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US-12624010-B2 - Dihydrooxazole and thiourea derivatives modulating the NLRP3 inflammasome pathway

US12624010B2US 12624010 B2US12624010 B2US 12624010B2US-12624010-B2

Abstract

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

Inventors

  • Emanuele Gabellieri
  • Jérôme MOLETTE
  • Véronique DEHLINGER

Assignees

  • AC IMMUNE SA

Dates

Publication Date
20260512
Application Date
20210618
Priority Date
20200619

Claims (12)

  1. 1 . A compound of formula (I′) or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a prodrug, a hydrate, or a solvate thereof; wherein X is independently selected from the group consisting of O, N and S; Y is independently selected from the group consisting of N and O; as valency permits, is a combination of a single bond and a double bond or is two single bonds; n is 1 or 2; R 0 is H or C 1 -C 3 alkyl; R 1 is wherein Z is independently selected from the group consisting of CH 2 and O provided that no more than two of Z are O; R 5 is independently selected from the group consisting of hydrogen and halogen; R 2 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl; and R 3 is independently selected from the group consisting of heteroC 3 -C 6 cycloalkyl, aryl or heteroaryl, wherein each of them can be optionally substituted with —C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, -Hal, or —C 1 -C 6 alkyl-OH.
  2. 2 . The compound according to claim 1 , having a formula (I) or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a prodrug, a hydrate, or a solvate thereof; wherein, X, Y, n, R 1 , R 2 and R 3 are as defined in claim 1 and wherein R 0 is H.
  3. 3 . The compound according to claim 1 , which is a compound of formula (Ic), a compound of formula (Ic′), a compound of formula (Id), or a compound of formula (Id′) or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a prodrug, a hydrate, or a solvate thereof, wherein , X, Y, R 1 , R 2 and R 3 are as defined in claim 1 , and wherein R 0 is C 1 -C 3 alkyl.
  4. 4 . The compound according to claim 3 , which is a compound of formula (Ic) wherein , X, Y, R 1 , R 2 and R 3 are as defined in claim 1 .
  5. 5 . The compound according to claim 1 , wherein X is O; Y is N; as valency permits, is the combination of a single bond and a double bond; R 1 is wherein Z is CH 2 ; R 5 is hydrogen; R 3 is each of them can be optionally substituted, and R 4 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl.
  6. 6 . The compound according to claim 1 , which is selected from or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a prodrug, a hydrate, or a solvate thereof.
  7. 7 . A pharmaceutical composition comprising a compound as defined in claim 1 , 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.
  8. 8 . A method for the treatment, or alleviation of a disease, 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, the method comprising: administering to a host in need thereof a compound according to claim 1 , or a stereoisomer, a racemic mixture, a tautomer, a polymorph, a pharmaceutically acceptable salt, a prodrug, a hydrate, or a solvate thereof, wherein the disease, the disorder or the abnormality is selected from amyotrophic lateral sclerosis, epilepsy, cryopyrin-associated periodic syndromes (CAPS), non-alcoholic fatty liver disease, hypertension, graft-versus host disease, type 2 diabetes, myelodysplastic syndrome, acne, pyogenic arthritis pyoderma gangrenosum and acne (PAPA), psoriasis, chronic obstructive pulmonary disorder (COPD), obesity, chronic kidney disease, osteoarthritis, Coronaviruses, and hidradenitis suppurativa (HS).
  9. 9 . The method according to claim 8 , wherein the modulation is the reduction and/or inhibition of IL-1 beta.
  10. 10 . The method according to claim 8 , wherein the component of the inflammasome pathway is NLRP3 inflammasome.
  11. 11 . The method according to claim 8 , wherein the activation of NLRP3 inflammasome pathway is inhibited.
  12. 12 . A pharmaceutical composition comprising a compound according to claim 1 , 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 comprising at least one pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

Description

FIELD OF THE INVENTION The present invention relates to novel compounds that are useful for the treatment, alleviation or prevention of a disease, disorder or abnormality which is responsive to the modulation, in particular inhibition of the activation, of a component of the NLRP3 inflammasome pathway. In particular, the component of the inflammasome pathway is NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome. More particularly, the compounds of the present invention have the capability to modulate, e.g., inhibit the activation of, the NLRP3 inflammasome pathway. Further, the compounds of the present invention have the capability to modulate, in particular decrease, IL-1 beta and/or IL-18 levels. The present invention relates to novel compounds for the treatment, alleviation or prevention of a disease, disorder or abnormality which is responsive to the inhibition of the activation of the NLRP3 inflammasome pathway. The present invention relates to novel compounds for the treatment, alleviation or prevention of a disease, disorder or abnormality which is responsive to the modulation of IL-1 beta and/or IL-18 levels. The present invention relates to pharmaceutical compositions comprising said compounds, methods of using said compounds in the treatment of various diseases, disorders or abnormalities which is responsive to the above-mentioned modulation, medicaments containing them and their uses thereof. BACKGROUND OF THE INVENTION Inflammasome protein complexes are the key components of inflammatory signalling. These complexes assemble in response to various danger signals such as molecules from infectious agents (pathogen-associated molecular patterns, PAMPs) as well as altered host molecules, products of sterile tissue damage and environmental factors (danger associated molecular patterns, DAMPs). 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. 213, 617-629 (2016)). Inflammasomes are typically composed of a sensor (a cytosolic pattern-recognition receptor, PRR) and an adaptor protein called apoptosis associated speck-like protein containing a caspase-recruitment domain (CARD) (ASC), and an effector such as the protease caspase-1 (Broz, P.; Dixit, V. M. Inflammasomes: Mechanism of Assembly, Regulation and Signalling. Nat. Rev. Immunol. 2016, 16, 407-420). NLRP3 (NOD-like receptor (NLR) family, pyrin domain-containing protein 3) inflammasome is one of the best-described family members. It is a tripartite protein of the NLR family and contains an amino-terminal PYRIN (PYD) domain, a nucleotide-binding NACHT domain and a carboxy-terminal leucine-rich repeat (LRR) domain. In response to various agents including aggregated proteins, crystals and altered cellular ion homeostasis, the NLRP3 sensor molecule assembles into a multi-molecular complex with apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC aka PYCARD) adaptor protein. ASC protein polymerization into a large complex (ASC speck) leads to activation of caspase-1 effector protein and subsequent cleavage of pro-IL-1 beta (B) and pro-IL18 into their active secreted forms and mediates pyroptosis (Heneka et al., 2018 Nat Rev Neurosci). IL-1 beta (β) acts through IL-1 beta (β) receptors, induces secondary pro-inflammatory signals including IL-6 and TNF alpha secretion, and attracts and activates cells of adaptive immune system at the sites of infection. NLRP3/ASC complexes seems to be released into the extracellular environment where they can propagate inflammation. Multiple genetic and pharmacological evidence highlight the importance of NLRP3 inflammasome in human disease. NLRP3 gain-of-function mutations lead to the inherited cryopyrin-associated periodic syndromes (CAPS) including Muckle-Wells syndrome (MWS), familial cold auto-inflammatory syndrome (FCAS) and neonatal-onset multisystem inflammatory disease (NOMID). Accumulation of tissue damage products associated with ageing results in activation of NLRP3 inflammasome in multiple diseases including metabolic disorders, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, atherosclerosis, obesity, lung diseases, liver diseases and gout. Vast experimental evidence from animal models points out the detrimental role of excessive NLRP3 activation in a wide spectrum of diseases. NLRP3-inflammasome genetic or pharmacological downregulation showed protection in models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndromes (