  • the present invention relates to pharmaceutical compositions comprising said compounds, methods of using said compounds in the treatment of various diseases, disorders or abnormalities which is responsive to the above-mentioned modulation, medicaments containing them and their uses thereof.
  • Inflammasome protein complexes are the key components of inflammatory signalling. These complexes assemble in response to various danger signals such as molecules from infectious agents (pathogen-associated molecular patterns, PAMPs) as well as altered host molecules, products of sterile tissue damage and environmental factors (danger associated molecular paterns, DAMPs).
  • the inflammasome family consists of NALP1-14, I RAF, and NAIP 1-6, with each family member providing specificity towards different PAMPs/DAMPs including nucleic acids, bacterial proteins, metabolites, protein aggregates and the activity of toxins (Sharma, D. & Kanneganti, T.D. The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation. J. Cell Biol.
  • Inflammasomes are typically composed of a sensor (a cytosolic pattern-recognition receptor, PRR) and an adaptor protein called apoptosis associated speck-like protein containing a caspase-recruitment domain (CARD) (ASC), and an effector such as the protease caspase-1 (Broz, P.; Dixit, V. M. Inflammasomes: Mechanism of Assembly, Regulation and Signalling, Nat. Rev. Immunol. 2016, 16, 407-420).
  • PRR cytosolic pattern-recognition receptor
  • ASC caspase-recruitment domain
  • NLRP3 NOD-like receptor (NLR) family, pyrin domain-containing protein 3 inflammasome is one of the best-described family members. It is a tripartite protein of the NLR family and contains an aminoterminal PYRIN (PYD) domain, a nucleotide-binding NACHT domain and a carboxy-terminal leucine- rich repeat (LRR) domain.
  • PYD PYRIN
  • LRR carboxy-terminal leucine- rich repeat
  • the NLRP3 sensor molecule assembles into a multi-molecular complex with apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC aka PYCARD) adaptor protein.
  • ASC caspase activation and recruitment domain
  • ASC protein polymerization into a large complex leads to activation of caspase-1 effector protein and subsequent cleavage of pro-IL-1 beta (p) and pro-IL18 into their active secreted forms and mediates pyroptosis (Heneka et al., 2018 Nat Rev Neurosci).
  • IL-1 beta (p) acts through IL-1 beta (p) receptors, induces secondary pro-inflammatory signals including IL-6 and TNF alpha secretion, and attracts and activates cells of adaptive immune system at the sites of infection.
  • NLRP3/ASC complexes seems to be released into the extracellular environment where they can propagate inflammation.
  • NLRP3 gain-of-function mutations lead to the inherited cryopyrin-associated periodic syndromes (CAPS) including Muckle-Wells syndrome (MWS), familial cold auto-inflammatory syndrome (FCAS) and neonatal-onset multisystem inflammatory disease (NOMID).
  • CUS cryopyrin-associated periodic syndromes
  • MFS Muckle-Wells syndrome
  • FCAS familial cold auto-inflammatory syndrome
  • NOMID neonatal-onset multisystem inflammatory disease
  • NLRP3 inflammasome Accumulation of tissue damage products associated with ageing results in activation of NLRP3 inflammasome in multiple diseases including metabolic disorders, Alzheimer’s disease, Parkinson's disease, amyotrophic lateral sclerosis, atherosclerosis, obesity, lung diseases, liver diseases and gout.
  • NLRP3-inflammasome genetic or pharmacological downregulation showed protection in models of Alzheimer’s disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, type 1 and type 2 diabetes, rheumatoid arthritis, and myelodysplastic syndrome, among others (Heneka et a/., Nat. Rev. Neurosci. 2018 Oct; 19(10):610-621; Mangan et a/., Nat.
  • NLRP3-related diseases include biologies targeting IL-1. These are the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1 beta (p) antibody canakinumab and the soluble decoy IL-1 receptor rilonacept. However, their activity is limited to downstream effectors of inflammasome and their bioavailability for central nervous system (CNS) applications is limited.
  • CNS central nervous system
  • sulfonylurea-based compounds include various chemical classes such as sulfonylurea-based compounds (glyburide, CP-456,773 (aka CRID3 and MCC950) and its derivatives); fenamate classes of non-steroidal anti-inflammatory drugs; hydroxysulfonamide analogue JC-171 : novel boron compound series; benzimidazole-containing structure Fc1 la-2; polyketide spirodalesol; acrylate and acrylamide derivatives; 3,4-methylenedioxy-p-nitrostyrene; p-sulfonyl nitrile molecule OLT1177; CY-09; BOT-4-one; and Michael acceptors. Most of these compounds have a promiscuous mode of action and limited potency.
  • WO2016131098, WO2017140778 and WO2018215818 referto sulfonylurea and related compounds and their use in treating or identifying a disease or condition responsive to inhibition of NLRP3 or inhibition of the activation of NLRP3 or related components of the inflammatory process.
  • WO2019008025, WO2019008029, WO2019034686, WO2019034688, WO2019034690, WO2019034692, WO2019034693, WO2019034696, WO2019034697, WO2019068772, W02019092170, W02019092171 and WO2019092172 refer to novel compounds (e.g. sulfonylureas, sulfonylthioureas, sulfoximine ureas and sulfoximine thioureas), useful in the treatment and prevention of medical disorders and diseases, most especially by NLRP3 inhibition.
  • novel compounds e.g. sulfonylureas, sulfonylthioureas, sulfoximine ureas and sulfoximine thioureas
  • WO2019079119 refer to chemical entities that are useful for treating a condition, disease, or disorder in which a decrease or increase in NLRP3 activity contributes to the pathology and/or symptoms and/or progression of the condition, disease, or disorder in a subject.
  • WO2021214284, WO2021209552, and WO2021209539 disclose compounds for inhibiting NLRP3 and/or NLRP3 inflarnmasome pathway.
  • WO2018136890 refers to sulfonylurea and sulfonyl thiourea compounds and their use in treating a disease or condition responsive to modulation of cytokines such as IL-1 beta (p) and IL-18, modulation of NLRP3 or inhibition of the activation of NLRP3 or related components of the inflammatory process.
  • WO2018225018 and WO2019043610 refer to NLRP3 modulators as well as to the use of the novel inhibitor compounds in the treatment of diseases or conditions as well as treatment of disease states mediated by NLRP3 as well as treatment of diseases or conditions in which interleukin 1 beta (P) activity and interleukin-18 (IL-18) are implicated.
  • P interleukin 1 beta
  • IL-18 interleukin-18
  • W02018015445 refers to sulfonylurea compounds which possess inflammasome inhibitory activity and are accordingly useful in methods of treatment of the human or animal body.
  • WO2020Q18975 discloses sulfonimidamide derivatives defined as inhibitors of interleukin-1 activity and NLRP3 modulators in connection with inflammatory processes.
  • WO9832733 refers to aryl and heleroaryl substituted sulfonyl ureas that are inhibitors of interleukin- 1 alpha (a) and interleu kin-1 beta (p) processing and release.
  • W02020018970 discloses sulfonylureas defined as inhibitors of interleukin-1 activity.
  • WO2020234715 discloses pyridazine-3-yl phenol compounds defined as inhibitors of NOD-like receptor protein 3 (NLRP3) inflammasome activity.
  • Z1 and Z2 are each selected from N and C whereby if Z1 is N, Z2 is C, and if Z1 is C, Z2 is N, preferably
  • Z1 is N and Z2 is C;
  • V, X and E are each independently selected from N and CRa; wherein at least one of V, X and E is CRa; indicates alternating single and double bonds;
  • Ra is independently selected from the group consisting of -H, -C-i-Caalkyl, -CF3 and halo;
  • Ro is selected from the group consisting of -H, -CrCsalkyl and -halo;
  • R1 is selected from the group consisting of -CF 3 , -OCF 3 , -OCHFa, -CN and -halo;
  • R2 is selected from the group consisting of -OH, -H, -OCF3, -OCHFz, -C1-C3alkyl, -halo and -CF 3 ;
  • R3 is selected from the group consisting of-H, -C T-C alkyl, -OH. -CF3 and -halo:
  • R4 is selected from the group consisting of-H, -C1-C3alkyl, -CF3 and -halo;
  • any reference to the compounds of formula (!) or (la), or the preferred embodiments thereof is intended to also refer to the stereoisomers, or racemic mixtures, or tautomers, or polymorphs, or pharmaceutically acceptable salts, or hydrates, or solvates thereof.
  • Compounds of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, are suitable for the treatment, alleviation or prevention of a disease, disorder or an abnormality which is responsive to the modulation, in particular inhibition, of a component of the NLRP3 inflammasome pathway, or which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels.
  • the component of the inflammasome pathway is the NLRP3 inflammasome.
  • Activation of the NLRP3 inflammasome pathway can trigger the formation of ASC specks, cleavage and activation of Caspase-1 and Caspase-8 and subsequent activation and release IL-1 beta, IL-18, gasdermin D cleavage and pore formation, pyroptosis, and release of IL-1 alpha, IL-33, IL-17 and High-Mobility Group Box (HMGB) protein.
  • the compounds of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof have the capability to modulate, in particular decrease, IL-1 beta and/or IL-18 levels.
  • the compounds of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, display high capability in modulating and, in particular inhibiting the activation of, a component of the NLRP3 inflammasome pathway, in particular wherein the component of the inflammasome pathway is the NLRP3 inflammasome.
  • these compounds display properties such as modulating or inhibiting the activation of the NLRP3 inflammasome pathway allowing them to be a successful medicament for the treatment, alleviation or prevention of diseases, disorders and abnormalities responsive to the modulation or inhibition of a component of the NLRP3 inflammasome pathway such as, for example, Alzheimer’s disease, Parkinson’s disease, CAPS, non-alcoholic faty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and gout.
  • a component of the NLRP3 inflammasome pathway such as, for example, Alzheimer’s disease, Parkinson’s disease, CAPS, non-alcoholic faty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and gout.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient
  • the present invention refers to a compound of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use as a medicament.
  • the present invention refers to a compound of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use in the treatment, alleviation or prevention of a disease, disorder, or abnormality which is responsive to the modulation, in particular inhibition of activation, of a component of the NLRP3 inflammasome pathway and/or which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels.
  • a further embodiment is concerned with the use of the compound of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for the manufacture of a medicament for treating, alleviating or preventing a disease, disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of a component of the NLRP3 inflammasome pathway and/or which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels.
  • the present invention is directed to a method of treating, alleviating or preventing a disease, disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of a component of the NLRP3 inflammasome pathway or which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels, the method comprising administering a therapeutically effective amount of a compound of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, to a subject in need thereof (e.g. a patient).
  • a pharmaceutical composition comprising a combination of a compound of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, and at least one further biologically active compound differing from the compound of formula (I) or (la), and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient, is also the subject-mater of the present invention.
  • the further biologically active compound can be one which is used for the treatment of a disease, disorder, or abnormality associated with a disease targeting different pathomechanism, e.g, an anti-amyloid beta antibody, anti-Tau antibody, amyloid beta small molecule inhibitor, Tau aggregation small molecule inhibitor, anti-alpha synuclein antibody or alpha-synuclein aggregation small molecule inhibitor, anti-TDP-43 antibody or anti-TDP-43 aggregation small molecule inhibitor, among others.
  • the dose of each compound may differ from the dose which is employed if the compound is used as a monotherapy.
  • An additional embodiment relates to the use of the compound of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, as an analytical reference or an in vitro screening tool.
  • the present invention relates to compounds of formula (I) or (la), including stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, hydrates, or solvates thereof.
  • Z1 and Z2 are each selected from N and C, whereby if Z1 is N, Z2 is C, and if Z1 is C, Z2 is N, preferably
  • Z1 is N and Z2 is C;
  • V, X and E are each independently selected from N and CR a ; wherein at least one of V, X and E is CR a ; indicates alternating single and double bonds;
  • Ra is independently selected from the group consisting of -H, -C1-C3alkyl, -CF3 and -halo;
  • Ro is selected from the group consisting of -H, -C1-C3alkyl and -halo;
  • Ri is selected from the group consisting of -CFs, -OCF3, -OCHF2, -CN and -halo;
  • R2 is selected from the group consisting of -OH, -H, -OCF3, -OCHF2, -C1-C3alkyl, -halo and -CF3;
  • Ra is selected from the group consisting of -H, -C1-C3alkyl, -OH, -CFrand -halo;
  • R4 is selected from the group consisting of -H, -C1-C3alkyl, -CF3 and -halo;
  • RA is a 7-, 8-, 9-, 10- or 11 -membered spiro or fused heterocycloalkyl bicyclic moiety containing one to three heteroatoms, wherein said heteroatom (s) is/are independently selected from N and O, and wherein the bicyclic moiety is optionally substituted at any available position with one or two substituents which are independently selected from the group consisting of C1-C4alkyl, haloC1-C4alkyl, hydroxyC1-C4alkyl, -OH and halo.
  • Ro is selected from -H and -C1-C3alkyl (such as preferably methyl or ethyl, more preferably methyl). In one more preferred embodiment Ro is -H.
  • R1 is selected from -CF3, or -halo (halogen). In one more preferred embodiment, Rt is -CF3 or -Cl (chloro).
  • R2 is -OH or -H, more preferably -OH
  • R3 is -OH or -H, more preferably -H.
  • Ro, R3, and R4 are -H, R1 is -CF3, and R2 is -OH.
  • X is CRa, wherein R a is selected from H and -C1-C3alkyl. In a preferred embodiment, X is CH.
  • Z1 is N and at least two of V, X, and E are CR a , wherein R a is as defined above.
  • Z1 is N and V, X and E are all CR a , wherein Ra is as defined above.
  • Z1 is N
  • X is N
  • V.and E are both CRa, wherein R a is as defined above.
  • Z1 is N
  • V is N
  • E and X are each CR a , wherein R a is as defined above.
  • Z1 is N
  • X is N
  • V and E are both CH.
  • Z1 is N, V is N, X and E are CR a ; or
  • Z1 is N and V, X, E are CR a ; or
  • B is N.
  • Z 2 is N and E is CH and V and X are independently selected from N and CR a , wherein R,.
  • Z 2 is N and V, X and E are all CRa, wherein R a is as defined above.
  • Z 2 is N and at least two of V, X, and E are CRa, wherein Ra is as defined above.
  • Z 2 is N and V, X and E are all CH.
  • Z 2 is N, E is N and V and X are each CR a , wherein R a is as defined above.
  • Z 2 is N, E is N and V and X are both CH.
  • Z 2 is N, V is N and E and X are each CR a , wherein R a is as defined above. In one embodiment, Z 2 is N, V is N and E and X are both CH. In another embodiment, Z 2 is N, X is N and V and E are each CR a , wherein R a is as defined above. In another embodiment, Z 2 is N, X is N and V and E are both CH.
  • Z1 is N, Z 2 is C; V, X are CR a , wherein R a is as defined above, and E is N. More preferably Z1 is N, Z 2 is C; V is CR a , wherein R a is as defined above, preferably R, is H or C1-C3alkyl, X is CH, and E is N.
  • a compound of formula (I) having the formula (la: or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof; wherein Ro, R1, R2, R3, R4, Ra and R* are as defined in any of the above embodiments, preferably Ra, is selected from the group consisting of -H and -C1-C3alkyl.
  • the present invention relates to the following compounds of formula (I) or
  • the present invention relates to the following compounds of or a stereoisomer, a racemic mixture, a tautomer; a polymorph, a pharmaceutically acceptable salt. a hydrate, or a solvate thereof.
  • the present invention relates farther to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.
  • the pharmaceutical composition comprises a compound of formula (I) or (la)as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.
  • the present invention relates to a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use as a medicament.
  • the present invention relates to a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use in the treatment, alleviation or prevention of a disease, disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of a component of the NLRP3 inflam masome pathway and/or which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels.
  • the modulation is the reduction and/or inhibition of IL-1 beta and/or IL-1 beta levels.
  • the modulation is the reduction and/or inhibition of IL-1 beta.
  • the present invention relates to a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use in a method of reducing and /or inhibiting IL-1 beta, in particular, inhibiting IL-1 beta.
  • the present invention relates to a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use in the treatment, alleviation or prevention of a disease, disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of a component of the NLRP3 inflammasome pathway.
  • the present invention relates to a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use in the treatment, alleviation or prevention of a disease, disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of NLRP3 inflam masome pathway.
  • the present invention relates to a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use in the treatment, alleviation or prevention of a disease, disorder or abnormality which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL- 18 levels.
  • the present invention relates to a method for treating, alleviating or preventing of a disease, disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of a component of the NLRP3 inflam masome pathway and/or which is responsive to the modulation, in particular decrease, of the IL-1 beta and/or IL-18 levels, wherein the method comprises administering a therapeutically effective amount of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, to a subject in need thereof (e.g. patient).
  • the present invention relates to a method for treating, preventing or alleviating a disease, a disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of a component of the NLRP3 inflammasome pathway, wherein the method comprises administering a therapeutically effective amount of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, to a subject in need thereof (e.g. a patient).
  • the present invention further relates to a method for treating, preventing or alleviating a disease, a disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of NLRP3 inflammasome pathway, wherein the method comprises administering a therapeutically effective amount of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, to a subject in need thereof (e.g. a patient).
  • the present invention relates to a method for treating, preventing or alleviating a disease, disorder or abnormality responsive to a modulation, in particular a decrease, of IL-1 beta and/or IL-18 levels, wherein the method comprises administering a therapeutically effective amount of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, ora solvate thereof, to a patient in need thereof.
  • the present invention relates to the use of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for the manufacture of a medicament.
  • the present invention relates to the use of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for the manufacture of a medicament for treating, alleviating or preventing a disease, disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of a component of the NLRP3 inflammasome pathway and/or which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels.
  • the disease, disorder, or abnormality is selected from the list disclosed herein.
  • the present invention relates to the use of a compound of formula (I) or (Ila) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for the manufacture of a medicament for treating, alleviating or preventing a disease, disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of a component of the NLRP3 inflammasome pathway.
  • the present invention relates to the use of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for the manufacture of a medicament for treating, alleviating or preventing a disease, disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of NLRP3 inflammasome pathway.
  • the present invention relates to the use of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for the manufacture of a medicament for treating, alleviating or preventing a disease, disorder or abnormality which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels.
  • the present invention relates to the use of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for the manufacture of a medicament for reducing and/or inhibiting IL-1 beta and/or IL-1 beta levels.
  • the present invention relates to the use of a compound of the invention, as defined herein, for the manufacture of a medicament for reducing and/or inhibiting IL-1 beta.
  • the present invention relates to the use of a compound of the invention, as defined herein, for the manufacture of a medicament for reducing IL-1 beta.
  • the present invention relates to a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use in the treatment, alleviation or prevention of a tauopathy by modulating a component of the inflammasome pathway, in particular, by modulating the NLRP3 inflammasome pathway.
  • the disease, the disorder or the abnormality is responsive to modulation of one or more of IL-1 p, IL-17, IL-18, IL- 1 a, IL-37, IL-33 and Th17 cells, preferably: IL-1 p and IL-18.
  • the disease, disorder, or abnormality is a disease, disorder, or abnormality selected from Alzheimer's disease, Parkinson's disease, multiple sclerosis, cryopyrin- associated periodic syndromes (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), obesity, hidradenitis suppurativa (HS) and gout, such as Alzheimer’s disease, Parkinson’s disease, cryopyrin-associated periodic syndromes (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and gout.
  • a disease, disorder, or abnormality selected from Alzheimer's disease, Parkinson's disease, multiple sclerosis, cryopyrin- associated periodic syndromes (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), obesity, hidradenitis suppurativa (HS) and gout such as Alzheimer’s disease, Parkinson’s disease
  • the disease, disorder, or abnormality is a disease, a disorder or an abnormality of the immune system.
  • the disease, disorder, or abnormality is an inflammatory disease, disorder, or abnormality.
  • the disease, disorder, or abnormality is an autoimmune disease, disorder, or abnormality.
  • the disease, the disorder, or the abnormality is a disease, a disorder, or an abnormality of the central nervous system (CNS).
  • the disease, the disorder, or the abnormality can be a disease, disorder or abnormality or condition of the skin.
  • the disease, the disorder or the abnormality can be a disease, disorder or abnormality or condition of the cardiovascular system.
  • the disease, the disorder or the abnormality or condition can be a cancer, tumour or other malignancy.
  • the disease, the disorder or the abnormality or condition can be a disease, disorder, or abnormality of the renal system.
  • the disease, the disorder or the abnormality or condition can be a disease, disorder, or abnormality of the gastrointestinal tract.
  • the disease, the disorder or the abnormality or condition can be a disease, disorder, or abnormality of the respiratory system.
  • the disease, the disorder or the abnormality or condition can be a disease, disorder, or abnormality of the endocrine system.
  • the disease, the disorder or the abnormality or condition can be liver related disease, disorder, or abnormality.
  • the diseases, the disorders or the abnormalities which are responsive to the modulation, in particular inhibition of activation, of a component of the NLRP3 inflammasome pathway can be selected from Alzheimer's disease, Parkinson’s disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudo-gout, inflammatory bowel disease (IBD) (including Crohn’s disease, ulcerative colitis), hepatitis, nonalcoholic faty liver disease, nonalcoholic steatohepatitis, hypertension, myocard ial infarction, heart failure, coronary artery disease, oxalate-induced nephropathy, graft-versus host disease, type 1 diabetes, type 2 diabetes, Edema (DME),
  • the disorder, disease or abnormality is selected from Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, demyelination, multiple sclerosis, encephalomyelitis, leukoencephalopathy, viral encephalitis, epilepsy, stroke, traumatic brain injury, spinal cord injury, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), gout, inflammatory bowel disease (IBD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft- versus host disease, obesity, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, lower-risk myelodysplastic syndromes (LR-MDS), anti-neutrophil cytoplasmic antibody- associated vasculitis (AAV), acute kidney disease, chronic kidney disease, lupus
  • the diseases, the disorders or the abnormalities are selected from Alzheimer’s disease, Parkinson's disease, cryopyrin-associated periodic syndromes (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), rheumatoid arthritis, chronic kidney disease obesity, hidradenitis suppurativa (HS) and gout
  • the diseases, the disorders or the abnormalities are selected from Alzheimer's disease, Parkinson’s disease, multiple sclerosis, cryopyrin-associated periodic syndromes (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) chronic kidney disease and gout.
  • the carriers, diluents, adjuvants and pharmaceutical excipients can be selected with regard to the intended route of administration and standard pharmaceutical practice. These compounds must be acceptable in the sense of being not deleterious to the recipient thereof.
  • Ac-Di-Sol® carboxymethyl starch-Na (sodium starch glycolate) (e.g,, Primojel® or Explotab®), preferably crosslinked PVP andfor croscarmellose sodium), glidants (such as colloidal S1O2 (e.g., Aerosil® 200), magnesium trisilicate, powdered cellulose, talc and combinations thereof), lubricating agents (such as magnesium stearate, aluminium or calcium silicate, stearic acid, hydrogenated castor oil, talc, glyceryl behenate, sodium stearate fumarate and combinations thereof), buffering agents, emulsifiers, wetting agents, suspending agents, sweetening agents, colorants, flavors, coating agents, preservatives, antioxidants, processing agents, drug delivery modifiers and enhancers (such as calcium phosphate), magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatine, cellulose, methylcellulose, sodium
  • the carrier is not particularly limited and will depend on the route of administration as well as the form of the pharmaceutical composition (i.e., solid, liquid, etc,).
  • Suitable carriers include, without limitation, polyols such as mannitol, sorbitol, xylitol; disaccharides such as lactose, sucrose, dextrose and maltose; polysaccharides such as maltodextrin and dextran; starches such as corn starch; celluloses such as microcrystalline cellulose, sodium carboxy methylcellulose, low-substituted hydroxypropyl cellulose, hydroxyl ethyl cellulose, hydroxypropyl cellulose or mixtures thereof; cyclodextrins and inorganic agents such as dicalcium phosphate, calcium hydrogen phosphate; hydroxyapatite, tricalcium phosphate, talcum and silica. Microcrystalline cellulose, sucrose and/or lactose are preferred as carriers. Combinations thereof can also be employed. Carr
  • the diluent is not particularly limited and will depend on the route of administration as well as the form of the pharmaceutical composition (i.e., solid, liquid, etc.). Diluents include, for instance, water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • the routes for administration (delivery) of the compounds of the invention include, but are not limited to, one or more of the following routes of administration: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical, mucosal (e. g.
  • nasal, parenteral e.g,, by an injectable form
  • gastrointestinal intraspinal, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravagina I, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transderma I, rectal, buccal, epidural and sublingual.
  • the compounds can be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
  • the tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxy propylcellulose (HPC), sucrose, gelatine and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatine capsules.
  • excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine
  • disintegrants such as starch (preferably corn, potato or tapioca starch), sodium star
  • Preferred excipients in this regard include starch, cellulose, milk sugar, e.g. lactose, or high molecular weight polyethylene glycols.
  • the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • the compounds of the present invention are administered parenterally, then examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously administering the compounds; and/or by using infusion techniques.
  • parenteral administration the compounds can be used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
  • the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
  • the preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • the compounds of the present invention can be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurized container, pump, spray or nebulizer with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA134AT) or 1 ,1,1,2,3,3,3-heptafluoropropane (HFA 227), carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA134AT) or 1 ,1,1,2,
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container, pump, spray or nebulizer may contain a solution or suspension of the active compound, e. g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e. g. sorbitan trioleate.
  • a lubricant e. g. sorbitan trioleate.
  • Capsules and cartridges (made, for example, from gelatine) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the compounds of the present invention can be administered in the form of a suppository or pessary, or it may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.
  • the compounds of the present invention, as defined herein may also be dermally or transdermally administered, for example, by the use of a skin patch.
  • the claimed compounds, as defined herein, can be used for the treatment, alleviation or prevention of the recited conditions alone or in combination with one or more other biologically active compounds, as defined herein.
  • the other biologically active compound can be one used for the treatment, alleviation, or prevention of the recited diseases.
  • compositions of the invention can be produced in a manner known per se to the skilled person as described, for example, in Remington's Pharmaceutical Sciences, 15 th Ed., Mack Publishing Co., New Jersey (1975).
  • the invention also includes all suitable isotopic variations of the compounds of the invention.
  • An isotopic variation of the compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulphur, fluorine and chlorine such as 2 H, 3 H, 13 C, t4 C, 15 N, 17 O, W O, 35 S, 18 F and *01 respectively.
  • Certain isotopic variations of the invention for example, those in which a radioactive isotope such as 3 H or 14 C is incorporated, are useful in drug and/or substrate tissue distribution studies.
  • Tritiated, i .e,, 3 H, and carbon-14, i.e., M C, isotopes are particularly preferred for their ease of preparation and detectability.
  • F-labeled compounds are particularly suitable for imaging applications such as PET.
  • substitution with isotopes such as deuterium, i.e., 2 H 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.
  • Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples and Preparations hereafter using appropriate isotopic variations of suitable reagents.
  • Said compounds of the invention may be useful in the treatment, alleviation or prevention of a disease, or a disorder or an abnormality which is responsive to the modulation of a component of the NLRP3 inflammasome pathway and/or which is responsive to the modulation of IL-1 beta and/or IL-18 levels,
  • a number of diseases, disorders or abnormalities have been shown to be involve in NLRP3 including, for example, one of the following:
  • Immune disease, disorder, or abnormality e.g. autoimmune disease, disorder or abnormality, and disease, disorder, or abnormality, involving the immune system
  • type 1 diabetes hidradenitis suppurativa (HS), Schnitzler syndrome, multiple sclerosis (MS) including primary progressive multiple sclerosis (PPMS), Sjogren's syndrome, secondary progressive multiple sclerosis (SPMS), TNF receptor associated periodic syndrome (TRAPS), graft-versus host disease or relapsing remitting multiple sclerosis (RRMS);
  • PPMS primary progressive multiple sclerosis
  • SPMS secondary progressive multiple sclerosis
  • TRAPS TNF receptor associated periodic syndrome
  • RRMS graft-versus host disease or relapsing remitting multiple sclerosis
  • Inflammatory disease including auto-inflammation and inflammation occurring as a result of an inflammatory disease, disorder, or abnormality, such as mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), acne, pyogenic arthritis, pyoderma gangrenosum and acne (PAPA), adult-onset Still's disease (AOSD), Majeed syndrome, PLCG2-associated antibody deficiency and immune dysregulation (PLAID), PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation (APLAID), pyogenic arthritis, haploinsufficiency of A20 (HA20), pediatric granulomatous arthritis (PGA), or sideroblastic anemia with B-cell immunodeficiency, periodic fevers, developmental delay (SIF
  • D. Skin disease, disorder, or abnormality such as hidradenitis suppurativa (HS), dermatitis, psoriasis, skin contact hypersensitivity, acne, periodic fever syndrome (HIDS), Sweet's syndrome, dermatitis, eczema, skin lesions, bum, wound, wound healing, trauma, sunburn, actinic keratosis, deficiency of interleukin 1 receptor (DIRA) antagonist, or alopecia areata;
  • HS hidradenitis suppurativa
  • dermatitis dermatitis
  • psoriasis skin contact hypersensitivity
  • acne periodic fever syndrome
  • Sweet's syndrome dermatitis
  • eczema skin lesions
  • bum bum
  • wound wound healing
  • trauma trauma
  • sunburn actinic keratosis
  • DIRA deficiency of interleukin 1 receptor
  • Ocular disease, disorder, or abnormality such as age-related macular degeneration (AMD), corneal infection, uveitis, glaucoma, dry eye, or demyelination;
  • AMD age-related macular degeneration
  • corneal infection uveitis
  • glaucoma glaucoma
  • dry eye or demyelination
  • Cardiovascular disease, disorder, or abnormality e.g. disease, disorder, or abnormality of the cardiovascular system
  • myocardial infarction hypertension
  • ischaemia reperfusion injury pericarditis including Dressier's syndrome
  • aneurysms including abdominal aortic aneurism, or stroke;
  • Metabolic disease, disorder, or abnormality such as type 2 diabetes, obesity, atherosclerosis, metabolic-dysfunction-associated hepatitis, gout, or pseudo-gout;
  • Liver disease, disorder, or abnormality e.g. hepatic disease, disorder or abnormality
  • hepatic disease, disorder or abnormality such as alcoholic liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH) including advanced fibrosis stages F3 and F4;
  • J. Renal disease, disorder, or abnormality e.g. disease, disorder or abnormality of the renal system
  • disease, disorder or abnormality of the renal system such as oxalate-induced nephropathy, diabetic nephropathy, chronic kidney disease, or kidney disease;
  • Cancer disease, disorter, or abnormality e.g. cancer, tumor, or malignancy
  • lung cancer e.g. lung cancer metastasis
  • pancreatic cancers gastric cancers
  • leukemia e.g. myelodysplastic syndrome (MOS)
  • MOS myelodysplastic syndrome
  • L. Infections including viral infections such as helminth infections (e.g. from schistosoma, roundworms, tapeworms or flukes), viral encephalitis, bacterial infection, human immunodeficiency virus (HIV), HIV-associated neurocognitive disorder, chronic nonbacterial osteomyelitis (CNO), chronic bacterial osteomyelitis, deficiency of interleukin 1 receptor (DIRA) antagonist, or epilepsy; alphavirus (e.g. Chikungunya virus and Ross River virus), flaviviruses (e.g. Dengue and Zika virus), Coronavirus-associated inflammatory pathologies, Coronaviruses, or influenza virus;
  • M Psychological disease, disorder, or abnormality, such as depression, and psychological stress
  • Inflammation including inflammation occurring as a result of an inflammatory disease, disorder, or abnormality, such as an autoinflammatory disease, inflammation occurring as a symptom of a non- inflammatory disorder, inflammation occurring as a result of infection, or inflammation secondary to trauma, injury or autoimmunity.
  • inflammation include inflammatory responses occurring in connection with, or as a result of: i.
  • a joint disease, disorder, or abnormality such as periodic fever syndrome (HIDS), rheumatoid arthritis, pustulosis, synovitis, osteoarthritis, chronic recurrent multifocal osteomyelitis (CRMO), systemic juvenile idiopathic arthritis, osteitis syndrome (SAPHO), hyperostosis, relapsing polychondritis, or adult-onset Still's disease;
  • HIDS periodic fever syndrome
  • rheumatoid arthritis pustulosis
  • synovitis synovitis
  • osteoarthritis chronic recurrent multifocal osteomyelitis
  • SAPHO systemic juvenile idiopathic arthritis
  • SAPHO systemic juvenile idiopathic arthritis
  • SAPHO systemic juvenile idiopathic arthritis
  • SAPHO systemic juvenile idiopathic arthritis
  • SAPHO systemic juvenile idiopathic arthritis
  • SAPHO systemic juvenile idiopathic arthritis
  • SAPHO systemic juvenile id
  • a muscular disease, disorder, or abnormality such as polymyositis, or myasthenia gravis; iv. A disease, disorder or abnormality of the endocrine system, such as, diabetes, parathyroid disease (e.g. hypothyroidism), tumors of the endocrine system, thyroid cancer, or hypoglycemia; and/or v. A vascular disease, disorder or abnormality, such as Behcet's disease.
  • the disease, disorder, or abnormality is selected from Alzheimer’s disease, Parkinson's disease, cryopyrin-associated periodic syndromes (CAPS), non-alcoholic faty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and gout.
  • CAPS cryopyrin-associated periodic syndromes
  • NAFLD non-alcoholic faty liver disease
  • NASH non-alcoholic steatohepatitis
  • gout gout.
  • the disease, disorder or abnormality is selected from: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelination, viral encephalitis, epilepsy, stroke, brain haemorrhage, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudo-gout, inflammatory bowel disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, lower-risk myelodysplastic syndromes (LR-MDS), familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), mevalonate
  • AApoAII apolipoprotein A-ll
  • AGel gelsolin
  • AFib fibrinogen
  • ALys lysozyme
  • Beta-2 Microglobulin amyloidosis iAPP amyloidosis
  • the disease, disorder or abnormality is selected from: Alzheimer’s disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudo-gout, inflammatory bowel disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, lower-risk myelodysplastic syndromes (LR-MDS), familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD
  • the disease, the disorder or the abnormality is selected from Alzheimer’s disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma and allergic inflammation, cryopyrin- associated periodic syndromes (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic kidney disease, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, obesity, type 1 and type 2 diabetes, hidradenitis suppurativa (HS), rheumatoid arthritis, myelodysplastic syndrome and lower-risk myelodysplastic syndromes (LR-MDS).
  • Alzheimer’s disease Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelination, viral encephalitis, epile
  • the disease, disorder, or abnormality is selected from Alzheimer’s disease, Parkinson’s disease and multiple sclerosis.
  • the disease, disorder, or abnormality is selected from cryopyrin-associated periodic syndromes (CAPS), non-alcoholic faty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic kidney disease gout, obesity and hidradenitis suppurativa (HS).
  • CAPS cryopyrin-associated periodic syndromes
  • NAFLD non-alcoholic faty liver disease
  • NASH non-alcoholic steatohepatitis
  • chronic kidney disease gout obesity
  • hidradenitis suppurativa hidradenitis suppurativa
  • the disease, the disorder or the abnormality is selected from Alzheimer’s disease, Parkinson's disease, cryopyrin-associated periodic syndromes (CAPS), non-alcoholic faty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), rheumatoid arthritis, chronic kidney disease, gout, obesity and hidradenitis suppurativa (HS).
  • CAPS cryopyrin-associated periodic syndromes
  • NAFLD non-alcoholic faty liver disease
  • NASH non-alcoholic steatohepatitis
  • rheumatoid arthritis chronic kidney disease
  • gout chronic kidney disease
  • obesity hidradenitis suppurativa
  • the disease, the disorder or the abnormality is hidradenitis suppurativa (HS) in an obese subject. In one embodiment the disease, the disorder or the abnormality is comorbid hidradenitis suppurativa (HS) and obesity.
  • the disease, disorder or abnormality is preferably an inflammatory disease, disorder or abnormality; or an autoimmune disease, disorder or abnormality; or a disease, disorder or abnormality of the skin (such as, for example, but not limited to, psoriasis, acne, eczema, alopecia areata, hidradenitis suppurativa (HS) or actinic keratosis); or a disease, disorder or abnormality of the cardiovascular system; or a disease, disorder, or abnormality such as a cancer, a tumor ora malignancy; or a disease, disorder or abnormality of the renal system; a disease, disorder or abnormality of the gastrointestinal tract; a disease, disorder or abnormality of the respiratory system; or a disease, disorder or abnormality of the endocrine system; or a disease, disorder or abnormality of the central nervous system (CNS); or a disease, disorder or abnormality of the liver.
  • a disease, disorder or abnormality of the skin such as, for example, but
  • Alkyl refers to a saturated straight or branched organic moiety consisting of carbon and hydrogen atoms.
  • suitable alkyl groups have 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, and (as appropriate) include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl.
  • C1-C4alkyr refers to an alkyl group having 1 to 4 carbon atoms.
  • C1-C3alkyl is to be construed accordingly.
  • Hal refers to F, Cl, Br, and I.
  • halogen is F or Cl.
  • halogen is Cl.
  • halogen is F.
  • “7-, 8-, 9- 10 or 11 -membered spiro or fused heterocycloalkyl bicyclic moiety” refers to a stable 7-, 8-, 9-, 10- or 11-membered heterocycloalkyl bicyclic moiety which contains two rings that can either be fused together (Le., a ring system in which two rings are linked via two adjacent common ring atoms) or attached in a spiro manner (i,e., a ring system in which two rings are linked via a single common ring atom).
  • Optionally substituted in reference to a certain group refers to said group as to optionally be substituted with one or more substituents (i.e. the substituent may be present or not).
  • compound of the present invention refers to compounds of formula (I) or (la) as disclosed herein, or sub-formulae thereof, as disclosed herein, or stereoisomers thereof, or racemic mixtures thereof, or tautomers thereof, or polymorphs thereof, or pharmaceutically acceptable salts thereof, thereof, or hydrates thereof, or solvates thereof.
  • Compounds of the present invention having one or more optically active carbons can exist as racemates and racemic mixtures (including mixtures in all ratios), stereoisomers (including diastereomeric mixtures and individual diastereomers, enantiomeric mixtures and single enantiomers, mixtures of conformers and single conformers), tautomers, atropisomers, and rotamers. All isomeric forms are included in the present invention.
  • Compounds described in this invention containing olefinic double bonds include E and Z geometric isomers. Also included in this invention are all pharmaceutically acceptable salts, hydrates and solvates of compounds of formula (I) or (la).
  • Solvates, hydrates as well as anhydrous forms of the salt are also encompassed by the invention.
  • the solvent included in the solvates is not particularly limited and can be any pharmaceutically acceptable solvent. Examples include water and C1-4 alcohols (such as methanol or ethanol).
  • “Pharmaceutically acceptable salts” are defined as derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic adds.
  • such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric add and the like; and the salts prepared from organic acids such as, but not limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic acid, and the like.
  • inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric add and the like
  • organic acids such as, but
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
  • Organic solvents include, but are not limited to, nonaqueous media like ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts can be found in Remington’s Pharmaceutical Sciences, 18 th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, the disclosure of which is hereby incorporated by reference.
  • “Pharmaceutically acceptable 1 ’ is defined as those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable beneflt/risk ratio,
  • the terms “patient” or “subject” mentioned in the present invention typically refer to an animal, particularly a mammal (e.g. rabbits, rats, dogs, mice, guinea pigs, pigs), more particularly primates (e.g. humans, male or female).
  • the subject is a human,
  • NLRP3 refers to NOD-like receptor (NLR) family, pyrin-domain containing protein 3 component of inflammasome.
  • Inflammasomes are intracellular supramolecular complexes comprising a sensor molecule, the adaptor apoptosis-associated speck-like protein containing a CARD (ASC) and the effector protease caspase 1 .
  • ASC apoptosis-associated speck-like protein containing a CARD
  • ASC apoptosis-associated speck-like protein containing a CARD
  • Active caspase 1 triggers the activation and release of interleukin-1 (IL-1) family proteins and enables the non-conventional secretion of numerous cytosolic proteins.
  • IL-1 interleukin-1
  • pro-inflammatory mediators released upon NLRP3 activation are IL-1 beta (P), IL-18, high-mobility group protein Bl (HMGB1), leukotrienes and prostaglandins.
  • NLRP3 inflammasome pathway activation is an important driver of inflammation interacting with the different cytokine pathways shaping the immune response to infection and injury. Formation of some pro-inflammatory cytokines is triggered by NLRP3 inflammasome pathway activation.
  • inhibitor refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or abnormality which is responsive to the modulation of a component of the NLRP3 inflammasome pathway, or a significant decrease in the baseline activity of a biological activity or process.
  • treat refers to alleviating or ameliorating or modulating the disease or disorder or abnormality (i.e., slowing or arresting the development of the disease, disorder or abnormality or at least one of the clinical symptoms thereof); or alleviating or ameliorating or modulating at least one physical parameter or biomarker associated with the disease or disorder or abnormality, including those which may not be discernible to the subject (e.g., patient).
  • '‘prevent”, “preventing” or “prevention” of any disease or disorder or abnormality which is responsive to the modulation of a component of the NLRP3 inflammasome pathway refer to the prophylactic treatment of the disease or disorder or abnormality; or delaying the onset or progression of the disease or disorder.
  • modulation refers to alteration, e.g., up-regulation, down-regulation, increase or decrease, preferably decrease.
  • the compounds of the present invention can be synthesized by those skilled in the art by using commonly known preparation steps, for instance those of the general methods shown in the following schemes. These methods are only given for illustrative purposes and should not be construed as limiting.
  • protecting groups for sensitive or reactive groups may be employed where necessary in accordance with general principles of chemistry.
  • Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G, M. Wilts (2014) Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those ski lied in the art.
  • Intermediate C Commercially available 5- membered heterocyclic ester can be condensed with hydrazine followed by carbamate formation allowing the synthesis of the intermediate B.
  • ring cyclization using CS? in presence of base can deliver intermediate D.
  • Selective alkylation using standard conditions followed by chlorination can give intermediate E.
  • SNAr followed by metal coupling using, for example, boronic acid and palladium catalyst can give compounds of formula (I) or (la).
  • Step 1 To a mixture of ethyl 1 H-imidazole-2-carboxylate (100 g, 713.57 mmol, 1 eq) in BOH (1 L) was slowly added N2H4 • HjO (225.41 ml, 3.72 mol, 5.21 eq). The mixture was stirred at 25 °C for 4 h. The reaction mixture was filtered. The filter cake was washed with H 2 O (300 ml_ x 3) and dried to afford 1 H-imidazole-2-carbohydrazide (70 g, 77%) as a white solid.
  • MeOH 200 mL
  • Step 3 To the solution of 5-sulfanylimidazo[1 ,2,4]triazin-8-ol (15 g, 89.19 mmol, 1.0 eq) in acetone (150 ml) was added K2CO3 (24.65 g, 178.38 mmol, 2 eq) and Mel (15.19 g, 107.03 mmol, 6.66 mL, 1.2 eq). The resulting reaction mixture was stirred at 20 °C for 3 h. The reaction solution was filtered to remove K2CO3 then concentrated to give the crude product. The crude product was triturated with DCE (1000 mL) at 80 °C for 30 min.
  • DCE 1000 mL
  • Step 4 To the solution of 5-methylsulfanylimidazo[1 ,2-d][1 ,2,4]triazin-8-ol (4 g, 21.95 mmol, 1 eq) in POCI3 (58.49 g, 381.46 mmol, 35.56 mL, 17.38 eq). The resulting reaction mixture was stirred at 100 °C for 5 h. The reaction mixture was poured onto 100 mL saturated aqueous NaHCOs solution and followed by 20 ml DCM. After that, the aqueous phase was separated and extracted with DCM (30 mL X 3).
  • Step 2 To a solution of tert-butyl 1-(5-methyteulfanylimidazo[1 ,2-d]E1,2,4]triazin-8-yl)-3,3a,4,5,7,7a- hexahydro-2H-pyrrolo[2,3-c]pyridine-6-carboxylate (800 mg, 2.05 mmol, 1 eq) in DCM (8 ml) was added TFA (2 mL) at 0 °C and the resulting reaction mixture was stirred at 20 °C for i h. The reaction mixture was poured onto 20 mL of H2O and adjusted the pH to 8 with saturated aqueous NaaCOa solution.
  • Step 3 To a solution of 8-(2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridin-1-yl)-5-methylsulfanyl- imidazo[1 ,2-d][1 ,2,4]triazine (600 mg, 2.07 mmol, 1 eq) in MeOH (6 mL) was added HCHO (124.08 mg, 4.13 mmol, 113.83 pL, 37% purity, 2 eq) in H2O, NaBHfOAcJs (656.87 mg, 3.10 mmol, 1.5 eq) and the resulting reaction mixture was stirred at 20 °C for 1 h.
  • the reaction mixture was poured onto 20 mL H2O and adjusted to pH 12 with saturated aqueous NaaCOa solution. Then, the resulting solution was extracted with EtOAc (20 mL X 2). The combined organic layer was successively washed with water (20 mL X 2) and brine (20 ml X 1), dried over anhydrous NazSO ⁇ filtered, and concentrated to give a residue. The residue was used for the next step directly without further purification.
  • Step 4 To a solution of 8-(6-methyl-3, 3a, 4,5,7, 7a-hexahydro-2H-pyrrolo[2, 3-c]pyridin-1 -yl)-5- methylsulfanyl-imidazo[1 ,2-d][1 ,2,4]triazine (530 mg, 1.74 mmol.
  • Step 5 2-[8-(6-Methyl-3 > 3a,4,5,7 > 7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)imidazo(1 > 2- d][1,2,4]triazin-5-yl]-5-(trifluoromethyl)phenol was separated by SFC (column: DAICEL CHIRALCEL OJ (250mm*30mm,10pm); mobile phase: [CO2-EtOH(0.1 %NH3H ⁇ O)]; B%:30%, isocratic elution mode) to give enantiopure 2-(8-[rel-(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrTolo[2,3- c]pyridin-1-yl]imidazo[1 ,2-d][1 ,2,4]triazin-5-yl]-5-(trifluoromethyl)phenol
  • Step 1 To a solution of 8-chloro-5-methylsulfanyl-imidazo[1 ,2-d][1 ,2.4]triazine (900 mg, 4.49 mmol, 1 eq) and 6-methyl-1 ,2,3,3a,4,5,7,7a-octahydropyrrolo[2,3-c]pyridine; dihydrochloride (1.15 g, 5.38 mmol, 1.2 eq) in DMSO (10 ml) was added KF (521 .18 mg, 8.97 mmol, 2 eq) and TEA (907.76 mg, 8.97 mmol, 1.25 ml, 2 eq). The mixture was stirred at 100 °C for 12 h.
  • Step 2 To- a solution of 8-(6-methyloctahydro-1 H-pyrrolo[2,3-c]pyridin-1-yi)-5- (methylthio)imidazo[1 ,2-d][1 ,2,4]triazine (300 mg, 985.50 pmol, 1 eq) and (4-chloro-2-methoxy-5- methyl-phenyl)boronic acid (237.03 mg, 1.18 mmol, 1.2 eq) in THF (5 mL) were added Pd(PPhg)4 (341 .64 mg, 295.65 pmol, 0,3 eq) and cuprous 2-hydroxy-3-m-ethyl-benzoate (528,93- mg, 2.46 mmol, 2.5- eq).
  • Step 3 To a solution of 5-(4-chloro-2-methoxy-5-methylphenyl)-8-(6-methyloctahydro-1H- pyrrolo[2,3-c]pyridin-1-yl)imidazo[1 ,2-d][1 ,2,4]triazine (200 mg, 339.05 pmol, 1 eq) in DCM (3 mL) was added BBra (424.70 mg, 1.70 mmol, 163.35 pL, 5 eq) at 0 °C. The mixture was stirred at 20 °C for 1 h. LCMS indicated that the reaction was completed.
  • reaction mixture was poured onto TO mL H2O and the pH was adjusted to 7 with saturated aqeuous NaHCCh solution. Then, the resulting solution was extracted with DCM (10 mL x 3), The combined organic layer was washed successively with water (20 mL x 2) and brine (20 ml x 1), dried over anhydrous NazSCM filtered, and concentrated to give a residue.
  • Step 4 5-chloro-4-methyl-2-(8-(6-methyloctahydro-1 H-pyrrolo[2,3-c]pyridin-1 -yl)imidazo[1 ,2- d][1 ,2,4]triazin-5-yl)phenol was purified by SFC (column: DAICEL CHIRALCEL OJ (250mm*30mm, 10pm); mobile phase: [CO2-MeOH(0.1%NH3H2O)]; B%:37%, isocratic elution mode) to give first eluting peak
  • Example 2a enantiopure 5-chloro-4-methyl-2-(8-((3aR,7aS)-6-methyloctahydro-1H- pyrrolo[2,3-c]pyridtn-1-yl)imidazo[1 ,2-d][1 ,2,4]triazin-5-yl)phenol (10.32 mg) as a white solid.
  • NLRP3 inhibition assay The following assays were used to determine the inhibitory activity of test compounds on the NLRP3 inflammasome pathway using common stimulus ATP (Invivogen).
  • HMDM cells Human monocyte-derived macrophages (HMDM) cells were prepared from buffy coat obtained from human anonymized healthy blood donors. Cells were isolated using a negative selection following a classical monocyte isolation protocol (Miltenyi, # 130-117-337). Cells were differentiated in growth medium (DMEM/F12 (Gibco, 31331-093)) supplemented with 10% heat inactivated human serum (HS; Sigma, H3667), 1% PS, 0.5 mM sodium pyruvate (ThermoFisher, 11360-070), 10 mM HEPES (ThermoFisher, 15630-080)) and containing 10 ng/mL of human macrophage colony stimulating factor (M-CSF; Miltenyi, 130-096-489) to induce differentiation toward macrophages.
  • DMEM/F12 Gibco, 31331-093
  • HS heat inactivated human serum
  • PS 1% PS
  • 0.5 mM sodium pyruvate ThermoFi
  • HMDM were primed with 10 ng/mL of LPS from Escherichia coli for 3 hours in growth medium without M-CSF. After 3 hours of LPS priming, concentrations of test compound in the range from 10 pM to 610 pM were added 30 min prior to NLRP3 inflammasome pathway stimulation with ATP 2 mM for 3 h.
  • IL-1P quantification For IL-1P quantification, supernatants were analyzed using a HTRF kit according to the manufacturer's instructions (Cisbio 62HIL1 BPEH). Briefly, in a 384-well ProxiPlateTM microplate, 8 pl of sample were mixed with 5 pl of Anti-ILI P Cryptate antibody (40x) and Anti-IL1 p XL antibody (40x). Then, the sample was incubated overnight at RT. Reading was done using an EnVision Reader (PerkinElmer). The ICao (concentration corresponding to 50% inhibition) were determined using GraphPad Prism 9,
  • the tested compounds showed significant inhibition of IL-1 beta release in human monocyte-derived macrophages using ATP as activator, see Table 1 ,

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Abstract

The present application relates to compounds of formula (I) for use in the treatment, alleviation or prevention of a group of diseases, disorders and abnormalities which are responsive to the modulation or inhibition of the activation of a component of the NLRP3 inflammasome pathway. In particular, the component of the inflammasome pathway is a NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome. More particularly, the compounds of the present invention have the capability to modulate the NLRP3 inflammasome pathway. Further, the compounds of the present invention are suitable for the treatment, alleviation or prevention of a group of diseases, disorders and abnormalities which are responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels.

Description

HETEROCYCLIC MODULATORS OF THE NLRP3 INFLAMMASOME PATHWAY
FIELD OF THE INVENTION
The present invention relates to novel compounds that are useful for the treatment, alleviation or prevention of a disease, disorder or abnormality which is responsive to the modulation, in particular inhibition of the activation, of a component of the NLRP3 inflammasome pathway. In particular, the component of the inflammasome pathway is NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome. More particularly, the compounds of the present invention have the capability to modulate, e.g., inhibit the activation of, the NLRP3 inflammasome pathway. Further, the compounds of the present invention have the capability to modulate, in particular decrease, IL-1 beta and/or IL-18 levels. The present invention relates to novel compounds for the treatment, alleviation or prevention of a disease, disorder or abnormality which is responsive to the inhibition of the activation of the NLRP3 inflammasome pathway. The present invention relates to novel compounds for the treatment, alleviation or prevention of a disease, disorder or abnormality which is responsive to the modulation of IL-1 beta and/or IL-18 levels. The present invention relates to pharmaceutical compositions comprising said compounds, methods of using said compounds in the treatment of various diseases, disorders or abnormalities which is responsive to the above-mentioned modulation, medicaments containing them and their uses thereof.
BACKGROUND OF THE INVENTION
Inflammasome protein complexes are the key components of inflammatory signalling. These complexes assemble in response to various danger signals such as molecules from infectious agents (pathogen-associated molecular patterns, PAMPs) as well as altered host molecules, products of sterile tissue damage and environmental factors (danger associated molecular paterns, DAMPs). The inflammasome family consists of NALP1-14, I RAF, and NAIP 1-6, with each family member providing specificity towards different PAMPs/DAMPs including nucleic acids, bacterial proteins, metabolites, protein aggregates and the activity of toxins (Sharma, D. & Kanneganti, T.D. The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation. J. Cell Biol. 213, 617-629 (2016)). Inflammasomes are typically composed of a sensor (a cytosolic pattern-recognition receptor, PRR) and an adaptor protein called apoptosis associated speck-like protein containing a caspase-recruitment domain (CARD) (ASC), and an effector such as the protease caspase-1 (Broz, P.; Dixit, V. M. Inflammasomes: Mechanism of Assembly, Regulation and Signalling, Nat. Rev. Immunol. 2016, 16, 407-420).
NLRP3 (NOD-like receptor (NLR) family, pyrin domain-containing protein 3) inflammasome is one of the best-described family members. It is a tripartite protein of the NLR family and contains an aminoterminal PYRIN (PYD) domain, a nucleotide-binding NACHT domain and a carboxy-terminal leucine- rich repeat (LRR) domain. In response to various agents including aggregated proteins, crystals and altered cellular ion homeostasis, the NLRP3 sensor molecule assembles into a multi-molecular complex with apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC aka PYCARD) adaptor protein. ASC protein polymerization into a large complex (ASC speck) leads to activation of caspase-1 effector protein and subsequent cleavage of pro-IL-1 beta (p) and pro-IL18 into their active secreted forms and mediates pyroptosis (Heneka et al., 2018 Nat Rev Neurosci). IL-1 beta (p) acts through IL-1 beta (p) receptors, induces secondary pro-inflammatory signals including IL-6 and TNF alpha secretion, and attracts and activates cells of adaptive immune system at the sites of infection. NLRP3/ASC complexes seems to be released into the extracellular environment where they can propagate inflammation.
Multiple genetic and pharmacological evidence highlight the importance of NLRP3 inflammasome in human disease. NLRP3 gain-of-function mutations lead to the inherited cryopyrin-associated periodic syndromes (CAPS) including Muckle-Wells syndrome (MWS), familial cold auto-inflammatory syndrome (FCAS) and neonatal-onset multisystem inflammatory disease (NOMID).
Accumulation of tissue damage products associated with ageing results in activation of NLRP3 inflammasome in multiple diseases including metabolic disorders, Alzheimer’s disease, Parkinson's disease, amyotrophic lateral sclerosis, atherosclerosis, obesity, lung diseases, liver diseases and gout.
Vast experimental evidence from animal models points out the detrimental role of excessive NLRP3 activation in a wide spectrum of diseases. NLRP3-inflammasome genetic or pharmacological downregulation showed protection in models of Alzheimer’s disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, type 1 and type 2 diabetes, rheumatoid arthritis, and myelodysplastic syndrome, among others (Heneka et a/., Nat. Rev. Neurosci. 2018 Oct; 19(10):610-621; Mangan et a/., Nat. Rev. Drug Discov. 2018 Aug; 17(8): 588-606).
For the reasons described above modulation of NLRP3 inflam masome pathway activity represents a promising therapeutic approach.
Current treatments for NLRP3-related diseases include biologies targeting IL-1. These are the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1 beta (p) antibody canakinumab and the soluble decoy IL-1 receptor rilonacept. However, their activity is limited to downstream effectors of inflammasome and their bioavailability for central nervous system (CNS) applications is limited.
Several small molecules have been shown to inhibit the NLRP3 inflammasome pathway (Baldwin, A. G., Brough, D. & Freeman, S. Inhibiting the NLRP3 inflammasome pathway: a chemical perspective. J. Med. Chem. 59, 1691-1710 (2016); reviewed in Mangan eta/., Nat Rev Drug Discov. 2018 Aug; 17(8) :588-606). These include various chemical classes such as sulfonylurea-based compounds (glyburide, CP-456,773 (aka CRID3 and MCC950) and its derivatives); fenamate classes of non-steroidal anti-inflammatory drugs; hydroxysulfonamide analogue JC-171 : novel boron compound series; benzimidazole-containing structure Fc1 la-2; polyketide spirodalesol; acrylate and acrylamide derivatives; 3,4-methylenedioxy-p-nitrostyrene; p-sulfonyl nitrile molecule OLT1177; CY-09; BOT-4-one; and Michael acceptors. Most of these compounds have a promiscuous mode of action and limited potency.
WO2016131098, WO2017140778 and WO2018215818 referto sulfonylurea and related compounds and their use in treating or identifying a disease or condition responsive to inhibition of NLRP3 or inhibition of the activation of NLRP3 or related components of the inflammatory process.
WO2019008025, WO2019008029, WO2019034686, WO2019034688, WO2019034690, WO2019034692, WO2019034693, WO2019034696, WO2019034697, WO2019068772, W02019092170, W02019092171 and WO2019092172 refer to novel compounds (e.g. sulfonylureas, sulfonylthioureas, sulfoximine ureas and sulfoximine thioureas), useful in the treatment and prevention of medical disorders and diseases, most especially by NLRP3 inhibition. WO2017184604, WO2017184623, WO2017184624, WO2019023145, WO2019023147 and
WO2019079119 refer to chemical entities that are useful for treating a condition, disease, or disorder in which a decrease or increase in NLRP3 activity contributes to the pathology and/or symptoms and/or progression of the condition, disease, or disorder in a subject.
WO2019211463, W02020021447, WO2021043966, WO2021239885, WO2021219784,
WO2021214284, WO2021209552, and WO2021209539 disclose compounds for inhibiting NLRP3 and/or NLRP3 inflarnmasome pathway.
WO2018136890 refers to sulfonylurea and sulfonyl thiourea compounds and their use in treating a disease or condition responsive to modulation of cytokines such as IL-1 beta (p) and IL-18, modulation of NLRP3 or inhibition of the activation of NLRP3 or related components of the inflammatory process.
WO2018225018 and WO2019043610 refer to NLRP3 modulators as well as to the use of the novel inhibitor compounds in the treatment of diseases or conditions as well as treatment of disease states mediated by NLRP3 as well as treatment of diseases or conditions in which interleukin 1 beta (P) activity and interleukin-18 (IL-18) are implicated.
W02018015445 refers to sulfonylurea compounds which possess inflammasome inhibitory activity and are accordingly useful in methods of treatment of the human or animal body.
WO2020Q18975 discloses sulfonimidamide derivatives defined as inhibitors of interleukin-1 activity and NLRP3 modulators in connection with inflammatory processes.
WO9832733 refers to aryl and heleroaryl substituted sulfonyl ureas that are inhibitors of interleukin- 1 alpha (a) and interleu kin-1 beta (p) processing and release.
W02020018970 discloses sulfonylureas defined as inhibitors of interleukin-1 activity.
WO2020234715 discloses pyridazine-3-yl phenol compounds defined as inhibitors of NOD-like receptor protein 3 (NLRP3) inflammasome activity.
WO2021193897 refers to substituted pyridazine compounds that are described as having suppressive action on NLRP3 inflammasome activity. The crosstalk between the NLRP3 inflammasome pathway and Tau pathology has been recently deciphered. Ising et al. (Nature 2019 Nov; 575(7784):669-673) investigated the important role of microglia and NLRP3 inflammasome pathway activation in the pathogenesis of tauopathies in the Tau22 mouse model of FrontoTemporal Dementia (FTD). Genetic ablation of components of the NLRP3 inflammasome pathway in Tau22 mice reduced Tau aggregation/phosphorylation as well as improved cognition. Stancu etal. (Acta Neuropathol. 2019; 137(4): 599-617) investigated the role of inflammasome activation in prion-like or templated seeding of Tau pathology. Significant inhibition of exogenously seeded Tau pathology was found in ASC deficient - PSI 9 Tau transgenic mice. Furthermore, it was demonstrated that chronic intracerebral administration of the NLRP3 inhibitor, MCC950, inhibits exogenously seeded Tau pathology. Finally, ASC deficiency also decreased non- exogenously seeded Tau pathology in PS 19 mice.
There is a need to identify and develop specific NLRP3 inflammasome pathway inhibitors and/or modulators of interleukin activity with beneficial pharmacological and/or physiological and/or physicochemical properties.
The present invention provides compounds of formula (I) or (la), which have surprisingly been found to be capable of modulating a component of the NLRP3 inflammasome pathway, in particular inhibiting the activation, of a component of the NLRP3 inflammasome pathway, such as NLRP3 inflammasome. Thus, such compounds are beneficial in the treatment of a disease, disorder, or abnormality which is responsive to the modulation of a component of the NLRP3 inflammasome pathway and/or which is responsive to the modulation of IL-1 beta and/or IL-18 levels that commonly lead to pathological inflammation.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides compounds that can be employed in the treatment, alleviation or prevention of a disease, disorder or an abnormality which is responsive to the modulation, in particular inhibition, of a component of the NLRP3 inflammasome pathway, or which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels.
Various embodiments of the invention are described herein. Within a certain aspect, provided herein is a compound of formula (I)
Figure imgf000007_0001
or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof; wherein
Z1 and Z2 are each selected from N and C whereby if Z1 is N, Z2 is C, and if Z1 is C, Z2 is N, preferably
Z1 is N and Z2 is C;
V, X and E are each independently selected from N and CRa; wherein at least one of V, X and E is CRa; indicates alternating single and double bonds;
Ra is independently selected from the group consisting of -H, -C-i-Caalkyl, -CF3 and halo;
Ro is selected from the group consisting of -H, -CrCsalkyl and -halo;
R1 is selected from the group consisting of -CF3, -OCF3, -OCHFa, -CN and -halo;
R2 is selected from the group consisting of -OH, -H, -OCF3, -OCHFz, -C1-C3alkyl, -halo and -CF3;
R3 is selected from the group consisting of-H, -C T-C alkyl, -OH. -CF3 and -halo:
R4 is selected from the group consisting of-H, -C1-C3alkyl, -CF3 and -halo; and
RA is a 7-, 8-, 9-, 10- or 11 -membered spiro or fused heterocycloalkyl bicyclic moiety containing one to three heteroatoms, wherein said heteroatom(s) is/are independently selected from N and O, and wherein the bicyclic moiety is optionally substituted at any available position with one or two substituents which are independently selected from the group consisting of C1-C4alkyl, haloC1-C4alkyl, hydroxyC1-C4alkyl, -OH and halo.
Within a preferred aspect, provided herein is a compound of formula (la)
Figure imgf000008_0001
or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof; wherein Ro, Ri, Ra, R3, R4, R« and R* are as defined above, preferably Ra is selected from the group consisting of -H and -C1-C3alkyl.
Within the present invention any reference to the compounds of formula (!) or (la), or the preferred embodiments thereof is intended to also refer to the stereoisomers, or racemic mixtures, or tautomers, or polymorphs, or pharmaceutically acceptable salts, or hydrates, or solvates thereof.
Compounds of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, are suitable for the treatment, alleviation or prevention of a disease, disorder or an abnormality which is responsive to the modulation, in particular inhibition, of a component of the NLRP3 inflammasome pathway, or which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels. In particular, the component of the inflammasome pathway is the NLRP3 inflammasome. Activation of the NLRP3 inflammasome pathway can trigger the formation of ASC specks, cleavage and activation of Caspase-1 and Caspase-8 and subsequent activation and release IL-1 beta, IL-18, gasdermin D cleavage and pore formation, pyroptosis, and release of IL-1 alpha, IL-33, IL-17 and High-Mobility Group Box (HMGB) protein. The compounds of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, have the capability to modulate, in particular decrease, IL-1 beta and/or IL-18 levels.
The compounds of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, display high capability in modulating and, in particular inhibiting the activation of, a component of the NLRP3 inflammasome pathway, in particular wherein the component of the inflammasome pathway is the NLRP3 inflammasome. Due to their unique design features, these compounds display properties such as modulating or inhibiting the activation of the NLRP3 inflammasome pathway allowing them to be a successful medicament for the treatment, alleviation or prevention of diseases, disorders and abnormalities responsive to the modulation or inhibition of a component of the NLRP3 inflammasome pathway such as, for example, Alzheimer’s disease, Parkinson’s disease, CAPS, non-alcoholic faty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and gout.
In a further embodiment, the invention relates to a pharmaceutical composition comprising a compound of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient
In another embodiment, the present invention refers to a compound of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use as a medicament.
Yet another embodiment, the present invention refers to a compound of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use in the treatment, alleviation or prevention of a disease, disorder, or abnormality which is responsive to the modulation, in particular inhibition of activation, of a component of the NLRP3 inflammasome pathway and/or which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels.
A further embodiment is concerned with the use of the compound of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for the manufacture of a medicament for treating, alleviating or preventing a disease, disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of a component of the NLRP3 inflammasome pathway and/or which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels.
In yet another embodiment, the present invention is directed to a method of treating, alleviating or preventing a disease, disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of a component of the NLRP3 inflammasome pathway or which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels, the method comprising administering a therapeutically effective amount of a compound of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, to a subject in need thereof (e.g. a patient). A pharmaceutical composition comprising a combination of a compound of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, and at least one further biologically active compound differing from the compound of formula (I) or (la), and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient, is also the subject-mater of the present invention.
In particular, the further biologically active compound can be one which is used for the treatment of a disease, disorder, or abnormality associated with a disease targeting different pathomechanism, e.g, an anti-amyloid beta antibody, anti-Tau antibody, amyloid beta small molecule inhibitor, Tau aggregation small molecule inhibitor, anti-alpha synuclein antibody or alpha-synuclein aggregation small molecule inhibitor, anti-TDP-43 antibody or anti-TDP-43 aggregation small molecule inhibitor, among others. When a compound of the invention is used in combination with a further biologically active compound, the dose of each compound may differ from the dose which is employed if the compound is used as a monotherapy.
An additional embodiment relates to the use of the compound of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, as an analytical reference or an in vitro screening tool.
The present invention is described hereinafter.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds of formula (I) or (la), including stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, hydrates, or solvates thereof.
Any of the definitions of Ro, Rt, Rj, Rs, R4, Ra, E, V, X, Z-t, Z2and R* which are given with respect to the compounds of formula (I) apply analogously to compounds of formula (la), wherever Ro, R1, R2, R3, R4, Ra, E, V, X, Zi, Z2 and/or R* are used. The present invention relates to compounds of formula (I) as defined below:
Figure imgf000011_0001
or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof; wherein
Z1 and Z2 are each selected from N and C, whereby if Z1 is N, Z2 is C, and if Z1 is C, Z2 is N, preferably
Z1 is N and Z2 is C;
V, X and E are each independently selected from N and CRa; wherein at least one of V, X and E is CRa; indicates alternating single and double bonds;
Ra is independently selected from the group consisting of -H, -C1-C3alkyl, -CF3 and -halo;
Ro is selected from the group consisting of -H, -C1-C3alkyl and -halo;
Ri is selected from the group consisting of -CFs, -OCF3, -OCHF2, -CN and -halo;
R2 is selected from the group consisting of -OH, -H, -OCF3, -OCHF2, -C1-C3alkyl, -halo and -CF3; Ra is selected from the group consisting of -H, -C1-C3alkyl, -OH, -CFrand -halo;
R4 is selected from the group consisting of -H, -C1-C3alkyl, -CF3 and -halo; and
RA is a 7-, 8-, 9-, 10- or 11 -membered spiro or fused heterocycloalkyl bicyclic moiety containing one to three heteroatoms, wherein said heteroatom (s) is/are independently selected from N and O, and wherein the bicyclic moiety is optionally substituted at any available position with one or two substituents which are independently selected from the group consisting of C1-C4alkyl, haloC1-C4alkyl, hydroxyC1-C4alkyl, -OH and halo.
In a preferred embodiment, Ro is selected from -H and -C1-C3alkyl (such as preferably methyl or ethyl, more preferably methyl). In one more preferred embodiment Ro is -H.
In a preferred embodiment, R1 is selected from -CF3, or -halo (halogen). In one more preferred embodiment, Rt is -CF3 or -Cl (chloro).
In one preferred embodiment, R2 is -OH or -H, more preferably -OH, In one preferred embodiment, R3 is -OH or -H, more preferably -H.
In one preferred embodiment, R4 is selected from -H and -C1-C3alkyl, wherein -C1-C3alkyl is preferably methyl (-Me or -CH3) or ethyl (-Et or -CH2CH3), more preferably methyl.
In a preferred embodiment, Ra is selected from -H and -C1-C3alkyl (such as preferably methyl or ethyl, more preferably methyl). In one more preferred embodiment Ra is -H.
In one preferred embodiment, Ro, R3, and R4 are -H, R1 is -CF3, and R2 is -OH.
In another preferred embodiment, Ro. R3. and R4 are -H, R1 is -Cl, and R2 is -OH.
In another preferred embodiment, Ro and R3 are -H, R1 is -CI, R4 is -Me, and R2 is -OH.
RA is a 7-, 8-, 9-, 10- or 11 -membered spiro or fused heterocycloalkyl bicyclic moiety containing one to three heteroatoms, wherein said heteroatom (s) is/are independently selected from N and O, and wherein the bicyclic moiety is optionally substituted at any available position with one or two substituents which are independently selected from the group consisting of C1-C4alkyl, haloC1-C4alkyl, hydroxyC1-C4alkyl, -OH and halo.
In a preferred embodiment RA is a 7-, 8-, 9- or 10-membered spiro or fused heterocycloalkyl bicyclic moiety containing one to three heteroatoms, wherein said heteroatom(s) is/are independently selected from N and O, and wherein the bicyclic moiety is optionally substituted at any available position with one or two substituents which are independently selected from the group consisting of C1-C4alkyl, haloC1-C4alkyl, hydraxyC1-C4alkyl, -OH and halo.
In one embodiment, the heterocycloalkyl bicyclic moiety is a spiro heterocycloalkyl bicyclic moiety. In a preferred embodiment, the heterocycloalkyl bicyclic moiety is a fused heterocycloalkyl bicyclic moiety.
The heterocycloalkyl bicyclic moiety preferably has 7, 8, 9 or 10 members, more preferably 8, 9 or 10 members, even more preferably 8 or 9 members.
The heterocycloalkyl bicyclic moiety contains one to three, preferably one or two, more preferably one heteroatom (s). The heteroatom is/are independently selected from N and O, preferably N. The optional substituents of the bicyclic moiety are independently selected from the group consisting of CrC4alkyl, haloC1-C4alkyl, hydroxy Ci-Colky I, -OH and halo and are preferably selected from Ci-Cjalkyl and haloC1-C4alkyl, more preferably CrC4alkyl (such as methyl). The optional substituent can be present at any available position and is, for instance, attached to a nitrogen atom. The number of substituents can be selected at choice and will be one or two, preferably one.
The heterocycloalkyl bicyclic moiety can be attached to the six-membered ring via any available atom of the heterocycloalkyl bicyclic moiety, typically the heterocycloalkyl bicyclic moiety is attached via an N atom which is contained in the heterocycloalkyl bicyclic moiety.
In one embodiment, R* is a 7- 8- 9- , 10- or 11 -membered spiro or fused heterocycloalkyl bicyclic moiety containing two heteroatoms, wherein said heteroatoms are N, and wherein the bicyclic moiety is optionally substituted at any available position with one or two substituents which are independently selected from the group consisting of CrQalkyl, haloCt-C4alkyl, hydroxyC1-C4alkyl, -OH and halo.
In one embodiment, RA is a 7-, 8-, 9- or 10-membered spiro or fused heterocycloalkyl bicyclic moiety containing two heteroatoms, wherein said heteroatoms are N, and wherein the bicyclic moiety is optionally substituted at any available position with one or two substituents which are independently selected from the group consisting of C1-C4alkyl, haloC1-C4alkyl, hydroxyC1-C4alkyl, -OH and halo.
In one preferred embodiment RA is a 7-, 8-, 9- or 10-membered spiro or fused heterocycloalkyl bicyclic moiety containing two heteroatoms, wherein said heteroatoms are N, and wherein the bicyclic moiety is optionally substituted at any available position with one substituent which is independently selected from the group consisting of C1-C4alkyl, preferably methyl.
In one preferred embodiment RA is selected from the group consisting of
Figure imgf000014_0001
wherein Rs is independently selected from -H or -C1-C3alkyl, preferably methyl.
Figure imgf000014_0002
wherein Rs is independently selected from -H or -C1-C3alkyl, preferably methyl. In one preferred embodiment, RA is selected from the group consisting of
Figure imgf000015_0001
In a preferred embodiment:
Ro is -H;
Ri is -CF3 or halo, preferably Cl,
R2 is -OH;
R3 is -H;
Figure imgf000015_0002
In some embodiments, one of V, X and E is CRa, wherein Ra is as defined above. In a preferred embodiment, Wo out of V, X and E are CRa, wherein Ra is as defined above.
In one preferred embodiment, X is CRa, wherein Ra is selected from H and -C1-C3alkyl. In a preferred embodiment, X is CH.
In preferred embodiments, Z1 is N and Z2 is C.
In some preferred embodiments, Z1 is N and at least two of V, X, and E are CRa, wherein Ra is as defined above.
In another preferred embodiment, Z1 is N, E is N and V and X are each CRa, wherein Ra is as defined above.
In one preferred embodiment, Z1 is N, E is N and V is CRa, wherein Ra is as defined above and X is CH.
In one preferred embodiment, Z1 is N, E is N and V is CR,, wherein R« is selected from H and C1-C3alkyl and X is CH.
In one preferred embodiment, Z1 is N, E is N and V is CRa, wherein Ra is methyl and X is CH.
In one preferred embodiment, Z1 is N, X and V are both CH, and E is N.
In another embodiment, Z1 is N and V, X and E are all CRa, wherein Ra is as defined above.
In another embodiment, Z1 is N, X is N and V.and E are both CRa, wherein Ra is as defined above.
In an embodiment, Z1 is N, X is N or CRa, wherein Ra is as defined above, and V and E are both CH.
In another embodiment, Z1 is N, V is N and E and X are each CRa, wherein Ra is as defined above.
In another embodiment, Z1 is N, V is N, E is CRa, wherein Ra is as defined above, and X is CH. In one embodiment, Z1 is N, V is N and E and X are both CH.
In another embodiment, Z1 is N, X is N and V and E are each CRa, wherein Ra is as defined above.
In another embodiment, Z1 is N, X is N and V and E are both CH.
In some embodiments:
Z1 is N, V is N, X and E are CRa; or
Z1 is N and V, X, E are CRa; or
Z1 is N and E is N, X and V are CRa.
In other aspects, B is N. In one embodiment Z2 is N and E is CH and V and X are independently selected from N and CRa, wherein R,. In one embodiment, Z2 is N and V, X and E are all CRa, wherein Ra is as defined above. In some embodiments, Z2 is N and at least two of V, X, and E are CRa, wherein Ra is as defined above. In one embodiment, Z2 is N and V, X and E are all CH. In another embodiment, Z2 is N, E is N and V and X are each CRa, wherein Ra is as defined above. In one embodiment, Z2 is N, E is N and V and X are both CH. In another embodiment, Z2 is N, V is N and E and X are each CRa, wherein Ra is as defined above. In one embodiment, Z2 is N, V is N and E and X are both CH. In another embodiment, Z2 is N, X is N and V and E are each CRa, wherein Ra is as defined above. In another embodiment, Z2 is N, X is N and V and E are both CH.
In the most preferred embodiment, Z1 is N, Z2 is C; V, X are CRa, wherein Ra is as defined above, and E is N. More preferably Z1 is N, Z2 is C; V is CRa, wherein Ra is as defined above, preferably R, is H or C1-C3alkyl, X is CH, and E is N.
In a preferred embodiment there is provided a compound of formula (I) having the formula (la:
Figure imgf000017_0001
or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof; wherein Ro, R1, R2, R3, R4, Ra and R* are as defined in any of the above embodiments, preferably Ra, is selected from the group consisting of -H and -C1-C3alkyl.
In a farther embodiment, the present invention relates to the following compounds of formula (I) or
(la):
Figure imgf000018_0001
or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof.
In a further preferred embodiment, the present invention relates to the following compounds of
Figure imgf000018_0002
Figure imgf000018_0003
or a stereoisomer, a racemic mixture, a tautomer; a polymorph, a pharmaceutically acceptable salt. a hydrate, or a solvate thereof.
The present invention relates farther to a pharmaceutical composition comprising a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.
In one embodiment, the pharmaceutical composition comprises a compound of formula (I) or (la)as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.
Various embodiments of the invention are described herein, it will be recognized that features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention.
The present invention relates to a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use as a medicament.
The present invention relates to a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use in the treatment, alleviation or prevention of a disease, disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of a component of the NLRP3 inflam masome pathway and/or which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels. In one embodiment, the modulation is the reduction and/or inhibition of IL-1 beta and/or IL-1 beta levels. Particularly, the modulation is the reduction and/or inhibition of IL-1 beta.
In another embodiment, the present invention relates to a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use in a method of reducing and /or inhibiting IL-1 beta, in particular, inhibiting IL-1 beta.
The present invention relates to a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use in the treatment, alleviation or prevention of a disease, disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of a component of the NLRP3 inflammasome pathway.
The present invention relates to a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use in the treatment, alleviation or prevention of a disease, disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of NLRP3 inflam masome pathway.
The present invention relates to a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use in the treatment, alleviation or prevention of a disease, disorder or abnormality which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL- 18 levels.
In other words, the present invention relates to a method for treating, alleviating or preventing of a disease, disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of a component of the NLRP3 inflam masome pathway and/or which is responsive to the modulation, in particular decrease, of the IL-1 beta and/or IL-18 levels, wherein the method comprises administering a therapeutically effective amount of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, to a subject in need thereof (e.g. patient).
In one embodiment, the present invention relates to a method for treating, preventing or alleviating a disease, a disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of a component of the NLRP3 inflammasome pathway, wherein the method comprises administering a therapeutically effective amount of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, to a subject in need thereof (e.g. a patient).
The present invention further relates to a method for treating, preventing or alleviating a disease, a disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of NLRP3 inflammasome pathway, wherein the method comprises administering a therapeutically effective amount of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, to a subject in need thereof (e.g. a patient).
In one embodiment, the present invention relates to a method for treating, preventing or alleviating a disease, disorder or abnormality responsive to a modulation, in particular a decrease, of IL-1 beta and/or IL-18 levels, wherein the method comprises administering a therapeutically effective amount of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, ora solvate thereof, to a patient in need thereof.
The present invention relates to the use of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for the manufacture of a medicament. In a further embodiment, the present invention relates to the use of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for the manufacture of a medicament for treating, alleviating or preventing a disease, disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of a component of the NLRP3 inflammasome pathway and/or which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels. In one embodiment, the disease, disorder, or abnormality is selected from the list disclosed herein.
The present invention relates to the use of a compound of formula (I) or (Ila) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for the manufacture of a medicament for treating, alleviating or preventing a disease, disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of a component of the NLRP3 inflammasome pathway.
The present invention relates to the use of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for the manufacture of a medicament for treating, alleviating or preventing a disease, disorder or abnormality which is responsive to the modulation, in particular inhibition of activation, of NLRP3 inflammasome pathway.
The present invention relates to the use of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for the manufacture of a medicament for treating, alleviating or preventing a disease, disorder or abnormality which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels.
The present invention relates to the use of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for the manufacture of a medicament for reducing and/or inhibiting IL-1 beta and/or IL-1 beta levels. In one embodiment, the present invention relates to the use of a compound of the invention, as defined herein, for the manufacture of a medicament for reducing and/or inhibiting IL-1 beta. In another embodiment, the present invention relates to the use of a compound of the invention, as defined herein, for the manufacture of a medicament for reducing IL-1 beta.
In one embodiment, the present invention relates to a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use in the treatment, alleviation or prevention of a tauopathy by modulating a component of the inflammasome pathway, in particular, by modulating the NLRP3 inflammasome pathway.
In another embodiment, the disease, the disorder or the abnormality is responsive to modulation of one or more of IL-1 p, IL-17, IL-18, IL- 1 a, IL-37, IL-33 and Th17 cells, preferably: IL-1 p and IL-18.
In yet another embodiment, the disease, disorder, or abnormality is a disease, disorder, or abnormality selected from Alzheimer's disease, Parkinson's disease, multiple sclerosis, cryopyrin- associated periodic syndromes (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), obesity, hidradenitis suppurativa (HS) and gout, such as Alzheimer’s disease, Parkinson’s disease, cryopyrin-associated periodic syndromes (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and gout.
In a farther embodiment, the disease, disorder, or abnormality is a disease, a disorder or an abnormality of the immune system. In an embodiment, the disease, disorder, or abnormality is an inflammatory disease, disorder, or abnormality. In yet another embodiment, the disease, disorder, or abnormality is an autoimmune disease, disorder, or abnormality. In yet another embodiment, the disease, the disorder, or the abnormality is a disease, a disorder, or an abnormality of the central nervous system (CNS). In yet another embodiment, the disease, the disorder, or the abnormality can be a disease, disorder or abnormality or condition of the skin. The disease, the disorder or the abnormality can be a disease, disorder or abnormality or condition of the cardiovascular system. The disease, the disorder or the abnormality or condition can be a cancer, tumour or other malignancy. The disease, the disorder or the abnormality or condition can be a disease, disorder, or abnormality of the renal system. The disease, the disorder or the abnormality or condition can be a disease, disorder, or abnormality of the gastrointestinal tract. The disease, the disorder or the abnormality or condition can be a disease, disorder, or abnormality of the respiratory system. The disease, the disorder or the abnormality or condition can be a disease, disorder, or abnormality of the endocrine system. The disease, the disorder or the abnormality or condition can be liver related disease, disorder, or abnormality.
In one embodiment, the diseases, the disorders or the abnormalities which are responsive to the modulation, in particular inhibition of activation, of a component of the NLRP3 inflammasome pathway can be selected from Alzheimer's disease, Parkinson’s disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudo-gout, inflammatory bowel disease (IBD) (including Crohn’s disease, ulcerative colitis), hepatitis, nonalcoholic faty liver disease, nonalcoholic steatohepatitis, hypertension, myocard ial infarction, heart failure, coronary artery disease, oxalate-induced nephropathy, graft-versus host disease, type 1 diabetes, type 2 diabetes, Edema (DME), Geographic Atrophy (GA), rheumatoid arthritis, myelodysplastic syndrome, lower-risk myelodysplastic syndromes (LR-MDS), familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D, periodic fever syndrome (HIDS), deficiency of interleukin 1 receptor (DIRA) antagonist, Majeed syndrome, pyogenic arthritis pyoderma gangrenosum and acne (PAPA), haploinsufficiency of A20 (HA20), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2- associated autoinflammation, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers, developmental delay (SIFD), chronic nonbacterial osteomyelitis (ONO), Sweet's syndrome, chronic recurrent multifocal osteomyelitis (CRMO), synovitis, pustulosis, skin contact hypersensitivity, sunburn, psoriasis, hidradenitis suppurativa (HS), dermatitis, skin lesions, bum, wound, trauma, epidermolysis bullosa, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteitis syndrome (SAPHO), vitiligo, atopic dermatitis, cutaneous lupus, multiple sclerosis (MS), Behcet's disease, Sjogren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disorder (COPD), asthma, steroid-resistant asthma, Coronavirus-associated inflammatory pathologies including Coronavirus-associated respiratory distress syndrome (CARDS), asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, obesity, age- related macular degeneration (AMD), corneal infection, uveitis, dry eye, acute kidney disease, chronic kidney disease, lupus nephritis, diabetic nephropathy, alcoholic liver disease, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, Chikungunya virus, Ross River virus, influenza, HIV, Coronaviruses, Dengue, Zika virus, primary biliary cholangitis, antiphospholipid syndrome, refractory celiac disease, pancreatitis, autoimmune pancreatitis, mucocutaneous lymph node syndrome, lung cancer metastasis, pancreatic cancers, gastric cancers, myelodisplastic syndrome, leukemia; polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurism, wound healing, migraine, depression, psychological stress, pericarditis including Dressier's syndrome, ischaemia reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorder, traumatic spinal cord injury, traumatic brain injury, inflammatory pain, chronic pain, neuropathic pain, metastatic cancer-induced bone pain, chemotherapy induced peripheral neuropathy; ankylosing spondylitis and cytokine release syndrome.
Preferably the disorder, disease or abnormality is selected from Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, demyelination, multiple sclerosis, encephalomyelitis, leukoencephalopathy, viral encephalitis, epilepsy, stroke, traumatic brain injury, spinal cord injury, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), gout, inflammatory bowel disease (IBD), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft- versus host disease, obesity, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, lower-risk myelodysplastic syndromes (LR-MDS), anti-neutrophil cytoplasmic antibody- associated vasculitis (AAV), acute kidney disease, chronic kidney disease, lupus nephritis, anti- glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), Focal Segmental Glomerulosclerosis, Minimal change disease (MCD), Psoriatic Arthritis, Hereditary Recurrent Fevers (HRFs), acne, atopic dermatitis, hidradenitis suppurativa (HS), and amyloidosis (including AL amyloidosis, AA amyloidosis, ATTR amyloidosis, hereditary amyloidoses (including apolipoprotein A-l (AApoAl), apolipoprotein A-l I (AApoAII), gelsolin (AGel), fibrinogen (AFib), and lysozyme (ALys)), Beta-2 microglobulin amyloidosis, iAPP amyloidosis).
In one embodiment, the diseases, the disorders or the abnormalities are selected from Alzheimer's disease, Parkinson’s disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma and allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), gout, inflammatory bowel disease, non-alcoholic faty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, obesity, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, lower-risk myelodysplastic syndromes (LR-MDS), anti- neutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, anti-glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), Focal Segmental Glomerulosclerosis, Minimal change disease (MOD), Psoriatic Arthritis, and Hereditary Recurrent Fevers (HRFs).
In another embodiment, the disease, the disorders or the abnormality is a skin disease, disorder, or abnormality selected from hidradenitis suppurativa (HS), dermatitis, psoriasis, skin contact hypersensitivity, acne, periodic fever syndrome (HI DS), Sweet’s syndrome, eczema, skin lesions, burn, wound, wound healing, trauma, sunburn, actinic keratosis, deficiency of interleukin 1 receptor (DIRA) antagonist, epidermolysis bullosa, vitiligo, atopic dermatitis, cutaneous lupus, and alopecia areata.
Preferably, the diseases, the disorders or the abnormalities are selected from Alzheimer’s disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma and allergic inflammation, cryopyrin- associated periodic syndromes (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic kidney disease, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, obesity, type 1 and type 2 diabetes, hidradenitis suppurativa (HS), rheumatoid arthritis, myelodysplastic syndrome and lower-risk myelodysplastic syndromes (LR-MDS),.
In one embodiment, the diseases, the disorders or the abnormalities are selected from Alzheimer’s disease, Parkinson's disease, cryopyrin-associated periodic syndromes (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), rheumatoid arthritis, chronic kidney disease obesity, hidradenitis suppurativa (HS) and gout In one embodiment, the diseases, the disorders or the abnormalities are selected from Alzheimer's disease, Parkinson’s disease, multiple sclerosis, cryopyrin-associated periodic syndromes (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) chronic kidney disease and gout.
In one embodiment the disease, the disorder or the abnormality is hidradenitis suppurativa (HS) in an obese subject. In one embodiment the disease, the disorder or the abnormality is comorbid hidradenitis suppurativa (HS) and obesity.
In one embodiment, the present invention relates to a compound of formula (I) or (la), as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use in the treatment, alleviation or prevention of a IL-18 and/or IL-1 beta related disease by modulating a component of the NLRP3 inflammasome pathway, in particular, by modulating NLRP3 inflammasome pathway. The IL-18 and/or IL-1 beta levels in a subject are decreased as a result of the administration of a compound of formula (I) or (la), as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof.
IL-18 and/or IL-1 beta related diseases, disorders or abnormalities are selected from chronic obstructive pulmonary disease (COPD), transfusion-related lung injury, bronchopulmonary dysplasia (BPD), acute respiratory distress syndrome (ARDS), pediatric autoinflammatory disease or condition, Still's disease, particularly Adult Still's disease or juvenile Still's disease, juvenile rheumatoid arthritis (JRA), juvenile idiopathic arthritis (JIA), systemic juvenile onset idiopathic arthritis (SoJIA), systemic juvenile idiopathic arthritis (sJIA), interstitial lung disease (ILD), macrophage activation syndrome (MAS) including primary, secondary and recurrent MAS, hemophagocytic lymphohistiocytosis (HLH), Familial (hereditary) hemophagocytic lymphohistiocytosis (FHLH) associated with gene defects in perforin, munc 13-4 and 18-2, synthaxin 11 , immune deficiencies such as Chediak-Higashi syndrome (CHS), Griscelli syndrome (GS), X-linked lymphoproliferative syndrome (XLP2), X-linked inhibitor of apoptosis protein deficiency (XIAP), acquired hemophagocytic lymphohistiocytosis associated with infectious conditions especially Herpes virus such as EBV and other pathogens, autoinflammatory syndrome associated with NLRC4 mutations, Giant Cell Arteritis (GCA), acne, pyogenic arthritis pyoderma gangrenosum and acne (PAPA), pulmonary sarcoidosis, heart failure, ischemic heart disease, dry eye disease (DED), keratitis, corneal ulcer and abrasion, iritis, glaucoma, Sjogren's syndrome, autoimmune uveitis, Behcet's disease, conjunctivitis, allergic conjunctivitis, diabetes type 2, solid organ and hematologic stem cell transplantation, ischemia reperfusion injury, familial Mediterranean fever (FMF), tumor necrosis factor receptor 1- associated periodic syndromes (TRAPS), hyper-lgD syndromes (mevalonate kinase gene mutation), gout, Schnitzler syndrome, Wegener's granulomatosis also called granulomatosis with polyangitis (GPA), Hashimoto's thyroiditis, Crohn’s disease, early onset inflammatory bowel disease (EOIBD), very EOIBD (VEOIBD), infantile IBD, neonatal IBD, ulcerative colitis and Blau syndrome (NOD-2 mutation).
The modulation of NLRP3 inflammasome pathway appears to be beneficial in diseases or disorders or abnormalities with altered IL-18 levels and / or IL-1 beta, which lead to pathological inflammation. The present invention relates to compound of formula (I) or (la) as defined in the present invention that are modulators of NLRP3 inflammasome activity and/or modulators of IL-18 and/or IL-1 b levels in a subject.
In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, and at least one further biologically active compound. Optionally, the pharmaceutical combination may comprise a pharmaceutically acceptable carrier, diluent, adjuvant or excipient as described herein.
In another embodiment, the present invention relates to a pharmaceutical composition comprising a combination of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, and at least one further biologically active compound differing from the compound of formula (I) or (la), and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.
In another embodiment, the present invention relates to a pharmaceutical composition comprising a combination of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, and at least one farther biologically active compound differing from the compound of formula (I) or (la), and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.
When a compound of the invention is used in combination with a further biologically active compound, the dose of each compound may differ from the dose if the compound is used as a monotherapy. Such biologically active compounds are well known from the literature. Such biological active compound is, for example, a chemical compound, peptide, antibody, antibody fragment, or nucleic add, which is therapeutically active or enhances the therapeutic activity when administered to a subject (e.g., patient) in combination with a compound of the invention.
For example, compounds of the invention may be used in combination with a further biologically active compound or therapy for treating Alzheimer’s disease, such as beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs) such as apazone, aspirin, celecoxib, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium, mefenamic acid, meloxicam, nabumetone, naproxen, oxa prozin, phenylbutazone, piroxicam, choline and magnesium salicylates, salsalate, and sulindac, vitamin E, and anti-amyloid antibodies amongst others; and/or the compounds of the invention may be used in combination with a further biologically active compound or therapy for treating depression (antidepressants) and/or schizophrenia (atypical or typical antipsychotics) such as amitriptyline, amoxapine, aripiprazole, asenapine, bupropion, chlordiazepoxide, citalopram, chlorpromazine, clozapine, desipramine, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, fluoxetine, fluphenazine, haloperidol, iloperidone, imipramine, isocarboxazid, lamotrigine, levomilnacipran, lurasidone, mirtazapine, nefazodone, nortriptyline, olanzapine, paliperidone, paroxetine, perphenazine, phenelzine, protriptyline, quetiapine, risperidone, selegiline, sertraline, tranylcypromine, trazodone, trimipramine, venlafaxine, vilazodone, and vortioxetine, and ziprasidone; and/or with a further biologically active compound or therapy for treating anxiety (anxiolytics), such as benzodiazepines (alprazolam, chlordiazepoxide, clobazepam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, prazepam, quazepam, temazepam, and triazolam), antihistamines (hydroxyzine), nonbenzodiazepines (eszopiclone, zaleplon, zolpidem, and zopiclone) and buspirone; and/or with a further biologically active compound or therapy for treating epilepsy (antiepileptics or anticonvulsants), such as acetazolamide, carbamazepine, clobazam, clonazepam, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, retigabine, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, and/or with a zonisamide acetylcholinesterase inhibitor such as galantamine, donepezil, rivastigmine, and/or with a NMDA receptor antagonist such as memantine.
In particular, the further biologically active compound can be one used for the treatment of a disease, disorder or abnormality which targets a different pathomechanism, e.g. an anti-amyloid beta antibody, anti-Tau antibody, amyloid beta targeting small molecule, Tau targeting small molecule, anti-alpha synuclein antibody or alpha-synuclein targeting small molecule, anti-TDP-43 antibody or anti-TDP- 43 targeting small molecule, among others.
For example, in some embodiments compounds of the invention may be used in combination with an anti-amyloid beta antibody. Non-limiting examples of such anti-amyloid abeta antibodies include crenezumab, solanezumab, bapineuzumab, aducanumab, gantenerumab, lecanemab, remtemetug, donanemab, trontinemab, ABBV-916 (AbbVie), MEDI-1814 (AstraZeneca), ACU193 (Acumen), PRX012 (Prothena), SHR-1707 (Jiangsu Hengrui Pharmaceuticals) and PMN-310 (ProMIS Neurosciences). In some embodiments, compounds of the invention may be used in combination with an anti-tau antibody. Non-limiting examples of such anti-tau antibodies include semorinemab, bepranemab tilavonemab, gosuranemab, zagotenemab, posdinemab, BIIB076 (Biogen), Lu AF87908 (Lundbeck), E-2814 (Eisai), BMS-986446 (Bristol-Myers Squibb), APN-005 (Aprinoia) and MK-2214 (Merck) amongst others. In some embodiments compounds of the invention may be used in combination with an anti-alpha-sy nuclein antibody. Non-limiting examples of such anti-alpha- synuclein antibodies include prasinezumab, MEDI-1341 (AstraZeneca), Lu AF82422 (Lundbeck), BAN0805 (BioArctic), UCB7853 (UCB) and ABL-301 (ABL Bio) amongst others. In some embodiments compounds of the invention may be used in combination with an anti-TDP-43 antibody. Non-limiting examples of such anti-TDP-43 antibodies include ACI-5891.9 (AC Immune SA) amongst others. In other embodiments compounds of the invention may be used in combination with an amyloid beta targeting small molecule, a Tau targeting small molecule, an alpha-synuclein targeting small molecule, or a TDP-43 targeting small molecule. Non-limiting examples of such tau targeting small molecules include Hydromethylthionine mesylate (TauRx Therapeutics) and OLX-07010 (Oligomerix Inc.) amongst others. Non-limiting examples of such anti-alpha-synuclein targeting small molecules include UCB0599 (UCB) and Anle138b (MODAG) amongst others.
In another embodiment, the present invention relates to a pharmaceutical composition comprising a combination comprising a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, and at least one further biologically active compound differing from the compound of formula (I) or (la), and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient, for use as a medicament
The term "combination" refers to either a fixed combination in one dosage unit form, or a combined administration where a compound of the present invention and a combination partner (e.g. another drug as explained above, also referred to as “therapeutic agent” or “further biologically active compound’’) may be administered independently at the same time or separately within time intervals.
In another embodiment, the present invention relates to combination, in particular a pharmaceutical combination, comprising a therapeutically effective amount of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, and at least one further biologically active compound, and optionally at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient. In particular, the at least one further biologically active compound is a compound differing from a compound of formula (I) or (la).
In another embodiment, the present invention relates to a combination comprising a therapeutically effective amount of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, and at least one further biologically active compound differing from the compound of formula (I) or (la), and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient, for use as a medicament
The present invention relates to the use of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, as an analytical reference or an in vitro screening tool. The compounds of the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, can be used as an analytical reference or an in vitro screening tool for characterization of cells with activated NLRP3 inflammasome pathway and for testing of compounds targeting the NLRP3 inflammasome pathway.
Accordingly, the invention provides the use of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for treating, alleviating or preventing a disorder or an abnormality which is responsive to the modulation of a component of the NLRP3 inflammasome pathway or which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels, wherein the medicament is prepared for administration with farther biologically active agent. The invention also provides the use of farther biologically active agent for treating alleviating or preventing a disorder or an abnormality which is responsive to the modulation of a component of the NLRP3 inflammasome pathway or which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels, wherein the farther biologically active agent is administered with a compound of the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof.
In another embodiment, the invention provides the use of a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for treating, alleviating or preventing a disorder or an abnormality which is responsive to the modulation of a component of the NLRP3 inflammasome pathway or which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels, wherein the modulation is the reduction and/or the inhibition of IL-1 beta and/or IL-1 beta levels. Preferably, the modulation is the reduction and/or the inhibition of IL-1 beta. Preferably, the modulation is the inhibition of IL-1 beta. In another embodiment, the invention provides a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use as a medicament, in particular for inhibiting IL-1 beta.
In another embodiment, the invention also provides a compound of formula (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use in a method of treating, alleviating or preventing a disease, disorder or abnormality which is responsive to the modulation of a component of the NLRP3 inflammasome pathway or which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels, wherein said compound of formula (I) or (la) is prepared for administration with a further biologically active compound (as defined herein).
In another embodiment, the present invention also provides a method of treating alleviating or preventing a disease, disorder or abnormality which is responsive to the modulation of a component of the NLRP3 inflammasome pathway or which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels, selected from Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudo-gout, inflammatory bowel disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, lower-risk myelodysplastic syndromes (LR-MDS), familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D, periodic fever syndrome (HIDS), deficiency of interleukin 1 receptor (DIRA) antagonist, Majeed syndrome, acne, pyogenic arthritis pyoderma gangrenosum and acne (PAPA), haploinsufficiency of A20 (HA20), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers, developmental delay (SIFD), chronic non bacteria I osteomyelitis (CNO), Sweet's syndrome, chronic recurrent multifocal osteomyelitis (CRMO), synovitis, pustulosis, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteitis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behcet’s disease, Sjogren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disorder (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin contact hypersensitivity, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, Chikungunya virus, Ross River virus, influenza, HIV, Coronaviruses, Dengue, Zika virus, hidradenitis suppurativa (HS), dermatitis, skin lesions, burn, wound, trauma, lung cancer metastasis, pancreatic cancers, gastric cancers, myelodisplastic syndrome, leukemia; polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurism, wound healing, depression, psychological stress, pericarditis including Dressier's syndrome, ischaemia reperfusion injury, frontotemporal dementia, HIV-associated neurocog nitive disorder, Coronavirus-associated inflammatory pathologies, and traumatic brain injury; preferably the disorder is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), gout, inflammatory bowel disease, non-alcoholic faty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, anti-glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), Focal Segmental Glomerulosclerosis , Minimal change disease (MOD), Psoriatic Arthritis, Hereditary Recurrent Fevers (HRFs), and amyloidosis (including AL amyloidosis, AA amyloidosis, ATTR amyloidosis, hereditary amyloidoses (including apolipoprotein A-l (AApoAl), apolipoprotein A-ll (AApoAll), gelsolin (AGel), fibrinogen (AFib), and lysozyme (ALys)), Beta-2 Microglobulin amyloidosis, (APR amyloidosis), comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or (la), as defined herein, or stereoisomers, or racemic mixtures, or tautomers, or polymorph, or pharmaceutically acceptable salts, or hydrates, or solvates thereof.
In another embodiment, the present invention also provides a method of inhibiting IL-1 beta in a subject in need, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or (la) or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof. In particular, the disease, disorder or abnormality is one which is responsive to the inhibition of activation of the NLRP3 inflammasome pathway. More particularly, the disease, disorder or abnormality is responsive to the modulation of one or more of, for example, but not limited to, IL-1 p or IH 8. For example, the disease, disorder, or abnormality is responsive to the modulation of one or more of IL-1 p, IL-17, IL-18, IL- 1 a, IL-37, IL-33 and Th17 cells, preferably the disease, disorder, or abnormality is responsive to the modulation of IL-1 p and/or IL-18.
Any combination of the embodiments, preferred embodiments and more preferred embodiments disclosed herein is also envisaged in the present invention.
PHARMACEUTICAL COMPOSITIONS
While it is possible for the compounds of the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, to be administered alone, it is preferable to formulate them into a pharmaceutical composition in accordance with standard pharmaceutical practice. Thus, the invention also provides a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, optionally in admixture with a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.
The term "a therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention (i.e. a compound of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof) that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, a disorder or an abnormality, etc. In one embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a subject in need thereof (e.g. a patient), is effective to at least partially alleviate, prevent and/or ameliorate a disease, a disorder, or an abnormality which is responsive to the modulation of a component of the NLRP3 inflammasome pathway or which is responsive to the modulation, in particular decrease, of IL-1 beta and/or IL-18.
Pharmaceutically acceptable carriers, diluents, adjuvants and excipients are well known in the pharmaceutical art and are described, for example, in Remington’s Pharmaceutical Sciences, 18th Ed. (Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, PA, 1990); Remington: the Science and Practice of Pharmacy 19th Ed. (Lippincott, Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3rd Ed. (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc, 1999); Pharmaceutical Codex: Principles and Practice of Pharmaceutics 12th Ed. (Walter Lund ed.; Pharmaceutical Press, London, 1994); The United States Pharmacopeia: The National Formulary (United States Pharmacopeial Convention); Fiedler’s “Lexikon der Hilfestoffe” 5th Ed., Edition Cantor Verlag Aulendorf 2002; “The Handbook of Pharmaceutical Excipients", 4th Ed., American Pharmaceuticals Association, 2003; and Goodman and Gilman's: the Pharmacological Basis of Therapeutics (Louis S. Goodman and Lee E. Limbird, eds.; McGraw Hill, 1992), the disclosures of which are hereby incorporated by reference.
The carriers, diluents, adjuvants and pharmaceutical excipients can be selected with regard to the intended route of administration and standard pharmaceutical practice. These compounds must be acceptable in the sense of being not deleterious to the recipient thereof.
Pharmaceutically useful excipients that may be used in the formulation of the pharmaceutical composition of the present invention may comprise, for example, vehicles, solvents (such as monohydric alcohols such as ethanol, isopropanol and polyhydric alcohols such as glycols), edible oils (such as soybean oil, coconut oil, olive oil, safflower oil, and cottonseed oil), oily esters (such as ethyl oleate and isopropyl myristate), binders (such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), pregelatinized starch and combinations thereof), solubilizers, thickening agents, stabilizers, disintegrants (such as carboxymethylcellulose calcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), crosslinked PVP (e.g., crospovidone, Polyplasdone® or Kollidorf6 XL), alginic add, sodium alginate, guar gum, cross-linked CMC (croscarmellose sodium, e.g. Ac-Di-Sol®), carboxymethyl starch-Na (sodium starch glycolate) (e.g,, Primojel® or Explotab®), preferably crosslinked PVP andfor croscarmellose sodium), glidants (such as colloidal S1O2 (e.g., Aerosil® 200), magnesium trisilicate, powdered cellulose, talc and combinations thereof), lubricating agents (such as magnesium stearate, aluminium or calcium silicate, stearic acid, hydrogenated castor oil, talc, glyceryl behenate, sodium stearate fumarate and combinations thereof), buffering agents, emulsifiers, wetting agents, suspending agents, sweetening agents, colorants, flavors, coating agents, preservatives, antioxidants, processing agents, drug delivery modifiers and enhancers (such as calcium phosphate), magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatine, cellulose, methylcellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting waxes, and ion exchange resins. The carrier is not particularly limited and will depend on the route of administration as well as the form of the pharmaceutical composition (i.e., solid, liquid, etc,). Suitable carriers include, without limitation, polyols such as mannitol, sorbitol, xylitol; disaccharides such as lactose, sucrose, dextrose and maltose; polysaccharides such as maltodextrin and dextran; starches such as corn starch; celluloses such as microcrystalline cellulose, sodium carboxy methylcellulose, low-substituted hydroxypropyl cellulose, hydroxyl ethyl cellulose, hydroxypropyl cellulose or mixtures thereof; cyclodextrins and inorganic agents such as dicalcium phosphate, calcium hydrogen phosphate; hydroxyapatite, tricalcium phosphate, talcum and silica. Microcrystalline cellulose, sucrose and/or lactose are preferred as carriers. Combinations thereof can also be employed. Carriers can include also protein and cell penetrating peptides which should be selected depending on the route of administration and target.
The diluent is not particularly limited and will depend on the route of administration as well as the form of the pharmaceutical composition (i.e., solid, liquid, etc.). Diluents include, for instance, water, ethanol, propylene glycol and glycerin, and combinations thereof.
An adjuvant is an additive which has few or no pharmacological effects by themselves, but that increases the efficacy or potency of the compounds of the invention if they are administered together.
The routes for administration (delivery) of the compounds of the invention include, but are not limited to, one or more of the following routes of administration: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical, mucosal (e. g. as a nasal spray or aerosol for inhalation), nasal, parenteral (e.g,, by an injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravagina I, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transderma I, rectal, buccal, epidural and sublingual.
For example, the compounds can be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxy propylcellulose (HPC), sucrose, gelatine and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatine capsules. Preferred excipients in this regard include starch, cellulose, milk sugar, e.g. lactose, or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
If the compounds of the present invention, as disclosed herein, are administered parenterally, then examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously administering the compounds; and/or by using infusion techniques. For parenteral administration, the compounds can be used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
As indicated, the compounds of the present invention can be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurized container, pump, spray or nebulizer with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA134AT) or 1 ,1,1,2,3,3,3-heptafluoropropane (HFA 227), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container, pump, spray or nebulizer may contain a solution or suspension of the active compound, e. g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e. g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatine) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch. Alternatively, the compounds of the present invention, as defined herein, can be administered in the form of a suppository or pessary, or it may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds of the present invention, as defined herein, may also be dermally or transdermally administered, for example, by the use of a skin patch.
They may also be administered by the pulmonary or rectal routes. They may also be administered by the ocular route. For ophthalmic use, the compounds can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.
For application topically to the skin, the compounds of the present invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.
The claimed compounds, as defined herein, can be used for the treatment, alleviation or prevention of the recited conditions alone or in combination with one or more other biologically active compounds, as defined herein. In particular, the other biologically active compound can be one used for the treatment, alleviation, or prevention of the recited diseases.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route. When administration is sequential, either the compound of the invention or the other biologically active compound may be administered first. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition. When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manners as are known for such compounds in the art.
The pharmaceutical compositions of the invention can be produced in a manner known per se to the skilled person as described, for example, in Remington's Pharmaceutical Sciences, 15th Ed., Mack Publishing Co., New Jersey (1975).
The compounds according to the present invention, as disclosed herein, can also be provided in the form of a mixture with at least one further biologically active compound and/or a pharmaceutically acceptable carrier, diluent, adjuvant, or excipient. The compound and/or the further biologically active compound are preferably present in a therapeutically effective amount.
The nature of the further biologically active compound will depend on the intended use of the mixture. The further biologically active substance or compound may exert its biological effect by the same or a similar mechanism as the compound according to the invention or by an unrelated mechanism of action or by a multiplicity of related and/or unrelated mechanisms of action.
The invention also includes all suitable isotopic variations of the compounds of the invention. An isotopic variation of the compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulphur, fluorine and chlorine such as 2H, 3H, 13C, t4C, 15N, 17O, WO, 35S, 18F and *01 respectively. Certain isotopic variations of the invention, for example, those in which a radioactive isotope such as 3H or 14C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i .e,, 3H, and carbon-14, i.e., MC, isotopes are particularly preferred for their ease of preparation and detectability. “F-labeled compounds are particularly suitable for imaging applications such as PET. Further, substitution with isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples and Preparations hereafter using appropriate isotopic variations of suitable reagents.
METHODS OF USE OF THE INVENTION
There is evidence for a role of NLRP3-induced IL-1 and IL-18 in the inflammatory responses occurring in connection with, or as a result of, a multitude of different diseases, disorders or abnormalities which is responsive to the modulation of a component of the NLRP3 inflammasome pathway and/or which is responsive to the modulation of IL-1 beta and/or IL-18 levels. (Menu et al., Clinical and Experimental Immunology, 2011, 166, 1-15; Strowig et al., Nature, 2012, 481, 278-286).
The invention provides a compound of formula (I) or (la) as defined herein, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, which exhibits valuable pharmacological properties, e.g. NRLP3 inhibiting properties on the NLRP3 inflammasome pathway. Said compounds of the invention may be useful in the treatment, alleviation or prevention of a disease, or a disorder or an abnormality which is responsive to the modulation of a component of the NLRP3 inflammasome pathway and/or which is responsive to the modulation of IL-1 beta and/or IL-18 levels, A number of diseases, disorders or abnormalities have been shown to be involve in NLRP3 including, for example, one of the following:
A. Central nervous system disease (CNS), disorder, or abnormality, such as Alzheimer’s disease, Parkinson's disease, dementia, frontotemporal dementia, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, motor neuron disease, traumatic brain injury, amyotrophic lateral sclerosis, or multiple sclerosis (MS);
B. Immune disease, disorder, or abnormality (e.g. autoimmune disease, disorder or abnormality, and disease, disorder, or abnormality, involving the immune system), such as type 1 diabetes, hidradenitis suppurativa (HS), Schnitzler syndrome, multiple sclerosis (MS) including primary progressive multiple sclerosis (PPMS), Sjogren's syndrome, secondary progressive multiple sclerosis (SPMS), TNF receptor associated periodic syndrome (TRAPS), graft-versus host disease or relapsing remitting multiple sclerosis (RRMS);
C. Inflammatory disease, including auto-inflammation and inflammation occurring as a result of an inflammatory disease, disorder, or abnormality, such as mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), familial Mediterranean fever (FMF), acne, pyogenic arthritis, pyoderma gangrenosum and acne (PAPA), adult-onset Still's disease (AOSD), Majeed syndrome, PLCG2-associated antibody deficiency and immune dysregulation (PLAID), PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation (APLAID), pyogenic arthritis, haploinsufficiency of A20 (HA20), pediatric granulomatous arthritis (PGA), or sideroblastic anemia with B-cell immunodeficiency, periodic fevers, developmental delay (SIFD);
D. Skin disease, disorder, or abnormality such as hidradenitis suppurativa (HS), dermatitis, psoriasis, skin contact hypersensitivity, acne, periodic fever syndrome (HIDS), Sweet's syndrome, dermatitis, eczema, skin lesions, bum, wound, wound healing, trauma, sunburn, actinic keratosis, deficiency of interleukin 1 receptor (DIRA) antagonist, or alopecia areata;
E. Ocular disease, disorder, or abnormality, such as age-related macular degeneration (AMD), corneal infection, uveitis, glaucoma, dry eye, or demyelination;
F. Cardiovascular disease, disorder, or abnormality (e.g. disease, disorder, or abnormality of the cardiovascular system) such as myocardial infarction, hypertension, ischaemia reperfusion injury, pericarditis including Dressier's syndrome, aneurysms including abdominal aortic aneurism, or stroke;
G. Metabolic disease, disorder, or abnormality, such as type 2 diabetes, obesity, atherosclerosis, metabolic-dysfunction-associated hepatitis, gout, or pseudo-gout;
H. Respiratory disease, disorder, or abnormality (e.g. disease, disorder or abnormality of the respiratory system), such as asbestosis, silicosis, cystic fibrosis, allergic inflammation, chronic obstructive pulmonary disorder (COPD), steroid-resistant asthma, or asthma;
I. Liver disease, disorder, or abnormality, (e.g. hepatic disease, disorder or abnormality) such as alcoholic liver disease, alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver disease (NAFLD), or non-alcoholic steatohepatitis (NASH) including advanced fibrosis stages F3 and F4;
J. Renal disease, disorder, or abnormality (e.g. disease, disorder or abnormality of the renal system) such as oxalate-induced nephropathy, diabetic nephropathy, chronic kidney disease, or kidney disease;
K. Cancer disease, disorter, or abnormality (e.g. cancer, tumor, or malignancy), such as lung cancer (e.g. lung cancer metastasis), pancreatic cancers, gastric cancers, leukemia, myelodysplastic syndrome (MOS), skin cancer, tumors of the endocrine system, or thyroid cancer;
L. Infections including viral infections, such as helminth infections (e.g. from schistosoma, roundworms, tapeworms or flukes), viral encephalitis, bacterial infection, human immunodeficiency virus (HIV), HIV-associated neurocognitive disorder, chronic nonbacterial osteomyelitis (CNO), chronic bacterial osteomyelitis, deficiency of interleukin 1 receptor (DIRA) antagonist, or epilepsy; alphavirus (e.g. Chikungunya virus and Ross River virus), flaviviruses (e.g. Dengue and Zika virus), Coronavirus-associated inflammatory pathologies, Coronaviruses, or influenza virus;
M. Psychological disease, disorder, or abnormality, such as depression, and psychological stress;
N. Inflammation, including inflammation occurring as a result of an inflammatory disease, disorder, or abnormality, such as an autoinflammatory disease, inflammation occurring as a symptom of a non- inflammatory disorder, inflammation occurring as a result of infection, or inflammation secondary to trauma, injury or autoimmunity. Examples of inflammation include inflammatory responses occurring in connection with, or as a result of: i. A joint disease, disorder, or abnormality, such as periodic fever syndrome (HIDS), rheumatoid arthritis, pustulosis, synovitis, osteoarthritis, chronic recurrent multifocal osteomyelitis (CRMO), systemic juvenile idiopathic arthritis, osteitis syndrome (SAPHO), hyperostosis, relapsing polychondritis, or adult-onset Still's disease; ii. A gastrointestinal disease, disorder, or abnormality (e.g. disease, disorder or abnormality of the gastrointestinal tact) such as colitis, ulcerative colitis, or inflammatory bowel disease; iii. A muscular disease, disorder, or abnormality, such as polymyositis, or myasthenia gravis; iv. A disease, disorder or abnormality of the endocrine system, such as, diabetes, parathyroid disease (e.g. hypothyroidism), tumors of the endocrine system, thyroid cancer, or hypoglycemia; and/or v. A vascular disease, disorder or abnormality, such as Behcet's disease.
In one embodiment, the disease, disorder, or abnormality is selected from Alzheimer’s disease, Parkinson's disease, cryopyrin-associated periodic syndromes (CAPS), non-alcoholic faty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and gout.
In particular, the disease, disorder or abnormality is selected from: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelination, viral encephalitis, epilepsy, stroke, brain haemorrhage, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudo-gout, inflammatory bowel disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, lower-risk myelodysplastic syndromes (LR-MDS), familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D, periodic fever syndrome (HIDS), deficiency of interleukin 1 receptor (DIRA) antagonist, Majeed syndrome, acne, pyogenic arthritis pyoderma gangrenosum and acne (PAPA), haploinsufflciency of A20 (HA20), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers, developmental delay (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic recurrent multifocal osteomyelitis (CRMO), synovitis, pustulosis, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteitis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behcet’s disease, Sjogren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disorder (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, obesity, age- related macular degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin contact hypersensitivity, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, Chikungunya virus, Ross River virus, influenza, HIV, Coronaviruses, Dengue, Zika virus, hidradenitis suppurativa (HS), dermatitis, skin lesions, burn, wound, trauma, lung cancer metastasis, pancreatic cancers, gastric cancers, myelodisplastic syndrome, leukemia; polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurism, wound healing, depression, psychological stress, pericarditis including Dressier's syndrome, ischaemia reperfusion injury; frontotemporal dementia, HIV-associated neurocognitive disorder, Coronavirus-associated inflammatory pathologies, and traumatic brain and spinal cord injury, inflammatory pain, chronic pain, neuropathic pain, metastatic cancer-induced bone pain, chemotherapy induced peripheral neuropathy and migraine; preferably the disorder is selected from Alzheimer’s disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft- versus host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, anti- glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), Focal Segmental Glomerulosclerosis , Minimal change disease (MCD), Psoriatic Arthritis, Hereditary Recurrent Fevers (HRFs), and amyloidosis (including AL amyloidosis, AA amyloidosis, ATTR amyloidosis, hereditary amyloidoses (including apolipoprotein A-l (AApoAl). apolipoprotein A-ll (AApoAII), gelsolin (AGel), fibrinogen (AFib), and lysozyme (ALys)), Beta-2 Microglobulin amyloidosis, iAPP amyloidosis).
In one embodiment, the disease, disorder or abnormality is selected from: Alzheimer’s disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudo-gout, inflammatory bowel disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, lower-risk myelodysplastic syndromes (LR-MDS), familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D, periodic fever syndrome (HIDS), deficiency of interleukin 1 receptor (DIRA) antagonist, Majeed syndrome, acne, pyogenic arthritis pyoderma gangrenosum and acne (PAPA), haploinsufficiency of A20 (HA20), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers, developmental delay (SIFD), chronic nonbacterial osteomyelitis (ONO), Sweet's syndrome, chronic recurrent multifocal osteomyelitis (CRMO), synovitis, pustulosis, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteitis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behcet's disease, Sjogren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disorder (COPD), steroid- resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin contact hypersensitivity, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still’s disease, relapsing polychondritis, Chikungunya virus, Ross River virus, influenza, HIV, Coronaviruses, Dengue, Zika virus, hidradenitis suppurativa (HS), dermatitis, skin lesions, burn, wound, trauma, lung cancer metastasis, pancreatic cancers, gastric cancers, myelodisplastic syndrome, leukemia; polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurism, wound healing, depression, psychological stress, pericarditis including Dressier's syndrome, ischaemia reperfusion injury, frontotemporal dementia, HIV- associated neurocognitive disorder, Coronavirus-associated inflammatory pathologies, and traumatic brain Injury; preferably the disorder is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), gout, inflammatory bowel disease, non-alcoholic faty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft- versus host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, anti- glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), Focal Segmental Glomerulosclerosis , Minimal change disease (MOD), Psoriatic Arthritis, and Hereditary Recurrent Fevers (HRFs).
In one embodiment, the disease, the disorder or the abnormality is selected from Alzheimer’s disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma and allergic inflammation, cryopyrin- associated periodic syndromes (CAPS), gout, inflammatory bowel disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic kidney disease, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, obesity, type 1 and type 2 diabetes, hidradenitis suppurativa (HS), rheumatoid arthritis, myelodysplastic syndrome and lower-risk myelodysplastic syndromes (LR-MDS).
In one embodiment, the disease, disorder, or abnormality is selected from Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. In another embodiment the disease, disorder, or abnormality is selected from cryopyrin-associated periodic syndromes (CAPS), non-alcoholic faty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic kidney disease gout, obesity and hidradenitis suppurativa (HS).
In one embodiment, the disease, the disorder or the abnormality is selected from Alzheimer’s disease, Parkinson's disease, cryopyrin-associated periodic syndromes (CAPS), non-alcoholic faty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), rheumatoid arthritis, chronic kidney disease, gout, obesity and hidradenitis suppurativa (HS).
In one embodiment the disease, the disorder or the abnormality is hidradenitis suppurativa (HS) in an obese subject. In one embodiment the disease, the disorder or the abnormality is comorbid hidradenitis suppurativa (HS) and obesity.
In yet another embodiment, the disease, disorder or abnormality is preferably an inflammatory disease, disorder or abnormality; or an autoimmune disease, disorder or abnormality; or a disease, disorder or abnormality of the skin (such as, for example, but not limited to, psoriasis, acne, eczema, alopecia areata, hidradenitis suppurativa (HS) or actinic keratosis); or a disease, disorder or abnormality of the cardiovascular system; or a disease, disorder, or abnormality such as a cancer, a tumor ora malignancy; or a disease, disorder or abnormality of the renal system; a disease, disorder or abnormality of the gastrointestinal tract; a disease, disorder or abnormality of the respiratory system; or a disease, disorder or abnormality of the endocrine system; or a disease, disorder or abnormality of the central nervous system (CNS); or a disease, disorder or abnormality of the liver.
DEFINITIONS
Within the meaning of the present application the following definitions apply unless specified otherwise, and when appropriate, terms used in the singular will also include the plural and vice versa:
"Alkyl" refers to a saturated straight or branched organic moiety consisting of carbon and hydrogen atoms. Examples of suitable alkyl groups have 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, and (as appropriate) include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl. The term “C1-C4alkyr refers to an alkyl group having 1 to 4 carbon atoms. The term “C1-C3alkyl" is to be construed accordingly.
"Hal", "halo" or "halogen" refers to F, Cl, Br, and I. Preferably halogen is F or Cl. In one aspect, halogen is Cl. In another aspect, halogen is F.
"7-, 8-, 9- 10 or 11 -membered spiro or fused heterocycloalkyl bicyclic moiety" refers to a stable 7-, 8-, 9-, 10- or 11-membered heterocycloalkyl bicyclic moiety which contains two rings that can either be fused together (Le., a ring system in which two rings are linked via two adjacent common ring atoms) or attached in a spiro manner (i,e., a ring system in which two rings are linked via a single common ring atom).
"Optionally substituted" in reference to a certain group refers to said group as to optionally be substituted with one or more substituents (i.e. the substituent may be present or not).
Unless specified otherwise, the term "compound of the present invention" refers to compounds of formula (I) or (la) as disclosed herein, or sub-formulae thereof, as disclosed herein, or stereoisomers thereof, or racemic mixtures thereof, or tautomers thereof, or polymorphs thereof, or pharmaceutically acceptable salts thereof, thereof, or hydrates thereof, or solvates thereof. Compounds of the present invention having one or more optically active carbons can exist as racemates and racemic mixtures (including mixtures in all ratios), stereoisomers (including diastereomeric mixtures and individual diastereomers, enantiomeric mixtures and single enantiomers, mixtures of conformers and single conformers), tautomers, atropisomers, and rotamers. All isomeric forms are included in the present invention. Compounds described in this invention containing olefinic double bonds include E and Z geometric isomers. Also included in this invention are all pharmaceutically acceptable salts, hydrates and solvates of compounds of formula (I) or (la).
Tautomers are isomers of a compound which differ only in the position of the protons and electrons. The skeleton of the compound is unchanged. Common tautomeric pairs include: ketone - enol (H"O"C=CH O=C-CH2), enamine - imine (H2N-ON HN=C-NH).
Solvates, hydrates as well as anhydrous forms of the salt are also encompassed by the invention. The solvent included in the solvates is not particularly limited and can be any pharmaceutically acceptable solvent. Examples include water and C1-4 alcohols (such as methanol or ethanol).
"Pharmaceutically acceptable salts" are defined as derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic adds. For example, such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric add and the like; and the salts prepared from organic acids such as, but not limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic acid, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Organic solvents include, but are not limited to, nonaqueous media like ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts can be found in Remington’s Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, the disclosure of which is hereby incorporated by reference.
"Pharmaceutically acceptable1’ is defined as those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable beneflt/risk ratio,
A used herein, the terms “patient” or “subject" mentioned in the present invention typically refer to an animal, particularly a mammal (e.g. rabbits, rats, dogs, mice, guinea pigs, pigs), more particularly primates (e.g. humans, male or female). In certain embodiments, the subject is a human,
"NLRP3" as used herein refers to NOD-like receptor (NLR) family, pyrin-domain containing protein 3 component of inflammasome. Inflammasomes are intracellular supramolecular complexes comprising a sensor molecule, the adaptor apoptosis-associated speck-like protein containing a CARD (ASC) and the effector protease caspase 1 . Upon activation of the inflammasome sensor molecule, ASC self-associates into a helical fibrillary assembly resulting in formation of the so-called ASC speck or pyroptosome, which acts as a molecular platform for the activation of pro-caspase 1 via proximity-induced autocatalytic activation. Active caspase 1 triggers the activation and release of interleukin-1 (IL-1) family proteins and enables the non-conventional secretion of numerous cytosolic proteins. Among the pro-inflammatory mediators released upon NLRP3 activation are IL-1 beta (P), IL-18, high-mobility group protein Bl (HMGB1), leukotrienes and prostaglandins.
NLRP3 inflammasome pathway activation is an important driver of inflammation interacting with the different cytokine pathways shaping the immune response to infection and injury. Formation of some pro-inflammatory cytokines is triggered by NLRP3 inflammasome pathway activation.
The terms “inhibit", "inhibition" or “inhibiting" refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or abnormality which is responsive to the modulation of a component of the NLRP3 inflammasome pathway, or a significant decrease in the baseline activity of a biological activity or process.
The terms “treat", “treating" or "treatment" of any disease, disorder or abnormality refer to alleviating or ameliorating or modulating the disease or disorder or abnormality (i.e., slowing or arresting the development of the disease, disorder or abnormality or at least one of the clinical symptoms thereof); or alleviating or ameliorating or modulating at least one physical parameter or biomarker associated with the disease or disorder or abnormality, including those which may not be discernible to the subject (e.g., patient).
The terms '‘prevent", “preventing" or “prevention” of any disease or disorder or abnormality which is responsive to the modulation of a component of the NLRP3 inflammasome pathway refer to the prophylactic treatment of the disease or disorder or abnormality; or delaying the onset or progression of the disease or disorder.
The term "in need of" a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
As used herein, "modulation" refers to alteration, e.g., up-regulation, down-regulation, increase or decrease, preferably decrease.
Figure imgf000048_0001
The definitions and preferred definitions given in the "Definition'-section apply to all the embodiments described herein unless stated otherwise.
General synthetic scheme for the preparation of compounds of this invention
The compounds of the present invention can be synthesized by those skilled in the art by using commonly known preparation steps, for instance those of the general methods shown in the following schemes. These methods are only given for illustrative purposes and should not be construed as limiting.
In all of the methods it is understood that protecting groups for sensitive or reactive groups may be employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G, M. Wilts (2014) Protective Groups in Organic Synthesis, 5th edition, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those ski lied in the art.
K
U
In the following general methods, Ro, Ri, Ra, R3, R« , Zi> Z2, E, V, X, R* and RA, are as previously defined in the above embodiments.
Figure imgf000049_0001
Figure imgf000050_0005
Scheme 1:
Figure imgf000050_0001
Intermediate A Intermediate B cyclization
Figure imgf000050_0002
Figure imgf000050_0003
Intermediate E i ntvrmedinU' l>
Intermediate C
Figure imgf000050_0004
Commercially available 5- membered heterocyclic ester can be condensed with hydrazine followed by carbamate formation allowing the synthesis of the intermediate B. Starting from intermediate B, ring cyclization using CS? in presence of base can deliver intermediate D. Selective alkylation using standard conditions followed by chlorination can give intermediate E. Finally, SNAr followed by metal coupling using, for example, boronic acid and palladium catalyst can give compounds of formula (I) or (la). EXAMPLES
The disclosure is further illustrated by the following examples and synthesis schemes, which are not to be construed as limiting the scope of the specific procedures herein described. It is understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of this disclosure is intended thereby.
Unless otherwise noted, all reagents and solvents were obtained from commercial sources and used without further purification. The chemical names were generated using ChemDraw from CambridgeSofL Temperatures are given in degrees Celsius. If not mentioned otherwise, all evaporations are performed under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20 - 133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, I R, NMR. 1H-NMR spectra were recorded on Broker 400 MHz-Avance Neo Nanobay NMR spectrometers in deuterated solvents. Chemical shifts (5) are reported in parts per million and coupling constants (J values) in hertz. Spin multiplicities are indicated by the following symbols: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), bs (broad singlet). Mass spectra (MS) were obtained on a Waters Alliance HPLC (Waters e2695 separation module), Waters Arc HPLC or Waters Acquity UPLC. Chromatography was performed using silica gel (SRL: Silica gel 100-200 mesh) and suitable solvents as indicated in specific examples. Flash purification was conducted with a
Com biFlash system and the solvent gradient indicated in specific examples. Thin layer chromatography (TLC) was carried out on silica gel plates with UV detection.
Intermediate 1
Figure imgf000051_0001
Step 1: To a mixture of ethyl 1 H-imidazole-2-carboxylate (100 g, 713.57 mmol, 1 eq) in BOH (1 L) was slowly added N2H4 • HjO (225.41 ml, 3.72 mol, 5.21 eq). The mixture was stirred at 25 °C for 4 h. The reaction mixture was filtered. The filter cake was washed with H2O (300 ml_ x 3) and dried to afford 1 H-imidazole-2-carbohydrazide (70 g, 77%) as a white solid.
1H NMR: (400 MHz, DMSO-cW) 6 = 12.64 (br s, 1H), 9.66 (s, 1 H), 7.14 (s, 2H), 4.60 (s, 2H).
MS: 127.3 (M+H]T
Step 2: To a mixture of 1H-imidazole-2-carbohydrazide (60 g, 475.75 mmol, 1 eq) in pyridine (1 .6 I) was added CSz (573.60 mL, 8.52 mol, 20.0 eq). The mixture was stirred at 100 °C for 16 hours. The reaction mixture was concentrated under vacuum, the residue was diluted with H?O (500 mL), then the pH was adjusted to pH=2 with 1M HCI. The resultant yellow solid was filtered and dried. The crude product was triturated with MeOH (200 mL) at 25°C for 16 h. The mixture was filtered and the filter cake was washed with MeOH (20 mL*3) and lyophilized to afford 5-mercaptoimidazo[1 ,2- d][1 ,2,4]triazin-8-ol (25.5 g, 31%) as a yellow solid.
1H NMR: (400 MHz, DMSO-cffi) 8 = 8.21 (d, 1 H), 7.72 (d, 1 H).
MS: 169,0 [M+HJ*.
Step 3: To the solution of 5-sulfanylimidazo[1
Figure imgf000052_0001
,2,4]triazin-8-ol (15 g, 89.19 mmol, 1.0 eq) in acetone (150 ml) was added K2CO3 (24.65 g, 178.38 mmol, 2 eq) and Mel (15.19 g, 107.03 mmol, 6.66 mL, 1.2 eq). The resulting reaction mixture was stirred at 20 °C for 3 h. The reaction solution was filtered to remove K2CO3 then concentrated to give the crude product. The crude product was triturated with DCE (1000 mL) at 80 °C for 30 min. 5-Methylsulfanylimidazo[1 ,2-d][1 ,2,4]triazin-8-ol (12 g, crude) was obtained as a yellow solid. ’H NMR (400 MHz, DMSO-d6) 6 = 12.62 (br s, 1H), 7.88 (d, 1H), 7.62 (d, 1H), 2.63 (s, 3H).
MS: 183.1 [M+H]+.
Step 4: To the solution of 5-methylsulfanylimidazo[1 ,2-d][1 ,2,4]triazin-8-ol (4 g, 21.95 mmol, 1 eq) in POCI3 (58.49 g, 381.46 mmol, 35.56 mL, 17.38 eq). The resulting reaction mixture was stirred at 100 °C for 5 h. The reaction mixture was poured onto 100 mL saturated aqueous NaHCOs solution and followed by 20 ml DCM. After that, the aqueous phase was separated and extracted with DCM (30 mL X 3). The combined organic layer was washed successively with water (20 mL X 2) and brine (20 ml X 1), dried over anhydrous Na2SCL, filtered, and concentrated to give a residue. The residue was purified by column chromatography (S1O2, DCM: MeOH-100/1 to 10/1). 8-Chloro-5- methylsulfanyl-imidazo[1 ,2-d][1 ,2,4]triazine (4.4 g, 50% yield) was obtained as a yellow solid.
1H NMR (400 MHz, DMSO-d6) 6 = 8.22 (d, 1 H), 7.97 (d, 1 H), 2.84 (s, 3H).
MS: 200.09 [M+H]+, Examples 1a and 1b: enantiopure 2-[8-(6-methyl-3,3a,4.5,7,7a-hexahydro-2H-pyrrolo[2,3- c]pyridin’1-yl)imidazo[1.2-d][1.2,4]triazin-5-yl]-5-(trifiuoromethyl)phenol
Figure imgf000053_0001
To a solution of 8-chloro-5-methylsulfanyl-imidazo[1 ,2-d][1 ,2,4]triazine (600 mg, 2.99 mmol,
1 eq) in DMSO (9 mL) was added tert-butyl 1,2,3,3a,4,5,7,7a-octahydropyrrolo[2,3-c]pyriciine-6- carboxylate (1.35 g, 5.98 mmol, 2 eq), and KF (347.47 mg, 5.98 mmol, 140.11 pL, 2 eq) and the resulting reaction mixture was stirred at 100 °C for 3 hr. The reaction mixture was poured onto 50 ml H2O and followed by 25 mL EtOAc. After that, the aqueous phase was separated and extracted with EtOAc (20 mL X 2). The combined organic layer was washed successively with water (20 mL X 2) and brine (20 ml X 1), dried over anhydrous NSZSOA, filtered, and concentrated to give a residue. The residue was purified by column chromatography (S1O2, DCM /MeOH =100/1 to 5/1 ) to give tertbutyl 1-(5-methylsulfanylimidazo[1 ,2-d][1 ,2,4]triazin-8-yl)-3,3a,4,5,717a-hexahydro-2H-pyrrolo [2,3- c]pyridine-6-carboxylate (900 mg, 77%) as a yellow oil.
1H NMR (400 MHz, CDCI3) δ = 7.65 - 7.59 (m, 1H), 7.50 - 7.44 (m, 1 H), 5.08 - 4.84 (m, 1H), 4,16 - 4.00 (m, 1 H), 3.99 - 3.84 (m, 1 H), 3.82 - 3.64 (m, 1 H), 3.21 - 3.03 (m, 1H), 2.80 - 2.78 (m, 3H), 2.61 - 2.55 (m, 1H), 2.19 - 1.89 (m, 4H), 1.87 - 1.67 (m, 2H), 1.43 - 1.32 (m, 9H)
MS: 391.3 [M+H]+. Step 2: To a solution of tert-butyl 1-(5-methyteulfanylimidazo[1 ,2-d]E1,2,4]triazin-8-yl)-3,3a,4,5,7,7a- hexahydro-2H-pyrrolo[2,3-c]pyridine-6-carboxylate (800 mg, 2.05 mmol, 1 eq) in DCM (8 ml) was added TFA (2 mL) at 0 °C and the resulting reaction mixture was stirred at 20 °C for i h. The reaction mixture was poured onto 20 mL of H2O and adjusted the pH to 8 with saturated aqueous NaaCOa solution. Then, the resulting solution was extracted with EtOAc (20 mL X 2). The combined organic layer was washed successively with water (20 mL X 2) and brine (20 ml X 1), dried over anhydrous NazSO4, filtered, and concentrated to give a residue. The residue was used for the next step directly without farther purification (600 mg, crude, yellow oil).
MS: 291.2 [M+H]+.
Step 3: To a solution of 8-(2,3,3a,4,5,6,7,7a-octahydropyrrolo[2,3-c]pyridin-1-yl)-5-methylsulfanyl- imidazo[1 ,2-d][1 ,2,4]triazine (600 mg, 2.07 mmol, 1 eq) in MeOH (6 mL) was added HCHO (124.08 mg, 4.13 mmol, 113.83 pL, 37% purity, 2 eq) in H2O, NaBHfOAcJs (656.87 mg, 3.10 mmol, 1.5 eq) and the resulting reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was poured onto 20 mL H2O and adjusted to pH 12 with saturated aqueous NaaCOa solution. Then, the resulting solution was extracted with EtOAc (20 mL X 2). The combined organic layer was successively washed with water (20 mL X 2) and brine (20 ml X 1), dried over anhydrous NazSO^ filtered, and concentrated to give a residue. The residue was used for the next step directly without further purification. 8-(6-Methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)-5-methylsulfanyl- imidazo[1 ,2-d][1 ,2,4] triazine was obtained (580 mg, crude, yellow oil)
MS: 305.2[M+H]+.
Step 4: To a solution of 8-(6-methyl-3, 3a, 4,5,7, 7a-hexahydro-2H-pyrrolo[2, 3-c]pyridin-1 -yl)-5- methylsulfanyl-imidazo[1 ,2-d][1 ,2,4]triazine (530 mg, 1.74 mmol. 1 eq) in THF (6 mL) was added [2- hydroxy-4-(trifluoromethyl)phenyl]boronic acid (537.79 mg, 2.61 mmol, 1.5 eq), cuprous 2-hydroxy- 3-methyl-benzoate (934.45 mg, 4.35 mmol, 2.5 eq), and Pd(PPh3)4 (603,57 mg, 522.32 ymol, 0.3 eq) and the resulting reaction mixture was stirred at 100 °C for 2 h. The reaction mixture was poured onto 20 mL H2O and followed by 10 mL EtOAc. After that, the aqueous phase was separated and extracted with EtOAc (20 mL X 2). The combined organic layer was washed successively with water (20 mL X 2) and brine (20 ml X 1), dried over anhydrous NazSO^ filtered, and concentrated to give a residue. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=30/1 to 1/1 , then DCM /MeOH=30/1 to 1/1 ). The product was further purified by prep-HPLC (column: Phenomenex Luna Cl 8 100*30mm*5pm; mobile phase: (H2O(0.2% FA)-ACN]; gradient: 3%-30% B over 8.0 min) to give the title product. The title product was added onto 10 mL H2O and then the pH was adjusted to 7 with a saturated aqueous NaHCOs solution. Then, the resulting solution was extracted with EtOAc (5 mL X 2). The combined organic layer was washed successively with water (10 mL X 2) and brine (10 ml X 1), dried over anhydrous NaaSCU, filtered, and concentrated to give 2-[8-(6-methyl-3l3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)imidazo[1,2- d][1,2,4)triazin-5-yl]-5-(trifluoromethyl)phenol (60 mg, 8%) as a white solid.
’H NMR (400 MHz, DMSO-cfc) 6 = 11.17 - 10.68 (m, 1H), 7.80 - 7.61 (m, 2H), 7.51 (d, 1 H), 7.36 - 7.26 (m, 2H), 5.36 - 4.88 (m, 1 H), 4.04 - 3.62 (m, 2H), 3.17 (br dd, 1 H), 2.55 (br s, 1 H), 2.46 - 2.37 (m, 1 H), 2.16 (s, 3H), 2.09 (br dd, 2H), 2.00 - 1.79 (m, 3H), 1 .72 (br d, 1 H).
MS: 419.2 [M+HJ*.
Step 5: 2-[8-(6-Methyl-3>3a,4,5,7>7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1-yl)imidazo(1>2- d][1,2,4]triazin-5-yl]-5-(trifluoromethyl)phenol was separated by SFC (column: DAICEL CHIRALCEL OJ (250mm*30mm,10pm); mobile phase: [CO2-EtOH(0.1 %NH3H^O)]; B%:30%, isocratic elution mode) to give enantiopure 2-(8-[rel-(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrTolo[2,3- c]pyridin-1-yl]imidazo[1 ,2-d][1 ,2,4]triazin-5-yl]-5-(trifluoromethyl)phenol example 1a (17.2 mg, first peak) as a white solid.
1H NMR (400 MHz, DMSO-d6) δ = 11.45 - 10.43 (m, 1 H), 7.65 (br d, 2H), 7.51 (d, 1 H), 7.29 (s, 2H), 5.42 - 4.84 (m, 1 H), 4.17 - 3.59 (m, 2H), 3.21 - 3.12 (m, 1H), 2.59 - 2.52 (m, 1H), 2.46 - 2.35 (m, 1 H), 2.16 (s, 3H), 2.13 - 2.01 (m, 2H), 2.01 - 1 .79 (m, 3H), 1.78 - 1.67 (m, 1 H).
MS: 419.2 [M+Hf.
And enantiopure 2-[8-[rel-(3aR,7aS)-6-methyl-3,3a,4,5,7,7a-hexahydro-2H-pyrrolo[2,3-c]pyridin-1- yl]imidazo[1,2-d][1 ,2,4]triazin-5-yl]5-(trifluoromethyl)phenol example 1b (13.7 mg, second peak) as a white solid.
1H NMR (400 MHz, DMSO-d6) δ = 10.97 (br s, 1 H), 7.73 - 7.62 (m, 2H), 7.51 (d, 1H), 7.35 - 7.25 (m, 2H), 5.40 - 4.92 (m, 1H), 4.08 - 3.65 (m, 2H), 3.16 (br dd, 1H), 2.55 (br s, 1H), 2.45 - 2.36 (m, 1H), 2.16 (s, 3H), 2.13 - 2.01 (m, 2H), 2.00 - 1.81 (m, 3H), 1.72 (br d, 1 H).
MS: 419.2
Examples 2a and 2b
Figure imgf000056_0001
Step 1 : To a solution of 8-chloro-5-methylsulfanyl-imidazo[1 ,2-d][1 ,2.4]triazine (900 mg, 4.49 mmol, 1 eq) and 6-methyl-1 ,2,3,3a,4,5,7,7a-octahydropyrrolo[2,3-c]pyridine; dihydrochloride (1.15 g, 5.38 mmol, 1.2 eq) in DMSO (10 ml) was added KF (521 .18 mg, 8.97 mmol, 2 eq) and TEA (907.76 mg, 8.97 mmol, 1.25 ml, 2 eq). The mixture was stirred at 100 °C for 12 h. LCMS indicated that the reaction was completed. The reaction was quenched by addition of HaO 10 mL. NasCOgwas added to- reach pH 12, and then the aqueous phase was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine 20 ml, dried over NazSCk, filtered and concentrated under reduced pressure to- give a residue. The residue was purified by column chromatography (S1O2, DCM/MeOH=1/0 to 95/5) to give 8-(6-methyloctahydro-1 H-pyrrolo[2,3-c]pyridin-1 -yl)-5- (methylthio)imidazo[1 ,2-d][1 ,2,4]tiiazine (900 mg, 66%) as a yellow oil.
1H NMR (400 MHz, DMSO-d6) δ = 7.86 (d, 1H), 7.72 (d, 1 H), 5.10 - 4.71 (m, 1 H), 3.97 - 3.64 (m, 2H), 3.11 - 3.02 (m, 1H). 2.70 (s, 3H), 2.49 (br s, 1H), 2.42 - 2.29 (m, 1 H), 2.12 (s, 3H), 2.08 - 1.99 (m, 2H), 1.97 - 1.90 (m, 1H), 1.89 - 1.81 (m, 1H), 1.77 (br t, 1H), 1.68 (br dd, 1H).
MS: 305.2 [M+H]+.
Step 2: To- a solution of 8-(6-methyloctahydro-1 H-pyrrolo[2,3-c]pyridin-1-yi)-5- (methylthio)imidazo[1 ,2-d][1 ,2,4]triazine (300 mg, 985.50 pmol, 1 eq) and (4-chloro-2-methoxy-5- methyl-phenyl)boronic acid (237.03 mg, 1.18 mmol, 1.2 eq) in THF (5 mL) were added Pd(PPhg)4 (341 .64 mg, 295.65 pmol, 0,3 eq) and cuprous 2-hydroxy-3-m-ethyl-benzoate (528,93- mg, 2.46 mmol, 2.5- eq). The mixture was stirred at 100 °C for 3 h. LCMS indicated that the reaction was completed. The reaction was quenched by addition of H2O 10 mL, and then the mixture was extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine 10 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, DCM/MeOH=1/0 to 30/1 ) and by prep-TLC (S-iCfe, PE:EtOAc = 0:1) to give 5- (4-chloro-2-methoxy-5-methylphenyl)-8-(6-methyloctahydro-1H-pyrrolo[2,3-c]pyridin-1- yl)imidazo[1,2-d][1 ,2,4]triazine (240 mg, 93%) as a yellow oil.
MS: 413.2 [M+H]+.
Step 3: To a solution of 5-(4-chloro-2-methoxy-5-methylphenyl)-8-(6-methyloctahydro-1H- pyrrolo[2,3-c]pyridin-1-yl)imidazo[1 ,2-d][1 ,2,4]triazine (200 mg, 339.05 pmol, 1 eq) in DCM (3 mL) was added BBra (424.70 mg, 1.70 mmol, 163.35 pL, 5 eq) at 0 °C. The mixture was stirred at 20 °C for 1 h. LCMS indicated that the reaction was completed. The reaction mixture was poured onto TO mL H2O and the pH was adjusted to 7 with saturated aqeuous NaHCCh solution. Then, the resulting solution was extracted with DCM (10 mL x 3), The combined organic layer was washed successively with water (20 mL x 2) and brine (20 ml x 1), dried over anhydrous NazSCM filtered, and concentrated to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10pm; mobile phase: [HaOflOmM NH^HCOaJ-ACN]; gradient: 30%-60% B over 6.0 min) to give 5-chloro-4-methyl-2-(8-(6-methyloctahydro-1 H-pyrrolo[2,3-c]pyridin-1-yl)imidazo[1 ,2- d][1 ,2,4]triazin-5-yl)phenol (80 mg, 59.%) as a white solid.
MS: 399.1 [M+H]+.
Step 4: 5-chloro-4-methyl-2-(8-(6-methyloctahydro-1 H-pyrrolo[2,3-c]pyridin-1 -yl)imidazo[1 ,2- d][1 ,2,4]triazin-5-yl)phenol was purified by SFC (column: DAICEL CHIRALCEL OJ (250mm*30mm, 10pm); mobile phase: [CO2-MeOH(0.1%NH3H2O)]; B%:37%, isocratic elution mode) to give first eluting peak Example 2a enantiopure 5-chloro-4-methyl-2-(8-((3aR,7aS)-6-methyloctahydro-1H- pyrrolo[2,3-c]pyridtn-1-yl)imidazo[1 ,2-d][1 ,2,4]triazin-5-yl)phenol (10.32 mg) as a white solid.
1H NMR (400 MHz, DMSO-d6) δ = 10.53 (br s, 1 H), 7.63 (s, 1H), 7.46 (d, 1 H), 7.42 (s, 1 H), 7.05 (s, 1H), 5.10 (br s, 1H), 3.82 (br s, 2H), 3.15 (br dd, 1 H), 2.56 - 2.52 (m, 1H), 2.45 - 2.37 (m, 1H), 2.28 (s, 3H), 2.15 (s, 3H), 2.12 - 2.00 (m, 2H), 1.99 - 1 .82 (m, 3H), 1 .71 (br d, 1H).
MS: 399.2 and second eluting peak Example 2b enantiopure 5-chloro-4-methyl-2-(8-((3aR,7aS)-6- methylocta hydro-1 H-pyrrolo[2,3-c]pyridin-1 -yl)imidazo[1 ,2-d][1 ,2,4}triazin-5-yl)phenol (13.95mg) as a white solid.
1H NMR (400 MHz, DMSO-d6) δ = 10.53 (br s, 1 H), 7.63 (s, 1H), 7.46 (d, 1 H), 7.42 (s, 1H), 7.05 (s, 1 H), 5.10 (br s, 1H), 3.82 (br s, 2H), 3.15 (br dd, 1H), 2.56 - 2.52 (m, 1H), 2.45 - 2.37 (m, 1 H), 2.28 (s, 3H), 2.15 (s, 3H), 2.12 - 2.00 (m, 2H), 1.99 - 1 .82 (m, 3H), 1.71 (br d, 1 H).
MS; 399.2 [M+Hf. BIOLOGICAL ASSAY DESCRIPTION
4.5 NLRP3 inhibition assay The following assays were used to determine the inhibitory activity of test compounds on the NLRP3 inflammasome pathway using common stimulus ATP (Invivogen).
Cell culture
Human monocyte-derived macrophages (HMDM) cells were prepared from buffy coat obtained from human anonymized healthy blood donors. Cells were isolated using a negative selection following a classical monocyte isolation protocol (Miltenyi, # 130-117-337). Cells were differentiated in growth medium (DMEM/F12 (Gibco, 31331-093)) supplemented with 10% heat inactivated human serum (HS; Sigma, H3667), 1% PS, 0.5 mM sodium pyruvate (ThermoFisher, 11360-070), 10 mM HEPES (ThermoFisher, 15630-080)) and containing 10 ng/mL of human macrophage colony stimulating factor (M-CSF; Miltenyi, 130-096-489) to induce differentiation toward macrophages.
NLRP3. inflammasome pathway . actiyatipn . assay
At DIV8, HMDM were primed with 10 ng/mL of LPS from Escherichia coli for 3 hours in growth medium without M-CSF. After 3 hours of LPS priming, concentrations of test compound in the range from 10 pM to 610 pM were added 30 min prior to NLRP3 inflammasome pathway stimulation with ATP 2 mM for 3 h.
Measurement of IL-1B
For IL-1P quantification, supernatants were analyzed using a HTRF kit according to the manufacturer's instructions (Cisbio 62HIL1 BPEH). Briefly, in a 384-well ProxiPlate™ microplate, 8 pl of sample were mixed with 5 pl of Anti-ILI P Cryptate antibody (40x) and Anti-IL1 p XL antibody (40x). Then, the sample was incubated overnight at RT. Reading was done using an EnVision Reader (PerkinElmer). The ICao (concentration corresponding to 50% inhibition) were determined using GraphPad Prism 9,
Table 1: Inhibition of IL-1 beta release in human monocyte-derived macrophages
Figure imgf000058_0001
Figure imgf000059_0002
Legend: 5nM: nM < X < 100nM; 00nM < X < 500nM;
Figure imgf000059_0001
500 nM;
The tested compounds showed significant inhibition of IL-1 beta release in human monocyte-derived macrophages using ATP as activator, see Table 1 ,

Claims

1 . A compound of formula (I)
Figure imgf000060_0001
or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof; wherein
Z1 and Z a2re each selected from N and C, whereby if Z1 is N, Z2 is C, and if Z1 is C, Z2 is N;
V, X and E are each independently selected from N and CRa; wherein at least one of V, X and E is CRa;
Ra is independently selected from the group consisting of -H, -C -C alkyl, -CF- and -halo;
Ro is selected from the group consisting of -H, -C1-C3alkyl and -halo;
Ri is selected from the group consisting of -CF3, -OCFg, -OCHF2, -CN and -halo;
Ra is selected from the group consisting of -OH, -H, -OCF3, -OCHF2, -C1-C3alkyl, -halo, and -CF3;
R3 is selected from the group consisting of -H, -C1-C3alkyl , -OH, -CF3 and -halo;
R4 is selected from the group consisting of -H, -C1-C3alkyl, -CF3 and -halo;
RA is a 7-, 8-, 9- , 10- or 11 -membered spiro or fused heterocycloalkyl bicyclic moiety containing one to three heteroatoms, wherein said heteroatom(s) is/are independently selected from N and O, and wherein the bicyclic moiety is optionally substituted at any available position with one or two substituents which are independently selected from the group consisting of C1-C4alkyl, haloC1-C4alkyl, hydroxyC1-C4alkyl, -OH and halo; and indicates alternating single and double bonds.
2. The compound according to claim 1, having the formula (la)
Figure imgf000061_0001
or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof: wherein Ro, Ra, R1, R2, R3, RA, and RA are as defined in claim 1.
3. The compound according to claim 2, wherein Ra is selected from the group consisting of -H and -CrCgalkyl.
4, The compound according to any one of the preceding claims, wherein RA is a 7-, 8-, 9- or 10- membered spiro or fused heterocycloalkyl bicyclic moiety containing two heteroatoms, wherein said heteroatoms are N, and wherein the bicyclic moiety is optionally substituted at any available position with one or two substituents which are independently selected from the group consisting of C1-C4alkyl, haloC1-C4alkyl, hydroxyC1-C4alkyl, -OH and halo.
5. The compound according to claim 4, wherein RA is a 7-, 8-, 9- or 10-membered spiro or fused heterocycloalkyl bicyclic moiety containing two heteroatoms, wherein said heteroatoms are N, and wherein the bicyclic moiety is optionally substituted at any available position with one substituent which is selected from the group consisting of Ci-TXjalkyl, preferably methyl.
6. The compound according to any one of the preceding claims, wherein RA is selected from the group consisting of
Figure imgf000062_0001
wherein R5 is independently selected from -H or -C1-C3alky I, preferably methyl.
7. The compound according to any one of the preceding ciaims, wherein Ro is -H;
R1 is -CF3 or -halo, preferably -Cl,
R2 is -OH;
R3 is -H;
R4 is -H or -CH3; and
Ra -H or-CH3.
8. The compound according to any one of the preceding claims, which is selected from
Figure imgf000063_0001
stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof.
9. The compound according to claim 8, which is selected from
Figure imgf000063_0002
or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof.
10. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 9, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.
11. The compound according to any one of claims 1 to 9, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use as a medicament.
12, The compound according to any one of claims 1 to 9, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, for use in the treatment, alleviation or prevention of a disease, or a disorder or an abnormality which is responsive to the modulation of a component of the NLRP3 inflammasome pathway and/or which is responsive to the modulation of IL-1 beta and/or IL-18 levels.
13. The compound for use according to claim 12, wherein the modulation is the reduction and/or inhibition of IL-1 beta.
14. The compound for use according to claim 12, wherein the component of the inflammasome pathway is NLRP3 inflammasome.
15. The compound for use according to claim 12 or 14, wherein the activation of NLRP3 inflammasome pathway is inhibited.
16. The compound for use according to any one of claims 12 to 15, wherein the disease, the disorder or the abnormality is selected from Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflam matory syndrome (FCAS), neonatal- onset multisystem inflammatory disease (NOMID), gout, pseudo-gout, inflammatory bowel disease (IBD) (including Crohn's disease, ulcerative colitis), hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hypertension, myocardial infarction, heart failure, coronary artery disease, oxalate-induced nephropathy, graft-versus host disease, type 1 diabetes, type 2 diabetes, Edema (DME), Geographic Atrophy (GA), rheumatoid arthritis, myelodysplastic syndrome, lower-risk myelodysplastic syndromes (LR-MDS), familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinemia D, periodic fever syndrome (HIDS), deficiency of interleukin 1 receptor (DIRA) antagonist, Majeed syndrome, pyogenic arthritis pyoderma gangrenosum and acne (PAPA), haploinsufficiency of A20 (HA20), PLCG2- associated antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers, developmental delay (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic recurrent multifocal osteomyelitis (CRMO), synovitis, pustulosis, skin contact hypersensitivity, sunburn, psoriasis, hidradenitis suppurativa (HS), dermatitis, skin lesions, bum, wound, trauma, epidermolysis bullosa, acne, eczema, alopecia areata, actinic keratosis, hyperostosis, osteitis syndrome (SAPHO), vitiligo, atopic dermatitis, cutaneous lupus, multiple sclerosis (MS), Behcet’s disease, Sjogren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disorder (COPD), asthma, steroid-resistant asthma, Coronavirus- associated inflammatory pathologies including Coronavirus-associated respiratory distress syndrome (CARDS), asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, acute kidney disease, chronic kidney disease, lupus nephritis, diabetic nephropathy, alcoholic liver disease, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, Chikungunya virus, Ross River virus, influenza, HIV, Coronaviruses, Dengue, Zika virus, primary biliary cholangitis, antiphospholipid syndrome, refractory celiac disease, pancreatitis, autoimmune pancreatitis, mucocutaneous lymph node syndrome, lung cancer metastasis, pancreatic cancers, gastric cancers, myelodisplastic syndrome, leukemia; polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurism, wound healing, migraine, depression, psychological stress, pericarditis including Dressier's syndrome, ischaemia reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorder, traumatic spinal cord injury, traumatic brain injury, inflammatory pain, chronic pain, neuropathic pain, metastatic cancer-induced bone pain, chemotherapy induced peripheral neuropathy; ankylosing spondylitis, cytokine release syndrome; encephalomyelitis, anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), anti-glomerular basement membrane (GMB) disease, glomerulonephritis (GN), systemic lupus erythematosus (SLE), Focal Segmental Glomerulosclerosis, Minimal change disease (MCD), Psoriatic Arthritis, Hereditary Recurrent Fevers (HRFs), amyloidosis (including AL amyloidosis, AA amyloidosis, ATTR amyloidosis, hereditary amyloidoses (including apolipoprotein A-l (AApoAl), apolipoprotein A-ll (AApoAII), gelsolin (AGel), fibrinogen (AFib), and lysozyme (ALys)), and beta-2 microglobulin amyloidosis, iAPP amyloidosis), preferably the disorder is selected from Alzheimer's disease, Parkinson’s disease, amyotrophic lateral sclerosis, demyelination, multiple sclerosis, encephalomyelitis, leukoencephalopathy, viral encephalitis, epilepsy, stroke, traumatic brain injury, spinal cord injury, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), gout, inflammatory bowel disease (IBD), non-alcoholic faty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), acute kidney disease, chronic kidney disease, lupus nephritis, anti-glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), Focal Segmental Glomerulosclerosis, Minimal change disease (MCD), Psoriatic Arthritis, Hereditary Recurrent Fevers (HRFs), acne, atopic dermatitis, hidradenitis suppurativa (HS), and amyloidosis (including AL amyloidosis, AA amyloidosis, ATTR amyloidosis, hereditary amyloidoses (including apolipoprotein A-l (AApoAl), apolipoprotein A- II (AApoAII), gelsolin (AGel), fibrinogen (AFib), and lysozyme (ALys)), Beta-2 microglobulin amyloidosis, IAPP amyloidosis).
17. The compound for use according to claim 16, wherein the disease, the disorder or the abnormality is selected from Alzheimer's disease, Parkinson's disease and multiple sclerosis.
18. The compound for use according to claim 16, wherein the disease, the disorder or the abnormality is selected from cryopyrin-associated periodic syndromes (CAPS), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), chronic kidney disease and gout.
19. The compound for use according to claim 16, wherein the disease, the disorder or the abnormality is a skin disease, disorder, or abnormality selected from hidradenitis suppurativa (HS), dermatitis, psoriasis, skin contact hypersensitivity, acne, periodic fever syndrome (HIDS), Sweet’s syndrome, eczema, skin lesions, burn, wound, trauma, sunburn, actinic keratosis, deficiency of interleukin 1 receptor (DIRA) antagonist, epidermolysis bullosa, vitiligo, atopic dermatitis, cutaneous lupus, and alopecia areata.
20. The compound for use according to claim 19, wherein the disease, the disorder or the abnormality is hidradenitis suppurativa (HS).
21. The compound for use according to claim 16, for use in the treatment, prevention or alleviation of comorbid hidradenitis suppurativa (HS) and obesity.
2. Use of a compound according to any one of claims 1 to 9, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a hydrate, or a solvate thereof, as an analytical reference or an in vitro screening tool.
PCT/EP2024/088193 2023-12-22 2024-12-20 Heterocyclic modulators of the nlrp3 inflammasome pathway Pending WO2025133307A1 (en)

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