TECHNICAL FIELD

The present disclosure relates to, in part, methods of treating a subject that include administration of an NLRP3 antagonist. The present disclosure also relates, in part, to methods, combinations and compositions for treating TFNa related diseases and anti- TNFa resistance in a subject that include administration of an NLRP3 antagonist, an NLRP3 antagonist and an anti-TNFa agent, or a composition comprising an NLRP3 antagonist and an anti-TNFa agent.

BACKGROUND The NLRP3 inflammasome is a component of the inflammatory process and its aberrant activation is pathogenic in inherited disorders such as the cryopyrin associated periodic syndromes (CAPS). The inherited CAPS Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal onset multi-system inflammatory disease (NOMID) are examples of indications that have been reported to be associated with gain-of-function mutations in NLRP3.

Alterations in NLRP3 have been associated with the pathogenesis of a number of complex diseases, including but not limited to intestinal diseases (e.g., Crohn’s disease (CD), ulcerative colitis (UC), inflammatory bowel disease (IBD)), kidney disease (e.g., acute and chronic kidney injury), lung diseases (e.g., asthma, chronic obstructive pulmonary disease (COPD), pulmonary idiopathic fibrosis), liver diseases (e.g., nonalcoholic steatohepatitis (NASH), viral hepatitis, cirrhosis), metabolic disorders (e.g., type 2 diabetes, atherosclerosis, obesity, gout), musculoskeletal diseases (e.g., scleroderma), pancreatic diseases (e.g., acute and chronic pancreatitis), skin diseases (e.g., psoriasis), autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus (SLE), autoimmune thyroiditis, Addison's disease), diseases of the central nervous system, (e.g., Alzheimer’s disease, multiple sclerosis, Amyotrophic Lateral Sclerosis and Parkinson disease), vessel disorders (e.g., giant cell arteritis), disorders of the bones (e.g., osteoarthritis , osteoporosis), eye diseases (e.g., glaucoma and macular degeneration), diseased caused by viral infection such as HIV and AIDS, pernicious anemia, cancer and aging.

Several patients having inflammatory or autoimmune diseases are treated with anti-TNFa agents. A subpopulation of such patients develop resistance to treatment with the anti-TNFa agents. It is desirable to develop methods for reducing a patient’s resistance to anti-TNFa agents.

In light of the above, it would also be desirable to provide alternative therapies for treating inflammatory or autoimmune diseases (for example NLRP3 inflammasome inhibitors) to avoid or minimise the use of anti-TNFa agents.

Intestinal bowel disease (IBD), encompassing Ulcerative Colitis (UC) and

Crohn’s disease (CD), are chronic diseases characterized by barrier dysfunction and uncontrolled inflammation and mucosal immune reactions in the gut. A number of inflammatory pathways have been implicated in the progression of IBD, and anti inflammatory therapy such as tumor necrosis factor-alpha (TNF-a) blockade has shown efficacy in the clinic ( Rutgeerts P et alN Engl JMed 2005; 353:2462-76). Anti-TNFa therapies, however, do not show complete efficacy, however, other cytokines such as IL- 1b, IL-6, IL-12, IL-18, IL-21, and IL-23 have been shown to drive inflammatory disease pathology in IBD Neurath ME Nat Rev Immunol 2014;14;329-42). IL- 1 b and IL-18 are produced by the NLRP3 inflammasome in response to pathogenic danger signals, and have been shown to play a role in IBD. Anti-IL- 1 b therapy is efficacious in patients with IBD driven by genetic mutations in CARD8 or IL-10R ( Mao L et al, J Clin Invest 2018;238:1793-1806, Shouval DS et al, Gastroenterology 2016; 151 : 1100-1104), IL-18 genetic polymorphisms have been linked to UC ( Kanai T et al, Curr Drug Targets 2013; 14: 1392-9), and NLRP3 inflammasome inhibitors have been shown to be efficacious in murine models of IBD ( Per era AP et al, Sci Rep 2018;8:8618). Resident gut immune cells isolated from the lamina propria of IBD patients can produce P,-Ib, either spontaneously or when stimulated by LPS, and this IL- 1 b production can be blocked by the ex vivo addition of a NLRP3 antagonist. Based on strong clinical and preclinical evidence showing that inflammasome-driven P,-Ib and IL-18 play a role in IBD pathology, it is clear that NLRP3 inflammasome inhibitors could be an efficacious treatment option for UC, Crohn’s disease, or subsets of IBD patients. These subsets of patients could be defined by their peripheral or gut levels of inflammasome related cytokines including Iί-ΐb, IL-6, and IL-18, by genetic factors that pre-dispose IBD patients to having NLRP3 inflammasome activation such as mutations in genes including ATG16L1, CARD8, IL-10R, or PTPN2 (Saitoh Tef al, Nature 2008;456:264, Spalinger MR, Cell Rep 2018; 22: 1835), or by other clinical rationale such as non-response to TNF therapy.

Though anti-TNF therapy is an effective treatment option for Crohn’s disease, 40% of patients fail to respond. One-third of non-responsive CD patients fail to respond to anti-TNF therapy at the onset of treatment, while another third lose response to treatment over time (secondary non-response). Secondary non-response can be due to the generation of anti-drug antibodies, or a change in the immune compartment that desensitizes the patient to anti-TNF ( Ben-Horin S et al, Autoimmun Rev 2014;13:24-30, Steenholdt C et al Gut 2014;63:919-27 ). Anti-TNF reduces inflammation in IBD by causing pathogenic T cell apoptosis in the intestine, therefore eliminating the T cell mediated inflammatory response ( Van den Brande et al Gut 2007:56:509-17). There is increased NLRP3 expression and increased production of IL-1 b in the gut of TNF-non- responsive CD patients (Leal RF et al Gut 2015;64:233-42) compared to TNF -responsive patients, suggesting NLRP3 inflammasome pathway activation. Furthermore, there is increased expression of TNF-receptor 2 (TNF-R2), which allows for TNF-mediated proliferation of T cells {Schmitt H et al Gut 2018;0:1-15). IL- 1 b signaling in the gut promotes T cell differentiation toward Thl/l7 cells which can escape anti-TNF-a mediated apoptosis. It is therefore likely that NLRP3 inflammasome activation can cause non-responsiveness in CD patients to anti-TNF-a therapy by sensitizing pathogenic T cells in the gut to anti-TNF-a mediated apoptosis. Experimental data from immune cells isolated from the gut of TNF-resistant Crohn’s patients show that these cells

spontaneously release IL- 1 b, which can be inhibited by the addition of an NLRP3 antagonist. NLRP3 inflammasome antagonists - in part by blocking IL-1 b secretion - would be expected to inhibit the mechanism leading to anti-TNF non-responsiveness, re sensitizing the patient to anti-TNF therapy. In IBD patients who are naive to anti-TNF therapy, treatment with an NLRP3 antagonist would be expected to prevent primary- and secondary-non responsiveness by blocking the mechanism leading to non-response.

NLRP3 antagonists that are efficacious locally in the gut can be efficacious drugs to treat IBD; in particular in the treatment of TNF-resistant CD alone or in combination with anti-TNF therapy. Systemic inhibition of both IL-l and TNF-a has been shown to increase the risk of opportunistic infections (Genovese MC et al, Arthritis Rheum

2004;50: 1412), therefore, only blocking the NLRP3 inflammasome at the site of inflammation would reduce the infection risk inherent in neutralizing both IL-l□ and TNF-a. NLRP3 antagonists that are potent in NLRP3 -inflammasome driven cytokine secretion assays in cells, but have low permeability in vitro in a permeability assay such as an MDCK assay, have poor systemic bioavailability in a rat or mouse pharmacokinetic experiment, but high levels of compound in the colon and/or small intestine could be a useful therapeutic option for gut restricted purposes.

The present invention provides alternative therapies for the treatment of inflammatory or autoimmune diseases, including IBD, that solves the above problems associated with anti-TNFa agents.

SUMMARY

The present invention is based on the discovery of mutations and mRNA/protein expression profiles that correlate with a subject’s sensitivity to treatment with an NLRP3 antagonist.

The present invention is also relates to the Applicant’s discovery that inhibition of

NLRP3 inflammasomes can increase a subject’s sensitivity to an anti-TNFa agent or can overcome resistance to an anti-TNFa agent in a subject, or indeed provide an alternative therapy to anti-TNFa agents. Provided herein are methods of treating a subject that include: (a) identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level; and (b) administering to the identified subject a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Provided herein are methods for the treatment of inflammatory or autoimmune disease including IBD, such as UC and CD in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of an NLRP3 agonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, wherein the NLRP3 antagonist is a gut-targeted NLRP3 antagonist.

Provided herein are methods of treating a subject that include: administering a therapeutically effective amount of an NLPR3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level.

Provided herein are methods of selecting a treatment for a subject that include: (a) identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level; and (b) selecting for the identified subject a treatment comprising a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Provided herein are methods of selecting a treatment for a subject, that include: selecting a treatment comprising a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof for a subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level.

Provided herein are methods of selecting a subject for treatment, that include: (a) identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level; and (b) selecting an identified subject for treatment with a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. Provided herein are methods of selecting a subject for treatment, that include: selecting a subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level, for treatment with a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Provided herein are methods of selecting a subject for participation in a clinical trial, that include: identifying a subject having a cancer cell that has an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level; and selecting the identified subject for participation in a clinical trial that comprises administration of a therapeutically effective amount of a NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Also provided herein are methods of selecting a subject for participation in a clinical trial, that include: selecting a subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level for participation in a clinical trial that comprises administration of a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having a gain-of-function mutation in an NLRP3 gene.

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity includes detecting a loss-of-function mutation in a CARD8 gene in a cell from the subject.

In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having a loss-of-function mutation in a CARD8 gene.

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity includes detecting a gain-of-function mutation in an NLRP3 gene and a loss-of-function mutation in a CARD8 gene in a cell from the subject. In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having a gain-of-function mutation in an NLRP3 gene and a loss-of-function mutation in a CARD8 gene.

In some embodiments of any of the methods described herein, the gain-of- function mutation in an NLRP3 gene results in the expression of a NLRP3 protein having a Q705K amino acid substitution.

In some embodiments of any of the methods described herein, the loss-of-function mutation in a CARD8 gene is a C allele at rs20432l 1.

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome expression includes detecting the level of one or more of NLRP3 protein, ASC protein, procaspase-l protein, and caspase-l protein.

In some embodiments of any of the methods described herein, identifying a subject having a cell that has an elevated level of NLRP3 inflammasome expression comprises detecting the level of one or more of NLRP3 mRNA, ASC mRNA, and procaspase-l mRNA.

In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome expression has been determined to have a cell having an elevated level of one or more of NLRP3 protein, ASC protein, procaspase-l protein, and caspase-l protein.

In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome expression has been determined to have a cell having an elevated level of one or more of NLRP3 mRNA, ASC mRNA, and procaspase-l mRNA.

In some embodiments of any of the methods described herein, the subject has or is suspected of having Crohn’s disease, inflammatory bowel disease (IBD), or other gastrointestinal, autoimmune, or autoinflammatory disorders.

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity includes detecting a mutation in an NLRP3 gene that results in the expression of a NLRP3 protein having one or both of a T350M and a R262M amino acid substitution in a cell from the subject.

In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having an NLRP3 gene that results in the expression of a NLRP3 protein having one or both of a T350M and a R262M amino acid substitution.

In some embodiments of any of the methods described herein, the subject has or is suspected of having hereditary periodic fever.

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity includes detecting a mutation in an NLRP3 gene that results in the expression of an NLRP3 protein having one or more of a A441 V, a V200M, a E629G, and a L355P amino acid substitution in a cell from the subject.

In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having an NLRP3 gene that results in the expression of an NLRP3 protein having one or more of a A441 V, a V200M, a E629G, and a L355P amino acid substitution.

In some embodiments of any of the methods described herein, the subject has or is suspected of having familial cold autoinflammatory syndrome (FCAS).

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity comprises detecting a mutation in an NLRP3 gene that results in the expression of an NLRP3 protein having one or more of a R260W, a G571R, and a A354V amino acid substitution in a cell from the subject.

In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having an NLRP3 gene that results in the expression of an NLRP3 protein having one or more of a R260W, a G571R, and a A354V amino acid substitution.

In some embodiments of any of the methods described herein, the subject has or is suspected of having Muckle-Wells syndrome (MWS).

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity includes detecting a mutation in an NLRP3 gene that results in the expression of an NLRP3 protein having one or both of a D305N and a F311 S amino acid substitution in a cell from the subject.

In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having an NLRP3 gene that results in the expression of an NLRP3 protein having one or both of a D305N and a F311 S amino acid substitution.

In some embodiments of any of the methods described herein, the subject has or is suspected of having Cinca syndrome.

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity includes detecting a mutation in an NLRP3 gene that results in the expression of an NLRP3 protein having one or both of a R920Q amino acid substitution in a cell from the subject.

In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having a mutation in an NLRP3 gene that results in the expression of an NLRP3 protein having a R920Q amino acid substitution.

In some embodiments of any of the methods described herein, the subject has or is suspected of having deafness with or without inflammation.

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity includes detecting a mutation in an NLRP3 gene that results in the expression of an NLRP3 protein having a D21H amino acid substitution in a cell from the subject. In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having an NLRP3 gene that results in the expression of an NLRP3 protein having a D21H amino acid substitution.

In some embodiments of any of the methods described herein, the subject has or is suspected of having keratoendotheliitis fugax hereditaria.

In some embodiments of any of the methods described herein, the subject has or is suspected of having an inappropriate host response to infectious diseases where active infection exists at any body site. In some embodiments, the inappropriate host response to infectious disease where active infection exists at any body site is selected from the group consisting of: septic shock, disseminated intravascular coagulation, and adult respiratory distress syndrome.

In some embodiments of any of the methods described herein, the subject has or is suspected of having acute or chronic inflammation due to antigen, antibody, and/or complement deposition.

In some embodiments of any of the methods described herein, the subject has or is suspected of having an inflammatory disease or condition. In some embodiments, the inflammatory disease or condition is selected from the group consisting of: arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury, vasculitis, osteoarthritis, COPD, periodontal disease, uveitis, cutaneous T-cell lymphoma, and mucositis such as oral mucositis, esophageal mucositis, and intestinal mucositis.

In some embodiments of any of the methods described herein, the subject has or is suspected of having acute and delayed hypersensitivity, graft rejection, or graft-versus- host disease (GVHD).

In some embodiments of any of the methods described herein, the subject has or is suspected of having an autoimmune disease selected from the group consisting of:

Type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus,

autoimmune thyroiditis, Addison’s disease, pernicious anemia, multiple sclerosis, an inflammatory bowel disease (IBD), scleroderma, and psoriasis. In some embodiments, the IBD is selected from the group consisting of: Crohn’s disease, ulcerative colitis, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by treatment with adoptive cell therapy, colitis associated with one or more alloimmune diseases such as GVHD, radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis, celiac disease, and inflammatory bowel syndrome.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a metabolic disorder. In some embodiments, the metabolic disorder selected from the group consisting of type 2 diabetes, atherosclerosis, obesity, gout, and pseudogout.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a disease of the central nervous system.

In some embodiments, the disease of the central nervous system is selected from the group consisting of: Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson’s disease.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a lung disease. In some embodiments, the lung disease is asthma, COPD, pulmonary idiopathic fibrosis, or cystic fibrosis.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a liver disease.

In some embodiments, the liver disease is selected from the group consisting of: NASH syndrome, viral hepatitis, and cirrhosis.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a pancreatic disease, such as acute or chronic pancreatitis.

In some embodiments of any of the methods described herein, the subject has or is suspected of having kidney disease, such as acute or chronic kidney injury.

In some embodiments of any of the methods described herein, the subject has or is suspected of having an intestinal disease, such as Crohn’s disease or ulcerative colitis.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a skin disease, such as psoriasis. In some embodiments of any of the methods described herein, the subject has or is suspected of having a musculoskeletal disease, such as scleroderma.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a vessel disorder, such as giant cell arteritis.

In some embodiments of any of the methods described herein, the subject has a bone disorder, such as osteoarthritis, osteoporosis, and osteopetrosis disorders.

In some embodiments of any of the methods described herein, the subject has or is suspected of having an eye disease, such as glaucoma or macular degeneration, such as age-related macular degeneration.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a disease caused by viral infection, such as HIV or AIDS.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a cancer, such as non-small cell lung cancer, acute lymphoblastic leukemia (ALL) (ALL in patients resistant to glucocorticoid treatment), multiple myeloma, promyelocytic leukemia, gastric cancer, and lung cancer metastasis.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a cardiovascular disease.

In some embodiments, the cardiovascular disease is myocardial infarction, stroke, or heart failure.

In some embodiments of any of the methods described herein, the subject has or is suspected of having: hereditary periodic fever, familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome, myelodysplastic syndrome (MDS), Langerhan’s cell histiocytosis (LCH), neonatal onset multisystem inflammatory disease, Cinca syndrome, deafness with inflammation, deafness without inflammation,

keratoendotheliitis fugax hereditaria, silicosis, asbestosis, or chronic neurologic cutaneous and articular syndrome.

In some embodiments of any of the methods described herein, the subject has been exposed to, or is suspected of having been exposed to, a toxic agent selected from the group consisting of: exogenous microbial stimuli, lipopolysaccharide (LPS), lipooligosaccharide, muramyl dipeptide (MDP), nigericin, maitotoxin, asbestos, and silica.

Provided herein are methods of treating a subject in need thereof, that include: (a) identifying a subject having resistance to an anti-TNFa agent; and (b) administering a treatment comprising a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to the identified subject.

Provided herein are methods of treating a subject in need thereof, that include: administering a treatment comprising a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject identified as having resistance to an anti-TNFa agent.

Provided herein are methods of selecting a treatment for a subject in need thereof, that include: (a) identifying a subject having resistance to an anti-TNFa agent; and (b) selecting for the identified subject a treatment comprising a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co- crystal thereof.

Provided herein are methods of selecting a treatment for a subject in need thereof, that include selecting a treatment comprising a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof for a subject identified as having resistance to an anti-TNFa agent.

Provided herein are methods of selecting a subject for treatment, that include: (a) identifying a subject having resistance to an anti-TNFa agent; and (b) selecting the identified subject for treatment with a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Provided herein are methods of selecting a subject for treatment, that include selecting a subject identified as having resistance to an anti-TNFa agent, for treatment with a therapeutically effective level of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Provided herein are methods of selecting a subject for participation in a clinical trial, that include: (a) identifying a subject having resistance to an anti-TNFa agent; and (b) selecting the identified subject for participation in a clinical trial that includes administration of a treatment comprising a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Provided herein are methods of selecting a subject for participation in a clinical trial, that include selecting a subject identified as having resistance to an anti-TNFa agent, for participation in a clinical trial that includes administration of a treatment comprising a therapeutically effective amount of an NLRP3 antagonist or a

pharmaceutically acceptable salt, solvate, or co-crystal thereof.

In some embodiments of any of the methods described herein, step (b) can further include identifying the subject as also having an elevated level of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level.

In some embodiments of any of the methods described herein, the identified subject also has an elevated level of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level.

In some embodiments, the identifying the subject as also having a cell that has an elevated level of NLRP3 inflammasome expression includes detecting the level of one or more of NLRP3 protein, ASC protein, procaspase-l protein, and caspase-l protein.

In some embodiments, the identifying the subject as also having a cell that has an elevated level of NLRP3 inflammasome expression includes detecting the level of one or more of NLRP3 mRNA, ASC mRNA, and procaspase-l mRNA.

In some embodiments, the identified subject also having a cell that has an elevated level of NLRP3 inflammasome expression has been determined to have a cell having an elevated level of one or more of NLRP3 protein, ASC protein, procaspase-l protein, and capsase-l protein.

In some embodiments, the identified subject also having a cell that has an elevated level of NLRP3 inflammasome expression has been determined to have a cell having an elevated level of one or more of NLRP3 mRNA, ASC mRNA, and procaspase- 1 mRNA. In some embodiments of any of the methods described herein, the treatment further includes a therapeutically effective amount of an anti-TNFa agent, in addition to the NLRP3 antagonist.

Provided herein are methods of treating a subject in need thereof, that include: (a) administering one or more doses of an anti-TNFa agent to the subject; (b) detecting an elevated level of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject after step (a) as compared to a reference level; and (c) administering a treatment comprising a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject determined to have an elevated level of NLRP3 inflammasome activity and/or expression as compared to the reference level in step (b).

Provided herein are methods of treating a subject in need thereof, that include: (a) detecting an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level in a cell obtained from a subject previously administered one or more doses of an anti-TNFa agent; and (b) administering a treatment comprising a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject determined to have an elevated level of NLRP3 inflammasome activity and/or expression as compared to the reference level in step (a).

Provided herein are methods of treating a subject in need thereof, that include administering a treatment comprising a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject determined to have an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level in a cell obtained from the subject after previous administration with one or more doses of an anti-TNFa agent.

In some embodiments of any of the methods described herein, the detecting an elevated level of NLRP3 inflammasome expression as compared to the reference level expression includes detecting the level of one or more of NLRP3 protein, ASC protein, procaspase-l protein, and caspase-l protein. In some embodiments of any of the methods described herein, the identifying the subject as also having a cell that has an elevated level of NLRP3 inflammasome expression includes detecting the level of one or more of NLRP3 mRNA, ASC mRNA, and procaspase-l mRNA.

In some embodiments of any of the methods described herein, the subject determined to have an elevated level of NLRP3 inflammasome expression as compared to a reference level has been determined to have a cell having an elevated level of one or more of NLRP3 protein, ASC protein, procaspase-l protein, and caspase-l protein.

In some embodiments, the subject determined to have an elevated level of NLRP3 inflammasome expression as compared to a reference level has been determined to have a cell having an elevated level of one or more of NLRP3 mRNA, ASC mRNA, and procaspase-l mRNA.

In some embodiments of any of the methods described herein, the treatment further includes a therapeutically effective amount of an anti-TNFa agent, in addition to the NLRP3 antagonist.

Provided herein are methods of treating a subject in need thereof, that include: (a) administering one or more doses of an anti-TNFa agent to the subject; (b) after step (a), detecting resistance to the anti-TNFa agent in the subject; and (c) administering a treatment comprising a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject determined to have resistance to the anti-TNFa agent in step (b).

Provided herein are methods of treating a subject in need thereof, that include: (a) detecting resistance to an anti-TNFa agent in a subject previously administered one or more doses of the anti-TNFa agent; and (b) administering a treatment comprising a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject determined to have resistance to the anti-TNFa agent in step (a).

Provided herein are methods of treating a subject in need thereof, that include: administering a treatment comprising a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject previously administered one or more doses of an anti-TNFa agent and determined to have resistance to the anti-TNFa agent.

In some embodiments of any of the methods described herein, the treatment further includes a therapeutically effective amount of an anti-TNFa agent, in addition to the NLRP3 antagonist.

Provided herein are methods of reducing the risk of developing resistance to an anti-TNFa agent in a subject in need thereof, that include: administering to a subject in need thereof a therapeutically effective amount of an anti-TNFa agent and a

therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

In some embodiments, the anti-TNFa agent and the NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof are administered at substantially the same time.

In some embodiments, the anti-TNFa agent and the NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof are formulated into a single dosage form.

In some embodiments, the NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof is administered to the subject prior to administration of the anti-TNFa agent.

In some embodiments, the anti-TNFa agent is administered to the subject prior to administration of the NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Provided herein are methods of predicting a subject’s responsiveness to an anti- TNFa agent, that include: (a) determining that a subject has an elevated level of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level; and (b) identifying that the subject determined to have an elevated level of NLRP3 inflammasome activity and/or expression in step (a) has an increased likelihood of being resistant to treatment with an anti-TNFa agent.

Provided herein are methods of predicting a subject’s responsiveness to an anti- TNFa agent, that include identifying a subject determined to have an elevated level of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as having an increased likelihood of being resistant to treatment with an anti-TNFa agent.

In some embodiments, the determining that a subject has an elevated level of NLRP3 inflammasome activity and/or expression includes detecting the level of one or more of NLRP3 protein, ASC protein, procaspase-l protein, and caspase-l protein.

In some embodiments, the determining that a subject has an elevated level of NLRP3 inflammasome expression includes detecting the level of one or more of NLRP3 mRNA, ASC mRNA, and procaspase-l mRNA.

In some embodiments, the subject determined to have an elevated level of NLRP3 inflammasome expression has been determined to have a cell having an elevated level of one or more of NLRP3 protein, ASC protein, procaspase-l protein, and capsase-l protein.

In some embodiments, the subject determined to have an elevated level of NLRP3 inflammasome expression has been determined to have a cell having an elevated level of one or more of NLRP3 mRNA, ASC mRNA, and procaspase-l mRNA.

In some embodiments of any of the methods described herein, the subject has not previously been administered a dose of an anti-TNFa antagonist.

In some embodiments of any of the methods described herein, the method further includes administering to the subject identified as having an increased likelihood of being resistant to treatment with an anti-TNFa agent, a treatment comprising (i) a

therapeutically effective amount of an anti-TNFa agent and (ii) a therapeutically effective amount of an NLRP3 antagonist.

Provided herein are methods of treating a subject in need thereof, that include: (a) identifying a subject having an elevated level of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level; and (b) administering a treatment comprising (i) a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and (ii) a therapeutically effective amount of an anti-TNFa agent to the identified subject.

Provided herein are methods of treating a subject in need thereof, that include: administering a treatment comprising (i) a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and (ii) a therapeutically effective amount of an anti-TNFa agent, to a subject identified as having an elevated level of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level.

Provided herein are methods of selecting a treatment for a subject in need thereof, that include: (a) identifying a subject having an elevated level of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level; and (b) selecting for the identified subject a treatment comprising (i) a

therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and (ii) a therapeutically effective amount of an anti-TNFa agent.

Provided herein are methods of selecting a treatment for a subject in need thereof, that include: selecting a treatment comprising (i) a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and (ii) a therapeutically effective amount of an anti-TNFa agent, for a subject identified as having an elevated level of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level.

Provided herein are methods of selecting a subject for treatment, that include: (a) identifying a subject having an elevated level of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level; and (b) selecting the identified subject for treatment with (i) a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and (ii) a therapeutically effective amount of an anti-TNFa agent.

Provided herein are methods of selecting a subject for treatment, that include: selecting a subject identified as having an elevated level of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level, for treatment with (i) a therapeutically effective level of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and (ii) a therapeutically effective amount of an anti-TNFa agent. Also provided herein are methods of selecting a subject for participation in a clinical trial, that include: (a) identifying a subject having an elevated level of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level; and (b) selecting the identified subject for participation in a clinical trial that includes administration of a treatment comprising (i) a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co- crystal thereof, and (ii) a therapeutically effective amount of an anti-TNFa agent.

Also provided herein are methods of selecting a subject for participation in a clinical trial, that include: selecting a subject identified as having an elevated level of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level, for participation in a clinical trial that includes

administration of a treatment comprising (i) a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and (ii) a therapeutically effective amount of an anti-TNFa agent.

In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is secretion of IL-18.

In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is secretion of Iί-ΐb.

In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is caspase-l activity.

In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is the level of lipocalin-2.

In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is the level of S100A8.

In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is the level of S100A9.

In some embodiments of any of the methods described herein, the identifying the subject as having a cell that has an elevated level of NLRP3 inflammasome expression includes detecting the level of one or more of NLRP3 protein, ASC protein, procaspase-l protein, and caspase-l protein. In some embodiments of any of the methods described herein, the identifying the subject as having a cell that has an elevated level of NLRP3 inflammasome expression includes detecting the level of one or more of NLRP3 mRNA, ASC mRNA, and procaspase-l mRNA.

In some embodiments of any of the methods described herein, the identified subject having a cell that has an elevated level of NLRP3 inflammasome expression has been determined to have a cell having an elevated level of one or more of NLRP3 protein, ASC protein, procaspase-l protein, and capsase-l protein.

In some embodiments of any of the methods described herein, the identified subject having a cell that has an elevated level of NLRP3 inflammasome expression has been determined to have a cell having an elevated level of one or more of NLRP3 mRNA, ASC mRNA, and procaspase-l mRNA.

In some embodiments of any of the methods described herein, the subject has not previously been administered an anti-TNFa agent.

In some embodiments of any of the methods described herein, the subject has been diagnosed or identified as having an inflammatory or an autoimmune disorder.

In some embodiments, the inflammatory or autoimmune disorder is selected from the group consisting of: sickle cell disease, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, Behcet’s disease, Takayasu’s arteritis,

atherosclerosis, gout, psoriasis, an infectious disease, asthma, peptic ulcer, periodontitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, systemic lupus erythematosus, nephritis, appendicitis, bursitis, cystitis, encephalitis, gingivitis, meningitis, myelitis, neuritis, pharyngitis, phlebitis, prostatitis, rhinitis, sinusitis, tendonitis, testiculitis, tonsillitis, urethritis, vasculitis, vaginitis, Celiac disease, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivities, interstitial cystitis, Lichen planus, mast cell activation syndrome, mastocystosis, otitis, pelvic inflammatory disease, reperfusion injury, rheumatic fever, rhinitis, sarcoidosis, graft versus host disease, vasculitis, allergy, cancer, HIV, AIDS, scleroderma, Sjogren’s syndrome, anti-phospholipid antibody syndrome, myocarditis, postmyocardial infarction syndrome, postpericardiotomy syndrome, subacute bacterial endocarditis, anti -glomerular basement membrane nephritis, interstitial cystitis, lupus nephritis, autoimmune nephritis, autoimmune hepatitis, autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, primary schlerosing cholangitis, anti synthetase syndrome, alopecia areata, autoimmune angioedema, autoimmune progesterone dermatitis, autoimmune urticaria, bullous pemphigoid, cicatricial pemphigoid, dermatitis herpetiformis, discoid lupus

erythematosus, epidermolysis bullosa acquisita, erythema nodosum, gestational pemphigoid, Lichen sclerosus, linear IgA disease, morphea, pemphigus vulgaris, pityriasis lichenoides et varioliforms acuta, Mucha-Habermann disease, psoriasis, systemic scleroderma, vitiligo, Addison’s disease, autoimmune poly endocrine syndrome type 1, 2, or 3, autoimmune pancreatitis, diabetes mellitus type 1, autoimmune thyroiditis, Ord’s thyroiditis, Graves’ disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjogren’s syndrome, autoimmune enteropathy, microscopic colitis,

antiphospholipid syndrome, aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, essential mixed cyroglobulinemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, adiposis dolorosa, adult- onset Still’s disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, enthesitis-related arthritis, eosinophilic fasciitis, Felty syndrome, IgG4-related disease, juvenile arthritis, Lyme disease, mixed connective tissue disease (MCTD), palindromic rheumatism, Parry Romberg syndrome, Parsonage-Turner syndrome, psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, sarcoidosis, Schnitzler syndrome, undifferentiated connective tissue disease,

dermatomyositis, fibromyalgia, inclusion body myositis, myasthenia gravis,

neuromyotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis, acute motor axonal neuropathy, anti-N-methyl-D-aspartate receptor encephalitis, Balo concentric sclerosis, Bickerstaff s encephalitis, chronic infllamatory demyelinating polyneuropathy, Guillain-Barre syndrome, Hashimoto’s encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenic syndrome, multiple sclerosis, Oshtoran syndrome, pediatric autoimmune neuropsychiatric disorder associated with Streptococcus , progressive inflammatory neuropathy, restless leg syndrome, Stiff person syndrome, Sydenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan syndrome, Graves ophthalmopathy, intermediate uveitis, ligneous conjunctivitis, Mooren’s ulcer, neuromyelitis optica, Opsoclonus myoclonus syndrome, optic neuritis, scleritis, Susac’s syndrome, sympathetic

ophthalmia, Tolosa-Hunt syndrome, autoimmune inner ear disease, Meniere’s disease, Behcet’s disease, eosinophilic graunulomatosis with polyangiitis, giant cell arteritis, graunulomatosis with polyangiitis, IgA vasculitis, Kawasaki’s disease, leukocytoclastic vasculitis, lupus vasculitis, microscopic polyangiitis, polyarteritis nodosa, polymyalgia rheumatica, urticarial vasculitis, vasculitis, primary immune deficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud’s phenomenon, primary immunodeficiency, and pyoderma gangrenosum.

In some embodiments, the inflammatory or autoimmune disorder is Crohn’s disease or ulcerative colitis.

In some embodiments, the inflammatory or autoimmune disorder is inflammatory bowel syndrome.

In some embodiments of any of the methods described herein, the anti-TNFa agent is an antibody or an antigen-binding antibody fragment, or a soluble TNFa receptor.

In some embodiments, the antibody is selected from the group consisting of: adalimumab, certolizumab, etanercept, golimumab, infliximab, CDP571, and

certolizumab pegol.

In some embodiments of any of the methods described herein, the anti-TNFa agent is a small molecule inhibitor of a signaling component downstream of a TNFa receptor.

In some embodiments of any of the methods described herein, the NLRP3 antagonist is an inhibitory nucleic acid. In some embodiments, the inhibitory nucleic acid is a short interfering RNA, an antisense nucleic acid, or a ribozyme. In some embodiments of any of the methods described herein, the NLRP3 antagonist is a compound of any one of Formulas I-XII, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

In some embodiments of any of the methods described herein, the NLRP3 antagonist is a compound shown in any one of Tables 1-18, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

In some embodiments of any of the methods described herein, the NLRP3 antagonist is a compound referred to or shown herein, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

As used herein, the term“antagonist of NLRP3” is an agent, a genetic mutation, or altered signaling pathways in a mammalian cell that results in a decrease in one or both of (i) the activity of an NLRP3 inflammasome (e.g., any of the exemplary activities of an NLRP3 inflammasome described herein) (e.g., as compared to the level of NLRP3 inflammasome activity in the absence of the agent) and (ii) the expression level of NLRP3 inflammasomes in a mammalian cell (e.g., using any of the exemplary methods of detection described herein) (e.g., as compared to the expression level of NLRP3 inflammasomes in a mammalian cell not contacted with the agent). Non-limiting examples of NLRP3 antagonists are described herein.

As used herein, the term“NLRP3” is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous NLRP molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

The term“NLRP3 inflammasome expression” means the level of one or more of NLRP3 protein, ASC protein, procaspase-l protein, caspase-l protein, NLRP3 mRNA, ASC mRNA, and procaspase-l mRNA in a mammalian cell (e.g., a mammalian cell obtained from a subject).

The term“acceptable” with respect to a formulation, composition, or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated. “API” refers to an active pharmaceutical ingredient.

The terms“effective amount” or“therapeutically effective amount,” as used herein, refer to a sufficient amount of an NLRP3 antagonist being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an“effective amount” for therapeutic uses is the amount of the composition comprising an NLRP3 antagonist disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate“effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.

The term“excipient” or“pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is“pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of

Pharmacy, 2lst ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et ah, Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical

Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009.

The term“pharmaceutically acceptable salt” may refer to pharmaceutically acceptable addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. The term“pharmaceutically acceptable salt” may also refer to pharmaceutically acceptable addition salts prepared by reacting a compound having an acidic group with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine,

tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salts not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described herein from with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

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

The term“subject” refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms“subject” and“patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human. In some embodiments of any of the methods described herein, the subject is 1 year old or older, 2 years old or older, 4 years old or older, 5 years old or older, 10 years old or older, 12 years old or older, 13 years old or older, 15 years old or older, 16 years old or older, 18 years old or older, 20 years old or older, 25 years old or older, 30 years old or older, 35 years old or older, 40 years old or older, 45 years old or older, 50 years old or older, 55 years old or older, 60 years old or older, 65 years old or older, 70 years old or older, 75 years old or older, 80 years old or older, 85 years old or older, 90 years old or older, 95 years old or older, 100 years old or older, or 105 years old or older,

In some embodiments of any of the methods described herein, the subject has been previously diagnosed or identified as having a disease associated with NLRP3 inflammasome activity (e.g., any of the types of NLRP3 inflammasome activity associated-diseases described herein or known in the art, e.g., an inflammatory disease or an autoimmune disease). In some embodiments of any of the methods described herein, the subject is suspected of having a NLRP3 inflammasome activity-associated disease (e.g., any of the types of NLRP3 inflammasome activity -associated diseases described herein or known in the art, e.g., an inflammatory disease or an autoimmune disease). In some embodiments of any of the methods described herein, the subject is presenting with one or more (e.g., two, three, four, or five) symptoms of a NLRP3 inflammasome activity -associated disease (e.g., any of the NLRP3 inflammasome activity-associated disease described herein or known in the art).

In some embodiments of any of the methods described herein, the subject has been previously diagnosed or identified as having a disease associated with an elevated level of TNFa activity and/or expression (e.g., any of the types of TNFa associated- diseases described herein or known in the art). In some embodiments of any of the methods described herein, the subject has been previously diagnosed or identified as having a disease associated with resistance to an anti-TNFa agent (e.g., any of the anti- TNFa agent described herein or known in the art).

In some embodiments of any of the methods described herein, the subject is a participant in a clinical trial. In some embodiments of any of the methods described herein, the subject has been previously administered a pharmaceutical composition and the different pharmaceutical composition was determined not to be therapeutically effective. In some embodiments of any of the methods described herein, the subject has been previously administered an anti-TNFa agent and the anti-TNFa agent was determined not to be therapeutically effective

The term“administration” or“administering” refers to a method of providing a dosage of a pharmaceutical composition or a compound to an invertebrate or a vertebrate, including a fish, a bird and a mammal (e.g., a human). In some aspects, administration is performed, e.g., orally, intravenously, subcutaneously, intranasally, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, intralymphatic, topically, intraocularly, vaginally, rectally, intrathecally, or intracystically. The method of administration can depend on various factors, e.g., the site of the disease, the severity of the disease, and the components of the pharmaceutical composition.

The terms“treat,”“treating,” and“treatment,” in the context of treating a disease or disorder, are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof.

The phrase“an elevated level” or“an increased level” as used herein can be an increase of 1. lx to lOOx, or higher (e.g., l. lx, l.2x, l.4x, l.6x, l.8x, 2x, 2.2x, 2.4x, 2.5x, 2.6x, 2.8x, 3x, 3.2x, 3.4x., 3.5x, 3.6x, 3.8x, 4x, 4.2x, 4.4x, 4.5x., 4.6x, 4.8x, 5x, 5.5x, 6x, 6.5x, 7x, 7.5x, 8x, 8.5x, 9x, 9.5x, lOx, 10.5x, l lx, 11.5x, 12c, 12.5x, 13c, 13.5x, 14c,

14.5x, 15c, 15.5x, 16c, 16.5c, 17c, 17.5c, 18c, 18.5x, 19c, l9.5x, 20x, 2lx, 22x, 23x, 24x, 25x, 26x, 27x, 28x, 29x, 30x, 32x, 34x, 36x, 38x, 40x, 42x, 44x, 45x, 46x, 48x, 50x, 52x, 54x, 55x, 56x, 58x, 60x, 62x, 64x, 65x, 66x, 68x, 70x, 72x, 74x, 75x, 76x, 78x, 80x, 82x, 84x, 85x, 86x, 88x, 90x, 92x, 94x, 95x, 96x, 98x, IOOc, 102c, 104c, 105c, l06x, l08x, l lOx, 112c, 114c, 115c, 116c, 118c, 120c, 122c, 124c, 126c, 128c, 130c, l32x, 134c, 135c, 136c, 138c, 140c, 142c, 144c, 145c, 146c, 148c, 150c, 160c, 170c, l80x, 190c, l95x, or 200x) e.g., as compared to a reference level (e.g., any of the exemplary reference levels described herein). In some aspects,“an elevated level” or“an increased level” can be an increase of at least 1% (e.g., at least 2%, at least 4, at least 6%, at least 8%, at least 10 %, at least 12%, at least 14%, at least 16%, at least 18%, at least 20%, at least 22%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, at least 200%, at least 220%, at least 250%, at least 280%, at least 300%, at least 320%, at least 350%, at least 380%, at least 400%, at least 420%, at least 450%, at least 480%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, at least 1000%, between 1% and 1000%, between 1% and 900%, between 1% and 800%, between 1% and 700%, between 1% and 600%, between 1% and 500%, between 1% and 450%, between 1% and 400%, between 1% and 350%, between 1% and 300%, between 1% and 250%, between 1% and 200%, between 1% and 180%, between 1% and 160%, between 1% and 140%, between 1% and 120%, between 1% and 100%, between 1% and 95%, between 1% and 90%, between 1% and 85%, between 1% and 80%, between 1% and 75%, between 1% and 70%, between 1% and 65%, between 1% and 60%, between 1% and 55%, between 1% and 50%, between 1% and 45%, between 1% and 40%, between 1% and 35%, between 1% and 30%, between 1% and 25%, between 1% and 20%, between 1% and 15%, between 1% and 10%, between 1% and 5%, between 5% and 1000%, between 5% and 900%, between 5% and 800%, between 5% and 700%, between 5% and 600%, between 5% and 500%, between 5% and 450%, between 5% and 400%, between 5% and 350%, between 5% and 300%, between 5% and 250%, between 5% and 200%, between 5% and 180%, between 5% and 160%, between 5% and 140%, between 5% and 120%, between 5% and 100%, between 5% and 95%, between 5% and 90%, between 5% and 85%, between 5% and 80%, between 5% and 75%, between 5% and 70%, between 5% and 65%, between 5% and 60%, between 5% and 55%, between 5% and 50%, between 5% and 45%, between 5% and 40%, between 5% and 35%, between 5% and 30%, between 5% and 25%, between 5% and 20%, between 5% and 15%, between 5% and 10%, between 10% and 1000%, between 10% and 900%, between 10% and 800%, between 10% and 700%, between 10% and 600%, between 10% and 500%, between 10% and 450%, between 10% and 400%, between 10% and 350%, between 10% and 300%, between 10% and 250%, between 10% and 200%, between 10% and 180%, between 10% and 160%, between 10% and 140%, between 10% and 120%, between 10% and 100%, between 10% and 95%, between 10% and 90%, between 10% and 85%, between 10% and 80%, between 10% and 75%, between 10% and 70%, between 10% and 65%, between 10% and 60%, between 10% and 55%, between 10% and 50%, between 10% and 45%, between 10% and 40%, between 10% and 35%, between 10% and 30%, between 10% and 25%, between 10% and 20%, between 10% and 15%, between 20% and 1000%, between 20% and 900%, between 20% and 800%, between 20% and 700%, between 20% and 600%, between 20% and 500%, between 20% and 450%, between 20% and 400%, between 20% and 350%, between 20% and 300%, between 20% and 250%, between 20% and 200%, between 20% and 180%, between 20% and 160%, between 20% and 140%, between 20% and 120%, between 20% and 100%, between 20% and 95%, between 20% and 90%, between 20% and 85%, between 20% and 80%, between 20% and 75%, between 20% and 70%, between 20% and 65%, between 20% and 60%, between 20% and 55%, between 20% and 50%, between 20% and 45%, between 20% and 40%, between 20% and 35%, between 20% and 30%, between 20% and 25%, between 30% and 1000%, between 30% and 900%, between 30% and 800%, between 30% and 700%, between 30% and 600%, between 30% and 500%, between 30% and 450%, between 30% and 400%, between 30% and 350%, between 30% and 300%, between 30% and 250%, between 30% and 200%, between 30% and 180%, between 30% and 160%, between 30% and 140%, between 30% and 120%, between 30% and 100%, between 30% and 95%, between 30% and 90%, between 30% and 85%, between 30% and 80%, between 30% and 75%, between 30% and 70%, between 30% and 65%, between 30% and 60%, between 30% and 55%, between 30% and 50%, between 30% and 45%, between 30% and 40%, between 30% and 35%, between 40% and 1000%, between 40% and 900%, between 40% and 800%, between 40% and 700%, between 40% and 600%, between 40% and 500%, between 40% and 450%, between 40% and 400%, between 40% and 350%, between 40% and 300%, between 40% and 250%, between 40% and 200%, between 40% and 180%, between 40% and 160%, between 40% and 140%, between 40% and 120%, between 40% and 100%, between 40% and 95%, between 40% and 90%, between 40% and 85%, between 40% and 80%, between 40% and 75%, between 40% and 70%, between 40% and 65%, between 40% and 60%, between 40% and 55%, between 40% and 50%, between 40% and 45%, between 50% and 1000%, between 50% and 900%, between 50% and 800%, between 50% and 700%, between 50% and 600%, between 50% and 500%, between 50% and 450%, between 50% and 400%, between 50% and 350%, between 50% and 300%, between 50% and 250%, between 50% and 200%, between 50% and 180%, between 50% and 160%, between 50% and 140%, between 50% and 120%, between 50% and 100%, between 50% and 95%, between 50% and 90%, between 50% and 85%, between 50% and 80%, between 50% and 75%, between 50% and 70%, between 50% and 65%, between 50% and 60%, between 50% and 55%, between 60% and 1000%, between 60% and 900%, between 60% and 800%, between 60% and 700%, between 60% and 600%, between 60% and 500%, between 60% and 450%, between 60% and 400%, between 60% and 350%, between 60% and 300%, between 60% and 250%, between 60% and 200%, between 60% and 180%, between 60% and 160%, between 60% and 140%, between 60% and 120%, between 60% and 100%, between 60% and 95%, between 60% and 90%, between 60% and 85%, between 60% and 80%, between 60% and 75%, between 60% and 70%, between 60% and 65%, between 70% and 1000%, between 70% and 900%, between 70% and 800%, between 70% and 700%, between 70% and 600%, between 70% and 500%, between 70% and 450%, between 70% and 400%, between 70% and 350%, between 70% and 300%, between 70% and 250%, between 70% and 200%, between 70% and 180%, between 70% and 160%, between 70% and 140%, between 70% and 120%, between 70% and 100%, between 70% and 95%, between 70% and 90%, between 70% and 85%, between 70% and 80%, between 70% and 75%, between 80% and 1000%, between 80% and 900%, between 80% and 800%, between 80% and 700%, between 80% and 600%, between 80% and 500%, between 80% and 450%, between 80% and 400%, between 80% and 350%, between 80% and 300%, between 80% and 250%, between 80% and 200%, between 80% and 180%, between 80% and 160%, between 80% and 140%, between 80% and 120%, between 80% and 100%, between 80% and 95%, between 80% and 90%, between 80% and 85%, between 90% and 1000%, between 90% and 900%, between 90% and 800%, between 90% and 700%, between 90% and 600%, between 90% and 500%, between 90% and 450%, between 90% and 400%, between 90% and 350%, between 90% and 300%, between 90% and 250%, between 90% and 200%, between 90% and 180%, between 90% and 160%, between 90% and 140%, between 90% and 120%, between 90% and 100%, between 90% and 95%, between 100% and 1000%, between 100% and 900%, between 100% and 800%, between 100% and 700%, between 100% and 600%, between 100% and 500%, between 100% and 450%, between 100% and 400%, between 100% and 350%, between 100% and 300%, between 100% and 250%, between 100% and 200%, between 100% and 180%, between 100% and 160%, between 100% and 140%, between 100% and 120%, between 120% and 1000%, between 120% and 900%, between 120% and 800%, between 120% and 700%, between 120% and 600%, between 120% and 500%, between 120% and 450%, between 120% and 400%, between 120% and 350%, between 120% and 300%, between 120% and 250%, between 120% and 200%, between 120% and 180%, between 120% and 160%, between 120% and 140%, between 140% and 1000%, between 140% and 900%, between 140% and 800%, between 140% and 700%, between 140% and 600%, between 140% and 500%, between 140% and 450%, between 140% and 400%, between 140% and 350%, between 140% and 300%, between 140% and 250%, between 140% and 200%, between 140% and 180%, between 140% and 160%, between 160% and 1000%, between 160% and 900%, between 160% and 800%, between 160% and 700%, between 160% and 600%, between 160% and 500%, between 160% and 450%, between 160% and 400%, between 160% and 350%, between 160% and 300%, between 160% and 250%, between 160% and 200%, between 160% and 180%, between 180% and 1000%, between 180% and 900%, between 180% and 800%, between 180% and 700%, between 180% and 600%, between 180% and 500%, between 180% and 450%, between 180% and 400%, between 180% and 350%, between 180% and 300%, between 180% and 250%, between 180% and 200%, between 200% and 1000%, between 200% and 900%, between 200% and 800%, between 200% and 700%, between 200% and 600%, between 200% and 500%, between 200% and 450%, between 200% and 400%, between 200% and 350%, between 200% and 300%, between 200% and 250%, between 250% and 1000%, between 250% and 900%, between 250% and 800%, between 250% and 700%, between 250% and 600%, between 250% and 500%, between 250% and 450%, between 250% and 400%, between 250% and 350%, between 250% and 300%, between 300% and 1000%, between 300% and 900%, between 300% and 800%, between 300% and 700%, between 300% and 600%, between 300% and 500%, between 300% and 450%, between 300% and 400%, between 300% and 350%, between 350% and 1000%, between 350% and 900%, between 350% and 800%, between 350% and 700%, between 350% and 600%, between 350% and 500%, between 350% and 450%, between 350% and 400%, between 400% and 1000%, between 400% and 900%, between 400% and 800%, between 400% and 700%, between 400% and 600%, between 400% and 500%, between 400% and 450%, about 450% to about 500%, between 500% and 1000%, between 500% and 900%, between 500% and 800%, between 500% and 700%, between 500% and 600%, between 600% and 1000%, between 600% and 900%, between 600% and 800%, between 600% and 700%, between 700% and 1000%, between 700% and 900%, between 700% and 800%, between 800% and 1000%, between 800% and 900%, or between 900% and

1000%), e.g., as compared to a reference level (e.g., any of the exemplary reference levels described herein).

The term“NLRP3 inflammasome activity” means direct activity of an NLRP3 inflammasome in a mammalian cell (e.g., caspase-l cleavage activity, secretion of IL-18, and secretion of IL-ld); an upstream activity or mutation (e.g., any of the exemplary mutations or single nucleotide polymorphisms described herein) in a mammalian cell that results in increased NLRP3 inflammasome activity in the mammalian cell (e.g., increased expression of one or more of lipocalin-2 protein, lipocalin-2 mRNA, S100A8 protein, S100A8 mRNA, S100A9 protein, and S100A9 mRNA, e.g., as compared to any of the exemplary reference levels described herein; detection of any of the exemplary types of gain-of-function or loss-of-function mutations, or single nucleotide polymorphisms described herein); and/or an increased downstream activity of an NLRP3 inflammasome activity in a mammalian cell (e.g., increased expression of one or more of increased expression of one or more of CRP protein, CRP mRNA, SAA protein, SAA mRNA, HP protein, HP mRNA, ceruloplasmin protein, ceruloplasmin mRNA, IL-6 protein, IP-6 mRNA, calprotectin (S100A8) protein, calprotectin (S100A8) mRNA, IL-8 protein, IL-8 mRNA, leukotriene B4 protein, leukotriene B4 mRNA, myeloperoxidase protein, and myeloperoxidase mRNA, e.g., as compared to any of the exemplary reference levels described herein). Non-limiting examples of human protein and human cDNA sequences for CRP protein, CRP mRNA, SAA protein, SAA mRNA, HP protein, HP mRNA, ceruloplasmin protein, ceruloplasmin mRNA, IL-6 protein, IP-6 mRNA, calprotectin (S100A8) protein, calprotectin (S100A8) mRNA, IL-8 protein, IL-8 mRNA, leukotriene B4 protein, leukotriene B4 mRNA, myeloperoxidase protein, and myeloperoxidase mRNA are shown below.

The sequences characterized by the Sequences ID NO: 1-34 are listed below and are being submitted in a separate and machine readable file.

Human C-Reactive Protein (CRP) Transcript Variant 1 cDNA (SEQ ID NO: 1), Human C-Reactive Protein (CRP) Transcript Variant 1 protein (SEQ ID NO: 2) Human C-Reactive Protein (CRP) Transcript Variant 2 cDNA (SEQ ID NO: 3) Human C-Reactive Protein (CRP) Transcript Variant 2 protein (SEQ ID NO: 4) Human C-Reactive Protein (CRP) Transcript Variant 3 cDNA (SEQ ID NO: 5) Human C-Reactive Protein (CRP) Transcript Variant 3 protein (SEQ ID NO: 6) Human Serum amyloid A1 (SAA) Transcript Variant 1 cDNA (SEQ ID NO: 7) Human Serum amyloid A1 (SAA) Transcript Variant 1 protein (SEQ ID NO: 8) Human Serum amyloid A1 (SAA) Transcript Variant 2 cDNA (SEQ ID NO: 9) Human Serum amyloid A1 (SAA) Transcript Variant 2 protein (SEQ ID NO: 10) Human Serum amyloid A1 (SAA) Transcript Variant 3 cDNA (SEQ ID NO: 11) Human Serum amyloid A1 (SAA) Transcript Variant 3 protein (SEQ ID NO: 12) Human Serum amyloid A1 (SAA) Transcript Variant 1 cDNA (SEQ ID NO: 13) Human Serum amyloid A1 (SAA) Transcript Variant 1 protein (SEQ ID NO: 14) Human Serum amyloid A1 (SAA) Transcript Variant 2 cDNA (SEQ ID NO: 15) Human Serum amyloid A1 (SAA) Transcript Variant 2 protein (SEQ ID NO: 16) Human Serum amyloid A1 (SAA) Transcript Variant 3 cDNA (SEQ ID NO: 17) Human Serum amyloid A1 (SAA) Transcript Variant 3 protein (SEQ ID NO: 18) Human Ceruloplasmin (CP) Transcript Variant 1 cDNA (SEQ ID NO: 19)

Human Ceruloplasmin (CP) Transcript Variant 1 protein (SEQ ID NO: 20)

Human Interleukin 6 (IL-6) Transcript Variant 1 cDNA (SEQ ID NO: 21),

Human Interleukin 6 (IL-6) Transcript Variant 1 protein (SEQ ID NO: 22), Human Interleukin 6 (IL-6) Transcript Variant 2 cDNA (SEQ ID NO: 23),

Human Interleukin 6 (IL-6) Transcript Variant 2 protein (SEQ ID NO: 24), Human Interleukin 8 (IL-8) Transcript Variant 1 cDNA (SEQ ID NO: 25),

Human Interleukin 8 (IL-8) Transcript Variant 1 protein (SEQ ID NO: 26), Human Interleukin 8 (IL-8) Transcript Variant 2 cDNA (SEQ ID NO: 27), Human Interleukin 8 (IL-8) Transcript Variant 2 protein (SEQ ID NO: 28),

Human Leukotriene B4 receptor (LTB4R) Transcript Variant 1 cDNA (SEQ ID NO: 29),

Human Leukotriene B4 receptor (LTB4R) Transcript Variant 1 protein (SEQ ID NO: 30),

Human Leukotriene B4 receptor (LTB4R) Transcript Variant 2 cDNA (SEQ ID NO: 31),

Human Leukotriene B4 receptor (LTB4R) Transcript Variant 2 protein (SEQ ID NO: 32),

Human Myeloperoxidase (MPO) Transcript Variant 1 cDNA (SEQ ID NO: 33), Human Myeloperoxidase (MPO) Transcript Variant 1 protein (SEQ ID NO: 34)

NLRP3 inflammasome activity can be detected, e.g., by determining the level of expression of one or more of NLRP3, ASC, CASP1, LCN2, IL-18, IL-lp, S100A8, and S100A9 in a mammalian cell; detection of a gain-of-function mutation in a NLRP3 gene (e.g., a NLRP3 protein having a Q705K amino acid substitution, a T350M amino acid substitution, a R262M amino acid substitution, a A441 V amino acid substitution, a V200M amino acid substitution, an E629G amino acid substitution, a L355P amino acid substitution, a R260W amino acid substitution, a G571R amino acid substitution, a A354V amino acid substitution, a D305N amino acid substitution, a F311 S amino acid substitution, a R920Q amino acid substitution, or a D21H amino acid substitution), each numbered according to the mature NLRP3 protein sequence of SEQ ID NO: 35;

detection of one or more of a loss-of-function mutation in one or more of a CARD8 gene (e.g., a C allele at rs20432l 1); detection of a T allele at rs3024505 flanking IL10 gene; detection of a R620W amino acid substitution in PTPN22; detection of a C allele at rs478582 in the PTPN2 gene; detection of a G allele at rs7l3875 in the MTMR3 gene; detection of a C allele at rsl042058 in the TPL2 gene; and detection of a ATG16L1 gene that encodes a ATG16L1 protein having a T300A amino acid substitution. Methods of detecting a level of each of these exemplary types of NLRP3 inflammasome activity are described herein. Additional examples of NLRP3 inflammasome activities are known in the art, as well as methods for detecting a level of the same.

As used herein,“gain-of-function mutation” refers to one or more nucleotide substitutions, deletions, and/or insertions in a gene that results in: an increase in the level of expression of the encoded protein as compared to the level of the expression by the corresponding wildtype gene, and/or the expression of a protein encoded by the gene that has one or more increased activities in a mammalian cell as compared to the version of the protein encoded by the corresponding wildtype gene.

As used herein,“loss-of-function mutation” refers to one or more nucleotide substitutions, deletions, and/or insertions in a gene that results in: a decrease in the level of expression of the encoded protein as compared to the level of the expression by the corresponding wildtype gene, and/or the expression of a protein encoded by the gene that has one or more decreased activities in a mammalian cell as compared to the version of the protein encoded by the corresponding wildtype gene.

As used herein, the phrase“resistance to an anti-TNFa agent” refers to a reduced or decreased level of sensitivity to treatment with an anti-TNFa agent in a subject (e.g., as compared to a similar subject or as compared to the level of sensitivity to the anti- TNFa agent at an earlier time point). For example, resistance to an anti-TNFa in a subject can be observed by a physician, e.g., by observing the requirement of a increasing dosage amounts of an anti-TNFa agent over time in order to achieve the same therapeutic effect in a subject, observing the requirement for an increased number of doses and/or an increased frequency of doses of an anti-TNFa agent over time in order to achieve the same therapeutic effect in a subject, a decrease in the observed therapeutic response to treatment with the same dosage of an anti-TNFa agent over time, or an observed progression of disease or disease relapse in a subject administered an anti-TNFa agent.

As used herein, the phrase“beneficial response” refers to a therapeutic benefit and/or an improved clinical outcome to a subject suffering from a TNFa-associated disease from or as a result of the treatment with a NLRP3 antagonist. In some embodiments, a beneficial response is a cellular response.

The terms“hydrogen” and“H” are used interchangeably herein.

The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

The term "alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non- limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl. The term "haloalkyl" refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halo.

The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH3).

The term "carbocyclic ring" as used herein includes an aromatic or nonaromatic cyclic hydrocarbon group having 3 to 10 carbons, such as 3 to 8 carbons, such as 3 to 7 carbons, which may be optionally substituted. Examples of carbocyclic rings include five-membered, six membered, and seven-membered carbocyclic rings.

The term“heterocyclic ring” refers to an aromatic or nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1- 3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocyclic rings include five-membered, six membered, and seven-membered heterocyclic rings.

The term "cycloalkyl" as used herein includes an aromatic or nonaromatic cyclic hydrocarbon radical having 3 to 10 carbons, such as 3 to 8 carbons, such as 3 to 7 carbons, wherein the cycloalkyl group which may be optionally substituted. Examples of cycloalkyls include five membered, six-membered, and seven-membered rings.

Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl,.

The term“heterocycloalkyl” refers to an aromatic or nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system radical having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1- 9 heteroatoms ofN, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of

heterocycloalkyls include five-membered, sixmembered, and seven-membered heterocyclic rings. Examples include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.

The term“hydroxy” refers to an OH group. The term“amino” refers to an NH2 group.

The term“oxo” refers to O. By way of example, substitution of a CH2 a group with oxo gives a C=0 group.

A gut-targeted NLRP3 antagonist is any NLRP3 antagonist, which has the following characteristics:

- potent NLRP3 inhibitors , e.g, <1 micromolar in cellular assay systems, as

assessed for example using a nigericin-stimulated XL-Ib secretion assay in THP-1 cells

- with low permeability as assessed in an MDCK assay (Pefflux < 2 x 10 ^L 6

cm/sec),

- poor systemic bioavailability, as assessed in a rat or mouse PK experiment,

high levels of compound in the colon, for example 500 nM or more of the NLRP3 antagonist in the colon, as assessed using tissue distribution models.

As used herein, the terms“patient” or“subject” refer to a mammalian organism, preferably a human being, who is diseased with the condition (i.e. disease or disorder) of interest and who would benefit from the treatment.

As used herein, the term“prevent”,“preventing” or "prevention" in connection to a disease or disorder refers to the prophylactic treatment of a subject who is at risk of developing a condition (e.g., specific disease or disorder or clinical symptom thereof) resulting in a decrease in the probability that the subject will develop the condition.

As used herein, the term“treat”,“treating" or "treatment" of any disease or disorder refers in one embodiment to ameliorating the disease or disorder (i.e. slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms or pathological features thereof). In another embodiment“treat”, "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter or pathological features of the disease, e.g. including those, which may not be discernible by the subject. In yet another embodiment,“treat”, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g. stabilization of at least one discernible or non-discernible symptom), physiologically (e.g. stabilization of a physical parameter) or both. In yet another embodiment,“treat”, "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder, or of at least one symptoms or pathological features associated thereof. In yet another embodiment,“treat”, "treating" or "treatment" refers to preventing or delaying progression of the disease to a more advanced stage or a more serious condition.

As used herein, the term "therapeutically effective amount" refers to an amount of the compound of the invention, e.g. a NLRP3 antagonist as herein defined, e.g. in free form or as a stereoisomer, an enantiomer, a pharmaceutically acceptable salt, solvate, prodrug, ester thereof and/or an amino acid conjugate thereof), or cenicriviroc (in free form or as a pharmaceutically acceptable salt, solvate, prodrug, and/or ester thereof, e.g. in free form or as a pharmaceutically acceptable salt thereof), which is sufficient to achieve the stated effect. Accordingly, a therapeutically effective amount used for the treatment or prevention of a liver disease or disorder as hereinabove defined is an amount sufficient for the treatment or prevention of such a disease or disorder.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims. DESCRIPTION OF THE DRAWINGS

Figures 1 : Expression levels of RNA encoding NLRP3 in Crohn’s Disease patients who are responsive and non-responsive to infliximab.

Figures 2: Expression levels of RNA encoding IE-1b in Crohn’s Disease patients who are responsive and non-responsive to infliximab. Figures 3: Expression levels of RNA encoding NLRP3 in Ulcerative Colitis (UC) patients who are responsive and non-responsive to infliximab.

Figures 4: Expression levels of RNA encoding IE-1b in Ulcerative Colitis (UC) patients who are responsive and non-responsive to infliximab.

DETAILED DESCRIPTION

The present inventions are based on the discovery that specific genetic mutations and/or protein/mRNA expression profiles correlate with increased NLRP3 inflammasome activity and expression, and can be used to identify subjects who are more likely to have a therapeutic response to treatment with an NLRP3 antagonist. In view of these discoveries, provided herein are methods of treating a subject that include: (a) identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level; and (b) administering to the identified subject a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. Also provided are methods of treating a subject that include administering a therapeutically effective amount of an NLPR3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level.

Also provided are methods of selecting a treatment for a subject that include: (a) identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level; and (b) selecting for the identified subject a treatment comprising a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. Also provided are methods of selecting a treatment for a subject that include selecting a treatment comprising a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof for a subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level. Also provided herein are methods of selecting a subject for treatment that include: (a) identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level; and (b) selecting an identified subject for treatment with a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. Also provided are methods selecting a subject for treatment that include selecting a subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level, for treatment with a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co- crystal thereof.

Also provided herein are methods of selecting a subject for participation in a clinical trial that include: identifying a subject having a cancer cell that has an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level; and selecting the identified subject for participation in a clinical trial that comprises administration of a therapeutically effective amount of a NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. Also provided herein are methods of selecting a subject for participation in a clinical trial that include selecting a subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level for participation in a clinical trial that comprises administration of a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

The present invention is also based on the discovery that a NLRP3 antagonist (e.g., any of the NLRP3 antagonists described herein) can reduce resistance to an anti- TNFa agent (e.g., any of the exemplary resistances to an anti-TNFa agent described herein or known in the art) in a subject. In view of these discoveries, provided herein are methods of treating a subject in need thereof that include (a) identifying a subject having resistance to an anti-TNFa agent (e.g., any of the exemplary resistances to an anti-TNFa agent described herein or known in the art) as compared to a reference level (e.g., any of the exemplary reference levels of NLRP3 inflammasome activity described herein or known in the art); and (b) administering a treatment comprising a therapeutically effective amount of an NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to the identified subject. Also provided herein are methods of treating a subject identified as having resistance to an anti-TNFa agent (e.g., any of the exemplary resistances to an anti-TNFa agent described herein or known in the art) with an NLRP3 antagonist (e.g., any of the exemplary NLRP3 antagonists described herein) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof

Non-liming aspects of these methods are described below, and can be used in any combination without limitation. Additional aspects of these methods are known in the art.

In one embodiment, the present invention relates to an NLRP3 antagonist for use in the treatment or the prevention of a condition mediated by TNF-a, in particular a gut disease or disorder, in a patient in need thereof, wherein the NLRP3 antagonist is administered to said patient at a therapeutically effective amount.

In one embodiment, the present invention relates to an NLRP3 antagonist for use in the treatment or the prevention of a condition, in particular a gut disease or disorder, in a patient in need thereof wherein the NLRP3 antagonist is administered to said patient at a therapeutically effective amount.

In one embodiment, the present invention relates to an NLRP3 antagonist for use in the treatment, stabilization or lessening the severity or progression of gut disease or disorder, in a patient in need thereof wherein the NLRP3 antagonist is administered to said patient at a therapeutically effective amount.

In one embodiment, the present invention relates to an NLRP3 antagonist for use in the slowing, arresting, or reducing the development of a gut disease or disorder, in a patient in need thereof wherein the NLRP3 antagonist is administered to said patient at a therapeutically effective amount.

In one embodiment, the present invention relates to an NLRP3 antagonist for use according to above listed embodiments wherein the NLRP3 antagonist is a gut-targeted NLRP3 antagonist.

In one embodiment, the present invention relates to an NLRP3 antagonist for use according to any of the above embodiments, wherein the gut disease is IBD. In one embodiment, the present invetion relates to an NLRP3 antagonist for use according to any of the above embodiments, wherein the gut disease is UC or CD.

In one embodiment, the present invetion relates to a method for the treatment or the prevention of a condition mediated by TNF-a, in particular a gut disease or disorder, in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a gut-targeted NLRP3 antagonist.

In one embodiment, the present invention relates to a method for the treatment or the prevention of a condition, in particular a gut disease or disorder, in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a gut-targeted NLRP3 antagonist.

In one embodiment, the present invention relates to a method for the treatment, stabilization or lessening the severity or progression of gut disease or disorder, in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a gut-targeted NLRP3 antagonist.

In one embodiment, the present invention relates to a method for slowing, arresting, or reducing the development of a gut disease or disorder, in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a gut-targeted NLRP3 antagonist.

In one embodiment, the present invention relates to a method according to any of the above embodiments, wherein the gut disease is IBD.

In one embodiment, the present invention relates to a method as described herein wherein the gut disease is UC or CD.

An exemplary sequence of human NLRP3 protein is being submitted in a separate and machine readable file. Mature Human NLRP3 Protein (SEQ ID NO: 35).

Methods of Treating

Provided herein are methods of treating a subject (e.g., any of the exemplary subjects described herein) that include: (a) identifying a subject having a cell that has an elevated level (e.g., an increase of l.lx to lOOx or higher, or any of the subranges of this range described herein) of NLRP3 inflammasome activity and/or expression as compared to a reference level; and (b) administering to the identified subject a therapeutically effective amount of an NLRP3 antagonist (e.g., any of the exemplary NLRP3 antagonists described herein) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Also provided herein are methods of treating a subject (e.g., any of the exemplary subjects described herein) that include: administering a therapeutically effective amount of an NLPR3 antagonist (e.g., any of the exemplary NLRP3 antagonists described herein) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject identified as having a cell that has an elevated level (e.g., an increase of l. lx to lOOx or higher, or any of the subranges of this range described herein) of NLRP3 inflammasome activity and/or expression as compared to a reference level.

In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is secretion of IL-18. In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is secretion of IL- 1 b. In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is caspase-l activity. In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is the level of lipocalin-2 (LCN2). In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is the level of S100A8. In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is the level of S100A9.

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity comprises detecting a gain-of-function mutation in an NLRP3 gene (e.g., a NLRP3 protein having a Q705K amino acid substitution, a T350M amino acid substitution, a R262M amino acid substitution, a A441V amino acid substitution, a V200M amino acid substitution, an E629G amino acid substitution, a L355P amino acid substitution, a R260W amino acid substitution, a G571R amino acid substitution, a A354V amino acid substitution, a D305N amino acid substitution, a F311 S amino acid substitution, a R920Q amino acid substitution, or a D21H amino acid substitution, each numbered according to the mature NLRP3 protein sequence of SEQ ID NO: 35) in a cell from the subject. In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having a gain-of-function mutation in an NLRP3 gene (e.g., a NLRP3 protein having a Q705K amino acid substitution, a T350M amino acid substitution, a R262M amino acid substitution, a A441 V amino acid substitution, a

V200M amino acid substitution, an E629G amino acid substitution, a L355P amino acid substitution, a R260W amino acid substitution, a G571R amino acid substitution, a A354V amino acid substitution, a D305N amino acid substitution, a F311 S amino acid substitution, a R920Q amino acid substitution, or a D21H amino acid substitution, each numbered according to the mature NLRP3 protein sequence of SEQ ID NO: 35).

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity comprises detecting a loss-of-function mutation in a CARD8 gene (e.g., a C allele at rs20432l 1) in a cell from the subject.

In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having a loss-of-function mutation in a CARD8 gene (e.g., a C allele at rs20432l 1).

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity comprises detecting a gain-of-function mutation in an NLRP3 gene (e.g., a NLRP3 protein having a Q705K amino acid substitution, a T350M amino acid substitution, a R262M amino acid substitution, a A441V amino acid substitution, a V200M amino acid substitution, an E629G amino acid substitution, a L355P amino acid substitution, a R260W amino acid substitution, a G571R amino acid substitution, a A354V amino acid substitution, a D305N amino acid substitution, a F311 S amino acid substitution, a R920Q amino acid substitution, or a D21H amino acid substitution, each numbered according to the mature NLRP3 protein sequence of SEQ ID NO: 35) and a loss-of-function mutation in a CARD8 gene (e.g., a C allele at rs20432l 1) in a cell from the subject. In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having a gain-of-function mutation in an NLRP3 gene (e.g., a NLRP3 protein having a Q705K amino acid substitution, a T350M amino acid substitution, a R262M amino acid substitution, a A441 V amino acid substitution, a V200M amino acid substitution, an E629G amino acid substitution, a L355P amino acid substitution, a R260W amino acid substitution, a G571R amino acid substitution, a A354V amino acid substitution, a D305N amino acid substitution, a F311 S amino acid substitution, a R920Q amino acid substitution, or a D21H amino acid substitution, each numbered according to the mature NLRP3 protein sequence of SEQ ID NO: 35) and a loss-of-function mutation in a CARD8 gene (e.g., a C allele at rs20432l 1).

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity comprises detecting a T allele at rs3024505 flanking an IL10 gene in a cell from the subject.

In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having a T allele at rs3024505 flanking IL10 gene in a cell.

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity comprises detecting a PTPN22 gene that encodes a PTPN22 protein having a R620W amino acid substitution in a cell from the subject.

In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having a PTPN22 gene that encodes a PTPN22 protein having a R620W amino acid substitution.

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity comprises detecting a C allele at rs478582 in the PTPN2 gene in a cell from the subject. In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having a C allele at rs478582 in the PTPN2 gene.

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity comprises detecting a G allele at rs7l3875 in the MTMR3 gene in a cell from the subject.

In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having a G allele at rs7l3875 in the MTMR3 gene.

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity comprises detecting a C allele at rsl042058 in the TPL2 gene in a cell from the subject.

In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having a C allele at rsl042058 in the TPL2 gene.

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity comprises detecting a ATG16L1 gene that encodes a ATG16L1 protein having a T300A amino acid substitution in a cell from the subject.

In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having a ATG16L1 gene that encodes a ATG16L1 protein having a T300A amino acid substitution.

In some embodiments of any of the methods described herein, the gain-of- function mutation in an NLRP3 gene results in the expression of a NLRP3 protein having a Q705K amino acid substitution. In some embodiments of any of the methods described herein, the loss-of-function mutation in a CARD8 gene is a C allele at rs20432l 1.

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome expression comprises detecting the level of one or more of NLRP3 protein, ASC protein, procaspase-l protein, caspase-l protein, IL-18 protein (e.g., mature or pro-IL-l8 protein), IL- 1 b protein (e.g., mature or pro-IL-1 ft protein), LCN2 protein, S100A8 protein, and S100A9 protein.

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome expression comprises detecting the level of one or more of NLRP3 mRNA, ASC mRNA, and procaspase-l mRNA, pro-IL-l8 mRNA, pro-IL- 1 b mRNA, LCN2 mRNA, S100A8 mRNA, and S100A9 mRNA.

In some embodiments of any of the methods described herein the subject identified as having a cell that has an elevated level of NLRP3 inflammasome expression has been determined to have a cell having an elevated level of one or more of NLRP3 protein, ASC protein, procaspase-l protein, caspase-l protein, IL-18 protein (e.g., mature or pro-IL-l8 protein), IL- 1 b protein (e.g., mature or pro-IL-1 b protein), LCN2 protein, S100A8 protein, and S100A9 protein.

In some embodiments of any of the methods described herein the subject identified as having a cell that has an elevated level of NLRP3 inflammasome expression has been determined to have a cell having an elevated level of one or more of NLRP3 mRNA, ASC mRNA, and procaspase-l mRNA.

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome expression comprises detecting the level of one or more of CRP protein, SAA protein, HP protein, ceruloplasmin protein, IL-6 protein (e.g., mature or pro-IL-6 protein), calprotectin (S100A8) protein, IL-8 protein (e.g., mature or pro-IL-8 protein), leukotriene B4 protein, and myeloperoxidase protein.

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome expression comprises detecting the level of one or more of CRP mRNA, SAA mRNA, HP mRNA, ceruloplasmin mRNA, pro-IL-6 mRNA, calprotectin (S100A8) mRNA, pro-IL-8 mRNA, leukotriene B4 mRNA, and myeloperoxidase mRNA. In some embodiments of any of the methods described herein the subject identified as having a cell that has an elevated level of NLRP3 inflammasome expression has been determined to have a cell having an elevated level of one or more of CRP protein, SAA protein, HP protein, ceruloplasmin protein, IL-6 protein (e.g., mature or pro-IL-6 protein), calprotectin (S100A8) protein, IL-8 protein (e.g., mature or pro-IL-8 protein), leukotriene B4 protein, and myeloperoxidase protein.

In some embodiments of any of the methods described herein the subject identified as having a cell that has an elevated level of NLRP3 inflammasome expression has been determined to have a cell having an elevated level of one or more of CRP mRNA, SAA mRNA, HP mRNA, ceruloplasmin mRNA, pro-IL-6 mRNA, calprotectin (S100A8) mRNA, pro-IL-8 mRNA, leukotriene B4 mRNA, and myeloperoxidase mRNA.

In some embodiments of any of the methods described herein the subject has or is suspected of having Crohn’s disease, inflammatory bowel disease (IBD), or other gastrointestinal, autoimmune, or autoinflammatory disorders.

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity comprises detecting a mutation in an NLRP3 gene that results in the expression of a NLRP3 protein having one or both of a T350M and a R262M amino acid substitution (each numbered according to the mature NLRP3 protein sequence of SEQ ID NO: 35) in a cell from the subject. In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having an NLRP3 gene that results in the expression of a NLRP3 protein having one or both of a T350M and a R262M amino acid substitution (each numbered according to the mature NLRP3 protein sequence of SEQ ID NO: 35). In some embodiments of these methods, the subject has or is suspected of having hereditary periodic fever.

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity comprises detecting a mutation in an NLRP3 gene that results in the expression of an NLRP3 protein having one or more of a A441 V, a V200M, a E629G, and a L355P amino acid substitution (each numbered according to the mature NLRP3 protein sequence of SEQ ID NO: 35) in a cell from the subject. In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having an NLRP3 gene that results in the expression of an NLRP3 protein having one or more of a A441 V, a V200M, a E629G, and a L355P amino acid substitution (each numbered according to the mature NLRP3 protein sequence of SEQ ID NO: 35). In some embodiments of these methods, the subject has or is suspected of having familial cold autoinflammatory syndrome (FCAS).

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity comprises detecting a mutation in an NLRP3 gene that results in the expression of an NLRP3 protein having one or more of a R260W, a G571R, and a A354V amino acid substitution (each numbered according to the mature NLRP3 protein sequence of SEQ ID NO: 35) in a cell from the subject. In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having an NLRP3 gene that results in the expression of an NLRP3 protein having one or more of a R260W, a G571R, and a A354V amino acid substitution (each numbered according to the mature NLRP3 protein sequence of SEQ ID NO: 35). In some of embodiments of these methods, the subject has or is suspected of having Muckle-Wells syndrome (MWS).

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity comprises detecting a mutation in an NLRP3 gene that results in the expression of an NLRP3 protein having one or both of a D305N and a F311 S amino acid substitution (each numbered according to the mature NLRP3 protein sequence of SEQ ID NO: 35) in a cell from the subject. In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having an NLRP3 gene that results in the expression of an NLRP3 protein having one or both of a D305N and a F311 S amino acid substitution (each numbered according to the mature NLRP3 protein sequence of SEQ ID NO: 35). In some embodiments of these methods, the subject has or is suspected of having Cinca syndrome.

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity comprises detecting a mutation in an NLRP3 gene that results in the expression of an NLRP3 protein having one or both of a R920Q amino acid substitution (each numbered according to the mature NLRP3 protein sequence of SEQ ID NO: 35) in a cell from the subject. In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having a mutation in an NLRP3 gene that results in the expression of an NLRP3 protein having a R920Q amino acid substitution (each numbered according to the mature NLRP3 protein sequence of SEQ ID NO: 35). In some embodiments of these methods, the subject has or is suspected of having deafness with or without inflammation.

In some embodiments of any of the methods described herein, the identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity comprises detecting a mutation in an NLRP3 gene that results in the expression of an NLRP3 protein having a D21H amino acid substitution (numbered according to the mature NLRP3 protein sequence of SEQ ID NO: 35) in a cell from the subject. In some embodiments of any of the methods described herein, the subject identified as having a cell that has an elevated level of NLRP3 inflammasome activity has been determined to have a cell having an NLRP3 gene that results in the expression of an NLRP3 protein having a D21H amino acid substitution (numbered according to the mature NLRP3 protein sequence of SEQ ID NO: 35). In some embodiments of these methods, the subject has or is suspected of having keratoendotheliitis fugax hereditaria.

In some embodiments of any of the methods described herein, the subject has or is suspected of having an inappropriate host response to infectious diseases where active infection exists at any body site. In some embodiments of these methods, the inappropriate host response to infectious disease where active infection exists at any body site is selected from the group of: septic shock, disseminated intravascular coagulation, and adult respiratory distress syndrome.

In some embodiments of any of the methods described herein, the subject has or is suspected of having acute or chronic inflammation due to antigen, antibody, and/or complement deposition. In some embodiments of any of the methods described herein, the subject has or is suspected of having an inflammatory disease or condition (e.g., an inflammatory disease or conditions selected from the group of arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury, vasculitis, osteoarthritis, COPD, periodontal disease, uveitis, cutaneous T-cell lymphoma, and mucositis such as oral mucositis, esophageal mucositis, and intestinal mucositis).

In some embodiments of any of the methods described herein, the subject has or is suspected of having acute and delayed hypersensitivity, graft rejection, or graft-versus- host disease (GVHD). In some embodiments of any of the methods described herein, the subject has or is suspected of having an autoimmune disease selected from the group consisting of: Type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus

erythematosus, autoimmune thyroiditis, Addison’s disease, pernicious anemia, multiple sclerosis, an inflammatory bowel disease (IBD) (e.g., an IBD selected from the group of Crohn’s disease, ulcerative colitis, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by treatment with adoptive cell therapy, colitis associated with one or more alloimmune diseases such as GVHD, radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis, celiac disease, and inflammatory bowel syndrome), scleroderma, and psoriasis.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a metabolic disorder (e.g., a metabolic disorder selected from the group of type 2 diabetes, atherosclerosis, obesity, gout, and pseudogout). In some embodiments of any of the methods described herein, the subject has or is suspected of having a disease of the central nervous system (e.g., a disease of the central nervous system selected from the group of Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson’s disease).

In some embodiments of any of the methods described herein, the subject has or is suspected of having a lung disease (e.g., asthma, COPD, pulmonary idiopathic fibrosis, or cystic fibrosis). In some embodiments of any of the methods described herein, the subject has or is suspected of having a liver disease (e.g., NASH syndrome, viral hepatitis, or cirrhosis). In some embodiments of any of the methods described herein, wherein the subject has or is suspected of having a pancreatic disease (e.g., acute or chronic pancreatitis). In some embodiments of any of the methods described herein, wherein the subject has or is suspected of having kidney disease (e.g., as acute or chronic kidney injury). In some embodiments of any of the methods described herein, the subject has or is suspected of having an intestinal disease (e.g., Crohn’s disease or ulcerative colitis).

In some embodiments of any of the methods described herein, the subject has or is suspected of having a skin disease (e.g., psoriasis). In some embodiments of any of the methods described herein, the subject has or is suspected of having a musculoskeletal disease (e.g., scleroderma). In some embodiments of any of the methods described herein, the subject has or is suspected of having a vessel disorder (e.g., giant cell arteritis). In some embodiments of any of the methods described herein, the subject has a bone disorder (e.g., osteoarthritis, osteoporosis, or osteopetrosis disorders).

In some embodiments of any of the methods described herein, the subject has or is suspected of having an eye disease (e.g., glaucoma or macular degeneration, e.g., age- related macular degeneration). In some embodiments of any of the methods described herein, the subject has or is suspected of having a disease caused by viral infection (e.g., HIV or AIDS). In some embodiments of any of the methods described herein, the subject has or is suspected of having a cancer (e.g., non-small cell lung cancer, acute

lymphoblastic leukemia (ALL) (e.g., ALL in patients resistant to glucocorticoid treatment), multiple myeloma, promyelocytic leukemia, gastric cancer, or lung cancer metastasis). In some embodiments of any of the methods described herein, the subject has or is suspected of having a cardiovascular disease (e.g., myocardial infarction, stroke, or heart failure).

In some embodiments of any of the methods described herein, the subject has or is suspected of having: hereditary periodic fever, familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome, myelodysplastic syndrome (MDS), Langerhan’s cell histiocytosis (LCH), neonatal onset multisystem inflammatory disease, Cinca syndrome, deafness with inflammation, deafness without inflammation, keratoendotheliitis fugax hereditaria, silicosis, asbestosis, or chronic neurologic cutaneous and articular syndrome. In some embodiments of any of the methods described herein, the subject has been exposed to, or is suspected of having been exposed to, a toxic agent selected from the group of: exogenous microbial stimuli,

lipopolysaccharide (LPS), lipooligosaccharide, muramyl dipeptide (MDP), nigericin, maitotoxin, asbestos, and silica.

Provided herein are methods of treating a subject (e.g., any of the exemplary subjects desecribed herein) in need thereof that include: (a) identifying a subject having resistance to an anti-TNFa agent (e.g., any of the exemplary types of resistance to an anti-TNFa agent described herein or known in the art, or any of the types of anti-TNFa agents described herein or known in the art); and (b) administering a treatment comprising a therapeutically effective amount of an NLRP3 antagonist (e.g., any of the exemplary NLRP3 antagonists described herein) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to the identified subject. In some examples of these methods, step (b) can further include identifying the subject as also having an elevated level of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level (e.g., any of the exemplary reference levels described herein). In some embodiments of these methods, the treatment can further include a therapeutically effective amount of an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein), in addition to the NLRP3 antagonist.

Also provided herein are methods of treating a subject (e.g., any of the exemplary subjects desecribed herein) in need thereof, that include: administering a treatment comprising a therapeutically effective amount of an NLRP3 antagonist (e.g., any of the exemplary NLRP3 antagonists described herein) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject identified as having resistance to an anti-TNFa agent (e.g., any of the exemplary types of resistance to an anti-TNFa agent described herein or known in the art, or any of the anti-TNFa agents described herein or known in the art). In some embodiments of these methods, the identified subject also has an elevated level of level of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level. expression in a cell obtained from the subject, as compared to a reference level (e.g., any of the exemplary reference levels described herein or known in the art). In some embodiments of these methods, the treatment further includes a therapeutically effective amount of an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein or known in the art), in addition to the NLRP3 antagonist.

Also provided herein are methods of treating a subject (e.g., any of the exemplary subjects desecribed herein) in need thereof, that include: (a) administering one or more doses of an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein) to the subject; (b) detecting an elevated level (e.g., an increase of 1% to 1000%, or any of the subranges of this range described herein) of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject after step (a) as compared to a reference level (e.g., any of the exemplary reference levels of NLRP3 inflammasome activity and/or expression described herein or known in the art); and (c) administering a treatment comprising a therapeutically effective amount of an NLRP3 antagonist (e.g., any of the exemplary NLRP3 antagonists described herein or known in the art) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject determined to have an elevated level (e.g., an increase of 1% to 1000%, or any of the subranges of this range described herein) of NLRP3 inflammasome activity and/or expression as compared to the reference level in step (b). In some embodiments of any of these methods, the treatment can further include a therapeutically effective amount of an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein or known in the art), in addition to the NLRP3 antagonist. In some embodiments of these methods, the treatment can further include a therapeutically effective amount of the previously administered anti- TNFa agent, in addition to the NLRP3 antagonist.

Also provided herein are methods of treating a subject (e.g., any of the exemplary subjects desecribed herein) in need thereof, that include: (a) detecting an elevated level (e.g., an increase of 1% to 1000%, or any of the subranges of this range described herein) of NLRP3 inflammasome activity and/or expression as compared to a reference level (e.g., any of the exemplary reference levels of NLRP3 inflammasome activity described herein or known in the art) in a cell obtained from a subject previously administered one or more doses of an anti-TNFa agent; and (b) administering a treatment comprising a therapeutically effective amount of an NLRP3 antagonist (e.g., any of the exemplary NLRP3 antagonsits described herein or known in the art) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject determined to have an elevated level (e.g., an increase of 1% to 1000%, or any of the subranges of this range described herein) of NLRP3 inflammasome activity and/or expression as compared to the reference level in step (a). In some embodiments of any of these methods, the treatment can further include a therapeutically effective amount of an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein or known in the art), in addition to the NLRP3 antagonist. In some embodiments of these methods, the treatment can further include a therapeutically effective amount of the previously administered anti-TNFa agent, in addition to the NLRP3 antagonist.

Also provided herein are methods of treating a subject (e.g., any of the exemplary subjects desecribed herein) in need thereof, that include: administering a treatment comprising a therapeutically effective amount of an NLRP3 antagonist (e.g., any of the exemplary NLRP3 antagonists described herein or known in the art) or a

pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject determined to have an elevated level (e.g., an increase of 1% to 1000%, or any of the subranges of this range described herein) of NLRP3 inflammasome activity and/or expression as compared to a reference level (e.g., any of the exemplary reference levels of NLRP3 inflammasome activity described herein or known in the art) in a cell obtained from the subject after previous administration with one or more doses of an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein or known in the art). In some

embodiments of these methods, the treatment can further include a therapeutically effective amount of an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein or known in the art), in addition to the NLRP3 antagonist. In some embodiments of these methods, the treatment can further include a therapeutically effective amount of the previously administered anti-TNFa agent, in addition to the NLRP3 antagonist.

Provided herein are methods of treating a subject (e.g., any of the exemplary subjects desecribed herein) in need thereof, that include: (a) administering one or more doses of an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein or known in the art) to the subject; (b) after step (a), detecting resistance to the anti-TNFa agent in the subject (e.g., any of the exemplary types of resistance to an anti- TNFa agent described herein or known in the art); and (c) administering a treatment comprising a therapeutically effective amount of an NLRP3 antagonist (e.g., any of the exemplary types of NLRP3 antagonists described herein or known in the art) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject determined to have resistance to the anti-TNFa agent in step (b). In some embodiments of these methods, the treatment further includes a therapeutically effective amount of an anti- TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein or known in the art), in addition to the NLRP3 antagonist. In some embodiments of these methods, the treatment can further include a therapeutically effective amount of the anti-TNFa agent administered in step (a), in addition to the NLRP3 antagonist.

Also provided herein are methods of treating a subject (e.g., any of the exemplary subjects desecribed herein) in need thereof, that include: (a) detecting resistance to an anti-TNFa agent (e.g., any of the exemplary types of resistance to an anti-TNFa agent described herein or known in the art) in a subject previously administered one or more doses of the anti-TNFa agent (e.g., any of the exemplary types of an anti-TNFa agent described herein or known in the art); and (b) administering a treatment comprising a therapeutically effective amount of an NLRP3 antagonist (e.g., any of the exemplary NLRP3 antagonists described herein or known in the art) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject determined to have resistance to the anti-TNFa agent in step (a). In some embodiments of these methods, the treatment further includes a therapeutically effective amount of an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein or known in the art), in addition to the NLRP3 antagonist. In some embodiments of these methods, the treatment can further include a therapeutically effective amount of the previously administered anti-TNFa agent, in addition to the NLRP3 antagonist.

Also provided herein are methods of treating a subject (e.g., any of the exemplary subjects desecribed herein) in need thereof, that include: comprising administering a treatment comprising a therapeutically effective amount of an NLRP3 antagonist (e.g., any of the exemplary NLRP3 antagonists described herein or known in the art) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject previously administered one or more doses of an anti-TNFa agent (e.g., any of the exemplary anti- TNFa agents described herein or known in the art) and determined to have resistance to the anti-TNFa agent (e.g., any of the exemplary types of resistance to an anti-TNFa agent described herein or known in the art). In some embodiments of these methods, the treatment further includes a therapeutically effective amount of an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein or known in the art), in addition to the NLRP3 antagonist. In some embodiments of these methods, the treatment can further include a therapeutically effective amount of the previously administered anti- TNFa agent, in addition to the NLRP3 antagonist.

Also provided herein are methods of treating a subject (e.g., any of the exemplary subjects desecribed herein) in need thereof, that include: (a) identifying a subject having an elevated level (e.g., an increase of 1% to 1000%, or any of the subranges of this range described herein) of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level (e.g., any of the exemplary reference levels of NLRP3 inflammasome activity described herein or known in the art); and (b) administering a treatment comprising (i) a therapeutically effective amount of an NLRP3 antagonist (e.g., any of the exemplary NLRP3 antagonists described herein or known in the art) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and (ii) a therapeutically effective amount of an anti-TNFa agent (e.g., any of the exemplary anti- TNFa agents described herein or known in the art) to the identified subject. In some embodiments of these methods, the subject has not previously been administered an anti- TNFa agent.

Also provided herein are methods of treating a subject (e.g., any of the exemplary subjects desecribed herein) in need thereof, that include: administering a treatment comprising (i) a therapeutically effective amount of an NLRP3 antagonist (e.g., any of the exemplary NLRP3 antagonists described herein or known in the art) or a

pharmaceutically acceptable salt, solvate, or co-crystal thereof, and (ii) a therapeutically effective amount of an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein or known in the art), to a subject identified as having an elevated level (e.g., an increase of 1% to 1000%, or any of the subranges of this range described herein) of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level (e.g., any of the exemplary reference levels of NLRP3 inflammasome activity described herein or known in the art). In some embodiments of these methods, the subject has not previously been administered an anti-TNFa agent.

In some embodiments of any of the methods described herein, the NLRP3 antagonist is a compound of any one of Formulas I-X, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and is administered to a subject in need thereof, in combination with an anti-TNFa agent; preferably in combination with Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab; more preferably in combination with Adalimumab; more preferably in combination with Adalimumab.

In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is secretion of IL-18 (processed IL-18). In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is secretion of IL-lp (processed IL-l&). In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is caspase-l activity. In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is the level of lipocalin- 2. In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is the level of S100A8. In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is the level of S100A9.

In some embodiments of any of the methods described herein, the identifying of the subject as having a cell that has an elevated level of NLRP3 inflammasome expression includes detecting the level of one or more of NLRP3 protein, ASC protein, procaspase-l protein, and caspase-l protein. In some embodiments of any of the methods described herein, the identifying the subject as also having a cell that has an elevated level of NLRP3 inflammasome expression includes detecting the level of one or more of NLRP3 mRNA, ASC mRNA, and procaspase-l mRNA.

In some embodiments of any of the methods described herein, the identifying of the subject as having a cell that has an elevated level of NLRP3 inflammasome activity includes detecting the level of one or more of CRP protein, SAA protein, HP protein, ceruloplasmin protein, IL-6 protein (e.g., mature or pro-IL-6 protein), calprotectin (S100A8) protein, IL-8 protein (e.g., mature or pro-IL-8 protein), leukotriene B4 protein, and myeloperoxidase protein. In some embodiments of any of the methods described herein, the identifying of the subject as having a cell that has an elevated level of one or more of CRP mRNA, SAA mRNA, HP mRNA, ceruloplasmin mRNA, pro-IL-6 mRNA, calprotectin (S100A8) mRNA, pro-IL-8 mRNA, leukotriene B4 mRNA, and

myeloperoxidase mRNA.

In some embodiments of any of the methods described herein, where the subject is administered a therapeutically effective amount of an NLRP3 antagonist and a therapeutically effective amount of an anti-TNFa agent, the NLRP3 antagonist and the anti-TNFa agent can be administered at substantially the same time (e.g., in different dosage forms or formulated together into a single dosage form). In some embodiments of any of the methods described herein, wherein the subject is administered a therapeutically effective amount of an NLRP3 antagonist and a therapeutically effective amount of an anti-TNFa agent, the subject can be first administered the NLRP3 antagonist and then be administered the anti-TNFa agent. In some embodiments of any of the methods described herein, wherein the subject is administered a therapeutically effective amount of an NLRP3 antagonist and a therapeutically effective amount of an anti-TNFa agent, the subject can be first administered the anti-TNFa agent and then be administered the NLRP3 antagonist.

In some embodiments of any of the methods described herein, the subject has been diagnosed or identified as having an inflammatory or an autoimmune disorder (e.g., any of the exemplary inflammatory or autoimmune disorders described herein or known in the art). For example, in some embodiments of any of the methods described herein, the subject can be diagnosed or identified as having Crohn’s disease, ulcerative colitis, or inflammatory bowel disease.

In some embodiments of any of the methods described herein, the anti-TNFa agent is an antibody or an antigen-binding antibody fragment (e.g., adalimumab, certolizumab, etanercept, golimumab, infliximab, CDP571, or certolizumab pegol), or a soluble TNFa receptor. In some embodiments of any of the methods described herein, the anti-TNFa agent is a small molecule inhibitor of a signaling component downstream of a TNFa receptor. In some embodiments of any of the methods described herein, the anti-TNFa agent is an inhibitory nucleic acid. In some embodiments of any of the methods described herein, the anti-TNFa agent is a fusion protein. In some embodiments of any of the methods described herein, the NLRP3 antagonist is an inhibitory nucleic acid (e.g., a short interfering RNA, an antisense nucleic acid, or a ribozyme). In some embodiments of any of the methods described herein, the NLRP3 antagonist is a compound of any one of Formulas I-X, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. In some embodiments of any of the methods described herein, the NLRP3 antagonist is a compound shown in any one of Tables 1-18, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

In some embodiments of any of the methods of treatment described herein, the method can result in a decreased risk (e.g., a 1% to a 99% decrease, e.g., a 1% to 95% decrease, a 1% to 90% decrease, a 1% to 85% decrease, a 1% to 80% decrease, a 1% to 75% decrease, a 1% to 70% decrease, a 1% to 65% decrease, a 1% to 60% decrease, a 1% to 55% decrease, a 1% to 50% decrease, a 1% to 45% decrease, a 1% to 40% decrease, a 1% to 35% decrease, a 1% to 30% decrease, a 1% to 25% decrease, a 1% to 20% decrease, a 1% to 15% decrease, a 1% to 10% decrease, a 1% to 5% decrease, a 5% to 99% decrease, a 5% to 95% decrease, a 5% to 90% decrease, a 5% to 85% decrease, a 5% to 80% decrease, a 5% to 75% decrease, a 5% to 70% decrease, a 5% to 65% decrease, a 5% to 60% decrease, a 5% to 55% decrease, a 5% to 50% decrease, a 5% to 45% decrease, a 5% to 40% decrease, a 5% to 35% decrease, a 5% to 30% decrease, a 5% to 25% decrease, a 5% decrease to 20% decrease, a 5% to 15% decrease, a 5% to 10% decrease, a 10% to 99% decrease, a 10% to 95% decrease, a 10% to 90% decrease, a 10% to 85% decrease, a 10% to 80% decrease, a 10% to 75% decrease, a 10% to 70% decrease, a 10% to 65% decrease, a 10% to 60% decrease, a 10% to 55% decrease, a 10% to 50% decrease, a 10% to 45% decrease, a 10% to 40% decrease, a 10% to 35% decrease, a 10% to 30% decrease, a 10% to 25% decrease, a 10% decrease to 20% decrease, a 10% to 15% decrease, a 15% to 99% decrease, a 15% to 95% decrease, a 15% to 90% decrease, a 15% to 85% decrease, a 15% to 80% decrease, a 15% to 75% decrease, a 15% to 70% decrease, a 15% to 65% decrease, a 15% to 60% decrease, a 15% to 55% decrease, a 15% to 50% decrease, a 15% to 45% decrease, a 15% to 40% decrease, a 15% to 35% decrease, a 15% to 30% decrease, a 15% to 25% decrease, a 15% decrease to 20% decrease, a 20% to 99% decrease, a 20% to 95% decrease, a 20% to 90% decrease, a 20% to 85% decrease, a 20% to 80% decrease, a 20% to 75% decrease, a 20% to 70% decrease, a 20% to 65% decrease, a 20% to 60% decrease, a 20% to 55% decrease, a 20% to 50% decrease, a 20% to 45% decrease, a 20% to 40% decrease, a 20% to 35% decrease, a 20% to 30% decrease, a 20% to 25% decrease, a 25% to 99% decrease, a 25% to 95% decrease, a 25% to 90% decrease, a 25% to 85% decrease, a 25% to 80% decrease, a 25% to 75% decrease, a 25% to 70% decrease, a 25% to 65% decrease, a 25% to 60% decrease, a 25% to 55% decrease, a 25% to 50% decrease, a 25% to 45% decrease, a 25% to 40% decrease, a 25% to 35% decrease, a 25% to 30% decrease, a 30% to 99% decrease, a 30% to 95% decrease, a 30% to 90% decrease, a 30% to 85% decrease, a 30% to 80% decrease, a 30% to 75% decrease, a 30% to 70% decrease, a 30% to 65% decrease, a 30% to 60% decrease, a 30% to 55% decrease, a 30% to 50% decrease, a 30% to 45% decrease, a 30% to 40% decrease, a 30% to 35% decrease, a 35% to 99% decrease, a 35% to 95% decrease, a 35% to 90% decrease, a 35% to 85% decrease, a 35% to 80% decrease, a 35% to 75% decrease, a 35% to 70% decrease, a 35% to 65% decrease, a 35% to 60% decrease, a 35% to 55% decrease, a 35% to 50% decrease, a 35% to 45% decrease, a 35% to 40% decrease, a 40% to 99% decrease, a 40% to 95% decrease, a 40% to 90% decrease, a 40% to 85% decrease, a 40% to 80% decrease, a 40% to 75% decrease, a 40% to 70% decrease, a 40% to 65% decrease, a 40% to 60% decrease, a 40% to 55% decrease, a 40% to 50% decrease, a 40% to 45% decrease, a 45% to 99% decrease, a 45% to 95% decrease, a 45% to 90% decrease, a 45% to 85% decrease, a 45% to 80% decrease, a 45% to 75% decrease, a 45% to 70% decrease, a 45% to 65% decrease, a 45% to 60% decrease, a 45% to 55% decrease, a 45% to 50% decrease, a 50% to 99% decrease, a 50% to 95% decrease, a 50% to 90% decrease, a 50% to 85% decrease, a 50% to 80% decrease, a 50% to 75% decrease, a 50% to 70% decrease, a 50% to 65% decrease, a 50% to 60% decrease, a 50% to 55% decrease, a 55% to 99% decrease, a 55% to 95% decrease, a 55% to 90% decrease, a 55% to 85% decrease, a 55% to 80% decrease, a 55% to 75% decrease, a 55% to 70% decrease, a 55% to 65% decrease, a 55% to 60% decrease, a 60% to 99% decrease, a 60% to 95% decrease, a 60% to 90% decrease, a 60% to 85% decrease, a 60% to 80% decrease, a 60% to 75% decrease, a 60% to 70% decrease, a 60% to 65% decrease, a 65% to 99% decrease, a 65% to 95% decrease, a 65% to 90% decrease, a 65% to 85% decrease, a 65% to 80% decrease, a 65% to 75% decrease, a 65% to 70% decrease, a 70% to 99% decrease, a 70% to 95% decrease, a 70% to 90% decrease, a 70% to 85% decrease, a 70% to 80% decrease, a 70% to 75% decrease, a 75% to 99% decrease, a 75% to 95% decrease, a 75% to 90% decrease, a 75% to 85% decrease, a 75% to 80% decrease, a 80% to 99% decrease, a 80% to 95% decrease, a 80% to 90% decrease, a 80% to 85% decrease, a 85% to 99% decrease, a 85% to 95% decrease, a 85% to 90% decrease, a 90% to 99% decrease, a 90% to 95% decrease, or a 95% to 99% decrease) of developing a comorbidity in the subject (e.g., as compared to the risk of developing a comorbidity in a subject having a similar elevated level of NLRP3 inflammasome activity and/or expression in a cell and/or a similar level of anti-TNFa resistance, but administered a different treatment or a placebo).

In some embodiments of any of the methods described herein, where the subject has inflammatory bowel disease, such as ulcerative colitis or Crohn’s, the methods can result in a decrease (e.g., a 1% to 99% decrease, or any of the subranges of this range described herein) in the disease activity index (DAI) for Crohn’s disease or ulcerative colitis in the subject (e.g., as compared to the DAI in the same subject prior to treatment).

In some embodiments of any of the methods described herein, wherein the subject has inflammatory bowel syndrome, such as Crohn’s disease or ulcerative colitis, the methods can result in an improvement in stool consistency in the subject (e.g., as compared to the stool consistency in the subject prior to treatment).

In some embodiments of any of the methods described herein, the methods can result in a decrease (e.g., a 1% to 99% decrease, or any of the subranges of this range) in the severity, duration, or number of symptoms of an inflammatory disease or autoimmune disease (e.g., any of the inflammatory diseases or autoimmune diseases described herein or known in the art, e.g., inflammatory bowel disease, such as ulcerative colitis, Crohn’s disease) in the subject. Non-limiting examples of symptoms of ulcerative colitis and Crohn’s disease in a subject include: abdominal pain, diarrhea, blood stool, fever, unintended weight loss, fatigue, abdominal cramping, and mouth sores.

Additional exemplary aspects that can be used or incorporated in these methods are described herein.

Methods of Predicting a Subject’s Responsiveness to an anti-TNFa agent

Also provided herein are methods of predicting a subject’s responsiveness (e.g., any of the exemplary subjects desecribed herein) to an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein or known in the art), that include: (a) determining that a subject has an elevated level (e.g., an increase of 1% to 1000%, or any of the subranges of this range described herein) of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level (e.g., any of the exemplary reference levels of NLRP3 inflammasome activity described herein or known in the art); and (b) identifying that the subject determined to have an elevated level of NLRP3 inflammasome activity and/or expression in step (a) has an increased likelihood of being resistant to treatment with an anti-TNFa agent. Also provided herein are methods of predicting a subject’s responsiveness (e.g., any of the exemplary subjects desecribed herein) to an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein or known in the art), that include:

identifying a subject determined to have an elevated level (e.g., an increase of 1% to 1000%, or any of the subranges of this range described herein) of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as having an increased likelihood of being resistant to treatment with an anti-TNFa agent.

In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is secretion of IL-18 (processed IL-18). In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is secretion of IL-lp (processed IL-ld). In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is caspase-l activity. In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is the level of lipocalin- 2. In some embodiments of any of the methods described herein, the NLRP3

inflammasome activity is the level of S100A8. In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is the level of S100A9.

In some embodiments of any of the methods described herein, the determining that a subject has an elevated level of NLRP3 inflammasome activity and/or expression includes detecting the level of one or more (e.g., 1, 2, 3, or 4) of NLRP3 protein, ASC protein, procaspase-l protein, and caspase-l protein. In some embodiments of any of the methods described herein, the determining that a subject has an elevated level of NLRP3 inflammasome expression includes detecting the level of one or more (e.g., 1, 2, 3, or 4) of NLRP3 mRNA, ASC mRNA, and procaspase-l mRNA.

In some embodiments of any of the methods described herein, the identifying of the subject as having a cell that has an elevated level of NLRP3 inflammasome activity includes detecting the level of one or more of CRP protein, SAA protein, HP protein, ceruloplasmin protein, IL-6 protein (e.g., mature or pro-IL-6 protein), calprotectin (S100A8) protein, IL-8 protein (e.g., mature or pro-IL-8 protein), leukotriene B4 protein, and myeloperoxidase protein. In some embodiments of any of the methods described herein, the identifying of the subject as having a cell that has an elevated level of one or more of CRP mRNA, SAA mRNA, HP mRNA, ceruloplasmin mRNA, pro-IL-6 mRNA, calprotectin (S100A8) mRNA, pro-IL-8 mRNA, leukotriene B4 mRNA, and

myeloperoxidase mRNA.

In some embodiments of any of the methods described herein, the subject determined to have an elevated level of NLRP3 inflammasome expression has been determined to have a cell having an elevated level of one or more of NLRP3 protein,

ASC protein, procaspase-l protein, and capsase-l protein. In some embodiments of any of the methods described herein, the subject determined to have an elevated level of NLRP3 inflammasome expression has been determined to have a cell having an elevated level of one or more of NLRP3 mRNA, ASC mRNA, and procaspase-l mRNA.

In some embodiments of any of the methods described herein, the subject has not previously been administered a dose of an anti-TNFa antagonist.

Some embodiments of any of the methods described herein can further include: administering to the subject identified as having an increased likelihood of being resistant to treatment with an anti-TNFa agent, a treatment including (i) a therapeutically effective amount of an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agent described herein) and (ii) a therapeutically effective amount of an NLRP3 antagonist (e.g., any of the exemplary NLRP3 antagonsits described herein or known in the art).

Some embodiments of any of the methods described herein can further include: recording the identification of the subject as having an increased likelihood of being resistant to treatment with an anti-TNFa agent in the subject’s clinical record (e.g., a computer readable medium). Some embodiments of any of the methods described herein can further include recording in the clinical record for the subject identified as having an increased likelihood of being resistant to treatment with an anti-TNFa agent, that the subject should be administered an NLRP3 antagonist (e.g., alone or in combination with an anti-TNFa agent). Additional exemplary aspects that can be used or incorporated in these methods are described herein.

In some embodiments of any of the methods described herein, the NLRP3 antagonist is an inhibitory nucleic acid (e.g., a short interfering RNA, an antisense nucleic acid, or a ribozyme). In some embodiments of any of the methods described herein, the NLRP3 antagonist is a compound of any one of Formulas I-X, or a

pharmaceutically acceptable salt, solvate, or co-crystal thereof. In some embodiments of any of the methods described herein, the NLRP3 antagonist is a compound shown in any one of Tables 1-18, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

In some embodiments of any of the methods described herein, the NLRP3 antagonist is a compound of any one of Formulas I-X, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and is administered to a subject in need thereof, in combination with an anti-TNFa agent; preferably in combination with Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab; more preferably in combination with Adalimumab; more preferably in combination with Adalimumab.

Some embodiments of any of the methods described herein can further include recording the selected treatment in the subject’s clinical record (e.g., a computer readable medium). Some embodiments of any of the methods described herein can further include administering one or more doses (e.g., at least two, at least four, at least six, at least eight, at least ten doses) of the selected treatment to the identified subject.

Additional exemplary aspects that can be used or incorporated in these methods are described herein.

Methods of Selecting a Subject for Treatment

Also provided herein are methods of selecting a treatment for a subject (e.g., any of the exemplary subjects desecribed herein) in need thereof, that include: (a) identifying a subject having resistance to an anti-TNFa agent (e.g., any of the exemplary resistances to an anti-TNFa agent described herein or known in the art); and (b) selecting for the identified subject a treatment comprising a therapeutically effective amount of an NLRP3 antagonist (e.g., any of the exemplary NLRP3 antagonists described herein or known in the art) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. In some embodiments of these methods, step (b) can further include identifying the subject as also having an elevated level of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level. In some embodiments of these methods, the treatment further includes a therapeutically effective amount of an anti-TNFa agent (e.g., a previously administered anti-TNFa agent), in addition to the NLRP3 antagonist.

Also provided herein are methods of selecting a treatment for a subject (e.g., any of the exemplary subjects desecribed herein) in need thereof, that include: selecting a treatment comprising a therapeutically effective amount of an NLRP3 antagonist (e.g., any of the exemplary NLRP3 antagonists described herein or known in the art) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof for a subject identified as having resistance to an anti-TNFa agent (e.g., any of the exemplary resistances to an anti- TNFa agent described herein or known in the art). In some embodiments of these methods, the identified subject also has an elevated level of level of NLRP3

inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level. In some embodiments of these methods, the treatment further includes a therapeutically effective amount of an anti-TNFa agent (e.g., a previously administered anti-TNFa agent), in addition to the NLRP3 antagonist.

Provided herein are methods of selecting a treatment for a subject (e.g., any of the exemplary subjects desecribed herein) in need thereof, that include: (a) identifying a subject having an elevated level (e.g., an increase of 1% to 1000%, or any of the subranges of this range described herein) of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level (e.g., any of the exemplary reference levels of NLRP3 inflammasome activity described herein or known in the art); and (b) selecting for the identified subject a treatment comprising (i) a therapeutically effective amount of an NLRP3 antagonist (e.g., any of the exemplary NLRP3 antagonists described herein or known in the art) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and (ii) a therapeutically effective amount of an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein or known in the art). In some embodiments of these methods, the subject has not previously been administered an anti-TNFa agent.

Also provided herein are methods of selecting a treatment for a subject (e.g., any of the exemplary subjects desecribed herein) in need thereof, that include: selecting a treatment comprising (i) a therapeutically effective amount of an NLRP3 antagonist (e.g., any of the exemplary NLRP3 antagonists described herein or known in the art) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and (ii) a therapeutically effective amount of an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein or known in the art), for a subject identified as having an elevated level (e.g., an increase of 1% to 1000%, or any of the subranges of this range described herein) of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level (e.g., any of the exemplary reference levels of NLRP3 inflammasome activity described herein or known in the art). In some embodiments of these methods, the subject has not previously been administered an anti-TNFa agent.

In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is secretion of IL-18 (processed IL-18). In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is secretion of IL-lp (processed IL-ld). In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is caspase-l activity. In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is the level of lipocalin- 2. In some embodiments of any of the methods described herein, the NLRP3

inflammasome activity is the level of S100A8. In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is the level of S100A9.

In some embodiments of any of the methods described herein, the identifying of the subject as having a cell that has an elevated level of NLRP3 inflammasome activity includes detecting the level of one or more of CRP protein, SAA protein, HP protein, ceruloplasmin protein, IL-6 protein (e.g., mature or pro-IL-6 protein), calprotectin (S100A8) protein, IL-8 protein (e.g., mature or pro-IL-8 protein), leukotriene B4 protein, and myeloperoxidase protein. In some embodiments of any of the methods described herein, the identifying of the subject as having a cell that has an elevated level of one or more of CRP mRNA, SAA mRNA, HP mRNA, ceruloplasmin mRNA, pro-IL-6 mRNA, calprotectin (S100A8) mRNA, pro-IL-8 mRNA, leukotriene B4 mRNA, and

myeloperoxidase mRNA. In some embodiments of any of the methods described herein, the identifying of the subject as having a cell that has an elevated level of NLRP3 inflammasome expression includes detecting the level of one or more of NLRP3 protein, ASC protein, procaspase-l protein, and caspase-l protein. In some embodiments of any of the methods described herein, the identifying the subject as also having a cell that has an elevated level of NLRP3 inflammasome expression includes detecting the level of one or more of NLRP3 mRNA, ASC mRNA, and procaspase-l mRNA.

In some embodiments of any of the methods described herein, where the selected treatment includes a therapeutically effective amount of an NLRP3 antagonist and a therapeutically effective amount of an anti-TNFa agent, the NLRP3 antagonist and the anti-TNFa agent can be administered to the subject at substantially the same time (e.g., in different dosage forms or formulated together into a single dosage form). In some embodiments of any of the methods described herein, wherein the selected treatment includes a therapeutically effective amount of an NLRP3 antagonist and a therapeutically effective amount of an anti-TNFa agent, the subject can be first administered the NLRP3 antagonist and then be administered the anti-TNFa agent. In some embodiments of any of the methods described herein, wherein the selected treatment includes a therapeutically effective amount of an NLRP3 antagonist and a therapeutically effective amount of an anti-TNFa agent, the subject can be first administered the anti-TNFa agent and then be administered the NLRP3 antagonist.

In some embodiments of any of the methods described herein, the NLRP3 antagonist is a compound of any one of Formulas I-X, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and is administered to a subject in need thereof, in combination with an anti-TNFa agent; preferably in combination with Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab; more preferably in combination with Adalimumab; more preferably in combination with Adalimumab.

In some embodiments of any of the methods described herein, the subject has been diagnosed or identified as having an inflammatory or an autoimmune disorder (e.g., any of the exemplary inflammatory or autoimmune disorders described herein or known in the art). For example, in some embodiments of any of the methods described herein, the subject can be diagnosed or identified as having Crohn’s disease, ulcerative colitis, or inflammatory bowel disease.

In some embodiments of any of the methods described herein, the anti-TNFa agent is an antibody or an antigen-binding antibody fragment (e.g., adalimumab, certolizumab, etanercept, golimumab, infliximab, CDP571, or certolizumab pegol), or a soluble TNFa receptor. In some embodiments of any of the methods described herein, the anti-TNFa agent is a small molecule inhibitor of a signaling component downstream of a TNFa receptor. In some embodiments of any of the methods described herein, the anti-TNFa agent is an inhibitory nucleic acid. In some embodiments of any of the methods described herein, the anti-TNFa agent is a fusion protein.

In some embodiments of any of the methods described herein, the NLRP3 antagonist is an inhibitory nucleic acid (e.g., a short interfering RNA, an antisense nucleic acid, or a ribozyme). In some embodiments of any of the methods described herein, the NLRP3 antagonist is a compound of any one of Formulas I-XII described herein, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. In some embodiments of any of the methods described herein, the NLRP3 antagonist is a compound shown in any one of Tables 1-18, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Some embodiments of any of the methods described herein can further include recording the selected treatment in the subject’s clinical record (e.g., a computer readable medium). Some embodiments of any of the methods described herein can further include administering one or more doses (e.g., at least two, at least four, at least six, at least eight, at least ten doses) of the selected treatment to the identified subject.

Also provided herein are methods of selecting a subject (e.g., any of the exemplary subjects desecribed herein) for treatment, that include: (a) identifying a subject having resistance to an anti-TNFa agent (e.g., any of the exemplary resistances to an anti- TNFa agent described herein or known in the art); and (b) selecting the identified subject for treatment with a therapeutically effective amount of an NLRP3 antagonist (e.g., any of the exemplary NLRP3 antagonists described herein or known in the art) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. In some embodiments of these methods, step (b) further includes identifying the subject as also having an elevated level of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level. In some embodiments of any of these methods, the treatment can further include a therapeutically effective amount of an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein or known in the art), in addition to the NLRP3 antagonist.

Also provided herein are methods of selecting a subject (e.g., any of the exemplary subjects desecribed herein) for treatment that include: selecting a subject identified as having resistance to an anti-TNFa agent (e.g., any of the exemplary resistances to an anti-TNFa agent described herein or known in the art), for treatment with a therapeutically effective level of an NLRP3 antagonist (e.g., any of the exemplary NLRP3 antagonists described herein or known in the art) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. In some embodiments of these methods, the identified subject also has an elevated level of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level. In some embodiments of these methods, the treatment further includes a therapeutically effective amount of an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein or known in the art), in addition to the NLRP3 antagonist.

Also provided herein are methods of selecting a subject (e.g., any of the exemplary subjects desecribed herein) for treatment, that include: (a) identifying a subject having an elevated level (e.g., an increase of 1% to 1000%, or any of the subranges of this range described herein) of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level (e.g., any of the exemplary reference levels of NLRP3 inflammasome activity described herein or known in the art); and (b) selecting the identified subject for treatment with (i) a therapeutically effective amount of an NLRP3 antagonist (e.g., any of the exemplary NLRP3 antagonists described herein or known in the art) or a pharmaceutically acceptable salt, solvate, or co crystal thereof, and (ii) a therapeutically effective amount of an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein or known in the art). In some embodiments of these methods, the subject has not previously been administered an anti- TNFa agent.

Also provided herein are methods of selecting a subject (e.g., any of the exemplary subjects desecribed herein) for treatment, that include: selecting a subject identified as having an elevated level (e.g., an increase of 1% to 1000%, or any of the subranges of this range described herein) of NLRP3 inflammasome activity and/or expression in a cell obtained from the subject, as compared to a reference level (e.g., any of the exemplary reference levels of NLRP3 inflammasome activity described herein or known in the art), for treatment with (i) a therapeutically effective level of an NLRP3 antagonist (e.g., any of the exemplary NLRP3 antagonists described herein or known in the art) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and (ii) a therapeutically effective amount of an anti-TNFa agent (e.g., any of the anti-TNFa agents described herein or known in the art). In some embodiments of these methods, the subject has not previously been administered an anti-TNFa agent.

In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is secretion of IL-18 (processed IL-18). In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is secretion of IL-lp (processed IL-l&). In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is caspase-l activity. In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is the level of lipocalin- 2. In some embodiments of any of the methods described herein, the NLRP3

inflammasome activity is the level of S100A8. In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is the level of S100A9.

In some embodiments of any of the methods described herein, the identifying of the subject as having a cell that has an elevated level of NLRP3 inflammasome expression includes detecting the level of one or more of NLRP3 protein, ASC protein, procaspase-l protein, and caspase-l protein. In some embodiments of any of the methods described herein, the identifying the subject as also having a cell that has an elevated level of NLRP3 inflammasome expression includes detecting the level of one or more of NLRP3 mRNA, ASC mRNA, and procaspase-l mRNA. In some embodiments of any of the methods described herein, the identifying of the subject as having a cell that has an elevated level of NLRP3 inflammasome activity includes detecting the level of one or more of CRP protein, SAA protein, HP protein, ceruloplasmin protein, IL-6 protein (e.g., mature or pro-IL-6 protein), calprotectin (S100A8) protein, IL-8 protein (e.g., mature or pro-IL-8 protein), leukotriene B4 protein, and myeloperoxidase protein. In some embodiments of any of the methods described herein, the identifying of the subject as having a cell that has an elevated level of one or more of CRP mRNA, SAA mRNA, HP mRNA, ceruloplasmin mRNA, pro-IL-6 mRNA, calprotectin (S100A8) mRNA, pro-IL-8 mRNA, leukotriene B4 mRNA, and

myeloperoxidase mRNA.

In some embodiments of any of the methods described herein, where the subject is selected for a treatment including (i) a therapeutically effective amount of an NLRP3 antagonist and (ii) a therapeutically effective amount of an anti-TNFa agent, the NLRP3 antagonist and the anti-TNFa agent can be administered at substantially the same time (e.g., in different dosage forms or formulated together into a single dosage form). In some embodiments of any of the methods described herein, where the subject is selected for a treatment including a therapeutically effective amount of an NLRP3 antagonist and a therapeutically effective amount of an anti-TNFa agent, the subject can be first administered the NLRP3 antagonist and then be administered the anti-TNFa agent. In some embodiments of any of the methods described herein, where the subject is selected for a treatment including a therapeutically effective amount of an NLRP3 antagonist and a therapeutically effective amount of an anti-TNFa agent, the subject can be first administered the anti-TNFa agent and then be administered the NLRP3 antagonist.

In some embodiments of any of the methods described herein, the subject has been diagnosed or identified as having an inflammatory or an autoimmune disorder (e.g., any of the exemplary inflammatory or autoimmune disorders described herein or known in the art). For example, in some embodiments of any of the methods described herein, the subject can be diagnosed or identified as having Crohn’s disease, ulcerative colitis, or inflammatory bowel disease. In some embodiments of any of the methods described herein, the anti-TNFa agent is an antibody or an antigen-binding antibody fragment (e.g., adalimumab, certolizumab, etanercept, golimumab, infliximab, CDP571, or certolizumab pegol), or a soluble TNFa receptor. In some embodiments of any of the methods described herein, the anti-TNFa agent is a small molecule inhibitor of a signaling component downstream of a TNFa receptor. In some embodiments of any of the methods described herein, the anti-TNFa agent is an inhibitory nucleic acid. In some embodiments of any of the methods described herein, the anti-TNFa agent is a fusion protein.

Additional exemplary aspects that can be used or incorporated in these methods are described herein.

In some embodiments of any of the methods described herein, the NLRP3 antagonist is an inhibitory nucleic acid (e.g., a short interfering RNA, an antisense nucleic acid, or a ribozyme). In some embodiments of any of the methods described herein, the NLRP3 antagonist is a compound of any one of Formulas I-X, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. In some embodiments of any of the methods described herein, the NLRP3 antagonist is a compound shown in any one of Tables 1-18, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

Additional exemplary aspects that can be used or incorporated in these methods are described herein.

Methods of Reducing the Risk of Developing Resistance to an Anti-TNFa

Agent

Provided herein are methods of reducing (e.g., a 1% to 99% decrease, or any of the subranges of this range described herein) the risk of developing resistance to an anti-

TNFa agent in a subject (e.g., any of the exemplary subjects desecribed herein) in need thereof, that include: administering to a subject in need thereof a therapeutically effective amount of an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein or known in the art) and a therapeutically effective amount of an NLRP3 antagonist (e.g., any of the exemplary NLRP3 antagonists described herein or known in the art) or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. In some embodiments of any of the methods described herein, the anti-TNFa agent and the NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co- crystal thereof are administered at substantially the same time. In some embodiments of these methods, the anti-TNFa agent and the NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof are formulated into a single dosage form.

In some embodiments of any of the methods described herein, the NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof is administered to the subject prior to administration of the anti-TNFa agent. In some embodiments of any of the methods described herein, the anti-TNFa agent is

administered to the subject prior to administration of the NLRP3 antagonist or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

In some embodiments of any of the methods described herein, the subject has been diagnosed or identified as having an inflammatory or an autoimmune disorder (e.g., any of the exemplary inflammatory or autoimmune disorders described herein or known in the art). For example, in some embodiments of any of the methods described herein, the subject can be diagnosed or identified as having Crohn’s disease, ulcerative colitis, or inflammatory bowel disease.

In some embodiments of any of the methods described herein, the anti-TNFa agent is an antibody or an antigen-binding antibody fragment (e.g., adalimumab, certolizumab, etanercept, golimumab, infliximab, CDP571, or certolizumab pegol), or a soluble TNFa receptor. In some embodiments of any of the methods described herein, the anti-TNFa agent is a small molecule inhibitor of a signaling component downstream of a TNFa receptor. In some embodiments of any of the methods described herein, the anti-TNFa agent is an inhibitory nucleic acid. In some embodiments of any of the methods described herein, the anti-TNFa agent is a fusion protein.

In some embodiments of any of the methods described herein, the NLRP3 antagonist is an inhibitory nucleic acid (e.g., a short interfering RNA, an antisense nucleic acid, or a ribozyme). In some embodiments of any of the methods described herein, the NLRP3 antagonist is a compound of any one of Formulas I-XII described herein, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof. In some embodiments of any of the methods described herein, the NLRP3 antagonist is a compound shown in any one of Tables 1-18, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.

In some embodiments of any of the methods described herein, the NLRP3 antagonist is a compound of any one of Formulas I-X, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, and is administered to a subject in need thereof, in combination with an anti-TNFa agent; preferably in combination with Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab; more preferably in combination with Adalimumab; more preferably in combination with Adalimumab. Additional exemplary aspects that can be used or incorporated in these methods are described herein.

Methods of Detecting the Level of NLRP3 Inflammasome Activity and/or Expression

In some embodiments of any of the methods described herein, the NLRP3 inflammmasome activity is the secretion of IL-18 (processed IL-18). In some embodiments of any of the methods described herein, the NLPR3 inflammasome activity is the secretion of IL-lP (processed IL-ld). In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is caspase-l activity in a mammalian cell (e.g., a mammalian cell obtained from the subject). Non-limiting examples of methods that can be used to detect the secretion of IL-18 (processed IL-18) and IL-lP (processed IL-l&) include immunohistochemistry, immunoassays, e.g., enzyme-linked immunosorbent assay (ELISA), sandwich ELISA, immunoprecipitation, and immunofluorescent assay. Non-limiting examples of commercially available assays for determining caspase-l activity include Caspase 1 Assay Kit (Fluormetric) (ab394l2) (Abeam), FAM-FLICA® Caspase-l Assay Kit (ImmunoChemistry), Caspase-l

Colorimetric Assay Kit (Kl 11) (Biovision, Inc.), and Caspase-l/ICE Colorimetric Assay Kit (R&D Systems).

In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity can be the level of expression of an upstream activator of NLRP3 inflammasomes (e.g., the level of one or more (e.g., two, three, four, five, or six) of lipocalin-2 protein, lipocalin-2 mRNA, S100A8 protein, S1008A8 mRNA, S100A9 protein, or S100A9 mRNA) in a mammalian cell (e.g., a mammalian cell obtained from a subject). Non-limiting assays that can be used to determine NLRP3 activity include: Southern blot analysis, Norther blot analysis, polymerase chain reaction (PCR)-based methods, e.g., next generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), TaqMan™, microarray analysis, immunohistochemistry,

immunoassays, e.g., enzyme-linked immunosorbent assay (ELISA), sandwich ELISA, immunoprecipitation, immunofluorescent assay, and flow cytometry.

In some embodiments of any of the methods described herein, the NLRP3 inflammasome expression can be determined by detecting the level of one or more (e.g., two, three, four, five, six, or seven) of: NLRP3 protein, ASC protein, procaspase-l protein, caspase-l protein, NLRP3 mRNA, ASC mRNA, and procaspase-l mRNA, in a mammalian cell (e.g., in a mammalian cell obtained from the subject). Non-limiting examples of assays that can be used to determine the level of NLRP3 protein, ASC protein, procaspase-l protein, and caspase-l protein include immunohistochemistry, immunoassays, e.g., enzyme-linked immunosorbent assay (ELISA), sandwich ELISA, immunoprecipitation, immunofluorescent assay, and flow cytometry. Non-limiting examples of assays that can be used to determine the level of NLRP3 mRNA, ASC mRNA, and procaspase-l mRNA include Southern blot analysis, Norther blot analysis, polymerase chain reaction (PCR)-based methods, e.g., next generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), TaqMan™, and microarray analysis.

In some embodiments of any of the methods described herein, the NLRP3 inflammasome expression can be determined by detecting the level of one or more of CRP protein, SAA protein, HP protein, ceruloplasmin protein, IL-6 protein (e.g., mature or pro-IL-6 protein), calprotectin (S100A8) protein, IL-8 protein (e.g., mature or pro-IL-8 protein), leukotriene B4 protein, myeloperoxidase protein, CRP mRNA, SAA mRNA,

HP mRNA, ceruloplasmin mRNA, pro-IL-6 mRNA, calprotectin (S100A8) mRNA, pro- IL-8 mRNA, leukotriene B4 mRNA, and myeloperoxidase mRNA. Non-limiting examples of assays that can be used to determine the level of CRP protein, SAA protein, HP protein, ceruloplasmin protein, IL-6 protein (e.g., mature or pro-IL-6 protein), calprotectin (S100A8) protein, IL-8 protein (e.g., mature or pro-IL-8 protein), leukotriene B4 protein, myeloperoxidase protein include immunohistochemistry, immunoassays, e.g., enzyme-linked immunosorbent assay (ELISA), sandwich ELISA, immunoprecipitation, immunofluorescent assay, and flow cytometry. Non-limiting examples of assays that can be used to determine the level of CRP mRNA, SAA mRNA, HP mRNA, ceruloplasmin mRNA, pro-IL-6 mRNA, calprotectin (S100A8) mRNA, pro-IL-8 mRNA, leukotriene B4 mRNA, and myeloperoxidase mRNA include Southern blot analysis, Norther blot analysis, polymerase chain reaction (PCR)-based methods, e.g., next generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), TaqMan™, and microarray analysis.

In some embodiments of any of the methods described herein, the level of the protein or mRNA can be detected in a biological sample including blood, serum, exosomes, plasma, tissue, urine, feces, sputum, and cerebrospinal fluid.

In some embodiments of any of the methods described herein, the level of at least one (e.g., 2, 3, 4, 5, 6, 7 or 8) NLRP3 inflammasome activity and/or expression can be determined, e.g., in any combination.

In one aspect, the cell can be a cell isolated from a subject who has been screened for the presence of an inflammatory disease or indication that is associated with a mutation in a NLRP3 activity.

Methods of Determining Resistance of an Anti-TNFa Agent

Resistance to an anti-TNFa agent (e.g., primary resistance) is a reduced or decreased level of sensitivity to treatment with an anti-TNFa agent in a subject (e.g., as compared to a similar subject or as compared to the level of sensitivity to the anti-TNFa agent at an earlier time point). For example, resistance to an anti-TNFa in a subject can be observed by a physician or trained medical professional, e.g., by observing the requirement of increasing dosage amounts of an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein or known in the art) over time in order to achieve the same therapeutic effect in a subject (e.g., any of the exemplary subjects described herein), observing the requirement for an increased number of doses and/or an increased frequency of doses of an anti-TNFa agent (e.g., any of the exemplary anti- TNFa agents described herein or known in the art) over time in order to achieve the same therapeutic effect in a subject (e.g., any of the exemplary subjects described herein), a decrease in the observed therapeutic response to treatment with the same dosage of an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein or known in the art) in a subject (e.g., any of the exemplary subjects described herein) over time, or an observed progression of disease or disease relapse (e.g., any of the inflammatory diseases or autoimmune diseases described herein) in a subject (e.g., any of the exemplary subjects described herein) administered an anti-TNFa agent (e.g., any of the exemplary anti-TNFa agents described herein or known in the art). Additional metrics and assessments of resistance to an anti-TNFa agent are known in the art.

Anti-TNFa Agents

The term“anti-TNFa agent” refers to an agent which directly or indirectly blocks, down-regulates, impairs, inhibits, impairs, or reduces TNFa activity and/or expression.

In some embodiments, an anti-TNFa agent is an antibody or an antigen-binding fragment thereof, a fusion protein, a soluble TNFa receptor (a soluble tumor necrosis factor receptor superfamily member 1 A (TNFR1) or a soluble tumor necrosis factor receptor superfamily 1B (TNFR2)), an inhibitory nucleic acid, or a small molecule TNFa antagonist. In some embodiments, the inhibitory nucleic acid is a ribozyme, small hairpin RNA, a small interfering RNA, an antisense nucleic acid, or an aptamer.

Exemplary anti-TNFa agents that directly block, down-regulate, impair, inhibit, or reduce TNFa activity and/or expression can, e.g., inhibit or decrease the expression level of TNFa or a receptor of TNFa (TNFR1 or TNFR2) in a cell (e.g., a cell obtained from a subject, a mammalian cell), or inhibit or reduce binding of TNFa to its receptor

(TNFR1 and/or TNFR2). Non-limiting examples of anti-TNFa agents that directly block, down-regulate, impair, inhibit, or reduce TNFa activity and/or expression include an antibody or fragment thereof, a fusion protein, a soluble TNFa receptor (e.g., a soluble TNFR1 or soluble TNFR2), inhibitory nucleic acids (e.g., any of the examples of inhibitory nucleic acids described herein), and a small molecule TNFa antagonist.

Exemplary anti-TNFa agents that can indirectly block, down-regulate, impair, inhibitreduce TNFa activity and/or expression can, e.g., inhibit or decrease the level of downstream signaling of a TNFa receptor (e.g., TNFR1 or TNFR2) in a mammalian cell (e.g., decrease the level and/or activity of one or more of the following signaling proteins: AP-l, mitogen-activated protein kinase kinase kinase 5 (ASK1), inhibitor of nuclear factor kappa B (IKK), mitogen-activated protein kinase 8 (INK), mitogen-activated protein kinase (MAPK), MEKK 1/4, MEKK 4/7, MEKK 3/6, nuclear factor kappa B (NF-kB), mitogen-activated protein kinase kinase kinase 14 (NIK), receptor interacting serine/threonine kinase 1 (RIP), TNFRSF1A associated via death domain (TRADD), and TNF receptor associated factor 2 (TRAF2), in a cell), and/or decrease the level of TNFa- induced gene expression in a mammalian cell (e.g., decrease the transcription of genes regulated by, e.g., one or more transcription factors selected from the group of activating transcription factor 2 (ATF2), c-Jun, and NF-kB). A description of downstream signaling of a TNFa receptor is provided in Wajant et al., Cell Death Differentiation 10:45-65,

2003 (incorporated herein by reference). For example, such indirect anti-TNFa agents can be an inhibitory nucleic acid that targets (decreases the expression) a signaling component downstream of a TNFa-induced gene (e.g., any TNFa-induced gene known in the art), a TNFa receptor (e.g., any one or more of the signaling components downstream of a TNFa receptor described herein or known in the art), or a transcription factor selected from the group of NF-kB, c-Jun, and ATF2.

In other examples, such indirect anti-TNFa agents can be a small molecule inhibitor of a protein encoded by a TNFa-induced gene (e.g., any protein encoded by a TNFa-induced gene known in the art), a small molecule inhibitor of a signaling component downstream of a TNFa receptor (e.g., any of the signaling components downstream of a TNFa receptor described herein or known in the art), and a small molecule inhibitor of a transcription factor selected from the group of ATF2, c-Jun, and NF-KB. In other embodiments, anti-TNFa agents that can indirectly block, down-regulate, impair, or reduce one or more components in a cell (e.g., acell obtained from a subject, a mammalian cell) that are involved in the signaling pathway that results in TNFa mRNA transcription, TNFa mRNA stabilization, and TNFa mRNA translation (e.g., one or more components selected from the group of CD14, c-Jun, ERK1/2, IKK, IKB, interleukin 1 receptor associated kinase 1 (IRAK), JNK, lipopolysaccharide binding protein (LBP), MEK1/2, MEK3/6, MEK4/7, MK2, MyD88, NF-kB, NIK, PKR, p38, AKT

serine/threonine kinase 1 (rac), raf kinase (raf), ras, TRAF6, TTP). For example, such indirect anti-TNFa agents can be an inhibitory nucleic acid that targets (decreases the expression) of a component in a mammalian cell that is involved in the signaling pathway that results in TNFa mRNA transcription, TNFa mRNA stabilization, and TNFa mRNA translation (e.g., a component selected from the group of CD14, c-Jun, ERK1/2, IKK,

IKB, IRAK, JNK, LBP, MEK1/2, MEK3/6, MEK4/7, MK2, MyD88, NF-kB, NIK,

IRAK, lipopolysaccharide binding protein (LBP), PKR, p38, rac, raf, ras, TRAF6, TTP). In other examples, an indirect anti-TNFa agents is a small molecule inhibitor of a component in a mammalian cell that is involved in the signaling pathway that results in TNFa mRNA transcription, TNFa mRNA stabilization, and TNFa mRNA translation (e.g., a component selected from the group of CD14, c-Jun, ERK1/2, IKK, IKB, IRAK, JNK, lipopolysaccharide binding protein (LBP), MEK1/2, MEK3/6, MEK4/7, MK2, MyD88, NF-kB, NIK, IRAK, lipopolysaccharide binding protein (LBP), PKR, p38, rac, raf, ras, TRAF6, TTP).

Antibodies

In some embodiments, the anti-TNFa agent is an antibody or an antigen binding fragment thereof (e.g., a Fab or a scFv). In some embodiments, an antibody or antigen-binding fragment of an antibody described herein can bind specifically to TNFa. In some embodiments, an antibody or antigen-binding fragment described herein binds specifically to any one of TNFa, TNFR1, or TNFR2. In some embodiments, an antibody or antigen-binding fragment of an antibody described herein can bind specifically to a TNFa receptor (TNFR1 or TNFR2). In some embodiments, the antibody can be a humanized antibody, a chimeric antibody, a multivalent antibody, or a fragment thereof. In some embodiments, an antibody can be a scFv-Fc, a VHH domain, a VNAR domain, a (scFv)2, a minibody, or a BiTE.

In some embodiments, an antibody can be a crossmab, a diabody, a scDiabody, a scDiabody-CFB, a Diabody-CFB, a DutaMab, a DT-IgG, a diabody-Fc, a scDiabody- HAS, a charge pair antibody, a Fab-arm exchange antibody, a SEEDbody, a Triomab, a LUZ-Y, a Fcab, a kk-body, an orthogonal Fab, a DVD-IgG, an IgG(H)-scFv, a scFv- (H)IgG, an IgG(L)-scFv, a scFv-(L)-IgG, an IgG (L,H)-Fc, an IgG(H)-V, a V(H)-IgG, an IgG(L)-V, a V(L)-IgG, an KIH IgG-scFab, a 2scFv-IgG, an IgG-2scFv, a scFv4-Ig, a Zybody, a DVI-IgG, a nanobody, a nanobody -HSA, a DVD-Ig, a dual-affinity re- targeting antibody (DART), a triomab, a kih IgG with a common LC, an ortho-Fab IgG, a 2-in-l-IgG, IgG-ScFv, scFv2-Fc, a bi-nanobody, tanden antibody, a DART-Fc, a scFv- HAS-scFv, a DAF (two-in-one or four-in-one), a DNL-Fab3, knobs-in-holes common LC, knobs-in-holes assembly, a TandAb, a Triple Body, a miniantibody, a minibody, a TriBi minibody, a scFv-CFB KIH, a Fab-scFv, a scFv-CH-CL-scFv, a F(ab')2-scFV2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a tandem scFv-Fc, an intrabody, a dock and lock bispecific antibody, an ImmTAC, a HSAbody, a tandem scFv, an IgG-IgG, a Cov-X-Body, and a scFvl-PEG-scFv2.

Non-limiting examples of an antigen-binding fragment of an antibody include an

Fv fragment, a Fab fragment, a F(ab')2 fragment, and a Fab' fragment. Additional examples of an antigen-binding fragment of an antibody is an antigen-binding fragment of an antigen-binding fragment of an IgA (e.g., an antigen-binding fragment of IgAl or IgA2) (e.g., an antigen-binding fragment of a human or humanized IgA, e.g., a human or humanized IgAl or IgA2); an antigen-binding fragment of an IgD (e.g., an antigen binding fragment of a human or humanized IgD); an antigen-binding fragment of an IgE (e.g., an antigen-binding fragment of a human or humanized IgE); an IgG (e.g., an antigen-binding fragment of IgGl, IgG2, IgG3, or IgG4) (e.g., an antigen-binding fragment of a human or humanized IgG, e.g., human or humanized IgGl, IgG2, IgG3, or IgG4); or an antigen-binding fragment of an IgM (e.g., an antigen-binding fragment of a human or humanized IgM).

Non-limiting examples of anti-TNFa agents that are antibodies that specifically bind to TNFa are described in Ben-Horin et al., Autoimmunity Rev. l3(l):24-30, 2014; Bongartz et al., JAMA 295(l9):2275-2285, 2006; Butler et al., Eur. Cytokine Network 6(4):225-230, 1994; Cohen et al., Canadian J Gastroenterol. Hepatol. l5(6):376-384, 2001; Elliott et al., Lancet 1994; 344: 1125-1127, 1994; Feldmann et al., Ann. Rev.

Immunol. 19(1): 163-196, 2001; Rankin et al., Br. J. Rheumatol. 2:334-342, 1995; Knight et al., Molecular Immunol. 30(16): 1443-1453, 1993; Lorenz et al., J. Immunol.

156(4): 1646-1653, 1996; Hinshaw et al., Circulatory Shock 30(3):279-292, 1990; Ordas et al., Clin. Pharmacol. Therapeutics 9l(4):635-646, 2012; Feldman, Nature Reviews Immunol. 2(5):364-37l, 2002; Taylor et al., Nature Reviews Rheumatol. 5(l0):578-582, 2009; Garces et al., Annals Rheumatic Dis. 72(12): 1947-1955, 2013; Palladino et al., Nature Rev. Drug Discovery 2(9):736-746, 2003; Sandborn et al., Inflammatory Bowel Diseases 5(2): 119-133, 1999; Atzeni et al., Autoimmunity Reviews l2(7):703-708, 2013; Maini et al., Immunol. Rev. 144(1): 195-223, 1995; Wanner et al., Shock 1 l(6):39l-395, 1999; and U.S. Patent Nos. 6,090,382; 6,258,562; and 6,509,015).

In certain embodiments, the anti-TNFa agent can include or is golimumab (golimumabTM), adalimumab (Humira™), infliximab (Remicade™), CDP571, CDP 870, or certolizumab pegol (Cimzia™). In certain embodiments, the anti-TNFa agent can be a TNFa inhibitor biosimilar. Examples of approved and late-phase TNFa inhibitor biosimilars include, but are not limited to, infliximab biosimilars such as Flixabi™ (SB2) from Samsung Bioepis, Inflectra® (CT-P13) from Celltrion/Pfizer, GS071 from Aprogen, Remsima™, PF-06438179 from Pfizer/Sandoz, NI-071 from Nichi-Iko Pharmaceutical Co., and ABP 710 from Amgen; adalimumab biosimilars such as Amgevita® (ABP 501) from Amgen and Exemptia™ from Zydus Cadila, BMO-2 or MYL-1401-A from Biocon/Mylan, CHS-1420 from Coherus, FKB327 from Kyowa Kirin, and BI 695501 from Boehringer Ingelheim;Solymbic®, SB5 from Samsung Bioepis, GP-2017 from Sandoz, ONS-3010 from Oncobiologics, M923 from Momenta, PF-06410293 from Pfizer, and etanercept biosimilars such as Erelzi™ from Sandoz/Novartis, Brenzys™ (SB4) from Samsung Bioepis, GP2015 from Sandoz, TuNEX® from Mycenax, LBEC0101 from LG Life, and CHS-0214 from Coherus.

In some embodiments of any of the methods described herein, the anti-TNFa agent is selected from the group consisting of: adalimumab, certolizumab, etanercept, golimumab, infliximabm, CDP571, and CDP 870.

In some embodiments, any of the antibodies or antigen-binding fragments described herein has a dissociation constant (KD) of less than 1 x 10 ⁵ M (e.g., less than 0.5 x 10 ⁵ M, less than 1 x 10 ⁶ M, less than 0.5 x 10 ⁶ M, less than 1 x 10 ⁷ M, less than 0.5 x 10 ⁷ M, less than 1 x 10 ⁸ M, less than 0.5 x 10 ⁸ M, less than 1 x 10 ⁹ M, less than 0.5 x 10 ⁹ M, less than 1 x 10 ¹⁰ M, less than 0.5 x 10 ¹⁰ M, less than 1 x 10 ¹¹ M, less than 0.5 x lO ^u M, or less than 1 x 10 ¹² M), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).

In some embodiments, any of the antibodies or antigen-binding fragments described herein has a KD of about 1 x 10 ¹² M to about 1 x 10 ⁵ M, about 0.5 x 10 ⁵ M, about 1 x 10 ⁶ M, about 0.5 x 10 ⁶ M, about 1 x 10 ⁷ M, about 0.5 x 10 ⁷ M, about 1 x 10 ⁸ M, about 0.5 x 10 ⁸ M, about 1 x 10 ⁹ M, about 0.5 x 10 ⁹ M, about 1 x 10 ¹⁰ M, about 0.5 x 10 ¹⁰ M, about 1 x 10 ¹¹ M, or about 0.5 x l0 ^u M (inclusive); about 0.5 x l0 ^u M to about 1 x 10 ⁵ M, about 0.5 x 10 ⁵ M, about 1 x 10 ⁶ M, about 0.5 x 10 ⁶ M, about 1 x 10 ⁷ M, about 0.5 x 10 ⁷ M, about 1 x 10 ⁸ M, about 0.5 x 10 ⁸ M, about 1 x 10 ⁹ M, about 0.5 x 10 ⁹ M, about 1 x 10 ¹⁰ M, about 0.5 x 10 ¹⁰ M, or about 1 x 10 ¹¹ M (inclusive); about 1 x l0 ^u M to about 1 x 10 ⁵ M, about 0.5 x 10 ⁵ M, about 1 x 10 ⁶ M, about 0.5 x 10 ⁶ M, about 1 x 10 ⁷ M, about 0.5 x 10 ⁷ M, about 1 x 10 ⁸ M, about 0.5 x 10 ⁸ M, about 1 x 10 ⁹ M, about 0.5 x 10 ⁹ M, about 1 x 10 ¹⁰ M, or about 0.5 x 10 ¹⁰ M (inclusive); about 0.5 x 10 ¹⁰ M to about 1 x 10 ⁵ M, about 0.5 x 10 ⁵ M, about 1 x 10 ⁶ M, about 0.5 x 10 ⁶ M, about 1 x 10 ⁷ M, about 0.5 x 10 ⁷ M, about 1 x 10 ⁸ M, about 0.5 x 10 ⁸ M, about 1 x 10 ⁹ M, about 0.5 x 10 ⁹ M, or about 1 x 10 ¹⁰ M (inclusive); about 1 x 10 ¹⁰ M to about 1 x 10 ⁵ M, about 0.5 x 10 ⁵ M, about 1 x 10 ⁶ M, about 0.5 x 10 ⁶ M, about 1 x 10 ⁷ M, about 0.5 x 10 ⁷ M, about 1 x 10 ⁸ M, about 0.5 x 10 ⁸ M, about 1 x 10 ⁹ M, or about 0.5 x 10 ⁹ M (inclusive); about 0.5 x 10 ⁹ M to about 1 x 10 ⁵ M, about 0.5 x 10 ⁵ M, about 1 x 10 ⁶ M, about 0.5 x 10 ⁶ M, about 1 x 10 ⁷ M, about 0.5 x 10 ⁷ M, about 1 x 10 ⁸ M, about 0.5 x 10 ⁸ M, or about 1 x 1 O ⁹ M (inclusive); about 1 x 10 ⁹ Mto about 1 x 10 ⁵ M, about 0.5 x 10 ⁵ M, about 1 x 10 ⁶ M, about 0.5 x 10 ⁶ M, about 1 x 10 ⁷ M, about 0.5 x 10 ⁷ M, about 1 x 10 ⁸ M, or about 0.5 x 10 ⁸ M (inclusive); about 0.5 x 10 ⁸ M to about 1 x 10 ⁵ M, about 0.5 x 10 ⁵ M, about 1 x 10 ⁶ M, about 0.5 x 10 ⁶ M, about 1 x 10 ⁷ M, about 0.5 x 10 ⁷ M, or about 1 x 10 ⁸ M (inclusive); about 1 x 10 ⁸ M to about 1 x 10 ⁵ M, about 0.5 x 10 ⁵ M, about 1 x 10 ⁶ M, about 0.5 x 10 ⁶ M, about 1 x 10 ⁷ M, or about 0.5 x 10 ⁷ M (inclusive); about 0.5 x 10 ⁷ Mto about 1 x 10 ⁵ M, about 0.5 x 10 ⁵ M, about 1 x 10 ⁶ M, about 0.5 x 10 ⁶ M, or about 1 x 1 O ⁷ M (inclusive); about 1 x 10 ⁷ Mto about 1 x 10 ⁵ M, about 0.5 x 10 ⁵ M, about 1 x 10 ⁶ M, or about 0.5 x 10 ⁶ M (inclusive); about 0.5 x 10 ⁶ M to about 1 x 10 ⁵ M, about 0.5 x 10 ⁵ M, or about 1 x 10 ⁶ M (inclusive); about 1 x 10 ⁶ M to about 1 x 10 ⁵ M or about 0.5 x 10 ⁵ M (inclusive); or about 0.5 x 10 ⁵ M to about 1 x 10 ⁵ M (inclusive), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).

In some embodiments, any of the antibodies or antigen-binding fragments described herein has a K _0ff of about 1 x 10 ⁶ s ¹ to about 1 x 10 ³ s ¹ , about 0.5 x 10 ³ s ¹ , about 1 x 10 ⁴ s ¹ , about 0.5 x 10 ⁴ s ¹ , about 1 x 10 ⁵ s ¹ , or about 0.5 x 10 ⁵ s ¹ (inclusive); about 0.5 x 10 ⁵ s ¹ to about 1 x 10 ³ s ¹ , about 0.5 x 10 ³ s ¹ , about 1 x 10 ⁴ s ¹ , about 0.5 x 10 ⁴ s ¹ , or about 1 x 10 ⁵ s ¹ (inclusive); about 1 x 10 ⁵ s ¹ to about 1 x 10 ³ s ¹ , about 0.5 x 10 ³ s ¹ , about 1 x 10 ⁴ s ¹ , or about 0.5 x 10 ⁴ s ¹ (inclusive); about 0.5 x 10 ⁴ s ¹ to about 1 x 10 ³ s ¹ , about 0.5 x 10 ³ s ¹ , or about 1 x 10 ⁴ s ¹ (inclusive); about 1 x 10 ⁴ s ¹ to about 1 x 10 ³ s ¹ , or about 0.5 x 10 ³ s ¹ (inclusive); or about 0.5 x 10 ⁵ s ¹ to about 1 x 10 ³ s ¹ (inclusive), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).

In some embodiments, any of the antibodies or antigen-binding fragments described herein has a K _0n of about 1 x 10 ² MV ¹ to about 1 x l0 ⁶ M ¹ s ¹ , about 0.5 x 10 ⁶ MV ¹ , about 1 x l0 ⁵ M ¹ s ¹ , about 0.5 x 10 ⁵ MV ¹ , about 1 x 10 ⁴ MV ¹ , about 0.5 x 10 ⁴ MV ¹ , about 1 x 10 ³ MV ¹ , or about 0.5 x 10 ³ MV ¹ (inclusive); about 0.5 x 10 ³ MV ¹ to about 1 x l0 ⁶ M ¹ s ¹ , about 0.5 x 10 ⁶ MV ¹ , about 1 x l0 ⁵ M ¹ s ¹ , about 0.5 x 10 ⁵ MV ¹ , about 1 x 10 ⁴ MV ¹ , about 0.5 x 10 ⁴ MV ¹ , or about 1 x 10 ³ MV ¹ (inclusive); about 1 x 10 ³ MV ¹ to about 1 x l0 ⁶ M ¹ s ¹ , about 0.5 x 10 ⁶ MV ¹ , about 1 x l0 ⁵ M ¹ s ¹ , about 0.5 x 10 ⁵ M V ¹ , about 1 x 10 ⁴ M V ¹ , or about 0.5 x 10 ⁴ M V ¹ (inclusive); about 0.5 x 10 ⁴ M Wo about 1 x l0 ⁶ M ¹ s ¹ , about 0.5 x 10 ⁶ M V ¹ , about 1 x l0 ⁵ M ¹ s ¹ , about 0.5 x 10 ⁵ M V ¹ , or about 1 x 10 ⁴ M V ¹ (inclusive); about 1 x 10 ⁴ M V ¹ to about 1 x l0 ⁶ M ¹ s ¹ , about 0.5 x 10 ⁶ M V ¹ , about 1 x l0 ⁵ M ¹ s ¹ , or about 0.5 x 10 ⁵ M V ¹ (inclusive); about 0.5 x 10 ⁵ M V ¹ to about 1 x l0 ⁶ M ¹ s ¹ , about 0.5 x 10 ⁶ M V ¹ , or about 1 x l0 ⁵ M ¹ s ¹ (inclusive); about 1 x l0 ⁵ M ¹ s ¹ to about 1 x l0 ⁶ M ¹ s ¹ , or about 0.5 x 10 ⁶ M V ¹ (inclusive); or about 0.5 x 10 ⁶ M V ¹ to about 1 x l0 ⁶ M ¹ s ¹ (inclusive), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).

Fusion Proteins

In some embodiments, the anti-TNFa agent is a fusion protein (e.g., an extracellular domain of a TNFR fused to a partner peptide, e.g., an Fc region of an immunoglobulin, e.g., human IgG) (see, e.g., Deeg et al., Leukemia 16(2): 162, 2002; Peppel et al., J. Exp. Med. 174(6): 1483-1489, 1991) or a soluble TNFR (e.g., TNFR1 or TNFR2) that binds specifically to TNFa. In some embodiments, the anti-TNFa agent includes or is a soluble TNFa receptor (e.g., Bjornberg et al., Lymphokine Cytokine Res. 13(3):203-211, 1994; Kozak et al., Am. J. Physiol. Reg. Integrative Comparative Physiol. 269(l):R23-R29, 1995; Tsao et al., Eur Respir J. l4(3):490-495, 1999; Watt et al., J Leukoc Biol. 66(6): 1005-1013, 1999; Mohler et al., J. Immunol. 151 (3): 1548- 1561 , 1993; Nophar et al., EMBO J. 9(l0):3269, 1990; Piguet et al., Eur. Respiratory J. 7(3): 515-518, 1994; and Gray et al., Proc. Natl. Acad. Sci. U.S.A. 87(l9):7380-7384, 1990). In some embodiments, the anti-TNFa agent includes or is etanercept (Enbrel™) (see, e.g., WO 91/03553 and WO 09/406,476, incorporated by reference herein). In some embodiments, the anti-TNFa agent inhibitor includes or is r-TBP-I (e.g., Gradstein et al., J. Acquir. Immune Defic. Syndr. 26(2): 111-117, 2001).

Inhibitory Nucleic Acids

Inhibitory nucleic acids that can decrease the expression of AP-l, ASK1, CD 14, c-jun, ERK1/2, IKB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA expression in a mammalian cell include antisense nucleic acid molecules, i.e., nucleic acid molecules whose nucleotide sequence is complementary to all or part of a AP-l, ASK1, CD14, c-jun, ERK1/2, IKB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA (e.g., complementary to all or a part of any one of SEQ ID NOs: 36-72).

The sequences characterized by the Sequences ID NO: 36 - 72 are listed below and are being submitted in a separate and machine readable file.

Human TNFa CDS (SEQ ID NO: 36), Human TNFR1 CDS (SEQ ID NO: 37), Human TNFR2 CDS (SEQ ID NO: 38), Human TRADD CDS (SEQ ID NO: 39), Human TRAF2 CDS (SEQ ID NO: 40), Human AP-l CDS (SEQ ID NO: 41), Human ASK1 CDS (SEQ ID NO: 42), Human CD14 CDS (SEQ ID NO: 43), Human ERK1 CDS (SEQ ID NO: 44), Human ERK2 CDS (SEQ ID NO: 45), Human IKK CDS (SEQ ID NO: 46), Human IKB CDS (SEQ ID NO: 47), Human IRAK CDS (SEQ ID NO: 48), Human JNK CDS (SEQ ID NO: 49), Human LBP CDS (SEQ ID NO: 50), Human MEK1 CDS (SEQ ID NO: 51), Human MEK2 CDS (SEQ ID NO: 52), Human MEK3 CDS (SEQ ID NO: 53), Human MEK6 CDS (SEQ ID NO: 54), Human MEKK1 CDS (SEQ ID NO: 55), Human MEKK 3 CDS (SEQ ID NO: 56), Human MEKK4 CDS (SEQ ID NO: 57), Human MEKK 6 CDS (SEQ ID NO: 58), Human MEKK7 CDS (SEQ ID NO: 59), Human MK2 CDS (SEQ ID NO: 60), Human MyD88 CDS (SEQ ID NO: 61), Human NF-kB CDS (SEQ ID NO: 62), Human NIK CDS (SEQ ID NO: 63), Human p38 CDS (SEQ ID NO: 64), Human PKR CDS (SEQ ID NO: 65), Human Rac CDS (SEQ ID NO: 66), Human Raf CDS (SEQ ID NO: 67), Human K-Ras CDS (SEQ ID NO: 68), Human N-Ras CDS (SEQ ID NO: 69), Human RIP CDS (SEQ ID NO: 70), Human TRAF6 CDS (SEQ ID NO: 71), and Human TTP CDS (SEQ ID NO: 72). An antisense nucleic acid molecule can be complementary to all or part of a non-coding region of the coding strand of a nucleotide sequence encoding an AP-l, ASK1, CD14, c-jun, ERK1/2, IKB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-KB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTPMEKK1 protein. Non-coding regions (5' and 3' untranslated regions) are the 5' and 3' sequences that flank the coding region in a gene and are not translated into amino acids.

Based upon the sequences disclosed herein, one of skill in the art can easily choose and synthesize any of a number of appropriate antisense nucleic acids to target a nucleic acid encoding an AP-l, ASK1, CD14, c-jun, ERK1/2, IKB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein described herein. Antisense nucleic acids targeting a nucleic acid encoding an AP-l, ASK1, CD 14, c-jun, ERK1/2, IKB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-KB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTPMEKK1 protein can be designed using the software available at the Integrated DNA Technologies website.

An antisense nucleic acid can be, for example, about 5, 10, 15, 18, 20, 22, 24, 25, 26, 28, 30, 32, 35, 36, 38, 40, 42, 44, 45, 46, 48, or 50 nucleotides or more in length. An antisense oligonucleotide can be constructed using enzymatic ligation reactions and chemical synthesis using procedures known in the art. For example, an antisense nucleic acid can be chemically synthesized using variously modified nucleotides or naturally occurring nucleotides designed to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides or to increase the biological stability of the molecules.

Examples of modified nucleotides which can be used to generate an antisense nucleic acid include l-methylguanine, l-methylinosine, 2,2-dimethylguanine, 2- methyladenine, 2-methylguanine, 3-methylcytosine, 2-methylthio-N6- isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2- thiocytosine, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5- carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 5- methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5- methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5'- methoxycarboxymethyluracil, 5-methoxyuracil, 5-methyl-2-thiouracil, 2-thiouracil, 4- thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6- diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest).

The antisense nucleic acid molecules described herein can be prepared in vitro and administered to a subject, e.g., a human subject. Alternatively, they can be generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding an AP-l, ASK1, CD14, c-jun, ERK1/2, IKB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein to thereby inhibit expression, e.g., by inhibiting transcription and/or translation. The hybridization can be by conventional nucleotide complementarities to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix.

The antisense nucleic acid molecules can be delivered to a mammalian cell using a vector (e.g., an adenovirus vector, a lentivirus, or a retrovirus).

An antisense nucleic acid can be an a-anomeric nucleic acid molecule. An a- anomeric nucleic acid molecule forms specific double-stranded hybrids with

complementary RNA in which, contrary to the usual, b-units, the strands run parallel to each other (Gaultier et al., Nucleic Acids Res. 15:6625-6641, 1987). The antisense nucleic acid can also comprise a chimeric RNA-DNA analog (Inoue et al., FEBS Lett. 215:327-330, 1987) or a 2'-0-methylribonucleotide (Inoue et al., Nucleic Acids Res. 15:6131-6148, 1987).

Another example of an inhibitory nucleic acid is a ribozyme that has specificity for a nucleic acid encoding an AP-l, ASK1, CD14, c-jun, ERK1/2, IKB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-KB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA, e.g., specificity for any one of SEQ ID NOs: 36-72). Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single- stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes (described in Haselhoff and Gerlach, Nature 334:585-591, 1988)) can be used to catalytically cleave mRNA transcripts to thereby inhibit translation of the protein encoded by the mRNA. An AP-l, ASK1, CD 14, c-jun, ERK1/2, IKB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al., Science 261 : 1411-1418, 1993.

Alternatively, a ribozyme having specificity for an AP-l, ASK1, CD 14, c-jun, ERK1/2, IKB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA can be designed based upon the nucleotide sequence of any of the AP-l, ASK1, CD14, c-jun, ERK1/2, IKB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK 1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA sequences disclosed herein. For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in an AP-l, ASK1, CD 14, c-jun, ERK1/2, IKB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA (see, e.g., U.S. Patent. Nos. 4,987,071 and 5,116,742).

An inhibitory nucleic acid can also be a nucleic acid molecule that forms triple helical structures. For example, expression of an AP-l, ASK1, CD14, c-jun, ERK1/2, IKB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP polypeptide can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the gene encoding the AP-l, ASK1, CD 14, c-jun, ERK1/2, IKB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-kB, NIK, p38, PKR, rac, ras, raf, RIP, TNFa, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP polypeptide (e g., the promoter and/or enhancer, e.g., a sequence that is at least 1 kb, 2 kb, 3 kb, 4 kb, or 5 kb upstream of the transcription initiation start state) to form triple helical structures that prevent transcription of the gene in target cells. See generally Maher, Bioassays 14(12):807-15, 1992; Helene, Anticancer Drug Des. 6(6):569-84, 1991; and Helene, Ann. N.Y. Acad. Sci. 660:27-36, 1992.

In various embodiments, inhibitory nucleic acids can be modified at the sugar moiety, the base moiety, or phosphate backbone to improve, e.g., the solubility, stability, or hybridization, of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see, e.g., Hyrup et ah, Bioorganic Medicinal Chem. 4(l):5-23, 1996). Peptide nucleic acids (PNAs) are nucleic acid mimics, e.g., DNA mimics, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs allows for specific hybridization to RNA and DNA under conditions of low ionic strength. PNA oligomers can be synthesized using standard solid phase peptide synthesis protocols (see, e.g., Perry-O'Keefe et ah, Proc. Natl. Acad. Sci. U.S.A. 93:14670-675, 1996). PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication.

Small Molecules

In some embodiments, the anti-TNFa agent is a small molecule. In some embodiments, the small molecule is a tumor necrosis factor-converting enzyme (TACE) inhibitor (e.g., Moss et ah, Nature Clinical Practice Rheumatology 4: 300-309, 2008). In some embodiments, the anti-TNFa agent is C87 (Ma et ah, J. Biol. Chem. 289(18): 12457-66, 2014). In some embodiments, the small molecule is LMP-420 (e.g., Haraguchi et al., AIDS Res. Ther. 3:8, 2006). In some embodiments, the TACE inhibitor is TMI-005 and BMS-561392. Additional examples of small molecule inhibitors are described in, e.g., He et al., Science 310(5750): 1022-1025, 2005.

In some examples, the anti-TNFa agent is a small molecule that inhibits the activity of one of AP-l, ASK1, IKK, JNK, MAPK, MEKK 1/4, MEKK4/7, MEKK 3/6, NIK, TRADD, RIP, NF-kB, and TRADD in a cell (e.g., in a cell obtained from a subject, a mammalian cell).

In some examples, the anti-TNFa agent is a small molecule that inhibits the activity of one of CD14, MyD88 (see, e.g., Olson et al., Scientific Reports 5: 14246,

2015), ras (e.g., Baker et al., Nature 497:577-578, 2013), raf (e.g., vemurafenib

(PLX4032, RG7204), sorafenib tosylate, PLX-4720, dabrafenib (GSK2118436), GDC- 0879, RAF265 (CHIR-265), AZ 628, NVP-BHG712, SB590885, ZM 336372, sorafenib, GW5074, TAK-632, CEP-32496, encorafenib (LGX818), CCT196969, LY3009120,

R05126766 (CH5126766), PLX7904, and MLN2480).

In some examples, the anti-TNFa agent TNFa inhibitor is a small molecule that inhibits the activity of one of MK2 (PF 3644022 and PHA 767491), JNK (e.g., AEG 3482, BI 78D3, CEP 1347, c-JUN peptide, IQ 1S, JIP-1 (153-163), SP600125, SU 3327, and TCS JNK6o), c-jun (e.g., AEG 3482, BI 78D3, CEP 1347, c-JUN peptide, IQ 1S, JIP-1 (153-163), SP600125, SU 3327, and TCS JNK6o), MEK3/6 (e.g., Akinleye et al.,

J. Hematol. Oncol. 6:27, 2013), p38 (e.g., AL 8697, AMG 548, BIRB 796, CMPD-l, DBM 1285 dihydrochloride, EO 1428, JX 401, ML 3403, Org 48762-0, PH 797804,

RWJ 67657, SB 202190, SB 203580, SB 239063, SB 706504, SCIO 469, SKF 86002,

SX 011, TA 01, TA 02, TAK 715, VX 702, and VX 745), PKR (e.g., 2-aminopurine or CAS 608512-97-6), TTP (e.g., CAS 329907-28-0), MEK1/2 (e.g., Facciorusso et al., Expert Review Gastroentrol. Hepatol. 9:993-1003, 2015), ERK1/2 (e.g., Mandal et al., Oncogene 35:2547-2561, 2016), NIK (e.g., Mortier et al., Bioorg. Med. Chem. Lett.

20:4515-4520, 2010), IKK (e.g., Reilly et al., Nature Med. 19:313-321, 2013), IKB (e.g., Suzuki et al., Expert. Opin. Invest. Drugs 20:395-405, 2011), NF-kB (e.g., Gupta et al., Biochim. Biophys. Acta 1799(10-12):775-787, 2010), rac (e.g., U.S. Patent No. 9,278,956), MEK4/7, IRAK (Chaudhary et al., J Med. Chem. 58(l):96-l 10, 2015), LBP (see, e.g., U.S. Patent No. 5,705,398), and TRAF6 (e.g., 3-[(2,5-Dimethylphenyl)amino]- 1 -phenyl-2-propen- 1 -one).

In some embodiments of any of the methods described herein, the inhibitory nucleic acid can be about 10 nucleotides to about 50 nucleotides (e.g., about 10 nucleotides to about 45 nucleotides, about 10 nucleotides to about 40 nucleotides, about 10 nucleotides to about 35 nucleotides, about 10 nucleotides to about 30 nucleotides, about 10 nucleotides to about 28 nucleotides, about 10 nucleotides to about 26

nucleotides, about 10 nucleotides to about 25 nucleotides, about 10 nucleotides to about 24 nucleotides, about 10 nucleotides to about 22 nucleotides, about 10 nucleotides to about 20 nucleotides, about 10 nucleotides to about 18 nucleotides, about 10 nucleotides to about 16 nucleotides, about 10 nucleotides to about 14 nucleotides, about 10 nucleotides to about 12 nucleotides, about 12 nucleotides to about 50 nucleotides, about 12 nucleotides to about 45 nucleotides, about 12 nucleotides to about 40 nucleotides, about 12 nucleotides to about 35 nucleotides, about 12 nucleotides to about 30

nucleotides, about 12 nucleotides to about 28 nucleotides, about 12 nucleotides to about 26 nucleotides, about 12 nucleotides to about 25 nucleotides, about 12 nucleotides to about 24 nucleotides, about 12 nucleotides to about 22 nucleotides, about 12 nucleotides to about 20 nucleotides, about 12 nucleotides to about 18 nucleotides, about 12 nucleotides to about 16 nucleotides, about 12 nucleotides to about 14 nucleotides, about 15 nucleotides to about 50 nucleotides, about l5nucleotides to about 45 nucleotides, about l5nucleotides to about 40 nucleotides, about l5nucleotides to about 35 nucleotides, about 15 nucleotides to about 30 nucleotides, about l5nucleotides to about 28

nucleotides, about l5nucleotides to about 26 nucleotides, about l5nucleotides to about 25 nucleotides, about l5nucleotides to about 24 nucleotides, about l5nucleotides to about 22 nucleotides, about l5nucleotides to about 20 nucleotides, about l5nucleotides to about 18 nucleotides, about l5nucleotides to about 16 nucleotides, about 16 nucleotides to about 50 nucleotides, about 16 nucleotides to about 45 nucleotides, about 16 nucleotides to about 40 nucleotides, about 16 nucleotides to about 35 nucleotides, about 16 nucleotides to about 30 nucleotides, about 16 nucleotides to about 28 nucleotides, about 16 nucleotides to about 26 nucleotides, about 16 nucleotides to about 25 nucleotides, about 16 nucleotides to about 24 nucleotides, about 16 nucleotides to about 22 nucleotides, about 16 nucleotides to about 20 nucleotides, about 16 nucleotides to about 18 nucleotides, about 18 nucleotides to about 20 nucleotides, about 20 nucleotides to about 50 nucleotides, about 20 nucleotides to about 45 nucleotides, about 20 nucleotides to about 40 nucleotides, about 20 nucleotides to about 35 nucleotides, about 20 nucleotides to about 30 nucleotides, about 20 nucleotides to about 28 nucleotides, about 20 nucleotides to about 26 nucleotides, about 20 nucleotides to about 25 nucleotides, about 20 nucleotides to about 24 nucleotides, about 20 nucleotides to about 22 nucleotides, about 24 nucleotides to about 50 nucleotides, about 24 nucleotides to about 45 nucleotides, about 24 nucleotides to about 40 nucleotides, about 24 nucleotides to about 35 nucleotides, about 24 nucleotides to about 30 nucleotides, about 24 nucleotides to about 28 nucleotides, about 24 nucleotides to about 26 nucleotides, about 24 nucleotides to about 25 nucleotides, about 26 nucleotides to about 50 nucleotides, about 26 nucleotides to about 45 nucleotides, about 26 nucleotides to about 40 nucleotides, about 26 nucleotides to about 35 nucleotides, about 26 nucleotides to about 30 nucleotides, about 26 nucleotides to about 28 nucleotides, about 28 nucleotides to about 50 nucleotides, about 28 nucleotides to about 45 nucleotides, about 28 nucleotides to about 40 nucleotides, about 28 nucleotides to about 35 nucleotides, about 28 nucleotides to about 30 nucleotides, about 30 nucleotides to about 50 nucleotides, about 30 nucleotides to about 45 nucleotides, about 30 nucleotides to about 40 nucleotides, about 30 nucleotides to about 38 nucleotides, about 30 nucleotides to about 36 nucleotides, about 30 nucleotides to about 34 nucleotides, about 30 nucleotides to about 32 nucleotides, about 32 nucleotides to about 50 nucleotides, about 32 nucleotides to about 45 nucleotides, about 32 nucleotides to about 40 nucleotides, about 32 nucleotides to about 35 nucleotides, about 35 nucleotides to about 50 nucleotides, about 35 nucleotides to about 45 nucleotides, about 35 nucleotides to about 40 nucleotides, about 40 nucleotides to about 50 nucleotides, about 40 nucleotides to about 45 nucleotides, about 42 nucleotides to about 50 nucleotides, about 42 nucleotides to about 45 nucleotides, or about 45 nucleotides to about 50 nucleotides) in length. One skilled in the art will appreciate that inhibitory nucleic acids may comprises at least one modified nucleic acid at either the 5’ or 3’ end of DNA or RNA.

In some embodiments, the inhibitory nucleic acid can be formulated in a liposome, a micelle (e.g., a mixed micelle), a nanoemulsion, or a microemulsion, a solid nanoparticle, or a nanoparticle (e.g., a nanoparticle including one or more synthetic polymers). Additional exemplary structural features of inhibitory nucleic acids and formulations of inhibitory nucleic acids are described in US 2016/0090598.

In some embodiments, the inhibitory nucleic acid (e.g., any of the inhibitory nucleic acid described herein) can include a sterile saline solution (e.g., phosphate- buffered saline (PBS)). In some embodiments, the inhibitory nucleic acid (e.g., any of the inhibitory nucleic acid described herein) can include a tissue-specific delivery molecule (e.g., a tissue-specific antibody). Indications

In some embodiments, methods for treating a subject having condition, disease or disorder in which a decrease or increase in NLRP3 activity (e.g., an increase, e.g.,

NLRP3 signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder are provided, comprising administering to a subject an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same). In some embodiments of any of the methods described herein, the subject can have, or be diagnosed or identified as having, an inflammatory disease or an anutoimmune disease. In some embodiments, the inflammatory disease or autoimmune disease. In some embodiments of any of the methods described herein, the subject can have, or be identified or diagnosed as having, any of the conditions, diseases, or disorders in which a decrease or increase in NLRP3 activity contributes to the pathology and/or symptoms and/or progression of the condition, disease, or disorder. In some embodiments of any of the methods described herein, the subject can be suspected of having or present with one or more symptoms of any of the conditions, diseases, or disorders described herein.

In some embodiments of any of the methods described herein, the subject can have, or be diagnosed or identified as having, an inflammatory disease or an

anutoimmune disease. In some embodiments, the condition, disease or disorder is selected from: inappropriate host responses to infectious diseases where active infection exists at any body site, such as septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome; acute or chronic inflammation due to antigen, antibody and/or complement deposition; inflammatory conditions including arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury and vasculitis, immune-based diseases such as acute and delayed hypersensitivity, graft rejection, and graft-versus-host disease; auto- immune diseases including Type 1 diabetes mellitus and multiple sclerosis. For example, the condition, disease or disorder may be an inflammatory disorder such as rheumatoid arthritis, osteoarthritis, septic shock, COPD and periodontal disease.

In some embodiments, the condition, disease or disorder is an autoimmune diseases. Non-limiting examples include rheumatoid arthritis, systemic lupus

erythematosus, multiple sclerosis, inflammatory bowel diseases (IBDs) comprising Crohn disease (CD) and ulcerative colitis (UC), which are chronic inflammatory conditions with polygenic susceptibility. In certain embodiments, the condition is an inflammatory bowel disease. In certain embodiments, the condition is Crohn’s disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by treatment with adoptive cell therapy, colitis associated by one or more alloimmune diseases (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In certain of these embodiments, the condition is alloimmune disease (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), celiac disease,

inflammatory bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (e.g., oral mucositis, esophageal mucositis or intestinal mucositis).

In some embodiments, the condition, disease or disorder is selected from major adverse cardiovascular events such as carbiovascular death, non-fatal myocardial infarction and non-fatal stroke in patients with a prior heart attack and inflammatory atherosclerosis (see for example, NCT01327846).

In some embodiments, the condition, disease or disorder is selected from metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout, as well as diseases of the central nervous system, such as Alzheimer’s disease and multiple sclerosis and Amyotrophic Lateral Sclerosis and Parkinson disease, lung disease, such as asthma and COPD and pulmonary idiopathic fibrosis, liver disease, such as NASH syndrome, viral hepatitis and cirrhosis, pancreatic disease, such as acute and chronic pancreatitis, kidney disease, such as acute and chronic kidney injury, intestinal disease such as Crohn’s disease and Ulcerative Colitis, skin disease such as psoriasis, musculoskeletal disease such as scleroderma, vessel disorders, such as giant cell arteritis, disorders of the bones, such as Osteoarthritis, osteoporosis and osteopetrosis disorders eye disease, such as glaucoma and macular degeneration, diseased caused by viral infection such as HIV and AIDS, autoimmune disease such as Rheumatoid Arthritis, Systemic Lupus

Erythematosus, Autoimmune Thyroiditis, Addison's disease, pernicious anemia, cancer and aging.

In some embodiments, the condition, disease or disorder is a cardiovascular indication. In some embodiments, the condition, disease or disorder is myocardial infraction. In some embodiments, the condition, disease or disorder is stroke.

In some embodiments, the condition, disease or disorder is obesity.

In some embodiments, the condition, disease or disorder is Type 2 Diabetes.

In some embodiments, the condition, disease or disorder is NASH.

In some embodiments, the condition, disease or disorder is Alzheimer’s disease..

In some embodiments, the condition, disease or disorder is gout.

In some embodiments, the condition, disease or disorder is SLE.

In some embodiments, the condition, disease or disorder is rheumatoid arthritis. In some embodiments, the condition, disease or disorder is IBD.

In some embodiments, the condition, disease or disorder is multiple sclerosis..

In some embodiments, the condition, disease or disorder is COPD.

In some embodiments, the condition, disease or disorder is asthma.

In some embodiments, the condition, disease or disorder is scleroderma.

In some embodiments, the condition, disease or disorder is pulmonary fibrosis.

In some embodiments, the condition, disease or disorder is age related macular degeneration (AMD).

In some embodiments, the condition, disease or disorder is cystic fibrosis. In some embodiments, the condition, disease or disorder is Muckle Wells syndrome.

In some embodiments, the condition, disease or disorder is familial cold autoinflammatory syndrome (FCAS).

In some embodiments, the condition, disease or disorder is chronic neurologic cutaneous and articular syndrome.

In some embodiments, the condition, disease or disorder is selected from: myelodysplastic syndromes (MDS); non-small cell lung cancer, such as non-small cell lung cancer in patients carrying mutation or overexpression of NLRP3; acute lymphoblastic leukemia (ALL), such as ALL in patients resistant to glucocorticoids treatment; Langerhan’s cell histiocytosis (LCH); multiple myeloma; promyelocytic leukemia; acute myeloid leukemia (AML) chronic myeloid leukemia (CML); gastric cancer; and lung cancer metastasis.

In some embodiments, the condition, disease or disorder is selected from: myelodysplastic syndromes (MDS); non-small cell lung cancer, such as non-small cell lung cancer in patients carrying mutation or overexpression of NLRP3; acute lymphoblastic leukemia (ALL), such as ALL in patients resistant to glucocorticoids treatment; Langerhan’s cell histiocytosis (LCH); multiple myeloma; promyelocytic leukemia; gastric cancer; and lung cancer metastasis.

In some embodiments, the condition, disease or disorder is MDS. In some embodiments, the condition, disease or disorder is non-small lung cancer in patients carrying mutation or overexpression of NLRP3.

In some embodiments, the condition, disease or disorder is ALL in patients resistant to glucocorticoids treatment.

In some embodiments, the condition, disease or disorder is LCH.

In some embodiments, the condition, disease or disorder is multiple myeloma.

In some embodiments, the condition, disease or disorder is promyelocytic leukemia.

In some embodiments, the condition, disease or disorder is gastric cancer.

In some embodiments, the condition, disease or disorder is lung cancer metastasis.

In some embodiments of any of the methods described herein, the subject has or is suspected of having Crohn’s disease, inflammatory bowel disease (IBD), or other gastrointestinal, autoimmune, or autoinflammatory disorders.

In some embodiments of any of the methods described herein, the subject has or is suspected of having hereditary periodic fever.

In some embodiments of any of the methods described herein, the subject has or is suspected of having Muckle-Wells syndrome (MWS).

In some embodiments of any of the methods described herein, the subject has or is suspected of having Cinca syndrome.

In some embodiments of any of the methods described herein, the subject has or is suspected of having deafness with or without inflammation.

In some embodiments of any of the methods described herein, the subject has or is suspected of having keratoendotheliitis fugax hereditaria.

In some embodiments of any of the methods described herein, the subject has or is suspected of having an inappropriate host response to infectious diseases where active infection exists at any body site. In some embodiments, the inappropriate host response to infectious disease where active infection exists at any body site is selected from the group consisting of: septic shock, disseminated intravascular coagulation, and adult respiratory distress syndrome. In some embodiments of any of the methods described herein, the subject has or is suspected of having acute or chronic inflammation due to antigen, antibody, and/or complement deposition.

In some embodiments of any of the methods described herein, the subject has or is suspected of having an inflammatory disease or condition. In some embodiments, the inflammatory disease or condition is selected from the group consisting of: arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury, vasculitis, osteoarthritis, COPD, periodontal disease, uveitis, cutaneous T-cell lymphoma, and mucositis such as oral mucositis, esophageal mucositis, and intestinal mucositis.

In some embodiments of any of the methods described herein, the inflammatory or autoimmune disorder is selected from the group consisting of: sickle cell disease, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, ulcerative colitis, Crohn’s disease, inflammatory bowel disease, Behcet’s disease, Takayasu’s arteritis, atherosclerosis, gout, psoriasis, an infectious disease, asthma, peptic ulcer, periodontitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, systemic lupus erythematosus, nephritis, appendicitis, bursitis, cystitis, encephalitis, gingivitis, meningitis, myelitis, neuritis, pharyngitis, phlebitis, prostatitis, rhinitis, sinusitis, tendonitis, testiculitis, tonsillitis, urethritis, vasculitis, vaginitis, Celiac disease, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivities, interstitial cystitis, Lichen planus, mast cell activation syndrome, mastocystosis, otitis, pelvic inflammatory disease, reperfusion injury, rheumatic fever, rhinitis, sarcoidosis, graft versus host disease, vasculitis, allergy, cancer, HIV, AIDS, scleroderma, Sjogren’s syndrome, anti-phospholipid antibody syndrome, myocarditis, postmyocardial infarction syndrome, postpericardiotomy syndrome, subacute bacterial endocarditis, anti-glomerular basement membrane nephritis, interstitial cystitis, lupus nephritis, autoimmune nephritis, autoimmune hepatitis, autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, primary schlerosing cholangitis, anti synthetase syndrome, alopecia areata, autoimmune angioedema, autoimmune progesterone dermatitis, autoimmune urticaria, bullous pemphigoid, cicatricial pemphigoid, dermatitis herpetiformis, discoid lupus erythematosus, epidermolysis bullosa acquisita, erythema nodosum, gestational pemphigoid, Lichen sclerosus, linear IgA disease, morphea, pemphigus vulgaris, pityriasis lichenoides et varioliforms acuta, Mucha-Habermann disease, psoriasis, systemic scleroderma, vitiligo, Addison’s disease, autoimmune poly endocrine syndrome type 1, 2, or 3, autoimmune pancreatitis, diabetes mellitus type 1, autoimmune thyroiditis, Ord’s thyroiditis, Graves’ disease, autoimmune oophoritis, endometriosis, autoimmune orchitis, Sjogren’s syndrome, autoimmune enteropathy, microscopic colitis,

antiphospholipid syndrome, aplastic anemia, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune neutropenia, autoimmune thrombocytopenic purpura, cold agglutinin disease, essential mixed cyroglobulinemia, Evans syndrome, pernicious anemia, pure red cell aplasia, thrombocytopenia, adiposis dolorosa, adult- onset Still’s disease, ankylosing spondylitis, CREST syndrome, drug-induced lupus, enthesitis-related arthritis, eosinophilic fasciitis, Felty syndrome, IgG4-related disease, juvenile arthritis, Lyme disease, mixed connective tissue disease (MCTD), palindromic rheumatism, Parry Romberg syndrome, Parsonage-Turner syndrome, psoriatic arthritis, reactive arthritis, relapsing polychondritis, retroperitoneal fibrosis, rheumatic fever, sarcoidosis, Schnitzler syndrome, undifferentiated connective tissue disease,

dermatomyositis, fibromyalgia, inclusion body myositis, myasthenia gravis,

neuromyotonia, paraneoplastic cerebellar degeneration, polymyositis, acute disseminated encephalomyelitis, acute motor axonal neuropathy, anti-N-methyl-D-aspartate receptor encephalitis, Balo concentric sclerosis, Bickerstaff s encephalitis, chronic infllamatory demyelinating polyneuropathy, Guillain-Barre syndrome, Hashimoto’s encephalopathy, idiopathic inflammatory demyelinating disease, Lambert-Eaton myasthenic syndrome, multiple sclerosis, Oshtoran syndrome, pediatric autoimmune neuropsychiatric disorder associated with Streptococcus, progressive inflammatory neuropathy, restless leg syndrome, Stiff person syndrome, Sydenham chorea, transverse myelitis, autoimmune retinopathy, autoimmune uveitis, Cogan syndrome, Graves ophthalmopathy, intermediate uveitis, ligneous conjunctivitis, Mooren’s ulcer, neuromyelitis optica, Opsoclonus myoclonus syndrome, optic neuritis, scleritis, Susac’s syndrome, sympathetic

ophthalmia, Tolosa-Hunt syndrome, autoimmune inner ear disease, Meniere’s disease, Behcet’s disease, eosinophilic graunulomatosis with polyangiitis, giant cell arteritis, graunulomatosis with polyangiitis, IgA vasculitis, Kawasaki’s disease, leukocytoclastic vasculitis, lupus vasculitis, microscopic polyangiitis, polyarteritis nodosa, polymyalgia rheumatica, urticarial vasculitis, vasculitis, primary immune deficiency, chronic fatigue syndrome, complex regional pain syndrome, eosinophilic esophagitis, gastritis, interstitial lung disease, POEMS syndrome, Raynaud’s phenomenon, primary immunodeficiency, and pyoderma gangrenosum.

In some embodiments of any of the methods described herein, the subject has or is suspected of having acute and delayed hypersensitivity, graft rejection, or graft-versus- host disease (GVHD).

In some embodiments of any of the methods described herein, the subject has or is suspected of having an autoimmune disease selected from the group consisting of:

Type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus,

autoimmune thyroiditis, Addison’s disease, pernicious anemia, multiple sclerosis, an inflammatory bowel disease (IBD), scleroderma, and psoriasis. In some embodiments, the IBD is selected from the group consisting of: Crohn’s disease, ulcerative colitis, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by treatment with adoptive cell therapy, colitis associated with one or more alloimmune diseases such as GVHD, radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis, celiac disease, and inflammatory bowel syndrome.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a metabolic disorder. In some embodiments, the metabolic disorder selected from the group consisting of type 2 diabetes, atherosclerosis, obesity, gout, and pseudogout.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a disease of the central nervous system. In some embodiments, the disease of the central nervous system is selected from the group consisting of:

Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson’s disease. In some embodiments of any of the methods described herein, the subject has or is suspected of having a lung disease. In some embodiments, the lung disease is asthma, COPD, pulmonary idiopathic fibrosis, or cystic fibrosis.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a liver disease. In some embodiments, the liver disease is selected from the group consisting of: NASH syndrome, viral hepatitis, and cirrhosis.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a pancreatic disease, such as acute or chronic pancreatitis.

In some embodiments of any of the methods described herein, the subject has or is suspected of having kidney disease, such as acute or chronic kidney injury.

In some embodiments of any of the methods described herein, the subject has or is suspected of having an intestinal disease, such as Crohn’s disease or ulcerative colitis.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a skin disease, such as psoriasis.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a musculoskeletal disease, such as scleroderma.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a vessel disorder, such as giant cell arteritis.

In some embodiments of any of the methods described herein, the subject has a bone disorder, such as osteoarthritis, osteoporosis, and osteopetrosis disorders.

In some embodiments of any of the methods described herein, the subject has or is suspected of having an eye disease, such as glaucoma or macular degeneration, such as age-related macular degeneration.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a disease caused by viral infection, such as HIV or AIDS.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a cancer, such as non-small cell lung cancer, acute lymphoblastic leukemia (ALL) (ALL in patients resistant to glucocorticoid treatment), multiple myeloma, promyelocytic leukemia, gastric cancer, and lung cancer metastasis. In some embodiments of any of the methods described herein, the subject has or is suspected of having a cardiovascular disease. In some embodiments, the

cardiovascular disease is myocardial infarction, stroke, or heart failure.

In some embodiments of any of the methods described herein, the subject has or is suspected of having Crohn’s disease, inflammatory bowel disease (IBD), or other gastrointestinal, autoimmune, or autoinflammatory disorders.

In some embodiments of any of the methods described herein, the subject has or is suspected of having hereditary periodic fever.

In some embodiments of any of the methods described herein, the subject has or is suspected of having Muckle-Wells syndrome (MWS).

In some embodiments of any of the methods described herein, the subject has or is suspected of having Cinca syndrome.

In some embodiments of any of the methods described herein, the subject has or is suspected of having deafness with or without inflammation.

In some embodiments of any of the methods described herein, the subject has or is suspected of having keratoendotheliitis fugax hereditaria.

In some embodiments of any of the methods described herein, the subject has or is suspected of having an inappropriate host response to infectious diseases where active infection exists at any body site. In some embodiments, the inappropriate host response to infectious disease where active infection exists at any body site is selected from the group consisting of: septic shock, disseminated intravascular coagulation, and adult respiratory distress syndrome.

In some embodiments of any of the methods described herein, the subject has or is suspected of having acute or chronic inflammation due to antigen, antibody, and/or complement deposition.

In some embodiments of any of the methods described herein, the subject has or is suspected of having an inflammatory disease or condition. In some embodiments, the inflammatory disease or condition is selected from the group consisting of: arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury, vasculitis, osteoarthritis, COPD, periodontal disease, uveitis, cutaneous T-cell lymphoma, and mucositis such as oral mucositis, esophageal mucositis, and intestinal mucositis.

In some embodiments of any of the methods described herein, the subject has or is suspected of having acute and delayed hypersensitivity, graft rejection, or graft-versus- host disease (GVHD).

In some embodiments of any of the methods described herein, the subject has or is suspected of having an autoimmune disease selected from the group consisting of:

Type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus,

autoimmune thyroiditis, Addison’s disease, pernicious anemia, multiple sclerosis, an inflammatory bowel disease (IBD), scleroderma, and psoriasis. In some embodiments, the IBD is selected from the group consisting of: Crohn’s disease, ulcerative colitis, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by treatment with adoptive cell therapy, colitis associated with one or more alloimmune diseases such as GVHD, radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis, celiac disease, and inflammatory bowel syndrome.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a metabolic disorder. In some embodiments, the metabolic disorder selected from the group consisting of type 2 diabetes, atherosclerosis, obesity, gout, and pseudogout.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a disease of the central nervous system. In some embodiments, the disease of the central nervous system is selected from the group consisting of:

Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson’s disease.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a lung disease. In some embodiments, the lung disease is asthma, COPD, pulmonary idiopathic fibrosis, or cystic fibrosis. In some embodiments of any of the methods described herein, the subject has or is suspected of having a liver disease. In some embodiments, the liver disease is selected from the group consisting of: NASH syndrome, viral hepatitis, and cirrhosis.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a pancreatic disease, such as acute or chronic pancreatitis.

In some embodiments of any of the methods described herein, the subject has or is suspected of having kidney disease, such as acute or chronic kidney injury.

In some embodiments of any of the methods described herein, the subject has or is suspected of having an intestinal disease, such as Crohn’s disease or ulcerative colitis.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a skin disease, such as psoriasis.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a musculoskeletal disease, such as scleroderma.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a vessel disorder, such as giant cell arteritis.

In some embodiments of any of the methods described herein, the subject has a bone disorder, such as osteoarthritis, osteoporosis, and osteopetrosis disorders.

In some embodiments of any of the methods described herein, the subject has or is suspected of having an eye disease, such as glaucoma or macular degeneration, such as age-related macular degeneration.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a disease caused by viral infection, such as HIV or AIDS.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a cancer, such as non-small cell lung cancer, acute lymphoblastic leukemia (ALL) (ALL in patients resistant to glucocorticoid treatment), multiple myeloma, promyelocytic leukemia, gastric cancer, and lung cancer metastasis.

In some embodiments of any of the methods described herein, the subject has or is suspected of having a cardiovascular disease. In some embodiments, the

cardiovascular disease is myocardial infarction, stroke, or heart failure. In some embodiments of any of the methods described herein, the subject has or is suspected of having: hereditary periodic fever, familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome, myelodysplastic syndrome (MDS), Langerhan’s cell histiocytosis (LCH), neonatal onset multisystem inflammatory disease, Cinca syndrome, deafness with inflammation, deafness without inflammation, keratoendotheliitis fugax hereditaria, silicosis, asbestosis, or chronic neurologic cutaneous and articular syndrome.

In some embodiments of any of the methods described herein, the subject has been exposed to, or is suspected of having been exposed to, a toxic agent selected from the group consisting of: exogenous microbial stimuli, lipopolysaccharide (LPS), lipooligosaccharide, muramyl dipeptide (MDP), nigericin, maitotoxin, asbestos, and silica.

Combination Therapy

This disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

In some embodiments, the methods described herein can further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and/or one or more therapeutic regimens) in combination with administration of the NLRP3 antagonist (e.g., any of the NLRP3 antagonists described herein or known in the art).

In certain embodiments, the second therapeutic agent or regimen is administered to the subject prior to contacting with or administering the NLRP3 antagonist (e.g., about one hour prior, or about 6 hours prior, or about 12 hours prior, or about 24 hours prior, or about 48 hours prior, or about 1 week prior, or about 1 month prior).

In other embodiments, the second therapeutic agent or regimen is administered to the subject at about the same time as contacting with or administering the NLRP3 antagonist. By way of example, the second therapeutic agent or regimen and the NLRP3 antagonist are provided to the subject simultaneously in the same dosage form. As another example, the second therapeutic agent or regimen and the NLRP3 antagonist are provided to the subject concurrently in separate dosage forms.

In still other embodiments, the second therapeutic agent or regimen is administered to the subject after contacting with or administering the NLRP3 antagonist (e.g., about one hour after, or about 6 hours after, or about 12 hours after, or about 24 hours after, or about 48 hours after, or about 1 week after, or about 1 month after).

Patient Selection

In some embodiments, the methods described herein include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related to NLRP3 polymorphism.

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related to NLRP3 where a polymorphism in a NLRP3 gene is a gain-of-function mutation (e.g., a NLRP3 protein having a Q705K amino acid substitution, a T350M amino acid substitution, a R262M amino acid substitution, a A441V amino acid substitution, a V200M amino acid substitution, an E629G amino acid substitution, a L355P amino acid substitution, a R260W amino acid substitution, a G571R amino acid substitution, a A354V amino acid substitution, a D305N amino acid substitution, a F311 S amino acid substitution, a R920Q amino acid substitution, or a D21H amino acid substitution, each numbered according to the mature NLRP3 protein sequence of SEQ ID NO: 1).

In some embodiments, the methods described herein include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related to NLRP3 polymorphism found in CAPS syndromes.

In some embodiments, the methods described herein include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related NLRP3 polymorphism where the polymorphism is VAR 014104 (R262W, numbered according to the mature NLRP3 protein sequence of SEQ ID NO: 1).

In some embodiments, the methods described herein include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related NLRP3 polymorphism where the polymorphism is a natural variant reported in www.uniprot.org/uniprot/Q96P20.

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related to a point mutation in a gene involved in NLRP3 signaling.

Methods of Detecting the Level of NLRP3 Inflammasome Activity and/or

Expression

In some embodiments of any of the methods described herein, the NLRP3 inflammmasome activity is the secretion of IL-18. In some embodiments of any of the methods described herein, the NLPR3 inflammasome activity is the secretion of IL-lp.

In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity is caspase-l activity in a mammalian cell (e.g., a mammalian cell obtained from the subject). Non-limiting examples of methods that can be used to detect the secretion of IL-18 and IL-lP include immunohistochemistry, immunoassays, e.g., enzyme-linked immunosorbent assay (ELISA), sandwich ELISA, immunoprecipitation, and

immunofluorescent assay. Non-limiting examples of commercially available assays for determining caspase-l activity include Caspase 1 Assay Kit (Fluormetric) (ab394l2) (Abeam), FAM-FLICA® Caspase-l Assay Kit (ImmunoChemistry), Caspase-l

Colorimetric Assay Kit (Kl 11) (Biovision, Inc.), and Caspase-l/ICE Colorimetric Assay Kit (R&D Systems).

In some embodiments of any of the methods described herein, the NLRP3 inflammasome activity can be the level of expression of an upstream activator of NLRP3 inflammasomes (e.g., the level of one or more (e.g., two, three, four, five, or six) of lipocalin-2 protein, lipocalin-2 mRNA, S100A8 protein, S1008A8 mRNA, S100A9 protein, or S100A9 mRNA) in a mammalian cell (e.g., a mammalian cell obtained from a subject). Non-limiting assays that can be used to determine NLRP3 activity include: Southern blot analysis, Norther blot analysis, polymerase chain reaction (PCR)-based methods, e.g., next generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), TaqMan™, microarray analysis, immunohistochemistry,

immunoassays, e.g., enzyme-linked immunosorbent assay (ELISA), sandwich ELISA, immunoprecipitation, immunofluore scent assay, mass spectrometry, immunoblot (Western blot), RIA, and flow cytometry. In some embodiments of any of the methods described herein, a mammalian cell have an increased level of NLRP3 activity can be identified by detecting the presence of one of more of the following the mammalian cell: a gain-of-function mutation in a NLRP3 gene (e.g., a NLRP3 protein having a Q705K amino acid substitution, a T350M amino acid substitution, a R262M amino acid substitution, a A441V amino acid substitution, a V200M amino acid substitution, an E629G amino acid substitution, a L355P amino acid substitution, a R260W amino acid substitution, a G571R amino acid substitution, a A354V amino acid substitution, a D305N amino acid substitution, a F311 S amino acid substitution, a R920Q amino acid substitution, or a D21H amino acid substitution, each numbered according to the mature NLRP3 protein sequence of SEQ ID NO: 1); a loss-of-function mutations in one or more of a CARD8 gene (e.g., a C allele at rs20432l 1); a T allele at rs3024505 flanking IL10 gene; detection of a R620W amino acid substitution in PTPN22; detection of a C allele at rs478582 in the PTPN2 gene; detection of a G allele at rs7l3875 in the MTMR3 gene; detection of an C allele at rs 1042058 in the TPL2 gene; and detection of a ATG16L1 gene that encodes a ATG16L1 protein having a T300A amino acid substitution. Non- limiting examples of assays that can be used to determine the level of the presence of any of these mutations (e.g., any of the mutations described herein) include Southern blot analysis, Norther blot analysis, polymerase chain reaction (PCR)-based methods, e.g., next generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), TaqMan™, and microarray analysis. In some embodiments of any of the methods described herein, the NLRP3 inflammasome expression can be determined by detecting the level of one or more (e.g., two, three, four, five, six, or seven) of: NLRP3 protein, ASC protein, procaspase-l protein, caspase-l protein, NLRP3 mRNA, ASC mRNA, and procaspase-l mRNA, in a mammalian cell (e.g., in a mammalian cell obtained from the subject). Non-limiting examples of assays that can be used to determine the level of NLRP3 protein, ASC protein, procaspase-l protein, and caspase-l protein include immunohistochemistry, immunoassays, e.g., enzyme-linked immunosorbent assay (ELISA), sandwich ELISA, immunoprecipitation, immunofluorescent assay, and flow cytometry. Non-limiting examples of assays that can be used to determine the level of NLRP3 mRNA, ASC mRNA, and procaspase-l mRNA include Southern blot analysis, Norther blot analysis, polymerase chain reaction (PCR)-based methods, e.g., next generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), TaqMan™, and microarray analysis.

In some embodiments of any of the methods described herein, the NLRP3 inflammasome expression can be determined by detecting the level of one or more of CRP protein, SAA protein, HP protein, ceruloplasmin protein, IL-6 protein (e.g., mature or pro-IL-6 protein), calprotectin (S100A8) protein, IL-8 protein (e.g., mature or pro-IL-8 protein), leukotriene B4 protein, myeloperoxidase protein, CRP mRNA, SAA mRNA,

HP mRNA, ceruloplasmin mRNA, pro-IL-6 mRNA, calprotectin (S100A8) mRNA, pro- IL-8 mRNA, leukotriene B4 mRNA, and myeloperoxidase mRNA. Non-limiting examples of assays that can be used to determine the level of CRP protein, SAA protein, HP protein, ceruloplasmin protein, IL-6 protein (e.g., mature or pro-IL-6 protein), calprotectin (S100A8) protein, IL-8 protein (e.g., mature or pro-IL-8 protein), leukotriene B4 protein, myeloperoxidase protein include immunohistochemistry, immunoassays, e.g., enzyme-linked immunosorbent assay (ELISA), sandwich ELISA, immunoprecipitation, immunofluorescent assay, and flow cytometry. Non-limiting examples of assays that can be used to determine the level of CRP mRNA, SAA mRNA, HP mRNA, ceruloplasmin mRNA, pro-IL-6 mRNA, calprotectin (S100A8) mRNA, pro-IL-8 mRNA, leukotriene B4 mRNA, and myeloperoxidase mRNA include Southern blot analysis, Norther blot analysis, polymerase chain reaction (PCR)-based methods, e.g., next generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), TaqMan™, and microarray analysis.

In some embodiments of any of the methods described herein, the level of the protein or mRNA can be detected in a biological sample including blood, serum, exosomes, plasma, tissue, urine, feces, sputum, and cerebrospinal fluid.

In some embodiments of any of the methods described herein, the level of at least one (e.g., 2, 3, 4, 5, 6, 7 or 8) NLRP3 inflammasome activity and/or expression can be determined, e.g., in any combination.

In one aspect, the cell can be a cell isolated from a subject who has been screened for the presence of an inflammatory disease or indication that is associated with a mutation in a NLRP3 activity.

Reference Levels

In some embodiments of any of the methods described herein, the reference can be a corresponding level detected in a similar cell or sample obtained from a healthy subject (e.g., a subject that has not been diagnosed or identified as having an

inflammatory disease or autoimmune disorder, or any disorder associated with aberrant NLRP3 inflammasome activity and/or expression) (e.g., a subject who is not suspected or is not at increased risk of developing an inflammatory disease or autoimmune disease, or any disorder associated with aberrant NLRP3 inflammasome activity and/or expression) (e.g., a subject that does not present with any symptom of an inflammatory disease or autoimmune disease, or any disorder associated with aberrant NLRP3 inflammasome activity and/or expression).

In some embodiments, a reference level can be a percentile value (e.g., mean value, 99% percentile, 95% percentile, 90% percentile, 85% percentile, 80% percentile,

75% percentile, 70% percentile, 65% percentile, 60% percentile, 55% percentile, or 50% percentile) of the corresponding levels detected in similar samples in a population of healthy subjects (e.g., a population of subjects that have not been diagnosed or identified as having an inflammatory disease or autoimmune disorder, or any disorder associated with aberrant NLRP3 inflammasome activity and/or expression) (e.g., a population of subjects who are not suspected or are not at increased risk of developing an inflammatory disease or autoimmune disease, or any disorder associated with aberrant NLRP3 inflammasome activity and/or expression) (e.g., a population of subjects that do not present with any symptom of an inflammatory disease or autoimmune disease, or any disorder associated with aberrant NLRP3 inflammasome activity and/or expression).

In some embodiments, a reference can be a corresponding level detected in a similar sample obtained from the subject at an earlier time point.

NLR Family Pyrin Domain Containing 3 (NLRP3) Antagonists

In any of the methods described herein, the NLRP3 antagonist can be any of the

NLRP3 antagonists described herein (e.g., any of the compounds described in this section). In any of the methods described herein, the NLRP3 antagonist

has an IC50 of between about 1 nM and about 10 mM (e.g., between about 1 nM and about 9 pM, between about 1 nM and about 8 pM, between about 1 nM and about 7 pM, between about 1 nM and about 6 pM, between about 1 nM and about 5 pM, between about 1 nM and about 4 pM, between about 1 nM and about 3 pM, between about 1 nM and about 2 pM, between about 1 nM and about 1 pM, between about 1 nM and about

950 nM, between about 1 nM and about 900 nM, between about 1 nM and about 850 nM, between about 1 nM and about 800 nM, between about 1 nM and about 750 nM, between about 1 nM and about 700 nM, between about 1 nM and about 650 nM, between about 1 nM and about 600 nM, between about 1 nM and about 550 nM, between about 1 nM and about 500 nM, between about 1 nM and about 450 nM, between about 1 nM and about

400 nM, between about 1 nM and about 350 nM, between about 1 nM and about 300 nM, between about 1 nM and about 250 nM, between about 1 nM and about 200 nM, between about 1 nM and about 150 nM, between about 1 nM and about 100 nM, between about 1 nM and about 95 nM, between about 1 nM and about 90 nM, between about 1 nM and about 85 nM, between about 1 nM and about 80 nM, between about 1 nM and about 75 nM, between about 1 nM and about 70 nM, between about 1 nM and about 65 nM, between about 1 nM and about 60 nM, between about 1 nM and about 55 nM, between about 1 nM and about 50 nM, between about 1 nM and about 45 nM, between about 1 nM and about 40 nM, between about 1 nM and about 35 nM, between about 1 nM and about 30 nM, between about 1 nM and about 25 nM, between about 1 nM and about 20 nM, between about 1 nM and about 15 nM, between about 1 nM and about 10 nM, between about 1 nM and about 5 nM, between about 1 nM and about 4 nM, between about 1 nM and about 3 nM, between about 1 nM and about 2 nM, between about 2 nM and about 10 mM, between about 2 nM and about 9 mM, between about 2 nM and about 8 mM, between about 2 nM and about 7 mM, between about 2 nM and about 6 mM, between about 2 nM and about 5 mM, between about 2 nM and about 4 mM, between about 2 nM and about 3 mM, between about 2 nM and about 2 mM, between about 2 nM and about 1 mM, between about 2 nM and about 950 nM, between about 2 nM and about 900 nM, between about 2 nM and about 850 nM, between about 2 nM and about 800 nM, between about 2 nM and about 750 nM, between about 2 nM and about 700 nM, between about 2 nM and about 650 nM, between about 2 nM and about 600 nM, between about 2 nM and about 550 nM, between about 2 nM and about 500 nM, between about 2 nM and about 450 nM, between about 2 nM and about 400 nM, between about 2 nM and about 350 nM, between about 2 nM and about 300 nM, between about 2 nM and about 250 nM, between about 2 nM and about 200 nM, between about 2 nM and about 150 nM, between about 2 nM and about 100 nM, between about 2 nM and about 95 nM, between about 2 nM and about 90 nM, between about 2 nM and about 85 nM, between about 2 nM and about 80 nM, between about 2 nM and about 75 nM, between about 2 nM and about 70 nM, between about 2 nM and about 65 nM, between about 2 nM and about 60 nM, between about 2 nM and about 55 nM, between about 2 nM and about 50 nM, between about 2 nM and about 45 nM, between about 2 nM and about 40 nM, between about 2 nM and about 35 nM, between about 2 nM and about 30 nM, between about 2 nM and about 25 nM, between about 2 nM and about 20 nM, between about 2 nM and about 15 nM, between about 2 nM and about 10 nM, between about 2 nM and about 5 nM, between about 2 nM and about 4 nM, between about 2 nM and about 3 nM, between about 5 nM and about 10 mM, between about 5 nM and about 9 mM, between about 5 nM and about 8 mM, between about 5 nM and about 7 mM, between about 5 nM and about 6 mM, between about 5 nM and about 5 mM, between about 5 nM and about 4 mM, between about 5 nM and about 3 mM, between about 5 nM and about 2 mM, between about 5 nM and about 1 mM, between about 5 nM and about 950 nM, between about 5 nM and about 900 nM, between about 5 nM and about 850 nM, between about 5 nM and about 800 nM, between about 5 nM and about 750 nM, between about 5 nM and about 700 nM, between about 5 nM and about 650 nM, between about 5 nM and about 600 nM, between about 5 nM and about 550 nM, between about 5 nM and about 500 nM, between about 5 nM and about 450 nM, between about 5 nM and about 400 nM, between about 5 nM and about 350 nM, between about 5 nM and about 300 nM, between about 5 nM and about 250 nM, between about 5 nM and about 200 nM, between about 5 nM and about 150 nM, between about 5 nM and about 100 nM, between about 5 nM and about 95 nM, between about 5 nM and about 90 nM, between about 5 nM and about 85 nM, between about 5 nM and about 80 nM, between about 5 nM and about 75 nM, between about 5 nM and about 70 nM, between about 5 nM and about 65 nM, between about 5 nM and about 60 nM, between about 5 nM and about 55 nM, between about 5 nM and about 50 nM, between about 5 nM and about 45 nM, between about 5 nM and about 40 nM, between about 5 nM and about 35 nM, between about 5 nM and about 30 nM, between about 5 nM and about 25 nM, between about 5 nM and about 20 nM, between about 5 nM and about 15 nM, between about 5 nM and about 10 nM, between about 10 nM and about 10 mM, between about 10 nM and about 9 mM, between about 10 nM and about 8 mM, between about 10 nM and about 7 mM, between about 10 nM and about 6 mM, between about 10 nM and about 5 mM, between about 10 nM and about 4 mM, between about 10 nM and about 3 mM, between about 10 nM and about 2 mM, between about 10 nM and about 1 mM, between about 10 nM and about 950 nM, between about 10 nM and about 900 nM, between about 10 nM and about 850 nM, between about 10 nM and about 800 nM, between about 10 nM and about 750 nM, between about 10 nM and about 700 nM, between about 10 nM and about 650 nM, between about 10 nM and about 600 nM, between about 10 nM and about 550 nM, between about 10 nM and about 500 nM, between about 10 nM and about 450 nM, between about 10 nM and about 400 nM, between about 10 nM and about 350 nM, between about 10 nM and about 300 nM, between about 10 nM and about 250 nM, between about 10 nM and about 200 nM, between about 10 nM and about 150 nM, between about 10 nM and about 100 nM, between about 10 nM and about 95 nM, between about 10 nM and about 90 nM, between about 10 nM and about 85 nM, between about 10 nM and about 80 nM, between about 10 nM and about 75 nM, between about 10 nM and about 70 nM, between about 10 nM and about 65 nM, between about 10 nM and about 60 nM, between about 10 nM and about 55 nM, between about 10 nM and about 50 nM, between about 10 nM and about 45 nM, between about 10 nM and about 40 nM, between about 10 nM and about 35 nM, between about 10 nM and about 30 nM, between about 10 nM and about 25 nM, between about 10 nM and about 20 nM, between about 10 nM and about 15 nM, between about 50 nM and about 10 mM, between about 50 nM and about 9 mM, between about 50 nM and about 8 mM, between about 50 nM and about 7 mM, between about 50 nM and about 6 mM, between about 50 nM and about 5 mM, between about 50 nM and about 4 mM, between about 50 nM and about 3 mM, between about 50 nM and about 2 mM, between about 50 nM and about 1 mM, between about 50 nM and about 950 nM, between about 50 nM and about 900 nM, between about 50 nM and about 850 nM, between about 50 nM and about 800 nM, between about 50 nM and about 750 nM, between about 50 nM and about 700 nM, between about 50 nM and about 650 nM, between about 50 nM and about 600 nM, between about 50 nM and about 550 nM, between about 50 nM and about 500 nM, between about 50 nM and about 450 nM, between about 50 nM and about 400 nM, between about 50 nM and about 350 nM, between about 50 nM and about 300 nM, between about 50 nM and about 250 nM, between about 50 nM and about 200 nM, between about 50 nM and about 150 nM, between about 50 nM and about 100 nM, between about 50 nM and about 95 nM, between about 50 nM and about 90 nM, between about 50 nM and about 85 nM, between about 50 nM and about 80 nM, between about 50 nM and about 75 nM, between about 50 nM and about 70 nM, between about 50 nM and about 65 nM, between about 50 nM and about 60 nM, between about 50 nM and about 55 nM, between about 100 nM and about 10 mM, between about 100 nM and about 9 mM, between about 100 nM and about 8 mM, between about 100 nM and about 7 mM, between about 100 nM and about 6 mM, between about 100 nM and about 5 mM, between about 100 nM and about 4 mM, between about 100 nM and about 3 mM, between about 100 nM and about 2 mM, between about 100 nM and about 1 mM, between about 100 nM and about 950 nM, between about 100 nM and about 900 nM, between about 100 nM and about 850 nM, between about 100 nM and about 800 nM, between about 100 nM and about 750 nM, between about 100 nM and about 700 nM, between about 100 nM and about 650 nM, between about 100 nM and about 600 nM, between about 100 nM and about 550 nM, between about 100 nM and about 500 nM, between about 100 nM and about 450 nM, between about 100 nM and about 400 nM, between about 100 nM and about 350 nM, between about 100 nM and about 300 nM, between about 100 nM and about 250 nM, between about 100 nM and about 200 nM, between about 100 nM and about 150 nM, between about 200 nM and about 10 mM, between about 200 nM and about 9 mM, between about 200 nM and about 8 mM, between about 200 nM and about 7 mM, between about 200 nM and about 6 mM, between about 200 nM and about 5 mM, between about 200 nM and about 4 mM, between about 200 nM and about 3 mM, between about 200 nM and about 2 mM, between about 200 nM and about 1 mM, between about 200 nM and about 950 nM, between about 200 nM and about 900 nM, between about 200 nM and about 850 nM, between about 200 nM and about 800 nM, between about 200 nM and about 750 nM, between about 200 nM and about 700 nM, between about 200 nM and about 650 nM, between about 200 nM and about 600 nM, between about 200 nM and about 550 nM, between about 200 nM and about 500 nM, between about 200 nM and about 450 nM, between about 200 nM and about 400 nM, between about 200 nM and about 350 nM, between about 200 nM and about 300 nM, between about 200 nM and about 250 nM, between about 250 nM and about 10 mM, between about 250 nM and about 9 mM, between about 250 nM and about 8 mM, between about 250 nM and about 7 mM, between about 250 nM and about 6 mM, between about 250 nM and about 5 mM, between about 250 nM and about 4 mM, between about 250 nM and about 3 mM, between about 250 nM and about 2 mM, between about 250 nM and about 1 mM, between about 250 nM and about 950 nM, between about 250 nM and about 900 nM, between about 250 nM and about 850 nM, between about 250 nM and about 800 nM, between about 250 nM and about 750 nM, between about 250 nM and about 700 nM, between about 250 nM and about 650 nM, between about 250 nM and about 600 nM, between about 250 nM and about 550 nM, between about 250 nM and about 500 nM, between about 250 nM and about 450 nM, between about 250 nM and about 400 nM, between about 250 nM and about 350 nM, between about 250 nM and about 300 nM, between about 500 nM and about 10 mM, between about 500 nM and about 9 mM, between about 500 nM and about 8 mM, between about 500 nM and about 7 mM, between about 500 nM and about 6 mM, between about 500 nM and about 5 mM, between about 500 nM and about 4 mM, between about 500 nM and about 3 mM, between about 500 nM and about 2 mM, between about 500 nM and about 1 mM, between about 500 nM and about 950 nM, between about 500 nM and about 900 nM, between about 500 nM and about 850 nM, between about 500 nM and about 800 nM, between about 500 nM and about 750 nM, between about 500 nM and about 700 nM, between about 500 nM and about 650 nM, between about 500 nM and about 600 nM, between about 500 nM and about 550 nM, between about 750 nM and about 10 mM, between about 750 nM and about 9 mM, between about 750 nM and about 8 mM, between about 750 nM and about 7 mM, between about 750 nM and about 6 mM, between about 750 nM and about 5 mM, between about 750 nM and about 4 mM, between about 750 nM and about 3 mM, between about 750 nM and about 2 mM, between about 750 nM and about 1 mM, between about 750 nM and about 950 nM, between about 750 nM and about 900 nM, between about 750 nM and about 850 nM, between about 750 nM and about 800 nM, between about 950 nM and about 10 mM, between about 950 nM and about 9 mM, between about 950 nM and about 8 mM, between about 950 nM and about 7 mM, between about 950 nM and about 6 mM, between about 950 nM and about 5 mM, between about 950 nM and about 4 mM, between about 950 nM and about 3 mM, between about 950 nM and about 2 mM, between about 950 nM and about 1 mM, between about 1 mM and about 10 mM, between about 1 mM and about 9 mM, between about 1 mM and about 8 mM, between about 1 mM and about 7 mM, between about 1 mM and about 6 mM, between about 1 mM and about 5 mM, between about 1 mM and about 4 mM, between about 1 mM and about 3 mM, between about 1 mM and about 2 mM, between about 2 mM and about 10 mM, between about 2 mM and about 9 mM, between bout 2 mM and about 8 mM, between about 2 mM and about 7 mM, between about 2 mM and about 6 mM, between about 2 mM and about 5 pM, between about 2 pM and about 4 pM, between about 2 pM and about 3 pM, between about 4 pM and about 10 pM, between about 4 pM and about 9 pM, between about 4 pM and about 8 pM, between about 4 pM and about 7 pM, between about 4 pM and about 6 pM, between about 4 pM and about 5 pM, between about 5 pM and about 10 pM, between about 5 pM and about 9 pM, between about 5 pM and about 8 pM, between about 5 pM and about 7 pM, between about 5 pM and about 6 pM, between about 6 pM and about 10 pM, between about 6 pM and about 9 pM, between about 6 pM and about 8 pM, between about 6 pM and about 7 pM; between about 7 pM and about 10 pM, between about 7 pM and about 9 pM, between about 7 pM and about 8 pM, between about 8 pM and about 10 pM, between about 8 pM and about 9 pM, or between about 9 pM and about 10 pM) for NLRP3.

In one aspect, an NLRP3 antagonist is a compound of Formula I,

Formula I

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is O, S, or NH;

X ² is N or CR ⁹ ;

X ³ is NH or O;

or when X ³ is NH, X ³ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ; or when X ³ is NH, X ³ and R ⁴ taken together with the atoms connecting them form a four- to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ;

Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl,

CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl; R ⁹ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

provided that at least one of R ² , R ³ , R ⁴ andR ⁵ is not hydrogen, and that R ² andR ⁴ are not both hydroxymethyl;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, Ci- C ₆ alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹ is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl; wherein R ¹ is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C6 alkoxy, NR ^U R ¹² , =NR ¹³ , COOC1-C6 alkyl, and CONR ^u R ¹² ;

R ¹⁰ is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl;

wherein R ¹⁰ is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C6 alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi -C ₆ alkyl, and CONR ^u R ¹² ;

or R ¹ and R ¹⁰ taken together with the atoms connecting them form a 3-to-8-membered carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C6 alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi- Ce alkyl, and CONR ^u R ¹² ;

R ¹³ is Ci-Ce alkyl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen, C1-C ₆ alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ; R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and Ci- Ce alkyl;

each R ¹⁶ is the same or different and is selected from H, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ .

In some embodiments, NLRP3 antagonist is a compound of Formula I, provided that if the compound of formula I comprises ring A and ring B; X ³ is NH; X ² is CH; and R ¹⁰ is H,

then (i) if X ¹ is O and R ¹ is C1-C ₆ alkyl optionally substituted with hydroxy, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, or CONR ^u R ¹² , then Y is not N, CF, CC1 or CH, (ii) if X ¹ is O and R ¹ is C1-C ₆ alkyl substituted with oxo, then Y is not CH, and (iii) if X ¹ is S, then Y is not CH;

and provided that if R ² and R ⁴ are each isopropyl; X ³ is NH; X ² is CH; R ¹⁰ is H; and R ¹ is C1-C ₆ alkyl optionally substituted with hydroxy, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, or CONR ^u R ¹² ,

then Y is not CH or CC1.

In another aspect, an NLRP3 antagonist is a compound of Formula I,

Formula I

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is O, S, or NH;

X ² is N or CR ⁹ ;

X ³ is NH or O;

or when X ³ is NH, X ³ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ; or when X ³ is NH, X ³ and R ⁴ taken together with the atoms connecting them form a four- to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ;

Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl,

CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ⁹ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl,

CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

provided that at least one of R ² , R ³ , R ⁴ andR ⁵ is not hydrogen, and that R ² andR ⁴ are not both hydroxymethyl;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

and ring B is

Ring B

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, Ci- C ₆ alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹ is selected from H, C1-C ₆ alkyl, C3-C6 cycloalkyl and C3-C ₆ heterocycloalkyl; wherein R ¹ is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi -C ₆ alkyl, and CONR ^u R ¹² ;

R ¹⁰ is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl and C3-C6

heterocycloalkyl;wherein R ¹⁰ is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C6 alkoxy, NR ^U R ¹² , =NR ¹³ , COOC1-C6 alkyl, and CONR ^u R ¹² ;

or R ¹ and R ¹⁰ taken together with the atoms connecting them form a 3-to-8- membered carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

R ¹³ is Ci-Ce alkyl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen,

Ci-Ce alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ;

R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C ₆ alkyl;

each R ¹⁶ is the same or different and is selected from H, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

provided that if the compound of formula I comprises ring A and ring B; X ³ is NH; X ² is CH; and R ¹⁰ is H,

then (i) if X ¹ is O and R ¹ is C1-C ₆ alkyl substituted with hydroxy, oxo, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² , then Y is not N, CF, CC1 or CH, and (ii) if X ¹ is S, then Y is not CH;

and provided that if R ² and R ⁴ are each isopropyl; X ³ is NH; X ² is CH; R ¹⁰ is H; and R ¹ is C1-C ₆ alkyl optionally substituted with hydroxy, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, or CONR ^u R ¹² ,

then Y is not CH or CC1.

In some embodiments of the compound of Formula I, X ¹ is O.

In some embodiments of the compound of Formula I, X ¹ is S.

In some embodiments of the compound of Formula I, X ¹ is NH.

In some embodiments of the compound of Formula I, X ² is CR ⁹ .

In some embodiments of the compound of Formula I, X ² is CH.

In some embodiments of the compound of Formula I, X ² is N.

In some embodiments of the compound of Formula I, X ³ is NH.

In some embodiments of the compound of Formula I, X ³ is O.

In some embodiments of the compound of Formula I, X ² is C(Ci-C6 alkyl). In some embodiments of the compound of Formula I, X ³ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ .

In certain of the foregoing embodiments of Formula I, X ³ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more H.

In some embodiments of the compound of Formula I, X ³ and R ⁴ taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ .

In certain of the foregoing embodiments of Formula I, X ³ and R ⁴ taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more C1-C ₆ alkyl.

In some embodiments of the compound of Formula I, Y is CR ⁸ .

In some embodiments of the compound of Formula I, Y is N.

In some embodiments of the compound of Formula I, R ² is hydrogen.

In some embodiments of the compound of Formula I, R ² is C1-C ₆ alkyl optionally substituted with hydroxy. For example, R ² can be isopropyl or methyl.

In some embodiments of the compound of Formula I, R ³ is hydrogen.

In some embodiments of the compound of Formula I, R ³ is C1-C ₆ alkyl optionally substituted with hydroxy. For example, R ³ can be isopropyl; or R ³ can be methyl.

In some embodiments of the compound of Formula I, R ⁴ is hydrogen.

In some embodiments of the compound of Formula I, R ⁴ is C1-C ₆ alkyl optionally substituted with hydroxy. For example, R ⁴ can be isopropyl; or R ⁴ can be methyl.

In some embodiments of the compound of Formula I, R ⁵ is hydrogen.

In some embodiments of the compound of Formula I, R ⁵ is C1-C ₆ alkyl optionally substituted with hydroxy. For example, R ⁵ can be isopropyl; or R ⁵ can be methyl.

In some embodiments of the compound of Formula I, R ² and R ³ taken together with the carbons connecting them form ring A.

In certain of the foregoing embodiments of Formula I, ring A is

Ring A

In some embodiments of the compound of Formula I, R ² and R ³ taken together with the carbons connecting them form ring B.

In certain of the foregoing embodiments of Formula I, ring B is

Ring B

In certain embodiments of the compound of Formula I (when one pair R ² and R ³ taken together with the carbons connecting them form ring A; and another pair of R ² and R ³ taken together with the carbons connecting them form ring B), ring A is the same as ring B.

In some embodiments of the compound of Formula I, nl is 3.

In some embodiments of the compound of Formula I, nl is 4.

In some embodiments of the compound of Formula I, n2 is 3.

In some embodiments of the compound of Formula I, n2 is 4.

In some embodiments of the compound of Formula I, R ⁶ is H.

In some embodiments of the compound of Formula I, R ⁸ is H; R ⁸ is CN; R ⁸ is Cl;

R ⁸ is F; R ⁸ is C1-C6 alkyl; or R ⁸ is C1-C6 haloalkyl (e.g., CF ₃ ).

In some embodiments of the compound of Formula I, R ⁹ is H; R ⁹ is CN; R ⁹ is Cl; or R ⁹ is F.

In some embodiments of the compound of Formula I, R ¹ is H.

In some embodiments of the compound of Formula I, R ¹ is C1-C6 alkyl optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo. In certain embodiments of the compound of Formula I, R ¹ is C1-C6 alkyl substituted with hydroxy. For example, R ¹ can be 2-hydroxy-2-propyl.

In some embodiments of the compound of Formula I, R ¹ is C3-C6 cycloalkyl optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo.

In certain embodiments of the compound of Formula I, R ¹ is C3-C6 cycloalkyl substituted with hydroxy. For example, R ¹ can be 1 -hydroxy- 1 -cyclopropyl; R ¹ can be 1- hydroxy-l-cyclobutyl; or R ¹ can be 1 -hydroxy- 1 -cyclopentyl.

In some embodiments of the compound of Formula I, R ¹⁰ is H.

In some embodiments of the compound of Formula I, R ¹⁰ is C1-C6 alkyl optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo.

In certain embodiments of the compound of Formula I, R ¹⁰ is C1-C6 alkyl substituted with hydroxy. For example, R ¹⁰ can be 2-hydroxy -2-propyl.

In some embodiments of the compound of Formula I, R ¹⁰ is C3-C6 cycloalkyl optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo.

In certain embodiments of the compound of Formula I, R ¹⁰ is C3-C6 cycloalkyl substituted with hydroxy. For example, R ¹⁰ can be l-hydroxy-l-cyclopropyl; R ¹⁰ can be 1- hydroxy-l-cyclobutyl; or R ¹⁰ can be 1 -hydroxy- 1 -cyclopentyl.

In some embodiments of the compound of Formula I, R ¹ and R ¹⁰ taken together with the atoms connecting them form a five-membered carbocyclic ring.

In some embodiments of the compound of Formula I, R ¹ and R ¹⁰ taken together with the atoms connecting them form a six-membered carbocyclic ring.

In some embodiments of the compound of Formula I, R ¹ and R ¹⁰ taken together with the atoms connecting them form a five-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments of the compound of Formula I, R ¹ and R ¹⁰ taken together with the atoms connecting them form a six-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S. In some embodiments of the compound of Formula I, the ring formed by R ¹ and R ¹⁰ is substituted with hydroxy.

In some embodiments of the compound of Formula I, the ring formed by R ¹ and R ¹⁰ is substituted with oxo.

In some embodiments of the compound of Formula I, the ring formed by R ¹ and R ¹⁰ is substituted with C1-C ₆ alkoxy.

In some embodiments of the compound of Formula I, each R ¹¹ is hydrogen.

In some embodiments of the compound of Formula I, each R ¹¹ is C1-C ₆ alkyl.

In some embodiments of the compound of Formula I, each R ¹² is hydrogen.

In some embodiments of the compound of Formula I, each R ¹² is C1-C ₆ alkyl.

In some embodiments of the compound of Formula I, each R ¹⁶ is hydrogen.

In some embodiments of the compound of Formula I, if the compound of Formula I comprises ring A and ring B; X ³ is NH; X ² is CH; and R ¹⁰ is H,

then (i) if X ¹ is O and R ¹ is C1-C ₆ alkyl substituted with hydroxy, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² , then Y is not N, CF, CC1 or CH, (ii) if X ¹ is O and R ¹ is C1-C ₆ alkyl substituted with oxo, then Y is not CH, and (iii) if X ¹ is S, then Y is not CH;

and if R ² and R ⁴ are each isopropyl; X ³ is NH; X ² is CH; R ¹⁰ is H; and R ¹ is optionally substituted C1-C ₆ alkyl,

then Y is not CH or CC1.

In some embodiments of the compound of Formula I, if the compound of formula I comprises ring A and ring B; X ³ is NH; X ² is CH; and R ¹⁰ is H,

then (i) if X ¹ is O and R ¹ is C1-C ₆ alkyl substituted with hydroxy, oxo, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² , then Y is not N, CF, CC1 or CH, and (ii) if X ¹ is S, then Y is not CH;

and if R ² and R ⁴ are each isopropyl; X ³ is NH; X ² is CH; R ¹⁰ is H; and R ¹ is optionally substituted C1-C ₆ alkyl,

then Y is not CH or CC1.

In some embodiments of the compound of Formula I, the compound of Formula I is a compound of Formula la

Formula la

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is O, S, or NH;

X ³ is NH or O;

or when X ³ is NH, X ³ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ; or when X ³ is NH, X ³ and R ⁴ taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ;

Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl and CONH2;

R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl,or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

provided that at least one of R ² , R ³ , R ⁴ and R ⁵ is not hydrogen, and that R ² andR ⁴ are not both hydroxymethyl;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B, or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A

and ring B is

Ring B

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C6 alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹ is selected from H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein R ¹ is optionally substituted with hydroxy, amino or oxo; R ¹⁰ is selected from H, C1-C ₆ alkyl and C3-C ₆ cycloalkyl, wherein R ¹⁰ is optionally substituted with hydroxy, amino or oxo;

wherein R ¹⁰ is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOC1-C ₆ alkyl, and CONR ^u R ¹² ;

or R ¹ and R ¹⁰ taken together with the atoms connecting them form a 3-to-8- membered carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

R ¹³ is Ci-Ce alkyl;

each of R ^{1 1} and R ¹² at each occurrence is independently selected from hydrogen, Ci-Ce alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ;

R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C ₆ alkyl;

each R ¹⁶ is the same or different and is selected from H, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ .

In some embodiments of the compound of Formula I, the compound of Formula I is a compound of Formula la

Formula la

or a pharmaceutically acceptable salt thereof,

wherein

X ¹ is O, S, or NH;

X ³ is NH or O; or when X ³ is NH, X ³ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ; or when X ³ is NH, X ³ and R ⁴ taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ;

Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl and CONH2;

R ² is hydrogen or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen or C1-C ₆ alkyl optionally substituted with hydroxy and is the same as R ² ;

R ⁵ is hydrogen or C1-C ₆ alkyl optionally substituted with hydroxy and is the same as R ³ ;

provided that at least one of R ² , R ³ , R ⁴ and R ⁵ is not hydrogen, and that R ² andR ⁴ are not both hydroxymethyl;

or R ² and R ³ taken together with the carbons connecting them form a five- membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a five-membered ring B,

wherein ring A is

wherein each R ⁶ in each ring is the same and is H or C1-C6 alkyl, and each R ⁷ in each ring is the same and is H or C1-C6 alkyl;

R ¹ is selected from H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein R ¹ is optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo;

R ¹⁰ is selected from H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein R ¹⁰ is optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo;

or R ¹ and R ¹⁰ taken together with the atoms connecting them form a five- membered, a six-membered, or a seven-membered carbocyclic or heterocyclic ring.

In some embodiments of the compound of Formula I, the compound is a compound of Formula Ia-i:

Formula la-i

or a pharmaceutically acceptable salt thereof,

wherein:

X ³ is NH or O;

Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C6 alkyl and CONH2;

R ² is C1-C6 alkoxy, halo, C1-C6 haloalkyl,or C1-C6 alkyl optionally substituted with hydroxy;

R ³ is hydrogen;

R ⁴ is C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen;

R ¹ is selected from H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein R ¹ is optionally substituted with hydroxy, amino or oxo; R ¹⁰ is selected from H, C1-C ₆ alkyl and C ₃ -C ₆ cycloalkyl, wherein R ¹⁰ is optionally substituted with hydroxy, amino or oxo;

or R ¹ and R ¹⁰ taken together with the atoms connecting them form a five- membered, a six-membered, or a seven-membered carbocyclic or heterocyclic ring.

In some embodiments of the compound of Formula I, the compound is a compound of Formula Ia-i:

Formula la-i

or a pharmaceutically acceptable salt thereof,

wherein:

X ³ is NH or O;

Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl and CONH2;

R ³ is C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl,or C1-C ₆ alkyl optionally substituted with hydroxy;

R ² is hydrogen;

R ⁵ is C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen;

R ¹ is selected from H, C1-C ₆ alkyl and C3-C ₆ cycloalkyl, wherein R ¹ is optionally substituted with hydroxy, amino or oxo;

R ¹⁰ is selected from H, C1-C ₆ alkyl and C3-C ₆ cycloalkyl, wherein R ¹⁰ is optionally substituted with hydroxy, amino or oxo;

or R ¹ and R ¹⁰ taken together with the atoms connecting them form a five- membered, a six-membered, or a seven-membered carbocyclic or heterocyclic ring. In some embodiments of the compound of Formula I, the compound is a compound of Formula Ia-i:

Formula la-i

or a pharmaceutically acceptable salt thereof,

wherein:

X ³ is NH or O;

Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C6 alkyl and CONH2;

R ² and R ³ taken together with the carbons connecting them form a four-membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A

and ring B is

Ring B

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5; ml is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C6 alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹ is selected from H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein R ¹ is optionally substituted with hydroxy, amino or oxo;

R ¹⁰ is selected from H, C1-C ₆ alkyl and C3-C ₆ cycloalkyl, wherein R ¹⁰ is optionally substituted with hydroxy, amino or oxo;

or R ¹ and R ¹⁰ taken together with the atoms connecting them form a five- membered, a six-membered, or a seven-membered carbocyclic or heterocyclic ring.

In some embodiments of the compound of Formula I, the compound is a compound of Formula Ia-i(A):

Formula la-i(A)

or a pharmaceutically acceptable salt thereof, wherein R ⁸ is H, CN, F, CO2C1-

C6 alkyl, or CONH2.

In some embodiments of the compound of Formula I, the compound is a compound of Formula Ia-i(B):

Formula la-i(B)

or a pharmaceutically acceptable salt thereof, wherein R ⁸ is H, CN, F, CO2C1-lkyl, or CONH2.

In some embodiments of the compound of Formula I, the compound of Formula la pound of Formula Ia-i(C):

Formula la-i(C)

or a pharmaceutically acceptable salt thereof, wherein R ⁸ is H, CN, Cl or F.

In some embodiments of the compound of Formula I, the compound of Formula la pound of Formula Ia-i(D):

Formula la-i(D)

or a pharmaceutically acceptable salt thereof, wherein R ⁸ is H, CN, Cl or F.

In some embodiments of the compound of Formula I, the compound of Formula la pound of Formula Ia-i(E):

Formula la-i(E)

or a pharmaceutically acceptable salt thereof, wherein R ⁸ is H, CN, F, CO2C1-lkyl, or CONH2.

In some embodiments of the compound of Formula I, the compound of Formula la pound of Formula Ia-i(F):

Formula la-i(F)

or a pharmaceutically acceptable salt thereof, wherein R ⁸ is H, CN, Cl or F.

In some embodiments of the compound of Formula I, the compound of Formula la pound of Formula Ia-i(G):

Formula la-i(G)

or a pharmaceutically acceptable salt thereof, wherein R ⁸ is H, CN, Cl or F.

In another aspect, an NLRP3 antagonist is a compound of Formula II,

Formula II

or a pharmaceutically acceptable salt thereof, wherein Formula II is selected from

X ² is N or CR ⁹ ;

X ³ is NH or O;

X ^3’ is O;

or when X ³ is NH, X ³ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ; or when X ³ is NH, X ³ and R ⁴ taken together with the atoms connecting them form a four- to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ;

Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl,

CONR ^u R ¹² , C1-C ₆ alkyl, C1-C ₆ haloalkoxy, and C1-C ₆ haloalkyl;

R ⁸ is selected from CN, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , and C1-C ₆ haloalkyl;

R ⁹ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C ₃ -C8 cycloalkyl,

CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ² is hydrogen, halo, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ² is hydrogen or C1-C ₆ alkyl;

R ³ is hydrogen, CN, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, halo, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, CN, or C1-C ₆ alkyl;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy; R ⁴ is hydrogen, halo, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen or C1-C ₆ alkyl;

R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, halo, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, CN, or C1-C ₆ alkyl;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A and ring B is

Ring B

wherein

ring A is a saturated carbocyclic ring;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a saturated carbocyclic ring;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, Ci-

C ₆ alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹ is selected from H, unsubstituted C1-C6 alkyl, C(R ¹⁹ )20H, C(0)C2-C ₆ alkyl, and C3-C6 cycloalkyl;

wherein each C(0)C2-C ₆ alkyl and C3-C6 cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, Ci- Ce alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

R ¹ is selected from unsubstituted C1-C6 alkyl, C(R ¹⁹ )20H, C(0)C2-Ce alkyl, and

C3-C6 cycloalkyl;

wherein each C(0)C2-C ₆ alkyl and C3-C6 cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, Ci- Ce alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

R ¹ is selected from unsubstituted C1-C6 alkyl, C(0)C2-C ₆ alkyl, and C3-C6 cycloalkyl; wherein each C(0)C2-Ce alkyl and C3-C6 cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

R ¹ is selected from C(R ¹⁹ )20H;

R ¹⁰ is selected from H, Cl, C1-C ₆ alkyl, C3-C ₆ cycloalkyl and C ₃ -C ₆

heterocycloalkyl;

wherein R ¹⁰ is optionally substituted with one or more substituents each independently selected from hydroxy, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOC1-C ₆ alkyl, and

CONR ^u R ¹² ;

R ¹⁰ is selected from H, Cl, C ₃ -C ₆ cycloalkyl and C ₃ -C ₆ heterocycloalkyl;

wherein R ¹⁰ is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOC1-C ₆ alkyl, and CONR ^u R ¹² ;

R ¹⁰ is selected from Cl, C1-C ₆ alkyl, C ₃ -C ₆ cycloalkyl, and C ₃ -C ₆ heterocycloalkyl; wherein R ¹⁰ is optionally substituted with one or more substituents each independently selected from hydroxy, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOC1-C ₆ alkyl, and

CONR ^u R ¹² ;

R ^10” is selected from Cl, C1-C ₆ alkyl substituted with hydroxy, C ₃ -C ₆ cycloalkyl, and C ₃ -C ₆ heterocycloalkyl;

wherein the C ₃ -C ₆ cycloalkyl, and C ₃ -C ₆ heterocycloalkyl above are each optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOC1-C ₆ alkyl, and CONR ^u R ¹² ;

or R ¹ and R ¹⁰ taken together with the atoms connecting them form a 3-to-8- membered carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

R ¹³ is Ci-Ce alkyl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen, Ci-Ce alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ; R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C ₆ alkyl;

each R ¹⁶ is the same or different and is selected from H, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

each R ¹⁹ is the same and is C1-C ₆ alkyl;

R ²⁰ is selected from H, halo, or C1-C ₆ alkyl optionally substituted with hydroxy; R ²¹ is selected from H, halo, or C1-C ₆ alkyl substituted with hydroxy;

provided that if (1) Formula

or C3-C6 heterocycloalkyl; then is not

and provided that if: (1) Formula

either of R ¹ or R ^1’ , when present, is C(R ¹⁹ )20H;

and (3) either of R ¹⁰ or R ^10’” , when present, is not Cl; then not

and provided that if: (1) Formula

Ci-Ce alkyl substituted with hydroxy; then

In another aspect, an NLRP3 antagonist is a compound of Formula II,

Formula II

or a pharmaceutically acceptable salt thereof, wherein Formula II is selected from

Y is N or CR'

R ⁸ is selected from H, CN, Cl, and F;

R ⁸ is selected from CN and CONR ^u R ¹² ;

R ⁹ is selected from H;

R ² is hydrogen or C1-C ₆ alkyl;

R ² is Ci-Ce alkyl;

R ³ is hydrogen, CN, C1-C ₆ alkoxy, or halo;

R ³ is hydrogen or halo;

R ⁴ is hydrogen or C1-C ₆ alkyl;

R ^4’ is Ci-Ce alkyl;

R ⁵ is hydrogen;

R ⁵ is hydrogen;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A, or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A

and ring B is

Ring B

wherein

ring A is a saturated carbocyclic ring;

nl is 3;

ml is 0;

wherein ring B is a saturated carbocyclic ring;

n2 is 3;

m2 is 0;

R ¹ is selected from H; R ¹ is selected from C(R ¹⁹ )20H and C3-C ₆ cycloalkyl;

wherein the C3-C ₆ cycloalkyl above is optionally substituted with one or more hydroxy;

R ^1” is selected from C ₃ -C ₆ cycloalkyl;

wherein the C ₃ -C ₆ cycloalkyl above is optionally substituted with one or more hydroxy;

R ¹ is selected from C(R ¹⁹ )20H;

R ¹⁰ is selected from H, Cl, C1-C ₆ alkyl, and C ₃ -C ₆ cycloalkyl;

wherein R ¹⁰ is optionally substituted with one or more substituents each independently selected from hydroxy;

R ¹⁰ is selected from H or Cl;

R ¹⁰ is selected from C1-C ₆ alkyl, and C ₃ -C ₆ cycloalkyl;

wherein R ¹⁰ is optionally substituted with one or more hydroxy;

R ¹⁰ is selected from C1-C ₆ alkyl and C ₃ -C ₆ cycloalkyl;

wherein R ¹⁰ is optionally substituted with one or more hydroxy;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen; each R ¹⁹ is the same and is selected from C1-C ₆ alkyl;

R ²⁰ is selected from H or C1-C ₆ alkyl optionally substituted with hydroxy;

R ²¹ is selected from H or C1-C ₆ alkyl substituted with hydroxy;

provided that if: (1) Formula

and (3) either of R ¹⁰ or R ^10’” , when present, is not Cl; then not

and provided that if: (1) Formula I

substituted with hydroxy; then

In some embodiments of the compound of Formula II, the compound of Formula

II is

or a pharmaceutically acceptable salt thereof, and wherein: X ² is N or CR ⁹ ;

X ³ is NH or O;

or when X ³ is NH, X ³ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ; or when X ³ is NH, X ³ and R ⁴ taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ;

Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl,

CONR ^u R ¹² , C1-C ₆ alkyl, C1-C ₆ haloalkoxy, and C1-C ₆ haloalkyl;

R ⁹ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl,

CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, CN, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A

and ring B is

Ring B

wherein

ring A is a saturated carbocyclic ring;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a saturated carbocyclic ring;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, Ci- C ₆ alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹ is selected from H, unsubstituted C1-C6 alkyl, C(R ¹⁹ )20H, C(0)C2-C ₆ alkyl, and C3-C6 cycloalkyl;

wherein each C(0)C2-C ₆ alkyl and C3-C6 cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, Ci- Ce alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

R ¹⁰ is selected from H, Cl, C1-C6 alkyl, C3-C6 cycloalkyl and C3-C6

heterocycloalkyl; wherein R ¹⁰ is optionally substituted with one or more substituents each independently selected from hydroxy, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOC1-C ₆ alkyl, and CONR ^u R ¹² ;

or R ¹ and R ¹⁰ taken together with the atoms connecting them form a 3-to-8- membered carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

R ¹³ is Ci-Ce alkyl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen,

Ci-Ce alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ;

R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C ₆ alkyl;

each R ¹⁶ is the same or different and is selected from H, C1-C ₆ alkyl, C1-C ₆ alkoxy,

NR ^U R ¹² , oxo, and =NR ¹³ ;

each R ¹⁹ is the same and is selected from C1-C ₆ alkyl.

In some embodiments of the compound of Formula II, X ² is CR ⁹ .

In some embodiments of the compound of Formula II, the compound of Formula II is

or a pharmaceutically acceptable salt thereof, and wherein:

X ³ is NH or O;

or when X ³ is NH, X ³ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ; or when X ³ is NH, X ³ and R ⁴ taken together with the atoms connecting them form a four- to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ;

Y is N or CR ⁸ ; R ⁸ is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl,

CONR ^u R ¹² , C1-C6 alkyl, C1-C6 haloalkoxy, and C1-C6 haloalkyl;

R ⁹ is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl,

CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ² is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;

R ³ is hydrogen, CN, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

wherein

ring A is a saturated carbocyclic ring;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a saturated carbocyclic ring;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, Ci- C ₆ alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ^1” is selected from unsubstituted C1-C6 alkyl, C(0)C2-C ₆ alkyl, and C3-C6 cycloalkyl;

wherein each C(0)C2-C ₆ alkyl and C3-C6 cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C6 alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

R ¹⁰ is selected from H, Cl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl;

wherein R ¹⁰ is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C6 alkoxy, NR ^U R ¹² , =NR ¹³ , COOC1-C6 alkyl, and CONR ^u R ¹² ;

R ¹³ is Ci-Ce alkyl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen, Ci-Ce alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ;

R ¹⁵ is C1-C6 alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C6 alkyl;

each R ¹⁶ is the same or different and is selected from H, C1-C6 alkyl, C1-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ . In some embodiments of the compound of Formula II, R ¹ is 1 -hydroxy cyclopropyl and R ¹⁰ is H.

In some embodiments of the compound of Formula II, the compound of Formula

II is

or a pharmaceutically acceptable salt thereof, and wherein:

X ³ is NH or O;

R ^8’ is selected from CN, CCkCi-Ce alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , Ci-Ce haloalkoxy, and C1-C ₆ haloalkyl;

R ⁹ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ² is hydrogen, halo, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ² is hydrogen or C1-C ₆ alkyl;

R ³ is hydrogen, halo, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, CN, or C1-C ₆ alkyl;

R ⁴ is hydrogen, halo, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen or C1-C ₆ alkyl;

R ⁵ is hydrogen, halo, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, CN, or C1-C ₆ alkyl; or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A

and ring B is

Ring B

wherein

ring A is a saturated carbocyclic ring;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a saturated carbocyclic ring;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C6 alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S; R ¹ is selected from C(R ¹⁹ )20H;

R ^10’ is selected from H, Cl, C3-C ₆ cycloalkyl and C3-C ₆ heterocycloalkyl;

wherein R ¹⁰ is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOC1-C ₆ alkyl, and CONR ^u R ¹² ;

R ¹³ is Ci-Ce alkyl;

each of R ^{1 1} and R ¹² at each occurrence is independently selected from hydrogen, Ci-Ce alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ;

R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C ₆ alkyl;

each R ¹⁶ is the same or different and is selected from H, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

each R ¹⁹ is the same and is selected from C1-C ₆ alkyl;

provided that if R ¹⁰ is H or C ₃ -C ₆ heterocycloalkyl; then is not

In some embodiments of the compound of Formula II, R ¹⁰ is H.

In some embodiments of the compound of Formula In some embodiments of the compound of Formula II, R ² and R ³ taken together with the carbons connecting them form a four-membered to seven-membered ring A, and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B.

In some embodiments of the compound of Formula II, R ⁸ is CN. In some embodiments of the compound of Formula

In some embodiments of the compound of Formula

In some embodiments of the compound of Formula

In some embodiments of the compound of Formula II, the compound of Formula

II is

or a pharmaceutically acceptable salt thereof, and wherein:

X ³ is NH or O;

or when X ³ is NH, X ³ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ; or when X ³ is NH, X ³ and R ⁴ taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ;

Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , C1-C ₆ alkyl, C1-C ₆ haloalkoxy, and C1-C ₆ haloalkyl; R ⁹ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, CN, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A

and ring B is

Ring B

wherein

ring A is a saturated carbocyclic ring; nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a saturated carbocyclic ring;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C ₆ alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹ is selected from unsubstituted C1-C ₆ alkyl, C(R ¹⁹ )20H, C(0)C2-C6 alkyl, and C3-C6 cycloalkyl;

wherein each C(0)C2-C6 alkyl and C3-C ₆ cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

R ¹⁰ is selected from H, Cl, C ₃ -C ₆ cycloalkyl and C ₃ -C ₆ heterocycloalkyl;

wherein R ¹⁰ is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOC1-C ₆ alkyl, and CONR ^u R ¹² ;

R ¹³ is C1-C ₆ alkyl;

each of R ^{1 1} and R ¹² at each occurrence is independently selected from hydrogen, Ci-Ce alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ;

R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C ₆ alkyl;

each R ¹⁶ is the same or different and is selected from H, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

each R ¹⁹ is the same and is selected from C1-C ₆ alkyl; provided that if (1) R ¹ is C(R ¹⁹ )20H; and (2) R ^10’ is not Cl; then not

In some embodiments of the compound of Formula II, R ¹ is C(R ¹⁹ )20H.

In some embodiments of the compound of Formula II, R ¹⁰ is H.

In some embodiments of the compound of Formula II, the compound of Formula

II is

or a pharmaceutically acceptable salt thereof, and wherein:

X ³ is NH or O;

or when X ³ is NH, X ³ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ; or when X ³ is NH, X ³ and R ⁴ taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ;

Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , C1-C6 alkyl, C1-C6 haloalkoxy, and C1-C6 haloalkyl;

R ⁹ is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ² is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy; R ³ is hydrogen, CN, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A

and ring B is

Ring B

wherein

ring A is a saturated carbocyclic ring;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a saturated carbocyclic ring;

n2 is from 2 to 5; m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C ₆ alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹ is selected from H, unsubstituted C1-C ₆ alkyl, C(R ¹⁹ )20H, C(0)C2-C6 alkyl, and C3-C6 cycloalkyl;

wherein each C(0)C2-C6 alkyl and C3-C ₆ cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

R ^10” is selected from Cl, C1-C ₆ alkyl substituted with hydroxy, C ₃ -C ₆ cycloalkyl, and C ₃ -C ₆ heterocycloalkyl;

wherein the C ₃ -C ₆ cycloalkyl, and C ₃ -C ₆ heterocycloalkyl above are each optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOC1-C ₆ alkyl, and CONR ⁿ R ¹² ;

R ¹³ is Ci-Ce alkyl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen, Ci-Ce alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ;

R ¹⁵ is C1-C ₆ alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C ₆ alkyl;

each R ¹⁶ is the same or different and is selected from H, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

each R ¹⁹ is the same and is selected from C1-C ₆ alkyl; provided that if (1) R ¹ is C(R ¹⁹ )20H; and (2) R ^10’” is not Cl; then not

and provided that if R ¹⁰ is C1-C6 alkyl substituted with hydroxy; then

is not

In some embodiments of the compound of Formula II, R ¹ is C(R ¹⁹ )20H.

In some embodiments of the compound of Formula II, R ¹ is H.

In some embodiments of the compound of Formula II, R ¹⁰ is C1-C6 alkyl substituted with hydroxyl.

In some embodiments of the compound of Formula II, R ¹⁰ is l-hydroxy-l- cyclopropyl.

In some embodiments of the compound of Formula II, R ¹⁰ is Cl.

In some embodiments of the compound of Formula II, the compound of Formula

II is

or a pharmaceutically acceptable salt thereof, and wherein:

X ³ is NH or O;

or when X ³ is NH, X ³ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ; or when X ³ is NH, X ³ and R ⁴ taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ;

Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , C1-C ₆ alkyl, C1-C ₆ haloalkoxy, and C1-C ₆ haloalkyl;

R ⁹ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl,

CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, CN, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A

and ring B is

Ring B

wherein

ring A is a saturated carbocyclic ring;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a saturated carbocyclic ring;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C6 alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹ is selected from unsubstituted C1-C6 alkyl, C(R ¹⁹ )20H, C(0)C2-C ₆ alkyl, and C3-C6 cycloalkyl;

wherein each C(0)C2-C ₆ alkyl and C3-C6 cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, C1-C6 alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

R ¹³ is Ci-Ce alkyl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen, Ci-Ce alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ; R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C ₆ alkyl;

each R ¹⁶ is the same or different and is selected from H, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

each R ¹⁹ is the same and is selected from C1-C ₆ alkyl.

In some embodiments of the compound of Formula II, R ¹ is C(R ¹⁹ )20H.

In some embodiments of the compound of Formula II, the compound of Formula

II is

or a pharmaceutically acceptable salt thereof, and wherein:

X ³ is NH or O;

or when X ³ is NH, X ³ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ; or when X ³ is NH, X ³ and R ⁴ taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ;

Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , C1-C ₆ alkyl, C1-C ₆ haloalkoxy, and C1-C ₆ haloalkyl;

R ⁹ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, CN, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy; R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A

and ring B is

Ring B

wherein

ring A is a saturated carbocyclic ring;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a saturated carbocyclic ring;

n2 is from 2 to 5;

m2 is from 1 to 10; wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C6 alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹ is selected from unsubstituted C1-C6 alkyl, C(R ¹⁹ )20H, C(0)C2-C ₆ alkyl, and C3-C6 cycloalkyl;

wherein each C(0)C2-C ₆ alkyl and C3-C6 cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, C1-C6 alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

R ¹⁰ is selected from H, Cl, C1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl;

wherein R ¹⁰ is optionally substituted with one or more substituents each independently selected from hydroxy, C1-C6 alkoxy, NR ^U R ¹² , =NR ¹³ , COOC1-C6 alkyl, and CONR ^u R ¹² ;

R ¹³ is Ci-Ce alkyl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen, Ci-Ce alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ;

R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C6 alkyl;

each R ¹⁶ is the same or different and is selected from H, C1-C6 alkyl, C1-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

each R ¹⁹ is the same and is selected from C1-C6 alkyl.

In some embodiments of the compound of Formula II, R ¹ is C(R ¹⁹ )20H and R ¹⁰ is

H.

In some embodiments of the compound of Formula II, the compound of Formula

II is

or a pharmaceutically acceptable salt thereof, and wherein:

X ³ is NH or O;

or when X ³ is NH, X ³ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ; or when X ³ is NH, X ³ and R ⁴ taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ;

Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , C1-C ₆ alkyl, C1-C ₆ haloalkoxy, and C1-C ₆ haloalkyl;

R ⁹ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, CN, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B, wherein ring A is

Ring A

and ring B is

Ring B

wherein

ring A is a saturated carbocyclic ring;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a saturated carbocyclic ring;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C ₆ alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹ is selected from H, unsubstituted C1-C ₆ alkyl, C(R ¹⁹ )20H, C(0)C2-C6 alkyl, and C3-C6 cycloalkyl;

wherein each C(0)C2-C6 alkyl and C3-C ₆ cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

R ¹⁰ is selected from Cl, C1-C ₆ alkyl, C ₃ -C ₆ cycloalkyl, and C ₃ -C ₆ heterocycloalkyl; wherein R ^10” is optionally substituted with one or more substituents each independently selected from hydroxy, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOC1-C ₆ alkyl, and CONR ^u R ¹² ;

R ¹³ is Ci-Ce alkyl;

each of R ^{1 1} and R ¹² at each occurrence is independently selected from hydrogen,

Ci-Ce alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ;

R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C ₆ alkyl;

each R ¹⁶ is the same or different and is selected from H, C1-C ₆ alkyl, C1-C ₆ alkoxy,

NR ^U R ¹² , oxo, and =NR ¹³ ;

each R ¹⁹ is the same and is selected from C1-C ₆ alkyl.

In some embodiments of the compound of Formula II, R ¹ is H and R ¹⁰ is C3-C ₆ cycloalkyl substituted with hydroxy.

In some embodiments of the compound of Formula II, the compound of Formula

II is

or a pharmaceutically acceptable salt thereof, and wherein:

X ³ is NH or O;

or when X ³ is NH, X ³ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ; or when X ³ is NH, X ³ and R ⁴ taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ;

Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl,

CONR ^u R ¹² , C1-C ₆ alkyl, C1-C ₆ haloalkoxy, and C1-C ₆ haloalkyl; R ⁹ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, CN, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A

and ring B is

Ring B

wherein

ring A is a saturated carbocyclic ring; nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a saturated carbocyclic ring;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C6 alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹³ is Ci-Ce alkyl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen, Ci-Ce alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ;

R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C6 alkyl;

each R ¹⁶ is the same or different and is selected from H, C1-C6 alkyl, C1-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ .

In some embodiments of the compound of Formula II, the compound of Formula II is

or a pharmaceutically acceptable salt thereof, and wherein:

X ³ is NH or O;

or when X ³ is NH, X ³ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ; or when X ³ is NH, X ³ and R ⁴ taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ; Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , C1-C ₆ alkyl, C1-C ₆ haloalkoxy, and C1-C ₆ haloalkyl;

R ⁹ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, CN, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A and ring B is

Ring B

wherein

ring A is a saturated carbocyclic ring;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a saturated carbocyclic ring;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C6 alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹ is selected from H, unsubstituted C1-C6 alkyl, C(R ¹⁹ )20H, C(0)C2-C ₆ alkyl, and

C3-C6 cycloalkyl;

wherein each C(0)C2-C ₆ alkyl and C3-C6 cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, C1-C6 alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

R ¹⁰ is selected from H, Cl, C1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl;

wherein R ¹⁰ is optionally substituted with one or more substituents each independently selected from hydroxy, C1-C6 alkoxy, NR ^U R ¹² , =NR ¹³ , COOC1-C6 alkyl, and CONR ^u R ¹² ;

or R ¹ and R ¹⁰ taken together with the atoms connecting them form a 3-to-8- membered carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

R ¹³ is Ci-Ce alkyl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen,

Ci-Ce alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ;

R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C ₆ alkyl;

each R ¹⁶ is the same or different and is selected from H, C1-C ₆ alkyl, C1-C ₆ alkoxy,

NR ^U R ¹² , oxo, and =NR ¹³ ;

each R ¹⁹ is the same and is selected from C1-C ₆ alkyl.

In some embodiments of the compound of Formula II, R ¹ is H and R ¹⁰ is C1-C ₆ alkyl substituted with hydroxy.

In some embodiments of the compound of Formula II, R ¹ is C(R ¹⁹ )20H and R ¹⁰ is

H.

In some embodiments of the compound of Formula II, the compound of Formula

II is

In some embodiments of the compound of Formula II, R ²⁰ is H and R ²¹ is C1-C ₆ alkyl substituted with hydroxyl.

In some embodiments of the compound of Formula II, R ²¹ is H and R ²⁰ is C1-C ₆ alkyl substituted with hydroxyl.

In some embodiments of the compound of Formula II, R ⁹ is H.

In some embodiments of the compound of Formula II, X ³ is NH.

In some embodiments of the compound of Formula II, each R ¹⁹ is methyl. In some embodiments of the compound of Formula II, R ² and R ³ taken together with the carbons connecting them form a five membered carbocyclic ring and R ⁴ and R ⁵ taken together with the carbons connecting them form a five membered carbocyclic ring.

In some embodiments of the compound of Formula II, R ² and R ⁴ are each isopropyl. In some embodiments of the compound of Formula II, R ³ and R ⁵ are each H.

In some embodiments of the compound of Formula II, R ³ is halo and R ⁵ is H.

In some embodiments of the compound of Formula II, R ³ is CN and R ⁵ is H.

In some embodiments of the compound of Formula II, R ⁸ is H.

In some embodiments of the compound of Formula II, R ⁸ is F.

In some embodiments of the compound of Formula II, R ⁸ is Cl.

In some embodiments of the compound of Formula II, R ⁸ is CN.

In another aspect, an NLRP3 antagonist is a compound selected from the group consisting of compounds in the Table 1 below and pharmaceutically acceptable salts thereof.

Table 1.

In another aspect, an NLRP3 antagonist is a compound selected from the group consisting of compounds in the Table 2 below and pharmaceutically acceptable salts thereof.

Table 2.

Compounds having Formula I and II, as well as methods of making and using the same, are further described in WO2017184624A1 (PCT/US2017/028167), filed on April 18, 2017; US Provisional 62/324,081, filed on April 18, 2016; and US Provisional 62/324,071, filed on April 18, 2016, each of which is incorporated herein by reference in its entirety.

In one aspect, an NLRP3 antagonist is a compound of Formula III

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is NH or O;

or when X ¹ is NH, X ¹ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ; or when X ¹ is NH, X ¹ and R ⁴ taken together with the atoms connecting them form a four- to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ;

Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

provided that at least one of R ² , R ³ , R ⁴ and R ⁵ is not hydrogen, and that R ² andR ⁴ are not both hydroxymethyl;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

and ring B is

Ring B

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C6 alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹ is selected from H, CN, Cl, or F;

R ¹⁴ is selected from H, CN, Cl, or F;

R ⁹ is selected from C1-C6 alkyl, C(R ¹⁰ )2OH, C(R ¹⁰ )2NR ^U R ¹² , C3-C6 cycloalkyl and C3-C6 heterocycloalkyl;

wherein, when R ⁹ is C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 heterocycloalkyl, R ⁹ is optionally substituted with one or more substituents each independently selected from =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

each R ¹⁰ is the same and is H or C1-C6 alkyl;

or two R ¹⁰ taken together with the carbon connecting them form a three- to -eight- membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, or a three-membered, six-membered, seven-membered, or eight-membered carbocyclic ring, wherein the heterocyclic ring or carbocyclic ring is optionally substituted with one or more substituents each independently selected from H, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

R ¹³ is Ci-Ce alkyl;

each of R ^{1 1} and R ¹² at each occurrence is independently selected from hydrogen, Ci-Ce alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ;

R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C ₆ alkyl;

each R ¹⁶ is the same or different and is selected from H, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

provided that if R ² and R ⁴ are each isopropyl; X ¹ is NH; each R ¹⁰ is C1-C ₆ alkyl; R ¹⁴ is H; and R ¹ is H, then R ⁸ is not F or Cl.

In another aspect, an NLRP3 antagonist is a compound of Formula III

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is NH or O;

or when X ¹ is NH, X ¹ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ;; or when X ¹ is NH, X ¹ and R ⁴ taken together with the atoms connecting them form a four- to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ;;

Y is N or CR ⁸ ; R ⁸ is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ² is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;

R ³ is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;

provided that at least one of R ² , R ³ , R ⁴ and R ⁵ is not hydrogen, and that R ² and R ⁴ are not both hydroxymethyl;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C6 alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹ is selected from H, CN, Cl, or F;

R ¹⁴ is selected from H, CN, Cl, or F;

R ⁹ is selected from C1-C6 alkyl, C(R ¹⁰ )2OH, C(R ¹⁰ )2NR ^U R ¹² , C3-C6 cycloalkyl and C3-C6 heterocycloalkyl;

wherein, when R ⁹ is C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 heterocycloalkyl, R ⁹ is optionally substituted with one or more substituents each independently selected from =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

each R ¹⁰ is the same and is H or C1-C6 alkyl;

R ¹³ is Ci-Ce alkyl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen, Ci-Ce alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ;

R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C6 alkyl;

each R ¹⁶ is the same or different and is selected from H, C1-C6 alkyl, C1-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ; provided that if R ² and R ⁴ are each isopropyl; X ¹ is NH; each R ¹⁰ is C1-C ₆ alkyl; R ¹⁴ is H; and R ¹ is H, then R ⁸ is not F or Cl.

In another aspect, an NLRP3 antagonist is a compound of Formula III

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is NH or O;

or when X ¹ is NH, X ¹ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ;; or when X ¹ is NH, X ¹ and R ⁴ taken together with the atoms connecting them form a four- to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ;;

Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

provided that at least one of R ² , R ³ , R ⁴ and R ⁵ is not hydrogen, and that R ² andR ⁴ are not both hydroxymethyl;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A, or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A

and ring B is

Ring B

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C6 alkyl, C1-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S; R ¹ is selected from H, CN, Cl, or F;

R ¹⁴ is selected from H, CN, Cl, or F;

R ⁹ is selected from C1-C6 alkyl, C(R ¹⁰ )2OH, C(R ¹⁰ )2NR ^U R ¹² , C3-C6 cycloalkyl and C3-C6 heterocycloalkyl;

wherein, when R ⁹ is C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 heterocycloalkyl, R ⁹ is optionally substituted with one or more substituents each independently selected from =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

each R ¹⁰ is the same and is H or C1-C6 alkyl;

R ¹³ is Ci-Ce alkyl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen,

Ci-Ce alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ;

R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C6 alkyl;

each R ¹⁶ is the same or different and is selected from H, C1-C6 alkyl, C1-C6 alkoxy,

NR ^U R ¹² , oxo, and =NR ¹³ ;

provided that if R ² and R ⁴ are each isopropyl; X ¹ is NH; each R ¹⁰ is C1-C6 alkyl; and R ¹ is H, then R ⁸ is not F or Cl.

In another aspect, an NLRP3 antagonist is a compound of Formula III

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is NH or O;

or when X ¹ is NH, X ¹ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ;

Y is N or CR ⁸ ; R ⁸ is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ² is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;

R ³ is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;

provided that at least one of R ² , R ³ , R ⁴ and R ⁵ is not hydrogen, and that R ² and R ⁴ are not both hydroxymethyl;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C ₆ alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹ is selected from H, CN, Cl, or F;

R ¹⁴ is selected from H, CN, Cl, or F;

R ⁹ is selected from C1-C ₆ alkyl, C(R ¹⁰ )2OH, C(R ¹⁰ )2NR ^U R ¹² , C3-C6 cycloalkyl and C3-C ₆ heterocycloalkyl;

wherein, when R ⁹ is C1-C ₆ alkyl, C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl, R ⁹ is optionally substituted with one or more substituents each independently selected from =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

each R ¹⁰ is the same and is H or C1-C ₆ alkyl;

R ¹³ is Ci-Ce alkyl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen, C1-C ₆ alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ;

R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C ₆ alkyl;

each R ¹⁶ is the same or different and is selected from H, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ; provided that if R ² and R ⁴ are each isopropyl; X ¹ is NH; each R ¹⁰ is C1-C ₆ alkyl; and R ¹ is H, then R ⁸ is not F or Cl.

In another aspect, an NLRP3 antagonist is a compound of Formula III

Formula III

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is NH or O;

Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

provided that at least one of R ² , R ³ , R ⁴ and R ⁵ is not hydrogen, and that R ² andR ⁴ are not both hydroxymethyl;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B, or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A

and ring B is

Ring B

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C6 alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹ is selected from H, CN, Cl, or F;

R ¹⁴ is selected from H, CN, Cl, or F; R ⁹ is selected from C1-C ₆ alkyl, C(R ¹⁰ )2OH, C(R ¹⁰ )2NR ^U R ¹² , C3-C ₆ cycloalkyl and C3-C ₆ heterocycloalkyl;

wherein, when R ⁹ is C1-C ₆ alkyl, C ₃ -C ₆ cycloalkyl or C ₃ -C ₆ heterocycloalkyl, R ⁹ is optionally substituted with one or more substituents each independently selected from =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

each R ¹⁰ is the same and is H or C1-C ₆ alkyl;

each of R ¹¹ , R ¹² and R ¹³ at each occurrence is independently selected from hydrogen and C1-C ₆ alkyl;

provided that if R ² and R ⁴ are each isopropyl; X ¹ is NH; each R ¹⁰ is C1-C ₆ alkyl; R ¹⁴ is H; and R ¹ is H, then R ⁸ is not F or Cl.

In another aspect, an NLRP3 antagonist is a compound of Formula III

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is NH or O;

Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl, CO2C ₃ -C8 cycloalkyl, CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy; or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring B

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C6 alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ; or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹ is selected from H, CN, Cl, or F;

R ¹⁴ is selected from H, CN, Cl, or F;

R ⁹ is selected from C1-C6 alkyl, C(R ¹⁰ )2OH, C(R ¹⁰ )2NR ^U R ¹² , C3-C6 cycloalkyl and C3-C6 heterocycloalkyl;

wherein, when R ⁹ is C1-C6 alkyl, C3-C6 cycloalkyl or C3-C6 heterocycloalkyl, R ⁹ is optionally substituted with one or more substituents each independently selected from =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

each R ¹⁰ is the same and is H or C1-C6 alkyl;

each of R ¹¹ , R ¹² and R ¹³ at each occurrence is independently selected from hydrogen and C1-C6 alkyl;

provided that if R ² and R ⁴ are each isopropyl; X ¹ is NH; each R ¹⁰ is C1-C6 alkyl; and R ¹ is H, then R ⁸ is not F or Cl.

In some embodiments of the compound of Formula III, X ¹ is NH.

In some embodiments of the compound of Formula III, X ¹ is O.

In some embodiments of the compound of Formula III, X ¹ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ .

In certain of the foregoing embodiments of Formula III, X ¹ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more C1-C6 alkyl .

In some embodiments of the compound of Formula III, X ¹ and R ⁴ taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more oxo.

In certain embodiments of the compound of Formula III, X ¹ and R ⁴ taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more methyl. In certain embodiments of the compound of Formula III, X ¹ and R ⁴ taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more C1-C ₆ alkoxy.

In some embodiments of the compound of Formula III, Y is CR ⁸ .

In some embodiments of the compound of Formula III, Y is N.

In some embodiments of the compound of Formula III, R ² is hydrogen.

In some embodiments of the compound of Formula III, R ² is C1-C ₆ alkyl optionally substituted with hydroxy. For example, R ² can be isopropyl; or R ² can be methyl.

In some embodiments of the compound of Formula III, R ³ is hydrogen.

In some embodiments of the compound of Formula III, R ³ is C1-C ₆ alkyl optionally substituted with hydroxy. For example, R ³ can be isopropyl; or R ³ can be methyl.

In some embodiments of the compound of Formula III, R ⁴ is hydrogen.

In some embodiments of the compound of Formula III, R ⁴ is C1-C ₆ alkyl optionally substituted with hydroxy. For example, R ⁴ can be isopropyl; or R ⁴ can be methyl.

In some embodiments of the compound of Formula III, R ⁵ is hydrogen.

In some embodiments of the compound of Formula III, R ⁵ is C1-C ₆ alkyl optionally substituted with hydroxy. For example, R ⁵ can be isopropyl; or R ⁵ can be methyl.

In some embodiments of the compound of Formula III, R ² and R ³ taken together with the carbons connecting them form ring A.

In certain of the foregoing embodiments of Formula III, ring A is

Ring A

In some embodiments of the compound of Formula III, R ² and R ³ taken together with the carbons connecting them form ring B.

In certain of the foregoing embodiments of Formula III, ring B is

Ring B

In some embodiments of the compound of Formula III (when one pair of R ² and R ³ taken together with the carbons connecting them form ring A; and another pair R ² and R ³ taken together with the carbons connecting them form ring B), ring A is the same as ring B.

In some embodiments of the compound of Formula III, nl is 3.

In some embodiments of the compound of Formula III, nl is 4.

In some embodiments of the compound of Formula III, n2 is 3.

In some embodiments of the compound of Formula III, n2 is 4.

In some embodiments of the compound of Formula III, R ⁶ is H.

In some embodiments of the compound of Formula III, R ⁸ is H; R ⁸ is CN; R ⁸ is Cl; R ⁸ is F; R ⁸ is C1-C6 alkyl; or R ⁸ is C1-C6 haloalkyl (e.g., R ⁸ can be CF ₃ ).

In some embodiments of the compound of Formula III, R ¹ is H; R ¹ is CN; R ¹ is Cl; or R ¹ is F.

In some embodiments of the compound of Formula III, R ¹⁴ is H; R ¹⁴ is CN; R ¹⁴ is

Cl; or R ¹⁴ is F.

In some embodiments of the compound of Formula III, R ⁹ is C(R ¹⁰ ) ₂ OH.

In some embodiments of the compound of Formula III, R ⁹ is C(R ¹⁰ )2NR ^U R ¹² .

In some embodiments of the compound of Formula III, R ⁹ is C1-C6 alkyl.

In some embodiments of the compound of Formula III, R ⁹ is C3-C6 cycloalkyl.

In some embodiments of the compound of Formula III, each R ¹⁰ is H.

In some embodiments of the compound of Formula III, each R ¹⁰ is C1-C6 alkyl. For example, each R ¹⁰ can be methyl.

In some embodiments of the compound of Formula III, two R ¹⁰ taken together with the carbon connecting them form a three- to -eight-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S. In some embodiments of the compound of Formula III, two R ¹⁰ taken together with the carbon connecting them form a three-membered, six-membered, seven-membered, or eight-membered carbocyclic ring.

In some embodiments of the compound of Formula III, the heterocyclic or carbocyclic ring formed by the two R ¹⁰ is optionally substituted with one or more substituents each independently selected from H, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ .

In some embodiments of the compound of Formula III, each R ¹¹ is hydrogen.

In some embodiments of the compound of Formula III, each R ¹¹ is C1-C ₆ alkyl.

In some embodiments of the compound of Formula III, each R ¹² is hydrogen.

In some embodiments of the compound of Formula III, each R ¹² is C1-C ₆ alkyl.

In some embodiments of the compound of Formula III, each R ¹⁶ is hydrogen.

In some embodiments of the compound of Formula III, if R ² and R ⁴ are each isopropyl; X ¹ is NH; each R ¹⁰ is C1-C ₆ alkyl; R ¹⁴ is H; and R ¹ is H, then R ⁸ is not F or Cl.

In some embodiments of the compound of Formula III, if R ² and R ⁴ are each isopropyl; X ¹ is NH; each R ¹⁰ is C1-C ₆ alkyl; and R ¹ is H, then R ⁸ is not F or Cl.

In some embodiments of the compound of Formula III, the compound is a compound of Formula III(A):

Formula 111(A)

or a pharmaceutically acceptable salt thereof, wherein

Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C ₆ alkyl and CONH2;

R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl,or C1-C ₆ alkyl optionally substituted with hydroxy; R ³ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

provided that at least one of R ² , R ³ , R ⁴ and R ⁵ is not hydrogen, and that R ² andR ⁴ are not both hydroxymethyl;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A

and ring B is

Ring B

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5; ml is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C6 alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹ is selected from H, CN, Cl, or F;

R ¹⁴ is selected from H, CN, Cl, or F;

R ⁹ is selected from C1-C6 alkyl, C(R ¹⁰ )2OH, C(R ¹⁰ )2NR ^U R ¹² , and C3-C6 cycloalkyl; each R ¹⁰ is the same and is H or C1-C6 alkyl;

each of R ¹¹ , R ¹² and R ¹³ at each occurrence is independently selected from hydrogen and C1-C6 alkyl;

provided that if R ² and R ⁴ are each isopropyl; X ¹ is NH; each R ¹⁰ is C1-C6 alkyl; R ¹⁴ is H; and R ¹ is H, then R ⁸ is not F or Cl.

In some embodiments of the compound of Formula III, the compound is a compound of Formula III(A):

Formula 111(A)

or a pharmaceutically acceptable salt thereof, wherein

Y is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C6 alkyl and CONH2; R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl,or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, or C1-C ₆ alkyl optionally substituted with hydroxy;

provided that at least one of R ² , R ³ , R ⁴ and R ⁵ is not hydrogen, and that R ² andR ⁴ are not both hydroxymethyl;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A

and ring B is

Ring B

wherein ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C6 alkyl, C1-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹ is selected from H, CN, Cl, or F;

R ¹⁴ is selected from H, CN, Cl, or F;

R ⁹ is selected from C1-C6 alkyl, C(R ¹⁰ )2OH, C(R ¹⁰ )2NR ^U R ¹² , and C3-C6 cycloalkyl; each R ¹⁰ is the same and is H or C1-C6 alkyl;

each of R ¹¹ , R ¹² and R ¹³ at each occurrence is independently selected from hydrogen and C1-C6 alkyl;

provided that if R ² and R ⁴ are each isopropyl; X ¹ is NH; each R ¹⁰ is C1-C6 alkyl; and R ¹ is H, then R ⁸ is not F or Cl.

In some embodiments of the compound of Formula III, the compound is a compound of Formula III(A)-i:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula III, the compound is a compound of Formula III(A)-ii:

Formula lll(A)-ii

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula III, the compound is a compound of Formula 111(B):

Formula lll(B)

wherein

R ⁸ is selected from H, CN, Cl, F, CO2C1-C6 alkyl and CONH2;

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

n2 is from 2 to 5;

m2 is from 1 to 10; wherein each R ⁶ in each ring is the same or different and is selected from H, Ci- C ₆ alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹ is selected from H, CN, Cl, or F;

R ¹⁴ is selected from H, CN, Cl, or F;

R ⁹ is selected from Ci-Ce alkyl, C(R ¹⁰ ) ₂ OH, C(R ¹⁰ ) ₂ NR ^U R ¹² , and C ₃ -C ₆ cycloalkyl;

each R ¹⁰ is the same and is H or C1-C6 alkyl;

and each of R ¹¹ , R ¹² and R ¹³ at each occurrence is independently selected from hydrogen and C1-C6 alkyl.

In some embodiments of the compound of Formula III, the compound is a compound of Formula III(B)-i:

R ^{1 0}

Formula lll(B)-i

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula III, the compound is a compound of Formula III(B)-ii:

Formula lll(B)-ii

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula III, the compound is a compound of Formula III(B)-iii:

Formula lll(B)-iii

or a pharmaceutically acceptable salt thereof.

In another aspect, an NLRP3 antagonist is a compound of Formula IV

Formula IV

wherein the compound of Formula II is selected from

or a pharmaceutically acceptable salt thereof, wherein:

or when X ¹ is NH, X ¹ and R ² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ; or when X ¹ is NH, X ¹ and R ⁴ taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R ¹⁶ ;

Y is N or CR ⁸ ;

Y’ is N or CR ^8’ ;

Z is N or CH;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , C1-C6 alkyl, C1-C6 haloalkoxy, and C1-C6 haloalkyl;

R ⁸ is selected from H, CN, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , C1-C6 alkyl, and C1-C6 haloalkyl; R ^8” is selected from CN, Cl, F, CCkCi-Ce alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , C1-C6 alkyl, and C1-C6 haloalkyl;

R ⁸ is selected from H, CN, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR ⁿ R ¹² , C1-C6 alkyl, and C1-C6 haloalkyl;

R ² is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;

R ³ is hydrogen, CN, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;

R ³ is hydrogen, CN, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, CN, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;

R ⁵ is hydrogen, CN, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;

provided that at least one of R ² , R ³ , R ⁴ and R ⁵ is not hydrogen, and that R ² and R ⁴ are not both hydroxymethyl;

or R ² and R ³ , if both present, taken together with the carbons connecting them form a four-membered to seven-membered ring A,

or R ⁴ and R ⁵ , if both present, taken together with the carbons connecting them form a four-membered to seven-membered ring B,

or R ² and R ³ , if both present, taken together with the carbons connecting them form a four-membered to seven-membered ring A and R ⁴ and R ⁵ , if both present, taken together with the carbons connecting them form a four-membered to seven-membered ring B,

R ² and R ³ , if both present, taken together with the carbons connecting them form a four-membered to seven-membered ring A and R ⁴ and R ⁵ , if both present, taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A

and ring B is

Ring B

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C6 alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

R ¹ is selected from CN, Cl, C(R ¹⁰ )2OH, or F;

R ¹ is selected from C(0)Ci-C6 alkyl or CO2C1-C6 alkyl;

R ¹ is selected from H or C(R ¹⁰ )2OH;

R ¹⁴ is selected from H, CN, Cl, or F;

R ¹⁴ is selected from CN or F;

R ¹⁴ is selected from CN, Cl, or F; R ⁹ is selected from H, Ci-Ce alkyl, C(R ¹⁰ ) ₂ OH, C(R ¹⁰ ) ₂ NR ^U R ¹² , C ₃ -C ₆ cycloalkyl, pyridyl, and morpholinyl;

wherein, when R ⁹ is C1-C ₆ alkyl, C3-C ₆ cycloalkyl or C3-C ₆ heterocycloalkyl, R ⁹ is optionally substituted with one or more substituents each independently selected from =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

R ^9’ is selected from Ci-Ce alkyl, C(R ¹⁰ ) ₂ OH, C(R ¹⁰ ) ₂ NR ^U R ¹² , C ₃ -C ₆ cycloalkyl, phenyl, pyridyl, and morpholinyl; each R ¹⁰ is the same and is H or C1-C ₆ alkyl;

or two R ¹⁰ taken together with the carbon connecting them form a three- to -eight- membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, or a three-membered, six-membered, seven-membered, or eight-membered carbocyclic ring, wherein the heterocyclic ring or carbocyclic ring is optionally substituted with one or more substituents each independently selected from H, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

R ¹³ is Ci-Ce alkyl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen,

Ci-Ce alkyl, COzR ¹⁵ and CONR ¹⁷ R ¹⁸ ;

R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C ₆ alkyl;

each R ¹⁶ is the same or different and is selected from H, C1-C ₆ alkyl, C1-C ₆ alkoxy,

NR ^U R ¹² , oxo, and =NR ¹³ .

In another aspect, an NLRP3 antagonist is a compound of Formula IV

Formula IV

wherein the compound of Formula II is selected from

or a pharmaceutically acceptable salt thereof, wherein:

X ¹ is NH;

Y is CR ⁸ ;

Y’ is CR ^8’ ;

Z is N or CH;

R ⁸ is selected from H, CN, Cl, F, and CONR ^u R ¹² ;

R ^8’ is H;

R ⁸ is selected from CN or F;

R ⁸ is selected from H, CN, CO2C1-C6 alkyl, or CONR ^u R ¹² ;

R ² is C1-C6 alkyl;

R ³ is hydrogen or halo;

R ³ is hydrogen or halo;

R ⁴ is Ci-Ce alkyl;

R ⁵ is hydrogen;

R ⁵ is hydrogen;

provided that at least one of R ² , R ³ , R ⁴ and R ⁵ is not hydrogen, and that R ² and R ⁴ are not both hydroxymethyl; or R ² and R ³ , if both present, taken together with the carbons connecting them form a four-membered to seven-membered ring A,

or R ⁴ and R ⁵ , if both present, taken together with the carbons connecting them form a four-membered to seven-membered ring B,

or R ² and R ³ , if both present, taken together with the carbons connecting them form a four-membered to seven-membered ring A and R ⁴ and R ⁵ , if both present, taken together with the carbons connecting them form a four-membered to seven-membered ring B,

R ² and R ³ , if both present, taken together with the carbons connecting them form a four-membered to seven-membered ring A and R ⁴ and R ⁵ , if both present, taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A

and ring B is

Ring B

wherein

ring A is a carbocyclic ring;

nl is 3;

ml is 1;

wherein ring B is a carbocyclic ring;

n2 is 3;

m2 is 1;

wherein each R ⁶ in each ring is the same or different and is selected from H;

R ¹ is selected from CN, Cl, C(R ¹⁰ )2OH, or F; R ¹ is selected from H or C(R ¹⁰ )2OH;

R ¹⁴ is selected from H or F;

R ¹⁴ is F;

R ⁹ is selected from C(R ¹⁰ )2OH, C3-C ₆ cycloalkyl, phenyl, pyridyl, or morpholinyl each R ¹⁰ is the same and is C1-C ₆ alkyl;

each of R ^{1 1} and R ¹² at each occurrence is independently selected from hydrogen, Ci-Ce alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ;

R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C ₆ alkyl.

In some embodiments of the compound of Formula IV, Formula IV is

In some embodiments of the compound of Formula IV, R ¹ is C(R ¹⁰ )2OH.

In some embodiments of the compound of Formula IV, R ¹ is CN.

In some embodiments of the compound of Formula IV, R ¹ is Cl.

In some embodiments of the compound of Formula IV, R ¹ is F.

In some embodiments of the compound of Formula IV, R ⁹ is pyridyl.

In some embodiments of the compound of Formula IV, R ⁹ is morpholinyl.

In some embodiments of the compound of Formula IV, R ⁹ is C3-C6 cycloalkyl In some embodiments of the compound of Formula IV, Formula IV is

In some embodiments of the compound of Formula IV, Z is N.

In some embodiments of the compound of Formula IV, Z is CH. In some embodiments of the compound of Formula IV, R ¹ is H.

In some embodiments of the compound of Formula IV, Formula IV is

In some embodiments of the compound of Formula IV, R ¹⁴ is F.

In some embodiments of the compound of Formula IV, Formula IV is

In some embodiments of the compound of Formula I

In some embodiments of the compound of Formula IV:

R ² and R ³ , taken together with the carbons connecting them form a five membered ring A and R ⁴ and R ⁵ , taken together with the carbons connecting them form a five-membered ring B;

ring A is a saturated carbocyclic ring;

ring B is a saturated carbocyclic ring;

nl is 3;

n2 is 3;

R ⁶ is H.

In some embodiments of the compound of Formula IV, R ⁸ is F. In some embodiments of the compound of Formula I

In some embodiments of the compound of Formula IV, R ³ is H or F, and R ⁵ is H. In some embodiments of the compound of Formula IV, R ^8”’ is H.

In some embodiments of the compound of Formula IV, R ^8”’ is CN.

In some embodiments of the compound of Formula IV, R ^8”’ is CONFh.

In some embodiments of the compound of Formula IV, R ^8”’ is COCFF.

In some embodiments of the compound of Formula IV, Formula IV is

In some embodiments of the compound of Formula IV, R ¹ is acetyl.

In some embodiments of the compound of Formula IV, R ¹⁴ is F.

In some embodiments of the compound of Formula IV, R ⁹ is H.

In some embodiments of the compound of Formula IV, X ¹ is NFL

In some embodiments of the compound of Formula IV, R ² and R ⁴ are each isopropyl.

In some embodiments of the compound of Formula IV, R ³ and R ⁵ are each H.

In some embodiments of the compound of Formula IV:

R ² and R ³ , taken together with the carbons connecting them form a five membered ring A and R ⁴ and R ⁵ , taken together with the carbons connecting them form a five-membered ring B;

ring A is a saturated carbocyclic ring;

ring B is a saturated carbocyclic ring;

nl is 3; n2 is 3;

R ⁶ is H.

In some embodiments of the compound of Formula IV, Y is CR ⁸ .

In some embodiments of the compound of Formula IV, R ⁸ is H.

In some embodiments of the compound of Formula IV, R ⁸ is CN.

In some embodiments of the compound of Formula IV, R ⁸ is Cl.

In some embodiments of the compound of Formula IV, R ⁸ is F.

In some embodiments of the compound of Formula IV, R ⁸ is CO2NH2.

In some embodiments of the compound of Formula IV, R ⁸ is CO2CH3.

In another aspect, an NLRP3 antagonist is a compound selected from the group consisting of compounds in the Table 3 below and pharmaceutically acceptable salts thereof.

Table 3.

In another aspect, an NLRP3 antagonist is a compound selected from the group consisting of compounds in Table 4 below and pharmaceutically acceptable salts thereof.

Table 4.



Compounds having Formula III and IV, as well as methods of making and using the same, are further described in WO2017184623 Al (PCT/US2017/028166), filed on April 18, 2017; US Provisional 62/324,071, filed on April 18, 2016; and US Provisional 62/324,081, filed on April 18, 2016, each of which is incorporated herein by reference in its entirety.

In one aspect, an NLRP3 antagonist is a compound of Formula V

Formula V

or a pharmaceutically acceptable salt thereof, wherein: X" x ^:

x °c

Ar is a heteroaryl group X or an aryl or heteroaryl group

X ^I is O, S, N, CR ⁴¹ or NR ⁴¹ ;

X ¹⁰ is O, S, N, CR ¹⁰ or NR ¹⁰ ;

X ^{I I} is O, S, N, CR ¹ or NR ¹ ;

X ² is O, S, N, CR ⁴² or NR ⁴² ;

X ³⁵ is N or CR ³⁵ ;

X ²¹ is N or CR ²¹ ;

X ³⁶ is N or CR ³⁶ ;

X ⁴ is CR ⁴ , N or NR ²⁴ ;

each R ²⁰ is the same or different and is independently selected from hydrogen and

Ci-Ce alkyl;

Y is N or CR ² ;

Z is N or CR ⁸ ;

R ⁸ is selected from H, CN, halo CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , C1-C ₆ alkyl, C1-C ₆ alkoxy, C1-C ₆ haloalkoxy, and C1-C ₆ haloalkyl;

R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, C3-C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, CN, C1-C ₆ haloalkoxy, C ₃ -C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, C ₃ -C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

R ²⁴ is absent and R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, CN, C1-C ₆ haloalkoxy, C ₃ -C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

or R ²⁴ is C1-C ₆ alkyl or C ₃ -C8 cycloalkyl and R ⁵ is =0;

provided that at least one of R ² , R ³ , R ⁴ andR ⁵ is not hydrogen;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A, or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A

and ring B is

Ring B

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, F, Ci- C6 alkyl, C1-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S; each of R ¹ , R ¹⁰ , R ⁴¹ and R ⁴² when bonded to carbon is independently selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, CN, halo, CCkCi-Ce alkyl, CO2C3-C8 cycloalkyl, Ce-Cio aryl, CONR ^u R ¹² , C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, Ci-Ce alkyl, Ci-Ce alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, Ce-Cio aryl, and CONR ^u R ¹² ;

and each of R ¹ , R ¹⁰ , R ⁴¹ and R ⁴² when bonded to nitrogen is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, C6-C10 aryl, CONR ^u R ¹² , C3-C7 cycloalkyl, S(02)Ci-C ₆ akyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ^U R ¹² , =NR ¹³ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ^u R ¹² ;

or R ¹ and R ¹⁰ taken together with the atoms connecting them form a 3-to-8- membered carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C6 alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

each of R ³⁴ , R ²⁹ , R ³⁵ , R ²¹ and R ³⁶ is independently selected from H, C1-C6 alkyl,

Ci-Ce haloalkyl, CN, halo, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, OC1-C6 alkyl, NH2, NHC1-C6 alkyl, N(Ci-Ce alkyl) ₂ , NO2, COCi-Ce alkyl, SFs and S(0 ₂ )Ci-C ₆ akyl;

wherein the C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, Ci-Ce alkoxy, Ci-Ce alkyl, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, CONR ^u R ¹² , C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to lO-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to lO-membered heteroaryl), NHCO(3- to 7- membered heterocycloalkyl), and NHCOC2-C6 alkynyl, wherein the C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, NHCOC ₆ -C1 ₀ aryl, NHCO(5- to lO-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C ₆ alkyl, and OC1-C ₆ alkyl,

or two groups selected from R ³⁴ , R ²⁹ , R ³⁵ , R ²¹ and R ³⁶ that are on adjacent ring carbon atoms taken together with the adjacent ring carbons form a 6-membered aromatic ring, a five-to-eight-membered carbocyclic non-aromatic ring, a five- or six-membered heteroaromatic ring or a five-to-eight-membered heterocyclic non-aromatic ring, wherein the ring formed by the two groups together with the adjacent ring carbons is optionally substituted with one or more OC1-C ₆ alkyl, NH2, NHC1-C ₆ alkyl, N(CI-C6 alkyl) ₂ ;

R ¹³ is Ci-Ce alkyl;

each of R ^{1 1} and R ¹² at each occurrence is independently selected from hydrogen, C1-C ₆ alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ; or R ^{1 1} and R ¹² taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to;

R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C ₆ alkyl.

In another aspect, an NLRP3 antagonist is a compound of Formula V-I

Formula V-I

or a pharmaceutically acceptable salt thereof, wherein:

X ^I is O, S, N, CR ⁴¹ or NR ⁴¹ ;

X ¹⁰ is O, S, N, CR ¹⁰ or NR ¹⁰ ;

X ^{I I} is O, S, N, CR ¹ or NR ¹ ;

X ² is O, S, N, CR ⁴² or NR ⁴² ;

X ⁴ is CR ⁴ , N or NR ²⁴ ; each R ²⁰ is the same or different and is independently selected from hydrogen and Ci-Ce alkyl;

Y is N or CR ² ;

Z is N or CR ⁸ ;

R ⁸ is selected from H, CN, halo, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl,

CONR ^u R ¹² , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C1-C6 haloalkyl;

R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, C3-C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, CN, C1-C ₆ haloalkoxy, C ₃ -C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, C ₃ -C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

R ²⁴ is absent and R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, CN, C1-C ₆ haloalkoxy, C ₃ -C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

or R ²⁴ is C1-C6 alkyl or C3-C8 cycloalkyl and R ⁵ is =0;

provided that at least one of R ² , R ³ , R ⁴ andR ⁵ is not hydrogen;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

and ring B is

Ring B

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, F, Ci- C ₆ alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

each of R ¹ , R ¹⁰ , R ⁴¹ and R ⁴² when bonded to carbon is independently selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, CN, halo, CCkCi-Ce alkyl, CO2C3-C8 cycloalkyl, Ce-Cio aryl, CONR ^u R ¹² , C3-C7 cycloalkyl, S(02)Ci-C ₆ akyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ^U R ¹² , =NR ¹³ , COOC1-C6 alkyl, Ce-Cio aryl, and CONR ^u R ¹² ;

and each of R ¹ , R ¹⁰ , R ⁴¹ and R ⁴² when bonded to nitrogen is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, C6-C10 aryl, CONR ^u R ¹² , C3-C7 cycloalkyl, S(02)Ci-C ₆ akyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, C1-C6 alkyl, oxo, C1-C6 alkoxy, NR ^U R ¹² , =NR ¹³ , COOC1-C6 alkyl, C6-C10 aryl, and CONR ^u R ¹² ;

or R ¹ and R ¹⁰ taken together with the atoms connecting them form a 3-to-8- membered carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C6 alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

R ¹³ is C1-C6 alkyl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen, C1-C6 alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ; or R ¹¹ and R ¹² taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to;

R ¹⁵ is C1-C6 alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C6 alkyl.

In another aspect, an NLRP3 antagonist is a compound of Formula V-II

Formula V-II

or a pharmaceutically acceptable salt thereof, wherein:

X ³⁵ is N or CR ³⁵ ;

X ²¹ is N or CR ²¹ ;

X ³⁶ is N or CR ³⁶ ;

X ⁴ is CR ⁴ , N or NR ²⁴ ; each R ²⁰ is the same or different and is independently selected from hydrogen and Ci-Ce alkyl;

Y is N or CR ² ;

Z is N or CR ⁸ ;

R ⁸ is selected from H, CN, halo, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl,

CONR ^u R ¹² , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C1-C6 haloalkyl;

R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, C3-C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, CN, C1-C ₆ haloalkoxy, C ₃ -C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, C ₃ -C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

R ²⁴ is absent and R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, CN, C1-C ₆ haloalkoxy, C ₃ -C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

or R ²⁴ is C1-C6 alkyl or C3-C8 cycloalkyl and R ⁵ is =0;

provided that at least one of R ² , R ³ , R ⁴ andR ⁵ is not hydrogen;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

and ring B is

Ring B

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, F, Ci- C ₆ alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

each of R ³⁴ , R ²⁹ , R ³⁵ , R ²¹ and R ³⁶ is independently selected from H, C1-C ₆ alkyl, Ci-Ce haloalkyl, CN, halo, CCkCi-Ce alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, C ₆ -C1 ₀ aryl, OC1-C ₆ alkyl, NH2, NHC1-C ₆ alkyl, N(Ci-Ce alkyl) ₂ , NO2, COCi-Ce alkyl, SFs and S(0 ₂ )Ci-C ₆ akyl;

wherein the C1-C ₆ alkyl, C ₃ -C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, Ci-Ce alkoxy, Ci-Ce alkyl, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, CONR ^u R ¹² , C ₃ -C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, NHCOC ₆ -C1 ₀ aryl, NHCO(5- to lO-membered heteroaryl), NHCO(3- to 7- membered heterocycloalkyl), and NHCOC2-C ₆ alkynyl, wherein the C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, NHCOC ₆ -C1 ₀ aryl, NHCO(5- to lO-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C ₆ alkyl, and OC1-C ₆ alkyl,

or two groups selected from R ³⁴ , R ²⁹ , R ³⁵ , R ²¹ and R ³⁶ that are on adjacent ring carbon atoms taken together with the adjacent ring carbons form a 6-membered aromatic ring, a five-to-eight-membered carbocyclic non-aromatic ring, a five- or six-membered heteroaromatic ring or a five-to-eight-membered heterocyclic non-aromatic ring, wherein the ring formed by the two groups together with the adjacent ring carbons is optionally substituted with one or more OC1-C ₆ alkyl, NH2, NHC1-C ₆ alkyl, N(CI-C6 alkyl) ₂ ;

R ¹³ is Ci-Ce alkyl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen, C1-C ₆ alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ; or R ¹¹ and R ¹² taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to;

R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C ₆ alkyl.

In another aspect, an NLRP3 antagonist is a compound of Formula V

Formula V

or a pharmaceutically acceptable salt thereof, wherein:

Ar is a heteroaryl group or an aryl or heteroaryl X ^I is O, S, N, CR ⁴¹ or NR ⁴¹ ;

X ¹⁰ is O, S, N, CR ¹⁰ or NR ¹⁰ ;

X ^II is O, S, N, CR ¹ or NR ¹ ;

X ² is O, S, N, CR ⁴² or NR ⁴² ;

X ³⁵ is N or CR ³⁵ ;

X ²¹ is N or CR ²¹ ;

X ³⁶ is N or CR ³⁶ ;

X ⁴ is CR ⁴ , N or NR ²⁴ ;

each R ²⁰ is the same or different and is independently selected from hydrogen and Ci-Ce alkyl;

Y is N or CR ² ;

Z is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, C3-C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, C ₃ -C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, C ₃ -C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

R ²⁴ is absent and R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, C ₃ -C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

or R ²⁴ is C1-C6 alkyl or C3-C8 cycloalkyl and R ⁵ is =0;

provided that at least one of R ² , R ³ , R ⁴ and R ⁵ is not hydrogen, and that R ² and R ⁴ are not both hydroxymethyl;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B, or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A

and ring B is

Ring B

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C6 alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

each of R ¹ , R ¹⁰ , R ⁴¹ and R ⁴² when bonded to carbon is independently selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, CN, halo, CCkCi-Ce alkyl, CO2C3-C8 cycloalkyl, Ce-Cio aryl, CONR ^u R ¹² , C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C ₆ alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, Ci-Ce alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, Ce-Cio aryl, and CONR ^u R ¹² ;

and each of R ¹ , R ¹⁰ , R ⁴¹ and R ⁴² when bonded to nitrogen is independently selected from H, C1-C ₆ alkyl, C1-C ₆ haloalkyl, CO2C1-C ₆ alkyl, CO2C ₃ -C8 cycloalkyl, C ₆ -C1 ₀ aryl, CONR ^u R ¹² , C ₃ -C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C ₆ alkyl, C ₃ -C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, Ce-Cio aryl, and CONR ^u R ¹² ;

or R ¹ and R ¹⁰ taken together with the atoms connecting them form a 3-to-8- membered carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C6 alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ;

each of R ³⁴ , R ²⁹ , R ³⁵ , R ²¹ and R ³⁶ is independently selected from H, C1-C ₆ alkyl, Ci-Ce haloalkyl, CN, halo, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, C ₆ -C1 ₀ aryl, OC1-C ₆ alkyl, NH2, NHC1-C ₆ alkyl, N(Ci-Ce alkyl) ₂ , NO2, COCi-Ce alkyl,

wherein the C1-C6 alkyl, C ₃ -C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, Ci-Ce alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, CONR ^u R ¹² , C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to lO-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to lO-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl,

wherein the C6-C10 aryl, 5- to lO-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to lO-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl, or two groups selected from R ³⁴ , R ²⁹ , R ³⁵ , R ²¹ and R ³⁶ that are on adjacent ring carbon atoms taken together with the adjacent ring carbons form a 6-membered aromatic ring, a five-to-eight-membered carbocyclic non-aromatic ring, a five- or six-membered heteroaromatic ring or a five-to-eight-membered heterocyclic non-aromatic ring, wherein the ring formed by the two groups together with the adjacent ring carbons is optionally substituted with one or more OC1-C ₆ alkyl, NH2, NHC1-C ₆ alkyl, N(CI-C6 alkyl) ₂ ;

R ¹³ is Ci-Ce alkyl;

each of R ^{1 1} and R ¹² at each occurrence is independently selected from hydrogen, Ci-Ce alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ;

R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C ₆ alkyl.

In another aspect, an NLRP3 antagonist is a compound of Formula V-I

Formula V-I

or a pharmaceutically acceptable salt thereof, wherein:

X ^I is O, S, N, CR ⁴¹ or NR ⁴¹ ;

X ¹⁰ is O, S, N, CR ¹⁰ or NR ¹⁰ ;

X ^II is O, S, N, CR ¹ or NR ¹ ;

X ² is O, S, N, CR ⁴² or NR ⁴² ;

X ⁴ is CR ⁴ , N or NR ²⁴ ;

each R ²⁰ is the same or different and is independently selected from hydrogen and Ci-Ce alkyl;

Y is N or CR ² ;

Z is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl; R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, C3-C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, C3-C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, C ₃ -C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

R ²⁴ is absent and R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, C ₃ -C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

or R ²⁴ is C1-C ₆ alkyl or C ₃ -C8 cycloalkyl and R ⁵ is =0;

provided that at least one of R ² , R ³ , R ⁴ and R ⁵ is not hydrogen, and that R ² and R ⁴ are not both hydroxymethyl;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A

and ring B is

Ring B

wherein ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C ₆ alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

each of R ¹ , R ¹⁰ , R ⁴¹ and R ⁴² when bonded to carbon is independently selected from H, Ci-Ce alkyl, Ci-Ce haloalkyl, CN, halo, CCkCi-Ce alkyl, CO2C3-C8 cycloalkyl, Ce-Cio aryl, CONR ^u R ¹² , C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C ₆ alkyl, C ₃ -C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, Ci-Ce alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, Ce-Cio aryl, and CONR ^u R ¹² ;

and each of R ¹ , R ¹⁰ , R ⁴¹ and R ⁴² when bonded to nitrogen is independently selected from H, C1-C ₆ alkyl, C1-C ₆ haloalkyl, CO2C1-C ₆ alkyl, CO2C ₃ -C8 cycloalkyl, C ₆ -C1 ₀ aryl, CONR ^u R ¹² , C ₃ -C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C ₆ alkyl, C ₃ -C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, Ce-Cio aryl, and CONR ^u R ¹² ;

or R ¹ and R ¹⁰ taken together with the atoms connecting them form a 3-to-8- membered carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C ₆ alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, and CONR ^u R ¹² ; R ¹³ is Ci-Ce alkyl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen, Ci-Ce alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ;

R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C6 alkyl.

In another aspect, an NLRP3 antagonist is a compound of Formula V-II

Formula V-II

or a pharmaceutically acceptable salt thereof, wherein:

X ³⁵ is N or CR ³⁵ ;

X ²¹ is N or CR ²¹ ;

X ³⁶ is N or CR ³⁶ ;

X ⁴ is CR ⁴ , N or NR ²⁴ ;

each R ²⁰ is the same or different and is independently selected from hydrogen and Ci-Ce alkyl;

Y is N or CR ² ;

Z is N or CR ⁸ ;

R ⁸ is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , Ci-Ce alkyl, and Ci-Ce haloalkyl;

R ² is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, C3-C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

R ³ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, C ₃ -C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

R ⁴ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, C ₃ -C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy; R ²⁴ is absent and R ⁵ is hydrogen, C1-C ₆ alkoxy, halo, C1-C ₆ haloalkyl, C3-C7 cycloalkyl or C1-C ₆ alkyl optionally substituted with hydroxy;

or R ²⁴ is C1-C ₆ alkyl or C3-C8 cycloalkyl and R ⁵ is =0;

provided that at least one of R ² , R ³ , R ⁴ and R ⁵ is not hydrogen, and that R ² andR ⁴ are not both hydroxymethyl;

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A,

or R ⁴ and R ⁵ taken together with the carbons connecting them form a four- membered to seven-membered ring B,

or R ² and R ³ taken together with the carbons connecting them form a four- membered to seven-membered ring A and R ⁴ and R ⁵ taken together with the carbons connecting them form a four-membered to seven-membered ring B,

wherein ring A is

Ring A

and ring B is

Ring B

wherein

ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

nl is from 2 to 5;

ml is from 1 to 10;

wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S; n2 is from 2 to 5;

m2 is from 1 to 10;

wherein each R ⁶ in each ring is the same or different and is selected from H, C1-C6 alkyl, Ci-C6 alkoxy, NR ^U R ¹² , oxo, and =NR ¹³ ;

or two R ⁶ taken together with the atom or atoms connecting them form a 3-to-8- membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;

each of R ³⁴ , R ²⁹ , R ³⁵ , R ²¹ and R ³⁶ is independently selected from H, C1-C ₆ alkyl, Ci-Ce haloalkyl, CN, halo, CCkCi-Ce alkyl, CO2C3-C8 cycloalkyl, CONR ^u R ¹² , C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, C ₆ -C1 ₀ aryl, OC1-C ₆ alkyl, NH2, NHC1-C ₆ alkyl, N(Ci-Ce alkyl) ₂ , NO2, COCi-Ce alkyl,

wherein the C1-C ₆ alkyl, C ₃ -C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, Ci-Ce alkoxy, NR ^U R ¹² , =NR ¹³ , COOCi-Ce alkyl, CONR ^u R ¹² , C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, NHCOC ₆ -C1 ₀ aryl, NHCO(5- to lO-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C ₆ alkynyl,

wherein the C6-C10 aryl, 5- to lO-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to lO-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl,

or two groups selected from R ³⁴ , R ²⁹ , R ³⁵ , R ²¹ and R ³⁶ that are on adjacent ring carbon atoms taken together with the adjacent ring carbons form a 6-membered aromatic ring, a five-to-eight-membered carbocyclic non-aromatic ring, a five- or six-membered heteroaromatic ring or a five-to-eight-membered heterocyclic non-aromatic ring, wherein the ring formed by the two groups together with the adjacent ring carbons is optionally substituted with one or more OC1-C6 alkyl, NH2, NHC1-C6 alkyl, N(CI-C ₆ alkyl)2;

R ¹³ is Ci-Ce alkyl;

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen, Ci-Ce alkyl, CO2R ¹⁵ and CONR ¹⁷ R ¹⁸ ; R ¹⁵ is Ci-Ce alkyl;

each of R ¹⁷ and R ¹⁸ at each occurrence is independently selected from hydrogen and C1-C6 alkyl.

In some embodiments of the compound of Formula V, the moiety is

In some embodiments of the compound of Formula V, the moiety is

R ¹

R (LHS2).

In some embodiments of the compound of Formula V, the moiety is

In certain of the foregoing embodiments of Formula V, X is N; and X is S.

In certain of the foregoing embodiments of Formula V, LHS7 is OH In some embodiments of the compound of Formula V, the moiety is

In some embodiments of the compound of Formula V, X ¹ is S; and X ² is CH.

In some embodiments of the compound of Formula V, the moiety ents of the compound of Formula V, the moiety

In some embodiments of the compound of Formula V, the moiety is

X y ^~ °

(LHS11). In some embodiments of the compound of Formula V, the moiety

In some embodiments of the compound of Formula V, the moiety

In some embodiments of the compound of Formula V, the moiety

In some embodiments of the compound of Formula

In some embodiments of the compound of Formula V, the moiety

In some embodiments of the compound of Formula V, the moiety

In certain of the foregoing embodiments of Formula V (when the moiety

In certain embodiments of Formula V (when the moiety

In certain embodiments of Formula V (when the moiety

In certain embodiments of Formula V (when the moiety

As a non-limiting example of above, RHS5 can

In certain embodiments of Formula V (when the moiety , (RHS6).

In certain embodiments of Formula V (when the moiety In certain embodiments of Formula V (when the moiety

In some embodiments of the compound of Formula V, X ¹⁰ is CR ¹⁰ .

In certain embodiments of the compound of Formula V, R ¹⁰ is 2-hydroxy-2-propyl; R ¹⁰ is 1 -hydroxy- 1 -cyclopropyl; R ¹⁰ is dimethylaminomethyl; or R ¹⁰ is S(02)CFF.

In some embodiments of the compound of Formula V, X ¹¹ is CR ¹ .

In certain embodiments of the compound of Formula V, R ¹ is 2-hydroxy -2-propyl; R ¹ is l-hydroxy-l-cyclopropyl; R ¹ is dimethylaminomethyl; or R ¹ is S(Cb)CFF

In some embodiments of the compound of Formula V, X ¹⁰ is NR ¹⁰ .

In certain embodiments of the compound of Formula V, R ¹⁰ is isopropyl; R ¹⁰ is methyl; R ¹⁰ is benzyl; or R ¹⁰ is phenyl.

In some embodiments of the compound of Formula V, X ³⁵ is CR ³⁵ .

In certain embodiments of the compound of Formula V, R ³⁵ is 2-hydroxy-2-propyl; R ³⁵ is l-hydroxy-l-cyclopropyl; R ³⁵ is dimethylaminomethyl; or R ³⁵ is S(02)CFF.

In some embodiments of the compound of Formula V, X ²¹ is CR ²¹ .

In certain embodiments of the compound of Formula V, R ²¹ is 2-hydroxy-2-propyl; R ²¹ is l-hydroxy-l-cyclopropyl; R ²¹ is dimethylaminomethyl; R ²¹ can be S(Cb)CFF; R ²¹ is halo; or R ²¹ is CFb.

In some embodiments of the compound of Formula V, R ²⁹ is 2-hydroxy-2-propyl; R ²⁹ is l-hydroxy-l-cyclopropyl; R ²⁹ is dimethylaminomethyl; R ²⁹ is S(Cb)CFF; R ²⁹ is halo; or R ²⁹ is CFb.

In some embodiments of the compound of Formula V, X ³⁶ is CR ³⁶ .

In certain embodiments of the compound of Formula V, R ³⁶ is halo; or R ³⁶ is CFb. In some embodiments of the compound of Formula V, R ³⁴ is halo; or R ³⁴ is CFF In some embodiments of the compound of Formula V, each R ²⁰ is hydrogen. In some embodiments of the compound of Formula V

Ar is a heteroaryl group , wherein

X ¹ is O, S, N or CH;

X ¹⁰ is N, CR ¹⁰ or NR ¹⁰ ;

X ¹¹ is N, CR ¹ or NR ¹ ;

X ² is O, S, N or CH;

each of R ¹ and R ¹⁰ when bonded to carbon is independently selected from H, Ci- C6 alkyl, C ₆ -C1 ₀ aryl, S(02)Ci-C6 akyl and C ₃ -C7 cycloalkyl, wherein the C1-C ₆ alkyl and C ₃ -C7 cycloalkyl is

optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C ₆ alkoxy, and NR ^u R ¹² ;

and each of R ¹ , R ¹⁰ when bonded to nitrogen is independently selected from H, Ci- C6 alkyl, C ₆ -C1 ₀ aryl, and C ₃ -C7 cycloalkyl, wherein the C1-C ₆ alkyl and C ₃ -C7 cycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy and C1-C ₆ alkoxy;

R ⁸ is selected from H, CN, Cl, F, C1-C ₆ alkyl, C1-C ₆ alkoxy, Ci-C6 haloalkoxy, and C1-C ₆ haloalkyl;

R ² is hydrogen, C1-C ₆ haloalkyl, C3-C7 cycloalkyl or C1-C ₆ alkyl;

R ³ is hydrogen or halo;

R ⁴ is hydrogen, C1-C ₆ haloalkyl, C3-C7 cycloalkyl or C1-C ₆ alkyl;

R ⁵ is hydrogen or halo.

In some embodiments of the compound of Formula V, the compound of Formula V is a compound of Formula V-Ia

Formula V-la

wherein

X ¹⁰ is N or CR ¹⁰ ;

and

X ² is O, S, or NR ⁴² .

In some embodiments of the compound of Formula V-Ia, X ¹⁰ is N; and X ² is O.

In some embodiments of the compound of Formula V-Ia, X ¹⁰ is N; and X ² is S.

In some embodiments of the compound of Formula V-Ia, X ¹⁰ is CR ¹⁰ ; and X ² is O. In some embodiments of the compound of Formula V-Ia, X ¹⁰ is CR ¹⁰ ; and X ² is S. In some embodiments of the compound of Formula V-Ia, the compound of Formula V is a compound of Formula V-Ib:

Formula V-lb

wherein

X ¹ is O, S, or NR ⁴¹ ;

and

X ² is N or CR ⁴² .

In some embodiments of the compound of Formula V-Ib, X ¹ is O; and X ² is N.

In some embodiments of the compound of Formula V-Ib, X ¹ is S; and X ² is N.

In some embodiments of the compound of Formula V-Ib, X ¹ is O; and X ² is CR ⁴² . In some embodiments of the compound of Formula V-Ib, X ¹ is S; and X ² is CR ⁴² .

In certain embodiments of the compound of Formula V-Ia or V-Ib, R ¹ is 2-hydroxy-

2-propyl; R ¹ is 1 -hydroxy- 1 -cyclopropyl; R ¹ is dimethylaminomethyl; or R ¹ is S(02)CFF In certain embodiments of the compound of Formula V-Ia or V-Ib, R ¹⁰ is 2- hydroxy -2-propyl; R ¹⁰ is l-hydroxy-l-cyclopropyl; R ¹⁰ is dimethylaminomethyl; or R ¹⁰ is S(0 ₂ )CH3.

In certain embodiments of the compound of Formula V-Ia or V-Ib (when X ¹ is NR ⁴¹ ), R ⁴¹ is 2-hydroxy-2-propyl; R ⁴¹ is l-hydroxy-l-cyclopropyl; R ⁴¹ is dimethylaminomethyl; or R ⁴¹ is S(0 ₂ )CH3.

In certain embodiments of the compound of Formula V-Ia or V-Ib, R ⁴² is 2- hydroxy -2-propyl; R ⁴² is l-hydroxy-l-cyclopropyl; R ⁴² is dimethylaminomethyl; or R ⁴² is S(0 ₂ )CH3.

In some embodiments of the compound of Formula V,

Ar is an aryl or heteroaryl group

X ³⁵ is CR ³⁵ ;

X ²¹ is N or CR ²¹ ;

X ³⁶ is CR ³⁶ ;

each of R ³⁴ , R ²⁹ , R ³⁵ , R ²¹ and R ³⁶ is independently selected from H, C1-C ₆ alkyl, halo, C ₃ -C7 cycloalkyl, 3- to 7-membered nonaromatic monocyclic heterocycloalkyl, C ₆ - C1 ₀ aryl, and S(0 ₂ )Ci-C ₆ alkyl;

wherein the C1-C ₆ alkyl, 3- to 7-membered nonaromatic monocyclic heterocycloalkyl, and C ₃ -C7 cycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxyl, C1-C6 alkyl, oxo, NR ^U R ¹² , and 3- to 7-membered heterocycloalkyl,

R ⁸ is selected from H, CN, Cl, F, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C1-C6 haloalkyl;

R ² is hydrogen, C1-C ₆ haloalkyl, C ₃ -C7 cycloalkyl or C1-C ₆ alkyl;

R ³ is hydrogen or halo;

R ⁴ is hydrogen, C1-C ₆ haloalkyl, C ₃ -C7 cycloalkyl or C1-C ₆ alkyl;

R ⁵ is hydrogen or halo. In certain embodiments of the compound of Formula V, R ³⁵ is 2-hydroxy-2-propyl; R ³⁵ is l-hydroxy-l-cyclopropyl; R ³⁵ is dimethylaminomethyl; R ³⁵ is S(Cb)CFF; R ³⁵ is methyl; or R ³⁵ is halo.

In certain embodiments of the compound of Formula V (when X ²¹ is R ²¹ ), R ²¹ is 2- hydroxy -2 -propyl; R ²¹ is l-hydroxy-l-cyclopropyl; R ²¹ is dimethylaminomethyl; R ²¹ is

S(02)CH ₃ ; R ²¹ is methy; or R ²¹ is halo.

In certain embodiments of the compound of Formula V, R ²⁹ is 2-hydroxy-2-propyl; R ²⁹ is l-hydroxy-l-cyclopropyl; R ²⁹ is dimethylaminomethyl; R ²⁹ is S(Cb)CFF; R ²⁹ is methyl; or R ²⁹ is halo.

In certain embodiments of the compound of Formula V, R ³⁶ is methyl; or R ³⁶ is halo.

In certain embodiments of the compound of Formula V, R ³⁴ is methyl; or R ³⁴ is halo.

In another aspect, an NLRP3 antagonist is a compound selected from the group consisting of the compounds below:

WO 2020/010118

and pharmaceutically acceptable salts thereof.

In another aspect, an NLRP3 antagonist is compound selected from the group consisting of the compounds in Table 5 below and pharmaceutically acceptable salts thereof.

Table 5.

Compounds having Formula V, as well as methods of making and using the same, are further described in WO2017184604A1 (PCT/US2017/028139), filed on April 18, 2017; US Provisional 62/324,071, filed on April 18, 2016; US Provisional 62/324,081, filed on April 18, 2016; and US Provisional 62/411,358, filed on October 21, 2016, each of which is incorporated herein by reference in its entirety.

In one aspect, an NLRP3 antagonist is a compound of Formula VI

or a pharmaceutically acceptable salt thereof,

wherein

m = 0, 1, or 2;

n = 0, 1, or 2;

p = 0, 1, or 2;

wherein

A is a 5-l0-membered monocyclic or bicyclic heteroaryl, a 5-l0-membered monocyclic or bicyclic heterocycloalkyl, a C6-C10 monocyclic or bicyclic aryl, or a C6-C10 monocyclic or bicyclic cycloalkyl;

R ¹ and R ² are each independently selected from C1-C ₆ alkyl, C1-C ₆ haloalkyl, Ci-

C ₆ alkoxy, C1-C ₆ haloalkoxy, halo, CN, NO2, COC1-C ₆ alkyl, CO2C1-C ₆ alkyl, CO-C ₆ -C1 ₀ aryl, CO-5- to lO-membered heteroaryl, CO2C3-C8 cycloalkyl, OCOC1-C ₆ alkyl, OCOC ₆ - C1 ₀ aryl, OCO(5- to lO-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, NH2, NHC1-C ₆ alkyl, N(CI-C ₆ alkyl)2, NHCOC1-C ₆ alkyl, NHCOC ₆ -C1 ₀ aryl, NHCO(5- to lO-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C ₆ alkynyl, NHCOOCC1-C ₆ alkyl, NH- (C=NR ¹³ )NR ^U R ¹² , CONR ⁸ R ⁹ , SFS, SCi-Ce alkyl, S(0 ₂ )Ci-C ₆ alkyl, S(0)Ci-Ce alkyl, S(0 ₂ )NR ^U R ¹² , S0 ₂ NR ⁸ R ⁹ , NR ^U S0 ₂ NR ^U R ¹² , NR ^U C0 ₂ R ¹² , NR ^U CONR ^U R ¹² ,

NR ^U S02R ¹² , C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C1-C ₆ alkyl, C1-C ₆ haloalkyl, C ₃ -C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOCi- C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, OCOC1-C ₆ alkyl, OCOC ₆ -C1 ₀ aryl, OCO(5- to lO-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C ₆ alkyl, NHCOC ₆ -C1 ₀ aryl, NHCO(5- to lO-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C ₆ alkynyl;

wherein each C1-C ₆ alkyl substituent and each C1-C ₆ alkoxy substituent of the R ¹ or R ² C ₃ -C7 cycloalkyl or of the R ¹ or R ² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR ⁸ R ⁹ , or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C1 ₀ aryl, 5- to 10- membered heteroaryl, NHCOC ₆ -C1 ₀ aryl, NHCO(5- to lO-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C ₆ alkyl, and OC1-C ₆ alkyl;

or at least one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form at least one Cri-Cx carbocyclic ring or at least one 5- to-8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C ₆ alkyl, C ₆ -C1 ₀ aryl, and CONR ⁸ R ^9, wherein the C1-C ₆ alkyl and C1-C ₆ alkoxy are optionally substituted with hydroxy, halo, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C ₆ alkyl, C ₆ -C1 ₀ aryl, and CONR ⁸ R ⁹ ;

Y is selected from a bond, O, S, SO2, NR ¹⁵ , or CR ¹⁶ R ¹⁷ ;

Z is selected from a 5- lO-membered monocyclic or bicyclic heteroaryl, a 5-10- membered monocyclic or bicyclic heterocycloalkyl, a C ₆ -C1 ₀ monocyclic or bicyclic aryl, a C ₆ -C1 ₀ monocyclic or bicyclic cycloalkyl, or a C2-C ₆ alkenyl, wherein Z is optionally substituted with one or more substituents independently selected from C1-C ₆ alkyl , C1-C ₆ alkoxy, C ₆ -C1 ₀ aryloxy, hydroxy, CN, halo, NR ⁸ R ⁹ , COOC1-C ₆ alkyl, S(02)Ci-C ₆ alkyl, S0 ₂ NR ⁸ R ⁹ , NR ^U S0 ₂ NR ^U R ¹² , NR ^U C0 ₂ R ¹² , NR ^U CONR ^U R ¹² , NR ^U S0 ₂ R ¹² , 3- to 7- membered heterocycloalkyl, C ₆ -C1 ₀ aryl, and CONR ⁸ R ⁹ , and wherein the C1-C ₆ alkyl or C1-C ₆ alkoxy that Z is substituted with is optionally substituted with one or more hydroxyl, NR ⁸ R ⁹ , or C ₆ -C1 ₀ aryl, or wherein Z is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

each R ⁷ is independently selected from C1-C ₆ alkyl, C1-C ₆ haloalkyl, C1-C ₆ alkoxy, C1-C ₆ haloalkoxy, halo, CN, NO2, COC1-C ₆ alkyl, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl, OCOC1-C ₆ alkyl, OCOC ₆ -C1 ₀ aryl, OCO(5- to lO-membered heteroaryl), OCO(3- to 7- membered heterocycloalkyl), C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, NH2, OH, NHCi- Ce alkyl, N(Ci-Ce alkyl) ₂ , CONR ⁸ R ⁹ , S0 ₂ NR ⁸ R ⁹ , NR ^u S0 ₂ NR ^u R ¹² , NR ^u C0 ₂ R ¹² , NR ^u CONR ^u R ¹² , NR ^U S0 ₂ R ¹² , SFS, S(0 ₂ )Ci-Ce alkyl, C3-C7 cycloalkyl, and 3- to 7- membered heterocycloalkyl,

wherein the C1-C ₆ alkyl, C1-C ₆ haloalkyl, C1-C ₆ alkoxy, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, OCOC1-C ₆ alkyl, OCOC ₆ -C1 ₀ aryl, OCO(5- to 10- membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C ₆ alkyl, NHCOC ₆ -C1 ₀ aryl, NHCO(5- to lO-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;

wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to lO-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;

each X is independently N or CR ⁶ ;

each R ⁶ is independently selected from hydrogen, C1-C ₆ alkyl, C1-C ₆ haloalkyl, Ci- C6 alkoxy, C1-C ₆ haloalkoxy, halo, CN, N0 ₂ , COC1-C ₆ alkyl, C0 ₂ Ci-C ₆ alkyl, C0 ₂ C ₃ -Cs cycloalkyl, OCOC1-C ₆ alkyl, OCOC ₆ -C1 ₀ aryl, OCO(5- to lO-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, NH ₂ , OH, NHCi-Ce alkyl, N(Ci-Ce alkyl) ₂ , CONR ⁸ R ⁹ , S0 ₂ NR ⁸ R ⁹ , NR ^u S0 ₂ NR ^u R ¹² , NR ^U C0 ₂ R ¹² , NR ^U CONR ^U R ¹² , NR ^U S0 ₂ R ¹² , SFS, S(0 ₂ )Ci-Ce alkyl, C ₃ -C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl,

wherein the C1-C ₆ alkyl, C1-C ₆ haloalkyl, C1-C ₆ alkoxy, C ₃ -C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, OCOC1-C ₆ alkyl, OCOC ₆ -C1 ₀ aryl, OCO(5- to 10- membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C ₆ alkyl, NHCOC ₆ -C1 ₀ aryl, NHCO(5- to lO-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C ₆ alkynyl;

wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C1 ₀ aryl, 5- to 10- membered heteroaryl, NHCOC ₆ -C1 ₀ aryl, NHCO(5- to lO-membered heteroaryl) and NHCO(3 - to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C ₆ alkyl, and OC1-C ₆ alkyl;

or at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one Cri-Cx carbocyclic ring or at least one 5- to-8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ⁸ R ⁹ , CH ₂ NR ⁸ R ⁹ , =NR ¹⁰ , COOCi-Ce alkyl, Ce-Cio aryl, and CONR ⁸ R ⁹ ;

each of R ⁴ and R ⁵ is independently selected from hydrogen, C1-C ₆ alkyl, C1-C ₆ alkoxy, NH2, NHC1-C ₆ alkyl, or N(CI-C6 alkyl)2.

R ¹⁰ is Ci-Ce alkyl;

each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, Ci- Ce alkyl, NH-(C=NR ¹³ )NR ^U R ¹² , S(0 ₂ )Ci-C ₆ alkyl, S(0 ₂ )NR ^u R ¹² , COR ¹³ , CO2R ¹³ and CONR ^u R ¹² ; wherein the C1-C ₆ alkyl is optionally substituted with one or more hydroxy, halo, C1-C ₆ alkoxy, C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, C3-C7 cycloalkyl or 3- to 7-membered heterocycloalkyl; or R ⁸ and R ⁹ taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to;

R ¹³ is C1-C ₆ alkyl, C ₆ -C1 ₀ aryl, or 5- to lO-membered heteroaryl;

each of R ^{1 1} and R ¹² at each occurrence is independently selected from hydrogen and C1-C ₆ alkyl;

R ¹⁵ is selected from H or C1-C ₆ alkyl;

R ¹⁶ is selected from H or C1-C ₆ alkyl; and

R ¹⁷ is selected from H or C1-C ₆ alkyl. In another aspect, an NLRP3 antagonist is a compound of Formula VI, wherein the compound is a compound of Formula VI-I

Formula VI-I wherein

m = 0, 1, or 2;

n = 0, 1, or 2;

p = 0, 1, or 2;

wherein

A is a 5-l0-membered monocyclic or bicyclic heteroaryl, a 5-l0-membered monocyclic or bicyclic heterocycloalkyl, a C6-C10 monocyclic or bicyclic aryl, or a C6-C10 monocyclic or bicyclic cycloalkyl;

R ¹ and R ² are each independently selected from C1-C ₆ alkyl, C1-C ₆ haloalkyl, Ci- C6 alkoxy, C1-C ₆ haloalkoxy, halo, CN, NO2, COC1-C ₆ alkyl, CO2C1-C ₆ alkyl, CO-C ₆ -C1 ₀ aryl, CO-5- to lO-membered heteroaryl, CO2C3-C8 cycloalkyl, OCOC1-C ₆ alkyl, OCOC ₆ - C1 ₀ aryl, OCO(5- to lO-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, NFh, NHC1-C ₆ alkyl, N(CI-C ₆ alkyl)2, NHCOC1-C ₆ alkyl, NHCOC ₆ -C1 ₀ aryl, NHCO(5- to lO-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C ₆ alkynyl, NHCOOCC1-C ₆ alkyl, NH- 8R ⁹ , NR ^U S0 ₂ NR ^U R ¹² , NR ^U C0 ₂ R ¹² , alkyl, S(0 ₂ )Ci-C ₆ alkyl, S(0)Ci-Ce alkyl, S(02)NR ^U R ¹² , C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C1-C ₆ alkyl, C1-C ₆ haloalkyl, C ₃ -C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOCi- C6 alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, OCOC1-C ₆ alkyl, OCOC ₆ -C1 ₀ aryl, OCO(5- to lO-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C ₆ alkyl, NHCOC ₆ -C1 ₀ aryl, NHCO(5- to lO-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C ₆ alkynyl;

wherein each C1-C ₆ alkyl substituent and each C1-C ₆ alkoxy substituent of the R ¹ or R ² C3-C7 cycloalkyl or of the R ¹ or R ² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR ⁸ R ⁹ , or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C1 ₀ aryl, 5- to 10- membered heteroaryl, NHCOC ₆ -C1 ₀ aryl, NHCO(5- to lO-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C ₆ alkyl, and OC1-C ₆ alkyl;

or at least one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form at least one Cri-Cx carbocyclic ring or at least one 5- to-8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C ₆ alkyl, C ₆ -C1 ₀ aryl, and CONR ⁸ R ^9, wherein the C1-C ₆ alkyl and C1-C ₆ alkoxy are optionally substituted with hydroxy, halo, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C ₆ alkyl, C ₆ -C1 ₀ aryl, and CONR ⁸ R ⁹ ;

Z is selected from a 5- lO-membered monocyclic or bicyclic heteroaryl, a 5-10- membered monocyclic or bicyclic heterocycloalkyl, a C ₆ -C1 ₀ monocyclic or bicyclic aryl, a C ₆ -C1 ₀ monocyclic or bicyclic cycloalkyl, or a C2-C ₆ alkenyl, wherein Z is optionally substituted with one or more substituents independently selected from C1-C ₆ alkyl , C1-C ₆ alkoxy, C ₆ -C1 ₀ aryloxy, hydroxy, CN, halo, NR ⁸ R ⁹ , COOC1-C ₆ alkyl, S(02)Ci-C6 alkyl, S0 ₂ NR ⁸ R ⁹ , NR ¹¹ S02NR ¹¹ R ¹² , NR ^U C0 ₂ R ¹² , NR ¹¹ C0NR ¹¹ R ¹² , NR ^U S0 ₂ R ¹² , 3- to 7- membered heterocycloalkyl, C ₆ -C1 ₀ aryl, and CONR ⁸ R ⁹ , and wherein the C1-C ₆ alkyl or Ci-Ce alkoxy that Z is substituted with is optionally substituted with one or more hydroxyl, NR ⁸ R ⁹ , or C6-C10 aryl;

or wherein Z is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

each R ⁷ is independently selected from C1-C ₆ alkyl, C1-C ₆ haloalkyl, C1-C ₆ alkoxy, C1-C ₆ haloalkoxy, halo, CN, NO2, COC1-C ₆ alkyl, CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl, OCOC1-C ₆ alkyl, OCOC ₆ -C1 ₀ aryl, OCO(5- to lO-membered heteroaryl), OCO(3- to 7- membered heterocycloalkyl), C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, NH2, OH, NHCi- Ce alkyl, N(Ci-Ce alkyl) ₂ , CONR ⁸ R ⁹ , S0 ₂ NR ⁸ R ⁹ , NR ^u S0 ₂ NR ^u R ¹² , NR ^u C0 ₂ R ¹² , NR ^u CONR ^u R ¹² , NR ^U S0 ₂ R ¹² , SFS, S(0 ₂ )CI-C ₆ alkyl, C3-C7 cycloalkyl, and 3- to 7- membered heterocycloalkyl,

wherein the C1-C ₆ alkyl, C1-C ₆ haloalkyl, C1-C ₆ alkoxy, C ₃ -C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, OCOC1-C ₆ alkyl, OCOC ₆ -C1 ₀ aryl, OCO(5- to 10- membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C ₆ alkyl, NHCOC ₆ -C1 ₀ aryl, NHCO(5- to lO-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C ₆ alkynyl;

wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to lO-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;

each X is independently N or CR ⁶ ;

each R ⁶ is independently selected from hydrogen, C1-C ₆ alkyl, C1-C ₆ haloalkyl, Ci- C6 alkoxy, C1-C ₆ haloalkoxy, halo, CN, NO2, COC1-C ₆ alkyl, CO2C1-C ₆ alkyl, CO2C ₃ -C8 cycloalkyl, OCOC1-C ₆ alkyl, OCOC ₆ -C1 ₀ aryl, OCO(5- to lO-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, NH2, OH, NHCi-Ce alkyl, N(Ci-Ce alkyl) ₂ , CONR ⁸ R ⁹ , S0 ₂ NR ⁸ R ⁹ , NR ^u S0 ₂ NR ^u R ¹² , NR ^U C0 ₂ R ¹² , NR ^U CONR ^U R ¹² , NR ^U S0 ₂ R ¹² , SFS, S(0 ₂ )Ci-Ce alkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl,

wherein the C1-C ₆ alkyl, C1-C ₆ haloalkyl, C1-C ₆ alkoxy, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, OCOC1-C ₆ alkyl, OCOC ₆ -C1 ₀ aryl, OCO(5- to 10- membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C ₆ alkyl, NHCOC ₆ -C1 ₀ aryl, NHCO(5- to lO-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC ₂ -C ₆ alkynyl;

wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10- membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to lO-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;

or at least one pair of R ⁶ and R ⁷ on adjacent atoms, taken together with the atoms connecting them, independently form at least one Cri-Cx carbocyclic ring or at least one 5- to-8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR ⁸ R ⁹ , CH ₂ NR ⁸ R ⁹ , =NR ¹⁰ , COOCi-Ce alkyl, Ce-Cio aryl, and CONR ⁸ R ⁹ ;

each of R ⁴ and R ⁵ is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, NH ₂ , NHC1-C6 alkyl, or N(Ci-C ₆ alkyl) _2.

R ¹⁰ is Ci-Ce alkyl;

each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, Ci-

Ce alkyl, NH-(C=NR ¹³ )NR ^U R ¹² , S(0 ₂ )Ci-Ce alkyl, S(0 ₂ )NR ^u R ¹² , COR ¹³ , C0 ₂ R ¹³ and CONR ^u R ¹² ; wherein the C1-C ₆ alkyl is optionally substituted with one or more hydroxy, halo, C1-C ₆ alkoxy, C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, C ₃ -C7 cycloalkyl or 3- to 7-membered heterocycloalkyl; or R ⁸ and R ⁹ taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to;

R ¹³ is Ci-Ce alkyl, C ₆ -C1 ₀ aryl, or 5- to lO-membered heteroaryl; and

each of R ¹¹ and R ¹² at each occurrence is independently selected from hydrogen and C1-C ₆ alkyl.

In some embodiments of the compound of Formula VI-I,

m = 0, 1, or 2;

n = 0, 1, or 2;

p = 0, 1, or 2;

wherein

A is a 5-l0-membered monocyclic or bicyclic heteroaryl, a 5-l0-membered monocyclic or bicyclic heterocycloalkyl, a C ₆ -C1 ₀ monocyclic or bicyclic aryl, or a C ₆ -C1 ₀ monocyclic or bicyclic cycloalkyl;

R ¹ and R ² are each independently selected from C1-C ₆ alkyl, C1-C ₆ alkoxy, halo, CN, NO2, COCi-Ce alkyl, CO2C1-C6 alkyl, NH2, NHCi-Ce alkyl, N(Ci-Ce alkyl) ₂ , NHCOCi-Ce alkyl, CONR ⁸ R ⁹ , S(0 ₂ )Ci-C ₆ alkyl, S(0)Ci-Ce alkyl, S(0 ₂ )NR ^u R ¹² , C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C1-C ₆ alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C ₆ alkyl, C1-C ₆ alkoxy, and NR ⁸ R ⁹ ,

Z is selected from a 5- lO-membered monocyclic or bicyclic heteroaryl, a 5-10- membered monocyclic or bicyclic heterocycloalkyl, a C ₆ -C1 ₀ monocyclic or bicyclic aryl, a C ₆ -C1 ₀ monocyclic or bicyclic cycloalkyl, or a C2-C ₆ alkenyl, wherein Z is optionally substituted with one or more substituents independently selected from C1-C ₆ alkyl , C1-C ₆ alkoxy, C ₆ -C1 ₀ aryloxy, CN, halo, COOC1-C ₆ alkyl, S(02)Ci-C ₆ alkyl, 3- to 7-membered heterocycloalkyl, and CONR ⁸ R ⁹ , and wherein the C1-C ₆ alkyl or C1-C ₆ alkoxy that Z is substituted with is optionally substituted with one or more hydroxyl, NR ⁸ R ⁹ , or C ₆ -C1 ₀ aryl; or wherein Z is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

each R ⁷ is independently selected from C1-C ₆ alkyl, C1-C ₆ haloalkyl, C1-C ₆ alkoxy, halo, CN, COCi-Ce alkyl, CO2C3-C8 cycloalkyl, NH2, OH, S(0 ₂ )Ci-C ₆ alkyl, and C3-C7 cycloalkyl,

wherein the C1-C ₆ alkyl and C1-C ₆ alkoxy is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ⁸ R ⁹ , and C ₆ -C1 ₀ aryl,

each X is independently N or CR ⁶ ;

each R ⁶ is independently selected from hydrogen, C1-C ₆ alkyl, C1-C ₆ haloalkyl, Ci- C ₆ alkoxy, halo, CN, COC1-C ₆ alkyl, CO2C ₃ -C8 cycloalkyl, NH2, OH, S(02)Ci-C ₆ alkyl, and C ₃ -C7 cycloalkyl,

wherein the C1-C ₆ alkyl and C1-C ₆ alkoxy is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ⁸ R ⁹ , C ₆ -C1 ₀ aryl;

each of R ⁴ and R ⁵ is independently selected from hydrogen, C1-C ₆ alkyl, C1-C ₆ alkoxy, NH2, NHC1-C ₆ alkyl, or N(Ci-C6 alkyl)2.

each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen, Ci- Ce alkyl, NH-(C=NR ¹³ )NR ^U R ¹² , S(0 ₂ )Ci-C ₆ alkyl, S(0 ₂ )NR ^u R ¹² , COR ¹³ , CO2R ¹³ and CONR ^u R ¹² ; wherein the C1-C ₆ alkyl is optionally substituted with one or more hydroxy, halo, C1-C ₆ alkoxy, C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, C ₃ -C7 cycloalkyl or 3- to 7-membered heterocycloalkyl; or R ⁸ and R ⁹ taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to;

R ¹³ is C1-C ₆ alkyl, C ₆ -C1 ₀ aryl, or 5- to lO-membered heteroaryl; and

each of R ^{1 1} and R ¹² at each occurrence is independently selected from hydrogen and C1-C ₆ alkyl.

In some embodiments of the compound of Formula VI-I,

m = 0 or 1 ; n = 0 or 1 ;

p = 0, 1, or 2;

wherein

A is a 5-l0-membered monocyclic or bicyclic heteroaryl, a 5-l0-membered monocyclic or bicyclic heterocycloalkyl, a C ₆ -C1 ₀ monocyclic or bicyclic aryl, or a C ₆ -C1 ₀ monocyclic or bicyclic cycloalkyl;

R ¹ and R ² are each independently selected from C1-C ₆ alkyl, C1-C ₆ alkoxy, halo, COCi-Ce alkyl, CO2C1-C ₆ alkyl, NH2, NHCi-Ce alkyl, CONR ⁸ R ⁹ , S(0 ₂ )Ci-C ₆ alkyl, S(02)NR ^U R ¹² , C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C1-C ₆ alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C ₆ alkyl, C1-C ₆ alkoxy, and NR ⁸ R ⁹ ,

Z is selected from a 5-l0-membered monocyclic or bicyclic heteroaryl, a 5-10- membered monocyclic or bicyclic heterocycloalkyl, a C ₆ -C1 ₀ monocyclic or bicyclic aryl, a C ₆ -C1 ₀ monocyclic or bicyclic cycloalkyl, or a C2-C ₆ alkenyl, wherein Z is optionally substituted with one or more substituents independently selected from C1-C ₆ alkyl , C1-C ₆ alkoxy, C ₆ -C1 ₀ aryloxy, CN, halo, COOC1-C ₆ alkyl, S(02)Ci-C ₆ alkyl, 3- to 7-membered heterocycloalkyl, and CONR ⁸ R ⁹ , and wherein the C1-C ₆ alkyl or C1-C ₆ alkoxy that Z is substituted with is optionally substituted with one or more hydroxyl, NR ⁸ R ⁹ , or C ₆ -C1 ₀ aryl;

or wherein Z is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

each R ⁷ is independently selected from C1-C ₆ alkyl, C1-C ₆ haloalkyl, C1-C ₆ alkoxy, halo, CN, COC1-C ₆ alkyl, CO2C ₃ -C8 cycloalkyl, NH2, OH, S(02)Ci-C ₆ alkyl, and C ₃ -C7 cycloalkyl,

wherein the C1-C ₆ alkoxy is optionally substituted with one or more C ₆ -C1 ₀ aryl, each X is independently N or CR ⁶ ; each R ⁶ is independently selected from hydrogen, C1-C ₆ alkyl, C1-C ₆ haloalkyl, Ci- C ₆ alkoxy, halo, CN, COC1-C ₆ alkyl, CO2C3-C8 cycloalkyl, NH2, OH, S(02)Ci-C ₆ alkyl, and C3-C7 cycloalkyl,

wherein the C1-C ₆ alkoxy is optionally substituted with one or more C ₆ -C1 ₀ aryl; each of R ⁴ and R ⁵ is independently selected from hydrogen, C1-C ₆ alkyl, C1-C ₆ alkoxy, NH2, NHC1-C ₆ alkyl, or N(Ci-C6 alkyl)2.

each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen and Ci-Ce alkyl.

In some embodiments of the compound of Formula VI-I,

m = 1;

n = 0;

p = 0 or 2;

wherein

A is a phenyl;

R ¹ is (dimethylamino)methyl;

Z is selected from a 5-l0-membered monocyclic or bicyclic heteroaryl, a 5-10- membered monocyclic or bicyclic heterocycloalkyl, a C6-C10 monocyclic or bicyclic aryl, a C6-C10 monocyclic or bicyclic cycloalkyl, or a C2-C6 alkenyl, wherein Z is optionally substituted with one or more substituents independently selected from C1-C6 alkyl , C1-C6 alkoxy, C6-C10 aryloxy, CN, halo, COOC1-C6 alkyl, S(02)Ci-C ₆ alkyl, 3- to 7-membered heterocycloalkyl, and CONR ⁸ R ⁹ , and wherein the C1-C6 alkyl or C1-C6 alkoxy that Z is substituted with is optionally substituted with one or more hydroxyl, NR ⁸ R ⁹ , or C6-C10 aryl;

or wherein Z is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

each R ⁷ is independently selected from C1-C ₆ alkyl and C1-C ₆ alkoxy,

wherein the C1-C ₆ alkoxy is optionally substituted with one or more C ₆ -C1 ₀ aryl, each X is CR ⁶ ; each R ⁶ is independently selected from hydrogen, C1-C6 alkyl and C1-C6 alkoxy, wherein the C1-C6 alkoxy is optionally substituted with one or more C6-C10 aryl; and

each of R ⁴ and R ⁵ is hydrogen

each of R ⁸ and R ⁹ at each occurrence is independently selected from hydrogen and

Ci-Ce alkyl.

In some embodiments of the compound of Formula VI or VI-I, A is thiazolyl optionally substituted with 1 or 2 R ¹ and optionally substituted with 1 or 2 R ² .

In some embodiments of the compound of Formula VI or VI-I, A is phenyl optionally substituted with 1 or 2 R ¹ and optionally substituted with 1 or 2 R ² .

In some embodiments of the compound of Formula VI or VI-I, m=l and n=0.

In some embodiments of the compound of Formula VI or VI-I, A is

In some embodiments of the compound of Formula VI or VI-I, A is R ¹

R ¹

In some embodiments of the compound of Formula VI or VI-I, A is In some embodiments of the compound of Formula VI or VI-I, A is

In some embodiments of the compound of Formula VI or VI-I, A is R ¹

R ¹

In some embodiments of the compound of Formula VI or VI-I, A is

In some embodiments of the compound of Formula VI or VI-I, A is In some embodiments of the compound of Formula VI or VI-I, A is

R ¹

In some embodiments of the compound of Formula VI or VI-T A is .

In some embodiments of the compound of Formula VI, A is

In some embodiments of the compound of Formula VI or VI-I, A is

In some embodiments of the compound of Formula

In some embodiments of the compound of Formula VI or VI-

In some embodiments of the compound of Formula VI or VI-I, A is

In some embodiments of the compound of Formula

In some embodiments of the compound of Formula VI or VI-I, A is

In some embodiments of the compound of Formula VI or VI-I, A is

In some embodiments of the compound of Formula VI or VI-I,

In some embodiments of the compound of Formula VI or VI-I, A is

In some embodiments of the compound of Formula VI or VI-I, A is

In some embodiments of the compound of Formula VI or VI-I, m=l and n=l.

In some embodiments of the compound of Formula VI or VI-I, A is

R ²

In some embodiments of the compound of Formula VI or VI-I, A is

In some embodiments of the compound of Formula

In some embodiments of the compound of Formula VI or VI-I, A is In some embodiments of the compound of Formula

In some embodiments of the compound of Formula

In some embodiments of the compound of Formula

In some embodiments of the compound of Formula

R ² In some embodiments of the compound of Formula VI or VI-I, A is

In some embodiments of the compound of Formula VI or VI-I, A is

In some embodiments of the compound of Formula

In some embodiments of the compound of Formula

In some embodiments of the compound of Formula VI or VI-I, A is In some embodiments of the compound of Formula

In some embodiments of the compound of Formula

In some embodiments of the compound of Formula

In some embodiments of the compound of Formula VI or VI-I, m=2 and n=l .

In some embodiments of the compound of Formula

In some embodiments of the compound of Formula

In some embodiments of the compound of Formula

In some embodiments of the compound of Formula VI or VI-I, A is

In some embodiments of the compound of Formula VI or VI-I, each of R ¹ and R ² , when present, is independently selected from the group consisting of C1-C ₆ alkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C ₆ alkoxy, or NR ⁸ R ⁹ ; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C ₆ alkoxy, C1-C ₆ alkyl, or NR ⁸ R ⁹ wherein the C1-C ₆ alkoxy or C1-C ₆ alkyl is further optionally substituted with one to three hydroxy, halo, NR ⁸ R ⁹ , or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C ₆ alkyl, or NR ⁸ R ⁹ wherein the C1-C ₆ alkoxy or C1-C ₆ alkyl is further optionally substituted with one to three hydroxy, halo, NR ⁸ R ⁹ , or oxo; C1-C ₆ haloalkyl; C1-C ₆ alkoxy; C1-C ₆ haloalkoxy; halo; CN; CO-C1-C ₆ alkyl; CO-C ₆ -C1 ₀ aryl; CO-5- to lO-membered heteroaryl; CO2C1-C ₆ alkyl; CO2C3-C8 cycloalkyl; OCOC1-C ₆ alkyl; OCOC ₆ -C1 ₀ aryl; OCO(5- to lO-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C ₆ -C1 ₀ aryl; 5- to lO-membered heteroaryl; NH2; NHCi-Ce alkyl; N(Ci-Ce alkyl) ₂ ; CONR ⁸ R ⁹ ; SFs; S(0 ₂ )NR ^u R ¹² ; S(0)Ci-Ce alkyl; and S(0 ₂ )Ci-C ₆ alkyl.

In certain embodiments of the compound of Formula VI or VI-I, R ¹ is selected from the group consisting of l-hydroxy-2-methylpropan-2-yl; methyl; isopropyl; 2-hydroxy-2- propyl; hydroxymethyl; 1 -hydroxy ethyl; 2-hydroxy ethyl; l-hydroxy-2-propyl; 1 -hydroxy -

1 -cyclopropyl; 1 -hydroxy- 1 -cyclobutyl; 1 -hydroxy- 1 -cyclopentyl; l-hydroxy-l- cyclohexyl; morpholinyl; l,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; l-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(0 ₂ )CH _3; and S(0 ₂ )NR ^u R ¹² .

In certain embodiments of the compound of Formula VI or VI-I, R ² is selected from the group consisting of fluoro, chloro, cyano, methyl; methoxy; ethoxy; isopropyl; 1- hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1 -hydroxy ethyl; 2- hydroxy ethyl; l-hydroxy-2-propyl; 1 -hydroxy- 1 -cyclopropyl; COCH ₃ ; COPh; 2-methoxy-

2-propyl; (dimethylamino)methyl; S(02)CH _3; and S(02)NR ^U R ¹² .

In certain embodiments of the compound of Formula VI or VI-I, R ¹ is C1-C6 alkyl.

In some embodiments of the compound of Formula VI or VI-I, A is

In some embodiments of the compound of Formula

In some embodiments of the compound of Formula VI or VI-I, each R ⁷ is independently selected from the group consisting of: C1-C ₆ alkyl, C3-C7 cycloalkyl, C1-C ₆ haloalkyl, C1-C ₆ alkoxy, C1-C ₆ haloalkoxy, halo, CN, C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, CO-C1-C ₆ alkyl; CONR ⁸ R ⁹ , and 4- to 6-membered heterocycloalkyl, wherein the C1-C ₆ alkyl, C1-C ₆ haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C ₆ alkyl, CONR ⁸ R ⁹ , 4- to 6-membered heterocycloalkyl, C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, OCOC1-C ₆ alkyl, OCOC ₆ -C1 ₀ aryl, OCO(5- to lO-membered heteroaryl), OCO(4- to 6- membered heterocycloalkyl), NHCOC1-C ₆ alkyl, NHCOC ₆ -C1 ₀ aryl, NHCO(5- to 10- membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C ₆ alkynyl.

In certain embodiments of the compound of Formula VI or VI-I, each R ⁷ is independently selected from the group consisting of: C1-C ₆ alkyl, C ₃ -C7 cycloalkyl, C1-C ₆ haloalkyl, C1-C ₆ alkoxy, C1-C ₆ haloalkoxy, wherein the C1-C ₆ alkyl, C1-C ₆ haloalkyl, and C ₃ -C7 cycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, or oxo.

In some embodiments of the compound of Formula VI or VI-I, p=2. In certain of these embodiments, each occurrence of R ⁸ and R ⁹ is independently selected from hydrogen and C1-C5 alkyl.

In certain of the foregoing embodiments of Formula VI or VI-I (when p=2 and/or each occurrence of R ⁸ and R ⁹ is independently selected from hydrogen and C1-C5 alkyl), Z is optionally substituted with one or more substituents independently selected from C1-C ₆ alkyl , C1-C ₆ alkoxy, C ₆ -C1 ₀ aryloxy, CN, halo, COOC1-C ₆ alkyl, S(02)Ci-C6 alkyl, 3- to 7-membered heterocycloalkyl, and CONR ⁸ R ⁹ , and wherein the C1-C ₆ alkyl or C1-C ₆ alkoxy that Z is substituted with is optionally substituted with one or more hydroxyl, NR ⁸ R ⁹ , or C ₆ -C1 ₀ aryl.

As a non-limiting example of the above, Z can be pyrazolyl, pyridinyl, pyrimidinyl, quinolinyl, indolyl, pyrimidin-2-one, thiazolyl, isoxazolyl, or furyl, wherein Z is optionally substituted with one or more substituents independently selected from C1-C ₆ alkyl , C1-C ₆ alkoxy, C ₆ -C1 ₀ aryloxy, CN, halo, COOC1-C ₆ alkyl, S(02)Ci-C6 alkyl, 3- to 7-membered heterocycloalkyl, and CONR ⁸ R ⁹ , and wherein the C1-C ₆ alkyl or C1-C ₆ alkoxy that Z is substituted with is optionally substituted with one or more hydroxyl, NR ⁸ R ⁹ , or C ₆ -C1 ₀ aryl.

In certain of the foregoing embodiments of Formula VI or VI-I (when p=2 and/or each occurrence of R ⁸ and R ⁹ is independently selected from hydrogen and C1-C5 alkyl), Z is a 5-l0-membered monocyclic or bicyclic heterocycloalkyl, wherein Z is optionally substituted with one or more substituents independently selected from C1-C ₆ alkyl , C1-C ₆ alkoxy, C ₆ -C1 ₀ aryloxy, CN, halo, COOC1-C ₆ alkyl, S(02)Ci-C6 alkyl, 3- to 7-membered heterocycloalkyl, and CONR ⁸ R ⁹ , and wherein the C1-C ₆ alkyl or C1-C ₆ alkoxy that Z is substituted with is optionally substituted with one or more hydroxyl, NR ⁸ R ⁹ , or C ₆ -C1 ₀ aryl.

In certain of the foregoing embodiments of Formula VI or VI-I (when p=2 and/or each occurrence of R ⁸ and R ⁹ is independently selected from hydrogen and C1-C5 alkyl), Z is a C ₆ -C1 ₀ monocyclic or bicyclic aryl, wherein Z is optionally substituted with one or more substituents independently selected from C1-C ₆ alkyl , C1-C ₆ alkoxy, C ₆ -C1 ₀ aryloxy, CN, halo, COOC1-C ₆ alkyl, S(02)Ci-C6 alkyl, 3- to 7-membered heterocycloalkyl, and CONR ⁸ R ⁹ , and wherein the C1-C ₆ alkyl or C1-C ₆ alkoxy that Z is substituted with is optionally substituted with one or more hydroxyl, NR ⁸ R ⁹ , or C ₆ -C1 ₀ aryl.

As a non-limiting example of the above, Z can be phenyl, naphthyl, or methylenedioxyphenyl, wherein Z is optionally substituted with one or more substituents independently selected from C1-C ₆ alkyl , C1-C ₆ alkoxy, C ₆ -C1 ₀ aryloxy, CN, halo, COOCi- Ce alkyl, S(02)Ci-C6 alkyl, 3- to 7-membered heterocycloalkyl, and CONR ⁸ R ⁹ , and wherein the C1-C ₆ alkyl or C1-C ₆ alkoxy that Z is substituted with is optionally substituted with one or more hydroxyl, NR ⁸ R ⁹ , or C ₆ -C1 ₀ aryl.

In certain of the foregoing embodiments of Formula VI or VI-I (when p=2 and/or each occurrence of R ⁸ and R ⁹ is independently selected from hydrogen and C1-C5 alkyl), Z is optionally substituted with one or more substituents independently selected from C1-C ₆ alkyl , C1-C ₆ alkoxy, C ₆ -C1 ₀ aryloxy, CN, halo, COOC1-C ₆ alkyl, S(02)Ci-C6 alkyl, 3- to 7-membered heterocycloalkyl, and CONR ⁸ R ⁹ , and wherein the C1-C ₆ alkyl or C1-C ₆ alkoxy that Z is substituted with is optionally substituted with one or more hydroxyl, NR ⁸ R ⁹ , or C ₆ -C1 ₀ aryl.

As a non-limiting example of the above, Z can be cycloalkenyl, wherein Z is optionally substituted with one or more substituents independently selected from C1-C ₆ alkyl , C1-C ₆ alkoxy, C ₆ -C1 ₀ aryloxy, CN, halo, COOC1-C ₆ alkyl, S(02)Ci-C6 alkyl, 3- to 7-membered heterocycloalkyl, and CONR ⁸ R ⁹ , and wherein the C1-C ₆ alkyl or C1-C ₆ alkoxy that Z is substituted with is optionally substituted with one or more hydroxyl, NR ⁸ R ⁹ , or C ₆ -C1 ₀ aryl.

In some embodiments of the compound of Formula VI or VI-I, each of R ⁴ and R ⁵ is hydrogen.

In another aspect, an NLRP3 antagonist is a compound selected from the group consisting of the compounds in Table 6 below and pharmaceutically acceptable salts thereof.

Table 6.

300 Compounds having Formula VI, as well as methods of making and using the same, are further described in US Provisional 62/573,562, filed on October 17, 2017, which is incorporated herein by reference in its entirety.

In one aspect, an NLRP3 antagonist is a compound of Formula VII

Formula VII

wherein

m = 0, 1, or 2

n = 0, 1, or 2

o = 1 or 2

p = 0, 1, 2, or 3

wherein

A is a 5- to lO-membered monocyclic or bicyclic heteroaryl or a C6-C10 monocyclic or bicyclic aryl;

B is a 5- to lO-membered monocyclic or bicyclic heteroaryl or a C6-C10 monocyclic or bicyclic aryl;

wherein

at least one R ⁶ is ortho to the bond connecting the B ring to the NH(CO) group of Formula VII;

R ¹ and R ² are each independently selected from C1-C ₆ alkyl, C1-C ₆ haloalkyl, Ci-

C6 alkoxy, C1-C ₆ haloalkoxy, halo, CN, NO2, COC1-C ₆ alkyl, CO-C ₆ -C1 ₀ aryl; CO(5- to lO-membered heteroaryl); CO2C1-C ₆ alkyl, CO2C3-C8 cycloalkyl, OCOC1-C ₆ alkyl, OCOC ₆ -C1 ₀ aryl, OCO(5- to lO-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, NFh, NHC1-C ₆ alkyl, N(Ci-Ce alkyl) ₂ , NHCOCi-Ce alkyl, NHCOCe-Cio aryl, NHCO(5- to lO-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOCCi-Ce alkyl, NH-(C=NR ¹³ )NR ^U R ¹² , CONR ⁸ R ⁹ , SFs, SCi-Ce alkyl, S(0 ₂ )Ci-C ₆ alkyl, S(0)Ci-C6 alkyl, S(02)NR ^U R ¹² , C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C1-C ₆ alkyl, C1-C ₆ haloalkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each

independently selected from hydroxy, halo, CN, oxo, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C ₆ alkyl, CONR ⁸ R ⁹ , 3- to 7-membered heterocycloalkyl, C ₆ -C1 ₀ aryl, 5- to lO-membered heteroaryl, OCOC1-C ₆ alkyl, OCOC ₆ -C1 ₀ aryl, OCO(5- to lO-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C ₆ alkyl, NHCOC ₆ -C1 ₀ aryl, NHCO(5- to lO-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C ₆ alkynyl;

wherein each C1-C ₆ alkyl substituent and each C1-C ₆ alkoxy substituent of the R ¹ or R ² C ₃ -C7 cycloalkyl or of the R ¹ or R ² 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR ⁸ R ⁹ , or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C ₆ -C1 ₀ aryl, 5- to 10- membered heteroaryl, NHCOC ₆ -C1 ₀ aryl, NHCO(5- to lO-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C ₆ alkyl, and OC1-C ₆ alkyl; or at least one pair of R ¹ and R ² on adjacent atoms, taken together with the atoms connecting them, independently form at least one C ₄ -Cx carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C ₆ alkyl, C1-C ₆ alkoxy, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C ₆ alkyl, C ₆ -C1 ₀ aryl, and CONR ⁸ R ⁹ wherein the C1-C ₆ alkyl and C1-C ₆ alkoxy are optionally substituted with hydroxy, halo, oxo, NR ⁸ R ⁹ , =NR ¹⁰ , COOC1-C ₆ alkyl, C ₆ -C1 ₀ aryl, and CONR ⁸ R ⁹ ;