Benzimidazole derivatives useful as inhibitors of nod-like receptor protein 3

Abstract

Novel compounds of Formula (I), and the pharmaceutically acceptable salts thereof, are inhibitors of NLRP3 and may be useful in the treatment, prevention, management, amelioration, control and suppression of diseases mediated by NLPR3. The compounds of the present invention may be useful in the treatment, prevention or management of diseases, disorders and conditions mediated by NLRP3 such as, but not limited to, obesity, gout, pseudogout, CAPS, NASH, MASH, fibrosis, heart failure, idiopathic pericarditis, atopic dermatitis, inflammatory bowel disease, Alzheimer's Disease, Parkinson's Disease, dementia with Lewy bodies (DLB), and traumatic brain injury.

Description

BENZIMIDAZOLE DERIVATIVES USEFUL AS INHIBITORS OF NOD-LIKE RECEPTOR PROTEIN 3CROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application Nos. 63 / 729,518, filed December 9, 2024; the disclosure of which is incorporated herein by reference in its entirety.FIELD

[0002] This disclosure relates generally to benzimidazole derivative compounds that modulate or inhibit nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 and that may be useful for therapy and / or prophylactic treatment.BACKGROUND

[0003] Inflammasomes function as central signaling hubs of the innate immune system. They are multi-protein complexes assembled after activation of intracellular pattern recognition receptors (PRRs) by a variety of pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). It has been shown that inflammasomes can be formed by nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and Pyrin and HIN200-domain-containing proteins (Van OpdenboschN and Lamkanfi M., Immunity, 2019 Jun 18; 50(6): 1352-1364). Inflammasome activation triggers a cascade of events that releases pro-inflammatory cytokines and promotes an inflammatory form of cell death called pyroptosis induced by the activation of Gasdermin. Pyroptosis is a unique form of inflammatory cell death that leads to the release of not only cytokines but also other intracellular components that promote a broader immune response both of the innate and of the acquired immune system. Thus, inflammasome activation is a major regulator of the inflammatory cascade.

[0004] The (NOD)-like receptor protein 3 (NLRP3) inflammasome is the most well-studied of all the inflammasomes. NLRP3 can be activated by numerous stimuli including environmental crystals, pollutants, host-derived DAMPs and protein aggregates (Tartey S and Kanneganti TD, Immunology, 2019 Apr; 156(4): 329-338). Danger-associated molecular patterns that engage NLRP3 include uric acid and cholesterol crystals that cause gout and atherosclerosis, amyloid-P fibrils that are neurotoxic in Alzheimer's disease, and asbestos particles that cause mesothelioma (Kelley et al., Int J Mol Sci, 2019 Jul 6; 20 (13)). Additionally, NLRP3 is activated by infectiousagents, such as vibno cholerae, fungal pathogens, such as Aspergillus Jumigatus and Candida albicans, adenoviruses, influenza A virus and SARS-CoV-2 (Tartey and Kanneganti, 2019 (see above); Fung et al., Emerg Microbes Infect, 2020 Mar 14; 9(l):558-570).

[0005] The NLRP3 activation mechanism in humans remains unclear. It has been suggested that the NLRP3 inflammasome requires regulation at both the transcriptional and thepost-transcriptional level (Yang Y et al., Cell Death Dis, 2019 Feb 12; 10(2): 128). TheNOD-like receptor protein 3 (NLRP3) is a protein-coding gene that encodes a protein consisting of a N-terminal pyrin domain, a nucleotide-binding site domain (NBD), and a leucine-rich repeat (LRR) motif on the C-terminal (Inoue et al., Immunology’, 2013, 139, 11-18: Sharif et al., Nature, 2019 Jun; 570 (7761): 338-343).

[0006] In response to sterile inflammatory’ danger signals PAMPs or DAMPs, NLRP3 interacts with the adaptor protein, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC). and with the protease caspase- 1 to form the NLRP3 inflammasome. Upon activation, procaspase- 1 undergoes autoproteolysis and cleaves gasdermin D (Gsdmd) to produce the N-terminal Gsdmd molecule that leads to pore-formation in the plasma membrane and results in a lytic form of cell death called pyroptosis. Alternatively, caspase-1 cleaves thepro-inflammatory' cytokines pro-IL-10 and pro-IL-18 to allow release of its biological active form (Kelley et al., 2019 - supra). The NLRP3 inflammasome activation results in the release of the inflammatory' cytokines IL-10 (interleukin-10) and IL- 18 (interleukin- 18), which when dysregulated can lead to a number of diseases.

[0007] Dysregulation of the NLRP3 inflammasome or its downstream mediators are associated with numerous immune diseases, inflammatory diseases, auto-immune diseases, and auto-inflammatory diseases. Activation of the NLRP3 inflammasome has been linked to the following diseases and disorders: Cryopyrin-associated Periodic Syndromes; sickle cell disease; systemic lupus ery thematosus; allodynia; graft versus host disease; hepatic disorders including nonalcoholic steatohepatitis (NASH), chronic liver disease, viral hepatitis, alcoholic steatohepatitis, and alcoholic liver disease; inflammatory bowel diseases including Crohn's disease and ulcerative colitis; inflammatory joint disorders including gout, pseudogout, arthropathy, osteoarthritis, rheumatoid arthritis; additional rheumatic diseases including dermatomyositis, Still’s disease, and juvenile idiopathic arthritis, kidney related diseases including hyperoxaluria, lupus nephritis, hypertensive nephropathy, hemodialysis related inflammation, diabetic nephropathy, and diabetic kidney disease, and other inflammatory diseases (Miyamae T, Paediatr Drugs, 2012 Apr 1, 14(2): 109-17; Szabo G and Petrasek J, Nat Rev Gastroenterol Hepatol, 2015 Jul; 12(7): 387-400; Zhen Y and Zhang H, Front Immunol, 2019 Feb 28; 10:276; Vande Walle Let al.. Nature, 2014 Aug 7; 512 (7512): 69-73; Knauf et al.. Kidney Int. 2013 Nov; 84(5):895-901; Krishnan et al., Br J Pharmacol, 2016 Feb; 1 73(4):752-65); Shahzad et al.. Kidney Int, 2015 Jan; 87(l):74-84; Jankovic, et al. J Exp Med. 2013 Sep 23; 210(10): 1899-910.). The onset and progression of neuroinflammation-related disorders, such as brain infection, acute injury, multiple sclerosis, amyotrophic lateral sclerosis, and additional neurodegenerative diseases such as Parkinson s and Alzheimer's disease have also been linked to NLRP3 inflammasome activation (Sarkar et al., NPJ Parkinsons Dis, 2017 Oct 17; 3:30).

[0008] Cardiovascular and metabolic disorders such as atherosclerosis, type I and ty pe II diabetes and diabetes complications including nephropathy and retinopathy, peripheral artery’ disease, acute heart failure, and hypertension have been associated with NLRP3 (Ridker et al., CANTOS Tnal Group. N Engl J Med, 2017 Sep 21; 377(12): 1119-1131; and Toldo S and Abbate A, Nat Rev Cardiol, 2018 Apr; 15(4):203-214). NLRP3 associated skin diseases include wound healing and scar formation; inflammatory skin diseases such as acne, atopic dermatitis, hidradenitis suppurativa, and psoriasis (Kelly et al., Br J Dermatol. 2015 Dec; 1 73(6)). NLRP3 inflammasome activity’ has also been linked to respiratory’ conditions such as asthma, sarcoidosis, acute respiratory’ distress syndrome, Severe Acute Respiratory’ Syndrome (SARS) (Nieto-Torres et al., Virology, 2015 Nov; 485:330-9)); and ocular diseases including age-related macular degeneration (AMD) and diabetic retinopathy (Doyle et al.. Nat Med, 2012 May; 18(5): 791 -8). Cancers linked to NLRP3 include myeloproliferative neoplasms, leukemias, myelodysplastic syndromes, myelofibrosis, lung cancer, and colon cancer (Ridker et al., Lancet, 2017 Oct 21; 390(10105): 1833-1842; Derangere et al., Cell Death Differ. 2014 Dec; 21(12): 1914-24;Basiorka et al., Lancet Haematol, 2018 Sep; 5(9): e393-e402, Zhang et al., Hum Immunol, 2018 Jan; 79(l):57-62).

[0009] Immune diseases and inflammatory' disorders are typically’ difficult to diagnose or treat efficiently and effectively. Most treatments include treatment of the symptoms, slowing down disease progression, lifesty le changes, and surgery'.

[0010] There remains a need for inhibitors of NLRP3 to provide new treatments for diseases and disorders associated wi th NLRP3 inflammasome activation and dysregulation. The compounds of the present invention are useful for the treatment and prevention of diseases, disorders, and conditions mediated by formation and propagation of the NLRP3 inflammasome.

[0011] NLRP3 inhibitors are disclosed in the following publications: Nat. 2022, 1; Cell. 2021, 184, 1; J. Mol. Biol. 2021, 433, 167308; J. Med. Chem. 2021, 64, 101; Nat. Chem. Biol. 2019, 15, 556; Nat. 2019, 570, 338; Nat. Chem. Biol. 2019, 15, 560; PLOS Biol. 2019, 1; Nat. Med. 2015, 21, 248; Cell. 2014, 156, 1193; Nat. Immunol. 2014, 15, 738; PNAS. 2007, 104, 8041;Nat. 2006, 440, 9; Immunity. 2006, 24, 317. Several patent applications describe NLRP3 inhibitors, including WO 2021 / 239885, WO 2021 / 209552, WO 2021 / 209539, WO 2021 / 193897, WO 2020 / 018975, WO 2020 / 037116, WO 2020 / 021447, WO 2020 / 010143, WO 2019 / 079119, WO 2019 / 0166621, WO 2019 / 121691, US 11,319,319, and US 2020 / 0361898.SUMMARY

[0012] The present disclosure relates to novel compounds of structural Formula (I):R4and pharmaceutically acceptable salts thereof.

[0013] The compounds of structural Formula (I), and embodiments thereof, are inhibitors of NOD-like receptor protein 3 (NLRP3) and may be useful in the treatment and prevention of diseases, disorders and conditions mediated by NLRP3 such as. but not limited to, obesity, gout, pseudogout (chondrocalcinosis), cryopyrin-associated periodic syndromes (CAPS), non-alcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, heart failure, idiopathic pericarditis, atopic dermatitis, inflammatory bowel disease, Alzheimer’s Disease, Parkinson’s Disease, dementia with Lewy bodies (DLB), and traumatic brain injury.

[0014] The present invention also relates to pharmaceutical compositions comprising the compounds of the present invention and a pharmaceutically acceptable carrier.

[0015] The present invention also relates to methods for the treatment, management, prevention, alleviation, amelioration, suppression, or control of disorders, diseases, and conditions that may be responsive to inhibition of the NLRP3 receptor in a subject in need thereof by administering the compounds and pharmaceutical compositions of the present invention.

[0016] The present invention also relates to the use of compounds of the present invention for manufacture of a medicament useful in treating diseases, disorders, and conditions that may be responsive to the inhibition of the NLRP3 receptor.

[0017] The present invention is also concerned with treatment or prevention of these diseases, disorders, and conditions by administering the compounds of the present invention in combination with a therapeutically effective amount of another agent that may be useful to treat the disease, disorder, and condition. The invention is further concerned with processes for preparing the compounds of this invention.26110

[0018] The summary of the technology described above is non-limiting and other features and advantages of the technology will be apparent from the following detailed description, and from the claims.DETAILED DESCRIPTION

[0019] The present disclosure is directed to compounds of Formula (I):and pharmaceutically acceptable salts thereof, whereinX is selected from:1) S, and2) NR5;R1is selected from:1) Ci-6 alkyl,2) Co-3 alkylene-(monocyclic Cs-8 cycloalkyl),3) Co-3 alkylene-(bicyclic C4-8 cycloalkyl),4) C0-3 alkylene-(Cs-io spiro-cycloalkyl),5) C0-3 alkylene-(tricyclic Cs-9 cycloalkyl),6) C0-3 alkylene-(cubyl),7) C0-3 alkylene-(3- to 9-membered monocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P),8) C0-3 alkylene-(4- to 9-membered bicyclic heterocycloalkyl containing 1. 2, or 3 ring heteroatoms selected from N, S, O, and P),9) C0-3 alkylene-(5- to 9-membered spirocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P), 10) C0-3 alkylene-(5- to 10-membered heteroaryl containing 1. 2, or 3 ring heteroatoms selected from N, S, O, and P),11) NH-C 1-6 alkyl,12) NH-C0-3 alkylene-(monocyclic C3-8 cycloalkyl),13) NH-C0-3 alkylene-(bicyclic C4-8 cycloalkyl),14) NH-C0-3 alkylene-(Cs-io spiro-cycloalkyl), and15) NH-C0-3 alky lene-(tri cyclic Ce-9 cycloalkyl),wherein said R1group is unsubstituted or substituted with 1 to 5 substituents independently selected from R6;R2is phenyl unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from:1) OH.2) halo,3) Ci-6 alkyl, and4) Ci-6 haloalkyl containing from 1 to 3 independently selected halogens; R3is selected from:1) H,2) halo, and3) Ci-6 alky l,R4is selected from:1) H. and2) Ci-6 alkyl,wherein said R4Ci-6 alkyl is unsubstituted or substituted with 1 to 5 substituents independently selected from:1) OH. and2) halo;R3is selected from:1) H,2) Ci-6 alkyl, and3) C3-7 cycloalky 1,wherein said R5C1-6 alkyl or R3C3-7 cycloalkyd is unsubstituted or substituted with 1 to 5 substituents independently selected from:1) OH,2) halo,3) CN,3) NRa2;wherein each Rais independently selected from H and C1-6 alkyl; and each R6is independently selected from:1) OH,2) halo,3) CN,4) oxo.5)6) Ci-6 alky l, which may be straight or branched and which is unsubstituted or substituted with 1 to 4 substituents selected from OH. halo, CN, oxo, and Ci-6 alkoxy,7) Ci-6 alkoxy, which may be straight or branched and which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, and Ci-6 alkoxy,8) C3-7 cycloalkyl, which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, C1-3 alkyl, C1-3 haloalkyl, and C1-6 alkoxy,9) 3- to 9-membered monocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N. S, O. and P, and which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, C1-3 alkyl, C1-3 haloalkyl, and C1-6 alkoxy,10) C5-7 aryl, which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, and C1-6 alkoxy.11) methylene-Cs-7 aryl, which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, and C1-6 alkoxy,12) 5- to 10-membered heteroary l containing at least one ring heteroatom selected from N, S, O, and P, and which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, C1-3 alkyl. C1-3 haloalkyl, and C1-6 alkoxy.

[0020] The invention has numerous embodiments, which are summarized beloyv. The invention includes the compounds as shown and also includes individual diastereoisomers, enantiomers, and epimers of the compounds, and mixtures of diastereoisomers and / or enantiomers thereof including racemic mixtures.

[0021] A first embodiment is directed to compounds of Formula (I) in which X is selected from S and NR5.

[0022] In a first aspect of this embodiment, X is S.

[0023] In a second aspect of the embodiment, X is NR5, R5is selected from H, C1-6 alkyl, and C3-7 cycloalkyl, and wherein the R5C1-6 alkyl, R5C1-6 alkoxy, or R5C3-7 cycloalkyl isunsubstituted or substituted with 1 to 5 substituents independently selected from OH, halo, and NRa2, where each Rais independently selected from H and Ci-6 alkyl.

[0024] In instances of this second aspect of the first embodiment, X is NR5, R5is selected from H, Ci-6 alky l, and C3-7 cycloalkyl, and wherein the R5C1-6 alkyl or R5C3-7 cycloalkyl is unsubstituted or substituted with 1 to 5 substituents independently selected from OH, halo, and NRa2, where each Rais independently selected from H and C1-6 alkyl. In specific instances of this second aspect of the first embodiment, R5is selected from H, methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl, and the R5methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl is unsubstituted or substituted with 1 to 2 substituents independently selected from OH, halo, and NRa2, where each Rais independently selected from H and C1-6 alkyl. In instances of this second aspect of the first embodiment, R5is selected from H, methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl, and the R5methyl, ethyl, isopropyl, cyclopropyl, and cyclobut l is unsubstituted or substituted with 1 to 2 substituents independently selected from OH, F, and NH2. In instances of this second aspect of the first embodiment, R5is selected from H, CH3, CH2OH, CF2H, CH2CH3, CHOHCHs, CH(NH2)CHS, C(CHS)2OH, cyclopropyl, and cyclobutyl. In specific aspects of the first embodiment, X is selected from NH, N-CH3, N-CH2OH, N-CF2H, N-CH2CH3, N-CHOHCH3, N-CH(NH2)CH3, N-C(CH3)2OH, N-cyclopropyl, and N-cyclobutyl. In a particular instance of this second aspect of the first embodiment, R5is selected from H. CH3, and CH2CH3. In specific instances of the second aspect of the first embodiment, X is selected from NH, N-CH3, and N-CH2CH3. In specific instances, of this second aspect of the first embodiment, R5is H. In specific instances, of this second aspect of the first embodiment, X is NH.

[0025] A second embodiment is directed to compounds of Formula (I) in which R1is selected from: C1-6 alkyl, C0-3 alkylene-(monocyclic C3-8 cycloalkyl), C0-3 alkylene-(bicychc C4-8 cycloalkyl), C0-3 alkylene-(C5-io spiro-cycloalkyl), C0-3 alkylene-(tricyclic Ce-9 cycloalkyl), C0-3 alkylene-(cubyl), C0-3 alkylene-(3- to 9-membered monocyclic heterocycloalk l containing 1, 2, or 3 ring heteroatoms selected fromN, S, O, and P), C0-3 alkylene-(4- to 9-membered bicyclic heterocycloalkyl containing 1. 2, or 3 ring heteroatoms selected from N, S. O, and P), C0-3 alkylene-(5- to 9-membered spirocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P), C0-3 alkylene-(5- to 10-membered heteroaryl containing 1, 2, or 3 ring heteroatoms selected fromN, S, O, and P), NH-C1-6 alkyl, NH-C0-3 alkylene-(monocyclic C3-8 cycloalkyl), NH-C0-3 alkylene-(bicyclic C4-8 cycloalkyl), NH-C0-3 alkylene-(C5-io spiro-cycloalkyl), andNH-Co-s alky lene-(tri cyclic Ce-9 cycloalkyl). Aspects of this second embodiment are directed to compounds of Formula (I) in which R1is selected from: C1-6 alkyl, C0-3 alkylenemonocyclic C3-8 cycloalkyl), C0-3 alkylene-(bicyclic C4-8 cycloalkyl), C0-3 alkylene-(C5-io spiro-26110cy cloalkyl), C0-3 alkylene-(tricyclic Ce-9 cycloalkyl), C0-3 alkylene-(3- to 9-membered monocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P), C0-3 alkylene-(4- to 9-membered bicyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected fromN, S, O, and P), C0-3 alkylene-(5- to 9-membered spirocyclic heterocycloalkyl containing 1. 2, or 3 ring heteroatoms selected from N, S. O, and P), and C0-3 alkylene-(5- to 10-membered heteroaryl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P), wherein said R1group is unsubstituted or substituted with 1 to 5 substituents independently selected from R6. In aspects of this second embodiment, R1is selected from: C1-4 alkyl, monocyclic C3-6 cycloalkyl, methylene-(monocyclic C3-6 cycloalkyl), bicyclic C5-8 cycloalkyl, tricyclic C7 cycloalkyl, 4- to 7-membered monocyclic heterocycloalkyl containing 1 or 2 ring heteroatoms selected fromN, S, and O, methylene-(4- to 7-membered monocyclic heterocycloalkyl containing 1 or 2 ring heteroatoms selected from N, S, and O), 4- to 9-membered bicyclic heterocycloalkyl containing 1. 2, or 3 ring heteroatoms selected fromN, S, and O, methylene-(4- to 9-membered bicyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, and O), 6- to 9-membered spirocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, and O), 5-membered heteroaryl containing 1 or 2 ring heteroatoms selected fromN, S, and O, and methylene-(5-membered heteroaryl containing 1 or 2 ring heteroatoms selected from N, S, and O). wherein said R1group is unsubstituted or substituted with 1 to 5 substituents independently selected from R6.

[0026] In aspects of this second embodiment, each R6is selected independently from OH, halo, CN, oxo,Q _6 which may be straight or branched and which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, and C1-6 alkoxy, C1-6 alkoxy, which may be straight or branched and which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, and C1-6 alkoxy, C3-7 cycloalkyd, which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, C1-3 alkyl, C1-3 haloalkyl, and C1-6 alkoxy, 3- to 9-membered monocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P, and which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, C1-3 alky l, C1-3 haloalkyl, and C1-6 alkoxy, C5-7 ary l, which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, and C1-6 alkoxy, methylene-Cs-7 aryl, which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, and C1-6 alkoxy, and 5- to 10-membered heteroaryl containing at least one ring heteroatom selected from N, S, O, and P, and which is unsubstitutedor substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, C1-3 alkyl, C1-3 haloalkyl, and C1-6 alkoxy.

[0027] In aspects of this second embodiment, each R1is selected fromHOFNCI ^NCX|-NCX / HO KX OA OX HO O2H_

[0028] A third embodiment is directed to compounds of Formula (I) in which R2is phenyl phenyl unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from: OH, halo, C1-6 alkyl, and C1-6 haloalkyl containing from 1 to 4 independently selected halogens. In aspects of this third embodiment, R2is phenyl substituted by 2 to 4 substituents independently selected from: OH, halo, Ci-6 alkyl, and Ci-6 haloalkyl containing from 1 to 3 independently selected halogens. In particular aspects, R2is phenyl substituted by 2 or 4 substituents independently selected from: OH, Cl, F, CH3, and CF3. In more particular aspects, R2is phenyl substituted by OH and CF3. In still more particular aspects, R2is phenyl substituted by OH, CH3, and CF3. In additional particular aspects, R2is phenyl substituted by OH, CH3, and Cl. In additional particular aspects, R2is phenyl substituted by OH, CH3, F, and Cl. In specific aspects,specific aspects, R2isF3C

[0029] A fourth embodiment is directed to compounds of Formula (I) in which R3is selected from H, halo, and C1-6 alkyl, wherein the R3C1-6 alkyl is unsubstituted or substituted with 1 to 5 substituents independently selected from OH and halo. In specific aspects of this embodiment, R3is H. In other specific aspects, R3is halogen. In specific instances of these aspects, R3is fluoro or chloro. In specific instances, R3is fluoro. In specific instances, R3is chloro. In specific instances, R3is H, Cl, or F.

[0030] A fifth embodiment is directed to compounds of Formula (I) in which R4is selected from H, and C1-6 alkyl, wherein the R4C1-6 alkyl is unsubstituted or substituted with 1 to 5 substituents independently selected from OH and halo. In specific aspects of this embodiment, R4is H. In other specific aspects, R4is C1-6 alky l, which is unsubstituted or substituted with 1 to 5 substituents independently selected from OH and halo. In instances of these aspects, R4is unsubstituted C1-6 alkyl. In specific instances of these aspects, the R4C1-6 alkyl is selected from26110methyl, ethyl, propyl, and isopropyl. In specific instances, R4Ci-6 alkyl is methyl. In specific instances, R4Ci-6 alkyl is ethyl. In specific instances, R4Ci-6 alky l is propyl. In specific instances, R4Ci-6 alkyl is isopropyl. In other instances, R4is selected from H, and methyl said methyl unsubstituted or substituted with 1 to 3 substituents selected from OH and halo. In yet another instance. R4is selected from H and methyl.

[0031] Embodiments of the disclosure are directed to compounds of Formula (I):R4or a pharmaceutically acceptable salt thereof, whereinX is S;R1is selected from:F261102611026110R2is phenyl, unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from:1) OH,2) halo,3) Ci-6 alkyd, and4) Ci-6 haloalkyl containing from 1 to 3 independently selected halogens; R3is selected from:1) H,2) halo, and3) Ci-6 alky 1:R4is selected from:1) H, and2) Ci-6 alkyl,wherein said R4Ci-6 alkyl is unsubstituted or substituted with 1 to 5 substituents independently selected from:1) OH, and261102) halo;

[0032] Embodiments of the disclosure are directed to compounds of Formula (I):R4or a pharmaceutically acceptable salt thereof, whereinX is N;R1is selected from:o oOHHO2611026110R2is phenyl, unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from:1) OH,2) halo,3) C1-6 alkyd, and4) C1-6 haloalkyl containing from 1 to 3 independently selected halogens; R3is selected from:H,halo, andCi-6 alkyd;R4is selected from:1) H, and2) Ci-6 alkyd,wherein said R4C1-3 alkyl is unsubstituted or substituted with 1 to 5 substituents independently selected from:1) OH, and2) halo.

[0033] Embodiments of the disclosure are directed to compounds of Formula (I):R4or a pharmaceutically acceptable salt thereof, wherein26110X is NR5;R1is selected from:261102611026110R2is phenyl, unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from:1) OH,2) halo,3) Ci-6 alkyl, and4) Ci-6 haloalkyl containing from 1 to 3 independently selected halogens; R3is selected from:1) H.2) halo, and3) Ci-6 alkyl;R4is selected from:1) H, and2) Ci-6 alkyl.wherein said R4Ci-6 alkyl is unsubstituted or substituted with 1 to 5 substituents independently selected from:1) OH, and2) halo;R5is selected from:1) H,2) Ci-6 alkyl, and3) C3-7 cycloalkyl,wherein said R5C1-6 alkyl or R5C3-7 cycloalkyl is unsubstituted or substituted with 1 to 5 substituents independently selected from:1) OH,2) halo,3) CN,4) NRa2,wherein each Rais independently selected from H and C1-6 alkyl; and26110each R6is independently selected from:1) OH,2) halo,3) CN,4) oxo.5),6) Ci-6 alky l, which may be straight or branched and which is unsubstituted or substituted with 1 to 4 substituents selected from OH. halo, CN, oxo, and Ci-6 alkoxy,7) Ci-6 alkoxy, which may be straight or branched and which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, and Ci-6 alkoxy,8) C3-7 cycloalkyl, which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, C1-3 alkyl, C1-3 haloalkyl, and C1-6 alkoxy,9) 3- to 9-membered monocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N. S, O. and P, and which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, C1-3 alkyl, C1-3 haloalkyl, and C1-6 alkoxy,10) C5-7 aryl, which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, and C1-6 alkoxy,11 ) methylene-Cs-7 aryl, which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, and C1-6 alkoxy, and 12) 5- to 10-membered heteroaryl containing at least one ring heteroatom selected from N, S, O, and P, and which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN. oxo, C1-3 alkyl. C1-3 haloalkyl, and C1-6 alkoxy.

[0034] Embodiments of the disclosure are directed to compounds of Formula (I):R4or a pharmaceutically acceptable salt thereof, whereinX is NR5;R1is selected from:oR2is phenyl, unsubstituted or substituted by 1, 2, or 3 substituents independently selected from:1) OH,2) halo,3) Ci-2 alkyl, and4) Ci-2 haloalkyl containing from 1 to 3 independently selected halogens; R3is selected from:1) H,2) Cl, and3) F;R4is selected from:1) H, and2) CH3;R5is selected from:1) H.2) CH3, and3) CH2CH3.

[0035] Embodiments of the disclosure are directed to compounds of Formula (I):R4or a pharmaceutically acceptable salt thereof, whereinX is NR5;R1is selected from:oR2is selected from:R3is H or F;R4is selected from:1) H, and2) CH3;R5is selected from:1) H.2) CH3, and3) CH2CH3.

[0036] Illustrative, but non-limiting, examples of compounds of embodiments that are useful as inhibitors of the NLRP3 are the following compounds:1. (< S')-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)- 1 -methyl- \H- imidazo[4,5-Z?]pyridin-2-yl)-l-methylpiperidin-2-one,2. (7?)-5-(5-(2-hydroxy-6-methyl-4-(trif1uoromethyl)phenyl)- l-methyl- IH- imidazo[4,5-6]pyridin-2-yl)-l-methylpiperidin-2-one,3. 2-f2-(33-difluorocyclobutyl)-l-methyl-imidazo[4,5-b]pyridin-5-yl]-3-methyl-5- (trifluoromethyl)phenol,4. 3-methyl-2-(l-methyl-2-tetrahydropyran-4-yl-imidazo[4,5-b]pyridin-5-yl)-5- (trifluoromethyl)phenol,5. 2-(2-((l,5S,6.s)-3-oxabicyclo[3.1.0]hexan-6-yl)-l-methyl-127-imidazo[4.5- 6]pyridin-5-yl)-3-methyl-5-(trifluoromethyl)phenoL6. 2-(2-((17?,55',6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-l-methyl-177-imidazo[4,5- 6]pyridin-5-yl)-3-methyl-5-(trifluoromethyl)phenol,7. (5 )-5-[l-ethyl-5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]imidazo[4.5- 6]pyridin-2-yl]-l-methyl-piperidin-2-one,8. (5S)-5-[l-ethyl-5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]imidazo[4,5- 6]pyridin-2-yl] - 1 -methyl-piperidin-2-one,9. 3-methyl-2-[l-methyl-2-[(67?)-5,6,7,8-tetrahydrotetrazolo[1.5-a]pyridin-6- yl]imidazo[4.5-6]pyridin-5-yl]-5-(trifluoromethyl)phenol,10. 3-methyl-2-[l-methyl-2-[(6S)-5,6,7,8-tetrahydrotetrazolo[l,5-a]pyridin-6- yl]imidazo[4,5-6]pyridin-5-yl]-5-(trifluoromethyl)phenol,11. (5 / ?)-5-| 5-| 2-hydroxy-6-methy l-4-(tri fluoromethy Ijpheny 11- 1 -methyl-imidazo[4,5- b] pyridin-2-y 1] - 1 -isopropy l-piperidin-2-one,12. (51S')-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-l-methyl-imidazo[4,5- 6]pyridin-2-yl] - 1 -isopropy l-piperidin-2-one,13. (5 / ?)-5-|5-|2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl|-l -methyl-imidazo|4.5- b] pyri din-2 -y 1] piperidin-2-one.14. (5S)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-l-methyl-imidazo[4,5- 6]pyridin-2-yl]piperidin-2-one,15. (5?)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-l-methyl-imidazo[4,5- 6|pyridin-2-yl |-l-|(3 / ?)-tetrahydrofuran-3-yl|piperidin-2-one.16. (5S)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-l-methyl-imidazo[4,5- 6]pyridin-2-yl]-l-[(37?)-tetrahydrofuran-3-yl]piperidin-2-one,17. (5?)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-l-methyl-imidazo[4,5- 6|pyridin-2-yl|-l-|(3, S')-tctrahydrofiiran-3-yl |pipendin-2-onc.2611018. (51S')-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-l-methyl-imidazo[4,5- 6]pyridin-2-yl]-l-[(31S)-tetrahydrofuran-3-yl]piperidin-2-one,19. 3-methyl-2-[l-methyl-2-[(65 or7?)-3-methyl-5,6,7,8-tetrahydro- [l,2,4]triazolo[4,3-a]pyridin-6-yl]imidazo[4,5-6]pyridin-5-yl]-5- (trifluoromethyl)phenol,20. (5l)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl) phenyl]-! -methyl-imidazo[4, 5- 6]pyridin-2-yl] - 1 -(2-methoxy ethyl)piperidin-2-one,21. (57?)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl) phenyl]-l-methyl- imidazo[4,5-6]pyridin-2-yl]-l-(2-methoxyethyl)piperidin-2-one,22. (S)-4-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl) phenyl] -1 -methyl-imidazo[4, 5- 6]pyridin-2-yl]methyl]-l-methyl-pyrrolidin-2-one,23. (7?)-4- [ [5 -[2-hy droxy-6-methy l-4-(trifluoromethyl) phenyl] - 1 -methyl-imidazo [4,5- 6|pyridin-2-yl |melhyl |-l -methyl-pyrrolidin-2-one.24. (R)- 1 -ethyl-5-(5-(2-hy droxy-6-methyl-4-(trifluoromethyl)pheny 1)- 1 -meth l-17 / - imidazo[4,5-A]pyridin-2-yl)piperidin-2-one,25. (< S)-1 -ethyl-5-(5-(2-hy droxy-6-methyl-4-(trifluoromethyl)phenyl)- 1 -methyl- 1H- imidazo[4,5-6]pyridin-2-yl)piperidin-2-one,26. (7?)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-l / 7- imidazo[4,5-£]pyridin-2-yl)-l-propylpiperidin-2-one,27. (S)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-177- imidazo[4,5-6]pyridin-2-yl)-l-propylpiperidin-2-one,28. (7?)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-l / 7- imidazo[4,5-6]pyridin-2-yl)-l-(2,2,2-trifluoroethyl)piperidin-2-one, 29. (5’)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-l / f- imidazo[4,5-Z>]pyridin-2-yl)-l-(2,2,2-trifluoroethyl)piperidin-2-one, 30. (7?)-5-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)-6-methyl-177-imidazo[4,5- 6]pyridin-2-yl)-l-methylpiperidin-2-one,31. (S)-5-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)-6-methyl- l / / -imidazo[4,5- &]pyridin-2-yl)-l-methylpiperi din-2 -one,32. (7?)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-7-methyl-17 / - imidazo[4,5-&]pyridin-2-yl)-l-methylpiperidin-2-one,33. (S)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-7-methyl-17 / - imidazo[4,5-i5]pyridin-2-yl)-l-methylpiperidin-2-one,2611034. 3-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-7-methyl-l / -imidazo[4,5- 6]pyridin-2-yl)bicyclo[l.1. l]pentane-l-carbonitrile,35. 3-methyl-2-(7-methyl-2-(l-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-l / 7- imidazo[4,5-Z>]pyridin-5-yl)-5-(trifluoromethyl)phenol,36. 2-(2-((lR,5S.6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-7-methyl-17f-imidazo[4,5- 6]pyridin-5-yl)-3-methyl-5-(trifluoromethyl)phenol,37. 2-(2-((lR,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)-7-methyl-177-imidazo[4,5- 6]pyridin-5-yl)-3-methyl-5-(trifluoromethyl)phenol,38. (57?)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-17 / - imidazo[4,5-Z>]pyridin-2-yl]piperidin-2-one,39. (5< S)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-l / f- imidazo[4,5-6]pyridin-2-yl]piperidin-2-one,40. (5?)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl) phenyl|-7-methyl-IT7- imidazo[4,5-6]pyridin-2-yl]-l-isopropyl-piperidin-2-one,41. (5S)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl) phenyl]-7-methyl-177- imidazo[4,5-Z>]pyridin-2-yl]-l-isopropyl-piperidin-2-one,42. (7?)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-7-methyl-177- irnidazo[4,5-6]pyridin-2-yl)-l-(2-methoxyethyl)piperidin-2-one, 43. (S)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-7-methyl-177- imidazo[4,5-Z?]pyridin-2-yl)-l-(2-methoxyethyl)piperidin-2-one, 44. 2-(2-((ls,3s)-3-fluorocyclobutyl)-7-methyl-177-imidazo[4,5-Z>]pyridin-5-yl)-3- methyl-5-(trifluoromethyl)phenol,45. 2-(2-((ls r)-3-fluorocyclobutyl)-7-methyl-l / / -imidazo[4,5-ri]pyridin-5-yl)-3- methyl-5-(trifluoromethyl)phenol,46. (R) 5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-7 -(trifluoromethyl)-377- imidazo[4,5-6]pyridin-2-yl)-l-methyl-513-piperidin-2-one,47. (S) 5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-7-(trifluoromethyl)-377- imidazo[4,5-&]pyridin-2-yl)-l-methyl-513-piperidin-2-one,48. (R) 5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-7- (trifluoromethyl)-177-imidazo[4,5-&]pyridin-2-yl)-l-methylpiperidin-2-one, 49. (S) 5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)- 1 -methyl-7 - (trifluoromethyl)- l7 / -imidazo|4.5- / )|pyridin-2-yl)-l-methylpiperidin-2-one. 50. (< S’)-3-methyl-2-(l-methyl-2-(2-methylmorpholino)-177-imidazo[4,5-6]pyridin-5- yl)-5-(trifluoromethyl)phenol,2611051. 2-(2-((3S’,4S')-3-fluoro-4-methoxypyrrolidin- 1-yl)- 1 -methyl- l / / -imidazo[4,5- 6]pyridin-5-yl)-3-methyl-5-(trifluoromethyl)phenol,52. (?)-2-(2-(3-fluoropyrrolidin-l-yl)-l-methyl-l / Z-imidazo[4,5-7>]pyridin-5-yl)-3- methyl-5-(trifluoromethyl)phenol,53. (S)- 1 -(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)- 1 -methyl-IH- imidazo[4,5- >]pyri din-2 -yl)pyrrolidine-3-carbonitrile,54. (7?)-2-(2-(3-methoxypyrrolidin-l-yl)-l-methyl-177-imidazo[4,5-S]pyridin-5-yl)-3- methyl-5-(trifluoromethyl)phenol,55. (17?,5J?,67?)-2-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-12 / - imidazo[4,5-6]pyridin-2-yl)-2-azabicyclo[3.2.0]heptan-6-ol,56. (R) 5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) thiazolo[4,5-?]pyridin- 2-yl)- 1 -methy lpiperidin-2-one, and57. (5) 5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)thiazolo[4.5-&]pyridin-2- yl)-l -methy lpiperidin-2-one,and pharmaceutically acceptable salts thereof.

[0037] Particular examples of compounds of embodiments include:1) (7?)-l-cyclopropyl-4-((6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-2H- pyrazolo[3,4-b]pyridin-2-yl)methyl)pyrrolidin-2-one;2) (S’)- 1 -cy clopropyl-4-((6-(2-hydroxy-6-methy l-4-(trifluoromethyl)phenyl)-2H- pyrazolo[3,4-b]pyridin-2-yl)methyl)pyrrolidin-2-one;3) 3-[6-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]pyrazolo [3,4-b]pyridin-2- yl]bicyclo[l.1.1] pentane- 1 -carbonitrile;4) (S')-2-(2-(3-isopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2H- pyrazolo[3,4-b]pyridin-6-yl)-3-methyl-5-(trifluoromethyl)phenol;5) (?)-2-(2-(3-isopropyl-5,6,7,8-tetrahydro-[l,2,4] triazolo[4,3-a]pyridin-6-yl)-2H- pyrazolo[3,4-b]pyridin-6-yl)-3-methyl-5-(trifluoromethyl)phenol;6) (S)-l-ethyl-5-(6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-2H- pyrazolo[3,4-b]pyridin-2-yl)piperidin-2-one;7) (?)-l-ethyl-5-(6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-2H- pyrazolo[3,4-b]pyri din-2 -yl)piperidin-2-one:8) (7?)-l-ethyl-4-((5-fluoro-6-(2-hydroxy-4-(trifluoromethyl) phenyl)-2H- pyrazolo[3,4-b]pyridin-2-yl)methyl)pyrrolidin-2-one;9) (S')- 1 -ethyl-4-((5-fluoro-6-(2-hy droxy-4-(trifluoromethyl) phenyl)-2H- pyrazolo[3,4-b]pyridin-2-yl)methyl)pyrrolidin-2-one;2611010) (< S')-5-(6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-3-((S)-l-hydroxyethyl)- 2H-pyrazolo[3,4-b]pyridin-2-yl)-l-methylpiperidin-2-one; and11) (< S)-5-(6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-3-((S)-l -hydroxyethyl)- 2H-pyrazolo[3,4-b]pyridin-2-yl)-l-methylpiperidin-2-one;and pharmaceutically acceptable salts thereof.

[0038] Illustrative, but non-limiting, examples of compounds of embodiments that are useful as inhibitors of the NLRP3 are compounds of the following structures:26110pharmaceutically acceptable salts thereof.

[0039] Although the specific stereochemistries described above are preferred, other stereoisomers, including diastereoisomers, enantiomers, epimers, and mixtures of these may also have utility in treating NLRP3 mediated diseases.

[0040] Synthetic methods for making the compounds are disclosed in the Examples shown below. Where synthetic details are not provided in the examples, the compounds are readily made by a person of ordinary skill in the art of medicinal chemistry or synthetic organic chemistry by applying the synthetic information provided herein. Where a stereochemical center is not defined, the structure represents a mixture of stereoisomers at that center. For such26110compounds, the individual stereoisomers, including enantiomers, diastereoisomers, and mixtures of these are also compounds of the invention.Definitions

[0041] Listed below are definitions of various terms used herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0042] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well-known and commonly employed in the art.

[0043] As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0044] As used herein, the term “about” in quantitative terms refers to plus or minus 10% of the value it modifies (rounded up to the nearest whole number if the value is not sub-dividable, such as a number of molecules or nucleotides).

[0045] All ranges disclosed herein are inclusive of the recited endpoint and independently combinable (for example, the range of “from 50 mg to 500 mg” is inclusive of the endpoints, 50 mg and 500 mg, and all the intermediate values). The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value; they are sufficiently imprecise to include values approximating these ranges and / or values.

[0046] As used herein, the term “comprising” may include the embodiments “consisting of’ and “consisting essentially of.” The terms “comprise(s),” “include(s),” “having,” “has,” “may,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients / steps and permit the presence of other ingredients / steps. However, such description should be construed as also describing compositions or processes as “consisting of’ and “consisting essentially of’ the enumerated components, which allows the presence of only the named components or compounds, along with any acceptable carriers or fluids, and excludes other components or compounds.

[0047] “Alkyl” means monovalent, saturated carbon chains, which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise. Other groups having the26110prefix “alk”, such as alkoxy and alkanoyl, also may be linear or branched, or combinations thereof, unless the carbon chain is defined otherwise. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.

[0048] “Alkylene” means bivalent saturated carbon chains, which may be linear, branched, or combinations thereof.

[0049] “Cycloalkyl” means a saturated monocyclic, bicyclic, tricyclic carbocyclic ring, having a specified number of carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Bicyclic carbocyclic rings, which feature two joined rings, may be fused (in which adjacent rings share at least twoatoms and bridgehead carbons are directly connected, such as<^^ / >) or bridged (in whichone or more atoms spans or bridges another ring of atoms, such as ’ CZZ ). Tricyclic carbocyclic rings similarly feature three fused or bridged rings. Spirocyclic rings, in which asingle carbon atom is shared by either two rings (such as ’ -P ). are also contemplated herein and may be formed by two substituents attached to the same carbon atom.

[0050] “Heterocycloalkyl” means monocyclic, bicyclic, or tricyclic ring or ring system having 3 to 14 ring atoms and containing at least one ring heteroatom selected from N (including NH and NR*, where R* is a substituent such as an alkyl group), S (including SO and SO2), O, and P (including PO, PO2, and POR*, where R* is a substituent such as an alkyl group). The heterocycloalkyl ring may be substituted on the ring carbons and / or the ring nitrogen, sulfur, or phosphorus. Heterocycloalky l rings may be non-aromatic or partially aromatic, in the case of bicyclic or tricyclic ring systems. Bicyclic heterocycloalkyls, which feature two joined rings, may be fused (in which adjacent rings share at least two atoms and bridgehead atoms are directlyconnected, such asI — <4 z° ) or bridged (in which one or more atoms spans or bridges another I — ( \ o I — r Nring of atoms, such asor \ — / ). Tricyclic heterocycloalkyls similarly feature three fused or bridged rings. Spirocyclic rings, in which a single atom is shared by either two rings(such as)arealso contemplated herein and may be formed by two substituents attached to the same atom. Non-limiting examples of heterocycloalky l groups include tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, azetidinyl, piperazinyl, piperidinyl,26110morpholinyl, oxetanyl, tetrahydropyranyl, thiomorpholine, tetrahydropyran, octahydro-lH-pyrrolo[2,3-c]pyridine, 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyridine, 4,5,6,7-tetrahydro-lH-benzo[d][l,2,3]triazole, 3-azabicyclo[3.1.0]hexane, 5-azaspiro[2.4]heptane, l-oxa-7-azaspiro[4.4]nonane, l-oxa-8-azaspiro[4.5]decane, 3-oxa-l,8-diazaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane. l-oxa-3,8-diazaspiro[4.5]decane, 2-oxa-8-azaspiro[4.5]decane, 1.8-diazaspiro[4.5]decane, and l-oxa-4,9-diazaspiro[5.5]undecane.

[0051] “Aryl” means a monocyclic, bicyclic, or tricyclic carbocyclic aromatic ring or ring system containing 6 to 14 carbon atoms, wherein at least one of the rings is aromatic. Nonlimiting examples of aryl include phenyl and naphthyl.

[0052] “Heteroaryl” means a monocyclic, bicyclic, or tricyclic ring or ring system containing 5 to 14 ring atoms and containing at least one ring heteroatom selected from N (including NH and NR*, where R* is a substituent such as an alkyl group), S (including SO and SO2), O, and P (including PO, PO2, and POR*, where R* is a substituent such as an alkyl group), wherein at least one of the heteroatom containing rings is aromatic. In embodiments, a heteroaryl group is monocyclic and has 5 or 6 ring atoms (“5- or 6-membered monocyclic heteroaryl”). In other embodiments, a heteroaryl group is bicyclic and has 8 to 10 ring atoms (“8- to 10-membered bicyclic heteroary l”). In other embodiments, a heteroary l group is bicyclic and has 9 to 11 ring atoms (“9- to 11-membered bicyclic heteroaryl”). Non-limiting examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, quinolyl, indolyl, isoquinolyl, quinazolinyl, dibenzofuranyl, and the like.

[0053] “Halogen” or “halo” includes fluorine, chlorine, bromine, and iodine. In one embodiment, halogen is fluorine, chorine, or bromine. In another embodiment, halogen is fluorine or chlorine. In another embodiment, halogen is chlorine or bromine. In another embodiment, halogen is fluorine or bromine. In another embodiment, halogen is fluorine. In another embodiment, halogen is chlorine. In another embodiment, halogen is bromine.

[0054] “Saturated” means containing only single bonds.

[0055] “Unsaturated” means containing at least one double or triple bond. In one embodiment, unsaturated means containing at least one double bond. In another embodiment, unsaturated means containing at least one triple bond.

[0056] When any variable (e.g., Raetc.) occurs more than one time in any constituent or in Formula (I), its definition on each occurrence is independent of its definition at every' other occurrence. Also, combinations of substituents and / or variables are permissible only if such26110combinations result in stable compounds. A squiggly or wavy line at the end of or across a bondin a substituent variable (such asor represents the point of attachment.

[0057] Under nomenclature used throughout this disclosure, the point of attachment is described first, followed by the terminal portion of the designated side chain. For example, a C1-5 alkylcarbonylamino C1-6 alkyl substituent is equivalent to:O-C1_5alkyl - C-NH-C-|.6alkyl

[0058] In choosing compounds of the present invention, one of ordinary skill in the art will recognize that the various substituents are to be chosen in conformity with well-known principles of chemical structure connectivity and stability.

[0059] The term ‘"substituted” shall be deemed to include multiple degrees of substitution by a named substituent. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

[0060] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, salts and / or dosage forms which are, using sound medical judgment, and following all applicable government regulations, safe and suitable for administration to a human being or an animal.

[0061] Compounds of Formula (I) may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to encompass all such isomeric forms of the compounds of Formula (I).

[0062] The independent syntheses of optical isomers and diastereoisomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology7disclosed herein. Their absolute stereochemistry7may be determined by the X-ray crystallography of crystalline products or cry stalline intermediates which are derivatized, if necessary7, with a reagent containing an asymmetric center of known absolute configuration or sufficient heavy atoms to make an absolute assignment.

[0063] If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well-known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound26110to form a diastereoisomeric mixture, followed by separation of the individual diastereoisomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diastereoisomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.

[0064] Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

[0065] Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.

[0066] Tautomers are defined as compounds that undergo rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula (I).

[0067] In the compounds of general Formula (I), the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominately found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of structural Formula (I). For example, different isotopic forms of hydrogen (H) include protium ('H), deuterium (2H), and tritium (3H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Tritium is radioactive and may therefore provide for a radiolabeled compound, useful as a tracer in metabolic or kinetic studies. Isotopically-enriched compounds within structural Formula (I), can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0068] Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition,26110some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.

[0069] It is generally preferable to administer compounds of the present invention as enantiomerically pure formulations. Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.Salts

[0070] It will be understood that, as used herein, references to the compounds of the present invention are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.

[0071] The compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt. The term ‘'pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term “pharmaceutically acceptable salt” refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, formic, fumarate, gluceptate, gluconate, glutamate, glycollylars-anilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxy naphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate, diphosphate, poly galacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, trifluoroacetate, and valerate. Where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic26110non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N, N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, poly amine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0072] Also, in the case of a carboxy lic acid (-COOH) or alcohol group being present in the compounds of the present invention, pharmaceutically acceptable esters of carboxylic acid derivatives, such as methyl, ethyl, or pivaloyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl, O-pivaloyl, O-benzoyl, and O-aminoacyl, can be employed. Included are those esters and acyl groups know n in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations.

[0073] The term "prodrug” means compounds that are rapidly transformed, for example, by hydrolysis in blood, in vivo to the parent compound, e.g., conversion of a prodrug of Formula (I) to a compound of Formula (I), or to a salt thereof; a thorough discussion is provided in T.Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, and in Edward B. Roche, ed., Biorev ersible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. This invention includes prodrugs of the novel compounds of this invention. Solvates, and in particular, the hydrates of the compounds of the present invention are included in the present invention as well.Utilities

[0074] The compounds of the present invention are potent inhibitors of NOD-Like Receptor Protein 3 (NLRP3). The compounds, and pharmaceutically acceptable salts thereof, may be efficacious in the treatment of diseases, disorders, and conditions that are mediated by the inhibition of NOD-Like Receptor Protein 3 (NLRP3).

[0075] The present invention relates to the treatment or prevention of a disease, disorder or condition mediated by NLRP3 such as inflammation, an auto-immune disease, a cancer, an infection, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a fibrotic disease or fibrosis, a respiratory disease, a kidney disease, a liver disease, an ophthalmic or ocular disease, a skin disease, a lymphatic disease, a rheumatic26110disease, graft versus host disease, allodynia, or an NLRP3-related disease in a subject that has been determined to cany7a germline or somatic non-silent mutation in NLRP3.

[0076] The disease, disorder or condition mediated by NLRP3 includes but is not limited to: obesity, gout, pseudogout, osteoarthritis, familial cold autoinflammatory syndrome, Muckle-Wells syndrome, neonatal onset multisystem inflammatory disease, diabetes, non-alcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), sepsis, age related macular degeneration, diabetic retinopathy, liver fibrosis, kidney fibrosis, atherosclerosis, heart failure, peripheral artery disease, myeloproliferative neoplasm, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer, colon cancer, Parkinson’s disease. Alzheimer’s disease, dementia with Lewy bodies (DLB), traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, atopic dermatitis, hidradenitis suppurativa, pericarditis, myocarditis, preeclampsia, dermatomyositis, Still’s disease, juvenile idiopathic arthritis, age related macular degeneration, diabetic retinopathy, acute kidney disease, a chronic kidney disease, or a rare kidney disease. Diseases, disorders, or conditions mediated by NOD-Like Receptor Protein 3 (NLPR3)), also include, but are not limited to, obesity, gout, pseudogout, CAPS, NASH, MASH, fibrosis, osteoarthritis, atherosclerosis, heart failure, idiopathic pericarditis, myocarditis, atopic dermatitis, hidradenitis suppurativa, inflammatory bowel disease, cancer, Alzheimer’s Disease, Parkinson’s Disease, dementia with Lewy bodies (DLB), and traumatic brain injury.

[0077] In one embodiment of the present invention, the condition, disease, or disorder is obesity.

[0078] In another embodiment of the present invention, the condition, disease, or disorder is an inflammatory joint disease such as gout, pseudogout, or osteoarthritis.

[0079] In another embodiment, the cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal onset multisystem inflammatory disease.

[0080] In another embodiment, the metabolic disease is diabetes.

[0081] In another embodiment, the liver disease is NASH.

[0082] In another embodiment, the liver disease is MASH.

[0083] In another embodiment, the infection is sepsis.

[0084] In another embodiment, the ophthalmic or ocular disease is age related macular degeneration or diabetic retinopathy.

[0085] In another embodiment, the fibrotic disease is liver fibrosis or kidney fibrosis.

[0086] In some embodiments, the cardiovascular disease is atherosclerosis, heart failure, or peripheral artery disease.26110

[0087] In another embodiment, the cancer is myeloproliferative neoplasm, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer, or colon cancer.

[0088] In another embodiment of the present invention, the condition, disease, or disorder of the central nervous system is Parkinson's disease, Alzheimer's disease, dementia with Lewy bodies (DLB), traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.

[0089] In another embodiment, the skin disease is atopic dermatitis or hidradenitis suppurativa (HS).

[0090] In another embodiment, the inflammatory disease is pericarditis or myocarditis.

[0091] In another embodiment, the inflammatory disease is preeclampsia.

[0092] In another embodiment, the rheumatic disease is dermatomyositis, Still’s disease, or juvenile idiopathic arthritis.

[0093] In another embodiment, the ocular disease is age related macular degeneration or diabetic retinopathy.

[0094] In another embodiment, the kidney disease is an acute kidney disease, a chronic kidney disease, or a rare kidney disease.

[0095] One or more of these conditions or diseases may be treated, managed, prevented, reduced, alleviated, ameliorated, or controlled by the administration of a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to a patient in need of treatment.

[0096] The compounds of the present invention may also be used for the manufacture of a medicament which may be useful for treating, preventing, managing, alleviating, ameliorating, or controlling one or more of these conditions, diseases, or disorders, including but not limited to: obesity, gout, pseudogout, osteoarthritis, familial cold autoinflammatory syndrome, Muckle-Wells syndrome, neonatal onset multisystem inflammatory disease, diabetes, NASH, MASH, sepsis, age related macular degeneration, diabetic retinopathy, liver fibrosis, kidney fibrosis, atherosclerosis, heart failure, peripheral artery disease, myeloproliferative neoplasm, leukemia, myelodysplastic syndrome, myelofibrosis, lung cancer, colon cancer, Parkinson’s disease, Alzheimer’s disease, dementia with Lewy bodies (DLB), traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, atopic dermatitis, hidradenitis suppurativa, pericarditis, myocarditis, preeclampsia, dermatomyositis, Still's disease, juvenile idiopathic arthritis, age related macular degeneration, diabetic retinopathy, acute kidney disease, a chronic kidney disease, or a rare kidney disease. The compounds of the present invention may also be used for the manufacture of a medicament which may be useful for treating, preventing,26110managing, alleviating, ameliorating or controlling one or more of these conditions, diseases or disorders, including but not limited to: obesity, gout, pseudogout, CAPS, NASH, MASH, fibrosis, osteoarthritis, atherosclerosis, heart failure, idiophathic pericarditis, myocarditis, atopic dermatitis, hidradenitis suppurativa, inflammatory bowel disease, cancer, Alzheimer’s Disease, Parkinson’s Disease, dementia with Lewy bodies (DLB), and traumatic brain injury.

[0097] Preferred uses of the compounds may be for the treatment of one or more of the following diseases by administering a therapeutically effective amount to a patient in need of treatment. The compounds may be used for manufacturing a medicament for the treatment of one or more of these diseases:1) obesity,2) gout,3) pseudogout,4) cryopyrin-associated periodic syndromes,5) non-alcoholic steatohepatitis,6) metabolic dysfunction-associated steatohepatitis,7) fibrosis,8) osteoarthritis,9) atherosclerosis.10) atopic dermatitis,11) hidradenitis suppurativa,12) Alzheimer’s Disease,13) dementia with Lewy bodies (DLB), and14) Parkinson’s Disease.

[0098] Treatment of a disease, disorder or condition mediated by NLPR3 or the NLPR3 inflammasome pathway refers to the administration of the compounds of the present invention to a subject with the disease, disorder, or condition.

[0099] One outcome of treatment may be reducing the disease, disorder, or condition mediated by NLPR3 or the NLPR3 inflammasome pathway. Another outcome of treatment may be alleviating the disease, disorder, or condition mediated by NLPR3 or the NLPR3 inflammasome pathway. Another outcome of treatment may be ameliorating the disease, disorder, or condition mediated by NLPR3 or the NLPR3 inflammasome pathway. Another outcome of treatment may be suppressing the disease, disorder, or condition mediated by mediated by NLPR3 or the NLPR3 inflammasome pathway. Another outcome of treatment may be managing the disease, disorder, or condition mediated by NLPR3 or the NLPR3 inflammasome pathway. Another26110outcome of treatment may be preventing the disease, disorder, or condition mediated by NLPR3 or the NLPR3 inflammasome pathway.

[0100] Prevention of the disease, disorder, or condition mediated by NLPR3 or the NLPR3 inflammasome pathway refers to the administration of the compounds of the present invention to a subject at risk of the disease, disorder, or condition. One outcome of prevention may be reducing the disease, disorder, or condition mediated by NLPR3 or the NLPR3 inflammasome pathway in a subject at risk of the disease, disorder, or condition. Another outcome of prevention may be suppressing the disease, disorder, or condition mediated by NLPR3 or the NLPR3 inflammasome pathway in a subject at risk of the disease, disorder, or condition. Another outcome of prevention may be ameliorating the disease, disorder, or condition mediated by NLPR3 or the NLPR3 inflammasome pathway in a subject at risk of the disease, disorder, or condition. Another outcome of prevention may be alleviating the disease, disorder, or condition mediated by NLPR3 or the NLPR3 inflammasome pathway in a subject at risk of the disease, disorder, or condition. Another outcome of prevention may be managing the disease, disorder, or condition mediated by NLPR3 or the NLPR3 inflammasome pathway in a subject at risk of the disease, disorder, or condition.

[0101] The terms "administration of' and or "administering a" compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual or mammal in need of treatment.

[0102] The administration of the compound of structural Formula (I) in order to practice the present methods of therapy is carried out by administering an effective amount of the compound of structural Formula (I) to the mammal in need of such treatment or prophylaxis. The need for a prophylactic administration according to the methods of the present invention is determined via the use of w ell-known risk factors. The effective amount of an individual compound is determined, in the final analysis, by the physician or veterinarian in charge of the case but depends on factors such as the exact disease to be treated, the severity of the disease and other diseases or conditions from which the patient suffers, the chosen route of administration other drugs and treatments which the patient may concomitantly require, and other factors in the physician's judgment.

[0103] The usefulness of the present compounds in these diseases or disorders may be demonstrated in animal disease models that have been reported in the literature.26110Administration and Dose Ranges

[0104] Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, intravenous, infusion, subcutaneous, transcutaneous, intramuscular, intradermal, transmucosal, intramucosal, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of the present invention are administered orally.

[0105] In the treatment or prevention of disorders, diseases and / or conditions which require inhibition of NLRP3 a suitable dosage level will generally be about 0.0001 to about 500 mg per kg patient body weight per day which can be administered in single or multiple doses. In one embodiment, a suitable dosage level may be about 0.001 to about 500 mg per kg patient body weight per day. In another embodiment, a suitable dosage level may be about 0.001 to about 250 mg / kg per day. In another embodiment, a suitable dosage level may be about 0.01 to about 250 mg / kg per day. In another embodiment, a suitable dosage level may be about 0.1 to about 100 mg / kg per day. In another embodiment, a suitable dosage level may be about 0.05 to about 100 mg / kg per day. In another embodiment, a suitable dosage level may be about 0.1 to about 50 mg / kg per day. In another embodiment, a suitable dosage level may be about 0.05 to about 0.5 mg / kg per day. In another embodiment, a suitable dosage level may be about 0.5 to about 5 mg / kg per day. In another embodiment, a suitable dosage level may be about 5 to about 50 mg / kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing about 0.01 to about 1000 mg of the active ingredient, particularly about 0.01, about 0.025, about 0.05, about 0.075, about 0.1, about 0.25, about 0.5, about 0.75, about 1.0, about 2.5, about 5.0, about 7.5, about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0, about 100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0. and about 1000.0 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 8 times per day; preferably, 1 to 4 times a day; more preferably once or twice per day, even more preferably once a day. This dosage regimen may be adjusted to provide the optimal therapeutic response.

[0106] It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode, and time of administration, rate26110of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

[0107] The compounds of this invention may be used in pharmaceutical compositions comprising (a) the compound(s) or pharmaceutically acceptable salts thereof, and (b) a pharmaceutically acceptable earner. The compounds of this invention may be used in pharmaceutical compositions in which the compound of the present invention or a pharmaceutically acceptable salt thereof is the only active ingredient. The compounds of this invention may also be used in pharmaceutical compositions that include one or more other active pharmaceutical ingredients.

[0108] The term “composition,” as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product that results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

[0109] Compounds of the present invention may be used in combination with other drugs that may also be useful in the treatment or amelioration of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. In the treatment of patients who suffer from chronic inflammatory’ conditions, more than one drug may be administered. The compounds of this invention may generally be administered to a patient who is already taking one or more other drugs for these conditions. Often the compounds will be administered to a patient who is already being treated with one or more anti-pain compounds when the patient’s pain is not adequately responding to treatment.

[0110] The combination therapy also includes therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules, ft is also contemplated that when used in combination with one or more other active ingredients, the compound of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention.26110

[0111] Examples of other active ingredients that may be administered in combination with a compound of the present invention, and either administered separately or in the same pharmaceutical composition, include but are not limited to:1) anti-steatotic agents;2) anti-inflammatory agents;3) immunooncology agent;4) lipid-lowering agents;5) cholesterol lowering agents;6) glucose-lowering agents, including SGLT2 inhibitors;7) anti-neovascular agents;8) nonsteroidal anti-inflammatory drugs (" NSAIDs");9) acety l-salicylic acid drugs (ASA) including aspirin;10) paracetamol;11) regenerative therapy treatments;12) checkpoint inhibitors including anti-PDl and anti-PDLl inhibitors;13) chemotherapy procedures;14) radiation therapy:15) surgical procedures;16) urate-lowering therapy;17) anabolics and cartilage regenerative therapy;18) anti-fibroti cs;19) JAK inhibitors;20) TN F -alpha inhi bitors;21) anti-hypertensive agents; and22) STING / cGAS antagonists, andpharmaceutically acceptable salts thereof.

[0112] In another embodiment, the pharmaceutical composition comprises:1) a compound as disclosed herein, or a pharmaceutically acceptable salt thereof; 2) one or more compounds, or pharmaceutically acceptable salts thereof, selected from the group:a. anti-steatotic agents;b. anti-inflammatory' agents;c. immunooncology' agent;d. lipid-lowering agents;26110e. cholesterol lowering agents;f. glucose-lowering agents, including SGLT2 inhibitors;g. anti-neovascular agents;h. nonsteroidal anti-inflammatory drugs (" NSAIDs");i. acetyl-salicylic acid drugs (ASA) including aspirin;j. paracetamol;k. regenerative therapy treatments;l. checkpoint inhibitors including anti-PDl and anti-PDLl inhibitors; m. chemotherapy procedures;n. radiation therapy;o. surgical procedures;p. urate-lowering therapy;q. anabolics and cartilage regenerative therapy;r. anti-fibrotics;s. JAK inhibitors;t. TNF-alpha inhibitors;u. anti-hypertensive agents; andv. STING / cGAS antagonists; andw. pharmaceutically acceptable salts thereof; and3) a pharmaceutically acceptable carrier.

[0113] Specific compounds of use in combination with a compound of the present invention include: anti-steatotic agents, including but not limited to. DGAT2 inhibitors.

[0114] Suitable anti-inflammatory agents include, but are not limited to, TNFa inhibitors, JAK inhibitors, and NSAIDs.

[0115] Suitable lipid-lowering agents include, but are not limited to, statins and PCSK9.

[0116] Suitable immune-oncology agents include, but are not limited to, PD-L1 inhibitors and PD-1 inhibitors, and STING antagonists.

[0117] Suitable glucose-lowering agents include, but are not limited to, insulin, SGLT2 inhibitors, metformin, and GLP1 -agonists.

[0118] Suitable anti-neovascular agents include, but are not limited to, anti-VEG-F treatment.

[0119] Suitable NSAIDs or non-steroidal anti-inflammatory drugs include, but are not limited to, aspirin, diclofenac, diflunisal, etodolac, fenoprofin, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, meloxicam, naproxen, naproxen sodium, oxaprozin, piroxicam, sulindac, and tolmetin.26110

[0120] Suitable analgesics include, but are not limited to, acetaminophen and duloxetine.

[0121] The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds. Non-limiting examples include combinations of compounds with two or more active compounds selected from: anti-steatotic agents, anti-inflammatory agents, lipid-lowering agents, anti-fibrosis, immunooncology agents, glucose-lowering agents, anti-neovascular agents, NSAIDs (nonsteroidal anti-inflammatory drugs), and analgesics.

[0122] The present invention also provides a method for the treatment or prevention of a NLRP3 mediated disease, disorder or condition, which method comprises administration to a patient in need of such treatment or at risk of developing aNLRP3 mediated disease with a therapeutically effective amount of a NLRP3 inhibitor and an amount of one or more active ingredients, such that together they give effective relief.

[0123] In a further aspect of the present invention, there is provided a pharmaceutical composition comprising a NLRP3 inhibitor and one or more active ingredients, together with at least one pharmaceutically acceptable carrier or excipient.

[0124] Thus, according to a further aspect of the present invention there is provided the use of a NLRP3 inhibitor and one or more active ingredients for the manufacture of a medicament for the treatment or prevention of an NLRP3 -mediated disease, disorder, or condition. In a further or alternative aspect of the present invention, there is therefore provided a product comprising a NLRP3 inhibitor and one or more active ingredients as a combined preparation for simultaneous, separate, or sequential use in the treatment or prevention of an NLRP3 -mediated disease, disorder, or condition. Such a combined preparation may be, for example, in the form of a twin pack.

[0125] It will be appreciated that for the treatment or prevention of cardiometabolic disease, neurodegenerative disease, inflammatory joint diseases, fibrosis, or cancer, a compound of the present invention may be used in conjunction with another pharmaceutical agent effective to treat that disease, disorder, or condition.

[0126] The present invention also provides a method for the treatment or prevention of chronic inflammatory conditions, which method comprises administration to a patient in need of such treatment an amount of a compound of the present invention and an amount of another pharmaceutical agent effective to threat that disorder, disease, or condition, such that together they give effective relief.

[0127] The present invention also provides a method for the treatment or prevention of chronic inflammatory conditions, which method comprises administration to a patient in need of such26110treatment an amount of a compound of the present invention and an amount of another pharmaceutical agent useful in treating that particular condition, disorder, or disease, such that together they give effective relief.

[0128] The term "therapeutically effective amount" means the amount the compound of structural Formula (I) that will elicit the biological or medical response of a cell, tissue, system, animal, or human that is being sought by the researcher, veterinarian, medical doctor, or other clinician, which includes alleviation of the symptoms of the disorder being treated. The novel methods of treatment of this invention are for disorders known to those skilled in the art. The term “mammal” includes humans, and companion animals such as dogs and cats.

[0129] The weight ratio of the compound of the Formula (I) to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the Formula (I) is combined with an anti-steatotic agent, the weight ratio of the compound of the Formula (I) generally range from about 1000: 1 to about 1: 1000, preferably about 200: 1 to about 1: 200. Combinations of a compound of the Formula (I) and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.Methods of Synthesis

[0130] The following reaction schemes and Examples illustrate methods which may be employed for the synthesis of the compounds of Formula (I) described in this invention. These reaction schemes and Examples are provided to illustrate the invention and are not to be construed as limiting the invention in any manner. All substituents are as defined above unless indicated otherwise. Several strategies based upon synthetic transformations known in the literature of organic synthesis may be employed for the preparation of the compounds of Formula (I). The scope of the invention is defined by the appended claims. Compound names were generated in Chemdraw Version 21.0.0.28.EXAMPLES

[0131] The following examples are meant to be illustrative and should not be construed as further limiting. The contents of the figures and all references, patents, and published patent applications cited throughout this application are expressly incorporated herein by reference.

[0132] Abbreviations used herein are set forth in Table 1.26110Table 1. Abbreviations* designates a stereocenter[M+H]+mass of protonated molecular ion[M-H]- mass of deprotonated molecular ion[Rh(COD)Cl]2chloro( 1,5-cy clooctadiene)rhodium(I) dimer°C degrees CelsiusNMR proton nuclear magnetic resonance spectroscopyAc acetylAcOH acetic acidAMD age-related macular degenerationaq. or aq aqueousASA acetyl-salicylic acid drugs (including aspirin)ASC apoptosis-associated speck-like protein containing a CARD ASC SPECK (defined in text)ATCC American type culture collectionEhPim bis(pinacolato)diboronBoc or boc tert-butoxy carbonylBPin ester boronic acid pinacol esterbr broadBSA bovine serum albuminBTFFH bis(tetramethylene)fluoroformamidinium hexafluorophosphate Bu or nBu n- butylBz benzoylCalc’d or calcd. calculatedCAPS cyvopyrin-associated periodic syndromesCDI 1, 1 '-carbonyl-diimidazolecGAS Cyclic GMP-AMP synthasecone. concentratedcPr cvclopropyld doubletDAMPS danger-associated molecular patternsDAST diethylaminosulfur trifluorideDCE dichloroethaneDCM dichloromethanedd doublet of doubletsDDQ 2,3-dichloro-5.6-dicvano-l,4-benzoquinoneDEA diethanolamineDess-Martin Periodinane 1,1,1 -tris(acety loxv)- 1, 1 -dihydro- 1,2-benziodoxol-3 -( 1 H)-one DFMS bis(((difluoromethvl)sulfinyl)oxy)zincDIAD diisopropyl azodicarboxylateDIC AA'-diisopropyl-carbodiimideDIPEA A\A-diisopropvlethvlamineDMA dimethyl acetami deDME dimethoxy ethaneDMF dimethylformamideDMSO dimethyl sulfoxideDMSO-rfe hexadeuterodimethyl sulfoxidedppf 1, 1’ -bis(diphenylphosphino)-ferrocenedqd doublet of a quartet of doublets26110Table 1. AbbreviationsDRAQ5™ DRAQ5™ Fluorescent Probe Solution (5 mM) (Thermo Scientific™ Catalog No. 62251dtbbpv 4,4'-di-tert-butyl-2,2'-dipyridylECso half maximal effective concentrationEDC l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide ee enantiomeric excessequiv equivalent(s)ESI electrosprav ionizationEt ethyl, CH2CH3Et2O diethvl etherEtOAc ethyl acetateEtOH ethanolEt3N triethylamineEt2Zn diethyl zincFA formic acidg gramsGLP1 glucagon-like peptide 1Gsdmd gasdermin Dh or hr(s) hour(s)HOAT 1 -Hydroxy -7-azabenzotri azoleHPLC high-performance liquid chromatographyHz HertzIL- 18 interleukin- 18IL-13 interleukin-ipiPrisopropyl, CH(CH3)2zPrMgCl isopropylmagnesium chloride‘PrOH or IPA isopropyl alcoholJ coupling constant, in MHzJAK Janus kinaseKF potassium fluoridekg kilogramKHMDS potassium bis(trimethylsilyl)amideL literLAH lithium aluminum hydrideLC liquid chromatographyLCMS liquid chromatography / mass spectrometryLRMS low resolution mass spectrometryLRR leucine-rich repeatm multipletM MolarMASH metabolic dysfunction-associated steatohepatitis Me methyl, CH3MeCN acetonitrileMeMgBr methylmagnesium bromideMeOH methanolmg milligram(s)MHz megahertzmin minute(s)26110Table 1. AbbreviationsmL milliliter(s)mM millimolarmm millimetermmol millimol e(s)mol mole(s)MPLC medium pressure liquid chromatographyMS mass spectroscopyNaHMDS sodium bis(trimethylsilyl)amideNaN3sodium azideNaSEt sodium ethanethiolateNASH non-alcoholic steatohepatitisNBD nucleotide-binding site domainNBS jV-bromosuccinimideNCS jV-chlorosuccinimideNF-KB nuclear factor kappa BNH4OAc ammonium acetateNHPT N-hvd roxvphthal 1 mi deO NLR NOD-like receptorsNLRP3 NOD-like receptor protein 3nM nanomolarNMO 4-methylmorpholine jV-oxideNMP JV-methylpyrrolidoneNOD nucleotide-binding oligomerization domainNSAIDs nonsteroidal anti-inflammatorv drugsOAc acetateoxoPAMP pathogen-associated molecular patternsPBS phosphate-buffered salinePCC pyridinium chlorochromatePCSK9 proprotein convertase subtilisin / kexin tvpe 9 Pd(dppf)Ch [l,r-bis-(diphenylphosphino)-ferrocene]dichloropalladium(II) Pd(OAc)2palladium(II) acetatePd(PPh3)4tetrakis(iriphenyl-phosphine)palladium(0)Pd(tBu3P)2 bis(tri-fert-butylphosphine)-palladium(0)Pd / C palladium on carbonPD1 programmed cell death protein 1PdCl2(PPh3)2dichlorobis(triphenylphosphine)palladium(II)PDL1 Programmed death-ligand 1PE petroleum etherPG protecting groupPh or ph phenylPMA phorbol 12-myristate 13-acetatePPm parts per millionpr propylprep preparativeprolL-ip pro-interleukin 1 betaPRR pattern recognition receptor26110Table 1. Abbreviationsq quartetrac racemicRPMI Roswell Park Memorial Institutert or RT room temperature, approximately 25 °Cs singletSARS severe acute respiratory syndromesat. or satd saturatedSEMC1 chloromethyl 2-trimethylsilylethyl etherSFC Supercritical Fluid ChromatographySGLT2 sodium-glucose cotransporter-2SNAr nucleophilic aromatic substitutionSTING Stimulator of Interferon Genest triplet / -AmOH 2-methylbutan-2-olTBAF tetrabutylammonium fluorideTBHP tert-butyl hydroperoxidezBu fert-butylfBuOH tert-butyl alcoholtd triplet of doubletTEA or EtsN triethylaminetert tertiaryTFA trifluoroacetic acidTfOH triflic acidTHF tetrahydrofuranTHP-1 Tohoku Hospital Pediatrics-1Ti(OEt)4 titanium (IV) ethoxideTi(OiPr)4titanium (IV) isopropoxideTLC thin layer chromatographyTMHD 2,2, 6, 6-tetramethy 1-3, 5 -heptanedioneTMS-Diazomethane trimethvlsilyl-di azomethaneTNF-alpha or TNFa Tumour necrosis factor aTs tosvlateTsCl 4-toluenesulfonyl chloridett triplet of tripletstween-20 polyethylene glycol sorbitan monolaurateUV ultravioletv / v volume / volumeVEG-F Vascular Endothelial Grow th Factorwt% Percentage by weightXPhos Pd G3 (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2- (2'-amino-l,r-biphenyl)|palladium(II) methanesulfonate 5 chemical shift|iL microliter26110Instrumentation and Chiral Separation Methods

[0133] Reverse phase chromatography was carried out on a Waters 150 equipped with a column selected from the following: Phenomenex Synergi Cl 8 (250mm x 30mm x 4 micron), Phenomenex Luna Cl 8 (250mm x 21mm x 5 micron), Agilent Zorbax Bonus-RP (150mm x 21mm x 5 micron), Waters X-Select CSH C18 (150mm x 19mm x 5 micron). Conditions included either high pH (0-100% acetonitrile / water eluent comprising 0.1% v / v NH4OH) or low pH (0-100% acetonitrile / water eluent comprising 0.1% v / v TFA or FA) and are noted for some examples.

[0134] SFC chiral resolution was carried out on Waters Thar 80 SFC or Berger MG II preparative SFC systems. The general preparative conditions of separating diastereomeric or enantiomeric mixtures of compounds using chiral SFC are as set forth in Table 2.Table 2. General Preparative ConditionsChiral Mobile Phase Method Chiral Mobile Phase Method Column Column45% MeOH (0.1%IC4 2A AS-H 34% ‘PrOH / CO T NH OH) / CO25-60% MeOHIC (0.1% B C2-5 40% MeOH / CO2U NH4OH) / CO220% MeOH (0.1%IG C AS-H 30%iPrOH / CO2V NH4OH) / CO215-55% MeOH25% MeOH (0.1%IC D IB (0.1%NH4OH) / CO2w NH4OH) / CO225% MeOH (0.1% 50% EtOH (0.1%IA E C9-5 X NH4OH) / CO2DIPEA) / CO25-50% MeOH35% MeOH (0.1%IC (0.1% F IB Y4NH H4OH) / CO NH O ) / CO2225% MeOH (0.1% 40% 'PrOH (0.1%IG G AS-HDIPEA) / CO2DEA) / CO2z 15% EtOH (0.1% 40% ‘PrOH (0.1%IC H A5-5 AA DIPEA) / CO2NH4OH) / CO220% MeOH (0.1% 35% MeOH (0.1%IA I IG A NH4OH) / CO2NH4B OH) / CO225% EtOH (0.1% 25% MeOH (0.1%IA J OD AC NH4OH) / CO2NH4OH) / CO240% MeOH (0.1% 30% EtOH (0.1%IG K AD AD NH4OH) / CO2NH4OH) / CO230% EtOH (0.1% 40% EtOH (0.1%IA L AD A NH4E OH) / CO2NH4OH) / CO220% MeOH (0.1%IC4 2M AD-H 35% MeOH / CO ANH OH) / CO2F26110Table 2. General Preparative ConditionsChiral Mobile Phase Method Chiral Mobile Phase Method Column Column30% MeOH (0.1%IC N AD-H 30% MeOH / CCh AG NH4OH) / CO2IC 20% MeOH / CO2O IC 40% MeOH / CO2AH 40%‘PrOH (0.1% 15% MeOH (0.1%IG P IH Al DIPEA) / CO2NH4OH) / CO230% MeOH (0.1%IC 30% MeOH / CCh R OD-H AJ DEA) / CO220% MeOH (0.1%IH SNH4OH) / CO2

[0135] Proton or1H NMR was acquired using a Bruker 500 MHz NEO NMR spectrometer equipped with a 5mm iProbe in accordance with standard analytical techniques, unless specified otherwise, and results of spectral analysis are reported. Chemical shift (5) values are reported in delta (5) units, parts per million (ppm). Chemical shifts for1H NMR spectra are given relative to signals for residual non-deuterated solvent (CDCh referenced at 57.26 ppm; DMSO-rfc referenced at 52.50 ppm or CD3OD referenced at 53.31 ppm).General SchemesScheme A,R2-BR2cat. [Pd] SuzukiCross-CouplingA-1 R2-BR2= aryl boronic acid, A-2BPin ester or BF3K saltY = Cl, Br, or I

[0136] Scheme A illustrates the synthesis of biaryl 2,3-diamines such as A-2 via palladium catalyzed Suzuki cross coupling between appropriate aryl halides, such as A-l, and an aryl boron reagent.Scheme B.R4R-CO2H, HATU, DIPEA LIAIH4or RC(O)CI,B-1 DIPEA R = OBn, alkyl R5= alkyl26110

[0137] Scheme B illustrates the synthesis of / V-alkyl biaryl 2,3-diamines such as A-2 from precursors of the formula B-l. First acylation of biaryl 2,3-diamines (B-l) affords the carbamate or amide derivatives of the formula B-2. Subsequent reduction using reagents, such as LiAIFU, affords A'-alky lated di-amines of the formula A-2.Scheme C.Ra1-4= H, alkyl

[0138] Scheme C illustrates the synthesis of substituted 6-oxo-piperi done-3 -carboxylic acids such as C-4. Vinylogous amides C-2 are prepared by conjugate addition of primary alkylamines with / c / 7-butyl alkynoic esters or (B-keto-esters, such as C-la or C-lb respectively. Then, substituted acroyl chlorides or anhydrides undergo a conjugate addition reaction followed by intramolecular cyclization cascade with vinylogous amides C-2 to afford dihydropiperidones of the formula C-3. Subsequent hydrogenation and tert-butyl ester deprotection give substituted lactam derivatives of the formula C-4.Scheme D.HATU, DIPEA AcOH, A or BTFFH, DIPEAAmide Coupling D-1

[0139] Scheme D illustrates the synthesis of substituted benzimidazoles such as D-2 from 2,3-diamino pyridines such as A-2. Amide coupling of 2,3-diamines (A-2) with carboxylic building blocks affords the amide intermediate D-1. Subsequently treating the amide derivatives, such as D-1, with acid, such as AcOH, and heating the reaction mixture affords the substituted benzimidazole derivatives of the formula D-2.26110Scheme E,LDA;R5-XR5= 1° or 2° alkyl

[0140] Scheme E illustrates the alkylation of 3-aminopyridine derivatives, such as E-l, with appropriate primary or secondary alkyl halides to afford JV-alkylated 3-aminopyridine derivatives of the formula E-2.Scheme F,PMBNH2, AE-1 (R5= H) or E-2 (R5= alkyl)R2-BR2= aryl boronic acid, BPin ester or BF3K saltF-3

[0141] Scheme F illustrates the synthesis of substituted benzimidazoles from aminopyridine derivatives, such as E-l or E-2. Nucleophilic aromatic substitution (S\Ar) with 4-methoxybenzylamine affords 2,3-diaminopyridine of the formula F-l. Subsequently heating 2,3-diamine derivatives (F-l) with various carboxylic acids in the presence of acid, such as PPA, affords the chlorobenzimidazole derivatives of the formula F-2. Cross coupling using an appropriate aryl nucleophile, such as aryl boronic acid, and palladium catalyst gives biaryl products, which are deprotected in situ, when applicable, to afford substituted benzimidazole compounds of the formula F-3.26110Scheme G.M / e CDI, Et3N POCI3R1G-1 G-2 G-3 G-4Ra= aryl and heteroaryl Rb2= H or alkylRc= H, alkyl

[0142] Scheme G illustrates the synthesis of N-substituted benzimidazoles such as G-2. The reaction of diamines (G-1) and CDI results in the formation of the intermediate G-2, which upon reaction with POCh results in the formation of intermediate G3. Reacting this intermediate with a primary or secondary amine, affords N-substituted imidazo pyrazine compounds of the formula G-4 via an SxAr.Scheme H,Cui, Na2S H2O POCI3, Py A H-2 H-3R2-BR2Suzuki cat. [Pd] Cross-Coupling then deprotection (when applicable) R2-BR2= aryl boronic acid, BPin ester or BF3K salt

[0143] Scheme H illustrates the synthesis of substituted benzothiazoles from aminopyridine derivatives such as H-l. Amide coupling with various carboxylic acids affords acylated intermediate of the formula H-2. Subsequently, a sequence of copper-catalyzed Ullman-coupling and cyclodehydration gives chloro-benzothiazole derivatives such as H-3. Cross-coupling using an appropriate aryl nucleophile, such as aryl boronic acid, and palladium catalyst gives biaryl products which are deprotected in situ, when applicable, to afford substituted benzothiazole compounds of the formula H-4.26110Intermediate 1: 2-(2-(ethoxyinethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolaneB

[0144] Step 1: 3-Methyl-5-(trifluoromethyl)phenol: To a solution of 3-bromo-5-(trifluoromethyl)phenol (500 g, 2.07 mol), K2CO3 (858.9 g, 6.22 mol) and Pd(dppf)Ch (75.8 g, 103.7 mmol) in 1,4-dioxane (7.5 L) under N2 atmosphere was added portion-wise trimethyl-1,3,5,2.4,6-trioxa-triborinane (1.04 kg, 4.15 mol, 50 wt% in THF). The resulting mixture was stirred for 12 h at 100 °C, then cooled to rt. The reaction was quenched with ice water at 0 °C, then diluted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous Na2SOr and concentrated under reduced pressure. The resulting crude residue was purified by silica gel chromatography (EtOAc: PE) to afford the title compound. LCMS [ M-l 1 ] = 175.1 (calcd. 175.0).

[0145] Step 2: 2-Iodo-3-methyl-5-(trifluoromethyl)phenol: NaH (128.5 g, 3.21 mol, 60 wt%) was added at 0 °C to a stirring solution of 3-methyl-5-(trifluoromethyl)phenol (283 g, 1.61 mol) in toluene (1.42 L) under N2 atmosphere. The resulting mixture w as stirred at 0 °C for 30 min, followed by the portion-wise addition of a solution of I2 (306.1 g, 1.21 mmol) in toluene (5.66 L). The resulting mixture was stirred at 20 °C for 3 h. then quenched by pouring onto a water / ice bath. The mixture was diluted with EtOAc, and the layers were separated. The organic layer was washed with brine, dried over anhydrous NaiSOr. and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification.

[0146] Step 3: l-(Ethoxymethoxy)-2-iodo-3-methyl-5-(trifluoromethyl)benzene: Chloromethyl ethyl ether (289.9 g, 3.07 mol) was added at 0 °C to a stirring solution of 2-iodo-3-methyl-5-(trifluoromethyl)phenol (463 g, 1.53 mol) and CS2CO3 (998.9 g, 3.07 mmol) in DMF (4.6 L) under N2 atmosphere. The resulting mixture w as stirred for 8 h at rt, then cooled to 0 °C, and quenched with addition of ice water. The resulting mixture was diluted with EtOAc, and the layers separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting crude residue w as purified by silica gel chromatography (EtOAc: PE) to afford the title compound.1H NMR (300 MHz, DMSO-r / e) 5 7.55 (s, 1H), 7.18 (s, 1H), 5.42 (s, 2H), 3.75-3.65 (m, 2H), 2.50 (s, 3H), 1.21-1.10 (m, 3H).

[0147] Step 4: 2-(2-(Ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4.4.5.5-tetramethyl-1.3.2-dioxaborolane: A mixture containing l-(ethoxymethoxy)-2-iodo-3-methyl-5-(trifluoromethyl) benzene (330 g, 916.4 mmol), E Pim (469.1 g, 3.67 mol), Et? N (556.4 g, 5.50 mol), Pd(0Ac)2 (10.3 g, 45.8 mmol), and (2-biphenyl)dicyclohexylphosphine (32.1 g, 91.6 mmol) in 1,4-dioxane (3.3 L) was placed under N2 atmosphere. The reaction mixture was stirred for 6 h at 100 °C, then cooled to 25 °C and quenched with ice water. The resulting mixture was filtered, and the residue was washed with EtOAc. The filtrate layers were separated. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The resulting crude residue was purified by silica gel chromatography (EtOAc: PE), and the solvent was removed under vacuum. The resulting residue was dissolved in hexanes and stirred for 5 min at -30 °C. Then the precipitate was collected by filtration to afford the title compound. 'H NMR (300 MHz, CDCh) 57.13-7.03 (m, 2H), 5.23 (s, 2H), 3.74 (q, J= 7.1 Hz, 2H), 2.41 (s, 3H), 1.41 (s, 12H), 1.24 (t, J= 7.1 Hz, 3H).Intermediate 2: 6-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)pyridine-2,3-diamine

[0148] 6-bromopyridine-2.3-diamine (7 g. 37.2 mmol), 2-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Intermediate 1, 16.09 g, 44.7 mmol) and K2CO3 (10.29 g, 74.5 mmol) were taken up in 1,4-dioxane (155 ml) and water (31.0 ml) at RT and sparged with N2 for 15 min. Pd(dppf)C12 (1.5 g, 1.86 mmol) was added, and the reaction mixture was then heated to 50°C for 4 h. Then the reaction mixture was cooled to RT and quenched with saturated aqueous NH4CI. The layers were separated, and the aqueous layer was extracted with EtOAc (x3). The combined organic layers were dried over MgSO4 and filtered, and the solvent was removed under reduced pressure. The resulting crude mixture was purified by silica gel chromatography (EtOAc: hexanes) to afford the title compound. LCMS [M+H]1= 342.3 (calcd. 342.1).

[0149] The compound listed in Table 3 was prepared using procedures similar to the procedure described for Intermediate 1 using the appropriate starting materials.Table 3Intermediate Structure Name LCMS [M+H]+6-(2-(ethoxymethoxy)-6- methyl-4- Calcd. 356.2.3 (trifluoromethyl)phenyl)- found 356.3 4-methylpyridine-2,3-diamineIntermediate 4: 2-(5,6-diamino-3-methylpyridin-2-yl)-5-(trifluoromethyl)phenol4I 0 C / XStep 1: 2-(6-amino-3-methyl-5-nit VCropyridin-2-yl)-5-(trifluoromethyl)phenol

[0150] 6-chloro-4-methyl-3-nitropy AMridin-2-amine (250 mg, 1.33 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (521 mg, 2.53 mmol) and K2CO3 (921 mg, 6.66 mmol) were taken up in 1,4-di oxane (5.5 ml) and water (1.1 ml) at RT and sparged with N2 for 15 min.0Pd(dppf)Ch (55 mg, 0.0 LL?7 mmol) was added, and the reaction mixture was then heated to 50°C for 4 h. Then the reaction mixture was cooled to RT and quenched with saturated aqueous NH4CI. The layers were separated, and the aqueous layer was extracted with EtOAc (x3). The combined organic layers were dried over MgSCh and filtered, and the solvent w as removed under reduced pressure. The resulting crude residue containing the title compound was used directly in the next step without further purification. LCMS [M+H]1= 314.2 (calcd. 314.1).Step 2: 2-(5.6-diamino-3-methylpyridin-2-yl)-5-(trifluoromethyl)phenol

[0151] MeOH (7.2 rnL) was added to a mixture of 2-(6-amino-3-methyl-5-nitropyridin-2-yl)-5-(trifluoromethyl)phenol (451 mg, 1.44 mmol) and NiC12(gylme) (15.8 mg, 0.072 mmol). The reaction mixture was cooled to 0°C followed by portion- wise addition of NaBH4 (109 mg, 37.8 mmol). Then the reaction was warmed up to RT and stirred overnight. The resulting heterogeneous solution was then filtered over a pad of diatomaceous earth (CELITECR)), and the solvents were removed under reduced pressure. The resulting crude residue containing the title compound was used without further purification. LCMS [M+H]+= 284.3 (calcd. 284.1).Intermediate 5: 6-(2-(ethoxyinethoxy)-6-methyl-4-(trifluoroniethyl)phenyl)-N?-methylpyridine-2,3-diamineIStep 1: benzyl (2-amino-6-(2-(ethoxyrnethoxy)-6-methyl-4- (trifluoromethyl)phenyl)pyridin-3-yl (carbamate

[0152] Benzylchloroformate (0.22 mL, 1.55 mmol) was added to a solution of 6-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)pyridine-2.3-diamine (Intermediate 2, 480 mg, 1.41 mmol) in THF (7.0 mL) at RT and then stirred for 12 h. The reaction mixture was then directly dry loaded onto a pad of diatomaceous earth (CELITE®) and purified by silica gel chromatography (EtOAc: hexanes) to afford the title compound. LCMS [M+H]+= 476.2 (calcd.476.2).Step 2: 6-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-N3-methylpyridine- 2.3-diamine

[0153] LiAlEL (1.8 mL, 3.63 mmol, 2M in THF) was added dropwise to a solution of benzyl(2-amino-6-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)pyridin-3-yl) carbamate (431 mg, 0.91 mmol) in THF (3.0 mL) at 0°C under N2 atmosphere. The reaction mixture was then warmed to RT and stirred for 12 h. Then the reaction mixture was carefully quenched with ice-cold IM HC1 and stirred for 30 min. The mixture was then diluted with EtOAc, the layers were separated, and the aqueous layer was extracted with EtOAc (x3). The combined organic layers were dried over MgSO4 and filtered, and the solvent was removed under reduced pressure. The resulting crude mixture was purified by silica gel chromatography (EtOAc: hexanes) to afford the title compound. LCMS [M+H]+= 356.4 (calcd. 356.2).

[0154] The compound listed in Table 4 was prepared using procedures similar to the procedure described for Intermediate 5 using the appropriate starting materials.Table 4Intermediate Structure Name LCMS [M+H]+H 6-(2-(ethoxymethoxy)-6- methyl-4- 6 1 x x Calcd. 370.2.(trifluoromethyl)phenyl)- found 370.2 N3-ethylpyridine-2,3-diamine26110Intermediate 7: (2S and R, 3S and 7?)-2-methyl-6-oxopiperidine-3-carboxylic acidHCk J^NHO IStep 1: tert-butyl (2S and 5. 3 and J?)-l-(2.4-dimethoxybenzyl)-2-methyl-6- oxopiperidine-3 -carboxylate

[0155] (2,4-dimethoxyphenyl)methanamine (265 mg, 1.6 mmol) was added to a solution of tert-butyl 3-oxobutanoate (0.26 mL, 1.59 mmol) in THF (1.6 mL) at 0°C. The reaction mixture was then heated to 60°C and stirred for 16 h. Then, acrylic anhydride (0.18 mL, 1.6 mmol) was added, and the reaction was stirred at 70°C reflux for 24 h. The reaction mixture was then cooled to RT, and the solvents were removed under reduced pressure. Then, Pd / C (26 mg, 5 wt%) was added to the crude residue, and the head space was evacuated and back filled with N2, followed by addition of EtOH (1.5 mL). The resulting solution was sparged with aHi balloon for 10 min and then stirred at RT for 12 h. Then the reaction mixture was sparged with N2 for 10 min. and the hetereogenous mixture was filtered over a pad of diatomaceous earth (CELITE®). The resulting filtrate was concentrated under a reduced pressure, and the crude residue containing the title compound was used directly in the next step without further purification. LCMS [M+H]+= 364.3 (calcd. 364.5).Step 2: (25 and R. 35 and7?)-2-methyl-6-oxopiperidine-3-carboxylic acid

[0156] TFA (3 mL) was added to a solution of the product of Step 1 (180 mg, 0.50 mmol) in anisole (1.35 ml, 12.4 mmol) at RT. The reaction mixture was then heated to 50°C and stirred for 16 h. Then the reaction mixture was cooled to RT, and the solvents were removed under reduced pressure. The resulting crude residue was re-suspended in hexanes / DCM and, upon sonication, a precipitated. The suspension was then filtered over a pad of diatomaceous earth (CELITE®), and the precipitate was washed with 2:1 hexanes / DCM. The precipitate was recovered, affording the title compound which was used in the next step without further purification. LCMS [M+H]+ = 158.2 (calcd. 158.2).

[0157] The compounds listed in Table 5 were prepared using procedures similar to the procedure described for Intermediate 7 using the appropriate starting materials.26110Table 5Intermediate Structure Name LCMS [M+H]+6-oxo- 1 -((A)- tetrahydrofuran-3- Calcd. 214.1.8Y 1 0 yl)piperidine-3- found 214.2 O C-V carboxylic acid6-oxo-l-((5)- tetrahydrofuran-3- Calcd. 214.1.9Y \ O yl)piperidine-3- found 214.2 O <- / carboxylic acidIntermediate 10: 2,6-dichloro-N-methyl-4-(trifluoromethyl)pyridin-3-amineCF3|X 1CI^N^CI

[0158] LDA (4.76 mL. 9.52 mmol, 2.0 M in THF / heptane / ethylbenzene) was added to a solution of 2,6-dichloro-4-(trifluoromethyl)pyridin-3-amine (2 g, 8.66 mmol) in THF (20 mL) at -78°C, and the reaction mixture was stirred at -78°C for 30 min. Then, Mel (0.81 mL, 13.0 mmol) was added, and the reaction mixture was warmed to RT and stirred for 2 h. The reaction mixture was then carefully quenched with ice water and diluted with EtOAc. The layers were then separated, and the aqueous layer was extracted with EtOAc (x3). The combined organic layers were dried over MgSO4 and fdtered, and the solvent was removed under reduced pressure. The resulting crude residue was purified by reverse phase MPLC (Cl 8 stationary phase, MeCN / FhO + 0.5% TFA) to afford the title compound. LCMS [M+H]+= 245.0 (calcd. 245.0).Intermediate 11: 6-chloro-N2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridine-2,3-diamine

[0159] A solution of 2,6-dichloro-4-(trifluoromethyl)pyridin-3-amine (1 g, 4.33 mmol) and (4-methoxyphenyl)methanamine (2.4 g, 17.32 mmol) in NMP (15 mL) was heated at 150°C for 4 h. The reaction mixture was then cooled to RT and diluted with H2O and EtOAc. The layers were then separated, and the aqueous layer was extracted with EtOAc (x3). The combined organic layers were dried over MgSO4 and filtered, and the solvent was removed under reduced pressure.26110The resulting crude residue was purified by silica gel chromatography (petroleum ether / EtOAc) to afford the title compound. LCMS [M+H]+ = 331.9 (calcd. 332.1).

[0160] The compound listed in Table 6 was prepared using procedures similar to the procedure described for Intermediate 11 using the appropriate starting materials.Table 6LCMSIntermediate Structure Name[M+H]+6-chloro-N2-(4- methoxybenzyl)-N3- Calcd. 346.1, 12 3”' methyl-4- o found 346.2 (trifluoromethyl)pyridine-2,3-diamineIntermediate 13: 5-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-l,3-dihy d ro-2 / / -imidazo [4,5-6] pyridin-2-oneMe

[0161] A mixture of 6-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-N’-methylpyridine-2,3-diamine (Intermediate 5, 300 mg, 0.844 mmol) in THF (3.4 mL) was treated with EtsN (0.588 mL, 4.22 mmol) and CDI (684 mg, 4.22 mmol). The reaction mixture was heated to 65°C for 3 h. After cooling to RT, the reaction was poured into water, then extracted with DCM (x3). The combined organic layers were dried over anhydrous MgSO-i. filtered, and concentrated. The resulting crude residue was purified by silica gel chromatography (25% EtOH in EtOAc: hexanes) to give the title compound. LCMS [M+H]+= 382.2 (calcd. 382.1).Intermediate 14: 2-(2-chloro-l-methyl-l / / -imidazo[4,5-6|pyridin-5-yl)-3-methyl-5-(trifluoromethyl)phenyl dihydrogen phosphateCH3„p-OHO' OH26110

[0162] A mixture of 5-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-L3-dihydro-27f-imidazo[4,5-Z>]pyridin-2-one (Intermediate 13, 452 mg, 1.19 mmol) in POCh (2.6 mL) was heated to 100°C for 3 h. After cooling to RT, the reaction was quenched with ice, then stirred for 5 min at RT. The reaction mixture was then poured into water and stirred for an additional 10 min at RT. Sat. sodium carbonate was used to modify the pH of the aqueous solution to 7. The solution was then washed with DCM (x2), and the resulting aqueous layer was concentrated. The resulting residue was taken up in a 1:1 mixture of DMSO and water, filtered and purified via preparative reverse-phase HPLC (C 18 stationary phase, MeCN / water + 0.1% TFA) to afford the title compound. LCMS [M+H]+= 422.2 (calcd. 422.0).Examples 1 and 2: (R or A)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-LH-imidazo[4,5-Z>]pyridin-2-yl)-l-methylpiperidin-2-one and ( ' or / ?)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-LZ / -imidazo[4,5-Z»]pyridin-2-yl)-l-methylpiperidin-2-one(Peak 1) (Peak 2)

[0163] DIPEA (7.0 ml, 12.7 mmol, 1.8 M in DCM) was added to a microwave vial containing solution of (R and A)- l-methyl-6-oxopiperidine-3 -carboxylic acid (0.5 g, 3.2 mmol) and BTFFH (1.07 g, 3.38 mmol) in DCM (11.3 ml) at RT, and the reaction mixture was stirred for 30 min. 6-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-N5-methylpyridine-2,3-diamine (Intermediate 5, 1.0 g, 2.81 mmol) was added to the reaction mixture, the vial was sealed, and the reaction mixture was then heated to 80°C and stirred for 16 h. Then the reaction mixture was cooled to RT, the solvents were removed under reduced pressure, and AcOH (10 mL, 175 mmol) was added to the resulting crude residue. The reaction mixture was then heated to 130°C and stirred for 4 h. Then the reaction mixture was cooled to RT. the solvents were removed under reduced pressure, and the resulting crude residue was diluted with EtOAc and H2O. The layers were then separated, and the aqueous layer was extracted with EtOAc (x3). The combined organic layers were dried over MgSO4 and filtered, and the solvent was removed under reduced pressure. The resulting crude residue was purified by reverse phase HPLC (Cl 8 stationary phase, MeCN / H2O + 0.1% TFA) to afford a racemic mixture of the title compounds. The title compounds were resolved by preparative chiral SFC with Method T. The faster eluting isomer of26110the title compound was obtained (Example 1. >99% ee). 'H NMR (500 MHz, Methanol-A) 5 8.06 (d, J= 8.3 Hz, 1H), 7.35 (d, J= 8.3 Hz, 1H), 7.08 (s, 1H), 7.02 (s, 1H), 3.97 (s, 3H), 3.92 (dd, J= 11.8, 10.2 Hz, 1H), 3.76 (tt, J= 9.8, 4.6 Hz, 1H), 3.68 (ddd, J= 12.0, 5.4, 1.4 Hz, 1H), 3.03 (s, 3H), 2.62 - 2.50 (m, 2H), 2.25 (dd, J= 10.5, 4.6 Hz, 2H), 2.15 (s, 3H). LCMS [M+H]+= 419.4 (calcd. 419.2). The slower eluting isomer of the title compound was obtained (Example 2, 99% ee). ‘H NMR (500 MHz, Methanol-^) 58.06 (d, J= 8.3 Hz, 1H), 7.35 (d, J= 8.3 Hz, 1H), 7.08 (s, 1H), 7.02 (s, 1H), 3.97 (s, 3H), 3.92 (dd, J= 11.8, 10.2 Hz, 1H), 3.76 (tt, J= 9.8, 4.6 Hz, 1H), 3.68 (ddd, J= 12.0, 5.4, 1.4 Hz, 1H), 3.03 (s, 3H), 2.62 - 2.50 (m, 2H), 2.25 (dd, J= 10.5, 4.6 Hz. 2H), 2.15 (s, 3H). LCMS [M+H]+= 419.4 (calcd. 419.2).

[0164] The compounds listed in Table 7 were prepared using procedures similar to the procedure described for Examples 1 and 2 using the appropriate starting materials.z TTai t)le 7LCMSExample Sth tructure Name[M+H]+2-[2-(3,3-difluorocyclobutyl)- o 1 -methyl-imidazo[4,5- Calcd. 398.1, 3b]pyridin-5-yl]-3-methyl-5- Found 398.2 (trifluoromethyl)phenol / 3-methyl-2-(l -methyl-2- 1 £ — ( p tetrahydropyran-4-yl- Calcd. 392.2, 4imidazo[4,5-b]pyridin-5-yl)- Found 392.0 4 5 -(trifluoromethy l)phenol2-(2-((lA,5S,6 s orr)-3- oxabicyclo[3.1.0]hexan-6-yl)- Calcd. 390.1, 5 1 -methyl- 17 / -imidazo[4,5- Found 390.00 6]pyridin-5-yl)-3-methyl-5- (trifluoromethyl)phenol2-(2-((lA,5S,6 r ors)-3- / Hoxabicyclo[3.1.0]hexan-6-yl)- Calcd. 390.1, 6 1 -methyl- 1 / 7-imi dazo[4,5- i in nH Found 390.4Z>]pyridin-5-yl)-3-methyl-5-(trifluoromethyl)phenol

[0165] The compounds listed in Table 8 were prepared using procedures similar to those described for Examples 1 and 2 using the appropriate starting materials. Enantio- and diastereomeric products were separated using chiral or achiral SFC methods specified in the table. For those pairs of isomers, the fast-eluting isomer was listed first. Addition of DIPEA was particularly important when the starting material amine was an acid salt.26110Table 8LCMS Chiral Example Structure Name[M+H]+Method (5R or S)-5-[l -ethy l-5-[2- / Calcd.hydroxy-6-methyl-4- 433.2, U 7 } 1 y- 1 >° (trifluoromethyl)phenyl]irmdazoFound Peak 1 > A^ CHOH [4,5 -6] py ridin-2-yl] - 1 -methy 1- F 433.3Z Zvpiperidin-2-one-- 3-methyl-2-[l-methyl-2-[(67? or / 5)-5, 6,7,8- Calcd.1 JL T> JXv X1oN tetrahy drotetrazol o [ 1, 5 - 430.2,8 C*T 'F JL J.N NNVFy^0H n]pyridin-6-yl]imidazo[4,5- Found 6]pyridin-5-yl]-5- 430.2 (trifluoromethyl)phenol3-methyl-2-[l -methy 1-2- [(6S or / 1 O o o 7?)-5, 6,7 Calcd.,8- 1 jj jC A=N 430.2, tetrahy drotetrazol o[ 1,5- 9 VFJI J N'Na]pyridin-6-yl]imidazo[4,5- FoundFV^OH$. F Z?]pyridin-5-yl]-5- 430.2(trifluoromethyl)phenolj Q(5R orS)-5-[5-[2-hydroxy-6- _tx Calcd.methyl-4- 447.2,10 w (trifluoromethyl)pheny 1] - 1 - Found methyl-imidazo[4,5-6]pyridin-2- 447.2 yl]-l-isopropyl-piperidin-2-one(5S or J?)-5-[5-[2-hydroxy-6- Calcd. methyl-4- 447.2,11 (trifluoromethyl)pheny 1] - 1 - w Found methyl-imidazo[4,5-6]pyridin-2- 447.2 yl]-l-isopropyl-piperidin-2-one(5R orS)-5-[5-[2-hydroxy-6- Calcd. methyl-4- 405.2,12 X (trifluoromethyl)pheny 1] - 1 - Found methyl-imidazo[4,5-6]pyridin-2- 405.2 yl]piperidin-2-one(5S or J?)-5-[5-[2-hydroxy-6- Calcd. methyl-4- 405.2,13 (trifluoromethyl)pheny 1] - 1 - X Found methyl-imidazo|4.5- / i|pyridin-2- 405.2 yl]piperidin-2-one26110Table 8LCMS Chiral Example Structure Name[M+H]+Method (SR or S)-5-[5-[2-hydroxy-6- ^X-N / / — \ methyl-4- Calcd.I L L LA L° (trifluoromethyl)pheny 1] -1- 475.2,14 -JY^NN^N- Y methyl-imidazo[4,5-6]pyridin-2- Found FFX> PA^LOHH<R";VLL0 / F y 1] - 1 - 1 (3 / ?)-tetrahy drofuran-3- 475.2yl]piperidin-2-one(5S or J?)-5-[5-[2-hydroxy-6- / methyl-4- Calcd.I L T LA L0(trifluoromethyl)pheny 1] -1- 475.2,15 LAN1'1Y methyl-imidazo[4,5-6]pyridin-2- Found x JGLH-YLy 1] - 1 - [(37?)-tetrahy drofuran-3- 475.2 yl]piperidin-2-one(SR or S)-5-[5-[2-hydroxy-6- / methyl-4- Calcd.I L L LA )=O(trifluoromethyl)pheny 1] - 1 - 475.2, AV AN16 Y F JL L, HI'YA methyl-imidazo[4,5-6]pyridin-2- FoundFy^^oH is; Lo / 475.2 yl]- 1 -[(3S)-tetrahy drofuran-3- yl]piperidin-2-one(SS or J?)-5-[5-[2-hydroxy-6- / methyl-4- Calcd.(trifluoromethyl)pheny 1] - 1 - 475.2, 1 L lH >°17 Y F JI L. methyl-imidazo[4,5-6]pyridin-2- Found yl]- 1 -[(3S)-tetrahy drofuran-3- 475.2 yl]piperidin-2-one3-methyl-2-[l-methyl-2-[(6S or / Calcd., N 7 - \ 7?)-3-methyl-5,6,7,8-tetrahydro- 1 L L L \ LN 443.2, Z 18 [l,2,4]triazolo[4,3-o]pyridin-6- < S^NN N\L Peak 2 Found yl]imidazo[4,5-6]pyridin-5-yl]-r443.45-(trifluoromethyl)phenol(SS or J?)-5-[5-[2-hydroxy-6- Calcd. methyl-4-(trifluoromethyl)463.2, AA 19 phenyl]-l-methyl-imidazo[4,5- Peak 2 Found Fx^k^oH ' b} pyridin-2-yl]- 1 -(2- F 463.4 methoxyethyl)piperidin-2-one(S or A)-4-[[5-[2-hydroxy-6- / Calcd. ^x^-N methyl-4-(trifluoromethyl)419.2, x X IN^v, phenyl]-l-methyl-imidazo[4,5- 20 S fl "l NN / \ FoundFJr LL^0HN^O 6]pyridin-2-yl]methyl]-l- 419.2 4 'methyl-pyrrolidin-2-one26110Table 8LCMS Chiral Example Structure Name[M+H]+Method o (R or S)-4-[[5-[2-hydroxy-6- / Calcd.methyl-4-(trifluoromethyl)419.2,21 4- phenyl]- l-methyl-imidazo[4,5- S N^O Found 6]pyridin-2-yl]methyl]-l- 4 i 419.2 methyl-pyrrolidin-2-one(7?orS)-l-ethyl-5-(5-(2- Calcd. hydroxy-6-methyl-4- 433.2, AF 22 (trifluoromethyl)pheny 1)- 1 - Found (Peak 2) methyl-lE7-imidazo[4,5- 433.2 &]pyridin-2-yl)piperidin-2-one(R or < S)-5-(5-(2-hydroxy-6- methyl-4- Calcd.1 O (trifluoromethyl)phenyl)-l - 447.2, AG 23methyl- l / 7-imi dazo[4.5- Found (Peak 2) Z>]pyridin-2-yl)-l- 447.4 propylpiperidin-2-one(R or 5)-5-(5-(2-hydroxy-6- h tmethyl-4- Calcd.Me [^|TN\ _1AA _ (trifluoromethyl)pheny 1)- 1 - 487.2, AH 24 o fYA '' ^-N methyl-lE7-imidazo[4,5- (Peak 1)31 JLv CF’ Found F C OH / ? | pyri din-2 -yl)- 1 -(2.2.2- 487.3trifluoroethyl)piperidin-2-oneExamples 25 and 26: (R orA)-5-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)-6-methyl-lH-imidazo|4,5- / >]pyridin-2-yl)-l-methylpiperidin-2-one and (S or / ?)-5-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)-6-methyl-LH-iinidazo[4,5-Z>]pyridin-2-yl)-l-methylpiperidin-2-one(Peak 1) (Peak 2)

[0166] To a vial containing (R and 5)-l-methyl-6-oxopiperidine-3-carboxylic acid (67 mg, 0.42 mmol), a solution of HATU (1.2 rnL, 0.53 mmol, 0.45 M in DMF), and a solution of DIPEA (1.2 mL, 1.41 mmol, 1.2 M in DMF) were added sequentially. The reaction mixture was then stirred for 5 min at RT, followed by addition of 2-(5.6-diamino-3-methylpyridin-2-yl)-5-(trifluoromethyl)phenol (Intermediate 4, 100 mg, 0.35 mmol) in DMF (1.2 mL). The reaction mixture was then heated to 100°C and stirred for 16 h. Then the reaction mixture was cooled to26110RT, the solvents were removed under reduced pressure, and AcOH (1 mL, 17.5 mmol) was added to the resulting crude residue. The reaction mixture was then heated to 130°C and stirred overnight. The reaction mixture was then cooled to RT, the solvents were removed under reduced pressure, and the resulting crude residue was purified by reverse phase HPLC (Cl 8 stationary phase, MeCN / H20 + 0.1% TFA) to afford a racemic mixture of the title compounds. The title compounds were resolved by preparative chiral SFC with Method AB. The faster eluting isomer of the title compound was obtained (Example 25, >99% ee).rH NMR (500 MHz, DMSO-Je) 5 7.84 (brs, 1H), 7.37 (d, J= 7.6 Hz, 1H), 7.25 - 7.22 (m, 3H), 3.77 - 3.62 (m, 2H), 3.53 - 3.20 (m, 1H), 2.88 (s, 3H), 2.46 - 2.29 (m, 2H), 2.21 (s, 3H). 2.18 - 2.10 (m, 2H). LCMS [M+H]+= 405.2 (calcd. 405.2). The slower eluting isomer of the title compound was obtained (Example 26, 99% ee). 'H NMR (500 MHz, DMSO- e) 'H NMR (500 MHz, DMSO- e) 57.84 (brs, 1H), 7.37 (d, J= 7.6 Hz, 1H), 7.25 - 7.22 (m, 3H), 3.77 - 3.62 (m, 2H), 3.53 - 3.20 (m, 1H), 2.88 (s, 3H), 2.46 - 2.29 (m, 2H), 2.21 (s, 3H), 2.18 - 2.10 (m, 2H). LCMS [M+H]+= 405.2 (calcd. 405.2).Examples 27 and 28: (R or A)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-7-methyl-lH-imidazo[4,5-Z>]pyridin-2-yl)-l-methylpiperidin-2-one and (S or / ?)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-7-methyl-l / / -imidazo[4,5- / >|pyridin-2-yl)-l-methylpiperidin-2-one(Peak 1) (Peak 2)

[0167] To a vial containing (R and S)-l-methyl-6-oxopiperidine-3-carboxylic acid (57.5 mg, 0.37 mmol), a solution of HATU (1.2 mL. 0.42 mmol, 0.36 M in DMF), and a solution of DIPEA (0.94 mL, 1.13 mmol, 1.2 M in DMF) were added sequentially. The reaction mixture was then stirred for 5 min at RT followed by addition of 6-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4-methylpyridine-2,3-diamine (Intermediates, 100 mg, 0.28 mmol). The reaction mixture was then heated to 100°C and stirred for 16 h. Then the reaction mixture was cooled to RT, the solvents were removed under reduced pressure, and the AcOH (1 mL. 17.5 mmol) was added to the resulting crude residue. The reaction mixture was then heated to 130°C and stirred for 16 h. The reaction mixture was then cooled to RT, the solvents were removed under reduced pressure, the resulting crude residue was purified, and the enantiomers were26110resolved by preparative chiral SFC with Method M. The faster eluting isomer of the title compound was obtained (Example 27, >99% ee).JH NMR (500 MHz, DMSO-tL) 57.08 (s, 1H), 7.04 (s, 1H), 6.98 (s, 1H), 3.79 - 3.63 (m, 3H), 2.88 (s, 3H), 2.54 (s, 3H), 2.39 (dt, J= 10.8, 5.9 Hz, 2H), 2.22 (s, 1H), 2.19 - 2.10 (m, 1H), 2.06 (s, 3H). LCMS [M+H]+= 419.4 (calcd. 419.2). The slower eluting isomer of the title compound was obtained (Example 28, 96% ee). 57.08 (s, 1H), 7.04 (s, 1H), 6.98 (s, 1H), 3.79 - 3.63 (m, 3H), 2.88 (s, 3H), 2.54 (s, 3H), 2.39 (dt, J= 10.8, 5.9 Hz, 2H), 2.22 (s, 1H), 2.19 - 2.10 (m, 1H), 2.06 (s, 3H). LCMS [M+H]+= 419.4 (calcd. 419.2).

[0168] The compounds listed in Table 9 were prepared using procedures similar to the procedure described for Examples 27 and 28 using the appropriate starting materials.Table 9Example Structure Name [M+H]+3-(5-(2-hydroxy-6-methyl-4- Calcd. Me (trifluoromethyl)phenyl)-7-methyl- 399.1, 29 177-imidazo[4,5-Zi]pyridin-2- Found yl)bicyclo[l.l.l]pentane-l- 399.4. carbonitrile1 H 3-methyl-2-(7-methyl-2-( 1 -methyl-2- Calcd. Me rstfSir'Nx oxabicy clo[2.1.1 ]hexan-4-y 1)- IH- 404.2, 30imidazo[4,5-Z>]pyridin-5-yl)-5- Found (trifluoromethyl)phenol 404.4. 2-(2-((lR,5S,6 r ors)-3- 1 H H Calcd.oxabicyclo[3.1.0]hexan-6-yl)-7- 390.1, 31 methyl-177-imidazo[4,5-6]pyridin-5- Found FaC^^OHN Nyl)-3-methyl-5- 390.0.(trifluoromethyl)phenol (Peak 2)

[0169] The compounds listed in Table 10 were prepared using procedures similar to those described for Examples 27 and 28 using the appropriate starting materials. Enantio- and diastereomeric products were separated using chiral or achiral SFC methods specified in the table. For those pairs of isomers, the fast-eluting isomer was listed first. Addition of DIPEA was particularly important when the starting material amine was an acid salt.26110Table 10LCMS Chiral Example Structure Name[M+H]+Method O (5R or S)-5-[5-[2-hydroxy-6- Calcd. methyl-4- 405.2,32 (trifluoromethyl)pheny 1] -7 - M Found methyl- l / 7-imidazo[4,5- 405.2Z ZIx6]pyridin-2-yl]piperidin-2-one(S8 or 7?)-5-[5-[2-hydroxy-6- Calcd. methyl-4- 5 405.2,33 o (trifluoromethyl)pheny 1] -7- M Found methyl-177-imidazo[4,5- 405.2 &]pyridin-2-yl]piperidin-2-one(SR or S)-5-[5-[2-hydroxy-6- Calcd.X\^N / — methyl-4-(trifluoromethyl)1 X X / >— ( >o 447.2,34 1 O o phenyl] -7 -methyl- 1 / 7- M Found imidazo[4,5-7>]pyridin-2-yl]- 1 - F 447.2isopropyl-piperidin-2-oneIZzxIZzx(SS or J?)-5-[5-[2-hydroxy-6- Calcd. methyl-4-(trifluoromethyl)447.2,35 phenyl] -7 -methyl- (H- M Found imidazo[4,5-6]pyridin-2-yl]-l- 447.2. isopropyl -piperidin-2-one(R or 5)-5-(5-(2-hydroxy-6- methyl-4- Calcd.1 HMer irN\_ J \=^ (trifluoromethyl)pheny l)-7 - 463.2,36 1 L H >=o Al jf jX'NNmethyl-17 / -imidazo[4,5- FoundOMe6]pyridin-2-yl)-l-(2- 463.3. methoxyethyl)piperidin-2-one(8 or 7?)-5-(5-(2-hydroxy-6- methyl-4- Calcd.1 HMe r rr^N\. / \ „ (trifluoromethy l)pheny l)-7 - 463.2,37 1 L L H )=o Al jT xXN^"N^N\ methyl-17 / -imidazo[4,5- FoundF3C OH OMe7>]pyridin-2-yl)-l-(2- 463.3. methoxyethyl)piperidin-2-one2-(2-((ls,35 orr)-3- Calcd. fluorocy clobuty l)-7-methy 1- IH- 380.1,38 imidazo[4,5-Z?]pyridin-5-yl)-3- 1 Found methyl-5- 380.2.(trifluoromethyl)phenol26110Table 10LCMS Chiral Example Structure Name[M+H]+Method 2-(2-((ls,3 r or s)-3- 1HCalcd.fluorocy clobuty l)-7 -methy 1- IH- 9MIeL r rLN / / ^— / <\ > " rF380.1,3 imidazo[4,5-d]pyridin-5-yl)-3- I Found methyl-5- 380.2.(trifluoromethyl)phenol (Peak 1)Examples 40 and 41: (R or S) 5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-7-(trifluoromethyl)-3 / 7-imidazo[4,5- / >|pyridin-2-yl)-l-methyl-513-piperidin-2-one and (S or R) 5-(5-(2-hydroxy-6-niethyl-4-(trifluoroniethyl)phenyl)-7-(trifluoroniethyl)-3 / / -imidazo[4,5- / > | pyridin-2-yl)- l-methyI-513-piperidin-2-one(Peak 1) (Peak 2)Step 1: (R and T5-(5-chloro-7-(trifluoromethyl)-37 / -imidazo[4.5- / ilpyridin-2-yl)-l- methylpiperidin-2-one:

[0170] A solution of 6-chloro-N2-(4-methoxybenzyl)-4-(trifluoromethyl)pyridine-2,3-diamine (Intermediate 11, 200 mg, 0.603 mmol) and (R and 5)-l-methyl-6-oxopiperidine-3-carboxylic acid (95 mg, 0.603 mmol) in PPA (4 mL) was heated to 150°C and stirred for 2 h. The reaction mixture was then cooled to RT, carefully quenched with sat. aqueous NaHCCh solution and diluted with EtOAc. The layers were then separated, and the aqueous layer was extracted with EtOAc (x3). The combined organic layers were dried over MgSO4 and filtered, and the solvent was removed under reduced pressure. The resulting crude residue was purified by MPLC (petroleum ether / EtOAc) to afford the title compound. LCMS [M+H]+= 333.1 (calcd. 333.1).Step 2: (R and1S')-5-(5-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-7-(trifluoromethyl)-3H-imidazo|4.5-6|pyridin-2-yl)- l-methylpiperidin-2-one:

[0171] To a solution of (R and 5)-5-(5-chloro-7-(trifluoromethyl)-3 / 7-imidazo[4,5-&]pyridin-2-yl)-l-methylpiperidin-2-one (30 mg, 0.090 mmol) and 2-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Intermediate 1, 39.0 mg, 0.11 mmol) in 1,4-dioxane (1 mL) and water (0.2 mL), K2CO3 (31.2 mg, 0.23 mmol) and Pd(dppf)Ch (9.9 mg, 0.014 mmol) were added. The reaction mixture was degassed with N2 for 10 min and then heated to 100°C and stirred for 12 h. The reaction mixture was then cooled to RT and26110diluted with EtOAc and H2O. The layers were then separated, and the aqueous layer was extracted with EtOAc (x3). The combined organic layers were dried over MgSO4 and filtered, and the solvent was removed under reduced pressure. The resulting crude residue was purified by preparative TLC (EtOAc) to afford the title compound. LCMS [M+H]+= 531.1 (calcd. 531.2).Step 3: (7? or, S') 5-(5-(2-hvdroxy-6-methyl-4-(trifluoromethyl)phenyl)-7- (trifluoromethyl)-3 / 7-imidazof4,5-61pyridin-2-yl)-l-methyl-513-piperidin-2-one and (S or R) 5-(5-(2-hvdroxy-6-methyl-4-(trifluoromethyl)phenyl)-7-(trifluoromethyl)-3 / 7- imidazo[4.5- ]pyridin-2-yl)-l-methyl-513-piperidin-2-one:

[0172] (R and < S’)-5-(5-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-7-(trifluoromethyl)-37 / -imidazo[4,5-6]pyridin-2-yl)-l-methylpiperidin-2-one (20 mg, 0.04 mmol) was dissolved in DCM (1 mL) and then TFA (30 pL, 0.38 mmol) was added at RT, and the reaction mixture was stirred for 2 h. Then the solvents were removed under reduced pressure, and the resulting crude residue was purified by reverse phase HPLC (C 18 stationary phase.MeCN / EbO + 0.1% TFA) to afford a racemic mixture of the title compounds. The title compounds were resolved by preparative chiral SFC with Method AC. The faster eluting isomer of the title compound was obtained (Example 40, >99% ee).NMR (400 MHz, CDsOD) 5 7.52 (s. 1H), 7.10 (s, 1H), 7.05 (s, 1H), 3.86-3.98 (m, 1H), 3.71 - 3.83 (m, 1H), 3.64 (tt, J= 9.9, 4.9 Hz. 1H), 3.03 (s, 3H), 2.52 - 2.62 (m, 2H), 2.24 - 2.41 (m, 2H), 2.16 (s, 3H). LCMS [M+H]+= 473.2 (calcd. 473.1). The slower eluting isomer of the title compound was obtained (Example 41, 99% ee). 'H NMR (400 MHz, CD3OD) 57.52 (s, 1H), 7.10 (s, 1H), 7.05 (s, 1H), 3.86-3.98 (m, 1H), 3.71 - 3.83 (m, 1H), 3.64 (tt, J= 9.9, 4.9 Hz, 1H), 3.03 (s, 3H), 2.52 - 2.62 (m, 2H), 2.24 - 2.41 (m. 2H), 2.16 (s, 3H). LCMS [M+H]+= 473.2 (calcd. 473.1).Examples 42 and 43: (R orS) 5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-7-(trifluoromethyl)-lH-imidazo[4,5-Z>]pyridin-2-yl)-l-methylpiperidin-2-one and (S or R) 5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-7-(trifluoromethyl)-l / / -imidazo|4,5- / >|pyridin-2-yl)-l-methylpiperidin- 2-one(Peak 1) (Peak 2)26110Step 1: (R and X)-5-(5-chloro-l-methyl-7-(trifluoromelhyl)-l / / -imidazo|4.5- / )|pyridin-2- yl)-l-methylpiperidin-2-one:

[0173] A mixture of 6-chloro-N’-methyl-4-(trifluoromethyl)pyridine-2,3-diamine (Intermediate 12, 75 mg, 0.33 mmol) and (R and S)-l-methyl-6-oxopiperidine-3-carboxylic acid (105 mg. 0.67 mmol) in PPA (1 mL) was heated to 150°C and stirred for 2 h. The reaction mixture was then cooled to RT, carefully quenched with sat. aqueous NaHCCh solution and diluted with EtOAc. The layers were then separated, and the aqueous layer was extracted with EtOAc (x3). The combined organic layers were dried over MgSO-i and filtered, and the solvent was removed under reduced pressure. The resulting crude residue was purified by reverse phase HPLC (C18 stationary phase, MeCN / H2O + 0.05% NH4OH + 10 mM NH4HCO3) to afford the title compound. LCMS [M+H]+= 347.1 (calcd. 347.1).Step 2: (R and1S)-5-(5-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-l- methyl-7 -(trifl uoromethyl)- 177-i midazol 4.5- / 11 pyridin-2-yl )- 1 -methylpiperidin-2-one:

[0174] To solution of (R and S)-5-(5-chloro-l-methyl-7-(trifluoromethyl)-l / 7-imidazo[4,5- / ]pyridin-2-yl)-l-methylpiperidin-2-one (15 mg, 0.04 mmol) and 2-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Intermediate 1, 17.1 mg, 0.05 mmol) in 1,4-dioxane (1.5 mL) and water (0.3 mL), CS2CO3 (35 mg. 0.11 mmol) and Pd(dtbpf)Cb (2.8 mg, 4.3 pmol) was added at RT. The reaction mixture was degassed with N2 for 10 min and then heated to 100°C and stirred for 12 h. The reaction mixture was then cooled to RT and diluted with EtOAc and H2O. The layers were then separated, and the aqueous layer was extracted with EtOAc (x3). The combined organic layers were dried over MgSO4 and filtered, and the solvent was removed under reduced pressure. The resulting crude residue was used in the next step without further purification. LCMS [M+H]+= 545.2 (calcd. 545.2).Step 3: (R or S) 5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-7- (trifluoromethyl)-17 / -imidazo[4.5-6]pyridin-2-yl)-l-methylpiperidin-2-one and (S or R) 5- (5 -(2-hvdroxy-6-methy l-4-(trifluoromethy Dpheny 1)- 1 -methyl-7 -(trifluoromethyl)- 1 / 7-imidazo[4.5-&1pyridin-2-yl)-l-methylpiperidin-2-one

[0175] To a solution of (R and S)-5-(5-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl) phenyl)-l-methyl-7-(trifluoromethyl)-177-imidazo[4,5-6]pyridin-2-yl)-l-methylpiperidin-2-one (12 mg, 0.02 mmol) in DCM (1 mL), TFA (8.5 pL, 0.11 mmol) was added at RT, and the reaction mixture was stirred for 1 h. Then the solvents were removed under reduced pressure, and the resulting crude residue was purified by reverse phase HPLC (Cl 8 stationary phase, MeCN / H2O + 0.05% NH4OH + 10 mM NH4HCO3) to afford a racemic mixture of the title compounds. The title compounds were resolved by preparative chiral SFC with Method AD. The26110faster eluting isomer of the title compound was obtained (Example 42, >99% ee). 'H NMR (400 MHz, CD3OD) 57.62 (s, 1H), 7.10 (s, 1H), 7.04 (s, 1H), 4.06 (s, 3H), 3.89-3.98 (m, 1H), 3.81 -3.89 (m, 1H), 3.68-3.77 (m, 1H), 3.04 (s, 3H), 2.51-2.68 (m, 2H), 2.19-2.37 (m, 2H), 2.16 (s, 3H). LCMS [M+H]+= 487.0((calcd. 487.2). The slower eluting isomer of the title compound was obtained (Example 43, 94% ee). 'H NMR (400 MHz, CD3OD) 57.62 (s, 1H). 7.10 (s, 1H), 7.04 (s, 1H), 4.06 (s, 3H), 3.89-3.98 (m, 1H), 3.81-3.89 (m, 1H), 3.68-3.77 (m, 1H), 3.04 (s, 3H), 2.51-2.68 (m, 2H), 2.19-2.37 (m, 2H), 2.16 (s, 3H). LCMS [M+H]+= 487.0 (calcd. 487.2).Example 44: (N)-3-methyl-2-(l-methyl-2-(2-methylmorpholino)-LH-imidazo[4,5-Z>]pyridin-5-yl)-5-(trifluoromethyl)phenol

[0176] A mixture of 2-(2-chloro- 1 -methyl- l / 7-imidazo|4.5-6|pyridin-5-yl)-3-methyl-5-(trifluoromethyl)phenyl dihydrogen phosphate (Intermediate 14. 9.7 mg, 0.024 mmol) and (S)-2-methylmorpholine hydrochloride (13.8 mg, 0.1 mmol) in n-butanol (0.9 mL) was heated to 100°C for 12 h. After cooling to RT, the reaction mixture was concentrated. The resulting crude residue was taken up in DMSO, filtered, and purified via preparative reverse phase HPLC (Cl 8 stationary phase, MeCN / water + 0.05% FA) to afford the title compound. LCMS [M+H]+= 407.0 (calcd. 407.2). 'H NMR (500 MHz, DMSO-tL) 57.70 (d, J= 5.0 Hz, 1H), 7.09 - 7.03 (m, 3H), 3.93 - 3.87 (m, 1H), 3.81 - 3.68 (m, 1H), 3.67 (s, 3H), 3.65 - 3.52 (m, 2H), 3.13 - 3.04 (m, 1H), 2.83 - 2.73 (m, 1H), 2.08 (s, 3H), 1.16 (d, J = 5.0 Hz, 3H). Two NMR signals could not be observed, overlapped with solvent peaks.

[0177] The compounds listed in Table 11 were prepared using procedures similar to the procedure described for Example 44 using the appropriate starting materials.Table 11Example Structure Name [M+H]+N,£> Me 2-(2-((3S.4S)-3-fluoro-4- Calcd.methoxy py rrolidin- 1 -y 1)- 1 -methyl- 425.2, 45NlH-imidazo[4,5-A]pyridin-5-yl)-3- Foundmethyl-5-(trifluoromethyl)phenol 425.3.26110Table 11Example Structure Name [M+H]+(7?)-2-(2-(3 -fluoropy rrolidin- 1 -y 1 ) - 1 - Cal cd. methyl-17 / -imidazo[4,5-6]pyridin-5- 395.1, 46yl)-3-methyl-5- Found (trifluoromethyl)phenol 395.6. (5)- 1 -(5-(2-hydroxy-6-methy 1-4- Cal cd. (trifluoromethy l)phenyl)- 1 -methy 1- 402.2, 47 A T XAAXVCII JXN 177-imidazo[4,5-6]pyridin-2- Found F3C'^ / T)H yl)pyrrolidine-3-carbonitrile 402.4.(7?)-2-(2-(3-methoxypyrrolidin-l-yl)- Calcd. 1 -methyl - 1 / / -i m i dazo [4,5-6] py ridin- 407.2, 48 ^OMe 5-yl)-3-methyl-5- Found(trifluoromethyl)phenol 407.3.

[0178] The compound listed in Table 12 were prepared using procedures similar to those described for Example 44 using the appropriate starting materials. Enantio- and diastereomeric products were separated using chiral or achiral SFC methods specified in the table. For those pairs of isomers, the fast-eluting isomer was listed first. Addition of DIPEA was particularly important when the starting material amine was an acid salt.Table 12LCMS Chiral Example Structure Name[M+H]+Method (U?,57?,67?)-2-(5-(2-hydroxy-6- methyl-4- Calcd.(trifluoromethyl)phenyl)-l - 419.2,49[I V^N^NH" X5.„ AJ OH methyl- l / 7-imidazo[4.5- Found F3C ^^ OH6]pyridin-2-yl)-2- 419.5.azabicyclo[3.2.0]heptan-6-olExample 50 and 51: (R or S) 5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) thiazolo|4, 5-6 |pyridin-2-yl)-l -methyl piperidin-2-one and (A or R) 5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)thiazolo [4,5-6] pyridin-2-yl)- l-methylpiperidin-2-one(Peak 1) (Peak 2)26110Step 1: (R and ■S’)-N-(6-chloro-3-iodopyridin-2-yl)-l-methyl-6-oxopiperidine-3- carboxamide:

[0179] To a solution of 6-chloro-3-iodopyridin-2-amine (500 mg, 1.97 mmol), (R and 5)-l-methyl-6-oxopiperidine-3-carboxylic acid (309 mg, 1.97 mmol) and pyridine (3.2 mL, 39.3 mmol) in DCM (10 mL) at 0°C, POCh (1.8 mL, 19.7 mmol) was added, and the reaction mixture was stirred at 0°C for 1 h. The reaction mixture was then carefully quenched with H2O and diluted with DCM. The layers were then separated, and the aqueous layer was extracted with DCM (x3). The combined organic layers were dried over MgSOr and filtered, and the solvent was removed under reduced pressure. The resulting crude residue was purified by silica gel chromatography (petroleum ether / EtOAc) to afford the title compound. LCMS [M+H]+= 393.9((calcd. 394.0).Step 2: (R and1S')-5-(5-chlorothiazolo[4.5-b1pyridin-2-yl)-l-methylpiperidin-2-one:

[0180] Cui (24.2 mg, 0.13 mmol) and Na2S 9H2O (610 mg, 2.54 mmol) was added to a solution of (R and S -N-(6-chloro-3-iodopyridin-2-yl)-l-methyl-6-oxopiperidine-3-carboxamide (200 mg, 0.51 mmol) in DMF (3 mL). The reaction mixture was then degassed with N2 for 10 min, and then heated to 80°C and stirred for 12 h. The reaction mixture then cooled to RT and filtered, and the solvents were removed under reduced pressure. The resulting crude residue was purified by reverse phase HPLC (Cl 8 stationary phase, MeCN / FLO + 0.1% TFA) to afford the title compound. LCMS [M+H]+= 282.1((calcd. 282.1).Step 3: (R and1S')-5-(5-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)thiazolo|4.5- / ?|pyridin-2-yl)-l-methylpiperidin-2-one:

[0181] A solution of (R and S)-5-(5-chlorothiazolo[4,5-Z>]pyridin-2-yl)-l-methylpiperidin-2-one (15 mg, 0.05 mmol) and 2-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (Intermediate 1, 19.2 mg, 0.05 mmol) in 1,4-dioxane (1 mL) and water (0.2 mL), K2CO3 (22.1 mg, 0.16 mmol) and PdC12(dtbpf) (3.5 mg, 5.3 pmol) was added at RT. The reaction mixture was degassed with N2 for 10 min and then heated to 100°C and stirred for 2 h. The reaction mixture was then cooled to RT and filtered, and the solvent was removed under reduced pressure. The resulting crude residue was used in the next step without further purification. LCMS [M+H]+= 480.3 (calcd. 480.2).Step 4: (R or S) 5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)thiazolo[4,5- 6|pyridin-2-yl)-l-methylpiperidin-2-one and (. S' or / ?) 5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)thiazolo[4.5-d]pyridin-2-yl)-l-methylpiperidin-2-one:

[0182] To a solution of (R and A)-5-(5-(2-(ethoxymethoxy)-6-methyl-4-(trifluoromethyl) phenyl)thiazolo[4,5-i5]pyridin-2-yl)-l-methylpiperidin-2-one (15 mg, 0.03 mmol) in DCM (126110mL), TFA (0.24 mL, 3.1 mmol) was added at RT, and the reaction mixture was stirred for 2 h. Then the solvents were removed under reduced pressure, and the resulting crude residue was purified by reverse phase HPLC (C18 stationary’ phase, MeCN / H₂O + 0.05%NH₄OH + 10 mM NH₄HCO₃) to afford a racemic mixture of the title compounds. The title compounds were resolved by preparative chiral SFC with Method AE. The faster eluting isomer of the title compound was obtained (Example 50, 95% ee). 'H NMR (400 MHz, CD3OD) 58.48 (d, J= 8.2 Hz, 1H), 7.39 (d, J= 8.2 Hz, 1H), 7.00 (s, 1H), 6.94 (s, 1H), 3.70-3.85 (m, 3H), 2.93 (s, 3H), 2.42-2.51 (m, 2H), 2.29-2.39 (m, 1H), 2.18-2.28 (m, 1H), 2.06 (s, 3H). LCMS [M+H]+= 422. l((calcd. 422.1). The slower eluting isomer of the title compound was obtained (Example 51, >99% ee). 'H NMR (400 MHz, CD3OD) 5 8.48 (d, J= 8.2 Hz, 1H), 7.39 (d, J= 8.2 Hz, 1H), 7.00 (s, 1H), 6.94 (s, 1H), 3.70-3.85 (m, 3H), 2.93 (s, 3H), 2.42-2.51 (m, 2H), 2.29-2.39 (m, 1H), 2.18-2.28 (m, 1H), 2.06 (s, 3H). LCMS [M+H]+= 422.1 (calcd. 422.1).NLRP3 Inflammasome Activity

[0183] Activation of the canonical NLRP3 inflammasome requires two steps, priming and activation. A priming signal such as a pathogen activated molecular patterns (PAMPs) or danger-activated molecular patterns (DAMPs) are recognized by Toll-like receptors leads to nuclear factor kappa B (NF-KB)-mediated signaling. This in turn, up-regulates transcription of inflammasome-related components, including inactive NLRP3 and prolL- 113 (Bauemfeind et al., J. Immunol. 2009, 183, 787 - 791; Franchi et al., Nat. Immunol. 2012, 13, 325 - 332; Franchi et al., J. Immunol. 2014, 193, 4214 - 4222). The second step is activation which induces oligomerization of NLRP3 and subsequent assembly of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and procaspase- 1 into an inflammasome complex. This triggers the transformation of procaspase-1 to caspase-1, and the production and secretion of mature IL-1 and IL-18 (Kim et al., J. Inflamm. 2015, 12, 41; Ozaki et al., J. Inflamm. Res. 2015, 8, 15 - 27; Rabeony et al., Eur. J. Immunol. 2015, 45, 2847). During inflammasome complex assembly, the oligomerization of NLRP3 triggers the nucleation of ASC and an event commonly referred to as “ASC SPECK’’ formation, as it is identified in the cell as a discrete puncta within the cell after staining and visualization of ASC using common immunocytochemical methods.

[0184] The ability of compounds to inhibit NLRP3 inflammasome activation was determined in vitro by monitoring formation of the ASC-SPECK in human monocytic THP-1 cells after stimulation. THP-1 cells (ATCC catalog #TIB-202) were maintained in complete grow th media containing Roswell Park Memorial Institute RPMI (ATCC catalog #30-2001), 10% heat26110inactivated fetal bovine serum, IX penicillin / streptomycin and 0.05mM 2-mercaptoethanol. At the start of the assay, undifferentiated THP-1 cells were plated at a density of 20,000 cells per well in a 384-well plate (Poly-D-lysine coated Cell Carrier Ultra microplate, Perkin Elmer catalog #6057500) in complete growth media supplemented with 10 ng / ml phorbol 12-myristate 13-acetate (PMA; Sigma catalog #P8139), and then incubated overnight. The next day, media was replaced with assay media (RPMI (Gibco catalog #11875-093), 0.01% bovine serum albumin (BSA)). Compounds were serially diluted in DMSO and then added to wells one hour prior to the addition of 12.5 pg / ml Gramicidin (Enzo Lifescience, catalog #ALX-350-233-M005). All incubations were carried out at 37 °C (5% CO2 / 95% air). Following a 3-hour treatment with gramicidin, cells are fixed with 4% paraformaldehyde and stored at 4 °C until immunofluorescence staining.

[0185] Immunofluorescence staining: Anti-ASC antibody (MBL catalog #D086-3) was desalted and labeled with Alexa 488 antibody labeling kit (Thermo catalog #A20181) prior to use as described below. After fixation, the following steps were carried out at rt. Cells were first permeabilized with 0.3% polyethylene glycol tert-octylphenyl ether (Triton X-100) in phosphate-buffered saline (PBS) for 15 min and then incubated in blocking buffer containing 5% goat serum, 0.3% polyethylene glycol sorbitan monolaurate (Tween-20) and 0.03% sodium azide in PBS for 1 h. Cells were stained with a mixture of the ASC-Alexa 488 antibody (diluted 1:200 in blocking buffer) and nuclear stain DRAQ5 (1:5000 in blocking buffer, Thermo catalog #62251) in blocking buffer for 1 h. Following a wash with 0.3% polyethylene glycol sorbitan monolaurate (Tween-20) in PBS, plates were imaged with an Opera Phenix High Content Screening System. The number of DRAQ5 positive cells containing ASC SPECKS were quantified in each well.

[0186] Data analysis: ECso values were calculated by standard curve-fitting analysis using an internally developed program in TIBCO Spotfire software.

[0187] The compounds of the present invention inhibit NLRP3 inflammasome activation in the above Biological Assay and have ECso values of less than 5 micromolar. Specific ECso values of the compounds of Examples 1-216 in the above Biological Assay are listed in Table 13.26110Table 13Ex. ECso(nM) Ex. EC50(nM) Ex. ECso(nM) Ex. ECso(nM) 1 1179 14 713 27 169 40 83 2 59 15 44 28 23 41 232 3 362 16 59 29 247 42 1552 4 447 17 662 30 88 43 90 5 691 18 267 31 98 44 524 6 420 19 64 32 18 45 414 7 442 20 1288 33 16 46 329 8 629 21 310 34 124 47 544 9 293 22 54 35 14 48 395 10 987 23 36 36 20 49 134 11 15 24 61 37 219 50 100 12 99 25 2123 38 167 51 3213 206 26 537 39 203

[0188] The disclosed subject matter is not to be limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the disclosure in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

[0189] All references (e.g.. publications or patents or patent applications) cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual reference (e.g., publication or patent or patent application) w as specifically and individually indicated to be incorporated by reference in its entirety' for all purposes. Other embodiments are within the follo ing claims.

Claims

WHAT IS CLAIMED IS:

1. A compound of F ormula (I):R4and pharmaceutically acceptable salts thereof, whereinX is selected from:1) S, and2) NR5;R1is selected from:1) C1-6 alkyl,2) Co-3 alky lene-(monocyclic C3-8 cycloalkyl),3) C0-3 alkylene-(bicyclic C4-8 cycloalkyl),4) C0-3 alkylene-(C5-io spiro-cycloalkyl),5) C0-3 alkylene-(tricyclic Ce-9 cycloalkyl),6) C0-3 alky lene-(cubyl),7) C0-3 alky lene-(3- to 9-membered monocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P),8) C0-3 alkylene-(4- to 9-membered bicyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P),9) C0-3 alky lene-(5- to 9-membered spirocyclic heterocycloalky l containing 1, 2. or 3 ring heteroatoms selected from N. S, O. and P).10) C0-3 alkylene-(5- to 10-membered heteroaryl containing 1, 2, or 3 ring heteroatoms selected from N, S, O, and P),11) NH-C 1-6 alkyl,12) NH-C0-3 alkylene-(monocyclic C3-8 cycloalkyl),13) NH-C0-3 alkylene-(bicyclic C4-8 cycloalkyl),14) NH-C0-3 alkylene-(C5-io spiro-cycloalkyl), and15) NH-C0-3 alkylene-(tri cyclic Ce-9 cycloalky l),wherein said R1group is unsubstituted or substituted with 1 to 5 substituents independently selected from R6;R2is phenyl, unsubstituted or substituted by 1, 2, 3, or 4 substituents independently- selected from:1) OH,2) halo,3) Ci-6 alkyl, and4) Ci-6 haloalkyl containing from 1 to 3 independently selected halogens; R3is selected from:1) H,2) halo, and3) Ci-6 alkyl;R4is selected from:1) H, and2) C1-6 alkyl.wherein said R4Ci-6 alkyl is unsubstituted or substituted with 1 to 5 substituents independently selected from:1) OH, and2) halo;R5is selected from:1) H,2) C i-6 alkyl, and3) C3-7 cycloalkyl,wherein said R5C1-6 alkyl or R5C3-7 cycloalkyl is unsubstituted or substituted with 1 to 5 substituents independently selected from:1) OH,2) halo,3) CN,4) NRa2,wherein each Rais independently selected from H and C1-6 alkyl; and each R6is independently selected from:1) OH,2) halo,3) CN,4) oxo,5),6) Ci-6 alkyd, which may be straight or branched and which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, and Ci-6 alkoxy,7) Ci-6 alkoxy, which may be straight or branched and which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, and Ci-6 alkoxy,8) C3-7 cycloalky l, which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, C1-3 alkyl, C1-3 haloalkyl, and C 1-6 alkoxy,9) 3- to 9-membered monocyclic heterocycloalkyl containing 1, 2, or 3 ring heteroatoms selected from N. S, O, and P, and which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN. oxo, C1-3 alkyl, C1-3 haloalkyl, and C1-6 alkoxy,10) C5-7 aryl, which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, and C1-6 alkoxy,11) methylene-Cs-7 aryl, which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, and C1-6 alkoxy, and 12) 5- to 10-membered heteroaryl containing at least one ring heteroatom selected fromN, S, O, and P, and which is unsubstituted or substituted with 1 to 4 substituents selected from OH, halo, CN, oxo, C1-3 alkyl. C1-3 haloalkyl, and C1-6 alkoxy.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is S.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is NR5.

4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein R5is selected from:1) H,2) methyl,261103) ethyl,4) isopropyl,5) cyclopropyl, and6) cyclobutyl.wherein said R5Ci-6 alkyl, R5Ci-6 alkoxy, or R5C3-7 cycloalkyl is unsubstituted or substituted with 1 to 5 substituents independently selected from: 1) OH,2) halo,3) NRa2, where each Rais independently selected from H and C1-6 alkyl,5. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein R5is selected from:1) H,2) CH3, and3) CH2CH3,6. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein R5is H.

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is selected from:OH26110OHOH8. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein R1is selected from:o9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl substituted by 2 to 4 substituents selected independently from:1) OH,2) halo,3) Ci-2 alkyl, and4) Ci-2 haloalky 1 containing from 1 to 3 independently selected halogens.2611010. The compound according to claim 9. or a pharmaceutically acceptable salt thereof, wherein R2is phenyl substituted by 2 to 4 substituents selected independently from:1) OH,2) Cl,3) F.4) CH3, and5) CF₃.

11. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl substituted by OH and CF₃.

12. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl substituted by OH, CH₃, and CF₃.

13. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl substituted by OH, CH3, and Cl.

14. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl substituted by OH, CH3, F, and Cl.

15. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R2is selected from16. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R2is17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R3is H.2611018. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R3is selected from F and Cl.

19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R4is H.

20. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R4is selected from: unsubstituted C1-3 alkyl.

21. The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein R4is CH3.

22. The compound according to claim 1. or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

1. (< S)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-177- imidazo[4,5-6]pyridin-2-yl)-l-methylpiperidin-2-one,2. (7?)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-l / / - imidazo[4,5-£]pyridin-2-yl)-l-methylpiperidin-2-one,3. 2-[2-(3,3-difluorocyclobutyl)-l-methyl-imidazo[4,5-b]pyridin-5-yl]-3-methyl-5- (trifluoromethyl)phenol,4. 3-methyl-2-(l-methyl-2-tetrahydropyran-4-yl-imidazo[4,5-b]pyridin-5-yl)-5- (trifluoromethyl)phenol,5. 2-(2-((17?,5S,65')-3-oxabicyclo[3.1.0]hexan-6-yl)-l-methyl-177-imidazo[4,5- &]pyridin-5-yl)-3-methyl-5-(trifluoromethyl)phenol,6. 2-(2-((lA,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-l-methyl-177-imidazo[4,5- 6]pyridin-5-yl)-3-methyl-5-(trifluoromethyl)phenol.

7. (57?)-5-[l-ethyl-5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]imidazo[4,5- 61 py ri di n-2-y 11 - 1 -methy l-piperidin-2-one,8. (5< S)-5-[l-ethyl-5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]imidazo[4,5- 6]pyridin-2-yl]-l-methyl-piperidin-2-one,9. 3-methyl-2-[l-methyl-2-[(67?)-5,6,7,8-tetrahydrotetrazolo[l,5-a]pyridin-6- yl]imidazo[4,5-6]pyridin-5-yl]-5-(trifluoromethyl)phenol,10. 3-methyl-2-[1-methyl-2-[(6S)-5,6,7,8-tetrahydrotetrazolo[1,5-a]pyridin-6-yl]imidazo[4,5-b]pyridin-5-yl]-5-(trifluoromethyl)phenol,11. (5R)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-imidazo[4,5-b]pyridin-2-yl]-1-isopropyl-piperidin-2-one,12. (5S)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-l-methyl-imidazo[4,5- 6]pyridin-2-yl] - 1 -isopropy l-piperidin-2-one,13. (5R)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-imidazo[4,5-b]pyridin-2-yl]piperidin-2-one,14. (5S)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-l-methyl-imidazo[4,5- 6]pyridin-2-yl]piperidin-2-one,15. (5R)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-imidazo[4,5-b]pyridin-2-yl]-1-[(3R)-tetrahydrofuran-3-yl]piperidin-2-one,16. (5S)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-imidazo[4,5-b]pyridin-2-yl]-1-[(3R)-tetrahydrofuran-3-yl]piperidin-2-one,17. (5R)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-imidazo[4,5-b]pyridin-2-yl]-1-[(3S)-tetrahydrofuran-3-yl]piperidin-2-one,18. (5< S)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-l-methyl-imidazo[4,5- 6]pyridin-2-yl]-l-[(3S)-tetrahydrofuran-3-yl]piperidin-2-one,19. 3-methyl-2-[l-methyl-2-[(6>5’ or7?)-3-methyl-5,6,7,8-tetrahydro- | l.2.4|triazolo|4.3-c7|pyridin-6-yl|imidazo|4.5- / ?|pyridin-5-yl|-5- (trifluoromethyl)phenol,20. (55)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl) phenyl]-l-methyl-imidazo[4,5- 6]pyridin-2-yl]-l-(2-methoxyethyl)piperidin-2-one,21. (5R)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-imidazo[4,5-b]pyridin-2-yl]-1-(2-methoxyethyl)piperidin-2-one,22. (< S)-4-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl) phenyl]-l-methyl-imidazo[4,5- 6]pyridin-2-yl]methyl]-l-methyl-pyrrolidin-2-one,23. (R)-4-[[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-1-methyl-imidazo[4,5-b]pyridin-2-yl]methyl]-1-methyl-pyrrolidin-2-one,24. (R)- 1 -ethy 1-5 -(5 -(2-hy droxy-6-methy l-4-(trifluoromethyl)pheny 1)- 1 -methyl-l / 7- imidazo[4,5-6]pyridin-2-yl)piperidin-2-one,25. (S)- 1 -ethyl-5-(5-(2-hy droxy-6-methy l-4-(trifluoromethyl)phenyl)- 1 -methyl- IH- imidazo[4,5-Z?]pyridin-2-yl)piperidin-2-one,26. (7?)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-l / / - imidazo[4,5-Z?]pyridin-2-yl)-l-propylpiperidin-2-one,27. (<S)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-l / 7- imidazo[4,5-Z>]pyridin-2-yl)-l-propylpiperidin-2-one,28. (7?)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-l / 7- imidazo[4,5-Z>]pyridin-2-yl)-l-(2,2,2-trifluoroethyl)piperidin-2-one,29. (S)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-l / 7- imidazo[4,5-6]pyridin-2-yl)-l-(2,2,2-trifluoroethyl)piperidin-2-one,30. (7?)-5-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)-6-methyl-l / 7-imidazo[4,5- 6]pyridin-2-yl)-l-methylpiperi din-2 -one,31. (< S’)-5-(5-(2-hydroxy-4-(trifluoromethyl)phenyl)-6-methyl-17f-imidazo[4,5- 6]pyridin-2-yl)-l-methylpiperidin-2-one,32. (7?)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-7-methyl-l / 7- imidazo[4,5- i]pyridin-2-yl)-l-methylpiperidin-2-one,33. (1S’)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-7-methyl-l / 7- imidazo[4,5-Z?]pyridin-2-yl)-l-methylpiperidin-2-one,34. 3-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-7-methyl-1H-imidazo[4,5-b]pyridin-2-yl)bicyclo[1.1.1]pentane-1-carbonitrile,35. 3-methyl-2-(7-methyl-2-(l-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)-17 / - imidazo[4,5-?]pyridin-5-yl)-5-(trifluoromethyl)phenol,36. 2-(2-((lR,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl)-7-methyl-177-imidazo[4,5- 6]pyridin-5-yl)-3-methyl-5-(trifluoromethyl)phenol,37. 2-(2-((lR,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)-7-methyl-l / / -imidazo[4,5- 6]pyridin-5-yl)-3-methyl-5-(trifluoromethyl)phenol,38. (5R)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-1H-imidazo[4,5-b]pyridin-2-yl]piperidin-2-one,39. (5S)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-l / f- imidazo[4,5-£]pyridin-2-yl]piperidin-2-one,40. (5?)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl) phenyl]-7-methyl-l / 7- imidazo[4,5-6]pyridin-2-yl]-l-isopropyl-piperidin-2-one,41. (5S)-5-[5-[2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl]-7-methyl-1H-imidazo[4,5-b]pyridin-2-yl]-1-isopropyl-piperidin-2-one,42. (7?)-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-7-methyl-l / 7- imidazo[4,5-6]pyridin-2-yl)-l-(2-methoxyethyl)piperidin-2-one,43. (< S')-5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-7-methyl-l / / - imidazo[4,5-Z?]pyridin-2-yl)-l-(2-methoxyethyl)piperidin-2-one, 44. 2-(2-((ls,3s)-3-fluorocyclobutyl)-7-methyl-177-imidazo[4,5-Z>]pyridin-5-yl)-3- methyl-5-(trifluoromethyl)phenol,45. 2-(2-((ls.3r)-3-fluorocyclobutyl)-7-methyl-l / 7-imidazo[4.5-i5]pyridin-5-yl)-3- methyl-5-(trifluoromethyl)phenol,46. (R) 5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-7 -(trifluoromethyl)-377- imidazo[4,5-Z>]pyridin-2-yl)-l-methyl-513-piperidin-2-one,47. (S) 5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-7-(trifluoromethyl)-3 7- imi dazo[4,5- >]pyri din-2 -yl)-l-methyl-513-piperidin-2-one,48. (R) 5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-7- (trifluoromethyl)-177-imidazo[4,5-i5]pyridin-2-yl)-l-methylpiperidin-2-one, 49. (S) 5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)- 1 -methyl-7 - (trifluoromethyl)-17 / -imidazo[4,5-Z>]pyridin-2-yl)-l-methylpiperidin-2-one, 50. (1S’)-3-methyl-2-(l-methyl-2-(2-methylmorpholino)-177-imidazo[4,5-?]pyridin-5- yl)-5-(trifluoromethyl)phenol,51. 2-(2-((3S,4S)-3-fluoro-4-methoxypyrrolidin-1-yl)-1-methyl-1H-imidazo[4,5-b]pyridin-5-yl)-3-methyl-5-(trifluoromethyl)phenol,52. (7?)-2-(2-(3-fluoropyrrolidin-l-yl)-l-methyl-177-imidazo[4,5-Z>]pyridin-5-yl)-3- methyl-5-(trifluoromethyl)phenol,53. (< S)-l-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-177- imidazo[4,5-6]pyridin-2-yl)pyrrolidine-3-carbonitrile,54. (7?)-2-(2-(3-methoxypyrrolidin-l-yl)-l-methyl-l / 7-imidazo[4,5-6]pyridin-5-yl)-3- methyl-5-(trifluoromethyl)phenol,55. (17?,57?,67?)-2-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)-l-methyl-177- imidazo[4,5-6]pyridin-2-yl)-2-azabicyclo[3.2.0]heptan-6-ol.

56. (R) 5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl) thiazolo[4,5-ft]pyridin- 2-yl)-l-methylpiperidin-2-one, and57. (S) 5-(5-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)thiazolo[4,5-6]pyridin-2- y 1)- 1 -methylpiperidin-2-one,and pharmaceutically acceptable salts thereof.

23. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:261102611024. A pharmaceutical composition comprising a compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

25. The use of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful for the treatment of a disorder, condition, or disease that is responsive to the inhibition of NLRP3 in a mammal in need thereof.

26. The use of a compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment, prevention or control of an inflammatory’ disorder, a fibrotic disorder, a cardiovascular disorder, a metabolic disorder, and a neurodegenerative disorder.2611027. The use of claim 26, wherein the disorder is an inflammatory disorder.

28. The use of claim 27, wherein the inflammatory disorder is selected from: an auto-immune disorder, an auto-inflammatory disorder, an inflammatory j oint disorder, an inflammatory skin disorder, and a neuroinflammatory disorder.

29. The use of claim 25, wherein the disorder is selected from: atherosclerosis, non-alcoholic steatohepatitis, Alzheimer's disease, Parkinson’s disease, and dementia with Lewy bodies (DLB).

30. The use of claim 25, wherein the disorder is obesity.

31. The use of claim 25, wherein the disorder is metabolic dysfunction-associated steatohepatitis.

32. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, for use in therapy.

33. A method of treating or preventing a disorder, condition or disease that is responsive to the inhibition of NLRP3 in a patient in need thereof comprising administration of a therapeutically effective amount of a compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof.

34. The method of claim 33, wherein the disorder is selected from: an inflammatory disorder, a fibrotic disorder, a cardiovascular disorder, a metabolic disorder, and a neurodegenerative disorder.

35. The method of claim 34. wherein the disorder is an inflammatory disorder.

36. The method of claim 35, wherein the inflammatory disorder is selected from: an autoimmune disorder, an auto-inflammatory disorder, an inflammatory joint disorder, an inflammatory skin disorder, and a neuroinflammatory disorder.2611037. The method of claim 33. wherein the disorder is selected from: atherosclerosis, nonalcoholic steatohepatitis, Alzheimer’s disease, Parkinson’s disease, and dementia with Lewy bodies (DLB).

38. The method of claim 33. wherein the disorder is obesity.

39. The method of claim 33, wherein the disorder is metabolic dysfunction-associated steatohepatitis.

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