Treatment of neuroinflammatory disorders

Abstract

The present invention relates to the development of therapeutic compounds for brain psychiatric diseases. Specifically, the present invention provides NLRP3 inhibitors or pharma- ceutically acceptable salts or suitable compositions thereof useful for the treatment of neuroinflammatory disorders or neurodegenerative disorder diseases. These severe and persistent diseases include traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of the disease.

Description

[Technical field]

[0001] TECHNICAL FIELD TO WHICH THEINVENTION BELONGS The present invention relates to the development of therapeutic compounds for the treatment of brain psychiatric diseases. Specifically, the present invention provides NLRP3 inhibitors or pharma- ceutically acceptable salts or suitable compositions thereof useful for the treatment of neuroinflammatory disorders or neurodegenerative disorder diseases. These severe and persistent illnesses include traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of disorders. [Background technology]

[0002] 2. Background of the Invention The nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain-containing 3 (NLRP3 or NALP3) inflammasome is the major source of mucosal interleukin (IL)-1β, and the inflammasome is subject to activation by multiple facets of mostly inflammation-associated stress. NLRP3 is a cytoplasmic pattern recognition receptor (PRR) that senses exogenous and endogenous danger signals. The NLRP3 protein is composed of three domains: a leucine-rich repeat domain (LRR), a NOD (NACHT) containing caspase activation and recruitment domain (CARD), and a pyrin domain (PYD). Upon activation, NLRP3 oligomerizes and induces the assembly of the CARD-containing adaptor apoptosis-associated speck-like protein (ASC) through PYD-PYD interactions. ASC fibers assemble into large structures called ASC specks and recruit procaspase-1, leading to its autoproteolytic activation. Activated caspase-1 can cleave proIL-1β and proIL-18 to generate the proinflammatory cytokines IL-1β and IL-18 ( Guo et al., 2015 ; Dinarello et al., 2012 ).

[0003] The involvement of the NLRP3 inflammasome in various types of diseases provides a new avenue for designing drugs that target the NLRP3 inflammasome. To date, clinical treatments for NLRP3-related diseases target IL-1β using IL-1β antibodies or recombinant IL-1β receptor antagonists, such as canakinumab and anakinra, respectively. In addition, several small molecule compounds, including MCC950, β-hydroxybutyrate (BHB), Bay 11-7082, dimethyl sulfoxide (DMSO), and type I interferons, have shown anti-inflammatory effects on NLRP3 inflammasome activation in vitro. However, most of these inhibitors are relatively nonspecific and have low efficacy. With regard to inhibitors targeting IL-1β, it should be noted that the secretion of IL-1β is not the only product of NLRP3 inflammasome activation; instead, other inflammatory cytokines, including high-mobility group box 1 (HMGB1) and IL18, may be involved in the pathogenesis of these diseases. In addition, IL-1β can be produced by inflammasome-independent pathways or other inflammasomes. Therefore, inhibitors targeting IL-1β may induce unintended immunosuppressive effects in addition to preventing the activation of NLRP3 inflammasome itself. For the treatment of NLRP3-related diseases, pharmacological inhibitors specific for NLRP3 inflammasome may be the best choice. (Yang et al., 2019).

[0004] Parkinson's disease (PD) is the most common synucleinopathy and the second most common neurodegenerative disorder worldwide, affecting approximately 2% of the population aged 60 years or older (Nat. Rev. Dis. Primers 3, 17013 (2017)).

[0005] Inflammasomes are multiprotein complexes that function as intracellular sensors of environmental and cellular stress (Nat. Rev. Neurosci. 15, 84-97 (2014).). The NLR family pyrin domain-containing 3 (NLRP3) inflammasome is composed of the NLRP3 sensor, the signaling adaptor apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain, and the caspase-1 protease. Assembly of the NLRP3 complex in immune cells upon cellular stress leads to caspase-1 activation and caspase-1-mediated release of interleukin-1β (IL-1β) and IL-18, thereby initiating an inflammatory response. In neurodegenerative conditions such as Alzheimer's disease (AD), persistent accumulation of misfolded protein aggregates can induce and maintain inflammasome activation, thereby driving central nervous system (CNS) inflammation and neuropathology (19). Recent findings in AD models have demonstrated that microglia-derived inflammasome components, such as ASC specks, can cross-seed pathogenic amyloid fibrils (20). In the brains of PD patients, the inflammasome pathway can be activated by oxidative stress and insoluble α-synuclein aggregates (PLOS ONE 8, e55375 (2013)).

[0006] The NLRP3 inflammasome plays a key role in PD-like pathophysiology in rodents and may represent a feasible therapeutic target to alleviate neurotoxic α-synuclein pathology and the resulting loss of nigrostriatal dopaminergic neurons in PD (Sci. Transl. Med. 10, eaah4066 (2018)).

[0007] Previously, we demonstrated that nanomolar doses of the small molecule NLRP3 inhibitor MCC950 abolished fibrillar α-synuclein-mediated inflammasome activation and extracellular ASC release in mouse microglial cells. Furthermore, oral administration of MCC950 in multiple rodent PD models suppressed inflammasome activation and effectively attenuated motor deficits, nigrostriatal dopaminergic degeneration, and accumulation of α-synuclein aggregates. These findings suggest that microglial NLRP3 may be responsible for persistent neuroinflammation that may drive the progression of dopaminergic neuropathology, highlighting NLRP3 as a potential target for disease-modifying treatment of PD (Sci. Transl. Med. 10, eaah4066 (2018)).

[0008] MCC950 inhibited NLRP activation in a mouse model of MWS. Peripheral blood mononuclear cells (PBMCs) from patients with low-penetrance NLRP3 variants (Q703K and V198M) have been shown to express enhanced IL-1β levels after inflammasome activation compared to healthy controls. Furthermore, IL-1β release has been shown to be NLRP3-dependent, as it was inhibited by MCC950 (Schuh et al., 2019). Anakinra, an IL-1 receptor antagonist, is used in a conventional manner to control symptoms of the syndrome, but patients relapse when treatment is discontinued.

[0009] Various drugs targeting the NLRP3 inflammasome are in various stages of phase 1 and 2 development (Freeman et al., 2020). Drugs such as MCC950, CY-09, OLT1177, tranilast, oridonin, and NT-0167 have displayed superior therapeutic properties because they directly target NLRP3 itself but not other components upstream / downstream of NLRP3 inflammasome activation (NEK7, ASC, caspase-1, or IL-1β). Moreover, these inhibitors are either in clinical use or are being studied in phase II clinical trials that have shown a relatively high safety profile (Yang et al., 2019).

[0010] NLRP3 in innate immune cells is activated by pathogen associated molecular patterns and death associated molecular patterns. The resulting NLRP3 inflammasome activates caspase-1, which then cleaves and releases IL-1β and IL-18. NLRP3 inflammasome inhibitors may reverse IL-1-mediated neurodegenerative disorders, including Parkinson's disease.

[0011] All current treatments are limited to injectable biologics that often have limited penetration into the central nervous system (CNS), which is especially important in NOMID patients with severe CNS disease. Thus, there remains an unmet clinical need for more targeted, preferably small molecule, alternatives to IL-1-targeted biologics. Summary of the Invention

[0012] The present invention provides therapeutic compounds of formula (I) and pharma- ceutically acceptable salts thereof for the prophylaxis and treatment of neuroinflammatory or neurodegenerative disorders such as traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of disorders.

[0013] EMBODIMENTS OF THE PRESENT DISCLOSURE In one embodiment, the present invention provides therapeutic compounds of formula (I) suitable for the treatment and prevention of neuroinflammatory or neurodegenerative disorders: [ka] These serious and persistent diseases include traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of the disease.

[0014] In one embodiment, the present invention provides compounds of formula (I) and their pharma- ceutically acceptable salts suitable for the treatment of neuroinflammatory or neurodegenerative disorders such as traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of disorders.

[0015] In yet another embodiment, the present invention provides for the administration of therapeutic compounds of formula (I) and their pharma- ceutically acceptable salts, alone or in combination, suitable for the treatment and prevention of neuroinflammatory or neurodegenerative disorders such as traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of disorders.

[0016] In a further embodiment, the present invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof for the treatment and prevention of neuroinflammatory or neurodegenerative disorders such as traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of disorders.

[0017] In another embodiment, the present invention provides a method of treating neuroinflammatory or neurodegenerative disorders such as traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of disorders with a pharmaceutical composition of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0018] In yet another embodiment, the present invention provides suitable compositions comprising compounds of formula (I) or suitable pharmaceutical compositions thereof for the treatment and prevention of neuroinflammatory or neurodegenerative disorders diseases such as traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of disorders. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Detailed Description of the Invention Definition: The term "treatment" or "treat" refers to the slowing, halting, or delaying the progression of a disease or clinical symptoms in a patient, as evidenced by a reduction or elimination of clinical or diagnostic symptoms of the disease, disorder, or condition.

[0020] A "patient" includes both humans and animals. "Mammal" means humans and other mammalian animals.

[0021] The term "prevention" refers to preventing a subject from acquiring a disorder or disease in the first place.

[0022] A "subject" is a mammal, preferably a human, but may also be an animal in need of veterinary treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.).

[0023] As used herein, "treating" includes partially or substantially achieving one or more of the following results: partially or completely reducing the severity of a disease, disorder or syndrome. Slowing, inhibiting or preventing the progression of a disease, disorder or syndrome includes, for example, slowing, inhibiting or preventing the progression of neuroinflammatory or neurodegenerative disorders such as traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of disorders.

[0024] The present invention describes methods of treating a subject suffering from a neuroinflammatory or neurodegenerative disorder, such as traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of disorders.

[0025] In one embodiment, the present invention provides compounds of formula (I) and their pharma- ceutically acceptable salts suitable for the treatment or prevention of neuroinflammatory or neurodegenerative disorders such as traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of disorders.

[0026] In a further embodiment, the present invention provides the use of compounds of formula (I) or suitable pharmaceutical compositions thereof for the treatment or prevention of neuroinflammatory or neurodegenerative disorders such as traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of disorders.

[0027] In a preferred embodiment, the neuroinflammatory or neurodegenerative disorder is Parkinson's disease (PD).

[0028] The method comprises reacting a compound of formula (I): [ka] administering to a subject an effective amount of a compound, such as a tautomer thereof, a stereoisomer thereof, an enantiomer thereof, a metabolite thereof, a deuterium analogue thereof, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising any of them, or a mixture thereof; In the above formula, X is O, NH, or NR 3 where R 3 is hydrogen, hydroxyl, halogen, nitro, cyano, haloalkyl, optionally (C 1 -C 10) alkyl, (C 1 -C 10 ) alkoxy, (C 3 -C 10 ) cycloalkyl, (C 2 -C 10 ) alkenyl, (C 2 -C 10 ) Alkynyl, SO 2 (C 1 -C 6 ) alkyl, thiol, thioalkyl, thioalkoxy, SO(C 1 -C 6 ) independently represents a substituted group selected from alkyl, benzyl, aryl, heteroaryl, and heterocyclyl; Y is O, S; R at each occurrence 1 is hydrogen, halogen, haloalkyl, cyano, optionally (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) alkoxy, (C 3 -C 7 ) cycloalkyl, (C 1 -C 6 )AlkylSO 2 (C 1 -C 6 ) alkyl, (C 1 -C 6 )AlkylN(C 1 -C 6 ) alkyl, (C 1 -C 6 )AlkylN(C 3 -C 7 ) cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, tert-butyloxycarbonyl, NH(C 1 -C 6 ) alkyl, N((C 1 -C 6 )Alkyl) 2 , NH(C 2 -C6 ) alkenyl, N((C 2 -C 6 )Alkenyl) 2 , -N-heterocyclyl, N(C 1 -C 6 )Alkyl-heterocyclyl, NR'R'', thiol, mercaptoalkyl, SO 2 (C 1 -C 6 ) Alkyl, SO 2 (C 3 -C 7 ) Cycloalkyl, SO 2 -Aryl, SO 2 -heterocyclyl, (C 1 -C 6 ) thioalkyl, (C 1 -C 6 ) thioalkoxy, (C 1 -C 6 )AlkylSO 2 NH 2 , -CONH 2 , -CO(C 1 -C 6 ) alkyl, -CO(C 1 -C 6 ) independently represent a substituted group selected from haloalkyl, -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, a 4-7 membered heterocycle, a 7-14 membered bicyclic heterocycle, a bridged ring system or a spiro ring system, optionally having one or more heteroatoms; In one embodiment, R 1 teeth, [ka] Represents: n independently represents an integer of 0 to 3; R', R'', and R at each occurrence 1’ , R 1 '', R 2 ' and R2'' are hydrogen, halogen, haloalkyl, cyano, optionally (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 2 -C 6) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 6 ) alkoxy, (C 3 -C 7 ) cycloalkyl, (C 1 -C 6 )AlkylSO 2 (C 1 -C 6 ) alkyl, (C 1 -C 6 )AlkylN(C 1 -C 6 ) alkyl, (C 1 -C 6 )AlkylN(C 3 -C 7 ) Cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, tert-butyloxycarbonyl, thiol, mercaptoalkyl, SO 2 (C 1 -C 6 ) Alkyl, SO 2 (C 3 -C 7 ) Cycloalkyl, SO 2 -Aryl, SO 2 -heterocyclyl, (C 1 -C 6 ) thioalkyl, (C 1 -C 6 ) thioalkoxy, (C 1 -C 6 )AlkylSO 2 NH 2 , -CONH 2 , -CO(C 1 -C 6 ) alkyl, -CO(C 1 -C 6 ) independently represent a substituted group selected from haloalkyl, -CO-aryl, -CO-heteroaryl, -CO-heterocyclyl, a 4-7 membered heterocycle, a 7-14 membered bicyclic heterocyclic ring system, a bridged ring system or a spiro ring system optionally having one or more heteroatoms; in one embodiment, R' and R'' optionally form a 4-7 membered heterocyclic ring system, R 2 is the ring system [ka] is selected from wherein X, Y, and Z at each occurrence are optionally substituted with C, N, S, SO 2 and independently represent O; R at each occurrence 4 is hydrogen, halogen, haloalkyl, cyano, optionally (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 1 -C 6 ) alkoxy, (C 3 -C 7 ) cycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, heterocyclic ring system, substituted amine, thiol, mercaptoalkyl, (C 1 -C 6 ) thioalkoxy groups; R at each expression 7 , R 8 , R 9 , R 10 , R 11 and R 12 Each of may be hydrogen, halogen, cyano, amide, sulfonamide, acyl, hydroxyl, optionally (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl, (C 3 -C 6 ) cycloalkyl, (C 1 -C 6 ) independently selected from substituted groups selected from alkoxy, benzyl, aryl, heteroaryl, heterocyclyl; in one embodiment, R 8 and R 9 , R 9 and R 10 , R 10 and R 11 , and R 11 and R 12 Each of the following, together as far as possible, is N, O, and S(O) pcan form a 4-7 membered saturated or partially saturated ring containing 0-2 additional heteroatoms selected from the group consisting of: p=1-2, Rx and Ry at each occurrence are independently hydrogen, halogen, optionally (C 1 -C 6 ) alkyl; or Rx and Ry together can form a 4-7 membered heterocyclic ring system; "M" is selected from aryl, heteroaryl, heterocyclyl; When any of the above defined groups are substituted, the substituents thereon are selected from those set forth above or are selected from hydrogen, hydroxy, cyano, halo, haloalkyl, haloalkyloxy, alkylthio, optionally (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 3 -C 10 ) Cycloalkyl, C 1 -C 6 Alkoxy, aryl, heterocyclyl, heteroaryl, -COR 11 , -CSR 11 , C(O)OR 11 , C(O)-R 11 , -C(O)-NR 11 R 12 , -C(S)-NR 11 R 12 , -SO 2 R 11 groups, where R 11 and R 12 Each of 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 3 -C 7 ) independently selected from substituted groups selected from cycloalkyl, aryl, heteroaryl, and heterocyclyl groups;

[0029] In a preferred embodiment, the groups, radicals may be selected from the following:

[0030] "Alkyl", as well as other groups having the prefix "alk", such as alkoxy and alkanoyl, means carbon chains which may be further substituted with oxygen atoms, and may be either linear or branched, and combinations thereof, as is well understood by one of ordinary skill in the art, unless the carbon chain is defined otherwise. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert.-butyl, pentyl, hexyl, and the like. Groups having a number of carbon atoms, such as, for example, C 3-10 Where permitted, the term alkyl also includes cycloalkyl groups, and combinations of cycloalkyl structures with linear or branched alkyl chains. If the number of carbon atoms is not specified, C 1-6 Substituted alkyl includes halo (e.g., CI, F, Br, and I); halogenated alkyl (e.g., CF 3 , 2-Br-ethyl, CH 2 F, C.H. 2 C.I., C.H. 2 CF 3 , or CF 2 CF 3 ); hydroxyl; amino; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate, as well as alkyl substituted with one or more moieties selected from the group consisting of those listed under the definition of "optionally substituted."

[0031] "Alkenyl" means a carbon chain containing at least one carbon-carbon double bond, and may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise. Examples of alkenyl include, but are not limited to, vinyl, allyl, isopropenyl, hexenyl, pentenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. When the number of carbon atoms specified is less than 1, e.g., C 5-10 Where permitted, the term alkenyl also includes cycloalkenyl groups and combinations of straight, branched and cyclic structures. If the number of carbon atoms is not specified, then C 2-6 ) is intended.

[0032] "Alkynyl" means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-l-pentynyl, and the like. If no number of carbon atoms is specified, one is intended.

[0033] A "thioalkyl" group, used alone or in combination with other radicals, refers to an alkyl group, as defined above, attached to a group of the formula -SR' (sulfur and its oxidized forms), where R' represents a hydrogen, an alkyl group, or an aryl group, such as thiomethyl, methylthiomethyl, phenylthiomethyl, and the like, which may be optionally substituted.

[0034] As used herein, "carbocycle" or "carbocyclic residue" is intended to mean a stable monocyclic, bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). In a broader sense, the term carbocycle is intended to include, where applicable, cycloalkyl, phenyl and other groups representing saturated, partially saturated or aromatic residues;

[0035] The terms "cycloalkyl" and "cycloalkenyl" refer to optionally substituted, saturated and unsaturated monocyclic, bicyclic, or tricyclic carbon groups. Where appropriate, the cycloalkyl or cycloalkenyl group may have a specific number of carbon atoms, e.g., C 3 -C 6 Cycloalkyl or cycloalkenyl includes within its scope carbocyclic groups having 3, 4, 5 or 6 carbon atoms. Examples of such substituents may be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like. Substituted cycloalkyl or cycloalkenyl include halo (e.g., CI, F, Br, and I); halogenated alkyl (e.g., CF 3 , 2-Br-ethyl, CH 2 F, C.H. 2 C.I., C.H. 2 CF 3 , or CF 2 CF 3); hydroxyl; amino; carboxylate; carboxamide; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate, as well as substituents at one or more moieties selected from the group consisting of those listed under the definition of "optionally substituted."

[0036] "Alkoxy" means a straight or branched chain alkoxide having the specified number of carbon atoms.

[0037] "Aryl" means a monocyclic or polycyclic aromatic ring system containing carbon ring atoms. Preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.

[0038] "Heterocyclyl" means a saturated, partially saturated or unsaturated, aromatic or non-aromatic monocyclic, bicyclic or tricyclic radical containing one or more heteroatoms selected from nitrogen, sulfur and oxygen, and optionally further including the oxidized forms of sulfur, i.e., SO and SO 2 Heterocyclyl systems may be attached to another site through any number of carbon atoms or heteroatoms of the radical and may be both saturated and unsaturated. Examples of heterocyclyl systems include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazoline, imidazolidine, pyrrolidine, pyrroline, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, and the like. The term "heterocycloalkyl" refers to a heterocyclic group as defined above linked to an alkyl group as defined above;

[0039] "Heteroaryl" refers to an aromatic or partially aromatic heterocycle containing at least one ring heteroatom selected from O, S, and N. Thus, heteroaryl includes heteroaryls fused to other types of rings, such as aryls, cycloalkyls, and non-aromatic heterocycles. Examples of heteroaryl groups include; pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzthiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoinyl, benzo ... and the like. Heterocyclyl; and heteroaryl groups include rings and ring systems containing 3 to 15 carbon atoms and forming 1 to 3 rings.

[0040] The term "haloalkyl" refers to an alkyl structure in which at least one hydrogen has been replaced with a halogen atom. In certain embodiments in which two or more hydrogen atoms have been replaced with halogen atoms, the halogen atoms are all the same as one another.

[0041] "Haloalkoxy" groups are selected from the appropriate haloalkyl as defined above directly bonded to an oxygen atom, more preferably selected from fluoromethoxy, chloromethoxy, fluoroethoxy, chloroethoxy, and the like;

[0042] In certain other embodiments where two or more hydrogen atoms are replaced with halogen atoms, the halogen atoms are not all the same as one another.

[0043] "Aryloxyalkyl" means an alkyl radical substituted with an aryloxy group, as defined herein.

[0044] "Aryloxyaryl" means an aryl radical substituted with an aryloxy group, as defined herein.

[0045] "Aryloxyheteroaryl" means a heteroaryl radical substituted with an aryloxy group, as defined herein.

[0046] "Halo / halogen" means fluorine, chlorine, bromine and iodine, with chlorine and fluorine being generally preferred.

[0047] Suitable groups and substituents on a radical may be selected from those described anywhere herein.

[0048] The term "substituted" as used herein means that any one or more hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the normal valences of the designated atom are not exceeded and that the replacement results in a stable compound. The term "substituted" as used herein means that any one or more hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the normal valences of the designated atom are not exceeded and that the replacement results in a stable compound.

[0049] "Pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds, where the parent compound has been modified by making acid or base salts thereof. Examples of pharma-ceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues. Such conventional non-toxic salts include 1,2-ethanedisulfonic acid, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolylsanilic acid, hexylresorcylic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthalene acid, hydroxyphenylsulfonic ... These include, but are not limited to, salts derived from inorganic and organic acids selected from phthalic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, and toluenesulfonic acid.

[0050] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl." Additionally, optionally substituted groups include unsubstituted groups.

[0051] Unless otherwise stated herein, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.

[0052] Particularly useful compounds may be selected from, but are not limited to, the following: N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide; N'-cyano-4-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(2-hydroxypropan-2-yl)benzenesulfonimidamide; N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide; (E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiazol-2-yl)ethenesulfonamide; (E)-2-(1-ethyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide; (E)-2-(1-ethyl-4-methyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide; (R,E)-2-(1-ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide; (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide; (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene-1-sulfonamide; (S,E)-2-(1-ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide; (R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide; (S,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide; Sodium (S,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide; Potassium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide; Sodium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide; (E)-N'-cyano-2-((S)-1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonimidamide; (E)-N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((R)-1-methylpyrrolidin-2-yl)ethene-1-sulfonimidamide; (E)-N'-cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((R)-1-methylpyrrolidin-2-yl)ethene-1-sulfonimidamide; (E)-N'-cyano-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonimidamide; N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((1S,8aR)-3,3,8a-trimethyloctahydropyrrolo[1,2-a]pyrazin-1-yl)methanesulfonamide; N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((4S,8aS)-2,3,3,8a-tetramethyloctahydropyrrolo[1,2-a]pyrazin-4-yl)methanesulfonamide; (E)-3-(dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide; Sodium (E)-((3-(dimethylamino)-3-methylbut-1-en-1-yl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide; (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide; (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide; (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide; (E)-3-(bis(methyl-d)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonamide; Sodium (R,E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)vinyl)sulfonyl)amide; N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((1S,8aR)-3,3,8a-trimethyl-2-(methyl-d)octahydropyrrolo[1,2-a]pyrazin-1-yl)methanesulfonamide; (R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5-tetrahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide; (E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((2-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide; (E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((3-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide; (E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide; or a pharma- ceutically acceptable salt of any of the above compounds.

[0053] Below is a list of abbreviations used in the description of the preparation of the compounds of the invention: μg: microgram 1 H NMR: Proton nuclear magnetic resonance bs: broad singlet CDC1 3 : Deuterated chloroform CHC1 3 :Chloroform d: doublet DAMPs: Damage-associated molecular patterns DBU: 1,8-diazabicyclo(5.4.0)undec-7-ene DCM: dichloromethane dd: doublet of doublet DMAC: N,N-(dimethylacetamide) DMAP: 4-(dimethylamino)pyridine DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide dt: triplet of doublet EDTA: Ethylenediaminetetraacetic acid EtOAc: ethyl acetate EtOH: Ethanol HCl(g): Hydrogen chloride (gas) IL1β: Interleukin 1β K 2 CO 3 : Potassium carbonate m:Multiplet MeOH: Methanol mmol: millimolar MS: Mass spectrum N 2 :nitrogen Na 2 CO 3 : Sodium carbonate ng: nanogram NIS: Niodosuccinimide PAMPs: pathogen-associated molecular patterns PMA: phorbol 12-myristate 13-acetate POCI3: Phosphoryl chloride RM: reaction mixture rt, RT: room temperature s: singlet t: triplet td: Triplet of doublets THF: tetrahydrofuran TLC: Thin Layer Chromatography TLR: Toll-like receptor TNFα: tumor necrosis factor α

[0054] In one embodiment, the present invention provides suitable compositions comprising compounds of formula (I) or suitable pharmaceutical compositions thereof for the treatment and prevention of neuroinflammatory or neurodegenerative disorders such as traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of disorders.

[0055] The term "pharmaceutical composition" refers to a mixture of an NLRP3 antagonist or other compound described herein with other chemical components, such as carriers, stabilizers, diluents, dispersants, suspending agents, and / or thickening agents (collectively referred to herein as "excipients"). A pharmaceutical composition facilitates administration of an NLRP3 antagonist or other compound to an organism. Multiple techniques of administering a compound exist in the art, including, but not limited to, rectal, oral, and intravenous administration, aerosol and parenteral administration, ophthalmic, pulmonary, and topical administration.

[0056] In one embodiment, the present invention provides an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, which may be selected from 1 mg to 500 mg; preferably 1 mg to 250 mg, and more preferably 1 mg to 150 mg, for the treatment and prevention of a neuroinflammatory or neurodegenerative disorder.

[0057] In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 150 mg on each day the compound is administered to the subject. For example, in certain embodiments, the compound is orally administered in an amount to provide a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 25 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 50 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 75 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 100 mg to about 125 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 125 mg to about 150 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 150 mg to about 175 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 175 mg to about 200 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 200 mg to about 225 mg on each day the compound is administered to the subject. In certain embodiments, the compound is administered orally in an amount to provide a range of about 225 mg to about 250 mg of a compound of formula (I) or a pharma- ceutically acceptable salt thereof on each day that the compound is administered to the subject.

[0058] In certain other embodiments, the compound is orally administered in an amount to provide a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 125 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 150 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 175 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 200 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 225 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 250 mg each day the compound is administered to the subject.

[0059] In one embodiment, the present invention provides an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, which may be administered by oral, topical, parenteral, intravenous or intramuscular routes of administration. In a preferred embodiment, the present invention provides an effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, which is administered by oral route of administration.

[0060] The compound of formula (I) or a pharma- ceutically acceptable salt thereof may be provided to a subject daily or weekly as prescribed by a physician to a person in need thereof.

[0061] In another embodiment, the present invention provides a method of treating a subject suffering from a neuroinflammatory or neurodegenerative disorder disease such as traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of disorders, preferably Parkinson's disease (PD), comprising treating a patient in need of such treatment with a compound of formula (I) or a pharma- ceutically acceptable salt thereof or a suitable pharmaceutical composition comprising same.

[0062] In one embodiment, the present invention provides a combination of a compound of formula (I) or a pharma- ceutically acceptable salt thereof together with other suitable agents as a therapeutic agent for the treatment of a neuroinflammatory or neurodegenerative disorder.

[0063] In one embodiment, the additional therapeutic agent used is selected from inhibitors of interleukin-1β (e.g., rilonacept, canakinumab, and anakinra); immunosuppressants (e.g., methotrexate, mercaptopurine, cyclophosphamide), metabolic disorder drugs, glucocorticoids, nonsteroidal anti-inflammatory drugs, gasdermin D inhibitors (e.g., necrosulfonamide); Cox-2 specific inhibitors, TNF-α binding proteins (e.g., infliximab, etanercept), interferon-13, interferons, interleukin-2, antihistamines, β-agonists, BTK inhibitors, anticholinergic drugs, anticancer drugs; antiviral drugs, such as: Remdesivir, Lopinavir / Ritonavir, Favipiravir, Molnupiravir, Tamiflu; antimalarial drugs, such as: chloroquinone, hydroxychloroquinone; or a suitable pharmaceutically acceptable salt thereof. Further examples for use in combination with non-alcoholic steatohepatitis (NASH) and fibrosis drugs; anti-cancer drugs; antibiotics such as azithromycin; hormones, aromatase inhibitors, colchicine, anticoagulants, antibodies, cytokines, anti-IL6 drugs; anti-parasitic drugs; vaccines; interferons; drug conjugates; drugs originally developed for SARS (ACE2 protein decoy); vitamin C infusions; mitogen-activated protein kinase signaling inhibitors (e.g.: BAY43-9006); Syk inhibitors; mTOR inhibitors; antibodies (Rituxan); and BCR / ABL antagonists.

[0064] The compounds of formula (I) of the present invention or pharma- ceutically acceptable salts thereof may further be used in any combination with one or more suitable pharma- ceutical active agents selected from the following therapeutic agents: MAO B inhibitors, selegiline (Zelapar), rasagiline (Azilect) and safinamide (Xadago); catechol O-methyltransferase (COMT) inhibitors, entacapone (Comtan) and opicapone (Ongentys); benztropine (Cogentin), trihexyphenidyl, amantadine; cholinesterase inhibitors, donepezil (Aricept), galantamine (Razadyne) and rivastigmine (Exelon), memantine (Namenda), aducanumab (Adhelm), riluzole (Rilutek), edaravone (Radicava); ocrelizumab (Ocrevus), prednisone and methylprednisolone; tetrabenazine (Xenazine) and deutetrabenazine (Austed), haloperidol (Haldol) and fluphenazine, risperidone (Risperdal), olanzapine (Zyprexa) and quetiapine (Seroquel), levetiracetam (Keppra, Elepsia XR, Splitam) and clonazepam (Klonopin); citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem) and sertraline (Zoloft), quetiapine (Seroquel), risperidone (Risperdal) and olanzapine (Zyprexa), divalproex (Depakote), carbamazepine (Carbatrol, Epitor) and lamotrigine (Lamictal).

[0065] The compounds and compositions of the invention are also intended for use in the general care provided to patients infected with Arenaviridae viruses, including parenteral fluids (including dextrose saline and lactated Ringer's) and nutrition, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylaxis, antipyretics, analgesics, antiemetics (such as metoclopramide) and / or antidiarrheals, vitamin and mineral supplements (including vitamins C and / or K, zinc sulfate), anti-inflammatories (such as ibuprofen), analgesics, and medications for other illnesses commonly found in the patient population, antimalarials (including artemether and artesunate-lumefantrine combination therapy), typhoid (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillin antibiotics such as ampicillin), or dysentery.

[0066] In yet another embodiment, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is provided in the form of a pharmaceutical composition.

[0067] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof for the treatment of neuroinflammatory or neurodegenerative disorders such as traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of disorders, preferably Parkinson's disease (PD), wherein the compound of formula (I) is [ka] That is,

[0068] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and suitable pharma- ceutically acceptable excipients for the treatment of neuroinflammatory or neurodegenerative disorders such as traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of disorders, preferably Parkinson's disease (PD).

[0069] The pharma- ceutically acceptable excipient may be selected from at least one of a diluent, a carrier, a binder, a disintegrant, a lubricant, a surface active agent, and the like.

[0070] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein an effective amount of the compound of formula (I) or a pharma- ceutically acceptable salt thereof for treating a neuroinflammatory disease or a neurodegenerative disorder may be selected from 1 mg to 500 mg; preferably 1 mg to 250 mg, and more preferably 1 mg to 150 mg.

[0071] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof, which may be administered by oral, topical, parenteral, intravenous or intramuscular routes of administration. In a preferred embodiment, the pharmaceutical composition may be administered by oral route of administration.

[0072] In another embodiment of the invention, there is provided a process for the preparation of a stable pharmaceutical composition of a compound of formula (1) or a pharma- ceutically acceptable salt thereof.

[0073] Stable pharmaceutical compositions can be prepared by dry blending, wet granulation or dry granulation techniques known to those skilled in the art.

[0074] In the wet granulation process, the drug is mixed with one or more pharmaceutical excipients, granulated with a suitable binding liquid as described above to form wet granules, the wet granules are dried and optionally sieved, the dried granules are mixed with one or more suitable excipients among those described elsewhere and then compressed into tablets or filled into capsules.

[0075] In the dry blending process, the drug is mixed with all the required pharmaceutical excipients. The blend is then mixed with one or more suitable excipients from those described elsewhere, and the final blend is compressed into tablets or filled into capsules.

[0076] In the dry granulation process, the drug is mixed with one or more pharmaceutical excipients, compressed into slugs, and these slugs are passed through the required sieve. The sieved granules are mixed with one or more suitable excipients from those described elsewhere and compressed into tablets or filled into capsules.

[0077] The one or more solvents or vehicles used in the formulation are selected from water, acetone, chloroform, dichloromethane, ethyl alcohol, ethyl acetate, methyl alcohol, isopropyl alcohol, and combinations thereof, as well as other such materials known to those of skill in the art.

[0078] The present invention further discloses the use of said compounds of formula (I) or suitable pharmaceutical compositions thereof for the treatment of neuroinflammatory or neurodegenerative disorders such as traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease, and other related forms of disorders, preferably Parkinson's disease (PD).

[0079] In another embodiment, the present invention provides a method for treating a neuroinflammatory or neurodegenerative disorder using a pharmaceutical composition of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In a preferred embodiment, the present invention provides a method for treating a neuroinflammatory or neurodegenerative disorder using a compound of formula (I) or a pharmaceutical composition thereof.

[0080] In a preferred embodiment, the present invention relates to a compound of formula (11) [ka] or a pharma- ceutical acceptable salt thereof suitable for treating neuroinflammatory or neurodegenerative disorders, including traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of the disease.

[0081] In a preferred embodiment, the neuroinflammatory or neurodegenerative disorder is Parkinson's disease (PD).

[0082] In a further preferred embodiment, the present invention provides the use of compounds of formula (11) or suitable pharmaceutical compositions thereof for the treatment of neuroinflammatory or neurodegenerative disorders such as traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of disorders, preferably Parkinson's disease (PD).

[0083] In another preferred embodiment, the present invention provides an effective amount of the compound of formula (11) or a pharma- ceutically acceptable salt thereof for the treatment of a neuroinflammatory disease or a neurodegenerative disorder, which can be selected from 1 mg to 500 mg; preferably 1 mg to 250 mg, and more preferably 1 mg to 150 mg.

[0084] In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 250 mg on each day the compound is administered to the subject. For example, in certain embodiments, the compound is orally administered in an amount to provide a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 25 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 50 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 75 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 100 mg to about 125 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 125 mg to about 150 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 150 mg to about 175 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 175 mg to about 200 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 200 mg to about 225 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 225 mg to about 250 mg each day the compound is administered to the subject.

[0085] In certain other embodiments, the compound is orally administered in an amount to provide a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 25 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 50 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 75 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 100 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 125 mg on each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 150 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 175 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 200 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 225 mg each day the compound is administered to the subject. In certain embodiments, the compound is orally administered in an amount to provide a compound of formula (11) or a pharma- ceutically acceptable salt thereof in the range of about 1 mg to about 250 mg each day the compound is administered to the subject.

[0086] In another preferred embodiment, the present invention provides an effective amount of a compound of formula (11) or a pharma- ceutically acceptable salt thereof by oral, topical, parenteral, intravenous or intramuscular administration routes. In a preferred embodiment, the present invention provides an effective amount of a compound of formula (11) or a pharma- ceutically acceptable salt thereof by oral administration routes.

[0087] The compound of formula (11) or a pharma- ceutically acceptable salt thereof can be provided to a subject on a daily or weekly basis as prescribed by a physician to a person in need thereof.

[0088] In one preferred embodiment, the present invention provides a combination of a compound of formula (11) and its pharma- ceutically acceptable salts, together with other suitable agents, as a therapeutic agent for the treatment of a neuroinflammatory or neurodegenerative disorder.

[0089] Here, other suitable therapeutic agents may be selected from inhibitors of interleukin-1β (e.g., rilonacept, canakinumab, and anakinra); immunosuppressants (e.g., methotrexate, mercaptopurine, cyclophosphamide), metabolic disorder drugs, glucocorticoids, nonsteroidal anti-inflammatory drugs, gasdermin D inhibitors (e.g., necrosulfonamide); Cox-2 specific inhibitors, TNF-α binding proteins (e.g., infliximab, etanercept), interferon-13, interferon, interleukin-2, antihistamines, β-agonists, BTK inhibitors, anticholinergic drugs, anticancer drugs; antiviral drugs, such as: Remdesivir, Lopinavir / Ritonavir, Favipiravir, Molnupiravir, Tamiflu; antimalarial drugs, such as: chloroquinone, hydroxychloroquinone; or suitable pharmaceutically acceptable salts thereof. Further examples for use in combination with non-alcoholic steatohepatitis (NASH) and fibrosis treatments; anti-cancer drugs; antibiotics, such as azithromycin; hormones, aromatase inhibitors, colchicine, anticoagulants, antibodies, cytokines, anti-IL6 drugs; anti-parasitic drugs; vaccines; interferons; drug conjugates; drugs originally developed for SARS (ACE2 protein decoy); vitamin C infusions; mitogen-activated protein kinase signaling inhibitors (e.g.: BAY 43-9006); Syk inhibitors; mTOR inhibitors; antibodies (Rituxan); and BCR / ABL antagonists can also be used in combination with the compounds of formula (11) for the treatment of neuroinflammatory or neurodegenerative disorders.

[0090] The compound of formula (11) of the present invention or a pharma- ceutically acceptable salt thereof may further be used in any combination with one or more suitable pharma- ceutical active agents selected from the following therapeutic agents: MAO B inhibitors, selegiline (Zelapar), rasagiline (Azilect), and safinamide (Xadago); catechol O-methyltransferase (COMT) inhibitors, entacapone (Comtan) and opicapone (Ongentys); benztropine (Cogentin), trihexyphenidyl, amantadine; cholinesterase inhibitors, donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon), memantine (Namenda), aducanumab (Adhelm); riluzole (Rilutek), edaravone (Radicava); ocrelizumab (Ocrevus), prednisone and methylprednisolone; tetrabenazine (Xenazine) and deutetrabenazine (Austed), haloperidol (Haldol) and fluphenazine, risperidone (Risperdal), olanzapine (Zyprexa) and quetiapine (Seroquel), levetiracetam (Keppra, Elepsia XR, Splitam) and clonazepam (Klonopin); citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem) and sertraline (Zoloft), quetiapine (Seroquel), risperidone (Risperdal) and olanzapine (Zyprexa), divalproex (Depakote), carbamazepine (Carbatrol, Epitor) and lamotrigine (Lamictal).

[0091] The compounds of formula (11) of the present invention and compositions thereof are also intended for use in the general care provided to patients with Arenaviridae virus infections, including parenteral fluids (including dextrose saline and lactated Ringer's) and nutrition, antibiotics (including metronidazole and cephalosporin antibiotics such as ceftriaxone and cefuroxime) and / or antifungal prophylaxis, antipyretics, analgesics, antiemetics (such as metoclopramide) and / or antidiarrheals, vitamin and mineral supplements (including vitamin C and / or K, zinc sulfate), anti-inflammatories (such as ibuprofen), analgesics, and medications for other illnesses commonly found in the patient population, antimalarials (including artemether and artesunate-lumefantrine combination therapy), typhoid (including quinolone antibiotics such as ciprofloxacin, macrolide antibiotics such as azithromycin, cephalosporin antibiotics such as ceftriaxone, or aminopenicillin antibiotics such as ampicillin), or dysentery.

[0092] In a preferred embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (11) or a pharma- ceutically acceptable salt thereof for the treatment of neuroinflammatory or neurodegenerative disorders, including traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of the disorder.

[0093] In a preferred embodiment, the neuroinflammatory or neurodegenerative disorder is Parkinson's disease.

[0094] In another preferred embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (11) and a suitable pharma- ceutically acceptable excipient for the treatment of a neuroinflammatory or neurodegenerative disorder.

[0095] The pharma- ceutically acceptable excipient may be at least one selected from a diluent, a carrier, a binder, a disintegrant, a lubricant, a surface active agent, and the like.

[0096] In another embodiment, the present invention further discloses the use of said compounds of formula (11) or suitable pharmaceutical compositions thereof for the treatment of neuroinflammatory or neurodegenerative diseases such as traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of disorders, preferably Parkinson's disease.

[0097] In another preferred embodiment, the present invention provides a method for treating a neuroinflammatory or neurodegenerative disorder using a pharmaceutical composition of a compound of formula (11) or a pharma- ceutically acceptable salt thereof. In a preferred embodiment, the present invention provides a method for treating a neuroinflammatory or neurodegenerative disorder using a compound of formula (11) or a pharmaceutical composition thereof.

[0098] In another preferred embodiment of the present invention, there is provided a process for preparing a stable pharmaceutical composition of a compound of formula (11).

[0099] Stable pharmaceutical compositions can be prepared by dry blending, wet granulation or dry granulation techniques known to those skilled in the art.

[0100] In the wet granulation process, the drug is mixed with one or more pharmaceutical excipients, granulated with a suitable binding liquid as described above to form wet granules, the wet granules are dried and optionally sieved, the dried granules are mixed with one or more suitable excipients among those described elsewhere and then compressed into tablets or filled into capsules.

[0101] In the dry blending process, the drug is mixed with all the required pharmaceutical excipients. The blend is mixed with one or more suitable excipients from those described elsewhere, and the final blend is compressed into tablets or filled into capsules.

[0102] In the dry granulation process, the drug is mixed with one or more pharmaceutical excipients, compressed into slugs, and these slugs are passed through a required sieve. The sieved granules are mixed with one or more suitable excipients from those described elsewhere and compressed into tablets or filled into capsules.

[0103] The one or more solvents or vehicles used in the formulation are selected from water, acetone, chloroform, dichloromethane, ethyl alcohol, ethyl acetate, methyl alcohol, isopropyl alcohol, and combinations thereof, as well as other such materials known to those of skill in the art.

[0104] In one embodiment, the pharma- ceutically acceptable excipient according to the present invention is at least one selected from diluents, carriers, binders, disintegrants, lubricants, surface active agents, and the like.

[0105] Diluents include, but are not limited to, polymethacrylates selected from lactose monohydrate, Eudragit, potassium chloride, sulfobutylether b-cyclodextrin, sodium chloride and spray dried lactose, combinations thereof, and other such materials known to those of skill in the art.

[0106] Carriers include, but are not limited to, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate and kaolin, microcrystalline cellulose and silicic acid, combinations thereof, and other such materials known to those of skill in the art.

[0107] Binders include, but are not limited to, carbopol, gellan, gum arabic, hydrogenated vegetable oils, polymethacrylates selected from Eudragit, xanthan, lactose and Zein, combinations thereof, and other such materials known to those of skill in the art.

[0108] Disintegrants include, but are not limited to, bicarbonate, chitin, gellan gum, polacrilin potassium and docusate sodium, combinations thereof, and other such materials known to those of skill in the art.

[0109] Lubricants include, but are not limited to, glycerin behenate, hydrogenated vegetable oils, sodium stearyl fumarate and myristic acid, combinations thereof, and other such materials known to those skilled in the art.

[0110] Surfactants include, but are not limited to, nonionic surfactants selected from alkyl polyglucosides, cocamide DEA, cocamide MBA, cocamide TEA, decyl maltoside, and octyl glucoside; anionic surfactants selected from arachinidic acid and arachidonic acid; cationic surfactants selected from cetyltrimethylammonium bromide and cetylpyridinium chloride, combinations thereof, and other such materials known to those skilled in the art.

[0111] General preparation process The novel compounds of the present invention can be prepared using the reactions and techniques described below, together with conventional techniques known to those skilled in the art of organic synthesis, or variations thereon as will be appreciated by those of skill in the art.

[0112] The reactions may be carried out in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. Preferred methods include, but are not limited to, those described below, in which all symbols are as defined above, unless otherwise defined below.

[0113] Compounds of general formula (I) may be prepared as depicted in the following schemes, with appropriate modifications / variations that are within the skill of the art. [ka] Here, R 1 , R2 Each of X, X, and Y is as defined above. Compounds 1 and 2 can be prepared by a variety of methods well known to those skilled in the art, including reported procedures. Treatment of compound (1) with isocyanato derivative (2) under appropriate conditions in the presence of a base such as sodium hydride and a suitable solvent provides compounds of formula (I).

[0114] The particular reaction conditions, solvents and other parameters required to carry out such steps are within the ability of those skilled in the art.

[0115] The present invention is further illustrated by the following non-limiting examples which describe preferred methods of practicing the invention and are provided without in any way limiting the scope of the invention.

[0116] Given in the Examples 1 H NMR spectral data (video infra) were recorded using a 400 MHz spectrometer (Bruker AVANCE-400) and are reported on the δ scale. Unless otherwise noted, the solvent used for NMR was CDCl with TMS as the internal standard. 3 It is. EXAMPLES

[0117] Example 1 N'-Cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide [ka] 1 H NMR (400MHz, DMSO-d 6):δ=7.95(bs,1H),7.23(d,J=4.0Hz,1H),6.82(d,J=4.0Hz,1H),6.81(s,1H),5.63(s,2H),2.77(t,J=7. 2Hz,4H),2.68-2.65(m,4H),1.94(qui,J=7.2Hz,4H),1.49(s,6H);MS(ESI):m / z(%)=445.10(100%)(M+H) + ,443.10(100%)(MH).

[0118] Example 2 N'-Cyano-4-fluoro-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-(2-hydroxypropan-2-yl)benzenesulfonimidamide [ka] 1 H NMR(400MHz,DMSO):δ=8.13(dd,J=2.4Hz,J=7.6Hz,1H),8.00(bs,1H),7.68-7.64(m,1H),7.24-7.19(m,2H),6.7 9(s,1H),2.76-2.60(m,8H),1.95-1.85(m,4H),1.50(s,3H),1.48(s,3H);MS(ESI):m / z(%)=456.88(100%)(M+H) + .

[0119] Example 3 N'-Cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonimidamide [ka] 1 H NMR (400MHz, DMSO-d 6):δ=8.10(bs,1H),7.55(s,1H),6.82(s,1H),6.79(s,1H),5.03(s,1H),2.77(t,J=7.2Hz,4H),2. 68(t,J=7.2Hz,4H),1.94(qui,J=7.2Hz,4H),1.38(s,6H);MS(ESI):m / z(%)=429.20(100%)(M+H) + ,427.30(100%)(MH).

[0120] Example 4 (E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(thiazol-2-yl)ethenesulfonamide [ka] 1 H NMR (400MHz, DMSO-d 6, D2O-X):δ=10.7(br,s,1H),8.23(s,1H),8.05(d,J=2.8Hz,1H),8.02(d,J=2.8Hz,1H),7.74(d,J=15.2Hz,1H),7.58(d,J=15. 2Hz,1H),6.96(s,1H),2.79(t,J=7.2Hz,4H),2.66(t,J=6.8Hz,4H),1.98-1.91(m,4H);MS(ESI):m / z(%)=389.92(100%)(M+H) + , 411.90(20%)(M+Na + ).

[0121] Example 5 (E)-2-(1-ethyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide [ka] 1H NMR (400MHz, DMSO): δ=10.55(bs,1H),8.20(s,1H),7.46-7.42(m,2H),7.29(d,J=14.8Hz,1H),7.13(s,1H),6.95(s,1H),4.16(q,J =7.2Hz,2H),2.82-2.78(m,4H),2.67-2.64(m,4H),1.98-1.91(m,4H),4.16(t,J=7.2Hz,3H);MS(ESI):m / z(%)=401.15(100%)(M+H) + ;423.15(50%)(M+Na) + .

[0122] Example 6 (E)-2-(1-ethyl-4-methyl-1H-imidazol-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethenesulfonamide [ka] 1 H NMR (400MHz, DMSO-d 6 ):δ=10.55(s,1H),8.16(s,1H),7.36(d,J=14.8Hz,1H),7.21(d,J=14.8Hz,1H),7.17(s,1H),6.95(s,1H),4.08(q,J=7.2Hz,2H),2.80 (t,J=7.2Hz,4H),2.66(t,J=7.2Hz,4H),2.12(s,3H),1.98-1.91(m,4H),1.27(d,J=7.2Hz,3H);MS(ESI):m / z(%)=415.18(100%)(M+H) + .

[0123] Example 7 (R,E)-2-(1-Ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide [ka] 1H NMR (400MHz, DMSO-d 6 ):δ=8.03(s,1H),6.92(s,1H),6.87(d,J=14.8Hz,1H),6.60-6.54(m,1H),3.27-3.16(m,3H),2.80(t,J=7.2Hz,4H),2.67(t,J=7 .2Hz,4H),2.35-2.33(m,2H),2.09-1.94(m,6H),1.81-1.73(m,2H),1.03(t,J=7.2Hz,3H);MS(ESI):m / z(%)=404.20(100%)(M+H) + .

[0124] Example 8 (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(pyrrolidin-2-yl)ethene-1-sulfonamide [ka] 1 H NMR (400MHz, DMSO-d 6 ):δ=9.71(brs,1H),7.49(s,1H),6.95(d,J=15.2Hz,1H),6.80(s,1H),6.36(dd,J=7.2Hz,J=15.2Hz,1H),4.08-4.02(m,1H),3.18-3.03(m,2H) ,2.77(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,4H),2.14-2.07(m,4H),2.03-1.80(m,6H),1.70-1.60(m,1H);MS(ESI):m / z(%)=376.10(100%)(M+H) + ,374.05(100%)(M-1).

[0125] Example 9 (R,E)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-methylpyrrolidin-2-yl)ethene-1-sulfonamide [ka] 1 H NMR (400MHz, DMSO-d 6 ):δ=10.53(brs,1H),7.97(s,1H),6.92(s,1H),6.84(d,J=15.2Hz,1H),6.53(d d,J=7.6Hz,J=15.2Hz,1H),3.13-3.04(m,1H),3.05-2.92(m,1H),2.80(t,J=7.2 Hz,4H),2.67(t,J=7.2Hz,4H),2.33-2.28(m,1H),2.26(s,3H),2.05-1.91(m,5 H),1.79-1.72(m,2H),1.59-1.54(m,1H);MS(ESI):m / z(%)=390.17(100%)(M+H) + , 388.07(30%)(M-1).

[0126] Example 10 (S,E)-2-(1-Ethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-ethanesulfonamide [ka] 1 H NMR (400MHz, DMSO-d 6 ):δ=8.03(s,1H),6.92(s,1H),6.87(d,J=14.8Hz,1H),6.60-6.54(m,1H),3.27-3.16(m,3H),2.80(t,J=7.2Hz,4H),2.67(t,J=7 .2Hz,4H),2.35-2.33(m,2H),2.09-1.94(m,6H),1.81-1.73(m,2H),1.03(t,J=7.2Hz,3H);MS(ESI):m / z(%)=404.20(100%)(M+H) + .

[0127] Example 11 (R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide [ka] 1 H NMR (400MHz, DMSO-d 6 ):δ=8.04(s,1H),6.93(s,1H),6.74(d,J=15.6Hz,1H),6.65(d,J=15.2Hz,1H),2.93-2.86(m,1H),2.80(t,J=7.2Hz,4H),2. 67(t,J=7.2Hz,4H),2.19(s,3H),1.99-1.91(m,5H),1.80-1.69(m,4H),1.13(s,3H),MS(ESI):m / z(%)=404.16(100%)(M+H) + .

[0128] Example 12 (S,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide [ka] 1H NMR(400MHz,DMSO-d6):δ=8.04(s,1H),6.93(s,1H),6.73(d,J=15.2Hz,1H),6.65(d,J=15.2Hz,1H),2.80(t,J=7.2Hz, 4H),2.68(t,J=7.2Hz,4H),2.20(s,3H),1.96(m,4H),1.72(m,4H),1.13(s,3H);MS(ESI):m / z(%)=404.25(100%)(M+1).

[0129] Example 13 Sodium (S,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide [ka] 1H NMR(400MHz,DMSO-d6):δ=7.33(s,1H),6.77(s,1H),6.56(d,J=15.2Hz,1H),6.16(d,J=16Hz,1H),2.76(t,J=7.2Hz,4H),2.69(t,J =7.2Hz,4H),2.62(m,1H),2.08(s,3H),1.90(m,4H),1.72(m,4H),1.60(m,3H),1.01(s,3H);MS(ESI):m / z(%)=404.20(100%)(M+1).

[0130] Example 14 Potassium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide [ka] 1 H NMR (400MHz, DMSO-d 6 ):δ=7.33(s,1H),6.77(s,1H),6.58(d,J=15.6Hz,1H),6.18(d,J=15.6Hz,1H),2.77-2.72(m,5H),2.69(t,J=7.2Hz,4H),2.64-2.58(m ,1H),2.08(s,3H),1.90(quin,J=7.6Hz,4H),1.75-1.70(m,3H),1.62-1.60(m,1H),1.01(s,3H);MS(ESI):m / z(%)=404.21(100%)(MK) + .

[0131] Example 15 Sodium (R,E)-((2-(1,2-dimethylpyrrolidin-2-yl)vinyl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide [ka] 1 H NMR (400MHz, DMSO-d 6):δ=7.36(s,1H),6.77(s,1H),6.57(d,J=15.6Hz,1H),6.19(d,J=15.6Hz,1H),2.76(t,J=7.2Hz,5H),2.69(t,J=7.2Hz,4H),2.64-2.59( m,1H),2.08(s,3H),1.91(quin,J=7.6Hz,4H),1.74-1.68(m,3H),1.62-1.60(m,1H),1.01(s,3H);MS(ESI):m / z(%)=404.17(100%)(M-Na) + .

[0132] Example 16 (E)-N'-Cyano-2-((S)-1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonimidamide [ka] 1 H NMR (400MHz, DMSO-d 6 ):δ=9.94(s,1H),8.06(s,1H),6.97(d,J=16.0Hz,1H),6.83(s,1H),6.56-6.48(m,1H),3.58(brs,1H),3.24-3.12(m,1H),2.77 (t,J=7.2Hz,4H),2.69(t,J=7.2Hz,7H),2.10-1.99(m,3H),1.95-1.88(m,5H),1.53-1.36(m,3H);ESI-Q-TOF-MS:m / z[M-HCl+H] + Calculate for [C22H30N5O2S] + :428.2120;found:428.2052.

[0133] Example 17 (E)-N'-Cyano-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-((R)-1-methylpyrrolidin-2-yl)ethene-1-sulfonimidamide [ka] 1 H NMR (400MHz, DMSO-d 6 ):δ=9.82(s,1H),8.06(s,1H),7.11-7.02(m,1H),6.83(s,1H),6.43-6.35(m,1H),4.99(brs,1H),3.62-3.61(m,1H),3.09-3.07( m,1H),2.77(t,J=7.2Hz,7H),2.70(t,J=7.2Hz,4H),2.33-2.27(m,1H),2.1-1.88(m,7H);MS(TOF):m / z(%)=414.1897(100%)(M+H) + , 412.1765(100%)(M-1) - .

[0134] Example 18 (E)-N'-Cyano-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonimidamide [ka] 1 H NMR (400MHz, DMSO-d 6 ):δ=9.98(s,1H),8.03(s,1H),6.94-6.90(m,1H),6.83(s,1H),6.54-6.51(m,1H),2.77(t,J=7.2Hz,5H),2.70(t,J=7.2Hz ,5H),2.62(brs,3H),1.99-1.90(brs,2H),1.97-1.93(m,6H),1.48-1.46(m,3H);MS(TOF):m / z(%)=428.2097(100%)(M+H) + , 426.1941(60%)(M-1) - .

[0135] Example 19 N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((1S,8aR)-3,3,8a-trimethyloctahydropyrrolo[1,2-a]pyrazin-1-yl)methanesulfonamide [ka] 1 H NMR (400MHz, DMSO-d 6 ):δ=7.92(s,1H),6.87(s,1H),3.42-3.26(m,5H),3.07-3.01(m,1H),2.89-2 .80(m,1H),2.89-2.80(m,1H),2.77(t,J=7.2Hz,4H),2.73-2.67(m,4H),2.5 8-2.44(m,1H),2.38-2.33(m,1H),1.98-1.92(m,4H),1.69-1.61(m,2H),1.3 1(s,3H),1.18(s,3H),0.78(s,3H);MS(TOF):m / z(%)=461.2537(100%)(M+H) + .

[0136] Example 20 N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((4S,8aS)-2,3,3,8a-tetramethyloctahydropyrrolo[1,2-a]pyrazin-4-yl)methanesulfonamide [ka] 1 H NMR (400MHz, DMSO-d 6):δ=8.03(s,1H),6.93(s,1H),3.52-3.48(m,2H),3.18-3.09(m,1H),3.09-3.0 1(m,1H),3.00-2.88(m,1H),2.81(t,J=7.2Hz,4H),2.70(t,J=7.2Hz,4H),2.36 -2.33(m,2H),2.19(s,3H),2.01-1.93(m,4H),1.76-1.69(m,1H),1.67-1.54(m ,3H),1.01-1.04(m,6H),0.86(s,3H);MS(TOF):m / z(%)=475.2709(100%)(M+H) + ,473.2593(20%)(M-1).

[0137] Example 21 (E)-3-(Dimethylamino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)prop-1-ene-1-sulfonamide [ka] 1 H NMR (400MHz, DMSO-d 6 ):δ=10.22(brs,1H),7.94(s,1H),6.91(s,1H),6.86(d,J=15.2Hz,1H),6.62-6.55(m,1H),3.27(t,J=6.0Hz,2H),2. 79(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.30(s,6H),1.99-1.91(m,4H);MS(ESI):m / z(%)=364.1513(100%)(M+H) + .

[0138] Example 22 Sodium (E)-((3-(dimethylamino)-3-methylbut-1-en-1-yl)sulfonyl)((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)amide [ka] 1H NMR (400MHz, DMSO-d 6 ):δ=7.36(s,1H),6.77(s,1H),6.51(d,J=15.6Hz,1H),6.23(d,J=15.6Hz,1H),2.76(t,J=7.2Hz,4H),2.6 9(t,J=7.2Hz,4H),2.11(s,1H),1.94-1.87(m,4H),1.06(s,6H);MS(TOF):m / z(%)=392.1987(100%)(M+H) + ,390.1841(20%)(M-1).

[0139] Example 23 (S,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide [ka] 1 H NMR (400MHz, DMSO-d 6 ):δ=7.93(s,1H),6.91(s,1H),6.71(d,J=15.2Hz,1H),6.60(d,J=15.6Hz,1H),2.85-2.83(m,1H),2.80(t,J=7.2Hz,4H),2.73-2.71(m,1H) ),2.67(t,J=7.2Hz,4H),2.15(s,2H),1.95(quin,J=7.2Hz,4H),1.81-1.69(m,4H),1.10(s,3H).ESI-Q-TOF-MS:m / z405.2268(100%)[M+H] + ,403.1901(100%)[MH] - .

[0140] Example 24 (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide [ka] 1 H NMR (400MHz, DMSO-d 6 ):δ=7.94(s,1H),6.91(s,1H),6.72(d,J=15.2Hz,1H),6.61(d,J=15.2Hz,1H),2.88-2.83(m,1H),2.80(t,J=7.2Hz,4H),2.75-2.71(m,1H) ),2.67(t,J=7.2Hz,4H),2.15(s,2H),1.95(quin,J=7.2Hz,4H),1.82-1.69(m,4H),1.11(s,3H),ESI-Q-TOF-MS:m / z405.2104(100%)[M+H] + ,403.1915(100%)[MH] - .

[0141] Example 25 (R,E)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-2-(1-(methyl-d)pyrrolidin-2-yl)ethene-1-sulfonamide [ka] 1 H NMR (400MHz, DMSO-d 6 ):δ=10.5(brs,1H),7.99(s,1H),6.92(s,1H),6.86(d,J=15.2Hz,1H),6.56(dd,J 1 =7.6Hz,J 2= 15.2Hz,1H),3.12-3.06(m,2H),2.80(t,J=7.2Hz,4H),2.67(t,J=7.2Hz,4H),2.38-2.32(m,1H),2.25(s,2H),2.08-2 .01(m,1H),1.95(quin,J=7.2Hz,4H),1.80-1.73(m,2H),1.63-1.54(m,1H),ESI-Q-TOF-MS:m / z391.1956(100%)[M+H] + ,389.1756(100%)[MH] - .

[0142] Example 26 (E)-3-(bis(methyl-d)amino)-N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-3-methylbut-1-ene-1-sulfonamide [ka] 1 H NMR (400MHz, DMSO-d 6 ):δ=7.87(s,1H),6.89(s,1H),6.73(d,J=15.2Hz,1H),6.61(d,J=15.2Hz,1H),2.79(t,J=7.6Hz,4H),2.6 7(t,J=7.2Hz,4H),2.30(s,4H),1.97-1.93(m,4H),1.21(s,6H),ESI-Q-TOF-MS:m / z394.2150(100%)[M+H] + ,392.1980(100%)[MH] - .

[0143] Example 27 Sodium (R,E)-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)((2-(2-methyl-1-(methyl-d)pyrrolidin-2-yl)vinyl)sulfonyl)amide [ka] 1 H NMR (400MHz, DMSO-d 6 ):δ=7.35(s,1H),6.77(s,1H),6.55(d,J=15.6Hz,1H),6.18(d,J=15.6Hz,1H),2.78-2.68(m,9H),2.64-2.59(m,1H),2.0 6(s,2H),1.94-1.87(m,4H),1.74-1.70(m,3H),1.60-1.57(m,1H),1.01(s,3H);MS(ESI):m / z(%)=405.2101(100%)(M+H) + , 403.1921(100%)(M-1).

[0144] Example 28 N-((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-1-((1S,8aR)-3,3,8a-trimethyl-2-(methyl-d)octahydropyrrolo[1,2-a]pyrazin-1-yl)methanesulfonamide [ka] 1 H NMR (400MHz, DMSO-d 6 ):δ=8.01(bs,1H),6.94(s,1H),3.54(s,2H),2.98-2.50(m,10H),2.45-2.09(m,5H),1.99-1.9 1(m,4H),1.81-1.65(m,4H),1.10(s,6H),0.8(s,3H);MS(TOF):m / z(%)=476.2797(100%)(M+H) + ;474.2623(100%)(M-1) - .

[0145] Example 29 (R,E)-2-(1,2-dimethylpyrrolidin-2-yl)-N-((1,2,3,5-tetrahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide [ka] 1 H NMR (400MHz, DMSO-d 6 ):δ=8.27(bs,1H),7.18(s,1H),6.79-6.73(m,2H),6.66-6.62(m,1H),6.46-6.45(m,1H),3.34-3.22(m,2H),2.90-2.86(m,3 H),2.78-2.72(m,3H),2.22(s,3H),2.03-1.96(m,2H),1.88-1.73(m,4H),1.15(s,3H);MS(TOF):m / z(%)=402.25(100%)(M+H) + .

[0146] Example 30 (E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((2-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide [ka] 1 H NMR (400MHz, DMSO-d 6 ):δ=10.5(bs,1H),8.10(s,1H),6.91(s,1H),6.77-6.65(m,2H),4.79(d,J=3.6Hz,1H),4.43(d,J=2.8Hz,1H),3.03- 2.97(m,3H),2.81-2.78(m,7H),2.33(s,3H),1.99-1.76(m,6H),1.16(s,3H);MS(TOF):m / z(%)=420.19(100%)(M+H) + .

[0147] Example 31 (E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((3-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide [ka] 1 H NMR (400MHz, DMSO-d 6 ):δ=8.05(s,1H),6.90(s,1H),6.75(t,J=15.2Hz,1H),6.60(t,J=15.6Hz,1H),5.01(t,J=3.2Hz,1H),3.18-2.89(m,2H),2.87-2.67(m ,3H),2.68-2.60(m,2H),2.32-2.19(m,4H),2.07-1.93(m,2H),1.90-1.79(m,6H),1.17(s,3H);MS(TOF):m / z(%)=420.1937(50%)(M+H) + ,418.1843(5%)(M-1).

[0148] Example 32 (E)-2-((R)-1,2-dimethylpyrrolidin-2-yl)-N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)ethene-1-sulfonamide [ka] 1 H NMR (400MHz, DMSO-d 6 ):δ=10.4(brs,1H),8.02(s,1H),7.02(s,1H),6.75(t,J=15.2Hz,1H),6.65(t,J =15.6Hz,1H),5.13(d,J=4.4Hz,1H),4.98(d,J=3.6Hz,1H),2.88-2.79(m,3H),2 .77-2.60(m,4H),2.56-2.54(m,1H),2.30-2.24(m,1H),2.20(s,3H),2.00-1.91 (m,2H),1.84-1.67(m,5H),1.13(s,3H);MS(TOF):m / z(%)=420.1947(100%)(M+H) + , 418.1800(20%)(M-1).

[0149] Biological activity: In vitro assay: THP1 monocytes were differentiated with PMA (100 ng / ml) and cultured for 20 hours at 37°C in the presence of 5% CO2. 2X10 5 Differentiated cells were plated. Cells were primed with 500ng / mL lipopolysaccharide and cultured under the same conditions for 4 hours. Cells were then treated with various concentrations of compounds for 30 minutes, followed by 5mM ATP for 1 hour. Supernatants were collected and analyzed with IL-1b (Mabtech Cat#3415-1H-20) or TNF-a (Mabtech; Cat#3510-1H-20) detection kits. Data were analyzed using GraphPad Prism V7.0. Dose-response curves (DRCs) were calculated by fitting cell viability data in GraphPad Prism using nonlinear regression analysis to obtain IC 50The IC values ​​were determined for the in vitro IL-1β inhibitory activity of representative compounds. 50 ) are shown in Table 1. [Table 1]

[0150] MPTP-induced NLRP3-assay of microglial cells in vitro: Adult mouse brains were used. Brains were washed with PBS, cut into pieces, and then mechanically homogenized. The homogenized suspension was digested with 0.25% trypsin-EDTA solution at 37°C for 10 min. The suspension was filtered through a cell strainer and centrifuged at 365g for 5 min at room temperature. The pellet was resuspended in RPMI complete medium and layered on 30% isotonic Percoll (SIP). This gradient mixture was centrifuged at 700g for 10 min at room temperature. The phase between PBS and 30% Percoll containing myelin was discarded. The pelleted cells containing microglia were washed and seeded at 50000 cells / well in poly-L-lysine coated 96-well plates and incubated at 37°C, 5% CO 2 The plates were cultured overnight in an incubator. After overnight culture, a test compound was added and the plates were cultured for another hour. LPS (1 μg / mL) was then added and the plates were cultured for 4 hours. Then, 20 μM nigericin was added to each well and the plates were cultured again for 1 hour. After 1 hour, the supernatant was collected and IL-1β secretion was measured using the Mouse R&D system ELISA kit (MLB00C). [Table 2]

[0151] result: When microglial cells were primed with LPS and activated with nigericin, significant induction of NLRP3 was observed through increased secretion of IL-1β. Both test compounds, compound 11 of the present invention and MCC950, inhibited inflammasome activation. Compound 11 of the present invention showed better activity compared to MCC950, with a half-maximal inhibitory concentration of 43 nM compared to 108 nM for MCC950.

[0152] In vivo efficacy studies: Demonstration of in vivo efficacy of test compounds in rats and mice, oral route of administration.

[0153] Animals: All animal experiments were performed with in-house bred female rats and mice. Animals were housed in groups of six per cage for one week to acclimate to the vivarium conditions (25 ± 4°C, 60-65% relative humidity, 12:12 h light / dark cycle, lights on at 7:30 am). All animal experiments were approved by the "Zydus Research Center Animal Ethics Committee" and performed in accordance with internationally valid guidelines.

[0154] In vivo LPS and ATP induced IL-1β assay: Female C57 mice (6-8 weeks) were injected intraperitoneally with 50 μg / mouse lipopolysaccharide (LPS) in PBS. Animals were immediately treated with test substances or vehicle. Two hours after LPS injection, animals received 12.5 mg / mouse ATP in PBS via the intraperitoneal route. Thirty minutes after ATP injection, serum was collected for IL-1β measurement by ELISA.

[0155] Pharmacokinetic analysis in plasma and brain tissue: The aim of the study was to investigate the intracerebral distribution of the test compound after a single oral dose of the test compound in C57 mice. The study was performed using male or female C57 mice (n=4 per time point). The animals had free access to food and water during the study period. The dosing formulation was prepared in 1% v / v Tween® 80, 99% v / v 0.5% methylcellulose, purified water. The animals were orally dosed with a 30 mg / kg test substance suspension formulation at a dose of 10.0 mL / kg. The formulation strength was 3.0 mg / mL. A total of six blood and brain tissue samples were taken at different time intervals. Blood samples were taken at specific time points after dosing, and then the animals were sacrificed for brain tissue. Blood and brain samples were taken at 0.25, 0.5, 1, 2, 4 and 8 hours after dosing (n=4 / time point). Blood was collected from the retroorbital plexus under mild isoflurane anesthesia in tubes containing Na-heparin (~20 IU / mL blood) and kept on ice. Blood samples were centrifuged at 4000 rpm for 15 min to obtain plasma, which was stored at -70 ± 20°C until analysis. Immediately after blood collection, animals were perfused under deep isoflurane anesthesia with 4 mL of 1X PBS buffer, and brain tissue was harvested. The harvested brain samples were immediately placed on ice and stored at -70 ± 20°C until homogenization. Brain tissue samples were homogenized in phosphate-buffered saline using a Polytron tissue homogenizer, and the brain homogenate concentration was kept at 0.2 g / mL. Plasma and brain tissue homogenate samples were analyzed for total and unbound test compound concentrations using a calibration curve compatible with a separately developed research LC-MS / MS assay. The calibration curve range was linear over the range of 5 to 2000 ng / mL for total concentrations of test substances and 0.2 to 200 ng / mL for the unbound fraction. [Table 3] [Table 4]

[0156] Phase 2a POC Study: A Phase 2a POC study of a test compound (compound 11 of the present invention) in Parkinson's disease patients. Parkinson's disease patients who are clinically diagnosed with Parkinson's disease, are between 45 and 75 years of age, and have a Modified Hoehn and Yahr Stage of less than 3 are included in the study. Approximately 15 Parkinson's disease patients are enrolled in the study. The study will be conducted for 14 days at a dose range of approximately 25-75 mg twice daily. Eligible patients will receive 27 doses of the test compound (compound 11 of the present invention) twice daily from day 1 to day 13, in the morning before breakfast and in the evening before dinner. On day 14, a single dose will be administered before breakfast.

[0157] Within 28 days of the screening period, eligible patients will be admitted to the clinical ward on Day (-1). Patients will continue to be admitted to the clinical ward for 12 hours after the first dose on Days 1 and 14 for safety assessments, and pharmacokinetic and pharmacodynamic sampling. Patients will report back to the site on Days 2, 4, 7, 10, 14, 15, and 21 (follow-up) for safety assessments, and pharmacokinetic and pharmacodynamic blood sampling.

[0158] The primary objective of this study is to evaluate the safety and tolerability of oral administration of the test compound (compound 11 of the present invention) in patients with Parkinson's disease. Secondary and exploratory objectives include evaluation of the pharmacokinetics and pharmacodynamics of the test compound (compound 11 of the present invention) administered orally twice daily for 14 days. Blood samples will be collected at multiple time points for pharmacokinetic and pharmacodynamic evaluation. Cerebrospinal fluid (CSF) will be collected 2 hours after the last dose to correlate the concentrations of the test compound (compound 11 of the present invention) in CSF and plasma. Exploratory parameters such as α-synuclein levels, NLRP3, soluble LAG-3, Toll binding protein and hs C-reactive protein will be measured in blood at defined time points.

[0159] Safety will be assessed by physical and neurological examinations, vital signs, laboratory tests, ECGs, and recording of AEs / SAEs at various time points during the study.

[0160] While the invention has been described in terms of specific embodiments thereof, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Claims

1. A pharmaceutical composition for the treatment of a neuroinflammatory or neurodegenerative disorder, comprising a compound of formula (11) 【Chemical 1】 or a pharmaceutically acceptable salt thereof.

2. 2. The pharmaceutical composition of claim 1, wherein the neuroinflammatory or neurodegenerative disorder is selected from traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of disorders.

3. The pharmaceutical composition according to claim 1, wherein the neuroinflammatory or neurodegenerative disorder is Parkinson's disease.

4. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount of the compound of formula (11) or a pharmaceutically acceptable salt thereof is selected from 1 mg to 500 mg, preferably selected from 1 mg to 250 mg, and more preferably selected from 1 mg to 150 mg.

5. 2. The pharmaceutical composition according to claim 1, wherein the compound of formula (11) or a pharmaceutically acceptable salt thereof is administered by oral, topical or parenteral administration route, preferably by oral administration route.

6. The pharmaceutical composition of claim 1, wherein the compound of formula (11) or a pharmaceutically acceptable salt thereof is administered in combination with other suitable therapeutic agents.

7. 10. Use of a compound of formula (11) according to claim 1 for preparing a medicament for the treatment of a neuroinflammatory or neurodegenerative disorder.

8. 8. The use of a compound of formula (11) according to claim 7, wherein the compound is administered in a daily dosage selected from 1 mg to 500 mg, preferably selected from 1 mg to 250 mg, more preferably selected from 1 mg to 150 mg.

9. 8. The use of a compound of formula (11) according to claim 7, wherein the neuroinflammatory or neurodegenerative disorder is selected from traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), Huntington's disease and other related forms of disorders.

10. 8. The use of the compound of formula (11) according to claim 7, wherein the neuroinflammatory or neurodegenerative disorder is Parkinson's disease.

11. 10. The pharmaceutical composition of claim 1, comprising a compound of formula (11) and other pharmaceutically acceptable excipients for the treatment of neuroinflammatory or neurodegenerative disorders.

12. The pharmaceutical composition of claim 1, wherein the compound of formula (11) or a pharmaceutically acceptable salt thereof is administered in combination with other suitable therapeutic agents.

13. 10. Use of the pharmaceutical composition of claim 1 for preparing a medicament for the treatment of a neuroinflammatory or neurodegenerative disorder.

14. 12. The pharmaceutical composition of claim 11, wherein the other pharmaceutically acceptable excipients are selected from diluents, carriers, binders, disintegrants, lubricants and surfactants.

15. 15. The pharmaceutical composition of claim 14, wherein the diluent is selected from lactose monohydrate, Eudragit, potassium chloride, polymethacrylates selected from sulfobutylether b-cyclodextrin, sodium chloride and spray dried lactose, and suitable combinations thereof.

16. 15. The pharmaceutical composition of claim 14, wherein the carrier is selected from lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate and kaolin, microcrystalline cellulose, silicic acid, and suitable combinations thereof.

17. 15. The pharmaceutical composition of claim 14, wherein the binder is a carbomer selected from carbopol, gellan, gum arabic, hydrogenated vegetable oil, polymethacrylates selected from Eudragit, xanthan, lactose and Zein, and suitable combinations thereof.

18. 15. The pharmaceutical composition of claim 14, wherein the disintegrant is selected from bicarbonate, chitin, gellan gum, polacrilin potassium, docusate sodium, and suitable combinations thereof.

19. 15. The pharmaceutical composition of claim 14, wherein the lubricant is selected from glycerin behenate, hydrogenated vegetable oil, sodium stearyl fumarate, myristic acid, and suitable combinations thereof.

20. 15. The pharmaceutical composition of claim 14, wherein the surfactant is a nonionic surfactant selected from alkyl polyglucosides, cocamide DEA, cocamide MBA, cocamide TEA, decyl maltoside and octyl glucoside; anionic surfactant selected from arachinidic acid and arachidonic acid; cationic surfactant selected from cetyltrimethylammonium bromide and cetylpyridinium chloride, and suitable combinations thereof.

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