NOVEL COMPOUNDS

Abstract

The present invention relates to novel compounds that can be employed in the treatment, alleviation or prevention of a group of diseases, disorders and abnormalities responsive to modulation or inhibition of the activation of a component of the inflammasome pathway. In particular, the component of the inflammasome pathway is NLRP3 inflammasome. More particularly, the compounds of the present invention have the capability to inhibit the NLRP3 inflammasome. Further, the compounds of the present invention modulate, in particular, decrease IL-1 beta and/or IL-18 levels.

Claims

1-24. (canceled)

25. A compound of formula (I): ##STR00387## or stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof; wherein is a single or double bond; A is selected from the group consisting of aryl and heteroaryl; wherein aryl and heteroaryl can be optionally substituted; R.sub.1 is selected from the group consisting of hydrogen, alkyl, carbocyclyl and heterocyclyl; wherein alkyl, carbocyclyl and heterocyclyl can be optionally substituted; R.sub.2 is selected from the following ring systems ##STR00388## R.sub.3 is selected from the group consisting of hydrogen, halogen, alkyl, NR*R* (with R* being independently selected from H and alkyl), aryl and heteroaryl, wherein the alkyl, aryl or heteroaryl can be optionally substituted; R.sub.4 is selected from the group consisting of hydrogen, halogen, alkyl, alkyl-O-alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl; wherein alkyl, alkyl-O-alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl can be optionally substituted; R.sub.5 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl; W is selected from the group consisting of C and N, in case of W being N no R.sub.4 is present; each X is independently selected from the group consisting of CH.sub.2 and O; Y is selected from the group consisting of NH, O and CRR; each R is independently selected from the group consisting of hydrogen, halogen, CH.sub.3, CH.sub.2F, CHF.sub.2, and CF.sub.3; Z and Z′ are independently selected from the group consisting of C and N, provided that when m is 0, Z′ is C; m is 0 or 1; n is 0 or 1; and each p is independently 0, 1, or 2.

26. The compound according to claim 25, which is a compound of formula (Ia): ##STR00389## wherein , A, R.sub.2, Y, Z, Z′, m and n are as defined in claim 25.

27. The compound according to claim 25, which is a compound of formula (Ib): ##STR00390## wherein , A, R.sub.2 and Y, are as defined in claim 25.

28. The compound according to claim 25, which is a compound of formula (Ic): ##STR00391## wherein , A and R.sub.2, are as defined in claim 25.

29. The compound according to claim 25, which is a compound of formula (Id): ##STR00392## wherein is a single or double bond, A is selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl can be optionally substituted, R.sub.2 is selected from the following ring systems ##STR00393## wherein X are independently selected from the group consisting of CH.sub.2 and O, each p is independently 1 or 2, W is selected from the group consisting of C and N, in case of W being N no R.sub.4 is present; R.sub.3 is selected from the group consisting of an optionally substituted heteroaryl, alkyl and halogen, R.sub.4 is selected from the group consisting of hydrogen, halogen, alkyl, alkyl-O-alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, wherein alkyl, alkyl-O-alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl can be optionally substituted, and R.sub.5 is selected from the group consisting of hydrogen, optionally substituted alkyl and optionally substituted heteroaryl.

30. The compound according to claim 25, which is a compound of formula (Ie): ##STR00394## wherein is a single or double bond, A is selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl can be optionally substituted, R.sub.2 is selected from the following ring systems ##STR00395## wherein X are independently selected from the group consisting of CH.sub.2 and O, each p is independently 1 or 2, W is selected from the group consisting of C and N, in case of W being N no R.sub.4 is present, R.sub.3 is selected from the group consisting of an optionally substituted heteroaryl, alkyl and halogen, R.sub.4 is selected from the group consisting of hydrogen, halogen, alkyl, alkyl-O-alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, wherein alkyl, alkyl-O-alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl can be optionally substituted, and R.sub.5 is selected from the group consisting of hydrogen, optionally substituted alkyl and optionally substituted heteroaryl.

31. The compound according to claim 25, wherein A is selected from the group consisting of ##STR00396## and wherein each of ##STR00397## can be optionally substituted.

32. The compound according to claim 25, wherein R.sub.3 is an optionally substituted pyridine.

33. The compound according to claim 25, which is selected from the list: ##STR00398## ##STR00399## ##STR00400## ##STR00401## ##STR00402## ##STR00403## ##STR00404##

34. A pharmaceutical composition comprising a compound as defined in claim 25 and optionally at least one selected from pharmaceutically acceptable excipients, carriers, diluents and adjuvants.

35. A method of treating, alleviating or preventing a disorder or abnormality responsive to modulation or inhibition of the activation of a component of the inflammasome pathway, wherein a therapeutically effective amount of a compound according to claim 25 is administered to a patient in need thereof.

36. The method according to claim 35, wherein the compound additionally modulates, in particular decreases, IL-1 beta and/or IL-18 levels.

37. The method according to claim 35, wherein the component of the inflammasome pathway is NLRP3 inflammasome.

38. The method according to claim 35, wherein the disease, disorder or abnormality is responsive to modulation of one or more of IL-1β, IL-17, IL-18, IL-1a, IL-37, IL-33 and Th17 cells.

39. The method according to claim 35, wherein the disease, disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudo-gout, inflammatory bowel disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinaemia D, periodic fever syndrome (HIDS), deficiency of interleukin 1 receptor (DIRA) antagonist, Majeed syndrome, pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA), haploinsufficiency of A20 (HA20), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers, developmental delay (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic recurrent multifocal osteomyelitis (CRMO), synovitis, pustulosis, acne, hyperostosis, osteitis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behcet's disease, Sjogren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disorder (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin contact hypersensitivity, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, Chikungunya virus, Ross River virus, influenza, HIV, Coronaviruses, Dengue virus, Zika virus, hidradenitis suppurativa (HS), lung cancer metastasis, pancreatic cancers, gastric cancers, myelodysplastic syndrome, leukemia; polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurism, wound healing, depression, psychological stress, pericarditis including Dressler's syndrome, ischaemia reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorder, Coronavirus-associated inflammatory pathologies, and traumatic brain injury.

40. The method according to claim 35, wherein the disease, disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic syndromes (CAPS), nonalcoholic fatty liver disease, NASH and gout.

41. A method of treating, alleviating or preventing a disorder or abnormality responsive to inhibition of activation of the NLRP3 inflammasome, wherein a therapeutically effective amount of a compound according to claim 25 is administered to a patient in need thereof.

42. The method according to claim 41, wherein the disease, disorder or abnormality is responsive to modulation of one or more of IL-1β, IL-17, IL-18, IL-1a, IL-37, IL-33 and Th17 cells.

43. The method according to claim 41, wherein the disease, disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudo-gout, inflammatory bowel disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinaemia D, periodic fever syndrome (HIDS), deficiency of interleukin 1 receptor (DIRA) antagonist, Majeed syndrome, pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA), haploinsufficiency of A20 (HA20), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers, developmental delay (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic recurrent multifocal osteomyelitis (CRMO), synovitis, pustulosis, acne, hyperostosis, osteitis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behcet's disease, Sjogren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disorder (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin contact hypersensitivity, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, Chikungunya virus, Ross River virus, influenza, HIV, Coronaviruses, Dengue virus, Zika virus, hidradenitis suppurativa (HS), lung cancer metastasis, pancreatic cancers, gastric cancers, myelodysplastic syndrome, leukemia; polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurism, wound healing, depression, psychological stress, pericarditis including Dressler's syndrome, ischaemia reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorder, Coronavirus-associated inflammatory pathologies, and traumatic brain injury.

44. The method according to claim 41, wherein the disease, disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic syndromes (CAPS), nonalcoholic fatty liver disease, NASH and gout.

45. A mixture comprising a compound as defined in claim 25 and at least one further biologically active compound selected from a therapeutic agent different from the compound as defined in claim 25, and optionally at least one selected from pharmaceutically acceptable carriers, diluents, adjuvants and excipients.

46. The mixture according to claim 45, wherein the further biologically active compound is selected from the group consisting of anti-amyloid beta antibody or amyloid beta small molecule inhibitor, anti-Tau antibody or 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.

47. An analytical reference or an in vitro screening tool comprising the compound according to claim 25.

48. A method of producing a compound of formula (Ic) or (Id) comprising the step of isocyanate derivative coupling reaction with a compound of formula (IId) in the presence of a solvent and a base ##STR00405## wherein A, R.sub.2 and R.sub.1 are as defined in claim 25.

49. A method of producing a compound of formula (Ie) comprising the step of isocyanate derivative coupling reaction of a compound of formula (IIe) in the presence of a solvent and a base ##STR00406## wherein A, R.sub.2 and R.sub.1 are as defined in claim 25.

50. The compound of formula (IId) or formula (IIe) as defined below ##STR00407## wherein A, and R.sub.1 are as defined in claim 25.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0126] The compounds of the present invention will be described in the following. It is to be understood that all possible combinations of the following definitions are also envisaged.

[0127] In one embodiment, the present invention relates to a compound of formula (I):

##STR00023##

[0128] or stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof.

[0129] For R.sub.1 being hydrogen tautomeric rearrangement is possible resulting for instance in compounds of the following formula (Ia) which is subject matter of a preferred embodiment

##STR00024##

[0130] Further preferred embodiments of the compounds of formula (Ia) are compounds of the following formula (Ib)

##STR00025##

[0131] Further preferred embodiments of the compounds of formula (Ia) and (Ib) are compounds of the following formula (Ic)

##STR00026##

[0132] The following definitions apply to formulae (I), (Ia), (Ib) and (Ic) as appropriate.

[0133] is a single or double bond.

[0134] A is selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl can be optionally substituted. Preferably A is selected from the group consisting of

##STR00027##

wherein each of these rings can be optionally substituted.

[0135] The optional substituent of A is preferably selected from the group consisting of optionally substituted C1-6 alkyl, halogen, hydroxyalkyl, NH.sub.s(alkyl).sub.t (wherein each of s and t can be 0, 1 or 2 as long as s+t=2; and wherein alkyl is C1-10 alkyl), optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, haloalkyl and CN. More preferably the optional substituent of A can be

##STR00028##

(for groups like:

##STR00029##

the substituent can be also bonded to the nitrogen, if available for substitutions, for example:

##STR00030##

and CN.

[0136] R.sub.1 is selected from the group consisting of hydrogen, alkyl and heterocyclyl (e.g. oxetanyl), preferably hydrogen and alkyl (e.g. Me); if R.sub.1 is hydrogen tautomeric rearrangement is possible. Alkyl and heterocyclyl can be optionally substituted.

[0137] R.sub.2 is selected from the following ring systems

##STR00031##

[0138] preferably it is selected from the following ring structures

##STR00032##

and more preferably R.sub.2 is selected from

##STR00033##

even more preferably R.sub.2 is selected from

##STR00034##

[0139] R.sub.3 is an optionally substituted heteroaryl, more preferably an optionally substituted pyridine; preferred substituents are —Oalkyl (e.g. —OCH.sub.3).

[0140] R.sub.4 is selected from the group consisting of hydrogen, halogen, alkyl, alkyl-O-alkyl, aryl and heteroaryl. More preferably R.sub.4 is selected from the group consisting of hydrogen and halogen.

[0141] W is selected from the group consisting of C and N.

[0142] X are independently selected from the group consisting of CH.sub.2 and O. More preferably X is CH.sub.2.

[0143] Y is selected from the group consisting of NH, O and CRR, preferably NH.

[0144] Each R is independently selected from the group consisting of hydrogen, halogen, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3.

[0145] R.sub.1 is selected from the group consisting of hydrogen, alkyl and heterocyclyl, wherein alkyl and heterocyclyl can be optionally substituted; preferably R.sub.1 is hydrogen.

[0146] m is 0 or 1.

[0147] n is 0 or 1.

[0148] Preferably n and m are selected such that a 5- or 6-membered ring results.

[0149] Each p is independently 0 or 1; preferably at least one p is 1 and more preferably both p are 1.

[0150] The compounds of formula (I) include a moiety of the following formula

##STR00035##

[0151] which is preferably selected from the group consisting of

##STR00036## ##STR00037## ##STR00038## ##STR00039## ##STR00040## ##STR00041## ##STR00042##

[0152] The compounds of formula (Ia) include a moiety of the following formula

##STR00043##

which is preferably selected from the group consisting of

##STR00044## ##STR00045## ##STR00046## ##STR00047## ##STR00048## ##STR00049## ##STR00050##

[0153] The moiety of the formula

##STR00051##

is preferably a moiety of the formula

##STR00052##

that is preferably selected from the group consisting of

##STR00053##

[0154] The ring A in the moieties

##STR00054##

can be optionally substituted, meaning that any H included in the ring A can be replaced by a substituent (comprising the H on the N).

[0155] Examples of compounds of formula (I) are

##STR00055## ##STR00056## ##STR00057## ##STR00058##

[0156] Preferred embodiments of the compound of formula (I) are as follows

##STR00059##

[0157] The following definitions apply to formulae (I), (Ia), (Ib), (Ic), (Id) and (Ie) as appropriate:

[0158] is a single or double bond, preferably a double bond.

[0159] A is selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl can be optionally substituted. Preferably A is selected from the group consisting of

##STR00060##

wherein each of these rings can be optionally substituted. More preferably, A is selected from the group consisting of

##STR00061##

wherein each of these rings can be optionally substituted. Even more preferably, A is selected from the group consisting of

##STR00062##

wherein each of these rings can be optionally substituted. Further more preferably, A is selected from the group consisting of

##STR00063##

wherein each of these rings can be optionally substituted. Further more preferably, A is selected from the group consisting of

##STR00064##

wherein each of these rings can be optionally substituted. Most preferably, A is

##STR00065##

which can be optionally substituted.

[0160] It is understood that the aryl and heteroaryl can be attached at any available position.

[0161] The optional substituent of A is preferably selected from the group consisting of optionally substituted alkyl (such as methyl or isopropyl), halogen (such as Cl, F or Br), NH.sub.s(alkyl).sub.t (wherein each of s and t can be 0, 1 or 2 as long as s+t=2), optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, —CN, —C(O)O-alkyl (such as —C(O)O-methyl), —S-alkyl (such as —S-methyl), and —O-alkyl (such as —O-methyl). The optional substituent of A is more preferably selected from the group consisting of alkyl, halogen, hydroxyalkyl, NH.sub.s(alkyl).sub.t (wherein each of s and t can be 0, 1 or 2 as long as s+t=2), optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, haloalkyl, —CN, —C(O)O-alkyl, —S-alkyl and —O-alkyl. The optional substituent of A is further more preferably selected from the group consisting of alkyl, halogen, hydroxyalkyl, NH.sub.s(alkyl).sub.t (wherein each of s and t can be 0, 1 or 2 as long as s+t=2), optionally substituted heteroaryl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, haloalkyl, —CN, —S-alkyl, and —Oalkyl. Even more preferably the optional substituent of A is selected from the group consisting of alkyl, halogen, haloalkyl, alkyl-OH, NH.sub.s(alkyl).sub.t (wherein each of s and t can be 0, 1 or 2 as long as s+t=2), —CN, —C(O)O-alkyl, and —O-alkyl. Even more preferably, the optional substituent of A is selected from the group consisting of —C(O)O-methyl, —CN, —Cl, —Br, —F, methoxy,

##STR00066##

Most preferably the optional substituent of A can be

##STR00067##

and CN.

[0162] In one embodiment, the optional substituent of A is selected from the group consisting of optionally substituted C1-6 alkyl, halogen, hydroxyalkyl, NH.sub.s(alkyl).sub.t (wherein each of s and t can be 0, 1 or 2 as long as s+t=2; and wherein alkyl is C1-10 alkyl), optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, haloalkyl and CN. In a further embodiment, the optional substituent of A can be

##STR00068##

and CN.

[0163] It is understood that if A contains a nitrogen ring atom which is not bonded to an adjacent ring atom via a double bond

##STR00069##

the substituent can be also bonded to the nitrogen, if available for substitution, for example:

##STR00070##

[0164] R.sub.1 is selected from the group consisting of hydrogen, alkyl (e.g., methyl), carbocyclyl and heterocyclyl (e.g., oxetanyl), wherein alkyl, carbocyclyl and heterocyclyl can be optionally substituted. In one embodiment, R.sub.1 is selected from the group consisting of hydrogen, alkyl and heterocyclyl (e.g. oxetanyl). Preferably R.sub.1 is hydrogen or alkyl, more preferably hydrogen. If R.sub.1 is hydrogen tautomeric rearrangement is possible. Possible tautomers are shown, e.g. in formulae (Ia) to (Ie). Alkyl and heterocyclyl can be optionally substituted.

[0165] R.sub.2 is selected from the following ring systems

##STR00071##

[0166] preferably R.sub.2 is selected from the following ring systems

##STR00072##

In one embodiment, R.sub.2 is selected from the following ring systems

##STR00073##

[0167] More preferably R.sub.2 is selected from the following ring structures

##STR00074##

[0168] and more preferably R.sub.2 is selected from

##STR00075##

[0169] even more preferably R.sub.2 is selected from

##STR00076##

[0170] R.sub.3 is selected from the group consisting of hydrogen, halogen (such as Cl, F or Br), alkyl (such as isopropyl), NR*R* ((with R* being independently selected from H and alkyl) such as NHMe), aryl (such as phenyl) and heteroaryl (such as pyridine), wherein the alkyl, aryl or heteroaryl can be optionally substituted. Preferably R.sub.3 is selected from the group consisting of halogen, alkyl, NR*R*, aryl and heteroaryl, wherein the alkyl, aryl or heteroaryl can be optionally substituted. More preferably R.sub.3 is selected from the group consisting of halogen, alkyl, aryl, and heteroaryl, wherein the alkyl, aryl or heteroaryl can be optionally substituted. In one embodiment, R.sub.3 is an optionally substituted heteroaryl, more preferably an optionally substituted pyridine. Preferably, R.sub.3 is an optionally substituted heteroaryl, isopropyl, Cl, F or Br. More preferably, R.sub.3 is optionally substituted pyridine, isopropyl, or Br, wherein the pyridine is, for example, substituted with —Oalkyl (e.g. —OCH.sub.3). Most preferably, R.sub.3 is optionally substituted pyridine.

[0171] The heteroaryl in R.sub.3 is preferably pyridine.

[0172] Preferred substituents of the heteroaryl in the R.sub.3 moiety are —Oalkyl (e.g. —OCH.sub.3).

[0173] R.sub.4 is selected from the group consisting of hydrogen, halogen (such as fluoro), alkyl, alkyl-O-alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, wherein alkyl, alkyl-O-alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl can be optionally substituted. More preferably R.sub.4 is selected from the group consisting of hydrogen and halogen. Even more preferably R.sub.4 is hydrogen or fluoro, most preferably R.sub.4 is hydrogen. In one embodiment, R.sub.4 is selected from the group consisting of hydrogen, halogen, alkyl, alkyl-O-alkyl, aryl and heteroaryl, for instance, R.sub.4 can be selected from the group consisting of hydrogen and halogen.

[0174] R.sub.5 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl (such as isopropyl), optionally substituted aryl, and optionally substituted heteroaryl, preferably R.sub.5 is selected from the group consisting of hydrogen, optionally substituted alkyl and optionally substituted heteroaryl, more preferably hydrogen, isopropyl, or optionally substituted pyridine, wherein pyridine is preferably substituted with —Oalkyl (e.g. —OCH.sub.3), More preferably, R.sub.5 is isopropyl or

##STR00077##

[0175] Preferred substituents of the aryl and heteroaryl in the R.sup.5 moiety are —Oalkyl (e.g. —OCH.sub.3).

[0176] W is selected from the group consisting of C and N, preferably W is C. More preferably, when W is C then R.sub.4 is hydrogen. In the case of W being N, no R.sub.4 is present.

[0177] Each X is independently selected from the group consisting of CH.sub.2 and O. More preferably X is CH.sub.2.

[0178] Y is selected from the group consisting of NH, O and CRR, preferably Y is NH.

[0179] Z and Z′ are independently selected from the group consisting of C and N, provided that when m is 0, Z′ is C. Preferably Z and Z′ are C.

[0180] Each R is independently selected from the group consisting of hydrogen, halogen, CH.sub.3, CH.sub.2F, CHF.sub.2, CF.sub.3, preferably R is hydrogen.

[0181] m is 0 or 1.

[0182] n is 0 or 1.

[0183] Preferably n and m are selected such that a 5- or 6-membered ring results.

[0184] Each p is independently 0, 1 or 2, preferably 1 or 2; more preferably at least one p is 1 and even more preferably both p are 1. In one embodiment, each p is independently 0 or 1, preferably at least one p is 1.

[0185] In one embodiment, R.sub.2 is

##STR00078##

wherein X are independently selected from the group consisting of CH.sub.2 and O, each p is independently 1 or 2, and

[0186] R.sub.4 is selected from the group consisting of hydrogen, halogen, alkyl, alkyl-O-alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl.

[0187] In this embodiment, preferably, X is CH.sub.2, at least one p is 1, and R.sub.4 is selected from the group consisting of hydrogen and halogen. In this embodiment, more preferably, X is CH.sub.2, both p are 1, and R.sub.4 is selected from the group consisting of hydrogen and F (fluoro).

[0188] In one embodiment, R.sub.2 is

##STR00079##

wherein X are independently selected from the group consisting of CH.sub.2 and O, and each p is independently 1 or 2.

[0189] In this embodiment, preferably, X is CH.sub.2 and at least one p is 1 and more preferably both p are 1.

[0190] In one embodiment, R.sub.2 is

##STR00080##

preferably

##STR00081##

wherein X are independently selected from the group consisting of CH.sub.2 and O, each p is independently 1 or 2,

[0191] R.sub.4 is selected from the group consisting of hydrogen, halogen, alkyl, alkyl-O-alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, and

[0192] R.sub.3 is an optionally substituted heteroaryl, alkyl and halogen.

[0193] In this embodiment, preferably, X is CH.sub.2, at least one p is 1 and more preferably both p are 1, R.sub.3 is an optionally substituted heteroaryl, isopropyl, Cl, F or Br, and R.sub.4 is selected from the group consisting of hydrogen and halogen. In this embodiment, more preferably, X is CH.sub.2, both p are 1, R.sub.3 is optionally substituted pyridine, isopropyl, or Br, wherein pyridine is preferably substituted with —Oalkyl (e.g. —OCH.sub.3) and R.sub.4 is hydrogen or F (fluoro).

[0194] In one embodiment, R.sub.2 is

##STR00082##

wherein W is selected from the group consisting of C and N, in case of W being N no R.sub.4 is present,

[0195] R.sub.4 is selected from the group consisting of hydrogen, halogen, alkyl, alkyl-O-alkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, and

[0196] R.sub.5 is hydrogen, optionally substituted alkyl or optionally substituted heteroaryl.

[0197] In this embodiment, preferably, W is C, R.sub.4 is selected from the group consisting of hydrogen and halogen, and R.sub.5 is hydrogen, isopropyl or optionally substituted pyridine, wherein pyridine is preferably substituted with —Oalkyl (e.g. —OCH.sub.3). In this embodiment, more preferably, W is C, R.sub.4 is hydrogen or F (fluoro), and R.sub.5 is isopropyl or

##STR00083##

[0198] A further embodiment of the invention is directed to compounds of the following formula (Id)

##STR00084##

or stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof, wherein

[0199] is a single or double bond,

[0200] A is selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl can be optionally substituted,

[0201] R.sub.2 is selected from the following ring systems

##STR00085##

[0202] wherein

[0203] each X is independently selected from the group consisting of CH.sub.2 and O,

[0204] each p is independently 1 or 2,

[0205] W is selected from the group consisting of C and N, in case of W being N no R.sub.4 is present,

[0206] R.sub.3 is selected from the group consisting of an optionally substituted heteroaryl, alkyl and halogen,

[0207] R.sub.4 is selected from the group consisting of hydrogen, halogen, alkyl, alkyl-O-alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, and

[0208] R.sub.5 is selected from the group consisting of hydrogen, optionally substituted alkyl or optionally substituted heteroaryl.

[0209] Preferably, is a double bond.

[0210] Preferably, A is selected from the group consisting of

##STR00086##

wherein each of these rings can be optionally substituted.

[0211] More preferably, A is selected from the group consisting of

##STR00087##

wherein each of these rings can be optionally substituted.

[0212] Even more preferably, A is selected from the group consisting of

##STR00088##

wherein each of these rings can be optionally substituted.

[0213] Even more preferably, A is selected from the group consisting of

##STR00089##

wherein each of these rings can be optionally substituted.

[0214] Even more preferably, A is selected from the group consisting of

##STR00090##

wherein each of these rings can be optionally substituted.

[0215] Even more preferably, A is

##STR00091##

which can be optionally substituted.

[0216] The optional substituent of A is preferably selected from the group consisting of optionally substituted alkyl, halogen, hydroxyalkyl, NH.sub.s(alkyl).sub.t (wherein each of s and t can be 0, 1 or 2 as long as s+t=2), optionally substituted heterocycloalkyl, optionally substituted cycloalkyl, haloalkyl, CN, alkyl, and alkoxy. More preferably, the optional substituent of A is selected from the group consisting of optionally substituted alkyl, preferably methyl or isopropyl; halogen, preferably Cl, F or Br; CN; alkyl carboxyl, preferably methyl carboxyl; and alkoxy, preferably methoxy. Further, alkyl can be optionally substituted with OH or halogen, preferably Cl, F or Br. Even more preferably, the optional substituent of A is methyl carboxyl, CN, Cl, Br, F, methoxy,

##STR00092##

[0217] Preferably, R.sub.2 is selected from the following ring structures

##STR00093##

[0218] Preferably, X is CH.sub.2.

[0219] Preferably at least one p is 1 and more preferably both p are 1.

[0220] Preferably, R.sub.3 is selected from the group consisting of an optionally substituted heteroaryl, isopropyl, Cl, F and Br. More preferably, R.sub.3 is selected from the group consisting of optionally substituted pyridine, isopropyl, and Br, wherein pyridine is preferably substituted with —Oalkyl (e.g. —OCH.sub.3).

[0221] Preferably R.sub.4 is selected from the group consisting of hydrogen and halogen, preferably hydrogen or F (fluoro). More preferably, R.sub.4 is hydrogen.

[0222] Preferably, R.sub.5 is hydrogen, isopropyl, or optionally substituted pyridine, wherein pyridine is preferably substituted with —Oalkyl (e.g. —OCH.sub.3). More preferably, R.sub.5 is isopropyl or

##STR00094##

[0223] Preferably, W is C. More preferably, when W is C then R.sub.4 is hydrogen.

[0224] In one embodiment, R.sub.2 is

##STR00095##

wherein

[0225] X are independently selected from the group consisting of CH.sub.2 and O, each p is independently 1 or 2, and

[0226] R.sub.4 is selected from the group consisting of hydrogen, halogen, alkyl, alkyl-O-alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl.

[0227] Preferably, X is CH.sub.2, at least one p is 1 and R.sub.4 is selected from the group consisting of hydrogen and halogen.

[0228] More preferably, X is CH.sub.2, both p are 1 and R.sub.4 is selected from the group consisting of hydrogen and F (fluoro).

[0229] In one embodiment, R.sub.2 is

##STR00096##

wherein X are independently selected from the group consisting of CH.sub.2 and O, and each p is independently 1 or 2.

[0230] Preferably, X is CH.sub.2 and at least one p is 1 and more preferably both p are 1.

[0231] In one embodiment, R.sub.2 is

##STR00097##

preferably

##STR00098##

wherein X is selected from the group consisting of CH.sub.2 and O,

[0232] each p is independently 1 or 2,

[0233] R.sub.4 is selected from the group consisting of hydrogen, halogen, alkyl, alkyl-O-alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, and

[0234] R.sub.3 is selected from the group consisting of an optionally substituted heteroaryl, alkyl and halogen.

[0235] Preferably, X is CH.sub.2, at least one p is 1 and more preferably both p are 1, R.sub.3 is selected from the group consisting of an optionally substituted heteroaryl, isopropyl, Cl, F and Br and R.sub.4 is selected from the group consisting of hydrogen and halogen.

[0236] More preferably, X is CH.sub.2, both p are 1, R.sub.3 is optionally substituted pyridine, isopropyl, or Br, wherein pyridine is preferably substituted with —Oalkyl (e.g. —OCH.sub.3) and R.sub.4 is hydrogen or F (fluoro).

[0237] In one embodiment, R.sub.2 is

##STR00099##

wherein W is selected from the group consisting of C and N, in case of W being N no R.sub.4 is present,

[0238] R.sub.4 is selected from the group consisting of hydrogen, halogen, alkyl, alkyl-O-alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, and

[0239] R.sub.5 is hydrogen, optionally substituted alkyl or optionally substituted heteroaryl.

[0240] Preferably, W is C, R.sub.4 is selected from the group consisting of hydrogen and halogen and R.sub.5 is hydrogen, isopropyl or optionally substituted pyridine, wherein pyridine is preferably substituted with —Oalkyl (e.g. —OCH.sub.3).

[0241] More preferably, W is C, R.sub.4 is hydrogen or F (fluoro) and R.sub.5 is isopropyl or

##STR00100##

[0242] Compounds of formula (Id) are

##STR00101## ##STR00102## ##STR00103## ##STR00104## ##STR00105## ##STR00106## ##STR00107##

[0243] The following enantiomers were identified. The elution peak* is indicated:

##STR00108## ##STR00109## ##STR00110## ##STR00111## ##STR00112## ##STR00113## ##STR00114##

[0244] A further embodiment of the invention is directed to compounds of the following formula (Ie)

##STR00115##

[0245] or stereoisomers, racemic mixtures, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and polymorphs thereof, wherein

[0246] is a single or double bond,

[0247] A is selected from the group consisting of aryl and heteroaryl, wherein aryl and heteroaryl can be optionally substituted,

[0248] R.sub.2 is selected from the following ring systems

##STR00116##

[0249] wherein

[0250] X are independently selected from the group consisting of CH.sub.2 and O,

[0251] each p is independently 1 or 2,

[0252] W is selected from the group consisting of C and N, in case of W being N no R.sub.4 is present,

[0253] R.sub.4 is selected from the group consisting of hydrogen, halogen, alkyl, alkyl-O-alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl,

[0254] R.sub.3 is selected from the group consisting of an optionally substituted heteroaryl, alkyl and halogen, and

[0255] R.sub.5 is selected from the group consisting of hydrogen, optionally substituted alkyl and optionally substituted heteroaryl.

[0256] Preferred definitions which were given with respect to the compounds of formula (Id) apply here.

[0257] A preferred compound of formula (Ie) is

##STR00117##

[0258] Any combination of the embodiments, preferred embodiments and more preferred embodiments disclosed herein is also envisaged in the present invention.

[0259] The present invention relates further to a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie) and optionally at least one pharmaceutically acceptable excipient, carrier, diluent and/or adjuvant.

[0260] In one embodiment, the pharmaceutical composition comprises a compound of formula (Id) and optionally at least one pharmaceutically acceptable excipient, carrier, diluent and/or adjuvant.

[0261] In a further embodiment, the pharmaceutical composition comprises a compound of formula (Ie) and optionally at least one pharmaceutically acceptable excipient, carrier, diluent and/or adjuvant.

[0262] Embodiments as defined above for the compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (Ie) apply here as well and can be combined with each other.

[0263] The present invention relates to a method for treating, alleviating or preventing a disease, disorder or abnormality comprising the step of administering a therapeutically effective amount of a compound of formula (I), in particular (Ic), (Id) or (Ie) as defined in herein, or a pharmaceutical composition thereof, to a patient in need thereof.

[0264] The present invention relates to a compound of formula (I), in particular (Ic)(Id) or (Ie) as defined herein, for use as a medicament.

[0265] The present invention relates to compounds of formula (I), in particular (Ic)(Id) or (Ie) as defined herein, for use in the treatment, alleviation or prevention of a disease, disorder or abnormality responsive to the modulation or inhibition of a component of the inflammasome pathway and/or for use in the modulation, in particular decrease, of IL-1 beta and/or IL-18 levels.

[0266] The present invention relates to a method for treating, alleviating or preventing of a disease, disorder or abnormality responsive to the modulation or inhibition of a component of the inflammasome pathway and/or for modulating, in particular decreasing, the IL-1 beta and/or IL-18 levels by administering a therapeutically effective amount of a compound of formula (I), in particular (Ic), (Id) or (Ie) as defined herein, to a patient in need thereof.

[0267] In one embodiment, the present invention relates to a method for treating, preventing or alleviating a disease, disorder or abnormality responsive to the modulation or inhibition of a component of the inflammasome pathway by administering a therapeutically effective amount of a compound of formula (I), in particular (Ic), (Id) or (Ie) as defined herein, to a patient in need thereof.

[0268] Preferably, the disease, disorder or the abnormality is responsive to the modulation of a component of the inflammasome pathway, in particular to the inhibition of the activation of a component of the inflammasome pathway. Preferably, the component of the inflammasome pathway is NLRP3 inflammasome.

[0269] In one embodiment, the present invention relates to the use or the 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.

[0270] In other word, the invention is directed 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 by administering a therapeutically effective amount of a compound of formula (I), in particular (Ic), (Id) or (Ie) as defined herein, to a patient in need thereof.

[0271] More preferably, the disease, disorder or the abnormality is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), neonatal-onset multisystem inflammatory disease (NOMID), gout, pseudo-gout, inflammatory bowel disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinaemia D, periodic fever syndrome (HIDS), deficiency of interleukin 1 receptor (DIRA) antagonist, Majeed syndrome, pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA), haploinsufficiency of A20 (HA20), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers, developmental delay (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic recurrent multifocal osteomyelitis (CRMO), synovitis, pustulosis, acne, hyperostosis, osteitis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behcet's disease, Sjogren's syndrome, Schnitzler syndrome, chronic obstructive pulmonary disorder (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis, dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin contact hypersensitivity, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, Chikungunya virus, Ross River virus, influenza, HIV, Coronaviruses, Dengue virus, Zika virus, hidradenitis suppurativa (HS), lung cancer metastasis, pancreatic cancers, gastric cancers, myelodysplastic syndrome, leukemia; polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurism, wound healing, depression, psychological stress, pericarditis including Dressler's syndrome, ischaemia reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorder, Coronavirus-associated inflammatory pathologies, and traumatic brain injury.

[0272] Preferably the disease, disorder or the abnormality is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma, allergic inflammation, cryopyrin-associated periodic syndromes (CAPS), gout, inflammatory bowel disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), lupus nephritis, anti-glomerular basement membrane (GMB) disease, IgA nephropathy, glomerulonephritis (GN), systemic lupus erythematosus (SLE), Focal Segmental Glomerulosclerosis, Minimal change disease (MCD), Psoriatic Arthritis, and Hereditary Recurrent Fevers (HRFs).

[0273] Preferably, the disease, disorder or the abnormality is 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, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis (NASH), hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, type 1 and type 2 diabetes, rheumatoid arthritis, and myelodysplastic syndrome.

[0274] More preferably, the disease, disorder or the abnormality is selected from Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic syndromes (CAPS), nonalcoholic fatty liver disease, NASH, rheumatoid arthritis and gout.

[0275] Even more preferably, the disease, disorder or the abnormality is selected from Alzheimer's disease, Parkinson's disease, cryopyrin-associated periodic syndromes (CAPS), rheumatoid arthritis and gout.

[0276] In one embodiment, the present invention relates to compounds of formula (I), in particular (Ic), (Id) or (Ie) as defined herein, for use in the treatment, alleviation or prevention of a tauopathy by modulating a component of the inflammasome pathway, in particular, by modulating NLRP3 inflammasome.

[0277] In one embodiment, the present invention relates to compounds of formula (I), in particular (Ic), (Id) or (Ie) as defined herein, for use in the treatment, alleviation or prevention of a IL-18 and/or IL-1 beta related disease or abnormality by modulating a component of the inflammasome pathway, in particular, by modulating NLRP3 inflammasome. The IL-18 and/or IL-1 beta levels in a subject are typically decreased in result of the administration of compounds of formula (I), in particular (Ic), (Id) or (Ie) as defined herein.

[0278] IL-18 and/or IL-1 beta related diseases and abnormalities can be selected from chronic obstructive pulmonary disease (COPD), transfusion-related lung injury, bronchopulmonary dysplasia (BPD), acute respiratory distress syndrome (ARDS), pediatric autoinflammatory disease or condition, Still's disease, particularly Adult Still's disease or juvenile Still's disease, juvenile rheumatoid arthritis (JRA), juvenile idiopathic arthritis (JIA), systemic juvenile onset idiopathic arthritis (SoJIA), systemic juvenile idiopathic arthritis (sJIA), interstitial lung disease (ILD), macrophage activation syndrome (MAS) including primary, secondary and recurrent MAS, hemophagocytic lymphohistiocytosis (HLH), Familial (hereditary) hemophagocytic lymphohistiocytosis (FHLH) associated with gene defects in perforin, munc 13-4 and 18-2, synthaxin 11, immune deficiencies such as Chediak-Higashi syndrome (CHS), Griscelli syndrome (GS), X-linked lymphoproliferative syndrome (XLP2), X-linked inhibitor of apoptosis protein deficiency (XIAP), acquired hemophagocytic lymphohistiocytosis associated with infectious conditions especially Herpes virus such as EBV and other pathogens, autoinflammatory syndrome associated with NLRC4 mutations, Giant Cell Arteritis (GCA), Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA), pulmonary saroidis, heart failure, ischemic heart disease, dry eye disease (DED), keratitis, corneal ulcer and abrasion, iritis, glaucoma, Sjogren's syndrome, autoimmune uveitis, Behcet's disease, conjunctivitis, allergic conjunctivitis, diabetes type 2, solid organ and hematologic stem cell transplantation, ischemia reperfusion injury, familial Mediterranean fever (FMF), tumor necrosis factor receptor 1-associated periodic syndromes (TRAPS), hyper-IgD syndromes (mevalonate kinase gene mutation), gout, Schnitzler syndrome, Wegener's granulomatosis also called granulomatosis with polyangiitis (GPA), Hashimoto's thyroiditis, Crohn's disease, early onset inflammatory bowel disease (EOIBD), very EOIBD (VEOIBD), infantile IBD, neonatal IBD, ulcerative colitis and Blau syndrome (NOD-2 mutation).

[0279] The modulation of NLRP3 inflammasome appears to be beneficial in diseases, disorders and abnormalities with altered IL-18 levels, which lead to pathological inflammation.

[0280] Embodiments as defined above for the compounds of formula (I) such as (Ia), (Ib), (Ic), (Id) or (Ie) apply here as well and can be combined with each other.

[0281] The present invention relates to the compound of formula (I), in particular (Ic), (Id) or (Ie) as defined herein, that is a modulator of NLRP3 inflammasome activity and/or a modulator of IL-18 and/or IL-1b levels in subject.

[0282] The present invention relates to a pharmaceutical composition comprising a combination of a compound of formula (I), in particular (Ic), (Id) or (Ie) as defined herein, and at least one further biologically active compound differing from the compound of formula (I), in particular (Ic), (Id) or (Ie), and optionally at least one selected from pharmaceutically acceptable excipients, carriers, diluents or adjuvants.

[0283] In particular, the further biologically active compound can be one used for the treatment of a disease, disorder or abnormality which targets a different pathomechanism, e.g. an anti-amyloid beta antibody, anti-Tau antibody, amyloid beta small molecule inhibitor, Tau aggregation small molecule inhibitor, anti-alpha synuclein antibody or alpha-synuclein aggregation small molecule inhibitor, anti-TDP-43 antibody or anti-TDP-43 aggregation small molecule inhibitor among others. When a compound of the invention is used in combination with a further biologically active compound, the dose of each compound may differ from the dose if the compound were to be used as a monotherapy.

[0284] The present invention relates to the use of a compound of formula (I), in particular (Ic), (Id) or (Ie), 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 and for testing of compounds targeting the NLRP3 inflammasome.

[0285] The present invention relates to a method for obtaining a compound of formula (I), in particular (Ic), (Id) or (Ie). In a further embodiment, the method is preferably suited for obtaining a compound of formula (Id) or (Ie).

[0286] In one embodiment, the method comprises the step of isocyanate derivative coupling reaction of a compound of formula (IId) for producing a compound of formula (Ic) or (Id) in the presence of a solvent and a base

##STR00118##

[0287] wherein A, R.sub.2 and R.sub.1 are as defined above.

[0288] The coupling reaction is conducted using a suitable solvent under strong basic conditions. The base is preferably NaH, triethylamine or pyridine. The solvent is preferably THF, DCM or CHCl.sub.3.

[0289] The coupling is preferably conducted at room temperature (rt).

[0290] Preferably the method comprises the step of isocyanate derivative coupling reaction of a compound of formula (IId) for producing a compound of formula (Id) in the presence of a solvent and a base

[0291] In one embodiment, the method comprises the step of isocyanate derivative coupling reaction of a compound of formula (IIe) for producing a compound of formula (Ie) in the presence of a solvent and a base

##STR00119##

[0292] wherein A, R.sub.2 and R.sub.1 are as defined above.

[0293] The coupling reaction is conducted using a suitable solvent under strong basic conditions. The base is preferably NaH, triethylamine or pyridine. The solvent is preferably THF, DCM or CHCl.sub.3. The coupling is preferably conducted at room temperature (rt).

[0294] The present invention further relates to compounds of formula (IId) and (Ile) as defined below

##STR00120##

wherein A, and R.sub.1 are as defined above.

[0295] Any combination of the embodiments, preferred embodiments and more preferred embodiments disclosed herein is also envisaged in the present invention.

[0296] Pharmaceutical Compositions

[0297] While it is possible for the compounds of the present invention to be administered alone, it is preferable to formulate them into a pharmaceutical composition in accordance with standard pharmaceutical practice. Thus, the invention also provides a pharmaceutical composition which comprises a therapeutically effective amount of a compound of formula (I) optionally in admixture with a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0298] Pharmaceutically acceptable carriers, diluents, adjuvants and excipients are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, 15.sup.th or 18.sup.th Ed. (Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, Pa., 1990); Remington: the Science and Practice of Pharmacy 19.sup.th Ed. (Lippincott, Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3rd Ed. (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc, 1999); Pharmaceutical Codex: Principles and Practice of Pharmaceutics 12th Ed. (Walter Lund ed.; Pharmaceutical Press, London, 1994); The United States Pharmacopeia: The National Formulary (United States Pharmacopeial Convention); Fiedler's “Lexikon der Hilfstoffe” 5.sup.th Ed., Edition Cantor Verlag Aulendorf 2002; “The Handbook of Pharmaceutical Excipients”, 4th Ed., American Pharmaceuticals Association, 2003; and Goodman and Gilman's: the Pharmacological Basis of Therapeutics (Louis S. Goodman and Lee E. Limbird, eds.; McGraw Hill, 1992), the disclosures of which are hereby incorporated by reference.

[0299] 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.

[0300] 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), pregelatinzed 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 (croscarmellose sodium, e.g. Ac-Di-Son, carboxymethyl starch-Na (sodium starch glycolate)(e.g., Primojel® or Explotab®), preferably crosslinked PVP and/or croscarmellose sodium), glidants (such as colloidal SiO.sub.2 (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, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidone, low melting waxes, and ion exchange resins.

[0301] 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 maltodextrine and dextranes; 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; cylodextrines and inorganic agents such as dicalcium phosphate, calcium hydrogen phosphate; hydroxyapatite, tricalcium phosphate, talcum and silica. Microcrystalline cellulose, sucrose and/or lactose are preferred as carriers. Combinations thereof can also be employed. Carriers can include also protein and cell penetrating peptides which should be selected depending on the route of administration and target.

[0302] 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.

[0303] 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.

[0304] The routes for administration (delivery) of the compounds of the invention include, but are not limited to, one or more of: oral (e. g. as a tablet, capsule, or as an ingestible solution), topical, mucosal (e. g. as a nasal spray or aerosol for inhalation), nasal, parenteral (e. g. by an injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, epidural and sublingual.

[0305] For example, the compounds can be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.

[0306] 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, gelatin 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 gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar e.g. lactose or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the agent may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

[0307] If 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. For parenteral administration, the compounds can be used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0308] As indicated, the compounds of the present invention can be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurized container, pump, spray or nebulizer with the use of a suitable propellant, e. g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA134AT) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container, pump, spray or nebulizer may contain a solution or suspension of the active compound, e. g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e. g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) 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.

[0309] Alternatively, 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 may also be dermally or transdermally administered, for example, by the use of a skin patch.

[0310] They may also be administered by the pulmonary or rectal routes. They may also be administered by the ocular route. For ophthalmic use, the compounds can be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.

[0311] For application topically to the skin, the compounds of the present invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0312] Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.

[0313] A proposed dose of the compounds according to the present invention for administration to a human (of approximately 70 kg body weight) is 0.1 mg to 1 g, preferably 1 mg to 500 mg of the active ingredient per unit dose. The unit dose may be administered, for example, 1 to 4 times per day. The dose will depend on the route of administration. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient as well as the severity of the condition to be treated. The precise dose and route of administration will ultimately be at the discretion of the attendant physician or veterinarian.

[0314] The claimed compound can be used for the treatment, alleviation or prevention of the recited diseases, disorders or abnormality alone or in combination with one or more further biologically active compounds. In particular the further biologically active compound can be one used for the treatment of diseases, disorders or abnormalities which target a different pathomechanism, e.g. an anti-amyloid beta antibody and/or anti-Tau antibody or Tau aggregation small molecule inhibitor in Alzheimer's disease, anti-alpha synuclein antibody or alpha-synuclein aggregation small molecule inhibitor, anti-TDP-43 antibody or anti-TDP-43 aggregation small molecule inhibitor among others. When a compound of the invention is used in combination with a further biologically active compound against the same diseases, disorders or abnormality, the dose of each compound may differ from that when the compound were to be used alone.

[0315] The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route. When administration is sequential, either the compound of the invention or the further biologically active compound may be administered first. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition. When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.

[0316] The pharmaceutical compositions of the invention can be produced in a manner known per se to the skilled person as described, for example, in Remington's Pharmaceutical Sciences, 15.sup.th Ed., Mack Publishing Co., New Jersey (1975).

[0317] Examples of the diseases, disorders or abnormalities which can be treated, alleviated or prevented include, but are not limited, to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma and allergic inflammation, cryopyrin-associated periodic syndromes (CAPS)(Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) and 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 and type 2 diabetes, rheumatoid arthritis, myelodysplastic syndrome, familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS), deficiency of interleukin 1 receptor (DIRA) antagonist, Majeed syndrome, pyogenic arthritis, pyoderma gangrenosum and acne (PAPA), haploinsufficiency of A20 (HA20), PLCG2-associated antibody deficiency and immune dysregulation (PLAID), pediatric granulomatous arthritis (PGA), PLCG2-associated autoinflammation, antibody deficiency and immune dysregulation (APLAID), sideroblastic anemia with B-cell immunodeficiency, periodic fevers, developmental delay (SIFD), chronic nonbacterial osteomyelitis (CNO), Sweet's syndrome, chronic recurrent multifocal osteomyelitis (CRMO) and synovitis, pustulosis, acne, hyperostosis, osteitis syndrome (SAPHO), multiple sclerosis (MS), psoriasis, Behcet's disease, Sjogren's syndrome and Schnitzler syndrome, chronic obstructive pulmonary disorder (COPD), steroid-resistant asthma, asbestosis, silicosis, cystic fibrosis, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, obesity, age-related macular degeneration (AMD), corneal infection, uveitis and dry eye, chronic kidney disease, diabetic nephropathy, alcoholic liver disease, skin contact hypersensitivity, sunburn, osteoarthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, relapsing polychondritis, Chikungunya and Ross River viruses, flu, HIV, Dengue virus, Zika viruses, hidradenitis suppurativa (HS), lung cancer metastasis, pancreatic cancers, gastric cancers, myelodysplastic syndrome, leukemia; polymyositis, colitis, helminth infection, bacterial infection, abdominal aortic aneurism, wound healing, depression, psychological stress, pericarditis including Dressler's syndrome, ischaemia reperfusion injury, frontotemporal dementia, HIV-associated neurocognitive disorder, and traumatic brain injury; preferably the disease, disorder or abnormality is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, demyelination, viral encephalitis, epilepsy, stroke, atherosclerosis, asthma and allergic inflammation, CAPS, gout, inflammatory bowel disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, hypertension, myocardial infarction, oxalate-induced nephropathy, graft-versus host disease, type 1 and type 2 diabetes, rheumatoid arthritis, and myelodysplastic syndrome.

[0318] 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 and for testing of compounds targeting the NLRP3 inflammasome.

[0319] The compounds according to the present invention can also be provided in the form of a mixture with at least one further biologically active compound and/or a pharmaceutically acceptable carrier and/or a diluent and/or an excipient and/or adjuvant. The compound and/or the further biologically active compound are preferably present in a therapeutically effective amount.

[0320] 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.

[0321] The invention also includes all suitable isotopic variations of the compounds of the invention. An isotopic variation of the compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N, .sup.17O, .sup.18O, .sup.35S, .sup.18F and .sup.36Cl, respectively. Certain isotopic variations of the invention, for example, those in which a radioactive isotope such as .sup.3H or .sup.14C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., .sup.3H, and carbon-14, i.e., .sup.14C, isotopes are particularly preferred for their ease of preparation and delectability. .sup.18F-labeled compounds are particularly suitable for imaging applications such as PET. Further, substitution with isotopes such as deuterium, i.e., .sup.2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples and Preparations hereafter using appropriate isotopic variations of suitable reagents.

[0322] 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 to be construed as limiting.

[0323] General Synthetic Schemes for the Preparation of Illustrative Compounds of this Invention:

##STR00121##

[0324] From commercially available chlorosulfonyl derivatives, sulfonamide can be synthetized using ammonia and an appropriate solvent. Appropriate (e.g., TBDMS, TBDPS) protection of the sulfonamide moiety can be achieved in a suitable solvent under basic conditions. A generic chlorinating agent can be used (e.g., Ph.sub.3PCl.sub.2, PCl.sub.5, SOCl.sub.2) followed by ammonia treatment. The derivative can undergo a deprotection step without isolation followed by intramolecular ring-closure (one-pot procedure) to afford a benzo[d]isothiazol-3-one 1-oxide derivative. Treatment with an appropriate isocyanate using a suitable solvent under strongly basic conditions can afford the desired urea derivative as a racemic mixture after purification. The enantiomers can be separated by chiral supercritical fluid chromatography (SFC) to obtain the desired single enantiomers, if desired.

##STR00122##

[0325] From commercially available chlorosulfonyl derivatives, sulfonamide can be synthetized using ammonia and an appropriate solvent. Appropriate (e.g., TBDMS, TBDPS) protection of the sulfonamide moiety can be achieved in a suitable solvent under basic conditions. A generic chlorinating agent can be used (e.g., Ph.sub.3PCl.sub.2, PCl.sub.5, SOCl.sub.2) followed by amine treatment. The derivatives can underdo a deprotection step without isolation followed by intramolecular ring-closure (one-pot procedure) to afford protected a benzo[d]isothiazol-3-one 1-oxide derivative. Deprotection in acid conditions using an appropriate solvent followed by treatment with an appropriate isocyanate using a suitable solvent under strong basic conditions can afford the desired urea derivative as a racemic mixture after purification. The enantiomers can be separated by chiral supercritical fluid chromatography (SFC) to obtain the desired single enantiomers, if desired.

PREPARATIVE EXAMPLES

Preparative Example 1

[0326] ##STR00123##

[0327] A solution of methyl 3-(chlorosulfonyl)thiophene-2-carboxylate (5.0 g, 20.77 mmol) in THF (500 mL) was cooled to −20° C. and ammonia gas was purged slowly through the solution for 30 min. Then the reaction mixture was allowed to stir at room temperature for 30 min. After the completion of the reaction, solid was removed. The reaction mixture was filtered through a Buchner funnel and the filtrate was concentrated under reduced pressure to obtain a crude product. Then the crude product was triturated with diethyl ether (2×20 ml), the resulting solid was filtered through a Buchner funnel and dried to afford methyl 3-sulfamoylthiophene-2-carboxylate (1.8 g, 39%) as a colorless crystalline solid.

[0328] MS: 220.1 [(M−H)].sup.−

Preparative Examples 2 to 14

[0329] Following the procedure of Preparative Example 1 using appropriate reagents indicated in the table below, the following compounds were prepared.

TABLE-US-00002 TABLE 1 1. Yield Product 2. .sup.1H-NMR Starting Material Preparative Example 3. MH.sup.+ (ESI) [00124] [00125] 2 1. 98% 2. .sup.1H NMR (400 MHz, DMSO-d6) δ = 8.79 (dd, 1H), 8.35 (dd, 1H), 7.81-7.78 (m, 1H), 3.86 (s, 3H). 3. 217.1 [00126] [00127] 3 1. 85% 2. .sup.1H NMR (400 MHz, CDCl3) δ = 8.76 (d, 1H), 8.29 (dd, 1H), 7.90 (d, 1H), 5.69 (s, 2H), 4.02 (s, 3H), 3.98 (s, 3H). 3. 272.2 [00128] [00129] 4 1. 71% 2. .sup.1H NMR (400 MHz, DMSO-d6) δ = 8.24- 8.21 (m, 2H), 8.11 (d, 1H), 7.68 (brs, 2H), 3.85(s. 3H). 3. 239.2 [00130] [00131] 5 1. 94% 2. .sup.1H NMR (400 MHz, DMSO-d6) δ = 7.96 (d, 1H), 7.84-7.81 (m, 1H), 7.77 (m, 1H), 7.38 (brs, 2H), 3.83 (s, 3H). 3. 248.2 [00132] [00133] 6 1. 91% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 7.78 (d, 1H), 7.57-7.52 (m, 2H), 7.32 (brs, 2H), 3.81 (s, 3H), 2.27 (s, 3H). 3. ND [00134] [00135] 7 1. 92% 2. .sup.1H NMR (400 MHz, CDCl3) δ = 7.91 (d, 1H), 7.71 (d, 1H), 7.06 (dd, 1H), 5.86 (s, 2H), 3.95 (s, 3H), 3.91 (s, 3H). 3. 244.3 [00136] [00137] 8 1. 94% 2. .sup.1H NMR (400 MHz, DMS0-d6) δ = 7.88 (d, 1H), 7.25-7.22 (m, 1H), 7.16-7.14 (m, 3H), 3.85 (s. 3H), 3.82 (s, 3H). 3. 246.2 [00138] [00139] 9 1. 97% 2. .sup.1H NMR (400 MHz, DMS0-d6) δ = 7.97 (dd, 1H), 7.89 (s, 1H), 7.88 (d, 1H), 7.30 (brs, 2H), 3.83 (s, 3H). 3. 292.2 [00140] [00141] 10 1. 91% 2. .sup.1H NMR (400 MHz, DMS0-d6) δ = 7.82 (m, 1H), 7.80-7.73 (m, 1H), 7.64-7.59 (m, 3H), 3.84 (s, 3H). 3. 232.1 [00142] [00143] 11 1. 92% 2. ND 3. 235.3 [00144] [00145] 12 1. 96% 2. .sup.1H NMR (400 MHz, DMS0-d6) δ = 8.29 (s, 1H), 8.11(d, 1H), 7.89 (dd, 1H), 7.34 (brs, 2H), 3.86 (s, 3H). 3. 267.2 [00146] [00147] 13 1. 91% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 7.79- 7.75 (m, 2H), 7.60-7.56 (m, 1H), 7.32 (brs, 2H) 3.83 (s, 3H). 3. 232.1 [00148] [00149] 14 1. 95% 2. .sup.1H NMR (500 MHz, CDCl3) δ = 8.38 (dd, 1H), 7.96 (d, 1 H), 7.83 (s, 2H), 3.87 (s, 3H) 3. 251.2

Preparative Example 15

[0330] ##STR00150##

[0331] A solution of methyl 2-sulfamoylnicotinate (0.5 g, 2.31 mmol) in DCM (20 mL) was cooled to 0° C. and triethylamine (0.97 mL, 6.9444 mmol) was added, followed by TBDMSCI (0.418 g, 2.77 mmol). The reaction mixture was stirred at RT for 16 h. After completion of the reaction, the reaction mixture was diluted with water and extracted with DCM (2×50 mL). The organic phase was separated, washed with water (50 ml), followed by saturated brine solution (50 ml), dried over Na.sub.2SO.sub.4 and subsequently filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash chromatography (neutral alumina; 0 to 50% ethyl acetate in petroleum ether). The pure fractions were collected and concentrated under vacuum to afford the title methyl 2-(N-(tert-butyldimethylsilyl)sulfamoyl)-nicotinate (0.48 g, 63%) as an off-white solid.

[0332] MS: 331.27 (M+H).sup.+.

Preparative Examples 16 to 34

[0333] Following the procedure of Preparative Example 15 using appropriate reagents indicated in the table below, the following compounds were prepared.

TABLE-US-00003 TABLE 2 1. Yield Product 2. .sup.1H-NMR Starting Material Preparative Example 3. MH.sup.+ (ESI) [00151] [00152] 16 1. 70% 2. .sup.1H NMR (400 MHz, CDCl3) δ = 12.0 (bs, 2H), 8.11 (dd, 1H), 7.63 (m, 2H), 7.54 (m, 1H), 4.99 (s, 2H), 4.01 (s, 3H), 0.92 (s, 9H), 0.2 (s, 6H). 3. 344.2 [00153] [00154] 17 1. 91% 2. .sup.1H NMR (400 MHz, CDCl3) δ = 7.56-7.53 (d, 1H), 7.50-7.49 (d, 1H), 6.31 (brs, 1H), 3.96 (s, 3H), 0.88 (s, 9H), 0.17 (s, 6H). 3. 334.3 [00155] [00156] 18 1. 87% 2. ND 3. 331.2 [00157] [00158] 19 1. 90% 2. ND 3. 331.2 [00159] [00160] 20 1. 79% 2. .sup.1H NMR (500 MHz, CDCl3) δ = 8.69 (d, 1H), 8.23 (dd, 1H), 7.87 (d, 1H), 6.04 (s, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 0.9(m, 9H), 0.24(s, 6H). 3. 386.4 [00161] [00162] 21 1. used crude without further purification 2. .sup.1H NMR (400 MHz, CDCl3) δ = 8.21 (d, 1H), 8.12 (d, 1H), 7.91 (dd, 1H), 6.14 (brs, 1H), 0.,88 (s, 9H), 1.23 (s, 6H). 3. ND [00163] [00164] 22 1. 96% 2. .sup.1H NMR (400 MHz, CDCl3) δ = 7.86 (dd, 1H), 7.58 (dd, 1H), 7.47 (dd, 1H), 5.06 (s, 1H), 4.02 (s, 3H), 0.89 (s, 9H), 0.21 (s, 6H). 3. 362.4 [00165] [00166] 23 1. used crude without further purification 2. ND 3. 362.4 [00167] [00168] 24 1. 69% 2. ND 3. 363.9 [00169] [00170] 25 1. 79% 2. .sup.1H NMR (400 MHz, DMSO-d6) δ = 7.77 (d, 1H), 7.58-7.53 (m, 2H), 7.51-7.49 (brs, 1H), 3.81 (s, 3H), 2.26 (s, 3H), 0.86 (s, 9H), 0.06 (s, 6H). 3. 342.4 [00171] [00172] 26 1. used crude 2. ND 3. 360.4 [00173] [00174] 27 1. used crude 2. .sup.1H NMR (500 MHz, CDCl3) δ = 8.00 (d, 1H), 7.32-7.27 (m, 1H), 7.05-7.03 (m, 1H), 6.04 (s, 1H), 3.98 (s, 3H), 3.90 (s, 3H), 0.91 (s, 9H), 0.21 (s, 6H). 3. 360.2 [00175] [00176] 28 1. used crude 2. .sup.1H NMR (400 MHz, CDCl3) δ = 7.96-7.94 (m, 2H), 7.75 (dd, 1H), 6.10 (s, 1H), 3.99 (s, 3H), 0.9 (s, 9H), 0.22 (s, 6H). 3. 406.1 [00177] [00178] 29 1. 72% 2. ND 3. 406.3 [00179] [00180] 30 1. used crude 2. ND 3. 346.4 [00181] [00182] 31 1. used crude 2. ND 3. 346.3 [00183] [00184] 32 1. 85% 2. .sup.1H NMR (400 MHz, CDCl3) δ = 8.35 (s, 1H), 7.92 (d, 1H), 7.84 (dd, 1H), 3.98 (s, 3H), 0.87 (s, 9H), 0.05 (s, 6H). 3. ND [00185] [00186] 33 1. 85% 2. ND 3. 346.2 [00187] [00188] 34 1. 86% 2. ND 3. [-TBDMS] 249.0

Preparative Example 35

[0334] ##STR00189##

[0335] To a suspension of Ph.sub.3PCl.sub.2 (0.581 g, 1.74 mmol) in CHCl.sub.3 (15 mL) was added triethylamine (0.61 mL, 4.36 mmol) and the mixture was stirred for 10 min at RT. Then the reaction mixture was cooled to 0° C., a solution of Preparative Example 19 (0.480 g, 1.4545 mmol) in CHCl.sub.3 was slowly added and the mixture was stirred for 20 min. Then the reaction mixture was cooled to −20° C. and ammonia gas was purged for 5 min. The mixture was warmed for 30 min at 0° C. After 30 min, a suspension was formed and the solid was removed by filtration. The filtrate was evaporated under reduced pressure to afford crude methyl 2-(N′-(tert-butyldimethylsilyl)-sulfamidimidoyl)nicotinate as an off-white solid (0.470 g crude). Although the compound was contaminated with PPh.sub.3O it was directly taken to the next step without further purification.

Preparative Examples 36 to 54

[0336] Following the procedure of Preparative Example 35 using appropriate reagents indicated in the table below, the following compounds were prepared.

TABLE-US-00004 TABLE 3 Product 1. Yield Starting Material Preparative Example 2. MH.sup.+ (ESI) [00190] [00191] 36 1. crude used to the next step 2. 343.2 [00192] [00193] 37 1. 20% 2. 335.3 [00194] [00195] 38 1. crude used to the next step 2. ND [00196] [00197] 39 1. crude used to the next step 2. 330.2 [00198] [00199] 40 1. crude used to the next step 2. 387.4 [00200] [00201] 41 1. crude used to the next step 2. ND [00202] [00203] 42 1. crude used to the next step 2. 363.3 [00204] [00205] 43 1. crude used to the next step 2. ND [00206] [00207] 44 1. crude used to the next step 2. ND [00208] [00209] 45 1. crude used to the next step 2. ND [00210] [00211] 46 1. crude used to the next step 2. 359.2 [00212] [00213] 47 1. crude used to the next step 2. ND [00214] [00215] 48 1. crude used to the next step 2. 407.4 [00216] [00217] 49 1. crude used to the next step 2. ND [00218] [00219] 50 1. crude used to the next step 2. ND [00220] [00221] 51 1. crude used to the next step 2. 347.3 [00222] [00223] 52 1. crude used to the next step 2. ND [00224] [00225] 53 1. crude used to the next step 2. ND [00226] [00227] 54 1. crude used to the next step 2. 364.2

Preparative Example 55

[0337] ##STR00228##

[0338] To a stirred solution of Preparative Example 37 (1.4 g, 4.18 mmol) in MeOH (15 mL) was added 2N NaOH solution (10.45 ml, 20.92 mmol) dropwise at 0° C. and the mixture was stirred at RT for 1 h. After completion of the reaction, the reaction mixture was diluted with brine solution (25 ml) and extracted with ethyl acetate (2×100 ml). The organic layer was separated and dried over Na.sub.2SO.sub.4, filtered and evaporated to afford 1-((tert-butyldimethylsilyl)amino)-3H-1,4-thieno[2,3-d]isothiazol-3-one 1-oxide (900 mg, crude) as an off-white foam solid. The crude compound was used to the next step without further purification

[0339] MS: 189.16 [(M−TBDMS)].sup.+

Preparative Example 56

[0340] ##STR00229##

[0341] To a stirred solution of Preparative Example 55 (0.9 g, 2.97 mmol) in 1,4-dioxane (15 mL) was added 4M HCl in 1,4-dioxane (2.97 ml, 11.90 mmol) dropwise at 0° C. and the mixture was stirred for 25 min. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to obtain a crude compound. The crude compound was purified by Grace automated purification (silica 24 g column, eluted with gradient mixture of MeOH in DCM (1 to 10%)). Collected pure fractions were concentrated under reduced pressure to afford 1-((tert-butyldimethylsilyl)amino)-3H-1,4-thieno[2,3-d]isothiazol-3-one 1-oxide (380 mg, 68% over two steps) as an off-white crystalline solid.

[0342] .sup.1H NMR (400 MHz, DMSO-d6) δ=8.24 (s, 2H), 8.14 (d, 1H), 7.41 (d, 1H).

[0343] MS: 189.1 [(M+H)].sup.+

Preparative Example 57

[0344] ##STR00230##

[0345] To a stirred solution of Preparative Example 40 (350 mg, 0.9 mmol) in 1,4-dioxane (5 mL) was added dropwise a solution of 1M HCl in dioxane (0.5 ml) at 0° C. and the mixture was allowed to stir at RT for 1 h. After completion of the reaction, the reaction mixture was evaporated under reduced pressure and the residue was purified by Grace automated purification (silica 12 g column, eluted with gradient mixture of MeOH in DCM (1 to 10%)). Collected pure fractions were concentrated under reduced pressure to afford methyl 1-amino-3-oxo-3H-1,4-benzo[d]isothiazole-6-carboxylate 1-oxide (60 mg, 40% overall two steps) as a yellow solid. 1H-NMR, (400 MHz, DMSO-d6) δ=8.43 (d, 1H), 8.36-8.38 (dd, 1H), 8.25 (s, 2H), 7.96 (d, 1H), 3.94 (s, 3H).

[0346] MS: 239.06 [(M−H)]+

Preparative Examples 58 and 59

[0347] Following the procedure of Preparative Example 57 using appropriate reagents indicated in the table below, the following compounds were prepared.

TABLE-US-00005 TABLE 4 1. Yield Product 2. .sup.1H-NMR Starting Material Preparative Example 3. MH.sup.+ (ESI) [00231] [00232] 58 1. 70% 2. .sup.1H NMR (400 MHz, DMSO- d6) δ = 8.20 (s, 2H), 7.90-7.93 (dd, 1H), 7.82-7.87 (m, 2H). 3. 217.2 [00233] [00234] 59 1. 86% 2. .sup.1H NMR (400 MHz, DMSO- d6) δ = 8.01-7.98 (m, 1H), 7.83 (brs, 2H), 7.71-7.62 (m, 2H). 3. 201.1

Preparative Example 60

[0348] ##STR00235##

[0349] To a stirred solution of Preparative Example 35 (0.47 g crude) in methanol (5 mL) was added NH.sub.4OH solution (8 mL) slowly at rt and the mixture was heated to reflux for 3 h. After the completion of the reaction, solvent was evaporated under reduced pressure to obtain a crude product. The crude product was purified by Grace automated purifier (SiO.sub.2, 12 g column; 0 to 5% methanol in DCM). Pure fractions were collected and concentrated under reduced pressure to afford 1-amino-3H-1,4-isothiazolo[5,4-b]pyridin-3-one 1-oxide (0.15 g, 57%).

[0350] MS: 184.18 (M+H).sup.+.

Preparative Examples 61 to 75

[0351] Following the procedure of Preparative Example 60 using appropriate reagents indicated in the table below, the following compounds were prepared.

TABLE-US-00006 TABLE 5 1. Yield Product 2. .sup.1H-NMR Starting Material Preparative Example 3. MH.sup.+ (ESI) [00236] [00237] 61 1. 35% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 7.96 (dd, 1H), 7.59-4.45 (m, 6H), 4.79 (d, H),4.65 (d, 1H). 3. 197.1 [00238] [00239] 62 1. 5% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 9.05 (s, 1H), 8.88 (d, 1H), 7.69 (d, 1H). 3. 184.2 [00240] [00241] 63 1. 60% 2. .sup.1H NMR (400 MHz, DMSO-d6) δ = 8.71 (dd, 1H), 8.18 (dd, 1H), 7.53 (dd, 1H), 6.39 (brs, 2H). 3. 184.4 [00242] [00243] 64 1. 44% 2. ND 3. 208.8 [00244] [00245] 65 1. used crude 2. ND 3. 217.2 [00246] [00247] 66 1. 50% 2. ND 3. 217.2 [00248] [00249] 67 1. used crude 2. ND 3. +H20 197.3 [00250] [00251] 68 1. 23% 2. ND 3. 213.1 [00252] [00253] 69 1. used crude 2. ND 3. 213.3 [00254] [00255] 70 1. used crude 2. ND 3. 261.0 [00256] [00257] 71 1. used crude 2. ND 3. 261.1 [00258] [00259] 72 1. used crude 2. ND 3. ND [00260] [00261] 73 1. used crude 2. ND 3. ND [00262] [00263] 74 1. used crude 2. ND 3. 201.1 [00264] [00265] 75 1. 68% 2. ND 3. 218.1

EXAMPLES

[0352] All reagents and solvents were obtained from commercial sources and used without further purification. .sup.1H-NMR spectra were recorded on Bruker 400 MHz-AVANCE III HD NMR and Bruker 500 MHz-AVANCE III HD NMR spectrometers in deuterated solvents. Chemical shifts (δ) are reported in parts per million and coupling constants (J values) in hertz. Spin multiplicities are indicated by the following symbols: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), bs (broad singlet). Mass spectra were obtained on a Water ACQUITY SQD2 UPLC/MS system. GC-MS data were collected using an Agilent 7890B gas chromatograph and 5977A mass spectrometer. Chromatography was performed using silica gel (Acme: Silica gel 60, 0.063-0.2 mm) and suitable solvents as indicated in the specific examples. Flash purification was conducted with a Biotage Isolera one or Reveleris X.sub.2 with KP—NH SNAP cartridges (Biotage) or Reveleris silica cartridges (Grace) and the solvent gradient indicated in the specific examples. Thin layer chromatography (TLC) was carried out on silica gel plates (Merck) with UV detection.

Example 1

[0353] ##STR00266##

[0354] Step A:

[0355] To a stirred solution of 1-amino-3H-1,4-benzo[d]isothiazol-3-one 1-oxide prepared following a literature procedure (ACS Med. Chem. Lett. 2017 May 1; 8(6):672-677) in THF (8 mL) was added NaH (60%)(26.0 mg, 0.659 mmol) slowly at 0° C. and the mixture was stirred for 15 min. A solution of commercially available 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (0.109 g, 0.549 mmol) in THF (4 ml) was added to the reaction mixture dropwise at 0° C. and the mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction was quenched with saturated NH.sub.4C.sub.1 solution (15 ml) and the mixture was extracted with EtOAc (2×40 ml). The organic phase was dried over Na.sub.2SO.sub.4, filtered and the filtrate was evaporated under reduced pressure to afford a crude product. The crude product was purified by flash chromatography (SiO.sub.2 230-400 mesh; 0-3% methanol in DCM). Pure compound fractions were collected and concentrated under reduced pressure to afford the racemic title compound Example 1 (0.075 g, 93.68%) as an off-white solid.

[0356] 1H-NMR, (400 MHz, DMSO-d6) δ=8.07-8.05 (d, 1H), 7.68-7.6 (m, 3H), 6.85 (s, 1H), 2.79-2.75 (t, 4H), 2.67-2.64 (t, 4H), 1.95-1.88 (m, 4H).

[0357] MS: 381.9 (M+H).sup.+.

Examples 2 to 29

[0358] Following the procedure of Example 1 using appropriate reagents indicated in the table below, the following compounds were prepared. THF solvent could be substituted by DCM or CHCl.sub.3 and NaH by triethylamine or pyridine.

TABLE-US-00007 TABLE 6 1. Yield Product 2. .sup.1H-NMR Starting Material Urea Example 3. MH.sup.+ (ESI) [00267] [00268] [00269] 2 1. 19% 2. .sup.1H NMR (400 MHz, DMSO-d6) δ = 8.66 (dd, 1H), 8.02-7.89 (m, 2H), 7.53 (dd, 1H), 6.77 (s, 1H), 2.71 (t, 4H), 2.67-2.54 (m, 4H), 1.91-1.87 (m, 4H). 3. 383.3 [00270] [00271] [00272] 3 1. 32% 2. .sup.1H NMR (400 MHz, DMSO-d6) δ = 7.87 (d, 1H), 7.72 (brs, 1H), 7.33-7.42 (m, 2H), 7.25 (d, 1H), 6.79 (s, 1H), 4.89 (d, 1H), 4.27 (d, 1H), 2.77-2.65 (m, 8H), 1.90 (m, 4H). 3. 396.3 [00273] [00274] [00275] 4 1. 68% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 8.08 (s, 1H), 7.77 (d, 1H), 7.25 (d, 1H), 6.82 (s, 1H), 2.76 (t, 4H), 2.68 (t, 4H), 1.94-1.88 (m, 4H). 3. 388.3 [00276] [00277] [00278] 5 1. 26% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 8.05-8.04 (m, 2H), 7.61-7.55 (m, 3H), 2.81-2.78 (t, 4H), 2.72-2.69 (t, 4H), 1.99-1.94 (m, 4H). 3. 400.3 [00279] [00280] [00281] 6 1. 36% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 8.07-8.05 (m, 1H), 7.73 (brs, 1H), 7.63-7.56 (m, 3H), 7.42 (s, 1H), 2.77-2.64 (m, 8H), 1.98-1.92 (m, 4H). 3. 382.3 [00282] [00283] [00284] 7 1. 23% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 9.24 (d, 1H), 8.82 (d, 1H), 8.19 (brs, 1H), 7.63 (dd, 1H), 6.83 (s, 1H), 2.76 (t, 4H), 2.65 (m, 4H), 1.92-1.89 (m, 4H). 3. 383.4 [00285] [00286] [00287] 8 1. 33% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 8.79 (brs, 1H), 8.45 (d, 1H), 8.2 (brs, 1H), 7.58-7.56 (m, 1H), 6.82 (s, 1H), 2.76 (t, 4H), 2.67-2.64 (m, 4H), 1.93-1.88 (m, 4H). 3. 383.5 [00288] [00289] [00290] 9 1. 33% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 8.64 (d, 1H), 8.37 (brs, 1H), 8.24-8.25 (dd, 1H), 6.85 (s, 1H), 3.94 (s, 3H), 2.78 (t, 4H), 2.65 (t, 4H), 1.91 (m, 4H). 3. 440.4 [00291] [00292] [00293] 10 1. 26% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 8.34-8.22 (m, 2H), 8.11-8.07 (m, 2H), 6.83 (s, 1H), 2.68-2.64 (m, 4H), 1.93-1.88 (m, 4H), 2.77-2.74 (t, 4H). 3. 407,4 [00294] [00295] [00296] 11 1. 92% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 8.06 (brs, 1H), 7.99-8.02 (m, 1H), 7.53-7.57 (m, 2H), 6.81 (s, 1H), 2.77 (t, 4H), 2.65 (t, 4H), 1.91 (m, 4H). 3. 416.3 [00297] [00298] [00299] 12 1. 24% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 8.10-8.05 (m, 2H), 7.65-7.63 (m, 1H), 7.57 (d, 1H), 6.82 (s, 1H), 2.77-2.74 (m, 4H), 2.67-2.64 (m, 4H), 1.92-1.89 (m, 4H). 3. 416.4 [00300] [00301] [00302] 13 1. 24% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 8.15-8.10 (brs, 2H), 7.66-7.60 (m, 2H), 6.83 (s, 1H), 2.78-2.75 (m, 4H), 2.68-2.65 (m, 4H), 1.92-1.90 (m, 4H). 3. 416.4 [00303] [00304] [00305] 14 1. 39% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 7.93 (brs, 1H), 7.89 (d,1H), 7.41 (t, 1H), 7.33-7.31 (d, 1H), 6.80 (s,1H), 2.77-2.74 (m, 4H), 2.67- 2.66 (m, 4H), 2.61 (brs, 3H) 1.98- 1.88(m, 4H). 3. 396.4 [00306] [00307] [00308] 15 1. 40% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 8.02 (brs, 1H), 7.64 (d, 1H), 7.49 (d, 1H), 7.11 (dd, 1H), 6.82 (s, 1H), 3.82 (s, 3H), 2.64-2.78 (m, 8H), 1.90 (m, 4H). 3. 412.48 [00309] [00310] [00311] 16 1. 51% 2. ND 3. 392.2 [00312] [00313] [00314] 17 1. 41% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 8.37 (brs, 1H), 8.03 (brs, 1H), 7.21-7.17 (m, 2H), 7.00-6.98 (m, 2H), 6.75 (brs, 2H), 3.81 (brs, 3H), 3.14 (brs, 1H), 1.12-1.10 (m, 6H). 3. 475.1 [00315] [00316] [00317] 18 1. 60% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 7.97 (d, 2H), 7.75 (d, 1H), 7.14- 7.10 (m, 2H), 7.06 (d, 1H), 6.90 (d, 1H), 6.71 (s, 1H), 3.78 (s, 3H), 2.92-2.89 (m, 2H), 2.82-2.73 (m, 2H), 1.99-1.96 (m, 2H) 3. 455.1 [00318] [00319] [00320] 19 1. 56% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 8.67 (brs, 1H), 8.13 (d, 1H), 7.48 (d, 1H), 2.81 (t, 4H), 2.69 (t, 4H), 2.02-1.96 (m, 4H). 3. 406.4 [00321] [00322] [00323] 20 1. 46% 2. ND 3. 527.3 [00324] [00325] [00326] 21 1. 67% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 8.61 (brs, 1H), 8.06 (d, 1H), 7.46 (d, 1H), 7.28 (d, 1H), 6.56 (.d, 1H), 4.53-4.49 (m, 2H), 3.09-3.02 (m, 2H). 3. 428.1 [00327] [00328] [00329] 22 1. 40% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 7.97-7.95 (m, 2H), 7.08-7.06 (m, 2H), 6.81 (s, 1H), 3.84 (s, 3H), 2.76 (t, 4H), 2.65 (t, 4H), 1.93-1.87 (m, 4H). 3. 412.4 [00330] [00331] [00332] 23 1. 8% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 8.09 (brs, 1H), 7.99 (d, 1H), 7.87 (dd, 1H), 7.70 (d, 1H), 6.82 (s, 1H), 2.76 (t, 4H), 2.66 (t, 4H), 1.95-1.90 (m, 4H). 3. 460.1 [00333] [00334] [00335] 24 1. 8% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 8.26 (s, 1H), 8.15 (brs, 1H), 7.79 (dd, 1H), 7.55 (d, 1H), 6.83 (s, 1H), 2.77 (t, 4H), 2.67 (t, 4H), 1.93-1.90 (m, 4H). 3. 460.1 [00336] [00337] [00338] 25 1. 57% 2. .sup.1H NMR (400 MHz, DMSO-d6) δ = 8.06 (s, 1H), 7.86 (d, 1H), 7.63- 7.58 (m, 1H), 7.36 (t, 1H), 6.81 (s, 1H), 2.76 (t, 4H), 2.65 (t, 4H), 1.93- 1.86 (m, 4H). 3. 400.5 [00339] [00340] [00341] 26 1. 61% 2. .sup.1H NMR (400 MHz, DMSO) δ = 8.12-8.08 (m, 2H), 7.44-7.41 (m, 1H), 7.39-7.32 (m, 1H), 6.82 (s, 1H), 2.78-2.74 (m, 4H), 2.6-2.64 (m, 4H), 1.94-1.87 (m, 4H). 3. 400.5 [00342] [00343] [00344] 27 1. ND 2. .sup.1H NMR (400 MHz, DMSO) δ = 8.12-8.08 (m, 2H), 7.44-7.41 (m, 1H), 7.39-7.32 (m, 1H), 6.82 (s, 1H), 2.78-2.74 (m, 4H), 2.6 -2.64 (m, 4H), 1.94-1.87 (m, 4H). 3. 450.4 [00345] [00346] [00347] 28 1. 18% 2. .sup.1H NMR (500 MHz, DMSO-d6) δ = 8.12 (brs, 1H), 7.83 (d, 1H), 7.65-7.62 (m, 1H), 7.43 (t, 1H), 6.83 (s, 1 H), 2.77 (t, 4H), 2.68-2.63 (m, 4H), 1.93-1.92 (m, 4H). 3. 400.2 [00348] [00349] [00350] 29 1. 18% 2. .sup.1H NMR ((500 MHz, DMSO-d6) δ = 8.47 (d, 1H), 8.27 (brs, 1H), 7.71 (d, 1H), 6.83 (s, 1H), 2.76 (t, 4H), 2.65 (t, 4H), 1.94-1.88 (m, 4H). 3. 417.3

Example 30

[0359] ##STR00351##

[0360] To a stirred solution of Example 9 (15 mg, 0.034 mmol) in dry tetrahydrofuran (0.2 ml) was added a solution of 2M MeMgBr in THF (0.05 ml, 0.01 mmol) at room temperature and the mixture was stirred for 1 h. After the completion of the reaction, saturated NH.sub.4Cl solution (1 ml) was added to the reaction mixture and the mixture was extracted with EtOAc (2×5 ml). The organic layer was dried over Na.sub.2SO.sub.4, filtered and evaporated under vacuum. The resulted residue was purified by Grace automated purifier (SiO.sub.2 4 g column; gradient elution of 0 to 10% MeOH in DCM). The collected pure compound fractions were evaporated and dried under vacuum to afford 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-(6-(2-hydroxypropan-2-yl)-1-oxido-3-oxo-3H-1,4-benzo[d]isothiazol-1-yl)urea (4.4 mg, 29%) as an off white solid.

[0361] .sup.1H-NMR, (500 MHz, DMSO-d6) δ=8.20 (d, 1H), 8.00 (bs, 1H), 7.70 (dd, 1H), 7.52 (d, 1H), 6.81 (s, 1H), 5.23 (s, 1H), 2.78-2.54 (m, 8H), 1.92-1.88 (m, 4H), 1.45 (s, 3H), 1.43 (s, 3H).

[0362] MS: 440.51 (M+H).sup.+

Example 31

[0363] Following the procedure of Example 30 using appropriate reagents indicated in the table below, the following compound was prepared.

TABLE-US-00008 TABLE 7 1. Yield 2. .sup.1H- NMR Product 3. MH.sup.+ Starting Material Example (ESI) [00352] [00353] 31 1. 23% 2. .sup.1H NMR (500 MHz, DMSO- d6) δ = 8.05 (s, 1H), 7.88 (s, 1H), 7.65 (s, 1H), 7.49 (s, 1H), 7.14 (s, 1H), 7.05 (d, 1H), 6.90 (d, 2 H), 6.74 (s, 1H), 4.78 (s, 1H), 3.80 (s, 3H), 3.20 (d, 1H), 1.45 (s, 6H), 1.09 (d, 6H). 3. 527.5

[0364] Separation of Enantiomers:

[0365] The racemic mixture was subjected to chiral separation by SFC to afford the pure enantiomers.

[0366] SFC Method: [0367] Column Name: Chiralpak IC (4.6*250) mm, 5 μm; [0368] Co-Solvent: 40% [0369] Co-Solvent Name: 0.5% DEA in methanol [0370] Injected Volume: 10 μl [0371] Flow Rate: 4 ml/min [0372] Outlet Pressure: 100 bar [0373] Temperature: 30° C.

[0374] First Eluting Peak (Rt=3.34):

[0375] The fraction was evaporated under reduced pressure and the resulting residue was triturated with diethyl ether to remove diethyl amine contamination to afford Example 1a as an off white solid with 99.97% chiral purity. 1H-NMR, (400 MHz, DMSO-d6) δ=8.06-8.04 (m, 1H), 7.86 (s, 1H), 7.61-7.5 (m, 3H), 6.80 (s, 1H), 2.77-2.74 (t, 4H), 2.68-2.66 (m, 4H), 1.98-1.87 (m, 4H).

[0376] MS: 382.28 (M+H).sup.+.

[0377] Second Eluting Peak (Rt=4.36):

[0378] The fraction was evaporated under reduced pressure and the resulting residue was triturated with diethyl ether to remove diethyl amine contamination to afford Example 1 b as an off white solid with 97.76% chiral purity.

[0379] 1H-NMR, (400 MHz, DMSO-d6) δ=8.07-8.05 (m, 1H), 7.99 (s, 1H), 7.61-7.54 (m, 3H), 6.81 (s, 1H), 2.77-2.74 (t, 4H), 2.67-2.65 (m, 4H), 1.91-1.878 (m, 4H).

[0380] MS: 382.33 (M+H).sup.+.

Examples 32 to 64

[0381] Following the chiral separation of Example 1, enantiopure compounds were obtained. Different column types, eluent, temperature, pressure and flow rate could have been used.

TABLE-US-00009 TABLE 8 Enantiopure Example 1. .sup.1H-NMR Racemate Eluting peak 2. MH.sup.+ (ESI) [00354] 32 First 1. .sup.1H NMR (400 MHz, DMSO-d6) δ = 8.84 (dd, 1H), 8.47 (bs, 1H), 8.22 (dd, 1H), 7.72 (dd, 1H), 6.82 (s, 1H), 2.73 (t, 4H), 2.68-2.58 (m, 4H), 1.92-1.85 (m, 4H) 2. 383.4 [00355] 33 First 1. .sup.1H NMR (400 MHz, DMSO-d6) δ = 8.47 (brs, 1H), 8.01 (d, 1H), 7.67 (t, 1H), 7.56 (t, 1H), 7.51 (d, 1H), 6.88 (s, 1H), 5.32 (d, 1H), 5.00 (d, 1H), 2.77 (t, 4H), 2.63 (brs, 4H), 1.96-1.91 (m, 4H). 2. 396.5 [00356] 34 Second 1. .sup.1H NMR (400 MHz, DMSO-d6) δ = 8.46 (brs, 1H), 8.01 (d, 1H), 7.66 (t, 1H), 7.56 (t, 1H), 7.50 (d, 1H), 6.88 (s, 1H), 5.32 (d, 1H), 5.01 (d, 1H), 2.77 (brs, 4H), 2.63 (brs, 4H), 1.91 (brs, 4H). 2. 396.5 [00357] 35 First 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.69 (bs, 1H), 8.16 (d, 1H), 7.51 (d, 1H), 6.88 (s, 1H), 2.77 (t, 4H), 2.65 (t, 4H), 1.94-1.88 (m, 4H). 2. 388.3 [00358] 36 Second 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.68 (bs, 1H), 8.16 (d, 1H), 7.51 (d, 1H), 6.88 (s, 1H), 2.77 (t, 4H), 2.65 (t, 4H), 1.94-1.88 (m, 4H). 2. 388.3 [00359] 37 Second 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.41 (brs, 1H), 8.11-8.09 (m, 1H), 7.77-7.74 (m, 3H), 2.81-2.78 (t, 4H), 2.70-2.66 (m, 4H), 2.00-1.94 (m, 4H). 2. 400.3 [00360] 38 Second 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 9.26 (d, 1H), 8.86 (d, 1H), 8.30 (bs, 1H), 7.68 (dd, 1H), 6.84 (s, 1H), 2.76 (t, 4H), 2.68-2.63 (m, 4H), 1.92-1.89 (m, 4H). 2. 383.4 [00361] 39 First 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.77 (brs, 1H), 8.44 (d, 1H), 8.13 (brs, 1H), 7.56 (s, 1H), 6.82 (s, 1H), 2.76 (t, 4H), 2.67-2.64 (m, 4H), 1.93-1.89 (m, 4H). 2. 383.5 [00362] 40 First 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.20 (d, 1H), 8.00 (brs, 1H), 7.70 (d, 1H), 7.52 (d, 1H), 6.81 (s, 1H), 5.23 (s, 1 H), 2.78-2.54 (m, 8H), 1.93-1.86 (m, 4H), 1.45 (s, 3H), 1.43 (s, 3H). 2. 440.4 [00363] 41 Second 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.20 (d, 1H), 8.00 (brs, 1H), 7.70 (d, 1H), 7.52 (d, 1H), 6.81 (s, 1H), 5.23 (brs, 1H), 2.78-2.54 (m, 8H), 1.93-1.87 (m, 4H), 1.45 (s, 3H), 1.43 (s, 3H). 2. 440.4 [00364] 42 First 1. .sup.1H-NMR: ((500 MHz, DMSO-d6) δ = 8.31 (brs, 1H), 8.05-8.04 (m, 1H), 7.67-7.65 (m, 2H), 6.84 (s, 1H), 2.77 (t, 4H), 2.65-2.62 (m, 4H), 1.93-1.89 (m, 4H). 2. 416.5 [00365] 43 Second 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.22 (brs, 1H), 8.05-8.04 (m, 1H), 7.64-7.61 (m, 2H), 6.83 (s, 1H), 2.77 (t, 4H), 2.64-2.62 (m, 4H), 1.93-1.89 (m, 4H). 2. 416.4 [00366] 44 First 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.07-8.05 (m, 2H), 7.64 (d, 1H), 7.57 (s, 1H), 6.82 (s, 1H), 2.76 (t, 4H), 2.66-2.63 (m, 4H), 1.92-1.89 (m, 4H). 2. 416.4 [00367] 45 Second 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.15-8.10 (brs, 2H), 7.67-7.60 (m, 2H), 6.83 (s, 1H), 2.78-2.75 (m, 4H), 2.68-2.65 (m, 4H), 1.92-1.89 (m, 4H). 2. 416.2 [00368] 46 First 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.68 (brs, 1H), 7.95 (d, 1H), 7.75 (t, 1H), 7.64 (d, 1H), 6.87(s, 1H), 2.78-2.74 (m, 4H), 2.62-2.58 (m, 4H), 2.65 (bs, 3H), 1.94-1.89 (m, 4H). 2. 396.2 [00369] 47 Second 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.69 (brs, 1H), 7.95 (d, 1H), 7.75 (t, 1H), 7.64 (d, 1H), 6.87 (s, 1H), 2.78-2.74 (m, 4H), 2.62-2.60 (m, 4H), 2.65 (brs, 3H), 1.93-1.89 (m, 4H). 2. 396.2 [00370] 48 Second 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.65 (brs, 1H), 7.79 (d, 1H), 7.67 (d, 1H), 7.33 (d, 1H), 6.87 (s, 1H), 3.90 (s, 3H), 2.59-2.77 (m, 8H), 1.91 (m, 4H). 2. 412.5 [00371] 49 Second 1. .sup.1H-NMR: (400 MHz, DMSO-d6) δ = 8.58 (brs, 1H), 8.11 (d, 1H), 7.45 (d, 1H), 6.95 (d, 1H), 6.58 (d, 1H), 4.46-4.41 (m, 2H), 3.07-2.93 (m, 3H), 1.06-1.03 (m, 6H). 2. 391.95 [00372] 50 First 1. .sup.1H-NMR: (400 MHz, DMSO-d6) δ = 8.40 (brs, 1H), 8.03 (d, 2H), 7.22-7.17 (m, 2H), 7.01-6.98 (m, 2H), 6.74 (brs, 1H), 3.81 (brs, 3H), 3.12 (brs, 1H), 1.12- 1.10 (m, 6H). 2. 475.3 [00373] 51 Second 1. .sup.1H-NMR: (400 MHz, DMSO-d6) δ = 8.45 (brs, 1H), 8.06 (d, 2H), 7.23-7.17 (m, 2H), 7.01-6.98 (m, 2H), 6.74 (brs, 1H), 3.81 (brs, 3H), 3.12 (brs, 1H), 1.13- 1.10 (m, 6H). 2. 475.4 [00374] 52 First 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.45 (brs, 1H), 8.0-7.99 (brs, 2H), 7.22 (d, 1H), 7.17 (d, 1H), 7.09 (d, 1H), 6.90 (d, 1H), 6.72 (s, 1H), 3.81 (s, 3H), 2.93-2.90 (m, 2H), 2.76-2.75 (m, 2H), 2.00-1.97 (m, 2H). 2. 455.1 [00375] 53 Second 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.50 (brs, 1H), 8.02 (brs, 2H), 7.23 (d, 1H), 7.17 ( d, 1H), 7.10-7.09 (d, 1H), 6.90 (d, 1H), 6.72 (s, 1H), 3.81 (s, 3H), 2.93- 2.90 (m, 2H), 2.76-2.75 (m, 2H), 2.01-1.97 (m, 2H). 2. 455.1 [00376] 54 First 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.67 (brs, 1H), 8.13 (d, 1H), 7.48 (d, 1H), 2.81 (t, 4H), 2.69 (t, 4H), 2.02-1.96 (m, 4H). 2. 406.4 [00377] 55 Second 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.69 (brs, 1H), 8.15 (d, 1H), 7.50 (d, 1H), 2.81 (t, 4H), 2.69 (t, 4H), 2.02-1.96 (m, 4H). 2. 406.4 [00378] 56 Second 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.66 (brs, 1H), 8.10 (d, 1H), 7.48 (d, 1H), 7.28 (d, 1H), 6.57 (d, 1H), 4.53-4.49 (m, 2H), 3.10-3.01 (m, 2H). 2. 428.03 [00379] 57 First 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.51 (brs, 1H), 8.03 (d, 1H), 7.32 (d, 2H), 6.87 (s, 1H), 3.90 (s, 3H), 2.75 (t, 4H), 2.67-2.55 (m, 4H), 1.94-1.88 (m, 4H). 2. 412.4 [00380] 58 First 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.32 (brs, 1H), 8.03 (d, 1H), 7.87 (dd, 1H), 7.82 (d, 1H), 6.84 (s, 1H), 2.78 (t, 4H), 2.63 (t, 4H), 1.95-1.90 (m, 4H). 2. 460.4 [00381] 59 Second 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.25 (brs, 1H), 8.02 (d, 1H), 7.84 (dd, 1H), 7.79 (d, 1H), 6.83 (s, 1H), 2.76 (t, 4H), 2.65 (t, 4H), 1.95-1.90 (m, 4H). 2. 460.4 [00382] 60 Second 1. .sup.1H-NMR: (500 MHz, DMSO) δ = 8.45 (s, 1H), 8.33 (s, 1H), 7.93-7.91 (m, 1H), 7.68 (d, 1H), 6.86 (s, 1H), 2.78-2.75 (t, 4H), 2.66-2.63 (m, 4H), 1.93-1.90 (m, 4H). 2. 460.1 [00383] 61 First 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.44 (brs, 1H), 7.93 (d, 1H), 7.79-7.76 (m, 1H), 7.53 (t, 1H), 6.85 (s, 1H), 2.76 (t, 4H), 2.65-2.61 (m, 4H), 1.93-1.89 (m, 4H). 2. 400.2 [00384] 62 First 1. .sup.1H-NMR: (500 MHz, DMSO) δ = 8.49 (s, 1H), 8.20-8.17 (m, 1H), 7.63-7.58 (m, 2H), 6.86 (s, 1H), 2.76 (t, 4H), 2.65-2.61 (m, 4H), 1.92-1.88 (m, 4H). 2. 400.3 [00385] 63 Second 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.48 (brs, 1H), 7.98 (dd, 1H), 7.84-7.82 (m, 1H), 7.61-7.57 (m, 1H), 6.86 (s, 1H), 2.77 (t, 4H), 2.64 (brs, 4H), 1.94-1.89 (m, 4H). 2. 400.2 [00386] 64 First 1. .sup.1H-NMR: (500 MHz, DMSO-d6) δ = 8.47 (d, 1H), 8.27 (brs, 1H), 7.72 (d, 1H), 6.83 (s, 1H), 2.77-2.76 (t, 4H), 2.65 (t, 4H), 1.94-1.88 (m, 4H). 2. 417.0

[0382] Biological Assay Description

[0383] NLRP3 Inhibition Assays

[0384] The following assays can be used to determine the inhibitory activity of test compounds on the NLRP3 inflammasome using common stimuli nigericin (Invivogen) or monosodium urate crystals (MSU)(Invivogen).

[0385] Cell Culture

[0386] Human monocyte-like cells are cultured in RPM11640 Glutamax medium supplemented with 10% heat inactivated FCS and 50 U/ml penicillin-streptomycin (Life Technologies). HMDM (Human Monocyte Derived Macrophage) are isolated from human blood with leucosep tubes and classical monocyte isolation kit from Miltenyi based on negative selection.

[0387] NLRP3 inflammasome activation assays Human monocyte-like cells are seeded at 75000 per well in a 96 well plate and differentiated overnight into macrophages with 10 ng/ml PMA (Phorbol Myristate Acetate). The following day, medium containing 10 ng/ml LPS (lipopolysaccharide) is added. After 3 h of LPS priming, concentrations of test compound in the range from 100 μM to 6 nM are added 30 min prior to NLRP3 inflammasome stimulation with Nigericin 3.75 μM or MSU 150 μg/ml for 3 h.

[0388] Primary human monocyte-derived macrophages (HMDM) are seeded at 30000 per well in a 96 well plate and differentiated into macrophages with 10 ng/ml Human M-CSF (Macrophage Colony Stimulating Factor). At DIV 8 (Day in vitro) medium containing 10 ng/ml LPS is added. After 3 h of LPS priming, concentrations of test compound in the range from 10 μM to 128 μM are added 30 min prior to NLRP3 inflammasome stimulation with Nigericin 2.5 μM or MSU 150 μg/ml for 3 h.

[0389] Measurement of IL-1 Beta

[0390] For IL-1β quantification, supernatants are analyzed using AlphaLISA kits according to the manufacturer's instructions (Perkin Elmer AlphaLISA AL220F).

[0391] IC.sub.50

[0392] IC.sub.50 (concentration corresponding to 50% inhibition) were determined using GraphPad Prism 8.

[0393] The following example compounds were measured:

TABLE-US-00010 IC.sub.50 IC.sub.50 Human Human IC.sub.50 monocyte- monocyte- IC.sub.50 HMDM cells like cells like cells HMDM cells Nigericin Examples MSU (μM) Nigericin (μM) MSU (μM) (μM) 1 +++ ++ +++ ++ 1b +++ ++ +++ ++ 2 +++ ++ ++ 3 +++ ++ +++ ++ 4 +++ +++ +++ ++ 5 +++ ++ +++ ++ 6 ++ ++ ++ 7 +++ ++ ++ 8 ++ ++ 9 ++ ++ 10 +++ ++ 11 +++ ++ ++ ++ 12 ++ ++ ++ 13 +++ ++ 14 +++ ++ ++ ++ 15 +++ +++ 17 +++ +++ 19 +++ +++ +++ +++ 22 +++ ++ 23 +++ ++ 24 +++ ++ ++ 25 +++ ++ +++ 26 +++ ++ +++ 27 +++ ++ 28 +++ ++ 30 +++ +++ +++ +++ 31 +++ +++ ++ ++ 32 +++ ++ 33 +++ ++ 34 +++ +++ +++ ++ 35 +++ ++ ++ 36 +++ +++ +++ +++ 37 +++ +++ +++ ++ 38 +++ ++ 39 ++ ++ 40 +++ ++ ++ 41 +++ +++ +++ +++ 42 +++ ++ +++ ++ 43 +++ ++ 44 +++ ++ 45 +++ ++ 46 +++ ++ 47 +++ ++ 48 +++ +++ +++ +++ 49 +++ ++ 50 ++ ++ 51 +++ +++ 52 ++ ++ 53 +++ +++ 54 +++ ++ ++ 55 +++ +++ +++ +++ 56 ++ + 57 +++ ++ 58 +++ ++ 59 ++ ++ 60 +++ +++ +++ ++ 61 +++ ++ 62 +++ +++ +++ ++ 63 +++ ++ ++ 64 +++ +++ ++ Legend: +++ IC.sub.50 < 1 μM; ++ IC.sub.50 1 < x <10 μM; + IC.sub.50 10 < x < 30 μM.

[0394] The tested compounds showed inhibition of IL-1 beta release in human monocyte-like and HMDM cells using MSU or Nigericin as activators.