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WO2025163069A1 - Nouveaux composés - Google Patents

Nouveaux composés

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Publication number
WO2025163069A1
WO2025163069A1 PCT/EP2025/052396 EP2025052396W WO2025163069A1 WO 2025163069 A1 WO2025163069 A1 WO 2025163069A1 EP 2025052396 W EP2025052396 W EP 2025052396W WO 2025163069 A1 WO2025163069 A1 WO 2025163069A1
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Prior art keywords
disease
syndrome
group
disorder
compound
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English (en)
Inventor
Jérôme Molette
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AC Immune SA
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AC Immune SA
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Publication of WO2025163069A1 publication Critical patent/WO2025163069A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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 patterns, DAMPs).
  • PAMPs pathogen-associated molecular patterns
  • DAMPs debris associated molecular patterns
  • the inflammasome family consists of NALP1-14, IPAF, 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
  • NLR NOD-like receptor
  • 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 amino-terminal PYRIN (PYD) domain, a nucleotide-binding NACHT domain and a carboxyterminal leucine-rich repeat (LRR) domain.
  • PYD PYRIN
  • LRR carboxyterminal 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, insecretion and 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) (also referred to as metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD)), non-alcoholic steatohepatitis (NASH) (also referred to as metabolic dysfunction-associated steatohepatitis (MASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, type 1 and type 2 diabetes, rheumatoid arthritis
  • 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.
  • IL-1 receptor antagonist anakinra the neutralizing IL-1 beta (P) antibody canakinumab
  • P neutralizing IL-1 beta
  • soluble decoy IL-1 receptor rilonacept Current treatments for NLRP3-related diseases.
  • CNS central nervous system
  • sulfonylureabased compounds include various chemical classes such as sulfonylureabased 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 Fc11a-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.
  • WC2016131098, WO2017/140778 and WO2018215818 refer to 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, WC2019034690, WO2019034692, WO2019034693, WO2019034696, WO2019034697, WC2019068772, WO2019092170, WO2019092171 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
  • WC2017184604, WO2017184623, WO2017184624, WO2019023145, WO2019023147 and WC2019079119 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, and WO2021043966, WO2021239885, WO2021219784, WO2021214284, WO2021209552, WO2021209539 disclose compounds for inhibiting NLRP3 and/or NLRP3 inflammasome 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.
  • cytokines such as IL-1 beta (P) and IL-18
  • 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
  • WO2018015445 refers to sulfonylurea compounds which possess inflammasome inhibitory activity and are accordingly useful in methods of treatment of the human or animal body.
  • W02020018975 discloses sulfonimidamide derivatives defined as inhibitors of interleukin-1 activity and NLRP3 modulators in connection with inflammatory processes.
  • WO9832733 refers to aryl and heteroaryl substituted sulfonyl ureas that are inhibitors of interleukin-1 alpha (a) and interleukin-1 beta (p) processing and release.
  • W02020018970 discloses sulfonylureas defined as inhibitors of interleukin-1 activity.
  • WO2020/234715 discloses pyridazine-3-yl phenol compounds defined as inhibitors of NOD-like receptor protein 3 (NLRP3) inflammasome activity.
  • WO2021/193897 refers to substituted pyridazine compounds that are described as having suppressive action on NLRP3 inflammasome activity.
  • the present invention provides compound of formula (I) 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.
  • a component of the NLRP3 inflammasome pathway such as NLRP3 inflammasome.
  • 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.
  • 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.
  • X’ is selected from CH or N;
  • W is selected from N, CH or CR c ;
  • Q is selected from N and C;
  • E is selected from NR a and CR a ;
  • Z is selected from N and C; wherein at least one of Q and Z is C, and/or E is CR a ;
  • R c is selected from the group consisting of -Ci-C4alkyl, -O-Ci-C4alkyl, -Ci-C4alkyl-OH, halo or -Ci-C4alkyl-Hal;
  • R a is selected from the group consisting of -H and -Ci-Csalkyl
  • Ro is selected from the group consisting of -H, -Ci-Csalkyl and halo;
  • Ri is selected from the group consisting of -CF3, -OCF3, -OCHF2 and halo;
  • R2 is selected from the group consisting of -OH, -H and -CF3;
  • Y is selected from NH, NRd, O or is a bond
  • Rd is selected from the group consisting of -C C4alkyl, -C C4alkyl-OH, or -Ci-Cjalkyl-Hal;
  • R3 is selected from the group consisting of
  • heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, wherein said heteroatom(s) is/are independently selected from N and O, substituted with one or two substituents independently selected from the group consisting of -CF 3 and -Ci- salkylNRsRe; and
  • R 5 and Re are independently selected from H and -Ci-Csalkyl; and m is 0, 1 or 2.
  • Ro is selected from the group consisting of -H, -Ci-Csalkyl and halo;
  • Ri is selected from the group consisting of -CF3, -OCF3, -OCHF2 and halo;
  • R2 is selected from the group consisting of -OH, -H and -CF3;
  • R3 is selected from the group consisting of
  • any reference to the compounds of formula (I) 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 prodrugs, 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 prodrug, 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.
  • 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.
  • HMGB High-Mobility Group Box
  • the compounds of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a prodrug, 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 prodrug, 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 fatty liver disease (NAFLD) (also referred to as metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction- associated steatotic liver disease (MASLD)), non-alcoholic steatohepatitis (NASH) (also referred to as metabolic dysfunction-associated steatohepatitis (MASH)), and gout.
  • NAFLD non-alcoholic fatty liver disease
  • MAFLD metabolic dysfunction-associated fatty liver disease
  • MASLD metabolic dysfunction-associated steatotic liver disease
  • NASH non-alcoholic steatohepatitis
  • MASH metabolic dysfunction-associated steatohepatitis
  • 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 prodrug, 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 prodrug, 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 prodrug, 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 prodrug, 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 prodrug, 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 prodrug, a hydrate, or a solvate thereof, and at least one further biologically active compound differing from the compound of formula (I) or (la), or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a prodrug, a hydrate, or a solvate thereof, and optionally comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient, is also the subject-matter 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.
  • 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 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 prodrug, 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), and to compounds of formula (la), including stereoisomers, racemic mixtures, tautomers, polymorphs, pharmaceutically acceptable salts, prodrugs, hydrates, or solvates thereof.
  • X’ is selected from CH or N;
  • W is selected from N, CH or CR c ;
  • Q is selected from N and C;
  • E is selected from NR a and CR a ;
  • Z is selected from N and C; wherein at least one of Q and Z is C, and/or E is CR a ;
  • R c is selected from the group consisting of -Ci-C4alkyl, -O-Ci-C4alkyl, -Ci-C4alkyl-OH, halo or -Ci-C4alkyl-Hal;
  • R a is selected from the group consisting of -H and -Ci-Csalkyl
  • Ro is selected from the group consisting of -H, -Ci-Csalkyl and halo;
  • Ri is selected from the group consisting of -CF3, -OCF3, -OCHF2 and halo;
  • R 2 is selected from the group consisting of -OH, -H and -CF 3 ;
  • Y is selected from NH, NRa, O or is a bond
  • Ra is selected from the group consisting of -Ci-C4alkyl, -Ci-C4alkyl-OH, or -Ci-C4alkyl-Hal;
  • R3 is selected from the group consisting of
  • heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, wherein said heteroatom(s) is/are independently selected from N and O, substituted with one or two substituents independently selected from the group consisting of -CF3 and -Ci- salkylNRsRe; and
  • Rs and Rs are independently selected from H and -Ci-Csalkyl; and m is 0, 1 or 2.
  • Q and Z are both C and E is CR a , wherein R a is as defined above.
  • Q and Z are both C and E is NR a , wherein R a is as defined above.
  • Q is N, Z is C and E is CR a , wherein R a is as defined above.
  • X’ is N. in another embodiment X’ is CH.
  • W is N. in a preferred embodiment W is CH. In another embodiment W is CR c with R c being -CH2-OH, -O-CHsor F.
  • Y is NH. In another embodiment Y is O. In another embodiment Y is N-CH3. In a preferred embodiment Y is a bond. m is 0, 1 or 2. In one embodiment m is 2. In another embodiment m is 1, In a preferred embodiment m is 0.
  • m is 0 and Y is a bond.
  • R a is selected from the group consisting of -H and -Ci-Csalkyl. In a preferred embodiment R a is H. In another embodiment R a is -Ci-Csalkyl, preferably methyl or ethyl, more preferably methyl.
  • Ro is selected from -H and -Ci-Csalkyl, more preferably -H or methyl. In one embodiment Ro is -H. In a preferred embodiment Ro is -Ci-Csalkyl, preferably methyl or ethyl, more preferably methyl.
  • R1 is selected from -CF3, -OCF 3 and -OCHF2. In one preferred embodiment R1 is -CF 3 . In another preferred embodiment R1 is -OCF3. In another preferred embodiment R1 is -OCHF2.
  • R1 is halo, preferably chloro.
  • R2 is -OH or H, more preferably -OH. In another embodiment R2 is -H. In another embodiment R2 is -CF3.
  • Ro is -H or -CH3
  • R1 is -halo
  • R2 is -OH. Even more preferably
  • Ro is -CH3
  • R1 is -Cl
  • R 2 is -OH.
  • R3 is selected from the group consisting of
  • heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, wherein said heteroatom(s) is/are independently selected from N and O, substituted with one or two substituents independently selected from the group consisting of -CF3 and -Ci-CsalkylNRsRe; and
  • R3 is selected from the group consisting of
  • R3 is selected from the group consisting of
  • R3 is selected from the group consisting of
  • R3 is selected from the group consisting of 4-, 5- or 6-membered heterocycloalkyl containing one heteroatom, wherein said heteroatom is N, substituted with one substituent selected from the group consisting of -CF 3 and -Ci-C 3 alkylNR 5 R6, wherein R 5 and Re are independently selected from H and -Ci-C 3 alkyl.
  • R3 is selected from the group consisting of
  • R3 is selected from the group consisting of wherein
  • R4 is independently selected from -Ci-C 3 alkylNR 5 R6 or -CF3;
  • Rs and Rs are independently selected from H or -Ci-C 3 alkyl, preferably H or -CH3;
  • R 7 is selected from H or -Ci-C 3 alkyl, preferably -CH 3 ; n is selected from 0, 1 or 2, preferably n is 1 ; and p is selected from 1 or 2.
  • R3 is selected from the group consisting of wherein
  • R4 is independently selected from -Ci-CsalkylNRsRe or -CF 3 ;
  • Rs and Re are independently selected from H or -Ci-Csalkyl, preferably -CH3;
  • R 7 is selected from H or -Ci-Csalkyl, preferably -CH3 and p is selected from 1 or 2.
  • R3 is selected from the group consisting of
  • Ro is selected from the group consisting of -H, -Ci-Csalkyl and halo;
  • R1 is selected from the group consisting of -CF3, -OCF3, -OCHF2 and halo;
  • R2 is selected from the group consisting of -OH, -H and -CF3;
  • R3 is selected from the group consisting of
  • heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, wherein said heteroatom(s) is/are independently selected from N and O, substituted with one substituent selected from the group consisting of -CF 3 and -Ci-CsalkylNRsRe; and
  • R a is selected from the group consisting of -H and -Ci-Csalkyl. In a preferred embodiment R a is H. In another embodiment R a is -Ci-Csalkyl, preferably methyl or ethyl, more preferably methyl.
  • Ro is selected from -H and -Ci-Csalkyl, more preferably -H or methyl. In one embodiment Ro is -H. In a preferred embodiment Ro is -Ci-Csalkyl, preferably methyl or ethyl, more preferably methyl.
  • R1 is selected from -CF 3 , -OCF 3 and -OCHF2. In one preferred embodiment R1 is -CF3. In another preferred embodiment R1 is -OCF 3 . In another preferred embodiment R1 is -OCHF2.
  • R1 is halo, preferably chloro.
  • R2 is -OH or H, more preferably -OH. In another embodiment R2 is -H. In another embodiment R2 is -CF3.
  • Ro is -H or -CH3
  • R1 is -halo
  • R 2 is -OH. Even more preferably
  • Ro is -CH 3 ;
  • R1 is -Cl
  • R 2 is -OH.
  • R 3 is selected from the group consisting of
  • heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, wherein said heteroatom(s) is/are independently selected from N and O, substituted with one or two substituents independently selected from the group consisting of -CF3 and -Ci-C 3 alkylNRsR6; and
  • R3 is selected from the group consisting of
  • heterocycloalkyl containing one or two heteroatoms, preferably one heteroatom, wherein said heteroatom(s) is/are independently selected from N and O, substituted with one or two substituents independently selected from the group consisting of -CF3 and -C CsalkylNRsRe; wherein R 5 and Rs are independently selected from H and -Ci-C 3 alkyl.
  • R 3 is selected from the group consisting of
  • R 3 is selected from the group consisting of
  • R3 is selected from the group consisting of
  • R3 is selected from the group consisting of
  • R3 is selected from the group consisting of wherein
  • R4 is independently selected from -Ci-CsalkylNRjRe or -CF3;
  • R 5 and Re are independently selected from H or -Ci-Csalkyl, preferably H or -CH3;
  • R 7 is selected from H or -Ci-Csalkyl, preferably -CH3; n is selected from 0, 1 or 2, preferably n is 1 ; and p is selected from 1 or 2.
  • R3 is selected from the group consisting of wherein
  • R4 is independently selected from -Ci-C 3 alkylNR 5 R6 or -CF 3 ;
  • Rs and Re are independently selected from H or -Ci-C 3 alkyl, preferably -CH 3 ;
  • R7 is selected from H or -Ci-C 3 alkyl, preferably -CH 3 and
  • p is selected from 1 or 2.
  • R 3 is selected from the group consisting of
  • the present invention relates to the following compounds of formula
  • R1 is -CF 3 or halo, preferably Cl
  • R2 is -OH.
  • the present invention relates to the following compounds of formula (I) or (la): or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a prodrug, a hydrate, or a solvate thereof.
  • the present invention relates to the following compounds of formula (I) or (la):
  • the present invention relates further 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 prodrug, 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 prodrug, 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 prodrug, 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.
  • the modulation is the reduction and/or inhibition of IL-1 beta and/or IL-18 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 prodrug, 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 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 prodrug, a hydrate, or a solvate thereof, for use in a method of reducing and /or inhibiting IL-1 beta and/or IL-18.
  • 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 prodrug, 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) defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a prodrug, 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 prodrug, 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 inflammasome.
  • 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 inflammasome 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 prodrug, a hydrate, or a solvate thereof, to a subject in need thereof (e.g. a patient).
  • the modulation is the reduction and/or inhibition of IL-1 beta and/or IL-18 beta levels.
  • the modulation is the reduction and/or inhibition of IL-1 beta.
  • 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 prodrug, 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, 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 prodrug, 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 prodrug, a hydrate, or a solvate thereof, to a patient in need thereof.
  • the modulation is the reduction and/or inhibition of IL-1 beta and/or IL-18 beta levels.
  • the modulation is the reduction and/or inhibition of IL-1 beta.
  • the present invention relates to the use of a compound of (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a prodrug, 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 prodrug, 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 modulation is the reduction and/or inhibition of IL-1 beta and/or IL-18 beta levels.
  • the modulation is the reduction and/or inhibition of IL-1 beta.
  • 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 prodrug, 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 prodrug, 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.
  • 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 prodrug, 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 prodrug, a hydrate, or a solvate thereof, for the manufacture of a medicament for reducing and/or inhibiting IL-1 beta and/or IL-18 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 or 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 prodrug, 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 , IL-17, IL-18, IL- 1 a, IL-37, IL-33 and Th17 cells, preferably: IL-1 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) (also referred to as metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD)), non-alcoholic steatohepatitis (NASH) (also referred to as metabolic dysfunction-associated steatohepatitis (MASH)), chronic kidney disease, 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) (also referred to as metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD)), non-alcoholic steatohepatitis (NASH) (also referred to as metabolic dysfunction-
  • 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, tumor 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 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 At
  • 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) (also referred to as metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction- associated steatotic liver disease (MASLD)), non-alcoholic steatohepatitis (NASH) (also referred to as metabolic dysfunction-associated steatohepatitis (MASH)), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, mye
  • 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 fatty liver disease (NAFLD) (also referred to as metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD)), non-alcoholic steatohepatitis (NASH) (also referred to as metabolic dysfunction-associated steatohepatitis (MASH)), 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), anti-neutrophil
  • the disease, the disorders or the abnormality is a skin disease, disorder, or abnormality selected from hidradenitis suppurativa (HS), dermatitis, generalised pustular psoriasis, palmoplantar pustular psoriasis, psoriasis, skin contact hypersensitivity, acne, periodic fever syndrome (HIDS), Sweet’s syndrome, eczema, skin lesions, burn, wound, wound healing, trauma, sunburn, actinic keratosis, deficiency of interleukin 1 receptor antagonist (DIRA), epidermolysis bullosa, vitiligo, atopic dermatitis, cutaneous lupus, and alopecia areata.
  • HS hidradenitis suppurativa
  • dermatitis dermatitis
  • generalised pustular psoriasis palmoplantar pustular psoriasis
  • psoriasis skin contact hypersensitivity
  • 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) (also referred to as metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD)), non-alcoholic steatohepatitis (NASH) (also referred to as metabolic dysfunction-associated steatohepatitis (MASH)), chronic kidney disease, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, type 1 and type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, hidradenitis suppurativa (HS),
  • 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) (also referred to as metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD)), non-alcoholic steatohepatitis (NASH) (also referred to as metabolic dysfunction-associated steatohepatitis (MASH)), rheumatoid arthritis, chronic kidney disease and gout.
  • CPS cryopyrin-associated periodic syndromes
  • NAFLD non-alcoholic fatty liver disease
  • MAFLD metabolic dysfunction-associated fatty liver disease
  • MASLD metabolic dysfunction-associated steatotic liver disease
  • NASH non-alcoholic steatohepatitis
  • rheumatoid arthritis chronic kidney disease 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) (also referred to as metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD)), non-alcoholic steatohepatitis (NASH) (also referred to as metabolic dysfunction-associated steatohepatitis (MASH)), chronic kidney disease, hidradenitis suppurativa (HS), generalised pustular psoriasis, palmoplantar pustular psoriasis, and gout.
  • CAPS cryopyrin-associated periodic syndromes
  • NAFLD non-alcoholic fatty liver disease
  • MAFLD metabolic dysfunction-associated fatty liver disease
  • MASLD metabolic dysfunction-associated steatotic liver disease
  • NASH non-alcoholic steatohepatitis
  • chronic kidney disease hidraden
  • 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 prodrug, 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 prodrug, 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), Coronavirus-associated respiratory distress syndrome (CARDS), 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, syntaxin 11 , immune
  • the modulation of NLRP3 inflammasome pathway appears to be beneficial in diseases or disorders or abnormalities with altered IL-18 levels and I or IL-1 beta, which lead to pathological inflammation.
  • the present invention relates to compound of formula (I) or (la) 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.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a prodrug, a hydrate, or a solvate thereof, and at least one further biologically active compound.
  • the pharmaceutical combination may comprise a pharmaceutically acceptable carrier, diluent, adjuvant or excipient as described herein.
  • the present invention relates to a pharmaceutical composition
  • 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 prodrug, 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.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a compound of formula (l(l) or (la) defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a prodrug, 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.
  • a compound of the invention 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.
  • 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 acid, which is therapeutically active or enhances the therapeutic activity when administered to a subject (e.g., a patient) in combination with a compound of the invention.
  • 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, oxaprozin, 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
  • 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.
  • 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.
  • compounds of the invention may be used in combination with an anti-amyloid beta antibody.
  • anti-amyloid abeta antibodies include crenezumab, solanezumab, bapineuzumab, aducanumab, gantenerumab, lecanemab, remternetug, donanemab, trontinemab, ABBV-916 (AbbVie), MEDI-1814 (AstraZeneca), ACU193 (Acumen), PRX012 (Prothena), SHR-1707 (Jiangsu Hengrui Pharmaceuticals) and PMN-310 (ProMIS Neurosciences).
  • compounds of the invention may be used in combination with an anti-tau antibody.
  • anti-tau antibodies include semorinemab, bepranemab, tilovonemab, 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.
  • compounds of the invention may be used in combination with an anti-alpha-synuclein 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.
  • 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.
  • 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.
  • 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.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a combination comprising a compound of formula (I) or (la) defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a prodrug, 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.
  • 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.
  • a combination partner e.g. another drug as explained above, also referred to as “therapeutic agent” or “further biologically active compound”
  • 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 prodrug, 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.
  • the at least one further biologically active compound is a compound differing from a compound of formula (I) or (la).
  • 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 prodrug, 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 prodrug, a hydrate, or a solvate thereof, as an analytical reference or an in vitro screening tool.
  • the compounds of the present invention 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.
  • 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 prodrug, 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 further biologically active agent.
  • the invention also provides the use of further 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 further 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 prodrug, a hydrate, or a solvate thereof.
  • the invention provides the use of a compound of (I) or (la) as defined in the present invention, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a prodrug, 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.
  • the modulation is the reduction and/or the inhibition of IL-1 beta.
  • the modulation is the inhibition of IL-1 beta.
  • 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 prodrug, a hydrate, or a solvate thereof, for use as a medicament, in particular for inhibiting IL-1 beta.
  • 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 prodrug, 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), is prepared for administration with further biologically active compound (as defined herein).
  • 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, rheumatoi
  • 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) as defined herein, or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a prodrug, a hydrate, or a solvate thereof.
  • 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 IL-18.
  • 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.
  • 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 prodrug, a hydrate, or a solvate thereof, optionally in admixture with a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.
  • 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 prodrug, 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.
  • 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, 18 th Ed. (Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, PA, 1990); Remington: the Science and Practice of Pharmacy 19 th Ed.(Lippincott, Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3 rd Ed. (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc, 1999); Pharmaceutical Codex: Principles and Practice of Pharmaceutics 12 th Ed.
  • 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 Kollidon® XL), alginic acid, sodium alginate, guar gum, cross-linked CMC (
  • Ac-Di-Sol® carboxymethyl starch-Na (sodium starch glycolate) (e.g., Primojel® or Explotab®), preferably crosslinked PVP and/or croscarmellose sodium), glidants (such as colloidal SiO2 (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. Carriers can include
  • 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.
  • nasal, parenteral e.g., by an injectable form
  • gastrointestinal intraspinal, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, 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), hydroxypropylcellulose (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 227EA), carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1 ,1 ,1 ,2-tetra
  • 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 compounds may also be administered by the pulmonary or rectal routes. They may also be administered by the ocular route.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • administration is sequential, either the compound of the invention or the other biologically active compound may be administered first.
  • administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition.
  • the two compounds 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.
  • they may be provided in any convenient formulation, conveniently in such manners as are known for such compounds in the art.
  • 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 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.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 0, 18 0, 35 S, 18 F and 36 CI 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., 14 C, isotopes are particularly preferred for their ease of preparation and delectability.
  • 18 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.
  • 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 prodrug, 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:
  • CNS Central nervous system disease
  • Parkinson’s disease dementia, frontotemporal dementia, Huntington's disease
  • cerebral malaria brain injury from pneumococcal meningitis, motor neuron disease, traumatic brain injury, encephalopathy, amyotrophic lateral sclerosis, or multiple sclerosis (MS);
  • 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, transplant rejection, or relapsing remitting multiple sclerosis (RRMS);
  • PPMS primary progressive multiple sclerosis
  • SPMS secondary progressive multiple sclerosis
  • TRAPS TNF receptor associated periodic syndrome
  • RRMS 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, generalised pustular psoriasis, palmoplantar pustular psoriasis, skin contact hypersensitivity, acne, periodic fever syndrome (HIDS), Sweet's syndrome, eczema, skin lesions, burn, wound, wound healing, trauma, sunburn, actinic keratosis, deficiency of interleukin 1 receptor antagonist (DIRA), skin inflammation or alopecia areata;
  • HS hidradenitis suppurativa
  • dermatitis dermatitis
  • psoriasis generalised pustular psoriasis
  • palmoplantar pustular psoriasis skin contact hypersensitivity
  • acne periodic fever syndrome
  • Sweet's syndrome eczema
  • DIRA interleukin 1 receptor antagonist
  • E. Ocular disease, disorder, or abnormality such as age-related macular degeneration (AMD), corneal infection, uveitis, glaucoma, dry eye, dry macular degeneration, diabetic retinopathy, ocular inflammation or demyelination;
  • ALD age-related macular degeneration
  • corneal infection e.g. corneal infection, uveitis, glaucoma, dry eye, dry macular degeneration, diabetic retinopathy, ocular inflammation or demyelination
  • F. Cardiovascular disease, disorder, or abnormality e.g. disease, disorder, or abnormality of the cardiovascular system
  • myocardial infarction e.g. disease, disorder, or abnormality of the cardiovascular system
  • Metabolic disease, disorder, or abnormality such as type 2 diabetes, obesity, atherosclerosis, metabolic-dysfunction-associated hepatitis, gout, or pseudo-gout;
  • Respiratory disease, disorder, or abnormality e.g. disease, disorder or abnormality of the respiratory system
  • disease, disorder or abnormality of the respiratory system such as asbestosis, silicosis, cystic fibrosis, allergic inflammation, chronic obstructive pulmonary disorder (COPD), acute respiratory distress syndrome, idiopathic pulmonary disease, steroid-resistant asthma, or asthma;
  • COPD chronic obstructive pulmonary disorder
  • 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), acute or chronic liver failure, non-alcoholic fatty liver disease (NAFLD) (also referred to as metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD)), or non-alcoholic steatohepatitis (NASH) (also referred to as metabolic dysfunction-associated steatohepatitis (MASH)) including advanced fibrosis stages F3 and F4;
  • AFLD alcoholic fatty liver disease
  • ASH alcoholic fatty liver disease
  • NASH non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • MASH metabolic dysfunction-associated steatohepatitis
  • 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, kidney fibrosis, chronic kidney disease, or kidney disease;
  • Cancer disease, disorder, 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 antagonist (DIRA), or epilepsy; alphavirus (e.g. Chikungunya virus and Ross River virus), flaviviruses (e.g. Dengue and Zika virus), Coronavirus-associated inflammatory pathologies, Coronaviruses, influenza virus, or sepsis;
  • helminth infections e.g. from schistosoma, roundworms, tapeworms or flukes
  • HIV-associated neurocognitive disorder e.g. from chronic nonbacterial osteomyelitis (CNO), chronic bacterial osteomyelitis, deficiency of interleukin 1 receptor antagonist (DIRA), or epile
  • M Psychological disease, disorder, or abnormality, such as depression, schizophrenia 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, neuroinflammation, chronic inflammation.
  • 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, neuroinflammation, chronic inflammation.
  • 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 tract
  • colitis ulcerative colitis
  • inflammatory bowel disease ill.
  • 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, 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
  • 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 fatty liver disease (NAFLD) (also referred to as metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD)), non-alcoholic steatohepatitis (NASH) (also referred to as metabolic dysfunction-associated steatohepatitis (MASH)), chronic kidney disease, gout and hidradenitis suppurativa (HS).
  • CAPS cryopyrin-associated periodic syndromes
  • NAFLD non-alcoholic fatty liver disease
  • MAFLD metabolic dysfunction-associated fatty liver disease
  • MASLD metabolic dysfunction-associated steatotic liver disease
  • NASH non-alcoholic steatohepatitis
  • chronic kidney disease gout and hidradenitis suppurativa
  • 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, hidradenitis suppurativa (HS), generalised pustular psoriasis, palmoplantar pustular psoriasis, eczema, alopecia areata, 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 or a 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);
  • 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 “Ci-Cealkyl” refers to an alkyl group having 1 to 6 carbon atoms.
  • the terms “Ci-C4alkyl”, “Ci-Csalkyl”, or “Cialkyl” are to be construed accordingly.
  • Hal refers to F, Cl, Br, and I.
  • halogen is F or Cl. More preferably, halogen is Cl. In another aspect, halogen is F.
  • 4-, 5- or 6-membered heterocycloalkyl refers to a stable 4-, 5- or 6-membered non-aromatic monocyclic ring radical which comprises 1 or 2 heteroatoms, preferably 1 heteroatom.
  • the heteroatom is independently selected from N or O, preferably N. Examples include azetidine, oxetane, pyrrolidine, tetrahydrofurane, oxazolidine, isoxazolidine, piperidine, and morpholine, preferably pyrrolidine, and piperidine, more preferably pyrrolidine.
  • 8-, 9- or 10-membered spiro bicyclic heterocycloalkyl refers to a stable 8-, 9- or 10-membered non-aromatic spiro bicyclic ring radical which comprises 1 , 2 or 3 heteroatoms, preferably 1 or 2 heteroatoms, more preferably 2 heteroatoms.
  • the heteroatom(s) is/are preferably independently selected from N or O, preferably N.
  • the dashed circle in the five-membered ring means that double bonds can be optionally present at any available position.
  • C which is an option of Z, E, and Q has four bonds to adjacent atoms and N which is an option of Z, E and Q has three bonds to adjacent atoms.
  • the bonds can be either single or double bonds.
  • 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, or prodrugs 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, prodrugs, 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 CM 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 acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric acid 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, pamoic, 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 acid 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.
  • prodrug means any covalently bonded compound which releases the active parent pharmaceutical due to in vivo biotransformation.
  • “Pharmaceutically acceptable” 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 benefit/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 B1 (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 refers 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. Wuts (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 skilled in the art.
  • Pg means a protecting group.
  • suitable protecting groups include -CH3, -MOM, or -MEM.
  • 3-bromo-6-chloropyrazin-2-amine can be functionalized to diamino pyrazines by amination with suitable amines. Then, cyclization using aldehydes, containing alcohol protecting groups such as CH3, employing an appropriate solvent in the presence of sodium bisulfite can provide the bicyclic intermediates after purification. The bicyclic intermediates can be further functionalized by nucleophilic substitution with suitable alcohols and amine or palladium catalysed Buchwald conditions employing suitable amines. Finally, the methyl protecting group can be cleaved under Lewis-acid conditions (boron tribromide) to afford compounds of formula of formula (I).
  • the mixture was flushed with argon and stirred at 100 °C for 1 h until completion.
  • the mixture was quenched with water and extracted twice with ethyl acetate.
  • the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated.
  • 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 (10 mL*2). The combined organic layer was washed successively with water (20 mL*2) and brine (20 ml*1 ), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue.
  • reaction mixture was poured onto 20 mL H2O and then adjusted the pH to 7 with an aqueous NaHCOs saturated solution. Then, the resulting solution was extracted with DCM (10 mL*2). The combined organic layer was washed successively with water (20 mL*2) and brine (20 ml*1 ), dried over anhydrous Na 2 SO4, filtered, and concentrated to give 5-chloro-2-[5-(1 ,7-diazaspiro[4.4]nonan-7-yl)-1-methyl-imidazo[4,5- b]pyrazin-2-yl]-3-methyl-phenol (190 mg, crude) as a yellow solid. The residue was directly used to the next step without further purification.
  • Example 3a and 3b enantiopure 5-chloro-3-methyl-2-f1-methyl-5-ri-methyl-1,7- i-7-yllimidazor4,5-i :in-2-
  • reaction mixture was poured onto 20 mL H2O and then adjusted the pH to 7 with sat. NaHCOs. Then, the resulting solution was extracted with DCM (10 mL*2). The combined organic layer was washed successively with water (20 mL*2), brine (20 ml*1 ), dried over anhydrous Na 2 SO4, filtered, and concentrated to give a residue. The residue was used for the next step directly without further purification. (190 mg, crude) as a light yellow solid.
  • reaction mixture was poured onto 20 mL H 2 O and then adjusted the pH to 12 with sat. Na 2 CO3. Then, the resulting solution was extracted with EtOAc (10 mL*2). The combined organic layer was washed successively with water (20 mL*2), brine (20 ml*1 ), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue.
  • the enantiomers were separated by SFC (column: DAICEL CHIRALPAK IG (250mm*30mm, 10 pm); mobile phase: [CC>2-MeOH (0.1% NH3H 2 O)]; gradient: 20%-45% B over 20.0 min) to give first eluting pic enantiopure 5-chloro-3-methyl-2-[1-methyl-5-[1-methyl-1 ,7-diazaspiro[3.4]octan- 7-yl]imidazo[4,5-b]pyrazin-2-yl]phenol example 3a (25.71 mg, 30 %) as a light yellow solid.
  • reaction mixture was poured onto 5 mL H2O.
  • the resulting solution was extracted with DCM (8 mL*4).
  • the combined organic layer was washed successively with water (10 mL*2) and brine (10 mL*1 ), dried over anhydrous Na2SO4, filtered, and concentrated to give a residue.
  • reaction mixture was poured into H 2 O 10 mL and extracted with EtOAc 60 mL (20 mL * 3). The combined organic layers were washed with brine 60 mL (20 mL * 3), dried over Na 2 SO4, filtered and concentrated under reduced pressure to give a residue.
  • the reaction mixture was poured into H2O 10 mL and concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10 pm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 30%-60% B over 8.0 min) and then purified by prep-HPLC (column: Phenomenex Luna C18 100*40mm*5 pm; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 3%-30% B over 8.0 min) to afford 5-chloro-3-methyl-2-[1- methyl-5-(2-methyl-2,6-diazaspiro[3.4]octan-6-yl)imidazo[4,5-b]pyrazin-2-yl]phenol (3.17 mg, 3%) as a yellow solid.
  • reaction mixture was quenched by addition of saturated Na2CO3 aqueous solution (10 mL), and then extracted with DCM (10 mL * 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • 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 0.5 mM sodium pyruvate
  • HMDM were primed with 10 ng/mL of LPS from Escherichia coli for 3 h 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-i p quantification supernatants were analyzed using HTRF kit according to the manufacturer's instructions (Cisbio 62HIL1 BPEH). Briefly, in a 384-well ProxiPlateTM microplate, 8 pl of sample was mixed, with 5 pl of Anti-ILi p Cryptate antibody (40x) and Anti-IL1 p XL antibody (40x). Then, incubated overnight at RT. Reading was done using an EnVision Reader (PerkinElmer). IC 5 o (concentration corresponding to 50% inhibition) were determined using GraphPad Prism 10.
  • the tested compounds showed good inhibition of IL-1 beta release in human monocyte-derived macrophages using ATP as activator, with IC50 in the nM range, see Table 1.

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Abstract

La présente invention concerne de nouveaux composés pour traiter, soulager ou prévenir un groupe de maladies, de troubles et d'anomalies qui sont sensibles à la modulation ou à l'inhibition de l'activation d'un composant de la voie de l'inflammasome NLRP3. En particulier, le composant de la voie de l'inflammasome est une famille de récepteurs de type NOD (NLR), la protéine 3 contenant le domaine pyrin (NLRP3). Plus particulièrement, les composés selon la présente invention ont la capacité de moduler la voie de l'inflammasome NLRP3. En outre, les composés selon la présente invention sont appropriés pour traiter, soulager ou prévenir un groupe de maladies, de troubles et d'anomalies qui sont sensibles à la modulation, en particulier à la diminution, des taux d'IL-1 bêta et/ou d'IL-18.
PCT/EP2025/052396 2024-01-31 2025-01-30 Nouveaux composés Pending WO2025163069A1 (fr)

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